Enantioselective conjugate addition of nitroalkanes to alkylidenemalonates promoted by thiourea-based bifunctional organocatalysts

Article abstract of DOI:10.1002/adsc.201100732

Cinchona alkaloids-derived bifunctional thioureas efficiently catalyse the enantioselective conjugate addition of nitroalkanes to alkylidenemalonates with syn-diastereopreference, opening a route to the synthesis of optically active γ-amino acid derivativ

Full text of DOI:10.1002/adsc.201100732

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DOI: 10.1002/adsc.201100732
Enantioselective Conjugate Addition of Nitroalkanes to
Alkylidenemalonates Promoted by Thiourea-Based Bifunctional
Organocatalysts
Michel Chiarucci,a Marco Lombardo,a Claudio Trombini,a
and Arianna Quintavallaa,*
a
Dipartimento di Chimica “G. Ciamician”, Universitꢀ degli Studi di Bologna, via Selmi 2, 40126 Bologna, Italy
Fax : (+39)-051-209-9456; phone: (+39)-051-209-9462; e-mail: arianna.quintavalla@unibo.it
Received: September 20, 2011; Published online: January 19, 2012
Dedicated to my beloved Shasa.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100732.
Abstract: Cinchona alkaloids-derived bifunctional
thioureas efficiently catalyse the enantioselective
conjugate addition of nitroalkanes to alkylidene-
malonates with syn-diastereopreference, opening a
route to the synthesis of optically active g-amino
acid derivatives.
among them g-amino acids.[2] The g-amino acid motif
is embodied in many natural and unnatural peptides
displaying biological activity,[3] and can provide inter-
esting folding properties[4] when incorporated in com-
plex structures. Among the synthetic precursors of g-
amino acids, an important role is played by g-nitro
carboxylic acid derivatives, useful intermediates for
the preparation of highly functionalised scaffolds,[5]
especially due to the versatility of the nitro group.[6]
In organocatalysis, one of the most studied asymmet-
ric approaches[7] to g-nitro acids is the addition of
malonates to simple nitroalkenes,[8] leading to g-un-
substituted g-nitro malonates [Scheme 1, Eq. (1)]. Al-
though excellent results have been reported in terms
of catalytic efficiency and stereoselectivity, no exam-
Keywords: alkylidenemalonates; asymmetric orga-
nocatalysis; bifunctional thioureas; Michael reac-
tion; nitro compounds
The Michael reaction is one of the most efficient ple is known for the addition of malonates to a-sub-
À
tools for the construction of C C bonds and recently stituted nitroolefins. We considered that the g-substi-
considerable attention has been given to its organoca- tuted g-nitro malonates 3 could be obtained using a
talytic asymmetric versions.[1] Since several nucleo- nitroalkane as Michael donor and an alkylidenemalo-
philes (donors) and electron-deficient alkenes (ac- nate as the acceptor [Scheme 1, Eq. (2)]. The result
ceptors) can be used, this reaction represents one of should be the optically active g-nitro esters 3, that can
the most flexible and widely employed approaches to be easily converted into the corresponding g-amino
the synthesis of important pharmaceutical scaffolds, acids without loss of optical purity.[9]
Scheme 1. Alternative approaches to g-nitro malonates.
364
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Adv. Synth. Catal. 2012, 354, 364 – 370

Enantioselective Conjugate Addition of Nitroalkanes to Alkylidenemalonates
The intermolecular asymmetric Michael addition of terested in organocatalysts derived from Cinchona al-
nitroalkanes to unsaturated esters is an open chal- kaloids, as they are easily accessible from cheap natu-
lenge in organocatalysis, due to the low reactivity and ral products.[15] We started screening the efficacy of a
probably to the poor binding capacity of these accept- set of thioureas derived from Cinchona alkaloids (A–
ors. Just recently, Cobb and co-workers reported an E, Figure 1) and from (1S,2S)-trans-1,2-cyclohexanedi-
intramolecular addition of nitronates to conjugated
ACHTUNGTRENaNGNU mine (F–H, Figure 1) in the addition of nitroethane
esters for the synthesis of cyclic amino acids.[10] The (1a) to diethyl 2-(4-nitrobenzylidene)malonate (2a)
limitations shown by a,b-enoates triggered several au- (Table 1).
