Convergent synthesis of polysubstituted furans via catalytic phosphine mediated multicomponent reactions

Article abstract of DOI:10.3390/molecules24244595

Tri- or tetrasubstituted furans have been prepared from terminal activated olefins and acyl chlorides or anhydrides by a multicomponental convergent synthesis mode. Instead of stoichiometric nBu₃P, only catalytic nBu₃P or nBu₃P=O is needed to furnish the furans in modest to excellent yields with a good functional group tolerance under the aid of reducing agent silane. This synthetic method features a silane-driven catalytic intramolecular Wittig reaction as a key annulation step and represents the first successful application of catalytic Wittig reaction in multicomponent cascade reaction.

Full text of DOI:10.3390/molecules24244595

molecules
Article
Convergent Synthesis of Polysubstituted Furans via
Catalytic Phosphine Mediated
Multicomponent Reactions
Xia Fan 1, Rongshun Chen 2,*, Jie Han 1 and Zhengjie He 1,
*
1
The State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China; fanxia0124@163.com (X.F.); hanjie@nankai.edu.cn (J.H.)
Jiangsu Key Laboratory of Pesticide Science, College of Sciences, Nanjing Agricultural University,
Nanjing 210095, China
2
*
Correspondence: rongshunchen@njau.edu.cn (R.C.); zhengjiehe@nankai.edu.cn (Z.H.);
Tel.: +86-15062214150 (R.C.); +86-18622231520 (Z.H.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 15 November 2019; Accepted: 13 December 2019; Published: 16 December 2019
Abstract: Tri- or tetrasubstituted furans have been prepared from terminal activated olefins and acyl
chlorides or anhydrides by a multicomponental convergent synthesis mode. Instead of stoichiometric
nBu3P, only catalytic nBu3P or nBu3P=O is needed to furnish the furans in modest to excellent yields
with a good functional group tolerance under the aid of reducing agent silane. This synthetic method
features a silane-driven catalytic intramolecular Wittig reaction as a key annulation step and represents
the first successful application of catalytic Wittig reaction in multicomponent cascade reaction.
Keywords: polysubstituted furans; multicomponent reaction; silanes; phosphine oxides; catalytic
Wittig reaction
1. Introduction
The Wittig reaction [1–4] provides a powerful tool for convenient construction of carbon-carbon
double bonds in synthetic chemistry. Despite the popularity of this reaction, some major drawbacks
are associated with the formation of stoichiometric phosphine oxides as by-products. The troublesome
purification of the by-products [
well-designed phosphines, especially chiral phosphine reagents [
hampers their applications in asymmetric Wittig reaction [16 25]. In this context, it is highly desired
5
] makes them valueless on an industrial scale [
6–8]. Also, most
9–
15], are very expensive and high cost
–
to develop a catalytic version of phosphine-mediated Wittig reaction by in-situ recycling by-product
phosphine oxide under the aid of a reducing agent. However, it is a challenging task to reuse phosphine
oxides to effect a catalytic Wittig reaction [26
reduced into the corresponding phosphines at a substantially fast rate under mild conditions; second,
the employed reducing agent should be safe for other functional groups of the substrates [29 30].
