Unified Approach to Benzo[ d]thiazol-2-yl-Sulfonamides

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Uniﬁed Approach to Benzo[d]thiazol-2-yl-Sulfonamides

̌

Frantisek Z á les á k, Ondrej Kov á c, Eliska Lachetov á , Nikola St ’astn á , and Jir í Posp í sil*

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ABSTRACT: In this paper, we report a uniﬁed approach to N-substituted

and N,N-disubstituted benzothiazole (BT) sulfonamides. Our approach to

BT-sulfonamides starts from simple commercially available building blocks

(benzo[d]thiazole-2-thiol and primary and secondary amines) that are

connected via (a) a S oxidation/S−N coupling approach, (b) a S−N

coupling/S-oxidation sequence, or via (c) a S-oxidation/S−F bond

formation/SuFEx approach. The labile N−H bond in N-monoalkylated

BT-sulfonamides (pK_a(BTSO₂N(H)Bn) = 3.34 0.05) further allowed

us to develop a simple weak base-promoted N-alkylation method and a

stereoselective microwave-promoted Fukuyama−Mitsunobu reaction. N-

Alkyl-N-aryl BT-sulfonamides were accessed with the help of the Chan−

Lam coupling reaction. Developed methods were further used in stereo

and chemoselective transformations of podophyllotoxin and several amino

alcohols.

reagent)^19,20or trans-sulfonylation (using SMOPS reagent)²¹

of alkyl halides. Generated sulﬁnic salts are usually thermally

and moisture insensitive solids that can be readily transformed

into the desired sulfonamides using various oxidative protocols.

In such cases, sulﬁnic salts are reacted with in situ generated

electrophilic brominating or iodinating species (in situ

generation of the corresponding sulfonyl halides) in the

presence of an excess of amine.²²⁻²⁶Alternatively, sulﬁnic salts

can also be oxidized in the presence of amines to sulfonamides

with the help of electrochemistry.²⁷Finally, sulﬁnic salts can be

readily converted to sulfonamides using the SuFEx chemistry

approach.^28,29The last approach, which is only scarcely used, is

based on the transformation of thiols into sulfenamides, which

are further oxidized to sulfonamides (Scheme 1C).³⁰⁻³²The

main drawback of this approach is the oxidation step that

yielded the desired sulfonamides in low yields.

INTRODUCTION

■

Sulfonamide-containing natural products¹⁻⁴occupy a priv-

ileged place in the group of biologically active compounds. The

biological activity of such compounds varies from antibacte-

rial,⁵antiviral,⁶antiretroviral,⁷and diuretic,⁸to anticonvulsant⁹

(Figure 1). Such a broad spectrum of biological activities

Figure 1. Two examples of sulfonamides containing antibiotic

(sulfamethoxazole) and diuretic⁸(polythiazide) drugs.

All three described methods are working well in the case of

alkyl or aryl sulfonamide synthesis. However, in the case of

heteroaryl sulfonamides (Scheme 2), generated reaction

intermediates are either unstable,³³prepared under harsh

reaction conditions (use of Cl₂(g)),^34,35obtained in low

reaction yields, or unsuitable for N,N-arylalkyl sulfonamide

synthesis.^26,34−36In our contribution, we wish to report a

uniﬁed approach to N-monoalkyl, N,N-dialkyl-, and N,N-

triggered the interest of the synthetic community and led to

the development of several interesting ways for sulfonamide

moiety synthesis (Scheme 1). The most commonly used

approach is based on the reaction of amines and sulfonyl

chlorides,¹⁰⁻¹²that are in their turn obtained via chlorosulfo-

nylation of (hetero)aryl compounds,^13,14via sulfochlorination

of hydrocarbons,¹⁵or via thiol oxidation¹⁶/chlorination¹⁷

sequence (Scheme 1A). The main drawbacks of these methods

are (a) low thermal stability of (heteroaryl) sulfonyl chlorides

and (b) rather limited functional group tolerance.

Received: February 9, 2021

These limitations led scientists to develop an alternative

synthetic route based on the use of sulﬁnic salts (Scheme 1B).

In this approach, sulﬁnic salts are smoothly prepared via

sulﬁnic ester hydrolysis,¹⁸or by sulfonylation (using DABSO

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A

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Scheme 1. Current Methods of Sulfonamide SynthesisGeneral Overview

alkylaryl benzothiazole sulfonamides. Several approaches to

target N-substituted and N,N-disubstituted benzothiazole

sulfonamides are (mechanistically) investigated, and scope

and limitations are established.

Even though we had a short and eﬃcient way to 3a starting

from sulﬁnic salt 2, an alternative way starting from sulﬁde 1

was searched. As demonstrated in Tables 1A and 1B, all

previously tested methods employ the same sequence, S^‑II/S^IV-

oxidation followed by the S−N bond formation. Interestingly,

the S−N³²bond formation followed by the S^‑II/S^IV-oxidation

approach is scarcely used in the literature when heterocyclic

sulfonamides are targeted.⁴²⁻⁴⁴The main drawback of such an

approach is the low-yielding oxidation step. After the careful

reaction optimization, the combination of Brownbridge’s³²

sulfenamide formation and Mo-promoted³⁷⁻³⁹H₂O₂-based

oxidation sequence was found to be the most suitable (Table 1,

entry 5). The reaction was again readily scalable up to a 10

mmol scale (Table 1, entry 6).

Having found suitable and robust reaction conditions for

sulfonamide 3a synthesis, the scope and limitations of both

methods were established (Table 2). In general, both methods

yielded the desired N-substituted sulfonamides 3 in good to

very good yields if unfunctionalized primary α-unbranched

amines were used as the starting material (3a−c). The

methods became supplementary if heteroaryl substituted

amine (3d), aryl-substituted amines (3f, 3g, 3m), and ester

or carbamoyl group bearing amines were used ((−)-3j−l).

Both methods tolerate the free hydroxy groups ((−)-3h,i). If a

diamino-substituted substrate was used, both amino groups

were transformed into the corresponding sulfonamides, albeit

in low reaction yield ((+)-3n). When homochiral amines with

α-stereogenic centers were used as a starting material

RESULTS AND DISCUSSION

■

Approaches Based on S Oxidation and S−N Bond

Formation Sequences. At the onset of our project was the

desire to extend our research interest from benzothiazoylsul-

fones³⁷⁻³⁹(BTSO₂R) to the corresponding amides

(BTSO₂NR₂). To do so, a short, practical, and convenient

way of BT-sulfonamides was searched. Unfortunately, most of

the common synthetic paths to such heteroaryl sulfonamides

proved to be either unpractical (e.g., use of Cl₂(g))^33,35or

failed in our hands (for selected examples, see Table 1, entries

1−3).^34,36Thus, the readily available BT-sulﬁnic acid salt 2

was used as a starting material for the sulfonamide synthesis. In

this regard, the conditions of Yan and co-workers²²proved to

be suitable and generated the desired sulfonamide 2a in 77%

yield (Table 1, entry 7). The protocol, however, lacks the atom

economy. Fortunately, the reaction mechanism evaluation

identiﬁed bromine cations as the key reagent of trans-

formation⁴⁰and a simpliﬁed version of the protocol based

on the use of Br₂(suitable for small-scale reactions) and NBS

(safer bromine cation source), respectively, (Table 1, entries 8

and 9) was developed.⁴¹Under such conditions, the reaction

was fast and yielded the desired sulfonamide 3a in excellent

isolated yields (86% and 91%, respectively) even on a 10 mmol

scale (Table 1, entry 10).

B

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Scheme 2. (A) Previous Approaches to Various Heteroarylsulfones,³⁴⁻³⁶and (B) our Uniﬁed Approach to Such Structures

((−)-3h−l, (+)-3n), no breach in stereo integrity was

observed.

microwave irradiation-promoted^40,46Fukuyama−Mitsunobu

alkylation reaction.⁴⁷Scope and limitations of these trans-

formations are highlighted in Table 3.

The reactivity of secondary amines proved to be problem-

atic, and the corresponding sulfonamides 4 were obtained in

reasonable yields only in the case of piperidine derivatives 4a

and b. The only exception was sulfonamide 4c that was

prepared in 34% yield.⁴⁰Aromatic amines and simple amine

sources such as NH₄Cl (to generate ammonia in situ) and

NH₂CN failed to generate the desired products. In both cases,

we speculate that the stability or inability to generate the key

intermediates, sulfonyl bromide (Method A) and sulfenyl

chloride (Method B), respectively, is responsible for the

observed nonreactivity.⁴⁰

N-Alkylation of N-Monosubstituted Sulfonamides.

Having easy access to N-monosubstituted sulfonamides, N-

alkylation of the prepared sulfonamides 3 seemed to use as the

best synthetic path to N,N-disubstituted sulfonamides. To

evaluate the feasibility of this approach, the pK_avalue of 3a was

determined.⁴⁵The low pK_avalue of sulfonamide N−H

hydrogen (pK_a(3a) = 3.34 5) suggested that two diﬀerent

approaches to N,N-disubstituted sulfonamide 4 can be

considered (Table 3). The ﬁrst approach relied on the

reaction with alkyl halides in the presence of K₂CO₃, and the

second explored sulfonamides 3 as N-nucleophiles in the

It was observed that both primary and secondary alkyl

halides react with N-monosubstituted 3a−c smoothly and

yielded the desired N,N-disubstituted sulfonamides 4d−i in

good to excellent yields (Table 3A). In addition, microwave-

promoted Fukuyama−Mitsunobu alkylation (FMA) reaction

of sulfonamides 3a−c with primary, allylic, and even secondary

alcohols resulted in the formation of N,N-disubstituted

sulfonamides 4d−o in good to excellent yields (Table 3A).

In all evaluated examples, microwave conditions tolerated a

wide range of functional groups (alkenes and alkynes (4e,f,i),

epoxide (4k), esters ((−)-4l−n), or lactone ((−)-4o)), and

the transformation proceeded with complete stereoinversion of

the hydroxy group bearing the carbon center ((−)-4l,m,o). If

several stereogenic centers were present, no inﬂuence of the

substrate on the FMA selectivity was observed. Using such an

approach, a meso sulfonamide meso-4n was prepared starting

from N-monosubstituted sulfonamide (−)-3l and methyl

lactate, and the C4-hydroxy group in podophyllotoxin was

transformed into BT-sulfonamide (−)-4o. No competitive

elimination was observed.

C

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that either Buchwald−Hartwig amination^48,49or Chan−Lam

coupling^50,51would smoothly accomplish such transformation.

Unfortunately, in our hands, Buchwald−Hartwig amination

failed to generate any traces of the desired arylated

sulfonamide 6a (Scheme 3A).⁴¹In most cases, only the

product of compound 3a formal SO₂extrusion, compound 7a,

was isolated (Scheme 3B, eq 1). In analogy with Ni⁰-promoted

SO₂extrusion observed in the case of sulfonamides,⁵²the same

mechanism of compound 7a formation was expected. Much to

our surprise, no product 7a was formed if Pd⁰-mediated SO₂

extrusion was attempted (Scheme 3B, eqs 2 and 3). Thus, the

role of phenyl iodide under the reaction conditions was

questioned (Scheme 3B, eq 4). It was observed that if 0.2 equiv

of phenyl iodide is used, SO₂-free compound 7a is obtained in

11% yield. This observation suggested that Pd^IIthat is

generated via oxidative addition of Pd⁰to phenyl iodide is

the real reaction promoter. To validate this hypothesis, the

reaction was carried out in the presence of a catalytic amount

of (PPh₃)₂PdCl₂(Scheme 3B, eq 5). Expected product 7 was

obtained in 6% isolated yield. When the transformation was

attempted in the presence of a base (Scheme 3B, eq 6),

compound 7a was isolated in 76% yield. The last two

observations led us to propose a tentative reaction mechanism

shown in Scheme 3B below. It is expected that Pd^IIinteracts

with 3a to yield intermediate A. The interaction with strong

Lewis acid increases the acidity of the sulfonamide-placed

hydrogen atom that might be readily removed with an external

base to yield intermediate B. A newly generated 5-membered

ring in B further undergoes intramolecular rearrangement via

intermediate C to anion D. The loss of SO₂followed by the

resulting amide anion reprotonation leads to the Pd^IIrelease

and the formation of ﬁnal product 7a.

Table 1. Selected Examples of N-Benzylbenzo[d]thiazole-2-

sulfonamide 3a Synthesis Optimization

Chan−Lam Coupling. Having failed to generate the

desired C−N bond in sulfonamides with Pd-mediated

coupling, our attention turned to copper-promoted Chan−

Lam coupling (Scheme 4).^50,51Being aware that the use of

heteroarylsulfonamides as substrates in Chan−Lam coupling

might be problematic,⁵³intensive reaction condition screening

was carried out.⁴⁰Based on the obtained data, we concluded

that the reaction has to be carried out starting from the

copper(I) precatalyst with a non-nucleophilic counter ion,

under an atmosphere of oxygen (1 atm), in the presence of a

bidentate diamine ligand and that DCE is an optimal solvent.

Using such reaction conditions, the scopes and limitations of

the transformation were established (Scheme 4A). Con-

sequently, a tentative reaction mechanism of sulfonamide-

based Chan−Lam coupling that is based on our experimental

results and previously published Chan−Lam coupling mech-

anistic studies^51,53,54was proposed (Scheme 4B). The key

observations are listed below:

a

b

Refers to the isolated yield. Performed on a 10 mmol scale of 2.

DIPEA, diisopropylethylamine; TBAB, tetrabutylammonium bro-

mide; mCPBA, m-chloroperbenzoic acid; NBS, N-bromosuccinimide;

and NCS, N-chlorosuccinimide.

• Copper: No reaction was observed when copper(II)

precatalysts were used to promote the reaction.⁵¹

• Anion: The nature of the copper(I) anion proved to be

essential for the reaction yields. In agreement with the

previously published observations, it was observed that if

strongly binding anions such as Cl⁻, Br⁻, I⁻, CN⁻, or

AcO⁻were present in the copper(I) precatalyst, weakly

nucleophilic BT-sulfonamides 3 were slow to replace

them. Consequently, low BT-sulfonamide 3 conversion

was observed.

