ZnCl2-Catalyzed [4+1] Annulation of Alkylthio-Substituted Enaminones and Enaminothiones with Sulfur Ylides

Article abstract of DOI:10.1002/chem.201905483

Concise construction of furan and thiophene units has played an important role in the synthesis of potentially bioactive compounds and functional materials. Herein, an efficient Lewis acid ZnCl₂ catalyzed [4+1] annulation of alkylthio-substituted enaminones is reported, that is, α-oxo ketene N,S-acetals with sulfur ylides to afford 2-acyl-3-aminofuran derivatives. In a similar fashion, [4+1] annulation of the corresponding enaminothiones, that is, α-thioxo ketene N,S-acetals, with sulfur ylides efficiently proceeded to give multisubstituted 3-aminothiophenes. This method features wide substrate scopes as well as broad functional group tolerance, offering a concise route to highly functionalized furans and thiophenes.

Full text of DOI:10.1002/chem.201905483

A Journal of
Accepted Article
Title: ZnCl 2 -Catalyzed [4+1] Annulation of Alkylthio-Substituted
Enaminones and Enaminothiones with Sulfur Ylides
Authors: Zhengkun Yu, Yuan He, Jiang Lou, and Yong-Gui Zhou
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To be cited as: Chem. Eur. J. 10.1002/chem.201905483
Link to VoR: http://dx.doi.org/10.1002/chem.201905483
Supported by

10.1002/chem.201905483
Chemistry - A European Journal
ZnCl2-Catalyzed [4+1] Annulation of Alkylthio-Substituted
Enaminones and Enaminothiones with Sulfur Ylides
Yuan He,[a,b] Jiang Lou,[a,b] Yong-Gui Zhou,*[a] and Zhengkun Yu*[a,c]
enynes,[14f] phosphine-mediated reductive condensation of γ-
acyloxybutynoates,[14g] Brønsted acid-promoted cyclization of
1,4-diketones,[15] and palladium-catalyzed condensation of N-
arylimines and alkynylbenziodoxolones[16] all afforded the
corresponding furan derivatives. A two-step reaction procedure
of aldehydes with propargylic alcohols was also developed for
the preparation of highly substituted furans.[17] In general, the
synthesis of thiophene derivatives involves either an indirect way
by functionalization of the thiophene ring[18] or a direct way via
ring closure of suitable precursors.[19] The latter approach is
obviously more versatile and attractive, but it has less been
developed. In this area, Fiesselmann,[20] Gewald,[21] Paal,[22] and
Hinsberg[23] reactions were developed for the direct construction
of a thiophene ring in specific thiophene derivatives. Internal
Abstract: Concise construction of furan and
thiophene units has played an important role in the
synthesis of potentially bioactive compounds and
functional materials. Herein, we report an efficient
Lewis acid ZnCl2-catalyzed [4+1] annulation of
alkylthio-substituted enaminones, that is, α-oxo
ketene N,S-acetals, with sulfur ylides, affording 2-
acyl-3-aminofuran derivatives. In a similar fashion,
[4+1]
annulation
of
the
corresponding
enaminothiones, that is, α-thioxo ketene N,S-acetals,
with sulfur ylides efficiently proceeded to give
multisubstituted 3-aminothiophenes. This method
features wide substrate scopes as well as broad
functional group tolerance, offering a concise route to
highly functionalized furans and thiophenes.
alkenes
building blocks to establish
-oxo ketene S,S-acetals[24a] were applied as the
thiophene ring.[24b] 3-
a
Aminothiophenes are considered as the important small
molecules for drug development,[7] but only a few methods were
documented for their synthesis.[25,26] Enaminothiones of type α-
thioxo ketene N,S-acetals[27] have been reported to react with
activated methylene compounds in the presence of
stoichiometric Hg(OAc)2[28] or with diazo compounds under Rh(II)
catalysis,[29] giving 3-aminothiophenes. Considerable advance
has recently been achieved in the synthesis of thiophenes, but
direct and concise methods are still strongly desired to access
highly functionalized thiophene derivatives.
