Transition-Metal-Promoted Direct C?H Cyanoalkylation and Cyanoalkoxylation of Internal Alkenes via Radical C?C Bond Cleavage of Cycloketone Oxime Esters

Title: Transition-Metal-Promoted Direct C-H Cyanoalkylation and

Cyanoalkoxylation of Internal Alkenes <i>via</i> Radical C-C

Bond Cleavage of Cycloketone Oxime Esters

Authors: Jiang Lou, Yuan He, Yunlong Li, and Zhengkun Yu

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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900402

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10.1002/adsc.201900402

Advanced Synthesis & Catalysis

FULL PAPER

DOI: 10.1002/adsc.201((will be filled in by the editorial staff))

Transition-Metal-Promoted Direct CH Cyanoalkylation and

Cyanoalkoxylation of Internal Alkenes via Radical CC Bond

Cleavage of Cycloketone Oxime Esters

Jiang Lou,^a,bYuan He,^a,bYunlong Li,^a,band Zhengkun Yu^a,c,*

a

Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, Liaoning 116023,

Peoples Republic of China

b

University of Chinese Academy of Sciences, Beijing 100049, Peoples Republic of China

State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of

c

Sciences, 354 Fenglin Road, Shanghai 200032, Peoples Republic of China

Fax: +86-411-8437-9227

E-mail: zkyu@dicp.ac.cn

Received: ((will be filled in by the editorial staff))

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please

delete if not appropriate))

Abstract. Transition-metal-catalyzed alkyl-Heck-type cross-coupling of olefinic C−H bonds has been a challenge in the

C−H activation area. Herein, we report FeCl₃-promoted efficient direct C−H cyanoalkylation of internal alkenes, that is,

ketene dithioacetals, with cycloketone oxime esters via radical C−C bond cleavage under the redox-neutral conditions.

With CuCl₂as the catalyst under a dioxygen atmosphere direct C−H cyanoalkoxylation of the same internal alkenes was

achieved. The cyanoalkylated tetrasubstituted alkene products could be diversely transformed to cyanoalkyl-

funtionalized N- and S-heterocyclic compounds. The mechanistic studies have revealed that these C−H cyanoalkylation

and cyanoalkoxylation reactions proceed through a radical pathway.

Keywords: cycloketone oxime esters; cyanoalkylation; cyanoalkoxylation; C−H functionalization; internal alkenes

Introduction

promising approach towards alkylated molecules via

single-electron transfer (SET) processes.^[10]Cyano-

alkyl radicals generated from nitrogen-centered-

radicals (NCRs), that is, iminyl radicals, have been

utilized as the useful coupling partners for C−C

cross-coupling reactions (Scheme 1a).^[11]Such

cyanoalkyl radicals resulted from transition-metal-

catalyzed CC bond cleavage of cycloketone oxime

esters via a SET process can react with terminal

alkenes or their surrogates, giving cyanoalkyl-

functionalized alkenes (Scheme 1b).¹²Zard and

coworkers reported the pioneering work on radical

C−C bond cleavage of cyclobutanone derivatives.^[13]

Nishimura and Uemura, et al. documented iridium

and palladium-catalyzed ring-opening reactions of

cyclobutanone oxime esters through β-carbon

scission.^[14]Shi, Chen and Xiao groups reported

Transition-metal-catalyzed direct C−H functiona-

lization is emerging as one of the most powerful and

straightforward tools for the construction of C−C and

C−heteroatom bonds.^[1]In this regard, direct olefinic

C−H functionalization seems to be a concise route to

multisubstituted alkenes,^[2]although the cross-

coupling reactions of halo-,^[3]oxygen-,^[4]boron-,^[5]

silicon-,^[6]and metal^[7]-functionalized ketene units

have been documented for the same goal. Direct C−H

functionalization of olefinic C−H bonds has recently

been paid much attention for the construction of

multisubstituted alkenes.^[2,8]However, the limitations

are often encountered including functional group

tolerance, substrate scopes, reaction types, time-

consuming procedures, and/or use of expensive

transition-metal catalysts. One of the challenges is the

alkyl-Heck-type reactions of olefinic C−H bonds due

to the inherent instability of the alkyl-metal species in

situ generated from the alkylative coupling partners,

which prefer β-H elimination over the insertion

reaction with the alkene substrates.^[9]Thus, new

catalytic systems as well as versatile coupling

partners are still highly desired for the direct olefinic

C−H functionalization.

copper-catalyzed

and

visible-light-driven

intermolecular Heck-like coupling of cyclobutanone

oxime esters with styrene derivatives, respectively.^[15]

Wu lab achieved a gallic acid-promoted SET process

for cyclobutanone oxime activation and carbonylative

alkylation of alkenes.^[16]Guo, et al. Synthesized

cyanoalkyl-functionalized alkenes,^[17a]arenes,^[17b]and

N-heterocycles^[17c,d]through iron, copper, or nickel-

catalyzed C−H cyanoalkylation of ,-unsaturated

carboxylic acids, arenes, and N-heterocyclic

compounds, with cycloketone oxime esters. Yu, et al.

The cross-coupling of olefinic C−H bonds with

alkyl radicals has recently been documented as a

1

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Advanced Synthesis & Catalysis

realized photoredox-catalyzed intermolecular C−H

and C−C vinylation with vinyl boronic acids.^[18]Very

recently, Chen, Xiao, and Guo, et al. reported the

C−C bond cleavage of cycloketone oxime esters

under the redox neutral conditions (Scheme 1d).

three-component

radical

cross-couplings of Results and Discussion

cyclobutanone oxime esters with styrenes and

boronic acids¹⁹or with B₂(OH)₄and pinacol.²⁰In all

the CH functiona-lization involved ring-opening

reactions of cyclo-ketone oxime esters, a cyanoalkyl

motif could be incorporated into a vinylic or aromatic

CH bond. Unfortunately, the alkene substrates are

only limited to terminal alkenes (Scheme 1b), and

direct CH cyanoalkylation of internal alkenes has

not yet been reported.

Initially, the reaction of α-benzoyl ketene di(methyl-

thio)acetal (1a) with O-benzoyl cyclobutanone oxime

ester 2a was conducted to optimize the reaction

conditions (Table 1). With 10 mol% FeCl₂as the

catalyst under a nitrogen atmosphere, the reaction of

1a and 2a in a 1:1.2 molar ratio underwent in 1,4-

o

dioxane at 100 C for 24 h, forming the target

cyanoalkylation product 3a in 31% yield (Table 1,

entry 1). FeCl₃exhibited a better catalytic activity

Table 1. Screening of cyanoalkylation conditions.^[a]

Temp Yield^[b]

2a

Entry Catalyst

Solvent

[^oC]

[%]

[equiv]

1^[c]

2

FeCl₂

FeBr₃

FeCl₃

1.2

1.5

1.8

2.0

1.8

1,4-dioxane

MeCN

100

90

31

30

3

34

4

29

5

PhCF₃

60

6

Toluene

PhCF₃

32

7

62

8

PhCF₃

70

9

PhCF₃

68

10

11

12

PhCF₃

56

PhCF₃

110

120

110

80

PhCF₃

76

13^[c,d]FeCl₃

14^[c,e]FeCl₃

15^[c,g]FeCl₃

16^[c,e]

PhCF₃

79

Scheme 1. C−H alkylation of alkenes.

PhCF₃

84 (79)^[f]

PhCF₃

81

During the ongoing investigation of direct C−H

functionalization of internal alkenes, we have

developed the effective strategy to activate an internal

olefinic C−H bond by introducing an electron-

withdrawing group (EWG), and one or two electron-

donating alkylthio moieties at the two termini of an

olefinic C=C bond, which has been successfully

applied in the direct C−H functionalization of internal

alkenes to construct C−C and C−X bonds.^[21]In our

hands, direct C−H alkylation of internal alkenes, that

is, α-oxo ketene dithioacetals, with styrenes and

activated alkanes was efficiently realized (Scheme

1c).^[22]To extend the generality of such an olefinic

CH activation/functionalization strategy, we

reasonably envisioned that the alkyl radicals

generated from the ring-opening of strained

carbocycles might be applied as the partners to be

coupled with internal olefinic C–H bonds. Herein, we

disclose FeCl₃-catalyzed direct cyanoalkylation as

well as CuCl₂-catalyzed direct cyanoalkoxylation of

internal alkenes -oxo ketene dithioacetals via radical

PhCF₃

53

^[a]Conditions: 1a (0.1 mmol), 2a, solvent (1.0 mL), catalyst (10 mol%),

0.1 MPa N₂, 24 h.

^[b]Determined by ¹H NMR analysis using 1,3,5-trimethoxylbenzene as the

internal standard.

^[c]1a (0.3 mmol), 2a (0.54 mmol).

^[d]PhCF₃(3.0 mL)

^[e]PhCF₃(1.5 mL).

^[f]Isolated yield given in parentheses.

^[g]PhCF₃(1.0 mL).

than FeCl₂(Table 1, entries 1-3). PhCF₃as the

solvent remarkably enhanced the yield to 60% (Table

1, entries 4-6). Increasing the loading of 2a improved

the reaction efficiency, and 70% yield was thus

obtained for 3a in the presence of 1.8 equiv of the

oxime ester (Table 1, entries 7-9). Elevating the

o

reaction temperature to 110 C further increased the

product yield to 80% (Table 1, entries 8 and 10-12).

