Nickelocene as an Air- And Moisture-Tolerant Precatalyst in the Regioselective Synthesis of Multisubstituted Pyridines

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Nickelocene as an Air- and Moisture-Tolerant Precatalyst in the

Regioselective Synthesis of Multisubstituted Pyridines

Il Young Cho, Woo Gyum Kim, Ji Hwan Jeon, Jeong Woo Lee, Jeong Kon Seo, Jongcheol Seo,*

and Sung You Hong *

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Supporting Information

ACCESS

ABSTRACT: Ni(COD)₂-catalyzed cycloaddition reactions to access pyr-

idines have been extensively studied. However, this catalyst typically requires

drying procedures and inert-atmosphere techniques for the reactions. Herein,

we report operationally simple nickel(0) catalysis to access substituted

pyridines from various nitriles and 1,6-diynes without the aid of air-free

techniques. The Ni-Xantphos-based catalytic manifold is tolerant to air,

moisture, and heat while promoting the [2 + 2 + 2] cycloaddition reactions

with high reaction yields and broad substrate scope. In addition, we disclose

that not only the steric eﬀect but also the frontier molecular orbital

interactions can play a critical role in determining the regiochemical outcome

of nickel-catalyzed [2 + 2 + 2] cycloaddition for the synthesis of substituted pyridines.

cobalt,^4cruthenium,^5band iridium catalyses,^8athe catalysts

react with diynes to generate ﬁve-membered metallacyclopen-

tadienes through an initial homo-oxidative coupling (also

known as oxidative cyclization) event.^3aSubsequent nitrile

insertion and reductive elimination produce substituted

pyridines. In sharp contrast, Ni(0)-NHC catalysis proceeds

through a hetero-oxidative coupling pathway with nitriles to

give ﬁve-membered azanickelacycle int. A as a key

intermediate (Scheme 1a), and the regioselectivity in the

cycloaddition is largely aﬀected by steric eﬀects of the diyne

substituents placing smaller R_Smoiety at the α-position.^9f,h

While the high σ-donacity of imidazolylidene- or imidazoliny-

lidene-based ligands eﬀectively promotes hetero-oxidative

coupling event of alkyne and nitrile, sterically hindered NHC

ligands are also associated with improved reductive elimination

and regioselective control of substituted pyridine formation.^9h

The Louie group also has comprehensively studied the

bidentate phosphine ligands for nickel catalysis. In particular,

a sterically bulky and rigid Xantphos with a wide-bite angle

oﬀers a wide diyne and nitrile scope with high reactivity.^9c,g

However, the complementary regioisomeric pattern (i.e., R_S

moiety on the β-position) has not been reported for nickel(0)-

catalyzed [2 + 2 + 2] cycloadditions. Herein, we report an air-

and moisture-tolerant method to aﬀord pyridine derivatives by

INTRODUCTION

■

Pyridine derivatives are privileged heterocyclic frameworks

ubiquitous in pharmaceuticals, natural products, agrochem-

icals, and ligands for transition-metal catalysis.^1,2Substituted

pyridines are frequently prepared by the [2 + 2 + 2]

cycloaddition from diynes and nitriles because these reactions

are straightforward and atom-economic,³typically catalyzed by

cobalt,⁴ruthenium,⁵rhodium,⁶iron,⁷iridium,⁸or nickel⁹

complexes. Louie and co-workers described a seminal nickel-

catalyzed route to pyridines employing unactivated aromatic

and aliphatic nitriles under mild reaction conditions (Scheme

1a).^9a,bHowever, the utilization of air- and moisture-sensitive

Ni(COD)₂(COD = 1,5-cyclooctadiene) typically requires

drying and degassing procedures along with glovebox or

Schlenk techniques.¹⁰Moreover, the Ni(COD)₂−N-hetero-

cyclic carbene (NHC) catalytic manifold requires a preactiva-

tion step.^9a,dRecently, air-stable nickel(0) precatalysts for

operationally simple nickel(0) catalytic reactions have been

independently introduced by several groups (Scheme 1b).¹¹

However, to the best of our knowledge, the catalytic reactions

using these precatalysts under aqueous conditions have not

been reported yet.¹¹Ni(II)−(σ-aryl) complexes developed by

Hartwig, Jamison, Buchwald, Percec, Doyle, Monfette, and

others have been recognized as excellent stable Ni(II)

precatalysts. However, they are typically activated through a

transmetalation-reductive elimination sequence. Thus, the

direct use of these complexes can be limited to the [2 + 2 +

2] cycloaddition reactions that do not include transmetalation

as an elementary step within the catalytic cycle.¹²

Received: March 10, 2021

Published: June 30, 2021

Transition-metal-catalyzed regioselective [2 + 2 + 2]

cycloadditions have unique metal-dependent mechanisms. In

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absence of nickelocene/Xantphos or Cs₂CO₃, the formation of

the desired product was limited (entries 2−4). The

replacement of Cp₂Ni with Ni(COD)₂or Ni(COD)(DQ)

gave slightly diminished yields (entries 5 and 6), and other

Ni(II) precatalysts were not eﬀective (see also the Supporting

Information, Table S1). This implies that the reductive ligand

displacement to give Ni(Xantphos)₂may be critical to Ni

catalysis.¹³Xantphos gave the highest yield among the

bidentate ligands screened (Table S2). In addition, the control

reaction performed in an inert atmosphere indicates that

molecular oxygen is not required for the catalyst activation step

(Scheme S1 and Figure S8).^14aAlthough DPEPhos and N-

Xantphos have similar structures to Xantphos, these ligands

aﬀorded 3aa in trace and 65% yields, respectively (entries 7

and 8).^14b,cThe pyridine product was isolated in a trace yield,

in case the amount of Cp₂Ni or Xantphos is reduced (entries 9

and 10). A shorter reaction time (2 h) gave the product in 80%

yield (entry 11). The conversion was low at room temperature

(entry 12); however, increased amounts of nickelocene and

Xantphos and a longer reaction time produced 3aa in 89%

yield (entry 13). Other solvents were not as eﬃcient as toluene

(entries 14−16). This catalysis was also feasible in water with

increased amounts of the precatalyst and ligand and a longer

reaction time (entry 17). Additionally, a 1.0 g scale (3.78

mmol) reaction of diyne 1a was also successfully performed

(entry 18).

Scheme 1. Nickel-Catalyzed Routes to Substituted Pyridines

We next studied the substrate scope using symmetric diynes

1 and nitriles 2 to aﬀord the desired pyridines 3 (Scheme 2).

Products 3ac−3af were smoothly obtained regardless of the

electronic nature of the nitriles. The ortho-OMe-substituted

nitrile substrate 2b, however, exhibited diminished yield,

presumably from steric hindrance. Heteroaryl nitriles (2g, 2h),

cyanamide 2i, and alkyl nitriles (2j−2l) provided the

corresponding pyridines in moderate to excellent yields.

Malonate-, sulfonamide-, and ether-bearing diynes (1a, 1b,

and 1c, respectively) successfully gave the desired products.

However, 2,7-nonadiyne (1d) aﬀorded 3da in only 36% yield,

indicating a lessened Thorpe−Ingold eﬀect. Late-stage

modiﬁcations of Letrozole 2n, a nonsteroidal, nitrile group-

bearing aromatase inhibitor, successfully provided 2:1 and 1:1

products (3an−3bn′). We also applied this method to access

bi- and terpyridines, which are prominent ligands in transition-

metal catalysis. Azine and diazine moieties on nitriles (2o−2t)

could be readily introduced to give the corresponding

oligoheteroarene products (3ao−3at, 3bo−3bs) in high yields.

Because the catalytic manifold tolerates air and moisture, we

optimized the reaction conditions for 1,6-diyne 1b and

benzonitrile (2a) in an aqueous solvent system (Table S4).

Water as a green, safe, and sustainable reaction medium has

gained much attention not only in synthetic organic chemistry

but also in the pharmaceutical industry thanks to its

nontoxicity, low ﬂammability, and natural abundance.¹⁵

Compared to organic solvents having unwanted air emissions,

water can minimize the environmental and human health

impact.¹⁵To our delight, pyridine synthesis was feasible under

mild, aqueous conditions. In the presence of ethanol as a

cosolvent, we successfully obtained the desired pyridine

derivative 3ba in 82% yield at 50 °C. We then investigated

the nitrile scope of the aqueous reaction with diyne 1b to

aﬀord products 3ba−3bf, 3bi, and 3bm. Good to excellent

yields were obtained regardless of the electronic nature of the

nitrile substituents. Malonate-based diyne 1a was also

incorporated to obtain product 3aa with a moderate yield of

using nickelocene and Xantphos (Scheme 1c). Cp₂Ni is

activated through the reductive ligand displacement reactions

to in situ generate Ni(0) species in the presence of phosphine

ligands.¹³The water-compatible reaction is conveniently

performed using a Cp₂Ni/Xantphos system while showing

high functional group tolerance. The reversed regioselectivity

patterns for the substituted pyridines were serendipitously

observed, and determinant factors were examined using density

functional theory (DFT) calculations, particularly the nickel−

alkyne frontier orbital interactions of unsymmetric 1,6-diynes.

RESULTS AND DISCUSSION

■

We tested our simple nickel(0)-catalyzed [2 + 2 + 2]

cycloaddition without the aid of an inert-atmosphere

technique, a preactivation step of the nickel precatalyst, or a

drying process (Table 1; see also the Supporting Information,

Tables S1 −S3). Readily available nickelocene (precatalyst) and

Xantphos (ligand) eﬃciently aﬀorded the desired [2 + 2 + 2]

product 3aa from equimolar amounts of 1,6-diyne 1a and

benzonitrile (2a) in 89% yield after 3 h (entry 1). In the

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a

Table 1. Optimization of Reaction Conditions

entry

change from above conditions

yield (%)

1

2

3

none

89

0

no Cp₂Ni precatalyst

no Xantphos

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

no Cs₂CO₃

40

78

75

<1

65

<1

80

11

89

0

Ni(COD)₂instead of Cp₂Ni

Ni(COD)(DQ) instead of Cp₂Ni

DPEPhos instead of Xantphos

N-Xantphos instead of Xantphos

Cp₂Ni (5 mol %)

Xantphos (10 mol %)

2 h

rt

Cp₂Ni (20 mol %), Xantphos (40 mol %), rt, 24 h

DCM instead of toluene

DMF instead of toluene

water instead of toluene

Cp₂Ni (20 mol %), Xantphos (40 mol %), water (instead of toluene), 24 h

1a (3.78 mmol), 2a (3.78 mmol)

68

29

76

84

b

a

Standard conditions: 1a (0.25 mmol), 2a (0.25 mmol), Cp₂Ni (10 mol %), Xantphos (20 mol %), Cs₂CO₃(1.0 equiv) in toluene (1.0 mL) at 80

b

°C for 3 h in air. Isolated yields are given. 1.0 g scale of 1a.

54%. To the best of our knowledge, pyridine synthesis under

aqueous conditions via metal-catalyzed [2 + 2 + 2]

cycloaddition has previously been limited to a few cases,

which require visible-light irradiation, activated alkynes, or

functionalized nitriles.¹⁶

regioisomers clearly indicates that steric hindrance does not

play a decisive role in aryl-substituted diynes. It is also

noteworthy that the Ni(0)−NHC catalytic system led to a

1:1.2 regioisomeric mixture of 5ga and 4ga.

Having obtained regioisomers that are disfavorable through

Louie’s model, we investigated the underlying driving force for

regioisomer selection using DFT calculations. All calculations

were performed using Gaussian 09^17aat the wB97xd^17blevel of

theory with LANL2DZ and 6-31G(d,p) basis sets for nickel

and other atoms, respectively, and with toluene as the

polarized continuum.^17cThe population analysis with the

natural bond orbital analysis^17dwas also performed to measure

orbital energies and visualize the frontier orbitals. The

structures of possible intermediates were found, optimized,

and used to construct the reaction pathway (Figure 1a).

A previous study^9gsuggested that the nickel(0)−Xantphos

complex a coordinates with nitrile. Triangular azanickelacycle

intermediate b may further react with various 1,6-diyne

substrates. Our calculations suggested that the nickel center

of b may interact with an alkyne in a 1,6-diyne substrate to give

Ni-cyclopropene (η²-alkyne) intermediate c, which may further

enable intramolecular rearrangement to form ﬁve-membered

azanickelacycle intermediate d. This step is diﬀerent from the

mechanism proposed by the Louie group. Instead of breaking

the Ni−C bond, cleavage of the Ni−N bond of complex c for

the rearrangement (i.e., subsequent cyclization with the alkyne

component) allows the formation of azanickelacycle d;

according to the optimized structure of c, the nitrogen is

readily detached from Ni upon alkyne coordination (see also

the Supporting Information, Figure S1) and can therefore

undergo nucleophilic attack at the η²-alkyne to give

intermediate d. The remaining alkyne may form a Ni-

(II)−η²-alkyne intermediate again, which promotes the

We next investigated [2 + 2 + 2] cycloaddition reactions of

unsymmetric diynes (1e−1l), which can give rise to two

regioisomers (Scheme 3). Among the factors aﬀecting the

regioselectivity pattern, such as steric eﬀects, electronic eﬀects,

and frontier molecular orbital (FMO) interactions, the Ni(0)−

NHC catalytic system is dominantly aﬀected by steric eﬀects

placing the less hindered R_Smoiety at the α-position (see also

Schemes 1a and 3).^9d,hWhen we employed diynes 1e (R_S= H,

R_L= Me) and 1f (R_S= Me, R_L= TMS) with nitriles 2a or 2o,

the corresponding products (4ea, 4eo, and 4fa) were aﬀorded

exclusively, supporting Louie’s mechanism. However, diynes

with aryl substituents (1g−1j) exclusively formed the

complementary regioisomers (5ga−5ja). We also attempted

the transformation using the unsymmetric diyne bearing both

phenyl and p-methoxyphenyl (PMP) moieties with 2j (see also

the Supporting Information, Section VII). However, the

desired product formation was not observed, which is likely

associated with the more sterically burdened conditions,

revealing the limited substrate scope. When the unsymmetri-

cally tethered diynes 1k and 1l were applied to Cp₂Ni/

Xantphos systems, the reversed regioselective nickel-catalyzed

[2 + 2 + 2] cycloaddition was also observed leaving the

sterically demanding phenyl group at the α-position. The

regiochemistry of the cycloaddition products was unambigu-

ously determined by nuclear Overhauser eﬀect spectroscopy

(NOESY) and heteronuclear multiple bond correlation nuclear

magnetic resonance (HMBC NMR) analyses (see also the

Supporting Information, Section V). The formation of these

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a

Scheme 2. Substrate Scope with Symmetric Diynes

a

b

Standard conditions, isolated yields are given. Conditions: 1 (0.4 mmol), 2 (0.4 mmol), Cp₂Ni (10 mol %), Xantphos (10 mol %), Cs₂CO₃(1.0

c

equiv) in water (1.35 mL), and ethanol (0.15 mL) at 50 °C for 12 h. Conditions: Ni(COD)(DQ) (10 mol %), Xantphos (10 mol %) in water

d

e

(1.35 mL), and ethanol (0.15 mL) at 50 °C for 12 h. Conditions: 1 (0.625 mmol, 2.5 equiv) for 24 h. Conditions: 2 (0.625 mmol, 2.5 equiv) for

f

g

24 h. Conditions: Cp₂Ni (20 mol %), Xantphos (40 mol %). Conditions: 1 (1.0 mmol, 4.0 equiv), Cp₂Ni (20 mol %), Xantphos (40 mol %).

insertion step to give heterocyclic intermediate e. The seven-

membered azanickelacycle readily undergoes reductive elimi-

nation to yield the heterocyclic-substituted pyridine product f.

