Bifunctional thiophosphinamide catalyzed highly enantioselective Michael addition of acetone to (E)-2-azido β-nitrostyrenes and the subsequent reductive cyclization

Article abstract of DOI:10.1016/j.tet.2018.08.052

We have proven that primary amine/thiophosphinamide incorporating (1R,2R)-1,2-diphenylethane-1,2-diamine is an efficient catalyst for the asymmetric Michael addition of acetone to (E)-2-azido β-nitrostyrenes. Under the optimal reaction conditions, the corresponding Michael addition products were obtained in excellent yields with almost perfect stereocontrol. Upon treatment with Et₃SiH/InCl₃, the Michael addition products could be successfully converted to the related 2-methyltetrahydroquinolines in acceptable yields with moderate to excellent diastereoselectivity and without appreciable loss in optical purity. This process provides a highly enantioselective pathway for the synthesis of biologically important 2-methyltetrahydroquinoline derivatives.

Full text of DOI:10.1016/j.tet.2018.08.052

Tetrahedron xxx (2018) 1e7
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Bifunctional thiophosphinamide catalyzed highly enantioselective
Michael addition of acetone to (E)-2-azido b-nitrostyrenes and the
subsequent reductive cyclization
Hao Zhang, Youming Wang, Zhenghong Zhou*
Institute and State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Collaborative Innovation Center of Chemical
Science and Engineering (Tianjin), Tianjin, 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
We have proven that primary amine/thiophosphinamide incorporating (1R,2R)-1,2-diphenylethane-1,2-
diamine is an efficient catalyst for the asymmetric Michael addition of acetone to (E)-2-azido b-nitro-
Received 27 June 2018
Received in revised form
3 August 2018
Accepted 31 August 2018
Available online xxx
styrenes. Under the optimal reaction conditions, the corresponding Michael addition products were
obtained in excellent yields with almost perfect stereocontrol. Upon treatment with Et3SiH/InCl3, the
Michael addition products could be successfully converted to the related 2-methyltetrahydroquinolines
in acceptable yields with moderate to excellent diastereoselectivity and without appreciable loss in
optical purity. This process provides a highly enantioselective pathway for the synthesis of biologically
important 2-methyltetrahydroquinoline derivatives.
Keywords:
Acetone
2-Azido b-nitrostyrene
© 2018 Elsevier Ltd. All rights reserved.
2-Methyltetrahydroquinoline
Michael addition
Reductive cyclization
Thiophosphinamide
1. Introduction
chemistry and asymmetric catalysis, the development of new
methodologies for the synthesis of 2-MeTHQ derivatives will be of
Among various nitrogen-containing heterocycles, the tetrahy-
droquinoline ring system is a fascinating and privileged structural
motif and is found in various biologically active natural products
and pharmacologically relevant therapeutic agents [1]. Particularly,
great importance and remains a challenging task. In contrast to the
great progress made in the asymmetric synthesis of optically active
THQ derivatives through either organo- or metal catalysis [9], the
methodology for the asymmetric synthesis of 2-MeTHQs with high
enantioselectivity has been rarely explored. Up to date, two stra-
tegies were developed for the organocatalytic asymmetric syn-
thesis of enantiomerically enriched 2-MeTHQs, one is the chiral
phosphoric acid catalyzed transfer hydrogenation of 2-
methylquinolines [10], the other is an in situ generated chiral su-
pramolecular assembly catalyst promoted asymmetric Michael
addition of acetone to 2-azido nitroolefins followed by reductive
cyclization [11]. However, the later protocol still suffers from some
limitations in the Michael addition step, such as low catalytic ac-
tivity (72 h is needed to ensure the full conversion), moderate
yields (50e65%, only one example is over 90%) and unsatisfactory
enantioselectivity (89e92% ee). Recently, we have proved that
primary amine/thiophosphinamides are efficient catalysts to pro-
mote the Michael addition of acetone to simple [12] and ortho-
hydroxyl nitroolefins [13] in a highly enantioselective manner. We
envisioned that this type of catalyst may demonstrate great
advantage over the aforementioned chiral supramolecular
their
2-methyl
substituted
analogues
(2-
methyltetrahydroquinolines, 2-MeTHQs) exhibit interesting
biochemical activities (Fig. 1). For example, Helquinoline (1) is a
new tetrahydroquinoline antibiotic from Janibacter limosus Hel 1
[2], compound 2, a kind of CRTH2 antagonists, is beneficial for the
treatment of allergic diseases [3], 1-benzenesulfonyl-2-MeTHQ (3)
demonstrated interesting activity against Trypanozoma cruzi with
low cytotoxicity [4], N-formyl-2-MeTHQ (4) functions as a potent
EPAC inhibitor [5], I-BET726 (5) [6] and 1-acetyl-2-MeTHQ (6) [7]
are selective BET bromodomain inhibitors. Moreover, as a key
scaffold of a variety of phosphoramidite ligands, 2-MeTHQ also has
wide application in asymmetric catalysis [8]. Due to the signifi-
cance of these structural units in drug discovery, medicinal
* Corresponding author.
E-mail address: z.h.zhou@nankai.edu.cn (Z. Zhou).
https://doi.org/10.1016/j.tet.2018.08.052
0040-4020/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: H. Zhang, et al., Bifunctional thiophosphinamide catalyzed highly enantioselective Michael addition of acetone
to (E)-2-azido -nitrostyrenes and the subsequent reductive cyclization, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.08.052
b

2
H. Zhang et al. / Tetrahedron xxx (2018) 1e7
Table 1
Catalyst evaluation.a
Entry
Catalyst
Time (day)
Yield (%)b
Ee (%)c
1
2
3
4
5
6
I
5
7
5.5
4
4
13
53
58
61
13
NR
84
95
96
98
ꢁ12
/
IIa
IIb
IIc
III
IV
7
a
All of the reactions were carried out with 7a (0.3 mmol), acetone (3.0 mmol) and
Fig. 1. 2-MeTHQ-based natural products and pharmaceuticals.
the catalyst (20 mol%) in 1.5 mL of dichloromethane at 20 ꢀC.
b
Yield of the isolated product after chromatography on silica gel.
Determination by HPLC analysis with a chiral stationary phase.
c
assembly catalyst in terms of both catalytic efficacy and enantio-
selectivity. Herein we report a stereoselective synthesis of 2-
MeTHQs via primary amine/thiophosphinamide catalyzed asym-
metric Michael addition of acetone to 2-azido nitroolefins and the
subsequent reductive cyclization. The corresponding cyclization
products were obtained in acceptable yields with good diaster-
eoselectivities and excellent enantioselectivities (93e>99% ee).
also have an obvious influence on the catalytic activity. The less
nucleophilic thiophosphinamide IV derived from (R)-1,10-
binaphthyl-2,20-diamine was completely inactive in the model re-
action and failed to afford product 8a.
With the promising catalyst IIc in hand, other factors, such as
acidic cocatalyst, solvent, catalyst loading, and reaction tempera-
ture, influencing the reaction were thoroughly investigated
employing the reaction between (E)-1-azido-2-(2-nitrovinyl)ben-
zene (7a) and acetone as the model. The results are summarized in
Table 2.
2. Results and discussion
We started our investigation by examination of the catalytic
activity and stereoselectivity of a series of bifunctional thio-
phosphoramide or thiophosphinamide-based primary amines IeIV
(Fig. 2) in the model reaction of (E)-1-azido-2-(2-nitrovinyl)ben-
zene (7a) and acetone in dichloromethane at 20 ꢀC. The results are
listed in Table 1.
