Enyne Amides to Fused Pyridones: Scope and Limitations

pubs.acs.org/joc

Note

Sharada S. Labadie, Karine Thai, Jessica M. Grandner, Yanzhou Liu, and Brendan T. Parr*

Cite This: https://doi.org/10.1021/acs.joc.1c00688

Read Online

sı

*

Metrics & More

Article Recommendations

Supporting Information

ACCESS

ABSTRACT: Herein we present an investigation into the scope and mechanism for the synthesis of cyclopentyl and heterocyclic

fused pyridones from the corresponding enyne amides. In the presence of a secondary amine, cyclization proceeds smoothly to form

5,6-bicyclic pyridones in 12−90% yield. The cyclization fails with enyne amides of six-membered and larger ring systems. The ring

closure reaction is catalytic in nature with respect to the secondary amine and proceeds via sequential 1,6-addition of the amine, 6-

exo-trig ring closure of the iminium intermediate, and subsequent elimination of the secondary amine. Computations show reduced

conjugation between the enyne and amide for six-membered and larger systems, thereby providing an explanation for the inability of

such enyne amides to form fused pyridones.

Pyridones are prevalent rings native to numerous natural

products and pharmacologically relevant molecules of varied

structural complexity (Figure 1). These compounds exhibit an

array of medicinal properties including anti-inﬂammatory,

idiopathic pulmonary ﬁbrocystic, anticancer, and antipara-

sitic.^1,2In addition, pyridones serve as valuable building blocks

and synthons and are useful in fragment-based lead

generation.^3,4Although the synthesis of pyridones has been

studied extensively, the methods described primarily enable the

synthesis of monocyclic pyridones.⁵A few reported syntheses

of fused bicyclic pyridones from 2-alkynylbenzamides via

ruthenium-catalyzed and electrophilic cyclization produce

isoquinolinones and isoindolinones.⁶⁻⁸6,6-Bicyclic pyrdones

(e.g., 5,6,7,8-tetrahydroisoquinolones) are obtained by the

hydrogenation of the isoquinolin-1(2H)-ones in the presence

of Adam’s catalyst in poor yields.⁹The formation of a highly

substituted cycloalkylpyridone 1 by electrophilic cyclization of

enyne amides (Scheme 1a) and rhodium(III)-catalyzed

C(sp²)−H functionalization and subsequent annulation to

form cyclobuta(c)-pyridones, such as 2 (Scheme 1b), have

been reported.^3,7To the best of our knowledge, a general

method enabling access to cycloalkyl and heterocyclic fused

pyridones has not been published. In the course of a medicinal

chemistry campaign, we were in need of a robust method to

access a variety of highly substituted fused cycloalkyl

pyridones. Due to the aforementioned lack of a versatile

method for the synthesis of such motifs, we initiated an

investigation to develop a general methodology. We chose to

explore the intramolecular ring closure of enyne amides, due to

their ease of synthesis from the corresponding β-keto esters

(Scheme 1c). We describe the optimization, scope, and

limitations of the ring closure of enyne amides in the synthesis

of highly substituted bicyclic pyridones. In addition, we

describe computational and mechanistic analysis of the

reaction pathway to understand the speciﬁcity of cyclization

for ﬁve-membered enyne amides.

To identify optimum ring closure conditions, 2-ethynylcyclo-

pent-1-ene-1-carboxamide 3a, generated from methyl 2-

oxocyclopentanecarboxylate, was used as a model substrate.

The range of ring closure conditions surveyed is summarized in

Table 1. N-Bromosuccinimide (NBS)-promoted cyclization

formed exclusively the 5-exo-dig cyclization product 4 (X = Br,

cis/trans mixture), and none of the desired pyridone 5 (X =

Br) was observed. Other electrophilic promoters, including N-

iodosuccinimide (NIS), iodine (I₂), and iodine monochloride

(ICl) (entries 2−4), resulted in products that were unstable,

and the structures of which could not be elucidated. Attempts

at Lewis acid-catalyzed cyclization with silver(I), dirhodium-

(II) or gold(I) complexes in reﬂuxing dichloromethane

(DCM) or 1,2-dichloroethane (DCE) (entries 5−7) returned

either unreacted starting material or complex reaction mixtures

with a trace of the desired product detected by mass

spectrometric analysis. Under vinylidene carbene forming

conditions with a ruthenium(II) catalyst, the desired ring

Special Issue: Enabling Techniques for Organic Syn-

thesis

Received: April 25, 2021

https://doi.org/10.1021/acs.joc.1c00688

J. Org. Chem. XXXX, XXX, XXX−XXX

A

The Journal of Organic Chemistry

pubs.acs.org/joc

Note

Figure 1. Pharmacologically important pyridone-containing molecules.

Scheme 1. (a−c) Examples of Reported Cycloalkyl Pyridone

Syntheses and This Work

Table 1. Survey of Ring Closure Conditions

yield (%)

entry

conditions

X

4

5

1

2

3

4

5

6

7

NBS (2 equiv), DCM, 22 °C, 0.5 h

NIS (3 equiv), DCM, 22 °C, 0.5 h

I₂(3 equiv), NaHCO₃, CAN 22 °C, 0.5 h

ICl (2 equiv), DCM, 22 °C, 0.5 h

AgOAc (0.1 equiv), AcOH, DCM, 22 °C, 20 h

Rh₂(OAc)₄(0.3 equiv), DCM, 22 °C, 20 h

Br

I

82

0

I

H

PPh₃AuCl (0.02 equiv) + AgN(Tf)₂(0.02

equiv), 1,2-DCE, 90 °C, 12 h

8

9

10

CpRuCl(PPh₃)₂(0.1 equiv), pyridine, 90 °C, 2 h

dimethylamine (10 equiv), MeOH, 80 °C, 20 h

dimethylamine (10 equiv), MeOH, 100 °C, 0.5

h, microwave

H

12

80

83

11

12

13

14

morpholine (2 equiv), MeOH, 100 °C, 0.5 h,

H

0

microwave

morpholine (5 equiv), MeOH, 100 °C, 0.5 h,

microwave

morpholine (10 equiv), MeOH, 100 °C, 0.5 h,

microwave

N-methylmorpholine (10 equiv), 100 °C, 0.5 h,

microwave

62

75

closure product 5a (X = H) was formed, albeit in low yield

(entry 8).

Gratifyingly, clean conversion of the amide 3a to pyridone

5a (X = H) occurred in excellent yield when heated at 80 °C

for 20 h in 1 M methanolic solution of dimethylamine (entry

9).⁸The reaction time was reduced to 0.5 h without detriment

to yield by heating the reaction mixture to 100 °C in a

microwave reactor (entry 10). With an interest to reduce the

amount of amine, we attempted the ring closure reaction with

less volatile morpholine as the nucleophile (entries 11−13).

Less than 50% conversion was observed with two equivalents

of morpholine in methanol at 100 °C in a microwave reactor.

The conversion improved with ﬁve equivalents of morpholine

(entry 12), and with ten equivalents (entry 13), the conversion

was complete. However, the isolated product yields suﬀered

due to increased formation of side products. In the presence of

N-methylmorpholine, none of the desired pyridone was

obtained (entry 14). Collectively, these results encouraged us

to pursue the dimethylamine-mediated ring closure to explore

the versatility of the method for the synthesis of fused

pyridones.

good-to-excellent yields were obtained for methyl, isopropyl,

cyclopentyl, and benzyl amides (3b−e) to generate the

corresponding N-substituted pyridones (5b−e). In general,

increased steric bulk correlated with slightly reduced yields,

indicative of impeded nucleophilic attack. Substitutions on the

alkyne were also investigated to obtain C3-diversiﬁed 2,5,6,7-

tetrahydro-1H-cyclopenta[c]pyridin-1-ones. The reaction pro-

gressed smoothly with phenyl, pyridyl, cyclopentyl, propyl,

propargyl ethers, and N,N-dimethylmethylamine-substituted

enyne amides (3f−l) to form the respective fused pyridones

(5f−l). Furthermore, an unprotected hydroxyl group could be

carried on in the synthesis (5m). As observed with the

substituted amides, increased steric bulk adjacent to the

electrophilic position resulted in lower yields, and a side

product was observed with phenyl and pyridyl groups. A

signiﬁcant increase in steric hindrance ﬂanking the alkyne (3n)

prevented the desired cyclization altogether. The crude

cyclization reaction mixture of 3n contained mostly the

starting enyne amides. Gratifyingly, the ring closure was

realized with substituents on both the amide and the alkyne to

form 2,3,5,6-tetrasubstituted pyridones (5o and 5p); however,

Next, we applied these reaction conditions to N-substituted

enyne amides to obtain the corresponding N-substituted

2,5,6,7-tetrahydro-1H-cyclopenta[c]pyridin-1-ones (Table 2).

We observed that elevated temperatures and increased reaction

times were required for acceptable yields with these substrates.

After heating for 1−2 h in a microwave reactor at 150−160 °C,

B

https://doi.org/10.1021/acs.joc.1c00688

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Note

Table 2. Substrate Scope of the Ring Closure Reaction (All Reported Yields Are for the Ring Closure Step and Are Not

Optimized)

a

b

c

d

100 °C, 0.5 h. 150 °C, 1.0−1.5 h. 160 °C, 1.5−2 h. 5−10% of a side product was observed. The side product structures were tentatively

assigned as N,N-dimethyl-3-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-1-amine and N,N-dimethyl-3-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta-

[c]pyridin-1-amine for 3f and 3g, respectively. Decomposition of starting material with no major isolable product.

e

the ring closure with a diphenyl-substituted enyne amide (3q)

was very sluggish and aﬀorded a poor yield of 5q. To further

expand the scope, we next evaluated heteroatom-containing

enyne amides. The enyne amides 6a−d, 7a−c, and 8a−c

derived from the corresponding 2-keto esters were successfully

converted to 3,5-dihydrofuro[3,4-c]pyridin-4(1H)-ones, (9a−

d), 3,5-dihydrothieno[3,4-c]pyridin-4(1H)-ones (10a−c), and

tert-butyl 4-oxo-1,3,4,5-tetrahydro-2H-pyrrolo[3,4-c]pyridine-

2-carboxylates (11a−c) in respectable yields. Gratifyingly,

the tert-butyl carbamoyl-protecting group was tolerated under

the ring closure conditions.

Encouraged by the robust substrate compatibility observed

for ﬁve-membered cyclopentyland heterocyclic enyne amides,

we desired to further expand the scope to larger ring systems.

C

https://doi.org/10.1021/acs.joc.1c00688

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Note

Initial attempts to generate six-membered and larger ring

ethynyl acid precursors needed for the synthesis of ethynyl

amides resulted in the formation of 3-hydroxyfuranones

(Scheme 2a) (see Supporting Information for details). A

closure of 12, 13, and 18 under optimized conditions failed to

form the fused pyridones 15, 16, and 19, respectively. The

crude cyclization reaction mixture of 12 and 13 shows

decompsotion of the stating material and that of 18 showed

starting material remaining with side products that could not

be characterized.

Scheme 2. (a) Formation of 3-Hydroxybenzofuranones; (b)

Synthesis and Attempted Cyclization of Six- and Larger

Orthogonal behavior of the larger ring systems in this route

was an unexpected limitation to the method. Nonetheless, the

route was highly amenable to ﬁve-membered fused pyridone

synthesis. On the basis of our collective results above, we

propose that the secondary amine-mediated ring closure

proceeds via 1,6-addition of the amine to enyne amide to

form enamine amide 20 (Figure 2a). The amide then

undergoes cyclization in a 6-endo-trig fashion to the enamine

or 6-exo-trig fashion to the iminium, followed by elimination of

the amine, completing the catalytic cycle with the formation of

the pyridone 5a. We did not detect the enamine intermediate

20 in dimethylamine-mediated ring closure. However, the

crude product of the morpholine-mediated reaction (Table 1,

entry 12) showed a 2:1 mixture of 5a and 20. The ratio

changed to 3.7:1 and 22:1 after standing in deutero-chloroform

in a NMR tube for 24 and 72 h, respectively, supporting the

involvement of an enamine intermediate in the reaction

(Figure 2b and Figure S1). These observations point to the

catalytic nature of the ring closure reaction in the secondary

amine. The catalytic nature was further conﬁrmed when

complete conversion of 3a to 5a was realized upon heating

with only 20−30% morpholine and dimethyl amine at 80 °C

for 20 h in a sealed vial with a minimal amount of methanol.

Using computation,¹⁰we determined that conformational

diﬀerences between 3a and 12 elucidate the origin of the

failure of larger rings to undergo cyclization. By closely

examining the conformation of the exocyclic amide of 3a, the

amide is conjugated with the enyne π-system (Figure 3a).

Alternatively, the exocyclic amide of 12 is out of plane with the

enyne π-system with a dihedral angle of >45° (Figure 3b). The

conformational diﬀerences are attributable to the smaller bond

angles of the exocyclic ring substituents in 12 compared to 3a

(shown in left most images of Figure 3), which requires the

amide to rotate out of the plane to avoid an intramolecular

a

Enyne Amides

a

Reagents and conditions: (i) 1 M LiOH, MeOH, THF, 50 °C, 5 h;

(ii) 2 M HCl, rt; (iii) NH₄Cl, HATU, DIPEA, 1,4-dioxane, rt, 20 h;

(iv) 1 M TBAF in THF, rt, 0.5 h; (v) 1 M dimethylamine, MeOH,

100 °C, 0.5 h, microwave; (vi) 1 M dimethylamine, MeOH, 150 °C,

1.0 h, microwave.

slightly modiﬁed method (Scheme 2b) was adopted to

generate the ethynyl amides 12 and 13. However, the ring

Figure 2. (a) Proposed catalytic cycle for the ring closure of cyclopentenyne amides. (b) NMR peaks showing vinyl protons of the enamine 20 and

aromatic protons of 5a in the crude reaction mixture of entry 12 Table 1 (see Figure S1 for more information).

D

https://doi.org/10.1021/acs.joc.1c00688

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Note

1

Teledyne Isco Combiﬂash Rf. H NMR spectra were recorded on a

Bruker Avance 400 spectrometer. Chemical shifts are expressed in δ

ppm referenced to an internal standard, tetramethylsilane (δ = 0

ppm). High-resolution mass spectra (HRMS) experiments were

performed on a Dionex LC Ultimate 3000 coupled with a Thermo

Scientiﬁc Q Exactive Orbitrap mass spectrometer using ESI as the

ionization source.

Computational Methods. All computations were performed

using Gaussian 09.¹⁰Geometry optimizations and frequency

calculations were performed at the M06−2x¹¹level using the 6-

31+G(d) basis set with the CPCM^12,13implicit solvent model for

highly polar (water) and moderately polar (tetrahydrofuran) solvents.

