Supported and Unsupported Chiral Squaramides as Organocatalysts for Stereoselective Michael Additions: Synthesis of Enantiopure Chromenes and Spirochromanes

Article abstract of DOI:10.1021/acs.joc.7b01177

Novel supported chiral bifunctional squaramides have been easily prepared starting from diamines derived from natural amino acids and commercially available aminoalkyl polystyrene resins. These squaramides behave as excellent stereoselective recoverable o

Full text of DOI:10.1021/acs.joc.7b01177

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Article
Supported and Unsupported Chiral Squaramides as
Organocatalysts for Stereoselective Michael Additions.
Synthesis of Enantiopure Chromenes and Spirochromanes
Jose Maria Andres, Jorge Losada, Alicia Maestro, Patricia Rodríguez-Ferrer, and Rafael Pedrosa
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01177 • Publication Date (Web): 24 Jul 2017
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The Journal of Organic Chemistry
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Supported and Unsupported Chiral Squaramides as Organocatalysts for
Stereoselective Michael Additions. Synthesis of Enantiopure Chromenes and
Spirochromanes
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José M. Andrés,* Jorge Losada, Alicia Maestro, Patricia Rodríguez-Ferrer, and
Rafael Pedrosa*
Instituto CINQUIMA and Departamento de Química Orgánica, Facultad de Ciencias,
Universidad de Valladolid, Paseo de Belén 7, 47011ꢀValladolid. Spain
Eꢀmail: pedrosa@qo.uva.es
E-mail: jmandres@qo.uva.es
O
O
R2
O
O
dr up to 63:37
er up to 99:1
R1
R3
catalyst (5 mol%)
NO2
R1
O
R3
NO2
+
Ar
neat, rt
Ar
R2
O
O2N
O2N
catalyst
(5 mol%)
neat, rt
CO2Me
NO2
+
or
OMe
O
O
O
O
dr >98:<2, er >99:<1
dr >98:<2, er >99:<1
OH
O
O
O
O
t-Bu
R
NMe2
NMe2
N
N
N
N
Ph
H
H
H
H
Abstract.
Novel supported chiral bifunctional squaramides have been easily prepared starting
from diamines derived from natural amino acids and commercially available
aminoalkyl polystyrene resins. These squaramides behave as excellent stereoselective
recoverable organocatalysts in different Michael additions, in neat conditions at room
temperature. The reaction on 2ꢀ(2ꢀnitrovinyl) phenol as electrophile lead, in excellent
yields and enantioselectivities, to intermediates that can be easily transformed into
4Hꢀchromenes, and spirochromanones.
Key words: Asymmetric synthesis. Chromenes. Michael addition. Organocatalysis.
Supported squaramides. Squaramides
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Introduction.
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The first chiral bifunctional squaramide derived from cinchonine was prepared a
decade ago, and successfully used in the enantioselective nitroꢀMichael reaction.1
Since then, a lot of squaramides, specially derived from cinchone alkaloids or transꢀ
1,2ꢀcyclohexane diamine, have been synthesized and used as organocatalysts in
different enantioselective transformations.2 Additionally, a few squaramides with a
common 3,5ꢀbis(trifluoromethyl) aniline and a chiral diamine derived from αꢀamino
acids have been described as excellent catalysts for different Michael additions,3 and
tandem reactions leading to complex structures.4
9
10
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The easy recovering of the catalyst is a mandatory fact for its practical application,
and the support onto a solid material is a good way to solve that problem. In spite of
the high volume of reports of novel squaramides, only a few antecedents have been
directed to the preparation and use of that kind of supported organocatalysts. The first
supported catalyst (I) was prepared by clickꢀchemistry grafting methodology of an
elaborated transꢀ1,2ꢀcyclohexane diamineꢀderived squaramide onto polystyrene resin,
and successfully used in batch,5 and continuous flow6 nitroꢀMichael additions.
O
CF3
N
O
O
HN
H
O
N
H
O
N
N
O
N
H
H
O
N
N
N
N
Pericàs, 20125,6a
Soós, 20137
I
II
O
O
O
O
N
H
N
H
Sebesta, 20168
N
H
N
H
IV
NR2
I-
III
HN
O
O
O
Si
N
N
Si
O
O
O
O
S
O
Si
OH
I-
O
N
Si
Si
N
N
N
Si
Si
H
HO
CF3
NH
N
H
OMe
O
I-
OH
O
N
O
CF3
n
m
N
V
Liu, 20149
Figure 1. Supported squaramides previously described.
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In parallel, a shorter synthesis of catalyst (II) was described by support of quinineꢀ
derived squaramide onto aminomethyl polystyrene,7 and very recently, the same resin
has been used as support for squaramides derived from transꢀ1,2ꢀcyclohexane
diamine (III), and 2ꢀmethylamino pyrrolidine (IV).8 A highly active heterogeneous
catalyst (V) was also prepared by immobilization of an squaramide derived from
cinchonidine onto an hybrid silica functionalized with imidoazolium groups9 (Figure
1).
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As a part of a project directed to the synthesis of different organocatalysts, we have
previously described supported prolinamides,10 and ureas and thioureas onto different
polystyrene resins,11 or obtained by coꢀpolymerization of monomeric thioureas with
styrene and divinylbenzene.12 Now we have addressed the preparation of highly
efficient and recoverable bifunctional squaramides, taking into account that the
synthesis must be as short as possible and starting from cheap commercially available
materials which allow the access to both enantiomers of the catalysts.
This idea led us to consider the twoꢀsteps synthesis of these materials starting from
different aminoalkyl polystyrenes as support, and bifunctional chiral squaramides
obtained by reaction of diethyl squarate and chiral diamines derived from natural
amino acids (Figure 2).
O
O
O
O
NR'2
NR'2
n
NH2
+
N
H
N
H
n
R
EtO
N
H
R
NR'2
R
O
O
CO2H
R
+
H2N
H2N
EtO
OEt
Figure 2. Proposed retrosynthetic analysis of the supported squaramides.
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Results and discussion.
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Four supported (5ꢀ8) and two unsupported (9ꢀ10) squaramides were prepared as
summarized in Scheme1 from semiꢀsquaramides 3 and 4 obtained, in very good
yields, by condensation of diethyl squarate and diamines 1 and 2 derived from Lꢀ
valine or Lꢀtertꢀleucine respectively.13 Immobilized materials 5-7, which differ in the
length of the tether linking the squaramide and the solid support, were prepared by
reaction of 3 with methylaminoꢀ, ethylaminoꢀ, and butylaminoꢀpolystyrene resins
respectively. Supported squaramide 8, with a bulkier substituent at the stereogenic
center, was also obtained from 4 and aminoethylꢀpolystyrene. Analytical data shown
that the incorporation of the monomers to the resins occurred in quantitative yields,
and that the effective functionalization (f) varies from 0.86 to 0.96 (Table 1, entries 1ꢀ
4). All these materials shown characteristic IR bands at 3250, 1795, and 1688 cmꢀ1.
For comparative purposes, unsupported squaramides 9 and 10 were also obtained, in
very good yields, by reaction of benzyl amine with 3 and 4 respectively (Table 1,
entries 5, 6).
9
10
11
12
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O
O
R
ii
NMe2
N
N
n
H
H
5: R = i-Pr, n = 1
6: R = i-Pr, n = 2
7: R = i-Pr, n = 4
8: R = t-Bu, n = 2
O
O
R
i
R
NMe2
NMe2
N
EtO
NH2
H
3: R = iPr 82%
4: R = tBu 94%
1:R = i-Pr
2: R = t-Bu
O
O
R
iii
NMe2
N
N
Ph
H
H
9: R = i-Pr
10: R = t-Bu
Scheme 1. Synthesis of supported and unsupported squaramides.
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Table 1. Supported and unsupported squaramides prepared in this work.
Yield (%)a fb
Entry Squaramide
R
n
1
2
4
f/fmax
100
100
100
100
ꢀ
1
2
3
4
5
6
iꢀPr
iꢀPr
iꢀPr
94
90
0.96
0.86
0.94
0.87
ꢀ
5
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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26
27
28
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31
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50
51
52
53
54
55
56
57
58
59
60
80
7
tꢀBu 2
iꢀPr
tꢀBu ꢀ
81
8
ꢀ
80c
85c
9
ꢀ
ꢀ
10
a Yields were calculated as a ratio of the mass of the starting and final product. b Determined from the
analytical data of the nitrogen atom in the polymers. c Yields of isolated pure compounds.
The activity of all the squaramides was studied in the addition of different
nucleophiles to βꢀsubstituted nitroolefins. The addition of acetylacetone (14a) to
transꢀβꢀnitrostyrene (13a) was initially selected as a model to compare the activity
and the length of the tether of the supported catalysts 5-8 with the homogeneous
squaramides 9, 10. To this end, transꢀβꢀnitrostyrene was reacted with two equivalents
of 2,4ꢀpentanedione, at room temperature without solvent, in the presence of 5 mol%
of catalysts 5ꢀ10, and the results are collected in Table 2 (entries 1ꢀ9).
The summarized results shown that all the catalysts were very active, leading to the
addition product 15aa in excellent yields and enantioselection, but the tertꢀbutylꢀ
substituted homogeneous squaramide 10 was slight more active than its homologous
isoꢀpropyl derivative 9 (compare entries 1, 2 in Table 2). The loading of catalyst can
be reduced to 2 mol% (entry 3) or 0.5 mol% (entry 4) without loss in the yield and
enantioselection, and the reaction can be scaled up to 6 mmol without loss of
enantioselectivity (entry 5). It is also noteworthy that the length of the spacer, in the
supported catalysts, play only a little influence in the reaction (entries 6ꢀ9 in Table 2),
but the better results were obtained for supported squaramides derived from
ethylamino polystyrene 6 and 8.
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Table 2. Reaction of different nitroolefins with acetylacetone catalyzed by
squaramides and thioureas.
