One-pot fluorination and asymmetric Michael addition promoted by recyclable fluorous organocatalysts

Article abstract of DOI:10.1039/c3ra42501k

A novel one-pot fluorination and asymmetric Michael addition reaction sequence promoted by recyclable fluorous bifunctional cinchona alkaloid-thiourea organocatalysts is introduced for the synthesis of α-fluoro-β- ketoesters bearing two chiral centers.

Full text of DOI:10.1039/c3ra42501k

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DOI: 10.1039/C3RA42501K
A novel one-pot fluorination and asymmetric Michael addition reaction
sequence promoted by recyclable fluorous bifunctional cinchona alkaloid-
thiourea organocatalysts is introduced for the synthesis of α-fluoro-β-
ketoesters bearing two chiral centers.

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COMMUNICATION
One-pot fluorination and asymmetric Michael addition promoted by
recyacable fluorous organocatalysts
Wen-Bin Yi,*a Zijuan Zhang,b Xin Huang,b Angela Tanner,b Chun Caia and Wei Zhang*b
5
reported in literature for asymmetric synthesis.
A novel one-pot fluorination and asymmetric Michael addition
reaction sequence promoted by recyclable fluorous bifunctional
cinchona alkaloid-thiourea organocatalysts is introduced for the
synthesis of α-fluoro-β-ketoesters bearing two chiral centers.
Catalysts used to explore the oneꢀpot fluorination and Michael
addition reactions are shown in Fig. 2 which include cinchona
50 alkaloids c-1 to c-4,18 bifunctional cinchona alkaloidꢀthioureas c-
5 to c-7,19 pyrrolidine derivative c-8, and bifunctional amineꢀ
thiourea c-9.14b Among them, five are fluorous bearing a
perfluorinated alkyl chain such as C6F13 or C8F17. SelectfluorTM
(FꢀTEDAꢀBF4) was used as a fluorine source and an equimolar
55 amount of βꢀketoester 1a and nitroalkene 2a were used for the
oneꢀpot synthesis. Under the reaction condition of using 20 mol%
of catalyst at 0 oC for 48 h, all the reactions generated target
product 3a except with catalysts c-9 (Table 1, entries 1–9). The
reaction with bifunctional cinchona alkaloidꢀthiourea catalysts c-
60 5, c-6 and c-7 gave product in high yield (93–96%), good
diastereoselectivity (5:1 to 6:1 dr), and enantioselectivity (80–
82% ee). These results obtained from our oneꢀpot reactions are
similar to those from the Michael additions of αꢀfluorinated βꢀ
ketoesters reported in literature.12b Bifunctional pyrrolidineꢀ
65 thiourea catalyst c-9 has the best diasteroselectivity (10:1 dr) but
low yield and enantioselectivity. Since fluorous catalysts c-5 and
c-6 are epimers, only c-5 was used for further investigation. It
was found that the reaction carried out under ꢀ20 oC for 48 h
using 1:1 MeCN/MePh as a solvent was the best condition which
70 gave product 3a in 95% ee and 9:1 dr. The configuration of 3a
was determined by comparing the chiral HPLC analytical data
with the literature data.12b
10 Asymmetric fluorination is an active topic in medicinal and
agricultural chemistry.1,2 Generation of αꢀfluorinated carbonyl
compounds with two adjacent stereogenic centers is highly
demanded in the synthesis of biologically active molecules such
as histone deacetylase inhibitor I,3
progestational and
15 antiinflammatory agent II,4 antiobesity and anticoronary agent
III,5 antimalarial candidate IV,6 acaricide and insecticide V,7 and
plant growth regulatory activator VI (Fig. 1).8 Synthesis of a
fluorinated quaternary stereocenter next to a tertiary stereocenter
can be accomplished by organocatalytic Michael addition of αꢀ
20 fluorinated βꢀketoesters with Michael acceptors such as
nitroalkenes, chalcones, α,βꢀunsaturated aldehydes, and Nꢀalkyl
maleimides. Pyrrolidine derivatives,9 guanidines,10 cinchona
alkaloids,11 bifunctional cinchona alkaloidꢀthioureas,12 and
bifunctional amineꢀthioureas13 have been developed as
25 organocatalysts for such a transformation.
