One-Pot Synthesis of γ-Azidobutyronitriles and Their Intramolecular Cycloadditions

SYNTHESIS

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K. L. Ivanov et al.

Feature

Synthesis

One-Pot Synthesis of -Azidobutyronitriles and Their Intramolecular

Cycloadditions

Konstantin L. Ivanov^a

Hamidulla B. Tukhtaev^a

Feruza O. Tukhtaeva^a

Stanislav I. Bezzubov^b

Mikhail Ya. Melnikov^a

Ekaterina M. Budynina*^a,c

^aLomonosov Moscow State University, Department of

Chemistry, Leninskie gory 1-3, Moscow 119991, Russian

Federation

ekatbud@kinet.chem.msu.ru

^bKurnakov Institute of General and Inorganic Chemistry,

Russian Academy of Sciences, Leninskiy pr. 31, Moscow

119991, Russian Federation

^cLebedev Physical Institute, Russian Academy of Sciences,

Leninskiy pr. 53, Moscow 119991, Russian Federation

Received: 19.05.2020

Accepted after revision: 22.06.2020

Published online: 04.08.2020

In the last few years, our group has been interested in

the nucleophilic ring opening of donor-acceptor cyclopro-

panes²with the azide ion³as an efficient approach to highly

functionalized azido-substituted building blocks (Scheme

1A).⁴The presence of the azido group in these structures

opens numerous ways to their transformations via azide re-

arrangements, cycloadditions or reduction into a broad va-

riety of N-containing compounds, including N-heterocycles.

Particularly, azides 3, simultaneously containing azido, cyano,

ester and pronucleophilic CH groups, can be efficiently

used for the synthesis of aminopyrrole derivatives and pyr-

role-fused polycyclic systems.^4eA convenient synthetic ap-

proach to 3, starting from commercial aldehydes and cyano-

acetates, includes three sequential steps: (i) Knoevenagel

condensation, (ii) Corey–Chaykovsky cyclopropanation and

(iii) nucleophilic ring opening of a cyclopropane with the

azide ion (Scheme 1B). We found that some tuning of the

reaction conditions allows for combining these steps into

an advanced one-pot process that is viable in terms of time

efficiency as well as yields of the target azides 3.

DOI: 10.1055/s-0040-1706402; Art ID: ss-2020-z0275-fa

Abstract Efficient gram-scale, one-pot approaches to azidocyanobu-

tyrates and their amidated or decarboxylated derivatives have been de-

veloped, starting from commercially available aldehydes and cyanoace-

tates. These techniques combine (1) Knoevenagel condensation, (2)

Corey–Chaykovsky cyclopropanation and (3) nucleophilic ring opening

of donor-acceptor cyclopropanes with the azide ion, as well as (4) Krap-

cho decarboxylation or (4′) amidation. The synthetic utility of the re-

sulting -azidonitriles was demonstrated by their transformation into

tetrazoles via intramolecular (3+2)-cycloaddition. A condition-depen-

dent activation effect of the -substituent was revealed in that case.

Thermally activated azide–nitrile interaction did not differentiate the

presence of an -electron-withdrawing substituent in -azidonitriles,

whereas the Lewis acid mediated (SnCl₄or TiCl₄) reaction proceeded

much easier for azidocyanobutyrates. This allowed us to develop an effi-

cient procedure for converting azidocyanobutyrates into the corre-

sponding tetrazoles.

Key words azides, nitriles, one-pot synthesis, 1,3-dipolar cycloaddi-

tion, tetrazoles, Knoevenagel condensation, Corey–Chaykovsky reac-

tion, nucleophilic ring opening

Moreover, the specific conditions of their subsequent

transformations can facilitate further extension of this one-

pot process. In this work, Krapcho decarboxylation and

amidation were combined with a three-step synthesis of

azides 3 within one-pot protocols, affording azidonitriles 4

and amides 5. The synthetic utility of 3 for the assembly of

five-membered N-heterocycles is exemplified by intramo-

lecular (3+2)-cycloaddition leading to bicyclic pyrrolo-

tetrazole systems 6 and 7.

For rapid access to structurally diverse molecules, ver-

satile building blocks with multiple strategically arranged

functional groups are in demand. The synthesis of such

functionalized structures starting from commercially avail-

able compounds usually includes several steps. Meanwhile,

one of the main trends of current organic chemistry is sus-

tainability; i.e., rational step-economic processes that re-

quire no isolation of intermediates. Therefore, the develop-

ment of synthetic strategies based on domino, tandem or

one-pot processes that can enhance efficiency and step

economy is important and sought-after.¹

One-Pot Synthesis of -Azidobutyronitriles

The feasibility of combining Knoevenagel (i), Corey–

Chaykovsky (ii) and nucleophilic ring opening (iii) steps

into a one-pot synthesis of azidocyanobutyrates 3 is

Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B

K. L. Ivanov et al.

Feature

Synthesis

Biographical sketches

Konstantin Ivanov was born in

Ulyanovsk, Russia. He graduated

from the Department of Chemis-

try, Lomonosov Moscow State

University, in 2012 and received

his PhD in organic chemistry in

2016 (PhD thesis ‘Nucleophilic

Ring Opening of Donor-Acceptor

Cyclopropanes with Azide Ion in

Synthesis of N-Heterocycles’) un-

der the supervision of Dr. Ekateri-

na Budynina. He is currently a

researcher at the Department of

Chemistry, Lomonosov Moscow

State University. His research is fo-

cused on the chemistry of activat-

ed cyclopropanes, organic azides,

and N-heterocycles, and on DFT

calculations.

Hamidulla Tukhtaev was born

in Tashkent, Uzbekistan. He grad-

uated from the Department of

Chemistry of Lomonosov Moscow

State University in 2018. Then he

worked as a research-intern at the

Institute of Bioorganic Chemistry

of Academy of Science of Uzbeki-

stan. He joined the research

group of Dr. Budynina in 2014.

Currently he is a PhD student at

Lomonosov Moscow State Univer-

sity. His research is focused on the

chemistry of organic azides, aza-

Wittig reactions, and the synthe-

sis of N-heterocycles.

Feruza Tukhtaeva was born in

Tashkent, Uzbekistan. She re-

ceived her bachelors degree at the

Department of Methods of Teach-

ing Chemistry of Nizami Tashkent

State Pedagogical University in

2017 and her Master’s degree at

the Faculty of Chemistry of Mirzo

Ulugbek National University of Uz-

bekistan in 2019. She worked in

the research group of Dr. Budyni-

na in 2019 (on behalf of the Lo-

gram). She is currently a PhD stu-

dent at the Laboratory of

Heteroatomic Compounds at the

Department of Chemistry of Lo-

monosov Moscow State Universi-

ty. Her research is focused on

petrochemistry.

monosov

Moscow

State

University student exchange pro-

Stanislav Bezzubov is a senior

researcher at the Kurnakov Insti-

tute of General and Inorganic

Chemistry of the Russian Acade-

my of Sciences, Moscow, Russia.

After completing his PhD at the

Lomonosov Moscow State Univer-

sity he transferred to the Kurna-

kov Institute in 2015. He worked

as a visiting researcher at Durham

University (with Prof. Judith How-

ard) in 2018 and has been in his

current position since 2019. His

research focuses on cyclometalat-

ed Ir(III) and Ru(II) complexes and

some aspects of chemical crystal-

lography, including solid-state su-

pramolecular chemistry via crystal

engineering.

Mikhail Melnikov was born in

Moscow, USSR. He graduated

from the Department of Chemis-

try of Lomonosov Moscow State

University in 1969. He is a full pro-

fessor (1991), ScD (1984), and the

head of the chair of Chemical Ki-

netics at Lomonosov Moscow

State University. His research is fo-

cused on the kinetics and mecha-

nisms of chemical and biological

processes, photochemistry, catal-

ysis and nanochemistry.

Ekaterina Budynina was born

in Moscow, Russia. She studied

chemistry at Lomonosov Moscow

State University and received her

specialist degree in 2001 and her

PhD in 2003. She worked at the

University of Nottingham (2004)

and Imperial College London

(2013) as a visiting researcher.

She is currently a leading re-

searcher at the Department of

Chemistry, Lomonosov Moscow

State University, focusing on the

chemistry of activated cyclopro-

panes.

C

K. L. Ivanov et al.

Feature

Synthesis

this step with a subsequent Corey–Chaykovsky reaction

that requires inert and anhydrous conditions. The cyclopro-

panation of cyanoacrylate 1a was completed in 1 h at ambi-

ent temperature, leading to cyclopropane 2a in good yield,

predominantly as the more stable trans-isomer (dr

>95:5).^3aTo optimize the conditions for the third step of our

one-pot synthesis of 3a, a series of experiments was carried

out while varying loads of NaN₃and proton sources, as well

as reaction temperature and time (Table 1). According to

our previous work, 2 equiv of NaN₃and 2 equiv of Et₃N·HCl

as a proton source were used for conversion of 2 into 3.^4eIn

our current work, we initiated optimization while using the

same loading of NaN₃and increasing the loading of Et₃N·HCl

by 50% to lower the increased basicity after the previous

step and shift the equilibrium between 2 and 3.^3aThis ex-

periment was carried out at room temperature for 12 h and

resulted in 3a in a 59% one-pot yield (entry 1), whereas the

three-step yield reported earlier amounted to 52%. The de-

crease in the loadings of NaN₃and Et₃N·HCl led to an in-

crease in the yield of 3a (62–67%) (entries 2–4). Similar ex-

periments with NH₄Cl instead of Et₃N·HCl led to 3a with

lower yields (55–58%) (entries 5 and 6). A slight increase in

temperature (35 °C) also led to a decrease in the yield of 3a

(44–54%) either for Et₃N·HCl or NH₄Cl (entries 7 and 8). A

further increase in temperature up to 50 °C (entry 9), al-

though allowing for a noticeably reduced reaction time (4

h), afforded 3a in only a moderate yield (26%). Therefore,

the use of 1.3 equiv of NaN₃and 1.4 equiv of Et₃N·HCl at

room temperature was found to be optimal for carrying out

the third step within this one-pot conversion of cyanoace-

tate and benzaldehyde into azide 3a (entry 3).

A. Our previous work

EWG

· pyrroles

· pyridines

· azepines

· triazoles

· tetrazoles

· spirooxindoles

N-Heterocyclic

systems

R

EWG'

· etc.

N₃

azide building blocks ref. 3g, 4

B. This work: Azidocyanobutyrates

One-pot scenarios for synthesis and evolution

CO₂R'

CN

iii

ii

i

CN

R

CN

O

R

CN

R

3

2

1

N₃

iv"

iv

iv'

R

R"

CONR'R"

CN

v

N

R

CN

R

N

N₃

5

4

6: R" = CO₂R'

7: R" = H

N

i: Knoevenagel

ii: Corey–Chaykovsky

One-pot

–

iii: S_N2 with N₃

i→iii three-step synthesis of 3

i→iv four-step synthesis of 4

i→iv' four-step synthesis of 5

iv: Krapcho

iv': Amidation

iv",v: (3+2)-Cycloaddition

Scheme 1 Current strategy

primarily related to mild conditions characteristic of these

reactions with cyano-derived precursors (cyanoacetates,

cyanoacrylates 1 and cyano-activated cyclopropanes 2) in

contrast to, for example, the malonate derivatives (Scheme

2).^3g,4e,5,6

CO₂Me

MeO₂C

CO₂Me

NC

CO₂Me

O

CN

1a

i

Δ

3 min

ref. 6

Ph

benzene, Δ

4 h

Ph

Table 1 Optimization of the Reaction Conditions for the Third Step of

the One-Pot Synthesis of Azide 3a

ii rt

ref. 4e 20 min

ii rt

ref. 5 5 h

ref. 5

i piperidine (10 mol%)

AcOH (20 mol%)

Me₃SOI

CO₂Me

piperidine

(2 mol%)

CO₂Me

CN

CO₂Me

CN

CO₂Me

(1.1 equiv)

NaN₃

CO₂Me

CN

ii Me₃SOI (1.1 equiv)

NaH (1.1 equiv)

DMSO/DMF, rt

[H⁺]

AcOH

(4 mol%) Ph

C₆H₆(1.5 M)

2a

CN

O

NaH

(1.1 equiv)

DMF (0.3 M)

rt, 1 h

Ph

iii 100 °C

Ph

N₃

3a

iii

Ph

2a, 67%

iii rt

ref 4e 12 h

Ph

iii NaN₃(2 equiv)

Et₃N·HCl (2 equiv)

DMF

1a, 98%

Ph

ref 3g 4 h

Δ, 2 h

i

CO₂Me

ii

Ph

CO₂Me

Ph

CN

Entry NaN₃

[H⁺]

(equiv)

T

(°C)

t

(h)

One-pot

yield 3a (%)

N₃

3a

(equiv)

Scheme 2 Comparison of the reaction conditions for the synthesis of

azidomalonate and azidocyanoester derivatives

1

2

3

4

5

6

7

8

9

2.0

Et₃N·HCl, 3.0

Et₃N·HCl, 1.8

Et₃N·HCl, 1.4

Et₃N·HCl, 1.2

NH₄Cl, 1.8

25

35

50

12

4

59

67

62

58

55

54

44

26

1.7

1.3

1.1

1.7

1.1

2.0

The classic Knoevenagel conditions implicate the use of

a high percentage of piperidine (up to 10 mol%) and AcOH

(up to 20 mol%) as catalytic additives. However, the relative

ease of cyanoacrylate 1 formation (for some aldehydes, it

even occurs at ambient temperature without azeotrope dis-

tillation) allowed us to minimize the amount of the catalyst

(Table 1).⁶This, along with rough water removal via azeo-

trope distillation, provided an opportunity for combining⁷

NH₄Cl, 1.2

Et₃N·HCl, 2.2

NH₄Cl, 2.2

Et₃N·HCl, 2.0

D

K. L. Ivanov et al.

Feature

Synthesis

To verify the efficiency of the proposed one-pot proce-

dure, we examined arylcarbaldehydes containing electron-

donating and electron-withdrawing groups as well as het-

aryl and alkenyl carbaldehydes under the optimized condi-

tions (Table 2). In all cases, the yields of 3 in one-pot syn-

theses were higher than those achieved in three-distinct-

step syntheses. In two cases (3d and 3l), we succeeded in

increasing the yields twofold via our one-pot procedure.

Moreover, in an appropriate reaction medium, this proce-

dure can be easily combined with Krapcho decarboxylation.

In several examples, we demonstrated that a one-pot, four-

step procedure involving a Krapcho step led to azidobutyro-

nitriles 4 in 22–44% overall yields. These yields are two to

three times higher than those for stepwise procedures.

An additional opportunity to modify azides 3 in a one-

pot manner is provided by amidation that can be intro-

duced as the fourth step (Scheme 3). The use of n-butyl-

amine, benzylamine and pyrrolidine as aliphatic primary

and secondary amines (or, alternatively, hydrazine) led to

amide or hydrazide derivatives 5a–d in 31–58% overall

yields. Piperidine unexpectedly gave a quite complex reac-

tion mixture that did not allow for the isolation of the cor-

responding amide in adequate yield. The use of less nucleo-

philic aromatic amines, for example, aniline, was found to

be inefficient in a one-pot process.

Table 2 One-Pot Synthesis of Azides 3 and 4^a

CO₂Me

CN

R

CN

O

i, ii, iii, iv

+

one pot

this work

N₃

R

4

i, ii, iii

i

iv

one pot

ref. 4e

CO₂Me

R

CO₂Me

ii

iii

CN

N₃

CN

3

dr ca. 50:50

R

CN

R

1

2

CO₂Me

Ph

CONRR'

O

i, ii, iii, vi

R

3

Yield 3 (%)

4

Yield 4 (%)

+

5a–c

CN

N₃

Ph

one pot

CN

Ph

three-

step^b

one-

pot

four-

step^b

one-

pot

dr ca. 1:1

CO₂Me

i, ii, iii

iv'

N₃

CN

Ph

a

52

36

46

32

36

–

67

58

54

64

41

53

52

51

56

68

51^d

54

69^d

38

28

47

50

44

27

50

58

a

21

39

3a

Conditions:

i

Ph^c

b

c

d

e

f

piperidine, AcOH, benzene,

Δ

5a: R = n-Bu, R' = H, rt, 22 h, 58%

5b: R = Bn, R' = H, 45 °C, 4 d, 31%

5c: R–R' = -(CH₂)₄-, rt, 26 h, 36%

5d: R = NH₂, R' = H, rt, 4 h, 54%

ii Me₃SOI, NaH, DMF, rt

iii NaN₃, Et₃N·HCl, DMF, rt

vi' RR'NH

4-MeC₆H₄

4-FC₆H₄

b

c

–

44

42

41

Scheme 3 One-pot synthesis of amides 5 involving the nucleophilic

acyl substitution step iv′

4-ClC₆H₄

2-ClC₆H₄

4-BrC₆H₄

4-MeOC₆H₄

3-MeOC₆H₄

d

g

h

i

45

34

–

e

f

12

–

36

42

Intramolecular Cycloadditions

An obvious possibility for the heterocyclization of 3 or 4

using their inherent functionalities is (3+2)-cycloaddition

between the azido and cyano groups, affording the assem-

bly of a fused tetrazole core.⁸In contrast to the azide–

alkyne click reaction, which allows extremely simple access

to triazoles from a broad variety of organic azides and

alkynes, tetrazole formation from azides and nitriles pro-

ceeds under much harsher conditions and has significant

limitations. The tetrazole synthesis via intermolecular

(3+2)-cycloadditions can be carried out efficiently only for

highly activated nitriles.⁹The intramolecular reactions pro-

ceed much more readily for various activated and non-acti-

vated azidonitriles containing three-,¹⁰four-^{3g,10a,c,e,i,j,11}and

five-atom¹²linkers between the azido and cyano groups.

However, even in these cases, high temperature or activa-

tion with strong Brønsted or Lewis acids were required. The

principal thermally activated reactions were typically car-

ried out under prolonged heating at ≥110 °C in DMSO, DMF,

toluene or xylene as solvents. Meanwhile, only a couple of

acid-activated reactions were reported with ClSO₃H,^10aH₂SO₄,^10a

TFA,^10land BF₃·OEt₂^10i,jused as activators at 0–40 °C.

