Stereoselective Synthesis of Tetrahydroquinolines via Asymmetric Domino Reaction Catalyzed by a Recyclable Ionic-Liquid-Supported Bifunctional Tertiary Amine

Article abstract of DOI:10.1002/ejoc.201801423

The most recyclable ionic liquid-supported bifunctional tertiary amine–squaramide organocatalyst for the asymmetric domino reaction has been found. Over this catalyst, ortho-aminochalcones protected with Tosyl or Nosyl groups underwent the aza-Michael/Michael domino reaction with nitroolefins to afford corresponding 2,3,4-trisubstituted tetrahydroquinolines as single diastereomers in nearly quantitative yield with up to 99 % ee. The catalyst was readily separated from the reaction mixture via a simple centrifugation/decantation workup and 19 times reused in the catalytic reaction without noticeable conversion or enantioselectivity reduction. The N-nosylated products proved their synthetic value for pharmacology given their facile conversion to fused pirrolidino-tetrahydroquinolines of high diastreomeric and enantiomeric purity via successive deprotection and reductive amination.

Full text of DOI:10.1002/ejoc.201801423

A Journal of
Accepted Article
Title: Stereoselective Synthesis of Tetrahydroquinolines via
Asymmetric Domino Reaction Catalyzed by Recyclable Ionic-
Liquid-supported Bifunctional Tertiary Amine
Authors: Rinat S. Tukhvatshin, Alexander S. Kucherenko, Yulia V.
Nelyubina, and Sergei G. Zlotin
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801423
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801423
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10.1002/ejoc.201801423
European Journal of Organic Chemistry
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Stereoselective Synthesis of Tetrahydroquinolines via
Asymmetric Domino Reaction Catalyzed by Recyclable Ionic-
Liquid-supported Bifunctional Tertiary Amine
Rinat S. Tukhvatshin[a], Alexander S. Kucherenko*[a], Yulia V. Nelyubina,[b] and Sergei G. Zlotin*[a]
Dedication ((optional))
Abstract: The most recyclable ionic liquid-supported bifunctional
tertiary amine–squaramide organocatalyst for the asymmetric
domino reaction has been found. Over this catalyst, ortho-
aminochalcones protected with Tosyl or Nosyl groups underwent the
aza-Michael/Michael domino reaction with nitroolefins to afford
corresponding 2,3,4-trisubstituted tetrahydroquinolines as single
diastereomers in nearly quantitative yield with up to 99% ee. The
catalyst was readily separated from the reaction mixture via a simple
centrifugation/decantation workup and 19 times reused in the
catalytic reaction without noticeable conversion or enantioselectivity
reduction. The N-nosylated products proved their synthetic value for
pharmacology given their facile conversion to fused pirrolidino-
tetrahydroquinolines of high diastreomeric and enantiomeric purity
via successive deprotection and reductive amination.
from products (often poorly soluble in organic solvents) which
can control reactions multiply (batch conditions) or continuously
(continuous flow conditions). The known α, α -diarylprolinole,[6]
prolinamide,[7] pyrrolidine[8] or benzotetramisole[9] derivatives
tagged to polymers or ionic groups efficiently promote cascade
reactions, which proceed through the formation of active iminium,
enamine or enolate-type intermediates, only over the first 3-6
cycles. Afterwards, their activity and, in some cases,
stereoinduction significantly reduce, apparently due to
undesirable by-side transformations of these intermediates
which destroy immobilized catalysts.[10]
On the other hand, polystyrene (PS) or textile-supported
chiral tertiary amines, in particular Cinchona alkaloid derivatives
capable of activating reagents via their deprotonation without the
formation of covalent bonds (hydrogen bonding), were found to
retain high yield and enantiomeric purity of products in
asymmetric α-aminations of 2-oxindoles[11] or desymmetrizations
of cyclic anhydrides[12] over 100 and 300 cycles, respectively.
We expected immobilized chiral tertiary amines to act as
sustainable catalysts in asymmetric domino reactions as well,
provided no active covalent intermediates responsible for their
unproductive by-side transformations are generated in either
step of the cascade process.
Introduction
Asymmetric organocatalysis is an extensively growing area of
modern organic chemistry.[1] It allows
a
straightforward
enantioselective synthesis of complex organic compounds from
available achiral or racemic precursors without a risk of their
contamination with toxic heavy metals inherent to organometal
catalysis. A major recent trend in this research area is
associated with the extensive application of organocatalysts for
promoting stereoselective domino reactions.[2] These reactions,
in which a generated intermediate spontaneously undergoes
further (often intramolecular) transformations without adding
fresh reagents and/or a catalyst,[3] are commonly less material-
and energy-consuming than sequences of corresponding
reactions performed separately, which makes them perspective
in terms of green chemistry.[4] In particular, domino reactions
significantly simplify a multi-step syntheses of valuable natural
compounds and enantiomerically pure medications.[5]
A highly diastereoselective and enantioselective synthesis of
2,3,4-trisubstituted tetrahydroquinolines via organocatalytic aza-
Michael (a) – intramolecular Michael (b) domino reactions of o-
N-tosylamino-chalcones with nitroolefins, developed by Du[13]
and Kim[14] with co-authors, belongs to this type of catalytic
reactions (Scheme 1). It is efficiently promoted by bifunctional
chiral tertiary amines I–III bearing thiourea[14] or squaramide
fragments[13,15] which activate reagents and properly locate them
in space solely by means of stereocontrolling hydrogen bonds.
