Selective synthesis of spiro and dispiro compounds using Mn(III)-based oxidation of tetracarbonyl compounds

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Selective synthesis of spiro and dispiro compounds using Mn(III)-based oxidation of

tetracarbonyl compounds

Suzuka Yokote, Satomi Nishikawa, Keisuke Shibuya, Kazuki Hisano, Hiroshi Nishino

PII:

S0040-4020(20)30300-8

https://doi.org/10.1016/j.tet.2020.131165

TET 131165

DOI:

Reference:

To appear in: Tetrahedron

Received Date: 4 March 2020

Revised Date: 26 March 2020

Accepted Date: 30 March 2020

Please cite this article as: Yokote S, Nishikawa S, Shibuya K, Hisano K, Nishino H, Selective synthesis

of spiro and dispiro compounds using Mn(III)-based oxidation of tetracarbonyl compounds, Tetrahedron

(2020), doi: https://doi.org/10.1016/j.tet.2020.131165.

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Selective synthesis of spiro and dispiro

compounds using Mn(III)-based oxidation of

tetracarbonyl compounds

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Suzuka Yokote, Satomi Nishikawa, Keisuke Shibuya, Kazuki Hisano, and Hiroshi Nishino*

Department of Chemistry, Graduate School of Science, Kumamoto University, Kurokami 2-39-1, Chûou-Ku,

Kumamoto 860-8555, Japan

1

Tetrahedron

journal homepage: www.elsevier.com

Selective synthesis of spiro and dispiro compounds using Mn(III)-based

oxidation of tetracarbonyl compounds

Suzuka Yokote, Satomi Nishikawa, Keisuke Shibuya, Kazuki Hisano and Hiroshi Nishino

Department of Chemistry, Graduate School of Science, Kumamoto University, Kurokami 2-39-1, Chûou-Ku, Kumamoto 860-8555, Japan

ARTICLE INFO

ABSTRACT

Article history:

Received

Received in revised form

Accepted

The

Mn(III)-based

oxidation

of

methylenebis(cyclohexanedione)s

and

methylenebis(piperidinedione)s as a tetracarbonyl compound was investigated under various

conditions, selectively producing spiro dihydrofurans and dispiro cyclopropanes depending on

the solvent. The mechanism for the formation of the spiro dihydrofurans and dispiro

cyclopropanes was discussed. In addition, a simple synthesis of a new type of alkaloid,

3,4,6,7,8,10-hexahydro-1H-pyrano[3,2-c:5,6-c']dipyridine-1,9(2H)-diones, was demonstrated.

Available online

Keywords:

Spiro dihydrofurans

.

Dispiro cyclopropanes

Methylenebis(cyclohexanedione)s

Methylenebis(piperidinedione)s

Pyranodipyridinediones

Manganese(III) oxidation

———

Corresponding author. Tel.: +81-96-342-3374; fax: +81-96-342-3374; e-mail: nishino@kumamoto-u.ac.jp

2

Tetrahedron

aldehydes. In general, spiro compounds bearing two rings linked

together by one common atom are structurally very interesting

because the spiro-atom is a quaternary carbon and the two rings

are often perpendicular so that some spiro compounds display an

axial chirality.¹⁰Furthermore, the heterocyclic spiro compounds

including the spiro-dihydrofuranyl scaffold are found in various

natural products as a significant unit.¹¹Therefore, it must be very

useful in organic chemistry to more simply and efficiently

synthesize the spiro compounds, thus we commenced to develop

the synthesis using our new technique in order to evaluate its

possibility and usefulness as an oxidative radical promoter of

manganese(III) acetate dihydrate, Mn(OAc)₃•2H₂O. The

Mn(OAc)₃•2H₂O as a single-electron transfer oxidant is stable in

air and easy to prepare on a large scale from an inexpensive

material,¹²so that it is a very useful and convenient oxidant.

Furthermore, we recently found the activation effect of the

Mn(III)-based reaction by adding formic acid.^13,10lWe now

describe the results in detail.

