Synthesis of Tetrasubstituted Furans through One-Pot Formal [3 + 2] Cycloaddition Utilizing [1,2]-Phospha-Brook Rearrangement

Article abstract of DOI:10.1021/acs.orglett.0c00619

An efficient method for the synthesis of tetrasubstituted furans was developed by utilizing the [1,2]-phospha-Brook rearrangement under Br?nsted base catalysis. The two-step one-pot formal [3 + 2] cycloaddition involves the nucleophilic addition of a propargyl anion, which is catalytically generated through the [1,2]-phospha-Brook rearrangement, to an aldehyde and the subsequent intramolecular cyclization mediated by N-iodosuccinimide to provide 2,4,5-trisubstituted-3-iodofurans. The present method with readily available substrates provides new access to a wide range of well-organized tetrasubstituted furans.

Full text of DOI:10.1021/acs.orglett.0c00619

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Letter
Synthesis of Tetrasubstituted Furans through One-Pot Formal [3 +
2] Cycloaddition Utilizing [1,2]-Phospha-Brook Rearrangement
Azusa Kondoh, Kohei Aita, Sho Ishikawa, and Masahiro Terada*
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ABSTRACT: An efficient method for the synthesis of tetrasubstituted furans was developed by utilizing the [1,2]-phospha-Brook
rearrangement under Brønsted base catalysis. The two-step one-pot formal [3 + 2] cycloaddition involves the nucleophilic addition
of a propargyl anion, which is catalytically generated through the [1,2]-phospha-Brook rearrangement, to an aldehyde and the
subsequent intramolecular cyclization mediated by N-iodosuccinimide to provide 2,4,5-trisubstituted-3-iodofurans. The present
method with readily available substrates provides new access to a wide range of well-organized tetrasubstituted furans.
ensely functionalized furans are important five-mem-
based on the [3 + 2] cycloaddition strategy utilizing the [1,2]-
Dbered heteroaromatic compounds found in numerous phospha-Brook rearrangement under Brønsted base catalysis
(Scheme 1a).10 The formal [3 + 2] cycloaddition involves the
biologically active natural products, synthetic pharmaceuticals,
and agrochemicals.1 In addition, they can be employed as a
construction of a pyrrole ring from propargyl alcohols 1 as a
useful building block in synthetic organic chemistry2 as well as
C3 subunit containing the requisite umpolung and imines as a
a potential skeleton in material science.3 Therefore, the
two-atom subunit containing nitrogen, providing a diverse
array of well-organized polysubstituted pyrroles.
development of general and efficient methods for the synthesis
of functionalized furans is an important subject, and massive
efforts have been undertaken over the years.4 One of the
straightforward approaches for the synthesis of functionalized
furans is the direct functionalization of existing furans.5
However, challenges remain in its reaction scope and efficiency
particularly for the synthesis of densely functionalized furans
including tetrasubstituted furans. The intramolecular cycliza-
tion of acyclic compounds is also a well-established approach.6
In that approach, the multistep synthesis of densely function-
alized precursors is required, which hinders efficient access to
diverse tetrasubstituted furans. Thus, in recent years, the
construction of tetrasubstituted furan rings through the
cycloaddition of multiple components has been intensively
studied.7,8 Although various types of reactions have been
developed, methods that provide efficient access to a wide
range of tetrasubstituted furans from readily available starting
compounds are still limited.
The [3 + 2] cycloaddition is a powerful strategy for the
construction of the five-membered heteroaromatic frameworks.
Indeed, several efficient approaches have been established in
the synthesis of multisubstituted pyrroles because various types
of nitrogen-containing subunits, such as imines, enamides, and
azomethyne ylides, and their reaction partners are easily
available.9 In this regard, we have recently established a
method for the synthesis of polysubstituted pyrroles, which is
In contrast to the efficient synthesis of multisubstituted
pyrroles based on the [3 + 2] cycloaddition strategy, the
reactions for the synthesis of multisubstituted furans are still
underdeveloped because of the limited scope of subunits for
the construction of a furan ring. We, hence, envisioned that our
methodology for the formal [3 + 2] cycloaddition would be
further applicable to the synthesis of tetrasubstituted furans.
The use of propargyl alcohols 1 as a C3 subunit and aldehydes
2 as a two-atom subunit containing oxygen would markedly
extend the usability of the [3 + 2] cycloaddition strategy and
potentially lead to a significant broadening of the accessible
tetrasubstituted furans. Specifically, the proposed two-step
formal [3 + 2] cycloaddition of propargyl alcohols 1 to
aldehydes 2 provides 2,4,5-trisubstituted-3-iodofurans 4 as
shown in Scheme 1b. The first step of the formal [3 + 2]
cycloaddition is the addition of propargyl alcohols 1 to
aldehydes 2 under the influence of a Brønsted base catalyst.
