Domino 1,4- And 1,6-Addition Reactions of Ketene Silyl Acetals to Dialkynyl Imines Promoted by Aluminum Chloride: Synthesis of Multifunctionalized β-Lactams

Article

pubs.acs.org/joc

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

Domino 1,4- and 1,6-Addition Reactions of Ketene Silyl Acetals to

Dialkynyl Imines Promoted by Aluminum Chloride: Synthesis of

Multifunctionalized β‑Lactams

Iwao Hachiya,*^,†Kenta Nakamura,^†Masaya Hara,^†Koki Sato,^†and Makoto Shimizu*^,†,‡

^†Department of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu Mie 514-8507, Japan

^‡School of Energy Science and Engineering, Nanjing Tech University, Nanjing, 211816 Jiangsu, China

S

* Supporting Information

ABSTRACT: Domino 1,4- and 1,6-addition reactions of ketene silyl

acetals to dialkynyl imines are disclosed. Aluminum chloride promoted

domino 1,4- and 1,6-addition reactions of ketene silyl acetals to dialkynyl

imines to give a variety of alkenyl iminocyclobutenones in moderate to

good yields. The chemoselective reduction of alkenyl iminocyclobute-

nones and the subsequent thermal rearrangement of resulting alkenyl

aminocyclobutenones in the presence of appropriate amines provided cis

or trans multifunctionalized β-lactams in moderate to high yields with

good to high diastereoselectivities.

key intermediate and considered use of the dialkynyl imine 1a

as a novel 1,4-addition acceptor (Scheme 2).⁶

INTRODUCTION

■

The development of eﬃcient synthetic methods for nitrogen-

containing compounds is extensively investigated because

many of them such as amino acids, β-lactams, and vitamins

show useful biological activities. Imines, one of the most useful

types of nitrogen-containing compounds, are typically prepared

by the condensation of carbonyl compounds with primary

amines via dehydration. Among various imines, there are α,β-

unsaturated alkynyl imines having a triple bond. We have

developed new eﬃcient synthetic methods for various

nitrogen-containing heterocycles using 1,4-additions of several

carbon nucleophiles such as malonic esters, β-keto esters, and

ethyl cyanoacetates to α,β-alkynyl imines.^1,2In 2009, we

developed the chemoselective reductions of iminocyclobute-

nones, which were synthesized using aluminum chloride-

promoted 1,4-additions of ketene silyl acetals to α,β-alkynyl

imines, to proceed using sodium cyanoborohydride under the

inﬂuence of an acid to give the racemic aminocyclobutenones

in high yields, and the subsequent thermal rearrangement of

aminocyclobutenones in the presence of an appropriate amine

aﬀorded either racemic cis- or trans-β-lactams in good yields

with high diastereoselectivities.³In 2014, we also reported

chiral either cis- or trans-β-lactam synthesis through the

enantioselective reduction of iminocyclobutenones catalyzed

by a chiral phosphoric acid and the subsequent thermal

rearrangement of chiral aminocyclobutenones in the presence

of appropriate amines (Scheme 1).⁴

First, we examined the 1,4-addition of an equivalent of

ketene silyl acetal 2a to dialkynyl imine 1a in the presence of

aluminum chloride. The desired alkynyl iminocyclobutenone 3

was not produced; however, the domino 1,4- and 1,6- addition

product 5a was obtained in 27% yield based on 2a (Scheme 3).

We considered the formation of 5a via the sequential 1,6-

addition of the second nucleophile 2a to the intermediate 3

generated in situ. 1,6-Addtion reactions of nucleophiles to

α,β,γ,δ-unsaturated carbonyl compounds are rare compared to

1,4-addition reactions.⁷Transition-metal-catalyzed asymmetric

1,6-addition reactions have been reported as a represented

example.⁸On the other hand, organocatalytic 1,6-addition

reactions have been also developed.⁹Among them, 1,6-

additon/1,4-addition cascade reactions have been reported

by Jørgensen and Ye, respectively.¹⁰Therefore, we were

interested in the formation of the domino 1,4- and 1,6-addition

product 5a albeit in a low yield. Here, we report a novel

domino 1,4- and 1,6-addition reaction of ketene silyl acetals to

dialkynyl imines.

RESULTS AND DISCUSSION

■

First, we screened the reaction conditions for the domino 1,4-

and 1,6-double addition reactions using more reactive

dialkynyl imine 1b compared to 1a. Table 1 summarizes the

results. Several equivalents of aluminum chloride were

We next envisioned the total synthesis of SCH48461,⁵which

is a cholesterol absorption inhibitor, via the synthesis of the

chiral β-lactam 4 using the alkynyl iminocyclobutenone 3 as a

Received: August 30, 2019

A

DOI: 10.1021/acs.joc.9b02364

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Scheme 1. Stereodivergent Synthesis of Cis- and Trans-β-Lactams

Scheme 2. Alkynyliminocyclobutenone Synthesis Directed to the Total Synthesis of SCH48461

Scheme 3. 1,4-Addition of Ketene Silyl Acetal 2a to Dialkynyl Imine 1a

examined (entries 1−4). When the reaction of imine 1b with 3

equiv of the ketene silyl acetal 2a was carried out in the

presence of 3 equiv of aluminum chloride, the desired domino

1,4- and 1,6-addition product 5b was obtained in 62% yield

(entry 3). We next investigated other Lewis acids. Although

ethylaluminum dichloride gave 5b in 57% yield, titanium

chloride was not eﬀective (entries 5 and 6).

With the optimized reaction conditions in hands, several

dialkynyl imines were subjected to the domino 1,4- and 1,6-

addition reaction. The results are summarized in Table 2. We

examined the aromatic substituents Ar²of the imino carbon.

The reaction of imine 1a under the optimized reaction

conditions gave 5a in 64% yield (entry 1). Dialkynyl imine 1c

having an electron-donating tolyl group aﬀorded 5c in 59%

yield (entry 3). Dialkynyl imine 1d having an electron-

withdrawing 4-chlorophenyl group produced 5d in 81% yield

(entry 4). The reaction of the sterically hindered 2-naphthyl

imine 1e proceeded to give 5e in 68% yield (entry 5). The

imines 1f and 1g having a heteroaromatic group gave 5f and 5g

in moderate yields (entries 6 and 7), respectively. We next

examined the aromatic substituents Ar¹of the terminal alkynyl

group. Dialkynyl imines 1h−1j having a monosubstituted

phenyl group aﬀorded 5h−5j in good to high yields (entries

8−10). The imine 1k possessing a sterically hindered 2-

naphthyl group gave 5k in 60% yield (entry 11). 2-Thienyl and

5-methyl-2-furyl imines 1l and 1m having a heteroaromatic

group worked well to give 5l and 5m in 70 and 59% yields,

respectively (entries 12 and 13). Finally, several ketene silyl

B

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Table 1. Optimization of 1,4- and 1,6-Double Nucleophilic Addition Reaction Conditions

entry

Lewis acid

equiv

yield (%)

1

2

3

4

5

6

AlCl₃

EtAlCl₂

TiCl₄

1

2

3

4

3

28

32

62

60

57

a

0 (76)

a

Yields of the recovered dialkynyl imine 1b in parenthesis.

Table 2. Scope of the Substrates in Domino 1,4- and 1,6-Addition Reaction and the Reduction of Iminocyclobutenones 5

a

g

entry

Ar¹

Ar²

PMP

R

5 (yield %)

10 (yield %)

b

1

2

3

4

5

6

7

8

Ph

Me

Et

5a (64)

10a (52)

10b (88)

h

Ph

5b (62)

c

4-MeC₆H₄

4-ClC₆H₄

2-naphthyl

2-thienyl

2-furyl

Ph

5c (59)

10c (78)

10d (75)

10e (73)

10f (59)

5d (81)

d

5e (68)

5f (56)

5g (48)

d

i

10g (62)

4-MeC₆H₄

PMP

5h (65)

5i (84)

10h (70)

10i (76)

10j (80)

10k (85)

10l (72)

9

e

10

11

12

13

4-ClC₆H₄

2-naphthyl

2-thienyl

5-methyl-2-furyl

Ph

5j (66)

5k (60)

d

5l (70)

j

Ph

5m (59)

10m (66)

h

f

14

5n (51)

5o (71)

10n (78)

10o (77)

d

15

Ph

−(CH₂)₄−

a

Conditions: dialkynyl imine 1 (0.1 mmol), ketene silyl acetal 2 (0.3 mmol), AlCl₃(0.3 mmol), CH₂Cl₂(2.0 mL), under Ar at −78 °C to rt, 2 h.

b

c

d

e

f

g

1a (0.50 mmol). 1c (0.40 mmol). 1 (1.0 mmol). 1f (0.50 mmol). 1b (0.11 mmol), 1.5 h. Conditions: See the Supporting Information for

h

i

j

details. 0.5 h. AcCl (0.5 equiv). AcCl (1.0 equiv).

acetals were investigated. The reaction of imine 1b with ketene

silyl acetal 2b having a diethyl group proceeded to aﬀord 5n on

51% yield (entry 14). The reaction of imine 1b with 2c

possessing a cyclopentyl group gave 5o in 71% yield (entry

15).^11,12

butenone 5. Regarding the regioselective 1,4-addition of the

ﬁrst ketene silyl acetal 2 at the β carbon to the dialkynyl imine

1, we presume the results of both electronic and steric eﬀects.

