Formation of substituted 2-iminooxazolidines via intermolecular 1,2-addition/intramolecular N-vinylation using 3-substituted-2-bromo-2-propen-1-ols as substrates

Accepted Manuscript

Formation of substituted 2-iminooxazolidines via intermolecular 1,2-addition /

intramolecular N-vinylation using 3-substituted-2-bromo-2-propen-1-ols as substrates

Heike Weischedel, Dietmar Schmidt, Jürgen Conrad, Uwe Beifuss

PII:

S0040-4020(18)31034-2

10.1016/j.tet.2018.08.051

TET 29771

DOI:

Reference:

To appear in: Tetrahedron

Received Date: 11 May 2018

Revised Date: 13 August 2018

Accepted Date: 30 August 2018

Please cite this article as: Weischedel H, Schmidt D, Conrad Jü, Beifuss U, Formation of substituted

2-iminooxazolidines via intermolecular 1,2-addition / intramolecular N-vinylation using 3-substituted-2-

bromo-2-propen-1-ols as substrates, Tetrahedron (2018), doi: 10.1016/j.tet.2018.08.051.

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ACCEPTED MANUSCRIPT

Graphical Abstract

Formation of substituted 2-

Leave this area blank for abstract info.

iminooxazolidines via intermolecular 1,2-

addition / intramolecular N-vinylation using

3-substituted-2-bromo-2-propen-1-ols as

substrates

Heike Weischedel, Dietmar Schmidt, Jürgen Conrad, Uwe Beifuss

Cu₂O-catalyzed or

copper-free

K₃PO₄, DMSO

N

Cy

N

Cy

C

N

Cy

O

+

100 °C, 24 h, MS 4A

Br

up to 80% yield

14 examples

OH

R¹

1

ACCEPTED MANUSCRIPT

Tetrahedron

journal homepage: www.elsevier.com

Formation of substituted 2-iminooxazolidines via intermolecular 1,2-addition /

intramolecular N-vinylation using 3-substituted-2-bromo-2-propen-1-ols as substrates

Heike Weischedel, Dietmar Schmidt, Jürgen Conrad, Uwe Beifuss

ARTICLE INFO

ABSTRACT

Article history:

Received

Received in revised form

Accepted

The Cu₂O-catalyzed reaction between equimolar amounts of easily available 3-substituted-2-

bromo-2-propen-1-ols and dicyclohexyl carbodiimide in DMSO at 100 °C using K₃PO₄as the

base and in the absence of any additive exclusively delivers substituted 2-iminooxazolidines

with yields up to 80%. The highly selective transformation is assumed to start with an

intermolecular 1,2-addition, which is followed by an intramolecular N-vinylation. The products

can also be obtained in the absence of Cu₂O, albeit in lower yields.

Available online

Dedicated to Professor Dietmar Stalke on the

occasion of his 60^thbirthday

.

Keywords:

1,2-Addition

N-Vinylation

Copper

Cross-coupling

Domino reaction

1. Introduction

domino intermolecular C-allylation

/

intramolecular O-

vinylation.^9b

In synthetic organic chemistry, oxazolidine-based compounds

are well known as chiral auxiliaries¹and protecting groups.²In

recent years, oxazolidines have gained increasing interest in

leather and polymer chemistry. In the leather industry, it has been

demonstrated that oxazolidines, which have been identified as a

new class of tanning substances, can help to reduce the use of

toxic, chromium-based tanning agents.³Another important

industrial application of easily hydrolysable oxazolidines comes

from the field of polymer industry. Here, oxazolidines are used as

moisture scavangers for the production of polyurethane adhesives

and coatings.⁴

Fig. 1. Biselectrophilic substrates for copper-catalyzed cross-coupling

reactions (X = Hal)

Cu(I)-catalyzed cross-couplings play a decisive role for the

efficient and selective construction of C-C and C-heteroatom

bonds.⁵For the Cu(I)-catalyzed formation of carbo- and

Apart from biselectrophiles, starting materials featuring both

nucleophilic and electrophilic properties have been employed for

the copper-catalyzed synthesis of heterocycles. Fig. 2 displays

some typical substrates of this type. In comparision to reactions

with aromatic compounds G and H,¹⁰only a small number of

copper-catalyzed reactions with vinylic substrates of types I-L

have found application in the field of heterocycle synthesis.¹¹

heterocycles

domino

reactions

with

bisfunctionalized

substrates^5g,6have proven particularly attractive and successful.

1,2- and 1,3-Aromatic biselectrophiles are among the most

frequently employed substrates (Fig. 1, A and B).^7,8In contrast,

much less is known about the use of vinylic 1,1-, 1,2- and 1,3-

biselectrophiles of types C-F in Cu(I)-catalyzed cross-couplings

(Fig. 1).⁹One recent example from our lab is the reaction

between 2,3-dihalo-1-propenes of type D and 1,3-dicarbonyls for

the synthesis of multisubstituted furan-derivatives by means of a

———

Corresponding author. Tel.: +49-711-459-22171; fax: +49-711-459-22951; e-mail: ubeifuss@uni-hohenheim.de

2

Tetrahedron

To further optimize the model reaction, the effects of different

ACCEPTED MANUSCRIPT

Y

bases, additives, catalysts and solvents, as well as the molar ratio

on the outcome of the transformation were studied in greater

detail. First, equimolar amounts of 1a and 2 were reacted with 10

mol% CuI in the presence of different bases under additive-free

conditions (Table 2, entries 1-9). The evaluation of several bases

revealed that Cs₂CO₃can be replaced with K₃PO₄(Table 2,

entries 1-4). With 2 equiv of K₃PO₄the yield of 3a amounted to

38% (Table 2, entry 1), with 4 equiv of K₃PO₄a slight increase to

43% was observed (Table 2, entry 2). A decrease of the amount

of K₃PO₄to 1.5 equiv and 1 equiv, respectively, resulted in lower

yields of 3a (Table 2, entries 3 and 4). It was found that K₂CO₃,

NaHCO₃and DABCO were unsuitable bases for this purpose

(Table 2, entries 5–9). Next, the effect of different additives on

the yield of the model reaction was addressed. For this purpose,

the reaction was run under the conditions of Table 2, entry 1 in

the presence of 30 mol% of different additives. It was established

that the reaction can be performed in the presence of acidic

additives, such as acetic acid, isovaleric acid, pivalic acid, and

picolinic acid (Table 2, entries 10-13), as well as in the presence

of bidentate chelators, such as 1,10-phenanthroline (Table 2,

entry 14) and N,N-DMEDA (Table 2, entry 15). Unexpectedly,

with L-proline as the additive, only traces of 3a could be detected

(Table 2, entry 16). In summary, with none of the additives

screened a substantial improvement of the yield of 3a could be

achieved. This is why the influence of different copper sources

and solvents on the outcome of the domino reaction was studied

under the conditions of Table 2, entry 1.

X

G

H

Y

X

K

I

L

J

Fig. 2. Substrates with both electrophilic and nucleophilic sites for copper-

catalyzed cross-coupling reactions (X = Hal, Y = NH, OH, SH)

The Cu(I)-¹²and Cu(II)¹³-catalyzed synthesis of heterocycles

using carbodiimides as starting materials is known. Typical

transformations between bisfunctionalized substrates and

carbodiimides include the reactions with o-halophenols, o-

haloanilines

and

o-halobenzylic

alcohols

to

form

benzoxazoles,^12b2-aminobenzimidazoles^12b,12cand benzoxazines,

respectively.^12fCu(I)- and Cu(II)-catalyzed reactions between

vinylic compounds I-L and carbodiimides have not been studied

so far. As an extension of earlier work from our lab^9bwe decided

to study the transformations of typical J-type starting materials,

namely 3-substituted-2-halo-2-propen-1-ols with suitable

substrates. Herein, we present our results on Cu(I)-catalyzed

reactions between 3-substituted-2-halo-2-propen-1-ols and

carbodiimides.

2. Results and discussion

It was envisaged that the copper-catalyzed reaction between a

3-substituted-2-halo-2-propen-1-ol 1 and a carbodiimide 2 results

in the formation of a 2-iminooxazolidine 3 as result of an

intermolecular 1,2-addition followed by an intramolecular N-

vinylation. To prove the feasibility of this approach, 1 equiv of 2-

bromo-3-phenyl-2-propen-1-ol (1a) was reacted with 6 equiv

dicyclohexyl carbodiimide (2) under conditions that have proven

successful in copper-catalyzed intermolecular C-allylation /

intramolecular O-vinylation processes.^9bUnder these conditions,

(4E)-3-cyclohexyl-2-cyclohexylimino-4-[phenyl-

methylidene]oxazolidine (3a) was isolated in 23% yield (Table 1,

entry 1). Encouraged by this result, we embarked on the

optimization of the model reaction. In a first set of experiments it

was demonstrated that the yield of 3a can be increased to 31%

when equimolar amounts of 1a and 2 are reacted (Table 1, entry

2). The yield could also be increased when the transformation

was run in the absence of hydroquinone (Table 1, entry 3).

Furthermore, the amount of CuI could be reduced to 10 mol%

without impairing the yield of 3a (Table 1, entry 4).

Table 2

Impact of different bases and additives on the Cu(I)-catalyzed domino

reaction^a

Entry

1

Base (equiv)

K₃PO₄(2)

K₃PO₄(4)

K₃PO₄(1.5)

K₃PO₄(1)

K₂CO₃(2)

K₂CO₃(4)

NaHCO₃(2)

NaHCO₃(4)

DABCO (2)

K₃PO₄(2)

Additive (mol %)

Yield 3a (%)

--

38

43

36

19

18

28

traces

5

2

--

3

--

4

--

5

--

6

--

7

--

8

--

Table 1

Initial experiments of the Cu(I)-catalyzed formation of 2-iminooxazolidine

9

--

3a^a

10

11

12

13

acetic acid (30)

isovaleric acid (30)

pivalic acid (30)

picolinic acid (30)

35

30

35

30

1,10-phenanthroline

(30)

14

K₃PO₄(2)

30

Cs₂CO₃

(equiv)

CuI

(mol%)

Hydroquinone

(equiv)

Yield 3a

(%)

Entry

2 (equiv)

15

16

K₃PO₄(2)

N,N-DMEDA (30)

39

--

1

2

3

4

6

1

4

2

20

10

1

23

31

37

36

L-proline (30)

^aAll reactions were performed with 0.5 mmol 1a, 0.5 mmol 2 and 10 mol%

CuI in 2 mL DMF in a 10 mL pressure glass vial.

--

^aAll reactions were performed with 0.5 mmol 1a and 0.5 mmol 2 in 2 mL

DMF in a 10 mL pressure glass vial.

The experiments to optimize the copper source clearly

demonstrated that the formation of 3a can not only be catalyzed

3

by CuI (Table 2, entry 1), but also by a range of other Cu(I)

compounds, such as CuBr, CuCl, Cu₂O and Cu(I)acetate (Table

3, entries 1-4). The best yield (42%) was achieved with 10 mol%

Cu₂O as catalyst (Table 3, entry 3). When Cu(II) salts like

Cu(II)acetate and Cu(OTf)₂or elemental copper were used the

yield of 3a did not exceed 34% (Table 3, entries 5-7). It came as

a big surprise that the yield of 3a under copper-free conditions

was almost as high as in the presence of a copper source (Table

3, entry 8). Regardless of this result, the optimization of the

solvents was performed with 10 mol% Cu₂O as catalyst (Table 3,

entry 3). For the optimization of the solvent, the model reaction

was run in a number of polar protic (water and isopropanol),

nonpolar (THF, 1,2-dichlorbenzene and toluene), and polar

aprotic solvents (DMA, acetonitrile and DMSO). Neither with

polar solvents (Table 3, entries 9 and 10) nor with nonpolar

solvents (Table 3, entries 11-13) any improvement could be

noticed. In acetonitrile, the yield of 3a amounted to 40% (Table

3, entry 15). The yield of 3a could only be improved with DMSO

as the solvent. Using this solvent, 3a was formed in 54% (Table

3, entry 16). Further experiments in DMSO at different

temperatures revealed that neither an increase (Table 3, entries 17

and 18) nor a decrease of the reaction temperature (Table 3,

entries 19 and 20) had a positive effect on the outcome of the

model reaction.

Starting from the conditions outlined in Table 3, entry 16 the

ACCEPTED MANUSCRIPT

last stage of the optimization focussed on the molar ratio between

the two substrates and the excess of K₃PO₄on the course of the

model reaction (Table 4). When the molar ratio between 1a and 2

was changed from 1/1 to 1/1.5 and 1/2, respectively, the yield of

3a dropped to 42 and 40%, respectively (Table 4, entries 1 and

2). When the excess of 2-bromoprop-2-en-1-ol 1a was increased,

also a decrease of the yield of 3a was recorded (Table 4, entries 3

and 4). It had been established earlier, that the excess of the bases

had an effect on the course of the reaction (Table 2, entries 2, 6

and 8). This is why the influence of increasing amounts of K₃PO₄

was studied in some detail. To our delight, we discovered that an

increase of the amount of K₃PO₄resulted in a substantial

improvement of the yield (Table 4, entries 5 and 6). With 3 equiv

K₃PO₄, the yield could be raised to 64%, and with 4 equiv 72%

of 3a were formed. The yield could be further increased to 80%

when the reaction was run in the presence of molecular sieves 4Å

(Table 4, entry 7). Taking into account the result presented in

Table 3, entry 8, it was decided to study the last experiment also

in the absence of any copper source. Remarkably, the yield

obtained under copper-free conditions was almost as high as in

the presence of 10 mol % Cu₂O (Table 4, entry 8).

Table 4

Influence of the molar ratio between 1a and 2 and the amount of K₃PO₄on

the model reaction^a

Table 3

Impact of different bases and additives on the Cu(I)-catalyzed domino

reaction^a

Catalyst

(mol%)

Yield

3a (%)

Entry

Molar ratio 1a/2

K₃PO₄

1

2

3

4

5

6

7

8

1 / 1.5

1 / 2

2

3

4

Cu₂O (10)

--

40

42

Catalyst

(mol %)

Yield 3a

(%)

Entry

Solvent

T (°C)

1

2

3

CuBr (10)

CuCl (10)

Cu₂O (10)

DMF

100

38

36

42

1.5 / 1

39

2 / 1

13

equimolar

64

Cu(I)acetate

(10)

Cu(II)acetate

(10)

72

4

DMF

100

41

80^b

75^b

5

6

7

DMF

100

34

31

34

Cu(OTf)₂(10)

^aThe reactions were performed in a 10 mL pressure glass vial in 2 mL DMSO

under argon.

The reactions were performed in the presence of molecular sieve 4 Å (5

Cu-powder

(10)

b

beads).

8

9

--

DMF

water

100

37

25

21

13

Cu₂O (10)

With optimized reaction conditions in hand, it was decided to

study the substrate scope under copper catalysis as well as under

copper-free conditions. The required 3-substituted-2-bromo-2-

propen-1-ols 1a-n were easily accessible from readily available

α,β-unsaturated aldehydes.¹⁴In the first step, the α,β-unsaturated

10

11

isopropanol

THF

1,2-

12

Cu₂O (10)

100

28

dichlorobenzene

carbonyls

were

converted

into

the

corresponding

13

14

15

16

17

18

19

20

Cu₂O (10)

toluene

DMA

100

130

150

80

35

30

40

54

45

43

51

7

diastereomerically pure (Z)-α-bromo-α,β-unsaturated carbonyls

by a bromination / dehydrobromination sequence (1.2 equiv Br₂,

NEt₃, 0 °C ꢀ rt, 1.5 h) with yields up to 86%.¹⁵In the second

step, the α-bromo-α,β-unsaturated carbonyls were treated with

acetonitrile

DMSO

16

NaBH₄(1.1 equiv NaBH₄, MeOH / CH₂Cl₂, rt, 45 min) to

deliver the 3-substituted-2-bromo-2-propen-1-ols 1 with yields

up to 98% (for details, see Experimental Section). All 3-

substituted-2-bromo-2-propen-1-ols

diasteremerically pure (Z)-isomers in the subsequent 2-

1

were

used

as

60

iminooxazolidine formation.

^aThe reactions were performed in a 10 mL pressure glass vial with 0.5mmol

1a and 0.5 mmol 2 in 2 mL solvent under argon.

4

Tetrahedron

ACCEPTED MANUSCRIPT

In summary, it has been demonstrated that the reactions of

several 3-substituted and 1-substituted-2-bromo-2-propen-1-ols

1a-n deliver the corresponding substituted 2-iminooxazolidines

3a-n exclusively under copper-catalyzed conditions with yields

up to 80%. It was found that the transformations can also be run

under copper-free conditions, however with lower yields.

Table 5

Domino reaction of 1a-n with 2 to the corresponding 2-iminooxazolidines 3a-

n^aunder copper catalysis (10 mol% Cu₂O) as well as under copper-free

conditions

Fig. 3. 1D-NOESY spectrum obtained by selective excitation of the signal at

δ = 4.46 ppm of 1c.

The (Z)-configuration of the 3-substituted-2-bromo-2-propen-

1-ols 1 was assigned using a 1D-NOESY experiment (see Fig. 3).

Selective excitation of the two protons attached to C-1 at δ = 4.46

ppm results in a high-intensity signal at δ = 7.21 ppm in the

vinylic region which can be assigned to 3-H. This result

unambigiously proves the Z-configuration of the 3-substituted-2-

bromo-2-propen-1-ols 1.

Yield

3a

(Cu(I)-

free)

Yield 3a

(10 mol%

Cu2O)

Entry

R¹

R²

First, a set of different 3-substituted-2-bromo-2-propen-1-ols 1a-

n was reacted with 2 in the presence of 10 mol% Cu₂O under the

conditions of Table 4, entry 7 (Table 5). It was found, that o-

bromo-, o-chloro- as well as p-chloro- and o-fluoroaryl-

substituted substrates 1b-e can easily be transformed into the

corresponding 2-iminooxazolidines 3b-e (Table 5, entries 2-5).

Also, a substrate with an aryl group carrying two halogen atoms,

1

H

80

57

61

60

51

64

35

72

75

48

46

43

42

51

29

54

Br

Cl

i.e.,

2-bromo-3-(2’,3’-dichlorophenyl)-2-propen-1-ol

(1f),

2

3

4

5

6

7

8

H

delivered the expected heterocyclic product 3f (Table 5, entry 6)

in good yield. Considering the reactions with methoxyaryl-

substituted-2-bromo-2-propen-1-ols, it was observed that

substrates with two methoxy groups, such as 1h delivered the

corresponding 2-iminooxazolidine 3h (Table 5, entry 8) with

significantly greater yields than the monomethoxy derivative 1g

(Table 5, entry 7). Further studies with substrates containing

disubstituted aryl substituents at C-3 demonstrated that

compounds with a phenolic hydroxyl group, such as 1j (Table 5,

entry 10), or a dimethylamino group, like 1k (Table 5, entry 11),

can also serve as starting materials. The experiment with 1l

proved that the method also tolerates 3-hetaryl-substituted-2-

bromo-2-propen-1-ols (Table 5, entry 12); the modest yield,

however, led us to refrain from further experiments. In contrast,

the n-alkyl-substituted substrate 1m delivered the n-

butylmethylidene-2-iminooxazolidine 3m with remarkably high

yield (75%) (Table 5, entry 13). Using the reaction with 3-

bromo-4-phenyl-3-buten-2-ol (1n) as substrate, it was

demonstrated that the method allows not only the preparation of

4-substituted- but also 4,5-disubstituted 2-iminooxazolidines.

Under standard conditions, 3n was formed exclusively in 58%

yield (Table 5, entry 14).

b

c

Cl

Preliminary experiments between 1a and diisopropyl

carbodiimide revealed that the reaction delivers the expected

product. Since the yield of the corresponding 2-

iminooxazolidine, however, was much lower than expected,

further optimization was abonded. Reactions between 1a and

phenyl isocyanate and phenyl isothiocyanate, respectively, were

not met with success. In no case the expected heterocycles could

be isolated.

f

Based on the results of the optimization (Table 4, entries 7 and 8)

all transformations were not only performed under copper

catalysis, but also under copper-free conditions (Table 5). It

could be established that all 2-iminooxazolidines 3a-n were also

formed in the absence of any copper source. Under these

conditions, however, the yields are up to 27% lower than with 10

mol% Cu₂O (Table 5, entry 9).

