Catalytic enantioselective addition of isocyanoacetate to 3-methyl-4-nitro-5-styrylisoxazoles under phase transfer catalysis conditions

Article abstract of DOI:10.1039/c5ob01880c

The reaction between 3-methyl-4-nitro-5-styrylisoxazoles and ethyl isocyanoacetate proceeded under phase transfer catalysis to give enantioenriched monoadducts in high enantiomeric excess (up to 99% ee). The resulting adducts were subsequently cyclised to give 2,3-dihydropyrroles and substituted pyrrolidines in identical high ees and as a single diastereoisomer.

Full text of DOI:10.1039/c5ob01880c

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DOI: 10.1039/C5OB01880C
Cite this: DOI: 10.1039/c0xx00000x
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ARTICLE TYPE
Catalytic enantioselective addition of Isocyanoacetate to 3-methyl-4-
nitro-5-styrylisoxazoles under phase transfer catalysis conditions.
Paolo Disetti,a Maria Moccia, b Diana Salazar Illera,a Suresh Surisettia and Mauro F. A. Adamoa*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
The reaction between 3-methyl-4-nitro-5-styrylisoxazoles and
Scheme 2 Comparison between selected existing literature
examples and this work.
ethyl isocyanoacetate proceeded under phase transfer
catalysis to give enantioenriched monoadducts in high
enantiomeric excess (up to 99% ee). The resulting adducts
10 were subsequently cyclised to give 2,3-dihydropyrroles and
substituted pyrrolidines in identical high ees and as a single
diastereoisomer.
55
Work of Gong
NO2
Cat*
R3
∗
R2OOC
NC
R3
eq. 1
eq. 2
NO2
∗ N
H
R2OOC
R1
R1
MeOOC
15 Herein we report a highly enantioselective (up to 99% ee)
Michael addition of un-substituted α-isocyanoester 2 to 3-methyl-
4-nitro-5-styrylisoxazoles 1a-m (Scheme 1) that run under phase
transfer catalysis. This reaction provided exclusively mono
alkylated compounds 3a-m, whose synthetic relevance was
20 demonstrated by their conversion to 2,3-dihydropyrroles 4a-m
and pyrrolidines 7-9. The methodology described in this work
allows the mono-addition of un-substituted α-isocyanoacetates to
Michael acceptors, which is difficult to control in basic media, by
using the soft electrophilic alkene 1. The reaction reported herein
25 provided enantiomers 3-4 and ent-3-4 in similar high ees.
O
O
O
R
AgIL*
∗
MeOOC
NC
MeOOC
R
∗
MeOOC
Ph
Ph
N
H
Work of Xu and Wang
Ph
O
CN
thiourea-based
Cat*
∗
MeOOC
NC
MeOOC
eq. 3
eq. 4
eq. 5
NR
NR
Ph
O
O
Work of Zhu
MeOOC NC
Cat*
MeOOC
NC
∗
PhO2Se
Ar
Scheme 1 Addition of α-isocyanoesters 2 to Michael acceptors 1
SeO2Ph
Ar
This work
EtOOC
NO2
NO2
NO2
PTC
R1
NC
N
N
N
NH
O
O
O
COOEt
NC
30
R1
R1
COOEt
Isocyanoacetates are popular reagents and their derivatives
have been widely used in organic, inorganic, coordination,
polymeric, combinatorial and medicinal chemistry.1 Products
obtained from isocyanoacetates are effective building blocks for
35 the synthesis of biologically active molecules, complex natural
products2 and heterocycles. Formation of carbon-carbon bonds
via addition of isocyanoacetates to aldehydes,4 imines,5
azodicarboxylates,6 nitroalkenes,7 α,β-unsaturated ketones,8
2
1
3
4
Recently, the same group reported a highly enantioselective
cycloaddition reaction of 2-substituted isocyanoesters and 2-
60 oxobutenoate esters, catalysed by a chiral silver complex (eq. 2,
Scheme 2).15 Xu and Wang developed a diastereoselective and
enantioselective
Michael
addition
of
2-substituted
maleimides,9
carbodiimides,10 alkynes,11 and aromatic
isocyanoacetates to N-aryl maleimides catalyzed by bifunctional
tertiary amine thioureas (eq. 3, Scheme 2).16 Zhu discovered a
65 catalytic enantioselective Cinchona alkaloid catalyzed Michael
addition of 2-aryl isocyanoacetates to vinyl phenylselenones,
resulting in adducts which are precursors to α-amino acids (eq. 4,
Scheme 2).17 On the contrary, the enantioselective addition of un-
substituted 2 to activated alkenes (eq. 5, Scheme 2, this work) is
70 undeveloped and remains a significant challenge, as it involves
controlling the stereoselectivity of the Michael addition and
suppressing a potential second Michael reaction.
