Organocatalytic Asymmetric Synthesis of Benzothiazolopyrimidines via [4 + 2] Cyclization of 2-Benzothiazolimines and Aldehydes

Article abstract of DOI:10.1021/acs.joc.0c02499

We report the direct asymmetric synthesis of pyrimido[2,1-b]benzothiazoles using a commercially available chiral amine catalyst. A variety of 2-benzothiazolimines and aldehydes were well tolerated under the reaction conditions and generated the corresponding products in 81-99% yields with excellent diastereoselectivities and enantioselectivities (up to >20:1 dr, 99% ee). Furthermore, the products could be easily converted to other useful chiral building blocks.

Full text of DOI:10.1021/acs.joc.0c02499

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Article
Organocatalytic Asymmetric Synthesis of Benzothiazolopyrimidines
via [4 + 2] Cyclization of 2‑Benzothiazolimines and Aldehydes
Xue-Ping Chen, Ke-Qiang Hou, Feng Zhou, Albert S. C. Chan, and Xiao-Feng Xiong*
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ABSTRACT: We report the direct asymmetric synthesis of
pyrimido[2,1-b]benzothiazoles using a commercially available
chiral amine catalyst. A variety of 2-benzothiazolimines and
aldehydes were well tolerated under the reaction conditions and
generated the corresponding products in 81−99% yields with
excellent diastereoselectivities and enantioselectivities (up to >20:1
dr, 99% ee). Furthermore, the products could be easily converted
to other useful chiral building blocks.
phosphoric acid catalysis,7 squaramide catalysis,8 and phos-
phonium salt catalysis,9 respectively (Scheme 1a). Although
INTRODUCTION
■
Benzothiazolopyrimidine and its derivatives are widely present
in pharmacologically active molecules,1 such as antitumor
agents,1a antitrypanosomal agents,1b phosphodiesterase inhib-
itors,1c and SHP2 inhibitors (Figure 1).1d Moreover, Lewis
Scheme 1. [4 + 2] Annulations for the Asymmetric
Synthesis of Benzothiazolopyrimidines
Figure 1. Examples of bioactive molecules and catalysts containing
tricyclic pyrimido[2,1-b]benzothiazoles.
these strategies mentioned above are effective and reliable,
there is still an urgent need for exploring optional methods that
start from inexpensive and readily available substrates for the
direct asymmetric synthesis of tricyclic pyrimido[2,1-b]-
benzothiazole derivatives, for which products can be easily
transformed to other attractive chiral molecules for further
applications.
base isothiourea catalysts containing the tricyclic pyrimido[2,1-
b]benzothiazole scaffold have proven to be precious catalysts
applied for kinetic resolution (KR),2 C-acylations,3 N-
acylations,4 etc. Despite the wide distribution of this scaffold
in biomolecules and organocatalysts, direct asymmetric
synthesis of this scaffold has been rarely reported.5 In 2014,
the Enders group reported the asymmetric synthesis of
benzothiazolopyrimidinones via chiral NHC-catalyzed Man-
nich/lactamization domino reaction of 2-benzothiazolimines
and α-chloroaldehydes.6 Later, a few stereoselective [4 + 2]
annulations for the synthesis of benzothiazolopyrimidines were
achieved by the groups of Masson, Song, and Wang, by using
Received: October 21, 2020
Published: January 6, 2021
https://dx.doi.org/10.1021/acs.joc.0c02499
© 2021 American Chemical Society
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The asymmetric Mannich reactions catalyzed by chiral
primary and secondary amines and bifunctional organo-
catalysts for new C−C bond formation have been widely
used in the effective synthesis of natural products and
pharmacologically active chiral compounds.10,11 Aldehydes
and α,β-unsaturated aldehydes activated by secondary amines
are frequently applied for the construction of multifunctional
heterocycles through [2 + 2], [3 + 2], and [4 + 2] cyclization,
in which the asymmetric Mannich reaction is working as the
key step.12,13 Recently, our group developed the secondary
chiral amine-catalyzed three-component asymmetric Povarov
reaction between anilines and aldehydes via chiral enamine
intermediates which serve as electron-rich olefins.14 As part of
our research interests in developing new catalytic strategies to
construct useful bioactive frameworks,15 we herein report the
direct asymmetric synthesis of benzothiazolopyrimidines via
chiral secondary amine-catalyzed [4 + 2] cyclization of 2-
benzothiazolimines and aldehydes (Scheme 1b). Furthermore,
the products can be easily converted to other useful chiral
building blocks.
Proline 4c could catalyze this reaction with good stereo-
selectivity and gave the syn-selective adduct 3a′ (the
diastereoisomer of 3a) with 60% yield (Table 1, entry 3).
The absolute configuration of 3a′ was confirmed by X-ray
crystallographic analysis (CCDC 2048709, see Supporting
Information for details). To our delight, α,α-diphenylprolinol
trimethylsilyl ether 4e provided the product 3a in 97% yield
with excellent diastereoselectivity (dr 13:1) and enantioselec-
tivity (98% ee) (Table 1, entry 5). Reducing the equivalent of
aldehyde 2a led to lower yield (Table 1, entry 7). In attempt to
further improve the diastereoselectivity, we tested different
solvents (DCE, PhMe, THF, and CH3CN) and an acid
additive (p-NO2-PhCOOH); however, no satisfactory im-
provements were achieved (Table 1, entries 8−12). Fortu-
nately, lowering the reaction temperature to 0 °C delivered the
product 3a in 94% yield, high diastereoselectivity (>20:1), and
enantioselectivity (99% ee) (Table 1, entry 13). Thus, the
optimized reaction conditions were established as 1.0 equiv of
2-benzothiazolimine 1a and 1.5 equiv of 3-phenylpropionalde-
hyde 2a, in the presence of chiral secondary amine 4e (10 mol
%) and benzoic acid (10 mol %) in DCM under 0 °C.
With the optimized reaction conditions in hand, we then
investigated the substrate scope of this protocol (Scheme 2).
Initially, various 2-benzothiazolimines 1 bearing different
substituents on the benzothiazole ring were reacted with 3-
phenylpropionaldehyde 2a. The electronic properties of the
substituents at the C6 position of benzothiazole rings displayed
negligible effects for the reactions; either electron-withdrawing
groups (F, Cl) or an electron-donating group (OCH3) gave
the corresponding products 3b−d with excellent yields (97−
98%), diastereoselectivities (14:1−19:1), and enantioselectiv-
ities (91−98% ee). Similarly, good results were attained with
the substituent at the C5 position of the benzothiazole ring
(3e). It is worth noting that 2-benzoxazolimine was also a
suitable substrate, giving the expected product 3f in 97% ee,
>20:1 dr, and 97% yield. Subsequently, 2-benzothiazolimines
bearing various substituents on the phenyl ring were
investigated. A wide range of substituents on the phenyl ring
of 2-benzothiazolimine, including CF3, Cl, F, CH3, and OCH3,
participated well in the reactions and afforded the correspond-
ing adducts 3g−k in 92−99% yields with excellent
enantioselectivities (95−99% ee). Furthermore, the absolute
configuration of 3h was confirmed by X-ray crystallographic
analysis (CCDC 2033715, see Supporting Information for
details), which turned out to be the anti-selective product and
different from 3a′. Notably, the 2-benzothiazolimines with
furanyl, thienyl, or pyridyl groups could also participate well
under the optimized reaction conditions, leading to 3l−n in
good yields (84−87%) and high enantioselectivities (94−99%
ee). Moreover, the 2-benzothiazolimine with a β-naphthyl
group was well tolerated and delivered the desired product 3o
with 98% yield and 98% ee.
