Enantioselective synthesis of 7H-pyrano[2,3-d]thiazoles via squaramide-catalyzed [2+4] annulation of malononitrile and 5-ylidenethiazol-4-ones

Article abstract of DOI:10.1016/j.tetasy.2016.08.014

An efficient catalytic asymmetric synthesis of 7H-pyrano[2,3-d]thiazoles has been developed on the basis of the organocatalyzed [4+2] annulation of malononitrile and 5-ylidenethiazol-4-ones. Under the catalysis of a bifunctional squaramide derived from L-tert-leucine, the reaction of malononitrile and a wide range of 5-ylidenethiazol-4-ones ran smoothly to afford the corresponding structurally diverse 7H-pyrano[2,3-d]thiazole derivatives in good yields (70–94%) and with moderate to excellent enantioselectivities (43–>99% ee).

Full text of DOI:10.1016/j.tetasy.2016.08.014

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective synthesis of 7H-pyrano[2,3-d]thiazoles via
squaramide-catalyzed [2+4] annulation of malononitrile
and 5-ylidenethiazol-4-ones
Lei Cui a, Youming Wang a, Zhenghong Zhou a,b,
⇑
a Institute and State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
b Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, 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:
An efficient catalytic asymmetric synthesis of 7H-pyrano[2,3-d]thiazoles has been developed on the basis
Received 23 June 2016
Accepted 16 August 2016
Available online xxxx
of the organocatalyzed [4+2] annulation of malononitrile and 5-ylidenethiazol-4-ones. Under the cataly-
sis of a bifunctional squaramide derived from L-tert-leucine, the reaction of malononitrile and a wide
range of 5-ylidenethiazol-4-ones ran smoothly to afford the corresponding structurally diverse 7H-pyr-
ano[2,3-d]thiazole derivatives in good yields (70–94%) and with moderate to excellent enantioselectivi-
ties (43–>99% ee).
Ó 2016 Published by Elsevier Ltd.
1. Introduction
aldehydes and 5-alkenyl thiazolones,4 while the other is the syn-
thesis of optically active thiazole-fused e-lactones through NHC-
Thiazole, a heterocyclic compound featuring both a nitrogen
atom and a sulfur atom as part of the aromatic five membered ring,
represents an important building block that exists in many bioac-
tive natural products as well as a great number of potent biologi-
cally active synthetic molecules. Over the past few decades,
biologically active thiazole derivatives have attracted much atten-
tion and been frequently introduced as chemotherapeutic agents,
such as antibacterial, antifungal, antitubercular, antiviral, anti-
cancer, and antiparasitic.1 In addition, owing to the interesting
applications of thiazoles in the field of drug discovery and agricul-
tural research, the fusion of such parent molecules to form poly-
cyclic systems, which adds functional diversity, is increasingly
becoming a fruitful area of study for their biological activity.2
The absolute configuration plays an important role in the bioactiv-
ity of chiral compounds, however, examples of the construction of
optically active fused thiazoles in organocatalytic asymmetric
ways are relatively limited despite the fact that asymmetric
organocatalysis has evolved as a powerful tool for the preparation
of enantiomerically enriched compounds.3 To date, only two asym-
metric catalytic versions have appeared for the synthesis of enan-
tiomerically enriched fused thiazole derivatives. One is the
synthesis of chiral thiazolopyrones via oxidative N-heterocyclic
carbine (NHC) catalyzed stereoselective annulation of simple
catalyzed annulation of enals and alkenyl thiazolones.5 Therefore,
it is still highly desirable to develop efficient catalytic asymmetric
methods to access novel polyfunctionalized fused thiazole deriva-
tives from readily available feedstocks. Currently, organocatalyzed
enantioselective tandem processes have become a powerful, fasci-
nating, and highly efficient tool for the rapid assembly of complex
structures.6 Undoubtedly, the application of these powerful
strategies to the synthesis of optically active biologically interest-
ing molecules will be of great importance. As part of our continued
interest in the synthesis of biologically relevant heterocycles,7
we herein report an organocatalyzed [2+4] annulation of
malononitrile and 5-ylidenethiazol-4-ones. By employing a chiral
bifunctional squaramide catalyst derived from
L-tert-leucine,
structurally diverse 7H-pyrano[2,3-d]thiazole derivatives8 were
obtained in good yields and with moderate to excellent
enantioselectivities.
2. Results and discussion
Initially, the reaction was performed at room temperature using
5-ylidenethiazol-4-one 1a and malononitrile 2 as the model sub-
strates in the presence of a catalytic amount (10 mol %) of bifunc-
tional thiourea-9 or squaramide-based double hydrogen bond
donor catalysts I–IV10 (Fig. 1) in dichloromethane at 20 °C. The
results are summarized in Table 1.
⇑
Corresponding author.
E-mail address: z.h.zhou@nankai.edu.cn (Z. Zhou).
http://dx.doi.org/10.1016/j.tetasy.2016.08.014
0957-4166/Ó 2016 Published by Elsevier Ltd.
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2
L. Cui et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
CF3
CF3
1,2-dichloroethane and toluene (entries
6 and 8). Markedly
O
O
decreased enantioselectivities were obtained by employing ace-
tonitrile and ethyl acetate as the solvent, respectively (entries 7
and 9). Almost perfect stereocontrol was achieved by replacing
dichloromethane with diethyl ether (entry 10). The reaction ran
smoothly even in the presence of 2 mol % of catalyst III, albeit with
a slightly decreased enantioselectivity (entry 11 vs. entry 10).
With the optimized reaction conditions in hand, the substrate
scope of this reaction was then investigated using various 5-yli-
denethiazol-4-ones 1 with malononitrile 2. The results are summa-
rized in Table 2.
