Enantioselective Construction of Polyfunctionalized Spiroannulated Dihydrothiophenes via a Formal Thio [3+2] Cyclization

Article abstract of DOI:10.1021/acs.joc.5b01357

A formal thio [3+2] cyclization catalyzed by Takemoto's organocatalyst has been reported for the construction of optically active spiroannulated dihydrothiophenes in high yields with excellent regio-, chemo-, diastereo-, and enantioselectivities.

Full text of DOI:10.1021/acs.joc.5b01357

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Note
Enantioselective Construction of Polyfunctionalized Spiroannulated
Dihydrothiophenes via a Formal Thio [3 + 2]-Cyclization
Xue-Mei Zeng, Chang-Yu Meng, Jia-Xin Bao, Dong-Cheng Xu, Jian-Wu Xie, and Wei-Dong Zhu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01357 • Publication Date (Web): 16 Oct 2015
Downloaded from http://pubs.acs.org on October 27, 2015
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Enantioselective Construction of Polyfunctionalized Spiroannulated
Dihydrothiophenes via a Formal Thio [3 + 2]ꢀCyclization
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XueꢀMei Zenga, ChangꢀYu Mengb, JiaꢀXin Baoa, DongꢀCheng Xua, JianꢀWu Xiea and WeiꢀDong Zhu a
*
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a Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry and Life Science, Zhejiang Normal
University, Jinhua 321004, P. R. China; Eꢀmail: xiejw@zjnu.cn
b Department of Chemistry and Materials, Yulin Normal University, Yulin 537000, P. R. China
Abstract A formal thio [3 + 2]ꢀcyclization catalyzed by Takemoto’s organocatalyst has been reported for the construction of
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optically active spiroannulated dihydrothiophenes in high yields with excellent regioꢀ, chemoꢀ, diastereoꢀ and enantioselectivities.
Keywords: Dihydrothiophenes, Organocatalysis , 1,3ꢀDicarbonyl Compounds, Nitrostyrenes, Thioamides
Thiophenes are unique sulfurꢀcontaining heterocycles and attracted particular attention due to their special place as building
blocks in natural products, pharmaceutical agents and materials. Especially, optically active and polyfunctionalized thiophenes are
of considerable interest as they possess a wide range of biological properties (Figure 1), such as essential coenzyme biotin with
important biological functions,[1] leukotriene antagonists,[2] potential inhibitors of HIV,[3] antitumor natural product[4] and human A3
adenosine receptor ligands.[5] In addition, the chiral thiophenes could serve as building blocks for new chiral ligands in asymmetric
metal catalysis[6] and chiral organocatalyst [7], as well as in natural product synthesis. Due to the importance of applications of chiral
thiophenes in the aboveꢀmentioned areas, the stereoselective synthesis of chiral dihydrothiophenes and tetrahydrothiophenes with
high atomic efficiency and, more importantly, good feasibility to assemble various substitution patterns, has become a very hot
topic in the current research efforts.[8]
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Figure 1 Some Representative Examples of Biologically Active Compounds Which Contain a Thiophene Ring
In addition, spirocyclic compounds are recognized as important precursors for the easy access of a variety of cyclic products
by rearrangement reaction due to their steric strain associated with the quaternary carbon.[9] Development of novel synthetic
methods for the construction of new spirocyclic compounds represents a major challenge in synthetic organic and medicinal
chemistry.[10] Surprisingly, practical and efficient approaches, especially catalytic asymmetric variants to assemble spiroannulated
dihydrothiophenes, have rarely been reported.[11] In addition, organocatalytic asymmetric reactions have been used as an efficient
tool for the synthesis of enantiopure molecules under mild, environmentally benign conditions over the past decades.[12] Meanwhile,
domino reactions have been served as a powerful tool for the rapid and efficient assembly of complex structures from simple
starting materials with minimized waste production.[13] Herein we present such an advance and its direct application in an
atomꢀeconomical synthesis of spiroannulated dihydrothiophenes based on the development of a new organocatalytic
enantioselective formal thio [3+2]ꢀcyclization of thioamides to (E)ꢀαꢀnitrostyrenes. Notably, the designed reactions are highly
regioꢀ, chemoꢀ, diastereoꢀ and enantioselective, which simultaneously give the desired multifunctional products with two vicinal
chiral carbon centers.
In the course of our investigations on the use of 1,3ꢀdicarbonyl compounds I in organic synthesis, the 1,3ꢀdicarbonyl
compounds I turned out to be highly reactive and versatile, and many Oꢀcontaining heterocycles have been prepared from
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1,3ꢀdicarbonyl compounds I in our group (Eq. a).[14] Encouraged by the successful results mentioned above, we conceived that
Sꢀheterocycles (e.g. thiophenes, dihydrothiophenes, and tetrahydrothiophenes) could be synthesized from 1,3ꢀdicarbonyl
compounds II containing a carbonyl and thiocarbonyl group (Eq. b). The substrate thioamide 3a containing a carbonyl and
thiocarbonyl group, which has been proved to be highly reactive, was prepared by the reaction of 2ꢀtetralone with sodium hydride
and isothiocyanatobenzene. [15aꢀd] We envisioned that the organocatalysts 1aꢀi (Figure 2) would be efficient for the domino formal
thio[3+2]ꢀcyclization of thioamide 3a with (E)ꢀαꢀnitrostyrene 2a to afford the chiral polyfunctionalized spiroannulated
dihydrothiophene 4aa (Scheme 1). The key step of the above reaction is the Michael addition of 2a to 3a yielding the saturated
nitroalkane III, which may exist in a tautomeric form IIIA or IIIB. Subsequently, the nucleophilic attack of the sulfur atom on the
αꢀcarbon atom attached to a nitro group and eliminated a water molecule afford spirotetrahydrothiophene 4aa.[15e]
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Table 1 shows some screening results for the reaction of 2a with 3a. Initially, quinine 1a was investigated as the organocatalyst
for the thio[3+2]ꢀcyclization. The reaction proceeded smoothly and chiral 4aa was formed in a moderate yield with good
diastereoselectivity, while the enantioselectivity was poor (Table 1, entry 1). Subsequently, organocatalysts 1bꢀg, which are readily
available from natural cinchona alkaloids, also exhibited a high catalytic activity when the thio[3+2]ꢀcyclization was carried out at
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25 C for 24 h (entries 2ꢀ7). Similar results were achieved when the thio[3+2]ꢀcyclization was catalyzed by quinine 1e and its
derivatives 1bꢀd (entries 2ꢀ5). Bifunctional thioureas 1fꢀi appeared to be efficient organocatalysts for the asymmetric additions of
nucleophiles to (E)ꢀαꢀnitrostyrenes.[16] As such, we envisioned that bifunctional organocatalysts 1fꢀi would be efficient for the
thio[3+2]ꢀcyclization of thioamide 3a with (E)ꢀαꢀnitrostyrene 2a. The domino reaction proceeded smoothly when the reaction
was carried out in the presence of organocatalyst 1f and the product 4aa was obtained in a moderate yield, while the
diastereoselectivity and enantioselectivity were very poor (entry 7). To our surprise, Takemoto’s catalyst 1h was proved to be
superior to other catalysts in this cascade reaction, and the product 4aa was obtained with good diastereoselectivity and moderate
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enantioselectivity (Table 1, entry 8). By lowering the temperature to ꢀ5 C, the enantioselectivity was dramatically increased when
the reaction was catalyzed by Takemoto’s catalyst 1h (entry 12), while the reaction time should be extended. Thus, catalyst 1h was
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chosen for further optimization of solvents and temperature (Table 2).
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Scheme 1 Organocatalytic Enantioselective formal [3+2]ꢀCyclization of Thioamide 3a to (E)ꢀαꢀNitrostyrene 2a
Figure 2 Structure of Organocatalysts 1aꢀi
TABLE 1 Catalyst Screening a)
Entry Cat.