FMA substitution can also be successfully applied in an

intramolecular fashion (Table 3B). Combination of the

primary BT-sulfonamide coupling with FMA step yields in a

two-pot inter/intramolecular approach to cyclic N,N-disub-

stituted sulfonamide 5 in 59% overall yield.

Buchwald−Hartwig Amination. Having secured the

synthesis of N,N-dialkyl-substituted sulfonamides 4 and 5,

our attention turned to N,N-alkylaryl sulfonamides 6. Based on

the literature analogy with phenylsulfonamides, we expected

• Ligand: The use of tetramethylenediamine (TMEDA) as

a ligand proved to be crucial to promote the coupling

D

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a

Table 2. Scope and Limitations of Sulfonamide 3 and 4 Synthesis

a

The reactions were performed with 2 mmol of substrate 2 (Method A) and 1 mmol of substrate 1 (Method B); Yields refer to pure isolated

compounds; Conditions. Method A: Substrate 2 (1 equiv), RNH₂(1.2 equiv), NBS (2 equiv), THF/EtOH, rt, 10 mins. Method B: Substrate 1 (1

equiv), NCS (1 equiv), RNH₂(3 equiv), CH₂Cl₂, rt, 30 min, then (NH₄)₆MoO₄·4H₂O (0.3 equiv), H₂O₂(20 equiv), EtOH, 0 °C to rt, 5 h. NBS-,

N-bromosuccinimide; NCS, N-chlorosuccinimide.

reaction. Based on the literature,⁵¹the presence of

TMEDA is increasing the electron density on copper(I)

intermediate and facilitates its oxidation to copper(II).

coordination place on copper (and protonate sulfonamide

anion) and yield intermediate I. Intermediate I can further

undergo intramolecular migration to yield complex J so that

upon oxidation (Cu^IIto Cu^III; intermediate K) and reductive

elimination, biphenyl and regenerated copper(I) complex are

observed.⁵⁶It should be noted that the products of

homocoupling reaction of boronic acids were commonly

present in the reaction mixture during all our experiments

since boronic acid was used in large excess.⁵⁶

In addition, the bidentate character of TMEDA⁵⁵seems

to be also beneﬁcial in regard to transmetalation of

intermediate F to G, and possibly also during the

selective C−N disproportionation reaction⁵⁵(G to H)

that generates product 6 and regenerates the copper(I)

complex. The amount of the TMEDA ligand proved in

our case also has a dramatic impact on the reaction yield.

It was observed that 4 equiv of TMEDA were the

optimal loading. If lower TMEDA loading was used, the

conversion of sulfonamide 3 dropped rapidly. Higher

loading of TMEDA increased the formation of biphenyl

side products.

Unfortunately, even under the optimized reaction con-

ditions, the scope of the Chan−Lam coupling proved to be

limited (Scheme 4A). Evaluated sulfonamides 3a−c reacted

under such conditions only with phenylboronic acid (yielding

sulfonamides 6a−c), 4-biphenyl (6h,i), 3-methoxyphenyl

(6d), and 3-ﬂuoro and 4-halogen-substituted phenylboronic

acids (6i−k). When heteroaryl substituted (expected products

6m−o), 4-carboxylic acid or ester-substituted phenyl (6s,t), 4-

methoxyphenyl (6j), styryl (6p,q), all tested 2-substituted

phenyl (6k,u,v), or cyclopentyl boronic acid (6r) were reacted,

no conversion of sulfonamide 3a was observed. The only

detected products in the reaction mixture were the

Based on these ﬁndings, we speculate that the biphenyl

formation can be traced to the intermediate G (Scheme 4B).

The presence of the excess of TMEDA (bidentate ligand)

around copper(II) intermediate G is presumably increasing the

lability of the sulfonamide ligand. Aryl boronic acid presented

in excess in the reaction mixture can further occupy the free

E

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a

Table 3. Synthesis of N,N-Disubstituted Sulfonamides 4 and 5

a

Reactions were performed with 1 mmol of 3; yields refer to pure isolated compounds. DIAD, diethyl azodicarboxylate; NBS, N-

bromosuccinimide; and μW, microwave irradiation.

homocoupling products generated from the boronic acid

employed.⁴⁰

side product 7c was observed even in the case of such sterically

undemanding amine (Scheme 5B). The observed phenomena

were even more pronounced when α-branched primary amines

(compounds 3q and 3n) and secondary amines (4b,c) were

reacted with 8. When cyclohexane-1,2-diamine was used as a

reaction partner, a mixture of bis-sulfonamide 3n, mono-

sulfonamide BT-amine 7f, and mono BT-amine 7g was formed

Benzothiazoyl Sulfonyl Fluoride. Facing the problems in

N,N-alkylaryl BT-sulfonamide synthesis related to either high

reactivity of phenylamines toward NBS (Table 2, Method A),

low phenylamine nucleophilicity (Table 2, Method B), or low

nucleophilicity of N-alkylsulfonamides 3 in Chan−Lam

coupling (Scheme 4), our attention turned to benzothiazoyl

sulfonyl ﬂuoride 8 (Scheme 5).⁵⁷We expected that BTSO₂F

(8) could be a shelf-stable but still very reactive BTSO₂Cl

equivalent. Sulfonyl ﬂuoride 8 was readily prepared by the

reaction of sulﬁnic salt 2 with Selectﬂuor in 73% yield (Scheme

5A). Thus, its reactivity toward a wide range of alkyl and aryl

amines could be readily evaluated (Scheme 5B).

1

in a 1:3:5 ratio (based on H NMR analysis). In the case of

tested anilines, only traces of the desired products were

detected. Nonreactivity of anilines toward sulfonyl ﬂuoride 8

was again attributed to their weak nucleophilicity since no

traces of possible side product 7 were detected. Control

experiments showed that the side product 7c is not generated

from sulfonamide 3c (Scheme 5C).

It was observed that primary and α-unbranched alkyl amines

react smoothly and yield the desired sulfonamides 3a−c,n in

moderate to good yields. Unfortunately, a competitive attack of

butylamine (sulfonamide 3c synthesis) to the C-electrophilic

center in the benzothiazole ring of 8 that yielded the undesired

Applications. Having assessed short and robust methods

for BT-sulfonamide synthesis, we wished to demonstrate their

synthetic utility. First, three representative sulfonamide

syntheses were carried out on a 10 mmol scale without any

signiﬁcant erosion in the reaction yields (Scheme 6A). Next,

F

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a

Scheme 3. Buchwald−Hartwig Amination of Sulfonamide 3a

a

(A) Attempted amination reactions. (B) Evaluation of the side product formation.

one-pot synthesis of orthogonally protected amino alcohols 9a

and b was carried out with excellent N- and O-chemo-

selectivity. Targeted products 10a and b were isolated in very

good overall yields (Scheme 6B). Finally, the BT-sulfonyl

group removal was achieved using either a thiolate anion or

NaBH₄(Scheme 6C).³⁸

CONCLUSIONS

■

In short, we have developed a uniﬁed approach to N-

monosubstituted and N,N-disubstituted BT-sulfonamides that

relies on several independent synthetic pathways. First,

targeted BT-sulfonamides are prepared from simple and

commercially available starting compounds, benzothiazole,

G

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a b

,

Scheme 4. Chan−Lam Coupling of Sulfonamides 3

a

b

(A) Scope and limitations. (B) Proposed reaction mechanism of copper-catalyzed Chan−Lam coupling of sulfonamides 3. Reactions were

performed on 1 mmol of 3; yields refer to pure isolated compounds. TMEDA, tetramethylethylenediamine; DCE, dichloroethane; and Bn, benzyl.

and primary and secondary amines, using three approaches

that diﬀer in their elemental steps. The ﬁrst approach is based

on the sulfur oxidation/S−N bond formation sequence, the

second on the S−N bond formation/sulfur oxidation process,

and the third one is based on the sulfur oxidation/S−F

formation/SuFEx coupling process. These approaches allowed

us to access N-monoalkyl BT-sulfonamides that were further

used as a starting building block for additional N,N-

disubstituted BT-sulfonamide synthesis. The alkylation pro-

cesses were achieved under mild reaction conditions using

weak base-promoted alkylation with alkyl halides, stereo-

speciﬁc microwave-assisted Fukuyama−Mitsunobu alkylation

using alcohols, and aryl substituents were installed with the

help of Chan−Lam coupling reaction. The key coupling

reaction sequences proved to be readily scalable (10 mmol

scale), chemoselective (N-sulfonylation in the presence of, e.g.,

free hydroxy group), and it was shown that BT groups can be

readily removed using either NaBH₄or thiolate anions.

H

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a

Scheme 5. SuFEx Approach to BT-Sulfonamides 3 and 4

a

(A) BT-sulfonyl ﬂuoride synthesis. (B) SuFEx approach-based scope and limitations. (C) Formation of the desired sulfonamide 3c and side

product 7cProposed mechanism. (D) Evaluation of the BT-sulfonamide 3c stability under the reaction conditions.

puriﬁcation unless otherwise stated. Progress of the reactions was

EXPERIMENTAL PART

■

monitored by thin-layer chromatography (TLC)aluminum plates

General Information. All reactions were performed in round-

bottom ﬂasks ﬁtted with rubber septa using standard laboratory

techniques. Reactions sensitive to air and/or moisture were performed

under a positive pressure of argon. Reactions run at elevated

temperatures were carried out in the oil bath, and the indicated

temperature refers to the oil bath temperature. All starting materials

were purchased from commercial suppliers and used without further

precoated with silica gel (silica gel 60 F254). Column chromatog-

raphy was performed on silica gel 60 (40−63 μm). Determination of

melting points was performed on a Buchi melting point apparatus and

̈

was uncorrected. ¹H NMR, ¹⁹F {¹H} NMR, and ¹³C {¹H} NMR

spectra were measured on a Jeol ECA400II (400 MHz, 376 MHz, and

100 MHz, respectively) or Jeol 500 ECA (500 and 126 MHz) in

CDCl₃or DMSO. Chemical shifts are reported in ppm and their

I

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a

Scheme 6. Demonstration of the Synthetic Utility of BT-Sulfonamides

a

(A) Three key sulfonamide preparations were carried out on a 10 mmol scale, (B) nitrogen atom selective chemoprotection, (C) BT-sulfonyl

group removal.

calibration was performed (a) in the case of ¹H NMR experiments on

the residual peak of nondeuterated solvent δ (CHCl₃) = 7.26 ppm; δ

(DMSO) = 2.50 ppm, and (b) in the case of ¹³C NMR experiments

on the middle peak of the ¹³C signal in deuterated solvent δ (CDCl₃)

= 77.2 ppm; δ (DMSO-d₆) = 39.5 ppm. Proton coupling patterns are

represented as singlet (s), doublet (d), doublet of doublet (dd), triplet

(t), triplet of triplet (tt), and multiplet (m). HRMS analyses were

performed on a Thermo Exactive Plus high-resolution mass

spectrometer with electrospray ionization (ESI) and an Orbitrap

analyzer operating at a positive or negative full scan mode in the range

of 60−800 m/z or on Agilent 6230 high-resolution mass spectrometer

with electrospray ionization (ESI) and a time-of-ﬂight analyzer

operating at a positive or negative full scan mode in the range of 100−

1700 m/z. SFC chiral analyses were performed using an Acquity

UPC2 system (Waters) consisting of a binary solvent manager,

sample manager, column manager, column heater, convergence

manager, PDA detector 2998, QDa mass detector and chiral analytical

column Chiralpak IA3 (4.6 mm × 100 mm, 3 μm particle size), and

Chiralpak IE3 (4.6 mm × 100 mm, 3 μm particle size). The

chromatographic runs were performed at a ﬂow rate of 2.2 mL/min,

column temperature of 38 °C, and ABPR 2000 psi. Microwave

irradiation experiments were carried out in a dedicated CEM-Discover

monomode microwave apparatus. The reactor was used in the

standard conﬁguration as delivered, including proprietary software.

The reactions were carried out in 10 mL glass vials sealed with a

silicone/PTFE Vial cap top, which can be exposed to a maximum of

250 °C and 20 bar internal pressure. The temperature was measured

with an IR sensor on the outer surface of the process vial. After the

irradiation period, the reaction vessel was cooled to ambient

temperature by gas jet cooling. Puriﬁcation using semiprep HPLC

was carried out on Agilent 1200 series using the C18 reverse-phase

column (YMC Pack ODS-A, 20 mm ×100 mm, 5 mm particles). The

gradient was formed from 10 mM aqueous ammonium acetate

(buﬀer) and CH₃CN with a ﬂow rate of 15 mL/min. Potentiometric

titration for the determination of a dissociation constant was carried

out using a benchtop meter pH 50+ DHS (Instruments XS, Italy)

equipped with an ATC glass electrode. Before each measurement, a

pH meter was calibrated with pH 4.01 and 7.00 buﬀer solutions. The

titration was performed using Titronic basic piston burette (Schott

Instruments, Germany). A 0.01 M basic solution was prepared by

dissolving an appropriate amount of 50% (w/v) aqueous sodium

hydroxide solution purchased from Sigma-Aldrich in deionized water

(Merck Millipore, USA). The titrant was added in 0.02 mL

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increments. Dissociation constants were calculated from titration

curves.

reduced pressure. The residue was suspended in EtOH (5 mL) and

(NH₄)₆Mo₇O₂₄·4H₂O (0.37 g, 0.3 equiv) was added at once. The

resulting mixture was cooled to 0 °C (ice/water bath), and a solution

of H₂O₂in water (2 mL, 20 equiv; 30% in water) was added dropwise

(AVOID metallic needle). After 30 min at 0 °C, the cooling bath was

removed, and the reaction mixture was allowed to warm to RT. The

progress was monitored by TLC. The resulting mixture was

repartitioned between CH₂Cl₂(25 mL) and H₂O (25 mL). The

resulting layers were separated, and the aqueous layer was extracted

with CH₂Cl₂(3 × 25 mL). Combined organic layers were washed

with brine (25 mL), dried over MgSO₄, ﬁltered, and the solvents were

removed under reduced pressure to yield the crude product.