2,3-(MeO)₂C₆H₃

3,4-(MeO)₂C₆H₃

3,4,5-(MeO)₃C₆H₂

2,4,6-(MeO)₃C₆H₂

4-NCC₆H₄

j

–

k

l

44

24

–

m

n

o

p

q

r

22

–

4-O₂NC₆H₄

1-Naph

38

–

1,4-(C₆H₄)-

(E)-styryl

46

26

37

–

g

h

i

–

22

37

28

2-furyl

s

2-thienyl

t

2-(N-methyl)indolyl

3-pyridyl

u

^aReaction conditions: i. Piperidine (2 mol%), AcOH (4 mol%), benzene (1.5

M), reflux, 2.5 h; ii. (CH₃)₃SOI (1.1 equiv), NaH (1.1 equiv), DMF (0.3 M), r.t.,

1 h; iii. NaN₃(1.3 equiv), Et₃N·HCl (1.4 equiv), r.t., 12–16 h; iv. LiCl (1.0

equiv), H₂O (4 mL), 125 °C, 3–6 h.

^bYields of three- and four-step synthesis are given according to our previ-

ous work.^4e

Our attempts to combine the thermal version of (3+2)-

cycloaddition with a one-pot synthesis of 3 or 4 led to un-

satisfactory yields of the corresponding tetrazoles 6 and 7

^ct-Bu ester was used. The yield was estimated for a two-step synthesis of 3b

from styrene and tert-butyl cyanoacetate via bromosulfonium bromide.^4e

^dReaction time 24 h.

E

K. L. Ivanov et al.

Feature

Synthesis

due to significant tarring under these harsh conditions

(140–160 °C). Moreover, the conversion of ester derivatives

3 into tetrazoles 6 was complicated by Krapcho decarboxyl-

ation.

Extremely mild conditions (0 °C to r.t.) for intramolecu-

lar tetrazole formation activated by BF₃·OEt₂were reported

by Hanessian and co-workers.^10i,jWe tried to combine our

BF₃-mediated (3+2)-cycloaddition with a one-pot synthesis

of the initial azides 3 and 4. However, it was found to be un-

tenable, apparently due to deactivation of a Lewis acid un-

der the studied conditions. Therefore, optimization of the

reaction conditions for (3+2)-cycloaddition was carried out

for the isolated azides 3a and 4a.

free azides 4 are only able to undergo the first step of this

reaction, yielding acyclic phosphazenes that are not prone

to aza-Wittig cyclization.

Under activation with BF₃·OEt₂, a short series of azides 3

and 4 containing electron-donating (Me) and electron-

withdrawing (F) groups at the aryl substituent was trans-

formed into tetrazoles 6b,c and 7b,c in moderate yields

(29–30%) (Table 4). Unfortunately, azide 3h, containing a

para-methoxyphenyl (PMP) substituent, underwent signifi-

Table 3 Optimization of Reaction Conditions for (3+2)-Cycloaddition

of 3a and 4a

Upon heating, (3+2)-cycloaddition for 3a and 4a pro-

ceeded slowly at ≥130 °C, accompanied by significant tar-

ring (Table 3, entries 1–4, 17, and 18). According to these re-

sults, ester 3a underwent (3+2)-cycloaddition faster than

its EWG-free derivative 4a. Activation with TFA was found

to be more efficient, providing slow conversion of 3a and 4a

into the corresponding tetrazoles 6a and 7a in 40 and 48%

yields at temperatures as low as 25 °C (entries 5, 6, and 19).

A stronger acid, TfOH, caused significant tarring, so that the

yield of 3a did not exceed 25% (entries 7 and 8). Next, we

tested BF₃·OEt₂as an activator while varying reaction tem-

perature and time. We found that the conversion of azides

3a and 4a into tetrazoles 6a and 7a in the presence of

BF₃·OEt₂(2 equiv) became detectable only at increased tem-

perature (entries 9–11 and 20–23). This is in contrast to the

mild conditions reported for intermolecular (3+2)-cyclo-

addition with participation of less sterically hindered sec-

ondary azides.^11hInterestingly, in DMF, the conversion of 3a

into 6a was indeed observed but only at increased tempera-

ture (140 °C). This implies thermal activation alone without

BF₃participation. The best yields of tetrazoles 6a (45%) and

7a (50%) were achieved in 10–11 h when reactions were

carried out at 70 °C (entries 10 and 23). An increase in tem-

perature to 90 °C led to a slight decline in the yield of 6a

(entry 11).

To estimate the relative rates of (3+2)-cycloadditions for

azides 3 and their ester-free derivatives 4, we carried out a

model experiment using 3a/4a mixture in a 1:1 ratio

(Scheme 4A). Quenched in 2 h, the reaction mixture con-

tained azides 3a and 4a as well as tetrazoles 6a and 7a in a

30:13:30:27 ratio. According to this experiment, the con-

version of 3a was slower than that of 4a. Therefore, surpris-

ingly, the presence of an ester group that, supposedly, acti-

vates the nitrile moiety toward (3+2)-cycloaddition does

not accelerate this reaction when BF₃·OEt₂is used as an ac-

tivator. Meanwhile, our recent study^4erelated to domino

Staudinger/aza-Wittig reaction of azides 3 and 4 revealed

that EWG (e.g., an ester group) located at an -position rela-

tive to the CN group plays a crucial activating role (Scheme

4B). Azides 3, containing an -CO₂Me group, readily under-

go a complete domino Staudinger/aza-Wittig transforma-

tion, leading to cyclic iminophosphazenes. However, ester-

Ph

R'

Ph

R'

conditions

N

N₃

CN

3a, 4a

3a, 6a: R = CO₂Me

4a, 7a: R = H

N

6a, 7a

Entry Additive (equiv) Solvent

T (°C) t (h)

Conv. (%) Yield (%)^d

R = CO₂Me: 3a → 6a

1

2

–

DMSO

DMF

130^a

160^a

150^a

160^a

r.t.

3

12

17

nd

40

nd^b

25^b

9

–

6

3

–

toluene

TFA

2.5

2

20

4

–

38

5

–

3

40

6

–

TFA

r.t.

27

>95

>50

>95

45

7

TfOH (1.0)

BF₃·OEt₂(2.0)

Zn(OTf)₂(0.3)

CH₂Cl₂

DMF

r.t.

1

25

4

8

r.t.

9

140

70

10

11

12

13

CH₃NO₂

DCE

11

2

>95

<5

45

40

nd

90

80

4

MgBr₂∙OEt₂

(0.2)

CH₃NO₂

101

1

5

14

15

16

CuI (0.05)

SnCl₄(1.2)

TiCl₄(1.2)

DMSO

CH₂Cl₂

90

r.t.

5

12

<5

>95

nd

88

86

R = H: 4a → 7a

17

18

19

20

21

22

23

24

–

DMSO

toluene

TFA

160^a

150^a

r.t.

43

20

8

17^b

nd

48

nd

53

50

39^c

–

2.5

–

36

4

>95

38

BF₃·OEt₂(2.0)

SnCl₄(1.2)

MeNO₂

CH₂Cl₂

50

60^a16

90

60

70

33

10

>95

95

r.t.

120

^aMicrowave heating.

^bSignificant tarring was observed.

^c4b → 7b transformation was studied.

^dnd – not determined.

F

K. L. Ivanov et al.

Feature

Synthesis

Table 4 Scope of Lewis Acid Activated (3+2)-Cycloaddition^a

A (3+2)-Cycloaddition

CO₂Me

Ph

CO₂Me

R

R'

conditions

A or B

R

R'

N

CN

3a

6a

N

(0.5 equiv)

N₃

CN

N

+

N

Ph

N₃

+

BF₃•OEt₂(2 equiv)

3, 4, 5

6, 7, 11

dr ca. 1:1

N

Ph

MeNO₂

70 °C, 2 h

3a/4a/6a/7a

30:13:30:27

CN

N

4a

7a

Product

R

R′

Yield

N

(0.5 equiv)

N₃

(conditions A; %) (conditions B; %)

N

B Domino Staudinger/aza-Wittig reaction (ref. 4e)

6a

6b

6c

Ph

CO₂Me

45

47

52

88

84

92

90

92

94

36

90

86^c

85^c

89

18

90

CO₂Me

Ar

4-MeC₆H₄

4-FC₆H₄

CO₂Me

CONHBu

H

CO₂Me

CN

PPh₃

N

3

b

R = CO₂Me

Ph₃P

N

Ar

N

6d

6e

6f

4-ClC₆H₄

2-ClC₆H₄

4-BrC₆H₄

4-MeOC₆H₄

3-MeOC₆H₄

4-NCC₆H₄

4-O₂NC₆H₄

1-naphthyl

2-thienyl

Ph

–

PPh₃

b

R

–

Ar

86%

CO₂Me

PPh₃

b

–

CN

N

6g

6h

6i

14

Ar

N₃

PPh₃

N

CN

dr 54:46

b

4

–

R = H

Ar

N

no reaction

b

–

> 95%

PPh₃

b

6j

–

Scheme 4 Relative reactivities of 3a and 4a in (3+2)-cycloaddition (A);

comparison with reactivities in domino Staudinger/aza-Wittig reaction

b

6k

6l

–

(B)

b

–

b

6m

7a^d

7b^d

7c^d

–

b

Ph

50

29

30

–

cant tarring under the studied conditions (see comment to

Scheme 5) and, thus, only gave tetrazole 6g in 14% yield. For

compounds 7a–c, which were found to be easily crystalliz-

able, single-crystal X-ray analysis was carried out.

Under identical conditions, azide 4f, with a PMP substit-

uent, gave pyrrolotetrazole 7d as a minor product, while

the alkylated derivative 8 was found to be the major prod-

uct (Scheme 5A). The formation of 8 can be associated with

intermediate formation of the PMP-stabilized benzylic cat-

4-MeC₆H₄

4-FC₆H₄

H

39^e

b

H

–

^aReaction conditions A: BF₃·OEt₂(2 equiv), MeNO₂, 70 °C, 11 h. Reaction

conditions B: SnCl₄(1.2 equiv), DCM, 25 °C, 6–12 h.

^bReaction was not carried out under these conditions

^cReaction time: 24 h.

^dSingle-crystal X-ray analysis was carried out

^eReaction time: 120 h.

–

ion (supposedly, as a tight ion pair with N₃) with the corre-

sponding styrene undergoing further dimerization after-

wards (Scheme 5B). The proposed mechanism is in accor-

dance with the precedent of para-methoxybenzylic cation

formation from para-methoxybenzylazide.¹³Moreover, the

moderate yields of other tetrazoles 6 and 7 (particularly,

those containing electron-donating stabilizing groups) can

also be explained by the formation of the proposed inter-

mediates and their further oligomerization.

In the case of 2 mmol-scale synthesis of tetrazole 7a,

isomeric tetrazole 7′a could be isolated in 2% yield along

with the main product (Scheme 6A). The presence of trace

amounts of tetrazoles 7′ was detected in all reaction mix-

tures after (3+2)-cycloaddition of azides 4. Tetrazoles 7′

were probably formed from isomeric azides 4′ that were

present in trace amounts in the reaction mixtures upon

Krapcho decarboxylation of azidoesters 3. Apparently, un-

der Krapcho conditions, there is an equilibrium between

azides 3 (attack on C2) and 3′ (attack on C3), the precursors

of 4 and 4′, respectively, via cyclopropanes 2. For the

malonate analogue of 2a, dimethyl 2-phenylcyclopropane-

1,1-dicarboxylate, the S_N2-like attack on C2 is favored over

that on C3 (ΔG^≠= 6.6 kcal/mol).^3gHowever, the thermody-

namic stabilities of the resulting azides are comparable. Ad-

ditionally, the signals of methylated derivative 9 were de-

tected in ¹H NMR and HRMS spectra. The resulting product

9 is apparently formed by (3+2)-cycloaddition within azide

10, formed upon the alkylation of the initial azide 3a with

MeCl (or its analogue), produced by the elimination of MeCl

from 3a under the Krapcho conditions.

Switching the order of the steps (the azide 3a undergo-

ing (3+2)-cycloaddition followed by Krapcho decarboxyl-

ation of tetrazole 6a) allowed us to avoid the formation of

isomer 7′a (Scheme 6B).

The examination of other potential activators of (3+2)-

cycloaddition revealed that weak Lewis acids (e.g., Zn(OTf)₂

or BF₃·OEt₂) did not induce noticeable 3a→6a conversion,

even at increased temperature (Table 3, entries 12 and 13).

The commonly used CuI also did not catalyze this reaction

(entry 14). However, strong Lewis acids (SnCl₄and TiCl₄)

G

K. L. Ivanov et al.

Feature

Synthesis

(entries 15 and 16). Encouraged by these results, we carried

out SnCl₄-activated (3+2)-cycloaddition for a representative

series of azides 3 with various (het)aryl substituents R (Ta-

ble 4). Overall, tetrazoles 6 were obtained in high yields

(84–94%). For example, 4-chlorophenyl-substituted azide

3e and its isomer 3f, with a sterically hindered 2-chloro-

phenyl substituent, gave the corresponding tetrazoles 6d

and 6e with the same efficiency. However, similar to the

BF₃-activated tetrazole synthesis, the transformation of

PMP-substituted azide 3h provided one of the exceptions,

affording tetrazole 6g in a low yield (36%). The decay of che-

moselectivity in this case could also be associated with the

possibility for easier generation of benzylic cations (poten-

tially stabilized by an electron-donating PMP group,¹³see

the discussion of Scheme 6). At the same time, the isomeric

azide 3i, with a 3-methoxyphenyl substituent that lacks the

ability to stabilize cationic species efficiently, was convert-

ed into tetrazole 6h in a 90% yield. Azide 3t, with an elec-

tron-donating 2-thienyl group, also gave tetrazole 6l in low

yield (18%). The slowest 3→6 conversion (24 h) was ob-

served for azides 3n and 3o containing the CN and NO₂

groups in their aryl fragments. This deceleration could be

related to partial coordination of SnCl₄with these groups.

Similarly, amide 5a was easily transformed into tetra-

zole 6m in 90% yield under activation with SnCl₄(Table 4).

Meanwhile, under identical conditions, the ester-free ana-

logues 4 undergo (3+2)-cycloaddition much less efficiently.

Thus, the model azide 4b was converted into tetrazole 7b in

five days with only 39% yield (Table 3, entry 24; Table 4).

It is accepted that, when performed at elevated tem-

perature, the reaction between azides and nitriles proceeds

via a concerted mechanism, whereas acidic activation al-

lows for switching to the stepwise pathway.^9bEfficient

SnCl₄- or TiCl₄-activation of ester- or amide-substituted

azides 3 and 5 in comparison with carbonyl-free analogues

4 could be associated with intermediate formation of reac-

tive tin or titanium enolate that undergoes stepwise (3+2)-

cycloaddition via an initial attack of an azido group on the

activated cyano group, followed by 1,5-cyclization (Scheme 7).

A

PMP

CN

N₃

4f

BF₃·OEt₂(2 equiv)

MeNO₂, 70 °C, 11 h

PMP = 4-MeOC₆H₄

PMP

2

NC

4

7'

3

6'

5'

H

8'

N

+

N

PMP

8, 36%

N

7d, 11%

dr 69:19:10:3 X-ray

B

CN

– HN₃

–

N₃

PMP

NC

N₃

PMP

4f

NC

PMP

CN

–

N₃

PMP

CN

(3+2)

PMP

N

N₃

8

N

Scheme 5 Formation of side product 8 in (3+2)-cycloaddition of azide

4f containing an electron-donating aryl substituent PMP

CO₂Me

CN

CO₂Me

CN

A

CO₂Me

3

2

Ph

1

2a

CN

2

3

Ph

N₃

+ HN₃

3a

3'a

LiCl, H₂O

Krapcho

MeCl

Krapcho

DMF, Δ

Me

N₃

Ph

+

CN

+

Ph

N₃

Ph

N₃

4a

10

4'a

BF₃•OEt₂

(2 equiv)

MeNO₂

70 °C, 2 h

Me

Ph

+

N

7'a, 2%

N

9, 0.5%

7a, 50%

N

B

CO₂Me

MCl₄

N

O

N

Ph

CN

3a

Ph

R'

∼H⁺

7a, 54%

N₃

MCl₄

CO₂Me

N

LiCl (2 equiv)

R

CN

3, 5

R

CN

R

(3+2)

H₂O (10 equiv)

N₃

NH

DMF

135 °C, 7 h

N

M = Sn or Ti

Ph

N

6a

MCl₄

Scheme 6 Formation of side products 7′a and 9 in the synthesis of 7a

(A); alternative approach to 7a (B)

O

COR'

R'

R

N

R

NH

N

NH

N

that are conventionally used to trigger Schmidt rearrange-

ment,¹⁴but not (3+2)-cycloaddition, were found to activate

3a toward the assembly of tetrazole 6a in yields that were

twice as high as those in the case of activation with BF₃·OEt₂

N

6, 11

N

Scheme 7 Proposed mechanism for MCl₄-activated (M = Sn or Ti)

(3+2)-cycloaddition of carbonyl-containing azides 3 and 5

H

K. L. Ivanov et al.

Feature

Synthesis

In this work, we developed an efficient one-pot ap-

proach to -azidocyanobutyrates and their decarboxylated

or amidated derivatives starting from commercially avail-

able aldehydes and cyanoacetates. Our basic technique,

combining the widely used Knoevenagel and Corey–

Chaykovsky reactions as well as nucleophilic ring opening

of the forming donor-acceptor cyclopropanes with the

azide ion, results in -azidocyanobutyrates and can be fol-

lowed by Krapcho decarboxylation or amidation. The syn-

thetic utility of the resulting compounds for the assembly

of five-membered aza-heterocycles is exemplified by intra-

molecular (3+2)-cycloaddition, affording pyrrolotetrazole

derivatives. Thermal activation at this step was shown to be

inefficient for both -azidocyanobutyrates and their decar-

boxylated derivatives. Meanwhile, Lewis acid triggered re-

actions led to the target tetrazoles in moderate to high

yields. Among the studied Lewis acids, SnCl₄and TiCl₄were

found to be the most powerful, inducing specific accelera-

tion of (3+2)-cycloadition for ester-substituted -azido-

nitriles. This allowed us to develop highly efficient synthe-

sis of pyrrolotetrazoles.

under reduced pressure. The residue was purified by column chroma-

tography on silica gel (PE–EtOAc). Spectral data for azides 3a–e, 3g,

3h, 3k, 3l, 3n, 3p, and 3r–t are consistent with those reported previ-

ously.^4e

Methyl 4-Azido-2-cyano-4-phenylbutyrate (3a)^4e

Obtained from benzaldehyde (3.18 g).

