Regioselective (Diacetoxyiodo)benzene-promoted halocyclization of unfunctionalized olefins

Article

pubs.acs.org/joc

Regioselective (Diacetoxyiodo)benzene-Promoted Halocyclization of

Unfunctionalized Oleﬁns

Gong-Qing Liu^†and Yue-Ming Li*^,†,‡

^†College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, People’s Republic

of China

^‡CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of

Sciences, 345 Lingling Road, Shanghai 200032, People’s Republic of China

S

* Supporting Information

ABSTRACT: A metal-free method for intramolecular hal-

ocyclization of unfunctionalized oleﬁns was detailed.

(Diacetoxyiodo)benzene (PIDA) was very eﬀective for

haloamidation, haloetheriﬁcation, and halolactonization of

unfunctionalized oleﬁns. In the presence of 1.1 equiv of

PIDA and suitable halogen sources, a variety of unfunction-

alized oleﬁns could be converted to the corresponding 1,2-

bifunctional cyclic skeletons in good to excellent isolated

yields, and key intermediates for biologically interesting

compounds could be obtained in high yields under mild

conditions via nucleophilic substitution of the thus obtained

halocyclization products.

assisted haloamination,⁷but application of this method was

generally limited due to the possible sensitivity of other

INTRODUCTION

Halogen containing 1,2-difunctional structures such as vicinal

■

functional groups toward dihalogens. Free radical chloroami-

haloamines are important functional groups in mechanism-

based anticancer/antitumor drugs (Figure 1).¹They are key

nation of CC double bonds with N-electron rich amines

could be realized by in situ generation of free radicals⁸or using

catalyst systems such as Cu(I)⁹or Lewis acid-TiCl₃.¹⁰

Intramolecular haloamination of amine or (sulfon)amide

substrates could also be carried out using palladium compounds

as catalysts in combination with a variety of additives,¹¹and

oleﬁnic substrates bearing sulfonamide, carboxylic amide, or

carbamate functional groups could be converted to the

corresponding N-substituted heterocyclic compounds in high

yields.^5bCu(II) was also reported to promote a variety of

aminocyclization reactions such as carboamination,¹²amonoox-

ygenation,¹³diamination,¹⁴and haloamination¹⁵of unfunction-

alized oleﬁns, and good to excellent enantioselectivities were

realized in the presence of appropriate chiral ligands.^13a,15,16

We have shown that Cu(II) was able to promote cyclization

of unfunctionalized oleﬁns under mild conditions, and

intramolecular chloroamination and bromoamination could be

realized for a variety of 4-penten-1-amine and 5-hexen-1-amine

substrates without the use of palladium. The reactions were

carried out using CuCl₂and CuBr₂as both the reaction

promoters and the halogen sources, and cyclization products 2-

chloromethylpyrrolidines, N-tosyl 2-bromomethylpyrrolidines,

N-tosyl 2-bromomethylpiperidines, and 3-bromo/3-chloropi-

peridines could all be obtained in good isolated yields at

Figure 1. Examples of bioactive vicinal haloamines.

intermediates for several biologically interesting skeletons²and

also appear as key structures in diﬀerent natural products.³To

this end, signiﬁcant eﬀorts have been made toward the

construction of vicinal haloamine structures.⁴

Haloamination of activated CC double bonds have been

well studied in the past decades,⁵and the reactions can be

carried out regio- and stereoselectively by ﬁne-tuning the

structures of the catalysts.⁶In contrast, only limited progress

was achieved for the haloamination of unactivated CC

double bonds due to the low reactivity of the substrates. Direct

formation of 1,2-haloamines could be realized via halogen-

Received: July 30, 2014

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ambient temperature without special care for air and

moisture.¹⁷In this paper, we wish to report our recent progress

on (diacetoxyiodo)benzene (PIDA)-promoted intramolecular

halocyclization of diﬀerent unfunctionalized oleﬁns as a

continuation of our program on the functionalization of

unactivated oleﬁns.

palladium-catalyzed CC double bond amination reactions²⁰

and as catalysts²¹in the functionalization of diﬀerent CC

double bonds.²²Encouraged by these literature results, we

proposed a (diacetoxyiodo)benzene (PIDA)-mediated haloa-

midation of unfunctionalized oleﬁns as shown in Scheme 2.

Scheme 2. Proposed Reaction Sequence for I(III)-Mediated

Intramolecular Haloamidations

RESULTS AND DISCUSSION

■

In our course of searching for new methods for intramolecular

haloamination of unfunctionalized oleﬁns, we found that zinc

iodide was able to promote the intramolecular iodoamination

of N-benzyl-2,2-diphenyl-4-penten-1-amine. Further study

indicated that the reaction was promoted by molecular iodine

temporally formed via oxidation of I⁻. On the basis of this

ﬁnding, we developed an iodine-catalyzed method for intra-

molecular chloro- and bromoamination of unfunctionalized

oleﬁns (Scheme 1).¹⁸

The CC double bond in substrate I was ﬁrst activated by

PIDA, and intramolecular nucleophilic attack of nitrogen atom

on the three-membered ring in II produced the intermediate

III, which was converted to product IV by the action of the

halogen source.

To test the feasibility of this proposed reaction sequence,

iodoamidation of an unfunctionalized CC double bond was

investigated using 1a as model substrate, and the preliminary

results were summarized in Table 1.

Scheme 1. Iodine-Catalyzed Haloamination of N-Benzyl-2,2-

diphenyl-4-penten-1-amine

Table 1. Intramolecular Iodoamidation of 1a with Diﬀerent

a

Promoters

b

entry

promoter

iodine source

solvent

isolated yield (%)

1

2

PIDA

NaI

ZnI₂

LiI

KI

CH₂Cl₂

MeOH

benzene

acetone

DMF

78

72

83

91

61

33

23

3

The substrate was ﬁrst activated via traditional electrophilic

addition pathway and nucleophilic opening of the iodonium

three-membered ring of the intermediate I produced

iodoamination compound II as a temporary product. In the

presence of an excess amount of halogen source, iodine was

replaced by chlorine or bromine, yielding the corresponding

chloro- or bromoamination compounds as the ﬁnal products.

The reaction was carried out with 2 mol % of molecular iodine

and appropriate amount of halogen source, a suitable oxidant

was required to regenerate I₂and to complete the catalytic

cycle. The reaction proceeded readily at ambient temperature,

and the products 3-chloro- or 3-bromopiperidines were

obtained in good to excellent isolated yields. However, the

reaction was only suitable for N-alkyl substrates, and no

reaction was observed for N-(sulfon)amide substrates. We

reasoned that the low reactivity was due to the low

nucleophilicity of the amide nitrogen atom which limited the

conversion of intermediate II to intermediate III. Without the

formation of intermediate III, the reaction was stopped at

intermediate II, and no chloro- or bromoamination products

could be formed.

4

5

KI

6

KI

7

KI

c

8

KI

ND

c

9

KI

DMSO

CH₂Cl₂

ND

c

10

11

12

13

14

15

16

NR

c

KI

I₂

NR

80

NIS

KI

78

(nBu)₄NI

PhI

NR

61

IBX

d

17

DMP

73

a

The reaction was carried out with 0.5 mmol of 1a, 0.55 mmol of

b

promoter, 1 mmol of iodine source, and 20 mL of solvent. Isolated

yields based on 1a. ND = not detectable, NR = no reaction. DMP =

Dess-Martin periodinane.

c

d

We were delighted to ﬁnd that exo cyclization of substrate 1a

proceeded readily in the presence of PIDA, giving the

kinetically favored product 2a in 78% yield in CH₂Cl₂without

the formation of the endo cyclization product (entry 1). The

sole formation of exo product may be attributed to the use of

sulfonamide which suppressed the rearrangement of the exo

product to the thermodynamically stable endo product.^17c

Iodine source investigation showed that KI gave the best result

(entries 1−4). The eﬀect of the solvents on the course of the

The potential application of vicinal haloamines drove us to

develop a general method for intramolecular haloamination of

unfunctionalized oleﬁns, and our attention focused on

hypervalent iodine compounds due to their good performance

in a variety of organic reactions. In addition to the widespread

application of periodinane I(V) in Dess-Martin oxidation of

primary and secondary alcohols,¹⁹hypervalent iodine com-

pounds were also found to have application as oxidants in

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reaction was also noteworthy (entries 4−9), and CH₂Cl₂was

the most suitable solvent for the reaction. Reaction in solvents

such as DMF or DMSO failed to occur, possibly due to the

solvation of PIDA which caused the decrease of the

electrophilicity of the latter (entries 8 and 9). No product

was obtained in the absence of iodine source, indicating that the

iodine atom in the product came from KI rather than from

PIDA (entry 10). No reaction occurred in the absence of PIDA,

indicating the important role that PIDA played in the reaction

(entry 11). Mocular iodine could promote the reaction (entry

12), but the workup was generally troublesome, and it was

diﬃcult to completely remove the deep color from the reaction

mixture. NIS was also able to promote the reaction but to a

lesser extent (entry 13). (nBu)₄NI or PhI was unable to

promote the reaction, and no product was observed when the

reaction was carried out with (nBu)₄NI or PhI under otherwise

identical conditions (entries 14 and 15). IBX or Dess-Martin

periodinane in combination with KI could also be used for

iodoamination of 1a, but the yields were generally lower than

PIDA-induced reactions (entries 16 and 17).

isolated yields (2e to 2m), and methyl, methoxy, halogen, and

cyano groups on benzene ring could all be tolerated during the

reactions. Comparing with I₂-mediated chloro- and bromoami-

nation of unfunctionalized oleﬁns in which strong Thorpe-

Ingold eﬀect was observed,¹⁸the current reaction system was

less dependent on the substituents on the main chain (2n to

2p), and substrates without substituents on the main chain

could also be converted to 2-iodomethylpyrrolidines in good to

excellent isolated yields (2q to 2s). Substituents on CC

double bonds showed some impact on the reaction, and slightly

lower yields were obtained for such substrates (2t and 2u).

When chiral substrates were used, cis products were isolated as

the major products (2v to 2x). The diastereomeric ratios

depended on the substituents on the main chain, and substrates

bearing larger substituent gave high regioselectivity. The cis

conﬁguration of 2v was further conﬁrmed by X-ray diﬀraction

experiment. The ORTEP drawing of compound 2v showed an

envelope conformation of the ﬁve-membered ring, the phenyl

and iodomethyl groups stayed at the equatorial positions and

were away from each other (Figure 2).

After optimization of the reaction conditions, diﬀerent

substrates were tested to study the scope of the reaction. The

reactions were carried out using 1.1 equiv of PIDA as reaction

promoter and 2 equiv of KI as iodine source, and the results are

summarized in Scheme 3.

Scheme 3. PIDA-Promoted Intramolecular Iodoamidation of

a

Diﬀerent Unfunctionalized Oleﬁns

Figure 2. ORTEP drawing of 2v. Hydrogen atoms were omitted for

clarity.

To prove the scalability of the current protocol, compound

2n was prepared on gram scale under the optimized reaction

conditions. The iodoamidation of 1n took place readily,

aﬀording the expected product 2n in 93% isolated yield

(Scheme 4). The iodine atom in 2n could be replaced by a

Scheme 4. Gram-Scale Iodoamidation of Substrate 1n

a

The reaction was carried out with 0.5 mmol of substrate, 0.55 mmol

of PIDA, 1 mmol of KI, and 20 mL of CH₂Cl₂. For 2d, reaction time =

b

48 h; for 2e−2m, reaction time = 24 h. Diastereoisomeric ratios were

1

determined by H NMR.

As shown in Scheme 3, 2-iodomethylpyrrolidines and 2-

iodomethylindoles could be obtained in good to excellent

isolated yields. Electronic eﬀect of the sulfonamides had some

impact on the course of the reaction (2a−2c vs 2d), and p-

nitrobenzenesulfonamide gave product 2d in moderate isolated

yield. This was possibly due to the low nucleophilicity of

sulfonamide caused by the strong electron withdrawing nitro

group at the para position of the benzene ring. Cyclization of

N-tosyl o-allyl aniline substrates could be realized in high

variety of nucleophiles such as azide (3a), phthalimide (3b),

acetate (3c), or benzenethiol (3d) under mild condition

(Scheme 5), and the current method therefore opened up a

new route to a variety of biologically interesting compounds.²³

After successful intramolecular iodoamidation of diﬀerent

unfunctionalized oleﬁns, the bromine variant of the reaction

was also tested using 1a as a model substrate. The reaction

conditions for iodoamidation were adopted, and diﬀerent

C

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and the results are listed in Scheme 6. Bromoamidation of

unfunctionalized oleﬁns generally gave results similar to

iodoamidations, and most products were isolated in good

yields. The reactions of N-alkenyl sulfonamides bearing

diﬀerent sulfonyl groups such as 4-toluenesulfonyl, methane-

sulfonyl, and benzenesulfonyl groups gave the corresponding

products in good yields (4a to 4c). A variety of substituted 2-

bromomethyl indolines were prepared using the optimized

reaction conditions, and the para substituents on the aromatic

rings showed little eﬀect on the course of the reaction (4d to 4i

and 4m). Again, Thorpe-Ingold eﬀect showed less impact on

the reaction, and substrates without gem disubstituents also

gave acceptable isolated yields (4j to 4l). Diﬀerent substituents

on the main chain did not signiﬁcantly inﬂuence the reaction

outcomes (4n to 4p), but adding substituents on the CC

double bond led to signiﬁcantly diminished yields (4q and 4r).

Chiral substrate also gave a product in good isolated yield and

high diastereoselectivity (4s). Reactions of 1-sulfonamido-5-

hexene substrates generally gave lower isolated yields, possibly

due to the unfavorable entropy feature for cyclization reactions

(4t to 4w).²⁴

Scheme 5. Derivatization of 2-Iodomethypyrrolidine 2n to

Diﬀerent Bioactive Structures

commercially available bromine sources were screened to ﬁnd

the most suitable reaction condition. As indicated in Table 2,

lithium bromide was the most suitable bromine source, and

product 4a was obtained in 87% isolated yield after 24 h.

Table 2. Bromoamidation of 1a with Diﬀerent Bromine

a

Sources

In addition to iodo- and bromoamidation of functionalized

oleﬁns, chloroamidation could also be realized under similar

conditions. After screening diﬀerent chlorine sources, pyridi-

nium chloride was found to be suitable for the reaction, and

several chloromethylpyrrolidine compounds were obtained in

good isolated yields for terminal oleﬁns (Table 3). Introduction

of substituents on CC double bonds led to drops of isolated

yields (Table 3, entries 14 and 15). Normal metal chlorides

failed to give good results possibly due to their poor solubility

in the reaction medium (Table 3, entries 1−5).

entry

bromine source

isolated yield (%)

1

2

3

4

5

LiBr

87

73

81

70

63

ZnBr₂

NaBr

MgBr₂

Py·HBr

a

The reactions were carried out with 0.5 mmol of 1a, 0.55 mmol of

PIDA, 1 mmol of bromides, and 20 mL of CH₂Cl₂.

Comparing to the successful intramolecular iodo-, bromo-,

and chloroamidation reactions, intramolecular ﬂuoroamidation

reactions^20f,25were relatively unsuccessful. Conventional metal

ﬂuorides or ﬂuorine sources could not give the corresponding

To explore the scope and limitation of PIDA-promoted

bromoamidation reactions, a variety of substrates were tested,

a

Scheme 6. PIDA-Meadited Intramolecular Bromoamidation of Diﬀerent Alkenes

a

The reaction was carried out with 0.5 mmol of substrate, 0.55 mmol of PIDA, 1 mmol of LiBr, and 20 mL of CH₂Cl₂.

D

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Table 3. PIDA-Mediated Intramolecular Chloroamidation of

Diﬀerent Unfunctionalized Oleﬁns

Table 4. PIDA-Mediated Intramolecular Fluoroamidation

Reactions

a

entry

[F] source

solvent

isolated yield (%)

b

1

2

MF

CH₂Cl₂

hexane

benzene

acetone

THF

NR

trace

NR

45

AgF

c

3

ﬂuoride salts

BF₃·OEt₂

HBF₄

4

d

5

ND

6

33

d

7

ND

d

8

ND

9

DCE

40

38

54

10

CH₂Cl₂

e

11

BF₃·OEt₂

a

The reaction was carried out with 0.5 mmol of substrates, 0.55 mmol

of PIDA, 1 mmol of ﬂuorine source, and 20 mL of solvent. For entries

1−3, reaction time = 24 h, and for entries 4−11, reaction time = 1 min.

b

c

MF = CaF₂, MgF₂, ZnF₂, CuF₂, KF, CsF, LiF, and NaF. Fluorine

d

salts = HF, NH₄F, Et₃N·HF, and TBAF. ND = not detectable.

e

Pyridine (2 equiv) was added.

