Organocatalytic enantioselective cascade aza-michael/michael addition for the synthesis of highly functionalized tetrahydroquinolines and tetrahydrochromanoquinolines

Article abstract of DOI:10.1002/adsc.201300670

An efficient organocatalytic highly asymmetric cascade aza-Michael/Michael addition reaction for the synthesis of tetrahydroquinolines and tetrahydrochromanoquinolines has been developed. This cascade reaction proceeds well at low catalyst loading with a broad substrate scope, furnishing the desired products in excellent yields with excellent diastereoselectivities and enantioselectivities (up to >99:1 dr, 99% ee) under mild conditions. Importantly, it is the first catalytic asymmetric method for tetrahydrochromanoquinolines. This protocol provides a straightforward entry to highly functionalized chiral tetrahydroquinoline and tetrahydrochromanoquinoline derivatives from simple starting materials. Copyright

Full text of DOI:10.1002/adsc.201300670

FULL PAPERS
DOI: 10.1002/adsc.201300670
Organocatalytic Enantioselective Cascade Aza-Michael/Michael
Addition for the Synthesis of Highly Functionalized
Tetrahydroquinolines and Tetrahydrochromanoquinolines
Wen Yang,a Hai-Xiao He,a Yu Gao,a and Da-Ming Dua,*
a
School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing 100081, Peopleꢀs Republic of
China
Fax : (+86)-010-68914985; e-mail: dudm@bit.edu.cn
Received: July 28, 2013; Published online: November 27, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300670.
Abstract: An efficient organocatalytic highly asym- ly, it is the first catalytic asymmetric method for tet-
metric cascade aza-Michael/Michael addition reac- rahydrochromanoquinolines. This protocol provides
tion for the synthesis of tetrahydroquinolines and a straightforward entry to highly functionalized
tetrahydrochromanoquinolines has been developed. chiral tetrahydroquinoline and tetrahydrochromano-
This cascade reaction proceeds well at low catalyst quinoline derivatives from simple starting materials.
loading with a broad substrate scope, furnishing the
desired products in excellent yields with excellent Keywords: cascade aza-Michael/Michael addition;
diastereoselectivities and enantioselectivities (up to organocatalysis; squaramide; tetrahydrochromano-
>99:1 dr, 99% ee) under mild conditions. Important- quinolines; tetrahydroquinolines
Introduction
ods for tetrahydroquinolines,[4,5] and none for tetrahy-
drochromanoquinolines. Among them, two reports on
Tetrahydroquinoline and tetrahydrochromanoquino-
line motifs are present in a number of natural and
pharmaceutical products, possessing diverse biological
activities.[1] Some typical examples are shown in
Figure 1. For example, the simple tetrahydroquinoline
angustureine, isolated from the bark of South Ameri-
can tree Galipea officinalis,[1c] shows anti-mycobacteri-
al and anti-malarial activities.[1d] Martinellic acid and
martinelline, extracted from the tropical plant Marti-
nella iquitosensis, exhibit modest antibiotic activity as
an eye medicine for conjunctivitis in South America
and possess potent antagonist activity toward bradyki-
nin (BK) receptors.[1e] L-689,560 is one of the most
potent antagonists for the NMDA receptor glycine
site.[1f] The tetrahydrochromanoquinoline derivative
figured displays anti-proliferative activity comparable
to that of tamoxifen on both MDA-MB-231 and
MCF-7 breast cancer cells.[1g] Additionally, some tet-
rahydroquinoline derivatives have been employed as
chiral ligands in asymmetric catalysis.[2]
In view of their great significance, tetrahydroquino-
lines[1a,b] and tetrahydrochromanoquinolines[3] have
become attractive synthetic targets, and many effi-
cient approaches have been established. However,
there are only a few catalytic enantioselective meth- Figure 1. Examples of tetrahydroquinoline derivatives.