Frequencies were used to conﬁrm the identiﬁcation of minima (zero

negative frequencies) and transition structures (exactly one negative

frequency). A correction to frequencies below 100 cm⁻¹was applied

to thermal corrections, calculated at 1 atm and 298.15 K, as described

by Truhlar and co-workers.^14,15Single-point energy calculations were

performed at the M06−2x¹¹level using the 6-311+G(2d,p) basis set

with the CPCM^12,13implicit solvent model for highly polar (water)

and moderately polar (tetrahydrofuran) solvents. 3D images were

made using CYLview.¹⁶Energy levels of LUMOs in Figure 3 were

obtained by importing formatted Gaussian checkpoint ﬁles of single-

point calculations into Avogadro.¹⁷

Figure 3. (a) Lowest energy conformation of 3a. (b) Lowest energy

conformation of 12.

GENERAL PROCEDURE FOR THE SYNTHESIS OF

FUSED PYRIDONES

clash with the alkyne (right most images of Figure 3). In

addition to the signiﬁcant out-of-plane rotation of 12, the

bonds involved in conjugation are slightly longer than those in

3a. The LUMO of 12, at the single-point level, is 0.376 eV

higher than the LUMO of 3a, a diﬀerence equivalent to 8.7

kcal/mol. The reduced conjugation seems to be suﬃcient to

impact the electronics of the enyne and prevent cyclization.

In conclusion, the secondary amine-mediated intramolecular

ring closure of cyclopentyl and heterocyclic enyne amides

derived from readily available β-keto esters occurs with good-

to-excellent yield to form highly substituted 5,6-fused

pyridones. The steric bulk on the alkyne and amide moieties

impedes the cyclization and can prove detrimental to the yield.

The reaction is tolerant of a range of functional groups

including Boc-protected amines and unprotected hydroxyl

groups. A secondary amine is needed to initiate the ring

closure reaction. We have shown that the enamine generated

by the conjugate addition of the amine to enyne amide is

eventually converted to the bicyclic pyridone regenerating the

secondary amine. Collectively, this conﬁrms that the ring

closure reaction is catalytic with respect to the secondary

amine. Surprisingly, the method fails for six-membered and

larger ring systems. Using computations, we were able to

determine that the small molecule conformation of the starting

material dictates whether the compound is activated toward

nucleophilic addition, which is the entry into the proposed

catalytic cycle.

■

Step 1: Sonogashira Coupling. A mixture of cyclo-

alkyltriﬂuoromethanesulfonate¹⁸(1 mmol), an alkyne (2

equiv), Pd(PPh₃)₂Cl₂(0.05 equiv), CuI (0.05 equiv) in

triethylamine (5 equiv), and dimethylformamide (10 equiv)

was heated in a sealed vial at 60 for 0.5 h. The reaction mixture

was cooled and diluted with 50% isopropyl acetate (IPAC)/

heptane mixture, and the solids were removed by ﬁltration.

The ﬁltrate was washed with brine, dried over sodium sulfate,

and concentrated. The residue was puriﬁed by column

chromatography (silica gel, 0−50% IPAC/heptane) to obtain

cycloalkenynecarboxylate.

Step 2: Ester Hydrolysis. To a solution of cyclo-

alkenynecarboxylate from step 1 (1 mmol) dissolved in a 1:1

mixture of THF/MeOH (6 mL) was added an aqueous lithium

hydroxide (1−3 equiv, 1 M) and heated at 50 °C for 1−5 h.

The reaction mixture was cooled and concentrated. The

residue was extracted with IPAC and the organic layer

discarded. The aqueous layer was acidiﬁed with aqueous

hydrochloric acid (2 M) and extracted with IPAC. The organic

layer was washed with brine, dried over sodium sulfate, and

concentrated to obtain cycloalkenynecarboxylic acid. This was

used in the next step without further puriﬁcation.

Step 3: Amide Formation. A mixture of cycloalkenyne-

carboxylic acid from step 2 (1 mmol), amine (2−5 equiv),

HATU (1.5 equiv), and diisopropylethylamine (3 equiv) in

DCM or 1,4-dioxane was stirred at room temperature for 20 h.

The reaction mixture was diluted with IPAC or DCM, washed

with water and brine, dried over sodium sulfate, and

concentrated. The residue was puriﬁed by column chromatog-

raphy (silica gel, 0−100% IPAC/heptane or 5% MeOH/

DCM) to obtain cycloalkenyneamide.

Step 4: Ring Closure. Cycloalkenyne amide from step 3 (1

mmol) in dimethylamine (10 equiv, 1 M in methanol) was

heated at 100−160 °C for 0.5 h−2.0 h in a microwave reactor

in a sealed microwave vial. The reaction mixture was cooled

and concentrated. The residue was puriﬁed by column

chromatography (silica gel, 0−5% MeOH/DCM) to obtain

fused pyridones.

EXPERIMENTAL SECTION

■

General Details. All chemicals and solvents were used directly as

received from commercial suppliers. Microwave reactions were

performed in a closed vessel in a Biotage Initiator, measuring

temperature by IR. Reactions were monitored by thin-layer

chromatography on silica plates and by HPLC-MS analysis with a

C18 column, UV detection at 254 nm, and dual ESI/APCI to a single

quadrupole mass analyzer. The method was conducted at a ﬂow rate

of 0.7 mL/min, whereby mobile phase A was 0.1% formic acid in

water and mobile phase B was acetonitrile. The method began at 2%

B, ramping linearly to 98% B over 2 min. The gradient was held at

98% B for 0.2 min and then ramped down to 2% B over 0.1 min and

held at 2% B for 0.1 min. Flash chromatographic puriﬁcations were

performed with Teledyne Isco RediSep Rf Gold silica cartridges on a

E

https://doi.org/10.1021/acs.joc.1c00688

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Note

1

2,5,6,7-Tetrahydro-1H-cyclopenta[c]pyridin-1-one (5a).

Methyl 2-((trimethylsilyl)ethynyl)cyclopent-1-ene-1-carboxy-

late (5.55 g, 88% yield) was obtained from methyl 2-

(triﬂuoromethylsulfonyloxy)cyclopentene-1-carboxylate (7.75

g) as described in step 1: brown liquid. ¹H NMR (400

MHz, CDCl₃): δ 3.78 (s, 3H), 2.81−2.57 (m, 4H), 2.01−1.86

(m, 2H), 0.25 (s, 9H).

step 4: white amorphous solid. H NMR (400 MHz, CDCl₃):

δ 7.19 (d, J = 7.0 Hz, 1H), 6.20 (d, J = 6.9 Hz, 1H), 5.45−5.20

(m, 1H), 2.96−2.70 (m, 4H), 2.16−1.92 (m, 2H), 1.37−1.33

(m, 6H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 160.5, 153.6,

132.3, 131.0, 104.5, 45.5, 34.0, 30.3, 23.5, 22.2. HRMS (ESI)

m/z: [M + H]⁺calcd for C₁₁H₁₆NO, 178.1226; found,

178.1232.

(Ethynyl)cyclopent-1-ene-1-carboxylic acid (1.28 g, 91%

yield) was obtained from 2-((trimethylsilyl)ethynyl)cyclopent-

1-ene-1-carboxylate (2.35 g, 10.6 mmol) as described in step 2:

yellow amorphous solid. ¹H NMR (400 MHz, CDCl₃): δ 3.65

(s, 1H), 2.85−2.63 (m, 4H), 2.11−1.89 (m, 2H).

2-Cyclopentyl-6,7-dihydro-5H-cyclopenta[c]pyridin-1-one

(5d). N-Cyclopentyl-2-ethynyl-cyclopentene-1-carboxamide 3d

(300 mg, 40% yield) was obtained from 2-ethynylcyclopen-

tene-1-carboxylic acid (500 mg 4.0 mmol) and cyclopentyl-

amine as described in step 3: pale yellow amorphous solid. ¹H

NMR (400 MHz, CDCl₃): δ 7.06 (s, 1H), 4.44−4.10 (m, 1H),

3.63 (s, 1H), 2.81−2.73 (m, 2H), 2.73−2.64 (m, 2H), 2.04−

1.94 (m, 2H), 1.94−1.83 (m, 2H), 1.75−1.57 (m, 4H), 1.52−

1.43 (m, 2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 163.4,

145.7, 123.9, 87.3, 80.0, 51.2, 38.9, 33.8, 33.0, 23.6, 21.7.

HRMS (ESI) m/z: [M + H]⁺calcd for C₁₃H₁₈NO, 204.1386;

found, 204.1383.

2-Ethynylcyclopentene-1-carboxamide 3a (300 mg, 72%

yield) was obtained from 2-(ethynyl)cyclopent-1-ene-1-carbox-

ylic acid (420 mg, 3.1 mmol) and ammonium chloride (5

equiv) in 1,4-dioxane as described in step 3: yellow amorphous

1

solid. H NMR (400 MHz, CDCl₃): δ 7.03 (s, 1H), 6.05 (s,

1H), 3.65 (s, 1H), 2.87−2.64 (m, 4H), 2.01−1.87 (m, 2H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ 166.0, 144.5, 126.7,

88.4, 79.8, 39.2, 33.7, 21.7. HRMS (ESI) m/z: [M + H]⁺calcd

for C₈H₁₀NO, 136.0757; found, 136.0755.

The title compound 5a (113 mg, 83% yield) was obtained

by heating 2-ethynylcyclopentene-1-carboxamide (135 mg, 1

mmol) at 100 °C for 0.5 h as described in step 4: pale yellow

amorphous solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.26 (s,

1H), 7.34−6.96 (m, 1H), 6.15 (d, J = 6.5 Hz, 1H), 2.82−2.72

(m, 2H), 2.60 (t, J = 7.5 Hz, 2H), 2.06−1.79 (m, 2H).

¹³C{¹H} NMR (101 MHz, DMSO): δ 161.3, 155.6, 133.8,

131.6, 103.6, 34.2, 29.9, 23.1. HRMS (ESI) m/z: [M + H]⁺

calcd for C₈H₁₀NO, 136.0757; found, 136.0755.

The title compound 5d (30 mg, 60% yield) was obtained

from N-cyclopentyl-2-ethynyl-cyclopentene (50 mg, 0.25

mmol) by heating at 160 °C for 2 h as described in step 4:

1

white amorphous solid. H NMR (400 MHz, DMSO-d₆): δ

7.56−7.42 (m, 1H), 6.23 (d, J = 6.9 Hz, 1H), 5.27−5.03 (m,

1H), 2.80−2.73 (m, 2H), 2.68−2.58 (m, 2H), 2.07−1.89 (m,

4H), 1.87−1.73 (m, 2H), 1.72−1.57 (m, 4H). ¹³C{¹H} NMR

(101 MHz, CDCl₃): δ 161.1, 153.6, 132.1, 131.9, 104.5, 55.6,

34.1, 32.5, 30.3, 24.6, 23.5. HRMS (ESI) m/z: [M + H]⁺calcd

for C₁₃H₁₈NO, 204.1386; found, 204.1383.

2-Benzyl-2,5,6,7-tetrahydro-1H-cyclopenta[c]pyridin-1-

one (5e). N-Benzyl-2-ethynyl-cyclopentene-1-carboxamide 3e

(90 mg, 54% yield) was obtained from 2-ethynylcyclopentene-

1-carboxylic acid (100 mg, 0.73 mmol) and benzyl amine as

2-Methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-1-one

(5b). 2-Ethynyl-N-methylcyclopent-1-ene-1-carboxamide 3b

(180 mg, 63% yield) was obtained from 2-ethynylcyclopen-

tene-1-carboxylic acid (260 mg, 1.91 mmol) and methylamine

hydrochloride in DCM as described in step 3: yellow solid. ¹H

NMR (400 MHz, CDCl₃): δ 6.97 (s, 1H), 3.58 (s, 1H), 3.00−

2.87 (m, 3H), 2.84−2.75 (m, 2H), 2.73−2.65 (m, 2H), 1.98−

1.83 (m, 2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 164.7,

145.4, 124.3, 87.3, 80.0, 39.0, 33.9, 26.1, 21.7. HRMS (ESI) m/

z: [M + H]⁺calcd for C₉H₁₂NO, 150.0913; found, 150.0911.

The title compound 5b (20 mg, 80% yield) was obtained by

heating 2-ethynyl-N-methyl-cyclopentene-1-carboxamide (25

mg, 0.17 mmol) at 160 °C for 1 h as described in step 4: pale

1

described in step 3: pale yellow amorphous solid. H NMR

(400 MHz, CDCl₃): δ 7.39−7.25 (m, 5H), 4.56 (d, J = 5.7 Hz,

2H), 3.49 (s, 1H), 2.91−2.77 (m, 2H), 2.75−2.60 (m, 2H),

2.00−1.80 (m, 2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ

163.9, 145.2, 138.2, 128.6, 127.7, 127.4, 124.8, 87.7, 79.9, 43.6,

39.0, 33.9, 21.7. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₅H₁₆NO, 226.1226; found, 226.1232.

The title compound 5e (18 mg, 60% yield) was obtained

from N-benzyl-2-ethynyl-cyclopentene-1-carboxamide (30 mg,

0.13 mmol) by heating at 160 °C for 1.5 h as described in step

1

yellow amorphous solid. H NMR (400 MHz, CDCl₃): δ

1

4: white amorphous solid. H NMR (400 MHz, CDCl₃): δ

7.24−7.01 (m, 1H), 6.21−6.08 (m, 1H), 3.54 (s, 3H), 2.91−

2.76 (m, 4H), 2.16−1.97 (m, 2H). ¹³C{¹H} NMR (101 MHz,

CDCl₃): δ 161.4, 154.7, 136.5, 132.4, 104.2, 37.1, 34.1, 30.1,

23.5. HRMS (ESI) m/z: [M + H]⁺calcd for C₉H₁₂NO,

150.0913; found, 150.0911.

2-Isopropyl-6,7-dihydro-5H-cyclopenta[c]pyridin-1-one

(5c). 2-Ethynyl-N-isopropyl-cyclopentene-1-carboxamide 3c

(320 mg, 50% yield) was obtained from 2-ethynylcyclopen-

tene-1-carboxylic acid (500 mg, 4.0 mmol) and isopropyl

amine as described in step 3: pale yellow amorphous solid. ¹H

NMR (400 MHz, CDCl₃): δ 6.88 (s, 1H), 4.29−3.98 (m, 1H),

3.58 (s, 1H), 2.82−2.74 (m, 2H), 2.72−2.64 (m, 2H), 1.97−

1.84 (m, 2H), 1.20 (d, J = 6.6 Hz, 6H). ¹³C{¹H} NMR (101

MHz, CDCl₃): δ 163.2, 145.7, 124.0, 87.3, 80.0, 41.5, 39.0,

33.9, 22.7, 21.7. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₁H₁₆NO, 178.1226; found, 178.1228.

7.39−7.23 (m, 5H), 7.18−7.11 (m, 1H), 6.13 (d, J = 6.8 Hz,

1H), 5.15 (s, 2H), 2.94−2.75 (m, 4H), 2.24−1.90 (m, 2H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ 160.9, 154.7, 137.0,

135.6, 132.8, 128.8, 128.1, 127.8, 104.6, 51.5, 34.2, 30.2, 23.5.