1,2-Addition would not proceed because of the steric

hindrance at the imino carbon. On the other hand, the delta

carbon is less hindered but distal to the electron-withdrawing

imino group, and therefore, the 1,6-addition of the ﬁrst ketene

silyl acetal 2 at the delta carbon would not occur. The second

ketene silyl acetal 2 would react rapidly at a delta carbon

because of the dual eﬀect of the electron-withdrawing imino

and keto carbonyl groups. We presume the intermediate 8

would be more reactive than the dialkynyl imine 1 as an

electrophile. As a result, the alkynyl iminocyclobutenone 8 was

not isolated.

A plausible reaction mechanism is shown in Scheme 4.

Metalloallenamine 6 would be generated via a 1,4-addition

reaction of the ﬁrst ketene silyl acetal 2 at the β carbon to the

dialkynyl imine 1 activated by aluminum chloride and undergo

an intramolecular cyclization to give the alkynyliminocyclobu-

tenoxide 7. The elimination of aluminum methoxide from the

alkynyliminocyclobutenoxide 7 would give the alkynyl

iminocyclobutenone 8. Subsequent 1,6-addition reaction of

the second ketene silyl acetal 2 at a delta carbon would

proceed to give the metallodienamine 9. The protonation of

the metallodienamine 9 with water to quench the reaction

would occur from the less hindered face of the allene moiety to

give the 1,4- and 1,6-addition product, Z-alkenyliminocyclo-

We next examined chemoselective reduction of iminocyclo-

butenones 5 having four reducible functional groups such as

imino, ketone and alkoxy carbonyl, and alkenyl under our

previously reported conditions.³When sodium cyanoborohy-

C

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Scheme 4. Plausible Reaction Mechanism

a

Table 3. Synthesis of Cis- or Trans-β-Lactams 11 through the Thermal Rearrangement

c

conditions A (conditions B)

conditions C

b

entry

Ar¹

Ar²

PMP

R

11

yield (%)

60

cis/trans

18/82

yield (%)

86

cis/trans

1

2

3

4

5

6

7

8

Ph

Me

Et

11a

11b

11c

11d

11e

11f

11g

11h

11i

11j

11k

11l

11m

11n

11o

85/15

86/14

88/12

90/10

84/16

74/26

60/40

87/13

85/15

91/9

87/13

85/15

88/12

78/22

88/12

d

j

Ph

69 (80)

74 (81)

23/77 (10/90)

23/77 (7/93)

21/79 (<1/>99)

17/83

23/77 (9/91)

35/65 (7/93)

18/82

21/79 (20/80)

23/77 (9/91)

18/82

45/55 (20/80)

55/45 (7/93)

16/84

e

4-MeC₆H₄

4-ClC₆H₄

2-naphthyl

2-thienyl

2-furyl

Ph

89

75

88

79

69

81

87

83

80

89

69

65 (68)

72

46 (75)

63 (54)

76

4-MeC₆H₄

PMP

9

80 (81)

73 (81)

e

10

11

12

13

14

15

4-ClC₆H₄

2-naphthyl

2-thienyl

5-methyl-2-furyl

Ph

82

66 (80)

f

Ph

45 (64)

g

82

78

79

h

i

h

Ph

−(CH₂)₄−

81 (97)

23/77 (14/86)

a

b

c

1

Conditions: see the Supporting Information for details. Determined from the H NMR spectra. Yields and diastereomeric ratios under

conditions B are in parentheses. 48 h. 46 h. 24 h. 31 h. 45 h. 60 h. 1,4-Dimethylpiperazine (2.0 equiv).

d

e

f

g

h

i

j

dride was used as a reducing reagent, the reduction of

iminocyclobutenones 5 in methanol in the presence of acetyl

chloride, which reacted with methanol to generate a limited

amount of hydrogen chloride in situ, proceeded chemo-

selectively at room temperature to give the desired amino-

cyclobutenones 10 in moderate to high yields (Table 2).

Thermal rearrangement of aminocyclobutenones 10 into β-

lactams 11 was next investigated. The results are summarized

in Table 3. When the thermal rearrangement of 10a was

carried out in octane at 110 °C for 5 h (conditions A), the

desired β-lactam 11a was obtained in 69% yield with trans

selectivity, which was diﬀerent from the cis selectivity of the

thermal rearrangement previously reported.³The thermal

rearrangement of other aminocyclobutenones 10b−o pro-

ceeded to give the β-lactams 11b−o in moderate to high yields

with trans selectivities except for the β-lactam 11m. However,

trans selectivities were moderate in some aminocyclobute-

nones 10. Therefore, the thermal rearrangement of amino-

cyclobutenones 10 was conducted in the presence of 1,8-

diazabicyclo[5.4.0]undec-7-ene (DBU) (conditions B). In

most cases except for the β-lactam 11i (entry 9), the β-

lactams 11 were obtained with higher trans selectivities

D

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(entries 2−4, 6, 7, 10, 12, 13, and 15). We next examined the

cis-β-lactam synthesis through the thermal rearrangement of

the aminocyclobutenones 10 in the presence of 1,4-

dimethylpiperazine (conditions C, Table 3). The desired cis-

β-lactams 11 were obtained in good to high yields with good to

high diastereoselectivities except for the β-lactam 11g (entry

7).

We undertook some control experiments to clarify the

diastereoselectivity in the thermal rearrangement of amino-

cyclobutenones 10 into cis- or trans-β-lactams 11. Isomer-

ization reactions of the isolated cis-β-lactam 11b were

examined (Table 4). Isomerization of the cis-β-lactam 11b

11b would be kinetically produced even in the presence of

DBU and then isomerize into the thermodynamically more

stable trans-β-lactam 11b.

A plausible reaction mechanism for the thermal rearrange-

ment of aminocyclobutenones 10 into β-lactams 11 is shown

in Scheme 5. The aminoketene 12 would be generated by ring

opening of the aminocyclobutenone 10 and undergo a

cyclization to give the ammonium intermediate 13 having a

trans stereochemistry between PMP and Ar²groups to

minimize their steric repulsion. An intramolecular proton

transfer of 13 would proceed directly from the α-face to give

the trans-β-lactam 11. On the other hand, the protonation of

the enol intermediate 14 would occur from the less hindered

β-face of the enol to give the cis-β-lactam 11 predominantly.

Regarding the role of 1,4-dimethylpiperazine and DBU, we

presume the formation of a bulky proton source to protonate

the enolate intermediate 15. In the presence of DBU having a

stronger basicity for a long reaction time, the cis-β-lactam 11

would isomerize into the thermodynamically more stable trans-

β-lactam 11 via the enolate 16.

Table 4. Control Experiments (1)

yield

a

entry

conditions

octane, 110 °C, 31 h

1,4-dimethylpiperazine (1.0 equiv), toluene,

110 °C, 31 h

(%)

cis/trans

CONCLUSIONS

■

1

2

98

99

100/0

We have developed the domino 1,4- and 1,6-addition reactions

of the ketene silyl acetals to the dialkynyl imines to give the

alkenyl iminocyclobutenones in moderate to good yields.¹³We

have also found that the chemoselective reduction of alkenyl

iminocyclobutenones and the subsequent thermal rearrange-

ment of alkenyl aminocyclobutenones in the presence of

appropriate amines provided cis or trans multifunctionalized β-

lactams in moderate to high yields with good to high

diastereoselectivities.¹⁴The present β-lactam synthesis via the

domino 1,4- and 1,6-addition reactions is attractive because β-

lactams having multifunctional groups such as alkenyl,

aromatic, imino, and alkoxycarbonyl can be obtained.

3

DBU (1.0 equiv), toluene, 110 °C, 48 h

quant

16/84

a

1

Determined from the H NMR spectra.

into the trans-lactam 11b did not occur under the

thermodynamic conditions and in the presence of 1,4-

dimethylpiperazine presumably due to a lower basicity (entries

1 and 2). On the other hand, isomerization of the cis-β-lactam

11b into the trans-β-lactam 11b proceeded in the presence of

DBU having a stronger basicity to give the β-lactam 11b in a

quantitative yield with the cis and trans ratio of 16 to 84 (entry

3).

The eﬀect of the reaction time in the presence of DBU was

further investigated (Table 5). When the reactions of 10b were

EXPERIMENTAL SECTION

■

General Aspects. Melting point (mp) determinations were

performed using a YAMATO MP-21 instrument and are uncorrected.

Infrared spectra were recorded on a JASCO FT/IR-460 Plus

spectrometer. ¹H NMR spectra were recorded on a JEOL JNM-

ECX400P spectrometer (400 MHz), a JEOL JNM α-500

spectrometer (500 MHz), or a JNM-ECZ500R spectrometer (500

MHz) with tetramethylsilane as an internal standard. ¹³C{¹H} NMR

spectra were recorded on a JEOL JNM-ECX400P spectrometer (100

MHz), a JEOL JNM α-500 spectrometer (125 MHz), or a JEOL

JNM-ECZ500R spectrometer (125 MHz). Chemical shifts are

reported in δ units, parts per million from the central peak of

CDCl₃(δ 77.0) as an internal reference. High-resolution mass spectra

(EI) were recorded on a JEOL JMS-700D mass spectrometer

employed with a quadrupole doublet based lens system. Benzene was

predried with CaCl₂, distilled, and stored over molecular sieves 4 Å.

