New enolate-carbodiimide rearrangement in the concise synthesis of 6-amino-2,3-dihydro-4-pyridinones from homoallylamines

DOI: 10.1039/C6OB00293E

New enolate-carbodiimide rearrangement in concise synthesis of 6-amino-

,3-dihydro-4-pyridinones from homoallylamines

2

[

a]

[a]

[a] †

[a][b] ‡

Kuznetsov N. Yu. *, Tikhov R. M. , Godovikov I. A. , Khrustalev V. N.

, Bubnov

[

a][c]

Yu. N.

A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,

Vavilov 28, 119991, Moscow, Russian Federation

*

[

a]

[

b]

Department of Inorganic Chemistry, Peoples’ Friendship University of Russia, Miklukho-

Maklay St., 6, Moscow 117198, Russian Federation

[

c]

N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky pr.

7, 119991 Moscow, Russia

4

Key words: 2,3-dihydro-4-pyridinones, adamantane, homoallylamines, rearrangement, nitrogen

heterocycles.

Three-step synthesis of 6-amino-2,3-dihydro-4-pyridinones from homoallylamines involving NBS

(

2

or I , PhSeCl)-mediated cyclization of N-(3-butenyl)ureas to 6-(bromomethyl)-2-iminourethanes,

dehydrohalogenation and the novel enolate-carbodiimide rearrangement as a key step has been

developed. The scope and limitations of the method as well as the mechanism of the rearrangement

supported by kinetic study and isolation of N-(1-adamantyl)carbodiimide are discussed. The final

products – imino-analogues of well known piperidine-2,4-diones are promising building blocks in

synthesis of bio-/pharmacological compounds.

_

_______________________________________________________________________________

Among heterocycles, composing a variety of natural products and important

pharmaceuticals, piperidines occupy one of the privileged places. The various types of biological

activity of this particular class of nitrogen heterocycles have stimulated the search for novel

syntheses of known molecules as well as the design of new piperidine derivatives. Subset of

piperidine - 6-amino-2,3-dihydro-4-pyridinones (ADP) does not only reveal the parent biological

activity, but are also valuable building blocks, having multiple sites at the piperidine ring available

for functionalization. Several biologically active aminopyridine derivatives are shown in Fig. 1.

†

‡

NMR experiments; X-Ray single crystal analysis.

1

Organic & Biomolecular Chemistry

Page 2 of 29

DOI: 10.1039/C6OB00293E

O

N

OH

N

CONHAr

N R'

HO

OH

Cl

Zolpidem (1)

N

H

NH

Cl

N

O

N

O

X

Kifunensine (2)

class I α-mannosidase inhibitor

pyrido[1,2-a]benzimidazoles (3)

GABA-A receptor agonists

imidazo[1,2-a]pyridines

NH₂

O

N

O

N

H

N

OH

N

H

O

OH

F

NVP-HSP990 (5) (2007, Novartis, Switzerland)

Heat Shock Protein 90 inhibitors

anticancer, antiviral etc. agents)

TAK-459 (4) (2009, Takeda, Japan)

(

Fig. 1.

Amid these products can be noted Zolpidem (1) - blockbuster drug against sleep disorder, a

member of numerous imidazo[1,2-a]pyridines, persisting as one of the most favorite groups in the

medicinal chemistry . The widespread use of imidazo[1,2-a]pyridines is mainly connected with

convenient access to this scaffold from easily available 2-aminopyridines. A saturated derivative of

imidazo[1,2-a]pyridine presented by alkaloid kifunensine (2) (a natural immunomodulator isolated

from actinobacterium Kitasatosporia kifunensine no. 9482) relates to potent class I α-mannosidase

inhibitor and is perspective for treatment of some genetic diseases, viral infections and cancer

metastases. Derivatives of pyrido[1,2-a]benzimidazole (3) possess a wide spectrum of biological

4

activity related to GABA-A receptor interaction. Of particular interest is the derivative of 2-

5

aminopyrimidine, built on piperidine-2,4-dione platform, TAK-459 (4) which is a hydroxyimino-

6

analogue of Novartis’ drug candidate NVP-HSP990 (5). Both compounds 4 and 5 are potent

inhibitors of heat shock protein 90 (HSP90 – class of chaperone proteins playing a key role in

mechanism of cell survival under a number of dangerous diseases including oncological, viral,

7

8

9

fungal, parasitic and even tuberculoses ) perspective for creation of new generation drugs with

variable applications. Synthesis of compounds 4 and 5 is carried out via corresponding 6-

arylpiperidine-2,4-dione followed by transformation into 2-thioamide under action of Davy methyl

reagent and further to final compound 4.

2

Page 3 of 29

Organic & Biomolecular Chemistry

DOI: 10.1039/C6OB00293E

Unlike various methods available for the preparation of imidazo[1,2a]pyridine derivatives,

ADP synthesis is limited to two main approaches. The first one is based on Dieckmann’s

condensation of amidine-esters or its modifications which is actually similar to the classical method

for synthesis of piperidine-2,4-diones. This route was realized in synthesis of 3-C-analogue of

0

4a

natural antibiotic TAN-1057A/B and GABA-A receptors agonists. Another approach is based on

substitution of thio-groups with amines. It was applied in synthesis of TAK-459 and different

ADPs. In the latter case the substitution of α-alkenoyl ketene-(S,S)-acetals can be performed

stepwise allowing incorporation of different amines residues into the final structure.

Recently, we have elaborated a new convenient method for transformation of N-Boc-

protected homoallylamines into 6-substituted piperidine-2,4-diones, which are versatile precursors

for preparation of different pharmaceutically relevant compounds, and also are a structural motif of

many alkaloids, biologically active small synthetic molecules, part of peptidomimetics . An

important feature of our method is the application of N-Boc-protected homoallylamines as the

starting material for the synthesis of diones (Scheme 1).

O

1

2

. NBS

R¹

_R1

_R2

. tBuOK (2 equiv.)

NHBoc

Br

_R2

N

O

0

H

2

0 C

NBS

Br

O

0

–

50 C

–

+

tBuOK

O

N

O

O K

R¹

R²

tBuOK

R¹

R²

R¹

R²

_R1

_R2

–

+

– +

O K

N

O K

N

O

H

O

E

enolate-isocyanate

Scheme 1. Proposed mechanism of the enolate-isocyanate rearrangement

Over this short synthetic chain consisting of cyclobromocarbamation, HBr-eliminaton and a key

stage - new enolate-isocyanate rearrangement, a homoallylamine fragment transforms into

piperidine ring in an atom-economic manner. The potassium salt of cyclic enolester (E) resulting

from dehydrobromination undergoes ring-opening reaction, generating, thereby, a highly reactive

0

intermediate enolate-isocyanate which effectively cyclizes to piperidine-2,4-dione even at -50 C,

0

though the whole transformation of bromide proceeds at 20 C. We considered that 2-imino-1,3-

oxazinanes would follow a similar scenario with generation of an enolate-carbodiimide followed by

closure into 2-imino-analogues of piperidine-2,4-diones or their tautomers – ADP (Scheme 2).

3

Organic & Biomolecular Chemistry

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DOI: 10.1039/C6OB00293E

O

–

+

O K

R²

O

_R2

_R1

R²

-

+

_R1

N

H

NR

_R1

N

H

NHR

N

NR K

N

_R1

NR

enolate-carbodiimide

ADP

Scheme 2.

Due to the high efficiency of this approach and the significance of the products obtained, we

intended to extend our methodology for ADP synthesis starting from N-(3-butenyl)ureas.

Results and Discussion

Starting butenylamines were prepared by different methods. Homoallylamine 6 was obtained

by the alkylation of potassium phtalimide with 4-bromo-1-butene under phase-transfer catalysis in

MeCN followed by hydrazinolysis of N-(3-butenyl)phtalimide. This procedure provides clean and

high-yielding synthesis of 6 with only filtration and evaporation treatment. α-Phenyl derivatives 7

and 8 were prepared via allylboration of 1-phenyl-N-trimethylsilylmethanimine or benzonitrile with

triallylborane (Scheme 3). For an asymmetric version of the rearrangement, amine (S)-7 was

synthesized in scalemic form. Diastereoselective allylation of (R)-phenyl-N-tert-butanesulfinylimine

9

with allylzinc bromide in the presence of equivalent amount of TMEDA in THF leads to allylated

amide 10 with 75% de.

O

TBAB

MeCN

1. N H / EtOH

2 4

+

–

+

N

Br

KN

NH Cl

3

, 88%

2. HCl in dioxane

6

9

6%

O

0

1. Ph

NTMS 20 C

1. Ph

N 110 C

Ph

B

3

2. NaOH

2. MeOH, NaOH

NH₂

7, 91%

8, 94%

O^–

ZnBr

Ph

+

HCl

S

Ph

N

Ph (S) N

(

R)

(R)

+

–

H

MeOH

NH Cl

3

TMEDA,

0

9

THF, 0 C

10, 85%, 75% de

(S)-7, 95%

Scheme 3.

Deprotection of 10 with HCl in MeOH gave crystalline hydrochloride (S)-7. We failed to enrich ee

of (S)-7 by crystallization of its N-Boc-derivative similarly to the described procedure, since the

4

Page 5 of 29

Organic & Biomolecular Chemistry

DOI: 10.1039/C6OB00293E

ee of the recrystallized product reached only 84% with much losses of N-Boc-amide. Therefore we

converted all the amount of N-Boc-derivative back to amine (S)-7.

Amines 6-8 were converted to the corresponding ureas by the reaction with isocyanates bearing

substituents with different electronical and sterical nature: aromatic (2-chloro(iodo)phenyl-),

aliphatic (methyl-, allyl-), hindered aliphatic (tert-butyl-, 1-adamantyl-) and electron deficient (2-

methoxyethyloxycarbonyl-,

ethyloxycarbonyl-,

tosyl-).

X

O

R²

^N^B^S^o^r^I2

N

O

tBuOK

O

tBuOK

O

R²

N

NR²

Solvent

N

NR²

N

H

13a-f

NHR²

+

-

DCM, Et N

3

DCM

NH Cl

N

3

H

6

11a-g

12a-g

14,15

Scheme 4.

Table 1.

2

R

Urea, % RBr, %

Conditions of the

ADP, %

rearrangement

MeO(CH

Cbz-

2

)

2

OC(O)- 11a, 92

11b, 93

12a, 85

12b, 92

DMF, 25 °C, 15 min

13a, 96

13b, 83

THF, 40 °C, 2h

1

4, 96

THF, 25 °C, 1 min

MeOH, 60 °C, 15 min

DMF, 25 °C, 5 min

a

Ts-

11c, 98

11d, 92

12c, 95

13c, 90

1

5, 92

b

2

-I-Ph-

-I-4-Br-Ph-

12d, 56 (RI) iPrOH, 25 °C, 3h

13d, 55

13e, 98

13f, 95

13g, NP

c

---

12e, 64

12f, 94

12g, 99

iPrOH, 40 °C, 1h

THF, 25 °C, 1h

Me

11f, 91

11g, 99

d

tBu

THF, DMF, iPrOH,

DMSO

1

13

a) 13c exists in the form keto-imine tautomer according to H and C NMR spectra; b) reaction with I

2

at 0 °C, 25% of

2

1

1d was recovered; c) R corresponds the structures 12e and 13e; d) no product

The reactions of amine hydrochloride 6 with isocyanates in the presence of Et

3

N at room

temperature gave rise to the corresponding ureas 11a-g which smoothly undergo cyclization to

(

bromomethyl)iminourethanes 12a-c and 12f,g on treatment with NBS at ambient temperature

Scheme 4, Table 1). However, the cyclization of iodophenyl-urea 11d under similar conditions is

complicated by mono- and dibromination of the aromatic ring; while 2-iodo-4-bromophenyl-

derivative 12e (64%) was obtained when the reaction was run at -20 °C. Alternatively to keep the 2-

5

Organic & Biomolecular Chemistry

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DOI: 10.1039/C6OB00293E

iodophenyl group intact, iodination of 11d at 0 °C was carried out to give 6-(iodomethyl)urethane

2d (56%) along with 11d (25%) recovered. Under the more forced conditions (20 °C or addition of

CO to neutralize HI), the reaction is also complicated by iodination of the aromatic ring.