HRMS (ESI) m/z: [M + H]⁺calcd for C₁₅H₁₆NO, 226.1226;

found, 226.1234.

3-Phenyl-2,5,6,7-tetrahydro-1H-cyclopenta[c]pyridin-1-

one (5f). Methyl 2-(phenylethynyl)cyclopent-1-ene-1-carbox-

ylate 3f (430 mg, 88% yield) was obtained from methyl 2-

(triﬂuoromethylsulfonyloxy)cyclopentene-1-carboxylate (560

mg, 2.0 mmol) and ethynylbenzene as described in step 1:

1

brown oil. H NMR (400 MHz, CDCl₃): δ 7.54−7.48 (m,

2H), 7.36−7.31 (m, 3H), 3.81 (s, 3H), 2.85−2.67 (m, 4H),

2.08−1.83 (m, 2H).

2-(2-Phenylethynyl)cyclopentene-1-carboxylic acid (150

mg, 80% yield) was obtained from methyl 2-(2-

phenylethynyl)cyclopentene-1-carboxylate (200 mg, 0.88

The title compound 5c (35 mg, 63% yield) was obtained

from 2-ethynyl-N-isopropyl-cyclopentene-1-carboxamide (55

mg, 0.31 mmol) by heating at 160 °C for 2 h as described in

1

mmol) as described in step 2: oﬀ-white amorphous solid. H

F

https://doi.org/10.1021/acs.joc.1c00688

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Note

NMR (400 MHz, CDCl₃): δ 7.53−7.46 (m, 2H), 7.38−7.28

(m, 3H), 2.79 (t, J = 7.6 Hz, 4H), 2.18−1.90 (m, 2H).

2-(Phenylethynyl)cyclopent-1-ene-1-carboxamide 3f (130

mg, 87% yield) was obtained from 2-(phenylethynyl)-

cyclopent-1-ene-1-carboxylic acid (150 mg, 0.71 mmol) and

ammonium chloride as described in step 3: oﬀ-white

(500 mg, 1.82 mmol) and ethylnylcyclopentane as described in

step 1: colorless oil. H NMR (400 MHz, CDCl₃): δ 3.75 (s,

1

3H), 2.86 (p, J = 7.4 Hz, 1H), 2.72−2.57 (m, 4H), 2.02−1.84

(m, 4H), 1.81−1.54 (m, 6H).

2-(2-Cyclopentylethynyl)cyclopentene-1-carboxylic acid

(325 mg, 93% yield) was obtained from methyl 2-(2-

cyclopentylethynyl)cyclopentene-1-carboxylate (375 mg, 1.72

1

amorphous solid. H NMR (400 MHz, CDCl₃): δ 7.49−7.44

1

(m, 2H), 7.40−7.33 (m, 3H), 7.13 (s, 1H), 5.82 (s, 1H),

2.88−2.67 (m, 4H), 2.07−1.84 (m, 2H). ¹³C{¹H} NMR (101

MHz, CDCl₃): δ 166.3, 142.4, 131.6, 129.4, 128.6, 128.0,

121.7, 100.3, 85.0, 39.5, 33.7, 21.8. HRMS (ESI) m/z: [M +

H]⁺calcd for C₁₄H₁₄NO, 212.1069; found, 212.1067.

The title compound 5f (60 mg, 60% yield) was obtained

from 2-(phenylethynyl)cyclopent-1-ene-1-carboxamide (100

mg, 0.47 mmol) by heating at 160 °C for 2 h as described

in step 4: white amorphous solid. ¹H NMR (400 MHz,

CDCl₃): δ 10.57 (s, 1H), 7.73−7.56 (m, 2H), 7.45 (m, 3H),

6.46 (s, 1H), 3.04−2.75 (m, 4H), 2.25−1.95 (m, 2H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ 162.2, 157.1, 144.6,

134.0, 131.0, 129.7, 129.2, 126.2, 103.0, 34.5, 29.5, 23.5;

HRMS (ESI) m/z: [M + H]⁺calcd for C₁₄H₁₄NO, 212.1069;

found, 212.107.

mmol) as described in step 2: oﬀ-white amorphous solid. H

NMR (400 MHz, CDCl₃): δ 2.87 (p, J = 7.1 Hz, 1H), 2.75−

2.59 (m, 4H), 2.04−1.88 (m, 4H), 1.82−1.53 (m, 6H).

2-(2-Cyclopentylethynyl)cyclopentene-1-carboxamide 3h

(115 mg, 61% yield) was obtained from 2-(2-

cyclopentylethynyl)cyclopentene-1-carboxylic acid (200 mg, 1

mmol) and ammonium chloride as described in step 3: oﬀ-

1

white amorphous solid. H NMR (400 MHz, CDCl₃): δ 7.26

(s, 1H), 6.31 (s, 1H), 2.84 (p, J = 7.3 Hz, 1H), 2.77−2.70 (m,

2H), 2.70−2.62 (m, 2H), 2.05−1.93 (m, 2H), 1.87 (p, J = 7.7

Hz, 2H), 1.82−1.50 (m, 6H). ¹³C{¹H} NMR (101 MHz,

CDCl₃): δ 166.8, 140.6, 129.0, 115.1, 107.0, 103.7, 96.6, 39.7,

33.8, 33.3, 31.0, 25.0, 21.6. HRMS (ESI) m/z: [M + H]⁺calcd

for C₁₃H₁₈NO, 204.1383; found, 204.1389.

The title compound 5h (22 mg, 44% yield) was obtained

from 2-(2-cyclopentylethynyl)cyclopentene-1-carboxamide

(50 mg, 0.25 mmol) by heating at 160 °C for 2.0 h as

3-(3-Pyridyl)-2,5,6,7-tetrahydrocyclopenta[c]pyridin-1-

one (5g). Methyl 2-[2-(3-pyridyl)ethynyl]cyclopentene-1-

carboxylate 3g (302 mg, 75%) from methyl 2-

(triﬂuoromethylsulfonyloxy)cyclopentene-1-carboxylate (500

mg, 1.82 mmol) and 3-ethynylpyridine as described in step

1

described in step 4: white amorphous solid. H NMR (400

MHz, CDCl₃): δ 11.22 (s, 1H), 6.05 (s, 1H), 2.94 (p, J = 8.4

Hz, 1H), 2.88−2.70 (m, 4H), 2.14−1.97 (m, 4H), 1.84−1.56

(m, 6H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 162.8, 157.3,

151.2, 128.8, 101.2, 43.3, 34.4, 32.3, 29.3, 25.3, 23.5. HRMS

(ESI) m/z: [M + H]⁺calcd for C₁₃H₁₈NO, 204.1383; found,

204.139.

1

1: white amorphous solid. H NMR (400 MHz, CDCl₃): δ

8.83−8.68 (m, 1H), 8.63−8.49 (m, 1H), 7.87−7.72 (m, 1H),

7.34−7.18 (m, 1H), 3.81 (s, 3H), 2.77 (t, J = 7.9 Hz, 4H),

2.10−1.87 (m, 2H).

3-Propyl-2,5,6,7-tetrahydrocyclopenta[c]pyridin-1-one

(5i). Methyl 2-pent-1-ynylcyclopentene-1-carboxylate (600 mg,

8 5 % y i e l d ) w a s o b t a i n e d f r o m m e t h y l 2 -

(triﬂuoromethylsulfonyloxy)cyclopentene-1-carboxylate (1.00

g, 3.65 mmol) and 1-pentyne as described in step 1: colorless

2-[2-(3-Pyridyl)ethynyl]cyclopentene-1-carboxylic aid (224

mg, 79% yield) was obtained from methyl 2-[2-(3-pyridyl)-

ethynyl]cyclopentene-1-carboxylate (300 mg, 1.33 mmol) as

1

described in step 2: white amorphous solid. H NMR (400

MHz, DMSO-d₆): δ 12.57 (s, 1H), 8.63 (s, 1H), 8.58 (d, J =

4.7 Hz, 1H), 7.92−7.80 (m, 1H), 7.56−7.36 (m, 1H), 2.79−

2.59 (m, 4H), 2.05−1.79 (m, 2H).

1

oil. H NMR (400 MHz, CDCl₃): δ 3.76 (s, 3H), 2.73−2.56

(m, 4H), 2.42 (t, J = 7.0 Hz, 2H), 1.96−1.84 (m, 2H), 1.69−

1.56 (m, 2H), 1.04 (t, J = 7.4 Hz, 3H).

2-[2-(3-Pyridyl)ethynyl]cyclopentene-1-carboxamide 3g (80

mg, 67% yield) was obtained from 2-[2-(3-pyridyl)ethynyl]-

cyclopentene-1-carboxylic acid (120 mg, 0.56 mmol) and

ammonium chloride as described in step 3: white amorphous

solid. ¹H NMR (400 MHz, CDCl₃): δ 8.71 (s, 1H), 8.60 (d, J

= 5.0 Hz, 1H), 7.76 (dd, J = 7.8, 1.9 Hz, 1H), 7.35−7.29 (m,

1H), 6.89 (s, 1H), 5.57 (s, 1H), 2.94−2.74 (m, 4H), 2.10−

1.89 (m, 2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 165.9,

152.1, 149.6, 143.6, 138.4, 127.2, 123.2, 119.2, 96.4, 88.1, 39.4,

33.9, 21.9. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₃H₁₃N₂O,

213.1022; found, 213.1027.

2-Pent-1-ynylcyclopentene-1-carboxylic acid (510 mg, 91%

yield) was obtained from methyl 2-pent-1-ynylcyclopentene-1-

carboxylate (600 mg, 3.12 mmol) as described in step 2: oﬀ-

1

white solid. H NMR (400 MHz, CDCl₃): δ 2.74−2.63 (m,

4H), 2.49−2.39 (m, 2H), 1.99−1.88 (m, 2H), 1.67−1.56 (m,

2H), 1.03 (t, J = 7.4 Hz, 3H).

2-Pent-1-ynylcyclopentene-1-carboxamide 3i (270 mg, 54%

yield) was obtained from 2-pent-1-ynylcyclopentene-1-carbox-

ylic acid (500 mg, 2.8 mmol) and ammonium chloride as

1

described in step 3: oﬀ-white solid. H NMR (400 MHz,

CDCl₃): δ 7.22 (s, 1H), 6.07 (s, 1H), 2.80−2.72 (m, 2H),

2.71−2.60 (m, 2H), 2.52−2.34 (m, 2H), 1.97−1.77 (m, 2H),

1.70−1.54 (m, 2H), 1.11−0.94 (m, 3H). ¹³C{¹H} NMR (101

MHz, CDCl₃): δ 166.7, 140.7, 128.9, 102.7, 77.3, 39.8, 33.3,

21.9, 21.8, 21.6, 13.5. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₁H₁₆NO, 178.1226; found, 178.1223.

The title compound 5i (40 mg, 80% yield) was obtained

from 2-pent-1-ynylcyclopentene-1-carboxamide (50 mg, 0.22

mmol) by heating at 160 °C for 2 h as described in step 4:

white amorphous solid. ¹H NMR (400 MHz, CDCl₃): δ 11.63

(s, 1H), 6.01 (s, 1H), 2.90−2.71 (m, 4H), 2.53 (t, J = 7.6 Hz,

2H), 2.05 (p, J = 7.5 Hz, 2H), 1.68 (h, J = 7.4 Hz, 2H), 0.96 (t,

J = 7.3 Hz, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 163.1,

157.4, 147.6, 128.7, 103.2, 35.0, 34.3, 29.3, 23.5, 22.0, 13.5.

The title compound 5g (20 mg, 40% yield) was obtained

from 2-[2-(3-pyridyl)ethynyl]cyclopentene-1-carboxamide (50

mg, 0.23 mmol) by heating at 160 °C for 2 h as described in

1

step 4: white amorphous solid. H NMR (400 MHz, CDCl₃):

δ 11.32 (s, 1H), 8.91 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 4.8 Hz,

1H), 8.13−7.98 (m, 1H), 7.55−7.36 (m, 1H), 6.51 (s, 1H),

3.06−2.79 (m, 4H), 2.27−1.92 (m, 2H). ¹³C{¹H} NMR (101

MHz, CDCl₃): δ 162.7, 157.2, 150.5, 147.7, 141.9, 133.8,

132.00, 130.0, 123.7, 103.9, 34.4, 29.5, 23.5. HRMS (ESI) m/

z: [M + H]⁺calcd for C₁₃H₁₃N₂O, 213.1022; found, 213.1028.

3-Cyclopentyl-2,5,6,7-tetrahydrocyclopenta[c]pyridin-1-

one (5h). Methyl 2-(2-cyclopentylethynyl)cyclopentene-1-

carboxylate (375 mg, 93% yield) was obtained from methyl

2-(triﬂuoromethylsulfonyloxy)cyclopentene-1-carboxylate

G

https://doi.org/10.1021/acs.joc.1c00688

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Note

HRMS (ESI) m/z: [M + H]⁺calcd for C₁₁H₁₆NO, 178.1226;

found, 178.1232.

142.9, 137.0, 128.6, 128.1, 128.0, 127.3, 96.7, 82.4, 72.1, 57.8,

39.4, 33.6, 21.7. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₆H₁₈NO₂, 256.1332; found, 256.1339.

3-(Phenoxymethyl)-2,5,6,7-tetrahydrocyclopenta[c]-

pyridin-1-one (5j). Methyl 2-(3-phenoxyprop-1-ynyl)-

cyclopentene-1-carboxylate (300 mg, 64% yield) was obtained

from methyl 2-(triﬂuoromethylsulfonyloxy)cyclopentene-1-

carboxylate (500 mg, 1.82 mmol) and (prop-2-yn-1-yloxy)-

The title compound 5k (42 mg, 84% yield) was obtained

from 2-(3-benzyloxyprop-1-ynyl)cyclopentene-1-carboxamide

(50 mg, 0.19 mmol) by heating at 160 °C for 2 h as described

in step 4: white amorphous solid. ¹H NMR (400 MHz,

CDCl₃): δ 9.80 (s, 1H), 7.41−7.29 (m, 5H), 6.08 (s, 1H), 4.58

(d, J = 1.5 Hz, 2H), 4.39 (s, 2H), 2.91−2.67 (m, 4H), 2.07 (p,

J = 7.6 Hz, 2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 161.8,

156.6, 142.1, 136.9, 131.5, 128.6, 128.2, 128.0, 102.5, 72.9,

67.7, 34.3, 29.5, 23.4. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₆H₁₈NO₂, 256.1332; observed, 256.1340.