1a
Yield (%)b)
Dr c)
Ee (%)d)
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1
55
65
68
60
58
55
51
71
60
63
62
69
45
87:13
90:10
81:19
89:11
90:10
55:45
65:35
93:7
78:22
92:8
92:8
95:5
90:10
2
3
4
5
6
1b
1c
1d
1e
1f
40
41
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43
0
25
46
40
48
50
74
54
7
8
9
1g
1h
1i
10e)
11 e)
12 e)
13 e)
1c
1d
1h
1i
a)
b)
c)
Unless otherwise noted, reactions performed with 0.12 mmol of 2a, 0.1 mmol of 3a, 20 mol% catalyst, in 1 mL DCM at 25 °C for 24 h. Isolated yield.
Determined by chiral HPLC analysis. d) Determined by chiral HPLC analysis. e) At ꢀ5 oC for 36 h.
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Most commonly used solvents are compatible with our asymmetric conditions and afforded good yields (55ꢀ68 %) with
excellent to good diastereoselectivities (up to 96:4) and varied enantioselectivities (Table 2, entries 1ꢀ6). When the reaction was
carried out in chlorinated solvents such as DCM and CHCl3, excellent diastereoselectivities and good enantioselectivities were
obtained (entries 1 and 6). The reaction in polar solvents such as THF and ether afforded 4aa with somewhat lower
enantioselectivities (entries 2 and 3). When the reaction was carried out in hydrocarbon solvents, product 4aa was isolated in almost
unchanged yields and slightly decreased enantioselectivities (entries 4 and 5). Then solvent DCM was chosen as candidate solvent
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for further screening of temperature. By lowing the temperature to ꢀ60 C, we got an excellent enantioselectivity (92% ee) and
diastereoselectivity (98:2) in the presence of 1h while the reaction time should be extended (entry 9). The ee was dramatically
decreased when the catalyst loading was reduced to 10 mol%. Based on the above screening, the optimal reaction conditions (1.2
equiv 2a and 1.0 equiv 3a in DCM with 20 mol % catalyst 1h at ꢀ60 oC) were established.
TABLE 2 Screening Studies of Organocatalytic Thio[3+2]ꢀCyclization of Thioamide 3a to (E)ꢀαꢀNitrostyrene 2a a)
Entry
1
2
3
4
Sol.
DCM
THF
Yield (%)b)
Dr c)
96:4
93:7
89:11
92:8
92:8
94:6
97:3
97:3
98:2
98:2
97:3
Ee (%)d)
74
68
65
54
55
57
65
69
66
70
64
50
32
62
68
52
66
83
87
91
Diethyl ether
Toluene
Hexane
CHCl3
DCM
5
6
7e)
8f)
9g)
10h)
11i)
DCM
DCM
DCM
DCM
90
78
a)
b)
c)
Unless otherwise noted, reactions performed with 0.12 mmol of 2a, 0.1 mmol of 3a, 20 mol% 1h, in 1 mL solvent at ꢀ5 °C for 36 h; Isolated yield;
Determined by chiral HPLC analysis; d) Determined by chiral HPLC analysis; e) At ꢀ30 oC for 48h; f) At ꢀ50 oC for 60 h; g) At ꢀ60 oC for 72 h; h) At ꢀ70 oC for 96 h;
i) 10 mol% 1h, at ꢀ60 oC for 72 h.
With the optimal reaction conditions in hand, the scope of the present organocatalytic asymmetric the thio[3+2]ꢀcyclization
using catalyst 1h was extended to various thioamides 3 and (E)ꢀαꢀnitrostyrenes 2. As shown in Table 3, this new methodology not
only provides a facile access to a range of multisubstituted spiroannulated dihydrothiophenes but also serves as a facile approach
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for the preparation of a range of substituted tricycles bearing adjacent quaternary and tertiary stereocenters in excellent
enantiomeric excesses and diastereoselectivities. The 1hꢀpromoted the thio[3+2]ꢀcyclizations process takes place with a variety of
(E)ꢀαꢀnitrostyrene Michael acceptors, which possess neutral, electronꢀdonating, electronꢀwithdrawing groups in the phenyl ring
(Table 3, entries 1ꢀ10). It appeared that substituents’ electronic and steric nature has minimal impact on efficiency,
enantioselectivity, and diastereoselectivity of the thio [3+2]ꢀcyclization. Not only aromatic groups but also heteroaromatic group
such as furyl could be successfully employed to afford product 4ma with excellent diastereoselectivity, while the enantioselectivity
decreased (Table 3, entry 12). (E)ꢀαꢀNitrostyrenes with substituents on the ortho position afford multiꢀfunctionalized spiroannulated
dihydrothiophenes with slightly inferior diastereoselectivities (Table 3, entries 4 and 7). To extend the scope of the
thio[3+2]ꢀcyclization further, various thioamides 3bꢀi were utilized as Michael donors in the reaction with (E)ꢀαꢀnitrostyrenes in the
presence of 1h (Table 3, entries 13 ꢀ20). The electronic nature of a substituent on the aromatic moiety of 3 has little effects on
efficiency, enantioselectivity, and diastereoselectivity of the thio [3+2]ꢀcyclization with our organocatalytic protocol. Thioamides 3,
which possess electronꢀdonating, electronꢀwithdrawing groups in the phenyl ring, afforded products 4 in good yields with high
enantioselectivities, and diastereoselectivities. However, poor ee was obtained in the reaction of linear thioamide 3j with
(E)ꢀαꢀnitrostyrene 2a, and 2,3ꢀdihydrothiophene 4aj was obtained with 33% ee in the thio [3+2]ꢀcyclization (Scheme 2, Eq. 1).
However, no desired product was obtained in the reaction of thioamide 3k with (E)ꢀαꢀnitrostyrene 2a, and the reaction still
remains to be explored (Scheme 2, Eq. 2). The absolute configuration of the polyfunctionalized spiroannulated dihydrothiophenes
confirmed by singleꢀcrystal Xꢀray analysis of representative enantiopure 4ae that bears a chlorine atom. As shown in Figure 3, it
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composes of (Z, R, S, Z) configuration (See Supporting information).
TABLE 3 Asymmetric Thio[3+2]ꢀCyclization of Thioamides 3 to (E)ꢀαꢀNitrostyrenes 2 a)
Entry
1
Ar1 (2)
R1
Ar2 (3)
Yield% (4) b)
Dr c)
Ee (%)d)
pꢀCH3C6H4(2a)
H
C6H5(3a)
70 (4aa)
98:2
91
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3
pꢀMeOC6H4(2b)
mꢀMeOC6H4(2c)
oꢀMeOC6H4(2d)
pꢀClC6H4 (2e)
mꢀClC6H4 (2f)
oꢀClC6H4( 2h )
pꢀBr C6H4 (2i)
C6H5 (2j)
H
H
C6H5(3a)
C6H5(3a)
55(4ba)
60 (4ca)
76 (4da)
78 (4ea)
70 (4fa)
64(4ha)
75(4ia)
70(4ja)
60(4ka)
55(4la)
65(4ma)
65(4ab)
70(4ac)
50(4ad)
78 (4ae)
75(4af)
58(4ag)
75(4ah)
68(4ai)
97:3
99:1
98:2
98:2
96:4
98:2
99:1
99:1
97:3
99:1
92:8
99:1
98:2
97:3
99:1
99:1
99:1
99:1
99:1
80
88
80
93
91
88
92
93
92
94
79
92
90
84
92
90
88
92
82
4
H
C6H5(3a)
5
H
C6H5(3a)
6
H
C6H5(3a)
7
H
C6H5(3a)
8
H
C6H5(3a)
9
H
C6H5(3a)
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pꢀNO2C6H4 (2k)
βꢀnaphthyl(2l)
2ꢀfuranyl(2m)
pꢀCH3C6H5(2a)
pꢀCH3C6H4(2a)
pꢀCH3C6H4(2a)
pꢀCH3C6H4(2a)
pꢀCH3C6H4(2a)
pꢀCH3C6H4(2a)
pꢀCH3C6H4(2a)
pꢀCH3C6H4(2a)
H
C6H5(3a)
H
C6H5(3a)
H
C6H5(3a)
6ꢀMeO
H
C6H5(3b)
pꢀCH3C6H5(3c)
pꢀClC6H5(3d)
mꢀClC6H5(3e)
oꢀClC6H5(3f)
H
H
H
H
H
H
mꢀMeOC6H5(3g)
oꢀMeOC6H5(3h)
βꢀnaphthyl (3i)
a) Unless otherwise noted, reactions performed with 0.12 mmol of 2, 0.1 mmol of 3, 20 mol% 1h, in 1 mL DCM at ꢀ60 °C for 72 h; b) Isolated yield; c) Determined by
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1H NMR analysis; d) Determined by chiral HPLC analysis.