RESULTS AND DISCUSSION
■
We initiated our studies by examining the reaction of 2-
benzothiazolimine 1a and 3-phenylpropionaldehyde 2a in the
presence of different chiral secondary amines 4 (10 mol %)
and benzoic acid (10 mol %) in DCM under room
temperature (Table 1). The MacMillan’s catalysts (4a, 4b)
could not promote the reaction (Table 1, entries 1 and 2). L-
a
Table 1. Optimization of the Reaction Conditions
yield
b
ee
c
d
entry cat.
additive
PhCOOH
solvent
(%)
dr
(%)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4e
4e
4e
4e
4e
4e
4e
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
PhMe
THF
CH3CN
DCM
DCM
−
−
60
−
−
−
−
97
−
98
88
98
92
97
91
96
97
99
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
p-NO2-PhCOOH
PhCOOH
g
1:20
−
−
97
98
88
95
93
96
98
95
94
13:1
5:1
13:1
4:1
11:1
6:1
e
Finally, other aliphatic aldehydes were explored in the
asymmetric reaction. In general, propionaldehyde, butyralde-
hyde, hexanal, and decanal reacted well to give the
corresponding products 3p−s in good to high yields (83−
90%) with high enantioselectivities (91−98% ee). When
phenylacetaldehyde was used, the reaction proceeded slowly,
which led to a slight decrease in the yield of product 3t (81%
yield, 4:1 dr, 94% ee). Furthermore, other aliphatic aldehydes
with heterocycles pyrimidine and thiophene side chains were
tolerated under the established reaction conditions and gave
the corresponding products 3u and 3v with satisfactory results
10
11
12
13
7:1
11:1
>20:1
f
a
Reactions conditions: 1a (0.1 mmol), 2a (0.15 mmol) in the
presence of catalyst 4 (0.01 mmol), and acid additive (0.01 mmol) in
b
solvent (1 mL) under room temperature for 1 h. Isolated yield of
c
d
1
both diastereomers. Determined by H NMR analysis. Determined
e
f
by chiral HPLC analysis. 0.12 mmol of 2a. Reaction was performed
at 0 °C. Isolated yield of 3a′ (the diastereoisomer of 3a).
g
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a
catalytic capability of the 2-aminobenzothiazole and self-
condensation of the aldehyde.16
Scheme 2. Substrate Scope of the Reactions
To further verify the practicality of this protocol, we
performed a gram-scale synthesis using 2-benzothiazolimine 1a
and 3-phenylpropionaldehyde 2a under the standard reaction
conditions. To our delight, product 3a was isolated in excellent
yield, good enantioselectivity, and good diastereoselectivity
(92%, 96% ee, and 7:1 dr) (Scheme 3a). By simple
Scheme 3. Gram-Scale Synthesis and Transformation of
Product 3a
recrystallization, 3a could be obtained in enantiomerically
pure form (>99% ee). The hydroxyl group of 3a could be
removed by reduction with Et3SiH/BF3·Et2O under 80 °C and
gave the product 5 as a single diastereoisomer (Scheme 3b). 5
was then treated with fluoroboric acid to afford tetrafluor-
oborate 6, and the structure was confirmed by X-ray
crystallographic analysis (CCDC 2033716, see Supporting
Information for details), suggesting that this synthetic strategy
can be applied to quickly construct the core scaffold of Lewis
base isothiourea catalysts. Additionally, the hydroxyl group of
3a could be replaced by allyl to give the product 7 after
treating with allyl-trimethylsilane/BF3·Et2O, and the stereo-
chemistry of the allyl substituent was confirmed by NOE
analysis (Scheme 3c).
To better understand this asymmetric [4 + 2] cyclization
reaction, we proposed a plausible reaction mechanism based
on the results and previous studies10b (Scheme 4). Initially, the
chiral secondary amine catalyst 4e reacted with aldehyde 2 to
give the iminium ion intermediate I, which rapidly
tautomerized to enamine intermediate II. Subsequently,
nucleophilic attack of the enamine intermediate II on 2-
benzothiazolimine 1 at the Re-face through a Mannich reaction
formed intermediate IV. Subsequent hydrolysis of the
intermediate IV led to the release of catalyst 4e and aldehyde
V, followed by V tautomerization to intermediate VI. Finally,
the intramolecular nucleophilic addition of intermediate VI
gave the product 3.
a
Reactions conditions: 1a (0.2 mmol), 2a (0.3 mmol) in the presence
of catalyst 4e (0.02 mmol) and PhCOOH (0.02 mmol) in DCM (2
mL) under 0 °C for 1−12 h. Yield: isolated yield of both
1
diastereomers. dr: determined by H NMR analysis. ee: determined
by chiral HPLC analysis.
CONCLUSIONS
(90−92% yields, 94−97% ee). The absolute configurations of
3a−g and 3i−v were assigned according to 3h. We also tested
the in situ-generated 2-benzothiazolimine from 2-amino-
benzothiazole and 3-phenylpropionaldehyde 2a to react with
3-phenylpropionaldehyde 2a; however, a mixture of by-
products was obtained. This might be due to the competitive
■
In summary, we have developed an efficient asymmetric [4 +
2] cyclization for the direct construction of chiral benzothia-
zolopyrimidines with high yields and excellent stereoselectiv-
ities. A wide variety of benzothiazolimines and aldehydes were
well tolerated under the mild reaction conditions. Further-
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General Procedure for the Synthesis of 2-Benzothiazoli-
mines. To a 50 mL flame-dried round-bottom flask were added 2-
aminobenzothiazole (1.0 mmol), benzaldehyde (1.1 mmol), and
toluene (10 mL). To the above solution were added 4 Å molecular
sieves (1.0 g). The mixture was refluxed for 12−20 h under an oil
bath. After the complete conversion of the starting material, the
mixture was filtered and the filtrate was concentrated by the
evaporator. The residue was quickly purified by flash chromatography
on silica gel, employing mixtures of petroleum ether and ethyl acetate
as eluents to afford the desired 2-benzothiazolimines.
Scheme 4. Proposed Mechanism of [4 + 2] Cyclization
General Procedure for the Asymmetric Synthesis of
Products 3. At 0 °C, aldehyde 2 (0.30 mmol, 1.5 equiv) in 2 mL
of DCM was added into a mixture of 2-benzothiazolimine 1 (0.20
mmol, 1.0 equiv), catalyst 4e (0.02 mmol, 10 mol %), and PhCOOH
(0.02 mmol, 10 mol %). Then the reaction mixture was stirred at 0 °C
for 1−12 h. After completion of the reaction, 2 mL of saturated
NaHCO3 solution was added and extracted with DCM and the
combined organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The reaction mixture was purified
by flash column chromatography using DCM/MeOH as the eluent to
get the products.
(2S,3R,4R)-3-Benzyl-2-phenyl-3,4-dihydro-2H-benzo[4,5]-
thiazolo[3,2-a]pyrimidin-4-ol (3a). White solid (70 mg, 94% yield,
DCM/MeOH = 100/1 as the eluent). mp 131.5−134.1 °C. 1H NMR
(400 MHz, CDCl3) δ 7.58 (t, J = 7.2 Hz, 2H), 7.49 (d, J = 7.6 Hz,
2H), 7.40 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 7.2 Hz, 2H), 7.16−7.06 (m,
2H), 7.01−6.84 (m, 4H), 6.74 (d, J = 7.6 Hz, 1H), 4.84 (d, J = 2.4
Hz, 1H), 4.23 (d, J = 11.6 Hz, 1H), 2.13−1.97 (m, 1H), 1.88−1.80
(m, 1H), 1.59 (t, J = 12.4 Hz, 1H). 13C{1H} NMR (100 MHz,
CDCl3) δ 159.1, 143.0, 139.8, 139.2, 129.3, 128.9, 128.4, 127.9, 126.1,
125.9, 123.5, 122.1, 121.2, 109.8, 74.4, 59.9, 46.4, 32.8. HRMS (ESI)
m/z: [M + H]+ Calcd for C23H21N2OS 373.1369; found 373.1357.
D
[α]20 +66° (c 1.0, CH2Cl2). HPLC: Chiralpak AD-H column, n-
more, this synthetic strategy could be applied to quickly
construct the core scaffold of Lewis base isothiourea catalysts
and other precious chiral building blocks. Further applications
of this protocol are currently underway in our lab.
hexane/i-PrOH = 88/12, flow rate = 1.0 mL/min, λ = 254 nm, tR
(minor) = 8.50 min, tR (major) = 20.78 min, >20:1 dr, 99% ee.
