Iodoarene-Catalyzed Oxyamination of Unactivated Alkenes to Synthesize 5-Imino-2-Tetrahydrofuranyl Methanamine Derivatives

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Iodoarene-Catalyzed Oxyamination of Unactivated Alkenes to

Synthesize 5‑Imino-2-Tetrahydrofuranyl Methanamine Derivatives

Xiao-Jun Deng, Hui-Xia Liu, Lu-Wen Zhang, Guan-Yu Zhang, Zhi-Xiang Yu,* and Wei He*

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ABSTRACT: Reported here is the room-temperature metal-free

iodoarene-catalyzed oxyamination of unactivated alkenes. In this

process, the alkenes are difunctionalized by the oxygen atom of the

amide group and the nitrogen in an exogenous HNTs₂molecule. This

mild and open-air reaction provided an eﬃcient synthesis to N-bistosyl-

substituted 5-imino-2-tetrahydrofuranyl methanamine derivatives, which

are important motifs in drug development and biological studies.

Mechanistic study based on experiments and density functional theory

calculations showed that this transformation proceeds via activation of the substrate alkene by an in situ generated cationic

iodonium(III) intermediate, which is subsequently attacked by an oxygen atom (instead of nitrogen) of amides to form a ﬁve-

membered ring intermediate. Finally, this intermediate undergoes an S_N2 reaction by NTs₂as the nucleophile to give the oxygen and

nitrogen difunctionalized 5-imino-2-tetrahydrofuranyl methanamine product. An asymmetric variant of the present alkene

oxyamination using chiral iodoarenes as catalysts also gave promising results for some of the substrates.

Recently, hypervalent iodine(III) reagents generated in situ

through the oxidation of iodoarenes have been used as green

alternatives to transition metals in the oxidative difunctional-

ization reaction- of alkenes.⁸Based on this strategy, various

iodoarene-catalyzed reactions have been developed, including

aminoﬂuorination,⁹dioxygenation,¹⁰diamination,¹¹diﬂuorina-

tion,¹²and others.¹³Surprisingly, iodoarene-catalyzed oxy-

amination cyclizations that simultaneously generate both C−O

and C−N bonds have rarely been reported. Although there are

several reports about hypervalent iodine-mediated intra-

molecular oxyamination cyclization of alkenes (Scheme 1b),

these reactions required stoichiometric amounts of hypervalent

iodine compounds, and the oxygen and nitrogen functional

groups need to be tethered in the substrate.¹⁴Inspired by

recent advances of iodoarene catalysis, we envisioned that the

traditional oxyamination cyclization reactions catalyzed by

transition metals could be replaced by iodoarenes. However,

there are two main challenges including the control of

chemoselectivity and the compatibility of nitrogen nucleo-

philes in an oxidizing environment. We speculated that this

transformation could be achieved by choosing an appropriate

iodoarene and oxidant in a suitable catalytic system.

INTRODUCTION

■

The oxyamination of alkenes can be used to synthesize useful

1,2-amino alcohol derivatives.¹A number of useful strategies

for alkene oxyamination have been developed, and the majority

of which are based on catalysis by transition metals such as

copper,²palladium,³osmium,⁴rhodium,⁵iron,⁶and others⁷

(Scheme 1a). However, some limitations of these reactions,

including prior synthesis of the coupling components, the use

of electron-rich nitrogen sources, and high reaction temper-

ature, have been encountered.

Scheme 1. Related Works Regarding the Oxyamination of

Alkenes

Received: August 25, 2020

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A

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a

Table 1. Optimization of Reaction Conditions

a

b

The reactions were conducted on 1a (0.2 mmol, 1.0 equiv) with HNTs₂(1.5 equiv) at room temperature for 7 h unless noted otherwise. Isolated

c

d

e

yield The ratio of 3a/3a′ was determined by the ¹H NMR spectrum The reaction time was extended to 15 h The reaction was conducted at 0

°C.

Herein, we report the practical iodoarene-catalyzed oxy-

amination reaction of unactivated alkenes (Scheme 1c). This

process uses HNTs₂as an exogenous nitrogen source to access

diverse 5-imino-2-tetrahydrofuranyl methanamine derivatives.

In addition, the reaction mechanism and regiochemistry have

also been investigated. Besides, an asymmetric version of this

reaction has been tested, ﬁnding that several substrates can

provide high enantioselectivity in the present alkene

difuctionalization. Furthermore, the products from the present

reaction are important motifs in drug development and

biological studies. For example, the structure analogues were

found to be studied as muscarinic receptors,¹⁵cardiac

arrhythmias inhibitors,¹⁶and inhibitors for the binding of

HIV GP120 to the CD4 receptor.¹⁷The present methodology

could become an eﬃcient approach to synthesize useful

compounds for future pharmaceutical investigation.

(CH₂Cl₂) at room temperature. The 3a/3a′ molar ratio was

2:1 with a 13% total yield (Table 1, entry 1). In addition, the

hydroxylation product 3a″ was isolated in 34% yield. This

compound originated from a side reaction of the unsaturated

amide 1a with mCPBA.¹⁸No diamination product was

detected, even though this is the major product resulting

from copper-catalyzed cyclization reactions.^2fAn extensive

solvent screening determined that hexaﬂuoroisopropanol

(HFIP) remarkably promoted the transformation. (Table S1)

The oxyamination reaction became dominant when HFIP was

used,¹⁹and gave 3a and 3a′ in 47% yield with slightly

increased regioselectivity (3a/3a′ 3:1, entry 2). The yield and

regioselectivity of the target compound were further improved

by increasing the catalyst loading to 15 mol % and the amount

of mCPBA to 1.5 equiv (entries 3 and 4), while further

increasing the amount of oxidant obtained a slightly lower

yield (entry 5). Among the diﬀerent oxidants tested, mCPBA

gave the best result for this reaction. (Table S3) To further

screen the reaction conditions, a variety of iodoarene catalysts

(2b−o) were investigated. (Table S4) Among these, 2,6-

dimethoxy iodobenzene 2h displayed the best catalytic activity,

aﬀording the target molecule in 89% yield with good

regioselectivity (3a/3a′ 8:1, entry 6). Satisfactory regioselec-

tivity (3a/3a′ 15:1) was obtained when 2j was used as the

RESULTS AND DISCUSSION

■

As an initial investigation, N-phenyl-2,2-dimethyl-4-pentena-

mide 1a was chosen as a model substrate and reacted with

various nitrogen-based nucleophiles. Products 3a (5-exo) and

3a′ (6-endo) were obtained when HNTs₂was used together

with 1-iodo-4-methoxybenzene (2a, 10 mol %) as a catalyst

and mCPBA (1.2 equiv) as an oxidant in dichloromethane

B

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a

Table 2. Substrate Scope of the Oxyamination

a

The reactions were conducted on a 0.2 mmol scale with 2h (15 mol %), HNTs₂(1.5 equiv), and mCPBA (1.5 equiv) at room temperature for 7 h

b

c

d

unless noted otherwise. Isolated yield. The ratio of 5-exo/6-endo as determined by the ¹H NMR spectrum. The reaction time was extended to 15

h. Using 2j (15 mol %) as the catalyst. dr = diastereoselectivity as determined by the H NMR spectrum. With an HFIP/tert-BuOMe mixture

e

f

g

1

(1:1, v/v) as the solvent.

catalyst, albeit with slightly lower yield (79%, entry 7).

Meanwhile, excellent regioselectivity (3a/3a′ 24:1) was

obtained when 2i was used as the catalyst, but the catalytic

activity was reduced (entry 8). These results indicated that the

ortho alkoxy substitution is beneﬁcial to the transformation,²⁰

and it was also apparent that catalysts with diﬀerent alkoxyl

substituents between their 2- and 6-positions produced higher

regioselectivity compared to more symmetric catalysts. Using

an HFIP/tert-BuOMe mixture as the solvent in an attempt to

inhibit the hydroxylation reaction resulted in both a reduced

yield (54%) and poor regioselectivity (entry 9).^11gThe

reaction temperature was found to be crucial, such that the

yield of the oxyamination products was only 31% at 0 °C

(entry 10).

tolerated in the reaction, aﬀording the desired oxyamination

products (3a−g) in good yields (62%−91%) and with good

regioselectivities. The structures of products 3c and 3f were

established by X-ray crystallographic analysis.²¹N-benzyl and

N-methoxyl substituted substrates were compatible with the

reaction, giving 3h in 55% yield and 3i in 80% yield,

respectively. The 2,2-diphenyl pentenamides with more highly

sterically hindered were also found to undergo the trans-

formation smoothly and give 3j in 95% yield with good

regioselectivity. Interestingly, single 5-exo oxyamination

products (3k−q) were obtained with excellent yields (85−

99%), and these good results can be understood by the

Thorpe−Ingold eﬀect. The 2,2-diphenyl pentenamide with N-

benzyl and N-methoxyl protecting groups were determined to

function as suitable substrates for the reaction, giving 3r and 3s

in 93% and 85% yields, respectively. In addition, substrates

with diﬀerent alkyl group substituents were compatible with

the reaction, aﬀording the corresponding tetrahydrofuranyl

methanamine products 3t and 3u in 92% and 94% yields,

With the optimized conditions in hand, various substituted

pentenamides were examined (Table 2). The eﬀects of

substituents on the N-phenyl group of the 2,2-dimethyl

pentenamide were initially assessed. The results showed that

both electron-rich and electron-deﬁcient substrates were

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respectively. To further investigate the substrate scope, various

unsaturated amides with more complex substitutions were

examined, giving corresponding products 3v−z in good yields

with trans conﬁguration predominant, which demonstrated by

the X-ray crystallographic analysis of 3w. Furthermore,

substrates with diﬀerent alkyl ring sizes could also be applied

to the reaction under the standard conditions, giving the

corresponding spiro-tetrahydrofuranyl methanamine products

(3aa−ac) in 79−91% yields. It is noteworthy that substrates

bearing heterocycles were also suitable, aﬀording the

corresponding azabicyclo 3ad and oxybicyclo 3ae in good

yields with high regioselectivities. Moreover, using a HFIP/

tert-BuOMe mixed solvent, the products 3af−ah with

quaternary carbon centers can be obtained in 52−72% yields.

Furthermore, substrates bearing a quaternary carbon center

also worked well under the standard conditions, giving the

oxyamination products 3ai−al in good yields (62−77%), and

these products have been found to function as cardiac

arrhythmia inhibitor candidates.¹⁶Further upscaling of the

oxyamination was facile and allowed us to prepare 3am on a

4.1 g scale in 63% yield. Notably, this product could potentially

serve as a precursor for the synthesis of tricyclic anti-

depressants.²²Unfortunately, 1an and 1am were unsuitable

for this oxyamination, which may indicate that the Thorpe−

Ingold eﬀect was an essential factor for the transformation.

Surprisingly, the aromatic skeleton structure substrate was

incompatible with the oxyamination but gave 3ap as the major

product, which originated from the elimination reaction of

benzylic hydrogen and hypervalent iodine(III),²³and the

detailed discussion of this process was present in our latest

study.^23d

On the basis of these data, a possible reaction mechanism

was proposed (Scheme 2). In this process, bisimido iodine(III)

compound I (generated in situ from Ar−I, HNTs₂and

mCPBA) exists in equilibrium with the electrophilic cationic

iodine(III) species in solution,^8f,11gwhich binds to and

activates the oleﬁn in the substrate for the nucleophilic attack,

giving the iodonium ion intermediate (Int1A). The oxygen

atom of the amide group subsequently attacks the activated

alkene in an intramolecular fashion, giving alkyl-iodine(III)

intermediate (Int2A) through Ts1A. Then, the iodine(III)

group of Int2A acts as a leaving group, enabling the

intermolecular S_N2 attack of ⁻NTs₂to regenerate the

iodoarene(Ar−I) and release the oxyamination product

through Ts2A.²⁴The dioxygenation byproduct generation

proceeds via oxidation of the substrate alkene by an in situ

generated epoxide intermediate (Int1E), which is subsequently

attacked by the carbonyl oxygen through Ts1E under the

acidic conditions.

To better understand the reaction mechanism and ration-

alize the preference for 5-exo products over 6-endo products,

DFT calculations were performed for a model reaction using

iodobenzene as catalyst and HNMs₂as the nitrogen source.

The results are shown in Figures 1 and 2. Initially, the

dissociation of the bisimido iodine(III) compound gives the

reactive (and high energy) cationic iodine fragment

[PhINMs₂]⁺, which is subsequently converted to Int1 upon

coordinating to the substrate. This intermediate then under-

goes the intramolecular cyclization reaction, which is also the

rate-determining step of the overall reaction, to give one of the

four possible products. Several other transition states for

diﬀerent nucleophile attacks by O and N to give 5- and 6-

membered rings have been computed, and their relative

energies are given, suggesting that the O-5-exo Ts1A is the

most favorable, while the O-6-endo Ts1B is slightly higher in

energy. These results suggest that the tetrahydrofuran would

be the major product, consistent with the experimental results.

It is known that the nitrogen in an amide moiety is usually less

nucleophilic than carbonyl oxygen,²⁵both transition states

Ts1C and Ts1D, which correspond to the intramolecular

nucleophilic attack by a nitrogen atom, are much higher in

energy. The resulting alkyl-iodine(III) intermediate Int2A

subsequently undergoes a direct S_N2 attack by an Ms₂N⁻

anion, resulting in the formation of the protonated ProdA and

the release of the iodobenzene catalyst. It is also possible for

the deprotonation to proceed ﬁrst, followed by S_N2 reaction

via Ts2A′ for this process (see note).²⁶Finally, a proton can be

abstracted from the protonated product by Ms₂N⁻to give the

neutral product, although this is an endergonic process. This

may indicate that in the presence of an excess of the acidic

Ms₂NH, the relatively basic product would remain protonated

until workup.

Control experiments were performed to obtain more

information regarding this transformation. The results showed

that the oxyamination did not proceed without the iodoarene

catalyst, such that only the hydroxylation product was obtained

(entry 1, Table 3). Then, replacing both 15 mol % 2h and 1.5

a

Table 3. Control Experiments

3a+3a′

3a/

3a″

b

entry

1

conditions

yield (%) 3a′

(%)

mCPBA (1.5 equiv), HNTs₂(1.5 equiv),

78

3 h

2

3

PhI(NTs₂)₂(1.2 equiv), 0.5 h

2h (15 mol %), mCPBA (1.5 equiv),

NaNTs₂(1.5 equiv), 15 h

83

1:1

19

a

The reactions were conducted in 1 mL of HFIP with 0.1 mmol 1a as

b

1

the substrate. Determined by the H NMR spectrum.

To demonstrate the practicability of this oxyamination,

further transformations of 3j was conducted (Scheme 3). The

useful 1-amino-5-anilinopentan-2-ol derivatives 4c and 4f were

obtained by simple reduction and deprotection.²⁷Additionally,

hydrolysis and deprotection of 3j gave the important

intermediate 4h. Subsequently, the 5-aminomethyldihydrofur-

an-2-one skeletons 4i and 4k were obtained from 4h by the

process of reductive amination and acetylation reactions,

respectively. These compounds could serve as potential

precursors for the preparation of antimuscarinics. Furthermore,

tetrahydrofurfurylamine molecular 4j with similar a structure

equiv of mCPBA directly with 1.2 equiv of PhI(NTs₂)₂

resulted in a shorter reaction time and considerably high

yield (entry 2). Finally, using NaNTs₂instead of HNTs₂to

prevent the formation of the bisimido iodine(III) and rendered

the reaction ineﬀective (entry 3). These results indicate that

the bisimido iodine(III) species generated in situ via the

oxidation of the iodoarene(I) and mCPBA catalyzed the

reaction.

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Scheme 2. Proposed Reaction Mechanism

investigated (Table 4). Solvents screening results show that

triﬂuorotoluene was most suitable for the asymmetric oxy-

amination, while HFIP could only obtain the racemic product

(entries 1 and 2). Then, a series of chiral iodoarene

compounds were synthesized and examined (entries 3−8),

and the results show that the chiral iodoarene with tertiary

amide side chain was conducive to chiral induction, while

secondary amine and ester structures were less eﬀective.

Finally, 94% ee of 3j* was obtained when 5g was used as a

catalyst. Under optimized conditions, optically enriched

products (3m*, 3n*, 3o*, 3q*, 3s*) were synthesized in

good yields (entries 9−13). Although the asymmetric reaction

is only suitable for 2,2-diphenyl substituent pentenamides

under current conditions, it provides evidence that chiral

iodoarene compounds could be used as green alternatives to

transition metals in the catalytic asymmetric cyclizations of

alkenes.

Figure 1. A comparison of the transition states that lead to all four

possible products.

to serotonin reuptake inhibitors was obtained by simple

transformations.²⁸

An asymmetric variant of the present alkene oxyamination

using chiral iodoarenes as catalysts was preliminarily

CONCLUSION

■

In conclusion, we demonstrated a simple, eﬀective iodoarene-

catalyzed intermolecular oxyamination of unactivated alkenes

Figure 2. Gibbs energy proﬁle for the oxyamination reaction.

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a

broad range of substrates, utilizing unadorned HNTs₂as an

exogenous nitrogen nucleophile and mCPBA as an oxidant in

HFIP at room temperature. The products from the present

reaction can be converted to 1,2-amino alcohol, methanamine-

lactone, and methanamine-tetrahydrofuran derivatives, which

could serve as useful molecules in medicinal research and other

ﬁelds. More importantly, a mechanistic study based on

experiments and density functional theory calculations has

provided insights regarding the overall catalytic cycle of the

reaction and the origin of the observed chemoselectivity and

regioselectivity. This information will be helpful in terms of

understanding the present reaction and will assist in the future

design of new catalytic oxyaminations and other iodoarene-

catalyzed alkene difunctionalization reactions. Finally, an

enantioselective catalytic oxyamination process was developed,

oﬀering a simple and practical methodology for the preparation

of optically enriched tetrahydrofuranyl methanamine deriva-

tives.

Scheme 3. Further Transformations

EXPERIMENTAL SECTION

a

■

Reaction conditions: (a) LiAlH₄, CH₂Cl₂, rt; (b) KOH, MeOH,

General. Unless noted, reactions were carried out in a 10 mL glass

reaction tube, which were sealed with a rubber stopper in air.

Tetrahydrofuran (THF) and dichloromethane (CH₂Cl₂) were

obtained by distillation from sodium metal. Triﬂuorotoluene

(PhCF₃) and hexaﬂuoroisopropanol (HFIP) were purchased from

Energy Chemical and used without further puriﬁcation. All other

commercially available compounds were purchased at the highest

commercial quality. Flash column chromatography was performed on

a glass column ﬁlled with (200−300 Mesh) silica gel, eluting with

petroleum ether/EtOAc or dichloromethane/methanol/Et₃N. Reac-

tions were monitored by analytical thin-layer chromatography (TLC,

0.2 mm) with visualization by exposure to a 254 nm UV lamp and a

phosphomolybdic acid ethanol solution. NMR spectra were recorded

at an ambient temperature on Agilent 400 or 600 MHz spectrometers.