Scaling up the reaction to 0.3 mmol for 1a yielded 3a

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Advanced Synthesis & Catalysis

in a comparable yield (79%) (Table, entry 13), and

the suitable substrate concentration was found to be

0.2 M for 1a, leading to the target product 3a in 79%

isolated yield (Table 1, entries 13-15). It is

noteworthy that the reaction also underwent in the

absence of the iron salt, forming the product in 53%

yield upon simple heating (Table 1, entry 16), and

microwave-promoted homolytic cleavage of the NO

bond of cycloketone oxime esters could also occur in

the absence of a transition-metal catalyst.^[23]

Under the optimized conditions, the scope of

ketene dithioacetals (1) was explored (Table 2). The

analogs of 1a, that is, substituted α-oxo ketene

dithioacetals, exhibited diverse reactivities to form

the target cyanoalkylation products of type 3 in good

to excellent yields. No obvious steric effects were

observed for the methyl-substituted α-benzoyl ketene

dithioacetal substrates, and their reactions with 2a

afforded products 3b-d (77-84%). The electronic

effects were not obvious either between the methoxy

ketene di(methylthio)acetals efficiently underwent

the reactions with 2a, affording compounds 3g-i in

75-83% yields. α-Heteroaroyl, that is, 2-furoyl and 2-

thienoyl-bearing ketene dithioacetals reacted with 2a

less efficiently, only yielding 3j and 3k in 42-46%

yields. Aliphatic α-acetyl, tert-butylcarbonyl, and

cyclopropylcarbonyl-functionalized ketene di(me-

thylthio)acetals reacted well to produce 3l-n in 70−

81% yields. α-Benzoyl ketene di(ethylthio)acetal and

the cyclic α-benzoyl and α-acetyl ketene dithioacetals

also efficiently reacted with 2a to form products 3o-r

(76-84%). It is noteworthy that the α-ester, and

cyano-functionalized ketene di(methylthio)acetals,

and 1,1-diphenyl-1-butene could smoothly undergo

the reactions with 2a, affording the target products

3s-u in moderate to good yields (54-71%).

Next, the protocol generality was investigated by

performing the reactions of α-oxo ketene dithio-

acetals 1 with a variety of cyclobutanone oxime

esters 2 (Table 3). Under the optimal conditions, the

Table 2. Scope of ketene dithioacetals (1).^[a]

Table 3. Scope of cycloketone oxime esters (2).^[a]

[a]

Conditions: 1d (0.3 mmol), 2 (0.54 mmol), FeCl₃(0.03 mmol), PhCF₃

(1.5 mL), 110 ^oC, 0.1 MPa N₂, 24 h. Yields refer to the isolated

products.

reaction of α-(4-methyl)benzoyl ketene di(methyl-

thio)acetal (1d) reacted with 3-hexylcyclobutanone

oxime ester 2b to afford the target cyanoalkylation

product 4a (68%). tert-Butyl 3-((benzoyloxy)imino)-

cyclobutanecarboxylate (2c) did not exhibit an

obvious electronic effect, and its reaction with 1d

gave compound 4b in 70% yield. 3-Benzyl

substituted cyclobutanone oxime ester 2d underwent

the reaction smoothly, efficiently yielding product 4c

^[a]Conditions: 1a (0.3 mmol), 2a (0.54 mmol), FeCl₃(0.03 mmol), PhCF₃

(1.5 mL), 110 ^oC, 0.1 MPa N₂, 24 h. Yields refer to the isolated

products.

and trifluoromethyl-substituted α-benzoyl-based

substrates, giving the corresponding products 3e and

3f in 75-80% yields. The halo-substituted α-benzoyl

3

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Advanced Synthesis & Catalysis

(78%). Bulky substituted tert-butyl and phenyl

groups at the 3-position of cyclobutanone oxime

esters rendered formation of products 4d (66%) and

4e (74%), respectively. 3-(4-tert-Butyl), 3-(4-

trifluoromethyl), 3-(4-chloro), and 3-(3-chloro)-

substituted phenyl-bearing cyclobutanone oxime

esters exhibited no obvious steric/electronic effects

on the reaction efficiency, and the related reactions

formed 4f-i in 63-66% yields. Unsymmetrical

cyclobutanone oxime esters such as 2-methyl and 2-

benzyl-substituted cyclobutanone oxime esters 2k

and 2l could also smoothly react with 1d to give the

target products 4j (80%) and 4k (70%), respectively.

It should be noted that the five to seven-membered O-

benzoyl cycloketone oxime esters I-V could not

undergo the same type of cyanoalkylation reactions

under the stated conditions, which is presumably

attributed to the lower reactivity of the less-strained

rings than the cyclobutanone oxime esters to the iron

catalysts.

metal catalyst.

A variety of -oxo ketene dithioacetals 1 were

applied in the copper catalysis system with

cyclobutanone oxime esters 2 as the coupling partners

(Table 4). α-Benzoyl ketene dithioacetal 1a reacted

with 2a to form the target product 5a in 50% yield. p-

Methyl, p-methoxy, and p-trifluoromethyl-substituted

α-benzoyl ketene dithioacetals underwent the

reactions smoothly, giving the corresponding

products 5b-d in 44-50% yields. o-, m-, and p-

Bromo-functionalized α-benzoyl ketene di(methyl-

thio)acetals reacted with 2a to afford compounds 5e-g

Figure 1. Molecular structure of compound 5b.

(41-52%). α-Benzoyl ketene di(ethylthio)acetal also

reacted well with 2a to yield the target product 5h

(43%). 2-Methyl cyclobutanone oxime ester 2k did

not exhibit an obvious steric effect, its reaction with

2a produced compound 5i in 50% yield. The

molecular structure of compound 5b was further

confirmed by the X-ray single crystallographic

determination (Figure 1, see the Supporting

Information for details). It is noteworthy that the

cyanoalkylation products of types 3 and 4 were

always accompanied as the byproducts in the reac-

tions of 1 and 2 under an oxygen atmosphere, which

During the screening of reaction conditions for the

C−H cyanoalkylation of -oxo ketene dithioacetal 1a

with oxime ester 2a, the reaction was tested under an

oxygen atmosphere. Unexpectedly, a C−H cyanoal-

koxylation process occurred to form compound 5a

(32%) as the major product [Eq. (1)]. Encouraged by

this finding, the conditions for the C−H cyanoal-

koxylation reaction was further optimized to be 10

mol % CuCl₂as the catalyst, PhCF₃as the solvent,

and the reaction was performed at 100 C under an

oxygen atmosphere (see the Supporting Information

for details). It is noteworthy that the cyanoalkoxy-

lation reaction could not occur without the transition-

Table 4. Cyanoalkoxylation of ketene dithioacetals.^[a]

led to a tedious isolation procedure for compounds 5,

and thus diminished their isolation yields.

To demonstrate the applicability of the present

synthetic protocol, gram-scale preparation of

compound 3l was carried out by means of the

reaction of 1l (7 mmol) with 2a. Under the standard

conditions, the target products 3l was obtained in

70% yield [Eq. (2)]. The potential applications of the

resultant tetrasubstituted alkene products were also

explored. Treatment of compound 3a with excess of

hydrazine hydrate in refluxing toluene afforded 4-

cyanoalkylpyrazole 6 in 81% yield [Eq. (3)]. In the

presence of NaOH base, tetrasubstituted α-alkenoyl

ketene dithioacetal 7 was produced (90%) from the

condensation of compound 3l and benzaldehyde [Eq.

(4)]. Compound 7 underwent [5C+1S] annulation

with Na₂S·9H₂O to form cyanoalkylated 2,3-dihydro-

thiopyran-4-one 8 in 75% yield [Eq. (5)]. With

Pd(PPh₃)₂Cl₂as the catalyst in the presence of Ph₃SiH

[a]

Conditions: 1 (0.3 mmol), 2 (0.6 mmol), CuCl₂(0.03 mmol), PhCF₃

(3.0 mL), 100 ^oC, 0.1 MPa O₂, 5 h. Yields refer to the isolated products.

4

10.1002/adsc.201900402

Advanced Synthesis & Catalysis

compound 3l reacted with ethyl isocyanoacetate to

yield cyanoalkyl-functionalized 5-hydroxy-α,β-unsa-

turated γ-lactam 9 (73%) via C−S bond activation/

cleavage and migratory isocyanide insertion [Eq. (6)].

The control experiments were conducted to probe

mechanisms for the cyanoalkylation and cyanoalko-

xylation reactions are proposed in Scheme 2. The

reaction may start with the formation of a reduced Feⁿ

or Cuⁿcatalyst, which is generated from the reduction

of the FeCl₃or CuCl₂precatalyst under the stated

conditions.^[11h]In addition, simple heating facilitated

the homolytic NO bond cleavage of the

cyclobutanone oxime ester to form a nitrogen-

centered-radical,^[23]which may initiate the catalytic

cycle to some extent (Table 1, entry 16). For the

cyanoalkylation (path a): Initially, interaction of an

iron or copper catalyst with O-benzoyl oxime ester 2a

undergoes a single-electron transfer (SET) process to

generate iminyl radical A and release BzO^-anion,

followed by ring-opening to form γ-cyanoalkyl

radical B via homolytic ,-C−C cleavage. Addition

of radical B to the ketene moiety of internal alkene 1a

produces a more stabilized, less reactive, and readily

oxidizable radical C. Such a radical is further

oxidized by Feⁿ⁺¹species to form cation D with con-

comitant regeneration of the catalytically active Feⁿ

into the reaction mechanism. Addition of 2 equiv of a

radical scavenger, that is, 2,2,6,6-tetramethyl-1-

piperidinyloxy (TEMPO) or 2,6-di-tert-butyl-4-

methylphenol (BHT), into the reaction system could

completely inhibit the cyanoalkylation/cyanoalkoxy-

lation reaction of 1a and 2a under the standard

conditions [Eq. (7)]. The adduct of the possible

cyanoalkyl radical intermediate with TEMPO, that is,

compound 10, was detected in the reaction mixtures

by high resolution mass spectrometry (see the

Supporting Information for details). It should be

noted that compounds of type 10 could be prepared

under microwave irridiation conditions.^[23]These

results have implicated that both the two reactions

may proceed through a radical pathway. The kinetic

isotope effect (KIE) experiments of cyanoalkylation

were explored by conducting the reactions of 1a and

its deuterated form 1a[D] with 2a under the standard

conditions, respectively [Eq. (8)]. A secondary

isotope effect^[24]was observed with k_H/k_D= 0.83,

suggesting that cleavage of the internal olefinic C−H

bond in 1a is not involved in the rate-determining

step of the overall catalytic cycle.