Treatment of 1 and 2 with a Brønsted base catalyst would
result in the deprotonation of 1 followed by the [1,2]-phospha-
Received: February 16, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00619
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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was carried out according to the reaction conditions for our
previous pyrrole synthesis (Table 1, entry 1).10 The reaction
Scheme 1. Our [3 + 2] Cycloaddition Strategies for
Construction of Heteroaromatic Frameworks
a
Table 1. Initial Screening of Reaction Conditions
b
yield (%)
c
c
entry
base
solvent
3aa (dr)
5aa (dr)
6a
7a
1
2
3
4
5
6
7
8
P1-tBu
P2-tBu
P4-tBu
DBU
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
THF
65 (60/40)
72 (60/40)
69 (61/39)
<1
63 (63/37)
74 (60/40)
74 (62/38)
68 (61/39)
27 (57/43)
31 (66/34)
14 (83/17)
18 (58/42)
15 (63/37)
13 (54/46)
<1
11 (63/37)
15 (66/34)
15 (59/41)
19 (57/43)
26 (70/30)
38 (55/45)
13 (81/19)
10
10
12
<1
16
9
9
6
26
18
11
1
3
1
<1
2
2
2
1
11
5
TBD
tBuOK
tBuONa
tBuOLi
tBuOK
tBuOK
tBuOK
d
9
10
11
toluene
8
a
Conditions: 1a (0.25 mmol), 2a (0.50 mmol), base (0.025 mmol),
b
c
solvent (1.0 mL), −60 °C, 3 h. NMR yields. Diastereomeric ratio
d
was determined by 31P NMR analysis. The reaction was conducted
Brook rearrangement,11,12 which is the migration of the
dimethoxyphosphoryl moiety from carbon to oxygen, to
generate α-oxygenated propargyl anion B. The addition of B
to the aldehyde at the γ-position and the subsequent
protonation by the conjugated acid of the Brønsted base or
1 would provide allenyl alcohol 3 along with regeneration of
the Brønsted base catalyst or alkoxide A. The second step is
the intramolecular cyclization. Based on our previous study,10
the electrophilic activation of the allene moiety of 3 by N-
iodosuccinimide (NIS) would cause the intramolecular
addition of the alcohol to the allene moiety, and the
aromatization would occur through the following elimination
of dimethyl phosphate to provide 3-iodofuran 4. Considering
that propargyl alcohols 1 are easily prepared from the
corresponding alkynyl ketones with a secondary phosphite by
treating with an appropriate Brønsted base,13 the method
could be regarded as the construction of a furan ring from two
readily available carbonyl compounds under mild reaction
conditions. Particularly, a variety of aldehydes, including
aromatic, aliphatic, and even densely functionalized ones, are
available, which is a substantial advantage compared to
conventional furan synthesis. Furthermore, the iodide moiety
on the furan ring would potentially function as a handle for
manipulation by various methods. Therefore, the method
would provide new efficient access to a wide range of well-
organized tetrasubstituted furans. Herein we report a two-step
one-pot formal [3 + 2] cycloaddition that provides 2,4,5-
trisubsituted-3-iodofurans. Further transformations of the
iodide moiety into various carbon-based substituents are also
described.
at −40 °C.
provided desired allenyl alcohol 3aa as the major product in
65% NMR yield along with some byproducts including
propargyl alcohol 5aa, which was formed through the addition
of the propargyl anion to 2a at the α-position followed by the
migration of the dimethoxyphosphoryl moiety, as well as
allenyl phosphate 6a and propargyl phosphate 7a, which were
formed by the direct protonation of propargyl anion at the γ-
and α-positions, respectively. Screening of Brønsted bases
including organobases having different basicities (entries 2−5)
and alkali tert-butoxides (entries 6−8) was carried out, and
potassium and sodium tert-butoxides provided 5aa in the
highest NMR yields (entries 6 and 7). Then, several solvents
were tested with potassium tert-butoxide (tBuOK) as the base
(entries 9−11). The effect of solvents was significant, and
DMF was the solvent of choice (entry 6 vs entries 9−11).
Next, the second step of the formal [3 + 2] cycloaddition
was examined. Allenyl alcohol 3aa was treated with 1.2 equiv
of NIS in DMF at room temperature to afford corresponding
3-iodofuran 4aa in high yield (eq 1).
We commenced our investigation by screening the reaction
conditions in the first step of the formal cycloaddition, that is,
the nucleophilic addition of propargyl alcohols 1 to aldehydes
2 catalyzed by a Brønsted base. As the initial substrate, 1a
having a phenyl group at the propargylic position and a butyl
group at the alkyne terminus was used. Treatment of 1a and
benzaldehyde (2a) with 10 mol % P1-tBu in DMF at −60 °C
B
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Based on this result, the one-pot synthesis of 4aa from 1a
and 2a was attempted (Scheme 2). 1a and 2a were treated
position (R1 = cC6H11) and the alkyne terminus (R2 = nBu)
was applied as the substrate (entry 11). On the other hand, in
the case of the propargyl alcohol having a phenyl group at the
alkyne terminus, an alkyl group, such as a cyclohexyl group,
could be used as a substituent at the propargylic position
(entry 12).
Scheme 2. One-Pot and Gram-Scale Synthesis
Next, the scope of aldehydes 2 was investigated (Scheme 3).