Yield: 4.89 g (67%); dr A/B 56:44; yellow oil; R_f= 0.47 (PE–EtOAc, 4:1).

¹Н NMR (CDCl₃, 600 MHz):  = 2.20 (ddd, ²J = 14.1, ³J = 10.3, ³J = 4.3 Hz,

1 H, CH₂, A), 2.36 (ddd, ²J = 14.0, ³J = 6.9, ³J = 6.8 Hz, 1 H, CH₂, B), 2.40

(ddd, ²J = 14.0, ³J = 8.5, ³J = 7.0 Hz, 1 H, CH₂, B), 2.41 (ddd, ²J = 14.1, ³J =

10.8, ³J = 5.0 Hz, 1 H, CH₂, A), 3.52 (dd, ³J = 7.0, ³J = 6.9, Hz, 1 H, C²H, B),

3.81 (s, 3 H, CH₃O, A), 3.83 (s, 3 H, CH₃O, B), 3.86 (dd, ³J = 10.3, ³J = 5.0,

Hz, 1 H, C²H, A), 4.74 (dd, ³J = 8.5, ³J = 6.8 Hz, 1 H, C⁴H, B), 4.76 (dd, ³J =

10.8, ³J = 4.3 Hz, 1 H, C⁴H, A), 7.35–7.37 (m, 2 + 2 H, Ph, A, B), 7.39–

7.41 (m, 1 + 1 H, Ph, A, B), 7.43–7.46 (m, 2 + 2 H, Ph, A, B).

tert-Butyl 4-Azido-2-cyano-4-phenylbutyrate (3b)^4e

Obtained from benzaldehyde (5.73 g, 54.0 mmol) and tert-butyl cya-

noacetate (6.16 g, 54.0 mmol).

Yield: 8.97 g (58%); dr A/B 56:44; yellow oil; R_f= 0.62 (PE–EtOAc, 4:1).

¹Н NMR (CDCl₃, 600 MHz):  = 1.50 (s, 9 H, CH₃, A), 1.53 (s, 9 H, CH₃,

B), 2.14 (ddd, ²J = 14.1, ³J = 10.4, ³J = 4.0 Hz, 1 H, CH₂, A), 2.30 (ddd, ²J =

14.0, ³J = 7.0, ³J = 6.7 Hz, 1 H, CH₂, B), 2.34 (ddd, ²J = 14.1, ³J = 11.0, ³J =

2

3

5.1 Hz, 1 H, CH₂, A), 2.37 (ddd, J = 14.0, J = 8.6, J = 7.0 Hz, 1 H, CH₂,

B), 3.40 (dd, ³J = 7.0, ³J = 7.0 Hz, 1 H, C²H, B), 3.72 (dd, ³J = 10.4, ³J =

5.1 Hz, 1 H, C²H, A), 4.72 (dd, ³J = 8.6, ³J = 6.7 Hz, 1 H, C⁴H, B), 4.75 (dd,

³J = 11.0, ³J = 4.0 Hz, 1 H, C⁴H, A), 7.35–7.37 (m, 2 + 2 H, Ph, A, B), 7.39–

7.41 (m, 1 + 1 H, Ph, A, B), 7.43–7.46 (m, 2 + 2 H, Ph, A, B).

Reagents were purchased from commercial sources and used without

further purification. NMR spectra were acquired with Bruker Avance

600 MHz spectrometers at r.t.; the chemical shifts () were measured

in ppm with respect to solvent (¹Н: CDCl₃,  = 7.27 ppm; ¹³C: CDCl₃, 

= 77.0 ppm). Splitting patterns are designated as s, singlet; d, doublet;

t, triplet; m, multiplet; dd, double doublet. Coupling constants (J) are

given in hertz (Hz). The structures of compounds were elucidated

with the aid of 1D NMR (¹H, ¹³C) and 2D NMR (¹H-¹H COSY, ¹H-¹H NO-

ESY, ¹H-¹³C HSQC and HMBC) spectroscopy. High-resolution and accu-

rate mass measurements were carried out with a BrukermicroTOF-

QTM ESI-TOF (Electro Spray Ionization / Time of Flight) and Thermo

ScientificTM LTQ Orbitrap mass spectrometers. Melting points (mp)

were determined with an Electrothermal IA 9100 capillary melting

point apparatus. Microwave reactions were performed with a Mono-

wave 300-Anton Paar microwave reactor in sealed reaction vessels.

Analytical thin-layer chromatography (TLC) was carried out with sili-

ca gel plates (silica gel 60, F254, supported on aluminium) visualized

with UV lamp (254 nm). Column chromatography was performed on

silica gel 60 (230–400 mesh). PE = petroleum ether.

Methyl 4-Azido-2-cyano-4-(p-tolyl)butyrate (3c)^4e

Obtained from p-tolualdehyde (3.60 g).

Yield: 4.22 g (54%); dr A/B 54:46; yellow oil; R_f= 0.56 (PE–EtOAc, 4:1).

¹Н NMR (CDCl₃, 600 MHz):  = 2.18 (ddd, ²J = 14.1, ³J = 10.2, ³J = 4.3 Hz,

1 H, CH₂, A), 2.33 (ddd, ²J = 14.0, ³J = 7.0, ³J = 6.9 Hz, 1 H, CH₂, B), 2.38

3

(s, 3 + 3 H, CH₃, A, B), 2.38–2.43 (m, 1 + 1 H, CH₂, A, B), 3.51 (dd, J =

7.0, ³J = 6.9 Hz, 1 H, C²H, B), 3.80 (s, 3 H, CH₃O, A), 3.82 (dd, ³J = 10.2,

³J = 5.1 Hz, 1 H, C²H, A), 3.84 (s, 3 H, CH₃O, B), 4.70 (dd, ³J = 8.5, ³J =

6.9 Hz, 1 H, C⁴H, B), 4.73 (dd, ³J = 10.8, ³J = 4.3 Hz, 1 H, C⁴H, A), 7.22–

7.26 (m, 4 + 4 H, Ar, A, B).

Methyl 4-Azido-2-cyano-4-(4-fluorophenyl)butyrate (3d)^4e

Obtained from 4-fluorobenzaldehyde (3.72 g).

One-Pot Synthesis of 4-Azido-2-cyanobutyrates 3

Yield: 5.04 g (64%); dr A/B 55:45; yellow oil; R_f= 0.66 (PE–EtOAc, 2:1).

¹Н NMR (CDCl₃, 600 MHz):  = 2.17 (ddd, ²J = 14.1, ³J = 10.4, ³J = 4.1 Hz,

1 H, CH₂, A), 2.32 (ddd, ²J = 14.1, ³J = 7.2, ³J = 6.4 Hz, 1 H, CH₂, B), 2.35–

2.41 (m, 1 + 1 H, CH₂, A, B), 3.52–3.55 (m, 1 H, C²H, B), 3.82 (s, 3 H,

OCH₃, A), 3.84 (dd, ³J = 10.4, ³J = 4.9 Hz, 1 H, C²H, A), 3.87 (s, 3 H, OCH₃,

B), 4.74 (dd, ³J = 8.8, ³J = 6.4 Hz, 1 H, C⁴H, B), 4.76 (dd, ³J = 11.0, ³J =

4.1 Hz, 1 H, C⁴H, A), 7.12–7.15 (m, 2 + 2 H, Ar, A, B), 7.34–7.37 (m, 2 +

2 H, Ar, A, B).

A mixture of the corresponding aldehyde (30 mmol), methyl cyanoac-

etate (2.97 g, 30 mmol), piperidine (60 L, 0.60 mmol) and acetic acid

(70 L 1.2 mmol) in benzene (40 mL) was heated to reflux with a 20-

mL Dean–Stark trap for 2.5 h. The reaction mixture was cooled to am-

bient temperature and then to 0 °C in an ice-water bath. The suspen-

sion of dimethylsulfoxonium methylide in anhydrous DMF (100 mL),

generated from NaH (1.32 g, 33 mmol, 60% suspension in mineral oil),

and Me₃SOI (7.26 g, 33 mmol) was added dropwise during 10 minutes

under vigorous stirring. The reaction mixture was then allowed to

warm to r.t. and stirred for 1 hour. To the resulting mixture, NaN₃

(2.54 g, 39 mmol) and Et₃N·HCl (5.78 g, 42 mmol) were sequentially

added. The resulting suspension was stirred at ambient temperature

for 12–16 h (mixture A), diluted with brine (200 mL) and extracted

with EtOAc (3 × 100 mL). The combined organic fractions were

washed with water (3 × 100 mL), dried with Na₂SO₄, and concentrated

Methyl 4-Azido-4-(4-chlorophenyl)-2-cyanobutyrate (3e)^4e

Obtained from 4-chlorobenzaldehyde (4.21 g).

Yield: 3.43 g (41%); dr A/B 48:52; yellow oil; R_f= 0.45 (PE–EtOAc, 4:1).

¹Н NMR (CDCl₃, 600 MHz):  = 2.16 (ddd, ²J = 14.1, ³J = 10.3, ³J = 4.1 Hz,

1 H, CH₂, A), 2.30 (ddd, ²J = 14.1, ³J = 7.1, ³J = 6.3 Hz, 1 H, CH₂, B), 2.35

2

3

2

(ddd, J = 14.1, J = 10.9, J = 5.0 Hz, 1 H, CH₂, A), 2.36 (ddd, J = 14.1,

I

K. L. Ivanov et al.

Feature

Synthesis

³J = 8.9, ³J = 6.6 Hz, 1 H, CH₂, B), 3.54 (dd, ³J = 7.1, ³J = 6.6 Hz, 1 H, C²H,

B), 3.79 (s, 3 H, OCH₃, A), 3.82 (dd, ³J = 10.3, ³J = 5.0 Hz, 1 H, C²H, A),

¹³С NMR (CDCl₃, 150 MHz):  = 34.1 (C²H), 34.6 (C²H), 35.5 (CH₂), 35.9

(CH₂), 53.48 (OCH₃), 53.53 (OCH₃), 55.1 (2 × OCH₃), 62.8 (C⁴H), 62.9

(C⁴H), 112.4 (2 × CH), 114.3 (CH), 114.4 (CH), 115.6 (2 × CN), 118.9

(2 × CH), 130.1 (CH), 130.2 (CH), 138.5 (C), 138.8 (C), 160.0 (C), 160.1

(C), 165.67 (CO₂Me), 165.70 (CO₂Me).

3

3.84 (s, 3 H, OCH₃, B), 4.73 (dd, J = 8.9, J = 6.3 Hz, 1 H, C⁴H, B), 4.74

(dd, ³J = 10.9, ³J = 4.1 Hz, 1 H, C⁴H, A), 7.29–7.32 (m, 2 + 2 H, Ar, A, B),

7.39–7.42 (m, 2 + 2 H, Ar, A, B).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₃H₁₅N₄O₃⁺: 275.1139; found:

275.1135.

Methyl 4-Azido-4-(2-chlorophenyl)-2-cyanobutyrate (3f)

Obtained from 2-chlorobenzaldehyde (4.21 g).

Methyl 4-Azido-2-cyano-4-(2,3-dimethoxyphenyl)butyrate (3j)

Obtained from 2,3-dimethoxybenzaldehyde (4.98 g).

Yield: 4.44 g (53%); dr A/B 50:50; yellow oil; R_f= 0.68 (PE–EtOAc, 2:1).

¹Н NMR (CDCl₃, 600 MHz):  = 2.25–2.28 (m, 2 H, CH₂, A), 2.28 (ddd,

²J = 14.3, ³J = 9.7, ³J = 5.4 Hz, 1 H, CH₂, B), 2.44 (ddd, ²J = 14.3, ³J = 7.8,

³J = 4.6 Hz, 1 H, CH₂, B), 3.72 (dd, ³J = 7.8, ³J = 5.4 Hz, 1 H, C²H, B), 3.82

(s, 3 H, OCH₃, A), 3.84–3.86 (m, 1 H, C²H, A), 3.88 (s, 3 H, OCH₃, B),

5.31 (dd, ³J = 9.7, ³J = 4.6 Hz, 1 H, C⁴H, B), 5.32 (dd, ³J = 7.8, ³J = 6.2 Hz,

1 H, C⁴H, A), 7.31–7.34 (m, 1 + 1 H, Ar, A, B), 7.36–7.39 (m, 1 + 1 H, Ar,

A, B), 7.43–7.45 (m, 1 + 1 H, Ar, A, B), 7.48–7.51 (m, 1 + 1 H, Ar, A, B).

¹³С NMR (CDCl₃, 150 MHz):  = 34.1 (C²H), 34.7 (C²H), 35.0 (CH₂), 35.1

(CH₂), 53.66 (OCH₃), 53.7 (OCH₃), 59.50 (C⁴H), 59.52 (C⁴H), 115.4 (CN),

115.6 (CN), 127.5 (CH), 127.6 (CH), 127.7 (CH), 127.8 (CH), 129.96

(CH), 130.01 (CH), 130.1 (2 × CH), 132.78 (C), 132.83 (C), 135.4 (C),

135.5 (C), 165.7 (CO₂Me), 165.8 (CO₂Me).

Yield: 6.25 g (68%); dr A/B 55:45; yellow oil; R_f= 0.57 (PE–EtOAc, 1:2).

¹Н NMR (CDCl₃, 600 MHz):  = 2.16 (ddd, ²J = 14.0, ³J = 10.2, ³J = 4.1 Hz,

1 H, CH₂, A), 2.34–2.38 (m, 2 H, CH₂, B), 2.39 (ddd, ²J = 14.0, ³J = 10.6,

³J = 5.1 Hz, 1 H, CH₂, A), 3.59–3.61 (m, 1 H, C²H, B), 3.77 (s, 3 H, OCH₃,

3

A), 3.79 (dd, J = 10.2, ³J = 5.1 Hz, 1 H, C²H, A), 3.81 (s, 3 H, OCH₃, B),

3.86 (s, 6 H, 2 × OCH₃, B), 3.88 (s, 3 H, OCH₃, A), 3.89 (s, 3 H, OCH₃, A),

5.12–5.14 (m, 1 H, C⁴H, B), 5.15 (dd, ³J = 10.6, ³J = 4.1 Hz, 1 H, C⁴H, A),

6.90–6.95 (m, 2 + 2 H, Ar, A, B), 7.08–7.11 (m, 1 + 1 H, Ar, A, B).

¹³С NMR (CDCl₃, 150 MHz):  = 34.3 (C²H), 34.6 (C²H), 34.9 (CH₂), 35.0

(CH₂), 53.4 (2 × OCH₃), 55.6 (2 × OCH₃), 57.09 (OCH₃), 57.15 (OCH₃),

60.9 (2 × C⁴H), 112.7 (2 × CH), 115.6 (CN), 115.7 (CN), 118.3 (CH),

118.4 (CH), 124.4 (CH), 124.5 (CH), 130.5 (C), 130.8 (C), 146.4 (C),

146.6 (C), 152.56 (C), 152.59 (C), 165.75 (CO₂Me), 165.76 (CO₂Me).

HRMS (ESI): m/z [M – H]^–calcd for C₁₂H₁₀ClN₄O₂^–: 277.0498; found:

277.0496.

HRMS (ESI): m/z [M + H]⁺calcd for C₁₄H₁₇N₄O₄⁺: 305.1244; found:

305.1240.

Methyl 4-Azido-4-(4-bromophenyl)-2-cyanobutyrate (3g)^4e

Obtained from 4-bromobenzaldehyde (5.55 g).

Methyl 4-Azido-2-cyano-4-(3,4-dimethoxyphenyl)butyrate (3k)^4e

Obtained from 3,4-dimethoxybenzaldehyde (4.98 g).

Yield: 5.07 g (52%); dr A/B 57:43; yellow oil; R_f= 0.41 (PE–EtOAc, 4:1).

¹Н NMR (CDCl₃, 600 MHz):  = 2.16 (ddd, ²J = 14.1, ³J = 10.4, ³J = 4.1 Hz,

1 H, CH₂, A), 2.33 (ddd, ²J = 14.1, ³J = 7.1, ³J = 6.4 Hz, 1 H, CH₂, B), 2.36

Yield: 4.69 g (51%); dr A/B 52:48; yellow oil; R_f= 0.44 (PE–EtOAc, 2:1).

2

3

2

(ddd, J = 14.1, J = 11.0, J = 4.9 Hz, 1 H, CH₂, A), 2.37 (ddd, J = 14.1,

³J = 8.8, ³J = 6.7 Hz, 1 H, CH₂, B), 3.53 (dd, ³J = 7.1, ³J = 6.7 Hz, 1 H, C²H,

B), 3.82 (s, 3 H, OCH₃, A), 3.84 (dd, ³J = 10.4, ³J = 4.9 Hz, 1 H, C²H, A),

¹Н NMR (CDCl₃, 600 MHz):  = 2.18 (ddd, ²J = 14.1, ³J = 10.2, ³J = 4.3 Hz,

1 H, CH₂, A), 2.32 (m, 1 H, CH₂, B), 2.38 (ddd, ²J = 14.0, ³J = 8.2, ³J =

7.3 Hz, 1 H, CH₂, B), 2.39 (ddd, ²J = 14.1, ³J = 10.8, ³J = 5.1 Hz, 1 H, CH₂,

A), 3.48 (dd, ³J = 7.3, ³J = 7.2 Hz, 1 H, C²H, B), 3.80 (s, 3 H, OCH₃, A),

3.81 (dd, ³J = 10.2, ³J = 5.1 Hz, 1 H, C²H, A), 3.84 (s, 3 H, OCH₃, B), 3.90

(s, 6 H, 2 × OCH₃, A), 3.91 (s, 6 H, 2 × OCH₃, B), 4.67 (dd, ³J = 8.2, ³J =

7.2 Hz, 1 H, C⁴H, B), 4.69 (dd, ³J = 10.8, ³J = 4.3 Hz, 1 H, C⁴H, A), 6.83–

6.85 (m, 1 + 1 H, Ar, A, B), 6.88–6.92 (m, 2 + 2 H, Ar, A, B).

3.87 (s, 3 H, OCH₃, B), 4.72 (dd, J = 8.8, J = 6.4 Hz, 1 H, C⁴H, B), 4.74

(dd, ³J = 11.0, ³J = 4.1 Hz, 1 H, C⁴H, A), 7.24–7.26 (m, 2 + 2 H, Ar, A, B),

7.56–7.59 (m, 2 + 2 H, Ar, A, B).