Scheme 2. Proposed mechanisms: (a) cyanoalkylation; (b)

cyanoalkoxylation.

On the basis of the present experimental results as

well as previous works,^[14-19,25]plausible reaction

5

10.1002/adsc.201900402

Advanced Synthesis & Catalysis

After cooled to ambient temperature, EtOAc and saturated

aqueous NaHCO₃(10 mL each) were successively added.

The organic phase was separated and the aqueous phase

was extracted with EtOAc (3×10 mL). The combined

organic phase was washed with water (3×10 mL), dried

over anhydrous Na₂SO₄, filtered, and concentrated under

reduced pressure. The resultant mixture was subjected to

purification by column chromatography on silica gel

species. Subsequently, the cationic intermediate

D

undergoes hydrogen abstraction by BzO^-anion to

afford the Heck-like cyanoalkylation product 3a.

However, heat-induced radical chain propagation

mechanism involving iminyl radical generation under the

stated conditions could not be ruled out.^[12d,23]For the

cyanoalkoxylation (path b): Under an oxygen

atmosphere, radical B is readily captured by O₂

molecule to form peroxy radical E which is

presumably reduced by Cuⁿspecies through the

Fenton-type mechanism to give alkoxy radical F.

Addition of species F to internal alkene 1a leads to

radical G. This radical intermediate can be further

oxidized by Cuⁿ⁺¹species to give cationic interme-

diate H with concomitant regeneration of the

catalytically active Cuⁿspecies. Eventually, interme-

diate H undergoes hydrogen abstraction by BzO^-

anion to provide the Heck-like cyanoalkoxylation

product 5a. It is noteworthy that the cyanoalkoxy-

lation process is always accompanied by the

cyanoalkylation product of type 3 or 4 as the

byproduct under an oxygen atmosphere.

o

(eluent: petroleum ether (60-90 C)/ethyl acetate = 20:1,

v/v) to afford the target product 3a.

5-Benzoyl-6,6-bis(methylthio)hex-5-enenitrile (3a): 69

mg, 79% yield, yellow liquid. ¹H NMR (400 MHz, CDCl₃)

δ 7.86, 7.57 and 7.47 (m each, 2:1:2 H, aromatic CH), 2.79

(dd, J = 8.6 and 6.9 Hz, 2 H, (C=O)CCH₂), 2.39 (m, 5 H,

CH₂CN and SMe), 2.07 (s, 3 H, SMe), 1.84 (m, 2 H,

CH₂CH₂CN). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 196.59

(Cq, C=O), 144.7, 136.8 and 136.5 (Cq), 133.5, 129.0 and

128.8 (aromatic CH), 119.3 (CN), 32.8 ((C=O)CCH₂), 24.3

(CH₂CH₂CN), 17.2 and 16.4 (SMe), 16.9 (CH₂CN).

HRMS Calcd for C₁₅H₁₇NOS₂[M+H]⁺: 292.0830;

Found:292.0829.

5-(2-Methylbenzoyl)-6,6-bis(methylthio)hex-5-

enenitrile (3b): 71.2 mg, 77% yield, yellow liquid. H

1

NMR (400 MHz, CDCl₃) δ 7.42 (d, J = 7.7 Hz, 1 H,

aromatic CH), 7.36 (m, 1 H, aromatic CH), 7.26 (m, 1 H,

aromatic CH), 7.21 (t, J = 7.5 Hz, 1 H, aromatic CH), 2.81

(m, 2 H, (C=O)CCH₂), 2.59 (s, 3 H, Me), 2.42 (t, J = 7.2

Hz, 2 H, CH₂CN), 2.36 (s, 3 H, SMe), 1.92 (m, 5 H, SMe

and CH₂CH₂CN). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

198.6 (Cq, C=O), 146.3, 140.2, 139.3 and 137.4 (Cq),

132.2, 131.7, 129.5 and 125.3 (aromatic CH), 119.4 (CN),

33.2 ((C=O)CCH₂), 24.4 (CH₂CH₂CN), 21.5 (Me), 17.0

and 16.5 (SMe), 16.7 (CH₂CN). HRMS Calcd for

C₁₆H₁₉NOS₂[M+H]⁺: 306.0986; Found: 306.0989.

Conclusions

In summary, efficient iron-promoted CH cyanoalky-

lation and copper-catalyzed CH cyanoalkoxylation

of internal alkenes with O-benzoyl cyclobutanone

oxime esters have been realized to access multi-

functionalized alkenes. The diversity of the

functionality including alkene categories, carbonyl

and alkylthio groups, makes these compounds good

candidates to serve as precursors for further synthetic

transformations. The present work has provided a

strategy for alkyl-Heck-type cross-coupling of

internal alkenes and offers a concise route to

tetrasubstituted alkenes.

5-(3-Methylbenzoyl)-6,6-bis(methylthio)hex-5-eneni-

1

trile (3c): 72.4 mg, 79% yield, yellow liquid. H NMR

(400 MHz, CDCl₃) δ 7.41 (d, J = 7.7 Hz, 1 H, aromatic

CH), 7.36 (m, 1 H, aromatic CH), 7.26 (d, J = 7.5 Hz, 1 H,

aromatic CH), 7.21 (t, J = 7.5 Hz, 1 H,aromatic CH), 2.82

(m, 2 H, (C=O)CCH₂), 2.59 (s, 3 H, Me), 2.42 (t, J = 7.2

Hz, 2 H, CH₂CN), 2.36 (s, 3 H, SMe), 1.90 (m, 5 H, SMe

and CH₂CH₂CN). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

198.6 (Cq, C=O), 146.4, 140.2, 139.3 and 137.4 (Cq),

132.2, 131.7, 129.5 and 125.3 (aromatic CH), 119.4 (CN),

33.2 ((C=O)CCH₂), 24.4 (CH₂CH₂CN), 21.5 (Me), 17.0

and 16.5 (SMe), 16.7 (CH₂CN). HRMS Calcd for

C₁₆H₁₉NOS₂[M+H]⁺: 306.0986; Found: 306.0984.

5-(4-Methylbenzoyl)-6,6-bis(methylthio)hex-5-eneni-

trile (3d): 77.7 mg, 84% yield, yellow solid, m.p.: 42-43

^oC. ¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, J = 8.1 Hz, 2 H,

aromatic CH), 7.20 (d, J = 7.9 Hz, 2 H, aromatic CH), 2.70

(m, 2 H, (C=O)CCH₂), 2.32 (m, 8 H, CH₂CN, SMe and

Me), 2.02 (s, 3 H, SMe), 1.76 (m, 2 H, CH₂CH₂CN).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 196.2 (Cq, C=O),

145.0, 144.5, 136.0 and 133.8 (Cq), 129.5 and 129.2

(aromatic CH), 119.3 (CN), 32.8 ((C=O)CCH₂), 24.2

(CH₂CH₂CN), 21.8 (Me), 17.2 and 16.3 (SMe), 16.8

(CH₂CN). HRMS Calcd for C₁₆H₁₉NOS₂[M+H]⁺:

306.0986; Found: 306.0986.

Experimental Section

General Considerations

¹H and ¹³C{¹H} NMR spectra were recorded on a 400

MHz spectrometer and all chemical shift values refer to

CDCl₃(δ(¹H), 7.26 ppm and δ(¹³C), 77.16 ppm). X-Ray

crystallographic analysis was achieved by the Analysis

Center, Dalian Institute of Chemical Physics, Chinese

Academy of Sciences. The HRMS analysis was obtained

by ESI on a GC-TOF mass spectrometer. Column

chromatographic purifications were performed on silica gel.

All the chemical reagents were purchased from

commercial sources and used as received unless otherwise

indicated.

General procedure for the synthesis of cyanoalkylated

ketene dithioacetals (3)

5-(4-Methoxybenzoyl)-6,6-bis(methylthio)hex-5-eneni

-trile (3e): 78 mg, 80% yield, yellow liquid. ¹H NMR (400

MHz, CDCl₃) δ 7.81 (d, J = 8.8 Hz, 2 H, aromatic CH),

6.94 (d, J = 8.8 Hz, 2 H, aromatic CH), 3.86 (s, 3 H, OMe),

2.76 (m, 2 H, (C=O)CCH₂), 2.36 (m, 5 H, CH₂CN and

Under a nitrogen atmosphere a mixture of ketene

dithioacetals (1) (0.30 mmol), O-benzoyl cyclobutanone

oxime ester (2a) (102 mg, 0.54 mmol), and FeCl₃(4.9 mg,

0.03 mmol) in 1.5 mL PhCF₃was stirred at 110 ^oC for 24 h.

6

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Advanced Synthesis & Catalysis

SMe), 2.10 (s, 3 H, SMe), 1.82 (m, 2 H, CH₂CH₂CN).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 195.3 (Cq, C=O),

163.9, 145.1, 135.4 and 129.1 (Cq), 131.4 and 114.1

(aromatic CH), 119.3 (CN), 55.6 (OMe), 32.8

((C=O)CCH₂), 24.2 (CH₂CH₂CN), 17.2 and 16.3 (SMe),

16.7 (CH₂CN). HRMS Calcd for C₁₆H₁₉NO₂S₂[M+H]⁺:

322.0935; Found: 322.0936.

