Recyclable C2-symmetric tertiary amine-squaramide organocatalysts: Design and application to asymmetric synthesis of γ-nitrocarbonyl compounds

Article abstract of DOI:10.1016/j.tet.2018.07.043

Simple C₂-symmetric chiral tertiary amines bearing squaramide fragments along with the 1,2-di(pyridin-2-yl)ethane spacer group have been synthesized. Among them, amine 8b with a different configuration of stereocenters in 1,2-di(pyridin-2-yl)et

Full text of DOI:10.1016/j.tet.2018.07.043

Accepted Manuscript
Recyclable C -symmetric tertiary amine-squaramide organocatalysts: Design and
2
application to asymmetric synthesis of γ-nitrocarbonyl compounds
Alexey A. Kostenko, Alexander S. Kucherenko, Sergei G. Zlotin
PII:
S0040-4020(18)30887-1
10.1016/j.tet.2018.07.043
TET 29703
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 June 2018
Revised Date: 18 July 2018
Accepted Date: 20 July 2018
Please cite this article as: Kostenko AA, Kucherenko AS, Zlotin SG, Recyclable C -symmetric tertiary
2
amine-squaramide organocatalysts: Design and application to asymmetric synthesis of γ-nitrocarbonyl
compounds, Tetrahedron (2018), doi: 10.1016/j.tet.2018.07.043.
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ACCEPTED MANUSCRIPT

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Recyclable C2-Symmetric Tertiary Amine-Squaramide Organocatalysts:
Design and Application to Asymmetric Synthesis of -Nitrocarbonyl
Compound
γ
s
Alexey A. Kostenko, Alexander S. Kucherenko*, and Sergei G. Zlotin*
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky
Prospect, 119991, Moscow, Russian Federation. Corresponding author: zlotin@ioc.ac.ru
Abstract
Simple C2-symmetric chiral tertiary amines bearing squaramide fragments along with the 1,2-
di(pyridin-2-yl)ethane spacer group have been synthesized. Among them, amine 8b with a
different configuration of stereocenters in 1,2-di(pyridin-2-yl)ethane and 1,2-
diaminocyclohexane units efficiently catalyzed asymmetric additions of β-dicarbonyl
compounds to nitroolefins and domino reaction of ortho-(tosylamino)chalcone with β-
nitrostyrene in wet (20 equiv. of H2O) DCM, affording corresponding adducts in up to 99% yield
and 94% ee. The developed procedure is scalable. Due to poor solubility in organic solvents and
water, the catalyst could be readily separated from the reaction mixture and over 10 times reused
in the reaction without compromising enantiomeric enrichment and yield of product.
Keywords: Organocatalysis, C2-Symmetric organocatalysts, Squaramides, Asymmetric Michael
reaction
1. Introduction
Asymmetric organocatalysis is a rapidly growing area of current organic chemistry.1 A powerful
impetus to amazing progress in this research area was the discovery of primary and secondary
chiral amines’ (first of all, proline and its derivatives) ability to catalyze enantioselectively
intermolecular aldol2 and Diels-Alder3 reactions of carbonyl compounds via stereospecific
formation of enamines or iminium ions. The covalent catalysis remains nowadays an efficient
tool for the asymmetric synthesis of natural compounds and their analogs.4 However, over the
recent years, mainstream researches have shifted towards catalytic processes based on non-
covalent interactions between a chiral catalyst and reagents, first of all, H-bonding interactions. 5
Commonly, corresponding catalysts contain H-bond donor and H-bond acceptor structural
fragments (modules) which accurately locate substrates in space (multicenter bonding) and
thereby provide excellent stereoselectivity of catalytic reactions. As a rule, the thiourea group,6
squaramide5b,7 or other acylamide units8 are used as H-bond donor fragments. Tertiary amino
groups are the most popular H-bond acceptor modules. Squaramide-derived catalysts are
commonly more available and chemically stable than corresponding thioureas.6d Furthermore,
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squaramides often allow faster reactions and higher catalyst turnovers due to their rigidity,
increased H-bond length and canted H-bond angle.5f
A majority of squaramide-based organocatalysts have C1-symmetry. To the best of our
knowledge, examples of C2-symmetric aminocatalysts that contain two H-donating squaramide
fragments capable of establishing an extended system of hydrogen bonds are limited to recently
prepared compounds I–III (Scheme 1). The presence of hardly available calix-4-arene or 3,3’-
bis(aminomethyl)BINOL units significantly complicates preparation of compounds I9 and II.10
Furthermore, significant lipophilicity made recycling of these catalysts after catalytic reactions
hardly possible. Convenient syntheses of (R,R)- and (S,S)-1,2-di(pyridinyl)ethane-1,2-diamines
(DPEDA pyridine analogs)11 recently developed by our team allowed facile preparation of
compound III12 in which those structural fragments acted as a linker between two (pyrrolidin-2-
yl)methyl squaramide groups. Readily available compound III in combination with TFA (0.5
equiv.) exhibited excellent activity and stereoinduction in asymmetric reactions between
cyclohexanone derivatives and β-nitrostyrenes (enamine-type catalysis) which was attributed to
the presence of electron-withdrawing pyridine fragments enhancing acidity of key squaramide
protons. Furthermore, compound III after protonation could be readily separated from products
and recycled in the catalytic reaction.