However, the applicability of organocatalytic domino
reactions in practice is limited by a lack of sustainable
(recyclable) versions of organocatalysts to be readily separated
[a]
[b]
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of
Sciences, 47 Leninsky Prospect, 119991, Moscow, Russian
Federation
E-mail: zlotin@ioc.ac.ru, alexkucherenko@ya.ru
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian
Academy of Sciences, 28, Vavilova str, 119991 Moscow, Russia.
Scheme 1. Known bifunctional organocatalysts I–III of asymmetric aza-
Michael–Michael domino reactions of o-N-tosylamino-chalcones with
nitroolefins.
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10.1002/ejoc.201801423
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However, PS-supported bifunctional tertiary amine
–
comparable conditions (catalyst loading 10 mol%, CH2Cl2, r.t.).
From the two, compound IVb proved to be a much more efficient
catalyst of the model reaction. Tetrahydroquinoline derivative 3a
thiourea catalyst could be recycled only 5 times in similar oxa-
Michael−aza-Henry cascade reaction between α-amido sulfones
derived from salicyladehydes and nitrostyrenes.[16] We
hypothesized that supported tertiary amines bearing resistant to
chemical reagents squaramide group[17] would be more robust
catalysts of domino reactions which include asymmetric Michael
addition step. To verify our hypothesis, we examined tertiary
amine-derived squaramides IVa and IVb, recently developed in
our laboratory,[18] which may be considered as ionic liquid-
supported[19] versions of catalyst III in the aforementioned
domino reactions (Figure 1). Catalyst IVb exhibited excellent
recyclability in asymmetric Michael additions of β-dicarbonyl
compounds to nitroolefins under “on-water” conditions and
retained its activity and high stereoinduction over 30 reaction
cycles. However, to our knowledge, no successful applications
of supported bifunctional tertiary amines to asymmetric domino
reactions controlled by stereoselective hydrogen bonds between
a chiral catalyst and reagents in corresponding transition state
have been reported so far.
generated in its presence in 98% yield was
a single
diastereomer with enantiomeric enrichment 98% ee. Its
performance was superior to that of catalyst IVa (72% yield and
74% ee) and the required reaction time was shorter (12 h vs. 20
h, Table 1, entries 1 and 2). Replacing of CH2Cl2 for another
aprotic (MePh, EtOAc) or proton-containing solvents (i-PrOH,
H2O) exerted a negative impact on enantioselectivity or the
reaction rate (Entries 3-6). Catalytic efficiency remained the
same in the reaction with the catalyst loading reduced to 5 mol%
(Entry 7); however, further reduction of the IVb amount (to 1
mol% or 0.5 mol%) noticeably decreased its activity and the
streoinduction level (Entries 8 and 9).
Table 1. Optimization of conditions for the model reaction between compounds 1a and
2a. [a]
entry
Catalyst
solvent
t, h
yield of
ee, %[c]
13a, %[b]
1
2
3
4
5
6
7
8
9
IVa (10)
IVb (10)
IVb (10)
IVb (10)
IVb (10)
IVb (10)
IVb (5)
CH2Cl2
CH2Cl2
Toluene
EtOAc
i-PrOH
H2O
CH2Cl2
CH2Cl2
CH2Cl2
20
12
18
12
12
120
12
24
24
72
99
99
75
46
50
98
93
90
74
98
95
85
90
97
98
94
93
Figure 1. Tertiary amine-derived ionic liquid-supported squaramides IVa and
IVb..
IVb (1)
IVb (0.5)
[a] Unless otherwise specified, all reactions proceeded with 1a (9.0 mg,
0.024 mmol), 2a (5.2 mg, 0.036 mmol), and an organic solvent (100 µL) at
ambient temperature. [b] Isolated yield after flash chromatography on silica
gel. [c] HPLC data (Chiralpak AD-H, n-hexane : i-PrOH = 90 : 10; 254 nm,
flow rate: 1.0 mL/min, tR(S) = 18.23 min (major), tR(R) = 32.63 min).
It should be noted that the tetrahydroquinoline scaffold is
present in a number of natural and synthetic bioactive molecules
which exhibit various biological activities functioning as
sodium[20] or calcium channel (BKCa) antagonists,[21]androgen
receptor agonists/antagonists,[22] bradykinin (BK) receptor
Next, we evaluated the capability of supported catalyst
IVb to promote domino reactions of chalcons 1a with various
nitroolefins 2. Much to our satisfaction, substrates 2 bearing
acceptor or donor groups at different positions of the aromatic
ring and heteroaromatic nitroolefin 1b were tolerant to the
proposed heterogeneous conditions and gave corresponding
compounds 3b-j in nearly quantitative yield with 93-99% ee
(Scheme 2). Furthermore, catalyst IVb allowed an easy
access to ferrocene and cymantren derivatives 3k and 3l of
high enantiomeric purity. Chiral metallocenes attract
considerable attention due to their potent anticancer
activity.[26] Importantly, the catalyst also appeared suitable for
facile preparation of tetrahydroquinoline derivatives 3m-o
containing a readily removable (unlike a tosyl group[27]) nosyl
protecting group.[28] Furthermore, nearly quantitative chemical
yields and excellent stereoselection were maintained at 3-5
mmol scaled reactions which makes the catalytic procedure
valuable for the asymmetric synthesis.
antagonists,[23] CEPT inhibitors,[24] liver
modulators,[25] etc. (Figure 2).
x receptor (LXR)
Figure 2. Bioactive tetrahydroquinoline derivatives.