Aromatic aldehydes 2b and 2c with an electron-donating
Scheme 3. Scope of Aldehydes
with 10 mol % tBuOK in DMF at −60 °C for 3 h. NIS was
then added at that temperature, and the resulting mixture was
allowed to warm to room temperature and stirred for an
additional 3 h to provide 4aa in 67% yield, which is
comparable to that obtained by the two-step protocol (70%
yield in two steps). In addition, this operationally simple
method was sufficiently reliable to permit the synthesis of 4aa
in gram scale.
The substrate scope was investigated by using the one-pot
protocol. First, the scope of propargyl alcohols 1 was examined
with benzaldehyde (2a) as the partner (Table 2). In addition
a
Table 2. Scope of Propargyl Alcohols
a
Reaction was conducted with NIS (1.0 equiv).
alkoxy group at the para position afforded corresponding
products 4ab and 4ac in good yields. In contrast, when 2d and
2e having a strong electron-withdrawing group, such as a cyano
group and a nitro group, at the para position were used,
significant amounts of α-adducts 5 were formed and the yields
of 4ad and 4ae were moderate. The reactions of 2-
chlorobenzaldehyde (2f) and quinolone-2-carboxaldehyde
(2g) proceeded without any problem to provide 4af and 4ag
in good yields. In the case of furfural (2h), the amount of NIS
for the second step influenced the reaction outcome (eq 2).
b
entry
R1
R2
4
yield (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
cC6H11
Ph
4ba
4ca
4da
4ea
4fa
4ga
4ha
4ia
61
53
43
c
4-MeOC6H4
4-ClC6H4
2-MeC6H4
2-thienyl
nBu
73
32
80
70
60
76
4-MeOC6H4
4-FC6H4
2-MeC6H4
2-thienyl
cC6H11
nBu
nBu
nBu
nBu
9
4ja
4ka
4la
c
10
11
12
70
<1
c
d
cC6H11
Ph
4ma
69
a
Conditions: 1 (0.25 mmol), 2a (0.30 mmol), tBuOK (0.025 mmol),
b
DMF (1.0 mL), − 60 °C, 3 h, then NIS (1.2 equiv), rt, 3 h. Isolated
yields unless otherwise noted. NMR yield. Reaction was conducted
with DMF (2.0 mL).
c
d
The use of 0.6 equiv of NIS provided 4ah selectively. In
contrast, an excess of NIS caused the iodination of the furan
ring derived from furfural, and 4ah′ was obtained exclusively.
Aliphatic aldehydes were also examined. Secondary alkyl-
substituted 2j provided the desired product in good yield,
whereas the use of primary and tertiary alkyl-substituted 2i and
2k resulted in low yields of 4. Functionalized aldehydes, such
as N-Boc prolinal (2l) and alkynyl aldehyde 2m, were also
applicable, and 4al and 4am were obtained in good yields,
respectively.14
Two types of double cycloaddition were attempted with
substrates having two reaction sites (Scheme 4). The reaction
of 1a with terephthalaldehyde (2n) gave two furan rings at
once, providing 4an with a teraryl core structure albeit in
moderate yield (Scheme 4a). On the other hand, diol 1n
to a primary alkyl group, a secondary alkyl group was
applicable as substituent R2 at the alkyne terminus (entry 1).
A variety of (hetero)aryl groups were applicable as substituents
R2 at the alkyne terminus, and the corresponding 3-iodofurans
were obtained in moderate to good yields (entries 2−6).
Among them, 1f having a sterically hindered ortho-tolyl group
provided α-adduct 5 as the major product, and thus the yield
of 4fa was moderate (entry 5). The substituent at propargylic
position R1 was screened with substrates possessing a butyl
group at the alkyne terminus (entries 7−10). The substrates
having (hetero)aryl groups underwent the reaction without any
problems, and the corresponding products were obtained in
good yields. However, no reaction occurred when propargyl
alcohol 1l possessing alkyl groups at both the propargylic
C
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coupling reaction, the Suzuki−Miyaura coupling reaction, the
Migita−Kosugi−Stille coupling reaction, and the Mizoroki−
Heck reaction, could be performed and corresponding
coupling products 8−11 were obtained in high yields (Scheme
5a). Furthermore, 4aa was amenable to lithiation through the
halogen−metal exchange followed by trapping with electro-
philes, such as an aldehyde and an acid chloride, providing
densely functionalized tetrasubstituted furans 12 and 13 in
good yields (Scheme 5b). As a different type of derivatization
of 4aa, the transformation of the furan ring was performed.
The Diels−Alder reaction with benzyne generated from 14 and
the subsequent deoxygenative aromatization15 provided
1,2,3,4-tetrasubstituted naphthalene 16 (Scheme 5c).
Scheme 4. Double Cycloaddition
In conclusion, we have established an efficient method for
the synthesis of tetrasubstituted furans on the basis of the [3 +
2] cycloaddition strategy utilizing the [1,2]-phospha-Brook
rearrangement under Brønsted base catalysis. The two-step
one-pot formal [3 + 2] cycloaddition involves the nucleophilic
addition of an α-oxygenated propargyl anion, which is
catalytically generated through the [1,2]-phospha-Brook
rearrangement, to the aldehyde at the γ-position and the
subsequent intramolecular cyclization mediated by NIS to
furnish 2,4,5-trisubstituted-3-iodofurans possessing various
substituents in a positional selective manner. The iodofurans
obtained by the cycloaddition were applicable to a variety of
transformations, including palladium-catalyzed cross-coupling
reactions, alkylation and acylation through halogen−metal
exchange, and the Diels−Alder reaction. Therefore, the present
method with readily available substrates provides new access to
a wide range of well-organized tetrasubstituted furans.
successfully participated in the double cycloaddition to afford
4na, the structural isomer of 4an (Scheme 4b).
