Scholarly article on 6-methoxy-3-nitro-2-trifluoromethyl-2H-chromene 1003573-84-9 from Tetrahedron p. 5122

Tetrahedron xxx (2017) 1e16

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Highly diastereoselective synthesis of novel 2,3,4-trisubstituted

chromanes via the reaction of 3-nitro-2-(trihalomethyl)- and 3-nitro-

2-phenyl-2H-chromenes with 1-morpholinocyclopentene

Vladislav Y. Korotaev^*, Igor B. Kutyashev, Alexey Y. Barkov, Vyacheslav Y. Sosnovskikh

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

a r t i c l e i n f o

a b s t r a c t

Article history:

The reaction of 3-nitro-2-triﬂuoro(trichloro)methyl- and 3-nitro-2-phenyl-2H-chromenes with 1-

morpholinocyclopentene under the conditions of kinetic or thermodynamic control led to the forma-

tion of products due to enamine addition at the C-4 atom of chromene as individual cis,trans- or

trans,trans-isomers, differing by the position of double bond in the enamine moiety. Hydrolysis of these

compounds in dilute HCl did not cause changes of pyran ring conﬁguration and provided the respective

4-(cyclopentanon-2-yl)chromanes with anti-conﬁguration of hydrogen atoms at the С-4 and С-2⁰atoms.

Stereochemistry of the obtained compounds was conﬁrmed by X-ray structural analysis.

Received 3 April 2017

Received in revised form

20 June 2017

Accepted 3 July 2017

Available online xxx

Keywords:

3-Nitro-2H-chromenes

1-Morpholinocyclopentene

Chromanes

Stereoselectivity

1. Introduction

equal amounts, differed by the relative conﬁguration at the C-2⁰

atom (Scheme 1).

Enamines that are based on cycloalkanones and secondary

amines provide readily available nucleophilic reagents capable of

diastereoselective addition at the activated double bonds of con-

jugated nitroalkenes under mild conditions in the absence of a

catalyst. Depending on the ring size of ketone molecule, the

structure of nitroalkene, and the reaction conditions, such pro-

cesses can result in the formation of nitroalkylated enamines¹

(conjugated addition), 1,2-oxazine N-oxides²([4 þ 2] hetero-

cyclization), or cyclobutanes^1b,2a,3([2 þ 2] carbocyclization). At the

same time, only very limited data are available in the literature

about reactions of these enamines with 3-nitro-2Н-chromenes, the

chemical properties of which are primarily deﬁned by the presence

We have recently shown⁶that diastereoselective nucleophilic

addition of 1-morpholinocyclohexene (3) at the double bond С-4

atom of 3-nitro-2-triﬂuoro(trichloro)methyl-2H-chromenes 2 in

acetonitrile at room temperature resulted in the isolation of either

1,2-oxazine-N-oxides 4 or trans,trans-Michael adducts 5 with tet-

rasubstituted double bond in the enamine moiety (Scheme 2).

In a continuation of our search for new stereoselective reactions

involving 3-nitro-2H-chromenes,^6,7we devoted the current work

to studying the interaction of 2-(trihalomethyl)-3-nitro-2Н-chro-

menes 2aen and 2-phenyl-3-nitro-2H-chromenes 2oeq with 1-

morpholinocyclopentene (6) under various conditions. This study

resulted in the development of a diastereoselective synthesis

leading to new representatives of 2,3,4-trisubstituted chromanes,

including their stereochemical characterization and identiﬁcation

of some structural features of the obtained Michael adducts.

of a b

-nitrostyrene moiety in the molecule.⁴It is only known⁵that

catalytic reactions of 2-unsubstituted 3-nitro-2H-chromene with

proline enamines of cyclopentanone and cyclohexanone, formed in

situ from proline and the respective ketones in the presence of

sodium acetate in methanol (enamine catalysis), after removal of

the solvent and puriﬁcation by ﬂash chromatography provided

mixtures of epimeric 3,4-trans-chromanes 1 in approximately

2. Results and discussion

We found that 2-CX₃-nitrochromenes 2aen reacted with 1-

morpholinocyclopentene (6) under the conditions of kinetic con-

trol (ꢀ18 or 20^ꢁС) in anhydrous acetonitrile, forming adducts ct-

7aen as individual cis,trans-isomers (ct-isomers) with trisubsti-

tuted double bond in the enamine moiety, which gradually

* Corresponding author.

E-mail address: korotaev.vladislav@urfu.ru (V.Y. Korotaev).

http://dx.doi.org/10.1016/j.tet.2017.07.003

Please cite this article in press as: Korotaev VY, et al., Highly diastereoselective synthesis of novel 2,3,4-trisubstituted chromanes via the reaction

of 3-nitro-2-(trihalomethyl)- and 3-nitro-2-phenyl-2H-chromenes with 1-morpholinocyclopentene, Tetrahedron (2017), http://dx.doi.org/

10.1016/j.tet.2017.07.003

2

V.Y. Korotaev et al. / Tetrahedron xxx (2017) 1e16

Therefore, the lower yields of 2-CF₃-chromanоenamines сt-7

compared to their 2-CCl₃-analogs were caused by their higher

solubility in acetonitrile. At the same time, the use of tert-butyl

methyl ether, dichloromethane or methanol as solvent in the re-

action of enamine 6 with chromene 2a (ꢀ18^ꢁС, 48 h) decreased the

yield of product сt-7a to 21e41%. Reduced yields of products ct-7

upon substituting acetonitrile with another solvent were also

observed in the series of 2-CCl₃-chromenes. For example, the re-

action of enamine 6 with chromene 2h in benzene, tert-butyl

methyl ether, dichloromethane, and methanol (20^ꢁС, 24 h) gave

chromane ct-7h in decreased yields (30e43%).

Similarly to the 2-CX₃-nitrochromenes 2aen, 3-nitro-2-phenyl-

2H-chromenes 2oeq reacted stereoselectively with enamine 6 at

20^ꢁС, forming the kinetically controlled products ct-7oeq. The

highest yields (58e81%) after the shortest reaction duration

(0.5e1 h) were obtained in tert-butyl methyl ether, due to the low

solubility of the formed products in this solvent and rapid shifting

Scheme 1. Synthesis of chromanes 1.

of equilibrium towards the chroman

Table 1).

оenamines ct-7oeq (Scheme 3,

When the reaction of 2-CF₃-nitrochromenes 2aee with

enamine 6 was performed in anhydrous methanol for 3e8 h at

35^ꢁС, the thermodynamically favored chroman

оenamines tt-8aee

with trans,trans-conﬁguration of substituents in the pyran ring and

tetrasubstituted double bond in the enamine moiety were obtained

in 39e78% yields (Scheme 3, Table 1). When the reaction was

performed in acetonitrile, the yields of these compounds decreased

by ~10%. Regardless of the selected solvent, chromanes tt-8, simi-

larly to their isomers ct-7, gradually crystallized from the reaction

mixtures as colorless prisms or white, ﬁne crystalline powders.

Increasing the reaction duration or raising the temperature to

40e60^ꢁС led to noticeable resiniﬁcation in both solvents. It should

be noted that chromanes tt-8a, tt-8c, and tt-8d were formed in 52,

39, and 40% yields, respectively, when chromenes 2a,c,d were

heated for 1 h with an excess of enamine 6 (1.5 equiv) under

solvent-free conditions at 60^ꢁС.

Scheme 2. Synthesis of compounds 4 and 5.

crystallized from the reaction mixture as colorless prisms (Scheme

3, Table 1). This process is equilibrium, and the rate of formation

and yields of products ct-7 are primarily related to their solubility.

Conversion of 2-trichloromethyl- and 2-phenyl-3-nitro-2Н-

chromenes to the respective trans,trans-chromanоenamines tt-8

proceeded at a higher temperature (Scheme 3, Table 1). For

example, 6-halosubstituted 2-CCl₃-chromanes tt-8k,l were syn-

thesised in 54 and 46% yields by heating a solution of the respective

chromene 2 and enamine 6 in methanol or acetonitrile for 6 h at

40^ꢁС, while 2-Ph-chromane tt-8o formed in acetonitrile after 4 h at

60^ꢁС. Product tt-8h could be obtained as a mixture with its ct-8h

isomer only upon microwave irradiation of the starting materials in

dichloromethane for 15 min at 100^ꢁС (69% combined yield). It is

interesting to note that, unlike in the case of cyclohexanone

enamine 3, the formation of 1,2-oxazine-N-oxides of type 4 was not

observed in any of the experiments.

Chromanоenamines tt-8 in CDCl₃or C₆D₆solutions were in

equilibrium with the epimeric chromanes tt-7 and tt-7′ containing

a trisubstituted double bond in the enamine moiety, with the only

difference between these compounds provided by the conﬁgura-

tion at the С-5⁰atom (Scheme 3). It was established that two new

sets of ¹H NMR signals emerged 5 min after dissolving mono-

crystals of products tt-8 in deuterated solvent. Each of these sets

contained not only the proton signals of pyran ring, but also a

characteristic broadened singlet of the vinyl proton, pointing to the

presence of a trisubstituted double bond in chromanes tt-7 and tt-7'

(the assignment of compounds tt-7 and tt-7′ as anti- or syn-isomers

and their preferred conformations in solution phase are described

below). The equilibrium tt-8 # tt-7þtt-7′ in С₆D₆solution was

reached within approximately a day and favored the chroma-

nоenamine tt-8 containing a tetrasubstituted double bond. The

isomeric chromanes tt-8a‒e,h, tt-7aee,h, and tt-7'a‒e,h existed in

Scheme 3. Synthesis of chromanes 7 and 8.

C₆D₆solution at room temperature in equilibrium mixtures that

Please cite this article in press as: Korotaev VY, et al., Highly diastereoselective synthesis of novel 2,3,4-trisubstituted chromanes via the reaction

of 3-nitro-2-(trihalomethyl)- and 3-nitro-2-phenyl-2H-chromenes with 1-morpholinocyclopentene, Tetrahedron (2017), http://dx.doi.org/

10.1016/j.tet.2017.07.003

V.Y. Korotaev et al. / Tetrahedron xxx (2017) 1e16

3

Table 1

Reaction conditions and yields of chromanоenamines сt-7 and tt-8.

Chromene

R¹

R²

R³

Solvent

Time, h

Temp., ^ꢁС

Chromane

Yield, %

2a

2b

2c

2d

2e

2f

2g

2h

2i

CF₃

CCl₃

Ph

H

MeO

H

Cl

Br

Cl

Br

H

MeO

H

Cl

Br

Cl

Br

H

MeO

Br

H

MeO

H

Cl

Br

H

Cl

Br

H

EtO

H

Cl

Br

H

EtO

H

MeCN

t-BuOMe

MeOH

CH₂Cl₂

MeOH

MeCN

48

6

ꢀ18

20

35

ct-7a

ct-7b

ct-7c

ct-7d

ct-7e

ct-7f

ct-7g

ct-7h

ct-7i

ct-7j

ct-7k

ct-7l

ct-7m

ct-7n

ct-7o

ct-7p

ct-7q

tt-8a

tt-8b

tt-8c

tt-8d

tt-8e

tt-8h

tt-8k

tt-8l

58

50

49

64

72

71

66

68

62

52

74

77

78

83

72

58

82

78

59

39

51

47

69^b

54

46

34

6

24

48

24

1

0.5

5

8

2j

2k

2l

H

2m

2n

2o

2p

2q

2a

2b

2c

2d

2e

2h

2k

2l

Cl

Br

H

EtO

H

Ph

CF₃

CCl₃

Ph

35

3

35

H

15 min

6

100^a

40

60

2o

4

tt-8o

a

Upon microwave irradiation.

A mixture of isomers in the ratio tt-8h:ct-8h ¼ 64:36.

b

were characterised by ¹H and ¹⁹F NMR spectroscopy, as shown in

Table 2.

the small values of spin-spin coupling constants J_2,3¼ 1.2e2.3 Hz

and J_3,4¼ 0e1.0 Hz.^7a,сIt should be noted that ¹H NMR spectra of 2-

CF₃-chromanes ct-7aeg and 2-Ph-chromanes ct-7oeq, which were

acquired in CDCl₃solution, showed the presence of 8e19% of the

respective chromenes 2 and enamine 6 due to a retro-Michael re-

action that occurred in this solvent. NMR spectra of the indicated

compounds were free of these impurities when acquired in a

nonpolar solvent (С₆D₆).

The thermodynamically favored adducts tt-8 with equatorial

conﬁguration of all three bulky substituents in the benzopyran

system and a tetrasubstituted double bond in the enamine moiety

were formed from the less stable kinetically favored products сt-7

featuring a trans-diaxially oriented nitro group and bulky enamine

moiety, as a result of a retro-Michael reaction with cleavage of the

C(4)eС(2⁰) bond. This conﬁrmed the results obtained by studying

the behaviour of compound ct-7a in C₆D₆solution in NMR ampule

by using ¹⁹F NMR spectroscopy. Thus, the reaction mixture after a

day at room temperature contained 38% of chromene 2a and 3% of

tt-isomers (tt-8 þ tt-7a þ tt-7'a). The amount of chromane ct-7a

decreased by almost three times after 3 days, while the content of

chromene 2a and the total amount of tt-isomers increased to 52

and 12%, respectively. The maximum content of tt-isomers in the

mixture (27%) was observed after 8 days, while the conversion of

chromane ct-7a reached 86%.

In order to conﬁrm the structure of chromanоenamines ct-7aeq

proposed on the basis of ¹H NMR spectral data, as well as for

establishing the relative conﬁguration of substituents at the C-5⁰

atom, we performed monocrystal X-ray structural study of chro-

mane ct-7h, which identiﬁed this compound as the cis,trans-isomer

with H-4 and H-5⁰hydrogen atoms in anti-conﬁguration (Fig. 1).

The trichloromethyl group in this molecule occupied an equatorial

position, while the nitro group and enamine moiety had a trans-

diaxial relationship. The pyran ring assumed a slightly twisted half-

¹H NMR spectra of compounds ct-7aeq contained characteristic

signals of H-2, H-3, and H-4 protons of the pyran ring, as well as a

broadened singlet of the vinylic H-2⁰proton, indicating the pres-

ence of a trisubstituted double bond in the ﬁve-membered ring.

The cis,trans-conﬁguration of chromanes ct-7aeq was evidenced by

Table 2

The equilibrium compositions for tautomeric mixtures of chromanes. tt-8aee,h, tt-

7aee,h, and tt-7'aee,h in C₆D₆at 22^ꢁС

Isomers in equilibrium mixture

Content of each isomer, %

tt-8

tt-7

tt-7⁰

tt-8a:tt-7a:tt-7'a

tt-8b:tt-7b:tt-7'b

tt-8c:tt-7c:tt-7'c

tt-8d:tt-7d:tt-7'd

tt-8e:tt-7e:tt-7'e

tt-8h:tt-7h:tt-7'h

67

61

59

67

21

27

24

26

17

12

15

16

Fig. 1. Molecular structure of ct-7h (ORTEP drawing, 50% probability level).

Please cite this article in press as: Korotaev VY, et al., Highly diastereoselective synthesis of novel 2,3,4-trisubstituted chromanes via the reaction

of 3-nitro-2-(trihalomethyl)- and 3-nitro-2-phenyl-2H-chromenes with 1-morpholinocyclopentene, Tetrahedron (2017), http://dx.doi.org/

10.1016/j.tet.2017.07.003

4

V.Y. Korotaev et al. / Tetrahedron xxx (2017) 1e16

chair conformation. The dihedral angle H(11)eC(11)ꢀC(4)eH(4)

was equal to 63.5^ꢁ, in agreement with the observed vicinal con-

stants J_4,5'¼ 2.3e3.1 Hz in ¹H NMR spectra of chromanes ct-7aeq.

¹H NMR spectra of compounds tt-8 contained characteristic

signals of pyran ring protons, with the H-4 proton appearing as a

doublet resulting from spin-spin coupling with only the H-3 pro-

ton. This fact, along with the lack of ¹H NMR signal due to vinylic

proton, pointed to the presence of a tetrasubstituted double bond in

the enamine moiety. The trans,trans-conﬁguration of substituents

at C-2, C-3, and C-4 atoms in chromanes tt-8 was deduced from the

Scheme 4. Hydrolysis of chromanes ct-7aeq.

large values of coupling constants J_2,3

¼

7.7e10.1 Hz and

Table 3

Yields of chromanes ct-9.

J_3,4¼ 10.2e11.0 Hz.^7b,8

The trans,trans-conﬁguration and double bond position in the

enamine moiety of chromanоenamines tt-8 was conﬁrmed by

Chromane

R¹

R²

R³

Yield, %

monocrystal X-ray structural analysis of compound tt-8a (Fig. 2). All

substituents in the pyran ring of molecule tt-8a were arranged in a

transoid conﬁguration and occupied equatorial positions. The py-

ran ring was in a half-chair conformation, with the dihedral angles

H(2)eC(2)ꢀC(3)ꢀH(3) and H(3)eC(3)ꢀC(4)eH(4) equal to ꢀ176

(2)^ꢁand 172 (2)^ꢁ, respectively. The double bond in the ﬁve-

membered ring was localised between the C(11) and C(15) atoms.

ct-9a

ct-9b

ct-9c

ct-9d

ct-9e

ct-9f

ct-9g

ct-9h

ct-9i

ct-9j

ct-9k

ct-9l

ct-9m

ct-9n

ct-9o

ct-9p

ct-9q

CF₃

CCl₃

Ph

H

MeO

H

Cl

Br

Cl

Br

H

MeO

H

Cl

Br

Cl

Br

H

MeO

Br

H

EtO

H

Cl

Br

H

EtO

H

90

71

78

83

80

85

89

71

70

87

99

91

84

81

94

91

84

Hydrolysis of chromanоenamines ct-7aeq in aqueous methanol

under mild conditions (dilute HCl, 20^ꢁС, 24 h for 2-CF₃-chromanes

ct-7aeg and 50^ꢁС, 5 h for 2-CСl₃- and 2-Ph-chromanes ct-7heq)

H

Cl

Br

H

led to the respective chromanоketones ct-9aeq with preservation

of conﬁguration at the С-2, С-3, С-4, and С-2⁰atoms (С-2⁰is

equivalent to the С-5⁰atom in chromanes ct-7) (Scheme 4, Table 3).

Ph

The hydrolysis of 2-CF₃-chromanо

enamines ct-7 at 50^ꢁС was

accompanied by the formation of 2-CF₃-chromenes 2 in a retro-

Michael reaction; moreover, in a range of cases the 2-CF₃-chro-

manоketones ct-9 were epimerised to the isomers tc-9 via the aci-

form, already previously observed for the ct-isomers of 2,3,4-

trisubstituted chromanes.^7a,с

The cis,trans-conﬁguration of pyran ring and the anti-orienta-

tion of H-4 and H-2⁰hydrogen atoms in the hydrolysis products ct-

9aeq were established by monocrystal X-ray structural analysis of

chromane ct-9l (Fig. 3). The molecular geometry of chroman

оke-

tones ct-9l was closely related to the chroman enamine ct-7h

о

(Fig. 1), with the CCl₃group also occupying equatorial position, the

nitro group and enamine moiety being in a trans-diaxial relation-

ship, and the pyran ring in half-chair conﬁguration. These data are

in a good agreement with the observed values of ¹Н NMR coupling

constants J_2,3¼ 1.5e2.6 Hz and J_3,4¼ 1.2e1.9 Hz for the hydrolysis

products obtained from enamines ct-7aeq. At the same time, the

absolute value of dihedral angle H(15)eC(15)ꢀC(4)eH(4) in the

molecule of compound ct-9l was larger (ꢀ86.3^ꢁ) than in the

Fig. 3. Molecular structure of ct-9l (ORTEP drawing, 50% probability level).

chromanе ct-7h (63.5^ꢁ), increasing the vicinal J_4,2constants in

0

chroman

man

enamines ct-7aeq (J_4,2'¼ 2.3e3.1 Hz).

Acidic hydrolysis of chroman enamines tt-8 under non-

epimerising conditions (dilute HCl, 20^ꢁС, 24 h) led to high yields

of chroman ketones tt-9 and tt-9′, which differed only by the

оketones ct-9aeq to 4.7e6.2 Hz, compared to the chro-

о

conﬁguration at C-2⁰atom. The major component was the more

stable epimer tt-9 with anti-conﬁguration of H-4 and H-2⁰

hydrogen atoms (Scheme 5, Table 4). When the hydrolysis of

chromanes tt-8a,b,d,k was performed for 5 h at 50^ꢁС, the content of

the respective epimers tt-9 increased to 81e90%, but the yield of 6-

chlorosubstituted chromane tt-9d at the same time decreased to

Fig. 2. Molecular structure of tt-8a (ORTEP drawing, 50% probability level).

Please cite this article in press as: Korotaev VY, et al., Highly diastereoselective synthesis of novel 2,3,4-trisubstituted chromanes via the reaction

of 3-nitro-2-(trihalomethyl)- and 3-nitro-2-phenyl-2H-chromenes with 1-morpholinocyclopentene, Tetrahedron (2017), http://dx.doi.org/

10.1016/j.tet.2017.07.003

V.Y. Korotaev et al. / Tetrahedron xxx (2017) 1e16

5

Scheme 5. Hydrolysis of chromanes tt-8.

Fig. 4. Molecular structure of tt-9c (ORTEP drawing, 50% probability level).

Table 4

Yields of chromanes tt-9 and tt-9'.

Chromane

R¹

R²

R³

Yield, %

tt-9:tt-9⁰ratio, %

tt-9a þ tt-9'a

tt-9b þ tt-9'b

tt-9c þ tt-9'c

tt-9d þ tt-9'd

tt-9e þ tt-9'e

tt-9h þ tt-9'h

tt-9k þ tt-9'k

tt-9l þ tt-9'l

tt-9o þ tt-9'o

CF₃

CCl₃

Ph

H

MeO

H

Cl

Br

H

Cl

Br

H

EtO

H

80

77

92

73

84

51^a

94

96

87

69:31

75:25

79:21

74:26

71:29

100:0^a

71:29

63:37

76:24

a

After puriﬁcation by column chromatography.

55% due to a retro-Michael side reaction. It is important to note that

epimerisation at the C-3 atom was not observed, while ketones tt-9

can be puriﬁed from an impurity of the minоr epimer tt-9′ by a

simple recrystallisation from hexane. Hydrolysis of the mixture

containing isomers tt-8h and ct-8h, which was obtained upon

microwave irradiation, followed by puriﬁcation of the reaction

product by column chromatography, gave the stereoisomer tt-9h as

an individual compound in 51% yield.

Fig. 5. Molecular structure of tt-9h (ORTEP drawing, 50% probability level).