Scheme 2 Synthesis of Chiral Monocyclic 2,3ꢀDihydrothiophene
Having established the catalytic asymmetric thio[3+2]ꢀcyclization methodology of thioamides 3 and (E)ꢀαꢀnitrostyrenes 2, the
synthetic utilities of these chiral polyfunctionalized spiroannulated dihydrothiophenes were further explored (Scheme 3). The
oxime group of spiroannulated dihydrothiophene 4aa could be converted to carbonyl group in the presence of nitric acid at room
temperature. The product 5aa was obtained with excellent enantioselectivity and high yields, while the diastereoselectivity was
decreased. The possible reason for the decreased diastereoselectivity was that an enolization reaction of 5aa was happened under
the strong acid reaction conditions (Please see Supporting Information).
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Scheme 3 Selective Transformation of Chiral Polyfunctionalized Spiroannulated Dihydrothiophenes
In summary, we have successfully demonstrated an efficient and highly enantioselective thio[3+2]ꢀcyclizations of thioamides 3
to (E)ꢀαꢀnitrostyrenes 2 with excellent regioꢀ, chemoꢀ, diastereoꢀ and enantioselectivities, by employing Takemoto’s catalyst as the
organocatalyst. This novel methodology provides a facile access to various enantioenriched multifunctional polyfunctionalized
spiroannulated dihydrothiophenes with two vicinal chiral carbon centers including an adjacent quaternary and a tertiary stereocenter.
Notably, the oxime group of spiroannulated dihydrothiophenes could be cleanly converted to the ketones without affecting the
enantioselectivities in the presence of nitric acid.
EXPERIMENTAL SECTION
General methods NMR spectra were recorded with tetramethylsilane as the internal standard. TLC was performed on
glassꢀbacked silica plates. Column chromatography was performed using silica gel (150ꢀ200 mesh) eluting with ethyl acetate and
1
petroleum ether. H NMR spectra were recorded at 600 MHz or 400MHz, and 13C NMR spectra were recorded at 150 MHz or 75
1
MHz. Chemical shifts (δ) are reported in ppm downfield from CDCl3 (δ = 7.26 ppm) or DMSO (δ = 2.50 ppm) for H NMR and
relative to the central CDCl3 resonance (δ = 77.0 ppm) or DMSO resonance (δ = 39.5 ppm) for 13C NMR spectroscopy. Coupling
constants (J) are given in Hz. ESIꢀHRMS spectrometer was measured with a Finnigan LCQDECA ion trap mass spectrometer. Optical
rotations were measured at 589 nm at 25 °C in a 1 dm cell and specific rotations are given in 10ꢀ1 deg cm2 gꢀ1. Enantiomeric excess
were determined by HPLC analysis using Chiralpak column (4.6mm*250mm, 5µm).
[15]
1. General procedure for synthesis of thioamides 3.
To a vigorously stirred suspension of sodium hydride (50 mmol) in 90
mL dry DMF at ꢀ10 oC, 2ꢀtetralone (7.30 g, 50 mmol) was added slowly, over a period of 1 h, so the temperature did not exceed 0
oC. After the gas was evolved, a solution of the appropriate aryl isothiocyanate (50 mmol) in 10 mL dry DMF was added dropwise.
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The mixture was stirred for 3 h at ꢀ10 C, left in a fridge overnight, then added slowly to 50 mL 1 M HCl, and acidified with 2 M
HCl. After 3 h most of the water–DMF solution was decanted. The oily residue was dissolved in CH2Cl2, washed twice with 1 M
HCl and water, then evaporated and purified by flash chromatography on silica gel using CH2Cl2 as eluent. The crude 3 was treated
with Et2O, cooled in a fridge, and collected by filtration. The crude 3 was dissolved in MeCN at 50 oC and treated with 50 mL 2 M
HCl for hydrolysis of imine side products. After evaporation of the solvent the product was purified again by flash chromatography
on silica gel, using CH2Cl2 as eluent, and crystallized from Et2O.
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3a The spectra are in accord with the literature. [15] 6.88 g, 49% yield; 1H NMR (600 MHz, CDCl3) δ 0.69 (s, 1H), 8.07 (t, J = 7.0
Hz, 1H), 7.78 (t, J = 8.8 Hz, 2H), 7.55 (td, J = 7.5, 1.1 Hz, 1H), 7.42 (t, J = 7.9 Hz, 2H), 7.35 (dd, J = 13.1, 5.6 Hz, 1H), 7.31 – 7.27
(m, 2H), 3.81 (q, J = 10.3, 4.9 Hz, 1H), 3.28 (dt, J = 16.8, 4.7 Hz, 1H), 3.11 – 3.04 (m, 1H), 2.87 – 2.81 (m, 1H), 2.80 – 2.72 (m,
1H). 13C NMR (151 MHz, CDCl3) δ 198.0, 197.4, 144.7, 138.9, 134.5, 132.0, 128.9 (d, J = 2.2 Hz), 128.0, 126.9 (d, J = 11.8 Hz),
123.9, 59.6, 29.8, 28.5.
3b The spectra are in accord with the literature.6.4 g, 41% yield; [15] H NMR (600 MHz, CDCl3) δ 10.85 (s, 1H), 8.03 (d, J = 8.8
Hz, 1H), 7.78 (d, J = 7.8 Hz, 2H), 7.39 (t, J = 7.8 Hz, 2H), 7.26 (t, J = 7.4 Hz, 1H), 6.85 (dd, J = 8.8, 2.3 Hz, 1H), 6.70 (d, J = 1.9
Hz, 1H), 3.88 (s, 3H), 3.74 (q, J = 8.5, 6.1 Hz, 1H), 3.24 (dt, J = 16.7, 4.9 Hz, 1H), 3.03 – 2.96 (m, 1H), 2.80 – 2.74 (m, 2H). 13C
NMR (151 MHz, CDCl3) δ 198.00 (s), 195.9, 164.5, 147.5, 139.0, 130.6, 128.8, 126.7, 125.4, 123.8, 113.8, 112.4, 59.1, 55.6, 29.6,
28.8.
3c The spectra are in accord with the literature. [15] 7.8 g, 53% yield; 1H NMR (600 MHz, CDCl3) δ 10.47 (s, 1H), 8.02 (d, J = 7.8
Hz, 1H), 7.59 (d, J = 8.9 Hz, 2H), 7.52 – 7.47 (m, 1H), 7.30 (q, J = 16.9, 8.4 Hz, 2H), 7.24 (d, J = 7.7 Hz, 1H), 6.88 (d, J = 8.9 Hz,
1H), 3.79 (s, 3H), 3.76 (q, J = 9.5, 4.3 Hz, 1H), 3.21 (dt, J = 16.7, 4.6 Hz, 1H), 3.07 – 2.98 (m, 1H), 2.79 – 2.66 (m, 2H). 13C NMR
(151 MHz, CDCl3) δ 198.0, 197.2, 158.1, 144.7, 134.4, 132.0 (d, J = 10.3 Hz), 128.9, 128.0, 126.9, 125.6, 114.3, 114.0, 59.6, 55.5,
29.8, 28.5.