Methanol (MeOH) was distilled from magnesium methoxide and

dried over molecular sieves 3 Å. Toluene was predried with CaCl₂,

distilled, and stored over molecular sieves 4 Å. Tetrahydrofuran was

distilled from benzophenone ketyl immediately before use or puriﬁed

by Glass Contour Organic Solvent Puriﬁcation System of Nikko

Hansen & Co., Ltd. Dichloromethane (CH₂Cl₂) was predried with

P₂O₅, distilled from CaH₂, and stored over molecular sieves 4 Å.

Octane was distilled and stored over molecular sieves 4 Å.

Triethylamine (Et₃N) was distilled from CaH₂and stored over

molecular sieves 4 Å. Puriﬁcation of products was performed by

column chromatography on silica gel (Kanto Chemical Co. Inc., Silica

Gel 60 N (spherical, neutral)) and/or preparative thin-layer

chromatography (TLC) on silica gel (Wakogel B-5F). All reactions

Table 5. Control Experiments (2)

a

entry

1

2

3

4

5

6

time (h)

11b (%)

cis/trans

10b (%)

3

5

10

24

48

78

57

79

80

68/32

30/70

54/46

48/52

22/78

10/90

7

15

b

a

b

1

Determined from the H NMR spectra. The reaction was carried

out in the absence of DBU.

carried out for a short reaction time, the cis-β-lactam 11b was

obtained predominantly (entries 1 and 3). The trans selectivity

improved as the reaction time became prolonged (entries 4−

6). On the other hand, when the reaction of 10b was carried

out in the absence of DBU in toluene at 110 °C for 3 h, the β-

lactam 11b was obtained in 57% yield with the cis and trans

ratio of 30:70 (entry 2). These results suggest that cis-β-lactam

E

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Scheme 5. Plausible Reaction Mechanism for the Thermal Rearrangement

1

were carried out under an argon atmosphere. For reactions that

require heating, an oil bath was used.

Procedure for the Preparation of Dialkynyl Imines 1 (See

Tables S1 −S3 in the Supporting Information). Amides S1a−g

were prepared according to the literature method.¹⁵⁻¹⁹

Yellow solid; mp 89−91 °C; H NMR (400 MHz, CDCl₃) δ

8.18−8.16 (m, 2H), 7.30−7.26 (m, 2H), 7.02−6.94 (m, 4H),

3.91 (s, 3H), 3.87 (s, 3H), 0.23 (s, 9H); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 161.8, 157.2, 147.5, 144.3, 130.3, 129.7, 129.6,

122.9, 113.6, 113.5, 104.1, 97.9, 55.4, 55.4, -0.7; IR (KBr)

2958, 2146, 1604, 1558, 1508, 1459, 1250, 1165, 1031, 840,

761, 509 cm⁻¹; HRMS (EI): calcd for C₂₀H₂₃NO₂Si (M)⁺

337.1498, found 337.1505.

Synthesis of Alkynyl Imines S3a−g (See Table S1 in the

Supporting Information). In a 50 mL two-neck round-bottom ﬂask

equipped with a magnetic stirring bar, a rubber septum, a Dimroth

condenser, and an argon balloon was placed amide S1a¹⁵(2.06 g, 8.0

mmol) in thionyl chloride (3.81 g, 32.0 mmol) at room temperature.

The reaction mixture was stirred at 75−80 °C for 1.5 h and then

cooled down to room temperature. The excess thionyl chloride and

volatile materials were evaporated and dried in vacuo to give the crude

imidoyl chloride S2a (2.19 g). In a 100 mL two-neck round-bottom

ﬂask equipped with a magnetic stirring bar, a rubber septum, a

Dimroth condenser, and an argon balloon were placed Pd(OAc)₂

(18.0 mg, 0.08 mmol), PPh₃(21.0 mg, 0.08 mmol), and the crude

imidoyl chloride S2a (2.19 g) in degassed triethylamine (12 mL) at

room temperature, and to the mixture was added trimethylsilylace-

tylene (1.18 g, 12.0 mmol). The reaction mixture was stirred at 70−

80 °C for 2 h and then cooled down to room temperature. The

mixture was diluted with diethyl ether (12 mL) and ﬁltered through a

Celite pad. The Celite pad was washed with diethyl ether (60 mL).

The combined organic layers were washed with H₂O (12 mL) and

brine (12 mL), dried over sodium sulfate, and ﬁltered. The solvents

were evaporated in vacuo and then the residue was puriﬁed by column

chromatography on silica gel (hexane/ethyl acetate = 14:1) to give

alkynyl imine S3a (2.11 g, 78% (two steps)) as a yellow solid.

(Z)-N,1-Bis(4-methoxyphenyl)-3-(trimethylsilyl)prop-2-yn-1-

imine (S3a).

In a 100 mL two-neck round-bottom ﬂask equipped with a

magnetic stirring bar, a rubber septum, a Dimroth condenser, and an

argon balloon was placed amide S1b²(3.97 g, 17.5 mmol) in thionyl

chloride (8.33 g, 70.0 mmol) at room temperature. The reaction

mixture was stirred at 75−80 °C for 1.5 h and then cooled down to

room temperature. The excess thionyl chloride and volatile materials

were evaporated and dried in vacuo to give the crude imidoyl chloride

S2b (4.28 g). In a 100 mL two-neck round-bottom ﬂask equipped

with a magnetic stirring bar, a rubber septum, a Dimroth condenser,

and an argon balloon were placed Pd(OAc)₂(39.2 mg, 0.175 mmol),

PPh₃(46.0 mg, 0.175 mmol), and the crude imidoyl chloride S2b

(4.28 g) in degassed triethylamine (15 mL) at room temperature, and

to the mixture was added trimethylsilylacetylene (2.58 g, 26.3 mmol).

The reaction mixture was stirred at 70−80 °C for 2 h and then cooled

down to room temperature. The mixture was diluted with diethyl

ether (15 mL) and ﬁltered through a Celite pad. The Celite pad was

washed with diethyl ether (75 mL). The combined organic layers

were washed with H₂O (15 mL) and brine (15 mL), dried over

sodium sulfate, and ﬁltered. The solvents were evaporated in vacuo

and then the residue was puriﬁed by column chromatography on silica

gel (hexane/ethyl acetate = 14:1) to give alkynyl imine S3b (3.01 g,

73% (two steps)) as a yellow oil.

F

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(Z)-N-(4-Methoxyphenyl)-1-phenyl-3-(trimethylsilyl)prop-2-yn-1-

reaction mixture was stirred at 70−80 °C for 2 h and then cooled

down to room temperature. The mixture was diluted with diethyl

ether (25 mL) and ﬁltered through a Celite pad. The Celite pad was

washed with diethyl ether (125 mL). The combined organic layers

were washed with H₂O (25 mL) and brine (25 mL), dried over

sodium sulfate, and ﬁltered. The solvents were evaporated in vacuo

and then the residue was puriﬁed by column chromatography on silica

gel (hexane/ethyl acetate = 14:1) to give alkynyl imine S3d (10.75 g,

95% (two steps)) as a yellow solid.

imine (S3b).

1

Yellow oil; H NMR (400 MHz, CDCl₃) δ 8.18−8.16 (m,

(Z)-1-(4-Chlorophenyl)-N-(4-methoxyphenyl)-3-(trimethylsilyl)-

prop-2-yn-1-imine (S3d).

2H), 7.45−7.42 (m, 3H), 7.29−7.25 (m, 2H), 6.93−6.90 (m,

2H), 3.82 (s, 3H), 0.19 (s, 9H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 157.5, 147.9, 144.0, 137.4, 130.7, 128.2, 127.9,

123.0, 113.5, 104.5, 97.9, 55.4, −0.7; IR (neat) 2958, 2146,

1666, 1601, 1504, 1448, 1248, 1176, 1040, 842, 759, 694 cm⁻¹;

HRMS (EI): calcd for C₁₉H₂₁NOSi (M)⁺307.1392, found

307.1382.

1

In a 100 mL two-neck round-bottom ﬂask equipped with a

magnetic stirring bar, a rubber septum, a Dimroth condenser, and an

argon balloon was placed amide S1c¹⁶(4.46 g, 18.5 mmol) in thionyl

chloride (8.80 g, 73.9 mmol) at room temperature. The reaction

mixture was stirred at 75−80 °C for 1.5 h and then cooled down to

room temperature. The excess thionyl chloride and volatile materials

were evaporated and dried in vacuo to give the crude imidoyl chloride

S2c (4.20 g). In a 100 mL two-neck round-bottom ﬂask equipped

with a magnetic stirring bar, a rubber septum, a Dimroth condenser,

and an argon balloon were placed Pd(OAc)₂(41.5 mg, 0.185 mmol),

PPh₃(48.5 mg, 0.185 mmol), and the crude imidoyl chloride S2c

(4.20 g) in degassed triethylamine (20 mL) at room temperature, and

to the mixture was added trimethylsilylacetylene (2.73 g, 27.8 mmol).