Finally, the derivatization of iodofuran 4aa obtained by the
two-step [3 + 2] cycloaddition was conducted (Scheme 5). As
the transformation utilizing an iodide moiety, a variety of
palladium-catalyzed reactions, such as the Sonogashira
Scheme 5. Derivatization of 4aa
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00619.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
Masahiro Terada − Department of Chemistry, Graduate School
of Science, Tohoku University, Sendai 980-8578, Japan;
orcid.org/0000-0002-0554-8652; Email: mterada@
tohoku.ac.jp
Authors
Azusa Kondoh − Research and Analytical Center for Giant
Molecules, Graduate School of Science, Tohoku University,
Sendai 980-8578, Japan; orcid.org/0000-0001-7227-8579
Kohei Aita − Department of Chemistry, Graduate School of
Science, Tohoku University, Sendai 980-8578, Japan
Sho Ishikawa − Department of Chemistry, Graduate School of
Science, Tohoku University, Sendai 980-8578, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00619
a
Condition A: PdCl2(PPh3)2 (10 mol %), CuI (10 mol %), Et3N, 50
°C, 8 h. Condition B: Pd(PPh3)4 (5.0 mol %), K3PO4 (2.0 equiv),
DMF, 100 °C, 24 h. Condition C: Pd(PPh3)4 (5.0 mol %), DMF, 120
°C, 19 h. Condition D: Pd(OAc)2 (5.0 mol %), PPh3 (15 mol %),
Notes
b
Et3N (2.0 equiv), DMF, 90 °C, 19 h. NMR yield.
The authors declare no competing financial interest.
D
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P. Silver & gold-catalyzed routes to furans and benzofurans. Org.
Biomol. Chem. 2016, 14, 9184−9205. (c) Gulevich, A. V.; Dudnik, A.
S.; Chernyak, N.; Gevorgyan, V. Transition Metal-Mediated Synthesis
of Monocyclic Aromatic Heterocycles. Chem. Rev. 2013, 113, 3084−
3213. (d) Godoi, B.; Schumacher, R. F.; Zeni, G. Synthesis of
Heterocycles via Electrophilic Cyclization of Alkynes Containing
Heteroatom. Chem. Rev. 2011, 111, 2937−2980. (e) Keay, B. A.
Synthesis of multi-substituted furan rings: the role of silicon. Chem.
Soc. Rev. 1999, 28, 209−215.
(5) (a) Melzig, L.; Rauhut, C. B.; Knochel, P. 2,3-Functionalization
of furans, benzofurans and thiophenes via magnesiation and sulfoxide-
magnesium exchange. Chem. Commun. 2009, 3536−3538. (b) Battace,
A.; Lemhadri, M.; Zair, T.; Doucet, H.; Santelli, M. Palladium-
Catalyzed Direct Arylation of Furans via C-H Functionalization at
Low Catalyst Loadings. Organometallics 2007, 26, 472−474.
(c) Wang, Y.; Pritchard, G. J.; Kimber, M. C. Total Synthesis of
the Tetrasubstituted Furan Fatty Acid Metabolite CeDFP via Au-
Catalyzed Intermolecular Alkyne Hydroarylation. Org. Lett. 2019, 21,
4892−4895.
ACKNOWLEDGMENTS
■
This research was supported by a Grant-in-Aid for Scientific
Research (S) (JP16H06354) and a Grant-in-Aid for Scientific
Research (C) (JP16K05680) from the Japan Society for the
Promotion of Science (JSPS).
REFERENCES
■
(1) (a) Riley, A. P.; Groer, C. E.; Young, D.; Ewald, A. W.; Kivell, B.
M.; Prisinzano, T. E. Synthesis and κ-Opioid Receptor Activity of
Furan-Substituted Salvinorin A Analogues. J. Med. Chem. 2014, 57,
10464−40475. (b) Hasegawa, F.; Niidome, K.; Migihashi, C.; Murata,
M.; Negoro, T.; Matsumoto, T.; Kato, K.; Fujii, A. Discovery of furan-
2-carbohydrazides as orally active glucagon receptor antagonists.
Bioorg. Med. Chem. Lett. 2014, 24, 4266−4270. (c) Yan, L.; Yan, C.;
Qian, K.; Su, H.; Kofsky-Wofford, S. A.; Lee, W.-C.; Zhao, X.; Ho, M.-
C.; Ivanov, I.; Zheng, Y. G. Diamidine Compounds for Selective
Inhibition of Protein Arginine Methyltransferase 1. J. Med. Chem.
