Gold-catalyzed Cycloisomerization of 2-Aryl-2-(arylamino)-3-butyn-1-ols toward 2-(2′-Aminoaryl)-2,5-dihydrofurans

Article abstract of DOI:10.1002/adsc.201701638

An interesting and highly selective gold-catalyzed cycloisomerization of 2-aryl-2-(arylamino)-3-butyn-1-ols to afford 2-(2′-aminoaryl)-2,5-dihydrofurans has been reported. The reaction is atom economic and highly efficient, and tolerates many functional groups including the cyano and allyl groups. A plausible mechanism for this new cycloismerization is also proposed. (Figure presented.).

Full text of DOI:10.1002/adsc.201701638

Title: Gold-catalyzed Cycloisomerization of 2-Aryl-2-(arylamino)-3-
butyn-1-ols toward 2-(2'-Aminoaryl)-2,5-dihydrofurans
Authors: Jianlin Yang, Yuanhua Wu, Ming Zhang, Dunru Zhu, and
Ruwei Shen
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701638
Link to VoR: http://dx.doi.org/10.1002/adsc.201701638

10.1002/adsc.201701638
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Gold-catalyzed Cycloisomerization of 2-Aryl-2-(arylamino)-3-
butyn-1-ols toward 2-(2'-Aminoaryl)-2,5-dihydrofurans
Jianlin Yang,a Yuanhua Wu,a Ming Zhang,a Dunru Zhu,a Ruwei Shena*
aState Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemical Engineering, Nanjing Tech
University, Nanjing 210009, China. E-mail: shenrw@njtech.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An interesting and highly selective gold-
catalyzed cycloisomerization of 2-aryl-2-(arylamino)-3-
butyn-1-ols to afford 2-(2'-aminoaryl)-2,5-dihydrofurans
has been reported. The reaction is atom economic and
highly efficient, and tolerates many functional groups
including the cyano and allyl groups. A plausible
mechanism for this new cycloismerization is also proposed.
Keywords: Gold catalysis; Cycloisomerization; Alkynols;
Selectivity; 2,5-Dihydrofurans
The gold-catalyzed cyclization of alkynes bearing
intramolecular nucleophiles represents one of the
most important methods for the synthesis of carbo-
and heterocyclic structures under mild conditions.[1]
In particular, the gold-catalyzed cyclization of
alkynols has been extensively developed to access
oxycyclic compounds.[1,2] More importantly, this
cyclization could further trigger a lot of tandem
processes to generate molecular complexity and
diversity from some specifically designed alkynol
Scheme 1. Gold-catalyzed cycloisomerization of alkynols.
derivatives since the initially formed enol ether
moiety can usually be activated by the same gold
catalyst or additional catalyst for other bond-forming
This novel transformation was occasionally found
reactions (Scheme 1a).[3,4] Previously Barluenga et al
during our study on the heteronucleophilic
developed the gold-catalyzed cycloisomerization of
substitution reactions of propargylic substrates.[6] We
benzyl-substituted alkynols to afford a variety of
recently developed a highly regioselective aminolysis
benzo-fused ethers (Scheme 1b).[5] The reaction is
of propargylic epoxides to provide a high-yielding
initiated by an intramolecular hydroalkoxylation to
synthesis of 2-aryl-2-(arylamino)-3-butyn-1-ols 1.[6e]
form the cyclic enol ethers, followed by the
intramolecular hydroarylation reaction promoted by
The easy availability of these polyfunctionalized
unsaturated materials led us to further explore their
the same catalyst. Herein we disclose our discovery
synthetic utility towards heterocycles. At the
on
a
highly
selective
gold-catalyzed
beginning, we performed the cyclization reaction of
2-(N-methylanilino)-2-phenyloct-3-yn-1-ol (1aa) in
the presence of a catalytic amount of (Ph3P)AuCl (5
mol%) and AgSbF6 (5 mol%), which gave 2-butyl-4-
phenylfuran (2aa) in 70% yield (Scheme 2, eq. 1).