The reaction pathway can bifurcate during the formation of

intermediate c for unsymmetric diynes (pathways A and B,

which lead to regioisomers f_Aand f_B, respectively), depending

on which alkyne is primarily interacting with the Ni center of

b. To gain insight into the preferred pathway, the relative

energies of the intermediates and products were examined for

substrate 1h (Z = O, R_A= Ph, R_B= Me) as a representative

example (Figure 1b). The reaction is initiated by the

exothermic coordination of benzonitrile to give triangular

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a

Scheme 3. Substrate Scope with Unsymmetric Diynes

a

Conditions: 1 (0.75 mmol), 2 (1.88 mmol, 2.5 equiv), Cp₂Ni (20 mol %), Xantphos (25 mol %), and Cs₂CO₃(1.0 equiv) in toluene (3.0 mL) at

b

c

80 °C for 24 h in air. Isolated yields are given. Ni(COD)₂(20 mol %) and Xantphos (25 mol %) in an argon atmosphere. Conditions: Ni(COD)₂

(20 mol %) and SIPr (25 mol %) in an argon atmosphere. Conditions: 2a (1.13 mmol, 1.5 equiv).

d

azanickelacycle b at −17.4 kcal mol⁻¹. The subsequent

formation of an η²-alkyne intermediate is not only endothermic

but also energetically discriminating between isomers c_Aand

c_B. The c_Aisomer, in which nickel is interacting with the

phenyl-substituted alkyne, is more stable than c_Bby 4.1 kcal

mol⁻¹, leading to the experimentally observed ﬁnal product f_A

(5ha). Therefore, the regioselectivity originates from the

formation of the ﬁrst η²-alkyne intermediate c, which is

governed by frontier orbital interactions as well as steric

factors.

The ﬁve highest occupied MOs of azanickelacycle b consist

of ﬁlled d-orbitals at the nickel center that can interact with

alkyne empty orbitals of the 1,6-diyne (Figure 1c; see also the

Supporting Information, Figure S2). In particular, the third-

highest occupied MO of b (d_xz) shows good overlap with an

empty π* orbital (π-type backdonation). This favorable orbital

interaction is energetically beneﬁcial for the formation of the

η²-alkyne intermediate. In an unsymmetric 1,6-diyne, the

alkyne with the lower-energy π* orbital will preferentially

interact with the nickel center. Our calculations indicate that

the lowest-energy empty π* orbital of substrate 1h is located at

the alkyne with a phenyl substituent. The π* orbital energy of

the alkyne with a methyl group is too high to interact with the

d-orbitals at the nickel center.

The LUMO of substrate 1e (Z = C(CO₂Et)₂, R_A= H, R_B=

Me) is located primarily at the alkyne with H. Diynes with an

aromatic substituent also have LUMOs located exclusively at

the alkyne with the aromatic substituent (see also the

Supporting Information, Figure S3). This predicts that the α-

position of the pyridine products will have H for 1e and

aromatic groups for 1g−1l, which matches the experimental

observations. This indicates that the energetic advantage from

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Figure 1. (a) Proposed reaction pathway. (b) Relative energies of the intermediates and products in the cycloaddition reaction of substrate 1h.

Pathways A and B are colored blue and red, respectively. The experimentally observed major reaction product, 5ha, is generated via pathway A. (c)

Orbital interactions between the ﬁlled d-orbitals at the nickel center of intermediate b and the lowest unoccupied molecular orbital (LUMO) of

diyne substrate 1h. The phenyl-substituted alkyne has empty π* orbitals as the LUMO that can interact with the nickel center via π-type

backdonation.

the preferred Ni-alkyne orbital interactions signiﬁcantly

contributes to the regioselectivity of the metal-mediated

sequential cycloaddition of unsymmetric diynes. The only

exception is 1f. Although 1f has favorable interactions with the

nickel center, the particularly bulky TMS group may sterically

hinder the primary interaction between the TMS-substituted

alkyne and the nickel center.

The calculation results provide a new mechanistic basis

(based on the FMO interactions), which can lead us to predict

regioisomers potentially diﬀerent from Louie group’s^9e,hor

Takeuchi group’s^8a,dprevious approaches. The regiodetermin-

ing step is associated with the selective formation of the η²-

alkyne intermediate c via preferred orbital interactions, and its

subsequent cyclization allows us to form a ﬁve-membered

azanickelacycle d. Furthermore, our result is also distinct from

Takeuchi’s Ir-catalyzed cycloaddition reactions. According to

Takeuchi’s studies, the electronic eﬀect of the phenyl

substituent in the unsymmetric 1,6-diyne makes little

contribution to the regioselectivity for Ir-catalyzed [2 + 2 +

2]-cycloaddition.^8dThe electronic eﬀect becomes signiﬁcant

when the 1,6-diyne contains a silyl substituent (electron

donating)^8dor a carbonyl group (electron withdrawing).^8a

Thus, the position of a phenyl substituent in the unsymmetric

diyne contributes to the regioselectivity largely by steric

interactions as the electronic eﬀect is insigniﬁcant. Thus, the Ir-

catalyzed cycloaddition using 1k and 1l substrates yield 6ka

and 6la, respectively,^8ashowing that the regioselectivity is

governed by the position of the ester group (electronic eﬀect).

However, in the present work using Ni-catalyzed cyclo-

addition, 1k and 1l substrates yield 6ka and 7la, respectively

(see also Scheme 3), indicating that the position of the phenyl

substituent (the position of LUMO) governs the regioselec-

tivity. Despite the presence of an electron-deﬁcient carbonyl

group on the methyl side of 1l, the LUMO is still located at the

alkyne with a phenyl substituent. The π* orbitals strongly

conjugated over alkyne and phenyl substituents have lower

orbital energies than those without a phenyl group, as shown in

Figure 2, leading to the preferred coordination to nickel and

subsequent formation of 7la. This shows that the reaction

mechanism and the factors governing the regioselectivity in the

Ni-catalyzed [2 + 2 + 2] cycloaddition in the present work are

clearly diﬀerent from those in the Ir-catalyzed cycloaddition.

CONCLUSIONS

■

We have developed an expedient nickel-catalyzed route to

access pyridines without the aid of inert-atmosphere

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equiv) in anhydrous tetrahydrofuran (THF) (25 mL), 60 wt %

sodium hydride in mineral oil (1.5 g, 37.6 mmol, 2.5 equiv) was

added at 0 °C. The reaction mixture was stirred for 15 min at room

temperature. To the reaction mixture, 1-bromo-2-butyne (5.0 g, 37.6

mmol, 2.5 equiv) was added dropwise. Once added, the reaction

mixture was stirred for 24 h. After completion of the reaction, the

mixture was diluted with dichloromethane (DCM) and washed with

aqueous NH₄Cl solution and brine. The organic layer was dried over

anhydrous Na₂SO₄and concentrated in vacuo. The residue was

puriﬁed by ﬂash column chromatography (hexane/DCM/ethyl

acetate, 25:10:1) to aﬀord the corresponding diyne 1a as colorless

oil (3.8 g, 95%); ¹H NMR (400 MHz, CDCl₃) δ 4.21 (q, J = 7.1 Hz,

4H), 2.89 (q, J = 2.5 Hz, 4H), 1.74 (t, J = 2.5 Hz, 6H), 1.25 (t, J = 7.1

Hz, 6H). The NMR spectrum of compound 1a was consistent with

the previously reported literature data.¹⁸

Figure 2. Calculated orbital energies (unit: hartree) of π* orbitals at

alkynes for 1k and 1l substrates. Even with the presence of an

electron-withdrawing carbonyl group, the LUMO is located at the

alkyne with a phenyl substituent.

N,N-Di(but-2-ynyl)-4-methylbenzenesulfonamide (1b). To the

solution of potassium carbonate (5.0 g, 36.0 mmol, 5.1 equiv) in

acetonitrile (60 mL), p-toluenesulfonamide (1.2 g, 7.0 mmol, 1.0

equiv) and 1-bromo-2-butyne (2.3 g, 17.5 mmol, 2.5 equiv) were

added at room temperature. The reaction mixture was reﬂuxed for 24

h. After completion of the reaction, the salts were ﬁltered oﬀ and the

organic layer was concentrated in vacuo. The residue was puriﬁed by

ﬂash column chromatography (hexane/ethyl acetate, 5:1) to aﬀord

techniques. As a result of excellent reactivity, selectivity, and

stability of the nickel catalytic manifold, the method exhibits

high yield, high regioselectivity, wide functional group

tolerance, and water and air compatibility. Furthermore, an

alternative regiochemical determinant has been proposed

based on previously unreported regioisomeric patterns in

nickel(0) catalysis. The regioselectivity observed for the

unsymmetric diyne substrates in the present work is inﬂuenced

by the preference in orbital interactions as well as the steric or

electronic eﬀect. DFT calculations suggest that frontier orbital

interactions between the nickel d-orbitals and the diyne

substrate LUMO inﬂuence the observed regioselectivity as

signiﬁcantly as the steric eﬀect. We hope this study will

advance water-compatible nickel(0)-catalyzed pyridine for-

mation. In addition, the proposed regiochemical determinant

will contribute to a more rational design of an improved nickel

catalytic manifold for pyridine synthesis.

1

the corresponding diyne 1b as a yellow solid (1.7 g, 88%); H NMR

(400 MHz, CDCl₃) δ 7.73−7.68 (m, 2H), 7.31−7.26 (m, 2H), 4.06

(q, J = 2.3 Hz, 4H), 2.41 (s, 3H), 1.64 (t, J = 2.3 Hz, 6H). The NMR

spectrum of compound 1b was consistent with the previously

reported literature data.¹⁹

1-(But-2-ynyloxy)but-2-yne (1c). To the solution of 2-butyn-1-ol

(560.9 mg, 8.0 mmol, 1.0 equiv) in anhydrous THF (18 mL), 60 wt %

sodium hydride in mineral oil (704.0 mg, 17.6 mmol, 2.2 equiv) and

1-bromo-2-butyne (1.3 g, 9.6 mmol, 1.2 equiv) were added at 0 °C.

Once added, the reaction mixture was stirred for 24 h at room

temperature. After completion of the reaction, the mixture was diluted

with DCM and washed with aqueous NH₄Cl solution and brine. The

organic layer was dried over anhydrous Na₂SO₄and concentrated in

vacuo. The residue was puriﬁed by ﬂash column chromatography

(hexane/Et₂O, 98:2) to aﬀord the corresponding diyne 1c as colorless

oil (572.0 mg, 59%); ¹H NMR (400 MHz, CDCl₃) δ 4.18 (q, J = 2.3

Hz, 4H), 1.85 (t, J = 2.4 Hz, 6H). The NMR spectrum of compound

1c was consistent with the previously reported literature data.²⁰

Nona-2,7-diyne (1d). To the solution of 1,6-heptadiyne (1.1 mL,

10.0 mmol, 1.0 equiv) in anhydrous THF (40 mL), 1.6 M n-BuLi in

hexane (15.6 mL, 25.0 mL, 2.5 equiv) was added dropwise at −78 °C.

After stirring the reaction mixture for 1 h, MeI (1.6 mL, 25.0 mmol,

2.5 equiv) was added dropwise. Once added, the reaction mixture was

stirred for 4 h at room temperature. After completion of the reaction,

the mixture was diluted with hexane and washed with aqueous NH₄Cl

solution and brine. The organic layer was dried over anhydrous

MgSO₄and concentrated in vacuo. The residue was puriﬁed by ﬂash

column chromatography with hexane to aﬀord the corresponding

EXPERIMENTAL SECTION

■

General Information. All reagents and solvents were purchased

from standard suppliers (Sigma-Aldrich, Alfa Aesar, or TCI) and were

used without further puriﬁcation. Especially, nickelocene was

purchased from Sigma-Aldrich (product number, N7524). Oil baths

were applied for heating the reaction mixtures. The progress of the

reaction was monitored by thin-layer chromatography (TLC) with a

Merck silica gel 60 F₂₅₄commercial glass plate (0.25 mm). TLC spots

were visualized by an ultraviolet lamp (254 nm). Melting points

(m.p.) were recorded on a Stuart SMP10 melting point apparatus and

were uncorrected. Compound puriﬁcation was carried out through

ﬂash column chromatography (Merck silica gel 60; mesh size, 230−

1

400). H, ¹³C{¹H}, and ¹⁹F{¹H} NMR spectra were recorded on a

diyne 1d as colorless oil (573.5 mg, 48%); H NMR (400 MHz,

Bruker Avance III HD 400 spectrometer (¹H NMR, 400 MHz;

¹³C{¹H} NMR, 101 MHz; ¹⁹F{¹H} NMR, 377 MHz). The chemical

shift was given on the δ-scale (ppm). The residual solvent peaks were

CDCl₃) δ 2.21 (tq, J = 7.2, 2.6 Hz, 4H), 1.76 (t, J = 2.6 Hz, 6H), 1.62

(quint, J = 7.1 Hz, 2H). The NMR spectrum of compound 1d was

consistent with the previously reported literature data.²⁰

1

Diethyl 2-(but-2-ynyl)malonate. To the solution of diethyl

malonate (42.2 g, 263.2 mmol, 5.0 equiv) in anhydrous THF (70

mL), 60 wt % sodium hydride in mineral oil (4.2 g, 105.3 mmol, 2.0

equiv) was added at 0 °C. The reaction mixture was stirred for 15 min

at room temperature. To the reaction mixture, 1-bromo-2-butyne (7.0

g, 52.6 mmol, 1.0 equiv) was added dropwise. Once added, the

reaction mixture was stirred for 24 h. After completion of the reaction,

the mixture was diluted with DCM and washed with aqueous NH₄Cl

solution and brine. The organic layer was dried over anhydrous

Na₂SO₄and concentrated in vacuo. The residue was puriﬁed by ﬂash

column chromatography (hexane/DCM/ethyl acetate, 25:10:1) to

aﬀord the corresponding alkyne as colorless oil (7.5 g, 67%); ¹H

NMR (400 MHz, CDCl₃) δ 4.22 (q, J = 7.1 Hz, 4H), 3.50 (t, J = 7.8

Hz, 1H), 2.75−2.67 (m, 2H), 1.74 (t, J = 2.5 Hz, 3H), 1.27 (t, J = 7.1

used as internal standards (CDCl₃at 7.26 ppm for H NMR, 77.16

ppm for ¹³C NMR). For ¹⁹F{¹H} NMR, anhydrous α,α,α-

triﬂuorotoluene (−62.61 ppm in CDCl₃) was used as an internal

standard. ¹H and ¹³C{¹H} NMR multiplicities were reported as

follows: singlet (s), doublet (d), triplet (t), quartet (q), quintet

(quint), multiplet (m), doublet of doublets (dd), doublet of triplets

(dt), triplet of doublets (td), triplet of quartets (tq), quartet of

doublets (qd), quartet of quartets (qq), and doublet of doublet of

doublets (ddd). Coupling constants J were given in hertz. High-

resolution mass spectrometry (HRMS) spectra were recorded on a Q

Exactive Plus Hybrid Quadrupole-Orbitrap mass spectrometer from

Thermo Scientiﬁc.