Consequently, although many new methods for reduction of phosphine oxides have emerged by using
reducing agents such as DIBAL-H [31 32], LiAlH4 [33 34], boron compounds [35 38], and others [39 45],
–28]. First, phosphine oxides are not generally easy to be
,
,
,
–
–
applicable ones for catalytic Wittig reactions remain rare. Recently, silanes have been recognized
as powerful reducing agents for in-situ deoxygenation of phosphine oxides with good functional
tolerance after a series of successful applications of silanes in the transformation of a stoichiometric
phosphine-mediated reaction into a catalytic one [46
catalytic Wittig reaction for efficient synthesis of alkenes in moderate to high yields by using silanes
such as diphenyl silane or trimethoxysilane to reuse in-situ by-product phosphine oxide [54 56]. In
2012, Beller and coworkers realized efficient and chemoselective reduction of tertiary and secondary
–52]. In 2009, O’Brien et al. [53] developed the first
–
Molecules 2019, 24, 4595; doi:10.3390/molecules24244595
www.mdpi.com/journal/molecules

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phosphine oxides to their corresponding phosphines by using silanes under the aid of catalytic copper
complexes [57] or specific Brønsted acids [58]. Under the reported conditions, various reducible
functional groups such as ketones, aldehydes, olefins, nitriles, and esters were well tolerated. Based
on these encouraging findings, a number of important stoichiometric phosphine-involved reactions,
including (aza-)Wittig [59
and others [88–93] have been successfully developed into the catalytic phosphine mediated ones.
Multicomponent reactions (MCRs) [94 96] have attracted much interest from organic chemists in
–75], Mitsunobu [76–78], Staudinger [79–84], Appel [85,86], Cadogan [87],
–
recent years as a highly efficient synthetic strategy. In 2012, our group [97] realized a stoichiometric
phosphine-mediated pseudo-three-component reaction between terminal activated olefins and acyl
chlorides or anhydrides, leading to a convenient and convergent synthesis of tetra-substituted furans in
moderate to excellent yields. The highly functionalized furan product was formed from one molecule
of activated olefin and two or three molecules of acyl chloride or anhydride under the mediation of
nBu3P through a multiple domino sequence consisting of C-acylation, O-acylation, and intramolecular
Wittig reaction (Scheme 1). A concomitant by-product nBu3P=O was also formed [97]. Considering its
high efficiency in synthesis of tetra-substituted furans and its characteristic of the multicomponent
cascade reaction, we were interested in exploring a catalytic version of this reaction by using silanes
as reducing agents. As mentioned above, although silanes have been successfully used as reducing
agents in a series of catalytic versions of important phosphine-mediated reactions like the Wittig
reaction [53–93], this silane-reduction strategy has never been applied to a stoichiometric phosphine
mediated multicomponent cascade reaction before. Furthermore, the addition of reducing agent silane
will certainly result in an increased complexity of a multiple domino reaction sequence. Herein we
report the relevant results from such challenging studies.
Scheme 1. Phosphine-mediated synthesis of tetra-substituted furans.
2. Results and Discussion
Our investigation started with a model reaction between tert-butyl acrylate 1a and 3-chlorobenzoyl
chloride 2a (Table 1). Under the similar conditions of our previous work [97], tert-butyl acrylate
(0.5 mmol) and 3-chlorobenzoyl chloride (1.8 mmol) were added to THF (2.0 mL) under N2, followed by
addition of catalytic nBu3P (0.1 mmol), NEt3 (2.7 mmol) and Ph2SiH2 (0.6 mmol), the resulting mixture
was stirred at room temperature for 24 h. The desired product 3aa was obtained, but only in 11% yield
(entry 1). The reaction was then conducted at 60 ◦C and the yield of 3aa was not substantially improved
(entry 2). Although only a trace amount of the product was observed in a PhSiH3 mediated reaction
run at room temperature in toluene (entry 3), to our delight, tetra-substituted furan 3aa was obtained
in 74% yield when the temperature was raised to 110 ◦C in refluxing toluene (entry 4). Other silanes
such as Ph2SiH2, (MeO)3SiH, polymethylhydrosiloxane (PMHS) and Ph3SiH were effective but offered
inferior results (entries 5-9); SiHCl3 were ineffective at all (entry 10). The loading amount of PhSiH3
was studied and a decreased loading (0.4 mmol) could also smoothly offer a yield of 84% (entries
11-13). A lower reaction temperature (80 ◦C) resulted in a decreased yield (entry 14). Solvents like
dioxane, xylene, and DMF only gave inferior results and acetonitrile was detrimental to the reaction
(entries 15-18). A lowered loading amount of nBu3P (0.05 mmol, 10 mol%) was investigated, only
giving the product in a moderate yield (entry 19). Other phosphines such as PPh3 and Ph2PMe were
totally ineffective as reported before [97]. Thus, the optimized conditions were established as those
shown in Table 1, entry 12.