(2S,3R,4R)-3-Benzyl-8-fluoro-2-phenyl-3,4-dihydro-2H-benzo-
[4,5]thiazolo[3,2-a]pyrimidin-4-ol (3b). White solid (77 mg, 98%
yield, DCM/MeOH = 100/1 as the eluent). mp 140.9−144.4 °C. 1H
NMR (400 MHz, CDCl3) δ 7.56 (t, J = 7.2 Hz, 2H), 7.48−7.36 (m,
3H), 7.19 (t, J = 7.2 Hz, 2H), 7.15−7.10 (m, 1H), 6.93 (d, J = 7.4 Hz,
2H), 6.84 (d, J = 6.4 Hz, 2H), 6.58 (d, J = 6.0 Hz, 1H), 4.78 (s, 1H),
4.20 (d, J = 10.8 Hz, 1H), 2.05 (d, J = 11.6 Hz, 1H), 1.84 (s, 1H),
1.60 (d, J = 12.4 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 158.7
EXPERIMENTAL SECTION
■
General Information. All reagents used in the synthesis were
obtained commercially and used without further purification. All
experiments were monitored by analytical thin layer chromatography
(TLC). UV light, I2, and a solution of KMnO4 were used to visualize
products. NMR spectra were recorded on a Bruker (400 or 500 MHz)
spectrometer. 1H, 19F, and 13C NMR were recorded at 400 MHz (1H
NMR), 100 MHz (13C {1H} NMR) and 376 MHz (19F{1H} NMR),
or 500 MHz (1H NMR) and 125 MHz (13C {1H} NMR),
respectively. Chemical shifts were reported in ppm from tetrame-
thylsilane with the solvent resonance as the internal standard (CDCl3:
1
(C−F, JC−F = 240.0 Hz), 158.7, 142.7, 139.0, 136.1, 129.3, 128.8,
128.5, 128.0, 126.2, 112.9(C−F, 2JC−F = 22.0 Hz), 110.3, 108.6 (C−F,
2JC−F = 26.0 Hz), 74.8, 59.7, 46.3, 32.8. 19F{1H} NMR (376 MHz,
CDCl3) δ −120.25. HRMS (ESI) m/z: [M + H]+ Calcd for
D
C23H20FN2OS 391.1275; found 391.1272. [α]20 +87° (c 1.0,
CH2Cl2). HPLC: Chiralpak AD-H column, n-hexane/i-PrOH = 88/
12, flow rate = 1.0 mL/min, λ = 254 nm, tR (minor) = 8.08 min, tR
(major) = 14.07 min, 14:1 dr, 93% ee.
δH = 7.26 ppm, δC = 77.16 ppm; DMSO-d6: δH = 2.50 ppm, δC
=
39.52 ppm). Multiplicity is indicated as follows: s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of
doublets), dt (doublet of (triplets). Coupling constants (J) are
reported in hertz (Hz). High resolution mass spectrometry (HRMS)
spectra were obtained on a Shimadzu LCMS-ITTOF mass
spectrometer. Melting points were measured on a WRS-1A digital
melting point apparatus and are uncorrected. Optical rotations were
recorded on a polarimeter with a sodium lamp of wavelength 589 nm
(2S,3R,4R)-3-Benzyl-8-chloro-2-phenyl-3,4-dihydro-2H-benzo-
[4,5]thiazolo[3,2-a]pyrimidin-4-ol (3c). White solid (79 mg, 97%
yield, DCM/MeOH = 100/1 as the eluent). mp 145.7−146.4 °C. 1H
NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.60 (t, J = 7.6 Hz, 2H),
7.50 (d, J = 7.6 Hz, 2H), 7.41 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 7.2 Hz,
2H), 7.15−7.05 (m, 2H), 6.91 (d, J = 7.2 Hz, 2H), 6.80 (d, J = 8.4
Hz, 2H), 4.76 (s, 1H), 4.20 (d, J = 11.6 Hz, 1H), 2.09−1.98 (m, 1H),
1.87−1.79 (m, 1H), 1.49 (t, J = 12.8 Hz, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ 158.4, 142.7, 138.9, 138.4, 129.3, 128.8, 128.6, 128.5,
128.1, 127.6, 126.3, 126.2, 124.9, 121.1, 110.6, 74.7, 59.9, 46.2, 32.8.
HRMS (ESI) m/z: [M + H]+ Calcd for C23H20ClN2OS 407.0979;
found 407.0971. [α]20D +39° (c 1.0, CH2Cl2). HPLC: Chiralpak AD-
H column, n-hexane/i-PrOH = 88/12, flow rate = 1.0 mL/min, λ =
254 nm, tR (minor) = 9.45 min, tR (major) = 17.47 min, 17:1 dr, 91%
ee.
T
and are reported as follows: [α]λ (c = g/100 mL, solvent).
Enantiomeric excesses were determined by chiral high-performance
liquid chromatography (HPLC) analysis. HPLC samples were
dissolved in HPLC grade 2-propanol (IPA) unless otherwise stated.
X-ray structural analysis was conducted on XtaLAB Synergy R, DW
system, HyPix diffractometer. All the 0 °C reactions were controlled
by magnetic agitation of the low temperature thermostat sink
(EYELA, PSL-1400). 2-Benzothiazolimines were synthesized accord-
ing to the literature procedures.8 Piperidine was used as the catalyst
for the preparation of the corresponding racemic products for HPLC
analysis. All the chiral secondary amine organic catalysts were
purchased from commercial sources such as Daicel Chiral Co.
(2S,3R,4R)-3-Benzyl-8-methoxy-2-phenyl-3,4-dihydro-2H-benzo-
[4,5]thiazolo[3,2-a]pyrimidin-4-ol (3d). White solid (78 mg, 97%
yield, DCM/MeOH = 100/1 as the eluent). mp 122.8−123.9 °C. 1H
NMR (400 MHz, CDCl3) δ 7.56 (t, J = 7.2 Hz, 2H), 7.48 (d, J = 7.2
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Hz, 2H), 7.38 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 7.2 Hz, 2H), 7.12 (t, J =
7.2 Hz, 1H), 6.95 (d, J = 7.2 Hz, 2H), 6.81 (d, J = 8.8 Hz, 1H), 6.67
(dd, J = 8.8, 0.8 Hz, 1H), 6.40 (s, 1H), 4.79 (s, 1H), 4.22 (d, J = 11.2
Hz, 1H), 3.74 (s, 3H), 2.07 (d, J = 12.0 Hz, 1H), 1.83 (t, J = 10.0 Hz,
1H), 1.62 (t, J = 12.0 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ
159.0, 155.6, 143.1, 139.3, 134.0, 129.3, 128.9, 128.4, 127.9, 126.1,
124.8, 111.1, 110.1, 107.6, 100.1, 74.5, 59.7, 56.0, 46.3, 32.9. HRMS
(ESI) m/z: [M + H]+ Calcd for C24H23N2O2S 403.1475; found
mL/min, λ = 254 nm, tR (minor) = 10.07 min, tR (major) = 30.17
min, >20:1 dr, 99% ee.
(2S,3R,4R)-3-Benzyl-2-(p-tolyl)-3,4-dihydro-2H-benzo[4,5]-
thiazolo[3,2-a]pyrimidin-4-ol (3i). White solid (72 mg, 94% yield,
DCM/MeOH = 100/1 as the eluent). mp 168.9−170.5 °C. 1H NMR
(400 MHz, CDCl3) δ 7.40 (dd, J = 15.6, 7.6 Hz, 4H), 7.20 (t, J = 7.2
Hz, 2H), 7.11 (dd, J = 15.2, 7.2 Hz, 2H), 7.00−6.86 (m, 4H), 6.76 (d,
J = 7.6 Hz, 1H), 4.83 (s, 1H), 4.22 (d, J = 11.2 Hz, 1H), 2.38 (s, 3H),
2.12 (d, J = 11.6 Hz, 1H), 1.86 (t, J = 11.6 Hz, 1H), 1.61 (t, J = 12.8
Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 158.7, 140.1, 139.8,
139.4, 137.4, 129.2, 129.1, 128.8, 128.4, 126.0, 125.8, 123.5, 122.1,
121.2, 109.8, 74.5, 59.6, 46.2, 32.9, 21.4. HRMS (ESI) m/z: [M + H]+
Calcd for C24H23N2OS 387.1526; found 387.1522. [α]20D +52° (c 1.0,
CH2Cl2). HPLC: Chiralpak AD-H column, n-hexane/i-PrOH = 88/
12, flow rate = 1.0 mL/min, λ = 254 nm, tR (minor) = 9.10 min, tR
(major) = 21.71 min, 6:1 dr, 95% ee.