2014, 57, 2611−2622. (d) Kumari, N.; Mishra, C. B.; Prakash, A.;
Kumar, N.; Mongre, R.; Luthra, P. M. Neurosci. Lett. 2014, 558, 203−
207. (e) Vitale, P.; Tacconelli, S.; Perrone, M. G.; Malerba, P.;
Simone, L.; Scilimati, A.; Lavecchia, A.; Dovizio, M.; Marcantoni, E.;
Bruno, A.; Patrignani, P. Synthesis, Pharmacological Characterization,
and Docking Analysis of a Novel Family of Diarylisoxazoles as Highly
Selective Cyclooxygenase-1 (COX-1) Inhibitors. J. Med. Chem. 2013,
56, 4277−4299. (f) Rao, A. U.; Xiao, D.; Huang, X.; Zhou, W.;
Fossetta, J.; Lundell, D.; Tian, F.; Trivedi, P.; Aslanian, R.; Palani, A.
Facile synthesis of tetracyclic azepine and oxazocine derivatives and
their potential as MAPKAP-K2 (MK2) inhibitors. Bioorg. Med. Chem.
Lett. 2012, 22, 1068−1072. (g) Wang, Y.; Luo, Y.-C.; Hu, X.-Q.; Xu,
P.-F. A Powerful Cascade Approach for Expeditious Synthesis of
Trifluoromethylated Furans. Org. Lett. 2011, 13, 5346−5349.
(2) (a) Lipshutz, B. H. Five-Membered Heteroaromatic Rings as
Intermediates in Organic Synthesis. Chem. Rev. 1986, 86, 795−819.
(b) Makarov, A. S.; Uchuskin, M. G.; Trushkov, I. V. Furan Oxidation
Reactions in the Total Synthesis of Natural Products. Synthesis 2018,
50, 3059−3086. (c) Hao, H.-D.; Trauner, D. Furans as Versatile
Synthons: Total Synthesis of Caribenol A and Caribenol B. J. Am.
Chem. Soc. 2017, 139, 4117−4122. (d) Plutschack, M. B.; Seeberger,
P. H.; Gilmore, K. Visible-Light-Mediated Achmatowicz Rearrange-
ment. Org. Lett. 2017, 19, 30−33. (e) Kalaitzakis, D.; Triantafyllakis,
M.; Alexopoulou, I.; Sofiadis, M.; Vassilikogiannakis, G. One-Pot
Transformation of Simple Furans into 4-Hydroxy-2-cyclopentenones
in Water. Angew. Chem., Int. Ed. 2014, 53, 13201−13205. (f) Ciufolini,
M. A.; Wood, C. Y. The Aza-Achmatowicz Rearrangement: A Route
to Useful Building Blocks for N-Containing Structures. Tetrahedron
Lett. 1986, 27, 5085−5088. (g) Achmatowicz, O., Jr.; Bukowski, P.;
Szechner, B.; Zwierzchowska, Z.; Zamojski, A. Synthesis of Methyl
2,3-Dideoxy-DL-Alk-2-enopyranosides from Furan Compounds. Tetra-
hedron 1971, 27, 1973−1996.
(6) For selected examples, see: (a) Xue, C.; Huang, X.; Wu, S.;
Zhou, J.; Dai, J.; Fu, C.; Ma, S. TfOH-catalyzed domino cyclo-
isomerization/hydrolytic defluorination of 2,3-allenyl perfluoroalkyl
ketones. Chem. Commun. 2015, 51, 17112−17115. (b) Xia, Y.; Xia, Y.;
Ge, R.; Liu, Z.; Xiao, Q.; Zhang, Y.; Wang, J. Oxidative Cross-
Coupling of Allenyl Ketones and Organoboronic Acids: Expeditious
Synthesis of Highly Substituted Furans. Angew. Chem., Int. Ed. 2014,
53, 3917−3921. (c) Cho, C.-H.; Shi, F.; Jung, D.-I.; Neuenswander,
B.; Lushington, G. H.; Larock, R. C. Solution-Phase Synthesis of a
Highly Substituted Furan Library. ACS Comb. Sci. 2012, 14, 403−414.
(d) Saito, A.; Konishi, T.; Hanzawa, Y. Synthesis of Pyrroles by
Gold(I)-Catalyzed Amino-Claisen Rearrangement of N-Propargyl
Enaminone Derivatives. Org. Lett. 2010, 12, 372−374. (e) Belting, V.;
Krause, N. Gold-catalyzed cycloisomerization of alk-4-yn-1-ones. Org.
Biomol. Chem. 2009, 7, 1221−1225. (f) Du, X.; Song, F.; Lu, Y.;
Chen, H.; Liu, Y. A general and efficient synthesis of substituted
furans and dihydrofurans via gold-catalyzed cyclization of (Z)-2-en-4-
yn-1-ols. Tetrahedron 2009, 65, 1839−1845. (g) Dudnik, A. S.;
Sromek, A. W.; Rubina, M.; Kim, J. T.; Kel’in, A. V.; Gevorgyan, V.
Metal-Catalyzed 1,2-Shift of Diverse Migrating Groups in Allenyl
Systems as a New Paradigm toward Densely Functionlized Hetero-
cycles. J. Am. Chem. Soc. 2008, 130, 1440−1452. (h) Schwier, T.;
Sromek, A. W.; Yap, D. M. L.; Chernyak, D.; Gevorgyan, V.
