Chemoselective Deprotection of Sulfonamides under Acidic Conditions: Scope, Sulfonyl Group Migration, and Synthetic Applications

Article

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Cite This: J. Org. Chem. XXXX, XXX, XXX −XXX

Chemoselective Deprotection of Sulfonamides Under Acidic

Conditions: Scope, Sulfonyl Group Migration, and Synthetic

Applications

Tomas Javorskis and Edvinas Orentas*

Department of Organic Chemistry, Vilnius University, Naugarduko 24, 03225 Vilnius, Lithuania

S

* Supporting Information

ABSTRACT: Chemoselective acidic hydrolysis of sulfona-

mides with triﬂuoromethanesulfonic acid has been evaluated as

a deprotection method and further extended to more complex

synthetic applications. In contrast to conventional troublesome

sulfonamide hydrolysis, a near-stoichiometric amount of acid

was found to be suﬃcient to bring about eﬃcient deprotection

of various neutral or electron-deﬁcient N-arylsulfonamides,

whereas electron-rich substrates provided sulfonyl group

migration products. The deprotection method developed is

fully selective for N-arylsulfonamides, and the possibility to

discriminate among various diﬀerent sulfonamides is demonstrated.

Obviously, such conditions can only be used with relatively

simple, robust compounds. For this reason, milder reductive

cleavage with Li or Na/naphthalene,¹¹Na/Hg,¹²Na/NH₃

(liq.),¹³SmI₂,¹⁴low-valent titanium (LVT),¹⁵Ni-

(acac)₂/ⁱPrMgCl,¹⁶Mg/MeOH,¹⁷HBr/CH₃COOH,¹⁸or

electrolysis¹⁹is often preferred. Again, the presence of redox-

sensitive functional groups may prevent the application of these

methods. In order to overcome the above obstacles, a 2-nitro-

or 4-nitrobenzenesulfonyl (nosyl, Ns) group, which can be

deprotected by an alternative way with thiolates via formation

of Jackson−Meisenheimer complex, was introduced.^4aOn the

other hand, a nosyl protecting group is only applicable in the

absence of nitro-speciﬁc chemistry such as reduction or

vicarious substitution, and it may not be compatible with

organolithium or Grignard reagents.²⁰Moreover, to the best of

our knowledge, discrimination of sulfonyl protecting groups

according to the type of amino group they are connected to has

not been investigated in detail, and no convenient chemo-

selective deprotection method has been developed.²¹⁻²³

Herein, we present our study on a new, near-stoichiometric

acid-mediated sulfonamide cleavage method which allows

chemoselective deprotection of an aniline amino group.

INTRODUCTION

■

Amines represent one of the most abundant and important

classes of organic compounds constituting the largest fraction

of biologically active compounds currently in use.¹The

synthetic methods enabling the introduction or manipulation

of amino functionality are therefore central for the advance-

ment of organic chemistry and have a huge impact on society.

On the other hand, due to the relatively high basicity and

nucleophilicity of the amine nitrogen atom, it is often necessary

to use some kind of protecting group either to screen the

unwanted reactivity or to simply make them easier to handle or

store. A large collection of reagents is available for amino group

protection that provides desired stability toward acids, bases,

and reducing or oxidizing agents.²Among all amine protecting

groups, a sulfonyl group, such as p-toluenesulfonyl (tosyl, Ts),

oﬀers several important advantages. Owing to a very strong N−

S bond in sulfonamides, they are compatible with strongly basic

conditions, including organolithium or Grignard reagents. Also,

introduction of a sulfonyl group on nitrogen increases the

acidity of the N−H bond in sulfonamides by several orders of

magnitude,³converting them into useful nucleophiles in

alkylation reaction under basic or Mitsunobu conditions,⁴and

transition metal catalyzed C(sp²/sp)−N bond formation.⁵⁻⁷As

compared with amides or carbamates, the nonambivalent

nature of sulfonamide anion and lower pK_avalues of the N−H

bond serve as additional attractive features of this protecting

group. In some cases, amino group conversion into sulfonamide

stabilizes an otherwise too reactive or unstable functional

group, such as ynamine.⁸Despite the aforementioned wide

synthetic utility of sulfonamides, the removal of this group is

notoriously hard. Hydrolytic acidic cleavage is possible,

however, typically under very harsh conditions using an excess

of concentrated mineral acids at elevated temperature.^9,10

RESULTS AND DISCUSSION

■

In the course of the synthesis of various polyamine substrates in

our group, the chemoselective deprotection of aniline-type

nitrogen in polytosylated substrates often emerged as a

hypothetical, highly desired transformation that would greatly

simplify the synthesis of the target molecule. Although the N−S

Received: October 3, 2017

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bond is known to be weaker in aniline-derived sulfonamides as

compared to aliphatic congeners, distinguishing these two types

of protected amino functionalities proved to be diﬃcult using

standard reductive cleavage procedures. As illustrated in

Scheme 1a with ditosylated diamine 1 as a model compound,

the reaction proceeded already at 50 °C; however, where

possible, the temperature was increased to 90 °C to shorten the

reaction times. The reaction scope is inevitably limited by the

acidic conditions; nevertheless, many functional groups such as

nitriles (5n), amides (5r, 5s), imides (5p, 5q), esters (5g),

ketones (5i), or aldehydes (5h) were compatible, as seen from

Table 1. Moreover, pyridine (5u, 5v), quinoline (5w, 5x),

pyrazole (5z), and thiazole-derived sulfonamides (5aa) were all

cleanly deprotected. Diarylamine 5y was readily deprotected

even at room temperature. The procedure was also successfully

applied on a gram scale with compound 5m with only a slight

decrease in yield. Typically, the electron-deﬁcient substrates

provided higher yields, in line with a much weaker N−S bond

in these sulfonamides, whereas very electron-rich derivatives

bearing alkoxy or several alkyl groups failed to aﬀord desired

anilines, and instead, intramolecular sulfonyl migration was

observed (vide infra). Besides p-toluenesulfonamides, nosyl,

mesyl, or 2,4,6-triisopropylbenzenesulfonamides were cleaved

under the same reaction conditions (Table 1, compounds 5ab−

5ah). According to the proposed reaction mechanism and

taking into account the larger basicity of the product as

compared to the starting material, at least 2.0 equiv of triﬂic

acid would be required for completion of the reaction.

However, in a few cases on a submilimolar scale, a smaller

amount of acid also provided deprotection products in good

yields. This might be attributed to possible generation of an

additional amount of acid from the residual water, degradation

of solvent, starting material, or mixed anhydride 4 at elevated

temperature.^27aThe screening of the reaction scope also

revealed that N-alkyl sulfonamides were generally more reactive

than the corresponding unsubstituted congeners. For instance,

a competition experiment between sulfonamides 5n and 7

using only 1.0 equiv of TfOH resulted in almost quantitative

deprotection of N-butyl derivative 5n, while the majority of

unsubstituted sulfonamide 7 was recovered together with N,N-

bis-sulfonyl aniline 8 (Scheme 2a). The latter was formed by

sulfonylation reaction of 7 with 4, released after deprotetion of

5n.

Taken together, these observations indicate a very subtle

balance between the basicity of the nitrogen atom and the

reactivity of the sulfonamide bond. In unsubstituted N-

arylsulfonamides, the nitrogen lone pair is eﬃciently delocalized

in the aromatic ring and, therefore, is less available for

hyperconjugation (anomeric eﬀect) with a sulfur atom, making

the N−S bond weaker as compared to aliphatic sulfonamides.

However, the basicity of the nitrogen atom is also markedly

reduced, resulting in a sluggish protonation step (Scheme 1b).

On the contrary, the nitrogen atom in N-alkylated aromatic

sulfonamides is signiﬁcantly more basic due to the positive

inductive eﬀect of the alkyl chain and steric distortion of the

nitrogen lone pair from coplanarity with the aromatic ring π

system. Therefore, both the basicity and the strength of the

sulfonamide bond are increased. Apparently, the increase in the

degree of protonation is more important and outweighs the

gain in bond strength. In the case of nonreactive dialkyl

sulfonamides, the N−S bond becomes so strong that even

complete protonation of the nitrogen is insuﬃcient to render it

reactive toward the weakly nucleophilic triﬂate anion.

Scheme 1. Acid-Catalyzed Selective Deprotection of the

Tosyl Group

the successful desired selective deprotection was only achieved

using HBr/AcOH mixture as a solvent, however, with

concomitant dibromination of the aniline aromatic ring. The

formation of product 2 is easily explained taking into account

the oxidation of HBr to molecular bromine by the liberated p-

toluenesulphinic acid. For this reason, successful use of this

deprotection procedure would require a large amount of

bromine scavenger, i.e., phenol, thioanisol, or pentamethylben-

zene.¹⁸To overcome this obstacle, we decided to use strong

nonredox-active triﬂuoromethanesulfonic acid (TfOH)²⁴as a

substitute for HBr. Indeed, by using a stoichiometric amount of

TfOH, fully selective deprotection was achieved in 1,2-

dichloroethane at 90 °C, aﬀording the target product in 96%

yield (Scheme 1a). The reaction mechanism most likely is

comprised of the initial protonation of the nitrogen atom

followed by nucleophilic attack of triﬂate on the sulfur atom of

the sulfonyl group (Scheme 1b). Although the protonation may

occur on both nitrogen and oxygen atoms of the sulfonyl group,

the former pathway is more likely, based on the results of the

study reported by Menger et al. and others.^25,26The proposed

reaction mechanism necessitates the formation of mixed

anhydride 4. Compound 4 was previously prepared from

TsBr and AgOTf and shown to be a powerful tosylation

agent.²⁷Indeed, although we have not experimentally identiﬁed

compound 4 in the reaction mixture, its formation was

indirectly proved by performing mild basic (satd NaHCO₃aq

solution) workup. We noticed that a large portion of the

starting material was regenerated upon basiﬁcation of the

mixture, indicating the presence of anhydride 4. The workup

procedure was therefore modiﬁed by ﬁrst quenching the

reaction mixture with a slight excess of 1,2-ethylenediamine to

scavenge 4 and convert it into the corresponding polar, water-

soluble monotosylate.²⁸In this way, the general deprotection

procedure was devised and further applied to a diversity of

substrates, summarized in Table 1. Unsubstituted or N-alkyl-

substituted (N-methyl or N-butyl aromatic sulfonamides as

representative derivatives) aromatic or heteroaromatic p-

toluenesulfonamides were used as substrates providing the

corresponding anilines in high yields. In the majority of cases,

Given the signiﬁcantly slower deprotection rate of unsub-

stituted aryl sulfonamides as compared to N-alkylated aryl

sulfonamides, we decided to explore this reactivity feature in a

one-pot hydroamination/deprotection reaction (Scheme 2b).

As exempliﬁed with norbornene 10 and sulfonamide 7, TfOH-

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Table 1. Scope of Sulfonamide Deprotection

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Scheme 2. Substitution-Selective Hydroamination/

Deprotection Strategy Using Sulfonamides

Scheme 3. Selective Deprotection of N-Aryl-p-

toluenesulfonamides and Its Application in Synthesis

catalyzed hydroamination reaction²⁹of relatively stable 7 with

alkene converted the former into more reactive N-alkylated

derivative 11, which then underwent fast deprotection to aﬀord

alkylated aniline 12 in acceptable yield. The optimal reaction

temperature was selected based on the previous experiment

(Scheme 2a) and was as low as possible to further discriminate

the rates of the deprotection reactions. The functionalized

norbornenes 13 and 14 were obtained under identical

conditions (Scheme 2b). The whole process formally

represents an acid-catalyzed alkene hydroamination reaction

with anilines and provide a convenient alternative to otherwise

problematic sulfonamide N-alkylation with secondary or

tertiary alkyl halides. In addition, by selectively providing exo-

diastereomers, this method complements endo-selective

reductive amination procedure.³⁰

with thiolate, furnishing the ﬁnal product 27. The use of two

diﬀerent sulfonamide protecting groups in this synthesis not

only allowed the activation of the amino groups for the

alkylation reaction but also enabled site-selective functionaliza-

tion of the substrate.

The electron-rich substrates displayed a completely diﬀerent

reactivity proﬁle aﬀording sulfonyl group migration products

(Scheme 4). Fries-type rearrangement (or 1,3-sulfonyl

Scheme 4. Intramolecular Sulfonyl Group Migration

Next, we explored the possibility to selectively deprotect p-

toluenesulfonyl group in the presence of other sulfonamides

present within the same substrate.²³As observed earlier (Table

1), deprotection of nosyl or mesyl derivatives was rather slow,

whereas sterically hindered and more basic 2,4,6-triisopropyl-

benzenesulfonamides were cleaved more readily. To our

delight, the selective deprotection of tosyl group was indeed

possible for the Ts−Ns (15, 17, 19) pair using 1.1−1.2 equiv of

TfOH at 50 °C (Scheme 3a). More importantly, selective

cleavage of the Ts group in 21 was also preferred over pyridine-

2-sulfonamide. The latter is usually regarded as one of the most

labile sulfonamides, and thus, the observed selectivity is

unprecedented.³¹

To implement the observed chemoselectivity into practical

synthetic context, synthesis of triamine 27 was accomplished

(Scheme 3b). The starting tosylated aniline 23 was converted

into bistosylated diamine 24 bearing arylalkyl and dialkyl

sulfonamide groups. After reduction of the nitro group and

protection with nosyl chloride, intermediate 17 was selectively

deprotected and alkylated using a reductive amination

procedure to aﬀord compound 25 in good overall yield. The

nosyl-protected amino group was then alkylated with butyl

bromide and eventually deprotected under standard conditions

rearrangement) of N-arylsulfonamides is well documented,

and several attempts have been made to develop this reaction

into a useful synthetic method.⁹For instance, in their recent

studies, Zanger and co-workers reported ortho- and para-

selective migration of arylsulfonyl group in various substrates,

however, using concentrated H₂SO₄, polyphosphoric acid, or

neat TfOH as a solvent at high temperature (>100 °C).³²We

felt that the synthetic utility of this reaction might be

signiﬁcantly broadened using more benign conditions, i.e.,

near-stoichiometric amount of TfOH and preferably lower

temperature. We were therefore delighted to ﬁnd that the

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rearranged products, amino diarylsulfones 29, 31, and 33, were

indeed obtained under the typical deprotection conditions

(TfOH (2.0 equiv), 80 °C) in moderate to good yields, as

shown in Scheme 4a. As indicated independently by the

crossover experiment between compound 28 and 1,3-

dimethoxybenzene, the sulfonyl group migration is an intra-

molecular process, in line with the reported mechanistic

speculations.³³Remarkably, the mesyl-protected anilines 34

and 36 also aﬀorded rearrangement products, in contrast to

literature data claiming complete inertness of methanesulfonyl

group in acid-catalyzed Fries rearrangement (Scheme 4b).⁹The

obtained sulfones containing an amino group are valuable

scaﬀolds for drug design,³⁴in particular, the ones derived from

mesitylated anilines. The presence of acidic methylsulfonyl

group hydrogen atoms in the latter opens the way for further

synthetic elaboration on these products.³⁵

deprotection reaction itself might serve as an attractive

synthetic method for monoarylureas.

Lastly, we sought to investigate whether other unsaturated

sulfonamides with a conjugated nitrogen lone pair could

similarly be deprotected. To our surprise, ynamide 45a and

enamide 46³⁹proved to be inert under reaction conditions. On

the basis of this observation, we combined a TfOH-catalyzed

cyclization reaction of ynamides and nitriles, recently developed

by the Maulide group,⁴⁰with a deprotection step to access

nonprotected aminopyrimidines in one-pot operation (Scheme

6b and 6c). During the reaction the sulfonamide group is

Scheme 6. One-Pot Deprotection−Cyclization

Transformations

On the basis of the proposed deprotection mechanism

(Scheme 1), we further speculated that the transfer of the

sulfonyl group can, in principle, be also realized in an

intermolecular fashion by taking advantage of the high

reactivity of the mixed anhydride 4 as a sulfonylation agent.

The above assumption was veriﬁed by deprotecting electron-

deﬁcient tosylated aniline 40 in the presence of electron-rich

aromatic compounds (Scheme 5). The deprotection reaction

Scheme 5. Intermolecular Sulfonyl Group Transfer from

Sulfonamide and Sulfonylurea

cleaved to provide product 47 as soon and only when the

pyrimidine ring is assembled via a [2 + 2 + 2] cycloaddition

process. Interestingly, bistosylated ynamide 48 was also

compatible with acidic conditions, providing unsubstituted

aminopyrimidine 49 in an overall 58% yield.

In another application of one-pot transformation, the

condensation reaction between the liberated amino group

and the pendant amide functionality was initiated after the

deprotection step (Scheme 6d). Treatment of 50 with TfOH at

80 °C provided 2-imidazoline 51 in 70% yield. The control

experiment with the modiﬁed substrate lacking a tosyl group

produced only a trace amount 51, indicating the essential role

of anhydride 4, which most likely serves as an eﬃcient

dehydrating agent. Indeed, according to the literature, imidazo-

line 51 and its derivatives are usually obtained under strongly

dehydrating conditions using Hendrickson reagent (PPh₃PO/

Tf₂O),⁴¹trimethylsilyl polyphosphate,⁴²or polyphosphoric

acid.⁴³Thus, the use of a tosyl protecting group might be

advantageous not only for aﬀecting the site-selective arylation

reaction en route to analogues of 50 using sulfonamide−amide-

functionalized ethylenediamines but also for activating the

substrate toward further cyclization reaction.

and simultaneous Friedel−Crafts sulfonylation took place at 60

°C and aﬀorded diaryl sulfones 41−43 in high yields. From a

practical point of view, the precursor 40 is an easily aﬀordable,

odorless, noncorrosive, and nonhygroscopic solid, convenient

to handle.

In further optimization of the above sulfonyl transfer

method, we noticed that heating of the reaction mixture was

required only for the deprotection step, while the sulfonyl

transfer by the anhydride 4 proceeded smoothly already at

room temperature.³⁶The more readily deprotectable sulfony-

lated substrate was then required to render the whole

procedure milder, operating at room temperature.³⁷This

problem was solved by engaging N-sulfonylated urea 44 as a

sulfonyl group donor. We found that the lability of N-sulfonyl

group under acidic conditions was increased drastically by

connecting the electron-withdrawing carbonyl group to the

same nitrogen atom. Gratifyingly, the sulfonylation products

41−42 were obtained at room temperature, albeit in somewhat

lower yields. N-Sulfonylureas of this type are available in high

yields in a single synthetic step from the corresponding anilines

and tosylisocyanate.³⁸Therefore, the structure of 44 could

potentially be tuned further toward higher yields, and the

CONCLUSIONS

■

In conclusion, we disclosed a simple, selective, and relatively

mild method for deprotection of N-arylsulfonamides under

acidic conditions. This procedure complements the existing

methods and might ﬁnd uses in manipulating polyamine

substrates containing several diﬀerent sulfonamide protecting

groups. By taking advantage of the high chemoselectivity of the

reaction, the high Brønsted acidity of triﬂic acid, and the innate

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Alternatively, the alkylation was performed in THF solution (unless

stated otherwise) of sulfonamide (1.0 equiv) using NaH (1.2 equiv), a

catalytic amount of tetrabutylammonium iodide, and alkyl halide (2.0

equiv) at 25−70 °C for the indicated time. The mixture was quenched

with 1.0 M HCl aq solution, extracted with EtOAc, washed with brine,

dried with Na₂SO₄, and evaporated in vacuo. The product was puriﬁed

by ﬂash column chromatography or crystallization.

N-([1,1′-Biphenyl]-2-yl)-N-butyl-4-methylbenzenesulfonamide

(5a). Following general procedure III using N-([1,1′-biphenyl]-2-yl)-4-

methylbenzenesulfonamide (316 mg, 0.98 mmol, 1.0 equiv), K₂CO₃

(203 mg, 1.47 mmol, 1.5 equiv), and 1-bromobutane (0.21 mL, 2.0

mmol, 2.0 equiv) for 17 h. The crude product was washed with MeOH

to aﬀord pure 5a (326 mg, 88%). R_f= 0.39 (EtOAc:Cyclohexane

1:10), mp 98−99 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, J = 8.0

Hz, 2H), 7.49−7.54 (m, 2H), 7.36−7.45 (m, 5H), 7.27−7.34 (m, 3H),

7.05 (d, J = 8.0 Hz, 1H), 3.16−3.27 (m, 2H), 2.47 (s, 3H), 1.16 (quint,

J = 7.2 Hz, 2H), 0.99 (sxt, J = 7.2 Hz, 2H), 0.70 (t, J = 7.2 Hz, 3H).

¹³C NMR (100 MHz, CDCl₃) δ 143.34, 143.26, 139.5, 137.2, 137.1,

reactivity of tolylsulfenic triﬂuoromethanesulfonic anhydride

byproduct, synthetic utility of the present method was extended

beyond simple deprotection by engaging the substrates in

various one-pot transformations of practical importance.