3

Methyl 4-Azido-2-cyano-4-(4-methoxyphenyl)butyrate (3h)^4e

Obtained from p-anisaldehyde (4.08 g).

Methyl 4-Azido-2-cyano-4-(3,4,5-trimethoxyphenyl)butyrate

(3l)^4e

Yield: 4.21 g (51%); dr A/B 56:44; yellow oil; R_f= 0.30 (PE–EtOAc, 4:1).

¹Н NMR (CDCl₃, 600 MHz):  = 2.17 (ddd, ²J = 14.1, ³J = 10.2, ³J = 4.3 Hz,

1 H, CH₂, A), 2.33 (m, 1 H, CH₂, B), 2.39 (ddd, ²J = 14.0, ³J = 8.4, ³J =

7.3 Hz, 1 H, CH₂, B), 2.43 (ddd, ²J = 14.1, ³J = 10.8, ³J = 5.1 Hz, 1 H, CH₂,

A), 3.49 (dd, ³J = 7.3, ³J = 6.9 Hz, 1 H, C²H, B), 3.81 (s, 3 H, OCH₃, A),

3.82 (dd, ³J = 10.2, ³J = 5.1 Hz, 1 H, C²H, A), 3.84 (s, 3 + 3 H, OCH₃, A, B),

3.85 (s, 3 H, OCH₃, B), 4.69 (dd ³J = 8.4, ³J = 7.2 Hz, 1 H, C⁴H, B), 4.72

(dd, ³J = 10.8, ³J = 4.3 Hz, 1 H, C⁴H, A), 6.94–6.96 (m, 2 + 2 H, Ar, A, B),

7.27–7.30 (m, 2 + 2 H, Ar, A, B).

Obtained from 3,4,5-trimethoxybenzaldehyde (5.89 g).

Yield: 5.40 g (54%); dr A/B 59:41; yellow oil; R_f= 0.42 (PE–EtOAc, 2:1).

¹Н NMR (CDCl₃, 400 MHz):  = 2.18 (ddd, ²J = 14.1, ³J = 10.3, ³J = 4.2 Hz,

1 H, CH₂, A), 2.28–2.33 (m, 1 H, CH₂, B), 2.35 (ddd, ²J = 14.1, ³J = 10.9,

³J = 4.9 Hz, 1 H, CH₂, A), 2.37 (ddd, ²J = 14.0, ³J = 8.4, ³J = 7.2 Hz, 1 H,

3

CH₂, B), 3.51 (dd, J = 7.2, J = 7.0 Hz, 1 H, C²H, B), 3.82 (s, 3 H, OCH₃,

A), 3.83 (dd, ³J = 10.3, ³J = 4.9 Hz, 1 H, C²H, A), 3.86 (s, 9 H, 3 × OCH₃),

3.89 (s, 12 H, 4 × OCH₃), 4.67 (dd, ³J = 8.4, ³J = 7.0 Hz, 1 H, C⁴H, B), 4.69

(dd, ³J = 10.9, ³J = 4.2 Hz, 1 H, C⁴H, A), 6.54–6.56 (m, 2 + 2 H, Ar, A, B).

Methyl 4-Azido-2-cyano-4-(3-methoxyphenyl)butyrate (3i)

Obtained from m-anisaldehyde (4.08 g).

Methyl 4-Azido-2-cyano-4-(2,4,6-trimethoxyphenyl)butyrate

(3m)

Yield: 4.61 g (56%); dr A/B 56:44; yellow oil; R_f= 0.73 (PE–EtOAc, 2:1).

2

3

¹Н NMR (CDCl₃, 600 MHz):  = 2.17 (ddd, J = 14.1, J = 10.2, J = 4.3,

Hz, 1 H, CH₂, A), 2.32 (m, 1 H, CH₂, B), 2.38 (ddd, ²J = 14.0, ³J = 8.5, ³J =

7.3 Hz, 1 H, CH₂, B), 2.39 (ddd, ²J = 14.1, ³J = 10.8, ³J = 5.0 Hz, 1 H, CH₂,

A), 3.52 (m, 1 H, C²H, B), 3.78 (s, 3 H, OCH₃, A), 3.78–3.80 (m, 1 H, C²H,

A), 3.81 (s, 3 + 3 H, OCH₃, A, B), 3.82 (s, 3 H, OCH₃, A), 4.70 (dd, ³J = 8.5,

³J = 6.8 Hz, 1 H, C⁴H, B), 4.72 (dd, ³J = 10.8, ³J = 4.3 Hz, 1 H, C⁴H, A),

6.85–6.96 (m, 3 + 3 H, Ar, A, B), 7.30–7.35 (m, 1 + 1 H, Ar, A, B).

Obtained from 2,4,6-trimethoxybenzaldehyde (5.89 g).

Yield: 6.94 g (69%); dr A/B 54:46; yellow oil; R_f= 0.52 (PE–EtOAc, 2:1).

¹Н NMR (CDCl₃, 600 MHz):  = 2.29 (ddd, ²J = 13.9, ³J = 9.3, ³J = 5.8 Hz,

1 H, CH₂, A), 2.59 (ddd, ²J = 13.6, ³J = 8.1, ³J = 6.4 Hz, 1 H, CH₂, B), 2.63

(ddd, ²J = 13.6, ³J = 8.1, ³J = 7.7 Hz, 1 H, CH₂, B), 2.81 (ddd, ²J = 13.9, ³J =

9.6, ³J = 5.6 Hz, 1 H, CH₂, A), 3.42 (dd, ³J = 8.1, ³J = 6.4 Hz, 1 H, C²H, B),

J

K. L. Ivanov et al.

Feature

Synthesis

3.67 (dd, ³J = 9.3, ³J = 5.6 Hz, 1 H, C²H, A), 3.76 (s, 3 H, OCH₃, A), 3.79 (s,

3 H, OCH₃, B), 3.81 (s, 6 H, 2 × OCH₃, B), 3.82 (s, 3 + 3 H, 2 × OCH₃, A,

B), 3.82 (s, 6 H, 2 × OCH₃, A), 5.30 (dd, ³J = 8.1, ³J = 7.7 Hz, 1 H, C⁴H, B),

5.33 (dd, ³J = 9.6, ³J = 5.8 Hz, 1 H, C⁴H, A), 6.13–6.15 (m, 2 + 2 H, Ar, A,

B).

¹³С NMR (CDCl₃, 150 MHz):  = 34.0 (C²H), 34.6 (C²H), 35.5 (CH₂), 35.8

(CH₂), 53.52 (OCH₃), 53.57 (OCH₃), 62.3 (C⁴H), 62.4 (C⁴H), 115.5

(2 × CN), 127.56 (2 × CH), 127.64 (2 × CH), 138.2 (C), 138.3 (C), 138.4

(C), 138.5 (C), 165.6 (2 × CO₂Me).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₈H₁₉N₈O₄⁺: 411.1524; found:

¹³С NMR (CDCl₃, 150 MHz):  = 32.66 (C²H), 32.69 (C²H), 34.8 (CH₂),

35.1 (CH₂), 53.35 (OCH₃), 53.39 (OCH₃), 53.41 (OCH₃), 53.45 (OCH₃),

55.2 (2 × OCH₃), 55.7 (2 × OCH₃+2 × C⁴H), 90.67 (2 × CH), 90.75

(2 × CH), 103.9 (C), 104.3 (C), 116.0 (2 × CN), 159.6 (2 × C), 159.7

(2 × C), 161.76 (C), 161.83 (C), 166.2 (2 × CO₂Me).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₅H₁₉N₄O₅⁺: 335.1350; found:

335.1350.

411.1523.

Methyl (E)-4-Azido-2-cyano-6-phenylhex-5-enoate (3r)^4e

Obtained from trans-cinnamaldehyde (3.97 g).

Yield: 3.55 g (44%); dr A/B 56:44; yellow oil; R_f= 0.62 (PE–EtOAc, 2:1).

¹Н NMR (CDCl₃, 600 MHz):  = 2.17 (ddd, ²J = 14.0, ³J = 9.7, ³J = 4.8 Hz,

1 H, CH₂, A), 2.22–2.27 (m, 1 + 2 H, CH₂, А, B), 3.68 (dd, ³J = 7.0, ³J =

6.8 Hz, 1 H, C²H, B), 3.81 (s, 3 H, OCH₃, A), 3.81 (dd, ³J = 9.7, ³J = 5.1 Hz,

1 H, C²H, A), 3.86 (s, 3 H, OCH₃, B), 4.32–4.38 (m, 1 + 1 H, C⁴H, A, B),

6.09 (dd, ³J = 15.7, ³J = 8.5 Hz, 1 H, CH=, B), 6.11 (dd, ³J = 15.7, ³J =

8.4 Hz, 1 H, CH=, A), 6.76 (d, ³J = 15.7 Hz, 1 + 1 H, CH=, A, B), 7.32–7.34

(m, 1 + 1 H, Ar, A, B), 7.36–7.39 (m, 2 + 2 H, Ar, A, B), 7.42–7.45 (m, 2 +

2 H, Ar, A, B).

Methyl 4-Azido-2-cyano-4-(4-cyanophenyl)butyrate (3n)^4e

Obtained from 4-cyanobenzaldehyde (3.93 g).

Yield: 3.07 g (38%); dr A/B 56:44; yellow oil; R_f= 0.26 (PE–EtOAc, 4:1).

¹Н NMR (CDCl₃, 600 MHz):  = 2.18 (ddd, ²J = 14.2, ³J = 10.6, ³J = 3.8 Hz,

1 H, CH₂, A), 2.30–2.39 (m, 1 + 2 H, CH₂, A, B), 3.61 (dd, ³J = 7.3, ³J =

6.1 Hz, 1 H, C²H, B), 3.82 (s, 3 H, OCH₃, A), 3.86 (dd, ³J = 10.6, ³J =

4.8 Hz, 1 H, C²H, A), 3.88 (s, 3 H, OCH₃, B), 4.82–4.84 (m, 1 + 1 H, C⁴H,

A, B), 7.49–7.52 (m, 2 + 2 H, Ar, A, B), 7.74–7.76 (m, 2 + 2 H, Ar, A, B).

Methyl 4-Azido-2-cyano-4-(furan-2-yl)butyrate (3s)^4e

Obtained from furfural (2.88 g).

Yield: 1.91 g (27%); dr A/B 56:44; brown oil; R_f= 0.67 (PE–EtOAc, 2:1).

Methyl 4-Azido-2-cyano-4-(4-nitrophenyl)butyrate (3o)

Obtained from 4-nitrobenzaldehyde (4.53 g).

¹Н NMR (CDCl₃, 600 MHz):  = 2.34 (ddd, ²J = 14.1, ³J = 10.2, ³J = 4.5 Hz,

1 H, CH₂, A), 2.50 (ddd, ²J = 14.1, ³J = 8.5, ³J = 6.8 Hz, 1 H, CH₂, B), 2.50–

2.55 (m, 1 H, CH₂, B), 2.57 (ddd, ²J = 14.1, ³J = 10.6, ³J = 5.1 Hz, 1 H, CH₂,

A), 3.61–3.63 (m, 1 H, C²H, B), 3.82 (dd, ³J = 10.2, ³J = 5.1 Hz, 1 H, C²H,

A), 3.84 (s, 3 H, OCH₃), 3.87 (s, 3 H, OCH₃), 4.77 (dd, ³J = 8.5, ³J = 6.8 Hz,

1 H, C⁴H, B), 4.79 (dd, ³J = 10.6, ³J = 4.5 Hz, 1 H, C⁴H, A), 6.41–6.42 (m,

1 + 1 H, Fu, A, B), 6.43–6.44 (m, 1 H, Fu), 6.44–6.45 (m, 1 H, Fu), 7.47–

7.48 (m, 1 + 1 H, Fu, A, B).

Yield: 2.41 g (28%); dr A/B 52:48; yellow oil; R_f= 0.49 (PE–EtOAc, 2:1).

¹Н NMR (CDCl₃, 600 MHz):  = 2.21 (ddd, ²J = 14.2, ³J = 10.6, ³J = 3.9 Hz,

1 H, CH₂, A), 2.34–2.39 (m, 1 + 2 H, CH₂, A, B), 3.65 (dd, ³J = 7.3, ³J =

6.0 Hz, 1 H, C²H, B), 3.81 (s, 3 H, OCH₃, A), 3.87 (s, 3 H, OCH₃, B), 3.89

(dd, ³J = 10.6, ³J = 4.8 Hz, 1 H, C²H, A), 4.89–4.91 (m, 1 + 1 H, C⁴H, A, B),

7.55–7.60 (m, 2 + 2 H, Ar, A, B), 8.27–8.30 (m, 2 + 2 H, Ar, A, B).

¹³С NMR (CDCl₃, 150 MHz):  = 33.9 (C²H), 34.6 (C²H), 35.7 (CH₂), 35.9

(CH₂), 53.8 (2 × OCH₃), 62.1 (C⁴H), 62.2 (C⁴H), 115.4 (2 × CN), 124.38

(2 × CH), 124.42 (2 × CH), 127.8 (2 × CH), 127.9 (2 × CH), 144.6 (C),

144.7 (C), 148.1 (2 × C), 165.4 (CO₂Me), 165.5 (CO₂Me)

Methyl 4-Azido-2-cyano-4-(thien-2-yl)butyrate (3t)^4e

Obtained from 2-thiophenecarboxaldehyde (3.36 g).

Yield: 3.76 g (50%); dr A/B 48:52; yellow oil; R_f= 0.46 (pethroleum

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₂N₅O₄⁺: 290.0884; found:

ether–EtOAc, 2:1).

¹Н NMR (CDCl₃, 600 MHz):  = 2.33 (ddd, ²J = 14.1, ³J = 10.0, ³J = 4.4 Hz,

1 H, CH₂, A), 2.41–2.49 (m, 2 H, CH₂, B), 2.50 (ddd, ²J = 14.1, ³J = 10.7,

³J = 5.2 Hz, 1 H, CH₂, A), 3.67 (dd, ³J = 7.1, ³J = 7.0 Hz, 1 H, C²H, B), 3.78

(s, 3 H, OCH₃, A), 3.80 (s, 3 H, OCH₃, B), 3.89 (dd, ³J = 10.0, ³J = 5.2 Hz,

1 H, C²H, A), 5.04 (dd, ³J = 8.7, ³J = 6.7 Hz, 1 H, C⁴H, B), 5.06 (dd, ³J =

10.7, ³J = 4.4 Hz, 1 H, C⁴H, A), 7.02–7.04 (m, 1 + 1 H, Th, A, B), 7.11–

7.15 (m, 1 + 1 H, Th, A, B), 7.36–7.39 (m, 1 + 1 H, Th, A, B).

290.0884.

Methyl 4-Azido-2-cyano-4-(naphthen-1-yl)butyrate (3p)^4e

Obtained from 1-naphthaldehyde (4.68 g).

Yield: 4.16 g (47%); dr A/B 53:47; yellow oil; R_f= 0.39 (PE–EtOAc, 4:1).

¹Н NMR (CDCl₃, 400 MHz):  = 2.40 (ddd, ²J = 14.3, ³J = 10.7, ³J = 3.6 Hz,

1 H, CH₂, A), 2.49–2.57 (m, 1 + 1 H, CH₂, A, B), 2.60 (ddd, ²J = 14.3, ³J =

7.7, ³J = 5.3 Hz, 1 H, CH₂, B), 3.75 (dd, ³J = 7.7, ³J = 5.5 Hz, 1 H, C²H, B),

3.80 (s, 3 H, OCH₃, A), 3.91 (s, 3 H, OCH₃, B), 3.98 (dd, ³J = 10.7, ³J =

4.7 Hz, 1 H, C²H, A), 5.55 (dd, ³J = 9.8, ³J = 5.3 Hz, 1 H, C⁴H, B), 5.58 (dd,

³J = 10.6, ³J = 3.6 Hz, 1 H, C⁴H, A), 7.52–7.64 (m, 4 + 4 H, Ar, A, B), 7.89–

7.92 (m, 1 + 1 H, Ar, A, B), 7.93–7.96 (m, 1 + 1 H, Ar, A, B), 8.12 (d, ³J =

8.4 Hz, 1 H, Ar, A), 8.17 (d, ³J = 8.5 Hz, 1 H, Ar, B).

Methyl 4-Azido-2-cyano-4-(1-methyl-1H-indol-2-yl)butyrate (3u)

Obtained from 1-methyl-1H-indole-2-carbaldehyde (4.78 g).

Yield: 5.18 g (58%); dr A/B 63:37; brown oil; R_f= 0.63 (PE–EtOAc, 2:1).

¹Н NMR (CDCl₃, 600 MHz):  = 2.53 (ddd, ²J = 14.1, ³J = 9.4, ³J = 4.7 Hz,

1 H, CH₂, A), 2.66–2.69 (m, 2 H, CH₂, B), 2.72 (ddd, ²J = 14.1, ³J = 10.3,

³J = 5.4 Hz, 1 H, CH₂, A), 3.73–3.75 (m, 1 H, C²H, B), 3.80 (s, 3 H, CH₃,

A), 3.82 (s, 3 H, CH₃, B), 3.83 (s, 3 H, CH₃, A), 3.88 (s, 3 H, CH₃, B), 3.91

Dimethyl 4,4′-Benzene-1,4-diylbis(4-azido-2-cyanobutyrate) (3q)

3

(dd, J = 9.4, J = 5.4 Hz, 1 H, C²H, A), 4.85–4.87 (m, 1 H, C⁴H, B), 4.88

(dd, ³J = 10.3, ³J = 4.7 Hz, 1 H, C⁴H, A), 6.60–6.65 (m, 1 + 1 H, Ar, A, B),

7.17–7.20 (m, 1 + 1 H, Ar, A, B), 7.31–7.34 (m, 1 + 1 H, Ar, A, B), 7.37–

7.39 (m, 1 + 1 H, Ar, A, B), 7.65–7.67 (m, 1 + 1 H, Ar, A, B).

Obtained from terephthalaldehyde (4.02 g).

Yield: 6.11 g (50%); dr A/B 50:50 (for two major isomers); yellow oil;

R_f= 0.74 (PE–EtOAc, 1:1).