Table 2
Optimization of reaction conditions.a
As shown in Table 1, both the chiral diamine skeleton and sub-
stituent on phosphorus atom have an important role on the
outcome of the reaction. The use of (1R,2R)-cyclohexane-1,2-
diamine derived thiophosphoramide I as the catalyst resulted in
the formation of the corresponding adduct 8a in a quite low yield
(13%) with 84% ee (entry 1). However, both the yield (53%) and
enantioselectivity (95% ee) were markedly improved by employing
thiophosphoramide II incorporating a (1R,2R)-1,2-diphenylethane-
1,2-diamine skeleton as the catalyst (entry 2 vs. entry 1). A slightly
improvement in both yield and ee value were obtained by replacing
the phenoxy group with either ethoxy or phenyl group (entries 3,4
vs. entry 2). Thiophosphinamide IIc proved to be the most prom-
ising catalyst candidate for this transformation affording the
product 3a in 61% yield with ee value of 98% (entry 4). It is worth
noting that increase the rigidity of the diamine skeleton is detri-
mental to the reaction. The use of thiophosphinamide III bearing a
Entry
Additive (x mol%)
Solvent
Time (h)
Yield (%)b
Ee (%)c
1
2
3
4
5
6
e
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
Acetone
CH3CN
Ether
Hexane
Toluene
Toluene
96
96
10
72
36
16
40
16
48
16
16
14
16
20
16
50
61
40
95
68
74
95
83
95
86
95
56
60
37
82
95
83
98
99
98
98
98
98
98
98
98
98
99
96
95
99
99
98
PhOH (20)
PhCO2H (20)
4-O2NC6H4CO2H (20)
4-MeOC6H4CO2H (20)
PhCO2H (5)
PhCO2H (1)
PhCO2H (5)
PhCO2H (5)
PhCO2H (5)
PhCO2H (5)
PhCO2H (5)
PhCO2H (5)
PhCO2H (5)
PhCO2H (5)
PhCO2H (5)
7
8d
9e
rigid
(R,R)-9,10-dihydro-9,10-ethanonanthracene-11,12-diamine
10d
11d
12d
13d
14d
15d
16d,f
scaffold resulted in sharply decrease both in yield and enantiose-
lectivity. Additionally, the nucleophilicity of the priamary amine
a
Unless otherwise specified, all of the reactions were carried out with 7a
(0.3 mmol), acetone (3.0 mmol) and catalyst IIc (20 mol%), acidic cocatalyst (x mmol
%) in 1.5 mL of solvent at 20 ꢀC.
b
Yield of the isolated product after chromatography on silica gel.
Determination by HPLC analysis with a chiral stationary phase.
The catalyst loading is 10 mol%.
The amount of catalyst is 5 mol%.
The reaction was performed at 0 ꢀC.
c
d
e
f
Fig. 2. Catalyst candidates.
Please cite this article in press as: H. Zhang, et al., Bifunctional thiophosphinamide catalyzed highly enantioselective Michael addition of acetone
to (E)-2-azido -nitrostyrenes and the subsequent reductive cyclization, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.08.052
b

H. Zhang et al. / Tetrahedron xxx (2018) 1e7
3
In an effort to further improve the yield of the model reaction,
we first examined the influence of acidic cocatalyst on the reaction
(entries 2e5). It was gratifying that unaltered enantioselectivity but
dramatically improvement both in the reaction rate and yield was
observed with the addition of 20 mol% of benzoic acid as the
cocatalyst (entry 3 vs. entry 1). Comparable results were obtained
by adjusting the amount of benzoic acid to 5 mol% (entry 6). Further
lowering the loading of benzoic acid to 1 mol% led to a sluggish
reaction accompanied with decreased yield albeit with maintained
ee value (entry 7). Moreover, the amount of catalyst IIc could be
successfully reduced to 10 mol% without any detrimental effect on
the reaction (entry 8). Although the enantioselectivity remained
unaltered, further reducing the catalyst loading to 5 mol % resulted
in a somewhat sluggish reaction and an obviously decreased yield
(entry 9). Additionally, solvent evaluation revealed that the reac-
tion medium have limited influence on the stereocontrol of the
reaction (entry 10e15, 95e99% ee). A slightly improved ee value of
99% with unaltered yield was observed by performing the reaction
in toluene. No fruitful results were obtained by lowering the reac-
tion temperature to 0 ꢀC (entry 16).
On the basis of the optimized conditions for (E)-1-azido-2-(2-
nitrovinyl)benzene 7a, the reaction was further extended to a se-
ries of functionalized 1-azido-2-(2-nitrovinyl)benzenes 1bem
(Table 3). As shown in Table 3, the reaction of other 1-azido-2-(2-
nitrovinyl)benzenes bearing either electron-withdrawing (entries
2e10) or electron-donating (entry 11) substituent on the benzene
ring ran smoothly to give the corresponding Michael addition
products in good to excellent yields (85e98%) with uniformly high
levels of enantioselectivity (96e>99% ee). In addition, fused 1-
azido-2-(2-nitrovinyl)benzene 7l also worked well to afford the
corresponding adduct 8l in excellent yield with perfect stereo-
control (entry 12). Moreover, 1-azido-2-naphthaldehyde derived
nitroolefin 7m proven to be a suitable reaction partner, giving the
desired product 8m in 91% yield. Unfortunately, the ee value of this
product cannot be determined since two enantiomers are insepa-
rable on all the tested chiral stationary phases (entry 13). These
results indicate that thiophosphinamide catalyst IIc is obviously
outperformed Ramachary's supramolecular-organocatalyst, with
which ee value ranging from 89% to 92% was obtained.
With these optically pure azido ketoes 8 in hand, the further
transformation of them into medicinally significant 2-
methyltetrahydroquinolines 9 was carried out through reductive
amination using the BencivennieNanni protocol (Table 4) [15].
Upon treatment with InCl3eEt3SiH in MeOH at 0e25 ꢀC, azido
ketoes 8 bearing electron-neutral (entry 1), electron-withdrawing
(entries 2e7), electron-donating group (entry 8) on the benzene
ring could be successfully to be converted into the corresponding
cis-2-MeTHQs 9aeh and 9k in acceptable yields without appre-
ciable loss in optical purity. With respect to diastereoselectivity,
except for 5-chloro substituted 2-MeTHQ 9e, which was obtained
as a single diastereomer, all the other 2-MeTHQs were obtained
with moderated diastereoselectivities (77/23e86/14 dr). Owing to
the existence of an additional azido group, the reductive cyclization
of Michael addition products 8i and 8j resulted in a complex re-
action mixture and failed to give the desired 2-MeTHQ derivatives.
Moreover, under the same conditions, the reaction of fused azido
ketones 8l and 8m only provided the corresponding aromatization
products 10 and 11 in moderate yield, which may be formed via the
elimination of nitromethane of the in situ generated 4-nitromethyl-
3,4-dihydroquinoline intermediates [14].
To determine the relative and absolute configuration of the
obtained chiral 2-MeTHQs, a crystalline N-tosylated derivative 12
was obtained in moderate yield through the reaction of 8a and tosyl
chloride in refluxing pyridine under nitrogen atmosphere (Scheme
1). The relative and absolute configurations of product 12 were
unequivocally determined to be cis and (2R,4S) by single-crystal X-
ray diffraction analysis [16]. Since none of the bonds to the ster-
eogenic carbon have been broken during the tosylation reaction,
the original configuration of compound 8a is retained.
The catalytic cycle of the Michael addition reaction was pro-
posed based on experiment results (Scheme 2). The primary amine
reacts first with acetone to form an enamine intermediate A with
the aid of benzoic acid. Subsequently, the enamine nucleophilic
attacks the nitro olefin from the Si-face to give the addition inter-
mediate B via the given transition state formed through hydrogen-
Table 3
Substrate scope of IIc-catalyzed asymmetric Michael addition of acetone to (E)-1-
Table 4
azido-2-(2-nitrovinyl)benzenes 7.a
Reductive cyclization of the Michael addition product 8.a
Entry
8 (X)
Time (h)
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
8a (H)
8b (4-F)
8c (4-Cl)
8d (5-Cl)
8e (6-Cl)
8f (4-Br)
8g (5-Br)
8h (4-CN)
8i (4-N3)
16
24
16
16
20
16
16
16
16
16
16
16
16
95
98
87
88
85
91
89
90
92
90
92
93
91
99
>99
99
>99
98
>99
96
Entry
9 (X)
Yield (%)b
Dr (cis/trans)c
Ee (cis/trans) (%)d
1
2
3
4
5
6
7
8
9
9a (H)
60
49
58
62
51
61
49
55
52
86/14
82/18
81/19
79/21
>99/1
82/18
84/16
84/16
77/23
98/98
99/>99
99/98
97/98
93
>99/>99
>99/>99
>99/98
99/99
9b (7-F)
9c (7-Cl)
9d (6-Cl)
9e (5-Cl)
9f (7-Br)
9g (6-Br)
9h (7-CN)
9k (7-Me)
99
9
>99
>99
>99
>99
ND
10
11
12
13
8j (6-N3)
8k (4-Me)
8l (4,5-OCH2O)
8m (3,4-CH]CHeCH]CH)
a
Reaction conditions: A mixture of 8 (0.2 mmol), Et3SiH (0.3 mmol) and InCl3
(0.3 mmol) in 2 mL of methanol was stirred at 0 ꢀC for 2 h, and then reacted at room
temperature for 12 h.
a
All of the reactions were carried out with 7 (0.3 mmol), acetone (3.0 mmol) and
catalyst IIc (10 mol%), PhCO2H (5 mmol %) in 1.5 mL of toluene at 20 ꢀC.
b
Yield of the isolated product after chromatography on silica gel.
b
c
Yield of the isolated product after chromatography on silica gel.
Determination by HPLC analysis with a chiral stationary phase.
