Rapid Assembly of Tetrasubstituted Furans via Pummerer-Type Rearrangement

Article abstract of DOI:10.1021/jacs.0c12194

Despite the many methods available for the synthesis of furans, few methods remain that allow for the custom-made assembly of fully substituted furans. Here we report a powerful protocol to rapidly construct tetrasubstituted, orthogonally functionalized furans under mild reaction conditions. The developed method involves the regioselective ring-opening of readily available 2,5-dihydrothiophenes followed by an oxidative cyclization to provide the heterocycle. The selective oxidation at sulfur is promoted by N-chlorosuccinimide as an inexpensive reagent and proceeds at ambient temperature in high yield within 30 min. The obtained furans serve as exceptionally versatile intermediates and were shown to participate in a series of valuable postmodifications. The fate of the initial sulfonium intermediate was investigated by mechanistic experiments, and computational studies revealed the existence of an unprecedented Pummerer-type rearrangement. The potential for organic synthesis is highlighted by the total synthesis of bisabolene sesquiterpenoids (pleurotins A, B, and D).

Full text of DOI:10.1021/jacs.0c12194

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Article
Rapid Assembly of Tetrasubstituted Furans via Pummerer-Type
Rearrangement
Franz-Lucas Haut,§ Christoph Habiger,§ Lukas A. Wein, Klaus Wurst, Maren Podewitz,*
and Thomas Magauer*
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ABSTRACT: Despite the many methods available for the synthesis
of furans, few methods remain that allow for the custom-made
assembly of fully substituted furans. Here we report a powerful
protocol to rapidly construct tetrasubstituted, orthogonally function-
alized furans under mild reaction conditions. The developed method
involves the regioselective ring-opening of readily available 2,5-
dihydrothiophenes followed by an oxidative cyclization to provide the
heterocycle. The selective oxidation at sulfur is promoted by N-
chlorosuccinimide as an inexpensive reagent and proceeds at ambient
temperature in high yield within 30 min. The obtained furans serve as
exceptionally versatile intermediates and were shown to participate in
a series of valuable postmodifications. The fate of the initial sulfonium
intermediate was investigated by mechanistic experiments, and computational studies revealed the existence of an unprecedented
Pummerer-type rearrangement. The potential for organic synthesis is highlighted by the total synthesis of bisabolene
sesquiterpenoids (pleurotins A, B, and D).
free reaction conditions (Scheme 1B). The key transformation
is promoted by selective S-chlorination of 1,3-diene 5 to
generate oxidized intermediate 6 and spontaneous Pummerer-
type rearrangement to release furan 7. The obtained furans
were shown to be exceptionally valuable substrates for a series
of selective postfunctionalizations and enabled synthesis access
to the family of pleurotin natural products.
INTRODUCTION
■
The custom-made synthesis of structurally diverse five-
membered heterocycles represents a fundamental process of
research and development in medicinal chemistry, crop
science, and natural product synthesis.1 Despite the numerous
synthetic methods available today, the synthesis of highly
substituted and electron-rich furans has remained challenging
for reasons that relate to their tendency to undergo hydrolysis
to give, for instance, 1,4-dicarbonyls or to suffer from oxidation
reactions (Scheme 1A).2 Therefore, fully intact furans as found
in pleurotin D (1)3 are underrepresented in natural products
and pharmaceuticals. Otherwise, furans are highly valuable
functional units that allow for the late-stage unmasking of
delicate carbonyl functions as demonstrated in numerous
elegant natural product syntheses.4 For example, the
butenolide motifs of leucosceptroid O (2)5 and caribenol A
(3)6 were revealed via the late-stage oxidation of an advanced
furan intermediate. The broad range of synthesis applications
of these heterocycles requires highly modular approaches that
allow for selective modification of the entire substitution
pattern (12 regioisomers in total).7 While condensation
chemistry has dominated classical furan syntheses in the
past,2 modern synthesis strategies are primarily based on the
cyclization of linear precursors employing transition-metal
catalysts.8 We now demonstrate the simple and rapid
conversion of readily available 2,5-dihydrothiophenes 4 into
tetrasubstituted furans 7 at ambient temperatures under metal-
RESULTS AND DISCUSSION
■
Reaction Development. During our recent studies on the
[3 + 2]-cycloaddition of thiocarbonyl ylides with electron-
deficient alkynes,9 we found that the exposure of 2,5-
dihydrothiophene 4a (R1 = Ph, R2 = Me) to Meerwein’s salt
(Me3OBF4) effected selective S-methylation and subsequent
addition of triethylamine induced immediate ring-opening.