5

correlations between proton 1’’’’-H_axand carbon atoms C-2 and

ACCEPTED MANUSCRIPT

3

C-4 as well as the J_CHcorrelation between 1’’’-H_axand C-2 in

the gHMBC spectrum (optimized for J_CH= 8 Hz). The J_CH

3

9

H

56

29

correlation between the two protons at C-5 and C-2 is a direct

proof of the intermolecular nucleophilic 1,2-addition of the OH-

group of 1a to the central carbon atom C-2 of the carbodiimide 2.

To verify the ring closure, i.e. the intramolecular N-vinylation,

the position of the quarternary carbon atom C-4 was assigned by

³J_CHcorrelation between 1’’’’-H_axand C-4 in the gHMBC

spectrum.

10

70

45

11

12

13

14

H

49

24

75

58

37

14

50

38

H

Fig. 5. a) ¹H NMR spectrum (500 MHz) and b) 1D-TOCSY subspectrum

obtained by selective excitation of the signal at δ = 3.91 ppm of 3a.

Me

n

For the assignment of all protons of the two cyclohexyl rings,

which was hampered by overlapping signals between δ = 1.0

ppm and δ = 2.5 ppm, selective 1D-TOCSY was employed

successfully (Fig. 5). Excitation of 1’’’-H and 1’’’’-H,

respectively, displays intense signals belonging to the

corresponding protons of the spin systems C and D. Excitation of

the axial proton 1’’’’-H_ax(δ = 3.91 ppm), for example, results in

six corresponding signals at δ = 2.35 ppm, δ = 1.86 ppm, δ = 1.70

ppm, δ = 1.69 ppm, δ = 1.39 ppm and δ = 1.21 ppm. These

signals can be assigned to 2’’’’-H_axand 6’’’’-H_ax(δ = 2.35 ppm),

3’’’’-H_eqand 5’’’’-H_eq(δ = 1.86 ppm), 2’’’’-H_eqand 6’’’’-H_eq(δ =

1.70 ppm), 4’’’’-H_eq(δ = 1.69 ppm), 3’’’’-H_axand 5’’’’-H_ax(δ =

1.39 ppm) and 4’’’’-H_ax(δ = 1.21 ppm). Finally, the gHSQC

experiment allowed the identification of the corresponding

carbon atoms at δ = 27.60 ppm (C-2’’’’ and C-6’’’’), δ = 26.19

ppm (C-3’’’’ and C-5’’’’) and δ = 25.54 ppm (C-4’’’’). In

summary, the assignment of all protons and carbons of spin

system D could be achieved.

^aAll reactions were performed in a 10 mL pressure glass vial with 0.5mmol

1a-n and 0.5 mmol 2 in 2 mL DMSO.

All products presented were characterized by UV, IR and

NMR spectroscopy as well as by mass spectrometry. The full

assignment of the ¹H and ¹³C chemical shifts and the

unambiguous structure elucidation are demonstrated for

compound 3a.

Fig. 4. ¹H spin systems and important gHMBC correlations (dark grey

arrows) and 1D-NOESY correlation (light gray arrow) for compound 3a.

Fig. 6. 1D-NOESY spectrum obtained by selective excitation of the signal at

δ = 5.02 ppm of 3a.

For the assignment of the configuration of the C-1’, C-4 double

bond a 1D-NOESY experiment was used (see Fig. 6). Selective

excitation of the two protons attached to C-5 at δ = 5.02 ppm

displays a high-intensity signal at δ = 7.00 ppm in the aromatic

region (see Fig. 4, grey arrow) which can be assigned to 2’’-H

The proton assignments of the individual spin systems and their

linkage were determined by analysis of the DQFCOSY and

gHSQC spectra. The assignment of the quaternary carbons C-2

3

and C-4 (black arrows) was achieved by means of the J_CH

6

Tetrahedron

ACCEPTED MANUSCRIPT

and 6’’-H of spin system B. This result unambigiously proves

Alternatively, it can be assumed that under the basic reaction

the E-configuration of the C-1’, C-4 double bond. In case of a Z-

configuration one would have expected an interaction between

the two protons attached to C-5 and the 1’-H proton resonating at

δ = 5.64 ppm.

conditions the transformation starts with HBr elimination from

vinyl bromide 1a to produce the propargylic alcohol and its anion

V, respectively (Scheme 1b). This is followed by intermolecular

nucleophilic attack of the propargylic anion V onto the central

carbon atom of the carbodiimide 2 to give the 1,2-adduct VI. The

coordination of the C,C-triple bond to copper facilitates the last

step of the transformation, namely the intramolecular

nucleophilic ring closure to the corresponding 2-

iminooxazolidine. Since 5-exo-dig cyclizations of this type are

known to proceed in a trans-fashion across the triple bond,¹⁷the

diastereoselective formation of the 2-iminooxazolidine with Z-

configuration across the exocyclic double bond was expected.

Again, the exclusive formation of (E)-3a can be understand by

means of a base-catalyzed isomerization of (Z)-3a.

The high degree of diastereoselectivity of the reaction is

noteworthy. Starting with diastereomerically pure (Z)-3-

substituted-2-bromo-2-propen-1-ols 1, in all cases the 2-

iminooxazolidines with an (E)-configured exocyclic C-4, C-1’

double bond were obtained exclusively. With regard to the

reaction mechanism it is plausible to assume that the reaction

between 1a and 2 starts with an intermolecular nucleophilic 1,2-

attack of the deprotonated 2-bromo-3-phenyl-2-propen-1-ol I

onto the central carbon atom of the carbodiimide 2 to deliver the

1,2-adduct II (Scheme 1a). Chelation of II with Cu(I) (II→III) is

followed by Cu-catalyzed oxidative addition of the vinyl bromide

to produce Cu-complex IV. Reductive elimination is expected to

N

Cy

C

N

Cy

Br

C

N

Cy

deliver

the

(4Z)-3-cyclohexyl-2-cyclohexylimino-4-

(Z)-3a. The exclusive

K₃PO₄

[phenylmethylidene]-oxazolidine

formation of products 3a-n with (E)-configured exocyclic C-4,

C-1’ double bond can be rationalized if one assumes a base-

catalyzed isomerization of the arylmethylene double bond

between C-4 and C-1’ of the initially formed compound with (Z)-

configuration. It is assumed that this (Z)→(E) isomerization

starts with a K₃PO₄-initiated abstraction of an allylic proton to

generate the corresponding allylic anion. Final protonation is

expected to provide a mixture of the (Z)- and (E)-diastereomers

OH

O

Cu(I)

N

Cy

N

Cy

C

O

Cy

N

O

according to their thermodynamic stabilities. However,

a

Cu(I)

temperature-initiated double bond isomerization cannot be

excluded. It must be mentioned that neither the base-initiated nor

the temperature-initiated mechanism can account for the

diastereoselective formation of the (E)-configured product. This

is why we assume that the diastereoselective transformation of

the (Z)-configured substrates 1 into the products 3 with (E)-

configuration of the double bond proceeds via a – so far –

unknown cyclization mechanism.

N

O

Cy

N

K₃PO₄, T

Scheme 1b. Possible reaction mechanism for the formation of the 2-

iminooxazolidine 3a assuming acetylenic intermediates.

The mechanism presented in Scheme 1b that implicates

acetylenic intermediates was supported by a control reaction

under DCC free conditions. When 2-bromo-3-phenyl-2-propen-

1-ol (1a) was reacted in the absence of DCC under the optimized

conditions of Table 4, entry 7 (1 equiv 1a, 4 equiv K₃PO₄and

molecular sieve in DMSO at 100°C for 24h under argon) we

found that the corresponding propargylic alcohol was formed.

The ¹³C NMR spectrum clearly displays two characteristic

signals of alkyne carbons at δ = 87 and 85 ppm. Further support

comes from the outcome of the reaction between 3-phenyl-2-

propyn-1-ol (4) and DCC. When 1 equiv 4 and 1 equiv DCC

were reacted under the optimized conditions of Table 4, entry 7,

the 2-iminooxazolidine (4E)-3a was formed, albeit in lower yield

(Scheme 2). The modest yield led us to refrain from studying the

reactions with propargylic alcohols as substrates in greater detail.

Scheme 1a. Possible reaction mechanism for the formation of the 2-

iminooxazolidine 3a assuming vinyl bromide I as intermediate.

Scheme 2. Synthesis of 2-iminooxazolidine 3a by reaction of 3-phenyl-2-

propyn-1-ol (4) and DCC (2).

7

Within this context, it should be mentioned that Pawsen et. al.

measurement of electrospray ionization mass spectra [ESI

(MS)] a Bruker Daltonik spectrometer micrOTOF-Q was used.

ACCEPTED MANUSCRIPT

have isolated diastereomerically pure (Z)-2-iminooxazolidines

upon reaction of propargylic alcohols with carbodiimides in the

presence of 10 mol% CuCl. They have also demonstrated that the

(Z)-2-iminooxazolidines undergo isomerization to the

4.2 Synthesis and characterization of starting materials 1a-

1o

correseponding (E)-2-iminooxazolidines

3

upon heating.¹⁸

General procedure I for the synthesis of starting materials

1a-n^{14, 15, 16}

Golding et al. have found that O-acetylenic isoureas which can

be obtained by Cu(I)-catalyzed addition of propargylic alcohols

to carbodiimides can be cyclized to diastereomerically pure (Z)-

2-iminooxazolidines in the presence of catalytic amounts of

transition metal catalysts, such as AgOTf. ¹⁹

To a cooled (0°C) stirring solution of an unsaturated aldehyde¹⁴

(22 mmol) in CH₂Cl₂(10 mL) a solution of bromine (26 mmol,

1.2 equiv) in CH₂Cl₂(15 mL) was added slowly. After stirring at

0 °C for 45 min, NEt₃(7 mL) was slowly added.¹⁵The solution

was allowed to warm to room temperature and stirred for 1.5 h.

The reaction mixture was washed with 2 N HCl (50 mL), H₂O

(50 mL) and brine (50 mL), dried over anhydrous MgSO₄and

concentrated in vacuo. The crude product was purified by flash

column chromatography on silica gel to afford the corresponding

2-bromo-2-propen-1-al.

Sodium borohydride (18 mmol, 1.1 equiv) was added to a

solution of methanol (20 mL) and CH₂Cl₂(20 mL) at room

temperature. After stirring for 5 min., a solution of the 2-bromo-

2-propen-1-al (16 mmol) in methanol (10 mL) and CH₂Cl₂(10

mL) was added slowly and the resulting mixture was stirred for

45 min.¹⁶The reaction mixture was poured into saturated NH₄Cl

(50 mL) and extracted with CH₂Cl₂(3 × 30 mL). The combined

organic layers were washed with brine (50 mL), dried over

anhydrous MgSO₄and concentrated in vacuo. The crude product

was purified by flash column chromatography on silica gel to

afford the corresponding 3-substituted-2-bromo-2-propen-1-ol 1.

3. Conclusions

In summary, it has been established that substituted 2-

iminooxazolidines can be obtained with yields up to 80% by

Cu₂O-catalyzed reaction between equimolar amounts of easily

available 3-substituted-2-bromo-2-propen-1-ols and dicyclohexyl

carbodiimide using K₃PO₄as

a base under additive-free

conditions in DMSO at 100 °C. Interestingly, it has been

demonstrated that the products can also be obtained in the

absence of Cu₂O, albeit in lower yields. The domino process

provides an efficient and selective access to an interesting

heterocyclic system in a one-pot reaction.

4. Experimental section

4.1 General

4.2.1 2-Bromo-3-phenyl-2-propen-1-ol (1a)

All commercially available reagents were used without further

purification. Glassware was dried for 24 h at 120 °C in an oven.

For the preparation of the 2-iminooxazolidines we used 10 mL

pressure glass vials from CEM. Solvents used in reactions were

distilled over appropriate drying agents prior to use. Solvents

used for extraction and purification were distilled prior to use.

Reaction temperatures are reported as bath temperatures. Thin-

layer chromatography (TLC) was performed on precoated

aluminium plates (silica gel Merck 60 F₂₅₄) and visualized by UV

light (254 nm) and/or by immersion in an ethanolic vanillin

solution or by immersion in a KMnO₄solution followed by

heating. Products were purified by flash chromatography on

silica gel (MN 60, 0.04–0.063 mm; Marcherey & Nagel).

According to general procedure I, commercially available 2-

bromocinnamaldehyde (3.4 g, 16 mmol) and sodium borohydride

(0.7 g, 18 mmol) were reacted. Column chromatography on silica

gel (petroleum ether:EtOAc=9:1) gave 2-bromo-3-phenyl-2-

propen-1-ol (1a) as a yellow oil in 98% yield (3.34 g, 15.68

mmol); R_f0.23 (petroleum ether:EtOAc=9:1); IR (ATR) ν 3333,

3024, 2915, 1638, 1490, 1445, 1408, 1332, 1284, 1069, 996, 858,

749, 691 cm^-1; UV (MeCN) λ_max(log ε) 202 (4.41), 249 (4.23)

nm; ¹H NMR (300 MHz, CDCl₃) δ 2.23 (s, 1H, OH), 4.42 (s, 2H,

1-H₂), 7.09 (s, 1H, 3-H), 7.33 (ov, 1H, 4’-H), 7.38 (ov, 2H, 3’-H

and 5’-H), 7.62 (d-like, ³J(3’-H, 2’-H)=7.2 Hz, ³J(5’-H, 6’-

H)=7.2 Hz, 2H, 2’-H and 6’-H); ¹³C NMR (75 MHz, CDCl₃) δ

69.40 (C-1), 125.30 (C-2), 127.82 (C-3), 128.20 (C-3’ and C-5’),

128.97 (C-2’ and C-6’), 134.94 (C-1’); MS (EI, 70 eV) m/z (%)

215 (5) [M+2]⁺≙ [C₉H₉⁸¹BrO]⁺, 213 (6) [M]⁺≙ [C₉H₉⁷⁹BrO]⁺,

212 (60) [M-1]⁺≙ [C₉H₈BrO]⁺, 211 (4) [M-H₂O]⁺≙ [C₉H₈Br]⁺,

133 (100) [M-Br]⁺≙ [C₉H₉O]⁺, 103 (35) [C₈H₇]⁺, 91 (13)

[C₇H₇]⁺, 77 (29)[C₆H₅]⁺, 55 (53) [C₄H₇]⁺.

Melting points were determined on a Büchi melting point

apparatus B-545 and are uncorrected. IR spectra were measured

on a Bruker Alpha FT-IR spectrometer. UV/Vis spectra were

recorded on a Cary 4E spectrophotometer. ¹H and ¹³C NMR

spectra were recorded at 300 MHz and 500 MHz on Varian Unity

Inova spectrometers and at 600 MHz on a Bruker Avance III HD

1

4.2.2 2-Bromo-3-(2’-bromophenyl)-2-propen-1-ol (1b)

spectrometer using CDCl₃or DMSO-d6 as the solvent. The H

and ¹³C chemical shifts were referenced to residual solvent

signals at δ H/C 7.26/77.02 (CDCl₃) or δ H/C 2.50/39.51

(DMSO-d6) relative to TMS as internal standard. COSY, HSQC-

, gHMBC-, gCOSY-, 1D-TOCSY-, 1D-NOESY- and bsgHSQC-

spectra were recorded on an NMR spectrometer at 300 MHz, 500

MHz or 600 MHz. Coupling constants J [Hz] were directly taken

from the spectra and are not averaged. Splitting patterns are

designated as s (singlet), bs (broad singlet), d (doublet), t (triplet),

q (quartet), quin (quintet), m (multiplet), and ov (overlapped).

Low-resolution electron impact mass spectra [MS (EI)] and high

resolution mass electron impact mass spectra [HRMS (EI)] were

obtained at 70 eV using a double focusing sector field mass

spectrometer Finnigan MAT 95. Intensities are reported as

percentages relative to the base peak (I = 100%). For the

According to general procedure I, commercially available 2’-

bromocinnamaldehyde (4.2 g, 20 mmol) was reacted with

bromine (3.8 g, 24 mmol) and NEt₃(7 mL). Column

chromatography on silica gel (petroleum ether:EtOAc=9:1) gave

2-bromo-3-(2’-bromophenyl)-2-propen-1-al as a yellow oil in

65% yield (3.8 g, 13 mmol).

2-Bromo-3-(2’-bromophenyl)-2-propen-1-al (2.1 g, 7.3 mmol)

was reduced with sodium borohydride (0.3 g, 8 mmol) according

to general procedure I. Column chromatography on silica gel

(petroleum

ether:EtOAc=9:1)

delivered

2-bromo-3-(2’-

bromophenyl)-2-propen-1-ol (1b) as a yellow solid in 93% yield

(1.9 g, 6.8 mmol): mp 44–45 °C; R_f0.37 (petroleum

ether:EtOAc=9:1); IR (ATR) ν 3288, 2899, 2852, 1645, 1463,

1425, 1295, 1046, 1003, 972, 842, 744 cm^-1; UV (MeCN) λ_max

8

Tetrahedron

ACCEPTED MANUSCRIPT

1

(log ε) 209 (4.30) nm, 246 (3.96); H NMR (300 MHz, CDCl₃)

(s, 2H, 1-H₂), 7.09 (bs, 1H, 3-H), 7.18 (d-like, ³J(2’-H, 3’-H) and

³J(6’-H, 5’-H)=8.0 Hz, 2H, 3’-H and 5’-H), 7.33 (d-like, ³J(3’-H,

δ 2.22 (s, 1H, OH), 4.46 (s, 2H, 1-H₂), 7.16 (s, 1H, 3-H), 7.19

3

4

3

(dd, J(5’-H, 6’-H)=7.9 Hz, J(4’-H, 6’-H)=1.4 Hz, 1H, 6’-H),

2’-H) and J(5’-H, 6’-H)=8.4 Hz, 2H, 2’-H and 6’-H); ¹³C NMR

7.33 (ddd, ³J(4’-H, 3’-H)=7.7 Hz, ⁴J(5’-H, 3’-H)=1.1 Hz, 1H, 3’-

(75 MHz, CDCl₃) δ 63.86 (C-1), 128.29 (C-2), 128.86 (C-2’ and

C-6’), 129.67 (C-3’ and C-5’), 133.82 (C-4’), 133.87 (C-3),

134.08 (C-1’); MS (EI, 70 eV) m/z (%) 250 (15) [M+4]⁺≙

[C₉H₈⁸¹Br³⁷ClO]⁺, 248 (63) [M+2]⁺≙ [C₉H₈⁷⁹Br³⁷ClO]⁺, 246 (48)

[M]⁺≙ [C₉H₈⁷⁹Br³⁵ClO]⁺, 169 (33) [M+2-Br]⁺≙ [C₉H₈³⁷ClO]⁺,

167 (100) [M-Br]⁺≙ [C₉H₈³⁵ClO]⁺, 149 (35) [C₉H₇³⁵Cl]⁺, 131

(23) [C₉H₇O]⁺, 103 (23) [C₈H₇]⁺, 77 (12) [C₆H₅]⁺, 55 (19)

[C₄H₇]⁺; HRMS (EI, M⁺) calculated for C₉H₈BrClO 245.9442

found 245.9442.