Results and Discussion
At first, we compared catalytic performance of ionic liquid-
supported catalysts IVa and IVb in a model reaction between
ortho-(N-tosylamino)chalcone 1a and β-nitrostyrene 1b under
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Furthermore, the fresh and the 19-fold used specimens
exhibited close catalytic activity in the experiments where
conversions were measured at a 4 h period (60% in the first
cycle vs 45% in the 20th) which provides a strong evidence of its
sustainability under the proposed conditions (See the Supporting
Information). As far as we know, such sustainability has not
been attained for supported organocatalysts in asymmetric
domino reactions so far.
Figure 3. Catalytic performance and recyclability of catalyst IVb in the
asymmetric domino reaction between 1a and 2a.
Scheme 2. Known bifunctional organocatalysts I–III of asymmetric aza-
Michael–Michael domino reactions of o-N-tosylamino-chalcones with
nitroolefins (Reaction conditions for 3a-l: 1a (29 mg, 0.079 mmol), 2 (0.11
mmol), IVb (5 mol %), CH2Cl2 (0.2 mL), r.t. Reaction conditions for 3m-o: 1b
(1.40 g, 3.4 mmol), 2m-o (5.1 mmol), IVb (5 mol %), CH2Cl2 (2.0 mL), r.t.
Yields were determined after chromatographic purification of the products, ee
values – by HPLC analysis on a chiral stationary phase).
The key point was sustainability of supported catalyst IVb in
the domino reaction. We studied its recyclability in a model
reaction between compounds 1a and 2a. To facilitate isolation of
product 3a and minimize the catalyst loss during the workup in
recycling experiments, we increased loadings of substrates 1a
and 2a to 1.20 g (3.40 mmol) and 0.76 g (5.10 mmol),
respectively, and that of catalyst IVb to 10 mol% with respect to
1a in the first cycle. The catalyst was recovered after each cycle
by centrifugation of the resulting reaction mixture followed by
separation from the clear product solution by simple decantation.
Fresh portions of reagents 1a and 2a were then added to the
vessel containing the pre-dried (20 Torr, 30 min) recovered
catalyst and the catalytic reaction was re-performed. In this
manner, a single catalyst specimen could be 19 times reused in
the reaction (total operation period ~230 h) without any negative
impact on the conversion of starting compounds or enantiomeric
purity of product 3a (Figure 3). These characteristics became a
somewhat lower in the 20th cycle only, which may be attributed
to catalyst mass reduction during multiple workups.
Figure 4. HRMS of freshly prepared and multiply used (after 20th cycle)
catalyst IVb.
The synthetic utility of prepared compounds
3 was
demonstrated by a facile conversion of N-nosylated products
3m-o to fused pirrolidino-tetrahydroquinolines 5a-c via
successive deprotection with PhSH/Cs2CO3 followed by
reductive amination of resulting tetrahydroquinolines 4a-c with
Zn/AcOH (Scheme 3).[29]
The tricyclic backbone of compounds 5 is incorporated into
Neurukin NK2 receptor antagonists, BKCa channel agonists,
and liver x receptor (LXR) modulators.[25] Compound 5b was
prepared earlier as a mixture of diastereomers (dr 87:13) from
Noteworthy is that HRMS of 19-fold used catalyst IVb was
similar to corresponding spectra of the freshly prepared
specimen (See Figure 4 and the Supporting Information).
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10.1002/ejoc.201801423
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MHz spectrometer. The chemical shifts of 1H and 13C were measured
relative to Me4Si, CDCl3, respectively. IR spectra were recorded using
BRUKER ALPHA-T instrument and are reported in wavenumbers (cm-1).
Optical rotations were measured on a polarimeter and calibrated with
pure solvent as a blank. Atoms in the X-ray image of compound 4a are
represented via thermal ellipsoids at the 50% probability level. CCDC
1827154 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre. The HPLC analyses were performed on
chiral stationary phase columns Chiralpak AD-H and Chiralcel OD-H
detection at 254 nm. Silica gel (0.060−0.200 mm) was used for column
chromatography. All reagents and solvents were purified according to
common methods. Centrifugation was performed at 3500 rpm. Racemic
compounds 3 were prepared from 1 and 2 using TEA as catalyst.
diastereomerically diverse tetrahydroquinoline 4b derived from
unprotected ortho-aminochalcone 1’.[30] Using N-nosylated
tetrahydroquinolines 3m-o, diastereomerically pure and readily
attainable via the IVb-catalyzed asymmetric cascade reaction of
1b with 2a, 2d and 2i, respectively, we fulfilled a convenient
stereospecific synthesis of compounds 4a-c and 5a-c as single
diastereomers. The absolute (2S,3R,4S)-configuration of
stereogenic centers in compounds 3-5 was unambiguously
confirmed by the X-ray analysis of deprotected compound 4a.
General procedure for the asymmetric aza-Michael–Michael reaction
Method 1. A mixture of chalcone 1 (0.08 mmol), nitroolefin 2 (0.11 mmol),
catalyst IVb (3.1 mg, 4.0 µmol, 5 mol%) and CH2Cl2 (0.2 mL) was stirred
at ambient temperature for 3-15 h (TLC-monitoring). The reaction mixture
was evaporated in vacuo and Et2O/n-hexane (8:2) mixture (5 mL) was
added to the residue. Finely dispersed catalyst IVb was collected at the
bottom of flask via centrifugation and the upper clear solution containing
product 3 and excess of 2, was carefully decanted. Then, fresh Et2O/n-
hexane (8:2) mixture (5 mL) was added to the residue and the
centrifugation procedure was four times re-performed as described
above. The combined organic extracts were evaporated under reduced
pressure (20 Torr). The remaining raw product was purified by column
chromatography (silica gel, n-hexane/EtOAc, 5:1 to 1:1) to afford
corresponding tetrahydroquinoline 3.