The chemical shifts are reported in parts per million (ppm) and are

reﬂux; (c) Na-naphthalenide, THF, rt; (d) Me₂SO₄, K₂CO₃, acetone,

60 °C; (e) HCl (aq), CH₂Cl₂, rt; (f) HBr/HOAc, phenol 80 °C; (g)

C₆H₅CHO, NaBH₃CN, MeOH, rt; (h) C₃H₅CHO, NaBH₄, MeOH,

rt; (i) acetyl chloride, NEt₃, CH₂Cl₂, rt.

a

Table 4. Asymmetric Oxyamination Investigations

1

referenced to TMS (δ = 0 ppm for H), CDCl₃(δ = 77.0 ppm for

¹³C). High-performance liquid chromatography was performed on

Agilent 1260 interfaced to an HP 71 series computer workstation.

High-Resolution mass spectral data were obtained on a Vion Ims Qtof

spectrometer in ESI mode.

General Procedure A for the Synthesis of Pentenamides.

Following a literature procedure.²⁹To a solution of 2,2-disubstituted

acid (1.0 equiv, 1 M) in MeOH was added SOCl₂(10 mol %) slowly,

and then the resulting mixture was allowed to stir at 80 °C oil bath

temperature. The reaction was monitored by TLC. After completion,

the mixture was quenched with H₂O, extracted with EtOAc, washed

with brine, dried over Na₂SO₄, ﬁltered, and concentrated under a

vacuum. The ester productwas directly used for the next step without

other puriﬁcation.

b

c

entry substrate catalyst

solvent

product yield (%)

ee (%)

b

1

1j

5e

5a

5b

5c

5d

5f

HFIP

3j*

3m*

3n*

3o*

3q*

3s*

89

90

80

70

50

60

95

89

84

91

89

87

3

53

0

27

7

20

94

64

93

95

59

98

2

3

4

5

6

7

PhCF₃

A solution of n-butyllithium (ⁿBuLi, 2.5 M in hexane, 2.5 equiv) in

THF was cooled to −78 °C in a low-temperature reactor under argon,

and esters (1.0 equiv, 0.5 M) dissolved in THF were added dropwise.

The resulting mixture was stired for 1 h, and then a solution of allyl

bromide (1.1 equiv) was added; the mixture was allowed to stir for

another 1 h. Then, the reaction was allowed to stir at room

temperature for 24 h. After completion, the mixture was quenched

with a saturated aqueous solution of NH₄Cl. The mixture was

extracted with EtOAc. The combined organic phase was washed with

brine, dried over Na₂SO₄, ﬁltered, and concentrated under a vacuum.

Then, the residue was puriﬁed by ﬂash column chromatography on

silica gel to give pentenoate.

Pentenoate (1.0 equiv, 0.5 M) was dissolved by a mixture of

MeOH/H₂O (3:1, v/v), and then NaOH (5.0 equiv) was added to

the residue. The mixture was heated to reﬂux overnight. After

completion, the solvent was removed under reduced pressure. The

residue was dissolved in H₂O, acidiﬁed with HCl (1 M, aq), and then

extracted with EtOAc. The organic phase was washed with brine,

8

9

10

11

12

13

1j

5g

1m

1n

1o

1q

1s

a

The reactions were conducted on the 0.1 mmol scale with 15 mol %

chiral iodoarenes as catalysts, HNTs₂(1.5 equiv), and mCPBA (1.5

equiv) at 0 °C for 15 h. Isolated yield. The ee was determined by

b

c

HPLC on a chiral stationary phase.

to aﬀord various 5-imino-2-tetrahydrofuranyl methanamine

derivatives. Notably, the present methodology tolerates a

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dried over Na₂SO₄, ﬁltered, and concentrated under a vacuum. The

crude pentenoic acid was used directly for the next step without

further puriﬁcation.

chromatography (15:1 petroleum ether/EtOAc): white solid; mp

91.0−92.7 °C; H NMR (400 MHz, CDCl₃) δ 7.51 (d, J = 8.0 Hz,

1

2H), 7.33 (q, J = 8.0, 6.8 Hz, 3H), 7.10 (t, J = 7.6 Hz, 1H), 5.85−5.70

(m, 1H), 5.24−5.02 (m, 2H), 2.41 (d, J = 7.6 Hz, 2H), 1.76−1.54 (m,

4H), 0.90 (t, J = 7.6 Hz, 6H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

174.6, 137.9, 134.0, 129.0, 124.3, 120.2, 118.3, 50.0, 37.8, 27.6, 8.4;

HRMS (ESI) m/z [M + H]⁺calcd for C₁₅H₂₂NO 232.1696, found

232.1698.

To a solution of pentenoic acid (1.0 equiv, 0.5 M) in

dichloromethane was added oxalyl chloride (3.0 equiv) under argon

at 0 °C, and then DMF (1 drop) was added carefully. After stirring for

1 h at 0 °C, the mixture was allowed to stir at room temperature for

another 5 h. Then, the resulting mixture was concentrated under a

vacuum to remove the solvent and the excessive oxalyl chloride. Then,

the residue was dissolved in CH₂Cl₂(0.5 M) under argon at 0 °C, and

then amine (1.2 equiv, dissolved in 2 mL of CH₂Cl₂) was slowly

added. After stirring for 30 min, Et₃N (2.0 equiv) was added. The

resulting mixture was stirred at room temperature overnight. Then,

the reaction mixture was quenched by HCl (1 M, aq) and extracted

with CH₂Cl₂. The organic phase was washed with brine, dried over

Na₂SO₄, ﬁltered, and concentrated under a vacuum. The crude

residue was puriﬁed by ﬂash column chromatography on silica gel to

give the pentenamide products.

General Procedure B for the Synthesis of Pentenamides.

Following a literature procedure,³⁰to a solution of the 2,2-

disubstituted acid (1.2 equiv) in CH₂Cl₂were added allylic alcohol

(1.0 equiv, 0.5 M), DMAP (0.2 equiv), and Et₃N (2.0 equiv). After

the mixture was stirred for 15 min at 0 °C, N,N-diisopropylcarbo-

diimide (DIC, 1.2 equiv) was added, and stirring was continued for 1

h. Then, the resulting mixture was allowed to stir at room temperature

for 15 h. After completion, the mixture was concentrated under a

vacuum. The residue was puriﬁed by ﬂash column chromatography on

silica gel to give the allylic ester product.

To a solution of allylic ester (1.0 equiv, 0.5 M) in THF was stirred

in a −78 °C low temperature reactor for 30 min under argon, and

then lithium diisopropylamide (LDA, 2.5 M in THF, 2.0 equiv) was

added dropwise, and the stirring was continued for 1 h. Then,

trimethylchlorosilane (TMSCl, 2.0 equiv) was added. After an

additional 1 h of stirring at −78 °C, the resulting mixture was

allowed to warmed to room temperature. After completion

(monitored by TLC), the reaction was quenched by HCl (1 M,

aq) and extracted with CH₂Cl₂. The organic phase was washed with

brine, dried over Na₂SO₄, ﬁltered, and concentrated under a vacuum.

The residue was puriﬁed by ﬂash column chromatography on silica gel

to give the carboxylic acid product.

To a solution of carboxylic acid (0.5 M in CH₂Cl₂, 1.0 equiv) was

added oxalyl chloride (3.0 equiv) under argon at 0 °C, and then 1

drop of DMF was added to carefully. After stirring for 1h, the mixture

was allowed to stir at room temperature for another 5 h. Then, the

resulting mixture was concentrated under a vacuum, and the residue

was dissolved in CH₂Cl₂(0.2 M) at 0 °C under argon, and then

amine (1.2 equiv, dissolved in 2 mL CH₂Cl₂.) was slowly added. The

resulting mixture was allowed stir for 0.5 h at 0 °C, and then Et₃N

(2.0 equiv) was added. Then, the reaction was warmed to room

temperature. After completion (monitored by TLC), the reaction

mixture was quenched by HCl (1 M, aq) and extracted with CH₂Cl₂.

The organic phase was washed with brine, dried over Na₂SO₄, ﬁltered,

and concentrated. The residue was puriﬁed by ﬂash column

chromatography on silica gel to give the desired products.

N-Phenyl-2,2-dipropyl-4-pentenamide (1u). Compound 1u was

prepared according to general procedure A and puriﬁed by column

chromatography (20:1 petroleum ether/EtOAc): white solid; mp

107.3−109.0 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.50 (d, J = 8.0 Hz,

2H), 7.40−7.27 (m, 3H), 7.10 (t, J = 7.6 Hz, 1H), 5.85−5.70 (m,

1H), 5.13 (dd, J = 14.0, 8.4 Hz, 2H), 2.42 (d, J = 7.6 Hz, 2H), 1.66−

1.45 (m, 4H), 1.38−1.20 (m, 4H), 0.92 (t, J = 7.2 Hz, 6H); ¹³C{¹H}

NMR (150 MHz, CDCl₃) δ 174.8, 137.9, 134.0, 129.0, 124.2, 120.2,

118.3, 49.5, 38.8, 38.0, 17.2, 14.7; IR ν_max(cm⁻¹) 3310, 2957, 1661,

1599, 1526, 1439, 1315, 1248, 916, 750, 694; HRMS (ESI) m/z [M +

H]⁺calcd for C₁₇H₂₆NO 260.2009, found 260.2009.

N-(4-Fluorophenyl)-3-methyl-2,2-diphenyl-4-pentenamide (1w).

Compound 1w was prepared according to the general procedure B

and puriﬁed by column chromatography (30:1 petroleum ether/

EtOAc): white solid; mp 126.4−127.1 °C; ¹H NMR (400 MHz,

CDCl₃) δ 7.49 (dd, J = 7.6, 2.0 Hz, 4H), 7.42−7.26 (m, 8H), 7.22 (s,

1H), 6.96 (t, J = 8.8 Hz, 2H), 5.89−5.74 (m, 1H), 5.07−4.95 (m,

2H), 4.15−4.00 (m, 1H), 0.99 (d, J = 6.8 Hz, 3H); ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 171.8, 159.4 (d, J = 242.0 Hz), 140.5, 140.2,

140.0, 133.8, 133.8, 130.1, 128.2, 128.1, 127.3, 121.7 (d, J = 8.0 Hz),

121.6, 116.2, 115.5 (d, J = 22.0 Hz), 65.8, 41.1, 16.6; HRMS (ESI)

m/z [M + H]⁺calcd for C₂₄H₂₃FNO 360.1758, found 360.1751.

N-Phenyl-2,2-diphenyl-3-ethyl-4-pentenamide (1x). Compound

1x was prepared according to the general procedure B and puriﬁed by

column chromatography (30:1 petroleum ether/EtOAc): white solid;

mp 101.7−102.4 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J = 7.6

Hz, 4H), 7.44−7.27 (m, 11H), 7.09 (t, J = 7.2 Hz, 1H), 5.55−5.42

(m, 1H), 5.23−5.12 (m, 2H), 3.62 (t, J = 9.6 Hz, 1H), 1.86−1.71 (m,

1H), 0.99 (t, J = 7.2 Hz, 3H), 0.80−0.67 (m, 1H); ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 171.7, 141.0, 140.8, 138.0, 137.9, 130.2, 130.0,

128.9, 128.1,128.1, 127.2,127.2, 124.3, 119.8 (2C), 118.6, 66.1, 50.2,

24.0, 12.4; IR ν_max(cm⁻¹) 3412, 2964, 1684, 1597, 1520, 1497, 1437,

1310, 1238, 918, 752, 719, 690, 561; HRMS (ESI) m/z [M + H]⁺

calcd for C₂₅H₂₆NO, 356.2009, found 356.2004.

N-Benzyl-2,2-diphenyl-3-methyl-4-pentenamide (1y). Com-

pound 1y was prepared according to the general procedure B and

puriﬁed by column chromatography (30:1 petroleum ether/EtOAc):

white solid; mp 125.0−126.8 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.38

(d, J = 8.4 Hz, 4H), 7.33−7.22 (m, 6H), 7.20−7.13 (m, 3H), 6.86

(dd, J = 6.4, 3.2 Hz, 2H), 5.84−5.70 (m, 2H), 4.95 (d, J = 14.0 Hz,

2H), 4.37 (t, J = 6.0 Hz, 2H), 4.05−3.91 (m, 1H), 0.92 (d, J = 6.8 Hz,

3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.5, 140.9, 140.5, 140.3,

138.2, 130.3, 128.5, 127.8, 127.8, 127.3, 127.2, 126.9, 126.9, 115.9

65.4, 43.8, 40.8, 16.5; IR ν_max(cm⁻¹) 3331, 3109, 1645, 1531, 1496,

1452, 1279, 1028, 916, 714, 696; HRMS (ESI) m/z [M + H]⁺calcd

for C₂₅H₂₆NO 356.2009, found 356.2000.

The spectrum of known reactants can be found in reported

literatures: 1a−g,²⁹1h,³¹1i,³²1j,³³1k,²⁹1m−r,²⁹1s,³²1v,²⁹1z,³⁴

1aa−ad,²⁹1af−ag,²⁹1an,³⁵1ao,³⁶1ap.³⁷The characterization of the

new compounds as follows:

N-(4-Methoxyphenyl)-2,2-diphenyl-4-pentenamide (1l). Com-

pound 1l was prepared according to the general procedure A and

puriﬁed by column chromatography (15:1 petroleum ether/EtOAc):

white solid; mp 103.0−103.7 °C; ¹H NMR(400 MHz, CDCl₃) δ

7.48−7.21 (m, 12H), 7.15 (s, 1H), 6.81 (d, J = 8.6 Hz, 2H), 5.89−

5.71 (m, 1H), 5.14−4.90 (m, 2H), 3.77 (s, 3H), 3.30 (d, J = 6.6 Hz,

2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 172.1, 156.5, 142.8, 135.2,

130.9, 129.0, 128.5, 127.2, 121.6, 118.1, 114.1, 61.3, 55.5, 43.5;

HRMS (ESI) m/z [M + H]⁺calcd for C₂₄H₂₄NO₂358.1802, found

358.1802.

N-Phenyl-(4-(N-tert-Butyloxycarbonyl-4-allyl)piperidino)-

carboxamide (1ae). Compound 1ae was prepared according to the

general procedure A and puriﬁed by column chromatography (20:1

petroleum ether/EtOAc): white solid; mp 106.6−107.3 °C; ¹H NMR

(400 MHz, CDCl₃) δ 7.48 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 8.0 Hz,

2H), 7.28−7.22 (m, 1H), 7.13 (t, J = 7.6 Hz, 1H), 5.85−5.70 (m,

1H), 5.19−5.08 (m, 2H), 3.77 (s, 2H), 3.20 (s, 2H), 2.37 (d, J = 7.6

Hz, 2H), 2.08 (d, J = 14.0 Hz, 2H), 1.61 (s, 2H), 1.46 (s, 9H);

¹³C{¹H} NMR (150 MHz, CDCl₃) δ 172.8, 154.9, 137.4, 132.5,

129.0, 124.6, 120.5, 119.4, 79.7, 45.8, 43.8, 33.2, 28.4, 26.9; IR ν_max

(cm⁻¹) 3303, 2976, 1695, 1668, 1525, 1501, 1437, 1420, 1366, 1246,

1175, 1155, 918, 750, 692; HRMS (ESI) m/z [M + H]⁺calcd for

C₂₀H₂₉N₂O₃345.2173, found 345.2165.

N-Phenyl-(1-(1-(2-methylallyl))cyclocyclohexyl)carboxamide

(1ah). Compound 1ah was prepared according to the general

procedure A and puriﬁed by column chromatography (20:1

N-Phenyl-2,2-diethyl-4-pentenamide (1t). Compound 1t was

prepared according to general procedure A and puriﬁed by column

G

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petroleum ether/EtOAc): white solid; mp 150.9−152.1 °C; ¹H NMR

(400 MHz, CDCl₃) δ 7.51 (d, J = 8.3, 2H), 7.37−7.28 (m, 3H), 7.11

(t, J = 7.6 Hz, 1H), 4.89 (s, 1H), 4.72 (s, 1H), 2.32 (s, 2H), 1.73−

1.63 (m, 5H), 1.58 (s, 3H), 1.54−1.39 (m, 4H), 1.37−1.29 (m, 1H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 174.3, 141.9, 137.9, 129.0,

124.2, 120.0, 114.9, 48.3, 47.2, 34.9, 25.9, 24.4, 23.0; IR ν_max(cm⁻¹)

3344, 3315, 2939, 1661, 1601, 1531, 1437, 1304, 891, 750, 694;

HRMS (ESI) m/z [M + H]⁺calcd for C₁₇H₂₄NO 258.1852, found

258.1854.

(0.20 mmol, 1.0 equiv) was added. The resulting mixture was stirred

for 7 h at room temperature. After completion (monitored by TLC),

the solvent was removed under a vacuum, and the residue was diluted

with NaOH (1.0 M, 10 mL, aq) and stirred for 10 min. Then, the

resulting mixture was extracted with CH₂Cl₂. The organic phase was

washed with brine, dried over Na₂SO₄, ﬁltered, and concentrated

under a vacuum. The residue was puriﬁed by ﬂash column

chromatography on silica gel to give the oxyamination product 3.

(Z)-N-((4,4-Dimethyl-5-(phenylimino)tetrahydrofuran-2-yl)-

methyl)-4-methyl-N-tosylbenzenesulfonamide (3a). The general

procedure was followed with 2j as the catalyst. The product was

puriﬁed by column chromatography (10:3 petroleum ether/EtOAc)

and obtained as a mixture of two inseparable isomers with 5-exo/6-

endo = 15:1: white solid, 93.6 mg, 79% yield; mp 90.0−91 °C. Major

N-Phenyl-2-methyl-2-phenyl-4-pentenamide (1ai). Compound

1ai was prepared according to the general procedure A and puriﬁed

by column chromatography (20:1 petroleum ether/EtOAc): white

1

solid; mp 91.1−92.7 °C; H NMR (400 MHz, CDCl₃) δ 7.44−7.29

(m, 7H), 7.27 (s, 2H), 7.06 (t, J = 7.6 Hz, 1H), 6.83 (s, 1H), 5.65−

5.50 (m, 1H), 5.14−5.00 (m, 2H), 2.93−2.77 (m, 2H), 1.63 (s, 3H);

¹³C{¹H} NMR (150 MHz, CDCl₃) δ 174.7, 142.9, 137.8, 133.9,

128.9, 128.9, 127.4, 127.0 124.2, 119.7, 118.6, 51.2, 43.6, 23.8; IR ν_max

(cm⁻¹) 3337, 2978, 1668, 1599, 1520, 1499, 1437, 1311, 1242, 916,

770, 754, 692; HRMS (ESI) m/z [M + H]⁺calcd for C₁₈H₂₀NO

266.1539, found 266.1541.