3

H), 7.59 (dd-like, J(4’-H, 5’-H) and J(6’-H, 5’-H)=7.9 Hz,

⁴J(3’-H, 5’-H)=1.2 Hz, 1H, 5’-H), 7.66 (dd-like, J(3’-H, 4’-H)

3

4

and J(5’-H, 4’-H)=7.9 Hz, 1H, 4’-H), J(6’-H, 4’-H)=1.4 Hz,

1H, 4’-H); ¹³C NMR (75 MHz, CDCl₃) δ 68.72 (C-1), 123.76 (C-

2’), 126.92 (C-3’), 127.52 (C-3), 128.27 (C-2), 129.46 (C-6’),

130.86 (C-4’), 132.46 (C-5’), 135.73 (C-1’); MS (EI, 70 eV) m/z

(%) 294 (22) [M+4]⁺≙ [C₉H₈⁸¹Br⁸¹BrO]⁺, 292 (46) [M+2]⁺≙

[C₉H₈⁷⁹Br⁸¹BrO]⁺, 290 (24) [M]⁺≙ [C₉H₈⁷⁹Br⁷⁹BrO]⁺, 213 (49)

[M+2-⁷⁹Br]⁺

≙

[C₉H₈⁸¹BrO]⁺, 211 (81) [M+2-⁸¹Br]⁺

≙

[C₉H₈⁷⁹BrO]⁺, 193 (15) [M]⁺≙ [C₉H₈⁷⁹Br⁷⁹BrO]⁺, 181 (10) [M]⁺

≙ [C₉H₈⁷⁹Br⁷⁹BrO]⁺, 132 (100) [M-2Br]⁺≙ [C₉H₈O]⁺, 103 (42)

[C₈H₇]⁺, 77 (35) [C₆H₅]⁺, 69 (35) [C₄H₅O]⁺, 57 (31) [C₃H₅O]⁺;

HRMS (EI, M⁺) calculated for C₉H₈Br₂O 289.8937 found

289.8938.

4.2.5 2-Bromo-3-(2’-fluorophenyl)-2-propen-1-ol (1e)

According to general procedure I, 2’-fluorocinnamaldehyde¹⁴

(1.4 g, 9.4 mmol) was reacted with bromine (1.8 g, 11.3 mmol)

and NEt₃(3.5 mL). Column chromatography on silica gel

(petroleum ether:EtOAc=9:1) gave 2-bromo-3-(2’-fluorphenyl)-

2-propen-1-al as a yellow oil in 70% yield (1.5 g, 6.6 mmol).

2-Bromo-3-(2’-fluorophenyl)-2-propen-1-al (1.5 g, 6.6 mmol)

was reduced with sodium borohydride (0.28 g, 7.3 mmol)

according to general procedure I. Column chromatography on

silica gel (petroleum ether:EtOAc=9:1) delivered 2-bromo-3-(2’-

fluorophenyl)-2-propen-1-ol (1e) as a yellow oil in 63% yield

(0.95 g, 4.1 mmol); R_f0.30 (petroleum ether:EtOAc=9:1); IR

(ATR) ν 3324, 2917), 1610, 1577, 1484, 1453, 1233, 1099, 1083,

1054, 1008, 853, 753 cm^-1; UV (MeCN) λ_max(log ε) 246 (4.13)

4.2.3 2-Bromo-3-(2’-chlorophenyl)-2-propen-1-ol (1c)

According to general procedure I, 2’-chlorocinnamaldehyde¹⁴

(3.7 g, 22 mmol) was reacted with bromine (4.3 g, 27 mmol) and

NEt₃(7 mL). Column chromatography on silica gel (petroleum

ether:EtOAc=9:1) gave 2-bromo-3-(2’-chlorophenyl)-2-propen-

1-al as a yellow oil in 72% yield (3.9 g, 16 mmol).

2-Bromo-3-(2’-chlorophenyl)-2-propen-1-al (3.9 g, 16 mmol)

was reduced with sodium borohydride (0.67 g, 17.7 mmol)

according to general procedure I. Column chromatography on

silica gel (petroleum ether:EtOAc=9:1) delivered 2-bromo-3-(2’-

chlorophenyl)-2-propen-1-ol (1c) as a white solid in 63% yield

(2.96 g, 10 mmol): mp 45–46 °C; R_f0.25 (petroleum

ether:EtOAc=9:1); IR (ATR) ν 3302, 2911, 1467, 1432, 1304,

1276, 1021, 972, 853, 749, 690 cm^-1; UV (MeCN) λ_max(log ε)

208 (4.04) nm, 246 (3.71); ¹H NMR (300 MHz, CDCl₃) δ 2.23 (t,

1

nm; H NMR (600 MHz, CDCl₃) δ 2.02 (bs, 1H, OH), 4.45 (d,

²J(1-H, 1-H)=1.2 Hz, 2H, 1-H₂), 7.06 (ddd, J(4’-H, 3’-H) and

3

³J(2’-F, 3’-H)=8.4 Hz, J(5’-H, 3’-H)=1.1 Hz, 1H, 3’-H), 7.16

4

(dd, J(4’-H, 5’-H) and ³J(6’-H, 5’-H)=7.8 Hz), J(3’-H, 5’-

3

4

H)=1.1 Hz, 1H, 5’-H), 7.18 (bs, 1H, 3-H), 7.33-7.28 (m, 1H, 4’-

3

4

H), 7.84 (dd, J(5’-H, 6’-H)=7.6 Hz, J(4’-H, 6’-H)=1.4 Hz, 1H,

6’-H); ¹³C NMR (125 MHz, CDCl₃) δ 69.16 (C-1), 115.32 (d,

²J(F-2’, C-3’)=21.6 Hz, C-3’), 120.77 (d, J(F-2’, C-3)=5.1 Hz,

3

1H, OH), 4.46 (dd, J(1-H^a, 1-H^b)=6.7 Hz, J(1-H_,1-H)=1.0 Hz,

2H, 1-H₂), 7.21 (bs, 1H, 3-H), 7.26 (ov, 1H, 3’-H), 7.28 (ov, 1H,

2

4

C-3), 123.10 (d, J(F-2’, C-1’)=13.4 Hz, C-1’), 123.58 (d, J(F-

2’, C-5’)=3.4 Hz, C-5’), 128.22 (d, J(F-2’, C-2)=2.1 Hz, C-2),

129.87 (d, J(F-2’, C-2)=18.5 Hz, C-2), 129.90 (d, J(F-2’, C-

6’)=13.3 Hz, C-6’), 160.12 (d, J(F-2’, C-2’)=249.0 Hz, C-2’);

4

3

5’-H), 7.39 (dd-like, J(3’-H, 4’-H) and J(5’-H, 4’-H)=6.6 Hz,

3

⁴J(6’-H, 4’-H)=2.6 Hz, 1H, 4’-H), 7.71 (dd-like, J(5’-H, 6’-

3

1

H)=6.4 Hz, 1H, 6’-H), J(4’-H, 6’-H)=2.7 Hz, 1H, 6’-H); ¹³C

4

NMR (75 MHz, CDCl₃) δ 68.85 (C-1), 125.25 (C-3), 126.30 (C-

5’), 128.38 (C-2), 129.27 (C-3’), 129.30 (C-4’), 130.65 (C-6’),

133.58 (C-1’), 133.84 (C-2’); MS (EI, 70 eV) m/z (%) 250 (13)

MS (EI, 70 eV) m/z (%) 232 (38) [M+2]⁺≙ [C₉H₈⁸¹BrFO]⁺, 230

(39) [M]⁺≙ [C₉H₈⁷⁹BrFO]⁺, 151 (100) [M-Br]⁺≙ [C₉H₈FO]⁺,

133 (43) [C₉H₆F]⁺, 120 (11) [C₈H₅F]⁺, 96 (9) [C₆H₄F]⁺, 77 (10)

[C₆H₅]⁺, 55 (21) [C₄H₇]⁺; HRMS (EI, M⁺) calculated for

C₉H₈BrFO 229.9738 found 229.9739.

[M+4]⁺

≙

[C₉H₈⁸¹Br³⁷ClO]⁺, 248 (50) [M+2]⁺

≙

[C₉H₈⁸¹Br³⁵ClO]⁺, 246 (42) [M]⁺≙ [C₉H₈⁷⁹Br³⁵ClO]⁺, 211 (11)

[M-Cl]⁺≙ [C₉H₈⁷⁹BrO]⁺, 167 (100) [M-Br]⁺≙ [C₉H₈³⁵ClO]⁺, 149

[C₉H₇³⁵Cl]⁺, (50), 131 (29) [C₉H₇O]⁺, 103 (27) [C₈H₇]⁺, 77 (16)

[C₆H₅]⁺, 55 (25) [C₄H₇]⁺; HRMS (EI, M⁺) calculated for

C₉H₈BrClO 245.9442 found 245.9437.

4.2.6 2-Bromo-3-(2’, 3’-dichlorophenyl)-2-propen-1-ol (1f)

According

to

general

procedure

I,

2’,3’-dichloro-

cinnamaldehyde¹⁴(2.7 g, 13.5 mmol) was reacted with bromine

(2.6 g, 16 mmol) and NEt₃(5 mL). Column chromatography on

silica gel (petroleum ether:EtOAc=9:1) gave 2-bromo-3-(2’,3’-

dichlorophenyl)-2-propen-1-al as a yellow oil in 67% yield (2.5

g, 9 mmol).

4.2.4 2-Bromo-3-(4’-chlorophenyl)-2-propen-1-ol (1d)

According to general procedure I, commercially available 4’-

chlorocinnamaldehyde (2.3 g, 13.8 mmol) was reacted with

bromine (2.7 g, 16.6 mmol) and NEt₃(4.5 mL). Column

chromatography on silica gel (petroleum ether:EtOAc=9:1) gave

2-bromo-3-(4’-chlorophenyl)-2-propen-1-al as a yellow oil in

71% yield (1.5 g, 6.3 mmol).

2-Bromo-3-(4’-chlorophenyl)-2-propen-1-al (0.5 g, 2 mmol) was

reduced with sodium borohydride (0.09 g, 2.4 mmol) according

to general procedure I. Column chromatography on silica gel

2-Bromo-3-(2’,3’-dichlorophenyl)-2-propen-1-al (2.5 g, 9 mmol)

was reduced with sodium borohydride (0.38 g, 9.2 mmol)

according to general procedure I. Column chromatography on

silica gel (petroleum ether:EtOAc=9:1) delivered 2-bromo-3-

(2’,3’-dichlorophenyl)-2-propen-1-ol (1f) as a white-yellow solid

in 91% yield (2.3 g, 8.2 mmol): mp 101–102 °C; R_f0.27

(petroleum ether:EtOAc=9:1); IR (ATR) ν 3250, 2914, 2861,

1653, 1556, 1449, 1370, 1301, 1183, 1083, 1046, 1021, 998, 839

(petroleum

ether:EtOAc=9:1)

delivered

2-bromo-3-(4’-

cm^-1; UV (MeCN) λ_max(log ε) 216 (4.34), 250 (3.91) nm; H

1

chlorophenyl)-2-propen-1-ol (1d) as a yellow oil in 80% yield

(0.43 g, 1.8 mmol); R_f0.28 (petroleum ether:EtOAc=9:1); IR

(ATR) ν 3218, 2890, 1619, 1488, 1439, 1363, 1306, 1092, 1058,

1026, 1011, 962, 872, 809 cm^-1; UV (MeCN) λ_max(log ε) 259

(4.25) nm; ¹H NMR (600 MHz, CDCl₃) δ 2.09 (bs, 1H, OH), 4.42

NMR (300 MHz, CDCl₃) δ 2.11 (bs, 1H, OH), 4.47 (d, ²J(1-H, 1-

4

H)=1.1 Hz, 2H, 1-H₂), 7.19 (d-like, J(1-H, 3-H)=1.0 Hz, 1H, 3-

3

H), 7.24 (d-like, J(4’-H, 5’-H) and J(6’-H, 5’-H)=8.0 Hz, 1H,

3

4

5’-H), 7.43 (dd, J(3’-H, 4’-H) and J(5’-H, 4’-H)=8.0 Hz, J(6’-

9

3

H, 4’-H)=1.5 Hz, 1H, 4’-H), 7.56 (dd, J(5’-H, 6’-H)=7.7 Hz,

H)=3.0 Hz, 1H, 6’-H); ¹³C NMR (150 MHz, CDCl₃) δ 55.83

ACCEPTED MANUSCRIPT

⁴J(4’-H, 6’-H)=1.0 Hz, 1H, 6’-H); ¹³C NMR (75 MHz, CDCl₃) δ

68.61 (C-1), 125.15 (C-3), 126.84 (C-5’), 128.96 (C-6’), 129.19

(C-2), 129.87 (C-4’), 131.78 (C-2’), 133.09 (C-1’), 136.19 (C-

(5’-OMe), 56.07 (2’-OMe), 69.52 (C-1), 111.45 (C-3’), 114.60

(C-4’), 115.29 (C-6’), 123.53 (C-3), 124.66 (C-1’), 126.39 (C-2),

151.44 (C-2’), 152.95 (C-5’); MS (EI, 70 eV) m/z (%) 274 (11)

[M+2]⁺≙ [C₁₁H₁₃⁸¹BrO₃]⁺, 272 (8) [M]⁺≙ [C₁₁H₁₃⁷⁹BrO₃]⁺, 193

(43) [M-Br]⁺≙ [C₁₁H₁₃O₃]⁺, 161 (38) [C₁₁H₁₃O]⁺, 138 (100)

[C₈H₉O₂]⁺, 118 (14) [C₉H₁₀]⁺, 91 (23) [C₇H₇]⁺, 77 (24) [C₆H₅]⁺,

3’); MS (EI, 70 eV) m/z (%) 286 (4) [M+6]⁺

≙

[C₉H₇⁸¹Br³⁷Cl³⁷ClO]⁺, 284 (28) [M+4]⁺≙ [C₉H₇⁸¹Br³⁷Cl³⁵ClO]⁺,

282 (67) [M+2]⁺≙ [C₉H₇⁸¹Br³⁵Cl³⁵ClO]⁺, 280 (41) [M]⁺

≙

55 (9) [C₄H₇]⁺; HRMS (ESI,

C₁₁H₁₃BrO₃Na 294.9940 found 294.9941.

[

M+Na]⁺) calculated for

[C₉H₇⁷⁹Br³⁵Cl³⁵ClO]⁺, 247 (8) [M+2-³⁵Cl]⁺≙ [C₉H₇⁸¹Br³⁵ClO]⁺,

245 (24) [M-³⁵Cl]⁺≙ [C₉H₇⁷⁹Br³⁵ClO]⁺, 205 (10) [M+4-⁷⁹Br]⁺≙

[C₉H₇³⁷Cl³⁷ClO]⁺, 203 (64) [M+2-⁷⁹Br]⁺≙ [C₉H₇³⁷Cl³⁵ClO]⁺, 201

(100) [M-⁷⁹Br]⁺≙ [C₉H₇³⁵Cl³⁵ClO]⁺, 165 (39) [C₈H₄³⁵Cl³⁵Cl]⁺,

149 (15) [C₉H₇³⁵Cl]⁺, 131 (32) [C₉H₇O]⁺, 101 (21) [C₈H₅]⁺, 76 (9)

[C₆H₄]⁺, 55 (18) [C₄H₇]⁺; HRMS (EI, M⁺) calculated for

C₉H₇BrCl₂O 279.9052 found 279.9042.

4.2.9 2-Bromo-3-(3’-bromo-4’-methoxyphenyl)-2-propen-1-ol

(1i)

According to general procedure I, commercially available p-

methoxycinnamaldehyde (3.5 g, 21.6 mmol) was reacted with

bromine (4.1 g, 26 mmol) and NEt₃(7 mL). Column

chromatography on silica gel (petroleum ether:EtOAc=9:1) gave

4.2.7 2-Bromo-3-(2’-methoxyphenyl)-2-propen-1-ol (1g)

2-bromo-3-(3’-bromo-4’-methoxyphenyl)-2-propen-1-al as

yellow oil in 86% yield (4.5 g, 18.5 mmol).

a

According to general procedure I, commercially available 2’-

methoxycinnamaldehyde (2 g, 12.4 mmol) was reacted with

bromine (3.9 g, 25 mmol) and NEt₃(5 mL). Column

chromatography on silica gel (petroleum ether:EtOAc=9:1) gave

2-bromo-3-(2’-methoxyphenyl)-2-propen-1-al as a yellow oil in

62% yield (1.8 g, 7.7 mmol).

2-Bromo-3-(3’-bromo-4’-methoxyphenyl)-2-propen-1-al (1.2 g,

5 mmol) was reduced with sodium borohydride (0.2 g, 5.5 mmol)

according to general procedure I. Column chromatography on

silica gel (petroleum ether:EtOAc=7:1) delivered 2-bromo-3-(3’-

bromo-4’-methoxyphenyl)-2-propen-1-ol (1i) as a white-yellow

solid in 79% yield (0.97 g, 3.97 mmol): mp 77–78 °C; R_f0.53

(petroleum ether:EtOAc=9:1); IR (ATR) ν 3229, 2909, 2834,

1596, 1494, 1396, 1368, 1281, 1269, 1252, 1078, 1059, 992, 896,

797 cm^-1; UV (MeCN) λ_max(log ε) 216 (4.32), 265 (4.21) nm; ¹H

NMR (300 MHz, CDCl₃) δ 2.08 (bs, 1H, OH), 3.91 (s, 3H, 4’-

OMe), 4.40 (d, ²J(1-H, 1-H)=0.9 Hz, 2H, 1-H₂), 6.89 (d, ³J(6’-H,

5’-H)=8.6 Hz, 1H, 5’-H), 6.96 (s, 1H, 3-H), 7.58 (dd, ³J(5’-H, 6’-

H)=8.5 Hz, ⁴J(2’-H, 6’-H)=2.0 Hz, 1H, 6’-H), 7.86 (d-like, ⁴J(6’-

H, 2’-H)=2.1 Hz, 1H, 2’-H); ¹³C NMR (75 MHz, CDCl₃) δ 56.27

(4’-OMe), 69.40 (C-1), 111.31 (C-5’), 124.77 (C-2), 126.04 (C-

3), 128.73 (C-1’), 129.40 (C-6’), 133.80 (C-2’), 155.64 (C-4’);

MS (EI, 70 eV) m/z (%) 324 (44) [M+4]⁺≙ [C₁₀H₁₀⁸¹Br⁸¹BrO₂]⁺,

2-Bromo-3-(2’-methoxyphenyl)-2-propen-1-al (1.2 g, 5 mmol)

was reduced with sodium borohydride (0.2 g, 5.5 mmol)

according to general procedure I. Column chromatography on

silica gel (petroleum ether:EtOAc=7:1) delivered 2-bromo-3-(2’-

methoxyphenyl)-2-propen-1-ol (1g) as a colourless oil in 67%

yield (0.80 g, 3.31 mmol); R_f0.33 (petroleum ether:EtOAc=9:1);

IR (ATR) ν 3376, 2935, 2836, 1710, 1597, 1486, 1460, 1435,

1243, 1110, 1046, 1022, 959, 751 cm^-1; UV (MeCN) λ_max(log ε)

212 (4.29), 251 (4.03), 292 (3.66) nm; ¹H NMR (600 MHz,

CDCl₃) δ 2.09 (bs, 1H, OH), 3.84 (s, 3H, 2’-OMe), 4.38 (s, 2H,

1-H₂), 6.89 (d, ³J(4’-H, 3’-H)=8.3 Hz, 1H, 3’-H), 6.95 (t-like, 1H,

3

4

5’-H), 7.15 (s, 1H, 3-H), 7.19 (dd, J(5’-H, 6’-H)=7.6 Hz, J(4’-

3

H, 6’-H)=1.2 Hz, 1H, 6’-H), 7.30 (dd-like, J(3’-H, 4’-H) and

322 (98) [M+2]⁺≙ [C₁₀H₁₀⁸¹Br⁷⁹BrO₂]⁺, 320 (57) [M]⁺

≙

³J(5’-H, 4’-H)=7.8 Hz, J(6’-H, 4’-H)=1.6 Hz, 1H, 4’-H); ¹³C

4

[C₁₀H₁₀⁷⁹Br⁷⁹BrO₂]⁺, 243 (24) [M+2-⁷⁹Br]⁺≙ [C₁₀H₁₀⁸¹BrO₂]⁺,

241 (49) [M-⁷⁹Br]⁺≙ [C₁₀H₁₀⁷⁹BrO₂]⁺, 212 (14) [C₉H₇BrO]⁺, 162

(100) [C₁₀H₁₀O₂]⁺, 145 (37) [C₁₀H₉O]⁺, 131 (30) [C₉H₇O]⁺, 77

(21) [C₆H₅]⁺, 55 (26) [C₄H₇]⁺; HRMS (EI, M⁺) calculated for

C₁₀H₁₀Br₂O₂319.9043 found 319.9034.

