Peroxides as "switches" of dialkyl H-phosphonate: Two mild and metal-free methods for preparation of 2-acylbenzothiazoles and dialkyl benzothiazol-2-ylphosphonates

Article abstract of DOI:10.1021/jo501791n

Two mild and metal-free methods for the preparation of two kinds of important benzothiazole derivatives, 2-acylbenzothiazoles and dialkyl benzothiazol-2-ylphosphonates, respectively, were developed. The dialkyl H-phosphonate (RO)₂P(O)H exists i

Full text of DOI:10.1021/jo501791n

Article
pubs.acs.org/joc
Peroxides as “Switches” of Dialkyl H‑Phosphonate: Two Mild and
Metal-Free Methods for Preparation of 2‑Acylbenzothiazoles and
Dialkyl Benzothiazol-2-ylphosphonates
Xiao-Lan Chen,*,† Xu Li,† Ling-Bo Qu,*,†,‡ Yu-Chun Tang,† Wen-Peng Mai,‡ Dong-Hui Wei,†
Wen-Zhu Bi,† Li-Kun Duan,† Kai Sun,† Jian-Yu Chen,† Dian-Dian Ke,† and Yu-Fen Zhao†,§
†College of Chemistry and Molecular Engineering, Zhengzhou University, Henan Province Zhengzhou, 450052, People’s Republic of
China
‡Chemistry and Chemical Engineering School, Henan University of Technology, Henan Province Zhengzhou 450052, People’s
Republic of China
§Department of Chemistry, Xiamen University, Xiamen 361005, People’s Republic of China
S
* Supporting Information
ABSTRACT: Two mild and metal-free methods for the preparation of two kinds of important benzothiazole derivatives, 2-
acylbenzothiazoles and dialkyl benzothiazol-2-ylphosphonates, respectively, were developed. The dialkyl H-phosphonate
(RO)2P(O)H exists in equilibrium with its tautomer dialkyl phosphite (RO)2POH. TBHP triggered α-carbon-centered
phosphite radical formation, whereas DTBP triggered phosphorus-centered phosphonate radical formation. The two types of
radicals led respectively to two different reaction processes, the direct C2-acylation of benzothiazoles and C2-phosphonation of
benzothiazoles.
INTRODUCTION
■
The importance of phosphorus compounds in organic
synthesis,1−3 materials,4 and medicinal chemistry5 has been
well documented for years. The dialkyl H-phosphonates occupy
a major position in organophosphorus chemistry, since they are
frequent intermediates in the synthesis of a variety of bioactive
products including aminophos-phosphonates, aminophos-
phonic acids, P−C phosphonates, hydroxyalkyl phosphonates,
amidophosphates, nucleoside H-phosphonates, poly(alkylene
H-phosphonates) and poly(alkylene phosphates), phosphorus-
containing polyesters, etc.6 The property that is most important
from the point of view of synthetic applications is the
tautomeric equilibrium between their phosphite and phospho-
nate forms: the tricoordinated phosphorus(III) form and the
tetracoordinated phosphorus(V) form (Figure 1). The strongly
polar character of the phosphoryl group of the H-phosphonates
is responsible to a great extent for the reactivity of this class of
compounds. The versatility of these compounds is determined
by the presence of two types of reaction centers in their
molecule: the phosphorus atom and the α-carbon atom of the
alkoxy groups.6g Herein, we wish to disclose a very new aspect
of H-phosphonate chemistry, which, due to “flexbility”, makes
dialkyl phosphites unexpectedly efficient synthetic precursors in
preparing two kinds of important benzothiazole derivatives, 2-
Figure 1. Tautomerization leading to different products.
acylbenzothiazoles and dialkyl benzothiazol-2-ylphosphonates
(Figure 1), respectively.
RESULTS AND DISCUSSION
■
As it is well-known that the parent compound benzothiazole is
not widely used, many of its derivatives are found in
commercial products or in nature and exhibit significant
biological and pharmacological activities.7 As derivatives of
benzothiazole, 2-acylbenzothiazoles have attracted considerable
attention due to their increasing applications in medical
Received: August 4, 2014
© XXXX American Chemical Society
A
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Scheme 1. Comparison of Previous Works with This Work
a
fields.8−16 It is especially worth noting that only a few methods
aiming to synthesize 2-acylbenzothiazoles with benzothiazoles
as starting materials have been developed. However, most
previous methods suffer from harsh conditions and metal salts.
For example, with both benzothiazoles and acyl chlorides as
starting materials, Koskinen et al. (Scheme 1, pathway A)
employed n-BuLi to activate the C2−H covalent bond of
benzothiazole at very low temperature, and meanwhile ZnCl2
and CuI were necessarily employed to form an active metal-
containing intermediate in the reaction process.17,18 Knochel’s
group carried out their reaction at relatively low temperature
(Scheme 1, pathway B) by employing the complicated catalyst
tmp3·La·MgCl2·5LiCl (tmp = 2,2,6,6-tetramethylpiperid) to
activate the C2−H bond.19 Ablordeppey’s group carried out a
method in 2012 (Scheme 1, pathway C) using esters instead of
unstable acyl chlorides as acylating agents; n-BuLi was still
needed to activate the C2−H bond at very low temperature,
and in addition, only a limited number of esters were tested.11
Wu’s group very recently developed a novel method to
synthesize 2-acylbenzothiazoles from benzothiazoles and aryl
ketones. However, it is worth noting that only aryl
benzothiazoyl ketones, not alkyl benzothiazoyl ketones, were
obtained via this method (Scheme 1, pathway D).20 In contrast,
we disclose herein a mild and metal-free approach, through
which a large variety of alkyl benzothiazoyl ketones was
synthesized (Scheme. 1).
Table 1. Optimization of the Reaction Conditions
amt of TBHP
(mmol)
amt of 2a
(mmol)
yield
b
entry
T(°C)
solvent
(%)
1
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
5
5
40
60
80
100
120
80
80
80
80
80
80
80
80
80
80
80
80
0
35
61
54
43
35
24
28
31
64
83
33
61
83
68
83
51
2
3
5
4
5
5
5
6
5
DMSO
DMF
7
5
8
5
toluene
CH2Cl2
acetone
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
5
10
11
12
13
14
15
16
17
5
5
1
3
10
5
15
10
5
5
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0−10.0 mmol), TBHP
(5.0−15.0 mmol), solvent (2.0 mL) for 24 h. Isolated yields.
b
It is well-known that both tert-butyl hydroperoxide (TBHP)
and di-tert-butyl peroxide (DTBP) are commonly used as
radical initiators in organic synthesis and polymer chemistry.
We initiated this unprecedented study, starting with establish-
ing optimal experimental conditions in the presence of TBHP.
The screening results are summarized in Table 1. The influence
of temperature on the model reaction was first investigated
under solvent-free conditions (Table 1, entries 1−5). No
reaction occurred when the reaction temperature was below 40
°C. The yield was increased over the temperature range of 60−
80 °C, from 35% to 61%, and then decreased to 54% when the
temperature reached 100 °C. The effect of solvents was also
investigated (Table 1, entries 6−11). A relatively higher yield of
3a was obtained when acetonitrile was used as a solvent (83%)
(Table 1, entry 11). Other solvents resulted in lower yields of
3a: i.e. DMSO (35%), DMF (24%), toluene (28%), CH2Cl2
(31%), and acetone (64%) (Table 1, entries 6−10). The
optimal amount of 2a and TBHP was also explored (Table 1,
entries 11−17). The amount of 2a and TBHP shown in entry
11 still brought about the most satisfied yield.