3670
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Organocatalytic Enantioselective Cascade Aza-Michael/Michael Addition
Scheme 1. Organocatalytic cascade aza-Michael/Michael addition for tetrahydroquinoline derivatives.
organocatalytic cascade reactions represent impres- a base catalyst could be transformed into nitrogen
sive examples.[5] Recently, Xu and co-workers succes- anion species, which display much higher nucleophi-
sively reported chiral thiourea-catalyzed highly enan- licity than arylamines. To verify the viability of this
tioselective cascade Michael/aza-Henry and aza-Mi- concept, we chose readily accessible 2-tosylaminochal-
chael/Michael reactions for the synthesis of tetrahy- cone 1a and b-methyl-b-nitrostyrene 2a as the model
droquinoline derivatives with three contiguous stereo- substrates. The utilization of b-methyl-b-nitrostyrene
centers (Scheme 1A). In the two reports, high yields 2a could lead to the formation of one quaternary ste-
and excellent enantioselectivities were always ach- reocenter albeit with relatively low reactivity. Initially,
ieved. But there were some shortcomings including the model reaction was performed in the presence of
relatively low reactivity, and only moderate to good 5 mol% quinine-derived squaramide I (Figure 2) at
diastereoselectivities in most cases. Given the limited room temperature. To our delight, the cascade aza-
successes, the development of efficient catalytic enan- Michael/Michael addition was completed within 12 h
tioselective methods for this important class of and afforded the desired tetrahydroquinoline 3aa in
hetero
G
excellent yield with excellent diastereoselectivity and
Organocatalytic cascade reactions have emerged as enantioselectivity (99:1 dr, 97% ee). When pg was an
a powerful tool for the one-pot construction of multi- Ac, Boc or Cbz group, no reaction occurred. This
ple bonds in the modern organic synthesis.[6] As a new result indicates the reaction requires sufficient acidity
class of good hydrogen-bonding organocatalysts,[7] of the NH group. With the above excellent result in
squaramides have been increasingly utilized in these hand, we evaluated a small library of organocatalysts
cascade reactions.[8] In keeping with our interest in or- for this cascade process. The results are presented in
ganocatalytic reactions using squaramide catalysts,[9] Table 1. Quinine-derived squaramide II bearing a 4-
we would like to document an efficient squaramide- CF3 group on the aromatic ring gave an inferior result
catalyzed highly asymmetric cascade aza-Michael/Mi- (Table 1, entry 2). When squaramides III and IV de-
chael addition reaction[10] for the synthesis of tetrahy- rived from quinidine were utilized, the opposite enan-
droquinolines and tetrahydrochromanoquinolines tiomers of 3aa were achieved with the same excellent
(Scheme 1B).
stereoselectivity, albeit with lower yield for the later
(Table 1, entries 3 and 4). We then turned our atten-
tion to squaramide catalysts V and VI derived from
(1S,2S)-cyclohexane-1,2-diamine (Table 1, entries 5
and 6). Squaramide VI gave almost the same result as
Results and Discussion
Inspired by Xuꢀs cascade aza-Michael/Michael strat- I and III. The C2-symmetrical quinine-derived squara-
egy, we envisioned that enhanced reactivity could be mide VII was also examined, but no better result was
achieved by employing N-pg-2-aminoenones instead observed (Table 1, entry 7). Given the facile synthesis
of 2-aminoenones in the bifunctional catalytic system and cheap starting material quinine, we favored
(where pg is a strong electron-withdrawing protecting squaramide I. In contrast to squar
ACHTUNGTRENaNGNU mide I, quinine-
group). This is because N-pg-2-aminoenones with derived thiourea VIII displayed significantly lower re-
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Figure 2. Structures of organocatalysts.
activity and enantioselectivity (Table 1, entry 8). In ers, but very low yields and enantioselectivities were
addition, quinine and quinidine were used as promot- obtained (Table 1, entries 9 and 10).
