Synthesis of Highly Substituted Furans by a Cascade of Formal anti-Carbopalladation/Hydroxylation and Elimination

Article abstract of DOI:10.1021/acs.orglett.8b03732

Highly substituted furans are generated by a cascade of formal anti-carbopalladation, attack of a nucleophilic hydroxy group, and aromatization by elimination of the emerging dihydrofuran derivative. Mono-, di-, and trisubstituted furans were obtained in good to excellent yields. When we attempted to access tetrasubstituted furan derivatives, an additional rearrangement was observed that resulted in the formation of chromenes. Follow-up chemistry shows the utility of TMS as a protecting group for the alkyne moiety.

Full text of DOI:10.1021/acs.orglett.8b03732

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Highly Substituted Furans by a Cascade of Formal
anti‑Carbopalladation/Hydroxylation and Elimination
Theresa Schitter,† Naveen J. Roy,† Peter G. Jones,‡ and Daniel B. Werz*,†
‡
†Institut fu
̈
r Organische Chemie and Institut fu
̈
r Anorganische und Analytische Chemie, Technische Universitat Braunschweig,
̈
Hagenring 30, 38106 Braunschweig, Germany
S
* Supporting Information
ABSTRACT: Highly substituted furans are generated by a cascade of formal anti-carbopalladation, attack of a nucleophilic
hydroxy group, and aromatization by elimination of the emerging dihydrofuran derivative. Mono-, di-, and trisubstituted furans
were obtained in good to excellent yields. When we attempted to access tetrasubstituted furan derivatives, an additional
rearrangement was observed that resulted in the formation of chromenes. Follow-up chemistry shows the utility of TMS as a
protecting group for the alkyne moiety.
Scheme 1. Formal anti-Carbopalladation of Internal Alkynes
Terminated by a Hydroxy Group and Our Extension to the
Synthesis of Furans
ne of the classical routes to 2,5-disubstituted furans, the
Owell-known Paal−Knorr synthesis, consists of a con-
densation reaction of 1,4-dicarbonyls induced by Brønsted or
Lewis acids. However, numerous other methods to access
these heterocyclic compounds have been designed over the last
century. Oxazoles can be employed in a Diels−Alder sequence
with alkynes as dienophiles to generate 3,4-disubstituted furan
derivatives;1 metathesis of bisallyl ethers and subsequent
oxidation or elimination is another possibility.2 Gold-catalyzed
transformations using allene intermediates have been used,
especially to furnish highly substituted derivatives.3,4
Recently, we designed a cascade consisting of a formal anti-
carbopalladation followed by an attack of a hydroxy group on
the emerging anti-carbopalladation intermediate.5 In this way,
tetrasubstituted enol ethers incorporated into six- or seven-
membered ring systems were obtained (Scheme 1, eq 1). For
the nucleophilic attack, primary, secondary, and tertiary
hydroxy groups were utilized. Furthermore, we showed that
by a slight variation of the starting material from tertiary
alcohols to cyclopropanols, ketones can be accessed in a
cascade reaction (Scheme 1, eq 2).6 Since common
carbopalladation reactions lead to a syn-attack on the alkyne
unit,7−10 a special substrate and ligand design was required to
achieve the crucial cis−trans-isomerization in the coordination
sphere of Pd.11−13 The key step was the use of a terminating
substituent (e.g., thioethers, tert-butyl, trimethylsilyl) at the
alkyne, which must be incapable of β-hydride elimination and a
sterically encumbered phosphine ligand that facilitates the
generation of a 14 VE (valence electron) complex. By
computational means, the latter was shown to be the decisive
intermediate for the anticipated isomerization. Unfortunately,
the cascade does not work with an aryl substituent or strongly
electron-withdrawing groups such as carbonyl moieties or CF3
groups attached to the alkyne.11 Experiments with bidentate
phosphine ligands revealed that the transformation is seriously
hindered, since a 14 VE intermediate is inaccessible when
employing such a ligand system.11
With the novel procedure of enol ether formation in hand,
we designed substrates that might undergo a further
elimination to disubstituted furan derivatives by using an
Received: November 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03732
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
appropriate leaving group and the correct tether length to
reach a five-membered heterocycle (Scheme 1, eq 3). The
driving force of this process should be the gain in aromaticity.
