Synthesis of γ-azido-β-ureido ketones and their transformation into functionalized pyrrolines and pyrroles via staudinger/aza-wittig reaction

Article

pubs.acs.org/joc

Synthesis of γ‑Azido-β-ureido Ketones and Their Transformation into

Functionalized Pyrrolines and Pyrroles via Staudinger/aza-Wittig

Reaction

Anastasia A. Fesenko and Anatoly D. Shutalev*

Department of Organic Chemistry, Moscow State University of Fine Chemical Technologies, 86 Vernadsky Avenue, 119571 Moscow,

Russian Federation

S

* Supporting Information

ABSTRACT: A simple two-step procedure yielding γ-azido-β-ureido ketones or/and their cyclic isomers, 6-(1-azidoalkyl)-4-

hydroxyhexahydropyrimidin-2-ones, has been developed. The synthesis includes three-component condensation of acetals of 2-

azidoaldehydes with urea or methylurea and p-toluenesulﬁnic acid in aqueous formic acid followed by reaction of the obtained N-

[(2-azido-1-tosyl)alkyl]ureas with sodium enolates of α-functionalized ketones. The azido ketones or their cyclic isomers are

transformed into ureido-substituted Δ¹- or/and Δ²-pyrrolines via Staudinger/aza-Wittig reaction promoted by PPh₃. The

obtained pyrrolines are converted into 3-functionalized 1H-pyrroles via elimination of urea under acidic conditions. Convenient

one-pot syntheses of 1H-pyrroles starting from N-[(2-azido-1-tosyl)alkyl]ureas or γ-azido-β-ureido ketones have been also

developed.

INTRODUCTION

■

The ring system of pyrrole¹occurs in many pharmacologically

active natural compounds, including hemes and chlorophylls,

bile pigments, alkaloids and antibiotics, etc.²Pyrroles,

particularly 3-functionalized ones, have signiﬁcant medicinal

and agrochemical applications. For example, atorvastatin 1 is a

top-selling synthetic drug that lowers blood contents of

cholesterol and triglycerides, acting as an inhibitor of 3-

hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase

(Figure 1).³Compound 2 shows dose-dependent antiprolifer-

ative and cytodiﬀerentiation activities against human acute

promyelocytic leukemia HL-60 cells.⁴Pyrrole 3 inhibits HIV-1

reverse transcriptase and is active against AZT-resistant HIV-1

(strain G9106).⁵3-Aroyl-substituted pyrrole derivatives (e.g.,

4) are COX-1/COX-2 inhibitors with anti-inﬂammatory

activity.⁶Chlorfenapyr 5 has been extremely eﬀective against

Figure 1. Selected examples of 3-funtionalized pyrroles with biological

insects and mites in agriculture for over 15 years.⁷

activity.

Most pyrrole syntheses rely on classical condensation

reactions, such as the Hantzsch reaction based on condensation

of α-haloketones with 1,3-dicarbonyl compounds and amines,⁸

as starting materials. The success of the method strongly

depends on the availability of these compounds. γ-Azido

ketones are prepared by reaction of γ-haloketones with sodium

the Paal−Knorr reaction involving cyclocondensation of 1,4-

diketones with amines⁹or the Knorr reaction using

azide,^14a,e,f,15oxidation of γ-azido alkohols,^14b,g,i,16ozonolysis of

condensation of α-aminoketones with β-keto esters or β-

γ-azido alkenes,¹⁷alkylation of ketone enolates with β-

diketones.¹⁰In addition, other synthetic approaches have been

developed.^1,2e,11,12Staudinger/intramolecular aza-Wittig reac-

tion provides an eﬃcient approach to pyrrolines that can be

converted into pyrroles.^13,14This protocol uses γ-azido ketones

Received: December 19, 2012

A

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azidoalkyl halides,^14d,jaldol reaction of ketones with α-azido

ketones,¹⁸and reaction of silyl ethers with acetals of α-azido

ketones.^18b,19The drawbacks of these methods are low

availability of starting compounds, multistep syntheses, small-

scale preparations, harsh reaction conditions, long reaction

times, poor yields, laborious procedures, etc. Thus, the

development of a new eﬀective approach to γ-azido ketones,

especially with functional groups at the α- and β-positions, is

highly desirable in the context of pyrrole synthesis.

Scheme 2. Synthesis of N-[(β-Azido-α-tosyl)alkyl]ureas

We hypothesized that amidoalkylation of enolates of α-

functionalized ketones with N-(β-azidoalkyl)amides A bearing a

leaving group at the α-position to nitrogen could give γ-azido

ketones B with an amido group at β-position, which

signiﬁcantly expands synthetic potential of these compounds

(Scheme 1). They could be transformed into pyrrolines C or/

Scheme 1. Retrosynthesis of Pyrrolines and Pyrroles via

Staudinger/aza-Wittig/Elimination Reactions

9a−c were demonstrated to be stable upon distillation and

were prepared with high purity in 64−85% yields.

We found that the reaction between acetal 9a, acid 7, and

urea in water at room temperature proceeded very slowly to

give sulfone 6a after 5 days in only 44% yield, presumably

because of decreased rate of hydrolysis of 9a into 8a due to

poor water solubility and low acidity of 7 (pK_a2.80 in water at

25 °C).²³The hydrolysis of acetal 9a smoothly proceeded in

80% formic acid at room temperature for 4 h. Then sulﬁnic acid

7 and urea were subsequently added followed by the addition

of water. The condensation completed in the resulting 25%

formic acid after 21 h to give 6a in 86% yield. Sulfone 6a

precipitated from the solution formed after the addition of all

reagents and was isolated by ﬁltration with 99% purity

according to ¹H NMR data for isolated crude material.

Analogously, N-methyl-substituted sulfone 6b was synthesized

from acetal 9a, sulﬁnic acid 7, and methylurea in 88% yield.

When 2-azidopropanal dimethyl acetal (9b) was used in

reaction with acid 7 and urea under the described conditions,

the corresponding sulfone 6c was isolated in only 18% yield,

and about 70% of acetal 9b was recovered by extraction of the

ﬁltrate, indicating a low rate of its hydrolysis (Table 1, entry 1).

and D using Staudinger/intramolecular aza-Wittig reaction.

Subsequent elimination of amide group from compounds C

and D would give 3-functionalized pyrroles E.

Recently we showed that readily available N-[(α-tosyl)alkyl]-

ureas possess high amidoalkylation reactivity toward enolates of

various ketones giving access to functionalized hexahydro-,

1,2,3,4-tetrahydro-, and 1,2-dihydropyrimidin-2-ones, tetrahy-

dro-1H-1,3-diazepin-2-ones, 4,5-dihydrofurans, and 1-carbamo-

yl-1H-pyrroles.²⁰Herein we report the synthesis of γ-azido-β-

ureido ketones by the reaction of N-[(2-azido-1-tosyl)alkyl]-

ureas with enolates of ethyl benzoyl acetate, dibenzoylmethane,

α-arylsulfonyl, and α-phenylthio ketones and transformation of

the obtained γ-azido-β-ureido ketones into functionalized

pyrrolines and then into pyrroles using Staudinger/aza-

Wittig/elimination sequence.

Table 1. Dependence of the Yield of Sulfone 6c from 9b on

the Conditions of the Hydrolytic Step

a

hydrolytic conditions

entry

temp (°C)

time (h)

isolated yield of 6c (%)

1

2

3

4

5

20

40

4

24

1.5

4

18

63

49

71

RESULTS AND DISCUSSION

■

Synthesis of α-Functionalized γ-Azido-β-ureido Ke-

tones. β-Azidoalkyl-substituted ureas 6a−d served as starting

amidoalkylation reagents (Scheme 2). Previously we obtained

N-[(α-tosyl)alkyl]ureas using three-component condensation

of aldehyde, p-toluenesulﬁnic acid (7), and urea in water at

room temperature.²⁰Since 2-azidoaldehydes 8a−c seem to be

unstable (at least 8a²¹), we used their acetals in the three-

component condensation. Acetals 9a−c were prepared

according to the literature procedure described for 9a²²and

based on the reaction of bromoacetals 10a−c with NaN₃(1.5

equiv) in the presence of KI (0.1 equiv) in DMSO at 90 °C.

6

a

Treatment of acetal 9b with 80% aqueous HCOOH. Subsequent

three-component condensation was carried out as described for

sulfone 6a (25% aqueous HCOOH, rt, 24 h).

The decrease in the rate of hydrolysis of 2-azidopropanal

dimethyl acetal (9b) compared with acetal 9a can be explained

by steric hindrance caused by the methyl group at the α-

position.

Prolongation of the hydrolytic step (24 h, rt) increased the

yield of 6c to 63% (entry 2). Table 1 shows that the optimal

conditions for the preparation of sulfone 6c include stirring of

9b in 80% HCOOH for 4 h upon heating at 40 °C (water bath)

1

The progress of the reactions was monitored by H NMR

spectroscopy, allowing the reaction time to be decreased to

46−88.5 h compared with the reported procedure (5 days).

Reduced reaction times led to increased product yields. Acetals

B

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Table 2. Reaction of Sulfones 6a−d with Sodium Enolates of Ketones 11a−h; Synthesis of γ-Azido-β-ureido Ketones 12 or/and

Their Cyclic Isomers 13

a

b

c

entry CH-acid sulfone

R

R²

R³

FG

ratio NaH:11

reaction conditions

product(s)

yield (%)

dr

1

11a

11b

11c

11d

11e

11f

6a

6b

6c

6d

6a

6c

6d

6a

6b

6c

6a

6b

6c

6d

6a

H

Me

H

Me

H

Me

H

Me

Ph

SO₂Ph

Ts

1.00:1.02

1.00:1.01

1.00:1.00

1.00:1.01

1.00:1.02

1.01:1.03

1.00:1.01

1.01:1.02

1.00:1.01

1.00:1.02

1.00:1.01

1.00:1.02

1.10:1.12

1.00:1.02

1.01:1.02

1.01:1.04

1.00:1.02

1.10:1.12

1.01:1.03

1.00:1.01

1.00:1.05

1.01:1.02

MeCN, 8 h, rt

THF, 8 h, rt

MeCN, 8 h, rt

MeCN, 24 h, rt

THF, 8 h, rt

MeCN, 8 h, rt

THF, 8 h, rt

MeCN, 9 h, rt

MeCN, 8 h, rt

THF, 9 h, rt

MeCN, 8 h, rt

THF, 8 h, rt

THF, 24 h, rt

THF, 8 h, rt

THF, 8 h, 40 °C

THF, 8 h, rt

MeCN, 8 h, rt

THF, 8 h, rt

THF, 24 h, rt

THF, 8 h, rt

THF, 12 h, rt

THF, 12 h, 40 °C

THF, 8 h, rt

MeCN, 8 h, rt

12a

74

84

61

60

71

69

92

94

96

93

86

98

16

66

40

73

41

28

37

54

60

53

58

38

48

27

30

77

39

65:35

90:10

63:37

2

H

13b

3

H

Ts

12c

4

Me

Et

Ts

12d

62:20:14:4

62:21:13:4

69:19:9:3

74:20:5:1

55:45

5

Ts

12d

6

Ts

12e

7

Et

Ts

12e

8

H

SO₂Ph

Ts

12f

9

H

Ph

12g

60:40

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

H

Ph

Ts

12g

60:40

Me

Et

Ph

Ts

12h

33:25:28:14

35:32:20:13

46:26:20:8

48:25:19:8

(35:23):(42:0)

52:48

Ph

Ts

12h

Ph

Ts

12i

Et

Ph

Ts

12i

d

H

Ph

SPh

Bz

12j + 13j

12j

H

Ph

H

Ph

12j

51:49

H

Ph

12k

72:28

Me

H

Ph

12l

39:29:20:12

36:32:28:4

Ph

12l

d

Ph

12l + 13l

13m

12n + 13n

13o

(12:5:18:3):(43:19)

48:41:11

Me

Ph

11f

H

43:38:19

11f

H

46:37:17

d

11f

H

(74:8):(9:9)

11f

Me

Et

40:50:10

50:45:5

11f

13o

11f

13o

48:42:10

d

11f

12p + 13p

12q

(44:0):(30:19:7)

11g

11h

H

Ph

CO₂Et

13r

100:0

a

b

c

d

The amount of the corresponding sulfone 6 is 1.00 equiv. Isolated yield. Determined by ¹H NMR of the crude isolated product. The ratio in the

ﬁrst parentheses is for 12, the ratio in the second parentheses is for 13.

followed by condensation with urea and sulﬁnic acid 7 (entry

4). Prolongation of the hydrolytic step at 40 °C had no eﬀect

on the yield (entry 5). Under the described optimal conditions

sulfone 6d was obtained by the reaction of 9c with acid 7 and

urea in 80% yield. Compounds 6c,d formed with high

selectivity as mixtures of two diastereomers in 97:3 and 90:10

ratio, respectively.

Sulfones 6a−d readily reacted with sodium enolates of α-

functionalized ketones generated by treatment of CH-acids

11a−h with NaH in dry solvent (MeCN or THF) to give

products of nucleophilic substitution of the tosyl group, γ-

azido-β-ureido ketones 12, or/and their cyclic isomers,

hydroxypyrimidinones 13. Experimental data for this reaction

are summarized in Table 2.

blocks for further functionalization allowing, for example, a

regioselective synthesis of tetrasubstituted pyrroles.²⁴

Thus, reactions of sulfones 6a−d with sodium enolates of α-

arylsulfonyl ketones 11a−d, with the exception of the reaction

of 6a with the Na-enolate of 11b, gave γ-azido ketones 12a,c−i

in 60−98% yields as mixtures of diastereomers (Table 2, entries

1, 3−14). The use of diﬀerent solvents (entries 4, 9, 11, 13 vs

entries 5, 10, 12, 14, respectively) and reaction time (entry 6 vs

entry 7) had a slight eﬀect on diastereoselectivity and yield of

the ﬁnal products.

The sodium enolate of tosylacetone (11b) reacted with urea

6a in MeCN to give the corresponding γ-azido ketone 12b,

which spontaneously and completely cyclized into hydroxypyr-

imidinone 13b under reaction conditions. Pyrimidine 13b was

isolated in 84% yield as a mixture of two diastereomers in a

ratio of 90:10 (Table 2, entry 2). The pure major isomer of 13b

was isolated after crystallization of the crude product from

EtOH. According to ¹H NMR data, the major diastereomer had

(4R*,5R*,6R*)-conﬁguration with equatorial orientation of the

We focused our attention on the synthesis of γ-azido ketones

bearing arylsulfonyl or arylthio groups, since they are the

starting materials for pyrroles with sulfur-containing substituent

at C-3. These pyrroles can be considered as useful building

C

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Scheme 3. Synthesis of Pyrrolines and Pyrroles via Staudinger/aza-Wittig Reaction

substituents at C-5 and C-6 (³J_H‑5,H‑6= 9.7, ³J_N(1)H,H‑6≈ 0 Hz)²⁵

and axial orientation of the hydroxyl group (⁴J_H‑5,OH= 1.3 Hz)

in DMSO-d₆. The relative conﬁguration of the minor

diastereomer was determined as (4R*,5S*,6S*) with axial

orientation of hydroxyl group and substituents at C-5 and C-6

(³J_H‑5,H‑6= 0.8, ⁴J_H‑5,OH= 0, ³J_N(1)H,H‑6= 4.6 Hz).^25,26Thus, the

diastereomers of 13b diﬀer only in conﬁguration at C-4. A

possible explanation of this result could lie in fully

diastereoselective reaction of 6a with the Na-enolate of 11b

to give (R*,R*)-12b followed by its cyclization to the isomeric

mixture of 13b. However, reaction of the same enolate with 6b

under the similar conditions proceeds with poor selectivity to

provide a 63:37 diastereomeric mixture of 12c (entry 3), which

does not cyclize to 13c due to steric hindrance caused by the N-

Me group. Thus in the case of 6a, poor selectivity of the

amidoalkylation step should be also expected. We suppose that

an initially formed diastereomeric mixture of 12b cyclizes to a

mixture of isomers of 13b followed by base-promoted

isomerization at C-5 to give the thermodynamically more

stable isomers of 13b. The diﬀerent results of the reactions of

6a with Na-enolates of 11a and 11b (entry 1 vs entry 2) can be

explained by diﬀerences in thermodynamic stability of acyclic

and cyclic forms of the obtained compounds.

N₍₁₎H and H-6 (broadened unresolved multiplet for N₍₁₎H,

half-height width = 7.1 Hz).²⁵After crystallization of crude

product from EtOH the ratio of (4R*,5R*,6R*)- and

(4R*,5S*,6R*)-diastereomers changed to 70:30, the second

minor diastereomer being completely removed.

The reaction of 6a with the Na-enolate of 11e smoothly

proceeded in THF; however, in contrast to the reaction of 6a

with 11f under the similar conditions, γ-azido ketone 12j was

exclusively obtained in 66% yield as a mixture of two

diastereomers (entry 16). Prolongation of the reaction time

decreased the yield of 12j and had no eﬀect on stereoselectivity

(entry 16 vs entry 17). Notably, when MeCN was used instead

of THF, the yield of the product was dramatically reduced, and

the crude isolated material contained hydroxypyrimidine

(4R*,5R*,6R*)-13j (42%) along with two diastereomers of γ-

azido ketone 12j (entry 15). The relative conﬁguration of 13j

1

was determined from the values of couplings in its H NMR

spectrum as described above for 13b,m.

Since the use of THF compared with MeCN signiﬁcantly

increased the product yields, all reactions of 6b−d with

phenythioketones 11e,f were carried out in THF. Sulfone 6b

reacted with the Na-enolate of 11e to give γ-azido ketone 12k

as a mixture of two diastereomers in 73% yield (entry 18).

Under the similar conditions, the product of the reaction

between 11f and 6b partially cyclized, aﬀording a mixture of

pyrimidine 13n (18%) along with azido ketone 12n (entry 25).

Reaction of 6c with 11e (THF, 8 h, rt) gave γ-azido ketone 12l

as diastereomeric mixture in relatively low yield (entry 19). Our

attempts to increase the yield of 12l using heating of the

reaction mixture at 40 °C (entry 20) or 10% excess of the

nucleophile (entry 21) failed. In the last case, a 38:62 mixture

of γ-azido ketone 12l and hydroxypyrimidine 13l was obtained

showing signiﬁcant inﬂuence of the basicity of the medium on

the cyclization of 12 into 13. Treatment of 6c with the Na-

enolate of 11f in THF under various conditions gave exclusively

pyrimidine 13o in 27−48% yields as mixtures of three

diastereomers with similar ratios (entries 26−28). The reaction

of 6d with the Na-enolate of 11f (THF, 8 h, rt) resulted in the

formation of a 44:56 mixture of 12p and 13p in rather low yield

(entry 29).

The reaction between Na-enolates of phenylthioketones

11e,f and sulfones 6a−d proceeded in more complex fashion.

The sodium enolate of phenylthioacetone (11f) reacted with 6a

to give hydroxypyrimidinone 13m as a mixture of three

diastereomers whose ratio slightly changed in diﬀerent solvents

(MeCN or THF), but the product yield slightly increased when

THF was used (entry 22 vs entry 23). Extension of the reaction

time from 8 to 24 h (THF, rt) had a small eﬀect on the results

obtained (entry 23 vs entry 24). The major diastereomer of

phenylthio-substituted pyrimidine 13m had (4R*,5S*,6R*)-

conﬁguration with axial orientation of the phenylthio-group

(³J_H‑5,H‑6= 2.8, ⁴J_H‑5,N(1)H= 1.3, ⁴J_H‑5,N(3)H= 1.3 Hz), equatorial

orientation of the azidomethyl-group at C-6 (³J_H‑6,N(1)H≈ 0

Hz), and presumably axial orientation of the OH-group²⁷in

DMSO-d₆solution. The ﬁrst minor diastereomer (38%, entry

23) had (4R*,5R*,6R*)-conﬁguration with equatorial orienta-

tion of the substituents at C-5 and C-6 and axial orientation of

3

4

the hydroxyl group (³J_H‑5,H‑6= 11.4, J_N(1)H,H‑6≈ 0, J_5‑H,OH

=

The reaction of sulfone 6a with an equimolar amount of the

Na-enolate of dibenzoylmethane (11g) in dry THF aﬀorded γ-

azido ketone 12q along with 10% of N-[(1-azido-4-oxo-4-

phenyl)but-2-yl]-N′-benzoylurea (¹H NMR data for isolated

crude material). The latter resulted from base-promoted

0.9 Hz). Conﬁguration of the second minor diastereomer could

not be unambiguously established from the H NMR spectra.

1

Only the orientation of the azidomethyl group could be

determined as axial from the high value of coupling between

D

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cleavage of the C(4)−C(5) bond in the corresponding

hydroxypyrimidine 13q. This type of cleavage was previously

observed for 5-acyl-substituted hydroxypyrimidines.²⁸When

the basicity of the reaction medium was lowered by the

addition of 5% excess of dibenzoylmethane (toward NaH), this

side reaction did not proceed. Under these conditions pure γ-

azido ketone 12q was isolated in 77% yield (entry 30). When

MeCN was used instead of THF, the completion of the

reaction between dibenzoylmethane and NaH was hampered

by formation of a dense suspension of the enolate, reducing the

yield and purity of 12q.

Sodium enolate of ethyl benzoyl acetate (11h) reacted with

6a in MeCN to give 4-hydroxypyrimidine 13r, which was

isolated in 39% yield as a single diastereomer with

(4R*,5S*,6R*)-conﬁguration (entry 31). The orientations of

the substituents at C-6, C-5, and C-4 were analogous to those

described for the major diastereomer of 13b. A decrease in the

yield of 13r can be explained by partial loss of the product

during aqueous workup because of high solubility of 13r in

water.

