Enantioselective Morita–Baylis–Hillman Reaction of Acrylates with Nitrobenzaldehydes Promoted by the Bifunctional Ferrocene-Based Phosphinothiourea Organocatalysts

Article abstract of DOI:10.1007/s10562-016-1759-9

Abstract: A series of ferrocene-based bifunctional phosphinothiourea organocatalysts were synthesized and applied to the enantioselective Morita–Baylis–Hillman reaction of acrylates with nitrobenzaldehydes, giving the desired products in up to 99.7?% ee.

Full text of DOI:10.1007/s10562-016-1759-9

Catal Lett (2016) 146:1429–1434
DOI 10.1007/s10562-016-1759-9
Enantioselective Morita–Baylis–Hillman Reaction of Acrylates
with Nitrobenzaldehydes Promoted by the Bifunctional
Ferrocene-Based Phosphinothiourea Organocatalysts
1
2
1
1
1
•
Chuang Li
1
Ru Jiang
•
Peng-Fei Ma
Wei-Ping Chen
•
Yang Lei
•
Hui Chen
•
Shao-Yu Guan
1
•
Received: 20 April 2016 / Accepted: 27 April 2016 / Published online: 24 May 2016
Ó Springer Science+Business Media New York 2016
Abstract A series of ferrocene-based bifunctional phos-
phinothiourea organocatalysts were synthesized and
applied to the enantioselective Morita–Baylis–Hillman
reaction of acrylates with nitrobenzaldehydes, giving the
desired products in up to 99.7 % ee. The strong electron-
withdrawing effect of nitro group and hydrogen bonding
interactions between the thiourea moiety of catalyst and
aldehyde might be crucial during the enantio-controlling
process.
Graphical Abstract
Keywords Acrylates Á Ferrocene-based Á MBH reaction Á
Nitrobenzaldehyde Á Phosphinothiourea
1
Introduction
Chuang Li and Peng-Fei Ma have contributed equally to this work.
Chiral phosphines, widely utilized as ligands in asymmetric
metal catalysis, have been considered to be the powerful
organocatalysts in recent years. Multifunctional chiral
phosphines, combination of a highly nucleophilic phos-
phorus center with the hydrogen bonding units in a catalyst
structure bearing a chiral skeleton, can synergistically
activate the substrates in an enantio-controlling manner
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-016-1759-9) contains supplementary
material, which is available to authorized users.
&
&
Ru Jiang
jiangru@fmmu.edu.cn
Wei-Ping Chen
wpchen@fmmu.edu.cn
[
1–4]. Furthermore, the catalytic activities and asymmetric
induction of these multifunctional chiral phosphine can be
finely tuned by simply varying the chiral skeleton, the
substituents on the phosphorus atom and the hydrogen
bond donors. Therefore, multifunctional chiral phosphine
1
2
Department of Medicinal Chemistry, School of Pharmacy,
Fourth Military Medical University, Xi’an 710032, China
Department of Pharmacy, The 60th Central Hospital of the
PLA, Dali 671003, China
123