2. Results and discussion

2.1. Reaction of methylenebis(cyclohexanedione)s 1a-q

1. Introduction

The

reaction

of

phenyl-substituted

Polycarbonyl compounds are important and convenient

building blocks in organic synthesis, especially for the Mn(III)-

based reaction, to induce the oxidative tandem cyclization that

produces heterocyclic compounds.¹We recently reported that the

reaction of tricarbonyl compounds, such as 3-acetylpentane-1,4-

diones, 2-acetyl-4-oxobutanoates, and 2-(2-oxoethyl)malonates,

methylenebis(cyclohexanedione) 1a with Mn(OAc)₃•2H₂O was

carried out in AcOH at room temperature until the oxidant was

completely consumed (Scheme 1). The reaction took 8 h and

phenyltetrahydrospiro[benzofuran-2,1'-cyclohexane] 2a was

obtained in 54% yield (Table 1, Entry 1). Since the long reaction

time caused the retro-Michael addition of 1a and might lead to

the moderate yield of the spiro dihydrofuran 2a, we explored the

reaction temperature in order to quickly consume the Mn(III)

oxidant. As a result, the reaction at reflux temperature resulted in

the best yield of 2a along with a small amount of isomeric spiro

dihydrofuran 3a (Entry 3). With the optimized conditions in

hand, other methylenebis(cyclohexanedione)s 1b-q underwent

the Mn(III)-based oxidation to give the corresponding spiro

dihydrofurans 2b-q in decent yields (Entries 4-21) except for 2j,

2k, and 2q (Entries 12, 13, and 21). The thienyl group of 1j

strongly coordinated with Mn(OAc)₃so that the reaction should

with

1,1-disubstituted

olefins

exactly

produced

tetrahydrofuro[2,3-b]furans and dihydropyrans during the

oxidative process.²Cyclic 1,3-diketones having a 2-oxoalkyl

group, such as 3-(2-oxoethyl)piperidine-2,4-diones, 2-

(oxoalkyl)cycloalkane-1,3-diones, and 3-(oxoalkyl)-1H-quinolin-

2-ones, also effectively underwent the tandem cyclization to give

dioxapropellanes³and endoperoxypropellanes.⁴To further

demonstrate the usefulness of polycarbonyl building blocks, we

applied the Mn(III)-based oxidation to tetraketones, such as 3,4-

diacetylheptane-2,6-dione, in order to obtain more complex

tandem cyclization products in one-pot. However, it was very

difficult to control the reaction under various conditions and no

desired products were isolated. The reaction probably developed

into various directions because of the flexible aliphatic

tetracarbonyls. To restrict the reaction directions, we envisioned

the use of tetracarbonyl compounds to limit the flexibility, such

as a cyclic carbonyl system. We then embarked on the reaction of

2,2’-methylenebis(cyclohexane-1,3-dione) derivatives as the

be

complicated.¹⁴

Although

(2-

furanylmethylene)bis(cyclohexanedione) also underwent the

reaction, an intractable mixture was obtained and no product was

isolated. The reaction of 1k at 70 °C led to a slight increase in the

yield

of

2k

(Entry

14).

Alkyl-substituted

methylenebis(cyclohexanedione)s 1m-q also produced dispiro

cyclopropanes 4m-q together with the desired spiro

dihydrofurans 2m-q (Entries 16, 18-21). When the reaction of

1m was continued to heat for 10 min after consumption of the

oxidant, the methyldispiro cyclopropane 4m disappeared and the

yield of 2m slightly increased (Entry 16 compared to Entry 17).

cyclic

polyketone.

2,2'-(Phenylmethylene)bis(5,5-

dimethylcyclohexane-1,3-dione) (1a) was first selected as the

substrate and underwent the Mn(III)-based oxidation to afford

4',4',6,6-tetramethyl-3-phenyl-3,5,6,7-tetrahydro-4H-

spiro[benzofuran-2,1'-cyclohexane]-2',4,6'-trione

(2a)^5,6

in

Especially,

the

isopropyl-substituted

methylenebis(cyclohexanedione) 1q mainly afforded the dispiro

cyclopropane 4q rather than the spiro dihydrofuran 2q (Entry

21), probably due to steric hindrance (vide infra).¹⁵

moderate yield (Scheme 1). Recently, the spiro compounds

including the dimedone framework were synthesized by various

methods. For example, the reaction of dimedone with alkanals in

the presence of iodine was carried out under mechanical ball

milling conditions at room temperature to give the spiro

compounds.⁶Electrolysis of dimedone in the presence of

aromatic aldehydes afforded the corresponding spiro products.⁷

Although the reaction using dimedone bismuthonium ylide also

proceeded in dry benzene via a Wittig-type condensation, two-

types of spiro compounds were also produced as a mixture in

poor yields.⁸The reaction using iodonium ylide under microwave

irradiation led to better results.⁹However, these methods were

limited because of the use of a special apparatus or limited

With the efficiency of the Mn(OAc)₃•2H₂O as the oxidative

radical promoter in the reaction of tetracarbonyl compounds, we

aimed to increase the product yield by the activation of the

Mn(III) initiator. Since we recently found that the addition of

formic acid, HCO₂H, caused an increase in the oxidative ability,

which resulted in shortening the reaction times and increased the

product yield,¹³the reaction in the presence of HCO₂H was also

explored.