Method C (Scheme 5B). Sulfonyl ﬂuoride 8 (0.050 g, 0.23 mmol, 1

equiv) was dissolved in CH₃CN (2.3 mL), and amine (0.69 mmol, 3

equiv) was added at RT. The reaction mixture was stirred overnight at

RT. Aq. sat. NH₄Cl (10 mL) was added, and the resulting layers were

separated. The aqueous layer was extracted with CH₂Cl₂(3 × 15

mL), and the organic layers were combined, washed with brine (10

mL), dried over MgSO₄, ﬁltered, and the solvents were removed

under reduced pressure to yield the crude product.

Sodium Benzo[d]thiazole-2-sulﬁnate (2) Synthesis.¹⁸Disul-

ﬁde (2.0 g, 6.0 mmol, 1 equiv) was dissolved in dry CH₂Cl₂(25 mL)

and MeOH (25 mL). NBS (5.36 g, 30 mmol, 5 equiv) was added

portionwise within 5 min and the reaction progress was followed by

TLC. After disulﬁde consumption, the reaction was quenched with

sat. aq. NaHCO₃(25 mL) and the whole mixture was extracted with

CH₂Cl₂(3 × 30 mL). Combined organic layers were washed with

brine (25 mL), dried over MgSO₄, and the solvents were evaporated

under reduced pressure. The residue was puriﬁed by ﬂash column

chromatography (SiO₂, EtOAc/petroleum ether = 1:3) and the

concentration of relevant fractions yielded the desired product as a

yellowish amorphous solid (0.83 g, 65%). ¹H NMR (400 MHz,

chloroform-d): δ 7.54 (ddd, J = 8.0, 7.2, 1.3 Hz, 1H), 7.60 (ddd, J =

8.3, 7.2, 1.4 Hz, 1H), 8.01 (ddd, J = 7.9, 1.4, 0.7 Hz, 1H), 8.18 (ddd, J

= 8.2, 1.4, 0.7 Hz, 1H), 3.74 (s, 3H); ¹³C {¹H} NMR (101 MHz,

chloroform-d): δ 175.0, 153.8, 136.2, 127.3, 127.3, 125.1, 122.5, 51.5;

MS (ESI) m/z (%) 214: [M + H]⁺(78); HRMS (ESI) m/z: [M +

H]⁺calcd for C₈H₈NO₂S₂, 213.9991; found 213.9994.

Methyl sulﬁnate (1.3 g, 6 mmol, 1 equiv) was dissolved in THF (3

mL), and H₂O (3 mL) was added. Sodium hydroxide (0.243 g, 6

mmol, 1 equiv; powder) was added to the suspension at RT. The

whole mixture became clear within 1 min, and the conversion of

starting methyl ester was monitored by TLC. After the reaction

completion, the organic solvents were evaporated under reduced

pressure and the remaining water was removed with the help of a

freeze-dry technique to yield compound 2 as a white powder (1.02 g,

93%). (Attention: all water content must be carefully removed to avoid

N-Benzylbenzo[d]thiazole-2-sulfonamide (3a). The crude prod-

uct was puriﬁed using ﬂash column chromatography (SiO₂; EtOAc/

hexane = 1:4) and obtained as a white solid.

Method A. Starting from 0.050 g (0.22 mmol) of 2, yielded 0.061 g

(91%); starting from 2.13 g (10.0 mmol) of 2, yielded 2.72 g (90%).

Method B. Starting from 0.167 g (1.0 mmol) of 1, yielded 0.279 g

(92% over two steps); starting from 1.67 g (10.0 mmol) of 1, yielded

2.86 g (94% over two steps).

Method C. Starting from 0.050 g (0.23 mmol) of 8, yielded 0.032 g

1

lousy reactivity of 2 in subsequent reactions). H NMR (400 MHz,

1

(65%). Mp = 108−112 °C; H NMR (400 MHz, chloroform-d): δ

DMSO-d₆): δ 7.39 (ddd, J = 8.1, 7.3, 1.3 Hz, 2H), 7.46 (ddd, J = 8.2,

7.3, 1.3 Hz, 2H), 7.92 (ddd, J = 8.1, 1.1, 0.6 Hz, 2H), 8.05 (ddd, J =

7.9, 1.2, 0.6 Hz, 2H); ¹³C {¹H} NMR (101 MHz, DMSO-d₆): δ

194.8, 153.9, 134.9, 125.6, 124.9, 122.9, 122.6.

8.17−8.14 (m, 1H), 7.99−7.96 (m, 1H), 7.62 (ddd, J = 8.1, 7.2, 1.5

Hz, 1H), 7.57 (ddd, J = 7.8, 7.2, 1.4 Hz, 1H), 5.46 (t, J = 5.4 Hz, 1H),

4.44 (d, J = 6.1 Hz, 2H); ¹³C{¹H} NMR (101 MHz, chloroform-d): δ

166.0, 152.4, 136.5, 135.7, 128.9, 128.3, 128.2, 127.8, 127.6, 125.2,

122.3, 48.2; MS (ESI) m/z (%) 305: [M + H]⁺(100); HRMS (ESI)

m/z: [M + H]⁺calcd for C₁₄H₁₃N₂O₂S₂, 305.0413; found, 305.0412.

N-Allylbenzo[d]thiazole-2-sulfonamide (3b). The crude product

was puriﬁed using ﬂash column chromatography (SiO₂; EtOAc/

hexane = 1:1) and obtained as a slightly yellow solid.

Preparation of Benzo[d]thiazole-2-sulfonyl Fluoride (8).

Sulﬁnic salt 2 (0.5 g, 2.26 mmol, 1 equiv) was suspended in

CH₂Cl₂(23 mL), and the resulting suspension was cooled to 0 °C

(ice/water). After 5 min at 0 °C, a Selectﬂuor (1.60 g, 4.52 mmol, 2

equiv) was added in ten portions. After 5 min at 0 °C, the mixture was

allowed to warm to RT (cooling bath removed), and the resulting

mixture was stirred for an additional 30 min at RT. Water (25 mL)

was added, and the resulting mixture was extracted with CH₂Cl₂(3 ×

50 mL). Combined organic layers were washed with brine (50 mL),

dried over MgSO₄, ﬁltered, and the solvents were removed under

reduced pressure to yield a white crystalline product (0.383 g, 78%).

Method A. Starting from 0.044 g (0.20 mmol) of 2, yielded 0.033 g

(65%).

Method B. Starting from 0.167 g (1.0 mmol) of 1, yielded 0.129 g

(51% over two steps).

Method C. Starting from 0.050 g (0.23 mmol) of 8, yielded 0.0292

1

g (72%). Mp = 106−110 °C; H NMR (400 MHz, chloroform-d): δ

Mp = 94−96 °C (litt.^57bmp = 95−96 °C); H NMR (400 MHz,

1

8.16 (ddd, J = 8.2, 1.3, 0.7 Hz, 1H), 7.96 (ddd, J = 7.8, 1.5, 0.7 Hz,

1H), 7.60 (ddd, J = 8.0, 7.2, 1.4 Hz, 1H), 7.55 (ddd, J = 8.1, 7.3, 1.5,

1H), 5.79 (ddt, J = 17.1, 10.2, 5.9 Hz, 1H), 5.46 (t, J = 6.2 Hz, 1H),

5.24 (dq, J = 17.1, 1.5 Hz, 1H), 5.11 (dq, J = 10.2, 1.3 Hz, 1H), 3.88

(tt, J = 6.0, 1.5 Hz, 2H); ¹³C{¹H} NMR (101 MHz, chloroform-d): δ

166.1, 152.4, 136.5, 132.5, 127.8, 127.6, 125.2, 122.3, 118.5, 46.5; MS

(ESI) m/z (%) 255: [M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺

calcd for C₁₀H₁₁N₂O₂S₂, 255.0256; found, 255.0257.

chloroform-d): δ 8.36−8.31 (m, 1H), 8.09−8.04 (m, 1H), 7.75−7.68

(m, 2H); ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 156.3 (d, J =

38.2 Hz), 152.1, 137.2, 129.5, 128.6, 126.5, 122.4; ¹⁹F{¹H} NMR

(376 MHz, chloroform-d): δ 64.2; MS (ESI) m/z (%) 218: [M + H]⁺

(100); HRMS (ESI) m/z: [M + H]⁺calcd for C₇H₅FNO₂S₂,

217.9746; found, 217.9755.

Sulfonamide 3, 4, and 10 Preparation. Method A (Table 2,

Method A). Sulﬁnic salt 2 (0.5 g, 2.22 mmol, 1 equiv) and amine

(2.71 mmol, 1.2 equiv) were added to the solvent mixture of THF/

EtOH = 4:1 (V/V) (25 mL) at RT. The resulting mixture was stirred

at RT for 5 min, and NBS (0.800 g, 4.52 mmol, 2 equiv) was added

portionwise over a period of 5 min. The reaction mixture turned the

color to orange upon the NBS addition. After an additional 10 min at

RT, the reaction mixture was partitioned between CH₂Cl₂(25 mL)

and water (25 mL). The resulting layers were separated, and the

aqueous layer was extracted with CH₂Cl₂(3 × 25 mL). The

combined organic layers were washed with brine (25 mL), dried over

MgSO₄, and ﬁltered, and the solvents were evaporated under reduced

pressure to provide the crude product.

N-Butyl Benzo[d]thiazole-2-sulfonamide (3c). The crude product

was puriﬁed using ﬂash column chromatography (SiO₂; EtOAc/

hexane = 1:3) and obtained as a colorless oil.

Method A. Starting from 0.044 g (0.20 mmol) of 2, yielded 0.036 g

(67%).

Method B. Starting from 0.167 g (1.0 mmol) of 1, yielded 0.178 g

(66% over two steps).

Method C. Starting from 0.050 g (0.23 mmol) of 8, yielded 0.035 g

1

(56%). H NMR (400 MHz, chloroform-d): δ 8.18−8.16 (m, 1H),

7.99−7.96 (m, 1H), 7.56 (ddd, J = 8.1, 7.2, 1.4 Hz, 1H), 7.61 (ddd, J

= 8.2, 7.2, 1.4 Hz, 1H), 5.18 (t, J = 6.0 Hz, 1H), 3.25 (td, J = 7.1, 6.1

Hz, 2H), 1.58−1.51 (m, 2H), 1.40−1.30 (m, 2H), 0.88 (t, J = 7.4 Hz,

3H); ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 166.2, 152.5, 136.6,

127.7, 127.6, 125.2, 122.3, 43.9, 31.9, 19.7, 13.6; MS (ESI) m/z (%)

271: [M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₁H₁₅N₂O₂S₂, 271.0569; found, 271.0569.

Method B (Table 2, Method B). Benzo[d]thiazole-2-thiol (0.167 g,

1 mmol, 1.0 equiv) and amine (3 mmol, 3.0 equiv) were dissolved in

CH₂Cl₂(5 mL) at RT, and NCS (0.133 g, 1 mmol, 1.0 equiv) was

added portionwise over a period of 5 min. The resulting mixture was

stirred at RT for 30 min before the solvent was removed under

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N-(Furan-2-ylmethyl)benzo[d]thiazole-2-sulfonamide (3d). The

crude product was puriﬁed using ﬂash column chromatography (SiO₂;

EtOAc/hexane = 1:1) and obtained as a colorless oil.

Method B. Starting from 0.167 g (1.0 mmol) of 1, yielded 0.114 g

(39% over two steps).

chloroform-d): δ 167.9, 151.5, 136.3, 127.8, 127.7, 124.9, 122.3, 62.9,

30.4, 19.3, 18.6; MS (ESI) m/z (%) 301: [M + H]⁺(100); HRMS

(ESI) m/z: [M + H]⁺calcd for C₁₂H₁₇N₂O₃S₂, 301.0675; found,

301.0677.

(−)-N-(2-Hydroxy-1-phenylethyl)benzo[d]thiazole-2-sulfona-

mide ((−)-3i). The crude product was puriﬁed using ﬂash column

chromatography (SiO₂; EtOAc/hexane = 4:5) and obtained as a

white solid.

Method C. Starting from 0.050 g (0.23 mmol) of 8, yielded 0.031 g

1

(45%). H NMR (400 MHz, chloroform-d): δ 8.14−8.13 (m, 1H),

7.97−7.96 (m, 1H), 7.56 (ddd, J = 8.3, 7.3, 1.3 Hz, 1H), 7.61 (ddd, J

= 8.3, 7.2, 1.3 Hz, 1H), 7.17 (m, 1H), 6.16 (dd, J = 3.1, 0.7 Hz, 1H),

6.13 (dd, J = 3.2, 1.9 Hz, 1H), 5.56−5.54 (m, 1H), 4.46 (d, J = 6.0

Hz, 2H); ¹³C{¹H} NMR (126 MHz, chloroform-d): δ 165.9, 152.5,

148.9, 143.0, 136.5, 127.8, 127.6, 125.2, 122.3, 110.5, 108.9, 40.9; MS

(ESI) m/z (%) 295: [M + H]⁺(100); HRMS (ESI) m/z: [M + K]⁺

calcd for C₁₂H₁₀KN₂O₃S₂, 332.9764; found, 332.9767.

Method A. Starting from 0.044 g (0.20 mmol) of 2, yielded 0.024 g

(37%).

Method B. Starting from 0.167 g (1.0 mmol) of 1, yielded 0.160 g

(47% over two steps). Mp = 118−120 °C; [α]²_D³= − 144° (c 0.25,

1

CH₂Cl₂); H NMR (400 MHz, chloroform-d): δ 8.07 (ddd, J = 7.9,

1.5, 0.5 Hz, 1H), 7.90 (ddd, J = 7.5, 1.5, 0.6 Hz, 1H), 7.60−7.51 (m,

2H), 7.27−7.25 (m, 2H), 7.22−7.13 (m, 3H), 4.84 (dd, J = 6.3, 4.3

Hz, 1H), 3.94 (dd, J = 11.7, 4.3 Hz, 1H), 3.86 (dd, J = 11.7, 6.4 Hz,

1H); ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 167.0, 151.8, 137.6,

136.5, 128.8, 128.3, 127.8, 127.6, 127.0, 125.0, 122.2, 66.1, 60.5; MS

(ESI) m/z (%) 335: [M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺

calcd for C₁₅H₁₅N₂O₃S₂, 335.0519; found, 335.0516.

tert-Butyl (2-(Benzo[d]thiazole-2-sulfonamido)ethyl)carbamate

(3e). The crude product was puriﬁed using ﬂash column

chromatography (SiO₂; EtOAc/hexane = 2:3) and obtained as a

white solid.