We propose that the ratio of hydrolysis products tt-9 and tt-9⁰

under conditions not conductive to epimerisation (Table 4) was

affected by the content of tautomers tt-8, tt-7 and tt-7′ in the so-

lution. An additional amount of the more stable epimer tt-9 with

anti-conﬁguration of H-4 and H-2⁰atoms was apparently formed

during the heating from the less stable chromane tt-9′, as a result of

epimerisation at the С-2⁰atom. It should be mentioned in particular

Apparently, 2-СХ₃-chromanоketones tt-9 existed in CDCl₃and

C₆D₆solutions as a dynamic equilibrium mixture of half-chair and

boat conformers (Scheme 6), resulting in a decrease of vicinal

coupling constants to J_2,3¼ 6.4e7.5 Hz and J_3,4¼ 2.7e6.5 Hz

compared to the chroman

о

enamines tt-8 (J_2,3¼ 7.7e10.1 Hz,

J_3,4¼ 10.2e11.0 Hz). However, the half-chair conformation was

predominant in solutions of 2-Ph-substituted chromane tt-9o, with

that the attempt to synthesise chromanоketones 9a,h from chro-

menes 2a,h and cyclopentanone under the conditions developed

by Yan and coworkers⁵for the 2-unsubstituted analogs 1 produced

a complex mixture of unidentiﬁed products in both cases.

The major isomers of chromanоketones tt-9 were stereo-

chemically identiﬁed by monocrystal X-ray structural analysis of

compounds tt-9c and tt-9h (Figs. 4 and 5). As shown in Fig. 4, the

pyran ring in the molecule of 2-CF₃-chromane tt-9c in the solid

state assumed a half-chair conformation, with all substituents

having transoid relationships and occupying equatorial positions.

The molecule of 2-CCl₃-chromanоketone tt-9h (Fig. 5) also had a

trans,trans-conﬁguration, but its pyran ring assumed a twist-boat

conformation with the O(1), C(3), and C(4) atoms deviating from

the plane of other atoms by 0.516, 0.348, and 0.687 Å, respectively.

For this reason, the bulky trichloromethyl group in the molecule of

compound tt-9h occupied an equatorial position, while the nitro

group and ketone moiety were oriented axially. The difference in

molecular conformations of compounds tt-9c and tt-9h was asso-

ciated with a decrease of dihedral angles H(2)eC(2)eC(3)eH(3)

and H(3)eC(3)eC(4)eH(4) from 178 (2) and ꢀ157 (2)^ꢁin chromanе

tt-9c to 131 (2) and ꢀ85 (3)^ꢁin chromanе tt-9h.

Scheme 6. The preferred conformations of epimeric chromanes tt-9 and tt-9′ in

solution.

Please cite this article in press as: Korotaev VY, et al., Highly diastereoselective synthesis of novel 2,3,4-trisubstituted chromanes via the reaction

of 3-nitro-2-(trihalomethyl)- and 3-nitro-2-phenyl-2H-chromenes with 1-morpholinocyclopentene, Tetrahedron (2017), http://dx.doi.org/

10.1016/j.tet.2017.07.003

6

V.Y. Korotaev et al. / Tetrahedron xxx (2017) 1e16

the С-5⁰atom. ¹H NMR characterization of the epimeric 2-CX₃-

chromanes tt-7 and tt-7′, regardless of the selected deuterated

solvent, revealed the same trends as for chroman ketones tt-9 and

о

tt-9′, the stereochemistry of which was established unequivocally

by X-ray structural analysis. Therefore, the preferred conformations

of epimeric chromanes tt-7 and tt-7′ in CDCl₃or C₆D₆solutions, as

well as the syn- or anti-conﬁgurations of H-4 and H-5⁰hydrogen

atoms could be deduced from the respective vicinal coupling

constants.

Similarly to ketones tt-9 and tt-9′, the anti-isomers of 2-CF₃-

chromanоenamines tt-7aee existed in solutions as two conformers,

while for the syn-isomers tt-7'aee the only stable conformation

0

was half-chair with lower values of J_4,5constants compared to the

anti-isomers tt-7aee (Scheme 7). In the series of 2-CCl₃-substituted

epimeric chromanоenamines tt-7h,k,l and tt-7'h,k,l, the contribu-

tion of the boat conformer to the overall conformational equilib-

rium in CDCl₃or C₆D₆solutions was observed for both epimers,

leading to a decrease of J_3,4constants to 3.5e3.9 Hz in anti- and

4.3e5.5 Hz in syn-isomers. Since the signal of H-4 proton in the

spectra of these compounds was not observed due to overlap, the

assignment of epimers was based on the different chemical shifts of

H-2 proton, the signal of which, as in the case of 2-CF₃-substituted

analogs, was better shielded in epimers tt-7, regardless of the

deuterated solvent used. In analogy to 2-CF₃-chromanes tt-7a¡e,

the epimers tt-7h,k,l with anti-conﬁguration of hydrogen atoms

differed from the syn-isomer with their lower values of J_3,4constant

(Scheme 7, chemical shifts of H-2 atom are reported for solutions of

compounds tt-7 and tt-7′ in C₆D₆).

Both of the epimeric 2-Ph-chromanes tt-7o and tt-7'o exhibited

similar chemical shifts of pyran ring protons and large values of

J_2,3¼ 10.0e10.2 Hz and J_3,4¼ 7.5e7.6 Hz, indicating that they

existed in C₆D₆solution exclusively in the half-chair conformation.

For this reason, we were unable to reliably assign these epimers as

anti- or syn-isomers, while the anti-conﬁguration of H-4 and H-5⁰

hydrogen atoms was postulated for the predominant epimer in the

solution (the tautomeric ratio tt-8o:tt-7o:tt-7'o ¼ 75:14:11).

3. Conclusion

Thus, 2-(trihalomethyl)- and 2-phenylsubstituted 3-nitro-2H-

chromenes

reacted

stereoselectively

with

1-

Scheme 7. The preferred conformations of epimeric chromanes tt-7 and tt-7′ in

morpholinocyclopentene and, depending on the reaction temper-

ature, formed Michael adducts 7 or 8 as individual cis,trans- or

trans,trans-isomers. Acidic hydrolysis of these compounds under

non-epimerising conditions proceeded with preservation of the

pyran ring conﬁguration and led to the respective 4-(cyclo-

pentanon-2-yl)chromane stereoisomers 9 with anti-conﬁguration

of H-4 and H-2⁰hydrogen atoms. The obtained 2,3,4-trisubstituted

chromanes are clearly of interest as starting materials for further

diastereoselective syntheses. For example, ketones 9 can be used

for the preparation of individual stereoisomers of annulated pyr-

roline-N-oxides and pyrrolidines as a result of reduction of the nitro

group.^5,9

solution.

the observed values of J_2,3¼ 9.6 Hz and J_3,4¼ 9.8 Hz.

The proposed trans,trans-conﬁguration of pyran ring in the

minor isomers tt-9′, which in solution assumed a half-chair

conformation with equatorial orientation of all substituents, was

supported by the large values of J_2,3

¼

7.1e9.8 Hz and

J_3,4¼ 7.5e9.8 Hz in their ¹H NMR spectra, as well as the data ob-

tained from a 2D ¹He¹H NOESY experiment for a mixture of 2-CCl₃-

chromanоketones tt-9l and tt-9'l, where both isomers showed

cross-peaks between the H-2 and H-4 atoms. The syn-orientation of

H-4 and H-2⁰hydrogen atoms in epimers tt-9′ was indicated by the

smaller vicinal coupling constant J_4,2'(2.8e4.0 Hz), compared to the

4. Experimental

epimers

tt-9

with

anti-orientation

of

these

atoms

(J_4,2'¼ 6.1e8.0 Hz) (Scheme 6). The exception was the 2-Ph-chro-

mane 9o again, for which both epimers had the value of

J_4,2'¼ 2.4 Hz.

4.1. General

NMR spectra were recorded on Bruker DRX-400 (¹He400 MHz

and ¹⁹Fe376 MHz) and AVANCE-500 (¹He500 MHz, ¹⁹Fe471 MHz

and ¹³Ce126 MHz) spectrometers in CDCl₃or C₆D₆with TMS and

C₆F₆as internal standards. IR spectra were recorded on a Nicolet

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

As shown above, the hydrolysis of compounds tt-8 under mild

conditions occurred without changing the conﬁguration of pyran

ring. Therefore, chroman

solution as an equilibrium mixture with compounds tt-8, were

trans,trans-isomers similarly to the chroman ketones tt-9 and tt-9′

and their only difference was the conﬁguration of substituents at

оenamines tt-7 and tt-7′, which existed in

о

Please cite this article in press as: Korotaev VY, et al., Highly diastereoselective synthesis of novel 2,3,4-trisubstituted chromanes via the reaction

of 3-nitro-2-(trihalomethyl)- and 3-nitro-2-phenyl-2H-chromenes with 1-morpholinocyclopentene, Tetrahedron (2017), http://dx.doi.org/

10.1016/j.tet.2017.07.003

V.Y. Korotaev et al. / Tetrahedron xxx (2017) 1e16

7

Bruker Daltonik GmbH. Elemental analyses were performed at the

6.67 (t, J ¼ 7.8 Hz, 1H, H-6); ¹⁹F NMR (376 MHz, C₆D₆)

d

87.7 (d,

Microanalysis Services of the Institute of Organic Synthesis, Ural

Branch, Russian Academy of Sciences. Melting points were deter-

mined on a Stuart SMP40 apparatus. All solvents used were dried

and distilled per standard procedures. The starting nitrochromenes

2aen and 2oeq were prepared according to described

procedures.^10,11

J

¼

6.6 Hz, CF₃). HRMS (ESI): calcd. for 443.1788 [MþH]^þ

C₂₁H₂₆F₃N₂O₅, found 443.1787.

4.2.4. 4-{(5R*)-[(2S*,3R*,4S*)-6-Chloro-3-nitro-2-(triﬂuoromethyl)

chroman-4-yl]cyclopenten-1-yl}morpholine (ct-7d)

Yield 0.28 g (64%), m.p. 121e122 ^ꢁC (decomp.). IR (ATR): 1630,

1555, 1481, 1455, 1443, 1415, 1373, 1326 cm^ꢀ^{1 1}H NMR (400 MHz,

;

4.2. General procedure for the synthesis of 2-CX₃-chromanes ct-

7aen

C₆D₆) d

1.26e2.07 (m, 8H, 2 CH₂, N(CH₂)₂), 2.59e2.65 (m, 1H, H-5⁰),

2.77 (br d, J ¼ 2.6 Hz, 1H, H-4), 2.79e2.90 (m, 2H, O(CHH)₂), 3.05

(ddd, J ¼ 11.2, 6.7, 2.9 Hz, 2H, O(CHH)₂), 4.25 (br s, 1H, ¼CH), 4.72

(qd, J ¼ 6.6, 2.0 Hz, 1H, H-2), 4.88 (dd, J ¼ 2.0, 0.8 Hz, 1H, H-3), 6.55

(d, J ¼ 8.5 Hz, 1H, H-8), 6.71 (d, J ¼ 2.5 Hz, 1H, H-5), 6.73 (dd, J ¼ 8.5,

The appropriate chromene 2 (1.0 mmol) was dissolved in

anhydrous acetonitrile (0.15 mL for 2-CF₃-chromenes or 0.50 mL for

2-CCl₃-chromenes) and treated by the addition of freshly distilled

1-morpholinocyclopentene (6) (0.16 g, 1.0 mmol), then maintained

at ꢀ18 or 20^ꢁС for the time indicated in Table 1. In the case if

chromanes ct-7aee did not precipitate within 24 h, the solution

was seeded with the respective chromane ct-7 or triturated, then

maintained at ꢀ18^ꢁС for the rest of the time. The precipitate that

formed was collected by ﬁltration and washed with cold acetoni-

trile (3 ꢂ 0.1 mL). Chromanes ct-7aen were isolated as colourless

prisms.

2.5 Hz, 1H, H-7); ¹⁹F NMR (376 MHz, C₆D₆)

d

87.5 (d, J ¼ 6.6 Hz, CF₃);

¹³C NMR (101 MHz, C₆D₆)

d 28.4, 29.0, 43.3, 46.9, 50.1, 65.8, 71.9 (q,

J ¼ 34.4 Hz, C-2), 77.1, 106.9, 118.6, 120.1, 122.9 (q, J ¼ 280.9 Hz, CF₃),

125.9, 128.5, 128.7, 150.3, 151.2. Anal. Calcd. for C₁₉H₂₀ClF₃N₂O₄: С,

52.73; Н, 4.66; N, 6.47. Found: С, 52.80; Н, 4.77; N, 6.57.

4.2.5. 4-{(5R*)-[(2S*,3R*,4S*)-6-Bromo-3-nitro-2-(triﬂuoromethyl)

chroman-4-yl]cyclopenten-1-yl}morpholine (ct-7e)

Yield 0.34 g (72%), m.p. 127e128 ^ꢁC (decomp.). IR (ATR): 1629,

4.2.1. 4-{(5R*)-[(2S*,3R*,4S*)-3-Nitro-2-(triﬂuoromethyl)chroman-

4-yl]cyclopent-1-yl}morpholine (ct-7a)

1555, 1477, 1453, 1410, 1374, 1327 cm^ꢀ^{1 1}H NMR (400 MHz, C₆D₆)

;

d

1.25e2.11 (m, 8H, 2 CH₂, N(CH₂)₂), 2.58e2.65 (m, 1H, H-5⁰), 2.77

Yield 0.23 g (58%), m.p. 117e118 ^ꢁC (decomp.). IR (ATR): 1626,

(br d, J ¼ 2.7 Hz, 1H, H-4), 2.78e2.88 (m, 2H, O(CHH)₂), 3.06 (ddd,

J ¼ 11.2, 6.6, 2.8 Hz, 2H, O(CHH)₂), 4.25 (br s, 1H, ¼CH), 4.70 (qd,

J ¼ 6.6, 1.9 Hz, 1H, H-2), 4.88 (dd, J ¼ 1.9, 1.0 Hz, 1H, H-3), 6.49 (d,

J ¼ 8.5 Hz, 1H, H-8), 6.84e6.89 (m, 2H, H-5, H-7); ¹⁹F NMR

1557, 1490, 1453, 1377, 1336 cm^ꢀ^{1 1}H NMR (400 MHz, C₆D₆)

;

d

1.31e2.13 (m, 8H, 2 CH₂, N(CH₂)₂), 2.74e2.90 (m, 3H, H-5⁰,

O(CHH)₂), 2.94 (br d, J ¼ 2.5 Hz, 1H, H-4), 3.08 (ddd, J ¼ 11.2, 6.6,

2.9 Hz, 2H, O(CHH)₂), 4.29 (br s, 1H, ¼CH), 4.85 (qd, J ¼ 6.6, 2.0 Hz,

1H, H-2), 4.97 (dd, J ¼ 2.0, 0.7 Hz, 1H, H-3), 6.59 (dd, J ¼ 7.9, 1.5 Hz,

1H, H-8), 6.64 (td, J ¼ 7.8,1.2 Hz,1H, H-7), 6.79 (td, J ¼ 8.0,1.5 Hz,1H,

H-6), 6.85 (dd, J ¼ 8.1, 1.2 Hz, 1H, H-5); ¹⁹F NMR (376 MHz, C₆D₆)

(376 MHz, C₆D₆)

d

87.5 (d, J ¼ 6.6 Hz, CF₃). Anal. Calcd. for

C₁₉H₂₀BrF₃N₂O₄: С, 47.81; Н, 4.22; N, 5.87. Found: С, 47.79; Н, 4.14;

N, 5.90.

d

87.5 (d, J ¼ 6.6 Hz, CF₃); ¹³C NMR (101 MHz, C₆D₆)

d 28.9, 29.3,

43.7, 47.1, 50.0, 65.8, 71.9 (q, J ¼ 34.1, C-2), 77.6, 106.5, 117.4, 121.1,

122.4, 123.1 (q, J ¼ 280.4, CF₃), 128.4, 129.0, 150.7, 152.8. Anal. Calcd.

for C₁₉H₂₁F₃N₂O₄: С, 57.28; Н, 5.31; N, 7.03. Found: С, 57.21; Н, 5.41;

N, 6.96.

4.2.6. 4-{(5R*)-[(2S*,3R*,4S*)-6,8-Dichloro-3-nitro-2-

(triﬂuoromethyl)chroman-4-yl]cyclopenten-1-yl}morpholine (ct-7f)

Yield 0.36 g (71%), m.p. 147e148 ^ꢁC (decomp.). IR (ATR): 1630,

1558, 1460, 1437, 1413, 1394, 1373, 1345, 1325 cm^ꢀ^{1 1}H NMR

;

(400 MHz, C₆D₆) d 1.20e2.02 (m, 8H, 2 CH₂, N(CH₂)₂), 2.51e2.57 (m,

1H, H-5⁰), 2.73 (br d, J ¼ 2.7 Hz, 1H, H-4), 2.80e2.90 (m, 2H,

O(CHH)₂), 3.08 (ddd, J ¼ 11.3, 6.6, 2.9 Hz, 2H, O(CHH)₂), 4.23 (br s,

1H, ¼CH), 4.70 (qd, J ¼ 6.4, 2.1 Hz, 1H, H-2), 4.85 (dd, J ¼ 2.1, 1.0 Hz,

1H, H-3), 6.53 (d, J ¼ 2.1 Hz, 1H, H-5/H-7), 6.97 (d, J ¼ 2.1 Hz, 1H, H-

4.2.2. 4-{(5R*)-[(2S*,3R*,4S*)-6-Methoxy-3-nitro-2-

(triﬂuoromethyl)chroman-4-yl]cyclopenten-1-yl}morpholine (ct-

7b)

Yield 0.21 g (50%), m.p. 120e121 ^ꢁC (decomp.). IR (ATR): 1627,

1558, 1496, 1469, 1450, 1426, 1379, 1333 cm^ꢀ1; ¹H NMR (400 MHz,

7/H-5); ¹⁹F NMR (376 MHz, C₆D₆)

d

87.6 (d, J ¼ 6.4 Hz, CF₃); ¹³C NMR

C₆D₆) d

1.20e2.23 (m, 8H, 2 CH₂, N(CH₂)₂), 2.82e2.89 (1H, m, H-5⁰),

(101 MHz, C₆D₆)

d 28.4, 29.2, 43.4, 47.0, 50.0, 65.9, 72.2 (q,

2.90e2.98 (m, 2H, O(CHH)₂), 3.00 (br d, J ¼ 2.5 Hz, 1H, H-4), 3.14

(ddd, J ¼ 11.4, 6.6, 2.8 Hz, 2H, O(CHH)₂), 3.26 (s, 3H, MeO), 4.30 (br s,

1H, ¼CH), 4.86 (qd, J ¼ 6.6, 1.9 Hz, 1H, H-2), 4.97 (dd, J ¼ 1.9, 0.9 Hz,

1H, H-3), 6.39 (dd, J ¼ 9.0, 2.9 Hz,1H, H-7), 6.50 (d, J ¼ 2.9 Hz,1H, H-

J ¼ 34.6 Hz, C-2), 76.8, 107.4, 119.3, 121.3, 122.6 (q, J ¼ 276.2 Hz, CF₃),

124.0, 127.1, 128.9147.3, 150.1. Anal. Calcd. for C₁₉H₁₉Cl₂F₃N₂O₄: С,

48.84; Н, 4.10; N, 6.00. Found: С, 49.00; Н, 4.30; N, 5.92.

5), 6.79 (d, J ¼ 9.0 Hz, 1H, H-8); ¹⁹F NMR (376 MHz, C₆D₆)

d 87.6 (d,

J ¼ 6.6 Hz, CF₃); ¹³C NMR (101 MHz, C₆D₆)

d

28.9, 29.3, 43.7, 47.2,

4.2.7. 4-{(5R*)-[(2S*,3R*,4S*)-6,8-Dibromo-3-nitro-2-

(triﬂuoromethyl)chroman-4-yl]cyclopenten-1-yl}morpholine (ct-

7g)

50.1, 55.5, 65.9, 71.7 (q, J ¼ 31.5 Hz, C-2), 77.7, 106.5, 113.6, 114.5,

118.0, 123.2 (q, J ¼ 279.8 Hz, CF₃), 124.6, 147.2, 150.7, 155.3. HRMS

(ESI): calcd. for 429.1632 [MþH]^þC₂₀H₂₄F₃N₂O₅, found 429.1636.

Yield 0.37 g (66%), m.p. 137e138 ^ꢁC (decomp.). IR (ATR): 1630,

1560, 1456, 1372 cm^ꢀ1; ¹H NMR (400 MHz, C₆D₆)

d 1.19e2.03 (m, 2

4.2.3. 4-{(5R*)-[(2S*,3R*,4S*)-8-Ethoxy-3-nitro-2-(triﬂuoromethyl)

chroman-4-yl]cyclopenten-1-yl}morpholine (ct-7c)

CH₂, 8H, N(CH₂)₂), 2.48e2.57 (m, 1H, H-5⁰), 2.71 (br d, J ¼ 2.8 Hz,1H,

H-4), 2.76e2.95 (m, 2H, O(CHH)₂), 3.09 (ddd, J ¼ 11.3, 6.6, 2.9 Hz,

2H, O(CHH)₂), 4.22 (br s,1H, ¼CH), 4.68 (qd, J ¼ 6.4, 2.2 Hz,1H, H-2),

4.83 (dd, J ¼ 2.2, 1.0 Hz, 1H, H-3), 6.73 (d, J ¼ 2.1 Hz, 1H, H-5/H-7),

Yield 0.22 g (49%), m.p. 118e119 ^ꢁC (decomp.). IR (ATR): 1620,

1589, 1563, 1474, 1450, 1399, 1378, 1340 cm^ꢀ1; ¹H NMR (400 MHz,

C₆D₆)

d

1.08 (t, J ¼ 7.0 Hz, 3H, Me), 1.34e2.19 (8H, m, 2 CH₂,

7.32 (d, J ¼ 2.1 Hz, 1H, H-7/H-5). ¹⁹F NMR (376 MHz, C₆D₆)

d 87.6 (d,

N(CH₂)₂), 2.87e2.99 (m, 3H, O(CHH)₂, H-5⁰), 3.03 (1H, d, J ¼ 2.4 Hz,

H-4), 3.15 (ddd, J ¼ 11.0, 6.6, 2.8, 2H, O(CHH)₂), 3.63 (dq, J ¼ 9.5,

7.0 Hz, 1H, OCHH), 3.69 (dq, J ¼ 9.5, 7.0 Hz, 1H, OCHH), 4.30 (br s,

1H, ¼CH), 4.90 (qd, J ¼ 6.6, 1.8 Hz, 1H, H-2), 5.00 (br d, J ¼ 1.8, 1H, H-

3), 6.36 (d, J ¼ 7.7 Hz, 1H, H-5/H-7), 6.51 (d, J ¼ 7.8 Hz, 1H, H-7/H-5),

J ¼ 3.3 Hz, CF₃); ¹³C NMR (101 MHz, C₆D₆)

d 28.4, 29.2, 43.4, 47.0,

50.0, 65.9, 72.3 (q, J ¼ 34.8 Hz, C-2), 76.8, 107.4, 112.4,114.5, 122.6 (q,

J ¼ 280.8 Hz, CF₃), 124.5, 130.7, 134.4, 148.6, 150.1. Anal. Calcd. for

C₁₉H₁₉Br₂F₃N₂O₄: С, 41.03; Н, 3.44; N, 5.04. Found: С, 41.07; Н, 3.50;

N, 5.02.