Mechanistically Diverse Copper-, Silver-, and Gold-Catalyzed Acyloxy
and Phosphatyloxy Migrations: Efficient Synthesis of Heterocycles via
Cascade Migration/Cycloisomerization Approach. J. Am. Chem. Soc.
2007, 129, 9868−9878. (i) Suhre, M. H.; Reif, M.; Kirsch, S. F.
Gold(I)-Catalyzed Synthesis of Highly Substituted Furans. Org. Lett.
2005, 7, 3925−3927. (j) Ma, S.; Zhang, J.; Lu, L. Pd0-Catalyzed
Coupling Cyclization Reaction of Aryl or 1-Alkenyl Halides with 1,2-
Allenyl Ketones: Scope and Mechanism. An Efficient Assembly of
2,3,4-, 2,3,5-Tri and 2,3,4,5-Tetrasubstituted Furans. Chem. - Eur. J.
2003, 9, 2447−2456.
(7) For selected recent examples, see: (a) Jin, H.; Rudolph, M.;
Rominger, F.; Hashmi, A. S. K. The Carbocation-Catalyzed
Intermolecular Formal [2 + 2+1] Cycloaddition of Ynamides with
Quinoxaline N-Oxides. ACS Catal. 2019, 9, 11663−11668.
(b) Tateishi, K.; Matsumoto, Y.; Saito, A. Formal [2 + 2+1] Synthesis
of Tetrasubstituted Furans from Aldehydes, Acetylenedicarboxylates,
and Acyl Compounds. Eur. J. Org. Chem. 2019, 2019, 5603−5609.
(c) Li, Q.; He, X.; Tao, J.; Xie, M.; Wang, H.; Li, R.; Shang, Y. Base-
mediated 1,4-Conjugated Addition/Intramolecular 5-exo-dig Annula-
tion of Propargylamines with Benzoylacetonitriles and β-Keto Estes
for Polysubstituted Furans and Furo[3,4-c]coumarins Formation. Adv.
Synth. Catal. 2019, 361, 1874−1886. (d) Wang, Q.; Liu, Z.; Lou, J.;
Yu, Z. Palladium-Catalyzed C-S Bond Cleavage with Allenoates:
Synthesis of Tetrasubstituted 2-Alkenylfuran Derivatives. Org. Lett.
2018, 20, 6007−6011. (e) Lou, J.; Wang, Q.; Wu, K.; Wu, P.; Yu, Z.
Iron-Catalyzed Oxidative C-H Functionalization of Internal Olefins
for the Synthesis of Tetrasubstituted Furans. Org. Lett. 2017, 19,
(3) (a) Gandini, A.; Belgacem, M. N. Furans in Polymer Chemistry.
Prog. Polym. Sci. 1997, 22, 1203−1379. (b) Song, B.; Hu, K.; Qin, A.;
Tang, B. Z. Oxygen as a Crucial Comonomer in Alkyne-Based
Polymerization toward Functional Poly(tetrasubstited furan)s. Macro-
molecules 2018, 51, 7013−7018. (c) Zeng, C.; Seino, H.; Ren, J.;
Hatanaka, K.; Yoshie, N. Self-healing bio-based furan polymers cross-
linked with various bis-maleimides. Polymer 2013, 54, 5351−5357.
(d) Zeng, C.; Seino, H.; Ren, J.; Hatanaka, K.; Yoshie, N. Bio-Based
Furan Polymers with Self-Healing Ability. Macromolecules 2013, 46,
1794−1802. (e) Ripaud, E.; Demeter, D.; Rousseau, T.; Boucard-
́
Cetol, E.; Allain, M.; Po, R.; Leriche, P.; Roncali, J. Structure-
properties relationships in conjugated molecules based on diketo-
pyrrolopyrrole for organic photovoltaics. Dyes Pigm. 2012, 95, 126−
133. (f) Wu, C.-C.; Hung, W.-Y.; Liu, T.-L.; Zhang, L.-Z.; Luh, T.-Y.
Hole-transport properties of a furan-containing oligoaryl. J. Appl. Phys.
2003, 93, 5465−5471.
(4) For selected reviews, see: (a) Kirsch, S. F. Syntheses of
polysubstituted furans: recent developments. Org. Biomol. Chem.
2006, 4, 2076−2080. (b) Blanc, A.; Beneteau, V.; Weibel, J.-M.; Pale,
́
́
E
https://dx.doi.org/10.1021/acs.orglett.0c00619
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
̈
(d) Demir, A. S.; Esiringu, I.; Gullu, M.; Reis, O. Catalytic
̈ ̈ ̈
3287−3290. (f) Han, Y.-Y.; Jiao, Y.-Y.; Ren, D.; Hu, Z.; Shen, S.; Yu,
S. Synthesis of Tetrasubstituted Furans by Using Photoredox-
Catalyzed Coupling of 2-Bromo-1,3-dicarbonyl Compounds with
Silyl Enol Ethers. Asian J. Org. Chem. 2017, 6, 414−417. (g) Zhao, Y.;
Li, S.; Zheng, X.; Tang, J.; She, Z.; Gao, G.; You, J. Ru/Cu-Catalyzed
Cascade [4 + 2] Vinylic C-H O-Annulation and Ring Contraction of
α-Aryl Enones with Alkynes in Air. Angew. Chem., Int. Ed. 2017, 56,
4286−4289. (h) Wang, S.; Liu, C.; Jia, J.; Zha, C.; Xie, M.; Zhang, N.
