Primary-tertiary diamine-catalyzed Michael addition of ketones to isatylidenemalononitrile derivatives

Article abstract of DOI:10.3762/bjoc.10.91

Simple primary-tertiary diamines easily derived from natural primary amino acids were used to catalyze the Michael addition of ketones with isatylidenemalononitrile derivatives. Diamine 1a in combination with D-CSA as an additive provided Michael adducts

Full text of DOI:10.3762/bjoc.10.91

Primary-tertiary diamine-catalyzed Michael addition
of ketones to isatylidenemalononitrile derivatives
Akshay Kumar and Swapandeep Singh Chimni*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 929–935.
Department of Chemistry, U.G.C. Centre of Advance Studies in
Chemistry, Guru Nanak Dev University, Amritsar, 143005, India; Fax:
(+)91-183-2258820
doi:10.3762/bjoc.10.91
Received: 01 February 2014
Accepted: 02 April 2014
Published: 24 April 2014
Email:
Swapandeep Singh Chimni* - sschimni@yahoo.com
Associate Editor: S. You
* Corresponding author
© 2014 Kumar and Chimni; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
3,3'-disubstituted oxindoles; Michael reaction; organocatalysis;
primary-tertiary diamine; spirooxindoles
Abstract
Simple primary-tertiary diamines easily derived from natural primary amino acids were used to catalyze the Michael addition of
ketones with isatylidenemalononitrile derivatives. Diamine 1a in combination with D-CSA as an additive provided Michael adducts
in high yield (up to 94%) and excellent enantioselectivity (up to 99%). The catalyst 1a was successfully used to catalyze the three-
component version of the reaction by a domino Knoevenagel–Michael sequence. The Michael adduct 4a was transformed into
spirooxindole 6 by a reduction with sodium borohydride in a highly enantioselective manner.
Introduction
The Michael reaction is one of the fundamental carbon–carbon acceptors, isatylidenemalononitriles, have attracted consider-
bond forming reactions in organic synthesis, since a plethora of able attention as novel substrates for the enantioselective syn-
carbon nucleophiles and activated olefins could be expected to thesis of 3,3'-disubstituted oxindoles [18-22]. The organocat-
give versatile arrangements [1-8]. Among the various Michael alytic Michael addition of ketones to isatylidenemalononitriles
acceptors, the oxindole-based Michael acceptors (Figure 1) are via enamine-catalysis has emerged as a useful tool for the syn-
considered as valuable electrophiles for catalytic Michael reac- thesis of 3,3'-disubstituted oxindoles, which serve as important
tions, as these provide a viable approach to procure 3,3'-disub- precursors to procure various structurally diverse spirooxin-
stituted oxindole frameworks [9-16]. The oxindole framework doles [23,24].
bearing a tetra-substituted carbon stereocenter at C-3 is a privi-
leged heterocyclic motif that is present in a large variety of Over the years, many chiral organocatalysts have been devel-
bioactive natural products and a series of pharmaceutically oped and explored for Michael reactions [1-8]. Recently,
active compounds [17]. In recent years, isatins derived Michael aminocatalysts – in particular those bearing a primary amine
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Beilstein J. Org. Chem. 2014, 10, 929–935.
Scheme 1: Diamine catalyzed Michael addition of acetone to isatyl-
idenemalononitrile.
Figure 1: Oxindole based Michael acceptors.