thors to find alternative and more active synthetic
Bifunctional catalysts A–E provided product 3a
equivalents. a,b-Unsaturated imides,[11] N-acylpyr- with high conversions in 24 h and high enantioselec-
roles,[12] and acyl phosphonates[13] have been reported, tivities. The diastereoselectivity was only moderate
but in most cases the donor is limited to nitromethane (up to anti/syn=27/73 with catalyst C), but surprising-
only. Maruoka and co-workers proposed the only ex- ly the syn was the favoured isomer. To the best of our
ample of enantioselective conjugated addition of ni- knowledge, this asymmetric organocatalytic procedure
troalkanes to alkylidenemalonates, carried out under is the first that displays a syn-diastereopreference,
phase-transfer conditions and mediated by a rather complementary to the results obtained by Maruoka.
complex and appropriately designed N-spiro C2-sym- The highest ees were achieved for the major syn
metrical chiral quaternary ammonium catalyst.[9] In isomer (ee=92% with C), but the enantioselectivity
terms of diastereoselectivity, the anti-adduct predomi- was good also for the anti product. As expected,
nated with an anti/syn ratio of the products around when pseudoenantiomeric thioureas (A and C, or B
85/15.
We decided to investigate a different approach to
and D, Figure 1) were used, the opposite enantiomers
the synthesis of g-nitro malonates, and here we report
the first intermolecular enantioselective Michael addi-
tion of nitroalkanes to alkylidenemalonates promoted
by thiourea-based bifunctional organocatalysts. We
envisioned that the bifunctional system could at the
same time generate the nitronate and activate the ac-
ceptor with hydrogen bonds.[14] We are particularly in-
Table 1. Catalysts screening in the addition of nitroethane
(1a) to diethyl 2-(4-nitrobenzylidene)malonate (2a).[a]
Catalyst Time [h] Conversion [%][b] anti/syn[b] ee [%][c,d]
anti syn
A
B
C
D
E
F
G
H
I
24
24
24
24
24
24
48
48
48
24
48
24
24
71
83
68
73
94
88
32
–
19
52
5
60
82
34/66
32/68
27/73
33/67
35/65
48/52
50/50
–
60/40
58/42
57/43
60/40
60/40
À73 À84
À82 À88
74
75
83
75
92
90
88
78
À3 À6
–
–
46
35
10
À9
J
K
L
M
À47 À17
À31 À4
À25 À7
[a]
Reaction conditions: 2a (0.1 mmol), catalyst (20 mol%),
1a (0.3 mL), room temperature.
Determined by H NMR of the crude reaction mixture.
Determined by HPLC on a chiral stationary phase.
Negative ee indicates the formation of the opposite enan-
tiomer. See Supporting Information for stereochemistry
determination.
[b]
[c]
[d]
1
Figure 1. Overview of catalysts employed.
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365

Michel Chiarucci et al.
COMMUNICATIONS
were obtained with no significant change of des and are dependant both on the presence of a basic tertiary
ees. We also checked thioureas F, G and H (Table 1), amine (capable of deprotonating the nitroalkane-pro-
observing that F displayed a reactivity similar to the nucleophile) and a hydrogen-bond donating thiourea
Cinchona-derived catalysts, but with a complete loss group (which activates the alkylidenemalonate elec-
of diastereocontrol. Regarding Jacobsenꢂs thioureas G trophile).
and H, the first was slow and not stereoselective at
The catalytic system was checked also on the sim-
all, whereas with the primary amine H we observed pler a,b-unsaturated ester 2aa (Scheme 2). For this
no reaction. To better understand the role of the thio- purpose, we selected two structurally different thiour-
urea moiety, we investigated the activity of Cinchona eas (C and F), but with both catalysts no traces of
alkaloids I–M (Figure 1), synthetic precursors of thio- product were isolated even after 7 days.