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2. General Procedure for the asymmetric thio[3+2]ꢀcyclization of thioamides 3 to (E)ꢀαꢀnitrostyrenes 2. A mixture of 2a 20.0
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Then flash chromatography on silica gel (10% ethyl acetate/petroleum ether) gave 4aa as a white solid (30 mg, 70% yield).
(2S,2'Z,4'R,5'Z)ꢀ5'ꢀ(hydroxyimino)ꢀ2'ꢀ(phenylimino)ꢀ4'ꢀ(pꢀtolyl)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀthiophen]ꢀ1ꢀ
one (4aa). 30 mg, 70% yield, mp 221 ꢀ 223°C. IR(KBr): υmax 3426, 1655, 1616, 829, 759 cmꢀ1. 1H NMR (600 MHz, CDCl3) δ 8.31
– 8.28 (m, 1H), 8.07 (d, J= 7.9 Hz, 1H), 7.41 (m, J = 7.5, 1.3 Hz, 1H), 7.31 (t, J = 7.9 Hz, 2H), 7.25 – 7.21 (m, 2H), 7.15 – 7.11 (m,
2H), 7.08 (d, J = 8.0 Hz, 2H), 6.87 – 6.84 (m, 2H), 5.37 (s, 1H), 3.31 (ddd, J = 16.4, 11.9, 4.2 Hz, 1H), 2.85 (dt, J = 16.7, 4.1 Hz,
1H), 2.44 (dt, J = 13.8, 4.2 Hz, 1H), 2.27 (s, 3H), 2.14 – 2.08 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 194.0, 167.2, 156.6, 150.5,
143.8, 137.9, 133.7, 132.2, 130.8, 130.4, 129.2, 128.6, 128.3, 126.8, 125.4, 119.8, 64.9, 53.9, 29.3, 25.6, 21.1. ESIꢀHRMS: calcd.
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for C26H22N2O2S+H 427.1470, found 427.1494. [α]25 = ꢀ52.0 (c 0.5, CHCl3); 91% ee; The enantiomeric ratio was determined by
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HPLC on Chiralpak AD column (25% 2ꢀpropanol/hexane, 1 mL/min), tmajor = 20.942 min, tminor = 7.953 min.
(2S,2'Z,4'R,5'Z)ꢀ5'ꢀ(hydroxyimino)ꢀ4'ꢀ(4ꢀmethoxyphenyl)ꢀ2'ꢀ(phenylimino)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀthi
ophen]ꢀ1ꢀone (4ba). 25 mg, 55% yield, 205 ꢀ 207°C. 1H NMR (400 MHz, CDCl3) δ 11.61 (s, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.55 (t,
J = 7.3 Hz, 1H), 7.38 (t, J = 7.9 Hz, 3H), 7.29 (q, J = 12.6, 8.3 Hz, 3H), 7.18 (t, J = 7.4 Hz, 1H), 6.88 (q, J = 14.6, 8.1 Hz, 4H), 5.17
(s, 1H), 3.71 (s, 3H), 3.23 – 3.09 (m, 1H), 2.91 (d, J = 17.1 Hz, 1H), 2.48 – 2.41 (m, 1H), 1.95 (d, J = 10.1 Hz, 1H). 13C NMR (151
MHz, DMSO) δ 194.4, 169.3, 159.2, 152.8, 150.8, 144.5, 134.6, 131.8, 129.9, 129.5, 127.9, 127.4, 127.1, 125.8, 119.9, 114.0, 64.7,
55.5, 53.3, 29.2, 25.2. ESIꢀHRMS: calcd. for C26H22N2O3S+H 443.1429, found 443.1452. [α]25D= ꢀ28.0 (c 0.5, CHCl3), 80% ee;
The enantiomeric ratio was determined by HPLC on Chiralpak AD column (25% 2ꢀpropanol/hexane, 1 mL/min), tmajor = 26.602
min, tminor = 9.914 min.
(2S,2'Z,4'R,5'Z)ꢀ5'ꢀ(hydroxyimino)ꢀ4'ꢀ(3ꢀmethoxyphenyl)ꢀ2'ꢀ(phenylimino)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀthi
ophen]ꢀ1ꢀone (4ca). 28 mg, 60% yield, 219 ꢀ 222°C. IR(KBr): υmax 3390, 1655, 1622, 1122, 1177, 869, 753 cmꢀ1.1H NMR (600
MHz, DMSO) δ 11.66 (s, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.41 – 7.37 (m, 3H), 7.32 (d, J = 7.7 Hz, 1H), 7.28
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(t, J = 7.4 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 6.96 – 6.91 (m, 2H), 6.88 (t, J = 8.9 Hz, 3H), 5.15 (s, 1H), 3.73 (s, 3H), 3.22 – 3.14 (m,
1H), 2.93 (d, J = 17.1 Hz, 1H), 2.47 (dd, J = 9.5, 4.5 Hz, 1H), 2.02 – 1.97 (m, 1H). 13C NMR (151 MHz, DMSO) δ 194.5, 169.4,
159.3, 152.6, 150.9, 144.5, 137.2, 134.6, 131.6, 130.0, 129.8, 129.5, 127.9, 127.4, 125.9, 122.5, 119.8, 116.7, 113.2, 64.7, 55.5,
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53.7, 29.3, 25.3. ESIꢀHRMS: calcd. for C26H22N2O3S+H 443.1429, found 443.1475. [α]25 = ꢀ30.0 (c 0.5, CHCl3), 88% ee; The
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enantiomeric ratio was determined by HPLC on Chiralpak AD column (25% 2ꢀpropanol/hexane, 1 mL/min), tmajor = 19.019 min,
tminor = 9.050 min.
(2S,2'Z,4'R,5'Z)ꢀ5'ꢀ(hydroxyimino)ꢀ4'ꢀ(2ꢀmethoxyphenyl)ꢀ2'ꢀ(phenylimino)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀthi
ophen]ꢀ1ꢀone (4da). 35 mg, 76% yield, 202 ꢀ 205°C. 1H NMR (400 MHz, DMSO) δ 11.48 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.58 (t,
J = 7.4 Hz, 1H), 7.41 (q, J = 7.7 Hz, 3H), 7.34 – 7.24 (m, 3H), 7.20 (t, J = 7.4 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.99 (t, J = 7.4 Hz,
1H), 6.91 (d, J = 7.5 Hz, 2H), 5.16 (s, 1H), 3.70 (s, 3H), 3.14 (dt, J = 11.4, 5.4 Hz, 1H), 2.76 – 2.67 (m, 1H), 2.58 – 2.52 (m, 1H),
2.00 – 1.95 (m, 1H). 13C NMR (151 MHz, DMSO) δ 195.5, 171.0, 157.0, 154.3, 151.3, 144.3, 134.7, 130.6, 130.0, 129.7, 129.4,
128.2, 127.4, 126.0, 125.7, 121.1, 119.8, 112.4, 63.9, 56.0, 29.0, 25.1. ESIꢀHRMS: calcd. for C26H22N2O3S+H 443.1429, found
443.1419. [α]25D= +108.0 (c 0.5, CHCl3); 80% ee; The enantiomeric ratio was determined by HPLC on Chiralpak AD column
(10% 2ꢀpropanol/hexane, 1 mL/min), tmajor = 29.895 min, tminor = 18.141 min.