Please cite this article in press as: Korotaev VY, et al., Highly diastereoselective synthesis of novel 2,3,4-trisubstituted chromanes via the reaction

of 3-nitro-2-(trihalomethyl)- and 3-nitro-2-phenyl-2H-chromenes with 1-morpholinocyclopentene, Tetrahedron (2017), http://dx.doi.org/

10.1016/j.tet.2017.07.003

8

V.Y. Korotaev et al. / Tetrahedron xxx (2017) 1e16

4.2.8. 4-{(5R*)-[(2S*,3R*,4S*)-3-Nitro-2-(trichloromethyl)chroman-

4-yl]cyclopenten-1-yl}morpholine (ct-7h)

1554, 1479, 1461, 1449, 1375, 1329 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃)

1.92e2.57 (m, 8H, 2 CH₂, N(CH₂)₂), 2.95e3.15 (m, 2H, O(CHH)₂),

d

Yield 0.30 g (68%), m.p. 151e152 ^ꢁC (decomp.). IR (ATR): 1622,

3.33 (ddd, J ¼ 11.3, 6.6, 3.0 Hz, 2H, O(CHH)₂), 3.36 (d, J ¼ 2.9 Hz, 1H,

H-4), 3.47e3.52 (m, 1H, H-5⁰), 4.81 (br s, 1H, ¼CH), 4.97 (d,

J ¼ 1.5 Hz, 1H, H-2), 5.41 (d, J ¼ 1.5 Hz, 1H, H-3), 7.04 (d, J ¼ 8.7 Hz,

1H, H-8), 7.37 (dd, J ¼ 8.7, 2.2 Hz, 1H, H-7), 7.44 (d, J ¼ 2.2 Hz, 1H, H-

1584, 1555, 1490, 1451, 1376, 1337 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

1.91e2.60 (m, 8H, 2 CH₂, N(CH₂)₂), 2.90e3.12 (m, 2H, O(CHH)₂),

3.21e3.30 (m, 2H, O(CHH)₂), 3.39 (d, J ¼ 2.7 Hz, 1H, H-4), 3.49e3.56

(m, 1H, H-5⁰), 4.78 (br s, 1H, ¼CH), 5.04 (d, J ¼ 1.4 Hz, 1H, H-2), 5.43

(d, J ¼ 1.4 Hz, 1H, H-3), 7.04 (td, J ¼ 7.5, 1.0 Hz, 1H, H-6), 7.13 (dd,

J ¼ 8.2, 1.0 Hz, 1H, H-8), 7.21e7.31 (m, 2H, H-5, H-7); ¹³C NMR

5); ¹³C NMR (126 MHz, CDCl₃)

d 29.1, 29.4, 45.8, 47.1, 49.9, 65.9, 77.4,

81.4, 95.6, 107.9, 114.5, 118.9, 123.5, 131.0, 131.1, 149.8, 152.5. Anal.

Calcd. for C₁₉H₂₀BrCl₃N₂O₄: С, 43.33; Н, 3.83; N, 5.32. Found: С,

43.33; Н, 3.73; N, 5.29.

(126 MHz, CDCl₃)

d 29.2, 29.4, 46.2, 47.2, 49.7, 65.9, 77.9, 81.3, 96.0,

107.3, 117.2, 121.2, 122.4, 128.2, 128.5, 150.1, 153.3. Anal. Calcd. for

₁₉H₂₁Cl₃N₂O₄: C, 50.97; Н, 4.73; N, 6.26. Found: С, 50.96; Н, 4.77;

N, 6.22.

C

4.2.13. 4-{(5R*)-[(2S*,3R*,4S*)-6,8-Dichloro-3-nitro-2-

(trichloromethyl)chroman-4-yl]cyclopenten-1-yl}morpholine (ct-

7m)

4.2.9. 4-{(5R*)-[(2S*,3R*,4S*)-6-Methoxy-3-nitro-2-

(trichloromethyl)chroman-4-yl]cyclopenten-1-yl}morpholine (ct-

7i)

Yield 0.40 g (78%), m.p. 194e195 ^ꢁC (decomp.). IR (ATP): 1627,

1553, 1461, 1439, 1372, 1335 cm^ꢀ^{1 1}H NMR (400 MHz, CDCl₃)

;

d

1.91e2.60 (m, 8H, 2 CH₂, N(CH₂)₂), 3.01e3.15 (m, 2H, O(CHH)₂),

Yield 0.30 g (62%), m.p. 164e165 ^ꢁC (decomp.). IR (ATR): 1631,

3.32e3.36 (m, 2H, O(CHH)₂), 3.37 (d, J ¼ 2.5 Hz, 1H, H-4), 3.43e3.49

(m, 1H, H-5⁰), 4.84 (br s, 1H, ¼CH), 4.97 (d, J ¼ 1.2 Hz, 1H, H-2), 5.41

(br s, 1H, H-3), 7.20 (d, J ¼ 2.1 Hz, 1H, H-5/H-7), 7.36 (d, J ¼ 2.1 Hz,

1556, 1495, 1449, 1424, 1378, 1332 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

1.92e2.59 (m, 8H, 2 CH₂, N(CH₂)₂), 2.97e3.16 (m, 2H, O(CHH)₂),

3.31 (ddd, J ¼ 11.2, 6.5, 3.0 Hz, 2H, O(CHH)₂), 3.36 (d, J ¼ 2.4 Hz, 1H,

H-4), 3.47e3.53 (m, 1H, H-5⁰), 3.78 (s, 3H, MeO), 4.79 (br s,

1H, ¼CH), 5.03 (d, 1H, J ¼ 1.4, H-2), 5.41 (d, J ¼ 1.4 Hz, 1H, H-3), 6.80

(d, J ¼ 2.8 Hz, 1H, H-5), 6.83 (dd, J ¼ 8.8, 2.8 Hz, 1H, H-7), 7.07 (d,

1H, H-7/H-5); ¹³C NMR (101 MHz, CDCl₃)

d 29.0, 29.3, 46.0, 47.3,

49.8, 66.0, 77.2, 81.6, 95.2, 108.4, 123.3, 124.3, 126.5, 127.0, 128.5,

147.9, 149.6. Anal. Calcd. for C₁₉H₁₉Cl₅N₂O₄: С, 44.17; Н, 3.71; N,

5.42. Found: С, 44.25; Н, 3.81; N, 5.62.

J ¼ 8.8 Hz, 1H, H-8); ¹³C NMR (101 MHz, CDCl₃)

d 29.3 (2C), 46.5,

47.2, 49.8, 55.8, 65.9, 77.8, 81.5, 96.0, 107.3, 113.3, 113.9, 117.8, 132.9,

147.5, 150.1, 154.9. Anal. Calcd for C₂₀H₂₃Cl₃N₂O₅: С, 50.28; Н, 4.85;

N, 5.86. Found: С, 50.26; Н, 4.72; N, 5.86.

4.2.14. 4-{(5R*)-[(2S*,3R*,4S*)-6,8-Dibromo-3-nitro-2-

(trichloromethyl)chroman-4-yl]cyclopenten-1-yl}morpholine (ct-

7n)

Yield 0.50 g (83%), m.p. 169e170 ^ꢁC (decomp.). IR (ATR): 1626,

4.2.10. 4-{(5R*)-[(2S*,3R*,4S*)-8-Ethoxy-3-nitro-2-

(trichloromethyl)chroman-4-yl]cyclopenten-1-yl}morpholine (ct-

7j)

1552, 1455, 1372,1333 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d 1.90e2.60

(m, 8H, 2 CH₂, N(CH₂)₂), 3.07 (br s, 2H, O(CHH)₂), 3.31e3.37 (m, 2H,

O(CHH)₂), 3.38 (d, J ¼ 3.0 Hz, 1H, H-4), 3.42e3.49 (m, 1H, H-5⁰), 4.84

(br s,1H, ¼CH), 4.96 (d, J ¼ 1.5 Hz,1H, H-2), 5.39 (d, J ¼ 1.5 Hz,1H, H-

3), 7.39 (d, J ¼ 2.1 Hz, 1H, H-5/H-7), 7.66 (dd, J ¼ 2.1 Hz, 1H, H-7/H-

Yield 0.26 g (52%), m.p. 142e143 ^ꢁC (decomp.). IR (ATR): 1629,

1583, 1556, 1486, 1467, 1450, 1378, 1349, 1337 cm^ꢀ^{1 1}H NMR

;

(400 MHz, CDCl₃)

d

1.43 (t, J ¼ 7.0 Hz, 3H, Me), 1.89e2.60 (m, 8H, 2

5); ¹³C NMR (126 MHz, C₆D₆)

d 28.9, 29.4, 45.7, 47.0, 50.0, 66.0, 77.3,

CH₂, N(CH₂)₂), 2.95e3.17 (m, 2H, O(CHH)₂), 3.24e3.34 (m, 2H,

O(CHH)₂), 3.47e3.55 (m, 1H, H-5⁰), 3.39 (d, J ¼ 2.3 Hz, 1H, H-4), 4.13

(dq, J ¼ 9.7, 7.0 Hz, 1H, OCHH), 4.16 (dq, J ¼ 9.7, 7.0 Hz, 1H, OCHH),

4.78 (br s, 1H, ¼CH), 5.04 (d, J ¼ 1.2 Hz, 1H, H-2); 5.42 (br s, 1H, H-3),

6.87 (dd, J ¼ 7.5, 1.7 Hz, 1H, H-5/H-7), 6.90 (dd, J ¼ 7.5, 1.7 Hz, 1H, H-

7/H-5), 6.94 (t, J ¼ 7.5 Hz, 1H, H-6); ¹³C NMR (126 MHz, CDCl₃)

82.1, 95.8, 107.9, 112.5, 114.2, 125.1, 130.4, 134.1, 149.8, 149.9. Anal.

Calcd. for C₁₉H₁₉Br₂Cl₃N₂O₄: С, 37.69; Н, 3.16; N, 4.63. Found: С,

37.56; Н, 3.10; N, 4.62.

4.3. General procedure for the synthesis of 2-Ph-chromanes ct-

7oeq

d

15.1, 29.3, 29.6, 46.3, 47.2, 50.0, 65.9, 66.1, 78.1, 82.0, 96.9, 106.9,

114.4, 120.9, 121.7, 122.6, 145.0, 148.4, 150.5. Anal. Calcd. for

₂₁H₂₅Cl₃N₂O₅: С, 51.29; Н, 5.12; N, 5.70. Found: С, 50.99; Н, 5.12; N,

Freshly distilled 1-morpholinocyclopentene (6) (0.19 g,

1.2 mmol) was added to a solution of the appropriate chromene 2

(1.0 mmol) in anhydrous t-butyl methyl ether (0.50e0.75 mL) and

the mixture was maintained at 20^ꢁС for the time indicated in

Table 1. The precipitate that formed was collected by ﬁltration and

washed with cold acetonitrile (3 ꢂ 0.1 mL). Chromanes ct-7oeq

were obtained as white powders.

C

5.75.

4.2.11. 4-{(5R*)-[(2S*,3R*,4S*)-6-Chloro-3-nitro-2-

(trichloromethyl)chroman-4-yl]cyclopenten-1-yl}morpholine (ct-

7k)

Yield 0.36 g (74%), m.p. 156e157 ^ꢁC (decomp.). IR (ATR): 1631,

1555, 1483, 1449, 1376, 1333 cm^ꢀ1

;

¹H NMR (500 MHz, CDCl₃)

4.3.1. 4-{(5R*)-[(2R*,3R*,4S*)-3-Nitro-2-phenylchroman-4-yl]

cyclopenten-1-yl}morpholine (ct-7o)

d

1.92e2.58 (m, 8H, 2 CH₂, N(CH₂)₂), 2.94e3.15 (m, 2H, O(CHH)₂),

3.33 (ddd, J ¼ 11.3, 6.6, 3.0 Hz, 2H, O(CHH)₂), 3.35 (d, J ¼ 3.1 Hz, 1H,

H-4), 3.46e3.52 (m, 1H, H-5⁰), 4.82 (br s, 1H, ¼CH), 4.98 (d,

J ¼ 1.5 Hz, 1H, H-2), 5.41 (d, J ¼ 1.5 Hz, 1H, H-3), 7.09 (d, J ¼ 8.8 Hz,

1H, H-8), 7.23 (dd, J ¼ 8.8, 2.3 Hz, 1H, H-7), 7.29 (d, J ¼ 2.3 Hz, 1H, H-

Yield 0.29 g (72%), m.p. 137e138 ^ꢁC (decomp.). IR (ATR): 1625,

1582, 1543, 1486, 1451, 1375, 1326 cm^ꢀ1; ¹H NMR (400 MHz, C₆D₆)

d

1.45e2.31 (m, 8H, 2 CH₂, N(CH₂)₂), 2.82e3.04 (m, 3H, H-5⁰,

O(CHH)₂), 3.09 (ddd, J ¼ 11.3, 6.7, 2.8 Hz, 2H, O(CHH)₂), 3.15 (d,

J ¼ 2.8 Hz,1H, H-4), 4.42 (br s,1H, ¼CH), 4.93 (d, J ¼ 2.0 Hz,1H, H-2),

5.42 (d, J ¼ 2.0 Hz, 1H, H-3), 6.72 (td, J ¼ 7.6, 1.0 Hz, 1H, H-7), 7.01

(dd, J ¼ 7.8, 1.0 Hz, 1H, H-8), 6.95 (td, J ¼ 7.6, 1.3 Hz, 1H, H-7), 7.07

(dd, J ¼ 7.8, 1.3 Hz, 1H, H-5), 7.10 (tt, J ¼ 7.4, 1.2 Hz, 1H, H_p), 7.20 (t,

J ¼ 7.5 Hz, 2H, H_m), 7.53 (br d, J ¼ 7.6 Hz, 2H, H_o); ¹³C NMR (126 MHz,

5); ¹³C NMR (126 MHz, CDCl₃)

d 29.1, 29.4, 46.0, 47.1, 49.9, 65.9, 77.5,

81.5, 95.7, 107.9, 118.6, 123.0, 128.1, 128.3, 134.5, 149.9, 152.0. Anal.

Calcd. for C₁₉H₂₀Cl₄N₂O₄: С, 47.33; Н, 4.18; N, 5.81. Found: С, 47.29;

Н, 4.11; N, 5.67.

4.2.12. 4-{(5R*)-[(2S*,3R*,4S*)-6-Bromo-3-nitro-2-

(trichloromethyl)chroman-4-y])cyclopenten-1-yl}morpholine (ct-

7l)

C₆D₆) d 29.5, 30.3, 44.1, 47.9, 50.8, 66.5, 75.0, 86.5, 105.6, 118.1, 121.9,

122.2, 126.6, 128.5, 129.4, 129.6, 129.7, 137.8, 152.7, 155.4. Anal.

Calcd. for C₂₄H₂₆N₂O₄: С, 70.92; Н, 6.45; N, 6.89. Found: С, 70.63; Н,

6.43; N, 6.80.

Yield 0.41 g (77%), m.p. 163e164 ^ꢁC (decomp.). IR (ATR): 1631,

Please cite this article in press as: Korotaev VY, et al., Highly diastereoselective synthesis of novel 2,3,4-trisubstituted chromanes via the reaction

of 3-nitro-2-(trihalomethyl)- and 3-nitro-2-phenyl-2H-chromenes with 1-morpholinocyclopentene, Tetrahedron (2017), http://dx.doi.org/

10.1016/j.tet.2017.07.003

V.Y. Korotaev et al. / Tetrahedron xxx (2017) 1e16

9

4.3.2. 4-{(5R*)-[(2R*,3R*,4S*)-6-Methoxy-3-nitro-2-

4.4.1.2. Compound tt-7a. ¹H NMR (500 MHz, C₆D₆)

d

1.13e2.62 (m,

phenylchroman-4-yl]cyclopenten-1-yl}morpholine (ct-7p)

8H, 3 CH₂, N(CH₂)₂), 2.94e3.02 (m, 1H, H-5⁰), 3.80 (dd, J ¼ 6.2,

4.4 Hz, 1H, H-4), 4.05 (dq, J ¼ 10.2, 5.5 Hz, 1H, H-2), 4.51 (br s,

1H, ¼CH), 5.02 (dd, J ¼ 10.2, 6.2 Hz, 1H, H-3) (signals of O(CH₂)₂and

Yield 0.25 g (58%), m.p. 149e150 ^ꢁC (decomp.). IR (ATR): 1630,

1545, 1493, 1453, 1440, 1427, 1376, 1354, 1322 cm^ꢀ^{1 1}H NMR

;

(500 MHz, C₆D₆)

d

1.44e2.40 (m, 8H, 2 CH₂, N(CH₂)₂), 2.92e3.06 (m,

aromatic protons are masked); ¹⁹F NMR (471 MHz, C₆D₆)

d

86.3 (d,

3H, H-5⁰, O(CHH)₂), 3.14 (ddd, J ¼ 10.9, 6.6, 2.8 Hz, 2H, O(CHH)₂),

3.20 (d, J ¼ 2.9 Hz, 1H, H-4), 3.33 (s, 3H, MeO), 4.42 (br s, 1H, ¼CH),

4.91 (d, J ¼ 2.2 Hz, 1H, H-2), 5.42 (d, J ¼ 2.2 Hz, 1H, H-3), 6.56 (dd,

J ¼ 8.9, 2.9 Hz, 1H, H-7), 6.64 (d, J ¼ 2.9 Hz, 1H, H-5), 6.99 (d,

J ¼ 8.9 Hz, 1H, H-8), 7.11 (tt, J ¼ 7.5, 1.2 Hz, 1H, H_p), 7.21 (t, J ¼ 7.5 Hz,

2H, H_m), 7.54 (br d, J ¼ 7.5 Hz, 2H, H_o). ¹³C NMR (101 MHz, C₆D₆)

J ¼ 5.5 Hz, CF₃); ¹³C NMR (101 MHz, C₆D₆)

d 23.6, 29.1, 42.1, 48.8,

49.5, 66.5, 75.4 (q, J ¼ 32.7 Hz, C-2), 81.1, 105.1, 117.6, 123.1 (q,

J ¼ 281.1 Hz, CF₃), 124.2, 124.9, 128.5, 149.9, 153.7 (one C is not

observed).

4.4.1.3. Compound tt-7'a. ¹H NMR (500 MHz, C₆D₆)

d 1.13e2.44 (m,

d

28.8, 29.7, 43.5, 47.6, 50.2, 55.4, 66.0, 74.7, 86.1, 105.1, 113.6, 114.5,

8H, 3 CH₂, N(CH₂)₂), 3.03e3.09 (m, 1H, H-5⁰), 3.40 (t, J ¼ 4.8 Hz, 4H,

O(CH₂)₂), 3.70 (dd, J ¼ 7.9, 2.5 Hz, 1H, H-4), 4.11 (dq, J ¼ 10.3, 5.4 Hz,

1H, H-2), 4.43 (br s, 1H, ¼CH), 5.04 (dd, J ¼ 10.3, 7.9 Hz, 1H, H-3)

(signals of aromatic protons are masked); ¹⁹F NMR (471 MHz, C₆D₆)

118.0, 122.2, 126.1, 128.9, 129.0, 137.4, 149.0, 152.1, 154.7. Anal. Calcd.

for C₂₅H₂₈N₂O₅: С, 68.79; Н, 6.47; N, 6.42. Found: С, 68.80; Н, 6.50;

N, 6.38.

d

86.0 (d, J ¼ 5.4 Hz, CF₃); ¹³C NMR (101 MHz, C₆D₆)

d 23.1, 24.3,

4.3.3. 4-{(5R*)-[(2R*,3R*,4S*)-6-Bromo-3-nitro-2-phenylchroman-

4-yl]cyclopenten-1-yl}morpholine (ct-7q)

42.6, 46.9, 50.0, 66.5, 74.2 (q, J ¼ 32.8 Hz, C-2), 83.8, 100.2, 117.3,

122.3, 123.2 (q, J ¼ 281.6 Hz, CF₃), 133.3, 129.3, 151.0, 153.5 (one C is

not observed). Anal. Calcd. for C₁₉H₂₁F₃N₂O₄: С, 57.28; Н, 5.31; N,

7.03. Found: С, 57.34; Н, 5.17; N, 7.11.

Yield 0.40 g (82%), m.p. 183e184 ^ꢁC (decomp.). IR (ATR): 1631,

1546, 1476, 1453, 1440, 1372, 1349, 1325 cm^ꢀ1; ¹H NMR (400 MHz,

C₆D₆)

d

1.35e2.26 (m, 8H, 2 CH₂, N(CH₂)₂), 2.75e2.90 (m, 3H, H-5⁰,

O(CHH)₂), 2.96 (d, J ¼ 3.1 Hz, 1H, H-4), 3.08 (ddd, J ¼ 10.8, 6.6,

2.8 Hz, 2H, O(CHH)₂), 4.37 (br s, 1H, ¼CH), 4.82 (d, J ¼ 2.2 Hz, 1H, H-

2), 5.27 (d, J ¼ 2.2 Hz, 1H, H-3), 6.71 (d, J ¼ 7.5 Hz, 1H, H-8), 7.01 (dd,

J ¼ 7.5, 2.3 Hz, 1H, H-7), 7.02 (d, J ¼ 2.3 Hz, 1H, H-5), 7.09 (tt, J ¼ 7.4,

1.2 Hz,1H, H_p), 7.18 (t, J ¼ 7.5 Hz, 2H, H_m), 7.18 (dd, J ¼ 7.6, 1.2 Hz, 2H,

4.4.2. 4-{2-[(2S*,3S*,4R*)-6-Methoxy-3-nitro-2-(triﬂuoromethyl)

chroman-4-yl]cyclopenten-1-yl}morpholine (tt-8b), 4-{(5S*)-

[(2S*,3S*,4R*)-6-methoxy-3-nitro-2-(triﬂuoromethyl)chroman-4-yl]

cyclopenten-1-yl}morpholine (tt-7b) and 4-{(5R*)-[(2S*,3S*,4R*)-6-

methoxy-3-nitro-2-(triﬂuoromethyl)chroman-4-yl]cyclopenten-1-

yl}morpholine (tt-7'b)

Yield in MeOH 0.25 g (59%), yield in MeCN 0.18 g (42%), m.p.

