Highly regio- and stereoselective 1,3-dipolar cycloaddition of stabilised azomethine ylides to 3,3,3-trihalogeno-1-nitropropenes: synthesis of trihalomethylated spiro[indoline-3,2′-pyrrolidin]-2-ones and spiro[indoline-3,3′-pyrrolizin]-2-ones

ACCEPTED MANUSCRIPT

Graphical Abstract

Highly regio- and stereoselective 1,3-dipolar cycloaddition of stabilised azomethine ylides to 3,3,3-trihalogeno-1-

nitropropenes: synthesis of trihalomethylated spiro[indoline-3,2'-pyrrolidin]-2-ones and spiro[indoline-3,3'-

pyrrolizin]-2-ones

Alexey Yu. Barkov, Nikolay S. Zimnitskiy, Vladislav Yu. Korotaev, Igor B. Kutyashev, Vladimir S. Moshkin,

Vyacheslav Ya. Sosnovskikh*

_

_______________________________________________________________________________________________________________________

2

ACCEPTED MANUSCRIPT

Highly regio- and stereoselective 1,3-dipolar cycloaddition of stabilised

azomethine ylides to 3,3,3-trihalogeno-1-nitropropenes: synthesis of

trihalomethylated spiro[indoline-3,2'-pyrrolidin]-2-ones and spiro[indoline-3,3'-

pyrrolizin]-2-ones

Alexey Yu. Barkov, Nikolay S. Zimnitskiy, Vladislav Yu. Korotaev, Igor B. Kutyashev,

Vladimir S. Moshkin, Vyacheslav Ya. Sosnovskikh*

Institute of Natural Sciences, Ural Federal University, 620000 Ekaterinburg, Russian Federation;

e-mail address: vy.sosnovskikh@urfu.ru

Keywords: 3,3,3-Trihalogeno-1-nitropropenes; Stabilised azomethine ylides; 1,3-Dipolar cycload-

dition; Spirooxindoles

________________________________________________________________________________

Reactions of 3,3,3-trihalogen-1-nitropropenes with N-alkyl-α-amino acids (sarcosine, proline) and

isatins proceed regio- and diastereoselectively to give a wide range of trihalomethylated

spiro[indoline-3,2'-pyrrolidin]-2-ones and spiro[indoline-3,3'-pyrrolizin]-2-ones in good yields as a

result of a 1,3-dipolar cycloaddition of the intermediate stabilised azomethine ylide at the double

bond of the nitroalkenes.

________________________________________________________________________________

Introduction

The 1,3-dipolar cycloaddition reaction of azomethine ylides with olefins is an efficient method-

ology for regio- and stereoselective synthesis of structurally complex pyrrolidines with a few chiral

1

centres from relatively simple precursors. Synthesis of oxindoles derivatives, in particular pyrroli-

dinyl 3-spirooxindoles, has attracted considerable attention due to their highly pronounced biologi-

cal activities. The presence of the chiral spiro carbon leads to the sterically constrained spiro struc-

ture and is one of the important factors of the biological activities. It is not surprising, therefore, that

the heterocyclic spirooxindole system containing one carbon atom common to two rings is a widely

2

distributed structural framework present in a number of pharmaceuticals and natural products.

3

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Compounds of this class represent a wide range of structural complexity, from the simpler members

3

4

such as horsfiline (1) and elacomine (2) to the more complex members such as spirotryprostatin A

3), in which the pyrrolidine portion is part of a tricyclic system. The latter was isolated from the

fermentation broth of Aspergillus fumigatus and has been shown to completely inhibit the G2/M

(

2

a

progression of mammalian tsFT210 cells. Moreover, the spirooxindole ring system is present in

pharmacologically important compounds. For instance, non-natural 3,3'-pyrrolidinyl spirooxin-

5

doles, such as compound 4, exhibit micromolar activities against bacterial cell division; the syn-

thetic derivatives 5 and 6 are representatives of a novel type of potent non-peptidic inhibitor of the

p53-MDM2 interaction that is crucial for the regulation of the tumour-suppressing activity of the

6

p53 protein (Fig. 1).

Fig. 1. Natural (1–3) and synthetic (4–6) spirocyclic oxindoles.

4

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Undoubtedly, the abandance of natural and unnatural bioactive oxindoles have encouraged the

design and synthesis of novel spirocyclic oxindoles with relevant and notable medicinal properties.

In this regard, many useful methods have been established for the construction of this valuable het-

7

erocyclic system. Thus, the 1,3-dipolar cycloadditions of azomethine ylides and 3-methylene-2-

oxindoles provided an efficient approach to highly functionalized 3,3'-pyrrolidinyl spirooxindoles

5

,8

with excellent regio- and stereoselectivities. Alternatively, the 1,3-dipolar cycloadditions of azo-

methine ylides generated from decarboxylative condensation of isatins and N-alkyl-α-amino acids

with electron-poor alkenes serve as an expedient route for the construction of 3,2'-pyrrolidinyl spi-

9

10

11

12

rooxindoles. Olefins, such as chalcone, β-nitrostyrenes, 3-nitro-2H-chromenes, acrylates, ma-

1

3

14

leimides, and various arylidene derivatives, have been used efficiently as trapping dipolarophiles

in good yield and high selectivity. Despite these recent advances, to the best of our knowledge a

stereoselective [3+2] cycloaddition reaction of azomethine ylides with trihalomethylated nitroal-

kenes has never been reported, while new advances in this area could afford a convenient approach

to CX -containing spirooxindoles derivatives.

3

Partially fluorinated heterocycles represent important molecules in organic and medicinal chem-

istry (undesirable metabolic transformations are often avoidable because the C−F bond is hard for

enzymes to cleave) and their one-pot preparation is one of the challenging problems in organic syn-

15

thesis. We envisaged that introduction of such powerful electron-withdrawing substituents like

CF , CCl and CBr groups into the conjugated nitroalkene moiety would increase their reactivity

3

toward 1,3-dipolar cycloaddition with azomethine ylides and open up a new synthetic usefulness of

these molecules. Of particular interest is the fact that introduction of a trihalomethyl group, espe-

cially a trifluoromethyl group, into bioactive spirooxindoles can have profound and unexpected re-

1

5a

sults on biological activity of the derived halogenated compounds.

Trihalomethylated nitroolefins possess unique chemical reactivity toward both nucleophilic and

cycloaddition reactions because of their reactive double bond. Owing to this, trans-3,3,3-

trifluoro(trichloro)-1-nitropropenes have attracted attention as excellent building blocks for the

5

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1

6

preparation of CX -containing compounds. Most pertinent to the present research is the 1,3-

3

dipolar cycloaddition of benzonitrile oxide and nitrones to CX -nitroalkenes (X = F, Cl) providing a

3

17

18

straightforward route to isoxazolines and isoxazolidines. These compounds were also used as

1

9

dienophiles in Diels–Alder reaction and as heterodienes in an inverse electron-demand Diels–

2

0

Alder reaction. However, published data on their participation in 1,3-dipolar cycloaddition reac-

tions with azomethine ylides is lacking. Moreover, there are no literature data for the participation

of trans-3,3,3-tribromo-1-nitropropene in any cycloaddition reactions.

In the present paper we wish to report that the cycloaddition of isatin azomethine ylides with

conjugated nitroolefins additionally activated by the trihalomethyl group provides a simple and

convenient synthesis of CX -containing 3,2'-pyrrolidinyl spirooxindoles (X = F, Cl, Br), which are

3

of interest from the view point of pharmacological activity because of their spiro skeleton and CX₃

functionality. The major products of the reaction with isatin–proline ylide showed different regiose-

lectivity from the reported spirooxindole derivatives, prepared from β-nitrostyrenes. The regio- and

1

19

13

stereochemistry of the cycloadducts has been established by H, F and C NMR spectroscopy and

X-ray diffraction analysis.

2. Results and discussion

The CF -containing 3-spirooxindole derivatives have emerged as attractive synthetic targets due

3

2

1

to their applications in such fields as pharmacy and medicine. In continuation of our research pro-

2

0,22

gram dedicated to the chemistry of trihalomethylated nitroolefins

we decided to study the reac-

tions of nitroolefins 1a–c with a set of stabilised azomethine ylides generated from decarboxylative

condensation of readily available isatins 2a–f and N-alkyl-α-amino acids such as sarcosine and pro-

line (Fig. 2). Nitroolefins 1a–c were synthesized by one of the known methods starting from nitro

alcohols, prepared by condensation of equimolecular amounts of nitromethane with the correspond-

2

3

ing trihaloacetaldehyde in the presence of K CO .

2

3

6

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F₃C

Cl C

Br C

3

NO₂

1

a

1b

1c

Br 2c

2f

O

O N

Br

2

O

N

H

2

a

2b

O

N

Me

Am

Bn

2

d

2e

Fig. 2. Nitroalkenes 1 and isatins 2 used in this study.

In the initial study we have developed the synthesis of the hitherto unknown spiro[indoline-3,2'-

pyrrolidin]-2-ones 3a–n starting from CX -nitroalkenes 1, isatins 2a,c–f and sarcosine by a one-pot,

3

three-component procedure depicted in Scheme 1. To our delight, the cycloaddition proceeds in a

high regio- and stereocontrolled fashion. We have found that refluxing of these reactants in isopro-

panol for 48 h resulted in the formation of cycloadducts 3a–n in 55–98% yields as single regioiso-

meric products, the structures of which were fully characterized by spectroscopic methods and X-

ray diffraction analysis (see below). The progress of the reaction was monitored by TLC, and the

results are summarized in Table 1. The desired 3-spirooxindoles precipitate upon dilution of the re-

action mixtures with brine and a simple filtration provides analytically pure material. Among differ-

ent solvents (benzene, ethanol, acetonitrile and isopropanol), which have been tested to perform the

reaction, isopropanol was identified as the best solvent in terms of yield and selectivity. It is neces-

sary to be mentioned that in the case of N-allylisatin the reaction led to a mixture of starting materi-

als and unidentified products. Isatin 2a and N-methylisatin 2d reacted especially smoothly with 1a–

c to give the desired products in 65–98% yields, while azomethine ylide from 5-nitroisatin 2b and

sarcosine did not work under our reaction conditions.

7

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O

H

X C

3

₊_R1

N

CO H

O +

2

NO₂

Me

N

1a-c

R

2a,c-f

O

i-PrOH

Me

N

R

N

Me

O

R¹

O

-

CO₂

N

R

A

X C

3

NO₂

O

R

N

Me

R¹

endo

5

'

CX₃

NO₂

CX₃

NO₂

4

'

Me

N

3'

N

R¹

+

R¹

O

N

R

3a-n

3'c-e

Scheme 1. Synthesis of compounds 3a–n by the reaction of nitroalkenes 1a–c with isatin–sarcosine ylides.