Preparation of Diynes. Diethyl 2,2-di(but-2-ynyl)malonate

(1a). To the solution of diethyl malonate (2.4 g, 15.0 mmol, 1.0

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Hz, 6H). The NMR spectrum of the compound was consistent with

the previously reported literature data.²¹

Diethyl 2-(but-2-ynyl)-2-(3-(4-ﬂuorophenyl)prop-2-ynyl)-

malonate (1i). Diyne 1i was prepared by the modiﬁed method

from the previous literature protocol to prepare analogous diynes.²⁵

To a three-necked Schlenk ﬂask, Pd(PPh₃)₂Cl₂(22.5 mg, 0.03 mmol,

1 mol %), and CuI (12.2 mg, 0.06 mmol, 2 mol %) were charged in an

argon atmosphere. To the charged ﬂask, the solution of diyne 1e (800

mg, 3.2 mmol, 1.0 equiv) and ﬂuoro-4-iodobenzene (732.6 mg, 3.3

mmol, 1.0 equiv) in NEt₃(12 mL) was added at room temperature.

Once added, the reaction mixture was stirred for 24 h. After

completion of the reaction, the organic layer was extracted with ethyl

acetate and concentrated in vacuo. The residue was puriﬁed by ﬂash

column chromatography (hexane/DCM, 3:2) to aﬀord 1i as yellow

Diethyl 2-(but-2-ynyl)-2-(prop-2-ynyl)malonate (1e). To the

solution of diethyl 2-(but-2-ynyl)malonate (7.0 g, 33.0 mmol, 1.0

equiv) in anhydrous THF (70 mL), 60 wt % sodium hydride in

mineral oil (2.0 g, 49.5 mmol, 1.5 equiv) was added at 0 °C. The

reaction mixture was stirred for 15 min at room temperature. To the

reaction mixture, propargyl bromide (6.7 g, 56.1 mmol, 1.7 equiv) was

added dropwise. Once added, the reaction mixture was stirred for 24

h. After completion of the reaction, the mixture was diluted with

DCM and washed with aqueous NH₄Cl solution and brine. The

organic layer was dried over anhydrous Na₂SO₄and concentrated in

vacuo. The residue was puriﬁed by ﬂash column chromatography

(hexane/DCM/ethyl acetate, 25:10:1) to aﬀord the corresponding

diyne 1e as colorless oil (7.1 g, 86%); ¹H NMR (400 MHz, CDCl₃) δ

4.22 (q, J = 7.1 Hz, 4H), 2.97 (d, J = 2.7 Hz, 2H), 2.92 (q, J = 2.6 Hz,

2H), 2.01 (t, J = 2.7 Hz, 1H), 1.75 (t, J = 2.6 Hz, 3H), 1.25 (t, J = 7.1

Hz, 6H). The NMR spectrum of compound 1e was consistent with

the previously reported literature data.²²

1

oil (918.2 mg, 83%); H NMR (400 MHz, CDCl₃) δ 7.37−7.29 (m,

2H), 6.99−6.92 (m, 2H), 4.23 (q, J = 7.1 Hz, 4H), 3.16 (s, 2H), 2.96

(q, J = 2.5 Hz, 2H), 1.76 (t, J = 2.6 Hz, 3H), 1.26 (t, J = 7.1 Hz, 6H);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 169.2, 162.4 (d, J = 248.9 Hz),

133.6 (d, J = 8.4 Hz), 119.4 (d, J = 3.5 Hz), 115.6 (d, J = 22.0 Hz),

84.2, 82.6, 79.3, 73.3, 62.0, 57.1, 23.6, 23.2, 14.2, 3.7; ¹⁹F{¹H} NMR

(377 MHz, CDCl₃) δ −111.40; HRMS (ESI): m/z [M + H]⁺calcd

for C₂₀H₂₂FO₄345.1497; found 345.1494.

Diethyl 2-(but-2-ynyl)-2-(3-(trimethylsilyl)prop-2-ynyl)malonate

(1f). To the solution of i-Pr₂NH (526.2 mg, 5.2 mmol, 1.3 equiv) in

anhydrous THF (18 mL), 1.6 M n-BuLi in hexane (3.3 mL, 5.2 mmol,

1.3 equiv) was added dropwise at 0 °C. After 30 min, the reaction

mixture was cooled to −78 °C and diethyl 2-(but-2-ynyl)-2-(prop-2-

ynyl)malonate 1e (1.0 g, 4.0 mmol, 1.0 equiv) was added. After

stirring the reaction mixture for 1 h at −78 °C, TMSCl (651.8 mg, 6.0

mmol, 1.5 equiv) was added. Once added, the reaction mixture was

stirred for additional 4 h. The mixture was diluted Et₂O, and washed

with water. The organic layer was dried over Na₂SO₄and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (hexane/ethyl acetate, 20:1) to aﬀord 1f as colorless

oil (514.5 mg, 40%). ¹H NMR (400 MHz, CDCl₃) δ 4.21 (qd, J = 7.1,

2.7 Hz, 4H), 2.97 (s, 2H), 2.89 (q, J = 2.5 Hz, 2H), 1.75 (t, J = 2.6

Hz, 3H), 1.25 (t, J = 7.1 Hz, 6H), 0.12 (s, 9H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 169.1, 101.4, 88.2, 79.0, 73.4, 61.9, 57.1, 24.0, 23.0,

14.2, 3.7, 0.1; HRMS (ESI): m/z [M + H]⁺calcd for C₁₇H₂₇O₄Si

323.1673; found 323.1672.

Diethyl 2-(but-2-ynyl)-2-(3-phenylprop-2-ynyl)malonate (1g).

To the solution of diethyl 2-(but-2-ynyl)malonate (500.0 mg, 2.4

mmol, 1.0 equiv) in anhydrous THF (5 mL), 60 wt % sodium hydride

(141.6 mg, 3.5 mmol, 1.5 equiv) was added at 0 °C. The reaction

mixture was stirred for 15 min at room temperature. To the reaction

mixture, 3-chloro-1-phenyl-1-propyne (533.1 mg, 3.5 mmol, 1.5

equiv) was added. Once added, the reaction mixture was stirred for 48

h. After completion of the reaction, the mixture was diluted with

DCM and washed with brine. The organic layer was dried over

anhydrous Na₂SO₄and concentrated in vacuo. The residue was

puriﬁed by ﬂash column chromatography (hexane/DCM, 1:1) to

aﬀord 1g as yellow oil (380.2 mg, 49%); ¹H NMR (400 MHz,

CDCl₃) δ 7.39−7.23 (m, 5H), 4.24 (q, J = 7.1 Hz, 4H), 3.18 (s, 2H),

2.97 (q, J = 2.5 Hz, 2H), 1.80−1.72 (m, 3H), 1.26 (t, J = 7.1 Hz, 6H).

The NMR spectrum of compound 1g was consistent with the

previously reported literature data.²³

(3-(But-2-ynyloxy)prop-1-ynyl)benzene (1h). To a two-necked

Schlenk ﬂask, 60 wt % sodium hydride (363.2 mg, 9.1 mmol, 1.2

equiv) was charged in an argon atmosphere. To the charged ﬂask, the

solution of 3-phenyl-2-propyn-1-ol (1.0 g, 7.6 mmol, 1.0 equiv) in

anhydrous THF (25 mL) was added dropwise at 0 °C. After stirring

the reaction mixture for 30 min, 1-bromo-2-butyne (1.2 g, 9.1 mmol,

1.2 equiv) was added. Once added, the reaction mixture was stirred

for 24 h at room temperature. After completion of the reaction, the

mixture was diluted with DCM and washed with brine. The organic

layer was dried over Na₂SO₄and concentrated in vacuo. The residue

was puriﬁed by ﬂash column chromatography (hexane/ethyl acetate,

20:1) to aﬀord the corresponding diyne 1h as yellow oil (753.6 mg,

58%); ¹H NMR (400 MHz, CDCl₃) δ 7.48−7.42 (m, 2H), 7.34−7.28

(m, 3H), 4.46 (s, 2H), 4.28 (q, J = 2.3 Hz, 2H), 1.88 (t, J = 2.3 Hz,

3H). The NMR spectrum of compound 1h was consistent with the

previously reported literature data.²⁴

Diethyl 2-(but-2-ynyl)-2-(3-(4-methoxyphenyl)prop-2-ynyl)-

malonate (1j). Diyne 1j was prepared by a modiﬁed method from

the previous literature protocol to prepare analogous diynes.²⁶To a

three-necked Schlenk ﬂask, Pd(PPh₃)₂Cl₂(140.4 mg, 0.2 mmol, 5 mol

%), CuI (76.2 mg, 0.4 mmol, 10 mol %), and 4-iodoanisole (1.2 g, 5.2

mmol, 1.3 equiv) were charged in an argon atmosphere. To the

charged ﬂask, the solution of diyne 1e (1.0 g, 4.0 mmol, 1.0 equiv) in

NEt₃(11.5 mL) and DMF (11.5 mL) was added at room

temperature. Once added, the reaction mixture was stirred for 19 h

at 80 °C. After completion of the reaction, the organic layer was

diluted with ethyl acetate and washed with aqueous NH₄Cl solution

and brine. The organic layer was dried over anhydrous Na₂SO₄and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (hexane/ethyl acetate, 6:1) to aﬀord 1j as yellow oil

1

(637.8 mg, 45%); H NMR (400 MHz, CDCl₃) δ 7.32−7.27 (m,

2H), 6.82−6.77 (m, 2H), 4.23 (q, J = 7.2 Hz, 4H), 3.79 (s, 3H), 3.15

(s, 2H), 2.96 (q, J = 2.5 Hz, 2H), 1.76 (t, J = 2.6 Hz, 3H), 1.26 (t, J =

7.1 Hz, 6H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 169.3, 159.5,

133.2, 115.5, 113.9, 83.4, 82.8, 79.1, 73.4, 61.9, 57.3, 55.4, 23.7, 23.2,

14.2, 3.7; HRMS (ESI): m/z [M + H]⁺calcd for C₂₁H₂₅O₅357.1697;

found 357.1693.

But-2-ynyl 3-phenylpropiolate (1k). To the solution of phenyl-

propiolic acid (1.0 g, 6.8 mmol), N,N′-dicyclohexylcarbodiimide (1.6

g, 7.7 mmol), and 4-dimethylaminopyridine (94.0 mg, 0.8 mmol) in

anhydrous DCM (15 mL), 2-butyn-1-ol (517.3 mg, 7.4 mmol) was

added at 0 °C. Once added, the reaction mixture was stirred for 24 h

at 0 °C. After completion of the reaction, the mixture was diluted with

DCM and ﬁltered through Celite. The organic layer was concentrated

in vacuo. The residue was puriﬁed by ﬂash column chromatography

(hexane/DCM, 1:1) to aﬀord the corresponding diyne 1k as pale

1

yellow oil (828.9 mg, 61%); H NMR (400 MHz, CDCl₃) δ 7.61−

7.56 (m, 2H), 7.49−7.43 (m, 1H), 7.41−7.35 (m, 2H), 4.80 (q, J =

2.4 Hz, 2H), 1.88 (t, J = 2.4 Hz, 3H). The NMR spectrum of

compound 1k was consistent with the previously reported literature

data.^27b

3-Phenylprop-2-ynyl but-2-ynoate (1l). Diyne 1l was prepared by

the modiﬁed method from the previous literature protocol.^27aTo the

solution of tetrolic acid (1.0 g, 11.9 mmol), N,N′-dicyclohexylcarbo-

diimide (2.8 g, 13.4 mmol), and 4-dimethylaminopyridine (163.7 mg,

1.3 mmol) in anhydrous DCM (30 mL), 3-phenyl-2-propyn-1-ol (1.7

g, 12.9 mmol) was added at 0 °C. Once added, the reaction mixture

was stirred for 24 h at 0 °C. After completion of the reaction, the

mixture was diluted with DCM and ﬁltered through Celite. The

organic layer was concentrated in vacuo. The residue was puriﬁed by

ﬂash column chromatography (hexane/DCM, 5:2) to aﬀord the

corresponding diyne 1l as pale yellow oil (1.2 g, 53%); ¹H NMR (400

MHz, CDCl₃) δ 7.49−7.42 (m, 2H), 7.37−7.28 (m, 3H), 4.98 (s,

2H), 2.01 (s, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 153.0, 132.0,

129.0, 128.4, 122.1, 87.3, 87.0, 82.1, 72.0, 54.1, 4.0; HRMS (ESI): m/

z [M + H]⁺calcd for C₁₃H₁₁O₂199.0754; found 199.0754.