__________________________________________________
__________________________________________________
Fig. 1 Biologically interested αꢀfluorinated carbonyl compounds
__________________________________________________
As part of our continuous effort on the development of
30 recyclable fluorous organocatalyts14 for asymmetric
synthesis,15 we recently developed oneꢀpot fluorination and
Michael addition reactions.16 We also reported asymmetric
fluorination reactions promoted by fluorous cinchona alkaloid
ester.17 Introduced in this paper is a step economic oneꢀpot
35 fluorination and asymmetric Michael addition sequence
promoted by recyclable fluorous catalysts. To the best of our
knowledge, no such a oneꢀpot transformation has been
__________________________________________________
aSchool of Chemical Engineering, Nanjing University of Science and
40 Technology, Xiao Ling Wei Street, Nanjing 210094, P. R. China. E-mail:
yiwenbin@mail.njust.edu.cn
75 Fig. 2 Organocatalysts tested for oneꢀpot reaction
__________________________________________________
bDepartment of Chemistry, University of Massachusetts Boston, 100
Electrophilic fluorination of 1a could occur without a catalyst
to afford racemic αꢀfluoroꢀβꢀketoester 4a.16 Resulted compound
4a bearing a more acidic αꢀproton facilitated the Michael
Morrissey
Boulevard,
Boston,
MA
02125,
USA.
Eꢀmail:
wei2.zhang@umb.edu
45 † Electronic Supplementary Information (ESI) available: Experimental
section and characterization data. See DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 1

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addition to generate product 3a with two stereogenic centers. To
It was found that recyclable fluorous catalysts c-5 and c-6
performed as well as their nonꢀfluorous counterpart c-7. Catalyst
c-5 was easily isolated from the reaction mixture by fluorous
solidꢀphase extraction (FꢀSPE) with 80:20 MeOH/H2O and
30 thenMeOH on a FluoroFlash® cartridge.20 The catalyst was
recovered from the MeOH fraction in 93% yield and 98% purity.
The reused catalyst has no significant change of product yield
and selectivity (Scheme 1).
confirm the mechanism of the cascade reaction, the reaction of 1a
and 2a under the optimized condition was monitored by LCꢀMS
analysis. Analytical results of the reaction mixtures at different
reaction time are shown in Fig. 3. The amount of racemic
fluorinated compound 4a was produced up to 30% in the first 6 h
and then slowly decreased. The amount of product 3a was
steadily increased during the reaction process. Only a small
amount of Michael addition product 5a was detected in the
5
__________________________________________________
10 reaction mixture. This experiment indicates that the facile
fluorination occurred first to form racemic αꢀflourinated
ketoester 4a followed by c-5 catalyzed asymmetric Michael
addition to form 3a.
15 Table 1 Catalyst screening for oneꢀpot fluorination and Michael addition
35 Scheme 1 Catalyst recycling for the oneꢀpot reaction
__________________________________________________
To explore the scope of catalyst c-5, a series of βꢀketoesters 1
were reacted with Michael acceptors 2 such as nitroalkenes,
chalcones, and α,βꢀunsaturated ketones/esters (Table 2).
40 Reactions of ethyl benzoylacetates with nitrostyrenes gave
excellent product yield and good to excellent enantioselectivity
(entries 1–6). The substituents on the aromatic rings of βꢀ
ketoesters and nitrostyrenes gave the products with decreased
diastereoselectivity. The reaction of methyl ketone afforded
45 product 3g in good yield but decreased enantioꢀ and
diastereoselectivities (entry 7). Furyl nitroalkene produced
product 3h in 96% yield with moderate enantioꢀ and
diastereoselectivities (62% ee and 3:1 dr). As a less reactive
Michael acceptor, the reaction of chalcone and its derivatives
50 were conducted using increased amounts of catalyst in the
presence of CsCO3. Even though the product yield and selectivity
Cat.