Determined by 1H NMR analysis.
c
d
Determination by HPLC analysis with a chiral stationary phase.
Please cite this article in press as: H. Zhang, et al., Bifunctional thiophosphinamide catalyzed highly enantioselective Michael addition of acetone
to (E)-2-azido -nitrostyrenes and the subsequent reductive cyclization, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.08.052
b

4
H. Zhang et al. / Tetrahedron xxx (2018) 1e7
was added (E)-2-azido
b-nitrostyrene (0.2 mmol) at the same
temperature. After the reaction is complete (monitored by TLC), the
reaction mixture was concentrated under reduced pressure to
afford the crude addition product 8 which were purified by column
chromatography on silica gel (200e300 mesh, petroleum ether/
ethyl acetate ¼ 20/1). The title compounds were fully characterized
by 1H NMR, 13C NMR, and specific rotation data. The enantiomeric
excess of the pure products was determined by HPLC analysis using
a chiral stationary phase.
Scheme 1. Tosylation of tetrahydroquinoline 8a and the X-ray crystal structure of the
tosylated product (2R,4S)-12. Most of the hydrogen atoms have been omitted for
clarity.
4.1.1. (S)-4-(2-Azidophenyl)-5-nitropentan-2-one (8a)
Pale yellow oil, 71 mg, 95% yield, ½a D20
þ20.2 (c 0.87, CHCl3), 99%
ꢂ
ee. 1H NMR (CDCl3, 400 MHz):
d
7.33 (t, J ¼ 7.6 Hz, 1 H), 7.18 (d,
J ¼ 7.6 Hz, 1 H), 7.17 (d, J ¼ 7.6 Hz, 1 H), 7.10 (d, J ¼ 7.6 Hz, 1 H), 4.74
(dd, J ¼ 12.4, 7.2 Hz, 1 H), 4.71 (dd, J ¼ 12.4, 6.8 Hz, 1 H), 4.21
(quintet, J ¼ 6.8 Hz, 1 H), 3.04 (dd, J ¼ 18.0, 7.6 Hz, 1 H), 2.95 (dd,
J ¼ 18.0, 6.4 Hz, 1 H), 2.15 (s, 3 H). 13C NMR (CDCl3, 100.6 MHz):
d
205.4, 137.8, 129.5, 129.4, 129.1, 125.2, 118.7, 44.6, 35.0, 30.2. HPLC
analysis (Chiralpak AD-H column, hexane/2-propanol ¼ 90:10, flow
rate ¼ 1.0 mL/min, wavelength ¼ 254 nm): tR ¼ 33.50 (major) and
36.47 min (minor).
4.1.2. (S)-4-(2-Azido-4-fluorophenyl)-5-nitropentan-2-one (8b)
Pale yellow oil, 78 mg, 98% yield, ½a D20
þ13.6 (c 0.60, CHCl3),
ꢂ
>99% ee. 1H NMR (CDCl3, 400 MHz):
d
7.17 (d, J ¼ 8.4 Hz, 1 H), 6.79
(dd, J ¼ 8.4, 1.2 Hz, 1 H), 6.76 (s, 1 H), 4.72 (dd, J ¼ 12.4, 7.6 Hz, 1 H),
4.68 (dd, J ¼ 12.4, 6.8 Hz, 1 H), 4.16 (quintet, J ¼ 6.8 Hz, 1 H), 3.02
(dd, J ¼ 18.0, 7.6 Hz, 1 H), 2.93 (dd, J ¼ 18.0, 6.4 Hz, 1 H), 2.15 (s, 3 H).
13C NMR (CDCl3, 100.6 MHz):
d
205.2, 162.6 (d, J ¼ 249.7 Hz), 139.5
(d, J ¼ 8.3 Hz), 130.9 (d, J ¼ 9.2 Hz), 125.3 (d, J ¼ 3.0 Hz), 112.3 (d,
J ¼ 21.2 Hz), 106.2 (d, J ¼ 24.9 Hz), 77.6, 44.5, 34.5, 30.2. HPLC
analysis (Chiralpak AD-H column, hexane/2-propanol ¼ 90:10, flow
rate ¼ 1.0 mL/min, wavelength ¼ 254 nm): tR ¼ 60.50 (major) and
70.23 min (minor).
Scheme 2. Proposed catalytic cycle.
bonding interaction between the acidic hydrogen of thio-
phosphinamide moiety and the nitro group. Finally, hydrolysis of
the resulting iminium ion intermediate B affords the product (S)-8a
and regenerates catalyst IIc.
4.1.3. (S)-4-(2-Azido-4-chlorophenyl)-5-nitropentan-2-one (8c)
Pale yellow oil, 74 mg, 87% yield, ½a D20
þ29.8 (c 0.95, CHCl3), 99%
ꢂ
ee. 1H NMR (CDCl3, 400 MHz):
d
7.14 (d, J ¼ 2.0 Hz, 1 H), 7.12 (d,
3. Conclusion
J ¼ 8.4 Hz, 1 H), 7.07 (dd, J ¼ 8.4, 2.0 Hz, 1 H), 4.72 (dd, J ¼ 12.4,
7.2 Hz, 1 H), 4.68 (dd, J ¼ 12.4, 6.4 Hz, 1 H), 4.17 (quintet, J ¼ 6.8 Hz,
1 H), 3.0 (dd, J ¼ 18.0, 7.6 Hz,1 H), 2.92 (dd, J ¼ 18.4, 6.4 Hz, 1 H), 2.15
In conclusion, the primary amine/thiophosphinamide catalyzed
Michael addition of acetone to (E)-1-azido-2-(2-nitrovinyl)ben-
zenes and the subsequent reductive cyclization have been investi-
gated. Under the catalysis of a chiral thiophosphinamide derived
from (1R,2R)-1,2-diphenylethane-1,2-diamine, the reaction of a
wide range of (E)-1-azido-2-(2-nitrovinyl)benzenes ran smoothly
to generate the corresponding Michael addition products in
excellent yields with uniformly high levels of enantioselectivity
(s, 3 H). 13C NMR (CDCl3, 100.6 MHz):
d 205.3, 141.1, 139.4, 130.8,
126.0, 115.5, 109.3, 77.6, 44.4, 34.6, 30.2. HRMS (ESI) m/z calcd for
C
11H11ClN4NaO3 [MþNa]þ: 305.0412, found 305.0415. HPLC anal-
ysis (Chiralpak AD-H column, hexane/2-propanol ¼ 90:10, flow
rate ¼ 1.0 mL/min, wavelength ¼ 254 nm): tR ¼ 12.94 (major) and
14.99 min (minor).
(96e>99% ee). Moreover, the obtained d-azido ketones were suc-
4.1.4. (S)-4-(2-Azido-5-chlorophenyl)-5-nitropentan-2-one (8d)
cessfully converted into 2-methyltetrahydroquinoline derivatives
upon treatment with InCl3eEt3SiH in MeOH in acceptable yields
and moderate to excellent diastereoselectivities without any
appreciable loss in the enantioselectivities. This method serves as a
useful tool for the highly enantioselective synthesis of medicinally
important 2-methyltetrahydroquinoline derivatives.
Pale yellow oil, 75 mg, 88% yield, ½a D20
þ18.4 (c 1.05, CHCl3),
ꢂ
>99% ee. 1H NMR (CDCl3, 400 MHz):
d
7.29 (dd, J ¼ 8.4, 2.4 Hz, 1 H),
7.17 (d, J ¼ 2.0 Hz, 1 H), 7.10 (d, J ¼ 8.8 Hz, 1 H), 4.72 (dd, J ¼ 13.2,
5.2 Hz, 1 H), 4.69 (dd, J ¼ 12.8, 6.8 Hz, 1 H), 4.17 (quintet, J ¼ 6.8 Hz,
1 H), 3.02 (dd, J ¼ 18.4, 7.6 Hz, 1 H), 2.92 (dd, J ¼ 18.0, 6.4 Hz, 1 H),
2.17 (s, 3 H). 13C NMR (CDCl3, 100.6 MHz):
d 204.9, 136.5, 131.3,
130.5, 129.5, 129.1, 119.9, 77.3, 44.3, 34.7, 30.1. HPLC analysis (Chir-
alpak AD-H column, flow
4. Experimental section
hexane/2-propanol ¼ 90:10,
rate ¼ 1.0 mL/min, wavelength ¼ 254 nm): tR ¼ 44.14 (major) and
4.1. General procedure for the IIc catalyzed asymmetric Michael
47.84 min (minor).
addition of acetone to (E)-1-azido-2-(2-nitrovinyl)benzenes 7
4.1.5. (S)-4-(2-Azido-6-chlorophenyl)-5-nitropentan-2-one (8e)
A
mixture the thiophosphinamide catalyst IIc (8.6 mg,
Pale yellow oil, 77 mg, 85% yield, ½a D20
þ14.9 (c 0.95, CHCl3), 98%
ꢂ
0.02 mmol), benzoic acid (1.2 mg, 0.01 mmol) and acetone
(0.6 mmol, 3 equivalents) in toluene (0.5 mL) was stirred at room
temperature to form a clear solution. Then, to the resulting solution
ee. 1H NMR (CDCl3, 400 MHz):
d
7.23 (d, J ¼ 8.0 Hz, 1 H), 7.20 (s, 1 H),
7.07 (d, J ¼ 8.8 Hz, 1 H), 4.80e4.93 (m, 3 H), 3.11e3.17 (m, 1 H),
2.99e3.04 (m, 1 H), 2.16 (s, 3 H). 13C NMR (CDCl3, 100.6 MHz):
Please cite this article in press as: H. Zhang, et al., Bifunctional thiophosphinamide catalyzed highly enantioselective Michael addition of acetone
to (E)-2-azido -nitrostyrenes and the subsequent reductive cyclization, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.08.052
b

H. Zhang et al. / Tetrahedron xxx (2018) 1e7
5
d
205.2, 139.8, 136.6, 129.4, 127.6, 126.8, 117.5, 76.4, 44.1, 29.9, 29.7.