ureas A–E. As summarized in Table 1, the reaction
From these findings, it became apparent that the
proceeded quickly with M, but the ees dropped to malonate group enhanced the electrophilicity of the
very poor levels with all members of this series. More- substrate to the level that makes the coupling with
over, catalysts I–M, having different relative configu- the nitronate ion possible. This observation is in ac-
rations at C-8 and C-9 compared to catalysts A–E, cordance with the Mayr reactivity scale for polar reac-
showed a limited anti-diastereopreference.
tions, which predicts that the reaction can occur on
These results demonstrate the key role played by the basis of a nucleophilicity value (N) of nitroethane
the thiourea moiety in promoting faster and much (in DMSO)=21.54 and an electrophilicity index
more enantioselective transformations. A widely ac- (E)=À17.67 for 2a.[17] A more sluggish reaction is an-
cepted interpretation[14–16] is that these catalysts oper- ticipated between nitroethane and unsubstituted ben-
ate bifunctionally, since their activity and selectivity zylidenemalonate 2f (E=À20.55).
In the catalyst screening we obtained the highest
reactivity with E and the best stereoselectivity with C,
so we selected these two thioureas to perform the op-
timisation of the reaction conditions (Table 2). First
of all, several solvents were screened, using C at
room temperature in the model reaction between 1a
and 2a. We stopped the reactions after 2 days and,
predictably, in all cases the formation of the product
3a was slower in the presence of a solvent (20 equiv.
Scheme 2. Addition of nitroethane (1a) to a,b-unsaturated
ester 2aa. Reaction conditions: 2aa (0.1 mmol), 1a (0.3 mL),
catalyst C or F (20 mol%), room temperature, 7 days.
Table 2. Optimization of the reaction conditions.[a]
Entry
Solvent
Catalyst [mol%]
Temperature [8C]
Time [d]
Conversion [%][b]
anti/syn[b]
ee [%][c]
anti
syn
1
2
3
4
5
6
7
8
hexane
toluene
DCM
C[d]
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
10
10
0
r.t.
r.t.
r.t.
r.t.
2
2
2
2
2
2
2
2
2
3
2
3
1
2
7
2
80
70
75
45
52
35
60
38
46
28
83
67
70
70
66
74
50/50
46/54
44/56
36/64
40/60
30/70
42/58
36/64
32/68
19/81
30/70
20/80
30/70
32/68
35/65
38/62
83
79
79
66
74
67
39
À10
61
67
75
71
76
77
81
75
87
86
86
87
84
87
72
À3
83
91
91
93
91
91
93
83
C[d]
C[d]
THF
C[d]
EtOAc
CH3CN
MeOH
DMSO
H2O
EtNO2
EtNO2
EtNO2[e]
EtNO2[e]
EtNO2
EtNO2
EtNO2
C[d]
C[d]
C[d]
C[d]
9
C[d]
10
11
12
13
14
15[f]
16[g]
C[d]
E[d]
E[d]
E (5%)
E (2.5%)
E (1%)
E[d]
[a]
Reaction conditions (unless noted otherwise): 2a (0.1 mmol), 1a (0.15 mL), solvent (0.15 mL).
Determined by H NMR of the crude reaction mixture.
Determined by HPLC on a chiral stationary phase.
20 mol% catalyst.
1a: 0.2 mL (28 equiv.).
2a (0.2 mmol), 1a (0.2 mL, 14 equiv.).
Diisopropyl 2-(4-nitrobenzylidene)malonate (2b) was used as acceptor.