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Table 1. Survey of the model reaction conditions.a.
Temp (◦C)
3 (%) b
Entry
Silane (mmol)
Solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19 c
Ph2SiH2 (0.6)
Ph2SiH2 (0.6)
PhSiH3 (0.6)
PhSiH3 (0.6)
Ph2SiH2 (0.6)
(MeO)3SiH (0.6)
PMHS (0.034)
PMHS (0.106)
Ph3SiH (1.2)
SiHCl3 (0.6)
PhSiH3 (0.25)
PhSiH3 (0.4)
PhSiH3 (0.75)
PhSiH3 (0.4)
PhSiH3 (0.4)
PhSiH3 (0.4)
PhSiH3 (0.4)
PhSiH3 (0.4)
PhSiH3 (0.4)
THF
THF
rt
60
rt
11
12
trace
74
42
33
26
30
18
trace
65
84
49
56
54
60
11
trace
48
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Dioxane
Xylene
DMF
110
110
110
110
110
110
rt
110
110
110
80
110
110
110
80
CH3CN
Toluene
110
a
Typical conditions: a mixture of 1a (0.5 mmol), 2a (1.8 mmol), nBu3P (0.1 mmol), NEt3 (2.7 mmol) and silane in the
b
c
specified solvent (2.0 mL) under N2 at indicated temperature for 24 h. Isolated yield based on 1a
. The loading
amount of nBu3P was 0.05 mmol.
Under the optimized conditions, the substrate scope of alkenes 1 and acyl chlorides 2 were further
examined (Table 2). Gratifyingly, reducible functional groups such as ketone, acyl chloride, olefin, nitro,
cyano, and ester were all well tolerated in this multicomponent reaction, and moderate to excellent
yields were generally obtained when different substrates were employed (Table 2). When tert-butyl
acrylate 1a was employed, a series of substituted benzoyl chlorides
2c and 4-nitrobenzoyl chloride 2f, readily afforded the corresponding tetra-substituted furans
2
, except o-chlorobenzoyl chloride
in
3
good yields (entries 1-6). Hetero-aryl acyl chloride like 2-thiofuroyl chloride (2g) was also effective in
this transformation, furnishing the corresponding tetrasubstituted furan 3ag in moderate yield (entry
7). Methyl, ethyl, n-butyl and benzyl acrylates (1b–e), acrylonitrile 1f were all good candidates for this
reaction and the expected products were readily delivered in moderate to good yields (entries 8-17).
Aliphatic anhydride 2a’ was also found to be a suitable substrate, albeit giving a lower yield (entry 18).
To further test the generality of the reaction, di-substituted alkene 1g and 1h were also studied
(Scheme 2). We found that α,β-unsaturated ketones were well compatible under standard conditions,
affording the corresponding tetra-substituted furans in satisfactory yields with different benzoyl
chlorides (Scheme 2).

