Bifunctional ferrocene-based squaramide-phosphine as an organocatalyst for highly enantioselective intramolecular Morita-Baylis-Hillman reaction

Article abstract of DOI:10.1039/c4ob00137k

This work demonstrates that, in accord with metal catalysis, ferrocene could be an excellent scaffold for organocatalysts. The simple and easily accessible bifunctional ferrocene-based squaramide-phosphine shows high enantioselectivity in the intramolecul

Full text of DOI:10.1039/c4ob00137k

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Bifunctional ferrocene-based squaramide-
phosphine as an organocatalyst for highly
enantioselective intramolecular
Cite this: Org. Biomol. Chem., 2014,
12, 2423
Morita–Baylis–Hillman reaction†
Xiaorui Zhang,‡a,b Pengfei Ma,‡a Dongxu Zhang,a Yang Lei,a Shengyong Zhang,a
Ru Jiang*a and Weiping Chen*a
Received 19th January 2014,
Accepted 22nd January 2014
This work demonstrates that, in accord with metal catalysis, ferrocene could be an excellent scaffold for
organocatalysts. The simple and easily accessible bifunctional ferrocene-based squaramide-phosphine
shows high enantioselectivity in the intramolecular Morita–Baylis–Hillman reaction of 7-aryl-7-oxo-5-
heptenals, giving a variety of 2-aroyl-2-cyclohexenols in up to 96% ee.
DOI: 10.1039/c4ob00137k
www.rsc.org/obc
Asymmetric organocatalysis has emerged in the past decade as activate the substrates in a stereocontrolled manner, leading to
a powerful tool in contemporary organic synthesis and has high enantioselectivities in asymmetric transformations. More
developed into three important areas of asymmetric catalysis importantly, the catalytic activities and enantioselectivities of
together with biocatalysis and metal catalysis.1 So far, numer- these multifunctional/bifunctional chiral phosphine organo-
ous organocatalysts, developed in the past decade, have been catalysts can be finely tuned by simply varying the chiral
rooted in several core structures, such as amino acids,2 scaffold, the phosphorus nucleophilicity and the hydrogen
β-amino alcohols,3 1,2-diamines,4 binaphthyl,5 cinchona alka- bond donors. Herein, we design bifunctional ferrocene-based
loids,6 etc. Ferrocene is a “privileged framework” for the con- squaramide-phosphine (RC,SFc)-1 (Fig. 1) for enantioselective
struction of effective chiral ligands in metal catalysis due to its intramolecular Morita–Baylis–Hillman (MBH) reaction.17 To
easy accessibility and derivatization, and special electronic and the best of our knowledge, this is the first example of a ferro-
steric properties.7 Surprisingly, ferrocene has not been cene-based bifunctional phosphine for highly enantioselective
exploited as a backbone of organocatalysts8 excepting for the organocatalysis.
use of the planar chiral DMAP9 and PIP10 as acyl transfer cata-
Ferrocene-based squaramide-phosphine (RC,SFc)-1 was
lysts for the kinetic resolution of racemic alcohols and amines, easily prepared by the condensation of (RC,SFc)-1-(1-amino-
as well as simple chiral ferrocene-based phosphines as nucleo- ethyl)-2-diphenylphosphinoferrocene (RC,SFc)-218 with diethyl
philic organocatalysts for the enantioselective boration of squarate 3 (Scheme 1). Thus, a solution of (RC,SFc)-2 and
olefins,11 dimerizations of ketenes,12 [3 + 2] cyclizations13 and diethyl squarate 3 (1.2 equivalent) in CH2Cl2 was refluxed for
(aza)-Morita–Baylis–Hillman reaction.14 As part of a project 24 h to give (RC,SFc)-1 in 94% yield.
developing ferrocene-based chiral ligands and catalysts,15 we
are interested in exploring the potential of ferrocene as a (RC,SFc)-1 exists as a mixture of two conformational isomers
scaffold for effective organocatalysts. (see ESI†), plausibly (RC,SFc)-1a and (RC,SFc)-1b (Scheme 2), in
Interestingly, the NMR spectra of (RC,SFc)-1 show that
Multifunctional chiral phosphines have proven to be power- which the rotation of four-membered squarate ring around
ful organocatalysts.16 The combination of a hydrogen bonding C–N bond is blocked by the hindered diphenylphosphino
motif with a highly nucleophilic phosphorus center within one
molecule bearing
a chiral framework can synergistically
aSchool of Pharmacy, Fourth Military Medical University, 169 Changle West Road,
Xi’an, 710032, P. R. China. E-mail: wpchen@fmmu.edu.cn
bDepartment of Pharmacy, the 323rd Hospital of PLA, 6 Jianshe West Road, Xi’an,
710054, P. R. China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob00137k
‡These authors contributed equally to this work.
