Three-Component Reaction of 3,3-Difluorocyclopropenes, s-Tetrazines, and (benzo) Pyridines

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Three-Component Reaction of 3,3-Diﬂuorocyclopropenes,

s ‑Tetrazines, and (benzo) Pyridines

Ilya V. Nechaev,* Georgij V. Cherkaev, Nikolay V. Boev, and Pavel N. Solyev

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ABSTRACT: A new three-component reaction leading to 1-α-(pyridyl-2-[1,2,4]triazolyl)-2-alkyl-ethanones has been discovered

while studying the reactivity of monosubstituted 3,3-diﬂuorocyclopropenes in an inverse electronic demand Diels−Alder (IEDDA)

cycloaddition−cycloreversion sequence with s-tetrazines. The reaction involving the above-mentioned reactants and (benzo)pyridine

as a third component results in a complex transformation proceeding in mild conditions in a stoichiometric ratio of reactants and has

high functional group tolerance (phenols, amides, ethers, carboxylic acids, ketones, and acrylic esters). As a result, simple pyridines

are selectively functionalized at the α-position in good isolated yields. The reaction mechanism includes a rare azaphilic [4 + 2]-

cycloaddition step between s-tetrazine and intermediate 1-hydroxyindolizine, suggested after byproduct identiﬁcation and tracked

with a deuterium label. To date, it is only the third known example of skewed azaphilic cycloaddition of tetrazine. The reaction is

truly three-component and cannot be eﬀectively performed stepwise.

9

INTRODUCTION

dienophiles; however, electron-poor alkenes and CN

■

1

0

11

heterodienophiles such as amidines, carbamates, and

nitriles also react in particular cases. Simple s-tetrazines are

deeply colored, weakly basic compounds that can behave as

reversible oxidizers and readily accept electrons, forming

stable anion radicals. Being highly electron-deﬁcient, s-

tetrazines are prone to nucleophilic attack at the carbon

The inverse electronic demand Diels−Alder (IEDDA) reaction

between s-tetrazines and simple alkenes or less reactive alkynes

with nitrogen loss leading to pyridazines was ﬁrst reported by

12

13

1

−3

Carboni and Lindsey

in 1959.

Being strained, cyclopropenes are highly reactive alkenes; in

terms of the IEDDA reaction, they found application in series

of works dedicated to bio-orthogonal ligation due to the

advantages of this type of conjugation: it proceeds fast,

quantitatively, tolerates aqueous media, and produces only

nitrogen as a byproduct. Another example is sequential

IEDDA, involving tetrazine and two molecules of cyclopropene

4

14

atom (with S, N, O nucleophiles) and more rarely at

1

5

nitrogen (with active C-nucleophiles). Besides normal

aromatic nucleophilic substitution at carbons, the

S_N(ANRORC) mechanism becomes operative, for example,

in the Chichibabin hydrazination of monosubstituted s-

tetrazines. Based on the IEDDA reaction of s-tetrazine with

four-membered dienophiles as the initial chemical act followed

by subsequent small ring expansion, interesting examples of

5

16

applied in construction of semibullvalenes and homotropili-

6

denes, as was reported by Sauer et al. Gem-dimethylcyclo-

propene normally forms diazanorkardienes upon reaction with

dimethyl s-tetrazine-3,6-dicarboxylate at a room temperature.

Reaction of cyclopropenes with 1,2,4-triazines leading to

azepines is much more rarely represented. To date, no

examples have been found concerning the behavior of 3,3-

dihalocyclopropenes in such type of [4 + 2]-cycloadditions

with triazines or s-tetrazines.

7

17

synthesized eight-membered heterocycles, such as diazocine

8

Received: October 25, 2020

On the other hand, s-tetrazines represent a class of electron-

deﬁcient aza-aromatic heterocycles, most noted as the 4-π

electron component in the IEDDA reaction with electron-rich

©

XXXX American Chemical Society

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A

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Scheme 1. Diﬂuorocyclopropenation of Acetylenes and Synthesis of Azines

a

Scheme 2. Initially Planned Transformations and the Unexpected Result

a

*NO reaction took place in high-boiling-point nonpolar solvents, leaving starting materials unreacted.

1

8

and triazocine, have been reported. However, four-mem-

RESULTS AND DISCUSSION

■

bered thietanones reacting with s-tetrazines led to pyrazol-4-

Initial IEDDA Experiments. We planned a study of the

1

9

Carboni−Lindsey reaction between 3,3-diﬂuorocyclopropene

and azines aiming to obtain unknown 4,4-diﬂuoro-4H-azepine

and 5,5-diﬂuoro-5H-[1,2]diazepine heterocycles, interesting

from the chemical point of view. Starting 4-(3,3-diﬂuoro-

cycloprop-1-enylmethyl)-N-Boc-4-methoxycarbonyl-piperidine

ols instead of the expected thiadiazocine system by a

nonobvious cascade of reactions, including cycloaddition,

recyclization, and sulfur extrusion.

The rich variety of chemical properties for both classes

2

was synthesized in near-quantitative yield, by adding 3.5

(as a

tetrazines and cyclopropenes, given as examples above

indicates that they can still conceal possible nonobvious

transformations.

equiv of the Ruppert−Parkash reagent TMS-CF

diﬂuorocarbene source) over 6 h to the acetylene 1 with a

catalytic amount of NaI in reﬂuxing tetrahydrofuran (THF)

3

20

(Scheme 1). The choice of the model acetylene 1 was made by

B

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1

13

Figure 1. Structural features of the proposed products in terms of { H- C} heteronuclear multiple-bond correlation spectroscopy (HMBC) (7 and

were rejected). Blue arrows, three-bond correlation (observed); gray arrows, four-bond correlation (not observed).

8

few criteria: it is nonvolatile, has functional groups (N-Boc,

COOMe), and it can be easily detected by liquid

chromatography−mass spectrometry (LC−MS) or speciﬁcally

stained on thin layer chromatography (TLC). Analogously,

hex-5-ynoic acid methyl 1a was diﬂuorocyclopropenated to

yield 2a. Other acetylenes with the acidic proton (e.g., OH,

NH-Boc) were not compatible with the chosen Ruppert−

Prakash reagent for the diﬂuorocyclopropenation procedure.

s-Tetrazines 3, 4 and 1,2,4-triazine 5 were prepared in two

steps from appropriate nitriles according to the known

proton multiplet at 7.3 ppm disappeared. No ﬂuorine atoms

1

9

were detected by F NMR, and the odd-numbered molecular

weight indicated that the product must contain an odd number

of nitrogen atoms. Along with the appearance of only one

methyl group, we postulated formal excision of acetonitrile

from dimethyltetrazine 3 in the reaction course and proposed

several alternative product structures 7−9 (Figure 1). It is

clearly seen that all three reaction components are incorpo-

rated in the proposed products.

The diﬀerence among triazepine 7, dihydrotriazine 8, and

triazole 9 was not obvious. Each of them has the same

molecular weight corresponding to the LC-MS data, retains

21,22

literature procedures.

Upon synthesis of 2,5-dimethylte-

trazine 3, we, however, met with some diﬃculties such as low

yield (<15%) and diﬃcult product handling as it sublimes

easily. As reduced pressure should be avoided upon

manipulations with dimethyltetrazine, we applied atmospheric

pressure solvent evaporation with a short Vigreux column to

prepare a ∼1 M solution in dichloromethane (DCM). The

triazine and N-Boc-piperidine rings, has the −CH -CH−

2

1

fragment observed as the ABX system by H NMR, and has

eight nitrogen atoms. Dihydrotriazine 8 is expected to

24

aromatize readily in oxidative conditions. We preliminarily

refuted 8 by the chemical criteria as no oxidation occurred in

the experiments. To distinguish between the rest of the

triazepinone 7 and triazole 9 alternative structures, and as a

test of the reaction scope, we switched the pyridine component

to ethylisonicotinate, and the three-component reaction (3-

CR) was performed using 1.5 equiv of 3,5-dimethyltetrazine 3

and ethylisonicotinate in relation to diﬂuorocyclopropene 2 in

reﬂuxing ethanol for 15 h. During that time, the reaction

mixture gradually changed color from the distinctive red to

brownish, indicating that most tetrazine was consumed. The 3-

CR product was isolated in 50% yield and was used for further

structure determination. The key structural diﬀerence between

alternative 7−9 is that triazole 9 has three bonds between

1

concentration was quantiﬁed by H NMR of the solution with

increased relaxation delay t of 10 s. A ﬁvefold excess of

1

hydrazine hydrate is generally used in the synthesis of the 1,4-

dihydro-s-tetrazine intermediate; caution should be applied

during the nitrous acid oxidative aromatization step, as

23

hydrazoic acid may form. Furthermore, unsubstituted s-

tetrazine may explode upon sublimation, as known from the

times of Theodor Curtius. We handled small quantities of

crystalline 2,5-dimethyltetrazine and found it to be stable to

friction albeit we observed its slow decomposition when

exposed to light at ambient temperature.

In initial IEDDA experiments (Scheme 2), diﬂuorocyclo-

propene 2 was heated with triazine 5 in high-boiling-point

nonpolar aprotic solvents with no chemical interaction

observed. In p-xylene at 130 °C, both reactants stayed intact

after 18 h, and we added dimethyltetrazine 3 as a more reactive

heterodiene to the reaction mixture. After heating for several

hours, no changes were observed with all three reactants (2, 5,

and 3) present, and the reaction vessel was cooled down to

room temperature. Triazine 5 precipitated, and ethanol was

added to homogenize the mixture, which was left overnight at

(

b)

(c)

carbonyl C

and pyridine proton H , allowing

1

13

{ H- C}HMBC observation, in contrast to triazepinone 7,

where C −H are separated with four bonds. The same

NMR criteria were additionally used to distinguish between

refuted dihydrotriazine 8 (four bonds between C

CH₂) and triazole 9 (three bonds between C and CH₂).

(

b)

(c)

(

b)

and

(

a)

(b)

(a)

3

Optimization of HMBC parameters for J ≈ 7 Hz coupling

H‑C

(

c)

(b)

revealed both important correlation peaks: H −C and

(

a)

(b)

CH −C , indicating that the correct 3-CR product

2

6

0 °C. After that, LC-MS indicated that a new product with a

structure is ﬁrmly consistent with triazole 9(14). Prototropic

1

molecular weight greater and not corresponding to the

expected ones (6, 6a) was cleanly formed.

tautomerism of triazole 14 was observed by H NMR in

dimethyl sulfoxide (DMSO)-d ; however, in CDCl , a single

6

3

1

3

Structure Elucidation of the New Products. This

reaction product with MW = 536.2 Da was isolated by high

performance liquid chromatography (HPLC) for further

structural studies. It was moderately UV-active and lower

tautomer was seen in the temperature range 25−70 °C. In C

NMR in DMSO-d , both carbons of the triazole ring fully

6

merged with the baseline but became observable in CDCl as

3

broadened signals. Gradual conformer stabilization (by intra-

molecular hydrogen-bonding between the keto-function and

1

than starting triazine 5 on TLC. H NMR preliminary analysis

showed that the N-Boc-piperidine part was present along with

the appearance of a new methyl group at 2.5 ppm as a singlet,

and the triazine cycle was conserved. Surprisingly, we found

that the pyridine ring of 3-pyridin-4-yl-[1,2,4]triazine 5 was

triazole NH, as assumed) was detected in CDCl solution at 50

°C by slow downﬁeld shifting (hours) of the triazole NH signal

from 7.5 to 13 ppm.

Next, we conducted experiments on exclusion of one or two

components of the reaction under study. At ﬁrst, stability of

diﬂuorocyclopropene 2 was tested in 3-CR conditions (entry 1,

3

substituted at the α-position, and the −CH -CH− fragment

2

emerged, while the characteristic 3,3′-diﬂuorocyclopropene

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Table 1. Reaction Component Exclusion Experiments

Table 1). On heating in ethanol at 78 °C for 18 h, clean

no changes after 7 day storage at room temperature and

surviving heating in inert solvents (e.g., 1,2-dichloroethane

(DCE), MeCN) for 18 h. We conducted component exclusion

experiments (Table 1, entries 2, 3) with cyclopropenone 10

instead of diﬂuorocyclopropene 2 and generally obtained the

same results, but the formation of dimeric-12 was much faster

hydrolysis of the CF group gave the corresponding cyclo-

2

propenone 10 along with the product of ring-openingethyl

2

5

acrylate 11. Further heating resulted in 11 as a sole product.

When dimethyltetrazine 3 was excluded from 3-CR (entry

2

), full conversion of diﬂuorocyclopropene after 18 h aﬀorded

a brownish product with a molecular weight of 918.4 in

contrast to the expected 1-hydroxyindolizine 12. Formally,

(

<2 h). Analogously, we noticed about a four times rate

26

increase in the reaction between cyclopropenone 10 and

dimethyltetrazine: the full conversion leading to 3-hydroxypyr-

azole 13 was achieved only after 12 h at 55 °C in ethanol.