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Table 2. Synthesis of tetra-substituted furans 3 from olefins 1 and acyl chlorides 2 or anhydride 20.a
R in 2 or 20
3 (%) b
Entry
EWG in 1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
CO2tBu (1a)
CO2tBu (1a)
CO2tBu (1a)
CO2tBu (1a)
CO2tBu (1a)
CO2tBu (1a)
CO2tBu (1a)
CO2Me (1b)
CO2Me (1b)
CO2Et (1c)
CO2Et (1c)
CO2nBu (1d)
CO2nBu (1d)
CO2Bn (1e)
CN (1f)
3-ClC6H4 (2a)
4-ClC6H4 (2b)
2-ClC6H4 (2c)
Ph(2d)
4-MeC6H4 (2e)
4-NO2C6H4 (2f)
2-thienyl (2g)
4-ClC6H4 (2b)
4-MeC6H4 (2e)
4-ClC6H4 (2b)
4-MeC6H4 (2e)
4-ClC6H4 (2b)
4-MeC6H4 (2e)
Ph (2d)
3aa, 84
3ab, 75
3ac, 33
3ad, 70
3ae, 90
3af, 37
3ag, 46
3bb, 81
3be, 84
3cb, 71
3ce, 84
3db, 85
3de, 83
3ed, 87
3fb, 38
3fd, 57
3fe, 44
3aa’, 27
4-ClC6H4 (2b)
Ph (2d)
CN (1f)
CN (1f)
CO2tBu (1a)
4-MeC6H4 (2e)
Me (20a)
a
Optimized conditions: under a N2 atmosphere and at 110 ◦C, alkenes
1 (0.5 mmol) and acyl chlorides 2 or
anhydride 20 (1.8 mmol) were added into toluene (2.0 mL), followed by additions of nBu3P (0.1 mmol), NEt3
(2.7 mmol) and PhSiH3 (0.4 mmol), the resulting mixture was stirred for 24 h. Isolated yield based on 1.
b
Scheme 2. Synthesis of tetra-substituted furans 3 from di-substituted alkene 1g and 1h.
To our surprise, methyl vinyl ketone (MVK) 1i was also effective under the catalytic conditions,
furnishing the corresponding tri-substituted furans 3id and 3ie in fair yields in the reactions with
benzoyl chlorides (Scheme 3). It is worthy to note that, in our previous work [97], the more reactive
alkene MVK 1i failed to deliver the expected furans in appreciable yields under the mediation of
stoichiometric nBu3P. Presumably, under the silane-driven catalytic conditions, the instant concentration
of nBu3P would be kept at a relatively low level in the reaction mixture. The low concentration of
nBu3P may diminish the possible side reactions of the highly reactive olefin like 1i.

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Scheme 3. Synthesis of tri-substituted furans 3 from methyl vinyl ketone 1i.
In order to gain more insights about the reaction, some control experiments were conducted
(Scheme 4). In a 31P NMR tracking experiment (a sealed capillary containing C6D6 was used for field
locking and shimming), a signal at δ −32.4 ppm was observed which was identified as nBu3P when
nBu3P=O (0.1 mmol) and silane PhSiH3 (0.4 mmol) were mixed with or without NEt3 (0.4 mmol) in
toluene in an NMR tube under N2 for 24 h (for details, see Supporting Information). These results
provided direct evidence for the regeneration of the nBu3P catalyst. As expected, tetra-substituted
furan 3aa was readily obtained in 51% isolated yield when nBu3P=O (20 mol%) was used instead of
nBu3P. In contrast, an increased loading of nBu3P=O (100 mol%) only brought in a modestly improved
yield (58%). The silane PhSiH3 alone could not effect the domino reaction. These results indicated that
nBu3P=O was the equivalent catalyst of nBu3P in the presence of silane PhSiH3. It is noticeable that
nBu3P=O was inactive as a catalyst in Lin’s report [68].
NMR tube experiment
toluene (0.75 mL)
+
nBu3P=O
PhSiH3
nBu3P
N2, 110 oC, 24 h
toluene (0.75 mL)
N2, 110 oC, 24 h
0.1 mmol
0.4 mmol
+
+
NEt3
nBu3P=O
PhSiH3
nBu3P
0.1 mmol
0.4 mmol 0.4 mmol
Cl
O
O
CO2tBu
Cl
CO2tBu
Standard Conditions
Cl
+
O
1a
2a
(1.8 mmol)
(0.5 mmol)
3aa
Cl
Cl
nBu3P=O (20 mol%) instead of nBu3P; 51% yield
nBu3P=O (100 mol%) instead of nBu3P; 58% yield
without nBu3P;
0% yield
Scheme 4. Control experiments.