1

isomer: H NMR (600 MHz, CDCl₃) δ 7.79 (d, J = 8.4 Hz, 4H),

7.29−7.24 (m, 2H), 7.19 (d, J = 8.4 Hz, 4H), 7.06 (d, J = 7.8 Hz,

2H), 7.02 (t, J = 7.2 Hz, 1H), 4.88−4.63 (m, 1H), 4.13 (dd, J = 15.6,

7.2 Hz, 1H), 3.57 (dd, J = 15.6, 3.6 Hz, 1H), 2.41 (s, 6H), 2.07 (dd, J

= 12.6, 6.0 Hz, 1H), 1.75 (dd, J = 12.6, 10.2 Hz, 1H), 1.37 (s, 3H),

1.30 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 167.0, 147.2,

145.0, 136.1, 129.5, 128.6, 128.5, 123.3, 122.4, 77.7, 51.6, 41.8, 40.8,

26.3, 26.3, 21.6; IR ν_max(cm⁻¹) 2968, 1701, 1595, 1492, 1373, 1352,

1167, 1164, 1045, 912, 815, 729, 663, 552; HRMS (ESI) m/z [M +

H]⁺calcd for C₂₇H₃₁N₂O₅S₂527.1669, found 527.1672.

N-Phenyl-2-ethyl-2-phenyl-4-pentenamide (1aj). Compound 1aj

was prepared according to the general procedure A and puriﬁed by

column chromatography (30:1 petroleum ether/EtOAc): white solid;

1

mp 93.1−95.5 °C; H NMR (400 MHz, CDCl₃) δ 7.46−7.36 (m,

6H), 7.36−7.25 (m, 3H), 7.09 (t, J = 6.8 Hz, 1H), 6.92 (s, 1H),

5.66−5.47 (m, 1H), 5.20−4.98 (m, 2H), 2.95−2.75 (m, 2H), 2.23−

2.05 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 174.0, 142.4, 137.9, 133.7, 128.9, 128.8, 127.4, 127.3, 124.2,

119.9, 118.4, 55.2, 39.5, 28.0, 8.5; IR ν_max(cm⁻¹) 3331, 2937, 1668,

1599, 1520, 1499, 1437, 1309, 1242, 914, 752, 700; HRMS (ESI) m/z

[M + H]⁺calcd for C₁₉H₂₂NO 280.1696, found 280.1690.

N-Phenyl-2-methyl-2-(3-chlorophenyl)-4-pentenamide (1ak).

Compound 1ak was prepared according to the general procedure A

and puriﬁed by column chromatography (30:1 petroleum ether/

EtOAc): white solid; mp 97.5−98.3 °C; ¹H NMR (400 MHz, CDCl₃)

δ 7.38 (d, J = 8.8 Hz, 3H), 7.29 (q, J = 8.8, 7.2 Hz, 5H), 7.08 (t, J =

7.6 Hz, 1H), 6.86 (s, 1H), 5.65−5.50 (m, 1H), 5.14−4.99 (m, 2H),

2.88−2.74 (m, 2H), 1.61 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃)

δ 173.7, 145.2, 137.6, 134.9, 133.4, 130.2, 128.9, 127.6, 127.0, 125.3,

124.4, 119.9, 119.1, 51.1 43.6, 23.6; IR ν_max(cm⁻¹) 3325, 2978, 1663,

1597, 1522, 1439, 1313, 1242, 918, 752, 692; HRMS (ESI) m/z [M +

H]⁺calcd for C₁₈H₁₉ClNO 300.1150, found 300.1150.

N-Phenyl-2-isopropyl-2-(3-chlorophenyl)-4-pentenamide (1al).

Compound 1al was prepared according to the general procedure A

and puriﬁed by column chromatography (30:1 petroleum ether/

EtOAc): white solid; mp 105.2−106.4 °C; ¹H NMR (400 MHz,

CDCl₃) δ 7.43−7.33 (m, 4H), 7.32−7.20 (m, 4H), 7.09 (t, J = 7.3

Hz, 1H), 6.98 (s, 1H), 5.76−5.61 (m, 1H), 5.17−4.98 (m, 2H),

2.95−2.69 (m, 2H), 2.65−2.53 (m, 1H), 0.96 (d, J = 6.8 Hz, 3H),

0.86 (d, J = 6.8 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 172.3,

137.9, 137.6, 133.6, 133.2, 130.7, 129.0, 128.3, 124.4, 120.0, 118.9,

59.4, 40.9, 32.0, 18.9, 18.0; HRMS (ESI) m/z [M + H]⁺calcd for

C₂₀H₂₃ClNO 328.1463, found 328.1456.

N-Phenyl-(9-(9-Allyl-9H-ﬂuorene)carboxamide (1am). Com-

pound 1am was prepared according to the general procedure A and

puriﬁed by column chromatography (30:1 petroleum ether/EtOAc):

pale yellow solid; mp 122.0−123.0 °C; ¹H NMR (400 MHz, CDCl₃)

δ 7.84 (d, J = 7.2 Hz, 2H), 7.73 (d, J = 7.6 Hz, 2H), 7.53−7.47 (m,

2H), 7.46−7.40 (m, 2H), 7.33−7.27 (m, 2H), 7.27−7.20 (m, 2H),

7.08−7.01 (m, 1H), 6.89 (s, 1H), 5.43−5.27 (m, 1H), 4.99−4.79 (m,

2H), 3.25 (d, J = 7.2 Hz, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

170.5, 145.1, 141.0, 137.5, 133.1, 128.8, 128.7, 128.1, 124.8, 124.3,

120.5, 119.9, 118.6, 62.9, 40.9; IR ν_max(cm⁻¹) 3406, 3063, 1682,

1597, 1518, 1501, 1475, 1439, 1312, 1238, 916, 739, 690, 561, 505;

HRMS (ESI) m/z [M + H]⁺calcd for C₂₃H₂₀NO 326.1539, found

326.1534.

(Z)-N-((4,4-Dimethyl-5-(4-methylphenylimino)tetrahydrofuran-

2-yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3b). The gen-

eral procedure was followed, and the product was puriﬁed by column

chromatography (5:1 petroleum ether/EtOAc). The product was

given as a mixture of two inseparable isomers with 5-exo/6-endo = 7:1:

1

white solid, 97.2 mg, 90% yield; mp 41−42 °C. Major isomer: H

NMR (600 MHz, CDCl₃) δ 7.80 (d, J = 8.4 Hz, 4H), 7.20 (d, J = 8.4

Hz, 4H), 7.06 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 4.75−

4.68 (m, 1H), 4.13 (dd, J = 15.6, 7.2 Hz, 1H), 3.57 (dd, J = 15.6, 4.2

Hz, 1H), 2.42 (s, 6H), 2.26 (s, 3H), 2.05 (dd, J = 12.6, 6.0 Hz, 1H),

1.74 (dd, J = 12.6, 10.2 Hz, 1H), 1.36 (s, 3H), 1.29 (s, 3H); ¹³C{¹H}

NMR (150 MHz, CDCl₃) δ 166.9, 145.0, 144.6, 136.2, 132.6, 129.6,

129.2, 128.6, 122.3, 77.5, 51.6, 41.9, 40.9, 26.4, 26.4, 21.7, 20.9; IR

ν_max(cm⁻¹) 2968, 1701, 1596, 1503, 1373, 1352, 1167, 1083, 1045,

914, 814, 663, 552; HRMS (ESI) m/z [M + H]⁺calcd for

C₂₈H₃₃N₂O₅S₂541.1825, found 541.1825.

(Z)-N-((4,4-Dimethyl-5-(2-chlorophenylimino)tetrahydrofuran-

2-yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3c). The gen-

eral procedure was followed, and the product was puriﬁed by column

chromatography (10:3 petroleum ether/EtOAc): white solid, 90.4

1

mg, 84% yield, mp 90−92 °C; H NMR (600 MHz, CDCl₃) δ 7.74

(d, J = 8.4 Hz, 4H), 7.37 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 8.4 Hz, 4H),

7.15 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.93 (t, J = 7.8 Hz,

1H), 4.81−4.68 (m, 1H), 4.11 (dd, J = 15.6, 7.2 Hz, 1H), 3.58−3.45

(m, 1H), 2.39 (s, 6H), 2.10 (dd, J = 12.6, 6.0 Hz, 1H), 1.77 (dd, J =

12.6, 10.2 Hz, 1H), 1.40 (s, 3H), 1.35 (s, 3H); ¹³C{¹H} NMR (150

MHz, CDCl₃) δ 168.5, 145.1, 144.9, 136.0, 129.5, 129.2, 128.3, 127.0,

125.6, 123.9, 122.9, 78.3, 51.6, 41.7, 40.9, 26.1, 26.0, 21.5; HRMS

(ESI) m/z [M + H]⁺calcd for C₂₇H₃₀ClN₂O₅S₂561.1279, found

561.1284.

(Z)-N-((4,4-Dimethyl-5-(3-chlorophenylimino)tetrahydrofuran-

2-yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3d). The gen-

eral procedure was followed with 2j as the catalyst, and the product

was puriﬁed by column chromatography (10:3 petroleum ether/

EtOAc). The product was given as a mixture of two inseparable

isomers with 5-exo/6-endo = 12:1: white solid, 88.5 mg, 79% yield; mp

94−95 °C. Major isomer: ¹H NMR (600 MHz, CDCl₃) δ 7.79 (d, J =

8.4 Hz, 4H), 7.22 (d, J = 8.4 Hz, 4H), 7.16 (t, J = 7.8 Hz, 1H), 7.05

(t, J = 1.8 Hz, 1H), 6.99−6.96 (m, 1H), 6.95−6.92 (m, 1H), 4.78−

4.71 (m, 1H), 4.12 (dd, J = 15.6, 7.8 Hz, 1H), 3.56 (dd, J = 15.6, 3.6

Hz, 1H), 2.42 (s, 6H), 2.09 (dd, J = 12.6, 6.0 Hz, 1H), 1.75 (dd, J =

12.6, 10.2 Hz, 1H), 1.36 (s, 3H), 1.30 (s, 3H); ¹³C{¹H} NMR (150

MHz, CDCl₃) δ 168.0, 148.8, 145.1, 136.2, 134.1, 129.7, 129.6, 128.5,

123.4, 122.5, 120.9, 78.1, 51.6, 41.8, 41.1, 26.4, 26.3, 21.70; IR ν_max

(cm⁻¹) 2970, 1754, 1703, 1589, 1467, 1373, 1352, 1167, 1050, 912,

General Procedure for the Oxyamination Reaction. Aryl

iodine catalyst (2h, 15% mol), HNTs₂(1.5 equiv), and mCPBA (1.5

equiv) were dissolved in 2.0 mL of HFIP (0.1 M). The mixture was

stirred at room temperature for 10 min, and then pentenamides 1

H

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815, 729, 663, 551; HRMS (ESI) m/z [M + H]⁺calcd for

C₂₇H₃₀ClN₂O₅S₂561.1279, found 561.1285.

°C; ¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, J = 8.0 Hz, 4H), 7.34 (d,

J = 8.0 Hz, 4H), 4.79−4.70 (m, 1H), 4.17 (dd, J = 15.6, 6.8 Hz, 1H),

3.85 (s, 3H), 3.74 (dd, J = 15.6, 5.2 Hz, 1H), 2.45 (s, 6H), 1.94 (dd, J

= 12.4, 5.6 Hz, 1H), 1.79−1.69 (m, 1H), 1.24 (s, 6H); ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 162.7, 145.2, 136.3, 129.6, 128.9, 79.1, 62.1,

51.2, 42.7, 40.3, 26.9, 26.0, 21.7; HRMS (ESI) m/z [M + H]⁺calcd

for C₂₂H₂₉N₂O₆S₂481.1462, found 481.1461.

(Z)-N-((4,4-Dimethyl-5-(4-chlorophenylimino)tetrahydrofuran-

2-yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3e). The gen-

eral procedure was followed with 2j as the catalyst, and the product

was puriﬁed by column chromatography (10:3 petroleum ether/

EtOAc). The product was given as a mixture of two inseparable

isomers with 5-exo/6-endo = 5:1: white solid, 69.4 mg, 62% yield; mp

66−67 °C. Major isomer: ¹H NMR (600 MHz, CDCl₃) δ 7.79 (d, J =

8.4 Hz, 4H), 7.19 (dd, J = 18.0, 8.4 Hz, 6H), 6.99 (d, J = 8.4 Hz, 2H),

4.83−4.74 (m, 1H), 4.12 (dd, J = 15.6, 7.8 Hz, 1H), 3.54 (dd, J =

15.6, 3.6 Hz, 1H), 2.43 (s, 6H), 2.10 (dd, J = 12.6, 6.0 Hz, 1H), 1.74

(dd, J = 12.6, 10.2 Hz, 1H), 1.36 (s, 3H), 1.31 (s, 3H); ¹³C{¹H}

NMR (150 MHz, CDCl₃) δ 167.8, 145.9, 145.2, 136.1, 129.6, 128.8,

128.6, 128.5, 124.0, 77.8, 51.5, 41.8, 41.1, 26.5, 26.5, 21.7; IR ν_max

(cm⁻¹) 2970, 1776, 1701, 1596, 1487, 1373, 1352, 1167, 1086, 925,

816, 729, 663, 552; HRMS (ESI) m/z [M + H]⁺calcd for

C₂₇H₃₀ClN₂O₅S₂561.1279, found 561.1282.

(Z)-N-((4,4-Dimethyl-5-(4-nitrophenylimino)tetrahydrofuran-2-

yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3f). The general

procedure was followed, and the product was puriﬁed by column

chromatography (10:3 petroleum ether/EtOAc): pale yellow solid,

104.0 mg, 91% yield; mp 115−116 °C; ¹H NMR (600 MHz, CDCl₃)

δ 8.07 (d, J = 9.0 Hz, 2H), 7.75 (d, J = 8.4 Hz, 4H), 7.19 (d, J = 8.4

Hz, 4H), 7.10 (d, J = 9.0 Hz, 2H), 4.91−4.77 (m, 1H), 4.10 (dd, J =

15.6, 8.4 Hz, 1H), 3.55 (dd, J = 15.6, 3.6 Hz, 1H), 2.40 (s, 6H), 2.17

(dd, J = 12.6, 6.0 Hz, 1H), 1.79 (dd, J = 12.6, 9.6 Hz, 1H), 1.38 (d, J

= 21.0 Hz, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 169.0, 154.2,

145.3, 143.7, 136.0, 129.6, 128.4, 124.5, 122.9, 78.3, 51.3, 41.6, 41.3,

26.6, 26.3, 21.6; IR ν_max(cm⁻¹3361, 2962, 1716, 1589, 1497, 1375,

1333, 1167, 933, 862, 663, 552; HRMS (ESI) m/z [M + H]⁺calcd for

C₂₇H₃₀N₃O₇S₂572.1520, found 572.1536.

(Z)-N-((4,4-Dimethyl-5-((4-(triﬂuoromethyl)phenyl)imino)-

tetrahydrofuran-2-yl)methyl)-4-methyl-N-tosylbenzenesulfona-

mide (3g). The general procedure was followed, and the product was

puriﬁed by column chromatography (10:3 petroleum ether/EtOAc):

white solid, 77.2 mg, 65% yield; mp 43−44 °C; ¹H NMR (600 MHz,

CDCl₃) δ 7.76 (d, J = 8.4 Hz, 4H), 7.49 (d, J = 8.4 Hz, 2H), 7.17 (d, J

= 8.4 Hz, 4H), 7.12 (d, J = 8.4 Hz, 2H), 4.86−4.79 (m, 1H), 4.12

(dd, J = 7.8, 3.6 Hz, 1H), 3.52 (dd, J = 15.6, 3.6 Hz, 1H), 2.40 (s,

6H), 2.14 (dd, J = 12.6, 6.0 Hz, 1H), 1.77 (dd, J = 12.6, 9.6 Hz, 1H),

1.40 (s, 3H), 1.35 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ

168.7, 150.6, 145.2, 136.0, 129.6, 128.5, 125.9 (q, J = 3.5 Hz), 125.4

(q, J = 274.2 Hz), 122.6, 78.3, 51.4, 41.7, 41.2, 26.5, 26.3, 21.6; IR

ν_max(cm⁻¹) 2970, 1776, 1703, 1610, 1373, 1325, 1167, 1118, 1065,

914, 816, 741, 663, 552; HRMS (ESI) m/z [M + H]⁺calcd for

C₂₈H₃₀F₃N₂O₅S₂595.1543, found 595.1560.

(Z)-N-((4,4-Dimethyl-5-benzyliminotetrahydrofuran-2-yl)-

methyl)-4-methyl-N-tosylbenzenesulfonamide (3h). The general

procedure was followed, and the reaction time was extended to 15

h. The product was puriﬁed by column chromatography (10:3

petroleum ether/EtOAc), giving as a mixture of two inseparable

isomers with 5-exo/6-endo = >20:1: white solid, 94.2 mg, 55% yield;

mp 104−105.0 °C. Major isomer shown: ¹H NMR (600 MHz,

CDCl₃) δ 7.93 (d, J = 8.3 Hz, 4H), 7.76 (d, J = 8.3 Hz, 1H), 7.29 (d, J

= 7.4 Hz, 1H), 7.24 (s, 6H), 7.21 (t, J = 7.2 Hz, 1H), 4.76−4.66 (m,

1H), 4.48−4.36 (m, 2H), 4.09 (dd, J = 15.7, 7.4 Hz, 1H), 3.66 (dd, J

= 15.6, 3.6 Hz, 1H), 2.40 (s, 6H), 2.04 (dd, J = 12.6, 5.4 Hz, 1H),

1.67 (dd, J = 12.6, 10.2 Hz, 1H), 1.23 (s, 3H), 1.23 (s, 3H); ¹³C{¹H}

NMR (150 MHz, CDCl₃) δ 168.1, 145.2, 143.4, 140.8, 139.3, 136.6,

129.7, 129.7, 128.4, 128.2, 127.4, 126.4, 126.3, 76.9, 52.2, 50.8, 42.4,

40.4, 26.4, 26.3, 21.7, 21.5; IR ν_max(cm⁻¹) 2962, 1717, 1589, 1497,

1375, 1333, 1300, 1167, 1109, 1041, 933, 862, 820, 729, 663, 552;

HRMS (ESI) m/z [M + H]⁺calcd for C₂₈H₃₃N₂O₅S₂541.1825,

found 541.1842.

(Z)-N-((4,4-Dimethyl-5-phenylimino-tetrahydrofuran-2-yl)-

methyl)-4-methyl-N-tosylbenzenesulfonamide (3j). The general

procedure was followed with 2j as the catalyst, and puriﬁed by

column chromatography (20:3 petroleum ether/EtOAc). The

product was given as a mixture of two inseparable isomers with 5-

exo/6-endo = 12:1: white solid, 123.5 mg, 95% yield; mp 133−134 °C.