Scheme 7. Intramolecular Fluoroamidation of Diﬀerent

a

Substrates

a

The reaction was carried out with 0.5 mmol of substrates, 0.55 mmol

of PIDA, 1 mmol of chlorine source, and 20 mL of CH₂Cl₂.

ﬂuoroamidation products,^21f,h,26and ﬂuoroamidation products

were obtained only when triﬂuoroborane in diethyl ether was

used as ﬂuorine source (Table 4).²⁷

Fast reactions were observed for most cases, and the

reactions could be completed in minutes. The corresponding

3-ﬂuoropiperidine compounds were isolated in moderate yields

with endo products as the sole isomer,^{20f,21f,h,27,28}plus the

formation of varied amount of 3-acetoxypiperidines (Scheme

7). The possible pathway for aminoacetoxylation is shown in

Scheme 8. Intermediate A may be formed during the reaction,

participation of sulfonamide oxygen produced the intermediate

B²⁹which could be converted to the corresponding 3-ﬂuoro- or

3-acetoxypiperidine upon F⁻or AcO⁻attack. Conversion of the

aminoacetoxylation product to the corresponding 3-ﬂuoropi-

peridines was diﬃcult,^21fand searching for suitable ﬂuorine

source and suitable reaction conditions to suppress the

aminoacetoxylation reaction are still underway.

a

The reaction was carried out with 0.5 mmol of substrate, 0.55 mmol

of PIDA, 1 mmol of BF₃·Et₂O, 1 mmol pyridine, and 20 mL of

CH₂Cl₂.

Scheme 8. Possible Pathway for the Formation of

Aminoacetoxylation Product

Haloamidation of substrates with diﬀerent functional groups

on nitrogen atoms were also tested under the respective

optimal conditions. No reaction occurred for N−Ac or N-Boc

substrates. When N-benzyl substrate was subjected to diﬀerent

haloamination reactions, 3-iodopiperidine was obtained along

with a small amount of 2-iodomethylpyrrolidine product (9:1,

Table 5, entry 1). 3-Bromopiperidine was obtained as the sole

product when the reaction was carried out with PIDA/LiBr

(Table 5, entry 2), and 2-chloromethylpyrrolidine was obtained

as the major product in the case of PIDA/Py·HCl (Table 5,

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Table 5. PIDA-Promoted Haloamination of N-Benzyl 4-

Scheme 10. Haloamination of 1a in the Presence of Anisole

Penten-1-amine Substrate

a

entry

halogen sources

conversion

a:b

1

2

3

4

KI

>99

0

10:90

0:100

87:13

Iodoaminations of 1a under dark environment and in the

presence of TEMPO were also carried out (Table 6). A similar

LiBr

Py·HCl

BF₃·Et₂O

Table 6. Inﬂuence of Light and TEMPO on Iodoamidation

of 1a

a

1

Determined H NMR analysis of the reaction mixture.

entry 3). Fluoroamination reaction was not observed under the

current conditions possibly due to the strong interaction

between the amino group and BF₃. Detailed results for

haloamination of diﬀerent N-benzyl substrates are summarized

in Scheme 9, and electronic perperty of the phenyl group

showed little eﬀects on the reactions.

a

entry

condition

conversion

isolated yield (%)

1

2

3

ambient light

dark

>99

42

91

93

30

TEMPO (1.5 equiv)

PIDA was known to produce Ph(AcO)I-X³⁰or AcO-X³¹

upon addition of metal halides, and a variety of X⁺-involved

reactions could be realized using PIDA in combination with

diﬀerent metal halides.^30,31Several control experiments were

then carried out under optimized conditions to see if the

reaction was proceeded via PIDA-promoted CC double

bond activation or proceeded via the formation of Ph(AcO)I-X

or AcO-X. At ﬁrst, 1 equiv of substrate 1a, 1 equiv of anisole,

0.5 equiv of PIDA, and 0.5 equiv of halogen source were

allowed to react together under optimal conditions. Anisole was

added as a competitive substrate based on the fact that it could

be quickly halogenated by PIDA/metal halides,³⁰and it was

expected to capture any possible X⁺formed during the reaction.

To our surprise, the haloamination reactions were not aﬀected

by the addition of anisole, and formation of p-haloanisoles was

not observed under the current reaction conditions (Scheme

10). We reasoned that the interaction between PIDA and C

C double bonds was more favorable than the interaction

between PIDA and halides X⁻. Given that halogenation of

anisole was faster than haloamination of 1a, it was reasonable to

believe that X⁺was not formed in the current reaction system.

a

Determined by crude NMR analysis.

result was obtained when the reaction was carried out under

dark environment at room temperature (Table 6, entries 1 and

2). No TEMPO-involved product was detected when the

reaction was carried out in the presence of TEMPO (Table 6,

entry 3). The conversion of 1a and the yield of 2a dropped

possibly due to the consumption of PIDA by TEMPO,³²and

the current results could possibly rule out the formation of free

radicals during the reaction.

After intramolecular haloamidation of a variety of un-

functionalized oleﬁns, intermolecular reactions of styrene with

p-toluenesulfonamide were carried out in the presence of

diﬀerent halogen sources. After optimization of reaction

conditions, iodoamidation of styrene gave α-iodo-β-sulfonami-

do-product in 63% isolated yield,³³and bromoamidation of

styrene gave a mixture of both isomers (Scheme 11). Chloro-

and ﬂuoroamidation of styrene was not successful under the

current reaction conditions.

Scheme 9. Haloamination of Diﬀerent N-Benzyl Substrates

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magnetic resonance spectra were recorded at ambient temperature

(unless otherwise stated) at 400 MHz (100 MHz for ¹³C) in CDCl₃.

Chemical shifts are reported in ppm (δ) using TMS as internal

standard, and spin−spin coupling constants (J) are given in Hz.

Infrared (IR) spectra were recorded with KBr pellet, and wavenumbers

are given in cm⁻¹. High resolution mass spectrometry (HRMS)

analyses were carried out on IonSpec 7.0T FTICR HR-ESI-MS.

Substrates used were prepared according to our previous works^17a,c,18

or procedures described by Muniz et al.^20e

Scheme 11. Intermolecular Haloamidation of Styrene

General Procedure for Intramolecular Iodoamidation. The

reaction was carried out in an open air system. To a 100 mL ﬂask were

added 0.5 mmol alkenylamine, 0.55 mmol PhI(OAc)₂, 1 mmol KI, and

20 mL of CH₂Cl₂. The reaction mixture was stirred at room

temperature for an indicated period. Then 10 mL of CH₂Cl₂was

added, and the mixture was washed with H₂O. The organic layer was

dried over MgSO₄and concentrated under reduced pressure. The

crude product was puriﬁed by silica gel column chromatography to

give the corresponding product.

2-(Iodomethyl)-4,4-diphenyl-1-tosylpyrrolidine (2a). Compound

2a was prepared according to the general procedure and isolated as a

white solid (235.1 mg, 91% yield) after ﬂash chromatography

(petroleum ether:ethyl acetate = 80:1); mp = 180−182 °C; ¹H

NMR (400 MHz, CDCl₃) δ = 7.50 (d, J = 8.1 Hz, 2H), 7.21−6.96 (m,

12H), 4.35 (d, J = 10.3 Hz, 1H), 3.82−3.72 (m, 1H), 3.67 (d, J = 10.3

Hz, 1H), 3.59 (dd, J = 9.5, 2.9 Hz, 1H), 2.77−2.71(m, 1H), 2.56 (dd, J

= 13.1, 5.2 Hz, 1H), 2.29 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ =

143.6, 143.3, 142.6, 132.8, 128.7, 127.7, 127.6, 126.3, 125.7, 125.5,

125.4, 125.2, 59.3, 58.1, 51.1, 42.7, 20.5, 10.5. The NMR data were in

agreement with reported results.¹⁵

Many γ-butyrolactone and substituted tetrahydrofuran

skeletons have shown important biological acitivity,³⁴and

halomethyl lactone or halomethyl tetrahydrofuran compounds

would be ideal intermediates for such structures. To further

extend the application scope of PIDA-promoted halocyclization

reactions, 2,2-diphenyl-4-penten-1-carboxylic acid and 2,2-

diphenyl-4-penten-1-ol were subjected to halocyclization

reactions, and both halomethyl substituted γ-butyrolactones

and halomethyl substituted tetrahydrofurans could be obtained

in good isolated yields (Scheme 12).

Scheme 12. I(III)-Promoted Halolactonization and

Haloetheriﬁcation Reactions

2-(Iodomethyl)-1-(methylsulfonyl)-4,4-diphenylpyrrolidine (2b).

Compound 2b was prepared according to the general procedure and

isolated as a white solid (191.7 mg, 87% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 100:1); mp =

166−167 °C; ¹H NMR (400 MHz, CDCl₃) δ = 7.59−6.79 (m, 10H),

4.25 (d, J = 11.0 Hz, 1H), 4.13 (d, J = 11.1 Hz, 1H), 3.80−3.75 (m,

1H), 3.54 (dd, J = 9.8, 2.5 Hz, 1H), 3.26−3.16 (m, 2H), 2.38 (dd, J =

13.3, 8.4 Hz, 1H), 2.24 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ =

144.6, 144.1, 129.0, 128.8, 127.3, 126.9, 126.9, 126.5, 60.2, 59.6, 53.4,

44.6, 36.8, 12.4. IR (KBr): 3053, 2960, 1590, 1493, 1333, 1263, 1147,

814, 754, 705, 662 cm⁻¹; HRMS-ESI (m/z): [M + H]⁺calcd for

C₁₈H₂₀INO₂S, 442.0338; found: 442.0337.

2-(Iodomethyl)-4,4-diphenyl-1-(phenylsulfonyl)pyrrolidine (2c).

Compound 2c was prepared according to the general procedure and

isolated as a white solid (213.2 mg, 85% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 80:1); mp = 153−

154 °C; ¹H NMR (400 MHz, CDCl₃) δ = 7.71−7.60 (m, 2H), 7.45 (t,

J = 7.5 Hz, 1H), 7.36−7.32 (m, 2H), 7.23−7.15 (m, 4H), 7.14−7.00

(m, 6H), 4.35 (d, J = 10.3 Hz, 1H), 3.85−3.77 (m, 1H), 3.74 (d, J =

10.3 Hz, 1H), 3.59 (dd, J = 9.6, 3.0 Hz, 1H), 2.82−2.69 (m, 2H), 2.60

(dd, J = 13.1, 5.3 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ = 143.5,

143.2, 136.1, 131.8, 128.1, 127.7, 127.6, 126.2, 125.8, 125.7, 125.0,

125.2, 59.4, 58.1, 51.1, 42.8, 10.3. IR (KBr): 3023, 2957, 1591, 1484,

1447, 1171, 1090, 753, 699, 662 cm⁻¹; HRMS-ESI (m/z): [M +

H]⁺calcd for C₂₃H₂₂INO₂S, 504.0494; found: 504.0485.

CONCLUSION

■

In summary, (diacetoxyiodo)benzene (PIDA) was eﬀective for

the functionalization of unactivated CC double bonds.

Intramolecular haloamidation (iodo-, bromo, and chloroami-

dation), haloetheriﬁcation and halolactonization reactions could

all be realized in the presence of 1.1 equiv of PIDA and suitable

halogen sources, giving the corresponding halocyclization

products in good to excellent isolated yields. Intramolecular

ﬂuoroamidation was relatively less successful; 3-ﬂuoropiper-

idine compounds were isolated in moderate yields along with

the formation of 3-acetoxy compounds as the byproducts. The

iodomethylpyrrolidine compounds could be converted to many

diﬀerent pyrrolidine derivatives upon nucleophilic substitution

reactions, and this method eventually oﬀered an eﬀective route

to a variety of biologically active structures. The good isolated

yields, high regioselectivity, mild conditions, and easy-to-

operate feature made the current reaction a more attractive

method for the syntheses of a variety of medicinal and

agrochemical interesting compounds.

2-(Iodomethyl)-1-(4-nitrophenylsulfonyl)-4,4-diphenylpyrrolidine

(2d). Compound 2d was prepared according to the general procedure

and isolated as a yellow solid (183.7 mg, 67% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 50:1); mp = 180−

1

182 °C; H NMR (400 MHz, CDCl₃) δ = 8.02(d, J = 8.9 Hz, 2H),

7.67(d, J = 8.9 Hz, 2H), 7.26−6.90 (m, 10H), 4.30 (d, J = 10.8 Hz,

1H), 4.09 (dd, J = 10.8, 1.3 Hz, 2H), 3.83−3.76 (m, 1H), 3.66 (dd, J =

9.8, 2.8 Hz, 1H), 3.16 (t, J = 9.4 Hz, 1H), 3.11−3.04 (m, 1H), 2.39

(dd, J = 13.5, 7.9 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ = 148.8,

143.5, 142.4, 142.3, 127.8, 127.7, 127.0, 125.9, 125.7, 125.4, 125.3,

123.2, 59.3, 59.2, 51.7, 43.4, 10.5; IR (KBr): 3028, 2960, 1601, 1526,

1451, 1352, 1161, 1089, 804, 749, 700, 661 cm⁻¹; HRMS-ESI (m/z):

[M + H]⁺calcd for C₂₃H₂₁IN₂O₄S, 549.0345; found: 549.0334.

2-(Iodomethyl)-1-tosylindoline (2e). Compound 2e was prepared

according to the general procedure and isolated as a white solid (185.3

mg, 90% yield) after ﬂash chromatography (petroleum ether:ethyl

EXPERIMENTAL SECTION

■

General Experimental Information. Reagents were used as

received without further puriﬁcation unless otherwise speciﬁed.

Solvents were dried and distilled prior to use. Reactions were

monitored with thin layer chromatography using silica gel GF₂₅₄plates.