6.90 (d, J ¼ 7.6 Hz, 1 H), 4.71 (dd, J ¼ 12.4, 7.6 Hz, 1 H), 4.68 (dd,
J ¼ 12.4, 6.4 Hz, 1 H), 4.16 (quintet, J ¼ 6.8 Hz, 1 H), 3.01 (dd, J ¼ 18.0,
7.2 Hz, 1 H), 2.92 (dd, J ¼ 18.0, 6.4 Hz, 1 H), 2.34 (s, 3 H), 2.14 (s, 3 H).
HRMS (ESI) m/z calcd for C11H11ClN4NaO3 [MþNa]þ: 305.0412,
found 305.0415. HPLC analysis (Chiralpak AD-H column, hexane/2-
propanol ¼ 90:10, flow rate ¼ 1.0 mL/min, wavelength ¼ 254 nm):
tR ¼ 43.71 (major) and 47.30 min (minor).
13C NMR (CDCl3, 100.6 MHz):
d 205.6, 139.4, 137.5, 129.2, 126.4,
126.1, 119.2, 77.9, 44.7, 34.7, 30.2, 21.0. HRMS (ESI) m/z calcd for
C
12H14N4NaO3 [MþNa]þ: 285.0958, found 285.0960. HPLC analysis
4.1.6. (S)-4-(2-Azido-4-bromophenyl)-5-nitropentan-2-one (8f)
(Chiralpak AD-H column, hexane/2-propanol ¼ 90:10, flow
rate ¼ 1.0 mL/min, wavelength ¼ 254 nm): tR ¼ 25.80 (major) and
27.84 min (minor).
Pale yellow oil, 89 mg, 91% yield, ½a D20
þ18.6 (c 1.2, CHCl3), >99%
ꢂ
ee. 1H NMR (CDCl3, 400 MHz):
d
7.29 (d, J ¼ 1.6 Hz, 1 H), 7.23 (dd,
J ¼ 8.4, 1.6 Hz, 1 H), 7.06 (d, J ¼ 8.0 Hz, 1 H), 4.72 (dd, J ¼ 12.4, 7.2 Hz,
1 H), 4.68 (dd, J ¼ 12.4, 6.4 Hz, 1 H), 4.16 (quintet, J ¼ 6.8 Hz, 1 H),
3.01 (dd, J ¼ 18.4, 7.6 Hz, 1 H), 2.92 (dd, J ¼ 18.4, 6.4 Hz, 1 H), 2.15 (s,
4.1.12. (S)-4-(6-Azidobenzo[d][1,3]dioxol-5-yl)-5-nitropentan-2-
one (8l)
3 H). 13C NMR (CDCl3, 100.6 MHz):
d
205.0, 136.5, 131.2, 130.4, 129.5,
Red oil, 82 mg, 93% yield, ½a D20
ꢂ
þ22.6 (c 0.77, CHCl3), >99% ee. 1H
129.1, 119.8, 77.3, 44.2, 34.6, 30.1. HRMS (ESI) m/z calcd for
C
ysis (Chiralpak AD-H column, hexane/2-propanol ¼ 90:10, flow
rate ¼ 1.0 mL/min, wavelength ¼ 254 nm): tR ¼ 48.84 (major) and
53.68 min (minor).
NMR (CDCl3, 400 MHz): d 6.66 (s, 1 H), 6.64 (s, 1 H), 5.97 (s, 2 H),
11H11BrN4NaO3 [MþNa]þ: 348.9907, found 348.9910. HPLC anal-
4.68 (dd, J ¼ 12.4, 7.6 Hz, 1 H), 4.64 (dd, J ¼ 12.4, 6.4 Hz, 1 H), 4.13
(quintet, J ¼ 6.8 Hz, 1 H), 2.98 (dd, J ¼ 18.0, 7.2 Hz, 1 H), 2.89 (dd,
J ¼ 18.0, 6.4 Hz, 1 H), 2.15 (s, 3 H). 13C NMR (CDCl3, 100.6 MHz):
d
205.5, 148.1, 145.2, 131.0, 122.2, 108.8, 101.9, 99.6, 77.9, 44.7, 34.7,
30.2. HRMS (ESI) m/z calcd for C12H12N4NaO5 [MþNa]þ: 315.0700,
found 315.0672. HPLC analysis (Chiralpak AD-H column, hexane/2-
propanol ¼ 90:10, flow rate ¼ 1.0 mL/min, wavelength ¼ 254 nm):
tR ¼ 17.56 (major) and 19.82 min (minor).
4.1.7. (S)-4-(2-Azido-5-bromophenyl)-5-nitropentan-2-one (8g)
Pale yellow oil, 87 mg, 89% yield, ½a D20
þ11.8 (c 1.7, CHCl3), 96%
ꢂ
ee. 1H NMR (CDCl3, 400 MHz):
d
7.15 (d, J ¼ 8.4 Hz, 1 H), 7.00 (dd,
J ¼ 8.4, 2.4 Hz, 1 H), 6.81 (d, J ¼ 2.4 Hz, 1 H), 4.73 (dd, J ¼ 12.4, 7.2 Hz,
1 H), 4.69 (dd, J ¼ 12.4, 6.4 Hz, 1 H), 4.17 (quintet, J ¼ 6.8 Hz, 1 H),
3.02 (dd, J ¼ 18.4, 7.6 Hz, 1 H), 2.93 (dd, J ¼ 18.0, 6.4 Hz, 1 H), 2.16 (s,
4.1.13. (S)-4-(1-Azidonaphthalen-2-yl)-5-nitropentan-2-one (8m)
Pale yellow oil, 81 mg, 91% yield, ½a D20
þ28.4 (c 0.86, CHCl3), the
ꢂ
3 H). 13C NMR (CDCl3, 100.6 MHz):
d
205.0, 137.1, 134.4, 131.3, 120.3,
two enantiomers of this compound are inseparable in all the tested
120.0, 119.5, 77.4, 44.3, 35.1, 30.2. HPLC analysis (Chiralpak AD-H
column, hexane/2-propanol ¼ 99:1, flow rate ¼ 0.8 mL/min, wave-
length ¼ 254 nm): tR ¼ 54.43 (major) and 59.50 min (minor).
chiral stationary phase. 1H NMR (CDCl3, 400 MHz):
d 8.13 (d,
J ¼ 8.4 Hz, 1 H), 7.86 (d, J ¼ 8.4 Hz, 1 H), 7.72 (d, J ¼ 8.4 Hz, 1 H), 7.63
(t, J ¼ 8.0 Hz, 1 H), 7.55 (t, J ¼ 8.0 Hz, 1 H), 7.29 (d, J ¼ 8.4 Hz, 1 H),
4.83 (dd, J ¼ 12.4, 6.8 Hz, 1 H), 4.78 (dd, J ¼ 12.4, 4.8 Hz, 1 H), 4.68
(quintet, J ¼ 6.8 Hz, 1 H), 3.07 (dd, J ¼ 18.0, 7.2 Hz, 1 H), 3.01 (dd,
J ¼ 18.0, 6.8 Hz, 1 H), 2.16 (s, 3 H). 13C NMR (CDCl3, 100.6 MHz):
4.1.8. (S)-3-Azido-4-(1-nitro-4-oxopentan-2-yl)benzonitrile (8h)
Pale yellow oil, 74 mg, 90% yield, ½a D20
þ21.3 (c 0.66, CHCl3), 99%
ꢂ
ee. 1H NMR (CDCl3, 400 MHz):
d
7.42 (d, J ¼ 1.2 Hz, 1 H), 7.40 (dd,
d 205.1, 133.8, 129.2, 128.8, 128.5, 127.4, 127.4, 126.8, 124.6, 121.9,
J ¼ 8.0, 1.2 Hz, 1 H), 7.33 (d, J ¼ 8.0 Hz, 1 H), 4.77 (dd, J ¼ 12.8, 7.2 Hz,
1 H), 4.72 (dd, J ¼ 12.8, 6.0 Hz, 1 H), 4.24 (quintet, J ¼ 6.8 Hz, 1 H),
3.05 (dd, J ¼ 18.4, 7.6 Hz, 1 H), 2.96 (dd, J ¼ 18.4, 6.4 Hz, 1 H), 2.17 (s,
78.3, 45.4, 35.0, 30.2.
