Further Developments in the Reaction of 2-Aza-1,3,5-trienes with Superbases: Competitive Formation of New 4,5-Dihydro-1,3-thiazoles, Dihydroazepines, and Azepines by Tandem Deprotonation-Cyclization

SYNTHESIS

0

3

9

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7

8

1

4

3

7

-

2

1

0

X

2015, 47, 3593–3610

paper

3593

N. A. Nedolya et al.

Paper

Synthesis

Further Developments in the Reaction of 2-Aza-1,3,5-trienes with

Superbases: Competitive Formation of New 4,5-Dihydro-1,3-thi-

azoles, Dihydroazepines, and Azepines by Tandem Deprotonation–

Cyclization

i. n-BuLi

Nina A. Nedolya*

THF–hexane

Ol’ga A. Tarasova

Alexander I. Albanov

Boris A. Trofimov

R²

ii. R²R³CHN=C=S

iii. R⁴CH₂Br

N

R³

OMe

iv. [1,5]-H shift

base

•

S

R⁴

one-pot

OR¹

A. E. Favorsky Irkutsk Institute of Chemistry of the Russian Academy

of Sciences, Siberian Branch, Favorsky Street 1, 664033 Irkutsk,

Russian Federation

R²

R³

R⁴

R⁵

OR¹

R⁵

OR¹

N

nina@irioch.irk.ru

+/or

R⁴

¹= Me, n-Bu, EtOCH(Me); R²= R³= Me, R²R³= (CH₂)₄; R⁴= vinyl, Ph; R⁵= H,

R³R⁵= (CH₂)₃, (CH₂)₂CH; Base: t-BuOK, t-BuONa, LDA, n-BuLi, etc.

+/or

R³

S

N

R¹O

R

Received: 08.05.2015

Accepted after revision: 05.06.2015

Published online: 03.08.2015

es an unprecedented structural reorganization of 2-aza-

1,3,5-trienes 1 into seven-membered azaheterocycles un-

der the action of potassium tert-butoxide (1.2–1.5 equiv) in

anhydrous tetrahydrofuran (0 °C, 10 min^12aor 15 °C, 30

min^13a) or in a mixture of dimethyl sulfoxide and tetrahy-

drofuran (ca. –30 °C, 30 min)^11–13according to Scheme 1

(through in situ generation and [1,7]-azaelectrocyclization

of azatrienyl-anions A), and represents a novel, general, and

facile entry to both dihydroazepines 2 and azepines 3 with

rare substituents.

We have also found that the yield and the ratio of 4,5-

dihydro-3H-azepines 2 and 3H-azepines 3 is strongly influ-

enced by both the reaction conditions and the structure

and nature of the substituents in both the ketimine and bu-

tadiene parts of the 2-aza-1,3,5-trienes 1 as well as at the

sulfur atom.^11–13

DOI: 10.1055/s-0034-1378805; Art ID: ss-2015-z0302-op

Abstract Allyl- and benzylsulfanyl-substituted 2-aza-1,3,5-trienes,

which are readily available from alkoxyallenes, isothiocyanates, and allyl

or benzyl bromide, are easily transformed into polyfunctionalized 4,5-

dihydro-1,3-thiazoles (2-thiazolines) through deprotonation of the acti-

vated SCH₂group upon treatment with superbase, followed by intra-

molecular [1,5]-ring-closing. Competitive deprotonation of the methyl

group or methylene fragment of the ketimine function of the same

molecule, followed by [1,7]-electrocyclization, leads to seven-mem-

bered azaheterocycles, dihydroazepines and/or azepines.

Key words allenes, isothiocyanates, superbases, carbanions, intramo-

lecular cyclizations, azepines, 2-thiazolines

Azatrienic systems, R²R³C=C=C(R¹)C(SAlk)=NR⁴, which

are easily attained from allenes or alkynes, isothiocyanates,

and alkylating agents in one preparative step in good to ex-

cellent yields, are used as direct atom-economic precursors

of important classes of nitrogen-containing heterocycles

such as pyrroles¹and quinolines,^2,3cyclobutenes,³as well as

another azatrienes, in particular, conjugated 2-aza-1,3,5-

trienes (through [1,5]-H shift).⁴The latter, in turn, are em-

ployed in the syntheses of other significant azaheterocy-

cles, namely, previously unavailable 2,3-dihydropyri-

dines,^1a,2b,3–5pyridines,⁶5,6-dihydropyridin-2(1H)-ones,⁷

5,6-dihydropyridin-3(4H)-ones,⁸pyridine-2(1H)-thiones,⁹

and 2-azabicyclo[3.2.0]hept-1-enes.^2b,4,10

R⁴

R²

R¹

R⁴

R²

R⁴

R²

R¹

t-BuOK

+/or

THF or

THF–DMSO

N

SAlk

1

3

2

t-BuOK

H₂O

R⁴

R²

– AlkS

R¹

R⁴

R¹

SAlk

K

R²

N

SAlk

A

B

C

R¹= OAlk, OAll, OCH(Me)OAlk, Ar, HetAr; R²= H, Alk; R⁴= H;

R²,R⁴= (CH₂)_n, n = 3–5

Recently, we have shown that alkylsulfanyl-substituted

2-aza-1,3,5-trienes, H₂C=CHC(R¹)=C(SAlk)N=CR²R³, can also

serve as direct precursors of a new series of azacyclohepta-

dienes and azacycloheptatrienes.^11–13The process compris-

Scheme 1 Synthesis of dihydroazepines 2 and azepines 3 through

structural reorganization of 2-aza-1,3,5-trienes 1 in the presence of po-

tassium tert-butoxide

3594

N. A. Nedolya et al.

Paper

Synthesis

For example, methylsulfanyl-substituted 2-aza-1,3,5-

triene 1a, which is the product of a sigmatropic [1,5]-H

shift in the 1-aza-1,3,4-triene 4a (derived from methoxyal-

lene, isopropyl isothiocyanate, and methyl iodide), contam-

inated with pyrrole 5a and 2,3-dihydropyridine 6a (import-

ant side products of the compound 1a synthesis) (Scheme

2), by treatment with potassium tert-butoxide (1.2 equiv)

in DMSO–THF (ca. 1:5, ca. –30 °C, 30 min)^12a,ccan be trans-

formed into 3-methoxy-7-methyl-2-(methylsulfanyl)-4,5-

dihydro-3H-azepine (2a) and 6-methoxy-2-methyl-3H-az-

epine (3a) in yields of 33 and 38%, respectively (Scheme 3).

sulfur atom) 2-aza-1,3,5-trienes, derived from alkoxyal-

lenes, isothiocyanates, and allyl or benzyl bromide, with su-

perbases.

Surprisingly,

allylsulfanyl-substituted

2-aza-1,3,5-

triene 1b, in contrast to alkylsulfanyl-substituted ana-

logues, including 2-aza-1,3,5-triene 1a (Schemes 1 and

2),^12a,cunder similar conditions, react with potassium tert-

butoxide yielding, instead of the expected 2-(allylsulfanyl)-

3-methoxy-6-methyl-4,5-dihydro-3H-azepine (2b), a prod-

uct that was first identified as 5-[(Z)-ethylidene]-2-(1-me-

thoxyallyl)-4,4-dimethyl-1,3-thiazole (7a) (ca. 18% yield),

along with 3H-azepine 3a (ca. 7% yield) (Scheme 4).¹⁴Later,

as a result of extensive NMR studies, the actual structure of

the product 7a was established as 2-[(Z)-1-methoxyprop-

1-enyl]-4,4-dimethyl-5-vinyl-4,5-dihydro-1,3-thiazole (7b).

Furthermore, the corresponding pyrrole 5b, which is pres-

ent in the starting 2-aza-1,3,5-triene 1b as a side product of

its synthesis, was isolated (ca. 13% yield), with the conver-

sion of 1b being 100% based on ¹H NMR spectroscopic anal-

ysis.

OMe

•

i. n-BuLi

OMe

THF–hexane

ii. i-PrN=C=S

SMe

iii. MeI

N

OMe

SMe

5a (~10%)

•

~65 °C

15 min

N

OMe

SMe

OMe

S

4a

N

SMe

N

•

N

1a

6a (~10%)

i. n-BuLi,

THF–hexane

ii. i-PrN=C=S

iii. CH₂=CHCH₂Br

6b

Scheme 2 Synthesis of azatrienes 4a and 1a, accompanied by partial

thermo-induced azaheterocyclization to pyrrole 5a and 2,3-dihydropyr-

idine 6a, respectively

X

OMe

S

OMe

S

Δ

S

+

•

N

OMe

SMe

t-BuOK

OMe

+

1b

THF–DMSO

ca. –30 °C

30 min

N

SMe

4b

5b (~13%)

THF–DMSO

ca. –30 °C

30 min

2a (33%)

1a

3a (38%)

t-BuOK

Scheme 3 Structural reorganization of 2-aza-1,3,5-triene 1a to 4,5-di-

hydro-3H-azepine 2a and 3H-azepine 3a under the action of potassium

tert-butoxide

X

N

S

N

S

OMe

N

S

MeO

However, the same compounds were obtained in a ratio

of approximately 3:1 when the reaction depicted in Scheme

3 was carried out in THF (in the absence of DMSO) at 0 °C

for 10 minutes.^12a

7a

2b

3a

7b

Scheme 4 Synthesis and structural reorganization of azatrienes 4b and

1b

The augmentation of the size of the alkyl substituent at

the sulfur atom in 2-aza-1,3,5-triene 1a leads to the in-

crease in the amount of 4,5-dihydro-3H-azepine in the

mixture of the products. Thus, on going from methylsulfa-

nyl to bulkier ethylsulfanyl and butylsulfanyl substituents,

the ratio of 4,5-dihydro-3H-azepine 2 to 3H-azepine 3

changed noticeably in favor of the corresponding 4,5-dihy-

dro-3H-azepine, from 1.2:1 to 2.3:1 and to 4:1, respective-

ly.^12c

Similarly, treatment of benzylsulfanyl-substituted 2-

aza-1,3,5-triene 1c with potassium tert-butoxide afforded a

new thiazole derivative, 2-[(Z)-1-methoxyprop-1-enyl]-

4,4-dimethyl-5-phenyl-4,5-dihydro-1,3-thiazole (7c) (20%

yield), along with 2-(benzylsulfanyl)-3-methoxy-7-methyl-

4,5-dihydro-3H-azepine (2c) (23% yield) and 3H-azepine 3a

(5% yield) (Scheme 5).^14b,15The presence of pyrrole 5c (ca.

10%) among the reaction products is caused by the compet-

itive heterocyclization of 1-aza-1,3,4-triene 4c mentioned

above, which occurs during its isomerization to 2-aza-

1,3,5-triene 1c.

Following on from our previous studies on the reactivity

and the synthetic utility of 2-aza-1,3,5-trienes, here we aim

to explore the reaction of functionally substituted (at the

3595

N. A. Nedolya et al.

Paper

Synthesis

In this context, the formation of the seven-membered

OMe

•

azaheterocycles is thought to proceed through a mecha-

nism similar to that depicted in Scheme 1 (via intermedi-

ates A–C). Deprotonation of the methyl group from the keti-

mine moiety of the 2-aza-1,3,5-trienic system accompa-

nied by [1,7]-electrocyclization of the carbanion A gives

azacycloheptadienyl anion C, which undergoes either pro-

tolysis or elimination of the sulfide anion (RCH₂S^–) leading

to 4,5-dihydro-3H-azepine or 3H-azepine, respectively

(Scheme 6).

i. n-BuLi

N

S

Ph

THF−hexane

ii. i-PrN=C=S

iii. PhCH₂Br

6c

X

OMe

S

OMe

S

Δ

S

Ph

+

•

Ph

N

Ph

N

1c

4c

5c (~10%)

However, the unexpected structural transformation of

2-aza-1,3,5-trienes 1b and 1c into 4,5-dihydro-1,3-thi-

azoles 7b and 7c appears to involve competitive deprotona-

tion of the allylsulfanyl or benzylsulfanyl substituent upon

treatment with potassium tert-butoxide, and most likely

proceeds via intermediates D–F according to Scheme 6. Ac-

tivation of the SCH₂moiety with a vinyl or phenyl group

makes its protons sufficiently acidic for easy deprotonation.

It should be emphasized that, apart from our short com-

munications,^14,15no data are available on either the synthe-

sis or thermo- or base-induced transformations of allyl-

and benzylsulfanyl-substituted azatrienic systems. Partici-

pation of the allylsulfanyl and benzylsulfanyl groups in the

process of deprotonation of the 2-aza-1,3,5-trienes 1b and

1c under the investigated conditions is also not anticipated

because allyl and benzyl sulfides are usually metallated by

n-BuLi¹⁶or lithium amides.^16a,17Moreover, because unsym-

metrically substituted allylic anions are ambident, and can

react with electrophiles at two positions (α- and γ-), the se-

lectivity of such reactions is not predictable.¹⁸In our case,

only the product derived from the α-carbanion is obtained.

Elimination of sulfur-centered allyl- and benzylsulfanyl

anions from allyl- and benzylsulfanyl-substituted azacyclo-

heptadienyl anions, type C (Scheme 6), leading to azepine

3a, is also unknown.

THF–DMSO

ca. –30 °C

30 min

t-BuOK

N

OMe

Ph

S

N

S

Ph

MeO

3a

7c

2c

Scheme 5 Structural reorganization of 2-aza-1,3,5-triene 1c in the

presence of potassium tert-butoxide

Such results arise from the fact that, in contrast to

methylsulfanyl-substituted 2-aza-1,3,5-triene 1a (Scheme

3),^12a,c2-aza-1,3,5-trienes 1b and 1c have two potential re-

active centers in their structure, and along with base-sensi-

tive ketimine fragment (N=CMe₂), the functional substitu-

ent at the sulfur atom, i.e., allyl or benzyl group, can also

participate in the reaction with potassium tert-butoxide

(Scheme 6).

K

OMe

N

S

R

A

B

C

H₂O

– RCH₂S

t-BuOK

On the basis of these findings and because of the high

value of both azepines¹⁹and thiazoles²⁰and their deriva-

tives (including 2-thiazolines²¹) of natural and synthetic or-

igin for pharmacology, medicine, and other important ar-

eas, we have studied the reactions of benzylsulfanyl-substi-

tuted conjugated azatrienic systems with different

superbases as a novel approach to 4,5-dihydro-1,3-thi-

azoles as well as to new representatives of 4,5-dihydro-3H-

azepines and 3H-azepines. It should be noted that despite

the high importance of thiazole-ring-containing products,

2-alkenyl-4,5-dihydro-1,3-thiazoles remain rare,²²but 2-

OMe

+/or

t-BuOK

N

2c

N

S

R

THF−DMSO

N

3a

ca. –30 °C

30 min

S

R

N

OMe

R

S

1b,c

MeO

7b,c

t-BuOK

H₂O

K

N

(1-alkoxyprop-1-enyl)-4,5-dihydro-1,3-thiazoles,

apart

R

S

R

S

from the two representatives 7b and 7c mentioned

MeO

OMe

above,^14,15are unknown.

E

F

D

R = CH₂=CH (b), Ph (c)

For simplicity, the study of the influence of the reaction

conditions on the course of the reaction, the yield, and the

ratio of products formed as a result of competitive reactions

of deprotonation on SCH₂fragment (leading to 4,5-dihydro-

1,3-thiazole) and on ketimine fragment (leading to dihy-

droazepine and azepine) was carried out by using benzyl-

Scheme 6 Plausible mechanisms of reorganization of 2-aza-1,3,5-

trienes 1b and 1c to 4,5-dihydro-1,3-thiazoles 7b and 7c, 4,5-dihydro-

3H-azepine 2c, and 3H-azepine 3a in the presence of potassium tert-

butoxide

3596

N. A. Nedolya et al.

Paper

Synthesis

sulfanyl-substituted 2-aza-1,3,5-triene 1c. The order and

rate of the mixing of reagents (adding azatriene to super-

base or superbase to azatriene; in one portion, portionwise,

or dropwise), their ratio, the concentration of the reaction

mixture, the nature of superbase [t-BuOK–DMSO, t-BuONa–

DMSO, n-BuLi, n-BuLi–TMEDA, n-BuLi–t-BuOK, lithium di-

isopropylamide (LDA), LDA–t-BuOK], counter-ion (Li⁺, Na⁺

or K⁺), solvent (THF–hexane, THF–hexane–DMSO), tem-

perature (from –100 to 45 °C), and time of the various stag-

es of the process (deprotonation/cyclization) have been var-

ied.

