Catalytic asymmetric conjugate addition of isocyanoacetate to (Z)-3-substituted-2-(4-pyridyl)-acrylonitrile, a reactive class of Michael acceptor

Article abstract of DOI:10.1039/c5cc08105j

(Z)-3-Substituted-2-(4-pyridyl)-acrylonitriles, a reactive class of Michael acceptors obtained exclusively as a single (Z) isomer, reacted with un-substituted isocyanoacetate esters mediated by phase-transfer catalysis to give, after base promoted cyclisation, functionalized imines in up to 94% ee and as a single diastereoisomer.

Full text of DOI:10.1039/c5cc08105j

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ARTICLE TYPE
Catalytic Asymmetric Conjugate Addition of isocyanoacetate to (Z)-3-
substituted-2-(4-pyridyl)-acrylonitrile, a reactive class of Michael
acceptor.
Claudia Del Fiandra,a Maria Moccia,b Valentina Cerulli, and Mauro F. A. Adamoa*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
effective building blocks for the synthesis of biologically active
molecules, complex natural products5 and heterocycles.6
Formation of carbonꢀcarbon bonds via addition of
55 isocyanoacetates to aldehydes,7 imines,8 azodicarboxylates,9
(Z)-3-substituted-2-(4-pyridyl)-acrylonitriles, a reactive class
of Michael acceptors obtained exclusively as a single (Z)
isomer, reacted with un-substituted isocyanoacetate esters
10 mediated by phase-transfer catalysis to give, after base
promoted cyclisation, functionalized imines in up to 94% ee
and as a single diastereoisomer.
nitroalkenes,10
α,βꢀunsaturated
ketones,11
maleimides,12
carbodiimides,13 alkynes,14 and aromatic isocyanides15 has been
previously described. In these reactions, the initially formed
Herein we report the synthesis of a reactive class of Michael
Michael adduct undergoes
a
subsequent intramolecular
15 acceptors,
(Z)ꢀ3ꢀsubstitutedꢀ2ꢀ(4ꢀpyridyl)ꢀacrylonitriles
1
60 nucleophilic addition to form oxazoles,7a, 7c, 7e, 7f, 7g, imidazoles,8h,
8i
(Scheme 1) which were obtained exclusively as a single (Z)
isomer from commercially available materials. During the
development of this chemistry Taunton and coꢀworkers described
the synthesis of alkene 1a as selective reactants for nucleophilic
20 cysteine.1 The synthetic relevance of this class of olefin was
demonstrated by their reaction with unꢀsubstituted
isocyanoacetate esters 2 which proceeded under phaseꢀtransfer
catalysis conditions to give only monoꢀadducts 3 even in the
presence of fiveꢀfold excess of reagent 2. The methodology
25 described is significant as monoꢀaddition of unꢀsubstituted αꢀ
isocyanoacetates to Michael acceptors is difficult to control in
basic media and required the use of an electrophilic alkene
acceptor that generates a stabilised anion upon addition. In
addition, base promoted cyclisation of 3 produced highly
30 enantioenriched cyclic imines 4 (in up to 94% ee) as a single
isoquinolines15b or pyrroles,14c effectively ꢀvia a formal [3 +2]
cycloaddition.
Scheme 2 Comparison of this work with existing literature.
65
diastereoisomer. Compounds
4 hold remarkable synthetic
potential as the pyridine, the nitrile and the imine contained could
be selectively reacted to generate other intermediates. In this
regards, we have described one of the many applications
35 (Scheme 3, vide infra) by reacting 4 and Danishefsky’s diene to
provide
bicyclic
indolizidine
core
with
complete
diastereoselection.
Scheme 1 Addition of αꢀisocyanoesters to alkenes 1 and cyclisation to
40 imines 4.
N
N
N
CN
CN
N
C
R
CO2Et
NC
N
PTC
NC
H
R
COOEt
R
45
COOEt
1
2
3
4
Isocyanide chemistry began in 1859 when Lieke2 obtained the
first prototype, while αꢀisocyano ester (isocyanoacetate 2) was
reported by Ugi in 1961.3 Isocyanoacetates are popular reagents
and their derivatives have been widely used in organic, inorganic
In contrast to the long history of nonꢀasymmetric variants,16 the
enantioselective catalytic addition of isocyanoesters with
70 electronꢀdeficient olefins has only recently been studied (Scheme
2).17ꢀ20 Gong and coꢀworkers reported a Cinchona alkaloid
catalysed highly enantioselective addition of 2ꢀsubstituted
50 coordination, polymeric, combinatorial and medicinal
chemistry.4 Products obtained from isocyanoacetates are
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DOI: 10.1039/C5CC08105J
isocyanoesters to nitroolefins to give 2,3ꢀdihydropyrroles (eq. 1,
Scheme 2).17
stabilised anion upon addition. This would allow only the first
addition to occur leading to desired 2ꢀsubstituted isocyanoesters,
40 i.e. 3 (Scheme 2). Based on our experience using Cinchona based
phase transfer catalysis (PTC),21 we anticipated these popular
catalysts would act as an effective means to control the
enantioselection in the formation of compounds 3. Herein we
report the preparation of a reactive class of soft Michael acceptor
45 1 and their enantioselective reaction with compound 2 under
phase transfer catalysis.