[b]
[c]
[d]
[e]
[f]
1
[g]
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Enantioselective Conjugate Addition of Nitroalkanes to Alkylidenemalonates
of 1a with respect to 2a) than using 1a as the solvent 11). The catalytic system has been successfully applied
(40 equiv. of 1a). In apolar solvents (Table 2, en- also on heteroaromatic substrates (2h–2j). With elec-
tries 1–3) conversion and enantioselectivity were good tron-poor ring derivatives we could lower the catalyst
but diastereoselectivity decreased. With more polar loading down to 2.5 mol% for 2j and to 1 mol% for 2i
solvents, from THF to water (Table 2, entries 4–9), we (Table 3, entries 27 and 23, respectively). On the con-
obtained lower conversions and moderate des. The trary, the electron-rich furyl alkylidenemalonate 2h
ees remained substantially high (especially for the syn required 10 mol% of catalyst and lower temperatures
isomer), except for MeOH (entry 7) and DMSO to achieve good stereoselectivity (Table 3, entries 18–
(entry 8), the last leading to virtually racemic prod- 20). With almost all aromatic compounds, using cata-
ucts. This behaviour could be ascribed to the capacity lyst E at 08C we were able to increase the dr, up to
of DMSO, as hydrogen-bond acceptor, to interfere 77–85% of the syn isomer (Table 3, entries 4, 7, 11,
with the catalyst-substrate coordination. Having se- 15, 20, 24 and 28), although longer reaction times
lected as solvent 1a, showing the best balance be- were required to achieve acceptable conversions.
tween reactivity and stereoselectivity, we studied the
Aliphatic alkylidenemalonates (2k and 2l) were
influence of the temperature. Using C at 108C we ob- very reactive in the conjugate addition, so that reac-
tained the same ees and a moderate increase of the tions at room temperature were fast but not very ste-
diastereoselection, but a heavy drop in the conversion reoselective. On working at À408C the ees improved,
(Table 2, entry 10). With E, we achieved at 08C good even if 10 mol% of E were required to reach good
conversions, maintaining high ees and increasing the conversions in reasonable times (Table 3, entries 30
diastereoselection (up to syn/anti=80/20, see Table 2, and 32). We also extended the protocol to vinylogous
entries 11 and 12). Thiourea E was also selected to in- alkylidenemalonates 2m and 2n. Similarly to aliphatic
vestigate deeply the potential of these bifunctional derivatives, a lower temperature was necessary to ach-
catalysts. The addition of 1a to 2a was performed at ieve a good stereocontrol, but in this case the poor
room temperature with lowering of the catalyst load- solubility of the starting materials did not allow us to
ing down to 2.5 mol%, and good conversions were ob- obtain good conversions (Table 3, entries 34 and 35).
tained without affecting stereoselectivity (Table 2, en- These results are promising, first of all because only
tries 13 and 14). We also demonstrated that 1 mol% one regioisomer was formed, resulting from the addi-
of E could promote efficiently this transformation tion of the nitroalkane to the double bond directly
(Table 2, entry 15), even though 7 days were required linked to the malonic system. Moreover, to the best
to have a good conversion.[18] It is interesting to note of our knowledge, to date the synthesis of this kind of
that we were able to decrease also the excess of 1a compounds has never been studied.
from 40 to 28 equiv. (Table 2, entries 13 and 14), and
Finally, several nitroalkanes (1b–1d) were screened
down to 14 equiv. (Table 2, entry 15). Ultimately, in the addition to diethyl 2-(4-nitrobenzylidene)malo-
when the bulkier diisopropyl 2-(4-nitrobenzylidene)- nate (2a), affording the corresponding products 4b–4d
malonate (2b) was employed instead of the diethyl in good yields and, most of all, with ees of the major
derivative 2a, the results were inferior (Table 2, syn isomer up to 91–92% (Table 4). Again, employing
entry 16).
catalyst E, the reactions run fast, allowing us to lower
This optimisation study demonstrated that both cat- the catalyst loading down to 2.5 mol% (Table 4, en-
alysts C and E promoted efficiently the conjugated tries 3, 7, 11). With the particularly reactive 1d, the
addition. While C is more stereoselective at room lowest thiourea catalyst loading of 0.5 mol% could be
temperature, E, being more reactive, allowed us to used (Table 4, entry 13). In the cases of more expen-
lower the temperature and to reach low catalyst load- sive and less volatile nitroalkanes 1c and 1d, used
ings (down to 1 mol%).