In experiments using LDA as deprotonating base [varied

order and rate of the mixing of reagents, temperature (from

–100 to 0 °C) and time (15–30 min) of the various stages of

the process, and the nature of the counter-ion (Li⁺, K⁺)], for-

mation of seven-membered azaheterocycles was sup-

pressed. In all cases, the main separable product of the re-

action was 4,5-dihydro-1,3-thiazole 7c in mixture with

pyrrole 5c in a ratio of approximately 1:1 to 1.5. However,

because of the side processes (tar-like material formation

and perhaps destruction of intermediates) the yield of 4,5-

dihydro-1,3-thiazole 7c remained rather low (ca. 10–20%).

When the reaction is carried out at –70 to –63 °C or at

–55 to –48 °C for 30 min, in the reaction mixture, along

with 4,5-dihydro-1,3-thiazole 7c and pyrrole 5c, starting 2-

aza-1,3,5-triene 1c was identified by ¹H NMR spectroscopic

analysis in a ratio of approximately 1.5:1.5:1. Its presence

can be explained by the incomplete conversion on depro-

tonation and/or by incomplete intramolecular cyclization of

formed carbanion D (with a lithium counter-ion) (Scheme

6). It is also possible that deprotonation of the ketimine

fragment is realized in this case; however, the reaction con-

ditions are not suitable for the ring-closure of formed car-

banion A (with a lithium counter-ion) to seven-membered

azaheterocycle (intermediate C; Scheme 6). In both cases,

treatment of the reaction mixture with water led to the re-

generation of initial 2-aza-1,3,5-triene 1c.

On deprotonation of 2-aza-1,3,5-triene 1c with n-BuLi

(a solution of n-BuLi in hexane was added dropwise to a

solution of 2-aza-1,3,5-triene 1c in THF in several minutes)

at –100 to –30 °C with subsequent addition of DMSO (to fa-

cilitate the intramolecular cyclization of generated carban-

ion D into thiazole intermediate E, Scheme 6), the forma-

tion of azepine structures 2c and/or 3a was also not ob-

served, but the yield of 4,5-dihydro-1,3-thiazole 7c was

only about 10%.

The use of a more basic system, n-BuLi–TMEDA, to

which the solution of 2-aza-1,3,5-triene 1c in THF was add-

ed in one portion and stirred for 30 min at –70 to –60°С, did

not lead to 4,5-dihydro-1,3-thiazole 7c or other products of

deprotonation/cyclization. After usual work-up, starting

compound 1c and pyrrole 5c were isolated in a ratio of ap-

proximately 58:42 (by ¹H NMR spectroscopic analysis) from

the reaction mixture. Like the experiments with the LDA,

this result may be due to incomplete deprotonation of 2-

aza-1,3,5-triene 1c under the studied conditions and/or the

absence of intramolecular cyclization of the formed carban-

ions (both A and D; Scheme 6) with a lithium counter-ion.

The change of a 2-aza-1,3,5-triene 1c/pyrrole 5c ratio from

approximately 90:10 (before treatment with superbase) to

approximately 58:42 (after treatment) evidences the insta-

bility of starting compound 1c or its derivatives (intermedi-

ate or final) under the reaction conditions.

Lithiation of 2-aza-1,3,5-triene 1c with n-BuLi (a solu-

tion of n-BuLi in hexane was added dropwise to a solution

of 2-aza-1,3,5-triene 1c in THF at –100 to –80 °C for a few

minutes, then the temperature was increased to –30 °C), re-

placement of the Li⁺cation with the K⁺cation (by adding t-

BuOK to the reaction mixture at –90 to –40 °C), addition of

a 1:1 mixture of THF and DMSO, and stirring for 30 min at

–35 to –25 °C led to a mixture of 4,5-dihydro-1,3-thiazole

7c, 4,5-dihydro-3H-azepine 2c, and pyrrole 5c in a ratio of

approximately 1.4:0.7:1 (by ¹H NMR spectroscopic analysis),

from which very pure 4,5-dihydro-1,3-thiazole 7c was easi-

ly isolated by column chromatography on neutral alumina

in 23% yield.

To increase the yield and selectivity of the process of

deprotonation of benzylsulfanyl-substituted 2-aza-1,3,5-

triene 1c leading to the formation of thiazole or dihydro-

azepine ring, various changes in experimental conditions

were also investigated in the presence of more easily han-

dled potassium or sodium tert-butoxide; the results are

summarized in Table 1.

As mentioned above, treatment of 2-aza-1,3,5-triene 1c

with potassium tert-butoxide (1.3 equiv) in DMSO–THF [ca.

–30 °C, 30 min (method A)] afforded 4,5-dihydro-3H-aze-

pine 2c, 3H-azepine 3a, and 4,5-dihydro-1,3-thiazole 7c in

23, 5, and 20% yield, respectively (Scheme 5 and Table 1, en-

try 4).

By varying the amount of potassium tert-butoxide and

the reaction time, it was found that 100% conversion of 2-

aza-1,3,5-triene 1c was reached within 5 minutes of stir-

ring of the reaction mixture at approximately –30 °С, as

with 2 and with 1.3 equivalents of base (Table 1, entries 3

and 5). A distinctive feature of the experiments that lasted

over 5 minutes, is the almost complete absence of visible

tar-like products. As can be seen in Table 1, 4,5-dihydro-

3H-azepine 2c was the main reaction product formed in all

cases. Its content in the product mixture ranged from 42 to

69%. The content of 4,5-dihydro-1,3-thiazole 7c varied from

2 to 22%, and was 10–15% in most experiments. In THF

(without DMSO), 100% conversion of 2-aza-1,3,5-triene 1c

was also attained easily and quickly, within 10 minutes at

–60 to 0 °C (Table 1, entry 8). In this case, the ratio of the

reaction products was comparable with the ratio of the

products obtained with 2 equivalents of potassium tert-bu-

toxide at –30 °C for 5 minutes (Table 1, entry 3). It was

found that the reaction could be carried out without DMSO

3597

N. A. Nedolya et al.

Paper

Synthesis

Table 1 Base-Induced Transformations of 2-Aza-1,3,5-triene 1c into Dihydrothiazole 7c, Dihydroazepine 2c, and Azepine 3a (Scheme 5)

Entry

t-BuOK

(equiv)

Solvent

Temp (°C)

Time (min) Ratio of products^a(yields (%)^b)

7c 2c

Total yield (%)

3a

10 (4)

5c^c

20 (8)

1

2

THF–DMSO

THF

–30 to –28

–32 to –28

–31 to –30

–33 to –26

–31 to –29

–32 to –28

–60 to 0

30

10

5

10 (5)

60 (25)

42

d

2

2 (–^d)

16 (9)

20 (20)^e

15 (9)

11 (–^d)

10 (5)

15 (9)

0^g

65 (–^d)

61 (35)

44 (23)^e

60 (36)

65 (–^d)

69 (31)

62 (35)

0^g

8 (–^d)

6 (2)

14 (5)^e

9 (5)

0

25 (–^d)

17 (10)

22 (11)^e

16 (10)

24 (–^d)

21 (11)

19 (11)

(ca. 10)

16 (–^d)

17 (10)

–

3

2

56

4

1.3

30

5

59^e

60

5

d

6

30

15

10

30

50

5

–

7

THF

0

47

8

THF

4 (2)

0^g

57

9^f

10^f

11^f

THF–DMSO

–33 to –23

–30 to 45

40–42

ca. 10

22 (–^d)

10 (6)

42 (–^d)^h

56 (35)

20 (–^d)

17 (11)

–

d

62

^aBased on ¹H NMR spectroscopic analysis of the crude product.

^bIsolated yield based on the reagent used in the synthesis of 4 in the lowest molar amount, namely, isothiocyanate.

^cPresent in starting 2-aza-1,3,5-triene.

^dNot estimated.

^eYield of isolated products.

^fWith t-BuONa.

^gNo reaction.

^hDihydroazepine 2c appeared in the reaction mixture when the temperature reached 20 °C.

and at lower temperature (ca. –30 °C) and, in this case, 3H-

azepine 3a was not formed within 15 and 30 minutes (Table

1, entries 6 and 7).

one-pot synthesis of 1-aza-1,3,4-trienes 4d–f in yields of

87–100%, and their thermally induced sigmatropic rear-

rangement (Scheme 7).

When sodium tert-butoxide was used instead of potas-

sium tert-butoxide in the reaction with 2-aza-1,3,5-triene

1c under similar conditions, no product formation was ob-

served (Table 1, cf. entries 4 and 9). The starting compound

was recovered from the reaction mixture. However, when a

mixture of 2-aza-1,3,5-triene 1c with sodium tert-butoxide

was heated in a solution of DMSO–THF at approximately

40 °C for 5 minutes (method B), a mixture of 4,5-dihydro-

1,3-thiazole 7c, 4,5-dihydro-3H-azepine 2c, 3H-azepine 3a,

and pyrrole 5c was obtained in a ratio of approximately

10:56:17:17 (Table 1, entry 11). The conversion of 2-aza-

1,3,5-triene 1c was quantitative.

To outline the scope and limitations of the developed

approach to 2-(1-alkoxyprop-1-enyl)-5-phenyl-4,5-dihy-

dro-1,3-thiazoles, despite the modest isolated yield of 4,5-

dihydro-1,3-thiazole 7c, the reactions of some benzylsulfa-

nyl-substituted 2-aza-1,3,5-trienes 1d–f with t-BuOK (un-

der conditions close to the optimum found for azatriene 1c)

as well as with other superbases (t-BuONa, LDA, and n-

BuLi–t-BuOK) were conducted for comparison.

OR¹

•

R²

R³

i. n-BuLi

N

S

Ph

THF−hexane

ii. R²R³CHN=C=S

iii. PhCH₂Br

6d–f

X

OR¹

S

OR¹

S

Ph

iv. Δ

R²

R³

•

+

Ph

R²

N

Ph

R²

5d–f

R³

4d–f

R³

1d–f

d: R¹= Me; R²,R³= (CH₂)₄

e: R¹= n-Bu; R²= R³= Me

f: R¹= EtOCH(Me); R²= R³= Me

Scheme 7 Synthesis of 1-aza-1,3,4-trienes 4d–f and subsequent rear-

rangement into 2-aza-1,3,5-trienes 1d–f and pyrroles 5d–f. Conditions:

(i) –100 to –50 °C, 5–10 min; (ii) –80 to –30 °C, 20 min; (iii) –80 to

18 °C, ca. 1 h; (iv) 50–60 °C/ca. 1 mmHg, 5–10 min.

The isomerization of 1-aza-1,3,4-trienes 4d–f into the

target 2-aza-1,3,5-trienes 1d–f was completed by heating

under reduced pressure on a rotary evaporator at 55–60 °C

for 10 minutes followed by vacuum treatment at 50–60 °C

(ca. 1 mmHg) for 5–10 minutes. This process was accompa-

nied by competitive intramolecular [1,5]-heterocyclization

of compounds 4d–f into pyrroles 5d–f (ca. 7–15% as mix-

New representatives of 2-aza-1,3,5-trienes, namely,

previously unknown and unavailable compounds 1d–f,

were prepared from α-lithiated alkoxyallenes [methoxy-,

butoxy-, and (1-ethoxyethoxy)allenes], isopropyl or cyclo-

pentyl isothiocyanates, and benzyl bromide through the

3598

N. A. Nedolya et al.

Paper

Synthesis

1

tures with 2-aza-1,3,5-trienes 1d–f) (Scheme 7), the con-

version of 1-aza-1,3,4-trienes 4d–f was 100%. The total

yield of compounds 1 and 5 was almost quantitative (ca.

84–100%). Unlike azatrienes 4a and 1a, side formation of

2,3-dihydropyridines 6d–f during the rearrangement of 1-

aza-1,3,4-trienes 4d–f into 2-aza-1,3,5-trienes 1d–f was

not observed.

Notably, parallel formation of pyrroles as by-products

during sigmatropic rearrangement of 1-aza-1,3,4-trienes

took place only in the case of alkoxy-substituted deriva-

tives.^1a,4Attempts to isolate 2-aza-1,3,5-trienes from the

mixture with pyrroles by using common techniques proved

unsuccessful. During distillation in vacuo the compounds

cyclized into 2,3-dihydropyridines,^4,5but upon chromato-

graphic separation on a column with Al₂O₃or SiO₂, com-

plete decomposition occurred. Thus, the crude 2-aza-1,3,5-

trienes 1 were used in the reaction with superbase without

further purification.

Apart from 2-aza-1,3,5-triene 1c, the influence of the

substituent in the ketimine part of the 2-aza-1,3,5-trienic

molecule was demonstrated with the example of 1d, de-

rived from methoxyallene and cyclopentyl isothiocyanate

(Scheme 7). Treatment with potassium tert-butoxide of 2-

aza-1,3,5-triene 1d, with a fragment of the imine of cyclo-

pentanone, afforded only 2-(benzylsulfanyl)-3-methoxy-

3,4,5,6,7,8-hexahydrocyclopenta[b]azepine (2d) and 3-meth-

oxy-5a,6,7,8-tetrahydrocyclopenta[b]azepine (3b) in a ratio

of approximately 95:5 (by H NMR spectroscopic analysis)

(Scheme 8). Isolated yields of 2d and 3b were 23 and 8%, re-

spectively. Azepine derivative 3b was obtained previously

from the methylsulfanyl analogue of 2-aza-1,3,5-triene 1d

in 12% yield.^11a

Formation of the expected 2-[(Z)-1-methoxyprop-1-

enyl]-4-phenyl-3-thia-1-azaspiro[4.4]non-1-ene (7d) was

not observed. This result may be due to the unfavorable

configuration of the carbanion, generated by deprotonation

of the benzylsulfanyl group, for closing of the five-

membered heterocyclic ring. One should not ignore the ratio

of the rates of two competing processes leading to five- and

seven-membered heterocycles.

When 2-aza-1,3,5-triene 1d was deprotonated with an

equimolar combination of butyllithium and potassium tert-

butoxide (a solution of compound 1d in THF was added to

superbase in one portion) at –100 to 0 °C, the main prod-

ucts of the reaction were homo- and heteroannular azacy-

cloheptadienes 2d and 2d′, which were isolated in a prepar-

ative yield of ca. 22% (Scheme 9).

Spirocyclic 4,5-dihydro-1,3-thiazole 7d was identified

by H NMR spectroscopic and mass spectrometric analyses

1

in only trace amounts (less than 1% yield). In contrast, bicy-

clic azepine 3b was not formed under these conditions.

Addition of 2-aza-1,3,5-triene 1d to a solution of butyl-

lithium and potassium tert-butoxide in THF–hexane in one

portion (at –100 to 0 °C) or dropwise at –86 to –78 °C for 12

minutes with further increase of the temperature to 0 °C for

20 minutes (method C), influences primarily the ratio of

isomeric dihydroazepines 2d and 2d′. In the first case, this

ratio was approximately 60:40 (total yield ca. 22%), but in

OMe

+

t-BuOK

N

S

Ph

THF–DMSO

N

1

3b

the latter case the ratio was approximately 80:20 (by H

2d

ca. –30 °C

30 min

S

Ph

NMR spectroscopic analysis) (total yield ca. 17%). In both

cases, 7d was present in the reaction mixtures in trace

amounts.