We wondered if the presence of the heterocyclic ‘proton-philic’ 1,2-di(pyridin-2-yl)ethane
spacer group in C2-symmetrical squaramide-based tertiary amines IV would allow the catalyst
recycling while retaining or even improving its stereoinduction in non-covalent-type catalytic
reactions.
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Scheme 1. Research strategy.
2. Results and Discussion
(R,R)- and (S,S)-enantiomers of 1,2-di(pyridin-2-yl)ethane-1,2-diamine
1
and
commercially available diamines 2 or 3 served as key building blocks for a straightforward
synthesis of novel C2-symmetric tertiary amines – squaramides. The synthetic scheme included
monoamidation of dimethyl squarate with diamines 1-3 followed by exhaustive amidation of
resulting compounds 4-6 with (S,S)- or (R,R)-antipode of diamine 7 bearing primary and tertiary
amino groups (Scheme 2). Both reactions proceeded in high yields (up to 91%) under simple
experimental conditions (MeOH, r.t.). The obtained diastereomers of squaramides 8-10 (Fig. 1)
had high melting points and poor solubility in a majority of organic solvents and water.
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Scheme 2. Synthesis of C2-symmetric tertiary amine – squaramides 8-10.
Fig. 1. Absolute configuration of stereocenters in the prepared bis-squaramides 8-10.
They were examined as organocatalysts in asymmetric additions of 1,3-dicarbonyl
compounds to nitroolefins. Asymmetric Michael reactions of this type are widely used for
enantioselective synthesis of
γ-nitrocarbonyl compounds, which are close precursors to
enantiomerically enriched bioactive compounds and pharmaceuticals. 13
First, we compared catalytic performance of compounds 8-10 in the model reaction of
acetylacetone 11a with
β-nitrostyrene 12a under comparable conditions (toluene, r.t., 72 h)
(Table 1, entries 1-6). In all cases, Michael adduct 13a was generated in high yield (72-93%).
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The best stereoinduction (91% ee) was attained in the presence of pyridine-containing catalyst
8b with different absolute configuration of stereocenters in the 1,2-di(pyridin-2-yl)ethane and
cyclohexan-1,2-diyl fragments (entry 2). To select the optimal reaction medium we studied the
8b–catalyzed model reaction in various organic solvents. The reactions completed faster (24 h)
in THF and especially in i-PrOH than in toluene though their enantioselectivity was much lower
(27-40% ee, entries 7 and 8). In solvent-free conditions reaction went quite fast, but ee was
moderate (entry 9). (Promising stereoinduction was attained in DCM over 48 h (entry 10).
However, the reaction in this solvent was rather sluggish: the yield of 13a did not exceed 5%
after 2 h. Reactivity enhanced dramatically in pure water (99% yield over 30 min), yet product
13a was generated in the aqueous medium with low enantioselectivity (27% ee, entry 11). We
managed to find a good compromise between activity and enantioselectivity by carrying out the
reaction in DCM in the presence of a small amount (~20 equiv. with respect to 12a) of protic co-
solvent, in particular water, i-PrOH, or HFIP (entries 12-14). Of the examined solvent systems
most promising was wet DCM where stereoinduction (88% ee) was comparable with that in dry
DCM, while the reaction rate increased significantly (full conversion in 2 h). Reducing the
reaction time or temperature did not improve the stereoinduction (see Table 1S in SI). Fully
protonated with strong organic acid (TFA) catalyst 8b did not catalyze the model reaction (entry
15). Interestingly, product 13a was generated with much lower enantioselectivity in other wet
solvents (toluene or THF) (entries 16 and 17). It should be noted that the model reaction
catalyzed by pyridine-free analogs 9a and 10b proceeded in wet DCM with lower yields (20-
55%) and enantioselectivity (75-79% ee) than in the presence of catalyst 8b; these data testify to
an essential role of pyridine fragments in catalytic reactions.
Table 1
Testing of catalysts 8-10 in the model reaction between 11a and 12a.a
entry
solvent
PhMe
PhMe
PhMe
t, h
72
72
72
yield of 13a, %b
ee, %c
79
8-10
8a
1
2
3
93
90
92
91
8b
83
9a
5

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4
PhMe
72
87
61
9b
5
6
PhMe
PhMe
72
72
80
72
73
81
10a
10b
8b
7
THF
48
92
40
8
i-PrOH
neat
24
99
27
8b
9
2
80
71
8b
10
11
12
DCM
48 (2d)
0.5
2
99 (5d)
90 (87d)
8b
H2O
99
27
8b
DCM/H2Oe
99
88
8b
13
14
15
16
17
DCM/i-PrOHe
DCM/HFIPe
DCM/TFAf
PhMe/H2O
THF/H2O
2
2
99
99
0
76
60
8b
8b
8b
8b
8b
24
2
n.d.
34
50
99
2
30
a The reactions were carried out with 8-10 (0.005 mmol), 11a (15.0 mg, 15.3 µL, 0.15 mmol)
and 12a (7.0 mg, 0.05 mmol) in the corresponding solvent (100 µL) at r.t.
b Isolated yield after flash chromatography on silica gel.
c
HPLC data (CHIRALPAC AD-H, n-hexane-iPrOH 90/10, 220 nm, 1 mL/min, tR (S) = 9.6
mim, tR (R) =12.6 min).
d The reaction was quenched after 2 h.
e Water, i-PrOH or HFIP (1,1,1,3,3,3-hexafluoro-2-propanol) additives (20 equiv.) were used.
f Amount of TFA was 0.4 equiv. with respect to 12a.