Previously discovered transformation of 6-(bromomethyl)urethanes to piperidine-2,4-diones has

1

K

2

3

been achieved by treatment with tBuOK in THF as a solvent (Scheme 1). As we expected, 6-

bromomethyl)-2-iminourethanes 12a-f were transformed to 6-amino-2,3-dihydro-4-pyridinones 13

(

in the presence of tBuOK, however, an optimal solvent has to be selected experimentally for each

compound 12. The most convenient solvents were found to be DMF, THF and iPrOH (see Table 1).

2

Among the synthesized cyclic bromides, compounds with electron-withdrawing groups R (12a-c)

are the most reactive ones. Thus ADP 13a is formed almoust quantitatively (96%) in 15 min at 25

°

C. We have found that treatment of bromides 12b and 12c with tBuOK in THF for very short time

(

1-5 min) gave rise to enolesters 14 and 15, which are intermediates in the transformation (Scheme

0

4

, Table 1). When the reaction with 12b was carried out at 40 C for 2 h, enolester 14 formed

initially is smoothly transformed to ADP 13b (83%). Bromide 12c reacts similarly, however 15

forms potassium salt which is precipitated from THF and DMF, but is readily soluble in MeOH.

0

Therefore, conducting the reaction of 12c in MeOH (at 60 C) leads to expected rearrangement

product 13c (90%). As we previously found iodides are not proper substrates for carring out the

6

rearrangement because of formation of side products. Nevertheless, ADP 13d (55%) was obtained

from 2-iodophenyl-derivative 12d which is in contrast to with transformation of bromide 12e into

ADP 13e (98%). Urea 11f (Table 1) reacts smoothly with NBS and bromide 12f thus obtained

transforms cleanly into ADP 13f (95%). On the other hand, bulky tBu-group in bromourethane 12g

completely suppress the rearrangement. Different conditions and solvents were used, but ADP 13g

was not obtained or detected.

Having the promising results with ureas 11a-f derived from 6, we studied the reactions with

monosubstituted phenylamine 7 as well as with (S)-7 to establish the absence of racemization of the

α-chiral center during the rearrangement (Scheme 5, Table 2).

Br

O

R²

O

tBuOK

Ph

N

•

O

NBS

O

tBuOK

O

R²

Ph

^N^H2

Ph

N

DCM

Solvent

DCM

_N_R2

_N_H_R2

Ph

N

Ph

N

H

N

H

18a-d

H

7

or (S)-7

16a-d

17a-d

19

Scheme 5.

6

Page 7 of 29

Organic & Biomolecular Chemistry

DOI: 10.1039/C6OB00293E

Table 2.

2

R

Urea, %

RBr, %

cis/trans

Conditions of

ADP, %

the rearrangement

0

EtOC(O)- 16a, 90

17a, 99

17b, 99

2.6/1

2.4/1

DMF, 25 C, 15 min

18a, 94

18b, 98

19, 97

0

Cbz-

16b, 88

16c, 99

16d, 96

THF, 40 C, 40 min

0

THF, 0 C, 1 min

a

tBu

17c, 95

17d, 90

3/1

THF, DMF, iPrOH,

DMSO

18c, NP

0

Me-

2.3/1

THF, 25 C, 30 min

18d, 96

0

b

DMSO, 25 C, <1 min 18d, >95

c

0

d

(S)-16d, 43 (S)-17d, 92

2.3/1

THF, 25 C, 30 min

(S)-18d, 95

1

a) no product; b) H NMR yield; c) first crystallization -61%, ee 94.7 %, second crystallization – 43%, ee 98.6%, HPLC

Chiralcel OD-H, hexane:iPrOH=9:1, 219nm, flow rate 1 ml/min; retention time (R)-16d 11.23 min; (S)-16d 13.40 min;

d) ee 99%, HPLC Chiralcel OD-H, hexane:iPrOH:Et

time (S)-16d 19.24 min; (R)-16d 22.12 min;

2 3

NH:Et N=80:20:0.1:0.1, 219nm, flow rate 1 ml/min; retention

Ureas 16a-d were synthesized by mixing amines 7 with isocyanates in DCM. Urea (S)-16d prepared

from scalemic amine (S)-7 (ee 75%) (see Scheme 3 and text above), was recrystallized twice from

n-C H :EtOAc = 4:1 mixture to produce (S)-16d with ee 98.6% (see Table 2, footnote c). The

6

14

cyclization of 16 with NBS proceeds cleanly to produce (bromomethyl)urethanes 17a-d as a mixture

1

of cis/trans-isomers in 2.1-3/1 ratio ( H NMR), their configurations were assigned by analogy with

previously studied isomeric (bromomethyl)urethanes. cis/trans-Isomers of 17b were separated by

chromatography and isolated in individual form. All the bromides 17 (except for 17c) are readily

transformed to ADPs 18 in the presence of tBuOK, but the compounds 17a and 17b are the most

0

reactive ones. As in the case of 12b (Scheme 4) a short treatment of urethane 17b with tBuOK (0 C,

1

min) produced unsaturated enolester 19 (97%) which undergoes the clean rearrangement to 18b

0

(

98%) upon further stirring with gentle heating (40 C, 40 min) of the reaction mixture. tBu-

Substituted bromourethane 17c gave a complex mixture of products instead of expected ADP 18c

independently of the solvent or conditions used. At the same time, methyl-analogue 17d reacts

1

smoothly in THF for 40 min or immediately in DMSO, producing 18d (>95% by H NMR, for less

then 1 min). Bromocyclization of enantiomerically pure urea (S)-16d gave urethane (S)-17d as a

mixture of isomers which were treated with tBuOK in THF that affords expected product (S)-18d.

7

Organic & Biomolecular Chemistry

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DOI: 10.1039/C6OB00293E

Formation of (S)-18d (ee 99%) from (S)-16d (ee 98.6%) evidently demonstrates the absence of

racemization during the whole reaction sequence.

Actually enolester 19 could be obtained through the silver-catalyzed homopropargylamine

7

cyclization. Yamada and co-workers have shown that intramolecular nucleophilic addition of

carbamate anion to silver-activated triple bond gave rise to enolesters of benzoxazine-2-one series.

That would be an advantageous to avoid the stage of dehydrobromination by metal-catalyzed

cyclization.

Cbz

MgBr

N

•

O

AgNO₃

O

Ph

NTMS

Cbz

DCM

THF

Ph

NH₂

Ph

N

DBU, DMSO

Ph

N

NCbz

H

9

0%

7

A

16A

19

Scheme 6.

Urea 16A was prepared from propargyl amine 7A. We tried similar condition using silver nitrate as

a catalyst, however, enolester 19 was not formed (Scheme 6). Probably, the carbonyl group is

insufficiently nucleophilic for such cyclization or vice versa for such triple bond.

Then, the preparation of 2,2-disubstituted ADP derived from amine 8 was studied (Scheme 7, Table

3

). Generally all the reactions of diallylated ureas 20a-d with NBS procced faster than with ureas 11

and 16. In the case of 20a, the reaction became more selective towards double bond in comparison

with 11d where the bromination of the aromatic ring takes place. Decreasing the reaction

0

temperature up to -15 C allowed the synthesis of only the product of bromocyclization reaction

2

1a (85%). Treatment of ureas 20a-d with NBS furnished cyclic bromoiminourethanes 21a-d with

different ratios of cis/trans-isomers (1:8-1:20).

Br

O

R²

O

tBuOK

Ph

N

•

Ph

NBS

Ph

R²

NH₂

N

H

N

DCM

N

NR²

Solvent

N

H

NR²

DCM

H

8

20a-c

21a-c

22a-c

Scheme 7.

Table 3.

2

a

R

Urea, %

RBr, % cis/trans

Conditions of

ADP, %

the rearrangement

b

0

2

-Cl-Ph-

20a, 99

21a, 85 1:20

THF (25 C, 2h)

22a, 47

22a, 71

0

DMF (25 C, 6h)

8

Page 9 of 29

Organic & Biomolecular Chemistry

DOI: 10.1039/C6OB00293E

0

iPrOH (45 C, 4h)

various

22a, 89

c

MeO(CH

tBu-

2

)

2

OC(O)- 20b, 90

20c, 70

21b, 98 1:15

21c, 89 1:19

21d, 72 1:10

22b, NP

c

various

22с, NP

22d, 45

22d, 52

0

Allyl-

20d, 85

THF (25 C, 2h)

0

DMF (25 C, 6h)

0

iPrOH (45 C, 24h) 22d, 15

0

Me-

20e, 98

21e,

1:8

THF (0 C, 2h)

22e, 48

22e, 45

0

DMF (25 C, 2h)

0

a) calculated from NMR spectra; b) the isomer ratio was obtained at -15 C; c) no product

Pure trans-isomer 21a was isolated by crystallization of the isomeric mixture (cis/trans = 1:20)

from n-C 14/EtOAc mixture and its structure was established by X-Ray single crystal analysis

Fig. 2). It should be noted that similar trans-selectivity was observed previously in the cyclization

6

H

(

of oxygen analogue of 20a into 4-allyl-6-(bromomethyl)-4-phenyl-1,3-oxazinan-2-one.

Fig. 2. Molecular structure of trans-isomer 21a (one of the two crystallographically independent

molecules is presented only).

Further rearrangement 21a→22a is strongly solvent dependent (Table 3); only gentle heating in

isopropanol provides high yield of ADP 22a (89%). The structure of 22a was also supported by X-

Ray single crystal analysis (Fig. 3).

9

Organic & Biomolecular Chemistry

Page 10 of 29

DOI: 10.1039/C6OB00293E

Fig. 3. The structure of ADP 22а.

2

Urea with the electron-withdrawing group 20b (R = MeO(CH)

2

OC(O)-) and corresponding

bromide 21b are formed cleanly. However, the following rearrangement step gave only traces of

product 22b (TLC-detection), which completely decomposed during workup and chromatography.

Urea 20c (70%) containing two bulky fragments (two tertiary carbons) in the molecule was prepared

by heating of amine 8 and tert-butyl isocyanate under reflux in DCM for 4h. Following reaction of

2

0c with NBS gave rise mainly to trans-isomer 21c (89%), but the latter does not produce ADP 22c

upon the treatment with tBuOK (see also Table 1 and 2), a complex mixture of products was

formed. In the case of N-allyl compound, the same transformations gave urea 20d and bromide 21d

in good yields, but the last transformation to ADP was not so efficient. The yield of ADP 22d in

DMF was higher (52%) then in THF (45%) and iPrOH (15%). The reasons for moderate yield of

2

2d as well as decomposition of tert-butyl derivatives (12g, 17c, 21c) under the treatment with

tBuOK are unclear.

Actually if one compares the syntheses of piperidine-2,4-diones

and ADPs from

(

bromomethyl)urethanes, the last transformations (21a-d → 22a-d) take longer time (up to 6 hs) and

are more capricious (21b,c). There are two key steps which can complicate the reaction. First step is

the dehydrobromination and second – rearrangement where enolate anion would add to

carbodiimide’s moiety (see Scheme 2). We decided to separate the processes of dehydrobromination

and rearrangement to understand the efficiency of the elimination step. Thus, two N-PMB-protected

ureas 24a,b were prepared by reductive amination of p-anisaldehyde with amine 8 followed by the

1

0

Page 11 of 29

Organic & Biomolecular Chemistry

DOI: 10.1039/C6OB00293E

reaction of amine 23 with isocyanates in refluxing MeCN with tBuOH as an additive (Scheme 8). It

should be pointed out that the reaction of 23 even after two days of reflux with excess of tBuNCO

did not run to completion, giving urea 24a in 70% yield. Similarly urea 24b was obtained in 88%

yield.