¹Н NMR (CDCl₃, 600 MHz):  = 2.17–2.23 (m, 1 H, CH₂), 2.33–2.42 (m,

3 H, CH₂), 3.56–3.59 (m, 1 H, C²H), 3.82 (s, 3 H, OCH₃), 3.83–3.86 (m,

1 H, C²H), 3.86 (s, 3 H, OCH₃), 4.76–4.81 (m, 2 H, C⁴H), 7.44–7.46 (m,

4 H, Ar).

¹³С NMR (CDCl₃, 150 MHz):  = 29.91 (C²H), 29.94 (C²H), 33.0 (CH₂),

33.3 (CH₂), 34.4 (NCH₃), 34.6 (NCH₃), 53.66 (OCH₃), 53.73 (OCH₃), 55.1

(2 × C⁴H), 101.5 (CH), 101.7 (CH), 109.3 (CH), 109.4 (CH), 115.4 (CN),

K

K. L. Ivanov et al.

Feature

Synthesis

115.5 (CN), 120.07 (CH), 120.11 (CH), 121.00 (CH), 121.03 (CH),

122.74 (CH), 122.79 (CH), 126.7 (2×C), 133.7 (C), 133.9 (C), 138.11 (C),

138.16 (C), 165.56 (CO₂Me), 165.61 (CO₂Me).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₅H₁₆N₅O₂⁺: 298.1299; found:

Yield: 2.69 g (41%); yellow oil; R_f= 0.61 (PE–EtOAc, 3:1).

2

3

¹Н NMR (CDCl₃, 600 MHz):  = 2.00 (dddd, J = 14.0, J = 7.8, J = 7.2,

³J = 5.6 Hz, 1 H, CH₂), 2.08 (dddd, ²J = 14.0, ³J = 9.0, ³J = 7.2, ³J = 6.2 Hz,

1 H, CH₂), 2.39 (ddd, ²J = 17.0, ³J = 7.2, ³J = 6.2 Hz, 1 H, CH₂), 2.50 (ddd,

²J = 17.0, ³J = 7.8, ³J = 7.2 Hz, 1 H, CH₂), 4.63 (dd, ³J = 9.0, ³J = 5.6 Hz,

1 H, CH), 7.27–7.30 (m, 2 H, Ar), 7.40–7.43 (m, 2 H, Ar).

298.1306.

¹³С NMR (CDCl₃, 150 MHz):  = 14.2 (¹J_C–H= 136 Hz, CH₂), 31.9 (¹J_C–H

=

One-Pot Synthesis of 4-Azidobutyronitriles 4

133 Hz, CH₂), 63.6 (¹J_C–H= 143 Hz, CH), 118.5 (CN), 128.1 (2 × CH),

To the mixture A, LiCl (1.30 g, 30 mmol) and water (4 mL) were se-

quentially added. The resulting mixture was heated for 3–6 h at

125 °C, then cooled, diluted with brine (200 mL), and extracted with

EtOAc (3 × 100 mL). The combined organic fractions were washed

with water (3 × 100 mL), dried with Na₂SO₄, and concentrated under

reduced pressure. The residue was purified by column chromatogra-

phy on silica gel (PE–EtOAc). Spectral data for azides 4a, 4e, and 4f are

consistent with those reported previously.^4e,15

129.4 (2 × CH), 134.8 (C), 136.3 (C).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₀H₁₀ClN₄⁺: 221.0589; found:

221.0589.

4-Azido-4-(4-bromophenyl)butyronitrile (4e)^4e

Obtained from 4-bromobenzaldehyde (5.55 g); reaction time 6 h.

Yield: 2.89 g (36%); orange oil; R_f= 0.62 (PE–EtOAc, 2:1).

2

3

4-Azido-4-phenylbutyronitrile (4a)^4e

¹Н NMR (CDCl₃, 600 MHz):  = 2.00 (dddd, J = 14.0, J = 7.8, J = 7.1,

³J = 5.6 Hz, 1 H, CH₂), 2.07 (dddd, ²J = 14.0, ³J = 8.9, ³J = 7.3, ³J = 6.1 Hz,

1 H, CH₂), 2.38 (ddd, ²J = 17.0, ³J = 7.1, ³J = 6.1 Hz, 1 H, CH₂), 2.50 (ddd,

²J = 17.0, ³J = 7.8, ³J = 7.3 Hz, 1 H, CH₂), 4.62 (dd, ³J = 8.9, ³J = 5.6 Hz,

1 H, CH), 7.22 (br d, ³J = 8.7 Hz, 2 H, Ar), 7.57 (br d, ³J = 8.7 Hz, 2 H, Ar).

Obtained from benzaldehyde (3.18 g); reaction time 6 h.

Yield: 2.20 g (39%); yellow oil; R_f= 0.50 (PE–EtOAc, 4:1).

¹Н NMR (CDCl₃, 600 MHz):  = 2.04 (dddd, J = 13.9, J = 7.7, J = 7.3,

³J = 5.8 Hz, 1 H, CH₂), 2.12 (dddd, ²J = 13.9, ³J = 8.8, ³J = 7.4, ³J = 6.2 Hz,

1 H, CH₂), 2.38 (ddd, ²J = 17.0, ³J = 7.3, ³J = 6.2 Hz, 1 H, CH₂), 2.49 (ddd,

²J = 17.0, ³J = 7.7, ³J = 7.4 Hz, 1 H, CH₂), 4.64 (dd, ³J = 8.8, ³J = 5.8 Hz,

1 H, CH), 7.32–7.34 (m, 2 H, Ph), 7.38–7.41 (m, 1 H, Ph), 7.42–7.45 (m,

2 H, Ph).

2

3

4-Azido-4-(4-methoxyphenyl)butyronitrile (4f)¹⁵

Obtained from p-anisaldehyde (4.08 g); reaction time 5 h.

Yield: 2.99 g (42%); yellow oil; R_f= 0.56 (PE–EtOAc, 3:1).

¹Н NMR (CDCl₃, 600 MHz):  = 2.00 (dddd, J = 13.9, J = 7.5, J = 7.3,

³J = 6.0 Hz, 1 H, CH₂), 2.10 (dddd, ²J = 13.9, ³J = 8.8, ³J = 7.4, ³J = 6.3 Hz,

1 H, CH₂), 2.35 (ddd, ²J = 17.1, ³J = 7.3, ³J = 6.3 Hz, 1 H, CH₂), 2.45 (ddd,

²J = 17.1, ³J = 7.5, ³J = 7.4 Hz, 1 H, CH₂), 3.82 (s, 3 H, CH₃O), 4.57 (dd, ³J =

8.8, ³J = 6.0 Hz, 1 H, CH), 6.94 (br d, ³J = 8.8 Hz, 2 H, Ar), 7.25 (br d, ³J =

8.8 Hz, 2 H, Ar).

2

3

4-Azido-4-(p-tolyl)butyronitrile (4b)

Obtained from p-tolualdehyde (3.60 g); reaction time 6 h.

Yield 2.67 g (44%); yellow oil; R_f= 0.53 (PE–EtOAc, 4:1).

¹Н NMR (CDCl₃, 600 MHz):  = 2.02 (dddd, J = 13.9, J = 7.6, J = 7.3,

³J = 5.9 Hz, 1 H, CH₂), 2.11 (dddd, ²J = 13.9, ³J = 8.7, ³J = 7.4, ³J = 6.2 Hz,

1 H, CH₂), 2.36 (ddd, ²J = 17.0, ³J = 7.3, ³J = 6.2 Hz, 1 H, CH₂), 2.38 (s,

3 H, CH₃), 2.47 (ddd, ²J = 17.0, ³J = 7.6, ³J = 7.4 Hz, 1 H, CH₂), 4.60 (dd,

³J = 8.7, ³J = 5.9 Hz, 1 H, CH), 7.21–7.25 (m, 4 H, Ar).

2

3

¹³С NMR (CDCl₃, 150 MHz):  = 14.2 (¹J_C–H= 136 Hz, CH₂), 31.8 (¹J_C–H

=

133 Hz, CH₂), 55.2 (¹J_C–H= 144 Hz, CH₃O), 63.9 (¹J_C–H= 142 Hz, CH),

114.4 (2 × CH), 118.7 (CN), 128.0 (2 × CH), 129.5 (C), 159.9 (C).

¹³С NMR (CDCl₃, 150 MHz):  = 14.3 (¹J_C–H= 136 Hz, CH₂), 21.1 (¹J_C–H

=

(5E)-4-Azido-6-phenylhex-5-enenitrile (4g)

126 Hz, CH₃), 31.9 (¹J_C–H= 133 Hz, CH₂), 64.1 (¹J_C–H= 142 Hz, CH),

Obtained from trans-cinnamaldehyde (3.96 g); reaction time 3 h.

Yield: 1.40 g (22%); yellow oil; R_f= 0.62 (PE–EtOAc, 3:1).

¹Н NMR (CDCl₃, 600 MHz):  = 1.90–1.97 (m, 2 H, CH₂), 2.43–2.53 (m,

118.7 (CN), 126.7 (2 × CH), 129.8 (2 × CH), 134.6 (C), 138.9 (C).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₃N₄⁺: 201.1135; found:

201.1137.

3

2 H, CH₂), 4.21–4.25 (m, 1 H, CH), 6.10 (dd, J = 15.8, J = 8.3 Hz, 1 H,

CH=), 6.73 (br d, ³J = 15.8 Hz, 1 H, CH=), 7.31–7.40 (m, 3 H, Ph), 7.43–

7.46 (m, 2 H, Ph).

4-Azido-4-(4-fluorophenyl)butyronitrile (4c)

Obtained from 4-fluorobenzaldehyde (3.72 g); reaction time 3 h.

¹³С NMR (CDCl₃, 150 MHz):  = 13.9 (CH₂), 30.3 (CH₂), 62.9 (CH), 118.7

(CN), 124.6 (CH), 126.7 (2 × CH), 128.5 (CH), 128.7 (2 × CH), 135.0

(CH), 135.2 (C).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₃N₄⁺: 213.1135; found:

213.1137.

Yield: 2.56 g (42%); yellow oil; R_f= 0.49 (PE–EtOAc, 3:1).

2

3

¹Н NMR (CDCl₃, 600 MHz):  = 2.00 (dddd, J = 14.0, J = 7.7, J = 7.2,

³J = 5.7 Hz, 1 H, CH₂), 2.08 (dddd, ²J = 14.0, ³J = 9.0, ³J = 7.3, ³J = 6.2 Hz,

1 H, CH₂), 2.38 (ddd, ²J = 17.0, ³J = 7.2, ³J = 6.2 Hz, 1 H, CH₂), 2.49 (ddd,

²J = 17.0, ³J = 7.7, ³J = 7.3 Hz, 1 H, CH₂), 4.63 (dd, ³J = 9.0, ³J = 5.7 Hz,

1 H, CH), 7.10–7.14 (m, 2 H, Ar), 7.30–7.34 (m, 2 H, Ar).

4-Azido-4-(thien-2-yl)butyronitrile (4h)

¹³С NMR (CDCl₃, 150 MHz):  = 14.2 (¹J_C–H= 136 Hz, CH₂), 32.0 (¹J_C–H

=

Obtained from 2-thiophenecarboxaldehyde (3.36 g); reaction time 4

h.

133 Hz, CH₂), 63.6 (¹J_C–H= 143 Hz, CH), 116.3 (²J_C–F= 22 Hz, 2 × CH),

118.5 (CN), 128.5 (³J_C–F= 8 Hz, 2 × CH), 133.6 (⁴J_C–F= 3 Hz, C), 162.8

(¹J_C–F= 248 Hz, C).

Yield: 2.14 g (37%); yellow oil; R_f= 0.62 (PE–EtOAc, 3:1).

2

3

¹Н NMR (CDCl₃, 600 MHz):  = 2.14 (dddd, J = 13.9, J = 7.7, J = 7.1,

³J = 6.0 Hz, 1 H, CH₂), 2.18 (dddd, ²J = 13.9, ³J = 8.6, ³J = 7.2, ³J = 6.3 Hz,

1 H, CH₂), 2.44 (ddd, ²J = 17.1, ³J = 7.1, ³J = 6.3 Hz, 1 H, CH₂), 2.53 (ddd,

²J = 17.1, ³J = 7.7, ³J = 7.2 Hz, 1 H, CH₂), 4.91 (dd, ³J = 8.6, ³J = 6.0 Hz,

1 H, CH), 7.05 (dd, ³J = 5.1, ³J = 3.5 Hz, 1 H, Th), 7.10 (ddd, ³J = 3.5, ⁴J =

1.2, ⁴J = 0.6 Hz, 1 H, Th), 7.37 (ddd, ³J = 5.1, ⁴J = 1.2, ⁵J = 0.4 Hz, 1 H, Th).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₀H₁₀FN₄⁺: 205.0884; found:

205.0887.

4-Azido-4-(4-chlorophenyl)butyronitrile (4d)

Obtained from 4-chlorobenzaldehyde (4.22 g); reaction time 3 h.

L

K. L. Ivanov et al.

Feature

Synthesis

¹³С NMR (CDCl₃, 150 MHz):  = 14.3 (CH₂), 32.3 (CH₂), 59.5 (CH), 118.4

(CN), 126.3 (CH), 126.4 (CH), 127.0 (CH), 140.3 (C).

HRMS (ESI): m/z [M + H]⁺calcd for C₈H₉N₄S⁺: 193.0542; found:

193.0543.

¹Н NMR (CDCl₃, 600 MHz):  = 2.19 (ddd, ²J = 14.2, ³J = 10.1, ³J = 4.2 Hz,

1 H, CH₂, A), 2.33 (ddd, ²J = 14.0, ³J = 9.0, ³J = 6.8 Hz, 1 H, CH₂, B), 2.38

(ddd, ²J = 14.0, ³J = 7.5, ³J = 6.3 Hz, 1 H, CH₂, B), 2.42 (ddd, ²J = 14.2, ³J =

10.9, ³J = 5.0 Hz, 1 H, CH₂, A), 3.46 (dd, ³J = 7.5, ³J = 6.8 Hz, 1 H, C²H, B),

3.72 (dd, ³J = 10.1, ³J = 5.0 Hz, 1 H, C²H, A), 4.38–4.43 (m, 2 H, CH₂N,

A), 4.41–4.47 (m, 2 H, CH₂N, B), 4.64 (dd, ³J = 9.0, ³J = 6.3 Hz, 1 H, C⁴H,

4-Azido-4-(pyridin-3-yl)butyronitrile (4i)

3

B), 4.72 (dd, J = 10.9, J = 4.2 Hz, 1 H, C⁴H, A), 7.01–7.05 (m, 1 + 1 H,

Obtained from 3-pyridinecarboxaldehyde (3.21 g); reaction time 3 h.

NH, A, B), 7.26–7.37 (m, 7 + 7 H, Ph, A, B), 7.38–7.44 (m, 3 + 3 H, Ph, A,

B).

Yield: 1.55 g (28%); yellow oil; R_f= 0.60 (EtOAc).

2

3

¹Н NMR (CDCl₃, 600 MHz):  = 2.02 (dddd, J = 14.0, J = 8.0, J = 7.0,

³J = 5.3 Hz, 1 H, CH₂), 2.09 (dddd, ²J = 14.0, ³J = 9.2, ³J = 7.2, ³J = 6.0 Hz,

1 H, CH₂), 2.41 (ddd, ²J = 17.1, ³J = 7.0, ³J = 6.0 Hz, 1 H, CH₂), 2.51 (ddd,

²J = 17.1, ³J = 8.0, ³J = 7.2 Hz, 1 H, CH₂), 4.66 (dd, ³J = 9.2, ³J = 5.3 Hz,

1 H, CH), 7.35 (dd, ³J = 7.9, ³J = 4.8 Hz, 1 H, Py), 7.64–7.66 (m, 1 H, Py),

8.59 (br d, ⁴J = 2.2 Hz, 1 H, Py), 8.62 (dd, ³J = 4.8, ⁴J = 1.6 Hz, 1 H, Py).

¹³С NMR (CDCl₃, 150 MHz):  = 35.0 (C²H), 35.6 (C²H), 35.8 (CH₂), 36.1

(CH₂), 44.07 (CH₂N), 44.10 (CH₂N), 63.1 (2 × C⁴H), 117.28 (CN), 117.30

(CN), 126.8 (4 × CH), 127.6 (4 × CH), 127.7 (2 × CH), 128.66 (2 × CH),

128.67 (2 × CH), 128.9 (CH), 128.97 (CH), 128.99 (2 × CH), 129.1

(2 × CH), 136.8 (C), 136.9 (C), 137.2 (C), 137.4 (C), 163.7 (CONH),

163.9 (CONH).

¹³С NMR (CDCl₃, 150 MHz):  = 14.2 (CH₂), 31.8 (CH₂), 61.9 (CH), 118.2

HRMS (ESI): m/z [M – H]^–calcd for C₁₈H₁₆N₅O^–: 318.1360; found:

(CN), 123.9 (CH), 133.6 (C), 134.1 (CH), 148.3 (CH), 150.4 (CH).

318.1361.

HRMS (ESI): m/z [M + H]⁺calcd for C₉H₁₀N₅⁺: 188.0931; found:

188.0929.

4-Azido-4-phenyl-2-(pyrrolidin-1-ylcarbonyl)butyronitrile (5c)

Obtained from the mixture A and pyrrolidine (1.42 g) at r.t.; reaction

time 26 h.

One-Pot Synthesis of 4-Azido-2-cyanobutyramides 5

To mixture A (starting from 10.0 mmol of benzaldehyde), the corre-

sponding amine (20.0 mmol) was added in one portion and the re-

sulting mixture was stirred under the specified conditions. The mix-

ture was then diluted with brine (100 mL) and extracted with EtOAc

(3 × 100 mL). The combined organic fractions were washed with wa-

ter (3 × 100 mL), dried with Na₂SO₄, and concentrated under reduced

pressure. The residue was purified by column chromatography on sil-

ica gel (PE–EtOAc).

Yield: 1.03 g (36%); dr A/B 53:47; yellow oil; R_f= 0.85 (PE–EtOAc, 1:1).