Organic solutions were concentrated in vacuo using a rotary

evaporator. Flash column chromatography was performed using silica

gel (200−300 meshes). Petroleum ether used had a boiling point

range of 60−90 °C. Melting points were measured on a digital melting

point apparatus without correction of the thermometer. Nuclear

G

dx.doi.org/10.1021/jo501739j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

acetate = 50:1); mp = 151−153 °C; ¹H NMR (400 MHz, CDCl₃) δ =

7.57 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.20−7.07 (m, 3H),

7.00−6.93 (m, 2H), 4.30−4.24 (m, 1H), 3.58 (dd, J = 9.7, 3.4 Hz,

1H), 3.18 (t, J = 9.9 Hz, 1H), 2.86 (dd, J = 16.7, 9.3 Hz, 1H), 2.76 (dd,

J = 16.7, 3.0 Hz, 1H), 2.27 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ =

144.3, 141.2, 134.4, 130.5, 129.8, 128.1, 127.1, 125.3, 124.9, 116.8,

62.5, 34.9, 21.6, 11.6. The NMR data were in agreement with reported

results.¹⁵

5-Chloro-2-(iodomethyl)-1-tosylindoline (2k). Compound 2k was

prepared according to the general procedure and isolated as a white

solid (191.3 mg, 86% yield) after ﬂash chromatography (petroleum

1

ether:ethyl acetate = 50:1); mp = 107−109 °C; H NMR (400 MHz,

CDCl₃) δ = 7.48 (dd, J = 8.2, 6.0 Hz, 3H), 7.11 (dd, J = 15.2, 4.9 Hz,

3H), 6.95 (s, 1H), 4.29−4.23 (m, 1H), 3.55 (dd, J = 9.8, 3.3 Hz, 1H),

3.20 (t, J = 9.8 Hz, 1H), 2.84 (dd, J = 16.9, 9.4 Hz, 1H), 2.73 (dd, J =

16.9, 3.1 Hz, 1H), 2.29 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ =

144.7, 139.9, 134.1, 132.4, 130.1, 129.9, 128.1, 127.1, 125.5, 117.7,

62.7, 34.8, 21.7, 11.4. The NMR data were in agreement with reported

results.^11c

2-(Iodomethyl)-5-methyl-1-tosylindoline (2f). Compound 2f was

prepared according to the general procedure and isolated as a white

solid (196.1 mg, 92% yield) after ﬂash chromatography (petroleum

1

5-Bromo-2-(iodomethyl)-1-tosylindoline (2l). Compound 2l was

prepared according to the general procedure and isolated as a white

solid (203.5 mg, 83% yield) after ﬂash chromatography (petroleum

ether:ethyl acetate = 40:1); mp = 153−154 °C; H NMR (400 MHz,

CDCl₃) δ = 7.45 (t, J = 9.1 Hz, 3H), 7.09 (d, J = 8.1 Hz, 2H), 6.94 (d,

J = 8.1 Hz, 1H), 6.78 (s, 1H), 4.27−4.21 (m, 1H), 3.55 (dd, J = 9.7,

3.5 Hz, 1H), 3.16 (t, J = 9.9 Hz, 1H), 2.79 (dd, J = 16.7, 9.2 Hz, 1H),

2.69 (dd, J = 16.7, 3.1 Hz, 1H), 2.27 (s, 3H), 2.19 (s, 3H); ¹³C NMR

(100 MHz, CDCl₃) δ = 143.1, 137.7, 133.7, 133.3, 129.5, 128.7, 127.6,

126.0, 124.8, 115.6, 61.6, 33.7, 20.6, 19.9, 10.5. The NMR data were in

agreement with reported results.¹⁵

1

ether:ethyl acetate = 50:1); mp = 95−97 °C; H NMR (400 MHz,

CDCl₃) δ = 7.48 (dd, J = 8.3, 5.4 Hz, 3H), 7.16−7.04 (m, 3H), 6.94

(s, 1H), 4.29−4.22 (m, 1H), 3.54 (dd, J = 9.8, 3.3 Hz, 1H), 3.21 (t, J =

7.9 Hz, 1H), 2.84 (dd, J = 16.9, 9.4 Hz, 1H), 2.73 (dd, J = 16.9, 3.0 Hz,

1H), 2.28 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ = 144.6, 139.9,

134.1, 132.4, 130.2, 129.9, 128.1, 127.1, 125.5, 117.7, 62.7, 34.7, 21.6,

11.2. IR (KBr): 3042, 2964, 1594, 1471, 1351, 1163, 1085, 743, 662,

cm⁻¹; HRMS-ESI (m/z): [M + H]⁺calcd for C₁₆H₁₅BrINO₂S,

491.9130; found: 491.9139.

2-(Iodomethyl)-6-methyl-1-tosylindoline (2g). Compound 2g was

prepared according to the general procedure and isolated as a white

solid (183.3 mg, 86% yield) after ﬂash chromatography (petroleum

1

ether:ethyl acetate = 40:1); mp = 142−143 °C; H NMR (400 MHz,

2-(Iodomethyl)-1-tosylindoline-5-carbonitrile (2m). Compound

2m was prepared according to the general procedure and isolated as

a white solid (188.0 mg, 86% yield) after ﬂash chromatography

CDCl₃) δ = 7.49 (t, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.11 (d,

J = 8.1 Hz, 2H), 7.05 (t, J = 7.8 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H),

4.34−4.21 (m, 1H), 3.62 (dd, J = 9.6, 3.3 Hz, 1H), 3.19 (t, J = 9.9 Hz,

1H), 2.79 (dd, J = 16.6, 9.5 Hz, 1H), 2.67 (dd, J = 16.6, 3.2 Hz, 1H),

2.28 (s, 3H), 2.05 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ = 143.2,

139.8, 133.8, 133.3, 128.7, 127.9, 127.1, 126.1, 124.7, 112.8, 61.3, 32.9,

20.5, 17.7, 10.9; IR (KBr): 3041, 2961, 1594, 1457, 1346, 1164, 1093,

1023, 807, 697, 662, 583 cm⁻¹; HRMS-ESI (m/z): [M + H]⁺calcd for

C₁₇H₁₈INO₂S, 428.0181; found: 428.0173..

1

(petroleum ether:ethyl acetate = 30:1); mp = 151−152 °C; H NMR

(400 MHz, CDCl₃) δ = 7.63 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.1 Hz,

2H), 7.45 (d, J = 8.4 Hz, 1H), 7.27 (s, 1H), 7.18 (d, J = 8.0 Hz, 2H),

4.34−4.29 (m, 1H), 3.59 (dd, J = 9.9, 2.8 Hz, 1H), 3.29 (t, J = 9.5 Hz,

1H), 3.01 (dd, J = 17.0, 9.8 Hz, 1H), 2.84 (dd, J = 17.1, 3.1 Hz, 1H),

2.31 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ = 145.3, 145.2, 134.2,

132.9, 131.3, 130.2, 128.9, 126.9, 118.8, 116.1, 107.7, 62.5, 34.8, 21.7,

11.4. The NMR data were in agreement with reported results.^11c

2-(Iodomethyl)-4,4-dimethyl-1-tosylpyrrolidine (2n). Compound

2n was prepared according to the general procedure and isolated as a

white solid (190.5 mg, 97% yield) after ﬂash chromatography

2-(Iodomethyl)-7-methyl-1-tosylindoline (2h). Compound 2h was

prepared according to the general procedure and isolated as a white

solid (183.2 mg, 86% yield) after ﬂash chromatography (petroleum

1

ether:ethyl acetate = 50:1); mp = 103−105 °C; H NMR (400 MHz,

CDCl₃) δ = 7.28 (dd, J = 15.0, 8.2 Hz, 2H), 7.14−7.02 (m, 3H), 6.99

(t, J = 7.4 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H), 4.42−4.33 (m, 1H), 3.29

(dd, J = 9.9, 5.0 Hz, 1H), 2.91 (t, J = 9.9 Hz, 1H), 2.49 (s, 3H), 2.38

(d, J = 16.4 Hz, 1H), 2.31 (s, 3H), 2.05 (dd, J = 16.4, 7.8 Hz, 1H); ¹³C

NMR (100 MHz, CDCl₃) δ = 144.3, 139.9, 135.4, 133.9, 133.1, 130.6,

129.5, 127.6, 126.9, 122.5, 64.6, 33.8, 21.7, 20.0, 8.7; IR (KBr): 3056,

2962, 1596, 1504, 1354, 1169, 1086, 1023, 938, 810, 697, 662 cm⁻¹;

HRMS-ESI (m/z): [M + H]⁺calcd for C₁₇H₁₈INO₂S, 428.0181;

found: 428.0179.

1

(petroleum ether:ethyl acetate = 30:1); mp = 92 °C; H NMR (400

MHz, CDCl₃) δ = 7.66 (d, J = 8.2 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H),

3.69 (dd, J = 9.5, 2.8 Hz, 1H), 3.65−3.57 (m, 1H), 3.31 (t, J = 9.2 Hz,

1H), 3.18−3.06 (m, 2H), 2.36 (s, 3H), 1.84 (dd, J = 12.8, 7.2 Hz, 1H),

1.52 (dd, J = 12.8, 8.5 Hz, 1H), 0.96 (s, 3H), 0.41 (s, 3H); ¹³C NMR

(100 MHz, CDCl₃) δ = 143.8, 134.8, 129.8, 127.5, 62.0, 60.1, 47.8,

37.5, 26.0, 25.9, 21.6, 13.4. The NMR data were in agreement with

reported results.^11c

3-(Iodomethyl)-2-tosyl-2-azaspiro[4.5]decane (2o). Compound

2o was prepared according to the general procedure and isolated as

a white solid (199.3 mg, 92% yield) after ﬂash chromatography

2-(Iodomethyl)-5-methoxy-1-tosylindoline (2i). Compound 2i was

prepared according to the general procedure and isolated as a white

solid (203.1 mg, 92% yield) after ﬂash chromatography (petroleum

1

(petroleum ether:ethyl acetate = 40:1); mp = 114−116 °C; H NMR

1

ether:ethyl acetate = 40:1); mp = 147−148 °C; H NMR (400 MHz,

(400 MHz, CDCl₃) δ = 7.67 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.0 Hz,

2H), 3.69 (dd, J = 9.5, 2.7 Hz, 1H), 3.54 (td, J = 8.8, 2.6 Hz, 1H),

3.37−3.23 (m, 2H), 3.09 (d, J = 11.0 Hz, 1H), 2.36 (s, 3H), 1.92 (dd, J

= 12.9, 7.2 Hz, 1H), 1.45 (dd, J = 13.0, 8.6 Hz, 1H), 1.39−1.26 (m,

4H), 1.20−0.95 (m, 4H), 0.72−0.65 (m, 1H), 0.54 (dd, J = 11.5, 5.9

Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ = 143.7, 134.7, 129.7, 127.5,

59.3, 59.2, 45.9, 41.4, 36.1, 33.9, 25.9, 23.7, 22.7, 21.6, 13.7; IR (KBr):

CDCl₃) δ = 7.47 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.10 (d,

J = 8.1 Hz, 2H), 6.69 (dd, J = 8.8, 2.4 Hz, 1H), 6.52 (d, J = 2.0 Hz,

1H), 4.31−4.17 (m, 1H), 3.68 (s, 3H), 3.53 (dd, J = 9.7, 3.6 Hz, 1H),

3.16 (t, J = 9.9 Hz, 1H), 2.78−2.60 (m, 2H), 2.28 (s, 3H); ¹³C NMR

(100 MHz, CDCl₃) δ = 157.6, 144.2, 134.4, 134.1, 132.5, 129.7, 127.1,

118.2, 113.2, 110.9, 62.9, 55.6, 34.9, 21.6, 11.3. The NMR data were in

agreement with reported results.^11c

3037, 2926, 2855, 1595, 1486, 1449, 1343, 1159, 1091, 1023, 815, 660

+

cm⁻¹; HRMS-ESI (m/z): [M + H]

calcd for C₁₇H₂₄INO₂S,

5-Fluoro-2-(iodomethyl)-1-tosylindoline (2j). Compound 2j was

prepared according to the general procedure and isolated as a white

solid (182.5 mg, 85% yield) after ﬂash chromatography (petroleum

434.0651; found: 434.0642.

4,4-Diallyl-2-(iodomethyl)-1-tosylpyrrolidine (2p). Compound 2p

was prepared according to the general procedure and isolated as an oil

(213.2 mg, 96% yield) after ﬂash chromatography (petroleum

1

ether:ethyl acetate = 50:1); mp = 114−115 °C; H NMR (400 MHz,

CDCl₃) δ = 7.52 (dd, J = 8.8, 4.6 Hz, 1H), 7.46 (d, J = 8.3 Hz, 2H),

7.13 (d, J = 8.1 Hz, 2H), 6.85 (td, J = 8.8, 2.6 Hz, 1H), 6.73−6.64 (m,

1H), 4.31−4.25 (m, 1H), 3.54 (dd, J = 9.8, 3.5 Hz, 1H), 3.19 (t, J = 9.9

Hz, 1H), 2.80 (dd, J = 17.0, 9.1 Hz, 1H), 2.72 (dd, J = 17.0, 3.3 Hz,

1H), 2.29 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ = 160.5 (d, J =

243.2 Hz), 144.5, 137.2, 134.0, 132.8 (d, J = 9.2 Hz), 129.9, 127.1,

118.1 (d, J = 8.6 Hz), 114.7 (d, J = 23.4 Hz), 112.5 (d, J = 24.1 Hz);

¹⁹F NMR (376 MHz, CDCl₃) δ = −117.7. The NMR data were in

agreement with reported results.^11c

1

ether:ethyl acetate = 50:1); H NMR (400 MHz, CDCl₃) δ = 7.67

(d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 5.67−5.56 (m, 1H),

5.49−5.39 (m, 1H), 5.05−4.88 (m, 3H), 4.73 (d, J = 16.9 Hz, 1H),

3.68−3.56 (m, 2H), 3.33 (t, J = 8.8 Hz, 1H), 3.22−3.11 (m, 2H), 2.36

(s, 3H), 2.03 (d, J = 7.3 Hz, 2H), 1.93 (dd, J = 13.1, 7.2 Hz, 1H),

1.62−1.50 (m, 2H), 1.42 (dd, J = 14.0, 7.9 Hz, 1H); ¹³C NMR (100

MHz, CDCl ) δ = 143.9, 135.1, 133.5, 133.1, 129.8, 127.5, 118.7,

3

59.4, 58.7, 43.7, 43.3, 40.4, 39.2, 21.6, 13.5; IR (KBr): 3072, 2971,

H

dx.doi.org/10.1021/jo501739j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

1640, 1597, 1487, 1442, 1344, 1159, 1095, 1011, 814, 665 cm⁻¹;

HRMS-ESI (m/z): [M + H] calcd for C₁₈H₂₄INO₂S, 446.0651;

found: 446.0652.

2H), 2.66−2.55 (m, 1H), 2.48−2.42 (m, 1H), 2.39 (s, 3H), 1.82 (dd, J

= 21.9, 11.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ = 144.1, 138.8,

134.8, 130.1, 128.8, 127.5, 127.3, 127.1, 60.6, 55.8, 43.2, 41.1, 21.7,

+

2-(Iodomethyl)-1-tosylpyrrolidine (2q). Compound 2q was pre-

pared according to the general procedure and isolated as a white solid

(167.6 mg, 92% yield) after ﬂash chromatography (petroleum

ether:ethyl acetate = 60:1); mp = 90 °C; ¹H NMR (400 MHz,

CDCl₃) δ = 7.65 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 3.65

(dd, J = 11.2, 5.4 Hz, 1H), 3.53 (dd, J = 9.5, 2.5 Hz, 1H), 3.40 (dd, J =

10.0, 5.9 Hz, 1H), 3.21−3.06 (m, 2H), 2.36 (s, 3H), 1.88−1.64 (m,

3H), 1.44 (dd, J = 11.3, 5.9 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ

= 143.8, 134.1, 129.9, 127.5, 60.7, 50.1, 31.9, 23.9, 21.6, 11.7. The

NMR data were in agreement with reported results.¹⁵

13.2; IR (KBr): 3063, 2964, 1596, 1493, 1441, 1340, 1159, 998, 821,

+

759, 706, 661 cm⁻¹; HRMS-ESI (m/z): [M + H]

calcd for

C₁₈H₂₀INO₂S, 442.0338; found: 442.0336.

Crystal data for 2v. C₁₈H₂₀INO₂S, M = 441.31, monoclinic, a =

10.911(2) Å, b = 15.095(3) Å, c = 11.664(2) Å, α = 90.00°, β =

113.30(3)°, γ = 90.00°, V = 1764.4(6) Å³, T = 113(2) K, space group

P2(1)/c, Z = 4, 20423 reﬂections measured, 4238 independent

reﬂections (R_int= 0.0501). The ﬁnal R₁values were 0.0307 (I > 2σ(I)).

The ﬁnal wR(F²) values were 0.0738 (I > 2σ(I)). The ﬁnal R₁values

were 0.0421 (all data). The ﬁnal wR(F²) values were 0.0809 (all data).

The goodness of ﬁt on F²was 0.973.

2-(Iodomethyl)-1-(phenylsulfonyl)pyrrolidine (2r). Compound 2r

was prepared according to the general procedure and isolated as a

white solid (154.3 mg, 88% yield) after ﬂash chromatography

4-Allyl-2-(iodomethyl)-1-tosylpyrrolidine (2w). Compound 2w was

prepared according to the general procedure and isolated as a white

solid (173.9 mg, 86% yield) after ﬂash chromatography (petroleum

1

(petroleum ether:ethyl acetate = 50:1); mp = 64−65 °C; H NMR

1

(400 MHz, CDCl₃) δ = 7.77 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.3 Hz,

1H), 7.48 (t, J = 7.6 Hz, 2H), 3.70−3.64 (m, 1H), 3.53 (dd, J = 9.7, 2.9

Hz, 1H), 3.46−3.38 (m, 1H), 3.19−3.09 (m, 1H), 1.86−1.64 (m, 3H),

1.48−1.38 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ = 136.9, 133.1,

129.3, 127.4, 60.7, 50.1, 31.9, 23.9, 11.7; IR (KBr): 3064, 2973, 1581,

1448, 1342, 1161, 1095, 817, 788, 710, 661 cm⁻¹; HRMS-ESI (m/z):

ether:ethyl acetate = 80:1); mp = 67−68 °C; H NMR (400 MHz,

CDCl₃) δ = 7.65 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 5.61−

5.48 (m, 1H), 4.96−4.87 (m, 2H), 3.62−3.52 (m, 3H), 3.29 (t, J = 9.0

Hz, 1H), 2.94 (t, J = 11.1 Hz, 1H), 2.37 (s, 3H), 2.21−2.25 (m, 1H),

2.03−1.88 (m, 2H), 1.57−1.44 (m, 1H), 1.33−1.24 (m, 1H); ¹³C

NMR (100 MHz, CDCl₃) δ = 143.9, 135.5, 134.7, 129.9, 127.4, 116.6,

60.7, 55.0, 39.8, 37.7, 36.1, 21.6, 13.2; IR (KBr): 3060, 2970, 1645,

1594, 1488, 1430, 1159, 1024, 998, 820, 761, 705, 660 cm⁻¹; HRMS-

+

[M + H] calcd for C₁₁H₁₄INO₂S, 351.9868; found: 351.9861.