Table 1

Isolated yields of compounds 3a–n (all structures are racemic)

Nitroalkene 1

Isatin 2

2a

2c

2d

2e

2f

2a

2c

2d

2e

2f

2a

2d

2e

Adduct 3

3a

3b

3c

3d

3e

3f

3g

3h

3i

3j

3k

3l

Yield (%)

1

a

b

c

89

66

90

68

55

a

b

c

70

67

98

79

71

69

65

66

59

c

3m

3n

2f

a

b

c

Ratio of 3c : 3'c = 93 : 7.

Ratio of 3d : 3'd = 86 : 14.

Ratio of 3e : 3'e = 95 : 5.

8

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2

4

Herein, some common comments are desired. It is well-known that a prediction of the regiose-

lectivity in the cycloaddition reaction of an unsymmetrical dipole and dipolarophile is based on the

preferred transition state, which involves interaction of the larger terminal coefficients. Steric ef-

fects also play an important part in these reactions and may influence the regioselectivity. In addi-

tion to regioselectivity issues, up to four new chiral centers are generated in such reactions, howev-

er, high levels of stereoselectivity are typically obtained. The chiral centers at C-2 and C-5 atoms of

the newly forming pyrrolidine ring derive from the azomethine ylide geometry (the W- and S-

shaped ylides), while the orientation of substituents at C-3 and C-4 derive from the alkene geome-

try. This result is expected on the basis of a concerted cycloaddition reaction, however, concerted

process may not always be operative and a stepwise pathway, involving zwitterionic intermediates,

cannot be ruled out. The relative configurations at C-2/C-3 and C-4/C-5 are determined by an en-

do/exo approach. The general preference is for the formation of the endo isomer, as found for the

isoelectronic Diels-Alder reaction. Stabilised azomethine ylides are not exclusion from this rule and

9

,10

usually show high endo selectivity to the electron-poor olefins.

As expected, azomethine ylides A derived from isatins and sarcosine are involved in the transi-

tion state where endo addition (with respect to the NO group) of nitroalkenes 1a–c to the triangle

2

of the ylide prevails and results in the formation of endo-adducts 3a–n with trans-arrangement of

9

c

the CX and NO groups due to the synchronism of the reaction (Scheme 1). Note that chalcone

3

2

1

0f

and β-nitrostyrene react with isatin–sarcosine ylides in a similar manner. Compounds 3 were

formed exclusively as the regioisomers with the NO group at C-3' and the CX group at C-4'. The

2

3

alternative regiochemistry does not look very favorable in terms of the steric repulsion of the bulky

CX group from the electron density of the amide moiety or a π-system of the benzene ring. In gen-

3

eral, in the case of ylides A and electron-poor alkenes (nitrostyrenes, chalcones, acrylates, cin-

namates), the more electrophilic alkene atom reacts with the more nucleophilic and accessible ter-

minal ylide atom. The indicated regio- and stereochemistry of spirooxindoles 3 was unambiguously

confirmed by X-ray single crystal analysis of 3k as a representative example (Fig. 3).

9

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Fig. 3. X-ray crystal structure of 3k (ORTEP drawing, 50% probability level).

Moreover, the assignment of structure 3 to the endo-adduct and 3'-NO -regioisomer is based on

2

1

the H NMR chemical shifts for the H-3' and H-4' protons. A comparison of these chemical shifts

with the data reported for the parent compound, prepared from isatin–sarcosine ylide A and β-

1

0f

nitrostyrene, supports the validity of the structures (Fig. 4).

1

Fig. 4. Diagnostic H NMR signals (

δ

, ppm, J/Hz, CDCl ) of spirooxindole 3a and its literature analog.

3

The nature of the CX group and the substitution pattern of the azomethine ylides used are not

3

very important for this transformation, however, replacement of the CCl and CBr groups with a

3

more electron-withdrawing CF group had some effect on the diastereoselectivity. Thus, the appear-

3

1

ance of the stereoisomers 3'c–e (5–14% according to the Н NMR spectroscopic data, the downfield

doublet of H-3' at δ = 5.17–5.23 ppm) was observed in the crude products (Scheme 1). Noteworthy

is the fact that minor adducts 3' are formed only with the acceptor CF -containing alkene 1a, and

3

we assume that it can react nonselectively and asynchronously, stabilizing the initial Michael inter-

mediate by retention of the negative charge up to the final stage of the second C–C bond formation.

10

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The stereochemistry of these by-products was not determined, however, coupling constants J = 6.8–

7.0 Hz between H-3' and H-4' in the structures 3'c–e make their trans-arrangement more preferable.

For further demonstrating the synthetic values of CX -nitroalkenes 1, the similar [3+2] cycload-

3

dition reaction of stabilised azomethine ylides derived from isatins 2a–f and proline was also inves-

tigated. This reaction under the conditions described above afforded hexahydrospiro[indoline-3,3'-

pyrrolizin]-2-ones 4a–q in 51–85% yields (Scheme 2, Table 2). In contrast to the results found in

the sarcosine series, when 5-nitroisatin 2b was employed, the corresponding nitropyrrolizines with

spirooxindole moieties 4b,h,n were obtained in good yields (59–63%). As in the cycloaddition re-

actions involving sarcosine, compounds 4a–q were formed mainly as the same regioisomer in rela-

tion to the position of the trihalomethyl and nitro groups. However, in the case of isatin–proline

ylides, the appearance of regioisomers 4'd,f,j,p was observed in the crude products (7–11% accord-

1

ing to the H NMR data). The pure cycloadducts 4d,f,j,p were obtained by recrystallizing the crude

reaction mixture from the mixture hexane/CH Cl (2:1). Thus, this three-component reaction has a

2

wide variety of substrates and proceeds with high efficiency and selectivity.

O

X C

3

+ R¹

O +

NO₂

CO H

N

R

2

N

H

1a-c

2a-f

i-PrOH

O

N

O

R¹

O

-

CO₂

N

R

B

R

7'

6'

7'a CX₃

NO₂

5'

1'

N

2

'

NO₂

CX₃

O

R¹

O

+

N

R

4a-q

4'd,f,j,p

Scheme 2. Synthesis of compounds 4a–q by the reaction of nitroalkenes 1a–c

with isatin–proline ylides.

11

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Table 2

Isolated yields of compounds 4a–q (all structures are racemic)

Nitroalkene 1

Isatin 2

2a

2b

2c

2d

2e

Adduct 4

4a

4b

4c

4d

4e

4f

4g

4h

4i

4j

4k

4l

Yield (%)

1

a

b

c

85

60

62

a,b

62

59

81

c

2f

2a

2b

2c

2d

2e

71

63

81

d

56

57

70

74

59

55

2f

2a

2b

2c

2d

2f

4m

4n

4o

4p

4q

c

e

72

51

a

b

c

d

e

Ratio of 4d : 4'd = 89 : 11.

Ratio of 4d : 4'd = 95 : 5 in hexafluoroisopropanol (yield 69%).

Ratio of 4f : 4'f = 91 : 9.

Ratio of 4j : 4'j = 93 : 7.

Ratio of 4p : 4'p = 91 : 9.

The structure of the spirooxindoles 4 was established by the usual spectroscopic analyses, and

the indicated regio- and stereochemistry was further unambiguously confirmed by X-ray single

crystal analysis performed for compound 4a (Fig. 5). The ORTEP diagram of 4a represents that the

trans-geometry of CX -nitroalkenes is preserved in the product and also shows the relative configu-

3

rations at all four chiral centers. The stereochemistry of cycloadducts is consistent with an ylide B

and subsequent cycloaddition by an endo transition state (endo-TS 1); the cycloadduct correspond-

ing to exo-TS 2 was not observed at all (Fig. 6). Possible structures for the minor regioisomers

4'd,f,j,p are also presented in Fig. 6 (endo-TS 3). Although these by-products were not isolated in a

1

pure state, their stereochemistry was established by 2D H– H NOESY experiment of a 89 : 11 mix-

ture of compounds 4d and 4'd. The most important proof of their stereochemistry was the NOE

connectivities indicated with pink and blue arrows in Fig. 7. The 2D NOESY experiment on 4d and

4'd demonstrates the spatial contiguity of H-1' to H-4 and H-2' to H-4 (pink arrows), respectively;

cross-peaks for H-1' with H-4 and H-2' with H-4 show that these protons are sited close to each oth-

er, thus establishing the indicated stereochemistry in Fig. 8 (about regiochemistry see below).

12

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Fig. 5. X-ray crystal structure of 4a (ORTEP drawing, 50% probability level).

X C

3

O N

2

NO₂

CX₃

NO₂

CX₃

X C

3

O N

2

R

O

R

O

R

O

R

N

R₁

TS 1

endo

TS 2

TS 3

endo

TS 4

exo

CX₃

NO₂

CX₃

NO₂

N

NO₂

O

CX₃

O

CX₃

O

R¹

O

N

R

N

R

4a-q

4'd,f,j,p

X C

3

X C

3

O N

2

O N

2

O N

2

O N

2

X C

3

X C

3

N

O

N

R¹

O

N

R

Fig. 6. Possible transition states for the formation of spirooxindoles 4a–q and 4'd,f,j,p.

13

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H

CF₃

H

NO

2

H

7

'a

7'a

1

'

1'

2'

H

N

2

'

4

NO₂

O

CF₃

O

N

Me

H

4d

4'd

1

Fig. 7. Diagnostic 2D H– H NOESY correlations of compounds 4d and 4'd.

1

Fig. 8. A fragment of the 2D H– H NOESY spectrum of compounds 4d and 4'd.

1

A characteristic feature of the H NMR spectra of compounds 4 and 4' in a CDCl solution is the

3

chemical shifts and multiplicity of the pyrrolizine methine protons. The assignment of structures 4'

1

to the 2'-CX -regioisomer is based on the H NMR chemical shifts of the protons H-1' and H-2'. A

3

comparison of these chemical shifts in by-products 4' with the values disclosed for 1'-CX₃-

regioisomers 4 supports the validity of their regiochemistry (Fig. 9). For example, for the minor

isomer 4'd, the pyrrolizine H-1' proton is shifted downfield to 2.18 ppm due to the NO group,

2

1

while the H-2' proton is shifted upfield to 1.28 ppm. The significant H NMR chemical shifts of the

pyrrolizine methine protons H-1', H-2' and H-7'a for regioisomeric pairs 4d,j,p and 4'd,j,p are pre-

1

3

sented in Fig. 9. The C NMR spectra of all synthesized spirooxindoles showed two peaks at δ

2.0–75.9 and 173.6–177.2 ppm for the spiro carbon and the oxindole carbonyl group, respectively.

