Ferrocene-based bifunctional organocatalyst for highly enantioselective intramolecular Rauhut–Currier reaction

Article abstract of DOI:10.1016/j.catcom.2018.12.016

Three series of novel ferrocene-based bifunctional chiral phosphines have been designed and synthesized. Thethiourea-phosphine A7 showed good performance in enantioselective intramolecular Rauhut–Currier reaction of bis(enones), giving the corresponding p

Full text of DOI:10.1016/j.catcom.2018.12.016

Accepted Manuscript
Ferrocene-based bifunctional organocatalyst for highly
enantioselective intramolecular Rauhut–Currier reaction
Xiaowei Zhou, Huifang Nie, Xian Liu, Xiaomei Long, Ru Jiang,
Weiping Chen
PII:
S1566-7367(18)30528-4
DOI:
Reference:
https://doi.org/10.1016/j.catcom.2018.12.016
CATCOM 5579
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
26 September 2018
20 November 2018
26 December 2018
Please cite this article as: Xiaowei Zhou, Huifang Nie, Xian Liu, Xiaomei Long, Ru Jiang,
Weiping Chen , Ferrocene-based bifunctional organocatalyst for highly enantioselective
intramolecular Rauhut–Currier reaction. Catcom (2018), https://doi.org/10.1016/
j.catcom.2018.12.016
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Ferrocene-Based Bifunctional organocatalyst for Highly Enantioselective
Intramolecular Rauhut–Currier Reaction
Xiaowei Zhou a, HuifangNiea, Xian Liua, XiaomeiLongb, Ru Jianga,*, Weiping
Chena,*
a School of Pharmacy, The Fourth Military Medical University, 169 Changle West
Road, Xi’an, 710032, P. R. China.
b Medical School, Xi’an Peihua University, 2 Baisha Road, Xi’an, 710000, P.R.
China.
* Corresponding author.
E-mail addresses: jiangru@fmmu.edu.cn (R. Jiang); wpchen@fmmu.edu.cn (Wp.
Chen).
Abstract
Three series of novel ferrocene-based bifunctional chiral phosphines have been
designed and synthesized. Thethiourea-phosphine A7 showed good performance in
enantioselective intramolecular Rauhut–Currier reaction of bis(enones), giving the
corresponding products in good yield with up to 98% ee. Moreover, with amino acid
derived amide-phosphine B3, optically active α-methylene-δ-valerolactone was
obtained in 88% yield and > 99.9% ee utilizing the enantioselective intramolecular
Rauhut-Currier reaction of chalcone derivative.
Keywords: Ferrocene-based organocatalyst; Rauhut–Currier reaction; Bifunctional
chiral phosphine; Enantioselective

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1. Introduction
Chiral phosphine catalysis, especially the use of bi- and multi-functional chiral
phosphines, has progressed at an astonishingly rate over last decade and it offers the
efficient creation of a diverse range of structural architectures [1]. Phosphines usually
show distinctive catalytic behaviors mainly because of stronger nucleophilicity and
weaker basicity compared to amine catalysts[2]. In a general mode of activation,
relying on the non-bonded electron pairs, a phosphine adds to activated alkenes,
allenes, or alkynes to form an ylide type zwitterionic intermediate, which reacts with
activated electrophilic partners, such as olefins, imines, and aldehydes, resulting in
diverse transformations such as Morita−Baylis−Hillman (MBH) [3], Rauhut−Currier
(RC) [4], and multiple annulation reactions [5].
Rauhut-Currier (RC) reaction [4, 6-9], also known as vinylogous MBH reaction,
is one of the oldest phosphine-catalyzed reactions, first reported as early as 1963 [10],
and is an efficient, atom-economic approach to densely functionalized alkenes via
forming a new carbon-carbon bond. One alkene is activated by nucleophilic catalysts
to serve as a latent enolate and the other is used as a Michael acceptorin RC reaction.
Asymmetric RC reactions presents significant challenges due to low reactivity and
poor control of chemo- and stereoselectivity of the process [4]. The first successful
enantioselective RC reaction was reported by Miller utilizing a cysteine-based catalyst
in 2007 [11]. The following years have witnessed different groups contributed to the
catalyst development, and a significant progress was achieved by the introduction of
bi- and multi-functional chiral phosphines [12-19]. Complementing the