The substrate scope of benzothiazoles and dialkyl phosphites
under the optimized reaction conditions was then examined
(Table 2). All of the dialkyl phosphites reacted well with
benzothiazole, giving the resulting 2-acylbenzothiazoles in
moderate to good yields from 69% to 83% (3a−f). It is
worth noting that the yield slightly decreased with the length of
B
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a
Table 2. Scope of Benzothiazoles and Alkyl Phosphonates
a
Reaction conditions: 1 (1.0 mmol), 2 (5.0 mmol), TBHP (10.0 mmol) in CH3CN (2.0 mL) at 80 °C for 24 h. The isolated yields are provided.
The scarcely formed 3y,z were detected by ESI/MS(+). 3aa,ab were detected by TLC.
the straight carbon chain of the corresponding dialkyl
phosphites, from 83% to 69% in the case of 3a−d. In
comparison with the straight-chain alkyl phosphites, two
branched dialkyl phosphites, diisopropyl and diisobutyl
phosphites, slightly enhanced the acylation reactivity, affording
3e,f in 78% and 74% yields, respectively. Furthermore,
benzothiazoles bearing electron-donating and electron-with-
drawing substituents (CH3, Br, Cl, OCH3, and NO2) were also
employed to react with dialkyl phosphites. Benzothiazoles
bearing methyl and methoxyl substituents gave higher yields
(3p−w) in comparison with nonsubstituted benzothiazole
(3a−f). Introducing a bromo or chloro group, weakly electron
withdrawing groups, on the benzothiazole ring slightly
weakened the acylation reactivity, giving the resulting 2-
acylbenzothiazoles in moderate to good yields from 66% to
73% (3g−o). Introducing a nitro group, a very strongly
electron withdrawing group, seriously slowed the reaction,
affording 3x in a medium yield (51%) and traces of products
3y,z. It is worth mentioning that thiazole and benzoxazole did
not progress well under the optimized reaction conditions
(3aa,ab). It is concluded that, in most cases, the representative
benzothiazoles and dialkyl phosphites reacted smoothly to
afford the desired products under the optimal reaction
conditions.
A plausible mechanism for the acylation reaction is proposed
in pathway I of Scheme 2. Diethyl phosphite has the tautomeric
forms phosphonate 2a and phosphite 3′a.21 TBHP initially
cleaved into tert-butoxy radical as well as hydroxyl radical,
which subsequently triggered hydrogen atom abstraction from
the 2-position sp2 C−H of benzothiazole 1a and the α-position
sp3 C−H bond of tautomer 3′a, respectively, forming the
corresponding radical 1a′22 and α-carbon-centered radical 3′a′.
Carbon−carbon bond formation via termination of two radicals
afforded the cross-coupling product 3, which further lost the
remaining α-hydrogen of 3, forming the tertiary radical 4. The
hydroxyl radical then coupled with 4 to form the tetrahedral
intermediate 5, immediately followed by an energetically
favorable elimination, leading to the final product 3a along
with ethyl hydrogen phosphonate 6 or 7. It is especially worth
noting that it is the α-carbon-centered radical 3′a′ formed by
hydrogen abstraction from the α-position sp3 C−H bond of
tautomer 3′a′ that led the reaction way to the final 2-
acylbenzothiazole 3a. 31P NMR traced the progress of the
reactions. The essentially related phosphorus-containing
compounds 3′a, 3, and 6 or 723 were all well tracked in proper
sequence, as shown in Figure 2. This 31P NMR stacks diagram
strongly backed the mechanism proposed.
More synthetic experiments were subsequently designed and
carried out to deepen the related mechanism studies. In order
C
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Scheme 2. Proposed Reaction Mechanisms of Benzothiazole with Diethyl Phosphite and TBHP (Pathway I) and with Diethyl
Phosphite and DTBP (Pathway II), Respectively
Figure 2. 31P NMR stacks diagram for Scheme 2 (pathway I). Reaction conditions: benzothiazole (1a; 1.0 mmol), diethyl phosphite (2a; 5.0 mmol),
and TBHP (10.0 mmol) under neat condtions at 80 °C for 12 h. The whole process was monitored by 31P NMR every 1.5 h (comp-2a, 8.0 ppm;
comp-3, 5.1 ppm; comp-7, 3.3 ppm).
to prove that the carbonyl oxygen of 3a was from TBHP rather
than from water or oxygen in the air, the reaction was carried
out under anhydrous conditions and nitrogen protection, using
the same amount of TBHP in anhydrous solution (Scheme 3I).
Once again, 3a was effectively obtained. It is especially worth
mentioning here that the hydroxyl radical, generated by
homolytic cleavage of TBHP, was indispensable for the
formation of intermediate 5 on the way to the final 2-
acylbenzothiazole 3a. It is reasonable to believe that hydrogen
peroxide (H2O2), another hydroxyl radical generator, might
also be employed for the synthesis of the α-acylbenzothiazoles,
whereas di-tert-butyl peroxide (DTBP), generating only tert-
butoxyl radicals, might otherwise lead to some other products
rather than 2-acylbenzothiazoles. The reactions shown in
Scheme 3 were carried out to examine the mechanism.
Under the optimized reaction conditions, 2-acylbenzothiazole
(3a) was prepared in 60% yield from diethyl phosphite (2a)
and benzothiazole (1a) using H2O2 as radical initiator (Scheme
3II), whereas, as shown in Scheme 3III, treatment of
benzothiazole (1a) and diethyl phosphite (2a) with DTBP
resulted accidentally in diethyl benzothiazol-2-ylphosphonate
(8a) in 70% yield. It is well-known that aryl phospsphonates
and their derivatives have found a wide range of applications in
medicinal chemistry, catalysis, and organic synthesis.24 It is
notable that the direct phosphonation of benzothiazoles with
dialkyl phosphites has been developed very recently by Li’s
group. However, under argon protection, palladium acetate
Pd(OAc)2, a metal salt, was still catalytically required along
with a nitrogen-containing ligand for the phosphonation to
occur.25 The relatively simple synthetic method shown in
Scheme 3III foreboded a novel, green, and metal-free approach
possibly leading to a variety of benzothiazol-2-ylphosphonates.
D
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in Scheme 2, pathway II. It is worth mentioning that Yang’s
research group has demonstrated that, catalyzed by AgNO3,
phosphorus-centered radicals were formed in the process of the
carbon phosphorylation reactions of alkenes with diphenyl-
phosphine oxide Ph2P(O)H or H-phosphonates (RO)2P(O)-
H.26 It can be seen here from pathway II that after two tert-
butoxy radicals were generated from a hemolytic cleavage of
DTBP, the tert-butoxy radical underwent hydrogen atom
abstraction from the P−H bond of tautomer 2a, rather than
a hydrogen atom abstraction from the α-position sp3 C−H
bond of tautomer 3′a as in the case of pathway I, actually
forming the phosphorus-centered radical 2a′. Meanwhile, the
tert-butoxy radical underwent hydrogen atom abstraction of the
2-position sp2 C−H of benzothiazole 1a, forming 1a′. Finally,
carbon−phosphorus bond formation via termination of two
radicals afforded diethyl benzothiazol-2-ylphosphonate (8a).