40 isocyanides12 has been previously described. In these reactions,
the initially formed Michael adduct undergoes a subsequent
intramolecular nucleophilic addition to form oxazoles,4a, 4c,4e, 4f, 4g
imidazoles,5h, 5i isoquinolines
formal [3 +2] cycloaddition.
or pyrroles,11c effectively via a
13b
45
In contrast to the long history of non-asymmetric variants,13
the enantioselective catalytic addition of α-isocyanoesters with
electron-deficient olefins has only recently been studied (Scheme
2).14-18 Gong and co-workers reported a Cinchona alkaloid
catalysed highly enantioselective addition of 2-substituted
With a view to developing a new organocatalytic synthetic
procedure involving reagent 2, we reasoned that enantioselective
75 mono-addition of 2 to alkenes required an alkene acceptor
50 isocyanoesters to nitroolefins to give 2,3-dihydropyrroles (eq. 1,
Scheme 2).14
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DOI: 10.1039/C5OB01P88a0gCe 2 of 4
cyclised compounds 4a. [d] Compound 3a was obtained as a 1 : 1
diastereoisomeric mixture.
possessing moderate (soft) reactivity. Styrylisoxazoles 1 are
cinnamate equivalents that possess high reactivity towards
stabilized (soft) nucleophiles.19,20 Compounds 1 are stable solids
that can be obtained in large quantities (10-100 mmol) as single
E-isomers by reacting commercially available 3,5-dimethyl-4-
nitroisoxazole and an aromatic or heteroaromatic aldehyde.21 The
preparation of aliphatic congeners has been recently reported,
thus expanding further the application of 4-nitroisoxazoles in
Reaction of 1a and 2 in the presence of quininium catalyst 5
45 furnished adduct 3a in low enantiomeric excess (Table 1, entry
1). A major improvement was then achieved by replacement of 5
with Cinchonidinium catalysts 6. A screening of catalysts 6a-m
(Table 1, entries 2-14) identified 3,5-bis-(trifluoromethyl)benzyl
derivative 6l as the best. Compound 3a was efficiently cyclised to
50 compound 4a by treatment with diisopropylethylamine (DIPEA)
at 30°C. Cyclised 4a was obtained as a single diastereoisomer in
99% ee. The absolute stereochemistry of compounds 4 were
determined by X-ray crystallographic analysis and assigned to be
2S, 3S.[27] The scope of reaction was shown by reacting
5
synthesis.22 The synthetic potential of
1 in a catalytic
10 enantioselective system has been recognized by Yuan,23 Wang24
and Enders25 who used 1 under the catalysis of bifuctional
aminothioureas. Jorgensen described
a
formal [4+2]
cycloaddition in which 1 reacted with trienamines (generated in
situ) to provide adducts in high ees and moderate
15 diastereoselectivity.26 Based on our experience using compounds
1 and Cinchona based phase transfer catalysis (PTC),19 we 55 styryilisoxazoles 1a-n with ethyl isocyanoacetate 2 under the
anticipated these popular catalysts would act as an effective
means to control the enantioselection in the formation of
compounds 3.
catalysis of either 6l or 6m (Table 2). The need to adjust the steric
bias of the phase transfer catalyst to the substrate to obtain high
enantiomeric excesses has been noted by others.28
20
Initially, we reacted 3-methyl-4-nitro-5-styryl-isoxazole 1a
and ethylisocyanoacetate 2 (3 equiv) in the presence of 10 mol%
of N-benzylquininium bromide and K2CO3 (2 equiv) as the base.
This reaction gave desired product 3a in an encouraging 50%
yield. A screening was then carried out involving different bases,
60 Table 2 Catalytic asymmetric addition of ethyl isocyanoacetate 2
to styrylisoxazoles 1a-n.
25 solvents and temperatures. This identified solid K2CO3, toluene
and -20°C as the most suitable conditions, as well as indicating
the requirement of 5 equiv of 2 to attain quantitative conversion.
With suitable conditions in hand, we screened a number of
quaternary ammonium salts derived from Cinchona alkaloids as
30 catalysts (Table 1).
En.
1
R1
3[a] Yield 4[b] Yield
Ee
[%][c][g]
99 [d]
93 [d]
97 [e]
[%] [f][g]
[%][f][g]
1
2
1a
C6H5
3a
88
91
85
83
93
91
85
87
92
91
86
4a
4b
4c
93
96
92
Table 1 Representative results from the screening of Cinchona
derived catalysts 5 and 6.[a] [d]
1b 4-MeC6H4 3b
1c 4-ClC6H4 3c
1d 2-MeOC6H4 3d
3
4
4d 96(94) 97(92) [g]
O2N
COOEt
cat. (10 mol%)
5
1e
1f
4-FC6H4
2-furyl
3e
3f
4e
4f
4g
4h
4i
91
88
89
84
79
91
93
94
89
88[e]
90[d]
89[e]
94[d]
88[d]
88[e]
86[e]
86[e]
77[d]
N
O
K2CO3 (5 equiv.)
toluene, -20oC, 24 h
NC
COOEt
NC
+
6
O
Ph
Ph
N
H
1a
2
3a
NO2
7
1g 4-MeOC6H4 3g
1h 3-MeC6H4 3h
1i 4-NO2C6H4 3i
1j 2,3-ClC6H3 3k
H
Br
HO
N
Br
HO
N
8
O
N
N
9
Ar
Ar
10
4j
6a-m
5
35
11 1k 2-Naphthyl 3l
12
13 1m
4l
Conv.[b] [%]
ee[c] [%]
1l 4-CNC6H4 3m 86
Isobutyl 3n
4l
Entry
Cat.