Table 3. Functionalized Pyrroline Synthesis by PPh₃-

Promoted Staudinger/aza-Wittig Reaction of γ-Azido

a

Ketones 12 and Hydroxypyrimidines 13

starting

reaction

time (h)

ratio of

b

entry material

solvent

THF

product(s)

products

1

12a

1.7

trans-15a + 16a

+ 17a

28:69:3

2

3

4

13b

THF

2

trans-15b + 16b

39:61

MeCN

1.6

3

39:61

1,4-

dioxane

trans-15b + 16b

+ 17b

31:55:14

5

6

7

12j

MeCN

4

5

1

trans-15i + cis-

80:20

15i

13m

13r

trans-15j +

cis-15j + 16j

64:20:16

59:13:28

trans-15l +

cis-15l + 16l

a

Reactions were carried out in reﬂuxing solvent using 1.2 equiv of

PPh₃. After their completion the solvent was removed under reduced

pressure, and the resulting crude products were analyzed by ¹H NMR

b

spectroscopy. Diastereomer ratios of 12 and 13 are shown in Table 2.

Synthesis of Functionalized Δ¹-Pyrrolines, Δ²-Pyrro-

lines, and Pyrroles. γ-Azido ketones 12 and hydroxypyr-

imidines 13 were used as starting materials in the synthesis of

functionalized pyrrolines via Staudinger/aza-Wittig reaction

promoted by PPh₃(1.2 equiv) in reﬂuxing solvent (Scheme 3).

Azido ketones 12f,g reacted with PPh₃in reﬂuxing THF for 1 h

40 min to give iminophosphoranes 14e,f, which spontaneously

cyclized into the corresponding 4-ureido-substituted Δ¹-

pyrrolines 15e,f and precipitated from the reaction mixture.

Due to low solubility in THF they were isolated by ﬁltration in

89% yield completely free from POPh₃. Though starting

ketones 12f,g were mixtures of two diastereomers (Table 2),

pyrrolines 15e,f were obtained as a single trans-diastereomer,

presumably due to base-promoted epimerization at the sulfur-

bearing carbon during the reaction under the action of

iminophosphoranes 14e,f.²⁹The trans-conﬁguration of 15e,f

follows from the values of vicinal coupling constants between

the protons at C-3, C-4, and C-5. Two of these constants were

close to zero, conﬁrming that the corresponding dihedral angles

were about 90°. Calculations of the geometries of cis- and trans-

15e,f using semiempirical methods AM1 and PM6³⁰showed

that these angles were in good agreement only with a trans-

conﬁguration of 15e,f. The Δ¹-pyrroline ring of trans-15e,f

adopts an envelope conformation (C-4 out of the plane) with

pseudoaxial orientations of the ureido and arylsulfonyl groups.

Table 3 shows that reactions of 12a,j and 13b,m,r with PPh₃

gave mixtures of the corresponding Δ¹- and Δ²-pyrrolines.

Some of these mixtures also contained aromatic pyrroles

(entries 1 and 4). No products precipitated from the reaction

mixtures, and therefore their isolation required column

chromatography to separate POPh₃. During chromatographic

puriﬁcation on silica gel, the 4-ureidopyrrolines partially

decomposed (especially 3-phenylthio-substituted ones) and

aromatized via elimination of urea. Our attempts to prepare

pure ureidopyrrolines 15 and 16, with the exception of 15e−g,

16n, failed.

The ﬁnal step of the pyrrole synthesis involved conversion of

the obtained ureidopyrrolines 15 or/and 16 into 3-function-

alized aromatic pyrroles 17. The experimental data for this

transformation are shown in Table 4.

We developed three diﬀerent synthetic procedures for the

preparation of pyrroles 17. Arylsulfonyl-substituted pyrroles

17a,c,d,h were obtained using a one-pot procedure based on

the reaction of the corresponding azido ketones 12a,d,e,i with

1.2 equiv of PPh₃(THF, reﬂux, 2−2.4 h) followed by the

addition of 0.5 equiv of TsOH (THF, reﬂux, 10−30 min)

(Table 4, entries 1, 4, 6, 10). Overall yields of 17a,c,d,h after

puriﬁcation by column chromatography were 69−93%. Pyrrole

17c was also prepared in 47% overall yield according to another

one-pot synthesis starting from sulfone 6c (entry 5). After the

reaction between sulfone 6c and the sodium enolate of

tosylacetone in THF was complete, PPh₃was added, the

obtained reaction mixture was reﬂuxed for 1 h, and then TsOH

(0.5 equiv) was added followed by reﬂux for 1.25 h. The overall

yield of pyrrole 17c obtained from 6c was higher than that from

12d. Analogously, using the above described one-pot

procedures, pyrrole 17l was synthesized from pyrimidine 13r

(entry 14) and sulfone 6a (entry 15) in 83% and 89% overall

yields, respectively. Sulfones 6a,c were used as starting

materials for the one-pot preparation of pyrroles 17b,m

(entries 2, 3, 16). The yield of pyrrole 17b increased when

the reaction was carried out in MeCN (Table 4, entry 2 vs entry

3).

1

trans-Conﬁguration of 15e was conﬁrmed in a H,¹H-NOESY

experiment. Diagnostic NOEs were observed between the NH

proton and pseudoequatorial H-3 and H-5 protons and

between ortho-protons of the phenylsulfonyl group and the

H-4 proton.

Analogously, reaction of 12h with PPh₃in reﬂuxing THF for

2 h gave Δ¹-pyrroline 15g, which was isolated by ﬁltration of

the precipitated solid in 74% yield. Compound 15g was

obtained as a mixture of two diastereomers in a ratio of 72:28,

which diﬀer only in the relative orientation of the methyl group

at C-5. In contrast to 12f−h, treatment of 12q with PPh₃

(THF, reﬂux, 4.5 h) aﬀorded 4-ureido-substituted Δ²-pyrroline

16n in 72% yield that formed as a result of imine-enamine

tautomeric shift in the intermediate Δ¹-pyrroline 15n.

We found that with the exception of 12f−h,q, other γ-azido

ketones 12 and hydroxypyrimidines 13 being reacted with PPh₃

aﬀorded complex mixtures of products. Selected experimental

data for this reaction are shown in Table 3.

The pyrroline formation from hydroxypyrimidine 13m using

Staudinger/aza-Wittig sequence strongly depended on the

reaction conditions. When 13m was reacted with PPh₃in

reﬂuxing THF for 1 h 10 min, TLC showed no starting

E

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Table 4. Synthesis of 3-Functionalized Pyrroles

entry

1

starting material

solvent

THF

reaction conditions

product

isolated yield (%)

93

12a

(i) PPh₃(1.23 equiv), reﬂux, 2 h

17a

(ii) TsOH (0.50 equiv), reﬂux, 10 min

(i) 11b (1.02 equiv), NaH (1.00 equiv), rt, 8 h

(ii) PPh₃(1.20 equiv), reﬂux, 1 h

2

3

11b + 6a

THF

17b

61

71

(iii) TsOH (0.51 equiv), reﬂux, 1 h

(i) 11b (1.02 equiv), NaH (1.00 equiv), rt, 8 h

(ii) PPh₃(1.19 equiv), reﬂux, 1 h

MeCN

(iii) TsOH (0.50 equiv), reﬂux, 1 h

(i) PPh₃(1.19 equiv), reﬂux, 2.4 h

(ii) TsOH (0.50 equiv), reﬂux, 15 min

(i) 11b (1.04 equiv), NaH (1.00 equiv), rt, 8 h

(ii) PPh₃(1.13 equiv), reﬂux, 1 h

4

5

12d

THF

17c

70

47

11b + 6c

(iii) TsOH (0.51 equiv), reﬂux, 1.25 h

(i) PPh₃(1.21 equiv), reﬂux, 2 h

6

12e

THF

17d

74

(ii) TsOH (0.50 equiv), reﬂux, 15 min

TsOH (0.10 equiv), reﬂux, 30 min

TsOH (0.30 equiv), reﬂux, 20 min

(i) PPh₃(1.13 equiv), reﬂux, 2 h

7

15e

15f

15g

12i

MeCN

THF

17e

17f

96

93

97

69

8

9

17g

17h

10

(ii) TsOH (0.50 equiv), reﬂux, 30 min

(i) PPh₃(1.19 equiv), reﬂux, 2 h

11

12

13

14

15

12j

THF

17i

17j

17k

17l

69

77

79

83

89

(ii) TsOH (0.50 equiv), reﬂux, 15 min

(i) PPh₃(1.09 equiv), reﬂux, 5 h

13m

13o

MeCN

(ii) TsOH (0.50 equiv), reﬂux, 5 min

(i) PPh₃(1.20 equiv), reﬂux, 4.5 h

(ii) TsOH (0.49 equiv), reﬂux, 15 min

(i) PPh₃(1.18 equiv), reﬂux, 1 h

13r

(ii) TsOH (0.10 equiv), reﬂux, 5 min

(i) 11h (1.00 equiv), NaH (1.00 equiv), rt, 8 h

(ii) PPh₃(1.25 equiv), reﬂux, 1.17 h

(iii) TsOH (0.20 equiv), reﬂux, 1 h

(i) 11h (1.04 equiv), NaH (1.00 equiv), rt, 8 h

(ii) PPh₃(1.23 equiv), reﬂux, 1 h

11h + 6a

16

11h + 6c

MeCN

17m

85

(iii) TsOH (0.20 equiv), reﬂux, 30 min

TsOH (0.10 equiv), reﬂux, 10 min

17

16n

MeCN

17n

96

material. After removal of solvent, no signals of expected

pyrrolines were observed in the ¹H NMR spectrum.

Analogously we studied the mixture formed in the reaction of

13m with PPh₃in reﬂuxing 1,4-dioxane for 3 h 50 min, but only

unidentiﬁed products of decomposition were detected.

However, reﬂux of 13m with PPh₃in MeCN for 5 h led to

desired recyclization of 13m into a mixture of trans-15j, cis-15j,

and 16j in a ratio of 64:20:16, respectively (Table 3, entry 6).

The subsequent aromatization of this mixture under the action

of TsOH gave pyrrole 17j in 77% overall yield (Table 4, entry

12). The similar procedure was used for the one-pot

preparation of 17k in 79% yield from pyrimidine 13o (entry

13).

proceeded without any side processes. The overall yield of 17i

was 69% after column chromatography (Table 4, entry 11).

Pyrrolines 15e−g and 16n were readily aromatized to

pyrroles 17e−g,n via elimination of urea in reﬂuxing MeCN in

the presence of TsOH in 93−97% yields (Table 4, entries 7−9,

17). Greater amount of TsOH for 5-methyl-substituted 15g

was used to decrease the reaction time (Table 4, entry 9).

CONCLUSION

■

We have developed an eﬃcient three-step protocol for

preparation of γ-azido-β-ureido ketones bearing arylsulfonyl-,

arylthio-, acyl-, and alkoxycarbonyl-substituents at the α-

position to the carbonyl group or their cyclic isomers, 6-(1-

azidoalkyl)-4-hydroxyhexahydropyrimidin-2-ones, involving

amidoalkylation of α-functionalized ketone enolates with N-

[(2-azido-1-tosyl)alkyl]ureas. Compared with the literature

approaches to γ-azido ketones, advantages of our approach

are high synthetic ﬂexibility, high availability of starting

materials and reagents, mild reaction conditions, and

introduction of additional functionalities to the α- and β-

positions of the target products. The obtained γ-azido-β-ureido

ketones or their cyclic isomers are transformed into ureido-

substituted Δ¹- or/and Δ²-pyrrolines via intramolecular

Staudinger/aza-Wittig reaction promoted by PPh₃. The pyrro-

Δ¹-Pyrroline 15i was obtained as a mixture of trans- and cis-

diastereomers in a ratio of 80:20 after reﬂux of 12j in MeCN

with PPh₃for 4 h (Table 3, entry 5). However, after reﬂux of

this mixture with 0.1 equiv of TsOH for 10 min, the resulting

reaction mixture unexpectedly contained 4% of 2-phenyl-1H-

1

pyrrole (according to H NMR spectrum of crude isolated

material³¹). The amount of this side product increased to 8%

when the reﬂux with TsOH was continued for 2 h. We found

that the formation of pyrrole 17i in the reaction of 12j with

PPh₃in THF (reﬂux, 2 h) followed by the treatment of the

obtained mixture with 0.50 equiv of TsOH (reﬂux, 15 min)

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3276 (m), 3212 (m) (NH), 3089 (w), 3065 (w), 3043 (m) (CH_arom),

2181 (m), 2111 (vs) (N₃), 1695 (s), 1667 (s) (amide-I), 1616 (m),

1599 (w) (CC_arom), 1516 (br s) (amide-II), 1308 (s), 1143 (s) (SO₂),

825 (m) (CH_arom) cm⁻¹; ¹H NMR (300.13 MHz, DMSO-d₆) δ 7.69−

lines readily eliminate urea under acidic conditions to give 3-

functionalized 1H-pyrroles. The latter can be readily prepared

using convenient one-pot procedures starting from N-[(2-

azido-1-tosyl)alkyl]ureas or γ-azido-β-ureido ketones. We

believe that the synthesis of pyrroles described in this article

is an attractive alternative to the classical pyrrole syntheses.

This has been illustrated by the successful preparation of

previously inaccessible pyrroles.

3

7.74 (m, 2H, ArH), 7.41−7.47 (m, 2H, ArH), 7.15 (d, J = 10.3 Hz,

1H, NH), 5.84 (s, 2H, NH₂), 5.17 (ddd, ³J = 10.3, ³J = 7.4, ³J = 4.3 Hz,

1H, CHN), 3.78 (dd, ²J = 13.3, ³J = 7.4 Hz, 1H, CH_AN₃), 3.76 (dd, ²J

= 13.3, ³J = 4.3 Hz, 1H, CH_BN₃), 2.41 (s, 3H, CH₃); ¹³C NMR (75.48

MHz, DMSO-d₆) δ 156.3 (CO), 144.7 (C), 134.1 (C), 129.7

(2CH), 128.8 (2CH), 69.1 (CHN), 48.1 (CH₂N₃), 21.1 (CH₃). Anal.

Calcd for C₁₀H₁₃N₅O₃S: C, 42.40; H, 4.63; N, 24.72. Found: C, 42.34;

H, 4.70; N, 24.64.

EXPERIMENTAL SECTION

■

General Procedures. All solvents were distilled prior to use; 95%

EtOH was used unless otherwise indicated. Petroleum ether had a

distillation range of 40−70 °C. Dry solvents (MeCN, THF, DMSO,

1,4-dioxane) were obtained according to standard procedures. p-

Toluenesulﬁnic acid (7) was synthesized by treatment of a saturated

aqueous solution of sodium p-toluenesulﬁnate³²with hydrochloric acid

at 0 °C, dried over P₂O₅, and stored at 0 °C. Sodium hydride (NaH)

(60% suspension in mineral oil) was thoroughly washed with dry

pentane and dried in a vacuum prior to use. NaN₃and KI were ﬁnely

powdered and dried in a vacuum desiccator over P₂O₅. All other

reagents were purchased from commercial sources and used without

additional puriﬁcation. IR spectra (in Nujol) were recorded using a

FT-IR spectrophotometer for crystallized compounds. Band character-

istics in IR spectra are deﬁned as very strong (vs), strong (s), medium

(m), weak (w), and shoulder (sh). ¹H and proton-decoupled ¹³C

NMR spectra (solutions in DMSO-d₆or CDCl₃) were acquired using

a 300 or 600 MHz spectrometer. ¹H NMR chemical shifts are

referenced to the residual proton signal in DMSO-d₆(2.50 ppm) or

CDCl₃(7.25 ppm). In ¹³C NMR spectra the DMSO-d₆signal (39.50

ppm) was used as a reference. Multiplicities are reported as singlet (s),

doublet (d), triplet (t), quartet (q), and some combinations of these,

multiplet (m). Selective ¹H−¹H decoupling, ¹H−¹H NOESY, and

DEPT-135 experiments were used to aid in the assignment of ¹H and

¹³C NMR signals. Thin-layer chromatography was carried out on silica

gel 60 F₂₅₄aluminum backed plates in chloroform/methanol (9:1, v/v)

and chloroform/methanol (5:1, v/v) as solvent systems. Spots were

visualized with iodine vapors or UV light. Column chromatography

was performed with silica gel 60 (0.04−0.063 mm). All yields refer to

isolated, spectroscopically and TLC pure compounds. The color of

substances was white, if not otherwise mentioned. Evaporation of

solvent from all the reaction mixtures formed after the reactions of

nucleophilic substitution and after one-pot syntheses of pyrroles (from

6) was carried out, at the beginning, upon cooling (temperature of

water bath about 5−10 °C) and low vacuum (about 100 mmHg),

otherwise the vigorous foaming complicated the evaporation. It is

important that pyrroles 17b,c left the column during puriﬁcation by

chromatography after POPh₃and contained the small amounts of

POPh₃(due to their close R_fvalues). To remove this impurity they

were recrystallized from EtOH. In the case of pyrrole 17a, which was

highly soluble in EtOH, the column was eluted with less polar system

(petroleum ether/CHCl₃, 1:1) until only the traces of POPh₃were

detected in the fractions (TLC). For pyrroles 17d,h the eluting system

was changed to petroleum ether/acetone and they left the column

before POPh₃(for 17a,b,c it did not work). Other puriﬁcations had no

diﬃculties.

N-[(2-Azido-1-tosyl)ethyl]-N′-methylurea (6b). Compound 6b

(29.43 g, 88%) was prepared from acetal 9a (17.97 g, 0.113 mol),

sulﬁnic acid 7 (17.63 g, 0.113 mol), N-methylurea (12.54 g, 0.169

mol), 80% HCOOH (56 mL), and H₂O (168 mL) (rt, 24 h) as

described for 6a. Mp 114.5 °C (decomp, MeCN); IR (Nujol) ν_max

3376 (s), 3286 (s), 3195 (m) (NH), 3088 (w), 3067 (w) (CH_arom),

2210 (w), 2147 (w), 2108 (s) (N₃), 1673 (s) (amide-I), 1595 (m)

(CC_arom), 1559 (br s), 1532 (m) (amide-II), 1492 (w) (CC_arom), 1293

(s), 1126 (s) (SO₂), 817 (m) (CH_arom) cm⁻¹; ¹H NMR (300.13 MHz,

DMSO-d₆) δ 7.67−7.73 (m, 2H, ArH), 7.41−7.47 (m, 2H, ArH), 7.12

(d, ³J = 10.3 Hz, 1H, NH), 6.02 (q, ³J = 4.7 Hz, 1H, NH), 5.18 (ddd,

³J = 10.3, ³J = 6.5, ³J = 5.4 Hz, 1H, CHN), 3.69−3.81 (m, 2H,

3

CH₂N₃), 2.43 (d, J = 4.7 Hz, 3H, NCH₃), 2.41 (s, 3H, CH₃in Ts);

¹³C NMR (75.48 MHz, DMSO-d₆) δ 156.4 (CO), 144.8 (C), 134.1

(C), 129.7 (2CH), 128.8 (2CH), 69.6 (CHN), 48.1 (CH₂N₃), 26.3

(NCH₃), 21.1 (CH₃in Ts). Anal. Calcd for C₁₁H₁₅N₅O₃S: C, 44.44;

H, 5.09; N, 23.55. Found: C, 44.50; H, 5.23; N, 23.44.

N-[(2-Azido-1-tosyl)propyl]urea (6c). To a freshly distilled 2-

azidopropanal dimethyl acetal (9b) (16.23 g, 0.112 mol) was added

80% formic acid (56 mL), the resulting solution was stirred in a water

bath (41 °C) for 4 h and cooled to room temperature, and p-

toluenesulﬁnic acid (7) (17.47 g, 0.112 mol) and H₂O (112 mL) were

added. The mixture was stirred for 30 min, and to the formed

suspension were added urea (33.58 g, 0.559 mol) and H₂O (56 mL).

The clear solution formed in 5 min followed by precipitation of a ﬁne

heavy solid. The suspension was stirred for 24 h and cooled to 0 °C,

the precipitate was ﬁltered, washed with ice-cold water (8 × 30 mL) so

that the smell of formic acid disappeared and petroleum ether, and

dried to give 6c (23.73 g, 71%) as a mixture of two diastereomers

(97:3), which was used without further puriﬁcation. Crystallization

from MeCN aﬀorded the pure major isomer. Mp 126.5 °C (decomp,

MeCN); IR (Nujol) ν_max3450 (s), 3369 (s), 3334 (sh), 3315 (br m),

3273 (m), 3215 (m) (NH), 3066 (w), 3044 (w), 3031 (w) (CH_arom),

2130 (s), 2101 (s), 2087 (s) (N₃), 1699 (s), 1666 (s) (amide-I), 1624

(w), 1599 (w) (CC_arom), 1525 (s) (amide-II), 1496 (w) (CC_arom),

1

1303 (s), 1146 (s) (SO₂), 812 (m) (CH_arom) cm⁻¹; H NMR of the

major diastereomer (300.13 MHz, DMSO-d₆) δ 7.68−7.74 (m, 2H,

ArH), 7.39−7.45 (m, 2H, ArH), 6.93 (d, ³J = 10.6 Hz, 1H, NH), 5.90

(s, 2H, NH₂), 5.02 (dd, ³J = 10.6, ³J = 2.0 Hz, 1H, CHN), 4.54 (dq, ³J

= 6.6, ³J = 2.0 Hz, 1H, CHN₃), 2.40 (s, 3H, CH₃in Ts), 1.21 (d, ³J =

6.6 Hz, 3H, CH₃); ¹H NMR the minor isomer (300.13 MHz, DMSO-

d₆) δ 7.23 (d, ³J = 10.8 Hz, 1H, NH), 5.82 (s, 2H, NH₂), 5.17 (dd, ³J =

3

10.8, J = 4.1 Hz, 1H, CHN), 4.14 (dq, J = 6.7, J = 4.1 Hz, 1H,

3

CHN₃), 2.40 (s, 3H, CH₃in Ts), 1.38 (d, J = 6.7 Hz, 3H, CH₃),

signals of other protons overlap with signals of analogous protons of

the major isomer; ¹³C NMR of the major diastereomer (75.48 MHz,

DMSO-d₆) δ 156.7 (CO), 144.5 (C), 134.8 (C), 129.6 (2CH),

128.7 (2CH), 71.9 (CHN), 54.8 (CHN₃), 21.1 (CH₃in Ts), 17.3

(CH₃). Anal. Calcd for C₁₁H₁₅N₅O₃S: C, 44.44; H, 5.09; N, 23.55.