150e151 ^ꢁC (decomp.). IR (ATR): 1559, 1541, 1520, 1496, 1461, 1421,

1371, 1340 cm^ꢀ1. Ratio of tautomers tt-8b:tt-7b:tt-7'b ¼ 76:17:7 in

5 min and 61:27:12 in 24 h (C₆D₆).

H_o); ¹³C NMR (126 MHz, C₆D₆)

d 29.0, 30.0, 43.4, 47.4, 50.6, 66.3,

75.0, 85.7, 105.8, 113.8, 119.6, 124.3, 126.3, 129.3, 129.4, 131.3, 132.1,

137.1, 152.1, 154.2. Anal. Calcd. for C₂₄H₂₅BrN₂O₄: С, 59.39; Н, 5.19;

N, 5.77. Found: С, 59.17; Н, 5.15; N, 5.96.

4.4. General procedure for the synthesis of 2-CF₃-chromanes tt-

8aee

4.4.2.1. Compound tt-8b. ¹H NMR (500 MHz, C₆D₆)

d 1.40e2.05 (m,

Freshly distilled 1-morpholinocyclopentene (6) (0.16 g,

1.0 mmol) was added to a solution of the appropriate chromene 2

(1.0 mmol) in acetonitrile or methanol (0.50 mL) and the mixture

was maintained at 35 ^ꢁC for the time indicated in Table 1. In the case

if no precipitate was obtained within 1 h, the solution was seeded

with the respective chromane tt-8 or triturated, then maintained at

35 ^ꢁC for the rest of the time. The precipitate that formed was

collected by ﬁltration and washed with cold acetonitrile or meth-

anol (3 ꢂ 0.1 mL). Chromanes tt-8aee were obtained as colourless

prisms or white powders.

6H, 3 CH₂), 2.37e2.46 (m, 4H, N(CH₂)₂), 3.24 (s, 3H, MeO),

3.53e3.61 (m, 4H, O(CH₂)₂), 4.31 (dq, J ¼ 10.1, 5.4 Hz, 1H, H-2), 4.89

(d, J ¼ 11.0 Hz, 1H, H-4), 5.02 (dd, J ¼ 11.0, 10.1 Hz, 1H, H-3), 6.41 (dd,

J ¼ 8.9, 2.8 Hz, 1H, H-7), 6.59 (d, J ¼ 2.8 Hz, 1H, H-5), 6.75 (d,

J ¼ 8.9 Hz, 1H, H-8); ¹⁹F NMR (471 MHz, C₆D₆)

d

86.0 (d, J ¼ 5.4 Hz,

CF₃); ¹³C NMR (101 MHz, C₆D₆)

d 21.2, 28.3, 28.8, 40.3, 51.6, 55.1,

67.0, 73.7 (q, J ¼ 32.6 Hz, C-2), 80.9, 113.5, 113.7, 117.8, 121.3, 121.9,

123.3 (q, J ¼ 281.5 Hz, CF₃), 145.7, 154.8, 155.8.

4.4.2.2. Compound tt-7b. ¹H NMR (500 MHz, C₆D₆)

d 1.18e2.49 (m,

8H, 3 CH₂, N(CH₂)₂), 3.00e3.06 (m, 1H, H-5⁰), 3.27 (s, 3H, MeO),

3.49e3.63 (m, 4H, O(CH₂)₂), 3.82 (br t, J ¼ 5.2 Hz, 1H, H-4), 4.16 (dq,

J ¼ 10.3, 5.5 Hz, 1H, H-2), 4.51 (br s, 1H, ¼CH), 5.06 (dd, J ¼ 10.3,

6.2 Hz,1H, H-3), 6.38 (dd, J ¼ 8.9, 2.8 Hz,1H, H-7), 6.63 (d, J ¼ 2.8 Hz,

1H, H-5), 6.77 (d, J ¼ 8.9 Hz, 1H, H-8); ¹⁹F NMR (471 MHz, C₆D₆)

4.4.1. 4-{2-[(2S*,3S*,4R*)-3-Nitro-2-(triﬂuoromethyl)chroman-4-

yl]cyclopenten-1-yl}morpholine (tt-8a), 4-{(5S*)-[(2S*,3S*,4R*)-3-

nitro-2-(triﬂuoromethyl)chroman-4-yl]cyclopenten-1-yl}

morpholine (tt-7a) and 4-{(5R*)-[(2S*,3S*,4R*)-3-nitro-2-

(triﬂuoromethyl)chroman-4-yl]cyclopenten-1-yl}morpholine (tt-

7'a)

Yield in MeOH 0.31 g (78%), yield in MeCN 0.27 g (68%), m.p.

164e165 ^ꢁC (decomp.). IR (ATR): 1669, 1562, 1478, 1450, 1415, 1359,

1328 cm^ꢀ1. Ratio of tautomers tt-8a:tt-7a:tt-7'a ¼ 87:9:4 in 5 min

and 70:22:8 in 24 h (C₆D₆).

d

86.4 (d, J ¼ 5.5 Hz, CF₃); ¹³C NMR (101 MHz, C₆D₆)

d 23.1, 29.1, 42.6,

49.5, 50.0, 55.2, 66.4, 75.9 (q, J ¼ 32.5 Hz, C-2), 81.3, 105.2, 112.9,

114.4, 118.3, 123.2 (q, J ¼ 281.3 Hz, CF₃), 126.2, 147.7, 150.0, 155.7.

4.4.2.3. Compound tt-7'b. ¹H NMR (500 MHz, C₆D₆)

d 1.18e2.59 (m,

8H, 3 CH₂, N(CH₂)₂), 3.07e3.11 (m, 1H, H-5⁰), 3.26 (s, 3H, MeO),

3.41e3.45 (m, 4H, O(CH₂)₂), 3.73 (dd, J ¼ 8.0, 2.4 Hz, 1H, H-4), 4.17

(dq, J ¼ 10.1, 5.5 Hz, 1H, H-2), 4.41 (br s, 1H, ¼CH), 6.49 (dd, J ¼ 8.9,

2.8 Hz, 1H, H-7), 6.72 (d, J ¼ 8.9 Hz, 1H, H-8), 6.76 (d, J ¼ 2.8 Hz, 1H,

4.4.1.1. Compound tt-8a. ¹H NMR (500 MHz, C₆D₆)

d 1.43e2.05 (m,

6H, 3 CH₂), 2.37e2.46 (m, 4H, N(CH₂)₂), 3.54e3.62 (m, 4H, O(CH₂)₂),

4.27 (dq, J ¼ 10.1, 5.4 Hz, 1H, H-2), 4.84 (d, J ¼ 11.0 Hz, 1H, 4-CH),

4.98 (dd, J ¼ 11.0, 10.1 Hz, 1H, H-3), 6.75 (td, J ¼ 6.8, 1.0 Hz, 1H, H-6),

6.78e6.82 (m, 2H, H-5, H-8), 6.84e6.89 (m, 1H, H-7); ¹⁹F NMR

H-5) (signal of H-3 is masked); ¹⁹F NMR (471 MHz, C₆D₆)

d

86.1 (d,

J ¼ 5.5 Hz, CF₃); ¹³C NMR (101 MHz, C₆D₆)

d 23.6, 23.8, 42.7, 46.8,

(471 MHz, C₆D₆)

d

85.9 (d, J ¼ 5.4 Hz, CF₃); ¹³C NMR (101 MHz, C₆D₆)

48.9, 55.0, 66.4, 74.5 (q, J ¼ 32.6 Hz, C-2), 84.2, 100.2, 113.9, 114.1,

117.9, 122.7, 123.3 (q, J ¼ 281.3 Hz, CF₃), 147.5, 151.0, 156.5. Anal.

Calcd. for C₂₀H₂₃F₃N₂O₅: С, 56.07; Н, 5.41; N, 6.54. Found: С, 56.13;

Н, 5.45; N, 6.36.

d

21.1, 28.4, 28.8, 40.1, 51.6, 67.0, 73.5 (q, J ¼ 32.6 Hz, C-2), 80.5, 117.1,

120.7, 121.1, 123.0, 123.2 (q, J ¼ 281.6 Hz, C-2), 127.9, 128.9, 151.8,

154.8.

Please cite this article in press as: Korotaev VY, et al., Highly diastereoselective synthesis of novel 2,3,4-trisubstituted chromanes via the reaction

of 3-nitro-2-(trihalomethyl)- and 3-nitro-2-phenyl-2H-chromenes with 1-morpholinocyclopentene, Tetrahedron (2017), http://dx.doi.org/

10.1016/j.tet.2017.07.003

10

V.Y. Korotaev et al. / Tetrahedron xxx (2017) 1e16

4.4.3. 4-{2-[(2S*,3S*,4R*)-8-Ethoxy-3-nitro-2-(triﬂuoromethyl)

chroman-4-yl]cyclopenten-1-yl}morpholine (tt-8c), 4-{(5S*)-

[(2S*,3S*,4R*)-8-ethoxy-3-nitro-2-(triﬂuoromethyl)chroman-4-yl]

cyclopenten-1-yl}morpholine (tt-7c) and 4-{(5R*)-[(2S*,3S*,4R*)-8-

ethoxy-3-nitro-2-(triﬂuoromethyl)chroman-4-y])cyclopenten-1-yl}

morpholine (tt-7'c)

Yield in MeOH 0.25 g (39%), yield in MeCN 0.18 g (41%), m.p.

137e138 ^ꢁC (decomp.). IR (ATR): 1586, 1557, 1475, 1371 cm^ꢀ1. Ratio

of tautomers tt-8c:tt-7c:tt-7'c ¼ 75:21:4 in 5 min and 61:27:12 in

24 h (C₆D₆).

4.4.4.2. Compound tt-7d. ¹H NMR (500 MHz, C₆D₆)

d 1.24e2.45 (m,

8H, 2 CH₂, N(CH₂)₂), 2.73e2.81 (m, 1H, H-5⁰), 3.58e3.64 (m, 5H,

O(CH₂)₂, H-4), 3.98 (dq, J ¼ 10.2, 5.5 Hz, 1H, H-2), 4.46 (br s,

1H, ¼CH), 4.93 (dd, J ¼ 10.2, 6.2 Hz, 1H, H-3), 6.48 (d, J ¼ 8.8 Hz, 1H,

H-8), 6.75 (dd, J ¼ 8.8, 2.2 Hz, 1H, H-7), 6.87 (d, J ¼ 2.2 Hz, 1H, H-5);

¹⁹F NMR (471 MHz, C₆D₆)

(101 MHz, C₆D₆) d 23.6, 28.9, 42.0, 48.5, 49.5, 66.4, 75.5 (q,

d

86.4 (d, J ¼ 5.5 Hz, CF₃); ¹³C NMR

J ¼ 32.8 Hz, C-2), 80.7, 105.1, 119.0, 122.9 (q, J ¼ 281.0 Hz, C-2), 126.8,

128.5, 129.3, 134.1, 149.7, 152.1.

4.4.4.3. Compound tt-7'd. ¹H NMR (500 MHz, C₆D₆)

d 1.19e2.51 (m,

8H, 2 CH₂, N(CH₂)₂), 2.96e3.02 (m, 1H, 5⁰eCH), 3.40 (t, J ¼ 4.8 Hz,

4H, O(CH₂)₂), 4.06 (dq, J ¼ 10.1, 5.4 Hz,1H, H-2), 4.44 (br s,1H, ¼CH),

4.91 (dd, J ¼ 10.1, 7.5 Hz, 1H, H-3), 6.45 (d, J ¼ 8.8 Hz, 1H, H-8), 6.76

(dd, J ¼ 8.8, 2.1 Hz,1H, H-7), 7.12 (d, J ¼ 2.2 Hz, 1H, H-5) (signal of H-

4.4.3.1. Compound tt-8c. ¹H NMR (500 MHz, C₆D₆)

d 1.12 (t,

J ¼ 6.9 Hz, 3H, Me), 1.47e2.07 (m, 6H, 3 CH₂), 2.39e2.49 (m, 4H,

N(CH₂)₂), 3.54e3.67 (m, 6H, O(CH₂)₂, OCH₂Me), 4.37 (dq, J ¼ 9.9,

5.4 Hz,1H, H-2), 4.90 (d, J ¼ 10.9 Hz,1H, H-4), 5.03 (t, J ¼ 10.4 Hz,1H,

4 is masked); ¹⁹F NMR (471 MHz, C₆D₆)

d

86.0 (d, J ¼ 5.4 Hz, CF₃);

H-3), 6.50e6.55 (m, 2H, H-5, H-7), 6.78 (t, J ¼ 7.9 Hz, 1H, H-6); ¹⁹

F

¹³C NMR (101 MHz, C₆D₆)

d 23.1, 23.9, 42.2, 46.9, 49.9, 66.3, 74.3 (q,

NMR (471 MHz, C₆D₆)

d

86.1 (d, J ¼ 5.4 Hz, CF₃); ¹³C NMR (101 MHz,

J ¼ 32.8 Hz, C-2), 83.4,100.2,118.4,122.9 (q, J ¼ 281.3 Hz, C-2),123.6,

128.4, 129.5, 133.3, 150.5, 152.0. Anal. Calcd. for C₁₉H₂₀ClF₃N₂O₄: С,

52.73; Н, 4.66; N, 6.47. Found: С, 52.67; Н, 4.58; N, 6.43.

C₆D₆)

d

14.7, 21.2, 28.5, 29.1, 40.2, 51.5, 65.0, 67.0, 73.8 (q, J ¼ 32.9 Hz,

C-2), 80.9, 113.4, 119.3, 121.4, 122.2, 122.8, 123.3 (q, J ¼ 281.7 Hz,

CF₃), 142.3, 148.6, 154.4.

4.4.5. 4-{2-[(2S*,3S*,4R*)-6-Bromo-3-nitro-2-(triﬂuoromethyl)

chroman-4-yl]cyclopenten-1-yl}morpholine (tt-8e), 4-{(5S*)-

[(2S*,3S*,4R*)-6-bromo-3-nitro-2-(triﬂuoromethyl)chroman-4-yl]

cyclopenten-1-yl}morpholine (tt-7e) and 4-{(5R*)-[(2S*,3S*,4R*)-6-

bromo-3-nitro-2-(triﬂuoromethyl)chroman-4-yl]cyclopent-1-yl}

morpholine (tt-7'e)

Yield in MeOH 0.22 g (47%), Yield in MeCN 0.25 g (52%), m.p.

154e155 ^ꢁC (decomp.). IR (ATR): 1668, 1562, 1477, 1449, 1409,

1370 cm^ꢀ1. Ratio of tautomers tt-8e:tt-7e:tt-7'e ¼ 71:20:9 in 5 min

and 59:25:16 in 24 h (C₆D₆).

4.4.3.2. Compound tt-7c. ¹H NMR (500 MHz, C₆D₆)

d 1.13 (t,

J ¼ 6.9 Hz, 3H, Me), 1.21e2.63 (m, 8H, 2 CH₂, N(CH₂)₂), 3.01e3.07

(m, 1H, H-5⁰), 3.49e3.71 (m, 6H, O(CH₂)₂, OCH₂Me), 3.86 (br t,

J ¼ 5.0 Hz, 1H, H-4), 4.12 (dq, J ¼ 10.2, 5.5 Hz, 1H, H-2), 4.51 (br s,

1H, ¼CH), 5.07 (dd, J ¼ 10.2, 6.2 Hz, 1H, H-3), 6.44 (d, J ¼ 7.8 Hz, 1H,

H-7), 6.51 (d, J ¼ 8.0 Hz, 1H, H-7), 6.82 (t, J ¼ 7.9 Hz, 1H, H-6); ¹⁹F

NMR (471 MHz, C₆D₆)

C₆D₆)

d

86.5 (d, J ¼ 5.5 Hz, CF₃); ¹³C NMR (101 MHz,

d

14.7, 23.0, 29.1, 42.6, 46.5, 49.5, 66.4, 67.7, 75.9 (q,

J ¼ 32.9 Hz, C-2), 81.4, 105.1, 112.7, 119.5, 123.2 (q, J ¼ 280.9 Hz, CF₃),

124.0, 124.7, 144.1, 148.9, 150.1.

4.4.5.1. Compound tt-8e. ¹H NMR (400 MHz, C₆D₆)

d 1.35e2.01 (m,

4.4.3.3. Compound tt-7'c. ¹H NMR (500 MHz, C₆D₆)

d 1.13 (t,

6H, 3 CH₂), 2.29e2.41 (m, 4H, N(CH₂)₂), 3.54 (t, J ¼ 4.7 Hz, 4H,

O(CH₂)₂), 4.21 (dq, J ¼ 10.0, 5.3 Hz, 1H, H-2), 4.73 (d, J ¼ 10.9 Hz, 1H,

H-4), 4.88 (dd, J ¼ 10.9, 10.0 Hz, 1H, H-3), 6.42 (d, J ¼ 8.8 Hz, 1H, H-

8), 6.93 (dd, J ¼ 8.8, 2.2 Hz, 1H, H-7), 7.10 (dd, J ¼ 2.2, 1.1 Hz, 1H, H-

J ¼ 6.9 Hz, 3H, Me),1.21e2.62 (m, 8H, 2 CH₂, N(CH₂)₂), 3.07e3.11 (m,

1H, H-5⁰), 3.42 (t, J ¼ 4.7 Hz, 4H, O(CH₂)₂), 3.73 (dd, J ¼ 7.5, 2.6 Hz,

1H, H-4), 4.21 (dq, J ¼ 10.0, 5.5 Hz, 1H, H-2), 4.47 (br s, 1H, ¼CH),

5.13 (dd, J ¼ 10.0, 7.5 Hz, 1H, H-3), 6.72 (t, J ¼ 7.9 Hz, 1H, H-6)

(signals of OCH₂and aromatic proton H-5, H-7 are masked); ¹⁹F

5); ¹⁹F NMR (376 MHz, C₆D₆)

d

85.8 (d, J ¼ 5.3 Hz, CF₃).

NMR (471 MHz, C₆D₆)

C₆D₆)

d

86.2 (d, J ¼ 5.5 Hz, CF₃); ¹³C NMR (101 MHz,

4.4.5.2. Compound tt-7e. ¹H NMR (400 MHz, C₆D₆)

d

1.21e3.53 (m,

d

14.7, 23.6, 28.8, 43.3, 47.3, 50.0, 64.9, 65.3, 74.8 (q,

8H, 2 CH₂, N(CH₂)₂), 2.74e2.82 (m, 1H, H-5⁰), 3.58e3.67 (m, 5H,

O(CH₂)₂, H-4), 3.99 (dq, J ¼ 10.2, 5.6 Hz, 1H, H-2), 4.46 (br s,

1H, ¼CH), 4.92 (dd, J ¼ 10.2, 6.2 Hz, 1H, H-3), 6.43 (d, J ¼ 8.7 Hz, 1H,

H-8), 6.91 (dd, J ¼ 8.7, 2.1 Hz, 1H, H-7), 7.05 (d, J ¼ 2.1 Hz, 1H, H-5);

J ¼ 33.2 Hz, C-2), 84.0, 100.2, 113.1, 119.9, 123.3 (q, J ¼ 281.1 Hz, CF₃),

123.9, 124.3, 144.2, 149.2, 151.2. Anal. Calcd. for C₂₁H₂₅F₃N₂O₅: С,

57.01; Н, 5.70; N, 6.33. Found: С, 56.64; Н, 5.60; N, 6.26.

¹⁹F NMR (376 MHz, C₆D₆)

d

86.4 (d, J ¼ 5.6 Hz, CF₃).

4.4.4. 4-{2-[(2S*,3S*,4R*)-6-Chloro-3-nitro-2-(triﬂuoromethyl)

chroman-4-yl]cyclopenten-1-yl}morpholine (tt-8d), 4-{(5S*)-

[(2S*,3S*,4R*)-6-chloro-3-nitro-2-(triﬂuoromethyl)chroman-4-yl)

cyclopenten-1-yl}morpholine (tt-7d) and 4-{(5R*)-[(2S*,3S*,4R*)-6-

chloro-3-nitro-2-(triﬂuoromethyl)chroman-4-yl]cyclopenten-1-yl}

morpholine (tt-7'd)

Yield in MeOH 0.22 g (51%), yield in MeCN 0.24 g (55%), m.p.

163e164 ^ꢁC (decomp.). IR (ATR): 1669, 1561, 1479, 1450, 1414, 1367,

1341 cm^ꢀ1. Ratio of tautomers tt-8d:tt-7d:tt-7'd ¼ 79:6:15 in 5 min

and 61:24:15 in 24 h (C₆D₆).

4.4.5.3. Compound tt-7'e. ¹H NMR (400 MHz, C₆D₆)

d 1.22e2.53 (m,

8H, 2 CH₂, N(CH₂)₂), 2.96e3.03 (m, 1H, H-5⁰), 3.41 (t, J ¼ 4.8 Hz, 4H,

O(CH₂)₂), 4.08 (dq, J ¼ 10.1, 5.4 Hz, 1H, H-2), 4.44 (br s, 1H, ¼CH),

4.91 (dd, J ¼ 10.1, 7.5 Hz, 1H, H-3), 6.39 (d, J ¼ 8.7 Hz, 1H, H-8), 6.90

(dd, J ¼ 8.7, 2.1 Hz, 1H, H-7), 7.27 (d, J ¼ 2.1 Hz, 1H, H-5) (signal of H-

4 is masked); ¹⁹F NMR (376 MHz, C₆D₆)

d

86.0 (d, J ¼ 5.4 Hz, CF₃).

HRMS (ESI): calcd. for 477.0631 [MþH]^þC₁₉H₂₁BrF₃N₂O₄, found

477.0634.

4.5. Synthesis of 2-CCl₃- and 2-Ph-chromanes tt-8h,k,l,o

4.4.4.1. Compound tt-8d. ¹H NMR (500 MHz, C₆D₆)

d 1.34e2.00 (m,

6H, 3 CH₂), 2.30e2.39 (m, 4H, N(CH₂)₂), 3.49e3.59 (m, 4H,

O(CH₂)₂), 4.17 (dq, J ¼ 10.1, 5.3 Hz, 1H, H-2), 4.73 (d, J ¼ 11.0 Hz, 1H,

H-4), 4.87 (dd, J ¼ 11.0, 10.1 Hz,1H, H-3), 6.47 (d, J ¼ 8.8 Hz, 1H, H-8),

6.79 (dd, J ¼ 8.8, 2.1 Hz, 1H, H-7), 6.95 (dd, J ¼ 2.1, 1.1 Hz, 1H, H-5);

4.5.1. 4-{2-[(2S*,3S*,4R*)-3-Nitro-2-(trichloromethyl)chroman-4-

yl]cyclopenten-1-yl}morpholine (tt-8h), 4-{(5S*)-[(2S*,3S*,4R*)-3-

nitro-2-(trichloromethyl)chroman-4-yl]cyclopenten-1-yl}

morpholine (tt-7h) and 4-{(5R*)-[(2S*,3S*,4R*)-3-nitro-2-

(trichloromethyl)chroman-4-yl]cyclopenten-1-yl}morpholine (tt-

7'h)

¹⁹F NMR (471 MHz, C₆D₆)

d

85.9 (d, J ¼ 5.3 Hz, CF₃); ¹³C NMR

(101 MHz, C₆D₆)

d 21.1, 28.4, 28.7, 39.9, 51.5, 67.0, 73.6 (q,

J ¼ 32.9 Hz, C-2), 80.1, 118.6, 120.1, 122.7, 123.0 (q, J ¼ 281.5 Hz, C-2),

These compounds were obtained as a mixture with ct-7h (tt-

8h:ct-7h ¼ 64:36) under microwave heating from chromene 2h

127.5, 128.3, 129.1, 150.3, 155.6.