6,6-Bis(methylthio)-5-(4-(trifluoromethyl)benzoyl)-

hex-5-enenitrile (3f): 81 mg, 75% yield, yellow liquid. ¹H

NMR (400 MHz, CDCl₃) δ 7.93 (d, J = 8.1 Hz, 2 H,

aromatic CH), 7.73 (d, J = 8.2 Hz, 2 H, aromatic CH), 2.80

(m, 2 H, (C=O)CCH₂), 2.40 (m, 5 H, CH₂CN and SMe),

2.05 (s, 3 H, SMe), 1.85 (m, 2 H, CH₂CH₂CN). ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 195.4 (Cq, C=O), 143.5, 139.8

and 139.1 (Cq), 134.4 (q, J = 32.4 Hz, i-C of CF₃C₆H₄),

129.1 (aromatic CH), 125.8 (q, J = 3.7 Hz, o-C of

CF₃C₆H₄), 123.7 (q, J = 271.0 Hz, CF₃), 119.2 (CN), 32.9

((C=O)CCH₂), 24.3 (CH₂CH₂CN), 17.1 and 16.4 (SMe),

16.9 (CH₂CN). HRMS Calcd for C₁₆H₁₆NOF₃S₂[M+H]⁺:

360.0704; Found: 360.0701.

5-(4-Fluorobenzoyl)-6,6-bis(methylthio)hex-5-eneni-

trile (3g): 70.5 mg, 75% yield, yellow solid, m.p.: 74-75

^oC. ¹H NMR (400 MHz, CDCl₃) δ 7.86 and 7,13 (m each,

2:2 H, aromatic CH), 2.77 (m, 2 H, (C=O)CCH₂), 2.38 (m,

5 H, CH₂CN and SMe), 2.08 (s, 3 H, SMe), 1.83 (m, 2 H,

CH₂CH₂CN). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 195.0

(Cq, C=O), 166.0 (d, J = 254 Hz, i-C of FC₆H₄), 144.2 and

137.1 (Cq), 132.8 (d, J = 2.9 Hz, p-C of FC₆H₄), 131.6 (d,

J = 9.4 Hz, m-C of FC₆H₄), 119.3 (CN), 116.0 (d, J = 21.9

16.7 (CH₂CN). HRMS Calcd for C₁₃H₁₅NO₂S₂[M+H]⁺:

282.0622; Found: 282.0619.

6,6-Bis(methylthio)-5-(thiophene-2-carbonyl)hex-5-

1

enenitrile (3k): 41.2 mg, 46% yield, yellow liquid. H

NMR (400 MHz, CDCl₃) δ 7.68 (dd, J = 4.9 and 1.1 Hz, 1

H, aromatic CH), 7.56 (dd, J = 3.8 and 1.1 Hz, 1 H,

aromatic CH), 7.13 (dd, J = 4.9 and 3.8 Hz, 1 H, aromatic

CH), 2.80 (m, 2 H, (C=O)CCH₂), 2.38 (m, 5 H, CH₂CN

and SMe), 2.15 (s, 3 H, SMe), 1.85 (m, 2 H, CH₂CH₂CN).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 189.1 (Cq, C=O),

144.6, 143.9 and 137.3 (Cq), 134.6, 133.2 and 128.4

(aromatic CH), 32.8 ((C=O)CCH₂), 24.3 (CH₂CH₂CN),

17.5 and 16.4 (SMe), 16.8 (CH₂CN). HRMS Calcd for

C₁₃H₁₅NOS₃[M+H]⁺: 298.0394; Found: 298.0394.

5-(Bis(methylthio)methylene)-6-oxoheptanenitrile

1

(3l): 51.8 mg, 75% yield, yellow liquid. H NMR (400

MHz, CDCl₃) δ 2.67 (m, 2 H, (C=O)CCH₂), 2.40 (s, 3 H,

Me), 2.35 (m, 5 H, CH₂CN and SMe), 2.29 (s, 3 H, SMe),

1.78 (m, 2 H, CH₂CH₂CN). ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 203.7 (Cq, C=O), 146.9 and 137.9 (Cq), 119.4

(CN), 32.3 ((C=O)CCH₂), 30.5 (Me), 24.4 (CH₂CH₂CN),

17.5 and 16.7 (SMe), 16.8 (CH₂CN). HRMS Calcd for

C₁₀H₁₅NOS₂[M+H]⁺: 230.0673; Found: 230.0677.

5-(Bis(methylthio)methylene)-7,7-dimethyl-6-oxooc-

1

tanenitrile (3m): 57.5 mg, 70% yield, yellow liquid. H

NMR (400 MHz, CDCl₃) δ 2.66 (t, J = 7.4 Hz, 2 H,

(C=O)CCH₂), 2.38 (t, J = 7.1 Hz, 2 H, CH₂CN), 2.28 and

2.22 (s each, 3:3 H, SMe), 1.76 (m, 2 H, CH₂CH₂CN), 1.21

(s, 9 H, tBu). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 213.9

Hz, o-C of FC₆H₄), 32.8 ((C=O)CCH₂), 24.3 (CH₂CH₂CN), (Cq, C=O), 147.6, 131.9 and 119.4 (Cq), 43.8 (C(CH₃)),

17.1 and 16.3 (SMe), 16.8 (CH₂CN). HRMS Calcd for

C₁₅H₁₆NOFS₂[M+H]⁺: 310.0736; Found: 310.0737.

5-(4-Chlorobenzoyl)-6,6-bis(methylthio)hex-5-eneni-

trile (3h): 77.5 mg, 79% yield, yellow solid, m.p.: 54-55

^oC. ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J = 8.5 Hz, 2 H,

aromatic CH), 7.43 (d, J = 8.5 Hz, 2 H, aromatic CH), 2.76

(m, 2 H, (C=O)CCH₂), 2.38 (m, 5 H, CH₂CN and SMe),

2.07 (s, 3 H, SMe), 1.81 (m, 2 H, CH₂CH₂CN). ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 195.3 (Cq, C=O), 143.9, 139.8,

137.6 and 135.0 (Cq), 130.3 and 129.1 (aromatic CH), 32.8

((C=O)CCH₂), 24.2 (CH₂CH₂CN), 17.1 and 16.4 (SMe),

16.8 (CH₂CN). HRMS Calcd for C₁₅H₁₆NOS₂Cl [M+H]⁺:

326.0440; Found: 326.0435.

31.9 ((C=O)CCH₂), 27.9 (C(CH₃)), 24.0 (CH₂CH₂CN),

17.1 and 16.3 (SMe), 16.4 (CH₂CN). HRMS Calcd for

C₁₃H₂₁NOS₂[M+H]⁺: 272.1143; Found: 272.1145.

5-(Cyclopropanecarbonyl)-6,6-bis(methylthio)hex-5-

1

enenitrile (3n): 62.1 mg, 81% yield, yellow liquid. H

NMR (400 MHz, CDCl₃) δ 2.71 (dd, J = 8.3 and 6.9 Hz, 2

H, (C=O)CCH₂), 2.35 (m, 5 H, SMe and CH₂CN), 2.29 (s,

3 H, SMe), 2.20 (m, 1 H, cyclopropyl CH), 1.79 (m, 2 H,

CH₂CH₂CN), 1.14 and 0.97 (m each, 2:2 H, cyclopropyl

CH). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 206.3 (Cq),

147.5 and 138.0 (Cq), 119.4 (CN), 32.7 ((C=O)CCH₂),

24.5 (CH₂CH₂CN), 22.1, 17.5, 16.7 and 16.6 (cyclopropyl

CH and CH₂CN), 12.8 (SMe). HRMS Calcd for

C₁₂H₁₇NOS₂[M+H]⁺: 256.0830; Found: 256.0830.

5-Benzoyl-6,6-bis(ethylthio)hex-5-enenitrile (3o): 73.5

mg, 76% yield, yellow liquid. ¹H NMR (400 MHz, CDCl₃)

δ 7.84, 7.57 and 7.45 (m each, 2:1:2 H, aromatic CH), 2.82

(m, 4 H, SCH₂and (C=O)CCH₂), 2.62 (q, J = 7.4 Hz, 2 H,

SCH₂), 2.38 (t, J = 7.2 Hz, 2 H, CH₂CN), 1.84 (m, 2 H,

CH₂CH₂CN), 1.30 (t, J = 7.3 Hz, 3 H, CH₂CH₃), 1.02 (t, J

= 7.4 Hz, 3 H, CH₂CH₃). ¹³C{¹H} NMR (100 MHz, CDCl₃)

δ 196.8 (Cq, C=O), 147.2, 136.2 and 133.6 (Cq), 133.5,

129.1 and 128.8 (aromatic CH), 119.4 (CN), 32.7

((C=O)CCH₂), 28.1, 27.3, 24.4, 16.7, 15.4 and 14.3 (CH₂

and CH₃). HRMS Calcd for C₁₇H₂₁NOS₂[M+H]⁺:

320.1143; Found: 320.1141.

5-(4-Bromobenzoyl)-6,6-bis(methylthio)hex-5-eneni-

trile (3i): 93.2 mg, 83% yield, yellow solid, m.p.: 64-65 ^oC.

¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, J = 8.4 Hz, 2 H,

aromatic CH), 7.60 (d, J = 8.4 Hz, 2 H, aromatic CH),2.77

(m, 2 H, (C=O)CCH₂), 2.39 (m, 5 H, CH₂CN and SMe),

2.07 (s, 3 H, SMe), 1.82 (m, 2 H, CH₂CH₂CN). ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 195.5 (Cq, C=O), 143.9, 137.7,

135.4 and 128.5 (Cq), 132.1 and 130.4 (aromatic CH),

119.3 (CN), 32.8 ((C=O)CCH₂), 24.3 (CH₂CH₂CN), 17.2

and 16.4 (SMe), 16.8 (CH₂CN). HRMS Calcd for

C₁₅H₁₆NOS₂Br [M+H]⁺: 369.9935; Found: 369.9939.

5-(Furan-2-carbonyl)-6,6-bis(methylthio)hex-5-eneni-

o

trile (3j): 36 mg, 42% yield, yellow solid, m.p.: 55-56 C.

¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J = 0.9 Hz, 1 H,

aromatic CH), 7.09 (d, J = 3.4 Hz, 1 H, aromatic CH), 6.55

(dd, J = 3.5 and 1.7 Hz, 1 H, aromatic CH), 2.78 (m, 2 H,

(C=O)CCH₂), 2.40 (m, 5 H, CH₂CN and SMe), 2.16 (s, 3

H, SMe), 1.83 (m, 2 H, CH₂CH₂CN). ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 184.5 (Cq), 152.6, 143.6 and 138.8 (Cq),

119.4 (CN), 147.2, 118.5 and 112.7 (aromatic CH), 32.7

((C=O)CCH₂), 24.3 (CH₂CH₂CN), 17.5 and 16.4 (SMe),

5-(1,3-Dithiolan-2-ylidene)-6-oxo-6-phenylhexaneni-

trile (3p): 66.2 mg, 76% yield, yellow liquid. H NMR

1

(400 MHz, CDCl₃) δ 7.44 (m, 5 H, aromatic CH), 3.38 (m,

4 H, SCH₂CH₂S), 2.73 (dd, J = 8.6 and 6.9 Hz, 2 H,

(C=O)CCH₂), 2.21 (t, J = 7.2 Hz, 2 H, CH₂CN), 1.75 (m, 2

H, CH₂CH₂CN). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

193.6 (Cq, C=O), 162.3, 139.4 and 122.9 (Cq), 130.9,

128.4 and 127.5 (aromatic CH), 119.2 (CN), 39.1, 36.5,

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Advanced Synthesis & Catalysis

33.8, 24.2 and 16.8 (CH₂). HRMS Calcd for C₁₅H₁₅NOS₂

[M+H]⁺: 290.0673; Found: 290.0672.

extracted with EtOAc (3×10 mL). The combined organic

phase was washed with water (3×10 mL), dried over

anhydrous Na₂SO₄, filtered, and concentrated under

reduced pressure. The resultant mixture was subjected to

purification by column chromatography on silica gel

5-(1,3-Dithiolan-2-ylidene)-6-oxoheptanenitrile (3q):

52.8 mg, 77% yield, yellow solid, m.p.: 77-78 ^oC. ¹H NMR

(400 MHz, CDCl₃) δ 3.34 (m, 4 H, SCH₂CH₂S), 2.70 (m, 2

H, (C=O)CCH₂), 2.41 (t, J = 7.0 Hz, 2 H, CH₂CN), 2.26 (s,

3 H, Me), 1.86 (m, 2 H, CH₂CH₂CN). ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 193.6 (Cq, C=O), 162.6 and 122.6 (Cq),

119.3 (CN), 39.4, 35.8, 33.2, 27.2, 24.1 and 17.1 (CH₂and

CH₃). HRMS Calcd for C₁₀H₁₃NOS₂[M+H]⁺: 228.0517;

Found: 228.0516.

o

(eluent: petroleum ether (60-90 C)/ethyl acetate = 20:1,

v/v) to afford the target product 4.

3-Argio-5-(4-methylbenzoyl)-6,6-bis(methylthio)hex-

1

5-enenitrile (4a): 80.2 mg, 68% yield, yellow liquid. H

NMR (400 MHz, CDCl₃) δ 7.74 (d, J = 8.2 Hz, 2 H,

aromatic CH), 7.27 (d, J = 8.0 Hz, 2 H, aromatic CH), 2.79

(dd, J = 14.1 and 9.1 Hz, 1 H, CH₂CN), 2.66 (dd, J = 14.1

and 5.6 Hz, 1 H, CH₂CN), 2.45 (d, J = 5.4 Hz, 2 H,

(C=O)CCH₂), 2.41 (s, 3 H, CH₃), 2.37 (s, 3 H, CH₃), 2.10

(s, 3 H, CH₃), 1.91 (m, 1 H, CHCH₂CN), 1.45 and 1.25 (m

each, 2:8 H, CH₂of nHex), 0.85 (t, J = 6.8 Hz, 3 H, CH₃of

nHex). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 196.2 (Cq,

C=O), 144.8, 144.5, 136.8 and 133.5 (Cq), 129.5 and 129.2

(aromatic CH), 118.6 (CN), 38.1, 34.5, 33.6, 31.7, 29.2,

26.5, 22.6, 21.8, 21.3, 17.2, 16.4 and 14.1 (CH, CH₂and

CH₃). HRMS Calcd for C₂₂H₃₁NOS₂[M+H]⁺: 390.1925;

Found: 390.1921.

5-(1,3-Dithian-2-ylidene)-6-oxo-6-phenylhexaneni-

1

trile (3r): 76.5 mg, 84% yield, yellow liquid. H NMR

(400 MHz, CDCl₃) δ 7.78, 7.53 and 7.43 (m each, 2:1:2 H,

aromatic CH), 3.01 (m, 2 H, CH₂), 2.76 (t, J = 6.7 Hz, 2 H,

CH₂), 2.68 (m, 2 H, (C=O)CCH₂), 2.34 (t, J = 7.2 Hz, 2 H,

CH₂), 2.11 (m, 2 H, CH₂), 1.80 (m, 2 H, CH₂). ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 196.1 (Cq, C=O), 139.9, 137.3

and 135.4 (Cq), 132.9, 128.8 and 128.7 (aromatic CH),

119.4 (CN), 31.4, 29.4, 28.9, 24.0, 23.9 and 16.7 (CH₂).

HRMS Calcd for C₁₆H₁₇NOS₂[M+H]⁺: 304.0830; Found:

304.0828.

Ethyl 2-(bis(methylthio)methylene)-5-cyanopentano-

ate (3s): 56 mg, 71% yield, yellow liquid. ¹H NMR (400

MHz, CDCl₃) δ 4.23 (q, J = 7.1 Hz, 2 H, OCH₂), 2.73 (m,

2 H, (C=O)CCH₂), 2.32 (m, 8 H, SMe and c), 1.82 (m, 2 H,

CH₂CH₂CN), 1.30 (t, J = 7.1 Hz, 3 H, CH₂CH₃). ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 167.7 (Cq, C=O), 142.2 and

137.0 (Cq), 119.4 (CN), 61.3 (OCH₂), 31.9 ((C=O)CCH₂),

24.6 (CH₂CH₂CN), 17.8, 17.0, 16.6 and 14.2 (SMe,

CH₂CH₃and CH₂CN). HRMS Calcd for C₁₁H₁₇NO₂S₂

[M+H]⁺: 260.0779; Found: 260.0776.

tert-Butyl 2-(cyanomethyl)-4-(4-methylbenzoyl)-5,5-

bis(methylthio)pent-4-enoate (4b): 85.6 mg, 70% yield,

yellow liquid. H NMR (400 MHz, CDCl₃) δ 7.75 (d, J =

1

8.1 Hz, 2 H, aromatic CH), 7.26 (d, J = 8.0 Hz, 2 H,

aromatic CH), 3.05 (m, 2 H, CH₂CN), 2.82 (m, 1 H,

CHCH₂CN), 2.67 (d, J = 6.2 Hz, 2 H, (C=O)CCH₂), 2.39

(6 H, Me and SMe), 2.07 (s, 3 H, SMe), 1.42 (s, 9 H,

(CH₃)₃). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 195.9 (Cq,

C=O), 170.6 (Cq, C=O), 144.5, 142.4, 138.7 and 133.7

(Cq), 129.5 and 129.2 (aromatic CH), 117.8 (CN), 82.5

(Cq, C(CH₃)₃), 41.4 (CH), 34.7 ((C=O)CCH₂), 27.9

(C(CH₃)₃), 21.8, 19.2, 17.1 and 16.4 (Me and CH₂CN).

HRMS Calcd for C₂₁H₂₇NO₃S₂[M+H]⁺: 406.1511; Found:

406.1511.

3-Benzyl-5-(4-methylbenzoyl)-6,6-bis(methylthio)-

hex-5-enenitrile (4c): 93 mg, 78% yield, yellow liquid. ¹H

NMR (400 MHz, CDCl₃) δ 7.68 (d, J = 8.1 Hz, 2 H,

aromatic CH), 7.18 and 7.08 (m each, 4:3 H, aromatic CH),

2.73 (m, 3 H, CH₂), 2.55 (dd, J = 13.8 and 9.4 Hz, 1 H,

CH₂), 2.324 (m, 7 H, Me and CH₂), 2.16 (m, 2 H, CH₂),

2.02 (s, 3 H, Me). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

196.1 (Cq, C=O), 144.5, 144.3, 138.6, 137.2 and 133.5

(Cq), 129.5, 129.2, 129.0, 128.6 and 126.6 (aromatic CH),

118.2 (CN), 39.5, 37.9, 36.6, 21.8, 20.7, 17.2 and 16.4 (CH,

CH₂and CH₃). HRMS Calcd for C₂₃H₂₅NOS₂[M+H]⁺:

396.1456; Found: 396.1454.

2-(Bis(methylthio)methylene)hexanedinitrile

(3t):

1

40.4 mg, 63% yield, yellow liquid. H NMR (400 MHz,

CDCl₃) δ 2.65 (m, 2 H, (C=O)CCH₂), 2.42 (m, 8 H, SMe

and (C=O)CCH₂), 1.99 – 1.93 (m, 2 H, c). ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 157.1 and 113.1 (Cq), 118.8 and

117.6 (CN), 31.7 ((C=O)CCH₂), 23.8 (CH₂CH₂CN), 18.2

and 16.5 (SMe), 17.3 (CH₂CN). HRMS Calcd for

C₉H₁₂N₂S₂[M+H]⁺: 213.0520; Found: 213.0524.

5-Methyl-6,6-diphenylhex-5-enenitrile (3u): 45.1 mg,

o

1

54% yield, yellow solid, m.p.: 35-36 C. H NMR (400

MHz, CDCl₃) δ 7.29 and 7.17 (m each, 4:6 H, aromatic

CH), 2.28 (m, 2 H, (C=O)CCH₂), 2.18 (m, 4 H, CH₂CH₃

and CH₂CN), 1.78 (m, 2 H, (C=O)CCH₂), 1.02 (t, J = 7.5

Hz, 3 H, CH₂CH₃). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

142.9, 139.8 and 138.2 (Cq), 129.1, 129.0, 128.4, 128.2,

126.6 and 126.5 (aromatic CH), 119.7 (CN), 30.5

((C=O)CCH₂), 25.0, 24.5, 17.1 and 13.4 (CH₂and CH₃).