4.2. General procedure for the reductive cyclization of Michael
products 8
3 H). 13C NMR (CDCl3, 100.6 MHz):
d
204.6, 139.4, 134.8, 130.6, 128.5,
121.7, 117.4, 113.2, 77.2, 44.0, 35.0, 30.2. HPLC analysis (Chiralpak
AD-H column, hexane/2-propanol ¼ 90:10, flow rate ¼ 1.0 mL/min,
wavelength ¼ 254 nm): tR ¼ 23.82 (major) and 28.36 min (minor).
To a stirring mixture of anhydrous InCl3 (66 mg, 0.3 mmol),
triethylsilane (70 mg, 0.6 mmol) in 2.0 mL of methanal was added a
solution of the Michael addition product 8 (0.2 mmol) in 2.0 mL of
methanol at 0 ꢀC. After stirring at the same temperature for 2 h, the
reaction mixture was warmed to room temperature and stirred for
12 h. The reaction was quenched with the addition of 10 mL of
water. The reaction mixture was extracted with ethyl acetate
(3 ꢃ 10 mL), the combined organic layer was washed with saturated
aqueous sodium chloride solution, dried with anhydrous magne-
sium sulfate, filtered and concentrated under reduced pressure to
give the crude tetrahydroquinoline 9, which was further purified by
column chromatography on silica gel (200e300 mesh, petroleum
ether/ethyl acetate ¼ 15/1). The title compounds were fully char-
acterized by 1H NMR, 13C NMR, and specific rotation data. The
enantiomeric excess of the pure tetrahydroquinolines was deter-
mined by HPLC analysis using a chiral stationary phase.
4.1.9. (S)-4-(2,4-Diazidophenyl)-5-nitropentan-2-one (8i)
Pale yellow oil, 80 mg, 92% yield, ½a D20
þ11.4 (c 0.63, CHCl3),
ꢂ
>99% ee. 1H NMR (CDCl3, 400 MHz):
d
7.17 (d, J ¼ 8.4 Hz, 1 H), 6.79
(dd, J ¼ 8.4, 2.0 Hz, 1 H), 6.76 (d, J ¼ 2.0 Hz, 1 H), 4.72 (dd, J ¼ 12.4,
7.2 Hz, 1 H), 4.68 (dd, J ¼ 12.4, 6.4 Hz, 1 H), 4.16 (quintet, J ¼ 6.8 Hz,
1 H), 3.02 (dd, J ¼ 18.0, 7.2 Hz, 1 H), 2.92 (dd, J ¼ 18.0, 6.4 Hz, 1 H),
2.15 (s, 3 H). 13C NMR (CDCl3,100.6 MHz):
d 205.3,141.1,139.4,130.8,
126.0, 115.5, 109.3, 77.6, 44.4, 34.7, 30.2. HPLC analysis (Chiralpak
AD-H column, hexane/2-propanol ¼ 95:5, flow rate ¼ 1.0 mL/min,
wavelength ¼ 254 nm): tR ¼ 19.53 (major) and 22.97 min (minor).
4.1.10. (S)-4-(2,6-Diazidophenyl)-5-nitropentan-2-one (8j)
Red oil, 78 mg, 90% yield, ½a D20
ꢂ
þ21.3 (c 0.72, CHCl3), >99% ee. 1H
NMR (CDCl3, 400 MHz):
d
7.34 (t, J ¼ 8.0 Hz, 1 H), 6.94 (d, J ¼ 8.0 Hz,
2 H), 4.82 (dd, J ¼ 12.4, 8.8 Hz, 1 H), 4.76 (dd, J ¼ 12.4, 6.8 Hz, 1 H),
4.59e4.67 (m, 1 H), 3.07 (dd, J ¼ 18.0, 8.0 Hz, 1 H), 2.95 (dd, J ¼ 18.0,
4.2.1. (2R,4S)-2-Methyl-4-(nitromethyl)-1,2,3,4-tetrahydro-
quinoline (9a)
6.0 Hz, 1 H), 2.15 (s, 3 H). 13C NMR (CDCl3, 100.6 MHz):
d
205.4,
Yellow solid, m.p. 49e50 ꢀC, 25 mg, 60% yield, ½a 2D0
¼ þ30.4 (c
ꢂ
140.3, 129.6, 121.0, 115.0, 76.8, 44.3, 31.1, 29.9. HPLC analysis
(Chiralpak AD-H column, hexane/2-propanol ¼ 99:1, flow
rate ¼ 0.5 mL/min, wavelength ¼ 254 nm): tR ¼ 61.82 min (major).
0.52, CHCl3), cis/trans ¼ 86/14, 98% ee for cis isomer, 98% ee for trans
isomer. 1H NMR (CDCl3, 400 MHz):
1 H), 6.97 (d, J ¼ 7.6 Hz, 1 H), 6.67 (t, J ¼ 7.6 Hz, 1 H), 4.93 (dd,
J ¼ 12.0, 4.8 Hz, 1 H), 4.38 (dd, J ¼ 11.6, 10.4 Hz, 1 H), 3.74e3.82 (m,
2 H), 3.41e3.48 (m, 1 H), 2.03e2.08 (m, 1 H), 1.48e1.56 (m, 1 H), 1.23
d
(cis-isomer) 7.04 (t, J ¼ 7.6 Hz,
4.1.11. (S)-4-(2-Azido-4-methylphenyl)-5-nitropentan-2-one (8k)
Pale yellow oil, 72 mg, 92% yield, ½a D20
ꢂ
þ11.8 (c 1.0, CHCl3), >99%
(d, J ¼ 6.0 Hz, 3 H);
d (trans-isomer, incomplete data) 4.56 (d,
ee. 1H NMR (CDCl3, 400 MHz):
d
7.05 (d, J ¼ 7.6 Hz, 1 H), 6.96 (s, 1 H),
J ¼ 8.0 Hz, 2 H), 3.63e3.69 (m, 1 H), 1.26 (d, J ¼ 6.0 Hz, 3 H).13C NMR
Please cite this article in press as: H. Zhang, et al., Bifunctional thiophosphinamide catalyzed highly enantioselective Michael addition of acetone
to (E)-2-azido -nitrostyrenes and the subsequent reductive cyclization, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.08.052
b

6
H. Zhang et al. / Tetrahedron xxx (2018) 1e7
(CDCl3, 100.6 MHz):
115.1, 80.6, 46.6, 35.6, 35.0, 22.4;
d
(cis-isomer), 145.5, 128.1, 126.3, 118.7, 117.8,
(trans-isomer, incomplete data),
120.0, 116.1, 80.1, 46.5, 35.0, 34.8, 22.2; d (trans-isomer), 143.2,
d
128.9, 128.5, 121.6, 120.00, 118.7, 115.6, 80.4, 42.2, 35.3, 34.77, 31.4,
22.3. HPLC analysis (Chiralpak AD-H column, hexane/2-
propanol ¼ 90:10, flow rate ¼ 1.0 mL/min, wavelength ¼ 254 nm):
tR ¼ 25.14 (major of trans-isomer), 31.88 (minor of trans-isomer),
33.43 (major of cis-isomer) and 51.27 min (minor of cis-isomer).
144.6, 129.4, 128.5, 118.6, 117.4, 114.5, 80.8, 42.2, 31.8, 22.5. HPLC
analysis (Chiralpak AD-H column, hexane/2-propanol ¼ 90:10, flow
rate ¼ 1.0 mL/min, wavelength ¼ 254 nm): tR ¼ 9.79 (major of
trans-isomer), 12.96 (minor of trans-isomer), 14.52 (major of cis-
isomer) and 22.31 min (minor of cis-isomer).