3 - [ ( D i m e t h y l a m i n o ) m e t h y l ] - 2 , 5 , 6 , 7 -

tetrahydrocyclopenta[c]pyridin-1-one (5l). Methyl 2-[3-

(dimethylamino)prop-1-ynyl]cyclopentene-1-carboxylate (235

mg, 59% yield) was obtained from methyl 2-

(triﬂuoromethylsulfonyloxy)cyclopentene-1-carboxylate (500

mg, 1.82 mmol) and N,N-dimethylprop-2-yn-1-amine as

described in step 1: brown oil. ¹H NMR (400 MHz,

CDCl₃): δ 3.76 (s, 3H), 3.51 (s, 2H), 2.73−2.61 (m, 4H),

2.35 (s, 6H), 1.96−1.85 (m, 2H).

1

benzene as described in step 1: colorless oil. H NMR (400

MHz, CDCl₃): δ 7.39−7.21 (m, 2H), 7.04−6.95 (m, 3H),

5.00−4.85 (m, 2H), 3.65 (s, 3H), 2.79−2.54 (m, 4H), 1.91 (tt,

J = 8.2, 7.2 Hz, 2H).

2-(3-Phenoxyprop-1-ynyl)cyclopentene-1-carboxylic acid

(235 mg, 82% yield) was obtained from methyl 2-(3-

phenoxyprop-1-ynyl)cyclopentene-1-carboxylate (300 mg,

1.17 mmol) as described in step 2: white amorphous solid.

¹H NMR (400 MHz, CDCl₃): δ 7.35−7.28 (m, 2H), 7.04−

6.96 (m, 3H), 4.91 (s, 2H), 2.76−2.64 (m, 4H), 1.94 (p, J =

7.6 Hz, 2H).

2-(3-Phenoxyprop-1-ynyl)cyclopentene-1-carboxamide 3j

(60 mg, 52% yield) was obtained from 2-(3-phenoxyprop-1-

ynyl)cyclopentene-1-carboxylic acid (115 mg, 0.47 mmol) and

ammonium chloride as described in step 3: white amorphous

1

solid. H NMR (400 MHz, CDCl₃): δ 7.44−7.22 (m, 2H),

Methyl 2-(3-(dimethylamino)prop-1-yn-1-yl)cyclopent-1-

ene-1-carboxylate (235 mg, 1.13 mmol) was converted to 2-

(3-(dimethylamino)prop-1-yn-1-yl)cyclopent-1-ene-1-carbox-

ylic acid as described in step 2. The acid could not be extracted

out of the aqueous layer. The aqueous layer was concentrated

and coevaporated with toluene two times and used as is in the

next step.

7.13−6.86 (m, 3H), 6.63 (s, 1H), 5.49 (s, 1H), 4.94 (d, J = 0.9

Hz, 2H), 2.77−2.71 (m, 2H), 2.70−2.64 (m, 2H), 1.88 (tt, J =

8.1, 7.2 Hz, 2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 165.8,

157.2, 143.5, 129.6, 126.6, 122.0, 115.1, 95.3, 83.2, 56.3, 39.2,

33.7, 21.7. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₅H₁₆NO₂,

242.1176; found, 242.1183.

The title compound 5j (40 mg, 80% yield) was obtained

from 2-(3-phenoxyprop-1-ynyl)cyclopentene-1-carboxamide

(50 mg, 0.21 mmol) by heating at 160 °C for 2 h as described

in step 4: white amorphous solid. ¹H NMR (400 MHz,

CDCl₃): δ 10.68 (s, 1H), 7.35−7.28 (m, 2H), 7.04−6.93 (m,

3H), 6.34−6.21 (m, 1H), 4.95 (s, 2H), 2.95−2.73 (m, 4H),

2.19−1.97 (m, 2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ

162.1, 157.7, 156.8, 141.3, 131.7, 129.7, 121.9, 114.9, 102.8,

66.0, 34.4, 29.5, 23.4. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₅H₁₆NO₂, 242.1176; found, 242.1183.

3-((Benzyloxy)methyl)-2,5,6,7-tetrahydro-1H-cyclopenta-

[c]pyridin-1-one (5k). Methyl 2-(3-benzyloxyprop-1-ynyl)-

cyclopentene-1-carboxylate (390 mg, 79% yield) was obtained

from methyl 2-(triﬂuoromethylsulfonyloxy)cyclopentene-1-

carboxylate (500 mg, 1.82 mmol) and ((prop-2-yn-1-yloxy)-

methyl)benzene as described in step 1: colorless oil. ¹H NMR

(400 MHz, CDCl₃): δ 7.42−7.27 (m, 5H), 4.68 (s, 2H), 4.41

(s, 2H), 3.75 (s, 3H), 2.78−2.60 (m, 4H), 1.94 (tt, J = 8.1, 7.2

Hz, 2H).

2-[3-(Dimethylamino)prop-1-ynyl]cyclopentene-1-carboxa-

mide 3l (40 mg, 20% yield) was obtained from crude 2-[3-

(dimethylamino)prop-1-ynyl]cyclopentene-1-carboxylic acid

(200 mg, 1.03 mmol) and ammonium chloride as described

in step 3: oﬀ-white solid. ¹H NMR (400 MHz, CDCl₃): δ 3.49

(s, 2H), 2.84−2.65 (m, 4H), 2.32 (s, 6H), 1.95−1.86 (m, 2H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ 166.3, 141.9, 127.9,

96.4, 81.6, 48.5, 44.2, 39.7, 33.5. HRMS (ESI) m/z: [M + H]⁺

calcd for C₁₁H₁₇N₂O, 193.1335; found, 193.1333.

The title compound 5l (12 mg, 52% yield) was obtained

from 2-[3-(dimethylamino)prop-1-ynyl]cyclopentene-1-car-

boxamide (23 mg, 0.12 mmol) by heating at 160 °C for 2 h

1

as described in step 4: white amorphous solid. H NMR (400

MHz, CDCl₃): δ 9.48 (s, 1H), 5.99 (s, 1H), 3.28 (s, 2H),

2.90−2.74 (m, 4H), 2.25 (s, 6H), 2.07 (p, J = 7.7 Hz, 2H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ 161.5, 156.6, 143.2,

131.0, 102.6, 60.1, 45.2, 34.2, 29.4, 23.5. HRMS (ESI) m/z:

[M + H]⁺calcd for C₁₁H₁₇N₂O, 193.1335; found, 193.1342.

3-(Hydroxymethyl)-2,5,6,7-tetrahydro-1H-cyclopenta[c]-

pyridin-1-one (5m). Methyl 2-(3-hydroxyprop-1-yn-1-yl)-

cyclopent-1-ene-1-carboxylate (220 mg, 67% yield) was

obtained from methyl 2-(triﬂuoromethylsulfonyloxy)-

cyclopentene-1-carboxylate (500 mg, 1.82 mmol) and

2-(3-Benzyloxyprop-1-ynyl)cyclopentene-1-carboxylic acid

(340 mg, 92% yield) was obtained from methyl 2-(3-

benzyloxyprop-1-ynyl)cyclopentene-1-carboxylate (390 mg,

1.44 mmol) as described in step 2: oﬀ-white amorphous

solid. ¹H NMR (400 MHz, CDCl₃): δ 8.56 (s, 1H), 7.39−7.30

(m, 5H), 4.64 (s, 2H), 4.35 (d, J = 0.9 Hz, 2H), 2.85−2.58 (m,

4H), 2.07−1.82 (m, 2H).

1

propargyl alcohol as described in step 1: oﬀ-white gum. H

NMR (400 MHz, CDCl₃): δ 4.50 (d, J = 5.0 Hz, 2H), 3.76 (s,

3H), 2.74−2.59 (m, 4H), 2.45 (t, J = 6.1 Hz, 1H), 2.00−1.87

(m, 2H).

2-(3-Hydroxyprop-1-ynyl)cyclopentene-1-carboxylic acid

(130 mg, 54% yield) was obtained from methyl 2-(3-

hydroxyprop-1-ynyl)cyclopentene-1-carboxylate (220 mg,

1.22 mmol) as described in step 2: oﬀ-white amorphous

solid. ¹H NMR (400 MHz, CDCl₃): δ 4.50 (s, 2H), 2.76−2.63

(m, 4H), 2.01−1.85 (m, 2H).

2-(3-Benzyloxyprop-1-ynyl)cyclopentene-1-carboxamide 3k

(270 mg, 80% yield) was obtained from 2-(3-benzyloxyprop-1-

ynyl)cyclopentene-1-carboxylic acid (340 mg, 1.33 mmol) and

ammonium chloride as described in step 3: white amorphous

1

solid. H NMR (400 MHz, CDCl₃): δ 7.44−7.28 (m, 5H),

6.96 (s, 1H), 5.57 (s, 1H), 4.62 (d, J = 1.4 Hz, 2H), 4.39 (s,

2H), 2.78 (t, J = 7.8 Hz, 2H), 2.74−2.67 (m, 2H), 1.92 (p, J =

7.7 Hz, 2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 165.9,

H

https://doi.org/10.1021/acs.joc.1c00688

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Note

2-(3-Hydroxyprop-1-yn-1-yl)cyclopent-1-ene-1-carboxamide

3m (75 mg, 58% yield) was obtained from 2-(3-hydroxyprop-

1-yn-1-yl)cyclopent-1-ene-1-carboxylic acid (130 mg, 0.78

mmol) and ammonium chloride as described in step 3:

(101 MHz, CDCl₃): δ 161.8, 157.8, 153.3, 141.5, 132.4, 129.7,

121.9, 114.8, 106.3, 67.7, 34.1, 30.6, 30.4, 23.4. HRMS (ESI)

m/z: [M + H]⁺calcd for C₁₆H₁₈NO₂, 256.1332; found,

256.1341.

1

white amorphous solid. H NMR (400 MHz, DMSO-d₆): δ

3-(Benzyloxymethyl)-2-[(4-methoxyphenyl)methyl]-6,7-

dihydro-5H-cyclopenta[c]pyridin-1-one (5p). 2-(3-

(Benzyloxy)prop-1-yn-1-yl)-N-(4-methoxybenzyl)cyclopent-1-

ene-1-carboxamide 3p (170 mg, 77% yield) was obtained from

2-(3-(benzyloxy)prop-1-yn-1-yl)cyclopent-1-ene-1-carboxylic

acid (150 mg, 0.58 mmol) and 4-methoxybenzylamine as step

7.31 (s, 1H), 7.02 (s, 1H), 5.34 (t, J = 6.0 Hz, 1H), 4.40−4.15

(m, 2H), 2.64−2.54 (m, 4H), 1.90−1.70 (m, 2H). ¹³C{¹H}

NMR (101 MHz, DMSO-d₆): δ 165.9, 143.0, 126.1, 99.8, 80.4,

50.1, 39.0, 34.0, 21.9. HRMS (ESI) m/z: [M + H]⁺calcd for

C₉H₁₂NO₂, 166.0863; found, 166.0861.

1

The title compound 5m (40 mg, 66% yield) was obtained

from 2-(3-hydroxyprop-1-yn-1-yl)cyclopent-1-ene-1-carboxa-

mide by heating (60 mg, 0.36 mmol) at 150 °C for 1 h as

3: white amorphous solid. H NMR (400 MHz, CDCl₃): δ

7.37−7.26 (m, 5H), 7.24−7.19 (m, 2H), 6.83−6.77 (m, 2H),

4.54−4.40 (m, 4H), 4.19 (d, J = 0.8 Hz, 2H), 3.74 (s, 3H),

2.87−2.74 (m, 2H), 2.73−2.61 (m, 2H), 2.00−1.84 (m, 2H).

¹³C{¹H} (101 MHz, CDCl₃): δ 164.0, 159.0, 143.8, 137.1,

130.3, 129.3, 128.5, 128.0, 128.0, 125.3, 114.1, 95.9, 82.5, 71.9,

57.7, 55.3, 43.1, 39.1, 33.8, 21.8. HRMS (ESI) m/z: [M + H]⁺

calcd for C₂₄H₂₆NO₃, 376.1906; found, 376.1901.

1

described in step 4: white amorphous solid. H NMR (400

MHz, DMSO-d₆): δ 11.04 (s, 1H), 6.13 (s, 1H), 5.32 (s, 1H),

4.26 (s, 2H), 2.78−2.70 (m, 2H), 2.58 (t, J = 7.5 Hz, 2H),

2.04−1.85 (m, 2H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆): δ

161.3, 155.8, 148.1, 129.2, 100.4, 59.9, 34.2, 29.7, 23.3. HRMS

(ESI) m/z: [M + H]⁺calcd for C₉H₁₂NO, 166.0863; found,

166.0862.

2-((Triisopropylsilyl)ethynyl)cyclopent-1-ene-1-carboxa-

mide (3n). Methyl 2-((triisopropylsilyl)ethynyl)cyclopent-1-

ene-1-carboxylate (553 mg, 90% yield) was obtained from

methyl 2-(triﬂuoromethylsulfonyloxy)cyclopentene-1-carboxy-

late (500 mg, 2 mmol) and ethynyltriisopropylsilane as

described in step 1: red liquid. ¹H NMR (400 MHz,

CDCl₃): δ 3.76 (s, 3H), 1.91 (tt, J = 8.1, 7.2 Hz, 2H), 1.11

(s, 21H).

The title compound 5p (23 mg, 46% yield) was obtained

from 2-(3-benzyloxyprop-1-ynyl)-N-[(4-methoxyphenyl)-

methyl]cyclopentene-1-carboxamide (50 mg, 0.13 mmol) by

heating at 160 °C for 2 h as described in step 4: white

1

amorphous solid. H NMR (400 MHz, CDCl₃): δ 7.39−7.28

(m, 5H), 7.08−6.94 (m, 2H), 6.88−6.70 (m, 2H), 6.22 (s,

1H), 5.37 (s, 2H), 4.51 (s, 2H), 4.29 (s, 2H), 3.76 (s, 3H),

2.97−2.74 (m, 4H), 2.20−2.02 (m, 2H). ¹³C{¹H} NMR (101

MHz, CDCl₃): δ 161.8, 158.7, 153.7, 142.9, 137.2, 132.3,

129.5, 128.6, 128.1, 128.0, 128.0, 114.0, 106.7, 72.4, 69.0, 55.3,

45.5, 34.2, 30.5, 23.4. HRMS (ESI) m/z: [M + H]⁺calcd for

C₂₄H₂₆NO₃, 376.1906; found, 376.1904.