NMR (150 MHz, CDCl₃) δ 55.54 (2’-OMe), 64.24 (C-1), 110.73

(C-3’), 120.57 (C-5’), 124.41 (C-1’), 127.49 (C-2), 129.70 (C-

4’), 129.89 (C-6’), 130.83 (C-3), 156.61 (C-2’); MS (EI, 70 eV)

m/z (%) 244 (36) [M+2]⁺≙ [C₁₀H₁₁⁸¹BrO₂]⁺, 242 (39) [M]⁺≙

[C₁₀H₁₁⁷⁹BrO₂]⁺, 211 (6) [C₉H₈BrO]⁺, 163 (100) [C₁₀H₁₀O₂]⁺, 131

(45) [C₉H₇O]⁺, 108 (79) [C₇H₇O]⁺, 91 (31) [C₇H₇]⁺, 77 (21)

[C₆H₅]⁺, 55 (35) [C₄H₇]⁺; HRMS (EI, M⁺) calculated for

C₁₀H₁₁BrO₂241.9937 found 241.9927.

4.2.10 2-Bromo-3-(2’-bromo- 5’-hydroxyphenyl)-2-propen-1-ol

(1j)

According to general procedure I, 3’-hydroxycinnamaldehyde¹⁴

(0.85 g, 5.67 mmol) was reacted with bromine (1.1 g, 6.9 mmol)

and NEt₃(2 mL). Column chromatography on silica gel

(petroleum ether:EtOAc=4:1) gave 2-bromo-3-(2’-bromo-5’-

hydroxyphenyl)-2-propen-1-al as a yellow oil in 68% yield (1.18

g, 3.88 mmol).

4.2.8 2-Bromo-3-(2’, 5’-dimethoxyphenyl)-2-propen-1-ol (1h)

According

to

general

procedure

I,

2’,5’-

dimethoxycinnamaldehyde¹⁴(1.14 g, 5.9 mmol) was reacted with

bromine (1.1 g, 7.0 mmol) and NEt₃(2.5 mL). Column

chromatography on silica gel (petroleum ether:EtOAc=9:1) gave

2-bromo-3-(2’,5’-dimethoxyphenyl)-2-propen-1-al as a yellow

oil in 73% yield (1.2 g, 4.3 mmol).

2-Bromo-3-(2’-bromo-5’-hydroxyphenyl)-2-propen-1-al (0.73 g,

2.34 mmol) was reduced with sodium borohydride (0.14 g, 3.57

mmol) according to general procedure I. Column

chromatography on silica gel (petroleum ether:EtOAc=4:1) gave

2-bromo-3-(2’-bromo-5’-hydroxyphenyl)-2-propen-1-ol (1j) as a

white solid in 69% yield (0.51 g, 1.65 mmol): mp 198–199 °C; R_f

0.24 (petroleum ether:EtOAc=4:1); IR (ATR) ν 3357, 3007,

2903, 2760, 1567, 1458, 1293, 1279, 1231, 1167, 1019, 981, 816

2-Bromo-3-(2’,5’-dimethoxyphenyl)-2-propen-1-al (0.6 g, 2.5

mmol) was reduced with sodium borohydride (0.1 g, 2.7 mmol)

according to general procedure I. Column chromatography on

silica gel (petroleum ether:EtOAc=9:1) delivered 2-bromo-3-

(2’,5’-dimethoxyphenyl)-2-propen-1-ol (1h) as a colourless oil in

86% yield (0.57 g, 2.1 mmol); R_f0.18 (petroleum

ether:EtOAc=9:1); IR (ATR) ν 3373, 2937, 2827, 1709, 1492,

1458, 1433, 1378, 1213, 1110, 1042, 1018, 752 cm^-1; UV

(MeCN) λ_max(log ε) 314 (3.67) nm; ¹H NMR (600 MHz, CDCl₃)

δ 2.16 (bs, 1H, OH), 3.79 (s, 3H, 2’-OMe), 3.80 (s, 3H, 5’-OMe),

1

cm^-1; UV (MeCN) λ_max(log ε) 203 (4.34), 295 (3.52) nm; H

2

NMR (300 MHz, DMSO-d6) δ 4.22 (dd, J(1-H, 1-H)=1.3 Hz,

⁴J(3-H, 1-H)=4.2 Hz, 2H, 1-H₂), 6.68 (dd, ³J(3’-H, 4’-H)=8.8 Hz,

4

⁴J(6’-H, 4’-H)=2.9 Hz, 1H, 4’-H), 7.06 (d, J(4’-H, 6’-H)=2.9

2

3

Hz, 1H, 6’-H), 7.10 (d-like, 1H, 3-H), 7.41 (d, ³J(4’-H, 3’-H)=8.8

Hz, 1H, 3’-H), 9.79 (s, 1H, OH phenol); ¹³C NMR (75 MHz,

DMSO-d6) δ 66.72 (C-1), 111.38 (C-2’), 116.99 (C-4’), 117.47

4.43 (d, J(1-H, 1-H)=1.1 Hz, 2H, 1-H₂), 6.81 (d, J(4’-H, 3’-

3

4

H)=8.9 Hz, 1H, 3’-H), 6.85 (dd, J(3’-H, 4’-H)=9.0 Hz, J(6’-H,

4’-H)=3.0 Hz, 1H, 4’-H), 7.21 (bs, 1H, 3-H), 7.42 (d, ⁴J(4’-H, 6’-

10

Tetrahedron

ACCEPTED MANUSCRIPT

(C-6’), 125.17 (C-3), 129.84 (C-2), 132.95 (C-3’), 136.31 (C-

129.15 (C-3’), 130.38 (C-4’), 139.65 (C-5’); MS (EI, 70 eV) m/z

1’), 156.45 (C-5’); MS (EI, 70 eV) m/z (%) 310 (45) [M+4]⁺≙

(%) 300 (52) [M+4]⁺≙ [C₇H₆⁸¹Br⁸¹BrOS]⁺, 298 (100) [M+2]⁺≙

[C₇H₆⁸¹Br⁷⁹BrOS]⁺, 296 (50) [M]⁺≙ [C₇H₆⁷⁹Br⁷⁹BrOS]⁺, 219

(87) [C₇H₆⁸¹BrOS]⁺, 217 (86) [C₇H₆⁷⁹BrOS]⁺, 188 (10)

[C₆H₃⁸¹BrS]⁺, 186 (8) [C₆H₃⁷⁹BrS]⁺, 136 (41) [C₂HBrS]⁺, 121

(23) [C₂H₂BrO]⁺, 108 (40) [C₆H₄S]⁺, 82 (9) [C₄H₂S]⁺, 63 (12)

[CH₃OS]⁺, 55 (35) [C₃H₃O]⁺; HRMS (EI, M⁺) calculated for

C₇H₆Br₂OS 295.8501 found 295.8502.

[C₉H₈⁸¹Br⁸¹BrO₂]⁺, 308 (100) [M+2]⁺≙ [C₉H₈⁸¹Br⁷⁹BrO₂]⁺, 306

(46) [M]⁺

≙

[C₉H₈⁷⁹Br⁷⁹BrO₂]⁺, 227 (13) [M-Br]⁺

≙

[C₉H₈⁷⁹BrO₂]⁺, 211 (80) [C₉H₇⁸¹BrO]⁺, 209 (83) [C₉H₇⁷⁹BrO]⁺,

183 (31) [C₈H₆⁸¹Br]⁺, 181 (32) [C₈H₆⁷⁹Br]⁺, 148 (77) [C₉H₈O₂]⁺,

118 (27) [C₉H₁₀]⁺, 102 (35) [C₈H₆]⁺, 91 (15) [C₇H₇]⁺; HRMS (EI,

M⁺) calculated for C₉H₈Br₂O₂305.8886 found 305.8893.

4.2.13 2-Bromo-2-hepten-1-ol (1m)

4.2.11 2-Bromo-3-(3’-bromo- 4’-(dimethylamino)phenyl)-2-

According to general procedure I, commercially available 2-

heptenal (3.37 g, 30 mmol) was reacted with bromine (5.75 g, 36

mmol) and NEt₃(9 mL). Column chromatography on silica gel

(petroleum ether:CH₂Cl₂= 3:2) gave 2-bromo-2-heptenal as a

yellow oil in 67% yield (3.8 g, 20.1 mmol).

propen-1-ol (1k)

According to general procedure I, commercially available 3-(4’-

(dimethylamino)phenyl)acrylaldehyde (2.5 g, 14.28 mmol) was

reacted with bromine (4.56 g, 28.6 mmol) and NEt₃(12 mL).

Coloumn chromatography on silica gel (petroleum

ether:EtOAc=9:1) gave 2-bromo-3-(3’-bromo-4’-(dimethyl-

amino)phenyl)-2-propen-1-al as a yellow oil in 63% yield (2.98

g, 9 mmol).

2-Bromo-3-(3’-bromo-4’-(dimethylamino)phenyl)-2-propen-1-al

(1.5 g, 4.53 mmol) was reduced with sodium borohydride (0.19

g, 4.99 mmol) according to general procedure I. Column

chromatography on silica gel (petroleum ether:EtOAc=9:1)

delivered 2-bromo-3-(3’-bromo-4’-(dimethylamino)phenyl)-2-

propen-1-ol (1k) as a yellow oil in 83% yield (1.25 g, 3.76

mmol); R_f0.21 (petroleum ether:EtOAc=9:1); IR (ATR) ν 3308,

2943, 2865, 2833, 2783, 1595, 1492, 1452, 1392, 1322, 1265,

1138, 1083, 1037, 1002, 944, 892 cm^-1; UV (MeCN) λ_max(log ε)

212 (4.34), 292 (4.14) nm; ¹H NMR (600 MHz, CDCl₃) δ 2.85 (s,

6H, 4’-NMe₂), 4.41 (d, ²J(1-H, 1-H)=5.9 Hz, 2H, 1-H₂), 6.97 (bs,

2-Bromo-2-heptenal (2.24 g, 11.74 mmol) was reduced with

sodium borohydride (0.49 g, 12.92 mmol) according to general

procedure I. Column chromatography on silica gel (petroleum

ether:EtOAc=4:1) deliverd 2-bromo-2-hepten-1-ol (1m) as a

colourless oil in 82% yield (1.86 g, 9.61 mmol); R_f0.58

(petroleum ether:EtOAc=4:1); IR (ATR) ν 3323, 2956, 2925,

2858, 1655, 1456, 1378, 1137, 1057, 1010, 834 cm^-1; UV

1

(MeCN) λ_max(log ε) no UV-absorption; H NMR (600 MHz,

CDCl₃) δ 0.91 (t-like, 3H, 7-H₃), 1.37-1.31 m (m, 2H, 6-H₂),

1.43-1.37 (m, 2H, 5-H₂), 1.92 (bs, 1H, OH), 2.20 (dd-like, 2H, 4-

H₂), 4.24 (dd-like, 2H, 1-H₂), 6.00 (dt-like, 1H, 3-H); ¹³C NMR

(150 MHz, CDCl₃) δ 13.87 (C-7), 22.27 (C-6), 30.37 (C-5), 30.52

(C-4), 68.55 (C-1), 126.54 (C-2), 130.67 (C-3); MS (EI, 70 eV)

m/z (%) 194 (49) [M+2]⁺≙ [C₇H₁₃⁸¹BrO]⁺, 192 (50) [M]⁺≙

[C₇H₁₃⁷⁹BrO]⁺, 134 (21) [C₄H₅⁸¹Br]⁺, 132 (21) [C₄H₅⁷⁹Br]⁺, 121

(10) [C₂H₃⁷⁹BrO]⁺, 95 (100) [C₇H₁₂]⁺, 73 (22) [C₄H₉O]⁺, 57 (54)

[C₄H₉]⁺, 41 (56) [C₃H₅]⁺; HRMS (EI, M⁺) calculated for

C₇H₁₃BrO 192.0145 found 192.0150.

3

1H, 3-H), 7.06(d, J(6’-H, 5’-H)=8.4 Hz, 1H, 5’-H), 7.58 (dd,

³J(5’-H, 6’-H)=8.4 Hz, J(2’-H, 6’-H)=2.1 Hz, 1H, 6’-H), 7.87

4

(d, J(6’-H, 2’-H)=2.3 Hz, 1H, 2’-H); ¹³C NMR (150 MHz,

CDCl₃) δ 44.01 (4’-NMe₂), 69.45 (C-1), 118.08 (C-1’), 119.72

(C-5’), 124.91 (C-2), 126.13 (C-3), 128.82 (C-6’), 130.40 (C-3’),

134.48 (C-2’), 151.58 (C-4’); MS (ESI, 70 eV) m/z (%) 360 (24)

[(M+4)+Na]⁺≙ [C₁₁H₁₃⁸¹Br⁸¹BrNONa]⁺, 358 (52) [(M+2)+Na]⁺

4.2.14 3-Bromo-4-phenyl-3-buten-2-ol (1n)

According to general procedure I, commercially available

benzylidene acetone (2 g, 13.7 mmol) was reacted with bromine

(4.4 g, 27.3 mmol) and NEt₃(6 mL). Column chromatography on

silica gel (petroleum ether:EtOAc=9:1) gave 3-bromo-4-phenyl-

3-buten-2-one as a yellow oil in 74% yield (2.29 g, 10.12 mmol).

3-Bromo-4-phenyl-3-buten-2-one (3.76 g, 16.74 mmol) was

reduced with sodium borohydride (0.7 g, 18.4 mmol) according

to genral procedure I. Column chromatography on silica gel

(petroleum ether:EtOAc=9:1) delivered 3-bromo-4-phenyl-3-

buten-2-ol (1n) as a colourless oil in 69% yield (0.51 g, 1.65

mmol); R_f0.22 (petroleum ether:EtOAc=9:1); IR (ATR) ν 3328,

2978, 1638, 1491, 1445, 1368, 1258, 1130, 1051, 962, 880, 750,

692 cm^-1; UV (MeCN) λ_max(log ε) 202 (4.33), 251 (4.17) nm; ¹H

≙

[C₁₁H₁₃⁸¹Br⁷⁹BrNONa]⁺,

356

(26)

[M+Na]⁺

≙

[C₁₁H₁₃⁷⁹Br⁷⁹BrNONa]⁺, 338 (25) [C₉H₇⁸¹Br⁸¹BrNONa]⁺, 336

(49) [C₉H₇⁸¹Br⁷⁹BrNONa]⁺, 334 (24) [C₉H₇⁷⁹Br⁷⁹BrNONa]⁺, 323

(49) [C₁₀H₁₁⁸¹Br⁸¹BrNO]⁺, 321 (100) [C₁₀H₁₁⁸¹Br⁷⁹BrNO]⁺, 319

(49) [C₁₀H₁₁⁷⁹Br⁷⁹BrNO]⁺, 242 (20) [C₁₀H₁₁⁸¹BrNO]⁺, 240 (21)

[C₁₀H₁₁⁷⁹BrNO]⁺, 185 (6) [C₈H₈⁸¹Br]⁺, 183 (6) [C₈H₈⁷⁹Br]⁺;

HRMS (ESI, [M+Na]⁺) calculated for C₁₁H₁₃Br₂NONa 355.9256

found 355.9249.

4.2.12 2-Bromo-3-(2’-bromothiophenyl)-2-propen-1-ol (1l)

According to general procedure I, 3-(thiophenyl)acrylaldehyde¹⁴

(1.50 g, 10.86 mmol) was reacted with bromine (3.5 g, 21.7

mmol) and NEt₃(6 mL). Column chromatography on silica gel

(petroleum ether:EtOAc=9:1) gave 2-bromo-3-(2’-bromo-

thiophenyl)-2-propen-1-al as a yellow oil in 61% yield (1.96 g,

6.62 mmol).

3

NMR (600 MHz, CDCl₃) δ 1.49 (d, J(2-H, 1-H)=6.3 Hz, 3H, 1-

H), 2.00 (bs, 1H, OH), 4.50 (q, 1H, 2-H), 7.08 (s, 1H, 4-H), 7.31

3

4

(ddd, J(3’-H, 4’-H) and J(5’-H, 4’-H)=7.4 Hz, J(2’-H, 4’-H)

4

3

and J(6’-H, 4’-H)=1.2 Hz, 1H, 4’-H), 7.37 (ddd, J(4’-H, 5’-H)

and ³J(6’-H, 5’-H)=7.3 Hz, ³J(2’-H, 3’-H) and ³J(4’-H, 3’-H)=7.3

4

2-Bromo-3-(2’-bromothiophenyl)-2-propen-1-al (0.82 g, 3.76

mmol) was reduced with sodium borohydride (0.15 g, 4.13

mmol) according to general procedure I. Column

chromatography on silica gel (petroleum ether:EtOAc=7:1)

delivered 2-bromo-3-(2’-bromothiophenyl)-2-propen-1-ol (1l) as

a yellow solid in 63% yield (0.7 g, 2.37 mmol): mp 93–94 °C; R_f

0.24 (petroleum ether:EtOAc=7:1); IR (ATR) ν 3172, 2909,

1513, 1421, 1363, 1325, 1241, 1198, 1084, 1028, 1005, 965, 842

Hz, J(3’-H, 5’-H) and J(5’-H, 3’-H)=1.8 Hz, 2H, 3’-H and 5’-

3

4

H), 7.60 (dd, J(3’-H, 2’-H) and J(5’-H, 6’-H)=7.6 Hz, J(4’-H,

2’-H) and J(4’-H, 6’-H)=1.4 Hz, 2H, 2’-H and 6’-H); ¹³C NMR

4

(150 MHz, CDCl₃) δ 22.57 (C-1), 73.64 (C-2), 126.98 (C-4),

128.12 (C-4’), 128.16 (C-5’), 129.10 (C-6’), 131.43 (C-3),

135.10 (C-1’); MS (EI, 70 eV) m/z (%) 228 (28) [M+2]⁺≙

[C₁₀H₁₁⁸¹BrO]⁺, 226 (28) [M]⁺≙ [C₁₀H₁₁⁷⁹BrO]⁺, 213 (8)

[C₉H₈⁸¹BrO]⁺, 211 (10) [C₉H₈⁷⁹BrO]⁺, 195 (6) [C₉H₇⁸¹Br]⁺, 193

(6) [C₉H₇⁷⁹Br]⁺, 147 (100) [C₁₀H₁₁O]⁺, 131 (24) [C₄H₂⁸¹Br]⁺, 129

(30) [C₄H₂⁷⁹Br]⁺, 103 (20) [C₈H₇]⁺, 77 (15) [C₆H₅]⁺, 51 (8)

[C₄H₃]⁺, 43 (20) [C₃H₇]⁺; HRMS (EI, M⁺) calculated for

C₁₀H₁₁BrO 225.9988 found 225.9989.

cm^-1; UV (MeCN) λ_max(log ε) 207 (4.14), 294 (4.29) nm; H

1

NMR (600 MHz, CDCl₃) δ 2.05 (bs, 1H, OH), 4.41 (s, 2H, 1-H₂),

3

6.98 (d, J(3’-H, 4’-H)=3.9 Hz, 1H, 4’-H), 7.02 (d, J(4’-H, 3’-

H)=4.0 Hz, 1H, 3’-H), 7.23 (s, 1H, 3-H); ¹³C NMR (150 MHz,

CDCl₃) δ 68.83 (C-1), 114.21 (C-2’), 122.12 (C-3), 123.15 (C-2),

11

3

4.3 Synthesis and characterization of 3a-n

1’-H) 7.00 (d, J(3’’-H, 2’’-H) and J(5’’-H, 6’’-H) =7.7 Hz,

ACCEPTED MANUSCRIPT

2H, 2’’-H and 6’’-H), 7.09 (t-like, 1H, 4’’-H), 7.29 (t-like, 2H,

3’’-H and 5’’-H); ¹³C NMR (75 MHz, CDCl₃) δ 24.88 (C-3’’’ and

C-5’’’), 25.54 (C-4’’’’), 26.06 (C-4’’’), 26.19 (C-3’’’’ and C-

5’’’’), 27.60 (C-2’’’’ and C-6’’’’), 34.85 (C-2’’’ and C-6’’’),

53.76 (C-1’’’’), 54.27 (C-1’’’), 67.83 (C-5), 95.98 (C-1’), 124.48

(C-4’’), 126.49 (C-2’’ and C-6’’), 128.61 (C-3’’ and C-5’’),

137.41 (C-1’’), 138.27 (C-4), 148.60 (C-2); MS (EI, 70 eV) m/z

(%) 338 (8) [M]⁺≙ [C₂₂H₃₀N₂O]⁺, 256 [C₁₆H₁₉N₂O]⁺(39), 174

(100) [C₁₀H₉N₂O]⁺, 130 (4) [C₉H₈N]⁺, 55 (5) [C₄H₇]⁺.