The effect of the alkoxy-substituent in the butadiene

part of the 2-aza-1,3,5-trienic molecule on the course of

the reaction and on the ratio of products was investigated

further with the example of methoxy-, butoxy-, and 1-

OMe

N

X

1d

Ph

S

MeO

7d

Scheme 8 Azaheterocyclizations of 2-aza-1,3,5-triene 1d upon treat-

ment with potassium tert-butoxide

OMe

X

N

3b

n-BuLi-t-BuOK

OMe

THF–hexane

OMe

N

*

+

H

–100 0 °C

S

Ph

N

S

Ph

OMe

2d

2d'

1d

N

Ph

S

OMe

7d

Scheme 9 Heterocyclizations of 2-aza-1,3,5-triene 1d upon treatment with an equimolar combination of butyllithium and potassium tert-butoxide

3599

N. A. Nedolya et al.

Paper

Synthesis

Table 2 Base-Induced Transformations of 2-Aza-1,3,5-trienes 1c, 1e, 1f into Dihydrothiazoles 7c, 7e, 7f, Dihydroazepines 2c, 2e, 2f, and Azepines 3a,

3c, 3d (Schemes 5, 10 and 11)

Entry

1

Base

Solvent

Temp (°C)

Time (min) Ratio of products^a(yields (%)^b)

Total

yield (%)

Equiv

7

2

3

5^c

17 (10)

1

2

3

4

5

6

7

8

1c

1e

1c

1e

1c

1e

1f

t-BuONa

1.3

1.1

1.3

THF–DMSO

THF–hexane

THF–DMSO

40–42

38–44

5

10 (6)

56 (35)

39 (19)

44 (23)

67 (40)

0

17 (11)

27 (8)

14 (5)

6 (8)

0

62

57

59

75

–

t-BuONa

t-BuOK

LDA

14 (21)

20 (20)

17 (13)

20 (9)

22 (11)

10 (7)

–

–33 to –26

–34 to –26

–100 to 0

40–42

30

15

5

(20)

LDA

(17)

13

0

present

17

–

t-BuONa

t-BuOK

57

13

–

1f

–33 to –26

30

6 (6)

85 (52)

0

9 (7)

65

^aDetermined by ¹H NMR spectroscopic analysis of the crude material.

^bIsolated yield based on the isothiocyanate.

^cPyrrole 5 was present in starting 2-aza-1,3,5-triene.

ethoxyethoxy-substituted 2-aza-1,3,5-trienes 1c, 1e, and

1f, respectively; the results are presented in Table 2 and in

Scheme 10 and Scheme 11.

deprotonation with potassium tert-butoxide (THF–DMSO,

−34 to −26 °C, 30 min) the yield of 4,5-dihydro-3H-azepine

2e was three times higher than the yield of 4,5-dihydro-

1,3-thiazole 7e (40 and 13%, respectively) (Scheme 10 and

Table 2, entries 2 and 4).

In the case of methoxy analogue 1c, under comparable

experimental conditions, the picture is opposite. With sodi-

um tert-butoxide, the yield of 4,5-dihydro-3H-azepine 2c

was six times higher than the yield of 4,5-dihydro-1,3-thi-

azole 7c (35 and 6%, respectively), and with potassium tert-

butoxide, the yields of 7c and 2c were comparable (20 and

23%, respectively) (Table 2, entries 1 and 3).

When 2-aza-1,3,5-triene 1e was deprotonated with

LDA, almost pure 4,5-dihydro-1,3-thiazole 7e was isolated

from the reaction mixture by column chromatography in

17% yield (Table 2, entry 6). Compounds 2e and 3c were not

identified among the products of the reaction.

Another representative of benzylsulfanyl-substituted 2-

aza-1,3,5-trienes, previously unknown (1-ethoxyethoxy)-

2-aza-1,3,5-triene 1f, was synthesized in 98% yield (with

ca. 7% admixture of pyrrole 5f) from (1-ethoxyethoxy)al-

lene, isopropyl isothiocyanate, and benzyl bromide accord-

ing to Scheme 7. Its involvement in the reaction with sodi-

Processing of butoxy-substituted 2-aza-1,3,5-triene 1e,

prepared according to Scheme 7 in 97% yield (with a small

admixture of pyrrole 5e), with sodium and potassium tert-

butoxide, as in the case of methoxy analogue 1c (Scheme 5),

led to a mixture of all three possible and previously un-

known heterocycles: 4,5-dihydro-1,3-thiazole 7e, 4,5-dihy-

dro-3H-azepine 2e, and 3H-azepine 3c, the ratio and the

yield of which depended on the nature of deprotonating

base and alkoxy substituent as well as on the temperature

and time of the reaction (Scheme 10 and Table 2).

With sodium tert-butoxide, the total yield of heterocy-

clic reaction products reached 57%, which was slightly less

than that from the methoxy analogue 1c (Table 2, entries 1

and 2), and in the case of potassium tert-butoxide the total

yield was 75%, which is 16% more than that from the

methoxy analogue 1c (Table 2, entries 3 and 4). In addition,

when 2-aza-1,3,5-triene 1e was deprotonated with sodium

tert-butoxide in THF−DMSO (38−44 °C, 5 min), 4,5-dihydro-

1,3-thiazole 7e and 4,5-dihydro-3H-azepine 2e were ob-

tained with comparable yields (21 and 19%), whereas on

t-BuOK

THF–DMSO

OBu

N

+

Ph

ca. –30 °C

S

N

S

Ph

30 min

BuO

N

3c (8%)

2e (40%)

7e (13%)

ratio (by ¹H NMR) = 19:74:7

S

Ph

t-BuONa

OBu

THF–DMSO

7e (21%)

ratio (by ¹H NMR) = 17:49:34

2e (19%)

+

3c (8%)

1e

38–44 °C

5 min

Scheme 10 Azaheterocyclization of 2-aza-1,3,5-triene 1e upon treatment with potassium and sodium tert-butoxide

3600

N. A. Nedolya et al.

Paper

Synthesis

OEt

Ph

t-BuOK

THF–DMSO

N

O

+

Ph

ca. –30 °C

30 min

S

N

S

EtO

O

N

7f (6%)

2f (52%)

OEt

ratio (by ¹H NMR) = 7:93

S

Ph

t-BuONa

THF–DMSO

EtO

O

1f

7f

+

2f

+

40–42 °C

5 min

N

ratio (by ¹H NMR) = 16:68:16

3d

Scheme 11 Azaheterocyclizations of 2-aza-1,3,5-triene 1f upon treatment with potassium and sodium tert-butoxide

um and potassium tert-butoxide shows that, in this case,

the nature of the superbase and the reaction conditions af-

fect not only the ratio and the yield of products, but also

their qualitative composition (Scheme 11 and Table 2, en-

tries 7 and 8).

which with t-BuOK under similar conditions (THF–DMSO,

ca. −30 °C, 30 min) gives methyl (Z)-N-[(Z)-but-1-enyl]-2-

methoxybut-2-enimidothioate instead of the expected sev-

en-membered azaheterocycles.²⁴

The stereochemistry of the 1-alkoxyprop-1-enyl sub-

stituent in 4,5-dihydro-1,3-thiazoles 7b–f was assigned on

Thus, upon deprotonation of 2-aza-1,3,5-triene 1f with

potassium tert-butoxide, azepine 3d was not formed, and

the content of 4,5-dihydro-3H-azepine 2f in the reaction

mixture increased to 85% (Scheme 11 and Table 2, entry 8).

The yield of 4,5-dihydro-1,3-thiazole 7f was only 6%. When

the reaction was carried out with sodium tert-butoxide, 7f,

2f, and 3d were formed in a ratio of approximately

1

the basis of H–¹H NOESY and H–¹³C HMBC spectroscopic

experiments. The 2D NMR spectra show that the methyl

group is in the Z-configuration relative to the alkoxy group

at the carbon–carbon double bond.

With the exception of azepines 3a, 3b, and 3d,^11a,12a,ball

synthesized compounds are new. Their structures and

yields are summarized in Table 3. 4,5-Dihydro-1,3-thiazoles

7b–f and the other heterocycles mentioned above were iso-

lated from their mixtures by column chromatography and

adequately characterized by spectral and elemental analy-

sis data, which are in good agreement with the structure of

the products.

1

13:57:13 (by H NMR spectroscopic analysis) (Scheme 11

and Table 2, entry 7). In addition, in both cases, pyrrole 5f

was identified in the reaction mixture.

Based on these results, it is possible to make a prelimi-

nary conclusion that, in the presence of t-BuOK, in the tran-

sition from methoxy- to butoxy- and to 1-ethoxyethoxy-

substituted 2-aza-1,3,5-trienes 1, the yield of 4,5-dihydro-

1,3-thiazoles 7 decreased (20→13→6%), and that of 4,5-di-

hydro-3H-azepines 2, in contrast, increased (23→40→52%)

(see Table 2). When t-BuONa was used as deprotonating

base, the picture was reversed: the yield of 4,5-dihydro-

1,3-thiazoles 7 increased and that of 4,5-dihydro-3H-aze-

pines 2 decreased.

The singularity of the discussed reactions lies in the fact

that, in the process of structural reorganization of the 2-

aza-1,3,5-trienes 1b–f into 4,5-dihydro-1,3-thiazoles 7b–f,

an unprecedented low-temperature (ca. –30 °C) isomeriza-

tion of the 1-alkoxyallyl groups into 1-alkoxyprop-1-enyl

groups takes place. It is known²³that allyl–propenyl isom-

erization in a number of allyl ethers, even in the presence of

a strong base, usually occurs under harsh conditions (at

temperatures above 100 °C, within several hours), and it is

generally very sensitive not only to the reaction parameters

(solvent, base, ratio of reagents, temperature, time, etc.),

but also to the structure of the allyl ether.

In conclusion, a novel strategy for 4,5-dihydro-1,3-thi-

azole ring construction through an unprecedented reorga-

nization of allyl- and benzylsulfanyl-substituted 2-aza-

1,3,5-trienes, derived from readily accessible alkoxyallenes,

isothiocyanates, and allyl or benzyl bromide, in the pres-

ence of superbases opens a novel and simple approach to

new families of fully substituted functionalized 2-thiazo-

lines, namely, 2-(1-alkoxyprop-1-enyl)-5-vinyl- and 2-(1-

alkoxyprop-1-enyl)-5-phenyl-4,5-dihydro-1,3-thiazoles.

Moreover, the synthetic potential of the discovered reaction

of competitive or selective mild deprotonation of allyl- and

benzylsulfanyl-substituted 2-aza-1,3,5-trienes leading to 2-

thiazolines with rare substituents is certainly not limited to

the described examples, and can clearly be the basis for a

novel approach to the simple synthesis of new classes of

multifunctional 4,5-dihydro-1,3-thiazoles that are unavail-

able by other means. Additionally, the reactions and struc-

tural transformations of functionally substituted azatrienic

systems described above allow the combinatorial synthesis

of the most significant five- and seven-membered azahet-

erocycles such as pyrrole, thiazole, azepine, and dihydroaz-

epine derivatives, which are interesting classes of com-

pounds with potential pharmacological properties. We be-

For the first time, we have observed low-temperature

prototropic isomerization for the example of N-(bu-

tylidene)-2-methoxy-1-(methylsulfanyl)buta-1,3-dien-1-

amine (2-aza-1,3,5-triene derived from methoxyallene, bu-

tyl isothiocyanate, and methyl iodide), the treatment of

3601

N. A. Nedolya et al.

Paper

Synthesis

Table 3 Structures and Yields of 1–5 and 7

1-Aza-1,3,4-trienes 4

2-Aza-1,3,5-trienes 1

Dihydrothiazoles 7

Dihydroazepines 2

Azepines 3

Pyrroles 5

OMe

S

OMe

N

OMe

•

S

N

S

N

S

N

S

MeO

OMe

4b (87%)

1b (84%)

7b (18%)

2b (0%)

3a (7%)

5b (13%)

OMe

S

Ph

OMe

N

OMe

N

•

S

Ph

N

S

Ph

S

N

Ph

MeO

OMe

4c (98%)

1c (89%)

7c (20%)

2c (35%)

3a (11%)

5c (11%)

OMe

N

S

Ph

S

Ph

2d (23%)^a

OMe

•

N

S

Ph

N

Ph

N

S

Ph

OMe

MeO

OMe

N

S

Ph

2d′

4d (ca. 100%)

1d (95%)

7d (<1%)

22% (for 2d and 2d′)^b

3b (8%)

5d (trace)

OBu

S

Ph

OBu

N

OBu

N

•

S

N

Ph

N

S

N

S

Ph

S

N

Ph

BuO

OBu

4e (97%)

1e (87%)

7e (21%)

2e (40%)

3c (8%)

5e (9%)

OEt

O

OEt

O

N

O

OEt

S

Ph

O

S

Ph

S

•

O

S

N

Ph

N

S

N

Ph

EtO

OEt

4f (98%)

1f (91%)

7f (6%)

2f (52%)

3d (14%)

5f (10%)

^aBy method A.

^bBy method C.

lieve that the obtained results provide important

information that will aid in the design of new medicinally

relevant heterocyclic scaffolds.

was used. All reactions were monitored by TLC on precoated Merck

silica gel 60 F254 plates, and were visualized by exposure to I₂vapor.

PE refers to light petroleum.

IR spectra were measured neat with a Bruker Vertex-70 infrared

spectrophotometer. ¹H (400.13 MHz), ¹³C (100.62 MHz), and ¹⁵N

(40.55 MHz) NMR spectra were recorded with Bruker DPX-400 and

Bruker AV-400 spectrometers in CDCl₃at r.t., referenced to HMDS (for

¹H), CDCl₃(for ¹³C), and MeNO₂(for ¹⁵N) as internal standards. Assign-

ments of spectra were carried out based on the results of 2D NMR ex-

periments. The mass spectra (EI, 70 eV) were recorded with a Shi-

madzu GCMS-QP5050A instrument. The microanalyses were per-

formed with a Flash EA 1112 Series elemental analyzer.

Alkoxyallenes and isothiocyanates were prepared as described previ-

ously.^4a,25,26n-BuLi (1.6 and 2.5 M solution in hexane), t-BuOK, t-BuONa,

diisopropylamine, allyl bromide, benzyl bromide, and solvents are

commercially available. All solvents were purified according to stan-

dard procedures. All reactions (with the exception of isomerization of

1-aza-1,3,4-trienes into 2-aza-1,3,5-trienes) were performed under

anhydrous conditions and under an argon atmosphere (with n-BuLi).

For all reactions at low temperatures, a cooling bath with liquid N₂

3602

N. A. Nedolya et al.

Paper

Synthesis

Full spectral data for all novel compounds are given below. The NMR

spectroscopic data for all known compounds were identical to those

reported. Overall yields were based on the isothiocyanate taken for

the synthesis of 1-aza-1,3,4-triene 4.

2-Aza-1,3,5-triene 1b

Yield (based on compound 4b): 8.75 g (84% with regard to the purity

~87%); brown mobile liquid.

¹H NMR: δ = 1.86 and 2.14 [both s, 6 H, (CH₃)₂C=N], 3.25 (dd, ³J =

7.5 Hz, ⁴J = 1.1 Hz, 2 Н, SCH₂), 3.63 (s, 3 H, OCH₃), 5.04 and 5.14 (both

ddt, ³J_trans= 17.0 Hz, ³J_cis= 10.0 Hz, ²J_gem= 1.6 Hz, ⁴J = 1.1 Hz, 2 H, СН₂=

allyl), 4.92 and 5.21 (both dd, J_trans= 17.2 Hz, J_cis= 10.9 Hz, J_gem

1.9 Hz, 2 H, CH₂= vinyl), 5.81 (ddt, J_trans= 17.0 Hz, J_cis= 10.0 Hz, J =

7.5 Hz, 1 H, CH= allyl), 5.88 (dd, J_trans= 17.2 Hz, J_cis= 10.9 Hz, 1 H,

2-[(Z)-1-Methoxyprop-1-enyl]-4,4-dimethyl-5-vinyl-4,5-dihydro-

1,3-thiazole (7b), 6-Methoxy-2-methyl-3H-azepine (3a), and 2-(Al-

lylsulfanyl)-1-isopropyl-3-methoxy-1H-pyrrole (5b)

3

2

=

3

To a vigorously stirred soln of methoxyallene (5.16 g, 74 mmol) in

THF (50 mL), n-BuLi (2.5 M in hexane, 55 mmol, 22 mL) was added at

–90 °C under argon. After stirring for an additional 10 min at –55 to

–52 °C, the soln was cooled to –85 °C, and a mixture of i-PrNCS (5.06

g, 50 mmol) and THF (5 mL) was added in one portion. The tempera-

ture was allowed to rise to ca. –30 °C, and the mixture was stirred at

this temperature for an additional 20 min. The mixture was then

cooled to –80 °C, and allyl bromide (7.89 g, 65 mmol) was added in

one portion, after which the cooling bath was removed and the tem-

perature was allowed to rise to 18 °C for 30 min. The mixture was

cooled to –80 °C, then the reaction was quenched with sat. aq NH₄Cl

(60 mL) and the mixture was extracted with Et₂O (3 × 30 mL). The

combined organic extracts were washed with H₂O (3 × 40 mL), dried

(MgSO₄), and concentrated on a rotary evaporator at a bath tempera-

ture of 20 °C to give a residue consisting of allyl N-isopropyl-2-

methoxybuta-2,3-dienimidothioate (1-aza-1,3,4-triene 4b) as a mix-

ture of the syn- and anti-isomers. The isomerization of the 1-aza-

1,3,4-triene 4b into (1Z)-1-(allylsulfanyl)-2-methoxy-N-(1-methylethyl-

idene)buta-1,3-dien-1-amine (2-aza-1,3,5-triene 1b) was effected by

rotating a sample (9.0 g, 43 mmol) on a rotary evaporator at a bath

temperature of 57–60 °C for 10 min followed by vacuum treatment at

50–55 °C (1 mmHg) for ca. 5 min. The residue consisted of 2-aza-

1,3,5-triene 1b (ca. 87%) and pyrrole 5b (ca. 13%) based on ¹H NMR

spectroscopic analysis. The crude product was used in the next step

without further purification.