2-((Triisopropylsilyl)ethynyl)cyclopent-1-ene-1-carboxylic

acid (450 mg, 86% yield) was obtained from methyl 2-

((triisopropylsilyl)ethynyl)cyclopent-1-ene-1-carboxylate (550

mg, 1.80 mmol) as described in step 2: pale yellow amorphous

2,3-Diphenyl-2,5,6,7-tetrahydro-1H-cyclopenta[c]pyridin-

1-one (5q). N-Phenyl-2-(phenylethynyl)cyclopent-1-ene-1-

carboxamide⁷(3q) (400 mg, 82% yield) was obtained from

2-(phenylethynyl)cyclopent-1-ene-1-carboxylic acid (360 mg,

1.7 mmol) and aniline as described in step 3: white amorphous

solid. ¹H NMR (400 MHz, CDCl₃): δ 9.15 (s, 1H), 7.61−7.56

(m, 2H), 7.54−7.49 (m, 2H), 7.44−7.36 (m, 3H), 7.35−7.28

(m, 2H), 7.12−7.06 (m, 1H), 3.06−2.74 (m, 4H), 1.98 (tt, J =

8.1, 7.2 Hz, 2H). ¹³C{H} NMR (101 MHz, CDCl₃): δ 162.2,

143.7, 138.1, 131.6, 129.6, 129.1, 128.8, 126.5, 124.1, 121.6,

119.5, 101.1, 84.9, 39.6, 33.9, 21.8. HRMS (ESI) m/z: [M +

H]⁺calcd for C₂₀H₁₈NO, 288.1382; found, 288.1382.

1

solid. H NMR (400 MHz, CDCl₃): δ 2.83−2.67 (m, 4H),

1.96 (p, J = 7.7 Hz, 2H), 1.19−1.07 (m, 21H).

The title compound 3n (107 mg, 82% yield) was obtained

from 2-((triisopropylsilyl)ethynyl)cyclopent-1-ene-1-carbox-

ylic acid (130 mg, 0.44 mmol) and ammonium chloride as

1

described in step 3: white amorphous solid. H NMR (400

MHz, CDCl₃): δ 7.34 (s, 1H), 5.64 (s, 1H), 2.86−2.65 (m,

4H), 1.90 (p, J = 7.8 Hz, 2H), 1.23−1.00 (m, 21H). ¹³C{¹H}

NMR (101 MHz, CDCl₃): δ 166.1, 143.2, 128.1, 104.2, 102.8,

39.6, 33.5, 21.7, 18.6, 11.1. HRMS (ESI) m/z: [M + H]⁺calcd

for C₁₇H₃₀NOSi, 292.2091; found, 292.2087.

The title compound (1 mg, 12% yield) was obtained from

N-phenyl-2-(phenylethynyl)cyclopent-1-ene-1-carboxamide (8

mg, 0.03 mmol) as described in step 4: tan ﬁlm. ¹H NMR (400

MHz, CDCl₃): δ 7.26−7.09 (m, 6H), 7.09−7.03 (m, 4H), 6.26

(s, 1H), 3.00−2.85 (m, 4H), 2.23−2.08 (m, 2H). ¹³C NMR

(101 MHz, CDCl₃): δ 161.4, 154.6, 148.0, 139.0, 136.3, 131.5,

129.3, 129.1, 128.5, 128.0, 127.8, 127.6, 106.4, 34.5, 30.4,

23.4.HRMS (ESI) m/z: [M + H]⁺calcd for C₂₀H₁₇NO,

288.1383; found, 288.1378.

2-Methyl-3-(phenoxymethyl)-6,7-dihydro-5H-cyclopenta-

[c]pyridin-1-one (5o). N-Methyl-2-(3-phenoxyprop-1-yn-1-

yl)cyclopent-1-ene-1-carboxamide 3o (88 mg, 68% yield)

was obtained from 2-(3-phenoxyprop-1-yn-1-yl)cyclopent-1-

ene-1-carboxylic acid (130 mg, 0.44 mmol) and methylamine

hydrochloride as described in step 3: white amorphous solid.

¹H NMR (400 MHz, CDCl₃): δ 7.38−7.29 (m, 2H), 7.06−

6.91 (m, 3H), 6.69 (s, 1H), 4.92 (s, 2H), 2.80−2.70 (m, 2H),

2.68−2.62 (m, 2H), 2.57 (d, J = 4.9 Hz, 3H), 1.91−1.82 (m,

2H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 164.6, 157.2,

144.4, 129.7, 124.2, 121.8, 114.7, 94.2, 83.4, 56.1, 38.9, 33.9,

25.8, 21.7. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₆H₁₈NO₂,

256.1332; found, 256.1340.

3,5-Dihydro-1H-furo[3,4-c]pyridin-4-one (9a). Methyl 4-

(2-trimethylsilylethynyl)-2,5-dihydrofuran-3-carboxylate (550

mg, 85% yield) was obtained from methyl 4-(triﬂuoromethyl-

sulfonyloxy)-2,5-dihydrofuran-3-carboxylate and (795 mg, 2.88

mmol) ethynyltrimethylsilane as described in step 1: colorless

The title compound 5o (15 mg, 75% yield) was obtained

from N-methyl-2-(3-phenoxyprop-1-yn-1-yl)cyclopent-1-ene-

1-carboxamide (20 mg, 0.08 mmol) by heating at 160 °C for

1

oil. H NMR (400 MHz, CDCl₃): δ 4.98−4.85 (m, 2H),

4.80−4.66 (m, 2H), 3.79 (s, 3H), 0.33−0.16 (m, 9H).

4-Ethynyl-2,5-dihydrofuran-3-carboxylic acid (162 mg, 82%

yield) was obtained from methyl 4-ethynyl-2,5-dihydrofuran-3-

carboxylate (350 mg,1.43 mmol) as described in step 2: oﬀ-

white amorphous solid. ¹H NMR (400 MHz, CDCl₃): δ 4.97−

1

2 h as described in step 4: white amorphous solid. H NMR

(400 MHz, CDCl₃): δ 7.37−7.30 (m, 2H), 7.07−6.99 (m,

1H), 6.99−6.95 (m, 2H), 6.31 (s, 1H), 4.89 (s, 2H), 3.60 (s,

3H), 2.96−2.75 (m, 4H), 2.19−1.99 (m, 2H). ¹³C{¹H} NMR

I

https://doi.org/10.1021/acs.joc.1c00688

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Note

4.90 (m, 2H), 4.82 (dd, J = 6.1, 4.2 Hz, 2H), 3.74 (t, J = 0.8

Hz, 1H).

The title compound 9c (40 mg, 80% yield) was obtained

from 4-(pent-1-yn-1-yl)-2,5-dihydrofuran-3-carboxamide (50

mg, 0.28 mmol) by heating at 150 °C for 1.5 h as described in

step 3: oﬀ-white amorphous solid. ¹H NMR (400 MHz,

CDCl₃): δ 12.69 (s, 1H), 6.03 (s, 1H), 5.17−4.85 (m, 5H),

2.59 (t, J = 7.6 Hz, 2H), 1.74−1.56 (m, 2H), 0.98 (t, J = 7.4

Hz, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 161.0, 152.7,

150.4, 124.0, 99.2, 74.6, 72.7, 35.0, 22.0, 13.5. HRMS (ESI) m/

z: [M + H]⁺calcd for C₁₀H₁₄NO₂, 180.1019; observed,

180.1015.

5-(2,4-Dimethoxybenzyl)-6-(methoxymethyl)-3,5-

dihydrofuro[3,4-c]pyridin-4(1H)-one (9d). Methyl 4-(3-me-

thoxyprop-1-ynyl)-2,5-dihydrofuran-3-carboxylate (156 mg,

44% yield) was obtained from 4-(triﬂuoromethylsulfony-

loxy)-2,5-dihydrofuran-3-carboxylate (500 mg, 1.8 mmol)

and 3-methoxyprop-1-yne as described in step 1: brown oil.

¹H NMR (400 MHz, CDCl₃): δ 4.94−4.86 (m, 2H), 4.80−

4.72 (m, 2H) 4.34 (d, J = 0.9 Hz, 2H), 3.79 (s, 3H), 3.45 (s,

3H).

4-Ethynyl-2,5-dihydrofuran-3-carboxamide 6a (60 mg, 60%

yield) was obtained from 4-ethynyl-2,5-dihydrofuran-3-carbox-

ylic acid (100 mg, 0.72 mmol) and ammonium chloride as

1

described in step 3: white amorphous solid. H NMR (400

MHz, DMSO-d₆): δ 7.55 (s, 1H), 7.15 (s, 1H), 4.80 (s, 1H),

4.79−4.77 (m, 2H), 4.69−4.63 (m, 2H). ¹³C{¹H} NMR (101

MHz, DMSO-d₆): δ 162.9, 140.2, 122.5, 92.8, 78.1, 76.0, 75.4.

HRMS (ESI) m/z: [M + H]⁺calcd for C₇H₈NO₂, 138.0550;

found, 138.0549.

The title compound 9a (27 mg, 91% yield) was obtained

from 4-ethynyl-2,5-dihydrofuran-3-carboxamide (30 mg, 0.22

mmol) by heating at 100 °C for 0.5 h as described in step 4:

oﬀ-white amorphous solid. ¹H NMR (400 MHz, DMSO-d₆): δ

4.84−4.76 (m, 3H), 4.71−4.62 (m, 2H). ¹³C{¹H} NMR (101

MHz, DMSO-d₆): δ 162.9, 162.9, 140.1, 122.6, 122.5, 92.8,

78.1, 76.0, 75.4. HRMS (ESI) m/z: [M + H]⁺calcd for

C₇H₈NO₂, 138.0550; found, 138.0549.

5-Methyl-3,5-dihydrofuro[3,4-c]pyridin-4(1H)-one (9b). 4-

Ethynyl-N-methyl-2,5-dihydrofuran-3-carboxamide 6b (42 mg,

76% yield) was obtained from 4-ethynyl-2,5-dihydrofuran-3-

carboxylic acid (50 mg, 0.36 mmol) and methylamine

hydrochloride as described in step 3: oﬀ-white amorphous

solid. ¹H NMR (400 MHz, CDCl₃): δ 6.90 (s, 1H), 5.06−4.95

(m, 2H), 4.89−4.74 (m, 2H), 3.70 (s, 1H), 2.93 (d, J = 5.0 Hz,

3H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 161.8, 140.7,

120.6, 90.0, 78.8, 76.8, 75.1, 26.1. HRMS (ESI) m/z: [M +

H]⁺calcd for C₈H₁₀NO₂, 152.0706; found, 152.0703.

The title compound 9b (28 mg, 90% yield) was obtained

from 4-ethynyl-N-methyl-2,5-dihydrofuran-3-carboxamide (30

mg, 0.20 mmol) by heating at 150 °C for 1 h as described in

step 4: oﬀ-white amorphous solid. ¹H NMR (400 MHz,

CDCl₃): δ 7.35−7.20 (m, 1H), 6.15 (d, J = 6.8 Hz, 1H), 5.10−

4.86 (m, 4H), 3.58 (s, 3H). ¹³C{¹H} NMR (101 MHz,

CDCl₃): δ 158.7, 150.0, 145.7, 138.5, 127.6, 100.1, 90.3, 74.6,

73.2, 37.0. HRMS (ESI) m/z: [M + H]⁺calcd for C₈H₁₀NO₂,

152.0706; found, 152.0706.

4-(3-Methoxyprop-1-ynyl)-2,5-dihydrofuran-3-carboxylic

acid (120 mg, 92% yield) was obtained from methyl 4-(3-

methoxyprop-1-ynyl)-2,5-dihydrofuran-3-carboxylate (140 mg,

0.71 mmol) as described in step 2: oﬀ-white amorphous solid.

¹H NMR (400 MHz, CDCl₃): δ 4 4.96−4.90 (m,2H), 4.82−

4.78 (m, 2H), 4.35 (d, J = 0.9 Hz, 2H), 3.44 (s, 3H).

N-(2,4-Dimethoxybenzyl)-4-(3-methoxyprop-1-yn-1-yl)-2,5-

dihydrofuran-3-carboxamide 6d (120 mg, 36% yield) was

obtained from 2-(3-methoxyprop-1-yn-1-yl)cyclopent-1-ene-1-

carboxylic acid (120 mg, 0.86 mmol) and 2,4-dimethox-

ybenzylamine as described in step 3: oﬀ-white amorphous

solid. ¹H NMR (400 MHz, CDCl₃): δ 7.17 (s, 1H), 6.93−6.75

(m, 3H), 5.07−4.97 (m, 2H), 4.85−4.75 (m, 2H), 4.47 (d, J =

5.5 Hz, 2H), 4.13 (d, J = 0.8 Hz, 2H), 3.88 (s, 3H), 3.87 (s,

3H), 3.24 (s, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ

161.1, 149.2, 148.6, 139.0, 130.3, 121.6, 120.2, 111.3, 111.3,

98.7, 78.7, 77.5, 76.7, 60.0, 57.9, 56.0, 55.9, 43.4. HRMS (ESI)

m/z: [M + H]⁺calcd for C₁₈H₂₂NO₅, 332.1492; found,

332.1487.

The title compound 9d (15 mg, 23% yield) was obtained

from N-(2,4-dimethoxybenzyl)-4-(3-methoxyprop-1-yn-1-yl)-

2,5-dihydrofuran-3-carboxamide (65 mg, 0.20 mmol) by

heating at 150 °C for 1.5 h as described in step 4: tan

amorphous solid. ¹H NMR (400 MHz, CDCl₃): δ 6.81 (d, J =

2.1 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 6.68−6.61 (m, 1H),

6.24 (s, 1H), 5.38 (s, 2H), 5.10 (t, J = 3.5 Hz, 2H), 5.05 (dd, J

= 4.3, 2.9 Hz, 2H), 4.28 (s, 2H), 3.84 (d, J = 1.0 Hz, 6H), 3.38

(s, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 159.2, 149.3,

149.2, 149.2, 148.4, 145.3, 129.3, 127.3, 118.7, 111.3, 110.3,

101.8, 74.7, 73.5, 71.2, 58.3, 56.0, 55.9, 45.7. HRMS (ESI) m/

z: [M + H]⁺calcd for C₁₈H₂₂NO₅, 332.1492; found, 332.1491.

3,5-Dihydrothieno[3,4-c]pyridin-4(1H)-one (10a). Methyl

4-((trimethylsilyl)ethynyl)-2,5-dihydrothiophene-3-carboxy-

late (650 mg, 79% yield) was obtained from methyl 4-

(((triﬂuoromethyl)sulfonyl)oxy)-2,5-dihydrothiophene-3-car-

boxylate (1.00 g, 3.42 mmol) and ethynyltrimethylsilane as

described in step 1: colorless oil. ¹H NMR (400 MHz,

CDCl₃): δ 3.90−3.81 (m, 2H), 3.81−3.70 (m, 2H), 3.61 (s,

3H), 0.06 (s, 9H).

6-Propyl-3,5-dihydrofuro[3,4-c]pyridin-4(1H)-one (9c).

Methyl 4-(pent-1-yn-1-yl)-2,5-dihydrofuran-3-carboxylate

(270 mg, 85% yield) was obtained from methyl 4-

(triﬂuoromethylsulfonyloxy)-2,5-dihydrofuran-3-carboxylate

(450 mg, 1.63 mmol) and 1-pentyne as described in step 1:

1

colorless oil. H NMR (400 MHz, CDCl₃): δ 4.95−4.84 (m,

2H), 4.76−4.61 (m, 2H), 3.78 (s, 3H), 2.50−2.37 (m, 2H),

1.71−1.52 (m, 2H), 1.04 (t, J = 7.4 Hz, 3H).