¹Н NMR (CDCl₃, 600 MHz):  = 1.87–1.96 (m, 2 + 2 H, CH₂, A, B), 1.97–

2.08 (m, 2 + 2 H, CH₂, A, B), 2.26 (ddd, ²J = 13.9, ³J = 9.5, ³J = 5.5 Hz, 1 H,

CH₂, B), 2.28 (ddd, ²J = 14.2, ³J = 9.7, ³J = 4.9 Hz, 1 H, CH₂, A), 2.33 (ddd,

²J = 14.2, ³J = 10.2, ³J = 5.7 Hz, 1 H, CH₂, A), 2.51 (ddd, ²J = 13.9, ³J = 9.1,

³J = 5.1 Hz, 1 H, CH₂, B), 3.39 (ddd, ²J = 9.8, ³J = 7.4, ³J = 6.0 Hz, 1 H, CH₂,

2

3

A), 3.45 (ddd, J = 9.8, J = 7.4, J = 6.0 Hz, 1 H, CH₂, B), 3.45–3.57 (m,

2 + 2 H, CH₂, A, B), 3.59 (dd, ³J = 9.1, ³J = 5.5 Hz, 1 H, C²H, B), 3.61–3.66

(m, 1 + 1 H, CH₂, A, B), 3.70 (dd, ³J = 9.7, ³J = 5.7 Hz, 1 H, C²H, A), 4.65

(dd, ³J = 9.5, ³J = 5.5 Hz, 1 H, C⁴H, B), 4.77 (dd, ³J = 10.2, ³J = 4.9 Hz, 1 H,

C⁴H, A), 7.33–7.37 (m, 2 + 2 H, Ph, A, B), 7.38–7.40 (m, 1 + 1 H, Ph, A,

B), 7.40–7.44 (m, 2 + 2 H, Ph, A, B).

4-Azido-N-butyl-2-cyano-4-phenylbutyramide (5a)

Obtained from mixture A and n-butylamine (1.46 g) at r.t.; reaction

time 22 h.

¹³С NMR (CDCl₃, 150 MHz):  = 24.10 (CH₂), 24.12 (CH₂), 25.98 (CH₂),

26.01 (CH₂), 32.4 (C²H), 33.6 (C²H), 35.8 (CH₂), 35.9 (CH₂), 46.76 (CH₂),

46.77 (CH₂), 46.82 (2 × CH₂), 63.1 (C⁴H), 63.2 (C⁴H), 116.5 (CN), 116.6

(CN), 126.79 (2 × CH), 126.81 (2 × CH), 128.95 (CH), 128.99 (CH),

129.1 (4 × CH), 137.7 (C), 137.8 (C), 161.2 (CON), 161.6 (CON).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₅H₁₈N₅O⁺: 284.1506; found:

284.1502.

Yield: 1.65 g (58%); dr A/B 55:45; brown oil; R_f= 0.25 (PE–EtOAc, 4:1).

¹Н NMR (CDCl₃, 600 MHz):  = 0.94 (t, ³J = 7.4 Hz, 3 H, CH₃, A), 0.95 (t,

³J = 7.4 Hz, 3 H, CH₃, B), 1.32–1.40 (m, 2 + 2 H, CH₂, A, B), 1.49–1.58

(m, 2 + 2 H, CH₂, A, B), 2.19 (ddd, ²J = 14.2, ³J = 10.0, ³J = 4.3 Hz, 1 H,

CH₂, A), 2.35 (ddd, ²J = 14.0, ³J = 8.9, ³J = 7.0 Hz, 1 H, CH₂, B), 2.42 (ddd,

²J = 14.0, ³J = 7.2, ³J = 6.4 Hz, 1 H, CH₂, B), 2.46 (ddd, ²J = 14.2, ³J = 10.8,

³J = 4.9 Hz, 1 H, CH₂, A), 2.26–2.34 (m, 2 + 2 H, CH₂, A, B), 3.39 (dd, ³J =

7.2, ³J = 7.0 Hz, 1 H, C²H, B), 3.65 (dd, ³J = 10.0, ³J = 4.9 Hz, 1 H, C²H, A),

4.71 (dd, ³J = 8.9, ³J = 6.4 Hz, 1 H, C⁴H, B), 4.74 (dd, ³J = 10.8, ³J = 4.3 Hz,

1 H, C⁴H, A), 6.29 (br s, 1 + 1 H, NH, A, B), 7.34–7.37 (m, 2 + 2 H, Ph, A,

B), 7.38–7.40 (m, 1 + 1 H, Ph, A, B), 7.40–7.44 (m, 2 + 2 H, Ph, A, B).

4-Azido-2-cyano-4-phenylbutyrhydrazide (5d)

Obtained from mixture A and hydrazine hydrate (1.00 mL) at r.t.; re-

action time 4 h.

¹³С NMR (CDCl₃, 150 MHz):  = 13.6 (2 × CH₃), 19.9 (2 × CH₂), 31.2

(2 × CH₂), 35.1 (C²H), 35.7 (C²H), 35.9 (CH₂), 36.3 (CH₂), 40.14 (CH₂N),

40.17 (CH₂N), 63.3 (C⁴H), 63.4 (C⁴H), 117.6 (2 × CN), 126.9 (4 × CH),

129.0 (2 × CH), 129.1 (2 × CH), 129.2 (2 × CH), 137.3 (C), 137.5 (C),

163.47 (CONH), 163.52 (CONH).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₅H₂₀N₅O⁺: 286.1662; found:

286.1659.

Yield: 1.31 g (54%); dr A/B 54:46; yellow oil; R_f= 0.27 (EtOAc).

¹Н NMR (CDCl₃, 600 MHz):  = 2.23 (ddd, ²J = 14.1, ³J = 10.1, ³J = 4.1 Hz,

1 H, CH₂, A), 2.34–2.42 (m, 1 + 2 H, CH₂, A, B), 3.48–3.50 (m, 1 H, C²H,

B), 3.73 (dd, ³J = 10.1, ³J = 5.0 Hz, 1 H, C²H, A), 4.13 (br s, 2 + 2 H, NH₂,

A, B), 4.66 (dd, ³J = 8.6, ³J = 6.5 Hz, 1 H, C⁴H, B), 4.74 (dd, ³J = 10.9, ³J =

4.1 Hz, 1 H, C⁴H, A), 7.32–7.35 (m, 2 + 2 H, Ph, A, B), 7.35–7.37 (m, 1 +

1 H, Ph, A, B), 7.39–7.41 (m, 2 + 2 H, Ph, A, B). 8.41 (br s, 1 + 1 H, NH, A,

B).

4-Azido-N-benzyl-2-cyano-4-phenylbutyramide (5b)

¹³С NMR (CDCl₃, 150 MHz):  = 33.5 (C²H), 34.1 (C²H), 35.7 (CH₂), 36.1

(CH₂), 63.05 (C⁴H), 63.07 (C⁴H), 116.9 (CN), 117.0 (CN), 126.8 (4 × CH),

129.01 (2 × CH), 129.06 (2 × CH), 129.13 (2 × CH), 137.1 (C), 137.3 (C),

164.8 (CONH), 165.0 (CONH).

Obtained from mixture A and benzylamine (2.14 g) at 45 °C; reaction

time 4 days.

Yield: 1.98 g (31%); dr A/B 55:45; brown oil; R_f= 0.30 (PE–EtOAc, 4:1).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₃N₆O⁺: 245.1145; found:

245.1146.

M

K. L. Ivanov et al.

Feature

Synthesis

BF₃-Mediated (3+2)-Cycloaddition within Azides 3 and 4

¹³С NMR (CDCl₃, 150 MHz):  = 21.1 (CH₃), 37.1 (CH), 42.9 (CH₂), 53.4

(CH₃O), 60.2 (CH), 126.1 (2 × CH), 129.9 (2 × CH), 133.1 (C), 139.33

(C), 159.89 (C), 168.6 (CO₂Me).

To a solution of azide 3 or 4 (1.0 mmol) in nitromethane (5 mL)

BF₃·OEt₂(0.25 mL, 2.0 mmol) was added in one portion. The resulting

solution was stirred for 10–11 h at 70 °C, then cooled, diluted with

brine, and extracted with EtOAc. The combined organic fractions

were washed once with water, dried with Na₂SO₄, and concentrated

under reduced pressure. The residue was purified by column chroma-

tography on silica gel (PE–EtOAc).

Isomer B

¹Н NMR (CDCl₃, 600 MHz):  = 2.35 (s, 3 H, CH₃), 3.23 (ddd, ²J = 14.0,

3

2

3

³J = 6.9, J = 6.7 Hz, 1 H, CH₂), 3.66 (ddd, J = 14.0, J = 9.4, J = 8.3 Hz,

1 H, CH₂), 3.82 (s, 3 H, CH₃O), 4.30 (dd, ³J = 9.4, ³J = 6.9 Hz, 1 H, CH),

5.58 (dd, ³J = 8.3, ³J = 6.7 Hz, 1 H, CH), 7.11–7.13 (m, 2 H, Ar), 7.18–

7.21 (m, 2 H, Ar).

SnCl₄-Mediated (3+2)-Cycloaddition within Azides 3 and 4

¹³С NMR (CDCl₃, 150 MHz):  = 21.1 (CH₃), 37.0 (CH), 42.0 (CH₂), 53.3

(CH₃O), 59.9 (CH), 126.4 (2 × CH), 129.8 (2 × CH), 133.3 (C), 139.25

(C), 159.85 (C), 168.6 (CO₂Me).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₃N₄O₂⁺: 245.1033; found:

245.1033.

To a solution of azide 3 or 4 (1.0 mmol) in CH₂Cl₂(10 mL), SnCl₄(1.2

mL of 1 mM solution in CH₂Cl₂, 1.2 mmol) was added slowly by using

a syringe. The resulting solution was stirred for 6–24 h (3) or 5 d (4b)

at r.t., then poured into aq NaHCO₃and extracted with EtOAc. The

combined organic fractions were washed once with brine, dried with

Na₂SO₄, and concentrated under reduced pressure. The residue was

purified by column chromatography on silica gel (PE–EtOAc).

Methyl 5-(4-Fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-d]tetra-

zole-7-carboxylate (6c)

Obtained from azide 3d (262 mg).

Methyl 5-Phenyl-6,7-dihydro-5H-pyrrolo[1,2-d]tetrazole-7-car-

boxylate (6a)

Yield: 135 mg (52%) (BF₃·OEt₂); 240 mg (92%) (SnCl₄); beige crystals,

mp 151–152 °C; dr A/B = 54:46; R_f= 0.26 (PE–EtOAc, 1:1).

Obtained from azide 3a (244 mg).

Isomer A

Yield: 110 mg (45%) (BF₃·OEt₂); 215 mg (88%) (SnCl₄); 210 mg (86%)

¹Н NMR (CDCl₃, 600 MHz):  = 3.12 (ddd, ²J = 13.9, ³J = 9.1, ³J = 6.9 Hz,

1 H, CH₂), 3.66 (ddd, ²J = 13.9, ³J = 7.7, ³J = 3.8 Hz, 1 H, CH₂), 3.81 (s,

3 H, CH₃O), 4.35 (ddd, ³J = 9.1, ³J = 3.8, ⁴J = 0.5 Hz, 1 H, CH), 5.76–5.79

(m, 1 H, CH), 7.07–7.11 (m, 2 H, Ar), 7.16–7.19 (m, 2 H, Ar).

(TiCl₄); yellow oil; dr A/B = 55:45; R_f= 0.34 (PE–EtOAc, 1:1).

Isomer A

¹Н NMR (CDCl₃, 600 MHz):  = 3.14 (ddd, ²J = 13.8, ³J = 9.1, ³J = 6.6 Hz,

1 H, C⁶H₂), 3.69 (ddd, ²J = 13.8, ³J = 7.8, ³J = 4.1 Hz, 1 H, C⁶H₂), 3.841 (s,

3 H, CH₃O), 4.37 (ddd, ³J = 9.1, ³J = 4.1, ⁴J = 0.6 Hz, 1 H, C⁷H), 5.80 (ddd,

³J = 7.8, ³J = 6.6, ⁴J = 0.6 Hz, 1 H, C⁵H), 7.15–7.18 (m, 2 H, Ph), 7.39–7.44

(m, 3 H, Ph).

Isomer B

¹Н NMR (CDCl₃, 600 MHz):  = 3.22 (ddd, ²J = 14.0, ³J = 6.7, ³J = 6.7 Hz,

1 H, CH₂), 3.70 (ddd, ²J = 14.0, ³J = 9.4, ³J = 8.4 Hz, 1 H, CH₂), 3.82 (s,

3 H, CH₃O), 4.32 (dd, ³J = 9.4, ³J = 6.7 Hz, 1 H, CH), 5.64 (dd, ³J = 8.4, ³J =

6.7 Hz, 1 H, CH), 7.07–7.11 (m, 2 H, Ar), 7.23–7.26 (m, 2 H, Ar).

¹³С NMR (CDCl₃, 150 MHz):  = 37.0 (¹J_C–H= 142 Hz, C⁷H), 42.8 (¹J_C–H

=

139 Hz, C⁶H₂), 53.3 (¹J_C–H= 148 Hz, CH₃O), 60.2 (¹J_C–H= 149 Hz, C⁵H),

126.1 (2 × CH), 129.17 (CH), 129.22 (2 × CH), 136.2 (C), 160.0 (C),

168.5 (CO₂Me).

Isomers A+B

¹³С NMR (CDCl₃, 150 MHz):  = 36.97 (CH), 37.03 (CH), 42.0 (CH₂),

42.9 (CH₂), 53.43 (CH₃O), 53.44 (CH₃O), 59.3 (CH), 59.7 (CH), 116.3

(²J_C–F= 22 Hz, 2 × CH), 116.4 (²J_C–F= 22 Hz, 2 × CH), 128.3 (³J_C–F= 9 Hz,

Isomer B

¹Н NMR (CDCl₃, 600 MHz):  = 3.29 (ddd, ²J = 14.0, ³J = 6.8, ³J = 6.7 Hz,

1 H, C⁶H₂), 3.70 (ddd, ²J = 14.0, ³J = 9.4, ³J = 8.3 Hz, 1 H, C⁶H₂), 3.839 (s,

3 H, CH₃O), 4.32 (dd, ³J = 9.4, ³J = 6.8 Hz, 1 H, C⁷H), 5.63 (dd, ³J = 8.3,

³J = 6.7 Hz, 1 H, C⁵H), 7.24–7.26 (m, 2 H, Ph), 7.39–7.44 (m, 3 H, Ph).

2 × CH), 128.6 (³J_C–F= 9 Hz, 2 × CH), 131.9 (⁴J_C–F= 3 Hz, C), 132.2 (⁴J_C–F

=

3 Hz, C), 160.0 (2 × C), 163.9 (¹J_C–F= 249 Hz, 2 × C), 168.5 (CO₂Me),

168.6 (CO₂Me).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₂FN₄O₂⁺: 263.0939; found:

263.0934.

¹³С NMR (CDCl₃, 150 MHz):  = 37.0 (¹J_C–H= 142 Hz, C⁷H), 42.0 (¹J_C–H

=

139 Hz, C⁶H₂), 53.2 (¹J_C–H= 148 Hz, CH₃O), 59.9 (¹J_C–H= 148 Hz, C⁵H),

126.4 (2 × CH), 129.1 (3 × CH), 136.4 (C), 160.0 (C), 168.6 (CO₂Me).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₃N₄O₂⁺: 245.1033; found:

245.1033.

Methyl 5-(4-Chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-d]tetra-

zole-7-carboxylate (6d)

Obtained from azide 3e (279 mg).

Methyl 5-(p-Tolyl)-6,7-dihydro-5H-pyrrolo[1,2-d]tetrazole-7-car-

boxylate (6b)

Yield: 250 mg (90%) (SnCl₄); white crystals, mp 140–141 °C; dr A/B =

54:46; R_f= 0.37 (PE–EtOAc, 1:1).

Obtained from azide 3c (258 mg).

Isomer A

¹Н NMR (CDCl₃, 600 MHz):  = 3.10 (ddd, ²J = 13.8, ³J = 9.1, ³J = 6.8 Hz,

Yield: 122 mg (47%) (BF₃·OEt₂); 217 mg (84%) (SnCl₄); yellow oil; dr

A/B = 52:48; R_f= 0.77 (EtOAc).

1 H, CH₂), 3.66 (ddd, ²J = 13.8, ³J = 7.8, ³J = 3.8 Hz, 1 H, CH₂), 3.79 (s,

3

3 H, CH₃O), 4.34 (dd, J = 9.1, J = 3.8 Hz, 1 H, CH), 5.74–5.77 (m, 1 H,

Isomer A

CH), 7.11–7.14 (m, 2 H, Ar), 7.34–7.38 (m, 2 H, Ar).

¹Н NMR (CDCl₃, 600 MHz):  = 2.35 (s, 3 H, CH₃), 3.12 (ddd, ²J = 13.8,

³J = 9.1, J = 6.7 Hz, 1 H, CH₂), 3.63 (ddd, J = 13.8, J = 7.8, J = 4.0 Hz,

1 H, CH₂), 3.81 (s, 3 H, CH₃O), 4.34 (ddd, ³J = 9.1, ³J = 4.0, ⁴J = 0.5 Hz,

1 H, CH), 5.72–5.75 (m, 1 H, CH), 7.03–7.06 (m, 2 H, Ar), 7.18–7.21 (m,

2 H, Ar).

3

2

3

Isomer B

¹Н NMR (CDCl₃, 600 MHz):  = 3.19 (ddd, ²J = 14.0, ³J = 6.7, ³J = 6.7 Hz,

1 H, CH₂), 3.71 (ddd, ²J = 14.0, ³J = 9.5, ³J = 8.3 Hz, 1 H, CH₂), 3.80 (s,

3 H, CH₃O), 4.32 (dd, ³J = 9.5, ³J = 6.7 Hz, 1 H, CH), 5.63 (dd, ³J = 8.3, ³J =

6.7 Hz, 1 H, CH), 7.17–7.20 (m, 2 H, Ar), 7.34–7.38 (m, 2 H, Ar).

Isomers A+B

N

K. L. Ivanov et al.

Feature

Synthesis

¹³С NMR (CDCl₃, 150 MHz):  = 36.9 (CH), 37.0 (CH), 41.9 (CH₂), 42.8

(CH₂), 53.39 (CH₃O), 53.41 (CH₃O), 59.3 (CH), 59.6 (CH), 127.7

(2 × CH), 127.9 (2 × CH), 129.4 (2 × CH), 129.5 (2 × CH), 134.6 (C),

134.9 (C), 135.2 (C), 135.3 (C), 160.0 (2 × C), 168.4 (CO₂Me), 168.5

(CO₂Me).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₂BrN₄O₂⁺: 323.0138; found:

323.0137.

Methyl 5-(4-Methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-d]tetra-

zole-7-carboxylate (6g)

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₂ClN₄O₂⁺: 279.0643; found:

Obtained from azide 3h.

279.0641.

BF₃·OEt₂-Mediated synthesis: 3h (274 mg, 1.0 mmol); yield 30 mg

(14%).