Found: C, 44.44; H, 5.18; N, 23.45.

N-[(2-Azido-1-tosyl)butyl]urea (6d). To a freshly distilled 2-

azidobutanal dimethyl acetal (9c) (19.01 g, 0.119 mol) was added 80%

formic acid (60 mL), resulting yellow solution was stirred in water

bath (41 °C) for 4 h and cooled to room temperature, and p-

toluenesulﬁnic acid (7) (18.66 g, 0.119 mol) and H₂O (120 mL) were

added. The mixture was stirred for 20 min, and to the formed

suspension were added urea (35.85 g, 0.597 mol) and H₂O (60 mL).

After 5 min in the resulting clear solution formed a white oily

N-[(2-Azido-1-tosyl)ethyl]urea (6a). To a freshly distilled 2-

azidoethanal diethyl acetal (9a) (7.879 g, 49.49 mmol) was added 80%

formic acid (25 mL), the resulting colorless solution was stirred at

room temperature for 5 h 30 min, and then p-toluenesulﬁnic acid (7)

(7.737 g, 49.53 mmol) and H₂O (50 mL) were added. The mixture

was stirred for 10 min, and to the formed clear solution were added

urea (14.869 g, 247.57 mmol) and H₂O (25 mL). Urea dissolved in 5

min followed by precipitation of a ﬁne heavy solid. The suspension

was stirred for 21 h and cooled to 0 °C, and the precipitate was

ﬁltered, washed with ice-cold water (8 × 15 mL) so that the smell of

formic acid disappeared and petroleum ether, and dried to give 6a

(12.096 g, 86%), which was used without further puriﬁcation. Mp 125

°C (decomp, MeCN); IR (Nujol) ν_max3458 (s), 3369 (s), 3358 (s),

G

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The Journal of Organic Chemistry

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precipitate. After 1 h the precipitate was triturated until the ﬁne solid

was obtained. The suspension was stirred for 23 h and cooled to 0 °C,

and the precipitate was ﬁltered, washed with ice-cold water (8 × 30

mL) so that the smell of formic acid disappeared and petroleum ether,

and dried to give 6d (29.64 g, 80%) as a mixture of two diastereomers

(90:10), which was used without further puriﬁcation. After

crystallization from MeCN the diastereomeric ratio changed to 94:6.

Mp 125.5 °C (decomp, MeCN); IR (Nujol) ν_max3450 (s), 3365 (br

s), 3277 (m), 3219 (m) (NH), 3096 (w), 3071 (w), 3052 (w), 3029

(w) (CH_arom), 2107 (s) (N₃), 1698 (s), 1666 (s) (amide-I), 1621 (m),

1599 (m) (CC_arom), 1520 (s) (amide-II), 1307 (s), 1144 (s) (SO₂),

NaH (0.084 g, 3.52 mmol) was added dry MeCN (7 mL), the mixture

was stirred in an ice-cold bath for 15 min, and to the resulting solution

were added sulfone 6a (0.992 g, 3.50 mmol) and MeCN (4 mL). The

suspension was stirred at room temperature for 8 h, and solvent was

removed in a vacuum. To a solid residue were added saturated aq

NaHCO₃(2 mL) and petroleum ether (10 mL), the obtained mixture

was triturated until complete crystallization, and the resulting

suspension was left overnight at room temperature and cooled to 0

°C. The precipitate was ﬁltered and washed with ice-cold water and

petroleum ether. The obtained solid was dried in a vacuum desiccator

(over P₂O₅) on the ﬁlter, cooled (−10 °C), washed with cold (−10

°C) diethyl ether (3 × 4 mL), and dried to give 12a (0.839 g, 74%) as

a mixture of two diastereomers (65:35). After crystallization from

EtOH the diastereomeric ratio did not change. Mp 121−121.5 °C

(decomp, EtOH); IR (Nujol) ν_max3444 (br s), 3371 (s), 3315 (sh),

3218 (br m) (NH), 3069 (w) (CH_arom), 2198 (m), 2163 (m), 2098

(vs) (N₃), 1712 (s) (CO), 1664 (s) (amide-I), 1610 (m) (CC_arom),

1542 (br s) (amide-II), 1300 (s), 1145 (s) (SO₂), 741 (s), 687 (s)

1

810 (m) (CH_arom) cm⁻¹; H NMR the major isomer (300.13 MHz,

DMSO-d₆) δ 7.69−7.75 (m, 2H, ArH), 7.40−7.46 (m, 2H, ArH), 6.94

(d, ³J = 10.6 Hz, 1H, NH), 5.89 (s, 2H, NH₂), 5.06 (dd, ³J = 10.6, ³J =

1.7 Hz, 1H, CHN), 4.30 (dt, ³J = 7.1, ³J = 1.7 Hz, 1H, CHN₃), 2.40 (s,

3

3H, CH₃in Ts), 1.43−1.58 (m, 2H, CH₂), 0.94 (t, J = 7.4 Hz, 3H,

1

CH₃in Et); H NMR the minor isomer (300.13 MHz, DMSO-d₆) δ

7.21 (d, ³J = 10.8 Hz, 1H, NH), 5.81 (s, 2H, NH₂), 5.15 (dd, ³J = 10.8,

³J = 5.5 Hz, 1H, CHN), 3.88 (ddd, ³J = 10.1, ³J = 5.5, ³J = 3.3 Hz, 1H,

CHN₃), 2.40 (s, 3H, CH₃in Ts), 0.98 (t, ³J = 7.4 Hz, 3H, CH₃in Et),

signals of other protons overlap with signals of analogous protons of

the major isomer; ¹³C NMR of the major isomer (75.48 MHz, DMSO-

d₆) δ 156.5 (CO), 144.5 (C), 134.6 (C), 129.6 (2CH), 128.7

(2CH), 70.6 (CHN), 60.8 (CHN₃), 25.2 (CH₂), 21.1 (CH₃in Ts),

10.0 (CH₃). Anal. Calcd for C₁₂H₁₇N₅O₃S: C, 46.29; H, 5.50; N,

22.49. Found: C, 46.32; H, 5.69; N, 22.47.

1

(CH_arom) cm⁻¹; H NMR of the major diastereomer (300.13 MHz,

DMSO-d₆) δ 7.60−7.90 (m, 5H, ArH), 6.26 (d, ³J = 9.1 Hz, 1H, NH),

3

5.76 (s, 2H, NH₂), 4.87 (d, ³J = 7.6 Hz, 1H, CHSO₂), 4.47 (ddt, J =

3

9.1, J = 7.6, J = 5.1 Hz, 1H, CHN), 3.50 (d, J = 5.1 Hz, 2H,

1

CH₂N₃), 2.20 (s, 3H, CH₃); H NMR of the minor diastereomer

(300.13 MHz, DMSO-d₆) δ 7.60−7.90 (m, 5H, ArH), 6.26 (d, ³J = 8.6

3

Hz, 1H, NH), 5.64 (s, 2H, NH₂), 4.99 (d, J = 7.7 Hz, 1H, CHSO₂),

3

4.23 (dddd, J = 8.6, J = 7.7, J = 7.2, J = 4.5 Hz, 1H, CHN), 3.44

2

3

2

3

2-Azidoethanal Diethyl Acetal (9a).³³Acetal 9a (42.33 g, 85%)

was prepared from 2-bromoethanal diethyl acetal (10a)³⁴(61.39 g,

0.311 mol), NaN₃(30.39 g, 0.475 mol), and KI (5.17 g, 0.031 mol) in

DMSO (232 mL) (90 °C, 88.5 h) as described for 9c. Bp 74.5−76.5

°C/20 mmHg; ¹H NMR (300.13 MHz, CDCl3) δ 4.58 (t, ³J = 5.3 Hz,

1H, CHO), 3.71 (dq, ²J = 9.2, ³J = 7.1 Hz, 2H, OCH₂), 3.57 (dq, ²J =

(dd, J = 12.8, J = 7.2 Hz, 1H, CH_AN₃), 3.38 (dd, J = 12.8, J = 4.5

Hz, 1H, CH_BN₃), 2.27 (s, 3H, CH₃); ¹³C NMR of the major

diastereomer (75.48 MHz, DMSO-d₆) δ 199.5 (CO), 157.29

(CONH), 137.6 (C), 134.7 (CH), 129.5 (2CH), 128.67 (2CH), 73.9

(CHSO₂), 53.5 (CH₂N₃), 48.2 (CHN), 31.6 (CH₃); ¹³C NMR of the

minor diastereomer (75.48 MHz, DMSO-d₆) δ 199.5 (CO), 157.34

(CONH), 138.3 (C), 134.4 (CH), 129.3 (2CH), 128.64 (2CH), 74.2

(CHSO₂), 52.4 (CH₂N₃), 48.8 (CHN), 32.7 (CH₃). Anal. Calcd for

C₁₂H₁₅N₅O₄S: C, 44.30; H, 4.65; N, 21.53. Found: C, 44.10; H, 4.68;

N, 21.62.

3

9.2, J = 7.1 Hz, 2H, OCH₂), 3.23 (d, J = 5.4 Hz, 2H, CH₂N₃), 1.22

3

(t, J = 7.1 Hz, 6H, CH₃in OEt).

2-Azidopropanal Dimethyl Acetal (9b).³⁵Acetal 9b (24.48 g,

75%) was prepared from 2-bromopropanal dimethyl acetal (10b)³⁶

(41.14 g, 0.225 mol), NaN₃(21.93 g, 0.337 mol), and KI (3.80 g,

0.023 mol) in DMSO (170 mL) (90 °C, 64 h) as described for 9c. Bp

60.5−62.5 °C/20 mmHg; ¹H NMR (300.13 MHz, CDCl₃) δ 4.14 (d,

6-(Azidomethyl)-4-hydroxy-4-methyl-5-tosylhexahydropyri-

midin-2-one (13b). Compound 13b (2.720 g, 84%) as a mixture of

(4R*,5R*,6R*)- and (4R*,5S*,6S*)-diastereomers (90:10) was

prepared from tosylacetone (11b) (2.051 g, 9.66 mmol), NaH

(0.230 g, 9.57 mmol), and sulfone 6a (2.699 g, 9.53 mmol) in dry

MeCN (19 mL) (8 h, rt) as described for 12a. After crystallization

from EtOH, the major isomer was obtained. Mp 119.5−120 °C

(decomp, EtOH); IR of the major isomer (Nujol) ν_max3324 (s), 3298

(s), 3246 (m) (NH, OH), 3100 (w), 3060 (w), 3033 (w) (CH_arom),

2110 (s) (N₃), 1703 (s), 1656 (s) (amide-I), 1598 (m) (CC_arom), 1491

(s) (amide-II), 1301 (s), 1156 (s) (SO₂), 813 (m) (CH_arom) cm⁻¹; ¹H

NMR of the major isomer (300.13 MHz, DMSO-d₆) δ 7.76−7.81 (m,

2H, ArH), 7.40−7.45 (m, 2H, ArH), 7.02 (d, ⁴J = 2.1 Hz, 1H, N₍₃₎H),

³J = 5.8 Hz, 1H, CHO), 3.47 (dq, J = 5.8, J = 6.8 Hz, 1H, CHN₃),

3

3.43 (s, 3H, OCH₃), 3.40 (s, 3H, OCH₃), 1.18 (d, J = 6.8 Hz, 3H,

CH₃).

2-Azidobutanal Dimethyl Acetal (9c). To a stirred solution of

freshly distilled 2-bromobutanal dimethyl acetal (10c)³⁶(56.22 g,

0.285 mol) in dry DMSO (215 mL) were added NaN₃(27.83 g, 0.428

mol) and KI (4.754 g, 0.029 mol), and the suspension was heated in

an oil bath (90 °C) for 46 h. After 3 h from beginning of heating a

dark solution formed. The progress of the reaction was monitored by

¹H NMR spectroscopy. After the reaction was complete the obtained

black solution was cooled to room temperature. The resulting solid

was dissolved in H₂O (325 mL), the solution was extracted with

diethyl ether (250 mL, 2 × 200 mL, 2 × 150 mL), and the combined

extracts were washed with brine (3 × 50 mL) and dried over Na₂SO₄

(transparent yellow liquid). After the solvent was removed in a vacuum

the residue was distilled to give 9c (29.12 g, 64%) as a colorless liquid.

4

3

4

6.69 (dd, J = 2.1, J = 1.0 Hz, 1H, N₍₁₎H), 5.98 (d, J = 1.3 Hz, 1H,

3

OH), 3.77 (dddd, J = 9.7, J = 3.3, J = 2.6, J = 1.0 Hz, 1H, H-6),

3.62 (dd, ²J = 13.0, ³J = 2.6 Hz, 1H, CH_AN₃), 3.57 (dd, ²J = 13.0, ³J =

3.3 Hz, 1H, CH_BN₃), 3.53 (dd, ³J = 9.7, ⁴J = 1.3 Hz, 1H, H-5), 2.40 (s,

1

3H, CH₃in Ts), 1.66 (s, 3H, 4-CH₃); H NMR of the minor isomer

(300.13 MHz, DMSO-d₆) δ 7.74−7.81 (m, 2H, ArH), 7.42−7.50 (m,

4

3

2H, ArH), 7.18 (dd, J = 1.8, J = 0.8 Hz, 1H, N₍₃₎H), 6.74 (dd, J =

4.6, ⁴J = 1.8 Hz, 1H, N₍₁₎H), 5.99 (s, 1H, OH), 3.74 (ddt, ³J = 7.2, ³J =

4.6, ³J = 0.8 Hz, 1H, H-6), 3.63 (unresolved m, half-height width =2.7

Hz, 1H, H-5), 3.56 (d, ³J = 7.2 Hz, 2H, CH₂N₃), 2.41 (s, 3H, CH₃in

Ts), 1.57 (s, 3H, 4-CH₃); ¹³C NMR of the major isomer (75.48 MHz,

DMSO-d₆) δ 154.2 (C-2), 144.4 (C), 136.7 (C), 129.4 (2CH), 129.1

(2CH), 79.4 (C-4), 67.0 (C-5), 53.1 (CH₂N₃), 49.0 (C-6), 27.9 (4-

CH₃), 21.0 (CH₃in Ts). ¹³C NMR of the minor isomer (75.48 MHz,

DMSO-d₆) δ 153.0 (C-2), 144.5 (C), 135.8 (C), 129.8 (2CH), 128.2

(2CH), 79.1 (C-4), 64.0 (C-5), 55.6 (CH₂N₃), 49.3 (C-6), 28.2 (4-

CH₃), 21.1 (CH₃in Ts). Anal. Calcd for C₁₃H₁₇N₅O₄S: C, 46.01; H,

5.05; N, 20.64. Found: C, 46.07; H, 5.27; N, 20.41.

Bp 71−72.5 °C/20 mmHg; n²⁰1.4321; IR (ﬁlm) ν_max2969 (m),

D

2938 (m), 2881 (m), 2835 (m) (CH₃, CH₂, CH), 2160 (sh), 2107 (s)

(N₃), 1464 (m) (CH₃, CH₂), 1380 (m) (CH₃), 1104 (s), 1080 (s),

1063 (s) (C−O) cm⁻¹; ¹H NMR (300.13 MHz, DMSO-d₆) δ 4.29 (d,

³J = 5.9 Hz, 1H, CHO), 3.41 (ddd, ³J = 9.4, ³J = 5.9, ³J = 3.6 Hz, 1H,

2

CHN₃), 3.38 (s, 3H, OCH₃), 3.35 (s, 3H, OCH₃), 1.58 (ddq, J =

14.2, ³J = 7.4, ³J = 3.6 Hz, 1H, CH_Ain CH₂), 1.34 (ddq, ²J = 14.2, ³J =

9.4, ³J = 7.4 Hz, 1H, CH_Bin CH₂), 0.93 (t, ³J = 7.5 Hz, 3H, CH₃); ¹³

C

NMR (75.48 MHz, DMSO-d₆) δ 105.5 (CHO), 63.8 (CHN₃), 54.8

(OCH₃), 54.4 (OCH₃), 22.0 (CH₂), 10.1 (CH₃in Et). Anal. Calcd for

C₆H₁₃N₃O₂: C, 45.27; H, 8.23; N, 26.40. Found: C, 44.80; H, 8.03; N,

26.76.³⁷

N-[(1-Azido-4-oxo-3-phenylsulfonyl)but-2-yl]urea (12a). To

a mixture of phenylsulfonylacetone (11a) (0.710 g, 3.58 mmol) and

N-[(1-Azido-4-oxo-3-tosyl)pent-2-yl]-N′-methylurea (12c).

Compound 12c (1.020 g, 84%) as a mixture of two diastereomers

(63:37) was prepared from tosylacetone (11b) (0.738 g, 3.48 mmol),

H

dx.doi.org/10.1021/jo302724y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

NaH (0.082 g, 3.43 mmol), and sulfone 6b (1.020 g, 3.43 mmol) in

dry MeCN (12 mL) (8 h, rt) as described for 12a. After two

crystallizations from EtOAc/petroleum ether (1:1) the diastereomeric

ratio did not change. Mp 119−119.5 °C (decomp, EtOAc/petroleum

ether, 1:1); IR (Nujol) ν_max3403 (s), 3342 (br s), ∼3301 (sh) (NH),

2113 (s), 2093 (s) (N₃), 1717 (s) (CO), 1667 (s), 1639 (s) (amide-

I), 1595 (w) (CC_arom), 1562 (s) (amide-II), 1508 (m) (CC_arom), 1319

(CH₃in Ts), 14.3 (CH₃). Anal. Calcd for C₁₄H₁₉N₅O₄S: C, 47.58; H,

5.42; N, 19.82. Found: C, 47.35; H, 5.52; N, 19.45.

Analogously, compound 12d was prepared in MeCN as a mixture of

four diastereomers (62:21:13:4) in 60% yield. In this case vigorous

foaming occurred during evaporation of the solvent from the reaction

mixture formed after completion of the reaction making the workup

diﬃcult.

1

(s), 1144 (s) (SO₂), 817 (m) (CH_arom) cm⁻¹; H NMR of the major

N-[(5-Azido-2-oxo-3-tosyl)hept-4-yl]urea (12e). Compound

12e (1.400 g, 71%) as a mixture of four diastereomers (69:19:9:3)

was prepared from tosylacetone (11b) (1.154 g, 5.43 mmol), NaH

(0.129 g, 5.38 mmol), and sulfone 6d (1.673 g, 5.37 mmol) in dry

MeCN (17 mL) (8 h, rt) as described for 12a. After crystallization

from EtOH the diastereomeric ratio changed to 78:21:1:0. Mp 131.5−

132 °C (decomp, EtOH); IR (Nujol) ν_max3468 (s), 3378 (m), 3357

(br s), 3215 (br m), 3203 (sh) (NH), 3062 (w), 3049 (w) (CH_arom),

2111 (br vs) (N₃), 1716 (s) (CO), 1665 (vs) (amide-I), 1613 (m),

1597 (m) (CC_arom), 1541 (vs) (amide-II), 1495 (w) (CC_arom), 1320

diastereomer (300.13 MHz, DMSO-d₆) δ 7.70−7.75 (m, 2H, ArH),

7.44−7.49 (m, 2H, ArH), 6.18 (d, ³J = 9.2 Hz, 1H, NH), 6.08 (q, ³J =

3

4.6 Hz, 1H, NH), 4.82 (d, J = 7.4 Hz, 1H, CHSO₂), 4.48 (ddt, J =

3

9.2, J = 7.4, J = 5.0 Hz, 1H, CHN), 3.49 (d, J = 5.0 Hz, 2H,

3

CH₂N₃), 2.50 (d, J = 4.6 Hz, 3H, NCH₃), 2.42 (s, 3H, CH₃in Ts),

2.20 (s, 3H, CH₃in Ac); ¹H NMR of the minor diastereomer (300.13

MHz, DMSO-d₆) δ 7.68−7.73 (m, 2H, ArH), 7.41−7.46 (m, 2H,

3

ArH), 6.21 (d, J = 8.5 Hz, 1H, NH), 5.82 (q, J = 4.7 Hz, 1H, NH),

3

4.99 (d, J = 7.9 Hz, 1H, CHSO₂), 4.19 (dddd, J = 8.5, J = 7.9, J =

7.7, ³J = 4.1 Hz, 1H, CHN), 3.45 (dd, ²J = 12.7, ³J = 7.7 Hz, 1H, H_Ain

CH₂N₃), 3.34 (dd, ²J = 12.7, ³J = 4.1 Hz, 1H, H_Bin CH₂N₃), 2.44 (d,

³J = 4.7 Hz, 3H, NCH₃), 2.42 (s, 3H, CH₃in Ts), 2.28 (s, 3H, CH₃in

Ac); ¹³C NMR of the major diastereomer (75.48 MHz, DMSO-d₆) δ

199.7 (CO), 157.1 (CONH), 145.4 (C), 134.7 (C), 129.9 (2CH),

128.72 (2CH), 73.9 (CHSO₂), 53.5 (CH₂N₃), 48.4 (CHN), 31.7

(CH₃in Ac), 26.21 (NCH₃), 21.12 (CH₃in Ts); ¹³C NMR of the

minor diastereomer (75.48 MHz, DMSO-d₆) δ 199.6 (CO), 157.1

(CONH), 144.9 (C), 135.5 (C), 129.6 (2CH), 128.66 (2CH), 74.2

(CHSO₂), 52.2 (CH₂N₃), 49.1 (CHN), 32.8 (CH₃in Ac), 26.14

(NCH₃), 21.11 (CH₃in Ts). Anal. Calcd for C₁₄H₁₉N₅O₄S: C, 47.58;

H, 5.42; N, 19.82. Found: C, 47.55; H, 5.57; N, 19.87.