2-(Iodomethyl)-1-(o-tolylsulfonyl)pyrrolidine (2s). Compound 2s

was prepared according to the general procedure and isolated as a

white solid (156.4 mg, 86% yield) after ﬂash chromatography

+

ESI (m/z): [M + H] calcd for C₁₅H₂₀INO₂S, 406.0338; found:

406.0338.

1

(petroleum ether:ethyl acetate = 50:1); mp = 36−37 °C; H NMR

4-Allyl-2-(iodomethyl)-4-phenyl-1-tosylpyrrolidine (2x). Com-

pound 2x was prepared according to the general procedure and

isolated as an oil (218.3 mg, 91% yield) after ﬂash chromatography

(petroleum ether:ethyl acetate = 100:1); ¹H NMR (400 MHz, CDCl₃)

δ = 7.45 (d, J = 8.2 Hz, 2H), 7.12−7.03 (m, 5H), 6.90 (dd, J = 7.5, 1.9

Hz, 2H), 5.33−5.17 (m, 1H), 4.89 (dd, J = 12.8, 8.5 Hz, 2H), 3.86

(dd, J = 9.5, 2.9 Hz, 1H), 3.74 (d, J = 10.1 Hz, 1H), 3.64−3.55 (m,

1H), 3.47 (d, J = 10.1 Hz, 1H), 3.34 (t, J = 9.8 Hz, 1H), 2.52−2.36 (m,

3H), 2.30 (s, 3H), 2.08 (dd, J = 13.5, 6.2 Hz, 1H). ¹³C NMR (100

MHz, CDCl₃) δ = 142.5, 142.3, 132.4, 132.3, 128.6, 127.4, 126.4,

125.3, 125.2, 117.6, 59.5, 59.2, 47.0, 44.6, 41.1, 20.5, 11.3.IR (KBr):

3058, 2961, 1597, 1492, 1448, 1343, 1159, 1092, 1022, 958, 806, 754,

701, 660 cm⁻¹; HRMS-ESI (m/z): [M + H] ⁺calcd for C₂₁H₂₄INO₂S,

482.0651; found: 482.0644.

General Procedure for Derivatization of 2-Iodomethypyrro-

lidine. 2-Iodomethypyrrolidine (2n) was dissolved in 2 mL of DMF,

the nucleophile of interest was added, and the reaction mixture was

stirred for a given time. Then 30 mL of CH₂Cl₂was added, and the

reaction mixture was washed with water, dried over MgSO₄, and

concentrated under reduced pressure. The crude product was puriﬁed

by silica gel column chromatography to give the corresponding

product.

(400 MHz, CDCl₃) δ = 7.85 (d, J = 8.3 Hz, 1H), 7.40 (t, J = 7.5 Hz,

1H), 7.27−7.23 (m, 2H), 4.01−3.90 (m, 1H), 3.37 (dd, J = 9.8, 2.9

Hz, 1H), 3.32−3.20 (m, 2H), 3.07 (t, J = 9.5 Hz, 1H), 2.60 (s, 3H),

2.06−1.95 (m, 1H), 1.94−1.80 (m, 2H), 1.80−1.66 (m, 1H); ¹³C

NMR (100 MHz, CDCl₃) δ = 138.1, 136.9, 133.1, 132.9, 129.6, 126.3,

59.8, 49.9, 32.4, 24.2, 20.9, 11.3; IR (KBr): 3047, 2974, 1590, 1453,

1337, 1159, 1097, 989, 814, 765, 701, 663 cm⁻¹; HRMS-ESI (m/z):

+

[M + H] calcd for C₁₂H₁₆INO₂S, 366.0025, found 366.0021.

2-(1-Iodoethyl)-4,4-diphenyl-1-tosylpyrrolidine (2t). Compound

2t was prepared according to the general procedure and isolated as

a white solid (231.2 mg, 87% yield) after ﬂash chromatography

(petroleum ether:ethyl acetate = 100:1); mp = 197−198 °C; ¹H NMR

(400 MHz, CDCl₃) δ = 7.43 (d, J = 8.1 Hz, 2H), 7.21−6.99 (m, 12H),

4.94 (dd, J = 7.0, 3.0 Hz, 1H), 4.40 (d, J = 10.6 Hz, 1H), 3.99 (d, J =

10.8 Hz, 1H), 3.01 (dd, J = 12.3, 6.1 Hz, 1H), 2.86 (dd, J = 12.6, 6.1

Hz, 1H), 2.48 (dd, J = 12.9, 9.5 Hz, 1H), 2.29 (s, 3H), 1.75 (d, J = 7.1

Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ = 145.4, 144.2, 142.9, 136.9,

129.5, 128.6, 128.6, 126.8, 126.7, 126.6, 126.3, 64.7, 59.1, 52.9, 42.1,

37.4, 24.5, 21.5; IR (KBr): 3058, 2984, 1596, 1492, 1340, 1156, 1085,

1033, 1011, 924, 805, 757, 698, 663 cm⁻¹; HRMS-ESI (m/z): [M +

+

H] calcd for C₂₅H₂₆INO₂S, 532.0807; found: 532.0797.

2-(Azidomethyl)-4,4-dimethyl-1-tosylpyrrolidine (3a). Compound

3a was prepared according to the general procedure and isolated as a

white solid (146.6 mg, 95% yield) after ﬂash chromatography

2-(2-Iodopropan-2-yl)-4,4-diphenyl-1-tosylpyrrolidine (2u). Com-

pound 2u was prepared according to the general procedure and

isolated as a white solid (117.6 mg, 43% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 50:1); mp = 64−

65 °C; ¹H NMR (400 MHz, CDCl₃) δ = 7.51 (d, J = 7.4 Hz, 2H), 7.42

(t, J = 7.7 Hz, 2H), 7.36−7.26 (m, 3H), 7.23−7.16 (m, 3H), 7.13 (d, J

= 8.3 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 5.29 (dd, J = 13.8, 2.7 Hz,

1H), 4.41 (dd, J = 13.3, 3.5 Hz, 1H), 3.70 (d, J = 13.8 Hz, 1H), 3.45−

3.40 (m, 1H), 2.92 (t, J = 13.8 Hz, 1H), 2.35 (s, 3H), 1.48 (s, 3H),

1.39 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ = 146.0, 143.1, 142.7,

140.1, 129.5, 129.1, 128.7, 128.0, 127.2, 126.8, 126.6, 125.9, 61.0, 50.1,

49.9, 46.0, 40.2, 30.3, 21.4, 18.1; IR (KBr): 3056, 2986, 1596, 1493,

1368, 1150, 1081, 1035, 954, 810, 774, 701, 629 cm⁻¹; HRMS-ESI

(m/z): [M + H] ⁺calcd for C₂₆H₂₈INO₂S, 546.0964; found: 546.0959.

2-(Iodomethyl)-4-phenyl-1-tosylpyrrolidine (2v). Compound 2v

was prepared according to the general procedure and isolated as a

white solid (196.5 mg, 89% yield) after ﬂash chromatography

(petroleum ether:ethyl acetate = 80:1); mp = 130 °C; ¹H NMR

(400 MHz, CDCl₃) δ = 7.72 (d, J = 7.6 Hz, 2H), 7.30 (d, J = 7.6 Hz,

2H), 7.25−7.12 (m, 3H), 7.03 (d, J = 7.1 Hz, 2H), 3.87−3.80 (m,

1H), 3.71 (d, J = 7.5 Hz, 1H), 3.64 (d, J = 9.6 Hz, 1H), 3.45−3.31 (m,

1

(petroleum ether:ethyl acetate = 50:1); mp = 71 °C; H NMR (400

MHz, CDCl₃) δ = 7.66 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H),

3.71−3.60 (m, 2H), 3.56−3.51 (m, 1H), 3.08 (q, J = 10.8 Hz, 2H),

2.36 (s, 3H), 1.63 (dd, J = 7.5, 2.7 Hz, 2H), 0.98 (s, 3H), 0.41 (s, 3H);

¹³C NMR (100 MHz, CDCl₃) δ = 143.8, 134.6, 129.8, 127.5, 61.6,

59.0, 55.0, 43.8, 37.5, 26.1, 25.6, 21.6; IR (KBr): 3031, 2960,2101,

1595, 1488, 1456, 1337, 1156, 1094, 1037, 917, 813, 730, 664, 590

+

cm⁻¹; HRMS-ESI (m/z): [M + H]

calcd for C₁₄H₂₀N₄O₂S,

309.1385; found: 309.1382.

2-((4,4-Dimethyl-1-tosylpyrrolidin-2-yl)methyl)isoindoline-1,3-

dione (3b). Compound 3b was prepared according to the general

procedure and isolated as a white solid (171.1 mg, 83% yield) after

ﬂash chromatography (petroleum ether:ethyl acetate = 20:1); mp =

1

177−179 °C; H NMR (400 MHz, CDCl₃) δ = 7.84−7.61 (m, 6H),

7.26 (d, J = 7.8 Hz, 2H), 4.35 (dd, J = 12.9, 4.5 Hz, 1H), 3.92−3.69

(m, 2H), 3.24 (d, J = 10.7 Hz, 1H), 3.04 (d, J = 10.7 Hz, 1H), 2.35 (s,

3H), 1.56 (dd, J = 12.5, 7.6 Hz, 1H), 1.49 (dd, J = 12.3, 7.4 Hz, 1H),

1.02 (s, 3H), 0.37 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ = 168.4,

I

dx.doi.org/10.1021/jo501739j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

143.6, 134.3, 134.1, 131.9, 129.7, 127.9, 123.6, 123.4, 62.2, 57.4, 44.6,

43.2, 37.3, 26.6, 26.1, 21.6; IR (KBr): 3204, 3031, 2959, 1767, 1718,

1602, 1463, 1390, 1365, 1166, 1088, 812, 716, 661, 590 cm⁻¹; HRMS-

J = 7.4 Hz, 1H), 7.36 (t, J = 7.7 Hz, 2H), 7.25−7.17 (m, 4H), 7.16−

6.98 (m, 6H), 4.32 (d, J = 10.2 Hz, 1H), 3.94−3.80 (m, 1H), 3.80−

3.60 (m, 2H), 2.89 (t, J = 9.9 Hz, 1H), 2.78−2.57 (m, 2H); ¹³C NMR

+

ESI (m/z): [M + H] calcd for C₂₂H₂₄N₂O₄S, 413.1535; found:

(100 MHz, CDCl ) δ = 144.6, 144.3, 137.1, 132.9, 129.2, 128.8,

3

413.1534.

128.7, 127.4, 126.9, 126.8, 126.6, 126.3, 60.0, 58.8, 52.3, 42.1, 35.7;

HRMS-ESI (m/z): [M + H] calcd for C₂₃H₂₂BrNO₂S, 456.0633;

+

(4,4-Dimethyl-1-tosylpyrrolidin-2-yl)methyl acetate (3c). Com-

pound 3c was prepared according to the general procedure and

isolated as a white solid (141.4 mg, 87% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 50:1); mp = 79−

80 °C; ¹H NMR (400 MHz, CDCl₃) δ = 7.67 (d, J = 8.2 Hz, 2H), 7.25

(d, J = 8.2 Hz, 2H), 4.39 (dd, J = 11.0, 3.8 Hz, 1H), 4.13 (dd, J = 11.0,

7.1 Hz, 1H), 3.82−3.75 (m, 1H), 3.07 (s, 2H), 2.36 (s, 3H), 1.95 (s,

3H), 1.65 (dd, J = 12.8, 7.7 Hz, 1H), 1.54 (dd, J = 11.3, 6.7 Hz, 1H),

0.98 (d, J = 7.4 Hz, 3H), 0.52 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ

= 169.7, 142.5, 134.0, 128.6, 126.4, 65.7, 60.5, 56.8, 42.6, 36.5, 25.3,

found: 456.0625. The NMR data were in agreement with reported

results.^17c

2-(Bromomethyl)-1-tosylindoline (4d). Compound 4d was pre-

pared according to the general procedure and isolated as a white solid

(147.2 mg, 81% yield) after ﬂash chromatography (petroleum

ether:ethyl acetate = 30:1); mp = 148−149 °C; ¹H NMR (400

MHz, CDCl₃) δ = 7.57 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H),

7.19−7.07 (m, 3H), 7.00−6.94 (m, 2H), 4.39−4.32 (m, 1H), 3.73 (dd,

J = 9.9, 3.6 Hz, 1H), 3.33 (t, J = 9.8 Hz, 1H), 2.84 (d, J = 6.0 Hz, 2H),

2.27 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ = 143.3, 140.0, 133.3,

129.6, 128.7, 126.9, 125.9, 124.3, 123.9, 115.8, 61.1, 34.9, 32.1, 20.5.

The NMR data were in agreement with reported results.^11b

24.9, 20.5, 19.8; IR (KBr): 2961, 1734, 1597, 1337, 1158, 1093, 1044,

807, 665, 590 cm⁻¹; HRMS-ESI (m/z): [M + H]

calcd for

+

C₁₆H₂₃NO₄S, 326.1426; found: 326.1422.

4,4-Dimethyl-2-(p-tolylthiomethyl)-1-tosylpyrrolidine (3d). Com-

pound 3d was prepared according to the general procedure and

isolated as a white solid (178.6 mg, 92% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 60:1); mp = 103

2-(Bromomethyl)-5-methyl-1-tosylindoline (4e). Compound 4e

was prepared according to the general procedure and isolated as a

white solid (147.5 mg, 78% yield) after ﬂash chromatography

(petroleum ether:ethyl acetate = 40:1); mp = 156−158 °C; ¹H

NMR (400 MHz, CDCl₃) δ = 7.46 (t, J = 8.6 Hz, 3H), 7.11 (d, J = 8.1

Hz, 2H), 6.95 (d, J = 8.2 Hz, 1H), 6.80 (s, 1H), 4.36−4.29 (m, 1H),

3.72 (dd, J = 9.9, 3.8 Hz, 1H), 3.32 (t, J = 9.9 Hz, 1H), 2.83−2.70 (m,

2H), 2.28 (s, 3H), 2.20 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ =

143.2, 137.6, 133.8, 133.3, 129.7, 128.7, 127.6, 126.1, 124.8, 115.7,

61.2, 34.9, 32.1, 20.5, 19.9; IR (KBr): 3021, 2961,1595, 1486, 1348,

1

°C; H NMR (400 MHz, CDCl₃) δ = 7.43 (d, J = 8.2 Hz, 2H), 7.28

(d, J = 8.2 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H),

3.82 (dd, J = 13.3, 3.0 Hz, 1H), 3.55−3.48 (m, 1H), 3.12 (d, J = 10.5

Hz, 1H), 2.93 (d, J = 10.4 Hz, 1H), 2.78 (dd, J = 13.3, 10.4 Hz, 1H),

2.30 (s, 3H), 2.28 (s, 3H), 1.76 (dd, J = 12.8, 7.6 Hz, 1H), 1.53 (dd, J

= 12.9, 7.8 Hz, 1H), 0.95 (s, 3H), 0.36 (s, 3H); ¹³C NMR (100 MHz,

CDCl₃) δ = 142.4, 135.2, 132.9, 130.6, 129.1, 128.8, 128.5, 126.5, 60.9,

58.1, 44.9, 39.2, 36.2, 25.4, 24.8, 20.5, 20.0; IR (KBr): 3030, 2961,

1695, 1494, 1449, 1333, 1154, 1092, 810, 710, 682 cm ⁻¹; HRMS-ESI

(m/z): [M + H] ⁺calcd for C₂₁H₂₇NO₂S₂,390.1561; found: 390.1560.