With squaramide I as the optimal catalyst, we in-
vestigated the effect of solvent and catalyst loading
for the optimal reaction conditions. The results are
shown in Table 2. All screened solvents afforded ex-
Table 1. Screening of organocatalysts.[a]
cellent stereoselectivities, but only chlorinated sol-
vents gave excellent yields (Table 2, entries 1–7). On
account of the best stereoselectivity in toluene, we
tried the mixtures of toluene and a chlorinated sol-
vent (Table 2, entries 8 and 9). Compared with
a single chlorinated solvent, the mixed solvent could
improve the stereoselectivity slightly and accelerate
the reaction. Subsequently, the effect of catalyst load-
ing was examined. Excellent stereoselectivity was
maintained with a reduced catalyst loading (2 or
1 mol%) (Table 2, entries 10 and 11). Considering the
yield and reaction time, 1 mol% catalyst loading was
an appropriate choice.
Entry
Catalyst
Yield [%][b]
dr[c]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
I
II
III
IV
V
VI
VII
VIII
quinine
quinidine
97
75
95
75
90
94
75
53
15
12
99:1
96:4
99:1
99:1
99:1
99:1
92:8
97:3
97:3
95:5
97
95
97[d]
97[d]
90
Having established the optimal reaction conditions,
we explored the scope of the asymmetric cascade re-
action for the synthesis of tetrahydroquinolines. The
results are summarized in Table 3. A variety of 2-
97
93
82
19
17[d]
tosyl
tosyl
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
[a]
Conditions: 1a (0.11 mmol), 2a (0.1 mmol), catalyst
(5 mol%), and CH2Cl2 (0.5 mL).
Isolated yield.
Determined by chiral HPLC analysis.
Opposite enantiomer.
reacted smoothly with b-methyl-b-nitrostyrene 2a to
afford the corresponding products in high yields with
excellent diastereoselectivities and enantioselectivities
(>99:1 dr, 97–99% ee) (Table 3, entries 1–6). Steric
[b]
[c]
[d]
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Organocatalytic Enantioselective Cascade Aza-Michael/Michael Addition
Table 2. Optimization of reaction conditions.[a]
Entry
Solvent
Loading [mol%]
Time [h]
Yield [%][b]
dr[c]
ee [%][c]
1
2
3
4
5
6
7
8
CH2Cl2
PhMe
THF
MeCN
i-PrOH
DCE
CHCl3
CH2Cl2/PhMe (1:1)
DCE/PhMe (1:1)
DCE/PhMe (1:1)
DCE/PhMe (1:1)
5
5
5
5
5
5
5
5
5
2
1
12
12
12
12
12
12
12
6
97
74
29
47
41
96
97
98
99
96
98
99:1
>99:1
99:1
98:2
99:1
99:1
99:1
>99:1
>99:1
>99:1
>99:1
96.7
98.5
96.7
96.9
94.7
97.3
95.6
97.3
97.6
98.1
97.8
9
10
11
6
12
24
[a]
Conditions: 1a (0.11 mmol), 2a (0.1 mmol), catalyst I, and solvent (0.5 mL).
Isolated yield.
Determined by chiral HPLC analysis.
[b]
[c]
hindrance of R1 group benefits the enantioselectivity. of tetrahydrochromanoquinolines. The reaction of 2-
2-Tosylaminoenones 1g and 1h with aliphatic R1 tosylaminochalcone 1a and 3-nitro-2H-chromene 4a
groups were viable substrates and gave 40% ee and was performed under the above optimal reaction con-
92% ee, respectively (Table 3, entries 7 and 8). Then ditions. Pleasingly, the reaction was completed within
we examined a wide array of different substituted 3 h and provided the desired tetrahydrochromanoqui-
a,b-disubstituted nitroalkenes 2b–m. In most cases, noline 5aa in excellent yield with excellent diastereo-
high yields and excellent stereoselectivities were ob- selectivity and enantioselectivity. So we directly ex-
tained (Table 3, entries 9–17). The results show that plored the scope of the asymmetric cascade aza-Mi-
the electronic nature and position of the substituents chael/Michael addition for tetrahydrochromanoquino-
on the aromatic rings have little influence on the cas- lines without re-optimizing the reaction conditions.