1

(s), 1144 (s) (SO₂), 818 (m) (CH_arom) cm⁻¹; H NMR of the major

diastereomer (300.13 MHz, DMSO-d₆) δ 7.74−7.79 (m, 2H, ArH),

7.44−7.50 (m, 2H, ArH), 6.08 (d, ³J = 9.6 Hz, 1H, NH), 5.70 (s, 2H,

NH₂), 4.69 (d, ³J = 8.3 Hz, 1H, CHSO₂), 4.62 (ddd, ³J = 9.6, ³J = 8.3,

³J = 1.8 Hz, 1H, CHN), 3.71 (dt, J = 7.0, J = 1.8 Hz, 1H, CHN₃),

2.42 (s, 3H, CH₃in Ts), 2.18 (s, 3H, CH₃in Ac), 1.39−1.62 (m, 2H,

CH₂, signals overlap with signals of the CH₂protons of the minor

3

1

isomer), 0.94 (t, J = 7.3 Hz, 3H, CH₃); H NMR of the ﬁrst minor

diastereomer (19%) (300.13 MHz, DMSO-d₆) δ 7.69−7.74 (m, 2H,

3

ArH), 7.38−7.44 (m, 2H, ArH), 5.90 (d, J = 9.9 Hz, 1H, NH), 5.58

(s, 2H, NH₂), 4.76 (d, ³J = 9.2 Hz, 1H, CHSO₂), 4.48 (ddd, ³J = 9.9, ³J

3

= 9.2, J = 2.1 Hz, 1H, CHN), 3.28−3.35 (m, 1H, CHN₃, signals

N-[(2-Azido-5-oxo-4-tosyl)hex-3-yl]urea (12d). Compound

12d (1.178 g, 61%) as a mixture of four diastereomers (62:20:14:4)

was prepared from tosylacetone (11b) (1.182 g, 5.57 mmol), NaH

(0.132 g, 5.49 mmol), and sulfone 6c (1.632 g, 5.49 mmol) in dry

THF (17 mL) (8 h, rt) as described for 12a. After crystallization from

EtOH the diastereomeric ratio changed to 71:23:4:2. Mp 107−110.5

°C (decomp, EtOH); IR (Nujol) ν_max3483 (s), 3379 (br s), 3330 (br

s), 3204 (m) (NH), 3055 (w) (CH_arom), 2125 (vs), 2092 (s) (N₃),

1720 (s) (CO), 1677 (s), 1664 (s) (amide-I), 1607 (m), 1597 (m)

(CC_arom), 1544 (s) (amide-II), 1493 (w) (CC_arom), 1320 (s), 1143 (s)

overlap with HOD signal), 2.41 (s, 3H, CH₃in Ts), 2.34 (s, 3H, CH₃

in Ac), 1.39−1.62 (m, 2H, CH₂, signals overlap with signals of the

CH₂protons of the major isomer), 0.89 (t, ³J = 7.4 Hz, 3H, CH₃); ¹H

NMR of the second minor diastereomer (9%) (300.13 MHz, DMSO-

3

d₆) δ 6.22 (d, J = 9.2 Hz, 1H, NH), 5.79 (s, 2H, NH₂), 4.81 (d, ³J =

5.2 Hz, 1H, CHSO₂), 2.31 (s, 3H, CH₃in Ac), 0.83 (t, ³J = 7.4 Hz, 3H,

CH₃), signals of other protons overlap with proton signals of the other

isomers; ¹H NMR of the third minor diastereomer (3%) (300.13

3

MHz, DMSO-d₆) δ 5.65 (s, 2H, NH₂), 5.01 (d, J = 8.6 Hz, 1H,

CHSO₂), 2.25 (s, 3H, CH₃in Ac), signals of other protons overlap

with proton signals of the other isomers; ¹³C NMR of the major

diastereomer (75.48 MHz, DMSO-d₆) δ 199.2 (CO), 157.5

(CONH), 145.4 (C), 134.8 (C), 129.9 (2CH), 128.7 (2CH), 74.8

(CHSO₂), 65.8 (CHN₃), 49.4 (CHNH), 31.2 (CH₃in Ac), 23.8

(CH₂), 21.1 (CH₃in Ts), 10.4 (CH₃); ¹³C NMR of the ﬁrst minor

diastereomer (19%) (75.48 MHz, DMSO-d₆) δ 200.2 (CO), 157.4

(CONH), 144.7 (C), 135.7 (C), 129.5 (2CH), 128.8 (2CH), 75.4

(CHSO₂), 64.9 (CHN₃), 49.7 (CHNH), 32.7 (CH₃in Ac), 23.5

(CH₂), 21.1 (CH₃in Ts), 10.3 (CH₃). Anal. Calcd for C₁₅H₂₁N₅O₄S:

C, 49.03; H, 5.76; N, 19.06. Found: C, 48.80; H, 5.92; N, 18.90.

N-[(1-Azido-4-oxo-4-phenyl-3-phenylsulfonyl)but-2-yl]urea

(12f). To a mixture of phenylsulfonylacetophenone (11c) (2.084 g,

8.00 mmol) and NaH (0.189 g, 7.89 mmol) was added dry THF (22

mL), the mixture was stirred at room temperature for 13 min, and to

the resulting dense suspension were added sulfone 6a (2.222 g, 7.84

mmol) and THF (3 mL). The suspension was stirred at room

temperature for 8 h, and solvent was removed in a vacuum. To a solid

residue was added saturated aq NaHCO₃(10 mL), the obtained

mixture was triturated until complete crystallization, and the resulting

suspension was left overnight at room temperature and cooled to 0 °C.

The precipitate was ﬁltered and washed with ice-cold water and

petroleum ether. The obtained slightly yellow solid was dried in a

vacuum desiccator (over P₂O₅) on the ﬁlter, cooled (−10 °C), washed

with cold (−10 °C) diethyl ether (3 × 10 mL), and dried to give 12f

(2.787 g, 92%) as a mixture of two diastereomers (55:45). After

crystallization from EtOH the diastereomeric ratio did not change. Mp

149.5 °C (decomp, EtOH); IR (Nujol) ν_max3448 (m), 3427 (m),

3363 (s), 3225 (br m) (NH), 3066 (w) (CH_arom), 2188 (w), 2160

(w), 2099 (vs) (N₃), 1672 (vs), 1663 (sh) (CO and amide-I), 1609

(w), 1595 (m), 1583 (w) (CC_arom), 1541 (br s), 1521 (sh) (amide-II),

1301 (s), 1144 (s) (SO₂), 750 (m), 739 (s), 682 (s) (CH_arom) cm⁻¹;

1

(SO₂), 817 (m) (CH_arom) cm⁻¹; H NMR of the major diastereomer

(300.13 MHz, DMSO-d₆) δ 7.73−7.78 (m, 2H, ArH), 7.43−7.49 (m,

2H, ArH), 6.10 (d, ³J = 9.8 Hz, 1H, NH), 5.73 (s, 2H, NH₂), 4.67 (d,

³J = 7.8 Hz, 1H, CHSO₂), 4.50 (ddd, ³J = 9.8, ³J = 7.8, ³J = 2.3 Hz, 1H,

CHN), 3.99 (dq, ³J = 6.5, ³J = 2.3 Hz, 1H, CHN₃), 2.42 (s, 3H, CH₃₁in

3

Ts), 2.19 (s, 3H, CH₃in Ac), 1.14 (d, J = 6.5 Hz, 3H, CH₃); H

NMR of the ﬁrst minor diastereomer (20%) (300.13 MHz, DMSO-d₆)

3

δ 7.66−7.72 (m, 2H, ArH), 7.38−7.43 (m, 2H, ArH), 5.92 (d, J =

3

10.0 Hz, 1H, NH), 5.59 (s, 2H, NH₂), 4.70 (d, J = 9.7 Hz, 1H,

3

CHSO₂), 4.35 (ddd, J = 10.0, J = 9.7, J = 2.5 Hz, 1H, CHN), 3.59

3

(dq, J = 6.5, J = 2.5 Hz, 1H, CHN₃), 2.41 (s, 3H, CH₃in Ts), 2.35

3

1

(s, 3H, CH₃in Ac), 1.11 (d, J = 6.5 Hz, 3H, CH₃); H NMR of the

second minor diastereomer (14%) (300.13 MHz, DMSO-d₆) δ 6.21

(d, ³J = 9.4 Hz, 1H, NH), 5.77 (s, 2H, NH₂), 4.80 (d, ³J = 5.8 Hz, 1H,

3

CHSO₂), 4.43 (ddd, J = 9.4, J = 5.8, J = 5.0 Hz, 1H, CHN), 3.65

(dq, ³J = 6.5, ³J = 5.0 Hz, 1H, CHN₃), 2.29 (s, 3H, CH₃in Ac), signals

1

of other protons overlap with proton signals of the other isomers; H

NMR of the third minor diastereomer (4%) (300.13 MHz, DMSO-d₆)

3

δ 5.65 (s, 2H, NH₂), 4.93 (d, J = 8.8 Hz, 1H, CHSO₂), 2.28 (s, 3H,

CH₃in Ac), signals of other protons overlap with proton signals of the

other isomers; ¹³C NMR of the major diastereomer (75.48 MHz,

DMSO-d₆) δ 199.3 (CO), 157.7 (CONH), 145.4 (C), 134.8 (C),

129.9 (2CH), 128.7 (2CH), 74.6 (CHSO₂), 59.31 (CHN₃), 51.2

(CHNH), 31.3 (CH₃in Ac), 21.1 (CH₃in Ts), 15.6 (CH₃); ¹³C NMR

of the ﬁrst minor diastereomer (20%) (75.48 MHz, DMSO-d₆) δ

200.1 (CO), 157.6 (CONH), 144.7 (C), 135.5 (C), 129.5 (2CH),

128.9 (2CH), 75.2 (CHSO₂), 58.4 (CHN₃), 51.2 (CHNH), 32.7

(CH₃in Ac), 21.1 (CH₃in Ts), 15.2 (CH₃); ¹³C NMR of the second

minor diastereomer (14%) (75.48 MHz, DMSO-d₆) δ 200.4 (CO),

157.4 (CONH), 145.3 (C), 134.6 (C), 129.8 (2CH), 128.8 (2CH),

72.1 (CHSO₂), 59.25 (CHN₃), 51.9 (CHNH), 32.3 (CH₃in Ac), 21.1

I

dx.doi.org/10.1021/jo302724y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

¹H NMR of the major diastereomer (300.13 MHz, DMSO-d₆) δ 7.43−

diastereomer (32%) (300.13 MHz, DMSO-d₆) δ 7.31−8.02 (m, 9H,

ArH, signals overlap with signals of the aromatic protons of other

isomers), 6.09 (d, ³J = 9.5 Hz, 1H, NH), 5.74 (s, 2H, NH₂), 5.72 (d, ³J

3

7.94 (m, 10H, ArH), 6.35 (d, J = 8.6 Hz, 1H, NH), 5.94 (d, J = 6.0

Hz, 1H, CHSO₂), 5.78 (s, 2H, NH₂), 4.62 (dddd, ³J = 8.6, ³J = 6.0, ³J

3

= 5.2 Hz, 1H, CHSO₂), 4.69 (ddd, ³J = 9.5, J = 5.2, ³J = 2.4 Hz, 1H,

3

2

3

= 6.0, J = 4.5 Hz, 1H, CHN), 3.58 (dd, J = 12.6, J = 6.0 Hz, 1H,

CHN), 4.04 (dq, ³J = 6.5, ³J = 2.4 Hz, 1H, CHN₃), 2.36 (s, 3H, CH₃in

2

3

1

CH_AN₃), 3.54 (dd, J = 12.6, J = 4.5 Hz, 1H, CH_BN₃); H NMR of

the minor diastereomer (300.13 MHz, DMSO-d₆) δ 7.43−7.94 (m,

3

1

Ts), 1.13 (d, J = 6.5 Hz, 3H, CH₃); H NMR of the second minor

diastereomer (20%) (300.13 MHz, DMSO-d₆) δ 7.31−8.02 (m, 9H,

ArH, signals overlap with signals of the aromatic protons of other

isomers), 6.09 (d, ³J = 9.5 Hz, 1H, NH), 5.68 (s, 2H, NH₂), 5.60 (d, ³J

3

10H, ArH), 6.32 (d, J = 8.3 Hz, 1H, NH), 5.93 (d, J = 8.2 Hz, 1H,

CHSO₂), 5.73 (s, 2H, NH₂), 4.42 (dddd, ³J = 8.3, ³J = 8.2, ³J = 6.6, ³J

2

3

= 4.5 Hz, 1H, CHN), 3.46 (dd, J = 12.9, J = 4.5 Hz, 1H, CH_AN₃),

3.42 (dd, ²J = 12.9, ³J = 6.6 Hz, 1H, CH_BN₃); ¹³C NMR of the major

diastereomer (75.48 MHz, DMSO-d₆) δ 192.3 (CO in Bz), 157.5

(CONH), 137.5 (C), 136.74 (C), 134.51 (CH), 134.2 (CH), 129.20

(2CH), 129.1 (2CH), 128.8 (2CH), 128.75 (2CH), 67.8 (CHSO₂),

53.5 (CH₂N₃), 49.5 (CHN); ¹³C NMR of the minor diastereomer

(75.48 MHz, DMSO-d₆) δ 191.7 (CO in Bz), 157.5 (CONH),

138.0 (C), 136.70 (C), 134.45 (CH), 134.4 (CH), 129.23 (2CH),

129.0 (4CH), 128.76 (2CH), 69.0 (CHSO₂), 52.5 (CH₂N₃), 49.8

(CHN). Anal. Calcd for C₁₇H₁₇N₅O₄S: C 52.71; H, 4.42; N, 18.08.

Found: C, 52.54; H, 4.55; N, 17.98.

3

= 9.7 Hz, 1H, CHSO₂), 4.53 (ddd, ³J = 9.7, J = 9.5, ³J = 2.4 Hz, 1H,

CHN), 3.50 (dq, ³J = 6.4, ³J = 2.4 Hz, 1H, CHN₃), 2.38 (s, 3H, CH₃in

3

1

Ts), 1.10 (d, J = 6.4 Hz, 3H, CH₃); H NMR of the third minor

diastereomer (13%) (300.13 MHz, DMSO-d₆) δ 5.84 (d, ³J = 9.3 Hz,

1H, CHSO₂), 5.76 (s, 2H, NH₂), 1.07 (d, J = 6.6 Hz, 3H, CH₃),

3

signals of other protons overlap with signals of analogous protons of

other isomers; ¹³C NMR of the diastereomeric mixture (34:35:22:9)

(75.48 MHz, DMSO-d₆) (shown only the nonaromatic carbon signals)

δ 199.7, 192.21, 192.20, 190.8 (CO), 157.8, 157.7, 157.4 (CONH),

70.3, 69.4, 68.1, 66.3 (CHSO₂), 60.0, 59.6, 58.8, 58.5 (CHN₃), 53.1,

52.9, 52.5, 52.3 (CHNH), 21.10, 21.08, 21.07 (CH₃in Ts), 15.7,

15.22, 15.21, 15.1 (CH₃). Anal. Calcd for C₁₉H₂₁N₅O₄S: C, 54.93; H,

5.09; N, 16.86. Found: C, 54.80; H, 5.21; N, 16.65.

N-[(1-Azido-4-oxo-4-phenyl-3-tosyl)but-2-yl]urea (12g).

Compound 12g (2.437 g, 96%) as a mixture of two diastereomers

(60:40) was prepared from tosylacetophenone (11d) (1.767 g, 6.44

mmol), NaH (0.153 g, 6.38 mmol), and sulfone 6a (1.790 g, 6.31

mmol) in dry THF (25 mL) (8 h, rt) as described for 12f. After

crystallization from MeCN the diastereomeric ratio did not change.

Mp 172 °C (decomp, MeCN); IR (Nujol) ν_max3446 (s), 3369 (s),

3348 (sh), 3211 (br m) (NH), 3062 (w) (CH_arom), 2193 (w), 2166

(w), 2099 (s) (N₃), 1670 (s) (CO), 1641 (s) (amide-I), 1608 (m),

1598 (m) (CC_arom), 1541 (s) (amide-II), 1296 (m), 1143 (s) (SO₂),

N-[(4-Azido-1-oxo-1-phenyl-2-tosyl)hex-3-yl]urea (12i).

Compound 12i (2.581 g, 98%) as a mixture of four diastereomers

(46:26:20:8) was prepared from tosylacetophenone (11d) (1.699 g,

6.19 mmol), NaH (0.147 g, 6.14 mmol), and sulfone 6d (1.909 g, 6.13

mmol) in dry MeCN (20 mL) (8 h, rt) as described for 12f. No

washings of the crude product with diethyl ether were carried out

(after addition of diethyl ether to the dried solid, it partially dissolved

and turned into an oily substance). After crystallization from MeCN

the diastereomeric ratio changed to 57:43:0:0, respectively. Mp 100−

105 °C (MeCN); IR (Nujol) ν_max3449 (s), 3399 (m), 3384 (m), 3313

(m), 3234 (m), 3201 (br s) (NH), 3043 (w), 3025 (w) (CH_arom),

2099 (s) (N₃), 1672 (vs) (CO and amide-I), 1619 (m), 1596 (m),

1580 (w) (CC_arom), 1524 (s) (amide-II), 1494 (w) (CC_arom), 1333 (s),

1154 (s) (SO₂), 811 (m), 750 (s), 688 (m) (CH_arom) cm⁻¹; ¹H NMR

of the major diastereomer (300.13 MHz, DMSO-d₆) δ 7.90−7.96 (m,

2H, ArH), 7.46−7.75 (m, 5H, ArH, signals overlap with signals of

analogous protons of other isomers), 7.31−7.40 (m, 2H, ArH, signals

overlap with signals of analogous protons of other isomers), 6.04 (d, ³J

1

821 (m), 742 (s), 688 (m) (CH_arom) cm⁻¹; H NMR of the major

diastereomer (300.13 MHz, DMSO-d₆) δ 7.31−7.93 (m, 9H, ArH),

6.33 (d, ³J = 8.7 Hz, 1H, NH), 5.88 (d, ³J = 6.2 Hz, 1H, CHSO₂), 5.77

3

(s, 2H, NH₂), 4.56 (dddd, ³J = 8.7, J = 6.2, ³J = 5.9, ³J = 4.5 Hz, 1H,

2

3

2

CHN), 3.57 (dd, J = 12.6, J = 5.9 Hz, 1H, CH_AN₃), 3.53 (dd, J =

3

1

12.6, J = 4.5 Hz, 1H, CH_BN₃), 2.34 (s, 3H, CH₃); H NMR of the

minor diastereomer (300.13 MHz, DMSO-d₆) δ 7.31−7.93 (m, 9H,

3

ArH), 6.32 (d, J = 8.4 Hz, 1H, NH), 5.88 (d, J = 8.2 Hz, 1H,

CHSO₂), 5.74 (s, 2H, NH₂), 4.37 (dddd, ³J = 8.4, ³J = 8.2, ³J = 6.6, ³J

2

3

= 4.3 Hz, 1H, CHN), 3.45 (dd, J = 12.8, J = 4.3 Hz, 1H, CH_AN₃),

3.40 (dd, ²J = 12.8, ³J = 6.6 Hz, 1H, CH_BN₃), 2.36 (s, 3H, CH₃); ¹³C

NMR of the major diastereomer (75.48 MHz, DMSO-d₆) δ 192.2

(CO in Bz), 157.38 (CONH), 145.1 (C), 136.81 (C), 134.6 (C),

134.0 (CH), 129.57 (2CH), 129.1 (2CH), 128.8 (2CH), 128.6

(2CH), 68.0 (CHSO₂), 53.4 (CH₂N₃), 49.5 (CHN), 21.05 (CH₃);

¹³C NMR of the minor diastereomer (75.48 MHz, DMSO-d₆) δ 191.7

(CO in Bz), 157.41 (CONH), 145.0 (C), 136.76 (C), 135.0 (C),

134.2 (CH), 129.60 (2CH), 129.0 (2CH), 128.9 (2CH), 128.7

(2CH), 69.1 (CHSO₂), 52.5 (CH₂N₃), 49.7 (CHN), 21.08 (CH₃).

Anal. Calcd for C₁₈H₁₉N₅O₄S: C, 53.86; H, 4.77; N, 17.45. Found: C,

53.67; H, 4.87; N, 17.42.