Heating was necessary as at room temperature no 13 was

obtained.

Scope of the Reaction. Next, we screened 3-CR

conditions on the same model reaction among diﬂuorocyclo-

propene 2, dimethyltetrazine 3, and ethylisonicotinate to shed

light on the possible 3-CR speciﬁcities (Table 2).

this product corresponds to 1-hydroxyindolizine 12 dimerized

1

with a loss of H . It was isolated by HPLC; however, H NMR

2

spectra showed signiﬁcantly broadened signals in the whole

spectral range, obscuring the structural information. Finally, in

the absence of the pyridine reaction component (entry 3), we

isolated the 3-hydroxypyrazole 13 product, formed after 48 h

in the reaction between tetrazine and diﬂuorocyclopropene in

reﬂuxing ethanol. Interestingly, when unsymmetrically sub-

stituted 3-(4-ﬂuorophenyl)-6-methyltetrazine 4 was taken

instead of dimethyltetrazine 3, the same 3-hydroxypyrazole

was obtained. The closest reactions in the literature reported

the interaction of 2,3-diphenylcyclopropenone with 1,2,3-

Generally, heating was necessary to push the reaction

forward and the presence of water was crucial (entries 5, 9, 12,

14, 16). In the absence of water, destructive side processes

became prevalent (1, 2, 4) or no reaction occurred (8, 10, 11).

Hence, higher temperature and anhydrous conditions had a

negative eﬀect, launching competing side reactions. The

minimal temperature range was found to be 50−60 °C for

the reaction completion in wet solvents (9, 12, and 16). In

anhydrous acidic media MeCN/HFIP (1/1) or THF/AcOH

2

7

triazines aﬀording condensation products; however, s-

tetrazines reactions were not surveyed. Next, we tested the

subsequent addition of ethylisonicotinate to 13 as well as

dimethyltetrazine to the dimer of 12, and after heating for 24 h

in ethanol, we did not observe any 3-CR product, proving that

neither 13 nor dimeric-12 was the 3-CR intermediate.

Obviously, upon exclusion of the diﬂuorocyclopropene

component (entry 4), no reaction took place between

dimethyltetrazine and ethylisonicotinate. Hence, only the

simultaneous presence of all three reagents furnished the 3-

CR product. Summarizing, we consider that cyclopropenone

(

8/2) at room temperature, each of the three reactants

remained intact. Elevating the reaction temperature to 55 °C in

a more acidic THF/AcOH mixture (entry 13) gave only traces

of the product at full conversion of diﬂuorocyclopropene 2 due

to the competing side reactions. When heating was employed

for the reaction in EtOH/HFIP (entry 19), slight reaction

acceleration was noticed, compared to EtOH alone (entry 15),

1

0 is the early 3-CR intermediate. It should be noted that it has

been observed neither in 3-CR-s studied later nor in

experiments 2 and 3 (Table 1) upon LC-MS monitoring,

indicating the high conversion rate of the intermediate 10 in 3-

CR.

due to the facilitated hydrolysis of the CF group of 2 in

2

slightly acidiﬁed media. On the other hand, DMSO media

greatly suppressed the reaction (entries 6, 7), probably due to

its basicity, indicating that protic catalysis was necessary. In wet

HFIP at room temperature, fast conversion (∼1 h) of 2 led

exclusively to the dimeric indolizine 12 product (entry 18), but

at 55 °C the corresponding 3-CR product/dimeric-12 ratio

was ∼3/7 (entry 19). Thus, heating was necessary to activate

the reaction with tetrazine and to suppress formation of

dimeric-12 at the same time.

We decided to synthesize 10 separately by hydrolyzing its

precursor 2. In wet THF under reﬂux conditions, no reaction

took place after 18 h even with acidic additives (SiO or

2

Amberlyst-15) present, but in wet 1,1,1,3,3,3-hexaﬂuoro-2-

propanol (HFIP), the full conversion was achieved after 20

min at room temperature, giving 10 in 70% isolated yield.

Cyclopropenone 10 was found to be stable enough, showing

D

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Table 2. Three-Component Reaction Condition Exploration

3 equiv excess of pyridine was employed in 3-CR, no reaction

occurred after 24 h, but taken stoichiometrically, ∼7%

conversion was observed at the same period of time. It was

not completed even after 96 h (85% conversion), and this

observation was in agreement with what we noticed above that

bases signiﬁcantly suppressed 3-CR at the ﬁrst limiting step,

i.e., hydrolysis of diﬂuorocyclopropene 2 to reactive cyclo-

propenone 10. We applied the trick found upon 3-CR

condition exploration: HFIP as an acidic additive accelerated

the reaction. In this case, 2 equiv of HFIP shortened the

reaction time to adequate 48 h.

3

-CR

entry

1

solvent

i-PrOH

T, °C time, h observations (LC-MS) product

a

80

70

72

full conversion,

complex mixture

traces

+

2

3

t-BuOH

full conversion,

complex mixture

t-BuOH/H O

full conversion, side

products

2

(

8/2)

4

5

dioxane

100

70

18

decomposition

full conversion, 30%

yield

−

+

dioxane/H O

2

(

8/2),

When symmetric 2,3-dimethylpyrazine was employed

instead of the pyridine 3-CR component (entry 13), the

6

7

DMSO

70

72

only starting materials

−

DMSO/H O

2

26

(

8/2)

known condensation took place, giving the appropriate

pyrrolo[1,2-a]pyrazinol 28 in 60% yield, whereas non-

participating dimethyltetrazine 3 was recovered. Conducting

an experiment between competitive 2,3-dimethylpyrazine and

ethylisonicotinate with diﬂuorocyclopropene 2, the major

product was dimeric-12 and no appropriate pyrrolo[1,2-

a]pyrazinol was obtained, showing the much higher reactivity

of pyridine toward 2/10.

8

9

MeCN

55

18

only starting materials

full conversion

−

++

MeCN/H O

2

(

8/2)

1

0

MeCN/HFIP

1/1)

55

7

only starting materials

−

(

1

2

THF

55

18

only starting materials

95% conversion

−

++

THF/H O

2

(

8/2)

2

-Bromopyridine and several other aromatic heterocycles,

1

3

THF/AcOH

8/2)

EtOH

55

18

full conversion,

complex mixture

full conversion

5−10% conversion

full conversion, 50%

yield

traces

(

preferentially containing the pyridine-type nitrogen, e.g.,

thiazole, 5-carboxy-thiazole, (1-methyl or 1H)-pyrazole, and

-methoxycarbonyloxazole, were also tested as the pyridine

component in 3-CR. They did not participate in the reaction,

and only 3-hydroxypyrazole 13 appeared as a reaction product.

Fairly basic dimethylaminopyridine showed no reaction,

terminating it at the ﬁrst step of CF hydrolysis, and only

starting materials were recovered.

Mechanism Discussion. Next, having some experience in

the reaction under study, we focused on understanding its

mechanism. Upon addition of ethylisonicotinate to cyclo-

propenone 10, immediate reaction mixture colorization

b

14

15

16

70

55

36

18

++

+

+++

5

EtOH/H O

2

(

8/2)

1

7

8

9

EtOH/HFIP

1/1)

55

25

55

7

2

1

30% conversion

++

−

(

HFIP/H O

0% yield, mostly dimer

12

3-CR product/dimer

12 ∼ 30/70

2

(

20/1)

HFIP/H O

+

2

(

20/1)

a

Conversion is related to limiting diﬂuorocyclopropene 2. Dime-

thyltetrazine and ethylisonicotinate were used in 1.5 equiv excess.

EtOH used, contained ∼4 vol % water.

b

(

yellow) occurred with notable heat generation. LC-MS

analysis immediately after mixing indicated the clean formation

of monomeric 1-hydroxyindolizine 12, which was isolated by

Further, with optimized reaction conditions in hand, we

focused on exploring variations, mainly in the pyridine

component as the most accessible 3-CR counterpart, to

understand the reaction scope and limitations. The successful

combinations of reagents are presented in Table 3.

Functional groups such as ester, carbamoyl, ketone, phenol,

and acrylic esters were well-tolerated. Isolated yields were on

average about 50%, and in cases of isonicotinamide and 4-

acetylpyridine, they were 70 and 75%, respectively (entries 3,

chromatography on SiO . However, we found that monomeric

2

1

2 oxidatively dimerized at a rate of ∼10% per hour at room

temperature in air but was stable at −20 °C or in an inert

atmosphere. Other oxidizers (e.g., DAIB) caused immediate

dimerization of 1-hydroxyindolizine 12. When unsubstituted

pyridine was introduced instead of ethylisonicotinate, the

initial monomer was not detected due to the much faster

dimerization rate of the appropriate 1-hydroxyindolizine.

Importantly, when the reaction between 10 and pyridine was

performed in the presence of dimethyltetrazine 3, the 3-CR

product 27 was detected in LC-MS spectra, indicating that

monomeric 1-hydroxyindolizine is a 3-CR intermediate.

For more detailed mechanistic investigations, we performed

deuterium labeling (Scheme 3). Deuterodiﬂuorocyclopropene

4

3

). In the case of quinolines (entries 6, 7, 10), some amount of

-hydroxypyrazole 13 emerged as a byproduct. Unsymmetri-

cally substituted tetrazine 4 gave two 3-CR products with

methyl and 4-ﬂuorophenyl substituents at the triazole ring in a

7

:3 ratio (entries 10, 11). For the cases of α-, γ-unsubstituted

pyridines and quinolines (entries 6−10), only α-positions of

the pyridine ring were selectively functionalized in the course

of 3-CR. Unsymmetrical nicotinic acid and (E)-3-pyridin-3-yl-

acrylic acid methyl ester (entries 8, 9) aﬀorded two isomeric

products, with the ratio dictated by the steric factor. In the

particular case of the ketoacid 21 (entry 8) with possible ring-

chain tautomerism, only the ring tautomer was found

2

-D was synthesized from deuterated acetylene 1-D. Stability

of the carbon−deuterium bond was tested by heating the

sample of 2-D in wet ethanol at 65 °C for 24 h. As expected,

partial hydrolysis of the CF group took place, and deuterium

2

was conserved in deuterodiﬂuorocyclopropene 2-D, and the

appropriate deuterocyclopropenone with no deuterium ex-

change was noticed.

Due to poor stability of the 1-hydroxyindolizine 12 3-CR

intermediate, it was generated in situ in the NMR tube for its

proper characterization.

1

13

according to H and C NMR in CDCl and DMSO-d .

3

6

The completion time of the reactions varied: 18 h (entries 1,

, 10, 14, 15), 25 h (entries 3, 9, 11), and 40 h (entries 5, 7, 8).

2

We tried to conduct 3-CR with simple unsubstituted pyridine.

28

It diﬀers from the common set, as it is more basic⁽^p^Kb(H₂

O)

We added a stoichiometric amount of ethylisonicotinate to

=

8.83) than the other used pyridines pK_b₍_H₂_O₎∼ 10. When the

cyclopropenone 10 in degassed CD OD and yellow 1-

3

E

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Table 3. Examples of a Three-Component Reaction

F

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Table 3. continued

a

Reaction conditions: 1 mmol of each component (diﬂuorocyclopropene 2 (or 2a), pyridine, tetrazine), EtOH (10 mL), H O (0.1 mL) at 65 °C.

2

b

c

Isolated yields are given. Isolated yield for both 3-CR products. With 2 equiv of HFIP additive, under an argon atmosphere.

d

Diﬂuorocyclopropene 2a was used.

a

Scheme 3. Deuterium Labeling of the Diﬂuorocyclopropene Reaction Component

a

Double-bond tautomerism and deuterium exchange in 1-hydroxyindolizine 12.

a

Scheme 4. Three-Component Reaction with D-Labeled Diﬂuorocyclopropene

a

*No deuterium was incorporated in the reaction products.

hydroxyindolizine 12 was quickly formed. As in the case of its

dimer, we met signiﬁcant broadening of the aromatic region

signals in NMR along with the unusually broad signals of the

CH group in the COOEt substituent and CH adjacent to the

was rationalized by deuterium exchange in acidic CD OD

3

(12 H ↔ 12 D).

Obviously, when deuterocyclopropenone 10-D was used

instead of 10 in the same NMR-tube experiment, 3-deutero-1-

+

2

pyrrole ring. We assumed that slow double-bond tautomerism

was responsible for this phenomenon, and protonation of 1-

hydroxyindolizine might block the interconversions. Indeed,

the observed NMR spectrum signal sharpening after hydro-

chloric acid addition supported the tautomerism hypothesis.

hydroxyindolizine 12-D was cleanly formed, but it led to

+

essentially the same charged tautomer 12 D after CF

COOD

3

acidiﬁcation. Finally, we detected the CH group in the pyrrole

2

+

ring of charged 12 H at 5.2 ppm (proton) and 62.2 ppm

(carbon) by H NMR and heteronuclear single quantum

1

More accurately, CF COOD acidiﬁcation was enough to

coherence (HSQC), using deuterium-free solvents (CHCl₃

acidiﬁed with triﬂuoroacetyl (TFA)) where deuterium

exchange is not possible.