The reaction mixture was stirred at 70−80 °C for 2 h and then cooled

down to room temperature. The mixture was diluted with diethyl

ether (20 mL) and ﬁltered through a Celite pad. The Celite pad was

washed with diethyl ether (100 mL). The combined organic layers

were washed with H₂O (20 mL) and brine (20 mL), dried over

sodium sulfate, and ﬁltered. The solvents were evaporated in vacuo

and then the residue was puriﬁed by column chromatography on silica

gel (hexane/ethyl acetate = 14:1) to give alkynyl imine S3c (2.22 g,

63% (two steps)) as a yellow solid.

Yellow solid; mp 81−82 °C; H NMR (400 MHz, CDCl₃) δ

8.11−8.09 (m, 2H), 7.42-7.40 (m, 2H), 7.29−7.25 (m, 2H),

6.92−6.90 (m, 2H), 3.84 (s, 3H), 0.20 (s, 9H); ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 157.7, 146.4, 143.7, 136.8, 135.9, 129.2,

123.2, 113.6, 105.0, 97.6, 55.5, -0.7; IR (KBr) 2958, 2147,

1604, 1591, 1502, 1401, 1247, 1167, 1041, 863, 760, 641 cm⁻¹;

HRMS (EI): calcd for C₁₉H₂₀ClNOSi (M)⁺341.1003, found

341.0995.

In a 100 mL two-neck round-bottom ﬂask equipped with a

magnetic stirring bar, a rubber septum, a Dimroth condenser, and an

argon balloon was placed amide S1e¹⁸(5.63 g, 20.3 mmol) in thionyl

chloride (9.66 g, 81.2 mmol) at room temperature. The reaction

mixture was stirred at 75−80 °C for 1.5 h and then cooled down to

room temperature. The excess thionyl chloride and volatile materials

were evaporated and dried in vacuo to give the crude imidoyl chloride

S2e (5.97 g). In a 100 mL two-neck round-bottom ﬂask equipped

with a magnetic stirring bar, a rubber septum, a Dimroth condenser,

and an argon balloon were placed Pd(OAc)₂(46.0 mg, 0.203 mmol),

PPh₃(53.0 mg, 0.203 mmol), and the crude imidoyl chloride S2e

(5.97 g) in degassed triethylamine (20 mL) at room temperature, and

to the mixture was added trimethylsilylacetylene (2.99 g, 30.5 mmol).

The reaction mixture was stirred at 70−80 °C for 2 h and then cooled

down to room temperature. The mixture was diluted with diethyl

ether (20 mL) and ﬁltered through a Celite pad. The Celite pad was

washed with diethyl ether (100 mL). The combined organic layers

were washed with H₂O (20 mL) and brine (20 mL), dried over

sodium sulfate, and ﬁltered. The solvents were evaporated in vacuo

and then the residue was puriﬁed by column chromatography on silica

gel (hexane/ethyl acetate = 14:1) to give alkynyl imine S3e (6.09 g,

84% (two steps)) as a yellow solid.

(Z)-N-(4-Methoxyphenyl)-1-(p-tolyl)-3-(trimethylsilyl)prop-2-yn-

1-imine (S3c).

1

Yellow solid; mp 61−63 °C; H NMR (400 MHz, CDCl₃) δ

(Z)-N-(4-Methoxyphenyl)-1-(naphthalen-2-yl)-3-(trimethylsilyl)-

8.06−8.04 (m, 2H), 7.25−7.22 (m, 4H), 6.91−6.89 (m, 2H),

3.82 (s, 3H), 2.41 (s, 3H), 0.18 (s, 9H); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 157.3, 148.0, 144.2, 141.1, 134.8, 129.0, 127.9,

123.0, 113.5, 104.2, 98.0, 55.5, 21.5, -0.7; IR (KBr) 2961, 2147,

1727, 1603, 1552, 1502, 1461, 1238, 1181, 1108, 1044, 865,

761, 744, 641 cm⁻¹; HRMS (EI): calcd for C₂₀H₂₃NOSi (M)⁺

321.1549, found 321.1551.

prop-2-yn-1-imine (S3e).

1

In a 50 mL two-neck round-bottom ﬂask equipped with a magnetic

stirring bar, a rubber septum, a Dimroth condenser, and an argon

balloon was placed amide S1d¹⁷(8.66 g, 33.1 mmol) in thionyl

chloride (15.7 g, 132.3 mmol) at room temperature. The reaction

mixture was stirred at 75−80 °C for 1.5 h and then cooled down to

room temperature. The excess thionyl chloride and volatile materials

were evaporated and dried in vacuo to give the crude imidoyl chloride

S2d (9.27 g). In a 100 mL two-neck round-bottom ﬂask equipped

with a magnetic stirring bar, a rubber septum, a Dimroth condenser,

and an argon balloon were placed Pd(OAc)₂(74.0 mg, 0.33 mmol),

PPh₃(87.0 mg, 0.33 mmol), and the crude imidoyl chloride S2d (9.27

g) in degassed triethylamine (25 mL) at room temperature, and to the

mixture was added trimethylsilylacetylene (4.91 g, 50.0 mmol). The

Yellow solid; mp 72−74 °C; H NMR (500 MHz, CDCl₃) δ

7.68−7.67 (m, 1H), 7.43−7.41 (m, 1H), 7.32-7.31 (m, 2H),

7.09−7.07 (m, 1H), 6.90−6.88 (m, 2H), 3.82 (s, 3H), 0.21 (s,

9H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 157.6, 147.8, 144.1,

135.0, 134.7, 132.9, 129.4, 129.1, 127.9, 127.7, 127.3, 126.3,

124.0, 123.1, 113.6, 104.7, 98.0, 55.5, -0.6; IR (KBr) 2957,

2143, 1604, 1502, 1353, 1290, 1251, 1190, 1128, 1039, 951,

841, 754 cm⁻¹; HRMS (EI): calcd for C₂₃H₂₃NOSi (M)⁺

357.1549, found 357.1557.

In a 50 mL two-neck round-bottom ﬂask equipped with a magnetic

stirring bar, a rubber septum, a Dimroth condenser, and an argon

balloon was placed amide S1f¹⁹(4.70 g, 20.0 mmol) in thionyl

G

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The Journal of Organic Chemistry

Article

chloride (9.52 g, 80.0 mmol) at room temperature. The reaction

mixture was stirred at 75−80 °C for 1.5 h and then cooled down to

room temperature. The excess thionyl chloride and volatile materials

were evaporated and dried in vacuo to give the crude imidoyl chloride

S2f (5.11 g). In a 100 mL two-neck round-bottom ﬂask equipped with

a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an

argon balloon were placed Pd(OAc)₂(48.4 mg, 0.200 mmol), PPh₃

(53.0 mg, 0.200 mmol), and the crude imidoyl chloride S2f (5.11 g)

in degassed triethylamine (20 mL) at room temperature, and to the

mixture was added trimethylsilylacetylene (1.96 g, 20.0 mmol). The

reaction mixture was stirred at 70−80 °C for 2 h and then cooled

down to room temperature. The mixture was diluted with diethyl

ether (20 mL) and ﬁltered through a Celite pad. The Celite pad was

washed with diethyl ether (100 mL). The combined organic layers

were washed with H₂O (20 mL) and brine (20 mL), dried over

sodium sulfate, and ﬁltered. The solvents were evaporated in vacuo

and then the residue was puriﬁed by column chromatography on silica

gel (hexane/ethyl acetate = 9:1) to give alkynyl imine S3f (6.22 g,

99% (two steps)) as a yellow oil.

(m, 1H), 6.52 (dd, J = 1.2, 2.9 Hz, 1H), 3.82 (s, 3H), 0.20 (s,

9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 157.6, 145.1, 143.0,

141.6, 130.5, 129.7, 127.4, 123.6, 113.4, 102.9, 97.1, 55.3,

−0.7; IR (neat) 2958, 2835, 2151, 1550, 1504, 1474, 1393,

1248, 1205, 1163, 1060, 1009, 841, 755, 594 cm⁻¹; HRMS

(EI): calcd for C₁₇H₁₉NO₂Si (M)⁺297.1185 found 297.1191.

Synthesis of Alkynyl Imines S4a−e (See Table S2 in the

Supporting Information). In a 100 mL two-neck round-bottom

ﬂask equipped with a magnetic stirring bar, a rubber septum, and an

argon balloon was placed alkynyl imine S3a (2.11 g, 6.25 mmol) in

methanol (65 mL) at room temperature, and to the mixture was

added anhydrous potassium carbonate (86.4 mg, 0.625 mmol). The

reaction mixture was stirred at room temperature for 0.5 h and then

cooled down to 0 °C. The mixture was ﬁltered, and the solid was

washed with cold methanol to give alkynyl imine S4a (1.42 g, 85%) as

a yellow solid.

(E)-N,1-Bis(4-methoxyphenyl)prop-2-yn-1-imine (S4a).

(E)-N-(4-Methoxyphenyl)-1-(thiophen-2-yl)-3-(trimethylsilyl)-

prop-2-yn-1-imine (S3f).