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nucleophilicity of the phosphine with a Lewis acidic functionality, the new generation
of bifunctional catalysts accessed several RC products in extraordinary yields and
selectivities [12,13,16,18]. However, even those catalysts have their limits, such as
high catalyst loading and limited substrate scope. Hence, the development of new
catalysts is still highly desirable.
Ferrocene has been recognized as a “privileged framework” for the construction
of effective chiral ligands in metal catalysis [20]. Surprisingly, ferrocene had not been
exploited as a chiral backbone of organocatalysts until 2014 [21], except for the use of
the planar chiral DMAP [22] and PIP [23] as acyl transfer catalysts for the kinetic
resolution of racemic alcohols and amines, as well as simple chiral ferrocene-based
phosphines as nucleophilic organocatalysts for the enantioselective boration of olefins
[24], dimerizations of ketenes [25], [3 + 2] cyclizations [26] and
(aza-)Morita–Baylis–Hillman reaction [27]. In 2014, we reported ferrocene-based
bifunctional amine–thiourea (RC,SFc)-1 (Fig. 1) for highly effective Michael addition
of acetylacetone to nitroolefins [28]. This work demonstrated that, in accord with
metal catalysis, ferrocene could be an excellent chiral scaffold for organocatalysts for
the first time. As a part of our ongoing project for the development of ferrocene-based
chiral ligands and catalysts [29-35], we became interested in developing new
ferrocene-based bifunctional phosphines as catalysts for enantioselective RC reaction.
Previously, we reported bifunctional ferrocene-based squaramide-phosphine,
FerroSquaPhos (Fig. 1), as an efficient organocatalyst for highly enantioselective
intramolecular MBHreaction (up to 96% ee, 82% yield) [33]. Due to the mechanistic

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similarity of MBH and RC, the FerroSquaPhos was first tested in the enantioselective
intramolecular RC reaction of bis(enone). Unfortunately, FerroSquaPhos did not show
any catalytic activity in the reaction. Then, three series of new ferrocene-based
bifunctional phosphines A-C were then designed (Fig.1). We envisioned that
replacement of diphenylphosphino moiety on ferrocene with dialkylphosphino groups
might increase the nucleophilicity, and hence enhances the catalytic activity of
bifunctional phosphines. Three different H-bonding donors were introduced since the
H-bonding donor of bifunctional phosphines also plays important role in catalysis.
Fig.1. Structures of the designed ferrocene-based bifunctional organocatalysts.
2. Results and discussion
The new bifunctional phosphines were easily prepared via a simple synthetic
route (Scheme 1). According to the “one-pot” synthesis that we developed previously
[29,31,33], lithiation of Ugi’s amine (R)-2 with tert-BuLi in t-butyl methyl ether
(TBME) at 0 °C, followed by reaction with PCl3 at −78 °C, and then reaction with
RMgBr to afford the PPFA derivatives (RC,SFc)-3. After reaction of 3 with Ac2O at
100 °C, followed by treatment with a large excess of ammonia in a mixture of water,
methanol and THF at 60 °C, the dimethylamino group of 3 was substituted by an
amino group to give primary amines (RC,SFc)-4. Finally, (RC,SFc)-4 was converted to
catalysts A-C.

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Scheme 1. Synthesis of ferrocene-based bifunctional phosphines A-C.
With the new ferrocene-based bifunctional phosphines in hand, the
enantioselective intramolecular RC reaction using
(2E,7E)-1,9-diphenylnona-2,7-diene-1,9-dione 5a as model substrate was tested
(Scheme 2). The reaction was performed using 10 mol% catalyst A-C with 0.1 mmol
of 5a in 2 mL of CH2Cl2 at room temperature for 24 h. As shown in Scheme 2, the
introduction of dialkylphosphino groups on ferrocene indeed increased the catalytic
activity. Thiourea-phosphines gave better results than other three types of catalysts.
The best result was achieved using A7 (R1 = Et, R2 = 3,5-(CF3)2-C6H3), giving 6a in
61% yield and 98% ee.
Scheme 2. Catalysts screening.
To optimize the reaction efficiency, various conditions were then examined
(Table 1). Unlike FerroSquaPhos-catalyzed enantioselective intramolecular
Morita–Baylis–Hillman (MBH) reaction [32], the A7 catalyzed enantioselective
intramolecular RC reaction of (2E,7E)-1,9-diphenylnona-2,7-diene-1,9-dione 5a
could take place in all solvents tested, although polar protic solvent MeOH gave very
poor result (entry 1). TBME, THF and EtOAc afforded higher yield and good
enantioselectivity (entry 2, 6 and 8). CH2Cl2 proved to be the best solvent in terms of
catalytic reactivity and enantioselectivity (entry 13). Lowering or increasing the