The Michael adduct 4a was isolated in 95% yield and 69% ee
moiety – have been found to catalyze a variety of (Table 1, entry 1). Encouraged by the outcome of the prelimi-
carbon–carbon bond-forming reactions [25-30]. Small peptides nary reaction, we optimized the reaction conditions by studying
derived from acyclic amino acids, primary-secondary diamines, the effect of different solvents and their amount as well as the
Cinchona-based primary amines, and thioureas with a primary effect of acid additives on this transformation (Tables 1–3). In
amine functionality etc., have found many successful applica- our previous studies [10], the diamine 1a afforded the best
tions in Michael addition reactions via an iminium–enamine result for aldol reactions with water as a solvent. Consequently,
catalysis [31-37]. A few applications of primary-tertiary di- the above transformation was performed with water as a
amine in aldol reactions have been published [39-43]. To the solvent. The Michael adduct 4a was obtained in good yield of
best of our knowledge, however, the catalytic potential of 87% and a moderate enantioselectivity of 55% ee (Table 1,
amino acids derived primary-tertiary diamine organocatalysts entry 2). It was planned to study the effect of different organic
for Michael reaction via enamine activation has not been solvents on the stereochemical outcome of this reaction. Inter-
investigated so far [38]. With readily available and inexpensive estingly, the reaction of 2a with 3a performed in tetrahydro-
natural amino acids as a chiral source, we developed very furan (THF) gave Michael adduct 4a in good yield of 91% and
simple primary-tertiary diamine organocatalysts (Figure 2) for a higher enantioselectivity of 84% ee (Table 1, entry 3). Other
asymmetric aldol reactions [44,45]. We describe herein that a etheral solvents, such as 1,4-dioxane and methyl tert-butyl ether
similar catalyst system could also efficiently catalyze the asym- (MTBE), provided Michael adduct 4a in 89% and 90% yield
metric Michael addition reaction between ketones 2 and isatyl- and 89% ee and 87% ee, respectively (Table 1, entries 4 and 5).
idenemalononitrile derivatives 3 to procure highly functional- In toluene, 4a was obtained in 89% yield and 90% ee (Table 1,
ized 3,3'-disubstituted oxindoles 4 which could easily be trans- entry 6). The chlorinated solvents such as dichloromethane,
formed into spirooxindoles.
chloroform and 1,2-dichloroethane (DCE) gave 4a in 90%, 89%
and 91% yield and 90% ee, 88% ee and 91% ee, respectively
(Table 1, entries 7–9). The utilization of methanol as a solvent
Results and Discussion
Initially, the Michael addition of acetone (2a) to isatylidene- led to the isolation of Michael adduct 4a in good yield but with
malononitrile (3a) catalyzed by chiral diamine 1a (10 mol %) a low enantioselectivity of 12% ee (Table 1, entry 11).
with trichloroacetic acid (10 mol %) as an additive under mild Dimethylformamide was also found to be an inferior solvent for
conditions at room temperature was investigated (Scheme 1).
this reaction (Table 1, entry 12). Thus, 1,2-dichloroethane
Figure 2: Primary-tertiary diamine organocatalysts.
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Beilstein J. Org. Chem. 2014, 10, 929–935.
Table 1: Solvent screening the Michael addition of acetone (2a) to
isatylidenemalononitrile (3a) catalyzed by 1a TCA.a
Table 2: Effect of the amount of solvent (DCE) on the enantio-
selectivity of the Michael addition of acetone (2a) to isatylidenemalono-
nitrile (3a) catalyzed by 1a TCA.a
Entry
Solvent
Time (h) Yield (%)b
ee (%)c
Entry Amount of
solvent (mL)
Time (h)
Yield (%)b
ee (%)c
1
–
6
95
87
91
89
90
89
90
89
91
90
88
82
69
55
84
89
87
90
90
88
91
87
12
20
2
water
48
30
30
30
36
36
36
36
36
40
40
1
2
3
4
5
6
0.25
0.50
0.75
1.00
1.50
2.00
24
26
32
40
60
96
93
93
92
90
90
88
91
91
92
93
95
96
3
THF
4
dioxane
MTBE
toluene
DCM
5
6
7
8
CHCl3
ClCH2CH2Cl
ethyl acetate
CH3OH
DMF
aReaction conditions: 1.5 mmol of acetone (2a), 0.125 mmol of isatyl-
idenemalononitrile (3a), 1,2-dichloroethane (0.25–2.00 mL), 10 mol %
of catalyst 1a, 10 mol % of TCA, at 25 °C. bIsolated yield determined
after chromatographic purification. cEnantiomeric excess determined
by chiral HPLC.