General Procedure for the Intramolecular Bromoamidation.

The reaction was carried out in an open air system. To a 100 mL ﬂask

were added 0.5 mmol alkenylamine, 0.55 mmol PhI(OAc)₂, 1 mmol

LiBr, and 20 mL of CH₂Cl₂. The reaction mixture was stirred at room

temperature for an indicated period. Then 10 mL of CH₂Cl₂was

added, and the mixture was washed with H₂O. The organic layer was

dried over MgSO₄and concentrated under reduced pressure. The

crude product was puriﬁed by silica gel column chromatography to

give the corresponding product.

+

1162, 1093, 809, 755, 662 cm⁻¹; HRMS-ESI (m/z): [M + H] calcd

for C₁₇H₁₈BrNO₂S, 380.0320; found: 380.0317.

2-(Bromomethyl)-5-methoxy-1-tosylindoline (4f). Compound 4f

was prepared according to the general procedure and isolated as a

white solid (167.4 mg, 85% yield) after ﬂash chromatography

(petroleum ether:ethyl acetate = 40:1); mp = 144−145 °C; ¹H

NMR (400 MHz, CDCl ₃) δ = 7.46 (dd, J = 17.1, 8.3 Hz, 3H), 7.11 (d,

J = 7.9 Hz, 2H), 6.69 (d, J = 8.4 Hz, 1H), 6.53 (s, 1H), 4.34−4.30 (m,

1H), 3.72−3.67 (m, 4H), 3.30 (t, J = 9.9 Hz, 1H), 2.82−2.63 (m, 2H),

2.29 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ = 156.6, 143.2, 133.3,

133.1, 131.6, 128.7, 126.1, 117.2, 112.1, 109.8, 61.5, 54.5, 34.8, 32.2,

20.6; IR (KBr): 3017, 2961, 1601, 1489, 1347, 1159, 1090, 1029, 960,

+

817, 806, 754, 700 cm⁻¹; HRMS-ESI (m/z): [M + H] calcd for

2-(Bromomethyl)-4,4-diphenyl-1-tosylpyrrolidine (4a). Com-

pound 4a was prepared according to the general procedure and

isolated as a white solid (206.1 mg, 88% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 40:1); mp = 163

°C;¹H NMR (400 MHz, CDCl₃) δ = 7.53 (d, J = 8.0 Hz, 2H), 7.25−

6.85 (m, 12H), 4.33 (d, J = 10.2 Hz, 1H), 3.96−3.81 (m, 1H), 3.72

(dd, J = 9.7, 3.1 Hz, 1H), 3.63 (d, J = 10.2 Hz, 1H), 2.86 (t, J = 9.9 Hz,

1H), 2.72−2.62 (m, 2H), 2.30 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

δ= 144.7, 144.4, 143.8, 133.8, 129.9, 128.8, 128.0, 127.5, 126.8, 126.6,

126.6, 126.4, 60.1, 58.9, 52.3, 42.1, 35.9, 21.6; HRMS-ESI (m/z): [M +

H] ⁺calcd for C₂₄H₂₄BrNO₂S, 470.0789; found: 470.0789. The NMR

data were in agreement with reported results.³⁵

C₁₇H₁₈BrNO₃S, 396.0269; found: 396.0257.

2-(Bromomethyl)-5-ﬂuoro-1-tosylindoline (4g). Compound 4g

was prepared according to the general procedure and isolated as a

white solid (164.2 mg, 86% yield) after ﬂash chromatography

(petroleum ether:ethyl acetate = 40:1); mp = 103−104 °C; ¹H

NMR (400 MHz, CDCl ₃) δ = 7.52 (dd, J = 8.8, 4.6 Hz, 1H), 7.46 (d,

J = 8.1 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 6.85 (td, J = 8.8, 2.1 Hz,

1H), 6.70 (d, J = 7.9 Hz, 1H), 4.40−4.33 (m, 1H), 3.70 (dd, J = 10.0,

3.7 Hz, 1H), 3.34 (t, J = 9.8 Hz, 1H), 2.85−2.71 (m, 2H), 2.30 (s,

3H); ¹³C NMR (100 MHz, CDCl₃) δ = 159.4 (d, J = 243.9 Hz), 143.5,

136.1, 132.9, 131.9 (d, J = 8.6 Hz), 128.8, 126.1, 117.1 (d, J = 8.7 Hz),

113.7(d, J = 23.4 Hz), 111.4 (d, J = 24.3 Hz), 61.2, 34.7, 32.1, 20.6; ¹⁹F

NMR (376 MHz, CDCl₃) δ = −117.6; IR (KBr): 3035, 2961,1601,

1599, 1481, 1353, 1170, 1090, 1028, 967, 993, 811, 755, 700 cm⁻¹;

2-(Bromomethyl)-1-(methylsulfonyl)-4,4-diphenylpyrrolidine

(4b). Compound 4b was prepared according to the general procedure

and isolated as a white solid (167.3 mg, 85% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 30:1); mp = 143−

+

HRMS-ESI (m/z): [M + H] calcd for C₁₆H₁₅BrFNO₂S, 384.0069;

1

found: 384.0061.

145 °C. H NMR (400 MHz, CDCl₃) δ = 7.41−6.91 (m, 10H), 4.22

2-(Bromomethyl)-5-chloro-1-tosylindoline (4h). Compound 4h

was prepared according to the general procedure and isolated as a

white solid (159.3 mg, 80% yield) after ﬂash chromatography

(petroleum ether:ethyl acetate = 40:1); mp = 123−124 °C; ¹H

NMR (400 MHz, CDCl ₃) δ = 7.49 (t, J = 8.0 Hz, 3H), 7.20−7.09 (m,

3H), 6.97 (d, J = 0.7 Hz, 1H), 4.40−4.31 (m, 1H), 3.71 (dd, J = 10.0,

3.6 Hz, 1H), 3.35 (t, J = 9.8 Hz, 1H), 2.88−2.76 (m, 2H), 2.30 (s,

3H); ¹³C NMR (100 MHz, CDCl₃) δ = 143.6, 138.9, 133.1, 131.6,

129.2, 128.9, 127.1, 125.9, 124.4, 116.7, 61.3, 34.8, 32.0, 20.6; IR

(KBr): 3030, 2960, 1694, 1470, 1354, 1166, 1027, 956, 878, 812, 702

(dd, J = 11.0, 1.7 Hz, 1H), 4.09 (d, J = 11.0 Hz, 1H), 4.00−3.93 (m,

1H), 3.68 (dd, J = 10.1, 2.9 Hz, 1H), 3.35 (dd, J = 10.1, 8.3 Hz, 1H),

3.15 (dd, J = 13.3, 6.9, 1H), 2.53 (dd, J = 13.4, 8.3 Hz, 1H), 2.30 (s,

3H). ¹³C NMR (100 MHz, CDCl₃) δ = 144.6, 144.1, 129.0, 128.8,

127.2, 126.9, 126.8, 126.5, 59.9, 59.5, 53.3, 42.7, 36.7, 36.6. HRMS-ESI

+

(m/z): [M + H]

calcd for C₁₈H₂₀BrNO₂S, 394.0476; found:

394.0468. The NMR data were in agreement with reported results.^17c

2-(Bromomethyl)-4,4-diphenyl-1-(phenylsulfonyl)pyrrolidine (4c).

Compound 4c was prepared according to the general procedure and

isolated as a white solid (182.1 mg, 80% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 50:1); mp = 162−

163 °C. ¹H NMR (400 MHz, CDCl₃) δ = 7.70−7.64 (m, 2H), 7.46 (t,

+

cm⁻¹; HRMS-ESI (m/z): [M + H] calcd for C₁₆H₁₅BrClNO₂S,

399.9774; found: 399.9756.

J

dx.doi.org/10.1021/jo501739j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

5-Bromo-2-(bromomethyl)-1-tosylindoline (4i). Compound 4i was

prepared according to the general procedure and isolated as a white

solid (190.3 mg, 86% yield) after ﬂash chromatography (petroleum

129.7, 127.5, 61.9, 60.0, 45.9, 37.5, 37.5, 26.1, 25.8, 21.6. The NMR

data were in agreement with reported results.^31a

3-(Bromomethyl)-2-tosyl-2-azaspiro[4.5]decane (4o). Compound

4o was prepared according to the general procedure and isolated as a

white solid (177.5 mg, 92% yield) after ﬂash chromatography

1

ether:ethyl acetate = 40:1); mp = 120−121 °C; H NMR (400 MHz,

CDCl ₃) δ = 7.49 (t, J = 8.1 Hz, 3H), 7.27−7.06 (m, 3H), 6.97 (d, J =

0.7 Hz, 1H), 4.44−4.29 (m, 1H), 3.72 (dd, J = 10.0, 3.7 Hz, 1H), 3.35

(t, J = 9.8 Hz, 1H), 2.96−2.70 (m, 2H), 2.30 (s, 3H). ¹³C NMR (100

MHz, CDCl₃) δ = 143.6, 138.9, 133.0, 131.6, 129.2, 128.9, 127.1,

126.0, 124.4, 116.7, 61.3, 34.8, 32.0, 20.6.IR (KBr): 3029, 2960,1694,

1468, 1354, 1325, 1150, 1027, 959, 814, 702, 664 cm⁻¹; HRMS-ESI

(m/z): [M + H] ⁺calcd for C₁₆H₁₅Br₂NO₂S, 443.9268; found:

443.9253.

1

(petroleum ether:ethyl acetate = 50:1); mp = 86−88 °C. H NMR

(400 MHz, CDCl₃) δ = 7.67 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.1 Hz,

2H), 3.86 (dd, J = 9.7, 3.0 Hz, 1H), 3.76−3.69 (m, 1H), 3.46−3.40

(m, 1H), 3.27 (d, J = 10.9 Hz, 1H), 3.07 (d, J = 10.9 Hz, 1H), 2.36 (s,

3H), 1.88 (dd, J = 13.1, 7.4 Hz, 1H), 1.56 (dd, J = 13.1, 8.4 Hz, 1H),

1.35−0.98 (m, 8H), 0.76−0.69 (m, 1H), 0.64−0.53 (m, 1H); ¹³C

NMR (100 MHz, CDCl₃) δ = 143.7, 134.8, 129.7, 127.5, 59.3, 59.1,

44.1, 41.4, 37.7, 36.2, 34.0, 25.8, 23.7, 22.8, 21.5. The NMR data were

in agreement with reported results.^31a

2-(Bromomethyl)-1-(phenylsulfonyl)pyrrolidine (4j). Compound

4j was prepared according to the general procedure and isolated as a

white solid (125.6 mg, 83% yield) after ﬂash chromatography

4,4-Diallyl-2-(bromomethyl)-1-tosylpyrrolidine (4p). Compound

4p was prepared according to the general procedure and isolated as an

oil (182.3 mg, 92% yield) after ﬂash chromatography (petroleum

ether:ethyl acetate = 30:1); ¹H NMR (400 MHz, CDCl₃) δ = 7.67 (d,

J = 8.2 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 5.67−5.56 (m, 1H), 5.53−

5.39 (m, 1H), 5.05−4.88 (m, 3H), 4.74 (d, J = 17.0 Hz, 1H), 3.83−

3.77 (m, 2H), 3.55−3.45 (m, 1H), 3.19−3.07 (m, 2H), 2.36 (s, 3H),

2.04 (d, J = 7.3 Hz, 2H), 1.96−1.85 (m, 1H), 1.71−1.54 (m, 2H), 1.44

(dd, J = 14.1, 7.9 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ = 143.9,

134.9, 133.4, 133.1, 129.8, 127.5, 118.7, 59.3, 58.6, 43.8, 41.3, 40.5,

39.2, 37.5, 21.6; IR (KBr): 3072, 2972,1640, 1598, 1444, 1346, 1162,

1

(petroleum ether:ethyl acetate = 30:1); mp = 58−59 °C; H NMR

(400 MHz, CDCl₃) δ = 7.77 (d, J = 7.6 Hz, 2H), 7.58−7.52 (m, 1H),

7.48 (t, J = 7.6 Hz, 2H), 3.81−3.73 (m, 1H), 3.68 (dd, J = 9.8, 3.2 Hz,

1H), 3.45−3.37 (m, 1H), 3.30 (t, J = 9.7 Hz, 1H), 3.11−3.05 (m, 1H),

1.91−1.82 (m, 1H), 1.82−1.72 (m, 1H), 1.64 (dq, J = 19.9, 7.5 Hz,

1H), 1.53−1.40 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ = 136.8,

133.1, 129.3, 127.5, 60.4, 49.9, 36.1, 30.2, 23.8. The NMR data were in

agreement with reported results.^31a

2-(Bromomethyl)-1-(o-tolylsulfonyl)pyrrolidine (4k). Compound

4k was prepared according to the general procedure and isolated as an

oil (120.5 mg, 76% yield) after ﬂash chromatography (petroleum

ether:ethyl acetate = 50:1); ¹H NMR (400 MHz, CDCl₃) δ = 7.85 (d,

J = 8.3 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.25 (dd, J = 7.2, 4.1 Hz,

2H), 4.10−4.04 (m, 1H), 3.52 (dd, J = 10.0, 3.1 Hz, 1H), 3.31−3.15

(m, 3H), 2.60 (s, 3H), 2.01−1.92 (m, 2H), 1.92−1.80 (m, 1H), 1.80−

1.69 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ = 138.1, 136.8, 133.1,

132.9, 129.6, 126.3, 59.5, 49.4, 35.9, 30.5, 24.2, 20.9; IR (KBr): 3060,

+

1097, 920, 813, 772, 665, 591 cm⁻¹HRMS-ESI (m/z): [M + H]

calcd for C₁₈H₂₄BrNO₂S, 398.0789; found: 398.0784.

2-(2-Bromopropan-2-yl)-4,4-diphenyl-1-tosylpyrrolidine (4q).

Compound 4q was prepared according to the general procedure and

isolated as a white solid (149.3 mg, 60% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 40:1); mp = 89−

90 °C. ¹H NMR (400 MHz, CDCl₃) δ = 7.46 (d, J = 7.7 Hz, 2H), 7.33

(t, J = 7.7 Hz, 2H), 7.24−7.18 (m, 3H), 7.17−7.11 (m, 5H), 7.01 (d, J

= 8.1 Hz, 2H), 5.16 (dd, J = 13.8, 2.6 Hz, 1H), 4.09 (dd, J = 13.0, 3.7

Hz, 1H), 3.55 (d, J = 13.8 Hz, 1H), 3.18−3.13 (m, 1H), 2.65 (t, J =

13.5 Hz, 1H), 2.28 (s, 3H), 1.33 (s, 3H), 1.30 (s, 3H). ¹³C NMR (100

MHz, CDCl₃) δ = 146.1, 143.1, 142.8, 140.1, 129.5, 129.0, 128.7,

127.9, 127.2, 126.8, 126.6, 125.9, 61.8, 58.2, 49.9, 48.8, 42.9, 27.9, 21.4,

16.3. HRMS-ESI ( m/z): [M + H]+ calcd for C₂₆H ₂₈BrNO₂S,

498.1102; found: 498.1101. The NMR data were in agreement with

reported results.^17c

2-(1-Bromoethyl)-4,4-diphenyl-1-tosylpyrrolidine (4r). Compound

4r was prepared according to the general procedure and isolated as a

white solid (152.2 mg, 63% yield) after ﬂash chromatography

(petroleum ether:ethyl acetate = 30:1); mp = 186−187 °C; ¹H

NMR (400 MHz, CDCl₃) δ = 7.45 (d, J = 8.2 Hz, 2H), 7.20−7.16 (m,

2H), 7.14−7.09 (m, 3H), 7.08−6.99 (m, 7H), 4.86−4.80 (m, 1H),

4.42 (dd, J = 10.6, 1.3 Hz, 1H), 3.90 (d, J = 10.7 Hz, 1H), 3.74 (ddd, J

= 9.5, 6.7, 2.9 Hz, 1H), 2.79 (dd, J = 12.3, 6.2 Hz, 1H), 2.66 (dd, J =

12.9, 9.4 Hz, 1H), 2.29 (s, 3H), 1.56 (d, J = 7.0 Hz, 3H). ¹³C NMR

(100 MHz, CDCl₃) δ = 144.3, 142.9, 141.8, 135.9, 128.4, 127.5, 125.7,

125.6, 125.5, 125.3, 63.1, 57.9, 53.9, 51.9, 38.1, 21.4, 20.5. HRMS-ESI

(m/z): [M + H]⁺calcd for C₂₅H₂₆BrNO₂S, 484.0946; found:

484.0937.