Based on the results of this work and previous reports [59
is proposed to rationalize the formation of tetra-substituted furans
cycle starts with the nucleophilic addition of nBu3P to an activate alkene
intermediate undergoes a C-acylation reaction with acyl chloride to give a phosphonium enolate
–
75
,
3
97], a multiple domino process
(Scheme 5, left). The catalytic
like acrylates, the resulting
1
2
A. The phosphorus ylide B, generated through the O-acylation reaction of intermediate A with acyl
chloride 2 in the presence of NEt3, engages in another C-acylation reaction to deliver an ylide C
under the aid of base NEt3. Finally, a polysubstituted furan is delivered through an intramolecular
Wittig reaction of ylide C with the release of nBu3P=O. The phosphine oxide nBu3P=O is then
in-situ reduced by silane PhSiH3 into nBu3P, which enters the next catalytic cycle. Regarding the
formation of the tri-substituted furans 3id and 3ie from MVK 1i, a similar triple domino sequence of
C-acylation/O-acylation/intramolecular Wittig reaction presumably occurs (Scheme 5, right).

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Scheme 5. Proposed mechanism.
3. Experimental Section
Unless otherwise noted, all reactions were carried out in a nitrogen atmosphere under anhydrous
1
conditions. Solvents were purified prior to use according to standard procedures. H and 13C NMR
spectra were recorded in CDCl3 with tetramethylsilane (TMS) as the internal standard. Column
chromatography was performed on silica gel (200–300 mesh) using a mixture of petroleum ether
(60–90 ◦C)/ethyl acetate as the eluant. 2-Acyl acrylates 1g
–h were prepared according to the reported
procedure [98].
Typical procedure for synthesis of highly functionalized furans 3: Under a N2 atmosphere, to
a solution of activated olefins 1a 1i (0.5 mmol), acylation agent (1.8 mmol) in toluene (2.0 mL) were
sequentially added nBu3P (25
–
2
µ
L, 0.1 mmol), Et3N (2.7 mmol) and silane (0.4 mmol) by means of
microsyringe. The resulting reaction mixture was stirred at 110 ◦C for 24 h. After completion of the
reaction as monitored by TLC, water (10 mL) was added. The mixture was extracted with CH2Cl2
(3
×
10 mL). The combined organic layer was washed with saturated brine (10 mL) and dried over
anhydrous sodium sulfate. After filtration, the solvent was removed on a rotary evaporator under
reduced pressure, and the residue was subjected to column chromatographic isolation on silica gel
(eluted with petroleum ether/ ethyl acetate (40:1–20:1) to give furans 3.
3aa–3de, 3fb–3he are known compounds in our previous report [97]. NMR spectra of compounds
3 are available in Supplementary Materials.
3aa, 221 mg, 84% yield; as a yellow solid; m.p. 110–111 ◦C; 1H-NMR (400 MHz, CDCl3)
δ 8.04 (d,
J = 0.7 Hz, 1H), 7.98 (t, J = 1.7 Hz, 1H), 7.97–7.92 (m, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 1.7 Hz,
1H), 7.60–7.53 (m, 1H), 7.48–7.38 (m, 4H), 7.31–7.22 (m, 2H), 1.23 (s, 9H).
3ab, 199 mg, 75% yield; as a yellow solid; m.p. 198–199 ◦C; 1H-NMR (400 MHz, CDCl3)
δ 8.00 (d,
J = 8.7 Hz, 2H), 7.92 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.46 (dd, J = 8.7, 6.7 Hz, 4H), 7.30 (d,
J = 8.7 Hz, 2H), 1.19 (s, 9H).
3ac, 87 mg, 33% yield; as a yellow solid; m.p. 118–120 ◦C; 1H-NMR (400 MHz, CDCl3)
δ 7.66 (dd,
J = 7.6, 1.5 Hz, 1H), 7.60 (dd, J = 7.4, 1.9 Hz, 1H), 7.53–7.46 (m, 2H), 7.42–7.34 (m, 2H), 7.34–7.27 (m,
3H), 7.27–7.24 (m, 1H), 7.23–7.16 (m, 2H), 1.22 (s, 9H).