1

Major isomer: H NMR (600 MHz, CDCl₃) δ 7.75 (d, J = 8.4 Hz,

4H), 7.41 (d, J = 7.8 Hz, 2H), 7.36 (t, J = 7.8 Hz, 4H), 7.34−7.26 (m,

5H), 7.26−7.21 (m, 1H), 7.20−7.13 (m, 6H), 7.05 (t, J = 7.8 Hz,

1H), 4.68−4.52 (m, 1H), 4.14 (dd, J = 15.6, 6.6 Hz, 1H), 3.69 (dd, J

= 15.6, 5.4 Hz, 1H), 2.92 (dd, J = 13.2, 5.4 Hz, 1H), 2.69 (dd, J =

13.2, 10.2 Hz, 1H), 2.40 (s, 6H); ¹³C{¹H} NMR (100 MHz, CDCl₃)

δ 162.7, 146.8, 145.1, 143.1, 141.7, 136.3, 129.7, 128.6, 128.6, 128.4,

128.4, 128.1, 127.8, 127.4, 127.0, 123.8, 122.6, 77.1, 57.9, 51.2, 42.6,

21.7; IR ν_max(cm⁻¹) 2924, 2550, 1693, 1596, 1575, 1490, 1417, 1375,

1303, 1275, 1163, 1083, 810, 750, 663, 552; HRMS (ESI) m/z [M +

H]⁺calcd for C₃₇H₃₅N₂O₅S₂651.1982, found 651.1982.

(Z)-N-((4,4-Diphenyl-5-(4-methylphenylimino)tetrahydrofuran-

2-yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3k). The gen-

eral procedure was followed, and the product was puriﬁed by column

chromatography (20:3 petroleum ether/EtOAc): white solid, 131.5

1

mg, 99% yield; mp 94−95 °C; H NMR (600 MHz, CDCl₃) δ 7.76

(d, J = 8.4 Hz, 4H), 7.40 (d, J = 7.8 Hz, 2H), 7.38−7.32 (m, 4H),

7.31−7.26 (m, 3H), 7.24−7.20 (m, 1H), 7.18 (d, J = 8.4 Hz, 4H),

7.09 (s, 4H), 4.62−4.52 (m, 1H), 4.13 (dd, J = 15.6, 6.6 Hz, 1H),

3.70 (dd, J = 15.4, 5.4 Hz, 1H), 2.90 (dd, J = 13.2, 5.4 Hz, 1H), 2.67

(dd, J = 13.2, 10.2 Hz, 1H), 2.40 (s, 6H), 2.29 (s, 3H); ¹³C{¹H}

NMR (150 MHz, CDCl₃) δ 162.3, 145.0, 144.0, 143.2, 141.8, 136.3,

133.1, 129.6, 129.1, 128.6, 128.4, 128.3, 128.1, 127.7, 127.3, 126.9,

122.6, 76.8, 57.8, 51.1, 42.6, 21.7, 20.9; HRMS (ESI) m/z [M + H]⁺

calcd for C₃₈H₃₇N₂O₅S₂665.2138, found 665.2139.

(Z)-N-((4,4-Diphenyl-5-(4-methoxyphenylimino)-

tetrahydrofuran-2-yl)methyl)-4-methyl-N-tosylbenzenesulfona-

mide (3l). The general procedure was followed, and the product was

puriﬁed by column chromatography (5:1 petroleum ether/EtOAc):

white solid, 133.3 mg, 98% yield; mp 81−82 °C; ¹H NMR (600 MHz,

CDCl₃) δ 7.78 (d, J = 8.4 Hz, 4H), 7.36 (dd, J = 15.6, 7.2 Hz, 6H),

7.31−7.27 (m, 3H), 7.20 (dd, J = 8.4, 3.0 Hz, 7H), 6.82 (d, J = 9.0

Hz, 2H), 4.62−4.52 (m, 1H), 4.13 (dd, J = 15.6, 6.6 Hz, 1H), 3.76−

3.72 (m, 4H), 2.89 (dd, J = 13.2 4.8 Hz, 1H), 2.67 (dd, J = 13.2, 10.2

Hz, 1H), 2.40 (s, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 161.7,

156.2, 145.1, 143.2, 141.9, 139.5, 136.3, 129.7, 128.6, 128.3, 128.0,

127.7, 127.3, 126.8, 124.4, 113.7, 76.7, 57.9, 55.4, 51.1, 42.5, 21.7;

HRMS (ESI) m/z [M + H]⁺calcd for C₃₈H₃₇N₂O₆S₂681.2088,

found 681.2088.

(Z)-N-((4,4-Diphenyl-5-(4-ﬂuorophenylimino)tetrahydrofuran-2-

yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3m). The general

procedure was followed, and the product was puriﬁed by column

chromatography (5:1 petroleum ether/EtOAc): white solid, 117.6

mg, 88% yield; mp 86−87 °C; ¹H NMR (600 MHz, CDCl₃) δ 7.79−

7.73 (m, 4H), 7.41−7.35 (m, 6H), 7.33−7.26 (m, 3H), 7.24 (t, J =

7.2 Hz, 1H), 7.21−7.12 (m, 6H), 6.95 (t, J = 9.0 Hz, 2H), 4.66−4.58

(m, 1H), 4.12 (dd, J = 15.6, 6.6 Hz, 1H), 3.70 (dd, J = 15.6, 4.8 Hz,

1H), 2.93 (dd, J = 13.2, 5.4 Hz, 1H), 2.69 (dd, J = 13.2, 10.2 Hz, 1H),

2.40 (s, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 162.9, 160.3,

158.7, 159.5(d, J = 240.0 Hz), 145.1, 142.9, 142.6, 142.5, 141.7,

136.3, 129.6, 128.6, 128.3, 128.1, 127.7, 127.4, 127.0, 124.3(d, J = 6.0

Hz), 115.1(d, J = 23.0 Hz), 77.0, 58.0, 51.1, 42.4, 21.7; IR ν_max(cm⁻¹)

3029, 2359, 2341, 1695, 1596, 1502, 1373, 1352, 1167, 1083, 816,

698, 662, 550; HRMS (ESI) m/z [M + H]⁺calcd for C₃₇H₃₄FN₂O₅S₂

669.1888, found 669.1888.

(Z)-N-((4,4-Dimethyl-5-methoxyimino-tetrahydrofuran-2-yl)-

methyl)-4-methyl-N-tosylbenzenesulfonamide (3i). The general

procedure was followed, and the reaction time was extended to 15

h. The product was puriﬁed by column chromatography (10:3

petroleum ether/EtOAc): white solid, 72.0 mg, 80% yield; mp 43−44

(Z)-N-((4,4-Diphenyl-5-(2-chlorophenylimino)tetrahydrofuran-2-

yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3n). The general

I

https://dx.doi.org/10.1021/acs.joc.0c02047

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

procedure was followed, and the product was puriﬁed by column

chromatography (5:1 petroleum ether/EtOAc): white solid, 116.3

mg, 85% yield; mp 138−139 °C; ¹H NMR (600 MHz, CDCl₃) δ 7.72

(d, J = 8.4 Hz, 4H), 7.52 (d, J = 7.8 Hz, 2H), 7.43−7.36 (m, 5H),

7.34−7.29 (m, 3H), 7.25−7.21 (m, 1H), 7.18 (d, J = 8.4 Hz, 5H),

7.09 (d, J = 7.8 Hz, 1H), 6.97 (t, J = 7.2 Hz, 1H), 4.64−4.56 (m, 1H),

4.16 (dd, J = 15.6, 6.6 Hz, 1H), 3.67 (dd, J = 15.6, 4.8 Hz, 1H), 3.02

(dd, J = 13.2, 4.8 Hz, 1H), 2.68 (dd, J = 13.2, 10.2 Hz, 1H), 2.41 (s,

6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 164.6, 145.1, 144.9, 142.9,

140.5, 136.2, 129.6, 129.5, 128.6, 128.4, 128.2, 127.9, 127.6, 127.0,

127.0, 126.1, 124.3, 123.1, 77.7, 58.0, 51.34, 42.9, 21.7; IR ν_max

(cm⁻¹) 3061, 1701, 1587, 1492, 1472, 1447, 1375, 1352, 1167, 1084,

910, 816, 729, 663, 552; HRMS (ESI) m/z [M + H]⁺calcd for

C₃₇H₃₄ClN₂O₅S₂685.1592, found 685.1591.

(Z)-N-((4,4-Diphenyl-5-(3-chlorophenylimino)tetrahydrofuran-2-

yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3o). The general

procedure was followed, and the product was puriﬁed by column

chromatography (5:1 petroleum ether/EtOAc): white solid, 117.7

mg, 86% yield; mp 127−128 °C; ¹H NMR (600 MHz, CDCl₃) δ 7.75

(d, J = 8.4 Hz, 4H), 7.39−7.27 (m, 9H), 7.26−7.23 (m, 1H), 7.19 (d,

J = 8.4 Hz, 5H), 7.14 (s, 1H), 7.02 (dd, J = 13.6, 8.4 Hz, 2H), 4.64−

4.56 (m, 1H), 4.13 (dd, J = 15.6, 6.6 Hz, 1H), 3.68 (dd, J = 15.6, 4.8

Hz, 1H), 2.94 (dd, J = 13.2, 4.8 Hz, 1H), 2.69 (dd, J = 13.2, 10.2 Hz,

1H), 2.40 (s, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 163.8, 148.3,

145.2, 142.9, 141.5, 136.2, 134.1, 129.7, 128.8, 128.3, 128.3, 128.2,

127.7, 127.6, 127.1, 123.8, 122.6, 121.0, 77.4, 58.0, 51.1, 42.5, 21.7; IR

ν_max(cm⁻¹) 2970, 1703, 1589, 1373, 1475, 1373, 1352, 1167, 1083,

816, 741, 663, 552; HRMS (ESI) m/z [M + H]⁺calcd for

C₃₇H₃₄ClN₂O₅S₂685.1592, found 685.1591.

126.2, 76.1, 57.4, 51.5, 51.0, 42.7, 21.6; IR ν_max(cm⁻¹) 3028, 1701,

1594, 1495, 1446, 1375, 1354, 1167, 1084, 910, 815, 733, 698, 663,

552; HRMS (ESI) m/z [M + H]⁺calcd for C₃₈H₃₇N₂O₅S₂665.2138,

found 665.2137.

(Z)-N-((4,4-Diphenyl-5-methoxyiminotetrahydrofuran-2-yl)-

methyl)-4-methyl-N-tosylbenzenesulfonamide (3s). The general

procedure was followed, and the product was puriﬁed by column

chromatography (5:1 petroleum ether/EtOAc): white solid, 102.7

1

mg, 85% yield; mp 53−54 °C; H NMR (400 MHz, CDCl₃) δ 7.91

(d, J = 8.2 Hz, 4H), 7.37−7.18 (m, 14H), 4.54−4.45 (m, 1H), 4.19

(dd, J = 15.5, 5.4 Hz, 1H), 3.94−3.85 (m, 4H), 2.79−2.63 (m, 2H),

2.43 (s, 6H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.3, 145.2,

142.2, 141.7, 136.4, 129.7, 128.6, 128.2, 128.0, 127.6, 127.3, 126.9,

78.2, 62.7, 57.4, 50.6, 43.1, 21.7; HRMS (ESI) m/z [M + H]⁺calcd

for C₃₂H₃₃N₂O₆S₂605.1775, found 605.1773.

(Z)-N-((4,4-Diethyl-5-phenyliminotetrahydrofuran-2-yl)methyl)-

4-methyl-N-tosylbenzenesulfonamide (3t). The general Procedure

was followed, and puriﬁed by column chromatography (5:1 petroleum

1

ether/EtOAc): white solid, 102.0 mg, 92% yield; mp 97−98 °C; H

NMR (600 MHz, CDCl₃) δ 7.79 (d, J = 8.4 Hz, 4H), 7.28−7.24 (m,

2H), 7.19 (d, J = 8.4 Hz, 4H), 7.01 (dd, J = 15.5, 7.8 Hz, 3H), 4.69−

4.60 (m, 1H), 4.09 (dd, J = 15.5, 7.3 Hz, 1H), 3.54 (dd, J = 15.6, 4.2

Hz, 1H), 2.41 (s, 6H), 1.99 (dd, J = 13.2, 6.6 Hz, 1H), 1.82 (dd, J =

13.2, 9.6 Hz, 1H), 1.73−1.64 (m, 4H), 0.97 (td, J = 7.2, 3.0 Hz, 6H);

¹³C{¹H} NMR (150 MHz, CDCl₃) δ 165.5, 147.6, 145.0, 136.3,

129.6, 128.6, 128.6, 123.2, 122.3, 77.9, 52.1, 48.6, 36.0, 31.0, 29.7,

21.7, 8.8; IR ν_max(cm⁻¹) 2959, 1701, 1596, 1495, 1373, 1354, 1184,

1167, 1086, 852, 732, 663, 552; HRMS (ESI) m/z [M + H]⁺calcd for

C₂₉H₃₅N₂O₅S₂555.1982, found 555.1985.

(Z)-N-((4,4-Diphenyl-5-(4-chlorophenylimino)tetrahydrofuran-2-

yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3p). The general

procedure was followed, and the product was puriﬁed by column

chromatography (5:1 petroleum ether/EtOAc): white solid, 123.2

mg, 90% yield; mp 126−127 °C; ¹H NMR (600 MHz, CDCl₃) δ 7.74

(d, J = 8.4 Hz, 4H), 7.40−7.34 (m, 6H), 7.31 (t, J = 7.8 Hz, 3H),

7.26−7.16 (m, 7H), 7.10 (d, J = 8.4 Hz, 2H), 4.68−4.59 (m, 1H),

4.10 (dd, J = 15.6, 7.2 Hz, 1H), 3.66 (dd, J = 15.6, 4.8 Hz, 1H), 2.95

(dd, J = 13.2, 5.4 Hz, 1H), 2.69 (dd, J = 13.2, 9.6 Hz, 1H), 2.41 (s,

6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 163.4, 145.3, 145.1, 142.8,

141.6, 136.2, 129.6, 128.9, 128.7, 128.5, 128.4, 128.3, 128.2, 127.6,

127.4, 127.0, 124.1, 77.1, 57.9, 51.0, 42.5, 21.7; IR ν_max(cm⁻¹) 2961,

2359, 2341, 1697, 1585, 1485, 1375, 1306, 1263, 1167, 1083, 730,

(Z)-N-((4,4-Dipropyl-5-phenyliminotetrahydrofuran-2-yl)-

methyl)-4-methyl-N-tosylbenzenesulfonamide (3u). The general

Procedure was followed, and puriﬁed by column chromatography

(5:1 petroleum ether/EtOAc): white solid, 109.5 mg, 94% yield; mp

1

125−126 °C; H NMR (600 MHz, CDCl₃) δ 7.79 (d, J = 8.4 Hz,

4H), 7.29−7.23 (m, 2H), 7.19 (d, J = 8.4 Hz, 4H), 7.05−6.96 (m,

3H), 4.67−4.58 (m, 1H), 4.09 (dd, J = 15.6, 7.4 Hz, 1H), 3.54 (dd, J

= 15.6, 4.2 Hz, 1H), 2.40 (s, 6H), 2.04−1.97 (m, 1H), 1.82 (dd, J =

13.2, 9.6 Hz, 1H), 1.73−1.63 (m, 1H), 1.61−1.54 (m, 3H), 1.48−

1.28 (m, 4H), 0.94 (q, J = 7.2 Hz, 6H); ¹³C{¹H} NMR (150 MHz,

CDCl₃) δ 165.8, 147.5, 144.9, 136.1, 129.5, 128.5, 128.4, 123.1, 122.2,

77.8, 51.9, 47.8, 40.9, 39.8, 36.9, 21.6, 17.6, 17.6, 14.5, 14.5; IR ν_max

(cm⁻¹) 2968, 2932, 1701, 1595, 1495, 1373, 1354, 1188, 1167, 1086,

816, 723, 663, 551; HRMS (ESI) m/z [M + H]⁺calcd for

C₃₁H₃₉N₂O₅S₂583.2295, found 583.2298.

663, 552; HRMS (ESI) m/z [M

C₃₇H₃₄ClN₂O₅S₂685.1592, found 685.1594.

+

H]⁺calcd for

(Z)-N-((4,4-Diphenyl-5-(4-bromophenylimino)tetrahydrofuran-

2-yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3q). The gen-

eral procedure was followed, and the product was puriﬁed by column

chromatography (5:1 petroleum ether/EtOAc): white solid, 132.6

mg, 91% yield; mp 109−110 °C; ¹H NMR (600 MHz, CDCl₃) δ 7.74

(d, J = 8.4 Hz, 4H), 7.40−7.33 (m, 8H), 7.31 (t, J = 7.8 Hz, 3H), 7.24

(d, J = 5.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 4H), 7.04 (d, J = 8.4 Hz, 2H),

4.69−4.60 (m, 1H), 4.10 (dd, J = 15.6, 7.2 Hz, 1H), 3.64 (dd, J =

15.6, 4.8 Hz, 1H), 2.96 (dd, J = 13.2, 5.4 Hz, 1H), 2.69 (dd, J = 13.2,

9.6 Hz, 1H), 2.42 (s, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ

163.4, 145.9, 145.2, 142.8, 141.6, 136.2, 131.5, 129.7, 128.7, 128.3,

128.3, 128.2, 127.7, 127.5, 127.1, 124.5, 116.7, 77.2, 57.9, 51.0, 42.5,

21.7; IR ν_max(cm⁻¹) 3059, 2361, 1693, 1596, 1492, 1483, 1446, 1373,

1167, 1083, 1068, 814, 732, 662, 552; HRMS (ESI) m/z [M + H]⁺

calcd for C₃₇H₃₄BrN₂O₅S₂729.1087, found 729.1088.

(2R,3R,Z)-N-((3-Methyl-4,4-diphenyl-5-phenyliminotetrahydro-

furan-2-yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3v). The

general procedure was followed, and the product was puriﬁed by

column chromatography (10:1 petroleum ether/EtOAc). The

product was given as a mixture of two inseparable isomers with dr

> 20:1, white solid, 89.0 mg, 67% yield; mp 156−157 °C. Major

isomer: ¹H NMR (600 MHz, CDCl₃) δ 7.78 (d, J = 8.4 Hz, 4H), 7.52

(d, J = 7.8 Hz, 2H), 7.34 (t, J = 7.8 Hz, 2H), 7.31−7.24 (m, 6H), 7.17

(d, J = 8.4 Hz, 4H), 7.10 (d, J = 7.8 Hz, 2H), 7.02 (t, J = 7.2 Hz, 1H),

6.86 (dd, J = 6.6, 3.0 Hz, 2H), 4.26 (dd, J = 15.6, 7.8 Hz, 1H), 4.19−

4.17 (m, 1H), 3.74 (dd, J = 15.6, 1.8 Hz, 1H), 3.12−3.00 (m, 1H),

2.41 (s, 6H), 0.88 (d, J = 6.6 Hz, 3H); ¹³C{¹H} NMR (150 MHz,

CDCl₃) δ 163.1, 147.1, 145.0, 141.2, 141.1, 136.4, 129.6, 129.2, 129.1,

128.7, 128.6, 128.0, 127.8, 127.3, 127.1, 123.6, 122.4, 82.3, 60.6, 50.8,

42.3, 21.8, 12.3; IR ν_max(cm⁻¹) 3043,1693, 1593, 1493, 1446, 1379,

1373, 1348, 1167, 1086, 1056, 843, 719, 698, 662, 550; HRMS (ESI)

m/z [M + H]⁺calcd for C₃₈H₃₇N₂O₅S₂665.2138, found 665.2140.