2-(Bromomethyl)-4-phenyl-1-tosylpyrrolidine (4s). Compound 4s

was prepared according to the general procedure and isolated as a

white solid (159.5 mg, 81% yield) after ﬂash chromatography

(petroleum ether:ethyl acetate = 80:1); mp = 114−116 °C; ¹H

NMR (400 MHz, CDCl₃) δ = 7.70 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.1

Hz, 2H), 7.23−7.10 (m, 3H), 7.06−6.96 (m, 2H), 3.94−3.88 (m, 1H),

3.82−3.75 (m, 2H), 3.52 (dd, J = 9.7, 8.4 Hz, 1H), 3.30 (t, J = 11.4 Hz,

1H), 2.62−2.53 (m, 1H), 2.46−2.33 (m, 4H), 1.96−1.87 (m, 1H); ¹³C

NMR (100 MHz, CDCl₃) δ = 144.0, 138.8, 134.9, 130.0, 128.7, 127.5,

127.3, 127.0, 60.5, 55.7, 43.1, 39.1, 37.6, 21.6; HRMS-ESI ( m/z): [M

+ H]⁺calcd for C₁₈H₂₀BrNO₂S, 394.0476; found: 394.0476. The

NMR data were in agreement with reported results.^17c

2970,1640, 1592, 1460, 1326, 1159, 1073, 984, 874, 812, 761, 969

+

cm⁻¹; HRMS-ESI (m/z): [M + H]

calcd for C₁₂H₁₆BrNO₂S,

318.0163; found: 318.0155.

2-(Bromomethyl)-1-tosylpyrrolidine (4l). Compound 4l was

prepared according to the general procedure and isolated as a white

solid (134.9 mg, 85% yield) after ﬂash chromatography (petroleum

ether:ethyl acetate = 40:1); mp = 86 °C. ¹H NMR (400 MHz, CDCl₃)

δ = 7.65 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 3.79−3.73 (m,

1H), 3.68 (dd, J = 9.9, 3.1 Hz, 1H), 3.42−3.35 (m, 1H), 3.29 (t, J = 9.7

Hz, 1H), 3.11−3.05 (m, 1H), 2.36 (s, 3H), 1.90−1.81 (m, 1H), 1.81−

1.73 (m, 1H), 1.71−1.62 (m, 1H), 1.56−1.36 (m, 1H); ¹³C NMR

(100 MHz, CDCl₃) δ = 143.9, 133.9, 129.9, 127.5, 60.4, 49.8, 36.2,

30.3, 23.8, 21.6. The NMR data were in agreement with reported

results.^31a

7-Allyl-2-(bromomethyl)-5-methyl-1-tosylindoline (4m). Com-

pound 4m was prepared according to the general procedure and

isolated as a white solid (161.7 mg, 77% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 50:1); mp = 123−

1

125 °C; H NMR (400 MHz, CDCl₃) δ = 7.28 (d, J = 8.2 Hz, 2H),

7.09 (d, J = 8.1 Hz, 2H), 6.89 (s, 1H), 6.64 (s, 1H), 5.95−5.86 (m,

1H), 5.14−4.95 (m, 2H), 4.41−4.34 (m, 1H), 3.79 (dd, J = 15.7, 6.4

Hz, 1H), 3.57 (dd, J = 15.8, 7.3 Hz, 1H), 3.46 (dd, J = 10.0, 5.0 Hz,

1H), 3.01 (t, J = 10.0 Hz, 1H), 2.32 (s, 3H), 2.26 (dd, J = 12.8, 4.9 Hz,

1H), 2.21 (s, 3H), 2.01 (dd, J = 16.4, 7.7 Hz, 1H); ¹³C NMR (100

MHz, CDCl₃) δ = 143.3, 136.2, 136.1, 136.1, 134.5, 133.4, 132.8,

129.2, 128.5, 126.7, 122.7, 115.1, 63.2, 35.8, 32.8, 31.2, 20.6, 20.1; IR

(KBr): 3014, 2966, 1640, 1598, 1467, 1434, 1344, 1166, 1090, 910,

+

874, 815, 702 cm⁻¹; HRMS-ESI (m/z): [M + H]

calcd for

C₂₀H₂₂BrNO₂S, 420.0633; found: 420.0623.

2-(Bromomethyl)-4,4-dimethyl-1-tosylpyrrolidine (4n). Com-

pound 4n was prepared according to the general procedure and

isolated as a white solid (155.4 mg, 90% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 30:1); mp = 94−

96 °C. ¹H NMR (400 MHz, CDCl₃) δ = 7.67 (d, J = 8.2 Hz, 2H), 7.26

(d, J = 8.2 Hz, 2H), 3.86 (dd, J = 9.6, 3.0 Hz, 1H), 3.83−3.77 (m, 1H),

3.45 (t, J = 9.1 Hz, 1H), 3.10 (q, J = 10.9 Hz, 2H), 2.36 (s, 3H), 1.81

(dd, J = 12.9, 7.2 Hz, 1H), 1.63 (dd, J = 12.9, 8.2 Hz, 1H), 0.98 (s,

3H), 0.46 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ = 143.7, 134.9,

2-(Bromomethyl)-5,5-diphenyl-1-tosylpiperidine (4t). Compound

4t was prepared according to the general procedure and isolated as a

white solid (152.3 mg, 63% yield) after ﬂash chromatography

(petroleum ether:ethyl acetate = 70:1); mp = 134−135 °C; ¹H

K

dx.doi.org/10.1021/jo501739j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

NMR (400 MHz, CDCl₃) δ = 7.49 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 7.9

Hz, 2H), 7.21−7.06 (m, 10H), 4.54 (d, J = 13.4 Hz, 1H), 4.03−3.94

(m, 1H), 3.45 (t, J = 10.8 Hz, 1H), 3.26 (dd, J = 9.9, 3.2 Hz, 1H), 3.08

(d, J = 13.4 Hz, 1H), 2.40 (dd, J = 14.1, 2.4 Hz, 1H), 2.33 (s, 3H),

2.21−2.13 (m, 1H), 2.07 (dd, J = 14.2, 1.8 Hz, 1H), 1.59 (t, J = 12.0

Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ = 145.9, 142.8, 142.3, 135.5,

2-(Chloromethyl)-4,4-dimethyl-1-tosylpyrrolidine (5b). Com-

pound 5b was prepared according to the general procedure and

isolated as a white solid (132.6 mg, 88% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 50:1); mp = 92−

94 °C; ¹H NMR (400 MHz, CDCl₃) δ = 7.66 (d, J = 8.1 Hz, 2H), 7.25

(d, J = 8.1 Hz, 2H), 4.00−3.93 (m, 1H), 3.82−3.75 (m, 1H), 3.60 (dd,

J = 10.4, 8.5 Hz, 1H), 3.07 (q, J = 10.5 Hz, 2H), 2.36 (s, 3H), 1.76 (dd,

J = 12.9, 7.4 Hz, 1H), 1.70−1.60 (m, 1H), 0.98 (s, 3H), 0.46 (s, 3H);

¹³C NMR (100 MHz, CDCl₃) δ = 143.7, 134.8, 129.7, 127.5, 61.8,

60.3, 48.1, 44.6, 37.5, 26.1, 25.8, 21.6. The NMR data were in

agreement with reported results.^11g

128.8, 127.5, 127.4, 126.8, 126.4, 125.6, 125.3, 125.1, 52.1, 47.6, 44.6,

+

27.6, 27.4, 20.7, 20.5; HRMS-ESI (m/z): [M + H]

calcd for

C₂₅H₂₆BrNO₂S, 484.0946; found: 484.0937. The NMR data were in

agreement with reported results.^17c

2-(Bromomethyl)-5,5-dimethyl-1-tosylpiperidine (4u). Compound

4u was prepared according to the general procedure and isolated as a

white solid (125.7 mg, 70% yield) after ﬂash chromatography

3-(Chloromethyl)-2-tosyl-2-azaspiro[4.5]decane (5c). Compound

5c was prepared according to the general procedure and isolated as a

white solid (129.9 mg, 76% yield) after ﬂash chromatography

1

(petroleum ether:ethyl acetate = 70:1); mp = 75 °C; H NMR (400

1

(petroleum ether:ethyl acetate = 40:1); mp = 73−75 °C; H NMR

MHz, CDCl₃) δ = 7.62 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H),

4.19 (dd, J = 17.3, 11.7 Hz, 1H), 3.38 (t, J = 10.5 Hz, 1H), 3.21 (d, J =

13.1 Hz, 1H), 3.10 (dd, J = 9.9, 4.0 Hz, 1H), 2.56 (d, J = 13.1 Hz, 1H),

2.34 (s, 3H), 1.91 (d, J = 14.3 Hz, 1H), 1.75−1.65 (m, 1H), 1.32−1.12

(m, 2H), 0.82 (s, 3H), 0.75 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ =

143.4, 137.8, 129.8, 126.9, 52.8, 51.4, 31.3, 30.1, 29.3, 28.8, 23.2, 21.6;

(400 MHz, CDCl₃) δ = 7.67 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.1 Hz,

2H), 3.96 (dd, J = 10.5, 2.9 Hz, 1H), 3.75−3.69 (m, 1H), 3.57 (dd, J =

10.3, 8.6 Hz, 1H), 3.25 (d, J = 10.8 Hz, 1H), 3.05 (d, J = 10.9 Hz, 1H),

2.35 (s, 3H), 1.83 (dd, J = 13.0, 7.4 Hz, 1H), 1.60 (dd, J = 13.0, 8.3

Hz, 1H), 1.34−1.26 (m, 3H), 1.22−1.01 (m, 4H), 0.81−0.68 (m, 2H),

0.62−0.54 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ = 143.7, 134.7,

129.7, 127.5, 59.5, 58.9, 48.4, 42.8, 41.4, 36.2, 33.9, 25.8, 23.7, 22.8,

21.5; IR (KBr): 3030, 2928, 1698, 1449, 1344, 1157, 1093, 1040, 966,

IR (KBr): 3020, 2953, 1595, 1451, 1333, 1154, 1089, 977, 909, 810,

+

773, 662 cm⁻¹; HRMS-ESI (m/z): [M + H]

calcd for

C₁₅H₂₂BrNO₂S, 360.0633; found: 360.0625.

+

811 cm ⁻¹; HRMS-ESI (m/z): [M + H] calcd for C₁₇H₂₄ClNO₂S,

3-(Bromomethyl)-2-tosyl-2-azaspiro[5.5]undecane (4v). Com-

pound 4v was prepared according to the general procedure and

isolated as an oil (135.2 mg, 68% yield) after ﬂash chromatography

342.1295; found: 342.1291.

2-(Chloromethyl)-1-tosylpyrrolidine (5d). Compound 5d was

prepared according to the general procedure and isolated as a white

solid (103.1 mg, 76% yield) after ﬂash chromatography (petroleum

1

(petroleum ether:ethyl acetate = 80:1); H NMR (400 MHz, CDCl₃)

δ = 7.63 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 4.22−4.04 (m,

1H), 3.55 (d, J = 13.3 Hz, 1H), 3.40 (t, J = 10.5 Hz, 1H), 3.19−3.07

(m, 1H), 2.45 (d, J = 13.3 Hz, 1H), 2.36 (s, 3H), 1.86 (d, J = 14.1 Hz,

1H), 1.74−1.66 (m, 1H), 1.43−1.04 (m, 12H); ¹³C NMR (100 MHz,

CDCl₃) δ = 142.3, 136.8, 128.7, 125.9, 52.3, 47.8, 36.9, 31.4, 29.6,

28.6, 28.5, 25.4, 20.5, 20.3, 20.3, 19.7; IR (KBr): 3031, 2927, 1597,

1

ether:ethyl acetate = 30:1); mp = 56−57 °C; H NMR (400 MHz,

CDCl₃) δ = 7.66 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 3.80

(dd, J = 10.6, 3.3 Hz, 1H), 3.76−3.69 (m, 1H), 3.48−3.31 (m, 2H),

3.12−3.00 (m, 1H), 2.36 (s, 3H), 1.91−1.82 (m, 1H), 1.82−1.70 (m,

1H), 1.68−1.56 (m, 1H), 1.54−1.45 (m, 1H); ¹³C NMR (100 MHz,

CDCl₃) δ = 142.8, 133.0, 128.9, 126.6, 59.5, 48.7, 46.0, 28.3, 22.8,

20.6. The NMR data were in agreement with reported results.^11g

4,4-Diallyl-2-(chloromethyl)-1-tosylpyrrolidine (5e). Compound

5e was prepared according to the general procedure and isolated as

an oil (155.6 mg, 88% yield) after ﬂash chromatography (petroleum

ether:ethyl acetate = 50:1); ¹H NMR (400 MHz, CDCl₃) δ = 7.67 (d,

J = 7.6 Hz, 2H), 7.27 (d, J = 7.6 Hz, 2H), 5.67−5.57 (m, 1H), 3.52−

3.42 (m, 1H), 5.07−4.91 (m, 3H), 4.76 (d, J = 16.9 Hz, 1H), 3.92 (d, J

= 10.7 Hz, 1H), 3.81 (q, J = 7.8 Hz, 1H), 3.62 (t, J = 9.2 Hz, 1H),

3.23−3.04 (m, 2H), 2.37 (s, 3H), 2.05 (d, J = 7.3 Hz, 2H), 1.87 (dd, J

= 13.1, 7.5 Hz, 1H), 1.74−1.58 (m, 2H), 1.53−1.43 (m, 1H); ¹³C

NMR (100 MHz, CDCl₃) δ = 143.9, 134.9, 133.5, 133.2, 129.8, 127.5,

118.7, 59.6, 58.5, 48.1, 43.8, 40.5, 40.1, 39.2, 21.6; IR (KBr): 3072,

1490, 1452, 1338, 1158, 1093, 940, 811, 766, 676 cm⁻¹; HRMS-ESI

+

(m/z): [M + H]

calcd for C₁₈H₂₆BrNO₂S, 400.0946; found:

400.0938.

2-(Bromomethyl)-1-tosylpiperidine (4w). Compound 4w was

prepared according to the general procedure and isolated as an oil

(94.4 mg, 57% yield) after ﬂash chromatography (petroleum

1

ether:ethyl acetate = 40:1); H NMR (400 MHz, CDCl₃) δ = 7.65

(d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 4.26−4.05 (m, 1H), 3.68

(d, J = 11.2 Hz, 1H), 3.44 (t, J = 10.1 Hz, 1H), 3.35 (dd, J = 10.1, 5.4

Hz, 1H), 2.93−2.83 (m, 1H), 2.36 (s, 3H), 1.96 (d, J = 10.6 Hz, 1H),

1.47 (d, J = 11.9 Hz, 2H), 1.42−1.35 (m, 2H), 1.27−1.15 (m, 1H);

¹³C NMR (100 MHz, CDCl₃) δ = 142.4, 136.9, 128.9, 126.0, 52.4,

40.1, 29.4, 24.2, 23.3, 20.6, 16.9. The NMR data were in agreement

with reported results.^11b

2967, 1640, 1597, 1444, 1344, 1159, 1094, 919, 808 cm⁻¹; HRMS-ESI

+

(m/z): [M + H]

calcd for C₁₈H₂₄ClNO₂S, 354.1295; found:

General Procedure for the Intramolecular Chloroamidation.

The reaction was carried out in an open air system. To a 100 mL ﬂask

were added 0.5 mmol alkenylamine, 0.55 mmol PhI(OAc)₂, 1 mmol

pyridium chloride, and 20 mL of CH₂Cl₂. The reaction mixture was

stirred at room temperature for an indicated period. Then 10 mL of 1

N HCl were added and the mixture was extracted with CH₂Cl₂. The

organic layer was dried over MgSO₄and concentrated under reduced

pressure. The crude product was puriﬁed by silica gel column

chromatography to give the corresponding product.