3

protonate indolizine 12 with full spectrum improvement.

1

Pyrrole ring proton disappearance from the H NMR spectrum

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Scheme 5. Three-Component Reaction Mechanism

In the 3-CR where labeled deuterodiﬂuorocyclopropene 2-D

reacted with ethylisonicotinate and dimethyltetrazine 3, we

observed deuterium loss in both the 3-CR product and

dimeric-12 (Scheme 4). As the deuterium label was conserved

in monomeric 1-hydroxyindolizine 12-D and its dimer

contained no deuterium atoms, we proposed that oxidative

dimerization of 1-hydroxyindolizine could occur at position 3,

which is the most electron-rich and reactive position for

protonation and electrophilic substitution.

Inﬂuence of air on 3-CR was qualitatively evaluated by LC-

MS, and we found that a less dimeric-12 byproduct was

formed in a degassed solvent under an argon atmosphere.

Hence, oxygen should be excluded from the reaction media.

With the collected experimental data in hands, we postulated

the reaction mechanism with the example of dimethyltetrazine

and unsubstituted pyridine (Scheme 5).

This mechanism is supported by LC-MS detection of

pyrazolo[1,2-a]tetrazin-6-one adducts with water and EtOH as

the reaction intermediates when 3 reacted with 10 at room

temperature.

CONCLUSIONS

■

The three-component reaction among monoalkyl substituted

3,3-diﬂuorocyclopropenes, s-tetrazines, and (benzo)pyridines

has been studied, and the 1,2,4-triazole product structure has

been reliably proved. The reaction mechanism based on the

studied 3-CR byproducts has been suggested and supported by

deuterium labeling experiments. To our knowledge, this is the

ﬁrst example of azaphilic cycloaddition between tetrazine and

unstable (oxygen-sensitive) 3-H-1-hydroxyindolizine. The

success of this cycloaddition is the slow formation of the 1-

hydroxyindolizine intermediate in the presence of tetrazine as

the heterodiene at elevated temperatures. Electron-with-

drawing groups (EWGs) at the pyridine component (or its

benzannulation) leads to basicity decrease, facilitating the

As follows from Scheme 5, proton in starting diﬂuorocyclo-

propene can be tracked to the triazole 3-CR product, where it

becomes exchangeable.

hydrolysis of the CF group in diﬂuorocyclopropene to aﬀord

2

As the obtained 3-CR products had an amorphous glass/

foam appearance, any attempts to grow a crystal were

unsuccessful even when NH of the piperidine ring was

deprotected and/or the methoxycarbonyl group was hydro-

reactive cyclopropenone, on the one hand, and suppressing

dimerization and heterodienophilicity of EWG-deactivated 1-

hydroxyindolizine, on the other hand. The kinetic balance

(

ﬁne-tuning) of these competing processes is responsible for

1

15

lyzed. However, we succeeded in obtaining { H- N} HMBC

optimized for 5 Hz coupling, with the correlation peaks

ultimately proving the correct triazole structure (Figure 2).

Finally, we have rationalized 3-hydroxypyrazole 13 3-CR

byproduct occurrence as follows in Scheme 6 .

the reaction rate and the product yields, which varied from 45

to 75%. Additionally, in the course of this study, the reactivity

of tetrazines as a net “hydrazine donor” for monoalkyl

substituted cyclopropenones has been discovered.

EXPERIMENTAL SECTION

■

General Information. Unless otherwise stated, reagents and

solvents were purchased from commercial suppliers (Sigma-Aldrich,

Apollo Scientiﬁc, Fisher, Acros Organics, and Alfa Aesar) and used

without further puriﬁcation. Ethyl alcohol contained 4 vol % water.

Chromatography solvents were of HPLC grade and used without

further puriﬁcation.

HPLC chromatography was performed on a C18 reverse-phase

2

HPLC Column YMC-Pack Pro C18 150 × 20 mm , particle size 10

μm, pore size 12 nm with a gradient elution, using as a mobile phase

various ratios of H O/MeCN with 0.1% formic acid. Flow rate was 15

mL/min, and elution time was 20 min. Analytical TLC was performed

2

1

15

Figure 2. Observed { H- N} HMBC correlations.

H

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Scheme 6. 3-Hydroxypyrazole 13 Byproduct Formation Mechanism

using TLC silica gel 60 F₂₅₄plates (Merck). Column chromatography

was performed on a Combiﬂash RF200 using Silica RediSep-Rf

disposable columns.

(10 mmol, 1.43 g, 1 equiv) in THF (30 mL), freshly prepared

lithiumdiisopropylamide (LDA; 1 M solution in THF, 12 mL, 1.2

equiv) was added at −60 °C over 5 min. The mixture was stirred for

0.5 h, and then, propargyl bromide (1.4 g, 1.2 equiv) in THF (5 mL)

was added dropwise. The reaction mixture was allowed to warm to 25

°C over 1 h. The reaction was quenched with saturated aqueous

1

13

H and C NMR (with carbon−proton interaction decoupling)

spectra were recorded on a Varian MERCURY plus 400 MHz

spectrometer or a Bruker AVANCE II 300 MHz spectrometer using

an internal deuterium lock at 50 °C unless otherwise stated. Chemical

shifts are given in parts per million (ppm) relative to the residual

NH Cl (10 mL) and extracted with EtOAc (2 × 15 mL). The

4

combined organic extracts were concentrated under reduced pressure,

1

13

solvent peak CDCl : ( H NMR 7.26 ppm, C NMR 77.0 ppm),

3

and the residue was puriﬁed on SiO , using hexane/EtOAc (8:2) as

2

1

13

1

DMSO-d : ( H NMR 2.50 ppm, C NMR 39.5 ppm), CD OD: H

NMR 3.25 ppm. In C NMR of deuterium-containing compounds,

6

3

the eluent to aﬀord 1 as a slowly crystallizing colorless liquid. Yield

13

9

0% (2.5 g).

Cr(acac) was added as a relaxation agent. Proton and carbon shifts

1

2

3

H NMR (400 MHz, CDCl ): δ 3,81 (m, J ∼ 14 Hz, 2H), 3.72 (s,

3

were additionally determined using HH and CH correlations

3

2

H), 3.00 (ddd, J = 13.9, 11.0, 3.0 Hz, 2H), 2.42 (d, J = 2.7 Hz, 2H),

correlation spectroscopy (COSY), HSQC, and HMBC (over ranges

2

.10 (m, J ∼ 13.6 Hz, 2H), 2.02 (t, J = 2.7 Hz, 1H), 1.55 (ddd, J =

2

3

of two and three bonds: J

, JH‑C‑C‑C⁾^.^S^t^r^u^c^t^u^r^a^l^a^s^sⁱ^gⁿ^m^eⁿ^t^s^w^e^r^e

H‑C‑C

13.6, 11.0, 4.4 Hz, 2H), 1.44 (s, 9H).

made with additional information from gCOSY, gHSQC, and

gHMBC experiments.

13

1

C{ H} NMR (100 MHz, CDCl ): δ 174.7, 154.8, 79.5, 79.2, 71.4,

3

52.0, 45.4, 41.1 (br.), 32.3, 29.0, 28.4.

LC-MS spectra were recorded on an Agilent 1100 Series

instrument using a Phenomenex Onyx Monolithic C18, 25 × 4.6

mp = 54−56 °C.

+

MS: Surveyor MSQ (APCI) m/z: 282.4 (M ), 267.4 (M − t-Bu +

2

mm column detected by a photodiode array (PDA) detector at 275

+

MeCN), 226.6 (M − t-Bu), 182.2 (M − Boc).

±

60 nm and by mass spectrometry (MS) APCI in positive ions.

+

HRMS (ESI-TOF) m/z: [M + H] calcd for C H NO 282.1706;

1

5

24

4

Mobile phase: A, 0.1% solution of formic acid in water; B, acetonitrile.

Flow rate was 1.5 mL/min, T_c_o_l_u_m_nwas 25 °C, and injection volume

was 5 μL. LC-MS spectra of reaction mixtures and starting materials

were recorded on Thermo Fisher Scientiﬁc Surveyor MSQ instrument

found: 282.1701.

Hex-5-ynoic Acid Methyl Ester (1a). Hex-5-ynoic acid (1.0 g, 9

mmol, 1 equiv) was dissolved in DMF (20 mL). Anhydrous K CO

2

3

2

(1.6 g, 1.3 equiv) was then added, and the suspension was cooled

ice/water bath). Iodomethane (1.9 g, 1.5 equiv) was added in one

portion, and the reaction mixture was stirred at +5 °C for 5 h. TLC

hexane/EtOAc = 9:1, staining with aq KMnO ) indicated full

using the Phenomenex Onyx Monoliythic C18 25 × 4.6 mm

(

detected by PDA at 200−800 nm, MS APCI in positive and negative

ions, and an evaporative light-scattering detector (ELSD) PL-ELS

(

4

2

100.

conversion, and the mixture was diluted with water (100 mL) and

extracted with EtOAc (2 × 20 mL). Organic extracts were combined

and carefully concentrated under reduced pressure (1a is volatile!),

and the crude product was puriﬁed by ﬂash chromatography on SiO₂

using EtOAc/hexane (1:15) as the eluent to aﬀord 1a as a light-yellow

High-resolution mass spectra (HRMS) were registered on a Bruker

micrOTOF-Q II hybrid quadrupole time-of-ﬂight mass spectrometer

using electrospray ionization (ESI); measurements were performed in

the positive ion mode. Voltage on the capillary 4500 V; range of

scanned masses m/z 50−3000; external calibration (Electrospray

Calibrant Solution; Fluka, Germany); nebulizer pressure 0.4 bar; ﬂow

rate 3 μL/min; nitrogen as dry gas (6 L/min); interface temperature

oil. Yield = 70% (0.9 g).

1

H NMR (400 MHz, CDCl ): δ 3.67 (s, 3H), 2.45 (t, J = 7.4 Hz,

3

2H), 2.26 (td, J = 6.9, 2.7 Hz, 2H), 1.95 (t, J = 2.7 Hz, 1H), 1.85 (p, J

1

80 °C. The samples were injected into the mass spectrometer

=

7.1 Hz, 2H).

chamber using a syringe injection or from the Agilent 1260 HPLC

1

3

1

C{ H} NMR (100 MHz, CDCl ): δ 173.4, 83.2, 69.0, 51.4, 32.7,

system equipped with an Agilent Poroshell 120 EC-C18 column (50

3

2

23.7, 17.9.

×

3.0 mm ; particle size 2.7 μm) and an identically packed security

MS: Surveyor MSQ (APCI), Agilent 1100 (APCI), HRMS (ESI-

TOF) m/z: not observable.

guard using an autosampler. The samples were dissolved in

acetonitrile (LC-MS grade; Panreac, Spain). The column was eluted

with a gradient of acetonitrile (A) concentrations in water (MilliQ

ultrapure water; Merck Millipore KGaA, Germany) with a ﬂow rate of

4

-(1-Deuteropropargyl)-N-Boc-4-methoxycarbonylpiperidine (1-

D). 4-Propargyl-N-Boc-4-methoxycarbonylpiperidine 1 (2.8 g, 10

mmol, 1 equiv) was dissolved in 20 mL of MeCN. Anhydrous K CO

4

00 μL/min in the following gradient parameters: 0−15% A for 6

2

3

(3.45 g, 2.5 equiv) was then added, and the suspension was stirred at

min, 15−85% A for 1.5 min, 85−0% A for 0.1 min, and 0% A for 2.4

min.

r.t. for 2 h. Deuterium oxide (4 mL, 20 equiv) was added thereto, and

the reaction mixture was stirred for 24 h at r.t. LC-MS analysis

showed deutero enrichment, and the reaction mixture was diluted

with EtOAc (50 mL). The organic phase was decanted and volatiles

were removed under reduced pressure to aﬀord 1-D with no

All solvent mixtures are quoted as volumes prior to mixing (v/v).

Starting Materials: Synthetic Procedures. 4-Propargyl-N-Boc-

4

-methoxycarbonylpiperidine (1)(CAS - 2199503-30-3). To a

stirred solution of N-Boc-piperidine-4-carboxylic acid methyl ester

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1

2

additional puriﬁcation necessary. According to NMR, 90% deutera-

H NMR (400 MHz, CDCl ): δ 3.82 (m, J ∼ 14 Hz, 2H), 3.73 (s,

3

tion was achieved. Yield = 99% (2.8 g).