(2S,2'Z,4'R,5'Z)ꢀ4'ꢀ(4ꢀchlorophenyl)ꢀ5'ꢀ(hydroxyimino)ꢀ2'ꢀ(phenylimino)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀthio
phen]ꢀ1ꢀone (4ea). 36 mg, 78% yield. 227 ꢀ 230°C. IR(KBr): υmax 3445, 1661, 1625, 1091, 759, 848, 695 cmꢀ1. 1H NMR (600 MHz,
DMSO) δ 11.75 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.3 Hz, 1H), 7.40 (s, 4H), 7.38 – 7.34 (m, 3H), 7.29 (d, J = 7.4 Hz,
1H), 7.17 (t, J = 7.1 Hz, 1H), 6.86 (d, J = 6.7 Hz, 2H), 5.31 (s, 1H), 3.20 (t, J = 13.6 Hz, 1H), 2.91 (d, J = 16.8 Hz, 1H), 2.48 – 2.41
(m, 1H), 1.93 (t, J = 12.2 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 194.1, 168.7, 152.2, 150.7, 144.5, 134.6, 134.2, 133.1, 132.6,
131.8, 129.9, 129.5, 128.6, 127.9, 127.3, 125.9, 119.9, 64.7, 53.1, 29.3, 25.3. ESIꢀHRMS: calcd. for C25H19N2O2SCl+H 447.0934,
found 447.0925. [α]25D= ꢀ96.0 (c 0.5, CHCl3); ꢀ93% ee; The enantiomeric ratio was determined by HPLC on Chiralpak AD column
(25% 2ꢀpropanol/hexane, 1 mL/min), tmajor = 18.887 min, tminor = 7.716 min.
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(2S,2'Z,4'R,5'Z)ꢀ4'ꢀ(3ꢀchlorophenyl)ꢀ5'ꢀ(hydroxyimino)ꢀ2'ꢀ(phenylimino)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀthio
phen]ꢀ1ꢀone (4fa). 32 mg, 70% yield, 220 ꢀ 223°C. 1H NMR (600 MHz, DMSO) δ 11.67 (s, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.43 (t, J
= 7.4 Hz, 1H), 7.33 (s, 1H), 7.26 (dd, J = 13.2, 9.1 Hz, 5H), 7.24 – 7.20 (m, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H),
6.74 (d, J = 7.8 Hz, 2H), 5.22 (s, 1H), 3.12 – 3.04 (m, 1H), 2.83 – 2.79 (m, 1H), 2.37 – 2.33 (m, 1H), 1.85 – 1.78 (m, 1H). 13C NMR
(151 MHz, DMSO) δ 194.0, 168.6, 152.0, 150.7, 144.5, 137.7, 134.6, 133.1, 131.8, 130.6, 130.0, 129.5, 128.9, 128.4, 127.9, 127.4,
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125.9, 124.7, 119.9, 64.7, 53.1, 29.3, 25.3. ESIꢀHRMS: calcd. for C25H19N2O2SCl+H 447.0934, found 447.0927. [α]25 = ꢀ52.0 (c
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0.5, CHCl3); 91% ee; The enantiomeric ratio was determined by HPLC on Chiralpak AD column (25% 2ꢀpropanol/hexane, 1
mL/min), tmajor = 11.884 min, tminor = 7.323 min.
(2S,2'Z,4'R,5'Z)ꢀ4'ꢀ(2ꢀchlorophenyl)ꢀ5'ꢀ(hydroxyimino)ꢀ2'ꢀ(phenylimino)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀthio
phen]ꢀ1ꢀone (4ha). 30 mg, 64% yield, mp 218 ꢀ 220°C. 1H NMR (600 MHz, DMSO) δ 11.67 (s, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.61
(t, J = 7.4 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.45 – 7.40 (m, 6H), 7.34 (d, J = 7.8 Hz, 1H), 7.22 (t, J = 7.3 Hz, 1H), 6.94 (d, J = 7.6
Hz, 2H), 5.29 (s, 1H), 3.25 – 3.16 (m, 1H), 2.77 – 2.69 (m, 1H), 2.61 – 2.55 (m, 1H), 2.10 – 2.02 (m, 1H). 13C NMR (151 MHz,
DMSO) δ 194.9, 169.8, 151.1, 144.2, 139.1, 135.1, 133.6, 132.5, 130.2, 130.1, 129.5, 128.9, 128.3, 127.6, 125.9, 124.7, 119.8,
63.9, 49.3, 29.0, 25.1. ESIꢀHRMS: calcd. for C25H19N2O2SCl+H 447.0934, found 447.0925. [α]25 = +130.0 (c 0.5, CHCl3); 88%
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ee; The enantiomeric ratio was determined by HPLC on Chiralpak AD column (8% 2ꢀpropanol/hexane, 1 mL/min), tmajor = 52.093
min, tminor =37.379 min.
(2S,2'Z,4'R,5'Z)ꢀ4'ꢀ(4ꢀbromophenyl)ꢀ5'ꢀ(hydroxyimino)ꢀ2'ꢀ(phenylimino)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀthio
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phen]ꢀ1ꢀone (4ia). 38 mg, 75% yield, mp 223 ꢀ 225°C. H NMR (600 MHz, DMSO) δ 11.70 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.56
(d, J = 8.3 Hz, 3H), 7.42 – 7.28 (m, 6H), 7.19 (t, J = 7.3 Hz, 1H), 6.86 (d, J = 7.7 Hz, 2H), 5.28 (s, 1H), 3.20 (t, J = 12.0 Hz, 1H),
2.92 (d, J = 17.1 Hz, 1H), 2.47 – 2.42 (m, 1H), 1.97 – 1.89 (m, 1H). 13C NMR (151 MHz, DMSO) δ 193.8, 168.3, 152.0, 150.6,
144.0, 134.1, 132.7, 132.0, 131.3, 129.5, 129.1, 127.9, 127.0, 125.6, 121.7, 119.7, 64.7, 53.2, 29.2, 25.4. ESIꢀHRMS: calcd. for
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ne (4ja). 30 mg, 70% yield, 211 ꢀ 213°C. H NMR (600 MHz, DMSO) δ 11.67 (s, 1H), 7.96 (d, J = 7.4 Hz, 1H), 7.56 – 7.49 (m,
1H), 7.41 – 7.33 (m, 7H), 7.29 (s, 2H), 7.18 (d, J = 4.5 Hz, 1H), 6.87 (d, J = 6.9 Hz, 2H), 5.22 (s, 1H), 3.22 – 3.12 (m, 1H), 2.95 –
2.86 (m, 1H), 2.49 – 2.42 (m, 1H), 2.00 – 1.92 (m, 1H). 13C NMR (151 MHz, DMSO) δ 194.3, 169.2, 152.6, 150.8, 144.5, 135.5,
134.6, 131.7, 130.6, 130.0, 129.5, 128.7, 128.3, 127.9, 127.4, 125.9, 119.9, 64.7, 53.9, 29.3, 25.3. ESIꢀHRMS: calcd. for
C25H20N2O2S+H 413.1324, found 413.1315. [α]25 = ꢀ46.0 (c 0.5, CHCl3); 93% ee; The enantiomeric ratio was determined by
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HPLC on Chiralpak AD column (25% 2ꢀpropanol/hexane, 1 mL/min), tmajor = 20.443 min, tminor = 7.964 min.