Ph
R
Ph
S
Ph
R
Ph
N
N
CF3
N
H
N
H
CF3
H
H
N
N
IIa, R-R = (CH2)5
I
b
, R = Me
OMe
N
CF3
N
O
O
tBu
H
N
NH
O
CF3
Me2N
N
N
CF3
Table 2
H
H
III-catalyzed asymmetric [4+2] annulation of 5-ylidenethiazol-4-ones 1 and malonon-
O
itrile 2a
III
CF3
IV
Ar
Ar
Figure 1. Screened double hydrogen bond donor catalysts.
CN
III
(10 mol%)
S
N
S
NC
CN
+
R
R
Et2O, 20 °C
N
O
NH2
As shown in Table 1, all of the tested bifunctional double hydro-
O
gen bond donor catalysts are indeed efficient catalysts for the
model reaction, providing the corresponding 7H-pyrano[2,3-d]thi-
azole 3a in good yields within 6 h. However, the enantioselectivity
of the reaction were highly dependent on the catalyst employed.
The use of thiourea I containing a piperidinyl group derived from
(1R,2R)-1,2-diphenylethane-1,2-diamine only provided racemic
3a (entry 1). A slightly improved enantioselectivity was observed
for squaramide IIa, which incorporated the same chiral diamine
scaffold bearing a piperidinyl group (entry 2). The substituents
on the nitrogen atom had a remarkable effect on the stereochem-
ical outcomes of the reaction. A dramatically enhanced ee value
was obtained by simply replacing the piperidinyl group with a
dimethylamino group (entry 3 vs. entry 2). Encouraged by this
result, we further screened other squaramide-based catalysts and
1a
r
3a−r
−
2
Entry
3 (R, Ar)
Time (h)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
3a (Ph, Ph)
3
70
24
4
92
74
76
78
82
82
70
72
77
72
79
93
75
76
54
94
75
75
>99
55
77
98
94
98
98
98
74
91
92
93
56
45
26
58
43
70
3b (4-FC6H4, Ph)
3c (2-FC6H4, Ph)
3d (4-ClC6H4, Ph)
3e (3-ClC6H4, Ph)
3f (2-ClC6H4, Ph)
3g (4-BrC6H4, Ph)
3h (3-BrC6H4, Ph)
3i (2-BrC6H4, Ph)
3j (4-MeC6H4, Ph)
3k (2-MeC6H4, Ph)
3l (3-Me-4-ClC6H3, Ph)
3m (4-MeOC6H4, Ph)
3n (3,5-(MeO)2FC6H3, Ph)
3o (MeS, Ph)
3p (Ph, 3-ClC6H4)
3q (Ph, 2-MeOC6H4)
3r (Ph, 2-Thienyl)
78
30
36
40
20
30
72
78
30
76
94
30
72
12
9
10
11
12
13
14
15
16
17
18
uncovered that squaramide III derived from L-tert-leucine was
the most promising catalyst candidate for this transformation,
delivering the annulation product 3a in 82% yield and with 96%
ee (entry 4). Further optimization of the reaction conditions
demonstrated that the reaction medium has a significant influence
on the stereocontrol of the reaction (entries 4, 6–10). Product 3a
was isolated with a comparable ee by performing the reaction in
a
All reactions were carried out with 1 (0.11 mmol), 2 (0.10 mmol) and catalyst III
(10 mol %) in diethyl ether (1 mL) at 20 °C.
b
Isolated yield.
c
Determined by HPLC analysis with a chiral stationary phase.
Table 1
At first, 5-ylidenethiazol-4-ones with different substituted aryls
at the C2 position were investigated. In all cases, the reactions pro-
ceeded smoothly to afford the corresponding 7H-pyrano[2,3-d]thi-
azoles 3a–n in high yields (entries 1–15, 54–93%) regardless of the
nature of the substituents and the substitution pattern. With
respect to the enantioselectivity, except for fluoro substituted sub-
strates 1b,c and 2-bromo substituted 1i (entries 2, 3 and 9), 5-yli-
denethiazol-4-ones 1d–h bearing electron-withdrawing groups on
the benzene ring reacted smoothly with malononitrile 2 to furnish
the corresponding annulation products 3dꢀh with high levels of
enantioselectivity (entries 4–8, 94–98% ee). In some cases, the sub-
stitution pattern had an obvious effect on the stereocontrol of the
reaction. For example, the ees of para- and meta-bromo substituted
3g, 3h were much higher than that of ortho-bromo substituted 3i
(entries 7, 8 vs. entry 9). Substrates 1j–l bearing electron-donating
methyl group also gave the desired cyclization product 3j–l with
excellent enantioselectivities irrespective of the substitution pat-
tern (entries 10–12, 91–93% ee). The sharply decreased enantiose-
lectivities observed in the cases of 3m and 3n (56% and 45% ee,
respectively), may be due to the strong electron-donating effect
of the methoxy group (entries 13 and 14). 2-Methylthio-5-benzyli-
denethiazol-4-one 1o proved to be less reactive, affording the cor-
responding adduct 3o over 94 h with 26% ee (entry 15). Next, the
Optimization of reaction conditionsa
Ph
O
Ph
CN
Cat. (10 mol%)
solvent, 20 °C
S
N
S
N
NC
CN
+
Ph
Ph
NH2
O
1a
2
3a
Entry
Catalyst
Solvent
Time (h)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
I
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
CH3CN
PhCH3
AcOEt
3
6
6
2.5
2.5
2
72
66
56
82
60
80
67
75
73
92
90
0
8
84
IIa
IIb
III
IV
III
III
III
III
III
III
ꢀ96
ꢀ65
ꢀ97
ꢀ40
ꢀ95
ꢀ2
3
3.5
2.5
3
9
10
Et2O
Et2O
ꢀ>99
ꢀ98
11d
4
a
All reactions were carried out with 1a (0.11 mmol), 2a (0.10 mmol) and catalyst
(10 mol %) in 1.0 mL of solvent at 20 °C.
b
Yield of the isolated product after chromatography on silica gel.