Obtained 1,3-diene 5a turned out to be surprisingly stable and
did not suffer from decomposition or dimerization even at
elevated temperatures.10 A screen of different reaction
conditions revealed that treating 5a with equimolar amounts
of N-chlorosuccinimide (NCS) at 0 °C in dichloromethane
Received: December 1, 2020
Published: January 5, 2021
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Scheme 1. Assembly of Tetrasubstituted Furans via a Pummerer-Type Strategy
(0.05 M) induced clean conversion to furan 7a within 30 min
(Scheme 1C). Simple purification via filtration through a plug
of Florisil afforded 7a in 85% yield (silica gel: 77%). A solvent
screen demonstrated the robustness of this transformation
providing 7a in high yields in chloroform (89%), acetonitrile
(84%), N,N-dimethylformamide (81%, 1 h) and acetone (77%,
3 h). Furan 7a was also obtained by employing ethyl acetate,
toluene, or tetrahydrofuran as the solvent, but despite extended
reaction times, no full consumption of diene 5a was observed
(40−61%). Dimethyl sulfoxide was not compatible with the
oxidant, and no product was formed.11 Related chlorinating
reagents such as Palau’Chlor (Cl-1 in chloroform, 56%)12 and
N-chlorophthalimide (Cl-2, 74%) also initiated furan for-
mation; however, 7a was consistently obtained in slightly lower
yields. A significant decrease in yield became apparent when
applying N-chlorosaccharin (Cl-3 in acetonitrile, 21%), 1,3-
dichloro-5,5-dimethylhydantoin (Cl-4, 29%), trichloro-cyanu-
ric acid (Cl-5 in acetonitrile, 25%), or iodobenzene dichloride
(PhICl2, 41%). The use of sodium hypochlorite did not lead to
any product formation in either dichloromethane or
acetonitrile as the solvent.
modular synthesis of 1,3-dienes also enabled rapid access to
substrates that carry alkynes as well as aliphatic residues
attached to the 3-position (7f−h, 53−90%). Because of the
tendency of the diene precursor to undergo dimerization,10
a
lower yield (51%) was obtained for trisubstituted furan 7i.
Next, we investigated the variation of the ketone residue (R2,
highlighted in blue). To our delight, aryl- and heteroaryl-
derived ketones allowed for the isolation of 7j and 7k,
respectively. The presence of a cyclopropane (7l) was also
tolerated; however, decomposition of the furan occurred upon
exposure to Florisil (36% yield). Therefore, the crude reaction
mixture was diluted with pentane to induce the precipitation of
succinimide. Subsequent filtration provided analytically pure
furan 7l in almost quantitative yield (95%). Similar behavior
was observed for styrene derivatives 7m−p (53−99%) during
the purification process. Finally, the standard reactions
conditions were used to access alkyne 7q (74%) and benzyl-
protected furfuryl alcohol 7r (69%).
By subjecting an aldehyde to our standard reaction
conditions, a mixture of unreacted diene and 5-chlorofuran
8a was obtained. This observation revealed the high reactivity
of furan 8b to undergo electrophilic aromatic substitution with
remaining NCS. Consequently, the use of 2 equiv of
chlorination reagent allowed for the rapid, clean formation of
8a (68%). It is noteworthy that the use of Palau’Chlor (Cl-1,
1.0 equiv) at a lower temperature (0 °C, 1 h) enabled the
selective synthesis of trisubstituted furan 8b. On the basis of
Synthesis Scope. At the outset, a panel of highly
functionalized 1,3-dienes was synthesized (34 examples, see
Supporting Information Section 3 for details) and subjected to
the optimized reaction conditions (Scheme 2). By varying the
aromatic moiety in the 3-position (R1, highlighted in red),
furans 7a−e were obtained in high yields (77−88%). The
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a
Scheme 2. Scope of Tetrasubstituted Furans
a
Standard conditions: substrate (0.2 mmol), NCS (1.0 equiv), CH2Cl2 (0.05 M), 0−23 °C, 0.5 h. See Supporting Information Section 4 for
1
2
experimental and substrate-specific details. Trituration with pentane followed by the removal of succinimide via filtration. Palau’Chlor (Cl-1)
used as the Cl+-source. Yield determined by adding nitromethane as an internal standard to the crude reaction mixture.