354.1291.

2-(Chloromethyl)-1-tosylindoline (5f). Compound 5f was prepared

according to the general procedure and isolated as a white solid (98.0

mg, 61% yield) after ﬂash chromatography (petroleum ether:ethyl

acetate = 50:1); mp = 130−132 °C; ¹H NMR (400 MHz, CDCl₃) δ =

7.68 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 7.6 Hz, 2H), 7.30−7.17 (m, 3H),

7.07 (q, J = 7.4 Hz, 2H), 4.44−4.40 (m, 1H), 3.95 (d, J = 10.6 Hz,

1H), 3.57 (t, J = 9.9 Hz, 1H), 3.02−2.81 (m, 2H), 2.38 (s, 3H); ¹³C

NMR (100 MHz, CDCl₃) δ = 144.3, 141.1, 134.5, 130.8, 129.8, 127.9,

127.1, 125.3, 125.0, 116.9, 62.3, 46.9, 32.3, 21.6. The NMR data were

in agreement with reported results.^11b

2-(2-Chloropropan-2-yl)-4,4-diphenyl-1-tosylpyrrolidine (5g).

Compound 5g was prepared according to the general procedure and

isolated as a white solid (84.1 mg, 37% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 40:1); mp = 55−

57 °C; ¹H NMR (400 MHz, CDCl₃) δ = 7.47 (d, J = 7.6 Hz, 2H), 7.32

(t, J = 7.7 Hz, 2H), 7.26−7.10 (m, 8H), 7.03 (d, J = 8.1 Hz, 2H), 5.13

(dd, J = 13.7, 2.5 Hz, 1H), 3.89 (dd, J = 12.7, 3.7 Hz, 1H), 3.48 (d, J =

13.7 Hz, 1H), 3.03−2.98 (m, 1H), 2.48 (t, J = 13.3 Hz, 1H), 2.29 (s,

3H), 1.32 (s, 3H), 1.20 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ =

146.1, 143.2, 142.9, 139.9, 129.5, 128.9, 128.7, 127.9, 127.2, 126.8,

126.6, 126.0, 63.9, 62.2, 50.0, 47.7, 41.6, 26.6, 21.5, 15.2. HRMS-ESI

2-(Chloromethyl)-4,4-diphenyl-1-tosylpyrrolidine (5a). Com-

pound 5a was prepared according to the general procedure and

isolated as a white solid (174.3 mg, 82% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 40:1); mp = 162−

1

164 °C; H NMR (400 MHz, CDCl₃) δ = 7.55 (d, J = 8.2 Hz, 2H),

7.23−6.93 (m, 12H), 4.31 (d, J = 10.2 Hz, 1H), 3.86−3.78 (m, 2H),

3.61 (d, J = 10.2 Hz, 1H), 2.98 (dd, J = 14.8, 7.0 Hz, 1H), 2.65 (d, J =

6.2 Hz, 2H), 2.32 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ = 144.7,

144.5, 143.7, 133.8, 129.8, 128.8, 128.7, 127.5, 126.8, 126.6, 126.5,

126.4, 60.2, 58.6, 52.3, 46.5, 40.9, 21.6; IR (KBr): 3031, 2960,1594,

1487, 1445, 1354, 1171, 1089, 1028, 867, 814, 734, 700, 661 cm⁻¹;

+

HRMS-ESI (m/z): [M + H] calcd for C₂₄H₂₄ClNO₂S, 426.1295;

found: 426.1292.

L

dx.doi.org/10.1021/jo501739j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(m/z): [M + H]+ calcd for C₂₅H₂₆ClNO₂S, C₂₆H₂₈ClNO₂S, 454.1608;

found: 454.1611.

2H), 7.27 (t, J = 7.7 Hz, 2H), 7.23−7.16 (m, 3H), 7.16−7.12 (m, 1H),

7.09 (t, J = 6.3 Hz, 2H), 4.45 (dm, J = 47.5 Hz, 1H), 4.46 (d, J = 13.2

Hz, 1H), 4.01−3.94 (m, 1H), 2.90 (t, J = 8.6 Hz, 1H), 2.35 (d, J = 12.4

Hz, 1H), 2.26−2.20 (m, 1H), 2.09 (dd, J = 21.3, 11.0 Hz, 1H); ¹³C

NMR (100 MHz, CDCl₃) δ = 144.3, 142.0, 134.1, 132.2, 128.3, 127.7,

127.6, 126.6, 125.9, 125.5, 125.4, 84.5 (d, J = 174.0 Hz), 52.8, 48.8 (d,

J = 31.2 Hz), 45.4 (d, J = 10.9 Hz), 39.9 (d, J = 18.8 Hz); ¹⁹F NMR

(376 MHz, CDCl₃) δ = −185.5 (d, J = 47.6 Hz). The NMR data were

in agreement with reported results.^21h

2-(1-Chloroethyl)-4,4-diphenyl-1-tosylpyrrolidine (5h). Com-

pound 5h was prepared according to the general procedure and

isolated as a white solid (131.2 mg, 60% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 40:1); mp = 166−

1

168 °C; H NMR (400 MHz, CDCl₃) δ = 7.47 (d, J = 8.2 Hz, 2H),

7.22−7.01 (m, 12H), 7.76−7.70 (m, 1H), 4.44 (d, J = 10.6 Hz, 1H),

3.98−3.90 (m, 1H), 3.83 (d, J = 10.6 Hz, 1H), 2.83−2.60 (m, 2H),

2.29 (s, 3H), 1.38 (d, J = 6.9 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ

= 144.4, 142.9, 141.8, 136.0, 128.4, 127.5, 127.5, 125.7, 125.6, 125.5,

125.5, 125.3, 63.0, 59.1, 57.9, 51.9, 36.4, 20.5, 20.5. HRMS−ESI (m/

z): [M + H]⁺calcd for C₂₅H₂₆ClNO₂S, 440.1451; found: 440.1453.

General Procedure for Intramolecular Fluoroamidation. The

reaction was carried out in an open air system. To a 100 mL ﬂask were

added 0.5 mmol alkenylamine, 0.55 mmol PhI(OAc)₂, 1 mmol BF₃·

OEt₂, 1 mmol pyridine, and 20 mL of CH₂Cl₂. The reaction mixture

was stirred at room temperature for an indicated period. The reaction

mixture was treated with sat. aqueous K₂CO₃(10 mL). The organic

phase was separated and the aqueous phase was extracted with CH₂Cl₂

(3 × 20 mL). The combined organic layer was washed with 1 N HCl,

dried over anhydrous MgSO₄and concentrated in vacuo to aﬀord the

crude product which was puriﬁed by ﬂash column chromatography.

5-Fluoro-3,3-diphenyl-1-tosylpiperidine (6a). Compound 6a was

prepared according to the general procedure and isolated as a white

solid (110.6 mg, 54% yield) after ﬂash chromatography (petroleum

5-Fluoro-3,3-dimethyl-1-tosylpiperidine (6e). Compound 6e was

prepared according to the general procedure and isolated as a white

solid (78.4 mg, 55% yield) after ﬂash chromatography (petroleum

1

ether:ethyl acetate = 30:1); mp = 83−84 °C; H NMR (400 MHz,

CDCl₃) δ = 7.57 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 4.81−

4.60 (dm, J = 43.3 Hz, 1H), 3.56−3.46 (m, 1H), 2.87 (d, J = 11.4 Hz,

1H), 2.60−2.53 (m, 1H), 2.36 (s, 3H), 2.32 (d, J = 11.4 Hz, 1H),

1.68−1.58 (m, 1H), 1.32−1.18 (m, 1H), 0.96 (s, 6H); ¹³C NMR (100

MHz, CDCl₃) δ = 143.8, 133.3, 129.8, 127.5, 85.8 (d, J = 175.3 Hz),

56.7, 49.8 (d, J = 28.6 Hz), 42.6 (d, J = 17.4 Hz), 31.9 (d, J = 7.4 Hz),

27.8, 25.9, 21.6; ¹⁹F NMR (376 MHz, CDCl₃) δ = −183.0 (d, J = 43.3

Hz). The NMR data were in agreement with reported results.^21h

4-Fluoro-2-tosyl-2-azaspiro[5.5]undecane (6f). Compound 6f was

prepared according to the general procedure and isolated as a white

solid (94.6 mg, 58% yield) after ﬂash chromatography (petroleum

1

ether:ethyl acetate = 20:1); mp = 104−105 °C; H NMR (400 MHz,

CDCl ₃) δ = 7.58 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 4.83−

4.59 (dm, J = 43.5 Hz, 1H), 3.58−3.51 (m, 1H), 3.12 (d, J = 11.6 Hz,

1H), 2.61−2.54 (m, 1H), 2.37 (s, 3H), 2.34 (d, J = 11.7 Hz, 1H),

1.82−1.69 (m, 1H), 1.48−1.11 (m, 11H); ¹³C NMR (100 MHz,

CDCl₃) δ = 143.7, 133.6, 129.8, 127.5, 86.4, 85.6 (d, J = 175.1 Hz),

84.7, 54.0, 50.2 (d, J = 28.6 Hz), 40.9, 36.3, 34.6 (d, J = 6.9 Hz), 33.9,

26.18, 21.6, 21.5, 21.3. ¹⁹F NMR (376 MHz, CDCl₃) δ = −182.5 (d, J

= 43.5 Hz). The NMR data were in agreement with reported results.^20f

3,3-Diallyl-5-ﬂuoro-1-tosylpiperidine (6g). Compound 6g was

prepared according to the general procedure and isolated as a white

solid (101.4 mg, 60% yield) after ﬂash chromatography (petroleum

1

ether:ethyl acetate = 30:1); mp = 165−166 °C; H NMR (400 MHz,

CDCl ₃) δ = 7.57 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 7.7 Hz, 2H), 7.26−

7.04 (m, 10H), 4.52 (dm, J = 47.2 Hz, 1H), 4.43 (d, J = 12.4 Hz, 1H),

4.00−3.93 (m, 1H), 2.97−2.83 (m, 1H), 2.35 (s, 3H), 2.32 (d, J = 12.4

Hz, 1H), 2.23−2.18 (m, 1H), 2.08 (dd, J = 21.3, 11.0 Hz, 1H); ¹³C

NMR (100 MHz, CDCl₃) δ = 145.4, 144.1, 143.2, 132.1, 129.9, 128.7,

128.6, 127.8, 127.8, 126.9, 126.6, 126.5, 85.6 (d, J = 173.6 Hz), 53.9,

49.9 (d, J = 31.3 Hz), 46.5, 41.1 (d, J = 18.7 Hz), 21.6; ¹⁹F NMR (376

MHz, CDCl₃) δ = −185.5 (d, J = 47.7 Hz). The NMR data were in

agreement with reported results.^21h

5-Fluoro-1-(methylsulfonyl)-3,3-diphenylpiperidine (6b). Com-

pound 6b was prepared according to the general procedure and

isolated as a white solid (103.3 mg, 62% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 30:1); mp = 161−

162 °C; ¹H NMR (400 MHz, CDCl₃) δ = 7.59−6.25 (m, 10H), 4.61−

4.43 (m, 2H), 3.97 (dd, J = 10.3, 5.1 Hz, 1H), 2.97 (t, J = 11.0 Hz,

1H), 2.88 (d, J = 12.6 Hz, 1H), 2.71 (dd, J = 10.1, 5.8 Hz, 1H), 2.67 (s,

3H), 2.31 (dd, J = 21.7, 10.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ

= 144.1, 141.9, 127.7, 127.7, 126.5, 125.9, 125.6, 125.4, 84.4 (d, J =

174.5 Hz), 52.8, 48.7 (d, J = 30.8 Hz), 45.6 (d, J = 10.3 Hz), 40.1 (d, J

= 18.7 Hz), 33.6; ¹⁹F NMR (376 MHz, CDCl₃) δ = −184.9 (d, J =

47.3 Hz). The NMR data were in agreement with reported results.^21h

5-Fluoro-1-(4-nitrophenylsulfonyl)-3,3-diphenylpiperidine (6c).

Compound 6c was prepared according to the general procedure and

isolated as a white solid (101.4 mg, 46% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 20:1);mp = 205−

1

ether:ethyl acetate = 40:1); mp = 62−63 °C; H NMR (400 MHz,

CDCl₃) δ = 7.57 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 5.76−

5.63 (m, 2H), 5.12−4.95 (m, 4H), 4.84−4.60 (dm, J = 43.5 Hz, 1H),

3.54−3.41 (m, 1H), 2.95 (d, J = 11.6 Hz, 1H), 2.64−2.56 (m, 1H),

2.39 (d, J = 11.7 Hz, 1H), 2.37 (s, 3H), 2.13−1.99 (m, 4H), 1.73−1.64

(m, 1H), 1.34−1.26 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ =

143.8, 133.1, 132.8, 132.6, 129.8, 127.6, 119.2, 119.1, 85.5 (d, J = 175.6

Hz), 53.6, 49.9 (d, J = 28.3 Hz), 40.9, 39.1, 38.3 (d, J = 18.0 Hz), 37.5

(d, J = 6.4 Hz), 21.6; ¹⁹F NMR (376 MHz, CDCl ₃) δ = −182.1 (d, J =

43.5 Hz). IR (KBr): 3065, 2929,1638, 1596, 1448, 1341, 1163, 1097,

923, 812, 710, 655 cm⁻¹; HRMS-ESI (m/z): [M + H] ⁺calcd for

C₁₈H₂₄FNO₂S, 338.1590; found: 338.1584.

3-Fluoro-1-tosylpiperidine (6h). Compound 6h was prepared

according to the general procedure and isolated as a white solid

(51.6 mg, 40% yield) after ﬂash chromatography (petroleum

1

ether:ethyl acetate = 20:1);mp = 101−103 °C; H NMR (400 MHz,

206 °C; H NMR (400 MHz, CDCl₃) δ = 8.30 (d, J = 8.7 Hz, 2H),

CDCl₃) δ = 7.59 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 4.60

(dm, J = 47.4, 1H), 3.34−3.35 (m, 1H), 3.10−3.00 (m, 1H), 2.95−

2.89 (m, 1H), 2.87−2.76 (m, 1H), 2.37 (s, 3H), 1.86−1.68 (m, 2H),

1.59−1.53 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ = 143.7, 133.4,

129.7, 127.7, 86.1 (d, J = 176.3 Hz), 49.7 (d, J = 26.8 Hz), 45.8, 29.3

(d, J = 20.0 Hz), 21.6, 21.2 (d, J = 7.0 Hz); ¹⁹F NMR (376 MHz,

CDCl₃) δ = −182.7 (m). The NMR data were in agreement with

reported results.^20f

1-Benzyl-5-iodo-3,3-diphenylpiperidine (7a). Compound 7a was

prepared according to the general procedure and isolated as an oil

(176.3 mg, 78% yield) after ﬂash chromatography (petroleum

ether:ethyl acetate = 100:1); ¹H NMR (400 MHz, CDCl₃) δ =

7.33−6.85 (m, 15H), 4.07−3.96 (m, 1H), 3.59 (d, J = 11.8 Hz, 1H),

3.50 (s, 2H), 3.25 (dd, J = 10.5, 3.8 Hz, 1H), 3.13 (d, J = 12.8 Hz, 1H),

2.58 (t, J = 12.7 Hz, 1H), 2.44 (t, J = 11.0 Hz, 1H), 2.29 (d, J = 12.1

Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ = 147.3, 144.6, 137.6, 137.5,

130.3, 129.3, 128.7, 128.4, 128.1, 127.4, 126.4, 125.9, 63.9, 62.4, 61.9,

7.87 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 7.7 Hz, 2H), 7.29 (t, J = 7.7 Hz,

2H), 7.21−7.13 (m, 4H), 7.07 (d, J = 7.4 Hz, 2H), 4.61−4.52 (dm, J =

47.5 Hz, 1H), 4.45 (d, J = 13.5 Hz, 1H), 4.02−3.94 (m, 1H), 2.92 (t, J

= 9.9 Hz, 1H), 2.46 (d, J = 12.3 Hz, 1H), 2.35−2.28 (m, 1H), 2.14

(dd, J = 21.6, 10.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ = 150.4,

144.9, 142.7, 141.1 128.9, 128.9, 128.8, 127.5, 127.2, 126.8, 126.4,

124.6, 85.1 (d, J = 175.0 Hz), 53.9, 49.7 (d, J = 31.4 Hz), 46.6 (d, J =

10.9 Hz), 40.9 (d, J = 18.6 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ =

−185.3 (d, J = 47.5 Hz). IR (KBr): 3031, 2961, 1600, 1499, 1355,

1167, 798, 754, 700, 661, 603 cm⁻¹; HRMS-ESI (m/z): [M + H]

⁺calcd for C₂₃H₂₁FN₂O₄S, 441.1284; found: 441.1273.