(2S,2'Z,4'R,5'Z)ꢀ5'ꢀ(hydroxyimino)ꢀ4'ꢀ(4ꢀnitrophenyl)ꢀ2'ꢀ(phenylimino)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀthiop
hen]ꢀ1ꢀone (4ka). 28 mg, 60% yield, 248 ꢀ 250°C. 1H NMR (600 MHz, DMSO) δ 11.72 (s, 1H), 8.15 (d, J = 8.8 Hz, 2H), 7.89 (dd,
J = 7.9, 1.0 Hz, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.50 – 7.46 (m, 1H), 7.33 – 7.29 (m, 2H), 7.24 (d, J = 7.7 Hz, 1H), 7.12 (t, J = 7.4
Hz, 1H), 6.83 – 6.77 (m, 2H), 5.42 (s, 1H), 3.19 – 3.12 (m, 1H), 2.86 (dt, J = 16.9, 4.1 Hz, 1H), 2.41 (dd, J = 9.0, 4.8 Hz, 1H), 1.85
(ddd, J = 13.9, 11.6, 4.4 Hz, 1H).13C NMR (151 MHz, DMSO) δ 193.8, 168.2, 151.8, 150.6, 147.5, 144.5, 143.0, 134.6, 132.2,
131.8, 129.9, 129.5, 128.0, 127.3, 126.0, 123.6, 119.9, 64.9, 53.2, 29.4, 25.4. ESIꢀHRMS: calcd. for C25H19N3O4S+H 458.1175,
found 458.1158. [α]25D = ꢀ52.0 (c 0.5, CHCl3); 92% ee; The enantiomeric ratio was determined by HPLC on Chiralpak AD column
(25% 2ꢀpropanol/hexane, 1 mL/min), tmajor = 25.934 min, tminor = 10.925 min.
(2S,2'Z,4'S,5'Z)ꢀ4'ꢀ(furanꢀ2ꢀyl)ꢀ5'ꢀ(hydroxyimino)ꢀ2'ꢀ(phenylimino)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀthiophen]
ꢀ1ꢀone (4ma). 27 mg, 65% yield, 166 ꢀ 168°C. H NMR (600 MHz, CDCl3) δ 8.12 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.35
(s, 1H), 7.31 (t, J = 7.5 Hz, 3H), 7.20 (d, J = 7.6 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 6.84 (d, J = 7.7 Hz, 2H), 6.42 (d, J = 3.0 Hz, 1H),
6.31 (s, 1H), 5.53 (s, 1H), 3.35 (ddd, J = 16.3, 12.1, 4.0 Hz, 1H), 2.95 – 2.86 (m, 1H), 2.51 (dt, J = 14.1, 4.1 Hz, 1H), 2.11 – 2.03
(m, 1H). 13C NMR (151 MHz, CDCl3) δ 193.5, 166.1, 153.9, 150.3, 147.9, 143.9, 142.9, 133.8, 132.0, 129.2, 128.7, 128.4, 126.9,
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125.5, 119.7, 111.1, 110.5, 64.6, 48.4, 29.4, 25.5. ESIꢀHRMS: calcd. for C23H18N2O3S+H 403.1116, found 403.1107. [α]25
=
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+34.0 (c 0.5, CHCl3); 79% ee; The enantiomeric ratio was determined by HPLC on Chiralpak AD column (25%
2ꢀpropanol/hexane, 1 mL/min), tmajor = 16.305 min, tminor = 8.274 min.
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(2S,2'Z,4'R,5'Z)ꢀ5'ꢀ(hydroxyimino)ꢀ4'ꢀ(naphthalenꢀ2ꢀyl)ꢀ2'ꢀ(phenylimino)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀthio
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phen]ꢀ1ꢀone (4la). 26 mg, 55% yield, 210 ꢀ 213°C. H NMR (600 MHz, DMSO) δ 11.63 (s, 1H, 7.84 (d, J = 7.9 Hz, 1H, 7.79 (s,
1H), 7.74 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 1H), 7.34 (s, 3H), 7.25 (t, J = 7.1 Hz, 2H), 7.18 (t, J = 7.5 Hz, 1H), 7.09 (d, J =
7.6 Hz, 1H), 7.03 (t, J = 7.3 Hz, 1H), 6.76 (d, J = 7.8 Hz, 2H), 5.32 (s, 1H), 3.03 (t, J = 12.2 Hz, 1H), 2.75 (d, J = 17.0 Hz, 1H),
2.40 (d, J = 14.0 Hz, 1H), 1.89 – 1.84 (m, 1H). 13C NMR (151 MHz, DMSO) δ 194.3, 169.1, 152.7, 150.9, 144.5, 134.5, 133.1 (d, J
= 17.8 Hz), 132.8, 131.8, 129.9 (d, J = 7.9 Hz), 129.5, 128.3 (d, J = 6.5 Hz), 128.0, 127.3, 126.8, 125.9,119.9, 65.0, 54.0, 29.5,
25.3. ESIꢀHRMS: calcd. for C29H22N2O2S+H 463.1480, found 463.1468. [α]25D = ꢀ86.0 (c 0.5, CHCl3); 94% ee; The enantiomeric
ratio was determined by HPLC on Chiralpak AD column (25% 2ꢀpropanol/hexane, 1 mL/min), tmajor = 21.910 min, tminor = 11.895
min.
(2S,2'Z,4'R,5'Z)ꢀ5'ꢀ(hydroxyimino)ꢀ6ꢀmethoxyꢀ2'ꢀ(phenylimino)ꢀ4'ꢀ(pꢀtolyl)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀth
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iophen]ꢀ1ꢀone (4ab). 31 mg, 65% yield, mp 210ꢀ 213oC. H NMR (600 MHz, DMSO) δ 11.48 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H),
7.23 (t, J = 7.8 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 7.02 (t, J = 7.4 Hz, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.76 – 6.69 (m, 3H), 6.65 (d, J =
2.2 Hz, 1H), 5.01 (s, 1H), 3.63 (s, 3H), 3.02 – 2.94 (m, 1H), 2.70 (dd, J = 12.5, 4.7 Hz, 1H), 2.25 (dt, J = 13.5, 4.4 Hz, 1H), 2.08 (s,
3H), 1.82 – 1.74 (m, 1H). 13C NMR (151 MHz, DMSO) δ 192.8, 169.5, 164.1, 152.9, 150.9, 147.1, 137.5, 132.6, 130.5, 129.9,
129.2, 125.8, 125.3, 119.9, 114.4, 112.9, 64.5, 56.0, 53.8, 29.3, 25.6, 21.1. ESIꢀHRMS: calcd. for C27H24N2O3S+H 457.1586, found
457.1573. [α]25D = +100 (c 0.5, CHCl3); ꢀ92% ee; The enantiomeric ratio was determined by HPLC on Chiralpak AD column (25%
2ꢀpropanol/hexane, 1 mL/min), tmajor = 81.738 min, tminor = 18.387 min.
(2S,2'Z,4'R,5'Z)ꢀ5'ꢀ(hydroxyimino)ꢀ4'ꢀ(pꢀtolyl)ꢀ2'ꢀ(pꢀtolylimino)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀthiophen]ꢀ1ꢀ
one (4ac). 32 mg, 70% yield, 210 ꢀ 213°C. IR(KBr): υmax 3420, 1661, 1625, 845, 750 cmꢀ1. 1H NMR (600 MHz, DMSO) δ 11.23 (s,
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1H), 7.55 (d, J = 7.8 Hz, 1H), 7.11 (s, 1H), 6.87 (d, J = 7.7 Hz, 1H), 6.83 (d, J = 7.9 Hz, 2H), 6.72 (d, J = 8.0 Hz, 2H), 6.56 – 6.52
(m, 2H), 6.45 (d, J = 8.8 Hz, 2H), 4.75 (s, 1H), 3.03 (s, 3H), 2.76 – 2.69 (m, 1H), 2.47 (dt, J = 16.7, 4.2 Hz, 1H), 2.02 (dt, J = 13.8,
4.4 Hz, 1H), 1.83 (s, 3H), 1.57 – 1.51 (m, 1H). 13C NMR (151 MHz, DMSO) δ 194.5, 168.1, 157.4, 153.0, 144.5, 143.8, 137.5,
134.5, 132.4, 131.8, 130.5, 129.5, 129.2, 127.9, 127.3, 121.5, 115.0, 64.8, 55.7, 29.3, 25.3, 21.1. ESIꢀHRMS: calcd. for
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C27H24N2O2S+H 441.1637, found 441.1643. [α]25 = 80.0 (c 0.5, CHCl3); ꢀ90% ee; The enantiomeric ratio was determined by
D
HPLC on Chiralpak AD column (25% 2ꢀpropanol/hexane, 1 mL/min), tmajor = 24.791 min, tminor = 9.800 min.