4.2.5. (2R,4S)-5-Chloro-2-methyl-4-(nitromethyl)-1,2,3,4-
4.2.2. (2R,4S)-7-Fluoro-2-methyl-4-(nitromethyl)-1,2,3,4-tetra-
tetrahydroquinoline (9e)
hydroquinoline (9b)
Yellow solid, m.p. 62e65 ꢀC, 25 mg, 51% yield, ½a 2D0
¼ þ19.6 (c
ꢂ
Yellow solid, m.p. 85e87 ꢀC, 22 mg, 49% yield, ½a 2D0
ꢂ
¼ þ18.7 (c
0.23, CHCl3), cis/trans >19/1, 93% ee. 1H NMR (CDCl3, 400 MHz):
0.42, CHCl3), cis/trans ¼ 82/18, 99% ee for cis-isomer, >99% ee for
d
6.97 (t, J ¼ 8.0 Hz, 1 H), 6.68 (d, J ¼ 7.6 Hz, 1 H), 6.40 (d, J ¼ 8.0 Hz,
trans-isomer. 1H NMR (CDCl3, 400 MHz):
d
(cis-isomer) 6.88 (dd,
1 H), 4.77 (dd, J ¼ 12.4, 4.0 Hz, 1 H), 4.42 (dd, J ¼ 12.4, 11.6 Hz, 1 H),
3.98e4.01 (m, 2 H), 3.49e3.57 (m, 1 H), 1.91 (d, J ¼ 18.0 Hz, 1 H), 1.60
(dd, J ¼ 12.8, 4.4 Hz, 1 H), 1.27 (d, J ¼ 6.0 Hz, 3 H). 13C NMR (CDCl3,
J ¼ 8.0, 6.8 Hz, 1 H), 6.35 (dt, J ¼ 8.4, 2.4 Hz), 6.55 (dd, J ¼ 10.4,
2.4 Hz, 1 H), 4.89 (dd, J ¼ 12.0, 4.8 Hz, 1 H), 4.38 (dd, J ¼ 12.0, 9.6 Hz,
1 H), 3.85 (br. s, 1 H), 3.68e3.75 (m, 1 H), 3.41e3.49 (m, 1 H),
2.02e2.07 (m, 1 H), 1.43e1.80 (m, 3 H), 1.23 (d, J ¼ 6.4 Hz, 3 H);
100.6 MHz):
d 146.1, 134.8, 129.1, 117.8, 114.3, 112.8, 77.3, 41.9, 33.5,
31.0, 22.3. HPLC analysis (Chiralpak AD-H column, hexane/2-
propanol ¼ 90:10, flow rate ¼ 1.0 mL/min, wavelength ¼ 254 nm):
tR ¼ 25.14 (major of trans-isomer), 31.88 (minor of trans-isomer),
33.43 (major of cis-isomer) and 51.27 min (minor of cis-isomer).
d
(trans-isomer, incomplete data) 6.95 (dd, J ¼ 8.0, 6.0 Hz, 1 H), 6.19
(dd, J ¼ 9.6, 2.4 Hz, 1 H), 4.52 (d, J ¼ 0.8 Hz, 1 H), 4.50 (s, 1 H), 3.95
(br. s, 1 H), 3.61e3.65 (m, 1 H), 1.86 (d, J ¼ 14.4 Hz, 2 H), 1.25 (d,
J ¼ 5.6 Hz, 3 H). 13C NMR (CDCl3, 100.6 MHz):
d (cis-isomer) 162.6 (d,
J ¼ 243.9 Hz), 146.8 (d, J ¼ 10.8 Hz), 127.5 (d, J ¼ 10.1 Hz), 114.3 (d,
J ¼ 2.6 Hz), 104.3 (d, J ¼ 22.0 Hz), 101.1 (d, J ¼ 24.3 Hz), 80.3, 46.5,
4.2.6. (2R,4S)-7-Bromo-2-methyl-4-(nitromethyl)-1,2,3,4-tetra-
hydroquinoline (9f)
35.2, 34.5, 22.2;
d
(trans-isomer, incomplete data) 145.9 (d,
Yellow solid, m.p. 79e81 ꢀC, 35 mg, 61% yield, ½a 2D0
¼ þ28.0 (c
ꢂ
J ¼ 10.9 Hz), 130.7 (d, J ¼ 10.3 Hz), 113.0 (d, J ¼ 2.4 Hz), 104.2 (d,
J ¼ 22.1 Hz), 100.5 (d, J ¼ 24.7 Hz), 80.6, 42.1, 35.0, 31.6, 22.3 HPLC
analysis (Chiralpak AD-H column, hexane/2-propanol ¼ 90:10, flow
rate ¼ 1.0 mL/min, wavelength ¼ 254 nm): tR ¼ 26.75 (major of
trans-isomer), 35.81 (minor of trans-isomer), 41.52 (major of cis-
isomer) and 68.78 min (minor of cis-isomer).
0.76, CHCl3), cis/trans ¼ 82/18, >99% ee for cis-isomer, >99% ee for
trans-isomer. 1H NMR (CDCl3, 400 MHz):
d (cis-isomer) 6.80 (d,
J ¼ 8.4 Hz, 1 H), 6.75 (d, J ¼ 8.0 Hz, 1 H), 6.67 (s, 1 H), 4.88 (dd,
J ¼ 12.0, 4.8 Hz, 1 H), 4.38 (dd, J ¼ 11.2, 6.4 Hz, 1 H), 3.82 (br. s, 1 H),
3.65e3.73 (m, 1 H), 3.40e3.46 (m, 1 H), 2.02e2.07 (m, 1 H),
1.45e1.54 (m, 1 H), 1.23 (d, J ¼ 6.4 Hz, 3 H);
d (trans-isomer,
incomplete data) 6.87 (d, J ¼ 8.0 Hz, 1 H), 6.66 (s, 1 H), 4.51 (d,
4.2.3. (2R,4S)-7-Chloro-2-methyl-4-(nitromethyl)-1,2,3,4-tetra-
J ¼ 8.0 Hz, 2 H), 3.91 (br. s, 1 H), 1.25 (d, J ¼ 6.0 Hz, 3 H). 13C NMR
hydroquinoline (9c)
(CDCl3, 100.6 MHz): d (cis-isomer) 146.6, 127.6, 121.6, 120.3, 117.5,
Yellow solid, m.p.: 77e80 ꢀC, 28 mg, 58% yield, ½a 2D0
ꢂ
¼ þ32.8 (c
117.3, 80.0, 46.5, 35.0, 34.6, 22.2; d (trans-isomer, incomplete data),
0.32, CHCl3), cis/trans ¼ 81/19, 99% ee for cis-isomer, 98% ee for
130.7, 120.0, 116.8, 80.3, 42.1, 31.4, 22.3. HRMS (ESI) m/z calcd for
trans-isomer. 1H NMR (CDCl3, 400 MHz):
d
(cis-isomer) 6.86 (d,
C
11H14BrN2O2 [MþH]þ: 285.0233, found 285.0236. HPLC analysis
J ¼ 8.4 Hz, 1 H), 6.61 (dd, J ¼ 8.0, 2.0 Hz, 1 H), 6.51 (d, J ¼ 2.0 Hz, 1 H),
4.88 (dd, J ¼ 12.0, 4.8 Hz, 1 H), 4.38 (dd, J ¼ 12.0, 9.6 Hz, 1 H), 3.83
(br. s, 1 H), 3.64e3.74 (m, 1 H), 3.40e3.48 (m, 1 H), 2.04 (ddd,
J ¼ 12.8, 6.0, 2.4 Hz, 1 H), 1.45e1.53 (m, 1 H), 1.23 (d, J ¼ 6.4 Hz, 3 H);
(Chiralpak AD-H column, hexane/2-propanol ¼ 90:10, flow
rate ¼ 1.0 mL/min, wavelength ¼ 254 nm): tR ¼ 29.16 (major of
trans-isomer), 39.68 (minor of trans-isomer), 48.67 (major of cis-
isomer) and 74.50 min (minor of cis-isomer).
d
(trans-isomer, incomplete data) 6.92 (d, J ¼ 8.0 Hz, 1 H), 6.59 (dd,
J ¼ 7.2, 2.0 Hz, 1 H), 4.50e4.52 (m, 2 H), 3.93 (br. s, 1 H), 1.25 (d,
4.2.7. (2R,4S)-6-Bromo-2-methyl-4-(nitromethyl)-1,2,3,4-
J ¼ 6.4 Hz, 3 H). 13C NMR (CDCl3, 100.6 MHz):
d
(cis-isomer), 144.0,
(trans-
tetrahydroquinoline (9g)
128.0, 126.2, 122.2, 120.0, 116.1, 80.1, 46.5, 35.0, 34.8, 22.2;
d
Yellow solid m.p. 54e55 ꢀC, 28 mg, 49% yield, ½a 2D0
þ29.8 (c 0.22,
ꢂ
isomer, incomplete data), 143.2, 128.9, 128.5, 115.6, 80.1, 42.2, 35.3,
31.4, 22.3. HRMS (ESI) m/z calcd for C11H14ClN2O2 [MþH]þ:
241.0738, found 241.0742. HPLC analysis (Chiralpak AD-H column,
CHCl3), cis/trans ¼ 84/16, >99% ee for cis-isomer, >99% ee for trans-
isomer. 1H NMR (CDCl3, 400 MHz):
d
(cis-isomer) 7.11 (dd, J ¼ 8.4,
2.0 Hz, 1 H), 7.06 (s, 1 H), 6.41 (dd, J ¼ 8.4, 2.0 Hz, 1 H), 4.89 (dd,
J ¼ 12.0, 4.8 Hz, 1 H), 4.38 (dd, J ¼ 11.2, 10.0 Hz, 1 H), 3.80 (br. s, 1 H),
3.69e3.74 (m, 1 H), 3.37e3.45 (m, 1 H), 2.02e2.07 (m, 1 H),
hexane/2-propanol ¼ 90:10,
flow
rate ¼ 1.0 mL/min,
wave-
length ¼ 254 nm): tR ¼ 36.84 (major of trans-isomer), 49.33 (minor
of trans-isomer), 53.52 (major of cis-isomer) and 87.75 min (minor
of cis-isomer).