At the outset of our studies, alkynol 1a was chosen to
explore suitable reaction conditions for the desired domino
reaction. The reaction was carried out in aprotic polar solvents
(DMF or DMA) at the relatively high temperature of 120 °C
for 2 h (Table 1). The examination of a suitable ligand (entries
Scheme 2. Synthesis of Furans with Various Leaving
Groups
a
a
Table 1. Optimization of the Domino Reaction
a
entry
ligand
base
solvent
T [°C]
yield [%]
Large scale synthesis (1.34 mmol) afforded product 2d in 78% yield.
1
2
3
4
5
6
7
PPh3
dppe
XPhos
[tBu3PH][BF4]
[tBu3PH][BF4]
[tBu3PH][BF4]
[tBu3PH][BF4]
[tBu3PH][BF4]
XPhos
NEt3
NEt3
NEt3
NEt3
NEt3
DIPEA
K2CO3
NEt3
NEt3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
120
120
120
120
100
120
120
120
120
73
traces
42
quant
61
72
54
85
65
Scheme 3. Synthesis of Furans with Various Residues at the
Aromatic Motif
b
8
9
a
General reaction conditions: 1 (100 μmol), solvent (3.0 mL); yields
represent isolated products; DIPEA = N,N-diisopropylethylamine;
DMF = dimethylformamide; DMA = dimethylacetamide; dppe = 1,2-
b
bis(diphenylphosphino)ethane. Pd(OAc)2 was used instead of
PdCl2(PhCN)2.
1−4) showed that the reaction works best with Fu’s salt,14
releasing the sterically demanding tris(tert-butyl)phosphine
(entry 4). The desired product was isolated in quantitative
yield. In contrast, the bidentate ligand dppe (1,2-bis-
(diphenylphosphino)ethane) gave only traces of the desired
product, which agrees with the previous investigations of this
isomerization process (see catalytic cycle, Scheme 5). By
reducing the temperature to 100 °C the product was formed in
61% yield. A change of the base (K2CO3 and DIPEA) resulted
in decreased product formation (entries 6 and 7). Other
Pd(II) sources, e.g., Pd(OAc)2, had only slight influence on the
product formation (entry 8). By using DMA instead of DMF
the yield was decreased (entry 9).
With the optimized reaction conditions in hand, the use of
various leaving groups for the cascade reaction was evaluated.
Besides phenol 2a, whose structure was confirmed by X-ray
crystallography,15 a thiol (2b, 64%), and tosylated amides (2c
and 2d) were accessed in good yields (Scheme 2). Variation of
substituent R2 on the alkyne moiety showed that both the tert-
butyl and the TMS group were tolerated (Scheme 2). One of
the great advantages of the TMS group is the possibility of
further functionalization (see Scheme 7).
products (2e−2g) were isolated in 52% to quantitative yields
(Scheme 3).
Our next investigation focused on the synthesis of furans
with a higher degree of substitution. The scope of the cascade
leading to trisubstituted furan derivatives shows that both alkyl
(2l, 72%) and aryl (2m, 71%) moieties in position R4 were
installed in moderate to good yields. The desilylation of 2m
with TBAF yielded the corresponding 2,4-disubstituted furan
2n in 78% yield (Scheme 4).
The proposed catalytic cycle for the anticipated Pd-catalyzed
cascade reaction is shown in Scheme 5. The starting point is
the oxidative addition into the C−Br bond of 1a forming
intermediate A. The following syn-carbopalladation with the
Scheme 4. Synthesis of Furans with Various Residues R4
Scheme 3 depicts the scope of the cascade reaction with
respect to variation of the residues at the aromatic motif. The
reaction worked smoothly with electron-donating (2e−2g, 2k)
and also with electron-withdrawing groups (2h, 2i) in
moderate to excellent yields. In the case of the methyl-
substituted derivative 2k, the yield was slightly decreased to
62%. By using an extended π-system (2j), a yield of 95% was
achieved. Moreover, additional halides, such as fluorine or
chlorine, did not hamper the reaction. The corresponding
B
DOI: 10.1021/acs.orglett.8b03732
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 5. Proposed Mechanism
Scheme 6. Synthesis of Chromenes
a
Scheme 7. Follow-Up Chemistry: Functionalization of the
TMS Group
Analogous to the Pd-allyl complex formed during a Tsuji-Trost-type
rearrangement which we observed in previous studies,5 the
elimination process might also by supported by the Pd catalyst.
neighboring carbon−carbon triple bond affords intermediate
B. Because of the absence of further reaction pathways, e.g., a
β-hydride elimination, the palladium isomerizes to the
opposite site of the emerging double bond via an η2-vinyl
transition state (TSsyn‑anti).11 The newly generated bonds are
now located in an anti-configuration (see intermediate C).