Synthesis of sulfonyl-substituted furans via copper-mediated annula-
tion of acetylenic sulfones and activated methylenes. Tetrahedron
2016, 72, 6684−6691. (i) Liu, J.; Ye, W.; Qing, X.; Wang, C. Solvent-
Free DABCO-Mediated [3 + 2] Cycloadditions of Donor-Acceptor
Cyclopropanes with Aldehydes: Strategy for Synthesis of Fully
Substituted Furans. J. Org. Chem. 2016, 81, 7970−7976. (j) Li, H.-
L.; Wang, Y.; Sun, P.-P.; Luo, X.; Shen, Z.; Deng, W.-P. α. β-Double
Electrophilic Addition of Allene-1,3-Dicarboxylic Esters for the
Construction of Polysubstituted Furans by KI/tert-Butyl Hydro-
peroxide (TBHP)-Promoted Oxidative Annulation. Chem. - Eur. J.
2016, 22, 9348−9355. (k) Reddy, C. R.; Mohammed, S. Z.;
Kumaraswamy, P. A [3 + 2]-annulation approach to tetrasubstituted
furans from MBH-carbonates of acetylenic aldehydes via sequential
substitution/cycloisomerization. Org. Biomol. Chem. 2015, 13, 8310−
8321.
(8) For other recent examples, see: (a) Kise, N.; Nagamine, H.;
Sakurai, T. Electroreductive Intermolecular Coupling of Chromanes
with Benzophenones: Synthesis of 2-Diarylmethylchromanones and
Tetrasubstituted Furans. Eur. J. Org. Chem. 2019, 2019, 3662−3676.
(b) Rajeshkumar, V.; Neelamegam, C.; Anandan, S. A one-pot metal-
free protocol for the synthesis of chalcogenated furans from 1,4-
enediones and thiols. Org. Biomol. Chem. 2019, 17, 982−991.
(c) Gharpure, S. J.; Padmaja; Prasath, V.; Shelke, Y. G. Cascade
Radical Cyclization on Alkynyl Vinylogous Carbonates for the
Divergent Synthesis of Tetrasubstituted Furans and Dihydrofurans.
Org. Lett. 2019, 21, 223−227. (d) Wang, X.; Lerchen, A.; Daniliuc, C.
G.; Glorius, F. Efficient Synthesis of Arylated Furans by a Sequential
Rh-Catalyzed Arylation and Cycloisomerization of Cyclopropenes.
Angew. Chem., Int. Ed. 2018, 57, 1712−1716. (e) Lee, C.-J.; Chang,
T.-H.; Yu, J.-K.; Reddy, G. M.; Hsiao, M.-Y.; Lin, W. Synthesis of
Functionalized Furans via Chemoselective Reduction/Wittig Reaction
Using Catalytic Triethylamine and Phosphine. Org. Lett. 2016, 18,
3758−3761. (f) Fournier, J.; Arseniyadis, S.; Cossy, J. A Modular and
Scalable One-Pot Synthesis of Polysubstituted Furans. Angew. Chem.,
Int. Ed. 2012, 51, 7562−7566. (g) Yoshida, M.; Ohno, S.; Shishido, K.
Synthesis of Tetrasubstituted Furans by Palladium-Catalyzed
Decarboxylative [3 + 2] Cyclization of Propargyl β-Keto Esters.
Chem. - Eur. J. 2012, 18, 1604−1607.
Intermolecular Aldehyde-Ketone Coupling via Acyl Phosphonates. J.
Org. Chem. 2009, 74, 2197−2199. (e) Demir, A. S.; Eymur, S.
Addition of Trifluoromethyltrimethylsilnae to Acyl Phophonates:
Synthesis of TMS-Protected 1-Alkyl-1-trifluoromethyl-1-hydroxy-
phophonates and 1-Aryldifluoroethenyl Phosphates. J. Org. Chem.
2007, 72, 8527−8530. (f) Bausch, C. C.; Johnson, J. S. Cyanide-
Catalyzed Additions of Acyl Phophonates to Aldehydes: A New Acyl
Donor for Benzoin-Type Reactions. Adv. Synth. Catal. 2005, 347,
̈
̇
̇
̆
1207−1211. (g) Demir, A. S.; Reis, O.; Igdir, A. Ç.; Esiringu, I.;
̈
Eymur, S. Generation of Acyl Anion Equivalents from Acylphosph-
onates via Phosphonate-Phosphate Rearrangement: A Highly
Practical Method for Cross-Benzoin Reaction. J. Org. Chem. 2005,
70, 10584−10587. (h) Kondoh, A.; Ishikawa, S.; Aoki, T.; Terada, M.