7

14

ACCEPTED MANUSCRIPT

19

The CF group in their F NMR spectra (CDCl ) manifests itself as a doublet at δ 91.9–93.4 ppm

3

due to coupling with the CH proton ( J = 7.3–8.4 Hz), all in good accordance with the given

F,H

structures.

4.25 (dt, J = 9.0, 6.8)

4.91 (dt, J = 8.9, 6.1)

5.96 (t, J = 9.2)

3.78 (tq, J = 9.3, 7.5)

CF₃

NO₂

N

NO₂₅

CF₃

O

.63 (d, J = 9.7)

4.35 (quint, J = 8.6)

O

N

Me

4d

4'd

4.33 (dt, J = 7.5, 6.8)

5.03 (m)

4.36 (t, J = 7.8)

5.81 (dd, J = 8.5, 7.3)

CCl₃

NO₂

N

NO₂

O

N

CCl₃

O

5.74 (d, J = 7.9)

5.02 (d, J = 7.3)

Me

4j

4'j

4.19 (dt, J = 8.1, 6.8)

5.01 (dt, J = 7.9, 6.5)

4.48 (dd, J = 8.1, 7.0)

5.68 (dd, J = 7.9, 6.0)

CBr₃

NO₂

N

NO₂₅

CBr₃

O

N

.65 (d, J = 8.0)

5.26 (d, J = 6.0)

O

N

Me

4p

4'p

1

Fig. 9. Diagnostic H NMR signals (δ, ppm, J/Hz, CDCl ) of regioisomeric pairs 4d,j,p and 4'd,j,p.

3

It should be noted that our result is in contrast to the commonly observed regioselectivity out-

come in this type of 1,3-dipolar cycloaddition reactions with β-nitrostyrenes. All previously pub-

lished studies concerning β-nitrostyrenes showed that the products were formed selectively through

an endo approach between the dipolarophile and S-shaped ylide B and almost exclusively as the

regioisomers with the NO group at C-1' (Fig. 6, TS 3). In fact, spirooxindoles 5 and 6 were previ-

2

1

0c

10a

ously obtained from β-nitrostyrene and 3,4-dimethoxy-β-nitrostyrene (Fig. 10). Since the ste-

1

0a

reochemistry of compound 6 has been indicated incorrectly, we repeated its synthesis and proved

the structure 6 using X-ray diffraction analysis (Fig. 11).

15

ACCEPTED MANUSCRIPT

1

Fig. 10. Diagnostic H NMR signals (δ, ppm, J/Hz, CDCl ) of known spirooxindoles 5 and 6.

3

Fig. 11. X-ray crystal structure of compound 6 (ORTEP drawing, 50% probability level).

Nitroalkenes 1 differ significantly from β-nitrostyrenes by the presence of a bulky CX group in-

3

stead of the planar benzene ring. Probably, in our case, 1'-NO -regioisomers 4' were formed in a

2

small amount due to the unfavorable steric interactions between a large CX group and an amide

3

fragment, which are absent in the nitrostyrene molecule. In accordance with this, from the literature

10c

it is known that the introduction of the bulky methyl group into β-nitrostyrene also changes the

regioselectivity and gives adducts of type 4.

3. Conclusion

In conclusion, we have successfully developed a highly selective, one-pot and three-component

method for the synthesis of a wide range of CX -containing 3-spirooxindoles by a [3+2] cycloaddi-

3

tion of 3,3,3-trihalogen-1-nitropropenes with isatins and N-alkyl-α-amino acids (sarcosine, proline).

16

ACCEPTED MANUSCRIPT

The products constitute an important structural subunit of a variety of biologically active com-

pounds, which may be of interest for medicinal chemistry. The advantages of this reaction included

usage of readily available starting compounds, milder reaction conditions, simple separation process

and good yields.

4

. Experimental

.1. General

4

1

19

NMR spectra were recorded on Bruker DRX-400 ( H – 400 MHz, F – 376 MHz) and

1

19

13

AVANCE-500 ( H – 500 MHz, F – 471 MHz, C – 126 MHz) spectrometers in DMSO-d and

6

CDCl with TMS and C F as internal standards, respectively. IR spectra were recorded on a Ni-

3

6 6

colet 6700 instruments (FTIR mode, ZnSe crystal). Mass spectra were recorded on a Waters Xevo

Q-ToF mass spectrometer (ESI) with Acquity UPLC system and maxis mass spectrometer Impact

HD Bruker Daltonik GmbH. Melting points were determined on a Stuart SMP40 apparatus. The

starting 3,3,3-trihalogen-1-nitroprop-1-enes 1a–c were prepared according to described proce-

2

3

dures.

4.2. General procedure for the preparation of spiro[indoline-3,2'-pyrrolidin]-2-ones 3 and

spiro[indoline-3,3'-pyrrolizin]-2-ones 4 and 6

A mixture of corresponding isatin 2 (1.0 mmol) and sarcosine (0.13 g, 1.5 mmol) or prolyne

(0.17 g, 1.5 mmol) was stirred in isopropanol (4 mL), and corresponding nitroalkene 1 (1.0 mmol)

was added in one portion. The resulting mixture was stirred at reflux for 48 h and the reaction pro-

gress was monitored by TLC. Upon completion, the mixture was diluted with brine (10 mL), result-

ing precipitate was filtered off and washed with water and hexane and vacuum dried. In some cases,

additional recrystallisation from the mixture hexane/CH Cl (2 : 1) was necessary.

2

4.2.1. (3R*,3'R*,4'S*)-1'-Methyl-3'-nitro-4'-(trifluoromethyl)spiro[indoline-3,2'-pyrrolidin]-2-one

–

1

(

3a). Yield 0.28 g (89%), mp 135–136 ºC, colorless prisms. IR (ATP): 3215, 1716, 1561,1375 cm ;

1

H NMR (500 MHz, CDCl ) δ 2.16 (s, 3H, Me), 3.44 (t, J = 9.1 Hz, 1H, H-5'a), 3.59 (dd, J = 9.5,

3

7.7 Hz, 1H, H-5'b), 4.22 (sept, J = 8.0 Hz, 1H, H-4'), 5.43 (d, J = 7.7 Hz, 1H, H-3'), 6.90 (d, J = 7.8

Hz, 1H, H-7), 7.06 (td, J = 7.6, 0.8 Hz, 1H, H-5), 7.10 (dd, J = 7.6, 1.5 Hz, 1H, H-4), 7.33 (td, J =

1

9

7

.7, 1.5 Hz, 1H, H-6), 8.05 (br s, 1H, NH); F NMR (471 MHz, CDCl ) δ 91.9 (d, CF , J = 8.4 Hz,

3 3

17

ACCEPTED MANUSCRIPT

1

3

2

CF ); C NMR (126 MHz, CDCl ) δ 34.9, 44.7 (q, J = 29.9 Hz, C-4'), 51.4 (br s), 73.7, 89.0,

3

1

10.8, 122.7, 123.6, 125.0, 125.4 (q, J = 277.9 Hz, CF ), 131.1, 141.4, 176.2. HRMS (ESI): calcd

3

+

for C H F N NaO [M+Na] 338.0723, found 338.0720.

1

3

12

3

4.2.2.

(3R*,3'R*,4'S*)-5,7-Dibromo-1'-methyl-3'-nitro-4'-(trifluoromethyl)spiro[indoline-3,2'-

pyrrolidin]-2-one (3b). Yield 0.31 g (66%), mp 171–172 ºС, yellowish powder. IR (ATP): 3177,

–

1 1

1

5

7

722, 1562, 1361 cm ; H NMR (400 MHz, CDCl ) δ 2.20 (s, 3H, Me), 3.44 (t, J = 8.9 Hz, 1H, H-

3

'a), 3.56 (t, J = 8.9 Hz, 1H, H-5'b), 4.18 (sept, J = 8.0 Hz, 1H, H-4'), 5.40 (d, J = 7.8 Hz, 1H, H-3'),

1

9

.15 (d, J = 1.5 Hz, 1H, H-4/6), 7.63 (d, J = 1.5 Hz, 1H, H-6/4), 7.75 (s, 1H, NH); F NMR (376

1

3

2

MHz, CDCl ) δ 92.1 (d, J = 8.2 Hz, CF ); C NMR (126 MHz, CDCl ) δ 35.0 (s), 44.9 (q, J = 30.3

3

1

Hz, C-4'), 51.4 (q, J = 2.5 Hz), 74.6, 89.4, 104.3, 116.5, 125.0 (q, J = 278.1 Hz, CF ), 126.1, 127.0,

3

+

1

4

36.2, 140.0, 174.7. HRMS (ESI): calcd for C H Br F N NaO [M+Na] 493.8933, found

13

10

2

3

93.8930.

4.2.3. (3R*,3'R*,4'S*)-1,1'-Dimethyl-3'-nitro-4'-(trifluoromethyl)spiro[indoline-3,2'-pyrrolidin]-2-

one (3с). Yield 0.30 g (90%), (3c:3'c = 93:7), mp 133–134 ºС, colorless prisms. IR (ATP): 1716,

–

1 1

1

561, 1375 cm ; H NMR (400 MHz, CDCl ) major isomer 3c (93%): δ 2.09 (s, 3H, Me-1'), 3.25

3

(

s, 3H, Me-1), 3.43 (t, J = 8.8 Hz, 1H, H-5'a), 3.61 (dd, J = 9.4, 8.1 Hz, 1H, H-5'b), 4.22 (sept, J =

.1 Hz, 1H, H-4'), 5.39 (d, J = 7.6 Hz, 1H, H-3'), 6.86 (d, J = 7.9 Hz, 1H, H-7), 7.04–7.12 (m, 2H,

H-4, H-5), 7.38 (ddd, J = 7.8, 7.1, 1.9 Hz, 1H, H-6), minor isomer 3'c (7%): δ 2.05 (s, 3H, Me),

8

3.15 (s, 3H, Me), 3.31 (dd, J = 9.9, 2.9 Hz, 1H, H-5'a), 3.80 (t, J = 9.8 Hz, 1H, H-5'b), 5.19 (d, J =

1

9

6

.8 Hz 1H, H-3') (other signals are masked by the major isomer); F NMR (376 MHz, CDCl ) ma-

3

jor isomer 3c (93%): δ 92.1 (d, CF , J = 8.4 Hz), minor isomer 3'c (7%): δ 90.3 (d, J = 9.1 Hz, CF );

3

1

3

2

C NMR (126 MHz, CDCl ) δ 26.4, 34.8, 44.9 (q, J = 30.0 Hz, C-4'), 51.3 (q, J = 2.5 Hz), 73.2,

3

1

8

9.4, 108.7, 122.5, 123.6, 124.6, 125.3 (q, J = 277.8 Hz, CF ), 131.1, 144.4, 174.3. HRMS (ESI):

3

+

calcd for C H F N NaO [M+Na] 352.0879, found 352.0879.