(2R,3R,Z)-N-((3-Methyl-4,4-diphenyl-5-(4-ﬂuorophenylimino)ote

trahydrofuran-2-yl)methyl)-4-methyl-N-tosylbenzenesulfonamide

(3w). The general procedure was followed, and the product was

puriﬁed by column chromatography (20:3 petroleum ether/EtOAc).

The product was given as a mixture of two inseparable isomers with

dr > 20:1, white solid, 83.2 mg, 61% yield; mp 89−90 °C. Major

isomer: ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J = 8.4 Hz, 4H), 7.50

(d, J = 7.2 Hz, 2H), 7.37−7.30 (m, 4H), 7.27 (d, J = 2.4 Hz, 2H),

7.21 (d, J = 8.4 Hz, 4H), 7.12 (dd, J = 10.4, 3.6 Hz, 2H), 6.95 (t, J =

(Z)-N-((4,4-Diphenyl-5-benzyliminotetrahydrofuran-2-yl)-

methyl)-4-methyl-N-tosylbenzenesulfonamide (3r). The general

procedure was followed, and the product was puriﬁed by column

chromatography (10:3 petroleum ether/EtOAc), white solid, 123.6

1

mg, 93% yield; mp 60−61 °C. Major isomer: H NMR (600 MHz,

CDCl₃) δ 7.86 (d, J = 8.4 Hz, 4H), 7.34−7.25 (m, 12H), 7.24−7.16

(m, 7H), 4.68−4.57 (m, 2H), 4.56−4.46 (m, 1H), 4.12 (dd, J = 15.4,

6.5 Hz, 1H), 3.78 (dd, J = 15.6, 4.8 Hz, 1H), 2.88 (dd, J = 13.2, 4.8

Hz, 1H), 2.59 (dd, J = 12.6, 10.2 Hz, 1H), 2.38 (s, 6H); ¹³C{¹H}

NMR (150 MHz, CDCl₃) δ 163.6, 145.1, 143.1, 141.7, 140.7, 136.5,

129.7, 128.4, 128.3, 128.2, 128.1, 127.9, 127.6, 127.6, 127.1, 126.7,

J

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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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Article

8.8 Hz, 2H), 6.83 (dd, J = 6.4, 2.8 Hz, 2H), 4.33−4.12 (m, 2H), 3.77

(d, J = 14.0 Hz, 1H), 3.02−3.03 (m, 1H), 2.42 (s, 6H), 0.88 (d, J =

6.8 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 163.3,159.5 (d, J =

240.0 Hz), 145.1, 142.8, 142.7, 141.1, 141.0, 136.4, 129.6, 129.5,

129.1, 129.0, 128.5, 128.0, 127.8, 127.3, 127.2, 124.3 (d, J = 8.0 Hz),

115.1 (d, J = 21.8 Hz), 82.0, 60.8, 50.8, 42.3, 21.7, 12.3; IR ν_max

(cm⁻¹) 2924, 2358, 1697, 1596, 1502, 1373, 1354, 1167, 1084, 843,

814, 720, 662, 552; HRMS (ESI) m/z [M + H]⁺calcd for

C₃₈H₃₆FN₂O₅S₂683.2044, found 683.2051.

14.9; IR ν_max(cm⁻¹) 2926, 1701, 1595, 1504, 1369, 1352, 1165, 1083,

814, 696, 663, 552; HRMS (ESI) m/z [M + H]⁺calcd for

C₂₇H₂₉N₂O₅S₂525.1512, found 525.1513.

(Z)-N-((1-phenylimino-2-oxaspiro[4.4]nonan-3-yl)methyl)- −4-

methyl-N-tosylbenzenesulfonamide (3ab). The general procedure

was followed, and the product was puriﬁed by column chromatog-

raphy (5:1 petroleum ether/EtOAc): white solid, 91.7 mg, 83% yield;

1

mp 62−63 °C; H NMR (600 MHz, CDCl₃) δ 7.80 (d, J = 8.4 Hz,

4H), 7.28−7.25 (m, 2H), 7.20 (d, J = 8.4 Hz, 4H), 7.06 (d, J = 7.8

Hz, 2H), 7.01 (t, J = 7.2 Hz, 1H), 4.70−4.61 (m, 1H), 4.14 (dd, J =

15.6, 7.4 Hz, 1H), 3.58 (dd, J = 15.6, 4.2 Hz, 1H), 2.41 (s, 6H), 2.31

(dd, J = 14.4, 5.4 Hz, 1H), 2.09 (dd, J = 12.6, 6.0 Hz, 1H), 1.98−1.88

(m, 3H), 1.75−1.63 (m, 5H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ

167.1, 147.4, 145.0, 136.2, 129.6, 128.6, 128.5, 123.3, 122.5, 78.2,

51.5, 51.2, 41.3, 38.8, 37.9, 25.2, 25.1, 21.7; IR ν_max(cm⁻¹) 2955,

1701, 1595, 1502, 1373, 1354, 1167, 1084, 912, 816, 742, 663, 552;

HRMS (ESI) m/z [M + H]⁺calcd for C₂₉H₃₃N₂O₅S₂553.1825,

found 553.1828.

(2R,3R,Z)-N-((3-ethyl-4,4-diphenyl-5-phenyliminotetrahydrofur-

an-2-yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3x). The

general procedure was followed, and the product was puriﬁed by

column chromatography (20:3 petroleum ether/EtOAc): white solid,

1

dr > 20:1, 99.2 mg, 73% yield; mp 171−172 °C. Major isomer: H

NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 8.4 Hz, 4H), 7.58 (d, J = 7.2

Hz, 2H), 7.39−7.30 (m, 4H), 7.27−7.24 (m, 4H), 7.17 (d, J = 8.4 Hz,

4H), 7.09 (d, J = 7.2 Hz, 2H), 7.00 (t, J = 7.6 Hz, 1H), 6.93 (dd, J =

6.8, 3.2 Hz, 2H), 4.41−4.32 (m, 1H), 4.20 (dd, J = 15.6, 9.2 Hz, 1H),

3.76 (dd, J = 15.6, 1.2 Hz, 1H), 2.95−2.82 (m, 1H), 2.41 (s, 6H),

1.54−1.43 (m, 1H), 1.04 (dd, J = 14.8, 6.8 Hz, 1H), 1.00−0.94 (m,

3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 163.1, 147.1, 144.8, 141.6,

141.3, 136.5, 129.6, 129.2, 128.6, 128.5, 128.0, 127.9, 127.4, 127.1,

123.5, 122.4, 82.1, 61.2, 51.8, 49.1, 21.8, 21.7, 13.1; IR ν_max(cm⁻¹)

2922, 2851, 1697, 1595, 1489, 1373, 1354, 1167, 1083, 815, 702, 663,

552; HRMS (ESI) m/z [M + H]⁺calcd for C₃₉H₃₉N₂O₅S₂679.2295,

found 679.2296.

(Z)-N-((1-Phenylimino-2-oxaspiro[4.5]decan-3-yl)methyl)-4-

methyl-N-tosylbenzenesulfonamide (3ac). The general procedure

was followed, and the product was puriﬁed by column chromatog-

raphy (5:1 petroleum ether/EtOAc): white solid, 103.0 mg, 91%

yield; mp 82−83 °C; ¹H NMR (600 MHz, CDCl₃) δ 7.80 (d, J = 8.4

Hz, 4H), 7.27−7.24 (m, 2H), 7.20 (d, J = 8.4 Hz, 4H), 7.08−6.99 (m,

3H), 4.70−4.63 (m, 1H), 4.12 (dd, J = 15.6, 7.2 Hz, 1H), 3.58 (dd, J

= 15.6, 4.2 Hz, 1H), 2.42 (s, 6H), 2.28 (dd, J = 12.6, 6.0 Hz, 1H),

2.00−1.93 (m, 1H), 1.81−1.55 (m, 7H), 1.41−1.16 (m, 3H);

¹³C{¹H} NMR (150 MHz, CDCl₃) δ 167.6, 147.2, 145.0, 136.2,

(2R,3R,Z)-N-((3-methyl-4,4-diphenyl-5-benzyliminotetrahydro-

furan-2-yl)methyl)-4-methyl -N-tosylbenzenesulfonamide (3y).

The general procedure was followed, and the reaction time was

extended to 15 h. The product was puriﬁed by column

chromatography (5:1 petroleum ether/EtOAc): white solid, dr >

129.6, 128.6, 128.5, 123.4, 122.4, 78.2, 51.8, 45.4, 37.2, 35.6, 33.4,

25.3, 22.8, 22.6, 21.7; IR ν_max(cm⁻¹) 2932, 1697, 1595, 1502, 1493,

1373, 1352, 1167, 1083, 912, 815, 732, 662, 552; HRMS (ESI) m/z

[M + H]⁺calcd for C₃₀H₃₅N₂O₅S₂567.1982, found 567.1985.

(Z)-N-((1-Phenylimino-2,8-oxaspiro[4.5]decan-3-yl) methyl)-4-

methyl-N-tosylbenzenesulfonamide (3ad). The general procedure

was followed with 2j as the catalyst, and the product was puriﬁed by

column chromatography (5:2 petroleum ether/EtOAc). The product

was obtained as a mixture of two inseparable isomers with 5-exo/6-

endo = 16:1: white solid, 88.6 mg, 78% yield; mp 92−92 °C. Major

1

20:1, 86.8 mg, 64% yield; mp 142−143 °C. Major isomer: H NMR

(400 MHz, CDCl₃) δ 7.96 (d, J = 7.2 Hz, 4H), 7.48 (d, J = 7.2 Hz,

2H), 7.36−7.22 (m, 11H), 7.19 (d, J = 6.8 Hz, 4H), 6.75 (d, J = 6.8

Hz, 2H), 4.66 (d, J = 16.0 Hz, 1H), 4.52 (d, J = 16.0 Hz, 1H), 4.22−

4.11 (m, 2H), 3.88 (d, J = 13.6 Hz, 1H), 2.97 (d, J = 13.6 Hz, 1H),

2.42 (s, 6H), 0.86 (d, J = 5.0 Hz, 3H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 163.56, 145.02 (2C), 141.6, 141.3, 141.2, 137.0, 129.7,

129.2, 129.1, 128.3, 128.0, 127.8, 127.6, 127.4, 127.1, 126.9, 126.0,

81.0, 60.3, 51.4, 50.7, 42.4, 21.7, 12.3. IR ν_max(cm⁻¹) 3125, 2931,

1772, 1699, 1596, 1508, 1446, 1373, 1354, 1167, 1086, 816, 700, 663,

551. HRMS (ESI) m/z [M + H]⁺calcd for C₃₉H₃₉N₂O₅S₂679.2295,

found 679.2260.

1

isomer: H NMR (600 MHz, CDCl₃) δ 7.80 (d, J = 8.4 Hz, 4H),

7.29−7.25 (m, 2H), 7.21 (d, J = 8.4 Hz, 4H), 7.08 (d, J = 7.2 Hz,

2H), 7.03 (t, J = 7.2 Hz, 1H), 4.75−4.66 (m, 1H), 4.14 (dd, J = 15.6,

7.2 Hz, 1H), 4.10−3.98 (m, 2H), 3.61 (dd, J = 15.6, 4.2 Hz, 1H),

3.56−3.50 (m, 1H), 3.50−3.43 (m, 1H), 2.42 (s, 6H), 2.33 (dd, J =

12.6, 6.0 Hz, 1H), 2.30−2.22 (m, 1H), 2.21−1.96 (m, 1H), 1.73 (dd,

J = 12.6, 10.2 Hz, 1H), 1.53 (dd, J = 25.2, 13.8 Hz, 2H); ¹³C{¹H}

NMR (150 MHz, CDCl₃) δ 165.0, 146.9, 145.2, 136.2, 129.7, 128.7,

128.6, 123.6, 122.6, 77.8, 64.6, 64.1, 51.6, 42.7, 37.8, 35.2, 33.9, 21.7;

IR ν_max(cm⁻¹) 2953, 2852, 1699, 1595, 1207,1188, 1373, 1352, 1167,

1107, 1083, 912, 816, 735, 663, 552; HRMS (ESI) m/z [M + H]⁺

calcd for C₂₉H₃₃N₂O₆S₂569.1775, found 569.1778.

(Z)-N-((8-tert-Butyloxycarbonyl-1-phenylimino-2-oxa-8-

azaspiro[4.5]decan-3-yl) methyl)-4-methyl-N-tosylbenzenesulfo-

namide (3ae). The general procedure was followed, and the product

was puriﬁed by column chromatography (5:1 petroleum ether/

EtOAc). The product was obtained as a mixture of two inseparable

isomers with 5-exo/6-endo = 20:1: white solid, 89.4 mg, 67% yield; mp

95−96 °C. Major isomer: ¹H NMR (600 MHz, CDCl₃) δ 7.80 (d, J =

8.4 Hz, 4H), 7.28 (dd, J = 7.8, 6.0 Hz, 2H), 7.21 (d, J = 8.4 Hz, 4H),

7.08−7.00 (m, 3H), 4.76−4.67 (m, 1H), 4.18−3.87 (m, 3H), 3.61

(dd, J = 15.6, 4.2 Hz, 1H), 3.09−2.90 (m, 2H), 2.41 (s, 6H), 2.25

(dd, J = 12.6, 6.0 Hz, 1H), 2.13−2.05 (m, 1H), 1.88−1.81 (m, 1H),

1.71 (dd, J = 12.6, 10.2 Hz, 1H), 1.62−1.50 (m, 2H), 1.46 (s, 9H);

¹³C{¹H} NMR (150 MHz, CDCl₃) δ 165.0, 154.5, 146.7, 145.1,

(2R,3R,Z)-N-((3,4,4-trimethyl-5-phenyliminotetrahydrofuran-2-

yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3z). The general

procedure was followed with 2j as the catalyst, and puriﬁed by column

chromatography (5:1 petroleum ether/EtOAc). The product was

obtained as inseparable isomers with 5-exo/6-endo = 10:1, dr >20:1,

1

white solid, 78.8 mg, 73% yield; mp 133−134 °C. Major isomer: H

NMR (600 MHz, CDCl₃) δ 7.77 (d, J = 8.2 Hz, 4H), 7.28 (t, J = 7.8

Hz, 2H), 7.16 (d, J = 8.1 Hz, 4H), 7.08 (d, J = 7.5 Hz, 2H), 7.01 (t, J

= 7.4 Hz, 1H), 4.34−4.29 (m, 1H), 4.15 (dd, J = 16.1, 8.0 Hz, 1H),

3.55−3.49 (m, 1H), 2.40 (s, 6H), 1.84−1.77 (m, 1H), 1.29 (s, 3H),

1.13 (s, 3H), 1.05 (d, J = 6.9 Hz, 3H); ¹³C{¹H} NMR (150 MHz,

CDCl₃) δ 167.4, 147.4, 144.9, 136.1, 129.6, 128.7, 128.7, 123.4, 122.4,

84.0, 50.9, 45.2, 43.2, 24.5, 21.7, 20.7, 10.1; IR ν_max(cm⁻¹) 2970,

1703, 1596, 1508, 1373, 1354, 1292, 1167, 1086, 1043, 945, 816, 733,

663, 552; HRMS (ESI) m/z [M + H]⁺calcd for C₂₈H₃₃N₂O₅S₂

541.1825, found 541.1828.

(Z)-N-((4-phenylimino-5-oxaspiro[2.4]heptan-6-yl) methyl)-4-

methyl-N-tosylbenzenesulfon amide (3aa). The general procedure

was followed, and the product was puriﬁed by column chromatog-

raphy (5:1 petroleum ether/EtOAc): white solid, 82.8 mg, 79% yield;

1

mp 63−64 °C; H NMR (600 MHz, CDCl₃) δ 7.81 (d, J = 8.3 Hz,

143.4, 139.2, 136.0, 129.6, 128.6, 128.5, 126.3, 123.6, 122.4, 79.6,

77.8, 51.5, 43.4, 37.2, 34.7, 28.4, 21.6, 21.4. IR ν_max(cm⁻¹) 2976,

1693, 1595, 1487, 1427, 1371, 1280, 1167, 1084, 1043, 912, 816, 733,

663, 552; HRMS (ESI) m/z [M + H]⁺calcd for C₃₄H₄₂N₃O₇S₂

668.2459, found 668.2455.

4H), 7.27−7.20 (m, 6H), 7.07−6.99 (m, 3H), 4.96−4.84 (m, 1H),

4.16 (dd, J = 15.4, 7.3 Hz, 1H), 3.64 (dd, J = 15.4, 4.6 Hz, 1H), 2.42

(s, 6H), 2.24 (dd, J = 12.7, 7.3 Hz, 1H), 2.07 (dd, J = 12.7, 6.7 Hz,

1H), 1.39−1.31 (m, 1H), 1.30−1.25 (m, 1H), 0.98−0.83 (m, 2H);

¹³C{¹H} NMR (150 MHz, CDCl₃) δ 164.1, 146.0, 145.0, 136.2,

129.6, 128.6, 128.5, 123.2, 122.8, 78.2, 51.29, 34.5, 21.7, 21.4, 15.4,

(Z)-N-((2-Methyl-4,4-diphenyl-5-phenyliminotetrahydrofuran-2-

yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3af). The general

K

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J. Org. Chem. XXXX, XXX, XXX−XXX

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Article

procedure was followed with mixture solvents (HFIP/tert-BuOMe=

1:1), and the reaction time was extended to 15 h. The product was

puriﬁed by column chromatography (10:1 petroleum ether/EtOAc):

white solid, 95.6 mg, 72% yield; mp 93−94 °C; ¹H NMR (600 MHz,

CDCl₃) δ 7.67 (d, J = 8.4 Hz, 4H), 7.58 (d, J = 7.8 Hz, 2H), 7.39 (d, J

= 7.8 Hz, 2H), 7.37−7.29 (m, 5H), 7.28 (d, J = 7.2 Hz, 2H), 7.23 (d,

J = 7.8 Hz, 3H), 7.11 (d, J = 8.4 Hz, 4H), 7.06 (t, J = 7.2 Hz, 1H),

4.00 (d, J = 16.2 Hz, 1H), 3.86 (d, J = 16.2 Hz, 1H), 3.05 (s, 2H),

2.35 (s, 6H), 1.08 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ

163.0, 147.3, 144.8, 144.5, 143.6, 136.4, 129.4, 128.6, 128.6, 128.4,

128.2, 128.0, 127.9, 127.9, 126.9, 126.7, 123.5, 122.5, 85.0, 58.0, 56.6,

48.4, 24.4, 21.6. IR ν_max(cm⁻¹) 3059, 1693, 1595, 1491, 1446, 1373,

1356, 1226, 1167, 1084, 910, 814, 766, 732, 662, 552; HRMS (ESI)

m/z [M + H]⁺calcd for C₃₈H₃₇N₂O₅S₂665.2138, found 665.2139.