4.3.1 General procedures II for the synthesis of 3a-n.

Method A: An oven-dried 10 mL pressure glass vial, equipped

with a magnetic stir bar, was charged with Cu₂O (0.05 mmol, 7

mg), DCC (0.5 mmol, 103 mg), the 3-substituted-2-bromo-2-

propen-1-ol 1 (0.5 mmol) and K₃PO₄(2 mmol, 425 mg). After

addition of molecular sieve 4Å (5 beads) the sealed tube was

evacuated and backfilled with argon (two times). Then, freshly

distilled DMSO (2 mL) was added and the reaction mixture was

stirred at 100 °C for 24 h. After cooling to room temperature, the

reaction mixture was diluted with saturated oxalic acid (30 mL)

and extracted with EtOAc (3×20 mL). The combined organic

layers were washed with saturated NaHCO₃(50 mL) and water

(50 mL), dried over anhydrous MgSO₄, filtered and the solvents

were evaporated in vacuo. The crude product was purified by

flash column chromatography on silica gel to afford the 2-

iminooxazolidine 3 in analytically pure form.

4.3.3 (4E)-4-[(2-bromophenyl)methylidene]-3-cyclohexyl-2-

cyclohexyliminooxazolidine (3b)

According to general procedure II, method A, 2-bromo-3-(2’-

bromophenyl)-2-propen-1-ol (1b) (146 mg, 0.5 mmol), DCC

(103 mg, 0.5 mmol), Cu₂O (7 mg, 10 mol%) and K₃PO₄(425 mg,

2.0 mmol) were reacted in DMSO (2 mL) at 100 °C for 24 h.

Column

chromatography

on

silica

gel

(petroleum

ether:EtOAc=9:1)

afforded

(4E)-4-[(2-bromophenyl)-

Method B: An oven-dried 10 mL pressure glass vial, equipped

with a magnetic stir bar, was charged with DCC (0.5 mmol, 103

mg), the 3-substituted-2-bromo-2-propen-1-ol 1 (0.5 mmol) and

methylidene]-3-cyclohexyl-2-cyclohexyliminooxazolidine (3b)

as a yellow oil in 57% yield (119 mg, 0.29 mmol). Under the

conditions of general procedure II, method B, 3b was obtained in

K₃PO₄(2 mmol, 425 mg). After addition of molecular sieve 4

Å

48% yield (100 mg, 0.24 mmol); R_f

0.65 (petroleum

(5 beads) the sealed tube was evacuated and backfilled with

argon (two times). Then, freshly distilled DMSO (2 mL) was

added and the reaction mixture was stirred at 100 °C for 24 h.

After cooling to room temperature, the reaction mixture was

diluted with saturated oxalic acid (30 mL) and extracted with

EtOAc (3×20 mL). The combined organic layers were washed

with saturated NaHCO₃(50 mL) and water (50 mL), dried over

anhydrous MgSO₄, filtered and the solvents were evaporated in

vacuo. The crude product was purified by flash column

chromatography on silica gel to afford the 2-iminooxazolidine 3

in analytically pure form.

ether:EtOAc=9:1); IR (ATR) ν 2925, 2851, 1707, 1585, 1467,

1392, 1360, 1344, 1305, 1257, 1228, 1194, 1043, 1022, 906, 890,

1

804, 729 cm^-1; UV (MeCN) λ_max(log ε) 302 (4.24) nm; H NMR

(600 MHz, CDCl₃) δ 1.21 (ddddd, 2×J(ax,ax)=²J_gem=13.2 Hz,

2×J(ax,eq)=3.4 Hz, 1H, 4’’’’-H_ax), 1.24 (ov, 1H, 4’’’-H_ax), 1.30

(ddddd, 2×J(ax,ax)=²J_gem=12.4 Hz, 2×J(ax,eq)=3.3 Hz, 2H, 2’’’-

H_axand 6’’’-H_ax), 1.31 (ddddd, 2×J(ax,ax)=²J_gem=12.3 Hz,

2×J(ax,eq)=3.3 Hz, 2H, 3’’’-H_axand 5’’’-H_ax), 1.41 (ddddd,

2×J(ax,ax)=²J_gem=13.3 Hz, 2×J(ax,eq)=3.2 Hz, 2H, 3’’’’-H_axand

2

5’’’’-H_ax), 1.56 (bd, J_gem=13.0 Hz, 1H, 4’’’-H_eq), 1.69 (ov, 2H,

2’’’-H_eqand 6’’’-H_eq), 1.70 (bd, ²J_gem=13.3 Hz, 2H, 2’’’’-H_eqand

6’’’’-H_eq), 1.73 (ov, 2H, 3’’’-H_eqand 5’’’-H_eq), 1.75 (bd,

2

²J_gem=12.2 Hz, 1H, 4’’’’-H_eq), 1.87 (bd, J_gem=13.5 Hz, 2H, 3’’’’-

4.3.2 (4E)-3-cyclohexyl-2-cyclohexylimino-4-[phenyl-

methylidene]oxazolidine (3a)

H_eqand 5’’’’-H_eq), 2.35 (ddddd, 2×J(ax,ax)=²J_gem=13.1 Hz,

2×J(ax,eq)=3.4 Hz, 2H, 2’’’’-H_axand 6’’’’-H_ax), 3.42 (tt,

J(ax,ax)=9.3 Hz, J(ax,eq)=3.6 Hz, 1H, 1’’’-H_ax), 4.04 (tt,

According to general procedure II, method A, 2-bromo-3-phenyl-

2-propen-1-ol (1a) (107 mg, 0.5 mmol), DCC (103 mg, 0.5

mmol), Cu₂O (7 mg, 10 mol%) and K₃PO₄(425 mg, 2.0 mmol)

were reacted in DMSO (2 mL) at 100 °C for 24 h. Column

chromatography on silica gel (petroleum ether:EtOAc=9:1)

2

J(ax,ax)=12.3 Hz, J(ax,eq)=3.6 Hz, 1H, 1’’’’-H_ax), 4.92 (d, J(5-

H, 5-H)=1.9 Hz, 2H, 5-H₂), 5.88 (bs, 1H, 1’-H), 6.94 (ov, 1H,

3

6’’-H), 6.96 (ov, 1H, 4’’-H), 7.23 (ddd, J(4’’-H, 5’’-H) and

4

³J(6’’-H, 5’’-H)=7.5 Hz, J(3’’-H, 5’’-H)=1.1 Hz, 1H, 5’’-H),

afforded

(4E)-3-cyclohexyl-2-cyclohexylimino-4-[phenyl-

3

7.57 (d, J(4’’-H, 3’’-H)=7.8 Hz, 1H, 3’’-H); ¹³C NMR (150

methylidene]oxazolidine (3a) as a yellow-white low-melting

solid in 80% yield (135 mg, 0.40 mmol). Under the conditions of

general procedure II, method B, 3a was obtained in 75% yield

(127 mg, 0.38 mmol); R_f0.60 (petroleum ether:EtOAc=9:1); IR

(ATR) ν 2925, 2852, 1704, 1639, 1617, 1594, 1445, 1400, 1365,

1260, 1226, 1197, 1182, 1075, 1046, 986, 889, 778, 753, 692 cm^-

MHz, CDCl₃) δ 24.97 (C-3’’’ and C-5’’’), 25.60 (C-4’’’’), 26.02

(C-4’’’), 26.16 (C-3’’’’ and C-5’’’’), 27.40 (C-2’’’’ and C-6’’’’),

34.81 (C-2’’’ and C-6’’’), 53.81 (C-1’’’’), 54.36 (C-1’’’), 67.34

(C-5), 96.03 (C-1’), 123.98 (C-2’’), 126.34 (C-4’’), 127.07 (C-

6’’), 127.38 (C-5’’), 132.97 (C-3’’), 137.00 (C-1’’), 139.15 (C-

4), 148.92 (C-2); MS (EI, 70 eV) m/z (%) 418 (13) [M+2]⁺≙

[C₂₂H₂₉N₂⁸¹BrO]⁺, 416 (13) [M]⁺≙ [C₂₂H₂₉N₂⁷⁹BrO]⁺, 336 (98)

[C₁₆H₁₈N₂⁸¹BrO]⁺, 334 (100) [C₁₆H₁₈N₂⁷⁹BrO]⁺, 293 (7)

[C₁₃H₁₃N₂BrO]⁺, 254 (22) [C₁₀H₆N₂⁸¹BrO]⁺, 252 (24)

[C₁₀H₆N₂⁷⁹BrO]⁺, 212 (9) [C₁₃H₁₂N₂O]⁺, 173 (10) [C₁₀H₈N₂O]⁺,

157 (7) [C₁₀H₇NO]⁺, 130 (20) [C₉H₈N]⁺, 115 (4) [C₈H₅N]⁺, 55 (8)

[C₄H₇]⁺; HRMS (EI, M⁺) calculated for C₂₂H₂₉N₂BrO 416.1458

found 416.1462.

1

¹; UV (MeCN) λ_max(log ε) 296 (4.07) nm; H NMR (500 MHz,

CDCl₃) δ 1.21 (ddddd, 2×J(ax,ax)=²J_gem=13.2 Hz, 2×J(ax,eq)=3.5

2

Hz, 1H, 4’’’’-H_ax), 1.25 (ddddd, 2×J(ax,ax)= J_gem=13.0 Hz,

2×J(ax,eq)=3.9

2×J(ax,ax)=²J_gem=12.3 Hz, 2×J(ax,eq)=3.3 Hz, 2H, 3’’’-H_axand

5’’’-H_ax), 1.29 (ddddd, Hz,

2×J(ax,ax)=²J_gem=12.1

Hz,

1H,

4’’’-H_ax),

1.29

(ddddd,

2×J(ax,eq)=3.1 Hz, 2H, 2’’’-H_axand 6’’’-H_ax), 1.39 (ddddd,

2×J(ax,ax)=²J_gem=13.3 Hz, 2×J(ax,eq)=3.5 Hz, 2H, 3’’’’-H_axand

2

5’’’’-H_ax), 1.56 (bd, J_gem=11.9 Hz, 1H, 4’’’-H_eq), 1.69 (bd,

2

²J_gem=13.8 Hz, 1H, 4’’’’-H_eq), 1.70 (bd, J_gem=13.7 Hz, 2H, 2’’’-

4.3.4 (4E)-4-[(2-chlorophenyl)methylidene]-3-cyclohexyl-2-

cyclohexyliminooxazolidine (3c)

2

H_eqand 6’’’-H_eq), 1.71 (bd, J_gem=12.7 Hz, 2H, 2’’’’-H_eqand

2

6’’’’-H_eq), 1.73 (bd, J_gem=13.5 Hz, 2H, 3’’’-H_eqand 5’’’-H_eq),

According to general procedure II, method A, 2-bromo-3-(2’-

chlorophenyl)-2-propen-1-ol (1c) (124 mg, 0.5 mmol), DCC (103

mg, 0.5 mmol), Cu₂O (7 mg, 10 mol%) and K₃PO₄(425 mg, 2.0

mmol) were reacted in DMSO (2 mL) at 100 °C for 24 h.

2

1.86 (bd, J_gem=13.5 Hz, 2H, 3’’’’-H_eqand 5’’’’-H_eq), 2.35

(ddddd, 2×J(ax,ax)=²J_gem=12.8 Hz, 2×J(ax,eq)=3.7 Hz, 2H, 2’’’’-

H_axand 6’’’’-H_ax), 3.44 (tt, J(ax,ax)=9.6 Hz, J(ax,eq)=4.0 Hz,

1H, 1’’’-H_ax), 3.91 (tt, J(ax,ax)=12.4 Hz, J(ax,eq)=3.9 Hz, 1H,

1’’’’-H_ax), 5.02 (d, ²J(5-H, 5-H)=1.8 Hz, 2H, 5-H₂), 5.64 (bs, 1H,

Column

chromatography

on

silica

gel

(petroleum

12

Tetrahedron

2

ether:EtOAc=9:1)

afforded

(4E)-4-[(2-chlorophenyl)-

H_eq), 1.69 (d-like, J_gem=9.2 Hz, 2H, 2’’’-H_eqand 6’’’-H_eq),1.70

ACCEPTED MANUSCRIPT

2

methylidene]-3-cyclohexyl-2-cyclohexyliminooxazolidine (3c) as

a yellow oil 61% yield (113 mg, 0.31 mmol). Under the

conditions of general procedure II, method B, 3c was obtained in

(bd, J_gem=12.5 Hz, 2H, 2’’’’-H_eqand 6’’’’-H_eq), 1.73 (d-like,

²J_gem=8.9 Hz, 2H, 3’’’-H_eqand 5’’’-H_eq), 1.86 (bd, ²J_gem=13.3 Hz,

2H, 3’’’’-H_eqand 5’’’’-H_eq), 2.34 (ddddd, 2×J(ax,ax)=²J_gem=12.8

Hz, 2×J(ax,eq)=3.2 Hz, 2H, 2’’’’-H_axand 6’’’’-H_ax), 3.43 (tt,

J(ax,ax)=9.0 Hz, J(ax,eq)=3.7 Hz, 1H, 1’’’-H_ax), 3.88 (tt,

46% yield (86 mg, 0.23 mmol); R_f

0.69 (petroleum

ether:EtOAc=9:1); IR (ATR) ν 2926, 2852, 1707, 1638, 1587,

1440, 1392, 1361, 1343, 1306, 1258, 1228, 1194, 1048, 1034,

907, 890, 803, 749, 730 cm^-1; UV (MeCN) λ_max(log ε) 302 (4.21)

2

J(ax,ax)=12.3 Hz, J(ax,eq)=3.6 Hz, 1H, 1’’’’-H_ax), 4.97 (d, J(5-

H, 5-H)=2.1 Hz, 2H, 5-H₂), 5.58 (bs, 1H, 1’-H), 6.91 (d-like,

nm; ¹H NMR (600 MHz, CDCl₃)

δ

1.22 (ddddd,

³J(3’’-H, 2’’-H) and J(5’’-H, 6’’-H)=8.5 Hz, 2H, 2’’-H and 6’’-

3

2×J(ax,ax)=²J_gem=13.2 Hz, 2×J(ax,eq)=3.3 Hz, 1H, 4’’’’-H_ax),

1.23 (ov, 1H, 4’’’-H_ax), 1.28 (ddddd, 2×J(ax,ax)=²J_gem=9.9 Hz,

2×J(ax,eq)=3.2 Hz, 2H, 3’’’-H_axand 5’’’-H_ax), 1.30 (ddddd,

2×J(ax,ax)=²J_gem=10.9 Hz, 2×J(ax,eq)=3.2 Hz, 2H, 2’’’-H_axand

H), 7.24 (d-like, J(2’’-H, 3’’-H) and J(6’’-H, 5’’-H) =8.5 Hz,

2H, 3’’-H and 5’’-H); ¹³C NMR (150 MHz, CDCl₃) δ 24.86 (C-

3’’’ and C-5’’’), 25.53 (C-4’’’’), 26.07 (C-4’’’), 26.19 (C-3’’’’

and C-5’’’’), 27.61 (C-2’’’’ and C-6’’’’), 34.80 (C-2’’’ and C-

6’’’), 53.84 (C-1’’’’), 54.27 (C-1’’’), 67.78 (C-5), 94.72 (C-1’),

127.62 (C-2’’ and C-6’’), 128.71 (C-3’’ and C-5’’), 129.85 (C-

4’’), 136.02 (C-1’’), 138.94 (C-4), 148.34 (C-2); MS (EI, 70 eV)

m/z (%) 374 (2) [M+2]⁺≙ [C₂₂H₂₉³⁷ClN₂O]⁺, 372 (5) [M]⁺≙

[C₂₂H₂₉³⁵ClN₂O]⁺, 292 (11) [C₁₆H₁₇³⁷ClN₂O]⁺, 290 (31)

[C₁₆H₁₇³⁷ClN₂O]⁺, 208 (10) [C₁₀H₇³⁷ClN₂O]⁺, 183 (50)

[C₁₁H₇N₂O]⁺, 139 (22) [C₆H₃ClNO]⁺, 125 (32) [C₇H₆Cl]⁺, 101

(12) [C₈H₅]⁺, 86 (61) [C₄H₂³⁷Cl]⁺, 84 (100) [C₄H₂³⁵Cl]⁺, 55 (6)

[C₄H₇]⁺; HRMS (EI, M⁺) calculated for C₂₂H₂₉ClN₂O 372.1963

found 372.1969.

3

6’’’-H_ax),

1.41

(ddddd,

2×J(ax,ax)=²J_gem=12.8

Hz,

2×J(ax,eq)=3.4 Hz, 2H, 3’’’’-H_axand 5’’’’-H_ax), 1.57 (bd,

²J_gem=10.9 Hz, 1H, 4’’’-H_eq), 1.69 (ov, 2H, 2’’’-H_eqand 6’’’-H_eq),

1.70 (bd, ²J_gem=13.7 Hz, 1H, 4’’’’-H_eq), 1.73 (ov, 2H, 3’’’-H_eqand

2

5’’’-H_eq), 1.75 (bd, J_gem=13.3 Hz, 2H, 2’’’’-H_eqand 6’’’’-H_eq),

2

1.87 (bd, J_gem=13.7 Hz, 2H, 3’’’’-H_eqand 5’’’’-H_eq), 2.34

(ddddd, 2×J(ax,ax)=²J_gem=12.8 Hz, 2×J(ax,eq)=3.4 Hz, 2H, 2’’’’-

H_axand 6’’’’-H_ax), 3.42 (tt, J(ax,ax)=9.0 Hz, J(ax,eq)=3.9 Hz,

1H, 1’’’-H_ax), 4.02 (tt, J(ax,ax)=12.5 Hz, J(ax,eq)=4.0 Hz, 1H,

1’’’’-H_ax), 4.94 (d, ²J(5-H, 5-H)=2.0 Hz, 2H, 5-H₂), 5.90 (bs, 1H,

1’-H) 6.96 (dd, ³J(5’’-H, 6’’-H)=7.9 Hz, ⁴J(4’’-H, 6’’-H)=1.3 Hz,

3

1H, 6’’-H), 7.05 (ddd, J(5’’-H, 4’’-H) and J(3’’-H, 4’’-H)=7.8

Hz, J(6’’-H, 4’’-H) =1.2 Hz, 1H, 4’’-H), 7.18 (ddd, J(4’’-H,

5’’-H) and J(6’’-H, 5’’-H) =7.7 Hz, J(3’’-H, 5’’-H) =1.1 Hz,

4.3.6 (4E)-3-cyclohexyl-2-cyclohexylimino-4-[(2-fluoro-phenyl)-

methylidene]oxazolidine (3e)

4

3

4

3

4

According to general procedure II, method A, 2-bromo-3-(2’-

fluorophenyl)-2-propen-1-ol (1e) (116 mg, 0.5 mmol), DCC (103

mg, 0.5 mmol), Cu₂O (7 mg, 10 mol%) and K₃PO₄(425 mg, 2.0

mmol) were reacted in DMSO (2 mL) at 100 °C for 24 h.