O

R²

O

NBS

Ph

NaBH(OAc)₃

DCM

N

O

Ph

R²

+

NH₂

N

NHPMB

MeCN, reflux

DCM

H

PMB

8

O

23, 85%

24a,b

Br

O

CAN

O

tBuOK

Ph

tBuOK

Ph

All

Ph

All

Ph

All

N

NR²

_N_H_R2

_N_R2

0 ⁰

C, 1-2h

THF

All

N

THF

MeCN/ H O

N

H

N

PMB

5a,b

2

H

PMB

2

26a,b

27a,b

22c,d

CAN - (NH ) Ce(NO )

3 6

4

2

PMB - p-methoxybenzyl-

Scheme 8.

Table 4.

2

a

R

Urea, % RBr, % cis/trans

PMB

Enol, % ADP, %

Enol , %

26a, 82

tBu-

24a, 70

25a, 77 1:12

25b, 72 1:10

27a, 84

22с, 72

22d, 85

b

Allyl- 24b, 88

26b, 94 27b, 68

0

a) calculated from NMR spectra; the isomer ratio was obtained at 0 C; b) reaction in iPrOH at 50 C gave 52% of 22d.

NBS mediated cyclization of ureas 24a and 24b gave rise to cyclic bromides 25a (77%) and 25b

(

72%) as a mixture of cis- and trans-isomers (ca 1:12). Dehydrobromination of bromourethanes

5a,b under the action of tBuOK in THF proved to be a slow process. Both of the reactions are

completed at 0 °C within 1-2 hours, producing the corresponding enolesters 26a (82%) and 26b

2

(

94%). Increasing the reaction temperature to 25 °C for acceleration of elimination stage provocates

1

the partial exo-endo-migration of the double bond (up to 25-30% by H NMR). Such reactivity is in

sharp contrast to the previously observed very fast HBr elimination (takes seconds at -20 °C) in

8,12a

similar tertiary 1,3-oxazin-2-ones.

This means the elimination of NH-urethanes 21a-d occuring

at room temperature (Scheme 7, Table 3) would be even more difficult process, growing up the

chance of any side reactions. Next PMB-deprotection of 26a,b has been carried out by the oxidation

with cerium(IV) ammonium nitrate (CAN) at 0 °C for 5h with portionwise addition of water

1

Organic & Biomolecular Chemistry

Page 12 of 29

DOI: 10.1039/C6OB00293E

solution of sodium acetate to neutralize nitric acid formed. It should be emphasized that in CAN

oxidation mainly the aromatic system is involved. Enolesters 27a (84%) and 27b (68%) thus

obtained were purified by flash chromatography on silica gel and subjected to rearrangement upon

the treatment of tBuOK at -30 °C. Notably, only under these conditions the expected product 22c

2

(

R = tBu) was obtained in 72% (see Table 3 and 4). Rearrangement of 27b in THF gave smoothly

2

2d (85%). The same transformation in iPrOH at 50 °C was completed in 10 minutes, giving 22d

(

52%); while at 0 °C it does not proceed at all. We also tried to use the same PMB-approach for the

synthesis of 18c (Scheme 5, Table 2), but observed mainly the bromination of p-methoxyphenyl

ring.

Having in hand a new method for construction of ADP with bulky tBu-group, we decided to extend

the method for adamantane derivatives. The lipophilic adamantane is an important pharmacophore

group composing many well proven drugs such as amantadine and memantine (neurodegenerative

9

deseases), tromantadine and remantadine (antiviral) etc. Moreover several adamantane containing

piperidine and pyrrolidine derivatives possess high antiviral activity towards influenza virus A

0

(

A

2

/Japan/305/1957 (H

2 2

N )). In order to overcome the problem of side bromination of PMB-

group, we envisaged an alternative route towards cyclic enolesters by using the syn-elimination of

selenoxides . Homoallylamine 28 was prepared by the reaction of dibutyl allylboronate, ammonia

and acetone according to the modified procedure (Scheme 10). Reactions of amines 6 and 28 with

-adamantyl isocyanate gave ureas 29a,b in good yield. Further phenylselenocyclocarbamation of

these ureas with phenylselenyl chloride was carried out in DCM solution similarly to the procedure

1

described previously. In the case of urea 16c, selenide 30c is formed as a mixture of cis/trans =

.9:1 isomers. Phenylselenides 30a-c were oxidized to selenoxides under optimized conditions in

a two-phase mixture NaIO (3 equiv.) in aqueous MeOH at 0 °С for 20 minutes and were used

1

4

further without purification. We found that heating selenoxides in dioxane solution at 70 °С

provides elimination products 31a-c in low yields (13-32%). The conducting the elimination stage

of selenoxide derived from 30c in the presence of diisopropylamine and vinyl acetate at higher

4

temperature gave enolester 31c in the lower yield.

1

2

Page 13 of 29

Organic & Biomolecular Chemistry

DOI: 10.1039/C6OB00293E

OBu

O

Me Me

+

^N^H3

B

^N^H2

OBu

Me

MeOH

SePh

28, 70%

R³

O

PhSeCl _R1

DCM

O

_R1

_R2

O

_R1

_R2

_R1

_R2

1. NaIO / MeOHaq.

N

•

O

4

R³

0

NR³

31a-c

NH₂

DCM

N

_R2

N

NR³

2. dioxane, 70 C

N

H

6, 7, 28

29a,b, 16c

30a-c

R³

tBuOK

3

1a-c

N

NH

0

THF, 5 min; -30 C

32a ~100%

1

2

3

Amine

R

Urea, % RSePh, % Enol , % Imid, %

6

H-

Ad-

29a, 98

29b, 85

30a, 73

30b, 81

31a, 13

32a, ~100

2

7

8

Me-

Ph-

Me-

H-

31b, 32 32a, ~100

a

b

c

tBu- 16c, 99

30c, 85

31c, 18

32b, NP

a) see Table 2; b) cis/trans = 1.9:1; c) no product detected

Scheme 10.

When enolesters 31a,b were treated with tBuOK in THF at -30 C, N-(1-adamantyl)carbodiimide

32a) was quantitatively obtained instead of the expected rearranged ADP products (Scheme 10). In

0

(

the case of enolester 31c, we failed to identify the expected N-(tert-butyl)carbodiimide. The

structure of 32a was confirmed by NMR and HRMS spectra. The reactions in other solvents (iPrOH,

3 4

DMF), in the presence of additives (BF -etherate, Ti(OiPr) ) and at different temperatures (-78 , -40

0

and 0 C) do not change the result: the only isolated product was carbodiimide 32a. Evidently, we

have succeeded in isolation of the compound derived from decay of the anticipated intermediate

enolate-carbodiimide (Schemes 2 and 11). The mechanism of carbodiimide 32a formation can be

described as E1cb elimination process (retro Michael decay) occurring in the enolate-carbodiimide

molecule that supports the analogous mechanistic pathway of the enolate-isocyanate rearrangement

discovered earlier. This result gives an insight into possible side processes accompanying the

reaction and explains our failures upon synthesis of sterically hindered ADPs. Apparently, the less

active (more crowded) the carbodiimide group in the intermediate, the greater possibility of such

type of its decay.

1

3

Organic & Biomolecular Chemistry

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DOI: 10.1039/C6OB00293E

O

O^–K⁺

O

_R1

_R2

R¹

N

NR K⁺

-

_R2

N

_R2

N

NHR

H

NR

enolate-carbodiimide

–

+

O K

H

R

_O_–_K+

N

NH

2a

O

3

N

R = Ad

NR

Scheme 11. Mechanism of enolate-carbodiimide rearrangement and formation of 32a.

We also carried out kinetic study of the rearrangement of enolester 19 to ADP 18b (Scheme 5)

which was monitored by proton NMR. The reaction was run in anhydrous DMSO-D

6

at 20.5 °C.

The recorded data were used to draw a kinetic curve (Fig. 4) which revealed the first-order of the

–

3 –1

reaction with a rate constant k = 4.3x10 s at 20.5 °C, confirming the monomolecular character of

the rearrangement. The rate constant was considerably lower than that of the enolate-isocyanate

–

2

–1

12a

rearrangement (k = 2.85x10 s at –48 °C) implying lower reactivity of the carbodiimide reactive

center.

Fig. 4. Kinetic curve of rearrangement enolester 19 to ADP 18b.

Conclusions

In summary, we have developed a new convenient strategy for the creation of 6-amino-2,3-dihydro-

4

-pyridinones (ADP). A series of 2,6-substituted ADP were synthesized. The strategy is based on

1

4

Page 15 of 29

Organic & Biomolecular Chemistry

DOI: 10.1039/C6OB00293E

rapid, facile and efficient transformation of N-(3-butenyl)ureas through the three-step sequence

involving NBS (or I , PhSeCl)-mediated cyclization to 6-(bromomethyl)-2-iminourethanes,

2

dehydrohalogenation and the novel anionic enolate-carbodiimide rearrangement as a key step. This

rearrangement is similiar to the enolate-isocyanate rearrangement previously discovered in our

group; however, it has some differences associated with the lower reactivity of carbodiimide

intermediate and nature of the substituent at the 6-amino-group. The more electron-withdrawing

character of N-substituent in (bromomethyl)urethanes, the easier their transformations to ADP

proceed. As a limitation of the process, difficulties in synthesis of ADPs with bulky 6-tert-

butylamino- and 6-(1-adamantyl)amino-groups should be noted. The mechanism of the

rearrangement was supported by the kinetic data and isolation of N-(1-adamantyl)carbodiimide – a

product of enolate-carbodiimide decay. The final piperidinone heterocycles are promising precursors

for the synthesis and design of drugs.

Experimental Section

General. The manipulations with sensitive to air compounds were carried out under inert

[

20]

atmosphere of dry Ar. Triallylborane was prepared according to described procedure.

NMR

spectra were recorded on Bruker Avance-300, 400 and 600 MHz instruments. Mass spectra were

recorded on Finnigan Polaris Q Ion Trap spectrometer. Monoisotopic mass spectra (HRMS) were

obtained from Bruker microTOF, Maxis. Optical rotation was measured on Perkin Elmer 341

instrument. Column chromatography was carried out using silica gel 60−230 mesh (Merck). Thin

layer chromatography was run on Alugram Sil G/UV254 (Macherey-Nagel). Melting poi nts were

measured on a Suart SMP10 capillary melting point apparatus. Compounds 7, 8, 9, 7A were

synthesized as described.

General procedure of synthesis of ureas 11a-d, 16a-d, 20a-c, 16A, 29a,b.

To the hydrochloride homoallylamine 6 (0.86 g, 8.0 mmol) solution in CHCl

free amines 7, 8, 7A, 28 and without Et N addition) was added corresponding isocyanate (8.0

mmol) and Et N (1.0 g, 1.39 ml, 10.0 mmol) dropwise with stirring. The mixture was stirred at

3

(15 ml) (or DCM for

3

ambient temperature for 30 min to ensure completion of the reaction. The progress of the reaction

was monitored by TLC. After then the mixture was washed consequently with 0.6N HCl and water.

Organic phase was dried with Na SO and evaporated to dryness. The residue was recrystallized or

2

4

purified by FC for elemental analysis.

N-methyl-N'-(1-phenyl-3-butenyl)urea (16d)

1

5

Organic & Biomolecular Chemistry

Page 16 of 29

DOI: 10.1039/C6OB00293E

1

Yield: 96%, as crystalline solid, m.p. 79-80 °C (n-C

NMR (400 MHz, CDCl ) (δ, ppm): 7.32-7.21 (m, 5H, Ph); 5.74-5.63 (m, 2H, NH and CH=); 5.28

br.s, 1H, NH); 5.08-5.03 (m, 2H, CH =); 4.78 (br.m, 1H, CHPh); 2.62 (s, 3H, Me); 2.51-2.40 (m,

). C NMR (100 MHz, CDCl ) (δ, ppm): 158.94; 143.00; 134.26; 128.41 2C; 126.96;

26.17 2C; 117.84; 53.77; 41.71; 26.79. C12 O (204.3): calcd. C 70.56, H 7.90, N 13.71; found

6 f 6

H14/EtOAc). R 0.25 (n-C H14/EtOAc, 1:1). H

3

(

2

13

2

1

H, CH

2

3

16 2

H N

C 70.61, H 8.15, N 13.71.