Scheme
3.
Chemical
transformations
of
N-nosyl-protected
tetrahydroquinolines 3m-o.
Method 2 (scaled procedure for compounds 3a, 3m, 3n and 3o). A
mixture of chalcone 1 (3.4 mmol), nitroolefin 2 (5.1 mmol), catalyst IVb
(0.138 g, 0.17 mmol, 5 mol%) and CH2Cl2 (2.0 mL) was stirred at
ambient temperature for 10-12 h (TLC-monitoring). The reaction mixture
was evaporated in vacuo and Et2O/n-hexane (8:2 solvent system (5 mL)
was added to the residue. Finely dispersed catalyst IVb was collected at
the bottom of flask via centrifugation and the upper clear solution
containing product 3 and excess of 2, was carefully decanted. Then,
fresh Et2O/n-hexane (8:2) mixture (5 mL) was added to the residue and
the centrifugation procedure was four times re-performed as described
above. The combined organic extracts were evaporated under reduced
pressure (20 Torr). The remaining raw product was purified by column
chromatography (silica gel, n-hexane/EtOAc, 5:1 to 1:1) to afford
corresponding tetrahydroquinoline 3.
Conclusions
To conclude, the most recyclable ionic liquid-supported
bifunctional tertiary amine–squaramide organocatalyst for the
asymmetric domino reaction has been found. Over this catalyst,
N-protected (with Ts or Nos groups) ortho-aminochalcones
underwent the aza-Michael/Michael domino reaction with
nitroolefins to afford corresponding 2,3,4-trisubstituted
tetrahydroquinolines as single diastereomers in nearly
quantitative yield with up to 99% ee. The catalyst could be
readily separated from the reaction mixture via a simple
centrifugation/decantation workup and 19 times reused in the
catalytic reaction without
a
noticeable conversion or
enantioselectivity reduction. The synthetic utility of N-nosylated
products was demonstrated by their facile conversion to
pharmacology-useful fused pirrolidino-tetrahydroquinolines of
high diastreomeric and enantiomeric purity via the
deprotection/reductive amination sequence.
General procedure for recycling of catalyst IVb.
After separation from the reaction mixture, catalyst IVb was dried under
reduced pressure (50 Torr, 50 oC) for 30 min. Then, fresh portions of
reagents (1a and 2a) and solvent (CH2Cl2) were added to the recovered
catalyst and the reaction was re-performed as described above.
Characterization data on novel compounds 3c,f,j-o prepared by methods
1 and 2 are given below.
Experimental Section
General remarks. HRMS (high-resolution mass spectrometry) spectra
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 tom/z = 3000 Da; external or internal calibration was done with an
electrospray calibrant solution. NMR spectra were recorded on a 300
2-((2S,3R,4S)-2-(4-Bromophenyl)-3-nitro-1-tosyl-1,2,3,4-
tetrahydroquinolin-4-yl)-1-phenylethanone (3c).
Colorless solid. Yield 46 mg (98%); m.p. 95-97 °C; [α]20D: -18.0 (c 1.6,
1
CHCl3); H NMR (300 MHz, CDCl3): δ = 7.86 (d, J = 7.3 Hz, 3H), 7.67 –
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10.1002/ejoc.201801423
European Journal of Organic Chemistry
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7.55 (m, 3H), 7.54 – 7.36 (m, 5H), 7.35 – 7.27 (m, 2H), 7.25 – 7.11 (m,
3H), 6.83 (d, J = 7.6 Hz, 1H), 6.04 (d, J = 7.0 Hz, 1H), 4.86 (dd, J = 10.3,
7.2 Hz, 1H), 3.31 (dd, J = 18.1, 8.1 Hz, 1H), 3.10 – 3.00 (m, 1H), 2.92 (dd,
J = 18.1, 3.3 Hz, 1H), 2.45 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 195.1,
144.8, 138.8, 135.9, 135.5, 135.1, 133.8, 132.3, 131.3, 130.0, 128.8,
128.6, 128.0, 127.9, 127.3, 127.2, 125.8, 122.6, 94.1, 62.2, 36.7, 35.8,
Violet solid. Yield 44 mg (87%); m.p. 130-132 °C; [α]20D: -8.0 (c 1.0,
CHCl3); 1H NMR (500 MHz, DMSO-d6): δ = 7.93 (d, J = 7.0 Hz, 2H), 7.73
– 7.63 (m, 1H), 7.59 – 7.49 (m, 5H), 7.44 – 7.32 (m, 3H), 7.25 (t, J = 6.5
Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 5.86 (d, J = 3.6 Hz, 1H), 5.19 – 5.11 (m,
2H), 5.00 (d, J = 14.2 Hz, 2H), 4.83 (s, 1H), 3.71 (dd, J = 18.6, 6.7 Hz,
1H), 3.24 (dd, J = 18.9, 3.0 Hz, 1H), 3.11 (s, 1H), 2.38 (s, 3H); 13C NMR
(75 MHz, DMSO-d6): δ = 229.5, 201.7, 149.9, 141.3, 140.4, 139.4, 138.9,
136.7, 135.4, 134.1, 133.2, 132.7, 132.2, 131.5, 106.6, 97.4, 90.8, 90.2,
89.3, 85.9, 61.9, 42.1, 40.2, 26.4. HRMS (ESI): m/z = 653.0777, calcd.
for C32H26N2O8SMn [M+H]+: 653.0785.