Determined by HPLC analysis with a chiral stationary phase.
In the presence of 2 mol % of catalyst III.
c
d
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L. Cui et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
influence of the Ar group on the reaction was also tested. It is evi-
dent that the variation of Ar group had a significant impact on the
stereochemical outcome of the reaction. It seems that the elec-
tronic nature of the substituent has an obvious impact on the enan-
tioselectivity of the reaction. For example, the introduction of
either electron-withdrawing or electron-donating group on the
phenyl ring all resulted in a marked loss of stereocontrol (entries
16 and 17). In addition, electron-rich 2-thienyl substituted sub-
strate 1r was also proved to be a suitable reaction partner with
malononitrile, furnishing the annulation product 3r in 75% yield
with 70% ee (entry 18).
with protonated III. Simultaneously, 5-ylidenethiazol-4-one
1
was fixed and activated by hydrogen bonding interaction between
the squaramide moiety and the carbonyl group of 1. Subsequently,
the nucleophilic anion predominantly attacks the si-face of the
electron-deficient 5-ylidenethiazol-4-one
1 to generate the
Michael addition intermediate A. The resulting intermediate A
undergoes an intramolecular nucleophilic addition on the cyano
group to form imine intermediate B, which upon isomerization
affords the corresponding 7H-pyrano[2,3-d]thiazoles 3 in a one-
pot fashion.
The multifunctional products obtained in these formal [4+2]
annulations would find more application in organic synthesis and
medicinal chemistry. For example, as outlined in Scheme 1, upon
treatment with cyclohexanone in the presence of aluminum chlo-
ride at room temperature, (R)-5-amino-2,7-diphenyl-7H-pyrano
[2,3-d]thiazole-6-carbonitrile 3a could be smoothly converted into
the corresponding biologically important polycyclic tetrahydroth-
iazolo[50,40:5,6]pyrano[2,3-b]quinoline derivative 4 in excellent
yield without any appreciable loss of enantiomeric purity.
The absolute configuration of compound 3j was determined
unambiguously as (R) based on the X-ray structure of 3j (Fig. 2)
and the stereochemistries of the other title compounds were
assigned by analogy.
3. Conclusions
In conclusion, we have developed an organocatalyzed asym-
metric [4+2] annulation of 5-ylidenethiazol-4-ones and malononi-
trile, and provided a convenient approach to the stereocontrolled
construction of 7H-pyrano[2,3-d]thiazole scaffold. Under the catal-
ysis of an enantiopure bifunctional squaramide derived from L-tert-
leucine, a wide range of 5-ylidenethiazol-4-ones were well toler-
ated in this cascade reaction to furnish structurally diverse 7H-pyr-
ano[2,3-d]thiazoles in good yields and with moderate to excellent
enantioselectivities.
4. Experimental
4.1. General procedure for squaramide III-catalyzed asymmetric
[4+2] annulation of 5-ylidenethiazol-4-ones and malononitrile
Figure 2. X-ray crystal structure of (R)-3j, most of the hydrogen atoms and
uncoordinated solvent have been omitted for clarity.
To a stirring solution of 5-ylidenethiazol-4-ones 1 (0.11 mmol),
and malononitrile 2 (0.10 mmol) in diethyl ether (1 mL) was added
chiral squaramide III (0.005 mmol) at 20 °C. After the reaction was
complete (monitored by TLC), the reaction mixture was directly
purified by column chromatography on silica gel (200–300 mesh,
Finally, a possible mechanism for this [4+2] cyclization reaction
is proposed on the basis of the observed results and the related lit-
erature (Fig. 3).11 The deprotonation of malononitrile 2 by catalyst
III generates the nucleophilic anion, which may form an ion pair
O
CN
Ar
+
N
S
CN
R
1
2
CF3
O
O
Me3C
N
H
N
N
CF3
CF3
H
H
O
O
N
Me3C
O
H
.
Me2N
N
N
CF3
N
Ar
H
R
H
S
III
N
R
H2N
NC
O
N
S
HN
NC
O
N
S
R
N
(R)
(R)
NC
C
O
H
Ar
Ar1
+
(R)
III
/H
+
Ar
III
/H
3
N
B
S
R
A
Figure 3. Proposed reaction mechanism.
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4
L. Cui et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
O
NH2
N
AlCl3
CN
S
N
S
+
CH2Cl2, rt, 6 h
N
O
NH2
O
92%
3a
4
, >99% ee
, 98.2% ee
(57 mg)
(50 mg, 0.15 mmol)
Scheme 1. Transformation of pyrano[2,3-d]thiazole 3a.
PE/EtOAc = 30/1) to afford the desired 7H-pyrano[2,3-d]thiazoles 3
as a white solid. The title compounds were fully characterized by
1H, 13C NMR, HRMS and specific rotation data. The enantiomeric
excesses of the products were determined by HPLC analysis with
a chiral stationary phase.
analysis (Chiralpak AD-H column, Hexane:2-propanol = 70:30,
flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 9.83 (major)
and 12.32 min (minor).
4.1.5. (R)-5-Amino-2-(3-chlorophenyl)-7-phenyl-7H-pyrano[2,-
3-d]thiazole-6-carbonitrile 3e
4.1.1. (R)-5-Amino-2,7-diphenyl-7H-pyrano[2,3-d]thiazole-6-
White solid, mp 221–223 °C, 82% yield, [a]
20 = +79.8 (c 0.38,
D
carbonitrile 3a
DMSO), 94% ee. 1H NMR (400 MHz, DMSO-d6): d 5.09 (s, 1H), 7.23
(s, 2H), 7.27–7.31 (m, 3H), 7.36–7.39 (m, 2H), 7.48 (t, J = 8.0 Hz,
1H), 7.54 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H).