3

= 9.5 Hz, 1H, NH), 5.73 (d, J = 5.5 Hz, 1H, CHSO₂), 5.69 (s, 2H,

NH₂), 4.80 (ddd, ³J = 9.5, ³J = 5.5, ³J = 2.0 Hz, 1H, CHN), 3.78 (dt, ³J

3

= 7.0, J = 2.0 Hz, 1H, CHN₃), 2.35 (s, 3H, CH₃in Ts), 1.43−1.57

(m, 2H, CH₂, signals overlap with signals of analogous protons of

3

1

other isomers), 0.93 (t, J = 7.3 Hz, 3H, CH₃); H NMR of the ﬁrst

minor diastereomer (26%) (300.13 MHz, DMSO-d₆) δ 7.96−8.03 (m,

2H, ArH), 7.46−7.75 (m, 5H, ArH, signals overlap with signals of

analogous protons of other isomers), 7.31−7.40 (m, 2H, ArH, signals

overlap with signals of analogous protons of other isomers), 6.04 (d, ³J

3

= 9.7 Hz, 1H, NH), 5.66 (d, J = 9.2 Hz, 1H, CHSO₂), 5.66 (s, 2H,

NH₂), 4.67 (ddd, ³J = 9.7, ³J = 9.2, ³J = 2.0 Hz, 1H, CHN), 3.20 (dt, ³J

N-[(4-Azido-1-oxo-1-phenyl-2-tosyl)pent-3-yl]urea (12h).

Compound 12h (1.294 g, 93%) as a mixture of four diastereomers

(33:25:28:14) was prepared from tosylacetophenone (11d) (0.928 g,

3.38 mmol), NaH (0.080 g, 3.35 mmol), and sulfone 6c (0.995 g, 3.35

mmol) in dry THF (15 mL) (8 h, rt) as described for 12f.

Analogously, compound 12h was prepared in MeCN as a mixture of

four diastereomers (35:32:20:13) in 86% yield. After crystallization

from EtOH the diastereomeric ratio changed to 34:35:22:9. Mp 158−

158.5 °C (decomp, EtOH); IR (Nujol) ν_max3449 (br s), 3379 (br s),

3320 (m), 3187 (br s) (NH), 3088 (w) (CH_arom), 2113 (br vs) (N₃),

1688 (vs), 1673 (br vs), 1663 (sh) (CO and amide-I), 1595 (m),

1580 (w) (CC_arom), 1529 (s), 1519 (s) (amide-II), 1320 (s), 1150 (s)

3

= 6.9, J = 2.0 Hz, 1H, CHN₃), 2.38 (s, 3H, CH₃in Ts), 1.43−1.57

(m, 2H, CH₂, signals overlap with signals of analogous protons of

other isomers), 0.86 (t, ³J = 7.3 Hz, 3H, CH₃); ¹H NMR of the second

3

minor diastereomer (20%) (300.13 MHz, DMSO-d₆) δ 6.37 (d, J =

9.0 Hz, 1H, NH), 5.85 (s, 2H, NH₂), 4.65 (ddd, ³J = 9.0, ³J = 5.4, ³J =

4.3 Hz, 1H, CHN), 3.30−3.38 (m, 1H, CHN₃, signals overlap with

HOD signal), 2.36 (s, 3H, CH₃in Ts), 0.87 (t, ³J = 7.3 Hz, 3H, CH₃),

signals of other protons overlap with signals of analogous protons of

other isomers; ¹H NMR of the third minor diastereomer (8%) (300.13

MHz, DMSO-d₆) δ 6.12 (d, ³J = 9.6 Hz, 1H, NH), 5.75 (s, 2H, NH₂),

5.91 (d, ³J = 9.1 Hz, 1H, CHSO₂), 4.49 (ddd, ³J = 9.6, ³J = 9.1, ³J = 7.9

3

1

(SO₂), 817 (m), 755 (s), 685 (m) (CH_arom) cm⁻¹; H NMR of the

Hz, 1H, CHN), 2.40 (s, 3H, CH₃in Ts), 0.79 (t, J = 7.4 Hz, 3H,

CH₃), signals of other protons overlap with signals of analogous

protons of other isomers; ¹³C NMR of the major diastereomer (75.48

MHz, DMSO-d₆) δ 199.1 (CO), 157.57 (CONH), 145.0 (C), 137.1

(C), 134.6 (C), 133.7 (CH), 129.5 (2CH), 129.2 (2CH), 128.7

(2CH), 128.6 (2CH), 68.3 (CHSO₂), 66.5 (CHN₃), 51.1 (CHNH),

24.0 (CH₂), 21.06 (CH₃in Ts), 10.5 (CH₃); ¹³C NMR of the ﬁrst

minor diastereomer (26%) (75.48 MHz, DMSO-d₆) δ 199.3 (CO),

major diastereomer (300.13 MHz, DMSO-d₆) δ 7.31−8.02 (m, 9H,

ArH, signals overlap with signals of the aromatic protons of other

isomers), 6.30 (d, ³J = 9.2 Hz, 1H, NH), 5.80 (s, 2H, NH₂), 5.72 (d, ³J

= 4.7 Hz, 1H, CHSO₂, signals overlap with signals of the CHN proton

of the ﬁrst minor isomer), 4.57 (ddd, ³J = 9.2, ³J = 5.7, ³J = 4.7 Hz, 1H,

CHN), 3.58 (dq, ³J = 6.7, ³J = 5.7 Hz, 1H, CHN₃), 2.36 (s, 3H, CH₃in

3

1

Ts), 1.17 (d, J = 6.7 Hz, 3H, CH₃); H NMR of the ﬁrst minor

J

dx.doi.org/10.1021/jo302724y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

157.59 (CONH), 144.8 (C), 136.7 (C), 135.1 (C), 134.3 (CH), 129.4

(2CH), 129.2 (2CH), 128.9 (2CH), 128.8 (2CH), 70.5 (CHSO₂),

65.1 (CHN₃), 50.9 (CHNH), 23.6 (CH₂), 21.09 (CH₃in Ts), 10.3

(CH₃). Anal. Calcd for C₂₀H₂₃N₅O₄S: C, 55.93; H, 5.40; N, 16.31.

Found: C, 55.91; H, 5.50; N, 16.32.

triturated, washed with cold diethyl ether until crystallization was

complete, washed with ice-cold water and petroleum ether, and dried

to give 12l (0.817 g, 41%) as a mixture of four diastereomers

(39:29:20:12) (white solid). After crystallization from EtOH the

diastereomeric ratio changed to 53:20:27:0, respectively. Mp 121.5−

123 °C (decomp, EtOH)) (under slow heating; less than 1 °C/min)

and 113−119 °C (decomp, EtOH) (under rapid heating; more than 1

°C/15 s); IR (Nujol) ν_max3400 (br s), 3361 (m), 3204 (br s) (NH),

3020 (w) (CH_arom), 2118 (s), 2089 (s) (N₃), 1664 (br vs), 1626 (m)

(CO and amide-I), 1595 (w), 1578 (w) (CC_arom), 1538 (s) (amide-

N-[(1-Azido-4-oxo-4-phenyl-3-phenylthio)but-2-yl]urea

(12j). Compound 12j (2.682 g, 66%) as a mixture of two

diastereomers (52:48) was prepared from phenylthioacetophenone

(11e) (2.619 g, 11.47 mmol), NaH (0.273 g, 11.38 mmol), and

sulfone 6a (3.218 g, 11.36 mmol) in dry THF (25 mL) (8 h, rt) as

described for 12a. After crystallization from EtOH the diastereomeric

ratio did not change. Mp 114.5−115.5 °C (decomp, EtOH); IR

(Nujol) ν_max3441 (s), 3386 (m), 3363 (m), 3343 (m), 3203 (br s)

(NH), 3073 (w), 3057 (w), 3025 (w) (CH_arom), 2161 (w), 2103 (vs)

(N₃), 1664 (vs) (CO and amide-I), 1605 (m), 1596 (m), 1579 (m)

1

II), 752 (s), 742 (s), 690 (s) (CH_arom) cm⁻¹; H NMR of the major

diastereomer (300.13 MHz, DMSO-d₆) δ 7.23−7.93 (m, 10H, ArH,

signals overlap with signals of the aromatic protons of other isomers),

6.29 (d, ³J = 9.9 Hz, 1H, NH), 5.74 (s, 2H, NH₂), 5.10 (d, ³J = 8.0 Hz,

3

1H, CHS), 4.33 (ddd, J = 9.9, J = 8.0, J = 7.0 Hz, 1H, CHN), 3.49

(dq, ³J = 7.0, ³J = 6.6 Hz, 1H, CHN₃), 1.17 (d, ³J = 6.6 Hz, 3H, CH₃);

¹H NMR of the ﬁrst minor diastereomer (29%) (300.13 MHz,

DMSO-d₆) δ 7.23−7.93 (m, 10H, ArH, signals overlap with signals of

the aromatic protons of other isomers), 6.29 (d, ³J = 9.9 Hz, 1H, NH),

(CC_arom), 1528 (s) (amide-II), 755 (m), 740 (s), 690 (s) (CH_arom

)

1

cm⁻¹; H NMR of the 52:48 diastereomeric mixture (300.13 MHz,

DMSO-d₆) δ 7.25−7.93 (m, 10H, ArH in both isomers), 6.41 (d, ³J =

8.6 Hz, 0.48H, NH in minor isomer), 6.39 (d, ³J = 8.6 Hz, 0.52H, NH

in major isomer), 5.75 (s, 0.96H, NH₂in minor isomer), 5.61 (s,

3

5.75 (s, 2H, NH₂), 4.82 (d, J = 10.3 Hz, 1H, CHS), 4.24 (ddd, J =

3

10.3, ³J = 9.9, J = 2.5 Hz, 1H, CHN), 3.61 (dq, J = 6.5, ³J = 2.5 Hz,

3

1.04H, NH₂in major isomer), 5.09 (d, J = 8.4 Hz, 1H, CHS in both

2

3

1

isomers), 4.18−4.29 (m, 1H, CHN in both isomers), 3.74 (dd, J =

1H, CHN₃), 1.21 (d, J = 6.5 Hz, 3H, CH₃); H NMR of the second

minor diastereomer (20%); (300.13 MHz, DMSO-d₆) δ 7.23−7.93

(m, 10H, ArH, signals overlap with signals of the aromatic protons of

other isomers), 6.18 (d, ³J = 9.5 Hz, 1H, NH), 5.51 (s, 2H, NH₂), 4.83

(d, ³J = 9.1 Hz, 1H, CHS), 4.38 (dq, ³J = 6.6, ³J = 2.4 Hz, 1H, CHN₃),

4.25 (ddd, ³J = 9.5, ³J = 9.1, ³J = 2.4 Hz, 1H, CHN), 1.24 (d, ³J = 6.6

Hz, 3H, CH₃); ¹H NMR of the third minor diastereomer (12%)

12.5, ³J = 6.5 Hz, 0.52H, CH_AN₃in major isomer), 3.68 (dd, ²J = 12.5,

³J = 4.3 Hz, 0.52H, CH_BN₃in major isomer), 3.45 (dd, ²J = 12.6, ³J =

2

3

4.6 Hz, 0.48H, CH_AN₃in minor isomer), 3.41 (dd, J = 12.6, J = 6.3

Hz, 0.48H, CH_BN₃in minor isomer); ¹³C NMR of the 52:48

diastereomeric mixture (75.48 MHz, DMSO-d₆) δ 194.6, 194.1 (C

O in Bz), 158.0, 157.8 (CONH), 135.8, 135.7 (C), 133.52, 133.49

(CH), 133.47 (2CH), 132.9 (2CH), 131.9, 131.5 (C), 129.3, 129.1,

128.8, 128.7, 128.5, 128.4, 128.2 (2CH), 53.1 (CHS), 53.0, 52.5

(CH₂N₃), 51.6 (CHS), 50.5, 49.9 (CHN). Anal. Calcd for

C₁₇H₁₇N₅O₂S: C, 57.45; H, 4.82; N, 19.70. Found: C, 57.47; H,

4.97; N, 19.65.

3

(300.13 MHz, DMSO-d₆) δ 6.39 (d, J = 10.1 Hz, 1H, NH), 5.72 (s,

2H, NH₂), 5.01 (d, ³J = 6.4 Hz, 1H, CHS), 3.77 (dq, ³J = 6.8, ³J = 6.6

3

Hz, 1H, CHN₃), 1.25 (d, J = 6.6 Hz, 3H, CH₃), signals of other

protons overlap with signals of analogous protons of other isomers;

¹³C NMR of the diastereomeric mixture (53:20:27) (75.48 MHz,

DMSO-d₆) (shown only the nonaromatic carbon signals) δ 194.3,

193.7, 193.5 (CO), 158.6, 158.0, 157.8 (CONH), 58.7, 58.6, 58.0

(CHN₃), 54.9, 54.3, 53.4, 52.3 (CHS, CHNH), 16.1, 16.0, 15.1 (CH₃).

Anal. Calcd for C₁₈H₁₉N₅O₂S: C, 58.52; H, 5.18; N, 18.96. Found: C,

58.50; H, 5.23; N, 18.90.

N-[(1-Azido-4-oxo-4-phenyl-3-phenylthio)but-2-yl]-N′-

methylurea (12k). Compound 12k (0.892 g, 73%) as a mixture of

two diastereomers (72:28) was prepared from phenylthioacetophe-

none (11e) (0.770 g, 3.37 mmol), NaH (0.080 g, 3.32 mmol), and

sulfone 6b (0.985 g, 3.31 mmol) in dry THF (14 mL) (8 h, rt) as

described for 12a. Crystallization from EtOH aﬀorded the pure major

isomer. Mp 183.5−184 °C (decomp, EtOH); IR of the major isomer

(Nujol) ν_max3342 (br s), 3308 (br s) (NH), 3074 (w), 3056 (w)

(CH_arom), 2106 (s) (N₃), 1662 (s) (amide-I), 1629 (s) (CO), 1595

(w) (CC_arom), 1577 (br s) (amide-II), 1525 (w) (CC_arom), 751 (m),

689 (m) (CH_arom) cm⁻¹; ¹H NMR of the major diastereomer (300.13

MHz, DMSO-d₆) δ 7.84−7.89 (m, 2H, ArH), 7.61−7.68 (m, 1H,

A 38:62 mixture (0.387 g, 37%) of azido ketone 12l (four

diastereomers, 33:13:47:7) and hydroxypyrimidine 13l (two diaster-

eomers, 69:31) was obtained from phenylthioacetophenone (11e)

(0.729 g, 3.19 mmol), NaH (0.075 g, 3.13 mmol), and sulfone 6c

(0.847 g, 2.85 mmol) in dry THF (12 mL) (8 h, rt) as described for

1

12l. H NMR of the major diastereomer of hydroxypyrimidine 13l

(300.13 MHz, DMSO-d₆) δ 7.19 (s, 1H, NH), 3.80 (dd, ³J = 11.5, ³J =

2.1 Hz, 1H, H-6), 2.92 (d, ³J = 11.5 Hz, 1H, H-5), 0.83 (d, ³J = 6.6 Hz,

3H, CH₃), signals of other protons overlap with proton signals of

3

ArH), 7.48−7.55 (m, 2H, ArH), 7.26−7.39 (m, 5H, ArH), 6.35 (d, J

3

= 8.6 Hz, 1H, NH), 6.05 (q, J = 4.7 Hz, 1H, NH), 5.11 (d, J = 8.6

3

1

Hz, 1H, CHS), 4.26 (ddt, J = 8.6, J = 8.6, J = 5.4 Hz, 1H, CHN),

3.43 (d, ³J = 5.4 Hz, 2H, CH₂N₃), 2.60 (d, ³J = 4.7 Hz, 3H, CH₃); ¹H

NMR of the minor diastereomer (300.13 MHz, DMSO-d₆) δ 6.33 (d,

³J = 8.4 Hz, 1H, NH), 5.91 (q, ³J = 4.7 Hz, 1H, NH), 5.10 (d, ³J = 8.2

other isomers; H NMR of the minor diastereomer of hydroxypyr-

imidine 13l (300.13 MHz, DMSO-d₆) δ 6.48 (s, 1H, OH), 4.13 (q, ³J

3

= 7.0 Hz, 1H, CHN₃), 3.59 (d, J = 11.1 Hz, 1H, H-6), 3.11 (d, J =

3

11.1 Hz, 1H, H-5), 1.46 (d, J = 7.0 Hz, 3H, CH₃), signals of other

Hz, 1H, CHS), 3.63−3.78 (m, 2H, CH₂N₃), 2.49 (d, ³J = 4.7 Hz, 3H,

CH₃), signals of other protons overlap with signals of analogous

protons of the major diastereomer; ¹³C NMR of the major

diastereomer (75.48 MHz, DMSO-d₆) δ 194.2 (CO), 158.0

(CONH), 135.7 (C), 133.5 (CH), 133.4 (2CH), 131.6 (C), 129.1

(2CH), 128.8 (2CH), 128.4 (CH), 128.2 (2CH), 53.0 (CHSO₂), 52.9

(CH₂N₃), 50.2 (CHN), 26.4 (NCH₃). Anal. Calcd for C₁₈H₁₉N₅O₂S:

C, 58.52; H, 5.18; N, 18.96. Found: C, 58.46; H, 5.29; N, 18.98.

N-[(4-Azido-1-oxo-1-phenyl-2-phenylthio)pent-3-yl]urea

(12l). To a mixture of phenylthioacetophenone (11e) (1.257 g, 5.50

mmol) and NaH (0.130 g, 5.43 mmol) was added dry THF (15 mL),

the mixture was stirred in an ice-cold bath for 15 min, and to the

resulting solution were added sulfone 6c (1.613 g, 5.42 mmol) and

THF (5 mL). The suspension was stirred at room temperature for 8 h,

and solvent was removed in a vacuum. The yellow oily residue was

triturated with petroleum ether (3 × 15 mL), to the formed oil was

added saturated aq NaHCO₃(2.5 mL) and petroleum ether (15 mL),

and the obtained mixture was left overnight at room temperature and

cooled to 0 °C. The resulting oily material was transferred to the ﬁlter,

protons overlap with proton signals of other isomers.

6-(Azidomethyl)-4-hydroxy-4-methyl-5-phenylthiohexahy-

dropyrimidin-2-one (13m). To a mixture of phenylthioacetone

(11f) (1.252 g, 7.53 mmol) and NaH (0.179 g, 7.46 mmol) was added

dry THF (11 mL), the mixture was stirred in an ice-cold bath for 20

min, and to the resulting solution were added sulfone 6a (2.098 g, 7.41

mmol) and THF (7 mL). The suspension was stirred at room

temperature for 8 h, and solvent was removed in a vacuum. The oily

residue was triturated with petroleum ether (3 × 15 mL), to the

formed yellow oil were added saturated aq NaHCO₃(2.5 mL) and

petroleum ether (15 mL), the obtained mixture was triturated until

complete crystallization, and the resulting suspension was left

overnight at room temperature and cooled to 0 °C. The precipitate

was ﬁltered and washed with ice-cold water and petroleum ether. The

obtained slightly yellow solid was dried in a vacuum desiccator (over

P₂O₅) on the ﬁlter, cooled (−10 °C), washed with cold (−10 °C)

diethyl ether (3 × 10 mL), and dried to give 13m (1.249 g, 60%) as a

mixture of three diastereomers (43:38:19). Crystallization of this

mixture from EtOH aﬀorded only two major isomers in a ratio of

K

dx.doi.org/10.1021/jo302724y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

30:70 with (4R*,5S*,6R*)- and (4R*,5R*,6R*)-conﬁgurations,

respectively. Mp 154.5−155.5 °C (decomp, EtOH); IR (Nujol) ν_max

3275 (br vs), 3109 (m) (NH, OH), 2111 (s) (N₃), 1681 (vs) (amide-

I), 1511 (s) (amide-II), 740 (s), 690 (m) (CH_arom) cm⁻¹; ¹H NMR of

the 30:70 mixture of (4R*,5S*,6R*)- and (4R*,5R*,6R*)-diaster-

eomers (300.13 MHz, DMSO-d₆) δ 7.19−7.51 (m, 5H, ArH in both

isomers), 7.14 (d, ⁴J = 2.2 Hz, 0.7H, N₍₃₎H in major isomer), 7.09 (dd,

°C (decomp, EtOH); IR (Nujol) ν_max3289 (br s), 3131 (br m), 3100

(br m), 3073 (br m) (NH, OH), 3020 (w) (CH_arom), 2113 (s), ∼2098

(sh) (N₃), 1662 (br s) (amide-I), 1582 (w) (CC_arom), 1510 (s), 1497

1

(s) (amide-II), 742 (s), 690 (m) (CH_arom) cm⁻¹; H NMR of the

major diastereomer (300.13 MHz, DMSO-d₆) δ 7.19−7.51 (m, 5H,

ArH, signals overlap with signals of the aromatic protons of other

4

isomers), 7.19 (br s, 1H, NH), 6.54 (br s, 1H, NH), 5.86 (d, J = 1.0

Hz, 1H, OH), 4.01 (dq, ³J = 7.0, ³J = 1.3 Hz, 1H, CHN₃), 3.43 (dd, ³J

= 11.2, ³J = 1.3 Hz, 1H, H-6), 3.14 (dd, ³J = 11.2, ⁴J = 1.0 Hz, 1H, H-

4

⁴J = 2.0, J = 1.3 Hz, 0.3H, N₍₃₎H in minor isomer), 6.72 (d, J = 2.2

4

Hz, 0.7H, N₍₁₎H in major isomer), 6.53 (dd, J = 2.0, J = 1.3 Hz,

0.3H, N₍₁₎H in minor isomer), 5.84 (d, ⁴J = 0.9 Hz, 0.7H, OH in major

isomer), 5.83 (s, 0.3H, OH in minor isomer), 4.13 (ddd, ³J = 8.5, ³J =

3

1

5), 1.56 (s, 3H, 4-CH₃), 1.41 (d, J = 7.0 Hz, 3H, CH₃); H NMR of

the ﬁrst minor diastereomer (45%) (300.13 MHz, DMSO-d₆) δ 7.19−

7.51 (m, 5H, ArH, signals overlap with signals of the aromatic protons

of other isomers), 7.16 (br s, 1H, NH), 6.45 (br s, 1H, NH), 5.78 (s,

1H, OH), 3.77−3.89 (m, 2H, H-6 and CHN₃), 3.43 (unresolved m,

half-height width =3.9 Hz, 1H, H-5), 1.45 (s, 3H, 4-CH₃), 1.45 (d, ³J =

3

5.9, J = 2.8 Hz, 0.3H, H-6 in minor isomer), 3.54−3.79 (m, 2.7H,

CH₂N₃in both isomers and H-6 in major isomer), 3.31 (ddd, ³J = 2.8,

⁴J = 1.3, ⁴J = 1.3 Hz, 0.3H, H-5 in minor isomer), 3.12 (dd, ³J = 11.4, ⁴J

= 0.9 Hz, 0.7H, H-5 in major isomer), 1.54 (s, 2.1H, CH₃in major

isomer), 1.48 (s, 0.9H, CH₃in minor isomer); ¹³C NMR of

(4R*,5R*,6R*)-diastereomer (75.48 MHz, DMSO-d₆) δ 154.5 (C-

2), 135.7 (C), 130.23 (2CH), 129.2 (2CH), 126.7 (CH), 80.0 (C-4),

54.3 (C-6), 53.1 (C-5), 51.5 (CH₂N₃), 27.1 (CH₃); ¹³C NMR of

(4R*,5S*,6R*)-diastereomer (75.48 MHz, DMSO-d₆) δ 154.6 (C-2),

136.0 (C), 130.18 (2CH), 129.3 (2CH), 126.6 (CH), 81.7 (C-4), 54.4

(C-6), 51.7 (CH₂N₃), 49.3 (C-5), 26.6 (CH₃). Anal. Calcd for

C₁₂H₁₅N₅O₂S: C, 49.13; H, 5.15; N, 23.87. Found: C, 49.23; H, 5.36;

N, 24.10.