21.7; HRMS (ESI): m/z
= 627.0554 and 629.0540, calcd. for
C30H25BrN2NaO5S [M+Na]+: 627.0560 and 629.0541.
2-((2S,3R,4S)-2-(2,4-Dichlorophenyl)-3-nitro-1-tosyl-1,2,3,4-
tetrahydroquinolin-4-yl)-1-phenylethanone (3f).
2-((2S,3R,4S)-3-Nitro-1-((2-nitrophenyl)sulfonyl)-2-phenyl-1,2,3,4-
tetrahydroquinolin-4-yl)-1-phenylethanone (3m):
Colorless solid. Yield 44 mg (95%); m.p. 103-105 °C; [α]20D: 11.0 (c 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3): δ = 7.94 – 7.81 (m, 3H), 7.61 (d, J =
7.9 Hz, 3H), 7.54 – 7.41 (m, 3H), 7.40 – 7.31 (m, 3H), 7.26 – 7.15 (m,
3H), 6.85 (d, J = 7.6 Hz, 1H), 6.35 (d, J = 7.3 Hz, 1H), 5.01 – 4.90 (m,
1H), 3.28 (dd, J = 18.1, 8.1 Hz, 1H), 3.16 – 3.05 (m, 1H), 2.97 – 2.85 (m,
1H), 2.46 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 195.2, 144.9, 136.1,
135.9, 135.1, 134.6, 133.8, 133.2, 130.5, 130.0, 129.9, 128.8, 128.6,
128.0, 127.9, 127.3, 127.0, 126.8, 126.0, 92.0, 59.4, 35.8, 21.7. HRMS
Colorless solid. Yield 1.80 g (99%); m.p. 108-110 °C; [α]20D: +8.7 (c 1.0,
1
CHCl3); H NMR (300 MHz, CDCl3): δ = 7.90 (d, J = 7.6 Hz, 1H), 7.86 –
7.77 (m, 2H), 7.72 (dd, J = 14.7, 7.5 Hz, 2H), 7.66 – 7.60 (m, 2H), 7.57 (d,
J = 8.2 Hz, 2H), 7.47 (dt, J = 14.8, 7.4 Hz, 5H), 7.33 (d, J = 5.2 Hz, 2H),
7.25 – 7.20 (m, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.16 (d, J = 7.1 Hz, 1H),
4.89 (dd, J = 10.8, 7.2 Hz, 1H), 3.56 – 3.39 (m, 2H), 3.04 (d, J = 15.0 Hz,
1H); 13C NMR (75 MHz, CDCl3): δ = 195.4, 139.1, 139.0, 135.9, 135.6,
134.5, 133.8, 132.1, 131.9, 131.82, 131.3, 130.9, 129.4, 129.1, 129.1,
128.8, 128.7, 128.7, 127.9, 127.9, 127.6, 126.4, 125.5, 124.1, 94.9, 62.9,
36.4. HRMS (ESI): m/z = 575.1598, calcd. for C29H27N4O7S [M+NH4]+:
575.1595.
(ESI): m/z
= 612.1111 and 614.1085, calcd. for C30H28Cl2N3O5S
[M+NH4]+: 612.1121 and 614.1094.
2-((2S,3R,4S)-2-(4-Butoxyphenyl)-3-nitro-1-tosyl-1,2,3,4-
tetrahydroquinolin-4-yl)-1-phenylethanone (3j)
Colorless solid. Yield 46 mg (98%); m.p. 68-70 °C; [α]20D: -15.0 (c 1,
CHCl3); 1H NMR (300 MHz, CDCl3): δ = 7.86 (d, J = 7.6 Hz, 3H), 7.60 (d,
J = 8.0 Hz, 3H), 7.48 (t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.34 –
7.27 (m, 2H), 7.18 (dd, J = 14.6, 8.1 Hz, 3H), 6.82 (d, J = 8.6 Hz, 3H),
6.05 (d, J = 6.9 Hz, 1H), 4.89 (dd, J = 10.2, 7.0 Hz, 1H), 3.93 (t, J = 6.4
Hz, 2H), 3.30 (dd, J = 18.1, 8.3 Hz, 1H), 3.15 – 3.03 (m, 1H), 2.89 (dd, J
= 18.1, 3.6 Hz, 1H), 2.44 (s, 3H), 1.83 – 1.69 (m, 2H), 1.58 – 1.40 (m,
2H), 0.99 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ = 195.2, 159.1,
144.5, 135.9, 135.7, 135.4, 133.6, 131.4, 131.3, 129.9, 128.7, 128.3,
127.9, 127.5, 127.2, 127.0, 126.9, 125.8, 115.0, 94.3, 67.7, 62.3, 37.1,
35.8, 31.2, 21.6, 19.2, 13.8; HRMS (ESI): m/z = 599.2231, calcd. for
C34H35N2O6S[M+H]+: 599.2210.