9
10
11
12
aReaction conditions: 1.5 mmol of acetone (2a), 0.125 mmol of isatyl-
idenemalononitrile (3a), 0.25 mL of solvent, 10 mol % of catalyst 1a,
10 mol % of TCA, at 25 °C. bIsolated yield determined after chromato-
graphic purification. cEnantiomeric excess determined by chiral HPLC.
tion of 4a in 92% yield and an enantioselectivity of 98% ee
after 30 hours (Table 3, entry 5). The D-camphorsulfonic acid
turned out to be the best acid additive providing 4a in high yield
emerged as the solvent of choice for this transformation and of 93% and excellent enantioselectivity of 99% ee after a reac-
was used for all further optimization studies (Table 1, entry 9). tion time of 24 hours (Table 3, entry 6) [46].
In order to see the effect of the reaction concentration, the
Table 3: Additive screening of the 1a catalyzed Michael addition of
amount of 1,2-dichloroethane was varied (Table 2). The use of
0.5 mL of 1,2-dichloroethane afforded 4a in good yield of 93%
and enantioselectivity of 91% ee (Table 2, entry 2). The reac-
tion carried out with 0.75 mL, 1.0 mL and 1.5 mL of 1,2-
dichloroethane provided 4a with an enhanced enantio-
selectivity of 92% ee, 93% ee and 95% ee, respectively
(Table 2, entries 3–5). On performing the reaction in 2.0 mL of
1,2-dichloroethane, 4a was obtained in 88% yield and increased
enantioselectivity of 96% ee after a long reaction time of
96 hours (Table 2, entry 6). There was a small difference in the
enantioselectivity of the product 4a on performing the reaction
in 1.5 mL and 2.0 mL of 1,2-dichloroethane, but the rate of the
reaction was faster when a lower amount of solvent was used.
So, we decided to employ 1.5 mL of 1,2-dichloroethane as a
solvent for the further optimization experiments.
acetone (2a) to isatylidenemalononitrile (3a)a.
Entry Additive
Time (h) Yield (%)b
ee (%)c
58
1
3,5-dinitrobenzoic 36
91
acid
2
3
4
5
6
chloroacetic acid
TsOH
36
60
48
30
24
90
86
89
92
93
60
97
96
98
99
TFA
L-CSA
D-CSA
aReaction conditions: 1.5 mmol of acetone (2a), 0.125 mmol of isatyl-
idenemalononitrile (3a), 1.5 mL of DCE, 10 mol % of catalyst 1a,
10 mol % of additive at 25 °C. bIsolated yield determined after
chromatographic purification. cEnantiomeric excess determined by
chiral HPLC.
Even though an excellent level of enantioselectivity of the prod-
In order to obtain a highly enantioselective transformation, the uct was observed with catalyst 1a we screened different di-
effect of different acid additives on the enantioselectivity of 4a amine catalysts in our quest for a superior catalyst. L-Isoleucine
was studied (Table 3). The reaction was performed with 3,5- derived primary-tertiary diamine catalysts having piperidinyl 1b
dinitrobenzoic acid and chloroacetic acid afforded 4a in good and pyrrolidinyl 1c groups gave Michael product 4a in high
yield of 91% and 90%; and moderate enantioselectivity of yield (>90%) and excellent enantioselectivity (98% ee each)
58% ee and 60% ee, respectively (Table 3, entries 1 and 2). The (Table 4, entries 2 and 3). The primary-tertiary diamine cata-
reaction carried out with strong acids such as trifluoromethane- lysts characterized by an acyclic tertiary amine, such as a N,N-
sulfonic acid (TsOH) and trifluoroacetic acid (TFA) gave 4a in dioctyl (1d) group, gave 4a in 89% yield and 96% ee (Table 4,
good yields of 86% and 89% and high enantioselectivities of entry 4). The L-leucine, L-valine and L-phenylalanine derived
97% ee and 96% ee (Table 3, entries 3 and 4). The application primary-tertiary diamine catalysts (1e–1g) also provide the
of L-camphorsulfonic acid as an additive resulted in the isola- Michael adduct 4a in good yield (92–94%) and an excellent
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Beilstein J. Org. Chem. 2014, 10, 929–935.