Please cite this article in press as: Korotaev VY, et al., Highly diastereoselective synthesis of novel 2,3,4-trisubstituted chromanes via the reaction

of 3-nitro-2-(trihalomethyl)- and 3-nitro-2-phenyl-2H-chromenes with 1-morpholinocyclopentene, Tetrahedron (2017), http://dx.doi.org/

10.1016/j.tet.2017.07.003

V.Y. Korotaev et al. / Tetrahedron xxx (2017) 1e16

11

and enamine 6 in CH₂Cl₂at 100 ^ꢁC for 15 min. Yield 0.31 g (69%),

white powder, m.p. 126e127 ^ꢁC (decomp.). Ratio of tautomers tt-

8h:tt-7h:tt-7'h ¼ 66:20:14 in 5 min (CDCl₃) and 74:14:12 in 5 min

(C₆D₆).

masked); ¹H NMR (500 MHz, C₆D₆)

d

1.24e2.45 (m, 8H, 2 CH₂,

N(CH₂)₂), 2.82e2.87 (m, 1H, H-5⁰), 3.33e3.51 (m, 5H, O(CH₂)₂, H-4),

4.51 (br s, 1H, ¼CH), 4.66 (d, J ¼ 8.4 Hz, 1H, H-2), 5.26 (dd, J ¼ 8.4,

3.9 Hz,1H, H-3), 6.58 (d, J ¼ 8.6 Hz,1H, H-8), 6.80 (dd, J ¼ 8.6, 2.4 Hz,

1H, H-7), 6.81 (d, J ¼ 2.4 Hz, 1H, H-5); ¹³C NMR (126 MHz, CDCl₃)

4.5.1.1. Compound tt-8h. ¹H NMR (500 MHz, CDCl₃)

d

1.88e2.50 (m,

d 24.8, 28.3, 44.9, 47.8, 49.0, 66.4, 84.8, 86.7, 96.8, 105.0, 118.4, 118.9,

6H, 3 CH₂), 2.60e2.72 (m, 4H, N(CH₂)₂), 3.64e3.71 (m, 4H, O(CH₂)₂),

4.84 (d, J ¼ 11.0 Hz, 1H, H-4), 5.11 (dd, J ¼ 11.0, 7.8 Hz, 1H, H-3), 5.45

(d, J ¼ 7.8 Hz, 1H, H-2), 6.98 (br d, J ¼ 7.5 Hz, 1H, H-5), 7.03 (t,

J ¼ 7.4 Hz,1H, H-6), 7.07 (d, J ¼ 8.2 Hz,1H, H-8), 7.10 (t, J ¼ 7.8 Hz,1H,

128.4, 128.5, 129.3, 150.7, 152.4.

4.5.2.3. Compound tt-7'k. ¹H NMR (400 MHz, CDCl₃)

d 1.20e2.94

(m, 8H, 2 CH₂, N(CH₂)₂), 3.39e3.44 (m, 1H, H-5⁰), 3.77 (t, J ¼ 4.7 Hz,

4H, O(CH₂)₂), 4.71 (br s, 1H, ¼CH), 5.01 (d, J ¼ 8.6 Hz, 1H, H-2), 5.24

(dd, J ¼ 8.6, 5.0 Hz, 1H, H-3), 7.02 (d, J ¼ 8.6 Hz, 1H, H-8), 7.08 (d,

J ¼ 2.3 Hz, 1H, H-5), 7.24 (dd, J ¼ 8.6, 2.3 Hz, 1H, H-7) (signal of H-4

H-7); ¹H NMR (500 MHz, C₆D₆)

d 1.42e2.40 (m, 6H, 3 CH₂), 2.43 (t,

J ¼ 4.6 Hz, 4H, N(CH₂)₂), 3.46e3.49 (m, 4H, O(CH₂)₂), 4.90 (br d,

J ¼ 10.4 Hz, 1H, H-4), 5.25 (dd, J ¼ 10.2, 8.0 Hz, 1H, H-3), 5.28 (d,

J ¼ 8.0 Hz, 1H, H-2), 6.77e6.97 (m, 4H, H-5, H-6, H-7, H-8).

is masked); ¹H NMR (500 MHz, C₆D₆)

d 1.21e2.59 (m, 8H, 2 CH₂,

N(CH₂)₂), 3.05e3.09 (m, 1H, H-5⁰), 4.40 (br s, 1H, ¼CH), 4.77 (d,

J ¼ 8.9 Hz, 1H, H-2), 6.56 (d, J ¼ 8.6 Hz, 1H, H-8), 6.82 (dd, J ¼ 8.6,

2.4 Hz, 1H, H-7), 7.05 (d, J ¼ 2.4 Hz, 1H, H-5) (signals of H-3, H-4 and

4.5.1.2. Compound tt-7h. ¹H NMR (500 MHz, CDCl₃)

d 1.64e2.78 (m,

8H, 2 CH₂, N(CH₂)₂), 3.23e3.31 (m, 1H, H-5⁰), 3.50e3.60 (m, 4H,

O(CH₂)₂, H-4), 4.79 (br s, 1H, ¼CH), 4.83 (d, J ¼ 8.7 Hz, 1H, H-2), 5.21

(dd, J ¼ 8.7, 3.8 Hz, 1H, H-3) (signals of aromatic protons are

O(CH₂)₂are masked); ¹³C NMR (126 MHz, CDCl₃)

d 23.8, 28.6, 43.9,

48.5, 49.5, 66.6, 85.2, 87.3, 97.1, 106.7, 118.4, 118.9, 128.3, 128.6,

129.4, 150.2, 152.3. Anal. Calcd. for C₁₉H₂₀Cl₄N₂O₄: С, 47.33; Н, 4.18;

N, 5.81. Found: С, 47.05; Н, 4.19; N, 5.83.

masked); ¹H NMR (500 MHz, C₆D₆)

d 1.19e2.48 (m, 8H, 2 CH₂,

N(CH₂)₂), 3.65e3.75 (m, 4H, O(CHH)₂), 4.33 (br s, 1H, ¼CH), 4.68 (d,

J ¼ 8.7 Hz,1H, H-2), 5.30 (dd, J ¼ 8.7, 3.7 Hz,1H, H-3) (signals of H-4,

H-5⁰and aromatic protons are masked).

4.5.3. 4-{2-[(2S*,3S*,4R*)-6-Bromo-3-nitro-2-(trichloromethyl)

chroman-4-yl]cyclopenten-1-yl}morpholine (tt-8l), 4-{(5S*)-

[(2S*,3S*,4R*)-6-bromo-3-nitro-2-(trichloromethyl)chroman-4-yl]

cyclopenten-1-yl}morpholine (tt-7l) and 4-{(5R*)-[(2S*,3S*,4R*)-6-

bromo-3-nitro-2-(trichloromethyl)chroman-4-yl]cyclopenten-1-yl}

morpholine (tt-7'l)

4.5.1.3. Compound tt-7'h. ¹H NMR (500 MHz, CDCl₃)

d 1.24e2.92

(m, 8H, 2 CH₂, N(CH₂)₂), 3.74 (t, J ¼ 4.7 Hz, 4H, O(CH₂)₂), 4.77 (br s,

1H, ¼CH), 5.03 (d, J ¼ 8.6 Hz, 1H, H-2), 5.28 (dd, J ¼ 8.6, 4.8 Hz, 1H,

H-3) (signals of H-4, H-5⁰and aromatic protons are masked); ¹H

NMR (500 MHz, C₆D₆)

d

1.19e2.48 (m, 8H, 2 CH₂, N(CH₂)₂), 4.40 (d,

This equilibrium mixture was obtained similarly to chromanes

tt-8aee in MeCN (0.5 mL) at 40 ^ꢁC for 6 h. Yield 0.24 g (46%), m.p.

192e193 ^ꢁC (decomp.). IR (ATR): 1662, 1641, 1564, 1476, 1447, 1407,

1372, 1359 cm^ꢀ1. Ratio of tautomers tt-8l:tt-7l:tt-7'l ¼ 69:17:14 in

5 min (CDCl₃) and 75:19:6 in 5 min (C₆D₆).

J ¼ 8.8 Hz, 1H, 2-CH), 4.89 (br s, 1H, ¼CH), 5.32 (dd, J ¼ 8.8, 4.3 Hz,

1H, H-3) (signals of H-4, H-5⁰, O(CH₂)₂and aromatic protons are

masked). Anal. Calcd. for C₁₉H₂₁Cl₃N₂O₄: С, 50.97; Н, 4.73; N, 6.26.

Found: С, 50.58; Н, 4.60; N, 6.29.

4.5.2. 4-{2-[(2S*,3S*,4R*)-6-Chloro-3-nitro-2-(trichloromethyl)

chroman-4-yl]cyclopenten-1-yl}morpholine (tt-8k), 4-{(5S*)-

[(2S*,3S*,4R*)-6-chloro-3-nitro-2-(trichloromethyl)chroman-4-yl]

cyclopenten-1-yl}morpholine (tt-7k) and 4-{(5R*)-[(2S*,3S*,4R*)-6-

chloro-3-nitro-2-(trichloromethyl)chroman-4-yl]cyclopenten-1-yl}

morpholine (tt-7'k)

This equilibrium mixture was obtained similarly to chromanes

tt-8aee in MeOH (0.5 mL) at 40 ^ꢁC for 6 h. Yield 0.26 g (54%), light

yellow prisms, m.p. 186e187 ^ꢁC (decomp.). IR (ATR): 1661, 1643,

1562, 1476, 1451, 1412, 1372, 1355 cm^ꢀ1. Ratio of tautomers tt-8k:tt-

7k:tt-7'k ¼ 71:17:12 in 5 min (CDCl₃); 73:22:5 in 5 min and

67:17:16 in 24 h (C₆D₆).

4.5.3.1. Compound tt-8l. ¹H NMR (500 MHz, CDCl₃)

d 1.91e2.53 (m,

6H, 3 CH₂), 2.61e2.73 (m, 4H, N(CH₂)₂), 3.64e3.73 (m, 4H, O(CH₂)₂),

4.80 (d, J ¼ 11.2 Hz, 1H, H-4), 5.07 (dd, J ¼ 11.2, 7.7 Hz, 1H, H-3), 5.46

(d, J ¼ 7.7 Hz, 1H, H-2), 6.96 (d, J ¼ 8.6 Hz, 1H, H-8), 7.06 (d,

J ¼ 2.4 Hz, 1H, H-5), 7.36 (dd, J ¼ 8.6, 2.4 Hz, 1H, H-7); ¹H NMR

(500 MHz, C₆D₆)

d

1.45e2.09 (m, 6H, 3 CH₂), 2.35 (t, J ¼ 4.6 Hz, 4H,

N(CH₂)₂), 3.45 (t, J ¼ 4.6 Hz, 4H, O(CH₂)₂), 4.81 (br d, J ¼ 10.6 Hz, 1H,

H-4), 5.15 (dd, J ¼ 10.6, 7.9 Hz, 1H, H-3), 5.20 (d, J ¼ 7.9 Hz, 1H, H-2),

6.57 (d, J ¼ 8.6 Hz, 1H, H-8), 7.00 (ddd, J ¼ 8.6, 2.3, 0.8 Hz, 1H, H-7),

7.20 (dd, J ¼ 2.3, 1.1 Hz, 1H, H-5).

4.5.3.2. Compound tt-7l. ¹H NMR (500 MHz, CDCl₃)

d 1.44e2.82 (m,

8H, 2 CH₂, N(CH₂)₂), 3.20e3.27 (m, 1H, H-5⁰), 3.45e3.60 (m, 4H,

O(CH₂)₂), 4.78 (br s, 1H, ¼CH), 4.86 (d, J ¼ 8.3 Hz, 1H, H-2), 5.21 (dd,

J ¼ 8.3, 3.5 Hz, 1H, H-3), 6.97 (d, J ¼ 8.6 Hz, 1H, H-8), 7.25 (d,

J ¼ 2.4 Hz, 1H, H-5), 7.39 (dd, J ¼ 8.6, 2.4 Hz, 1H, H-7) (signal of H-4

4.5.2.1. Compound tt-8k. ¹H NMR (400 MHz, CDCl₃)

d 1.90e2.53 (m,

6H, 3 CH₂), 2.61e2.73 (m, 4H, N(CH₂)₂), 3.63e3.73 (m, 4H, O(CH₂)₂),

4.80 (d, J ¼ 11.1 Hz, 1H, H-4), 5.08 (dd, J ¼ 11.1, 7.7 Hz, 1H, H-3), 5.46

(d, J ¼ 7.7 Hz, 1H, H-2), 6.92 (br dd, J ¼ 2.2, 1.0 Hz, 1H, H-5), 7.01 (d,

J ¼ 8.6 Hz, 1H, H-8), 7.22 (dd, J ¼ 8.6, 2.2 Hz, 1H, H-7); ¹H NMR

is masked); ¹H NMR (500 MHz, C₆D₆)

d 1.22e2.43 (m, 8H, 2 CH₂,

N(CH₂)₂), 2.82e2.88 (m, 1H, H-5⁰), 3.32e3.50 (m, 5H, O(CH₂)₂, H-4),

4.50 (br s, 1H, ¼CH), 4.66 (d, J ¼ 8.3 Hz, 1H, H-2), 5.25 (dd, J ¼ 8.3,

3.9 Hz,1H, H-3), 6.51 (d, J ¼ 8.6 Hz,1H, H-8), 6.95 (dd, J ¼ 8.6, 2.4 Hz,

1H, H-7), 6.97 (d, J ¼ 2.4 Hz, 1H, H-5).

(500 MHz, C₆D₆)

d

1.45e2.31 (m, 6H, 3 CH₂), 2.35 (t, J ¼ 4.6 Hz, 4H,

N(CH₂)₂), 3.45 (dd, J ¼ 6.3, 4.6 Hz, 4H, O(CH₂)₂), 4.81 (br d,

J ¼ 10.6 Hz, 1H, H-4), 5.16 (dd, J ¼ 10.6, 7.8 Hz, 1H, H-3), 5.20 (d,

J ¼ 7.8 Hz, 1H, H-2), 6.63 (d, J ¼ 8.6 Hz, 1H, H-8), 6.86 (ddd, J ¼ 8.6,

2.3, 0.8 Hz, 1H, H-7), 7.05 (dd, J ¼ 2.3, 1.1 Hz, 1H, H-5); ¹³C NMR

4.5.3.3. Compound tt-7'l. ¹H NMR (500 MHz, CDCl₃)

d 1.20e2.94

(126 MHz, CDCl₃)

d

21.1, 28.8, 28.9, 39.7, 51.2, 67.0, 84.7, 85.1, 98.6,

(m, 8H, 2 CH₂, N(CH)₂), 3.39e3.44 (m, 1H, H-5⁰), 3.77 (t, J ¼ 4.6 Hz,

4H, O(CH₂)₂), 4.72 (br s, 1H, ¼CH), 5.01 (d, J ¼ 8.9 Hz, 1H, H-2), 5.24

(dd, J ¼ 8.9, 5.0 Hz, 1H, H-3), 7.01 (d, J ¼ 8.6 Hz, 1H, H-8), 7.24 (d,

J ¼ 2.4 Hz, 1H, H-5), 7.35 (dd, J ¼ 8.6, 2.4 Hz, 1H, H-7); ¹H NMR

118.3, 118.8, 123.8, 126.6, 128.4, 129.0, 151.7, 155.6.

4.5.2.2. Compound tt-7k. ¹H NMR (400 MHz, CDCl₃)

d 1.66e2.80

(m, 8H, 2 CH₂, N(CH₂)₂), 3.21e3.27 (m, 1H, H-5⁰), 3.45e3.59 (m, 4H,

O(CH₂)₂), 4.78 (br s, 1H, ¼CH), 4.86 (d, J ¼ 8.4 Hz, 1H, H-2), 5.21 (dd,

J ¼ 8.4, 3.6 Hz, 1H, H-3), 7.07 (d, J ¼ 8.6 Hz, 1H, H-8), 7.12 (d,

J ¼ 2.3 Hz,1H, H-5), 7.21 (dd, J ¼ 8.6, 2.3 Hz,1H, H-7) (signal of H-4 is

(500 MHz, C₆D₆) d 1.22e2.60 (m, 8H, 2 CH₂, N(CH)₂), 3.04e3.09 (m,

1H, H-5⁰), 3.22e3.50 (m, 5H, O(CH₂)₂, H-4), 4.41 (br s, 1H, ¼CH),

4.77 (d, J ¼ 8.9 Hz, 1H, H-2), 5.19 (dd, J ¼ 8.9, 5.5 Hz, 1H, H-3), 6.49

(d, J ¼ 8.6 Hz, 1H, H-8), 6.96 (dd, J ¼ 8.6, 2.4 Hz, 1H, H-7), 7.21 (d,

Please cite this article in press as: Korotaev VY, et al., Highly diastereoselective synthesis of novel 2,3,4-trisubstituted chromanes via the reaction

of 3-nitro-2-(trihalomethyl)- and 3-nitro-2-phenyl-2H-chromenes with 1-morpholinocyclopentene, Tetrahedron (2017), http://dx.doi.org/

10.1016/j.tet.2017.07.003

12

V.Y. Korotaev et al. / Tetrahedron xxx (2017) 1e16

J ¼ 2.4 Hz, 1H, H-5) (signals of H-3

и

H-4 are masked). Anal. Calcd.

4.6.2. (2R*)-[(2S*,3R*,4S*)-6-Methoxy-3-nitro-2-(triﬂuoromethyl)

chroman-4-yl]cyclopentan-1-one (ct-9b)

for C₁₉H₂₀BrCl₃N₂O₄: С, 43.33; Н, 3.83; N, 5.32. Found: С, 43.28; Н,

3.63; N, 5.31.

Yield 0.25 g (71%), m.p. 117e118 ^ꢁC. IR (ATR): 1728, 1560, 1497,

1370, 1333 cm^ꢀ1. ¹H NMR (400 MHz, CDCl₃)

d 1.50e2.53 (m, 7H, 3

CH₂, H-2⁰), 3.73 (s, 3H, MeO), 3.97 (br d, J ¼ 4.7 Hz, 1H, H-4), 4.58

(qd, J ¼ 5.9, 2.4 Hz, 1H, H-2), 5.46 (t, J ¼ 2.0 Hz, 1H, H-3), 6.48 (d,

J ¼ 2.9 Hz, 1H, H-5), 6.81 (dd, J ¼ 9.0, 2.9 Hz, 1H, H-7), 6.96 (d,

4.5.4. 4-{2-[(2R*,3S*,4R*)-3-Nitro-2-phenylchroman-4-yl]

cyclopenten-1-yl}morpholine (tt-8o), 4-{(5S*)-[(2R*,3S*,4R*)-3-

nitro-2-phenylchroman-4-yl]cyclopenten-1-yl}morpholine (tt-7o)

and 4-{(5R*)-[(2R*,3S*,4R*)-3-nitro-2-phenylchroman-4-yl]

cyclopenten-1-yl}morpholine (tt-7'o)

J ¼ 9.0 Hz, 1H, H-8); ¹⁹F NMR (376 MHz, CDCl₃)

86.8 (d, J ¼ 5.9 Hz,

d

CF₃); ¹³C NMR (101 MHz, CDCl₃)

d 20.2, 27.6, 38.1, 38.4, 54.3, 55.6,

71.1 (q, J ¼ 34.4 Hz, C-2), 78.9, 113.2, 115.1, 118.0, 118.9, 122.0 (q,

J ¼ 281.4 Hz, CF₃), 145.7, 155.0, 216.8. Anal. Calcd. for C₁₆H₁₆F₃NO₅:

С, 53.49; Н, 4.49; N, 3.90. Found: С, 53.57; Н, 4.73; N, 3.87.

This equilibrium mixture was obtained similarly to chromanes

tt-8aee in MeCN (0.5 mL) at 40 ^ꢁC for 6 h. Yield 0.14 g (34%), light

yellow prisms, m.p. 174e175 ^ꢁC (decomp.). IR (ATR): 1662, 1630,

1581, 1548, 1482, 1455, 1374, 1347, 1331 cm^ꢀ1. Ratio of tautomers tt-

8o:tt-7o:tt-7'o ¼ 75:14:11 in 5 min (C₆D₆).

4.6.3. (2R*)-[(2S*,3R*,4S*)-8-Ethoxy-3-nitro-2-(triﬂuoromethyl)

chroman-4-yl]cyclopentan-1-one (ct-9c)

Yield 0.29 g (78%), m.p. 96e97 ^ꢁC. IR (ATR): 1733, 1578, 1557,

4.5.4.1. Compound tt-8o. ¹H NMR (500 MHz, C₆D₆)

d 1.50e2.24 (m,

1484, 1470, 1406, 1367, 1312 cm^ꢀ1. ¹H NMR (400 MHz, CDCl₃)

d 1.43

6H, 3 CH₂), 2.46e2.56 (m, 4H, N(CH₂)₂), 3.59e3.70 (m, 4H, O(CH₂)₂),

5.02 (d, J ¼ 9.7 Hz, 1H, H-2), 5.06 (t, J ¼ 10.0, 7.9 Hz, 1H, H-3), 5.23

(br d, J ¼ 10.3 Hz,1H, H-4), 6.87 (td, J ¼ 7.6, 1.4 Hz,1H, H-6), 6.97 (dd.