5-Fluoro-3,3-diphenyl-1-(phenylsulfonyl)piperidine (6d). Com-

pound 6d was prepared according to the general procedure and

isolated as a white solid (108.4 mg, 55% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 30:1); mp = 178−

1

179 °C; H NMR (400 MHz, CDCl₃) δ = 7.70 (d, J = 7.3 Hz, 2H),

7.55 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.40 (d, J = 7.6 Hz,

M

dx.doi.org/10.1021/jo501739j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

+

50.2, 48.8, 23.1. HRMS-ESI (m/z): [M + H] calcd for C₂₄H₂₄IN,

454.1032; found: 454.1073.

2-Benzyl-4-bromo-2-azaspiro[5.5]undecane (7h). Compound 7h

was prepared according to the general procedure and isolated as an oil

(143.6 mg, 89% yield) after ﬂash chromatography (petroleum

5-Iodo-1-(4-methoxybenzyl)-3,3-diphenylpiperidine (7b). Com-

pound 7b was prepared according to the general procedure and

isolated as an oil (192.8 mg, 80% yield) after ﬂash chromatography

(petroleum ether:ethyl acetate = 100:1); ¹H NMR (400 MHz, CDCl₃)

δ = 7.25−7.04 (m, 10H), 6.99 (d, J = 7.5 Hz, 2H), 6.79 (d, J = 8.4 Hz,

2H), 4.04−3.94 (m, 1H), 3.73 (s, 3H), 3.58 (d, J = 12.1 Hz, 1H), 3.46

(d, J = 13.0 Hz, 1H), 3.40 (d, J = 13.0 Hz, 1H), 3.27−3.19 (m, 1H),

3.12 (d, J = 12.6 Hz, 1H), 2.57 (t, J = 12.7 Hz, 1H), 2.42 (t, J = 11.0

Hz, 1H), 2.23 (d, J = 12.1 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ =

157.9, 146.2, 143.6, 129.4, 128.5, 127.7, 127.3, 127.0, 126.1, 125.3,

124.8, 112.6, 62.8, 60.6, 60.6, 54.2, 49.1, 47.8, 22.2. HRMS-ESI (m/z):

1

ether:ethyl acetate = 70:1); H NMR (400 MHz, CDCl₃) δ = 7.23−

7.15 (m, 5H), 4.20−4.14 (m, 1H), 3.48 (d, J = 13.4 Hz, 1H), 3.35 (dd,

J = 13.4, 5.4 Hz, 1H), 3.15 (dd, J = 10.5, 4.3 Hz, 1H), 2.65 (d, J = 11.3

Hz, 1H), 2.19 (dd, J = 11.0, 1.8 Hz, 1H), 2.12 (t, J = 10.8 Hz, 1H),

1.57 (d, J = 11.3 Hz, 2H), 1.36−1.08 (m, 10H). ¹³C NMR (100 MHz,

CDCl₃) δ = 137.6, 127.5, 127.2, 126.0, 62.1, 61.3, 45.3, 37.3, 36.1,

31.6, 25.6, 20.5, 20.5. The NMR data were in agreement with reported

results.^17c

1-Benzyl-2-(chloromethyl)-4,4-diphenylpyrrolidine (7i). Com-

pound 7i was prepared according to the general procedure and

isolated as an oil (115.8 mg, 64% yield) after ﬂash chromatography

(petroleum ether:ethyl acetate = 100:1); ¹H NMR (400 MHz, CDCl₃)

δ = 7.54−7.27 (m, 15H), 4.20 (d, J = 13.2, 1H), 4.01 (d, J = 9.8, 1H),

3.74 (d, J = 13.2, 1H), 3.50 (dd, J = 10.4, 4.2, 1H), 3.40−3.35 (m,

1H),3.17−3.07 (m, 3H), 2.79 (dd, J = 13.1, 3.4,1H). ¹³C NMR (100

MHz, CDCl₃) δ = 129.4, 128.7, 128.6, 128.5, 128.3, 127.9, 127.4,

127.3, 126.9, 126.6, 126.3, 126.0, 65.3, 64.4, 59.7, 53.0, 47.3, 42.5. The

NMR data were in agreement with reported results.^17a

+

[M + H] calcd for C₂₅H₂₆INO, 484.1137; found: 484.1139.

1-(4-Fluorobenzyl)-5-iodo-3,3-diphenylpiperidine (7c). Com-

pound 7c was prepared according to the general procedure and

isolated as an oil (181.6 mg, 77% yield) after ﬂash chromatography

(petroleum ether:ethyl acetate = 100:1); ¹H NMR (400 MHz, CDCl₃)

δ = 7.21−6.84 (m, 14H), 4.03−4.95 (m, 1H), 3.55 (d, J = 12.1 Hz,

1H), 3.47−3.36 (m, 2H), 3.19 (dd, J = 10.5, 3.7 Hz, 1H), 3.12 (d, J =

12.7 Hz, 1H), 2.55 (t, J = 12.7 Hz, 1H), 2.47−2.38 (m, 1H), 2.23 (dd,

J = 21.2, 8.4 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ = 161.1 (d, J =

245.4 Hz), 146.1, 143.4, 132.2 129.6 (d, J = 7.8 Hz), 127.5, 127.3,

127.1, 125.3, 125.2, 124.9, 114.09 (d, J = 21.1 Hz), 62.7, 60.7, 60.4,

49.0, 47.6, 21.8. ¹⁹F NMR (376 MHz, CDCl₃) δ = −115.0; HRMS-ESI

(m/z): [M + H]⁺calcd for C₂₄H₂₃FIN, 472.0937; found: 472.0925.

1-Benzyl-5-bromo-3,3-diphenylpiperidine (7d). Compound 7d

was prepared according to the general procedure and isolated as an

oil (172.1 mg, 85% yield) after ﬂash chromatography (petroleum

ether:ethyl acetate = 100:1); ¹H NMR (400 MHz, CDCl₃) δ = 7.26−

6.98 (m, 15H), 3.90−3.85 (m, 1H), 3.49 (q, J = 13.2 Hz, 3H), 3.18

(dd, J = 10.4, 3.8 Hz, 1H), 3.01 (d, J = 12.5 Hz, 1H), 2.40 (t, J = 12.4

Hz, 1H), 2.30−2.18 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ =

147.4, 144.8, 137.6, 129.4, 128.7, 128.5, 128.2, 127.5, 126.5, 126.1,

62.6, 62.0, 49.2, 46.8, 45.5. The NMR data were in agreement with

reported results.^17c

2-(Chloromethyl)-1-(4-methylbenzyl)-4,4-diphenylpyrrolidine

(7j). Compound 7j was prepared according to the general procedure

and isolated as an oil (135.3 mg, 72% yield) after ﬂash

1

chromatography (petroleum ether:ethyl acetate = 100:1); H NMR

(400 MHz, CDCl₃) δ = 7.29−7.05 (m, 14H), 3.95 (d, J = 13.1, 1H),

3.78 (d, J = 9.8, 1H), 3.51 (s, 1H), 3.28 (dd, J = 10.3, 3.8, 1H), 3.17−

3.14 (m, 1H), 2.95−2.84 (m, 3H), 2.56 (dd, J = 13.1, 2.5, 1H), 2.32 (s,

3H). ¹³C NMR (100 MHz, CDCl₃) δ = 129.4, 129.3, 128.8, 128.7,

128.5, 128.3, 128.2, 127.4, 126.9, 126.6, 126.3, 125.9, 65.2, 64.3, 59.4,

52.9, 47.3, 42.5, 21.4. The NMR data were in agreement with reported

results.^17a

N-(2-Iodo-2-phenylethyl)-4-methylbenzenesulfonamide (8).

Compound 8 was prepared according to the general procedure and

isolated as a white solid (126.4 mg, 63% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 50:1); mp = 117−

1

118 °C; H NMR (400 MHz, CDCl₃) δ = 7.64 (d, J = 8.2 Hz, 2H),

5-Bromo-1-(4-methoxybenzyl)-3,3-diphenylpiperidine (7e). Com-

pound 7e was prepared according to the general procedure and

isolated as a white solid (191.1 mg, 88% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 80:1); mp = 88−

7.25 (d, J = 8.1 Hz, 2H), 7.20−7.18 (m, 5H), 4.94 (t, J = 7.8 Hz, 1H),

4.69 (t, J = 6.4 Hz, 1H), 3.66−3.59 (m, 1H), 3.48−3.41 (m, 1H), 2.38

(s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ = 143.9, 139.9, 137.0, 129.9,

129.1, 128.8, 127.6, 127.1, 51.3, 29.9, 21.6. The NMR data were in

1

91 °C; H NMR (400 MHz, CDCl₃) δ = 7.41−6.92 (m, 12H), 6.78

33

agreement with reported results.

(d, J = 7.7 Hz, 2H), 3.87 (t, J = 11.3 Hz, 1H), 3.71 (s, 3H), 3.51 (d, J =

12.1 Hz, 1H), 3.44 (s, 2H), 3.21−3.16 (m, 1H), 3.01 (d, J = 12.3 Hz,

1H), 2.40 (t, J = 12.4 Hz, 1H), 2.30−2.14 (m, 2H). ¹³C NMR (100

MHz, CDCl₃) δ = 159.0, 147.4, 144.8, 130.5, 129.3, 128.7, 128.4,

128.1, 127.8, 126.4, 125.9, 113.7, 61.9, 61.9, 61.7, 55.3, 49.2, 46.8, 45.6.

The NMR data were in agreement with reported results.^17c

1

Compounds 9a and 9b could be separated. H NMR (400 MHz,

CDCl₃) δ = 7.73 (d, 2H, J = 8.4 Hz, 9a); 7.62 (d, J = 8.4 Hz, 9b),

7.19−7.34 (m, 9a and 9b), 7.10−7.13 (m, 9b), 5.38 (d, J = 6.7 Hz,

9b), 4.92 (t, J = 6.4 Hz, 9a), 4.82 (dd, J = 13.9, 6.2 Hz, 9a), 4.570 (q, J

= 6.2 Hz, 9b), 3.61−3.41(m, 9a and 9b), 2.36 (s, 9a), 2.31 (s, 9b). ¹³C

NMR (100 MHz, CDCl₃) (9a + 9b) δ = 143.9, 143.6, 138.2, 137.7,

136.9, 136.9, 129.9, 129.6, 129.2, 129.1, 128.7, 128.3, 127.7, 127.2,

127.1, 126.8, 58.1, 52.6, 50.1, 36.7, 21.6, 21.6. The NMR data were in

agreement with reported results.³⁶

5-(Iodomethyl)-3,3-diphenyldihydrofuran-2(3H)-one (10a). Com-

pound 10a was prepared according to the general procedure and

isolated as a white solid (156.9 mg, 83% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 60:1); mp = 115−

117 °C; ¹H NMR (400 MHz, CDCl₃) δ = 7.42−7.23 (m, 10H), 4.27−

4.18 (m, 1H), 3.44 (dd, J = 10.3, 4.8 Hz, 1H), 3.33 (dd, J = 10.3, 7.1

Hz, 1H), 3.09 (dd, J = 12.7, 4.8 Hz, 1H), 2.80 (dd, J = 12.7, 10.1 Hz,

1H); ¹³C NMR (100 MHz, CDCl₃) δ = 175.3, 142.1, 140.8, 128.9,

128.6, 128.2, 127.9, 127.7, 127.5, 76.5, 59.9, 45.8, 6.7. The NMR data

were in agreement with reported results.³⁷

5-(Bromomethyl)-3,3-diphenyldihydrofuran-2(3H)-one (10b).

Compound 10b was prepared according to the general procedure

and isolated as a white solid (132.3 mg, 80% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 40:1); mp = 86−88

°C; ¹H NMR (400 MHz, CDCl₃) δ = 7.40−7.01 (m, 10H), 4.51−4.44

(m, 1H), 3.53 (dd, J = 10.8, 4.7 Hz, 1H), 3.44 (dd, J = 10.8, 6.5 Hz,

1H), 3.09 (dd, J = 13.2, 5.2 Hz, 1H), 2.74 (dd, J = 13.2, 9.9 Hz, 1H);

¹³C NMR (100 MHz, CDCl₃) δ = 176.2, 141.5, 139.4, 129.1, 128.5,

5-Bromo-1-(4-nitrobenzyl)-3,3-diphenylpiperidine (7f). Com-

pound 7f was prepared according to the general procedure and

isolated as a white solid (187.2 mg, 83% yield) after ﬂash

chromatography (petroleum ether:ethyl acetate = 60:1); mp = 149−

1

151 °C; H NMR (400 MHz, CDCl₃) δ = 8.10 (d, J = 8.6 Hz, 2H),

7.36 (d, J = 8.6 Hz, 2H), 7.29−7.06(m, 8H), 7.04(d, J = 7.3 Hz, 2H),

3.94−3.87 (m, 1H), 3.66−3.50 (m, 3H), 3.12 (dd, J = 10.2, 4.6 Hz,

1H), 3.06 (d, J = 12.8 Hz, 1H), 2.43−2.29 (m, 3H). ¹³C NMR (100

MHz, CDCl₃) δ = 146.3, 145.8, 144.4, 143.3, 128.6, 127.4, 127.3,

127.2, 125.5, 125.3, 125.1, 122.6, 61.15, 60.8, 60.5, 48.1, 45.3, 43.6.

The NMR data were in agreement with reported results.^17c

1-Benzyl-5-bromo-3,3-dimethylpiperidine (7g). Compound 7g

was prepared according to the general procedure and isolated as an

oil (119.5 mg, 85% yield) after ﬂash chromatography (petroleum

1

ether:ethyl acetate = 100:1); H NMR(400 MHz, CDCl₃) δ = 7.29−

7.16 (m, 5H), 4.19−4.13 (m, 1H), 3.48 (d, J = 13.4 Hz, 1H), 3.35 (d, J

= 13.4 Hz, 1H), 3.15 (d, J = 6.6 Hz, 1H), 2.35 (d, J = 11.1 Hz, 1H),

2.07 (t, J = 10.8 Hz, 1H), 1.99−1.94 (m, 1H),1.70 (d, J = 11.0 Hz,

1H), 1.46 (t, J = 12.5 Hz, 1H), 0.99 (s, 3H), 0.80 (s, 3H). ¹³C NMR

(100 MHz, CDCl₃) δ = 137.4, 127.6, 127.2, 126.0, 63.4, 61.4, 61.2,

48.2, 45.4, 33.4, 28.2, 23.8. The NMR data were in agreement with

reported results.^17c

N

dx.doi.org/10.1021/jo501739j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

127.9, 127.7, 127.5, 127.3, 74.9, 58.2, 42.2, 32.7. The NMR data were

in agreement with reported results.³⁸

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ASSOCIATED CONTENT

■

S

* Supporting Information

Copies of NMR spectra for the obtained compounds and X-ray

structure and crystal information ﬁle for compound 2v. This

material is available free of charge via the Internet at http://

pubs.acs.org.

AUTHOR INFORMATION

■

Corresponding Author

*E-mail: ymli@nankai.edu.cn

Notes

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L.; Li, Y.-M. Tetrahedron 2013, 69, 5867−5873. (c) Liu, G.-Q.; Ding,

Z.-Y.; Zhang, L.; Li, T.-T.; Li, L.; Duan, L.; Li, Y.-M. Adv. Synth. Catal.

2014, 356, 2303−2310.

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We acknowledge the ﬁnancial support from National Natural

Science Foundation of China (NSFC 20972072, NSFC

21272121). G.-Q.L. acknowledges the support from The

Ph.D. Student Innovative Research Program of Nankai

University (68140001).

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Regioselective (Diacetoxyiodo)benzene-promoted halocyclization of unfunctionalized olefins

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