Fig. 1 (RC,SFc)-PPFA and ferrocene-based squaramide-phosphine (RC,SFc)-1.
Org. Biomol. Chem., 2014, 12, 2423–2426 | 2423
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somewhat low. Thus, in the presence of 20 mol% of (RC,SFc)-1,
the reaction in EtOH at room temperature for 7 days gave the
desired product 5a in 83% ee and 68% yield (Table 1, entry 1).
To optimize the reaction efficiency, various solvents were then
examined. The reaction hardly took place with nonpolar sol-
vents such as n-hexane and toluene (entries 2 and 3) and polar
aprotic solvents such as Et2O, acetonitrile, THF and dioxane
(entries 4–7). The reactions performed in polar protic solvents
MeOH and i-PrOH as well as chlorinated solvents CHCl3 and
CH2Cl2 proceeded smoothly (entries 8–11). CH2Cl2 proved to
be the best solvent in terms of catalytic reactivity and enantio-
selectivity (entry 11). Lowering of the catalyst loading to 5 mol%
and 10 mol% led to a significant decrease in both yield and
enantioselectivity (entries 12–13). Interestingly, a lower reac-
tion temperature did not improve the enantioselectivity
(entries 14 and 15). As expected, reaction at elevated tempera-
ture increased the catalytic activity but deteriorated the
enantioselectivity (entry 16). The squaramide moiety of
(RC,SFc)-1 plays a crucial role in the enantioselective induction.
When (RC,SFc)-PPFA, replacing the squaramide moiety of
(RC,SFc)-1 with a dimethylamino group, was used as a catalyst,
the intramolecular MBH reaction of 7-phenyl-7-oxo-5-heptenal
4a gave the product 5a in 76% yield but as a racemic mixture
(entry 17).
Scheme 1 Synthesis of (RC,SFc)-1.
Scheme 2 Plausible conformers of (RC,SFc)-1.
group. The ratio of the two conformers is about 2 : 1 in CDCl3
(assignment by 1H NMR and 31P NMR) while the ratio changes
to about 1 : 1 in MeOH-d4 and DMSO-d6 (assignment by
31P NMR).
The efficiency of (RC,SFc)-1 was first investigated in the
enantioselective intramolecular MBH reaction of 7-phenyl-7-
oxo-5-heptenal 4a (Table 1). To our delight, (RC,SFc)-1 exhibited
high enantioselectivity in the reaction albeit the activity was
Following initial establishment of appropriate solvent,
amount of catalyst, reaction time and temperature, the sub-
strate scope was explored in the (RC,SFc)-1 catalyzed enantio-
selective intramolecular MBH reaction. As shown in Table 2,
the reactions worked well with 7-aryl-7-oxo-5-heptenals 4a–h,
bearing hydrogen or electron-withdrawing substituents in the
para- and meta-position of the phenyl ring, and 2-naphthyl
Table 1 The enantioselective intramolecular MBH reaction of
7-phenyl-7-oxo-5-heptenal catalyzed by (RC,SFc)-1a
Table 2 The enantioselective intramolecular MBH reaction of 7-aryl-7-
oxo-5-heptenals catalyzed by (RC,SFc)-1a
(RC,SFc)-1
(mol%)
Temp.
(°C)
Yieldb
(%)
eec
(%)
Entry
Solvent
1
2
3
4
5
6
7
8
20
20
20
20
20
20
20
20
20
20
20
5
EtOH
25
25
25
25
25
25
25
25
25
25
25
25
25
0
68
83
n-Hexane
Toluene
Et2O
CH3CN
THF
Dioxane
MeOH
i-PrOH
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Trace
Trace
Trace
Trace
Trace
Trace
67
62
68
70
20
ND
ND
ND
ND
ND
ND
81
60
73
91
75
Entry
Ar
Product
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
C6H5 (4a)
4-NO2C6H4 (4b)
4-FC6H4 (4c)
5a
5b
5c
5d
5e
5f
5g
5h
5i
70
85
82
81
82
83
72
73
72
68
41
74
73
91
94
96
92
92
83
87
92
93
88
87
10
11
9
4-BrC6H4 (4d)
4-ClC6H4 (4e)
4-CF3C6H4 (4f)
3-BrC6H4 (4g)
3-ClC6H4 (4h)
2-Naphthyl (4i)
4-MeC6H4 (4j)
4-MeOC6H4 (4k)
2-BrC6H4 (4l)
2-ClC6H4 (4m)
10
11
12
13
14
15
16d
17e
10
20
20
20
35
45
22
68
83
91
91
83
9
−10
40
25
10
11
12
13
5j
5k
5l
76
∼0
5m
a Unless otherwise specified, the reactions were performed with
0.2 mmol of 4a in 1.0 mL of solvent for 7 days. b Isolated yield.