CH= vinyl).

¹³C NMR: δ = 21.48 and 27.91 [(CH₃)₂C=N], 32.66 (SCH₂), 58.53

(OCH₃), 110.34 (CH₂= vinyl), 116.79 (CH₂= allyl), 126.40 (CH= vinyl),

133.29 (=C–S), 134.65 (CH= allyl), 138.83 (=C–O), 173.70 (C=N).

¹H–¹³C HMBC 2D experiments provided additional support for the

proposed structure.

The data are consistent with those previously reported.^14a

Treatment of 2-Aza-1,3,5-triene 1b with Potassium tert-Butoxide

Method A: To a stirred soln of the product mixture (8.67 g, 41 mmol)

containing ca. 87% of 2-aza-1,3,5-triene 1b and ca. 13% of pyrrole 5b

in THF (62 mL), DMSO (12 mL), and t-BuOK (5.52 g, 49 mmol) were

added sequentially at –60 °C. The temperature of the mixture was al-

lowed to rise to ca. –30 °C, and this temperature was maintained for

an additional 30 min. The mixture was then cooled to –60 °C, the re-

action was quenched with H₂O (ca. 50 mL), and the mixture was ex-

tracted with Et₂O (4 × 50 mL). The combined organic extracts were

washed with a ca. 5% aq KOH (2 × 20 mL) and with H₂O (2 × 40 mL),

dried (MgSO₄), and concentrated at r.t. under reduced pressure. From

the residue (7.8 g; a dark-brown mobile liquid), the products were

separated and purified in the following way. Initially, column chro-

matography (neutral alumina; PE and PE–Et₂O, 10:1) gave two frac-

tions. Fraction 1 (4.78 g) consisted of 4,5-dihydro-1,3-thiazole 7b (ca.

28%), pyrrole 5b (ca. 18%), and unidentified compounds (remainder),

based on ¹H NMR spectroscopic analysis. Fraction 2 (0.79 g) consisted

of 3H-azepine 3a (ca. 40%) and unidentified compounds (remainder).

Fraction 1 as a soln in Et₂O (50 mL) was shaken vigorously for a few

seconds with ca. 3.7% HCl soln (5 × 10 mL), and the organic layer was

separated. From the organic fractions, 1.68 g (in total) of substances,

containing ca. 58% pyrrole 5b (¹H NMR), were isolated. Each acidic

aqueous layer was neutralized (separately) with ca. 20% aq KOH,

treated with Et₂O (3 × 5 mL), washed with H₂O (3 × 20 mL), and dried

(MgSO₄). Three of the five fractions (2.25 g in total) contained thi-

azole 7b (from 13 to 79%), and two fractions (0.41 g) contained un-

identified products. Pure thiazole 7b (0.60 g) was isolated from the

richest fraction (79% in 1.32 g) by column chromatography (neutral

alumina; PE and PE–Et₂O, 10:1, 5:1). Pyrrole 5b was isolated similarly

from the enriched fraction (58% in 1.68 g). Pyrrole 5b can be obtained

selectively by intramolecular cyclization of 1-aza-1,3,4-triene 4b in

the presence of CuBr or CuI.^1b,4dThe 3H-azepine 3a was not purified

further because it had previously been obtained in 38% yield.^12a

1-Aza-1,3,4-triene 4b

Yield: 9.22 g (87%); tawny liquid; purity ca. 95%; ratio major/minor

(¹H NMR) ca. 62:38.

IR (neat): 3083, 3005, 2968, 2932, 2869, 2832, 1947 (С=С=С), 1651,

1636, 1611, 1460, 1449, 1433, 1377, 1361, 1341, 1265, 1218, 1202,

1168, 1132, 1049, 989, 942, 917, 893, 862, 824, 739, 706 cm⁻¹

.

¹H NMR: δ (major isomer) = 1.18 [d, ³J = 6.3 Hz, 6 H, (CH₃)₂CH], 3.50 (s,

3 H, OCH₃), 3.55 (m, 2 Н, SCH₂), 4.02 [sept, ³J = 6.3 Hz, 1 H, (CH₃)₂CH],

3

2

5.08 (dq, J_cis= 10.1 Hz, J_gem= 1.2 Hz, ⁴J = 1.2 Hz, 1 H, CH₂=СН), 5.15

(ddt, ³J_trans= 16.8 Hz, ²J_gem= 1.2 Hz, ⁴J = 1.4 Hz, 1 H, CH₂=СН), 5.73 (s, 2

Н, СН₂=С=), 5.83 (ddt, J_trans= 16.8 Hz, J_cis= 10.1 Hz, ³J = 7.1 Hz, 1 H,

CH₂=СН); δ (minor isomer) = 1.11 [d, ³J = 6.3 Hz, 6 H, (CH₃)₂CH], 3.43

(s, 3 H, OCH₃), 3.55 (m, 2 Н, SCH₂), 3.98 [sept, ³J = 6.3 Hz, 1 H,

3

(CH₃)₂CH], 5.03 (ddt, J_cis= 10.0 Hz, J_gem= 1.3 Hz, ⁴J = 0.8 Hz, 1 H,

3

2

СН₂=СН), 5.18 (ddt, J_trans= 17.0 Hz, J_gem= 1.3 Hz, ⁴J = 1.5 Hz, 1 H,

3

2

3

СН₂=СН), 5.65 (s, 2 Н, СН₂=С=), 5.85 (ddt, J_trans= 17.0 Hz, J_cis

=

10.0 Hz, ³J = 7.1 Hz, 1 H, CH₂=СН).

13

C

NMR: δ (major isomer) = 22.87 [(CH₃)₂CH], 35.84 (SCH₂), 54.14

jmod

2-[(Z)-1-Methoxyprop-1-enyl]-4,4-dimethyl-5-vinyl-4,5-dihydro-

[(CH₃)₂CH], 56.35 (OCH₃), 92.91 (СН₂=С=), 117.57 (CH₂=СН), 133.83

(=C–O), 134.41 (CH₂=СН), 153.72 (C=N), 200.88 (=C=); δ (minor iso-

mer) = 24.03 [(CH₃)₂CH], 32.76 (SCH₂), 53.90 [(CH₃)₂CH], 55.92

(OCH₃), 93.38 (СН₂=С=), 116.97 (CH₂=СН), 132.74 (=C–O), 133.51

(CH₂=СН), 152.34 (C=N), 198.35 (=C=).

¹H–¹³C HMBC 2D experiments provided additional support for the

proposed structure.

1,3-thiazole (7b)

1

Yield: 1.33 g (18%, H NMR) after separation on alumina; 0.60 g (8%)

after additional separation with HCl followed by purification on alu-

mina; orange-yellow mobile liquid; n_D^21.51.5290.

IR (neat): 3083, 3044, 2972, 2931, 2866, 2858, 2839, 1651, 1635,

1592, 1554, 1461, 1453, 1418, 1402, 1379, 1360, 1342, 1326, 1308,

1288, 1276, 1241, 1205, 1187, 1152, 1124, 1111, 1095, 1072, 993,

The data are consistent with those previously reported.^14a

980, 924, 811, 779, 766, 711, 690, 654, 629, 565 cm⁻¹

.

3603

N. A. Nedolya et al.

Paper

Synthesis

¹H NMR: δ = 1.21 and 1.39 [both s, 6 Н, (CH₃)₂C], 1.76 (d, ³J = 7.1 Hz, 3

Н, СН₃СН=), 3.65 (s, 3 Н, ОCH₃), 4.04 (d, ³J = 9.6 Hz, 1 H, SСН), 5.09 and

5.18 (both d, ³J_trans= 16.9 Hz, ³J_cis= 10.0 Hz, 2 H, СН₂=СН), 5.76 (q, ³J =

tion. The temperature of the reaction mixture was allowed to rise to

ca. –30 °C, and was maintained at –32 to –30 °C for an additional 20

min. The mixture was then cooled to –80 °C and PhCH₂Br (6.98 g, 40

mmol) was added in one portion, after which the cooling bath was re-

moved. After increasing the temperature to –30 °C (in 8 min), stirring

was continued for an additional 30 min at –30 to –23 °C. The tem-

perature was then allowed to rise slowly to 7 °C (overall alkylation

time 65 min). The mixture was cooled to –80 °C, and then quenched

with sat. aq NH₄Cl (50 mL). After separation of the layers, the products

were extracted from the aqueous fraction with Et₂O (2 × 40 mL). The

combined organic fractions were washed with H₂O (50 mL), dried

(MgSO₄), and concentrated under reduced pressure at a bath tem-

perature of ca. 30 °C (on rotary evaporator, then at ca. 1 mmHg) to

give benzyl N-isopropyl-2-methoxybuta-2,3-dienimidothioate (1-

aza-1,3,4-triene 4c) as a mixture of syn- and anti-isomers with ad-

3

7.1 Hz, 1 H, СН₃СН=), 5.84 (dt, J_trans= 16.9 Hz, J_cis= 10.0 Hz, ³J =

9.6 Hz, 1 H, СН₂=СН).

13

C

NMR: δ = 10.89 (СН₃СН=), 21.77 and 26.94 [(CH₃)₂C], 59.39

jmod

(ОСН₃), 63.01 (SСН), 79.37 (С4), 117.61 (СН₂=СН), 119.70 (СН₃СН=),

134.05 (СН₂=СН), 150.02 (=C−O), 160.21 (С=N).

¹H–¹⁵N HMBC: δ = –56.5. The data are consistent with those previous-

ly reported.^14a

Homo- and heteronuclear ¹H–¹H COSY, ¹H–¹H NOESY, ¹H–¹³C HSQC,

and ¹H–¹³C HMBC 2D experiments provided additional support for

the proposed structure. The Me group is in Z-configuration relative to

the MeO group at the C=C bond.

MS (EI): m/z (%) = 211 (11) [M]⁺.

mixture

of

(1Z)-1-(benzylsulfanyl)-2-methoxy-N-(1-methyle-

thylidene)buta-1,3-dien-1-amine (2-aza-1,3,5-triene 1c) in a ratio of

ca. 3:1 (by H NMR spectroscopic analysis). The complete isomeriza-

Anal. Calcd for C₁₁H₁₇NOS: С, 62.52; Н, 8.11; N, 6.63; S, 15.17. Found:

С, 62.40; Н, 8.05; N, 6.57; S, 15.10.

1

tion of 1-aza-1,3,4-triene 4c into 2-aza-1,3,5-triene 1c was effected

by vacuum treatment of a sample (10.1 g, 38.7 mmol) at 55–60 °C for

10 min on a rotary evaporator and then at 50–55 °C (ca. 1 mmHg) for

5 min. The residue consisted of 2-aza-1,3,5-triene 1c (ca. 90%) and

pyrrole 5c (ca. 10%) (by ¹H NMR spectroscopic analysis). In other syn-

theses of compound 1c by this procedure its content in mixture with

pyrrole 5c ranged from 85 to 93% (by ¹H NMR spectroscopic analysis).

The crude product was used in the next step without further purifica-

tion.

6-Methoxy-2-methyl-3H-azepine (3a)

Yield: 0.33 g (7%, ¹H NMR) after separation on alumina; light-yellow

liquid.

¹H NMR: δ = 2.10 (s, 3 Н, CH₃), 2.48 (m, 2 Н, Н-3), 3.65 (s, 3 Н, ОCH₃),

5.30 (dt, ³J = 9.3 Hz, ³J = 7.1 Hz, 1 H, Н-4), 6.16 (dd, ³J = 9.3 Hz, ⁴J =

2.5 Hz, 1 H, Н-5), 6.90 (d, ⁴J = 2.5 Hz, 1 H, Н-7).

13

C

NMR: δ = 25.55 (СН₃), 37.23 (С3), 56.02 (ОСН₃), 118.00 (С7),

jmod

121.14 (С5), 124.58 (С4), 147.82 (С6), 150.36 (C=N).

MS (EI): m/z (%) = 137 (87) [M]⁺, 136 (22) [M – 1]⁺, 122 (100), 107

(20), 94 (30).

1-Aza-1,3,4-triene 4c

Yield: 10.2 g (98%); brown liquid; ratio major/minor (¹H NMR) ca.

58:42.

¹H NMR: δ = 1.12 [m, 6 H, (CH₃)₂CH], 3.40 and 3.50 (both s, 3 H, OCH₃),

3.95 and 4.02 [both m, 1 H, (CH₃)₂CH], 4.10 and 4.12 (both s, 2 H,

SСН₂), 5.62 and 5.69 (both s, 2 H, CH₂=C=), 7.27 (br m, 5 H, Ph-H).

The data are consistent with those previously reported.^12a,14a,27

2-(Allylsulfanyl)-1-isopropyl-3-methoxy-1H-pyrrole (5b)

Yield: 0.97 g (11%, ¹H NMR) after separation on alumina.

3

¹H NMR: δ = 1.34 [d, J = 6.9 Hz, 6 Н, (CH₃)₂CH], 3.18 (dd, J = 7.3 Hz,

2-Aza-1,3,5-triene 1c

⁴J = 1.0 Hz, 2 Н, SCH₂), 3.78 (s, 3 Н, ОCH₃), 4.72 [sept, ³J = 6.9 Hz, 1 H,

Yield (based on compound 4c): 10 g (89% with regard to the purity ca.

90%); brown mobile liquid.

¹H NMR: δ = 1.55 and 2.02 [both s, 6 H, (CH₃)₂C=N], 3.56 (s, 3 H,

3

2

(CH₃)₂CH], 4.87 (ddt, J_trans= 17.1 Hz, J_gem= 1.1 Hz, ⁴J = 1.0 Hz, 1 H,

3

СН₂=СН), 4.92 (d, J_cis= 9.9 Hz, 1 H, СН₂=СН), 5.81 (ddt, J_trans

=

17.1 Hz, ³J_cis= 9.9 Hz, ³J = 7.3 Hz, 1 H, СН₂=СН), 5.89 (d, ³J = 3.1 Hz, 1 H,

Н-4), 6.64 (d, ³J = 3.1 Hz, 1 H, Н-5).

3

OCH₃), 3.82 (s, 2 H, SСН₂), 4.88 and 5.17 (both dd, J_trans= 17.0 Hz,

2

3

³J_cis= 11.0 Hz, J_gem= 1.9 Hz, 2 H, CH₂=CH), 5.84 (dd, J_trans= 17.0 Hz,

¹³C NMR: δ = 23.5 [(CH₃)₂CH], 40.5 (SCH₂), 46.4 (NCH), 57.9 (ОCH₃),

94.4 (С4), 102.8 (С2), 116.3 (С5), 116.8 (СН₂=СН), 134.2 (СН₂=СН),

152.0 (С3).