Next, to identify optimal conditions, we examined whether the activity of catalyst 8b and
enantiomeric enrichment of Michael adduct 13a depended on the water content in wet DCM.
The reaction was found to accelerate dramatically (100% yield of 13a over 2 h) when a minor
quantity of water (7 equiv. with respect to 12a) was added to DCM, while a further water amount
increase did not noticeably influence the catalyst activity (Fig. 2). These data are in good
agreement with recent reports14a,b on favorable impact of small water additives on asymmetric
reactions. The reaction enantioselectivity also depended on the water content in the binary
solvent system (Fig. 2). On the whole, it reduced with water amount increasing (90% ee in dry
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DCM vs. 27% ee in “pure” water). However, the plot ‘ee vs. water content’ had the local
maximum which corresponded to ~20 equiv. of H2O with respect to 12a. At this point,
enantioselectivity (88% ee) was very similar to that attained in dry DCM (90% ee) whereas the
reaction rate was significantly higher. The unexpected enantioselectivity enhancement may be
attributed to the formation of finely dispersed DCM / water biphasic solvent system in which
poorly soluble in both phases bifunctional catalyst is located in the interfacial area where
enantioselective transformation efficiently occur (so called “on water” catalysis14c). Further
increasing water amount apparently resulted in ripening water droplets and reduction of the
important for catalysis interfacial area. Moreover, both yield and ee values of 13a here were
superior to those reported for the corresponding reaction in the presence of the C1-symmetric
tertiary amine–squaramide catalyst.15
100
90
80
70
60
50
% ee
% yield
40
30
20
10
0
0
20
40
60
80
100
120
Water content, equiv. with respect to 12a
Fig. 2. Yield and ee of Michael adduct 13a generated in the presence of 8b versus water content
in the DCM/H2O solvent system.
Various 1,3-dicarbonyl compounds and
α-nitroolefins appeared suitable substrates in the
optimal conditions (Table 2). -Nitrostyrene derivatives 12b-f bearing donor and/or acceptor
β
groups in the aromatic ring and furan-derived nitroolefin 12g reacted with 11a affording
corresponding Michael adducts 13b-g in quantitative yield and enantioselectivity up to 94% ee
(Entries 2-7). As a rule, these results are superior to those obtained in the presence of known C1-
or C2-symmetric squaramides (for references see footnotes to Table 2). Furthermore,
enantiomeric purity of products 13b and 13g could be readily improved (from 80% to 96% ee)
by a single recrystallization from a hexane-EtOAc solvent system. The reaction of 11a with
nitrodiene 12h proceeded regioselectively under the proposed conditions yielding 1,2-adduct 13h
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with the moderate enantiomeric enrichment (80% ee, entry 8). Dimethyl malonate (11b) was less
active than -diketone 11a in the reactions with -nitrostyrene 12a and its cymantrenyl analog
β
β
12i. Nevertheless, prolonged reaction time (24 h vs. 2 h for 11a) allowed attaining corresponding
Michael adducts 13i and 13j in preparative yields (73-85%) and with reasonable enantiomeric
purity (up to 86% ee, entries 9 and 10). Cyclic malonate (Meldrum’s acid) exhibited higher
activity in the reactions with nitroolefins 12a and 12f in wet DCM and gave functionalized nitro
compounds 13k and 13l in quantitative yield. We failed to measure ee values of products 13k
and 13l directly by HPLC due to their irreversible adsorption on the chiral phase. Therefore, they
were converted to corresponding ethyl 3-aryl-4-nitrobutanoates 13k’ and 13l’ suitable for the
HPLC analysis by the known method.6a Moderate enantiomeric enrichments of the latter (48%
and 34%, respectively, entries 11, 12) may be attributed to partial racemization of unstable
primary adducts 13k and 13l under drastic derivatization conditions rather than to lower
stereoinduction of the catalytic reactions themselves. This assumption is in agreement with
scanty reliable data on highly selective catalytic Michael reactions of
α-nitroolefins with
Meldrum’s acid in the literature.16
γ-Nitrocarbonyl compounds 13 are valuable building blocks
for enantioselective synthesis of amino acids,17 nitrocyclopropanes,18 piperidinones and
bispidines,19 isoxazoles,20 tetrahydropyridines,21 and cyclohexane derivatives22. Some of them
could be further transformed to pharmaceutically valuable GABA analogs Phenibut, Rolipram,
Baclofen, Pregabalin, etc.23a The developed catalytic procedure is readily scalable: the ten-fold
increase of reagents (11a and 12a) and catalyst 8b amount did not compromise yield and
enantiomeric enrichment of product 13a (see Fig. 3).