3H), 3.05 (ddd, J = 13.9, 10.8, 3.0 Hz, 2H), 2.75 (t, J = 2.6 Hz, 2H),

1

2

H NMR (400 MHz, CDCl ): δ 3,82 (m, J ∼ 14 Hz, 2H), 3.74 (s,

2.14 (m, J ∼ 13.6 Hz, 2H), 1.48 (ddd, J = 13.6, 11.0, 4.4 Hz, 2H),

3

(

9

H), 3.00 (ddd, J = 13.9, 11.0, 3.0 Hz, 2H), 2.44 (s, Hz, 2H), 2.11

1.45 (s, 9H).

2

13

1

2

m, J ∼13.6 Hz, 2H), 1.56 (ddd, J = 13.6, 11.0, 4.4 Hz, 2H), 1.46 (s,

C{ H} NMR (100 MHz, CDCl

3

): δ 174.4, 154.7, 134.0 (t, JC−F

1

2

1

H).

= 11 Hz), 119.3 (tt, JC−D = 34.6 Hz, JC−F = 11.6 Hz), 101.5 (t, JC−F

= 270.5 Hz), 79.6, 52.1, 40.8 (br.), 33.8, 32.8, 28.4.

1

3

1

C{ H} NMR (100 MHz, CDCl ): δ 174.7, 154.7, 79.4, 78.7 (t,

3

²J_C₋_D= 7.5 Hz), 71.2 (t, J

1

= 38 Hz), 51.9, 45.3, 41.0 (br.), 32.2,

+

MS: Surveyor MSQ (APCI) m/z: 318.5 (M − t-Bu + MeCN),

C−D

+

2

3

67.1 (M − 65), 257.4 (M − 76), 233.3 (M − Boc).

2

8.9, 28.3.

+

HRMS (ESI-TOF) m/z: [M + H] calcd for C H F NO D

MS: Surveyor MSQ (APCI) m/z: 283.4 (M ), 268.3 (M − t-Bu +

16 23

2

4

+

33.1736; found: 333.1737.

4

peridine (10). 4-(3,3-Diﬂuorocycloprop-1-enylmethyl)-N-Boc-4-me-

thoxycarbonylpiperidine 2 (330 mg, 1 mmol, 1 equiv) was dissolved

in hexaﬂuoroisopropanol (HFIP) (3.5 mL), and H O (0.35 mL) was

then added at room temperature upon stirring. After 20 min, volatiles

were removed under reduced pressure and the crude product was

MeCN), 227.3 (M − t-Bu), 183.2 (M − Boc).

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C H NO D

-(3-Oxocycloprop-1-enylmethyl)-N-Boc-4-methoxycarbonylpi-

1

5

23

4

2

83.1768; found: 283.1751.

-(3,3-Diﬂuorocycloprop-1-enylmethyl)-N-Boc-4-methoxycarbo-

nylpiperidine (2). 4-Propargyl-N-Boc-4-methoxycarbonylpiperidine 1

2 g, 7.1 mmol, 1 equiv) was dissolved in dry THF (15 mL), and

4

2

(

ﬁnely ground NaI (0.38 g, 0.36 equiv) was added at room

temperature. The reaction vessel was degassed by sequential

evacuation and releasing vacuum with argon (three times). Then,

the reaction vessel was placed in a preheated (70 °C) oil bath and 2

puriﬁed by ﬂash chromatography on SiO using EtOAc as the eluent

2

⁽Rf (10) ∼ 0.4) to aﬀord 10 as a light-pink oil. Yield = 70% (215 mg).

1

2

H NMR (400 MHz, CD OD): δ 8,68 (s, 1H), 3.73 (m, J ∼ 14

3

Hz, 2H), 3.68 (s, 3H), 3.08 (ddd, J = 13.7, 10.3, 3.2 Hz, 2H), 2.97 (s,

M solution of TMS-CF in THF (12.5 mL, 3.5 equiv) was pumped

3

2

1

H), 2.12 (m, J ∼ 14 Hz, 2H), 1.54 (ddd, J = 14.1, 10.3, 4.2 Hz, 2H),

over 6 h upon stirring and left at reﬂux for 40 h. After reaction

completion according to LC-MS and TLC (hexane/EtOAc = 7:3, R_f

.39 (s, 9H).

1

2

H NMR (400 MHz, CDCl ): δ 8.44 (s, 1H), 3.81 (m, J ∼ 14 Hz,

3

(

1) ∼ 0.60, R (2) ∼ 0.55), volatiles were removed under reduced

f

2

1

H), 3.74 (s, 3H), 3.08 (ddd, J = 13.7, 10.6, 3.2 Hz, 2H), 2.90 (s,

pressure and the crude product was puriﬁed by chromatography on

2

H), 2.20 (m, J ∼ 14 Hz, 2H), 1.54 (ddd, J = 14.1, 10.3, 4.2 Hz, 1H),

SiO using EtOAc/hexane (3:7) as the eluent to aﬀord 2 as a light-

2

.45 (s, 9H).

yellow oil, which slowly crystallized on standing. Yield = 99% (2.3 g).

1

3

1

C{ H} NMR (100 MHz, CDCl

): δ 174.3, 166.9, 156.2, 154.7,

3

H NMR (400 MHz, CDCl ): δ 7.30 (tt, J = 1.9, 0.9 Hz, 1H), 3.82

3

2

149.8, 79.8, 52.4, 44.6, 40.8 (br.), 37.3, 32.9, 28.4.

(

2

(

m, J ∼14 Hz, 2H), 3.73 (s, 3H), 3.05 (ddd, J = 13.9, 10.8, 3.0 Hz,

+

2

MS: Surveyor MSQ (APCI) m/z: 310.4 (M ), 254.3 (M − t-Bu),

H), 2.76 (td, J = 2.6, 0.8 Hz, 2H), 2.14 (m, J ∼ 13.6 Hz, 2H), 1.48

+

2

10.2 (M − Boc).

ddd, J = 13.6, 11.0, 4.4 Hz, 2H), 1.45 (s, 9H).

+

13

1

2

HRMS (ESI-TOF) m/z: [M + H] calcd for C16

H

24NO

5

310.1655;

C{ H} NMR (100 MHz, CDCl ): δ 174.5, 154.8, 134.4 (t, J

3

C−F

2

1

found: 310.1648.

4

=

11.2 Hz), 119.6 (t, J

= 12.1 Hz), 101.7 (t, J

= 270.7 Hz),

C−F

-(2-Deutero-3-oxocycloprop-1-enylmethyl)-N-Boc-4-methoxy-

7

9.7, 52.2, 44.5, 40.9 (br.), 33.9, 32.9, 28.4.

mp = 65−66 °C.

carbonylpiperidine (10-D). The product was prepared from 4-(2-

deutero-3,3-diﬂuorocycloprop-1-enylmethyl)-N-Boc-4-methoxycarbo-

nylpiperidine 2-D (0.66 g, 2 mmol, 1 equiv) according to the

procedure described for 10 and was isolated as a light-pink oil. Yield =

+

MS: Surveyor MSQ (APCI) m/z: 317.4 (M − t-Bu + MeCN),

+

2

3

67.3 (M − 65), 256.3 (M − 76).

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C H F NO

2

1

6

24

2

4

90% (0.43 g), 90% H.

32.1674; found: 332.1662.

1

2

H NMR (400 MHz, CDCl ): δ 3.80 (m, J ∼ 14 Hz, 2H), 3.73 (s,

3

4-(3,3-Diﬂuorocycloprop-1-enyl)-butyric Acid Methyl Ester (2a).

2

3

∼

H), 3.07 (ddd, J = 13.7, 10.6, 3.2 Hz, 2H), 2.89 (s, 2H), 2.20 (m, J

Hex-5-ynoic acid methyl ester 1a (0.9 g, 5 mmol, 1 equiv) was

dissolved in dry THF (15 mL), and ﬁnely ground NaI (0.27 g, 0.36

equiv) was added at room temperature. The reaction vessel was

degassed by sequential evacuation and releasing vacuum with argon

14 Hz, 2H), 1.53 (ddd, J = 13.7, 10.6, 4.3 Hz, 2H), 1.44 (s, 9H).

1

2

H NMR (400 MHz, CD OD): δ 3.73 (m, J ∼ 14 Hz, 2H), 3.68

3

(

s, 3H), 3.08 (ddd, J = 13.7, 10.3, 3.2 Hz, 2H), 2.97 (s, 2H), 2.12

dddd, J = 13.6, 5.1, 3.3, 1.5 Hz, 2H), 1.54 (ddd, J = 14.1, 10.3, 4.2

(

three times). Then, the reaction vessel was placed in a preheated (70

Hz, 2H), 1.40 (s, 9H).

°

C) oil bath and 2M solution of TMS-CF in THF (12.5 mL, 3.5

equiv) was pumped over 6 h upon stirring and left at reﬂux for 18 h.

13

1

3

C{ H} NMR (100 MHz, CDCl ): δ 174.2, 166.5, 156.0, 154.6,

3

1

49.4 (t, J

= 32.1 Hz), 79.7, 52.3, 44.5, 40.7 (br.), 37.2, 32.8,

C−D

After reaction completion according to TLC (hexane/EtOAc = 9:1, R_f

28.3.

+

(

1a) ∼ 0.60, R (2a) ∼ 0.42), volatiles were removed under reduced

f

MS: Surveyor MSQ (APCI) m/z: 311.4 (M ), 255.3 (M − t-Bu),

+

pressure and the crude product was puriﬁed by chromatography on

2

11.2 (M − Boc); Agilent 1100 (APCI) m/z = 228.0, 210.0, 182.0.

+

SiO using EtOAc/hexane (2:8) as the eluent to aﬀord 2a as a light-

2

HRMS (ESI-TOF) m/z: [M + H] calcd for C H NO 311.1718;

1

5

25

4

yellow oil. Yield = 75% (0.65 g).

found: 311.1702.

Product 2a showed partial (∼30%) decomposition after two weeks

General Three-Component Reaction Procedure (Synthesis of

Compounds 9, 14−26). A 20 mL screw-cap clear vial was charged

with 4-(3,3-diﬂuorocycloprop-1-enylmethyl)-N-Boc-4-methoxycarbo-

nylpiperidine (2) (330 mg, 1 mmol, 1 equiv), 3,5-dimethyltetrazine

(8) (110 mg, 1 equiv), and appropriate pyridine or (iso)quinoline (1

mmol, 1 equiv) followed by addition of ethanol (10 mL) and water

(0.1 mL). The reaction mixture was evacuated and the vacuum was

released with argon (3 times); then, it was sealed and heated with

stirring at 65 °C for 18−48 h. The red color of the reaction mixture

gradually disappeared, indicating that tetrazine was consumed. Full

conversion of 2 was ensured according to LC-MS. Volatiles were

removed under reduced pressure, and the residue was redissolved in a

minimal amount of MeCN (∼2 mL) for puriﬁcation by HPLC with

gradient elution from 25 to 55% MeCN (20 min). Alternatively,

of storage at −20 °C.

1

H NMR (400 MHz, CDCl ): δ 7.24 (tt, J = 1.8, 1.0 Hz, 1H), 3.66

3

(

s, 3H), 2.56 (ttd, J = 7.3, 2.6, 0.9 Hz, 2H), 2.40 (t, J = 7.3 Hz, 2H),

1

.95 (p, J = 7.5 Hz, 2H).

13

1

2

C{ H} NMR (100 MHz, CDCl ): δ 172.6, 137.1 (t, J

= 10.1

3

C−F

2

1

Hz), 117.4 (t, J

= 11.5 Hz), 102.2 (t, J

= 269.7 Hz), 51.2,

C−F

3

2.5, 22.7, 21.4.

MS: Surveyor MSQ (APCI), Agilent 1100 (APCI) m/z: not

observable.

HRMS (ESI-TOF): m/z: [M + H] calcd for C H F O − 2(HF)

+

8

11

2

+

H O 155.0708; found: 155.0704.

2

4

-(2-Deutero-3,3-diﬂuorocycloprop-1-enylmethyl)-N-Boc-4-me-

thoxycarbonylpiperidine (2-D). The product was prepared from 4-

1-deuteropropargyl)-N-Boc-4-methoxycarbonylpiperidine 1-D (1.4

(

column chromatography on SiO may be performed, with gradient

2

g, 5 mmol.) according to the procedure described for 2 and was

isolated as a light-yellow oil. Yield = 90% (1.5 g), 90% H.

elution from EtOAc to EtOAc/MeOH (9:1) for the compounds 9,

14−19, 22, 23, 25, 29, and 30. Solvents from the collected fractions

2

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were evaporated to provide compounds 9 and 14−26 as amorphous

1H), 2.63 (dd, J = 14.4, 7.2 Hz, 1H), 2.39 (s, 3H), 2.29 (dd, J = 14.4,

solids.