1S)-N-methyl-N'-(1-phenyl-3-butenyl)urea ((S)-16d).

A crude urea (S)-16d obtained through the general procedure from (S)-7 (ee 74%) was crystallized

from the n-C 14:EtOAc = 4:1 mixture to give of (S)-16d, yield: 61%, ee 94.7%; second

crystallization furnishes (S)-16d, yield: 43% (calculated on crude urea), ee 98.6% as crystalline

(

6

H

2

5

solid, m.p. 86-87 °C (n-C H /EtOAc, 4:1). [α] -29.7 (C 1, CHCl ). HPLC Chiralcel OD-H, n-

6

14

D

3

hexane:iPrOH=9:1, 219 nm, flow rate 1 ml/min; retention time (R)-16d 11.23 min; (S)-16d 13.40

min.

N-(1-Allyl-1-phenyl-3-butenyl)-N'-(tert-butyl)-N-(4-methoxybenzyl)urea (24a).

PMB-amine 23 (0.50 g, 1.62 mmol) and tert-butyl isocyanate (0.32 g, 3.25 mmol) in a mixture of

MeCN (1 ml)/tBuOH (0.12 ml) were heated at reflux for 2 days. The mixture was concentrated

under reduced pressure followed by chromatography separation on silica gel (n-C

6

H

14/EtOAc, 6:1)

that gave target urea 24a (0.46 g, 70%) as crystalline solid, m.p. 98-99 °C (n-C

6

H

14). R 0.28 (n-

f

1

C

6

H

14/EtOAc, 6:1). H NMR (300 MHz, CDCl

3

) (δ, ppm): 7.40 (d, J = 8.6 Hz, 2H, Ar); 7.36-7.29

=);

Ar); 4.20 (s, 1H, NH); 3.86 (s, 3H, OMe); 3.12 (dd, J = 7.6, 12.8 Hz, 2H, CH );

) (δ, ppm):

58.13; 157.92; 145.78; 134.04; 133.34 2C; 128.81 2C; 128.74 2C; 127.23; 126.31 2C; 119.20 2C;

(

m, 5H, Ph); 6.95 (d, J = 8.6 Hz, 2H, Ar); 5.53-5.39 (m, 2H, 2CH=); 5.15-5.10 (m, 2H, 2CH

.81 (s, 2H, CH

.69 (dd, J = 6.7, 12.8 Hz, 2H, CH

2

4

2

1

8

2

1

3

2

); 1.05 (s, 9H, tBu). C NMR (75 MHz, CDCl

3

13.69 2C; 64.97; 55.12; 50.48; 47.36; 40.73 2C; 28.87 3C. C26

.43, N 6.89; found C 76.77, H 8.44, N 6.97.

34 2 2

H N O (406.6): calcd. C 76.81, H

N-(1-Allyl-1-phenyl-3-butenyl)-N'-(allyl)-N-(4-methoxybenzyl)urea (24b)

A solution of PMB-amine 23 (1.17 g, 3.79 mmol) and AllNCO (0.47 g, 5.7 mmol, 1.5 eq.) in a

mixture of MeCN (8 ml) / tBuOH (1 ml) were heated under reflux for 18 h with stirring, then more

AllNCO (0.31 g, 3.7 mmol) was added and the heating was continued for another 24 h. The progress

6 f

of the reaction was monitored by TLC (n-C H14/EtOAc, 6:1), R (24b) = 0.2. The volatiles were

removed under reduced pressure and the residue was subjected to FC on silica gel that affords urea

1

2

4b (1.15 g, 88%) as white solid, m.p. 75-76 °C (n-C

6

H

14). H NMR (400 MHz, CDCl

3

) (δ, ppm):

1

6

Page 17 of 29

Organic & Biomolecular Chemistry

DOI: 10.1039/C6OB00293E

7

1

4

1

.39 (d, J = 8.6 Hz, 2H, Ar); 7.36-7.22 (m, 5H, Ph); 6.93 (d, J = 8.6 Hz, 2H, Ar); 5.59 (ddt, J = 5.3,

0.4, 17.2 Hz, 1H, CH=, NAllyl); 5.50-5.35 (m, 2H, 2CH=); 5.13-5.08 (m, 4H, 2CH =); 4.88 (d, J =

0.4 Hz, 1H, CH =, NAllyl); 4.80 (s, 2H, CH Ar); 4.73 (d, J = 17.2 Hz, 1H, CH = NAllyl);

.28 (t, J = 5.3 Hz, 1H, NH); 3.84 (s, 3H, OMe); 3.63 (t, J = 5.3 Hz, 2H, HNCH ); 3.14 (dd, J = 7.5,

2

A

H

B

2

A B

H

2

1

3

3.0 Hz, 2H, CH

) (δ, ppm): 158.90; 158.47; 145.59; 135.16; 133.40 2C; 130.92; 128.86 2C; 128.83 2C;

27.30; 126.19 2C; 119.33 2C; 114.67; 113.95 2C; 65.39; 55.26; 48.37; 43.31; 40.80 2C.

(390.5): calcd. C 76.89, H 7.74, N 7.17; found C 76.94, H 7.69, N 7.20.

A B A B

H Allyl); 2.70 (dd, J = 6.8, 13.0 Hz, 2H, CH H Allyl). C NMR (100 MHz,

CDCl

3

1

25 30 2 2

C H N O

N-(1-adamantyl)-N'-(3-butenyl)urea (29a).

1

2 f 6

Yield: 98%, as white solid, m.p. 163-164 °C (EtOH/H O). R 0.6 (n-C H14/EtOAc, 1:1). H NMR

(

400 MHz, CDCl

3

) (δ, ppm): 5.75 (ddt, J = 6.8, 10.1, 17.2 Hz, 1H, CH=); 5.07 (d, J = 17.2 Hz, 1H,

=); 4.68 (br.s, 1H, NH); 4.44 (br.s, 1H, NH); 3.18 (d, J

CH =); 5.03 (d, J = 10.2 Hz, 1H, CH H

A

H

B

A B

=

6.7 Hz, 1H, CH N); 2.21 (dt, J = 6.4, 6.7 Hz, 2H, CH CH=); 2.03 (br.s, 3H, Ad); 1.93 (br.s, 6H,

2

1

3

Ad); 1.63 (br.s, 6H, Ad). C NMR (100 MHz, CDCl

2.46 3C; 39.22; 36.38 3C; 34.43; 29.49 3C. C15

found C 72.40, H 9.91, N 10.98.

3

) (δ, ppm): 157.39; 135.74; 116.76; 50.66;

4

24 2

H N O (248.4): calcd. C 72.54, H 9.74, N 11.28;

N-(1-adamantyl)-N'-(2-methylpent-4-en-2-yl)urea (29b).

1

f 6

Yield: 85%, as white solid, sublimation point 245 °C (DCM). R 0.15 (n-C H14/EtOAc, 1:1). H

NMR (300 MHz, CDCl

3

) (δ, ppm): 5.78 (ddt, J = 7.5, 9.2, 17.7 Hz, 1H, CH=); 5.07-5.02 (m, 2H,

CH =); 2.37 (d, J = 7.5 Hz, 2H, CH CH=); 2.30 (br.s, 2H, 2NH); 2.01 (br.s, 3H, Ad); 1.89 (m, 6H,

2

1

3

Ad); 1.62 (br.s, 6H, Ad); 1.24 (s, 6H, 2Me). C NMR (100 MHz, CDCl

3

) (δ, ppm): 156.78; 134.66;

17.96; 52.15; 50.54; 45.26; 42.40 3C; 36.36 3C; 29.47 3C; 27.49 2C. C17 O (276.4): calcd. C

3.87, H 10.21, N 10.13; found C 73.69, H 10.33, N 10.27.

1

7

28 2

H N

General procedure for NBS mediated cyclobromocarbamation, synthesis of bromides 12a-g,

1

2

7a-d, 21a-d, 25a,b.

-Methoxyethyl N-[6-(bromomethyl)-1,3-oxazinan-2-yliden]carbamate (12a).

To a solution of urea 11a (0.37 g, 1.7 mmol) in DCM (4 ml) NBS (0.36 g, 2.04 mmol) was added

with stirring at ambient temperature. The solution was stirred for 40 min. until disappearance of

starting urea 11a. After evaporation of DCM the residue was dissolved in a mixture of Et

4:1, 15 ml) and 10% solution of NaOH (5 ml) was added. The mixture was vigorously stirred for 10

min, the organic layer was separated, dried with K CO , evaporated and purified through a column

of silica gel (EtOAc/MeOH, 10:1) to furnish 12a (0.43 g, 85%) as oil. R 0.20 (MeOH/EtOAc,10:1).

2

O/EtOAc

(

2

3

f

1

7

Organic & Biomolecular Chemistry

Page 18 of 29

DOI: 10.1039/C6OB00293E

1

H NMR (300 MHz, CDCl

3

) (δ, ppm): 9.42 (br.s, 1H, NH); 4.44-4.37 (m, 1H, CHO); 4.06-4.03 (m,

OC(O)); 3.51-3.36 (m, 6H, CH Br, CH N, CH OMe); 3.22 (s, 3H, OMe); 2.20-2.12 (m,

CHO); 1.94-1.80 (m, 1H, CH CHO). C NMR (75 MHz, CDCl ) (δ, ppm): 163.88;

2

1

5

H, CH

2

1

3

A

H

B

A

H

B

3

61.77; 74.89; 70.26; 63.76; 58.55; 37.33; 32.00; 24.05. C

.12, N 9.49; found C 36.72, H 5.16, N 9.37.

9

H

15BrN

2

O

4

(295.1): calcd. C 36.63, H

Benzyl N-[6-(bromomethyl)-1,3-oxazinan-2-yliden]carbamate (12b).

Yield: 92% as a white solid, m.p. 82–84 °С. R 0.12 (n-C

CDCl

1

f

6

H

14/EtOAc, 1:1). H NMR (400 MHz,

3

) (δ, ppm): 8.98 (br.s, 1H, NH); 7.44–7.23 (m, 5H, Ph); 5.12 (s, 2H, CH

H, CHO); 3.58 (dd, J = 4.4, 10.8 Hz, 1H, CH Br); 3.53–3.37 (m, 3H, CH

.21 (m, 1H, CH CHO); 2.03–1.90 (m, 1H, CH

2

Ph); 4.52–4.44 (m,

Br, CH N); 2.31–

CHO). C NMR (100 MHz, CDCl ) (δ,

1

2

A

H

B

A

H

B

2

1

3

A

H

B

A

H

B

3

ppm): 164.08; 162.03; 136.80; 128.20 2C; 127.60; 127.49 2C; 75.22; 66.72; 37.53; 31.75; 24.29.

(329.2): calcd. С, 47.72; Н, 4.62; N, 8.56; found С, 47.72; Н, 4.86; N, 8.46.

13 2 3

C H17BrN O

N-[6-(Bromomethyl)-1,3-oxazinan-2-yliden]-4-methylbenzenesulfonamide (12c).

Bromo-derivative 12c is precipitated during the reaction from DCM solution. After evaporation of

DCM, the precipitate was suspended in water/Et

2

O mixture then filtered and dried on air. Yield:

1

9

5% as a white solid, m.p. 199–201 °С (dec.). R 0.14 (n-C H /EtOAc, 1:1). H NMR (400 MHz,

f

6

14

DMSO-D

6

) (δ, ppm): 8.66 (s, 1H, NH); 7.70 (d, J = 7.6 Hz, 2H, Ar); 7.29 (d, J = 7.6 Hz, 2H, Ar);

Br); 3.57 (br.dd, J = 5.1, 11.1 Hz,

N); 3.34 (s, 3H, Me); 2.02 (br.d, J = 12.7, 1H, CH CHO);

CHO). C NMR (100 MHz, DMSO-D ) (δ, ppm): 156.15; 141.83; 141.54;

29.41 2C; 126.86 2C; 77.27; 37.65; 34.37; 24.20; 21.40. C H BrN O S (347.2): calcd. С, 41.51;

4

.57 (br.s, 1H, CHO); 3.67 (br.dd, J = 3.2, 11.1 Hz, 1H, CH

H, CH Br); 3.27 (br.s, 2H, CH

.02 (m, 1H, CH

6

A B

H

1

A

H

B

2

A B

H

1

3

2

A

H

B

1

2

15

2

3

Н, 4.35; N, 8.07; found С, 41.57; Н, 4.28; N, 8.08.