cade process. Although the substrates 2k and 2m dis- The results are presented in Table 4. A range of dif-
played relatively low reactivity, comparable results ferent substituted 2-tosylaminochalcones 1a–f and 3-
were achieved by strengthening the reaction condi- nitro-2H-chromenes 4a–g were tested. Different elec-
tions (Table 3, entries 18 and 20). The alkene 2l dra- tronic and steric variations were tolerated. In almost
matically diminished the yield as compared to 2k, all cases, the corresponding products were obtained in
which may be due to the electron-rich and sterically excellent yields with excellent diastereoselectivities
hindered nature of the cyclohexyl ring (Table 3, and enantioselectivities (>99:1 dr, 94–99% ee)
entry 19 vs. entry 18). In addition, we also examined (Table 4, entries 1–6, 10–15). Only 3-nitro-2H-chro-
a small library of b-substituted nitroalkenes 2n–r. mene 4h bearing a naphthyl ring afforded 90% ee
These substrates exhibited much higher reactivity and (Table 4, entry 16). 2-Tosylaminoenones 1g and 1h
provided the corresponding products in excellent with aliphatic R1 groups worked well in this cascade
yields with excellent diastereoselectivities and enan- process (Table 4, entries 7 and 8). 2-Tosylaminoenoate
tioselectivities (>99:1 dr, 97–98% ee) (Table 3, en- 1i was also a viable substrate and gave a comparable
tries 21–25). Pleasingly, 2-tosylaminoenoate 1i also re- result in a prolonged time (Table 4, entry 9). These re-
acted with nitroalkene 2n to furnish the correspond- sults show that there is not much difference in the re-
ing tetrahydroquinoline 3in with a comparable result activity between 3-nitro-2H-chromenes and b-substi-
(Table 3, entry 26). The absolute configuration of 3aa tuted nitroalkenes in this cascade process. The abso-
was unambiguously established to be 2R,3S,4R by X- lute configuration of 5aa was also determined to be
ray analysis (Figure 3),[11] and those of other products 6aS,7R,12aR by X-ray analysis (Figure 4),[11] and those
were assigned by analogy.
of other products were assigned by analogy.
With the above success, we tried to extend the sub-
As shown in Scheme 2, the further substrate scope
strate scope to 3-nitro-2H-chromenes for the synthesis with other cyclic nitroalkenes was investigated. When
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Table 3. Scope of asymmetric cascade aza-Michael/Michael addition for tetrahydroquinolines.[a]
Entry
R1
R2
R3
Time [h]
Product
Yield [%][b]
dr[c]
ee [%][c,d]
1
2
3
4
5
6
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-FC6H4
4-ClC6H4
2-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
2-MeOC6H4
2-furyl
cinnamyl
i-Pr
cyclohexyl
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
24
24
24
48
48
48
24
24
24
24
24
24
24
48
48
24
48
48
48
24
2
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
98
92
96
85
89
96
90
95
97
94
95
95
95
89
89
98
83
89
49
92
99
99
99
95
97
93
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
99:1
>99:1
>99:1
>99:1
99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
98
98
97
99
99
98
40
92
97
97
96
97
97
97
95
97
97
98
97
94
97
97
97
97
98
97
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
2-MeOC6H4
Me
t-Bu
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
7[e]
8[e]
9
10
11
12
13
14
15
16
17
18[e]
19[e,f]
20[e,f]
21
22
23
24
25
26[e]
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
OEt
3am
3an
3ao
3ap
3aq
3ar
3in
C6H5
H
H
H
H
H
H
4-ClC6H4
4-MeOC6H4
2-MeOC6H4
2-thienyl
C6H5
2
2
3
2
24
[a]
Conditions: 1 (0.22 mmol), 2 (0.2 mmol), catalyst I (1 mol%), and DCE/PhMe (1:1, 1 mL). DCE=1,2-dichloroethane.