¹H–¹⁵N HMBC: δ = –207.5.

MS (EI, 70 eV): m/z (%) = 211 (33) [М]⁺.

³J_cis= 11.0 Hz, 1 H, CH₂=CH), 7.13–7.32 (m, 5 H, Ph-H).

¹³C NMR: δ = 20.92 and 27.83 [(CH₃)₂C=N], 34.00 (SCH₂), 58.41

(OCH₃), 110.18 (CH₂=CH), 126.27 (CH₂=CH), 126.63 (C-p), 128.15 and

128.59 (C-o,m), 128.79 (C-i), 133.70 (=C−S), 138.34 (=C−O), 174.03

(C=N).

Anal. Calcd for C₁₁H₁₇NOS: С, 62.52; Н, 8.11; N, 6.63; S, 15.17. Found:

С, 62.24; Н, 8.31; N, 6.47; S, 15.28.

¹H–¹³C HMBC 2D experiments provided additional support for the

proposed structure.

The data are consistent with those previously reported.^14a

The data are consistent with those previously reported.¹⁵

2-[(Z)-1-Methoxyprop-1-enyl]-4,4-dimethyl-5-phenyl-4,5-dihy-

dro-1,3-thiazole (7c), 2-(Benzylsulfanyl)-3-methoxy-7-methyl-4,5-

dihydro-3H-azepine (2c), 6-Methoxy-2-methyl-3H-azepine (3a),

and 2-(Benzylsulfanyl)-1-isopropyl-3-methoxy-1H-pyrrole (5c)

Treatment of 2-Aza-1,3,5-triene 1c with Superbases

Method A: To a stirred soln of the product mixture (5.24 g, 20 mmol)

containing ca. 90% 2-aza-1,3,5-triene 1c and ca. 10% pyrrole 5c in THF

(31 mL), DMSO (6 mL) and t-BuOK (2.69 g, 24 mmol) were added se-

quentially at –60 °C. The mixture was stirred for 30 min while the

temperature was kept between –38 and –26 °C, and H₂O (30 mL) was

added. After separation of the layers, the products were extracted

from the aqueous fraction with Et₂O (3 × 40 mL). The combined or-

ganic fractions were washed with H₂O (3 × 50 mL), dried (MgSO₄),

and concentrated under reduced pressure to give a dark-brown vis-

To a vigorously stirred soln of methoxyallene (4.0 g, 57 mmol) in THF

(40 mL), n-BuLi (ca. 1.6 M in hexane, 43 mmol, 27 mL) was added at

–90 °C under argon. The temperature of the reaction mixture was al-

lowed to rise to ca. –50 °C, and was maintained at –52 to –50 °C for an

additional 10 min. The soln was then cooled to –80 °C and a mixture

of i-PrNCS (4.05 g, 40 mmol) and THF (5 mL) was added in one por-

3604

N. A. Nedolya et al.

Paper

Synthesis

cous liquid (4.81 g) consisting of 4,5-dihydro-1,3-thiazole 7c, 4,5-di-

hydro-3H-azepine 2c, 3H-azepine 3a, and pyrrole 5c in a ratio of ca.

20:44:14:22 (by ¹H NMR spectroscopic analysis), traces of the original

azatriene 1c, and unidentified impurities. Flash column chromatogra-

phy of the products (neutral alumina; 4 cm layer; hexane and hex-

ane–Et₂O, 10:1) gave three fractions. Fraction 1 (main fraction; 2.27

g; hexane as eluent) consisted of 4,5-dihydro-3H-azepine 2c, 4,5-di-

hydro-1,3-thiazole 7c, and pyrrole 5c in a ratio of ca. 53:23:24 (by ¹H

NMR spectroscopic analysis); the total content of the main substanc-

es was 90%. Fraction 2 (0.36 g; hexane then hexane–Et₂O, 10:1) con-

sisted of 4,5-dihydro-1,3-thiazole 7c, pyrrole 5c, and the original 2-

2-[(Z)-1-Methoxyprop-1-enyl]-4,4-dimethyl-5-phenyl-4,5-dihy-

dro-1,3-thiazole (7c)

Yield: 0.93 g (20%, ¹H NMR, method A) after rough separation on alu-

mina; 0.18 g (4%) after an additional separation with HCl followed by

purification on alumina; 0.12 g (6%, method B); orange viscous liquid;

n_D²³1.5805.

IR (neat): 3085, 3061, 3029, 2970, 2930, 2859, 2839, 1650, 1614,

1595, 1549, 1495, 1463, 1453, 1395, 1378, 1360, 1339, 1326, 1307,

1286, 1240, 1218, 1201, 1178, 1139, 1119, 1094, 1071, 1031, 1016,

1003, 980, 925 cm^–1

.

3

¹H NMR: δ = 1.01 and 1.48 [both s, 6 H, (CH₃)₂C], 1.79 (d, J = 7.0 Hz,

3 H, СН₃СН=), 3.71 (s, 3 H, OCH₃), 4.63 (s, 1 H, SCH), 5.85 (q, ³J =

7.0 Hz, 1 H, СН₃СН=), 7.28 (m, 5 H, Ph-H).

1

aza-1,3,5-triene 1c in a ratio of ca. 83:9:8 (by H NMR spectroscopic

analysis); the total content of the main substances was ca. 100%. Frac-

tion 3 (0.62 g; hexane–Et₂O, 10:1) consisted of 4,5-dihydro-1,3-thi-

azole 7c, 3H-azepine 3a, and 2-aza-1,3,5-triene 1c in a ratio of ca.

52:41:7 (by ¹H NMR spectroscopic analysis); total content of the main

substances was 51%. The yields of products (calculated from the ¹H

NMR spectra of the isolated fractions) were: 4,5-dihydro-1,3-thiazole

7c (0.93 g, 20%), 4,5-dihydro-3H-azepine 2c (1.06 g, 23%), 3H-azepine

3a (0.13 g, 5%), and pyrrole 5c (0.52 g, 11%); the conversion of 2-aza-

1,3,5-triene 1c was 99%. Individual compounds, 4,5-dihydro-1,3-thi-

azole 7c, 4,5-dihydro-3H-azepine 2c, and pyrrole 5c, were isolated

from fraction 1 as follows. A soln of a mixture of products from frac-

tion 1 (2.27 g) in Et₂O (27 mL) was shaken vigorously for few seconds

with ca. 3.7% HCl soln (4 × 5 mL), and the organic layer was separated.

The acidic aqueous layer was neutralized with ca. 20% aq KOH soln

and treated with Et₂O (3 × 15 mL). Extracts were washed with H₂O

(20 mL), dried (K₂CO₃), and concentrated on a rotary evaporator. Col-

umn chromatography (neutral alumina; hexane and hexane–Et₂O,

10:1) of the residue (0.55 g) gave 4,5-dihydro-1,3-thiazole 7c (0.18 g).

The organic fraction (after separation with ca. 3.7% HCl soln), consist-

ing of 4,5-dihydro-3H-azepine 2c (68%) and pyrrole 5c (32%) was

treated with ca. 15% HCl soln (4 × 5 mL), and the layers were separat-

ed. The acidic aqueous layer was neutralized with ca. 20% aq KOH

soln and treated with Et₂O (3 × 15 mL). Extracts were washed with

H₂O (20 mL), dried (K₂CO₃), and concentrated on rotary evaporator.

Column chromatography (neutral alumina; hexane) of the residue

(0.54 g) gave 4,5-dihydro-3H-azepine 2c (0.23 g). The organic fraction

(ethereal soln after separation with a 15% HCl soln) was washed with

H₂O (20 mL), dried (K₂CO₃), and concentrated on rotary evaporator.

Column chromatography (neutral alumina; hexane) of the residue

(0.99 g) gave pyrrole 5c (0.17 g). 3H-Azepine 3a was isolated as a mix-

ture with 4,5-dihydro-1,3-thiazole 7c (0.28 g, ca. 48:52) by column

chromatography (neutral alumina; hexane) from fraction 3 (0.62 g)

and identified by ¹H and ¹³C NMR spectra in comparison with the

spectra of known sample.^12a

¹³C NMR: δ = 11.13 (СН₃СН=), 23.64 and 28.12 [(CH₃)₂C], 59.69

(OCH₃), 63.85 (SСH), 80.73 [(CH₃)₂C], 120.04 (СН₃СН=), 127.69 (C-p),

128.26 and 128.37 (C-o,m), 137.91 (C-i), 150.22 (=C−O), 160.90 (C=N).

¹H–¹⁵N HMBC: δ = −59.0.

¹H–¹H NOESY and ¹H–¹³C HMBC 2D experiments provided additional

support for the proposed structure.

Anal. Calcd for С₁₅H₁₉NOS: C, 68.93; H, 7.33; N, 5.36; S, 12.27. Found:

C, 68.75; H, 7.28; N, 5.31; S, 12.12.

The data are consistent with those previously reported.¹⁵

2-(Benzylsulfanyl)-3-methoxy-7-methyl-4,5-dihydro-3H-azepine

(2c)

Yield: 1.06 g (23%, ¹H NMR, method A) after rough separation on alu-

mina; 0.23 g (5%) after an additional separation with HCl followed by

purification on alumina; 0.69 g (35%, method B); light-yellow viscous

liquid; n_D²³1.5760.

IR (neat): 3085, 3062, 3029, 2974, 2940, 2926, 2856, 2826, 1632,

1600, 1571, 1542, 1495, 1453, 1439, 1428, 1376, 1349, 1336, 1310,

1298, 1247, 1207, 1175, 1136, 1111, 1083, 1072, 1058, 1030, 1005,

963, 915, 886, 800, 782, 771, 712, 698, 587, 567, 530, 476 cm^–1

.

¹H NMR: δ = 1.72 and 1.88 (both m, 2 H, H-5), 1.88 (s, 3 H, CH₃), 2.07

and 2.45 (both m, 2 H, H-4), 3.34 (s, 3 H, OCH₃), 4.00 (t, ³J = 8.3 Hz,

1 H, OCH), 4.17 (s, 2 H, SCH₂), 5.19 (br t, ³J = 6.0 Hz, 1 H, H-6), 7.18 (m,

1 H, H-p), 7.25 (m, 2 H, H-m), 7.35 (m, 2 H, H-o).

¹³C NMR: δ = 20.90 (C5), 21.97 (CH₃), 32.93 (SCH₂), 42.58 (C4), 59.07

(OCH₃), 81.79 (OCH), 110.11 (C6), 126.85 (C-p), 128.30 and 129.17 (C-

o,m), 138.10 (C-i), 147.12 (С7), 173.66 (C=N).

¹H–¹⁵N HMBC: δ = –90.6.

¹H–¹H COSY and ¹H–¹³C HMBC 2D experiments provided additional

support for the proposed structure.

Method B: To a stirred soln of the product mixture (2.32 g, 8.9 mmol)

containing ca. 85% 2-aza-1,3,5-triene 1c and ca. 15% pyrrole 5c in THF

(12 mL), DMSO (3 mL) and t-BuONa (1.11 g, 11 mmol) were added at

r.t. sequentially. The mixture was heated to 40 °C and stirred for 5

min at 40 to 42 °C, and was then cooled to r.t., and H₂O (20 mL) was

added. After separation of the layers, the products were extracted

from the aqueous fraction with Et₂O (3 × 20 mL). The combined or-

ganic fractions were washed with H₂O (3 × 20 mL), dried (MgSO₄),

and concentrated under reduced pressure to give a brown mobile liq-

uid (2.09 g) consisting of 4,5-dihydro-1,3-thiazole 7c, 4,5-dihydro-

3H-azepine 2c, 3H-azepine 3a, and pyrrole 5c in a ratio of ca.

10:56:17:17 (by ¹H NMR spectroscopic analysis). Compounds 7c, 2c,

3a, and 5c were separated by column chromatography (neutral alu-

mina; hexane, hexane–Et₂O, 10:1, 3:1) in yields of 6, 35, 11, and 10%,

respectively.

Anal. Calcd for С₁₅H₁₉NOS: C, 68.93; H, 7.33; N, 5.36; S, 12.27. Found:

C, 68.85; H, 7.31; N, 5.35; S, 12.23.

The data are consistent with those previously reported.¹⁵

2-(Benzylsulfanyl)-1-isopropyl-3-methoxy-1H-pyrrole (5c)

Yield: 0.52 g (11%, ¹H NMR, method A) after rough separation on alu-

mina; 0.17 g (ca. 4%) after an additional separation with HCl followed

by purification on alumina; 0.23 g (10%, method B); yellow viscous

liquid; n_D²³1.5758.

IR (neat): 3108, 3085, 3061, 3028, 2973, 2930, 2873, 2855, 2829,

1601, 1571, 1544, 1495, 1460, 1454, 1411, 1395, 1385, 1367, 1322,

1272, 1231, 1202, 1179, 1156, 1131, 1098, 1069, 1028, 1004, 966,

939, 913, 877, 804, 766, 698, 665, 621, 596, 564, 477 cm^–1

.

3605

N. A. Nedolya et al.

Paper

Synthesis

¹H NMR: δ = 1.05 [d, ³J = 6.7 Hz, 6 H, (CH₃)₂CH], 3.69 (s, 2 H, SCH₂),

3.76 (s, 3 H, OCH₃), 4.21 [sept, ³J = 6.7 Hz, 1 H, (CH₃)₂CH], 5.87 (d, ³J =

3.2 Hz, 1 H, H-4), 6.55 (d, ³J = 3.2 Hz, 1 H, H-5), 7.01 (m, 2 H, H-o), 7.16

(m, 3 H, H-m,p).

¹³C NMR: δ = 23.20 [(CH₃)₂CH], 41.67 (SCH₂), 46.49 [(CH₃)₂CH], 57.95

(OCH₃), 94.30 (C4), 102.80 (C2), 116.31 (C5), 126.72 (C-p), 128.21 and

128.84 (C-o,m), 138.72 (C-i), 152.08 (C3).

¹H–¹⁵N HMBC: δ = –206.7.

¹H–¹³C HMBC 2D experiments provided additional support for the

proposed structure.

Treatment of 2-Aza-1,3,5-triene 1d with Superbases

Method A: To a stirred soln of 2-aza-1,3,5-triene 1d (6.04 g, 21 mmol)

in THF (32 mL), DMSO (7 mL) and t-BuOK (2.8 g, 25 mmol) were

added sequentially at –60 °C. The mixture was stirred for 30 min at

ca. –30 °C, then cooled to –60 °C, and H₂O (30 mL) was added. After

separation of the layers, the products were extracted from the aque-

ous fraction with Et₂O (3 × 40 mL). The combined organic fractions

were washed with H₂O (3 × 50 mL), dried (MgSO₄), and concentrated

under reduced pressure to give a reddish-brown viscous liquid (5.37

g) consisting of 3,4,5,6,7,8-hexahydrocyclopenta[b]azepine 2d and

5a,6,7,8-tetrahydrocyclopenta[b]azepine 3b in a ratio of ca. 95:5 (by

¹H NMR spectroscopic analysis). Compounds 2d and 3b were separat-

ed by column chromatography (neutral alumina; hexane–Et₂O, 3:1).

Anal. Calcd for С₁₅H₁₉NOS: C, 68.93; H, 7.33; N, 5.36; S, 12.27. Found:

C, 68.87; H, 7.30; N, 5.33; S, 12.17.

The data are consistent with those previously reported.¹⁵

Method C: a. To n-BuLi (ca. 1.6 M in hexane, 25 mmol, 16 mL) a soln of

t-BuOK (2.8 g, 25 mmol) in THF (15 mL) was added at –100 °C (the

temperature quickly rose to 0 °C). The mixture was cooled to –100 °C

and a soln of 2-aza-1,3,5-triene 1d (7.3 g, 25 mmol) in THF (11 mL)

was added in one portion, after which the cooling bath was removed.

After increasing the temperature to 0 °C, the mixture was again

cooled to –40 °C, and H₂O (15 mL) was added with vigorous stirring.

