Chiral phosphine-squaramides as enantioselective catalysts for the intramolecular Morita-Baylis-Hillman reaction

Article abstract of DOI:10.1039/c0cc03187a

Novel squaramides containing tertiary phosphine were developed as chiral bifunctional organic catalysts to promote the asymmetric intramolecular Morita-Baylis-Hillman reaction of ω-formyl-enones. The adducts were obtained in high yields with good-to-excel

Full text of DOI:10.1039/c0cc03187a

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Chiral phosphine-squaramides as enantioselective catalysts for the
intramolecular Morita–Baylis–Hillman reactionw
Hong-Liang Song,a Kui Yuana and Xin-Yan Wu*ab
Received 11th August 2010, Accepted 11th October 2010
DOI: 10.1039/c0cc03187a
Novel squaramides containing tertiary phosphine were developed
as chiral bifunctional organic catalysts to promote the asymmetric
intramolecular Morita–Baylis–Hillman reaction of x-formyl-
enones. The adducts were obtained in high yields with good-to-
excellent enantioselectivity (up to 93% ee).
o-formyl-enone 4a. When the reaction was carried out at
room temperature using 20 mol% of the catalyst, the desired
product, 5a, was formed in 92% ee and 85% yield (Table 1,
entry 1). Encouraged by this result, solvent effects on the
cyclization reaction were next probed. As shown in Table 1,
the MBH reaction is relatively sensitive to the solvent used.
Less polar solvents such as CH2Cl2, CHCl3, n-hexane, toluene
and ether resulted in good-to-excellent enantioselectivity
(80–93% ee) with 73–94% isolated yields (Table 1, entries
1–5). When polar aprotic solvents such as CH3CN were used,
the MBH reaction was achieved in 97% ee, albeit with a 76%
yield (Table 1, entry 6). Notably, in the cases of alcohols as
solvents, the reaction was accelerated and completed in a
shorter time (entries 8–13). Excellent yields and enantio-
selectivity were observed in EtOH and i-PrOH, and also in a
mixed solvent of CH3CN and EtOH. Since the MBH reaction
was completed within 6 h and afforded a nearly quantitative
yield with 93% ee in ethanol, it was selected as the solvent for
further studies of this reaction.
In the last decade, the use of organic molecules as chiral
catalysts has attracted great attention.1 Electrophile activation
by hydrogen bonding has become a powerful approach in
asymmetric organocatalysis.2 Among the different hydrogen
bond donator catalysts reported to date, thioureas have
proven to be privileged organocatalysts and have been widely
applied in enantioselective transformations. Very recently the
squaramide core has been explored as a novel hydrogen
bonding catalaphore by Rawal’s group.3 The bisamides of
squaric acid can provide two hydrogen bonds to electrophiles,
and the two hydrogen atoms are further apart than those in
thioureas. However, the application of squaramide derivatives
as chiral organocatalysts has been scarce until now.3–7 Since
Rawal’s pioneering work, several chiral aminosquaramide
derivatives have been developed as chiral bifunctional
organocatalysts for Michael addition,4 the Friedel–Crafts
reaction,5 a-amination6 and dynamic kinetic resolution.7
To the best of our knowledge, there have been no reports on
squaramide-based catalysts involving phosphine in asymmetric
reactions. In addition, the application of the monoamide of
squarate as a hydrogen bond donator in organocatalysis has
not been explored. Nucleophilic phosphines are known to be
useful catalysts.8 Therefore, the introduction of a chiral
phosphine backbone into the squaramide core might develop
a new class of bifunctional organocatalysts that combine both
nucleophilic and electrophilic scaffolds. Herein, we report the
first example of chiral phosphine-squaramide catalysts that
promote the intramolecular Morita–Baylis–Hillman (MBH)
reaction with a high efficiency.9,10
A survey of catalyst loading indicated that phosphine-
squaramide 3a maintained a high yield and enantioselectivity
with a reduced catalyst loading from 20 to 3 mol%, with only
an extension of the reaction time. The catalyst loading when
reduced to 1 mol% resulted in an obvious decrease of chemical
yield with retained enantioselectivity (Table 1, entries 10 and
15–17 vs. 18). In comparison with EtOH as the solvent, the
reaction conversion was more sensitive to the catalyst loading
in CH3CN–EtOH (9 : 1 CH3CN–EtOH, entry 14 vs. 13). The
effect of the reaction temperature was also studied in EtOH.
A slight decrease of enantioselectivity was observed when the
reaction was carried out at 0 1C or 40 1C, and a longer reaction
time was required for the lower reaction temperature.