2-((2S,3R,4S)-2-(2-Bromophenyl)-3-nitro-1-((2-nitrophenyl)sulfonyl)-
1,2,3,4-tetrahydroquinolin-4-yl)-1-phenylethanone (3n)
Yellow solid. Yield 2.00 g (95%); m.p. 95-97 °C; [α]20D: +15.2 (c 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3): δ = 8.02 (d, J = 7.0 Hz, 1H), 7.87 (d,
J = 7.7 Hz, 2H), 7.84 – 7.72 (m, 3H), 7.71 – 7.55 (m, 4H), 7.47 (dd, J =
13.3, 6.9 Hz, 3H), 7.32 (d, J = 7.9 Hz, 1H), 7.16 (dd, J = 20.7, 7.3 Hz, 2H),
6.97 (d, J = 7.4 Hz, 1H), 6.50 (d, J = 7.2 Hz, 1H), 5.04 (dd, J = 10.3, 7.4
Hz, 1H), 3.60 (t, J = 9.1 Hz, 1H), 3.41 (dd, J = 17.9, 8.3 Hz, 1H), 3.07 (d,
J = 15.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 195.5, 138.9, 136.2, 135.9,
134.6, 133.8, 133.6, 131.9, 131.5, 131.0, 130.2, 128.8, 128.8, 128.4,
127.9, 127.6, 126.9, 125.9, 124.5, 122.3, 93.1, 61.6, 36.5; HRMS (ESI):
m/z = 652.0257 and 660.0225, calcd. for C29H22BrN3NaO7S [M+Na]+:
658.0254 and 660.0235.
2-((2S,3R,4S)-3-Nitro-2-ferrocenyl-1-tosyl-1,2,3,4-tetrahydroquinolin-
4-yl)-1-phenylethanone (3k)
2-((2S,3R,4S)-2-(3-Methoxyphenyl)-3-nitro-1-((2-
nitrophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-4-yl)-1-
phenylethanone (3o)
Reddish-violet solid. Yield 44 mg (89%); m.p. 107-109 °C; [α]20D: -10.0 (c
0.7, CHCl3); 1H NMR (300 MHz, DMSO-d6): δ = 7.95 (d, J = 7.6 Hz, 2H),
7.76 – 7.64 (m, 1H), 7.60 – 7.51 (m, 5H), 7.39 (d, J = 8.2 Hz, 2H), 7.32 (d,
J = 7.9 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 5.96 (d,
J = 4.5 Hz, 1H), 5.39 (dd, J = 9.1, 4.4 Hz, 1H), 4.21 (s, 1H), 4.17 (s, 1H),
4.11 (s, 1H), 4.01 (s, 5H), 3.96 (s, 1H), 3.65 (dd, J = 18.4, 6.2 Hz, 1H),
3.29 (d, J = 4.6 Hz, 1H), 3.25 – 3.15 (m, 1H), 2.38 (s, 3H); 13C NMR (75
MHz, DMSO-d6): δ = 201.9, 149.7, 141.4, 140.7, 140.4, 138.8, 136.3,
135.2, 134.0, 133.3, 132.3, 132.1, 131.9, 131.2, 98.5, 93.5, 74.1, 73.8,
73.2, 71.5, 63.4, 42.3, 40.3, 26.4; HRMS (ESI): m/z = 634.1217, calcd.
for C34H30N2O5SFe [M]+: 634.1220.
Yellow solid. Yield 1.90 g (98%); m.p. 86-88 °C; [α]20D: +17.0 (c 1.0,
CHCl3); IR (KBr) 3422, 3070, 3018, 2939, 2838, 1686, 1602, 1544, 1489,
1451, 1372, 1278, 1228, 1174, 1127, 1042, 990, 852, 755, 691, 589 cm-
1; 1H NMR (300 MHz, CDCl3): δ = 7.90 (d, J = 7.5 Hz, 2H), 7.83 (t, J = 7.6
Hz, 2H), 7.72 (dd, J = 13.5, 7.4 Hz, 2H), 7.63 (dd, J = 6.7, 5.3 Hz, 2H),
7.54 – 7.41 (m, 3H), 7.23 (d, J = 7.9 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H),
6.81 (dd, J = 18.2, 10.2 Hz, 3H), 6.13 (d, J = 7.0 Hz, 1H), 4.89 (dd, J =
10.5, 7.1 Hz, 1H), 3.85 (d, J = 10.6 Hz, 1H), 3.75 (s, 3H), 3.56 – 3.39 (m,
2H), 3.03 (d, J = 15.0 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ = 195.4,
159.9, 140.6, 135.9, 135.5, 134.5, 133.8, 131.9, 130.9, 130.3, 128.8,
128.7, 128.0, 127.8, 127.4, 125.6, 124.2, 118.5, 114.1, 112.1, 94.7, 62.7,
2-((2S,3R,4S)-3-Nitro-2-cymantrenyl-1-tosyl-1,2,3,4-
tetrahydroquinolin-4-yl)-1-phenylethanone (3l)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801423
European Journal of Organic Chemistry
FULL PAPER
55.2, 36.4; HRMS (ESI): m/z = 588.1430, calcd. for C30H26N3O8S [M+H]+:
588.1435.
127.9, 127.5, 127.2, 121.3, 119.5, 119.1, 114.7, 114.5, 112.8, 90.4, 59.4,
55.3, 41.2, 36.9; HRMS (ESI): m/z = 403.1647, calcd. for C24H23N2O4
[M+H]+: 403.1652.
Synthesis of 5a-c (general procedure)
Synthesis of 4a-c (general procedure)
Zinc powder (30 equiv., 0.51 g) was added to a stirred solution of 4 (0.26
mmol) in AcOH (4.0 mL). The reaction mixture was heated with stirring at
70 ºC for 4.0 h (TLC monitoring). Inorganic materials were filtered off.