Single-crystal X-ray diffraction was successfully conducted to
confirm the proposed structures of 3k and 8i (Scheme 4).27
The two types of radicals, α-carbon-centered phosphite
radical 3′a′ and phosphorus-centered phosphonate radical 2a′,
played very different roles in determining in which path the
chemical reaction would proceed through. In order to
understand the reason the α-carbon-centered phosphite radical
3′a′ was formed in the presence of TBHP or H2O2, whereas the
phosphorus-centered phosphonate radical 2a′ was formed in
the presence of TDBP (Scheme 2), four possible pathways
(pathways a−d) have been theoretically investigated using
density functional theory (DFT). As shown in Scheme 5, the
Scheme 3. Proposed Reaction of Benzothiazole and Dialkyl
Phosphite with Different Peroxides
a
a
Isolated yields are provided. Reaction conditions: (a) 1a (1.0 mmol),
2a (5.0 mmol), TBHP (10.0 mmol, 5−6 M in decane) in anhydrous
CH3CN (2.0 mL) at 80 °C under N2 protection for 24 h; (b) 1a (1.0
mmol), 2a (5.0 mmol), H2O2 (10.0 mmol) in CH3CN (2.0 mL) at 80
°C for 24 h; (c) 1a (1.0 mmol), 2a (5.0 mmol), DTBP (10.0 mmol) in
CH3CN (2.0 mL) at 80 °C for 24 h.
Using DTBP as radical initiator, the substrate scope of
representative benzothiazoles, including those bearing elec-
tron-donating and electron-withdrawing groups (CH3, Br, Cl,
and OCH3), and dialkyl phosphites was subsequently extended
(Table 3). All of the corresponding reactions went smoothly,
giving the resulting dialkyl benzothiazol-2-ylphosphonates 8a−
u in moderate to good yields from 63% to 85%. A plausible
mechanism concerning the novel synthetic method is proposed
a
Table 3. Scope of Dialkyl Benzothiazol-2-yl Phosphonates
a
Reaction condition: 1 (1.0 mmol), 2 (5.0 mmol), DTBP (10.0 mmol) in CH3CN (2.0 mL) at 80 °C for 30 h. Isolated yield provided.
E
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Scheme 4. Single-Crystal X-ray Structures of 3k and 8i
Scheme 6. C−C Coupling Reaction with Diisopropyl
a
Phosphonate and Benzothiazole
a
Reaction condition: 1a (1.0 mmol), 2d (5.0 mmol), TBHP (10.0
mmol) in CH3CN (2.0 mL) at 80 °C for 24 h.
Scheme 7. Proposed Reaction Mechanism of Benzothiazole
with Diisopropyl Phosphite and TBHP (Pathway III)
free energy barriers of pathways a−d are 12.58, 15.87, 7.11, and
3.69 kcal/mol, indicating that radical 2a′ can be generated
easily in the absence of the OH radical, and radical 3′a′ can be
generated much more easily in the presence of the OH radical,
which is in good agreement with our experimental results.
One more synthetic experiment was subsequently designed
for further deepening our understanding of the related
mechanisms. It is worth emphasizing that it is one secondary
α-carbon of diethyl phosphite that finally was transferred into
the carbonyl carbon of 3a, suggesting that only secondary α-
carbon containing dialkyl phosphites can possibly be employed
for preparation of 2-acylbenzothiazoles. Scheme 6 illustrates
what happened to the reaction in the case when diisopropyl
phosphite, a tertiary α-carbon containing dialkyl phosphite, was
employed. 7d, a benzothiazole-containing ether, was obtained
in that case. A related mechanism is proposed in Scheme 7
(pathway III). Again, TBHP cleaved to tert-butoxy radical and
hydroxyl radical. Accordingly, α-carbon-centered phosphite
radical 3′d′ was generated much more easily in the presence
of the OH radical. Again, benzothiazole 1a underwent
hydrogen atom abstraction, forming the radical 1a′. Carbon−
carbon bond formation via termination of the two radicals 1a′
and 3′d′ afforded the cross-coupling product 3d. An SN1
reaction was then followed, which proceeded initially with a
heterolytic cleavage of 3d, forming the monoisopropyl
phosphite 5d (d′) and the tertiary carbocation 4d. Acting as
a nucleophile, the tert-butyl alcohol formed in the reaction
subsequently reacted with 4d to give rise to the protonated
ether 6d, which was subsequently deprotonated to the final
product 7d. The synthetic experiment testified again how
Scheme 5. Four Possible Proton Transfer Pathways and the Corresponding Free Energy Barriers
F
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166.6, 195.6; HRMS (ESI) calcd for C13H15NOS [M + H]+, 234.0947,
found 234.0954.
TBHP regioselectively affected the formation of the radical
intermediates.
1-(Benzo[d]thiazol-2-yl)-2-methylpropan-1-one (3e): yellow
1
liquid (0.160 g, 78% yield); H NMR (400 MHz, CDCl3) δ 1.33 (d,
CONCLUSION
■
J = 6.9 Hz, 6H), 3.98 (m, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 7.2
Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 8.18(d, J = 8.1 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 18.7, 36.3, 122.4, 125.4, 126.9, 127.6, 137.3,
153.6, 166.0, 199.2; HRMS (ESI) calcd for C11H11NOS [M + H]+,
206.0634, found 206.0639.
In conclusion, two mild and metal-free methods, for the
preparation of two kinds of important benzothiazole deriva-
tives, 2-acylbenzothiazoles and dialkyl benzothiazol-2-ylphosph-
onates, were respectively developed. The TBHP triggered
carbon-centered phosphite radical formation, whereas DTBP
triggered phosphorus-centered phosphonate radical formation.
The two types of radicals played very different roles in
determining in which path the chemical reaction would proceed
through. The direct C2-acylation of benzothiazoles was realized
by the reaction of benzothiazoles with secondary α-carbon
containing dialkyl phosphites in the presence of TBHP,
whereas the direct C2-phosphonation of benzothiazoles was
realized by the reaction of benzothiazoles with dialkyl
phosphites, in the presence of DTBP. The work disclosed a
very new aspect of H-phosphonate chemistry, which, due to
“flexibility”, makes H-dialkyl phosphonates unexpectedly
efficient synthetic precursors in the preparation of the two
types of very important benzothiazole derivatives.
1-(Benzo[d]thiazol-2-yl)-3-methylbutan-1-one (3f): yellow liquid
1
(0.162 g, 74% yield); H NMR (400 MHz, CDCl3) δ 1.05 (d, J = 6.7
Hz, 6H), 2.40 (m, 1H), 3.15 (d, J = 7.0 Hz, 2H), 7.50 (t, J = 7.8 Hz,
1H), 7.56 (t, J = 7.4 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 8.18 (d, J = 8.2
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 22.7, 25.1, 47.2, 122.4,
125.4, 126.9, 127.6, 137.3, 153.6, 166.9, 195.2; HRMS (ESI) calcd for
C12H13NOS [M + H]+, 220.0791, found 220.0798.
1-(6-Bromobenzo[d]thiazol-2-yl)ethanone (3g): white solid
(0.182 g, 71% yield); mp 150−153 °C; 1H NMR (400 MHz,
CDCl3) δ 2.81 (s, 3H), 7.66 (dd, J = 8.8 Hz, 1H), 8.01 (d, J = 8.8 Hz,
1H), 8.10 (d, J = 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 26.1,
121.9, 125.0, 126.5, 130.7, 138.9, 152.3, 166.9, 192.8; HRMS (ESI)
calcd for C9H6BrNOS [M + H]+, 255.9426, found 255.9426.
1-(6-Bromobenzo[d]thiazol-2-yl)propan-1-one (3h): yellow solid
(0.195 g, 72% yield); mp 104−106 °C; 1H NMR (400 MHz, CDCl3)
δ 1.29 (t, J = 7.2 Hz, 3H), 3.27(q, J = 7.3 Hz, 2H), 7.65 (d, J = 8.7 Hz,
1H, 5-H), 8.00 (d, J = 8.7 Hz, 1H), 8.10 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 7.8, 32.1, 121.8, 125.0, 126.4, 130.6, 138.7, 152.4, 166.7,
195.6; HRMS (ESI) calcd for C10H8BrNOS [M + H]+, 269.9583,
found 269.9585.