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catalyst loading slightly affected both yield and enantioselectivity (entries 14-15).
Surprisingly, lower reaction temperature deteriorated significantly the
enantioselectivity and catalytic reactivity (entry 16). In addition, the addition of NaI,
K2CO3, phenol and AcOH as an additive also could not improve the performance.
Table 1.
Optimization of the reaction conditions.a
Entry
Solvent
Temp. (°C) Yield (%)b ee (%)c
A7
(mol%)
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
10
10
10
10
MeOH
TBME
Toluene
Et2O
25
25
25
25
25
25
25
25
25
25
26
74
46
56
41
73
53
77
62
29
15
65
65
75
90
88
74
78
85
77
CH3CN
THF
Dioxane
EtOAc
Acetone
DMSO

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11
12
13
14
10
10
10
5
DMF
25
25
25
25
28
42
61
54
91
95
98
95
CHCl3
CH2Cl2
CH2Cl2
15
16
20
10
CH2Cl2
CH2Cl2
25
0
67
14
95
89
18d
19e
10
10
CH2Cl2
CH2Cl2
25
25
26
65
98
98
aUnless otherwise specified, the reactions were performed with 0.1 mmol of 5a in 1.0
mL of solvent for 24 h. bIsolated yield. cDetermined by HPLC using a Chiralpak
AD-H column. Absolute configuration was assigned by comparing the optical rotation
values with those reported in the literature [11,18]. dReaction for 12 h. eReaction for
48 h.
Following initial establishment of appropriate solvent, the substrate scope was
explored in the A7 catalyzed enantioselective intramolecular RC reaction. As shown
in Table 2, the reactions worked well with
(2E,7E)-1,9-diarylnona-2,7-diene-1,9-diones 5a–n, bearing hydrogen, halo and
electron-donating substituents on the para- and meta-position of the phenyl ring to
give the desired products in excellent enantioselectivity (92–98% ee) (Table 2, entries
1–10). However, the (2E,7E)-1,9-diarylnona-2,7-diene-1,9-diones bearing strong
electron-withdrawing substituents on the para- and meta-position of the phenyl ring

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significantly descreased the enatioselectivity (entries 11–12). The low
enantioselectivity of meta-nitro substituted substrate is understandable (entry 12)
since nitro can interact with thiourea, and hence interferes with the catalysis. Notably,
the substrates bearing ortho-substituents on the phenyl ring gave very poor
enantioselectivity (entries 13-14), possibly due to the steric hindrance.
Table 2.
Substrate scope of asymmetric intramolecular RC reaction catalyzed by A7.a
Entry Ar
Product
Yield
(%)
ee (%)b
1
2
3
4
5
6
7
8
9
C6H5 (5a)
6a
6b
6c
6d
6e
6f
61
56
68
75
47
35
42
73
41
98
96
98
97
95
93
96
94
92
4-CH3C6H4 (5b)
4-FC6H4 (5c)
4-BrC6H4 (5d)
4-ClC6H4 (5e)
4-CH3OC6H4 (5f)
3-CH3OC6H4 (5g)
3-FC6H4 (5h)
6g
6h
6i
3-ClC6H4 (5i)

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10
11
12
13
14
3-BrC6H4 (5j)
4-CF3C6H4 (5k)
3-NO2C6H4 (5l)
2-ClC6H4 (5m)
6j
91
85
63
88
40
93
82
62
40
38
6k
6n
6l
2-CH3O-C6H4 (5n) 6m
aThe reaction conditions were the same with those in Table 1, entry 13.
bDetermined by HPLC using Chiralpak AS-H or Chiralpak AD-H column.
According to the above experimental results and related reports [16,18,19], a
plausible transition state for A7 catalyzed intramolecular RC reaction is presented in
Figure 3. A nucleophilic addition of the phosphine to the β-position of the Michael
acceptor generates an enolate, while the bis(enones) are activated by the electrophilic
thiourea through hydrogen-bonding interactions. The planar and carbon-centered
chiral ferrocenyl scaffold forces the phosphinoyl-associated enolate to attack the
activated C=C of the bis(enones) from the si-face in a highly enantioselective way to
afford the product with an (S)-configuration.
Fig. 2. Proposed transition state for the A7 catalyzed intramolecular RC reaction.
Preliminarily, catalysts A-C were also screened in the enantioselective
intramolecular RC reaction of (E)-2-(3-oxo-3-phenylprop-1-enyl)phenyl acrylate 7,
and catalyst B3 gave very promising results, providingα-methylene-δ-valerolactone 8