The furan and thiophene motifs are important structural units
abundant in many biologically active natural products,
pharmaceuticals, and agrochemicals.[1] Furan and thiophene
derivatives can also function as versatile building blocks for the
synthesis of organic functional polymers due to their interesting
electrochemical and optical properties.[2] For example, 3-
aminobenzofuran motif has been widely used as the key
structural unit for the construction of pharmaceutical agents such
as androgen receptors[3] and HCV protease inhibitors,[4] and 2-
carboxamidefuran derivatives can act as NHE-1 inhibitors.[5] 3-
Aminothiophene derivatives have also been medically
considered as the potent inhibitors of p38 kinase,[6] IKKβ,[7] and
islet amyloid polypeptide (IAPP)[8] (Figure 1). Continuous efforts
have been devoted to the synthesis of substituted furans by
means of cyclization of the suitable precursor compounds.[9] In
this
regard,
transition-metal-catalyzed
dehydrogenative
heterocylization has been used to construct furan-fused
carbocycles or multisubstituted furans.[10,11] Intramolecular
cyclizations[12] involving alkynyl epoxides,[13] allenyl ketones,[14a]
allenyl or homopropargylic alcohols,[14b] vinyl diazoesters,[14c] and
allene-1,3-dicarboxylic esters[14d] were employed for the same
purpose. Copper-catalyzed intermolecular heterocyclization of
alkynyl ketones and imines,[14e] iron-catalyzed cyclization of 1,6-
Figure 1. Furan and Thiophene Motifs in Selected Biologically Active
Molecules.
Sulfur ylides are among the most important and widely
applied reagents in organic synthesis,[30] which are usually
perceived as the 1,1'-dipole reagents for the synthesis of three-
membered carbo- and heterocycles through [2+1] annulation.[31]
Sulfur ylide-involved [3+3] and [4+2] cycloaddition reactions
were also realized.[32] However, [4+1] annulation of sulfur ylides
has been paid less attention in recent years although it can be
used as a powerful method to access diverse five-membered
rings.[33] In this regard, Xiao, et al. reported a formal [4+1]
annulation of stabilized sulfur ylides with α,β-unsaturated imines
to prepare polysubstituted pyrroles by a one-pot, two-step
[a] Y. He, J. Lou, Prof. Dr. Y.-G. Zhou, Prof. Dr. Z. K. Yu
Dalian Institute of Chemical Physics, Chinese Academy of Sciences
457 Zhongshan Road, Dalian 116023 (P. R. China)
E-mail: zkyu@dicp.ac.cn; ygzhou@dicp.ac.cn
[b] Y. He, J. Lou
University of Chinese Academy of Sciences
Beijing 100049 (P. R. China)
[c] Prof. Dr. Z. K. Yu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (P. R. China)
Supporting information for this article is given via a link at the end of the
document.
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10.1002/chem.201905483
Chemistry - A European Journal
FULL PAPER
process.[34] Chandrasekhar, et al. developed a highly efficient
[2+2]/[4+1] cycloaddition cascade of arynes and stable sulfur
ylides to synthesize 2-aroyl benzofurans.[35]
methyl and methoxy groups facilitated the reaction, while 3-Me,
3-Cl, 4-Cl, and 4-CF3 diminished the product yields to 61-66%,
Table 1. Screening of reaction conditions.[a]
Yield[b]
[%]
Entry
Lewis Acid
Solvent
T(oC)
1
2
AlCl3
LiCl
toluene
toluene
toluene
toluene
toluene
DMSO
DMF
110
110
110
110
110
110
110
100
120
120
120
120
120
120
29
39
3
Zn(OTf)2
ZnBr2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
24
4
25
5
63
6
70
7
72
8
9[
DMF
60
74 (72)[c]
61
Scheme 1. [4+1] Annulations of α-Oxo (Thioxo) Ketene N,S-Acetals.
DMF
10[d]
11[e]
12[f]
13[g]
14
DMF
We recently found that alkylthio-substituted enaminones and
enaminothiones, that is, α-oxo (thioxo) ketene N,S-acetals, could
undergo carbene insertion reaction to establish O- and S-
heterocycles under copper(II) catalysis[27a] or metal-free
conditions[27b] (Scheme 1a), and cycloketone oxime esters were
also used as the C1 building blocks to react with
enaminothiones in the presence of a copper(I) catalyst to give
thiophene derivatives (Scheme 1b).[36] Thus, we envisioned that
sulfur ylides might also act as the suitable C1 building blocks to
react with alkylthio-substituted enaminones and enaminothiones
to execute [4+1] annulation to afford multisubstituted furan and
thiophene derivatives (Scheme 1c).