EXPERIMENTAL SECTION

■

General Experimental Procedures. All reagents and starting

materials were obtained from commercial sources and used as

received. Reaction solvents 1,2-dichloroethane and acetonitrile were

distilled from CaH₂, and THF was distilled from sodium/

benzophenone. Brine refers to a saturated solution of sodium chloride

All moisture-sensitive reactions were performed in oven-dried (230

°C) glassware under an atmosphere of dry argon.

Thin-layer chromatography was performed on Merck silica gel

plates with QF-254 indicator. Visualization was accomplished with UV

(254 nm), potassium permanganate (KMnO₄), ninhydrin, or vanillin.

Column chromatography was performed using Merck silica 60 (40−63

μm particle size).

131.7, 129.6, 129.5, 128.8, 128.3, 128.1, 128.0, 127.9, 127.3, 51.5, 29.8,

21.6, 19.8, 13.6. FT-IR v_max/cm⁻¹3282w, 1339m, 1158m. HRMS-

ESI⁺: m/z [M + H]⁺calcd for C₂₃H₂₆NO₂S, 380.1679; found,

380.1690.

¹H and ¹³C NMR spectra were recorded on a NMR spectrometer at

400 MHz for ¹H and 101 MHz for ¹³C, respectively. ¹H and ¹³C NMR

spectra are referenced to residual solvent (CDCl₃, 7.26 and 77.16

ppm; d₆-DMSO, 2.50 and 39.52 ppm; d₆-acetone, 2.05 and 29.84 ppm

for ¹H NMR and ¹³C NMR, respectively). When necessary,

assignments were obtained by reference to COSY, HSQC, and

HMBC correlations. Chemical shifts are reported in ppm, and

multiplicities are indicated by br (broad), s (singlet), d (doublet), t

(triplet), q (quartet), quint (quintet), sxt (sextet), sept (septet), m

(multiplet), and combinations thereof. Infrared spectra (IR) were

recorded on a FTIR spectrometer equipped with a diamond ATR unit.

Peaks are reported in cm⁻¹with indicated relative intensities: s

(strong, 67−100%), m (medium, 34−66%), w (weak, 0−33%).

Melting points were determined in open capillary tubes and are

uncorrected. High-resolution mass spectra (HRMS) were recorded on

an ESI/QTOF instrument.

N-(2-Bromophenyl)-N-butyl-4-methylbenzenesulfonamide (5b).

Following general procedure III using N-tosyl-2-bromoaniline (173

mg, 0.53 mmol, 1.0 equiv), K₂CO₃(110 mg, 0.80 mmol, 1.5 equiv),

and 1-bromobutane (0.12 mL, 1.10 mmol, 2.0 equiv) for 19 h.

Puriﬁcation by ﬂash column chromatography (SiO₂EtOAc:PE 1:15)

aﬀorded 5b (180 mg, 89%) as a colorless oil. R_f= 0.41

1

(EtOAc:Cyclohexane 1:10). H NMR (400 MHz, CDCl₃) δ 7.61−

7.68 (m, 3H), 7.26−7.32 (m, 3H), 7.18−7.24 (m, 1H), 7.06−7.11 (m,

1H), 3.43−3.67 (m, 2H), 2.45 (s, 3H), 1.25−1.52 (m, 4H), 0.87 (t, J =

7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 143.5, 138.2, 136.6,

134.0, 131.8, 129.7, 129.5, 127.93, 127.91, 126.0, 51.1, 30.5, 21.6, 19.9,

13.7. FT-IR v_max/cm⁻¹1348m, 1164m. HRMS-ESI⁺: m/z [M + H]⁺

calcd for C₁₇H₂₁BrNO₂S, 384.0451; found, 384.0456.

Abbreviations: DCE, 1,2-dichloroethane; DCM, dichloromethane;

DMF, dimethylformamide; DMSO, dimethylsulfoxide; EtOAc, ethyl

acetate; Hex, - hexane; MeOH, methanol; PE, petrol ether (40−60 °C

fraction); Py, pyridine; TfOH, triﬂuoromethanesulfonic acid.

Preparation of Starting Materials. Monosubstituted sulfona-

mides were prepared from the corresponding anilines and sulfonyl

chlorides in pyridine using standard conditions. N-Alkylated

sulfonamides were obtained via N-alkylation reaction of monosub-

stituted sulfonamides with butyl bromide or methyl iodide (K₂CO₃/

DMF or THF/NaH). Sulfonamides 5h−i and 5t were obtained by

Buchwald N-arylation reaction^5bof the corresponding aryl bromides

with N,4-dimethylbenzenesulfonamide and N-butyl-4-methylbenzene-

sulfonamide, respectively.

General Procedure I: Hydrogenation of Nitroarenes. A solution of

nitroarene (1.0 equiv) in MeOH was ﬂushed with argon, vacuumed,

and reﬁlled with argon. Pd/C-10% (10% w/w) was added in one

portion followed by vacuuming and reﬁlling with H₂(repeated twice).

The reaction mixture was vigorously stirred for the indicated time,

ﬁltered through a small pad of Celite, washed with MeOH, and

evaporated in vacuo. The crude product was used in the next step

without further puriﬁcation.

General Procedure II: Preparation of Sulfonamides. To a solution

of aniline (1.0 equiv) in pyridine (0.18 M), sulfonyl chloride (1.05−2.2

equiv) was added in one portion. The mixture was stirred at 25−80

°C. The mixture was quenched with 1.0 M HCl aq solution, extracted

with EtOAc, washed with brine, dried with Na₂SO₄, and evaporated in

vacuo. The product was puriﬁed via silica gel ﬂash column

chromatography or crystallization.

General Procedure III: N-Alkylation of Sulfonamides. To a

solution of sulfonamide (1.0 equiv) in DMF were added K₂CO₃

(1.5 equiv) and alkyl bromide (2.0 equiv). The mixture was heated at

80 °C for the indicated time and then quenched with 1.0 M HCl aq

solution, extracted with EtOAc, washed with brine, dried with Na₂SO₄,

and evaporated in vacuo. The product was puriﬁed by ﬂash column

chromatography or crystallization.

N-Butyl-4-methyl-N-(3-((4-methylphenyl)sulfonamido)phenyl)-

benzenesulfonamide (5c). Following general procedure I using 5m

(500 mg, 1.43 mmol, 1.0 equiv) for 21 h. The crude product was

converted to 5c following general procedure II using 4-toluenesulfonyl

chloride (317 mg, 1.66 mmol, 1.2 equiv) for 20 h at room temperature.

Puriﬁcation by ﬂash column chromatography (SiO₂EtOAc:PE 1:3)

aﬀorded 5c (520 mg, 77%) as a brownish solid. R_f= 0.64 (EtOAc:PE

1:2), mp 120−121 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J = 8.0

Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.21−7.27 (m, 4H), 7.18 (t, J = 8.0

Hz, 1H), 7.05−7.09 (m, 1H), 6.92 (s, 1H), 6.85 (t, J = 2.0 Hz, 1H),

6.77−6.81 (m, 1H), 3.41−3.48 (m, 2H), 2.43 (s, 3H), 2.39 (s, 3H),

1.23−1.30 (m, 4H), 0.80−0.87 (m, 3H). ¹³C NMR (100 MHz,

CDCl₃) δ 144.0, 143.5, 140.1, 137.2, 135.8, 135.0, 129.7, 129.6, 129.5,

127.6, 127.3, 125.3, 122.2, 121.1, 49.9, 30.0, 21.6, 21.5, 19.5, 13.6. FT-

IR v_max/cm⁻¹3233w, 1330m, 1154m. HRMS-ESI⁺: m/z [M + H]⁺

calcd for C₂₄H₂₉N₂O₄S₂, 473.1563; found, 473.1574.

N-Butyl-N-(3,5-dimethylphenyl)-4-methylbenzenesulfonamide

(5d). Following general procedure II using 6d (93 mg, 0.53 mmol, 1.0

equiv) and 4-toluenesulfonyl chloride (107 mg, 0.56 mmol, 1.1 equiv)

for 20 h at room temperature. Puriﬁcation by ﬂash column

chromatography (SiO₂EtOAc:PE 1:30) aﬀorded 5d (150 mg, 86%)

as a white solid. R_f= 0.48 (EtOAc:PE 1:10), mp 69−70 °C. ¹H NMR

(400 MHz, CDCl₃) δ 7.52 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz,

2H), 6.94 (s, 1H), 6.66 (s, 2H), 3.48 (t, J = 7.2 Hz, 2H), 2.45 (s, 3H),

2.27 (s 6H), 1.29−1.45 (m, 4H), 0.88 (t, J = 7.2 Hz, 3H). ¹³C NMR

(100 MHz, CDCl₃) δ 143.1, 139.1, 138.4, 135.7, 129.5, 129.2, 127.8,

126.5, 50.4, 30.3, 21.5, 21.2, 19.6, 13.6. FT-IR v_max/cm⁻¹1341m,

1162m. HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₉H₂₆NO₂S, 332.1679;

found, 332.1683.

N-(3,5-Bis(triﬂuoromethyl)phenyl)-N-butyl-4-methylbenzenesul-

fonamide (5f). Following general procedure III using N-[3,5-

bis(triﬂuoromethyl)phenyl]-4-methylbenzenesulfonamide (263 mg,

0.69 mmol, 1.0 equiv), NaH (60% dispersion, 33 mg, 0.82 mmol,

1.2 equiv), and 1-bromobutane (0.15 mL, 1.37 mmol, 2.0 equiv) for 24

h at 80 °C. Puriﬁcation by ﬂash column chromatography (SiO₂

F

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The Journal of Organic Chemistry

Article

EtOAc:PE 1:10) aﬀorded 5f (282 mg, 94%) as a white solid. R_f= 0.38

(EtOAc:PE 1:10), mp 74−75 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.83

(s, 1H), 7.50 (s, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz,

2H), 3.56 (d, J = 6.8 Hz, 2H), 2.46 (s, 3H), 1.30−1.45 (m, 4H), 0.90

(t, J = 6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 144.3, 141.3,

134.2, 132.4 (q, J = 33.6 Hz), 129.7, 128.8 (d, J = 3.6 Hz), 127.6, 122.7

(q, J = 271.1 Hz), 121.4, 49.9, 30.1, 21.5, 19.5, 13.4. FT-IR v_max/cm⁻¹

1349m, 1163m. HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₉H₂₀F₆NO₂S,

440.1113; found, 440.1124.

Methyl 2-((N-Butyl-4-methylphenyl)sulfonamido)benzoate (5g).

Following general procedure III using methyl N-tosylanthranilate (310

mg, 1.02 mmol, 1.0 equiv), NaH (60% dispersion, 49 mg, 1.22 mmol,

1.2 equiv), and 1-bromobutane (0.22 mL, 2.03 mmol, 2.0 equiv) for 46

h at 80 °C. Puriﬁcation by ﬂash column chromatography (SiO₂

EtOAc:PE 1:10) aﬀorded 5g (270 mg, 74%) as a yellowish oil. R_f=

0.27 (EtOAc:PE 1:10). ¹H NMR (400 MHz, CDCl₃) δ 7.86−7.90 (m,

1H), 7.50 (d, J = 8.0 Hz, 2H), 7.38−7.46 (m, 2H), 7.25 (d, J = 8.0 Hz,

2H), 6.96 (dd, J = 7.6, 1.6 Hz, 1H), 3.82 (s, 3H), 3.58 (br, 2H), 2.43

(s, 3H), 1.55 (br, 2H), 1.32 (sxt, J = 7.2 Hz, 2H), 0.88 (t, J = 7.2 Hz,

3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.7, 143.1, 138.3, 136.5, 132.9,

131.9, 131.3, 130.0, 129.3, 128.0, 127.6, 52.2, 51.4, 30.7, 21.5, 20.0,

13.7. FT-IR v_max/cm⁻¹1725w, 1345m, 1161m. HRMS-ESI⁺: m/z [M +

H]⁺calcd for C₁₉H₂₄NO₄S, 362.1421; found, 362.1427.

HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₇H₂₁N₂O₄S, 349.1217; found,

349.1228.

N-Butyl-N-(4-cyanophenyl)-4-methylbenzenesulfonamide (5n).

Following general procedure III using 7 (360 mg, 1.32 mmol, 1.0

equiv), NaH (60% dispersion, 64 mg, 1.60 mmol, 1.2 equiv), and 1-

bromobutane (0.29 mL, 2.64 mmol, 2.0 equiv) for 23 h at 80 °C.

Puriﬁcation by ﬂash column chromatography (SiO₂EtOAc:Cyclohex-

ane 1:3.5) aﬀorded 5n (431 mg, 99%) as a white solid. R_f= 0.63

(EtOAc:Cyclohexane 1:2), mp 58−59 °C. ¹H NMR (400 MHz,

CDCl₃) δ 7.63 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.27 (d, J

= 8.0 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 3.56 (t, J = 7.2 Hz, 2H), 2.44

(s, 3H), 1.29−1.43 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H). ¹³C NMR (100

MHz, CDCl₃) δ 144.0, 143.6, 134.7, 132.9, 129.6, 128.8, 127.5, 118.2,

111.1, 49.5, 30.1, 21.6, 19.6, 13.5. FT-IR v_max/cm⁻¹1342m, 1163m.

HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₈H₂₁N₂O₂S, 329.1318; found,

329.1330

N-(2-Butyl-1,3-dioxoisoindolin-5-yl)-4-methylbenzenesulfona-

mide (5p). Following general procedure II using 6p (177 mg, 0.81

mmol, 1.0 equiv) and 4-toluenesulfonyl chloride (162 mg, 0.85 mmol,

1.1 equiv) for 24 h at 80 °C. The crude product was triturated with

DCM/PE mixture to aﬀord 5p (260 mg, 86%) as a yellowish solid. R_f

= 0.4 (EtOAc:PE 1:2), mp 204−205 °C. ¹H NMR (400 MHz, CDCl₃)

δ 7.93 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.58

(d, J = 1.6 Hz, 1H), 7.45 (dd, J = 8.0, 1.6 Hz, 1H), 7.30 (d, J = 8.4 Hz,

2H), 3.65 (t, J = 7.6 Hz, 2H), 2.41 (s, 3H), 1.63 (quint, J = 7.6 Hz,

2H), 1.35 (sxt, J = 7.6 Hz, 2H), 0.94 (t, J = 7.6 Hz, 3H). ¹³C NMR

(100 MHz, CDCl₃) δ 167.8, 167.7, 144.8, 142.5, 135.5, 134.0, 130.1,

127.4, 127.3, 124.6, 123.7, 113.7, 37.9, 30.6, 21.6, 20.1, 13.6. FT-IR

v_max/cm⁻¹3232w, 1688m, 1396m, 1162m. HRMS-ESI⁺: m/z [M +

H]⁺calcd for C₁₉H₂₁N₂O₄S, 373.1217; found, 373.1222.

N-(3-((4-Methylphenyl)sulfonamido)phenyl)benzamide (5r). Fol-

lowing general procedure I using 40 (283 mg, 0.97 mmol, 1.0 equiv)

for 20 h. The crude product was dissolved in DCM (15 mL) at 0 °C,

and triethylamine (0.14 mL, 1.04 mmol, 1.1 equiv) was added

followed by benzoyl chloride (0.11 mL, 0.97 mmol, 1.0 equiv). The

mixture was stirred for 25 h at room temperature, quenched with 1.0

M HCl aq solution, extracted with DCM, washed with brine, dried

with Na₂SO₄, and evaporated in vacuo. Puriﬁcation by ﬂash column

chromatography (SiO₂EtOAc:PE 1:1.5) aﬀorded 5r (230 mg, 65%) as

a slightly yellow solid. R_f= 0.53 (EtOAc:PE 1:1), mp 137−138 °C. ¹H

NMR (400 MHz, CDCl₃) δ 7.98 (s, 1H), 7.84−7.88 (m, 2H), 7.70 (d,

J = 8.0 Hz, 2H), 7.53−7.59 (m, 2H), 7.43−7.52 (m, 3H), 7.28 (s, 1H),

7.21 (d, J = 8.0 Hz, 2H), 7.14 (s, 1H), 6.90 (dd, J = 8.0, 1.2 Hz, 1H),

2.37 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.9, 144.0, 138.9,

137.5, 136.0, 134.6, 132.0, 129.9, 129.7, 128.8, 127.3, 127.1, 116.7,

116.6, 112.6, 21.5. FT-IR v_max/cm⁻¹3352w, 3149w, 1645w, 1602w,

1152m. HRMS-ESI⁺: m/z [M + Na]⁺calcd for C₂₀H₁₈N₂NaO₃S,

389.0930; found, 389.0941.

N-(4-Formylphenyl)-N,4-dimethylbenzenesulfonamide (5h). To a

pressure vial charged with 4-bromobenzaldehyde (397 mg, 2.15 mmol,

1.2 equiv), N,4-dimethylbenzenesulfonamide (331 mg, 1.79 mmol, 1.0

equiv), Pd(OAc)₂(4 mg, 0.018 mmol, 0.01 equiv), Xanthphos (16 mg,

0.028 mmol, 0.015 equiv), and Cs₂CO₃(816 mg, 2.50 mmol, 1.4

equiv) under argon, 1,4-dioxane (6.0 mL) was added. The reaction vial

was capped and heated at 100 °C for 5 h. After cooling to room

temperature, the mixture was diluted with DCM, ﬁltered, and

evaporated in vacuo. Puriﬁcation by ﬂash column chromatography

(SiO₂EtOAc:PE 1:3.5) aﬀorded 5h (500 mg, 97%) as a yellowish

1

solid. R_f= 0.48 (EtOAc:PE 1:2), mp 103−104 °C. H NMR (400

MHz, CDCl₃) δ 10.00 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.42 (d, J =

8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 3.22 (s,

3H), 2.42 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 191.1, 147.0,

144.1, 134.3, 133.2, 130.3, 129.6, 127.7, 125.9, 37.6, 21.6. FT-IR v_max

/

cm⁻¹1702w, 1346m, 1168m. HRMS-ESI⁺: m/z [M + H]⁺calcd for

C₁₅H₁₆NO₃S, 290.0845; found, 290.0853.

N-(4-Benzoylphenyl)-N,4-dimethylbenzenesulfonamide (5i). To a

pressure vial charged with 4-bromobenzophenone (200 mg, 0.77

mmol, 1.0 equiv), N,4-dimethylbenzenesulfonamide (170 mg, 0.92

mmol, 1.2 equiv), Pd(OAc)₂(3.4 mg, 0.015 mmol, 0.02 equiv),

Xanthphos (13.3 mg, 0.023 mmol, 0.03 equiv), and Cs₂CO₃(350 mg,

1.07 mmol, 1.4 equiv) under argon, 1,4-dioxane (4.0 mL), was added.

The reaction vial was capped and heated at 100 °C for 20 h. After

cooling to room temperature, the mixture was diluted with DCM,

ﬁltered, and evaporated in vacuo. Puriﬁcation by ﬂash column

chromatography (SiO₂EtOAc:PE 1:4) aﬀorded 5i (258 mg, 92%)

as a white solid. R_f= 0.58 (EtOAc:PE 1:2), mp 109−110 °C. ¹H NMR

(400 MHz, CDCl₃) δ 7.76−7.83 (m, 4H), 7.59−7.65 (m, 1H), 7.45−

7.54 (m, 4H), 7.26−7.30 (m, 4H), 3.23 (s, 3H), 2.44 (s, 3H). ¹³C

NMR (100 MHz, CDCl₃) δ 195.7, 145.4, 144.0, 137.4, 135.6, 133.4,

N-(3-((N-Butyl-4-methylphenyl)sulfonamido)phenyl)benzamide

(5s). Following general procedure I using 5m (290 mg, 0.83 mmol, 1.0

equiv) for 22 h. The crude product was dissolved in THF (14 mL) at 0

°C, triethylamine (0.13 mL, 0.93 mmol, 1.12 equiv) and benzoyl

chloride (0.1 mL, 0.86 mmol, 1.03 equiv) were added, and the mixture

was stirred for 26 h at room temperature. The mixture was quenched

with water, extracted with EtOAc, washed with brine, dried with

Na₂SO₄, and evaporated in vacuo. Puriﬁcation by ﬂash column

chromatography (SiO₂EtOAc:PE 1:4.5) aﬀorded 5s (250 mg, 71%) as

132.6, 130.8, 130.0, 129.6, 128.4, 127.8, 125.5, 37.7, 21.6. FT-IR v_max

/

cm⁻¹1656w, 1343m, 1174m. HRMS-ESI⁺: m/z [M + H]⁺calcd for

C₂₁H₂₀NO₃S, 366.1158; found, 366.1164.

1

a white solid. R_f= 0.17 (EtOAc:PE 1:5), mp 139−140 °C. H NMR

N-Butyl-4-methyl-N-(2-nitrophenyl)benzenesulfonamide (5k).

Following general procedure III using 5g (387 mg, 1.32 mmol, 1.0

equiv), NaH (60% dispersion, 64 mg, 1.59 mmol, 1.2 equiv), and 1-

bromobutane (0.29 mL, 2.64 mmol, 2.0 equiv) for 48 h at 80 °C.