The filtrate was diluted with EtOAc (10 mL) and neutralized with
concentrated aq. NaHCO3. The mixture was extracted with EtOAc (3 x 10
mL), washed with brine and dried over anhydrous sodium sulfate. The
solvent was evaporated in vacuo. The residue was purified by column
chromatography (n-hexane/EtOAc 6:1) to afford corresponding
compound 5.
Thiophenol (0.28 mL, 2.72 mmol) and Cs2CO3 (1.12 g, 4.30 mmol) were
added to a solution of 3 (2.50 mmol) in MeCN (30 ml). The reaction
mixture was stirred at ambient temperature for 12 h. The solvents were
evaporated in vacuo and the residue diluted with EtOAc (20 mL).
Inorganic materials were filtrated off, the resulting solution of the raw
product was purified by column chromatography on silica gel (n-
hexane/EtOAc, 3:1) to afford corresponding compound 4.
2-((2S,3R,4S)-3-Nitro-2-phenyl-1,2,3,4-tetrahydroquinolin-4-yl)-1-
phenylethanone (4a)
(2S,3aR,4S,9bS)-2,4-Diphenyl-2,3,3a,4,5,9b-hexahydro-1H-
pyrrolo[2,3-c]quinoline (5a)
Yellow solid. Yield 0.79 g (85%); m.p. 172-174 °C; [α]20D: +41.0 (c 1.0,
CHCl3); IR (KBr) 3373, 3060, 3016, 2903, 2880, 1685, 1545, 1495, 1478,
1325, 1305, 1230, 980, 748, 696 cm-1; 1H NMR (300 MHz, CDCl3): δ =
8.02 (d, J = 7.0 Hz, 1H), 7.87 (d, J = 7.7 Hz, 2H), 7.84 – 7.72 (m, 3H),
7.71 – 7.55 (m, 4H), 7.47 (dd, J = 13.3, 6.9 Hz, 3H), 7.32 (d, J = 7.9 Hz,
1H), 7.16 (dd, J = 20.7, 7.3 Hz, 2H), 6.97 (d, J = 7.4 Hz, 1H), 6.50 (d, J =
7.2 Hz, 1H), 5.04 (dd, J = 10.3, 7.4 Hz, 1H), 3.60 (t, J = 9.1 Hz, 1H), 3.41
(dd, J = 17.9, 8.3 Hz, 1H), 3.07 (d, J = 15.3 Hz, 1H); 13C NMR (75 MHz,
CDCl3): δ = 196.8, 142.9, 137.9, 136.4, 133.4, 129.1, 129.1, 128.6, 127.9,
127.8, 127.4, 127.3, 121.4, 119.2, 114.6, 90.7, 59.6, 41.1, 37.0; HRMS
(ESI): m/z = 373.1549, calcd. for C23H21N2O3 [M+H]+: 373.1547.
Yellow solid. Yield 70 mg (83%); m.p. 120-122 °C; [α]20D: -140.0 (c 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3): δ = 7.56 – 7.45 (m, 5H), 7.42 – 7.30
(m, 5H), 7.24 (br s, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.95 (d, J = 7.3 Hz, 1H),
6.69 (t, J = 7.3 Hz, 1H), 6.58 (d, J = 7.9 Hz, 1H), 4.72 (d, J = 8.8 Hz, 1H),
4.61 – 4.49 (m, 1H), 3.32 – 3.16 (m, 2H), 2.47 – 2.30 (m, 2H); 13C NMR
(75 MHz, CDCl3): δ = 145.9, 143.9, 142.4, 128.6, 128.1, 127.9, 127.2,
126.8, 126.6, 125.5, 122.8, 116.4, 112.0, 65.8, 62.9, 60.4, 42.1, 36.5;
HRMS (ESI): m/z = 327.1858, calcd. for C23H23N2 [M+H]+: 327.1856.
(2S,3aR,4S,9bS)-4-(2-Bromophenyl)-2-phenyl-2,3,3a,4,5,9b-
hexahydro-1H-pyrrolo[2,3-c]quinoline (5b)
2-((2S,3R,4S)-2-(2-Bromophenyl)-3-nitro-1,2,3,4-tetrahydroquinolin-
4-yl)-1-phenylethanone (4b)
Brownish solid. Yield 97 mg (93%); m.p. 94-96 °C; [α]20D: -109.0 (c 1.0,
CHCl3); IR (KBr) 3391, 3040, 2916, 1668, 1585, 1550, 1490, 1351, 1259,
990, 756, 690 cm-1; 1H NMR (300 MHz, CDCl3): δ = 7.63 (dd, J = 6.7, 3.2
Hz, 1H), 7.59 – 7.49 (m, 3H), 7.38 (dd, J = 14.0, 6.7 Hz, 5H), 7.13 – 7.07
(m, 1H), 6.98 (d, J = 7.2 Hz, 1H), 6.73 (t, J = 7.2 Hz, 1H), 6.60 (dd, J =
16.0, 8.1 Hz, 1H), 5.30 (d, J = 8.9 Hz, 1H), 4.85 (d, J = 9.3 Hz, 1H), 4.67
– 4.56 (m, 2H), 3.37 (dd, J = 17.5, 9.2 Hz, 1H), 3.25 (dd, J = 20.9, 11.2
Hz, 1H), 2.43 (dd, J = 13.2, 7.7 Hz, 2H); 13C NMR (75 MHz, CDCl3): δ =
143.9, 141.6, 133.3, 129.5, 128.8, 128.5, 127.6, 127.4, 127.3, 126.8,
125.8, 116.9, 112.4, 66.1, 61.6, 43.1, 36.3; HRMS (ESI): m/z = 405.0961
and 407.0950, calcd. for C23H22BrN2 [M+H]+: 405.0961 and 407.0941.