The formation of 2aa was ascribed to the ease of a
deamination-aromatization process of the gold-
induced cycloetherification intermediate 3aa. The
detection of the fragment byproduct N-methylaniline
supports this assumption.
cycloisomerization of arylamino-substituted alkynols
1 to provide an efficient and unique synthesis of 2-
aminoaryl-substituted 2,5-dihydrofurans 2 (Scheme
1c). Interestingly, this reaction may involve a series
of
consecutive
transformations
including
intramolecular hydroalkoxylation (C–O bond
formation), arylation (C–C bond formation) and a
rare C–N bond cleavage process.
1
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10.1002/adsc.201701638
Advanced Synthesis & Catalysis
greatly improved for a favored formation of 2a when
AgOTs was used (entry 5). Thus, when 1a was heated
with 5 mol% of (Ph3P)AuCl and 5 mol% of AgOTs at
o
80 C in toluene for 0.5 h, 2a was produced in 55%
yield and only a trace amount of 3a was detected by
TLC. The use of either Ph3PAuCl or AgOTs alone
was ineffective to catalyze the reaction (entries 7 and
8). Particularly, the reaction using AgOTs alone
afforded the cyclization-deamination product 3-
phenylfuran in 35% yield as the major product (entry
8), suggesting that the gold catalyst plays a
substantial role in the reaction. The selective
formation of 2a was also observed when
(Ph3P)AuNTf2 was used, but in a slightly low yield
(entry 6). Further optimizations revealed that the
yield of 2a could be improved to 65% when DCE
was used as a solvent (entry 9). However, MeCN
gave a yield less than 50% (entry 11). The reaction in
THF also produced 2a selectively in 60% yield (entry
11). The best result was obtained when the reaction
o
was performed in PhCF3 at 80 C, and 2a was
obtained in 72% yield (entry 13). The reaction could
also be performed at a lower temperature (e.g., 40 oC),
however, a prolonged reaction time was required and
the product yield dropped to 67% (entry 14).
Table 1. Optimization on reaction conditions [a]
Scheme 2. Preliminary investigation on the gold-catalyzed
cycloisomerization of 2-aryl-2-(arylamino)-3-butyn-1-ols.
Interestingly, when the terminal alkynyl amino
alcohol 1a was subjected to similar conditions,
differently, two products 2a and 3a were obtained in
44% and 20% yield, respectively (Scheme 2, eq. 2).
While the product 3a was presumed as a result of the
intramolecular hydroarylation[7] of the triple bond in
1a and was easily identified by 1H NMR spectra with
the characteristic signals of the vinyl hydrogen atoms
and the hydroxyl hydrogen, the structure of 2a was
not well assigned at first. Fortunately, single crystals
of 2a suitable for an X-ray diffraction study were
obtained from a hexane-CH2Cl2 solution by slow
evaporation, ultimately confirming the 2,5-
dihydrofuran structure as shown in Scheme 2.[8]
It is well known that 2,5-dihydrofurans are not
only important heterocycles frequently used as
building blocks in organic synthesis, but also have
been found in many bioactive reagents,
pharmaceuticals, flavor chemicals and natural
products.[9,10] Thus, new and efficient synthetic
methods for functionalized 2,5-dihydrofurans is still
in highly demand.[11] In this context, we attempted to
improve the selectivity of the reaction for a useful
synthesis of the 2,5-dihydrofuran product. Several
gold catalysts generated from the bench available
(Ph3P)AuCl and various silver salts were then
evaluated (Table 1). No improvements were observed
when the reaction was performed with a combination
of (Ph3P)AuCl with AgOTf, AgBF4 or AgClO4
(entries 2-4). Fortunately, the selectivity could be
Yield (%)[b]
run
catalyst
solvent
2a
44
3a
1
2
Ph3PAuCl/AgSbF6
Ph3PAuCl/AgOTf
Ph3PAuCl/AgBF4
Ph3PAuCl/AgClO4
Ph3PAuCl/AgOTs
Ph3PAuNTf2
toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCE
20
41
20
3
35
16
4
28
11
5
55
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
6
50
7
8[c]
Ph3PAuCl
trace
trace
65
AgOTs
9
Ph3PAuCl/AgOTs
Ph3PAuCl/AgOTs
Ph3PAuCl/AgOTs
Ph3PAuCl/AgOTs
Ph3PAuCl/AgOTs
Ph3PAuCl/AgOTs
10[d]
11
12
13
14[e]
[a]
DCE
64
MeCN
THF
48
60
PhCF3
PhCF3
72
67
Unless otherwise noted, 1a (0.2 mmol) was treated with
5 mol% [Au] and 5 mol% [Ag] at 80 C for 0.5 h in a
o
solvent (2 mL).