Table 2
Scope of the catalytic Michael reaction.a
entry
R1, R1
R2
product
yield, %b
99 (99d, 95e)
99
ee, %c
13a (ent-
13a)
88 (-87d,
80e)
1
2
Me (11a)
Me (11a)
Ph (12a)
2-BrC6H4 (12b)
80 (96f)
13b
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3
4
4-ClC6H4 (12c)
99 (75g)
99 (50h)
70 (70g)
78 (70h)
13c
Me (11a)
Me (11a)
3-MeOC6H4 (12d)
2,4-Cl2C6H3 (12e)
13d
13e
94 (55h,
89i)
5
6
98 (87h, 99i)
Me (11a)
Me (11a)
3-MeO-4-cyclopentyl-
99
78
13f
OC6H3 (12f)
80 (96f,
77j)
7
8
2-Furyl (12g)
PhCH=CH- (12h)
Ph (12a)
97 (90j)
95 (97i)
13g
13h
13i
Me (11a)
Me (11a)
80 (79i)
86 (55i,
88l)
9k
MeO (11b)
MeO (11b)
73 (99i, 83l)
10k
11
Cymantrenyl (12i)
Ph (12a)
85
99
68
13j
48m (20n)
13k
-OC(Me)2O- (11c)
-OC(Me)2O- (11c)
3-MeO-4-cyclopentyl-
12
99
34l
13l
OC6H3 (12f)
a
Unless otherwise specified, the reactions were carried out with catalyst 8b (3.7 mg, 0.005
-dicarbonyl compound 11 (0.15 mmol), nitroolefin 12 (0.05 mmol) and H2O (18 mg, 18
mmol),
β
ꢀL, 1.0 mmol) in DCM (82 µL) at r.t. for 2-24 h.
b Isolated yield after flash chromatography on silica gel.
c HPLC data (AD-H, OD or OJ-H columns).
d
Data for the corresponding reaction in the presence of enantiomeric catalyst ent-8b to afford
antipode ent-13a.
e Data from ref. 15
f The ee data after a single recrystallization from hexane-EtOAc 10:1.
g Data from ref.24
h Data from ref.9
i Data from ref.25
j Data from ref.18b
k Reaction time was 24 h.
l Data from ref.26
m Data for the derivatization product, ethyl 3-aryl-4-nitrobutanoate.
n Data from ref.16a for the corresponding derivatization product.
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Catalyst 8b efficiency was also proved in a more complex domino reaction of ortho-
(tosylamino)chalcone (14) with -nitrostyrene (12a) which involves aza-Michael and
β
intramolecular Michael addition steps and allowed facile construction of densely functionalized
tetrahydroquinoline (15) in a single operation (Scheme 3).23b
Scheme 3. The 8b-catalyzed asymmetric synthesis of tetrahydroquinoline (15)
Given poor solubility of catalyst 8b in organic solvents and water, the aforementioned
reactions proceeded under heterogeneous conditions allowing easy product removal and catalyst
recycling. These let skip conventional time- and labor-consuming «heterogenization» protocols
based on catalyst tagging to the polymer27 or ionic unit,25,28 by means of an extra-functional
group. It was enough to evaporate the solvent from the reaction mixture and extract products
with Et2O. The remained catalyst, 8b, could be reused as is. This protocol is scalable and
preferential to the known procedures for recycling of homogeneous catalysts which require ionic
liquids,29 acid-base extraction30 and/or chomatography.31 In this manner, we 10 times recycled
the original sample of catalyst 8b in the asymmetric reaction of 11a with 12a and detected only a
slight increase of the reaction time needed for high conversion (1.5 h in the 1st cycle vs. 3.5 h in
the 10th cycle, Fig. 3). It was not the catalyst destruction that caused gradual deactivation: the 1H
NMR spectrum of the 10-time reused sample was very similar to that of freshly prepared 8b (see
SI). A plausible reason was mechanical «washing-away» of finely suspended 8b with diethyl
ether during the products extraction. Somewhat reduced enantioselectivity in the 10th cycle could
also be attributed to the catalyst mass loss (see Supporting Information, Table 1S, entries 5,6).
Nevertheless, catalyst 8b exhibited better sustainability in the catalytic reaction than the known
homogeneous catalysts, a majority of which became much less active after the 1st or the 2nd
recovery.
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Fig. 3. Recyclability of catalyst 8b in the model reaction between 11a and 12a. Reactions were
carried out with 11a (0.15 g, 0.147 mL, 1.5 mmol) and 12a (74.5 mg, 0.5 mmol) in DCM (0.82
mL) and H2O (0.18 mL, 10 mmol); the initial catalyst loading was 37 mg (0.05 mmol). The
reaction time was 2 h for cycles 1-6, 2.5 h for cycles 7-9 and 3.5 h for cycle 10.
3. Conclusions
Simple C2-symmetric chiral tertiary amines bearing squaramide fragments and the 1,2-
di(pyridin-2-yl)ethane spacer group were synthesized. Diamines 8b and ent-8b with the different
absolute configuration of stereogenic centers in 1,2-di(pyridin-2-yl)ethane and 1,2-
diaminocyclohexane units efficiently catalyzed asymmetric reactions of
β-dicarbonyl
compounds with α-nitroolefins and domino reaction of ortho-(tosylamino)chalcone with β-
nitrostyrene in wet DCM affording corresponding Michael adducts in up to 99% yield and 94%
ee. The plot ‘enantioselectivity vs. water’ has the local maximum that corresponds to 20 equiv.
of H2O with respect to the nitroolefin amount. The developed procedure is readily scalable.