Column

ether:EtOAc=9:1) afforded (4E)-3-cyclohexyl-2-cyclohexyl-

imino-4-[(2-fluorophenyl)methylidene]oxazolidine (3e) as

yellow oil in 51% yield (91 mg, 0.26 mmol). Under the

conditions of general procedure II, method B, 3e was obtained in

42% yield (75 mg, 0.21 mmol); R_f

ether:EtOAc=9:1); IR (ATR) ν 2923, 2854, 1698, 1639, 1605,

1453, 1405, 1362, 1343, 1260, 1258, 1232, 1097, 1036, 989, 950,

888, 807, 741, 719 cm^-1; UV (MeCN) λ_max(log ε) 227 (3.92), 304

(4.24) nm; ¹H NMR (600 MHz, CDCl₃) δ 1.21 (ddddd,

2×J(ax,ax)=²J_gem=13.2 Hz, 2×J(ax,eq)=3.4 Hz, 1H, 4’’’’-H_ax),

1.25 (ddddd, 2×J(ax,ax)=²J_gem=13.3 Hz, 2×J(ax,eq)=4.4 Hz, 1H,

1H, 5’’-H), 7.37 (dd, J(4’’-H, 3’’-H)=8.0 Hz, J(5’’-H, 3’’-H)

=1.0 Hz, 1H, 3’’-H); ¹³C NMR (150 MHz, CDCl₃) δ 24.95 (C-

3’’’ and C-5’’’), 25.58 (C-4’’’’), 26.03 (C-4’’’), 26.16 (C-3’’’’

and C-5’’’’), 27.41 (C-2’’’’ and C-6’’’’), 34.81 (C-2’’’ and C-

6’’’), 53.82 (C-1’’’’), 54.34 (C-1’’’), 67.47 (C-5), 93.14 (C-1’),

126.01 (C-4’’), 126.73 (C-5’’), 126.98 (C-6’’), 129.70 (C-3’’),

132.80 (C-2’’), 135.32 (C-1’’), 139.30 (C-4), 148.83 (C-2); MS

(EI, 70 eV) m/z (%) 374 (7) [M+2]⁺≙ [C₂₂H₂₉³⁷ClN₂O]⁺, 372

(20) [M]⁺≙ [C₂₂H₂₉³⁵ClN₂O]⁺, 292 (34) [C₁₆H₁₇³⁷ClN₂O]⁺, 290

(100) [C₁₆H₁₇³⁵ClN₂O]⁺, 247 (10) [C₁₃H₁₂ClN₂O]⁺, 208 (13)

[C₁₀H₇³⁷ClN₂O]⁺, 206 (31) [C₁₀H₇³⁵ClN₂O]⁺, 183 (92)

[C₁₁H₇N₂O]⁺, 173 (9) [C₁₀H₈N₂O]⁺, 149 (14) [C₈H₄ClN]⁺, 130

(10) [C₉H₈N]⁺, 101 (24) [C₈H₅]⁺, 57 (21) [C₃H₅O]⁺; HRMS (EI,

M⁺) calculated for C₂₂H₂₉ClN₂O 372.1963 found 372.1964.

chromatography

on

silica

gel

(petroleum

a

0.72 (petroleum

4.3.5 (4E)-4-[(4-chlorophenyl)methylidene]-3-cyclohexyl-2-

cyclohexyliminooxazolidine (3d)

4’’’-H_ax),

1.29

(ddddd,

2×J(ax,ax)=²J_gem=11.4

Hz,

2×J(ax,eq)=3.7 Hz, 2H, 3’’’-H_axand 5’’’-H_ax), 1.30 (ddddd,

According to general procedure II, method A, 2-bromo-3-(4’-

chlorophenyl)-2-propen-1-ol (1d) (124 mg, 0.5 mmol), DCC

(103 mg, 0.5 mmol), Cu₂O (7 mg, 10 mol%) and K₃PO₄(425 mg,

2.0 mmol) were reacted in DMSO (2 mL) at 100 °C for 24 h.

Column

ether:EtOAc=9:1)

methylidene]-3-cyclohexyl-2-cyclohexyliminooxazolidine (3d)

as a yellow oil 60% yield (111 mg, 0.29 mmol). Under the

conditions of general procedure II, method B, 3d was obtained in

2×J(ax,ax)=²J_gem=11.5 Hz, 2×J(ax,eq)=3.8 Hz, 2H, 2’’’-H_axand

6’’’-H_ax),

1.39

(ddddd,

2×J(ax,ax)=²J_gem=13.1

Hz,

2×J(ax,eq)=3.7 Hz, 2H, 3’’’’-H_axand 5’’’’-H_ax), 1.56 (d-like,

²J_gem=12.9 Hz, 1H, 4’’’-H_eq), 1.68 (d-like, J_gem=12.1 Hz, 1H,

2

4’’’’-H_eq), 1.69 (d-like, J_gem=9.8 Hz, 2H, 2’’’-H_eqand 6’’’-H_eq),

chromatography

on

afforded

silica

gel

(petroleum

2

1.71 (d-like, J_gem=13.3 Hz, 2H, 2’’’’-H_eqand 6’’’’-H_eq), 1.73 (d-

(4E)-4-[(4-chlorophenyl)-

like, ²J_gem=9.2 Hz, 2H, 3’’’-H_eqand 5’’’-H_eq), 1.86 (bd, ²J_gem=13.6

Hz,

2H,

3’’’’-H_eq

and

5’’’’-H_eq),

2.35

(ddddd,

2×J(ax,ax)=²J_gem=12.7 Hz, 2× J(ax,eq)=3.6 Hz, 2H, 2’’’’-H_axand

6’’’’-H_ax), 3.43 (tt, J(ax,ax)=8.9 Hz, J(ax,eq)=4.0 Hz, 1H, 1’’’-

H_ax), 3.94 (tt, J(ax,ax)=12.4 Hz, J(ax,eq)=3.8 Hz, 1H, 1’’’’-H_ax),

43% yield (80 mg, 0.22 mmol); R_f

0.54 (petroleum

ether:EtOAc=9:1); IR (ATR) ν 2927, 2851, 1701, 1635, 1586,

1557, 1447, 1394, 1361, 1337, 1310, 1254, 1225, 1196, 1046,

1006, 948, 827, 811, 720, 696 cm^-1; UV (MeCN) λ_max(log ε) 304

(4.48) nm; ¹H NMR (600 MHz, CDCl₃) δ 1.21 (ddddd,

2×J(ax,ax)=²J_gem=13.2 Hz, 2×J(ax,eq)=3.4 Hz, 1H, 4’’’’-H_ax),

1.25 (ddddd, 2×J(ax,ax)=²J_gem=12.6 Hz, 2×J(ax,eq)=2.8 Hz, 1H,

2

4.95 (d, J(5-H, 5-H)=2.1 Hz, 2H, 5-H₂), 5.71 (bs, 1H, 1’-H),

6.93 (ddd, ³J(5’’-H, 6’’-H)=7.5 Hz, ⁴J(4’’-H, 6’’-H)=2.0 Hz, 1H,

3

6’’-H), 7.02 (ddd, J(4’’-H, 3’’-H) and J(2’’-F, 3’’-H)=6.9 Hz,

⁴J(5’’-H, 3’’-H)=2.2 Hz, 1H, 3’’-H), 7.06 (dd-like, J(4’’-H, 5’’-

3

4

H) and J(6’’-H, 5’’-H) =7.1 Hz, J(3’’-H, 5’’-H)=1.9 Hz, 1H,

3

4’’’-H_ax),

1.29

(ddddd,

2×J(ax,ax)=²J_gem=11.7

Hz,

5’’-H), 7.08 (ddd, J(3’’-H, 4’’-H) and J(5’’-H, 4’’-H)=7.3 Hz,

⁴J(6’’-H, 4’’-H)=2.0 Hz, 1H, 4’’-H); ¹³C NMR (150 MHz,

CDCl₃) δ 24.89 (C-3’’’ and C-5’’’), 25.52 (C-4’’’’), 26.06 (C-

4’’’), 26.17 (C-3’’’’ and C-5’’’’), 27.49 (C-2’’’’ and C-6’’’’),

34.81 (C-2’’’ and C-6’’’), 53.83 (C-1’’’’), 54.28 (C-1’’’), 67.74

(d, ⁵J(2’’-F, C-5)=2.9 Hz, C-5), 87.55 (d, ³J(2’’-F, C-1’)=6.2 Hz,

2×J(ax,eq)=2.5 Hz, 2H, 3’’’-H_axand 5’’’-H_ax), 1.30 (ddddd,

2×J(ax,ax)=²J_gem=11.9 Hz, 2×J(ax,eq)=2.7 Hz, 2H, 2’’’-H_axand

6’’’-H_ax),

1.39

(ddddd,

2×J(ax,ax)=²J_gem=13.3

Hz,

2×J(ax,eq)=3.3 Hz, 2H, 3’’’’-H_axand 5’’’’-H_ax), 1.57 (d-like,

2

²J_gem=12.6 Hz, 1H, 4’’’-H_eq), 1.69 (bd, J_gem=12.5 Hz, 1H, 4’’’’-

13

2

C-1’), 115.37 (d, J(2’’-F, C-3’’)=22.1 Hz, C-3’’), 123.98 (d,

(103 mg, 0.5 mmol), Cu₂O (7 mg, 10 mol%) and K₃PO₄(425

ACCEPTED MANUSCRIPT

⁴J(2’’-F, C-5’’)=3.7 Hz, C-5’’), 125.19 (d, J(2’’-F, C-1’’)=13.2

mg, 2.0 mmol) were reacted in DMSO (2 mL) at 100 °C for 24 h.

Column chromatography on silica gel (petroleum

ether:EtOAc=9:1) afforded (4E)-3-cyclohexyl-2-cyclohexyl-

imino-4-[(2-methoxyphenyl)methylidene]-oxazolidine (3g) as a

yellow oil in 35% yield (65 mg, 0.18 mmol). Under the

conditions of general procedure II, method B, 3g was obtained in

2

Hz, C-1’’), 126.07 (d, ³J(2’’-F, C-4’’)=7.8 Hz, C-4’’), 127.15 (d,

³J(2’’-F, C-6’’)=3.3 Hz, C-6’’), 139.56 (C-4), 148.67 (C-2),

1

159.27 (d, J(2’’-F, C-2’’)=245 Hz, C-2’’); MS (EI, 70 eV) m/z

(%) 356 (11) [M]⁺≙ [C₂₂H₂₉N₂FO]⁺, 274 (76) [C₁₆H₁₉N₂FO]⁺,

257 (6) [C₁₅H₁₆N₂FO]⁺, 231 (14) [C₁₃H₁₂N₂FO]⁺, 192 (100)

[C₁₀H₈N₂FO]⁺, 183 (33) [C₁₁H₇N₂O]⁺, 147 (20) [C₉H₁₀NO]⁺, 131

(24) [C₈H₅NO]⁺, 122 (20) [C₈H₆F]⁺, 83 (8) [C₃H₃N₂O]⁺, 55 (14)

[C₄H₇]⁺; HRMS (EI, M⁺) calculated for C₂₂H₂₉N₂FO 356.2259

found 356.2257.

29% yield (54 mg, 0.15 mmol); R_f

0.60 (petroleum

ether:EtOAc=9:1); IR (ATR) ν 2926, 2852, 1695, 1632, 1589,

1450, 1405, 1364, 1345, 1286, 1240, 1107, 1043, 1025, 890, 821,

737, 720 cm^-1; UV (MeCN) λ_max(log ε) 302 (4.21) nm; H NMR

1

(500 MHz, CDCl₃) δ 1.21 (ddddd, 2×J(ax,ax)=²J_gem=13.2 Hz,

2×J(ax,eq)=3.3

Hz,

1H,

4’’’’-H_ax),

1.23

(ddddd,

4.3.7 (4E)-4-[(2,3-dichlorophenyl)methylidene]-3-cyclohexyl-2-

cyclohexyliminooxazolidine (3f)

2×J(ax,ax)=²J_gem=12.8 Hz, 2×J(ax,eq)=3.7 Hz, 1H, 4’’’-H_ax),

1.29 (ov, 2H, 3’’’-H_axand 5’’’-H_ax), 1.29 (ov, 2H, 2’’’-H_axand

2×J(ax,ax)=²J_gem=13.2

Hz,

According to general procedure II, method A, 2-bromo-3-(2’,3’-

dichlorophenyl)-2-propen-1-ol (1f) (141 mg, 0.5 mmol), DCC

(103 mg, 0.5 mmol), Cu₂O (7 mg, 10 mol%) and K₃PO₄(425 mg,

2.0 mmol) were reacted in DMSO (2 mL) at 100 °C for 24 h.

6’’’-H_ax),

1.39

(ddddd,

2×J(ax,eq)=3.5 Hz, 2H, 3’’’’-H_axand 5’’’’-H_ax), 1.55 (bd,

²J_gem=11.9 Hz, 1H, 4’’’-H_eq), 1.67 (d-like, ²J_gem=9.9 Hz, 2H, 2’’’-

H_eqand 6’’’-H_eq), 1.68 (bd, ²J_gem=13.4 Hz, 1H, 4’’’’-H_eq), 1.72 (d-

like, ²J_gem=9.0 Hz, 2H, 3’’’-H_eqand 5’’’-H_eq), 1.73 (bd, ²J_gem=12.5

Column

ether:EtOAc=9:1)

chromatography

afforded

on

silica

gel

(petroleum

(4E)-4-[(2,3-dichlorophenyl)-

2

Hz, 2H, 2’’’’-H_eqand 6’’’’-H_eq), 1.86 (bd, J_gem=13.5 Hz, 2H,

methylidene]-3-cyclohexyl-2-cyclohexyliminooxazolidine (3f) as

a yellow oil in 64% yield (130 mg, 0.32 mmol). Under the

conditions of general procedure II, method B, 3f was obtained in

3’’’’-H_eqand 5’’’’-H_eq), 2.36 (ddddd, 2×J(ax,ax)=²J_gem=12.7 Hz,

2×J(ax,eq)=3.5 Hz, 2H, 2’’’’-H_axand 6’’’’-H_ax), 3.41 (tt,

J(ax,ax)=9.6 Hz, J(ax,eq)=3.7 Hz, 1H, 1’’’-H_ax), 3.85 (s, 3H, 2’’-

OMe), 3.94 (tt, J(ax,ax)=12.4 Hz, J(ax,eq)=3.8 Hz, 1H, 1’’’’-

51% yield (106 mg, 0.26 mmol); R_f

0.59 (petroleum

ether:EtOAc=9:1); IR (ATR) ν 2926, 2852, 1704, 1636, 1576,

1449, 1394, 1355, 1304, 1255, 1217, 1153, 1042, 906, 788, 768,

730 cm^-1; UV (MeCN) λ_max(log ε) 310 (4.26) nm; ¹H NMR (600

2

H_ax), 4.93 (d, J(5-H, 5-H)=2.2 Hz, 2H, 5-H₂), 5.86 (bs, 1H, 1’-

3

H), 6.85 (bd, J(4’’-H, 3’’-H)=8.2 Hz, 1H, 3’’-H), 6.89 (bd,

⁴J(4’’-H, 6’’-H)=3.4 Hz, 1H, 6’’-H), 6.90 (ddd, J(3’’-H, 4’’-H)

3

MHz, CDCl₃)

δ

1.20 (ddddd, 2×J(ax,ax)=²J_gem=13.1 Hz,

3

4

and J(5’’-H, 4’’-H) =8.0 Hz, J(6’’-H, 4’’-H) =2.7 Hz, 1H, 4’’-

2×J(ax,eq)=3.2

Hz,

1H,

4’’’’-H_ax),

1.23

(ddddd,

3

H), 7.11 (ddd, J(4’’-H, 5’’-H) and J(6’’-H, 5’’-H) =8.5 Hz,

⁴J(3’’-H, 5’’-H)=3.3 Hz, 1H, 5’’-H); ¹³C NMR (75 MHz, CDCl₃)

δ 24.96 (C-3’’’ and C-5’’’), 25.60 (C-4’’’’), 26.08 (C-4’’’), 26.21

(C-3’’’’ and C-5’’’’), 27.52 (C-2’’’’ and C-6’’’’), 34.88 (C-2’’’

and C-6’’’), 53.69 (C-1’’’’), 54.25 (C-1’’’), 55.60 (2’’-OMe),

67.79 (C-5), 90.76 (C-1’), 110.55 (C-3’’), 120.53 (C-4’’), 126.15

(C-6’’), 126.31 (C-1’’), 126.83 (C-5’’), 137.92 (C-4), 149.09 (C-

2), 155.91 (C-2’’); MS (EI, 70 eV) m/z (%) 368 (20) [M]⁺≙

[C₂₃H₃₂N₂O₂]⁺, 325 (8) [C₂₀H₂₅N₂O₂]⁺, 286 (47) [C₁₇H₂₁N₂O₂]⁺,

243 (7) [C₁₄H₁₅N₂O₂]⁺, 204 (12) [C₁₁H₁₁N₂O₂]⁺, 183 (100)

[C₁₁H₇N₂O]⁺, 163 (29) [C₁₀H₁₀O₂]⁺, 131 (9) [C₉H₇O]⁺, 121 (24)

[C₈H₉O]⁺, 91 (17) [C₇H₇]⁺, 55 (8) [C₄H₇]⁺; HRMS (EI, M⁺)

calculated for C₂₃H₃₂N₂O₂368.2459 found 368.2461.

2×J(ax,ax)=²J_gem=12.4 Hz, 2×J(ax,eq)=4.2 Hz, 1H, 4’’’-H_ax),

1.29 (ddddd, 2×J(ax,ax)=²J_gem=10.3 Hz, 2×J(ax,eq)=3.2 Hz, 2H,

3’’’-H_axand 5’’’-H_ax), 1.30 (ddddd, 2×J(ax,ax)=²J_gem=12.3 Hz,

2×J(ax,eq)=2.9 Hz, 2H, 2’’’-H_axand 6’’’-H_ax), 1.41 (ddddd,

2×J(ax,ax)=²J_gem=13.1 Hz, 2×J(ax,eq)=3.5 Hz, 2H, 3’’’’-H_axand

2

5’’’’-H_ax), 1.56 (bd, J_gem=12.8 Hz, 1H, 4’’’-H_eq), 1.68 (ov, 2H,

2

2’’’-H_eqand 6’’’-H_eq), 1.69 (bd, J_gem=13.0 Hz, 1H, 4’’’’-H_eq),

1.72 (ov, 2H, 3’’’-H_eqand 5’’’-H_eq), 1.74 (bd, ²J_gem=13.0 Hz, 2H,

2

2’’’’-H_eqand 6’’’’-H_eq), 1.88 (bd, J_gem=13.4 Hz, 2H, 3’’’’-H_eq

and 5’’’’-H_eq), 2.33 (ddddd, 2×J(ax,ax)=²J_gem=12.6 Hz,

2×J(ax,eq)=3.7 Hz, 2H, 2’’’’-H_axand 6’’’’-H_ax), 3.42 (tt,

J(ax,ax)=9.6 Hz, J(ax,eq)=4.1 Hz, 1H, 1’’’-H_ax), 4.01 (tt,

2

J(ax,ax)=12.4 Hz, J(ax,eq)=4.0 Hz, 1H, 1’’’’-H_ax), 4.91 (d, J(5-

H, 5-H)=2.0 Hz, 2H, 5-H₂), 5.86 (bs, 1H, 1’-H), 6.87 (dd, J(5’’-

H, 6’’-H)=7.7 Hz, J(4’’-H, 6’’-H)=1.0 Hz, 1H, 6’’-H), 7.11 (t-

3

4.3.10 (4E)-3-cyclohexyl-2-cyclohexylimino-4-[(2,5-dimethoxy-

phenyl)methylidene]oxazolidine (3h)

4

like, 1H, 5’’-H), 7.22 (dd, ³J(5’’-H, 4’’-H)=8.0 Hz, ⁴J(6’’-H, 4’’-

H)=1.2 Hz, 1H, 4’’-H); ¹³C NMR (150 MHz, CDCl₃) δ 24.91 (C-

3’’’ and C-5’’’), 25.56 (C-4’’’’), 26.03 (C-4’’’), 26.14 (C-3’’’’

and C-5’’’’), 27.42 (C-2’’’’ and C-6’’’’), 34.78 (C-2’’’ and C-

6’’’), 53.93 (C-1’’’’), 54.35 (C-1’’’), 67.41 (C-5), 93.31 (C-1’),

125.06 (C-6’’), 126.74 (C-4’’), 126.94 (C-5’’), 130.90 (C-2’’),

133.54 (C-3’’), 137.67 (C-1’’), 140.44 (C-4), 148.62 (C-2); MS

(EI, 70 eV) m/z (%) 410 (2) [M+4]⁺≙ [C₂₂H₂₈N₂³⁷Cl³⁷ClO]⁺, 408

According to general procedure II, method A, 2-bromo-3-(2’,5’-

dimethoxyphenyl)-2-propen-1-ol (1h) (137 mg, 0.5 mmol), DCC

(103 mg, 0.5 mmol), Cu₂O (7 mg, 10 mol%) and K₃PO₄(425 mg,

2.0 mmol) were reacted in DMSO (2 mL) at 100 °C for 24 h.