D
403.1461. [α]20 +47° (c 1.0, CH2Cl2). HPLC: Chiralpak AD-H
column, n-hexane/i-PrOH = 88/12, flow rate = 1.0 mL/min, λ = 254
nm, tR (minor) = 11.66 min, tR (major) = 25.22 min, 19:1 dr, 98% ee.
(2S,3R,4R)-3-Benzyl-7-chloro-2-phenyl-3,4-dihydro-2H-benzo-
[4,5]thiazolo[3,2-a]pyrimidin-4-ol (3e). White solid (78 mg, 96%
yield, DCM/MeOH = 100/1 as the eluent). mp 115.6−116.6 °C. 1H
NMR (400 MHz, CDCl3) δ 7.60 (t, J = 7.2 Hz, 2H), 7.50 (d, J = 7.2
Hz, 2H), 7.41 (t, J = 7.2 Hz, 1H), 7.21 (t, J = 7.2 Hz, 2H), 7.18−7.10
(m, 1H), 6.85−6.75 (m, 4H), 6.69 (d, J = 8.8 Hz, 1H), 4.78 (d, J =
1.6 Hz, 1H), 4.21 (d, J = 11.2 Hz, 1H), 2.07 (d, J = 12.4 Hz, 1H),
1.85 (t, J = 11.6 Hz, 1H), 1.53 (t, J = 12.8 Hz, 1H). 13C{1H} NMR
(100 MHz, CDCl3) δ 158.7, 142.6, 140.8, 138.8, 132.3, 129.3, 128.8,
128.6, 128.2, 126.3, 122.2, 121.9, 121.6, 110.3, 74.7, 60.0, 46.3, 32.8.
HRMS (ESI) m/z: [M + H]+ Calcd for C23H20ClN2OS 407.0979;
found 407.0965. [α]20D +43° (c 1.0, CH2Cl2). HPLC: Chiralpak AD-
H column, n-hexane/i-PrOH = 88/12, flow rate = 1.0 mL/min, λ =
254 nm, tR (minor) = 7.62 min, tR (major) = 23.17 min, 6:1 dr, 99%
ee.
(2S,3R,4R)-3-Benzyl-2-(4-methoxyphenyl)-3,4-dihydro-2H-
benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ol (3j). White solid (75 mg,
93% yield, DCM/MeOH = 100/1 as the eluent). mp 152.8−154.1
°C. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.4 Hz, 2H), 7.20 (t, J
= 7.2 Hz, 2H), 7.15−7.05 (m, 4H), 7.01−6.87 (m, 4H), 6.76 (d, J =
7.2 Hz, 1H), 4.84 (s, 1H), 4.22 (d, J = 11.2 Hz, 1H), 3.81 (s, 3H),
2.14 (d, J = 12.0 Hz, 1H), 1.82 (t, J = 11.2 Hz, 1H), 1.68 (t, J = 12.4
Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.4, 158.8, 139.9,
139.3, 135.2, 129.8, 129.3, 128.4, 126.1, 125.9, 123.6, 122.1, 121.2,
113.8, 109.8, 74.5, 59.2, 55.6, 46.5, 33.0. HRMS (ESI) m/z: [M + H]+
D
Calcd for C24H23N2O2S 403.1475; found 403.1471. [α]20 +53° (c
(2S,3R,4R)-3-Benzyl-2-phenyl-3,4-dihydro-2H-benzo[4,5]-
oxazolo[3,2-a]pyrimidin-4-ol (3f). White solid (69 mg, 97% yield,
1.0, CH2Cl2). HPLC: Chiralpak AD-H column, n-hexane/i-PrOH =
88/12, flow rate = 1.0 mL/min, λ = 254 nm, tR (minor) = 12.55 min,
tR (major) = 33.21 min, 6:1 dr, 98% ee.
1
DCM/MeOH = 100/1 as the eluent). mp 91.3−94.3 °C. H NMR
(400 MHz, CDCl3) δ 8.50 (s, 1H), 7.56 (t, J = 7.2 Hz, 2H), 7.45−
7.37 (m, 3H), 7.19 (t, J = 7.2 Hz, 2H), 7.15−7.08 (m, 1H), 7.03 (t, J
= 7.6 Hz, 1H), 6.96 (d, J = 7.4 Hz, 2H), 6.91 (d, J = 7.6 Hz, 1H), 6.81
(t, J = 7.6 Hz, 1H), 5.53 (d, J = 7.6 Hz, 1H), 4.84 (s, 1H), 4.30 (d, J =
10.8 Hz, 1H), 2.04 (d, J = 12.4 Hz, 1H), 1.79 (t, J = 11.2 Hz, 1H),
1.72−1.59 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 154.4,
144.2, 142.9, 139.4, 131.8, 129.5, 128.9, 128.3, 127.9, 126.1, 123.3,
121.0, 109.3, 107.4, 74.4, 58.6, 47.1, 32.9. HRMS (ESI) m/z: [M +
H]+ Calcd for C23H21N2O2 357.1598; found 357.1595. [α]20D +71° (c
1.0, CH2Cl2). HPLC: Chiralpak AD-H column, n-hexane/i-PrOH =
88/12, flow rate = 1.0 mL/min, λ = 254 nm, tR (minor) = 10.87 min,
tR (major) = 30.00 min, >20:1 dr, 97% ee.
(2S,3R,4R)-3-Benzyl-2-(2-fluorophenyl)-3,4-dihydro-2H-benzo-
[4,5]thiazolo[3,2-a]pyrimidin-4-ol (3k). White solid (77 mg, 98%
yield, DCM/MeOH = 100/1 as the eluent). mp 125.2−131.5 °C. 1H
NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.40−7.30 (m, 2H), 7.23−
7.17 (m, 3H), 7.16−7.08 (m, 2H), 7.00−6.92 (m, 3H), 6.91−6.81
(m, 2H), 4.94 (s, 1H), 4.68 (s, 1H), 2.28 (d, J = 10.4 Hz, 1H), 2.21−
1.98 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 161.0 (C−F,
1JC−F = 245.0 Hz), 158.7, 139.6, 138.9, 130.6, 130.0, 129.3, 129.2,
2
128.4, 126.2, 125.9, 124.5, 123.4, 122.2, 121.3, 115.6 (C−F, JC−F
=
23.0 Hz), 109.7, 74.1, 54.6, 45.4, 33.0. 19F{1H} NMR (376 MHz,
CDCl3) δ −114.42. HRMS (ESI) m/z: [M + H]+ Calcd for
D
(2S,3R,4R)-3-Benzyl-2-(4-(trifluoromethyl)phenyl)-3,4-dihydro-
2H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ol (3g). White solid (87
mg, 99% yield, DCM/MeOH = 100/1 as the eluent). mp 123.0−
C23H20FN2OS 391.1275; found 391.1279. [α]20 +33° (c 1.0,
CH2Cl2). HPLC: Chiralpak AD-H column, n-hexane/i-PrOH = 88/
12, flow rate = 1.0 mL/min, λ = 254 nm, tR (minor) = 8.10 min, tR
(major) = 15.27 min, 7:1 dr, 97% ee.