Method A. Starting from 0.221 g (1.0 mmol) of 2, yielded 0.172 g

1

(67%). Mp = 142−146 °C; H NMR (400 MHz, chloroform-d): δ

(S)-Diethyl (Benzo[d]thiazol-2-ylsulfonyl)glutamate ((−)-3j).

Method B (the method was slightly modiﬁed since hydrochloride

salt was used): ^L-glutamate hydrochloride (0.215 g, 0.9 mmol) was

suspended in CH₂Cl₂(3 mL) at RT, and Et₃N (0.125 mL, 0.9 mmol,

9 equiv) followed by 1 (0.050 g, 0.3 mmol, 3 equiv) were added. After

5 min at RT, N-chlorosuccinimide (0.040 g, 0.3 mmol, 3.0 equiv) was

added, and the resulting mixture was stirred at RT for 2 h. CH₂Cl₂

(20 mL) and H₂O (20 mL) were added, and the resulting layers were

separated. The aqueous layer was extracted with CH₂Cl₂(3 × 15

mL), and the combined organic layers were washed with brine (10

mL), dried over MgSO₄, ﬁltered, and the solvents were removed

under reduced pressure. The residue was suspended in EtOH (2 mL),

and (NH₄)₆M₇O₄·4H₂O (0.123 g, 0.1 mmol, 0.1 equiv) was added.

The resulting slurry was cooled to 0 °C (ice/water), and H₂O₂in

water (0.610 mL, 20 equiv; 30% in water) was added dropwise. The

resulting mixture was stirred at 0 °C for 5 min before the cooling bath

was removed. After 12 h at RT, the whole mixture was diluted with

CH₂Cl₂(20 mL) and H₂O (20 mL) and the resulting layers were

separated. The aqueous layer was extracted with CH₂Cl₂(3 × 15

mL), and combined organic layers were washed with brine (15 mL),

dried over MgSO₄, ﬁltered, and the solvents were removed under

reduced pressure. The puriﬁcation of the crude product using ﬂash

column chromatography (SiO₂; EtOAc/petroleum ether = 1:3)

8.17 (ddd, J = 8.3, 1.5, 0.7 Hz, 1H), 7.97 (ddd, J = 7.6, 1.3, 0.6 Hz,

1H), 7.61 (ddd, J = 7.9, 7.2, 1.4 Hz, 1H), 7.56 (ddd, J = 7.9, 7.2, 1.5

Hz, 1H), 6.01 (bs, 1H), 5.05 (t, J = 5.2 Hz, 1H), 3.44−3.41 (m, 2H),

3.44−3.30 (m, 2H), 1.39 (s, 9H); ¹³C{¹H} NMR (101 MHz,

chloroform-d): δ 166.3, 156.7, 152.3, 136.5, 127.7, 127.5, 125.2,

122.3, 80.2, 44.8, 40.4, 28.4; MS (ESI) m/z (%) 356: [M + H]⁺

(100); HRMS (ESI) m/z [M + K]⁺calcd for C₁₄H₁₉N₃O₄S₂K,

396.0449; found, 396.0452.

N-(1-(4-Chlorophenyl)ethyl)benzo[d]thiazole-2-sulfonamide

(3f). The crude product was puriﬁed using ﬂash column

chromatography (SiO₂; EtOAc/hexane = 1:10) and obtained as a

colorless oil.

Method A. Starting from 0.044 g (1.0 mmol) of 2, yielded 0.052 g

(74%).

Method C. Starting from 0.050 g (0.23 mmol) of 8, yielded 0.0196

1

g (24%). H NMR (400 MHz, chloroform-d): δ 8.07 (ddd, J = 8.2,

1.3, 0.6 Hz, 1H), 7.92 (ddd, J = 7.8, 1.3, 0.6 Hz, 1H), 7.60 (ddd, J =

8.2, 7.2, 1.4 Hz, 1H), 7.55 (ddd, J = 8.4, 7.3, 1.3 Hz, 2H), 7.12 (dt, J =

8.8, 2.0 Hz, 2H), 7.05 (dt, J = 8.9, 2.4 Hz, 2H), 5.74 (d, J = 7.4 Hz,

1H), 4.77 (p, J = 7.0 Hz, 1H), 1.53 (d, J = 6.9 Hz, 3H); ¹³C{¹H}

NMR (101 MHz, chloroform-d): δ 166.5, 152.2, 139.8, 136.5, 133.7,

128.7, 127.8, 127.7, 127.5, 125.0, 122.1, 54.2, 23.2; MS (ESI) m/z

(%) 351: [M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₅H₁₄ClN₂O₂S₂, 353.0180; found, 353.0178.

yielded 0.114 g (66% over two steps) of 3j as a viscose syrup. [α]_D²⁰

=

−112° (c 0.44, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d): δ 8.11

(ddd, J = 8.2, 1.6, 0.6 Hz, 1H), 7.97 (ddd, J = 7.7, 1.6, 0.7 Hz, 1H),

7.62−7.53 (m, 2H), 5.80 (bs, 1H), 4.47 (dd, J = 8.8, 4.6 Hz, 1H),

4.13 (q, J = 7.1 Hz, 2H), 4.04−3.98 (m, 2H), 2.60−2.46 (m, 2H),

2.25 (dtd, J = 14.2, 7.5, 4.7 Hz, 1H), 2.00 (dddd, J = 14.3, 8.8, 7.8, 6.4

Hz, 1H), 1.25 (t, J = 7.2 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H); ¹³C{¹H}

NMR (101 MHz, chloroform-d): δ 172.7, 171.0, 165.7, 152.4, 136.5,

127.8, 127.6, 125.1, 122.3, 62.3, 60.9, 56.3, 30.0, 28.5, 14.3, 14.1; MS

(ESI) m/z (%) 401: [M + H]⁺(100); HRMS (ESI) m/z: [M + K]⁺

calcd for C₁₆H₂₀KN₂O₆S₂, 439.0394; found, 439.0396.

(−)-Methyl (Benzo[d]thiazol-2-ylsulfonyl)-^L-phenylalaninate

((−)-3k). Method B (the method was slightly modiﬁed since

hydrochloride salt was used): Methyl ^L-phenylalaninate hydrochloride

(0.193 g, 0.9 mmol) was suspended in CH₂Cl₂(3 mL) at RT, and

Et₃N (0.125 mL, 0.9 mmol, 9 equiv) followed by 1 (0.050 g, 0.3

mmol, 3 equiv) were added. After 5 min at RT, N-chlorosuccinimide

(0.040 g, 0.3 mmol, 3.0 equiv) was added, and the resulting mixture

was stirred at RT for 2 h. CH₂Cl₂(20 mL) and H₂O (20 mL) were

added, and the resulting layers were separated. The aqueous layer was

extracted with CH₂Cl₂(3 × 15 mL), and the combined organic layers

were washed with brine (10 mL), dried over MgSO₄, ﬁltered, and the

solvents were removed under reduced pressure. The residue was

suspended in EtOH (2 mL), and (NH₄)₆M₇O₄·4H₂O (0.123 g, 0.1

mmol, 0.1 equiv) was added. The resulting slurry was cooled to 0 °C

(ice/water), and H₂O₂in water (0.610 mL, 20 equiv; 30% in water)

was added dropwise. The resulting mixture was stirred at 0 °C for 5

N-(Benzo[d][1,3]dioxol-5-ylmethyl)benzo[d]thiazole-2-sulfona-

mide (3g). The crude product was puriﬁed using ﬂash column

chromatography (SiO₂; EtOAc/hexane = 3:4) and obtained as a

white solid.

Method B. Starting from 0.167 g (1.0 mmol) of 1, yielded 0.150 g

1

(43% over two steps). Mp = 140−141 °C; H NMR (400 MHz,

chloroform-d): δ 8.14 (d, J = 8.1 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H),

7.61 (dt, J = 7.2, 1.1 Hz), 7.56 (dt, J = 8.1, 1.4 Hz, 1H), 7.59−7.54

(m, 1H), 6.76 (s, 1H), 6.72 (d, J = 8.6 Hz, 1H), 6.65 (d, J = 8.6 Hz,

1H), 5.84 (s, 2H), 5.76−5.60 (bs, 1H), 4.32 (d, J = 5.5 Hz, 1H);

¹³C{¹H} NMR (101 MHz, chloroform-d): δ 166.3, 152.4, 148.1,

147.6, 136.5, 129.5, 127.7, 127.6, 125.2, 122.3, 121.9, 108.8, 108.4,

101.3, 48.0; MS (ESI) m/z (%) 349: [M + H]⁺(100); HRMS (ESI)

m/z: [M + H]⁺calcd for C₁₅H₁₃N₂O₄S₂, 349.0311; found, 349.0307.

(−)-(S)-N-(1-Hydroxy-3-methylbutan-2-yl)benzo[d]thiazole-2-

sulfonamide ((−)-3h). The crude product was puriﬁed using ﬂash

column chromatography (SiO₂; EtOAc/hexane = 1:1) and obtained

as a colorless oil.

Method A. Starting from 0.044 g (0.20 mmol) of 2, yielded 0.038 g

(64%).

Method B. Starting from 0.167 g (1.0 mmol) of 1, yielded 0.135 g

(45% over two steps). [α]_D²¹= −335° (c 0.2, MeOH); ¹H NMR (400

MHz, chloroform-d): δ 8.11 (ddd, J = 7.4, 1.6, 0.5 Hz, 1H), 7.98−

7.96 (m, 1H), 7.62−7.54 (m, 2H), 5.25 (d, J = 8.3 Hz, 1H), 3.74−

3.65 (m, 2H), 3.58−3.52 (m, 1H), 3.10 (t, J = 5.9 Hz, 1H), 1.94 (oct,

J = 6.8 Hz, 1H), 0.99 (d, J = 6.8 Hz, 6H); ¹³C{¹H} NMR (101 MHz,

L

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min before the cooling bath was removed. After 12 h at RT, the whole

mixture was diluted with CH₂Cl₂(20 mL) and H₂O (20 mL) and the

resulting layers were separated. The aqueous layer was extracted with

CH₂Cl₂(3 × 15 mL), and combined organic layers were washed with

brine (15 mL), dried over MgSO₄, ﬁltered, and the solvents were

removed under reduced pressure. The puriﬁcation of the crude

product using ﬂash column chromatography (SiO₂; EtOAc/

petroleum ether = 1:3) yielded 0.27 g (80% over two steps) of 3k

yielded 0.031 g (30%). [α]²_D¹= −5.63° (c 0.16, CH₂Cl₂); H NMR

(400 MHz, chloroform-d): δ 9.43 (d, J = 3.2 Hz, 2H), 8.31 (dt, J =

8.3, 1.0 Hz, 2H), 7.95−7.89 (m, 2H), 7.61 (ddd, J = 8.4, 7.2, 1.3 Hz,

2H), 7.54 (ddd, J = 8.4, 7.2, 1.3 Hz, 2H), 3.58−3.49 (m, 2H), 2.49

(dt, J = 14.0, 2.7 Hz, 2H), 1.79−1.67 (m, 2H), 1.64−1.45 (m, 4H);

¹³C{¹H} NMR (101 MHz, Chloroform-d): δ 168.6, 149.8, 136.1,

128.2, 128.13, 125.2, 122.3, 57.8, 35.9, 24.4; MS (ESI) m/z (%) 510:

[M + H]⁺(100); HRMS (ESI) m/z: [M + K]⁺calcd for

C₂₀H₂₁N₄O₄S₄, 509.0440; found, 509.0442.

1

as a viscose syrup. [α]_D²³= −129° (c 0.51, CH₂Cl₂); H NMR (400

1

MHz, chloroform-d): δ 8.12 (ddd, J = 7.9, 1.7, 0.6 Hz, 1H), 7.95

(ddd, J = 7.7, 1.5, 0.6 Hz, 1H), 7.60 (ddd, J = 8.2, 7.2, 1.5 Hz, 1H),

7.55 (ddd, J = 7.9, 7.2, 1.4 Hz, 1H), 7.26−7.14 (m, 3H), 7.11−7.09

(m, 2H), 5.58 (bs, 1H), 4.72 (t, J = 5.8 Hz, 1H), 3.55 (s, 3H), 3.19

(dd, J = 13.9, 5.7 Hz, 1H), 3.13 (dd, J = 13.9, 5.9 Hz, 1H); ¹³C{¹H}

NMR (101 MHz, chloroform-d): δ 170.9, 165.6, 152.4, 136.5, 134.7,

129.5, 128.7, 127.8, 127.5, 127.4, 125.2, 122.3, 57.6, 52.7, 39.5; MS

(ESI) m/z (%) 377: [M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺

calcd for C₁₇H₁₇N₂O₄S₂, 377.0624; found, 377.0627.

1-(Benzo[d]thiazol-2-ylsulfonyl)piperidin-4-ol (4a). The crude

product was puriﬁed using ﬂash column chromatography (SiO₂;

EtOAc/hexane = 1:1 ≥ 4:3 ≥ 8:3) and obtained as a colorless oil.

Method A. Starting from 0.044 g (0.20 mmol) of 2, yielded 0.045 g

1

(76%). H NMR (400 MHz, chloroform-d): δ 8.20−8.17 (m, 1H),

7.99−7.96 (m, 1H), 7.63−7.54 (m, 2H), 3.91−3.86 (m, 1H), 3.71−

3.64 (m, 2H), 3.34−3.28 (m, 2H), 2.00−1.94 (m, 2H), 1.72−1.68

(m, 2H); ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 164.1, 152.8,

136.4, 127.7, 127.5, 125.4, 122.2, 65.8, 43.7, 33.4; MS (ESI) m/z (%)

290: [M + H]⁺(100); HRMS (ESI) m/z, [M + H]⁺calcd for

C₁₂H₁₅N₂O₃S₂, 299.0519; found, 299.0521.