The optimized reaction conditions were then used to assess
the effectiveness of several phosphine-squaramides and related
phosphine-based H-bonding catalysts with the same chiral
backbone (Fig. 1, Table 2). The results indicate that the chiral
phosphine-squaramides 3a–c, containing different alkoxyl
scaffolds, all exhibited high catalytic activities, and the
MBH adducts were obtained in very good yields and enantio-
selectivities (Table 2, entries 1–3). Interestingly, chiral
phosphine-squaramide 6 was an ineffective catalyst for the
Phosphine-squaramides 3a–c were easily prepared by
the condensation of (R,R)-2-amino-1-(diphenylphosphino)
cyclohexane (1)11 with the corresponding squarate in
CH2Cl2 (Scheme 1).12 To evaluate the ability of the newly
developed bifunctional catalysts, phosphine-squaramide 3a
was initially tested in the intramolecular MBH reaction of
a Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology,
Shanghai 200237, P. R. China. E-mail: xinyanwu@ecust.edu.cn;
Fax: +86 21 64252758; Tel: +86 21 64252011
b State Key Laboratory of Elemento-organic Chemistry,
Nankai University, Tianjin 300071, P. R. China
w Electronic supplementary information (ESI) available: Experimental
details, characterization data and NMR spectra for the phosphine-
squaramides 3a–c, HPLC spectra for the Morita–Baylis–Hillman
products. See DOI: 10.1039/c0cc03187a
Scheme 1 Synthesis of chiral phosphine-squaramide catalysts 3a–c.
c
1012 Chem. Commun., 2011, 47, 1012–1014
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Table 1 Optimization of the reaction conditions using 3a as the
catalysta
Table 2 Survey of phosphine-squaramides and their related H-bond-
ing catalystsa
Yield (%)b
ee (%)c
Entry 3a (mol%) Solvent
Time/d Yield (%)b ee (%)c
Entry
Catalyst
Time/d
1
2
3
4
5
6
7
8
20
20
20
20
20
20
20
20
20
20
20
20
20
10
10
5
CH2Cl2
CHCl3
3.5
3.5
5
5
5
85
94
97
73
83
76
39
86
94
99
99
98
98
55
98
99
98
86
94
99
92
93
92
80
89
97
86
72
94
93
91
90
95
94
93
93
93
93
91
90
1
2
3
4
3a
3b
3c
6
7
8
2.5
2.5
2.5
4
7
2
98
94
90
Trace
14
92
93
92
n-Hexane
Toluene
Diethyl ether
CH3CN
DMF
CH3OH
i-PrOH
EtOH
9 : 1 EtOH–CH3CN 0.33
1 : 1 EtOH–CH3CN 0.67
1 : 9 EtOH–CH3CN 2.33
1 : 9 EtOH–CH3CN 4
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
91
n.d.d
66
5
6e
85
4
4.5
0.5
1.5
0.25
a
Unless stated otherwise, the reactions were performed with 3 mol%
of catalyst and 0.2 mmol of 4a in 1.0 mL EtOH (0.2 M) at 25 1C.
Isolated yields. Determined by HPLC analysis using a Chiralcel
9
b
c
10
11
12
13
14
15
16
17
18
19d
20e
d
OD-H column. Not determined. Ref. 10e, t-BuOH as the solvent.
e
0.75
1.5
2.5
7
7
2
Table 3 Enantioselective intramolecular MBH reactions of various
substrates catalyzed by phosphine-squaramide 3aa
3
1
3
3
a
Unless stated otherwise, the reactions were performed with 3a,
b
0.2 mmol of 4a in 1.0 mL of solvent (0.2 M) at 25 1C. Isolated
yields. Determined by HPLC analysis using a Chiralcel OD-H
c
d
e
column. The reaction was performed at 0 1C. The reaction was
performed at 40 1C.
Entry Substrate Ar
Time/d Yield (%)b ee (%)c
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4h
4i
C6H5
4-NO2C6H4
4-FC6H4
2.5
2
3
2
1.5
2
2
7
3
4
5
7
3.5
7
2
98
97
96
95
99
96
98
78
99
94
97
70
91
64
91
94
93
92
93
93
92
92
92
80
80
92
92
88
88
88
88
92
4-ClC6H4
3-ClC6H4
4-BrC6H4
3-BrC6H4
2-BrC6H4
2-BrC6H4
4-MeC6H4
3-MeC6H4
2-MeC6H4
2-MeC6H4
4-MeOC6H4
4-MeOC6H4
Naphth-2-yl
9d
10
11
12
13d
14
15d
16
4j
4k
4k
4l
4l
4m
4
Fig.