1.44e1.53 (m, 1 H), 1.23 (d, J ¼ 6.4 Hz, 3 H);
d (trans-isomer,
incomplete data) 7.13 (dd, J ¼ 8.0, 2.0 Hz, 1 H), 6.39 (d, J ¼ 8.0 Hz,
1 H), 4.52e4.24 (m, 2 H), 3.91 (s, 1 H), 3.06e3.15 (m, 1 H), 1.2 (d,
4.2.4. (2R,4S)-6-Chloro-2-methyl-4-(nitromethyl)-1,2,3,4-tetra-
J ¼ 6.4 Hz, 3 H). 13C NMR (CDCl3, 100.6 MHz):
d
(cis-isomer) 144.4,
hydroquinoline (9d)
130.9, 129.0, 120.6, 116.5, 109.1, 80.1, 46.5, 35.0, 34.8, 22.2; d (trans-
Yellow solid, m.p. 64e66 ꢀC, 30 mg, 62% yield, ½a 2D0
ꢂ
¼ þ30.3 (c
isomer, incomplete data), 143.6,131.8, 131.3, 119.3, 116.0, 108.5, 80.4,
42.2, 35.2, 31.3, 22.3. HPLC analysis (Chiralpak AD-H column, hex-
0.62, CHCl3), cis/trans ¼ 79/21, cis/trans ¼ 79/21, 97% ee for cis-iso-
mer, 98% ee for trans-isomer. 1H NMR (CDCl3, 400 MHz):
d
(cis-
ane/2-propanol ¼ 95:5,
flow
rate ¼ 1.0 mL/min,
wave-
isomer) 6.98 (dd, J ¼ 8.4, 2.0 Hz, 1 H), 6.93 (s, 1 H), 6.46 (d, J ¼ 8.8 Hz,
1 H), 4.89 (dd, J ¼ 12.4, 4.8 Hz, 1 H), 4.38 (dd, J ¼ 12.0, 10.0 Hz, 1 H),
3.79 (br. s, 1 H), 3.72 (quintet, J ¼ 5.2 Hz, 1 H), 3.37e3.48 (m, 1 H),
2.05 (ddd, J ¼ 12.4, 5.6, 2.4 Hz, 1 H), 1.45e1.54 (m, 1 H), 1.23 (d,
length ¼ 254 nm): tR ¼ 14.08 (major of trans-isomer), 17.10 (minor
of trans-isomer), 18.32 (major of cis-isomer) and 28.56 min (minor
of cis-isomer).
J ¼ 6.4 Hz, 3 H);
d
(trans-isomer, incomplete data) 6.44 (d, J ¼ 8.8 Hz,
4.2.8. (2R,4S)-2-Methyl-4-(nitromethyl)-1,2,3,4-tetrahydro-
1 H), 4.53 (d, J ¼ 8.0 Hz, 2 H), 3.89 (br. s, 1 H), 3.61e3.66 (m, 1 H),
quinoline-7-carbonitrile (9h)
1.83e1.87 (m, 1 H), 1.61e1.69 (m, 1 H), 1.25 (d, J ¼ 6.0 Hz, 3 H) 13C
Yellow solid, m.p. 140e141 ꢀC, 25 mg, 55% yield, ½a 2D0
¼ þ16.4 (c
ꢂ
NMR (CDCl3, 100.6 MHz):
d
(cis-isomer) 144.0, 128.0, 126.2, 122.1,
0.34, CHCl3), cis/trans ¼ 84/16, >99% ee for cis-isomer, 98% ee for
Please cite this article in press as: H. Zhang, et al., Bifunctional thiophosphinamide catalyzed highly enantioselective Michael addition of acetone
to (E)-2-azido -nitrostyrenes and the subsequent reductive cyclization, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.08.052
b

H. Zhang et al. / Tetrahedron xxx (2018) 1e7
Chem. Rev. 111 (2011) 7157. For recent examples, see:;
7
trans-isomer. 1H NMR (CDCl3, 400 MHz):
d (cis-isomer) 7.01 (d,
(b) L. Juen, M. Brachet-Botineau, C. Parmenon, J. Bourgeais, O. Herault,
F. Gouilleux, M.-C. Viaud-Massuard, G. Prie, J. Med. Chem. 60 (2017) 6119;
(c) H. Jo, M. Choi, A.S. Kumar, Y. Jung, S. Kim, J. Yun, J.-S. Kang, Y. Kim, S.-
b. Han, J.-K. Jung, J. Cho, K. Lee, J.-H. Kwak, H. Lee, ACS Med. Chem. Lett. 7
(2016) 385;
(d) T.O. Schrader, M. Kasem, A. Ren, K. Feichtinger, B. Al Doori, J. Wei, C. Wu,
H. Dang, M. Le, J. Gatlin, K. Chase, J. Dong, K.T. Whelan, C. Sage, A.J. Grottick,
G. Semple, Bioorg. Med. Chem. Lett. 26 (2016) 5877;
(e) G. Spadoni, A. Bedini, S. Lucarini, M. Mari, D.-H. Caignard, J.A. Boutin,
P. Delagrange, V. Lucini, F. Scaglione, A. Lodola, F. Zanardi, D. Pala, M. Mor,
S. Rivara, J. Med. Chem. 58 (2015) 7512;
(f) A.R. Soares, N. Engene, S.P. Gunasekera, J.M. Sneed, V.J. Paul, J. Nat. Prod. 78
(2015) 534.
J ¼ 8.0 Hz, 1 H), 6.90 (d, J ¼ 8.0 Hz, 1 H), 6.75 (s, 1 H), 4.90 (dd,
J ¼ 12.4, 5.2 Hz, 1 H), 4.44 (dd, J ¼ 12.4, 9.2 Hz, 1 H), 3.99 (br. s, 1 H),
3.72e3.80 (m, 1 H), 3.47e3.52 (m, 1 H), 2.06e2.10 (m, 1 H),
1.49e1.70 (m, 3 H), 1.26 (d, J ¼ 6.4 Hz, 3 H);
d (trans-isomer,
incomplete data) 7.08 (d, J ¼ 7.6 Hz, 1 H), 6.88 (d, J ¼ 8.4 Hz, 1 H),
4.52 (d, J ¼ 8.0 Hz, 2 H), 4.01 (br. s, 1 H), 1.99e2.02 (m, 1 H),
1.88e1.93 (m, 2 H), 1.28 (d, J ¼ 6.4 Hz, 3 H). 13C NMR (CDCl3,
100.6 MHz):
111.8, 79.4, 46.5, 35.0, 34.5, 22.1;
130.1, 120.1, 117.1, 80.0, 42.3, 35.4, 31.1, 22.2. HPLC analysis (Chir-
alpak AD-H column, flow
d (cis-isomer) 145.7, 126.9, 123.4, 120.5, 118.8, 117.4,
d
(trans-isomer, incomplete data)
€
[2] R.N. Asolkar, D. Schroder, R. Heckmann, S. Lang, I. Wagner-Dobler, H. Laatsch,
hexane/2-propanol ¼ 90:10,
J. Antibiot. 54 (2004) 17.
rate ¼ 1.0 mL/min, wavelength ¼ 254 nm): tR ¼ 12.56 (major of
trans-isomer), 16.87 (minor of trans-isomer), 18.51 (major of cis-
isomer) and 25.13 min (minor of cis-isomer).