1
123.7 °C. H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 2H),
7.52 (d, J = 8.0 Hz, 2H), 7.21 (t, J = 7.8 Hz, 2H), 7.17−7.13 (m, 2H),
6.97 (t, J = 7.6 Hz, 1H), 6.90 (t, J = 6.8 Hz, 3H), 6.82 (d, J = 7.6 Hz,
1H), 4.91 (d, J = 2.8 Hz, 1H), 4.25 (d, J = 11.2 Hz, 1H), 2.07 (d, J =
12.8 Hz, 1H), 1.91 (t, J = 11.6 Hz, 1H), 1.74 (t, J = 12.4 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3) δ 159.5, 147.1, 139.5, 138.1, 130.5
(2S,3R,4R)-3-Benzyl-2-(furan-2-yl)-3,4-dihydro-2H-benzo[4,5]-
thiazolo[3,2-a]pyrimidin-4-ol (3l). White solid (63 mg, 87% yield,
1
DCM/MeOH = 100/1 as the eluent). mp 99.4−100.8 °C. H NMR
(400 MHz, DMSO-d6) δ 7.60 (d, J = 0.8 Hz, 1H), 7.46 (dd, J = 7.6,
0.8 Hz, 1H), 7.28 (t, J = 7.2 Hz, 2H), 7.21−7.15 (m, 4H), 7.20−6.95
(m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.45−6.37 (m, 2H), 5.15 (dd, J =
6.4, 2.4 Hz, 1H), 4.58 (d, J = 11.6 Hz, 1H), 2.71−2.62 (m, 1H),
2.40−2.25 (m, 2H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 156.1,
155.3, 142.5, 139.5, 139.3, 129.3, 128.8, 126.5, 126.4, 122.6, 122.5,
122.0, 110.7, 109.1, 107.8, 73.3, 54.1, 42.0, 33.7. HRMS (ESI) m/z:
2
(C−F, JC−F = 32.0 Hz), 129.1, 129.1, 129.0, 128.6, 126.5, 126.2,
125.6,124.4 (C−F, 1JC−F = 242.0 Hz), 122.6, 121.4, 109.8, 74.3, 59.8,
45.9, 33.0. 19F{1H} NMR (376 MHz, CDCl3) δ −62.37. HRMS
(ESI) m/z: [M + H]+ Calcd for C24H20F3N2OS 441.1243; found
D
441.1224. [α]20 +56° (c 1.0, CH2Cl2). HPLC: Chiralpak AD-H
D
[M + H]+ Calcd for C21H19N2O2S 363.1162; found 363.1161. [α]20
column, n-hexane/i-PrOH = 88/12, flow rate = 1.0 mL/min, λ = 254
nm, tR (minor) = 7.20 min, tR (major) = 25.51 min, 8:1 dr, 99% ee.
(2S,3R,4R)-3-Benzyl-2-(4-chlorophenyl)-3,4-dihydro-2H-benzo-
[4,5]thiazolo[3,2-a]pyrimidin-4-ol (3h). White solid (75 mg, 92%
yield, DCM/MeOH = 100/1 as the eluent). mp 136.6−137.6 °C. 1H
NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.0
Hz, 2H), 7.23 (t, J = 7.2 Hz, 2H), 7.20−7.08 (m, 2H), 6.95 (t, J = 7.6
Hz, 3H), 6.90 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 4.88 (d, J
= 2.0 Hz, 1H), 4.19 (d, J = 11.2 Hz, 1H), 2.13 (d, J = 10.4 Hz, 1H),
1.85 (t, J = 11.6 Hz, 1H), 1.73 (t, J = 12.8 Hz, 1H). 13C{1H} NMR
(100 MHz, CDCl3) δ 159.3, 141.5, 139.6, 138.5, 133.8, 130.0, 129.1,
128.7, 128.6, 126.4, 126.1, 123.3, 122.4, 121.4, 109.8, 74.3, 59.4, 46.0,
33.0. HRMS (ESI) m/z: [M + H]+ Calcd for C23H20ClN2OS
+90° (c 1.0, CH2Cl2). HPLC: Chiralpak AD-H column, n-hexane/i-
PrOH = 85/15, flow rate = 1.0 mL/min, λ = 254 nm, tR (minor) =
7.35 min, tR (major) = 16.69 min, >20:1 dr, 94% ee.
(2S,3R,4R)-3-Benzyl-2-(thiophen-2-yl)-3,4-dihydro-2H-benzo-
[4,5]thiazolo[3,2-a]pyrimidin-4-ol (3m). White solid (63 mg, 84%
1
yield, DCM/MeOH = 100/1 as the eluent). mp 92.3−96.7 °C. H
NMR (400 MHz, CDCl3) δ 7.42 (d, J = 5.2 Hz, 1H), 7.35 (d, J = 2.8
Hz, 1H), 7.22 (d, J = 7.6 Hz, 2H), 7.19−7.09 (m, 3H), 7.06 (d, J =
7.2 Hz, 2H), 6.94 (t, J = 7.6 Hz, 2H), 6.75 (d, J = 8.0 Hz, 1H), 4.91
(d, J = 2.0 Hz, 1H), 4.72 (d, J = 11.2 Hz, 1H), 2.33 (d, J = 11.2 Hz,
1H), 2.01 (t, J = 11.6 Hz, 1H), 1.90 (t, J = 12.4 Hz, 1H). 13C{1H}
NMR (100 MHz, CDCl3) δ 159.0, 147.3, 139.7, 139.1, 129.4, 128.5,
126.6, 126.2, 126.1, 126.0, 125.2, 123.4, 122.3, 121.2, 110.0, 74.5,
56.3, 46.9, 33.2. HRMS (ESI) m/z: [M + H]+ Calcd for C21H19N2OS2
D
407.0979; found 407.0961. [α]20 +66° (c 1.0, CH2Cl2). HPLC:
Chiralpak AD-H column, n-hexane/i-PrOH = 88/12, flow rate = 1.0
1671
https://dx.doi.org/10.1021/acs.joc.0c02499
J. Org. Chem. 2021, 86, 1667−1675

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
D
379.0933; found 379.0926. [α]20 +30° (c 1.0, CH2Cl2). HPLC:
0.40 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 158.5, 143.1,
140.2, 128.7, 128.0, 127.4, 125.9, 123.7, 122.0, 121.3, 109.8, 75.2,
60.0, 43.4, 28.5, 26.5, 22.8, 14.0. HRMS (ESI) m/z: [M + H]+ Calcd
Chiralpak AD-H column, n-hexane/i-PrOH = 88/12, flow rate = 1.0
mL/min, λ = 254 nm, tR (minor) = 8.15 min, tR (major) = 22.74 min,
>20:1 dr, 99% ee.
D
for C20H23N2OS 339.1526; found 339.1522. [α]20 +31° (c 1.0,
(2S,3R,4R)-3-Benzyl-2-(pyridin-3-yl)-3,4-dihydro-2H-benzo[4,5]-
thiazolo[3,2-a]pyrimidin-4-ol (3n). White solid (64 mg, 86% yield,
DCM/MeOH = 100/2 as the eluent). mp 185.2−186.5 °C. 1H NMR
(400 MHz, DMSO-d6) δ 8.59 (d, J = 1.6 Hz, 1H), 8.50 (d, J = 4.8 Hz,
1H), 7.78 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.38 (dd, J =
8.0, 5.2 Hz, 1H), 7.26−7.21 (m, 2H), 7.20−7.13 (m, 2H), 7.12−7.05
(m, 3H), 7.01 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 5.12 (dd, J
= 6.4, 2.8 Hz, 1H), 4.53 (d, J = 11.6 Hz, 1H), 2.69 (dd, J = 13.6, 11.2
Hz, 1H), 2.35−2.25 (m, 1H), 2.21 (dd, J = 13.6, 3.6 Hz, 1H).
13C{1H} NMR (100 MHz, DMSO-d6) δ 155.6, 150.0, 148.8, 139.6,
CH2Cl2). HPLC: Chiralpak AD-H column, n-hexane/i-PrOH = 88/
12, flow rate = 1.0 mL/min, λ = 254 nm, tR (minor) = 7.76 min, tR
(major) = 15.12 min, 19:1 dr, 98% ee.