(Z)-N-((2-Methyl-4,4-diethyl-5-phenyliminotetrahydrofuran-2-

yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3ag). The gen-

eral procedure was followed with mixture solvents (HFIP/tert-

BuOMe= 1:1), and the reaction time was extended to 15 h. The

product was puriﬁed by column chromatography (10:1 petroleum

procedure was followed, and the product was puriﬁed by column

chromatography (10:1 petroleum ether/EtOAc). The product were

inseparable isomers with d.r.= 3:2, white solid, 87.9 mg, 73% yield;

1

mp 83−84 °C; H NMR (400 MHz, CDCl₃), distinguishable signals

for the minor diastereoisomer are reported in italics: δ 7.81 (d, J = 8.4

Hz, 4H), 7.77−7.68 (m, 4H), 7.52 (d, J = 9.0 Hz, 4H), 7.48−7.29 (m,

5H), 7.24 (d, J = 8.2 Hz, 4H), 7.20 (d, J = 7.3 Hz, 4H), 7.10 (q, J =

7.1 Hz, 1H), 4.94−4.84 (m, 1H), 4.55−4.41 (m, 1H), 4.18 (dd, J =

15.5, 6.4 Hz, 1H), 3.85−3.75 (m, 1H), 3.74−3.68 (m, 1H), 3.40−3.33

(m, 1H), 2.71−2.56 (m, 1H), 2.48 (s, 6H), 2.43 (s, 6H), 2.20−2.00

(m, 2H), 1.01 (t, J = 7.3 Hz, 3H), 0.92 (t, J = 7.3 Hz, 3H); ¹³C NMR

(100 MHz, CDCl₃, distinguishable signals for the minor diaster-

eoisomer are reported in italics) δ 163.5, 163.4, 147.3, 147.0, 145.1,

144.8, 143.2, 140.8, 136.4, 136.3, 129.7, 129.6, 128.7, 128.6, 128.5,

128.5, 128.4, 127.2, 127.0, 126.9, 126.5, 123.7, 123.4, 122.6, 122.5,

77.5, 77.1, 53.5, 5.19, 51.7, 51.4, 38.4, 37.8, 34.0, 33.2, 21.7, 21.7, 9.4.

IR ν_max(cm⁻¹) 2926, 1697, 1595, 1493, 1373, 1353, 1166, 1085, 816,

764, 731, 700, 663, 552; HRMS (ESI) m/z [M + H]⁺calcd for

C₃₃H₃₅N₂O₅S₂603.1982, found 603.1993.

1

ether/EtOAc): white solid, 62.5 mg, 55% yield; mp 81.0−82 °C; H

(Z)-N-((4-Methyl-4-(3-chlorophenyl)-5-phenyliminotetrahydro-

furan-2-yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3ak).

The general procedure was followed, and the product was puriﬁed

by column chromatography (20:3 petroleum ether/EtOAc). The

product were inseparable isomers with d.r.= 1:1, white solid, 95.7 mg,

NMR (600 MHz, CDCl₃) δ 7.72 (d, J = 8.4 Hz, 4H), 7.30−7.22 (m,

2H), 7.15 (d, J = 8.4 Hz, 4H), 7.02 (d, J = 7.2 Hz, 2H), 6.98 (t, J = 7.2

Hz, 1H), 4.20 (d, J = 15.6 Hz, 1H), 3.74 (d, J = 15.6 Hz, 1H), 2.39 (s,

6H), 1.99 (d, J = 1.2 Hz, 2H), 1.79−1.65 (m, 4H), 1.24 (s, 3H),

1.04−0.96 (m, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 166.1,

148.3, 144.8, 136.7, 129.4, 128.8, 128.7, 123.0, 122.0, 84.5, 57.4, 48.8,

42.1, 31.9, 31.8, 25.6, 21.7, 9.1, 9.0; IR ν_max(cm⁻¹) 2966, 1699, 1595,

1489, 1373, 1356, 1232, 1167, 1086, 1061, 964, 914, 733, 665, 552;

HRMS (ESI) m/z [M + H]⁺calcd for C₃₀H₃₇N₂O₅S₂569.2138,

found 569.2142.

1

77% yield; mp 79−81 °C; H NMR (600 MHz, CDCl₃) δ 7.7−7.71

(m, 8.2 Hz, 8H), 7.56 (s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.38 (s, 1H),

7.36−7.25 (m, 9H), 7.22−7.15 (m, 12H), 7.08 (q, J = 7.6 Hz, 2H),

4.90−4.82 (m, 1H), 4.46−4.28 (m, 1H), 4.14 (dd, J = 15.3, 6.3 Hz,

1H), 3.89 (dd, J = 15.6, 8.0 Hz, 1H), 3.67 (dd, J = 15.3, 5.5 Hz, 1H),

3.40 (dd, J = 15.6, 3.5 Hz, 1H), 2.52 (dd, J = 12.9, 4.8 Hz, 1H), 2.45

(dd, J = 13.1, 7.1 Hz, 1H), 2.41 (s, 6H), 2.40 (s, 7H), 2.33 (dd, J =

13.1, 6.8 Hz, 1H), 2.13−2.01 (m, 1H), 1.70 (s, 3H), 1.65 (s, 3H); ³C

NMR{¹H}(150 MHz, CDCl₃) δ 1164.4, 163.6, 146.7, 146.5, 145.1,

145.0, 136.2, 136.1, 134.6, 134.4, 130.0, 129.9, 129.6, 129.6, 129.6,

128.7, 128.6, 128.4, 128.3, 127.4, 127.1, 126.8, 126.3, 124.9, 124.1,

124.0, 123.7, 122.7, 122.5, 77.7, 76.7, 51.2, 51.0, 49.7, 48.4, 42.8, 42.7,

27.3, 27.2, 21.6, 21.6; IR ν_max(cm⁻¹) 2978, 1697, 1595, 1496, 1373,

1352, 1165, 1188, 1086, 912, 815, 734, 696, 663, 552; HRMS (ESI)

m/z [M + H]⁺calcd for C₃₂H₃₂ClN₂O₅S₂623.1436, found 623.1435.

(Z)-N-((4-Isopropyl-4-(3-chlorophenyl)-5-phenyliminotetrahy-

drofuran-2-yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3al).

The general procedure was followed with 2j as the catalyst, and

puriﬁed by column chromatography (20:3 petroleum ether/EtOAc).

The products were inseparable isomers with dr = 4:1, white solid, 80.7

mg, 62% yield; mp 112−113 °C. Major isomer: ¹H NMR (600 MHz,

CDCl₃) δ 7.78 (d, J = 8.4 Hz, 4H), 7.67 (d, J = 8.3 Hz, 1H), 7.54 (d, J

= 8.7 Hz, 2H), 7.33 (s, 1H), 7.28 (d, J = 7.5 Hz, 2H), 7.19 (d, J = 8.2

Hz, 4H), 7.08 (d, J = 7.3 Hz, 2H), 7.04 (t, J = 7.4 Hz, 1H), 4.47−4.42

(m, 1H), 4.14 (dd, J = 15.6, 6.3 Hz, 1H), 3.69 (dd, J = 15.6, 5.1 Hz,

1H), 2.53 (dd, J = 13.3, 4.8 Hz, 1H), 2.44 (dd, J = 13.5, 6.7 Hz, 1H),

2.40 (s, 6H), 2.11−2.04 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H), 0.68 (d, J

= 6.9 Hz, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 162.8, 146.9,

145.2, 138.4, 136.3, 133.2, 129.7,129.7, 128.7, 128.6, 128.5, 128.3,

128.3, 123.7, 122.4, 77.3, 56.3, 51.5, 35.9, 31.6, 21.7, 18.5, 18.0. IR

ν_max(cm⁻¹) 2958, 1697, 1595, 1492, 1373, 1352, 1165, 1086, 934,

843, 815, 737, 700, 663, 552; HRMS (ESI) m/z [M + H]⁺calcd for

C₃₄H₃₆ClN₂O₅S₂651.1749, found 651.1753.

(Z)-N-((3-Methyl-1-phenylimino-2-oxaspiro[4.5]decan-3-yl)-

methyl)-4-methyl-N-tosylbenzenesulfonamide (3ah). The general

procedure was followed, and with mixture solvents (HFIP/tert-

BuOMe = 1:1) and 2j as the catalyst, the reaction time extend to 15 h.

The product was puriﬁed by column chromatography (5:1 petroleum

ether/EtOAc): white solid, 60.4 mg, 52% yield; mp 150−151 °C; ¹H

NMR (600 MHz, CDCl₃) δ 7.73 (d, J = 8.4 Hz, 4H), 7.30−7.24 (m,

2H), 7.17 (d, J = 8.4 Hz, 4H), 7.07 (d, J = 7.8 Hz, 2H), 7.00 (t, J = 7.2

Hz, 1H), 4.12 (d, J = 16.2 Hz, 1H), 3.82 (d, J = 16.2 Hz, 1H), 2.40 (s,

6H), 2.07−1.99 (m, 2H), 1.90−1.82 (m, 1H), 1.82−1.70 (m, 4H),

1.66 (s, 1H), 1.49 (d, J = 13.2 Hz, 1H), 1.38−1.27 (m, 3H), 1.25 (s,

3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 167.7, 148.0, 144.8, 136.6,

129.4, 128.8, 128.6, 123.1, 122.4, 85.1, 57.2, 45.8, 43.6, 37.5, 36.8,

25.9, 25.2, 22.8, 22.8, 21.7; IR ν_max(cm⁻¹) 2935, 2854, 1682, 1593,

1487, 1362, 1348, 1240, 1191, 1173, 1163, 1083, 1034, 973, 815, 775,

555; HRMS (ESI) m/z [M + H]⁺calcd for C₃₁H₃₇N₂O₅S₂581.2138,

found 581.2135.

(Z)-N-((4-Methyl-4-phenyl-5-phenyliminotetrahydrofuran-2-yl)-

methyl)-4-methyl-N-tosylbenzenesulfonamide (3ai). The general

procedure was followed, and the product was puriﬁed by column

chromatography (10:1 petroleum ether/EtOAc). The product was

obtained as inseparable isomers with dr = 1:1, white solid, 90.6 mg,

77% yield; mp 67−68 °C; ¹H NMR (600 MHz, CDCl₃) δ 7.75 (d, J =

8.4 Hz, 4H), 7.71 (d, J = 8.4 Hz, 4H), 7.59 (d, J = 7.2 Hz, 2H), 7.42−

7.35 (m, 6H), 7.33−7.27 (m, 6H), 7.19 (t, J = 8.4 Hz, 8H), 7.14 (d, J

= 8.4 Hz, 4H), 7.07 (t, J = 7.2 Hz, 2H), 4.90−4.83 (m, 1H), 4.43−

4.37 (m, 1H), 4.14 (dd, J = 15.6, 6.6 Hz, 1H), 3.85 (dd, J = 15.6, 8.4

Hz, 1H), 3.66 (dd, J = 15.6, 5.4 Hz, 1H), 3.33 (dd, J = 15.6, 3.6 Hz,

1H), 2.55 (dd, J = 12.6, 4.8 Hz, 1H), 2.48−2.43 (m, 1H), 2.42−2.39

(m, 7H), 2.38 (s, 6H), 2.04 (dd, J = 12.6, 11.4 Hz, 1H), 1.72 (s, 3H),

1.66 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 165.0, 164.4,

147.1, 146.8, 145.0, 144.9, 144.4, 142.9, 136.3, 136.2, 129.6, 129.5,

128.7, 128.7, 128.6, 128.6, 128.4, 128.4, 127.1, 126.9, 126.5, 125.8,

123.8, 123.5, 122.7, 122.5, 77.8, 76.9, 51.3, 51.10, 49.8, 48.5, 42.9,

42.8, 27.5, 27.2, 21.7, 21.6; IR ν_max(cm⁻¹) 2976, 1705, 1595, 1493,

1446, 1373, 1352, 1167, 1086, 912, 816, 768, 733, 700, 663, 552;

HRMS (ESI) m/z [M + H]⁺calcd for C₃₂H₃₃N₂O₅S₂589.1825,

found 589.1821.

(Z)-N-((2′-(Phenylimino)-4′,5′-dihydro-2′H-spiro[ﬂuorene-9,3′-

furan]-5′-yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (3am).

The general procedure was followed and used 1am (10 mmol) as a

substrate; the reaction time was extended to 15 h. The product was

puriﬁed by column chromatography (7:1 petroleum ether/EtOAc):

1

pale yellow solid, 4.1 g, 63% yield; mp 67−68 °C; H NMR (400

MHz, CDCl₃) δ 7.87 (d, J = 8.4 Hz, 4H), 7.82−7.74 (m, 2H), 7.48−

7.33 (m, 6H), 7.29−7.22 (m, 6H), 7.06−6.93 (m, 3H), 5.31−5.25

(m, 1H), 4.46 (dd, J = 15.2, 6.0 Hz, 1H), 3.82 (dd, J = 15.7, 4.4 Hz,

1H), 2.70−2.63 (m, 1H), 2.52−2.47 (m, 1H), 2.44 (s, 6H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 162.4, 148.2, 147.0, 146.6, 145.2, 141.0,

140.1, 136.2, 129.7, 128.6, 128.5, 128.4, 128.3, 127.9, 124.0, 123.6,

122.7, 122.2, 120.7, 120.3, 78.9, 59.4, 51.8, 41.1, 21.7; IR ν_max(cm⁻¹)

(Z)-N-((4-Ethyl-4-phenyl-5-phenyliminotetrahydrofuran-2-yl)-

methyl)-4-methyl-N-tosylbenzenesulfonamide (3aj). The general

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3065, 1697, 1595, 1493, 1448, 1373, 1354, 1167, 1084, 910, 815, 733,

663,552; HRMS (ESI) m/z [M

C₃₇H₃₃N₂O₅S₂649.1825, found 649.1824.

heated to reﬂux for 48 h. Subsequently the mixture was concentrated

under vacuum and diluted with water. The mixture was extracted with

EtOAc. The combined organic phase was washed with brine, dried

over Na₂SO₄, ﬁltered, and concentrated. The residue was puriﬁed by

ﬂash column chromatography on silica gel (10:1 petroleum ether/

EtOAc) to give 4d as a white solid, 147.3 mg, 85% yield; mp 167.6−

168.4 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.86−7.76 (m, 4H), 7.41−

7.18 (m, 16H), 6.84 (d, J = 8.2 Hz, 2H), 6.73 (t, J = 7.2 Hz, 1H), 4.59

(d, J = 14.4 Hz, 1H), 3.96 (d, J = 14.4 Hz, 1H), 3.85 (m, 1H), 3.71

(dd, J = 15.1, 9.7 Hz, 1H), 3.54 (dd, J = 15.0, 2.7 Hz, 1H), 2.59−2.51

(m, 1H), 2.48 (s, 6H), 2.30 (s, 3H), 2.28−2.22 (m, 1H), 1.78(s, 1H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 151.3, 147.5, 146.3, 144.8,

136.8, 129.6, 129.0, 128.9, 128.6, 128.4, 128.2, 128.0, 126.4, 116.6,

113.3, 67.3, 61.7, 54.6, 51.8, 41.3, 41.1, 21.7; IR ν_max(cm⁻¹) 3055,

2924, 1597, 1506, 1495, 1445, 1371, 1352, 1165, 1084, 814, 750, 733,

700, 663, 552; HRMS (ESI) m/z [M + H]⁺calcd for

C₃₈H₄₁N₂O₅S₂669.2451, found 669.2442.

N-(2-Hydroxy-5-(methyl(phenyl)amino)-4,4-diphenylpentyl)-4-

methyl-N-tosylbenzenesulfonamide (4e). A solution of KOH (4 mL,

1M) was added 4d (233.2 mg, 0.34 mmol, 1.0 equiv), and the

reaction mixture was heated to reﬂux. After completion, the mixture

was quenched with HCl (1 M, aq) and extracted with CH₂Cl₂. The

organic phase was washed with brine, dried over Na₂SO₄, ﬁltered, and

concentrated. The ﬁltrate was concentrated under a vacuum, and the

residue was puriﬁed by ﬂash column chromatography on silica gel

(7:1 petroleum ether/EtOAc) to give 4e as a white solid (157.0 mg,

89% yield): mp 100.3−101.8 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.65

(d, J = 7.8 Hz, 2H), 7.37−7.00 (m, 15H), 6.76−6.57 (m, 3H), 4.14

(s, 2H), 3.65 (d, J = 7.9 Hz, 1H), 2.86−2.66 (m, 1H), 2.61−2.47 (m,

1H), 2.45 (s, 3H), 2.34−2.12 (m, 6H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 150.9, 146.5, 146.4, 143.0, 137.3, 129.6, 129.0, 128.5, 128.5,

128.3, 127.1, 126.7, 126.6, 117. 2, 113.5, 67.6, 61.1, 51.4, 49.1, 41.9,

41.2, 21.5; IR ν_max(cm⁻¹) 3057, 2922, 2359, 1597, 1506, 1497, 1447,

1329, 1159, 1092, 814, 750, 700, 552; HRMS (ESI) m/z [M + H]⁺

calcd for C₃₁H₃₅N₂O₃S 515.2363, found 515.2364.