Initially, the reaction of enaminone α-oxo ketene N,S-acetal
(1a) with S,S-dimethyl sulfur ylide (2a) was conducted to screen
the reaction conditions (Table 1). Various Lewis acids were first
tested as the catalysts, and ZnCl2 was found to be the most
efficient one to facilitate the desired reaction among the
screened metal chlorides AlCl3, LiCl, Zn(OTf)2, ZnBr2, and ZnCl2
(Table 1, entries 1-5). In the presence of 10 mol% ZnCl2 as the
catalyst, DMF acted as the reaction medium which was superior
to other solvents (Table 1, entries 5-7). 120 C seemed to be the
suitable reaction temperature (Table 1, entries 7-9). Under the
optimal conditions, the reaction of 1a and 2a in a 1:2 molar ratio
afforded the target annulation product, that is, (5-methyl-3-
(phenylamino)furan-2-yl)-(phenyl)methanone (3a), in 75%
isolated yield (Table 1, entry 12). Use of 5 mol% ZnCl2 as the
catalyst dramatically diminished the yield of 3a to 34%, and the
reaction did not occur in the absence of ZnCl2 catalyst (Table 1,
entry 14).
DMF
45
79 (75)[c]
DMF
DMF
34
DMF
0
[a] Conditions: 1a (0.3 mmol), 2a (0.6 mmol), Lewis acid (10 mol%), solvent
(3.0 mL), 0.1 MPa N2, 24 h. [b] Determined by 1H NMR analysis by using
1,3,5-trimethoxybenzene as the internal standard. [c] Isolated yield given in
parentheses. [d] Solvent (2.0 mL). [e] Solvent (4.0 mL). [f] 1a (0.5 mmol), 2a
(1.0 mmol). [g] Lewis acid (5 mol%).
and 2-Br led to 72% yield for 3f. The bulky 1-naphthylamine-
derived enaminone 1j reacted smoothly to give 3j (70%). α-Aroyl
ketene N,S-acetals 1k-1s also efficiently reacted with 2a to form
3k-3s (57-82%), and an obvious negative electronic effect was
observed for 3-positioned Me, OMe, Cl, and CF3 groups on the
α-aroyl moieties of enaminones 1. α-(1-Naphthoyl) ketene N,S-
acetal 1t reacted well with 2a to afford the target product 3t
(85%), exhibiting no steric effect. However, α-(2-furoyl) and -(2-
thienoyl)-based substrates only achieved a moderate reaction
efficiency to form 3u (53%) and 3v (40%), respectively. α-
Cinnamoyl-functionalized ketene N,S-acetals 1w and 1x also
effectively reacted with 2a, yielding 3w and 3x in 65-70% yields.
It should be noted that alkylamine and benzylamine-derived -
oxo ketene N,S-acetals could not execute the same type of
annulation reaction under the stated conditions, and secondary
amine-based enaminones did not react either. These results
have suggested that an N-H functionality in the enaminone
substrates is crucial for the [4+1] annulation reaction in which
the sulfur ylides acted as the C1 building blocks. Electron-
donating methyl and methoxy, and bromo-substituted sulfur
ylides 2b-2d efficiently reacted with 1a to give the target
products 3y-3z1 in excellent yields (85-96%), while 3-CF3-
bearing sulfur ylide (2e) only reached 66% yield for the target
product 3z2 in the reaction with 1a. The bulky adamantyl and
tert-butyl-functionalized sulfur ylides 2f and 2g reacted much
less efficiently than their aryl-based analogs with 1a and 1k to
Under the optimized reaction conditions, the protocol
generality for the synthesis of furans 3 was explored (Table 2).
With -acetyl ketene N,S-acetals 1b-1i as the substrates,
compounds 3b-3i were obtained in 61-82% yields from their
reactions with sulfur ylide 2a. Functional groups methyl, methoxy,
chloro, bromo, and trifluoromethyl were tolerated on the anilino
groups (NHAr) in which 2- and 4-positioned electron-donating
2
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10.1002/chem.201905483
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form 3z3 (38%) and 3z4 (35%), respectively. Unexpectedly, the
sulfur ylide 2a to give the target thiophene product 5a in 71%
yield. With α-acetyl ketene N,S-acetals 4b and 4c as the
substrates, thiophene derivatives 5b and 5c were obtained in
fully substituted enaminones 1y (R3 = MeCO) and 1z (R3
=
PhCO) also effectively reacted with sulfur ylide 2a, giving the
corresponding tetrasubstituted furan 3z5 (76%) and 3z6 (60%),
respectively.