Puriﬁcation by ﬂash column chromatography (SiO₂EtOAc:PE 1:5)

aﬀorded 5k (457 mg, 97%) as a yellowish solid. R_f= 0.22 (EtOAc:PE

1:5), mp 74−75 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.89 (dd, J = 8.0,

1.6 Hz, 1H), 7.47−7.58 (m, 4H), 7.28 (d, J = 8.0 Hz, 2H), 7.11 (dd, J

= 8.0, 1.6 Hz, 1H), 3.60 (br, 2H), 2.45 (s, 3H), 1.57 (br, 2H), 1.25−

1.38 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃)

δ 149.7, 143.9, 135.4, 132.7, 132.6, 131.1, 129.6, 129.0, 127.8, 125.4,

51.3, 30.5, 21.6, 19.9, 13.7. FT-IR v_max/cm⁻¹1531m, 1350m, 1165m.

(400 MHz, CDCl₃) δ 7.94 (s, 1H), 7.80−7.91 (m, 3H), 7.46−7.61 (m,

5H), 7.35−7.40 (m, 1H), 7.23−7.34 (m, 3H), 6.74 (dd, J = 8.0, 1.2

Hz, 1H), 3.55 (t, J = 6.8 Hz, 2H), 2.44 (s, 3H), 1.28−1.49 (m, 4H),

0.88 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.7, 143.4,

139.8, 138.7, 135.2, 134.7, 132.0, 129.44, 129.42, 128.9, 127.7, 127.0,

123.8, 121.0, 119.6, 50.1, 30.2, 21.6, 19.6, 13.6. FT-IR v_max/cm⁻¹

3332w, 3064w, 1675m, 1602m, 1332m. HRMS-ESI⁺: m/z [M + H]⁺

calcd for C₂₄H₂₇N₂O₃S, 423.1737; found, 423.1736.

N-Butyl-N-(3,4-dichlorophenyl)-4-methylbenzenesulfonamide

(5t). To a pressure vial charged with 1-bromo-3,4-dichlorobenzene

(200 mg, 0.89 mmol, 1.0 equiv), N-butyl-4-methylbenzenesulfonamide

(241 mg, 1.06 mmol, 1.2 equiv), Pd(OAc)₂(4 mg, 0.018 mmol, 0.02

G

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The Journal of Organic Chemistry

Article

equiv), Xanthphos (15 mg, 0.026 mmol, 0.03 equiv), and Cs₂CO₃

(404 mg, 1.24 mmol, 1.4 equiv) under argon, 1,4-dioxane (4.0 mL)

was added. The reaction vial was capped and heated at 100 °C for 24

h. After cooling to room temperature, the mixture was diluted with

DCM, ﬁltered, and evaporated in vacuo. Puriﬁcation by ﬂash column

chromatography (SiO₂EtOAc:PE 1:15) aﬀorded 5t (264 mg, 80%) as

N-(5-Bromo-1-butyl-1H-pyrazol-4-yl)-4-methylbenzenesulfona-

mide (5z). Following general procedure II using 1-butyl-1H-pyrazol-4-

amine (792 mg, 4.15 mmol, 1.0 equiv) and 4-toluenesulfonyl chloride

(750 mg, 3.94 mmol, 0.95 equiv) for 19 h at room temperature. The

crude product was dissolved in CHCl₃(20 mL), and NBS (813 mg,

4.57 mmol, 1.1 equiv) was added in one portion. The reaction mixture

was stirred for 1 h at room temperature, quenched with water,

extracted with CHCl₃, dried with Na₂SO₄, and evaporated in vacuo to

aﬀord 5z (1.24 g, 80%) as a light orange solid. R_f= 0.35 (EtOAc:PE

1

a white solid. R_f= 0.38 (EtOAc:PE 1:10), mp 60−61 °C. H NMR

(400 MHz, CDCl₃) δ 7.48 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.8 Hz,

1H), 7.29 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 1.6 Hz, 1H), 6.94 (dd, J =

8.8, 1.6 Hz, 1H), 3.46−3.52 (m, 2H), 2.45 (s, 3H), 1.30−1.43 (m,

4H), 0.86−0.91 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 143.8,

138.8, 134.7, 132.7, 132.0, 130.50, 130.47, 129.6, 128.0, 127.7, 50.0,

30.1, 21.6, 19.6, 13.5. FT-IR v_max/cm⁻¹1347m, 1166m. HRMS-ESI⁺:

m/z [M + H]⁺calcd for C₁₇H₂₀Cl₂NO₂S, 372.0586; found, 372.0591.

N-Butyl-N-(5-chloropyridin-2-yl)-4-methylbenzenesulfonamide

(5u)/N-(1-Butyl-5-chloropyridin-2(1H)-ylidene)-4-methylbenzene-

sulfonamide (5v). Following general procedure III using N-(5-

chloropyridin-2-yl)-4-methylbenzenesulfonamide (216 mg, 0.76 mmol,

1.0 equiv), K₂CO₃(158 mg, 1.15 mmol, 1.5 equiv), and 1-

bromobutane (0.17 mL, 1.53 mmol, 2.0 equiv) for 21 h. Puriﬁcation

by ﬂash column chromatography (SiO₂EtOAc:PE 1:7, 2:1) aﬀorded

5u and 5v.

1

1:2), mp 74−75 °C. H NMR (400 MHz, CDCl₃) δ 7.64 (d, J = 8.0

Hz, 2H), 7.48 (s, 1H), 7.26 (d, J = 8.0 Hz, 2H), 6.24−6.29 (m, 1H),

4.06 (t, J = 7.2 Hz, 2H), 2.43 (s, 3H), 1.74 (quint, J = 7.2 Hz, 2H),

1.25 (sxt, J = 7.2 Hz, 2H), 0.92 (t, J = 7.2 Hz, 3H). ¹³C NMR (100

MHz, CDCl₃) δ 144.0, 137.2, 135.8, 129.6, 127.6, 117.6, 111.2, 50.8,

31.6, 21.6, 19.5, 13.6. FT-IR v_max/cm⁻¹3105w, 1595w, 1161s. HRMS-

ESI⁺: m/z [M + H]⁺calcd for C₁₄H₁₉BrN₃O₂S, 374.0356; found,

374.0359.

N-Butyl-4-methyl-N-(4-phenylthiazol-2-yl)benzenesulfonamide

(5aa). Following general procedure III using N-butyl-4-phenylthiazol-

2-amine (486 mg, 1.47 mmol, 1.0 equiv), K₂CO₃(406 mg, 2.94 mmol,

2.0 equiv), and 1-bromobutane (0.24 mL, 2.22 mmol, 1.5 equiv) for 16

h. Puriﬁcation by ﬂash column chromatography (SiO₂EtOAc:PE

1:10) aﬀorded 5aa (495 mg, 87%) as a white solid. R_f= 0.36

5u: colorless solid, 125 mg (48%). R_f= 0.65 (EtOAc:PE 1:5), mp

1

(EtOAc:PE 1:10), mp 56−57 °C. H NMR (400 MHz, CDCl₃) δ

60−61 °C. H NMR (400 MHz, CDCl₃) δ 8.28 (d, J = 2.4 Hz, 1H),

7.79−7.83 (m, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.38−7.43 (m, 2H),

7.31−7.35 (m, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.18 (s, 1H), 4.00−4.05

(m, 2H), 2.42 (s, 3H), 1.75−1.82 (m, 2H), 1.44 (sxt, J = 7.2 Hz, 2H),

0.97 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 160.3, 150.7,

144.5, 135.4, 134.3, 129.8, 128.7, 128.0, 127.3, 125.9, 109.1, 50.0, 30.4,

21.6, 19.9, 13.7. FT-IR v_max/cm⁻¹1349m, 1168m. HRMS-ESI⁺: m/z

[M + H]⁺calcd for C₂₀H₂₃N₂O₂S₂, 387.1195; found, 387.1197.

2,4,6-Triisopropyl-N-(3-nitrophenyl)benzenesulfonamide (5ab).

Following general procedure II using 6ab (206 mg, 1.49 mmol, 1.0

equiv) and 2,4,6-triisopropylphenylsulfonyl chloride (543 mg, 1.79

mmol, 1.2 equiv) for 70 h at 65 °C. The crude product was

recrystallized from EtOAc/PE mixture to aﬀord 5ab (450 mg, 75%) as

7.70 (dd, J = 8.8, 2.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.0

Hz, 2H), 7.25 (d, J = 8.00 Hz, 2H), 3.74 (t, J = 7.2 Hz, 2H), 2.41 (s,

3H), 1.44 (quint, J = 7.2 Hz, 2H), 1.32 (sxt, J = 7.2 Hz, 2H), 0.88 (t, J

= 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 150.8, 146.8, 143.7,

137.4, 135.3, 129.57, 129.56, 127.5, 124.0, 47.7, 30.5, 21.5, 19.8, 13.6.

FT-IR v_max/cm⁻¹1346m, 1161m. HRMS-ESI⁺: m/z [M + H]⁺calcd

for C₁₆H₂₀ClN₂O₂S, 339.0929; found, 339.0931.

5v: colorless solid, 75 mg (29%). R_f= 0.6 (CHCl₃:MeOH 1:10),

mp 132−133 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 8.0 Hz,

2H), 7.74 (d, J = 9.6 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.43 (dd, J =

9.6, 2.4 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 4.11 (t, J = 7.2 Hz, 2H),

2.40 (s, 3H), 1.75 (quint, J = 7.2 Hz, 2H), 1.34 (sxt, J = 7.2 Hz, 2H),

0.92 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 153.9, 141.9,

140.7, 140.2, 136.3, 129.2, 126.3, 119.1, 117.1, 53.8, 30.6, 21.4, 19.7,

13.6. FT-IR v_max/cm⁻¹1629w, 1351m, 1132m. HRMS-ESI⁺: m/z [M +

H]⁺calcd for C₁₆H₂₀ClN₂O₂S, 339.0929; found, 339.0933.

N,4-Dimethyl-N-(quinolin-8-yl)benzenesulfonamide (5w). Fol-

lowing general procedure III using 4-methyl-N-(quinolin-8-yl)-

benzenesulfonamide (114 mg, 0.38 mmol, 1.0 equiv), NaH (60%

dispersion, 18 mg, 0.46 mmol, 1.2 equiv), and methyl iodide (0.05 mL,

0.80 mmol, 2.1 equiv) in DMF for 17 h at 75 °C. Puriﬁcation by ﬂash

column chromatography (SiO₂EtOAc:PE 1:2.5) aﬀorded 5w (110

mg, 92%) as a white solid. R_f= 0.4 (EtOAc:PE 1:2), mp 74−75 °C. ¹H

NMR (400 MHz, CDCl₃) δ 8.65 (dd, J = 4.0, 1.2 Hz, 1H), 8.15 (dd, J

= 8.0, 1.6 Hz, 1H), 7.74−7.83 (m, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.54

(t, J = 8.0 Hz, 1H), 7.35 (dd, J = 8.0, 4.0 Hz, 1H), 7.19 (d, J = 8.0 Hz,

2H), 3.50 (s, 3H), 2.41 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ

149.7, 145.1, 142.9, 138.4, 136.3, 136.2, 131.3, 129.5, 129.1, 128.5,

128.0, 126.3, 121.2, 39.3, 21.5. FT-IR v_max/cm⁻¹1335m, 1148m.

HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₇H₁₇N₂O₂S, 313.1005; found,

313.1018.

1

a brownish solid. R_f= 0.66 (EtOAc:PE 1:3), mp 158−159 °C. H

NMR (400 MHz, CDCl₃) δ 7.91−7.96 (m, 1H), 7.79−7.82 (m, 1H),

7.40−7.48 (m, 2H), 7.33−7.37 (m, 1H), 7.21 (s, 2H), 4.20 (sep, J =

6.8 Hz, 2H), 2.92 (sep, J = 6.8 Hz, 1H), 1.24−1.29 (m, 18H). ¹³C

NMR (100 MHz, CDCl₃) δ 154.1, 150.8, 148.8, 138.5, 131.5, 130.1,

126.4, 124.3, 119.3, 114.9, 34.2, 30.0, 24.7, 23.5. FT-IR v_max/cm⁻¹

3246w, 1532m, 1148m. HRMS-ESI⁺: m/z [M + Na]⁺calcd for

C₂₁H₂₈N₂NaO₄S, 427.1662; found, 427.1666.

N-Butyl-2,4,6-triisopropyl-N-(3-nitrophenyl)benzenesulfonamide

(5ac). Following general procedure III using 5ab (141 mg, 0.35 mmol,

1.0 equiv), K₂CO₃(63 mg, 0.46 mmol, 1.3 equiv), and 1-bromobutane

(0.08 mL, 0.74 mmol, 2.1 equiv) for 19 h. After workup, removal of

solvent in vacuo aﬀorded pure 5ac (159 mg, 99%) as oﬀ-white solid. R_f

= 0.38 (EtOAc:PE 1:10), mp 64−65 °C. ¹H NMR (400 MHz, CDCl₃)

δ 8.16 (ddd, J = 8.4, 2.0, 0.8 Hz, 1H), 7.99 (t, J = 2.0 Hz, 1H), 7.67−

7.71 (m, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.14 (s, 2H), 3.94 (sep, J = 6.8

Hz, 2H), 3.67−3.73 (m, 2H), 2.87−2.93 (m, 1H), 1.28−1.47 (m, 4H),

1.26 (d, J = 6.8 Hz, 6H), 1.18 (d, J = 6.8 Hz, 12H), 0.86 (t, J = 7.2 Hz,

3H). ¹³C NMR (100 MHz, CDCl₃) δ 153.8, 151.5, 148.6, 140.9, 135.7,

130.7, 129.9, 124.2, 124.0, 122.5, 49.4, 34.2, 30.1, 29.6, 24.8, 23.5, 19.7,

13.5. FT-IR v_max/cm⁻¹1523m, 1166w. HRMS-ESI⁺: m/z [M + H]⁺

calcd for C₂₅H₃₇N₂O₄S, 461.2469; found, 461.2479.

1-Tosyl-1,2,3,4-tetrahydro-1,10-phenanthroline (5x). Following

general procedure II using 6x (60 mg, 0.33 mmol, 1.0 equiv) and 4-

toluenesulfonyl chloride (75 mg, 0.39 mmol, 1.2 equiv) for 46 h at 60

°C. Puriﬁcation by ﬂash column chromatography (SiO₂

CHCl₃:MeOH 100:1, 50:1) aﬀorded 5x (70 mg, 64%) as a reddish

4-Nitro-N-(2-((4-nitrophenyl)sulfonamido)ethyl)-N-phenylbenze-

nesulfonamide (5ad). Following general procedure II using N-(2-

aminoethyl)benzeneamine (155 mg, 1.14 mmol, 1.0 equiv) and 4-

nitrobenzenesulfonyl chloride (555 mg, 2.50 mmol, 2.2 equiv) for 20 h

at room temperature. The crude product was recrystallized from

DCM/PE mixture to aﬀord 5ad (420 mg, 73%) as a yellowish solid. R_f

1

solid. R_f= 0.27 (CHCl₃:MeOH 50:1), mp 117−118 °C. H NMR

(400 MHz, CDCl₃) δ 8.81 (dd, J = 4.0, 1.6 Hz, 1H), 8.09−8.15 (m,

3H), 7.64 (d, J = 8.4 Hz, 1H), 7.35−7.41 (m, 3H), 7.33 (d, J = 8.4 Hz,

1H), 3.84 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 6.8 Hz, 2H), 2.49 (s, 3H),

2.30 (quint, J = 6.8 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 148.6,

143.9, 143.1, 138.8, 136.3, 135.3, 134.8, 129.1, 128.1, 127.5, 125.6,

120.8, 46.6, 26.3, 23.6, 21.6. FT-IR v_max/cm⁻¹1343m, 1158m. HRMS-

ESI⁺: m/z [M + H]⁺calcd for C₁₉H₁₉N₂O₂S, 339.1162; found,

339.1178.

1

= 0.45 (EtOAc:PE 1:2), mp 189−190 °C. H NMR (400 MHz, d₆-

DMSO) δ 8.34−8.41 (m, 4H), 8.25 (br, 1H), 7.97 (d, J = 8.4 Hz, 2H),

7.79 (d, J = 8.4 Hz, 2H), 7.32−7.38 (m, 3H), 7.04−7.10 (m, 2H),

3.62−3.69 (m, 2H), 2.82−2.89 (m, 2H). ¹³C NMR (100 MHz, d₆-

DMSO) δ 150.5, 150.0, 146.2, 143.4, 138.4, 129.8, 129.34, 129.26,

129.0, 128.5, 125.1, 51.1, 41.6. FT-IR v_max/cm⁻¹3287w, 3111w,

H

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The Journal of Organic Chemistry

Article

1526m, 1351m, 1159m. HRMS-ESI⁺: m/z [M + NH₄]⁺calcd for

C₂₀H₂₂N₅O₈S₂, 524.0904; found, 524.0914.

N-Butyl-4-methyl-N-(3-((4-nitrophenyl)sulfonamido)phenyl)-

benzenesulfonamide (15b). Following general procedure I using 5m

(210 mg, 0.60 mmol, 1.0 equiv) for 24 h. The crude product was

converted to 15b following general procedure II using 4-nitro-

benzenesulfonyl chloride (147 mg, 0.66 mmol, 1.1 equiv) for 26 h at

room temperature. The crude product was recrystallized from DCM/

PE mixture to aﬀord 15b (200 mg, 66%) as a white solid. R_f= 0.26

N-(2-Butyl-1,3-dioxoisoindolin-5-yl)-4-nitrobenzenesulfonamide

(5ae). Following general procedure II using 6p (164 mg, 0.75 mmol,

1.0 equiv) and 4-nitrobenzenesulfonyl chloride (175 mg, 0.79 mmol,

1.1 equiv) for 68 h at 80 °C. The crude product was recrystallized

from DCM/PE mixture to aﬀord 5ae (285 mg, 94%) as a white solid.

R_f= 0.58 (EtOAc:PE 1:1), mp 194−195 °C. ¹H NMR (400 MHz, d₆-

acetone) δ 10.1 (s, 1H), 8.43 (d, J = 8.8 Hz, 2H), 8.19 (d, J = 8.8 Hz,

2H), 7.77 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.65 (dd, J =

8.0, 1.6 Hz, 1H), 3.61 (t, J = 7.2 Hz, 2H), 1.61 (quint, J = 7.2 Hz, 2H),

1.33 (sxt, J = 7.2 Hz, 2H), 0.92 (t, J = 7.2 Hz, 3H). ¹³C NMR (100

MHz, d₆-acetone) δ 167.2, 167.1, 150.7, 144.8, 142.7, 134.1, 128.7,

1

(EtOAc:PE 1:3), mp 148−149 °C. H NMR (400 MHz, CDCl₃) δ

8.28 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.4 Hz,

2H), 7.27 (d, J = 8.4 Hz, 2H), 7.21 (t, J = 8.0 Hz, 1H), 7.05−7.12 (m,

3H), 6.69−6.75 (m, 1H), 3.46 (t, J = 6.8 Hz, 2H), 2.45 (s, 3H), 1.23−

1.32 (m, 4H), 0.83 (t, J = 6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃)

δ 150.3, 144.4, 143.8, 140.4, 136.3, 134.9, 129.9, 129.6, 128.7, 127.6,

125.0, 124.3, 123.7, 121.5, 49.8, 30.1, 21.6, 19.5, 13.5. FT-IR v_max/cm⁻¹

3207w, 1530m, 1321m, 1149m. HRMS-ESI⁺: m/z [M + H]⁺calcd for

C₂₃H₂₆N₃O₆S₂, 504.1258; found, 504.1257.

127.8, 124.7, 124.41, 124.35, 113.7, 37.3, 30.4, 19.7, 13.0. FT-IR v_max

/

cm⁻¹3110w, 1694m, 1353m, 1166m. HRMS-ESI⁺: m/z [M + H]⁺

calcd for C₁₈H₁₈N₃O₆S, 404.0911; found, 404.0921.

N-Butyl-4-nitro-N-(3-nitrophenyl)benzenesulfonamide (5af). Fol-

lowing general procedure III using 4-nitro-N-(3-nitrophenyl)-

benzenesulfonamide (225 mg, 0.70 mmol, 1.0 equiv), K₂CO₃(144

mg, 1.04 mmol, 1.5 equiv), and 1-bromobutane (0.15 mL, 1.39 mmol,

2.0 equiv) for 23 h. Puriﬁcation by ﬂash column chromatography

(SiO₂EtOAc:PE 1:3.5) aﬀorded 5af (200 mg, 76%) as a yellowish

solid. R_f= 0.58 (EtOAc:PE 1:3), mp 82−83 °C. ¹H NMR (400 MHz,

CDCl₃) δ 8.35 (d, J = 8.4 Hz, 2H), 8.21−8.25 (m, 1H), 7.90 (t, J = 2.0

Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.60 (t, J = 8.0 Hz, 1H), 7.49−7.53

(m, 1H), 3.64 (t, J = 7.2 Hz, 2H), 1.31−1.49 (m, 4H), 0.89 (t, J = 7.2

Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 150.3, 148.7, 143.4, 139.7,

134.9, 130.2, 128.7, 124.4, 123.2, 123.0, 50.5, 30.1, 19.5, 13.5. FT-IR

v_max/cm⁻¹1531m, 1351m, 1168m. HRMS-ESI⁺: m/z [M + H]⁺calcd

for C₁₆H₁₈N₃O₆S, 380.0911; found, 380.0923.