Recently, the same group reported a highly enantioselective
cycloaddition reaction of 2ꢀsubstituted isocyanoesters with 2ꢀ
oxobutenoate esters, catalysed by a chiral silver complex (eq. 2,
5
Scheme 2).18 The group of Xu and Wang developed
a
diastereoselective and enantioselective Michael addition of 2ꢀ
substituted isocyanoacetates to Nꢀaryl maleimides catalyzed by
bifunctional tertiary amine thioureas (eq. 3, Scheme 2).19 Lately
10 Zhu and his group discovered a catalytic enantioselective
Cinchona alkaloid catalyzed Michael addition of 2ꢀaryl
isocyanoacetates to vinyl phenylselenones, resulting in adducts
which are precursors to αꢀamino acids (eq. 4, Scheme 2).20 It is
evident from these reports that exquisite procedures exist to react
15 2ꢀsubstituted isocyanoacetates and electrophilic alkenes.17ꢀ20
While these procedures17ꢀ20 were effective at reacting 2ꢀ
substituted isocyanoacetates, none of them worked when unꢀ
Table 2. Representative results from the screening of Cinchonaꢀderived
catalysts 7, 8, 9, 10 and 11a-e.[a]
50
55
60
65
substituted
2 was employed. In this regards, Gong has
specifically stated that the addition of 2 to αꢀnitrostyrene did not
20 proceed at all.17
Therefore the enantioselective addition of unꢀsubstituted 2 to
activated alkenes (eq. 5, Scheme 2, this work) is undeveloped
and remains a synthetic challenge, as it would involve controlling
the stereoselectivity of the Michael addition and suppressing a
25 potential second Michael reaction leading to 2,2ꢀdisubstituted
compounds which would be racemic.
Table 1 Library of olefins 1a-m[a]
Entry
Cat.
Ratios of
Yield 4a[c]
[%]
ee% 4a[d]
3a:4a[b]
1
2
3
4
5
6
7
8
9
7
1:1
1:1
1:1
1:2
1:2
1:2
1:2
1:2
1:2
34
37
31
45
47
42
39
41
42
60
77
52
43
94
55
61
85
78
8
Entry
R
Prod.
Time/h
Yield[b] [%]
9
1[c]
C6H5
1a
1b
1c
1d
1e
1f
120
120
120
120
120
120
120
120
120
120
120
144
144
90
86
93
87
89
89
87
95
88
90
87
70
75
10
2[c]
4ꢀOCH3ꢀC6H4
2,3ꢀCl2ꢀC6H3
4ꢀFꢀC6H4
11a
11b
11c
11d
11e
3[c]
4[c]
5[c]
4ꢀBrꢀC6H4
2ꢀThienyl
6[c]
7[c]
2ꢀFuryl
1g
1h
1i
[a] Reaction conditions: 3ꢀphenylꢀ2ꢀ(4ꢀpyridyl)ꢀacrylonitrile 1a (0.1
70 mmol), ethyl isocyanoacetate 2 (0.5 mmol), K2CO3 50% (0.5 mmol), cat.
(10 mol%), DCM (1.0 mL) at room temperature. [b] Conversion was
8[c]
2,3ꢀO(CH2)2ꢀC6H3
4ꢀClꢀC6H4
3,4ꢀ(OCH3)2ꢀC6H3
3ꢀClꢀC6H4
nꢀHexyl
9[c]
1
determined by H NMR analysis. [c] Isolated yields after flash column
10[c]
11[c]
12[d]
13[d]
1j
chromatography. [d] The enantiomeric excess (ee) of the product was
determined by chiral stationary phase HPLC on compound 4a.
75
1k
1l
Compounds 1a-m (Table 1) were obtained by reacting
commercially available 4ꢀpyridylacetonitrile hydrochloride 5
with an aromatic, heteroaromatic or aliphatic aldehyde 6 in the
presence of Et3N. Compounds 1a–m are stable solids that can be
80 obtained in large quantities (10–100 mmol) and as single Zꢀ
isomers, as it was confirmed by n.O.e. experiments.22 Aliphatic,
aromatic and heteroaromatic aldehydes reacted equally well
ensuring similar high yields of desired compounds 1a-m.