(−)-Methyl (Benzo[d]thiazol-2-ylsulfonyl)alaninate ((−)-3l).

Method B (the method was slightly modiﬁed since hydrochloride

salt was used): Methyl alaninate hydrochloride (0.125 g, 0.9 mmol)

was suspended in CH₂Cl₂(3 mL) at RT, and Et₃N (0.125 mL, 0.9

mmol, 9 equiv) followed by 1 (0.050 g, 0.3 mmol, 3 equiv) were

added. After 5 min at RT, N-chlorosuccinimide (0.040 g, 0.3 mmol,

3.0 equiv) was added, and the resulting mixture was stirred at RT for

2 h. CH₂Cl₂(20 mL) and H₂O (20 mL) were added, and the

resulting layers were separated. The aqueous layer was extracted with

CH₂Cl₂(3 × 15 mL), and the combined organic layers were washed

with brine (10 mL), dried over MgSO₄, ﬁltered, and the solvents were

removed under reduced pressure. The residue was suspended in

EtOH (2 mL), and (NH₄)₆M₇O₄·4H₂O (0.123 g, 0.1 mmol, 0.1

equiv) was added. The resulting slurry was cooled to 0 °C (ice/

water), and H₂O₂in water (0.610 mL, 20 equiv; 30% in water) was

added dropwise. The resulting mixture was stirred at 0 °C for 5 min

before the cooling bath was removed. After 12 h at RT, the whole

mixture was diluted with CH₂Cl₂(20 mL) and H₂O (20 mL) and the

resulting layers were separated. The aqueous layer was extracted with

CH₂Cl₂(3 × 15 mL), and combined organic layers were washed with

brine (15 mL), dried over MgSO₄, ﬁltered, and the solvents were

removed under reduced pressure. The puriﬁcation of the crude

product using ﬂash column chromatography (SiO₂; EtOAc/

petroleum ether = 1:3) yielded 0.059 g (66% over two steps) of 3l

2-(Piperidin-1-ylsulfonyl)benzo[d]thiazole (4b). The crude prod-

uct was puriﬁed using ﬂash column chromatography (SiO₂; EtOAc/

CHCl₃= 1:1 ≥ 0:1) and obtained as a white solid.

Method A. Starting from 0.044 g (0.20 mmol) of 2, yielded 0.031 g

(55%). Method C: starting from 0.050 g (0.23 mmol) of 8, yielded

0.0156 g (24%). Mp = 109−113 °C; ¹H NMR (400 MHz,

chloroform-d): δ 8.20 (ddd, J = 8.2, 1.3, 0.7 Hz, 1H), 7.98 (ddd, J

= 7.9, 1.4, 0.7 Hz, 1H), 7.61 (ddd, J = 8.2, 7.2, 1.4 Hz, 1H), 7.56

(ddd, J = 7.9, 7.2, 1.4 Hz, 1H), 3.40−3.37 (m, 4H), 1.71−1.66 (m,

4H), 1.56−1.50 (m, 2H); ¹³C{¹H} NMR (101 MHz, chloroform-d):

δ 164.6, 152.8, 136.4, 127.6, 127.4, 125.3, 122.2, 47.6, 25.4, 23.6; MS

(ESI) m/z (%) 283: [M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺

calcd for C₁₂H₁₅N₂O₂S₂, 283.0569; found, 283.0570.

N-Cyclohexyl-N-methylbenzo[d]thiazole-2-sulfonamide (4c).

The crude product was puriﬁed using ﬂash column chromatography

(SiO₂; EtOAc/hexane = 1:3) and obtained as a white solid.

Method B. Starting from 0.167 g (1.0 mmol) of 1, yielded 0.107 g

(34%).

Method C. Starting from 0.050 g (0.23 mmol) of 8, yielded 0.011 g

(22%). Mp = 80−82 °C; ¹H NMR (400 MHz, chloroform-d): δ

8.18−8.16 (m, 1H), 7.97−7.95 (m, 1H), 7.59 (ddd, J = 8.3, 7.2, 1.4

Hz, 1H), 7.56−7.52 (m, 1H), 3.98 (tt, J = 11.6, 3.8 Hz, 1H), 2.98 (s,

3H), 1.77−1.59 (m, 5H), 1.43−1.29 (m, 4H), 1.07−0.98 (m, 1H);

¹³C{¹H} NMR (101 MHz, chloroform-d): δ 166.4, 152.8, 136.4,

as a viscose syrup. [α]²_D⁰= −18.2° (c 0.45, CHCl₃); H NMR (400

1

MHz, chloroform-d): δ 8.14 (ddd, J = 8.3, 1.3, 0.6 Hz, 1H), 7.97

(ddd, J = 7.7, 1.4, 0.6 Hz, 1H), 7.58−7.65 (m, 1H), 7.50−7.60 (m,

1H), 5.84 (bs, 1H), 4.48 (bs, 1H), 3.61 (s, 3H), 1.51 (d, J = 7.2 Hz,

3H); ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 172.4, 165.9, 152.4,

136.5, 127.8, 127.6, 125.2, 122.4, 53.0, 52.6, 20.1; MS (ESI) m/z (%)

301: [M + H]⁺(100); HRMS (ESI) m/z: [M + K]⁺calcd for

C₁₁H₁₂KN₂O₄S₂, 338.9870; found, 338.9873.

127.5, 127.4, 125.3, 122.2, 58.1, 30.6, 29.5, 25.8, 25.4; MS (ESI) m/z

(%) 311: [M + H]⁺(100); HRMS (ESI) m/z: [M + K]⁺calcd for

C₁₄H₁₉N₂O₂S₂, 311.0882; found, 311.0886.

Synthesis of Fully Protected Amino Alcohols 10. 3-(N-

(Benzo[d]thiazol-2-ylsulfonyl)acetamido)propyl Acetate (10a)

(Scheme 5B, Equation 4). Prepared using the Method A from 2

(0.100 g, 0.45 mmol). The crude product obtained using the Method

A was dissolved in pyridine (2 mL), and Ac₂O (0.128 mL, 1.35 mmol,

3.0 equiv) was added at RT. The resulting mixture was stirred for 12 h

at RT before sat. aq. NH₄Cl (5 mL) was added. The resulting mixture

was extracted with EtOAc (3 × 15 mL), and the resulting organic

layers were combined and washed with brine (10 mL), dried over

MgSO₄, ﬁltered, and the solvents were removed under reduced

pressure. The crude product was puriﬁed by ﬂash column

chromatography (SiO₂; EtOAc:hexane = 1:2) to yield 0.113 g (71%

over two steps) of 10a and obtained as a colorless oil. ¹H NMR (400

MHz, chloroform-d): δ 8.18−8.16 (m, 1H), 8.00−7.98 (m, 1H),

7.66−7.58 (m, 2H), 4.13 (t, J = 6.1 Hz, 2H), 4.00−3.96 (m, 2H),

2.58 (s, 3H), 2.11−2.08 (m, 2H), 2.04 (s, 3H); ¹³C{¹H} NMR (101

MHz, chloroform-d): δ 171.2, 170.5, 164.1, 152.1, 136.6, 128.5, 128.0,

125.7, 122.3, 61.9, 45.1, 28.8, 25.6, 21.1; MS (ESI) m/z (%) 357: [M

+ H]⁺(100); HRMS (ESI) m/z [M + H]⁺calcd for C₁₄H₁₇N₂O₅S₂,

357.0573; found, 357.0576.

N-(1-(Naphthalen-1-yl)ethyl)benzo[d]thiazole-2-sulfonamide

(3m). The crude product was puriﬁed using ﬂash column

chromatography (SiO₂; EtOAc/hexane = 1:3) and obtained as a

colorless oil.

Method A. Starting from 0.050 g (0.226 mmol) of 2, yielded 0.029

g (36%). ¹H NMR (400 MHz, chloroform-d): δ 8.02−7.98 (m, 2H),

7.84−7.82 (m, 1H), 7.75−7.71 (m, 1H), 7.61 (d, J = 8.2 Hz, 1H),

7.56−7.48 (m, 2H), 7.44 (dd, J = 7.2, 1.1 Hz, 1H), 7.42−7.36 (m,

2H), 7.24 (dd, J = 8.2, 7.3 Hz, 1H), 5.65−5.63 (m, 1H), 1.72 (d, J =

6.5 Hz, 1H); ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 166.5,

152.3, 137.1, 136.6, 133.9, 130.2, 128.9, 128.6, 127.6, 127.4, 126.6,

125.9, 125.2, 125.1, 123.6, 122.7, 122.1, 50.9, 23.2; MS (ESI) m/z

(%) 370: [M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₉H₁₇N₂O₄S₂, 369.0726; found, 369.0734.

(+)-N-((1R,2R)-2-(Benzo[d]thiazole-2-sulfonamido)cyclohexyl)-

benzo[d]thiazole-2-sulfonamide ((+)-3n). The crude product was

puriﬁed using ﬂash column chromatography (SiO₂; EtOAc/hexane =

1:5 ≥ 1:3) and obtained as a viscose syrup.

Method A. Starting from 0.100 g (0.452 mmol, 2.2 equiv) of 2, and

(1R,2R)-cyclohexane-1,2-diamine (0.0235 g, 0.205 mmol, 1.0 equiv);

N-(Benzo[d]thiazol-2-ylsulfonyl)-N-(6-((tert-butyldimethylsilyl)-

oxy)hexyl)acetamide (10b) (Scheme 5B, Equation 5). Prepared

using the Method A from 2 (0.100 g, 0.45 mmol). The crude product

M

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obtained using the Method A was dissolved in DMF (9 mL) at RT,

and imidazole (0.183 g, 2.7 mmol, 6 equiv) was added. After 5 min at

RT, TBSCl (0.202 g, 1.35 mmol, 3.0 equiv) was added and the

resulting mixture was stirred at RT for 12 h. The solvent was removed

from the reaction mixture by a freeze-drying technique. The crude

product was suspended in pyridine (4 mL), and Ac₂O (0.127 mL,

1.35 mmol, 3.0 equiv) was added at RT. The resulting mixture was

stirred for an additional 12 h before sat. aq. NH₄Cl (10 mL) was

added. The resulting mixture was extracted with CH₂Cl₂(3 × 15

mL), and the resulting organic layers were combined, washed with

brine (10 mL), dried over MgSO₄, ﬁltered, and the solvents were

removed under reduced pressure. The crude product was puriﬁed by

ﬂash column chromatography (SiO₂; EtOAc:hexane = 1:3) to yield

0.279 g (66% over 3 steps) of 10b and obtained as a colorless oil. ¹H

NMR (400 MHz, chloroform-d): δ 8.17 (dd, J = 7.6, 1.6 Hz, 1H),

7.99 (dd, J = 7.5, 1.7 Hz, 1H), 7.65−7.57 (m, 2H), 3.87−3.84 (m,

2H), 3.58 (t, J = 6.5 Hz, 1H), 2.58 (s, 3H), 1.78−1.70 (m, 2H),

1.53−1.46 (m, 2H), 1.36−1.32 (m, 4H), 0.89−0.88 (m, 9H), 0.04−

0.03 (m, 6H); ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 170.5,

164.5, 152.1, 136.7, 128.3, 127.9, 125.6, 122.3, 63.2, 47.9, 32.8, 29.7,

26.6, 26.1, 25.6, 25.5, 18.5, -5.2; MS (ESI) m/z (%) 472: [M + H]⁺

(100); HRMS (ESI) m/z: [M + H]⁺calcd for C₂₁H₃₅N₂O₄S₂Si,

471.1802; found, 417.1805.

7.32 (m, 5H), 4.74 (s, 2H), 4.06 (s, 2H), 1.87−1.86 (m, 1H);

¹³C{¹H} NMR (101 MHz, chloroform-d): δ 164.8, 152.8, 136.5,

134.4, 129.0, 128.9, 128.5, 127.6, 127.5, 125.4, 122.2, 75.7, 74.3, 51.1,

36.4; MS (ESI) m/z (%) 343: [M + H]⁺(100); HRMS (ESI) m/z:

[M + H]⁺calcd for C₁₈H₁₆N₂O₂S₂, 343.0569; found, 343.0571.

N-Benzyl-N-(2-methylallyl)benzo[d]thiazole-2-sulfonamide (4f).

The crude product was puriﬁed using ﬂash column chromatography

(SiO₂; EtOAc/hexane = 1:6 ≥ 1:3) and obtained as a colorless oil.

FM Alkylation. Starting from 0.055 g (0.18 mmol) of 3a, yielded

0.026 g (40%).

Base-Promoted Alkylation. Starting from 0.055 g (0.18 mmol) of

1

3a, carried out at RT, yielded 0.056 g (87%). H NMR (400 MHz,

chloroform-d): δ 8.17 (ddd, J = 8.5, 1.3, 0.7 Hz, 2H), 7.96 (ddd, J =

7.9, 1.3, 0.6 Hz, 1H), 7.63−7.59 (m, 1H), 7.58−7.53 (m, 1H), 7.27−

7.22 (m, 5H), 4.87−4.86 (m, 1H), 4.79−4.78 (m, 1H), 4.59 (s, 2H),

3.94 (s, 2H); ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 166.3,

152.5, 139.5, 136.3, 135.2, 129.0, 128.5, 128.0, 127.6, 127.4, 125.2,

122.2, 115.5, 54.2, 51.6, 19.9; MS (ESI) m/z (%) 359: [M + H]⁺

(100); HRMS (ESI) m/z: [M + H]⁺calcd for C₂₁H₁₉N₂O₂S₂,

359.0882; found, 359.0880.

N,N-Dibenzylbenzo[d]thiazole-2-sulfonamide (4g). The crude

product was puriﬁed using ﬂash column chromatography (SiO₂;

EtOAc/hexane = 1:3) and obtained as a colorless oil.

N-Alkylation of N-Monosubstituted Sulfonamides (Table 3).