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General Procedures for [2 + 2 + 2] Cycloaddition to Access

Multisubstituted Pyridines. General Procedure A. To the solution

of Cp₂Ni (4.7 mg, 0.025 mmol, 10 mol %), Xantphos (28.9 mg, 0.05

mmol, 20 mol %), and Cs₂CO₃(81.5 mg, 0.25 mmol, 1.0 equiv) in

toluene (1.0 mL), diyne 1 (0.25 mmol, 1.0 equiv) and nitrile 2 (0.25

mmol, 1.0 equiv) were added in an ambient air atmosphere. The

reaction mixture was vigorously stirred for 3 h at 80 °C in a closed

vial. The residue was puriﬁed by ﬂash column chromatography.

General Procedure B. To the solution of Cp₂Ni (7.6 mg, 0.04

mmol, 10 mol %), Xantphos (23.1 mg, 0.04 mmol, 10 mol %), and

Cs₂CO₃(130.3 mg, 0.4 mmol, 1.0 equiv) in water (1.35 mL) and

ethanol (0.15 mL), diyne 1 (0.4 mmol, 1.0 equiv) and nitrile 2 (0.4

mmol, 1.0 equiv) were added in an ambient air atmosphere. The

reaction mixture was vigorously stirred for 12 h at 50 °C in a closed

vial. After completion of the reaction, the mixture was diluted with

additional water, and the organic layer was extracted with DCM. The

organic layer was dried over anhydrous Na₂SO₄and concentrated in

vacuo. The residue was puriﬁed by ﬂash column chromatography.

General Procedure C. To the solution of Cp₂Ni (28.3 mg, 0.15

mmol, 20 mol %), Xantphos (108.5 mg, 0.19 mmol, 25 mol %), and

Cs₂CO₃(244.4 mg, 0.75 mmol, 1.0 equiv) in toluene (3.0 mL), diyne

1 (0.75 mmol, 1.0 equiv) and nitrile 2 (1.88 mmol, 2.5 equiv) were

added in an ambient air atmosphere. The reaction mixture was

vigorously stirred for 24 h at 80 °C in a closed vial. The residue was

puriﬁed by ﬂash column chromatography.

Synthesis of Multisubstituted Pyridines via Nickel-Cata-

lyzed [2 + 2 + 2] Cycloaddition. Diethyl 1,4-dimethyl-3-phenyl-

5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3aa). Pyridine

derivative 3aa was obtained by three diﬀerent procedures. (1)

General procedure A was used with diyne 1a (66.1 mg, 0.25 mmol,

1.0 equiv) and benzonitrile (2a) (25.8 mg, 0.25 mmol, 1.0 equiv).

The residue was puriﬁed by ﬂash column chromatography (hexane/

ethyl acetate, 5:2) to aﬀord the corresponding product 3aa as pale

yellow oil (81.6 mg, 89%). (2) General procedure B was used with

diyne 1a (105.7 mg, 0.4 mmol, 1.0 equiv) and benzonitrile (2a) (41.2

mg, 0.4 mmol, 1.0 equiv). The residue was puriﬁed by ﬂash column

chromatography (hexane/ethyl acetate, 5:2) to aﬀord the correspond-

ing product 3aa as pale yellow oil (79.1 mg, 54%). (3) 1.0 g scale

reaction: To the solution of Cp₂Ni (71.4 mg, 0.38 mmol, 10 mol %),

Xantphos (437.4 mg, 0.76 mmol, 20 mol %), and Cs₂CO₃(1.2 g, 3.78

mmol, 1.0 equiv) in toluene (15.0 mL), diyne 1a (1.0 g, 3.78 mmol,

1.0 equiv) and benzonitrile (2a) (388.9 mg, 3.78 mmol, 1.0 equiv)

were added. The reaction mixture was stirred for 3 h at 80 °C. The

residue was puriﬁed by ﬂash column chromatography (hexane/ethyl

acetate, 5:2) to aﬀord the corresponding product 3aa as pale yellow

oil (1.2 g, 84%); ¹H NMR (400 MHz, CDCl₃) δ 7.48−7.29 (m, 5H),

4.24 (q, J = 7.1 Hz, 4H), 3.61 (s, 2H), 3.58 (s, 2H), 2.47 (s, 3H), 2.18

(s, 3H), 1.28 (t, J = 7.1 Hz, 6H). The NMR spectrum of compound

3aa was consistent with the previously reported literature data.^5d

Diethyl 1,4-dimethyl-3-(2-methoxyphenyl)-5H-cyclopenta[c]-

pyridine-6,6(7H)-dicarboxylate (3ab). General procedure A was

used with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and 2-

methoxybenzonitrile (2b) (33.3 mg, 0.25 mmol, 1.0 equiv). The

residue was puriﬁed by ﬂash column chromatography (hexane/ethyl

acetate, 1:1) to aﬀord the corresponding product 3ab as yellow oil

(14.0 mg, 14%); ¹H NMR (400 MHz, CDCl₃) δ 7.34 (td, J = 8.3, 1.7

Hz, 1H), 7.22 (dd, J = 7.4, 1.8 Hz, 1H), 7.05−6.99 (m, 1H), 6.94 (d, J

= 8.2 Hz, 1H), 4.25 (q, J = 7.1 Hz, 4H), 3.76 (s, 3H), 3.62 (s, 2H),

3.59 (s, 2H), 2.47 (s, 3H), 2.00 (s, 3H), 1.29 (t, J = 7.1 Hz, 6H);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.8, 171.6, 156.7, 154.9,

4.22 (q, J = 7.1 Hz, 4H), 3.81 (s, 3H), 3.59 (s, 2H), 3.56 (s, 2H), 2.45

(s, 3H), 2.19 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 171.5, 159.2, 156.6, 150.3, 149.5, 133.3, 132.2, 130.4,

124.1, 113.6, 62.0, 59.6, 55.3, 40.1, 39.0, 21.9, 16.3, 14.1; HRMS

(ESI): m/z [M + H]⁺calcd for C₂₃H₂₈NO₅398.1962; found

398.1960.

Diethyl 1,4-dimethyl-3-(2-(triﬂuoromethyl)phenyl)-5H-

cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3ad). General proce-

dure A was used with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and

2-(triﬂuoromethyl)benzonitrile (2d) (42.8 mg, 0.25 mmol, 1.0 equiv).

The residue was puriﬁed by ﬂash column chromatography (hexane/

ethyl acetate, 3:1) to aﬀord the corresponding product 3ad as a white

solid (67.0 mg, 62%); m.p. 89−91 °C; ¹H NMR (400 MHz, CDCl₃)

δ 7.72 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.7 Hz,

1H), 7.25 (d, J = 7.9 Hz, 1H), 4.24 (q, J = 7.2 Hz, 4H), 3.62 (s, 2H),

3.57 (s, 2H), 2.44 (s, 3H), 1.91 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.7, 171.4, 155.0, 149.9,

148.9, 139.8, 133.4, 131.8, 130.9, 128.7 (q, J = 30.4 Hz), 128.0, 126.5

(q, J = 5.0 Hz), 125.2, 124.1 (q, J = 274.3 Hz), 62.2, 59.6, 40.0, 39.2,

21.8, 15.6, 14.2; ¹⁹F{¹H} NMR (377 MHz, CDCl₃) δ -58.94; HRMS

(ESI): m/z [M + H]⁺calcd for C₂₃H₂₅F₃NO₄436.1730; found

436.1727.

Diethyl 1,4-dimethyl-3-(4-(triﬂuoromethyl)phenyl)-5H-

cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3ae). General proce-

dure A was used with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and

4-(triﬂuoromethyl)benzonitrile (2e) (42.8 mg, 0.25 mmol, 1.0 equiv).

The residue was puriﬁed by ﬂash column chromatography (hexane/

ethyl acetate, 4:1) to aﬀord the corresponding product 3ae as a yellow

solid (97.9 mg, 90%); m.p. 117−119 °C; ¹H NMR (400 MHz,

CDCl₃) δ 7.66 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 4.24 (q, J

= 7.1 Hz, 4H), 3.62 (s, 2H), 3.59 (s, 2H), 2.47 (s, 3H), 2.18 (s, 3H),

1.28 (t, J = 7.2 Hz, 6H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.4,

155.5, 150.9, 149.8, 144.4, 144.4, 133.4, 129.7 (q, J = 32.3 Hz), 129.6,

125.2 (q, J = 3.8 Hz), 124.4, 124.3 (q, J = 272.1 Hz), 62.1, 59.5, 40.1,

39.1, 21.9, 16.1, 14.1; ¹⁹F{¹H} NMR (377 MHz, CDCl₃) δ -62.40;

HRMS (ESI): m/z [M + H]⁺calcd for C₂₃H₂₅F₃NO₄436.1730;

found 436.1727.

Diethyl 1,4-dimethyl-3-(4-ﬂuorophenyl)-5H-cyclopenta[c]-

pyridine-6,6(7H)-dicarboxylate (3af). General procedure A was

used with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and 4-

ﬂuorobenzonitrile (2f) (30.3 mg, 0.25 mmol, 1.0 equiv). The residue

was puriﬁed by ﬂash column chromatography (hexane/ethyl acetate,

4:1) to aﬀord the corresponding product 3af as pale yellow oil (86.5

mg, 90%); ¹H NMR (400 MHz, CDCl₃) δ 7.47−7.35 (m, 2H), 7.13−

7.01 (m, 2H), 4.23 (q, J = 7.1 Hz, 4H), 3.60 (s, 2H), 3.57 (s, 2H),

2.45 (s, 3H), 2.16 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H). The NMR

spectrum of compound 3af was consistent with previously reported

literature data.²⁸

Diethyl 1,4-dimethyl-3-(2-thienyl)-5H-cyclopenta[c]pyridine-

6,6(7H)-dicarboxylate (3ag). General procedure A was used with

diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and thiophene-2-

carbonitrile (2g) (27.3 mg, 0.25 mmol, 1.0 equiv). The residue was

puriﬁed by ﬂash column chromatography (hexane/ethyl acetate, 5:1)

to aﬀord the corresponding product 3ag as a white solid (84.7 mg,

91%); m.p. 94−96 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.34 (dd, J =

5.1, 1.0 Hz, 1H), 7.31 (dd, J = 3.7, 1.0 Hz, 1H), 7.07 (dd, J = 5.1, 3.7

Hz, 1H), 4.23 (q, J = 7.1 Hz, 4H), 3.59 (s, 2H), 3.58 (s, 2H), 2.45 (s,

3H), 2.39 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 171.4, 150.6, 149.9, 149.7, 144.7, 132.5, 127.3, 126.7,

123.6, 62.1, 59.5, 40.1, 39.0, 21.9, 16.8, 14.1; HRMS (ESI): m/z [M +

H]⁺calcd for C₂₀H₂₄NO₄S 374.1421; found 374.1420.

Diethyl 1,4-dimethyl-3-(2-furanyl)-5H-cyclopenta[c]pyridine-

6,6(7H)-dicarboxylate (3ah). General procedure A was used with

diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and 2-furonitrile (2h) (23.3

mg, 0.25 mmol, 1.0 equiv). The residue was puriﬁed by ﬂash column

chromatography (hexane/ethyl acetate, 4:1) to aﬀord the correspond-

ing product 3ah as a brown solid (60.4 mg, 68%); m.p. 80−83 °C; ¹H

NMR (400 MHz, CDCl₃) δ 7.53 (dd, J = 1.8, 0.8 Hz, 1H), 6.77 (dd, J

= 3.3, 0.8 Hz, 1H), 6.48 (dd, J = 3.4, 1.8 Hz, 1H), 4.21 (q, J = 7.1 Hz,

4H), 3.58 (s, 2H), 3.57 (s, 2H), 2.47 (s, 3H), 2.38 (s, 3H), 1.26 (t, J =

150.3, 148.6, 132.8, 130.9, 130.0, 129.3, 126.1, 120.9, 110.8, 62.1,

59.6, 55.5, 40.1, 39.3, 29.8, 22.0, 15.5, 14.3, 14.2; HRMS (ESI): m/z

[M + H]⁺calcd for C₂₃H₂₈NO₅398.1962; found 398.1960.

Diethyl 1,4-dimethyl-3-(4-methoxyphenyl)-5H-cyclopenta[c]-

pyridine-6,6(7H)-dicarboxylate (3ac). General procedure A was

used with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and anisonitrile

(2c) (33.3 mg, 0.25 mmol, 1.0 equiv). The residue was puriﬁed by

ﬂash column chromatography (hexane/ethyl acetate, 2:1) to aﬀord

the corresponding product 3ac as pale yellow oil (84.9 mg, 85%); ¹H

NMR (400 MHz, CDCl₃) δ 7.42−7.34 (m, 2H), 6.96−6.90 (m, 2H),

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7.1 Hz, 6H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.4, 153.6,

150.8, 149.9, 146.4, 142.7, 132.7, 123.8, 111.2, 110.7, 62.1, 59.4, 40.1,

39.1, 22.0, 16.2, 14.1; HRMS (ESI): m/z [M + H]⁺calcd for

C₂₀H₂₄NO₅358.1649; found 358.1648.

reaction, the mixture was diluted with additional water, and the

organic layer was extracted with DCM. The organic layer was dried

over anhydrous Na₂SO₄and concentrated in vacuo. The residue was

puriﬁed by ﬂash column chromatography (hexane/ethyl acetate, 5:2)

to aﬀord the corresponding product 3ba as a white solid (18.3 mg,

12%); ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J = 8.3 Hz, 2H), 7.44−

7.32 (m, 7H), 4.64 (s, 2H), 4.61 (s, 2H), 2.42 (s, 6H), 2.14 (s, 3H).