level of enantioselectivity (97–98% ee) (Table 4, entries 5–7). The methodology was found to be suitable for both N-substi-
All primary-tertiary diamine catalysts 1a–1g gave 4a in high tuted isatylidenemalononitrile and N–H isatylidenemalono-
yield (89–94%) with an excellent level of enantioselectivity nitrile derivatives. Acetone (2a) reacts well with various N–H
(96–99% ee). In contrast, the primary-secondary diamine 1h isatylidenemalononitrile derivatives (3a–f) providing corres-
catalyst afforded Michael adduct 4a in 10% yield after a long ponding Michael adducts 4a–f in excellent enantioselectivity
reaction time (Table 4, entry 8). The screening study highlights (96–99% ee) after a reaction time of 24–36 hours. The 5-fluo-
the importance of the primary-tertiary diamine skeleton in the roisatylidenemalononitrile (3b), 5-chloroisatylidenemalononi-
catalysis of the addition of acetone (2a) to isatylidenemalono- trile (3c), 5-bromoisatylidenemalononitrile (3d) and
nitrile (3a). Thus, the best reaction conditions consist of 5-iodoisatylidenemalononitrile (3e) gave corresponding
10 mol % of catalyst 1a, 10 mol % of D-camphorsulfonic acid Michael adducts 4b–e in 93%, 95%, 94% and 91% yield and
as an additive and 1.5 mL of 1,2-dichloroethane at room 98% ee, 98% ee, 98% ee and 99% ee, respectively (Table 5,
temperature providing Michael adduct 4a in 93% yield and 99% entries 2–5). The reaction of 5,7-dibromoisatylidenemalononi-
ee.
trile (3f) with acetone (2a) proceeds with a high yield of 92%
and a high enantioselectivity of 96% ee (Table 5, entry 6). The
N-substituted isatylidenemalononitriles 3g–i react slowly with
acetone (2a) to afford Michael adducts 4g–i in good yield
(85–87%) and good enantioselectivity (88–92% ee) (Table 5,
entries 7–9). Acetone (2a) reacts well with N-allyl isatylidene-
malononitrile derivatives 3g and 3h to provide the respective
Michael adducts 4g and 4h in 85% and 87% yield and 89% ee
and 92% ee, respectively (Table 5, entries 7 and 8). Using
N-benzyl isatylidenemalononitrile (3i), the Michael adduct 4i
was isolated in 86% yield and 88% ee (Table 5, entry 9). A
recently reported similar reaction catalyzed by Cinchona alka-
loid-based primary amine catalyst requires high catalyst loading
and is only suitable for N-unprotected isatylidenemalononitrile
derivatives [5]. In contrast, our methodology is suitable for both
N-unprotected and N-protected isatylidenemalononitrile deriva-
tives and is highly enantioselective. Next, the substrate scope of
the reaction was extended to different acyclic ketones 2b and
2c. Under the optimized conditions, the Michael addition of
Table 4: Catalyst screening of the enantioselective Michael addition of
acetone (2a) to isatylidenemalononitrile (3a).a
Entry
Catalyst
Time (h)
Yield (%)b ee (%)c
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
24
24
24
30
30
24
30
96
93
93
91
89
93
94
92
10
99
98
98
96
98
98
97
–
1g
1h
aReaction conditions: 1.5 mmol of acetone (2a), 0.125 mmol of isatyl-
idenemalononitrile (3a), 1.5 mL of 1,2-dichloroethane, 10 mol % of
catalyst 1a–1h, 10 mol % of D-CSA at 25 °C. bIsolated yield deter-
mined after chromatographic purification. cEnantiomeric excess deter-
mined by chiral HPLC.
Once the optimized reaction conditions have been found, the methyl isobutyl ketone (2b) and 2-octanone (2c) with 3a
substrate scope was investigated by using different ketones provided Michael adducts 4j and 4k in 24% and 41% yield and
2a–c and isatylidenemalononitrile derivatives 3a–i (Scheme 2). 97% ee and 96% ee, respectively (Table 5, entries 10 and 11).