Column

chromatography

on

silica

gel

(petroleum

ether:EtOAc=9:1) afforded (4E)-3-cyclohexyl-2-cyclohexyl-

imino-4-[(2,5-dimethoxyphenyl)methylidene]-oxazolidine (3h)

as a yellow oil in 72% yield (143 mg, 0.36 mmol). Under the

conditions of general procedure II, method B, 3h was obtained in

(9) [M+2]⁺

≙

[C₂₂H₂₈N₂³⁷Cl³⁵ClO]⁺, 406 (15) [M]⁺

≙

[C₂₂H₂₈N₂³⁵Cl³⁵ClO]⁺, 328 (9) [C₁₆H₁₆N₂³⁷Cl³⁷ClO]⁺, 326 (63)

[C₁₆H₁₆N₂³⁷Cl³⁵ClO]⁺, 324 (100) [C₁₆H₁₆N₂³⁵Cl³⁵ClO]⁺, 281 (7)

[C₁₃H₁₁N₂³⁵Cl³⁵ClO]⁺, 244 (17) [C₁₀H₆N₂³⁷Cl³⁷ClO]⁺, 242 (27)

[C₁₀H₆N₂³⁷Cl³⁵ClO]⁺, 240 (7) [C₁₀H₆N₂³⁵Cl³⁵ClO]⁺, 207 (9)

[C₉H₃N₂³⁵Cl³⁵Cl]⁺, 164 (14) [C₉H₇NCl]⁺, 149 (6) [C₈H₄NCl]⁺, 55

(7) [C₄H₇]⁺; HRMS (EI, M⁺) calculated for C₂₂H₂₈N₂Cl₂O

406.1574 found 406.1569.

54% yield (108 mg, 0.27 mmol); R_f

0.46 (petroleum

ether:EtOAc=9:1); IR (ATR) ν 2925, 2852, 1701, 1643, 1601,

1494, 1449, 1361, 1282, 1214, 1179, 1121, 1044, 1026, 924, 801,

718 cm^-1; UV (MeCN) λ_max(log ε) 220 (4.18), 288 (4.06), 324

(4.02) nm; ¹H NMR (600 MHz, CDCl₃) δ 1.21 (ddddd,

2×J(ax,ax)=²J_gem=12.9 Hz, 2×J(ax,eq)=3.7 Hz, 1H, 4’’’’-H_ax),

1.23 (ddddd, 2×J(ax,ax)=²J_gem=12.6 Hz, 2×J(ax,eq)=4.0 Hz, 1H,

4’’’-H_ax), 1.29 (ov, 2H, 3’’’-H_axand 5’’’-H_ax), 1.29 (ov, 2H, 2’’’-

H_axand 6’’’-H_ax), 1.39 (ddddd, 2×J(ax,ax)=²J_gem=13.3 Hz,

2×J(ax,eq)=3.7 Hz, 2H, 3’’’’-H_axand 5’’’’-H_ax), 1.55 (bd,

4.3.8 (4E)-3-cyclohexyl-2-cyclohexylimino-4-[(2-methoxy-

phenyl)methylidene]oxazolidine (3g)

²J_gem=11.6 Hz, 1H, 4’’’-H_eq), 1.67 (bd, J_gem=11.2 Hz, 2H, 2’’’-

H_eqand 6’’’-H_eq), 1.68 (bd, J_gem=12.4 Hz, 1H, 4’’’’-H_eq), 1.72

2

According to general procedure II, method A, 2-bromo-3-(2’-

methoxyphenyl)-2-propen-1-ol (1g) (121 mg, 0.5 mmol), DCC

2

14

Tetrahedron

2

(bd, J_gem=12.7 Hz, 2H, 2’’’’-H_eqand 6’’’’-H_eq), 1.72 (bd,

[C₁₁H₁₀N₂⁷⁹BrO₂]⁺, 269 (5) [C₁₁H₉N⁸¹BrO₂]⁺, 267 (5)

ACCEPTED MANUSCRIPT

²J_gem=12.6 Hz, 2H, 3’’’-H_eqand 5’’’-H_eq), 1.86 (bd, J_gem=13.5

[C₁₁H₉N⁷⁹BrO₂]⁺, 212 (8) [C₉H₇BrO]⁺, 187 (8) [C₇H₇BrO]⁺, 132

(3) [C₉H₇O]⁺, 55 (8) [C₄H₇]⁺; HRMS (EI, M⁺) calculated for

C₂₃H₃₁N₂BrO₂446.1564 found 446.1560.

2

Hz,

2H,

3’’’’-H_eq

and

5’’’’-H_eq),

2.35

(ddddd,

2×J(ax,ax)=²J_gem=12.8 Hz, 2× J(ax,eq)=3.9 Hz, 2H, 2’’’’-H_axand

6’’’’-H_ax), 3.42 (tt, J(ax,ax)=9.6 Hz, J(ax,eq)=3.8 Hz, 1H, 1’’’-

H_ax), 3.76 (s, 3H, 5’’-OMe), 3.80 (s, 3H, 2’’-OMe), 3.94 (tt,

4.3.12 (4E)-4-[(2-bromo-5-hydroxyphenyl)methylidene]-3-

2

J(ax,ax)=12.6 Hz, J(ax,eq)=4.3 Hz, 1H, 1’’’’-H_ax), 4.96 (d, J(5-

cyclohexyl-2-cyclohexyliminooxazolidine (3j)

H, 5-H)=2.2 Hz, 2H, 5-H₂), 5.84 (bs, 1H, 1’-H), 6.46 (d, ⁴J(4’’-H,

According to general procedure II, method A, 2-bromo-3-(2’-

bromo-5’-hydroxyphenyl)-2-propen-1-ol (1j) (153 mg, 0.5

mmol), DCC (103 mg, 0.5 mmol), Cu₂O (7 mg, 10 mol%) and

K₃PO₄(425 mg, 2.0 mmol) were reacted in DMSO (2 mL) at 100

°C for 24 h. Column chromatography on silica gel (petroleum

ether:EtOAc=7:1) afforded (4E)-4-[(2-bromo-5-hydroxyphenyl)-

methylidene]-3-cyclohexyl-2-cyclohexylimino-oxazolidine (3j)

as a yellow oil in 70% yield (151 mg, 0.35 mmol). Under the

conditions of general procedure II, method B, 3j was obtained in

3

6’’-H)=3.0 Hz, 1H, 6’’-H), 6.63 (dd, J(3’’-H, 4’’-H)=8.8 Hz,

⁴J(6’’-H, 4’’-H)=2.9, 1H, 4’’-H), 6.78 (d, J(4’’-H, 3’’-H)=8.8

3

Hz, 1H, 3’’-H); ¹³C NMR (150 MHz, CDCl₃) δ 24.94 (C-3’’’ and

C-5’’’), 25.59 (C-4’’’’), 26.08 (C-4’’’), 26.20 (C-3’’’’ and C-

5’’’’), 27.52 (C-2’’’’ and C-6’’’’), 34.86 (C-2’’’ and C-6’’’),

53.71 (C-1’’’’), 54.26 (C-1’’’), 55.68 (5’’-OMe), 56.34 (2’’-

OMe), 67.81 (C-5), 90.60 (C-1’), 109.89 (C-4’’), 111.67 (C-3’’),

113.34 (C-6’’), 127.46 (C-1’’), 138.41 (C-4), 148.95 (C-2),

150.50 (C-2’’), 153.57 (C-5’’); MS (EI, 70 eV) m/z (%) 398 (55)

[M]⁺≙ [C₂₄H₃₄N₂O₃]⁺, 316 (85) [C₁₈H₂₃N₂O₃]⁺, 285 (11)

[C₁₆H₁₇N₂O₃]⁺, 234 (13) [C₁₂H₁₃N₂O₃]⁺, 197 (8) [C₁₂H₉N₂O]⁺,

183 (72) [C₁₁H₇N₂O]⁺, 162 (100) [C₁₀H₁₀O₂]⁺, 147 (78)

[C₉H₁₀NO]⁺, 84 (37) [C₃H₄N₂O]⁺; HRMS (EI, M⁺) calculated for

C₂₄H₃₄N₂O₃398.2564 found 398.2574.

45% yield (97 mg, 0.23 mmol); R_f

0.34 (petroleum

ether:EtOAc=7:1); IR (ATR) ν 2928, 2853, 1638, 1559, 1448,

1367, 1334, 1299, 1258, 1214, 1167, 1059, 889, 810, 731 cm^-1;

1

UV (MeCN) λ_max(log ε) 302 (4.21) nm; H NMR (600 MHz,

CDCl₃) δ 1.17 (ddddd, 2×J(ax,ax)=²J_gem=13.2 Hz, 2×J(ax,eq)=3.3

Hz, 1H, 4’’’’-H_ax), 1.20 (ov, 1H, 4’’’-H_ax), 1.30 (ov, 2H, 3’’’-H_ax

and 5’’’-H_ax), 1.32 (ov, 2H, 2’’’-H_axand 6’’’-H_ax), 1.32 (ddddd,

2×J(ax,ax)=²J_gem=13.6 Hz, 2× J(ax,eq)=3.4 Hz, 2H, 3’’’’-H_axand

4.3.11 (4E)-4-[(3-bromo-4-methoxyphenyl)methylidene]-3-

cyclohexyl-2-cyclohexyliminooxazolidine (3i)

2

5’’’’-H_ax), 1.57 (bd, J_gem=12.7 Hz, 1H, 4’’’-H_eq), 1.65 (bd,

²J_gem=12.6 Hz, 1H, 4’’’’-H_eq), 1.71 (bd, J_gem=12.5 Hz, 2H, 2’’’’-

2

According to general procedure II, method A, 2-bromo-3-(3’-

bromo-4’-methoxyphenyl)-2-propen-1-ol (1i) (160 mg, 0.5

mmol), DCC (103 mg, 0.5 mmol), Cu₂O (7 mg, 10 mol%) and

K₃PO₄(425 mg, 2.0 mmol) were reacted in DMSO (2 mL) at 100

°C for 24 h. Column chromatography on silica gel (petroleum

ether:EtOAc=7:1) afforded (4E)-4-[(3-bromo-4-methoxyphenyl)-

methylidene]-3-cyclohexyl-2-cyclohexylimino-oxazolidine (3i)

as a yellow oil in 56% yield (125 mg, 0.28 mmol). Under the

conditions of general procedure II, method B, 3i was obtained in

H_eqand 6’’’’-H_eq), 1.71 (ov, 2H, 2’’’-H_eqand 6’’’-H_eq), 1.73 (ov,

2

2H, 3’’’-H_eqand 5’’’-H_eq), 1.83 (bd, J_gem=13.5 Hz, 2H, 3’’’’-H_eq

and 5’’’’-H_eq), 2.29 (ddddd, 2×J(ax,ax)=²J_gem=13.1 Hz, 2×

J(ax,eq)=3.7 Hz, 2H, 2’’’’-H_axand 6’’’’-H_ax), 3.45 (tt,

J(ax,ax)=9.6 Hz, J(ax,eq)=4.0 Hz, 1H, 1’’’-H_ax), 4.07 (tt,

J(ax,ax)=12.6 Hz, J(ax,eq)=3.3 Hz, 1H, 1’’’’-H_ax), 4.95 (bs, 2H,

4

5-H₂), 5.90 (bs, 1H, 1’-H), 6.49 (d, J(4’’-H, 6’’-H)=2.9 Hz, 1H,

3

4

6’’-H), 6.54 (dd, J(3’’-H, 4’’-H)=8.5 Hz, J(6’’-H, 4’’-H)=2.9

Hz, 1H, 4’’-H), 7.38 (d, ³J(4’’-H, 3’’-H)=8.6 Hz, 1H, 3’’-H); ¹³

C

29% yield (65 mg, 0.15 mmol); R_f

0.34 (petroleum

NMR (150 MHz, CDCl₃) δ 25.16 (C-3’’’ and C-5’’’), 25.48 (C-

4’’’), 25.83 (C-4’’’’), 25.92 (C-3’’’’ and C-5’’’’), 27.57 (C-2’’’’

and C-6’’’’), 34.65 (C-2’’’ and C-6’’’), 53.95 (C-1’’’’), 54.92 (C-

1’’’), 67.63 (C-5), 97.48 (C-1’), 113.99 (C-4’’), 114.22 (C-2’’),

114.26 (C-6’’), 133.53 (C-3’’), 137.52 (C-1’’), 138.44 (C-4),

150.77 (C-2), 155.80 (C-5’’); MS (EI, 70 eV) m/z (%) 434 (23)

[M+2]⁺≙ [C₂₂H₂₉⁸¹BrN₂O₂]⁺, 432 (24) [M]⁺≙ [C₂₂H₂₉⁷⁹BrN₂O₂]⁺,

352 (98) [C₁₆H₁₈⁸¹BrN₂O₂]⁺, 350 (100) [C₁₆H₁₈⁷⁹BrN₂O₂]⁺, 311

(12) [C₁₃H₁₃⁸¹BrN₂O₂]⁺, 309 (12) [C₁₃H₁₃⁷⁹BrN₂O₂]⁺, 228 (17)

[C₉H₇BrO₂]⁺, 189 (20) [C₁₀H₈N₂O₂]⁺, 173 (8) [C₁₀H₇NO₂]⁺, 146

(40) [C₉H₆O₂]⁺, 82 (7) [C₃H₂N₂O]⁺, 55 (13) [C₄H₈]⁺; HRMS (EI,

M⁺) calculated for C₂₂H₂₉BrN₂O₂432.1412 found 432.1415.

ether:EtOAc=7:1); IR (ATR) ν 2925, 2851, 1701, 1643, 1496,

1448, 1392, 1346, 1255, 1226, 1183, 1050, 1018, 907, 890, 813,

729, 698 cm^-1; UV (MeCN) λ_max(log ε) 203 (4.20), 297 (4.08)

nm; ¹H NMR (500 MHz, CDCl₃)

δ

1.21 (ddddd,

2×J(ax,ax)=²J_gem=13.2 Hz, 2×J(ax,eq)=3.4 Hz, 1H, 4’’’’-H_ax),

1.24 (ddddd, 2×J(ax,ax)=²J_gem=12.7 Hz, 2×J(ax,eq)=3.6 Hz, 1H,

4’’’-H_ax),

1.29

(ddddd,

2×J(ax,ax)=²J_gem=12.5

Hz,

2×J(ax,eq)=3.9 Hz, 2H, 3’’’-H_axand 5’’’-H_ax), 1.30 (ddddd,

2×J(ax,ax)=²J_gem=11.4 Hz, 2×J(ax,eq)=3.1 Hz, 2H, 2’’’-H_axand

6’’’-H_ax), 1.43 (bs, 2H, 3’’’’-H_axand 5’’’’-H_ax), 1.56 (bd,

²J_gem=10.3 Hz, 1H, 4’’’-H_eq), 1.62 (bs, 1H, 4’’’’-H_eq), 1.68 (d-

2

like, J_gem=10.1 Hz, 2H, 2’’’-H_eqand 6’’’-H_eq), 1.70 (bd,

²J_gem=12.6 Hz, 2H, 2’’’’-H_eqand 6’’’’-H_eq), 1.73 (d-like, ²J_gem=9.5

Hz, 2H, 3’’’-H_eqand 5’’’-H_eq), 1.85 (bd, ²J_gem=13.6 Hz, 2H, 3’’’’-

H_eqand 5’’’’-H_eq), 2.31 (ddddd, 2×J(ax,ax)=²J_gem=12.8 Hz,

2×J(ax,eq)=3.8 Hz, 2H, 2’’’’-H_axand 6’’’’-H_ax), 3.42 (tt,

J(ax,ax)=9.6 Hz, J(ax,eq)=3.9 Hz, 1H, 1’’’-H_ax), 3.88 (s, 3H, 4’’-

OMe), 3.87 (ov, 1H, 1’’’’-H_ax), 4.96 (d, ²J(5-H, 5-H)=2.1 Hz, 2H,

4.3.13 (4E)-4-[(3-bromo-4-dimethylaminophenyl)methylidene]-

3-cyclohexyl-2-cyclohexyliminooxazolidine (3k)

According to general procedure II, method A, 2-bromo-3-(3’-

bromo-4’-(dimethylamino)phenyl)-2-propen-1-ol (1k) (167 mg,

0.5 mmol), DCC (103 mg, 0.5 mmol), Cu₂O (7 mg, 10 mol%)

and K₃PO₄(425 mg, 2.0 mmol) were reacted in DMSO (2 mL) at

100 °C for 24 h. Column chromatography on silica gel

(petroleum ether:EtOAc=9:1) afforded (4E)-4-[(3-bromo-4-

dimethylaminophenyl)methylidene]-3-cyclohexyl-2-cyclohexyl-

iminooxazolidine (3k) as a yellow oil in 49% yield (113 mg, 0.25

mmol). Under the conditions of general procedure II, method B,

3k was obtained in 37% yield (85 mg, 0.19 mmol); R_f0.63

(petroleum ether:EtOAc=9:1); IR (ATR) ν 2924, 2851, 2779,

1702, 1641, 1495, 1449, 1391, 1343, 1302, 1257, 1226, 1190,

1048, 946, 729 cm^-1; UV (MeCN) λ_max(log ε) 212 (4.17), 309

(4.44) nm; ¹H NMR (600 MHz, CDCl₃) δ 1.20 (ddddd,

2×J(ax,ax)=²J_gem=13.1 Hz, 2× J(ax,eq)=3.6 Hz, 1H, 4’’’’-H_ax),

3

5-H₂), 5.52 (bs, 1H, 1’-H), 6.83 (d, J(6’’-H, 5’’-H)=8.5 Hz, 1H,

3

4

5’’-H), 6.88 (dd, J(5’’-H, 6’’-H)=8.5 Hz, J(2’’-H, 6’’-H)=2.1

Hz, 1H, 6’’-H), 7.22 (d, ⁴J(6’’-H, 2’’-H)=2.2 Hz, 2H, 2’’-H); ¹³

C

NMR (75 MHz, CDCl₃) δ 24.89 (C-3’’’ and C-5’’’), 25.53 (C-

4’’’’), 26.07 (C-4’’’), 26.18 (C-3’’’’ and C-5’’’’), 27.59 (C-2’’’’

and C-6’’’’), 34.82 (C-2’’’ and C-6’’’), 53.74 (C-1’’’’), 54.27 (C-

1’’’), 56.32 (4’’-OMe), 67.63 (C-5), 94.04 (C-1’), 111.90 (C-3’’),

112.14 (C-5’’), 126.23 (C-6’’), 131.52 (C-2’’), 131.71 (C-1’’),

137.93 (C-4), 148.53 (C-2), 152.99 (C-4’’); MS (EI, 70 eV) m/z

(%) 448 (32) [M+2]⁺≙ [C₂₃H₃₁N₂⁸¹BrO₂]⁺, 446 (33) [M]⁺≙

[C₂₃H₃₁N₂⁷⁹BrO₂]⁺, 366 (98) [C₁₇H₂₀N₂⁸¹BrO₂]⁺, 364 (100)

[C₁₇H₂₀N₂⁷⁹BrO₂]⁺, 325 (9) [C₁₄H₁₅N₂⁸¹BrO₂]⁺, 323 (9)

[C₁₄H₁₅N₂⁷⁹BrO₂]⁺, 284 (29) [C₁₁H₁₀N₂⁸¹BrO₂]⁺, 282 (32)

15

1.23 (ddddd, 2×J(ax,ax)=²J_gem=12.2 Hz, 2× J(ax,eq)=3.4 Hz, 1H,

126.93 (C-4’’), 129.72 (C-5’’), 133.47 (C-3’’), 136.02 (C-2’’),

ACCEPTED MANUSCRIPT

4’’’-H_ax), 1.30 (ov, 2H, 3’’’-H_axand 5’’’-H_ax), 1.30 (ov, 2H, 2’’’-

H_axand 6’’’-H_ax), 1.37 (ddddd, 2×J(ax,ax)=²J_gem=13.4 Hz, 2×

J(ax,eq)=3.4 Hz, 2H, 3’’’’-H_axand 5’’’’-H_ax), 1.56 (bd,

152.87 (C-4), 161.83 (C-2); MS (EI, 70 eV) m/z (%) 424 (3)

[M+2]⁺[C₂₀H₂₇⁸¹BrN₂OS]⁺, [M]⁺

422 (3)

≙

[C₂₀H₂₇⁷⁹BrN₂OS]⁺, 390 (3) [C₁₈H₂₀BrN₂OS]⁺, 360 (10)

[C₁₆H₁₃⁸¹BrN₂OS]⁺, 358 (100) [C₁₆H₁₃⁷⁹BrN₂OS]⁺, 344 (27)

[C₁₄H₁₈⁸¹BrN₂OS]⁺, 342 (10) [C₁₄H₁₈⁷⁹BrN₂OS]⁺, 276 (87)

[C₁₅H₁₈N₂OS]⁺, 262 (75) [C₁₄H₁₇N₂OS]⁺, 219 (7) [C₇H₆BrOS]⁺,

194 (89) [C₉H₈N₂OS]⁺, 180 (27) [C₈H₇N₂OS]⁺, 136 (7)

[C₇H₆OS]⁺, 123 (24) [C₇H₆S]⁺, 83 (3) [C₄H₃S]⁺; HRMS (EI, M⁺)

calculated for C₂₀H₂₇BrN₂OS 422.1022 found 422.1037.