N-[6-(Iodomethyl)-1,3-oxazinan-2-yliden]-N-(2-iodophenyl)amine (12d).

Iodine (0.93 g, 3.65 mmol) and K CO powder (5.0 g, 36.18 mmol) were added to a solution of 11d

1.1 g, 3.48 mmol) in DCM (25 ml). The reaction mixture was stirred for 2 h (TLC control),

Na solution was added and two-phase system was vigorously stirred for 20 min. Organic layer

was separated, dried with Na SO and evaporated under reduced pressure. Recrystallization from

2

3

(

2 2 3

S O

2

4

EtOAc gives 12d (0.72, 51%) as a yellow powder, m.p. 106–108 °С. Filtrate was evaporated and

passed through a short column of silica gel (EtOAc/DCM, 1:3) to give additional 12d (0.06 g, 5%)

1

and unreacted 11d (0.28 g, 25%). R

f

0.32 (EtOAc/DCM, 1:3). H NMR (400 MHz, CDCl

3

) (δ,

ppm): 7.74 (d, J = 7.9 Hz, 1H, Ar); 7.50 (d, J = 8.0 Hz, 1H, Ar); 7.26 (t, J = 7.8 Hz, 1H, Ar); 6.71 (t,

J = 7.6 Hz, 1H, Ar); 6.45 (s, 1H, NH); 4.26–4.20 (m, 1H, CHO); 3.47–3.34 (m, 2H, CH N); 3.33

2

1

8

Page 19 of 29

Organic & Biomolecular Chemistry

DOI: 10.1039/C6OB00293E

(

dd, J = 5.3, 10.5 Hz, 1H, CH

A

H

B

Br); 3.26 (dd, J = 6.8, 10.5 Hz, 1H, CH

A

H

B

Br); 2.18–2.12 (m,

CHO). C NMR (100 MHz, CDCl ) (δ, ppm):

12 2 2

49.11; 144.75; 138.59; 128.67; 123.57; 122.41; 92.87; 75.22; 39.26; 27.00; 6.18. C11H I N O

1

3

1

H, CH

A

H

B

CHO); 1.89–1.79 (m, 1H, CH

A

H

B

3

1

(

442.0): calcd. С, 29.89; Н, 2.74; N, 6.34; found С, 29.81; Н, 2.67; N, 6.24.

N-(4-Bromo-2-iodophenyl)-N-[6-(bromomethyl)-1,3-oxazinan-2-yliden]amine (12e).

A solution of NBS (4.38 g, 24.6 mmol) in MeCN (40 ml) was added by syringe pump for 1h to a

solution of urea 11d (3.89 g, 12.3 mmol) in a mixture of DCM (30 ml) / THF (40 ml) at -15 °C, after

then the stirring was continued at this temperature for another hour. The reaction was quenched by

careful addition of Na

2 2 3

S O solution in water (50 ml). The mixture was diluted with water (50 ml),

organic layer was separated and aqueous one exctracted with DCM (20 ml x 3). The combined

extracts were dried with K

2

CO

3

and evaporated. The residue was purified by FC (EtOAc/MeOH,

1

5:1) that gave 12e (3.70 g, 64%) as beige solid, m.p. 124-125 °С. R

f

0.55 (EtOAc/MeOH, 9:1). H

NMR (300 MHz, CDCl ) (δ, ppm): 7.85 (d, J = 2.0 Hz, 1H, Ar); 7.32 (dd, J = 2.0, 8.5 Hz, 1H, Ar);

3

7

.25 (br.d, J = 8.5, 1H. Ar); 6.49 (br.s, 1H, NH); 4.43-4.35 (m, 1H, CHO); 3.51-3.31 (m, 4H,

1

3

CH

2

Br, CH

2

N); 2.15-2.07 (m, 1H, CH

) (δ, ppm): 149.3; 145.52; 140.17; 131.49; 123.70; 114.43; 94.01; 75.09; 38.75; 32.73;

IN O (473.9): calcd. С, 27.88; Н, 2.34; N, 5.91; found С, 27.83; Н, 2.27; N, 5.88.

A B A B

H CHO); 1.97-1.84 (m, 1H, CH H CHO). C NMR (75

MHz, CDCl

3

2

5.37. C11

H

11Br

2

N-[6-(bromomethyl)-1,3-oxazinan-2-yliden]-N-methylamine (12f)

1

Yield: 94% as a viscous oil, R 0.43 (EtOAc:MeOH, 1:1). H NMR (400 MHz, CDCl ) (δ, ppm):

f

3

4

2

1

.61 (br.s, 1H, NH); 4.34-4.28 (m, 1H, CHO); 3.49-3.43 (m, 1H, CH

A

H

B

N); 3.44 (d, J = 5.7 Hz,

H, CH

2

Br); 3.36 (ddd, J = 4.8, 10.5, 14.9 Hz, 1H, CH

A B

H N); 2.71 (s, 3H, NMe); 1.98 (dm, J =

1

3

3.6 Hz, 1H, CH

A

H

B

CHO); 1.74 (dtd, J = 5.7, 10.5, 13.7 Hz, 1H, CH H CHO). C NMR (100

A B

MHz, CDCl ) (δ, ppm): 152.73; 74.65; 40.59; 33.56; 27.98; 26.12. C H BrN O (207.0): calcd. С,

3

6

11

2

3

4.80; Н, 5.35; N, 13.53; found С, 34.86; Н, 5.32; N, 13.47.

General procedure for phenylselenocyclocarbamation. Synthesis of selenides 30a-c.

-Methyl-N-{4-phenyl-6-[(phenylselanyl)methyl]-1,3-oxazinan-2-yliden}-2-propanamine (30с).

2

Urea 16c (0.368 g, 1.5 mmol) was added to a stirred solution of phenylselenyl chloride (0.383 g, 2.0

mmol, 30% excess) in DCM (10 mL)/MeCN (1 ml). The reaction mixture was stirred for 10 min.

iPr EtN (0.258 g, 0.33 mL, 2.0 mmol) was added and the mixture was stirred for additional 2 h

2

(

TLC control) and then washed with NaOAc solution, dried with Na

2 4

SO and passed through the

short pad of silica gel, washed with EtOAc/MeOH (9:1) and evaporated under reduced pressure to

8

gave 30с (0.51 g, 85%) as slowly solidifying oil, mixture of cis/trans-isomers (1.9:1),

f

R 0.5

1

9

Organic & Biomolecular Chemistry

Page 20 of 29

DOI: 10.1039/C6OB00293E

1

(

EtOAc/MeOH, 9:1). H NMR (400 MHz, CDCl

3

) (δ, ppm): 7.55-7.53 (m, 0.66x2H, Ph, cis); 7.45-

7

.42 (m, 0.33x2H, Ph, trans); 7.35-7.19 (m, 8H, 2Ph, cis and trans); 4.65 (t, J = 6.4 Hz, 0.33x1H,

CHN, trans); 4.52 (dd, J = 4.4, 11.4 Hz, 0.66x1H, CHN, cis); 4.39 (dddd, J = 2.2, 6.0, 11.4, 6.7 Hz,

0

.66x1H, CHO, cis); 4.12 (dtd, J = 4.8, 8.6, 12.1 Hz, 0.33x1H, CHO, trans); 3.82 (br.s, 1H, NH);

.13 (dd, J = 8.8, 16.7 Hz, 0.33x1H, CH SePh, trans); 3.11 (dd, J = 6.8, 12.8 Hz, 0.66x1H,

SePh, cis); 3.00 (dd, J = 5.8, 12.8 Hz, 0.66x1H, CH SePh, cis); 2.96 (dd, J = 8.8, 17.0

Hz, 0.33x1H, CH SePh, trans); 2.33 (ddd, J = 2.3, 4.6, 13.4 Hz, 0.66x1H, CH CHO, cis);

.08 (ddd, J = 7.5, 11.7, 17.8 Hz, 0.33x1H, CH CHO, trans); 1.97 (dt, J = 4.8, 17.8 Hz,

.33x1H, CH CHO, trans); 1.45 (dt, J = 11.4, 13.4 Hz, 0.66x1H, CH

3

A

H

B

CH

A

H

B

A B

H

A

H

B

A B

H

2

0

3

1

5

A B

H

A

H

B

A

H

B

CHO, cis); 1.36 (s,

+

.33x9H, tBu trans); 1.35 (s, 0.66x9H, tBu cis). MS (70 eV, EI): m/z (%) = 402/400 (M , 1.8/0.9);

14(15); 265(15); 189(21); 157(22); 155(15); 154(43); 147(12); 146(100); 145(18); 132(16);

29(25); 128(16); 117(29); 115(18); 106(70); 105(36); 104(41); 91(18); 79(22); 78(13); 77(49);

26 2

8(32); 51(14). HRMS (ESI): calcd. for C21H N OSe (M+H) 403.1283, found: 403.1284.

N-{6-[(Phenylselanyl)methyl]-1,3-oxazinan-2-yliden}-1-adamantanamine (30а).

1

Yield: 73% as a colorless solid, m.p. 95-97 °C. R

MHz, CDCl ) (δ, ppm): 7.56-7.50 (m, 2H, Ph); 7.32-7.22 (m, 3H, Ph); 4.28-4.19 (m, 1H, CHO);

.38 (ddd, J = 3.0, 5.9, 14.9 Hz, 1H, CH N); 3.30 (ddd, J = 5.1, 10.5, 14.9 Hz, 1H, CH N);

f 3

0.15 (EtOAc/iPrOH/Et N, 14:7:1). H NMR (400

3

A

H

B

A B

H

.16 (dd, J = 7.0, 12.7 Hz, 1H, CH H SePh); 3.03 (dd, J = 5.9, 12.7 Hz, 1H, CH H SePh); 2.07

A

B

A

B

(

narrow m, 3H, 3CH Ad); 2.01-1.95 (m, 1H, CH

A

H

B

CHO); 1.93-1.92 (m, 6H, 3CH

Ad). C NMR (100 MHz, CDCl

29.76; 129.11 2C; 127.18; 74.66; 50.77; 42.46 3C; 41.41; 36.34 3C; 32.31; 29.15 3C; 27.73. Se

2

Ad); 1.71-1.61

1

3

m, 7H, CH

A

H

B

CHO and 3CH

2

3

) (δ, ppm): 151.27; 132.87 2C;

7

1

3 28 2

NMR (95 MHz, CDCl ) (δ, ppm): 264.44. HRMS Calcd for C21H N OSe: 405.1440(M+H).

+

Found: 405.1430 (MH ).

N-{4,4-Dimethyl-6-[(phenylselanyl)methyl]-1,3-oxazinan-2-yliden}-1-adamantanamine (30b).

1

Yield: 81% as a colorless solid, m.p. 176-177 °C. R

CDCl

H, CHO); 3.16 (dd, J = 7.2, 13.0 Hz, 1H, CH

CH SePh); 2.03-2.01 (m, 4H, 11H, CH CHO and 3CH Ad); 1.97-1.88 (m, 6H, 3CH

.69 (dd, J = 12.2, 13.6 Hz, 1H, CH CHO); 1.58 (narrow m, 6H, 3CH Ad); 1.36 (s, 3H, Me);

.25 (s, 3H, Me). C NMR (100 MHz, CDCl ) (δ, ppm): 156.81; 133.34 2C; 129.43 2C; 128.11;

28.00; 76.11; 54.23; 50.46; 41.54 3C; 39.63; 35.67 3C; 30.80; 29.75; 29.16 3C; 28.97. Se NMR

f

0.54 (EtOAc/iPrOH, 3:1). H NMR (400 MHz,

3

) (δ, ppm): 8.88 (br.s, 1H, NH); 7.48-7.46 (m, 2H, Ph); 7.26-7.25 (m, 3H, Ph); 4.49-4.43 (m,

SePh); 3.07 (dd, J = 5.1, 13.0 Hz, 1H,

Ad);

1

A B

H

A

H

B

A

H

B

2

1

A

H

B

2

1

3

7

2

0

Page 21 of 29

Organic & Biomolecular Chemistry

DOI: 10.1039/C6OB00293E

(

3

32 2

95 MHz, CDCl ): δ 269.35. HRMS Calcd for C23H N OSe: 433.1754 (M+H). Found: 433.1739

+

MH ).