The NMR spectrum of compound 3ba was consistent with the

previously reported literature data.^9a

4,7-Dimethyl-6-(4-methoxyphenyl)-2-tosyl-1,3-dihydropyrrolo-

[3,4-c]pyridine (3bc). Pyridine derivative 3bc was obtained by two

diﬀerent procedures. (1) General procedure A was used with diyne 1b

(68.8 mg, 0.25 mmol, 1.0 equiv) and anisonitrile (2c) (33.3 mg, 0.25

mmol, 1.0 equiv). The residue was puriﬁed by ﬂash column

chromatography (hexane/ethyl acetate, 1:1) to aﬀord the correspond-

ing product 3bc as a white solid (70.4 mg, 69%). (2) The general

procedure B was used with diyne 1b (110.1 mg, 0.4 mmol, 1.0 equiv)

and anisonitrile (2c) (53.3 mg, 0.4 mmol, 1.0 equiv). The residue was

puriﬁed by ﬂash column chromatography (hexane/ethyl acetate, 1:1)

to aﬀord the corresponding product 3bc as a white solid (114.5 mg,

70%); ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J = 8.3 Hz, 2H), 7.40−

7.31 (m, 4H), 6.97−6.90 (m, 2H), 4.63 (s, 2H), 4.59 (s, 2H), 3.82 (s,

3H), 2.41 (d, J = 2.2 Hz, 6H), 2.14 (s, 3H). The NMR spectrum of

compound 3bc was consistent with previously reported literature

data.²⁹

4,7-Dimethyl-6-(4-(triﬂuoromethyl)phenyl)-2-tosyl-1,3-

dihydropyrrolo[3,4-c]pyridine (3be). The pyridine derivative 3be is

obtained by two diﬀerent procedures. (1) General procedure A was

used with diyne 1b (68.8 mg, 0.25 mmol, 1.0 equiv) and 4-

(triﬂuoromethyl)benzonitrile (2e) (42.8 mg, 0.25 mmol, 1.0 equiv).

The residue was puriﬁed by ﬂash column chromatography (hexane/

ethyl acetate, 7:2) to aﬀord the corresponding product 3be as a white

solid (104.7 mg, 94%). (2) General procedure B was used with diyne

1b (110.1 mg, 0.4 mmol, 1.0 equiv) and 4-(triﬂuoromethyl)-

benzonitrile (2e) (64.8 mg, 0.4 mmol, 1.0 equiv). The residue was

puriﬁed by ﬂash column chromatography (hexane/ethyl acetate, 7:2)

to aﬀord the corresponding product 3be as a white solid (162.2 mg,

91%); ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J = 8.3 Hz, 2H), 7.66

(d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H),

4.64 (d, J = 2.2 Hz, 2H), 4.62 (d, J = 2.3 Hz, 2H), 2.42 (s, 6H), 2.14

(s, 3H). The NMR spectrum of compound 3be was consistent with

the previously reported literature data.²⁹

Diethyl 1,4-dimethyl-3-(piperidin-1-yl)-5H-cyclopenta[c]-

pyridine-6,6(7H)-dicarboxylate (3ai). General procedure A was

used with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and

piperidine-1-carbonitrile (2i) (27.6 mg, 0.25 mmol, 1.0 equiv). The

residue was puriﬁed by ﬂash column chromatography (hexane/ethyl

acetate, 6:1) to aﬀord the corresponding product 3ai as yellow oil

(83.6 mg, 89%); ¹H NMR (400 MHz, CDCl₃) δ 4.20 (q, J = 7.1 Hz,

4H), 3.47 (s, 2H), 3.45 (s, 2H), 3.08−2.88 (m, 4H), 2.32 (s, 3H),

2.12 (s, 3H), 1.66 (quint, J = 5.8 Hz, 4H), 1.55 (quint, J = 5.5 Hz,

2H), 1.25 (t, J = 7.1 Hz, 6H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

171.7, 161.6, 150.2, 148.0, 127.7, 118.1, 61.9, 59.9, 51.6, 39.9, 38.6,

26.5, 24.7, 21.7, 14.4, 14.1; HRMS (ESI): m/z [M + H]⁺calcd for

C₂₁H₃₁N₂O₄375.2278; found 375.2275.

Diethyl 1,3,4-trimethyl-5H-cyclopenta[c]pyridine-6,6(7H)-dicar-

boxylate (3aj). General procedure A was used with diyne 1a (66.1

mg, 0.25 mmol, 1.0 equiv) and acetonitrile (2j) (10.3 mg, 0.25 mmol,

1.0 equiv). The residue was puriﬁed by ﬂash column chromatography

(hexane/ethyl acetate, 1:1) to aﬀord the corresponding product 3aj as

1

pale yellow oil (57.3 mg, 75%); H NMR (400 MHz, CDCl₃) δ 4.19

(q, J = 7.1 Hz, 4H), 3.49 (s, 2H), 3.48 (s, 2H), 2.40 (s, 3H), 2.36 (s,

3H), 2.13 (s, 3H), 1.23 (t, J = 7.2 Hz, 6H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 171.5, 154.7, 149.6, 148.5, 131.5, 124.6, 62.0, 59.7,

39.8, 39.0, 22.1, 21.7, 15.1, 14.1; HRMS (ESI): m/z [M + H]⁺calcd

for C₁₇H₂₄NO₄306.1700; found 306.1697.

Diethyl 1,4-dimethyl-3-propyl-5H-cyclopenta[c]pyridine-6,6(7H)-

dicarboxylate (3ak). General procedure A was used with diyne 1a

(66.1 mg, 0.25 mmol, 1.0 equiv) and butyronitrile (2k) (17.3 mg,

0.25 mmol, 1.0 equiv). The residue was puriﬁed by ﬂash column

chromatography (hexane/ethyl acetate, 7:2) to aﬀord the correspond-

1

ing product 3ak as pale yellow oil (51.3 mg, 62%); H NMR (400

MHz, CDCl₃) δ 4.20 (q, J = 7.1 Hz, 4H), 3.51 (s, 2H), 3.50 (s, 2H),

2.75−2.63 (m, 2H), 2.38 (s, 3H), 2.17 (s, 3H), 1.70−1.52 (m, 2H),

1.25 (t, J = 7.1 Hz, 6H), 0.96 (t, J = 7.3 Hz, 3H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 171.6, 158.5, 149.8, 148.8, 131.3, 124.1, 62.0, 59.6,

40.0, 39.0, 37.4, 23.0, 21.7, 14.7, 14.3, 14.1; HRMS (ESI): m/z [M +

H]⁺calcd for C₁₉H₂₈NO₄334.2013; found 334.2011.

Diethyl 1,4-dimethyl-3-octyl-5H-cyclopenta[c]pyridine-6,6(7H)-

dicarboxylate (3al). General procedure A was used with diyne 1a

(66.1 mg, 0.25 mmol, 1.0 equiv) and nonanenitrile (2l) (34.8 mg,

0.25 mmol, 1.0 equiv). The residue was puriﬁed by ﬂash column

chromatography (hexane/ethyl acetate, 4:1) to aﬀord the correspond-

ing product 3al as colorless oil (34.7 mg, 34%); ¹H NMR (400 MHz,

CDCl₃) δ 4.21 (q, J = 7.1 Hz, 4H), 3.51 (s, 2H), 3.50 (s, 2H), 2.74−

2.67 (m, 2H), 2.38 (s, 3H), 2.17 (s, 3H), 1.62−1.53 (m, 2H), 1.40−

1.23 (m, 16H), 0.88−0.84 (m, 3H); ¹³C{¹H} NMR (101 MHz,

CDCl₃) δ 171.6, 158.8, 149.9, 148.8, 131.3, 124.0, 62.0, 59.6, 40.0,

39.1, 35.6, 32.0, 30.0, 29.9, 29.7, 29.4, 22.8, 21.8, 14.8, 14.2, 14.1;

HRMS (ESI): m/z [M + H]⁺calcd for C₂₄H₃₈NO₄404.2795; found

404.2794.

4,7-Dimethyl-6-phenyl-2-tosyl-1,3-dihydropyrrolo[3,4-c]pyridine

(3ba). Pyridine derivative 3ba was obtained by three diﬀerent

procedures. (1) General procedure A was used with diyne 1b (68.8

mg, 0.25 mmol, 1.0 equiv) and benzonitrile (2a) (25.8 mg, 0.25

mmol, 1.0 equiv). The residue was puriﬁed by ﬂash column

chromatography (hexane/ethyl acetate, 5:2) to aﬀord the correspond-

ing product 3ba as a white solid (60.2 mg, 64%). (2) General

procedure B was used with diyne 1b (110.1 mg, 0.4 mmol, 1.0 equiv)

and benzonitrile (2a) (41.2 mg, 0.4 mmol, 1.0 equiv). The residue

was puriﬁed by ﬂash column chromatography (hexane/ethyl acetate,

5:2) to aﬀord the corresponding product 3ba as a white solid (124.3

mg, 82%). (3) Comparative experiment: To the solution of

Ni(COD)(DQ) (13.2 mg, 0.04 mmol, 10 mol %) and Xantphos

(23.1 mg, 0.04 mmol, 10 mol %) in water (1.35 mL) and ethanol

(0.15 mL), diyne 1b (110.1 mg, 0.4 mmol, 1.0 equiv) and benzonitrile

(2a) (41.2 mg, 0.4 mmol, 1.0 equiv) were added. The reaction

mixture was stirred for 12 h at 50 °C. After completion of the

4,7-Dimethyl-6-(4-ﬂuorophenyl)-2-tosyl-1,3-dihydropyrrolo[3,4-

c]pyridine (3bf). General procedure B was used with diyne 1b (110.1

mg, 0.4 mmol, 1.0 equiv) and 4-ﬂuorobenzonitrile (2f) (48.4 mg, 0.4

mmol, 1.0 equiv). The residue was puriﬁed by ﬂash column

chromatography (hexane/ethyl acetate, 2:1) to aﬀord the correspond-

1

ing product 3bf as a white solid (140.5 mg, 89%); H NMR (400

MHz, CDCl₃) δ 7.82−7.78 (m, 2H), 7.42−7.32 (m, 4H), 7.08 (t, J =

8.8 Hz, 2H), 4.63 (d, J = 2.2 Hz, 3H), 4.60 (t, J = 2.1 Hz, 2H), 2.41

(d, J = 2.5 Hz, 6H), 2.12 (s, 3H). The NMR spectrum of compound

3bf was consistent with the previously reported literature data.²⁸

4,7-Dimethyl-6-(thiophen-2-yl)-2-tosyl-1,3-dihydropyrrolo[3,4-

c]pyridine (3bg). General procedure A was used with diyne 1b (68.8

mg, 0.25 mmol, 1.0 equiv) and thiophene-2-carbonitrile (2g) (27.3

mg, 0.25 mmol, 1.0 equiv). The residue was puriﬁed by ﬂash column

chromatography (hexane/ethyl acetate, 4:1) to aﬀord the correspond-

ing product 3bg as a white solid (74.3 mg, 77%); m.p. 173−176 °C;

¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, J = 8.3 Hz, 2H), 7.37−7.30

(m, 4H), 7.07 (dd, J = 5.1, 3.7 Hz, 1H), 4.60 (s, 4H), 2.40 (s, 3H),

2.38 (s, 3H), 2.32 (s, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

150.5, 149.5, 146.2, 144.0, 133.7, 130.1, 128.7, 127.5, 127.3, 127.1,

122.0, 53.6, 52.8, 21.7, 21.6, 16.7; HRMS (ESI): m/z [M + H]⁺calcd

for C₂₀H₂₁N₂O₂S₂385.1039; found 385.1036.

4,7-Dimethyl-6-(piperidin-1-yl)-2-tosyl-1,3-dihydropyrrolo[3,4-

c]pyridine (3bi). General procedure B was used with diyne 1b (110.1

mg, 0.4 mmol, 1.0 equiv) and piperidine-1-carbonitrile (2i) (44.1 mg,

0.4 mmol, 1.0 equiv). The residue was puriﬁed by ﬂash column

chromatography (hexane/ethyl acetate, 5:1) to aﬀord the correspond-

ing product 3bi as a yellow solid (94.5 mg, 61%); m.p. 165−168 °C;

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¹H NMR (400 MHz, CDCl₃) δ 7.81−7.73 (m, 2H), 7.32 (d, J = 8.0

Hz, 2H), 4.51 (s, 2H), 4.48 (s, 2H), 3.01−2.93 (m, 4H), 2.40 (s, 3H),

2.26 (s, 3H), 2.06 (s, 3H), 1.70−1.60 (m, 4H), 1.61−1.50 (m, 2H);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 162.1, 147.2, 146.3, 143.9,

133.8, 123.0, 127.6, 123.9, 116.5, 53.4, 52.5, 51.4, 26.3, 24.7, 21.7,

21.6, 14.4; HRMS (ESI): m/z [M + H]⁺calcd for C₂₁H₂₈N₃O₂S

386.1897; found 386.1895.

10 mol %), Xantphos (28.9 mg, 0.05 mmol, 20 mol %), and Cs₂CO₃

(81.5 mg, 0.25 mmol, 1.0 equiv) in toluene (1.0 mL), diyne 1a (66.1

mg, 0.25 mmol, 1.0 equiv) and Letrozole (2n) (178.3 mg, 0.625

mmol, 2.5 equiv) were added. The reaction mixture was stirred for 24

h at 80 °C. The residue was puriﬁed by ﬂash column chromatography

(DCM/ethyl acetate, 2:3) to aﬀord 3an′ as a white solid (87.2 mg,

63%); m.p. 100−103 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J =

2.9 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.23

(dd, J = 8.1, 1.3 Hz, 4H), 6.81 (s, 1H), 4.24 (q, J = 7.1 Hz, 4H), 3.61

(s, 2H), 3.58 (s, 2H), 2.47 (s, 3H), 2.18 (s, 3H), 1.28 (t, J = 7.1 Hz,

6H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.4, 155.5, 152.7, 150.8,

150.0, 143.8, 143.5, 141.8, 135.8, 133.3, 133.0, 132.7, 130.3, 128.7,

128.5, 124.5, 118.3, 112.6, 67.2, 62.2, 59.5, 40.1, 39.1, 21.9, 16.2, 14.1;

HRMS (ESI): m/z [M + H]⁺calcd for C₃₂H₃₂N₅O₄550.2449; found

550.2448.

4,7-Dimethyl-6-propyl-2-tosyl-1,3-dihydropyrrolo[3,4-c]pyridine

(3bk). General procedure A was used with diyne 1b (68.8 mg, 0.25

mmol, 1.0 equiv) and butyronitrile (2k) (17.3 mg, 0.25 mmol, 1.0

equiv). The residue was puriﬁed by ﬂash column chromatography

(hexane/ethyl acetate, 1:1) to aﬀord the corresponding product 3bk

1

as a yellow solid (35.8 mg, 42%); m.p. 170−172 °C; H NMR (400

MHz, CDCl₃) δ 7.81−7.74 (m, 2H), 7.37−7.29 (m, 2H), 4.55 (d, J =

2.8 Hz, 4H), 2.74−2.65 (m, 2H), 2.41 (s, 3H), 2.34 (s, 3H), 2.12 (s,

3H), 1.68−1.53 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H); ¹³C{¹H} NMR

(101 MHz, CDCl₃) δ 159.6, 148.9, 145.1, 144.0, 133.9, 130.1, 127.9,

127.6, 122.8, 53.5, 52.8, 37.2, 22.9, 21.7, 14.7, 14.3; HRMS (ESI): m/

z [M + H]⁺calcd for C₁₉H₂₅N₂O₂S 345.1631; found 345.1630.