After separation of the layers, the products were extracted from the

aqueous fraction with Et₂O (3 × 40 mL). The combined organic frac-

tions were washed with H₂O (3 × 50 mL), dried (MgSO₄), and concen-

trated under reduced pressure to give a dark-brown viscous liquid

(6.49 g) consisting of 3,4,5,6,7,8-hexahydrocyclopenta[b]azepine 2d

and 3,4,5,5a,6,7-hexahydrocyclopenta[b]azepine 2d′ (in a ratio of ca.

60:40), thiazole derivative 7d, and 2-(benzylsulfanyl)-1-cyclopentyl-

3-methoxy-1H-pyrrole (5d) in a ratio of ca. 88:9:3 (by ¹H NMR spec-

troscopic analysis). Column chromatography of the products (neutral

alumina; hexane, hexane–Et₂O, 10:1) gave two fractions. Fraction

1 (main fraction; 1.61 g; dark-brown liquid) consisted of homo- and

heteroannular dihydroazepines 2d and 2d′ in a ratio of ca. 60:40 and

pyrrole 5d (trace amount) (by ¹H NMR spectroscopic analysis).

Fraction 2 (0.27 g) consisted of 3-thia-1-azaspiro[4.4]non-1-ene 7d

(ca. 30%) and unidentified compounds (by ¹H NMR spectroscopic

analysis). The yield of compounds 2d and 2d′ was 22% and that of thi-

azole derivative 7d was ca. 1%.

2-[(Z)-1-Methoxyprop-1-enyl]-4-phenyl-3-thia-1-azaspi-

ro[4.4]non-1-ene (7d), 2-(Benzylsulfanyl)-3-methoxy-3,4,5,6,7,8-

hexahydrocyclopenta[b]azepine (2d), 2-(Benzylsulfanyl)-3-meth-

oxy-3,4,5,5a,6,7-hexahydrocyclopenta[b]azepine (2d′), and 3-

Methoxy-5a,6,7,8-tetrahydrocyclopenta[b]azepine (3b)

To a vigorously stirred soln of methoxyallene (10.0 g, 143 mmol) in

THF (100 mL), n-BuLi (ca. 1.6 M in hexane, 102 mmol, 64 mL) was

added at –100 °C under argon. After stirring for 5 min at –60 to

–50 °C, the soln was cooled to –70 °C and c-C₅H₉NCS (12.72 g, 100

mmol) was added in one portion. The temperature of the mixture

was allowed to rise to ca. –30 °C, and stirred at this temperature for

an additional 20 min. The mixture was then cooled to –80 °C and

PhCH₂Br (17.46 g, 102 mmol) was added in one portion, after which

the cooling bath was removed. After increasing the temperature to

18 °C (in 1 h), stirring was continued for another 30 min at 20 °C. The

mixture was again cooled to –80 °C, then the reaction was quenched

with sat. aq NH₄Cl (100 mL) and extracted with Et₂O (3 × 40 mL). The

combined organic extracts were washed with H₂O (3 × 50 mL), dried

(MgSO₄), and concentrated under reduced pressure at a bath tem-

perature of ca. 30 °C followed by vacuum treatment (ca. 1 mmHg) to

give a pure (1Z)-1-(benzylsulfanyl)-N-cyclopentyliden-2-methoxybu-

ta-1,3-dien-1-amine (2-aza-1,3,5-triene 1d) (¹H NMR spectroscopic

analysis). Its precursor, benzyl N-cyclopentyl-2-methoxybuta-2,3-di-

enimidothioate (1-aza-1,3,4-triene 4d), was not identified in the ¹H

NMR spectrum of the product. This means that during removal of sol-

vent, complete isomerization of 1-aza-1,3,4-triene 4d into 2-aza-

1,3,5-triene 1d took place. The crude product was used in the next

step without further purification.

b. To n-BuLi (ca. 1.6 M in hexane, 29 mmol, 18 mL) a soln of t-BuOK

(3.21 g, 29 mmol) in THF (20 mL) was added at –100 °C (the tempera-

ture quickly rose to 0 °C). The mixture was cooled to –100 °C and a

soln of 2-aza-1,3,5-triene 1d (8.22 g, 29 mmol) in THF (15 mL) was

added dropwise for 12 min at –86 to –78 °C, after which the cooling

bath was removed. After increasing the temperature to 0 °C (in 20

min), the mixture was again cooled to –35 °C, and H₂O (25 mL) was

added with vigorous stirring. After separation of the layers, the prod-

ucts were extracted from the aqueous fraction with Et₂O (3 × 40 mL).

The combined organic fractions were washed with H₂O (3 × 50 mL),

dried (MgSO₄), and concentrated under reduced pressure to give a

dark-brown viscous liquid (7.12 g) consisting of 3,4,5,6,7,8-hexahy-

drocyclopenta[b]azepine 2d and 3,4,5,5a,6,7-hexahydrocyclopen-

ta[b]azepine 2d′ in a ratio of ca. 80:20, thiazole derivative 7d and pyr-

2-Aza-1,3,5-triene 1d

Yield: 29.4 g (95% with regard to the purity ca. 95%); brown mobile

liquid.

IR (neat): 3086, 3061, 3028, 2958, 2871, 2826, 1665, 1604, 1563,

1495, 1453, 1414, 1257, 1187, 1165, 1123, 1070, 1049, 1029, 988,

976, 958, 892, 755, 699, 606, 564, 477, 461 cm^–1

.

1

¹H NMR: δ = 1.59 and 1.69 (quint, ³J = 7.3 Hz, 4 H, H-3′, H-4′), 1.94 and

2.36 (both t, ³J = 7.6 Hz, 4 H, H-2′, H-5′), 3.56 (s, 3 H, OCH₃), 3.87 (s,

2 H, SCH₂), 4.91 and 5.20 (both dd, ³J_trans= 17.2 Hz, ³J_cis= 10.8 Hz, ²J_gem

role 5d (in trace amounts) (by H NMR spectroscopic analysis). Flash

column chromatography of the ethereal soln of the products on neu-

tral alumina (Et₂O; hexane–Et₂O, 3:1) followed by concentration un-

der reduced pressure gave a dark-brown liquid (5.09 g), from which

two fractions were separated by column chromatography (neutral

alumina; hexane, hexane–Et₂O, 10:1). A dark resinous product (1.3 g)

remained in the flask. Fraction 1 (main fraction; 1.45 g; orange mo-

bile liquid) consisted mostly of homo- and heteroannular dihydroaze-

pines 2d and 2d′ (in a ratio of ca. 75:25) and pyrrole 5d in a ratio of ca.

98.5:1.5 and traces of thiazole derivative 7d. Fraction 2 (0.51 g, bur-

gundy viscous liquid) consisted of thiazole derivative 7d (ca. 10%) and

3

= 2.1 Hz, 2 H, CH₂=CH), 5.96 (dd, J_trans= 17.2 Hz, J_cis= 10.8 Hz, 1 H,

CH₂=CH), 7.17 (m, 1 H, H-p), 7.25 (m, 2 H, H-m), 7.32 (m, 2 H, H-o).

¹³C NMR: δ = 24.03 and 24.62 (C3′, C4′), 31.78 and 36.05 (C2′, C5′),

34.50 (SCH₂), 58.75 (OCH₃), 110.70 (CH₂=CH), 126.68 (CH₂=CH),

126.87 (C-p), 128.41 and 128.70 (C-o,m), 134.96 (=C–S), 138.67 (=C–

O), 139.12 (C-i), 187.62 (C=N).

3606

N. A. Nedolya et al.

Paper

Synthesis

13

unidentified products. Repetitive purification by column chromatog-

raphy gave compounds 2d and 2d′ in ca. 17% yield and thiazole deriv-

ative 7d in ca. 1% yield.

C

NMR: δ = 24.56 (C7), 30.91 (C6), 33.26 (C8), 44.42 (C5a), 56.07

jmod

(OCH₃), 121.95 (C2), 122.76 (C5), 123.21 (C4), 150.52 (C3), 160.54

(С8a).

The data are consistent with those previously reported.^11a

2-[(Z)-1-Methoxyprop-1-enyl]-4-phenyl-3-thia-1-azaspi-

ro[4.4]non-1-ene (7d)

Yield: 0.07 g (<1%, ¹H NMR, method C).

¹H NMR: δ = 1.78 (d, ³J = 7.0 Hz, 3 H, СН₃СН=), 1.80–1.92 (m, 8 H, H-3′,

H-4′, H-5′, H-6′), 3.71 (s, 3 H, OCH₃), 4.54 (s, 1 H, SCH), 5.85 (q, ³J =

7.0 Hz, 1 H, СН₃СН=), 7.20–7.22 (m, 5 H, Ph-H).

2-[(Z)-1-Butoxyprop-1-enyl]-4,4-dimethyl-5-phenyl-4,5-dihydro-

1,3-thiazole (7e), 2-(Benzylsulfanyl)-3-butoxy-7-methyl-4,5-dihy-

dro-3H-azepine (2e), 6-Butoxy-2-methyl-3H-azepine (3c), and 2-

(Benzylsulfanyl)-3-butoxy-1-isopropyl-1H-pyrrole (5e)

To a vigorously stirred soln of butoxyallene (5.6 g, 50 mmol) in THF

(50 mL), n-BuLi (ca. 2.5 M in hexane, 41 mmol, 16.5 mL) was added at

–95 °C under argon. The temperature was allowed to rise to –38 °C,

after which the soln was cooled to –60 °C and stirred at this tempera-

ture for 5 min. The soln was then cooled to –80 °C and a mixture of i-

PrNCS (4.05 g, 40 mmol) and THF (5 mL) was added in one portion.

The temperature of the mixture was allowed to rise to ca. –30 °C, and

stirred at this temperature for an additional 20 min. The mixture was

then cooled to –80 °C and benzyl bromide (6.98 g, 40 mmol) was add-

ed in one portion, after which the cooling bath was removed. After

increasing the temperature to 14 °C (in 1 h), the mixture was again

cooled to –80 °C, and H₂O (20 mL) was added. After separation of the

layers, the products were extracted from the aqueous fraction with

Et₂O (2 × 40 mL). The combined organic fractions were washed with

H₂O (2 × 50 mL), dried (MgSO₄), and concentrated under reduced

pressure at ca. 30 °C on rotary evaporator, then at 53–60 °C (ca. 1

mmHg) for 8 min to give (1E)-1-(benzylsulfanyl)-2-butoxy-N-(1-

methylethylidene)buta-1,3-dien-1-amine (2-aza-1,3,5-triene 1e) and

pyrrole 5e in a ratio of ca. 90:10 (¹H NMR spectroscopic analysis). The

crude product was used in the next step without further purification.

2-(Benzylsulfanyl)-3-methoxy-3,4,5,6,7,8-hexahydrocyclopen-

ta[b]azepine (2d)

Yield: 5.1 g (ca. 84%, ¹H NMR) crude; 1.39 g (23%, method A) after sep-

aration on alumina; yellow-orange liquid; n_D²⁴1.6022.

IR (neat): 3085, 3061, 3028, 2938, 2893, 2830, 1624, 1590, 1495,

1453, 1343, 1325, 1312, 1290, 1242, 1197, 1178, 1128, 1110, 1070,

1029, 1016, 995, 980, 939, 769, 724, 698, 566, 548, 470 cm^–1

.

¹H NMR: δ = 1.54–2.80 (m, 10 H, H-4, H-5, H-6, H-7, H-8), 3.39 (s, 3 H,

3

OCH₃), 3.92 (dd, J = 10.1 Hz, J = 2.2 Hz, 1 H, OCH), 4.06 and 4.13 (q,

²J_AB= 13.3 Hz, 2 H, SCH₂), 7.17 (m, 1 H, H-p), 7.15–7.34 (m, 4 H, Ph-H).

13

C

NMR: δ = 20.42 (C4), 26.72 (C7), 31.91 (SCH₂), 33.55 (C5),

jmod

37.39 and 37.67 (C6, C8), 59.00 (OCH₃), 82.92 (OCH), 125.01 (C5a),

126.77 (C-p), 128.26 and 129.22 (C-o,m), 138.30 (C-i), 142.92 (С8a),

170.82 (C=N).

COSY 2D experiments provided additional support for the proposed

structure.

Anal. Calcd for С₁₇H₂₁NOS: C, 71.04; H, 7.36; N, 4.87; S, 11.16. Found:

C, 70.88; H, 7.40; N, 4.80; S, 11.32.

2-Aza-1,3,5-triene 1e

Yield: 11.79 g (87% with regard to the purity ca. 90%); brown mobile

liquid.

2-(Benzylsulfanyl)-3-methoxy-3,4,5,5a,6,7-hexahydrocyclopen-

ta[b]azepine (2d′)

¹H NMR: δ = 0.93 [t, ³J = 7.4 Hz, 3 H, CH₃(CH₂)₃O], 1.46 [m, 2 H,

CH₃CH₂(CH₂)₂O], 1.56 and 2.03 [both s, 6 H, (CH₃)₂C=N], 1.68 (m, 2 H,

EtCH₂CH₂O), 3.70 (t, ³J = 6.6 Hz, 2 H, PrCH₂O), 3.83 (s, 2 H, SСН₂), 4.87

Obtained as a mixture of diastereomers in a ratio of ca. 93:7; insepa-

rable mixture with compound 2d.

3

2

Total yield: 1.61 g (22%, ratio 2d/2d′ ca. 60:40, method C-a) after sep-

aration on alumina; 1.40 g (17%, ratio 2d/2d′ ca.75:25, method C-b)

after repetitive purification on alumina.

and 5.18 (both dd, J_trans= 17.1 Hz, J_cis= 10.9 Hz, J_gem= 1.9 Hz, 2 H,

3

CH₂=CH), 5.86 (dd, J_trans= 17.1 Hz, J_cis= 10.9 Hz, 1 H, CH₂=CH), 7.16

(m, 1 H, H-p), 7.24 (m, 2 H, H-m), 7.30 (m, 2 H, H-o).

¹H NMR: δ (major diastereomer) = 1.60–2.04 (m, 7 H, H-4, H-5, H-5a,

H-6), 2.31 (m, 2 H, H-7), 3.38 (s, 3 H, OCH₃), 3.69 (m, 1 H, OCH), 4.03

and 4.09 (q, ²J_AB= 13.3 Hz, 2 H, SCH₂), 5.13 (br t, ³J_8,7= 2.4 Hz, 1 H, H-

8), 7.15–7.34 (m, 5 H, Ph-H).

¹³C NMR: δ = 13.87 [CH₃(CH₂)₃O], 19.21 [CH₃CH₂(CH₂)₂O], 21.04 and

27.91 [(CH₃)₂C=N], 32.19 (EtCH₂CH₂O), 34.14 (SCH₂), 70.69 (PrCH₂O),

110.08 (CH₂=CH), 126.67 (CH₂=CH), 126.88 (C-p), 128.06 and 128.71

(C-o,m), 133.88 (=C−S), 137.43 (=C−O), 138.51 (C-i), 173.96 (C=N).

13

C

NMR: δ (major diastereomer) = 29.17 (C4), 29.94 (C5), 31.24

jmod

(SCH₂), 33.09 (C6), 33.98 (C5a), 42.79 (C7), 59.11 (OCH₃), 83.88 (OCH),

114.56 (C8), 126.88 (C-p), 128.32 and 129.19 (C-o,m), 137.68 (C-i),

152.91 (С8a), 172.78 (C=N).

Treatment of 2-Aza-1,3,5-triene 1e with Superbases

Method A: To a stirred soln of the product mixture (3.9 g, 12 mmol)

containing ca. 90% 2-aza-1,3,5-triene 1e and ca. 10% pyrrole 5e in THF

(20 mL), DMSO (4 mL) and t-BuOK (1.73 g, 15 mmol) were added se-

quentially at –60 °C. The mixture was stirred for 30 min at ca. –30 °C,

then cooled to –60 °C, and H₂O (30 mL) was added. After separation of

the layers, the products were extracted from the aqueous fraction

with Et₂O (3 × 40 mL). The combined organic fractions were washed

with H₂O (3 × 50 mL), dried (MgSO₄), and concentrated under reduced

pressure to give a residue (3.64 g) consisting of 4,5-dihydro-1,3-thi-

azole 7e, 4,5-dihydro-3H-azepine 2e, 3H-azepine 3c, and pyrrole 5e

in a ratio of ca. 17:67:6:10 (by ¹H NMR spectroscopic analysis). Com-

pounds 7e, 2e, 3c, and 5e were separated by column chromatography

(neutral alumina; hexane, hexane–Et₂O, 10:1, 3:1) in yields of 13, 40,

8, and 7%, respectively.