N-Butyl-N-(4-cyanophenyl)methanesulfonamide (5ag). Follow-

ing general procedure III using N-(4-cyanophenyl)-

methanesulfonamide (660 mg, 3.36 mmol, 1.0 equiv), K₂CO₃(697

mg, 5.04 mmol, 1.5 equiv), and 1-bromobutane (0.73 mL, 6.72 mmol,

2.0 equiv) for 23 h. After workup, removal of solvent in vacuo aﬀorded

pure 5ag (840 mg, 99%) as a yellowish oil. R_f= 0.5 (EtOAc:PE 1:1).

¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J = 8.4 Hz, 2H), 7.49 (d, J =

8.4 Hz, 2H), 3.75 (t, J = 7.2 Hz, 2H), 2.90 (s, 3H), 1.43−1.52 (m,

2H), 1.35 (sxt, J = 7.2 Hz, 2H), 0.89 (t, J = 7.2 Hz, 3H). ¹³C NMR

(100 MHz, CDCl₃) δ 143.5, 133.3, 128.1, 118.1, 111.2, 49.8, 37.6,

30.5, 19.5, 13.5. FT-IR v_max/cm⁻¹1604w, 1338m, 1156m. HRMS-

ESI⁺: m/z [M + H]⁺calcd for C₁₂H₁₇N₂O₂S, 253.1005; found,

253.1019.

N-Butyl-N-phenylmethanesulfonamide (5ah). Following general

procedure III using N-phenylmethanesulfonamide (300 mg, 1.75

mmol, 1.0 equiv), K₂CO₃(363 mg, 2.63 mmol 1.5 equiv), and 1-

bromobutane (0.38 mL, 3.50 mmol, 2.0 equiv) for 23 h. After workup,

removal of solvent in vacuo aﬀorded pure 5ah (360 mg, 90%) as a

white solid. R_f= 0.46 (EtOAc:PE 1:2), mp 64−65 °C. ¹H NMR (400

MHz, CDCl₃) δ 7.33−7.46 (m, 5H), 3.69 (t, J = 7.2 Hz, 2H), 2.89 (s,

3H), 1.48 (quint, J = 7.2 Hz, 2H), 1.36 (sxt, J = 7.2 Hz, 2H), 0.89 (t, J

= 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 139.3, 129.4, 128.5,

128.0, 50.4, 37.0, 30.6, 19.6, 13.6. FT-IR v_max/cm⁻¹1328m, 1149m.

HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₁H₁₈NO₂S, 228.1053; found,

228.1065.

3-((4-Methylphenyl)sulfonamido)-5-((4-nitrophenyl)sulfon-

amido)-N-phenylbenzamide (19). Following general procedure I

using 3-((4-methylphenyl)sulfonamido)-5-nitro-N-phenylbenzamide

(340 mg, 0.83 mmol, 1.0 equiv) for 16 h. The crude product was

converted to 19 following general procedure II using 4-nitro-

benzenesulfonyl chloride (211 mg, 0.95 mmol, 1.15 equiv) for 15 h

at room temperature. After workup, removal of solvent in vacuo

aﬀorded pure 19 (460 mg, 98%) as a reddish solid. R_f= 0.43

1

(MeOH:CHCl₃1:10), mp 160−161 °C. H NMR (400 MHz, d₆-

DMSO) δ 10.90 (s, 1H), 10.56 (s, 1H), 10.31 (s, 1H), 8.38 (d, J = 8.8

Hz, 2H), 7.98 (d, J = 8.8 Hz, 2H), 7.60−7.69 (m, 4H), 7.27−7.37 (m,

5H), 7.22−7.25 (m, 2H), 7.07−7.12 (m, 1H), 2.34 (s, 3H). ¹³C NMR

(100 MHz, d₆-DMSO) δ 165.4, 150.4, 145.0, 144.0, 139.4, 139.3,

138.3, 138.0, 136.8, 130.2, 129.1, 128.8, 127.2, 125.1, 124.3, 120.7,

115.1, 115.0, 113.0, 21.4. FT-IR v_max/cm⁻¹1597m, 1532m, 1314m,

1150m. HRMS-ESI⁺: m/z [M + H]⁺calcd for C₂₆H₂₃N₄O₇S₂,

567.1003; found, 567.1018.

N-Butyl-N-(3-((4-methylphenyl)sulfonamido)phenyl)pyridine-2-

sulfonamide (21). Following general procedure I using N-butyl-iN-(3-

nitrophenyl)pyridine-2-sulfonamide (102 mg, 0.30 mmol, 1.0 equiv)

for 22 h. The crude product was converted to 21 following general

procedure II using 4-toluenesulfonyl chloride (67 mg, 0.35 mmol, 1.15

equiv) for 42 h at room temperature. Puriﬁcation by ﬂash column

chromatography (SiO₂EtOAc:PE 1:1.5) aﬀorded 21 (138 mg, 99%)

as a yellowish solid. R_f= 0.43 (MeOH:CHCl₃1:10), mp 131−132 °C.

¹H NMR (400 MHz, CDCl₃) δ 8.74−8.77 (m, 1H), 7.81 (td, J = 8.0,

1.6 Hz, 1H), 7.68−7.72 (m, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.46−7.50

(m, 1H), 7.18−7.23 (m, 3H), 7.14 (t, J = 8.0 Hz, 1H), 6.91−7.02 (m,

3H), 3.79 (t, J = 6.8 Hz, 2H), 2.38 (s, 3H), 1.26−1.34 (m, 4H), 0.85

(t, J = 6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 157.2, 150.1,

144.0, 139.9, 137.8, 137.4, 135.8, 129.69, 129.65, 127.3, 126.7, 125.9,

123.0, 121.9, 120.9, 52.1, 30.5, 21.5, 19.5, 13.6. FT-IR v_max/cm⁻¹

3230w, 1597w, 1349m, 1174m, 1153m. HRMS-ESI⁺: m/z [M + H]⁺

calcd for C₂₂H₂₆N₃O₄S₂, 460.1359; found, 460.1370.

N-Butyl-N-(3,4-dimethoxyphenyl)-4-methylbenzenesulfonamide

(30). Following general procedure III using N-(3,4-dimethoxyphenyl)-

4-methylbenzenesulfonamide (545 mg, 1.77 mmol, 1.0 equiv), K₂CO₃

(368 mg, 2.66 mmol, 1.5 equiv), and 1-bromobutane (0.38 mL, 3.55

mmol, 2.0 equiv) for 13 h. Puriﬁcation by ﬂash column

chromatography (SiO₂EtOAc:PE 1:2.5) aﬀorded 30 (638 mg, 99%)

4-Methyl-N-(3-((4-nitrophenyl)sulfonamido)phenyl)benzene-

sulfonamide (15a). Following general procedure I using 40 (193 mg,

0.66 mmol, 1.0 equiv) for 20 h. The crude product was converted to

15a following general procedure II using 4-nitrobenzenesulfonyl

chloride (161 mg, 0.73 mmol, 1.1 equiv) for 24 h at room temperature.

The crude product was recrystallized from DCM/PE mixture to aﬀord

15a (240 mg, 81%) as a brownish solid. R_f= 0.3 (EtOAc:PE 1:2), mp

86−87 °C. ¹H NMR (400 MHz, d₆-DMSO) δ 10.63 (s, 1H), 10.30 (s,

1H), 8.35 (d, J = 8.0 Hz, 2H), 7.93 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 7.6

Hz, 2H), 7.31 (d, J = 7.6 Hz, 2H), 7.02−7.11 (m, 2H), 6.68−6.76 (m,

2H), 2.33 (s, 3H). ¹³C NMR (100 MHz, d₆-DMSO) δ 150.3, 145.2,

143.8, 139.2, 138.2, 137.0, 130.4, 130.1, 128.7, 127.1, 125.0, 116.0,

115.9, 111.4, 21.4. FT-IR v_max/cm⁻¹3282w, 1597w, 1325m, 1160m.

HRMS-ESI⁺: m/z [M + NH₄]⁺calcd for C₁₉H₂₁N₄O₆S₂, 465.0897;

found, 465.0910.

1

as a white solid. R_f= 0.5 (EtOAc:PE 1:2), mp 53−54 °C. H NMR

(400 MHz, CDCl₃) δ 7.51 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz,

2H), 6.75−6.79 (m, 1H), 6.54−6.58 (m, 2H), 3.89 (s, 3H), 3.76 (s,

3H), 3.49 (t, J = 7.2 Hz, 2H), 2.44 (s, 3H), 1.29−1.46 (m, 4H), 0.88

(t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 148.8, 148.6,

143.2, 135.4, 132.0, 129.3, 127.8, 121.0, 112.6, 110.7, 55.92, 55.88,

50.5, 30.3, 21.5, 19.6, 13.6. FT-IR v_max/cm⁻¹1344m, 1157m, 1025m.

HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₉H₂₆NO₄S, 364.1577; found,

364.1583.

N-Butyl-N-(3,4-dimethoxyphenyl)-4-nitrobenzenesulfonamide

(32). Following general procedure II using 3,4-dimethoxyaniline (208

mg, 1.36 mmol, 1.0 equiv) and 4-nitrobenzenesulfonyl chloride (331

mg, 1.49 mmol, 1.1 equiv) for 14 h at room temperature. The crude

product was converted to 32 following general procedure III using

I

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Article

K₂CO₃(282 mg, 2.04 mmol, 1.5 equiv) and 1-bromobutane (0.29 mL,

2.72 mmol, 2.0 equiv) for 21 h. Puriﬁcation by ﬂash column

chromatography (SiO₂EtOAc:PE 1:3) aﬀorded 32 (475 mg, 89%) as a

with 3 drops of neat ethylenediamine and subsequently diluted with

1.0 M NaOH aq solution. The biphasing resulting mixture was

extracted with DCM. The combined organic extracts were dried over

Na₂SO₄, ﬁltered, and then concentrated in vacuo. The product was

puriﬁed by ﬂash column chromatography.

General Procedure VI: One-Pot Ynamide−Acetonitrile Cycliza-

tion−Sulfonamide Deprotection. An oven-dried pressure tube

equipped with a stir bar and a rubber septum was charged with

ynamide (1.0 equiv), acetonitrile (∼0.06 M), and TfOH (1.0−4.0

equiv) at 0 °C under argon. The septum was then replaced with a

heat-resistant screw cap containing PFET membrane. The mixture was

heated at 90 °C for an indicated period of time, quenched with satd

NaHCO₃aq solution, and extracted with EtOAc. The combined

organic extracts were dried over Na₂SO₄, ﬁltered, and then

concentrated in vacuo. The product was puriﬁed by ﬂash column

chromatography.

N-(2-((2,4-Dibromophenyl)amino)ethyl)-4-methylbenzenesulfo-

namide (2). A mixture of sulfonamide 1 (124 mg, 0.28 mmol) and

AcOH/HBr (30% solution, 1.0 mL) was stirred for 4 h at room

temperature. The mixture was quenched with satd NaHCO₃aq

solution, extracted with EtOAc, dried with Na₂SO₄, and evaporated in

vacuo. Puriﬁcation by ﬂash column chromatography (SiO₂EtOAc:PE

1:1.5) aﬀorded 2 (96 mg, 77%) as slightly brown solid. R_f= 0.5

(EtOAc:PE 1:1), mp 75−76 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.75

(d, J = 8.0 Hz, 2H), 7.53 (d, J = 2.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H),

7.22 (dd, J = 8.4, 2.0 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.01 (t, J = 6.0

Hz, 1H), 4.54 (br, 1H), 3.28−3.34 (m, 2H), 3.17−3.24 (m, 2H), 2.43

(s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 143.8, 143.3, 136.6, 134.5,

1

yellow solid. R_f= 0.42 (EtOAc:PE 1:3), mp 103−104 °C. H NMR

(400 MHz, CDCl₃) δ 8.32 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 8.8 Hz,

2H), 6.76 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 2.0 Hz, 1H), 6.43 (dd, J =

8.4, 2.0 Hz, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.55 (t, J = 7.2 Hz, 2H),

1.31−1.48 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz,

CDCl₃) δ 150.0, 149.2, 149.1, 144.2, 130.9, 128.9, 123.9, 120.2, 112.9,

110.8, 56.1, 56.0, 51.0, 30.3, 19.6, 13.6. FT-IR v_max/cm⁻¹1509w,

1344m, 1162m, 1071w. HRMS-ESI⁺: m/z [M + H]⁺calcd for

C₁₈H₂₃N₂O₆S, 395.1271; found, 395.1282.

N-Butyl-N-(p-tolyl)methanesulfonamide (34). Following general

procedure III using N-(p-tolyl)methanesulfonamide (394 mg, 2.13

mmol, 1.0 equiv), K₂CO₃(441 mg, 3.19 mmol, 1.5 equiv), and 1-

bromobutane (0.46 mL, 4.25 mmol, 2.0 equiv) for 17 h. Puriﬁcation

by ﬂash column chromatography (SiO₂EtOAc:PE 1:3) aﬀorded 34

(490 mg, 95%) as a white solid. R_f= 0.6 (EtOAc:PE 1:2), mp 48−49

1

°C. H NMR (400 MHz, CDCl₃) δ 7.19−7.27 (m, 4H), 3.66 (t, J =

7.2 Hz, 2H), 2.88 (s, 3H), 2.38 (s, 3H), 1.47 (quint, J = 7.2 Hz, 2H),

1.36 (sxt, J = 7.2 Hz, 2H), 0.89 (t, J = 7.2 Hz, 3H). ¹³C NMR (100

MHz, CDCl₃) δ 138.1, 136.6, 130.1, 128.4, 50.4, 36.9, 30.6, 21.1, 19.6,

13.6. FT-IR v_max/cm⁻¹1327m, 1149m. HRMS-ESI⁺: m/z [M + H]⁺

calcd for C₁₂H₂₀NO₂S, 242.1209; found, 242.1222.

N-(2-Bromoethyl)-N-(3,4-dimethoxyphenyl)methanesulfonamide

(36). Following general procedure III using N-(3,4-dimethoxyphenyl)-

methanesulfonamide (985 mg, 4.26 mmol, 1.0 equiv), NaH (60%

dispersion, 196 mg, 4.90 mmol, 1.15 equiv), and 1,2-dibromoethane

(1.84 mL, 21.3 mmol, 5.0 equiv) in DMF for 43 h at room

temperature. Puriﬁcation by ﬂash column chromatography (SiO₂

MeOH:CHCl₃1:30) aﬀorded 36 (962 mg, 67%) as a white solid. R_f

131.2, 129.8, 127.0, 112.3, 110.4, 108.8, 43.4, 41.8, 21.5. FT-IR v_max

/

cm⁻¹3422w, 3253w, 1303m, 1151s. HRMS-ESI⁺: m/z [M + H]⁺calcd

for C₁₅H₁₇Br₂N₂O₂S, 448.9352; found, 448.9361.

1

= 0.4 (MeOH:CHCl₃1:20), mp 93−94 °C. H NMR (400 MHz,

4-Methyl-N-(2-(phenylamino)ethyl)benzenesulfonamide (3). Fol-

lowing general procedure IV using 1 (101 mg, 0.227 mmol, 1.0 equiv)

and TfOH (0.02 mL, 0.23 mmol, 1.0 equiv) at 90 °C. Puriﬁcation of

the crude product by ﬂash column chromatography (SiO₂EtOAc:PE

1:2.5) aﬀorded 3 (63 mg, 96%). ¹H and ¹³C NMR data are identical to

those reported in the literature.⁴⁴

CDCl₃) δ 6.84−6.96 (m, 3H), 4.00 (t, J = 6.8 Hz, 2H), 3.87−3.93 (m,

6H), 3.41 (t, J = 6.8 Hz, 2H), 2.99 (s, 3H). ¹³C NMR (100 MHz,

CDCl₃) δ 149.6, 149.5, 131.2, 120.8, 113.0, 111.3, 56.2, 56.1, 52.7,

38.2, 29.4. FT-IR v_max/cm⁻¹1321m, 1140m, 1083m. HRMS-ESI⁺: m/z

[M + H]⁺calcd for C₁₁H₁₇BrNO₄S, 340.0036; found, 340.0040.

N-Butyl-4-methyl-N-(3-(methylsulfonamido)phenyl)benzene-

sulfonamide (38). Following general procedure I using 5m (221 mg,

0.63 mmol, 1.0 equiv) for 20 h. The crude product was converted to

38 following general procedure II using methanesulfonyl chloride

(0.06 mL, 0.78 mmol, 1.2 equiv) for 23 h at room temperature.

Puriﬁcation by ﬂash column chromatography (SiO₂EtOAc:PE 1:2)

aﬀorded 38 (230 mg, 91%) as a white solid. R_f= 0.43 (EtOAc:PE 1:1),

N-Butyl-[1,1′-biphenyl]-2-amine (6a). Following general procedure

IV using 5a (96 mg, 0.25 mmol, 1.0 equiv), TfOH (0.04 mL, 0.40

mmol, 1.6 equiv), and benzaldehyde (0.05 mL, 0.506 mmol, 2.0 equiv)

at 90 °C. Puriﬁcation of the crude product by ﬂash column

chromatography (SiO₂EtOAc:Hex 1:40) aﬀorded 6a (43 mg, 75%)

1

as a brownish oil. R_f= 0.19 (EtOAc:Hex 1:40). H NMR (400 MHz,

CDCl₃) δ 7.38−7.54 (m, 5H), 7.28−7.34 (m, 1H), 7.16 (dd, J = 7.6,

1.2 Hz, 1H), 6.76−6.85 (m, 2H), 3.99 (br, 1H), 3.16 (t, J = 7.2 Hz,

2H), 1.59 (quint, J = 7.2 Hz, 2H), 1.41 (sxt, J = 7.2 Hz, 2H), 0.98 (t, J

= 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 145.3, 139.7, 130.2,

129.4, 128.9, 128.8, 127.6, 127.2, 116.7, 110.4, 43.8, 31.5, 20.4, 13.9.

FT-IR v_max/cm⁻¹3423w, 733m. HRMS-ESI⁺: m/z [M + H]⁺calcd for

C₁₆H₂₀N: 226.1590; found, 226.1594.

1

mp 92−93 °C. H NMR (400 MHz, CDCl₃) δ 7.49 (d, J = 8.4 Hz,

2H), 7.25−7.32 (m, 3H), 7.18−7.23 (m, 1H), 7.03−7.06 (m, 1H),

6.82−6.87 (m, 2H), 3.53 (t, J = 7.2 Hz, 2H), 3.01 (s, 3H), 2.44 (s,

3H), 1.27−1.44 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H). ¹³C NMR (100

MHz, CDCl₃) δ 143.6, 140.5, 137.5, 135.1, 130.0, 129.5, 127.6, 124.8,

121.2, 119.8, 50.0, 39.4, 30.2, 21.5, 19.6, 13.6. FT-IR v_max/cm⁻¹3248w,

1339m, 1314m, 1147m. HRMS-ESI⁺: m/z [M + H]⁺calcd for

C₁₈H₂₅N₂O₄S₂, 397.1250; found, 397.1251.

Note: the use of benzaldehyde additive was necessary with this

rather sensitive compound to scavenge the byproduct 4.

General Procedure IV: Deprotection of Sulfonamides. An oven-

dried pressure tube equipped with a stir bar and a rubber septum was

charged with substrate (1.0 equiv), DCE (∼0.04 M), and TfOH (1.0−

3.0 equiv) at 0 °C under argon. The septum was then replaced with a

heat-resistant screw cap containing PFET membrane. The mixture was

stirred at 25−90 °C for an indicated period of time and then quenched

with 3 drops of neat ethylenediamine and subsequently diluted with

1.0 M NaOH aq solution. The biphasing resulting mixture was

extracted with DCM. The combined organic extracts were dried over

Na₂SO₄, ﬁltered, and then concentrated in vacuo. The product was

puriﬁed via silica gel ﬂash column chromatography.

General Procedure V: One-Pot Sulfonamide Deprotection−

Norbornene Hydroamination. An oven-dried pressure tube equipped

with a stir bar and a rubber septum was charged with sulfonamide (1.0

equiv), norbornene (2.0 equiv), DCE (∼0.07 M), and TfOH (1.6−2.1

equiv) at 0 °C under argon. The septum was then replaced with a

heat-resistant screw cap containing PFET membrane. The mixture was

heated at 50−80 °C for an indicated period of time and then quenched

2-Bromo-N-butylaniline (6b). Following general procedure IV

using 5b (100 mg, 0.26 mmol, 1.0 equiv) and TfOH (0.05 mL, 0.57

mmol, 2.15 equiv) at 90 °C. Puriﬁcation of the crude product by ﬂash

column chromatography (SiO₂EtOAc:Heptane 1:20) aﬀorded the

1

title compound (54 mg, 90%). H and ¹³C NMR data are identical to

those reported in the literature.⁴⁵

N¹-Butylbenzene-1,3-diamine (6c). Following general procedure

IV using 5c (89 mg, 0.19 mmol, 1.0 equiv), TfOH (0.03 mL, 0.28

mmol, 1.5 equiv), and benzaldehyde (0.02 mL, 0.19 mmol, 1.0 equiv)

at 90 °C. Puriﬁcation of the crude product by ﬂash column

chromatography (SiO₂EtOAc:Cyclohexane 1:20, 1:5, 1:3) aﬀorded

6c (25 mg, 81%) as a brown oil. R_f= 0.32 (EtOAc:Cyclohexane 1:2).