General procedure of selenides 30a-c oxidation to selenoxides and their thermal elimination

with formation of enolesters 31a-c.

N-(Adamantan-1-yl)-6-methylene-1,3-oxazinan-2-imine (31a).

A solution of NaIO

4

(0.44 g, 2.28 mmol) in water (5 mL) was added to a mixture of 30a (0.31 g,

0

.76 mmol) in MeOH/DCM (3:2, 10 mL) at 0 °C. The reaction mixture was stirred for 20 min (TLC

control). The mixture was diluted with DCM (20 ml) and saturated solution of NH Cl (20 ml). The

4

organic phase was separated and aqueous phase extracted with DCM (2x10 mL). The combined

2 4

extracts were dried over Na SO and evaporated to dryness under reduced pressure. The selenoxide

was dissolved in dioxane (10 mL) and heated with stirring for 1h at 70 °C. The solvent was

evaporated and the residue was purified by FC on silica gel in EtOAc/n-C H /Et N (10:10:1) to

6

14

3

give 31a (0.025 g, 13%) as a beige solid, m.p. 114-116 °C. R

f

0.63 (EtOAc/n-C

=); 4.09 (s, 1H, CH

CHO); 2.04 (narrow m, 3H, 3CH Ad);

6

H

14//Et

3

N,

1

3

1

0:10:1). H NMR (400 MHz, CDCl

3

) (δ, ppm): 4.42 (s, 1H, CH

N); 2.36 (t, J = 6.0 Hz, 2H, CH

Ad); 1.63 (narrow m, 6H, 3CH

A

H

B

A B

H

=);

.32 (t, J = 6.0 Hz, 2H, CH

.92 (narrow m, 6H, 3CH

2

1

3

2

Ad). C NMR (100 MHz, CDCl

3

) (δ,

ppm): 154.08; 148.76; 89.43; 51.11; 42.23 3C; 41.29; 36.34 3C; 29.43 3C; 26.16. C15

246.4): calcd. C, 73.13; H, 9.00; N, 11.37; found С, 73.19; Н, 9.12; N, 11.26.

N-(Adamantan-1-yl)-4,4-dimethyl-6-methylene-1,3-oxazinan-2-imine (31b).

Yield: 32% as a white solid, m.p. 95-97 °C. R 0.66 (EtOAc/n-C N, 10:10:1). H NMR (400

MHz, CDCl ) (δ, ppm): 4.50 (s, 1H, CH =); 4.09 (narrow m, 1H, CH =); 2.18 (s, 2H,

CH CHO); 2.03 (narrow m, 3H, 3CH Ad); 1.90 (narrow m, 6H, 3CH Ad); 1.63 (narrow m, 6H,

) (δ, ppm): 153.11; 147.92; 90.47; 51.11;

22 2

H N O

(

1

f

6 3

H14/Et

3

A

H

B

A B

H

2

1

3

4

9

2 3

CH Ad); 1.11 (s, 6H, 2Me). C NMR (100 MHz, CDCl

26 2

9.46; 42.49 3C; 39.00; 36.40 3C; 29.80 2C; 29.56 3C. C17H N O (274.4): calcd. С, 74.41; Н,

.55; N, 10.21; found С, 74.25; Н, 9.62; N, 10.27.

N-(tert-Butyl)-N-(6-methylene-4-phenyl-1,3-oxazinan-2-yliden)amine (31c).

1

Yield: 18% as oil. R 0.66 (EtOAc/MeOH, 9:1). H NMR (400 MHz, CDCl ) (δ, ppm): 7.34-7.33

f

3

(

m, 4H, Ph); 7.27-7.21 (m, 1H, Ph); 4.57 (dd, J = 4.5, 9.2 Hz, 1H, CHN); 4.49 (s, 1H, CH

.19 (br. s, 1H, NH); 4.09 (s, 1H, CH =); 2.74 (dd, J = 4.5, 14.2 Hz, 1H, CH CHO); 2.26

dd, J = 9.2, 14.2 Hz, 1H, CH CHO); 1.40 (s, 9H, tBu). C NMR (100 MHz, CDCl ) (δ, ppm):

A B

H =);

4

A

H

B

A B

H

1

3

(

A

H

B

3

1

3

53.02 C; 148.47 C; 144.47 C; 128.24 2CH; 126.69 CH; 126.26 2CH; 90.28 C; 54.80 CH; 50.75 C;

+

5.03 CH

2

; 29.23 3CH

3

. MS (70 eV, EI): m/z (%) = 244 (M , 11); 202(6); 189(11); 188(33);

2

1

Organic & Biomolecular Chemistry

Page 22 of 29

DOI: 10.1039/C6OB00293E

1

20 2

46(20); 145(18); 105(15); 104(100); 103(17); 78(28); 77(22); 32(13). C15H N O (244.3): calcd.

С, 73.74; Н, 8.25; N, 11.47; found С, 73.81; Н, 8.17; N, 11.37.

N-(1-Adamantyl)carbodiimide (32a).

tBuOK (0.168 g, 1.5 mmol) was added to a solution of 31b (0.274 g, 1.0 mmol) in THF (10 mL) at -

0 °C and stirred for 10 min, TLC shows immediate disappearance of the starting 31b. The reaction

mixture was quenched with AcOH (0.108 ml, 1.8 mmol), filtered through a pad of silica gel, washed

3

with EtOAc/n-C

6

H

14 (3 x 20 mL), evaporated and subjected to FC on silica gel to yield 32a (177

1

mg, 100%) as a white solid, m.p. 136-138 °C. R

MHz, CDCl

f

0.7 (EtOAc/n-C

6

H

14/Et

3

N, 10:10:1). H NMR (400

1

3

) (δ, ppm): 3.40 (1H, s), 2.22-2.12 (3H, m), 1.84-1.78 (6H, m), 1.68 (6H, m). CNMR

100 MHz, CDCl ) (δ, ppm): 114.17; 52.97; 42.37 3C; 35.64 3C; 29.43 3C. MS (70 eV, EI): m/z

%) = 177 (30, MH ); 176(1, M ); 136(11); 135(100); 108(12); 107(37); 93(79); 92(11); 91(41);

(

3

+

8

1

16 2

1(24); 80(87); 77(43); 67(24); 51(11); 44(14); 39(15); 28(11). HRMS Calcd for C11H N :

+

77.1386(M+H). Found: 177.1394(MH ).

General procedure of ADPs synthesis from bromourethanes.

-Methoxyethyl N-(4-oxo-1,4,5,6-tetrahydro-2-pyridinyl)carbamate (13a).

A solution of bromide 12a (0.30 g, 1.0 mmol) in dry DMF (2 ml) was treated with tBuOK (0.34 g,

.0 mmol) at 25 °C and the mixture was stirred for 15 min, when TLC control shows no more

2

3

starting material, then AcOH (0.15 ml, 2.5 mmol) was added to acidify the potassium salt of 13a.

The mixture was passed through the pad of Super Cel, volitiles were evaporated in vacuum and the

residue was subjected to FC on silica gel (EtOAc/MeOH, 9:1) that furnished 13a (0.206 g, 96%) as

1

crystalline solid, m.p. 145-146 °C. R

f

0.52 (EtOAc/MeOH, 9:1). H NMR (300 MHz, CDCl

3

) (δ,

ppm): 9.84 (br.s, 1H, NH); 7.89 (s, 1H, NH); 4.88 (d, J = 1.4 Hz, 1H, CH=); 4.27-4.24 (m, 2H,

CH OC=O); 3.60-3.57 (m, 2H, CH OMe); 3.51 (td, J = 2.2, 7.5 Hz, 2H, CH N); 3.33 (s, 3H, OMe);

) (δ, ppm): 191.24; 158.31; 154.17;

(214.2): calcd. C, 50.46; H, 6.59; N, 13.08;

2

1

3

2

.37 (t, J = 7.6 Hz, 2H, CH

2 3

C=O). C NMR (75 MHz, CDCl

8

6.00; 70.10; 64.41; 58.63; 40.39; 34.56. C

9

14 2 4

H N O

found C, 50.44; H, 6.58; N, 13.14.

-(2-Iodoanilino)-2,3-dihydro-4(1H)-pyridinone (13d).

6

Transformation of iodide 12d was carried out in iPrOH at 25 °C for 3h. Yield 13d: 55%, as light-

1

yellow solid, m.p. 213-214 °C (EtOAc). R

f

0.19 (EtOAc/MeOH, 6:1). H NMR (400 MHz, DMSO-

D

=

6

) (δ, ppm): 8.18 (s, 1H, NH); 7.90 (d, J = 7.9 Hz, 1H, Ar); 7.40 (t, J = 7.0 Hz, 1H, Ar); 7.26 (d, J

7.8 Hz, 1H, Ar); 7.00 (t, J = 7.0 Hz, 1H, Ar); 6.62 (s, 1H, NH); 4.13 (s, 1H, CH=); 3.37–3.28 (m,

1

3

2

2 2 6

H, CH N); 2.09 (t, J = 7.0 Hz, 2H, CH C=O). C NMR (100 MHz, DMSO-D ) (δ, ppm): 187.80,

2

Page 23 of 29

Organic & Biomolecular Chemistry

DOI: 10.1039/C6OB00293E

1

60.39, 139.78, 139.33, 129.11, 127.77, 127.75, 98.33, 82.10, 39.73, 35.45. C11

calcd. С, 42.06; Н, 3.53; N, 8.92; found С, 42.05; Н, 3.60; N, 8.85.

-(4-Bromo-2-iodoanilino)-2,3-dihydro-4(1H)-pyridinone (13e).

2

H11IN O (314.1):

6

The reaction was carried out in iPrOH at 40 °C for 1h. Yield: 98%, as brown powder, m.p. 197-200

1

°

C (dec.) (EtOAc/DCM). R

f

0.36 (EtOAc/MeOH, 9:1). H NMR (600 MHz, DMSO-D

6

) (δ, ppm):

8

.24 (s, 1H, NH); 8.07 (s, 1H, Ar); 7.57 (d, J = 7.8 Hz, 1H, Ar); 7.19 (d, J = 8.2 Hz, 1H, Ar); 6.67

1

3

(

s, 1H, NH); 4.18 (s, 1H, CH=); 3.32-3.30 (m, 2H, CH

150 MHz, DMSO-D ) (δ, ppm): 187.98 C; 160.07 C; 140.76 CH; 139.56 C; 131.99 CH; 128.90

; 35.43 CH O (393.0): calcd. С, 33.62;

Н, 2.56; N, 7.13; found С, 33.59; Н, 2.70; N, 7.16.

-(Methylamino)-2,3-dihydro-4(1H)-pyridinone (13f).

2 2

N); 2.10-2.08 (m, 2H, CH C=O). C NMR

(

6

CH; 118.80 C; 99.58 C; 82.41 CH; 39.66 CH

2

2 2

. C11H10BrIN

6

The reaction was carried out in THF at 25 °C for 1h. Yield: 95%, as white solid, m.p. 218-219 °C

1

(

EtOAc/MeCN). R

f

0.24 (EtOAc/MeOH, 2:1). H NMR (500 MHz, DMSO-D

6

) (δ, ppm): 6.75 (br.s,

N); 2.61 (d, J = 4.9

C=O). C NMR (125 MHz, DMSO-D ) (δ, ppm):

86.71; 163.52; 80.54; 40.29; 35.76; 28.19. HRMS Calcd for C O: 127.0866 (M+H). Found:

1

H, NH); 6.72 (br.s, 1H, NH); 4.23 (s, 1H, CH=); 3.23 (t, J = 7.1 Hz, 2H, CH

2

1

3

Hz, 3H, CH

3

N); 2.03 (t, J = 7.2 Hz, 2H, CH

2

6

1

6 10 2

H N

+

27.0863 (MH ).