+

H]⁺calcd for

N-(2-Hydroxy-4,4-diphenyl-5-(phenylamino)pentyl)-4-methyl-N-

tosylbenzenesulfonamide (4a). A solution 3j (325 mg, 0.50 mmol,

1.0 equiv, dissolved in 5 mLCH₂Cl₂) cooled to 0 °C under argon, and

H₄LiAl (2.5 M in THF, 1.0 mL) was added dropwise. Then, the

mixture was allowed to stir at room temperature for 5 h. Then, the

reaction was quenched with NaOH (1.0 M). The mixture was

extracted with EtOAc. The combined organic phase was washed with

brine, dried over Na₂SO₄, ﬁltered, and concentrated. The residue was

puriﬁed by ﬂash column chromatography on silica gel (10:1

petroleum ether/EtOAc) to give 4a as a white solid (309.4 mg,

1

95% yield). mp 138−139 °C. H NMR (400 MHz,CDCl₃) δ 7.85−

7.74 (m, 4H), 7.47−7.40 (m, 2H), 7.39−7.29 (m, 6H), 7.29−7.24

(m, 6H), 7.23−7.15 (m, 2H), 7.00−6.76 (m, 1H), 6.67−6.59 (m,

2H), 4.05 (d, J = 11.5 Hz, 1H), 4.01−3.86 (m, 2H), 3.78 (dd, J =

15.3, 9.2 Hz, 1H), 3.58 (dd, J = 15.3, 2.9 Hz, 1H), 3.43 (s, 1H), 2.58

(dd, J = 14.3, 7.7 Hz, 2H), 2.46 (s, 6H), 2.39 (dd, J = 14.3, 2.5 Hz,

1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 148.3, 146.7, 145.1, 144.9,

136.5, 129.6, 129.2, 128.6, 128.5, 128.5, 128.2, 127.8, 126.7, 126.7,

118.1, 113.9, 67.5, 54.9, 51.4, 42.8, 21.7. IR ν_max(cm⁻¹) 3053, 2359,

1601, 1504, 1495, 1371, 1165, 1084, 814, 700, 663, 552; HRMS

(ESI) m/z [M + H]⁺calcd for C₃₇H₃₉N₂O₅S₂655.2295, found

655.2288.

N-(2-Hydroxy-4,4-diphenyl-5-(phenylamino)pentyl)-4-methyl-

benzenesulfonamide (4b). A solution of KOH (1 M in MeOH, 5

mL) was added 4a (273.4 mg, 0.42 mol, 1.0 equiv), and the reaction

mixture was heated to reﬂux. After completion, the mixture was

quenched with HCl (1.0 M, aq) and extracted with CH₂Cl₂. The

organic phase was washed with brine, dried over Na₂SO₄, ﬁltered, and

concentrated. The residue was puriﬁed by ﬂash column chromatog-

raphy on silica gel (5:1, petroleum ether/EtOAc) to give 4b as a white

solid (189.1 mg, 90% yield). mp 75−76 °C. ¹H NMR (400

1

MHz,CDCl₃): H NMR (400 MHz, CDCl₃: δ 7.70 (d, J = 8.0 Hz,

2H), 7.42−7.18 (m, 15H), 6.82 (t, J = 7.3 Hz, 1H), 6.66 (d, J = 8.0

Hz, 2H), 5.43−5.32 (m, 1H), 4.03 (d, J = 11.3 Hz, 1H), 3.83 (d, J =

11.3 Hz, 1H), 3.67 (q, J = 6.0, 4.8 Hz, 1H), 3.40 (s, 1H), 2.95−2.85

(m, 1H), 2.82−2.68 (m, 1H), 2.53 (dd, J = 14.7, 8.0 Hz, 1H), 2.45 (s,

3H), 2.36 (d, J = 14.6 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

147.9, 146.4, 144.9, 143.3, 136.8, 129.8, 129.3, 128.8, 128.7, 127.9,

127.6, 127.1, 126.8, 119.0, 114.4, 67.1, 51.6, 49.6, 49.6, 42.7, 21.6;

HRMS (ESI) m/z [M + H]⁺calcd for C₃₀H₃₃N₂O₃S, 501.2206, found

501.2204.

1-Amino-4,4-diphenyl-5-(phenylamino)pentan-2-ol (4c). Follow-

ing a literature procedure.³⁸To a solution of sodium naphthalenide

[prepared by stirring a mixture of sodium (5.2 equiv, 1.0 mmol, 23.0

mg) and naphthalene (5.5 equiv, 1.0 mmol, 130.8 mg) in THF (4.5

mL) under argon at room temperature until the metal sodium is

completely consumed]. After that, a solution of 4b (95.0 mg, 0.19

mmol, 1.0 equiv) in 2 mL THF was added. The resulting reaction

mixture was allowed to stir at room temperature for 3 h, and the

reaction was quenched by the addition of ice−water, extracted with

dichloromethane, and the combined organic layers were dried over

Na₂SO₄. The ﬁltered was concentrated and the residue was puriﬁed

by ﬂash column chromatography on silica gel (20:1:0.01 dichloro-

methane/Methanol/NEt₃) to give 4c as a colorless oil (62.2 mg, 95%

yield). ¹H NMR (400 MHz, CDCl₃) δ 7.41−7.18 (m, 11H), 7.04 (t, J

= 7.6 Hz, 2H), 6.63 (t, J = 7.3 Hz, 1H), 6.52 (d, J = 7.8 Hz, 2H), 4.07

(d, J = 11.3 Hz, 1H), 3.69 (d, J = 10.9 Hz, 1H), 3.61 (s, 1H), 2.63

(dd, J = 14.0, 7.6 Hz, 1H), 2.51 (t, J = 10.7 Hz, 1H), 2.25 (d, J = 12.6

Hz, 1H), 1.98 (d, J = 14.2 Hz, 1H), 1.23−1.10 (m, 3H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 148.3, 146.9, 145.6, 129.2, 128.5, 128.5,

128.1, 127.8, 126.6, 126.6, 118.1, 113.8, 68.87, 51.61, 49.8, 48.4, 42.9;

HRMS (ESI) m/z [M + H]⁺calcd for C₂₃H₂₇N₂O 347.2118, found

347.2113.

1-Amino-5-(methyl(phenyl)amino)-4,4-diphenylpentan-2-ol

(4f). Following literature procedure,³⁸to a solution of sodium

naphthalenide [prepared by stirring a mixture of sodium (32.0 mg, 1.4

mmol, 5.2 equiv) and naphthalene (189.8 mg, 1.5 mmol, 5.5 equiv) in

THF (4.5 mL) at room temperature until the metal sodium is

completely consumed]. After that, a solution of 4e (90.0 mg, 0.18

mmol, 1.0 equiv) in THF (2 mL) was added. The resulting reaction

mixture was allowed stirring at room temperature for 1 h, and the

reaction was quenched by the addition of ice−water, extracted with

dichloromethane, and the combined organic layers were dried over

Na₂SO₄. The ﬁltered was concentrated and the residue was puriﬁed

by ﬂash column chromatography on silica gel (30:1:0.01 dichloro-

methane/Methanol/NEt₃) to give 4f as a colorless oil (57.6 mg, 89%

yield). ¹H NMR (400 MHz, CDCl₃) δ 7.35−7.31 (m, 4H), 7.30−7.23

(m, 6H), 7.19−7.14 (t, J = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 6.68

(t, J = 8.4 Hz, 1H), 4.29 (d, J = 14.4 Hz, 1H), 4.17 (d, J = 14.4 Hz,

1H), 3.53−3.46 (m, 1H), 2.46−2.20 (m, 8H), 2.17−2.08 (m, 2H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 151.1, 147.1, 146.7, 128.8,

128.8, 128.7, 128.2, 128.1, 126.5, 126.4, 116.8, 113.3, 69.6, 61.4, 51.7,

48.0, 42.0, 41.1. IR ν_max(cm⁻¹) 3057, 2924, 2881, 1599, 1558, 1506,

1497, 1445, 1373, 1267, 1034, 910, 748, 732, 700; HRMS (ESI) m/z

[M + H]⁺calcd for C₂₄H₂₉N₂O 361.2274, found 361.2276.

N-((5-Oxo-4,4-diphenyltetrahydrofuran-2-yl)methyl)-4-methyl-

N-tosylbenzenesulfonamide (4g). A solution 3j (325.4 mg, 0.50

mmol, 0.1 M in CH₂Cl₂) was add two drops concentrated

hydrochloric acid, the solution was allowed stir 2 h at room

temperature. Subsequently the reaction solution was diluted with

water, extracted with CH₂Cl₂. The combined organic phase was

washed with brine, dried over Na₂SO₄, ﬁltered, and concentrated. The

residue was puriﬁed by ﬂash column chromatography on silica gel

(8:1 petroleum ether/EtOAc) to give 4g as a white solid (284.3 mg,

98% yield). mp 186−187 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.94 (d,

J = 8.1 Hz, 4H), 7.43−7.08 (m, 14H), 4.66−4.60 (m, 1H), 4.19 (dd, J

= 15.7, 6.2 Hz, 1H), 3.90 (dd, J = 15.8, 4.8 Hz, 1H), 2.98 (dd, J =

13.1, 5.0 Hz, 1H), 2.71 (dd, J = 12.8, 10.7 Hz, 1H), 2.46 (s, 6H);

N-(2-Hydroxy-5-(methyl(phenyl)amino)-4,4-diphenylpentyl)-4-

methylbenzenesulfonamide (4d). To a solution of 4a (170.0 mg,

0.26 mmol) in 2 mL anhydrous acetone was added K₂CO₃(72.8 mg,

0.52 mmol) and dimethyl sulfate (29.4 μL, 0.32 mmol), and then

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¹³C{¹H} NMR (100 MHz, CDCl₃):δ 176.0, 145.4, 141.4, 139.4,

136.3, 129.8, 129.0, 128.6, 128.4, 127.8, 127.7, 127.3, 127.2, 75.2,

57.8, 51.2, 41.0, 21.7; IR ν_max(cm⁻¹) 3061, 1776, 1597, 1493, 1448,

1375, 1354, 1167, 1084, 816, 698, 663, 552; HRMS (ESI) m/z [M

+NH₄]⁺calcd for C₃₁H₃₃N₂O₆S₂593.1775, found 593.1773.

ethyl acetate, dried over Na₂SO₄, ﬁltered, and concentrated. The

residue was puriﬁed by ﬂash column chromatography on silica gel

(1.5:1:0.01 petroleum ether/EtOAc/NEt₃) to give 4k as a colorless

1

oil, 84.3 mg, 91% yield. H NMR (400 MHz, CDCl₃) δ 7.41−7.18

(m, 10H), 6.63−6.53 (m, 1H), 4.53−4.39 (m, 1H), 3.79−3.72 (m,

1H), 4.40−3.34 (m, 1H), 3.02 (dd, J = 13.1, 5.0 Hz, 1H), 2.67 (dd, J

= 13.1, 10.6 Hz, 1H), 1.96 (s, 3H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 177.1, 170.9, 141.7, 139.5, 129.0, 128.5, 127.9, 127.7, 127.4,

127.2, 76.4, 58.1, 42.2, 40.0, 23.0. IR ν_max(cm⁻¹) 3058, 2931, 1764,

1598, 1494 1558, 1446, 1495, 1348, 1176, 1130, 1174, 1027, 966,

750, 698, 650; HRMS (ESI) m/z [M + H]⁺calcd for

C₁₉H₂₀NO₃310.1438, found 310.1438.

5-(Aminomethyl)-3,3-diphenyldihydrofuran-2(3H)-one (4h). In a

thick-walled reaction tube was added phenol (66.5 mg, 0.7 mmol), 4g

(150 mg, 0.36 mmol) and a solution of hydrogen bromide in acetic

acid (2 mL, 35 wt %). The reaction tube was sealed with a Teﬂon

stopper, and the mixture was allowed to stir at 80 °C oil bath

temperature for 5 h. Then, the acetic acid was removed under

vacuum, and the brown residue was dissolved in water (30 mL), and

washed with ether. The aqueous phase was added excess saturated

sodium carbonate until PH > 7, then the mixture was extracted with

dichloromethane, dried over Na₂SO₄, ﬁltered, and concentrated. The

residue was puriﬁed by ﬂash column chromatography on silica gel

(20:1:0.01 dichloromethane/Methanol/NEt₃) to give 4h as a

(2R,2′R)-Diethyl 2,2′-((2-Iodo-5-methyl-1,3-phenylene)bis(oxy)-

dipropanoate (5a). Following a procedure by Du,³⁹to a solution

of 2-iodo-5-methylbenzene-1,3-diol (2.50 g, 10.0 mmol), PPh₃(6.56

g, 25.0 mmol), and ethyl ^L(−)-lactate (2.81 mL, 25.0 mmol) in THF

(50 mL) was added slowly diisopropyl azodicarboxylate (DIAD, 1.9

M in toluene, 25.0 mmol, 13.2 mL) at 0 °C. The reaction mixture was

allowed to warm to room temperature. After stirring for 6 h, the

resulting mixture was concentrated in vacuo. The residue was puriﬁed

by ﬂash column chromatography on silica gel (20:1 petroleum ether/

EtOAc) to give 5a as a colorless oil: 3.69 g, 82% yield; ¹H NMR (400

MHz, CDCl₃) δ 6.21 (s, 2H), 4.73 (q, J = 6.9 Hz, 2H), 4.22 (q, J =

7.1 Hz, 4H), 2.24 (s, 3H), 1.68 (d, J = 6.7 Hz, 6H), 1.31−1.22 (m,

6H).

1

colorless oil, 71.1 mg, 74% yield; H NMR (400 MHz, CDCl₃) δ

7.55−7.25 (m, 10H), 4.49−4.35 (m, 1H), 3.09 (dd, J = 13.8, 3.6 Hz,

1H), 3.02−2.88 (m, 2H), 2.80 (dd, J = 12.9, 10.5 Hz, 1H), 1.62 (s,

2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 177.1, 141.9, 139.9, 129.0,

128.4, 127.8, 127.7, 127.3, 127.23, 78.6, 58.2, 45.4, 40.2; IR ν_max

(cm⁻¹) 3462, 2928, 1758, 1596, 1495, 1447, 1173, 966, 757, 698;

HRMS (ESI) m/z [M + H]⁺calcd for C₁₇H₁₈NO₂268.1332, found

268.1328.

(2R,2′R)-2,2′-((2-Iodo-5-methyl-1,3-phenylene)bis(oxy)-

dipropanoic Acid (5b). To a solution of 5a (3.15 g, 7.0 mmol) in 50

mL of the mixed solvent THF/MeOH (1:1, v:v) was added 25 mL of

NaOH (2.0 M, aq) and stirred overnight at room temperature. The

reaction mixture was cooled to 0 °C, quenched with HCl (2 M, aq),

and extracted with EtOAc. The organic layers were dried over

anhydrous Na₂SO₄, and the solvents were removed in vacuo to give

pure 5b as a white solid: 2.65 g, 96% yield; spectroscopic data in

accordance with literature;^10f¹H NMR (400 MHz; DMSO-d₆) δ 6.29

(s, 2H), 4.84 (q, J = 6.9 Hz, 2H), 2.22 (s, 3H), 1.55 (dd, J = 6.8, 2.3

Hz, 6H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 173.1, 157.9,

139.9, 107.4, 76.3, 73.2, 21.9, 18.8.

General Procedure for the Synthesis of 5c−5g. To a solution

of corresponding (2R,2′R)-2,2′-((2-iodo-1,3-phenylene)bis(oxy)-

dipropanoic acid (2.0 mmol, 1.0 equiv) in CH₂Cl₂(10 mL) was

added oxalyl chloride (0.63 mL,4.0 equiv) under argon at 0 °C, and

then DMF (1 drop) was added carefully. After stirring for 1 h at 0 °C,

the mixture was allowed to stir at room temperature for another 5 h.

Then, the resulting mixture was concentrated under vacuum to

remove the solvent and the excessive oxalyl chloride. Then, the

residue was dissolved in 10 mL CH₂Cl₂under argon at 0 °C, and then

corresponding amine (2.4 mmol, 1.2 equiv) was slowly added. After

stirring for 30 min, Et₃N (0.55 mL, 2.0 equiv) was added. The

resulting mixture was stirred at room temperature for 5 h. Then, the

reaction mixture was quenched by HCl (1 M, aq) and extracted with

CH₂Cl₂. The organic phase was washed with brine, dried over

Na₂SO₄, ﬁltered, and concentrated under a vacuum. The crude

residue was puriﬁed by ﬂash column chromatography on silica gel to

give the desire products.

5-((Benzylamino)methyl)-3,3-diphenyldihydrofuran-2(3H)-one

(4i). To a solution of 4h (80.6 mg, 0.30 mmol, 1.0 equiv, in 2 mL

MeOH) was added benzaldehyde 46 μL (0.45 mmol, 1.5 equiv). The

reaction mixture was stirred for 2 h at room temperature, and then

sodium cyanoborohydride (38 mg, 0.6 mmol, 2.0 equiv) was added.

The resulting mixture was stirred for 24 h at room temperature. After

completion, the reaction solution was diluted with saturated sodium

bicarbonate, extracted with ethyl acetate, dried over Na₂SO₄, ﬁltered,

and concentrated. The residue was puriﬁed by ﬂash column

chromatography on silica gel (10:1 petroleum ether/EtOAc) to give

4i as a colorless oil, 87.8 mg, 82% yield. ¹H NMR (400 MHz, CDCl₃)

δ 7.53−7.20 (m, 15H), 4.59−4.53 (m, 1H), 3.88 (d, J = 2.9 Hz, 2H),

3.12−2.95 (m, 2H), 2.94−2.86 (m, 2H), 1.77(s, 1H); ¹³C

NMR{¹H}(100 MHz, CDCl₃) δ 177.1, 142.0, 139.8, 129.0 128.5,

128.4, 128.2, 127.8, 127.4, 127.3, 127.2, 77.0, 58.1, 53.9, 52.2, 40.8. IR

ν_max(cm⁻¹) 3026, 2932, 1765, 1495, 1447, 1176, 966, 750, 698;

HRMS (ESI) m/z [M + H]⁺calcd for C₂₄H₂₄NO₂358.1802, found

358.1794.

1-Cyclopropyl-N-((5,5-diphenyltetrahydrofuran-3-yl)methyl)-

methanamine (4j). To a solution of 4h (250 mg, 0.94 mmol, 1.0

equiv, in 3 mL MeOH) was added cyclopropanecarboxaldehyde (60

μL, 1.1 equiv). The reaction mixture was stirred for 2 h at room

temperature, and then sodium borohydride (113.4 mg, 3.0 equiv) was

added. The resulting mixture was stirred for 24 h at room

temperature. After completion, the reaction solution was diluted

with saturated sodium bicarbonate, extracted with ethyl acetate (3×

15 mL), dried over Na₂SO₄, ﬁltered, and concentrated. The residue

was puriﬁed by ﬂash column chromatography on silica gel (2:1:0.01

petroleum ether/EtOAc/NEt₃) to give 4j as a colorless oil, 203.6 mg,

1

71% yield. H NMR (400 MHz, CDCl₃) δ 7.36 (s, 2H), 7.27−7.19

(2R,2′R)-2,2′-((2-Iodo-1,3-phenylene)bis(oxy))bis(N-mesitylpro-

panamide) (5c). The compound was puriﬁed by ﬂash column

chromatography on silica gel (3:1 petroleum ether/EtOAc) to give 5c

as a white solid: 503 mg, 41% yield; spectroscopic data in accordance

with literature;^10f¹H NMR (400 MHz, CDCl₃) δ 8.02 (d, J = 6.4 Hz,

2H), 7.39−7.31 (m, 1H), 6.90 (s, 4H), 6.65 (dd, J = 8.3, 2.2 Hz, 2H),

5.09−4.93 (m, 2H), 2.27 (s, 6H), 2.15 (s, 12H), 1.87−1.72 (m, 6H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 169.6, 157.0, 137.3, 135.1,

(m, 6H), 7.14−7.08 (m, 2H), 3.74−3.64 (m, 1H), 3.50−3.30 (m,

1H), 2.99−2.86 (m, 1H), 2.66−2.44 (m, 2H), 2.39 (dd, J = 12.8, 6.5

Hz, 1H), 2.30 (dd, J = 12.8, 6.8 Hz, 1H), 2.25−2.03 (m, 3H), 1.03−

0.88 (m, 1H), 0.61−0.48 (m, 2H), 0.15 (d, J = 5.1 Hz, 2H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 148.0, 146.9, 128.3, 128.1, 128.0, 127.0,

126.1, 125.8, 65.8, 63.3, 62.3, 61.1, 46.4, 43.6, 8.4, 4.4, 3.9; IR ν_max

(cm⁻¹) 3334, 2942, 2772, 1496, 1447, 1208, 1067, 1050, 911, 755,

730, 699; HRMS (ESI) m/z [M + H]⁺calcd for C₂₁H₂₆NO 308.2009,

found 308.2005.