1

4

14

3

4.2.4.

(3R*,3'R*,4'S*)-1'-Methyl-3'-nitro-1-pentyl-4'-(trifluoromethyl)spiro[indoline-3,2'-

pyrrolidin]-2-one (3d). Yield 0.26 g (68%), (3d:3'd = 86:14), mp 64–65 ºC, beige powder. IR

–

1 1

(

ATP): 1716, 1559, 1371 cm ; H NMR (500 MHz, CDCl ) major isomer 3d (86%): δ 0.90 (t, J =

3

6

.9 Hz, 3H, CH Me), 1.31–1.41 (m, 4H, (CH ) ), 1.75–1.59 (m, 2H, CH ), 2.09 (s, 3H, Me-1'), 3.43

2 2 2 2

(

t, J = 9.0 Hz, 1H, H-5'a), 3.60 (dd, J = 9.2, 8.0 Hz, 1H, H-5'b), 3.72 (t, J = 7.3 Hz, 2H, NCH₂),

.21 (sept, J = 8.2 Hz, 1H, H-4'), 5.39 (d, J = 7.7 Hz, 1H, H-3'), 6.86 (d, J = 7.9 Hz, 1H, H-7), 7.05

td, J = 7.5, 0.6 Hz, 1H, H-5), 7.10 (dd, J = 7.5, 1.3 Hz, 1H, H-4), 7.36 (td, J = 7.7, 1.3 Hz, 1H, H-

4

(

6

9

), minor isomer 3'd (14%): δ 0.89 (t, J = 6.9 Hz, 3H, CH Me), 2.05 (s, 3H, Me-1'), 3.31 (dd, J =

2

.8, 2.9 Hz, 1H, H-5'a), 3.66 (dt, J = 14.0, 7.4 Hz, 1H, NCHH), 3.80 (t, J = 10.0 Hz, 1H, H-5'b),

18

ACCEPTED MANUSCRIPT

5

.17 (d, 1H, J = 7.0 Hz, H-3'), 6.87 (d, J = 7.6 Hz, 1H, H-7), 7.17 (td, J = 7.6, 0.7 Hz, 1H, H-5),

1

9

7

.39 (td, J = 7.8, 1.1 Hz, 1H, H-6) (other signals are masked by the major isomer); F NMR (471

MHz, CDCl ) major isomer 3d (86%): δ 92.0 (d, J = 8.4 Hz, CF ), minor isomer 3'd (14%): δ 90.4

3

+

(

d, J = 9.1 Hz, CF ). HRMS (ESI): calcd for C H F N O [M+Na] 408.1505, found 408.1505.

3 18 22 3 3 3

4.2.5.

(3R*,3'R*,4'S*)-1-Benzyl-1'-methyl-3'-nitro-4'-(trifluoromethyl)spiro[indoline-3,2'-

pyrrolidin]-2-one (3e). Yield 0.22 g (55%), (3e:3'e = 95:5), mp 115–116 ºC, beige powder. IR

–

1 1

(

ATP): 1715, 1565, 1367 cm ; H NMR (400 MHz, CDCl ) major isomer 3e (95%): δ 2.12 (s, 3H,

3

Me), 3.46 (t, J = 9.0 Hz, 1H, H-5'a), 3.63 (dd, J = 9.3, 8.0 Hz, 1H, H-5'b), 4.24 (sept, J = 8.2 Hz,

H, H-4'), 4.92 (d, J = 15.6 Hz, 1H, CHH), 4.98 (d, J = 15.6 Hz, 1H, CHH), 5.48 (d, J = 7.8 Hz, 1H,

H-3'), 6.73 (d, J = 7.8 Hz, 1H, H-7), 7.03 (td, J = 7.5, 0.7 Hz, 1H, H-5), 7.11 (dd, J = 7.6, 1.1 Hz,

1

H, H-4), 7.23–7.37 (m, 6H, H-6, Ph), minor isomer 3'e (5%): δ 2.09 (s, 3H, Me), 3.34 (dd, J = 9.9,

.2 Hz, 1H, H-5'a), 3.84 (t, 1H, J = 9.9 Hz, H-5'b), 5.23 (d, 1H, J = 6.9 Hz, H-3') (other signals are

3

1

9

masked by the major isomer); F NMR (376 MHz, CDCl ) major isomer 3e (95%): δ 92.0 (d, J =

3

1

3

8

3

1

.3 Hz, CF ), minor isomer 3'e (5%): δ 90.4 (d, J = 9.2 Hz, CF ); C NMR (126 MHz, CDCl ) δ

3

2

4.9, 44.1, 44.8 (q, J = 30.0 Hz, C-4'), 51.5 (q, J = 2.2 Hz), 73.2, 89.3, 109.9, 122.5, 123.5, 124.7,

1

25.4 (q, J = 277.7 Hz, CF ), 127.1, 127.9, 128.9, 131.0, 135.0, 143.5, 174.5. HRMS (ESI): calcd

3

+

for C H F N NaO [M+Na] 428.1192, found 428.1197.

2

0

18

3

4.2.6. (3R*,3'R*,4'S*)-1'-Methyl-3'-nitro-4'-(trichloromethyl)spiro[indoline-3,2'-pyrrolidin]-2-one

–

1

(

3f). Yield 0.25 g (70%), mp 263–264 ºC, beige powder. IR (ATP): 3243, 1749, 1558, 1366 cm ;

1

H NMR (400 MHz, DMSO-d ) δ 1.92 (s, 3H, Me), 3.41 (dd, J = 10.3, 4.6 Hz, 1H, H-5'a), 3.59 (t, J

6

=

9.7 Hz, 1H, H-5'b), 4.87–4.95 (ddd, J = 8.8, 7.4, 4.8 Hz, 1H, H-4'), 5.35 (d, J = 7.4 Hz, 1H, H-3'),

6.89 (d, J = 7.8 Hz, 1H, H-7), 7.01 (t, J = 7.5 Hz, 1H, H-5), 7.32 (t, J = 7.6 Hz, 1H, H-6), 7.41 (d, J

1

3

=

7.5 Hz 1H, H-4), 10.88 (s, 1H, NH); C NMR (126 MHz, CDCl ) δ 35.0, 55.4, 60.9, 74.6, 91.9,

3

9

8.1, 110.4, 122.9, 123.5, 125.4, 131.1, 141.2, 175.8. HRMS (ESI): calcd for C H Cl N O

13 12 3 3 3

+

[

M+Na] 385.9836, found 385.9836.

4.2.7.

(3R*,3'R*,4'S*)-5,7-Dibromo-1'-methyl-3'-nitro-4'-(trichloromethyl)spiro[indoline-3,2'-

pyrrolidin]-2-one (3g). Yield 0.34 g (67%), mp 235–238 ºC, beige powder. IR (ATP): 3172, 1719,

–

1 1

1

5

559, 1363 cm ; H NMR (400 MHz, CDCl ) δ 2.19 (s, 3H, Me), 3.59 (dd, J = 9.5, 8.4 Hz, 1H, H-

3

'a), 3.70 (dd, J = 9.6, 7.7 Hz, 1H, H-5'b), 4.71 (q, J = 7.8 Hz, 1H, H-4'), 5.50 (d, J = 7.3 Hz, 1H,

1

3

H-3'), 7.21 (d, J = 1.6 Hz, 1H, H-4/6), 7.63 (d, J = 1.6 Hz, 1H, H-6/4), 7.69 (s, 1H, NH); C NMR

(

126 MHz, DMSO-d ) δ 34.5, 55.3, 58.0, 75.9, 91.0, 99.5, 104.0, 114.6, 124.9, 127.4, 135.7, 141.5,

6

+

1

73.6. HRMS (ESI): calcd for C H Br Cl N O [M+Na] 541.8047, found 541.8048.

1

3

10

2

3

19

ACCEPTED MANUSCRIPT

4

.2.8. (3R*,3'R*,4'S*)-1,1'-Dimethyl-3'-nitro-4'-(trichloromethyl)spiro[indoline-3,2'-pyrrolidin]-2-

–

1

one (3h). Yield 0.37 g (98%), mp 131–132 ºC, colorless prisms. IR (ATP): 1709, 1561, 1366 cm ;

1

H NMR (500 MHz, CDCl ) δ 2.09 (s, 3H, Me-1'), 3.24 (s, 3H, Me-1), 3.59 (dd, J = 9.4, 8.2 Hz,

3

1

H, H-5'a), 3.75 (dd, J = 9.4, 7.8 Hz, 1H, H-5'b), 4.75 (q, J = 7.8 Hz, 1H, H-4'), 5.48 (d, J = 7.3 Hz,

H, H-3'), 6.85 (d, J = 7.7 Hz, 1H, H-7), 7.08 (td, J = 7.6, 0.7 Hz, 1H, H-5), 7.16 (dd, J = 7.5, 1.2

1

3

Hz, 1H, H-4), 7.38 (td, J = 7.7, 1.2 Hz, 1H, H-6); C NMR (126 MHz, CDCl ) δ 26.3, 34.8, 55.2,

3

61.1, 74.2, 92.2, 98.0, 108.6, 122.7, 123.5, 124.9, 131.1, 144.3, 174.5. HRMS (ESI): calcd for

+

C H Cl N O [M+Na] 399.9993, found 399.9991.

14

3

4.2.9.

(3R*,3'R*,4'S*)-1'-Methyl-3'-nitro-1-pentyl-4'-(trichloromethyl)spiro[indoline-3,2'-

pyrrolidin]-2-one (3i). Yield 0.34 g (79%), mp 104–105 ºC, beige powder. IR (ATP): 1706, 1561,

–

1 1

1

359 cm ; H NMR (400 MHz, CDCl ) δ 0.90 (t, J = 6.7 Hz, 3H, CH Me), 1.29–1.42 (m, 4H,

3

2

(

CH ) ), 1.63–1.74 (m, 2H, CH ), 2.10 (s, 3H, Me-1'), 3.60 (t, J = 8.9 Hz, 1H, H-5'a), 3.69–3.77 (m,

2 2 2

3

H, H-5'b, NCH ), 4.76 (q, J = 7.6 Hz, 1H, H-4'), 5.48 (d, J = 7.3 Hz, 1H, H-3'), 6.86 (d, J = 7.8

2

Hz, 1H, H-7), 7.07 (t, J = 7.6 Hz, 1H, H-5), 7.18 (d, J = 7.5 Hz, 1H, H-4), 7.36 (t, J = 7.6 Hz, 1H,

1

3

H-6); C NMR (126 MHz, CDCl ) δ 13.9, 22.3, 26.9, 28.9, 34.9, 40.3, 55.3, 60.9, 74.2, 92.1, 98.1,

3

+

108.9, 122.7, 123.2, 125.1, 131.0, 143.7, 174.2. HRMS (ESI): calcd for C H Cl N O [M+H]

18 23 3 3 3

434.0800, found 434.0807.