Ethyl (4-oxo-6-phenyl-1,4,5,6-tetrahydropyridin-2-yl)carbamate (18a).

The reaction was carried out in THF at 25 °C for 1h. Yield: 95%, as white powder, m.p. 188-189 °C

1

(

dec.). R

f

0.13 (EtOAc). H NMR (400 MHz, DMSO-D

6

) (δ, ppm): 10.28 (s, 1H, NH); 7.86 (s, 1H,

NH); 7.40-7.31 (m, 5H, Ph); 4.81-4.77 (m, 2H, CHPh and CH= cycle); 4.14 (q, J = 7.0 Hz, 2H,

1

3

OCH

MHz, DMSO-D

2.02; 55.26; 43.24; 14.61. C H N O (260.3): calcd. C, 64.60; H, 6.20; N, 10.76; found C, 64.58;

2

CH

3

); 2.46-2.38 (m, 2H, CH

2 2 3

C=O); 1.23 (t, J = 7.0 Hz, 2H, OCH CH ). C NMR (100

6

) (δ, ppm): 188.78; 157.14; 154.17; 141.39; 129.12 2C; 128.20; 126.80 2C; 85.85;

6

1

4

16

2

3

H, 6.27; N, 10.78.

Benzyl (4-oxo-6-phenyl-1,4,5,6-tetrahydropyridin-2-yl)carbamate (18b).

The reaction was carried out in THF at 40 °C for 40 min. Yield: 98%, as white powder, m.p. 82-83

1

°

C. R

f

0.2 (EtOAc). H NMR (400 MHz, CDCl

3

) (δ, ppm): 10.11 (br.s, 1H, NH); 8.24 (s, 1H, NH);

Ph); 5.13 (d, J = 12.3 Hz, 1H,

Ph); 5.05 (s, 1H, CH= cycle); 4.71 (dd, J = 4.8, 14.1 Hz, 1H, CHPh); 2.65 (dd, J = 14.1,

7

.40-7.28 (m, 10H, 2Ph); 5.17 (d, J = 12.3 Hz, 1H, CH

CH

6.4 Hz, 1H, CH

CDCl ) (δ, ppm): 190.26; 158.64; 154.30; 139.70; 135.01; 128.98 2C; 128.53 2C; 128.46; 128.36;

A B

H

A

H

B

1

3

1

A B A B

H C=O); 2.48 (dd, J = 4.8, 16.4 Hz, 1H, CH H C=O). C NMR (100 MHz,

3

2

3

Organic & Biomolecular Chemistry

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DOI: 10.1039/C6OB00293E

1

28.03 2C; 126.44 2C; 86.18; 67.63; 56.79; 42.95. C19

H

18

N

2

O

3

(322.4): calcd. C, 70.79; H, 5.63;

N, 8.69; found C, 70.77; H, 5.49; N, 8.59.

rac- and (S)-6-(Methylamino)-2-phenyl-2,3-dihydro-4(1H)-pyridinone (18d) and ((S)-18d).

The reaction was carried out in THF at 25 °C for 30 min. Yield: 96%, as white powder, 18d: m.p.

2

5

2

05-206 °C; (S)-18d: m.p. 222-223 °C; [α]

D

−32.2 (C 0.5, MeOH). R

) (δ, ppm): 7.36-7.30 (m, 4H, Ph); 7.26-7.23 (m, 1H, Ph); 6.71 (br.s,

H, NH); 6.35 (br.s, 1H, NH); 4.57 (dd, J = 7.2, 8.2 Hz, 1H, CHPh); 4.26 (s, 1H, CH=); 2.63 (d, J =

f

0.30 (EtOAc/MeOH, 4:1).

1

H NMR (400 MHz, DMSO-D

6

1

4

1

3

.8 Hz, 3H, NMe); 2.28 – 2.18 (m, 2H, CH

85.36 br.; 162.97; 142.33; 128.40 2С; 127.36; 126.51 2С; 79.67 br.; 55.17; 43.77; 28.05.

O (202.3): calcd. С, 71.26; Н, 6.98; N, 13.85; found С, 71.37; Н, 7.11; N, 13.74.

-(2-Chlorophenylamino)-2-allyl-2,3-dihydro-2-phenylpyridin-4(1H)-one (22a).

2 6

C=O). C NMR (100 MHz, DMSO-D ) (δ, ppm):

12 14 2

C H N

6

The reaction was carried out in iPrOH at 45 °C for 4h. Yield: 89%, as white solid, m.p. 208-209 °C.

1

R

f

0.23 (EtOAc/MeOH, 10:1). H NMR (600 MHz, DMSO-D

6

) (δ, ppm): 8.33 (s, 1H, NH); 7.59 (d,

J = 7.7 Hz, 1H, Ar); 7.45-7.37 (m, 6H, Ph, Ar); 7.29 (t, J = 6.8 Hz, 1H, Ar); 7.25 (t, J = 6.9 Hz, 1H,

Ar); 7.10 (s, 1H, NH); 5.56-5.49 (m, 1H, CH=, allyl); 5.18-5.14 (m, 2H, CH = allyl); 4.18 (s, 1H,

C=O). C NMR (100 MHz, DMSO-D ) (δ, ppm):

87.51, 159.46, 144.33, 135.66, 133.16, 130.45, 128.62 2C, 128.27, 128.25, 127.28, 127.27, 126.93,

2

1

3

CH=); 2.72-2.63 (m, 4H, CH

2

allyl and CH

2

6

1

8

6

25.85 2C, 120.10, 82.46, 60.59, 47.06, 46.36. C20

.27; found C, 70.74; H, 5.66; N, 8.19.

2

H19ClN O (338.8): calcd. C, 70.90; H, 5.65; N,

-(tert-Butylamino)-2-phenyl-2-prop-2-en-1-yl-2,3-dihydropyridin-4(1H)-one (22c).

To a solution of enolester 27a (0.284 g, 1.0 mmol) in THF (4 ml) was added tBuOK (0.168 g, 1.5

mmol) at -30 °C and the mixture was stirred for 1h at this temperature. Then AcOH (0.108 ml, 1.8

mmol) was added for neutralization, the mixture was filtered through the pad of Super Cel,

evaporated and the solid residue was recrystallized from n-C

as white powder, m.p. 121-122 °C (n-C O). R

6

H

14/Et

2

O to give 22c (0.204 g, 72%)

1

6

H

14/Et

2

f

0.12 (EtOAc/MeOH, 9:1). H NMR (400

MHz, CDCl ) (δ, ppm): 7.58 (br.s, 1H, NH); 7.31-7.23 (br.m, 6H, Ph and NH); 5.47 (br.s, 1H, CH=

3

allyl); 4.97 (br. s, 2H, CH

CH allyl); 1.27 (s, 9H, tBu). C NMR (100 MHz, CDCl

32.23; 128.28 2C; 126.81; 125.27 2C; 119.58; 84.08; 59.74; 51.39; 46.85; 44.41 br.; 29.88 3C.

O (284.4): calcd. С, 76.02; Н, 8.51; N, 9.85; found С, 75.98; Н, 8.55; N, 9.82.

-Phenyl-2-prop-2-en-1-yl-6-(prop-2-en-1-ylamino)-2,3-dihydropyridin-4(1H)-one (22d).

2

= allyl); 4.80 (br.s, 1H, CH=); 2.74 (br.s, 2H, CH

2

cycle); 2.55 (br.s, 2H,

1

3

2

3

) (δ, ppm): 184.69 br.; 161.73; 143.78;

1

18 24 2

C H N

2

4

Page 25 of 29

Organic & Biomolecular Chemistry

DOI: 10.1039/C6OB00293E

1

Yield: 85% as oil. R

f

0.25 (EtOAc/MeOH, 9:1). H NMR (400 MHz, CDCl

3

) (δ, ppm): 7.76 (br.s,

1

H, NH); 7.66 (br.s, 1H, NH); 7.30-7.18 (m, 5H, Ph); 5.75-5.66 (m, 1H, CH= Nallyl); 5.50-5.40 (m,

H, CH= allyl); 5.13 (d, J = 17.0 Hz, 1H, CH = Nallyl); 5.07 (d, J = 10.2 Hz, 1H, CH

= allyl); 4.60 (br.s, 1H, CH= cycle); 3.59 (br.s, 2H, CH N); 2.74 (s,

) (δ, ppm): 185.45;

62.82; 143.82; 132.24; 132.08; 128.26 2C; 126.93; 125.19 2C; 119.61; 116.58; 81.42; 59.84;

1

A

H

B

A B

H =

Nallyl); 5.01-4.97 (m, 2H, CH

2

1

3

2

1

4

7

2

2 2 3

H, CH C=O); 2.59-2.49 (m, 2H, CH allyl). C NMR (100 MHz, CDCl

6.50; 44.38; 44.28. C17

.48; N, 10.42.

20 2

H N O (268.4): calcd. С, 76.09; Н, 7.51; N, 10.44; found С, 76.14; Н,

-Allyl-6-(methylamino)-2-phenyl-2,3-dihydropyridin-4(1H)-one (22e).

0.2 (EtOAc/MeOH, 5:1). H NMR (400 MHz,

) (δ, ppm): 7.28-7.15 (m, 7H, 2NH and Ph); 5.50-5.39 (m, 1H, CH= Nallyl); 5.01-4.96 (m,

H, CH = allyl); 4.54 (br.s, 1H, CH= cycle); 2.75 (d, J = 16.6 Hz, 1H, CH C=O); 2.70 (d, J =

6.6 Hz, 1H, CH H C=O); 2.63 (s, 3H, NMe); 2.56 (dd, J = 6.7, 14.0 Hz, 1H, CH H allyl); 2.51

1

Yield: 48% as yellow solid, m.p. 83-84 °C. R

CDCl

f

3

2

1

2

A B

H

A

B

A

B

1

3

(

dd, J = 8.3, 14.0 Hz, 1H, CH

43.84; 132.31; 128.33 2C; 126.96; 125.29 2C; 119.61; 80.85; 59.93; 46.52; 45.38; 28.53.

O (242.3): calcd. С, 74.35; Н, 7.49; N, 11.56; found С, 74.27; Н, 7.53; N, 11.48.

A B 3

H allyl). C NMR (100 MHz, CDCl ) (δ, ppm): 186.27; 163.30;

1

15 18 2

C H N

Kinetic experiment of rate constant determination of rearrangement 19 to 18b.

tBuOK (7.8 mg, 0.0694mmol) was added to a solution of 19 (11.2 mg, 0.0347) in dry DMSO-D

6

1

(

0.55 mL) in a NMR tube. Reaction mixture was analyzed by H NMR (20 scans per hour) at 20.5

°

C. The integration was performed for the peaks at δ = 2.75 ppm (for 19) and δ = 7.16 ppm (for t-

BuPh (internal standard)).

X-ray structures determination.

The X-ray crystal structure analyses were made on Bruker SMART APEX2 CCD (21a and 22a;

MoK radiation, graphite monochromator, ϕ and ω scan mode). The data sets were corrected for

α

9

30

absorption with SADABS and crystal structures were solved w ith the ShelXT structure solution

0,31

program using Direct Methods and refined with the ShelXL

refinement package using Least

Squares minimization. Non-hydrogen atoms were refined anisotropically. The absolute structures

were defined by the refinement of the Flack parameters. The hydrogen atoms of the amino groups

were localized in the difference-Fourier maps and refined isotropically with displacement

parameters [Uiso(H) = 1.2Ueq(N)]. The other hydrogen atoms were placed in calculated positions

and refined within riding model with fixed isotropic displacement parameters [Uiso(H) = 1.2Ueq(C)].