[b] Isolated yields.
[c] 3-Phenylfuran was obtained in 35% yield.
[d] Room temperature, 3 h.
[e] 40 oC, 6 h.
2
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10.1002/adsc.201701638
Advanced Synthesis & Catalysis
Table 2. Gold-catalyzed cycloisomerization of 1 to produce 2[a]
[a]
Reaction conditions: 1 was treated with 5 mol% of (Ph3P)AuCl and 5 mol% of AgOTs in PhCF3 at 80 oC for the specific
time. Isolated yields were given.
[b] The ratio was deduced from the 1H NMR spectra.
[c] A complex mixture was formed.
Table 2 shows the results on the preparation of
various 2,5-dihydrofurans from the corresponding 2-
arylamino homopropargyl alcohols by taking
advantage of the gold-catalyzed protocol. The
reactions proceeded smoothly with a lot of substituted
2-arylamino homopropargyl alcohols to give the
desired products with high selectivity. The
substituents R1 such as methyl, chloro, methoxy,
bromo and trifluoromethyl groups on the phenyl ring
are tolerated. Comparatively, relatively low yields
were obtained in case of R1 as electron-withdrawing
groups. When R1 is a methyl at the meta-position of
the phenyl ring, two regioisomers 2j and 2j’ were
obtained in a combined yield of 76% with a ratio of
2/1. Interestingly, when 2-(N-methyl(3-(tert-
of substrates bearing different substituents R2. In
addition to the methyl group, substrates bearing butyl,
isopropyl, and benzyl groups are all smoothly
converted into the corresponding products 2l-2n in
good yields. The reaction of a tetrahydroquinoline-
derived homopropargyl alcohol also took place
smoothly to give rise to the expected product 2o in
73% yield. A cyano group is also compatible in the
present reaction, as illustrated by the successful
preparation of the compound 2p in a moderate yield.
Particularly interesting is that the allyl group in 1q
also survived in the reaction to afford 2q in 61%
yield. This result indicates that the present tandem
transformation is prior to the Au-catalyzed skeletal
reorganization of 1,6-enynes to afford 1-
vinylcycloalkenes.[12] In addition, the ally group did
not migrated from the N-atom to the phenyl ring in
the final product, suggesting that the formation of a
reactive vinyl ether is a necessity for the reaction.
butyl)anilino)-2-phenyl-but-3-yn-1-ol
(2k)
was
treated with the gold catalyst, the less sterically
demanding product 2k was formed exclusively in
55% yield. Moreover, we also examined the reactions
3
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10.1002/adsc.201701638
Advanced Synthesis & Catalysis
However, when 2-phenyl-2-(anilino)but-3-yn-1-ol
(1r) in which R2 as a hydrogen atom was subjected to
the gold catalytic condition, a complex mixture was
generated and the desired 2,5-dihydrofuran was not
detected.[13]
To shed light on the mechanism of the reaction, a
crossover experiment using a 1/1 mixture of 1b and
1f was performed (Scheme 3). The reaction did not
give any crossover product, indicating that a possible
stepwise process, involving the formation of a cyclic
allylic carbocation species directly from the C–N
bond cleavage followed by the attack of the electron-
rich aniline can be excluded.
Scheme 4. The deuterium-labelled experiments
to the C=C double bond of C in the following step
leads to the formation of the oxonium intermediate
D’, and induces the nucleophilic attack of the
electron-rich aniline scaffold to afford the iminium
intermediate E. Accordingly, the formation of two
products 2j and 2j’ (Table 2) can be explained by the
assumption that an intermediate like D could accept
the attack of the electron-rich aniline scaffold on both
sides and the steric effect led to a favored formation
of the less sterically demanding product 2j. This
steric effect becomes extremely apparent when a
large t-Bu group is incorporated on the meta-position
of the aniline scaffold leading to the exclusive
formation of the product 2k (Table 2). Furthermore,
the results of lower product yields and longer reaction
time for the substrates bearing electron-withdrawing
groups on the aniline scaffold (Table 2, 2g-2i) are
also consisted with such an assumption. The
intermediate E may then evolve to the ammonium
intermediate F via a rapid 1,3-H shift. Finally, the β-
elimination reaction takes place to give the final
product and liberates the gold catalyst. Alternatively,
a route via the formation of the intermediate G from
the β-elimination of E followed by 1,3-H shift is also
possible to form the final product.