13C NMR (100.6 MHz, DMSO-d6): d 38.5, 55.6, 111.0, 119.8, 124.2,
124.8, 127.3, 127.6, 128.9, 130.5, 131.2, 134.0, 134.1, 144.0, 152.7,
160.4, 162.0. HRMS (ESI) m/z calcd for C19H13ClN3OS [M+H]+:
366.0462, found 366.0460. HPLC analysis (Chiralpak AS-H column,
Hexane:2-propanol = 95:5, flow rate = 1.0 mL/min, wavelength =
254 nm): Rt = 85.42 (minor) and 98.72 min (major).
White solid, mp 204–206 °C, 92% yield, [a]
20 = +29.8 (c 0.68,
D
DMSO), >99% ee. 1H NMR (400 MHz, DMSO-d6): d 5.07 (s, 1H),
7.21–7.48 (m, 10H), 7.83 (s, 2H). 13C NMR (100.6 MHz, DMSO-
d6): d 38.5, 55.7, 109.9, 119.9, 125.4, 127.3, 127.6, 128.9, 129.3,
130.9, 132.1, 144.1, 152.6, 160.5, 163.9. HRMS (ESI) m/z calcd for
C
19H14N3OS [M+H]+: 332.0852, found 332.0852. HPLC analysis
(Chiralpak AD-H column, Hexane:2-propanol = 70:30, flow
rate = 1.0 mL/min, wavelength = 254 nm): Rt = 8.90 (major) and
11.17 min (minor).
4.1.6. (R)-5-Amino-2-(2-chlorophenyl)-7-phenyl-7H-pyrano[2,-
3-d]thiazole-6-carbonitrile 3f
4.1.2. (R)-5-Amino-2-(4-fluorophenyl)-7-phenyl-7H-pyrano[2,3-
d]thiazole-6-carbonitrile 3b
White solid, mp 212–214 °C, 82% yield, [a]
20 = +216.7 (c 0.17,
D
White solid, mp 208–210 °C, 74% yield, [
a]
20 = +84.9 (c 0.37,
DMSO), 98% ee. 1H NMR (400 MHz, DMSO-d6): d 5.13 (s, 1H),
7.23 (s, 2H), 7.27–7.31 (m, 3H), 7.36–7.40 (m, 2H), 7.47–7.49 (m,
2H), 7.59–7.61 (m, 1H), 8.14–8.16 (m, 1H). 13C NMR (100.6 MHz,
DMSO-d6): d 38.4, 55.7, 111.8, 119.9, 127.3, 127.6, 127.9, 128.9,
129.8, 130.0, 130.6, 131.0, 131.6, 144.1, 152.2, 159.0, 160.5. HRMS
D
DMSO), 55% ee. 1H NMR (400 MHz, DMSO-d6): d 5.06 (s, 1H),
7.20 (s, 2H), 7.28–7.33 (m, 5H), 7.30–7.39 (m, 2H), 7.89 (dd,
J = 8.8, 4.8 Hz, 2H). 13C NMR (100.6 MHz, DMSO-d6): d 38.5, 55.7,
110.0, 116.4 (d, J = 22.3 Hz), 119.9, 127.3, 127.6, 127.9 (d,
J = 8.8 Hz), 128.8 (d, J = 2.6 Hz), 128.9, 144.1, 152.6, 160.4, 162.8,
163.5 (d, J = 249.0 Hz). HRMS (ESI) m/z calcd for C19H13FN3OS [M
+H]+: 350.0758, found 350.0756. HPLC analysis (Chiralpak AD-H
column, Hexane:2-propanol = 80:20, flow rate = 1.0 mL/min, wave-
length = 254 nm): Rt = 13.14 (major) and 17.77 min (minor).
(ESI) m/z calcd for
C
19H13ClN3OS [M+H]+: 366.0462, found
366.0458. HPLC analysis (Chiralpak OD-H column, Hexane:2-pro-
panol = 70:30, flow rate = 1.0 mL/min, wavelength = 254 nm):
Rt = 7.38 (major) and 9.35 min (minor).
4.1.7. (R)-5-Amino-2-(4-bromophenyl)-7-phenyl-7H-pyrano[2,-
3-d]thiazole-6-carbonitrile 3g
4.1.3. (R)-5-Amino-2-(2-fluorophenyl)-7-phenyl-7H-pyrano[2,3-
d]thiazole-6-carbonitrile 3c
White solid, mp 229–231 °C, 70% yield, [a]
20 = +382.5 (c 0.08,
D
White solid, mp 222–224 °C, 76% yield, [
a]
20 = +50.8 (c 0.49,
DMSO), 98% ee. 1H NMR (400 MHz, DMSO-d6): d 5.06 (s, 1H),
7.22 (s, 2H), 7.35–7.36 (m, 5H), 7.65 (d, J = 8.0 Hz, 2H), 7.76 (d,
J = 8.0 Hz, 2H). 13C NMR (100.6 MHz, DMSO-d6): d 38.5, 55.7,
110.5, 119.8, 124.2, 127.3 (2 C), 127.6, 128.9, 131.7, 132.2, 144.0,
152.7, 160.4, 162.6. HRMS (ESI) m/z calcd for C19H13BrN3OS [M
+H]+: 409.9957, found 409.9949. HPLC analysis (Chiralpak AD-H
D
DMSO), 77% ee. 1H NMR (400 MHz, DMSO-d6): d 5.10 (s, 1H),
7.23 (s, 2H), 7.29–7.41 (m, 7H), 7.50–7.55 (m, 1H), 8.10 (t,
J = 7.6 Hz, 1H). 13C NMR (100.6 MHz, DMSO-d6): d 38.4, 55.6,
111.2 (d, J = 10.1 Hz), 116.5 (d, J = 21.3 Hz), 119.7, 119.8, 125.3 (d,
J = 2.7 Hz), 127.2, 127.6 (2 C), 128.9, 132.4 (d, J = 9.0 Hz), 144.1,
152.3, 156.3 (d, J = 4.6 Hz), 159.4 (d, J = 250.9 Hz), 160.5. HRMS
column,
Hexane:2-propanol = 80:20,
flow
rate = 1.0
(ESI) m/z calcd for
C
19H13FN3OS [M+H]+: 350.0758, found
mL/min, wavelength = 254 nm): Rt = 13.16 (major) and 16.41 min
(minor).