Yellow solid; mp 137−139 °C; ¹H NMR (400 MHz, CDCl₃) δ

8.14−8.11 (m, 2H), 7.17−7.15 (m, 2H), 6.97−6.91 (m, 4H),

3.87 (s, 3H), 3.83 (s, 3H), 3.33 (s, 1H); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 162.0, 157.2, 147.0, 144.2, 130.1, 129.7, 122.5,

113.8, 113.7, 84.9, 76.9, 55.4; IR (KBr) 3169, 2952, 2090,

1607, 1554, 1508, 1468, 1315, 1249, 1207, 1170, 1108, 1027,

838, 738, 671 cm⁻¹; HRMS (EI): calcd for C₁₇H₁₅NO₂(M)⁺

265.1103, found 265.1108.

In a 200 mL two-neck round-bottom ﬂask equipped with a

magnetic stirring bar, a rubber septum, and an argon balloon was

placed alkynyl imine S3b (5.41 g, 17.6 mmol) in methanol (90 mL) at

room temperature, and to the mixture was added anhydrous

potassium carbonate (243 mg, 1.76 mmol). The reaction mixture

was stirred at room temperature for 0.5 h and then cooled down to 0

°C. The mixture was ﬁltered and the solid was washed with cold

methanol to give alkynyl imine S4b (3.01 g, 73%) as a yellow solid.

(E)-N-(4-Methoxyphenyl)-1-phenylprop-2-yn-1-imine (S4b).

1

Yellow oil; H NMR (400 MHz, CDCl₃) δ 7.71−7.70 (m,

1H), 7.43−7.33 (m, 3H), 7.10−7.08 (m, 1H), 6.92−6.90 (m,

2H), 3.82 (s, 3H), 0.23 (s, 9H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 157.6, 145.1, 143.0, 141.6, 130.5, 129.7, 127.4,

123.6, 113.4, 102.9, 97.1. 55.3, −0.7; IR (neat) 2958, 2146,

1604, 1556, 1500, 1426, 1248, 1202, 1165, 1035, 984, 839,

760, 711 cm⁻¹; HRMS (EI): calcd for C₁₇H₁₉NOSSi (M)⁺

313.0957, found 313.0968.

In a 50 mL two-neck round-bottom ﬂask equipped with a magnetic

stirring bar, a rubber septum, a Dimroth condenser, and an argon

balloon was placed amide S1g¹⁹(2.65 g, 12.2 mmol) in thionyl

chloride (5.81 g, 48.8 mmol) at room temperature. The reaction

mixture was stirred at 75−80 °C for 1.5 h and then cooled down to

room temperature. The excess thionyl chloride and volatile materials

were evaporated and dried in vacuo to give the crude imidoyl chloride

S2g (2.52 g). In a 50 mL two-neck round-bottom ﬂask equipped with

a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an

argon balloon were placed Pd(PPh₃)₂Cl₂(86.0 mg, 0.122 mmol) and

the crude imidoyl chloride S2g (2.52 g) in degassed benzene (18 mL)

at room temperature, and to the mixture was added trimethyl-

[(tributylstannyl)ethynyl]silane²⁰(5.20 g, 13.4 mmol). The reaction

mixture was stirred at 70 °C for 5 h and then cooled down to room

temperature. After benzene was evaporated, the mixture was diluted

with diethyl ether (30 mL), ﬁltered through a Celite pad, washed with

H₂O (20 mL) and brine (20 mL), dried over sodium sulfate, and

ﬁltered. The solvents were evaporated in vacuo and then the residue

was puriﬁed by column chromatography on silica gel (hexane/ethyl

acetate = 4:1) to give alkynyl imine S3g (2.35 g, 70% (two steps)) as

a yellow oil.

Yellow solid; mp 101−102 °C; ¹H NMR (400 MHz, CDCl₃) δ

8.20−8.17 (m, 2H), 7.47−7.44 (m, 3H), 7.23−7.19 (m, 2H),

6.94−6.92 (m, 2H), 3.82 (s, 3H), 3.35 (s, 1H); ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 157.5, 147.4, 143.9, 137.1, 131.0, 128.3,

127.9, 122.6, 113.8, 85.2, 76.8, 55.4; IR (KBr) 3175, 2955,

2087, 1604, 1558, 1505, 1443, 1249, 1207, 1108, 1031, 1033,

839, 750, 693 cm⁻¹; HRMS (EI): calcd for C₁₆H₁₃NO (M)⁺

235.0997, found 235.0991.

(E)-1-(Furan-2-yl)-N-(4-methoxyphenyl)-3-(trimethylsilyl)prop-2-

yn-1-imine (S3g).

In a 200 mL two-neck round-bottom ﬂask equipped with a

magnetic stirring bar, a rubber septum, and an argon balloon was

placed alkynyl imine S3c (4.56 g, 14.2 mmol) in methanol (60 mL) at

room temperature, and to the mixture was added anhydrous

potassium carbonate (196 mg, 1.42 mmol). The reaction mixture

was stirred at room temperature for 0.5 h and then cooled down to 0

°C. The mixture was ﬁltered and the solid was washed with cold

methanol to give alkynyl imine S4c (2.22 g, 63%) as a yellow solid.

Yellow oil; ¹H NMR (500 MHz, CDCl₃) δ 7.57 (d, J = 1.2 Hz,

1H), 7.35−7.32 (m, 2H), 7.03 (d, J = 2.9 Hz, 1H), 6.91−6.88

H

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The Journal of Organic Chemistry

Article

(E)-N-(4-Methoxyphenyl)-1-(p-tolyl)prop-2-yn-1-imine (S4c).

In a 30 mL two-neck round-bottom ﬂask equipped with a magnetic

stirring bar, a rubber septum, and an argon balloon was placed alkynyl

imine S3f (498 mg, 1.6 mmol) in methanol (3.5 mL) at room

temperature, and to the mixture was added anhydrous potassium

carbonate (22.1 mg, 0.16 mmol). The reaction mixture was stirred at

room temperature for 0.5 h and then cooled down to 0 °C. Methanol

was evaporated in vacuo. The mixture was diluted with ethyl acetate

(20 mL), washed with H₂O (10 mL) and brine (10 mL), dried over

sodium sulfate, and ﬁltered. The solvents were evaporated in vacuo

and then the residue was puriﬁed by column chromatography on silica

gel (hexane/ethyl acetate = 8:1) to give alkynyl imine S4f (338 mg,

87%) as a yellow oil.

Yellow solid; mp 101−102 °C; ¹H NMR (400 MHz, CDCl₃) δ

8.08−8.06 (m, 2H), 7.26−7.24 (m, 2H), 7.19−7.17 (m, 2H),

6.93−6.91 (m, 2H), 3.83 (s, 3H), 3.34 (s, 1H), 2.41 (s, 3H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 157.3, 147.6, 144.0,

141.5, 134.6, 129.1, 127.9, 122.5, 113.8, 85.0, 76.9, 55.4, 21.5;

IR (KBr) 3188, 2954, 2092, 1606, 1559, 1503, 1449, 1295,

1253, 1209, 1174, 1110, 1028, 838, 822, 744, 668 cm⁻¹;

HRMS (EI): calcd for C₁₇H₁₅NO (M)⁺249.1154, found

249.1146.

(E)-N-(4-Methoxyphenyl)-1-(thiophen-2-yl)prop-2-yn-1-imine

(S4f).

In a 100 mL two-neck round-bottom ﬂask equipped with a

magnetic stirring bar, a rubber septum, and an argon balloon was

placed alkynyl imine S3d (3.42 g, 10.0 mmol) in methanol (70 mL) at

room temperature, and to the mixture was added anhydrous

potassium carbonate (138 mg, 1.00 mmol). The reaction mixture

was stirred at room temperature for 0.5 h and then cooled down to 0

°C. The mixture was ﬁltered and the solid was washed with cold

methanol to give alkynyl imine S4d (2.09 g, 77%) as a yellow solid.

(E)-1-(4-Chlorophenyl)-N-(4-methoxyphenyl)prop-2-yn-1-imine

(S4d).

1

Yellow oil; H NMR (400 MHz, CDCl₃) δ 7.70−7.68 (m,

1H), 7.43−7.42 (m, 1H), 7.26−7.23 (m, 2H), 7.08−7.06 (m,

1H), 6.91−6.89 (m, 2H), 3.80 (s, 3H), 3.32 (s, 1H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 157.4, 144.7, 142.8, 141.4, 131.0,

130.1, 127.5. 123.1, 113.7, 83.8, 76.2, 55.3; IR (neat) 3280,

2955, 2097, 1605, 1564, 1502, 1441, 1426, 1355, 1202, 1166,

1107, 1031, 956, 836, 751, 714, 683 cm⁻¹; HRMS (EI): calcd

for C₁₄H₁₁NOS (M)⁺241.0561, found 241.0563.

In a 100 mL two-neck round-bottom ﬂask equipped with a

magnetic stirring bar, a rubber septum, and an argon balloon was

placed alkynyl imine S3g (2.35 g, 8.60 mmol) in methanol (38 mL) at

room temperature, and to the mixture was added anhydrous

potassium carbonate (119 mg, 0.86 mmol). The reaction mixture

was stirred at room temperature for 0.5 h and then cooled down to 0

°C. Methanol was evaporated in vacuo. The mixture was diluted with

ethyl acetate (40 mL), washed with H₂O (20 mL) and brine (20 mL),

dried over sodium sulfate, and ﬁltered. The solvents were evaporated

in vacuo and then the residue was puriﬁed by column chromatog-

raphy on silica gel (hexane/ethyl acetate = 4:1) to give alkynyl imine

S4g (1.24 g, 64%) as an orange oil.