Table 2. Substrate Scopes for the Synthesis of Furans (3).[a]
76-79% yields. 1-Naphthylamine-derived enaminothione 4d
efficiently reacted to form product 5d (83%), while (E)-1-
cyclopropyl-3-(methylthio)-3-(phenylamino)prop-2-ene-1-thione
(4e) exhibited a lower reactivity to 2a, yielding the target
thiophene product 5e in 65% yield. Benzylamine-derived α-
thioxo ketene N,S-acetal (4f) also reacted well with 2a to afford
the product 5f (82%). In comparison to the synthesis of furans
3k (73%) and 3l (81%) (Table 2), the corresponding thiophene
compounds 5g (93%) and 5h (80%) were readily accessed.
Steric and electronic effects were observed from the 2-OMe and
3-CF3 substituents on the aryl groups of the α-arylthioxo
moieties, leading to thiophenes 5i and 5l in yields (67-70%)
lower than those (83-84%) for 5j and 5k. 2-Furyl-substituted
thiophene 5m was obtained in a much higher yield (75%) than
its furan analog 3u (53%) (Table 2). It should be noted that the
benzylamine-derived enaminothiones 4n-4v reacted with 2a to
give the corresponding thiophene products 5n-5v in high yields
(53-83%), among which 2-furyl and 2-thienyl-substituted
thiophenes 5u and 5v were generated in much higher yields (80-
83%) than 3u and 3v (40-53%), whereas the corresponding
benzylamine-derived enaminones of type 1 could not react with
2a to form furan products under the same conditions due to the
ready decomposition of the substrates during the reaction.
Diverse aryl and alkyl sulfur ylides could also act as the effective
partners to couple with various enaminothiones, producing
functionalized thiophenes 5w-5z1 (45-73%). Interestingly, chiral
benzylamino-based enaminothiones reacted with 2a to yield the
corresponding chiral thiophene derivatives 5z2 (53%) and 5z3
(60%) with unchanged enantiopurity (99% ee). Secondary
amine-derived enaminothiones of type 4 could not react with the
sulfur ylides, further demonstrating the crucial role of an N-H
functionality at the S-functionalized terminus of the internal C=C
backbone in 1 and 4. The molecular structures of compounds 3
and 5 were further confirmed by the X-ray single crystal
[a] Conditions: 1 (0.5 mmol), 2 (1.0 mmol), ZnCl2 (0.05 mmol), DMF (3 mL),
0.1 MPa N2, 120 oC, 24 h.
S,S-Diphenyl sulfur ylide (2h) was also applied in the
reaction with 2a, giving the target product 3a in 34% yield [Eq.
(1)]. By means of the corresponding oxide of sulfur ylide 2a, that
is, benzoyl sulfoxonium ylide (2i), as the coupling partner, 3a
was obtained in a low yield (20%) [Eq. (2)]. The fully substituted
sulfur ylide 2j exhibited a poor reactivity to 2a, and it could not
execute the reaction to form the desired product 3z7 [Eq. (3)]. In
the cases of using PhNH-, MeO-, or methyl-functionalized -oxo
ketene N,N-acetal 1aa, N,O-acetal 1ab, and enaminone 1ac, the
reaction with 2a could hardly occur [Eq. (4)]. These results have
revealed the crucial role of the alkylthio functionality at the N-
functionalized terminus of the internal C=C backbone in the
enaminone substrates.
Next, the protocol was employed to synthesize thiophene
derivatives (Table 3). Under the optimal conditions, (E)-4-
(methylthio)-4-(phenylamino)but-3-ene-2-thione,
that
is,
enaminothione (α-thioxo ketene N,S-acetal) 4a, reacted with
3
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structural determinations of furan 3a and thiophene 5h (Figure 2,
see the Supporting Information for details).
To demonstrate the applicability of the present synthetic
protocol, gram-scale preparation was carried out under the
standard conditions by means of the reactions of 1k and 4g with
2a [Eq. (5)]. The target products 3k and 5g were obtained in
75% and 91% yields, respectively, demonstrating a reaction
efficiency comparable to those on a smaller reaction scale.
Control experiments were conducted to probe into the
reaction mechanism. Thus, the reaction of 1a with 2a was
performed in the presence of 4.0 equiv of 2,2,6,6-tetramethyl-1-
piperi-dinyloxy (TEMPO) or 2,6-di-tert-butyl-4-methylphenyl
(BHT) (see the Supporting Information for details). Under the
Table 3. Substrate Scopes for the Synthesis of Thiophenes (5).[a]
standard conditions, these radical-trapping reagents could not
inhibit the annulation reaction, leading to 3a in 63-70% yields.