6
7
8
O
O
O
O
catalyst (5 mol%)
NO2
+
Ar
NO2
9
neat, rt
Ar
13a-h
14a
15aa-ha
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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O
O
R
O
O
R
NMe2
R
NMe2
S
NMe2
( )
N
H
N
Ph
n N
N
H
H
H
N
H
N
H
9: R = iPr
10: R = tBu
5: n = 1; R = iPr
6: n = 2; R = iPr
7: n = 4; R = iPr
8: n = 2; R = tBu
11: R = iPr
12: R = tBu
Entrya
Erc
(Configuration)
97:3 (S)
Time Product
Ar
Catalyst
(Yield)b
(h)
1
2
3
C6H5
C6H5
C6H5
2
15aa (80)
9
0.5 15aa (92)
99:1 (S)
10
10d
1
15aa (82)
99:1 (S)
4
5
C6H5
C6H5
10e
2
2
15aa (89)
15aa (70)
99:1 (S)
99:1 (S)
10e,f
6
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
2
2
15aa (89)
15aa (80)
15aa (88)
15aa (97)
15aa (96)
15aa (74)
15aa (74)
15aa (70)
97:3 (S)
98:2 (S)
96:4 (S)
99:1 (S)
96:4 (S)
92:8 (S)
87:13 (S)
81:19 (S)
99:1 (S)
97:3 (S)
>99:<1 (S)
99:1 (S)
98:2 (S)
5
6
7
8
2
7
9
1
8
10
11
12
13
14
15
16
17
18
8e
8e,f
11
12
10
8
2
16
1
1
pꢀClC6H4
pꢀClC6H4
1.5 15ba (88)
2
1
15ba (80)
15ca (76)
pꢀCF3C6H4
pꢀCF3C6H4
oꢀNO2C6H4
10
8
1.5 15ca (78)
15da (87)
1
10
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oꢀNO2C6H4
pꢀMeOC6H4
pꢀMeOC6H4
1ꢀnaphthyl
1ꢀnaphthyl
2ꢀnaphthyl
2ꢀnaphthyl
2ꢀfuryl
1.5 15da (88)
1.5 15ea (95)
99:1 (S)
98:2 (S)
99:1 (S)
99:1 (S)
99:1 (S)
97:3 (S)
95:5 (S)
97:3 (S)
96:4 (S)
8
10
8
2
1
2
15ea (86)
15fa (75)
15fa (90)
10
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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57
58
59
60
1.5 15ga (85)
2.5 15ga (83)
10
8
1
1
15ha (77)
15ha (84)
10
8
2ꢀfuryl
a The reactions were carried out at 0.3 mmol scale with 2 fold excess of acetylacetone without solvent,
at rt. b Numbers in parenthesis correspond to isolated products after flash chromatography. c
Determined by chiral HPLC. d Only 2 mol% of catalyst was used in this reaction. e Only 0.5 mol% of
catalyst was used in this reaction. f The reaction was scaled up to 6 mmol, and the yield refers to pure
compound obtained after recrystallization.
Additionally, the results obtained with squaramide 8 were very similar to those
provided by its homolog unsupported squaramide 10, indicating that the anchorage of
the active structure does not modify the activity of the catalysts (compare entries 2
versus 9 in Table 2). Only an slight longer reaction times were observed for the
reactions promoted by the supported catalyst. Squaramide 8 also worked very well
with a catalyst loading of 0.5 mol% (entry 10), and when the reaction was scaled up
to 6 mmol, although increasing the reaction time (entry 11 in Table 2). For
comparative purposes, supported thioureas 11 and 1214 were also tested as catalysts in
the same reaction conditions, but the reaction occurred in much lower
enantioselection (entries 12, 13).
Supported catalyst 8 was next used in the conjugate addition of 2,4ꢀpentane dione 14a
to different βꢀarylꢀsubstituted nitroolefins (14bꢀh) under the described reaction
conditions (entries 14ꢀ27 in Table 2). The Michael adducts (15baꢀ15ha) were isolated
in very good yields and excellent enantioselectivities in short reaction times. The
position or the electronic character of the substituents at the phenyl group play only
negligible effect on the yield of the reaction, and only slight decrease in the
enantioselectivity was observed in the reactions of 2ꢀnaphthylꢀ (15g) or 2ꢀfurylꢀ
substituted (15h) nitroolefins (entries 24, 27 in Table 2).
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The study was first extended to the reaction of different acyclic nucleophiles (14bꢀi)
with transꢀβꢀnitrostyrene by using the most active catalysts in the described reaction
conditions except when both reactants were solid. In those cases, DCM was used as a
solvent (Scheme 2, and Table 3).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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37
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50
51
52
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58
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60
O
O
R2
R1
R3
O
O
catalyst (5 mol%)
NO2
NO2
+
R1
R3
rt
R2
14b: R1 = R3 = Ph; R2 = H
14c: R1 = Ph; R3 = Me; R2 = H
14d: malononitrile
15ab-ai
13a
14e: R1 = R3 = OEt; R2 = H
14f: R1 = R3 = OMe; R2 = Cl
14g: R1 = Me; R3 = OEt; R2 = H
14h: R1 = R2 = R3 = Me
14i: R1 = Me; R3 = OEt; R2 = Me
Scheme 2. Addition of different acyclic nucleophiles to nitrostyrene.
Both homogeneous (10) and heterogeneous (8) catalysts promote the addition of
dibenzoylmethane (14b) and benzoylacetone (14c) to transꢀβꢀnitrostyrene in very
good yields and enantioselectivities (entries 1, 2 and 5, 6 in Table 3). The reaction can
be carried without solvent under ballꢀmilling conditions, maintaining both the yield
and enantioselection (entry 3 in Table 3). The reaction failed when malononitrile
(14d) was used as nucleophile, because the addition product 15ad was isolated in
moderate yield and poor enantioselectivity (entries 7, 8 in Table 3).
The less acidic diethyl malonate (14e) also reacted very slowly, in neat conditions,
yielding the addition product (15ae) in low yield, although moderate
enantioselectivity (entry 9). Dimethyl 2ꢀchloro malonate (14f) reacted faster than 14e,
leading to 15af in good yield and enantioselectivity when the reaction was catalyzed
10 (entry 10), but very poor enantioselection in the presence of 8 (entry 11 in Table
3). On the contrary, the reaction of ethyl 3ꢀoxoꢀbutyrate (14g) with transꢀβꢀ
nitrostyrene occurred easily, yielding 15ag in good yield, moderate diastereoselection
but excellent enantioselectivity (entries 12, 13 in Table 3).
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Table 3. Reaction of transꢀβꢀnitrostyrene (13a) with different acyclic nucleophiles
catalyzed by squaramides 6, 8, 10.a
6
7
8
9
drc
erd
Entry
Time
(h)
48
Product
(Yield)b
Reagent Catalyst
Solvent
(Config)
94:6 (S)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2
CH2Cl2 15ab (82)
CH2Cl2 15ab (73)
ꢀ
ꢀ
ꢀ
ꢀ
14b
14b
14b
14b
10
8
24
91:9 (S)
3e,f
4e
5
72
neat
15ab (75)
91:9 (S)
10
6
17
CH2Cl2 15ab (80)
82:18 (S)
96:4 (S, S)
(95:5) (R, S)
94:6 (S, S)
(93:7) (R, S)
60:40 (S)
52:48 (S)
83:17 (S)
85:15 (S)
65:35 (S)
8
8
CH2Cl2 15ac (86) 60:40
CH2Cl2 15ac (96) 61:39
14c
14c
10
8
6
7
8
6
9
CH2Cl2 15ad (67)
CH2Cl2 15ad (47)
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
14d
14d
14e
14f
14f
10
8
9
120
3
neat
neat
neat
15ae (40)g
15af (82)
15af (75)
10
10
8
10
11
12
18
63:37 98:2 (S, S)
(97:3) (S, R)
1
2
neat
neat
15ag (73)
14g
14g
10
8
13
96:4 (S, S)
15ag (78) 62:38
(94:6) (S, R)
99:1 (R)
14
15
16
17
17
86
neat
neat
neat
15ah (89)
15ah (53) g
15ah (45) g
ꢀ
ꢀ
ꢀ
14h
14h
14h
10
6
96:4 (R)
120
98:2 (R)
8
62:38 92:8 (R, R)
(94:6) (S, R)
24
54
neat
neat
15ai (70)
14i
14i
10
8
18
83:17 (R, R)
15ai (74) 58:42
(94:6) (S, R)
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8
a The reactions were carried out at 0.3 mmol scale with 2 fold excess of nucleophile, at rt. b Numbers in
parenthesis correspond to isolated products after flash chromatography. c Determined by 1HNMR in the
reaction mixtures. d Determined by chiral HPLC, and numbers in parenthesis correspond to the er of the
f
minor diastereoisomers. e Only 1.5 excess of nucleophile was used in these reactions. The reaction
was carried out under ballꢀmilling conditions. g The values given do not correspond to yields, but to
conversions, and were determined by 1HNMR of the reaction mixtures.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Tertiary pronucleophile 3ꢀmethylꢀ2,4ꢀpentanedione (14h) reacted slower than
unsubstituted diketone 14a, in the presence of homogeneous squaramide 10 although
maintaining good yield and excellent enantioselection (compare entry 14 in Table 3
versus entry 2 in Table 2). Supported catalysts 6 and 8 were also able to promote the
same addition reaction maintaining the good enantioselectivity, but at expenses of
increasing the reaction time and diminishing the yield (entries 15, 16 in Table 3). The
same fact was observed for the reaction of ethyl 2ꢀmethylꢀ3ꢀoxoꢀbutyrate (14i) with
respect to the unsubstituted homolog 14g. In both cases the yields and
stereoselectivities were quite similar, but in much longer reaction time (compare
entries 17, 18 versus 12, 13 in Table 3).
It is interesting to note that the enantioselection in the addition process was generally
very good, but the diastereoselectivity was moderate (ca. 3:2) when prochiral
substrates (14c, g, i) were used as nucleophiles. This fact is in agreement with
previously reported results.5, 7
Prochiral cyclic βꢀdifunctionalized substrates also act as nucleophiles in the addition
reaction, but the reactivity and stereochemical behavior are highly dependent on their
structure (Scheme 3).
O
O
Ph
NO2
catalyst (5 mol%)
COR
NO2
X
X
neat, rt
( )n
COR
( )n
16a: n = 1; X = CH2; R = OEt
16b: n = 2; X = CH2; R = OEt
16c: n = 3; X = CH2; R = OMe
16d: n = 1; X = CH2; R = Me
16e: n = 1; X = O; R = Me
13a
17aa-ae
Scheme 3. Addition of different cyclic nucleophiles to transꢀβꢀnitrostyrene.