130.7, 130.1, 129.0, 107.1, 80.5, 76.2, 20.9, 18.8, 18.3.

(2R,2′R)-2,2′-((2-Iodo-5-methyl-1,3-phenylene)bis(oxy))bis(N-

(2,6-diisopropylphenyl)propanamide) (5d). The compound was

puriﬁed by ﬂash column chromatography on silica gel (3:1 petroleum

ether/EtOAc) to give 5d as a white solid: 949 mg, 68% yield;

spectroscopic data in accordance with literature;^10f¹H NMR (400

MHz, CDCl₃) δ 8.05 (d, J = 38.4 Hz, 2H), 7.41 (t, J = 8.3 Hz, 1H),

7.32 (d, J = 15.6 Hz, 2H), 7.20 (d, J = 7.7 Hz, 4H), 6.72 (d, J = 8.4

N-((5-Oxo-4,4-diphenyltetrahydrofuran-2-yl)methyl)acetamide

(4k). To a solution of 4h (80.2 mg, 0.30 mmol, 1.0 equiv, in 2.0 mL

CH₂Cl₂) was added acetyl chloride (22 μL, 1.0 equiv). The resulting

mixture was allowed stir for 0.5 h at room tenperature, and then NEt₃

(100 μL, 2.5 equiv) was added. The reaction mixture was stirred for 2

h, and then diluted with saturated sodium bicarbonate, extracted with

N

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Hz, 2H), 5.08 (q, J = 6.7 Hz, 2H), 3.09−2.80 (m, 4H), 1.81 (d, J =

6.6 Hz, 6H), 1.33−0.98 (m, 24H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 170.5, 157.0, 146.2, 130.6, 130.1, 128.6, 123.6, 107.2, 80.6,

76.1, 28.7, 23.6, 18.7.

(R,Z)-N-((4,4-Diphenyl-5-(3-chlorophenylimino)tetrahydrofuran-

2-yl)methyl)-N-tosyl-(4-me thylbenzenesulfon)amide (3o*): [α]_D²⁰

−27.40 (c 0.10, MeOH, 95% ee). HPLC analysis: Chiracel-IA3, n-

hexane/isopropanol = 90:10, ﬂow rate 0.8 mL/min, λ = 210 nm.

Retention time: t_major= 8.70 min, t_minor= 12.09 min. The absolute

conﬁguration was tentatively assigned by analogy with 3n*.

(R, Z)-N-((4, 4-Diphenyl-5-(4-bromophenylimino)-

tetrahydrofuran-2-yl)methyl)-N-tosyl-(4-meth ylbenzenesulfon)-

amide (3q*): [α]²_D⁰−16.46 (c 0.10, MeOH, 59% ee). HPLC analysis:

Chiracel-IA3, n-hexane/isopropanol = 90:10, ﬂow rate 0.8 mL/min, λ

= 254 nm. Retention time: t_major= 10.34 min, t_minor= 14.09 min. The

absolute conﬁguration was tentatively assigned by analogy with 3n*.

(R,Z)-N-((4,4-Diphenyl-5-methoxyiminotetrahydrofuran-2-yl)-

methyl)-N-tosyl-(4-methylbenze nesulfon)amide (3s*): [α]_D²⁰

+32.81 (c 0.10, MeOH, 98% ee). HPLC analysis: Chiracel-IA3, n-

hexane/isopropanol = 90:10, ﬂow rate 0.8 mL/min, λ = 210 nm.

Retention time: t_major= 7.68 min, t_minor= 10.39 min. The absolute

conﬁguration was tentatively assigned by analogy with 3n*.

Procedure for Control Experiments. There are three reaction

tubes numbered 1, 2, and 3. No. 1 reaction tube contains mCPBA

(30.5 mg, 85 wt %, 0.15 mmol, 1.5 equiv), HNTs₂(48.8 mg, 0.15

mmol, 1.5 equiv), and HFIP (1.0 mL). The reaction tube was capped,

and the resulting mixture was stirred 10 min at room temperature.

Then, 1a (20.3 mg, 0.1 mmol, 1.0 equiv) was added. The mixture was

stirred at room temperature, and 1a was complete consumption in 3 h

(monitored by TLC). It needs to mention that we did not detect the

formation of 3a. Then the solvent was removed under a vacuum, and

the residue was diluted with aqueous NaOH (1.0 M, 10 mL) and

stirred for 10 min. Then, the resulting mixture was extracted with

dichloromethane. The organic phase was washed with brine, dried

over Na₂SO₄, ﬁltered, and concentrated under a vacuum. The residue

was puriﬁed by ﬂash column chromatography on silica gel to give 3a″

as a colorless oil: 17.1 mg, 78% yield.²⁹

No. 2 reaction tube contained PhI(NTs₂)₂(102.2 mg, 0.12 mmol,

1.2 equiv), HFIP (1.0 mL), and 1a (20.3 mg, 0.1 mmol, 1.0 equiv).

The reaction tube was capped, and the resulting mixture was stirred at

room temperature. We have found that 1a was consumed completely

in 30 min (monitored by TLC), and the mixture of 3a and 3a′ was

the only product. Then, the solvent was removed under vacuum,

diluted with aqueous NaOH (1.0 M, 10 mL), extracted with CH₂Cl₂.

The organic phase was washed with brine, dried over Na₂SO₄, ﬁltered,

and concentrated under a vacuum. The residue was puriﬁed by ﬂash

column chromatography on silica gel to give the oxyamination

products 3a and 3a′: 43.7 mg, 83% yield.

(2R,2′R)-((2-Iodo-5-methyl-1,3-phenylene)bis(oxy))bis(N,N-diiso-

propylpropanamide) (5e). The compound was puriﬁed by ﬂash

column chromatography on silica gel (10:1 petroleum ether/EtOAc)

to give 5e as a white solid: 997 mg, 89% yield; spectroscopic data in

accordance with literature;^11g¹H NMR (400 MHz, CDCl₃) δ 6.36 (d,

J = 2.7 Hz, 2H), 4.87−4.74 (m, 2H), 4.50 (hept, J = 5.9, 5.3 Hz, 2H),

3.31 (hept, J = 6.9 Hz, 2H), 2.22 (s, 3H), 1.66 (dd, J = 6.7, 2.8 Hz,

6H), 1.42 (d, J = 6.7 Hz, 6H), 1.30 (dd, J = 6.9, 2.7 Hz, 6H), 1.18

(dd, J = 6.5, 3.6 Hz, 6H), 0.91 (d, J = 6.6 Hz, 6H); ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 169.6, 157.4, 140.5, 107.1, 77.6, 74.6, 47.6, 21.7,

20.9, 20.9, 20.6, 20.6, 20.4, 19.8, 19.7, 17.9.

(2R,2′R)-2,2′-((2-Iodo-5-methyl-1,3-phenylene)bis(oxy))bis(N-iso-

propyl-N-phenylpropanamide) (5f). The compound was puriﬁed by

ﬂash column chromatography on silica gel (4:1 petroleum ether/

EtOAc) to give 5e as a white solid: 427 mg, 34% yield; mp 72.2−73.0

°C; ¹H NMR (400 MHz, CDCl₃) δ 7.48−7.30 (m, 6H), 7.06 (d, J =

7.5 Hz, 2H), 6.89 (dd, J = 23.0, 7.5 Hz, 2H), 6.14 (s, 2H), 5.09−4.99

(m, 2H), 4.42−4.33 (m, 2H), 2.23 (s, 3H), 1.47 (d, J = 6.5 Hz, 6H),

1.06 (d, J = 6.8 Hz, 6H), 1.02 (d, J = 6.8 Hz, 6H); ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 169.8, 157.7, 139.0, 137.0, 130.2, 129.2, 128.6,

110.4, 109.7, 79.5, 73.6, 46.6, 21.4, 20.7, 18.2. IR ν_max(cm⁻¹) 2976,

1668, 1580, 1493, 1450, 1398, 1277, 1244, 1138, 1101, 706; HRMS

(ESI) m/z [M + H]⁺calcd for C₃₁H₃₈IN₂O₄629.1871, found

629.1875.

(2R,2′R)-2,2′-((2-Iodo-5-methyl-1,3-phenylene)bis(oxy))bis(N-cy-

clohexyl-N-isopropylpropanamide) (5g). The compound was

puriﬁed by ﬂash column chromatography on silica gel (5:1 petroleum

ether/EtOAc) to give 5g as a white solid: 591 mg, 47% yield; mp

63.4−64.0 °C; ¹H NMR (400 MHz, CDCl₃) δ 6.29 (s, 2H), 4.85 (dp,

J = 14.3, 7.0 Hz, 2H), 4.04 (d, J = 11.8 Hz, 2H), 3.40−3.24 (m, 2H),

3.26−3.05 (m, 2H), 2.19 (s, 3H), 1.71−0.89 (m, 32H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 170.0, 157.6, 140.3, 107.1,77.3, 77.2,

75.2, 55.8, 37.1, 32.0, 31.5, 26.0, 25.3, 21.8, 18.2, 14.2; IR ν_max(cm⁻¹)

2931, 2856, 1647, 1635, 1578, 1452, 1429, 1375, 1242, 1132, 1101,

735; HRMS (ESI) m/z [M + H]⁺calcd for C₂₉H₄₆IN₂O₄613.2497,

found 613.2495.

General Procedure for the Asymmetric Amino-Tetrahydro-

furan Reaction. A solution of PhCF₃(1.0 mL) was charged with 5g

(8.8 mg, 15% mol), HNTs₂(30.5 mg, 1.5 equiv), and mCPBA (40.5

mg, 2.0 equiv, 85 wt %), and the resulting mixture was stirred for 15

min at 0 °C in a low-temperature reactor. Then, the 2,2-diphenylpent-

4-enamide (0.1 mmol, 1.0 equiv) was added. The mixture was stirred

for 15 h at 0 °C. After completion, the resulting mixture was diluted

with aqueous NaOH (2.0 M, 5 mL) and extracted with dichloro-

methane. The organic phase was washed with brine, dried over

Na₂SO₄, ﬁltered, and concentrated under a vacuum. The residue was

puriﬁed by ﬂash column chromatography on silica gel to give chiral 5-

imino-2-tetrahydrofuranyl methanamine derivatives.

No. 3 reaction tube contained iodoarene 2h (4.0 mg, 0.015 mmol,

15 mol %), mCPBA (30.5 mg, 85 wt %, 0.15 mmol, 1.5 equiv),

NaNTs₂(52.0 mg, 0.15 mmol, 1.5 equiv), and HFIP (1.0 mL). The

reaction tube was capped, and the resulting mixture was stirred 10

min at room temperature. Then, 1a (20.3 mg, 0.1 mmol, 1.0 equiv)

was added. The mixture was stirred at room temperature for 15 h. It

should be mentioned that we did not detect the formation of 3a.

Then the solvent was removed under a vacuum, and the residue was

diluted with aqueous NaOH (1.0 M, 10 mL) and stirred for 10 min.

Then, the resulting mixture was extracted with CH₂Cl₂. The organic

phase was washed with brine, dried over Na₂SO₄, ﬁltered, and

concentrated under a vacuum. The residue was puriﬁed by ﬂash

column chromatography on silica gel to give 1a recovered (10.6 mg,

47% conversion) and 3a″: 4.1 mg, 19% yield.

(R,Z)-N-((4,4-Dimethyl-5-phenylimino-tetrahydrofuran-2-yl)-

methyl)-N-tosyl-(4-methylbenzenesulfon)amide (3j*): [α]²_D⁰−27.68

(c 0.1, MeOH, 94% ee). HPLC analysis: Chiracel-IA3, n-hexane/

isopropanol = 90:10, ﬂow rate 0.8 mL/min, λ = 210 nm. Retention

time: t_major= 8.54 min, t_minor= 13.05 min. The absolute conﬁguration

was tentatively assigned by analogy with 3n*.

Computational Methods. DFT calculations were performed

with the Gaussian 09 software package, E.01 version.⁴⁰Geometric

optimizations of intermediates and transition states were calculated at

the B3LYP/def2-SVP level,^41a,bwith the default ECP applied to

iodine atoms. The D3 version of Grimme’s dispersion with Becke−

Johnson damping were also applied.⁴²Vibrational frequency

calculations were also performed at the same level to conﬁrm that

the stationary points identiﬁed were either without imaginary

frequencies or with one imaginary frequency. Thermal corrections

to Gibbs free energy values at 298.15 K and 1 atm, including zero-

point energy corrections, were calculated at the same level. Standard

state concentrations of 1.0 mol/L were used for all species. Quasi-

(R,Z)-N-((4,4-Diphenyl-5-(4-ﬂuorophenylimino)tetrahydrofuran-

2-yl)methyl)-N-tosyl-(4-methylbenzenesulfon)amide (3m*): [α]_D²⁰

−28.45 (c = 0.10, MeOH, 64% ee). HPLC analysis: Chiracel-IA3,

n-hexane/isopropanol = 90:10, ﬂow rate 0.8 mL/min, λ = 254 nm.

Retention time: t_major= 9.33 min, t_minor= 14.70 min. The absolute

conﬁguration was tentatively assigned by analogy with 3n*.

(R,Z)-N-((4,4-Diphenyl-5-(2-chlorophenylimino)tetrahydrofuran-

2-yl)methyl)-N-tosyl-(4-meth ylbenzenesulfon)amide (3n*): [α]_D²⁰

−28.63 (c 0.10, MeOH, 93% ee). HPLC analysis: Chiracel-IA3, n-

hexane/isopropanol = 90:10, ﬂow rate 0.8 mL/min, λ = 210 nm.

Retention time: t_major= 9.16 min, t_minor= 14.39 min. The absolute

conﬁguration was established by X-ray crystallography analysis.

O

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harmonic corrections considering the contributions to the entropy of

low-frequency vibrations were also applied to each structure by

increasing all non-negative frequencies below 100 cm⁻¹to 100 cm⁻¹.

Single-point energies were calculated at the M062X/def2-TZVP

level^41b,cand were added to the thermal corrections calculated

previously to obtain the ﬁnal Gibbs free energy values. All calculations

were performed in HFIP implied using the SMD⁴³model deﬁned as a

generic solvent with the following properties: Eps = 16.7; EpsInf =

1.631; HbondAcidity = 0.77; HbondBasicity = 0.03; SurfaceTensio-

nAtInterface = 17.6; CarbonAromaticity = 0; ElectronegativeHaloge-

nicity = 0.60. For more details, please see the Supporting Information.

and Development Program (project no. 2014ZX09J14104-

06C) and the Shaanxi Province Key Research and Develop-

ment Program (grant no. S2019ZDLSF03-03). We thank

Professor Shengyong Zhang for valuable discussions.

REFERENCES

■

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The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c02047.

1

Copies of H and ¹³C{¹H} NMR, IRν_max, HRMS (ESI)

spectra for all new compounds, tables of detailed

reaction condition screening, crystal data, and DFT

computational data (PDF)

Accession Codes

CCDC 1906232−1906234 and 1906236 contain the supple-

mentary crystallographic data for this paper. These data can be

obtained free of charge via www.ccdc.cam.ac.uk/data_request/

cif, or by emailing data_request@ccdc.cam.ac.uk, or by

contacting The Cambridge Crystallographic Data Centre, 12

Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

AUTHOR INFORMATION

Corresponding Authors

■

Zhi-Xiang Yu − Beijing National Laboratory for Molecular

Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry

and Molecular Engineering of Ministry of Education, College

of Chemistry, Peking University, Beijing 100871, China;

orcid.org/0000-0003-0939-9727; Email: yuzx@

pku.edu.cn

Wei He − Department of Chemistry, School of Pharmacy,

Fourth Military Medical University, Xi’an 710032, China;

orcid.org/0000-0002-6703-6855; Email: weihechem@

fmmu.edu.cn

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Evidence for cis -Aminopalladation and S_N2 C-O Bond Formation. J.

Am. Chem. Soc. 2006, 128, 7179−7181. (c) Desai, L. V.; Sanford, M.

S. Construction of Tetrahydrofurans by Pd^II/Pd^IV-Catalyzed Amino-

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(d) Ahmed, N.; Khatoon, S. Facile Electrochemical Intramolecular

Amination of Urea Tethered Terminal Alkenes for the Synthesis of

Cyclic Ureas. ChemistryOpen 2018, 7, 576−582. (e) Qi, X.-X.; Chen,

C.-H.; Hou, C.-Q.; Fu, L.; Chen, P.-H.; Liu, G.-S. Enantioselective

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(f) Wen, K.; Wu, Z.-X.; Huang, B.-R.; Ling, Z.; Gridnev, I. D.; Zhang,

W.-B. Solvent-Controlled Pd(II)-Catalyzed Aerobic Chemoselective

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Authors

Xiao-Jun Deng − Department of Chemistry, School of

Pharmacy, Fourth Military Medical University, Xi’an

710032, China

Hui-Xia Liu − Department of Chemistry, School of Pharmacy,

Fourth Military Medical University, Xi’an 710032, China

Lu-Wen Zhang − Department of Chemistry, School of

Pharmacy, Fourth Military Medical University, Xi’an

710032, China

Guan-Yu Zhang − Beijing National Laboratory for Molecular

Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry

and Molecular Engineering of Ministry of Education, College

of Chemistry, Peking University, Beijing 100871, China

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c02047

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

This work was supported by the National Science and

Technology Major Project of China Key New Drug Creation

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J. Org. Chem. XXXX, XXX, XXX−XXX

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Iodoarene-Catalyzed Oxyamination of Unactivated Alkenes to Synthesize 5-Imino-2-Tetrahydrofuranyl Methanamine Derivatives

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