4.2.10. (3R*,3'R*,4'S*)-1-Benzyl-1'-methyl-3'-nitro-4'-(trichloromethyl)spiro[indoline-3,2'-

pyrrolidin]-2-one (3j). Yield 0.32 g (71%), mp 182–184 ºC, beige powder. IR (ATP): 1705, 1563,

–

1 1

1

366 cm ; H NMR (500 MHz, CDCl ) δ 2.12 (s, 3H, Me), 3.61 (dd, J = 9.6, 8.2 Hz, 1H, H-5'a),

3

3.76 (dd, J = 9.6, 7.4 Hz, 1H, H-5'b), 4.77 (q, J = 7.6 Hz, 1H, H-4'), 4.91 (d, J = 15.7 Hz, 1H,

CHH), 4.97 (d, J = 15.7 Hz, 1H, CHH), 5.57 (d, J = 7.3 Hz, 1H, H-3'), 6.73 (d, J = 7.9 Hz, 1H, H-

13

7

), 7.04 (t, J = 7.6 Hz, 1H, H-5), 7.17 (d, J = 7.2 Hz, 1H, H-4), 7.23–7.35 (m, 6H, H-6, Ph); C

NMR (126 MHz, CDCl ) δ 35.0, 44.1, 55.4, 60.9, 74.3, 92.1, 98.1, 109.8, 122.6, 123.5, 125.0,

3

+

127.1, 127.9, 128.9, 131.0, 135.0, 143.4, 174.6. HRMS (ESI): calcd. for C H Cl N O [M+Na]

20 18 3 3 3

476.0306, found 476.0307.

4.2.11. (3R*,3'R*,4'S*)-1'-Methyl-3'-nitro-4'-(tribromomethyl)spiro[indoline-3,2'-pyrrolidin]-2-one

–

1

(

3k). Yield 0.34 g (69%), mp 244–245 ºC, white powder. IR (ATP): 3249, 1748, 1554, 1363 cm ;

1

H NMR (500 MHz, DMSO-d ) δ 1.92 (s, 3H, Me), 3.30 (dd, J = 10.4, 4.6 Hz, 1H, H-5'a), 3.59 (t, J

6

=

9.6 Hz, 1H, H-5'b), 4.90 (ddd, J = 8.8, 7.3, 4.6 Hz, 1H, H-4'), 5.20 (d, J = 7.3 Hz, 1H, H-3'), 6.88

(d, J = 7.8 Hz, 1H, H-7), 7.01 (t, J = 7.5 Hz, 1H, H-5), 7.31 (t, J = 7.6 Hz, 1H, H-6), 7.43 (d, J = 7.5

1

3

Hz, 1H, H-4), 10.86 (s, 1H, NH); C NMR (126 MHz, DMSO-d ) δ 34.5, 42.0, 57.2, 60.6, 75.2,

6

20

ACCEPTED MANUSCRIPT

9

2.5, 110.4, 121.7, 122.0, 125.9, 130.8, 142.5, 174.2. HRMS (ESI): calcd for C H Br N O

13 12 3 3 3

+

[

M+H] 499.8466, found 499.8472.

4.2.12. (3R*,3'R*,4'S*)-1,1'-Dimethyl-3'-nitro-4'-(tribromomethyl)spiro[indoline-3,2'-pyrrolidin]-

–1

2

-one (3l). Yield 0.33 g (65%), mp 193–194 ºC, beige powder. IR (ATP): 1721, 1552, 1367 cm ;

1

H NMR (400 MHz, CDCl ) δ 2.09 (s, 3H, Me-1'), 3.24 (s, 3H, Me-1), 3.63–3.73 (m, 2H, CH ),

3

2

4.89 (q, J = 7.5 Hz, 1H, H-4'), 5.37 (d, J = 7.2 Hz, 1H, H-3'), 6.85 (d, J = 7.9 Hz, 1H, H-7), 7.09 (td,

1

3

J = 7.5, 0.9 Hz, 1H, H-5), 7.18 (d, J = 7.5 Hz, 1H, H-4), 7.39 (td, J = 7.7, 1.0 Hz, 1H, H-6); C

NMR (126 MHz, CDCl ) δ 26.3, 34.9, 38.6, 57.4, 63.3, 74.6, 93.4, 108.6, 122.8, 123.5, 125.0,

3

+

1

31.1, 144.2, 174.4. HRMS (ESI): calcd for C H Br N O [M+H] 509.8663, found 509.8648.

1

4

15

3

4.2.13.

(3R*,3'R*,4'S*)-1'-Methyl-3'-nitro-1-pentyl-4'-(tribromomethyl)spiro[indoline-3,2'-

pyrrolidin]-2-one (3m). Yield 0.38 g (66%), mp 176–177 ºC, beige powder. IR (ATP): 1698, 1560,

–

1 1

1

357 cm ; H NMR (400 MHz, CDCl ) δ 0.90 (t, J = 7.0 Hz, 3H, CH Me), 1.41–1.32 (m, 4H,

3

2

(

CH ) ), 1.74–1.64 (m, 2H, CH ), 2.09 (s, 3H, Me), 3.66 (d, J = 7.2 Hz, 2H, CH ), 3.68‒3.77 (m,

2 2 2 2

2

H, NCH ), 4.89 (q, J = 7.5 Hz, 1H, H-4'), 5.37 (d, J = 7.2 Hz, 1H, H-3'), 6.85 (d, J = 7.9 Hz, 1H,

2

H-7), 7.07 (td, J = 7.5, 0.5 Hz, 1H, H-5), 7.18 (dd, J = 7.5, 1.2 Hz, 1H, H-4), 7.37 (td, J = 7.7, 1.2

13

Hz, 1H, H-6); C NMR (126 MHz, CDCl ) δ 13.9, 22.3, 26.9, 28.9, 34.9, 39.0, 40.3, 57.6, 63.1,

3

7

4.6, 93.3, 108.9, 122.8, 123.2, 125.1, 131.0, 143.7, 174.2. HRMS (ESI): calcd for C H Br N O

18 22 3 3 3

+

[

M+H] 567.9290, found 567.9227.

4.2.14.

(3R*,3'R*,4'S*)-1-Benzyl-1'-methyl-3'-nitro-4'-(tribromomethyl)spiro[indoline-3,2'-

pyrrolidin]-2-one (3n). Yield 0.35 g (59%), mp 196–197 ºC, beige powder. IR (ATP): 1699, 1559,

–

1 1

1

345 cm ; H NMR (500 MHz, CDCl ) δ 2.12 (s, 3H, Me), 3.65–3.72 (m, 2H, CH ), 4.91 (q, J =

3 2

7.6 Hz, 1H, H-4'), 4.91 (d, J = 15.7 Hz, 1H, CHH), 4.98 (d, J = 15.7 Hz, 1H, CHH), 5.45 (d, J = 7.2

Hz, 1H, H-3'), 6.73 (d, J = 7.8 Hz, 1H, H-7), 7.05 (td, J = 7.7, 0.6 Hz, 1H, H-5), 7.19 (d, J = 7.5 Hz,

13

1

H, H-4), 7.23–7.36 (m, 6H, H-6, Ph); C NMR (126 MHz, CDCl ) δ 35.0, 44.1, 57.6, 63.0, 74.8,

3

77.2, 93.3, 109.8, 122.6, 123.4, 125.1, 127.2, 127.9, 128.9, 131.0, 135.0, 143.3, 174.5. HRMS

+

(

ESI): calcd for C H Br N O [M+H] 585.8977, found 585.9008.

2

0

18

3

4.2.15. (1'R*,2'S*,3S*,7a'R*)-2'-Nitro-1'-(trifluoromethyl)-1',2',5',6',7',7a'-hexahydrospiro[indol-

ine-3,3'-pyrrolizin]-2-one (4a). Yield 0.29 g (85%), mp 179–180 ºC, colorless prisms. IR (ATP):

–

1 1

3

299 1747, 1559, 1361 cm ; H NMR (500 MHz, CDCl ) δ 1.75–2.34 (m, 4H, 2CH ), 2.61–2.75

3 2

(

m, 2H, NCH ), 3.74–3.84 (m, 1H, H-1'), 4.19 (q, J = 7.6 Hz, 1H, H-7'a), 5.68 (d, J = 10.1 Hz, 1H,

2

H-2'), 6.92 (d, J = 7.8 Hz, 1H, H-7), 7.06 (t, J = 7.5 Hz, 1H, H-5), 7.11 (d, J = 7.5 Hz, 1H, H-4),

1

9

7

.33 (t, J = 7.7 Hz, 1H, H-6), 8.28 (s, 1H, NH); F NMR (471 MHz, CDCl ) δ 93.2 (d, J = 7.3 Hz,

3

21

ACCEPTED MANUSCRIPT

13

2

CF ); C NMR (126 MHz, CDCl ) δ 27.2, 31.8, 47.4, 50.6 (q, J = 28.3 Hz, C-1'), 63.4 (q, J = 2.7

3

1

Hz), 73.2, 91.0, 111.1, 122.1, 123.0, 125.2 (q, J = 278.7 Hz, CF ), 125.9, 131.3, 141.6, 177.2.

3

+

HRMS (ESI): calcd for C H F N O [M+H] 342.1060, found 342.1058.

1

5

15

3

4.2.16.

(1'S*,2'R*,3R*,7a'S*)-2',5-Dinitro-1'-(trifluoromethyl)-1',2',5',6',7',7a'-hexahydrospiro-

[

indoline-3,3'-pyrrolizin]-2-one (4b). Yield 0.25 g (60%), mp 233–234 ºC, orange powder. IR

–1 1

(

ATP): 3156, 1747, 1563, 1341 cm ; H NMR (500 MHz, DMSO-d ) δ 1.67–2.09 (m, 4H, 2CH ),

6 2

2

.43–2.52 (m, 2H, NCH ), 3.93 (dt, J = 8.7, 7.1 Hz, 1H, H-7'a), 4.68–4.78 (m, 1H, H-1'), 5.79 (d, J

2

=

10.7 Hz, 1H, H-2'), 7.11 (d, J = 9.3 Hz, 1H, H-7), 8.26–8.31 (m, 2H, H-4, H-6), 11.54 (s, 1H,

1

9

13

NH); F NMR (471 MHz, DMSO-d ) δ 95.2 (d, J = 7.6 Hz, CF ); C NMR (126 MHz, DMSO-d )

6

3

6

2

δ 26.9, 30.1, 47.1, 47.6 (q, J = 27.3 Hz, C-1'), 63.3 (br s), 72.3, 90.2, 110.9, 121.8, 123.0, 125.5 (q,

1

+

J = 278.6 Hz, CF ), 128.2, 142.4, 149.2, 176.8. HRMS (ESI): calcd for C H F N NaO [M+Na]

3

15 13

3

4

5

409.0730, found 409.0729.