¹H NMR (400 MHz, CDCl₃) δ 6.98 (t, J = 8.0 Hz, 1H), 6.09 (dd, J =

8.0, 2.0 Hz, 2H), 5.96−6.01 (m, 1H), 3.49 (br, 3H), 3.10 (t, J = 7.2

Hz, 2H), 1.62 (quint, J = 7.2 Hz, 2H), 1.45 (sxt, J = 7.2 Hz, 2H), 0.98

(t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 149.7, 147.5,

130.1, 104.7, 104.0, 99.4, 43.7, 31.7, 20.3, 13.9. FT-IR v_max/cm⁻¹

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The Journal of Organic Chemistry

Article

3349w, 1609m, 1212m. HRMS-ESI⁺: m/z [M + H]⁺calcd for

C₁₀H₁₇N₂: 165.1386; found, 165.1400.

Note: the use of benzaldehyde additive was necessary with this

rather sensitive compound to scavenge the byproduct 4.

mmol, 2.2 equiv) at 90 °C. Puriﬁcation of the crude product by ﬂash

column chromatography (SiO₂, EtOAc:PE 1:2) aﬀorded 6l (79 mg,

1

96%). H and ¹³C NMR data are identical to those reported in the

literature.⁵¹

N-Butyl-3,5-dimethylaniline (6d). Following general procedure IV

using 5d (73 mg, 0.22 mmol, 1.0 equiv) and TfOH (0.04 mL, 0.45

mmol, 2.05 equiv) at 80 °C. Puriﬁcation of the crude product by ﬂash

column chromatography (SiO₂EtOAc:PE 1:25) aﬀorded 6d (33 mg,

N-Butyl-3-nitroaniline (6m). Following general procedure IV using

5m (136 mg, 0.39 mmol, 1.0 equiv) and TfOH (0.055 mL, 0.62 mmol,

1.6 equiv) at 90 °C. Puriﬁcation of the crude product by ﬂash column

chromatography (SiO₂EtOAc:PE 1:10) aﬀorded 6m (69 mg, 91%).

Gram-scale reaction: Following general procedure IV using 5m

(1.05 g, 3.01 mmol, 1.0 equiv) and TfOH (0.53 mL, 6.02 mmol, 2.0

equiv) at 90 °C. Puriﬁcation of the crude product by ﬂash column

chromatography (SiO₂EtOAc:PE 1:10) aﬀorded 6m (510 mg, 87%).

From nosyl-protected precursor 5af: Following general procedure

IV using 5af (66 mg, 0.17 mmol, 1.0 equiv) and TfOH (0.03 mL, 0.34

mmol, 2.0 equiv) at 90 °C. Puriﬁcation of the crude product by ﬂash

column chromatography (SiO₂EtOAc:PE 1:10) aﬀorded 6m (33 mg,

98%).

1

83%). H and ¹³C NMR data are identical to those reported in the

literature.⁴⁶

3,4-Dihydro-2H-benzo[b][1,4]thiazine (6e). Following general

procedure IV using 5e (42 mg, 0.14 mmol, 1.0 equiv) and TfOH

(0.02 mL, 0.23 mmol, 1.6 equiv) at 90 °C. Puriﬁcation of the crude

product by ﬂash column chromatography (SiO₂EtOAc:PE 1:10)

1

aﬀorded 6e (19 mg, 91%). H and ¹³C NMR data are identical to

those reported in the literature.⁴⁷

N-Butyl-3,5-bis(triﬂuoromethyl)aniline (6f). Following general

procedure IV using 5f (101 mg, 0.23 mmol, 1.0 equiv) and TfOH

(0.04 mL, 0.46 mmol, 2.0 equiv) at 90 °C. Puriﬁcation of the crude

product by ﬂash column chromatography (SiO₂EtOAc:PE 1:15)

aﬀorded 6f (63 mg, 96%) as a dark oil. R_f= 0.64 (EtOAc:PE 1:10). ¹H

NMR (400 MHz, CDCl₃) δ 7.16 (s, 1H), 6.95 (s, 2H), 4.26 (br s,

1H), 3.18 (t, J = 7.2 Hz, 2H), 1.66 (quint, J = 7.2 Hz, 2H), 1.48 (sxt, J

= 7.2 Hz, 2H), 1.00 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃)

δ 148.8, 132.4 (q, J = 32.4 Hz), 123.6 (q, J = 270.9 Hz), 111.8 (d, J =

3.0 Hz), 109.9 (q, J = 3.9 Hz), 43.4, 31.2, 20.2, 13.8. FT-IR v_max/cm⁻¹

3442w, 1168m. HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₂H₁₄F₆N:

286.1025; found, 286.1027.

From 2,4,6-triisopropylbenzene sulfonyl-protected precursor 5ac:

Following general procedure IV using 5ac (111 mg, 0.24 mmol, 1.0

equiv) and TfOH (0.05 mL, 0.57 mmol, 2.4 equiv) at 70 °C.

Puriﬁcation of the crude product by ﬂash column chromatography

1

(SiO₂EtOAc:PE 1:10) aﬀorded 6m (46 mg, 99%). H and ¹³C NMR

data are identical to those reported in the literature.⁵⁰

4-(Butylamino)benzonitrile (6n). Following general procedure IV

using 5n (88 mg, 0.27 mmol, 1.0 equiv) and TfOH (0.05 mL, 0.57

mmol, 2.1 equiv) at 70 °C. Puriﬁcation of the crude product by ﬂash

column chromatography (SiO₂EtOAc:Cyclohexane 1:5) aﬀorded 6n

(54 mg, 79%). ¹H and ¹³C NMR data are identical to those reported in

the literature.⁵²

From mesyl-protected precursor 5ag: Following general procedure

IV using 5ah (130 mg, 0.52 mmol, 1.0 equiv) and TfOH (0.09 mL,

1.04 mmol, 2.0 equiv) at 80 °C. Puriﬁcation of the crude product by

ﬂash column chromatography (SiO₂EtOAc:PE 1:3) aﬀorded 6n (67

mg, 75%).

Methyl 2-(Butylamino)benzoate (6g). Following general proce-

dure IV using 5g (100 mg, 0.28 mmol, 1.0 equiv) and TfOH (0.05 mL,

0.57 mmol, 2.04 equiv) at 90 °C. Puriﬁcation of the crude product by

ﬂash column chromatography (SiO₂EtOAc:PE 1:15) aﬀorded 6g (54

1

mg, 93%) as a brown oil. R_f= 0.88 (EtOAc:PE 1:5). H NMR (400

MHz, CDCl₃) δ 7.90−7.95 (m, 1H), 7.81 (br, 1H), 7.35−7.41 (m,

1H), 6.72 (d, J = 8.4 Hz, 1H), 6.57−6.63 (m, 1H), 3.88 (s, 3H), 3.22

(t, J = 7.2 Hz, 2H), 1.71 (quint, J = 7.2 Hz, 2H), 1.50 (sxt, J = 7.2 Hz,

2H), 1.00 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 169.1,

151.1, 134.6, 131.6, 114.4, 111.4, 109.8, 51.4, 42.7, 31.2, 20.4, 13.9. FT-

IR v_max/cm⁻¹3365w, 1682m, 1233s. HRMS-ESI⁺: m/z [M + H]⁺calcd

for C₁₂H₁₈NO₂: 208.1332; found, 208.1341.

4-Bromo-2-methylaniline (6o). Following general procedure IV

using 5o (107 mg, 0.31 mmol, 1.0 equiv) and TfOH (0.06 mL, 0.68

mmol, 2.2 equiv) at 50 °C. Puriﬁcation of the crude product by ﬂash

column chromatography (SiO₂EtOAc:PE 1:4.5) aﬀorded 6o (40 mg,

1

68%). H and ¹³C NMR data are identical to those reported in the

literature.⁵³

4-(Methylamino)benzaldehyde (6h). Following general procedure

IV using 5h (188 mg, 0.65 mmol, 1.0 equiv) and TfOH (0.12 mL, 1.36

mmol, 2.1 equiv) at room temperature. Puriﬁcation of the crude

product by ﬂash column chromatography (SiO₂EtOAc:PE 1:2)

5-Amino-2-butylisoindoline-1,3-dione (6p). Following general

procedure IV using 5p (123 mg, 0.33 mmol, 1.0 equiv) and TfOH

(0.06 mL, 0.68 mmol, 2.1 equiv) at 85 °C. Puriﬁcation of the crude

product by ﬂash column chromatography (SiO₂EtOAc:PE 1:1.5)

aﬀorded 6p (51 mg, 70%).

From nosyl-protected precursor 5ae. Following general procedure

IV using 5ae (118 mg, 0.29 mmol, 1.0 equiv) and TfOH (0.05 mL,

0.57 mmol, 1.9 equiv) at 90 °C. Puriﬁcation of the crude product by

ﬂash column chromatography (SiO₂EtOAc:PE 1:1.5) aﬀorded 6p (35

mg, 55%). ¹H and ¹³C NMR data are identical to those reported in the

literature.⁵⁴

1

aﬀorded 6h (71 mg, 81%). H and ¹³C NMR data are identical to

those reported in the literature.⁴⁸

(4-(Methylamino)phenyl)(phenyl)methanone (6i). Following gen-

eral procedure IV using 5i (100 mg, 0.27 mmol, 1.0 equiv) and TfOH

(0.05 mL, 0.57 mmol, 2.1 equiv) at 90 °C. Puriﬁcation of the crude

product by ﬂash column chromatography (SiO₂EtOAc:PE 1:2.5)

aﬀorded 6i (57 mg, 99%) as a yellowish solid. R_f= 0.42 (EtOAc:PE

1

1:2), mp 92−93 °C. H NMR (400 MHz, CDCl₃) δ 7.72−7.80 (m,

2-Butyl-5-(butylamino)isoindoline-1,3-dione (6q). Following gen-

eral procedure IV using 5q (92 mg, 0.22 mmol, 1.0 equiv) and TfOH

(0.04 mL, 0.45 mmol, 2.1 equiv) at 90 °C. Puriﬁcation of the crude

product by ﬂash column chromatography (SiO₂EtOAc:PE 1:10)

aﬀorded 6q (53 mg, 90%) as a yellow solid. R_f= 0.3 (EtOAc:PE 1:5),

4H), 7.51−7.57 (m, 1H), 7.43−7.50 (m, 2H), 6.60 (d, J = 8.4 Hz,

2H), 4.54 (br, 1H), 2.91 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ

195.3, 153.1, 139.2, 133.0, 131.2, 129.5, 128.1, 126.0, 111.0, 30.1. FT-

IR v_max/cm⁻¹3356w, 1586m, 1280m. HRMS-ESI⁺: m/z [M + H]⁺

calcd for C₁₄H₁₄NO: 212.1070; found, 212.1073.

1

mp 91−92 °C. H NMR (400 MHz, CDCl₃) δ 7.58 (d, J = 8.0 Hz,

2-Nitroaniline (6j). Following general procedure IV using 5j (131

mg, 0.49 mmol, 1.0 equiv) and TfOH (0.08 mL, 0.98 mmol, 2.0 equiv)

at 90 °C. Puriﬁcation of the crude product by ﬂash column

chromatography (SiO₂EtOAc:PE 1:3) aﬀorded 6j (61 mg, 99%).

¹H and ¹³C NMR data are identical to those reported in the

literature.⁴⁹

N-Butyl-2-nitroaniline (6k). Following general procedure IV using

5k (94 mg, 0.27 mmol, 1.0 equiv) and TfOH (0.05 mL, 0.57 mmol,

2.1 equiv) at 90 °C. Puriﬁcation of the crude product by ﬂash column

chromatography (SiO₂, EtOAc:PE 1:5) aﬀorded 6k (48 mg, 92%). ¹H

and ¹³C NMR data are identical to those reported in the literature.⁵⁰

N-Methyl-2,4-dinitroaniline (6l). Following general procedure IV

using 5l (146 mg, 0.42 mmol, 1.0 equiv) and TfOH (0.08 mL, 0.90

1H), 6.97 (s, 1H), 6.69−6.75 (m, 1H), 4.67 (br, 1H), 3.63 (t, J = 7.2

Hz, 2H), 3.22 (t, J = 7.2 Hz, 2H), 1.59−1.70 (m, 4H), 1.45 (sxt, J =

7.2 Hz, 2H), 1.36 (sxt, J = 7.2 Hz, 2H), 0.90−1.01 (m, 6H). ¹³C NMR

(100 MHz, CDCl₃) δ 169.1, 168.8, 153.2, 135.1, 124.8, 119.0, 115.7,

106.0, 43.4, 37.5, 31.1, 30.8, 20.2, 20.1, 13.8, 13.7. FT-IR v_max/cm⁻¹

3375w, 1685m, 1399m, 1045m. HRMS-ESI⁺: m/z [M + H]⁺calcd for

C₁₆H₂₃N₂O₂: 275.1754; found, 275.1760.

N-(3-Aminophenyl)benzamide (6r). Following general procedure

IV using 5r (106 mg, 0.29 mmol, 1.0 equiv) and TfOH (0.03 mL, 0.34

mmol, 1.2 equiv) at 90 °C. Puriﬁcation of the crude product by ﬂash

column chromatography (SiO₂EtOAc:PE 1:1.5) aﬀorded 6r (42 mg,

1

68%). H and ¹³C NMR data are identical to those reported in the

literature.⁵⁵

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Article

N-(3-(Butylamino)phenyl)benzamide (6s). Following general

procedure IV using 5s (96 mg, 0.23 mmol, 1.0 equiv) and TfOH

(0.04 mL, 0.46 mmol, 2.0 equiv) at 50 °C. Puriﬁcation of the crude

product by ﬂash column chromatography (SiO₂EtOAc:PE 1:4)

aﬀorded 6s (43 mg, 70%) as a yellow solid. R_f= 0.2 (EtOAc:PE 1:5),

(48 mg, 71%). ¹H and ¹³C NMR data are identical to those reported in

the literature.⁶¹

3-Nitroaniline (6ab). Following general procedure IV using 5ab

(104 mg, 0.26 mmol, 1.0 equiv) and TfOH (0.05 mL, 0.57 mmol, 2.2

equiv) at 80 °C. Puriﬁcation of the crude product by ﬂash column

chromatography (SiO₂EtOAc:PE 1:3) aﬀorded 6ab (34 mg, 96%). ¹H

and ¹³C NMR data are identical to those reported in the literature.⁶²

4-Nitro-N-(2-(phenylamino)ethyl)benzenesulfonamide (6ad).

Following general procedure IV using 5ad (101 mg, 0.20 mmol, 1.0

equiv) and TfOH (0.02 mL, 0.22 mmol, 1.1 equiv) at 90 °C.

Puriﬁcation of the crude product by ﬂash column chromatography

(SiO₂EtOAc:PE 1:1.5) aﬀorded 6ad (34 mg, 53%) as a yellow solid.

1

mp 77−78 °C. H NMR (400 MHz, CDCl₃) δ 7.82−7.91 (m, 3H),

7.46−7.58 (m, 3H), 7.21−7.24 (m, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.79

(dd, J = 8.0, 1.6 Hz, 1H), 6.42 (dd, J = 8.0, 1.6 Hz, 1H), 3.66 (br, 1H),

3.14 (t, J = 7.2 Hz, 2H), 1.63 (quint, J = 7.2 Hz, 2H), 1.45 (sxt, J = 7.2

Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ

165.7, 149.3, 139.0, 135.3, 131.7, 129.7, 128.7, 127.0, 109.0, 108.7,

104.5, 43.7, 31.6, 20.3, 13.9. FT-IR v_max/cm⁻¹3398w, 3299w, 1592m,

1286m. HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₇H₂₁N₂O: 269.1648;

found, 269.1656.

1

R_f= 0.55 (EtOAc:PE 1:1), mp 109−110 °C. H NMR (400 MHz,

CDCl₃) δ 8.28 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 7.15 (dd,

J = 8.4, 7.2 Hz, 2H), 6.72−6.77 (m, 1H), 6.51−6.55 (m, 2H), 5.36−

5.42 (m, 1H), 3.30−3.35 (m, 2H), 3.22−3.28 (m, 2H). ¹³C NMR

(100 MHz, CDCl₃) δ 150.0, 146.8, 145.5, 129.4, 128.2, 124.4, 118.6,

113.1, 43.4, 42.3. FT-IR v_max/cm⁻¹3404w, 3320w, 1523m, 1347m.

HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₄H₁₆N₃O₄S, 322.0856; found,

322.0866.

N-Butyl-3,4-dichloroaniline (6t). Following general procedure IV

using 5t (61 mg, 0.16 mmol, 1.0 equiv) and TfOH (0.03 mL, 0.34

mmol, 2.1 equiv) at 90 °C. Puriﬁcation of the crude product by ﬂash

column chromatography (SiO₂EtOAc:PE 1:10) aﬀorded 6t (36 mg,

99%). ¹H NMR data are identical to those reported in the literature.⁵⁶

N-Butyl-5-chloropyridin-2-amine (6u). Following general proce-

dure IV using 5u (93 mg, 0.27 mmol, 1.0 equiv) and TfOH (0.06 mL,

0.69 mmol, 2.5 equiv) at 90 °C. Puriﬁcation of the crude product by

ﬂash column chromatography (SiO₂EtOAc:PE 1:2) aﬀorded 6u (50

mg, 99%). ¹H and ¹³C NMR data are identical to those reported in the

literature.⁵⁷

N-Butylaniline (6ah). Following general procedure IV using 5ah

(104 mg, 0.46 mmol, 1.0 equiv) and TfOH (0.08 mL, 0.92 mmol, 2.0

equiv) at 80 °C. Puriﬁcation of the crude product by ﬂash column

chromatography (SiO₂EtOAc:PE 1:10) aﬀorded 6ah (41 mg, 60%).

1

Volatile! H and ¹³C NMR data are identical to those reported in the

literature.⁶³

1-Butyl-5-chloropyridin-2(1H)-imine (6v). Following general pro-

cedure IV using 5v (57 mg, 0.17 mmol, 1.0 equiv) and TfOH (0.04

mL, 0.45 mmol, 2.7 equiv) at 90 °C. Puriﬁcation of the crude product

by ﬂash column chromatography (SiO₂DCM:MeOH 10:1) aﬀorded

4-Bicyclo[2.2.1]heptan-2-ylamino)benzonitrile (12). Following

general procedure V using 12 (95 mg, 0.35 mmol, 1.0 equiv),

norbornene (66 mg, 0.70 mmol, 2.0 equiv), and TfOH (0.05 mL, 0.57

mmol, 1.6 equiv) at 50 °C for 4 h. Puriﬁcation of the crude product by

ﬂash column chromatography (SiO₂EtOAc:PE 1:6) aﬀorded 12 (45

mg, 61%) as a colorless solid. R_f= 0.37 (EtOAc:PE 1:5), mp 117−118

°C. ¹H NMR (400 MHz, CDCl₃) δ 7.41 (d, J = 8.4 Hz, 2H), 6.52 (d, J

= 8.4 Hz, 2H), 4.16−4.22 (m, 1H), 3.23−3.29 (m, 1H), 2.26−2.36 (m,

2H), 1.83−1.90 (m, 1H), 1.50−1.64 (m, 2H), 1.42−1.48 (m, 1H),

1.17−1.29 (m, 4H). ¹³C NMR (100 MHz, CDCl₃) δ 150.6, 133.6,

1

6v (27 mg, 87%) as a dark oil. R_f= 0.18 (CHCl₃:MeOH 10:1). H

NMR (400 MHz, CDCl₃) δ 7.02 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 9.6,

2.4 Hz, 1H), 6.49 (d, J = 9.6 Hz, 1H), 5.90 (br, 1H), 3.90 (t, J = 7.2

Hz, 2H), 1.74 (quint, J = 7.2 Hz, 2H), 1.40 (sxt, J = 7.2 Hz, 2H), 0.96

(t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 157.4, 135.6,

134.7, 121.8, 110.0, 51.5, 29.9, 19.8, 13.8. FT-IR v_max/cm⁻¹3023w,

1578m. HRMS-ESI⁺: m/z [M + H]⁺calcd for C₉H₁₄ClN₂: 185.0840;

found, 185.0841.

120.7, 112.5, 98.1, 56.2, 41.3, 40.9, 35.6, 35.5, 28.3, 26.3. FT-IR v_max

/

cm⁻¹3352w, 2210m. HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₄H₁₇N₂:

213.1386; found, 213.1389.