3-Methoxy-5a,6,7,8-tetrahydrocyclopenta[b]azepine (3b)

Yield: 0.37 g (8%, method A) after separation on alumina; brown vis-

cous liquid.

IR (neat): 2955, 2869, 2830, 1735, 1633, 1615, 1532, 1466, 1451,

1422, 1343, 1312, 1287, 1214, 1162, 1118, 1055, 1018, 983, 962, 919,

838, 759, 693, 677, 626, 601, 586, 519 cm^–1

.

¹H NMR: δ = 1.75 and 2.11 (both m, 2 H, H-7), 1.83 (m, 1 H, H-5a),

2.13 (m, 2 H, H-6), 2.33 and 2.55 (both m, 2 H, H-8), 3.66 (s, 3 H,

OCH₃), 5.02 (dd, ³J_5,4= 9.5 Hz, ³J_5,5a= 4.6 Hz, 1 H, H-5), 6.11 (ddd, ³J_4,5

9.5 Hz, ⁴J_4,2≈ ⁴J_4,5a= 2.2 Hz, 1 H, H-4), 6.99 (s, 1 H, H-2).

=

3607

N. A. Nedolya et al.

Paper

Synthesis

Method B: To a stirred soln of the product mixture (3.92 g, 12 mmol)

containing ca. 90% 2-aza-1,3,5-triene 1e and ca. 10% pyrrole 5e in THF

(17 mL), DMSO (4.3 mL) and t-BuONa (1.61 g, 16 mmol) were added

at r.t. The mixture was heated to 40 °C and stirred for 5 min at 38 to

44 °C, and was then cooled to r.t., and H₂O (20 mL) was added. After

separation of the layers, the products were extracted from the aque-

ous fraction with Et₂O (3 × 20 mL). The combined organic fractions

were washed with H₂O (3 × 20 mL), dried (MgSO₄), and concentrated

under reduced pressure to give a reddish-brown mobile liquid (3.65

g) consisting of 4,5-dihydro-1,3-thiazole 7e, 4,5-dihydro-3H-azepine

2e, 3H-azepine 3c, and pyrrole 5e in a ratio of ca. 14:39:27:20 (by ¹H

NMR spectroscopic analysis). Compounds 7e, 2e, 3c, and 5e were sep-

arated by column chromatography (neutral alumina; hexane, hex-

ane–Et₂O, 10:1).

IR (neat): 3146, 3068, 3036, 2960, 2935, 2872, 1620, 1531, 1495,

1463, 1429, 1373, 1339, 1290, 1260, 1238, 1213, 1171, 1068, 1026,

996, 969, 945, 897, 839, 820, 756, 730, 702, 641, 613, 563, 513,

450 cm^–1

.

¹H NMR: δ = 0.93 [t, ³J = 7.3 Hz, 3 H, CH₃(CH₂)₃O], 1.43 [m, 2 H,

CH₃CH₂(CH₂)₂O], 1.66 (m, 2 H, EtCH₂CH₂O), 2.11 (s, 3 H, CH₃), 2.49 (br

3

m, 2 H, H-3), 3.79 (t, J = 6.6 Hz, 2 H, PrCH₂O), 5.33 (dt, J_4,5= 9.3 Hz,

³J_3,4= 7.2 Hz, 1 H, H-4), 6.18 (dd, ³J_5,4= 9.3 Hz, ⁴J_5,7= 2.3 Hz, 1 H, H-5),

6.94 (d, ⁴J_7,5= 2.3 Hz, 1 H, H-7).

13

C

NMR: δ = 13.75 [CH₃(CH₂)₃O], 19.14 [CH₃CH₂(CH₂)₂O], 26.36

jmod

(CH₃), 31.40 (EtCH₂CH₂O), 37.13 (C3), 68.60 (PrCH₂O), 117.51 (C4),

122.47 (C7), 124.80 (C5), 147.26 (C2), 149.53 (C6).

¹H–¹⁵N HMBC: δ = –89.5.

Anal. Calcd for С₁₁H₁₇NO: C, 73.70; H, 9.56; N, 7.81. Found: C, 73.56;

2-[(Z)-1-Butoxyprop-1-enyl]-4,4-dimethyl-5-phenyl-4,5-dihydro-

H, 9.31; N, 7.74.

1,3-thiazole (7e)

Yield: 0.46 g (13%, method A) after separation on alumina; 0.74 g

2-(Benzylsulfanyl)-3-butoxy-1-isopropyl-1H-pyrrole (5e)

(21%, method B); yellow-brown liquid; n_D²¹1.5543.

Yield: 0.27 g (7%, method A) after separation on alumina; 0.35 g (9%,

method B).

IR (neat): 3166, 3084, 3061, 3029, 2962, 2871, 1648, 1596, 1494,

1454, 1379, 1360, 1324, 1309, 1240, 1197, 1176, 1138, 1118, 1072,

1047, 1007, 967, 919, 874, 859, 808, 766, 738, 700, 623, 564, 536, 504,

¹H NMR: δ = 0.96 [t, ³J = 7.2 Hz, 3 H, CH₃(CH₂)₃O], 1.06 [d, ³J = 6.8 Hz,

6 H, (CH₃)₂CH], 1.48 [m, 2 H, CH₃CH₂(CH₂)₂O], 1.74 (m, 2 H,

EtCH₂CH₂O), 3.70 (s, 2 H, SCH₂), 3.93 (t, ³J = 6.6 Hz, 2 H, PrCH₂O), 4.25

(sept, ³J = 6.8 Hz, 1 H, NCH), 5.85 (d, ³J = 3.2 Hz, 1 H, H-4), 6.54 (d, ³J =

3.2 Hz, 1 H, H-5), 7.02–7.15 (m, 5 H, Ph-H).

¹³C NMR: δ = 13.88 [CH₃(CH₂)₃O], 19.24 [CH₃CH₂(CH₂)₂O], 23.15

[(CH₃)₂CH], 33.64 (EtCH₂CH₂O), 41.49 (SCH₂), 46.42 [(CH₃)₂CH], 70.57

(PrCH₂O), 95.32 (C4), 110.07 (C2), 116.13 (C5), 126.63 (C-p), 128.14

and 128.79 (C-o,m), 138.78 (C-i), 151.17 (С3).

471 cm^–1

.

¹H NMR: δ = 0.93 [t, ³J = 7.3 Hz, 3 H, CH₃(CH₂)₃O], 0.99 and 1.46 [both

s, 6 H, (CH₃)₂C], 1.44 [m, 2 H, CH₃CH₂(CH₂)₂O], 1.67 (m, 2 H,

EtCH₂CH₂O), 1.77 (d, ³J = 7.1 Hz, 3 H, СН₃СН=), 3.86 and 3.88 (both dt,

²J = 9.5 Hz, ³J = 6.7 Hz, 2 H, PrCH₂O), 4.61 (s, 1 H, SCH), 5.87 (q, ³J =

7.1 Hz, 1 H, СН₃СН=), 7.22–7.29 (m, 5 H, Ph-H).

¹³C NMR:

δ

=

11.22 (СН₃СН=), 13.90 [CH₃(CH₂)₃O], 19.18

[CH₃CH₂(CH₂)₂O], 23.71 and 28.20 [(CH₃)₂C], 32.01 (EtCH₂CH₂O),

63.84 (SСH), 71.80 (PrCH₂O), 80.76 [(CH₃)₂C], 118.80 (СН₃СН=),

127.69 (C-p), 128.28 and 128.43 (C-o,m), 138.10 (C-i), 149.10 (=C−O),

161.69 (C=N).

2-[(Z)-1-(1-Ethoxyethoxy)prop-1-enyl]-4,4-dimethyl-5-phenyl-

4,5-dihydro-1,3-thiazole (7f), 2-(Benzylsulfanyl)-3-(1-ethoxy-

ethoxy)-7-methyl-4,5-dihydro-3H-azepine (2f), 6-(1-Ethoxy-

ethoxy)-2-methyl-3H-azepine (3d), and 2-(Benzylsulfanyl)-3-(1-

ethoxyethoxy)-1-isopropyl-1H-pyrrole (5f)

¹H–¹⁵N HMBC: δ = −57.8.

Anal. Calcd for С₁₈H₂₅NOS: C, 71.24; H, 8.30; N, 4.62; S, 10.57. Found:

To a vigorously stirred soln of 1-(1-ethoxyethoxy)allene (5.13 g, 40

mmol) in THF (40 mL), n-BuLi (ca. 2.5 M in hexane, 41 mmol, 16.5 mL)

was added at –95 °C under argon. The temperature was allowed to

rise to –38 °C, after which the soln was cooled to –60 °C and stirred at

this temperature for 5 min. The soln was then cooled to –80 °C and a

mixture of i-PrNCS (4.05 g, 40 mmol) and THF (5 mL) was added in

one portion. The temperature was allowed to rise to ca. –30 °C, and

the mixture was stirred at this temperature for an additional 20 min.

The mixture was then cooled to –80 °C and benzyl bromide (6.98 g,

40 mmol) was added in one portion, after which the cooling bath was

removed. After increasing the temperature to 14 °C (in 1 h), the mix-

ture was again cooled to –80 °C, and H₂O (20 mL) was added. After

separation of the layers, the products were extracted from the aque-

ous fraction with Et₂O (2 × 40 mL). The combined organic fractions

were washed with H₂O (2 × 50 mL), dried (MgSO₄), and concentrated

under reduced pressure at ca. 30 °C on rotary evaporator, then at 50–

55 °C (ca. 1 mmHg) for 5 min to give (1E)-1-(benzylsulfanyl)-2-(1-

C, 71.02; H, 8.03; N, 4.70; S, 10.37.

2-(Benzylsulfanyl)-3-butoxy-7-methyl-4,5-dihydro-3H-azepine

(2e)

Yield: 1.4 g (40%, method A) after separation on alumina; 0.67 g (19%,

method B); colorless liquid.

¹H NMR: δ = 0.87 [t, ³J = 7.4 Hz, 3 H, CH₃(CH₂)₃O], 1.34 [sext, ³J =

7.4 Hz, 2 H, CH₃CH₂(CH₂)₂O], 1.52 (m, 2 H, EtCH₂CH₂O), 1.72 and 1.86

(both m, 2 H, H-4), 1.88 (s, 3 H, CH₃), 2.10 and 2.42 (both m, 2 H, H-5),

3.29 and 3.56 (both dt, ²J = 9.0 Hz, ³J = 6.7 Hz, 2 H, PrCH₂O), 4.08 (dd,

3

2

³J_3,4= 10.6 Hz, J_3,4′= 7.9 Hz, 1 H, OCH), 4.12 and 4.20 (d, J = 13.5 Hz,

2 H, SCH₂), 5.19 (ddq, ³J_6,5= 5.4 Hz, ³J_6,5′= 7.8 Hz, ⁴J = 1.3 Hz, 1 H, H-6),

7.19 (m, 1 H, H-p), 7.26 (m, 2 H, H-m), 7.35 (m, 2 H, H-o).

¹³C NMR: δ = 13.96 [CH₃(CH₂)₃O], 19.23 [CH₃CH₂(CH₂)₂O], 21.06 (C5),

22.06 (CH₃), 31.88 (EtCH₂CH₂O), 33.09 (SCH₂), 42.89 (C4), 71.49

(PrCH₂O), 80.07 (OCH), 110.18 (C6), 126.84 (C-p), 128.31 and 129.24

(C-o,m), 138.34 (C-i), 147.14 (С7), 174.55 (C=N).

ethoxyethoxy)-N-(1-methylethylidene)-1,3-butadien-1-amine

(2-

aza-1,3,5-triene 1f) and pyrrole 5f in a ratio of ca. 93:7 (by ¹H NMR

spectroscopic analysis). The crude product was used in the next step

without further purification.

¹H–¹⁵N HMBC: δ = –74.3.

Anal. Calcd for С₁₈H₂₅NOS: C, 71.24; H, 8.30; N, 4.62; S, 10.57. Found:

C, 71.18; H, 8.39; N, 4.67; S, 10.43.

2-Aza-1,3,5-triene 1f

6-Butoxy-2-methyl-3H-azepine (3c)

Yield: 0.17 g (8%, methods A and B); ruby oily liquid; n_D²¹1.5149.

Yield: 12.5 g (91% with regard to the purity ca. 93%); brown mobile

liquid.

3608

N. A. Nedolya et al.

Paper

Synthesis

¹H NMR: δ = 1.13 (t, ³J = 7.0 Hz, 3 H, CH₃CH₂O), 1.41 [d,³J = 5.3 Hz, 3 H,

CH₃CHO), 1.60 and 2.06 [both s, 6 H, (CH₃)₂C=N], 3.51 and 3.85 (both

dq, ²J = 9.4 Hz, ³J = 7.0 Hz, 2 H, CH₃CH₂O), 3.82 and 3.83 (d, ²J =

¹³C NMR: δ = 11.74 and 11.75 (CH₃CH=), 15.39 (CH₃CH₂O), 20.89 and

20.93 (CH₃CHO), 23.49, 23.81, 20.13, and 28.18 [(CH₃)₂C], 63.77 and

64.04 (CH₃CH₂O), 63.66 and 63.72 (C5), 80.67 and 80.86 [(CH₃)₂C],

101.05 and 101.05 (OCHO), 121.19 and 121.26 (CH₃CH=), 127.73 and

127.75 (C-p), 128.30, 128.36, 128.42, and 128.48 (C-o,m), 137.63 and

138.13 (C-i), 146.43 and 146.55 (=C−O), 161.31 and 161.40 (C=N).

3

14.0 Hz, 2 H, SCH₂), 4.91 and 5.31 (both dd, J_trans= 17.2 Hz, J_cis

=

2

3

11.0 Hz, J_gem= 1.9 Hz, 2 H, CH₂=CH), 5.09 (q, J = 5.3 Hz, 1 H, OCHO),

5.96 (dd, ³J_trans= 17.2 Hz, ³J_cis= 11.0 Hz, 1 H, CH₂=CH), 7.18 (m, 1 H, H-

p), 7.26 (m, 2 H, H-m), 7.31 (m, 2 H, H-o).

Anal. Calcd for С₁₈H₂₅NO₂S: C, 67.67; H, 7.89; N, 4.38; S, 10.04. Found:

C, 67.57; H, 7.89; N, 4.39; S, 9.91.

13

C

NMR: δ = 15.54 (CH₃CH₂O), 21.31 (CH₃CHO), 21.53 and 28.09

jmod

[(CH₃)₂C=N], 34.63 (SCH₂), 64.61 (CH₃CH₂O), 102.22 (OCHO), 111.42

(CH₂=CH), 126.93 (CH₂=CH), 128.44 and 128.92 (C-o,m), 128.45 (C-p),

134.20 (=C−S), 136.21 (=C−O), 138.53 (C-i), 174.17 (C=N).

¹H–¹⁵N HMBC: δ = −66.0.

¹H–¹³C HMBC 2D experiments provided additional support for the

proposed structure.

2-(Benzylsulfanyl)-3-(1-ethoxyethoxy)-7-methyl-4,5-dihydro-3H-

azepine (2f)

Yield: 2.08 g (52%, method A); 1.15 g (31%, method B); ca. 2.6:1 mix-

ture of diastereomers; yellow mobile liquid; n_D²⁴1.5521.

IR (neat): 3105, 3086, 3062, 3030, 2976, 2940, 2920, 2885, 2860,

1633, 1601, 1574, 1495, 1453, 1443, 1393, 1377, 1360, 1341, 1328,

1311, 1244, 1176, 1140, 1085, 1055, 1029, 1005, 980, 948, 932, 918,

Treatment of 2-Aza-1,3,5-triene 1f with Superbases

899, 871, 843, 801, 783, 771, 714, 698, 588, 567, 537, 470 cm^–1

.