4.2.17.

(1'S*,2'R*,3R*,7a'S*)-5,7-Dibromo-2'-nitro-1'-(trifluoromethyl)-1',2',5',6',7',7a'-hexa-

hydrospiro[indoline-3,3'-pyrrolizin]-2-one (4c). Yield 0.31 g (62%), mp 204–205 ºC, beige powder.

–1

1

IR (ATP): 3159, 1719, 1563, 1364 cm ; H NMR (400 MHz, DMSO-d ) δ 1.69–2.07 (m, 4H,

6

2

CH ), 2.28–2.53 (m, 2H, NCH ), 3.87 (q, J = 7.7 Hz, 1H, H-7'a), 4.54–4.68 (m, 1H, H-1'), 5.75 (d,

2 2

J = 10.9 Hz, 1H, H-2'), 7.76 (d, J = 1.4 Hz, 1H, H-4/6), 7.82 (d, J = 1.4 Hz, 1H, H-6/4), 11.26 (s,

1

9

1

H, NH); F NMR (376 MHz, DMSO-d ) δ 95.1 (d, J = 7.4 Hz, CF ). HRMS (ESI): calcd for

6

3

+

C H Br F N O [M+H] 499.9255, found 499.9255.

15

13

2

3

4

.2.18.

(1'S*,2'R*,3R*,7a'S*)-1-Methyl-2'-nitro-1'-(trifluoromethyl)-1',2',5',6',7',7a'-hexahydro-

(4d) and 1-methyl-1'-nitro-2'-(trifluoromethyl)-

',2',5',6',7',7a'-hexahydrospiro[indoline-3,3'-pyrrolizin]-2-one (4'd). Yield 0.22 g (62%), (4d:4'd

spiro[indoline-3,3'-pyrrolizin]-2-one

1

–1 1

=

89:11), mp 173–174 ºC, beige powder. IR (ATP): 1724, 1559, 1375 cm ; H NMR (500 MHz,

CDCl ) major isomer 4d (89%): δ 1.78–2.32 (m, 4H, 2CH ), 2.63–2.73 (m, 2H, NCH ), 3.24 (s, 3H,

3

2

Me), 3.78 (tq, J = 9.3, 7.5 Hz, 1H, H-1'), 4.25 (dt, J = 9.0, 6.8 Hz, 1H, H-7'a), 5.63 (d, J = 9.7 Hz,

1

4

3

1

5

H, H-2'), 6.86 (d, J = 7.8 Hz, 1H, H-7), 7.07 (t, J = 7.2 Hz, 1H, H-5), 7.13 (d, J = 6.9 Hz, 1H, H-

), 7.39 (td, J = 7.6, 1.2 Hz, 1H, H-6), minor isomer 4'd (11%): δ 1.37–2.20 (m, 4H, 2CH ), 2.75–

2

.06 (m, 2H, NCH ), 3.19 (s, 3H, Me), 4.35 (quint, J = 8.6 Hz, 1H, H-2'), 4.91 (td, J = 8.9, 6.1 Hz,

2

H, H-7'a), 5.96 (t, J = 9.2 Hz, 1H, H-1'), 6.87 (d, J = 7.8 Hz, 1H, H-7), 7.14 (t, J = 7.2 Hz, 1H, H-

1

9

) 7.42 (td, J = 7.6, 1.0 Hz, 1H, H-6), 7.47 (d, J = 6.9 Hz, 1H, H-4); F NMR (471 MHz, CDCl )

3

major isomer 4d (89%): δ 93.4 (d, J = 7.5 Hz, CF ), minor isomer 4'd (11%): δ 97.4 (d, J = 8.5 Hz,

3

+

CF ). HRMS (ESI): calcd for C H F N NaO [M+Na] 378.1036, found 378.1039.

3

16 16

3

22

ACCEPTED MANUSCRIPT

4.2.19.

(1'S*,2'R*,3R*,7a'S*)-2'-Nitro-1-pentyl-1'-(trifluoromethyl)-1',2',5',6',7',7a'-hexahydro-

spiro[indoline-3,3'-pyrrolizin]-2-one (4e). Yield 0.24 mg (59%), mp 73–74 ºC, beige powder. IR

–

1 1

(

ATP): 1731, 1556, 1364 cm ; H NMR (500 MHz, CDCl ) δ 0.90 (t, J = 7.0 Hz, 3H, CH Me),

3

2

1

.28–1.43 (m, 4H, 2CH ), 1.62–1.73 (m, 2H, NCH ), 1.74–2.31 (m, 4H, 2CH ), 2.57–2.67 (m, 2H,

2 2 2

NCH ), 3.63–3.82 (m, 3H, NCH , H-1'), 4.20 (td, J = 8.5, 7.2 Hz, 1H, H-7'a), 5.65 (d, J = 10.1 Hz,

2

1H, H-2'), 6.87 (d, J = 7.9 Hz, 1H, H-7), 7.05 (t, J = 7.5 Hz, 1H, H-5), 7.11 (d, J = 7.5 Hz, 1H, H-

1

9

13

4

), 7.36 (td, J = 7.7, 1.1 Hz, 1H, H-6); F NMR (471 MHz, CDCl ) δ 93.2 (d, J = 7.3 Hz, CF ); C

3

2

NMR (126 MHz, CDCl ) δ 13.9, 22.3, 26.8, 27.2, 28.9, 31.7, 40.5, 47.2, 50.6 (q, J = 28.2 Hz, C-

3

1

'), 63,3 (q, J = 2.3 Hz), 72.6, 91.1, 109.4, 121.9, 122.6, 125.4 (q, J = 278.3 Hz, CF ), 125.7, 131.1,

3

+

44.1, 175.2. HRMS (ESI): calcd for C H F N NaO [M+Na] 434.1662, found 434.1660.

2

0

24

3

4.2.20.

(1'S*,2'R*,3R*,7a'S*)-1-Benzyl-2'-nitro-1'-(trifluoromethyl)-1',2',5',6',7',7a'-hexahydro-

spiro[indoline-3,3'-pyrrolizin]-2-one (4f) and 1-benzyl-1'-nitro-2'-(trifluoromethyl)-1',2',5',6',7',7a'-

hexahydrospiro[indoline-3,3'-pyrrolizin]-2-one (4'f). Yield 0.35 g (81%), (4f:4'f = 91:9), mp 149–

–

1 1

1

50 ºC, beige powder. IR (ATP): 1720, 1563, 1366 cm ; H NMR (400 MHz, DMSO-d ) major

6

isomer 4f (91%): δ 1.67–2.12 (m, 4H, 2CH ), 2.30–2.53 (m, 2H, NCH ), 3.95 (q, J = 7.8 Hz, 1H, H-

2

7'a), 4.42–4.54 (m, 1H, H-1'), 4.92 (d, J = 15.9 Hz, 1H, CHH), 4.98 (d, J = 15.9 Hz, 1H, CHH),

5.81 (d, J = 10.7 Hz, 1H, H-2'), 6.94 (d, J = 7.9 Hz, 1H, H-7), 7.06 (t, J = 7.6 Hz, 1H, H-5), 7.23–

7.36 (m, 6H, H-6, Ph), 7.52 (d, J = 7.4 Hz, 1H, H-4), minor isomer 4'f (9%): δ 6.12 (t, J = 9.9 Hz,

1H, H-1'), 6.96 (d, J = 7.9 Hz, 1H, H-7), 7.11 (td, J = 7.7, 1.0 Hz, 1H, H-5), 7.96 (d, J = 7.4 Hz, 1H,

1

9

H-4) (other signals are masked by the major isomer); F NMR (471 MHz, CDCl ) major isomer 4f

3

(91%): δ 93.2 (d, J = 7.3 Hz, CF ), minor isomer 4'f (9%): δ 97.7 (d, J = 8.4 Hz, CF ). HRMS

3 3

+

(

ESI): calcd for C H F N NaO [M+Na] 454.1349, found 454.1346.

2

20

3

4.2.21. (1'S*,2'R*,3R*,7a'S*)-2'-Nitro-1'-(trichloromethyl)-1',2',5',6',7',7a'-hexahydrospiro[indol-

ine-3,3'-pyrrolizin]-2-one (4g). Yield 0.27 g (71%), mp 263–264 ºC, white powder. IR (ATP):

–

1 1

1

742, 1563, 1366, 3162 cm ; H NMR (500 MHz, CDCl ) δ 1.85–2.43 (m, 4H, 2CH ), 2.61–2.73

3 2

(

m, 2H, NCH ), 4.26 (q, J = 7.2 Hz, 1H, H-7'a), 4.38 (t, J = 7.9 Hz, 1H, H-1'), 5.80 (d, J = 8.5 Hz,

2

1

4

6

H, H-2'), 6.89 (d, J = 7.8 Hz, 1H, H-7), 7.07 (t, J = 7.6 Hz, 1H, H-5), 7.18 (d, J = 7.6 Hz, 1H, H-

1

3

), 7.32 (t, J = 7.7 Hz, 1H, H-6), 8.04 (s, 1H, NH); C NMR (126 MHz, CDCl ) δ 27.1, 32.7, 46.6,

3

5.7, 67.6, 73.1, 95.1, 98.2, 110.8, 122.7, 123.1, 126.2, 131.2, 141.5, 177.0. HRMS (ESI): calcd for

+

C H Cl N NaO [M+Na] 411.9993, found 411.9990.

15

14

3

4.2.22.

(1'S*,2'R*,3R*,7a'S*)-2',5-Dinitro-1'-(trichloromethyl)-1',2',5',6',7',7a'-hexahydro-

spiro[indoline-3,3'-pyrrolizin]-2-one (4h). Yield 0.26 mg (63%), mp 250 ºC (dec.), beige powder.