(2S,3R,4R)-3-Octyl-2-phenyl-3,4-dihydro-2H-benzo[4,5]thiazolo-
[3,2-a]pyrimidin-4-ol (3s). White solid (70 mg, 89% yield, DCM/
1
MeOH = 100/1 as the eluent). mp 112.8−113.9 °C. H NMR (400
MHz, CDCl3) δ 7.42 (t, J = 7.6 Hz, 2H), 7.34−7.25 (m, 3H), 7.19
(dd, J = 15.2, 7.6 Hz, 2H), 6.98 (t, J = 7.2 Hz, 1H), 6.79 (d, J = 7.6
Hz, 1H), 5.27 (d, J = 2.4 Hz, 1H), 3.98 (d, J = 11.6 Hz, 1H), 1.45 (t, J
= 10.8 Hz, 1H), 1.31−1.22 (m, 4H), 1.21−1.11 (m, 3H), 1.10−1.00
(m, 2H), 0.90−1.00 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H), 0.85−0.75 (m,
1H), 0.56 (t, J = 11.9 Hz, 1H), 0.48−0.35 (m, 1H). 13C{1H} NMR
(100 MHz, CDCl3) δ 158.6, 143.1, 140.2, 128.8, 128.0, 127.4, 125.9,
123.7, 122.0, 121.2, 109.8, 75.2, 59.9, 43.4, 31.9, 29.8, 29.5, 29.4, 26.7,
26.3, 22.8, 14.2. HRMS (ESI) m/z: [M + H]+ Calcd for C24H31N2OS
139.4, 139.2, 136.1, 129.3, 128.8, 126.5, 126.5, 123.9, 122.6, 122.5,
122.1, 109.1, 73.5, 58.2, 43.7, 33.7. HRMS (ESI) m/z: [M + H]+
D
Calcd for C22H20N3OS 374.1322; found 374.1319. [α]20 +102° (c
1.0, MeOH). HPLC: Chiralpak AD-H column, n-hexane/i-PrOH =
85/15, flow rate = 1.0 mL/min, λ = 254 nm, tR (minor) = 13.37 min,
tR (major) = 22.84 min, 17:1 dr, 97% ee.
D
395.2152; found 395.2147. [α]20 +37° (c 1.0, CH2Cl2). HPLC:
Chiralpak AD-H column, n-hexane/i-PrOH = 85/15, flow rate = 1.0
mL/min, λ = 254 nm, tR (minor) = 5.42 min, tR (major) = 8.35 min,
12:1 dr, 97% ee.
(2S,3R,4R)-3-Benzyl-2-(naphthalen-2-yl)-3,4-dihydro-2H-benzo-
[4,5]thiazolo[3,2-a]pyrimidin-4-ol (3o). White solid (82 mg, 98%
yield, DCM/MeOH = 100/1 as the eluent). mp 119.8−122.0 °C. 1H
NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.4
Hz, 1H), 7.95−7.83 (m, 2H), 7.64 (t, J = 7.2 Hz, 1H), 7.57 (d, J = 8.4
Hz, 1H), 7.48 (t, J = 7.2 Hz, 1H), 7.19−7.02 (m, 4H), 7.00−6.90 (m,
2H), 6.80 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 6.4 Hz, 2H), 4.88 (s, 1H),
4.49 (d, J = 11.2 Hz, 1H), 1.96−1.80 (m, 2H), 1.47 (t, J = 15.6 Hz,
1H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.2, 140.3, 139.9, 138.9,
133.3, 129.1, 128.3, 128.1, 128.0, 127.8, 126.7, 126.5, 126.2, 126.0,
126.0, 123.5, 122.2, 121.3, 109.8, 74.5, 60.0, 46.0, 32.9. HRMS (ESI)
m/z: [M + H]+ Calcd for C27H23N2OS 423.1526; found 423.1529.
(2S,3R,4R)-2,3-Diphenyl-3,4-dihydro-2H-benzo[4,5]thiazolo[3,2-
a]pyrimidin-4-ol (3t). White solid (58 mg, 81% yield, DCM/MeOH
1
= 100/1 as the eluent). mp 126.8−127.4 °C. H NMR (400 MHz,
DMSO-d6) δ 7.50 (dd, J = 7.6, 0.8 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H),
7.26−7.20 (m, 2H), 7.19−7.13 (m, 4H), 7.13−7.08 (m, 3H), 7.08−
7.01 (m, 3H), 6.89 (d, J = 6.4 Hz, 1H), 5.58 (dd, J = 6.4, 2.8 Hz, 1H),
5.03 (d, J = 12.4 Hz, 1H), 3.37 (dd, J = 12.4, 2.8 Hz, 1H). 13C{1H}
NMR (100 MHz, DMSO-d6) δ 154.5, 144.1, 139.8, 138.9, 130.7,
128.6, 128.1, 128.1, 126.9, 126.8, 126.4, 122.6, 122.4, 122.1, 109.4,
76.2, 59.1, 49.0. HRMS (ESI) m/z: [M + H]+ Calcd for C22H19N2OS
D
[α]20 +60° (c 1.0, CH2Cl2). HPLC: Chiralpak AD-H column, n-
D
359.1213; found 359.1197. [α]20 +59° (c 1.0, CH2Cl2). HPLC:
hexane/i-PrOH = 88/12, flow rate = 1.0 mL/min, λ = 254 nm, tR
(minor) = 11.56 min, tR (major) = 36.48 min, 6:1 dr, 98% ee.
(2S,3R,4R)-3-Methyl-2-phenyl-3,4-dihydro-2H-benzo[4,5]-
thiazolo[3,2-a]pyrimidin-4-ol (3p). White solid (49 mg, 83% yield,
DCM/MeOH = 100/1 as the eluent). mp 123.6−127.7 °C. 1H NMR
(400 MHz, CDCl3) δ 7.40 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.2 Hz,
1H), 7.25−7.15 (m, 4H), 7.01 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 5.2 Hz,
1H), 5.19 (s, 1H), 4.01 (d, J = 10.4 Hz, 1H), 1.64 (s, 1H), 0.38 (d, J =
4.4 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 158.7, 142.9,
140.0, 128.5, 128.1, 127.4, 126.0, 123.5, 122.1, 121.4, 109.6, 100.1,
60.3, 38.8, 13.0. HRMS (ESI) m/z: [M + H]+ Calcd for C17H17N2OS
Chiralpak AD-H column, n-hexane/i-PrOH = 88/12, flow rate = 1.0
mL/min, λ = 254 nm, tR (minor) = 17.16 min, tR (major) = 19.70
min, 4:1 dr, 94% ee.
(2S,3R,4R)-2-Phenyl-3-(pyridin-3-ylmethyl)-3,4-dihydro-2H-
benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ol (3u). White solid (67 mg,
90% yield, DCM/MeOH = 100/2 as the eluent). mp 95.6−108.6 °C.
1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 3.6 Hz, 1H), 8.20 (s, 1H),
7.56 (t, J = 8.0 Hz, 2H), 7.48 (d, J = 7.2 Hz, 2H), 7.39 (t, J = 7.2 Hz,
1H), 7.31 (d, J = 8.0 Hz, 1H), 7.18−7.06 (m, 2H), 6.95 (t, J = 7.6 Hz,
1H), 6.86 (dd, J = 16.4, 8.0 Hz, 2H), 4.85 (s, 1H), 4.29 (d, J = 11.2
Hz, 1H), 2.15−2.04 (m, 1H), 1.95−1.84 (m, 1H), 1.83−1.72 (m,
1H). 13C{1H} NMR (100 MHz, CDCl3) δ 158.8, 150.5, 147.6, 142.8,
139.6, 137.1 134.7 128.7, 128.6, 128.1 126.0, 123.5, 123.3, 122.4,
121.4, 109.6, 74.1, 60.0, 45.7, 30.5. HRMS (ESI) m/z: [M + H]+
Calcd for C22H20N3OS 374.1322; found 374.1320. [α]20D +50° (c 1.0,
CH2Cl2). HPLC: Chiralpak AD-H column, n-hexane/i-PrOH = 85/
15, flow rate = 1.0 mL/min, λ = 254 nm, tR (minor) = 9.97 min, tR
(major) = 31.30 min, 6:1 dr, 94% ee.