J ¼ 8.0, 1.4 Hz, 1H, H-8), 6.99 (d, J ¼ 7.7 Hz, 1H, H-5), 7.02e7.08 (m,

4H, H-7, H_m, H_p), 6.79 (dd, J ¼ 8.0, 1.3 Hz, 2H, H_o); ¹³C NMR

(t, J ¼ 7.0 Hz, 3H, Me), 1.52e2.51 (m, 7H, 3 CH₂, H-2⁰), 4.01 (dd,

J ¼ 4.7, 1.5 Hz,1H, H-4), 4.07 (dd, J ¼ 9.5, 7.0 Hz,1H, OCHH), 4.08 (dd,

J ¼ 9.5, 7.0 Hz, 1H, OCHH), 4.68 (qd, J ¼ 6.0, 2.6 Hz, 1H, H-2), 5.50 (t,

J ¼ 2.3 Hz, 1H, H-3), 6.54 (ddd, J ¼ 7.7, 1.5, 0.5 Hz, 1H, H-5), 6.84 (dd,

J ¼ 8.2, 1.5 Hz, 1H, H-7), 6.90 (t, J ¼ 7.9 Hz, 1H, H-6); ¹⁹F NMR

(101 MHz, C₆D₆)

d 21.2, 28.4, 29.2, 41.8, 51.7, 67.1, 79.0, 88.1, 117.4,

(376 MHz, CDCl₃)

CDCl₃)

2), 78.8, 113.6, 119.2, 120.5, 122.1 (q, J ¼ 281.9 Hz, CF₃), 122.6, 142.1,

147.8, 216.8. HRMS (ESI): calcd. for 396.1029 [MþNa]^þ

C₁₇H₁₈F₃NNaO₅, found 396.1031.

d

87.2 (d, J ¼ 6.0 Hz, CF₃); ¹³C NMR (101 MHz,

121.8, 122.1, 127.3, 127.4, 128.5, 128.6, 128.9, 129.7, 135.9, 153.7,

154.6.

d

14.7, 20.3, 27.6, 38.1, 38.2, 54.2, 65.2, 71.0 (q, J ¼ 34.5 Hz, C-

4.5.4.2. Compound tt-7o. ¹H NMR (500 MHz, C₆D₆)

d 1.24e2.65 (m,

8H, 2 CH₂, N(CH₂)₂), 3.23e3.16 (m, 1H, H-5⁰), 3.47e3.52 (m, 4H,

O(CH₂)₂), 4.11e4.17 (m, 1H, H-4), 4.50 (br s, 1H, ¼CH), 4.79 (d,

J ¼ 10.0 Hz, 1H, H-2) (signals of H-3 and aromatic protons are

4.6.4. (2R*)-[(2S*,3R*,4S*)-6-Chloro-3-nitro-2-(triﬂuoromethyl)

chroman-4-yl]cyclopentan-1-one (ct-9d)

masked); ¹³C NMR (101 MHz, C₆D₆)

d 24.1, 27.1, 29.4, 42.3, 49.5,

Yield 0.30 g (83%), m.p. 95e96 ^ꢁC. IR (ATR): 1735, 1560, 1480,

66.4, 81.2, 89.2, 104.3, 117.8, 122.3, 122.8, 123.1, 125.4, 129.7, 129.0,

129.5, 136.4, 150.4, 156.4.

1367, 1332 cm^ꢀ1. ¹H NMR (400 MHz, CDCl₃)

d 1.50e2.56 (m, 7H, 3

CH₂, H-2⁰), 3.88 (br d, J ¼ 5.7 Hz, 1H, H-4), 4.63 (qd, J ¼ 5.9, 2.3 Hz,

1H, H-2), 5.59 (t, J ¼ 1.9 Hz, 1H, H-3), 6.96e6.99 (m, 2H, H-5, H-8),

4.5.4.3. Compound tt-7'o. ¹H NMR (500 MHz, C₆D₆)

d 1.24e2.68 (m,

7.22 (dd, J ¼ 8.7, 2.4 Hz, 1H, H-7); ¹⁹F NMR (376 MHz, CDCl₃)

d 86.9

(d, J ¼ 5.9 Hz, CF₃). HRMS (ESI): calcd. for 386.0377 [MþNa]^þ

8H, 2 CH₂, N(CH₂)₂), 4.11e4.17 (m, 1H, H-4), 4.46 (br s, 1H, ¼CH),

4.79 (d, J ¼ 10.0 Hz, 1H, H-2), 4.94 (dd, J ¼ 10.2, 7.5 Hz, 1H, H-3),

3.44e3.64 (m, 4H, O(CH₂)₂) (signals aromatic protons are masked);

C₁₅H₁₃ClF₃NNaO₄, found 386.0377.

¹³C NMR (101 MHz, C₆D₆)

d 22.9, 29.0, 31.9, 42.7, 50.1, 66.6, 79.7,

4.6.5. (2R*)-[(2S*,3R*,4S*)-6-Bromo-3-nitro-2-(triﬂuoromethyl)

chroman-4-yl]cyclopentan-1-one (ct-9e)

91.9, 100.2, 117.5, 122.3, 122.5, 123.1, 125.4, 129.6, 128.9, 129.4, 136.1,

151.6, 156.3. Anal. Calcd. for C₂₄H₂₆N₂O₄: С, 70.92; Н, 6.45; N, 6.89.

Found: С, 70.71; Н, 6.75; N, 7.12.

Yield 0.33 g (80%), m.p. 110e111 ^ꢁC. IR (ATR): 1738, 1562, 1479,

1368, 1340 cm^ꢀ1. ¹H NMR (400 MHz, CDCl₃)

d 1.57e2.54 (m, 7H, 3

CH₂, H-2⁰), 3.87 (br d, J ¼ 5.4 Hz, 1H, H-4), 4.63 (qd, J ¼ 5.9, 2.1 Hz,

1H, H-2), 5.60 (t, J ¼ 2.1 Hz, 1H, H-3), 6.92 (d, J ¼ 8.8 Hz, 1H, H-8),

7.13 (d, J ¼ 2.3 Hz, 1H, H-5), 7.36 (dd, J ¼ 8.8, 2.3 Hz, 1H, H-7); ¹⁹F

4.6. General procedure for hydrolysis of chromanes 7 and 8

A

mixture of the appropriate chromanоenamine 7 or 8

NMR (376 MHz, CDCl₃)

d

86.9 (d, J ¼ 5.9 Hz, CF₃). HRMS (ESI): calcd.

for 429.9872 [MþNa]^þC₁₅H₁₃BrF₃NNaO₄, found 429.9869.

(1.0 mmol), MeOH (5 mL), H₂O (10 mL), and conc. HCl (0.25 mL) was

stirred at room temperature (2-CF₃-chromanes) or 50 ^ꢁC (the rest of

the compounds) for 24 or 5 h, respectively. The precipitate was

collected by ﬁltration and washed with water (3 ꢂ 1 mL). Chro-

manes 9 were obtained as white powders. Products tt-9a¡d were

isolated as individual compounds by recrystallisation of the ste-

reoisomeric mixture from hexane.

4.6.6. (2R*)-[(2S*,3R*,4S*)-6,8-Dichloro-3-nitro-2-(triﬂuoromethyl)

chroman-4-yl]cyclopentan-1-one (ct-9f)

Yield 0.34 g (85%), m.p. 150e151 ^ꢁC. IR (ATR): 1733, 1563, 1462,

1369, 1313 cm^ꢀ1. ¹H NMR (400 MHz, CDCl₃)

d 1.56e2.55 (m, 7H, 3

CH₂, H-2⁰), 3.88 (br d, J ¼ 5.5 Hz, 1H, H-4), 4.71 (qd, J ¼ 5.7, 2.6 Hz,

1H, H-2), 5.64 (t, J ¼ 1.9 Hz, 1H, H-3), 6.91 (d, J ¼ 2.3 Hz, 1H, H-5/H-

7), 7.36 (d, J ¼ 2.3 Hz, 1H, H-7/H-5); ¹⁹F NMR (376 MHz, CDCl₃)

4.6.1. (2R*)-[(2S*,3R*,4S*)-3-Nitro-2-(triﬂuoromethyl)chroman-4-

yl]cyclopentan-1-one (ct-9a)

d

87.0 (d, J ¼ 5.7 Hz, CF₃); ¹³C NMR (101 MHz, CDCl₃)

d 20.1, 26.1,

Yield 0.30 g (90%), m.p. 94e95 ^ꢁC. IR (ATR): 1730, 1587, 1559,

37.0, 38.5, 49.6, 72.9 (q, J ¼ 33.0 Hz, C-2), 80.1, 122.9 (q, J ¼ 283.3 Hz,

1489, 1474, 1396, 1373, 1322 cm^ꢀ1

d

.

¹H NMR (400 MHz, CDCl₃)

CF₃), 123.1, 123.8, 127.9, 128.8, 130.6, 146.8, 215.7. Anal. Calcd. for

1.58e2.51 (m, 7H, 3 CH₂, H-2⁰), 3.96 (br d, J ¼ 5.1 Hz, 1H, H-4), 4.64

C₁₅H₁₂Cl₂F₃NO₄: С, 45.25; Н, 3.04; N, 3.52. Found: С, 45.13; Н, 3.03;

N, 3.51.

(qd, J ¼ 5.7, 2.3 Hz, 1H, H-2), 5.57 (t, J ¼ 1.9 Hz, 1H, H-3), 6.96e7.28

(m, 4H, Ar); ¹⁹F NMR (376 MHz, CDCl₃)

NMR (101 MHz, CDCl₃)

d

86.9 (d, J ¼ 5.7 Hz, CF₃); ¹³

C

d

20.3, 27.9, 38.2, 38.4, 54.1, 70.8 (q,

4.6.7. (2R*)-[(2S*,3R*,4S*)-6,8-Dibromo-3-nitro-2-

J ¼ 34.5 Hz, C-2), 78.5, 117.2, 118.3, 122.0 (q, J ¼ 281.7 Hz, CF₃), 122.9,

129.0, 129.1, 151.7, 216.8. HRMS (ESI): calcd. for 352.0767 [MþNa]^þ

C₁₅H₁₄F₃NNaO₄, found 352.0770.

(triﬂuoromethyl)chroman-4-yl]cyclopentan-1-one (ct-9g)

Yield 0.43 g (89%), m.p. 176e177 ^ꢁC. IR (ATR): 1731, 1563, 1454,

1368 cm^ꢀ1. ¹H NMR (400 MHz, CDCl₃)

d 1.56e2.55 (m, 7H, 3 CH₂, H-

Please cite this article in press as: Korotaev VY, et al., Highly diastereoselective synthesis of novel 2,3,4-trisubstituted chromanes via the reaction

of 3-nitro-2-(trihalomethyl)- and 3-nitro-2-phenyl-2H-chromenes with 1-morpholinocyclopentene, Tetrahedron (2017), http://dx.doi.org/

10.1016/j.tet.2017.07.003

V.Y. Korotaev et al. / Tetrahedron xxx (2017) 1e16

13

2⁰), 3.86 (br d, J ¼ 5.7 Hz, 1H, H-4), 4.72 (qd, J ¼ 5.7, 2.5 Hz, 1H, H-2),

N, 3.04.

5.65 (t, J ¼ 1.9 Hz, 1H, H-3), 7.09 (d, J ¼ 2.3 Hz, 1H, H-5/H-7), 7.65 (d,

J ¼ 2.2 Hz, 1H, H-7/H-5); ¹⁹F NMR (376 MHz, CDCl₃)

d

87.1 (d,

4.6.13. (2R*)-[(2S*,3R*,4S*)-6,8-Dichloro-3-nitro-2-

J ¼ 5.7 Hz, CF₃); ¹³C NMR (101 MHz, CDCl₃)

d

20.2, 28.1, 38.1, 38.7,

(trichloromethyl)chroman-4-yl]cyclopentan-1-one (ct-9m)

53.6, 71.5 (q, J ¼ 35.1 Hz, C-2), 77.5, 112.2, 114.9, 121.6 (q,

J ¼ 281.5 Hz, CF₃), 121.8, 130.7, 135.3, 147.7, 216.1. Anal. Calcd. for

Yield 0.38 g (84%), m.p. 157e158 ^ꢁC. IR (ATR): 1731, 1559, 1459,

1362, 1340, 1311 cm^ꢀ1. ¹H NMR (400 MHz, CDCl₃)

d 1.57e2.56 (m,

C

₁₅H₁₂Br₂F₃NO₄: С, 36.99; Н, 2.48; N, 2.88. Found: С, 37.01; Н, 2.46;

7H, 3 CH₂, H-2⁰), 3.86 (br d, J ¼ 5.7 Hz, 1H, H-4), 4.68 (d, J ¼ 1.9 Hz,

1H, H-2), 6.07 (t, J ¼ 1.6 Hz, 1H, H-3), 6.92 (d, J ¼ 2.4 Hz, 1H, H-5/H-

N, 2.92.

7), 7.37 (d,

J

¼

2.4 Hz, 1H, H-7/H-5). Anal. Calcd. for

4.6.8. (2R*)-[(2S*,3R*,4S*)-3-Nitro-2-(trichloromethyl)chroman-4-

yl]cyclopentan-1-one (ct-9h)

C₁₅H₁₂Cl₅NO₄∙0.67H₂O: С, 39.21; Н, 2.92; N, 3.05. Found: С, 39.00;

Н, 2.63; N, 3.05.

Yield 0.27 g (71%), m.p. 165e166 ^ꢁC. IR (ATR): 1733, 1556, 1489,

1456, 1400, 1369, 1341 cm^ꢀ1. ¹H NMR (400 MHz, CDCl₃)

d

1.58e2.53

4.6.14. (2R*)-[(2S*,3R*,4S*)-6,8-Dibromo-3-nitro-2-

(m, 7H, 3 CH₂, H-2⁰), 3.94 (br d, J ¼ 5.2 Hz, 1H, H-4), 4.62 (d,

J ¼ 1.5 Hz,1H, H-2), 6.02 (t, J ¼ 1.5 Hz,1H, H-3), 6.97e7.02 (m, 2H, H-

6, H-8), 7.11 (d, J ¼ 8.2 Hz,1H, H-5), 7.24e7.31 (m, 1H, H-7); ¹³C NMR

(trichloromethyl)chroman-4-yl]cyclopentan-1-one (ct-9n)

Yield 0.43 g (81%), m.p. 167e168 ^ꢁC. IR (ATR): 1731, 1556, 1454,

1400, 1366, 1352, 1338 cm^ꢀ1. ¹H NMR (400 MHz, CDCl₃)

d 1.58e2.56

(126 MHz, CDCl₃)

d

20.3, 28.0, 38.2, 40.1, 54.5, 79.5, 80.9, 95.6, 117.2,

(m, 7H, 2 CH₂, H-2⁰), 3.83 (br d, J ¼ 5.9 Hz, 1H, H-4), 4.69 (d,

J ¼ 1.9 Hz, 1H, H-2), 6.08 (t, J ¼ 1.6 Hz, 1H, H-3), 7.10 (d, J ¼ 2.2 Hz,

1H, H-5/H-7), 7.67 (d, J ¼ 2.2 Hz, 1H, H-7/H-5); ¹³C NMR (126 MHz,

118.4, 122.8, 128.9, 129.0, 152.8, 216.7. Anal. Calcd. for

C

₁₅H₁₄Cl₃NO₄∙0.25H₂O: С, 47.02; Н, 3.81; N, 3.66. Found: С, 47.12;

Н, 3.75; N, 3.67.

CDCl₃) d 20.2, 28.3, 38.1, 40.3, 54.0, 78.5, 81.4, 94.9, 112.2, 114.7,

121.9, 130.5, 135.1, 148.8, 216.0. Anal. Calcd. for C₁₅H₁₂Br₂Cl₃NO₄: С,

33.59; Н, 2.25; N, 2.61. Found: С, 33.29; Н, 2.58; N, 2.59.

4.6.9. (2R*)-[(2S*,3R*,4S*)-6-Methoxy-3-nitro-2-(trichloromethyl)

chroman-4-yl]cyclopentan-1-one (ct-9i)

Yield 0.29 g (70%), m.p. 155e156 ^ꢁC. IR (ATR): 1727, 1557, 1497,

4.6.15. (2R*)-[(2R*,3R*,4S*)-3-Nitro-2-phenylchroman-4-yl]

cyclopentan-1-one (ct-9o)

1359, 1316 cm^ꢀ1. ¹H NMR (400 MHz, CDCl₃)

d 1.56e2.53 (m, 7H, 3

CH₂, H-2⁰), 3.74 (s, 3H, MeO), 3.94 (br d, J ¼ 4.8 Hz, 1H, H-4), 4.56 (d,

J ¼ 1.6 Hz, 1H, H-2), 5.90 (t, J ¼ 1.6 Hz, 1H, H-3), 6.50 (d, J ¼ 2.8 Hz,

1H, H-5), 6.84 (dd, J ¼ 9.0, 2.8 Hz, 1H, H-7), 7.04 (d, J ¼ 9.0 Hz,1H, H-

8). Anal. Calcd. for C₁₆H₁₆Cl₃NO₅: С, 47.03; Н, 3.95; N, 3.43. Found:

С, 46.95; Н, 3.84; N, 3.44.

Yield 0.32 g (94%), m.p. 168e169 ^ꢁC. IR (ATR): 1740, 1547, 1487,

1454, 1373, 1336 cm^ꢀ1. ¹H NMR (400 MHz, CDCl₃)

d 1.68e2.52 (m,

7H, 3 CH₂, H-2⁰), 3.96 (br d, J ¼ 5.8 Hz, 1H, H-4), 5.44 (d, J ¼ 2.3 Hz,

1H, H-2), 5.95 (dd, J ¼ 2.3, 1.8 Hz, 1H, H-3), 6.95 (td, J ¼ 7.5, 1.0 Hz,

1H, H-6), 7.01 (dd, J ¼ 7.8, 1.5 Hz, 1H, H-5), 7.04 (br d, J ¼ 8.3 Hz, 1H,

H-8), 7.24 (ddd, J ¼ 8.3, 7.2, 1.5 Hz, 1H, H-7), 7.34e7.48 (m, 5H, Ph);

4.6.10. (2R*)-[(2S*,3R*,4S*)-8-Ethoxy-3-nitro-2-(trichloromethyl)

chroman-4-yl]cyclopentan-1-one (ct-9j)

¹³C NMR (126 MHz, CDCl₃)

d 20.4, 28.1, 38.6, 38.8, 54.4, 73.3, 86.0,

117.2, 118.7, 121.7, 125.6, 128.7, 128.8, 129.0, 135.7, 153.6, 217.6 (one C

is not observed). Anal. Calcd. for C₂₀H₁₉NO₄∙0.33H₂O: С, 69.96; Н,

5.77 8; N, 4.08. Found: С, 70.07; Н, 5.37; N, 4.16.

Yield 0.37 g (87%), m.p. 170e171 ^ꢁC. IR (ATR): 1723, 1559, 1468,

1398, 1372, 1358, 1336 cm^ꢀ^{1 1}H NMR (400 MHz, CDCl₃)

. d 1.42 (t,

J ¼ 7.0 Hz, 3H, Me), 1.56e2.51 (m, 7H, 3 CH₂, H-2⁰), 3.96 (br d,

J ¼ 4.8 Hz, 1H, H-4), 4.09 (dd, J ¼ 9.2, 7.0 Hz, 1H, OCHH), 4.13 (dd,

J ¼ 9.2, 7.0 Hz, 1H, OCHH), 4.62 (d, J ¼ 1.7 Hz, 1H, H-2), 5.95 (t,

J ¼ 1.5 Hz, 1H, H-3), 6.55e6.61 (m, 1H, H-7), 6.86e6.93 (m, 2H, H-5,

4.6.16. (2R*)-[(2R*,3R*,4S*)-6-Methoxy-3-nitro-2-phenylchroman-

4-yl]cyclopentan-1-one (ct-9p)

Yield 0.33 g (91%), m.p. 166e167 ^ꢁC. IR (ATR): 1738, 1550, 1495,

H-6); ¹³C NMR (126 MHz, CDCl₃)

d

15.0, 20.3, 27.9, 38.1, 40.1, 54.7,

1457, 1336 cm^ꢀ1. ¹H NMR (500 MHz, CDCl₃)

d 1.68e2.53 (m, 7H, 3

65.9, 79.7, 81.1, 95.6, 114.9, 119.3, 120.9, 122.4, 143.7, 147.7, 216.7.

Anal. Calcd. for C₁₇H₁₈Cl₃NO₅∙0.33H₂O: С, 47.63; Н, 4.39; N, 3.27.

Found: С, 47.62; Н, 4.28; N, 3.27.

CH₂, H-2⁰), 3.74 (s, 3H, MeO), 3.99 (br d, J ¼ 5.0 Hz, 1H, H-4), 5.37 (d,

J ¼ 2.5 Hz, 1H, H-2), 5.43 (dd, J ¼ 2.5, 1.7 Hz, 1H, H-3), 6.53 (d,

J ¼ 2.9 Hz, 1H, H-5), 6.82 (d, J ¼ 8.9, 2.9 Hz, 1H, H-7), 6.97 (d,

J ¼ 8.9 Hz, 1H, H-8), 7.35e7.45 (m, 5H, Ph); ¹³C NMR (126 MHz,

4.6.11. (2R*)-[(2S*,3R*,4S*)-6-Chloro-3-nitro-2-(trichloromethyl)

chroman-4-yl]cyclopentan-1-one (ct-9k)

CDCl₃) d 20.4, 28.0, 38.5, 38.8, 54.7, 55.7, 73.6, 86.5, 113.2, 114.9,

118.0, 119.3, 125.6, 128.7, 128.8, 135.8, 147.7, 154.2, 217.6. Anal. Calcd.

for C₂₁H₂₁NO₅: С, 68.65; Н, 5.76; N, 3.81. Found: С, 68.60; Н, 6.00; N,

3.86.

Yield 0.41 g (99%), m.p. 142e143 ^ꢁC. IR (ATR): 1739, 1556, 1481,

1367, 1339 cm^ꢀ1. ¹H NMR (500 MHz, CDCl₃)

d 1.60e2.54 (m, 7H, 3

CH₂, H-2⁰), 3.85 (br d, J ¼ 5.6 Hz, 1H, H-4), 4.61 (d, J ¼ 1.8 Hz, 1H, H-

2), 6.03 (t, J ¼ 1.6 Hz, 1H, H-3), 6.99 (d, J ¼ 2.4 Hz, 1H, H-5), 7.05 (d,

J ¼ 8.8 Hz, 1H, H-8), 7.24 (dd, J ¼ 8.8, 2.4 Hz, 1H, H-7); ¹³C NMR

4.6.17. (2R*)-[(2R*,3R*,4S*)-6-Bromo-3-nitro-2-phenylchroman-4-

yl]cyclopentan-1-one (ct-9q)

(101 MHz, CDCl₃)

d

20.2, 28.1, 38.1, 40.0, 54.2, 78.8, 81.0, 95.3, 118.5,

Yield 0.35 g (84%), m.p. 164e165 ^ꢁC. IR (ATR): 1741, 1550, 1480,

120.2, 127.7, 128.5, 129.1, 151.4, 216.3. Anal. Calcd. for C₁₅H₁₃Cl₄NO₄:

С, 43.62; Н, 3.17; N, 3.39. Found: С, 43.52; Н, 2.89; N, 3.29.