Yellow solid; mp 123−124 °C; ¹H NMR (400 MHz, CDCl₃) δ

8.13−8.11 (m, 2H), 7.43−7.41 (m, 2H), 7.25−7.21 (m, 2H),

6.94−6.92 (m, 2H), 3.84 (s, 3H), 3.39 (s, 1H); ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 157.8, 145.9, 143.5, 137.1, 135.7, 129.2,

128.5, 122.7, 113.8, 85.5, 76.6, 55.4; IR (KBr) 3183, 3006,

2091, 1712, 1576, 1506, 1363, 1224, 1173, 1110, 1027, 839,

750, 664 cm⁻¹; HRMS (EI): calcd for C₁₆H₁₂ClNO (M)⁺

269.0607, found 269.0608.

(E)-1-(Furan-2-yl)-N-(4-methoxyphenyl)prop-2-yn-1-imine (S4g).

In a 100 mL two-neck round-bottom ﬂask equipped with a

magnetic stirring bar, a rubber septum, and an argon balloon was

placed alkynyl imine S3e (6.03 g, 16.9 mmol) in methanol (60 mL) at

room temperature, and to the mixture was added anhydrous

potassium carbonate (234 mg, 1.69 mmol). The reaction mixture

was stirred at room temperature for 0.5 h and then cooled down to 0

°C. The mixture was ﬁltered and the solid was washed with cold

methanol to give alkynyl imine S4e (4.12 g, 85%) as a yellow solid.

(E)-N-(4-Methoxyphenyl)-1-(naphthalen-2-yl)prop-2-yn-1-imine

(S4e).

1

Orange oil; H NMR (400 MHz, CDCl₃) δ 7.69−7.68 (m,

1H), 7.42−7.41 (m, 1H), 7.25−7.24 (m, 2H), 7.07−7.05 (m,

1H), 6.91−6.89 (m, 2H), 3.78 (s, 3H), 3.32 (s, 1H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 157.6, 144.6, 142.7, 141.3, 130.9,

130.1, 127.5, 123.1, 113.6, 83.8, 76.1, 55.2; IR (KBr) 3280,

2095, 1601, 1499, 1470, 1295, 1244, 1202, 1168, 1041, 835,

751, 571 cm⁻¹; HRMS (EI): calcd for C₁₄H₁₁NO₂(M)⁺

225.0790, found 225.0794.

Yellow solid; mp 163−165 °C; ¹H NMR (400 MHz, CDCl₃) δ

8.62 (s, 1H), 8.35−8.32 (m, 1H), 7.97-7.86 (m, 3H), 7.55−

7.53 (m, 2H), 7.27−7.21 (m, 2H), 6.96−6.94 (m, 2H), 3.84

(s, 3H), 3.44 (s, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

157.6, 174.3, 143.9, 134.8, 132.9, 129.6, 129.1, 128.0, 127.7,

127.4, 126.5, 123.8, 122.7, 113.8, 85.3, 76.9, 55.4; IR (KBr)

3181, 2962, 2091, 1605, 1565, 1506, 1398, 1294, 1253, 1206,

1168, 1094, 1030, 837, 742 cm⁻¹; HRMS (EI): calcd for

C₂₀H₁₅NO (M)⁺285.1154, found 285.1159.

Synthesis of Dialkynyl Imines 1a−o (See Table S3 in the

Supporting Information). In a 100 mL two-neck round-bottom

ﬂask equipped with a magnetic stirring bar, a rubber septum, a

Dimroth condenser, and an argon balloon were placed PdCl₂(PPh₃)₂

(351 mg, 0.50 mmol), CuI (191 mg, 1.00 mmol), PPh₃(262 mg, 1.00

mmol), and alkynyl bromide S5a²¹(1.09 g, 6.00 mmol) in degassed

triethylamine (30 mL) at room temperature, and to the mixture was

added alkynyl imine S4a (1.33 g, 5.00 mmol). The reaction mixture

was stirred at 60−65 °C for 2 h and then cooled down to room

temperature. The mixture was ﬁltered through a Celite pad and it was

I

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The Journal of Organic Chemistry

Article

washed with dichloromethane (120 mL). The combined organic

layers were washed with H₂O (20 mL) and brine (20 mL), dried over

sodium sulfate, and ﬁltered. The solvents were evaporated in vacuo

and then the residue was puriﬁed by column chromatography on silica

gel (hexane/ethyl acetate = 12:1) to give dialkynyl imine 1a (0.603 g,

33%) as a yellow solid.

(Z)-N,1-Bis(4-methoxyphenyl)-5-phenylpenta-2,4-diyn-1-imine

(1a). Yellow solid; mp 115−116 °C; ¹H NMR (400 MHz, CDCl₃) δ

8.13−8.11 (m, 2H), 7.50−7.49 (m, 2H), 7.35−7.25 (m, 5H), 6.95−

6.93 (m, 4H), 3.82 (s, 3H), 3.79 (s, 3H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 162.0, 157.6, 146.1, 144.0, 132.7, 130.4, 129.9, 129.6, 128.5,

122.9, 120.8, 113.9, 113.7, 84.7, 80.6, 75.0, 73.1, 55.4; IR (KBr) 3052,

2996, 2954, 2927, 2907, 2837, 2207, 2138, 1602, 1576, 1547, 1507,

1461, 1442, 1337, 1295, 1250, 1204, 1176, 1169, 1109, 1025, 950,

837, 763, 745 cm⁻¹; HRMS (EI): calcd for C₂₅H₁₉NO₂(M)⁺

365.1416, found 365.1407.

In a 100 mL two-neck round-bottom ﬂask equipped with a

magnetic stirring bar, a rubber septum, a Dimroth condenser, and an

argon balloon were placed PdCl₂(PPh₃)₂(1.05 g, 1.5 mmol), CuI

(574 mg, 3.0 mmol), PPh₃(787 mg, 3.0 mmol), and alkynyl bromide

S5a²¹(3.26 g, 18.0 mmol) in degassed triethylamine (35 mL) at room

temperature, and to the mixture was added alkynyl imine S4b (3.53 g,

15.0 mmol). The reaction mixture was stirred at 60−65 °C for 2 h

and then cooled down to room temperature. The mixture was ﬁltered

through a Celite pad and it was washed with dichloromethane (120

mL). The combined organic layers were washed with H₂O (20 mL)

and brine (20 mL), dried over sodium sulfate, and ﬁltered. The

solvents were evaporated in vacuo and then the residue was puriﬁed

by column chromatography on silica gel (hexane/ethyl acetate = 9:1)

to give dialkynyl imine 1b (2.13 g, 38%) as a yellow solid.

5.0 mmol). The reaction mixture was stirred at 60−65 °C for 2 h and

then cooled down to room temperature. The mixture was ﬁltered

through a Celite pad and it was washed with dichloromethane (80

mL). The combined organic layers were washed with H₂O (20 mL)

and brine (20 mL), dried over sodium sulfate, and ﬁltered. The

solvents were evaporated in vacuo and then the residue was puriﬁed

by column chromatography on silica gel (hexane/ethyl acetate =

10:1) to give dialkynyl imine 1d (642 mg, 37%) as a yellow solid.

(Z)-1-(4-Chlorophenyl)-N-(4-methoxyphenyl)-5-phenylpenta-

2,4-diyn-1-imine (1d). Yellow solid; mp 101−102 °C; ¹H NMR (400

MHz, CDCl₃) δ 8.13−8.10 (m, 2H), 7.54−7.52 (m, 2H), 7.44−7.31

(m, 7H), 6.98−6.95 (m, 2H), 3.85 (s, 3H); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 158.1, 145.1, 143.4, 137.0, 136.0, 132.7, 130.0, 129.1,

128.6, 128.6, 123.2, 120.7, 113.9, 85.3, 81.3, 74.5, 72.9, 55.4; IR (KBr)

3060, 3042, 3013, 2985, 2971, 2943, 2209, 1617, 1602, 1563, 1502,

1446, 1328, 1290, 1243, 1208, 1170, 1033, 956, 832, 752, 691, 665,

634, 591 cm⁻¹; HRMS (EI): calcd for C₂₄H₁₆ClNO (M)⁺369.0920,

found 369.0910.

In a 30 mL two-neck round-bottom ﬂask equipped with a magnetic

stirring bar, a rubber septum, a Dimroth condenser, and an argon

balloon were placed PdCl₂(PPh₃)₂(107 mg, 0.15 mmol), CuI (57.1

mg, 0.30 mmol), PPh₃(78.9 mg, 0.30 mmol), and alkynyl bromide

S5a²¹(489 mg, 2.7 mmol) in degassed triethylamine (4.5 mL) at

room temperature, and to the mixture was added alkynyl imine S4e

(430 mg, 1.5 mmol). The reaction mixture was stirred at 60−65 °C

for 2 h and then cooled down to room temperature. The mixture was

ﬁltered through a Celite pad and it was washed with dichloromethane

(40 mL). The combined organic layers were washed with H₂O (10

mL) and brine (10 mL), dried over sodium sulfate, and ﬁltered. The

solvents were evaporated in vacuo and then the residue was puriﬁed

by column chromatography on silica gel (hexane/ethyl acetate = 9:1)

to give dialkynyl imine 1e (346 mg, 60%) as a yellow solid.