Despite the non-supported structure, catalyst 8b can be readily separated from products due to
poor solubility in organic solvents or water and recycled 10 times in the same reaction without
significant rate and enantioselectivity reduction.
4. Experimental section
4.1.
General procedures
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The NMR spectra were recorded on a 300 and 500 MHz spectrometer. The high-resolution mass
spectra (HRMS) were measured using electrospray ionization (ESI) and a time-of-flight (TOF)
mass analyzer. The measurements were taken in the positive ion mode (interface capillary
voltage 4500 V) in the mass range from m/z = 50 Da to m/z = 3000 Da; external or internal
calibration was done with the electrospray calibrant solution. The IR spectra were recorded on
KBr pellets. Optical rotations were measured on a polarimeter and calibrated with a pure solvent
as a blank. HPLC analyses were performed on an HPLC system equipped with chiral stationary
phase columns (AD-H, OD-H, OJ-H), detection at 220 nm. Silica gel (0.060−0.200 mm) was
used for column chromatography. All reagents and solvents were purified and dried according to
common procedures. Starting amines 2, 3 are commercially available and used directly.
4.2.
Synthesis of 4 – 6 (General Procedure)
Dimethyl squarate (0.70 g, 4.91 mmol) was added to a solution of corresponding diamine 1, 2 or
3 (2.33 mmol) in MeOH (2 mL) in one portion. After 20 h of stirring at room temperature the
precipitate was filtered, washed with EtOAc (3 x 10 mL) and dried under reduced pressure (10
Torr) to afford corresponding compound 4, 5 or 6.
4.2.1. 4,4'-(((1R,2R)-1,2-di(pyridin-2-yl)ethane-1,2-diyl)bis(azanediyl))bis(3-methoxycyclobut-
3-ene-1,2-dione) ((1R,2R)-4)
Colorless solid (0.88 g, 87%). Mp: >230°C dec. 1H NMR (300 MHz, DMSO-d6): δ 9.57-9.29 (m,
2H), 8.53 (s, 2H), 7.67 (s(br), 2H), 7.22 (s(br), 4H), 6.00 (d, J = 6.8 Hz, 1H), 5.53 (s, 1H), 4.26
(s, 6H). 13C NMR (75 MHz, DMSO-d6): δ 189.1, 183.2, 177.9, 172.8, 157.8, 149.7, 137.4,
+
123.5, 123.1, 62.4, 61.3, 60.7. HRMS (ESI): m/z M + H+ calcd for C22H19N4O6 435.1299, found
435.1327.
4.2.2. 4,4'-(((1S,2S)-1,2-di(pyridin-2-yl)ethane-1,2-diyl)bis(azanediyl))bis(3-methoxycyclobut-
3-ene-1,2-dione) ((1S,2S)-4)
Colorless solid (0.91 g, 90%). Mp: >230°C dec. 1H NMR (300 MHz, DMSO-d6): δ 9.57-9.29 (m,
2H), 8.53 (s, 2H), 7.65 (s(br), 2H), 7.22 (s(br), 4H), 5.99 (s(br), 1H), 5.52 (s, 1H), 4.22 (s, 6H).
13C NMR (75 MHz, DMSO-d6): δ 194.0, 188.1, 182.7, 177.6, 162.8, 154.6, 142.3, 128.4, 128.1,
+
67.2, 66.1, 65.6. HRMS (ESI): m/z M + H+ calcd for C22H19N4O6 435.1299, found 435.1292.
4.2.3. 4,4'-(((1R,2R)-1,2-diphenylethane-1,2-diyl)bis(azanediyl))bis(3-methoxycyclobut-3-ene-
1,2-dione) ((1R,2R)-5)
1
Colorless solid (0.92 g, 91%). H NMR (300 MHz, DMSO-d6): δ 9.77-9.70 (m, 1H), 9.53-9.40
(m, 1H), 7.25-7.09 (m, 10H), 5.54 (s(br), 1H), 5.05 (s(br), 1H), 4.29-4.25 (m, 6H). 13C NMR (75
MHz, DMSO-d6): δ 189.5, 183.0, 178.0, 172.6, 139.9, 139.3, 128.9, 128.3, 127.6, 62.8, 61.8,
+
60.7. HRMS (ESI): m/z M + H+ calcd for C24H21N2O6 433.1394, found 433.1325.
12

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4.2.4. 4,4'-(((1S,2S)-1,2-diphenylethane-1,2-diyl)bis(azanediyl))bis(3-methoxycyclobut-3-ene-
1,2-dione) ((1S,2S)-5)
1
Colorless solid (0.82 g, 81%). Mp: >230°C dec. H NMR (300 MHz, DMSO-d6): δ 7.22 (m,
10H), 5.53 (s(br), 2H), 5.05 (s(br), 1H), 4.29-4.23 (d, 6H), 4.11 (s, 1H). 13C NMR (75 MHz,
DMSO-d6): δ 189.5, 183.0, 178.0, 172.6, 139.9, 139.3, 128.9, 128.3, 127.6, 62.8, 61.8, 60.7.
+
HRMS (ESI): m/z M + H+ calcd for C24H21N2O6 433.1394, found 433.1337.