HRMS Calcd for C₂₀H₂₁N [M+H]⁺: 276.1752; Found:

276.1754.

Methyl

4-(cyanomethyl)-3,3-dimethyl-6-(4-methyl-

benzoyl)-7,7-bis(methylthio)hept-6-enoate (4d): 83.1 mg,

1

66% yield, yellow liquid. H NMR (400 MHz, CDCl₃) δ

7.76 (d, J = 8.2 Hz, 2 H, aromatic CH), 7.27 (d, J = 7.9 Hz,

2 H, aromatic CH), 3.49 (s, 3 H, OMe), 3.02, 2.65, 2.53,

2.29 and 1.98 (m each, 1:2:1:2:1 H, CH and CH₂), 2.40,

2.09 and 1.07 (s each, 3:3:3:3:3 H, Me). ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 195.9 and 171.7 (Cq, C=O), 144.4,

144.3, 137.2 and 133.6 (Cq), 129.5 and 119.6 (aromatic

CH), 51.2, 44.34, 41.9, 36.4, 33.5, 25.2, 24.6, 21.7, 17.0,

16.8 and 16.3 (CH, CH₂and CH₃). HRMS Calcd for

C₂₂H₂₉NO₃S₂[M+H]⁺: 420.1667; Found: 420.1667.

General procedure for the synthesis of cyanoalkylated

ketene dithioacetals (4).

Under

a nitrogen atmosphere a mixture of α-(p-

methylbenzoyl) ketene di(methylthio)acetal (1d) (72 mg,

0.30 mmol), O-benzoyl cyclobutanone oxime ester (2)

(0.54 mmol), and FeCl₃(4.9 mg, 0.03 mmol) in 1.5 mL

o

PhCF₃was stirred at 110 C for 24 h. After cooled to

5-(4-Methylbenzoyl)-6,6-bis(methylthio)-3-phenyl-

hex-5-enenitrile (4e): 85.5 mg, 74% yield, yellow liquid.

¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J = 8.2 Hz, 2 H,

aromatic CH), 7.19 and 7.12 (m each, 4:3 H, aromatic CH),

ambient temperature, EtOAc and saturated aqueous

NaHCO₃(10 mL each) were successively added. The

organic phase was separated and the aqueous phase was

8

10.1002/adsc.201900402

Advanced Synthesis & Catalysis

3.17 (m, 1 H, CH), 3.06 (d, J = 7.5 Hz, 2 H, CH₂CN), 2.63

MHz, CDCl₃) δ 195.6 (Cq, C=O), 148.3, 144.2, 135.5 and

(m, 2 H, (C=O)CCH₂), 2.32, 2.18 and 1.95 (s each, 3 H,

135.0 (Cq), 129.4 and 129.2 (aromatic CH), 119.9 (CN),

Me). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 196.2 (Cq, C=O), 37.5, 31.5, 21.8, 18.9, 16.9, 16.4 and 15.4 (CH, CH₂and

144.2, 143.6, 140.7, 138.0 and 133.7 (Cq), 129.4, 129.2,

128.7, 127.7 and 127.6 (aromatic CH), 118.3 (CN), 40.9,

39.2, 24.3, 21.8, 17.2 and 16.3 (CH, CH₂and CH₃). HRMS

Calcd for C₂₂H₂₃NOS₂[M+H]⁺: 382.1299; Found:

382.1296.

CH₃). HRMS Calcd for C₁₇H₂₁NOS₂[M+H]⁺: 320.1143;

Found: 320.1145.

4-Benzyl-5-(4-methylbenzoyl)-6,6-bis(methylthio)-

hex-5-enenitrile (4k): 83 mg, 70% yield, yellow solid,

o

1

m.p.: 110-111 C. H NMR (400 MHz, CDCl₃) δ 7.62 and

7.14 (m, 2:7 H, aromatic CH), 3.83 (m, 1 H, CH), 2.83 (dd,

J = 13.7 and 6.5 Hz, 1 H, CH₂Bn), 2.37 (m, 6 H, CH₂and

CH₃), 2.20 (s, 3 H, CH₃), 1.97 (s, 3 H, CH₃), 1.70 (m, 2 H,

CH₂). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 195.5 (Cq,

C=O), 145.9, 144.2, 138.9, 138.3 and 134.8 (Cq), 129.3,

129.2, 128.5 and 126.5 (aromatic CH), 119.7 (CN), 44.9,

40.0, 28.5, 21.8, 16.9, 16.4 and 15.5 (CH, CH₂and CH₃).

HRMS Calcd for C₂₃H₂₅NOS₂[M+H]⁺: 396.1456; Found:

396.1452.

3-(4-(tert-Butyl)phenyl)-5-(4-methylbenzoyl)-6,6-bis-

(methylthio)hex-5-enenitrile (4f): 84 mg, 64% yield,

1

yellow liquid. H NMR (400 MHz, CDCl₃) δ 7.45 (d, J =

8.2 Hz, 2 H, aromatic CH), 7.14 and 7.04 (m each, 2:4 H,

aromatic CH), 3.07 (m, 3 H, CH and CH₂CN), 2.58 (m, 2

H, (C=O)CCH₂), 2.26, 2.14, 1.91 and 1.14 (s each, 3:3:3:9

H, Me). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 196.2 (Cq,

C=O), 150.4, 143.9, 143.8, 138.0, 137.6 and 133.7 (Cq),

129.2, 129.1, 127.2 and 125.5 (aromatic CH), 118.5 (CN),

40.6, 39.3, 34.4, 31.3, 24.4, 21.7, 17.2 and 16.3 (CH, CH₂

and CH₃). HRMS Calcd for C₂₆H₃₁NOS₂[M+H]⁺:

438.1925; Found: 438.1925.

General procedure for the synthesis of cyanoalko-

xylated ketene dithioacetals (5)

5-(4-Methylbenzoyl)-6,6-bis(methylthio)-3-(4-(trifluo-

romethyl)phenyl)hex-5-enenitrile (4g): 88 mg, 65% yield,

yellow liquid. H NMR (400 MHz, CDCl₃) δ 7.56 (d, J =

Under an atmospheric dioxygen atmosphere a mixture of

ketene dithioacetal (1) (0.3 mmol), O-benzoyl

cyclobutanone oxime ester 2 (0.6 mmol), and CuCl₂(4 mg,

1

8.0 Hz, 2 H, aromatic CH), 7.51 (d, J = 8.1 Hz, aromatic

CH), 7.39 (d, J = 8.1 Hz, 2 H, aromatic CH), 7.18 (d, J =

8.0 Hz, 2 H, aromatic CH), 3.32 (m, 1 H, CH), 3.14 (m, 2

H, CH₂CN), 2.73 (m, 2 H, (C=O)CCH₂), 2.38, 2.25 and

2.03 (s each, 3:3:3 H, Me). ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 196.1 (Cq, C=O), 144.6, 144.4, 142.5, 138.7 and

133.5 (Cq), 130.0 (q, J = 32.3 Hz, i-C of CF₃C₆H₄), 129.4,

129.1 and 128.2 (aromatic CH), 125.7 (q, J = 3.7 Hz, o-C

of CF₃C₆H₄), 124.0 (q, J = 270.4 Hz, CF₃), 117.9 (CN),

40.9, 38.9, 24.2, 21.7, 17.1 and 16.3 (CH, CH₂and CH₃).

HRMS Calcd for C₂₃H₂₂NOF₃S₂[M+H]⁺: 450.1173; Found:

450.1170.

o

0.03 mmol) in 3 mL PhCF₃was stirred at 100 C for 5 h.

After cooled to ambient temperature, EtOAc and saturated

aqueous NaHCO₃(10 mL each) were successively added.

The organic phase was separated and the aqueous phase

was extracted with EtOAc (3×10 mL). The combined

organic phase was washed with water (3×10 mL), dried

over anhydrous Na₂SO₄, filtered, and concentrated under

reduced pressure. The resultant mixture was subjected to

purification by column chromatography on silica gel

o

(eluent: petroleum ether (60-90 C)/ethyl acetate = 20:1,

v/v) to afford the target product 5.

3-(4-Chlorophenyl)-5-(4-methylbenzoyl)-6,6-bis(me-

thylthio)hex-5-enenitrile (4h): 83 mg, 66% yield, yellow

liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.50 (d, J = 8.1 Hz, 2

H, aromatic CH), 7.13 (m, 6 H, aromatic CH), 3.15 (m, 1

H, CH), 3.02 and 2.60 (m each, 2:2 H, CH₂), 2.32, 2.18

and 1.95 (s each, 3:3:3 H, Me). ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 196.0 (Cq, C=O), 144.3, 142.9, 139.0, 138.3,

133.6 and 133.4 (Cq), 129.4, 129.1 and 128.8 (aromatic

CH), 118.1 (CN), 40.4, 39.1, 24.4, 21.8, 17.1 and 16.3 (CH,

CH₂and CH₃). HRMS Calcd for C₂₂H₂₂NOS₂Cl [M+H]⁺:

416.0910; Found: 416.0908.

3-(3-Chlorophenyl)-5-(4-methylbenzoyl)-6,6-bis(me-

thylthio)hex-5-enenitrile (4i): 79 mg, 63% yield, yellow

liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J = 8.1 Hz, 2

H, aromatic CH), 7.13 (m, 6H), 3.06 (m, 3 H, CH and

CH₂CN), 2.61 (m, 2 H, (C=O)CCH₂), 2.32, 2.18 and 1.95

(s each, 3:3:3 H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

195.9 (Cq, C=O), 144.4, 142.7, 142.5, 138.4, 134.4 and

133.5 (Cq), 130.0, 129.3, 129.1, 127.9, 127.8 and 126.0

(aromatic CH), 118.0 (CN), 40.7, 38.9, 24.2, 21.8, 17.1 and

16.3 (CH, CH₂and CH₃). HRMS Calcd for C₂₂H₂₂NOS₂Cl

[M+H]⁺: 416.0910; Found: 416.0914.