1333 cm^ꢀ1. ¹H NMR (400 MHz, CDCl₃)

d 1.68e2.56 (m, 7H, 3 CH₂, H-

2⁰), 3.88 (br d, J ¼ 6.2 Hz, 1H, H-4), 5.42 (d, J ¼ 2.5 Hz, 1H, H-2), 5.58

(dd, J ¼ 2.5, 1.7 Hz, 1H, H-3), 6.93 (d, J ¼ 8.7 Hz, 1H, H-8), 7.15 (d,

J ¼ 2.3 Hz, 1H, H-5), 7.34 (dd, J ¼ 8.7, 2.3 Hz, 1H, H-7), 7.36e7.47 (m,

4.6.12. (2-R*)-[(2S*,3R*,4S*)-6-Bromo-3-nitro-2-(trichloromethyl)

chroman-4-yl]cyclopentan-1-one (ct-9l)

5H, Ph); ¹³C NMR (126 MHz, CDCl₃)

d 20.4, 28.3, 38.6, 38.7, 54.1,

Yield 0.42 g (91%), m.p. 181e182 ^ꢁC. IR (ATR): 1738, 1557, 1479,

73.4, 85.4, 113.8, 119.1, 121.1, 125.6, 128.8, 129.0, 131.5, 131.8, 135.3,

152.8, 217.2. Anal. Calcd. for C₂₀H₁₈BrNO₄: С, 57.71; Н, 4.36; N, 3.36.

Found: С, 57.73; Н, 4.34; N, 3.34.

1366, 1339 cm^ꢀ1. ¹H NMR (500 MHz, CDCl₃)

d 1.60e2.55 (m, 7H, 3

CH₂, H-2⁰), 3.84 (br d, J ¼ 5.7 Hz, 1H, H-4), 4.61 (d, J ¼ 1.8 Hz, 1H, H-

2), 6.05 (t, J ¼ 1.6 Hz, 1H, H-3), 7.00 (d, J ¼ 8.8 Hz, 1H, H-8), 7.14 (d,

J ¼ 2.3 Hz, 1H, H-5), 7.38 (dd, J ¼ 8.8, 2.3 Hz, 1H, H-7); ¹³C NMR

4.6.18. (2S*)-[(2S*,3S*,4R*)-3-Nitro-2-(triﬂuoromethyl)chroman-4-

yl]cyclopentan-1-one (tt-9a) and (2R*)-[(2S*,3S*,4R*)-3-nitro-2-

(triﬂuoromethyl)chroman-4-yl]cyclopentan-1-one (tt-9'a)

(126 MHz, CDCl₃) d 20.3, 28.1, 38.2, 39.9, 54.2, 78.8, 80.9, 95.3, 115.0,

118.9, 120.7, 131.4, 132.0, 151.9, 216.3. Anal. Calcd. for

₁₅H₁₃BrCl₃NO₄: С, 39.38; Н, 2.86; N, 3.06. Found: С, 39.36; Н, 2.84;

C

Yield 0.26 g (80%), m.p. 75e76 ^ꢁC. IR (ATR): 1738, 1566, 1490,

Please cite this article in press as: Korotaev VY, et al., Highly diastereoselective synthesis of novel 2,3,4-trisubstituted chromanes via the reaction

of 3-nitro-2-(trihalomethyl)- and 3-nitro-2-phenyl-2H-chromenes with 1-morpholinocyclopentene, Tetrahedron (2017), http://dx.doi.org/

10.1016/j.tet.2017.07.003

14

V.Y. Korotaev et al. / Tetrahedron xxx (2017) 1e16

1455, 1397, 1374 cm^ꢀ1. Ratio of diastereomers tt-9a:tt-9'a ¼ 69:31.

masked); ¹⁹F NMR (376 MHz, CDCl₃)

d

85.1 (d, J ¼ 5.6 Hz, CF₃); ¹⁹

F

NMR (376 MHz, C₆D₆)

d

86.4 (d, J ¼ 5.7 Hz, CF₃). HRMS (ESI): calcd.

4.6.18.1. Compound tt-9a. This compound was obtained in a pure

state by recrystallisation of the diastereomeric mixture from hex-

ane. Yield 0.11 g (64%), m.p. 89e90 ^ꢁC. ¹H NMR (400 MHz, CDCl₃)

for 382.0873 [MþNa]^þC₁₆H₁₆F₃NNaO₅, found 382.0870.

4.6.20. (2S*)-[(2S*,3S*,4R*)-8-Ethoxy-3-nitro-2-(triﬂuoromethyl)

chroman-4-yl]cyclopentan-1-one (tt-9c) and (2R*)-[(2S*,3S*,4R*)-

8-ethoxy-3-nitro-2-(triﬂuoromethyl)chroman-4-yl]cyclopentan-1-

one (tt-9'c)

d

1.39e2.58 (m, 7H, 3 CH₂, H-2⁰), 4.04 (t, J ¼ 5.8 Hz, 1H, H-4), 4.97

(dq, J ¼ 7.2, 6.2 Hz, 1H, H-2), 5.60 (1H, dd, J ¼ 7.2, 5.4 Hz, H-3), 6.98

(1H, dd, J ¼ 7.6, 1.6 Hz, H-5), 7.04 (td, J ¼ 7.5, 1.1 Hz, 1H, H-6), 7.06

(dd, J ¼ 8.2, 1.1 Hz, 1H, H-8), 7.26 (td, J ¼ 7.7, 1.6 Hz, 1H, H-7); ¹H

Yield 0.34 g (92%), m.p. 124e125 ^ꢁC. IR (ATR): 1731, 1588, 1556,

1486, 1469, 1396, 1370, 1346, 1328 cm^ꢀ1. Ratio of diastereomers tt-

9c:tt-9'c ¼ 79:21.

NMR (400 MHz, C₆D₆)

d

0.73e2.06 (m, 7H, 3 CH₂, H-2⁰), 3.90 (t,

J ¼ 5.5 Hz, 1H, H-4), 4.37 (dq, J ¼ 7.4, 6.2 Hz, 1H, H-2), 5.52 (dd,

J ¼ 7.4, 6.2 Hz, 1H, H-3), 6.64 (dd, J ¼ 7.6, 1.4 Hz, 1H, H-5), 6.69 (td,

J ¼ 7.5, 1.0 Hz, 1H, H-6), 6.76 (dd, J ¼ 8.2, 1.0 Hz, 1H, H-8), 6.81 (td,

4.6.20.1. Compound tt-9c. This compound was obtained in a pure

state by recrystallisation of the diastereomeric mixture from hex-

ane. Yield 0.23 g (87%), mp 131e132 ^ꢁC. ¹H NMR (500 MHz, CDCl₃)

J ¼ 7.7, 1.4 Hz, 1H, H-7); ¹⁹F NMR (376 MHz, CDCl₃)

d 85.0 (d,

J ¼ 6.2 Hz, CF₃); ¹⁹F NMR (376 MHz, C₆D₆)

86.1 (d, J ¼ 6.2 Hz, CF₃);

d

¹³C NMR (101 MHz, CDCl₃)

d

19.9, 26.3, 38.4, 40.7; 50.2, 75.2 (q,

d

1.42e2.61 (m, 7H, 3 CH₂, H-2⁰),1.45 (t, J ¼ 7.0 Hz, 3H, Me), 3.98 (dd,

J ¼ 33.1 Hz, C-2), 83.0, 118.0, 122.6 (q, J ¼ 280.7 Hz, CF₃), 122.7, 124.1,

J ¼ 6.8, 4.7 Hz, 1H, H-4), 4.08 (q, J ¼ 7.0 Hz, 2H, OCH₂), 4.98 (quint,

J ¼ 6.5 Hz, 1H, H-2), 5.73 (dd, J ¼ 6.8, 4.7 Hz, 1H, H-3), 6.58 (dd,

J ¼ 7.5, 1.1 Hz, 1H, H-5), 6.86 (dd, J ¼ 8.4, 1.1 Hz, 1H, H-7), 6.96 (t,

128.5, 129.4, 152.8, 217.5.

4.6.18.2. Compound tt-9'a. ¹H NMR (400 MHz, CDCl₃)

d

1.67e2.80

J ¼ 8.0 Hz, 1H, H-6); ¹H NMR (400 MHz, C₆D₆)

d 0.78e2.13 (m, 7H, 3

(m, 7H, 3 CH₂, H-2⁰), 4.20 (dd, J ¼ 8.3, 2.8 Hz, 1H, H-4), 4.85 (dq,

J ¼ 9.7, 5.5 Hz, 1H, H-2), 5.00 (1H, dd, J ¼ 9.7, 8.3 Hz, H-3), 7.10 (td,

J ¼ 7.6, 1.1 Hz, 1H, H-6), 7.22 (d, J ¼ 7.7 Hz, 1H, H-5) (signals of H-7

CH₂, H-2⁰), 1.09 (t, J ¼ 7.0 Hz, 3H, Me), 3.59 (dq, J ¼ 9.4, 7.0 Hz, 1H,

OCHH), 3.60 (dq, J ¼ 9.4, 7.0 Hz, 1H, OCHH), 3.90 (t, J ¼ 5.7 Hz,1H, H-

4), 4.53 (dq, J ¼ 7.2, 6.3 Hz, 1H, H-2), 5.71 (dd, J ¼ 7.2, 5.2 Hz, 1H, H-

3), 6.42 (dd, J ¼ 7.5,1.1 Hz,1H, H-5), 6.47 (dd, J ¼ 8.4,1.1 Hz,1H, H-7),

and H-8 are masked); ¹H NMR (400 MHz, C₆D₆)

d 0.69e2.11 (m, 7H,

3 CH₂, H-2⁰), 3.98 (dd, J ¼ 8.5, 3.6 Hz, 1H, H-4), 4.20 (dq, J ¼ 9.7,

5.5 Hz, 1H, H-2), 4.93 (t, J ¼ 9.1 Hz, 1H, H-3), 6.74 (dd, J ¼ 8.2, 1.1 Hz,

1H, H-8) (signals of H-5, H-7 and H-8 are masked); ¹⁹F NMR

6.68 (t, J ¼ 8.0 Hz, 1H, H-6); ¹⁹F NMR (376 MHz, CDCl₃)

d 85.2 (d,

d 14.8, 19.9, 26.8, 38.5,

J ¼ 6.3 Hz, CF₃); ¹³C NMR (126 МGц, CDCl₃)

41.0, 49.8, 65.0, 75.5 (q, J ¼ 33.2 Hz, C-2), 83.1, 113.7, 120.0, 122.6 (q,

(376 MHz, CDCl₃)

d

85.03 (d, J ¼ 5.5 Hz, CF₃); ¹⁹F NMR (376 MHz,

J ¼ 280.5 Hz, CF₃), 124.1, 124.7, 142.4, 148.7, 218.0.

C₆D₆)

d

86.3 (d, J ¼ 5.6 Hz, CF₃); ¹³C NMR (101 MHz, CDCl₃)

d 20.3,

24.7, 37.8, 38.6, 52.7, 74.7 (q, J ¼ 32.6 Hz, C-2), 80.9, 117.7, 122.5 (q,

J ¼ 280.7 Hz, CF₃),122.2,123.9,126.9,129.0,152.7, 215.4. Anal. Calcd.

for C₁₅H₁₄F₃NO₄: С, 54.72; Н, 4.29; N, 4.25. Found: С, 54.86; Н, 4.27;

N, 4.26.

4.6.20.2. Compound tt-9'c. ¹H NMR (500 MHz, CDCl₃)

d 1.44 (t,

J ¼ 6.8 Hz, 3H, Me), 1.65e2.76 (m, 7H, 3 CH₂, H-2⁰), 4.18 (dd, J ¼ 7.8,

3.3 Hz, 1H, H-4), 4.85 (dq, J ¼ 9.3, 5.6 Hz, 1H, H-2), 6.77 (br d,

J ¼ 7.5 Hz, 1H, H-5), 6.85 (br d, J ¼ 8.4 Hz, 1H, H-7), 7.01 (1H, t,

J ¼ 8.0 Hz, H-6) (signals of H-3 and OCH₂are masked); ¹H NMR

4.6.19. (2S*)-[(2S*,3S*,4R*)-6-Methoxy-3-nitro-2-(triﬂuoromethyl)

chroman-4-yl]cyclopentan-1-one (tt-9b) and (2R*)-[(2S*,3S*,4R*)-

6-methoxy-3-nitro-2-(triﬂuoromethyl)chroman-4-yl]cyclopentan-

1-one (tt-9'b)

(400 MHz, C₆D₆)

d

0.74e2.16 (m, 7H, 3 CH₂, H-2⁰), 1.10 (t, J ¼ 7.0 Hz,

3H, Me), 4.05 (dd, J ¼ 7.9, 3.5 Hz, 1H, H-4), 4.27 (dq, J ¼ 9.3, 5.8 Hz,

1H, H-2), 4.99 (dd, J ¼ 9.3, 7.9 Hz, 1H, H-3), 6.36 (br d, J ¼ 7.8 Hz, 1H,

H-5), 6.73 (t, J ¼ 8.1 Hz, 1H, H-6) (signals of H-7 and OCH₂are

Yield 0.28 g (77%), m.p. 93e94 ^ꢁC. IR (ATR): 1739, 1558, 1499,

1468, 1370 cm^ꢀ1. Ratio of diastereomers tt-9b:tt-9'b ¼ 75:25.

masked); ¹⁹F NMR (376 MHz, CDCl₃)

d

85.2 (d, J ¼ 5.6 Hz, CF₃). Anal.

Calcd. for C₁₇H₁₈F₃NO₅: С, 54.69; Н, 4.86; N, 3.75. Found: С, 54.55;

Н, 4.59; N, 3.75.

4.6.19.1. Compound tt-9b. This compound was obtained in a pure

state by recrystallisation of the diastereomeric mixture from hex-

ane. Yield 0.18 g (86%), m.p. 104e105 ^ꢁC. ¹H NMR (400 MHz, CDCl₃)

4.6.21. (2S*)-[(2S*,3S*,4R*)-6-Chloro-3-nitro-2-(triﬂuoromethyl)

chroman-4-yl]cyclopentan-1-one (tt-9d) and (2R*)-[(2S*,3S*,4R*)-

6-chloro-3-nitro-2-(triﬂuoromethyl)chroman-4-yl]cyclopentan-1-

one (tt-9'd)

d

1.39e2.61 (m, 7H, 3 CH₂, H-2⁰), 3.74 (s, 3H, MeO), 3.97 (dd, J ¼ 6.2,

4.7 Hz, 1H, H-4), 4.92 (quint, J ¼ 6.6 Hz, 1H, H-2), 5.65 (dd, J ¼ 7.0,

4.7 Hz,1H, H-3), 6.53 (d, J ¼ 2.9 Hz,1H, H-5), 6.79 (dd, J ¼ 8.8, 2.9 Hz,

1H, H-7), 7.00 (d, J ¼ 8.8 Hz, 1H, H-8); ¹H NMR (400 MHz, C₆D₆)

Yield 0.27 g (73%), m.p. 82e83 ^ꢁC. IR (ATR): 1745, 1561, 1484,

1420, 1352, 1328 cm^ꢀ1. Ratio of diastereomers tt-9d:tt-9'd ¼ 74:26.

d

0.73e2.12 (m, 7H, 3 CH₂, H-2⁰), 3.20 (s, 3H, MeO), 3.83 (t,

J ¼ 5.7 Hz, 1H, H-4), 4.48 (dq, J ¼ 7.1, 6.3 Hz, 1H, H-2), 5.68 (dd,

4.6.21.1. Compound tt-9d. This compound was obtained in a pure

state by recrystallisation of the diastereomeric mixture from hex-

ane. Yield 0.13 g (65%), m.p. 89e90^ꢁС. ¹H NMR (400 MHz, CDCl₃)

J ¼ 7.1, 5.2 Hz, 1H, H-3), 6.42e6.48 (m, 2H, H-5, H-7), 6.67e6.74 (1H,

m, H-8); ¹⁹F NMR (376 MHz, CDCl₃)

d

85.0 (d, J ¼ 6.2 Hz, CF₃); ¹⁹F

NMR (376 MHz, C₆D₆)

CDCl₃)

83.0, 113.5, 114.7, 118.8, 122.6 (q, J ¼ 280.6 Hz, CF₃), 124.0, 146.6,

d

86.2 (d, J ¼ 6.3 Hz, CF₃); ¹³C NMR (101 MHz,

d

1.41e2.57 (m, 7H, 3 CH₂, H-2⁰), 3.95 (dd, J ¼ 6.9, 4.7 Hz, 1H, H-4),

d

19.9, 26.6, 38.5, 41.2, 50.2, 55.6, 75.5 (q, J ¼ 32.9 Hz, C-2),

4.98 (quint, J ¼ 6.4 Hz, 1H, H-2), 5.73 (dd, J ¼ 6.6, 4.7 Hz, 1H, H-3),

7.00 (d, J ¼ 2.4 Hz, 1H, H-5), 7.02 (d, J ¼ 8.7 Hz, 1H, H-8), 7.24 (dd,

155.9, 217.9.

J ¼ 8.7, 2.4 Hz, 1H, H-7); ¹⁹F NMR (376 MHz, CDCl₃)

d 85.1 (d,

d 19.9, 26.9, 38.4, 40.6,

J ¼ 6.2 Hz, CF₃). ¹³C NMR (101 MHz, CDCl₃)

4.6.19.2. Compound tt-9'b. ¹H NMR (400 MHz, CDCl₃)

d

1.67e2.74

49.6, 75.4 (q, J ¼ 33.4 Hz, C-2), 82.3, 119.5, 122.4 (q, J ¼ 280.7 Hz,

(m, 7H, 3 CH₂, H-2⁰), 3.78 (s, 3H, MeO), 4.15 (dd, J ¼ 7.8, 3.4 Hz, 1H,

H-4), 4.77 (dq, J ¼ 9.3, 5.6 Hz, 1H, H-2), 4.97 (dd, J ¼ 9.3, 7.8 Hz, 1H,

H-3), 6.72 (d, J ¼ 2.9 Hz, 1H, H-5), 6.80 (dd, J ¼ 8.7, 2.9 Hz, 1H, H-7),

CF₃), 124.7, 126.9, 128.3, 129.5, 151.2, 217.4.

4.6.21.2. Compound tt-9'd. ¹H NMR (400 MHz, CDCl₃)

d 1.69e2.75

6.98 (d, J ¼ 8.7 Hz, 1H, H-8); ¹H NMR (400 MHz, C₆D₆)

d

0.73e2.12

(m, 7H, 3 CH₂, H-2⁰), 4.15 (dd, J ¼ 8.2, 3.8 Hz, 1H, H-4), 4.84 (dq,

J ¼ 9.1, 5.5 Hz, 1H, H-2), 5.00 (dd, J ¼ 9.1, 8.2 Hz, 1H, H-3), 6.91 (d,

J ¼ 2.4 Hz, 1H, H-5), 6.95 (d, J ¼ 8.7 Hz, 1H, H-8), 7.19 (dd, J ¼ 8.7,

(m, 7H, 3 CH₂, H-2⁰), 3.24 (s, 3H, MeO), 4.00 (dd, J ¼ 7.7, 4.0 Hz, 1H,

H-4), 4.27 (dq, J ¼ 9.1, 5.7 Hz, 1H, H-2), 4.98 (dd, J ¼ 9.1, 7.7 Hz, 1H,

H-3), 6.40 (dd, J ¼ 9.1, 2.8 Hz, 1H, H-7) (signals of H-5 and H-8 are

2.4 Hz, 1H, H-7); ¹⁹F NMR (376 MHz, CDCl₃)

d

85.0 (d, J ¼ 5.5 Hz,

Please cite this article in press as: Korotaev VY, et al., Highly diastereoselective synthesis of novel 2,3,4-trisubstituted chromanes via the reaction

of 3-nitro-2-(trihalomethyl)- and 3-nitro-2-phenyl-2H-chromenes with 1-morpholinocyclopentene, Tetrahedron (2017), http://dx.doi.org/

10.1016/j.tet.2017.07.003

V.Y. Korotaev et al. / Tetrahedron xxx (2017) 1e16

15

CF₃); ¹³C NMR (101 MHz, CDCl₃)

J ¼ 33.1 Hz, C-2), 80.4, 119.2, 122.4 (q, J ¼ 281.9 Hz, CF₃), 124.0, 129.1,

129.2,129.3,151.1, 215.2. Anal. Calcd. for C₁₅H₁₃ClF₃NO₄: С, 49.53; Н,

3.60; N, 3.85. Found: С, 49.64; Н, 3.40; N, 3.81.

d

20.3, 24.7, 37.6, 38.3, 52.6, 74.7 (q,

J ¼ 2.3 Hz, 1H, H-5), 7.11 (d, J ¼ 8.6 Hz, 1H, H-8), 7.28 (dd, J ¼ 8.6,

2.3 Hz, 1H, H-7); ¹³C NMR (101 MHz, CDCl₃)

19.7, 27.7, 38.3, 43.1,

49.7, 86.1, 87.4, 96.9, 119.7, 126.9, 128.3, 129.5, 129.6, 152.5, 217.0.

d

4.6.24.2. Compound tt-9'k. ¹H NMR (400 MHz, CDCl₃)

d 1.51e2.77

4.6.22. (2S*)-[(2S*,3S*,4R*)-6-Bromo-3-nitro-2-(triﬂuoromethyl)

chroman-4-yl]cyclopentan-1-one (tt-9e) and (2R*)-[(2S*,3S*,4R*)-

6-bromo-3-nitro-2-(triﬂuoromethyl)chroman-4-yl]cyclopentan-1-

one (tt-9'e)

(m, 7H, 3 CH₂, H-2⁰), 3.95 (dd, J ¼ 8.4, 3.6 Hz, 1H, H-4), 5.10 (dd,

J ¼ 8.4, 7.1 Hz, 1H, H-3), 5.42 (d, J ¼ 7.1 Hz, 1H, H-2), 7.06 (d,

J ¼ 8.6 Hz, 1H, H-8), 7.13 (br d, J ¼ 2.3 Hz, 1H, H-5), 7.27 (dd, J ¼ 8.6,

2.3 Hz, 1H, H-7); ¹³C NMR (101 MHz, CDCl₃)

d 20.3, 24.7, 37.4, 39.3,

Yield 0.34 g 84%, m.p. 78e79 ^ꢁC. IR (ATR): 1727, 1561, 1480, 1408,

1351, 1320 cm^ꢀ1. Ratio of diastereomers tt-9e:tt-9'e ¼ 71:29.

50.1, 84.8, 86.6, 100.0, 119.6, 125.2, 126.5, 129.1, 129.3, 152.6, 214.9.