4.2.5. 4,4'-((1R,2R)-cyclohexane-1,2-diylbis(azanediyl))bis(3-methoxycyclobut-3-ene-1,2-
dione) ((1R,2R)-6)
Colorless solid (0.61 g, 78%). Mp: >230°C dec. 1H NMR (300 MHz, DMSO-d6): δ 8.95-8.84 (m,
1H), 8.65 (s(br), 1H), 4.31-4.24 (m, 6H), 3.76 (s(br), 1H), 1.95-1.89 (d, 2H), 1.72-1.66 (d, 2H),
13
1.50-1.35 (m, 2H). C NMR (75 MHz, DMSO-d6): δ 177.8, 172.4, 60.7, 58.2, 57.6, 33.0, 32.4,
+
24.4. HRMS (ESI): m/z M + H+ calcd for C16H19N2O6 335.1238, found 335.1182.
4.2.6. 4,4'-((1S,2S)-cyclohexane-1,2-diylbis(azanediyl))bis(3-methoxycyclobut-3-ene-1,2-dione)
((1S,2S)-6)
Colorless solid (0.58 g, 74%). Mp: >230°C dec. 1H NMR (300 MHz, DMSO-d6): δ 8.95-8.84 (m,
1H), 8.65 (s(br), 1H), 4.31-4.24 (m, 6H), 3.76 (s(br), 1H), 1.95-1.89 (d, 2H), 1.72-1.66 (d, 2H),
13
1.50-1.35 (m, 2H). C NMR (75 MHz, DMSO-d6): δ 177.8, 172.4, 60.7, 58.2, 57.6, 33.0, 32.4,
+
24.4. HRMS (ESI): m/z M + H+ calcd for C16H19N2O6 335.1238, found 335.1245.
4.3. Synthesis of organocatalysts 8-10 (General Procedure)
Compound 4, 5 or 6 (1.85 mmol) was added to the solution of 2-(piperidin-1-
yl)cyclohexanamine 7 (0.69 g, 3.77 mmol) in MeOH (2 mL). After stirring at room temperature
for 20 h, the precipitate was filtered, washed with Et2O (3 x 10 mL) and dried under reduced
pressure (10 Torr) to afford corresponding product 8, 9 or 10.
4.3.1. (R,R)-4,4'-(((1R,2R)-1,2-di(pyridin-2-yl)ethane-1,2-diyl)bis(azanediyl))bis(3-(((1R,2R)-2-
(piperidin-1-yl)cyclohexyl)amino)cyclobut-3-ene-1,2-dione) (8a)
1
Light yellow solid (1.2 g, 88%). Mp: >230°C dec. H NMR (500 MHz, DMSO-d6): δ 8.53 (s,
2H), 7.85 (s, 2H), 7.55 (s, 2H), 7.37-7.18 (m, 4H), 6.99 (s, 2H), 5.94 (s, 2H), 3.80 (s, 2H), 2.23-
2.07 (m, 7H), 1.69 (m, 6H), 1.18 (s, 16H). 13C NMR (75 MHz, DMSO-d6): δ 183.4, 182.4,
169.3, 167.6, 157.9, 149.8, 137.2, 123.6, 123.3, 68.9, 62.3, 54.3, 49.7, 34.7, 26.5, 25.3, 25.0,
24.8, 24.1. IR (KBr): ṽ = 1459, 1655, 1797, 2345, 2366, 2932, 3163, 3448 cm–1. HRMS (ESI):
+
m/z M + H+ calcd for C42H55N8O4 735.4341, found 735.4370.
4.3.2. (R,R)-4,4'-(((1S,2S)-1,2-di(pyridin-2-yl)ethane-1,2-diyl)bis(azanediyl))bis(3-(((1R,2R)-2-
(piperidin-1-yl)cyclohexyl)amino)cyclobut-3-ene-1,2-dione) (8b)
Light yellow solid (1.23 g, 91%). Mp: >230°C dec. 1H NMR (300 MHz, DMSO-d6): δ 8.56 (d, J
= 4.0 Hz, 2H), 8.00 (s(br), 2H), 7.56 (t, J = 7.4 Hz, 2H), 7.42 (m, 2H), 7.20 (t, J = 5.0 Hz, 2H),
13

ACCEPTED MANUSCRIPT
6.94 (d, J = 8.5 Hz, 2H), 5.92 (d, J = 6.9 Hz, 2H), 3.78 (s(br), 2H), 2.17-1.96 (m, 9H), 1.77-1.63
(m, 7H), 1.13 (s(br), 20H). 13C NMR (75 MHz, DMSO-d6): δ 183.2, 182.4, 169.3, 167.7, 156.8,
149.9, 137.3, 123.6, 68.8, 62.5, 54.3, 49.6, 34.7, 26.5, 25.3, 24.9, 24.7, 24.2. IR (KBr): ṽ = 1459,
1571, 1655, 1799, 2345, 2366, 2935, 3168, 3449 cm–1. HRMS (ESI): m/z M + H+ calcd for
+
C42H55N8O4 735.4341, found 735.4305.
4.3.3. (S,S)-4,4'-(((1R,2R)-1,2-di(pyridin-2-yl)ethane-1,2-diyl)bis(azanediyl))bis(3-(((1S,2S)-2-
(piperidin-1-yl)cyclohexyl)amino)cyclobut-3-ene-1,2-dione) (ent-8b)
1
Light yellow solid (1.12 g, 82%). Mp: >230°C dec. H NMR, 13C NMR and IR spectra was
identically 8b.