At the onset of this study, 3ꢀphenylꢀ2ꢀ(4ꢀpyridyl)ꢀacrylonitrile 1a
85 and ethyl isocyanoacetate 2 were reacted in the presence of 10
mol% of Cinchonaꢀderived quaternary ammonium salts, suitable
combinations of inorganic bases and solvents, at room
nꢀHeptyl
1m
30 [a] Reaction conditions: 4ꢀpyridylacetonitrile hydrochloride 1 (3.23
mmol), aldehydes 2a-m (6.46 mmol), Et3N, anhydrous CH2Cl2 (15.5 mL)
at rt. [b] Isolated yields after flash column chromatography. [c] 5.0 eqs.
of Et3N were used. [d] 1.0 eq. of Et3N were used.
With a view to developing a new organocatalytic synthetic
35 procedure involving reagent 2, we reasoned that enantioselective
monoaddition of 2 to alkenes could be realized by a careful
selection of an electrophilic alkene acceptor that generates a
2
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temperature (Table 2). To our delight, the reaction furnished the
Micheal adduct 3a alongside variable amounts of imine 4a. Data
and characterization of compounds 3a (Table 2) and their
derivatives 3b-m (Table 3) are reported in the supporting
information. This reaction provided monoꢀadducts 3a unꢀ
contaminated by the compound of double addition, even in the
presence of fiveꢀfold excess of reagent 2.
60 Table 3. Catalytic asymmetric addition of ethyl isocyanoacetate 2 to (Z)ꢀ
3ꢀsubstitutedꢀ2ꢀ(4ꢀpyridyl)ꢀacrylonitrile derived 1a-m[a] and subsequent
cyclization.[b]
5
65
Compound 3a was obtained as
diastereoisomers, a result often observed when generating 2ꢀalkyl
10 isocyanate esters containing a stereogenic centre.4 Conversely,
compound 4a was consistently obtained as single
a
1
:
1
mixture of
a
Entry
R
Prod.
Time/h
Yield
ee%
4a[c]
4a[d]
diastereoisomer, presumably as a result of a base promoted
cyclisation which selected the most thermodynamic stable
diastereosisomer. Any attempt to measure the enantioselectivity
15 of 3a proved impossible. Therefore, the 3a : 4a mixture, thus
obtained, was completely converted to compound 4a by heating
in THF at 45 °C in presence of diisopropylethylamine (DIPEA).
We screened a number of conditions in order to achieve complete
conversion of 3a to 4a, including solvent, temperature, amount
20 and type of organic base. In conclusion, this study identified in
DIPEA, THF and 45 °C as the best condition to obtain
compound 4a in the best yield. The reaction of 1a and 2
proceeded well under the catalysis of Cinchonaꢀderived phaseꢀ
transfer catalysts 7ꢀ11 and a summary of the most relevant data is
25 provided below: (i) desired product 4a was obtained together
with adduct 3a in a 1 : 1 ratio when catalysts 7, 8 and 9, were
employed (Table 2, entries 1ꢀ3), while catalysts 10 and 11
provided twice as much of 4a relative to 3a (Table 2, entries 4ꢀ
9); (ii) catalysts 7, 8 and 9 gave only low to moderate
30 enantioselectivity, (Table 2, entries 1ꢀ3); (iii) Nꢀ
benzylquinidinium bromide 11a furnished compound 4a in 94%
enantiomeric excess which was the highest ee obtained.