1

5.7 Hz, 3H, CH₃); H NMR of the second minor diastereomer (5%)

(300.13 MHz, DMSO-d₆) δ 6.22 (br s, 1H, NH), 5.90 (s, 1H, OH),

4.25 (dq, ³J = 6.6, ³J = 2.0 Hz, 1H, CHN₃), 3.64 (dd, ³J = 11.7, ³J = 2.0

3

Hz, 1H, H-6), 2.99 (d, J = 11.7 Hz, 1H, H-5), 1.60 (s, 3H, 4-CH₃),

signals of other protons overlap with signals of analogous protons of

other isomers; ¹³C NMR of the major diastereomer (75.48 MHz,

DMSO-d₆) δ 154.9 (C-2), 135.9 (C), 130.0 (2CH), 129.3 (2CH),

126.7 (CH), 79.9 (C-4), 57.4 (CHN₃), 56.1 (C-5), 54.5 (C-6), 27.2

(4-CH₃), 15.5 (CH₃); ¹³C NMR of the ﬁrst minor diastereomer (45%)

(75.48 MHz, DMSO-d₆) δ 154.9 (C-2), 136.1 (C), 130.0 (2CH),

129.2 (2CH), 126.5 (CH), 81.6 (C-4), 57.5 (CHN₃), 55.5 (C-5), 54.3

(C-6), 26.6 (4-CH₃), 16.0 (CH₃). Anal. Calcd for C₁₃H₁₇N₅O₂S: C,

50.80; H, 5.57; N, 22.78. Found: C, 50.83; H, 5.66; N, 22.90.

N-[(1-Azido-4-oxo-3-phenylthio)pent-2-yl]-N′-methylurea

(12n). A 82:18 mixture (1.042 g, 58%) of azido ketone 12n (two

diastereomers, 90:10) and hydroxypyrimidine 13n (two diastereomers,

50:50) was obtained from phenylthioacetone (11f) (0.997 g, 5.99

mmol), NaH (0.141 g, 5.90 mmol) and sulfone 6b (1.752 g, 5.89

mmol) in dry THF (19 mL) (8 h, rt) as described for 12a. After

crystallization from EtOH, pure oxoalkylurea 12n was obtained as a

mixture of two diastereomers (78:22). Mp 116−117.5 °C (decomp,

EtOH); IR (Nujol) ν_max3359 (s), 3311 (s), 3183 (w), 3133 (w)

(NH), 3058 (w), 3022 (w) (CH_arom), 2146 (m), 2103 (s) (N₃), 1699

(s) (CO), 1636 (s) (amide-I), 1580 (s), 1533 (m) (amide-II), 757

6-(1-Azidopropyl)-4-hydroxy-4-methyl-5-phenylthiohexa-

hydropyrimidin-2-one (13p). A 44:56 mixture (0.584 g, 30%) of

azido ketone 12p (a single diastereomer) and hydroxypyrimidine 13p

(three diastereomers, 54:33:13) was prepared from phenylthioacetone

(11f) (1.015 g, 6.10 mmol), NaH (0.145 g, 6.03 mmol), and sulfone

6d (1.872 g, 6.01 mmol) in dry THF (19 mL) (8 h, rt) as described

for 12l. After crystallization from EtOH, pure hydroxypyrimidine 13p

was obtained as a mixture of three diastereomers (52:43:5). Mp

149.5−150 °C (decomp, EtOH); IR (Nujol) ν_max3289 (br s), 3114

(br m), 3085 (br m) (NH, OH), 2111 (s) (N₃), 1666 (sh), 1657 (br

vs) (amide-I), 1580 (w) (CC_arom), 1510 (m), 1494 (s) (amide-II), 741

1

(s), 692 (m) (CH_arom) cm⁻¹; H NMR of the major diastereomer

(300.13 MHz, DMSO-d₆) δ 7.29−7.47 (m, 5H, ArH), 6.26 (d, ³J = 9.1

Hz, 1H, NH), 5.93 (q, ³J = 4.6 Hz, 1H, NH), 4.21 (dddd, ³J = 9.5, ³J =

9.1, ³J = 6.1, ³J = 3.9 Hz, 1H, CHN), 3.92 (d, ³J = 9.5 Hz, 1H, CHS),

3.65 (dd, ²J = 12.6, ³J = 6.1 Hz, 1H, CH_AN₃), 3.59 (dd, ²J = 12.6, ³J =

1

(s), 690 (m) (CH_arom) cm⁻¹; H NMR of the major diastereomer

3

(300.13 MHz, DMSO-d₆) δ 7.19−7.51 (m, 5H, ArH, signals overlap

with signals of the aromatic protons of other isomers), 7.16 (br s, 1H,

N₍₃₎H), 6.43 (br s, 1H, N₍₁₎H), 5.79 (s, 1H, OH), 3.90 (dd, ³J = 10.1,

³J = 2.5 Hz, 1H, H-6), 3.63−3.71 (m, 1H, CHN₃, signals overlap with

the CHN₃signals of the ﬁrst minor isomer), 3.46 (unresolved m, half-

height width =4.8 Hz, 1H, H-5), 1.61−2.14 (m, 2H, CH₂, signals

overlap with the CH₂signals of the ﬁrst minor isomer), 1.44 (s, 3H, 4-

CH₃), 0.96 (t, ³J = 7.2 Hz, 3H, CH₃in Et); ¹H NMR of the ﬁrst minor

diastereomer (33%) (300.13 MHz, DMSO-d₆) δ 7.19−7.51 (m, 5H,

ArH, signals overlap with signals of the aromatic protons of other

isomers), 7.19 (br s, 1H, N₍₃₎H), 6.47 (br s, 1H, N₍₁₎H), 5.87 (d, ⁴J =

0.9 Hz, 1H, OH), 3.63−3.71 (m, 1H, CHN₃, signals overlap with the

3.9 Hz, 1H, CH_BN₃), 2.53 (d, J = 4.6 Hz, 3H, NCH₃), 2.18 (s, 3H,

CH₃in Ac); ¹H NMR of the minor diastereomer (300.13 MHz,

DMSO-d₆) δ 7.29−7.47 (m, 5H, ArH, signals overlap with signals of

3

the aromatic protons of the major isomer), 6.31 (d, J = 8.3 Hz, 1H,

NH), 5.96 (q, ³J = 4.7 Hz, 1H, NH), 4.14−4.26 (m, 2H, NCH−CHS,

signals overlap with signals of the CHN proton of the major isomer),

3.31 3.44 (m, 2H, CH₂N₃, signals partly overlap with the HOD signal),

2.58 (d, ³J = 4.7 Hz, 3H, NCH₃), 2.23 (s, 3H, CH₃in Ac); ¹³C NMR

of the major diastereomer (75.48 MHz, DMSO-d₆) δ 203.1 (CO),

157.5 (CONH), 132.8 (C), 131.7 (2CH), 129.4 (2CH), 128.0 (CH),

58.3 (CHSO₂), 52.6 (CH₂N₃), 49.8 (CHN), 26.9 (CH₃in Ac), 26.29

(NCH₃); ¹³C NMR of the minor diastereomer (75.48 MHz, DMSO-

d₆) δ 202.8 (CO), 157.9 (CONH), 132.8 (C), 131.9 (2CH), 129.2

(2CH), 127.8 (CH), 59.7 (CHSO₂), 52.9 (CH₂N₃), 49.5 (CHN), 28.3

(CH₃in Ac), 26.35 (NCH₃). Anal. Calcd for C₁₃H₁₇N₅O₂S: C, 50.80;

H, 5.57; N, 22.78. Found: C, 50.93; H, 5.48; N, 22.84.

3

CHN₃signals of the major isomer), 3.54 (dd, J = 11.2, J = 1.4 Hz,

3

4

1H, H-6), 3.18 (dd, J = 11.2, J = 0.9 Hz, 1H, H-5), 1.61−2.14 (m,

2H, CH₂, signals overlap with the CH₂signals of the major isomer),

1.56 (s, 3H, 4-CH₃), 0.92 (t, ³J = 7.3 Hz, 3H, CH₃in Et); ¹H NMR of

the second minor diastereomer (13%) (300.13 MHz, DMSO-d₆) δ

6.25 (br s, 1H, N₍₁₎H), 5.93 (s, 1H, OH), 3.11 (d, ³J = 11.4 Hz, 1H, H-

5), 1.62 (s, 3H, 4-CH₃), 0.47 (t, ³J = 7.3 Hz, 3H, CH₃in Et); signals of

other protons overlap with proton signals of other isomers; ¹³C NMR

of the diastereomeric mixture (52:43:5) (75.48 MHz, DMSO-d₆)

(shown only the signals of two major isomers) δ 154.91, 154.85 (C-2),

136.0, 135.8 (C), 129.9, 129.4, 129.33, 129.25 (2CH), 126.7, 126.3

(CH), 81.7, 79.9 (C-4), 63.7, 62.6 (CHN₃), 55.44, 55.38, 54.1, 51.9

(C-6 and C-5), 27.2, 26.5 (4-CH₃), 23.3, 23.0 (CH₂), 11.0, 9.6 (CH₃

in Et). Anal. Calcd for C₁₄H₁₉N₅O₂S: C, 52.32; H, 5.96; N, 21.79.

Found: C, 52.25; H, 6.12; N, 22.07.

¹H NMR of hydroxypyrimidine 13n (diastereomeric mixture,

50:50) (300.13 MHz, DMSO-d₆) δ 7.18−7.56 (m, 5H, ArH), 6.88

(br s, 0.5H, NH), 6.68 (br s, 0.5H, NH), 6.14 (s, 0.5H, OH), 6.12 (s,

0.5H, OH), 4.06−4.14 (m, 0.5H, H-6), 3.50−3.80 (m, 2.5H, CH₂N₃

and H-6), 3.40 (unresolved m, half-height width = 5.4 Hz, 0.5H, H-5),

3.27 (d, ³J = 10.7 Hz, 0.5H, H-5), 2.85 (s, 1.5H, NCH₃), 2.80 (s, 1.5H,

NCH₃), 1.70 (s, 1.5H, 4-CH₃), 1.58 (s, 1.5H, 4-CH₃).

6-(1-Azidoethyl)-4-hydroxy-4-methyl-5-phenylthiohexahy-

dropyrimidin-2-one (13o). Compound 13o (0.460 g, 48%) as a

mixture of three diastereomers (50:45:5) was prepared from

phenylthioacetone (11f) (0.580 g, 3.49 mmol), NaH (0.082 g, 3.43

mmol), and sulfone 6c (0.924 g, 3.11 mmol) in dry THF (13 mL) (12

h, rt) as described for 12l. After crystallization from EtOH the

diastereomeric ratio changed to 53:47:0, respectively. Mp 148−148.5

¹H NMR of oxoalkylurea 12p (300.13 MHz, DMSO-d₆) δ 6.17 (d,

³J = 9.9 Hz, 1H, NH), 5.64 (s, 2H, NH₂), 4.22 (ddd, ³J = 10.8, ³J = 9.9,

3

³J = 1.9 Hz, 1H, CHN), 4.02 (dt, J = 7.1, J = 1.9 Hz, 1H, CHN₃),

L

dx.doi.org/10.1021/jo302724y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

3.75 (d, ³J = 10.8 Hz, 1H, CHS), 2.19 (s, 3H, CH₃in Ac), 0.99 (t, ³J =

7.1 Hz, 3H, CH₃in Et), signals of other protons overlap with proton

signals of cyclic isomers.

complete, the mixture was evaporated to half of its volume in a

vacuum, the resulting suspension was cooled to −10 °C, the

precipitate was ﬁltered on a cold (−10 °C) ﬁlter and washed with

THF (3 × 10 mL, −10 °C), diethyl ether (2 × 10 mL, −10 °C), and

petroleum ether, and dried to give trans-15e (1.852 g, 89%). Mp

167.5−171 °C (decomp, EtOH); IR (Nujol) ν_max3438 (s), 3339 (m),

3311 (w), 3213 (br s), 3068 (br s) (NH), 1664 (s) (amide-I), 1603

(s) (CN), 1584 (s), 1573 (br s), 1562 (s) (amide-II), 1322 (vs),

1148 (vs) (SO₂), 767 (s), 750 (s), 697 (m), 687 (s) (CH_arom) cm⁻¹;

¹H NMR (600.13 MHz, DMSO-d₆) δ 7.82−7.85 (m, 2H, ArH), 7.77−

7.80 (m, 2H, ArH), 7.68−7.72 (m, 1H, ArH), 7.53−7.58 (m, 2H,

N-[(1-Azido-4-oxo-4-phenyl-3-benzoyl)but-2-yl]urea (12q).

Compound 12q (3.044 g, 77%) was prepared from dibenzoylmethane

(11g) (2.645 g, 11.79 mmol), NaH (0.270 g, 11.25 mmol), and

sulfone 6a (3.188 g, 11.25 mmol) in dry THF (25 mL) (8 h, rt) as

described for 12a. Compound 12q formed a strong solvate (with

EtOH) being crystallized from EtOH. Heating of this solvate in a

vacuum at 56 °C for about 8 h led to partial decomposition of 12q

without complete removal of EtOH (¹H NMR data). Drying in high

vacuum over P₂O₅for 1 week at rt gave 12q with 25% of EtOH (¹H

NMR, elemental analysis). Puriﬁcation of 12q by crystallization from

other solvents or their mixtures failed because of its high solubility or

the tendency to transformations upon heating. Mp 83−85 °C

(decomp, EtOH); IR (Nujol) ν_max3511 (w), 3454 (br s), 3357 (br

s), 3282 (br s), 3206 (m), 3069 (m) (NH), 2170 (m), 2107 (vs) (N₃),

1695 (s), 1685 (s), 1666 (s) (CO and amide-I), 1594 (s), 1580 (m)

3

ArH), 7.42−7.46 (m, 1H, ArH), 7.34−7.38 (m, 2H, ArH), 6.59 (d, J

= 7.7 Hz, 1H, NH), 5.45 (s, 2H, NH₂), 5.35 (dd, ⁴J = 1.5, ³J = 1.1 Hz,

1H, H-4), 4.64 (dddd, ³J = 7.7, ³J = 5.8, ³J = 1.1, ³J = 1.1 Hz, 1H, H-3),

2

3

4

2

3.91 (ddd, J = 17.2, J = 5.8, J = 1.5 Hz, 1H, H_A-2), 3.81 (dd, J =

17.2, J = 1.1 Hz, 1H, H_B-2); ¹³C NMR (150.90 MHz, DMSO-d₆) δ

3

164.3 (C-5), 157.3 (CO), 137.6 (C), 134.2 (CH), 133.1 (C), 130.5

(CH), 129.2 (2CH), 128.6 (2CH), 128.4 (2CH), 128.0 (2CH), 76.6

(C-4), 67.8 (C-2), 52.4 (C-3). Anal. Calcd for C₁₇H₁₇N₃O₃S: C, 59.46;

H, 4.99; N, 12.24. Found: C, 59.44; H, 5.11; N, 12.46.

1

(CC_arom), 1557 (s) (amide-II), 764 (s), 695 (s) (CH_arom) cm⁻¹; H

NMR (300.13 MHz, DMSO-d₆) δ 7.92−8.05 (m, 4H, ArH), 7.61−

7.72 (m, 2H, ArH), 7.47−7.60 (m, 4H, ArH), 6.33 (d, ³J = 9.5 Hz, 1H,

trans-5-Phenyl-4-tosyl-3-ureido-3,4-dihydro-2H-pyrrole

(trans-15f). Compound trans-15f (1.098 g, 89%) was prepared from

urea 12g (1.384 g, 3.45 mmol) and PPh₃(1.055 g, 4.02 mmol) in dry

THF (26 mL) (reﬂux, 1 h 40 min) as described for trans-15e. Mp

174.5−176 °C (decomp, EtOH); IR (Nujol) ν_max3466 (s), 3361 (m),

3266 (br m), 3223 (br m), 3078 (br s) (NH), 1676 (m), 1656 (s)

(amide-I), 1615 (m), 1596 (s), 1580 (m), 1570 (m) (amide-II and

CN), 1317 (s), 1132 (s) (SO₂), 817 (m), 769 (s), 697 (m)

3

NH), 6.08 (d, J = 5.3 Hz, 1H, CHCOPh), 5.65 (s, 2H, NH₂), 4.61

(dddd, ³J = 9.5, ³J = 8.2, ³J = 5.3, ³J = 4.8 Hz, 1H, CHN), 3.58 (dd, ²J

= 12.4, ³J = 8.2 Hz, 1H, H_Ain CH₂N₃), 3.46 (dd, ²J = 12.4, ³J = 4.8 Hz,

1H, H_Bin CH₂N₃); ¹³C NMR (75.48 MHz, DMSO-d₆) δ 195.8 (C

O in Bz), 195.0 (CO in Bz), 157.7 (CONH), 136.0 (C), 135.4 (C),

133.9 (CH), 133.8 (CH), 129.1 (2CH), 129.0 (2CH), 128.5 (2CH),

128.3 (2CH), 56.7 (CHBz), 53.1 (CH₂N₃), 49.8 (CHN). Anal. Calcd.

for C₁₈H₁₇N₅O₃× 0.25C₂H₅OH: C, 61.23; H, 5.14; N, 19.30. Found:

C, 61.18; H, 5.34; N, 19.20.

1

(CH_arom) cm⁻¹; H NMR (300.13 MHz, DMSO-d₆) δ 7.80−7.86 (m,

2H, ArH), 7.62−7.68 (m, 2H, ArH), 7.41−7.48 (m, 1H, ArH), 7.32−

7.40 (m, 4H, ArH), 6.60 (d, ³J = 7.6 Hz, 1H, NH), 5.47 (s, 2H, NH₂),

5.31 (dd, ⁴J = 1.1, ³J = 1.1 Hz, 1H, H-4), 4.61 (dddd, ³J = 7.6, ³J = 5.2,

Ethyl 6-(Azidomethyl)-4-hydroxy-2-oxo-4-phenylhexahy-

dropyrimidine-5-carboxylate (13r). To a stirred suspension of

NaH (0.140 g, 5.82 mmol) in dry MeCN (6 mL) cooled in an ice-cold

bath was added a solution of ethyl benzoyl acetate (11h) (1.162 g,

5.89 mmol) in MeCN (6 mL), and the resulting mixture was stirred

for 12 min. The ice-bath was removed, and to the obtained solution

were added sulfone 6a (1.632 g, 5.76 mmol) and MeCN (5 mL). The

suspension was stirred at room temperature for 8 h, and solvent was

removed in a vacuum. The oily residue was triturated with petroleum

ether (3 × 15 mL), to the formed oil were added saturated aq

NaHCO₃(2 mL) and petroleum ether (15 mL), and the obtained

mixture was left overnight at room temperature and cooled to 0 °C.