1
430
C. Li et al.
organocatalysts have attracted increasing attention and
have been successfully applied in asymmetric organocat-
alytic reactions [5–19].
asymmetric MBH reaction of aromatic aldehydes with
acrylate, 83 % ee value was obtained. After that, Lu et al.
[53] also reported L-threonine-derived phosphinothiourea
catalysts 5 for the highly enantioselective MBH reaction
between methyl acrylate with aromatic aldehydes (up to
90 % ee). Encouraged by these results, we design bifunc-
tional ferrocene-based phosphinothiourea (R ,S )-5
With a project of developing ferrocene-based chiral cat-
alysts, we recently embarked on exploring novel bifunc-
tional chiral phosphines derived from ferrocene scaffolds
[20–29], and demonstrated its effectiveness in the enan-
C
Fc
tioselective intramolecular Morita–Baylis–Hillman (MBH)
reaction [25]. Therefore, it is highly desirable to apply them
to the more challenging substrates of the MBH reaction.
The enantioselective MBH reaction has been known as
an efficient synthetic tool for the formation of carbon–
carbon bond, it produces polyfunctional chiral molecules in
a single step from simple substrates [30–35]. In the last
decade, considerable progress has been made in the
asymmetric MBH reaction of enone with aldehydes, aza-
MBH reactions and asymmetric intramolecular [36–42].
However, the highly enantioselective MBH reaction
between acrylates and aldehydes remains a challenge, and
only a few effective chiral catalysts have been applied to
this process. The first enantioselective MBH reaction of
acrylates and aldehydes was reported by Soai [43],
affording corresponding adduct in 9–44 % ee. Then,
Hatakeyama [44–46] developed the b-ICD/HFIPA
(Fig. 2), and examined their efficiency in the asymmetric
MBH reaction of acrylates and aldehydes.
2 Results and Discussion
Phosphinothiourea (R ,S )-5 were conveniently prepared
C
Fc
by condensation of aminophosphine 8 with 1.1 equiv of the
corresponding isothiocyanate at room temperature
(Scheme 1). Compound 8 was prepared from readily
accessible (R)-Ugi’s amine 6 according to published pro-
1
cedures [54]. The catalysts were characterized by H NMR,
31
1
3
C NMR, P NMR and mass spectrometry, in which the
structure of (R ,S )-5e has been confirmed by X-ray
crystal structure analysis [55].
C
Fc
The efficiency of (R ,S )-5 was first investigated in the
C
Fc
MBH reaction of 4-nitrobenzaldehyde 9 with HFIPA 10 in
THF at 25 °C. To our delight, catalysts 5a–g exhibited
obvious catalytic activity and enantioselectivity in the
reaction (Table 1). The thiourea structure of catalyst
affected the enantioselectivities and chemical yields of 11
significantly. Compared with 5a, the ferrocenylphosphine 8
without a thiourea structure showed very low activity
(Table 1, entry 1 vs 8). The aromatic thiourea unit led to
higher yields and enantioselectivities than the aliphatic or
alicyclic thiourea unit (entries 1–5 vs entries 6 and 7).
Furthermore, substituents on the aromatic ring of thiourea
unit had a pronounced influence on MBH reaction. The
(
1,1,1,3,3,3-hexafluoroisopropyl acrylate) method, provid-
ing desired products with up to 99 % ee (Fig. 1). But when
the unactivated acrylates were used, such as methyl acry-
late, the enantioselectivities dropped to 8 % ee. Similarly,
Rinaldi et al. [47] demonstrated that b-ICD derivatives 1
could efficiently promote the enantioselective MBH reac-
tion of electron-deficient acrylates (DMNPA or HFIPA)
with aldehydes (up to 99 % ee). Shi et al. [48] also applied
b-ICD to the MBH reaction of aldehydes with a-naphthyl
acrylate to obtain as high as 92 % ee. In Carretero et al.
[
49] adopt commercial chiral phosphine ligand Mandyphos
as organocatalyst in the asymmetric MBH reaction
between p-nitrobenzaldehyde and benzyl acrylate to obtain
corresponding product in 65 % ee. The first example of
bifunctional chiral phosphine-catalyzed enantioselective
MBH reaction of acrylates with aldehydes was reported by
Wu et al. [50–52] in 2009. They synthesized chiral phos-
phinothioureas (2 and 3, Fig. 1) and applied them in the
stronger electron-withdrawing group (–CF ) gave higher ee
3
and yield than others (Table 1, entries 1–3 vs entries 4 and
5). Meanwhile, combining chiral phosphine 8 with the
simple phenyl thiourea did not improve the activity under
the optimized conditions (Table 1, entry 9), which imply
that both the nucleophilic phosphine and the hydrogen
bonding donor are indispensable in the structure of catalyst
Fig. 1 Effective chiral organocatalysts for the enantioselective MBH reaction of acrylates with aldehydes
1
23