4,7-Dimethyl-6-(4-acetylphenyl)-2-tosyl-1,3-dihydropyrrolo[3,4-

c]pyridine (3bm). General procedure B was used with diyne 1b

(110.1 mg, 0.4 mmol, 1.0 equiv) and 4-acetylbenzonitrile (2m) (58.1

mg, 0.4 mmol, 1.0 equiv). The residue was puriﬁed by ﬂash column

chromatography (hexane/ethyl acetate, 2:3) to aﬀord the correspond-

ing product 3bm as a yellow solid (120.6 mg, 72%); m.p. 103−105

°C; ¹H NMR (400 MHz, CDCl₃) δ 8.04−7.95 (m, 2H), 7.80 (d, J =

8.3 Hz, 2H), 7.54−7.47 (m, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.66−4.62

(m, 2H), 4.62−4.59 (m, 2H), 2.61 (s, 3H), 2.41 (s, 6H), 2.13 (s,

3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 197.9, 156.6, 149.8, 146.1,

144.6, 144.1, 136.5, 133.7, 130.1, 129.8, 129.4, 128.4, 127.6, 123.2,

53.5, 52.8, 26.8, 21.8, 21.6, 16.0; HRMS (ESI): m/z [M + H]⁺calcd

for C₂₄H₂₅N₂O₃S 421.1580; found 421.1579.

6,6′-(((1H-1,2,4-Triazol-1-yl)methylene)bis(4,1-phenylene))bis-

(4,7-dimethyl-2-tosyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine) (3bn).

To the solution of Cp₂Ni (4.7 mg, 0.025 mmol, 10 mol %), Xantphos

(28.9 mg, 0.05 mmol, 20 mol %), and Cs₂CO₃(81.5 mg, 0.25 mmol,

1.0 equiv) in toluene (1.0 mL), diyne 1b (172.1 mg, 0.625 mmol, 2.5

equiv) and Letrozole (2n) (71.3 mg, 0.25 mmol, 1.0 equiv) were

added. The reaction mixture was stirred for 24 h at 80 °C. The

residue was puriﬁed by ﬂash column chromatography (ethyl acetate/

methanol, 99:1) to aﬀord 3bn as a white solid (206.4 mg, 99%); m.p.

1

206−208 °C; H NMR (400 MHz, CDCl₃) δ 8.03 (d, J = 12.8 Hz,

2H), 7.81 (d, J = 8.2 Hz, 4H), 7.44 (d, J = 8.2 Hz, 4H), 7.35 (d, J =

8.0 Hz, 4H), 7.22 (d, J = 8.2 Hz, 4H), 6.83 (s, 1H), 4.65 (s, 4H), 4.61

(s, 4H), 2.42 (d, J = 2.5 Hz, 12H), 2.14 (s, 6H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 156.9, 152.5, 149.8, 146.1, 144.2, 137.7, 133.8, 130.2,

129.8, 129.6, 128.3, 127.7, 123.2, 67.6, 53.6, 52.9, 21.9, 21.7, 16.2, 1.2;

HRMS (ESI): m/z [M + H]⁺calcd for C₄₇H₄₆N₇O₄S₂836.3047;

found 836.3046.

4-((4-(4,7-Dimethyl-2-tosyl-2,3-dihydro-1H-pyrrolo[3,4-c]-

pyridin-6-yl)phenyl)(1H-1,2,4-triazol-1-yl)methyl)benzonitrile

(3bn′). To the solution of Cp₂Ni (4.7 mg, 0.025 mmol, 10 mol %),

Xantphos (28.9 mg, 0.05 mmol, 20 mol %), and Cs₂CO₃(81.5 mg,

0.25 mmol, 1.0 equiv) in toluene (1.0 mL), diyne 1b (68.8 mg, 0.25

mmol, 1.0 equiv) and Letrozole (2n) (178.3 mg, 0.625 mmol, 2.5

equiv) were added. The reaction mixture was stirred for 24 h at 80 °C.

The residue was puriﬁed by ﬂash column chromatography (ethyl

acetate/methanol, 99:1) to aﬀord 3bn′ as a white solid (82.8 mg,

59%); m.p. 130−132 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J =

6.7 Hz, 2H), 7.79 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.47

(d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.24 (dd, J = 8.3, 1.8 Hz,

4H), 6.81 (s, 1H), 4.63 (s, 2H), 4.60 (s, 2H), 2.41 (s, 6H), 2.13 (s,

3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 156.4, 152.8, 149.8, 146.2,

144.1, 143.3, 140.9, 136.3, 133.7, 132.7, 130.1, 129.7, 128.7, 128.5,

127.6, 123.1, 118.3, 112.6, 67.0, 53.5, 52.8, 21.8, 21.6, 16.1; HRMS

(ESI): m/z [M + H]⁺calcd for C₃₂H₂₉N₆O₂S 561.2067; found

561.2064.

4,7-Dimethyl-6-phenyl-1,3-dihydrofuro[3,4-c]pyridine (3ca).

General procedure A was used with diyne 1c (30.6 mg, 0.25 mmol,

1.0 equiv) and benzonitrile (2a) (25.8 mg, 0.25 mmol, 1.0 equiv).

The residue was puriﬁed by ﬂash column chromatography (hexane/

ethyl acetate, 3:1) to aﬀord the corresponding product 3ca as a white

solid (48.1 mg, 85%); ¹H NMR (400 MHz, CDCl₃) δ 7.50−7.33 (m,

5H), 5.17 (s, 2H), 5.12 (s, 2H), 2.46 (s, 3H), 2.17 (s, 3H). The NMR

spectrum of compound 3ca was consistent with the previously

reported literature data.²⁸

1,4-Dimethyl-3-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridine

(3da). General procedure A was used with diyne 1d (30.0 mg, 0.25

mmol, 1.0 equiv) and benzonitrile (2a) (25.8 mg, 0.25 mmol, 1.0

equiv). The residue was puriﬁed by ﬂash column chromatography

(hexane/ethyl acetate, 4:1) to aﬀord the corresponding product 3da

1

as yellow oil (20.3 mg, 36%); H NMR (400 MHz, CDCl₃) δ 7.53−

7.30 (m, 5H), 2.92 (dt, J = 13.4, 7.6 Hz, 4H), 2.49 (s, 3H), 2.22−2.11

(m, 5H). The NMR spectrum of compound 3da was consistent with

the previously reported literature data.^9c

Diethyl 1,4-dimethyl-3-(pyridin-2-yl)-5,7-dihydro-cyclopenta[c]-

pyridine-6,6-dicarboxylate (3ao). General procedure A was used

with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and 2-

pyridinecarbonitrile (2o) (26.0 mg, 0.25 mmol, 1.0 equiv). The

residue was puriﬁed by ﬂash column chromatography (hexane/ethyl

Tetraethyl 3,3′-(((1H-1,2,4-triazol-1-yl)methylene)bis(4,1-

phenylene))bis(1,4-dimethyl-5,7-dihydro-6H-cyclopenta[c]-

pyridine-6,6-dicarboxylate) (3an). To the solution of Cp₂Ni (4.7 mg,

0.025 mmol, 10 mol %), Xantphos (28.9 mg, 0.05 mmol, 20 mol %),

and Cs₂CO₃(81.5 mg, 0.25 mmol, 1.0 equiv) in toluene (1.0 mL),

diyne 1a (165.2 mg, 0.625 mmol, 2.5 equiv) and Letrozole 2n (71.3

mg, 0.25 mmol, 1.0 equiv) were added. The reaction mixture was

stirred for 24 h at 80 °C. The residue was puriﬁed by ﬂash column

chromatography (DCM/ethyl acetate, 1:3) to aﬀord 3an as a white

solid (176.0 mg, 86%); m.p. 101−103 °C; ¹H NMR (400 MHz,

CDCl₃) δ 8.01 (s, 2H), 7.45 (d, J = 8.2 Hz, 4H), 7.19 (d, J = 8.2 Hz,

4H), 6.82 (s, 1H), 4.20 (q, J = 7.1 Hz, 8H), 3.58 (s, 4H), 3.55 (s,

4H), 2.43 (s, 6H), 2.16 (s, 6H), 1.24 (t, J = 7.1 Hz, 12H); ¹³C{¹H}

NMR (101 MHz, CDCl₃) δ 171.6, 156.1, 152.4, 150.7, 149.8, 143.8,

141.2, 137.3, 133.0, 129.9, 128.2, 124.5, 67.8, 62.2, 59.6, 40.2, 39.2,

22.0, 16.3, 14.2; HRMS (ESI): m/z [M + H]⁺calcd for C₄₇H₅₂N₅O₈

814.3810; found 814.3812.

1

acetate, 2:5) to aﬀord 3ao as pale yellow oil (81.2 mg, 88%); H

NMR (400 MHz, CDCl₃) δ 8.69−8.57 (m, 1H), 7.76 (td, J = 7.7, 1.8

Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.28−7.20 (m, 1H), 4.23 (q, J =

7.1 Hz, 4H), 3.60 (s, 2H), 3.59 (s, 2H), 2.48 (s, 3H), 2.30 (s, 3H),

1.27 (t, J = 7.1 Hz, 6H). The NMR spectrum of compound 3ao was

consistent with previously reported literature data.^4c

Diethyl 1,4-dimethyl-3-(pyridin-3-yl)-5,7-dihydro-cyclopenta[c]-

pyridine-6,6-dicarboxylate (3ap). General procedure A was used

with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and 3-

pyridinecarbonitrile (2p) (26.0 mg, 0.25 mmol, 1.0 equiv). The

residue was puriﬁed by ﬂash column chromatography (hexane/ethyl

1

acetate, 1:10) to aﬀord 3ap as pale yellow oil (79.0 mg, 86%); H

NMR (400 MHz, CDCl₃) δ 8.67 (dd, J = 2.3, 0.8 Hz, 1H), 8.55 (dd, J

= 4.9, 1.7 Hz, 1H), 7.76 (dt, J = 7.9, 2.0 Hz, 1H), 7.35−7.28 (m, 1H),

4.20 (q, J = 7.1 Hz, 4H), 3.58 (s, 2H), 3.55 (s, 2H), 2.44 (s, 3H), 2.17

Diethyl 3-(4-((4-cyanophenyl)(1H-1,2,4-triazol-1-yl)methyl)-

phenyl)-1,4-dimethyl-5,7-dihydro-6H-cyclopenta[c]pyridine-6,6-di-

carboxylate (3an′). To the solution of Cp₂Ni (4.7 mg, 0.025 mmol,

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(s, 3H), 1.24 (t, J = 7.1 Hz, 6H); ¹³C{¹H} NMR (101 MHz, CDCl₃)

δ 171.3, 153.6, 151.0, 150.1, 149.8, 148.7, 136.6, 136.4, 133.4, 124.7,

123.1, 62.1, 59.5, 40.0, 39.0, 21.8, 16.1, 14.0; HRMS (ESI): m/z [M +

H]⁺calcd for C₂₁H₂₅N₂O₄369.1809; found 369.1808.

4,7-Dimethyl-6-(pyrazin-2-yl)-2-tosyl-1,3-dihydropyrrolo[3,4-c]-

pyridine (3br). General procedure A was used with diyne 1b (68.8

mg, 0.25 mmol, 1.0 equiv) and pyrazinecarbonitrile (2r) (26.3 mg,

0.25 mmol, 1.0 equiv). The residue was puriﬁed by ﬂash column

chromatography (DCM/ethyl acetate, 1:3) to aﬀord 3br as a white

solid (85.9 mg, 90%); m.p. 189−191 °C; ¹H NMR (400 MHz,

CDCl₃) δ 9.02 (d, J = 1.5 Hz, 1H), 8.55 (dd, J = 2.6, 1.5 Hz, 1H),

8.51 (d, J = 2.6 Hz, 1H), 7.80−7.73 (m, 2H), 7.31 (d, J = 8.0 Hz,

2H), 4.63 (d, J = 2.3 Hz, 2H), 4.61 (d, J = 2.5 Hz, 2H), 2.41 (s, 3H),

2.38 (s, 3H), 2.29 (s, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

153.8, 152.1, 149.7, 146.6, 145.9, 144.1, 143.3, 142.7, 133.6, 130.8,

130.0, 127.5, 125.3, 53.5, 52.8, 21.7, 21.6, 15.7; HRMS (ESI): m/z

[M + H]⁺calcd for C₂₀H₂₁N₄O₂S 381.1380; found 381.1380.

Diethyl 1,4-dimethyl-3-(pyridin-4-yl)-5,7-dihydro-cyclopenta[c]-

pyridine-6,6-dicarboxylate (3aq). General procedure A was used

with diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and 4-

pyridinecarbonitrile (2q) (26.0 mg, 0.25 mmol, 1.0 equiv). The

residue was puriﬁed by ﬂash column chromatography (hexane/ethyl

acetate, 1:10) to aﬀord 3aq as colorless oil (91.8 mg, 99%); ¹H NMR

(400 MHz, CDCl₃) δ 8.63−8.59 (m, 2H), 7.37−7.33 (m, 2H), 4.20

(q, J = 7.1 Hz, 4H), 3.58 (s, 2H), 3.55 (s, 2H), 2.43 (s, 3H), 2.16 (s,

3H), 1.24 (t, J = 7.1 Hz, 6H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

171.3, 154.0, 151.1, 149.9, 149.7, 148.4, 133.8, 124.4, 124.0, 62.1,

59.4, 40.0, 39.0, 21.8, 15.9, 14.0; HRMS (ESI): m/z [M + H]⁺calcd

for C₂₁H₂₅N₂O₄369.1809; found 369.1808.