2

²J_gem=12.0 Hz, 1H, 4’’’-H_eq), 1.68 (bd, J_gem=12.6 Hz, 1H, 4’’’’-

2

H_eq), 1.68 (d-like, J_gem=9.8 Hz, 2H, 2’’’-H_eqand 6’’’-H_eq), 1.73

2

(d-like, J_gem=9.2 Hz, 2H, 2’’’’-H_eqand 6’’’’-H_eq), 1.86 (bd,

²J_gem=13.4 Hz, 2H, 3’’’’-H_eqand 5’’’’-H_eq), 2.32 (ddddd,

2×J(ax,ax)=²J_gem=12.7 Hz, 2× J(ax,eq)=3.7 Hz, 2H, 2’’’’-H_axand

6’’’’-H_ax), 2.78 (s, 6H, NMe₂), 3.42 (tt, J(ax,ax)=9.4 Hz,

J(ax,eq)=3.8 Hz, 1H, 1’’’-H_ax), 3.87 (tt, J(ax,ax)=12.4 Hz,

2

J(ax,eq)=3.8 Hz, 1H, 1’’’’-H_ax), 4.98 (d, J(5-H, 5-H)=2.2 Hz,

3

2H, 5-H₂), 5.51 (bs, 1H, 1’-H), 6.87 (dd, J(5’’-H, 6’’-H) =8.4

4

3

4.3.15 (4E)-4-[butylmethylidene]-3-cyclohexyl-2-cyclohexyl-

iminooxazolidine (3m)

Hz, J(2’’-H, 6’’-H) =2.2 Hz, 1H, 6’’-H), 7.00 (d, J(6’’-H, 5’’-

4

H)=8.4 Hz, 1H, 5’’-H), 7.23 (d, J(6’’-H, 2’’-H) =2.1 Hz, 1H,

2’’-H); ¹³C NMR (75 MHz, CDCl₃) δ 24.88 (C-3’’’ and C-5’’’),

25.53 (C-4’’’’), 26.07 (C-4’’’), 26.19 (C-3’’’’ and C-5’’’’), 27.59

(C-2’’’’ and C-6’’’’), 34.81 (C-2’’’ and C-6’’’), 44.34 (NMe₂)

53.78 (C-1’’’’), 54.28 (C-1’’’), 67.73 (C-5), 94.19 (C-1’), 119.45

(C-3’’), 120.44 (C-5’’), 125.76 (C-6’’), 131.89 (C-2’’), 133.72

(C-1’’), 138.24 (C-4), 148.36 (C-2), 148.50 (C-4’’); MS (EI, 70

eV) m/z (%) 461 (73) [M+2]⁺≙ [C₂₄H₃₄⁸¹BrN₃O]⁺, 459 (73) [M]⁺

≙ [C₂₄H₃₄⁷⁹BrN₃O]⁺, 379 (100) [C₁₈H₂₃⁸¹BrN₃O]⁺, 377 (100)

[C₁₈H₂₃⁷⁹BrN₃O]⁺, 336 (8) [C₁₅H₁₈BrN₃O]⁺, 253 (6)

[C₁₁H₁₂BrNO]⁺, 225 (21) [C₁₀H₁₁BrN]⁺, 172 (6) [C₁₁H₁₂N₂]⁺, 143

(4) [C₁₀H₉N]⁺, 101 (6) [C₇H₃N]⁺, 83 (8) [C₅H₉N]⁺, 55 (10)

[C₄H₈]⁺; HRMS (EI, M⁺) calculated for C₂₄H₃₄BrN₃O 459.1880

found 459.1884.

According to general procedure II, method A, 2-bromo-2-hepten-

1-ol (1m) (95 mg, 0.5 mmol), DCC (103 mg, 0.5 mmol), Cu₂O (7

mg, 10 mol%) and K₃PO₄(425 mg, 2.0 mmol) were reacted in

DMSO (2 mL) at 100 °C for 24 h. Column chromatography on

silica gel (petroleum ether:EtOAc=9:1) afforded (4E)-4-

[buthylmethylidene]-3-cyclohexyl-2-cyclohexyliminooxazolidine

(3m) as a yellow oil in 75% yield (119 mg, 0.38 mmol). Under

the conditions of general procedure II, method B, 3m was

obtained in 50% yield (80 mg, 0.25 mmol); R_f0.51 (petroleum

ether:EtOAc=9:1); IR (ATR) ν 2926, 2853, 1672, 1559, 1449,

1376, 1344, 1257, 1222, 1051, 891, 844, 758 cm^-1; UV (MeCN)

1

λ_max(log ε) no UV-absorption; H NMR (500 MHz, CDCl₃) δ

0.88 (m, 3H, 5’-H₃), 0.90 (ov, 1H, 4’’-H_ax), 1.15 (ddddd,

2×J(ax,ax)=²J_gem=12.6 Hz, 2× J(ax,eq)=3.8 Hz, 1H, 4’’’-H_ax),

1.25 (ov, 2H, 4’-H₂), 1.26 (ov, 2H, 3’’-H_axand 5’’-H_ax), 1.31 (ov,

2H, 2’’-H_axand 6’’-H_ax), 1.34 (ddddd, 2×J(ax,ax)=²J_gem=13.4 Hz,

2× J(ax,eq)=3.4 Hz, 2H, 3’’’-H_axand 5’’’-H_ax), 1.34 (ov, 2H, 3’-

H₂), 1.55 (d, ²J_gem=11.2 Hz, 1H, 4’’-H_eq), 1.62 (bd, ²J_gem=12.8 Hz,

2H, 2’’’-H_eqand 6’’’-H_eq), 1.64 (ov, 1H, 4’’’-H_eq), 1.68 (d-like,

4.3.14 (4E)-4-[(5-bromothiophen-2-yl)methylidene]-3-

cyclohexyl-2-cyclohexyliminooxazolidine (3l)

According to general procedure II, method A, 2-bromo-3-(5’-

bromothiophenyl)-2-propen-1-ol (1l) (148 mg, 0.5 mmol), DCC

(103 mg, 0.5 mmol), Cu₂O (7 mg, 10 mol%) and K₃PO₄(425 mg,

2.0 mmol) were reacted in DMSO (2 mL) at 100 °C for 24 h.

2

²J_gem=12.3 Hz, 2H, 2’’-H_eqand 6’’-H_eq), 1.72 (d-like, J_gem=11.6

2

Hz, 2H, 3’’-H_eqand 5’’-H_eq), 1.80 (bd, J_gem=13.8 Hz, 2H, 3’’’-

H_eqand 5’’’-H_eq), 1.84 (ov, 2H, 2’-H₂), 2.17 (ddddd,

2×J(ax,ax)=²J_gem=12.1 Hz, 2×J(ax,eq)=3.5 Hz, 2H, 2’’’-H_axand

6’’’-H_ax), 3.37 (tt, J(ax,ax)=9.4 Hz, J(ax,eq)=3.9 Hz, 1H, 1’’-

H_ax), 3.78 (tt, J(ax,ax)=12.3 Hz, J(ax,eq)=4.1 Hz, 1H, 1’’’-H_ax),

4.17 (t-like, 1H, 1’-H), 4.68 (bs, 2H, 5-H₂); ¹³C NMR (75 MHz,

CDCl₃) δ 13.86 (C-5’), 22.36 (C-4’), 24.69 (C-4’’’), 25.70 (C-3’’

and C-5’’), 25.94 (C-4’’), 26.11 (C-3’’’ and C-5’’’), 28.39 (C-

2’’’ and C-6’’’), 29.61 (C-2’), 31.31 (C-3’), 35.68 (C-2’’ and C-

6’’), 52.49 (C-1’’’), 54.71 (C-1’’), 66.60 (C-5), 93.31 (C-1’),

134.82 (C-4), 150.21 (C-2); MS (EI, 70 eV) m/z (%) 318 (29)

Column

ether:EtOAc=9:1)

yl)methylidene]-3-cyclohexyl-2-cyclohexyliminooxazolidine (3l)

as a yellow oil in 24% yield (51 mg, 0.12 mmol). Under the

conditions of general procedure II, method B, 3l was obtained in

chromatography

afforded

on

silica

gel

(petroleum

(4E)-4-[(5-bromothiophen-2-

14% yield (30 mg, 0.07 mmol); R_f

0.70 (petroleum

ether:EtOAc=9:1); IR (ATR) ν 2928, 2854, 1744, 1698, 1626,

1411, 1376, 1346, 1300, 1259, 1172, 1113, 1047, 989, 894, 774,

728, 698 cm^-1; UV (MeCN) λ_max(log ε) 259 (3.79), 355 (4.08)

[M]⁺

≙

[C₂₀H₃₄N₂O]⁺, 275 (19) [C₁₇H₂₇N₂O]⁺, 236 (42)

nm; ¹H NMR (500 MHz, CDCl₃)

δ

1.01 (ddddd,

[C₁₄H₂₃N₂O]⁺, 207 (19) [C₁₂H₁₉N₂O]⁺, 193 (100) [C₁₁H₁₇N₂O]⁺,

180 (71) [C₁₀H₁₆N₂O]⁺, 154 (12) [C₈H₁₃N₂O]⁺, 125 (15)

[C₈H₁₃O]⁺, 111 (25) [C₇H₁₁O]⁺, 95 (31) [C₇H₁₁]⁺, 67 (26) [C₅H₇]⁺;

HRMS (EI, M⁺) calculated for C₂₀H₃₄N₂O 318.2666 found

318.2636.

2×J(ax,ax)=²J_gem=13.1 Hz, 2× J(ax,eq)=3.4 Hz, 1H, 4’’’’-H_ax),

1.23 (ov, 1H, 4’’’-H_ax), 1.30 (ov, 2H, 3’’’-H_axand 5’’’-H_ax), 1.30

(ov, 2H, 2’’’-H_axand 6’’’-H_ax), 1.36 (ov, 2H, 3’’’’-H_axand 5’’’’-

H_ax), 1.55 (bd, J(eq,eq)=12.6 Hz, 1H, 4’’’’-H_eq),1.56 (bd,

²J_gem=12.2 Hz, 1H, 4’’’-H_eq), 1.69 (bd, J_gem=11.3 Hz, 2H, 2’’’-

2

H_eqand 6’’’-H_eq), 1.73 (d-like, J_gem=13.5 Hz, 2H, 3’’’-H_eqand

5’’’-H_eq), 1.77 (bd, J_gem=11.4 Hz, 2H, 3’’’’-H_eqand 5’’’’-H_eq),

4.3.16 (4E)-3-cyclohexyl-2-cyclohexylimino-5-methyl-4-[phenyl-

methylidene]oxazolidine (3n)

2

1.82 (d-like, J_gem=12.8 Hz, 2H, 2’’’’-H_eqand 6’’’’-H_eq), 2.17

(ddddd, 2×J(ax,ax)=²J_gem=12.6 Hz, 2× J(ax,eq)=3.7 Hz, 2H, 2’’’’-

H_axand 6’’’’-H_ax), 3.85 (t-like, J(ax,ax)=12.2 Hz, 1H, 1’’’-H_ax),

4.02 (tt, J(ax,ax)=12.4 Hz, J(ax,eq)=4.0 Hz, 1H, 1’’’’-H_ax), 4.99

According to general procedure II, method A, 3-bromo-4-phenyl-

3-buten-2-ol (1n) (114 mg, 0.5 mmol), DCC (103 mg, 0.5 mmol),

Cu₂O (7 mg, 10 mol%) and K₃PO₄(425 mg, 2.0 mmol) were

reacted in DMSO (2 mL) at 100 °C for 24 h. Column

chromatography on silica gel (petroleum ether:EtOAc=9:1)

2

(d, J(5-H, 5-H)=2.2 Hz, 2H, 5-H₂), 6.64 (bs, 1H, 1’-H), 7.06 (d,

³J(3’’-H, 4’’-H)=3.7 Hz, 1H, 4’’-H), 7.51 (d, ³J(4’’-H, 3’’-

H)=3.8 Hz, 1H, 3’’-H); ¹³C NMR (75 MHz, CDCl₃) δ 25.29 (C-

4’’’’), 25.95 (C-3’’’’ and C-5’’’’), 26.21 (C-4’’’), 26.93 (C-3’’’

and C-5’’’), 29.49 (C-2’’’ and C-6’’’), 29.72 (C-2’’’’ and C-

6’’’’), 51.53 (C-1’’’’), 53.21 (C-1’’’), 68.00 (C-5), 109.58 (C-1’),

afforded

(4E)-3-cyclohexyl-2-cyclohexylimino-5-methyl-4-

[phenylmethylidene]oxazolidine (3n) as a yellow oil in 58%

yield (102 mg, 0.29 mmol). Under the conditions of general

procedure II, method B, 3n was obtained in 38% yield (67 mg,

0.19 mmol); R_f0.75 (petroleum ether:EtOAc=9:1); IR (ATR) ν

16

Tetrahedron

(d) Keller M, Miller AD. Bioorg Med Chem. 2001;11:

2927, 2853, 1698, 1644, 1597, 1558, 1448, 1370, 1256, 1229,

ACCEPTED MANUSCRIPT

1185, 1028, 909, 893, 729, 697 cm^-1; UV (MeCN) λ_max(log ε)

297 (3.89) nm; ¹H NMR (600 MHz, CDCl₃) δ 1.19 (ddddd,

2×J(ax,ax)=²J_gem=12.7 Hz, 2× J(ax,eq)=3.3 Hz, 1H, 4’’’’-H_ax),

1.23 (ddddd, 2×J(ax,ax)=²J_gem=11.6 Hz, 2× J(ax, eq)=3.4 Hz, 1H,

857–859;

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2002;43:2303-2306;

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1775.

3

4’’’-H_ax), 1.28 (d-like, J(5-H, 5-Me)=6.3 Hz, 3H, 5-Me), 1.29

3

(a) Sundarapandiyan S, Brutto PE, Siddhartha G, Ramesh

(ov, 2H, 3’’’-H_axand 5’’’-H_ax), 1.29 (ov, 2H, 2’’’-H_axand 6’’’-

R, Ramanaiah B, Saravanan P. J Hazmat. 2011;190:802

–

H_ax), 1.38 (ddddd, 2×J(ax,ax)=²J_gem=13.2 Hz, 2× J(ax,eq)=3.3 Hz,

809;

2

2H, 3’’’’-H_axand 5’’’’-H_ax), 1.56 (bd, J_gem=12.0 Hz, 1H, 4’’’-

(b) Musa AE, Gasmelseed GA. Int J Adv Ind Eng. 2013;1:

2

H_eq), 1.68 (d-like, J_gem=11.5 Hz, 2H, 2’’’’-H_eqand 6’’’’-H_eq),

9–15.

1.69 (ov, 1H, 4’’’’-H_eq), 1.70 (d-like, ²J_gem=11.7 Hz, 2H, 2’’’-H_eq

4

5

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2

and 6’’’-H_eq), 1.73 (d-like, J_gem=9.0 Hz, 2H, 3’’’-H_eqand 5’’’-

2

H_eq), 1.85 (bd, J_gem=11.4 Hz, 2H, 3’’’’-H_eqand 5’’’’-H_eq), 2.35

(ddddd, 2×J(ax,ax)=²J_gem=13.1 Hz, 2× J(ax,eq)=3.5 Hz, 2H, 2’’’’-

H_axand 6’’’’-H_ax), 3.41 (tt, J(ax,ax)=9.3 Hz, J(ax,eq)=3.4 Hz,

1H, 1’’’-H_ax), 3.88 (tt, J(ax,ax)=12.4 Hz, J(ax,eq)=3.2 Hz, 1H,

1’’’’-H_ax), 5.51 (q, ³J(5-Me, 5-H)=6.1 Hz, 1H, 5-H), 5.59 (bs, 1H,

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1’-H), 7.09 (t-like, 1H, 4’’-H), 7.12 (d, J(3’’-H, 2’’-H) and

³J(5’’-H, 6’’-H)=7.6 Hz, 2H, 2’’-H and 6’’-H), 7.27 (t-like, 2H,

3’’-H and 5’’-H); ¹³C NMR (150 MHz, CDCl₃) δ 24.95 (C-3’’’

and C-5’’’), 25.56 (C-4’’’’), 26.11 (C-4’’’), 26.23 (d, ⁷J(Me-5, C-

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1460;

7

3’’’’) and J(Me-5, C-5’’’’) =8.8 Hz, C-3’’’’ and C-5’’’’), 27.65

(d, ⁶J(Me-5, C-2’’’’) and ⁶J(Me-5, C-6’’’’) =13.8 Hz, C-2’’’’ and

2008;108:3054–3131;

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7

–

C-6’’’’), 34.83 (d, J(Me-5, C-2’’’) and J(Me-5, C-6’’’) =6.1

Hz, C-2’’’ and C-6’’’), 53.54 (C-1’’’’), 54.18 (C-1’’’), 74.43 (C-

5), 95.49 (C-1’), 124.81 (C-4’’), 127.51 (C-2’’ and C-6’’),

128.53 (C-3’’ and C-5’’), 137.13 (C-1’’), 143.23 (C-4), 148.30

(C-2); MS (EI, 70 eV) m/z (%) 352 (25) [M]⁺≙ [C₂₃H₃₂N₂O]⁺,

270 (100) [C₁₇H₂₂N₂O]⁺, 227 (11) [C₁₄H₁₅N₂O]⁺, 197 (22)

[C₁₂H₉N₂O]⁺, 145 (7) [C₁₀H₉O]⁺, 105 (9) [C₆H₄NO]⁺, 55 (7)

[C₄H₈]⁺; HRMS (EI, M⁺) calculated for C₂₃H₃₂N₂O 352.2510

found 352.2522.

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Acknowledgements

We thank Mr. Mario Wolf (Institut für Chemie, Universität

Hohenheim) for recording NMR spectra and Mr. Joachim

Trinkner (Institut für Organische Chemie, Universität Stuttgart),

Dr. Alevtina Mikhael and Dr. Christina Braunberger (Institut für

Chemie, Universität Hohenheim) for recording ESI MS and EI

MS spectra.

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ACCEPTED MANUSCRIPT

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Tetrahedron

ACCEPTED MANUSCRIPT

Article Doi

Formation of substituted 2-iminooxazolidines via intermolecular 1,2-addition/intramolecular N-vinylation using 3-substituted-2-bromo-2-propen-1-ols as substrates

DOI: 10.1016/j.tet.2018.08.051

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