Scheme 2: Substrate scope of the addition of 2 with 3 catalyzed by 1a D-CSA.
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Beilstein J. Org. Chem. 2014, 10, 929–935.
Due to the low reactivity of these ketones, these experiments the one-pot process compared to the stepwise process was due
were carried out after a slight modification of the optimized to the competing reaction of isatin and acetone to form aldol
conditions, i.e., a higher catalyst loading of 20 mol % of 1a and adduct 5 (8% yield). The reaction involves the initial formation
1.0 mL of 1,2-dichloroethane as a solvent. The 20 mol % of 1a of isatylidenemalononitrile by Knoevenagel condensation of
catalyzes the Michael addition of 2b with 3a providing Michael isatin with malononitrile followed by the addition of acetone to
adduct 4j in 80% yield and 96% ee after a reaction time of provide Michael adduct 4a. Thus, catalyst 1a also finds its
7 days (Table 5, entry 12). The 2-octanone (2c) gave Michael successful application in the multicomponet version of this
adduct 4k in 85% yield and 97% ee after a reaction time of reaction without compromising enantioselectivity – albeit with
6 days (Table 5, entry 13). The R absolute configuration of a slight loss in yield.
Michael adducts was assigned by comparing the HPLC chro-
matograms of Michael adducts with that reported in the litera- We further demonstrated that Michael adducts could be
ture [23,24].
transformed into spirooxindoles by following a simple
strategy. The reduction of Michael adduct 4a with sodium boro-
hydride in ethanol followed by spontaneous cyclization gave
spirooxindole product 6 in 90% yield, 82:18 dr and 98% ee
(Scheme 4).
Table 5: Substrate scope of 1a D-CSA catalyzed asymmetric Michael
reaction of ketones 2 with isatylidenemalononitrile derivatives 3.a
Entry
2
3
Time (h)
4
Yield (%)b ee (%)c
1
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2b
2c
3a
3b
3c
3d
3e
3f
26
4a
4b
4c
4d
4e
4f
92
93
95
94
91
92
85
87
86
24
41
80
85
99
98
98
98
99
96
89
92
88
97
96
96
97
2
26
3
26
4
30
5
36
6
24
7
3g
3h
3i
72
4g
4h
4i
8
78
9
78
10
11
12d
13d
3a
3a
3a
3a
168
168
168
144
4j
4k
4j
Scheme 4: Cascade reduction–cyclization for the synthesis of
4k
spirooxindole.
aReaction conditions: 1.5 mmol of ketones 2, 0.125 mmol of isatyl-
idenemalononitrile derivatives 3, 1.5 mL of 1,2-dichloroethane,
10 mol % of catalyst 1a, 10 mol % of additive D-CSA at 25 °C.
bIsolated yield determined after chromatographic purification.
cEnantiomeric excess determined by chiral HPLC. dThe reaction is
performed with 20 mol % catalyst 1a and 1.0 mL of 1,2-dichloroethane.
Conclusion
In conclusion, we successfully demonstrated the use of
the very simple primary-tertiary diamine catalyst 1a in combi-
nation with D-CSA as an additive for the enantioselective catal-
ysis of a Michael addition of acetone to isatylidenemalononi-
Next, we studied the multicomponent version of this reaction. triles. A three component process involving a domino Knoeve-
Acetone, isatin and malononitrile react in one pot providing nagel–Michael sequence was developed. 3,3'-Disubstituted
Michael product 4a in a good yield of 80% and a high enantio- oxindole could be transformed into spirooxindoles by reduction
selectivity of 98% ee (Scheme 3). The slightly lower yield of with NaBH4.
Scheme 3: One-pot, three-component Knoevenagel condensation–Michael addition.
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Beilstein J. Org. Chem. 2014, 10, 929–935.
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Supporting Information File 1
Experimental procedures, copies of 1H and 13C NMR
spectra of Michael adducts, and HPLC chromatogram of
products 4.
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Acknowledgements
We are grateful for the financial support from CSIR, India to
SSC (research Grant No. 02(0009)/11/EMR-II) and a RA
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