EXPERIMENTAL SECTION
■
General Information. All commercial reagents and solvents were
used without further purification. 1H and 13C NMR spectra were
recorded in CDCl3 with tetramethylsilane (TMS) as the internal
standard, and 31P NMR spectra were obtained in CDCl3 with H3PO4
as the internal standard. High-resolution mass spectra (HRMS) were
obtained on a Q-TOF mass spectrometer. Column chromatography
was carried out with columns of silica gel (200−300 mesh).
Experimental Procedures for the Synthesis of 2-Acylbenzo-
thiazoles (3a−3ab). A mixture of benzothiazole (135.0 mg, 1.0
mmol), phosphonate (5.0 mmol), and TBHP (10.0 mmol) in CH3CN
(2.0 mL) was stirred at 80 °C for 24 h. The reaction mixture was
quenched with water (5.0 mL) and extracted with ethyl acetate (3 ×
5.0 mL). The combined organic layers were washed with brine (15.0
mL) and dried over anhydrous MgSO4. After filtration, the solvent was
evaporated in vacuo. The crude product was purified by silica gel
chromatography (petroleum ether/ethyl acetate 20/1) to give the
desired product.
1-(6-Bromobenzo[d]thiazol-2-yl)butan-1-one (3i): yellow solid
1
(0.193 g, 68% yield); mp 97−101 °C; H NMR (400 MHz, CDCl3)
δ 1.05 (t, J = 7.4 Hz, 3H), 1.84 (m, 2H), 3.23 (t, J = 7.3 Hz, 2H), 7.66
(dd, J = 8.8, 2.0 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 1.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 13.8, 17.5, 40.5, 121.8, 125.0,
126.4, 130.7, 138.8, 152.4, 167.0, 195.2; HRMS (ESI) calcd for
C11H10BrNOS [M + H]+, 283.9739, found 283.9744.
1-(6-Bromobenzo[d]thiazol-2-yl)hexan-1-one (3j): white solid
1
(0.206 g, 66% yield); mp 89−91 °C; H NMR (400 MHz, CDCl3)
δ 0.92 (t, J = 7.2 Hz, 3H), 1.39 (m, 4H), 1.81 (m, 2H), 3.24 (t, J = 7.5
Hz, 2H), 7.67 (dd, J = 8.8, 1.9 Hz, 1H, 5-H), 8.06 (d, J = 8.8 Hz, 1H,
4-H), 8.12 (d, J = 1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.9,
22.4, 23.6, 31.3, 38.6, 121.8, 125.0, 126.5, 130.7, 138.8, 152.4, 167.1,
195.4; HRMS (ESI) calcd for C13H14BrNOS [M + Na]+, 333.9872,
found 333.9876.
1-(Benzo[d]thiazol-2-yl)ethanone (3a): white solid (0.147 g, 83%
yield); mp 107−110 °C; 1H NMR (400 MHz, CDCl3) δ 2.83 (s, 3H),
7.53 (td, J = 7.6, 1.3 Hz, 1H), 7.58 (td, J = 8.0, 1.3 Hz, 1H), 7.98 (d, J
= 8.0 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 26.2, 122.5, 125.5, 127.0, 127.7, 137.5, 153.6, 166.5, 193.2; HRMS
(ESI) calcd for C9H7NOS [M + H]+, 178.0321, found 178.0320.
1-(Benzo[d]thiazol-2-yl)propan-1-one (3b): white solid (0.152 g,
80% yield); mp 63−65 °C; 1H NMR (400 MHz, CDCl3) δ 1.29 (t, J =
7.3 Hz, 3H), 3.30 (q, J = 7.3 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.57 (t,
J = 7.2 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 7.89, 32.1, 122.5, 125.3, 126.9, 127.6,
137.2, 153.6, 166.4, 196.0; HRMS (ESI) calcd for C10H9NOS [M +
H]+, 192.0478, found 192.0484.
1-(Benzo[d]thiazol-2-yl)butan-1-one (3c): yellow solid (0.146 g,
71% yield); mp 43−45 °C; 1H NMR (400 MHz, CDCl3) δ 1.06 (t, J =
7.4 Hz, 3H), 1.85(m, 2H), 3.27 (t, J = 7.4 Hz, 2H), 7.53 (t, J = 7.2 Hz,
1H), 7.58 (t, J = 7.2 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 8.0
Hz). 13C NMR (100 MHz, CDCl3) δ 13.8, 17.5, 40.5, 122.5, 125.4,
127.0, 127.6, 137.2, 153.6, 166.6, 195.5; HRMS (ESI) calcd for
C11H11NOS [M + H]+, 206.0634, found 206.0641.
1-(6-Bromobenzo[d]thiazol-2-yl)-2-methylpropan-1-one (3k):
white solid (0.202 g, 71% yield); mp 73−76 °C; 1H NMR (400
MHz, CDCl3) δ 1.32 (d, J = 6.9 Hz, 6H), 3.93 (m, 1H), 7.64 (d, J =
8.8 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 8.09 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 18.6, 36.4, 121.8, 124.9, 126.4, 130.6, 138.9, 152.4,
166.5, 198.8; HRMS (ESI) calcd for C11H10BrNOS [M + H]+,
283.9739, found 283.9745.
1-(6-Bromobenzo[d]thiazol-2-yl)-3-methylbutan-1-one (3l):
white solid (0.209 g, 70% yield); mp 71−73 °C; 1H NMR (400
MHz, CDCl3) δ 1.04 (d, J = 6.7 Hz, 3H), 2.39 (m, 1H), 3.12 (d, J =
6.9 Hz, 2H), 7.64 (d, J = 8.8 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 8.09 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 22.6, 25.0, 47.2, 121.8, 125.0,
126.4, 130.6, 138.8, 152.4, 167.3, 194.9; HRMS (ESI) calcd for
C12H12BrNOS [M + H]+, 297.9896, found 297.9900.
1-(6-Chlorobenzo[d]thiazol-2-yl)ethanone (3m): white solid
(0.152 g, 72% yield); mp 150−151 °C; 1H NMR (400 MHz,
CDCl3) δ 2.82 (s, 3H), 7.53 (dd, J = 2.0 Hz, J = 8.8 Hz, 1H), 7.94 (d, J
= 2.0 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 26.1, 122.0, 126.2, 128.1, 134.0, 138.5, 152.0, 166.9, 192.8; HRMS
(ESI) calcd for C9H6ClNOS [M + H]+, 211.9931, found 211.9930.
1-(6-Chlorobenzo[d]thiazol-2-yl)propan-1-one (3n): yellow solid
(0.160 g, 70% yield); mp 120−121 °C; 1H NMR (400 MHz, CDCl3)
δ 1.29 (t, J = 7.2 Hz, 14.4 Hz, 3H), 3.27 (q, J = 6.8 Hz, 14.0 Hz, 2H),
7.53 (d, J = 8.8 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 8.10 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 7.8, 32.1, 122.0, 126.1, 128.0, 133.9, 138.3,
1-(Benzo[d]thiazol-2-yl)hexan-1-one (3d): white solid (0.161 g,
69% yield); mp 50−53 °C; 1H NMR (400 MHz, CDCl3) δ 0.91 (t, J =
6.8 Hz, 3H), 1.39(m, 2H), 1.40(m, 2H), 1.81 (m, 2H), 3.26 (t, J = 7.4
Hz, 2H), 7.51 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.97 (d, J =
8.0 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
13.9, 22.5, 31.4, 23.7, 38.6, 122.4, 125.4, 126.9, 127.6, 137.3, 153.6,
G
dx.doi.org/10.1021/jo501791n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
152.1, 166.8, 195.7; HRMS (ESI) calcd for C10H8ClNOS [M + H]+,
226.0088, found 226.0087.
122.1, 126.0, 137.5, 146.6, 156.9, 171.4, 192.4; HRMS (ESI) calcd for
C9H6N2O3S [M + H]+, 223.0172, found 223.0175.