General Procedure for Fukuyama−Mitsunobu Alkylation (FM

Alkylation). A sulfonamide 3 (0.18 mmol, 1.0 equiv) was dissolved

in dry THF (4.5 mL) at RT in a 10 mL microwave vial, and alcohol

(0.36 mmol, 2 equiv), PPh₃(0.070 g, 0.27 mmol, 1.5 equiv) and

DIAD (0.052 mL, 0.27 mmol, 1.5 equiv) were successfully added. The

microwave vial was placed in the microwave reactor and heated for 10

min at 50 °C (100 W power). The resulting reaction mixture was

placed in a 25 mL ﬂask and the solvents were removed under reduced

pressure to yield the crude product.

General Procedure for Base-Promoted Alkylation Using Alkyl

Halides (Base-Promoted Alkylation). A sulfonamide (0.098 mmol,

1.0 equiv) was added to DMF (2 mL) at RT. The whole mixture was

cooled to 0 °C and alkyl halide (0.196 mmol, 2.0 equiv) followed by

the addition of K₂CO₃(0.196 mmol, 2.0 equiv) were added. The

resulting mixture was stirred at 0 °C for 5 min. The cooling bath was

removed and the whole mixture was stirred for 12 h at rt (for primary

alkyl halides) or at 50 °C (for secondary alkyl halides; external

temperature, oil bath). Sat. aq. NH₄Cl (10 mL) was added and the

resulting mixture was extracted with CH₂Cl₂(3 × 15 mL). Combined

organic layers were washed with brine (10 mL), dried over MgSO₄,

ﬁltered, and the solvents were removed under reduced pressure to

give the crude product.

FM Alkylation. Starting from 0.070 g (0.23 mmol) of 3a, yielded

0.065 g (72%);

Base-Promoted Alkylation. Starting from 0.030 g (0.09 mmol) of

1

3a, carried out at RT, yielded 0.031 g (81%). H NMR (400 MHz,

chloroform-d): δ 8.17 (ddd, J = 8.3, 1.2, 0.5 Hz, 1H), 7.97 (ddd, J =

7.9, 1.3, 0.5 Hz, 1H), 7.62 (ddd, J = 8.2, 7.3, 1.4 Hz, 1H), 7.57 (ddd, J

= 7.9, 7.2, 1.3 Hz, 1H), 7.21−7.15 (m, 10H), 4.55 (s, 4H); ¹³C{¹H}

NMR (101 MHz, chloroform-d): δ 166.4, 152.5, 136.3, 134.9, 128.9,

128.6, 128.0, 127.6, 127.4, 125.2, 122.2, 51.5; MS (ESI) m/z (%) 395:

[M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺calcd for

C₂₁H₁₉N₂O₂S₂, 395.0882; found, 395.0885.

N-Butyl-N-isopropylbenzo[d]thiazole-2-sulfonamide (4h). The

crude product was puriﬁed using ﬂash column chromatography

(SiO₂; EtOAc/hexane = 2:5) and obtained as a colorless oil.

FM Alkylation. Starting from 0.045 g (0.17 mmol) of 3c, yielded

0.049 g (88%);

Base-Promoted Alkylation. Starting from 0.024 g (0.09 mmol) of

3c, carried out at 50 °C, yielded 0.028 g (94%). ¹H NMR (400 MHz,

chloroform-d): δ 8.16 (ddd, J = 8.4, 1.3, 0.6 Hz, 1H), 7.96 (ddd, J =

7.8, 1.4, 0.6 Hz, 1H), 7.61−7.55 (m, 1H), 7.53 (ddd, J = 8.0, 7.3, 1.4

Hz, 3H), 4.35 (hept, 1H), 3.31−3.27 (m, 2H), 1.76−1.68 (m, 2H),

1.35 (sext, 2H), 1.17 (d, 6H), 0.94 (t, 3H); ¹³C{¹H} NMR (101

MHz, chloroform-d): δ 167.00, 152.7, 136.4, 127.4, 127.3, 125.2,

122.1, 51.1, 44.0, 34.0, 21.5, 20.3, 13.8; MS (ESI) m/z (%) 313: [M +

H]⁺(100); HRMS (ESI) m/z: [M + H]⁺calcd for C₁₄H₂₁N₂O₂S₂,

313.1039; found, 313.1041.

N-Allyl-N-(prop-2-yn-1-yl)benzo[d]thiazole-2-sulfonamide (4i).

The crude product was puriﬁed using ﬂash column chromatography

(SiO₂; EtOAc/hexane = 1:3) and obtained as a colorless oil.

FM Alkylation. Starting from 0.025 g (0.098 mmol) of 3b, yielded

0.022 g (77%).

N-Benzyl-N-isopropylbenzo[d]thiazole-2-sulfonamide (4d). The

crude product was puriﬁed using ﬂash column chromatography (SiO₂;

EtOAc/hexane = 1:3) and obtained as a colorless oil.

FM Alkylation. Starting from 0.030 g (0.09 mmol) of 3a, yielded

0.030 g (90%).

Base-Promoted Alkylation. Starting from 0.030 g (0.09 mmol) of

3a, carried out at 50 °C, yielded 0.032 g (97%). ¹H NMR (400 MHz,

chloroform-d): δ 8.18−8.17 (m, 1H), 7.97−7.95 (m, 1H), 7.62−7.58

(m, 1H), 7.56−7. 52 (m, 1H), 7.46−7.44 (m, 2H), 7.34−7.24 (m,

3H), 4.61 (s, 2H), 4.39 (hept, J = 6.8 Hz, 1H), 1.06 (d, J = 6.8 Hz,

6H); ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 166.9, 152.7, 138.1,

136.5, 128.6, 128.0, 127.7, 127.6, 127.4, 125.3, 122.2, 51.8, 48.0, 21.5;

MS (ESI) m/z (%) 347: [M + H]⁺(100); HRMS (ESI) m/z: [M +

H]⁺calcd for C₁₇H₁₉N₂O₂S₂, 347.0882; found, 347.0884.

N-Benzyl-N-(prop-2-yn-1-yl)benzo[d]thiazole-2-sulfonamide

(4e). The crude product was puriﬁed using ﬂash column

chromatography (SiO₂; EtOAc/hexane = 1:4) and obtained as a

colorless oil.

Base-Promoted Alkylation. Starting from 0.023 g (0.09 mmol) of

1

3b, carried out at RT, yielded 0.024 g (86%). H NMR (400 MHz,

chloroform-d): δ 8.20 (ddd, J = 8.2, 1.4, 0.7 Hz, 1H), 7.98 (ddd, J =

7.9, 1.5, 0.7 Hz, 1H), 7.61 (ddd, J = 8.2, 7.2, 1.4 Hz, 1H), 7.56 (ddd, J

= 7.9, 7.2, 1.4 Hz, 1H), 5.78 (ddt, J = 17.1, 10.0, 6.5 Hz, 1H), 5.36

(dq, J = 17.1, 1.4 Hz, 1H), 5.28 (dq, J = 10.1, 1.2 Hz, 1H), 4.22 (d, J =

2.5 Hz, 2H), 4.18 (d, J = 6.5, 2H), 1.90 (t, J = 2.5 Hz, 1H); ¹³C{¹H}

NMR (101 MHz, chloroform-d): δ 164.9, 152.7, 136.5, 131.4, 127.6,

127.4, 125.3, 122.2, 120.7, 76.0, 73.9, 50.2, 36.6; MS (ESI) m/z (%)

293: [M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₃H₁₃N₂O₂S₂, 293.0413; found, 293.0416.

(S)-N-Benzyl-N-(octan-2-yl)benzo[d]thiazole-2-sulfonamide

((−)-4j). The crude product was puriﬁed using ﬂash column

chromatography (SiO₂; EtOAc/hexane = 1:8) and obtained as a

colorless oil.

FM Alkylation. Starting from 0.030 g (0.09 mmol) of 3a, yielded

0.031 g (94%).

Base-Promoted Alkylation. Starting from 0.030 g (0.09 mmol) of

1

3a, carried out at RT, yielded 0.024 g (72%). H NMR (400 MHz,

chloroform-d): δ 8.23 (ddd, J = 8.2, 1.3, 0.6 Hz, 2H), 8.00 (ddd, J =

7.9, 1.4, 0.6 Hz, 2H), 7.67−7.60 (m, 1H), 7.60−7.54 (m, 1H), 7.42−

N

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FM Alkylation. Starting from 0.060 g (0.18 mmol) of 3a and (R)-

octan-2-ol (0.057 mL, 0.36 mmol, e.r. ≥ 99:1), yielded 0.051 g (62%),

e.r. ≥ 98:2;

puriﬁed using ﬂash column chromatography (SiO₂; acetone/

petroleum ether = 1:2) and obtained as a colorless oil.

FM Alkylation. Starting from 0.023 g (0.08 mmol) of 3m and

methyl (R)-2-hydroxypropanoate (0.016 mL, 0.16 mmol, e.r. ≥ 99:1),

Base-Promoted Alkylation. Starting from 0.060 g (0.18 mmol) of

3a and ( )-2-bromooctan (0.063 mL, 036 mmol), carried out at 50

yielded 0.010 g (33%, d.r. ≥ 20:1). [α]²_D³= 0° (c 0.1, CH₂Cl₂); H

1

22

°C, yielded 0.068 g (91%), e.r. = 51:49. [α]_D= −183° (c 0.3,

NMR (400 MHz, chloroform-d): δ 8.13 (ddd, J = 8.2, 1.4, 0.6 Hz,

1H), 7.97 (ddd, J = 7.8, 1.5, 0.6 Hz, 1H), 7.62−7.58 (m, 1H), 7.57−

7.53 (m, 1H), 4.82 (q, J = 7.3 Hz, 1H), 3.67 (s, 6H), 1.56 (d, J = 7.3

Hz, 6H); ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 171.4, 167.2,

152.4, 136.4, 127.7, 127.5, 125.1, 122.3, 55.3, 52.7, 17.0; MS (ESI)

m/z (%) 387: [M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺calcd

for C₁₅H₁₉N₂O₄S₂, 387.0679; found, 387.0684.

CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d): δ 8.18−8.16 (m, 1H),

7.96 (ddd, J = 7.9, 1.3, 0.6 Hz, 1H), 7.60 (ddd, J = 8.2, 7.3, 1.4 Hz,

1H), 7.54 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.46−7.45 (m, 2H), 7.33−

7.24 (m, 3H), 4.64 (d, J = 15.9 Hz, 1H), 4.51 (d, J = 15.9 Hz, 1H),

4.12 (hept, J = 6.8 Hz, 1H), 1.39−1.30 (m, 1H), 1.26−1.18 (m, 1H),

1.12−1.05 (m, 4H), 1.03 (d, J = 6.8 Hz, 3H), 1.02−0.93 (m, 4H),

0.76 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (101 MHz, chloroform-d): δ

166.9, 152.7, 137.8, 136.5, 128.6, 128.5, 127.8, 127.5, 127.4, 125.2,

122.2, 56.2, 48.3, 35.6, 31.7, 29.0, 26.5, 22.6, 19.6, 14.2; MS (ESI) m/

z (%) 417: [M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₉H₂₁N₂O₄S₂, 417.1665; found, 417.1667; HPLC (Chiralpak IA3,

CO₂/MeOH = 93/7, ﬂow rate = 2.2 mL/min, I = 272 nm) tR = 4.21

min (minor), 4.51 min (major).

(5R,5aR,8aS,9S)-9-(Benzo[d]thiazol-2-yl(benzyl)amino)-5-(3,4,5-

trimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3′,4′:6,7]naphtho[2,3-

d][1,3]dioxol-6(5aH)-one ((−)-4o). The crude product was puriﬁed

using ﬂash column chromatography (SiO₂; EtOAc/hexane = 1:8) and

obtained as a colorless solid.

FM Alkylation. Starting from 0.096 g (0.32 mmol) of 3a, yielded

0.067 g (30%, d.r. ≥ 20:1) as a white solid. Mp = 139-141 °C; [α]_D²¹

=

−64.6° (c 3.51, CH₂Cl₂); ¹H NMR (500 MHz, chloroform-d): δ

8.35−8.33 (m, 1H), 8.09−8.06 (m, 1H), 7.75−7.65 (m, 2H), 7.35−

7.33 (m, 3H), 7.05−7.03 (m, 2H), 6.78 (s, 1H), 6.50 (s, 1H), 6.11 (s,

2H), 5.98−5.97 (m, 2H), 5.78 (d, J = 5.1 Hz, 1H), 4.87 (d, J = 15.5

Hz, 1H), 4.47 (dd, J = 9.2, 7.5 Hz, 1H), 4.26 (dd, J = 11.0, 9.2 Hz,

1H), 4.06 (d, J = 5.5 Hz, 1H), 3.77 (s, 3H), 3.71 (s, 3H), 3.60 (d, J =

15.4 Hz, 1H), 2.82 (dddd, J = 14.7, 10.9, 7.6, 5.0 Hz, 1H), 1.51 (dd, J

= 14.7, 5.5 Hz, 1H); ¹³C{¹H} NMR (126 MHz, chloroform-d): δ

174.1, 165.5, 152.7, 152.6, 149.1, 147.7, 137.3, 137.2, 136.6, 134.8,

134.8, 129.4, 129.3, 129.2, 128.3, 128.2, 125.3, 124.2, 122.5, 110.7,

109.8, 108.2, 101.9, 69.8, 60.9, 58.9, 56.4, 49.5, 43.7, 40.6, 37.6; MS

(ESI) m/z (%) 701: [M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺

calcd for C₃₆H₃₃N₂O₉S₂, 701.1622; found, 701.1625.

N-Butyl-N-(oxiran-2-ylmethyl)benzo[d]thiazole-2-sulfonamide

(4k). The crude product was puriﬁed using ﬂash column

chromatography (SiO₂; EtOAc/hexane = 1:35) and obtained as a

colorless oil.