3
these results, the syntheses of bromide 8c (N-bromosuccini-
mide, 69%), iodide 8d (N-iodosuccinimide, 71%), and
aldehyde 8e (Vilsmeier reagent, 71%) were realized by simply
telescoping the reaction. Weinreb amides and (thio)esters (R2
= N(OMe)Me, SC12H25, OMe) were reluctant to form furans,
and only complex product mixtures were observed. The
exchange of the S-methyl unit for S-ethyl, S-benzyl, or S-allyl
substituents led to furans 9a−c in good yields (56−81%). For
the electron-poor S-phenyl derivative, only the use of
Palau’Chlor instead of NCS enabled the formation of furan
9d (27%). We concluded our studies of furan formation by
using dienes derived from cyclohexenones as substrates: while
the clean formation of furan 10a was observed in the crude
reaction mixture (71% NMR yield), purification led to
instantaneous hydrolysis to give alcohol 11a. To simplify the
purification process, silver(I) nitrate-mediated hydrolysis of the
chlorides was performed after complete formation of the furan
to afford 11a−d in synthetically useful yields (45−62%). For
sterically more hindered substrates possessing a gem-dimethyl
group (11c−d), only Palau’Chlor was effective at promoting
furan formation.
Postmodifications. In our previous work on tetrahydro-
and dihydrothiophene syntheses, we often relied on high-
pressure conditions for the key [3 + 2]-cycloaddition steps.9
To make the current chemistry more accessible, we generated
the substrates for the furan synthesis from triflate 12, which
was synthesized in one step from commercially available
starting material (Scheme 3A).13 The robustness and
scalability of the furan formation was demonstrated by the
synthesis of more than 1.5 g of furan 7a in a single run.
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a
Scheme 3. Postmodifications
a
1
See Supporting Information Section 6 for experimental details. Obtained after two cycles.
Remarkably, the standard reaction conditions once more
enabled quick separation of the desired product from
succinimide (13) by simple trituration followed by filtration.
Recovered 13 allows for recycling by conversion to NCS.14
With significant quantities of 7a in hand, we investigated its
synthesis potential for the modification of both the benzylic
chloride (4-position) and the methyl sulfide (2-position) to
realize complete control of the furan substitution pattern
(Scheme 3B). We first explored the ability of highly reactive
chloride 7a to undergo C−C bond formation via nucleophilic
displacement reactions. Furans 14a−c were formed in excellent
yields (81−99%) employing copper catalysis. Exposure to
sodium cyanide provided 14d (53%) and reductive displace-
ment of the chloride with Superhydride gave 14e in nearly
quantitative yield. In addition, malonate 14f was accessible in
71% yield. The formation of C−O bonds was accomplished by
the addition of cesium acetate to deliver furan 14g (78%) or by
oxidation under Kornblum conditions (DMSO, NaHCO3) to
give aldehyde 14h (45%). The iron(III)-catalyzed cross-
coupling of 7a with bis(pinacolato)diboron provided boronic
ester 14i (33%),15 and the introduction of nitrogen was
realized by the synthesis of azide 14j (95%). In addition, Wittig
salt 14k was readily accessible in 87% yield upon exposure of
7a to triphenylphosphine, and furan 7j was smoothly
converted to sulfone 14l in the presence of sodium p-
toluenesulfinate (75%). To our surprise, 7a underwent an
unprecedented palladium-catalyzed [4 + 4]-dimerization
reaction (Pd(OAc)2, rac-BINAP) to release eight-membered
carbocycle 15 whose structure was ultimately proven by single-
crystal X-ray analysis.
Having established the synthetic utility of the chloride by a
broad range of substitution reactions, we turned our attention
to the 2-position of furan 14a. Selective oxidation of the sulfide
to sulfoxide 16a, keeping the electron-rich furan untouched,
was realized in nearly quantitative yield (m-CPBA, 98%).