1-(6-Chlorobenzo[d]thiazol-2-yl)-2-methylpropan-1-one (3o):
Experimental Procedure for the Direct Phosphonation of
Benzothiazoles with Dialkyl Phosphites (8a−u). A mixture of
benzothiazole (135.0 mg, 1.0 mmol), phosphonate (5.0 mmol), and
DTBP (10.0 mmol) in CH3CN (2.0 mL) was stirred at 80 °C for 30 h.
The reaction mixture was quenched with water (5.0 mL) and extracted
with ethyl acetate (3 × 5.0 mL). The combined organic layers were
washed with brine (15.0 mL) and dried over anhydrous MgSO4. After
filtration, the solvent was evaporated in vacuo. The crude product was
purified by silica gel chromatography (petroleum ether/ethyl acetate
10/1) to give the desired product.
1
yellow liquid (0.175 g, 73% yield). H NMR (400 MHz, CDCl3) δ
1.33 (d, J = 7.2 Hz, 6H), 3.96 (m, 1H), 7.55 (dd, J = 2.0 Hz, 8.8 Hz,
1H), 7.97 (d, J = 2.0 Hz, 1H), 8.1 (d, J = 8.8 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 18.6, 36.4, 122.0, 126.2, 127.9, 133.9, 138.4, 152.2,
166.5, 198.9; HRMS (ESI) calcd for C11H10ClNOS [M + H]+,
240.0244, found 240.0232.
1-(6-Methylbenzo[d]thiazol-2-yl)ethanone (3p): white solid
1
(0.161 g, 84% yield); mp 88−90 °C; H NMR (400 MHz, CDCl3)
δ 2.52 (s, 3H), 2.81 (s, 3H), 7.38 (dd, J = 8.5, 1.2 Hz, 1H), 7.74 (s,
1H), 8.05 (d, J = 8.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.8,
26.1, 120.0, 124.9, 129.0, 137.7, 138.4, 151.7, 165.5, 193.2; HRMS
(ESI) calcd for C10H9NOS [M + H]+, 192.0478, found 192.0484.
1-(6-Methylbenzo[d]thiazol-2-yl)propan-1-one (3q): yellow solid
Diethyl benzo[d]thiazol-2-ylphosphonate (8a): light yellow oil
1
(0.190 g, 70% yield); H NMR (400 MHz, CDCl3) δ 1.32 (t, J = 7.2
Hz, 6H), 4.19−4.34 (m, 4H), 7.42−7.52 (m, 2H), 7.93 (d, J = 8.0 Hz,
1H), 8.16 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 16.2
(d, J = 6.0 Hz), 64.0 (d, J = 6.0 Hz), 121.9 (d, J = 1.0 Hz), 124.9,
126.8, 127.0, 136.3 (d, J = 2.0 Hz), 154.6 (d, J = 29 Hz)), 161.2 (d, J =
237.0 Hz); 31P NMR (162 MHz, CDCl3) δ 3.97 (s); HRMS (ESI)
calcd for C11H14NO3PS [M + H]+, 272.0505, found 272.0510; [M +
Na]+, 294.0324, found 294.0330;
1
(0.166 g, 81% yield); mp 76−78 °C; H NMR (400 MHz, CDCl3) δ
1.29 (t, J = 7.3 Hz, 3H), 2.52 (s, 3H), 3.29 (q, J = 7.3 Hz, 2H), 7.38
(dd, J = 8.5, 1.2 Hz, 1H), 7.75 (s, 1H), 8.04 (d, J = 8.5 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 7.9, 21.8, 32.0, 120.0, 124.8, 129.0, 137.4,
138.2, 151.7, 165.4, 196.0; HRMS (ESI) calcd for C11H11NOS [M +
H]+, 206.0634, found 206.0643.
Diisopropyl benzo[d]thiazol-2-ylphosphonate (8b): light yellow
1
oil (0.195 g, 65% yield); H NMR (400 MHz, CDCl3) δ 1,36−1.26
3-Methyl-1-(6-methylbenzo[d]thiazol-2-yl)butan-1-one (3r): yel-
1
(dd, J = 6.0 Hz, 34.0 Hz, 12H), 4.89−4.81 (m, 2H), 7.50−7.40 (m,
2H), 7.92 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 23.7, 73.1 (d, J = 6.0 Hz), 121.8 (d, J = 1.0 Hz),
124.8, 126.7, 126.8, 136.3 (d, J = 1.0 Hz), 154.6 (d, J = 28.0 Hz), 162.5
(d, J = 237.0 Hz); 31P NMR (162 MHz, CDCl3) δ 1.87 (s); HRMS
(ESI) calcd for C13H18NO3PS [M + Na]+, 322.0637, found 322.0641.
Dipropyl benzo[d]thiazol-2-ylphosphonate (8c): light yellow oil
low solid (0.177 g, 76% yield); mp 48−50 °C; H NMR (400 MHz,
CDCl3) δ 1.04 (d, J = 6.7 Hz, 6H), 2.40 (m, 1H), 2.52 (s, 3H), 3.14(d,
J = 7.0 Hz, 2H), 7.38 (dd, J = 8.2, 1H), 7.75 (s, 1H), 8.05 (d, J = 8.4
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.8, 22.7, 25.1, 47.1, 122.0,
124.9, 128.8, 137.6, 138.2, 151.8, 160.0, 195.3; HRMS (ESI) calcd for
C13H15NOS [M + H]+, 234.0947, found 234.0947.
1-(4-Methylbenzo[d]thiazol-2-yl)ethanone (3s): white solid (0.159
g, 83% yield); mp 66−70 °C; 1H NMR (400 MHz, CDCl3) δ 2.80 (s,
3H, -CH3), 2.83 (s, 3H), 7.36 (d, J = 7.2 Hz, 1H), 7.41 (t, J = 8.0 Hz,
15.2 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 18.2 (-CH3), 26.1, 119.8, 127.2, 127.7, 135.8, 137.5, 153.2, 165.1,
193.5; HRMS (ESI) calcd for C10H9NOS [M + H]+, 192.0478, found
192.0478.
1
(0.207 g, 69% yield); H NMR (400 MHz, CDCl3) δ 0.97 (t, J = 7.2
Hz, 6H), 1.82−1.73 (m, 4H), 4.29−4.16 (m, 4H), 7.60−7.51 (m, 2H),
7.93 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 9.9, 23.7 (d, J = 7.0 Hz), 69.5 (d, J = 6.0 Hz), 121.9
(d, J = 1.0 Hz), 124.9, 126.9, 127.0, 136.4, 154.5 (d, J = 29.0 Hz),
161.1 (d, J = 237.0 Hz); 31P NMR (162 MHz, CDCl3) δ 4.14 (s);
HRMS (ESI) calcd for C13H18NO3PS [M + H]+, 300.0818, found
300.0819.
1-(4-Methylbenzo[d]thiazol-2-yl)propan-1-one (3t): white solid
1
(0.164 g, 80% yield); mp 65−68 °C; H NMR (400 MHz, CDCl3) δ
Diethyl 6-methylbenzo[d]thiazol-2-ylphosphonate (8d): light
yellow oil (0.205 g, 72% yield); 1H NMR (400 MHz, CDCl3) δ
1.39−1.35 (t, J = 7.2 Hz, 6H), 2.49 (s, 3H), 4.33−4.26 (m, 4H), 7.36−
7.34 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 16.2 (d, J = 6.0 Hz), 21.6, 64.0 (d, J = 6.0
Hz), 121.4, 124.3, 127.8, 128.6, 137.5 (d, J = 83.0 Hz), 152.8 (d, J =
28.0 Hz), 160.0 (d, J = 238.0 Hz); 31P NMR (162 MHz, CDCl3) δ
4.27 (s); HRMS (ESI) calcd for C12H16NO3PS [M + H]+, 286.0661,
found 286.0661.