4-Pent-1-ynyl-2,5-dihydrofuran-3-carboxylic acid (210 mg,

87% yield) was obtained from methyl 4-pent-1-ynyl-2,5-

dihydrofuran-3-carboxylate (260 mg, 1.34 mmol) as described

1

in step 2: oﬀ-white amorphous solid. H NMR (400 MHz,

CDCl₃): δ 4.95−4.84 (m, 2H), 4.76−4.61 (m, 2H), 2.50−2.37

(m, 2H), 1.71−1.52 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H).

4-(Pent-1-yn-1-yl)-2,5-dihydrofuran-3-carboxamide 6c (110

mg, 73% yield) was obtained from 4-(pent-1-yn-1-yl)-2,5-

dihydrofuran-3-carboxylic acid (150 mg, 0.83 mmol) and

ammonium chloride as described in step 3: oﬀ-white

1

amorphous solid. H NMR (400 MHz, CDCl₃): δ 7.03 (s,

1H), 5.99 (s, 1H), 5.03−4.86 (m, 2H), 4.87−4.69 (m, 2H),

2.45 (t, J = 7.0 Hz, 2H), 1.63 (h, J = 7.3 Hz, 2H), 1.03 (t, J =

7.4 Hz, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 163.7,

136.0, 125.3, 105.7, 79.2, 76.4, 72.4, 21.8, 21.7, 13.5. HRMS

(ESI) m/z: [M + H]⁺calcd for C₁₀H₁₄NO₂, 180.1019;

observed, 180.1015.

4-Ethynyl-2,5-dihydrothiophene-3-carboxylic acid (160 mg,

92% yield) was obtained from methyl 4-ethynyl-2,5-dihydro-

thiophene-3-carboxylate (280 mg, 1.15 mmol) as described in

step 2: oﬀ-white amorphous solid. ¹H NMR (400 MHz,

J

https://doi.org/10.1021/acs.joc.1c00688

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Note

CDCl₃): δ 4.09−4.04 (m, 2H), 4.03−3.99 (m, 2H), 3.71 (s,

1H).

The title compound 10c (10 mg, 50% yield) was obtained

from 4-(phenylethynyl)-2,5-dihydrothiophene-3-carboxamide

(20 mg, 0.09 mmol) by heating at 150 °C for 1.5 h as

described in step 4: oﬀ-white amorphous solid. ¹H NMR (400

MHz, DMSO-d₆): δ 11.80 (s, 1H), 7.76−7.63 (m, 2H), 7.52−

7.39 (m, 3H), 6.56 (s, 1H), 4.24 (dd, J = 4.1, 2.5 Hz, 2H),

4.12−3.80 (m, 2H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆): δ

161.2, 152.7, 133.8, 130.1, 129.3, 127.3, 102.3, 39.5, 36.1.

HRMS (ESI) m/z: [M + H]⁺calcd for C₁₃H₁₂NOS, 230.0634;

found, 230.0630.

tert-Butyl 4-Oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-2-

carboxylate (11a). 1-(tert-Butyl) 3-ethyl 4-((trimethylsilyl)-

ethynyl)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate(4.55 g, 81%

yield) was obtained from 1-(tert-butyl) 3-ethyl 4-

(((triﬂuoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1,3-

dicarboxylate (6.45 g, 16.7 mmol) and ethynyltrimethylsilane

as described in step 1: brown oil. ¹H NMR (400 MHz,

CDCl₃): δ 4.47−4.19 (m, 6H), 1.48 (s, 9H), 1.37−1.26 (m, J

= 8.9, 7.1 Hz, 3H), 0.24 (s, 9H).

4-Ethynyl-2,5-dihydrothiophene-3-carboxamide 7a (90 mg,

60% yield) was obtained from 4-ethynyl-2,5-dihydrothiophene-

3-carboxyclic acid (150 mg, 0.97 mmol) as described in step 3:

oﬀ-white amorphous solid. ¹H NMR (400 MHz, DMSO-d₆): δ

7.51 (s, 1H), 7.39 (s, 1H), 4.63 (s, 1H), 3.99−3.93 (m, 2H),

3.92−3.86 (m, 2H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆): δ

165.1, 143.2, 123.1, 90.3, 78.3, 42.1, 39.2, HRMS (ESI) m/z:

[M + H]⁺calcd for C₇H₈NOS, 154.0321; found, 154.0319.

The title compound 10a (29 mg, 73% yield) was obtained

from 4-ethynyl-2,5-dihydrothiophene-3-carboxamide (40 mg,

0.28 mmol) by heating at 100 °C for 0.5 h as described in step

4: tan amorphous solid. ¹H NMR (400 MHz, CD₃OD): δ 7.32

(d, J = 6.7 Hz, 1H), 6.38 (d, J = 6.7 Hz, 1H), 4.28−4.16 (m,

2H), 4.10−4.02 (m, 2H). ¹³C{¹H} NMR (101 MHz,

CD₃OD): δ 161.7, 154.4, 133.3, 129.5, 104.7, 38.8, 35.0.

HRMS (ESI) m/z: [M + H]⁺calcd for C₇H₈NOS, 154.0321;

found, 154.0319.

5-Methyl-3,5-dihydrothieno[3,4-c]pyridin-4(1H)-one

(10b). 4-Ethynyl-N-methyl-2,5-dihydrothiophene-3-carboxa-

mide 7b (125 mg, 77% yield) was obtained from 4-ethynyl-

N-methyl-2,5-dihydrothiophene-3-carboxylic acid (150 mg,

0.97 mmol) and methylamine hydrochloride as described in

step 3: oﬀ-white amorphous solid. ¹H NMR (400 MHz,

CDCl₃): δ 7.03 (s, 1H), 4.19−4.09 (m, 2H), 4.00 (dd, J = 5.7,

3.8 Hz, 2H), 2.92 (d, J = 4.9 Hz, 3H). ¹³C{¹H} NMR (101

MHz, CDCl₃): δ 163.3, 143.3, 122.2, 88.6, 78.0, 43.0, 39.7,

26.3. HRMS (ESI) m/z: [M + H]⁺calcd for C₈H₁₀NOS,

168.0478; found, 168.0476.

The title compound 10b (42 mg, 83% yield) was obtained

from 4-ethynyl-N-methyl-2,5-dihydrothiophene-3-carboxamide

(50 mg, 0.3 mmol) by heating 150 °C for 1 h as described in

step 4: oﬀ-white amorphous solid. ¹H NMR (400 MHz,

CDCl₃): δ 7.26−7.15 (m, 1H), 6.11 (d, J = 6.9 Hz, 1H), 4.23−

4.07 (m, 4H), 3.55 (s, 3H). ¹³C{¹H} NMR (101 MHz,

CDCl₃): δ 160.5, 150.9, 137.1, 130.2, 103.3, 39.7, 37.0, 36.7.

HRMS (ESI) m/z: [M + H]⁺calcd for C₈H₁₀NOS, 168.0478;

found, 168.0475.

6-Phenyl-3,5-dihydrothieno[3,4-c]pyridin-4(1H)-one

(10c). Methyl 4-(phenylethynyl)-2,5-dihydrothiophene-3-car-

boxylate (250 mg, 85% yield) was obtained from methyl 4-

(((triﬂuoromethyl)sulfonyl)oxy)-2,5-dihydrothiophene-3-car-

boxylate (350 mg, 1.2 mmol) and phenylacetylene as described

in step 1: colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 7.57−

7.44 (m, 2H), 7.40−7.30 (m, 3H), 4.13−4.00 (m, 4H), 3.83

(s, 3H).

1-tert-Butoxycarbonyl-4-ethynyl-2,5-dihydropyrrole-3-car-

boxylic acid (3.00 g, 94% yield) was obtained from ethyl 1-tert-

butoxycarbonyl-4-ethynyl-2,5-dihydropyrrole-3-carboxylate

(4.50 g, 12.6 mmol) as described in step 2: pale yellow

amorphous solid. H NMR (400 MHz, CDCl₃): δ 4.50−4.30

(m, 4H), 3.81−3.61 (m, 1H), 1.48 (s, 9H).

1

tert-Butyl 3-carbamoyl-4-ethynyl-2,5-dihydro-1H-pyrrole-1-

carboxylate 8a (210 mg, 70% yield) was obtained from 1-

(tert-butoxycarbonyl)-4-ethynyl-2,5-dihydro-1H-pyrrole-3-car-

boxylic acid (300 mg, 8.89 mmol) and ammonium chloride as

described in step 3: tan amorphous solid. ¹H NMR (400 MHz,

DMSO-d₆) (mixture of rotamers): δ 7.55 (s, 1H), 7.20 (s,

1H), 4.77 (s, 0.43H), 4.72 (s, 0.4H), 4.36−4.10 (m, 4H), 1.42

(s, 9H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆) (mixture of

rotamers): δ 162.2, 162.1, 152.2, 138.3, 137.9, 120.2, 119.7,

90.8, 90.4, 78.6, 75.6, 55.8, 55.7, 52.8, 52.6, 27.4, 27.4. HRMS

(ESI) m/z: [M + H]⁺calcd for C₁₂H₁₇N₂O₃, 237.1234; found,

237.1226.

The title compound 11a (30 mg, 60% yield) was obtained

from tert-butyl 3-carbamoyl-4-ethynyl-2,5-dihydro-1H-pyrrole-

1-carboxylate (50 mg, 0.21 mmol) by heating at 100 °C for 0.5

h as described in step 4: white amorphous solid. ¹H NMR (400

MHz, DMSO-d₆): δ 11.31 (s, 1H), 7.43−7.13 (m, 1H), 6.19

(d, J = 6.6 Hz, 1H), 4.48 (t, J = 3.2 Hz, 2H), 4.30 (t, J = 3.1

Hz, 2H), 1.45 (s, 9H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆)

(mixture of rotamers): δ 159.3, 153.8, 153.8, 149.7, 149.2,

135.8, 135.7, 125.8, 125.4, 101.3, 79.4, 53.7, 53.5, 51.0, 50.7,

28.6, 28.6. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₂H₁₇N₂O₃, 237.1234; found, 237.1229.

tert-Butyl 4-Oxo-6-propyl-1,3,4,5-tetrahydro-2H-pyrrolo-

[3,4-c]pyridine-2-carboxylate (11b). 1-(tert-Butyl) 3-ethyl 4-

(pent-1-yn-1-yl)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate

(240 mg, 86% yield) was obtained from 1-(tert-butyl) 3-ethyl

4-(((triﬂuoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-

1,3-dicarboxylate (350 mg, 0.90 mmol) and 1-pentyne as

described in step 1: brown oil. ¹H NMR (400 MHz, CDCl₃): δ

4.46−4.18 (m, 6H), 2.43 (t, J = 7.0 Hz, 2H), 1.71−1.58 (m,

2H), 1.48 (s, 9H), 1.38−1.26 (m, 3H), 1.08−0.97 (m, 3H).

1-tert-Butoxycarbonyl-4-pent-1-ynyl-2,5-dihydropyrrole-3-

carboxylic acid (180 mg, 90% yield) was obtained from ethyl 1-

tert-butoxycarbonyl-4-pent-1-ynyl-2,5-dihydropyrrole-3-car-

boxylate (240 mg, 0.79 mmol) as described in step 2: pale

yellow solid.

4-(2-Phenylethynyl)-2,5-dihydrothiophene-3-carboxylic acid

(200 mg, 86% yield) was obtained from methyl 4-(2-

phenylethynyl)-2,5-dihydrothiophene-3-carboxylate (230 mg,

0.94 mmol) as described in step 2: pale yellow amorphous

1

solid. H NMR (400 MHz, CDCl₃): δ 7.53−7.48 (m, 2H),

7.38−7.30 (m, 3H), 4.16−4.07 (m, 4H).

4-(Phenylethynyl)-2,5-dihydrothiophene-3-carboxamide 7c

(120 mg, 60% yield) was obtained from 4-(phenylethynyl)-

2,5-dihydrothiophene-3- carboxylic acid (150 mg, 0.87 mmol)

and ammonium chloride as described in step 3: oﬀ-white

1

amorphous solid. H NMR (400 MHz, DMSO): δ 7.60−7.36

(m, 7H), 4.08−3.89 (m, 4H). ¹³C{¹H} NMR (101 MHz,

DMSO): δ 165.3, 142.2, 131.9, 129.8, 129.2, 123.8, 122.2,

98.0, 84.4, 42.0, 39.2. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₃H₁₂NOS, 230.0634; found, 230.0630

K

https://doi.org/10.1021/acs.joc.1c00688

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Note

tert-Butyl 3-carbamoyl-4-(pent-1-yn-1-yl)-2,5-dihydro-1H-

pyrrole-1-carboxylate 8b (70 mg, 64%) from tert-butyl 3-

carbamoyl-4-(pent-1-yn-1-yl)-2,5-dihydro-1H-pyrrole-1-car-

boxylic acid (110 mg, 0.39 mmol) and ammonium chloride as

153.8, 139.7, 129.7, 129.1, 119.5, 114.1, 89.4, 88.9, 80.2, 80.1,

76.3, 6.1, 57.0, 55.3, 54.0, 53.7, 28.4, 21.8. HRMS (ESI) m/z:

[M + H]⁺calcd for C₂₀H₂₅N₂O₄, 357.1809; found, 357.1802.

The title compound 11d (32 mg, 64% yield) was obtained

from tert-butyl 3-ethynyl-4-[(4-methoxyphenyl)-

methylcarbamoyl]-2,5-dihydropyrrole-1-carboxylate (50 mg,

0.14 mmol) by heating at 150 °C for 1 h as described in

1

described in step 3: white amorphous solid. H NMR (400

MHz, CDCl₃): δ 7.21−6.96 (m, 1H), 5.84 (s, 1H), 4.53−4.27

(m, 4H), 2.44 (q, J = 5.6, 4.2 Hz, 2H), 1.73−1.57 (m, 2H),

1.47 (s, 9H), 1.02 (t, J = 7.3 Hz, 3H). ¹³C{¹H} NMR (101

MHz, CDCl₃): (mixture of rotamers) 164.0, 163.8, 153.8,

153.5, 135.5, 135.2, 123.7, 123.5, 104.8, 104.1, 80.1, 79.9, 73.9,

57.7, 57.5, 53.5, 53.3, 28.4, 21.7, 21.7, 13.5, 13.5. HRMS (ESI)

m/z: [M + H]⁺calcd for C₁₅H₂₃N₂O₃, 279.1703; found,

279.1699.