In summary, we have reported a gold-catalyzed
cycloisomerization sequence of 2-aryl-2-(arylamino)-
3-butyn-1-ols by using (Ph3P)AuCl and AgOTs as the
optimal catalysts. The reaction is highly selective and
shows a good tolerance of functional groups,
providing an efficient method for the synthesis of 2-
aminoaryl-substituted 2,5-dihydrofurans in moderate
to good yields under mild conditions. Further study
on the reaction scope and application of this method
is being pursued.
Scheme 3. A crossover experiment
The labelling studies with deuterated substrates
were also performed. The reaction of [D3]-1a under
the optimal condition afforded [D2]-2a in 70% yield
(Scheme 4, eq. 1). About 7% of D atom was observed
in the vinyl position of [D2]-2a. The loss of other D
atom from the product should be a result of the H/D
exchange of the N-deuterated amino group (formed
according to the proposed mechanism showed below)
when purifying the product
by column
chromatography on silica. Furthermore, the treatment
of a 1/1 mixture of 1a and [D3]-1a under the catalytic
condition for 2 min afforded 2a and [D2]-2a as a 1/1
mixture in ca. 10% yield. This result indicates that the
cleavage of the ortho C–H bond in the aniline ring is
rapid and not rate-determining during the reaction,
since no isotopic effect was observed.
Based on the above results and literature reports,[5]
a plausible mechanism was proposed in Scheme 5.
The coordination of the Au(I) species to 1 first
activates the C≡C triple bond. The selective
intramolecular nucleophilic attack of the hydroxyl
oxygen to the activated alkyne in a 5-endo-dig
manner then occurs to produce the intermediate B,
protodeauration of which leads to the formation of
the amino dihydrofuran C and regenerate the
catalyst.[14] The gold catalyst should play a substantial
role in the following steps to form the final product,
as indicated by the results in entry 8 of Table 1 that
the intermediate C may prudentially undergo the
deamination process to give the furan product in the
absence of the gold catalyst. It is reasonable to
presume that further coordination of the gold catalyst
4
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10.1002/adsc.201701638
Advanced Synthesis & Catalysis
Scheme 5. The proposed mechanism
References
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Typical
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cycloisomerization of 2-aryl-2-(arylamino)-3-butyn-1-
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108.9−110.5 oC. 1H NMR (CDCl3, 400 MHz): δ 7.42−7.32
(m, 5H), 7.27−7.23 (m, 1H), 7.14 (dd, J1 = 8.0 Hz, J2 = 1.4
Hz, 1H), 6.71−6.68 (m, 2H), 6.44 (dd, J1 = 4.0 Hz, J2 = 2.0
Hz, 1H), 6.05−6.02 (m, 1H), 5.15−5.05 (m, 2H), 4.57 (br,
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140.1, 132.3, 129.5, 128.8, 128.4, 127.1, 126.0, 124.9,
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m/z = 252.1379, calcd for C17H18NO [MH+] 252.1388. The
structure of this compound was further determined by an
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Acknowledgements
Financial support from the NSFC (21302095, 21476115),
Jiangsu Provincial NSF (BK20130924) and Nanjing Tech
University is acknowledged. J. Yang and Y. Wu contributed
equally to this work.
5
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10.1002/adsc.201701638
Advanced Synthesis & Catalysis
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6
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10.1002/adsc.201701638
Advanced Synthesis & Catalysis
UPDATE
Gold-catalyzed Cycloisomerization of 2-Aryl-2-
(arylamino)-3-butyn-1-ols toward 2-(2'-
Aminoaryl)-2,5-dihydrofurans
Adv. Synth. Catal. Year, Volume, Page – Page
Jianlin Yang, Yuanhua Wu, Ming Zhang, Dunru
Zhu, Ruwei Shen*
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