350.0753. HPLC analysis (Chiralpak AD-H column, Hexane:2-pro-
panol = 80:20, flow rate = 1.0 mL/min, wavelength = 254 nm):
Rt = 9.27 (minor) and 11.13 min (major).
4.1.8. (R)-5-Amino-2-(3-bromophenyl)-7-phenyl-7H-pyrano[2,-
3-d]thiazole-6-carbonitrile 3h
4.1.4. (R)-5-Amino-2-(4-chlorophenyl)-7-phenyl-7H-pyrano[2,3-d]-
White solid, mp 227–229 °C, 72% yield, [a]
20 = +90.0 (c 0.40,
D
thiazole-6-carbonitrile 3d
DMSO), 98% ee. 1H NMR (400 MHz, DMSO-d6): d 5.06 (s, 1H), 7.22
(s, 2H), 7.35–7.36 (m, 5H), 7.65 (d, J = 8.0 Hz, 2H), 7.76 (d,
J = 8.0 Hz, 2H). 13C NMR (100.6 MHz, DMSO-d6): d 38.5, 55.6,
111.1, 119.8, 122.5, 124.6, 127.3, 127.6, 128.9, 131.5, 133.4, 134.2,
144.0, 152.7, 160.4, 161.9. HRMS (ESI) m/z calcd for C19H13BrN3OS
[M+H]+: 409.9957, found 409.9947. HPLC analysis (Chiralpak OD-
White solid, mp 219–221 °C, 78% yield, [a]
20 = +35.0 (c 0.80,
D
DMSO), 98% ee. 1H NMR (400 MHz, DMSO-d6): d 5.06 (s, 1H),
7.22 (s, 2H), 7.27–7.30 (m, 3H), 7.35–7.39 (m, 2H), 7.51 (d,
J = 8.8 Hz, 2H), 7.83 (d, J = 8.8 Hz, 2H). 13C NMR (100.6 MHz,
DMSO-d6): d 38.5, 55.7, 110.5, 119.8, 127.1, 127.3, 127.6, 128.9,
129.3, 131.0, 135.4, 144.1, 152.7, 160.4, 162.5. HRMS (ESI) m/z
calcd for C19H13ClN3OS [M+H]+: 366.0462, found 366.0459. HPLC
H
column, Hexane:2-propanol = 90:10, flow rate = 0.8 mL/min,
wavelength = 220 nm): Rt = 28.01 (major) and 32.04 min (minor).
Please cite this article in press as: Cui, L.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.08.014

L. Cui et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
4.1.9. (R)-5-Amino-2-(2-bromophenyl)-7-phenyl-7H-pyrano[2,-
4.1.14. (R)-5-Amino-2-(3,5-dimethoxyphenyl)-7-phenyl-7H-
pyrano[2,3-d]thiazole-6-carbonitrile 3n
3-d]thiazole-6-carbonitrile 3i
White solid, mp 229–231 °C, 77% yield, [
a]
20 = +86.4 (c 0.36,
White solid, mp 211–213 °C, 76% yield, [a]
20 = +64.6 (c 0.48,
D
D
DMSO), 74% ee. 1H NMR (400 MHz, DMSO-d6): d 5.13 (s, 1H),
7.25 (s, 2H), 7.27–7.31 (m, 3H), 7.36–7.41 (m, 3H), 7.50 (t,
J = 7.6 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 8.04 (dd, J = 8.0, 1.2 Hz,
1H). 13C NMR (100.6 MHz, DMSO-d6): d 38.4, 55.7, 111.8, 119.9,
120.4, 127.3, 127.6, 128.3, 128.9, 130.7, 131.7, 132.1, 134.4,
144.1, 152.2, 160.5, 160.7. HRMS (ESI) m/z calcd for C19H13BrN3OS
[M+H]+: 409.9957, found 409.9947. HPLC analysis (Chiralpak AS-H
column, Hexane:2-propanol = 90:10, flow rate = 1.0 mL/min, wave-
length = 254 nm): Rt = 39.41 (minor) and 45.05 min (major).
DMSO), 45% ee. 1H NMR (400 MHz, DMSO-d6): d 3.78 (s, 6H),
5.06 (s, 1H), 6.61 (t, J = 2.0 Hz, 1H), 6.93 (d, J = 2.0 Hz, 2H), 7.20
(s, 2H), 7.28–7.30 (m, 3H), 7.37 (t, J = 7.6 Hz, 2H). 13C NMR
(100.6 MHz, DMSO-d6): d 38.5, 55.5, 55.7, 102.9, 103.2, 110.2,
119.9, 127.3, 127.6, 128.9, 133.9, 144.1, 152.4, 160.4, 160.9,
163.6. HRMS (ESI) m/z calcd for C21H18N3O3S [M+H]+: 392.1063,
found 392.1061. HPLC analysis (Chiralpak AD-H column,
Hexane:2-propanol = 70:30,
flow
rate = 1.0 mL/min,
wave-
length = 254 nm): Rt = 22.15 (minor) and 26.78 min (major).