Ar
88 4m
1
5
C6H5
C6H5
99
50
71
79
62
68
86
91
60
43
60
68
76
99
81
65 a] Conditions: styrylisoxazole 1a (0.1 mmol), ethyl isocyanoacetate 2
(0.50 mmol), cat. 6l or 6m (0.010 mmol), K2CO3 (0.50 mmol), toluene
(0.5 mL), -20 0 °C. [b] Conditions: 3a (0.1 mmol), THF (1.0 mL), DIPEA
(0.2 mmol), 30°C, 2h; [c] Determined by chiral stationary phase HPLC;
[d] obtained using catalyst 6l; [e] obtained using catalyst 6m; [f] isolated
70 yields after column chromatography; [g] Results in brackets refer to the
opposite enantiomer ent-4d obtained using 6m’ as the catalyst.
2
6a
6b
6c
6d
6e
6f
99
3
2-FC6H4
>95
99
4
2-NO2C6H4
2-naphthyl
4-CF3C6H4
2,3,4-F-C6H2
4-CH3OC6H4
2-CF3C6H4
4-NO2C6H4
C6F5
5
90
6
>95
>95
>95
>95
>95
>95
>95
>95
>95
7
8
6g
6h
6i
The results collected point to the following facts: i) compounds
containing either electron withdrawing or electron donating
75 groups on the phenyl were equally good substrates (Table 2,
entries 2-10); ii) the presence of a bulky substituent gave good
enantiomeric excess (Table 2, entry 11); iii) the use of quasi-
enantiomeric catalysts 6m’, derived from Cinchonine, allowed
the preparation of compound ent-4d with enantioselectivity
80 comparable to the one obtained with catalyst 6m (Table 2, entry
4 values in brackets).
9
10
11
12
13
14
6j
6k
6l
2,3-F-C6H3
3,5-(CF3)2C6H3
3,5-(tBu)2C6H3
6m
[a] Conditions: styrylisoxazole 1a (0.1 mmol), ethyl isocyanoacetate 2a
(0.50 mmol), cat. 5 or 6a-m (0.010 mmol), K2CO3 (0.50 mmol), toluene
(0.5 mL), -20°C, 24 h. [b] Determined by 1H NMR spectroscopy. [c]
The synthetic potential of compounds 4 was demonstrated in
the synthesis of pyrrolidine dicarboxylate 9 (Scheme 3). Hence,
40 Determined by chiral stationary phase HPLC run on corresponding
2
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Scheme 3. Synthetic elaboration of compound 4a: preparation of
10 pyrrolidines 7-9.
NH
O2N
N
NH
O2N
COOEt
Et3SiH
TFA
COOEt
73%
O
Ph
O
N
Ph
7
4a
Boc
Boc
N
O2N
N
KMnO4
N
DMAP, TEA
6 D. Monge, K. L. Jensen, I. Marín, K. A. Jørgensen, Org. Lett. 2011, 13,
328.
7 C. Guo, M.-X. Xue, M.-K. Zhu, L.-Z. Gong, Angew. Chem. Int. Ed.
2008, 47, 3414.
COOEt
70%
COOEt
83%
HOOC
(Boc)2O, DCM
O
Ph
Ph
8
9
80 8 (a) C. Arróniz, A. Gil-González, V. Semak, C. Escolano, J. Bosch, M.
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In conclusion, we have reported herein a unique procedure to
15 react unsubstituted 2 and alkenes 1a-m to give monoadducts 3a-
m in high enantioselectivity, which were subsequently converted
to 2,3-dihydropyrroles 4a-m with complete control of
diastereoselectivity. This procedure compares well to other
related syntheses in terms of yields, diastereoselectivity,
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We acknowledge Dr. J. O’Brien and Dr. T. McCabe (Trinity
College Dublin) for n.O.e. and X-ray analysis. MM gratefully
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Notes and references
35 *a Centre for Synthesis and Chemical Biology (CSCB), Department of
Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in
Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland. Fax: (+353) 1
4022168; E-mail: madamo@rcsi.ie.
b
National Research Council-Institute of Crystallography, Via G.
40 Amendola 122/O, 70126 Bari, Italy.
†Electronic Supplementary Information (ESI) available: Experimental
procedures, characterization data, and spectra of new compounds. This
material is available free of charge via the Internet. See
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