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Table 4. Michael additions of cyclic nucleophiles to transꢀβꢀnitrostyrene.a
5
6
7
8
Time
(h)
1
Product
(Yield)b
Anti:sync Er (anti)d
Entry Reagent Catalyst
9
1
2
17aa (92)
17aa (90)
17aa (82)
17aa (88)
17aa (80)
17aa (85)
17ab (58)e
17ab (82)
17ab (77)
17ac (98)
17ac (76)
17ad (94)
17ad (96)
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
82:18
99:1
98:2
16a
16a
16a
16a
16a
16a
16b
16b
16b
16c
16c
16d
16d
9
10
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
3
6
99:1
4
2
98:2
6
5
4
>99:<1
>99:<1
98:2
7
6
3
8
7
48
48
96
8
9
8
98:2
10
6
9
98:2
10
11
12
13
>99:<1
>99:<1
>99:<1
98:2
10
6
22
2
10
8
5
85:15
>99:<1
(97:3)f
92:8
14
15
1.5
40
17ae (80)
17ae (72)
56:44
53:47
16e
16e
10
8
(92:8)f
a The reactions were carried out at 0.3 mmol scale with 2 fold excess of nucleophile, at rt. b Numbers in
parenthesis correspond to isolated products after flash chromatography. c Determined by 1HNMR in the
reaction mixtures. d Determined by chiral HPLC, and numbers in parenthesis correspond to the er of the
minor diastereoisomers. e 40% of unreacted nitrostyrene was recovered from the reaction mixture.
f
numbers in parenthesis correspond to the er for the syn diastereoisomer.
The influence of the nature of the functional groups and the size of the cyclic structure
was tested by using as nucleophiles 2ꢀalkoxycarbonyl substituted cycloalkanones 16aꢀ
c, that differ in the size of the ketone, and 2ꢀacetyl cyclopentanone (16d) and 2ꢀacetyl
butyrolactone (16e). The process was studied by reacting transꢀβꢀnitrostyrene with
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two equivalents of nucleophile and 5 mol% of catalysts at room temperature in neat
conditions (Table 4).
6
7
8
9
Fortunately, both homogeneous (9, 10) and supported (5ꢀ8) squaramides were able to
promote the addition of 16a to 13a in very good yields and excellent enantioselection,
leading to 17aa as a single nearly enantiopure diastereoisomer (entries 1ꢀ6 in Table
4). The only differences observed was that the reactions promoted by supported or
tertꢀLeucineꢀderived catalysts were slight slower than those catalyzed by
homogeneous or Valineꢀderived ones.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cycloheptanone derivative 16c easily added to transꢀβꢀnitrostyrene in the presence of
homogeneous (10) or supported (6) catalysts leading to 17ac in good yields and total
stereoselectivity (entries 10, 11 in Table 4). On the contrary, 2ꢀethoxycarbonyl
cyclohexanone 16b showed to be much less reactive than its homologs, although the
reaction occurred with excellent stereoselection (compare entries 7ꢀ9 versus 1, 2, 4 in
Table 4). To our surprise, the supported catalyst 8 was not able to promote the
reaction of 16b with transꢀβꢀnitrostyrene, in the described conditions, and the starting
reagents were recovered unchanged after 96 h.
2ꢀAcetyl cyclopentanone 16d easily reacted with transꢀ βꢀnitrostyrene in the presence
of catalysts 8 and 10, leading to the addition product 17ad in excellent yield and
enantioselectivity, but moderate diastereoselection (entries 12, 13 in Table 4). Finally,
2ꢀacetyl butyrolactone 16e quickly reacted catalyzed by homogeneous 10, but slowly
in the presence of supported catalyst 8. In both cases the level of enantioselection was
maintained although 17ae was obtained as a near equimolar mixture of
diastereoisomers (entries 14, 15 in Table 4).
The recovering and reusing of the catalysts were studied for supported catalysts 6 and
8 in the addition of 2,4ꢀpentanedione (14a), and 2ꢀethoxycarbonyl cyclopentanone
(16a) to transꢀβꢀnitrostyrene. The recycling experiments were done in neat
conditions, at room temperature, with 5 mol% of catalysts. The reaction time was
maintained constant in each cycle (1 h. for the reaction of 13a with 14a; 3h. for the
addition of 16a to 13a in the presence of 8, and 2h. for the same reaction catalyzed by
6), and the results are collected in Table 5. The catalyst was recovered after each
cycle by filtration, washed with DCM, dried, and reused in the next cycle. To our
delight, both the diastereoꢀ and enantioselection were maintained along all the cycles.
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5
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7
8
9
1HNMR spectra of the reaction mixtures showed total conversion, and only a very
slight deterioration in the activity was observed for catalyst 8 in the last cycle of the
reaction between 13a and 14a (98%). It is also very important to note that 84ꢀ98% of
catalyst was recovered by filtration in each cycle, and that no appreciable leaching
was observed, because the analytical data of catalyst 8 shown the same effective
functionalization after six cycles than the starting material (f = 0.85 versus 0.87 in
entry 4 in Table 1).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. Recyclability of supported catalysts 6 and 8 in the reactions of 13a with 14a
and 16a.
drc
erd
Entry Cycle
Catalyst
Recovered (%)a
8
Time
(h)
1
Product
(Yield)b
Reagents
1
2
1
2
3
4
5
6
1
2
3
4
5
6
1
2
3
4
5
15aa (97)
15aa (92)
15aa (96)
15aa (94)
15aa (94)
15aa (89)
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
99:1
>99:<1
98:2
13a/14a
13a/14a
13a/14a
13a/14a
13a/14a
13a/14a
13a/16a
13a/16a
13a/16a
13a/16a
13a/16a
13a/16a
13a/16a
13a/16a
13a/16a
13a/16a
13a/16a
8 (86)
8 (84)
8 (92)
8 (88)
8 (87)
8
1
3
1
4
1
>99:<1
98:2
5
1
6
1
98:2
7
3
17aa (85) >98:<2
17aa (86) >98:<2
17aa (82) >98:<2
17aa (83) >98:<2
99:1
8
8 (85)
8 (84)
8 (98)
8 (85)
8 (98)
6
3
99:1
9
3
99:1
10
11
12
13
14
15
16
3
98:2
3
17aa (80) >98:<2 98.5:1.5
3
17aa (85) >98:<2
17aa (88) >98:<2
17aa (84) >98:<2
17aa (86) >98:<2
17aa (86) >98:<2
98:2
98:2
98:2
98:2
98:2
98:2
2
6 (85)
6 (84)
6 (85)
6 (98)
2
2
2
17
2
17aa (87) >98:<2
a
b
Numbers in parenthesis refer to the amount of catalyst recovered after each cycle. Numbers in
parenthesis to isolated compounds after flash chromatography. c Determined by HNMR in the reaction
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d
mixture, and the values means that a single diastereoisomer was detected. Determined by Chiral
HPLC.
5
6
7
8
Aimed by the results described above, we envisaged that the use of ortoꢀsubstituted
nitroolefins derived from phenol as electrophiles gave intermediates that could be able
to participate in subsequent annulation leading to hemiacetals easily transformed into
chromenes or related derivatives. Benzopyran and related framework can be found in
many types of natural and biological active compounds,15 and the organocatalytic
stereoselective synthesis of that kind of compounds has recently received some
attention,16 but there are no antecedents on the use of supported catalysts in that
transformation. To that end, we reacted 2ꢀ(2ꢀnitrovinyl) phenol derivatives (13i-k)
with different proꢀnucleophiles (14a, b, j, k) in the presence of supported squaramide
(8), and unsupported one (10) for comparative purposes (Scheme 4 and Table 6).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The reaction of transꢀ2ꢀhydroxyꢀβꢀnitrostyrene 13i with acetylacetone (14a), in neat
conditions at rt, and 5 mol% of thiourea 10 was completed after 1 h, but hemiacetal
(18) was obtained as a mixture of diastereoisomers. To avoid that problem, the
o
reaction mixture was directly dehydrated by heating at 100 C for 2 h with catalytic
PTSA,16b leading to 4Hꢀchromene 19ia in excellent yield (93%), and near total
enantioselection (er 99:1) (entry 1 in Table 6). In the same conditions, the reaction
promoted by supported squaramide 8 was slower (14h), leading to 19ia in lower,
although acceptable, yield (72%), but maintaining the excellent level of
enantioselectivity (er 97:3) (entry 2 in Table 6).
NO2
catalyst
(5 mol%)
neat, rt
O2N
O
O
R
O
+
R2
R1
R
R2
OH
13i: R = H
13j: R = Br
14a: R1 = R2 = Me
14j: R1 = R2 = Et
14k: R1 = Me; R2 = OMe
R1
OH
O
18
13k: R = Me
TsOH
O
O
catalyst
(5 mol%)
neat, rt
Toluene
100 oC, 2 h
Ph
Ph
14b
O2N
O
O2N
O2N
O
R
O
R2
R
Ph
Ph
Ph
R1
O
19ia-ka
O
OCOPh
20ib
O
H
Scheme 4. Sequential nitroꢀMichael, hemiacetalization, dehydration to 4Hꢀ
chromenes.
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Table 6. Oneꢀpot enantioselective synthesis of 4Hꢀchromenes.a
5
6
7
8
Erd
Product
t (h)b
Entry Reagents Catalyst
(Yield)c
(Configuration)
99:1 (S)
9
1
2
1
14
3
19ia (93)
19ia (72)
20ib (80)
20ib (78)
19ij (84)
19ij (65)
19ik (72)
19ik (60)
19ja (82)
19ja (70)
19ka (77)
13i/14a
13i/14a
13i/14b
13i/14b
13i/14j
13i/14j
13i/14k
13i/14k
13j/14a
13j/14a
13k/14a
13k/14a
10
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
97:3 (S)
3
93:7 (R)
10
8
4
9
62:38 (R)
99:1 (S)
5
1
10
8
6
14
1
96:4 (S)
7
>99:<1 (S)
97:3 (S)
10
8
8
24
1
9
99:1 (S)
10
8
10
11
12
14
1
97:3 (S)
>99:<1 (S)
96:4 (S)
10
8
14 19ka (67)
a The reactions were carried out at 0.3 mmol scale with 2 fold excess of nucleophile at rt. b Reaction
times refer to the Michael addition step. c Numbers in parenthesis correspond to isolated products after
flash chromatography. d Determined by chiral HPLC.
Similar results were obtained when 3,5ꢀheptanedione (14j) or methyl acetoacetate
(14k) were used as nucleophiles in the reactions catalyzed by 8 or 10. The additionꢀ
hemiacetalizationꢀelimination products 19ij and 19ik were obtained in good yields
and total enantioselection (entries 5ꢀ8 in Table 6). A drastic change in the reaction
was observed for dibenzoylmethane (14b) as pronucleophile. In the described reaction
conditions, compound 20ib was isolated in good yields and enantiomeric excess for
the reaction promoted by squaramide 10, or with very moderate enantioselectivity
when supported squaramide 8 was used as catalysts (entries 3, 4 in Table 6). Product
20ib could be formed by a retroaldol reaction in the intermediate hemiacetal, and it
has been previously observed in related reactions.17
The electronic nature of additional substituents in the phenol derivative does not play
significant influence in the reaction. Both 4ꢀbromoꢀsubstitued (13j) and 4ꢀmethylꢀ2ꢀ
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(2ꢀnitrovinyl) phenol (13k) gave chromenes 19ja and 19ka, respectively, in very good
yields and excellent enantioselectivities (entries 9ꢀ12 in Table 6).