4,7-Dimethyl-6-(pyridin-2-yl)-2-tosyl-1,3-dihydropyrrolo[3,4-c]-

pyridine (3bo). General procedure A was used with diyne 1b (68.8

mg, 0.25 mmol, 1.0 equiv) and 2-pyridinecarbonitrile (2o) (26.0 mg,

0.25 mmol, 1.0 equiv). The residue was puriﬁed by ﬂash column

chromatography (hexane/ethyl acetate, 1:10) to aﬀord 3bo as a white

solid (75.6 mg, 80%); m.p. 185−187 °C; ¹H NMR (400 MHz,

CDCl₃) δ 8.61 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.81−7.72 (m, 3H),

7.66 (dt, J = 7.9, 1.1 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.25 (ddd, J =

7.5, 4.9, 1.3 Hz, 1H), 4.63 (d, J = 2.2 Hz, 2H), 4.61 (d, J = 2.2 Hz,

2H), 2.41 (s, 3H), 2.39 (s, 3H), 2.25 (s, 3H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 158.3, 155.5, 149.3, 148.6, 146.3, 144.0, 136.7, 133.6,

130.1, 130.0, 127.5, 124.3, 122.7, 53.6, 52.9, 21.8, 21.6, 15.7; HRMS

(ESI): m/z [M + H]⁺calcd for C₂₁H₂₂N₃O₂S 380.1427; found

380.1425.

Diethyl 1,4-dimethyl-3-(pyrimidin-2-yl)-5,7-dihydro-cyclopenta-

[c]pyridine-6,6-dicarboxylate (3as). To the solution of Cp₂Ni (9.4

mg, 0.05 mmol, 20 mol %), Xantphos (57.8 mg, 0.1 mmol, 40 mol %),

and Cs₂CO₃(81.5 mg, 0.25 mmol, 1.0 equiv) in toluene (1.0 mL),

diyne 1a (66.1 mg, 0.25 mmol, 1.0 equiv) and pyrimidinecarbonitrile

(2s) (26.3 mg, 0.25 mmol, 1.0 equiv) were added. The reaction

mixture was stirred for 3 h at 80 °C. The residue was puriﬁed by ﬂash

column chromatography (DCM/ethyl acetate/methanol, 48:48:4) to

1

aﬀord 3as as pale yellow oil (75.6 mg, 82%); H NMR (400 MHz,

CDCl₃) δ 8.83 (d, J = 4.8 Hz, 2H), 7.24 (t, J = 4.9 Hz, 1H), 4.18 (q, J

= 7.1 Hz, 4H), 3.58 (s, 2H), 3.57 (s, 2H), 2.48 (s, 3H), 2.26 (s, 3H),

1.22 (t, J = 7.1 Hz, 6H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.2,

166.3, 157.1, 153.0, 150.9, 150.1, 134.7, 126.1, 119.5, 62.0, 59.6, 39.9,

39.1, 21.9, 15.6, 14.0; HRMS (ESI): m/z [M + H]⁺calcd for

C₂₀H₂₄N₃O₄370.1761; found 370.1761.

4,7-Dimethyl-6-(pyrimidin-2-yl)-2-tosyl-1,3-dihydropyrrolo[3,4-

c]pyridine (3bs). General procedure A was used with diyne 1b (68.8

mg, 0.25 mmol, 1.0 equiv) and 2-pyrimidinecarbonitrile (2s) (26.3

mg, 0.25 mmol, 1.0 equiv). The residue was puriﬁed by ﬂash column

chromatography (DCM/methanol, 96:4) to aﬀord 3bs as a white

solid (64.1 mg, 67%); m.p. 166−168 °C; ¹H NMR (400 MHz,

CDCl₃) δ 8.84 (d, J = 4.9 Hz, 2H), 7.79−7.73 (m, 2H), 7.31 (d, J =

8.0 Hz, 2H), 7.29−7.26 (m, 1H), 4.63 (d, J = 2.3 Hz, 2H), 4.61 (d, J

= 2.4 Hz, 2H), 2.43 (s, 3H), 2.38 (s, 3H), 2.23 (s, 3H); ¹³C{¹H}

NMR (101 MHz, CDCl₃) δ 165.6, 157.2, 153.8, 149.9, 146.4, 144.1,

133.6, 130.9, 130.0, 127.4, 124.9, 119.8, 53.6, 52.9, 21.8, 21.6, 15.6;

HRMS (ESI): m/z [M + H]⁺calcd for C₂₀H₂₁N₄O₂S 381.1380;

found 381.1380.

Tetraethyl 3,3′-(pyridine-2,6-diyl)bis(1,4-dimethyl-5,7-dihydro-

cyclopenta[c]pyridine-6,6-dicarboxylate) (3at). To the solution of

Cp₂Ni (9.4 mg, 0.05 mmol, 20 mol %), Xantphos (57.8 mg, 0.1

mmol, 40 mol %), and Cs₂CO₃(81.5 mg, 0.25 mmol, 1.0 equiv) in

toluene (1.0 mL), diyne 1a (264.5 mg, 1.0 mmol, 4.0 equiv) and 2,6-

pyridinedicarbonitrile (2t) (32.3 mg, 0.25 mmol, 1.0 equiv) were

added. The reaction mixture was stirred for 3 h at 80 °C. The residue

was puriﬁed by ﬂash column chromatography (DCM/ethyl acetate,

1:3) to aﬀord 3at as a white solid (141.9 mg, 86%); m.p. 200−203

°C; ¹H NMR (400 MHz, CDCl₃) δ 7.86−7.81 (m, 1H), 7.67 (d, J =

7.7 Hz, 2H), 4.19 (q, J = 7.2 Hz, 8H), 3.58 (s, 4H), 3.55 (s, 4H), 2.45

(s, 6H), 2.29 (s, 6H), 1.23 (t, J = 7.1 Hz, 12H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 171.3, 157.8, 154.8, 150.0, 149.8, 137.2, 133.4, 125.7,

123.0, 61.9, 59.5, 39.9, 39.0, 21.8, 16.0, 14.0; HRMS (ESI): m/z [M +

H]⁺calcd for C₃₇H₄₄N₃O₈658.3123; found 658.3120.

4,7-Dimethyl-6-(pyridin-3-yl)-2-tosyl-1,3-dihydropyrrolo[3,4-c]-

pyridine (3bp). General procedure A was used with diyne 1b (68.8

mg, 0.25 mmol, 1.0 equiv) and 3-pyridinecarbonitrile (2p) (26.0 mg,

0.25 mmol, 1.0 equiv). The residue was puriﬁed by ﬂash column

chromatography (DCM/ethyl acetate/methanol, 48:48:4) to aﬀord

1

3bp as a brown solid (87.1 mg, 92%); m.p. 133−135 °C; H NMR

(400 MHz, CDCl₃) δ 8.67 (s, 1H), 8.60 (d, J = 3.9 Hz, 1H), 7.84−

7.72 (m, 3H), 7.41−7.30 (m, 3H), 4.64 (d, J = 2.2 Hz, 2H), 4.61 (d, J

= 2.2 Hz, 2H), 2.41 (d, J = 2.0 Hz, 6H), 2.15 (s, 3H); ¹³C{¹H} NMR

(101 MHz, CDCl₃) δ 154.6, 150.1, 150.0, 149.1, 146.2, 144.1, 136.7,

135.7, 133.7, 130.1, 130.0, 127.6, 123.5, 123.3, 53.5, 52.8, 21.8, 21.7,

16.0; HRMS (ESI): m/z [M + H]⁺calcd for C₂₁H₂₂N₃O₂S 380.1427;

found 380.1424.

4,7-Dimethyl-6-(pyridin-4-yl)-2-tosyl-1,3-dihydropyrrolo[3,4-c]-

pyridine (3bq). General procedure A was used with diyne 1b (68.8

mg, 0.25 mmol, 1.0 equiv) and 4-pyridinecarbonitrile (2q) (26.0 mg,

0.25 mmol, 1.0 equiv). The residue was puriﬁed by ﬂash column

chromatography (DCM/ethyl acetate/methanol, 48:48:4) to aﬀord

1

3bq as a yellow solid (83.1 mg, 88%); m.p. 128−130 °C; H NMR

(400 MHz, CDCl₃) δ 8.68 (d, J = 5.8 Hz, 2H), 7.87−7.73 (m, 2H),

7.43−7.30 (m, 4H), 4.65 (d, J = 2.2 Hz, 2H), 4.63 (d, J = 2.3 Hz,

2H), 2.43 (s, 6H), 2.16 (s, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

154.9, 150.1, 149.8, 147.6, 146.2, 144.1, 133.6, 130.3, 130.1, 127.6,

123.9, 123.2, 53.5, 52.7, 21.8, 21.6, 15.8; HRMS (ESI): m/z [M +

H]⁺calcd for C₂₁H₂₂N₃O₂S 380.1427; found 380.1426.

Diethyl 1,4-dimethyl-3-(pyrazin-2-yl)-5,7-dihydro-cyclopenta[c]-

pyridine-6,6-dicarboxylate (3ar). To the solution of Cp₂Ni (9.4 mg,

0.05 mmol, 20 mol %), Xantphos (57.8 mg, 0.1 mmol, 40 mol %), and

Cs₂CO₃(81.5 mg, 0.25 mmol, 1.0 equiv) in toluene (1.0 mL), diyne

1a (66.1 mg, 0.25 mmol, 1.0 equiv) and pyrazinecarbonitrile (2r)

(26.3 mg, 0.25 mmol, 1.0 equiv) were added. The reaction mixture

was stirred for 3 h at 80 °C. The residue was puriﬁed by ﬂash column

chromatography (DCM/ethyl acetate, 1:1) to aﬀord 3ar as a white

solid (79.4 mg, 86%); m.p. 84−87 °C; ¹H NMR (400 MHz, CDCl₃)

δ 9.00 (d, J = 1.5 Hz, 1H), 8.55 (dd, J = 2.6, 1.5 Hz, 1H), 8.49 (d, J =

2.6 Hz, 1H), 4.20 (q, J = 7.1 Hz, 4H), 3.59 (s, 2H), 3.58 (s, 2H), 2.46

(s, 3H), 2.32 (s, 3H), 1.24 (t, J = 7.1 Hz, 6H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 171.2, 154.5, 151.5, 150.9, 150.3, 146.0, 143.0, 142.8,

134.5, 126.5, 62.1, 59.5, 39.9, 39.1, 21.8, 15.7, 14.1; HRMS (ESI): m/

z [M + H]⁺calcd for C₂₀H₂₄N₃O₄370.1761; found 370.1761.

Diethyl 4-methyl-3-phenyl-5,7-dihydro-cyclopenta[c]pyridine-

6,6-dicarboxylate (4ea). General procedure C was used with diyne

1e (187.7 mg, 0.75 mmol, 1.0 equiv) and benzonitrile (2a) (193.4

mg, 1.88 mmol, 2.5 equiv). The residue was puriﬁed by ﬂash column

chromatography (hexane/ethyl acetate, 6:1) to aﬀord 4ea as yellow

1

oil (102.8 mg, 39%); H NMR (400 MHz, CDCl₃) δ 8.35 (s, 1H),

7.48−7.31 (m, 5H), 4.23 (q, J = 7.1 Hz, 4H), 3.68 (s, 2H), 3.58 (s,

2H), 2.24 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 171.3, 157.2, 149.9, 142.3, 140.5, 134.5, 129.1, 128.1,

127.8, 126.9, 62.1, 60.0, 39.8, 38.6, 16.5, 14.1; HRMS (ESI): m/z [M

+ H]⁺calcd for C₂₁H₂₄NO₄354.1700; found 354.1697.

Diethyl 4-methyl-3-(pyridin-2-yl)-5,7-dihydro-cyclopenta[c]-

pyridine-6,6-dicarboxylate (4eo). General procedure C was used

with diyne 1e (187.7 mg, 0.75 mmol, 1.0 equiv) and 2-

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pyridinecarbonitrile (2o) (195.2 mg, 1.88 mmol, 2.5 equiv). The

residue was puriﬁed by ﬂash column chromatography (DCM/ethyl

acetate, 3:2) to aﬀord 4eo as yellow oil (110.4 mg, 42%); H NMR

(400 MHz, CDCl₃) δ 8.59 (s, 1H), 8.32 (s, 1H), 7.73 (t, J = 7.6 Hz,

1H), 7.66 (d, J = 7.7 Hz, 1H), 7.24−7.17 (m, 1H), 4.17 (q, J = 7.1

Hz, 4H), 3.63 (s, 2H), 3.55 (s, 2H), 2.33 (s, 3H), 1.21 (t, J = 7.1 Hz,

6H). The NMR spectrum of compound 4eo was consistent with the

previously reported literature data.^4c

74.0, 73.0, 16.5; HRMS (ESI): m/z [M + H]⁺calcd for C₂₀H₁₈NO

288.1383; found 288.1382.

1

Diethyl 1-(4-ﬂuorophenyl)-4-methyl-3-phenyl-5,7-dihydro-

cyclopenta[c]pyridine-6,6-dicarboxylate (5ia). General procedure

C was used with diyne 1i (258.3 mg, 0.75 mmol, 1.0 equiv) and

benzonitrile (2a) (193.3 mg, 1.88 mmol, 2.5 equiv). The residue was

puriﬁed by ﬂash column chromatography (hexane/ethyl acetate, 8:1)

to aﬀord 5ia as a yellow solid (194.9 mg, 58%); m.p. 122−124 °C; ¹H

NMR (400 MHz, CDCl₃) δ 7.85−7.76 (m, 2H), 7.57 (dt, J = 8.1, 1.8

Hz, 2H), 7.48−7.41 (m, 2H), 7.41−7.34 (m, 1H), 7.18−7.09 (m,

2H), 4.24 (qd, J = 7.1, 2.7 Hz, 4H), 3.84 (s, 2H), 3.65 (s, 2H), 2.32

(s, 3H), 1.28 (t, J = 7.1 Hz, 6H); ¹³C{¹H} NMR (101 MHz, CDCl₃)

δ 171.3, 162.9 (d, J = 247.5 Hz), 157.5, 151.2, 150.1, 140.6, 135.9 (d,

J = 3.2 Hz), 131.5, 130.4 (d, J = 8.3 Hz), 129.4, 128.1, 127.9, 125.7,

115.3 (d, J = 21.4 Hz), 62.2, 60.1, 40.5, 39.9, 16.5, 14.1; ¹⁹F{¹H}

NMR (377 MHz, CDCl₃) δ −113.77; HRMS (ESI): m/z [M + H]⁺

calcd for C₂₇H₂₇FNO₄448.1919; found 448.1914.