Enantioselective Morita–Baylis–Hillman Reaction of Acrylates with Nitrobenzaldehydes Promoted…
1431
Fig. 2 Bifunctional ferrocenyl
phosphinothiourea
C
organocatalysts (R ,SFc)-5
Scheme 1 Synthesis of catalyst (R
C
,SFc)-5
Table 1 Screening of the
catalysts in the MBH reaction of
4-nitrobenzaldehyde with
HFIPA
a
b
Entry
Catalyst
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
5a
54
43
37
41
50
60
34
25
5b
50
5c
49
5d
68
5e
65
5f
38
5g
35
c
8
Trace
Trace
n.d.
c
8? phenyl thiourea
n.d.
The reactions were carried out on a 0.2 mmol scale of aldehyde, with 10 mol% of catalyst 5 (with respect to
aldehyde) and 3 equiv of HFIPA in THF (1 mL) at 25 °C for 48 h. The absolute configuration was
determined by comparing the specific rotation with the literature value [44]
a
Isolated yields
b
Determined by chiral HPLC using Chiralcel OD-H column after the MBH adduct was derivatized [56]
c
Not determined
for obtaining a high catalytic activity and asymmetric
induction.
and the catalyst loadings were investigated to optimize the
reaction (Table 3). The best result was observed at 25 °C,
with 5 equiv of acrylate and 10 mol% catalyst with respect
to the substrate aldehyde (Table 3, entry 5). Increase of the
catalyst loading from 10 mol% to 20 mol% gave no benefit
to enantioselectivity (Table 3, entry 5 vs 7).
The screen of solvents showed that THF was the optimal
one for the reaction (Table 2, entry 3). Although the reaction
proceeded quickly in toluene, the enantioselectivity was
poor (Table 2, entry 4). In the protonic solvent, such as
methanol and ethanol, few MBH product formed (Table 2,
entries 8 and 9). In addition, temperatures, substrate ratio
It is noteworthy that the base additives have a pro-
nounced influence on MBH reaction (Table 4). Except
123

1
432
C. Li et al.
Table 2 The effect of the
solvents on the asymmetric
MBH reaction
a
b
Entry
Solvent
CH Cl
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
2
2
56
13
3
CHCl
THF
3
48
65
60
29
47
17
50
Toluene
CH CN
79
3
53
DMSO
DMF
33
48
c
MeOH
EtOH
Trace
Trace
n.d.
c
n.d.
The reactions were carried out on a 0.2 mmol scale of aldehyde, with 10 mol% of catalyst 5e and 3 equiv of
HFIPA in solvent (1 mL) at 25 °C for 48 h
a
Isolated yields
b
Determined by chiral HPLC using Chiralcel OD-H column after the MBH adduct was derivatized [56]
c
Not determined
Table 3 Further optimization
of reaction conditions
a
b
Entry
10/9 (mol/mol)
Catalyst loading (mol%)
Temperature (°C)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
1/2
1/1
2/1
3/1
5/1
5/1
5/1
5/1
5/1
5/1
5/1
10
10
10
10
10
5
25
25
25
25
25
25
25
-55
0
63
64
68
65
72
42
75
9
39
46
53
60
85
53
85
20
71
83
80
20
10
10
10
10
45
68
63
1
1
0
1
10
40
All reactions were carried out on a 0.2 mmol scale of aldehyde in THF(1 mL) for 48 h. The reaction
temperature, catalyst loading, molar ratio for 4-nitrobenzaldehyde and HFIPA were changed according to
the table
a
Isolated yields
b
Determined by chiral HPLC using Chiralcel OD-H column after the MBH adduct was derivatized [56]
for triethylamine, addition of organic base in the reaction
gave the corresponding adduct in good yields, but lower
enantioselectivities (Table 4, entries 1–5). Interestingly,
the inorganic base additives improved both chemical
yield and enantioselectivity significantly (Table 4, entries
aldehyde gave the best result (Table 4, entry 8).
Reducing the amount of sodium hydroxide from 5 to
1 mol% caused a drop in the enantioselectivity and
yield (Table 4, entry 10). We speculated that the
sodium cation would activate generating zwitterionic
intermediates.
6
–10), and 5 mol% NaOH with respect to the substrate
1
23