(Z)-N-(4-Methoxyphenyl)-1,5-diphenylpenta-2,4-diyn-1-imine

1

(1b). Yellow solid; mp 80−82 °C; H NMR (400 MHz, CDCl₃) δ

8.18−8.16 (m, 2H), 7.52−7.45 (m, 5H), 7.34−7.30 (m, 5H), 6.97−

6.95 (m, 2H), 3.83 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

157.8, 146.6, 143.7, 137.4, 132.7, 132.4, 130.9, 129.9, 129.2, 128.6,

128.5, 128.4, 127.8, 123.0, 120.7, 113.9, 85.0, 81.0, 74.9, 73.0, 55.4; IR

(KBr) 3418, 3183, 2835, 2360, 2088, 1885, 1505, 1444, 1251, 1108,

1031. 839, 743, 690, 524, 518 cm⁻¹; HRMS (EI): calcd for

C₂₄H₁₇NO (M)⁺335.1310, found 335.1317.

In a 100 mL two-neck round-bottom ﬂask equipped with a

magnetic stirring bar, a rubber septum, a Dimroth condenser, and an

argon balloon were placed PdCl₂(PPh₃)₂(421 mg, 0.60 mmol), CuI

(230 mg, 1.20 mmol), PPh₃(315 mg, 1.20 mmol), and alkynyl

bromide S5a²¹(1.41 g, 7.80 mmol) in degassed triethylamine (30

mL) at room temperature, and to the mixture was added alkynyl

imine S4c (1.50 g, 6.0 mmol). The reaction mixture was stirred at

60−65 °C for 2 h and then cooled down to room temperature. The

mixture was ﬁltered through a Celite pad and it was washed with

dichloromethane (120 mL). The combined organic layers were

washed with H₂O (20 mL) and brine (20 mL), dried over sodium

sulfate, and ﬁltered. The solvents were evaporated in vacuo and then

the residue was puriﬁed by column chromatography on silica gel

(hexane/dichloromethane = 1:1) to give dialkynyl imine 1c (1.06 g,

51%) as a yellow solid.

(Z)-N-(4-Methoxyphenyl)-5-phenyl-1-(p-tolyl)penta-2,4-diyn-1-

imine (1c). Yellow solid; mp 80−82 °C; ¹H NMR (400 MHz,

CDCl₃) δ 8.07−8.05 (m, 2H), 7.51−7.49 (m, 2H), 7.38−7.35 (m,

1H), 7.32−7.24 (m, 6H), 6.95−6.93 (m, 2H), 3.81 (s, 3H), 2.40 (s,

3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 157.7, 146.7, 144.0, 141.4,

134.9, 132.7, 129.9, 129.1, 128.5, 127.9, 122.9, 120.9, 113.9, 84.8,

80.7, 75.0, 73.1, 55.4, 21.5; IR (KBr) 3095, 3053, 2925, 2833, 2207,

2138, 1604, 1573, 1544, 1499, 1460, 1334, 1292, 1249, 1206, 1166,

1108, 1031, 950, 836, 760, 714, 688 cm⁻¹; HRMS (EI): calcd for

C₂₅H₁₉NO (M)⁺349.1467, found 349.1467.

In a 30 mL two-neck round-bottom ﬂask equipped with a magnetic

stirring bar, a rubber septum, a Dimroth condenser, and an argon

balloon were placed PdCl₂(PPh₃)₂(351 mg, 0.50 mmol), CuI (190

mg, 1.0 mmol), PPh₃(262 mg, 1.0 mmol), and alkynyl bromide S5a²¹

(1.36 g, 7.5 mmol) in degassed triethylamine (20 mL) at room

temperature, and to the mixture was added alkynyl imine S4d (1.35 g,

(Z)-N-(4-Methoxyphenyl)-1-(naphthalen-2-yl)-5-phenylpenta-

2,4-diyn-1-imine (1e). Yellow solid; mp 101−102 °C; ¹H NMR (400

MHz, CDCl₃) δ 8.60 (s, 1H), 8.34−8.32 (m, 2H), 8.01−7.99 (m,

1H), 7.91−7.89 (m, 2H), 7.58−7.53 (m, 4H), 7.42−7.34 (m, 5H),

7.00−6.98 (m, 2H), 3.86 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃)

δ 157.8, 146.5, 143.8, 135.1, 132.9, 132.8, 130.0, 129.4, 129.1, 128.6,

128.1, 127.8, 127.4, 126.5, 123.9, 123.1, 113.9, 85.0, 81.0, 75.0, 73.2,

55.5;;IR (KBr) 3069, 3001, 2959, 2926, 2833, 2208, 2135, 1598,

1563, 1499, 1461, 1355, 1328, 1292, 1239, 1211, 1193, 1128, 1100,

1031, 932, 875, 835, 799, 757, 684 cm⁻¹; HRMS (EI): calcd for

C₂₈H₁₉NO (M)⁺385.1467, found 385.1464.

In a 30 mL two-neck round-bottom ﬂask equipped with a magnetic

stirring bar, a rubber septum, a Dimroth condenser, and an argon

balloon were placed PdCl₂(PPh₃)₂(107 mg, 0.15 mmol), CuI (57.1

mg, 0.30 mmol), PPh₃(78.9 mg, 0.30 mmol), and alkynyl bromide

S5a²¹(543 mg, 3.0 mmol) in degassed triethylamine (7.0 mL) at

room temperature, and to the mixture was added alkynyl imine S4f

(360 mg, 1.5 mmol). The reaction mixture was stirred at 60−65 °C

for 2 h and then cooled down to room temperature. The mixture was

ﬁltered through a Celite pad and it was washed with dichloromethane

(40 mL). The combined organic layers were washed with H₂O (10

mL) and brine (10 mL), dried over sodium sulfate, and ﬁltered. The

solvents were evaporated in vacuo and then the residue was puriﬁed

by column chromatography on silica gel (hexane/ethyl acetate =

10:1) to give dialkynyl imine 1f (211 mg, 42%) as a yellow solid.

(E)-N-(4-Methoxyphenyl)-5-phenyl-1-(thiophen-2-yl)penta-2,4-

diyn-1-imine (1f). Yellow solid; mp 95−96 °C; ¹H NMR (400 MHz,

CDCl₃) δ 7.72−7.71 (m, 1H), 7.52−7.51 (m, 2H), 7.44−7.32 (m,

6H), 7.10−7.08 (m, 1H), 6.94−6.93 (m, 2H), 3.81 (s, 3H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 158.0, 144.9, 142.8, 140.6, 132.7, 130.7,

130.0, 129.9, 128.5, 127.6, 123.4, 120.6, 113.8, 84.9, 79.6, 73.9, 72.9,

55.3; IR (KBr) 3051, 3007, 2926, 2866, 2212, 2124, 1600, 1554,

1498, 1423, 1335, 1292, 1247, 1202, 1168, 1031, 903, 850, 835, 760,

718, 689 cm⁻¹; HRMS (EI): calcd for C₂₂H₁₅NOS (M)⁺341.0847,

found 341.0859.

In a 100 mL two-neck round-bottom ﬂask equipped with a

magnetic stirring bar, a rubber septum, a Dimroth condenser, and an

argon balloon were placed PdCl₂(PPh₃)₂(360 mg, 0.51 mmol), CuI

J

DOI: 10.1021/acs.joc.9b02364

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(197 mg, 1.0 mmol), PPh₃(270 mg, 1.0 mmol), and alkynyl bromide

S5a²¹(1.11 g, 6.2 mmol) in degassed triethylamine (25 mL) at room

temperature, and to the mixture was added alkynyl imine S4g (1.16 g,

5.1 mmol). The reaction mixture was stirred at 60−65 °C for 5 h and

then cooled down to room temperature. The mixture was ﬁltered

through a Celite pad and it was washed with dichloromethane (120

mL). The combined organic layers were washed with H₂O (20 mL)

and brine (20 mL), dried over sodium sulfate, and ﬁltered. The

solvents were evaporated in vacuo and then the residue was puriﬁed

by column chromatography on silica gel (hexane/ethyl acetate =

10:1) to give dialkynyl imine 1g (646 mg, 39%) as a yellow semisolid.

(E)-1-(Furan-2-yl)-N-(4-methoxyphenyl)-5-phenylpenta-2,4-

diyn-1-imine (1g). Yellow semisolid; ¹H NMR (400 MHz, CDCl₃) δ

7.73−7.72 (m, 1H), 7.54−7.52 (m, 2H), 7.46−7.32 (m, 6H), 7.11−

7.10 (m, 1H), 6.96−6.93 (m, 2H), 3.84 (s, 3H); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 158.0, 144.9, 142.9, 140.6, 132.7, 130.7, 130.0, 130.0,

128.5, 127.6, 123.5, 120.7, 113.9, 85.0, 79.6, 74.0, 73.0, 55.4; IR

(neat) 3144, 3051, 3010, 2961, 2920, 2839, 2193, 2136, 1600, 1564,

1501, 1471, 1447, 1323, 1290, 1236, 1205, 1167, 1098, 1073, 1032,

960, 829, 754, 689, 663, 590 cm⁻¹; HRMS(EI): calcd for C₂₂H₁₅NO₂

(M)⁺325.1103, found 325.1101.