1
Structures of other related phosphine-based H-bonding
a
Unless stated otherwise, the reactions were performed with 3 mol%
b
catalysts.
3a and 0.2 mmol substrate in 1.0 mL EtOH at 25 1C. Isolated
yields. Determined by chiral HPLC analysis. With 10 mol% of
3a as the catalyst.
c
d
present reaction, although it is regarded as a dual H-bonding
catalyst (Table 2, entry 4). Chiral phosphine-amide 7, without
a squarate catalaphore, provided a poor yield with moderate
ee (Table 2, entry 5). In our previous work,10e phosphine-
thiourea 8 could promote the intramolecular MBH reaction to
obtain 92% chemical yield with an 82% ee, whereas t-BuOH
was the optimum solvent. Thus, it can be seen that phosphine-
squaramides 3a–c provide a better enantioselectivity than their
thiourea analogue, 8, in the MBH reaction of o-formyl-enone
4a (Table 2, entries 1–3 vs. 6). This survey showed that catalyst
3a afforded the best yield and enantioselectivity.
electron-withdrawing substituents on the phenyl group, to give
the desired adducts in high yield (95–99%) and excellent
enantioselectivity (92–93% ee) (Table 3, entries 1–7). As
for substrates 4i–m, with electron-donating groups on the
aromatic ring, the reactions proceeded slowly (Table 3, entries
10–12, 14 and 16), and lower yields were observed for
substrates 4k and 4l (Table 3, entries 12 and 14). In comparison
with their para- and meta-substituted analogues, substrates 4h
and 4k provided both a lower yield and a lower enantio-
selectivity, probably due to the ortho-effect (Table 3, entry
8 vs. 6 and 7, and entry 12 vs. 10 and 11). In the case of
Finally, the substrate scope was explored in the presence of
phosphine-squaramide 3a. As shown in Table 3, the reactions
worked well with acyclic precursors 4a–g, bearing hydrogen or
c
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Scheme 2 Proposed transition state.
o-formyl-enones 4h, 4k and 4l, the cyclic products were
achieved in excellent yields (91–99%) by increasing the catalyst
loading from 3 to 10 mol% (Table 3, entries 9, 13 and 15).
The absolute configuration of the intramolecular MBH
products was assigned as (S) by comparing the optical rotation
value with those reported in the literature.10b A possible
mechanism for the chiral phosphine-squaramide-catalyzed
intramolecular MBH reaction is proposed in Scheme 2. The
nucleophilic phosphine attacks the b-position of the Michael
acceptor to generate an enolate, and the electrophilic squaramide
activates the aldehyde moiety of substrates 4 by forming a
hydrogen bond with the oxygen atom of the carbonyl. Then,
the chiral cyclohexyl scaffold forces the phosphinoyl-associated
enolate to attack the activated carbonyl from the si-face to
generate the product with an (S)-configuration.10d,e
7 J. W. Lee, T. H. Ryu, J. S. Oh, H. Y. Bae, H. B. Jang and
C. E. Song, Chem. Commun., 2009, 7224–7226.
8 For a recent review, see: A. Marinetti and A. Voituriez, Synlett,
2009, 174–194.
In summary, we have developed a new class of bifunctional
squaramide-based organocatalyst that show a high catalytic
activity and a good-to-excellent enantioselectivity in the
asymmetric intramolecular MBH reactions of o-formyl-enones,
affording a variety of cyclic hydroxyl enones. Work is now
actively under way to expand the use of these bifunctional
phosphine-squaramide organocatalysts to other valuable
transformations.
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C. Housseman and J. Zhu, Angew. Chem., Int. Ed., 2007, 46,
4614–4628; (b) D. Basavaiah, K. V. Rao and R. J. Reddy, Chem.
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We are grateful for financial support from the National
Natural Science Foundation of China (20772029), the Program
for New Century Excellent Talents in University (NCET-07-
0286) and the Fundamental Research Funds for the Central
Universities. We are also grateful to the anonymous reviewers
of this article for their valuable suggestions.
Notes and references
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and X.-Y. Wu, Tetrahedron Lett., 2008, 49, 6262–6264.
12 For the preparation of phosphine-squaramides 3a–c, see the ESIw.
1 For recent reviews on asymmetric organocatalysis, see:
(a) P. I. Dalko, Enantioselective Organocatalysis: Reactions and
Experimental Procedures, Wiley-VCH, Weinheim, 2007; (b) B. List,
Asymmetric Organocatalysis, Springer-Verlag, Heidelberg, 2010;
c
1014 Chem. Commun., 2011, 47, 1012–1014
This journal is The Royal Society of Chemistry 2011