Methyl 5-(2-Chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-d]tetra-

SnCl₄-Mediated synthesis: 3h (97 mg, 0.35 mmol); yield 35 mg (36%).

Yellow oil; dr A/B = 54:46; R_f= 0.31 (PE–EtOAc, 1:1).

Isomer A

zole-7-carboxylate (6e)

Obtained from azide 3f (279 mg).

Yield: 258 mg (92%) (SnCl₄); colorless oil; dr A/B = 51:49; R_f= 0.38

(PE–EtOAc, 1:1).

¹Н NMR (CDCl₃, 600 MHz):  = 3.13 (ddd, ²J = 13.8, ³J = 9.0, ³J = 6.8 Hz,

2

3

1 H, CH₂), 3.64 (ddd, J = 13.8, J = 7.7, J = 3.8 Hz, 1 H, CH₂), 3.827 (s,

3 H, CH₃O), 3.85 (s, 3 H, CH₃O), 4.36 (ddd, ³J = 9.0, ³J = 3.8, ⁴J = 0.5 Hz,

1 H, CH), 5.74–5.77 (m, 1 H, CH), 6.92–6.96 (m, 2 H, Ar), 7.10–7.13 (m,

2 H, Ar).

Isomer A

¹Н NMR (CDCl₃, 600 MHz):  = 3.06 (ddd, ²J = 13.9, ³J = 9.3, ³J = 6.0 Hz,

1 H, CH₂), 3.75 (ddd, ²J = 13.9, ³J = 8.3, ³J = 4.7 Hz, 1 H, CH₂), 3.76 (s,

3

4

3 H, CH₃O), 4.30 (ddd, J = 9.3, J = 4.7, J = 0.5 Hz, 1 H, CH), 6.09 (dd,

³J = 8.3, ³J = 6.0 Hz, 1 H, CH), 6.73 (br d, ³J = 7.8 Hz, 1 H, Ar), 7.19–7.23

(m, 1 H, Ar), 7.25–7.30 (m, 1 H, Ar), 7.38–7.41 (m, 1 H, Ar).

Isomer B

¹Н NMR (CDCl₃, 600 MHz):  = 3.29 (ddd, ²J = 14.0, ³J = 6.9, ³J = 6.7 Hz,

2

3

1 H, CH₂), 3.65 (ddd, J = 14.0, J = 9.4, J = 8.3 Hz, 1 H, CH₂), 3.829 (s,

3 H, CH₃O), 3.86 (s, 3 H, CH₃O), 4.30 (dd, ³J = 9.4, ³J = 6.9 Hz, 1 H, CH),

5.58 (dd, ³J = 8.3, ³J = 6.7 Hz, 1 H, CH), 6.92–6.96 (m, 2 H, Ar), 7.20–

7.23 (m, 2 H, Ar).

Isomer B

¹Н NMR (CDCl₃, 600 MHz):  = 3.07 (ddd, ²J = 14.0, ³J = 6.0, ³J = 6.0 Hz,

1 H, CH₂), 3.83 (ddd, ²J = 14.0, ³J = 9.6, ³J = 8.6 Hz, 1 H, CH₂), 3.70 (s,

3 H, CH₃O), 4.33 (dd, ³J = 9.6, ³J = 6.0 Hz, 1 H, CH), 6.02 (dd, ³J = 8.6, ³J =

6.0 Hz, 1 H, CH), 6.79 (br d, ³J = 7.8 Hz, 1 H, Ar), 7.19–7.23 (m, 1 H, Ar),

7.25–7.30 (m, 1 H, Ar), 7.38–7.41 (m, 1 H, Ar).

Isomers A+B

¹³С NMR (CDCl₃, 150 MHz):  = 37.1 (CH), 37.2 (CH), 42.0 (CH₂), 43.0

(CH₂), 53.5 (2 × CH₃O), 55.39 (CH₃O), 55.40 (CH₃O), 59.8 (CH), 60.1

(CH), 114.7 (2 × CH), 114.8 (2 × CH), 127.7 (2 × CH), 128.0 (C), 128.08

(2 × CH), 128.13 (C), 159.7 (C), 159.8 (C), 160.4 (2 × C), 168.70

(CO₂Me), 168.73 (CO₂Me).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₃H₁₅N₄O₃⁺: 275.1139; found:

275.1134.

Isomers A+B

¹³С NMR (CDCl₃, 150 MHz):  = 36.65 (CH), 36.70 (CH), 41.0 (CH₂),

41.3 (CH₂), 53.2 (CH₃O), 53.3 (CH₃O), 57.1 (CH), 57.7 (CH), 126.5 (CH),

126.6 (CH), 127.5 (CH), 127.6 (CH), 129.9 (CH), 130.1 (CH), 130.2

(2 × CH), 132.0 (C), 132.2 (C), 134.1 (C), 134.5 (C), 160.58 (C), 160.64

(C), 168.3 (2 × CO₂Me).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₂ClN₄O₂⁺: 279.0643; found:

279.0641.

Methyl 5-(3-Methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-d]tetra-

zole-7-carboxylate (6h)

Obtained from azide 3i (279 mg).

Methyl 5-(4-Bromophenyl)-6,7-dihydro-5H-pyrrolo[1,2-d]tetra-

Yield: 250 mg (90%) (SnCl₄); colorless oil; dr A/B = 54:46; R_f(A) = 0.26,

R_f(B) = 0.18 (PE–EtOAc, 1:1).

zole-7-carboxylate (6f)

Obtained from azide 3g (323 mg).

Isomer A

Yield: 305 mg (94%) (SnCl₄); yellow oil; dr A/B = 53:47; R_f= 0.30 (PE–

¹Н NMR (CDCl₃, 600 MHz):  = 3.12 (ddd, ²J = 13.8, ³J = 9.1, ³J = 6.6 Hz,

1 H, CH₂), 3.63 (ddd, ²J = 13.8, ³J = 7.9, ³J = 4.2 Hz, 1 H, CH₂), 3.74 (s,

3 H, CH₃O), 3.78 (s, 3 H, CH₃O), 4.33 (ddd, ³J = 9.1, ³J = 4.2, ⁴J = 0.5 Hz,

1 H, CH), 5.72 (dd, ³J = 7.9, ³J = 6.6 Hz, 1 H, CH), 6.66–6.70 (m, 2 H, Ar),

6.86–6.90 (m, 1 H, Ar), 7.26–7.29 (m, 1 H, Ar).

¹³С NMR (CDCl₃, 150 MHz):  = 37.0 (CH), 42.7 (CH₂), 53.3 (CH₃O),

55.2 (CH₃O), 60.1 (CH), 112.0 (CH), 114.4 (CH), 118.1 (CH), 130.4 (CH),

137.7 (C), 160.0 (C), 160.1 (C), 168.5 (CO₂Me).

EtOAc, 1:1).

Isomer A

¹Н NMR (CDCl₃, 600 MHz):  = 3.07 (ddd, ²J = 13.8, ³J = 9.2, ³J = 6.9 Hz,

1 H, CH₂), 3.60 (ddd, ²J = 13.8, ³J = 7.8, ³J = 3.8 Hz, 1 H, CH₂), 3.72 (s,

3

3 H, CH₃O), 4.31 (dd, J = 9.2, J = 3.8 Hz, 1 H, CH), 5.69–5.73 (m, 1 H,

CH), 7.02–7.05 (m, 2 H, Ar), 7.43–7.47 (m, 2 H, Ar).

Isomer B

¹Н NMR (CDCl₃, 600 MHz):  = 3.10 (ddd, ²J = 14.0, ³J = 6.6, ³J = 6.5 Hz,

1 H, CH₂), 3.69 (ddd, ²J = 14.0, ³J = 9.5, ³J = 8.4 Hz, 1 H, CH₂), 3.73 (s,

3 H, CH₃O), 4.29 (dd, ³J = 9.5, ³J = 6.6 Hz, 1 H, CH), 5.60 (dd, ³J = 8.4, ³J =

6.5 Hz, 1 H, CH), 7.06–7.09 (m, 2 H, Ar), 7.43–7.47 (m, 2 H, Ar).

Isomer B

¹Н NMR (CDCl₃, 600 MHz):  = 3.18 (ddd, ²J = 14.0, ³J = 6.7, ³J = 6.5 Hz,

1 H, CH₂), 3.68 (ddd, ²J = 14.0, ³J = 9.5, ³J = 8.4 Hz, 1 H, CH₂), 3.73 (s,

3 H, CH₃O), 3.77 (s, 3 H, CH₃O), 4.29 (dd, ³J = 9.5, ³J = 6.7 Hz, 1 H, CH),

5.58 (dd, ³J = 8.4, ³J = 6.5 Hz, 1 H, CH), 6.73–6.78 (m, 2 H, Ar), 6.85–

6.88 (m, 1 H, Ar), 7.24–7.28 (m, 1 H, Ar).

¹³С NMR (CDCl₃, 150 MHz):  = 36.9 (CH), 41.9 (CH₂), 53.2 (CH₃O),

55.1 (CH₃O), 59.8 (CH), 112.1 (CH), 114.5 (CH), 118.5 (CH), 130.2 (CH),

137.9 (C), 160.0 (2 × C), 168.6 (CO₂Me).

Isomers A+B

¹³С NMR (CDCl₃, 150 MHz):  = 36.79 (CH), 36.83 (CH), 41.7 (CH₂),

42.5 (CH₂), 53.17 (CH₃O), 53.19 (CH₃O), 59.1 (CH), 59.5 (CH), 123.0

(C), 123.1 (C), 127.9 (2 × CH), 128.1 (2 × CH), 132.1 (2 × CH), 132.2

(2 × CH), 135.0 (C), 135.4 (C), 159.9 (C), 160.0 (C), 168.2 (CO₂Me),

168.4 (CO₂Me).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₂ClN₄O₂⁺: 275.1139; found:

275.1137.

O

K. L. Ivanov et al.

Feature

Synthesis

Methyl 5-(4-Cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-d]tetra-

zole-7-carboxylate (6i)

¹Н NMR (CDCl₃, 600 MHz):  = 3.12 (ddd, ²J = 13.7, ³J = 9.1, ³J = 5.4 Hz,

1 H, CH₂), 3.88 (ddd, ²J = 13.7, ³J = 8.3, ³J = 5.5 Hz, 1 H, CH₂), 3.80 (s,

3 H, CH₃O), 4.30 (dd, ³J = 9.0, ³J = 5.5 Hz, 1 H, CH), 6.51 (dd, ³J = 8.2, ³J =

5.4 Hz, 1 H, CH), 6.73–6.76 (m, 1 H, Ar), 7.32–7.37 (m, 1 H, Ar), 7.49–

7.58 (m, 2 H, Ar), 7.79–7.85 (m, 2 H, Ar). 7.87–7.90 (m, 1 H, Ar).

Obtained from azide 3n (269 mg).

Yield: 231 mg (86%) (SnCl₄); yellow oil; dr A/B = 49:51; R_f= 0.13 (PE–

EtOAc, 1:1).

Isomer B

Isomer A

¹Н NMR (CDCl₃, 600 MHz):  = 3.19 (ddd, ²J = 13.8, ³J = 5.7, ³J = 5.6 Hz,

1 H, CH₂), 3.93 (ddd, ²J = 14.0, ³J = 9.7, ³J = 8.5 Hz, 1 H, CH₂), 3.67 (s,

3 H, CH₃O), 4.37 (dd, ³J = 9.7, ³J = 5.6 Hz, 1 H, CH), 6.39 (dd, ³J = 8.5, ³J =

5.7 Hz, 1 H, CH), 6.90–6.93 (m, 1 H, Ar), 7.32–7.37 (m, 1 H, Ar), 7.49–

7.58 (m, 2 H, Ar), 7.79–7.85 (m, 2 H, Ar). 7.87–7.90 (m, 1 H, Ar).

¹Н NMR (CDCl₃, 600 MHz):  = 3.11 (ddd, ²J = 13.9, ³J = 9.1, ³J = 6.9 Hz,

1 H, CH₂), 3.70 (ddd, ²J = 13.9, ³J = 7.9, ³J = 3.8 Hz, 1 H, CH₂), 3.76 (s,

3

3 H, CH₃O), 4.35 (dd, J = 9.1, J = 3.8 Hz, 1 H, CH), 5.83–5.87 (m, 1 H,

CH), 7.32–7.34 (m, 2 H, Ar), 7.65–7.68 (m, 2 H, Ar).

¹³С NMR (CDCl₃, 150 MHz):  = 36.87 (CH), 42.5 (CH₂), 53.34 (CH₃O),

59.5 (CH), 113.1 (C), 117.7 (C), 127.1 (2 × CH), 133.0 (2 × CH), 141.1

(C), 160.3 (C), 168.1 (CO₂Me).

Isomers A+B

¹³С NMR (CDCl₃, 150 MHz):  = 36.7 (CH), 36.9 (CH), 41.9 (CH₂), 42.2

(CH₂), 53.1 (CH₃O), 53.3 (CH₃O), 57.3 (CH), 57.5 (CH), 121.76 (CH),

121.81 (CH), 122.1 (CH), 122.7 (CH), 125.1 (2 × CH), 126.1 (CH), 126.3

(CH), 127.0 (CH), 127.1 (CH), 129.07 (CH), 129.12 (CH), 129.3 (CH),

129.4 (CH), 129.54 (C), 129.57 (C), 132.3 (C), 132.6 (C), 133.67 (C),

133.74 (C), 160.54 (C), 160.61 (C), 168.37 (CO₂Me), 168.40 (CO₂Me).

Isomer B

¹Н NMR (CDCl₃, 600 MHz):  = 3.16 (ddd, ²J = 14.0, ³J = 6.5, ³J = 6.4 Hz,

1 H, CH₂), 3.75 (s, 3 H, CH₃O), 3.78 (ddd, ²J = 14.0, ³J = 9.4, ³J = 8.5 Hz,

1 H, CH₂), 4.34 (dd, ³J = 9.4, ³J = 6.5 Hz, 1 H, CH), 5.75 (dd, ³J = 8.5, ³J =

6.4 Hz, 1 H, CH), 7.35–7.37 (m, 2 H, Ar), 7.65–7.68 (m, 2 H, Ar).

¹³С NMR (CDCl₃, 150 MHz):  = 36.85 (CH), 41.7 (CH₂), 53.32 (CH₃O),

59.1 (CH), 113.0 (C), 117.8 (C), 127.2 (2 × CH), 132.9 (2 × CH), 141.5

(C), 160.4 (C), 168.3 (CO₂Me).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₆H₁₅N₄O₂⁺: 295.1190; found:

295.1187.

Methyl 5-(Thiophen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-d]tetra-

zole-7-carboxylate (6l)

HRMS (ESI): m/z [M – H]⁺calcd for C₁₃H₁₀N₅O₂^–: 268.0840; found:

268.0838.

Obtained from azide 3t (250 mg).

Yield: 45 mg (18%) (SnCl₄); colorless oil; dr A/B = 54:46; R_f= 0.25 (PE–

EtOAc, 1:1).

Methyl 5-(4-Nitrophenyl)-6,7-dihydro-5H-pyrrolo[1,2-d]tetra-

zole-7-carboxylate (6j)

Isomer A

Obtained from azide 3o (289 mg).

¹Н NMR (CDCl₃, 600 MHz):  = 3.30 (ddd, ²J = 13.9, ³J = 8.9, ³J = 6.4 Hz,

1 H, CH₂), 3.72 (ddd, ²J = 13.9, ³J = 7.7, ³J = 4.3 Hz, 1 H, CH₂), 3.84 (s,

3 H, CH₃O), 4.40 (ddd, ³J = 8.9, ³J = 4.3, ⁴J = 0.5 Hz, 1 H, CH), 6.06–6.09

(m, 1 H, CH), 7.03–7.05 (m, 1 H, Th), 7.16–7.17 (m, 1 H, Th), 7.38–7.40

(m, 1 H, Th).

Yield: 247 mg (85%) (SnCl₄); yellow oil; dr A/B = 47:53; R_f= 0.17 (PE–

EtOAc, 1:1).

Isomer A

¹Н NMR (CDCl₃, 600 MHz):  = 3.15 (ddd, ²J = 13.9, ³J = 9.1, ³J = 7.0 Hz,

1 H, CH₂), 3.77 (ddd, ²J = 13.9, ³J = 7.9, ³J = 3.7 Hz, 1 H, CH₂), 3.81 (s,

3 H, CH₃O), 4.39 (ddd, ³J = 9.1, ³J = 3.7, ⁴J = 0.5 Hz, 1 H, CH), 5.91–5.94

(m, 1 H, CH), 7.41–7.43 (m, 2 H, Ar), 8.22–8.26 (m, 2 H, Ar).

¹³С NMR (CDCl₃, 150 MHz):  = 37.0 (CH), 42.7 (CH₂), 53.5 (CH₃O),

59.4 (CH), 124.5 (2 × CH), 127.4 (2 × CH), 143.0 (C), 148.3 (C), 160.37

(C), 168.2 (CO₂Me).

Isomer B

¹Н NMR (CDCl₃, 600 MHz):  = 3.46 (ddd, ²J = 14.0, ³J = 6.4, ³J = 6.4 Hz,

1 H, CH₂), 3.74 (ddd, ²J = 14.0, ³J = 9.4, ³J = 8.3 Hz, 1 H, CH₂), 3.85 (s,

3 H, CH₃O), 4.32 (dd, ³J = 9.4, ³J = 6.4 Hz, 1 H, CH), 5.91 (dd, ³J = 8.3, ³J =

6.4 Hz, 1 H, CH), 7.03–7.05 (m, 1 H, Th), 7.20–7.21 (m, 1 H, Th), 7.38–

7.40 (m, 1 H, Th).

Isomer B

Isomers A+B

¹Н NMR (CDCl₃, 600 MHz):  = 3.23 (ddd, ²J = 14.0, ³J = 6.3, ³J = 6.2 Hz,

1 H, CH₂), 3.80 (s, 3 H, CH₃O), 3.83 (ddd, ²J = 14.0, ³J = 9.5, ³J = 8.7 Hz,

1 H, CH₂), 4.38 (dd, ³J = 9.5, ³J = 6.3 Hz, 1 H, CH), 5.83 (dd, ³J = 8.6, ³J =

6.2 Hz, 1 H, CH), 7.44–7.46 (m, 2 H, Ar), 8.22–8.26 (m, 2 H, Ar).

¹³С NMR (CDCl₃, 150 MHz):  = 37.0 (CH), 37.1 (CH), 41.9 (CH₂), 42.9

(CH₂), 53.50 (CH₃O), 53.53 (CH₃O), 55.5 (CH), 56.0 (CH), 127.0 (CH),

127.2 (CH), 127.4 (CH), 127.48 (CH), 127.51 (CH), 127.6 (CH), 138.0

(C), 138.1 (C), 159.0 (C), 159.1 (C), 168.2 (CO₂Me), 168.4 (CO₂Me).