4-((1,1-Bis(methylthio)-3-oxo-3-phenylprop-1-en-2-

yl)-oxy)butanenitrile (5a): 46.5 mg, 50% yield, yellow

liquid. H NMR (400 MHz, CDCl₃) δ 7.91 (m, 2 H,

1

aromatic CH), 7.59 (t, J = 7.4 Hz, 1 H, aromatic CH), 7.49

(t, J = 7.6 Hz, 2 H, aromatic CH), 3.89 (t, J = 5.6 Hz, 2 H,

OCH₂), 2.57 (t, J = 7.2 Hz, 2 H, CH₂CN), 2.39 (s, 3 H,

SMe), 2.05 (s, 3 H, SMe), 1.97 (m, 2 H, OCH₂CH₂).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 191.4 (Cq, C=O),

152.5, 136.6 and 121.5 (Cq), 133.9, 129.2 and 128.8

(aromatic CH), 119.2 (CN), 68.7 (OCH₂), 25.9 (OCH₂CH₂),

17.8, 15.7 and 14.1 (SMe and CH₂CN). HRMS Calcd for

C₁₅H₁₇NO₂S₂[M+H]⁺: 308.0779; Found: 308.0779.

4-((1,1-Bis(methylthio)-3-oxo-3-(p-tolyl)prop-1-en-2-

yl)-oxy)butanenitrile (5b): 43.2 mg, 44% yield, yellow

o

solid, m.p.: 43-44 C. ¹H NMR (400 MHz, CDCl₃) δ 7.86

(d, J = 8.1 Hz, 2 H, aromatic CH), 7.32 (d, J = 8.0 Hz, 2 H,

aromatic CH), 3.91 (t, J = 5.6 Hz, 2 H, OCH₂), 2.59 (t, J =

7.2 Hz, 2 H, CH₂CN), 2.45 and 2.42 (s each, 3:3 H, SMe

and Me), 2.10 (s, 3 H, SMe), 1.98 (m, 2 H, OCH₂CH₂).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 190.9 (Cq, C=O),

152.8, 145.0, 133.9 and 120.0 (Cq), 129.5 and 129.3

(aromatic CH), 119.1 (CN), 68.5 (OCH₂), 25.9, 21.8, 17.8,

15.5 and 14.0 (CH₂and CH₃). HRMS Calcd for

C₁₆H₁₉NO₂S₂[M+H]⁺: 322.0935; Found: 322.0935.

4-Methyl-5-(4-methylbenzoyl)-6,6-bis(methylthio)-

hex-5-enenitrile (4j): 77.5 mg, 80% yield, yellow solid,

o

1

m.p.: 69-70 C. H NMR (400 MHz, CDCl₃) δ 7.70 and

7.19 (d each, J = 8.1 Hz, 2:2 H, aromatic CH), 3.56 (m, 1

H, CH), 2.41 (m, 2 H, CH₂CN), 2.33 (d, 6 H, CH₃), 2.00 (s,

3 H, CH₃), 1.84 (m, 1 H, CHCH₂), 1.68 (m, 1 H, CHCH₂),

0.95 (d, J = 7.0 Hz, 3 H, CHCH₃). ¹³C{¹H} NMR (100

CCDC-1873200

contains

the

supplementary

crystallographic data for this compound. These data can be

obtained free of charge from The Cambridge

9

10.1002/adsc.201900402

Advanced Synthesis & Catalysis

Crystallographic

www.ccdc.cam.ac.uk/data_request/cif.

Data

Centre

via

(CN), 68.9 (OCH₂), 25.9, 17.8, 15.7 and 14.1 (CH₂and

CH₃). HRMS Calcd for C₁₅H₁₆NO₂S₂Br [M+H]⁺:

385.9884; Found: 385.9880.

4-((3-(4-Methoxyphenyl)-1,1-bis(methylthio)-3-oxo-

prop-1-en-2-yl)oxy)butanenitrile (5c): 48.2 mg, 47%

yield, yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.91

and 6.96 (m each, 2:2 H, aromatic CH), 3.88 (m, 5 H, OMe

and OCH₂), 2.57 (t, J = 7.2 Hz, 2 H, CH₂CN), 2.38 and

2.08 (s each, 3:3 H, SMe), 1.96 (m, 2 H, OCH₂CH₂).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 190.0 (Cq, C=O),

164.4, 153.1, 129.3 and 119.3 (Cq), 131.8 and 114.2

(aromatic CH), 119.2 (CN), 68.6 (OCH₂), 55.7 (OMe),

25.9, 17.9, 15.6 and 14.1 (CH₂and CH₃). HRMS Calcd for

C₁₆H₁₉NO₃S₂[M+H]⁺: 338.0885; Found: 338.0888.

4-((1,1-Bis(ethylthio)-3-oxo-3-phenylprop-1-en-2-yl)-

oxy)butanenitrile (5h): 44 mg, 43% yield, yellow liquid.

¹H NMR (400 MHz, CDCl₃) δ 7.92 (m, 2 H, aromatic CH),

7.59 (t, J = 7.4 Hz, 1 H, aromatic CH), 7.48 (t, J = 7.6 Hz,

2 H, aromatic CH), 3.87 (t, J = 5.6 Hz, 2 H, OCH₂), 2.88 (q,

J = 7.3 Hz, 2 H, SCH₂), 2.58 (m, 4 H, SCH₂and CH₂CN),

1.95 (m, 2 H, OCH₂CH₂), 1.31 (t, J = 7.3 Hz, 3 H,

CH₂CH₃), 1.04 (t, J = 7.4 Hz, 3 H, CH₂CH₃). ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 191.6 (Cq, C=O), 154.3, 136.4

and 118.5 (Cq), 133.9, 129.3 and 128.8 (aromatic CH),

119.2 (CN), 68.9 (OCH₂), 28.4, 26.6, 25.9, 15.55, 14.2 and

14.0 (CH₂and CH₃). HRMS Calcd for C₁₇H₂₁NO₂S₂

[M+H]⁺: 336.1092; Found: 336.1090.

4-((1,1-Bis(methylthio)-3-oxo-3-(4-(trifluoromethyl)-

phenyl)prop-1-en-2-yl)oxy)butanenitrile (5d): 57 mg,

50% yield, yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ

8.01 (d, J = 7.9 Hz, 2 H, aromatic CH), 7.74 (d, J = 7.9 Hz,

4-((1,1-Bis(methylthio)-3-oxo-3-phenylprop-1-en-2-

2 H, aromatic CH), 3.91 (t, J = 5.6 Hz, 2 H, OCH₂), 2.59 (t, yl)oxy)pentanenitrile (5i): 49 mg, 50% yield, yellow

J = 7.1 Hz, 2 H, CH₂CN), 2.41 (s, 3 H, SMe), 2.00 (m, 5 H, liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.90 (d, J = 8.0 Hz, 2

SMe and OCH₂CH₂). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

190.2 (Cq, C=O), 151.5, 139.8 and 125.3 (Cq), 134.7 (q, J

H, aromatic CH), 7.59 (t, J = 7.0 Hz, 1 H, aromatic CH),

7.48 (t, J = 7.7 Hz, 2 H, aromatic CH), 4.00 (m, 1 H, OCH),

= 32.4 Hz, i-C of CF₃C₆H₄), 129.3 (aromatic CH), 125.8 (q, 2.42 (m, 5 H, SMe and CH₂), 2.05 (s, 3 H, SMe), 1.88 (m,

J = 3.7 Hz, o-C of CF₃C₆H₄), 123.6 (q, J = 271.0 Hz, CF₃),

119.1 (CN), 69.1 (OCH₂), 25.9, 17.8, 15.8 and 14.1 (CH₂

and CH₃). HRMS Calcd for C₁₆H₁₆NO₂F₃S₂[M+H]⁺:

376.0653; Found: 376.0655.

2 H, CH₂), 1.22 (d, J = 6.2 Hz, 3 H, CHCH₃). ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 191.6 (Cq, C=O), 151.9, 136.4

and 122.1 (Cq), 133.9, 129.2 and 128.8 (aromatic CH),

119.5 (CN), 75.6 (OCH), 32.3, 20.1, 18.0, 15.5 and 13.2

(CH₂and CH₃). HRMS Calcd for C₁₆H₁₉NO₂S₂[M+H]⁺:

322.0935; Found: 322.0934.

4-((3-(2-Bromophenyl)-1,1-bis(methylthio)-3-oxo-

prop-1-en-2-yl)oxy)butanenitrile (5e): 48.2 mg, 41%

yield, yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.60

(dd, J = 7.9 and 0.8 Hz, 1 H, aromatic CH), 7.47 (dd, J =

7.6 and 1.6 Hz, 1 H, aromatic CH), 7.37 (td, J = 7.5 and

1.0 Hz, 1 H, aromati CH), 7.29 (td, J = 7.7 and 1.7 Hz, 1 H,

aromatic CH), 3.96 (t, J = 5.6 Hz, 2 H, OCH₂), 2.50 (t, J =

7.2 Hz, 2 H, CH₂CN), 2.43 (s, 3 H, SMe), 2.04 (s, 3 H,

SMe), 1.96 (m, 2 H, OCH₂CH₂). ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 190.1 (Cq, C=O), 151.1, 140.8, 136.3 and 120.5

(Cq), 119.5 (CN), 133.7, 131.8, 130.1 and 127.2 (aromatic

CH), 69.1 (OCH₂), 26.2, 17.9, 16.4 and 14.1 (CH₂and

CH₃). HRMS Calcd for C₁₅H₁₆NO₂S₂Br [M+H]⁺:

385.9884; Found: 385.9881.