both as donors and solvents, we tried to move towards
On the basis of data collected in Table 2, we decid- more economical conditions, first using 10 equiv. of
ed to expand the scope of the new protocol using ni- nitroalkane (130 mL for 1c, 135 mL for 1d; Table 4, en-
troethane (1a) and differently substituted diethyl al- tries 7 and 10 respectively), then employing only
kylidenemalonates (2c–2n, Table 3). We started using 8.5 equiv. of 1d (Table 4, entry 13).
both catalysts C and E at room temperature with the
aim to find the best reaction conditions for each sub- lecular enantioselective conjugated addition of nitro-
strate. alkanes to alkylidenemalonates promoted by bifunc-
In conclusion, we have developed the first intermo-
With all aromatic substrates we obtained good re- tional thiourea organocatalysts, easily derived from
sults, the electron-withdrawing substituted ones giving cheap Cinchona alkaloids. The reaction efficiently
particularly fast reactions. In these latter cases, we re- proceeds with a wide range of substrates and with low
corded high ees with only 2.5 mol% of E (Table 3, en- catalyst loading, providing the desired product as the
tries 3 and 10). We noted also that both para- and major syn isomer with high ees. It has to be noted
ortho-substituents were well tolerated by the thiourea that the enantioenriched syn adduct, suitable for
catalyst (Table 3, entries 5–7 compared with entries 8– many pharmaceutical applications,[19] is not directly
Adv. Synth. Catal. 2012, 354, 364 – 370
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Michel Chiarucci et al.
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Table 3. Michael addition of nitroethane (1a) to alkylidenemalonates 2c–n promoted by thiourea-based bifunctional organo-
catalysts.[a]
Entry
2
Catalyst (mol%)
Time [d]
Conversion [%][b] (Yield [%])[c]
anti/syn[b]
ee [%][d]
anti
syn
1
2
2c
C (10%)
E (5%)
E (2.5%)
E (10%)
C (10%)
E (5%)
E (10%)
C (10%)
E (5%)
E (2.5%)
E (10%)
C (10%)
E (10%)
E (5%)
E (10%)
C (10%)
E (10%)
C (10%)
E (10%)
E (10%)
C (5%)
E (2.5%)
E (1%)
E (5%)
5
4
7
4
6
7
6
4
4
5
5
7
4
7
6
7
7
8
7
7
2
2
5
2
4
3
7
5
4
7
6
11
4
11
9
73 (70)
69 (65)
49 (44)
59 (55)
63 (60)
71 (68)
56 (51)
72 (68)
76 (72)
68 (64)
58 (54)
65 (61)
70 (67)
58 (54)
46 (40)
36
50 (46)
50 (45)
62 (58)
42 (37)
71 (68)
79 (77)
72 (68)
65 (60)
70 (67)
73 (69)
63 (59)
56 (52)
83 (81)
55 (51)
76 (73)
53 (48)
79 (77)
33
38/62
30/70
32/68
18/82
36/64
39/61
20/80
33/67
36/64
36/64
19/81
30/70
36/64
37/63
18/82
31/69
36/64
39/61
40/60
22/78
29/71
29/71
36/64
15/85
37/63
39/61
42/58
23/77
30/70
28/72
28/72
30/70
32/68
13/87
26/74
84
80
80
62
83
83
70
84
82
83
69
85
85
82
67
86
82
67
66
57
80
82
83
71
81
79
82
78
18
34
5
90
91
91
93
93
91
94
93
92
92
94
91
90
90
95
94
91
81
77
84
90
91
89
93
81
86
82
88
71
85
69
85
63
82
72
3
4[e]
5
2d
2e
6
7[e]
8
9
10
11[e]
12
2f
13
14
15[e]
16
2g
2h
17
18
19
20[e]
21
2i
2j
22
23[f]
24[e]
25
C (10%)
E (5%)
26
27
E (2.5%)
E (10%)
E (20%)
E (10%)
E (20%)
E (10%)
E (20%)
E (20%)
E (20%)
28[e]
29[e,g]
30[h]
31[e,g]
32[h]
33[e,g]
34[g,h]
35[g,i]
2k
2l
28
7
2m
2n
nd[j]
5
46 (41)
[a]
Reaction conditions (unless noted otherwise): 2 (0.1 mmol), 1a (0.2 mL), room temperature.