Corresponding sulfilimine 16b (chloramine-T, 77%),16 sulfone
16c (H2O2·urea, 61%),17 and sulfoximine 16d (ammonium
carbamate, PIDA, 52%)18 were accessible in good to moderate
yields. Treating sulfoxide 16a with triflic anhydride initiated
the conversion of the furan to butenolide 17a in 45% yield.
The hydrolysis of 14a under acidic conditions (HCl (aq.), t-
BuOH, reflux) gave 17b, and oxidation with singlet oxygen in
ethanol led to the rapid formation of γ-hydroxybutenolide 17c
and γ-ethoxybutenolide 17d (52−84%).19 When treating 14a
with aqueous NBS, the desired tetrasubstituted alkene, 18, was
formed. Upon standing in CDCl3 at 23 °C, slow rearrangement
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Scheme 4. Total Synthesis of Pleurotins A, B, and D
(4 days) triggered by initial lactone formation and the
subsequent 1,2-alkylthio shift delivered α-butenolide 17e.20
As expected, 14a smoothly participated in Diels−Alder
cycloaddition with N-benzylmaleimide accompanied by acid-
promoted aromatization to give thioanisole 19 (75%).21 To
conclude, we investigated the utility of heteroaryl sulfide when
participating in cross-coupling reactions.22 The use of
Ni(dppp)Cl2 (20 mol %) enabled successful cross-coupling
with Grignard reagents, providing furans 20a (MeMgBr, 85%)
and 20b (PhMgBr, 44%).23 In addition, the sulfide was also
exploited as a traceless auxiliary group, and reductive
desulfurization with Raney nickel provided trisubstituted
furan 20c (76%).24 Finally, a palladium-NHC-catalyzed
cross-coupling reaction (PEPPSI-IPr) gave alkynyl-substituted
furan 20d in 67% yield.25
Total Synthesis of Pleurotin Natural Products. The
presence of a tetrasubstituted furan as the core structure of
bisabolene sesquiterpenoid pleurotins A−D (2, 26−28)3
revealed furan 7n as an ideal starting material (2.5 g prepared
in a single batch, Scheme 4). Allylation of the chloride utilizing
2-methallylmagnesium chloride (21) followed by S-oxidation
(m-CPBA, NaHCO3) furnished sulfoxide 22 in 70% overall
yield. Sulfoxide−magnesium exchange employing ethylmagne-
sium bromide (EtMgBr) followed by exposure to chloride 23
gave 24 (64%).26 Ring-closing metathesis of 24 (4 mol %
second generation Grubbs catalyst, 40 °C) forged the
cyclohexene motif of 25 in 74% yield.
Having secured ample quantities (200 mg) of common
precursor 25, pleurotin A (26) was prepared by dehydrogen-
ation of the benzylic position employing Pd/C (40%). The
presence of dimethyl fumarate as a hydrogen scavenger
prevented unwanted reduction of the enone.27 On the other
hand, Sharpless dihydroxylation of 25 provided (+) pleurotin
B (27) in 69% yield but only 32% ee.28 It is noteworthy that
several attempts to accomplish the selective C−H oxidation of
27 to access pleurotin C (28) were unsuccessful. Finally,
pleurotin D (2) was obtained from pleurotin B (27) in two
steps involving epoxidation under Scheffer−Weitz conditions
(LiOH, H2O2), followed by reductive ring-opening of the
oxirane (Zn, NH4Cl).
combining experimental and quantum chemical methods
(Scheme 5). By changing the solvent from dichloromethane
to water, sulfoxide 29 was obtained in 85% yield from 1,3-
diene 5a.29 Upon exposure to oxalyl chloride, 29 underwent
rapid rearrangement to deliver furan 7a (77%). In addition,
trans-1,3-diene 30 was successfully converted to 7a by
employing the standard conditions (61% NMR yield).
Notably, the use of alternative oxidant N-fluorobenzene-
sulfonimide (NFSI) or [bis(trifluoroacetoxy)iodo]benzene
(PIFA) in ethanol allowed for the direct incorporation of
nitrogen and oxygen as shown for furans 31 and 32.30
However, when diene 33 was subjected to the standard
conditions, a classical Pummerer rearrangement31 to give 34
(73%) was observed.