6
7
8
9
The cyclic pronucleophile derived from cyclopentanone behaves in a similar way than
acyclic ones (Scheme 5). The reaction of 2ꢀmethoxycarbonyl cyclopentanone (16f)
with 13i catalyzed by unsupported squaramide (10) occurred very easily leading to a
mixture of Michael adduct 21 and hemiacetal 22. When the mixture was heated with
catalytic amount of PTSA (Method A) no dehydration product was formed, and
spirochromanone 23if, resulting from the lactonization of the Michael adduct, was
isolated in good yield as a single stereoisomer (entry 1 in Table 7). In contrast,
cyclopenta[b]chromene 24if was obtained in moderate yield and total enantioselection
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
by treatment the mixture with P2O5 at – 20 C16a (Method B) (entry 2 in Table 7).
Total stereoselection, yet lower yield and longer reaction time was observed for the
reaction catalyzed by supported squaramide 8 (entry 3), but the reaction time was
shortened, maintaining the stereoselection, when the Michael addition was carried out
at 50 oC (entry 4 in Table 7).
O2N
TsOH
NO2
Toluene
O
O
100 oC, 2 h
catalyst
(5 mol%)
neat, rt
O
OH
+
Method A
R = OMe
NO2
O
OMe
O
O
OH
23if
CO2Me
13i
16f
21
O2N
O2N
CO2Me
CO2Me
P2O5
DCM, -20 oC
Method B
O
HO
O
24if
22
Scheme 5. Michael addition of methyl 2ꢀoxocyclopentyl carboxylate to 2ꢀ(2ꢀ
nitrovinyl) phenol promoted by 8 and 10.
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Table 7. One pot synthesis of chromane derivatives.
5
6
7
8
Nucleophile
Method Product
(Yield)c
t (h)b
Drd
Ere
Entry Catal.
9
1
2
1
1
23if (70) >98:<2 >99:<1
>99:<1
10
10
8
16f
16f
16f
16f
A
B
B
B
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
24if (64) >98:<2
3
96
6
24if (54) >98:<2 99:1
24if (50) >98:<2 99:1
4f
8
a The reactions were carried out at 0.3 mmol scale with 2 fold excess of nucleophile at rt. b Reaction
times refer to the Michael addition step. c Numbers in parenthesis correspond to isolated products after
flash chromatography. Determined by 1HNMR, and the given values mean that only a single
d
e
f
diastereoisomer was detected. Determined by chiral HPLC. Michael additionꢀhemiacetalization
performed at 50 ºC.
Conclusions
In summary, we have prepared in two steps novel supported and unsupported
bifunctional chiral squaramides from diamines derived from natural amino acids and
commercially available alkylamino polystyrenes. Both the homogeneous catalysts and
the supported materials are able to catalyze stereoselective Michael additions of
different nucleophiles to nitrostyrene derivatives with very good yields and excellent
diastereoꢀ and enantioselection. Additionally, the reactions were carried out at rt
without solvent, and we have demonstrated that the supported most active catalyst is
easily recoverable and reusable for six cycles. Starting from 2ꢀ(2ꢀnitrovinyl) phenol as
electrophile, a series of some 4Hꢀchromenes, and spirochromanes have been prepared,
in one pot, with good yields and total stereoselection by hemiacetalizationꢀ
dehydration or lactonization of the Michael intermediates.
Experimental
General
1H NMR (500 MHz) and 13C NMR (126 MHz) spectra were recorded in CDCl3 or
DMSOꢀd6 as solvent. Chemical shifts for protons are reported in ppm from TMS with
the residual CHCl3 resonance as internal reference. Chemical shifts for carbons are
reported in ppm from TMS and are referenced to the carbon resonance of the solvent.
Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t =
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triplet, q = quartet, m = multiplet, br = broad), coupling constants in Hertz, and
integration. Specific rotations were measured on a digital polarimeter using a 5ꢀmL
cell with a 1ꢀdm path length, and a sodium lamp, and concentration is given in g per
100 mL. FT–IR data are reported in frequency of absorption (only the structurally
most important peaks are given). Melting points were obtained with open capillary
tubes and are uncorrected. Flash chromatography was carried out using silica gel
(230–240 mesh). Chemical yields refer to pure isolated substances. TLC analysis was
performed on glassꢀbacked plates coated with silica gel 60 and an F254 indicator, and
visualized by either UV irradiation or by staining with phosphomolybdic acid
solution. Chiral HPLC analysis was performed using different chiral columns.
Elemental analyses were carried out at the Elemental Analysis Center of the
Complutense University of Madrid. HRMS were measured by positive electrospray
ionization using quadrupoleꢀtimeꢀofꢀflight detector instrument.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Commercially available organic and inorganic compounds were used without further
purification. Solvents were dried and stored over microwave–activated 4 Å molecular
sieves. Aminomethyl polystyrene resin (particle size: 160ꢀ200 µm, loading: 1.11
mmol/g.), aminoethyl polystyrene resin (particle size: 160ꢀ200 µm, loading: 1.05
mmol/g.) and 4ꢀAminobutyl polystyrene (particle size: 160ꢀ200 µm, loading: 1.01
mmol/g.) are commercially available.
Diamines 1-2,13 supported thioureas 11-12,14 nitroolefins 13c-d,f-g,18 and 2ꢀ(2ꢀ
nitrovinyl)phenols 13i-k,18 were prepared according to literature procedures.
(S)-3-((1-(Dimethylamino)-3-methylbutan-2-yl)amino)-4-ethoxycyclobut-3-ene-1,2-
dione (3). To a solution of 3,4ꢀdiethoxyꢀ3ꢀcyclobutaneꢀ1,2ꢀdione (0.44 mL, 3 mmol)
in DCM (12 mL) was added diamine 1 (0.41 mg, 3.15 mmol) in the same solvent (3
mL). The reaction mixture was stirred at room temperature until complete
disappearance of diethyl squarate as monitored by TLC (18 h). The reaction was
concentrated in vacuo and the residue was purified by flash chromatography
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(DCM/MeOH: 9:1) to afford 3: 623 mg (2.45 mmol, 82%). Colorless oil. [α]D
=
+26.4 (c = 1.2, CHCl3). 1HꢀNMR (500 MHz, CDCl3) δ 0.90 (d, 3H, J = 6.8 Hz); 0.92
(d, 3H, J = 7.0 Hz); 1.43 (t, 3H, J = 7.1 Hz); 187 (m, 1H); 2.20 (s, 6H); 2.27 (dd, 1H, J
= 12.9, 4.2 Hz); 2.49 (dd, 1H, J = 12.9, 9.9 Hz); 3.59 (m, 1H); 4.77 (q, 2H, J = 7.1
Hz); 6.73 (br s, 1H); 13CꢀNMR (126 MHz, CDCl3) δ 15.8, 17.1, 18.9, 31.4, 45.7, 58.6,
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61.1, 69.6, 172.8, 176.6, 182.6, 189.7. IR (ATR): 3481; 3224, 2943, 1802, 1702,
1591, 1426, 1341, 1138, 1026, 865, 827, 730 cmꢀ1; HRMS (ESIꢀQTOF) m/z: [M +
H]+ Calcd for C13H23N2O3 255.1703; Found 255.1704.
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(S)-3-((1-(Dimethylamino)-3,3-dimethylbutan-2-yl)amino)-4-ethoxy cyclobut-3-ene-
1,2-dione (4). This compound was obtained from diamine 2 (454 mg, 3.15 mmol) by
reaction with 3,4ꢀdiethoxyꢀ3ꢀcyclobutaneꢀ1,2ꢀdione (0.44 mL, 3 mmol, 0.95 equiv)
in DCM as described for 3 and purified by flash chromatography (DCM/MeOH: 9:1)
to afford 4: 761 mg (2.83 mmol, 94%). Colorless oil. [α]D23 = +18.9 (c = 1.1, CHCl3).
1HꢀNMR (500 MHz, CDCl3) δ 0.93 (s, 9H), 1.45 (t, J = 7.1 Hz, 3H), 2.19 (s, 6H),
2.34 (dd, J = 13.0, 2.9 Hz, 1H), 2.45 (m, 1H), 3.47 (m, 1H), 4.75 (q, J = 7.1 Hz, 2H),
6.23 (br s, 1H); 13CꢀNMR (126 MHz, CDCl3) δ 15.9, 26.2, 34.6, 45.6, 59.4, 62.3,
69.5, 173.1, 176.4, 182.4, 189.7; IR (ATR): 3231, 2962, 1802, 1699, 1595, 1422,
1337, 1107, 1037, 819, 727 cmꢀ1; HRMS (ESIꢀQTOF) m/z: [M + H]+ Calcd for
C14H25N2O3 269.1860; Found 269.1861.
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Preparation of resin 5. To a suspension of (aminomethyl)polystyrene (368 mg,
0.405 mmol) in anhydrous DCM (2.5 mL) was added a solution of 3 (206 mg, 0.81
mmol, 2 equiv) in DCM (2 mL) at 0 °C under nitrogen atmosphere. The resulting
suspension was stirred for 48h at room temperature. The resin was collected by
filtration, washed with DCM, and dried under vacuum to give 423 mg of polymer 5
(94% yield). IR (ATR): 3262, 3024, 2928, 1798, 1668, 1587, 1533, 1491, 1453, 1345,
1026, 757, 699 cmꢀ1. A 100% yield of functionalization was calculated on the basis of
nitrogen elemental analysis calcd. (%): N, 3.79. Found: C, 82.25; H, 7.40; N, 4.05; f
= 0.96 mmol gꢀ1.
Preparation of resin 6. This compound was obtained from (2ꢀaminoethyl)
polystyrene (340 mg, 0.35mmol) by reaction with 3 (181 mg, 0.7 mmol, 2 equiv) as
described for resin 5 to give 372 mg of polymer 6 (90% yield). IR (ATR): 3235, 2924,
1794, 1688, 1587, 1491, 1453, 1353, 1026, 757, 696 cmꢀ1. A 100% yield of
functionalization was calculated on the basis of nitrogen elemental analysis calcd.
(%): N, 3.62. Found: C, 83.12; H, 7.74; N, 3.60; f = 0.86 mmol gꢀ1.