1

step 4: white amorphous solid. H NMR (400 MHz, CDCl₃)

(mixture of rotamers): δ 7.31−7.23 (m, 3H), 6.90−6.84 (m,

2H), 6.14 (d, J = 6.9 Hz, 0.55H), 6.09 (d, J = 6.9 Hz, 0.31H),

5.08 (d, J = 2.8 Hz, 2H), 4.68−4.47 (m, 4H), 3.79 (s, 3H),

1.49 (s, 9H). ¹³C{¹H} NMR (101 MHz, CDCl₃) (mixture of

rotamers): δ 159.5, 158.8, 158.8, 154.3, 154.0, 148.0, 147.9,

137.3, 137.2, 129.8, 129.8, 128.4, 127.1, 126.8, 114.3, 114.1,

114.1, 113.9, 101.8, 101.5, 80.0, 79.9, 55.3, 55.3, 53.5, 53.2,

52.8, 51.2, 51.1, 51.1, 50.9, 28.5, 28.5. HRMS (ESI) m/z: [M +

H]⁺calcd for C₂₀H₂₅N₂O₄, 357.1809; found, 357.1802.

The title compound 11b (45 mg, 80% yield) was obtained

from tert-butyl 3-carbamoyl-4-(pent-1-yn-1-yl)-2,5-dihydro-

1H-pyrrole-1-carboxylate by heating (55 mg, 0.20 mmol) at

150 °C for 1.5 h as described in step 4: white amorphous solid.

¹H NMR (400 MHz, CDCl₃) (mixture of rotamers): δ 12.41

(s, 1H), 6.06 (s, 0.6H), 5.99 (s, 0.4H), 4.68−4.38 (m, 4H),

2.58 (t, J = 7.6 Hz, 2H), 1.71 (h, J = 7.3 Hz, 2H), 1.51 (s, 9H),

0.97 (t, J = 7.4 Hz, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃)

(mixture of rotamers): δ 161.5, 161.4, 154.4, 154.1, 150.7,

150.6, 150.2, 150.1, 122.9, 122.8, 100.7, 100.4, 79.9, 79.9, 53.5,

53.3, 50.5, 50.2, 35.1, 28.5, 22.0, 13.4. HRMS (ESI) m/z: [M +

H]⁺calcd for C₁₅H₂₃N₂O₃, 279.1703; found, 279.1698.

tert-Butyl 5-Methyl-4-oxo-1,3,4,5-tetrahydro-2H-pyrrolo-

[3,4-c]pyridine-2-carboxylate (11c). tert-Butyl 3-ethynyl-4-

(methylcarbamoyl)-2,5-dihydro-1H-pyrrole-1-carboxylate 8c

(110 mg, 87% yield) was obtained from tert-butyl 3-

carbamoyl-4-(pent-1-yn-1-yl)-2,5-dihydro-1H-pyrrole-1-car-

boxylic acid (120 mg, 0.50 mmol) and methylamine hydro-

2-Ethynylcyclohex-1-ene-1-carboxamide (12). Methyl 2-

((triisopropylsilyl)ethynyl)cyclohex-1-ene-1-carboxylate (1.14

g, 85% yield) was obtained from methyl 2-

(triﬂuoromethylsulfonyloxy)cyclohexane-1- carboxylate (1.2

g, 4.2 mmol)¹⁹and triisopropylacetylene as described in step

1

1: red liquid. H NMR (400 MHz, CDCl₃): δ 3.75 (s, 3H),

2.46−2.25 (m, 4H), 1.74−1.57 (m, 4H), 1.20−0.97 (m, 21H).

2-((Triisopropylsilyl)ethynyl)cyclohex-1-ene-1-carboxylic

acid (950 mg, 90% yield) was obtained from 2-

((trimethylsilyl)ethynyl)cyclopent-1-ene-1-carboxylate (1.10

g, 3.43 mmol) by heating for 5 h as described in step 2: pale

1

yellow amorphous solid. H NMR (400 MHz, CDCl₃): δ

2.49−2.31 (m, 4H), 1.73−1.51 (m, 4H), 1.13−1.03 (m, 21H).

2-((Triisopropylsilyl)ethynyl)cyclohex-1-ene-1-carboxamide

12c (790 mg, 84% yield) was obtained from 2-

((triisopropylsilyl)ethynyl)cyclohex-1-ene-1-carboxylic acid

(940 mg, 3.07 mmol) and ammonium chloride as described

in step 3: white amorphous solid. ¹H NMR (400 MHz,

CDCl₃): δ 7.41 (s, 1H), 5.59 (s, 1H), 2.49−2.42 (m, 2H),

2.40−2.33 (m, 2H), 1.64 (p, J = 3.3 Hz, 4H), 1.12−1.06 (m,

21H). ¹³C NMR (101 MHz, CDCl₃): δ 169.3, 138.4, 123.4,

106.6, 100.5, 32.4, 26.0, 21.8, 21.7, 18.6, 11.2. HRMS (ESI) m/

z: [M + H]⁺calcd for C₁₈H₃₁NOSi, 306.2248; found,

306.2249.

1

chloride as described in step 3: oﬀ-white amorphous solid. H

NMR (400 MHz, CDCl₃)(mixture of rotamers): δ 6.99 (s,

0.6H), 6.88 (s, 0.4H), 4.56−4.43 (m, 2H), 4.43−4.31 (m, 2H),

3.66 (s, 0.6H), 3.63 (s, 0.4H), 2.93 (d, J = 4.9 Hz, 3H), 1.47 (s,

9H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 162.1, 153.8,

139.9, 119.1, 89.1, 88.6, 80.2, 80.1, 76.4, 57.1, 57.0, 54.0, 53.8,

28.4, 26.20. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₃H₁₉N₂O₃, 251.1390; found, 251.1385.

The title compound 11c (30 mg, 60% yield) was obtained

from tert-butyl 3-ethynyl-4-(methylcarbamoyl)-2,5-dihydro-

1H-pyrrole-1-carboxylate (50 mg, 0.2 mmol) by heating at

150 °C for 1 h as described in step 4: white amorphous solid.

¹H NMR (400 MHz, CDCl₃) (mixture of rotamers): δ 7.35−

7.16 (m, 1H), 6.17 (d, J = 6.8 Hz, 0.65H), 6.11 (d, J = 6.8 Hz,

0.35H), 4.61−4.56 (m, 2H), 4.56−4.51 (m, 2H), 3.57 (s, 3H),

1.50 (s, 9H). ¹³C{¹H} NMR (101 MHz, CDCl₃) (mixture of

rotamers): 159.3, 159.2, 154.4, 154.0, 148.2, 148.1, 138.4,

126.7, 126.5, 101.5, 101.2, 80.0, 79.9, 53.5, 53.2, 51.1, 50.8,

37.2, 28.5, 28.5. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₃H₁₉N₂O₃, 251.1390; found, 251.1385

To a solution of 2-((triisopropylsilyl)ethynyl)cyclohex-1-

ene-1-carboxamide (400 mg, 1.3 mmol) in THF (10 mL) was

added TBAF (1.0 M solution in THF, 2.0 mL, 1.5 equiv), and

the mixture was stirred at an ambient temperature for 30 min.

The reaction mixture was diluted with IPAC, washed with

water and brine, dried over sodium sulfate, and concentrated.

The residue was puriﬁed by ﬂash chromatography (silica gel,

0−100% IPAC/heptane) to obtain the title compound 12

1

(135 mg, 69%): white amorphous solid. H NMR (400 MHz,

CDCl₃): δ 6.89 (s, 1H), 5.69 (s, 1H), 3.43 (t, J = 1.0 Hz, 1H),

2.51−2.39 (m, 2H), 2.36−2.31 (m, 2H), 1.75−1.52 (m, 4H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ 169.7, 140.2, 121.5,

85.0, 83.2, 31.6, 26.2, 21.7, 21.6. HRMS (ESI) m/z: [M + H]⁺

calcd for C₉H₁₂NO, 150.0913; found, 150.0913.

tert-Butyl 5-[(4-Methoxyphenyl)methyl]-4-oxo-1,3-

dihydropyrrolo[3,4-c]pyridine-2-carboxylate (11d). tert-

Butyl 3-ethynyl-4-[(4-methoxyphenyl)methylcarbamoyl]-2,5-

dihydropyrrole-1-carboxylate 8d (125 mg, 75% yield) was

obtained from tert-butyl 3-carbamoyl-4-(pent-1-yn-1-yl)-2,5-

dihydro-1H-pyrrole-1-carboxylic acid (110 mg, 0.46 mmol)

and 4-methoxybenzylamine as described in step 3: oﬀ-white

2-Ethynylcyclohept-1-ene-1-carboxamide (13). Methyl 2-

((triisopropylsilyl)ethynyl)cyclohept-1-ene-1-carboxylate (1.02

g, 92% yield) was obtained from methyl 2-

(triﬂuoromethylsulfonyloxy)cycloheptane-1-carboxylate¹⁹(1.0

g, 3.31 mmol) and triisopropylacetylene as described in step 1:

1

amorphous solid. H NMR (400 MHz, CDCl₃) (mixture of

rotamers): δ 7.32−7.22 (m, 3H), 6.93−6.81 (m, 2H), 4.58−

4.45 (m, 4H), 4.42−4.27 (m, 2H), 3.80 (s, 3H), 3.55 (s,

0.55H), 3.52 (s, 0.27H), 1.47 (s, 9H). ¹³C{¹H} NMR (101

MHz, CDCl₃) (mixture of rotamers): δ 161.3, 161.2, 159.1,

1

red oil. H NMR (400 MHz, CDCl₃): δ 3.75 (s, 3H), 2.58−

2.50 (m, 4H), 1.82−1.73 (m, 2H), 1.64−1.52 (m, 4H), 1.12−

1.06 (m, 21H).

L

https://doi.org/10.1021/acs.joc.1c00688

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Note

2-((Triisopropylsilyl)ethynyl)cyclohept-1-ene-1-carboxylic

acid (950 mg, 96% yield) was obtained from methyl 2-

((triisopropylsilyl)ethynyl)cyclohept-1-ene-1-carboxylate (1.02

g, 3.06 mmol) as described in step 2: oﬀ-white amorphous

solid. H NMR (400 MHz, CDCl₃): δ 7.26 (s, 1H), 5.52 (s,

1H), 2.68−2.61 (m, 2H), 2.58−2.49 (m, 2H), 1.86−1.73 (m,

2H), 1.68−1.49 (m, 6H), 1.14−1.03 (m, 21H).

was extracted with IPAC. The organic layer was separated,

washed with brine, dried over sodium sulfate, and concen-

trated. The residue was puriﬁed by ﬂash chromatography

(silica gel, 0−100% IPAC/heptane) to obtain the title

compound 15a (380 mg, 88% yield): pale yellow amorphous

1

solid. H NMR (400 MHz, DMSO-d₆): δ 7.24 (s, 1H), 2.28−

2.17 (m, 2H), 2.11−1.99 (m, 2H), 1.75−1.54 (m, 4H), 1.50−

1.43 (m, 3H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆): δ 170.9,

163.8, 126.2, 106.2, 24.2, 21.6, 21.5, 21.4, 19.7. HRMS (ESI)

m/z: [M + H]⁺calcd for C₉H₁₃O₃, 169.0859; observed,

169.0857.

2-(2-Triisopropylsilylethynyl)cycloheptene-1-carboxamide

13c (200 mg, 80% yield) was obtained from 2-

((triisopropylsilyl)ethynyl)cyclohept-1-ene-1-carboxylic acid

(250 mg, 0.78 mmol) as described in step 3: white amorphous

1

solid. H NMR (400 MHz, CDCl₃): δ 7.28 (s, 1H), 5.67 (s,

3-Hydroxy-3-methyl-3,4,5,6,7,8-hexahydro-1H-

cyclohepta[c]furan-1-one (16a). Methyl 2-((trimethylsilyl)-

ethynyl)cyclohept-1-ene-1-carboxylate (0.86 g, 87%) from

methyl 2-(triﬂuoromethylsulfonyloxy)cycloheptene-1-carboxy-

1H), 2.63 (s, 2H), 2.59−2.51 (m, 2H), 1.83−1.74 (m, 2H),

1.66−1.57 (m, 2H), 1.57−1.49 (m, 2H), 1.17−0.99 (m, 21H).

¹³C NMR (101 MHz, CDCl₃): δ 169.9, 144.5, 128.7, 107.9,

101.6, 37.33, 32.1, 29.4, 25.9, 25.5, 18.6, 11.2.HRMS (ESI) m/

z: [M + H]⁺calcd for C₁₉H₃₃NOSi, 320.2404; found,

320.2399.

1

late (1.2 g, 4.0 mmol) as described is step 1: brown liquid. H

NMR (400 MHz, CDCl₃): δ 3.76 (s, 3H), 2.59−2.41 (m, 4H),

1.82−1.72 (m, 2H), 1.63−1.57 (m, 2H), 1.57−1.49 (m, 2H),

0.20 (s, 9H).

The title compound 13 (50 mg, 70% yield) was obtained

from 2-(2-triisopropylsilylethynyl)cycloheptene-1-carboxamide

(140 mg, 0.44 mmol) as described for compound 12^:: white

The title compound 16a (554 mg, 87.9% yield) was

obtained from methyl 2-((trimethylsilyl)ethynyl)cyclohept-1-

ene-1-carboxylate (866 mg, 3.45 mmol) as described for

1

amorphous solid. H NMR (400 MHz, CDCl₃): δ 6.80 (s,

1H), 6.42 (s, 1H), 3.53 (s, 1H), 2.61−2.56 (m, 2H), 2.56−

2.47 (m, 2H), 1.84−1.73 (m, 2H), 1.67−1.47 (m, 4H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ 170.61, 146.3, 126.7,

85.9, 84.5, 36.3, 32.1, 29.9, 26.0. HRMS (ESI) m/z: [M + H]⁺

calcd for C₁₀H₁₄NO, 164.1069; found, 164.1068.

1

compound 15a: pale yellow amorphous solid. H NMR (500

MHz, DMSO): δ 7.14 (s, 1H), 2.39−2.33 (m, 2H), 2.26 (s,

2H), 1.81−1.51 (m, 6H), 1.46 (s, 3H). ¹³C{¹H} NMR (101

MHz, DMSO-d₆): δ 170.9, 163.8, 126.2, 106.2, 24.2, 21.6,

21.5, 21.4, 19.7. HRMS (ESI) m/z: [M + H]⁺for C₁₀H₁₅O₃,

183.1016; observed, 183.1014.

2-(Pent-1-yn-1-yl)cyclohex-1-ene-1-carboxamide (18).

Methyl 2-(pent-1-yn-1-yl)cyclohex-1-ene-1-carboxylate (410

mg, 95% yield) was obtained from methyl 2-

(triﬂuoromethylsulfonyloxy)cyclohexane-1-carboxylate (600

3-Hydroxy-3-methyl-4,5,6,7,8,9-hexahydrocycloocta[c]-

furan-1(3H)-one (17a). Ethyl (Z)-2-((trimethylsilyl)ethynyl)-

cyclooct-1-ene-1-carboxylate (800 mg, 79% yield) was

obtained from ethyl 2-(((triﬂuoromethyl)sulfonyl)oxy)-

cyclooct-1-ene-1-carboxylate (1.12 g, 3.63 mmol) as described

1

mg, 2.08 mmol) as described in step 1: colorless oil. H

NMR (400 MHz, CDCl₃): δ 3.75 (s, 3H), 2.47−2.24 (m, 6H),

1.72−1.52 (m, 6H), 1.02 (t, J = 7.4 Hz, 3H).