3ad, 149 mg, 70% yield; as a white solid; m.p. 181–183 ◦C; 1H-NMR (400 MHz, CDCl3)
δ
8.14–7.94
(m, 4H), 7.69–7.62 (m, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.53–7.41 (m, 5H), 7.37–7.26 (m, 3H), 1.16 (s, 9H).
3ae, 210 mg, 90% yield; as a white solid; m.p. 160–162 ◦C; 1H-NMR (400 MHz, CDCl3)
7.84 (d,
δ
J = 8.2 Hz, 2H), 7.79 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.0
Hz, 2H), 6.97 (d, J = 8.1 Hz, 2H), 2.27 (s, 3H), 2.25 (s, 3H), 2.15 (s, 3H), 1.06 (s, 9H).

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3af, 102 mg, 37% yield; as a yellow solid; m.p. 178–180 ◦C; 1H-NMR (400 MHz, CDCl3)
δ
8.37 (t,
J = 9.6 Hz, 4H), 8.30 (d, J = 8.7 Hz, 2H), 8.23 (d, J = 8.6 Hz, 2H), 8.18 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 8.6
Hz, 2H), 1.22 (s, 9H).
3ag, 101 mg, 46% yield; as a oil; 1H-NMR (400 MHz, CDCl3)
δ 8.10 (dd, J = 3.8, 1.0 Hz, 1H), 7.69
(dd, J = 4.9, 1.0 Hz, 1H), 7.61–7.59 (m, 1H), 7.48 (dd, J = 5.0, 1.0 Hz, 1H), 7.45 (dd, J = 3.7, 1.0 Hz, 1H),
7.32 (dd, J = 5.0, 1.0 Hz, 1H), 7.15 (dd, J = 5.0, 3.9 Hz, 1H), 7.09 (dd, J = 4.8, 3.9 Hz, 1H), 7.02 (dd, J = 5.0,
3.8 Hz, 1H), 1.25 (s, 9H).
3bb,196 mg, 81% yield; as a yellow solid; m.p. 185–186 ◦C; 1H-NMR (400 MHz, CDCl3)
δ 7.99 (d,
J = 8.4 Hz, 2H), 7.87 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.51–7.41 (m, 4H), 7.31 (d, J = 8.4 Hz,
2H), 3.50 (s, 3H).
3be, 190 mg, 84% yield; as a yellow solid; m.p. 185–186 ◦C; 1H-NMR (400 MHz, CDCl3)
δ 7.93 (d,
J = 8.0 Hz, 2H), 7.85 (d, J = 7.9 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 7.8
Hz, 2H), 7.10 (d, J = 7.9 Hz, 2H), 3.46 (s, 3H), 2.41 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H).
3cb, 178 mg, 71% yield; as a white solid; m.p. 177–178 ◦C; 1H-NMR (400 MHz, CDCl3)
δ 8.01 (d, J
= 8.4 Hz, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.45 (t, J = 9.2 Hz, 4H), 7.31 (d, J = 8.4 Hz,
2H), 4.00 (q, J = 7.1 Hz, 2H), 0.93 (t, J = 7.1 Hz, 3H).
3ce, 195 mg, 84% yield; as a white solid; m.p. 134–136 ◦C; 1H-NMR (400 MHz, CDCl3)
δ 7.95 (d, J
= 7.9 Hz, 2H), 7.88 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 7.9
Hz, 2H), 7.10 (d, J = 7.9 Hz, 2H), 3.97 (q, J = 7.0 Hz, 2H), 2.41 (s, 3H), 2.38 (s, 3H), 2.29 (s, 3H), 0.90 (t, J =
7.1 Hz, 3H).
3db, 224 mg, 85% yield, as a yellow solid; m.p. 142–143 ◦C; 1H-NMR (400 MHz, CDCl3)
δ 8.01 (d,
J = 8.6 Hz, 2H), 7.90 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.44 (t, J = 8.6 Hz, 4H), 7.29 (d, J = 8.6
Hz, 2H), 3.96 (t, J = 6.6 Hz, 2H), 1.28–1.23 (m, 2H), 1.09–1.07 (m, 2H), 0.77 (t, J = 7.3 Hz, 3H).