5.3 Hz, 1H), 2.11 (m, 2H), 1.44 (s, 9H), 1.43 (m, 2H).

1

3

1

4-[2-(5-Methyl-4H-[1,2,4]triazol-3-yl)-3-oxo-3-(4-[1,2,4]triazin-3-

C{ H} NMR (75 MHz, CDCl , 25 °C): δ = 197.0, 175.3, 167.1,

3

yl-pyridin-2-yl)-propyl]-N-Boc-4-methoxycarbonylpiperidine (9).

The product was obtained from 2 (330 mg, 1 mmol), 3,5-

dimethyltetrazine 3 (110 mg, 1 equiv), and 3-pyridin-4-yl-[1,2,4]-

triazine 5 (158 mg, 1 equiv) and was isolated as a gray foam. Yield =

158.7 (br.), 155.2, 154.9, 152.5, 150.1, 141.9, 125.7, 120.2, 79.8, 52.0,

45.2, 41.4 (br.), 40.9 (br.), 40.1, 39.9, 33.4 (br.), 28.4, 12.0.

+

MS: Agilent 1100 (APCI) m/z: 501.1 (M ), 445.1 (M − t-Bu),

+

401.1 (M − Boc).

+

5

0% (268 mg).

HRMS (ESI-TOF) m/z: [M + H] calcd for C H N O

2

4

33

6

1

H NMR (300 MHz, DMSO-d ): δ 9.49 (d, J = 2.4 Hz, 1H), 9.01

501.2462; found: 501.2457.

6

(

d, J = 2.4 Hz, 1H), 8.94 (dd, J = 5.0, 0.8 Hz, 1H), 8.84 (t, J = 1.8, 0.8

4-[3-(4-Acetyl-pyridin-2-yl)-2-(5-methyl-2H-[1,2,4]triazol-3-yl)-3-

oxopropyl]-N-Boc-4-methoxycarbonylpiperidine (16). The product

was obtained from 2 (330 mg, 1 mmol), 3,5-dimethyltetrazine 3 (110

mg, 1 equiv), and 4-acetylpyridine (121 mg, 1 equiv) and was isolated

Hz, 1H), 8.51 (dd, J = 5.0, 1.8 Hz, 1H), 5.60 (dd, J = 7.5, 4.9 Hz,

2

3

1

2

H), 3.69 (m, J ∼ 14 Hz, J ∼ 4.5 Hz, 2H), 3.50 (s, 3H), 2.86 (m,

H), 2.57 (dd, J = 14.4, 7.5 Hz, 1H), 2.28 (dd, J = 14.4, 4.9 Hz, 1H),

.23 (s, 3H), 2.02 (m, 2H), 1.45 (m, 2H), 1.40 (s, 9H).

H NMR (400 MHz, CDCl ): δ 9.27 (d, J = 2.4 Hz, 1H), 9.05 (dd,

as a brownish foam. Yield = 75% (375 mg).

1

H NMR (400 MHz, CDCl ): δ 8.86 (dd, J = 5.0, 0.8 Hz, 1H),

3

J = 1.7, 0.8 Hz, 1H), 8.85 (dd, J = 5.0, 0.8 Hz, 1H), 8.75 (d, J = 2.4

Hz, 1H), 8.53 (dd, J = 5.0, 1.7 Hz, 1H), 5.79 (dd, J = 7.5, 5.3 Hz,

8.43 (dd, J = 1.7, 0.8 Hz, 1H), 7.90 (dd, J = 5.0, 1.7 Hz, 1H), 5.74

(dd, J = 7.5, 5.3 Hz, 1H), 3.84 (m, 2H), 3.57 (s, 3H), 2.88 (m, 1H),

2.81 (m, 1H), 2.70 (dd, J = 14.4, 7.5 Hz, 1H), 2.66 (s, 3H), 2.39 (s,

3H), 2.32 (dd, J = 14.4, 5.3 Hz, 1H), 2.13 (m, 2H), 1.44 (s, 9H), 1.43

(m, 2H).

1

(

1

H), 3.82 (m, 2H), 3.54 (s, 3H), 2.86 (m, 1H), 2.79 (m, 1H), 2.71

dd, J = 14.4, 7.5 Hz, 1H), 2.37 (s, 3H), 2.33 (dd, J = 14.4, 5.3 Hz,

H), 2.13 (m, 2H), 1.44 (m, 2H), 1.42 (s, 9H).

13

1

13

1

C{ H} NMR (100 MHz, CDCl ): δ 196.6, 175.1, 162.0, 158.7

C{ H} NMR (100 MHz, CDCl ): δ 197.0, 196.4, 175.3, 159.3

3

(

br.), 156.1 (br.), 154.7, 153.4, 149.9, 148.8, 148.8, 143.5, 125.1,

21.2, 79.5, 51.8, 45.4, 41.3 (br.), 40.4, 40.0, 33.7, 33.5, 28.5, 12.8.

(br.), 155.9 (br.), 154.8, 153.7, 150.2, 144.2, 124.4, 120.6, 79.5, 51.7,

45.3, 41.2 (br.), 40.4, 39.8, 33.6, 33.4, 28.4, 26.6, 12.5.

1

4

5

+

MS: Agilent 1100 (APCI) m/z: 537.1 (M ), 481.1 (M − t-Bu),

MS: Agilent 1100 (APCI) m/z: 500.0 (M ), 443.9 (M − t-Bu),

+

37.1 (M − Boc).

400.0 (M − Boc).

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C H N O

HRMS (ESI-TOF) m/z: [M + H] calcd for C H N O

+

2

6

33

8

5

25 34

5

6

37.2574; found: 537.2566.

-[3-(4-Ethoxycarbonylpyridin-2-yl)-2-(5-methyl-4H-[1,2,4]-

triazol-3-yl)-3-oxopropyl]-N-Boc-4-methoxycarbonylpiperidine

14). The product was obtained from 2 (330 mg, 1 mmol), 3,5-

500.2509; found: 500.2503.

4

4-[3-Isoquinolin-1-yl-2-(5-methyl-4H-[1,2,4]triazol-3-yl)-3-oxo-

propyl]-N-Boc-4-methoxycarbonylpiperidine (17). The product was

obtained from 2 (330 mg, 1 mmol), 3,5-dimethyltetrazine 3 (110 mg,

1 equiv), and isoquinoline (129 mg, 1 equiv) and was isolated as a

(

dimethyltetrazine 3 (110 mg, 1 equiv), and ethylisonicotinate (151

mg, 1 equiv) and was isolated as a brownish foam. Yield = 50% (264

mg₁).

greenish foam. Yield = 55% (280 mg).

1

H NMR (300 MHz, DMSO-d ): δ = 8.58 (m, 2H), 8.01 (m, 2H),

6

H NMR (400 MHz, DMSO-d )major tautomer (80%): δ 13.1

7.79 (ddd, J = 8.2, 6.9, 1.4 Hz, 1H), 7.72 (ddd, J = 8.2, 6.9, 1.5 Hz,

1H), 5.61 (dd, J = 6.7, 5.4 Hz, 1H), 3.69 (m, 2H), 3.50 (s, 3H), 2.86

(m, 2H), 2.59 (dd, J = 14.4, 6.8 Hz, 1H), 2.27 (dd, J = 14.4, 5.4 Hz,

6

(

s, 1H), 8.88 (d, J = 5.0 Hz, 1H), 8.27 (dd, J = 1.6, 0.8 Hz, 1H), 8.01

(

dd, J = 5.0, 1.6 Hz, 1H), 5.51 (dd, J = 8.4, 3.9 Hz, 1H), 4.38 (q, J =

3

2

7

8

1

3

.1 Hz, 2H), 3.68 (m, 2H), 3.41 (s, 3H), 2.74 (m, 2H), 2.49 (m, J ∼

Hz, 1H), 2.21 (s, 3H), 2.15 (dd, J = 14.3, 3.9 Hz, 1H), 2.02 (m,

H), 1.92 (m, 1H), 1.36 (s, 9H), 1.35 (m, 2H), 1.34 (t, J = 7.1 Hz,

H₁).

1H), 2.17 (s, 3H), 2.03 (m, J ∼ 14 Hz, 2H), 1.42 (m, 2H), 1.40 (s,

9H).

1

H NMR (400 MHz, CDCl ): δ = 8.89 (d, J = 8.4 Hz, 1H), 8.53

3

(d, J = 5.5 Hz, 1H), 7.80 (dd, J = 8.0, 1.4 Hz, 1H), 7.75 (d, J = 5.5 Hz,

1H), 7.66 (ddd, J = 8.2, 6.7, 1.4 Hz, 1H), 7.61 (ddd, J = 8.2, 6.8, 1.5

Hz, 1H), 5.87 (t, J = 6.3 Hz, 1H), 3.80 (m, 2H), 3.50 (s, 3H), 2.84

(m, 2H), 2.70 (dd, J = 14.4, 6.7 Hz, 1H), 2.38 (dd, J = 14.4, 5.9 Hz,

1H), 2.31 (s, 3H), 2.13 (m, 2H), 1.44 (m, 2H), 1.42 (s, 9H).

H NMR (400 MHz, CDCl ): δ 10.88 (br. s, 1H), 8.81 (dd, J = 4.9,

3

0

1

.8 Hz, 1H), 8.54 (t, J = 1.7, 0.8 Hz, 1H), 8.00 (dd, J = 4.9, 1.7 Hz,

H), 5.73 (dd, J = 7.5, 5.2 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 4.43 (q,

J = 7.1 Hz, 2H), 3.83 (m, 2H), 3.55 (s, 3H), 2.87 (m, 1H), 2.80 (m,

1

3

1

5

7

H), 2.70 (dd, J = 14.4, 7.5 Hz, 1H), 2.37 (s, 3H), 2.32 (dd, J = 14.4,

.2 Hz, 1H), 2.13 (m, 2H), 1.45 (m, 2H), 1.44 (s, 9H), 1.41 (t, J =

.1 Hz, 3H).

C{ H} NMR (100 MHz, CDCl ): δ 199.1, 175.4, 158.9, 156.5,

3

154.8, 151.4, 141.0, 137.1, 130.4, 129.2, 126.9, 126.8, 126.6, 124.9,

79.5, 51.7, 45.4, 42.4, 41.2, 39.6, 33.6, 33.4, 28.4, 12.7.

13

1

+

C{ H} NMR (100 MHz, CDCl ): δ 196.8, 175.3, 164.3, 159.2

MS: Agilent 1100 (APCI) m/z: 508.1 (M ), 452.1 (M − t-Bu).

3

+

(

5

br.), 155.9 (br.), 154.8, 153.3, 149.8, 139.3, 126.3, 122.1, 79.5, 62.1,

HRMS (ESI-TOF) m/z: [M + H] calcd for C H N O

2

7

34

5

1.7, 45.3, 41.2 (br.), 40.4, 39.9, 33.6, 33.4, 28.4, 14.1, 12.5.

508.2560; found: 508.2559.

1

5

N NMR (30 MHz, CDCl ) δ 323.5, 251.7, 246.0, 231.3, 86.1.

4-[3-(6-Chloroquinolin-2-yl)-2-(5-methyl-4H-[1,2,4]triazol-3-yl)-

3-oxopropyl]-N-Boc-4-methoxycarbonylpiperidine (18). The prod-

uct was obtained from 2 (330 mg, 1 mmol), 3,5-dimethyltetrazine 3

(110 mg, 1 equiv), and 6-chloroquinoline (164 mg, 1 equiv) and was

3

+

MS: Agilent 1100 (APCI) m/z: 530.0 (M ), 473.9 (M − t-Bu),

+

4

5

29.9 (M − Boc).

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C H N O

2

6

36

5

7

30.2615; found: 530.2605.

-[3-(4-Carbamoylpyridin-2-yl)-2-(5-methyl-4H-[1,2,4]triazol-3-

isolated as a brownish foam. Yield = 50% (270 mg).

1

4

H NMR (400 MHz, CDCl ): δ 8.17 (d, J = 8.6 Hz, 1H), 8.14 (d, J

3

yl)-3-oxopropyl]-N-Boc-4-methoxycarbonylpiperidine (15). The

product was obtained from 2 (330 mg, 1 mmol), 3,5-dimethylte-

trazine 3 (110 mg, 1 equiv), and isonicotinamide (122 mg, 1 equiv)

= 9.0 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.71

(dd, J = 9.0, 2.3 Hz, 1H), 5.97 (dd, J = 7.2, 5.7 Hz, 1H), 3.84 (m,

2H), 3.53 (s, 3H), 2.90 (m, 1H), 2.82 (m, 1H), 2.70 (dd, J = 14.4, 7.2

Hz, 1H), 2.38 (dd, J = 14.4, 5.7 Hz, 1H), 2.38 (s, 3H), 2.16 (m, 2H),

1.50 (m, 2H), 1.44 (s, 9H).

and was isolated as a white foam. Yield = 70% (350 mg).