(2S,2'Z,4'R,5'Z)ꢀ2'ꢀ((4ꢀchlorophenyl)imino)ꢀ5'ꢀ(hydroxyimino)ꢀ4'ꢀ(pꢀtolyl)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀthi
ophen]ꢀ1ꢀone (4ad). 32 mg, 50% yield, 231 ꢀ 233°C. 1H NMR (600 MHz, DMSO) δ 11.69 (s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.55 (t,
J = 7.4 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.8 Hz, 4H), 7.14 (d, J = 7.5 Hz, 2H), 6.94 – 6.90 (m,
1H), 5.17 (s, 1H), 3.15 (t, J = 11.9 Hz, 1H), 2.90 (d, J = 17.1 Hz, 1H), 2.44 (d, J = 13.9 Hz, 1H), 2.25 (s, 3H), 1.99 – 1.93 (m,
1H).13C NMR (151 MHz, DMSO) δ 194.4 , 170.1, 159.3, 152.5 , 147.1, 144.5, 137.6, 134.6, 132.4, 131.7, 130.4, 129.5, 129.2,
127.9, 127.4, 121.9 (d, J = 8.4 Hz), 116.7, 116.6, 64.8, 53.6, 29.2, 25.2, 21.1. ESIꢀHRMS: calcd. for C26H21N2O2SCl+H 461.1091,
found 461.1064. [α]25D = ꢀ48.0 (c 0.5, CHCl3); 84% ee; The enantiomeric ratio was determined by HPLC on Chiralpak AD column
(25% 2ꢀpropanol/hexane, 1 mL/min), tmajor = 17.322 min, tminor = 7.495 min.
(2S,2'Z,4'R,5'Z)ꢀ2'ꢀ((3ꢀchlorophenyl)imino)ꢀ5'ꢀ(hydroxyimino)ꢀ4'ꢀ(pꢀtolyl)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀthi
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ophen]ꢀ1ꢀone (4ae). 37 mg, 78% yield, 228 ꢀ 230°C. H NMR (600 MHz, DMSO) δ 11.68 (s, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.52
(dd, J = 9.3, 5.3 Hz, 1H), 7.41 – 7.39 (m, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.25 – 7.21 (m, 2H), 7.13 (d, J =
8.0 Hz, 2H), 6.97 – 6.93 (m, 1H), 6.84 (d, J = 7.9 Hz, 1H), 5.21 (s, 1H), 3.22 – 3.14 (m, 1H), 2.89 (dt, J = 16.8, 4.5 Hz, 1H), 2.46
(dt, J = 13.8, 4.6 Hz, 1H), 2.26 (s, 3H), 2.02 – 1.95 (m, 1H). 13C NMR (151 MHz, DMSO) δ 194.1, 171.1, 152.2 (d, J = 17.0 Hz),
144.4, 137.5, 134.5, 134.3, 132.2, 131.7, 131.6, 130.4, 129.4, 129.2, 127.9, 127.2, 125.5, 119.8, 118.6, 64.8, 53.7, 29.2, 25.3, 21.1.
ESIꢀHRMS: calcd. for C26H21N2O2SCl+H 461.1091, found 461.1085. [α]25 = ꢀ20.0 (c 0.5, CHCl3); ꢀ92% ee; The enantiomeric
D
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ratio was determined by HPLC on Chiralpak AD column (25% 2ꢀpropanol/hexane, 1 mL/min), tmajor = 17.311 min, tminor = 6.704
min.
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(2S,2'Z,4'R,5'Z)ꢀ2'ꢀ((2ꢀchlorophenyl)imino)ꢀ5'ꢀ(hydroxyimino)ꢀ4'ꢀ(pꢀtolyl)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀthi
ophen]ꢀ1ꢀone (4af). 36 mg, 75% yield, 213 ꢀ 216°C. 1H NMR (600 MHz, DMSO) δ 11.62 (s, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.49 –
7.40 (m, 2H), 7.28 (t, J = 7.6 Hz, 2H), 7.20 (dd, J = 14.3, 7.9 Hz, 3H), 7.11 (t, J = 7.7 Hz, 1H), 7.06 (d, J = 7.9 Hz, 2H), 6.86 (dd, J
= 7.9, 1.3 Hz, 1H), 5.13 (s, 1H), 3.29 – 3.21 (m, 1H), 2.81 (dt, J = 16.8, 4.5 Hz, 1H), 2.37 (dt, J = 13.9, 4.7 Hz, 1H), 2.16 (s, 3H),
1.95 – 1.90 (m, 1H). 13C NMR (151 MHz, DMSO) δ 194.0, 172.6, 152.3, 147.8, 144.6, 137.6, 134.6, 132.5, 131.5, 130.5 , 130.3,
129.5, 129.3, 128.9, 128.0, 127.3, 127.1, 123.8, 121.0, 64.7, 54.2, 29.1, 25.1, 21.1. ESIꢀHRMS: calcd. for C26H21N2O2SCl+H
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461.1091, found 461.1081. [α]25 = +140 (c 0.5, CHCl3); 90% ee; The enantiomeric ratio was determined by HPLC on Chiralpak
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AD column (25% 2ꢀpropanol/hexane, 1 mL/min), tmajor = 22.988 min, tminor = 7.736 min.
(2S,2'Z,4'R,5'Z)ꢀ5'ꢀ(hydroxyimino)ꢀ2'ꢀ((3ꢀmethoxyphenyl)imino)ꢀ4'ꢀ(pꢀtolyl)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀt
hiophen]ꢀ1ꢀone (4ag). 27 mg, 58% yield, 188 ꢀ 191°C. IR(KBr): υmax 3426, 1665, 1622, 1238, 1143, 835, 765, 698 cmꢀ1. 1H NMR
(600 MHz, DMSO) δ 11.62 (s, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.29 (t, J = 7.8 Hz,
2H), 7.23 (d, J = 7.9 Hz, 2H), 7.14 (d, J = 7.8 Hz, 2H), 6.75 (d, J = 8.2 Hz, 1H), 6.43 (d, J = 7.8 Hz, 1H), 6.38 (s, 1H), 5.17 (s, 1H),
3.74 (s, 3H), 3.19 – 3.11 (m, 1H), 2.89 (d, J = 17.2 Hz, 1H), 2.44 (dd, J = 9.5, 4.6 Hz, 1H), 2.24 (s, 3H), 1.97 – 1.91 (m, 1H). 13C
NMR (151 MHz, DMSO) δ 194.4, 169.4, 160.5, 152.7, 152.1, 144.5, 137.5, 134.6, 132.3, 131.8, 130.9, 130.5, 129.5, 129.2, 127.9,
127.3, 111.9, 111.6, 105.4, 64.7, 55.7, 53.6, 29.3, 25.3, 21.1. ESIꢀHRMS: calcd. for C27H24N2O3S+H 457.1586, found 457.1576.
[α]25 = ꢀ80.0 (c 0.5, CHCl3); 88% ee; The enantiomeric ratio was determined by HPLC on Chiralpak AD column (25%
D
2ꢀpropanol/hexane, 1 mL/min), tmajor = 22.733 min, tminor = 8.555 min.