3de, 193 mg, 83% yield, as a white solid; m.p. 120–121 ◦C; 1H-NMR (400 MHz, CDCl3)
δ 7.95 (d, J
= 8.1 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.0
Hz, 2H), 7.09 (d, J = 8.1 Hz, 2H), 3.93 (t, J = 6.5 Hz, 2H), 2.40 (s, 3H), 2.37 (s, 3H), 2.28 (s, 3H), 1.35–1.15
(m, 2H), 1.07–1.05 (m, 2H), 0.74 (t, J = 7.3 Hz, 3H).
3ed, 200 mg, 87% yield, as a white solid; m.p. 124–126 ◦C; 1H-NMR (400 MHz, CDCl3)
δ 8.07 (dd,
J = 6.5, 2.7 Hz, 2H), 7.92 (d, J = 7.6 Hz, 2H), 7.68 (d, J = 7.9 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.53–7.47 (m,
2H), 7.41 (t, J = 7.7 Hz, 2H), 7.38–7.31 (m, 3H), 7.30–7.22 (m, 2H), 7.05 (d, J = 7.1 Hz, 2H), 5.00 (s, 2H);
13C NMR (101 MHz, CDCl3)
δ 192.2, 162.2, 156.3, 150.1, 137.3, 134.6, 133.4, 129.9, 129.3, 128.9, 128.8,
128.7, 128.6, 128.5, 128.3, 128.2, 128.2, 128.0, 125.9, 121.8, 115.1, 66.7. HRMS-ESI calcd. for C31H23O4 [M
+ H]+ 459.1591; found 459.1593.
3fb, 85 mg, 38% yield, as a yellow solid; m.p. 181–182 ◦C; 1H-NMR (400 MHz, CDCl3) 8.03 (d, J =
8.6 Hz, 2H), 7.81 (d, J = 8.5 Hz, 2H), 7.52 (dd, J = 8.3, 6.2 Hz, 4H), 7.41 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.6
Hz, 2H).
3fd, 100 mg, 57% yield, as a white solid; m.p. 152–154 ◦C; 1H-NMR (400 MHz, CDCl3)
δ
8.18–8.07
(m, 2H), 7.88 (d, J = 7.3 Hz, 2H), 7.62–7.48 (m, 6H), 7.39 (t, J = 7.7 Hz, 2H), 7.32 (t, J = 6.4 Hz, 3H).
3fe, 85 mg, 44% yield, as a yellow solid; m.p. 165–167 ◦C; 1H-NMR (400 MHz, CDCl3)
7.99 (d, J
δ
= 8.1 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 7.9
Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 2.42 (s, 3H), 2.37 (s, 3H), 2.31 (s, 3H).
3aa’, 32 mg, 27% yield; as a oil; 1H-NMR (400 MHz, CDCl3)
δ 2.46 (s, 3H), 2.43 (s, 3H), 2.34 (s, 3H),
1.55 (s, 9H).
3gb, 133 mg, 57% yield; as a white solid; m.p. 135–137 ◦C; 1H-NMR (400 MHz, CDCl3)
δ
8.06–8.00
(m, 2H), 7.94–7.89 (m, 2H), 7.59–7.53 (m, 2H), 7.52–7.46 (m, 3H), 7.46–7.42 (m, 2H), 7.33–7.28 (m, 2H),
4.00 (q, J = 7.1 Hz, 2H), 0.94 (t, J = 7.1 Hz, 3H).