Anal. Calcd. for C₁₅H₁₃Cl₄NO₄: С, 43.62; Н, 3.17; N, 3.39. Found: С,

44.07; Н, 3.08; N, 3.28.

4.6.22.1. Compound tt-9e. ¹H NMR (400 MHz, CDCl₃)

d 1.39e2.58

(m, 7H, 3 CH₂, H-2⁰), 3.95 (dd, J ¼ 6.4, 4.8 Hz, 1H, H-4), 4.99 (quint,

J ¼ 6.4 Hz, 1H, H-2), 5.73 (dd, J ¼ 6.4, 4.8 Hz, 1H, H-3), 6.97 (d,

J ¼ 8.6 Hz, 1H, H-8), 7.15 (d, J ¼ 2.2 Hz, 1H, H-5), 7.38 (dd, J ¼ 8.6,

4.6.25. (2S*)-[(2S*,3S*,4R*)-6-Bromo-3-nitro-2-(trichloromethyl)

chroman-4-yl]cyclopentan-1-one (tt-9l) and (2R*)-[(2S*,3S*,4R*)-6-

bromo-3-nitro-2-(trichloromethyl)chroman-4-yl]cyclopentan-1-

one (tt-9'l)

2.2 Hz, 1H, H-7); ¹H NMR (400 MHz, C₆D₆)

d 0.54e1.99 (m, 7H, 3

CH₂, H-2⁰), 3.58 (dd, J ¼ 6.8, 5.0 Hz, 1H, H-4), 4.39 (quint, J ¼ 6.6 Hz,

1H, H-2), 5.73 (dd, J ¼ 6.7, 5.0 Hz, 1H, H-3), 6.39 (d, J ¼ 8.6 Hz, 1H, H-

Yield 0.44 g (96%), m.p. 140e141 ^ꢁC. IR (ATR): 1732, 1553, 1478,

1451, 1405, 1374, 1358 cm^ꢀ1. Ratio of diastereomers tt-9l: tt-

9'l ¼ 63:37.

8), 6.88e6.93 (m, 2H, H-5, H-7); ¹⁹F NMR (376 MHz, CDCl₃)

d

85.1

(d, J ¼ 6.3 Hz, CF₃); ¹⁹F NMR (376 MHz, C₆D₆)

d

86.2 (d, J ¼ 6.4 Hz,

CF₃); ¹³C NMR (101 MHz, CDCl₃)

d

19.9, 26.9, 38.4, 40.5, 49.6, 75.3 (q,

4.6.25.1. Compound tt-9l. ¹H NMR (400 MHz, CDCl₃)

d 1.44e2.78

J ¼ 33.4 Hz, C-2), 82.3, 111.6, 119.9, 122.4 (q, J ¼ 280.6 Hz, CF₃), 125.2,

(m, 7H, 3 CH₂, H-2⁰), 3.63 (dd, J ¼ 8.0, 2.7 Hz, 1H, H-4), 5.19 (d,

J ¼ 6.6 Hz, 1H, H-2), 6.08 (dd, J ¼ 6.6, 2.7 Hz, 1H, H-3), 7.06 (d,

J ¼ 8.6 Hz, 1H, H-8), 7.17 (d, J ¼ 2.3 Hz, 1H, H-5), 7.43 (dd, J ¼ 8.6,

129.8, 132.5, 151.7, 217.4.

4.6.22.2. Compound tt-9'e. ¹H NMR (400 MHz, CDCl₃)

d

1.68e2.74

2.3 Hz, 1H, H-7); ¹³C NMR (101 MHz, CDCl₃)

d 19.7, 27.7, 38.3, 43.1,

(m, 7H, 3 CH₂, H-2⁰), 4.16 (dd, J ¼ 8.2, 3.4 Hz, 1H, H-4), 4.84 (dq,

J ¼ 9.2, 5.6 Hz, 1H, H-2), 4.97 (dd, J ¼ 9.2, 8.2 Hz, 1H, H-3), 6.95 (d,

J ¼ 8.6 Hz,1H, H-8), 7.33e7.38 (m, 2H, H-5, H-7); ¹H NMR (400 MHz,

49.7, 86.0, 87.4, 96.9, 117.0, 120.1, 127.3, 131.1, 132.5, 153.0, 217.0.

4.6.25.2. Compound tt-9'l. ¹H NMR (400 MHz, CDCl₃)

d 1.51e2.78

C₆D₆)

d

0.64e1.84 (m, 7H, 3 CH₂, H-2⁰), 3.83 (dd, J ¼ 8.4, 3.4 Hz, 1H,

(m, 7H, 3 CH₂, H-2⁰), 3.96 (dd, J ¼ 8.3, 4.0 Hz, 1H, H-4), 5.10 (dd,

J ¼ 8.3, 7.1 Hz, 1H, H-3), 5.41 (д, J ¼ 7.1 Hz, 1H, H-2), 7.01 (d,

J ¼ 8.6 Hz, 1H, H-8), 7.28 (dd, J ¼ 2.3, 1.0 Hz, 1H, H-5), 7.41 (dd,

H-4), 4.12 (dd, J ¼ 9.3, 5.6 Hz, 1H, H-2), 4.79 (dd, J ¼ 9.3, 8.4 Hz, 1H,

H-3), 6.35 (d, J ¼ 8.6 Hz, 1H, H-8), 6.86e6,93 (m, 2H, H-5, H-7); ¹⁹

F

NMR (376 MHz, CDCl₃)

d

85.0 (d, J ¼ 5.6 Hz, CF₃); ¹⁹F NMR

J ¼ 8.6, 2.3 Hz, 1H, 1H, H-7); ¹³C NMR (101 MHz, CDCl₃)

d 20.3, 24.6,

(376 MHz, C₆D₆)

CDCl₃)

116.5, 119.5, 122.3 (q, J ¼ 282.2 Hz, CF₃), 124.4, 129.8, 132.2, 151.6,

215.2. Anal. Calcd. for C₁₅H₁₃BrF₃NO₄$0.5H₂O: С, 43.19; Н, 3.38; N,

3.36. Found: С, 43.10; Н, 3.27; N, 3.36.

d

86.3 (d, J ¼ 5.6 Hz, CF₃); ¹³C NMR (101 MHz,

37.4, 39.1, 50.1, 84.7, 86.5, 98.1, 116.5, 120.0, 125.6, 129.3, 132.3, 153.1,

215.0. Anal. Calcd. for C₁₅H₁₃BrCl₃NO₄: С, 39.38; Н, 2.86; N, 3.06.

Found: С, 39.53; Н, 2.93; N, 3.28.

d

20.3, 24.6, 37.6, 38.2, 52.6, 74.6 (q, J ¼ 32.9 Hz, C-2), 80.4,

4.6.26. (2S*)-[(2R*,3S*,4R*)-3-Nitro-2-phenylchroman-4-yl]

cyclopentan-1-one (tt-9o) and (2R*)-[(2R*,3S*,4R*)-3-nitro-2-

phenylchroman-4-yl]cyclopentan-1-one (tt-9'o)

4.6.23. (2S*)-[(2S*,3S*,4R*)-3-Nitro-2-(trichloromethyl)chroman-

4-yl]cyclopentan-1-one (tt-9h)

This compound was obtained by hydrolysis of the mixture tt-

8h:ct-8h ¼ 64:36 and puriﬁed by column chromatography over

silica gel (eluent e CHCl₃). Yield 0.19 g (51%), m.p. 162e163 ^ꢁC. IR

(ATR): 1731, 1554, 1487, 1462, 1419, 1363 cm^ꢀ1. ¹H NMR (500 MHz,

Yield 0.29 g (87%), m.p. 180e182 ^ꢁC. IR (ATR): 1732, 1552, 1468,

1452, 1362 cm^ꢀ1. Ratio of diastereomers tt-9o:tt-9'o ¼ 76:24.

4.6.26.1. Compound tt-9o. ¹H NMR (400 MHz, CDCl₃)

d 1.44e2.51

(m, 7H, 3 CH₂, H-2⁰), 4.50 (dd, J ¼ 9.8, 2.4 Hz, 1H, H-4), 4.95 (t,

J ¼ 9.7 Hz, 1H, H-3), 5.18 (d, J ¼ 9.6 Hz, 1H, H-2), 6.90 (d, J ¼ 7.6 Hz,

1H, H-8), 6.93e6.99 (m, 2H, H-5, H-6), 7.19 (t, J ¼ 7.5 Hz, 1H, H-7),

CDCl₃)

d

1.40e2.74 (m, 7H, 3 CH₂, H-2⁰), 3.70 (dd, J ¼ 7.6, 3.0 Hz, 1H,

H-4), 5.21 (d, J ¼ 6.8 Hz, 1H, H-2), 6.03 (dd, J ¼ 6.8, 3.0 Hz, 1H, H-3),

7.02 (dd, J ¼ 7.5, 1.2 Hz, 1H, H-5), 7.08 (td, J ¼ 7.5, 0.8 Hz, 1H, H-6),

7.36e7.46 (m, 5H, Ph); ¹³C NMR (101 MHz, CDCl₃)

d 20.3, 23.8, 38.6,

7.16 (br d, J ¼ 7.7 Hz, 1H, H-8), 7.31 (td, J ¼ 7.9, 1.2 Hz, 1H, H-7); ¹³

C

40.3, 52.2, 78.9, 90.2, 117.9, 120.5, 218.2, 122.5, 127.2, 128.1, 128.6,

128.9, 129.8, 135.1, 154.9.

NMR (126 MHz, CDCl₃) d 19.8, 27.4, 38.4, 43.2, 50.2, 86.6, 87.2, 97.2,

118.3, 124.5, 124.9, 128.4, 129.5, 154.0, 217.5. Anal. Calcd. for

₁₅H₁₄Cl₃NO₄: С, 47.58; Н, 3.73; N, 3.70. Found: С, 47.54; Н, 3.50; N,

3.64.

C

4.6.26.2. Compound tt-9'o. ¹H NMR (400 MHz, CDCl₃)

d 1.70e2.88

(m, 7H, 3 CH₂, H-2⁰), 4.46 (dd, J ¼ 9.6, 2.4 Hz, 1H, H-4), 4.99 (t,

J ¼ 9.7 Hz, 1H, H-3), 5.12 (d, J ¼ 9.8 Hz, 1H, H-2), 6.93e7.30 (m, 4H,

H-5, H-6, H-7, H-8), 7.36e7.46 (m, 5H, Ph); ¹³C NMR (101 MHz,

4.6.24. (2S*)-[(2S*,3S*,4R*)-6-Chloro-3-nitro-2-(trichloromethyl)

chroman-4-yl]cyclopentan-1-one (tt-9k) and (2R*)-[(2S*,3S*,4R*)-

6-chloro-3-nitro-2-(trichloromethyl)chroman-4-yl]cyclopentan-1-

one (tt-9'k)

CDCl₃)

126.9, 127.4, 128.4, 128.9, 129.8, 135.0; 154.8, 216.4. Anal. Calcd. for

₂₀H₁₉NO₄: С, 71.20; Н, 5.68; N, 4.15. Found: С, 71.16; Н, 5.49; N,

d 20.5; 24.4, 38.0, 39.2, 53.4, 79.0, 90.2, 117.8, 121.9, 122.7,

C

4.18.

Yield 0.39 g (94%), m.p. 156e157 ^ꢁC. IR (ATR): 1731, 1555, 1481,

1453, 1404, 1374, 1359 cm^ꢀ1. Ratio of diastereomers tt-9k:tt-

9'k ¼ 71:29.

4.7. X-ray diffraction study of compounds ct-7h, tt-8a, ct-9l, tt-9c

and tt-9h

4.6.24.1. Compound tt-9k. ¹H NMR (400 MHz, CDCl₃)

d 1.44e2.77

(m, 7H, 3 CH₂, H-2⁰), 3.64 (dd, J ¼ 8.0, 2.7 Hz, 1H, H-4), 5.19 (d,

J ¼ 6.6 Hz, 1H, H-2), 6.08 (dd, J ¼ 6.6, 2.7 Hz, 1H, H-3), 7.02 (d,

Intensity data for the compounds ct-7h, tt-8a and ct-9l, tt-9c, tt-

9h, were collected on

a “Xcalibur S” or “Xcalibur Eos”

Please cite this article in press as: Korotaev VY, et al., Highly diastereoselective synthesis of novel 2,3,4-trisubstituted chromanes via the reaction

of 3-nitro-2-(trihalomethyl)- and 3-nitro-2-phenyl-2H-chromenes with 1-morpholinocyclopentene, Tetrahedron (2017), http://dx.doi.org/

10.1016/j.tet.2017.07.003

16

V.Y. Korotaev et al. / Tetrahedron xxx (2017) 1e16

diffractometer, corresponding at 295 (2) K (Mo-K

(compound tt-8a) radiation, graphite monochromator,

a

u

or Cu-K

-scan). The

a

data). Largest different peak and hole: 0.212 and ꢀ0.251 eÅ^ꢀ3

.

Completeness to

1541655.

q

¼ 28.22^ꢁ(99.98%). Deposition number CCDC

structures were solved by direct methods and reﬁned by full-

matrix least-squares method using the SHELX-97 program pack-

age.¹²All non-hydrogen atoms were reﬁned with anisotropic

atomic displacement and hydrogen atoms were included at calcu-

lated position using a riding model.

4.7.5. Crystal data for tt-9h

₁₅H₁₄Cl₃NO₄, M ¼ 378.63. Triclinic crystals space group P-1,

C

a ¼ 9.4893 (6), b ¼ 9.5851 (6), c ¼ 10.6764 (7) Å,

a

¼ 79.477 (6),

b

¼ 73.457 (6),

g

¼ 61.813 (6)^ꢁ, V ¼ 819.15 (9) Å³, D_c¼ 1.535 g/cm³,

4.7.1. Crystal data for ct-7h

absorption coefﬁcient

m

¼ 0.577 mm^ꢀ1, Z ¼ 2. The intensities of

C

₁₉H₂₁Cl₃N₂O₄, M ¼ 447.74. Monoclinic crystals space group C2/

4498 independent reﬂections (R_int¼ 0.0218) were measured. The

ﬁnal discrepancy factors R₁¼ 0.0495, wR₂¼ 0.1423, GooF ¼ 1.01 for

c, a ¼ 29.367 (4), b ¼ 8.5321 (8), c ¼ 18.145 (3) Å,

a

¼

g

¼ 90.00,

b

¼ 116.269 (5)^ꢁ, V ¼ 4077.0 (10) Å³, D_c¼ 1.459 g/cm³, absorption

3261 reﬂections with I > 2

s

(I); R₁¼ 0.0729, wR₂¼ 0.1697 (all data).

coefﬁcient

m

¼ 0.478 mm^ꢀ1, Z ¼ 8. The intensities of 4995 inde-

Largest different peak and hole: 0.510 and ꢀ0.459 eÅ^ꢀ3

.

pendent reﬂections (R_int¼ 0.0287) were measured. The ﬁnal

Completeness to

1541654.

q

¼ 28.22^ꢁ(100.00%). Deposition number CCDC

discrepancy factors R₁¼ 0.0382, wR₂¼ 0.0848, GooF ¼ 1.003 for

2452 reﬂections with I > 2

s

(I); R₁¼ 0.0869, wR₂¼ 0.0910 (all data).

Largest different peak and hole: 0.345 and ꢀ0.359 eÅ^ꢀ3

.

Completeness to

1541656.

q

¼ 28.3^ꢁ(98.6%). Deposition number CCDC

References

1. (a) Risaliti A, Forchiassin M, Valentin E. Tetrahedon Lett . 1966;7:6331e6335;

(b) Colonna FP, Valentin E, Pitacco G, Risaliti A. Tetrahedron . 1973;29:

3011e3017;

(c) Molteni M, Consonni R, Giovenzana T, Malpezzi L, Zanda M. J Fluor Chem .

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deleev Commun . 2011;21:112e114.

2. (a) Nielsen AT, Archibald TG. Tetrahedron . 1970;26:3475e3485;

(b) Daneo S, Pitacco G, Risaliti A, Valentin E. Tetrahedron . 1982;38:1499e1503;

(c) Barbarella G, Pitacco G, Russo C, Valentin E. Tetrahedron Lett . 1983;24:

1621e1622;

4.7.2. Crystal data for tt-8a

₁₉H₂₁F₃N₂O₄, M ¼ 398.38. Triclinic crystals space group P-1,

C

a ¼ 9.171 (9), b ¼ 10.247 (10), c ¼ 11.403 (13) Å,

a

¼ 86.08 (9),

b

¼ 67.90 (10),

g

¼ 69.73 (9)^ꢁ, V ¼ 929.0 (17) Å³, D_c¼ 1.424 g/cm³,

absorption coefﬁcient

m

¼ 1.029 mm^ꢀ1, Z ¼ 2. The intensities of

3103 independent reﬂections (R_int¼ 0.0381) were measured. The

ﬁnal discrepancy factors R₁¼ 0.0514, wR₂¼ 0.1579, GooF ¼ 1.015

for 2502 reﬂections with I > 2

s

(I); R₁¼ 0.0593, wR₂¼ 0.1655 (all

(d) Benedetti F, Drioli S, Nitti P, Pitacco G, Valentin E. ARKIVOC . 2001;v:

140e155;

data). Largest different peak and hole: 0.274 and ꢀ0.245 eÅ^ꢀ3

.

Completeness to

1541653.

q

¼ 65.5^ꢁ(94.4%). Deposition number CCDC

(e) Korotaev VY, Barkov AY, Slepukhin PA, Sosnovskikh VY. Russ Chem Bull Int

Ed . 2012;61:1750e1760 [Izv. Akad. Nauk, Ser. Khim . 2012, 1734e1744].

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(b) Kuehne ME, Foley L. J Org Chem . 1965;30:4280e4284;

(c) Patora-Komisarska K, Benohoud M, Ishikawa H, Seebach D, Hayashi Y. Helv

Chim Acta . 2011;94:719e745;

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1736e1749 [Izv. Akad. Nauk, Ser. Khim. 2012, 1720e1733].

4. Korotaev VY, Sosnovskikh VY, Barkov AY. Russ Chem Rev . 2013;82:1081e1116

[Usp. Khim. 82 , 2013, 1081e1116].

5. Hu ZP, Zhang J-M, Lou C-L, Wang J-J, Nie S-Z, Yan M. ARKIVOC . 2010;x:17e33.

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hedron . 2014;70:5161e5167.

7. (a) Korotaev VY, Kutyashev IB, Barkov AY, Sosnovskikh VY. Chem Heterocycl

Compd . 2015;51:440e446 [Khim. Geterotsikl. Soedin . 51 , 2015, 440e446];

(b) Korotaev VY, Barkov AY, Ezhikova MA, Kodess MI, Sosnovskikh VY. Chem

Heterocycl Compd . 2015;51:531e540 [Khim. Geterotsikl. Soedin. 51 , 2015,

531e540];

4.7.3. Crystal data for ct-9l

₁₅H₁₃BrCl₃NO₄, M ¼ 457.53. Ortorombic crystals space group

C

P2₁2₁2₁, a ¼ 10.9805 (7), b ¼ 10.9040 (6), c ¼ 30.9588 (15) Å,

a

¼

b

¼

g

¼ 90.00^ꢁ, V ¼ 3538.6 (4) Å³, D_c¼ 1.718 g/cm³, absorption

coefﬁcient

m

¼ 2.795 mm^ꢀ1, Z ¼ 8. The intensities of 8302 inde-

pendent reﬂections (R_int¼ 0.0321) were measured. The ﬁnal

discrepancy factors R₁¼ 0.0506, wR₂¼ 0.0882, GooF ¼ 1.005 for

5463 reﬂections with I > 2

s

(I); R₁¼ 0.0967, wR₂¼ 0.1071 (all data).

Largest different peak and hole: 0.561 and ꢀ0.695 eÅ^ꢀ3

.

Completeness to

1541657.

q

¼ 28.22^ꢁ(99.82%). Deposition number CCDC

(c) Korotaev VY, Barkov AY, Kutyashev IB, et al. Tetrahedron . 2015;71:

2658e2669;

(d) Korotaev VY, Kotovich IV, Barkov AY, Kutyashev IB, Kodess MI,

Sosnovskikh VY. Tetrahedron . 2016;72:216e226.

4.7.4. Crystal data for tt-9c

₁₇H₁₈F₃NO₅, M ¼ 373.11. Triclinic crystals space group P-1,

C

8. (a) Korotaev VY, Sosnovskikh VY, Kutyashev IB, Kodess MI. Russ Chem Bull Int

Ed . 2006;55:317e330 [Izv. Akad. Nauk, Ser. Khim. 2006, 309e321];

(b) Korotaev VY, Sosnovskikh VY, Kutyashev IB, Kodess MI. Russ Chem Bull Int

Ed . 2006;55:2020e2031 [Izv. Akad. Nauk, Ser. Khim. 2006, 1945e1955].

9. Zhao Y, Wang X-J, Lin Y, Cai C-X, Liu J-T. Tetrahedron . 2014;70:2523e2528.

10. Korotaev VY, Kutyashev IB, Sosnovskikh VY. Heteroat Chem . 2005;16:492e496.

11. Sakakibara T, Koezuka M, Sudoh R. Bull Chem Soc Jpn . 1978;51:3095e3096.

12. Sheldrick GM. Acta Crystallogr Sect A . 2008;64:112e122.

a ¼ 9.1032 (7), b ¼ 9.3424 (8), c ¼ 10.6210 (9) Å,

a

¼ 69.803 (8),

b

¼ 81.215 (7),

g

¼ 81.790 (7)^ꢁ, V ¼ 833.83 (12) Å³, D_c¼ 1.487 g/cm³,

absorption coefﬁcient

4525 independent reﬂections (R_int¼ 0.0188) were measured. The

ﬁnal discrepancy factors R₁¼ 0.0492, wR₂¼ 0.1363, GooF ¼ 1.008

m

¼ 0.130 mm^ꢀ1, Z ¼ 2. The intensities of

for 3106 reﬂections with I > 2

s

(I); R₁¼ 0.0803, wR₂¼ 0.1606 (all

Please cite this article in press as: Korotaev VY, et al., Highly diastereoselective synthesis of novel 2,3,4-trisubstituted chromanes via the reaction

of 3-nitro-2-(trihalomethyl)- and 3-nitro-2-phenyl-2H-chromenes with 1-morpholinocyclopentene, Tetrahedron (2017), http://dx.doi.org/

10.1016/j.tet.2017.07.003

Article Doi

Highly diastereoselective synthesis of novel 2,3,4-trisubstituted chromanes via the reaction of 3-nitro-2-(trihalomethyl)- and 3-nitro-2-phenyl-2H-chromenes with 1-morpholinocyclopentene

DOI: 10.1016/j.tet.2017.07.003

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Article abstract of DOI:10.1016/j.tet.2017.07.003

Full text of DOI:10.1016/j.tet.2017.07.003

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