4-((3-(3-Bromophenyl)-1,1-bis(methylthio)-3-oxo-

prop-1-en-2-yl)oxy)butanenitrile (5f): 56.2 mg, 48%

yield, yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ 8.04 (t,

J = 1.7 Hz, 1 H, aromatic CH), 7.82 (d, J = 7.8 Hz, 1 H,

aromatic CH), 7.71 (m, 1 H, aromatic CH), 7.37 (t, J = 7.9

Hz, 1 H, aromatic CH), 3.89 (t, J = 5.6 Hz, 2 H, OCH₂),

2.59 (t, J = 7.2 Hz, 2 H, CH₂CN), 2.41 (s, 3 H, SMe), 2.07

(s, 3 H, SMe), 1.98 (m, 2 H, OCH₂CH₂). ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 189.9 (Cq, C=O), 151.5, 138.6, 124.4

and 123.1 (Cq), 136.5, 131.8, 130.4 and 127.6 (aromatic

CH), 69.1 (OCH₂), 25.9, 17.8, 15.8 and 14.2 (CH₂and

CH₃). HRMS Calcd for C₁₅H₁₆NO₂S₂Br [M+H]⁺:

385.9884; Found: 385.9886.

Condensation of cyanoalkylation product 3a with

hydrazine hydrate

A mixture of 3a (58 mg, 0.20 mmol), hydrazine hydrate

(118 mg, 2.0 mmol, aq 85%) in toluene (2 mL) was stirred

o

in a 10 mL sealed tube at 110 C. When TLC monitoring

on silica gel indicated complete consumption of the

substrate over a period of 72 h, the reaction mixture was

cooled to ambient temperature, and all the volatiles were

removed under reduced pressure. The resultant residue was

purified by silica gel column chromatography (eluent:

o

petroleum ether (60-90 C)/ethyl acetate = 10:1, v/v) to

afford the target product 6.

4-(5-(Methylthio)-3-phenyl-1H-pyrazol-4-yl)butane-

nitrile (6): 42 mg, 81% yield, white solid, m.p.: 102-103

1

^oC. H NMR (400 MHz, CDCl₃) δ 8.70 (brs, 1 H, NH),

7.42 (m, 5 H, aromatic CH), 2.75 (m, 2 H, CH₂CN), 2.42 (s,

3 H, SMe), 2.25 (t, J = 7.2 Hz, 2 H, CCH₂), 1.83 (m, 2 H,

CH₂CH₂CN). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 144.4

and 143.8 (Cq), 130.6 and 116.6 (Cq), 129.1, 128.7 and

127.5 (aromatic CH), 119.5 (CN), 25.9, 22.6, 17.2 and 16.7

(CH₂and CH₃). HRMS Calcd for C₁₄H₁₅N₃S [M+H]⁺:

258.1065; Found: 258.1062.

4-((3-(4-Bromophenyl)-1,1-bis(methylthio)-3-oxo-

prop-1-en-2-yl)oxy)butanenitrile (5g): 61 mg, 52% yield,

General procedure for the synthesis of α-cinnamyl

ketene dithioacetal (7)

o

yellow solid, m.p.: 61-62 C. ¹H NMR (400 MHz, CDCl₃)

δ 7.78 (d, J = 8.5 Hz, 2 H, aromatic CH), 7.62 (d, J = 8.5

Hz, 2 H, aromatic CH), 3.88 (t, J = 5.6 Hz, 2 H, OCH₂),

2.58 (t, J = 7.2 Hz, 2 H, CH₂CN), 2.39 (s, 3 H, SMe), 2.06

(s, 3 H, SMe), 1.95 (m, 2 H, OCH₂CH₂). ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 190.3 (Cq, C=O), 151.8, 135.5, 129.0

and 123.1 (Cq), 132.2 and 130.6 (aromatic CH), 119.2

A

mixture of 5-(bis(methylthio)methylene)-6-oxohep-

tanenitrile (3l) (460 mg, 2.0 mmol), benzaldehyde (233 mg,

2.2 mmol) and NaOH (160 mg, 4.0 mmol) in EtOH (5 mL)

was stirred at ambient temperature for 2 h. After 3l was

completely consumed as indicated by TLC monitoring

after 2 h, 20 mL of water was added, extracted with

10

10.1002/adsc.201900402

Advanced Synthesis & Catalysis

CH₂Cl₂(3×20 mL). The combined organic extracts were

washed with saturated aqueous NaCl (3×15 mL), dried

over anhydrous MgSO₄, filtered, and concentrated under

reduced pressure to yield the crude product, which was

purified by silica gel chromatography (eluent, petroleum

ether/ethyl acetate: 5/1, v/v) to afford the target product 7.

(E)-5-(Bis(methylthio)methylene)-6-oxo-8-phenyloct-

resulting residue was purified by silica gel chromatography

(eluent, petroleum ether/ethyl acetate: 12/1, v/v) to afford

the target product 9.

Ethyl

2-(3-(3-cyanopropyl)-2-hydroxy-2-methyl-4-

(me-thylthio)-5-oxo-2,5-dihydro -1H-pyrrol-1-yl)acetate

(9): 46 mg, 73% yield, yellow liquid. ¹H NMR (400 MHz,

CDCl₃) δ 4.28 and 3.89 (d each, J = 17.8 Hz, 1:1 H, NCH₂),

4.18 (q, J = 7.1 Hz, 2 H, CH₂CH₃), 3.63 (s, 1 H, OH), 2.69

(m, 1 H, CH2), 2.54–2.38 (m, 6 H, SMe and CH2), 2.12–

1.93 (m, 2 H, CH2), 1.43 (s, 3 H, CH3), 1.27 (t, J = 7.1 Hz,

3 H, CH₂CH₃). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.7

and 167.3 (Cq, C=O), 158.4 and 128.7 (Cq), 119.3 (CN),

89.3 (COH), 62.1 (OCH₂), 40.2 (NCH₂), 25.4, 23.9, 21.8,

17.3, 15.1 and 14.2 (CH₃and CH₂). HRMS Calcd for

C₁₄H₂₀N₂O₄S [M+Na]⁺: 335.1041; Found: 335.1037.

1

7-enenitrile (7): 572 mg, 90% yield, yellow liquid. H

NMR (400 MHz, CDCl₃) δ 7.53 and 7.37 (m each, 2:3 H,

aromatic CH), 7.45 and 6.90 (d each, J = 16.1 Hz, 1:1 H,

CH), 2.84–2.69 (m, 2 H, CCH₂), 2.42–2.32 (m, 5 H, SMe

and CH₂), 2.26 (s, 3 H, SMe), 1.89–1.74 (m, 2 H,

CH₂CH₂CN). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 195.4

(Cq, C=O), 145.7, 138.6 and 134.5 (Cq), 143.0 and 126.6

(CH), 130.5, 129.0 and 128.3 (aromatic CH), 119.3 (CN),

32.8, 24.3, 17.5, 16.7 and 16.5 (CH₃and CH₂). HRMS

Calcd for C₁₇H₁₉NOS₂[M+H]⁺: 318.0986; Found:

318.0983.

Acknowledgements

General procedure for the synthesis of 2,3-

dihydrothiopyran-4-one (8)

We are grateful to the National Natural Science

Foundation of China (21871253 and 21472185) and the

National

Basic

Research

Program

of

China

(2015CB856600) for support of this research. Professor

Hongmei Wang is thanked for her kind suggestions and

helpful discussion.

A mixture of (E)-5-(bis(methylthio)methylene)-6-oxo-8-

phenyloct-7-enenitrile (7) (64 mg, 0.2 mmol) and

Na₂S·9H₂O (53 mg, 0.22 mmol) in DMF (2 mL) was

stirred at 80 °C for 1 h. After cooled to ambient

temperature, the reaction was quenched with saturated

aqueous Na₂CO₃(10 mL) and the mixture was extracted References

with CH₂Cl₂(3×20 mL). The combined organic extracts

[1] a) Z. Dong, Z. Ren, S. J. Thompson, Y. Xu, G. B. Dong,

were washed with brine (3×20 mL), dried over MgSO₄,

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4-(6-(Methylthio)-4-oxo-2-phenyl-3,4-dihydro-2H-

thiopyran-5-yl)butanenitrile (8): 46 mg, 75% yield,

o

1

yellow solid, m.p.: 97-98 C. H NMR (400 MHz, CDCl₃)

δ 7.48–7.30 (m, 5 H, aromatic CH), 4.61 (dd, J = 14.1 and

2.9 Hz, 1 H, CH), 3.14 (dd, J = 16.3 and 14.2 Hz, 1 H,

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2.79–2.63 (m, 2 H, CCH₂), 2.52 (s, 3 H, CH₃), 2.36 (t, J =

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304.0830; Found: 304.0829.

General procedure for the synthesis of 4-cyanoalkyl-5-

hydroxy-α,β-unsaturated γ-lactam (9)

Under a nitrogen atmosphere, a mixture of compound 3l

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(3×15 mL). The combined organic extracts were washed

with brine (3×15 mL), dried over anhydrous MgSO₄,

filtered, and concentrated under reduced pressure. The

11

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Advanced Synthesis & Catalysis

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Advanced Synthesis & Catalysis

FULL PAPER

Transition-Metal-Promoted Direct CH

Cyanoalkylation and Cyanoalkoxylation of

Internal Alkenes via Radical CC Bond

Cleavage of Cycloketone Oxime Esters

Adv. Synth. Catal. Year, Volume, Page – Page

Jiang Lou, Yuan He, Yunlong Li, and Zhengkun

Yu*

13

Article Doi

Transition-Metal-Promoted Direct C?H Cyanoalkylation and Cyanoalkoxylation of Internal Alkenes via Radical C?C Bond Cleavage of Cycloketone Oxime Esters

DOI: 10.1002/adsc.201900402

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