Method A: To a stirred soln of the product mixture (4.3 g, 13 mmol)

containing ca. 93% 2-aza-1,3,5-triene 1f and ca. 7% pyrrole 5f in THF

(22 mL), DMSO (4 mL) and t-BuOK (1.83 g, 16 mmol) were added se-

quentially at –60 °C. The mixture was stirred for 30 min at ca. –30 °C,

then cooled to –60 °C, and H₂O (20 mL) was added. After separation of

the layers, the products were extracted from the aqueous fraction

with Et₂O (3 × 40 mL). The combined organic fractions were washed

with H₂O (3 × 50 mL), dried (MgSO₄), and concentrated under re-

duced pressure to give a dark-brown viscous liquid (4.1 g) consisting

of 4,5-dihydro-1,3-thiazole 7f, 4,5-dihydro-3H-azepine 2f, and pyr-

role 5f in a ratio of ca. 6:85:9 (by ¹H NMR spectroscopic analysis).

Compounds 7f, 2f, and 5f were separated by column chromatography

(neutral alumina; hexane) in 6, 52, and 7% yield, respectively.

¹H NMR: δ (major diastereomer) = 1.13 (t, ³J = 7.0 Hz, 3 H, CH₃CH₂O),

1.31 [d, ³J = 5.4 Hz, 3 H, CH₃CHO), 1.73 and 1.86 (both m, 2 H, H-4),

1.87 (d, ⁴J = 0.9 Hz, 3 H, CH₃), 2.15 and 2.38 (both m, 2 H, H-5), 3.45

and 3.50 (both dq, ²J = 9.3 Hz, ³J = 7.0 Hz, 2 H, CH₃CH₂O), 4.14 and 4.16

(q, ²J_AB= 13.4 Hz, 2 H, SCH₂), 4.53 (dd, ³J_3,4= 10.5 Hz, ³J_3,4′= 7.9 Hz, 1 H,

OCH), 4.67 (q, ³J = 5.4 Hz, 1 H, OCHO), 5.21 (m, 1 H, H-6), 7.18 (m, 1 H,

H-p), 7.24 (m, 2 H, H-m), 7.34 (m, 2 H, H-o).

¹H NMR: δ (minor diastereomer) = 1.12 (t, ³J = 7.1 Hz, 3 H, CH₃CH₂O),

1.25 (d, ³J = 5.4 Hz, 3 H, CH₃CHO), 1.73 and 1.86 (both m, 2 H, H-4),

1.87 (d, ⁴J = 0.9 Hz, 3 H, CH₃), 2.15 and 2.38 (both m, 2 H, H-5), 3.46

and 3.69 (both dq, ²J = 9.5 Hz, ³J = 7.1 Hz, 2 H, CH₃CH₂O), 4.14 and 4.17

(q, ²J_AB= 13.4 Hz, 2 H, SCH₂), 4.52 (dd, ³J_3,4= 10.5 Hz, ³J_3,4′= 7.8 Hz, 1 H,

OCH), 4.74 (q, ³J = 5.4 Hz, 1 H, OCHO), 5.19 (m, 1 H, H-6), 7.18 (m, 1 H,

H-p), 7.24 (m, 2 H, H-m), 7.34 (m, 2 H, H-o).

Method B: To a stirred soln of the product mixture (4.0 g, 12 mmol)

containing ca. 93% 2-aza-1,3,5-triene 1f and ca. 7% pyrrole 5f in THF

(17 mL), DMSO (4.2 mL) and t-BuONa (1.56 g, 16 mmol) were added

at r.t. The mixture was heated to 40 °C and stirred for 5 min at 38 to

44 °C, then cooled to r.t., and H₂O (20 mL) was added. After separation

of the layers, the products were extracted from the aqueous fraction

with Et₂O (3 × 20 mL). The combined organic fractions were washed

with H₂O (3 × 20 mL), dried (MgSO₄), and concentrated under reduced

pressure to give a reddish-brown mobile liquid (3.77 g) consisting of

4,5-dihydro-1,3-thiazole 7f, 4,5-dihydro-3H-azepine 2f, 3H-azepine

13

C

NMR: δ (major diastereomer) = 15.38 (CH₃CH₂O), 19.53

jmod

(CH₃CHO), 21.10 (C5), 22.03 (CH₃), 33.15 (SCH₂), 43.31 (C4), 58.92

(CH₃CH₂O), 75.30 (OCH), 99.42 (OCHO), 110.23 (C6), 126.79 (C-p),

128.25 and 129.13 (C-o,m), 138.17 (C-i), 147.03 (С7), 173.58 (C=N).

13

C

NMR: δ (minor diastereomer) = 15.08 (CH₃CH₂O), 19.53

jmod

(CH₃CHO), 21.04 (C5), 21.96 (CH₃), 33.22 (SCH₂), 43.47 (C4), 62.01

(CH₃CH₂O), 72.48 (OCH), 99.01 (OCHO), 110.07 (C6), 126.74 (C-p),

128.20 and 129.11 (C-o,m), 138.25 (C-i), 147.11 (С7), 173.91 (C=N).

1

3d, and pyrrole 5f in a ratio of ca. 13:57:13:17 (by H NMR spectro-

Anal. Calcd for С₁₈H₂₅NO₂S: C, 67.67; H, 7.89; N, 4.38; S, 10.04. Found:

C, 67.55; H, 7.94; N, 4.30; S, 10.11.

scopic analysis). Compounds 7f, 2f, 3d, and 5f were separated by col-

umn chromatography (neutral alumina; hexane, hexane–Et₂O, 10:1,

3:1, 1:1) in 5, 31, 14, and 10% yield, respectively.

6-(1-Ethoxyethoxy)-2-methyl-3H-azepine (3d)

Yield: 0.32 g (14%, method B); yellow-orange liquid; n_D²³1.5070.

2-[(Z)-1-(1-Ethoxyethoxy)prop-1-enyl]-4,4-dimethyl-5-phenyl-

4,5-dihydro-1,3-thiazole (7f)

IR (neat): 2975, 2932, 2875, 1655, 1617, 1526, 1459, 1443, 1425,

1413, 1382, 1340, 1289, 1241, 1204, 1170, 1129, 1111, 1093, 1077,

1047, 990, 950, 932, 901, 887, 858, 825, 759, 729, 712, 680, 648, 630,

Yield: 0.24 g (6%, method A); 0.19 g (5%, method B); ca. 1.2:1 mixture

of diastereomers; light-brown mobile liquid; n_D²¹1.5382.

574, 528, 516, 439 cm^–1

.

IR (neat): 3085, 3061, 3029, 2976, 2932, 2864, 1648, 1587, 1495,

1451, 1380, 1363, 1339, 1323, 1285, 1240, 1176, 1140, 1097, 1079,

1027, 965, 949, 930, 889, 850, 810, 768, 739, 700, 680, 662, 623, 563,

¹H NMR: δ = 1.16 (t, ³J = 6.6 Hz, 3 H, CH₃CH₂O), 1.38 (d, ³J = 5.4 Hz, 3 H,

CH₃CHO), 2.13 (s, 3 H, CH₃), 2.33 and 2.62 (both m, 2 H, H-3), 3.50 and

3.77 (dq, ³J = 6.6 Hz, 2 H, CH₃CH₂O), 5.06 (q, ³J = 5.4 Hz, 1 H, OCHO),

536, 504, 477, 448 cm^–1

.

3

¹H NMR: δ = 0.97, 1.00, 1.46, and 1.47 [all s, 6 H, (CH₃)₂C], 1.18 and

1.20 (t, ³J = 7.0 Hz, 3 H, CH₃CH₂O), 1.42 and 1.43 (d, ³J = 5.1 Hz, 3 H,

CH₃CHO), 1.83 (d, ³J = 7.0 Hz, 3 H, CH₃CH=), 3.43, 3.63, and 3.88 (dq,

²J = 16.4 Hz, ²J = 9.5 Hz, ³J = 7.1 Hz, 2 H, CH₃CH₂O), 4.61 and 4.65 (s,

1 H, SCH), 5.31 (q, ³J = 5.1 Hz, 1 H, OCHO), 5.89 and 5.91 (q, ³J = 7.0 Hz,

1 H, CH₃CH=), 7.27 and 7.37 (m, 5 H, Ph-H).

5.32 (dt, J_4,5= 9.0 Hz, J_4,3= 7.1 Hz, 1 H, H-4), 6.25 (dd, J_5,4= 9.0 Hz,

⁴J_5,7= 1.5 Hz, 1 H, H-5), 7.18 (br s, 1 H, H-7).

¹³C NMR: δ = 15.10 (CH₃CH₂O), 20.52 (CH₃CHO), 26.32 (CH₃), 37.72

(C3), 62.02 (CH₃CH₂O), 101.24 (OCHO), 116.81 (C4), 125.34 (C5),

128.92 (C7), 146.70 (C6), 147.62 (C=N).

Anal. Calcd for С₁₁H₁₇NO₂: C, 67.66; H, 8.78; N, 7.17. Found: C, 67.75;

H, 8.70; N, 7.05.

3609

N. A. Nedolya et al.

Paper

Synthesis

The data are consistent with those previously reported.^12b

(5) (a) Nedolya, N. A.; Brandsma, L.; Trofimov, B. A. Dokl. Chem.

(Engl. Transl.) 1996, 350, 210. (b) Nedolya, N. A.; Brandsma, L.;

Trofimov, B. A. Russ. Chem. Bull. 1996, 45, 2670. (c) Nedolya, N.

A.; Brandsma, L.; Zinov’eva, V. P.; Trofimov, B. A. Russ. J. Org.

Chem. (Engl. Transl.) 1998, 34, 1494.

(6) (a) Nedolya, N. A.; Brandsma, L.; de Lang, R.-J.; Trofimov, B. A.

Russ. J. Org. Chem. 1997, 33, 580. (b) Nedolya, N. A.;

Schlyakhtina, N. I.; Klyba, L. V.; Ushakov, I. A.; Fedorov, S. V.;

Brandsma, L. Tetrahedron Lett. 2002, 43, 9679. (c) Nedolya, N. A.;

Brandsma, L.; Schlyakhtina, N. I.; Fedorov, S. V. Chem. Hetero-

cycl. Compd. (Engl. Transl.) 2002, 38, 622. (d) Nedolya, N. A.;

Tarasova, O. A.; Albanov, A. I.; Trofimov, B. A. Chem. Heterocycl.

Compd. (Engl. Transl.) 2011, 46, 1536.

2-(Benzylsulfanyl)-3-(1-ethoxyethoxy)-1-isopropyl-1H-pyrrole

(5f)

Yield: 0.30 g (7%, method A) after separation on alumina; 0.4 g (10%,

method B); light-yellow liquid; n_D²¹1.5465.

IR (neat): 3108, 3084, 3061, 3029, 2975, 2931, 2876, 1600, 1575,

1536, 1530, 1495, 1453, 1412, 1383, 1318, 1274, 1220, 1179, 1134,

1083, 1052, 998, 949, 933, 874, 847, 817, 806, 766, 700, 673, 623, 588,

565, 519, 474 cm^–1

.

¹H NMR: δ = 1.05 [d, ³J = 6.7 Hz, 6 H, (CH₃)₂CH], 1.23 (t, ³J = 7.1 Hz, 3 H,

CH₃CH₂O), 1.46 (d, ³J = 5.3 Hz, 3 H, CH₃CHO), 3.60 and 3.91 (dq, ²J =

9.3 Hz, ³J = 7.1 Hz, 2 H, CH₃CH₂O), 3.72 (s, 2 H, SCH₂), 4.23 [sept, ³J =

6.7 Hz, 1 H, (CH₃)₂CH], 5.17 (q, ³J = 5.3 Hz, 1 H, OCHO), 5.96 (d, ³J =

2.9 Hz, 1 H, H-4), 6.55 (d, ³J = 2.9 Hz, 1 H, H-5), 7.02 (m, 2 H, H-o), 7.17

(m, 3 H, H-m,p).

(7) Nedolya, N. A.; Albanov, A. I.; Klyba, L. V.; Zhanchipova, E. R.

Russ. J. Org. Chem. 2006, 42, 455.

(8) Nedolya, N. A.; Tolmachev, S. V.; Brandsma, L. Russ. J. Org. Chem.

2007, 43, 478.

(9) Nedolya, N. A.; Brandsma, L.; Trofimov, B. A. Chem. Heterocycl.

Compd. (Engl. Transl.) 2002, 38, 1230.

¹³C NMR: δ = 15.29 (CH₃CH₂O), 20.56 (CH₃CHO), 23.26 [(CH₃)₂CH],

41.77 (SCH₂), 46.64 (NCH), 62.27 (CH₃CH₂O), 99.08 (OCHO), 101.80

(C4), 106.30 (C2), 116.44 (C5), 126.82 (C-p), 128.31 and 128.84 (C-

o,m), 138.69 (C-i), 147.53 (C3).

(10) (a) Brandsma, L.; Nedolya, N. A.; van der Kerk, A. C. H. T. M.;

Heerma, W.; Lutz, E. T. H. G.; de Lang, R.-J.; Afonin, A. V.;

Trofimov, B. A. Russ. Chem. Bull. 1997, 46, 832. (b) Brandsma, L.;

Nedolya, N. A.; Heerma, V.; van der Kerk, A. C. H. T. M.; Lutz, E. T.

H. G.; de Lang, R.-J.; Afonin, A. V.; Trofimov, B. A. Chem. Hetero-

cycl. Compd. (Engl. Transl.) 1997, 33, 493. (c) Nedolya, N. A.;

Brandsma, L.; van der Kerk, A. C. H. T. M.; Heerma, V.; Lutz, E. T.

H. G.; Afonin, A. V.; de Lang, R.-J.; Trofimov, B. A. Russ. J. Org.

Chem. 1997, 33, 1359. (d) Trofimov, B. A.; Nedolya, N. A.;

Brandsma, L.; Frolov, Yu. L.; Larionova, E. Yu.; Toryashinova, D.-

S. D.; Kobychev, V. B.; Vitkovskaya, N. M. Sulfur Lett. 1999, 22,

249.

Anal. Calcd for С₁₈H₂₅NO₂S: C, 67.67; H, 7.89; N, 4.38; S, 10.04. Found:

C, 67.58; H, 7.72; N, 4.36; S, 10.11.

Acknowledgment

The authors are grateful for the financial support from the Russian

Foundation for Basic Research (Grant No. 13-03-00691a).

(11) (a) Volostnykh, O. G. Ph.D. Dissertation; Irkutsk Institute of

Chemistry: Russian Federation, 2011. (b) Nedolya, N. A.;

Trofimov, B. A. Chem. Heterocycl. Compd. (Engl. Transl.) 2013, 49,

152.

Supporting Information

Supporting information for this article is available online at

http://dx.doi.org/10.1055/s-0034-1378805.

S

u

p

ortiInfogrmoaitn

S

u

p

ortioInfgrmoaitn

(12) (a) Nedolya, N. A.; Dmitrieva, L. L.; Albanov, A. I.; Klyba, L. V.;

Tarasova, O. A.; Ushakov, I. A. Russ. J. Org. Chem. 2006, 42, 465.

(b) Nedolya, N. A.; Tarasova, O. A.; Albanov, A. I.; Volostnykh, O.

G.; Brandsma, L.; Trofimov, B. A. Mendeleev Commun. 2008, 18,

164. (c) Nedolya, N. A.; Tarasova, O. A.; Volostnykh, O. G.;

Albanov, A. I.; Trofimov, B. A. J. Organomet. Chem. 2011, 696,

3359.

(13) (a) Nedolya, N. A.; Tarasova, O. A.; Albanov, A. I.; Klyba, L. V.;

Trofimov, B. A. Russ. J. Gen. Chem. (Engl. Transl.) 2009, 79, 1041.

(b) Nedolya, N. A.; Tarasova, O. A.; Volostnykh, O. G.; Albanov, A.

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Article Doi

Further Developments in the Reaction of 2-Aza-1,3,5-trienes with Superbases: Competitive Formation of New 4,5-Dihydro-1,3-thiazoles, Dihydroazepines, and Azepines by Tandem Deprotonation-Cyclization

DOI: 10.1055/s-0034-1378805

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