4.3.4. (R,R)-4,4'-(((1R,2R)-1,2-diphenylethane-1,2-diyl)bis(azanediyl))bis(3-(((1R,2R)-2-
(piperidin-1-yl)cyclohexyl)amino)cyclobut-3-ene-1,2-dione) (9a)
1
Light yellow solid (0.99 g, 73%). Mp: >230°C dec. H NMR (300 MHz, DMSO-d6): δ 7.88
(s(br), 2H), 7.26 (s, 10H), 5.63 (s, 2H), 3.76 (s(br), 2H), 2.57 (s(br), 2H), 2.30-2.00 (m, 12H),
2.00-1.66 (m, 9H), 1.23 (s(br), 16H). 13C NMR (75 MHz, DMSO-d6): δ 183.2, 182.5, 169.4,
166.8, 159.3, 158.9, 138.1, 129.2, 128.6, 127.7, 68.1, 63.9, 52.3, 51.1, 48.8, 35.0, 31.1, 24.4,
24.1, 23.9, 23.0, 22.7, 21.7. IR (KBr): ṽ = 1466, 1568, 1654, 1799, 2343, 2362, 3163, 3448 cm–1.
HRMS (ESI): m/z M + H+ calcd for C44H55N6O4 733.4436, found 733.4470.
+
4.3.5. (R,R)-4,4'-(((1S,2S)-1,2-diphenylethane-1,2-diyl)bis(azanediyl))bis(3-(((1R,2R)-2-
(piperidin-1-yl)cyclohexyl)amino)cyclobut-3-ene-1,2-dione) (9b)
1
Light yellow solid (1.06 g, 78%). Mp: >230°C dec. H NMR (300 MHz, DMSO-d6): δ 8.00
(s(br), 2H), 7.51-7.00 (m, 12H), 5.67 (s, 2H), 3.67 (s(br), 2H), 2.57 (s(br), 2H), 2.25 (s(br), 5H),
13
2.09 (s, 1H), 1.95 (m, 2H), 1.81-1.59 (t, 6H), 1.43 (m, 18H). C NMR (75 MHz, DMSO-d6): δ
183.2, 168.0, 159.2, 158.7, 149.8, 129.0, 128.4, 127.8, 68.1, 63.4, 51.9, 50.8, 49.5, 34.7, 31.1,
24.8, 24.1, 23.4, 22.9, 21.7. IR (KBr): ṽ = 1466, 1561, 1655, 1796, 2346, 3189, 3449 cm–1.
HRMS (ESI): m/z M + H+ calcd for C44H55N6O4 733.4436, found 733.4420.
+
4.3.6. (R,R)-4,4'-((1R,2R)-cyclohexane-1,2-diylbis(azanediyl))bis(3-(((1R,2R)-2-(piperidin-1-
yl)cyclohexyl)amino)cyclobut-3-ene-1,2-dione) (10a)
Light yellow solid (0.91 g, 78%). Mp: >230°C dec. 1H NMR (300 MHz, DMSO-d6): δ 7.50-7.25
(m, 4H), 3.90-3.69 (m, 4H), 2.59-2.53 (m, 4H), 2.26 (s(br), 6H), 1.99 (s(br), 4H), 1.82-1.57 (m,
13
9H), 1.40-1.14 (m, 23H). C NMR (75 MHz, DMSO-d6): δ 182.6, 181.6, 168.9, 167.7, 159.3,
158.8, 68.4, 58.9, 52.1, 51.6, 48.3, 34.1, 31.9, 24.5, 24.1, 23.1, 22.9, 21.8. IR (KBr): ṽ = 1466,
1571, 1649, 1799, 2345, 2798, 2854, 2933, 3168, 3423 cm–1. HRMS (ESI): m/z M + H+ calcd
+
for C36H55N6O4 635.4279, found 635.4210.
4.3.7. (R,R)-4,4'-((1S,2S)-cyclohexane-1,2-diylbis(azanediyl))bis(3-(((1R,2R)-2-(piperidin-1-
yl)cyclohexyl)amino)cyclobut-3-ene-1,2-dione) (10b)
14

ACCEPTED MANUSCRIPT
Light yellow solid (0.95 g, 81%). Mp: >230°C dec. 1H NMR (300 MHz, DMSO-d6): δ 7.50-7.25
(m, 4H), 3.90-3.69 (m, 4H), 2.59-2.53 (m, 4H), 2.26 (s(br), 6H), 1.99 (s(br), 4H), 1.82-1.57 (m,
13
9H), 1.40-1.14 (m, 23H). C NMR (75 MHz, DMSO-d6): δ 182.8, 182.4, 169.2, 167.4, 159.3,
158.8, 67.9, 58.3, 52.1, 51.3, 50.2, 35.1, 32.0, 25.4, 24.4, 24.0, 23.8, 23.5, 23.1, 21.6. IR (KBr): ṽ
= 1460, 1571, 1654, 1795, 2345, 2798, 2855, 2932, 3187 cm–1. HRMS (ESI): m/z M + H+ calcd
+
for C36H55N6O4 635.4279, found 635.4255.