In addition, NMR monitoring of the reaction of 5a at 0 °C
revealed the formation of intermediate 35 which rapidly
converted to furan 7a upon warming to 23 °C (Scheme 5B, for
NMR spectra see Supporting Information Section 8.2).
Comparison of the 13C NMR shift of the S-methyl group in
35 and 5a (Δδexp = 19.6 ppm) further supported the
hypothesis of an initial S-oxidation. The use of 15N-labled
NCS excluded the formation of an intermediate in which
succinimide is covalently bound to sulfur as suggested for
related systems (no 1H−15N HMBC coupling observed),32 and
calculation confirmed this reaction to be endergonic
(Supporting Information Section 9.2). Moreover, the addition
of potassium hydroxide to 35 led to a mixture of sulfoxide 29
and furan 7a (ratio = 1.0:1.2). Since 29 readily undergoes
furan formation upon exposure to hydrochloric acid, we
speculated about the existence of potential intermediates A and
B. The formation of tetravalent sulfur intermediate B is also in
agreement with seminal work by Pummerer.31a Indeed,
quantum chemical calculation confirmed a stabilization of B
compared to A by ΔG = −3.3 kcal/mol. The comparison of
experimental and calculated 13C NMR shifts provided further
support for the formation of B (Δδexp = 19.6 ppm and Δδcalc
=
22.4 ppm compared to Δδcalc = 25.5 ppm for A, see Supporting
Information Section 9.2).
The equilibrium between A and B is considered to be slow
at 0 °C; otherwise, B would not be detectable on the NMR
time scale. The possibility of B being the reactive species that
releases chloride was excluded due to a thermodynamically
unfavorable reaction pathway (Supporting Information Figure
Mechanistic Investigations. The high selectivity and
efficiency of the oxidative cyclization attracted our attention to
the study of the detailed mechanism of this transformation by
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a
Scheme 5. Mechanistic Investigations
a
Proposed reaction mechanism as calculated with B3LYP-D3(BJ)/6-311++G(2d,2p) in dichloromethane treated as an implicit solvent (details in
Supporting Information Section 9.1). Relative Gibbs free energies at 298 K are given in kcal/mol, whereas the energy of 5a plus N-
chlorosuccinimide and hydrochloride is arbitrarily set to zero. The additive Pummerer pathway is highlighted in black, and the elimination pathway
1
is highlighted in red. Hydrochloride that is regenerated when forming TS-D and TS-I is omitted for clarity. Yield determined by adding
nitromethane as an internal standard to the crude reaction mixture.
S9e). According to these results, 5a is first oxidized by NCS to
the sulfonium chloride A (ΔG = −2.3 kcal/mol).33 The
presence of acid turned out to be crucial since no reaction was
observed under basic conditions (K2CO3), which was further
confirmed by calculations in which a reaction Gibbs free
energy of ΔG = +23.9 kcal/mol in the absence of HCl was
found (Supporting Information Section 9.2). From there, key
intermediate A can enter either an additive Pummerer pathway
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(Michael-type addition of chloride, highlighted in black) or a
classical Pummerer elimination pathway (highlighted in red).
According to the Curtin−Hammett principle, the Michael
addition (TS-C) is strongly favored by ΔΔG⧧ = −11.7 kcal/
mol. Hence, intermediate C is formed (ΔG = −4.9 kcal/mol),
where a second chloride is already in loose interaction with the
Michael acceptor. Consequently, a 1,4-addition of chloride
leads to F, which undergoes 6π electrocyclic ring-opening
(ΔG⧧ = 2.7 kcal/mol, TS-F). The obtained thionium
intermediate G, is energetically strongly favored (ΔG =
−13.7 kcal/mol) and resembles the reactive species generated
from additive Pummerer reaction pathways.34 All attempts to
find a transition state for a direct chloride displacement
connecting intermediates C and G were unsuccessful and
identified F as part of the reaction pathway. Ring closure in G
(ΔG⧧ = 2.3 kcal/mol, TS-G) furnishes I, and furan 7a is
formed under the deprotonation and regeneration of HCl. The
low reaction barriers of this pathway are consistent with the
rapid conversion of 1,3-diene 5a to furan 7a at ambient
temperature. In the Pummerer elimination pathway (depicted
in red), intermediate D is formed, where a second chloride is
in loose contact with the vinylic proton (ΔG = −7.5 kcal/mol).