Diisopropyl 6-methylbenzo[d]thiazol-2-ylphosphonate (8e): light
yellow oil (0.197 g, 63% yield); 1H NMR (400 MHz, CDCl3) δ 1.44−
1.34 (dd, J = 6.0 Hz, 35.6 Hz, 12H), 2.54 (s, 3H), 4.95−4.90 (m, 2H),
7.40−7.38 (d, J = 8.0 Hz, 1H), 7.80 (d, 1H), 8.13−8.11 (d, J = 8.0 Hz,
1H, 4-H). 13C NMR (100 MHz, CDCl3) δ 21.7, 24.1−23.7 (dd, J =
5.0 Hz, 28 Hz), 73.2−73.1 (d, J = 6.0 Hz), 121.4, 121.5, 124.4, 128.6,
137.4 (d, J = 58.0 Hz), 153.0 (d, J = 29 Hz), 161.3 (d, J = 239.0 Hz).
31P NMR (162 MHz, CDCl3) δ 2.27 (s); HRMS (ESI) calcd for
C14H20NO3PS [M + H]+, 314.0974, found 314.0976.
Dipropyl 6-methylbenzo[d]thiazol-2-ylphosphonate (8f): light
yellow oil (0.219 g, 70% yield); 1H NMR (400 MHz, CDCl3) δ
1.00−0.97 (t, J = 7.2 Hz, 6H), 1.83−1.74 (m, 4H), 4.29−4.16 (m,
4H), 7.42−7.40 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 8.15−8.13 (d, J = 8.4
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 9.9, 21.7, 23.7 (d, J = 6.0
Hz), 69.4 (d, J = 6.0 Hz), 121.4, 124.4, 128.6, 136.7, 137.5, 152.6 (d, J
= 28 Hz), 159.8 (d, J = 238.0 Hz); 31P NMR (162 MHz, CDCl3) δ
4.46 (s); HRMS (ESI) calcd for C14H20NO3PS [M + H]+, 314.0974,
found 314.0978.
1.30 (t, J = 7.2 Hz, J = 14.4 Hz, 3H,), 2.80 (s, 3H, -CH3), 3.32 (q, J =
7.2 Hz, 14.4 Hz, 2H), 7.36 (d, J = 7.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 15.2
Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
8.0, 18.2 (-CH3), 32.0, 119.7, 127.1, 127.6, 135.7, 137.3, 153.2, 165.0,
196.3; HRMS (ESI) calcd for C11H11NOS [M + H]+, 206.0634, found
206.0633.
1-(4-Methylbenzo[d]thiazol-2-yl)-2-methylpropan-1-one (3u):
1
yellow liquid (0.171 g, 78% yield); H NMR (400 MHz, CDCl3) δ
1.34 (d, J = 6.8 Hz, 6H), 2.80 (s, 3H, -CH3), 4.0 (m, 1H), 7.35 (d, J =
7.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 15.2 Hz, 1H), 7.79 (d, J = 8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 18.2 (-CH3), 18.8, 36.3, 119.7,
127.1, 127.5, 135.7, 137.4, 153.2, 164.7, 199.4; HRMS (ESI) calcd for
C12H13NOS [M + H]+, 220.0791, found 220.0790.
1-(6-Methoxybenzo[d]thiazol-2-yl)ethanone (3v): white solid
(0.162 g, 78% yield); mp 138−140 °C; 1H NMR (400 MHz,
CDCl3) δ 2.81 (s, 3H), 3.93 (s, 3H, −OCHH3), 7.20 (dd, J = 2.4 Hz,
8.8 Hz, 1H), 7.94 (d, J = 2.8 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 26.0, 55.9 (-OCH3), 103.6, 117.7, 126.1,
139.5, 148.1, 159.8, 164.0, 193.0; HRMS (ESI) calcd for C10H9NO2S
[M + H]+, 208.0427, found 208.0429.
1-(6-Methoxybenzo[d]thiazol-2-yl)propan-1-one (3w): yellow
1
solid (0.155 g, 70% yield); mp 118−120 °C; H NMR (400 MHz,
CDCl3) δ 1.30 (t, J = 7.2 Hz, 14.4 Hz, 3H), 3.28 (q, J = 7.2 Hz, 14.4
Hz, 2H), 3.93 (s, 3H, -OCHH3), 7.20 (dd, J = 2.4 Hz, 9.2 Hz, 1H),
7.40 (d, J = 2.4 Hz, 1H), 8.0 (d, J = 9.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 8.0, 31.9, 55.8 (-OCH3), 103.7, 117.6, 126.0, 139.2, 148.1,
159.7, 163.9, 195.8; HRMS (ESI) calcd for C11H11NO2S [M + H]+,
222.0583, found 222.0585.
Diethyl 6-bromobenzo[d]thiazol-2-ylphosphonate (8g): yellow
1
1-(6-Nitrobenzo[d]thiazol-2-yl)ethanone (3x): yellow solid (0.133
oil (0.221 g, 63% yield); H NMR (400 MHz, CDCl3) δ 1.39 (t, J =
1
g, 51% yield); mp 191−192 °C; H NMR (400 MHz, CDCl3) δ 2.86
7.2 Hz, 6H), 4.40−4.25 (m, 4H), 7.67−7.65 (q, 1H), 8.07 (d, J = 8.8
Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
16.3 (d, J = 6.0 Hz), 64.2 (d, J = 5.0 Hz), 121.2, 124.5 (d, J = 1.0 Hz),
(s, 3H), 8.31 (d, J = 9.1 Hz, 1H), 8.42 (dd, J = 9.1, 2.2 Hz, 1H), 8.93
(d, J = 2.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 26.2, 119.1,
H
dx.doi.org/10.1021/jo501791n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
125.9, 130.6, 138.0, 153.4 (d, J = 28 Hz), 161.9 (d, J = 237.0 Hz); 31
P
Diphenyl 6-methylbenzo[d]thiazol-2-ylphosphonate (8o): white
solid (0.297 g, 85% yield); mp 205−207 °C; H NMR (400 MHz,
1
NMR (162 MHz, CDCl3) δ 3.34 (s); HRMS (ESI) calcd for
C11H13BrNO3PS [M + H]+, 349.9610, found 349.9608;
CDCl3) δ 2.80 (s, 3H), 7.40−7.34 (m, 2H), 7.53−7.42 (m, 4H),
7.60−7.57 (m, 2H), 7.85−7.83 (d, J = 7.6 Hz, 1H), 8.05−8.0 (m, 4H).
13C NMR (100 MHz, CDCl3): 18.4, 119.4, 126.6 (d, J = 34.0 Hz),
128.6 (d, J = 13.0 Hz), 130.9, 131.9 (d, J = 7.0 Hz), 132.0, 132.5 (d, J
= 3.0 Hz), 134.9, 136.7, 154.9 (d, J = 21 Hz), 164.3 (d, J = 129.0 Hz);
31P NMR (162 MHz, CDCl3) δ 19.30 (s); HRMS (ESI) calcd for
C20H16NOPS [M + H]+, 350.0763, found 350.0776
Dipropyl 6-bromobenzo[d]thiazol-2-ylphosphonate (8h): yellow
1
oil (0.242 g, 64% yield); H NMR (400 MHz, CDCl3) δ 0.97 (t, J =
7.2 Hz, 6H), 1.82−1.73 (m, 4H), 4.30−4.16 (m, 4H), 7.70−7.67 (dd, J
= 1.6 Hz, 8.4 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 2.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 9.9, 23.7 (d, J = 6.0 Hz), 69.6
(d, J = 6.0 Hz), 121.1, 124.5 (d, J = 2.0 Hz), 125.9, 130.5, 137.9 (d, J =
1.0 Hz), 153.3 (d, J = 28 Hz), 161.9 (d, J = 237.0 Hz); 31P NMR (162
MHz, CDCl3) δ 3.37 (s); HRMS (ESI) calcd for C13H17BrNO3PS [M
+ H]+, 377.9923, found 377.9925; [M + Na]+, 399.9742, found
399.9746.