(2S,2'Z,4'R,5'Z)ꢀ5'ꢀ(hydroxyimino)ꢀ2'ꢀ((2ꢀmethoxyphenyl)imino)ꢀ4'ꢀ(pꢀtolyl)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀt
hiophen]ꢀ1ꢀone (4ah). 36 mg, 75% yield, 190 ꢀ 193°C. 1H NMR (400 MHz, DMSO) δ 11.63 (s, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.55
(t, J = 7.3 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.29 (t, J = 6.5 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 6.76 (d, J =
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8.2 Hz, 1H), 6.44 (d, J = 7.8 Hz, 1H), 6.39 (s, 1H), 5.18 (s, 1H), 3.75 (s, 3H), 3.22 – 3.11 (m, 1H), 2.94 – 2.85 (m, 1H), 2.44 (dd, J
= 9.5, 4.6 Hz, 1H), 2.25 (s, 3H), 1.94 (dd, J = 17.4, 7.2 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 194.3, 169.4, 160.5, 152.7, 152.1,
144.5, 137.5, 134.6, 132.3, 131.7, 130.9, 130.5, 129.5, 129.2, 127.9, 127.3, 111.9, 111.6, 105.4, 64.7, 55.7, 53.6, 29.3, 25.2, 21.1.
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ESIꢀHRMS: calcd. for C27H24N2O3S+H 457.1586, found 457.1578. [α]25 = ꢀ88.0 (c 0.5, CHCl3); 92% ee; The enantiomeric ratio
D
was determined by HPLC on Chiralpak AD column (25% 2ꢀpropanol/hexane, 1 mL/min), tmajor = 22.779 min, tminor = 8.598 min.
(R,Z)ꢀ(5ꢀ(hydroxyimino)ꢀ2ꢀ(phenylamino)ꢀ4ꢀ(pꢀtolyl)ꢀ4,5ꢀdihydrothiophenꢀ3ꢀyl)(phenyl)methanone (4aj). 23 mg, 55% yield, 150
ꢀ 153°C. 1H NMR (600 MHz, DMSO) δ 12.79 (s, 1H), 11.68 (s, 1H), 7.50 – 7.43 (m, 4H), 7.35 – 7.29 (m, 4H), 7.25 (t, J = 7.4 Hz,
2H), 6.90 (d, J = 7.9 Hz, 2H), 6.79 (d, J = 7.8 Hz, 2H), 5.49 (s, 1H), 2.15 (s, 3H). 13C NMR (150 MHz, DMSO) δ 189.0, 162.6,
153.7, 141.6, 139.8 (d, J = 7.0 Hz), 136.1, 130.1 (d, J = 12.1 Hz), 129.2, 128.3, 127.2, 126.8 (d, J = 18.4 Hz), 123.4, 106.6, 53.0,
21.1. ESIꢀHRMS: calcd. for C24H20N2O2S+H 401.1324, found 401.1324. [α]25D = +18.0 (c 0.5, CHCl3); 33% ee; The enantiomeric
ratio was determined by HPLC on Chiralpak AD column (25% 2ꢀpropanol/hexane, 1 mL/min), tmajor = 13.840 min, tminor = 23.509
min.
(2S,2'Z,4'R,5'Z)ꢀ5'ꢀ(hydroxyimino)ꢀ2'ꢀ(naphthalenꢀ2ꢀylimino)ꢀ4'ꢀ(pꢀtolyl)ꢀ3,4,4',5'ꢀtetrahydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀthio
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phen]ꢀ1ꢀone (4ai). 34 mg, 68% yield, mp 120 ꢀ 123°C. H NMR (600 MHz, DMSO) δ 11.62 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.94
(d, J = 7.9 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 7.0 Hz, 3H), 7.53 – 7.48 (m, 2H), 7.38 (t, J = 7.2 Hz, 1H), 7.32 (d, J = 7.4
Hz, 1H), 7.27 (d, J = 7.6 Hz, 2H), 7.15 (d, J = 7.1 Hz, 2H), 7.04 (d, J = 7.2 Hz, 1H), 5.19 (s, 1H), 3.30 – 3.22 (m, 1H), 2.96 (d, J =
17.0 Hz, 1H), 2.55 (d, J = 14.0 Hz, 1H), 2.26 (s, 3H), 2.06 (t, J = 10.1 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 194.9, 170.6, 152.8,
147.0, 144.5, 137.6, 134.7, 134.1, 132.7, 131.7, 130.3, 129.6, 129.3, 128.5, 128.0, 127.5, 127.2, 126.7, 126.4, 125.9, 125.8, 122.8,
114.68, 65.1, 53.6, 29.2, 25.4, 21.1. ESIꢀHRMS: calcd. for C30H24N2O2S+H 477.1637, found 477.1622. [α]25 = ꢀ106.0 (c 0.5,
D
CHCl3); 82% ee; The enantiomeric ratio was determined by HPLC on Chiralpak AD column (25% 2ꢀpropanol/hexane, 1 mL/min),
tmajor = 29.007 min, tminor = 8.372 min.
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(2S,4'R,Z)ꢀ2'ꢀ(phenylimino)ꢀ4'ꢀ(pꢀtolyl)ꢀ3,4ꢀdihydroꢀ1H,2'Hꢀspiro[naphthaleneꢀ2,3'ꢀthiophene]ꢀ1,5'(4'H)ꢀdione (5aa). 66 mg,
80% yield, mp 161 ꢀ 164°C. 1H NMR (600 MHz, CDCl3) δ 8.04 (d, J = 7.5 Hz, 1H), 7.58 (t, J = 10.7, 4.1 Hz, 1H), 7.47 (t, J = 7.8
Hz, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.28 (t, J = 7.4 Hz, 1H), 7.25 – 7.19 (m, 3H), 7.17 (d, J = 8.1 Hz, 2H), 7.14 – 7.09 (m, 2H), 5.14
(s, 1H), 2.96 – 2.78 (m, 3H), 2.35 (s, 3H), 2.24 – 2.19 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 195.5, 166.6, 150.2, 142.3, 140.3,
135.9, 134.5, 130.3, 130.0, 129.8 (d, J = 10.0 Hz), 129.3 (d, J = 13.6 Hz), 128.7, 127.5, 126.4, 119.7, 66.9, 55.5, 29.6, 25.0, 21.2.
ESIꢀHRMS: calcd. for C26H21NO2S+H 412.1371, found 412.1373. [α]25D = +242.0 (c 0.5, CHCl3); ꢀ92% ee; The enantiomeric ratio
was determined by HPLC on Chiralpak AD column (2% 2ꢀpropanol/hexane, 1 mL/min), tmajor = 20.271 min, tminor = 15.195 min.
Crystal data for 4ae C26H21ClN2O2S (460.96), (CCDC number: 1405299) monoclinic, P21, a = 10.0744(3)Å, alpha = 90.00 deg. b
= 10.4491(3) Å, beta = 95.102(2) deg. c = 21.6791(6) Å, gamma = 90.00 deg. U =2273.08(11) Å3, Z = 4, T = 296(2) K, absorption
coefficient 0.286 mmꢀ1, reflections collected 83234, unique 10421 [R(int) = 0.0413], refinement by Fullꢀmatrix leastꢀsquares on F2,
data/ restraints/ parameters 10421 / 1 / 650, goodnessꢀofꢀfit on F2 = 1.071, final R indices [I>2sigma(I)] R1 = 0.0393, wR2 = 0.0867,
R indices (all data) R1 = 0.0487, wR2 = 0.0924, largest diff. peak and hole 0.328 and ꢀ0.043e.Åꢀ3.
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ACKNOWLEDGMENT We are grateful for the financial support from the National Natural Science Foundation of P. R. of China
(No. 21272214).
Supporting Information Available: 1H NMR and 13C NMR spectra for all new compounds and Xꢀray structural data for 4ae (CIF).
This material is available free of charge via the Internet at http://pubs.acs.org.
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