N-Methylquinolin-8-amine (6w). Following general procedure IV

using 5w (84 mg, 0.27 mmol, 1.0 equiv) and TfOH (0.07 mL, 0.81

mmol, 3.0 equiv) at 90 °C. Puriﬁcation of the crude product by ﬂash

column chromatography (SiO₂EtOAc:PE 1:4) aﬀorded 6w (30 mg,

N-(2-Nitrophenyl)bicyclo[2.2.1]heptan-2-amine (13). Following

general procedure V using 5j (100 mg, 0.34 mmol, 1.0 equiv),

norbornene (64.5 mg, 0.68 mmol, 2.0 equiv), and TfOH (0.06 mL,

0.68 mmol, 2.0 equiv) at 65 °C for 67 h. Puriﬁcation of the crude

product by ﬂash column chromatography (SiO₂EtOAc:PE 1:20)

aﬀorded 13 (74 mg, 93%) as a red oil. R_f= 0.46 (EtOAc:PE 1:20). ¹H

NMR (400 MHz, CDCl₃) δ 8.18 (dd, J = 8.8, 1.6 Hz, 1H), 7.98−8.06

(m, 1H), 7.39−7.46 (m, 1H), 6.81−6.86 (m, 1H), 6.60−6.66 (m, 1H),

3.41−3.47 (m, 1H), 2.36−2.41 (m, 2H), 1.93 (ddd, J = 12.8, 7.6, 2.4

Hz, 1H), 1.54−1.67 (m, 3H), 1.39−1.46 (m, 1H), 1.21−1.33 (m, 3H).

¹³C NMR (100 MHz, CDCl₃) δ 144.7, 136.0, 131.9, 126.9, 115.0,

114.7, 56.1, 41.7, 41.1, 35.8, 35.7, 28.4, 26.3. FT-IR v_max/cm⁻¹3375w,

1571m. HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₃H₁₇N₂O₂: 233.1285;

found, 233.1289.

N-Bicyclo[2.2.1]heptan-2-yl)-5-chloropyridin-2-amine (14). Fol-

lowing general procedure V using N-(5-chloropyridin-2-yl)-4-methyl-

benzenesulfonamide (135 mg, 0.48 mmol, 1.0 equiv), norbornene (90

mg, 0.96 mmol, 2.0 equiv), and TfOH (0.09 mL, 1.02 mmol, 2.1

equiv) at 50 °C for 96 h. Puriﬁcation of the crude product by ﬂash

column chromatography (SiO₂EtOAc:PE 1:4) aﬀorded 14 (55 mg,

52%) as a brownish solid. R_f= 0.78 (EtOAc:PE 1:2), mp 61−62 °C.

¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, J = 2.8 Hz, 1H), 7.37 (dd, J =

8.8, 2.8 Hz, 1H), 6.30 (d, J = 8.8 Hz, 1H), 4.59−4.68 (m, 1H), 3.32−

3.41 (m, 1H), 2.23−2.34 (m, 2H), 1.81−1.89 (m, 1H), 1.43−1.60 (m,

3H), 1.14−1.28 (m, 4H). ¹³C NMR (100 MHz, CDCl₃) δ 156.6,

146.6, 137.1, 119.3, 107.0, 55.5, 41.6, 40.9, 35.7, 35.4, 28.4, 26.4. FT-IR

v_max/cm⁻¹3252w, 1597m. HRMS-ESI⁺: m/z [M + H]⁺calcd for

C₁₂H₁₆ClN₂: 223.0997; found, 223.1003.

1

71%). H and ¹³C NMR data are identical to those reported in the

literature.⁵⁸

1,2,3,4-Tetrahydro-1,10-phenanthroline (6x). Following general

procedure IV using 5x (125 mg, 0.37 mmol, 1.0 equiv) and TfOH

(0.065 mL, 0.74 mmol, 2.0 equiv) at 90 °C. Puriﬁcation of the crude

product by ﬂash column chromatography (SiO₂CHCl₃) aﬀorded 6x

(61 mg, 90%). ¹H and ¹³C NMR data are identical to those reported in

the literature.⁵⁹

Bis(4-bromophenyl)amine (6y). Following general procedure IV

using 5y (92 mg, 0.19 mmol, 1.0 equiv) and TfOH (0.04 mL, 0.45

mmol, 2.4 equiv) at room temperature. Puriﬁcation of the crude

product by ﬂash column chromatography (SiO₂EtOAc:PE 1:20)

1

aﬀorded 6y (59 mg, 94%). H and ¹³C NMR data are identical to

those reported in the literature.⁶⁰

5-Bromo-1-butyl-1H-pyrazol-4-amine (6z). Following general

procedure IV using 5z (100 mg, 0.27 mmol, 1.0 equiv) and TfOH

(0.05 mL, 0.57 mmol, 2.1 equiv) at 90 °C. Puriﬁcation of the crude

product by ﬂash column chromatography (SiO₂EtOAc:PE 1:2)

aﬀorded 6z (53 mg, 90%) as a dark oil. R_f= 0.23 (EtOAc:PE 1:2). ¹H

NMR (400 MHz, CDCl₃) δ 7.22 (s, 1H), 4.06 (t, J = 7.2 Hz, 2H), 2.96

(s, 2H), 1.77 (quint, J = 7.2 Hz, 2H), 1.32 (sxt, J = 7.2 Hz, 2H), 0.93

(t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 130.4, 127.5,

101.6, 50.3, 31.9, 19.7, 13.6. FT-IR v_max/cm⁻¹3398w, 1587m, 1311m.

HRMS-ESI⁺: m/z [M + H]⁺calcd for C₇H₁₃BrN₃: 218.0287; found,

218.0288.

N-Butyl-4-phenylthiazol-2-amine (6aa). Following general proce-

dure IV using 5aa (113 mg, 0.29 mmol, 1.0 equiv) and TfOH (0.05

mL, 0.57 mmol, 1.9 equiv) at 90 °C. Puriﬁcation of the crude product

by ﬂash column chromatography (SiO₂EtOAc:PE 1:10) aﬀorded 6aa

N-(3-Aminophenyl)-4-nitrobenzenesulfonamide (16a). Following

general procedure IV using 15a (89 mg, 0.20 mmol, 1.0 equiv) and

TfOH (0.02 mL, 0.22 mmol, 1.1 equiv) at 50 °C. Puriﬁcation of the

L

DOI: 10.1021/acs.joc.7b02507

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

crude product by ﬂash column chromatography (SiO₂EtOAc:CHCl₃

1:10, 1:5) aﬀorded 16a (52 mg, 89%) as a yellowish solid. R_f= 0.65

(EtOAc:PE 1:1), mp 176−178 °C. ¹H NMR (400 MHz, d₆-DMSO) δ

10.28 (s, 1H), 8.37 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 6.84

(t, J = 8.0 Hz, 1H), 6.33−6.37 (m, 1H), 6.20−6.27 (m, 2H), 5.16 (br,

2H). ¹³C NMR (100 MHz, d₆-DMSO) δ 150.2, 149.9, 145.7, 137.9,

130.0, 128.7, 125.0, 111.1, 108.5, 106.4. FT-IR v_max/cm⁻¹3439w,

3356w, 1606w, 1528m, 1350m. HRMS-ESI⁺: m/z [M + H]⁺calcd for

C₁₂H₁₂N₃O₄S, 294.0543; found, 294.0530.

0.78 mmol, 1.0 equiv) in dry DMF (5.0 mL) was stirred at 100 °C for

4 days. After quenching with 1.0 M HCl aq solution, the mixture was

extracted with EtOAc, washed with brine, dried with Na₂SO₄, and

evaporated in vacuo. Puriﬁcation by ﬂash column chromatography

(SiO₂EtOAc:PE 1:5) aﬀorded 25 (400 mg, 94%) as a white solid. R_f=

1

0.41 (EtOAc:PE 1:3), mp 96−97 °C. H NMR (400 MHz, CDCl₃) δ

8.18−8.23 (m, 1H), 7.91−7.94 (m, 1H), 7.50−7.59 (m, 4H), 7.45 (d, J

= 8.4 Hz, 2H), 7.25−7.32 (m, 4H), 3.76−3.82 (m, 2H), 3.22−3.28 (m,

2H), 3.09−3.16 (m, 2H), 2.46 (s, 3H), 2.42 (s, 3H), 1.46−1.54 (m,

2H), 1.26−1.35 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H). ¹³C NMR (100

MHz, CDCl₃) δ 148.5, 144.6, 143.6, 141.2, 135.8, 134.3, 133.9, 129.9,

129.7, 127.6, 127.3, 127.1, 123.0, 122.7, 50.5, 49.6, 47.3, 30.6, 21.6,

21.5, 19.8, 13.6. FT-IR v_max/cm⁻¹1533m, 1344m, 1150m, 1089m.

HRMS-ESI⁺: m/z [M + H]⁺calcd for C₂₆H₃₂N₃O₆S₂, 546.1727;

found, 546.1738.

N-(3-(Butylamino)phenyl)-4-nitrobenzenesulfonamide (16b).

Following general procedure IV using 15b (70 mg, 0.14 mmol, 1.0

equiv) and TfOH (0.015 mL, 0.17 mmol, 1.2 equiv) at 50 °C.

Puriﬁcation of the crude product by ﬂash column chromatography

(SiO₂EtOAc:CHCl₃1:100, 2:25) aﬀorded 16b (40 mg, 83%) as a

1

brownish oil. R_f= 0.23 (EtOAc:CHCl₃2:25). H NMR (400 MHz,

CDCl₃) δ 8.27 (d, J = 8.8 Hz, 2H), 7.98 (d, J = 8.8 Hz, 2H), 7.07 (br,

1H), 7.01 (t, J = 8.0 Hz, 1H), 6.37−6.42 (m, 2H), 6.28−6.33 (m, 1H),

3.71 (br, 1H), 3.04 (t, J = 7.2 Hz, 2H), 1.57 (quint, J = 7.2 Hz, 2H),

1.41 (sxt, J = 7.2 Hz, 2H), 0.96 (t, J = 7.2 Hz, 3H). ¹³C NMR (100

MHz, CDCl₃) δ 150.2, 149.6, 144.7, 136.4, 130.2, 128.6, 124.2, 110.6,

110.1, 105.8, 43.5, 31.4, 20.2, 13.9. FT-IR v_max/cm⁻¹3412w, 3104w,

1607m, 1346m. HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₆H₂₀N₃O₄S,

350.1169; found, 350.1171.

N-Butyl-4-methyl-N-(2-(4-methyl-N-(3-(4-nitrophenylsulfon-

amido)phenyl)phenylsulfonamido)ethyl)benzenesulfonamide (17).

A solution of 24 (73 mg, 0.13 mmol, 1.0 equiv) in MeOH/EtOAc (14

mL, 2.5:1 v/v) was ﬂushed with argon, vacuumed, and reﬁlled with

argon. Pd/C-10% (10% w/w) was added in one portion followed by

vacuuming and reﬁlling with H₂(repeated twice). The reaction

mixture was vigorously stirred for 3.5 h, ﬁltered through a small pad of

Celite, washed with EtOAc, and evaporated in vacuo. The crude

product was dissolved in pyridine (5.0 mL), 4-nitrobenzenesulfonyl

chloride (36 mg, 0.16 mmol, 1.2 equiv) was added, and the mixture

was stirred at room temperature for 19 h. The mixture was quenched

with 1.0 M HCl aq solution, extracted with EtOAc, washed with brine,

dried with Na₂SO₄, and evaporated in vacuo. Puriﬁcation by column

chromatography (SiO₂EtOAc:PE 1:2) aﬀorded 17 (80 mg, 85%) as a

yellowish oil. R_f= 0.28 (EtOAc:PE 1:2). ¹H NMR (400 MHz, CDCl₃)

δ 8.24 (d, J = 8.8 Hz, 2H), 7.99 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.4

Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.20−7.28 (m, 5H), 7.15 (s, 1H),

7.10−7.13 (m, 1H), 7.05−7.09 (m, 1H), 6.80−6.84 (m, 1H), 3.69−

3.75 (m, 2H), 3.16−3.22 (m, 2H), 3.04−3.10 (m, 2H), 2.45 (s, 3H),

2.43 (s, 3H), 1.40−1.49 (m, 2H), 1.22−1.32 (m, 2H), 0.90 (t, J = 7.2

Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 150.3, 144.3, 144.2, 143.6,

140.8, 136.5, 135.8, 134.4, 130.1, 129.8, 129.7, 128.7, 127.5, 127.1,

124.8, 124.3, 122.5, 121.0, 50.4, 49.4, 47.3, 30.4, 21.6, 21.5, 19.8, 13.6.

FT-IR v_max/cm⁻¹3240w, 3107w, 1600w, 1531w, 1346w, 1154m.

HRMS-ESI⁺: m/z [M + H]⁺calcd for C₃₂H₃₇N₄O₈S₃: 701.1768;

found, 701.1760.

N-Butyl-4-methyl-N-(2-((3-(4-nitrophenylsulfonamido)phenyl)-

(propyl)amino)ethyl)benzenesulfonamide (25). To a round-bottom

ﬂask containing compound 18 (136 mg, 0.25 mmol, 1.0 equiv) in

DCM (10 mL) under argon atmosphere, propionaldehyde (0.04 mL,

0.56 mmol, 2.24 equiv), glacial acetic acid (3 drops), and sodium

triacetoxyborohydride (158 mg, 0.75 mmol, 3.0 equiv) were added.

The reaction mixture was stirred for 68 h at room temperature,

quenched with 1.0 M NaOH aq solution, extracted with DCM, dried

with Na₂SO₄, and evaporated in vacuo. Puriﬁcation by column

chromatography (SiO₂EtOAc:PE 1:3) aﬀorded 25 (127 mg, 87%) as

an orange oil. R_f= 0.25 (EtOAc:PE 1:3). ¹H NMR (400 MHz, CDCl₃)

δ 8.26 (d, J = 8.8 Hz, 2H), 7.99 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.0

Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.02−7.13 (m, 2H), 6.36−6.52 (m,

3H), 3.46−3.55 (m, 2H), 3.07−3.22 (m, 6H), 2.44 (s, 3H), 1.44−1.57

(m, 4H), 1.25−1.36 (m, 2H), 0.86−0.93 (m, 6H). ¹³C NMR (100

MHz, CDCl₃) δ 150.1, 148.5, 144.9, 143.5, 136.8, 136.2, 130.3, 129.8,

128.7, 127.1, 124.1, 109.4, 109.2, 105.4, 53.1, 51.1, 49.8, 45.4, 31.1,

21.5, 20.4, 19.8, 13.7, 11.3. FT-IR v_max/cm⁻¹3250w, 1605w, 1346m,

1151s. HRMS-ESI⁺: m/z [M + H]⁺calcd for C₂₈H₃₇N₄O₆S₂,

589.2149; found, 589.2147.

N-Butyl-4-methyl-N-(2-((3-(4-nitrophenylsulfonamido)phenyl)-

amino)ethyl)benzenesulfonamide (18). Following general procedure

IV using 17 (146 mg, 0.21 mmol, 1.0 equiv) and TfOH (0.02 mL, 0.23

mmol, 1.1 equiv) at 50 °C. Puriﬁcation of the crude product by ﬂash

column chromatography (SiO₂EtOAc:PE 1:3) aﬀorded 18 (83 mg,

1

73%) as a brownish oil. R_f= 0.26 (EtOAc:PE 1:2). H NMR (400

MHz, CDCl₃) δ 8.24 (d, J = 8.8 Hz, 2H), 7.98 (d, J = 8.8 Hz, 2H),

7.70 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.20 (s, 1H), 7.02 (t,

J = 8.0 Hz, 1H), 6.37−6.46 (m, 3H), 3.28 (s, 4H), 3.08−3.15 (m, 2H),

2.45 (s, 3H), 1.42−1.51 (m, 2H), 1.24−1.31 (m, 2H), 0.86 (t, J = 7.2

Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 150.1, 148.7, 144.8, 143.7,

136.7, 136.1, 130.3, 129.9, 128.6, 127.2, 124.2, 110.7, 110.5, 105.9,

49.4, 47.4, 42.9, 30.8, 21.5, 19.8, 13.6. FT-IR v_max/cm⁻¹3400w, 3250w,

1608w, 1529w, 1346w. HRMS-ESI⁺: m/z [M + H]⁺calcd for

C₂₅H₃₁N₄O₆S₂, 547.1680; found, 547.1689.

N-(3-Amino-5-(4-nitrophenylsulfonamido)phenyl)benzamide

(20). Following general procedure IV using 19 (115 mg, 0.20 mmol,

1.0 equiv) and TfOH (0.02 mL, 0.22 mmol, 1.1 equiv) at 90 °C.

Puriﬁcation of the crude product by ﬂash column chromatography

(SiO₂MeOH:CHCl₃1:25) aﬀorded 20 (40 mg, 48%) as an oﬀ-white

1

solid. R_f= 0.34 (MeOH:CHCl₃1:10), mp 139−140 °C. H NMR

(400 MHz, d₆-DMSO) δ 10.50 (br, 1H), 10.11 (s, 1H), 8.40 (d, J =

8.8 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 7.6 Hz, 2H), 7.28−

7.35 (m, 2H), 7.04−7.10 (m, 1H), 6.72−6.78 (m, 2H), 6.53−6.57 (m,

1H), 5.47 (s, 2H). ¹³C NMR (100 MHz, d₆-DMSO) δ 166.6, 150.3,

150.0, 145.6, 139.7, 138.2, 137.7, 129.0, 128.7, 125.1, 123.9, 120.6,

109.9, 108.3, 107.8. FT-IR v_max/cm⁻¹3414w, 3334w, 3108w, 1597w,

1525m, 1345m, 1184m. HRMS-ESI⁺: m/z [M + H]⁺calcd for

C₁₉H₁₇N₄O₅S, 413.0914; found, 413.0913.

N-(3-Aminophenyl)-N-butylpyridine-2-sulfonamide (22). Follow-

ing general procedure IV using 21 (55 mg, 0.12 mmol, 1.0 equiv) and

TfOH (0.02 mL, 0.23 mmol, 1.9 equiv) at 50 °C. Puriﬁcation of the

crude product by ﬂash column chromatography (SiO₂EtOAc:PE 2:1)

aﬀorded 22 (25 mg, 69%) as a reddish solid. R_f= 0.6 (MeOH:CHCl₃

1

1:10), mp 75−76 °C. H NMR (400 MHz, CDCl₃) δ 8.75−8.79 (m,

1H), 7.78−7.85 (m, 1H), 7.71−7.77 (m, 1H), 7.45−7.52 (m, 1H),

6.98−7.05 (m, 1H), 6.55−6.62 (m, 2H), 6.36−6.42 (m, 1H), 3.85 (t, J

= 7.2 Hz, 2H), 3.57 (br, 2H), 1.48 (quint, J = 7.2 Hz, 2H), 1.37 (sxt, J

= 7.2 Hz, 2H), 0.89 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃)

δ 157.6, 149.9, 146.9, 139.8, 137.6, 129.6, 126.4, 123.2, 118.5, 116.5,

114.8, 52.3, 30.8, 19.6, 13.7. FT-IR v_max/cm⁻¹3421w, 3328w, 1341m,

1177m, 1115m. HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₅H₂₀N₃O₂S,

306.1271; found, 306.1280.

N-Butyl-N-(3-((2-(N-butyl-4-methylphenylsulfonamido)ethyl)-

(propyl)amino)phenyl)-4-nitrobenzenesulfonamide (26). To a

round-bottom ﬂask charged with 25 (58 mg, 0.10 mmol, 1.0 equiv),

dry DMF (3.0 mL), and K₂CO₃(21 mg, 0.15 mmol, 1.5 equiv) under

argon, 1-bromobutane (0.03 mL, 0.28 mmol, 2.8 equiv) was added

dropwise, and the reaction mixture was heated at 70 °C for 19 h. The

mixture was quenched with 1.0 M HCl aq solution, extracted with

EtOAc, washed with brine, dried with Na₂SO₄, and evaporated in

vacuo. Puriﬁcation by column chromatography (SiO₂EtOAc:PE 1:3.5)

N-Butyl-4-methyl-N-(2-(4-methyl-N-(3-nitrophenyl)phenylsulfon-

amido)ethyl)benzenesulfonamide (24). A mixture of N-(2-bro-

moethyl)-N-butyl-4-methylbenzenesulfonamide (340 mg, 1.02 mmol,

1.3 equiv), K₂CO₃(162 mg, 1.17 mmol, 1.5 equiv), and 23 (229 mg,

M

DOI: 10.1021/acs.joc.7b02507

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

aﬀorded 26 (60 mg, 94%) as a brownish oil. R_f= 0.52 (EtOAc:PE

1:3.5). ¹H NMR (400 MHz, CDCl₃) δ 8.30 (d, J = 8.8 Hz, 2H), 7.82

(d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H),

7.13 (t, J = 8.0 Hz, 1H), 6.63−6.70 (m, 1H), 6.50 (s, 1H), 6.15−6.22

(m, 1H), 3.49−3.61 (m, 4H), 3.08−3.25 (m, 6H), 2.44 (s, 3H), 1.28−

1.62 (m, 10H), 0.87−0.95 (m, 9H). ¹³C NMR (100 MHz, CDCl₃) δ

149.9, 148.1, 144.4, 143.4, 139.4, 136.2, 129.8, 129.7, 128.9, 127.2,

123.9, 115.1, 113.1, 111.6, 53.3, 51.3, 50.7, 49.8, 45.4, 31.1, 30.4, 21.5,

20.4, 19.8, 19.6, 13.7, 13.6, 11.3. FT-IR v_max/cm⁻¹1600w,, 1347m,

1154m. HRMS-ESI⁺: m/z [M + H]⁺calcd for C₃₂H₄₅N₄O₆S₂,

645.2775; found, 645.2778.