–1

1

IR (ATP): 1340, 1558, 1723, 3140 cm ; H NMR (400 MHz, DMSO-d ) δ 1.71–2.24 (m, 4H,

6

23

ACCEPTED MANUSCRIPT

2

CH ), 2.42–2.54 (m, 2H, NCH ), 4.00 (q, J = 7.3 Hz, 1H, H-7'a), 5.02 (dd, J = 9.3, 7.3 Hz, 1H, H-

2 2

1

'), 5.70 (d, J = 9.3 Hz, 1H, H-2'), 7.10 (d, J = 8.6 Hz, 1H, H-7), 8.27 (d, J = 2.3 Hz, 1H, H-4), 8.30

1

3

(

dd, J = 8.6, 2.3 Hz, 1H, H-6), 11.54 (s, 1H, NH); C NMR (126 MHz, DMSO-d ) δ 26.8, 31.3,

6

46.3, 62.8, 67.5, 72.4, 94.4, 98.5, 110.9, 122.3, 123.1, 128.2, 142.5, 149.1, 176.5. HRMS (ESI):

+

calcd for C H Cl N O [M+Na] 456.9844, found 456.9844.

1

5

13

3

4

5

4.2.23.

(1'S*,2'R*,3R*,7a'S*)-5,7-Dibromo-2'-nitro-1'-(trichloromethyl)-1',2',5',6',7',7a'-hexa-

hydrospiro[indoline-3,3'-pyrrolizin]-2-one (4i). Yield 0.44 g (81%), mp 244–245 ºC, yellow pow-

–1 1

der. IR (ATP): 1361, 1553, 1725, 3153 cm ; H NMR (500 MHz, DMSO-d ) δ 1.71–2.22 (m, 4H,

6

2CH ), 2.32–2.54 (m, 2H, NCH ), 3.92 (dt, J = 8.7, 6.9 Hz, 1H, H-7'a), 4.99 (dd, J = 9.7, 6.9 Hz,

2 2

1H, H-1'), 5.64 (d, J = 9.7 Hz, 1H, H-2'), 7.78 (d, J = 1.7 Hz, 1H, H-4/6), 7.82 (d, J = 1.7 Hz, 1H,

1

3

H-6/4), 11.30 (s, 1H, NH); C NMR (126 MHz, DMSO-d ) δ 27.0, 31.5, 46.3, 61.8, 68.0, 74.2,

6

93.8, 98.7, 103.9, 114.4, 125.8, 128.7, 135.9, 141.7, 175.6. HRMS (ESI): calcd for

+

C H Br Cl N O [M+H] 549.8339, found 549.8345.

15

13

2

3

4

.2.24.

(1'S*,2'R*,3R*,7a'S*)-1-Methyl-2'-nitro-1'-(trichloromethyl)-1',2',5',6',7',7a'-hexahydro-

(4j) and 1-methyl-1'-nitro-2'-(trichloromethyl)-

',2',5',6',7',7a'-hexahydrospiro[indoline-3,3'-pyrrolizin]-2-one (4'j). Yield 0.23 g (56%), (4j:4'j =

spiro[indoline-3,3'-pyrrolizin]-2-one

1

–

1

9

3:7), mp 157–158 ºC, beige powder. IR (ATP): 1373, 1559, 1724 cm ; H NMR (500 MHz,

CDCl ) major isomer 4j (93%): δ 1.84–2.42 (m, 4H, 2CH ), 2.58–2.74 (m, 2H, NCH ), 3.23 (s, 3H,

3

2

Me), 4.33 (dt, J = 7.5, 6.8 Hz, 1H, H-7'a), 4.36 (t, J = 7.8 Hz, 1H, H-1'), 5.74 (d, J = 7.9 Hz, 1H, H-

2'), 6.85 (d, J = 7.9 Hz, 1H, H-7), 7.08 (td, J = 7.6, 0.8 Hz, 1H, H-5), 7.19 (d, J = 6.9 Hz, 1H, H-4),

7.38 (td, J = 7.8, 1.1 Hz, 1H, H-6), minor isomer 4'j (7%): δ 3.20 (s, 3H, Me), 5.00–5.06 (m, 2H, H-

7'a), 5.02 (d, J = 7.3 Hz, 1H, H-2'), 5.81 (dd, J = 8.5, 7.3 Hz, 1H, H-1'), 6.83 (d, J = 7.9 Hz, 1H,

Ar), 7.13 (td, Ar, J = 7.6, 0.9 Hz, 1H, H-5), 7.57 (d, J = 7.7 Hz, 1H, H-4) (other signals are masked

1

3

by the major isomer); C NMR (126 MHz, CDCl ) δ 26.5, 26.9, 32.1, 46.7, 66.4, 67.0, 72.0, 95.8,

3

9

8.0, 108.8, 122.4, 123.1, 125.7, 131.1, 144.5, 175.3. HRMS (ESI): calcd for C H Cl N O

16 16 3 3 3

+

[

M+Na] 426.0149, found 426.0147.

4.2.25.

(1'S*,2'R*,3R*,7a'S*)-2'-Nitro-1-pentyl-1'-(trichloromethyl)-1',2',5',6',7',7a'-hexahydro-

spiro[indoline-3,3'-pyrrolizin]-2-one (4k). Yield 0.25 g (57%), mp 99–100 ºC, beige powder. IR

–1 1

(

ATP): 1361, 1555, 1732 cm ; H NMR (500 MHz, CDCl ) δ 0.89 (t, J = 7.0 Hz, 3H, Me), 1.27–

3

2

8

7

.65 (m, 12H, 6CH ), 3.65–3.76 (m, 2H, NCH ), 4.27 (dt, J = 7.5, 6.5 Hz, 1H, H-7'a), 4.36 (dd, J =

2 2

.5, 7.5 Hz, 1H, H-1'), 5.76 (d, J = 8.5 Hz, 1H, H-2'), 6.85 (d, J = 7.9 Hz, 1H, H-7), 7.06 (td, J =

1

3

.5, 0.8 Hz, 1H, H-5), 7.18 (dd, J = 7.5, 1.2 Hz, 1H, H-4), 7.36 (td, J = 7.7, 1.2 Hz, 1H, H-6); C

NMR (126 MHz, CDCl ): δ 13.9, 22.3, 26.8, 27.1, 28.9, 32.4, 40.4, 46.3, 65.8, 67.4, 72.4, 95.4,

3

24

ACCEPTED MANUSCRIPT

9

8.2, 109.1, 122.6, 122.7, 125.9, 131.0, 144.0, 175.2. HRMS (ESI): calcd for C H Cl N O

20 24 3 3 3

+

[

M+Na] 482.0775, found 482.0775.

4.2.26.

(1'S*,2'R*,3R*,7a'S*)-1-Benzyl-2'-nitro-1'-(trichloromethyl)-1',2',5',6',7',7a'-hexahydro-

spiro[indoline-3,3'-pyrrolizin]-2-one (4l). Yield 0.33 g (70%), mp 217–218 ºC, beige powder. IR

–

1 1

(

ATP): 1364, 1556, 1730 cm ; H NMR (500 MHz, CDCl ) δ 1.86–2.42 (m, 4H, 2CH ), 2.56–2.70

3 2

(

m, 2H, NCH ), 4.29 (dt, J = 7.5, 7.0 Hz, 1H, H-7'a), 4.40 (dd, J = 8.5, 7.5 Hz, 1H, H-1'), 4.94 (s,

2

5

3

1

H, CH -1), 5.86 (d, J = 8.5 Hz, 1H, H-2'), 6.70 (d, J = 7.9 Hz, 1H, H-7), 7.04 (t, J = 7.5 Hz, 1H, H-

2

13

), 7.19 (d, J = 7.4 Hz, 1H, Ar), 7.36–7.22 (m, 6H, H-6, Ph); C NMR (126 MHz, CDCl ) δ 27.1,

3

2.5, 44.1, 46.4, 65.7, 67.6, 72.6, 95.3, 98.2, 110.0, 122.4, 123.0, 125.8, 127.0, 127.8, 128.9, 131.0,

+

35.0, 143.6, 175.6. HRMS (ESI): calcd for C H Cl N O [M+Na] 502.0462, found 502.0457.

2

20

3

4.2.27.

(1'S*,2'R*,3R*,7a'S*)-2'-nitro-1'-(tribromomethyl)-1',2',5',6',7',7a'-hexahydrospiro-

[

indoline-3,3'-pyrrolizin]-2-one (4m). Yield 0.39 g (74%), mp 235 ºC (dec.), white powder. IR

–1 1

(

ATP): 1361, 1554, 1742, 3180 cm ; H NMR (400 MHz, DMSO-d ) δ 1.65–2.56 (m, 6H, 3CH ),

6 2

3.80 (dt, J = 9.0, 6.2 Hz, 1H, H-7'a), 4.59 (dd, J = 9.0, 6.2 Hz, 1H, H-1'), 5.50 (d, J = 9.0 Hz, 1H,

H-2'), 6.85 (d, J = 7.7 Hz, 1H, H-7), 7.02 (td, J = 7.6, 0.8 Hz, 1H, H-5), 7.31 (td, J = 7.7, 1.0 Hz,

1

3

1

3

H, H-6), 7.42 (d, J = 7.5 Hz, 1H, H-4), 10.75 (s, 1H, NH); C NMR (126 MHz, DMSO-d ) δ 26.6,

6

2.5, 41.1, 46.4, 64.9, 70.0, 73.9, 95.4, 110.3, 121.9, 122.4, 126.9, 130.9, 142.8, 175.8. HRMS

+

(

ESI): calcd for C H Br N O [M+H] 521.8663, found 521.8645.

1

5

14

3

4.2.28.

(1'S*,2'R*,3R*,7a'S*)-2',5-Dinitro-1'-(tribromomethyl)-1',2',5',6',7',7a'-hexahydro-

spiro[indoline-3,3'-pyrrolizin]-2-one (4n). Yield 0.34 g (59%), mp 250 ºC (dec), beige powder. IR

–1 1

(

ATP): 1340, 1560, 1757, 3150 cm ; H NMR (400 MHz, DMSO-d ) δ 1.69–2.35 (m, 4H, 2CH ),

6 2

2

.36–2.56 (m, 2H, NCH ), 3.85 (dt, J = 8.4, 6.6 Hz, 1H, H-7'a), 4.88 (dd, J = 8.9, 6.6 Hz, 1H, H-1'),

2

5.57 (d, J = 9.0 Hz, 1H, H-2'), 7.09 (d, J = 8.7 Hz, 1H, H-7), 8.24 (d, J = 2.2 Hz, 1H, H-4), 8.29 (dd,

13

J = 8.7, 2.2 Hz, 1H, H-6), 11.52 (s, 1H, NH); C NMR (126 MHz, DMSO-d ) δ 26.7, 32.0, 40.5,

6

46.2, 64.2, 69.9, 72.9, 96.0, 110.9, 122.3, 123.4, 128.2, 142.5, 149.1, 176.4. HRMS (ESI): calcd for

+

C H Br N O [M+H] 566.8514, found 566.8521.