Diphenyl benzo[d]thiazol-2-ylphosphonate (8i): white solid
(0.282 g, 84% yield); mp 162−164 °C; 1H NMR (400 MHz,
CDCl3) δ 7.47−7.39 (m, 8H), 7.48−7.50 (m, 5H), 7.51 (d, J = 2.8 Hz,
1H); 13C NMR (100 MHz, CDCl3): 122.1, 124.7 126.7 (d, J = 4.0
Hz), 128.7 (d, J = 13.0 Hz), 130.5, 131.6, 131.9 (d, J = 10.0 Hz), 132.6
(d, J = 3.0 Hz), 136.7, 155.4 (d, J = 22 Hz), 167.4 (d, J = 126.0 Hz);
31P NMR (162 MHz, CDCl3) δ 19.80 (s); HRMS (ESI) calcd for
C19H14NOPS [M + H]+, 336.0606, found 336.0611; [M + Na]+,
358.0426, found 358.0430.
Diethyl 6-methoxybenzo[d]thiazol-2-ylphosphonate (8p): light
yellow oil (0.211 g, 70% yield); 1H NMR (400 MHz, CDCl3) δ 1.43−
1.40 (t, J = 6.8 Hz, 14.0 Hz, 6H), 3.93 (s, 3H, −OCHH3), 4.39−4.27
(m, 4H), 7.21−7.18 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 7.42−7.43 (d, J = 2.4
Hz, 1H), 8.12−8.14 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 16.1 (d, J = 7.0 Hz), 55.8 (-OCH3), 63.5 (d, J = 6.0 Hz),
103.2 (d, J = 1.0 Hz), 117.3, 125.4, 138.2, 149.1 (d, J = 28.0 Hz),
159.2, 157.9 (d, J = 240.0 Hz); 31P NMR (162 MHz, CDCl3) δ 4.37
(s); HRMS (ESI) calcd for C12H16NO4PS [M + H]+, 302.0610, found
302.0613.
Diisopropyl 6-methoxybenzo[d]thiazol-2-ylphosphonate (8q):
1
light yellow oil (0.204 g, 62% yield); H NMR (400 MHz, CDCl3)
δ 1.44−1.34 (dd, J = 6.4 Hz, 35.2 Hz, 11H), 3.92 (s, 3H, −OCHH3),
4.97−4.85 (m, 2H), 7.20−7.17 (dd, J = 2.4 Hz, 9.2 Hz, 1H), 7.42−
7.41 (d, J = 2.4 Hz), 8.13−8.11 (d, J = 8.8 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 24.1−23.7 (dd, J = 5.0 Hz, 27.0 Hz), 55.8(s, -OCH3),
73.2−73.1 (d, J = 6.0 Hz), 103.3 (d, J = 10.0 Hz), 117.1, 125.4, 138.3,
149.5 (d, J = 29.0 Hz), 159.0, 159.4 (d, J = 240.0 Hz); 31P NMR (162
MHz, CDCl3) δ 2.20 (s); HRMS (ESI) calcd for C14H20NO4PS [M +
H]+, 330.0923, found 330.0927.
Diphenyl 6-methylbenzo[d]thiazol-2-ylphosphonate (8j): yellow
1
solid (0.300 g, 86% yield); mp 122−124 °C; H NMR (400 MHz,
CDCl3) δ 2.51 (s, 3H, -CH3), 7.37−7.35 (dd, J = 1.2 Hz, 8.4 Hz, 1H),
7.51−7.47 (m, 4H), 7.51−7.59 (m, 2H), 7.80 (s, 1H), 7.98−7.93 (m,
4H), 8.05 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.6
(-CH3), 121.6, 124.1, 128.5, 128.7 (d, J = 13.0 Hz), 130.5, 131.6, 131.9
(d, J = 10.0 Hz), 132.6 (d, J = 3.0 Hz,) 137.1 (d. J = 14.0 Hz), 153.4
(d, J = 22.0 Hz), 165.8 (d, J = 127.0 Hz); 31P NMR (162 MHz,
CDCl3) δ 20.01 (s); HRMS (ESI) calcd for C20H16NOPS [M + H]+,
350.0763, found 350.0768; [M + Na]+, 372.0582, found 372.0582
Diphenyl 6-bromobenzo[d]thiazol-2-ylphosphonate (8k): yellow
Diphenyl 6-methoxybenzo[d]thiazol-2-ylphosphonate (8r): light
1
yellow oil (0.274 g, 75% yield); H NMR (400 MHz, CDCl3) δ 3.80
(s, −OCHH3), 7.11−7.07 (dd, J = 2.8 Hz, 9.2 Hz 1H), 7.35 (d, J = 2.4
Hz, 1H), 7.46−7.42 (m, 4H), 7.53−7.48 (m, 2H), 7.97−7.92 (m, 4H),
8.00 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 103.4, 117.2,
125.2, 128.6 (d, J = 13.0 Hz), 130.5, 131.7, 131.8 (t, J = 6.0 Hz, 16.0
Hz), 132.6 (d, J = 4.0 Hz), 138.6, 150.0 (d, J = 22.0 Hz), 158.9, 162.6
(d, J = 129.0 Hz); 31P NMR (162 MHz, CDCl3) δ 19.84 (s); HRMS
(ESI) calcd for C20H16NO2PS [M + H]+, 366.0712, found 366.0729.
Diethyl 6-chlorobenzo[d]thiazol-2-ylphosphonate (8s): yellow
1
solid (0.331 g, 75% yield); mp 126−128 °C; H NMR (400 MHz,
CDCl3) δ 7.47−7.39 (m, 7H), 7.48−7.50 (m, 5H), 7.51 (d, J = 2.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 120.8, 124.6, 125.7, 128.8 (d, J =
13.0 Hz), 130.1 (d, J = 18.0 Hz), 131.2 (s), 131.8 (d, J = 10.0 Hz),
132.8 (d, J = 3.0 Hz), 138.4, 155.4 (d, J = 22 Hz), 167.4 (d, J = 124.0
Hz); 31P NMR (162 MHz, CDCl3) δ 19.74 (s); HRMS (ESI) calcd for
C19H13BrNOPS [M + H]+, 413.9712, found 413.9712
1
liquid (0.193 g, 63% yield); H NMR (400 MHz, CDCl3) δ1.40−
1.44 (t, J = 7.2 Hz, 14.4 Hz, 6H), 4.29−4.41 (m, 4H), 7.54−7.57 (dd, J
= 2.0 Hz, 8.8 Hz, 1H), 8.00−8.01 (d, J = 2.0 Hz, 1H), 8.15−8.17 (d, J
= 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 16.3 (t, J = 1.6 Hz, 2.4
Hz), 64.2 (d, J = 6.0 Hz), 121.5, 125.7, 127.9, 133.6, 137.6, 153.3 (d, J
= 29.0 Hz), 159.6 (d, J = 239.0 Hz); 31P NMR (162 MHz, CDCl3) δ
3.37 (s); HRMS (ESI) calcd for C11H13ClNO3PS [M + H]+, 306.0115,
found 306.0118.