3ge, 117 mg, 55% yield; as a white solid; m.p. 128–130 ◦C; 1H-NMR (400 MHz, CDCl3)
δ 8.09–8.02
(m, 2H), 7.88 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.51–7.41 (m, 3H), 7.24 (d, J = 8.1 Hz, 2H), 7.12
(d, J = 8.1 Hz, 2H), 3.97 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 2.31 (s, 3H), 0.90 (t, J = 7.1 Hz, 3H).

Molecules 2019, 24, 4595
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3hb, 149 mg, 60% yield; as a yellow solid; m.p. 150–151 ◦C; 1H-NMR (400 MHz, CDCl3)
δ
8.03 (d,
J = 8.9 Hz, 2H), 7.91 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.7
Hz, 2H), 7.00 (d, J = 8.9 Hz, 2H), 3.99 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 0.92 (t, J = 7.1 Hz, 3H).
3he, 150 mg, 66% yield; as a white solid; m.p. 132–133 ◦C; 1H-NMR (400 MHz, CDCl3)
δ 8.04 (d, J
= 8.6 Hz, 2H), 7.87 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.1
Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 3.96 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 2.40 (s, 3H), 2.30 (s, 3H), 0.89 (t, J =
7.1 Hz, 3H).
3id, 38 mg, 29% yield; as a yellow oil; 1H-NMR (400 MHz, CDCl3)
δ
7.77–7.73 (m, 2H), 7.58 (dd,
J = 7.8, 1.7 Hz, 2H), 7.44–7.35 (m, 2H), 7.28 (dd, J = 13.2, 5.4 Hz, 2H), 7.21–7.15 (m, 2H), 6.21 (d, J =
0.8 Hz, 1H), 2.31 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ 191.9, 154.5, 151.1, 138.2, 132.6, 130.0, 129.7,
128.6, 128.2, 128.1(overlap), 127.2, 121.7, 109.7, 13.4; HRMS-ESI calcd. for C18H15O2 [M + H]+ 263.1067;
found 263.1071.
3ie, 55 mg, 38% yield; as a yellow oil; 1H-NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.1 Hz, 2H), 7.58
(d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.1 Hz, 2H), 6.24 (d, J = 0.8 Hz, 1H), 2.38 (s, 6H),
2.31 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ 191.7, 154.3, 150.6, 143.4, 138.5, 135.7, 129.8, 128.9 (overlap),
127.3, 127.0, 121.3, 109.7, 21.6, 21.3, 13.4; HRMS-ESI calcd. for C20H19O2 [M + H]+ 291.1380; found
291.1383.
4. Conclusions
In conclusion, a convergent synthetic method for tri- or tetra-substituted furans has been developed
by catalytic phosphine mediated multicomponental cascade reactions. Instead of stoichiometric nBu3P,
only catalytic nBu3P or nBu3P=O is needed to deliver the furans in modest to excellent yields. A broad
scope of substrates, bearing various reducible functional groups including ketone, acyl chloride, olefin,
nitro, cyano, and ester, are all well tolerated in the presence of reducing agent silane. This synthetic
method features a silane-driven catalytic intramolecular Wittig reaction as a key step and represents the
first successful application of catalytic Wittig reaction in a multicomponent cascade reaction. Future
efforts in our laboratory will be directed toward exploring the asymmetric reactions involving catalytic
chiral phosphine mediated Wittig reaction, the results of which will be reported in due course.
Supplementary Materials: The supplementary materials are available online.
Author Contributions: R.C. and Z.H. conceived and designed the experiments; X.F. performed the experiments;
J.H. checked and analyzed the data; R.C. wrote the paper; Z.H. revised the manuscript.
Funding: This research was funded by the National Natural Science Foundation of China (Grant Nos. 21472096,
21801134, J1103306).
Acknowledgments: Financial support from the National Natural Science Foundation of China (Grant Nos.
21472096, 21801134, J1103306) is gratefully acknowledged.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 3 are not available from the authors.
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