Temp
Time
(h)
Yield
(%)b
ee
drd
(%)c
(oC)
1
2
c-1
c-2
c-3
c-4
c-5
c-6
c-7
c-8
c-9
c-5
c-5
c-5
c-5
c-5
c-5
0
0
48
48
48
48
48
48
48
72
72
24
24
24
24
36
48
80
36
31
86
96
95
93
50
ꢀ
ꢀ58
42
46
ꢀ71
81
ꢀ80
ꢀ82
25
ꢀ
3:1
3:1
4:1
3:1
6:1
6:1
5:1
10:1
ꢀ
3
0
4
0
5
0
6
0
7
0
8
0
9
0
10e
11f
12g
13
14
15
25
25
25
25
ꢀ10
ꢀ20
71
67
94
97
95
92
36
41
58
66
90
95
1:1
1:1
2:1
2:1
6:1
9:1
Table 2 Oneꢀpot fluorination and Michael addition catalysed by c-5a
aReaction condition: 0.1 mmol of 1a, 0.1 mmol of SelectfluorTM, 0.1 mmol of
2a, 20 mol% of catalyst in 1:1 CH3CN/MePh; bIsolated yield; cDetermined by
chiral HPLC; dDetermined by 1H NMR; eCH3CN as solvent; fMePh as solvent;
20 gCH3CN/CF3Ph as solvent.
Yield ee
R1
R2
R3
R4
3
drd
(%)b (%)c
__________________________________________________
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Et
Et
Et
Et
Et
Me
Et
Et
Et
Et
Et
Ph
4ꢀBrPh
4ꢀMePh
3ꢀBrPh
Ph
Ph
2ꢀFuryl
Ph
NO2
NO2
NO2
NO2
NO2
3a
3b
3c
3d
3e
3f
3g
3h
3i
92 95
96 96
90 91
91 83
94 85
87 57
96 62
59 36
47 37
71 20
9/1
5/1
3/1
3/1
4/1
2/1
3/1
3/1
4/1
2/1
4/1
Yield (%)
100
Ph
80
4ꢀMePh
Me
Ph
Ph
Ph
NO2
NO2
1a
4a
6
0
PhCO
4ꢀMeOPhCO
PhCO
40
20
5a
3a
9
10
11
Ph
4ꢀNO2Ph
Ph
Ph
Ph
3j
PhCH=CHCO 3k
42
8
55 aReaction condition: 0.1 mmol of 1, 0.1 mmol of SelectfluorTM, 0.1 mmol
of 2 and 20 mol% c-5 in 1:1 CH3CN/MePh at ꢀ20 oC for 48 h; in chalcone
cases 50 mol% c-5 and 20 mol% of Cs2CO3 were used; bIsolated yield;
cDetermined by chiral HPLC; dDetermined by 1H NMR.
0
6
12
18
24
30
36
42
48
Time (h)
Fig. 3 Compound distribution of c-5 catalyzed oneꢀpot reaction
25 __________________________________________________
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DOI: 10.1039/C3RA42501K
were still low (entries 10ꢀ11). Dibenzylideneacetone with two
Michael acceptor sites gave the single Michael addition product
3l in 8% ee (entry 12). We concluded that nitroalkenes constitute
the best electrophiles to obtain high enantioselective Michael
additions.
45 which was then reacted with 4ꢀperfluorooctylaniline under
microwave heating to afford c-5 in 27% overall yield after FꢀSPE
purification.