1

H NMR (400 MHz, DMSO-d ): δ = 8.82 (dd, J = 5.0, 0.8 Hz,

6

1

3

1

2

H), 8.33 (dd, J = 1.7, 0.8 Hz, 1H), 8.33 (br. s, 1H), 7.98 (dd, J = 5.0,

.7 Hz, 1H), 7.69 (br. s, 1H), 5.57 (dd, J = 8.0, 4.4 Hz, 1H), 3.70 (m,

H), 3.43 (s, 3H), 2.78 (m, 1H), 2.73 (m, 1H), 2.47 (m, J ∼ 14 Hz,

C{ H} NMR (75 MHz, CDCl , 70 °C): δ 197.5, 175.3, 158.9,

3

156.0, 154.9, 152.1, 145.5, 136.2, 135.0, 132.2, 131.2, 130.2, 126.3,

2

119.8, 79.5, 51.6, 45.4, 41.2 (br.), 40.2, 40.0, 33.6, 33.5, 28.4, 12.4.

3

15

J ∼ 8 Hz, 1H), 2.21 (s, 3H), 2.16 (dd, J = 14.3, 4.5 Hz, 1H), 2.02 (m,

N NMR (30 MHz, CDCl ): δ 311.6, 240.4, 258.4, 225.6, 85.9.

3

+

1

H), 1.95 (m, 1H), 1.38 (s, 9H), 1.35 (m, 2H).

MS: Agilent 1100 (APCI) m/z: 542.1 (M ), 486.0 (M − t-Bu),

1

+

H NMR (400 MHz, CDCl ): δ = 8.75 (d, J = 4.9 Hz, 1H), 8.31

442.0 (M − Boc).

3

+

35

(

br. d, J = 1.6 Hz, 1H), 7.90 (dd, J = 4.9, 1.6 Hz, 1H), 5.74 (dd, J =

HRMS (ESI-TOF) m/z: [M + H] calcd for C H ClN O

27 33 5 5

7

.2, 5.5 Hz, 1H), 7.83 (m, 2H), 3.54 (s, 3H), 2.86 (m, 1H), 2.79 (m,

542.2170; found: 542.2165.

K

https://dx.doi.org/10.1021/acs.joc.0c02292

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

1

4

-[3-(6-Hydroxyquinolin-2-yl)-2-(5-methyl-4H-[1,2,4]triazol-3-

H NMR (400 MHz, CDCl ): δ 8.77 (d, J = 2.0 Hz, 1H), 8.05 (d, J

3

yl)-3-oxopropyl]-N-Boc-4-methoxycarbonylpiperidine (19). The

product was obtained from 2 (330 mg, 1 mmol), 3,5-dimethylte-

trazine 3 (110 mg, 1 equiv), and 6-hydroxy-quinoline (145 mg, 1

= 8.1 Hz, 1H), 7.92 (dd, J = 8.1, 2.0 Hz, 1H), 7.68 (d, J = 16.1 Hz,

1H), 6.57 (d, J = 16.1 Hz, 1H), 5.71 (dd, J = 7.5, 5.1 Hz, 1H), 3.83 (s,

3H), 3.83 (m, 2H), 3.54 (s, 3H), 2.86 (m, 1H), 2.80 (m, 1H), 2.68

(dd, J = 14.4, 7.5 Hz, 1H), 2.36 (s, 3H), 2.30 (dd, J = 14.4, 5.1 Hz,

1H), 2.12 (m, 2H), 1.43 (m, 2H), 1.43 (s, 9H).

equiv) and was isolated as a pinkish foam. Yield = 50% (260 mg).

1

H NMR (300 MHz, CDCl , 70 °C): δ 10.86 (br, s, 1H), 7.83 (d, J

3

1

3

1

=

(

1

8.6 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.13

dd, J = 9.2, 2.6 Hz, 1H), 6.87 (d, J = 2.6 Hz, 1H), 6.05 (t, J = 6.4 Hz,

H), 3.80 (m, 2H), 3.51 (s, 3H), 2.91 (m, 2H), 2.64 (dd, J = 14.3, 6.4

C{ H} NMR (100 MHz, CDCl ): δ 196.6, 175.3, 166.3, 158.9

3

(br.), 156.4 (br.), 154.8, 152.9, 148.8, 139.8, 135.3, 133.7, 123.0,

122.4, 79.5, 52.0, 51.7, 45.3, 41.2 (br.), 40.2, 39.9, 33.6, 33.4, 28.4,

12.7.

3

Hz, 1H), 2.43 (dd, J ∼ 6.5 Hz, 1H), 2.41 (s, 3H), 2.15 (m, 2H), 1.45

+

(

m, 2H), 1.44 (s, 9H).

MS: Agilent 1100 (APCI) m/z: 542.2 (M ), 486.1 (M − t-Bu),

13

1

+

C{ H} NMR (75 MHz, CDCl , 70 °C): δ 197.3, 175.4, 158.1

432.0 (M − Boc).

3

+

(

br.), 158.0, 156.4 (br.), 155.1, 148.6, 142.3, 135.1, 132.1, 131.5,

HRMS (ESI-TOF) m/z: [M + H] calcd for C H N O

2

7

36

5

7

1

2

23.1, 119.0, 108.6, 79.9, 51.8, 45.5, 41.3 (br.), 40.0, 39.7, 33.8, 33.3,

542.2615; found: 542.2608.

8.5, 12.3.

4-[3-[3-((E)-2-Methoxycarbonylvinyl)-pyridin-2-yl]-2-(5-methyl-

4H-[1,2,4]triazol-3-yl)-3-oxopropyl]-N-Boc-4-methoxycarbonylpi-

peridine (23). The minor isomer (83/17) was not isolated as a pure

+

MS: Agilent 1100 (APCI) m/z: 524.2 (M ), 468.1 (M − t-Bu),

+

4

5

3

24.0 (M − Boc).

1

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C H N O

compound, and nonoverlapping signals of the H NMR aromatic

2

7

34

5

6

region (6−9 ppm) are given.

24.2509; found: 524.2502.

-[3-(5-Carboxypyridin-2-yl)-2-(5-methyl-4H-[1,2,4]triazol-3-yl)-

-oxo-propyl]-N-Boc-4-methoxycarbonylpiperidine (20). The prod-

1

H NMR (400 MHz, DMSO-d ): δ 8.66 (dd, J = 4.7, 1.5 Hz, 1H),

4

6

8.22 (dd, J = 8.0, 1.6 Hz, 1H), 7.98 (d, J = 16.0 Hz, 1H), 7.61 (dd, J =

8.0, 4.6 Hz, 1H), 6.56 (d, J = 16.0 Hz, 1H), 5.44 (dd, J = 7.4, 4.7 Hz,

1H).

uct was obtained from 2 (330 mg, 1 mmol), 3,5-dimethyltetrazine 3

(

110 mg, 1 equiv), and nicotinic acid (123 mg, 1.1 mmol) and was

¹H NMR (400 MHz, CDCl

): δ 8.60 (d, J = 4.4 Hz, 1H), 8.23 (d, J

isolated as a brownish foam. The major isomer had a greater retention

3

time on LC-MS (45/55). Yield = 137 mg, 50% (for both isomers).

= 16.0 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.41 (dd, J = 7.8, 4.4 Hz,

1H), 6.23 (d, J = 16.0 Hz, 1H).

1

H NMR (300 MHz, CDCl ): δ 12.00 (br. s, 2H), 9.22 (d, J = 2.0

3

Hz, 1H), 8.36 (dd, J = 8.1, 2.0 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 5.83

MS (Mixture with regioisomer 22): Agilent 1100 (APCI) m/z:

+

(

2

dd, J = 7.1, 5.5 Hz, 1H), 3.85 (m, 2H), 3.55 (s, 3H), 2.87 (m, 2H),

.71 (dd, J = 14.5, 7.1 Hz, 1H), 2.41 (s, 3H), 2.38 (dd, J = 5.5 Hz,

542.2 (M ), 486.1 (M − t-Bu), 432.0 (M − Boc).

3

HRMS (Mixture with regioisomer 22) (ESI-TOF) m/z: [M + H]⁺

1

H), 1.45 (m, 2H), 1.44 (s, 9H).

calcd for C27H N O 542.2615; found: 542.2598.

36 5 7

13

1

C{ H} NMR (75 MHz, CDCl ): δ 196.4, 175.3, 166.5, 158.3

4-{3-(6-Chloroquinolin-2-yl)-2-[5-(4-ﬂuorophenyl)-2H-[1,2,4]-

3

triazol-3-yl]-3-oxopropyl}-N-Boc-4-methoxycarbonylpiperidine

(

br.), 156.1 (br.), 155.1, 154.6, 150.7, 138.5, 129.6, 122.5, 79.9, 51.8,

(

24). The product was obtained from 2 (330 mg, 1 mmol), 3-(4-

4

5

5.4, 41.3 (br.), 40.3, 39.4, 33.7, 33.5, 28.5, 12.3.

+

ﬂuorophenyl)-6-methyltetrazine 4 (190 mg, 1 equiv), and 6-

chloroquinoline (164 mg, 1 equiv) along with the major product

(18) and was isolated as a brown foam. Minor product (70/30). Yield

MS: Agilent 1100 (APCI) m/z: 502.1 (M ), 446.1 (M − t-Bu),

+

02.1 (M − Boc).

_H_R_M_S₍_E_S_I_-_T_O_F₎_m_/_z_:_[_M₊_H_]+ calcd for C H N O

2

4

32

5

7

=

93 mg, 50% (for both products).

02.2295; found: 502.2296.

-[(R)-2-((R)-1-Hydroxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-2-

5-methyl-1H-[1,2,4]triazol-3-yl)-ethyl]-N-Boc-4-methoxycarbonyl-

piperidine (21). The product was obtained from 2 (330 mg, 1 mmol),

,5-dimethyltetrazine 3 (110 mg, 1 equiv), and nicotinic acid (123

1

H NMR (400 MHz, CDCl ): δ 8.19 (d, J = 8.6 Hz, 1H), 8.13 (d, J

3

4

=

8.6 Hz, 1H), 8.12 (d, J = 9.0 Hz, 1H), 8.00 (m, 2H), 7.84 (d, J = 2.3

(

Hz, 1H), 7.70 (dd, J = 9.0, 2.3 Hz, 1H), 7.06 (m, 2H), 6.01 (t, J = 6.5

Hz, 1H), 3.84 (m, 2H), 3.48 (s, 3H), 2.97 (m, 1H), 2.85 (m, 1H),

3

2

.72 (dd, J = 14.5, 6.5 Hz, 1H), 2.52 (dd, J = 14.5, 6.5 Hz, 1H), 2.25

mg, 1 equiv) and was isolated as a white foam. The minor isomer had

a smaller retention time on LC-MS (45/55). Yield = 110 mg, 50%

2

(

m, J ∼ 14 Hz, 1H), 2.15 (m, J ∼ 14 Hz, 1H), 1.57 (m, 1H), 1.47

m, 1H), 1.44 (s, 9H).

(

for both isomers).

H NMR (400 MHz, CDCl ): δ 8.73 (dd, J = 4.8, 1.5 Hz, 1H),

1

3

1

C{ H} NMR (75 MHz, CDCl , 60 °C): δ 196.7, 175.4, 163.8 (d,

3

¹^JC−F = 249.3 Hz), 159.8 (br.), 156.4, 154.9, 151.7, 145.4, 136.6,

135.4, 132.0, 131.6, 130.4, 128.6 (d, JC−F = 8.4 Hz), 126.5, 126.1

(br.), 119.9, 115.6 (d, JC−F = 21.7 Hz), 79.7, 51.9, 45.3, 41.2 (br.),

8

.52 (br. s, 2H), 8.11 (dd, J = 7.8, 1.5 Hz, 1H), 7.47 (dd, J = 7.8, 4.8

3

Hz, 1H), 4.72 (br. s, 1H), 3.75 (m, 2H), 3.47 (s, 3H), 2.87 (m, 1H),

2

.80 (m, 1H), 2.51 (br. d, J ∼ 14.5 Hz, 1H), 2.39 (br. d, J ∼ 14.5

2

Hz, 1H) 2.38 (s, 3H), 2.10 (m, J ∼ 13.5 Hz, 1H), 2.00 (m, J ∼ 13.5

Hz, 1H), 1.42 (s, 9H), 1.35 (m, 2H).

40.0, 39.9, 33.9, 33.3, 28.5.

+

MS: Agilent 1100 (APCI) m/z: 622.1 (M ), 566.1 (M − t-Bu),

13

1

+

C{ H} NMR (100 MHz, CDCl ): δ 175.2, 167.6, 159.2 (br.),

522.1 (M − Boc).

3

+

34³⁵ClFN

1

4

58.6, 155.5, 155.0, 152.3, 136.5, 126.0 (br.), 125.4, 108.9, 79.8, 51.8,

HRMS (ESI-TOF) m/z: [M + H] calcd for C32

H

5

O

5

5.2, 42.5, 41.1 (br.), 38.3, 33.5, 33.0, 28.4, 12.0.