Diethyl 1-methyl-3-phenyl-4-(trimethylsilyl)-5,7-dihydro-

cyclopenta[c]pyridine-6,6-dicarboxylate (4fa). General procedure

C was used with diyne 1f (241.8 mg, 0.75 mmol, 1.0 equiv) and

benzonitrile (2a) (193.3 mg, 1.88 mmol, 2.5 equiv). The residue was

puriﬁed by ﬂash column chromatography (hexane/ethyl acetate, 4:1)

1

to aﬀord 4fa as brown oil (188.0 mg, 59%); H NMR (400 MHz,

CDCl₃) δ 7.37−7.29 (m, 5H), 4.23 (q, J = 7.1 Hz, 4H), 3.68 (s, 2H),

3.55 (s, 2H), 2.47 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H), −0.02 (s, 9H);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.3, 164.0, 156.1, 152.9,

Diethyl 1-(4-methoxyphenyl)-4-methyl-3-phenyl-5,7-dihydro-

cyclopenta[c]pyridine-6,6-dicarboxylate (5ja). To the solution of

Cp₂Ni (28.3 mg, 0.15 mmol, 20 mol %), Xantphos (108.5 mg, 0.19

mmol, 25 mol %), and Cs₂CO₃(244.4 mg, 0.75 mmol, 1.0 equiv) in

toluene (3.0 mL), diyne 1j (267.3 mg, 0.75 mmol, 1.0 equiv) and

benzonitrile (2a) (116.0 mg, 1.13 mmol, 1.5 equiv) were added. The

reaction mixture was stirred for 24 h at 80 °C. The residue was

puriﬁed by ﬂash column chromatography (hexane/ethyl acetate, 4:1)

to aﬀord 5ja as a yellow solid (237.1 mg, 69%); m.p. 107−109 °C; ¹H

NMR (400 MHz, CDCl₃) δ 7.86−7.78 (m, 2H), 7.64−7.57 (m, 2H),

7.44 (t, J = 7.4 Hz, 2H), 7.41−7.34 (m, 1H), 7.04−6.96 (m, 2H),

4.24 (qq, J = 7.2, 3.7 Hz, 4H), 3.90 (s, 2H), 3.83 (s, 3H), 3.66 (s,

2H), 2.33 (s, 3H), 1.28 (t, J = 7.1 Hz, 6H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 171.3, 159.6, 157.1, 150.9, 150.6, 140.7, 132.4, 131.0,

129.7, 129.4, 127.9, 127.6, 124.9, 113.7, 62.0, 59.9, 55.2, 40.5, 39.7,

16.4, 14.0; HRMS (ESI): m/z [M + H]⁺calcd for C₂₈H₃₀NO₅

460.2118; found 460.2113.

7-Methyl-4,6-diphenylfuro[3,4-c]pyridin-3(1H)-one (6ka). Gener-

al procedure C was used with diyne 1k (148.7 mg, 0.75 mmol, 1.0

equiv) and benzonitrile (2a) (193.3 mg, 1.88 mmol, 2.5 equiv). The

residue was puriﬁed by ﬂash column chromatography (hexane/ethyl

acetate, 6:1) to aﬀord 6ka as a brown solid (22.0 mg, 10%); ¹H NMR

(400 MHz, CDCl₃) δ 8.05−7.98 (m, 2H), 7.70−7.63 (m, 2H), 7.54−

7.44 (m, 6H), 5.31 (s, 2H), 2.40 (s, 3H). The NMR spectrum of

compound 6ka was consistent with the previously reported literature

data.^8a

144.4, 131.8, 129.1, 128.0, 127.7, 125.9, 62.0, 59.9, 42.7, 37.8, 22.2,

14.1, 1.2; HRMS (ESI): m/z [M + H]⁺calcd for C₂₄H₃₂NO₄Si

426.2095; found 426.2094.

Diethyl 4-methyl-1,3-diphenyl-5,7-dihydro-cyclopenta[c]-

pyridine-6,6-dicarboxylate (5ga). General procedure C was used

with diyne 1g (244.8 mg, 0.75 mmol, 1.0 equiv) and benzonitrile (2a)

(193.3 mg, 1.88 mmol, 2.5 equiv). The residue was puriﬁed by ﬂash

column chromatography (hexane/DCM, 1:1) to aﬀord 5ga as a white

solid (260.3 mg, 81%); m.p. 93−95 °C; ¹H NMR (400 MHz, CDCl₃)

δ 7.90−7.82 (m, 2H), 7.66−7.58 (m, 2H), 7.47 (td, J = 7.4, 3.8 Hz,

4H), 7.38 (dd, J = 8.5, 6.2 Hz, 2H), 4.25 (qq, J = 7.2, 3.7 Hz, 4H),

3.92 (s, 2H), 3.68 (s, 2H), 2.35 (s, 3H), 1.29 (t, J = 7.1 Hz, 6H);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.2, 157.3, 151.0, 150.9,

140.6, 139.8, 131.6, 129.4, 128.4, 128.3, 128.1, 128.0, 127.7, 125.5,

62.0, 60.0, 40.4, 39.8, 16.4, 14.0; HRMS (ESI): m/z [M + H]⁺calcd

for C₂₇H₂₈NO₄430.2013; found 430.2010.

Diethyl 1-methyl-3,4-diphenyl-5,7-dihydro-cyclopenta[c]-

pyridine-6,6-dicarboxylate (4ga). To the solution of Ni(COD)₂

(41.3 mg, 0.15 mmol, 20 mol %) and SIPr (73.1 mg, 0.19 mmol,

25 mol %) in toluene (3.0 mL), diyne 1g (244.8 mg, 0.75 mmol, 1.0

equiv) and benzonitrile (2a) (193.3 mg, 1.88 mmol, 2.5 equiv) were

added in an argon atmosphere. The reaction mixture was stirred for

24 h at 80 °C. The residue was puriﬁed by ﬂash column

chromatography (hexane/ethyl acetate, 6:1) to aﬀord 4ga as yellow

1

oil (115.4 mg, 36%); H NMR (400 MHz, CDCl₃) δ 7.31−7.18 (m,

5H), 7.21−7.11 (m, 3H), 7.14−7.06 (m, 2H), 4.21 (qd, J = 7.1, 2.2

Hz, 4H), 3.68 (s, 2H), 3.48 (s, 2H), 2.58 (s, 3H), 1.25 (t, J = 7.2 Hz,

6H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.3, 155.7, 152.4, 149.3,

140.3, 138.0, 132.9, 130.3, 130.0, 129.8, 128.3, 127.7, 127.2, 127.0,

62.0, 59.8, 40.6, 39.0, 22.2, 14.1; HRMS (ESI): m/z [M + H]⁺calcd

for C₂₇H₂₈NO₄430.2013; found 430.2011.

7-Methyl-4,6-diphenylfuro[3,4-c]pyridin-1(3H)-one (7la). General

procedure C was used with diyne 1l (148.7 mg, 0.75 mmol, 1.0 equiv)

and benzonitrile (2a) (193.3 mg, 1.88 mmol, 2.5 equiv). The residue

was puriﬁed by ﬂash column chromatography (hexane/ethyl acetate,

10:1) to aﬀord 7la as a brown solid (37.9 mg, 17%); m.p. 193−195

°C; ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 7.1 Hz, 2H), 7.64 (d,

J = 6.9 Hz, 2H), 7.54−7.44 (m, 6H), 5.57 (s, 2H), 2.75 (s, 3H);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 170.1, 160.2, 150.0, 139.2,

Diethyl 3,4-dimethyl-1-phenyl-5,7-dihydro-cyclopenta[c]-

pyridine-6,6-dicarboxylate (5gj). General procedure C was used

with diyne 1g (244.8 mg, 0.75 mmol, 1.0 equiv) and acetonitrile (2j)

(77.0 mg, 1.88 mmol, 2.5 equiv). The residue was puriﬁed by ﬂash

column chromatography (hexane/ethyl acetate, 7:1) to aﬀord 5gj as a

137.4, 136.4, 133.0, 129.7, 129.6, 129.4, 129.2, 128.7, 128.4, 127.7,

68.6, 14.3; HRMS (ESI): m/z [M + H]⁺calcd for C₂₀H₁₆NO₂

302.1176; found 302.1175.

1

brown solid (105.1 mg, 38%); m.p. 119−121 °C; H NMR (400

MHz, CDCl₃) δ 7.78−7.66 (m, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.35 (t,

J = 7.3 Hz, 1H), 4.19 (qq, J = 7.1, 3.6 Hz, 4H), 3.76 (s, 2H), 3.57 (s,

2H), 2.54 (s, 3H), 2.25 (d, J = 2.5 Hz, 3H), 1.23 (t, J = 7.1 Hz, 6H);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.3, 155.5, 150.6, 149.6,

140.0, 130.6, 128.3, 127.9, 125.9, 61.9, 60.1, 40.2, 39.5, 22.4, 15.2,

14.0; HRMS (ESI): m/z [M + H]⁺calcd for C₂₂H₂₆NO₄368.1856;

found 368.1852.

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c00577.

■

sı

Optimization studies, NMR (¹H, ¹³C{¹H}, ¹⁹F{¹H},

NOESY, and HMBC) spectra, and calculational details

(PDF)

7-Methyl-4,6-diphenyl-1,3-dihydrofuro[3,4-c]pyridine (5ha).

General procedure C was used with diyne 1h (136.2 mg, 0.75

mmol, 1.0 equiv) and benzonitrile (2a) (193.3 mg, 1.88 mmol, 2.5

equiv). The residue was puriﬁed by ﬂash column chromatography

(hexane/DCM, 2:5) to aﬀord 5ha as a yellow solid (99.7 mg, 46%);

AUTHOR INFORMATION

Corresponding Authors

■

1

m.p. 100−103 °C; H NMR (400 MHz, CDCl₃) δ 7.86−7.78 (m,

Jongcheol Seo − Department of Chemistry, Pohang University

of Science and Technology (POSTECH), Pohang 37673,

Korea; Email: jongcheol.seo@postech.ac.kr

2H), 7.69−7.61 (m, 2H), 7.52−7.37 (m, 6H), 5.44 (s, 2H), 5.17 (s,

2H), 2.31 (s, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 157.6, 150.5,

148.6, 140.2, 139.2, 130.7, 129.5, 128.7, 128.2, 128.0, 127.8, 123.0,

9340

https://doi.org/10.1021/acs.joc.1c00577

J. Org. Chem. 2021, 86, 9328−9343

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

K.; Goswami, A.; Ohtaki, K.; Tanabe, E.; Saino, N.; Okamoto, S. On-

Demand Generation of an Efficient Catalyst for Pyridine Formation

from Unactivated Nitriles and α ,ω -Diynes Using CoCl₂-6H₂O, dppe,

and Zn. Org. Lett. 2007, 9, 931−934. (c) Goswami, A.; Ohtaki, K.;

Kase, K.; Ito, T.; Okamoto, S. Synthesis of Substituted 2,2 ′-

Bipyridines and 2,2 ′:6 ′,2 ″-Terpyridines by Cobalt-Catalyzed Cyclo-

addition Reactions of Nitriles and α ,ω -Diynes with Exclusive

Regioselectivity. Adv. Synth. Catal. 2008, 350, 143−152. (d) Sugiyama,

Y.-k.; Okamoto, S. Regioselective Syntheses of Substituted Pyridines

and 2,2 ′-Bipyridines by Cobalt-Catalyzed [2+2+2] Cycloaddition of

α ,ω -Diynes with Nitriles. Synthesis 2011, 14, 2247−2254.

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Y.; Kinpara, K.; Saigoku, T.; Takagishi, H.; Okuda, S.; Nishiyama, H.;

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Alkynylnitriles. Adv. Synth. Catal. 2018, 360, 1876−1882.

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Nishida, G.; Hirano, M. Synthesis of Perfluoroalkylated Benzenes and

Pyridines through Cationic Rh(I)/Modified BINAP-Catalyzed

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9, 1907−1910. (b) Garcia, L.; Pla-Quintana, A.; Roglans, A.; Parella,

T. Microwave-Enhanced Rhodium-Catalyzed [2+2+2] Cycloaddition

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Eur. J. Org. Chem. 2010, 2010, 3407−3415. (c) Kashima, K.; Teraoka,

K.; Uekusa, H.; Shibata, Y.; Tanaka, K. Rhodium-Catalyzed

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Diynes with Nitriles: Effect of Ortho Substituents on Regio- and

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(7) For iron-catalyzed reactions, see: (a) Wang, C.; Li, X.; Wu, F.;

Wan, B. A Simple and Highly Efficient Iron Catalyst for A [2+2+2]

Cycloaddition to Form Pyridines. Angew. Chem., Int. Ed. 2011, 50,

7162−7166. (b) Lane, T. K.; D’Souza, B. R.; Louie, J. Iron-Catalyzed

Formation of 2-Aminopyridines from Diynes and Cyanamides. J. Org.

Chem. 2012, 77, 7555−7563. (c) Wang, C.; Wang, D.; Xu, F.; Pan, B.;

Wan, B. Iron-Catalyzed Cycloaddition Reaction of Diynes and

Cyanamides at Room Temperature. J. Org. Chem. 2013, 78, 3065−

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R. J.; Witulski, B.; Renaud, J.-L. Iron(II)-catalysed [2+2+2]

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Lane, T. K.; Louie, J. Regioselective Iron-Catalyzed [2+2+2]

Cycloaddition Reaction Forming 4,6-Disubstituted 2-Aminopyridines

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234−242.

Sung You Hong − Department of Chemistry and Department

of Chemical Engineering, Ulsan National Institute of Science

and Technology (UNIST), Ulsan 44919, Korea;

Email: syhong@unist.ac.kr

Authors

Il Young Cho − Department of Chemistry and Department of

Chemical Engineering, Ulsan National Institute of Science

and Technology (UNIST), Ulsan 44919, Korea

Woo Gyum Kim − Department of Chemistry, Ulsan National

Institute of Science and Technology (UNIST), Ulsan 44919,

Korea; Department of Chemistry, School of Science, The

University of Tokyo, Tokyo 113-0033, Japan

Ji Hwan Jeon − Department of Chemistry, Ulsan National

Institute of Science and Technology (UNIST), Ulsan 44919,

Korea

Jeong Woo Lee − Department of Chemistry and Department

of Chemical Engineering, Ulsan National Institute of Science

and Technology (UNIST), Ulsan 44919, Korea

Jeong Kon Seo − UNIST Central Research Facility, Ulsan

44919, Korea

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00577

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

This project was ﬁnancially supported by the National

Research Foundation of Korea (NRF) (grants

2020M3H4A3081883 and 2019R1C1C1008414) and the

UNIST research fund (1.190118.01).

DEDICATION

■

This paper is dedicated to the memory of Prof. Malcolm L. H.

Green.

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Nickelocene as an Air- And Moisture-Tolerant Precatalyst in the Regioselective Synthesis of Multisubstituted Pyridines

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