Preparation of resin 7. This compound was obtained from (4ꢀaminobutyl)
polystyrene (378 mg, 0.38 mmol) by reaction with the squaric ester monoamide 3
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9
(194 mg, 0.76 mmol, 2 equiv) as described for resin 5 to give 265 mg of polymer 7
(60% yield). IR (ATR): 3250, 3028, 2920, 1791, 1688, 1587, 1533, 1495, 1452, 1361,
1030, 757, 696 cmꢀ1. A 100% yield of functionalization was calculated on the basis of
nitrogen elemental analysis calcd. (%): N, 3.51. Found: C, 82.14; H, 7.68; N, 3.95; f
= 0.94 mmol gꢀ1.
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Preparation of resin 8. This compound was obtained from (2ꢀaminoethyl)
polystyrene (438mg, 0.46 mmol) by reaction with the squaric ester monoamide 4 (246
mg, 0.92 mmol, 2 equiv) as described for resin 5 to give 436 mg of polymer 8 (81%
yield). IR (ATR): 3259, 3029, 2921, 1797, 1667, 1586, 1532, 1490, 1451, 1352; 1029,
757, 699 cmꢀ1. A 100% yield of functionalization was calculated on the basis of
nitrogen elemental analysis calcd. (%): N, 3.58. Found: C, 82.93; H, 7.59; N, 3.60; f
= 0.86 mmol gꢀ1.
(S)-3-(Benzylamino)-4-((1-(dimethylamino)-3-methylbutan-2-yl)amino) cyclobut-3-
ene-1,2-dione (9). To a solution of the squaric ester monoamide 3 (422 mg, 1.66
mmol, 1 equiv) in DCM (30 mL) was added benzylamine (0.2 mL, 1.83 mmol, 1.1
equiv), and the mixture was stirred at room temperature for 18 h. The white
precipitate was filtered and washed with DCM to afford essentially pure 9: 419 mg
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(1.33 mmol, 80%). Colorless solid, mp 237ꢀ240 ºC (decomp.). [α]D = + 41.6 (c =
0.5, DMSO). 1HꢀNMR (500 MHz, DMSOꢀd6) δ 0.80 (d, J = 6.8 Hz, 3H), 0.84 (d, J =
6.8 Hz, 3H), 1.78 (m, 1H), 2.11 (s, 6H), 2.19 (dd, J = 12.7, 4.6 Hz, 1H), 2.34 (m, 1H),
4.03 (m, 1H), 4.72 (br s, 2H), 7.18 (br s, 1H), 7.26ꢀ7.41 (m, 5H), 7.63 (br s, 1H); 13Cꢀ
NMR (126 MHz, DMSOꢀd6) δ 19.7, 31.1, 45.7, 47.3, 56.7, 61.9, 127.9, 128.1, 129.1,
139.3, 167.5, 168.7, 182.6; IR (ATR): 3193, 2970, 1798, 1649, 1556, 1449, 1349,
1034, 745, 696 cmꢀ1; HRMS (ESIꢀQTOF) m/z: [M + H]+ Calcd for C18H26N3O2
316.202; Found 316.2025.
(S)-3-(Benzylamino)-4-((1-(dimethylamino)-3,3-dimethylbutan-2-yl)amino) cyclobut-
3-ene-1,2-dione (10). This compound was obtained from the squaric ester monoamide
4 (169 mg, 0.63 mmol) by reaction with benzylamine (0.075 mL, 0.69 mmol, 1.1
equiv) as described for 9. The formed white precipitate was filtered and dried in
vacuo to give 10: 176 mg (0.535 mmol, 85%). Colorless solid, mp 248ꢀ250 ºC
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(decomp.). [α]D = +59.6 (c = 0.5, DMSO). HꢀNMR (500 MHz, DMSOꢀd6) δ 0.85
(s, 9H), 2.11 (s, 6H), 2.29 (m, 2H), 3.92 (m, 1H), 4.72 (m, 2H), 7.16ꢀ7.41 (m, 6H),
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7.57 (br s, 1H); CꢀNMR (126 MHz, DMSOꢀd6) δ 26.4, 34.6, 45.7, 47.3, 59.8, 60.1,
127.9, 128.2, 129.2, 139.3, 167.3, 168.9, 182.5, 182.7; IR (ATR): 3166, 2951, 2763,
1798, 1641, 1549, 1453, 1341, 1260, 1042, 746. 696 cmꢀ1; HRMS (ESIꢀQTOF) m/z:
[M + H]+ Calcd for C19H28N3O2 330.2176; Found 330.2179.
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General procedure for the catalytic nitro-Michael reaction. To a mixture of transꢀ
βꢀnitrostyrene (0.3 mmol) and the catalyst (0.015 mmol, 0.05 equiv), was added the
corresponding 1,3ꢀdicarbonyl compound (0.6 mmol, 2 equiv) and the reaction mixture
was stirred at rt in wheaton vial until consumption of the starting material (TLC). If
the used catalyst was homogeneous, the reaction mixture was directly purified by flash
chromatography to afford the Michael product. For the reactions catalyzed by
supported materials, the catalyst was filtered off and washed with DCM and MeOH.
After removal of the solvent under reduced pressure, the crude mixture was purified
by flash chromatography to afford the addition product. The diastereomeric ratio was
1
determined by HNMR spectroscopy of the purified product, and the enantiomeric
excess was determined by chiralꢀphase HPLC analysis using mixtures of
hexane/isopropanol as eluent. Racemic mixtures of the products were synthesized
according to the general procedure, but using 1,4ꢀdiazabicyclo[2.2.2]octane (DABCO)
(2 mg, 0.015 mmol) as catalyst.
Recyclability of the supported squaramide catalysts in Nitro Michael reaction.
After each cycle, the catalysts were recovered by filtration and washed with DCM and
MeOH. After being dried, the supported catalysts could be reused directly without
further purification.
(S)-3-(2-Nitro-1-phenylethyl)pentane-2,4-dione (15aa).19a Colorless solid (69 mg,
92% yield), mp 122ꢀ123 ºC. (Lit.19b mp 124ꢀ126 ºC); [α]D23 = +216.2 (c = 1.0, CHCl3,
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er >99:1). [Lit.19b [α]D = +196.7 (c = 1, CHCl3, er 94:6)]. 1H NMR (500 MHz,
CDCl3) δ 1.92 (s, 3H), 2.27 (s, 3H); 4.22 (m, 1H), 4.35 (d, J = 10.8 Hz, 1H), 4.62 (m,
2H), 7.15ꢀ7.17 (m, 2H), 7.22ꢀ7.35 (m, 3H); HPLC (Luxꢀamyloseꢀ1,
hexane/isopropanol 90:10, λ = 220 nm, 1.0 mL/min): tR = 12.9 min (major, S), 17.4
min (minor, R). (er > 99:1).
(S)-3-(1-(4-Chlorophenyl)-2-nitroethyl)pentane-2,4-dione (15ba).19a Colorless solid
(68 mg, 80% yield), mp 124ꢀ125 ºC. (Lit.20 mp 119ꢀ121 ºC); [α]D23 = +181.2 (c = 1.4,
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CHCl3, er >99:1). [Lit.20 [α]D = ꢀ132.5 (c = 1, CHCl3, er 6:94, (R)]. H NMR (500
MHz, CDCl3) δ 1.98 (s, 3H), 2.30 (s, 3H), 4.23 (ddd, J = 10.7, 7.6, 5.0 Hz, 1H), 4.33
(d, 1H, J = 10.7 Hz), 4.59 (dd, J = 12.5 Hz, 5.0 Hz, 1H), 4.62 (dd, J = 12.5, 7.6 Hz,
1H), 7.13 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H); HPLC (Luxꢀamyloseꢀ1,
hexano/isopropanol 80:20, λ = 210 nm, 1.0 mL/min): tR = 10.2 min (major, S), 24.8
min (minor, R). (er 97:3).
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(S)-3-(2-Nitro-1-(4-(trifluoromethyl)phenyl)ethyl)pentane-2,4-dione
Colorless solid (74 mg, 78% yield), mp 138ꢀ140 ºC. (Lit.20 mp 144ꢀ146 ºC). [α]D
(15ca).21
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=
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+117.2 (c = 1.2, CHCl3, er 99:1). (Lit.20 [α]D = ꢀ78.1 (c = 1.1, CHCl3, 91% ee, (R)).
1H NMR (500 MHz, CDCl3) δ 1.98 (s, 3H), 2.30 (s, 3H), 4.32 (m, 1H), 4.38 (d, 1H, J
= 10.6 Hz), 4.63 (dd, J = 12.9 Hz, 4.7 Hz, 1H), 4.67 (dd, J = 12.9, 8.0 Hz, 1H), 7.33 (d,
J = 8.1 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H); HPLC (Chiralcel OD, hexane/isopropanol
95:5, λ = 220 nm, 1.0 mL/min): tR = 40.6 min (major, S), 48.9 min (minor, R). (er
99:1).
(S)-3-(2-Nitro-1-(2-nitrophenyl)ethyl)pentane-2,4-dione (15da).22 Colorless solid (78
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mg, 88% yield), mp 104ꢀ105 ºC. (Lit.1 mp 112ꢀ114 ºC). [α]D = +84.3 (c = 1.4,
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CHCl3, er 99:1). (Lit.1 [α]D = ꢀ123.1 (c = 1, CHCl3, 97% ee, (R)). H NMR (500
MHz, CDCl3) δ 2.12 (s, 3H), 2.29 (s, 3H), 4.65 (d, J = 8.7 Hz, 1H), 4.73 (ddd, J = 8.7
Hz, 7.3 Hz, 3.7 Hz), 4.82 (dd, J = 13.3 Hz, 3.7 Hz, 1H), 4.95 (dd, J = 13.3 Hz, 7.2 Hz,
1H), 7.35 (dd, J = 7.9 Hz, 1.4 Hz, 1H), 7.46 (m, 1H), 7.58 (ddd, J = 15.3 Hz, 7.9 Hz,
1.4 Hz, 1H), 7.90 (dd, J = 8.1 Hz, 1.4 Hz, 1H); HPLC (Luxꢀamylose 1,
hexane/isopropanol 90:10, λ = 210 nm, 1.0 mL/min): tR = 20.7 min (major, S), 22.9
min (minor, R). (er 99:1).