Diethyl 4-methylbenzo[d]thiazol-2-ylphosphonate (8l): light
yellow oil (0.200 g, 70% yield); 1H NMR (400 MHz, CDCl3) δ
1.40−1.43 (t, J = 7.2 Hz, 14.0 Hz, 6H), 2.82 (s, 3H), 4.29−4.40 (m,
4H), 7.35−7.37 (d, J = 6.8 Hz, 1H), 7.40−7.44 (t, J = 7.6 Hz, 15.2 Hz
1H), 7.81−7.83 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
16.2 (d, J = 6.0 Hz) 18.4, 64.1 (d, J = 6.0 Hz), 119.0, 119.3, 126.9,
127.0, 135.1 (d, J = 121.0 Hz), 154.3 (d, J = 28.0 Hz), 158.6 (d, J =
239.0 Hz, 2-C); 31P NMR (162 MHz, CDCl3) δ 3.38 (s); HRMS
(ESI) calcd for C12H16NO3PS [M + H]+, 286.0661, found 286.0662.
Diisopropyl 4-methylbenzo[d]thiazol-2-ylphosphonate (8m):
Ethyl phenyl (6-chlorobenzo[d]thiazol-2-ylphosphonate (8t):
1
yellow liquid (0.248 g, 70% yield); H NMR (400 MHz, CDCl3) δ
1.45 (t, J = 7.2 Hz, 14.0 Hz, 3H), 4.37−4.25 (m, 2H), 7.39−7.31 (m,
2H), 7.54−7.49 (m, 3H), 7.62−7.58 (m, 1H), 7.97 (d, J = 2.0 Hz,
1H), 8.08−8.02 (m, 2H), 8.11−8.10 (d, J = 8.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 16.5 (d, J = 7.0 Hz), 62.9 (d, J = 7.0 Hz), 121.6,
125.6, 127.8, 128.1, 128.7 (d, J = 15.0 Hz), 129.5, 132.2 (d, J = 5.0
Hz), 133.3 (t, J = 15.0 Hz, 18.0 Hz), 137.9, 153.6 (d, J = 24.0 Hz),
165.7 (d, J = 165.0 Hz); 31P NMR (162 MHz, CDCl3) δ 20.31 (s);
HRMS (ESI) calcd for C15H13ClNO3PS [M + H]+, 354.0115, found
354.0128.
Diphenyl 6-chlorobenzo[d]thiazol-2-ylphosphonate (8u): light
yellow solid (0.277 g, 75% yield); mp 112−113 °C; 1H NMR (400
MHz, CDCl3) δ 7.51−7.45 (m, 5H), 7.59−7.54 (m, 2H), 7.99−7.94
(m, 5H), 8.08−8.05 (d, J = 7.2 Hz, 2H). 13C NMR (100 MHz,
CDCl3): 121.6, 125.5, 127.7, 128.7 (d, J = 13.0 Hz), 130.2, 131.3,
131.9 (d, J = 5.0 Hz), 132.8 (t, J = 2.0 Hz, 16.0 Hz) δ 138.0, 153.8 (d, J
= 21 Hz), 168.3 (d, J = 124.0 Hz); 31P NMR (162 MHz, CDCl3) δ
19.76 (s); HRMS (ESI) calcd for C19H13ClNOPS [M + H]+,
370.0217, found 370.0229.
1
light yellow oil (0.194 g, 62% yield); H NMR (400 MHz, CDCl3)
δ 1.46−1.38 (dd, J = 6.0 Hz, 23.6 Hz, 12H), 2.83 (s, 3H), 4.99−4.91
(m, 2H), 7.35−7.37 (d, J = 7.2 Hz, 1H), 7.43−7.39 (t, J = 8.0 Hz, 15.2
Hz 1H), 7.84−7.82 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 18.4, 24.1−23.7 (dd, J = 5.0 Hz, 31.0 Hz), 73.1 (d, J = 6.0 Hz),
119.0, 119.2, 126.8, 127.0, 135.1 (d, J = 132.0 Hz), 154.3 (d, J = 28.0
Hz), 158.6 (d, J = 239.0 Hz); 31P NMR (162 MHz, CDCl3) δ 2.31 (s);
HRMS (ESI) calcd for C14H20NO3PS [M + H]+, 314.0974, found
314.0976.
Ethyl phenyl (4-methylbenzo[d]thiazol-2-yl)phosphonate (8n):
1
yellow liquid (0.250 g, 75% yield); H NMR (400 MHz, CDCl3) δ
1.45 (t, J = 7.2 Hz, 14.0 Hz, 3H), 2.80 (s, 3H), 4.38−4.28(m, 2H),
7.39−7.31 (m, 2H), 7.52−7.48 (m, 2H), 7.60−7.56 (m, 1H), 7.81−
7.79 (d, J = 7.6 Hz, 1H), 8.11−8.01 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ 16.5 (d, J = 6.0 Hz), 18.4, 62.8 (d, J = 6.0 Hz), 119.3, 126.8,
127.0, 128.6 (d, J = 14.0 Hz, 28.0 Hz), 130.1, 132.2 (d, J = 10.0 Hz),
133.0 (d, J = 3.0 Hz), 135.1, 136.7, 154.5 (d, J = 23 Hz), 161.5 (d, J =
168.0 Hz); 31P NMR (162 MHz, CDCl3) δ 20.38 (s); HRMS (ESI)
calcd for C16H16NO3PS [M + H]+, 334.0661, found 334.0671.
2-(2-(tert-Butoxy)propan-2-yl)benzo[d]thiazole (7d). white oil
1
(0.130 g, 52% yield); H NMR (400 MHz, CDCl3): 1.26 (s, 9H),
1.74(s, 6H), 7.35 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.88 (d,
I
dx.doi.org/10.1021/jo501791n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
J = 7.9 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 26.3, 26.6, 79.8, 82.6, 121.6, 123.0, 124.8, 125.5, 135.8,
152.8, 178.0; HRMS (ESI) calcd for C14H19NOS [M + H]+, 250.1260,
found 250.1260.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Text, tables, figures, and CIF files giving density functional
theory (DFT) data, NMR spectra for all compounds, and
crystallographic data for 3k and 8i. This material is available
free of charge via the Internet at http://pubs.acs.org.
Crystallographic data have also been deposited at the
Cambridge Crystallographic Data Centre (CCDC) as supple-
mentary publication numbers CCDC 953163 (3k) and CCDC
953164 (8i).
AUTHOR INFORMATION
Corresponding Authors
*E-mail for X.-L.C.: chenxl@zzu.edu.cn.
*E-mail for L.-B.Q.: qulingbo@zzu.edu.cn.
■
Notes
The authors declare no competing financial interest.
(15) Zhou, C. Y.; Garcia-Calvo, M.; Pinto, S.; Lombardo, M.; Feng,
Z.; Bender, K.; Pryor, K. D.; Bhatt, U. R.; Chabin, R. M.; Geissler, W.
M.; Shen, Z.; Tong, X.; Zhang, Z.; Wong, K.-K.; Roy, R. S.; K.
Chapman, T.; Yang, L.; Xiong, Y. J. Med. Chem. 2010, 53, 7251−7263.
(16) Jeong, J. K.; Szabo, G.; Kelly, K.; Diano, S. Endocrinology 2012,
153, 683−689.
ACKNOWLEDGMENTS
■
We thank The National Natural Science Foundation of China
(No. 21072178), Innovation Specialist Projects of Henan
Province (No. 114200510023), Technology and Science talent
Cultivation Project in Zhengzhou City (No. 112PLJRC359),
The Special Fund for the Doctoral Program of Higher
Education (No. 20124101110003), and Foundational and
Frontier Technology Research Foundation of Henan Province
(No. 132300410027) for their financial support.
(17) Myllymaki, M. J.; Saario, S. M.; Kataja, A. O.; Castillo-Melendez,
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