622.2233; found: 622.2224.

+

MS: Agilent 1100 (APCI) m/z: 501.9 (M ).

4-[2-(5-Methyl-2H-[1,2,4]triazol-3-yl)-3-oxo-3-(4-triﬂuoromethyl-

pyridin-2-yl)-propyl]-N-Boc-4-methoxycarbonylpiperidine (25).

The product was obtained from 2 (330 mg, 1 mmol), 3-(4-

ﬂuorophenyl)-6-methyltetrazine 4 (190 mg, 1 equiv), and 6-

chloroquinoline (164 mg, 1 equiv) along with the minor product

(26) and was isolated as a brownish foam. Major product (70/30).

_H_R_M_S₍_E_S_I_-_T_O_F₎_m_/_z_:_[_M₊_H_]+ calcd for C H N O

2

4

32

5

7

5

02.2302; found: 502.2296.

-[3-[5-((E)-2-Methoxycarbonylvinyl)-pyridin-2-yl]-2-(5-methyl-

H-[1,2,4]triazol-3-yl)-3-oxopropyl]-N-Boc-4-methoxycarbonylpi-

4

2

peridine (22). The product was obtained from 2 (330 mg, 1 mmol),

3

,5-dimethyltetrazine 3 (110 mg, 1 equiv), and (E)-3-pyridin-3-yl

Yield = 165 mg, 45% (for both products).

1

acrylic acid methyl ester (163 mg, 1 equiv) along with the minor

H NMR (400 MHz, CDCl ): δ 8.84 (d, J = 5.0 Hz, 1H), 8.23 (m,

3

product (23) and was isolated as a brown foam. Major isomer (83/

1H), 7.65 (dd, J = 5.0, 1.7 Hz, 1H), 5.72 (dd, J = 7.6, 5.1 Hz, 1H),

3.83 (m, 2H), 3.54 (s, 3H), 2.86 (m, 1H), 2.79 (m, 1H), 2.67 (dd, J =

14.4, 7.6 Hz, 1H), 2.37 (s, 3H), 2.30 (dd, J = 14.4, 5.1 Hz, 1H), 2.12

(m, 2H), 1.44 (m, 2H), 1.42 (s, 9H).

1

7). Yield = 110 mg, 50% (for both isomers).

1

H NMR (400 MHz, DMSO-d ): δ 8.98 (d, J = 2.2 Hz, 1H), 8.31

6

(

dd, J = 8.2, 2.2 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 16.2

1

3

1

Hz, 1H), 6.88 (d, J = 16.2 Hz, 1H), 5.54 (dd, J = 8.1, 4.3 Hz, 1H),

C{ H} NMR (100 MHz, CDCl

3

): δ 196.4, 175.3, 159.5 (br.),

2

3

1

2

.76 (s, 3H), 3.70 (m, 2H), 3.44 (s, 3H), 2.75 (m, 2H), 2.49 (m, J ∼

155.6 (br.), 154.9, 153.6, 150.1, 139.8 (q, JC−F = 34.8 Hz), 122.6 (q,

3

1

3

4 Hz, J ∼ 8 Hz, 1H), 2.21 (s, 3H), 2.15 (dd, J = 14.3, 4.3 Hz, 1H),

JC−F = 3.4 Hz), 122.5 (q, JC−F = 273.4 Hz), 118.6 (q, JC−F = 3.6

.05 (m, 1H), 1.95 (m, 1H), 1.38 (s, 9H), 1.34 (m, 2H).

Hz), 79.6, 51.8, 45.3, 41.2 (br.), 40.4, 39.9, 33.6, 33.4, 28.4, 12.4.

L

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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

+

1

MS: Agilent 1100 (APCI) m/z: 526.0 (M ), 469.9 (M − t-Bu),

H NMR (400 MHz, DMSO-d ): δ 8.53 (s, 1H), 6.91 (s, 1H), 3.71

6

+

4

5

25.9 (M − Boc).

(dt, J = 13.5, 4.3 Hz, 2H), 3.62 (s, 3H), 2.83 (s, 3H), 2.29 (s, 6H),

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C H F N O

26.2278; found: 526.2268.

-[2-[5-(4-Fluorophenyl)-2H-[1,2,4]triazol-3-yl]-3-oxo-3-(4-tri-

ﬂuoromethyl-pyridin-2-yl)-propyl]-N-Boc-4-methoxycarbonylpiper-

idine (26). The product was obtained from 2 (330 mg, 1 mmol), 3-

4-ﬂuorophenyl)-6-methyltetrazine 4 (190 mg, 1 equiv), and 6-

chloroquinoline (164 mg, 1 equiv) along with the major product (25)

and was isolated as a brown foam. Minor product (70/30). Yield = 81

1.92 (m, J ∼ 13.7 Hz, 2H), 1.42 (ddd, J = 14.3, 10.9, 4.2 Hz, 2H),

2

4

31

3

5

1.36 (s, 9H).

1

3

1

4

C{ H} NMR (100 MHz, DMSO-d ): δ 174.8, 153.8, 138.5,

6

136.8, 129.0, 119.7, 115.3, 111.3, 109.2, 78.4, 51.4, 46.5, 40.7 (br.),

32.5, 32.1, 27.9, 19.0, 12.8.

MS: Agilent 1100 (APCI) m/z: 418.1 (M ).

HRMS (ESI-TOF) m/z: [M + H] calcd for C H N O

418.2342; found: 418.2337.

+

(

+

2

32

3

5

mg, 45% (for both products).

6-(6-Chloroquinolin-2-yl)-5-(5-methyl-2H-[1,2,4]triazol-3-yl)-6-

oxohexanoic Acid Methyl Ester (29). The product was obtained from

2a (176 mg, 1 mmol), 3,5-dimethyltetrazine 3 (110 mg, 1 equiv), and

ethylisonicotinate (151 mg, 1 equiv) according to the general 3-CR

procedure and was isolated as a dark-yellow foam. Yield = 45% (165

mg).

1

H NMR (400 MHz, CDCl ): δ 8.86 (d, J = 5.0 Hz, 1H), 8.27 (m,

H), 7.97 (m, 2H), 7.69 (dd, J = 5.0, 1.7 Hz, 1H), 7.07 (m, 2H), 5.78

t, J = 6.4 Hz, 1H), 3.85 (m, 2H), 3.52 (s, 3H), 2.94 (m, 1H), 2.83

m, 1H), 2.70 (dd, J = 14.5, 6.7 Hz, 1H), 2.44 (dd, J = 14.5, 6.2 Hz,

3

1

(

1

2

H), 2.20 (m, J ∼ 14 Hz, 1H), 2.14 (m, J ∼ 14 Hz, 1H), 1.49 (m,

¹H NMR (400 MHz, CDCl

): δ 10.00 (br. s, 1H) 8.04 (m, 3H),

H), 1.44 (s, 9H).

3

13

1

C{ H} NMR (100 MHz, CDCl ): δ 195.5, 175.4, 163.8 (d, J

249.5 Hz), 159.7, 156.7, 154.9, 153.3, 150.1, 140.1 (q, J

7.75 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 9.0, 2.3 Hz, 1H), 5.81 (dd, J =

7.8, 6.5 Hz, 1H), 3.57 (s, 3H), 2.37 (s, 3H), 2.36 (t, J = 7.5 Hz, 2H),

2.16 (m, 2H), 1.71 (p, J = 7.5 Hz, 2H).

3

C−F

2

=

= 34.9

C−F

3

4

Hz), 128.5 (d, J

= 8.3 Hz), 126.0 (d, J

= 3.2 Hz), 123.0 (q,

C−F

1

3

1

3

1

3

C{ H} NMR (100 MHz, CDCl ): δ 198.6, 173.7, 158.1, 156.1,

J_C₋_F= 3.1 Hz), 122.4 (q, J

= 273.5 Hz), 118.9 (q, J

= 21.9 Hz), 79.7, 51.9, 45.2, 41.2 (br.), 40.3,

= 3.5

C−F

3

C−F

2

151.9, 145.3, 136.2, 134.9, 132.1, 131.1, 130.1, 126.2, 119.5, 51.4,

3.8, 33.5, 30.9, 22.7, 12.3.

MS: Agilent 1100 (APCI) m/z: 386.9 (M ).

HRMS (ESI-TOF) m/z: [M + H] calcd for C H ClN O

19 20 4 3

387.1224; found: 387.1218.

2

noyl]-isonicotinic Acid Ethyl Ester (30). The product was obtained

from 2a (176 mg, 1 mmol), 3,5-dimethyltetrazine 3 (110 mg, 1

equiv), and 6-chloroquinoline (164 mg, 1 equiv) according to the

general 3-CR procedure and was isolated as a dark-yellow foam. Yield

Hz), 115.7 (d, J

C−F

4

3

5

6

9.7, 33.7, 33.3, 28.5.

+

MS: Agilent 1100 (APCI) m/z: 606.2 (M ), 550.1 (M − t-Bu),

+

35

+

06.1 (M − Boc).

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C H F N O

06.2340; found: 606.2339.

-[2-(5-Methyl-2H-[1,2,4]triazol-3-yl)-3-oxo-3-pyridin-2-yl-prop-

yl]-N-Boc-4-methoxycarbonylpiperidine (27). A 20 mL screw-cap

clear vial was charged with 4-(3,3-diﬂuoro-cycloprop-1-enylmethyl)-

N-Boc-4-methoxycarbonylpiperidine 2 (330 mg, 1 mmol, 1 equiv),

2

9

32

4

5

-[5-Methoxycarbonyl-2-(5-methyl-2H-[1,2,4]triazol-3-yl)-penta-

4

=

45% (173 mg).

3

,5-dimethyltetrazine 8 (110 mg, 1 equiv), and pyridine (79 mg, 1

1

H NMR (400 MHz, CDCl ): δ 9.18 (br. s, 1H), 8.75 (dd, J = 4.9,

3

equiv) followed by addition of ethanol (10 mL), water (0.1 mL), and

HFIP (340 mg, 2 equiv). The reaction mixture was evacuated and the

vacuum was released with argon (three times); then, it was sealed and

heated with stirring at 70 °C for 48 h. The red color of the reaction

mixture gradually disappeared, indicating that tetrazine was

consumed. Full conversion of 2 was ensured according to LC-MS.

Volatiles were removed under reduced pressure, and the residue was

redissolved in a minimal amount of MeCN (∼2 mL) for puriﬁcation

by HPLC with gradient elution from 20 to 50% MeCN (20 min).

Solvents from the collected fractions were evaporated to provide 27 as

0

1

3

7

.8 Hz, 1H), 8.51 (dd, J = 1.7, 0.8 Hz, 1H), 7.96 (dd, J = 4.9, 1.6 Hz,

H), 5.56 (dd, J = 7.8, 6.6 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.59 (s,

H), 2.36 (s, 3H), 2.33 (t, J = 7.4 Hz, 2H), 2.14 (m, 2H), 1.68 (p, J =

.6 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H).

1

3

1

C{ H} NMR (100 MHz, CDCl ): δ 198.1, 173.7, 164.3, 158.3,

3

1

2

56.4, 153.4, 149.8, 139.2, 126.3, 122.0, 62.1, 51.4, 44.5, 33.6, 30.5,

2.7, 14.1, 12.5.

MS: Agilent 1100 (APCI) m/z: 375.0 (M ).

HRMS (ESI-TOF) m/z: [M + H] calcd for C H N O

+

1

8

23

4

5

3

75.1669; found: 375.1662.

a light-brown foam. Yield = 60% (274 mg).

Three-Component Reaction Byproducts and Intermediates.

1

H NMR (400 MHz, CDCl ): δ 8.63 (dt, J = 4.7, 1.4 Hz, 1H), 8.00

dt, J = 7.9, 1.0 Hz, 1H), 7.78 (td, J = 7.7, 1.7 Hz, 1H), 7.42 (ddd, J =

.6, 4.7, 1.2 Hz, 1H), 5.74 (dd, J = 7.3, 5.5 Hz, 1H), 3.80 (m, 2H),

.50 (s, 3H), 2.84 (m, 1H), 2.77 (m, 1H), 2.63 (dd, J = 14.4, 7.3 Hz,

3

4-(7-Ethoxycarbonyl-1-hydroxyindolizin-2-ylmethyl)-N-Boc-4-me-

(

+

thoxycarbonylpiperidine (12), (12 )NMR-Tube Experiment. 4-(3-

7

3

1

Oxocycloprop-1-enylmethyl)-N-Boc-4-methoxycarbonylpiperidine 10

1

(

16 mg, 0.05 mmol, 1 equiv) was dissolved in CD OD, and H NMR

was recorded. Then, ethylisonicotinate (9 mg, 1.2 equiv) was added in

the NMR tube and mixed. Immediate yellow colorization appeared,

and H NMR indicated the disappearance of starting materials and

formation of 12 in slow equilibrium with its double-bond tautomer.