4.1.10. (R)-5-Amino-2-(4-methylphenyl)-7-phenyl-7H-pyrano[2,-
3-d]thiazole-6-carbonitrile 3j
4.1.15. (R)-5-Amino-2-(methylthio)-7-phenyl-7H-pyrano[2,3-d]-
thiazole-6-carbonitrile 3n
White solid, mp 218–220 °C, 72% yield, [
a
]
D
20 = +51.6 (c 0.50,
White solid, mp 210–212 °C, 54% yield, [a]
20 = +40.0 (c 0.20,
D
DMSO), 91% ee. 1H NMR (400 MHz, DMSO-d6): d 2.32 (s, 3H),
5.04 (s, 1H), 7.19 (s, 2H), 7.26–7.29 (m, 5H), 7.37 (t, J = 7.6 Hz,
2H), 7.71 (d, J = 8.4 Hz, 2H). 13C NMR (100.6 MHz, DMSO-d6): d
21.0, 38.5, 55.7, 109.2, 119.9, 125.3, 127.2, 127.6, 128.9, 129.6,
129.8, 140.9, 144.2, 152.5, 160.5, 164.1. HRMS (ESI) m/z calcd for
DMSO), 26% ee. 1H NMR (400 MHz, DMSO-d6): d 2.60 (s, 3H),
4.95 (s, 1H), 7.14 (s, 2H), 7.24 (d, J = 7.6 Hz, 2H), 7.27 (t,
J = 7.2 Hz, 1H), 7.36 (t, J = 7.2 Hz, 2H). 13C NMR (100.6 MHz,
DMSO-d6): d 15.8, 38.5, 55.9, 108.0, 119.7, 127.1, 127.5, 128.8,
143.9, 151.3, 160.3, 164.9. HRMS (ESI) m/z calcd for C14H12N3OS
[M+H]+: 302.0416, found 302.0558. HPLC analysis (Chiralpak
AD-H column, Hexane:2-propanol = 85:15, flow rate = 1.0 mL/
min, wavelength = 254 nm): Rt = 11.83 (minor) and 13.61 min
(major).
C
20H16N3OS [M+H]+: 346.1009, found 346.1012. HPLC analysis
(Chiralpak AD-H column, Hexane:2-propanol = 70:30, flow
rate = 1.0 mL/min, wavelength = 254 nm): Rt = 10.48 (major) and
13.95 min (minor).
4.1.11. (R)-5-Amino-2-(2-methylphenyl)-7-phenyl-7H-pyrano[2,-
3-d]thiazole-6-carbonitrile 3k
4.1.16. (R)-5-Amino-7-(3-chlorophenyl)-2-phenyl-7H-pyrano-
[2,3-d]thiazole-6-carbonitrile 3p
White solid, mp 224–226 °C, 79% yield, [
a
]
D
20 = ꢀ20.0 (c 0.20,
White solid, mp 207–209 °C, 94% yield, [
a]
20 = ꢀ27.1 (c 0.14,
D
DMSO), 92% ee. 1H NMR (400 MHz, DMSO-d6): d 2.50 (s, 3H),
5.09 (s, 1H), 7.21 (s, 2H), 7.25–7.30 (m, 4H), 7.33–7.39 (m, 4H),
7.66 (d, J = 7.6 Hz, 1H). 13C NMR (100.6 MHz, DMSO-d6): d 21.4,
38.4, 55.7, 110.1, 119.9, 126.6, 127.3, 127.6, 128.8, 128.9, 130.2,
131.2, 131.9, 135.8, 144.1, 152.2, 160.6, 163.9. HRMS (ESI) m/z
calcd for C20H16N3OS [M+H]+: 346.1009, found 346.1012. HPLC
analysis (Chiralpak AD-H column, Hexane:2-propanol = 70:30,
flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 10.48 (major)
and 13.95 min (minor).
EtOAc), 58% ee. 1H NMR (400 MHz, DMSO-d6): d 5.13 (s, 1H), 7.27
(s, 1H), 7.29 (s, 2H), 7.36–7.42 (m, 3H), 7.44–7.48 (m, 3H), 7.83–
7.85 (m, 2H). 13C NMR (100.6 MHz, DMSO-d6): d 38.1, 55.1, 55.7,
109.1, 119.8, 125.5, 126.2, 127.1, 127.7, 129.3, 130.9, 131.0,
132.1, 133.5, 146.6, 152.7, 160.6, 164.2. HRMS (ESI) m/z calcd for
C
19H13ClN3OS [M+H]+: 366.0462, found 366.0459. HPLC analysis
(Chiralpak AD-H column, Hexane:2-propanol = 80:20, flow
rate = 1.0 mL/min, wavelength = 254 nm): Rt = 10.57 (major) and
13.43 min (minor).
4.1.12. (R)-5-Amino-2-(4-chloro-3-methylphenyl)-7-phenyl-7H-
pyrano[2,3-d]thiazole-6-carbonitrile 3l
4.1.17. (R)-5-Amino-7-(2-methoxyphenyl)-2-phenyl-7H-pyrano-
[2,3-d]thiazole-6-carbonitrile 3q
White solid, mp 234–236 °C, 93% yield, [
a]
20 = +154.9 (c 0.03,
White solid, mp 198–200 °C, 75% yield, [a]
20 = +125.4 (c 0.41,
D
D
EtOAc), 93% ee. 1H NMR (400 MHz, DMSO-d6): d 2.36 (s, 3H), 5.08
(s, 1H), 7.21 (s, 2H), 7.27–7.31 (m, 3H), 7.36–7.40 (m, 2H), 7.50
(d, J = 8.4 Hz, 1H), 7.68 (dd, J = 8.4, 2.0 Hz, 1H), 7.84 (d, J = 1.6 Hz,
1H). 13C NMR (100.6 MHz, DMSO-d6): d 19.5, 38.5, 55.6, 110.4,
119.8, 124.5, 127.3, 127.6, 128.0, 128.9, 129.8, 131.0, 135.7,
DMSO), 43% ee. 1H NMR (400 MHz, DMSO-d6): d 3.90 (s, 3H),
5.28 (s, 1H), 6.98 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 7.21
(d, J = 7.2 Hz, 1H), 7.25 (s, 2H), 7.28 (t, J = 7.6 Hz, 1H), 7.41–7.47
(m, 3H), 7.81–7.83 (m, 2H). 13C NMR (100.6 MHz, DMSO-d6): d
32.7, 53.2, 55.5, 109.2, 111.3, 120.0, 120.1, 125.4, 127.5, 128.8,
129.9, 130.8, 130.9, 132.3, 152.7, 156.1, 161.6, 163.3. HRMS (ESI)
m/z calcd for C20H16N3O2S [M+H]+: 362.0958, found 362.0955.