Base-mediated coordination of the hydroxy group to Pd results
in intermediate D. By reductive elimination, the catalyst is
regenerated and the intermediate E is formed. The
dihydrofuran E directly isomerizes to the corresponding
furan derivative 2a by elimination of phenol (Scheme 5).
However, when we tried to address the preparation of
tetrasubstituted furans by this methodology, a further Pd-
catalyzed rearrangement was observed yielding chromenes of
type 4 (Scheme 6). In position R3 were installed both alkyl
(3a) and aryl (3b) residues. The corresponding products 4a
and 4b were isolated in moderate to good yields (49−71%).
The structure of 4a was unequivocally confirmed by X-ray
analysis. Our mechanistic proposal is shown in Scheme 6. After
the formation of dihydrofuran E the Pd(0) coordinates to the
double bond, whereupon elimination of the highly stabilized
phenolate leads to an allylic complex F. This allyl complex is
easily converted into the more stable allyl complex G, whereby
ring-opening and generation of a carbonyl unit are the major
driving force. The attack of the phenolate in intermediate G′
closes the six-membered ring affording chromene 4 (Scheme
6).
Lewis acid. Under Buchwald−Hartwig conditions, furyl-fused
indole 8 was obtained in quantitative yield (Scheme 7).
In summary, we have demonstrated a Pd-catalyzed domino
process involving a formal anti-carbopalladation of internal
alkynes for the syntheses of highly substituted furans. Thereby,
the cascade was terminated by the nucleophilic attack of a
hydroxy group followed by the elimination of a good leaving
group. With this method, mono-, di-, and trisubstituted furan
derivatives were generated in good to excellent yields.
However, when we tried to access tetrasubstituted furan
derivatives, an unprecedented rearrangement to chromene
derivatives was observed. By a subsequent functionalization of
the TMS group, a broad variety of residues was installed in the
α-position of the furan.
Finally, we demonstrated the utility of the TMS group for
further functionalization (Scheme 7). Disubstituted furan 2d
was desilylated with TBAF, yielding monosubstituted deriva-
tive 5 in 59% yield. Reaction of 2d with NBS gave brominated
furan 6 in 51% yield. The corresponding iodinated derivative 7
(98% yield) was obtained by using NIS in the presence of a
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03732.
■
S
C
DOI: 10.1021/acs.orglett.8b03732
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Detailed experimental procedures and analytical data for
Letter
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all new compounds (PDF)
Accession Codes
CCDC 1879172 and 1879173 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(i) Tietze, L. F.; Hungerland, T.; Eichhorst, C.; Dufert, A.; Maaß, C.;
̈
Stalke, D. Angew. Chem., Int. Ed. 2013, 52, 3668. (j) Charpenay, M.;
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: d.werz@tu-braunschweig.de.
ORCID
(10) For our recent contributions: (a) Milde, B.; Leibeling, M.;
Pawliczek, M.; Grunenberg, J.; Jones, P. G.; Werz, D. B. Angew. Chem.,
Int. Ed. 2015, 54, 1331. (b) Milde, B.; Leibeling, M.; Hecht, A.;
Visscher, A.; Stalke, D.; Jones, P. G.; Grunenberg, J.; Werz, D. B.
Chem. - Eur. J. 2015, 21, 16136. (c) Leibeling, M.; Werz, D. B.
Beilstein J. Org. Chem. 2013, 9, 2194. (d) Wallbaum, J.; Neufeld, R.;
Stalke, D.; Werz, D. B. Angew. Chem., Int. Ed. 2013, 52, 13243.
(e) Leibeling, M.; Pawliczek, M.; Kratzert, D.; Stalke, D.; Werz, D. B.
Org. Lett. 2012, 14, 346. (f) Leibeling, M.; Werz, D. B. Chem. - Eur. J.
2012, 18, 6138. (g) Leibeling, M.; Milde, B.; Kratzert, D.; Stalke, D.;
Werz, D. B. Chem. - Eur. J. 2011, 17, 9888. (h) Leibeling, M.; Koester,
D. C.; Pawliczek, M.; Schild, S. C.; Werz, D. B. Nat. Chem. Biol. 2010,
6, 199.
Daniel B. Werz: 0000-0002-3973-2212
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the German Research Foundation (DFG,
Grant WE 2932/7-1) for funding. T.S. thanks D. Koteska (TU
Braunschweig) for her experimental help.
(11) Pawliczek, M.; Schneider, T. F.; Maaß, C.; Stalke, D.; Werz, D.
B. Angew. Chem., Int. Ed. 2015, 54, 4119.
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DOI: 10.1021/acs.orglett.8b03732
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