D
297.1056; found 297.1057. [α]20 +35° (c 1.0, CH2Cl2). HPLC:
Chiralpak AD-H column, n-hexane/i-PrOH = 85/15, flow rate = 1.0
mL/min, λ = 254 nm, tR (minor) = 7.97 min, tR (major) = 14.84 min,
5:1 dr, 94% ee.
(2S,3R,4R)-3-Ethyl-2-phenyl-3,4-dihydro-2H-benzo[4,5]thiazolo-
[3,2-a]pyrimidin-4-ol (3q). White solid (53 mg, 87% yield, DCM/
1
MeOH = 100/1 as the eluent). mp 151.4−153.1 °C. H NMR (500
MHz, CDCl3) δ 7.41 (t, J = 7.0 Hz, 2H), 7.30 (t, J = 7.0 Hz, 1H),
7.25−7.20 (m, 3H), 7.18 (d, J = 7.5 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H),
6.81 (t, J = 7.0 Hz, 1H), 5.31 (s, 1H), 3.99 (d, J = 11.5 Hz, 1H),
1.45−1.35 (m, 1H), 0.84−0.57 (m, 4H), 0.46 (dd, J = 11.0, 6.0 Hz,
1H). 13C{1H} NMR (125 MHz, CDCl3) δ 158.5, 143.1, 140.1, 128.7,
128.0, 127.3, 125.9, 123.6, 122.0, 121.3, 109.7, 74.8, 60.0, 45.0, 19.7,
10.9. HRMS (ESI) m/z: [M + H]+ Calcd for C18H19N2OS 311.1213;
found 311.1206. [α]20D +20° (c 1.0, CH2Cl2). HPLC: Chiralpak AD-
H column, n-hexane/i-PrOH = 88/12, flow rate = 1.0 mL/min, λ =
254 nm, tR (minor) = 10.40 min, tR (major) = 19.27 min, 19:1 dr,
91% ee.
(2S,3R,4R)-2-Phenyl-3-(thiophen-2-ylmethyl)-3,4-dihydro-2H-
benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ol (3v). White solid (70 mg,
92% yield, DCM/MeOH = 100/1 as the eluent). mp 96.6−100.3 °C.
1H NMR (400 MHz, CDCl3) δ 7.55 (t, J = 7.2 Hz, 2H), 7.48−7.35
(m, 3H), 7.16 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 5.2 Hz, 1H), 7.02−6.92
(m, 2H), 6.86 (dd, J = 4.8, 3.2 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.66
(s, 1H), 5.06 (s, 1H), 4.18 (d, J = 10.4 Hz, 1H), 2.21 (t, J = 11.2 Hz,
1H), 1.99−1.81 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.0,
142.5 141.2, 139.8 128.8 128.5, 128.0, 127.0, 126.1, 126.0, 123.7,
122.3 121.3, 109.8, 100.1, 74.5 59.6, 46.3 27.4. HRMS (ESI) m/z: [M
D
+ H]+ Calcd for C21H19N2OS2 379.0933; found 379.0928. [α]20
(2S,3R,4R)-3-Butyl-2-phenyl-3,4-dihydro-2H-benzo[4,5]thiazolo-
[3,2-a]pyrimidin-4-ol (3r). White solid (60 mg, 90% yield, DCM/
+72° (c 1.0, CH2Cl2). HPLC: Chiralpak AD-H column, n-hexane/i-
PrOH = 85/15, flow rate = 1.0 mL/min, λ = 254 nm, tR (minor) =
7.63 min, tR (major) = 19.16 min, 10:1 dr, 97% ee.
Procedure for the Synthesis of Product 3a′. To a 5 mL flame-
dried tube was added 3-phenylpropionaldehyde 2a (0.15 mmol, 1.5
equiv) in 1 mL of DCM into a mixture of 2-benzothiazolimine 1a
(0.10 mmol, 1.0 equiv), catalyst 4c (0.01 mmol, 10 mol %), and
1
MeOH = 100/1 as the eluent). mp 88.9−91.1 °C. H NMR (400
MHz, CDCl3) δ 7.41 (t, J = 7.2 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H),
7.26−7.20 (m, 3H), 7.19 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H),
6.80 (d, J = 7.6 Hz, 1H), 5.28 (s, 1H), 3.98 (d, J = 11.6 Hz, 1H), 1.45
(t, J = 10.8 Hz, 1H), 1.31−1.20 (m, 1H), 1.06−0.94 (m, 2H), 0.85−
0.74 (m, 1H), 0.71 (t, J = 7.2 Hz, 3H), 0.52−0.63 (m, 1H), 0.52−
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PhCOOH (0.01 mmol, 10 mol %). Then the reaction mixture was
stirred at room temperature. After completion of the reaction, 2 mL of
saturated NaHCO3 solution was added and extracted with DCM and
the combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The reaction mixture was
purified by flash column chromatography using DCM/MeOH as the
eluent to get the products.
(2S,3S,4R)-3-Benzyl-2-phenyl-3,4-dihydro-2H-benzo[4,5]-
thiazolo[3,2-a]pyrimidin-4-ol (3a′). White solid (22 mg, 60% yield,
DCM/MeOH = 100/1 as the eluent). mp 130.1−135.2 °C. 1H NMR
(500 MHz, CDCl3) δ 7.36−7.31 (m, 1H), 7.29−7.23 (m, 3H), 7.15−
7.06 (m, 3H), 7.04 (t, J = 7.0 Hz, 2H), 6.86−6.81 (m, 1H), 6.69 (s,
2H), 6.51 (s, 2H), 5.13 (s, 1H), 4.67 (s, 1H), 2.24 (d, J = 13.5 Hz,
1H), 2.05 (d, J = 8.5 Hz, 1H), 2.01−1.85 (m, 1H). 13C{1H} NMR
(125 MHz, CDCl3) δ 159.1, 141.0, 140.2, 139.4, 129.0, 128.5, 128.4,
127.9, 126.7, 126.3, 126.1, 123.4, 122.4, 121.4, 109.8, 76.6, 56.9, 45.5,
30.6. HRMS (ESI) m/z: [M + H]+ Calcd for C23H21N2OS 373.1369;
found 373.1357. [α]20D +30° (c 1.0, CH2Cl2). HPLC: Chiralpak AD-
H column, n-hexane/i-PrOH = 88/12, flow rate = 1.0 mL/min, λ =
254 nm, tR (minor) = 11.27 min, tR (major) = 12.97 min, 1:20 dr,
97% ee.
Procedure for the Synthesis of Product 5. To a 5 mL flame-
dried tube were added 3a (37 mg, 0.1 mmol) and Et3SiH (160 μL, 1.0
mmol) in DCE (1 mL), and then BF3·Et2O (253 μL, 2.0 mmol) was
slowly added at room temperature. Then the reaction mixture was
stirred at 80 °C in an oil bath for 6 h. After completion of the
reaction, saturated NaHCO3 solution was added until pH > 7 and
extracted with DCM and the combined organic layers were washed
with brine, dried over Na2SO4, filtered, and concentrated in vacuo.
The crude products were purified by flash column chromatography
(DCM/MeOH = 100/1) to give the product 5.
The crude products were purified by flash column chromatography
(DCM/MeOH = 100/1) to give the product 7.
(2S,3S,4R)-4-Allyl-3-benzyl-2-phenyl-3,4-dihydro-2H-benzo[4,5]-
thiazolo[3,2-a]pyrimidine (7). White solid (35 mg, 88% yield, DCM/
1
MeOH = 100/1 as the eluent). mp 132.8−134.9 °C. H NMR (400
MHz, CDCl3) δ 7.35 (d, J = 7.6 Hz, 1H), 7.33−7.28 (m, 4H), 7.26−
7.20 (m, 3H), 7.20−7.13 (m, 4H), 7.01 (t, J = 7.6 Hz, 1H), 6.57 (d, J
= 8.0 Hz, 1H), 5.30−5.18 (m, 1H), 4.84−4.81 (m, 2H), 4.26 (d, J =
17.2 Hz, 1H), 3.79 (dd, J = 10.8, 3.2 Hz, 1H), 3.00−2.86 (m, 1H),
2.77−2.70 (m, 2H), 2.16−2.06 (m, 1H), 2.14−1.60 (m, 1H).