1

2-(Pent-1-yn-1-yl)cyclohex-1-ene-1-carboxylic acid (350 mg,

87% yield) was obtained from methyl 2-(pent-1-yn-1-yl)-

cyclohex-1-ene-1-carboxylate (410 mg, 2 mmol) as described

as described in step 2 by heating for 5 h and carried on to the

in step 1: brown liquid. H NMR (400 MHz, CDCl₃): δ 4.23

(q, J = 7.1 Hz, 2H), 2.52−2.40 (m, 4H), 1.75−1.62 (m, 2H),

1.54−1.42 (m, 4H), 1.37−1.27 (m, 3H), 0.19 (s, 9H).

Title compound 17a (120 mg, 85%) from ethyl (Z)-2-

((trimethylsilyl)ethynyl)cyclooct-1-ene-1-carboxylate (200 mg,

0.72 mmol) as described for compound 15a: oﬀ-white

1

next step without puriﬁcation: tan amorphous solid. H NMR

(400 MHz, CDCl₃): δ 2.48−2.28 (m, 6H), 1.72−1.51 (m,

1

6H), 1.09−0.90 (m, 3H).

amorphous solid. H NMR (400 MHz, DMSO-d₆): δ 7.16

The title compound 18 (180 mg, 53% yield) was obtained

from 2-(pent-1-yn-1-yl)cyclohex-1-ene-1-carboxylic acid (340

mg, 1.77 mmol) and ammonium chloride as described in step

(s, 1H), 2.48−2.40 (m, 2H), 2.37−2.30 (m, 2H), 1.82−1.68

(m, 2H), 1.55−1.37 (m, 9H). ¹³C{¹H} NMR (101 MHz,

DMSO-d₆): δ 170.5, 163.5, 125.3, 105.2, 26.8, 26.3, 26.1,

25.00, 24.7, 24.0, 21.4. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₁H₁₇O₃, 197.1171; found, 197.1171.

1

3: white amorphous solid. H NMR (400 MHz, CDCl₃): δ

7.27 (s, 1H), 5.96 (s, 1H), 2.45−2.36 (m, 4H), 2.34−2.28 (m,

2H), 1.66−1.55 (m, 6H), 1.09−0.90 (m, 3H). ¹³C{¹H} NMR

(101 MHz, CDCl₃): δ 169.9, 136.3, 123.9, 99.2, 80.8, 32.6,

25.9, 21.9, 21.8, 21.6, 13.5. HRMS (ESI) m/z: [M + H]⁺calcd

for C₁₂H₁₈NO, 192.1383; found, 192.138.

3-Methylene-3,4,5,6,7,8-hexahydro-1H-cyclohepta[c]-

furan-1-one (13f in Supporting Information). To 2-

(triisopropylsilyl)ethynyl)cyclohept-1-ene-1-carboxylic acid

(180 mg, 0.56 mmol) dissolved in THF (3 mL) and acetic

acid (0.32 mL, 10 equiv) was added TBAF (1.12 mL, 1 M, 2

equiv), and the mixture was stirred overnight at 25 °C. The

reaction mixture was diluted with IPAC, washed with water

and brine, dried over sodium sulfate, and concentrated. The

residue was puriﬁed by ﬂash chromatography (silica gel; 0−

50%) to obtain the title compound as a white solid (70 mg,

76%): oﬀ-white amorphous solid. ¹H NMR (500 MHz,

CDCl₃): δ 5.06 (d, J = 2.7 Hz, 1H), 4.84 (d, J = 2.7 Hz,

1H), 2.56−2.52 (m, 2H), 2.52−2.47 (m, 2H), 1.87−1.80 (m,

2H), 1.76−1.68 (m, 2H), 1.65 (p, J = 5.9 Hz, 2H). ¹³C{¹H}

NMR (126 MHz, CDCl₃): δ 170.3, 155.2, 152.5, 131.8, 92.4,

30.6, 26.6, 26.5, 26.1, 24.9.

3-Hydroxy-3-methyl-4,5,6,7-tetrahydroisobenzofuran-

1(3H)-one (15a). Methyl 2-((trimethylsilyl)ethynyl)cyclohex-

1-ene-1-carboxylate (610 mg, 76% yield) was obtained from

methyl 2-(((triﬂuoromethyl)sulfonyl)oxy)cyclohex-1-ene-1-

carboxylate (1.00 g, 3.37 mmol) as described in step 1:

1

brown liquid. H NMR (400 MHz, CDCl₃): δ 3.76 (s, 3H),

2.43−2.28 (m, 4H), 1.67−1.58 (m, 4H), 0.21 (s, 9H).

A mixture of methyl 2-(2-trimethylsilylethynyl)cyclohexene-

1-carboxylate (610 mg, 2.58 mmol) in methanol−THF (5 mL,

1:1) and lithium hydroxide (5 mL, 1 N) was heated at 60 °C

for 2 h. The reaction mixture was cooled, concentrated, and

redissolved in IPAC/water. The organic layer separated and

discarded. The aqueous layer was acidiﬁed with 2 N HCl and

M

https://doi.org/10.1021/acs.joc.1c00688

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Note

̀

(3) Saiegh, T. J.; Chedotal, H.; Meyer, C.; Cossy, J. Rhodium(III)-

Catalyzed C(sp2)-H Functionalization of Cyclobutenes. Access to

Cyclobuta[c]pyridones and -pyridines. Org. Lett. 2019, 21, 8364−

8368.

ASSOCIATED CONTENT

■

sı

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c00688.

(4) Talamas, F. X.; Ao-Ieong, G.; Brameld, K. A.; Chin, E.; de

Vicente, J.; Dunn, J. P.; Ghate, M.; Giannetti, A. M.; Harris, S. F.;

Labadie, S. S.; Leveque, V.; Li, J.; Lui, A. S-T.; McCaleb, K. L.; Nájera,

I.; Schoenfeld, R. C.; Wang, B.; Wong, A. De novo fragment design: a

medicinal chemistry approach to fragment-based lead generation. J.

Med. Chem. 2013, 56, 3115−3119.

¹H and ¹³C{H} NMR, proposed mechanism for the

conversion of enyne acids to 3-hydroxyfuranones,

coordinates, energies, and corrections for computations

(PDF)

(5) (a) Hamama, W. S.; Waly, M.; El-Hawary, I.; Zoorob, H. H.

Developments in the chemistry of 2-pyridone. Synth. Commun. 2014,

44, 1730−1759. (b) Chen, Y.; Li, T.; Sieburth, S. M. Pyridone

Annulation by 4+ 2 Coupling of Dienolates with Nitriles and Nitrile

Equivalents. A Solution to the Acetonitrile Problem. J. Org. Chem.

2001, 66, 6826−6828.

(6) Fan, J.; Dai, Y.; Shao, J.; Peng, X.; Wang, C.; Cao, S.; Zhao, B.;

Ai, J.; Geng, M.; Duan, W. Design, synthesis and biological evaluation

of pyrazolylaminoquinazoline derivatives as highly potent pan-

fibroblast growth factor receptor inhibitors. Bioorg. Med. Chem. Lett.

2016, 26, 2594−2599.

(7) Yao, T.; Larock, R. C. Regio-and stereoselective synthesis of

isoindolin-1-ones via electrophilic cyclization. J. Org. Chem. 2005, 70,

1432−1437.

(8) Albrecht, B. K.; Bauer, D.; Bellon, S.; Bode, C. M.; Booker, S.;

Boezio, A.; Choquette, D.; D’Amico, D.; Harmange, J.-C.; Hirai, S.;

Hungate, R. W.; Kim, T.-S.; Lewis, R. T.; Liu, L.; Lohman, J.;

Norman, M. H.; Potashman, M.; Siegmund, A. C.; Springer, S. K.;

Stec, M.; Xi, N.; Yang, K. Fused heterocyclic derivatives as HGF

modulators and their preparation and methods of use.

US20090318436.

AUTHOR INFORMATION

■

Corresponding Author

Brendan T. Parr − Genentech, Inc., South San Francisco,

California 94080, United States; orcid.org/0000-0001-

5774-8122; Email: parr.brendan@gene.com

Authors

Sharada S. Labadie − Genentech, Inc., South San Francisco,

California 94080, United States

Karine Thai − Genentech, Inc., South San Francisco,

California 94080, United States

Jessica M. Grandner − Genentech, Inc., South San Francisco,

California 94080, United States

Yanzhou Liu − Genentech, Inc., South San Francisco,

California 94080, United States

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00688

(9) Kaila, N.; Follows, B.; Leung, L.; Thomason, J.; Huang, A.;

Moretto, A.; Janz, K.; Lowe, M.; Mansour, T. S.; Hubeau, C.; Page,

K.; Morgan, P.; Fish, S.; Xu, X.; Williams, C.; Saiah, E. Discovery of

Isoquinolinone Indole Acetic Acids as Antagonists of Chemo-

attractant Receptor Homologous Molecule Expressed on Th2 Cells

(CRTH2) for the Treatment of Allergic Inflammatory Diseases. J.

Med. Chem. 2014, 57, 1299−1322.

(10) Frisch, M. J.; et al. Gaussian 09, Revision E.01; Gaussian, Inc.:

Wallingford, CT, 2013. (See Supporting Information for full

reference).

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

The authors thank Sushant Malhotra for support and

encouragement, Kewei Xu for acquisition of high-resolution

mass spectrometric data, and Genentech for the Summer

Intern Program.

(11) Zhao, Y.; Truhlar, D. G. The M06 suite of density functionals

for main group thermochemistry, thermochemical kinetics, non-

covalent interactions, excited states, and transition elements: two new

functionals and systematic testing of four M06-class functionals and

12 other functionals. Theor. Chem. Acc. 2008, 120, 215−241.

(12) Barone, V.; Cossi, M. Quantum calculation of molecular

energies and energy gradients in solution by a conductor solvent

model. J. Phys. Chem. A 1998, 102, 1995−2001.

(13) Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. On the

performance of continuum solvation methods. A comment on

“Universal approaches to solvation modeling. J. Comput. Chem.

2003, 24, 669−681.

(14) Zhao, Y.; Truhlar, D. G. Computational characterization and

modeling of buckyball tweezers: density functional study of concave-

convex π π interactions. Phys. Chem. Chem. Phys. 2008, 10, 2813−

2818.

(15) Ribeiro, R. F.; Marenich, A. V.; Cramer, C. J.; Truhlar, D. G.

Use of solution-phase vibrational frequencies in continuum models

for the free energy of solvation. J. Phys. Chem. B 2011, 115, 14556−

14562.

REFERENCES

■

(1) (a) Chou, S. S. P.; Chen, P. W. Cycloaddition reactions of 4-

sulfur-substituted dihydro-2-pyridones and 2-pyridones with con-

jugated dienes. Tetrahedron 2008, 64, 1879. (b) Chou, S. S. P.; Wang,

H. C.; Chen, P. W.; Yang, C. H. [4+ 2] Cycloaddition reactions of 4-

sulfur-substituted 2-pyridones with electron-deficient dienophiles.

Tetrahedron 2008, 64, 5291.

(2) (a) Oku, H.; Shimizu, T.; Kawabata, T.; Nagira, M.; Hikita, I.;

Ueyama, A.; Matsushima, S.; Torii, M.; Arimura, A. Antifibrotic action

of pirfenidone and prednisolone: Different effects on pulmonary

cytokines and growth factors in bleomycin-induced murine

pulmonary fibrosis. Eur. J. Pharmacol. 2008, 590 (1−3), 400−408.

(b) Zhang, C.; Jin, L.; Mondie, B.; Mitchell, S. S.; Castelhano, A. L.;

Cai, W.; Bergenhem, N. Leporin B: a novel hexokinase II gene

inducing agent from an unidentified fungus. Bioorg. Med. Chem. Lett.

2003, 13, 1433−1435. (c) Adams, D. J.; Wahl, M. L.; Flowers, J. L.;

Sen, B.; Colvin, B. M.; Dewhirst, M. W.; Manikumar, G.; Wani, M. C.

Camptothecin analogs with enhanced activity against human breast

cancer cells. II. Impact of the tumor pH gradient. Cancer Chemother.

Pharmacol. 2006, 57 (2), 145−154. (d) Crawford, J. J.; Johnson, A.

R.; Misner, D. L.; Belmont, L. D.; Castanedo, G.; Choy, R.; Coraggio,

M.; Dong, L. M.; Eigenbrot, C.; Erickson, R.; Ghilardi, N.; Hau, J.;

Katewa, A.; Kohli, P. B.; Lee, W.; Lubach, J. W.; McKenzie, B. S.;

Ortwine, D. F.; Schutt, L.; Tay, S.; Wei, B. Q.; Reif, K.; Liu, L. C.;

Wong, H.; Young, W. B. Discovery of GDC-0853: a potent, selective,

and noncovalent Bruton ’s tyrosine kinase inhibitor in early clinical

development. J. Med. Chem. 2018, 61, 2227−2245.

́

(16) Legault, C. Y. Universite de Sherbrooke, 2020. (http://www.

cylview.org).

(17) (a) Avogadro: an open-source molecular builder and

visualization tool. Version 1.2.0. http://avogadro.cc/. (b) Hanwell,

M. D.; Curtis, D. E.; Lonie, D. C.; Vandermeersch, T.; Zurek, E.;

Hutchison, G. R. Avogadro: An advanced semantic chemical editor,

visualization, and analysis platform. J. Cheminf. 2012, 4, 17.

N

https://doi.org/10.1021/acs.joc.1c00688

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Note

(18) Calvin, J. R.; Frederick, M. O.; Laird, D. L. T.; Remacle, J. R.;

May, S. A. Rhodium-catalyzed and Zinc (II)-triflate-promoted

asymmetric hydrogenation of tetrasubstituted α , β -unsaturated

ketones. Org. Lett. 2012, 14, 1038−1041.

(19) Chen, M.; Su, N.; Deng, T.; Wink, D. J.; Zhao, Y.; Driver, T. G.

Controlling the Selectivity Patterns of Au-Catalyzed Cyclization-

Migration Reactions. Org. Lett. 2019, 21, 1555−1558.

O

https://doi.org/10.1021/acs.joc.1c00688

J. Org. Chem. XXXX, XXX, XXX−XXX

Article Doi

Enyne Amides to Fused Pyridones: Scope and Limitations

DOI: 10.1021/acs.joc.1c00688

Source and publish data:

Authors:

Article abstract of DOI:10.1021/acs.joc.1c00688

Full text of DOI:10.1021/acs.joc.1c00688

Products guided by the article

R&D Labs maybe for 1192253-42-1

Relevant to this article

Hot Product