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with 88% yield and > 99.9% ee, which is a common structural motif in a large family
of natural products with a broad range of biological activities (Fig.3) [17].
Fig.3. Enantioselective intramolecular Rauhut-Currier reaction of
(E)-2-(3-oxo-3-phenylprop-1-enyl)phenyl acrylate 7 catalyzed by B3
3. Conclusion
Three series of new ferrocene-based bifunctional phosphines have been designed
and synthesized. The ferrocene-based bifunctional thiourea-phosphine A7, with
diethylphosphino group, is a highly efficient catalyst for the enantioselective
intramolecular Rauhut-Currier reaction of
(2E,7E)-1,9-diarylnona-2,7-diene-1,9-diones, giving the products with up to 91%
yield and up to 98% ee enantioselectivity. In a preliminary test, in the enantioselective
intramolecular Rauhut-Currier reaction of (E)-2-(3-oxo-3-phenylprop-1-enyl)phenyl
acrylate amino acid derived bifunctional phosphine B3 afforded product in 88% yield
and > 99.9% ee. These results are comparable to the best results so far reported. Work
is actively under way in our lab to expand its application to other substrates.
4. Experimental section
4.1 Synthesis of catalysts A
Isothiocyanate (2 mmol) in dry THF (3 mL) was added dropwise into a solution of
(RC,SFc)-4 (1 mmol) in dry THF (8 mL) at room temperature under an N2 atmosphere,
and the corresponding mixture was stirred at this temperature until the reaction

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completed (monitoring by TLC). The solvent was removed under reduced pressure
and the residue was purified by column chromatography (petroleum ether/ethyl
acetate 5:1) to afford the afford the desired catalysts A.
4.2 Synthesis of catalysts B
Boc-protected amino acid (1.0 mmol),(RC,SFc)-4 (1.0 mmol) and EDCI (1.5 mmol)
were added into dry THF (10 mL) under an N2 atmosphere. After the mixture was
cooled to 0 °C, DMAP (0.3 mmol) in dry CH2Cl2 (2 mL) was added dropwise into the
solution. Then the mixture was gradually warmed to room temperature and stirred
until the reaction completed (monitoring by TLC). The solvent was removed under
reduced pressure and the residue was purified by column chromatography (petroleum
ether/ethyl acetate 10:1) to afford the afford the catalysts B.
4.3 Synthesis of catalysts C[33]
To a solution of (RC,SFc)-4(1 g, 2.4 mmol) in dry THF (5 mL) was added n-BuLi
(1 mL, 2.4 mmol, 2.4 M) at -30 °C under an N2 atmosphere, and the mixture was
stirred for 10 min. A solution of enantiopure tert-butanethiosulfinate (0.47 g, 2.4
mmol) in 1 mL of dry THF was added slowly to the lithium amine solution. Then the
mixture was stirred for 2 h at -30 °C, and then ice water were carefully added. The
volatile material was removed, and the residue was extracted with CH2Cl2 (3×20 mL).
The combined organic layers were dried (Na2SO4), concentrated and purified by flash
chromatography (petroleum ether/ethyl acetate 4:1) to afford the catalysts C.
4.4Enantioselective intramolecular RC reaction of
(2E,7E)-1,9-diarylnona-2,7-diene-1,9-diones 5

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To a solution of ferrocene-based phosphine catalyst (0.01 mmol) in CH2Cl2 (1.0
mL) was added the bis(enones) 5 (0.1 mmol) at 25 ℃. The mixture was stirred at the
same temperature for 24 h. Then the solvent was removed under reduced pressure and
the residue was purified by column chromatography on silica gel to afford the desired
cyclic products 6. The ee values were determined by HPLC analysis with Chiralpak
AS-H or Chiralpak AD-H column.
4.5Enantioselective intramolecular Rauhut-Currier reaction of
(E)-2-(3-oxo-3-phenylprop-1-enyl)phenyl acrylate 7
To a stirring solution of catalyst B3 (0.01 mmol) in CH2Cl2 (1.0 mL) was added
(E)-2-(3-oxo-3-phenylprop-1-enyl)phenyl acrylate 7 (0.1 mmol) at 25 ℃. The mixture
was stirred at the same temperature for 24 h. Then the solvent was removed under
reduced pressure and the residue was purified by column chromatography on silica
gel to afford α-methylene-δ-valerolactone 8. The ee value was determined by HPLC
analysis with Chiralpak AD-H column.
Acknowledgements
We thank the National Natural Science Foundation of China (21272271,
21472240) for financial support.
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Highlights
 Chiral ferrocene-based organocatalystforintramolecular Rauhut-Currier reaction.
 H-bonding donor has a synergistic effect with nucleophilic dialkylphosphino
group.
 Ferrocene could be an excellent chiral scaffold for chiral organocatalyst.