Determined by H NMR of the crude reaction mixture.
Yield of isolated product.
Determined by HPLC on a chiral stationary phase.
Carried out at 08C.
2 (0.2 mmol).
1a (0.3 mL).
Carried out at À408C.
Carried out at À208C.
nd=not determined.
[b]
[c]
[d]
[e]
[f]
1
[g]
[h]
[i]
[j]
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Enantioselective Conjugate Addition of Nitroalkanes to Alkylidenemalonates
Table 4. Michael addition of nitroalkanes 1b–d to alkylidenemalonate 2a promoted by thiourea-based bifunctional organoca-
talysts.[a]
Entry
1
Catalyst (mol%)
Time [d]
Conversion [%][b] (Yield [%])[c]
anti/syn[b]
ee [%][d]
anti
syn
1
2
1b
C (10%)
E (5%)
E (2.5%)
E (10%)
C (10%)
E (5%)
E (2.5%)
E (10%)
C (10%)
C (2.5%)
E (2.5%)
E (1%)
3
2
5
5
4
3
7
6
2
2
2
3
5
4
75 (72)
75 (71)
71 (67)
74 (71)
75 (71)
60 (55)
65 (62)
56 (53)
74 (71)
80 (77)
80 (76)
74 (70)
63 (59)
75 (71)
27/73
30/70
30/70
26/74
33/67
34/66
37/63
23/77
30/70
29/71
30/70
32/68
32/68
28/72
59
61
63
55
71
66
68
45
50
53
53
54
57
48
91
90
91
92
89
87
86
90
88
87
84
83
85
89
3
4[e]
5
1c
6
7[f]
8[e]
9
1d
10[f]
11
12[f,g]
13[g,h]
14[e]
E (0.5%)
E (5%)
[a]
Reaction conditions (unless noted otherwise): 2a (0.1 mmol), 1 (0.2 mL), room temperature.
Determined by H NMR of the crude reaction mixture.
Yield of isolated product.
Determined by HPLC on a chiral stationary phase.
Carried out at 08C.
10 equiv. of RNO2.
2a (0.2 mmol).
8.5 equiv. of 1d.
[b]
[c]
[d]
[e]
[f]
1
[g]
[h]
achievable through other asymmetric organocatalytic Acknowledgements
methods. This protocol represents a useful route to
optically active g-amino acids[9,10] and to other scaf-
folds deriving from the nitro functionality.[6] Applica-
tions to the synthesis of bioactive molecules are pres-
ently under investigation in our laboratory.
The University of Bologna, MIUR, and Fondazione del
Monte (Bologna) are acknowledged for financial support.
References
Experimental Section
[1] For reviews, see: a) Asymmetric Organocatalysis, in:
Topics in Current Chemistry, (Volume Editor: B. List),
Vol. 291, Springer, Berlin, Heidelberg, 2010; b) H. Pel-
lissier, Tetrahedron 2007, 63, 9267–9331; c) D. Almas¸i,
D. A. Alonso, C. Nꢃjera, Tetrahedron: Asymmetry
2007, 18, 299–365; d) S. B. Tsogoeva, Eur. J. Org.
Chem. 2007, 1701–1716; e) P. I. Dalko, L. Moisan,
Angew. Chem. 2004, 116, 5248–5286; Angew. Chem.
Int. Ed. 2004, 43, 5138–5175. See also: f) A. Berkessel,
H. Grçger, in: Asymmetric Organocatalysis, Wiley-
VCH, Weinheim, 2005.
General Procedure
Alkylidenemalonate 2 (0.1 mmol, 1 equiv.) and nitroalkane
1 (200 mL) were added at the desired temperature to a vial
containing the thiourea catalyst E (0.005 mmol, 5 mol%).
The mixture was stirred at the same temperature and the
1
conversion was monitored by TLC and H NMR. After the
reported time, the crude reaction mixture was directly puri-
fied by flash chromatography on silica gel (cyclohexane/
ethyl acetate mixtures).
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370
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Adv. Synth. Catal. 2012, 354, 364 – 370