The oily substance was transferred on the ﬁlter, the liquids were

ﬁltered, and the substance was triturated on the ﬁlter and washed with

small portions of cold (−10 °C) diethyl ether until crystallization was

complete, washed with ice-cold water (2 × 3 mL) and petroleum

ether, and dried to give 13r (0.720 g, 39%) as a single (4R*,5S*,6R*)-

diastereomer. Note: the product is moderately soluble in diethyl ether

and water. Mp 92.5−99 °C (decomp, EtOAc/petroleum ether, 2:1);

IR (Nujol) ν_max3480 (m), 3313 (s), 3235 (br s), 3089 (br m), 3073

(br m) (NH, OH), 2108 (vs) (N₃), 1725 (s) (CO), 1676 (vs)

(amide-I), 1492 (s) (amide-II), 1260 (s), 1157 (s) (C−O), 761 (s),

3

2

3

4

³J = 1.5, J = 1.1 Hz, 1H, H-3), 3.86 (ddd, J = 17.2, J = 5.2, J = 1.1

Hz, 1H, H_A-2), 3.78 (dd, ²J = 17.2, ³J = 1.5 Hz, 1H, H_B-2), 2.38 (s, 3H,

CH₃); ¹³C NMR (75.48 MHz, DMSO-d₆) δ 164.4 (C-5), 157.4 (C

O), 144.9 (C), 134.7 (C), 133.2 (C), 130.5 (CH), 129.7 (2CH), 128.7

(2CH), 128.5 (2CH), 128.0 (2CH), 76.7 (C-4), 67.9 (C-2), 52.4 (C-

3), 21.1 (CH₃). Anal. Calcd for C₁₈H₁₉N₃O₃S: C, 60.49; H, 5.36; N,

11.76. Found: C, 60.17; H, 5.56; N, 11.96.

2-Methyl-5-phenyl-4-tosyl-3-ureido-3,4-dihydro-2H-pyrrole

(15g). To urea 12h (1.270 g, 3.06 mmol) and PPh₃(0.967 g, 3.69

mmol) was added dry THF (15 mL), and the obtained mixture was

reﬂuxed under stirring for 2 h. A clear solution formed at the

beginning of reﬂux, and after 15 min the product precipitated to give a

suspension. After the reaction was complete, the mixture was

evaporated to a quarter of its volume in a vacuum, the resulting

suspension was cooled to −10 °C and transferred on a cold (−10 °C)

ﬁlter with cold diethyl ether, and the precipitate was ﬁltered, washed

with THF (2 mL, −10 °C), diethyl ether (2 × 5 mL, −10 °C), and

petroleum ether, and dried to give 15g (0.846 g, 74%) as a mixture of

two diastereomers (72:28). After crystallization from EtOH the

diastereomeric ratio changed to 73:27. Mp 191−193 °C (decomp,

EtOH); IR (Nujol) ν_max3407 (s), 3276 (s), 3202 (s), 3084 (s) (NH),

3029 (w) (CH_arom), 1655 (s) (amide-I), 1616 (s) (CN), 1598 (w)

(CC_arom), 1564 (s) (amide-II), 1494 (w) (CC_arom), 1318 (s), 1148 (s)

1

700 (s) (CH_arom) cm⁻¹; H NMR (300.13 MHz, DMSO-d₆) δ 7.41−

7.48 (m, 2H, ArH), 7.26−7.38 (m, 3H, ArH), 7.13 (d, ⁴J = 1.8 Hz, 1H,

4

N₍₃₎H), 6.85 (d, J = 1.8 Hz, 1H, N₍₁₎H), 6.31 (d, J = 0.8 Hz, 1H,

3

1

OH), 4.04 (ddd, J = 11.4, ³J = 3.4, J = 3.4 Hz, 1H, H-6), 3.62−3.77

(SO₂), 810 (m), 767 (s), 699 (s) (CH_arom) cm⁻¹; H NMR of the

(m, 2H, OCH₂), 3.65 (dd, J = 13.1, ³J = 3.4 Hz, 1H, H_Ain CH₂N₃),

major diastereomer (300.13 MHz, DMSO-d₆) δ 7.26−7.84 (m, 9H,

ArH, signals overlap with signals of the aromatic protons of the minor

isomer), 6.48 (d, ³J = 9.6 Hz, 1H, NH), 5.44 (s, 2H, NH₂), 5.31 (dd, ⁴J

= 0.9, ³J = 0.9 Hz, 1H, H-4), 4.79 (ddd, ³J = 9.6, ³J = 5.9, ³J = 0.9 Hz,

1H, H-3), 4.03 (ddq, ³J = 7.2, ³J = 5.9, ⁴J = 0.9 Hz, 1H, H-2), 2.37 (s,

2

3.23 (dd, ²J = 13.1, ³J = 3.4 Hz, 1H, H_Bin CH₂N₃), 2.75 (dd, ³J = 11.4,

⁴J = 0.8 Hz, 1H, H-5), 0.71 (t, J = 7.1 Hz, 3H, CH₃); ¹³C NMR

3

(75.48 MHz, DMSO-d₆) δ 168.3 (CO), 154.9 (C-2), 142.9 (C),

127.7 (CH), 127.6 (2CH), 126.2 (2CH), 81.8 (C-4), 59.7 (OCH₂),

52.6 (C-5), 52.2 (CH₂N₃), 49.1 (C-6), 13.4 (CH₃). Anal. Calcd for

C₁₄H₁₇N₅O₄: C, 52.66; H, 5.37; N, 21.93. Found: C, 52.41; H, 5.48;

N, 21.82.

trans-5-Phenyl-4-phenylsulfonyl-3-ureido-3,4-dihydro-2H-

pyrrole (trans-15e). To urea 12f (2.338 g, 6.04 mmol) and PPh₃

(1.857 g, 7.08 mmol) was added dry THF (21 mL), and the obtained

mixture was reﬂuxed under stirring for 1 h 40 min. A clear solution

formed at the beginning of reﬂux, and after 2 min the product

precipitated to give a dense suspension. After the reaction was

3

1

3H, CH₃in Ts), 1.17 (d, J = 7.2 Hz, 3H, 2-CH₃); H NMR of the

minor diastereomer (300.13 MHz, DMSO-d₆) δ 7.26−7.69 (m, 9H,

ArH, signals overlap with signals of the aromatic protons of the major

isomer), 6.55 (d, ³J = 7.6 Hz, 1H, NH), 5.54 (s, 2H, NH₂), 5.35 (d, ³J

= 2.9 Hz, 1H, H-4), 4.18 (ddd, ³J = 7.6, ³J = 2.9, ³J = 2.6 Hz, 1H, H-3),

4.03 (dq, ³J = 7.1, ³J = 2.6 Hz, 1H, H-2), 2.37 (s, 3H, CH₃in Ts), 1.18

3

(d, J = 7.1 Hz, 3H, 2-CH₃); ¹³C NMR of the major diastereomer

(75.48 MHz, DMSO-d₆) δ 163.1 (C-5), 157.5 (CO), 144.9 (C),

135.0 (C), 133.0 (C), 130.5 (CH), 129.7 (2CH), 128.6 (2CH), 128.4

M

dx.doi.org/10.1021/jo302724y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(2CH), 127.9 (2CH), 77.8 (C-4), 69.8 (C-2), 54.9 (C-3), 21.1 (CH₃

in Ts), 14.7 (2-CH₃); ¹³C NMR of the minor diastereomer (75.48

MHz, DMSO-d₆) δ 162.5 (C-5), 157.6 (CO), 144.7 (C), 134.9 (C),

133.5 (C), 130.1 (CH), 129.6 (2CH), 128.52 (2CH), 128.47 (2CH),

127.8 (2CH), 77.5 (C-2), 76.2 (C-2), 57.4 (C-3), 21.1 (CH₃in Ts),

19.5 (2-CH₃). Anal. Calcd for C₁₉H₂₁N₃O₃S: C, 61.44; H, 5.70; N,

11.31. Found: C, 61.31; H, 5.90; N, 11.20.

recrystallized from EtOH to give 17b (0.395 g, 61%). The mother

liquor was concentrated in a vacuum to aﬀord 0.064 g of a 55:45

mixture of 17b and POPh₃(according to H NMR spectrum). Mp

1

204.5−205.5 °C (EtOH); IR (Nujol) ν_max3296 (br vs), 3126 (m)

(NH), 3020 (w) (CH_arom), 1595 (m), 1563 (m), 1492 (m) (CC_arom),

1278 (s), 1137 (vs) (SO₂), 816 (m) (CH_arom) cm⁻¹; ¹H NMR (300.13

MHz, DMSO-d₆) δ 11.49 (br s, 1H, NH), 7.68−7.73 (m, 2H, ArH),

3

4-Benzoyl-5-phenyl-3-ureido-2,3-dihydro-1H-pyrrole (16n).

Compound 16n (0.347 g, 72%) as a yellow solid was prepared from

urea 12q (0.552 g, 1.57 mmol) and PPh₃(0.490 g, 1.87 mmol) in dry

THF (8 mL) (reﬂux, 4 h 30 min) as described for 15g. Mp 133−134

°C (decomp, EtOH) (rate of heating 1 °C per 11−13 s), mp 145−146

°C (decomp, EtOH) (rate of heating 1 °C per 1 min, decomposition

before melting); IR (Nujol) ν_max3428 (m), 3396 (br s), 3356 (m),

3210 (br s), 3170 (br s), 3146 (br s), 3084 (br m), 3069 (br m), 3060

(br m) (NH), 3027 (m), 3002 (w) (CH_arom), 1645 (s) (amide-I and

CO), 1621 (m) (CC), 1581 (w) (CC_arom), 1524 (s) (amide-II),

725 (s), 697 (s) (CH_arom) cm⁻¹; ¹H NMR (300.13 MHz, DMSO-d₆) δ

7.91 (br s, 1H, H-1), 7.04−7.22 (m, 8H, ArH), 6.92−6.99 (m, 2H,

ArH), 6.08 (d, ³J = 5.1 Hz, 1H, NH), 5.49 (s, 2H, NH₂), 4.94 (ddd, ³J

= 8.3, ³J = 5.1, ³J = 2.5 Hz, 1H, H-3), 3.76 (dd, ²J = 12.0, ³J = 8.3 Hz,

7.32−7.37 (m, 2H, ArH), 6.71 (dd, J = 3.1, J = 2.4 Hz, 1H, H-5),

6.33 (dd, ³J = 3.1, ⁴J = 2.6 Hz, 1H, H-4), 2.35 (s, 3H, CH₃in Ts), 2.34

(s, 3H, 2-CH₃); ¹³C NMR (75.48 MHz, DMSO-d₆) δ 142.6 (C), 141.5

(C), 132.0 (C-2), 129.6 (2CH), 126.0 (2CH), 118.8 (C-3), 117.3 (C-

5), 108.6 (C-4), 20.9 (CH₃in Ts), 11.4 (2-CH₃). Anal. Calcd for

C₁₂H₁₃NO₂S: C, 61.25; H, 5.57; N, 5.95. Found: C, 61.27; H, 5.67; N,

5.98.

Method B. Pyrrole 17b (0.453 g, 71%) was prepared from

tosylacetone (11b) (0.590 g, 2.78 mmol), NaH (0.065 g, 2.73 mmol),

and sulfone 6a (0.773 g, 2.73 mmol) in MeCN (16 mL) (rt, 8 h), then

PPh₃(0.855 g, 3.25 mmol) (reﬂux, 1 h), and then TsOH·H₂O (0.260

g, 1.37 mmol) (reﬂux, 1 h) as described in Method A. The crude

product was puriﬁed by column chromatography on silica gel 60 (25

g) eluting with petroleum ether/CHCl₃(from 35:65 to 1:4) (Note: the

fraction with the product came after POPh₃). The main fraction was

concentrated in a vacuum, and the solid residue was recrystallized from

EtOH.

2

3

1H, H_A-2), 3.40 (ddd, J = 12.0, J = 2.5, J = 1.4 Hz, 1H, H_B-2); ¹³C

NMR (75.48 MHz, DMSO-d₆) δ 189.1 (CO in Bz), 164.6 (C-5),

158.4 (CONH), 141.6 (C), 131.8 (C), 129.4 (CH), 128.8 (3CH),

127.9 (2CH), 127.5 (2CH), 126.9 (2CH), 107.9 (C-4), 53.9 (C-3),

53.8 (C-2). Anal. Calcd for C₁₈H₁₇N₃O₂: C, 70.34; H, 5.58; N, 13.67.

Found: C, 70.35; H, 5.68; N, 13.50.

2,5-Dimethyl-3-tosyl-1H-pyrrole (17c). Method A. Pyrrole 17c

(0.250 g, 47%) was prepared from tosylacetone (11b) (0.471 g, 2.21

mmol), NaH (0.051 g, 2.14 mmol), and sulfone 6c (0.636 g, 2.14

mmol) in THF (13 mL) (rt, 8 h), then PPh₃(0.634 g, 2.42 mmol)

(reﬂux, 1 h), and then TsOH·H₂O (0.208 g, 1.09 mmol) (reﬂux, 1 h

10 min) as described in Method A for 17b. The crude product was

puriﬁed by column chromatography on silica gel 60 (20 g) eluting with

petroleum ether/CHCl₃(from 1:1 to 1:4) (Note: the fraction with the

product came after POPh₃). The main fraction was concentrated in a

vacuum, and the solid residue was recrystallized from EtOH. Mp

188.5−189.5 °C (EtOH); IR (Nujol) ν_max3302 (br vs), 3186 (m)

(NH), 3084 (w), 3032 (w) (CH_arom), 1596 (m), 1526 (m), 1495 (w)

2-Methyl-3-phenylsulfonyl-1H-pyrrole (17a). A solution of 12a

(0.358 g, 1.10 mmol) and PPh₃(0.355 g, 1.35 mmol) in dry THF (7

mL) was reﬂuxed under stirring for 2 h, then TsOH·H₂O (0.105 g,

0.55 mmol) was added, and reﬂux was continued for 10 min. The

solvent was removed in a vacuum, and the obtained residue was

dissolved in CHCl₃(15 mL), subsequently washed with saturated aq

NaHCO₃(10 mL), H₂O (3 × 10 mL), and brine (2 × 10 mL), and

dried over Na₂SO₄. Then the solvent was removed in a vacuum, and

the obtained residue was puriﬁed by column chromatography on silica

gel 60 (16 g) eluting with petroleum ether/CHCl₃(from 1:1 to 1:3).

(Note: the fraction with the product came after POPh₃). The main

fraction was concentrated in a vacuum, the solid residue was triturated

with H₂O (2 mL) and cooled, and the precipitate was ﬁltered and

dried to give 17a (0.225 g, 93%). Mp 112.5−113 °C (EtOAc/

petroleum ether, 1:1); IR (Nujol) ν_max3329 (vs), ∼3289 (sh) (NH),

3068 (w), 3056 (w) (CH_arom), 1560 (m) (CC_arom), 1297 (vs), 1137

1

(CC_arom), 1282 (s), 1144 (s) (SO₂), 822 (m) (CH_arom) cm⁻¹; H

NMR (300.13 MHz, DMSO-d₆) δ 11.25 (br s, 1H, NH), 7.65−7.70

4

(m, 2H, ArH), 7.31−7.36 (m, 2H, ArH), 5.97 (dq, J = 2.7, J = 1.0

Hz, 1H, H-4), 2.34 (br s, 3H, 2-CH₃), 2.30 (s, 3H, CH₃in Ts), 2.07

4

(d, J = 1.0 Hz, 3H, 5-CH₃); ¹³C NMR (75.48 MHz, DMSO-d₆) δ

142.4 (C), 141.7 (C), 130.8 (C-2), 129.6 (2CH), 126.7 (C-5), 125.9

(2CH), 118.1 (C-3), 105.7 (C-4), 20.9 (CH₃in Ts), 12.1 (5-CH₃),

11.4 (2-CH₃). Anal. Calcd for C₁₃H₁₅NO₂S: C, 62.62; H, 6.06; N,

5.62. Found: C, 62.68; H, 6.27; N, 5.56.

Method B. Pyrrole 17c (0.317 g, 70%) was prepared from urea 12d

(0.643 g, 1.82 mmol) and PPh₃(0.572 g, 2.18 mmol) in THF (9 mL)

(reﬂux, 2 h 25 min) and then TsOH·H₂O (0.174 g, 0.92 mmol)

(reﬂux, 15 min) as described for 17a. The crude product was puriﬁed

by column chromatography on silica gel 60 (20 g) eluting with

petroleum ether/CHCl₃(from 1:3 to 1:5). The main fraction was

concentrated in a vacuum, and the solid residue was recrystallized from

EtOH.

1

(vs) (SO₂), 758 (s), 729 (vs), 686 (s) (CH_arom) cm⁻¹; H NMR

(300.13 MHz, DMSO-d₆) δ 11.53 (br s, 1H, NH), 7.77−7.88 (m, 2H,

ArH), 7.50−7.64 (m, 3H, ArH), 6.72 (dd, ³J = 3.1, ³J = 2.0 Hz, 1H, H-

3

4

5), 6.35 (dd, J = 3.1, J = 2.2 Hz, 1H, H-4), 2.36 (s, 3H, CH₃); ¹³C

NMR (75.48 MHz, DMSO-d₆) δ 144.2 (C), 132.33 (CH), 132.27 (C-

2), 129.2 (2CH), 125.9 (2CH), 118.3 (C-3), 117.5 (C-5), 108.7 (C-

4), 11.5 (CH₃). Anal. Calcd for C₁₁H₁₁NO₂S: C, 59.71; H, 5.01; N,

6.33. Found: C, 59.78; H, 5.14; N, 6.43.

2-Methyl-3-tosyl-1H-pyrrole (17b). Method A. To a mixture of

tosylacetone (11b) (0.570 g, 2.69 mmol) and NaH (0.063 g, 2.63

mmol) was added dry THF (10 mL), the mixture was stirred in an ice-

cold bath for 10 min, and to the resulting solution were added sulfone

6a (0.744 g, 2.63 mmol) and dry THF (5 mL). The suspension was

stirred at room temperature for 8 h, PPh₃(0.826 g, 3.15 mmol) was

added, and the reaction mixture was reﬂuxed under stirring for 1 h 5

min. Vigorous foaming occurred during all of the reﬂuxing time (use of

a straight condenser and periodic shaking of the ﬂask is

recommended). Then TsOH·H₂O (0.256 g, 1.35 mmol) was added,

and reﬂux was continued for 1 h 10 min (foaming slightly decreased

but continued). The solvent was removed in a vacuum, the obtained

residue was dissolved in CHCl₃(25 mL), subsequently washed with

saturated aq NaHCO₃(20 mL), H₂O (5 × 20 mL), and brine (2 × 10

mL), and dried over Na₂SO₄. Then the solvent was removed in a

vacuum, and the residue was puriﬁed by column chromatography on

silica gel 60 (25 g) eluting with petroleum ether/CHCl₃(from 1:1 to

1:5) (Note: the fraction with the product came after POPh₃). The

main fraction was concentrated in a vacuum, and the solid residue was

5-Ethyl-2-methyl-3-tosyl-1H-pyrrole (17d). Pyrrole 17d (0.346

g, 74%) was prepared from urea 12e (0.667 g, 1.77 mmol) and PPh₃

(0.561 g, 2.14 mmol) in THF (9 mL) (reﬂux, 2 h) and then

TsOH·H₂O (0.169 g, 0.89 mmol) (reﬂux, 15 min) as described for

17a. The crude product was puriﬁed by column chromatography on

silica gel 60 (25 g) eluting with petroleum ether/acetone (from 5:1 to

4.5:1). Mp 129−130.5 °C (EtOAc/petroleum ether, 1:3); IR (Nujol)

ν_max3269 (br vs), 3177 (m) (NH), 3100 (w), 3060 (w), 3030 (w)

(CH_arom), 1594 (m), 1520 (m), 1492 (w) (CC_arom), 1284 (s), 1141 (s)

(SO₂), 809 (s) (CH_arom) cm⁻¹; ¹H NMR (300.13 MHz, DMSO-d₆) δ

11.26 (br s, 1H, NH), 7.66−7.71 (m, 2H, ArH), 7.31−7.37 (m, 2H,

ArH), 5.99 (dt, ⁴J = 2.8, ⁴J = 1.0 Hz, 1H, H-4), 2.43 (dq, ³J = 7.5, ⁴J =

1.0 Hz, 2H, CH₂in Et), 2.34 (br s, 3H, 2-CH₃), 2.32 (s, 3H, CH₃in

3

Ts), 1.10 (t, J = 7.5 Hz, 3H, CH₃in Et); ¹³C NMR (75.48 MHz,

DMSO-d₆) δ 142.4 (C), 141.7 (C), 133.1 (C-5), 130.9 (C-2), 129.6

(2CH), 125.9 (2CH), 117.9 (C-3), 104.2 (C-4), 20.9 (CH₃in Ts),

19.8 (CH₂), 13.3 (CH₃in Et), 11.4 (2-CH₃). Anal. Calcd for

N

dx.doi.org/10.1021/jo302724y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

C₁₄H₁₇NO₂S: C, 63.85; H, 6.51; N, 5.32. Found: C, 63.77; H, 6.59; N,

5.38.