15

13

3

4

5

4.2.29.

(1'S*,2'R*,3R*,7a'S*)-5,7-Dibromo-2'-nitro-1'-(tribromomethyl)-1',2',5',6',7',7a'-hexa-

hydrospiro[indoline-3,3'-pyrrolizin]-2-one (4o). Yield 0.37 g (55%), mp 239–240 ºC, yellow

–1 1

powder. IR (ATP): 1361, 1552, 1723, 3157 cm ; H NMR (500 MHz, DMSO-d ) δ 1.70–2.26 (m,

6

4

H, 2CH ), 2.28–2.55 (m, 2H, NCH ), 3.76 (dt, J = 8.0, 6.3 Hz, 1H, H-7'a), 4.88 (dd, J = 9.3, 6.3

2 2

Hz, 1H, H-1'), 5.53 (d, J = 9.3 Hz, 1H, H-2'), 7.77 (d, J = 1.7 Hz, 1H, H-4/6), 7.82 (d, J = 1.7 Hz,

1

3

1

H, H-6/4), 11.28 (s, 1H, NH); C NMR (126 MHz, DMSO-d ) δ 26.9, 32.0, 41.0, 46.3, 63.3, 70.4,

6

25

ACCEPTED MANUSCRIPT

7

4.7, 95.5, 103.8, 114.4, 126.1, 128.8, 135.8, 141.7, 175.6. HRMS (ESI): calcd for C H Br N O

15 13 5 3 3

+

[

M+H] 683.6812, found 683.6834.

4

.2.30.

(1'S*,2'R*,3R*,7a'S*)-1-Methyl-2'-nitro-1'-(tribromomethyl)-1',2',5',6',7',7a'-hexahydro-

(4p) and 1-methyl-1'-nitro-2'-(tribromomethyl)-

',2',5',6',7',7a'-hexahydrospiro[indoline-3,3'-pyrrolizin]-2-one (4'p). Yield 0.39 g (72%), (4p:4'p

spiro[indoline-3,3'-pyrrolizin]-2-one

1

–1 1

=

91:9), mp 160–161 ºC, beige powder. IR (ATP): 1374, 1558, 1729 cm ; H NMR (500 MHz,

CDCl ) major isomer 4p (91%): δ 1.82–2.09 (m, 4H, 2CH ), 2.57–2.69 (m, 2H, NCH ), 3.23 (s, 3H,

3

2

Me), 4.19 (dt, J = 8.1, 6.8 Hz, 1H, H-7'a), 4.48 (dd, J = 8.1, 7.0 Hz, 1H, H-1'), 5.65 (d, J = 8.0 Hz,

H, H-2'), 6.85 (d, J = 7.8 Hz, 1H, H-7), 7.08 (td, J = 7.6, 0.8 Hz 1H, H-5), 7.20 (d, J = 7.7 Hz, 1H,

H-4), 7.38 (td, J = 7.8, 1.0, Hz 1H, H-6), minor isomer 4'p (9%): δ 3.21 (s, 3H, Me), 5.01 (dt, J =

.9, 6.5 Hz, 1H, H-7'a), 5.26 (d, J = 6.0 Hz, 1H, H-2'), 5.68 (dd, J = 7.9, 6.0 Hz, 1H, H-1'), 6.81 (d,

1

7

J = 8.0 Hz, 1H, Ar), 7.15 (t, J = 7.3 Hz, 1H, Ar), 7.62 (d, J = 7.5 Hz, 1H, Ar) (other signals are

+

masked by the major isomer). HRMS (ESI): calcd for C H Br N O [M+H] 535.8820, found

1

6

16

3

353.8838.

4.2.31.

(1'S*,2'R*,3R*,7a'S*)-1-Benzyl-2'-nitro-1'-(tribromomethyl)-1',2',5',6',7',7a'-hexahydro-

spiro[indoline-3,3'-pyrrolizin]-2-one (4q). Yield 0.31 g (51%), mp 185–187 ºC, beige powder. IR

–1 1

(

ATP): 1365, 1553, 1720 cm ; H NMR (400 MHz, CDCl ) δ 1.85–2.73 (m, 6H, 3CH ), 4.16 (dt, J

3 2

=

8.1, 6.5 Hz, 1H, H-7'a), 4.52 (dd, J = 8.1, 6.6 Hz, 1H, H-1'), 4.93 (d, J = 16.0 Hz, 1H, CHH), 4.97

(d, J = 16.0 Hz, 1H, CHH), 5.77 (d, J = 8.2 Hz, 1H, H-2'), 6.70 (d, J = 7.8 Hz, 1H, H-7), 7.04 (td, J

1

3

=

7.4, 0.5 Hz 1H, H-5), 7.18–7.36 (m, 7H, H-4, H-6, Ph); C NMR (126 MHz, CDCl ) δ 27.0,

3

33.0, 39.5, 44.2, 46.3, 67.3, 70.1, 73.1, 96.7, 109.9, 122.6, 123.0, 125.8, 127.0, 127.8, 128.9, 131.0,

+

1

35.0, 143.6, 175.6. HRMS (ESI): calcd for C H Br N O [M+H] 613.9113, found 613.9117.

2

20

3

4.2.32.

(1'S*,2'S*,3S*,7a'S*)-2'-(3,4-Dimethoxyphenyl)-1-methyl-1'-nitro-1',2',5',6',7',7a'-

hexahydrospiro[indoline-3,3'-pyrrolizin]-2-one (6). Yield 0.31 g (84%, 90% in EtOH), mp 146–147

9

a

1

ºC (lit. mp 103–105 ºC), white powder. H NMR (400 MHz, CDCl ) δ 1.45−2.23 (m, 4H, 2CH ),

3

2

2.89 (t, J = 7.2 Hz, 1H, CH), 2.94 (s, 3H, NMe), 3.25−3.33 (m, 1H, CH), 3.60 (s, 3H, MeO), 3.76

(s, 3H, MeO), 4.45 (d, J = 10.5 Hz, 1H, H-2'), 4.89 (dt, J = 9.0, 7.9 Hz, 1H, H-7'a), 6.29 (dd, J =

1

0.5, 9.6 Hz, 1H, H-1'), 6.47 (d, J = 1.9 Hz, 1H, H-2''), 6.61 (d, J = 8.4 Hz, 1H, H-6''), 6.64 (d, J =

.9 Hz, 1H, H-7), 6.68 (dd, J = 8.4, 1.9 Hz, 1H, H-5''), 7.12 (td, J = 7.6, 0.8 Hz, 1H, H-5), 7.30 (td,

7

J = 7.8, 1.0 Hz, 1H, H-6), 7.59 (d, J = 7.5 Hz, 1H, H-4).

4.3. X-ray diffraction study of compounds 3k, 4a and 6

26

ACCEPTED MANUSCRIPT

Intensity data for the compounds 3k, 4a and 6 were collected on a "Xcalibur E" diffractometer at

95(2) and 120(10) K, corresponding (Mo-Kα radiation, graphite monochromator, -scan, radiation

wavelength = 0.7107). The structures were solved by direct methods and refined by full-matrix

2

ω

2

5

least-squares method using the SHELX-97 program package. All non-hydrogen atoms were re-

fined with anisotropic atomic displacement and hydrogen atoms were included at calculated posi-

tion using a riding model.

4

.3.1. Crystal data for 3k. C H Br N O , M = 497.97. Ortorombic crystals space group P2 2 2 , a

13 12 3 3 3 1 1 1

3

=

8.6851(3), b = 10.9040(6), c = 16.7223(7) Å,

α

= β = γ = 90.00°, V = 1583.64(12) Å , D =

c

3

–1

2

.089g/cm , absorption coefficient

µ

= 7.657 mm , Z = 4. The intensities of 3790 independent re-

flections (R = 0.0295) were measured. The final discrepancy factors R = 0.0427, wR = 0.1032,

int

1

2

GooF = 1.002 for 2734 reflections with I > 2σ(I); R = 0.0768, wR = 0.1404 (all data). Largest dif-

1

2

–

3

ferent peak and hole: 0.813 and −1.076 eÅ . Completeness to θ = 28.22° (99.96%). Deposition

number CCDC 1477914.

4

.3.2. Crystal data for 4a. C H F N O , M = 341.29. Monoclinic crystals space group P2 /c, a =

15 14 3 3 5 1

3

12.6467(7), b = 8.3854(4), c = 14.6826(7) Å,

α

=

γ

= 90.00, β = 110.114(6)°, V = 1462.09(13) Å ,

3

–1

D = 1.550 g/cm , absorption coefficient

µ

= 0.135 mm , Z = 4. The intensities of 3939 independ-

c

ent reflections (R = 0.0236) were measured. The final discrepancy factors R = 0.0508, wR =

int

1

2

0

.1629, GooF = 1.032 for 3187 reflections with I > 2σ(I); R = 0.0640, wR = 0.1794 (all data).

1 2

–

3

Largest different peak and hole: 0.556 and −0.296 eÅ . Completeness to θ = 28.22° (99.95%).

Deposition number CCDC 1477917.

4

.3.3. Crystal data for 6. C H N O , M = 341.29. Monoclinic crystals space group P2 /c, a =

23 25 3 5 1

3

1

0.7513(8), b = 26.4813(15), c = 8.8733(7) Å, α = γ = 90.00, β = 108.766(8)°, V = 2392.01 Å , D

c

3

–1

=

1.176 g/cm , absorption coefficient

µ

= 0.084 mm , Z = 4. The intensities of 5683 independent

reflections (R = 0.0283) were measured. The final discrepancy factors R = 0.0575, wR = 0.1446,

int

1

2

GooF = 1.000 for 3079 reflections with I > 2σ(I); R = 0.1081, wR = 0.1663 (all data). Largest dif-

1

2

–

3

ferent peak and hole: 0.227 and −0.177 eÅ . Completeness to θ = 28.22° (95.67%). Deposition

number CCDC 1477919.

Acknowledgments

This work was financially supported by the Russian Science Foundation (Grant 14-13-00388).

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Article Doi

Highly regio- and stereoselective 1,3-dipolar cycloaddition of stabilised azomethine ylides to 3,3,3-trihalogeno-1-nitropropenes: synthesis of trihalomethylated spiro[indoline-3,2′-pyrrolidin]-2-ones and spiro[indoline-3,3′-pyrrolizin]-2-ones

DOI: 10.1016/j.tet.2016.09.017

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