c Determined by HPLC using a Chiralpak OD-H column. d Reacted for
4 days. e 20 mol% of (RC,SFc)-PPFA was used as catalyst.
a The reaction conditions were the same with those in Table 1, entry
11. b Determined by HPLC using Daicel Chiralcel OD-H, Chiralpak
AS-H or Chiralpak AD-H column.
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derivative 4i, to give the desired products in excellent enantio- step in the MBH reactions has been proposed,20a and later was
selectivities (91–96% ee) (Table 2, entries 1–5 and 8–9) except supported by computational work by Aggarwal and co-
for the 4-CF3 and 3-Br substituted derivatives (entries 6 and 7). workers.20b The excellent performance of this intramolecular
Unsurprisingly, the reaction was slower for the substrates with MBH reaction in protic solvents agrees well with Aggarwal’s
electron-donating groups on the phenyl ring (entries 10 and proposal.
11). It is worth noting that, like the enantioselective intramole-
cular MBH reaction catalyzed by the amino acids derivatived
thiourea-phosphines17d and the cyclohexane-based thiourea-
Conclusions
phosphines,17e the substrates bearing 2-Br and 2-Cl on the
phenyl ring gave very poor enantioselectivities (entries 12
and 13).
In summary, the easily accessible bifunctional ferrocene-based
squaramide-phosphine (RC,SFc)-1 shows high enantioselectivity
in the intramolecular Morita–Baylis–Hillman reaction of
7-aryl-7-oxo-5-heptenals, giving a variety of 2-aroyl-2-cyclohexe-
nols in up to 96% ee. This work demonstrates that, in accord
with metal catalysis, ferrocene could be an excellent scaffold
for organocatalysts. Work is actively under way in our lab to
optimize bifunctional ferrocene-based phosphine, expand its
application to other valuable transformations and develop
other types of organocatalysts based on a ferrocene backbone.
The absolute configuration of the intramolecular MBH pro-
ducts was assigned as (S) by comparing the optical rotation
values with those reported in the literature.17 A plausible tran-
sition state A for the (RC,SFc)-1 catalyzed intramolecular MBH
reaction is presented in Fig. 2. A hydrogen-bonding interaction
between the electrophilic squaramide and the oxygen atom of
aldehyde forms, and the nucleophilic phosphine attacks the
α,β-unsaturated ketone to generate the transition state A,17d,e,g
which is stabilized by the hydrogen-bonding interaction and is
rigid. The planar and carbon-centered chiral ferrocenyl
scaffold forces the enolate to attack the activated carbonyl of
the aldehyde from the si-face in a highly enantioselective way Acknowledgements
to afford the product with an (S)-configuration. The extremely
We thank the National Natural Science Foundation of China
(21272271) for financial support.
poor enantioselectivity of 2-Br and 2-Cl derivatives (Table 2,
entries 12 and 13) in the reaction can be explained utilizing a
possible transition state B. The electrophilic squaramide
might prefer forming a hydrogen-bonding interaction with the
oxygen atom of ketone and 2-Br or 2-Cl via a six-membered
ring, and the nucleophilic phosphine attacks the activated
α,β-unsaturated ketone to generate the transition state B,
which is flexible with respect to aldehyde moiety, leading to
very low enantioselectivity in the addition of the enolate to the
unactivated aldehyde.
Catalyst-substrate hydrogen-bonding interactions in non-
enzymatic catalysis usually occur in aprotic solvents.19
However, the (RC,SFc)-1 catalyzed intramolecular MBH reaction
gave excellent results in polar protic solvents EtOH, MeOH and
i-PrOH. The influence of hydrogen-bond donors, e.g. protic sol-
vents, products or additives, on the acceleration of the rates of
the MBH reactions has been well documented. The partici-
pation of a catalytic quantity of alcohol in the proton transfer
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