4.4. Catalytic Michael reaction between 11 and 12 (General Procedure)
CH-acid 11 (0.15 mmol) was added to a suspension of catalyst 8b (3.7 mg, 0.005 mmol), H2O (1
mmol, 18 ꢀL) and 12 (0.05 mmol) in DCM (82 ꢀL). After stirring at room temperature for 2 h,
H2O and DCM were evaporated under reduced pressure (10 Torr). The residue was extracted
with Et2O (3 × 4 mL). The combined extracts were purified by flash chromatography (n-
hexane/EtOAc 1:1) to afford 13. Spectroscopic data for 13a,c32 13b,d,e9, 13g33, 13h25, 13i26 are
in agreement with the literature.
4.4.1. (R)-3-(1-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-nitroethyl)pentane-2,4-dione (13f)
20
Colorless solid. Mp: 121-123°C. αD -78.4 (c 0.4, CH2Cl2). Ee: 78%. For HPLC data see the
1
Supporting Information. H NMR (300 MHz, CDCl3): δ 6.91 (s, 1H), 6.85 (d, J = 8.2 Hz, 1H),
6.76 (d, J = 8.2 Hz, 1H), 4.80-4.67 (m, 3H), 4.62 (d, J = 11.1 Hz, 1H), 4.03-3.94 (m, 1H), 3.7 (s,
3H), 2.23 (s, 3H), 1.91 (s, 3H), 1.86 (m, 2H), 1.70-1.55 (m, 6H). 13C NMR (75 MHz, DMSO-d6):
δ 202.4, 202.2, 149.6, 147.2, 129.2, 121.3, 115.5, 115.4, 112.6, 112.5, 79.9, 78.9, 69.6, 55.8,
+
43.0, 32.6, 31.1, 31.0, 24.0. HRMS (ESI): m/z M + H+ calcd for C19H26NO6 364.1755, found
364.1788.
4.4.2. (R)-Dimethyl-2-(2-Nitro-1-cymantrenyl)malonate. (13j)
20
Colorless oil. αD -12.3 (c 0.2, CH2Cl2). Ee: 68%. For HPLC data see the Supporting
1
Information. H NMR (300 MHZ, DMSO-d6): δ 5.34 (s, 1H), 5.14 (s, 1H), 4.99-4.92 (m, 2H),
4.80 (m, 2H), 4.01 (m, 1H), 3.92 (m, 1H), 3.66 (d, J = 7.0 Hz, 6H). 13C NMR (75 MHz, DMSO-
d6): δ 225.0, 167.6, 100.4, 86.8, 86.1, 84.1, 80.0, 76.9, 55.7, 53.3, 35.6. HRMS (ESI): m/z M +
+
H+ calcd for C15H15MnNO9 408.0127, found 408.0149.
4.5. General method for recycling of catalyst 8b (Large scale procedure).
The catalytic reaction was performed as described above with acetylacetone 11a (150 mg, 0.15
mL, 1.5 mmol), β-nitrostyrene 12a (74.5 mg, 0.5 mmol), catalyst 8b (37 mg, 0.05 mmol), H2O
(10 mmol, 0.18 mL) in DCM (0.82 mL). After stirring at room temperature for the time indicated
in Fig. 3, H2O and DCM were evaporated under reduced pressure (10 Torr). The residue was
15

ACCEPTED MANUSCRIPT
washed with Et2O (3 × 40 mL). After each washing, the finely dispersed catalyst was
centrifugated and the transparent liquid phase was separated from solid catalyst by simple
decantation. Michael adduct 13a was isolated from the combined mother liquids by flash
chromatography (n-hexane/EtOAc 2:1). The recovered catalyst 8b was dried under reduced
pressure (1.0 Torr) for 10 min. Then, fresh portions of DCM (0.82 mL), H2O (10 mmol, 0.18
mL) and reagents (11a (150 mg, 147 ꢀL, 1.5 mmol), 12a (74.5 mg, 0.5 mmol) were added to the
catalyst and the reaction was re-performed as described above.
4.6.Derivatization of 13k and 13l
A solution of 13k or 13l (0.05 mmol) and conc. H2SO4 (25ꢀL) in EtOH (1.5mL) was refluxed for
8 h. The mixture was diluted with EtOAc, washed with aq. sat. NaHCO3 and organic phase was
dried over MgSO4. The solvent was evaporated in vacuo (10 Torr) and the residue was purified
by flash chromatography (EtOAc) to afford derivation product 13k’ or 13l’. Spectroscopic data
for 13k’34 and 13l’35 are in agreement with the literature.
4.7. Catalytic domino Michael reaction between 14 and 12a.
Ortho-(tosylamino)chalcone 14 (18.85 mg, 0.05 mmol) was added to a suspension of catalyst 8b
(3.7 mg, 0.005 mmol), H2O (1 mmol, 18 ꢀL) and 12a (7.45 mg, 0.05 mmol) in DCM (82 ꢀL).
After stirring at room temperature for 2 h, the solvent was evaporated under reduced pressure (10
Torr). The residue was extracted with Et2O (3 × 4 mL). The combined extracts were purified by
flash chromatography (n-hexane/EtOAc 2:1) to afford 15. Spectroscopic data for 1523b,c is in
agreement with the literature.
Acknowledgements
The research was supported by the Russian Science Foundation (Project 16-13-10470).
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