Synthesis of 2,3-allenylamides utilizing [1,2]-phospha-Brook rear-
rangement and their application to gold-catalyzed cycloisomerization
providing 2-aminofuran derivatives. Chem. Commun. 2016, 52,
12513−12516. (i) Kondoh, A.; Terada, M. Brønsted Base Catalyzed
[2,3]-Wittig/Phospha-Brook Tandem Rearragement Sequence. Org.
Lett. 2013, 15, 4568−4571. (j) Hayashi, M.; Nakamura, S. Catalytic
Enantioselective Protonation of α-Oxygenated Ester Enolates
Prepared through Phospha-Brook Rearrangement. Angew. Chem.,
Int. Ed. 2011, 50, 2249−2252. (k) El Kaïm, L.; Gaultier, L.; Grimaud,
L.; Dos Santos, A. Formation of New Phosphates from Aldehydes by
a DBU-Catalysed Phospha-Brook Rearrangement in a Polar Solvent.
Synlett 2005, 2335−2236.
(12) (a) Kondoh, A.; Aoki, T.; Terada, M. Intramolecular
Cyclization of Alkynyl α-Ketoanilide Utilizing [1,2]-Phospha-Brook
Rearrangement Catalyzed by Phosphazene Base. Org. Lett. 2014, 16,
3528−3531. (b) Kondoh, A.; Aoki, T.; Terada, M. Synthesis of
Phenanthrene Derivatives by Intramolecular Cyclization Utilizing the
[1,2]-Phospha-Brook Rearrangemnet Catalyzed by a Brønsted Base.
Chem. - Eur. J. 2015, 21, 12577−12580. (c) Kondoh, A.; Terada, M.
Brønsted base-catalyzed three-component coupling reaction of α-
ketoesters, imines, and diethyl phosphite utilizing [1,2]-phospha-
Brook rearrangement. Org. Biomol. Chem. 2016, 14, 4704−4711.
(d) Kondoh, A.; Aoki, T.; Terada, M. Generation and Application of
Homoenolate Equivalents Utilizing [1,2]-phospha-Brook Rearran-
gemnt under Brønsted Base Catalysis. Chem. - Eur. J. 2017, 23, 2769−
2773. (e) Kondoh, A.; Ozawa, R.; Aoki, T.; Terada, M. Intramolecular
addition of benzyl anion to alkyne utilizing [1,2]-phospha-Brook
rearrangement under Brønsted base catalysis. Org. Biomol. Chem.
2017, 15, 7277−7281. (f) Kondoh, A.; Terada, M. Brønsted Base-
Catalyzed Umpolung Intramolecular Cyclization of Alkynyl Imines.
Chem. - Eur. J. 2018, 24, 3998−4001.
(13) See the Supporting Information and ref 9 for details.
(14) When enantioenriched 2l was used, racemization occurred
during the reaction, and racemic 4al was obtained.
(15) Xing, Y. D.; Huang, N. Z. Deoxygenation of 7-
Oxabicyclo[2.2.1]hepta-2,5-diene Systems to Substituted Benzenes
by Titanium Tetrachloride-Lithium Aluminum Hydride. J. Org. Chem.
1982, 47, 140−142.
́
(9) For selected recent reviews, see: (a) Estevez, V.; Villacampa, M.;
́
Menendez, J. C. Multicomponent reactinos for the synthesis of
́
pyrroles. Chem. Soc. Rev. 2010, 39, 4402−4421. (b) Estevez, V.;
Villacampa, M.; Menendez, J. C. Recent advances in the synthesis of
́
pyrroles by multicomponent reactions. Chem. Soc. Rev. 2014, 43,
4633−4657. (c) Zhou, N.-N.; Zhu, H.-T.; Yang, D.-S.; Guan, Z.-H.
Recent developments in the group-1B-metal-catalyzed synthesis of
pyrroles. Org. Biomol. Chem. 2016, 14, 7136−7149.
(10) Kondoh, A.; Iino, A.; Ishikawa, S.; Aoki, T.; Terada, M.
Efficient Synthesis of Polysubstituted Pyrroles Based on [3 + 2]
Cycloaddition Strategy Utilizing [1,2]-Phospha-Brook Rearrangement
under Brønsted Base Catalysis. Chem. - Eur. J. 2018, 24, 15246−
15253.
(11) For selected recent examples, see: (a) Horwitz, M. A.; Zavesky,
B. P.; Martinez-Alvarado, J. I.; Johnson, J. S. Asymmetric Organo-
catalytic Reductive Coupling Reactions between Benzylidene
Pyruvates and Aldehydes. Org. Lett. 2016, 18, 36−39. (b) Horwitz,
M. A.; Tanaka, N.; Yokosaka, T.; Uraguchi, D.; Johnson, J. S.; Ooi, T.
Enantioselective reducitive multicomponent coupling reactions
between isatins and aldehydes. Chem. Sci. 2015, 6, 6086−6090.
(c) Corbett, M. T.; Uraguchi, D.; Ooi, T.; Johnson, J. S. Base-
Catalyzed Direct Aldolization of α-Alkyl-α-Hydroxy Trialkyl
Phosphonoacetates. Angew. Chem., Int. Ed. 2012, 51, 4685−4689.
F
https://dx.doi.org/10.1021/acs.orglett.0c00619
Org. Lett. XXXX, XXX, XXX−XXX