In a 100 mL two-neck round-bottom ﬂask equipped with a

magnetic stirring bar, a rubber septum, a Dimroth condenser, and an

argon balloon were placed PdCl₂(PPh₃)₂(421 mg, 0.60 mmol), CuI

(230 mg, 1.2 mmol), PPh₃(315 mg, 1.2 mmol), and alkynyl bromide

S5b²²(1.40 g, 7.2 mmol) in degassed triethylamine (30 mL) at room

temperature, and to the mixture was added alkynyl imine S4b (1.41 g,

6.0 mmol). The reaction mixture was stirred at 60−65 °C for 2 h and

then cooled down to room temperature. The mixture was ﬁltered

through a Celite pad and it was washed with dichloromethane (120

mL). The combined organic layers were washed with H₂O (20 mL)

and brine (20 mL), dried over sodium sulfate, and ﬁltered. The

solvents were evaporated in vacuo and then the residue was puriﬁed

by column chromatography on silica gel (hexane/dichloromethane =

1:1) to give dialkynyl imine 1h (662 mg, 30%) as a yellow solid.

(Z)-N-(4-Methoxyphenyl)-1-phenyl-5-(p-tolyl)penta-2,4-diyn-1-

imine (1h). Yellow solid; mp 82−83 °C; ¹H NMR (400 MHz,

CDCl₃) δ 8.19−8.16 (m, 2H), 7.46−7.40 (m, 5H), 7.30 (m, 2H),

7.13−7.11 (m, 2H), 6.97−6.94 (m, 2H), 3.82 (s, 3H), 2.34 (s, 3H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 157.8, 146.6, 143.7, 140.5,

In a 50 mL two-neck round-bottom ﬂask equipped with a magnetic

stirring bar, a rubber septum, a Dimroth condenser, and an argon

balloon were placed PdCl₂(PPh₃)₂(140 mg, 0.20 mmol), CuI (76.2

mg, 0.40 mmol), PPh₃(104 mg, 0.40 mmol), and alkynyl bromide

S5d²²(780 g, 3.6 mmol) in degassed triethylamine (10 mL) at room

temperature, and to the mixture was added alkynyl imine S4b (470

mg, 2.0 mmol). The reaction mixture was stirred at 60−65 °C for 2 h

and then cooled down to room temperature. The mixture was ﬁltered

through a Celite pad and it was washed with dichloromethane (40

mL). The combined organic layers were washed with H₂O (10 mL)

and brine (10 mL), dried over sodium sulfate, and ﬁltered. The

solvents were evaporated in vacuo and then the residue was puriﬁed

by column chromatography on silica gel (hexane/dichloromethane =

1:1) to give dialkynyl imine 1j (407 mg, 55%) as a yellow solid.

(Z)-5-(4-Chlorophenyl)-N-(4-methoxyphenyl)-1-phenylpenta-

1

2,4-diyn-1-imine (1j). Yellow solid; mp 88−90 °C; H NMR (400

MHz, CDCl₃) δ 8.17−8.15 (m, 2H), 7.48−7.44 (m, 5H), 7.33−7.29

(m, 4H), 6.97−6.95 (m, 2H), 3.82 (s, 3H); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 157.9, 146.5, 143.7, 137.3, 136.2, 133.9, 131.0, 129.0,

128.4, 127.8, 123.0, 119.3, 113.9, 83.6, 80.6, 75.4, 74.0, 55.4; IR (KBr)

3031, 2992, 2953, 2834, 2208, 2134, 1602, 1579, 1548, 1503, 1462,

1448, 1338, 1291, 1247, 1206, 1173, 1106, 1072, 1034, 952, 927, 836,

816, 774, 760, 694 cm⁻¹; HRMS (EI): calcd for C₂₄H₁₆ClNO (M)⁺

369.0920, found 369.0932.

In a 100 mL two-neck round-bottom ﬂask equipped with a

magnetic stirring bar, a rubber septum, a Dimroth condenser, and an

argon balloon were placed PdCl₂(PPh₃)₂(421 mg, 0.60 mmol), CuI

(230 mg, 1.20 mmol), PPh₃(315 mg, 1.20 mmol), and alkynyl

bromide S5e²³(1.80 g, 7.80 mmol) in degassed triethylamine (30

mL) at room temperature, and to the mixture was added alkynyl

imine S4b (1.41 g, 6.0 mmol). The reaction mixture was stirred at

60−65 °C for 2 h and then cooled down to room temperature. The

mixture was ﬁltered through a Celite pad and it was washed with

dichloromethane (120 mL). The combined organic layers were

washed with H₂O (20 mL) and brine (20 mL), dried over sodium

sulfate, and ﬁltered. The solvents were evaporated in vacuo and then

the residue was puriﬁed by column chromatography on silica gel

(hexane/dichloromethane = 1:1) to give dialkynyl imine 1k (1.00 g,

43%) as a yellow solid.

(Z)-N-(4-Methoxyphenyl)-5-(naphthalen-2-yl)-1-phenylpenta-

2,4-diyn-1-imine (1k). Yellow solid; mp 166−167 °C; ¹H NMR (400

MHz, CDCl₃) δ 8.20−8.18 (m, 2H), 8.07 (s, 1H), 7.79−7.77 (m,

3H), 7.52−7.46 (m, 6H), 7.34−7.32 (m, 2H), 6.99−6.97 (m, 2H),

3.84 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 157.9, 146.7,

143.8, 137.5, 133.7, 133.5, 132.7, 130.9, 128.4, 128.3, 128.2, 127.9,

127.9, 127.8, 127.6, 126.9, 123.0, 118.0, 114.0, 85.5, 81.2, 75.2, 73.4,

55.4; IR (KBr) 3073, 2964, 2898, 2833, 2168, 1547, 1503, 1442,

1417, 1368, 1317, 1292, 1251, 1195, 935, 911, 835, 774, 755, 739,

693, 665 cm⁻¹; HRMS (EI): calcd for C₂₈H₁₉NO (M)⁺385.1467,

found 385.1481.

In a 100 mL two-neck round-bottom ﬂask equipped with a

magnetic stirring bar, a rubber septum, a Dimroth condenser, and an

argon balloon were placed PdCl₂(PPh₃)₂(421 mg, 0.60 mmol), CuI

(230 mg, 1.20 mmol), PPh₃(315 mg, 1.20 mmol), and alkynyl

bromide S5f²³(1.46 g, 7.8 mmol) in degassed triethylamine (30 mL)

at room temperature, and to the mixture was added alkynyl imine S4b

(1.41 g, 6.0 mmol). The reaction mixture was stirred at 60−65 °C for

2 h and then cooled down to room temperature. The mixture was

ﬁltered through a Celite pad and it was washed with dichloromethane

(120 mL). The combined organic layers were washed with H₂O (20

mL) and brine (20 mL), dried over sodium sulfate, and ﬁltered. The

solvents were evaporated in vacuo and then the residue was puriﬁed

by column chromatography on silica gel (hexane/dichloromethane =

1:1) to give dialkynyl imine 1l (729 mg, 36%) as a yellow solid.

(Z)-N-(4-Methoxyphenyl)-1-phenyl-5-(thiophen-2-yl)penta-2,4-

diyn-1-imine (1l). Yellow solid; mp 92−93 °C; ¹H NMR (500 MHz,

CDCl₃) δ 8.17−8.15 (m, 2H), 7.48−7.44 (m, 3H), 7.39−7.38 (m,

1H), 7.36−7.34 (m, 1H), 7.31−7.29 (m,2H), 7.00−6.95 (m, 3H),

3.84 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 157.7, 146.3,

143.5, 137.1, 135.3, 130.8, 129.7, 128.2, 127.6, 127.1, 122.8, 120.8,

137.4, 132.6, 130.9, 129.3, 128.3, 127.8, 123.0, 117.6, 113.9, 85.4,

81.3, 74.7, 72.5, 55.3, 21.6; IR (KBr) 3084, 3034, 2954, 2898, 2832,

2208, 1600, 1554, 1503, 1461, 1444, 1338, 1292, 1245, 1207, 1172,

1102, 1031, 951, 926, 836, 816, 777, 757, 694, 661 cm⁻¹; HRMS

(EI): calcd for C₂₅H₁₉NO (M)⁺349.1467, found 349.1467.

In a 100 mL two-neck round-bottom ﬂask equipped with a

magnetic stirring bar, a rubber septum, a Dimroth condenser, and an

argon balloon were placed PdCl₂(PPh₃)₂(421 mg, 0.60 mmol), CuI

(230 mg, 1.2 mmol), PPh₃(315 mg, 1.2 mmol), and alkynyl bromide

S5c²²(1.52 g, 7.2 mmol) in degassed triethylamine (30 mL) at room