[3] J. Liu, Y. Wang, Y. Sun, D. Marshall, S. Miao, G. Tonn, P. Anders, J. Tocker,
H.L. Tang, J. Medina, Bioorg. Med. Chem. Lett. 19 (2009) 6840.
[4] R.J. Pagliero, S. Lusvarghi, A.B. Pierini, R. Brun, M.R. Mazzieri, Bioorg. Med.
Chem. 18 (2010) 142.
[5] Y.A. Sonawane, Y. Zhu, J.C. Garrison, E.L. Ezell, M. Zahid, X. Cheng, A. Natarajan,
ACS Med. Chem. Lett. 8 (2017) 1183.
4.2.9. (2R,4S)-2,7-Dimethyl-4-(nitromethyl)-1,2,3,4-tetrahydro-
[6] R. Gosmini, V.L. Nguyen, J. Toum, C. Simon, J.-M.G. Brusq, G. Krysa, O. Mirguet,
A.M. Riou-Eymard, E.V. Boursier, L. Trottet, P. Bamborough, H. Clark, C.-
w. Chung, L. Cutler, E.H. Demont, R. Kaur, A.J. Lewis, M.B. Schilling, P.E. Soden,
S. Taylor, A.L. Walker, M.D. Walker, R.K. Prinjha, E. Nicodeme, J. Med. Chem. 57
(2014) 8111.
[7] K.W. Bair, T. Herbertz, G.S. Kauffman, K.J. KaysekBricker, G.P. Luke,
M.W. Martin, D.S. Millan, S.E.R. Schiller, A.C. Talbot, WO 2015074064 (2015),
Chem. Abstr. 162 (2015), 670698.
quinoline (9k)
Yellow solid, m.p. 71e73 ꢀC, 23 mg, 52% yield. ½a 2D0
¼ þ12.8 (c
ꢂ
0.60, CHCl3), cis/trans ¼ 77/23, 99% ee for cis-isomer, 99% ee for
trans-isomer. 1H NMR (CDCl3, 400 MHz):
d (cis-isomer) 6.85 (d,
J ¼ 7.6 Hz, 1 H), 6.50 (dd, J ¼ 7.6, 0.8 Hz, 1 H), 6.37 (s, 1 H), 4.91 (dd,
J ¼ 12.0, 4.8 Hz, 1 H), 4.35 (dd, J ¼ 12.0, 10.0 Hz, 1 H), 3.70e3.78 (m,
2 H), 3.38e3.43 (m, 1 H), 2.22 (s, 3 H), 2.04 (ddd, J ¼ 8.8, 6.0, 2.8 Hz,
[8] (a) Y. Wang, C. Zheng, S.-L. You, Angew. Chem. Int. Ed. 56 (2017) 15093;
(b) Z.-P. Yang, C. Zheng, L. Huang, C. Qian, S.-L. You, Angew. Chem. Int. Ed. 56
(2017) 1530;
1 H), 1.45e1.54 (m, 1 H), 1.22 (d, J ¼ 6.0 Hz, 3 H);
d (trans-isomer,
incomplete data) 6.92 (d, J ¼ 7.6 Hz, 1 H), 6.48 (dd, J ¼ 7.6, 1.2 Hz,
1 H), 6.35 (s, 1 H), 4.54 (s, 1 H), 4.52 (d, J ¼ 1.6 Hz,1 H), 3.61e3.60 (m,
1 H), 3.44e3.49 (m, 1 H), 1.84 (dt, J ¼ 14.0, 2.4 Hz, 1 H), 1.63e1.71 (m,
(c) X. Zhang, W.-B. Liu, H.-F. Tu, S.-L. You, Chem. Sci. 6 (2015) 4525;
(d) W.-B. Liu, C.M. Reeves, S.C. Virgil, B.M. Stoltz, J. Am. Chem. Soc. 135 (2013)
10626;
(e) W.-B. Liu, C. Zheng, C.-X. Zhuo, L.-X. Dai, S.-L. You, J. Am. Chem. Soc. 134
(2012) 4812;
1 H), 1.24 (d, J ¼ 6.0 Hz, 3 H). 13C NMR (CDCl3, 100.6 MHz):
d (cis-
(f) W.-B. Liu, H. He, L.-X. Dai, S.-L. You, Synthesis (2009) 2076.
[9] For reviews, see: (a) J.S. Bello Forero, J. Jones Jr., F.M. da Silva, Curr. Org. Synth.
13 (2016) 157;
isomer) 145.3, 138.0, 126.2, 118.8, 115.5, 114.9, 80.6, 46.5, 35.7, 34.7,
22.3, 21.0;
d (trans-isomer) 144.5, 138.4, 129.3, 118.5, 115.8, 114.6,
80.9, 42.1, 35.2, 31.9, 22.4, 21.1. HRMS (ESI) m/z calcd for C12H17N2O2
[MþH]þ: 221.1285, found 221.1287. HPLC analysis (Chiralpak AD-H
column, hexane/2-propanol ¼ 90:10, flow rate ¼ 1.0 mL/min,
wavelength ¼ 254 nm): tR ¼ 17.68 (major of trans-isomer), 22.73
(minor of trans-isomer), 25.43 (major of cis-isomer) and 45.83 min
(minor of cis-isomer).
(b) Y. Wang, H. Lu, P.-F. Xu, Acc. Chem. Res. 48 (2015) 1832;
(c) G.D. Munoz, G.B. Dudley, Org. Prep. Proced. Int. 47 (2015) 179;
(d) A.R. Katritzky, S. Rachwal, B. Rachwal, Tetrahedron 52 (1996) 15031.
[10] Q.-S. Guo, D.-M. Du, J.-X. Xu, Angew. Chem. Int. Ed. 47 (2008) 759.
[11] D.B. Ramachary, K.S. Shruthi, Org. Biomol. Chem. 12 (2014) 4300.
[12] (a) A. Lu, T. Liu, R. Wu, Y. Wang, Z. Zhou, G. Wu, J. Fang, C. Tang, Eur. J. Org.
Chem. (2010) 5777;
(b) A. Lu, T. Liu, R. Wu, Y. Wang, G. Wu, Z. Zhou, J. Fang, C. Tang, J. Org. Chem.
76 (2011) 3872.
[13] J. Pan, Y. Wang, S. Chen, Y. Wang, Z. Zhou, Tetrahedron 72 (2016) 240.
Acknowledgments
[14] 6-Methyl-[1,3]dioxolo[4,5-g]quinolone (10): white solid, m.p. 152e154 ꢀC, 20
mg, 54% yield. 1H NMR (CDCl3, 400 MHz):
d
7.85 (d, J ¼ 8.4 Hz, 1 H), 7.31 (s, 1
We are grateful to the Key laboratory of Elemento-Organic
Chemistry and Collaborative Innovation Center of Chemical Sci-
ence and Engineering for generous financial support for our
programs.
H), 7.13 (d, J ¼ 8.4 Hz, 1 H), 7.01 (s, 1 H), 6.08 (s, 2 H), 2.67 (s, 3 H). 13C NMR
(CDCl3, 100.6 MHz):
d 156.6, 150.5, 147.1, 146.1, 135.0, 123.1, 120.1, 105.4,
102.6, 101.5, 24.9. 2-Methylbenzo[h]quinolone (11): Pale yellow oil, 24 mg,
61% yield. 1H NMR (CDCl3, 400 MHz):
d
9.33 (d, J ¼ 8.0 Hz, 1 H), 8.06 (d, J ¼ 8.0
Hz, 1 H), 7.76 (d, J ¼ 8.8 Hz, 1 H), 7.72 (dt, J ¼ 8.0, 1.6 Hz, 1 H), 7.67 (dt, J ¼ 8.0,
1.6 Hz, 1 H), 7.66 (d, J ¼ 8.8 Hz, 1 H), 2.85 (s, 3 H). 13C NMR (CDCl3, 100.6
MHz):
d 157.7, 145.9, 135.9, 133.7, 131.3, 127.9, 127.7, 126.7, 126.6, 125.2,
Appendix A. Supplementary data
124.4, 124.1, 122.1, 25.4.
[15] (a) N. Hayashi, I. Shibata, A. Baba, Org. Lett. 6 (2004) 4981;
(b) L. Benati, G. Bencivenni, R. Leardini, D. Nanni, M. Minozzi, P. Spagnolo,
R. Scialpi, G. Zanardi, Org. Lett. 8 (2006) 2499.
[16] CCDC-1850996 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.08.052.
References
[1] For a general reviews, see: (a) V. Sridharan, P.A. Suryavanshi, J.C. Menendez,
Please cite this article in press as: H. Zhang, et al., Bifunctional thiophosphinamide catalyzed highly enantioselective Michael addition of acetone
to (E)-2-azido -nitrostyrenes and the subsequent reductive cyclization, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.08.052
b