In particular, dichloromethane and a 50% solution of K2CO3 in
water were found to be the optimal media for the conversion of
35 1a and 2 to the desired 4a. With a suitable set of conditions in
hand, we then screened Nꢀbenzylquinidinium salts 11b-e (Table
2, entries 6ꢀ9). Catalysts 11b-c, containing an electronically
diverse group on the orthoꢀposition gave 4a in only 55% and
61% ee respectively (Table 2, entries 6 and 7). Catalysts 11d-e,
40 comprising two metaꢀsubstituents furnished 4a in 85% and 78%
ee respectively (Table 2, entries 8 and 9). Catalyst 11a, therefore,
performed the best in this series. Hence, catalyst 11a,
dichloromethane, 50% aqueous K2CO3 and room temperature
(19ºC) emerged as the optimal set of conditions for the
45 preparation of compound 4a. The scope of the reaction was then
shown by reacting (Z)ꢀ3ꢀsubstitutedꢀ2ꢀ(4ꢀpyridyl)ꢀacrylonitrile
1
C6H5
4a
4b
4c
4d
4e
4f
48h
96h
96h
96h
96h
96h
96h
96h
72h
96h
72h
120h
120h
86%
79%
84%
77%
85%
64%
73%
85%
74%
73%
85%
60%
65%
94
85
93
88
89
90
90
70
91
91
87
75
77
2
4ꢀOCH3ꢀC6H4
2,3ꢀCl2ꢀC6H3
4ꢀFꢀC6H4
3
4
5
4ꢀBrꢀC6H4
2ꢀThienyl
6
7
2ꢀFuryl
4g
4h
4i
8
2,3ꢀO(CH2)2C6H3
4ꢀClꢀC6H4
3,4ꢀ(OCH3)2C6H3
3ꢀClꢀC6H4
nꢀHexyl
9
10
11
12
13
4j
4k
4l
nꢀHeptyl
4m
[a] Reaction conditions: (Z)ꢀ3ꢀsubstitutedꢀ2ꢀ(4ꢀpyridyl)ꢀacrylonitrile 1a-
70 m (0.1 mmol), ethyl isocyanoacetate 2 (0.5 mmol), K2CO3 50% (0.5
mmol), 11a (10 mol%), DCM (1.0 mL) at room temperature. [b]
Reaction conditions: DIPEA (0.2 mmol), THF (1.0 mL) at 45 °C. [c]
Isolated yields after flash column chromatography. [d] The enantiomeric
excess (ee) of the product was determined by chiral stationary phase
75 HPLC on compounds 4a-m.
The absolute configuration of adduct 4e was determined by Xꢀ
ray crystallographic analysis and the three chiral centres were
assigned as 2R, 3R, and 4R. The configurations of the other
imines 4 (Table 3) were therefore assigned by analogy. The
80 synthetic potential of compound 4a was demonstrated by its
reaction with compound 12 (Danishefsky’s diene) which
provided indolizidinone 14 as a single diastereoisomer via a
substrate controlled Diels Alder reaction (Scheme 3).23
1a-m with ethyl isocyanoacetate
2 under the optimised
conditions (Table 3). The results collected pointed out the
following facts: (i) compounds containing either electron
50 withdrawing or electron donating groups at the paraꢀposition on
the phenyl were equally good substrates (Table 3, entries 2, 4, 5
and 9) providing the corresponding compounds 4 in high yield
and enantioselectivity; (ii) compounds containing electron
withdrawing groups at the orthoꢀ and metaꢀ position on the
85
Sheme 3. DielsꢀAlder reaction between cyclic imine 4a and diene 12
55 phenyl group gave corresponding imines
4
in high
We have interpreted the selective formation of compounds 4
considering that in the presence of Cinchona ammonium species
11 compound 3 were obtained as (3S) enantiomers.. Cyclisation
90 of compound 3 lead to compounds 4 as a single diasteroisomer. It
should be noted that both the new formed stereogenic centres
arose from acidic positions whcih could be scrambled in the
presence on the base. Under this set of condition, it is possible
enantioselectivity (Table 3, entries 3 and 11); (iii) long chain
alkyl substituted substrates reacted equally well giving aliphatic
imines 4l and 4m in good ee (Table 3, entries 12 and 13).
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that transition state 15 (Scheme 4) in which the two sterically
demanding groups, namely the pyridine and the carbetoxy
assumed a pseudoꢀequatorial position prior to cyclisation, hence
55
60
65
70
leading to the observed compound 4.
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N
C
O
N
OEt
C
CN
11a
R
N
N
NC
H
1
2
3
R
COOEt
N
N
CN
N
Base
CN
N
COOEt
R
R
COOEt
15
4
5
Scheme 4. Proposed model to explain the enantioselective formation of
compounds 3 and 4.
9
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In conclusions, we have synthetized a reactive class of Michael
acceptors 1a-m and showed for the first time
a highly
10 enantioselective and complete diastereosective addition of
isocyanoacetate 2. Monoꢀadducts 3a-m, were subsequently
converted to imines 4a-m in high enantioselectivity and complete
diastereoselectivity. This procedure compares well to other
related syntheses24 and it provides imines with a unique
15 substitution pattern and functional groups. Compound 4a was
employed to prepare indolizidine 14 with complete
diastereoselectivity. Therefore the procedure herein described
will be of interest to those involved in the preparation of imines
and their use to access precursors bioactive compounds.
20
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We acknowledge financial support from IRCSET for a PhD
Fellowship to CDF; “Fondazione con il Sud” for financial
support to MM.
Notes and references
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25 *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; Eꢀmail: madamo@rcsi.ie.
b National Research Council, Institute of Crystallography, Via G.
30 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
DOI: 10.1039/b000000x/
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