FM Alkylation. Starting from 0.048 g (0.18 mmol) of 3c, yielded

0.043 g (74%). ¹H NMR (400 MHz, chloroform-d): δ 8.16 (ddd, J =

8.5, 1.3, 0.6 Hz, 1H), 7.98 (ddd, J = 8.0, 1.5, 0.8 Hz, 1H), 7.63−7.59

(m, 1H), 7.58−7.53 (m, 1H), 4.00 (dd, J = 15.1, 3.0 Hz, 1H), 3.56−

3.45 (m, 1H), 3.34−3.36 (m, 1H), 3.24−3.22 (m, 1H), 3.16 (dd, J =

15.0, 6.6 Hz, 1H), 2.81 (t, J = 4.3 Hz, 1H), 2.59 (ddd, J = 4.6, 2.5, 1.0

Hz, 1H), 1.71−1.61 (m, 2H), 1.41−1.29 (m, 2H), 0.92 (t, J = 7.4 Hz,

3H); ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 165.7, 152.6, 136.3,

127.6, 127.5, 125.2, 122.2, 51.8, 50.9, 50.0, 45.2, 30.6, 19.8, 13.7; MS

(ESI) m/z (%) 327: [M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺

calcd for C₁₄H₁₉N₂O₃S₂, 327.0832; found, 327.0838.

Intramolecular Cyclization of Aminoalcohol Based on N-BT-

Sulfonylation/Intramolecular Fukuyama−Mitsunobu Alkyla-

tion (Table 3B). 2-(Azepan-1-ylsulfonyl)benzo[d]thiazole (5).

Sulﬁnic salt 2 (0.200 g, 0.9 mmol, 1.0 equiv) was added to a mixture

of THF (8 mL) and H₂O (2 mL) at RT, and the resulting mixture

was stirred for 5 min. 6-Aminohexan-1-ol (0.107 g, 1 mmol, 1.1

equiv) followed by NBS (0.318 g, 1.8 mmol, 2.0 equiv) were added.

After 10 min at RT, the whole mixture was diluted with CH₂Cl₂(10

mL) and H₂O (10 mL) and the resulting layers were separated. The

aqueous layer was extracted with CH₂Cl₂(3 × 15 mL), and the

combined organic layers were washed with brine (10 mL), dried over

MgSO₄, ﬁltered, and the solvents were removed under reduced

pressure. The crude product was placed into a microwave reaction

vessel and dissolved in THF (8 mL). DIAD (0.264 mL, 1.35 mmol,

1.5 equiv) and PPh₃(0.262 g, 1.35 mmol, 1.5 mmol) were added and

the reaction mixture was heated in a microwave reactor for 10 min at

50 °C (100 W). The reaction mixture was transferred to a ﬂask and

the solvents were removed under reduced pressure. The resulting

crude product was puriﬁed by ﬂash column chromatography (SiO₂;

EtOAc/hexane = 3:8) to yield the desired cyclized sulfonamide 5

Ethyl N-(Benzo[d]thiazol-2-ylsulfonyl)-N-benzylalaninate

((−)-4l). The crude product was puriﬁed using ﬂash column

chromatography (SiO₂; EtOAc/hexane = 1:4) and obtained as a

slightly yellow oil.

FM Alkylation. Starting from 0.054 g (0.17 mmol) of 3a, yielded

0.066 g (92%). [α]²_D³= − 440° (c 0.25, CH₂Cl₂); H NMR (400

1

MHz, chloroform-d): δ 8.19−8.17 (m, 1H), 7.99−7.96 (m, 1H), 7.61

(ddd, J = 8.3, 7.2, 1.4 Hz, 1H), 7.56 (ddd, J = 8.5, 7.2, 1.4 Hz, 1H),

7.44−7.42 (m, 2H), 7.34−7.24 (m, 3H), 4.93 (d, J = 16.4 Hz, 1H),

4.86 (q, J = 7.3 Hz, 1H), 4.54 (d, J = 16.4 Hz, 1H), 3.70−3.88 (m,

2H), 1.34 (d, J = 7.4 Hz, 1H), 0.96 (t, J = 7.1 Hz, 1H); ¹³C{¹H}

NMR (101 MHz, chloroform-d): δ 170.7, 165.6, 152.7, 137.0, 136.5,

128.6, 128.2, 127.9, 127.7, 127.5, 125.2, 122.2, 61.6, 56.4, 50.3, 16.9,

13.8; MS (ESI) m/z (%) 405: [M + H]⁺(100); HRMS (ESI) m/z:

[M + H]⁺calcd for C₁₉H₂₁N₂O₄S₂, 405.0937; found, 405.0938.

Methyl N-(Benzo[d]thiazol-2-ylsulfonyl)-N-butyl-L-alaninate

((−)-4m). The crude product was puriﬁed using ﬂash column

chromatography (SiO₂; EtOAc/hexane = 1:3) and obtained as a

colorless solid.

1

(0.139 g, 59% over two steps) in the form of colorless oil. H NMR

(400 MHz, chloroform-d): δ 8.17 (ddd, J = 8.2, 1.2, 0.6 Hz, 2H), 7.97

(ddd, J = 7.8, 1.3, 0.6 Hz, 2H), 7.62−7.58 (m, 1H), 7.56−7.52 (m,

1H), 3.55−3.52 (m, 4H), 1.83−1.76 (m, 4H), 1.64−1.61 (m, 4H);

¹³C{¹H} NMR (101 MHz, chloroform-d): δ 165.6, 152.7, 136.3,

127.4, 127.3, 125.2, 122.2, 49.1, 29.2, 27.0; MS (ESI) m/z (%) 297:

[M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₃H₁₇N₂O₂S₂, 297.0726; found, 297.0728.

N-Benzylbenzo[d]thiazol-2-amine (7a) Synthesis (Scheme

3B, Equation 6). A solution of sulfonamide 3a (0.127 g, 0.42 mmol,

1.0 equiv) and Cs₂CO₃(0.274 g, 0.84 mmol, 2.0 equiv) were added to

1,4-dioxane (5 mL), and the resulting mixture was degassed using the

freeze−pump−thaw technique (three times). (PPh₃)₂PdCl₂(0.059 g,

0.084 mmol, 0.2 equiv) was added and the resulting mixture was

heated at 100 °C (external temperature, oil bath) for 24h. The

resulting mixture was cooled to RT, diluted with CH₂Cl₂(25 mL),

and ﬁltered through a pad of Celite. The ﬁlter cake was washed with

additional CH₂Cl₂(3 × 25 mL) and the combined ﬁltrates were

FM Alkylation. Starting from 0.048 g (0.17 mmol) of 3c and

methyl (R)-2-hydroxypropanoate (0.032 mL, 0.34 mmol, e.r. ≥ 99:1),

yielded 0.053 g (84%, e.r. ≥ 98:1). Mp = 53−55 °C; [α]²_D³= −101° (c

0.25, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d): δ 8.17−8.15 (m,

1H), 7.98−7.95 (m, 1H), 7.61−7.57 (m, 1H), 7.56−7.52 (m, 1H),

4.85 (q, J = 7.3 Hz, 2H), 3.57 (ddd, J = 15.6, 10.9, 5.2 Hz, 1H), 3.45

(s, 3H), 3.22 (ddd, J = 15.2, 10.9, 5.5 Hz, 1H), 1.84 − 1.73 (m, 1H),

1.68−1.58 (m, 1H), 1.51 (d, J = 7.3 Hz, 3H), 1.40−1.27 (m, 2H),

0.93 (t, J = 7.4 Hz, 2H); ¹³C{¹H} NMR (101 MHz, chloroform-d): δ

171.6, 165.6, 152.6, 136.4, 127.6, 127.4, 125.2, 122.2, 56.2, 52.5, 46.9,

33.3, 20.2, 16.7, 13.8; MS (ESI) m/z (%) 358: [M + H]⁺(100);

HRMS (ESI) m/z: [M + H]⁺calcd for C₁₅H₂₁N₂O₄S₂, 357.0937;

found, 357.0936; HPLC (Chiralpak IE3, CO₂/MeOH = 95/5, ﬂow

rate = 2.2 mL/min, I = 272 nm) tR = 5.50 min (minor), 5.89 min

(major).

Methyl N-(Benzo[d]thiazol-2-ylsulfonyl)-N-((R)-1-methoxy-1-ox-

opropan-2-yl)-^L-alaninate (meso-4n). The crude product was

O

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evaporated under reduced pressure. The residue was puriﬁed by ﬂash

column chromatography (SiO₂; EtOAc/petroleum ether = 1:5 ≥ 1:2

≥ 1:1) to yield the desired product 7a (0.077 g, 76%) as a colorless

solid. Mp = 163−165 °C (164−168 °C lit ); H NMR (500 MHz,

chloroform-d): δ 7.58 (d, J = 7.9 Hz, 1H), 7.33−7.20 (m, 7H), 7.06

(t, J = 7.8 Hz, 1H), 6.84 (broad s, 1H), 4.64 (s, 2H); ¹³C{¹H} NMR

(126 MHz, chloroform-d): δ 165.9, 153.3, 136.6, 129.3, 128.8, 128.0,

127.9, 123.9, 121. 9, 121.1, 119.8, 50.5; MS (ESI) m/z (%) 241: [M +

H]⁺(100); HRMS (ESI) m/z: [M + H]⁺calcd for C₁₄H₁₃N₂S,

241.0794; found, 241.0796.

General Procedure for Chan−Lam Coupling. Sulfonamide 3

(0.1 mmol, 1 equiv) was dissolved in dry DCE (2.0 mL, 0.05 M), and

boronic acid (0.2 mmol, 2 equiv), TMEDA (0.06 mL, 0.4 mmol, 4

equiv), and [Cu(CH₃CN)₄]PF₆(0.015 g, 0.04 mmol, 0.4 equiv) were

added. The resulting mixture was placed under an atmosphere of O₂

(1 atm) and stirred for 4h at RT. The whole mixture was ﬁltered over

a pad of Celite, and the ﬁlter cake was washed with CH₂Cl₂(3 × 25

mL). The resulting ﬁltrates were combined and the solvents were

removed under reduced pressure.

N-Benzyl-N-phenylbenzo[d]thiazole-2-sulfonamide (6a). Pre-

pared starting from sulfonamide 3a (0.030 g, 0.09 mmol) and

phenylboronic acid (0.022 g, 0.18 mmol). The crude product was

puriﬁed using ﬂash column chromatography (SiO₂; EtOAc/hexane =

1:3) to yield 0.025 g (67%) of 6a obtained as a colorless oil. ¹H NMR

(400 MHz, chloroform-d): δ 8.31 (ddd, J = 8.2, 1.3, 0.7 Hz, 1H), 7.99

(ddd, J = 8.1, 1.3, 0.7 Hz, 1H), 7.68 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H),

7.61 (ddd, J = 8.3, 7.2, 1.2 Hz, 1H), 7.33−7.23 (m, 8H), 7.17−7.12

(m, 2H), 5.13 (s, 1H); ¹³C{¹H} NMR (101 MHz, chloroform-d): δ

165.7, 152.6, 138.2, 136.7, 135.6, 129.3, 128.9, 128.7, 128.6, 128.1,

127.7, 127.5, 125.4, 122.3, 56.9; MS (ESI) m/z (%) 381: [M + H]⁺

(100); HRMS (ESI) m/z: [M + H]⁺calcd for C₂₀H₁₇N₂O₂S₂,

381.0726; found, 381.0728

1H), 6.77 (ddd, J = 8.4, 2.3, 1.1 Hz, 1H), 6.69−6.66 (m, 2H), 5.07 (s,

2H), 3.62 (s, 3H); ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 165.8,

160.1, 152.6, 139.3, 136.7, 135.7, 129.8, 128.9, 128.6, 128.1, 127.7,

127.5, 125.4, 122.3, 121.3, 115.2, 114.7, 56.9, 55.4; MS (ESI) m/z

(%) 411: [M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺calcd for

C₂₁H₁₉N₂O₃S₂, 411.0832; found, 411.0833.

58

1

N-Benzyl-N-(4-chlorophenyl)benzo[d]thiazole-2-sulfonamide

(6e). Prepared starting from sulfonamide 3a (0.030 g, 0.09 mmol) and

4-chlorophenylboronic acid (0.028 g, 0.18 mmol). The crude product

was puriﬁed using ﬂash column chromatography (SiO₂; EtOAc/

petroleum ether = 1:6) to yield 0.026 g (65%) of 6e obtained as a

1

colorless oil. H NMR (400 MHz, chloroform-d): δ 8.27 (d, J = 8.1

Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.66 (ddd, J = 8.3, 7.3, 1.3 Hz,

1H), 7.59 (ddd, J = 8.2, 7.3, 1.2 Hz, 1H), 7.30−7.19 (m, 7H), 7.15 (t,

J = 7.9 Hz, 1H), 7.03 (ddd, J = 7.9, 2.0, 1.2 Hz, 1H), 5.05 (s, 2H);

¹³C{¹H} NMR (101 MHz, chloroform-d): δ 165.2, 152.6, 139.4,

136.6, 135.1, 134.7, 130.2, 129.6, 129.0, 128.9, 128.7, 128.3, 127.9,

127.7, 127.6, 125.5, 122.3, 56.7; MS (ESI) m/z (%) 415: [M + H]⁺

(100); HRMS (ESI) m/z: [M + H]⁺calcd for C₂₀H₁₆ClN₂O₂S₂,

415.0336; found, 415.0341.

N-Benzyl-N-(3-ﬂuorophenyl)benzo[d]thiazole-2-sulfonamide

(6f). Prepared starting from sulfonamide 3a (0.030 g, 0.09 mmol) and

3-ﬂuorophenylboronic acid (0.025 g, 0.18 mmol). The crude product

was puriﬁed using ﬂash column chromatography (SiO₂; EtOAc/

petroleum ether = 1:3) to yield 0.017 g (45%) of 6f obtained as a

colorless oil. ¹H NMR (400 MHz, chloroform-d): δ 8.27 (dd, J = 9.2,

0.9 Hz, 1H), 7.97 (dd, J = 8.4, 1.5 Hz, 1H), 7.66 (ddd, J = 8.4, 7.2, 1.3

Hz, 1H), 7.59 (ddd, J = 8.3, 7.2, 1.2 Hz, 1H), 7.28−7.23 (m, 5H),

7.19 (td, J = 8.2, 6.3 Hz, 1H), 6.97−6.90 (m, 3H), 5.07 (s, 2H);

¹³C{¹H} NMR (101 MHz, chloroform-d): δ 165.3, 162.66 (d, J =

248.6 Hz), 152.6, 139.6 (d, J = 9.7 Hz), 136.6, 135.2, 130.3 (d, J = 9.0

Hz), 128.9, 128.7, 128.3, 127.9, 127.7, 125.5, 125.0 (d, J = 3.3 Hz),

122.3, 116.7 (d, J = 22.8 Hz), 115.9 (d, J = 20.8 Hz), 56.8; ¹⁹F{¹H}

NMR (376 MHz, chloroform-d): δ -110.8; MS (ESI) m/z (%) 399:

[M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺calcd for

C₂₁H₃₅N₂O₄S₂Si, 399.0632; found, 399.0635.