Isolated yield.
Determined by chiral HPLC analysis.
Enantiomeric excess of the major diastereomer.
5 mol% of catalyst I.
[b]
[c]
[d]
[e]
[f]
508C.
1,2-dihydro-3-nitronaphthalene 4i was used, the prod- the excellent stereoselectivity being retained by two
uct 5ai was obtained in good yield with excellent ste- simple steps (Scheme 4).
reoselectivity. 1-Nitrocyclohexene 4j gave comparable
stereoselectivity, but showed very low reactivity.
We found that the catalytic model proposed by
Xuꢀs group could not explain our observed stereo-
To highlight the synthetic value of this methodolo- chemical result.[5b] The configurations of products de-
gy, the gram-scale preparations of 3aa and 5aa, and duced following Xuꢀs model are opposite to those de-
synthetic transformation were described. The cascade termined by X-ray analysis. After reconfirming that
reactions of 1a and 2a or 4a on a gram scale were per- the X-ray crystal structures of 3aa, 5aa, and 6 were
formed well in the presence of 0.5 mol% I without correct, we thought that the introduction of a Ts
any significant changes in yield or stereoselectivity group could change the model. On the basis of the
(Scheme 3). Tetrahydrochromanoquinoline 5aa was absolute configuration of 3aa, a different possible
easily converted into amine 6 by Pd/C-catalyzed hy- transition state model was proposed for this cascade
drogenation; its structure was also determined by X- process (Figure 5). 2-Tosylaminochalcone 1a is depro-
ray analysis.[11] Tetrahydrochromanoquinoline 5ia was tonated by the basic nitrogen atom of the quinine
readily transformed into g-lactam 7 in good yield with moiety, and its sulfonamide moiety is coordinated to
the squaramide one. Meanwhile, nitroalkene 2a is ori-
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Organocatalytic Enantioselective Cascade Aza-Michael/Michael Addition
Figure 3. X-ray crystal structure of 3aa.
Figure 4. X-ray crystal structure of 5aa (hydrogen atoms are
omitted for clarity).
ented and activated by the quinine moiety through
hydrogen bonding. The intermolecular aza-Michael dergo intramolecular Michael addition through the
addition first gives R-configured intermediate through Re face attack, forming the 2R,3S,4R-configured prod-
the Re face attack. Then the intermediate could un- uct 3aa.
Table 4. Scope of asymmetric cascade aza-Michael/Michael addition for tetrahydrochromanoquinolines.[a]
Entry
R1
R4
Product
Yield [%][b]
dr[c]
ee [%][c,d]
1
2
3
4
5
6
C6H5
H
H
H
H
H
H
H
H
5aa
5ba
5ca
5da
5ea
5fa
5ga
5ha
5ia
5ab
5ac
5ad
5ae
5af
5ag
5ah
98
98
99
98
91
99
98
98
90
98
97
97
97
99
98
97
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
97
97
98
99
97
97
88
99
99
96
98
96
94
99
97
90
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
2-MeOC6H4
Me
t-Bu
EtO
C6H5
C6H5
7[e]
8[e]
9[e,f]
10
11
12
13
14
15
16
H
6-Cl
6-Br
6,8-Cl2
6,8-Br2
8-OMe
8-OEt
benzo
C6H5
C6H5
C6H5
C6H5
C6H5
[a]
Conditions: 1 (0.22 mmol), 4 (0.2 mmol), catalyst I (1 mol%), and DCE/PhMe (1:1, 1 mL).
Isolated yield.
Determined by chiral HPLC analysis.
Enantiomeric excess of the major diastereomer.
5 mol% of catalyst I.
[b]
[c]
[d]
[e]
[f]
Reaction for 48 h.
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Wen Yang et al.
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Scheme 2. Further investigation of substrate scope.
Scheme 3. The gram-scale preparation.