(S)-3-(1-(4-Methoxyphenyl)-2-nitroethyl)pentane-2,4-dione (15ea).19a Colorless solid
(72 mg, 86% yield), mp 113ꢀ114 ºC. (Lit.20 mp 116ꢀ118 ºC). [α]D23 = +156.3 (c = 0.3,
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CHCl3, er 98:2). (Lit.20 [α]D = ꢀ137.1 (c = 1.1, CHCl3, 88%ee, (R)). H NMR (500
MHz, CDCl3) δ 1.94 (s, 3H), 2.29 (s, 3H), 3.77 (s, 3H), 4.19 (ddd, J = 10.9, 7.4, 5.3
Hz, 1H), 4.33 (d, J = 10.9 Hz, 1H), 4.59 (m, 2H), 6.84 (d, J = 8.7 Hz, 2H), 7.10 (d, J =
8.7 Hz, 2H); HPLC (Luxꢀamyloseꢀ1, hexane/isopropanol 80:20, λ = 210 nm, 1.0
mL/min): tR = 14.9 min (major, S), 27.8 min (minor, R). (er 99:1).
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(S)-3-(1-Naphthalen-1-yl-2-nitro-ethyl)-pentane-2,4-dione (15fa).23 Colorless oil (81
mg, 90% yield). [α]D = +190.3 (c = 1.2, CHCl3, er 99:1). (Lit.20 [α]D = ꢀ182.0 (c =
1.1, CHCl3, 95% ee, (R)) .1H NMR (500 MHz, CDCl3) δ 1.87 (s, 3H), 2.33 (s, 3H),
4.71 (d, J = 10.5 Hz, 1H), 4.73 (dd, J = 12.2, 4.8 Hz, 1H), 4.82 (dd, J = 12.2, 6.5 Hz,
1H), 5.21 (m, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H); 7.55 (t, J = 7.5
Hz, 1H), 7.64 (m, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 8.18 (d, J =
8.6 Hz, 1H); HPLC (Chiralpak ASꢀH, hexane/isopropanol 80:20, λ = 210nm, 0.8
mL/min): tR = 13.9 min (major, S), 17.1 min (minor, R). (er 99:1).
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(S)-3-(1-Naphthalen-2-yl-2-nitro-ethyl)-pentane-2,4-dione (15ga).19a Colorless solid
(75 mg, 83% yield), mp 138ꢀ140 ºC. [α]D23 = +98.0 (c = 0.9, CHCl3, er 95:5).1H NMR
(500 MHz, CDCl3) δ 1.95 (s, 3H), 2.32 (s, 3H), 4.42 (ddd, J = 10.7, 8.1, 4.4 Hz, 1H),
4.50 (d, J = 10.7 Hz, 1H), 4.69 (dd, J = 12.5, 4.4 Hz, 1H), 4.75 (dd, J = 12.4, 8.1 Hz,
1H), 7.30 (dd, J = 8.5, 1.9 Hz, 1H), 7.49 (m, 2H), 7.65 (m, 1H), 7.80 (m, 2H), 7.83 (d,
J = 8.5 Hz, 1H); HPLC (Luxꢀamyloseꢀ1, hexane/isopropanol 90:10, λ = 210 nm, 1.0
mL/min): tR = 18.3 min (major, S), 23.4 min (minor, R). (er 95:5).
(R)-3-(1-(Furan-2-yl)-2-nitroethyl)pentane-2,4-dione (15ha).1 Colorless solid (60 mg,
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84% yield), mp 100ꢀ102 ºC. (Lit.1 mp 94ꢀ95 ºC). [α]D = +148.7 (c = 1.0, CHCl3, er
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97:3). (Lit.1 [α]D = ꢀ162.4 (c = 1, CHCl3, 97% ee, (S)). H NMR (500 MHz, CDCl3)
δ 2.05 (s, 3H), 2.23 (s, 3H), 4.31 (m, 1H), 4.36 (d, 1H, J = 9.7 Hz), 4.64 (m, 2H), 6.14
(d, J = 3.3 Hz, 1H), 7.26 (dd, J = 3.3, 1.9 Hz, 1H), 7.32 (dd, J = 1.9, 0.7 Hz, 1H);
HPLC (Luxꢀamyloseꢀ1, hexano/isopropanol 90:10, λ = 220 nm, 1.0 mL/min): tR =
13.2 min (major, R), 15.6 min (minor, R). (er 96:4).
(S)-2-(2-Nitro-1-phenylethyl)-1,3-diphenylpropane-1,3-dione (15ab).19a Colorless
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solid (92 mg, 82% yield), mp 144ꢀ146 ºC. [α]D = +16.1 (c = 1.6, CH2Cl2, er 91:9).
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[Lit.24 [α]D = +21.3 (c = 1, CH2Cl2, er 99:1)]. HꢀNMR (500 MHz, CDCl3,) δ 4.63
(m, 1H), 4.99 (d, J = 6.8 Hz, 2H), 5.83 (d, J = 7.9 Hz, 1H), 7.16ꢀ7.24 (m, 5H), 7.34ꢀ
7.41 (m, 4H), 7.49ꢀ7.56 (m, 2H), 7.77ꢀ7.79 (m, 2H), 7.85ꢀ7.87 (m, 2H); HPLC (Luxꢀ
amyloseꢀ1, hexane/isopropanol 75:25, λ = 210 nm, 1.0 mL/min): tR = 11.1 min (major,
S), 27.4 min (minor, R). (er 94:6).
(S)-2-((S)-2-Nitro-1-phenylethyl)-1-phenylbutane-1,3-dione (15ac).5,25 Colorless solid
1
(80 mg, 86% yield as a mixture 60:40 of diastereoisomers). HꢀNMR (500 MHz,
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CDCl3, major diast.): δ 1.93 (s, 3H), 4.53 (ddd, J = 10.0, 8.6, 4.6 Hz, 1H), 4.67 (dd, J
= 12.6, 8.5 Hz, 1H), 4.72 (dd, J = 12.6, 4.6 Hz, 1H), 5.17 (d, J = 10.1 Hz, 1H), 7.25ꢀ
7.35 (m, 5H), 7.51 (m, 2H), 7.64 (m, 1H), 8.03 (m, 2H); 1HꢀNMR (500 MHz, CDCl3,
minor diast.): δ 2.22 (s, 3H), 4.43 (ddd, J = 10.1, 8.6, 4.3 Hz, 1H), 4.76 (dd, J = 12.8,
4.3 Hz, 1H), 4.85 (dd, J = 12.8, 8.6 Hz, 1H), 5.19 (d, J = 10.2 Hz, 1H), 7.13ꢀ7.21 (m,
5H), 7.43 (m, 2H), 7.57 (m, 1H), 7.81 (m, 2H); HPLC (Luxꢀamyloseꢀ1,
hexane/isopropanol 97:3, λ = 210 nm, 1.0 mL/min): tR (major diast.) = 34.6 min
(major, S,S), 49.4 min (minor, R,R). (er 96:4). tR (minor diast.) = 31.1 min (major,
R,S), 44.0 min (minor, S,R). (er 95:5).
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3-((S)-2-Nitro-1-phenylethyl)-2,4-dioxopentanedinitrile (15ad).26a Yellow oil (30 mg,
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47% yield). [α]D = ꢀ1.5 (c = 0.7, CHCl3, er 60:40). [Lit.26b [α]D = + 5.4 (c = 0.5,
1
CHCl3, er 90:10, (R)]. HꢀNMR (500 MHz, CDCl3,): δ 4.08 (m, 1H), 4.44 (d, J = 5.9
Hz, 1H), 4.92 (dd, J = 14.3, 6.0 Hz, H), 4.99 (dd, J = 14.3, 8.1 Hz, 1H), 7.34ꢀ7.38 (m,
2H), 7.46ꢀ7.50 (m, 3H); HPLC (Chiralcel OD, hexane/isopropanol 50:50, λ = 210 nm,
1.0 mL/min): tR (minor, R) =11.3 min, 42.6 min (major, S). (er 52:48).
Diethyl (S)-2-(2-Nitro-1-phenylethyl)malonate (15ae).19b Colorless solid (35 mg, 38%
23
yield), mp 42ꢀ43 ºC, (Lit.19b mp 41ꢀ42 ºC). [α]D = +4.8 (c = 1.0, CHCl3, er 83:17).
23
1
(Lit.19b [α]D = +6.8 (c = 1.0, CHCl3, 95% ee)). HꢀNMR (500 MHz, CDCl3): δ 1.03
(t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H), 3.80 (d, J = 9.4 Hz, 1H), 3.99 (q, J = 7.1
Hz, 2H), 4.22 (m, 3H), 4.84 (dd, J = 13.0, 9.0 Hz, 1H), 4.91 (dd, J = 13.0, 5.0 Hz, 1H),
7.20ꢀ7.32 (m, 5H); HPLC (Luxꢀamyloseꢀ1, hexane/isopropanol 80:20, λ = 220 nm, 1.0
mL/min): tR = 10.8 min (minor, R), 30.4 min (major, S). (er 83:17).
Dimethyl 2-Chloro-2-((S)-2-nitro-1-phenylethyl)malonate (15af).13 Colorless solid (71
23
mg, 75% yield), mp 172ꢀ174 ºC. [α]D = +1.6 (c = 1.0, CHCl3, er 65:35). (Lit.13
[α]D23 = +4.6 (c = 0.9, CHCl3, er > 99:1)). 1HꢀNMR (500 MHz, CDCl3) δ 3.60 (s, 3H),
3.85 (s, 3H), 4.64 (dd, J = 10.4, 3.4 Hz, 1H), 5.00 (dd, J = 13.6, 10.4 Hz, 1H), 5.22
((dd, J = 13.6, 3.4 Hz, 1H), 7.30ꢀ7.38 (m, 5H); HPLC (Chiralcel OD,
hexane/isopropanol 90:10, λ = 220 nm, 1.0 mL/min): tR (major, S) = 10.3 min, 18.1
min (minor, R). (er 65:35).
(2S,3S)-Ethyl 2-Acetyl-4-nitro-3-phenylbutanoate (15ag).19 Colorless solid (65 mg,
1
78% yield). HꢀNMR (500 MHz, CDCl3) δ 0.98 (t, J = 7.1 Hz, 1.8H), 1.25 (t, J = 7.1
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Hz, 1.2H), 2.03 (s, 1.2H), 2.28 (s, 1.8H), 3.94 (q, J = 7.1 Hz, 1.2H), 4.02 (d, J = 9.7
Hz, 0.4H), 4.10 (d, J = 10.0 Hz, 0.6H), 4.22 (m, 1.8H) 4.73 (m, 1.2H), 4.78 (dd, J =
12.9 Hz, J = 8.9 Hz, 0.4H), 4.83 (dd, J = 12.9 Hz, J = 4.9 Hz, 0.4H), 7.17ꢀ7.19 (m,
2H), 7.24ꢀ7.30 (m, 3H); HPLC (Luxꢀamyloseꢀ1, hexane/isopropanol 95:5, λ = 220 nm,
1.0 mL/min): tR (major diast.) = 27.1 min (major, 2S,3S), 39.4 min (minor, 2R,3R). (er
96:4). tR (minor diast.) = 41.5 min (minor, 2S,3R), 68.6 min (major, 2R,3S). (er 94:6).