¹³С NMR (CDCl₃, 150 MHz):  = 36.9 (CH), 41.8 (CH₂), 53.5 (CH₃O),

58.9 (CH), 124.4 (2 × CH), 127.6 (2 × CH), 143.3 (C), 148.2 (C), 160.44

(C), 168.3 (CO₂Me).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₀H₁₁N₄O₂S⁺: 251.0597; found:

251.0596.

HRMS (ESI): m/z [M – H]⁺calcd for C₁₂H₁₀N₅O₄^–: 288.0738; found:

N-Butyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-d]tetrazole-7-car-

288.0739.

boxamide (6m)

Obtained from azide 5a (285 mg).

Methyl 5-(Naphthalen-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-d]tetra-

zole-7-carboxylate (6k)

Yield: 257 mg (90%) (SnCl₄); yellow oil; dr A/B = 56:44. Diastereomers

were separated.

Obtained from azide 3p (294 mg).

trans-6m

Yield: 262 mg (89%) (SnCl₄); yellow oil; dr A/B = 53:47; R_f= 0.28 (PE–

EtOAc, 1:1).

R_f= 0.39 (PE–EtOAc, 1:1).

¹Н NMR (CDCl₃, 600 MHz):  = 0.90 (t, ³J = 7.4 Hz, 3 H, CH₃), 1.30–1.37

(m, 2 H, CH₂), 1.47–1.53 (m, 2 H, CH₂), 3.08 (ddd, ²J = 13.7, ³J = 9.1, ³J =

6.0 Hz, 1 H, C⁶H₂), 3.19–3.25 (m, 1 H, CH₂), 3.30–3.36 (m, 1 H, CH₂),

Isomer A

P

K. L. Ivanov et al.

Feature

Synthesis

3.82 (ddd, ²J = 13.7, ³J = 8.1, ³J = 4.5 Hz, 1 H, C⁶H₂), 4.28 (dd, ³J = 9.1, ³J =

4.5 Hz, 1 H, C⁷H), 5.81 (dd, ³J = 8.1, ³J = 6.0 Hz, 1 H, C⁵H), 7.12 (br s,

1 H, NH), 7.14–7.17 (m, 2 H, Ar), 7.34–7.40 (m, 3 H, Ar).

¹Н NMR (CDCl₃, 600 MHz):  = 2.32 (s, 3 H, CH₃), 2.83 (dddd, ²J = 13.5,

³J = 9.3, ³J = 6.2, ³J = 6.0 Hz, 1 H, CH₂), 3.06 (ddd, ²J = 16.8, ³J = 9.2, ³J =

6.2 Hz, 1 H, CH₂), 3.15 (ddd, ²J = 16.8, ³J = 9.3, ³J = 5.2 Hz, 1 H, CH₂),

2

3

3.37 (dddd, J = 13.5, J = 9.2, J = 8.2, J = 5.2 Hz, 1 H, CH₂), 5.58 (dd,

¹³С NMR (CDCl₃, 150 MHz):  = 13.6 (¹J_C–H= 126 Hz, CH₃), 19.9 (¹J_C–H

=

³J = 8.2, ³J = 6.0 Hz, 1 H, CH), 6.99–7.03 (m, 2 H, Ar), 7.14–7.18 (m, 2 H,

125 Hz, CH₂), 31.2 (¹J_C–H= 126 Hz, CH₂), 37.7 (¹J_C–H= 139 Hz, C⁷H), 40.0

(¹J_C–H= 138 Hz, CH₂), 42.4 (¹J_C–H= 139 Hz, C⁶H₂), 60.8 (¹J_C–H= 151 Hz,

C⁵H), 126.1 (2 × CH), 129.1 (CH), 129.3 (2 × CH), 136.6 (C), 161.3 (C⁸),

166.2 (CO).

Ar).

¹³С NMR (CDCl₃, 150 MHz):  = 18.5 (CH₂), 21.0 (CH₃), 38.3 (CH₂), 60.5

(CH), 125.9 (2 × CH), 129.7 (2 × CH), 134.2 (C), 138.8 (C), 162.4 (C).

cis-6m

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₃N₄⁺: 201.1135; found:

201.1136.

R_f= 0.23 (PE–EtOAc, 1:1).

¹Н NMR (CDCl₃, 600 MHz):  = 0.90 (t, ³J = 7.4 Hz, 3 H, CH₃), 1.31–1.38

(m, 2 H, CH₂), 1.50–1.55 (m, 2 H, CH₂), 3.24–3.30 (m, 1 H, CH₂), 3.32–

3.38 (m, 1 H, CH₂), 3.38 (ddd, ²J = 14.0, ³J = 7.1, ³J = 7.0 Hz, 1 H, C⁶H₂),

3.57 (ddd, ²J = 14.0, ³J = 9.3, ³J = 8.4 Hz, 1 H, C⁶H₂), 4.20 (dd, ³J = 9.3, ³J =

7.1 Hz, 1 H, C⁷H), 5.55–5.58 (m, 1 H, C⁵H), 7.20 (br s, 1 H, NH), 7.25–

7.28 (m, 2 H, Ar), 7.35–7.40 (m, 3 H, Ar).

5-(4-Fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-d]tetrazole (7c)

Obtained from azide 4c (204 mg).

Yield: 61 mg (30%) (BF₃·OEt₂); beige crystals, mp 123–124 °C; R_f= 0.67

(EtOAc).

2

3

¹Н NMR (CDCl₃, 600 MHz):  = 2.86 (dddd, J = 13.5, J = 9.3, J = 6.4,

³J = 6.1 Hz, 1 H, CH₂), 3.12 (ddd, ²J = 16.8, ³J = 9.3, ³J = 6.4 Hz, 1 H, CH₂),

3.20 (ddd, ²J = 16.9, ³J = 9.3, ³J = 5.0 Hz, 1 H, CH₂), 3.42 (dddd, ²J = 13.5,

³J = 9.3, ³J = 8.2, ³J = 5.0 Hz, 1 H, CH₂), 5.64 (dd, ³J = 8.2, ³J = 6.1 Hz, 1 H,

CH), 7.06–7.10 (m, 2 H, Ar), 7.13–7.16 (m, 2 H, Ar).

¹³С NMR (CDCl₃, 150 MHz):  = 13.6 (¹J_C–H= 126 Hz, CH₃), 19.9 (¹J_C–H

=

125 Hz, CH₂), 31.2 (¹J_C–H= 126 Hz, CH₂), 37.8 (¹J_C–H= 137 Hz, C⁷H), 40.0

(¹J_C–H= 138 Hz, CH₂), 41.5 (¹J_C–H= 139 Hz, C⁶H₂), 60.6 (¹J_C–H= 149 Hz,

C⁵H), 126.7 (2 × CH), 129.16 (2 × CH), 129.23 (CH), 136.3 (C), 161.0

(C⁸), 166.1 (CO).

¹³С NMR (CDCl₃, 150 MHz):  = 18.6 (CH₂), 38.5 (CH₂), 60.1 (CH), 116.3

(²J_C–F= 22 Hz, 2 × CH), 128.0 (³J_C–F= 9 Hz, 2 × CH), 133.0 (⁴J_C–F= 3 Hz,

C), 162.5 (C), 162.9 (¹J_C–F= 249 Hz, C).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₅H₂₀N₅O⁺: 286.1662; found:

286.1661.

HRMS (ESI): m/z [M + H]⁺calcd for C₁₀H₁₀FN₄⁺: 205.0884; found:

205.0883.

5-Phenyl-6,7-dihydro-5H-pyrrolo[1,2-d]tetrazole (7a)

Obtained from azide 4a (372 mg, 2.0 mmol).

5-(4-Methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-d]tetrazole (7d)

Obtained from azide 4f (216 mg).

Yield: 185 mg (50%) (BF₃·OEt₂); beige crystals, mp 108–109 °C; R_f=

0.71 (EtOAc).

2

3

¹Н NMR (CDCl₃, 600 MHz):  = 2.82 (dddd, J = 13.5, J = 9.3, J = 6.3,

Yield: 24 mg (11%) (BF₃·OEt₂); yellow oil; R_f= 0.59 (EtOAc).

³J = 5.9 Hz, 1 H, C⁶H₂), 3.05 (ddd, ²J = 16.9, ³J = 9.3, ³J = 6.3 Hz, 1 H,

¹Н NMR (CDCl₃, 600 MHz):  = 2.85–2.92 (m, 1 H, CH₂), 3.12 (ddd, ²J =

16.8, ³J = 9.3, ³J = 6.3 Hz, 1 H, CH₂), 3.22 (ddd, ²J = 16.8, ³J = 9.2, ³J =

5.1 Hz, 1 H, CH₂), 3.34–3.41 (m, 1 H, CH₂), 3.82 (s, 3 H, CH₃O), 5.58–

5.61 (m, 1 H, CH), 6.90–6.93 (m, 2 H, Ar), 7.08–7.11 (m, 2 H, Ar).

¹³С NMR (CDCl₃, 150 MHz):  = 18.7 (CH₂), 38.5 (CH₂), 55.4 (CH₃O),

60.4 (CH), 114.7 (2 × CH), 127.5 (2 × CH), 129.2 (C), 160.1 (C), 162.3

(C).

C⁷H₂), 3.12 (ddd, J = 16.9, J = 9.3, J = 5.2 Hz, 1 H, C⁷H₂), 3.37 (dddd,

²J = 13.5, ³J = 9.3, ³J = 8.2, ³J = 5.2 Hz, 1 H, C⁶H₂), 5.60 (dd, ³J = 8.2, ³J =

5.9 Hz, 1 H, C⁵H), 7.07–7.11 (m, 2 H, Ph), 7.29–7.35 (m, 3 H, Ph).

2

3

¹³С NMR (CDCl₃, 150 MHz):  = 18.4 (C⁷H₂), 38.3 (C⁶H₂), 60.5 (C⁵H),

125.9 (2 × CH), 128.7 (CH), 129.0 (2 × CH), 137.2 (C), 162.5 (C).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₀H₁₁N₄⁺: 187.0978; found:

187.0983.

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₃N₄O⁺: 217.1084; found:

217.1083.

6-Phenyl-6,7-dihydro-5H-pyrrolo[1,2-d]tetrazole (7′a)

Obtained as a side product in the synthesis of 7a.

Yield: 8 mg (2%); yellow oil; R_f= 0.42 (PE–EtOAc, 1:1).

4-(4-Methoxyphenyl)-4-[5-(4-methoxyphenyl)-6,7-dihydro-5H-

pyrrolo[1,2-d]tetrazol-6-yl]butanenitrile (8)

¹Н NMR (CDCl₃, 600 MHz):  = 3.18 (dd, ²J = 16.8, ³J = 7.9 Hz, 1 H,

C⁷H₂), 3.55 (ddd, ²J = 16.8, ³J = 8.9, ⁴J = 0.7 Hz, 1 H, C⁷H₂), 4.35 (dd, ²J =

11.5, ³J = 7.8 Hz, 1 H, C⁵H₂), 4.50–4.56 (m, 1 H, C⁶H).4.80 (ddd, ²J =

11.5, ³J = 8.7, ⁴J = 0.7 Hz, 1 H, C⁵H₂), 7.26–7.28 (m, 2 H, Ph), 7.34–7.43

(m, 3 H, Ph).

¹³С NMR (CDCl₃, 150 MHz):  = 27.9 (C⁷H₂), 48.0 (C⁶H), 51.8 (C⁵H₂),

126.8 (2 × CH), 128.2 (CH), 129.4 (2 × CH), 139.4 (C), 161.5 (C).

Obtained as the major product in the synthesis of 7d.

Yield: 70 mg (36%); yellowish crystals, mp 186–187 °C; dr A/B/C/D =

69:19:10:3; R_f= 0.76 (EtOAc).

Isomer A

¹Н NMR (CDCl₃, 600 MHz):  = 1.71–1.77 (m, 1 H, C³H₂), 1.98 (ddd, ²J =

16.4, ³J = 9.1, ³J = 7.1 Hz, 1 H, C²H₂), 2.06–2.11 (m, 1 H, C³H₂), 2.16

3

(ddd, ²J = 16.4, J = 6.8, J = 4.3 Hz, 1 H, C²H₂), 2.77 (dd, ²J = 17.0, ³J =

7.9 Hz, 1 H, C^7′H₂), 3.02 (dd, ²J = 17.0, ³J = 8.5 Hz, 1 H, C^7′H₂), 3.05 (ddd,

³J = 12.1, ³J = 9.2, ³J = 3.4 Hz, 1 H, C⁴H), 3.51–3.57 (m, C^6′H), 3.82 (s, 3 H,

CH₃O), 3.84 (s, 3 H, CH₃O), 5.30 (d, ³J = 7.1 Hz, 1 H, C^5′H), 6.92–6.94 (m,

2 H, Ar), 6.96–6.98 (m, 2 H, Ar), 7.10–7.12 (m, 2 H, Ar), 7.19–7.21 (m,

2 H, Ar).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₀H₁₁N₄⁺: 187.0978; found:

187.0978.

5-(p-Tolyl)-6,7-dihydro-5H-pyrrolo[1,2-d]tetrazole (7b)

Obtained from azide 4b (401 mg, 2.0 mmol).

¹³С NMR (CDCl₃, 150 MHz):  = 15.2 (C²H₂), 23.7 (C^7′H₂), 29.8 (C³H₂),

47.3 (C⁴H), 55.3 (CH₃O), 55.4 (CH₃O), 58.4 (C^6′H), 65.0 (C^5′H), 115.0

(4 × CH), 118.8 (CN), 128.2 (C), 128.7 (2 × CH), 129.0 (2 × CH), 129.9

(C), 159.4 (C), 160.0 (C^8′), 160.5 (C).

Yield: 115 mg (29%) (BF₃·OEt₂); 155 mg (39%) (SnCl₄); colorless crys-

tals, mp 147–148 °C; R_f= 0.70 (EtOAc).

Q

K. L. Ivanov et al.

Feature

Synthesis

HRMS (ESI): m/z [M + H]⁺calcd for C₂₂H₂₄N₅O₂⁺: 390.1925; found:

390.1919.

(7) (a) Clemens, J. J.; Asgian, J. L.; Busch, B. B.; Coon, T.; Ernst, J.;

Kaljevic, L.; Krenitsky, P. J.; Neubert, T. D.; Schweiger, E. J.;

Termin, A.; Stamos, D. J. Org. Chem. 2013, 78, 780. (b) Fraser, W.;

Suckling, C. J.; Wood, H. C. S. J. Chem. Soc., Perkin Trans. 1 1990,

3137.

Funding Information

(8) Sarvary, A.; Maleki, A. Mol. Divers. 2015, 19, 189.

(9) (a) Carpenter, W. R. J. Org. Chem. 1962, 27, 2085. (b) Himo, F.;

Demko, Z. P.; Noodleman, L.; Sharpless, K. B. J. Am. Chem. Soc.

2002, 124, 12210.

Research related to the development of a one-pot synthetic approach

to azidonitriles was supported by the Russian Science Foundation

(19-73-00244). Research related to the development of synthetic pro-

cedures for converting azidonitriles into tetrazoles was supported by

the Russian Foundation for Basic Research (18-53-41009), and by the

Ministry of Innovative Development of the Republic of Uzbekistan

(10) (a) Foldi, Z. US2020937, 1935. (b) Davis, B.; Brandstetter, T. W.;

Smith, C.; Hackett, L.; Winchester, B. G.; Fleet, G. W. J. Tetrahe-

dron Lett. 1995, 36, 7507. (c) Davis, B. G.; Brandstetter, T. W.;

Hackett, L.; Winchester, B. G.; Nash, R. J.; Watson, A. A.;

Griffiths, R. C.; Smith, C.; Fleet, G. W. J. Tetrahedron 1999, 55,

4489. (d) Davis, B. G.; Nash, R. J.; Watson, A. A.; Smith, C.; Fleet,

G. W. J. Tetrahedron 1999, 55, 4501. (e) Demko, Z. P.; Sharpless,

K. B. Org. Lett. 2001, 3, 4091. (f) Himo, F.; Demko, Z. P.;

Noodleman, L.; Sharpless, K. B. J. Am. Chem. Soc. 2003, 125, 9983.

(g) Bliznets, I. V.; Shorshnev, S. V.; Aleksandrov, G. G.; Stepanov,

A. E.; Lukyanov, S. M. Tetrahedron Lett. 2004, 45, 9127.

(h) Lukyanov, S. M.; Bliznets, I. V.; Shorshnev, S. V.; Aleksandrov,

G. G.; Stepanov, A. E.; Vasil’ev, A. A. Tetrahedron 2006, 62, 1849.

(i) Hanessian, S.; Simard, D.; Deschênes-Simard, B.; Chenel, C.;

Haak, E. Org. Lett. 2008, 10, 1381. (j) Hanessian, S.; Deschênes-

Simard, B.; Simard, D.; Chenel, C.; Haak, E.; Bulat, V. Pure Appl.

Chem. 2010, 82, 1761. (k) Biswas, D.; Ding, F.-X.; Dong, S.; Gu, X.;

Jiang, J.; Pasternak, A.; Suzuki, T.; Vacca, J.; Xu, S. PCT Int. Appl

WO2015103756, 2015. (l) Sarvary, A.; Khosravi, F.; Ghanbari,

M. Monatsh. Chem. 2018, 149, 39.

(MRU-FA-74/2017).

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Acknowledgment

The NMR measurements were carried out at the Center for Magnetic

Tomography and Spectroscopy, Faculty of Fundamental Medicine of

Lomonosov Moscow State University. X-ray diffraction studies were

performed at the Centre of Shared Equipment of IGIC RAS.

Supporting Information

Supporting information for this article is available online at

https://doi.org/10.1055/s-0040-1706402.

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References

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Brennan, P. J.; Fleet, G. W. J. Tetrahedron Lett. 1996, 37, 8569.

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Article Doi

One-Pot Synthesis of γ-Azidobutyronitriles and Their Intramolecular Cycloadditions

DOI: 10.1055/s-0040-1706402

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