Conclusions
In conclusion, we have developed an efficient highly
asymmetric cascade aza-Michael/Michael reaction cat-
alyzed by a chiral bifunctional tertiary amine-squara-
mide catalyst for the synthesis of tetrahydroquinolines
and tetrahydrochromanoquinolines. This cascade re-
action proceeded well at low catalyst loading
(1 mol%) with a broad scope of substrates under mild
conditions, and afforded the corresponding adducts in
excellent yields with excellent diastereoselectivities
and enantioselectivities (up to >99:1 dr, 99% ee). Im-
portantly, it is the first catalytic asymmetric method
for chiral tetrahydrochromanoquinolines. This proto-
col provides an easy and straightforward entry to
highly functionalized chiral tetrahydroquinoline and
tetrahydrochromanoquinoline derivatives with three
Scheme 4. The synthetic transformation of products.
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Organocatalytic Enantioselective Cascade Aza-Michael/Michael Addition
Figure 5. Proposed transition state model.
contiguous stereocenters including one quaternary
center from simple starting materials.
References
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Experimental Section
Typical Procedure for Asymmetric Cascade Aza-
Michael/Michael Addition for Tetrahydroquinoline
Derivative 3aa
A mixture of nitroalkene 2a (32.6 mg, 0.2 mmol) and cata-
lyst I (1.3 mg, 0.002 mmol, 1 mol%) in DCE/toluene (1:1,
1 mL) was stirred at room temperature for 10 min. Then 1a
(83.0 mg, 0.22 mmol) was added in one portion. After stir-
ring for 24 h, the reaction mixture was concentrated and di-
rectly purified by silica gel column chromatography to
afford the product 3aa as a white solid; yield: 105.7 mg
(98%); mp 215–2168C. The diastereoselectivity and enantio-
selectivity were determined by HPLC (Daicel Chiralpak
column IA, n-hexane/2-propanol=90:10, flow rate
1.0 mLminÀ1, detection at 254 nm): tminor =9.7 min, tmajor
=
11.0 min, 98% ee, >99:1 dr; [a]2D0: À27.3 (c 0.88, CH2Cl2);
1H NMR (400 MHz, CDCl3): d=8.01 (d, J=8.0 Hz, 1H),
7.87 (d, J=7.2 Hz, 2H), 7.62–7.55 (m, 3H), 7.49–7.41 (m,
3H), 7.34–7.29 (m, 5H), 7.20–7.14 (m, 3H), 6.69 (d, J=
7.6 Hz, 1H), 6.26 (s, 1H), 3.37–3.24 (m, 2H), 2.51 (d, J=
16.8 Hz, 1H), 2.43 (s, 3H), 0.67 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=194.4, 144.8, 138.5, 135.9, 135.8,
134.3, 133.6, 133.1, 130.0, 128.8, 128.7, 128.3, 128.2, 127.9,
127.3, 127.1, 126.6, 125.2, 109.7, 98.2, 67.5, 40.8, 34.8, 21.7,
16.4; IR (KBr): n=3065, 3039, 2922, 1691, 1597, 1543, 1487,
1453, 1356, 1242, 1356, 1242, 1168, 1083, 1061, 981, 926, 808,
756, 700, 689, 663, 652, 570, 535 cmÀ1; HR-MS (ESI): m/z=
558.20581, calcd. for C31H32N3O5S [M+NH4]+: 558.20572.
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Acknowledgements
We are grateful for financial support from the National Natu-
ral Science Foundation of China (Grant no. 21272024), the
Science and Technology Innovation Program of Beijing Insti-
tute of Technology (Grant No. 2011CX01008).
Adv. Synth. Catal. 2013, 355, 3670 – 3678
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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[11] CCDC 943636, CCDC 943637 and CCDC 943638 con-
tain the supplementary crystallographic data for com-
pounds 3aa, 5aa and 6 in this paper. These data can be
obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
3678
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Adv. Synth. Catal. 2013, 355, 3670 – 3678