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(R)-3-Methyl-3-(2-nitro-1-phenylethyl)pentane-2,4-dione (15ah).11b Colorless oil (70
mg, 89% yield). [α]D23 = +32.5 (c = 1.0, CHCl3, er 99:1). (Lit.11b [α]D23 = +29.0 (c = 1,
1
CHCl3, er 93:7)). HꢀNMR (500 MHz, CDCl3,) δ 1.39 (s, 3H), 2.00 (s, 3H), 2.06 (s,
3H), 4.19 (dd, J = 11.0, 3.6 Hz, 1H), 4.75 (dd, J = 13.4, 3.6 Hz, 1H), 4.85 (dd, J =
13.4, 11.0 Hz, 1H), 7.14ꢀ7.16 (m, 2H), 7.24ꢀ7.30 (m, 3H); HPLC (Luxꢀamyloseꢀ1,
hexane/isopropanol 95:5, λ = 210 nm, 1.0 mL/min): tR = 17.1 min (minor, S), 20.1 min
(major, R). (er 99:1).
(2R,3R)-Ethyl 2-Acetyl-2-methyl-4-nitro-3-phenylbutanoate (15ai).27 Colorless solid
1
(65 mg, 74% yield). HꢀNMR (500 MHz, CDCl3, major diast.) δ 1.18 (t, J = 7.2 Hz,
1.8H), 1.22 (s, 1.2H), 1.29 (t, J = 7.1 Hz, 1.2H), 1.42 (s, 1.8H), 2.10 (s, 1.8H), 2.15 (s,
1.2H), 3.98–4.15 (m, 1.6H), 4.22 (m, 0.6H), 4.26 (q, J = 7.1 Hz, 0.8H), 4.86–4.98 (m,
2H), 7.11–7.13 (m, 0.8H), 7.19–7.22 (m, 1.2H), 7.25–7.30 (m, 3H); HPLC (Chiralcel
OD, nꢀhexane/2ꢀpropanol = 98/2, 1 mL/min, λ = 220 nm): tR (major diastereoisomer)
= 16.1 min (major, 2R,3R), 24.6 min (minor, 2S,3S); tR (minor diastereoisomer) = 14.3
min (major, 2S,3R), 34.5 min (minor, 2R,3S).
(S)-Ethyl
1-((R)-2-Nitro-1-phenylethyl)-2-oxocyclopentanecarboxylate
(17aa).27
23
Colorless oil (78 mg, 85% yield). [α]D = +32.8 (c = 1.0, CHCl3, er >99:1). (Lit.27
[α]D23 = +30.8 (c = 1, CHCl3, er 96:4)). 1H NMR (500 MHz, CDCl3) δ 1.27 (t, J = 7.2
Hz, 3H), 1.81ꢀ2.06 (m, 4H), 2.36 (m, 2H), 4.07 (dd, J = 10.9, 3.8 Hz, 1H), 4.21 (m,
2H), 5.01 (dd, J = 13.6, 11.0 Hz, 1H), 5.17 (dd, J = 13.6, 3.8 Hz, 1H), 7.25ꢀ7.32 (m,
5H); HPLC (Chiralcel OD, hexane/isopropanol 80:20, λ = 220 nm, 1.0 mL/min,): tR
(major diast.) = 8.1 min (major, S,R), 11.1 min (minor, R,S). (er > 99:1).
(S)-Ethyl
1-((R)-2-Nitro-1-phenylethyl)-2-oxocyclohexanecarboxylate
(17ab).27
Colorless solid (79 mg, 82% yield). mp 101ꢀ103 ºC. [α]D23 = ꢀ88.2 (c = 1.0, CHCl3, er
23
1
98:2). (Lit.27 [α]D = ꢀ86.5 (c = 1, CHCl3, er 97:3)). H NMR (500 MHz, CDCl3) δ
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1.24 (t, J = 7.1 Hz, 3H), 1.42ꢀ1.73 (m, 4H), 2.05 (m, 2H), 2.45 (m, 2H), 3.98 (dd, J =
11.2, 3.2 Hz, 1H), 4.19 (m, 2H), 4.78 (dd, J = 13.4, 11.2 Hz, 1H), 5.04 (dd, J = 13.4,
3.2 Hz, 1H), 7.13 (m, 2H), 7.25 (m, 3H); HPLC (Chiralcel OD, hexane/isopropanol
95:5, λ = 220 nm, 1.0 mL/min): tR (major diast.) = 10.5 min (major, S,R), 14.9 min
(minor, R,S). (er 98:2).
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(S)-Methyl 1-((R)-2-Nitro-1-phenylethyl)-2-oxocycloheptanecarboxylate (17ac).27
23
1
Colorless oil (98 mg, 98% yield). [α]D = ꢀ27.3 (c = 0.8, CHCl3, er >99:1). HꢀNMR
(500 MHz, CDCl3,): δ 1.42 (m, 1H); 1.52ꢀ1.61 (m, 4H), 1.67 (m, 1H); 1.76 (m, 1H);
1.90 (m, 1H); 2.51 (m, 1H), 2.61 (m, 1H), 3.77 (s, 3H), 4.06 (dd, J = 10.1, 4.1 Hz, 1H),
4.92 (dd, J = 13.6, 10.1 Hz, 1H), 4.96 (dd, J = 13.6, 4.1 Hz, 1H), 7.13ꢀ7.16 (m, 2H),
7.27ꢀ7.32 (m, 3H); HPLC (Chiralcel OD, hexane/isopropanol 95:5, λ = 220 nm, 1.0
mL/min): tR (major diast.) = 12.9 min (major, S,R). (er 100:0).
(R)-2-Acetyl-2-((R)-2-nitro-1-phenylethyl)cyclopentanone (17ad).27 Colorless solid (78
1
mg, 94% yield, as a mixture of anti/syn (81: 19) diastereoisomers). HꢀNMR (500
MHz, CDCl3, major diast.): δ 1.68ꢀ1.76 (m, 3H), 1.97 (m, 1H), 2.19 (m, 1H), 2.33 (s,
3H), 2.57 (m, 1H), 4.39 (dd, J = 11.5, 3.9 Hz, 1H), 4.51 (dd, J = 13.5, 3.9 Hz, 1H),
4.86 (dd, J = 13.5, 11.5 Hz, 1H), 7.24ꢀ7.33 (m, 5H); HPLC (Chiralcel OD,
hexane/isopropanol 70:30, λ = 220 nm, 1.0 mL/min): tR (major diast.) = 10.6 min
(major, R,R), 43.4 min (minor, S,S). (er 100:0). tR (minor diast.) = 12.6 min (major,
S,R), 18.6 min (minor, R,S). (er 100:0).
(R)-3-Acetyl-dihydro-3-((R)-2-nitro-1-phenylethyl)furan-2(3H)-one (17ae).27 Colorless
1
solid (66 mg, 80% yield, as a mixture of anti/syn (56: 44) diastereoisomers). HꢀNMR
(500 MHz, CDCl3, major diast.): δ 2.25ꢀ2.35 (m, 1H) 2.49 (s, 3H), 2.84 (m, 1H), 3.85
(td, J = 8.9, 4.2 Hz, 1H), 4.03 (dt, J = 8.9, 7.8 Hz, 1H), 4.49ꢀ4.56 (m, 2H), 4.85 (dd, J
= 13.1, 10.9 Hz, 1H), 7.33ꢀ7.37 (m, 5H); 1HꢀNMR (500 MHz, CDCl3, minor diast.): δ
2.22ꢀ2.31 (m, 1H), 2.34 (s, 3H), 2.57 (m, 1H), 3.85 (td, J = 8.9, 4.2 Hz, 1H), 4.09 (td,
J = 8.9, 5.6 Hz, 1H), 4.34 (dd, J = 11.2, 3.6 Hz, 1H), 4.74 (m, J = 13.4, 3.6 Hz, 1H),
5.06 (dd, J = 13.4, 11.2 Hz, 1H), 7.28ꢀ7.32 (m, 2H), 7.33ꢀ7.39 (m, 3H); HPLC
(Chiralcel OD, hexane/isopropanol 70:30, λ = 220 nm, 1.0 mL/min): tR (major diast.)
= 10.6 min (major, R,R). (er 100:0). tR (minor diast.) = 12.8 min (major, S,R), 20.9 min
(minor, R,S). (er 97:3).
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General procedure for One-Pot synthesis of 19 and 23. To a mixture of (E)ꢀ2ꢀ(2ꢀ
nitrovinyl)phenol (0.3 mmol) and catalyst (0.015 mmol, 0.05 equiv), 1,3ꢀdicarbonyl
compound (0.6 mmol, 2 equiv) was added and the reaction mixture was stirred at rt in
wheaton vial until consumption of the starting material (TLC). In the reactions
catalyzed by homogeneous catalyst 10, toluene (5 mL per mmol) and PTSA
monohydrate (20 mol%) were added, and the mixture was heated for 2h at 100 oC. The
solution was cooled to rt, the solvent eliminated under vacuum, and the residue was
purified by flash chromatography to afford the product. The same experimental
procedure was followed for the reactions catalyzed by supported squaramide 8, except
that the catalyst was separated by filtration before treatment with Toluene/PTSA. The
enantiomeric excess was determined by chiralꢀphase HPLC analysis using mixtures of
hexane/isopropanol as eluent.
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(S)-1-(2-Methyl-4-(nitromethyl)-4H-chromen-3-yl)ethan-1-one
(19ia).