Furthermore, no EPR signal was observed from the reaction
mixture, which excludes a radical pathway in the catalytic cycle.
The adduct of 1a with stoichiometric ZnCl2 was considered as
the reaction intermediate, but it was not successfully prepared
from the 1:1 molar ratio reaction of 1a and ZnCl2 at ambient
temperature or under heating conditions. Based on the possible
Lewis acid catalysis pathway, a plausible reaction mechanism is
proposed in Scheme 3. Initially, Lewis acid ZnCl2 interacts with
enaminone 1 or enaminothione 4 through coordination to the
metal center by the oxygen or sulfur atom of the C=X
functionality and the amino nitrogen atom. Reactant 1 or 4 is
thus activated to form adduct 1(4)ZnCl2 (A)/zwitterion species B.
Nucleophilic attack of sulfur ylide 2 at the iminium carbon of
species B yields species C. Subsequent release of dimethyl
sulfide results in intermediate D from which methanethiol is
further eliminated to generate adduct intermediate E.
Regeneration of the Lewis catalyst gives the target product 3 or
5, finishing a catalytic cycle.
[a] Conditions: 4 (0.5 mmol), 2 (1.0 mmol), ZnCl2 (0.05 mmol), DMF (3
mL), 0.1 MPa N2, 120 oC, 24 h.
(3a)
(5h)
Figure 2. Molecular structures of compound 3a and 5h.
Scheme 3. Proposed mechanism.
4
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10.1002/chem.201905483
Chemistry - A European Journal
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[6]
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N-Dearylation of 3-aminofurans (3) and 3-aminothiophenes
(5) was tried to cleave the aryl on the nitrogen functionality by
means of ceric ammonium nitrate (CAN)[37] or silver(II) persulfate
J. J. Huang, X. W. Wu, J. M. Jia, X. K. Guo, X. Xue, Z. Y. Jiang, S. L.
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[38]
[Ag(Py)4]S2O8 according to the literature methods, but failed.
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product was not isolated.
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In summary, an efficient Lewis acid-catalyzed protocol has
been developed for the synthesis of 2-acyl-3-amino-substituted
furan and thiophene derivatives from enaminones and
enaminothiones, that is, -oxo (thioxo) ketene N,S-acetals, and
sulfur ylides. The [4+1] annulation is featured broad substrate
scopes, high efficiency, and good functional group tolerance.
This work has demonstrated the potential applicability of the
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and thiophene derivatives.
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Experimental Section
General procedure for the synthesis of 3
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Synthesis of 3a: Under a nitrogen atmosphere, a mixture of (E)-4-
(methylthio)-4-(phenylamino)but-3-en-2-one (1a) (104 mg, 0.5 mmol),
S,S-dimethyl sulfur ylide (2a) (180 mg, 1.0 mmol), and ZnCl2 (7 mg, 0.05
mmol) in DMF (3 mL) was stirred at 120 oC for 24 h. After cooled to
ambient temperature, 5 mL CH2Cl2 was added and the resultant mixture
was filtered through a short pad of celite, followed by rinsing with 10 mL
CH2Cl2. The combined filtrate was concentrated under reduced pressure.
The resulting residue was purified by silica gel column chromatography
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o
(eluent: petroleum ether (60-90 C)/EtOAc = 50:1, v/v) to afford 3a as a
yellow solid (104 mg, 75%).
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (21871253 and 21672209) and the National Basic
Research Program of China (2015CB856600) for support of this
research.
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Keywords: zinc • enaminones • enaminothiones • sulfur ylides
• annulation
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Entry for the Table of Contents
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Y. He, J. Lou, Y.-G. Zhou,* and Z. K.
Yu*
Page No. – Page No.
ZnCl2-Catalyzed [4+1] Annulation of
Alkylthio-Substituted Enaminones
and Enaminothiones with Sulfur
Ylides
Direct access to multisubstituted furans and thiophenes! Lewis acid ZnCl2-
catalyzed [4+1] annulation of enaminones and enaminothiones with sulfur ylides
efficiently afforded 2-acyl-3-aminofurans and 3-aminothiophenes derivatives,
respectively. This method features wide substrate scopes as well as broad
functional group tolerance.
7
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