In summary, the fluorous bifunctional cinchona alkaloidꢀ
thiourea organocatalysts c-5 and its epimer c-6 have been
50 successfully employed in the oneꢀpot fluorination and
enantioselective Michael addition reactions for the synthesis of
αꢀfluoroꢀβꢀketoesters containing two stereogenic centers. The
new bifunctional cinchona alkaloidꢀthiourea organocatalysts can
be readily applied to other asymmetric transformations such as
55 Henry, FriedelꢀCrafts, DielsꢀAlder, and MoritaꢀBaylisꢀHillman
reactions.22
This paper is dedicated to Professor Dennis P. Curran on the
occasion of his 60th birthday. We thank the University of
Massachusetts Boston, Centre for Green Chemistry for the
60 support of this project. W.Y. acknowledges financial support
from NUST Research Funding (2011ZDJH07), Jiangsu
Provincial Natural Science Foundation of China for Key Projects
(BK2010070), and National Natural Science Foundation of China
(20902047).
5
Maleimides are reactive Michael acceptors.21 Oneꢀpot reaction
by mixing all the reaction components together afforded a low
yield of expected product because of the competition of the direct
Michael addition and the fluorination. A oneꢀpot but twoꢀstep
10 procedure was developed to address this issue. The Michael
donor was first fluorinated with SelectfluorTM before the addition
of the maleimide. Maleimides with different Nꢀalkylation groups
reacted with βꢀketoester generated products in excellent yields
(89–98%) with good ee (77–94%) and dr (>20:1) (Table 3). The
15 diastereoselectivity is significantly improved comparing to that
shown in Table 2.
Table 3 Oneꢀpot fluorination and Michael addition with maleimidesa
65 Notes and references
1
I. Ojima, Fluorine in Medicinal Chemistry and Chemical Biology,
Wiley-Blackwell, 2009.
Yield
(%)b
93
91
90
96
92
95
98
ee
(%)c
90
86
87
91
77
91
80
Entry
R1
R2
R3
Pd
drd
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Ph
PhCH2
Et
PhCH2
Et
3l
3m
3n
3o
3p
3q
3r
> 20:1
> 20:1
> 20:1
> 20:1
> 20:1
> 20:1
> 20:1
> 20:1
2
Selected reviews: (a) K. Mikami, Y. Itoh and M. Yamanaka, Chem.
Rev., 2004, 104, 1–16; (b) H. Ibrahim and A. Togni, Chem.
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70
75
80
Ph
4ꢀMePh
4ꢀMePh
4ꢀNO2Ph
4ꢀNO2Ph
3
4
5
6
A. E. Oberster andL. H. Sarett, US 3088951, 1963.
A. G. Schwartz and M. L. Lewbart, US 5175154, 1992.
A. Abad, C. Agullo, A. C. Cunat, A. GonzalezꢀColoma and D. Pardo,
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PhCH2
3s
96
94
aReaction condition: 0.1 mmol of βꢀketoester and 0.1 mmol of
20 SelectfluorTM with 20 mol% of c-5 in 1:1 CH3CN/CH2Cl2 at 25 oC for 24
h, then add 0.1 mmol of maleimide at ꢀ20 oC for 8 h; bIsolated yield;
cDetermined by chiral HPLC and by comparing with the data in ref. 10;
d
7
8
9
R. G. Hall, H. Szczepanski, I. Bruce, G. Cooke, L. J. Diorazio, M.
Dobler and F. Cedebaum, DE 19934952, 2000.
1
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25
The synthesis of fluorous version bifunctional cinchona
alkaloidꢀthioureas organocatalyst c-5 was accomplished
following the reported procedures (Scheme 2).19b
Hydroquinidine c-1 was converted to azide 6 by reacting with
diphenyl phosphorazidate (DPPA) in the present of triphenyl
30 phosphine (TPP) and diisopropyl azodicarboxylate (DIAD).
The reaction of azide 6 with TPP and CS2 afforded 7
__________________________________________________
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100
Scheme 2 Synthesis of fluorous catalyst c-5
______________________________________
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