HPLC analysis (Chiralpak AD-H column, Hexane:2-propa-
nol = 80:20, flow rate = 1.0 mL/min, wavelength = 254 nm):
Rt = 8.88 (major) and 11.46 min (minor).
136.7, 144.1, 152.6, 160.5, 162.7. HRMS (ESI) m/z calcd for C20H15
ClN3OS [M+H]+: 380.0619, found 380.0610. HPLC analysis (Chiral-
pak AD-H column, Hexane:2-propanol = 70:30, flow
-
rate = 1.0 mL/min, wavelength = 254 nm): Rt = 10.80 (major) and
12.99 min (minor).
4.1.13. (R)-5-Amino-2-(4-methoxyphenyl)-7-phenyl-7H-pyrano-
[2,3-d]thiazole-6-carbonitrile 3m
4.1.18. (S)-5-Amino-2-phenyl-7-(thiophen-2-yl)-7H-pyrano[2,3-
d]thiazole-6-carbonitrile 3r
White solid, mp 211–213 °C, 79% yield, [
a]
20 = +82.5 (c 0.05,
White solid, mp 198–200 °C, 75% yield, [a]
20 = +84.0 (c 0.10,
D
D
EtOAc), 55% ee. 1H NMR (400 MHz, DMSO-d6): d 3.80 (s, 3H), 5.02
(s, 1H), 7.01 (d, J = 8.4 Hz, 1H), 7.17 (s, 2H), 7.28–7.29 (m, 3H),
7.37 (t, J = 7.2 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H). 13C NMR
(100.6 MHz, DMSO-d6): d 38.5, 55.4, 55.8, 108.5, 114.6, 119.9,
124.9, 127.1, 127.2, 127.5, 128.9, 144.2, 152.3, 160.5, 161.4,
163.9. HRMS (ESI) m/z calcd for C20H16N3O2S [M+H]+: 362.0958,
found 362.0956. HPLC analysis (Chiralpak AD-H column, Hex-
DMSO), 70% ee. 1H NMR (400 MHz, DMSO-d6): d 5.48 (s, 1H),
6.99 (dd, J = 3.6 and 4.8 Hz, 1H), 7.10 (d, J = 3.6 Hz, 1H), 7.28 (s,
2H), 7.46–7.56 (m, 4H), 7.85–7.87 (m, 2H). 13C NMR (100.6 MHz,
DMSO-d6): d 33.8, 56.3, 109.9, 119.6, 124.9, 125.4, 125.9, 126.9,
129.3, 131.0, 132.1, 149.1, 152.2, 160.2, 164.0. HRMS (ESI) m/z
calcd for C17H12N3OS2 [M+H]+: 338.0416, found 338.0418. HPLC
analysis (Chiralpak AD-H column, Hexane:2-propanol = 85:15,
flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 16.59 (major)
and 22.89 min (minor).
ane:2-propanol = 70:30,
flow
rate = 1.0 mL/min,
wave-
length = 254 nm): Rt = 20.11 (major) and 28.72 min (minor).
Please cite this article in press as: Cui, L.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.08.014

6
L. Cui et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
2. (a) Andreani, A.; Burnelli, S.; Granaiola, M.; Guardigli, M.; Leoni, A.; Locatelli, A.;
4.1.19. Preparation of compound 4
Morigi, R.; Rambaldi, M.; Rizzoli, M.; Varoli, L.; Roda, A. Eur. J. Med. Chem. 2008,
43, 657; (b) Xiong, H. Y. Wu.; Lehr, S. G.; Blackwell, W.; Steelman, G.; Hulsizer,
J.; Urbanek, R. A. Tetrahedron Lett. 2012, 53, 5833; (c) Ding, C.; Zhang, Y.; Chen,
H.; Yang, Z.; Wild, C.; Chu, L.; Liu, H.; Shen, Q.; Zhou, J. J. Med. Chem. 2013, 56,
5048; (d) Nagaraju, A.; Ramulu, B. J.; Shukla, G.; Srivastava, A.; Verma, G. K.;
Raghuvanshi, K.; Singh, M. S. Tetrahedron 2015, 71, 3422; (e) Wang, N.-Y.; Xu,
Y.; Zuo, W.-Q.; Xiao, K.-J.; Liu, L.; Zeng, X.-X.; You, X.-Y.; Zhang, L.-D.; Gao, C.;
Liu, Z.-H.; Ye, T.-H.; Xia, Y.; Xiong, Y.; Song, X.-J.; Lei, Q.; Peng, C.-T.; Tang, H.;
Yang, S.-Y.; Wei, Y.-Q.; Yu, L.-T. J. Med. Chem. 2015, 58, 2764.
To a mixture of (R)-5-Amino-2,7-diphenyl-7H-pyrano[2,3-d]
thiazole-6-carbonitrile 3a (50 mg, 0.15 mmol) and AlCl3 (40 mg,
0.30 mmol) in dichloromethane (1 mL) was added cyclohexanone
(393 mg, 4.0 mmol). Then the reaction solution was stirred at room
temperature until the disappearance of the starting material 3a
(monitored by TLC). After removal of the solvent under reduced
pressure, the crude product was purified by column chromatogra-
phy on silica gel (petroleum ether/EtOAc as the eluent) to furnish
the corresponding product 4 (57 mg).