Deprotonation by chloride proceeds via an activation barrier of
ΔG⧧ = 16.6 kcal/mol (TS-D) to deliver unprecedented
thioketenium complex E (ΔG = −3.8 kcal/mol). Consecutive
rotation around the central σ-bond closes dihydrofuran H
(ΔG⧧ = 1.7 kcal/mol, TS-E), and a 1,3-chloride shift (ΔG⧧ =
10.7 kcal/mol, TS-H) then furnishes furan 7a.
X-ray crystallographic data for 5b (Supporting Informa-
tion Table 2), 7l, 11d, 14l, 15, and 29 (CIF)
AUTHOR INFORMATION
■
Corresponding Authors
Maren Podewitz − Institute of General, Inorganic &
Theoretical Chemistry, Leopold-Franzens-University
Innsbruck, 6020 Innsbruck, Austria; orcid.org/0000-
0001-7256-1219; Email: maren.podewitz@uibk.ac.at
Thomas Magauer − Institute of Organic Chemistry and
Center for Molecular Biosciences, Leopold-Franzens-
University Innsbruck, 6020 Innsbruck, Austria; orcid.org/
0000-0003-1290-9556; Email: thomas.magauer@
uibk.ac.at
Authors
Franz-Lucas Haut − Institute of Organic Chemistry and
Center for Molecular Biosciences, Leopold-Franzens-
University Innsbruck, 6020 Innsbruck, Austria
Christoph Habiger − Institute of Organic Chemistry and
Center for Molecular Biosciences, Leopold-Franzens-
University Innsbruck, 6020 Innsbruck, Austria
Lukas A. Wein − Institute of Organic Chemistry and Center
for Molecular Biosciences, Leopold-Franzens-University
Innsbruck, 6020 Innsbruck, Austria
Klaus Wurst − Institute of General, Inorganic & Theoretical
Chemistry, Leopold-Franzens-University Innsbruck, 6020
Innsbruck, Austria
It is noteworthy that direct ring closure of E to 7a is also
feasible, requiring a similar activation energy (ΔG⧧ = 1.7 kcal/
mol). However, because of the high reaction barrier to form E,
this pathway can be excluded. Similarly, mechanisms involving
vinylogous chlorination or intramolecular 1,5-chloride transfer
from 5a to form an intermediate strongly resembling G can
also be ruled out (Supporting Information Section 9.2).
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c12194
Author Contributions
§F.-L.H. and C.H. contributed equally.
Notes
CONCLUSIONS
The authors declare no competing financial interest.
■
The developed protocol enables the rapid assembly of a variety
of tetrasubstituted furans under mild conditions. The required
2,5-dihydrothiophenes are readily available and amenable to
broad diversification. The inherent orthogonal substitution
pattern allows for the selective functionalization along the
periphery of the heterocyclic core structure. The Pummerer-
type rearrangement represents a powerful alternative to
conventional furan syntheses based on condensation chemistry
or transition-metal catalysis. The potential of this method was
showcased by a series of postmodifications that culminated in
the total synthesis of pleurotins A, B, and D. The underlying
mechanism of the rearrangement was studied in detail by
combining experimental and DFT investigations considering
various pathways. The efficiency and selectivity observed under
these mild reaction conditions are in agreement with the low
energy barriers obtained for the additive Pummerer pathway.
An extension of this methodology to other heterocycles is
underway in our laboratories and will be reported in due
course.
ACKNOWLEDGMENTS
■
This work was supported by the Austrian Science Fund FWF
(P31023-NBL to T.M. and M2005 to M.P.), the Center for
Molecular Biosciences CMBI, and the Tyrolean Science Fund
TWF (UNI-0404/2340 to F.-L.H. and F.16642/5-2019 to
L.A.W). We are grateful to Prof. Christoph Kreutz, Prof.
Thomas Muller, and Dr. Christina Meisenbichler (University
̈
of Innsbruck) for help with NMR and HRMS studies. The
computational results presented here have been achieved using
the LEO HPC infrastructure at the University of Innsbruck.
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c12194.
Experimental details and spectroscopic data (PDF)
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