13C{1H} NMR (100 MHz, CDCl3) δ 156.7, 144.2, 140.2, 139.6,
132.8, 129.4, 128.8, 128.4, 126.7, 126.7, 126.6, 126.0, 122.9, 122.1,
122.0, 118.9, 107.8, 60.8, 54.8, 41.3, 39.4, 35.4. HRMS (ESI) m/z: [M
+ H]+ Calcd for C26H25N2S 397.1733; found 397.1723. [α]20D − 4° (c
1.0, CH2Cl2). HPLC: Chiralpak AD-H column, n-hexane/i-PrOH =
88/12, flow rate = 1.0 mL/min, λ = 254 nm, tR (minor) = 11.27 min,
tR (major) = 20.93 min, 98% ee.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02499.
HPLC and NMR spectra and crystallographic data for
3h, 6, and 3a′ (PDF)
Accession Codes
CCDC 2033715−2033716 and 2048709 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(2S,3S)-3-Benzyl-2-phenyl-3,4-dihydro-2H-benzo[4,5]thiazolo-
[3,2-a]pyrimidine (5). White solid (28 mg, 78% yield, DCM/MeOH
1
= 100/1 as the eluent). mp 158.1−160.1 °C. H NMR (400 MHz,
CDCl3) δ 7.37−7.30 (m, 3H), 7.30−7.25 (m, 4H), 7.25−7.18 (m,
2H), 7.15 (td, J = 8.0, 1.2 Hz, 1H), 7.11−7.06 (m, 2H), 7.00 (td, J =
7.6, 0.8 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 4.54 (d, J = 5.6 Hz, 1H),
3.49−3.34 (m, 2H), 2.88 (dd, J = 13.6, 5.2 Hz, 1H), 2.52 (dd, J =
13.6, 10.0 Hz, 1H), 2.34−2.25 (m, 1H). 13C{1H} NMR (100 MHz,
CDCl3) δ 157.8, 143.8, 140.6, 139.2, 129.1, 128.8, 128.7, 127.2, 127.2,
126.6, 126.0, 122.8, 122.0, 122.0, 107.6, 64.0, 43.0, 38.9, 38.0. HRMS
(ESI) m/z: [M + H]+ Calcd for C23H21N2S 357.1420; found
AUTHOR INFORMATION
Corresponding Author
■
Xiao-Feng Xiong − Guangdong Provincial Key Laboratory of
Chiral Molecules and Drug Discovery, School of
Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou
510006, China; orcid.org/0000-0001-7868-8448;
Email: xiongxf7@mail.sysu.edu.cn
D
357.1406. [α]20 +74° (c 1.0, CH2Cl2). HPLC: Chiralpak AD-H
column, n-hexane/i-PrOH = 88/12, flow rate = 1.0 mL/min, λ = 254
nm, tR (minor) = 20.62 min, tR (major) = 34.48 min, 99% ee.
Procedure for the Synthesis of Product 6. To a 5 mL flame-
dried tube was added 5 (35 mg, 0.1 mmol) in DCE (1 mL), and
fluoroboric acid (18 mg, 0.2 mmol) was slowly added at room
temperature for 2 h. After completion of the reaction. The crude
products were purified by flash column chromatography (DCM/
MeOH = 100/2) to give the product 6.
Authors
Xue-Ping Chen − Guangdong Provincial Key Laboratory of
Chiral Molecules and Drug Discovery, School of
Pharmaceutical Sciences, Sun Yat-Sen University,
Guangzhou 510006, China
Ke-Qiang Hou − Guangdong Provincial Key Laboratory of
Chiral Molecules and Drug Discovery, School of
Pharmaceutical Sciences, Sun Yat-Sen University,
Guangzhou 510006, China; orcid.org/0000-0001-6640-
9771
Feng Zhou − Guangdong Provincial Key Laboratory of Chiral
Molecules and Drug Discovery, School of Pharmaceutical
Sciences, Sun Yat-Sen University, Guangzhou 510006, China
Albert S. C. Chan − Guangdong Provincial Key Laboratory of
Chiral Molecules and Drug Discovery, School of
Pharmaceutical Sciences, Sun Yat-Sen University,
Guangzhou 510006, China; orcid.org/0000-0003-1583-
8503
(2S,3S)-3-Benzyl-2-phenyl-1,2,3,4-tetrahydrobenzo[4,5]thiazolo-
[3,2-a]pyrimidin-5-ium Tetrafluoroborate (6). White solid (40 mg,
91% yield, DCM/MeOH = 100/2 as the eluent). mp 160.2−162.1
1
°C. H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.2 Hz, 1H), 7.43−
7.37 (m, 1H), 7.35−7.27 (m, 4H), 7.25−7.16 (m, 6H), 7.09 (d, J =
6.8 Hz, 2H), 4.75 (d, J = 6.0 Hz, 1H), 4.04 (dd, J = 12.8, 6.4 Hz, 1H),
3.77 (dd, J = 12.8, 4.0 Hz, 1H), 2.75−2.65 (m, 1H), 2.65−2.48 (m,
2H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.0, 138.0, 137.5, 137.2,
129.3, 129.1, 129.0, 129.0, 128.2, 127.1, 126.8, 126.0, 123.0, 122.2,
112.2, 59.5, 45.0, 38.1, 35.9. HRMS (ESI) m/z: [M + H]+ Calcd for
C23H21N2S 357.1420; found 357.1424.
Procedure for the Synthesis of Product 7. To a 5 mL flame-
dried tube were added 3a (37 mg, 0.1 mmol) and allyl-trimethylsilane
(158 μL, 1.0 mmol) in DCE (1 mL), and then BF3·Et2O (253 μL, 2.0
mmol) was slowly added at room temperature. Then the reaction
mixture was stirred at 80 °C in an oil bath for 6 h. After completion of
the reaction, saturated NaHCO3 solution was added until pH > 7 and
extracted with DCM and the combined organic layers were washed
with brine, dried over Na2SO4, filtered, and concentrated in vacuo.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02499
Notes
The authors declare no competing financial interest.
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Article
(6) Ni, Q.; Song, X.; Xiong, J.; Raabe, G.; Enders, D. Regio- and
Stereoselective Synthesis of Benzothiazolo-pyrimidinones via an
NHC-Catalyzed Mannich/lactamization Domino Reaction. Chem.
Commun. 2015, 51, 1263−1266.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support by Guangdong
Natural Science Funds for Distinguished Young Scholar (no.
2018B030306017), Guangdong Province Universities and
Colleges Pearl River Scholar Funded Scheme (2018), The
Fundamental Research Funds for the Central Universities
(20ykzd15), Key-Area Research and Development Program of
Guangdong Province (2020B1111110003), and Key Lab of
Advanced Drug Preparation Technologies, Ministry of
Education of China (ZKF202002).
̌
(7) Jarrige, L.; Glavac, D.; Levitre, G.; Retailleau, P.; Bernadat, G.;
Neuville, L.; Masson, G. Chiral Phosphoric Acid-Catalyzed
Enantioselective Construction of Structurally Diverse Benzothiazolo-
pyrimidines. Chem. Sci. 2019, 10, 3765−3769.
(8) Ni, Q.; Wang, X.; Xu, F.; Chen, X.; Song, X. Organocatalytic
Asymmetric [4 + 2] Cyclization of 2-Benzothiazolimines with
Azlactones: Access to Chiral Benzothiazolopyrimidine Derivatives.
Chem. Commun. 2020, 56, 3155−3158.
(9) Lu, D.; Wu, J. H.; Pan, J.; Chen, X.; Ren, X.; Wang, T.
Asymmetric Synthesis of Benzothiazolopyrimidines with High
Catalytic Efficiency and Stereoselectivity under Bifunctional Phos-
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(10) For selected reviews, see: (a) Cheng, D. J.; Shao, Y. D.
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