Yellow solid. Yield 1.00 g (89%); m.p. 71-73 °C; [α]20D: +151.0 (c 2.0,
CHCl3); 1H NMR (300 MHz, CDCl3): δ = 7.74 (d, J = 7.5 Hz, 2H), 7.66 (d,
J = 7.6 Hz, 1H), 7.58 – 7.48 (m, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.38 – 7.31
(m, 1H), 7.21 – 7.03 (m, 3H), 6.83 – 6.75 (m, 1H), 6.74 – 6.69 (m, 1H),
5.59 – 5.47 (m, 2H), 4.54 – 4.45 (m, 1H), 3.24 (d, J = 6.1 Hz, 2H);; 13C
NMR (75 MHz, CDCl3) δ 196.80, 137.23, 136.35, 133.84, 133.44, 130.22,
129.11, 128.58, 128.13, 128.11, 127.99, 127.87, 123.52, 119.56, 114.91,
86.63, 57.37, 41.82, 36.22; HRMS (ESI): m/z = 451.0657 and 453.0640,
calcd. for C23H20BrN2O3 [M+H]+: 451.0652 and 453.0633.
2-((2S,3R,4S)-2-(3-Methoxyphenyl)-3-nitro-1,2,3,4-
tetrahydroquinolin-4-yl)-1-phenylethanone (4c)
(2S,3aR,4S,9bS)-4-(3-Methoxyphenyl)-2-phenyl-2,3,3a,4,5,9b-
hexahydro-1H-pyrrolo[2,3-c]quinoline (5c)
Yellow solid. Yield 0.95 g (95%); m.p. 81-83 °C; [α]20D: +249.2 (c 2.0,
CHCl3); IR (KBr) 3350, 3058, 3023, 2968, 2943, 2898, 2839, 1683, 1610,
1585, 1545, 1487, 1450, 1410, 1359, 1287, 1229,1156, 1045, 983, 754,
688 cm-1; 1H NMR (300 MHz, CDCl3): δ = 7.88 (d, J = 7.4 Hz, 1H), 7.60 (t,
J = 7.2 Hz, 1H), 7.55 – 7.43 (m, 3H), 7.33 (t, J = 7.5 Hz, 2H), 7.24 (d, J =
6.8 Hz, 1H), 7.11 (t, J = 7.6 Hz, 2H), 7.06 – 6.99 (m, 1H), 6.86 (dd, J =
8.2, 2.1 Hz, 1H), 6.76 (t, J = 7.4 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 5.23 (t,
J = 8.4 Hz, 1H), 4.90 (d, J = 8.1 Hz, 1H), 4.48 – 4.39 (m, 1H), 3.78 (s,
3H), 3.39 (qd, J = 18.5, 5.3 Hz, 2H); 13C NMR (75 MHz, CDCl3): δ =
196.9, 160.0, 142.8, 139.6, 136.4, 133.5, 130.1, 129.1, 128.6, 128.0,
Brownish solid. Yield 83 mg (90%); m.p. 75-76 °C; [α]20D: -78.0 (c 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3): δ = 7.52 – 7.46 (m, 2H), 7.40 – 7.35
(m, 2H), 7.32 (d, J = 7.0 Hz, 1H), 7.27 – 7.23 (m, 1H), 7.18 – 7.04 (m,
4H), 6.95 (d, J = 7.4 Hz, 1H), 6.86 (dd, J = 8.3, 2.0 Hz, 1H), 6.69 (t, J =
7.4 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 4.86 – 4.66 (m, 1H), 4.54 – 4.46 (m,
1H), 3.94 (d, J = 11.5 Hz, 1H), 3.82 (s, 3H), 3.33 – 3.20 (m, 1H), 3.18 –
3.08 (m, 1H), 2.42 – 2.33 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 159.9,
144.9, 143.9, 137.4, 129.9, 128.9, 128.4, 127.7, 127.5, 127.2, 126.5,
125.8, 125.4, 119.5, 116.8, 112.4, 68.1, 65.9, 55.2, 42.4, 38.7; HRMS
(ESI): m/z = 357.1954, calcd. for C24H25N2O [M+H]+: 357.1961.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801423
European Journal of Organic Chemistry
FULL PAPER
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Keywords: Asymmetric catalysis • Supported organocatalysts •
squaramides • Asymmetric domino reaction •
Tetrahydroquinolines
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10.1002/ejoc.201801423
European Journal of Organic Chemistry
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Asymmetric aza-Michael /
Michael domino reaction of
N-Ts or N-Nos ortho-
aminochalcones with
nitroolefins has been
performed in the presence
of highly recyclable (19
cycles) IL-supported tertiary
amine–squaramide
organocatalyst to afford
trisubstituted tetrahydro-
quinolines as single
diastereomers with up to
99% ee. N-Nosylated
products were converted to
fused pirrolidino-
Organocatalysis
Rinat S. Tukhvatshin,
Alexander S. Kucherenko,*
Yulia V. Nelyubina,. Sergei G.
Zlotin*
Page No. – Page No.
Stereoselective Synthesis
of Tetrahydroquinolines via
Asymmetric Domino
Reaction Catalyzed by
Recyclable Ionic-Liquid-
supported Bifunctional
Tertiary Amine
tetrahydroquinolines.
This article is protected by copyright. All rights reserved.