(7 mL) was reﬂuxed under stirring for 2 h, then TsOH·H₂O (0.115 g,

0.61 mmol) was added, and reﬂux was continued for 15 min. The

solvent was removed in a vacuum, the obtained residue was dissolved

in CHCl₃(20 mL), subsequently washed with saturated aq NaHCO₃

(10 mL), H₂O (3 × 10 mL), and brine (2 × 10 mL), and dried over

Na₂SO₄. Then the solvent was removed in a vacuum, and the obtained

residue was puriﬁed by column chromatography on silica gel 60 (15 g)

eluting with petroleum ether/acetone (from 100:1 to 20:1). The main

fraction was concentrated in a vacuum to give 17i (0.213 g, 69%) as a

slightly yellow oil. This oil crystallized upon prolonged trituration with

water to give a slightly violet solid. Mp 58.5−59.5 °C; IR (Nujol) ν_max

3410 (br vs) (NH), 1600 (m), 1581 (s), 1546 (m), 1494 (s) (CC_arom),

2-Phenyl-3-phenylsulfonyl-1H-pyrrole (17e).³⁸A solution of

trans-15e (0.599 g, 1.75 mmol) and TsOH·H₂O (0.033 g, 0.17 mmol)

in MeCN (7 mL) was reﬂuxed for 30 min under stirring, and then the

solvent was removed in a vacuum. The solid residue was triturated

with saturated aq NaHCO₃(2 mL) and petroleum ether (5 mL) and

cooled (0 °C), and the precipitate was ﬁltered, washed with ice-cold

water and petroleum ether, and dried to give 17e (0.475 g, 96%). Mp

156−157 °C (EtOAc/petroleum ether, 1:1); IR (Nujol) ν_max3299 (br

vs) (NH), 3029 (w), 3020 (w) (CH_arom), 1605 (m), 1584 (m), 1557

(m), 1499 (m) (CC_arom), 1298 (s), 1141 (s) (SO₂), 761 (s), 755 (s),

1

772 (s), 742 (s), 689 (s) (CH_arom) cm⁻¹; H NMR (300.13 MHz,

1

688 (s) (CH_arom) cm⁻¹; H NMR (300.13 MHz, DMSO-d₆) δ 12.02

3

DMSO-d₆) δ 11.72 (br s, 1H, NH), 7.63−7.68 (m, 2H, ArH), 7.32−

7.39 (m, 2H, ArH), 7.19−7.27 (m, 3H, ArH), 7.00−7.09 (m, 3H,

ArH), 7.03 (dd, ³J = 2.8, ³J = 2.8 Hz, H-5), 6.27 (dd, ³J = 2.8, ⁴J = 2.4

Hz, H-4); ¹³C NMR (75.48 MHz, DMSO-d₆) δ 140.1 (C), 134.6 (C-

2), 131.8 (C), 128.9 (2CH), 128.3 (2CH), 126.8 (CH), 126.6 (2CH),

124.8 (2CH), 124.5 (CH), 119.6 (C-5), 116.3 (C-4), 103.5 (C-3).

Anal. Calcd for C₁₆H₁₃NS: C, 76.46; H, 5.21; N, 5.57. Found: C,

76.12; H, 5.48; N, 5.54.

(br s, 1H, NH), 7.35−7.65 (m, 10H, ArH), 6.98 (d, J = 3.0 Hz, 1H,

H-5), 6.61 (d, ³J = 3.0 Hz, 1H, H-4); ¹³C NMR (75.48 MHz, DMSO-

d₆) δ 143.6 (C), 134.2 (C-2), 132.5 (CH), 130.3 (C), 129.2 (2CH),

129.0 (2CH), 128.4 (CH), 128.0 (2CH), 126.1 (2CH), 119.8 (C-3),

119.0 (C-5), 111.0 (C-4). Anal. Calcd for C₁₆H₁₃NO₂S: C, 67.82; H,

4.62; N, 4.94. Found: C, 67.83; H, 4.88; N, 5.05.

2-Phenyl-3-tosyl-1H-pyrrole (17f). Pyrrole 17f (0.436 g, 93%)

was prepared from trans-15f (0.567 g, 1.57 mmol) and TsOH·H₂O

(0.029 g, 0.15 mmol) in MeCN (10 mL) (reﬂux, 30 min) as described

for 17e. Mp 154−155 °C (EtOH); IR (Nujol) ν_max3252 (br s) (NH),

3029 (m), 3019 (w) (CH_arom), 1592 (m), 1558 (m), 1498 (m)

(CC_arom), 1309 (s), 1138 (s) (SO₂), 819 (m), 767 (s), 701 (s)

(CH_arom) cm⁻¹; ¹H NMR (300.13 MHz, DMSO-d₆) δ 11.98 (br s, 1H,

NH), 7.46−7.54 (m, 4H, ArH), 7.35−7.46 (m, 3H, ArH), 7.23−7.28

(m, 2H, ArH), 6.96 (d, ³J = 3.0 Hz, 1H, H-5), 6.58 (d, ³J = 3.0 Hz, 1H,

H-4), 2.30 (s, 3H, CH₃); ¹³C NMR (75.48 MHz, DMSO-d₆) δ 142.8

(C), 140.8 (C), 133.9 (C-2), 130.4 (C), 129.4 (2CH), 129.2 (2CH),

128.3 (CH), 128.0 (2CH), 126.1 (2CH), 120.2 (C-3), 118.9 (C-5),

111.0 (C-4), 20.9 (CH₃). Anal. Calcd for C₁₇H₁₅NO₂S: C, 68.66; H,

5.08; N, 4.71. Found: C, 68.53; H, 5.21; N, 4.75.

2-Methyl-3-phenylthio-1H-pyrrole (17j).³⁹A solution of

pyrimidine 13m (0.564 g, 1.92 mmol) and PPh₃(0.608 g, 2.09

mmol) in dry MeCN (9 mL) was reﬂuxed under stirring for 5 h, then

TsOH·H₂O (0.037 g, 0.20 mmol) was added, and reﬂux was continued

for 5 min. The solvent was removed in a vacuum, and the obtained

residue was dissolved in CHCl₃(20 mL), subsequently washed with

saturated aq NaHCO₃(10 mL), H₂O (5 × 10 mL), and brine (2 × 10

mL), and dried over Na₂SO₄. The solvent was removed in a vacuum,

and the residue was puriﬁed by column chromatography on silica gel

60 (28 g) eluting with petroleum ether/CHCl₃(from 4:1 to 1:2). The

main fraction was concentrated in a vacuum, and the obtained oily

substance was triturated with water (2 mL) until crystallization was

complete (rapid crystallization). The precipitate was ﬁltered and dried

to give 17j (0.281 g, 77%) as a slightly yellow solid. Mp 61−62.5 °C;

IR (Nujol) ν_max3327 (br vs) (NH), 3029 (w), 3020 (w) (CH_arom),

5-Methyl-2-phenyl-3-tosyl-1H-pyrrole (17g). Pyrrole 17g

(0.431 g, 97%) was prepared from 15g (0.530 g, 1.43 mmol) and

TsOH·H₂O (0.083 g, 0.43 mmol) in MeCN (8 mL) (reﬂux, 20 min)

as described for 17e. Mp 181−182 °C (MeCN); IR (Nujol) ν_max3276

(vs), 3192 (w), 3168 (w), 3124 (w) (NH), 3069 (w), 3043 (w), 3029

(w) (CH_arom), 1594 (sh), 1587 (m), 1519 (w), 1492 (w) (CC_arom),

1283 (s), 1139 (s) (SO₂), 811 (br m), 768 (m), 760 (m), 728 (m),

1579 (s), 1562 (m), 1488 (m) (CC_arom), 742 (s), 694 (s) (CH_arom

)

cm⁻¹; H NMR (300.13 MHz, DMSO-d₆) δ 11.14 (br s, 1H, NH),

7.16−7.24 (m, 2H, ArH), 7.00−7.07 (m, 1H, ArH), 6.93−6.99 (m,

2H, ArH), 6.76 (dd, ³J = 2.9, ³J = 2.6 Hz, 1H, H-5), 6.06 (dd, ³J = 2.9,

⁴J = 2.5 Hz, 1H, H-4), 2.16 (s, 3H, CH₃); ¹³C NMR (75.48 MHz,

DMSO-d₆) δ 140.5 (C), 132.9 (C-2), 128.7 (2CH), 124.6 (2CH),

124.2 (CH), 117.1 (C-5), 113.4 (C-4), 102.5 (C-3), 10.8 (CH₃). Anal.

Calcd for C₁₁H₁₁NS: C, 69.80; H, 5.86; N, 7.40. Found: C, 69.58; H,

6.06; N, 7.34.

1

699 (s) (CH_arom) cm⁻¹; H NMR (300.13 MHz, DMSO-d₆) δ 11.69

(br s, 1H, NH), 7.46−7.52 (m, 4H, ArH), 7.33−7.44 (m, 3H, ArH),

4

7.23−7.28 (m, 2H, ArH), 6.25 (dq, J = 2.7, J = 0.9 Hz, 1H, H-4),

2.30 (s, 3H, CH₃in Ts), 2.19 (d, ⁴J = 0.9 Hz, 3H, 5-CH₃); ¹³C NMR

(75.48 MHz, DMSO-d₆) δ 142.7 (C), 141.0 (C), 132.7 (C-2), 130.6

(C), 129.4 (2CH), 129.0 (2CH), 128.5 (C-5), 128.0 (CH), 127.9

(2CH), 126.1 (2CH), 119.7 (C-3), 108.5 (C-4), 20.9 (CH₃in Ts),

12.1 (5-CH₃). Anal. Calcd for C₁₈H₁₇NO₂S: C, 69.43; H, 5.50; N,

4.50. Found: C, 69.45; H, 5.65; N, 4.53.

2,5-Dimethyl-3-phenylthio-1H-pyrrole (17k).⁴⁰Pyrrole 17k

(0.354 g, 79%) as a slightly yellow solid was prepared from pyrimidine

13o (0.679 g, 2.21 mmol) and PPh₃(0.697 g, 2.66 mmol) in MeCN

(8 mL) (reﬂux, 4 h 30 min) followed by addition of TsOH·H₂O

(0.208 g, 1.09 mmol) (reﬂux, 15 min) as described for 17j. The crude

product was puriﬁed twice by column chromatography: (1) silica gel

60 (20 g) eluting with petroleum ether/acetone (from 12:1 to 8:1);

(2) silica gel 60 (5 g) eluting with petroleum ether/acetone (from

100:1 to 10:1). Crystallization from EtOAc/petroleum ether (1:9, v/v)

gave 17k as a white solid. Mp 121.5−122.5 °C (EtOAc/petroleum

ether, 1:8); IR (Nujol) ν_max3392 (vs) (NH), 3067 (w), 3056 (w),

3028 (w) (CH_arom), 1597 (w), 1581 (s), 1516 (m) (CC_arom), 744 (s),

692 (m) (CH_arom) cm⁻¹; ¹H NMR (300.13 MHz, DMSO-d₆) δ 10.87

(br s, 1H, NH), 7.16−7.23 (m, 2H, ArH), 6.99−7.06 (m, 1H, ArH),

5-Ethyl-2-phenyl-3-tosyl-1H-pyrrole (17h). Pyrrole 17h (0.347

g, 69%) was prepared from urea 12i (0.667 g, 1.55 mmol) and PPh₃

(0.486 g, 1.75 mmol) in THF (8 mL) (reﬂux, 2 h) and then

TsOH·H₂O (0.147 g, 0.77 mmol) (reﬂux, 30 min) as described for

17a. The crude product was puriﬁed by column chromatography on

silica gel 60 (22 g) eluting with petroleum ether/acetone (from 7:1 to

6:1). Mp 174−175 °C (EtOAc/petroleum ether, 1:2); IR (Nujol) ν_max

3285 (vs), 3163 (w) (NH), 3059 (w), 3024 (w) (CH_arom), 1595 (w),

1584 (m), 1515 (w), 1492 (w) (CC_arom), 1280 (s), 1140 (s) (SO₂),

1

814 (s), 768 (m), 697 (s) (CH_arom) cm⁻¹; H NMR (300.13 MHz,

4

DMSO-d₆) δ 11.68 (br s, 1H, NH), 7.46−7.52 (m, 4H, ArH), 7.33−

6.94−6.99 (m, 2H, ArH), 5.72 (dq, J = 2.7, J = 1.0 Hz, 1H, H-4),

4

2.15 (d, J = 1.0 Hz, 3H, 5-CH₃), 2.12 (s, 3H, 2-CH₃); ¹³C NMR

7.44 (m, 3H, ArH), 7.23−7.28 (m, 2H, ArH), 6.28 (dt, J = 2.5, J =

0.9 Hz, 1H, H-4), 2.55 (dq, ³J = 7.6, ⁴J = 0.9 Hz, 2H, CH₂in Et), 2.30

(75.48 MHz, DMSO-d₆) δ 140.7 (C), 131.6 (C-2), 128.7 (2CH),

126.3 (C-5), 124.6 (2CH), 124.1 (CH), 110.7 (C-4), 101.8 (C-3),

12.7 (5-CH₃), 10.8 (2-CH₃). Anal. Calcd for C₁₂H₁₃NS: C, 70.89; H,

6.45; N, 6.89. Found: C, 70.85; H, 6.63; N, 6.94.

Ethyl 2-Phenyl-1H-pyrrole-3-carboxylate (17l). Method A. A

solution of pyrimidine 13r (0.626 g, 1.96 mmol) and PPh₃(0.607 g,

2.32 mmol) in dry MeCN (10 mL) was reﬂuxed under stirring for 1 h,

then TsOH·H₂O (0.037 g, 0.19 mmol) was added, and reﬂux was

continued for 5 min. The solvent was removed in a vacuum, and the

3

(s, 3H, CH₃in Ts), 1.18 (t, J = 7.6 Hz, 3H, CH₃in Et); ¹³C NMR

(75.48 MHz, DMSO-d₆) δ 142.7 (C), 141.0 (C), 134.9 (C-5), 132.8

(C-2), 130.6 (C), 129.4 (2CH), 129.1 (2CH), 128.1 (CH), 127.9

(2CH), 126.1 (2CH), 119.5 (C-3), 106.9 (C-4), 20.9 (CH₃in Ts),

19.8 (CH₂), 13.3 (CH₃in Et). Anal. Calcd for C₁₉H₁₉NO₂S: C, 70.13;

H, 5.89; N, 4.30. Found: C, 70.05; H, 5.96; N, 4.30.

2-Phenyl-3-phenylthio-1H-pyrrole (17i). A solution of 12j

(0.436 g, 1.23 mmol) and PPh₃(0.384 g, 1.46 mmol) in dry THF

O

dx.doi.org/10.1021/jo302724y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

obtained residue was dissolved in CHCl₃(30 mL), subsequently

washed with saturated aq NaHCO₃(10 mL), H₂O (3 × 10 mL), and

brine (2 × 10 mL), and dried over Na₂SO₄. Then the solvent was

removed in a vacuum, and the residue was puriﬁed by column

chromatography on silica gel 60 (28 g) eluting with petroleum ether/

CHCl₃(from 3:1 to 3:2). The main fraction was concentrated in a

vacuum, and the obtained oily substance was triturated with H₂O (2

mL) until rapid crystallization was complete. The precipitate was

ﬁltered and dried to give 17l (0.353 g, 83%). Mp 73.5−75 °C (lit.⁴¹

mp 68 °C); IR (Nujol) ν_max3330 (s), 3266 (vs) (NH), 3055 (w),

3020 (w) (CH_arom), 1679 (vs) (CO), 1607 (w), 1580 (m), 1563

(m) (CC_arom), 1292 (vs), 1143 (vs) (C−O), 764 (s), 697 (m)

(CH_arom) cm⁻¹; ¹H NMR (300.13 MHz, DMSO-d₆) δ 11.62 (br s, 1H,

NH), 7.56−7.61 (m, 2H, ArH), 7.31−7.44 (m, 3H, ArH), 6.85 (dd, ³J

= 2.9, ³J = 2.5 Hz, 1H, H-5), 6.54 (dd, ³J = 2.9, ⁴J = 2.5 Hz, 1H, H-4),

4.11 (q, ³J = 7.1 Hz, 2H, OCH₂), 1.18 (t, ³J = 7.1 Hz, CH₃); ¹³C NMR

(75.48 MHz, DMSO-d₆) δ 164.2 (CO), 136.2 (C-2), 132.0 (C),

129.0 (2CH), 127.7 (2CH), 127.6 (CH), 118.5 (C-5), 111.3 (C-4),

111.1 (C-3), 58.8 (OCH₂), 14.2 (CH₃).

δ 164.2 (CO), 135.1 (C-2), 132.2 (C), 128.8 (2CH), 127.9 (C-5),

127.6 (2CH), 127.3 (CH), 110.8 (C-3), 109.0 (C-4), 58.6 (OCH₂),

14.2 (CH₃in OEt), 12.3 (5-CH₃).

3-Benzoyl-2-phenyl-1H-pyrrole (17n).⁴³Pyrrole 17n (0.193 g,

96%) as a slightly yellow solid was prepared from 16n (0.252 g, 0.82

mmol) and TsOH·H₂O (0.016 g, 0.08 mmol) in MeCN (5 mL)

(reﬂux, 10 min) as described for 17e. After crystallization from EtOH

the color of the product did not change. Mp 153−154 °C (EtOH); IR

(Nujol) ν_max3234 (br vs), 3185 (br vs) (NH), 3059 (m), 3020 (w)

(CH_arom), 1626 (vs), 1610 (vs), 1595 (vs) (CO and CC_arom), 1571

1

(vs), 1494 (s) (CC_arom), 754 (s), 701 (vs) (CH_arom) cm⁻¹; H NMR

(300.13 MHz, DMSO-d₆) δ 11.81 (br s, 1H, NH), 7.64−7.70 (m, 2H,

ArH), 7.21−7.53 (m, 8H, ArH), 6.93 (dd, ³J = 2.9, ³J = 2.3 Hz, 1H, H-

3

4

5), 6.38 (dd, J = 2.9, J = 2.0 Hz, 1H, H-4); ¹³C NMR (75.48 MHz,

DMSO-d₆) δ 191.3 (CO), 139.6 (C), 136.2 (C-2), 132.1 (C), 131.5

(CH), 129.0 (2CH), 128.5 (2CH), 128.0 (2CH), 127.9 (2CH), 127.4

(CH), 119.7 (C-3), 118.6 (C-5), 112.7 (C-4). Anal. Calcd for

C₁₇H₁₃NO: C, 82.57; H, 5.30; N, 5.66. Found: C, 82.43; H, 5.45; N,

5.59.

Method B. To a stirred suspension of NaH (0.080 g, 3.33 mmol) in

dry MeCN (6 mL) cooled in an ice-cold bath was added a solution of

ethyl benzoyl acetate (11h) (0.677 g, 3.43 mmol) in MeCN (4 mL),

and the resulting mixture was stirred for 8 min. The ice-bath was

removed, and to the obtained solution were added sulfone 6a (0.942 g,

3.33 mmol) and MeCN (3 mL). The suspension was stirred at room

temperature for 8 h, PPh₃(1.088 g, 4.15 mmol) was added, and the

reaction mixture was reﬂuxed under stirring for 1 h. Then TsOH·H₂O

(0.129 g, 0.68 mmol) was added, and reﬂux was continued for 1 h

(TLC control). The solvent was removed in a vacuum, and the

obtained residue was dissolved in CHCl₃(45 mL), subsequently

washed with saturated aq NaHCO₃(10 mL), H₂O (5 × 10 mL), and

brine (2 × 10 mL), and dried over Na₂SO₄. Then the solvent was

removed in a vacuum, and the residue was puriﬁed twice by column

chromatography: (1) silica gel 60 (30 g) eluting with petroleum ether/

CHCl₃(from 3:1 to 2:1); (2) silica gel 60 (28 g) eluting with

petroleum ether/CHCl₃(from 3:1 to 3:2). The main fraction was

concentrated in a vacuum, and the obtained oily substance was

triturated with H₂O (2 mL) upon cooling until crystallization was

complete (about 30 min). The precipitate was ﬁltered, and dried to

give 17l (0.636 g, 89%).

ASSOCIATED CONTENT

* Supporting Information

■

S

Copies of ¹H and ¹³C NMR and IR spectra of all the

synthesized compounds; ¹H,¹H-NOESY of trans-15e; ¹H NMR

spectra of the reaction mixtures formed from 12a,j,13b,m,r and

PPh₃. This material is available free of charge via the Internet at

http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author

*E-mail: shutalev@orc.ru.

Notes

■

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

This research was supported by Russian foundation for basic

research no. 01201274375 and the Presidential grant for young

scientists no. MK-4400.2011.3.

Ethyl 5-Methyl-2-phenyl-1H-pyrrole-3-carboxylate (17m).

To a stirred suspension of NaH (0.054 g, 2.25 mmol) in dry MeCN

(4 mL) cooled in an ice-cold bath was added a solution of ethyl

benzoyl acetate (11h) (0.459 g, 2.33 mmol) in MeCN (3.5 mL), and

the resulting mixture was stirred for 10 min. The ice-bath was

removed, and to the obtained solution were added sulfone 6c (0.668 g,

2.25 mmol) and MeCN (4.5 mL). The suspension was stirred at room

temperature for 8 h, PPh₃(0.724 g, 2.76 mmol) was added, and the

reaction mixture was reﬂuxed under stirring for 1 h (pink coloring of

reaction mixture appeared). Then TsOH·H₂O (0.217 g, 1.14 mmol)

was added, and reﬂux was continued for 30 min (pink coloring

changed to slightly yellow). The solvent was removed in a vacuum,

and the obtained residue was dissolved in CHCl₃(26 mL),

subsequently washed with saturated aq NaHCO₃(10 mL), H₂O (5

× 10 mL), and brine (2 × 10 mL), and dried over Na₂SO₄. Then the

solvent was removed in a vacuum, and the residue was puriﬁed by

column chromatography on silica gel 60 (22 g) eluting with petroleum

ether/CHCl₃(from 5:1 to 3:1). The main fraction was concentrated in

a vacuum, and the obtained oily substance was triturated with water (2

mL) upon cooling until crystallization was complete (about 1.5−2 h).

The precipitate was ﬁltered and dried to give 17m (0.439 g, 85%). Mp

77.5−78.5 °C (benzene/petroleum ether, 1:4) (lit.⁴²mp 81 °C); IR

(Nujol) ν_max3306 (vs), 3267 (vs), 3198 (m), 3179 (m) (NH), 3077

(w), 3058 (w), 3029 (w) (CH_arom), 1689 (sh), 1672 (br vs) (CO),

1613 (w), 1592 (m), 1576 (w), 1532 (m) (CC_arom), 1241 (s), 1161

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Q

dx.doi.org/10.1021/jo302724y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

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R

dx.doi.org/10.1021/jo302724y | J. Org. Chem. XXXX, XXX, XXX−XXX

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Synthesis of γ-azido-β-ureido ketones and their transformation into functionalized pyrrolines and pyrroles via staudinger/aza-wittig reaction

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