Enantioselective Morita–Baylis–Hillman Reaction of Acrylates with Nitrobenzaldehydes Promoted…
1433
Table 4 The effect of base on
the asymmetric MBH reaction
a
b
ee (%)
Entry
Base
Amount (mol%)
Yield (%)
1
2
3
4
5
6
7
8
9
Imidazole
DABCO
PS
5
5
5
5
5
5
5
5
5
1
81
76
71
75
72
76
81
85
82
83
25
10
40
0
DMAP
Et
NaHCO
Na CO
NaOH
3
N
85
85
91
98
91
91
3
2
3
t-BuOK
NaOH
1
0
The reactions were carried out on a 0.2 mmol scale of aldehyde, with 10 mol% of catalyst 5e, 5 equiv of
HFIPA, and base additive in THF (1 mL) at 25 °C for 48 h
PS proton sponge
a
Isolated yields
b
Determined by chiral HPLC using Chiralcel OD-H column after the MBH adduct was derivatized [56]
Encouraged by these results, the substrate scope for 5e-
Table 5 The MBH reactions between nitrobenzaldehyde with dif-
ferent acrylates
catalyzed MBH reactions was next investigated. Surpris-
ingly, only nitrobenzaldehyde reacted with acrylate pro-
viding the desired products (Table 5). No significant
reaction occurred when other aromatic aldehydes were
used, such as benzaldehyde, pyridine carboxaldehydes and
aromatic aldehydes with other electron withdrawing sub-
a
b
stituent (4-CF , 4-Ms, 4-F, 4-Cl, 2,4-dichloro) or electron
3
i
donating group (4-Me, 4- Pr, 4-MeO, 4-OH). We speculate
Entry Ar
R
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
4-NO
2
2
2
2
2
2
2
C
C
C
C
C
C
C
6
6
6
6
6
6
6
H
H
H
H
H
H
H
4
4
4
4
4
4
4
(14a)
(14b)
(14c)
(14d)
(14e)
(14f)
(14g)
Me
Et
55
53
49
41
85
45
84
80
26
62
32
35
that the strong electron-withdrawing effect of nitro group
and hydrogen bonding interactions between the thiourea
moiety of catalyst and aldehyde might be crucial during the
enantio-controlling process. On the other hand, HFIPA
reacted with nitrobenzaldehyde providing higher ee and
yield than other acrylates (Table 5, entries 5–8). Further
studies focusing on the modification of the catalysts are
currently underway.
4-NO
4-NO
4-NO
4-NO
2-NO
3-NO
Bn
t-Bu
c
98
CH(CF
CH(CF
CH(CF
(14h) CH(CF
3
)
3
)
3
)
3
)
2
2
2
2
c
90
c
94
c
4-Cl-3-NO
2
C
H
6 3
99.7
The reactions were carried out on a 0.2 mmol scale of aldehyde, with
0 mol% of catalyst 5e, 5 equiv of acrylic ester, and 5 mol% of
1
NaOH additive in THF (1 mL) at 25 °C for 48 h. The absolute
configuration was determined by comparing the specific rotation with
a literature value [44, 50, 51]
3
Conclusion
In conclusion, a series of ferrocene-based phosphinoth-
iourea bifunctional organocatalysts have been synthesized
and applied to the asymmetric MBH reaction for the first
time. The MBH reaction between nitrobenzaldehyde with
acrylates catalyzed by 5e is highly effective, giving the
a
Isolated yields
b
The MBH adduct was determined directly by chiral HPLC using
Chiralcel column
c
Determined by chiral HPLC using Chiralcel OD-H column after the
MBH adduct was derivatized [56]
123

1
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C. Li et al.
desired products in up to 99.7 % ee and 80 % yield,
although the substrate scope is limited.
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Acknowledgments We thank the National Natural Science Founda-
tion of China (21472240, 21272271) for financial support.
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