N-Butyl-N-(2-((3-(butylamino)phenyl)(propyl)amino)ethyl)-4-

methylbenzenesulfonamide (27). To a solution of 26 (56 mg, 0.087

mmol, 1.0 equiv) in dry DMF (3.0 mL), 2-mercaptoethanol (0.12 mL,

1.74 mmol, 20 equiv), and DBU (0.26 mL, 1.74 mmol, 20 equiv) were

added. After stirring for 22 h at room temperature, the mixture was

quenched with 1.0 M HCl aq solution, extracted with EtOAc, washed

with brine, dried with Na₂SO₄, and evaporated in vacuo. Puriﬁcation

by column chromatography (SiO₂EtOAc:PE 1:2.5) aﬀorded 27 (34

mg, 84%) as a dark oil. R_f= 0.7 (EtOAc:PE 1:2). ¹H NMR (400 MHz,

CDCl₃) δ 7.71 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.01−7.07

(m, 1H), 5.99−6.11 (m, 3H), 3.51−3.58 (m, 2H), 3.11−3.24 (m, 8H),

2.43 (s, 3H), 1.32−1.64 (m, 10H), 0.90−0.98 (m, 9H). ¹³C NMR

(100 MHz, CDCl₃) δ 149.9, 148.6, 143.2, 136.4, 130.1, 129.7, 127.2,

101.5, 101.4, 96.3, 53.3, 51.0, 49.8, 45.6, 43.7, 31.8, 31.2, 21.5, 20.8,

20.3, 19.9, 14.0, 13.7, 11.5. FT-IR v_max/cm⁻¹3402w, 1336w, 1152m.

HRMS-ESI⁺: m/z [M + H]⁺calcd for C₂₆H₄₂N₃O₂S, 460.2992; found,

460.2999.

1139m, 1090m, 1047m. HRMS-ESI⁺: m/z [M + H]⁺calcd for

C₁₈H₂₃N₂O₆S, 395.1271; found, 395.1285.

N-Butyl-4-methyl-2-(methylsulfonyl)aniline (35). Following gen-

eral procedure IV using 34 (135 mg, 0.56 mmol, 1.0 equiv) and TfOH

(0.1 mL, 1.12 mmol, 2.0 equiv) at 80 °C. Puriﬁcation of the crude

product by ﬂash column chromatography (SiO₂EtOAc:PE 1:5)

aﬀorded 35 (110 mg, 81%) as a white wax-like solid. R_f= 0.64

1

(EtOAc:PE 1:3). H NMR (400 MHz, CDCl₃) δ 7.58 (d, J = 1.6 Hz,

1H), 7.27 (dd, J = 8.4, 1.6 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 5.90 (br,

1H), 3.15 (t, J = 7.2 Hz, 2H), 3.04 (s, 3H), 2.28 (s, 3H), 1.68 (quint, J

= 7.2 Hz, 2H), 1.47 (sxt, J = 7.2 Hz, 2H), 0.99 (t, J = 7.2 Hz, 3H). ¹³C

NMR (100 MHz, CDCl₃) δ 145.1, 136.3, 129.6, 125.5, 121.1, 112.5,

43.1, 42.2, 31.2, 20.3, 20.0, 13.8. FT-IR v_max/cm⁻¹3391w, 1347w,

1162m. HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₂H₂₀NO₂S, 242.1209;

found, 242.1211.

N-(2-Bromoethyl)-4,5-dimethoxy-2-(methylsulfonyl)aniline (37).

Following general procedure IV using 36 (371 mg, 1.10 mmol, 1.0

equiv) and TfOH (0.2 mL, 2.30 mmol, 2.1 equiv) at 80 °C.

Puriﬁcation of the crude product by ﬂash column chromatography

(SiO₂MeOH:CHCl₃1:60) aﬀorded 37 (184 mg, 50%) as an oﬀ-white

1

solid. R_f= 0.36 (MeOH:CHCl₃1:50), mp 109−110 °C. H NMR

(400 MHz, CDCl₃) δ 7.28 (s, 1H), 6.24 (s, 1H), 6.20 (br, 1H), 3.94

(s, 3H), 3.85 (s, 3H), 3.56−3.68 (m, 4H), 3.08 (s, 3H). ¹³C NMR

(100 MHz, CDCl₃) δ 155.4, 142.1, 140.9, 112.7, 112.5, 95.9, 56.7,

56.1, 45.0, 42.7, 30.7. FT-IR v_max/cm⁻¹3360w, 1283m, 1122m, 1054w.

HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₁H₁₇BrNO₄S, 340.0036;

found, 340.0042.

N-(3-(Butylamino)-2-tosylphenyl)methanesulfonamide (39). Fol-

lowing general procedure VI using 38 (107 mg, 0.27 mmol, 1.0 equiv)

and TfOH (0.03 mL, 0.34 mmol, 1.3 equiv) at 50 °C. Puriﬁcation of

the crude product by ﬂash column chromatography (SiO₂EtOAc:PE

1:4) aﬀorded 39 (53 mg, 50%) as a brownish solid. R_f= 0.62

N-Butyl-4-phenoxy-2-tosylaniline (29). Following general proce-

dure IV using 28 (124 mg, 0.31 mmol, 1.0 equiv) and TfOH (0.055

mL, 0.62 mmol, 2.0 equiv) at 90 °C. Puriﬁcation of the crude product

by ﬂash column chromatography (SiO₂EtOAc:PE 1:20) aﬀorded 29

(93 mg, 75%) as a yellowish solid. R_f= 0.48 (EtOAc:PE 1:10), mp

1

(EtOAc:PE 1:2), mp 120−121 °C. H NMR (400 MHz, CDCl₃) δ

1

79−80 °C. H NMR (400 MHz, CDCl₃) δ 7.79 (d, J = 8.4 Hz, 2H),

7.83 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.16 (t, J = 8.0 Hz,

1H), 6.66 (dd, J = 8.0, 2.0 Hz, 1H), 6.46 (dd, J = 8.0, 2.0 Hz, 1H),

6.32−6.35 (m, 1H), 3.86 (br, 1H), 3.51 (s, 3H), 2.99−3.07 (m, 2H),

2.47 (s, 3H), 1.58 (quint, J = 7.2 Hz, 2H), 1.42 (sxt, J = 7.2 Hz, 2H),

0.97 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 149.3, 145.1,

135.9, 134.7, 129.8, 129.5, 128.9, 119.3, 114.7, 114.6, 43.8, 43.5, 31.4,

21.7, 20.2, 13.9. FT-IR v_max/cm⁻¹3402w, 1363m, 1348m, 1164m.

HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₈H₂₅N₂O₄S₂, 397.1250;

found, 397.1261.

7.67 (d, J = 2.8 Hz, 1H), 7.28−7.35 (m, 4H), 7.13 (dd, J = 8.8, 2.8 Hz,

1H), 7.07 (t, J = 7.2 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.8

Hz, 1H), 6.13 (br, 1H), 3.12 (t, J = 7.2 Hz, 2H), 2.43 (s, 3H), 1.66

(quint, J = 7.2 Hz, 2H), 1.44 (sxt, J = 7.2 Hz, 2H), 0.98 (t, J = 7.2 Hz,

3H). ¹³C NMR (100 MHz, CDCl₃) δ 158.4, 145.9, 144.1, 143.7, 138.5,

129.7, 129.6, 127.8, 127.1, 122.6, 122.1, 121.5, 117.2, 113.6, 43.3, 31.1,

21.6, 20.2, 13.8. FT-IR v_max/cm⁻¹3395w, 1316m, 1140m, 1089m.

HRMS-ESI⁺: m/z [M + H]⁺calcd for C₂₃H₂₆NO₃S, 396.1628; found,

396.1630.

2,4-Dimethoxy-1-tosylbenzene (41). Method 1, using 40 as

sulfonyl group transfer agent. To a pressure vial charged with 40

(103 mg, 0.35 mmol, 1.2 equiv) and 1,3-dimethoxybenzene (0.04 mL,

0.30 mmol, 1.0 equiv) in dry DCE (5.0 mL) under argon, TfOH (0.06

mL, 0.68 mmol, 2.2 equiv) was added dropwise. The reaction vial was

capped and heated to 60 °C for 70 h. The mixture was quenched with

ethylenediamine (2 drops) and 1.0 M NaOH aq solution, extracted

with EtOAc, washed with brine, dried with Na₂SO₄, and evaporated in

vacuo. Puriﬁcation by column chromatography (SiO₂EtOAc:PE 1:2.5)

aﬀorded 41 (76 mg, 85%) as a colorless solid.

Method 2, using 44 as sulfonyl group transfer agent. To a pressure

vial charged with 44 (111 mg, 0.35 mmol, 1.2 equiv) and 1,3-

dimethoxybenzene (0.04 mL, 0.32 mmol, 1.0 equiv) in dry DCE (5

mL) under argon gas, TfOH (0.07 mL, 0.79 mmol, 2.4 equiv) was

added dropwise. The reaction vial was capped and stirred at room

temperature for 69 h. The mixture was quenched with ethylenedi-

amine (2 drops) and 1.0 M NaOH aq solution, extracted with EtOAc,

washed with brine, dried with Na₂SO₄, and evaporated in vacuo.

Puriﬁcation by column chromatography (SiO₂EtOAc:PE 1:2.5)

aﬀorded 41 (60 mg, 67%) as a colorless solid. R_f= 0.4 (EtOAc:PE

1:2), mp 139−140 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J = 8.8

Hz, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.57 (dd, J

= 8.8, 2.4 Hz, 1H), 6.38 (d, J = 2.4 Hz, 1H), 3.82 (s, 3H), 3.73 (s, 3H),

2.39 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.5, 158.6, 143.4,

139.2, 131.5, 129.1, 128.1, 121.6, 104.7, 99.4, 55.9, 55.7, 21.5. FT-IR

v_max/cm⁻¹1284m, 1152m, 1090m, 1060m. HRMS-ESI⁺: m/z [M +

H]⁺calcd for C₁₅H₁₇O₄S, 293.0842; found, 293.0848.

N-Butyl-4,5-dimethoxy-2-tosylaniline (31). Following general

procedure IV using 30 (128 mg, 0.35 mmol, 1.0 equiv) and TfOH

(0.06 mL, 0.68 mmol, 1.9 equiv) at 90 °C. Puriﬁcation of the crude

product by ﬂash column chromatography (SiO₂EtOAc:PE 1:3)

aﬀorded 31 (63 mg, 80%) as a brownish solid. R_f= 0.3 (EtOAc:PE

1

1:3), mp 95−96 °C. H NMR (400 MHz, CDCl₃) δ 7.75 (d, J = 8.0

Hz, 2H), 7.37 (s, 1H), 7.26 (d, J = 8.0 Hz, 2H), 6.13 (s, 1H), 5.99−

6.03 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.05−3.12 (m, 2H), 2.39 (s,

3H), 1.63 (quint, J = 7.2 Hz, 2H), 1.41 (sxt, J = 7.2 Hz, 2H), 0.95 (t, J

= 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 155.4, 143.8, 143.4,

140.0, 139.6, 129.5, 126.5, 113.0, 111.2, 95.7, 56.8, 55.9, 43.2, 31.2,

21.5, 20.2, 13.8. FT-IR v_max/cm⁻¹3393w, 1264m, 1130m, 1039m.

HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₉H₂₆NO₄S, 364.1577; found,

364.1590.

N-Butyl-4,5-dimethoxy-2-((4-nitrophenyl)sulfonyl)aniline (33).

Following general procedure IV using 32 (123 mg, 0.31 mmol, 1.0

equiv) and TfOH (0.06 mL, 0.68 mmol, 2.2 equiv) at 90 °C.

Puriﬁcation of the crude product by ﬂash column chromatography

(SiO₂EtOAc:PE 1:3.5) aﬀorded 33 (76 mg, 62%) as a brownish solid.

1

R_f= 0.33 (EtOAc:PE 1:3), mp > 110 °C (decomp.). H NMR (400

MHz, CDCl₃) δ 8.30 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H),

7.31 (s, 1H), 6.15 (s, 1H), 6.03−6.10 (m, 1H), 3.90 (s, 3H), 3.86 (s,

3H), 3.05−3.13 (m, 2H), 1.65 (quint, J = 7.2 Hz, 2H), 1.42 (sxt, J =

7.2 Hz, 2H), 0.97 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ

156.4, 150.0, 148.2, 144.6, 140.5, 127.6, 124.2, 112.7, 108.8, 95.8, 56.8,

56.0, 43.2, 31.2, 20.2, 13.8. FT-IR v_max/cm⁻¹3396w, 1520m, 1346m,

N

DOI: 10.1021/acs.joc.7b02507

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The Journal of Organic Chemistry

Article

2,4-Dimethyl-1-tosylbenzene (42). Method 1, using 40 as sulfonyl

group transfer agent. To a pressure vial charged with 40 (110 mg, 0.38

mmol, 1.15 equiv) and 1,3-dimethylbenzene (0.04 mL, 0.33 mmol, 1.0

equiv) in dry DCE (5.0 mL) under argon, TfOH (0.06 mL, 0.68

mmol, 2.1 equiv) was added dropwise. The reaction vial was capped

and heated to 60 °C for 70 h. The mixture was quenched with

ethylenediamine (2 drops) and 1.0 M NaOH aq solution, extracted

with EtOAc, washed with brine, dried with Na₂SO₄, and evaporated in

vacuo. Puriﬁcation by column chromatography (SiO₂EtOAc:PE 1:3.5)

aﬀorded 42 (84 mg, 99%).

(0.12 mL, 1.36 mmol, 4.0 equiv) at 90 °C for 72 h. Puriﬁcation of the

crude product by ﬂash column chromatography (SiO₂MeOH:DCM

1:40, 1:25) aﬀorded 50 (39 mg, 58%) as a brownish solid. R_f= 0.31

(MeOH:DCM 1:25), mp 183−185 °C. ¹H NMR (400 MHz, CDCl₃)

δ 7.44−7.51 (m, 2H), 7.36−7.43 (m, 1H), 7.21−7.27 (m, 2H), 5.04

(br, 2H), 2.48 (s, 3H), 2.13 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ

165.6, 162.4, 161.2, 134.7, 129.7, 129.5, 128.2, 114.4, 25.6, 22.2. FT-IR

v_max/cm⁻¹3313w, 3149w, 1557m. HRMS-ESI⁺: m/z [M + H]⁺calcd

for C₁₂H₁₄N₃: 200.1182; found, 200.1191.

1,2-Diphenyl-4,5-dihydro-1H-imidazole (51). Following general

procedure IV using 50 (140 mg, 0.36 mmol, 1.0 equiv) and TfOH

(0.035 mL, 0.4 mmol, 1.1 equiv) at 90 °C for 24 h. Puriﬁcation of the

crude product by ﬂash column chromatography (SiO₂DCM:MeOH

Method 2, using 44 as sulfonyl group transfer agent. To a pressure

vial charged with 44 (118 mg, 0.37 mmol, 1.1 equiv) and 1,3-

dimethylbenzene (0.04 mL, 0.33 mmol, 1.0 equiv) in dry DCE (5.0

mL) under argon, TfOH (0.07 mL, 0.79 mmol, 2.4 equiv) was added

dropwise. The reaction vial was capped and stirred at room

temperature for 67 h. The mixture was quenched with ethylenedi-

amine (2 drops) and 1.0 M NaOH aq solution, extracted with EtOAc,

washed with brine, dried with Na₂SO₄, and evaporated in vacuo.

Puriﬁcation by column chromatography (SiO₂EtOAc:PE 1:3.5)

1

10:1) aﬀorded 51 (55 mg, 70%). H and ¹³C NMR data are identical

to those reported in the literature.⁶⁵

Competition Experiment (Scheme 3a). To a pressure vial

charged with 5n (133 mg, 0.40 mmol, 1.0 equiv) and 7 (110 mg, 0.40

mmol, 1.0 equiv) in dry DCE (6.0 mL) at 0 °C under argon, TfOH

(0.036 mL, 0.40 mmol, 1.0 equiv) was added dropwise. The ice bath

was removed, the reaction vial was capped and heated at 50 °C for 26

h. The mixture was quenched with ethylenediamine (2 drops) and 1.0

M NaOH aq solution, extracted with DCM, dried with Na₂SO₄, and

evaporated in vacuo. Puriﬁcation by column chromatography

(EtOAc:PE 1:4, 1:2, 20:1) aﬀorded inseparable mixture of 5n (7%)

and 6n (89%) (72 mg, molar ratio was determined by NMR) and pure

7 (53 mg, 48%), 9 (4.5 mg, 9%), and 8 (63 mg, 37%).

1

aﬀorded 42 (74 mg, 87%). H and ¹³C NMR data are identical to

those reported in the literature.⁶⁴

1,3,5-Trimethyl-2-tosylbenzene (43). To a pressure vial charged

with 40 (97 mg, 0.33 mmol, 1.15 equiv) and 1,3,5-trimethylbenzene

(0.04 mL, 0.29 mmol, 1.0 equiv) in dry DCE (5.0 mL) under argon,

TfOH (0.05 mL, 0.57 mmol, 2.0 equiv) was added dropwise. The

reaction vial was capped and heated to 60 °C for 72 h. The mixture

was quenched with ethylenediamine (2 drops) and 1.0 M NaOH aq

solution, extracted with EtOAc, washed with brine, dried with Na₂SO₄,

and evaporated in vacuo. Puriﬁcation by column chromatography

1

8: brownish solid. R_f= 0.75 (EtOAc:PE 1:2), mp 184−185 °C. H

NMR (400 MHz, CDCl₃) δ 7.80 (d, J = 8.0 Hz, 4H), 7.67 (d, J = 8.0

Hz, 2H), 7.37 (d, J = 8.0 Hz, 4H), 7.18 (d, J = 8.0 Hz, 2H), 2.49 (s,

6H). ¹³C NMR (100 MHz, CDCl₃) δ 145.6, 138.5, 136.1, 133.0, 132.5,

129.8, 128.6, 117.7, 114.1, 21.8. FT-IR v_max/cm⁻¹2228w, 1387m,

1360m, 1163m, 1083m. HRMS-ESI⁺: m/z [M + Na]⁺calcd for

C₂₁H₁₈N₂NaO₄S₂, 449.0600; found, 449.0612.

1

(SiO₂EtOAc:PE 1:4.5) aﬀorded 43 (65 mg, 82%). H and ¹³C NMR

data are identical to those reported in the literature.^37b

N-Butyl-2,6-dimethyl-5-phenylpyrimidin-4-amine (47a). Follow-

ing general procedure VI using 45a (70 mg, 0.21 mmol, 1.0 equiv) and

TfOH (0.02 mL, 0.23 mmol, 1.1 equiv) at 90 °C for 4 h. Puriﬁcation

of the crude product by ﬂash column chromatography (SiO₂

EtOAc:Hex 1:3, 1:1) aﬀorded 47a (39 mg, 71%) as yellowish solid.

ASSOCIATED CONTENT

* Supporting Information

■

S

1

R_f= 0.26 (EtOAc:Hex 2:1), mp 65−66 °C. H NMR (400 MHz,

The Supporting Information is available free of charge on the

ACS Publications website at DOI: 10.1021/acs.joc.7b02507.

CDCl₃) δ 7.35−7.52 (m, 3H), 7.20 (d, J = 7.2 Hz, 2H), 4.29−4.37 (m,

1H), 3.34−3.42 (m, 2H), 2.54 (s, 3H), 2.08 (s, 3H), 1.44 (quint, J =

7.2 Hz, 2H), 1.21−1.33 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H). ¹³C NMR

(100 MHz, CDCl₃) δ 165.7, 160.4, 160.2, 134.9, 129.9, 129.5, 128.1,

114.5, 40.6, 31.6, 26.1, 22.0, 20.0, 13.8. FT-IR v_max/cm⁻¹3288w,

1557m. HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₆H₂₂N₃: 256.1808;

found, 256.1818.

1

Copies of H and ¹³C NMR spectra (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: edvinas.orentas@chf.vu.lt

■

N-Butyl-2,5,6-trimethylpyrimidin-4-amine (47b). Following gen-

eral procedure VI using 45b (90 mg, 0.34 mmol, 1.0 equiv) and TfOH

(0.03 mL, 0.34 mmol, 1.0 equiv) at 90 °C for 5 h. Puriﬁcation of the

crude product by ﬂash column chromatography (SiO₂MeOH:DCM

1:100, 1:10) aﬀorded 47b (30 mg, 46%) as a brownish solid. R_f= 0.48

ORCID

Edvinas Orentas: 0000-0002-7257-5634

Notes

The authors declare no competing ﬁnancial interest.