2

5

Organic & Biomolecular Chemistry

Page 26 of 29

DOI: 10.1039/C6OB00293E

2

1a

OClBr

22a

Empirical formula

C

20

H

20

N

2

20 19 2

C H N OCl

Formula weight

419.74

100

338.82

100

T, K

Crystal system

triclinic

P-1

orthorhombic

Space group

P2 2 2

1 1

1

Z

4

a, Å

b, Å

c, Å

α, °

β, °

γ, °

10.5960(8)

13.0323(10)

15.0398(11)

89.548(2)

69.846(2)

82.380(2)

1930.9(3)

1.444

6.684(2)

11.847(4)

22.594(7)

66.112(2)

84.616(2)

83.113(2)

1789.1(9)

1.258

3

V, Å

3

d

calc, г/см

-1

µ, см

2.277

0.222

F(000)

856

712

2

θ

max, °

60.0

52.2

Reflections collected

25436

17046

Independent reflections

11212

3541

Reflections wth I>2σ(I)

7918

1680

Parameters

R1

185

211

0.049

0.061

wR2

0.125

0.150

GOF

1.001

1.000

Flack

-

0.10(14)

*

Parsons`s quotient

Crystallographic data for the investigated compounds have been deposited with the Cambridge

Crystallographic Data Center, CCDC 1440015 (21a) and CCDC 1440016 (22a). Copies of this

information may be obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge

CB2 1EZ, UK (fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk or www.ccdc.cam.ac.uk ).

2

6

Page 27 of 29

Organic & Biomolecular Chemistry

DOI: 10.1039/C6OB00293E

Supporting Information (see footnote on the first page of this article): Experimental details, copies

1

13

of the H and C NMR spectra, HPLC traces, and selected crystallographic data.

Acknowledgments

This work was financially supported by the Russian Science Foundation (grant No. 15-13-00109).

The authors are grateful to Dr. S. Lubimov and Dr. D. Ozolin for chiral HPLC analysis.

References

1

a) G. M. Strunz, J. A. Findlay in The Alkaloids (Ed.: A. Brossi), Academic Press, Orlando, 1985, vol. 26,

pp. 89–183, b) G. B. Fodor, B. Colasanti in Alkaloids: Chemical and Biological Perspectives (Ed.: S. W.

Pelletier), Wiley, New York, 1985, vol. 3, pp. 1–90, piperidine-2-ones c) T. H. Jones, M. S. Blum, in

Alkaloids: Chemical and Biological Perspectives (Ed.: S. W. Pelletier), Wiley, New York, 1983, vol. 1,

pp 33–84.

2

F. Couty and G. Evano, in Comprehensive Heterocyclic Chemistry III (Ed.: A. R. Katritzky, C. A. Ramsden, E. F. V.

Scriven and R. J. K. Taylor), Elsevier, Oxford, 2008, vol. 11, p. 409.

3

a) H. Kayakiri, S. Takase, T. Shibata, M. Okamoto, H. Terano, M. Hashimoto, J. Org. Chem., 1989, 54, 4015; b) K. W.

Hering, K. Karaveg, K. W. Moremen, W. H. Pearson, J. Org. Chem., 2005, 70, 9892.

4

a) B. E. Maryanoff, W. Ho, D. F. McComsey, A. B. Reitz, P. P. Grow, S. O. Nortey, R. P. Shank, B. Dubinsky, R. J.

Taylor, J. F. Gardocki, J. Med. Chem., 1995, 38, 16; b) A. D. Jordan, A. H. Vaidya, D. I. Rosenthal, B. Dubinsky, C. P.

Kordik, P. J. Sanfilippo, W.-N. Wub, A. B. Reitz, Bioorg. Med. Chem. Lett., 2002, 12, 2381; c) A. B. Reitz, A. D.

Jordan, P. J. Sanfilippo, M. C. Scott, A. V. Smith. Patent EP 0935598B1, 2003.

5

Y. K. Chen, E. W. Co, P. Guntupalli, J. D. Lawson, W. R. L. Notz, J. A. Stafford, H.-T. Ton-Nu. Patent WO

2

009097578 A1, 2009.

6

a) T. D. Machajewski, C. M. Shafer, C. Mcbride et al. Patent WO2007/041362, 2007; b) D. L. Menezes, P. Taverna,

M. Jensen, T. Abrams, D. Stuart, G. K. Yu, D. Duhl, T. Machajewski, W. R. Sellers, N. Pryer, Z. Gao, Mol. Cancer

Ther., 2012, 11, 730.

7

L. Neckers, P. Workman, Clin. Cancer Res., 2012, 18, 64.

8

A. K. Rochani, M. Singh, U. Tatu, Curr. Pharm. Des., 2013, 19, 377.

9

S. D. Shekhawat, R. K. Jain, H. M. Gaherwar, H. J. Purohit, G. M. Taori, H. F. Daginawala, R. S. Kashyap Human

Immunology, 2014, 75, 151.

1

0

L. Zhang, C. U. Kim, L. Xu, Tetrahedron Lett., 2007, 48, 3273.

a) D. Li, X. Xu, Q. Liu, S. Dong Synthesis, 2008, 1895; b) L. Zhao, F. Liang, X. Bi, S. Sun, Q. Liu J. Org. Chem.,

1

2

006, 71, 1094-1098; c) D. Dong, X. Bi, Q. Liu, F. Cong J. Chem. Soc. Chem. Commun., 2005, 3580.

12

a) N. Yu. Kuznetsov, V. I. Maleev, V. N. Khrustalev, A. F. Mkrtchyan, I. A. Godovikov, T. V. Strelkova, Yu. N.

Bubnov, Eur. J. Org. Chem., 2012, 334; b) N.Yu. Kuznetsov, V.N. Khrustalev, T.V. Strelkova, Yu.N. Bubnov,

Tetrahedron: Asymmetry, 2014, 25, 667.

2

7

Organic & Biomolecular Chemistry

Page 28 of 29

DOI: 10.1039/C6OB00293E

13

piperidine-2-ones a) J. W. Daly, J. Nat. Prod., 1998, 61, 162; b) (Ciliatamide C) Y. Nakao, S. Kawatsu, C.

Okamoto, M. Okamoto, Y. Matsumoto, S. Matsunaga, R. W. M. van Soest, N. Fusetani, J. Nat. Prod., 2008, 71, 469; c)

Adalinine) G. Lognay, J. L. Hemptinne, F. Y. Chan, C. H. Gaspar, M. Marlier, J. C. Braekman, D. Daloze, J. M.

(

Pasteels, J. Nat. Prod., 1996, 59, 510; d) Tasipeptins A and B: P. G. Williams, W. Y. Yoshida, R. E. Moore, V. J.

Paul, J. Nat. Prod., 2003, 66, 620; e) Micropeptins: V. Reshef, S. Carmeli, Tetrahedron, 2001, 57, 2885; f)

Paraherquamides, brevianamides, and asperparalines: R. M. Williams, R. J. Cox, Acc. Chem. Res., 2003, 36, 127; g)

(

Strychnine) J. Bonjoch, D. Sole, Chem. Rev., 2000, 100, 3455.

14

a) D. Bell, M. R. Davies, F. J. L. Finney, G. R. Geen, P. M. Kincey, I. S. Mann, Tetrahedron Lett., 1996, 37, 3895

(

potassium channel activator BRL 55834); b) H. G. Bull, M. Garcia-Calvo, S. Andersson, W. F. Baginsky, H. K.

Chan, D. E. Ellsworth, R. R. Miller, R. A. Stearns, R. K. Bakshi, G. H. Rasmusson, R. L. Tolman, R. W. Myers, J. W.

Kozarich, G. S. Harris, J. Am. Chem. Soc., 1996, 118, 2359 (finasteride MK-906 inhibitor of the human prostate

enzyme); c) G. A. Reichard, J. Spitler, I. Mergelsberg, A. Miller, G. Wong, R. Raghavan, J. Jenkins, T. Gan, A. T.

McPhail, Tetrahedron: Asymmetry, 2002, 13, 939 (SCH206272 NK

Eishima, M. Hara, Y. Takahashi, S. Otaki, R. J. Foglesong, P. F. Hughes, S. Turkington, Y. Kanda, J. Med. Chem.,

003, 46, 2467 (anticancer drugs Farnesyltransferase (FTase) inhibitors); e) Z. Pei, X. Li, T. W. von Geldern, K.

1 2

\NK antagonist); d) S. Nara, R. Tanaka, J.

2

Longenecker, D. Pireh, K. D. Stewart, B. J. Backes, C. Lai, T. H. Lubben, S. J. Ballaron, D. W. A. Beno, A. J. Kempf-

Grote, H. L. Sham, J. M. Trevillyan, J. Med. Chem., 2007, 50, 1983 (Dipeptidyl peptidase IV (DPP4) inhibitors,

treatment of type 2 diabetes); f) E. Vanotti et al. J. Med. Chem., 2008, 51, 487 (Cdc7 Kinase Inhibitors); g) Y.

Nishimura, H. Adachi, T. Satoh, E. Shitara, H. Nakamura, F. Kojima, T. Takeuchi, J. Org. Chem., 2000, 65, 4871

(

glycosidase inhibitors).

1

5

a) L. Halab, F. Gosselin, W. D. Lubell, Biopolymers, 2000, 55, 101; b) S. Hanessian, G. McNaughton-Smith, H.-G.

Lombart, W. D. Lubell, Tetrahedron, 1997, 53, 12789; c) K. Weber, U. Ohnmacht, P. Gmeiner, J. Org. Chem., 2000,

5, 7406; d) F. E. Dutton, B. H. Lee, S. S. Johnson, E. M. Coscarelli, P. H. Lee, J. Med. Chem., 2003, 46, 2057; e) D.

Xin, L. M. Perez, T. R. Ioerger, K. Burgess, Angew. Chem. Int. Ed., 2014, 53, 3594.

6

1

6

Unpublished data

17

a) T. Ishida, S. Kikuchi, T. Tsubo, T. Yamada, Org. Lett., 2013, 15, 848; b) T.Ishida, S. Kikuchi, T. Yamada, Org.

Lett., 2013, 15, 3710;

1

2

8

9

0

N. Yu. Kuznetsov, V. N. Khrustalev, I. A. Godovikov, Yu. N. Bubnov, Eur. J. Org. Chem., 2007, 2015.

L. Wanka, K. Iqbal, P. R. Schreiner, Chem. Rev., 2013, 113, 3516.

G .Stamatiou, G. B. Foscolos, G. Fytas, A. Kolocouris, N. Kolocouris, C. Pannecouque, M. Witvrouw, E. Padalko, J.

Neyts, E. De Clercq, Bioorg. Med. Chem., 2003, 11, 5485.

2

1

T. Wirth, Organoselenium Chemistry: Synthesis and Reactions, Wiley-VCH, 2011, pp 462.

B. Dhudshia, J. Tiburcio, A. N. Thadani, Chem. Commun., 2005, 5551.

22

2

3

4

S. Mangelinckx, Y. Nural, H. A. Dondas, B. Denolf, R. Sillanpaa, N. De Kimpe, Tetrahedron, 2010, 66, 4115.

K. C. Nicolau, K. C. Fylaktakidou, H. J. Mitchell, F. L. van Delft, R. M. Rodriguez, S. R. Conley, Z. Jin, Chem. Eur.

J., 2000, 6, 3166.

2

5

6

7

8

Yu. N. Bubnov, V. S. Bogdanov, B. M. Mikhailov, Russ. J. Gen. Chem., 1968, 38, 260.

M. J. García-Muñoz, F. Zacconi, F. Foubelo, M. Yus, Eur. J. Org. Chem., 2013, 1287.

L. Leboutet, G. Courtois, L. Miginiac, J. Organomet. Chem., 1991, 420, 155.

S. Magnelinckx, Y. Nural, H. A. Dondas, B. Denolf, R. Sillanpaa, N. De Kimpe, Tetrahedron, 2010, 66, 4115.

2

8

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