3. (a) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis: From Biomimetic
Concepts to Applications in Asymmetric Synthesis; Wiley-VCH: Weinheim, 2005;
(b) Dalko, P. I. Enantioselective Organocatalysis: Reactions and Experimental
Procedures; Wiley-VCH: Weinheim, 2007; (c) Organocatalysis; Reetz, M. T., List,
B., Jaroch, S., Weinmann, H., Eds.; Springer, 2007; (d) List, B. Chem. Rev. 2007,
107, 5413; (e) Barbas, C. F., III Angew. Chem., Int. Ed. 2008, 47, 42; (f) MacMillan,
D. W. C. Nature 2008, 455, 304; (g) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev.
2009, 38, 2178.
4. Lin, L.; Yang, Y.; Wang, M.; Lai, L.; Guo, Y.; Wang, R. Chem. Commun. 2015, 8134.
5. Liang, Z.-Q.; Yi, L.; Chen, K.-Q.; Ye, S. J. Org. Chem. 2016, 81, 4841.
6. For recent reviews, see: (a) Pellissier, H. Chem. Rev. 2013, 113, 442; (b)
Pellissier, H. Adv. Synth. Catal. 2012, 354, 237; (c) Fustero, S.; Sanchez-Rosello,
M.; del Pozo, C. Pure Appl. Chem. 2010, 82, 669; (d) Enders, D.; Grondal, C.;
Hüttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570.
7. (a) Zheng, Y.; Cui, L.; Wang, Y.; Zhou, Z. J. Org. Chem. 2016, 81, 4340; (b) Wu, L.;
Zheng, Y.; Wang, Y.; Zhou, Z. RSC Adv. 2016, 6, 11602; (c) Wang, Y.; Pan, J.;
Chen, S.; Wang, Y.; Zhou, Z. Adv. Synth. Catal. 2016, 358, 195; (d) Pan, J.; Wang,
Y.; Chen, S.; Wang, Y.; Zhou, Z. Tetrahedron 2016, 76, 240; (e) Wang, Y.; Cui, L.;
Wang, Y.; Zhou, Z. Tetrahedron: Asymmetry 2016, 27, 85; (f) Cui, L.; Wang, Y.;
Chen, S.; Wang, Y.; Zhou, Z. RSC Adv. 2015, 5, 88133; (g) Zheng, Y.; Wang, Y.;
Zhou, Z. Chem. Commun. 2015, 16652; (h) Wang, H.; Wu, L.; Wang, Y.; Zhou, Z.
RSC Adv. 2015, 5, 42836.
4.1.20. (R)-2,11-Diphenyl-7,8,9,11-tetrahydro-6H-thiazolo-[50,40:5,-
6]pyrano[2,3-b]quinolin-10-amine 4
White solid, mp 260 °C (Dec.), 92% yield, [a]
20 = +129.0 (c 0.2,
D
DMSO), 98% ee. 1H NMR (400 MHz, CDCl3): 1.73 (br. s, 4H),
2.22–2.35 (m, 2H), 2.63 (br. s, 2H), 5.48 (br. s, 2H), 5.63 (s, 1H),
7.18–7.23 (m, 1H), 7.30 (d, J = 4.4 Hz, 4H), 7.46–7.48 (m, 3H),
7.84–7.87 (m, 2H). 13C NMR (100.6 MHz, CDCl3): 22.0, 22.3, 23.0,
32.0, 36.7, 96.0, 109.6, 112.9, 125.4, 127.0, 127.1, 128.8, 129.2,
130.6, 132,5, 144.2, 151.9, 153.1, 154.8, 163.2. HRMS (ESI) m/z
calcd for C25H22N3OS [M+H]+: 412.1478, found 412.1482. HPLC
analysis (Chiralpak OD-H column, Hexane:2-propanol = 80:20,
flow rate = 0.9 mL/min, wavelength = 254 nm): Rt = 16.10 (minor)
and 23.02 min (major).
8. The synthesis of racemic pyrano[2,3-d]thiazoles, see: (a) Wardakhan, W. W.;
Ibrahim, D. A.; Zaki, M. Y. Heterocycl. Commun. 2011, 17, 155; (b) Ismail, N. A.;
Khalifa, F. A.; Fekry, R. M.; Abel Azim, Y. N. Phosphorus, Sulfur Silicon Relat. Elem.
1992, 66, 29.
9. For reviews on thiourea-based organocatalysis, see: (a) Fang, X.; Wang, C.-J.
Chem. Commun. 2015, 1185; (b) Serdyuk, O. V.; Heckel, C. M.; Tsogoeva, S. B.
Org. Biomol. Chem. 2013, 11, 7051; (c) Siau, W.-Y.; Wang, J. Catal. Sci. Technol.
2011, 1, 1298; (d) Han, B.; Li, J.-L.; Xiao, Y.-C.; Zhou, S.-L.; Chen, Y.-C. Curr. Org.
Chem. 2011, 15, 4128; (e) Takemoto, Y. Chem. Pharm. Bull. 2010, 58, 593; (f)
Connon, S. J. Chem. Eur. J. 2006, 12, 5418.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (No. 21421062), the Key Laboratory of Elemento-Organic
Chemistry and Collaborative Innovation Center of Chemical Science
and Engineering for generous financial support for our programs.
10. For reviews of squaramide-based organocatalysis, see: (a) Chauhan, P.;
Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Adv. Synth. Catal. 2015, 357, 253;
(b) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem. Eur. J. 2011, 17, 6890.
11. (a) Zheng, Y.; Yao, Y.; Ye, L.; Shi, Z.; Li, X.; Zhao, Z.; Li, Y. Tetrahedron 2016, 72,
973; (b) Lv, W.; Guo, C.; Dong, Z.; Tang, S.; Liu, B.; Dong, C. Tetrahedron:
Asymmetry 2016, 27, 670; (c) Gao, Y.; Du, D.-M. Chem. Asian J. 2014, 9, 2970;
(d) Hu, K.; Wang, Y.; Zhou, Z.; Tang, C. Tetrahedron 2014, 70, 181.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.08.
014.
References
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Please cite this article in press as: Cui, L.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.08.014