1

(MeOH:DCM 1:10), mp 54−56 °C. H NMR (400 MHz, CDCl₃) δ

4.45 (br, 1H), 3.44−3.51 (m, 2H), 2.47 (s, 3H), 2.33 (s, 3H), 1.95 (s,

3H), 1.59 (quint, J = 7.2 Hz, 2H), 1.40 (sxt, J = 7.2 Hz, 2H), 0.95 (t, J

= 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 163.9, 160.8, 160.0,

106.7, 40.8, 31.9, 25.8, 21.6, 20.1, 13.8, 10.9. FT-IR v_max/cm⁻¹3330w,

1579m. HRMS-ESI⁺: m/z [M + H]⁺calcd for C₁₁H₂₀N₃: 194.1652;

found, 194.1658.

ACKNOWLEDGMENTS

■

This research was funded by the Research Council of Lithuania

(grant no. S-MIP-17-46). T.J. acknowledges ﬁnancial support

from the Research Council of Lithuania.

N-Benzyl-2,6-dimethyl-5-phenylpyrimidin-4-amine (47c). Follow-

ing general procedure VI using 45c (86 mg, 0.24 mmol, 1.0 equiv) and

TfOH (0.025 mL, 0.29 mmol, 1.2 equiv) at 90 °C for 4 h. Puriﬁcation

of the crude product by ﬂash column chromatography (SiO₂

EtOAc:Hex 1:1.5) aﬀorded 47c (40 mg, 58%) as a brownish solid.

REFERENCES

■

(1) Lawrence, S. A. Amines: Synthesis, Properties and Applications;

Cambridge University Press: Cambridge, UK, 2005.

(2) (a) Wuts, P. G. M.’ Ed. Greene’s Protective Groups in Organic

Synthesis, 5th ed.; John Wiley & Sons: NJ, 2014. (b) Kocienski, P. J.

Protecting Groups, 2nd ed.; Thieme: Stuttgart, 2000.

(3) Dauphin, G.; Kergomard, A. Bull. Soc. Chim. Fr. 1961, 3, 486.

(4) (a) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.

(b) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,

36, 6373.

(5) For selective examples employing Pd catalysis, see: (a) (a) Yin, J.;

Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043. (b) Yin, J.;

Buchwald, S. L. Org. Lett. 2000, 2, 1101. (c) Wolfe, J. P.; Rennels, R.

1

R_f= 0.23 (EtOAc:Hex 1:1), mp 109−110 °C. H NMR (400 MHz,

CDCl₃) δ 7.45−7.51 (m, 2H), 7.37−7.42 (m, 1H), 7.22−7.34 (m,

7H), 4.73 (t, J = 5.2 Hz, 1H), 4.67 (d, J = 5.2 Hz, 2H), 2.58 (s, 3H),

2.14 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.8, 160.8, 160.2,

139.3, 134.6, 129.9, 129.6, 128.5, 128.2, 127.4, 127.1, 114.7, 44.6, 26.1,

22.1. FT-IR v_max/cm⁻¹3205w, 1559m. HRMS-ESI⁺: m/z [M + H]⁺

calcd for C₁₉H₂₀N₃: 290.1652; found, 290.1662.

2,6-Dimethyl-5-phenylpyrimidin-4-amine (49). Following general

procedure VI using 48 (144 mg, 0.34 mmol, 1.0 equiv) and TfOH

O

DOI: 10.1021/acs.joc.7b02507

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

A.; Buchwald, S. L. Tetrahedron 1996, 52, 7525. (d) He, H.; Wu, Y.-J.

Tetrahedron Lett. 2003, 44, 3385. (e) Burton, G.; Cao, P.; Li, G.;

Rivero, R. Org. Lett. 2003, 5, 4373. (f) Steinhuebel, D.; Palucki, M.;

Askin, D.; Dolling, U. Tetrahedron Lett. 2004, 45, 3305. (g) Ikawa, T.;

Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc. 2007,

129, 13001. (h) Shekhar, S.; Dunn, T. B.; Kotecki, B. J.; Montavon, D.

K.; Cullen, S. C. J. Org. Chem. 2011, 76, 4552. (i) Rosen, B. R.; Ruble,

J. C.; Beauchamp, T. J.; Navarro, A. Org. Lett. 2011, 13, 2564.

(6) For selective examples employing Cu catalysis, see: (a)

(a) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem. -

Eur. J. 2004, 10, 5607. (b) Deng, W.; Liu, L.; Zhang, C.; Liu, M.; Guo,

Q.-X. Tetrahedron Lett. 2005, 46, 7295. (c) Baffoe, J.; Hoe, M. Y.;

(20) 4-Cyanobenzenesulfonyl group has recently been evaluated as a

substitute for nosyl group: Schmidt, M. A.; Stokes, R. W.; Davies, M.

L.; Roberts, F. J. Org. Chem. 2017, 82, 4550.

(21) One interesting example of selective deprotection of tert-

butylsulfonamides of secondary over primary amines with TfOH/

anisole has been reported by Weinreb, et al., see ref 10a.

(22) Even though the higher reactivity of N-arylsulfonamides over N-

alkylsulfonamides toward hydrolytic cleavage has been known for a

long time, to the best of our knowledge, no systematic study has been

dedicated to gauge its synthetic utility. Only a short note with three

substrates has been reported on this matter, see: Carpenter, P. D.;

Lennon, M. J. Chem. Soc., Chem. Commun. 1973, 664.

(23) Some reported methods allow discrimination of diﬀerent

sulfonamide protecting groups. Methanesulfonamides can be

selectively deprotected with n-BuLi/O₂, see: Naito, H.; Hata, T.;

Urabe, H. Org. Lett. 2010, 12, 1228. 2,4-Dinitrobenzenesulfonamide

can be selectively deprotected in the presence of 2-nitrobenzenesulfo-

namide, see: Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T.

Tetrahedron Lett. 1997, 38, 5831. 2-Naphthalenesulfonamide can be

selectively reduced in the presence of p-toluenesulfonamide with Mg/

MeOH, see ref 17. Preliminary results on relative deprotection rates in

ref 16 suggest that o-anisylsulfonamides could, in principle, be

selectively deprotected in the presence of p-toluenesulfonamides

with Ni(acac)₂/ⁱPrMgCl.

́

Toure, B. B. Org. Lett. 2010, 12, 1532. (d) Han, X. Tetrahedron Lett.

2010, 51, 360. (e) Teo, Y.- C.; Yong, F.-F. Synlett 2011, 2011, 837.

(f) Wang, X.; Guram, A.; Ronk, M.; Milne, J. E.; Tedrow, J. S.; Faul,

M. M. Tetrahedron Lett. 2012, 53, 7.

(7) Chan-Lam arylation of sulfonamides: (a) Lam, P. Y. S.; Vincent,

G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42,

3415. (b) Sanjeeva Rao, K.; Wu, T.-S. Tetrahedron 2012, 68, 7735.

(c) Lan, J.-B.; Zhang, G.-L.; Yu, X.-Q.; You, J.- S.; Chen, L.; Yan, M.;

Xie, R.-G. Synlett 2004, 6, 1095. (d) Kantam, M. L.; Neelima, B.;

Reddy, C. V.; Neeraja, V. J. Mol. Catal. A: Chem. 2006, 249, 201.

(e) Pan, C.; Cheng, J.; Wu, H.; Ding, J.; Liu, M. Synth. Commun. 2009,

39, 2082.

(24) Howells, R. D.; Mc Cown, J. D. Chem. Rev. 1977, 77, 69.

(25) Menger, F. M.; Mandell, L. J. Am. Chem. Soc. 1967, 89, 4424.

(26) (a) Birchall, T.; Gillespie, R. J. Can. J. Chem. 1963, 41, 2642.

(b) Laughlin, R. G. J. Am. Chem. Soc. 1967, 89, 4268. (c) Kricheldorf,

H. R. Angew. Chem., Int. Ed. Engl. 1978, 17, 442.

(8) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang,

Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064 and references cited

therein.

(9) Searles, S.; Nukina, S. Chem. Rev. 1959, 59, 1077.

(10) Some acid-labile sulfonamides have been designed to avoid

harsh reaction conditions: (a) Sun, P.; Weinreb, S. M.; Shang, M. J.

Org. Chem. 1997, 62, 8604. (b) Sakamoto, I.; Izumi, N.; Yamada, T.;

Tsunoda, T. Org. Lett. 2006, 8, 71.

(11) (a) Ji, S.; Gortler, L. B.; Waring, A.; Battisti, A. J.; Bank, S.;

Closson, W. D.; Wriede, P. A. J. Am. Chem. Soc. 1967, 89, 5311.

(b) Alonso, E.; Ramon, D. J.; Yus, M. Tetrahedron 1997, 53, 14355.

(12) (a) Birkinshaw, T. N.; Holmes, A. B. Tetrahedron Lett. 1987, 28,

813. (b) Tanner, D.; Ming, H. H.; Bergdahl, M. Tetrahedron Lett.

1988, 29, 6493.

(13) Roemmele, R. C.; Rapoport, H. J. Org. Chem. 1988, 53, 2367.

(14) (a) Vedejs, E.; Lin, S. J. Org. Chem. 1994, 59, 1602. (b) Alonso,

D. A.; Andersson, P. G. J. Org. Chem. 1998, 63, 9455. (c) Fujihara, H.;

Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000, 122, 12055.

(d) Hayashi, T.; Kawai, M.; Tokunaga, N. Angew. Chem., Int. Ed.

2004, 43, 6125. (e) Kuriyama, M.; Soeta, T.; Hao, X.; Chen, Q.;

Tomioka, K. J. Am. Chem. Soc. 2004, 126, 8128. (f) Grach, G.;

(27) (a) Effenberger, F.; Huthmacher, K. Angew. Chem., Int. Ed. Engl.

1974, 13, 409. (b) Effenberger, F.; Huthmacher, K. Chem. Ber. 1976,

109, 2315. (c) Repichet, S.; Le Roux, C.; Hernandez, P.; Dubac, J.;

́

Desmurs, J.-R. J. Org. Chem. 1999, 64, 6479.

(28) More basic conditions using organic-phase wash with sodium or

potassium hydroxide (1.0 M aq solution) seems to completely destroy

anhydride 4. However, the modiﬁed workup procedure was used in all

cases to obtain comparable results.

(29) (a) Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.; Utsunomiya,

M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179. (b) Schlummer, B.;

Hartwig, J. F. Org. Lett. 2002, 4, 1471. (c) Taylor, J. G.; Adrio, L. A.;

Hii, K. K. M. Dalton Trans 2010, 39, 1171.

(30) Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G. Tetrahedron

Lett. 1990, 31, 5595.

(31) (a) Pak, C. S.; Lim, D. S. Synth. Commun. 2001, 31, 2209.

(b) Goulaouic- Dubois, C.; Guggisberg, A.; Hesse, M. J. Org. Chem.

1995, 60, 5969.

(32) (a) Newcomer, R.; McKee, J.; Zanger, M. Synth. Commun. 2016,

46, 949. (b) Meseroll, L. M. N.; McKee, J. R.; Zanger, M. Synth.

Commun. 2011, 41, 2557.

́

Sopkova-de Oliveira Santos, J.; Lohier, J.; Mojovic, L.; Ple, N.; Turck,

A.; Reboul, V.; Metzner, P. J. Org. Chem. 2006, 71, 9572. (g) Duan, H.;

Jia, Y.; Wang, L.; Zhou, Q. Org. Lett. 2006, 8, 2567. (h) Ankner, T.;

Hilmersson, G. Org. Lett. 2009, 11, 503.

(33) Dewar, M. J. S. In Molecular Rearrangements; de Mayo, P., Ed.;

Wiley: New York, 1963; p 308.

(15) (a) Nayak, S. K. Synthesis 2000, 2000, 1575. (b) Vellemae, E.;

̈

(34) (a) Williams, T. M.; Ciccarone, T. M.; MacTough, S. C.;

Rooney, C. S.; Balani, S. K.; Condra, J. H.; Emini, E. A.; Goldman, M.

E.; Greenlee, W. J.; Kauffman, L. R.; O’Brien, J. A.; Sardana, V. V.;

Schleif, W. A.; Theoharides, A. D.; Anderson, P. S. J. Med. Chem. 1993,

36, 1291. (b) Neamati, N.; Mazumdar, A.; Zhao, H.; Sunder, S.; Burke;

Terrence, R., Jr.; Schultz, R. J.; Pommier, Y. Antimicrob. Agents

Chemother. 1997, 41, 385. (c) McMahon, J. B.; Gulakowski, R. J.;

Weislow, O. S.; Schultz, R. J.; Narayanan, V. L.; Clanton, D. J.;

Pedemonte, R.; Wassmundt, F. W.; Buckheit, R. W., Jr.; Decker, W.

D.; White, E. L.; Bader, J. P.; Boyed, M. R. Antimicrob. Agents

Chemother. 1993, 37, 754.

Lebedev, O.; Maeorg, U. Tetrahedron Lett. 2008, 49, 1373. (c) Shohji,

N.; Kawaji, T.; Okamoto, S. Org. Lett. 2011, 13, 2626.

̈

(16) Milburn, R. R.; Snieckus, V. Angew. Chem., Int. Ed. 2004, 43,

892.

(17) (a) Nyasse, M.; Grehn, L.; Ragnarsson, U. Chem. Commun.

1997, 1017. (b) Grehn, L.; Nyasse, B.; Ragnarsson, U. Synthesis 1997,

1997, 1429. (c) Alonso, D. A.; Andersson, P. G. J. Org. Chem. 1998,

63, 9455. (d) Grehn, L.; Ragnarsson, U. J. Org. Chem. 2002, 67, 6557.

(e) Nyasse, B.; Grehn, L.; Maia, H. L. S.; Monteiro, L. S.; Ragnarsson,

U. J. Org. Chem. 1999, 64, 7135.

(18) Snyder, H. R.; Heckert, R. E. J. Am. Chem. Soc. 1952, 74, 2006.

(19) (a) Maia, H. L. S.; Medeiros, M. J.; Montenegro, M. I.; Court,

D.; Pletcher, D. J. Electroanal. Chem. Interfacial Electrochem. 1984, 164,

347. (b) Civitello, E. R.; Rapoport, H. J. Org. Chem. 1992, 57, 834.

(c) Coeffard, V.; Thobie-Gautier, C.; Beaudet, I.; Le Grognec, E.;

Quintard, J. P. Eur. J. Org. Chem. 2008, 2008, 383. (d) Senboku, H.;

Nakahara, K.; Fukuhara, T.; Hara, S. Tetrahedron Lett. 2010, 51, 435.

(35) For a recent review on the synthesis of sulfones, see: Liu, N.-W.;

Liang, S.; Manolikakes, G. Synthesis 2016, 48, 1939.

(36) This was demonstrated by observing the formation of

sulfonylated product after introducing 1,3-dimethoxybenzene into a

cooled deprotection mixture of 40.

(37) (a) Yao, B.; Zhang, Y. Tetrahedron Lett. 2008, 49, 5385.

(b) Alizadeh, A.; Khodaei, M. M.; Nazari, E. Tetrahedron Lett. 2007,

P

DOI: 10.1021/acs.joc.7b02507

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

48, 6805. (c) Olah, G. A.; Mathew, T.; Surya Prakash, G. K. Chem.

Commun. 2001, 17, 1696. (d) Singh, R. P.; Kamble, R. M.; Chandra, K.

L.; Saravanan, P.; Singh, V. K. Tetrahedron 2001, 57, 241.

(e) Choudary, B. M.; Chowdari, N. S.; Kantam, M. L. J. Chem. Soc.,

Perkin Trans. 1 2000, 16, 2689.

(38) Howbert, J. J.; Grossman, C. S.; Crowell, T. A.; Rieder, B. J.;

Harper, R. W.; Kramer, K. E.; Tao, E. V.; Aikins, J.; Poore, G. A.;

Rinzel, S. M. J. Med. Chem. 1990, 33, 2393.

(39) Javorskis, T.; Bagdziunas, G.; Orentas, E. Chem. Commun. 2016,

̌

̅

52, 4325.

(40) Xie, L.-G.; Niyomchon, S.; Mota, A. J.; Gonzal

N. Nat. Commun. 2016, 7, 10914.

́

ez, L.; Maulide,

(41) (a) You, S.-L.; Kelly, J. W. Org. Lett. 2004, 6, 1681.

(b) Pemberton, N.; Pinkner, J. S.; Edvinsson, S.; Hultgren, S. J.;

Almqvist, F. Tetrahedron 2008, 64, 9368. (c) Liu, H.; Du, D.-M. Adv.

Synth. Catal. 2010, 352, 1113. (d) Davis, T. A.; Johnston, J. N. Chem.

Sci. 2011, 2, 1076. (e) Du, X.; Liu, H.; Du, D.-M. Eur. J. Org. Chem.

2011, 2011, 786. (f) Loughlin, W. A.; Jenkins, I. D.; Petersson, M. J. J.

Org. Chem. 2013, 78, 7356. (g) Davis, T. A.; Vilgelm, A. E.; Richmond,

A.; Johnston, J. N. J. Org. Chem. 2013, 78, 10605.

(42) Perillo, I.; Caterina, M. C.; Lopez, J.; Salerno, A. Synthesis 2004,

851.

(43) Perillo, I.; Lamdan, S. J. Heterocycl. Chem. 1970, 7, 791.

(44) Zhu, M.; Moasser, B. Tetrahedron Lett. 2012, 53, 2288.

(45) Barbero, N.; Carril, M.; SanMartin, R.; Domínguez, E.

Tetrahedron 2008, 64, 7283.

(46) Qian, X.; Yu, Z.; Auffrant, A.; Gosmini, C. Chem. - Eur. J. 2013,

19, 6225.

(47) Qiao, Z.; Liu, H.; Xiao, X.; Fu, Y.; Wei, J.; Li, Y.; Jiang, X. Org.

Lett. 2013, 15, 2594.

(48) Cai, S.; Yang, K.; Wang, D. Z. Org. Lett. 2014, 16, 2606.

(49) Pawar, G. G.; Brahmanandan, A.; Kapur, M. Org. Lett. 2016, 18,

448.

(50) Kubo, T.; Katoh, C.; Yamada, K.; Okano, K.; Tokuyama, H.;

Fukuyama, T. Tetrahedron 2008, 64, 11230.

(51) Feng, Y.-S.; Mao, L.; Bu, X.-S.; Dai, J.-J.; Xu, H.-J. Tetrahedron

2015, 71, 3827.

(52) Louie, J.; Driver, M. S.; Hamann, B. C.; Hartwig, J. F. J. Org.

Chem. 1997, 62, 1268.

(53) van der Werf, A.; Selander, N. Org. Lett. 2015, 17, 6210.

(54) Saroja, G.; Samanta, A. J. Chem. Soc., Faraday Trans. 1998, 94,

3141.

(55) Ueda, S.; Nagasawa, H. J. Org. Chem. 2009, 74, 4272.

(56) Caubere, L. Bull. Soc. Chim. Fr 1974, 1983.

(57) Martínez-Barrasa, V.; Delgado, F.; Burgos, C.; Luis García-

Navío, J.; Luisa Izquierdo, M.; Alvarez-Builla, J. Tetrahedron 2000, 56,

2481.

́

(58) Gonzalez, I.; Mosquera, J.; Guerrero, C.; Rodríguez, R.; Cruces,

J. Org. Lett. 2009, 11, 1677.

(59) Wu, J.; Barnard, J. H.; Zhang, Y.; Talwar, D.; Robertson, C. M.;

Xiao, J. Chem. Commun. 2013, 49, 7052.

(60) Ishow, E.; Brosseau, A.; Clavier, G.; Nakatani, K.; Pansu, R. B.;

Vachon, J.-J.; Tauc, P.; Chauvat, D.; Mendonca

Am. Chem. Soc. 2007, 129, 8970.

̧ , C. R.; Piovesan, E. J.

(61) Keshari, T.; Kapoorr, R.; Yadav, L. D. S. Tetrahedron Lett. 2015,

56, 5623.

(62) Sharma, S.; Kumar, M.; Kumar, V.; Kumar, N. J. Org. Chem.

2014, 79, 9433.

(63) Zhang, G.; Yin, Z.; Zheng, S. Org. Lett. 2016, 18, 300.

(64) Yang, Y.; Chen, Z.; Rao, Y. Chem. Commun. 2014, 50, 15037.

(65) Davis, O. A.; Hughes, M.; Bull, J. A. J. Org. Chem. 2013, 78,

3470.

Q

DOI: 10.1021/acs.joc.7b02507

J. Org. Chem. XXXX, XXX, XXX−XXX

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Chemoselective Deprotection of Sulfonamides under Acidic Conditions: Scope, Sulfonyl Group Migration, and Synthetic Applications

DOI: 10.1021/acs.joc.7b02507

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