Conc. HCl_a_q(10 μL) or, alternatively, 10 μL of CF COOD was then

added in the reaction mixture NMR tube, and line-sharpening of the

signals was observed along with ∼1.4 ppm downﬁeld shift of the

pyridine ring proton signals (in the experiment with HCl ) and

disappearance of the proton (7.0 ppm), adjacent to the pyrrole cycle

of the indolizine core due to H−D exchange. Upon attempted

isolation of 12 by SiO chromatography, slow oxidative dimerization

progressed and the color changed from yellow to brown-green,

aﬀording ﬁnally dimeric-12. R (for 12 and dimeric-12) (hexane/

3

2

H), 2.35 (s, 3H), 2.29 (dd, J = 14.4, 5.5 Hz, 1H), 2.09 (m, J ∼ 14

Hz, 2H), 1.41 (s, 9H), 1.40 (m, 2H).

13

1

C{ H} NMR (100 MHz, CDCl ): δ 197.2, 175.2, 158.6, 156.1,

3

1

3

54.8, 152.1, 149.0, 137.0, 127.3, 122.9, 79.6, 51.7, 45.2, 41.1, 40.0,

9.8, 33.5, 33.4, 28.4, 12.4.

3

+

MS: Agilent 1100 (APCI) m/z: 458.0 (M ), 402.0 (M − t-Bu),

+

3

4

58.0 (M − Boc).

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C H N O

58.2404; found: 458.2405.

-(8-Hydroxy-3,4-dimethyl-pyrrolo[1,2-a]pyrazin-7-ylmethyl)-N-

Boc-4-methoxycarbonylpiperidine (28). A 20 mL screw-cap clear

vial was charged with 4-(3,3-diﬂuoro-cycloprop-1-enylmethyl)-N-Boc-

-methoxycarbonylpiperidine 2 (330 mg, 1 mmol, 1 equiv) and 2,3-

dimethylpyrazine (119 mg, 1.1 equiv) followed by addition of ethanol

10 mL) and water (0.1 mL). The reaction mixture was heated with

2

3

32

5

aq

1

4

2

4

f

EtOAc 7/3) ∼ 0.5, yellow spot (vis.).

1

(

H NMR (400 MHz, neutral CD OD): δ 8.08 (br. s, 1H), 7.67 (br.

3

stirring at 65 °C for 7 h. Full conversion of 2 was ensured according

to LC-MS. Volatiles were removed under reduced pressure, and the

residue was puriﬁed by column chromatography on SiO (R (28) ∼

s, 1H), 7.03 (br. s, 1H), 6.67 (br. s, 1H), 4.25 (br. s, 2H), 3.78 (dt, J =

2

13.8, 4.2 Hz, 2H), 3.64 (s, 3H), 2.88 (m, J ∼ 11 Hz, 2H), 2.83 (br. s,

2

f

2H), 2.01 (m, J ∼ 14 Hz, 2H), 1.46 (ddd, J = 13.9, 11.1, 4.3 Hz, 2H),

0

.45 in EtOAc, yellow spot (vis.)) with gradient elution from hexane/

1.37 (s, 9H), 1.30 (t, J = 7.1 Hz, 3H).

1

EtOAc (1/1) to pure EtOAc. Solvent from the collected fractions was

evaporated to provide 28 as a dark-yellow foam. Yield = 60% (250

mg).

H NMR (400 MHz, acidic (HCl₍_a_q₎/CD OD ∼ 1/55)): δ 9.11

3

(dd, J = 6.3, 0.9 Hz, 1H), 8.42 (t, J = 1.7, 0.9 Hz, 1H), 8.15 (dd, J =

6.4, 1.7 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 3.74 (s, 3H), 2.97 (m, 2H),

M

https://dx.doi.org/10.1021/acs.joc.0c02292

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

2

.88 (s, 2H), 2.10 (m, J ∼ 14 Hz, 2H), 1.52 (ddd, J = 14.3, 10.8, 4.2

20 to 40% MeCN (20 min). Solvents from the collected fractions

Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.39 (s, 9H).

H NMR (400 MHz, acidic (CF COOD/CD OD ∼ 1/55)): δ

.06 (dd, J = 1.9, 0.9 Hz, 1H), 7.65 (dd, J = 7.4, 0.9 Hz, 1H), 6.66

dd, J = 7.4, 1.8 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.77 (dt, J = 13.9,

.3 Hz, 2H), 3.64 (s, 3H), 2.88 (ddd, J = 13.9, 11.1, 3.0 Hz, 2H), 2.83

s, 2H), 2.00 (dt, J = 13.3, 3.0 Hz, 2H), 1.46 (ddd, J = 13.7, 11.0, 4.2

were evaporated to provide 13 as a white solid. (R (13) ∼ 0.3 in

f

1

EtOAc). Yield = 25% (85 mg).

3

1

8

(

4

(

H NMR (400 MHz, DMSO-d ): δ 10.30 (br, s, 2H), 7.05 (s, 1H),

6

2

3.70 (m, J ∼ 14 Hz, 2H), 3.61 (s, 3H), 2.84 (m, J ∼ 14 Hz, 2H),

2 2 2

1.38 (s, 9H), 1.38 (s, 9H), 1.35 (m, J ∼ 14, J ∼ 10.6, J ∼ 4.3 Hz,

2H).

1

3

1

Hz, 2H), 1.37 (s, 9H), 1.30 (t, J = 7.1 Hz, 3H).

C{ H} NMR (100 MHz, DMSO-d ): δ 174.9, 159.5 (br.), 153.8,

6

13

1

C{ H} NMR (75 MHz, acidic (CF COOD/CDCl ∼ 1/55)): δ

78.1, 161.9, 156.2, 154.2, 146.8, 145.5, 141.4, 122.2, 121.8, 119.1,

2.9, 64.2, 62.2, 53.4, 46.4, 40.7, 32.9, 32.7, 28.1, 13.6.

MS (for 12): Agilent 1100 (APCI) m/z: 461.0 (M ), 404.9 (M −

t-Bu), 361.0 (M − Boc).

HRMS (for 12) (ESI-TOF) m/z: [M + H] calcd for C H N O

7

128.8 (br.), 97.7, 78.4, 51.3, 46.3, 40.7 (br.), 31.9, 31.3, 27.9.

3

1

8

mp = 208−210 °C.

+

MS: Agilent 1100 (APCI) m/z: 340.0 (M ), 284.0 (M − t-Bu),

+

240.0 (M − Boc).

+

HRMS (ESI-TOF) m/z: [M + H] calcd for C H N O

1

6

26

3

5

+

340.1873; found: 340.1861.

24

33

2

4

61.2288; found: 461.2278.

+

MS (for dimeric-12): Agilent 1100 (APCI) m/z: 919.0 (M ), 863.0

ASSOCIATED CONTENT

sı Supporting Information

■

+

(

M − t-Bu), 819.0 (M − Boc), 762.9 (M − Boc − t-Bu).

*

HRMS (for dimeric-12) (ESI-TOF) m/z: [M + H]⁺calcd for

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c02292.

C H N O 919.4318; found: 919.4336.

48

63

4

14

Boc-Deprotected Dimeric-(12)Attempted NMR Characteriza-

1

13

1

tion. As H NMR of dimeric-12 was even more obscured by the signal

broadening in the full spectral range than in 1-hydroxyindolizine 12,

we removed two Boc groups by the following procedure: dimeric-12

Copies of LC-MS, H, and C{ H} NMR and HRMS

spectral data (PDF )

(

40 mg) was dissolved in 2 mL of 4M HCl in dioxane and left stirring

AUTHOR INFORMATION

Corresponding Author

for 18 h. After that, LC-MS indicated that both Boc groups were

removed, the solvent was evaporated under reduced pressure, and the

residue was puriﬁed by HPLC with gradient elution from 5 to 15%

MeCN (0.1% HCOOH) for 20 min. Solvents from the collected

fractions were evaporated to provide Boc-deprotected dimeric-12 as a

dark-yellow solid. Yield = 80% (35 mg). H NMR (CD OD) of the

■

Ilya V. Nechaev − Asinex, 125480 Moscow, Russia;

orcid.org/0000-0002-1443-0488; Email: inechaev@

asinex.com

1

3

obtained product was still broadened in the full spectral range and

ⁿ^oⁿⁱⁿ^t^e^r^p^r^e^t^a^b^l^e^.^A^d^dⁱ^tⁱ^oⁿ^o^f^c^oⁿ^c^.^H^C^laq (10 μL) to the NMR

sample revealed the signals of the piperidine substituent.

Authors

Georgij V. Cherkaev − Enikolopov Institute of Synthetic

Polymeric Materials, a Foundation of the Russian Academy of

Sciences, 117393 Moscow, Russia

Nikolay V. Boev − Asinex, 125480 Moscow, Russia

Pavel N. Solyev − Engelhardt Institute of Molecular Biology,

Russian Academy of Sciences, 119991 Moscow, Russia;

orcid.org/0000-0002-5546-4975

1

H NMR (400 MHz, acidic (HCl₍CD OD)): δ 4.32 (br. s, 2H),

aq)

3

2

3

1

(

.29 (br. s, 3H), 3.10 (br. d, J ∼ 13 Hz, 1H), 2.90 (br. d, J ∼ 13 Hz,

2

H), 2.70 (br. t, J ∼ 12 Hz, 1H), 2.63 (br. t, J ∼ 12 Hz, 1H), 1.90

2

3

br. d, J ∼ 12 Hz, 2H), 1.70 (br. t, J ∼ 13 Hz, 1H), 1.30 (t, J ∼ 7

Hz, 3H), 1.30 (m, 1H).

+

MS: Agilent 1100 (APCI) m/z: 718.9 (M ).

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C H N O

3

8

47

4

10

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c02292

7

19.3293; found: 719.3288.

4

-(7-Ethoxycarbonyl-1-hydroxy-3-deuteroindolizin-2-ylmethyl)-

N-Boc-4-methoxycarbonylpiperidine (12-D)NMR Tube Experi-

Notes

ment. The experiment was conducted analogously as for 12 using 4-

(

2-deutero-3-oxocycloprop-1-enylmethyl)-N-Boc-4-methoxycarbonyl-

The authors declare no competing ﬁnancial interest.

piperidine 10-D. CF COOD (10 μL) acidiﬁcation of the sample led

to (12 ). Again, slow oxidative dimerization progressed and the color

changed from yellow to brown-green. LC-MS spectra of the dimer

were identical to dimeric-12 fragmentation, indicating that deuterium

3

+

ACKNOWLEDGMENTS

This work was supported by the grant of the Russian Science

Foundation (RSF grant 20-74-10121).

■

atoms are lost during oxidative dimerization.

1

H NMR (400 MHz, neutral CD OD): δ 8.06 (br. s, 1H), 7.65 (br.

3

REFERENCES

s, 1H), 6.66 (br. s, 1H), 4.25 (br. s, 2H), 3.78 (dt, J = 13.8, 4.3 Hz,

■

2

(

9

H), 3.64 (s, 3H), 2.88 (m, J ∼ 12 Hz, 2H), 2.83 (br. s, 2H), 2.01

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An Alternative Route for Carboni −Lindsey Reaction: N, N

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(2) De Rosa, M.; Arnold, D.; Yennawar, H. Acid-catalyzed reaction

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2

m, J ∼ 14 Hz, 2H), 1.46 (ddd, J = 14.6, 11.1, 4.3 Hz, 2H), 1.37 (s,

H), 1.30 (t, J = 7.1 Hz, 3H).

MS (for 12-D): Agilent 1100 (APCI) m/z: 462.0 (M ), 405.9 (M

+

−

t-Bu), 362.0 (M − Boc).

HRMS (for 12-D) (ESI-TOF) m/z: [M + H]⁺calcd for

C H N O D 462.2338; found: 462.2347.

24

32

2

7

4

-(5-Hydroxy-1H-pyrazol-4-ylmethyl)-N-Boc-4-methoxycarbo-

nylpiperidine (13). A 20 mL screw-cap clear vial was charged with 4-

(

3,3-diﬂuorocycloprop-1-enylmethyl)-N-Boc-4-methoxycarbonylpi-

peridine 2 (330 mg, 1 mmol, 1 equiv) and 3,5-dimethyltetrazine 8

133 mg, 1.2 equiv) followed by addition of ethanol (10 mL) and

water (0.1 mL). The reaction mixture was heated with stirring at 78

C for 48 h. The red color of the reaction mixture gradually faded,

(

°

indicating that tetrazine was consumed. Full conversion of 2 was

ensured according to LC-MS. Volatiles were removed under reduced

pressure, and the residue was redissolved in minimal amount of

MeCN (∼2 mL) for puriﬁcation by HPLC with gradient elution from

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Three-Component Reaction of 3,3-Difluorocyclopropenes, s-Tetrazines, and (benzo) Pyridines

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