This
compound was purified by column chromatography on silica gel (eluent:
hexane/EtOAc 8/1): 69 mg (93% yield). Colorless oil. [α]D23 = ꢀ23.7 (c = 0.5, CHCl3)
(er 99:1). 1HꢀNMR (500 MHz, CDCl3) δ 2.46 (s, 3H), 2.47 (s, 3H), 4.37 (dd, J = 11.6,
8.0 Hz, 1H), 4.49 (dd, J = 11.6, 4.2 Hz, 1H), 4.65 (dd, J = 8.0, 4.2 Hz, 1H), 7.06 (d, J
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= 8.1Hz, 1H), 7.09ꢀ7.15 (m, 1H), 7.18 (dd, J = 7.6, 1.8 Hz), 7.24ꢀ7.32 (m, 1H); Cꢀ
NMR (126 MHz, CDCl3) δ 20.9, 30.9, 35.1, 80.2, 111.4, 116.3, 120.6, 125.2, 128.1,
128.9, 150.5, 163.7, 196.7; IR (ATR): 2919, 1680, 1629, 1582, 1543, 1487, 1460,
1377, 1357, 1227, 1188, 943, 758 cmꢀ1; HRMS (ESIꢀQTOF) m/z: [M + H]+ Calcd for
C13H14NO4 248.0917; Found 248.0921; HPLC (Chiralcel OD, hexane/isopropanol
90:10, λ = 254 nm, 1.0 mL/min): tR =14.2 min (major, S), 18.0 min (minor, R).
(S)-1-(2-Ethyl-4-(Nitromethyl)-4H-chromen-3-yl)propan-1-one (19ij). This compound
was purified by column chromatography on silica gel (eluent: hexane/EtOAc 15/1): 69
mg (84% yield). Colorless oil. [α]D23 = ꢀ36.6 (c = 1.2, CHCl3) (er 99:1). 1HꢀNMR (500
MHz, CDCl3) δ 1.16 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.5 Hz, 3H); 2.74 (m, 4H), 4.31
(dd, J = 11.7, 8.5 Hz, 1H), 4.48 (dd, J = 11.7, 4.4 Hz, 1H), 4.63 (dd, J = 8.5, 4.4 Hz,
1H), 7.05ꢀ7.10 (m, 1H), 7.12 (dd, J = 7.4, 1.0 Hz, 1H), 7.16 (dd, J = 7.6, 1.7 Hz, 1H),
7.24ꢀ7.32 (m, 1H); 13CꢀNMR (126 MHz, CDCl3) δ 8.7, 11.7, 26.6, 35.0, 35.5, 80.2,
110.1, 116.2, 120.8, 125.0, 128.0, 128.9, 150.8, 166.9, 200.3; IR (ATR): 2978, 2935,
1684, 1629, 1582, 1546, 1487, 1460, 1377, 1361, 1227, 1188, 919, 758 cmꢀ1; HRMS
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(ESIꢀQTOF) m/z: [M + H]+ Calcd for C15H18NO4 276.1230; Found 276.1233; HPLC
(Chiralcel OD, hexane/isopropanol: 98:2, λ = 254 nm, 1 mL/min): tR = 11.0 min
(major, S), 24.5 min (minor, R).
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(S)-Methyl 2-Methyl-4-(nitromethyl)-4H-chromene-3-carboxylate (19ik).16b This
compound was purified by column chromatography on silica gel (eluent:
hexane/EtOAc 8/1): 57 mg (72% yield). Colorless solid. mp 91ꢀ92 ºC. (Lit.16b mp 93
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ºC). [α]D = ꢀ64.0 (c = 0.5, CHCl3). (er >99:<1). [Lit.16b [α]D = +88.4 (c = 1.0,
CHCl3, 98% ee) for (R) enantiomer]. 1HꢀNMR (500 MHz, CDCl3) δ 2.47 (s, 3H), 3.82
(s, 3H), 4.41 (dd, J = 11.6, 7.8 Hz, 1H), 4.56 (dd, J = 11.6, 4.4 Hz, 1H), 4.65 (dd, J =
7.8, 4.4 Hz, 1H), 7.04 (dd, J = 8.2, 1.2 Hz, 1H), 7.12 (td, J = 7.4, 1.2 Hz, 1H), 7.17 (dd,
J = 7.7, 1.9 Hz, 1H), 7.24ꢀ7.32 (m, 1H); HPLC (Chiralpak IA, hexane/isopropanol
95:5, λ = 254 nm, 0.5 mL/min): tR = 16.1 min (major, S), 16.8 min (minor, R).
(S)-1-(6-Bromo-2-methyl-4-(nitromethyl)-4H-chromen-3-yl)ethanone (19ja). This
compound was purified by column chromatography on silica gel (eluent:
hexane/EtOAc 4/1): 80 mg (82% yield). Colorless oil. [α]D23 = +53.4 (c = 0.8, CHCl3)
(er 99:1). 1HꢀNMR (500 MHz, CDCl3) δ 2.44 (s, 3H), 2.45 (s, 3H), 4.40 (dd, J = 12.0,
7.4 Hz, 1H), 4.46 (dd, J = 12.0, 4.2 Hz, 1H), 4.58 (dd, J = 7.4, 4.2 Hz, 1H), 6.93 (d, J =
8.6 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.37 (dd, J = 8.6, 2.4 Hz); 13CꢀNMR (126 MHz,
CDCl3) δ 20.9, 31.0, 34.8, 79.9, 111.2, 117.5, 118.1, 122.8, 130.7, 132.0, 149.7, 163.5,
196.5; IR (ATR): 2923, 1680, 1625, 1546, 1479, 1377, 1231, 1184, 817, 730 cmꢀ1;
HRMS (ESIꢀQTOF) m/z: [M + Na]+ Calcd for C13H12BrNO4Na 347.9842; Found
347.9856; HPLC (Chiralcel OD, hexane/isopropanol 90:10, λ = 254 nm, 1.0 mL/min):
tR = 18.7 min (major, S), 22.6 min (minor, R).
(S)-1-(2,6-Dimethyl-4-(nitromethyl)-4H-chromen-3-yl)ethanone
(19ka).
This
compound was purified by column chromatography on silica gel (eluent:
hexane/EtOAc 4/1): 60 mg (77% yield). Colorless oil. [α]D23 = +14.0 (c = 0.8, CHCl3)
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(er >99:<1). HꢀNMR (500 MHz, CDCl3): δ 2.15 (s, 3H), 2.44 (s, 3H), 2.45 (s, 3H),
4.40 (dd, J = 12.0, 7.5 Hz, 1H), 4.46 (dd, J = 12.0, 4.2 Hz, 1H), 4.58 (dd, J = 7.5, 4.2
Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H); 7.32 (d, J = 2.3 Hz, 1H), 7.37 (dd, J = 8.6, 2.3 Hz,
13
1H); CꢀNMR (126 MHz, CDCl3) δ 20.8, 21.0, 30.9, 35.2, 80.2, 111.2, 116.0, 120.3,
128.2, 129.6, 134.9, 148.5, 164.0, 196.8; IR (ATR): 2923, 1685, 1625, 1546, 1499,
1424, 1377, 1254, 1211, 947, 817, 734, 671 cmꢀ1; HRMS (ESIꢀQTOF) m/z: [M + H]+
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Calcd for C14H16NO4
262.1074; Found 262.1076; HPLC (Chiralcel OD,
hexane/isopropanol 90:10, λ = 254 nm, 1.0 mL/min): tR = 11.1 min (major, S), 14.9
min (minor, R).
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(R)-2-(1-Nitro-4-oxopentan-2-yl)phenyl benzoate (20ib).17a To a mixture of (E)ꢀ2ꢀ(2ꢀ
nitrovinyl)phenol (50 mg, 0.3 mmol), and catalyst 10 (5 mg, 0.015 mmol, 0.05 equiv),
was added a solution of dibenzoylmethane (135 mg, 0.6 mmol, 2 equiv) in DCM (0.4
mL), and the reaction mixture was stirred at rt in a wheaton vial until consumption of
the starting material (TLC). The crude reaction mixture was purified by flash
chromatography (hexane/ethyl acetate 4/1) to yield 20ib (93 mg, 80% yield). Colorless
oil. [α]D23 = +7.0 (c = 0.9, CHCl3) (er 93:7). 1HꢀNMR (500 MHz, CDCl3) δ 3.41 (dd, J
= 17.6, 7.9 Hz, 1H), 3.49 (dd, J = 17.6, 6.0 Hz, 1H), 4.47 (m, 1H), 4.76 (dd, J = 12.7,
7.4 Hz, 1H), 4.81 (dd, J = 12.7, 6.9 Hz, 1H), 7.24 (m, 2H), 7.37 (m, 3H), 7.52 (m, 2H),
7.65 (m, 1H), 7.85 (d, J = 7.8 Hz, 2H), 8.22 (d, J = 7.7 Hz, 2H); HPLC (Luxꢀamyloseꢀ
1, hexane/isopropanol 90:10, λ = 220 nm, 1.0 mL/min): tR = 25.2 min (major, S), 26.8
min (minor, R).
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(1'S,4R)-4-(Nitromethyl)spiro[chroman-3,1'-cyclopentane]-2,2'-dione (23if).16a This
compound was purified by column chromatography on silica gel (eluent:
hexane/EtOAc 4/1): 58 mg (70% yield). Colorless solid. mp 157ꢀ159 ºC. (Lit.16a mp
23
23
159 ºC). [α]D = ꢀ36.0 (c = 0.4, CHCl3) (er >99:<1). [Lit.16a [α]D = ꢀ42.4 (c = 1.0,
CHCl3, 99% ee) for (1'S,4R) stereoisomer]. 1HꢀNMR (500 MHz, CDCl3) δ 1.93ꢀ2.10
(m, 3H), 2.18 (m, 1H), 2.47 (m, 1H), 2.68 (m, 1H), 3.78 (dd, J = 10.1, 5.0 Hz, 1H),
4.40 (dd, J = 13.5, 10.1 Hz, 1H), 5.54 (dd, J = 13.5, 5.0 Hz, 1H), 7.00ꢀ7.20 (m, 3H),
7.38 (ddd, J = 8.2, 7.0, 2.0 Hz, 1H); HPLC (Chiralcel OD, hexane/isopropanol 90:10,
λ = 220 nm, 1 mL/min): tR = 35.2 min (major), 46.2 min (minor).
Methyl (9R,9aS)-9-(Nitromethyl)-1,2,9,9a-tetrahydrocyclopenta [b]chromene-9a-
carboxylate (24if).16a To a mixture of (E)ꢀ2ꢀ(2ꢀnitrovinyl)phenol (50 mg, 0.3 mmol)
and catalyst 10 (5 mg, 0.015 mmol, 0.05 equiv), was added methyl 2ꢀ
oxocyclopentanecarboxylate (0.075 mL, 0.6 mmol, 2 equiv) and the reaction mixture
was stirred at rt in a wheaton vial and monitored by TLC. After complete conversion
of the starting material, DCM (1.8 mL) and P2O5 (128 mg, 0.9 mmol, 3 equiv) were
added and stirred for 2d at ꢀ20 ºC. The crude reaction mixture was then filtered
through a small pad of silica gel and purified by flash chromatography (DCM/pentane:
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