N-Benzyl-N-(4-bromophenyl)benzo[d]thiazole-2-sulfonamide

(6g). Prepared starting from sulfonamide 3a (0.030 g, 0.09 mmol) and

4-bromophenylboronic acid (0.036 g, 0.18 mmol). The crude product

was puriﬁed using ﬂash column chromatography (SiO₂; EtOAc/

hexane = 1:3) and the collected fractions containing the product were

concentrated under reduced pressure. The resulting crude product

was puriﬁed by semiprep HPLC (MeCN/buﬀer, gradient 9:1 to 3:2

over 6 min) to yield 0.0107 g (26%) of 6g obtained as a colorless oil.

¹H NMR (400 MHz, chloroform-d): δ 8.26 (ddd, J = 8.3, 1.2, 0.7 Hz,

1H), 7.97 (ddd, J = 8.0, 1.3, 0.7 Hz, 1H), 7.66 (ddd, J = 8.3, 7.2, 1.3

Hz, 1H), 7.59 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.36−7.33 (m, 2H),

7.27−7.25 (m, 9H), 7.02−6.98 (m, 2H), 5.05 (s, 2H); ¹³C{¹H} NMR

(101 MHz, chloroform-d): δ 165.3, 152.6, 137.2, 135.2, 132.6, 130.9,

128.9, 128.8, 128.3, 127.9, 127.7, 125.5, 122.8, 122.3, 56.8; MS (ESI)

m/z (%) 459: [M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺calcd

for C₂₀H₁₆BrN₂O₂S₂, 458. 9831; found 458.9833.

N-([1,1′-Biphenyl]-4-yl)-N-benzylbenzo[d]thiazole-2-sulfona-

mide (6h). Prepared starting from sulfonamide 3a (0.030 g, 0.09

mmol) and [1,1′-biphenyl]-4-ylboronic acid (0.036 g, 0.18 mmol).

The crude product was puriﬁed using ﬂash column chromatography

(SiO₂; EtOAc/petroleum ether = 1:3) to yield 0.026 g (65%) of 6h

obtained as a colorless oil. ¹H NMR (400 MHz, chloroform-d): δ 8.27

(d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.66−7.62 (m, 1H),

7.59−7.55 (m, 1H), 7.49−7.35 (m, 6H), 7.32−7.24 (m, 6H), 7.17−

7.15 (m, 2H), 5.12 (s, 2H); ¹³C{¹H} NMR (101 MHz, chloroform-

d): δ 165.6, 152.6, 141.4, 139.9, 137.2, 136.6, 135.6, 129.5, 128.9,

128.6, 128.0, 127.9, 127.8, 127.6, 127.5, 127.1, 125.4, 122.2, 56.8; MS

(ESI) m/z (%) 457: [M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺

calcd for C₂₆H₂₁N₂O₂S₂, 457.1039; found 457.1040.

N-Allyl-N-phenylbenzo[d]thiazole-2-sulfonamide (6b). Prepared

starting from sulfonamide 3b (0.024 g, 0.09 mmol) and phenyl-

boronic acid (0.022 g, 0.18 mmol). The crude product was puriﬁed

using ﬂash column chromatography (SiO₂; EtOAc/hexane = 1:3) to

1

yield 0.020 g (63%) of 6b obtained as a colorless oil. H NMR (400

MHz, Chloroform-d): δ 8.25−8.23 (m, 1H), 7.95−7.93 (m, 1H), 7.63

(ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.56 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H),

7.34−7.30 (m, 3H), 7.23−7.21 (m, 2H), 5.87 (ddt, J = 16.6, 10.2, 6.4

Hz, 1H), 5.15 (dd, J = 17.0, 1.5 Hz, 1H), 5.11 (dd, J = 9.7, 1.4 Hz,

1H), 4.54 (dt, J = 6.5, 1.3 Hz, 2H); ¹³C{¹H} NMR (101 MHz,

chloroform-d): δ 165.6, 152.6, 138.3, 136.7, 132.6, 129.4, 129.2,

128.7, 127.7, 127.5, 125.4, 122.3, 119.6, 55.6; MS (ESI) m/z (%) 331:

[M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₆H₁₅N₂O₂S₂, 331.0569; found, 331.0573.

N-Butyl-N-phenylbenzo[d]thiazole-2-sulfonamide (6c). Prepared

starting from sulfonamide 3c (0.062 g, 0.22 mmol) and phenylboronic

acid (0.054 g, 0.44 mmol). The crude product was puriﬁed using ﬂash

column chromatography (SiO₂; EtOAc/hexane = 1:4) to yield 0.044

g (58%) of 6c obtained as a colorless oil. ¹H NMR (400 MHz,

chloroform-d): δ 8.24−8.22 (m, 1H), 7.95−7.92 (m, 1H), 7.62 (ddd,

J = 8.3, 7.2, 1.3 Hz, 1H), 7.55 (ddd, J = 8.3, 7.3, 1.3 Hz, 1H), 7.34−

7.30 (m, 3H), 7.23−7.20 (m, 2H), 3.92 (t, J = 7.1 Hz, 2H), 1.53−

1.47 (m, 2H), 1.43−1.34 (m, 2H), 0.89 (t, J = 7.3 Hz, 2H); ¹³C{¹H}

NMR (101 MHz, chloroform-d): δ 165.5, 152.7, 138.4, 136.6, 129.4,

129.2, 128.7, 127.6, 127.4, 125.4, 122.2, 52.5, 30.7, 19.7, 13.7; MS

(ESI) m/z (%) 347: [M + H]⁺(100); HRMS (ESI) m/z: calcd for

C₁₇H₁₉N₂O₂S₂, 347.0882; found, 347.0885.

N-Benzyl-N-(3-methoxyphenyl)benzo[d]thiazole-2-sulfonamide

(6d). Prepared starting from sulfonamide 3a (0.030 g, 0.09 mmol) and

3-methoxyphenylboronic acid (0.027 g, 0.18 mmol). The crude

product was puriﬁed using ﬂash column chromatography (SiO₂;

EtOAc/hexane = 1:5 ≥ 1:3) and the collected fractions containing the

product were concentrated under reduced pressure. The resulting

crude product was puriﬁed by semiprep HPLC (MeCN/buﬀer,

gradient 9:1 to 3:2 over 6 min) to yield 0.0155 g (42%) of 6d

N-([1,1′-Biphenyl]-4-yl)-N-allylbenzo[d]thiazole-2-sulfonamide

(6i). Prepared starting from sulfonamide 3b (0.030 g, 0.09 mmol) and

[1,1′-biphenyl]-4-ylboronic acid (0.036 g, 0.18 mmol). The crude

product was puriﬁed using ﬂash column chromatography (SiO₂;

EtOAc/petroleum ether = 1:3) and the collected fractions containing

1

obtained as a colorless oil. H NMR (400 MHz, chloroform-d): δ

8.28−8.25 (m, 1H), 7.98−7.95 (m, 1H), 7.67−7.63 (m, 1H), 7.60−

7.55 (m, 1H), 7.30−7.23 (m, 5H), 7.11 (ddd, J = 8.3, 7.9, 0.8 Hz,

P

https://doi.org/10.1021/acs.joc.1c00317

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

the product were concentrated under reduced pressure. The resulting

crude product was puriﬁed by semiprep HPLC (MeCN/buﬀer,

gradient 9:1 to 3:2 over 6 min) to yield 0.026 g (72%) of 6i obtained

̌

Eliska Lachetová − Department of Organic Chemistry, Faculty

of Science, Palacky University, CZ-771 46 Olomouc, Czech

Republic

1

as a colorless oil. H NMR (400 MHz, chloroform-d): δ 8.26 (ddd, J

̌

Nikola St’astná − Department of Organic Chemistry, Faculty

of Science, Palacky University, CZ-771 46 Olomouc, Czech

Republic

= 8.3, 1.3, 0.7 Hz, 1H), 7.96 (ddd, J = 8.0, 1.3, 0.7 Hz, 1H), 7.65

(ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.58 (ddd, J = 8.1, 7.2, 1.3 Hz, 1H),

7.52 (ddd, J = 7.8, 1.8, 1.1 Hz, 1H), 7.43 (td, J = 2.0, 0.4 Hz, 2H),

7.41−7.30 (m, 6H), 7.20 (ddd, J = 7.9, 2.1, 1.1 Hz, 1H), 5.90 (ddt, J

= 16.5, 10.2, 6.4 Hz, 1H), 5.17 (ddd, J = 16.9, 2.6, 1.3 Hz, 1H), 5.13

(ddd, J = 10.1, 2.3, 1.1 Hz, 1H), 4.56 (dt, J = 6.4, 1.3 Hz, 2H);

¹³C{¹H} NMR (101 MHz, chloroform-d): δ 165.6, 152.7, 142.6,

140.0, 138.8, 136.7, 132.6, 129.7, 129.0, 128.0, 127.9, 127.9, 127.7,

127.6, 127.4, 127.2, 125.4, 122.3, 119.7, 55.7; MS (ESI) m/z (%) 407:

[M + H]⁺(100); HRMS (ESI) m/z: [M + H]⁺calcd for C₂₂H₁₉

N₂O₂S₂, 407.0882; found, 407.0886.

Benzo[d]thiazol-2-ylsulfonyl Group Cleavage (Scheme 6C).

Ethanethiolysis (Scheme 6C, Equation 6). N,N-Dibenzylsulfonamide

4g (0.050 g, 0.12 mmol) was dissolved in CH₃CN (1.2 mL) at RT,

and EtSLi (0.024 g, 0.36 mmol, 3.0 equiv) was added. The resulting

mixture was stirred at RT for 12 h. Solvents were removed under

reduced pressure, and the resulting crude product was puriﬁed with

ﬂash column chromatography (SiO₂; EtOAc/hexane = 1:1) to yield

compound 11 (0.022 g, 95%) as a yellowish oil.

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00317

Author Contributions

F.Z. performed most of the experiments and analyzed the

experimental data. O.K. carried out the experiments and

analyzed the experimental data. F.Z., E.L., and O.K. performed

and optimized Chan−Lam coupling. F.Z., O.K., and N.S.

performed and optimized SuFEX experiments. F.Z. partially

designed the experimental plans. J.P. initiated the project, led

the project team, designed the experiments, and analyzed

results. F.Z. and J.P. co-wrote the paper with input from all

authors. All authors have given approval to the ﬁnal version of

the manuscript.

NaBH₄Reduction (Scheme 6C, Equation 7). N,N-Dibenzylsulfo-

namide 4g (0.129 g, 0.33 mmol) was dissolved in EtOH (2 mL) at

RT, and NaBH₄(0.049 g, 1.3 mmol, 4.0 equiv) was added. The

resulting mixture was stirred at RT for 12 h. The whole mixture was

diluted with CH₂Cl₂(10 mL) and H₂O (10 mL), and the layers were

separated. The aqueous layer was extracted with CH₂Cl₂(2 ×15 mL),

and the organic layers were combined, washed with brine (10 mL),

dried over Na₂SO₄, ﬁltered, and the solvents were removed under

reduced pressure. The crude product was puriﬁed by ﬂash column

chromatography (SiO₂; EtOAc/hexane = 1:1) to give the desired

compound 11 (0.063 g, 98%) as a yellowish oil.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

The ﬁnancial support by the Ministry of Education, Youth and

Sports of the Czech Republic (grant LO1304 from the

National Program of Sustainability and grant LO1204 from the

National Program of Sustainability I) as well as by the Internal

Grant Agency of Palacky University (IGA_PrF_2021_024) is

gratefully acknowledged. JP is grateful for support from the

European Regional Development Fund-Project “Center for

Experimental Plant Biology” (no. CZ.02.1.01/0.0/0.0/

Dibenzylamine (11). ¹H NMR (400 MHz, chloroform-d): δ 7.37−

7.32 (10H), 3.82 (4 H); ¹³C{¹H} NMR (101 MHz, chloroform-d): δ

140.3, 128.6, 128.3, 127.1, 53.2; MS (ESI) m/z (%) 198: [M + H]⁺

(100); HRMS (ESI) m/z: [M + H]⁺calcd for C₁₄H₁₆N, 198.1277;

found 198.1277.

̌

16_019/0000738) and to prof. M. Strnad, Dr. K. Dolezal,

and prof. J. Hlavác (Palacky University) for their continuous

support. JP is grateful to Hana Omámiková (Laboratory of

̌

ASSOCIATED CONTENT

Growth Regulatorsperforming HRMS measuring) and

■

̌

Adam Pribylka (Department of Organic ChemistrypK_a

sı

* Supporting Information

determination) for their technical assistance.

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c00317.

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AUTHOR INFORMATION

■

Corresponding Author

̌

Jirí Pospísil − Department of Organic Chemistry, Faculty of

Science, Palacky University, CZ-771 46 Olomouc, Czech

Republic; Laboratory of Growth Regulators, Palacky

University & Institute of Experimental Botany AS CR, CZ-

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Frantisek Zálesák − Department of Organic Chemistry,

Faculty of Science, Palacky University, CZ-771 46 Olomouc,

Czech Republic

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Ondrej Kovác − Department of Organic Chemistry, Faculty of

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S

https://doi.org/10.1021/acs.joc.1c00317

J. Org. Chem. XXXX, XXX, XXX−XXX

Article Doi

Unified Approach to Benzo[ d]thiazol-2-yl-Sulfonamides

DOI: 10.1021/acs.joc.1c00317

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Full text of DOI:10.1021/acs.joc.1c00317

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