Surprisingly, when the reaction of 1a was conducted in the

presence of HCO₂H at the reflux temperature, intramolecular

3

dehydration preferentially occurred and 3,3,6,6-tetramethyl-9-

phenyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (5a)

was quantitatively produced (Entry 22).¹⁶On the other hand, a

similar reaction of 1a was carried out at room temperature, and to

our delight, the reaction times considerably shortened, giving the

desired phenylspiro dihydrofuran 2a in high yield (Entry 23

compared to Entry 1). The tendency was also observed in the

reaction of 1n (Entries 37 compared to Entry 36). With the

activation of Mn(OAc)₃•2H₂O in hand, we applied the conditions

to other methylenebis(cyclohexanedione)s 1b-q (Entries 24-41)

and obtained the corresponding spiro dihydrofurans 2b-q with

much better yields except for 2g-j (Entries 29-32).¹⁷In addition,

for the reaction of the non-substituted 1l and alkyl-substituted

methylenebis(cyclohexanedione)s 1m-q, only using HCO₂H led

to rather better results, giving 2l-q (Entries 34, 35, 38-41).

Although the yield of isopropylspiro dihydrofuran 2q also

increased under the stated conditions, the isopropyldispiro

cyclopropane 4q was preferentially produced (Entry 41).

extremely shifted upfield (δ 2.37 and ca. 2.10) compared to

those of the starting material’s 1q methine protons (δ 3.46 and

ca. 2.93) by the magnetic anisotropy of two pairs of the carbonyl

group in the rigid structure (See supporting information). In

addition, it must be theoretically formed by the oxidative radical

coupling during the reaction. We then scrutinized the reaction

using ethyl-substituted methylenebis(cyclohexanedione) 1n in

protic and aprotic solvents (Table 2). Although the reaction

afforded both the ethylspiro dihydrofuran 2n and ethyldispiro

cyclopropane 4n in EtOH, benzene, toluene, N,N-

dimethylformamide (DMF), and dimethylsulfoxide (DMSO)

(Entries 1-5), the dispiro cyclopropane 4n was selectively

produced in acetonitrile (MeCN) (Entry 6). After optimization of

the reaction, the best yield of 4n was accomplished in MeCN (1

mL) at the reflux temperature for 5 min (Entry 8). The reactions

of other methylenebis(cyclohexanedione)s 1l-q were carried out

under similar conditions to mainly give the dispiro cyclopropanes

4l-q (Entries 9-14), especially, 4q was exclusively produced

(Entry 14). We also applied the conditions to the aryl-substituted

methylenebis(cyclohexanedione) 1a-k in order to obtain the

corresponding dispiro cyclopropane, however, the attempt failed

probably due to the insolubility in MeCN.

2.2. Predominant production of dispiro cyclopropanes in

various solvents

We were very interested in the production of the

isopropyldispiro cyclopropane 4q from the standpoint of the D_3h

symmetric highly-strained structure of cyclopropane¹⁸and the

formation mechanism.¹⁹The H-13 methine proton of the

cyclopropane ring and the isopropylmethine proton were

2.3. Reaction of methylenebis(piperidinedione)s 6a-e.

4

Tetrahedron

Table 1

Oxidation of methylenebis(cyclohexanedione)s 1a-q with Mn(OAc)₃•2H₂O ^a

b

Entry

1

Substrate

1a

X

R

Ph

1:Mn(OAc)₃

1:2.5

1:3

Solvent/mL

AcOH/10

Temp/°C

rt

Time/min

Product yield/%^c

2a (54)

C(Me)₂

CH₂

8 h

45

3

2

1a

Ph

70

2a (48)

2a (72)

2b (65)

2c (66)

2d (68)

2e (58)

2f (71)

2g (63)

2h (79)

2i (54)

2j (32)

2k (32)

2k (38)

2l (69)

2m (51)

2m (60)

2n (53)

2o (49)

2p (43)

2q (8)

3

1a

Ph

reflux

70

3a (8)

4

1b

1c

4-FC₆H₄

4-ClC₆H₄

4-BrC₆H₄

4-NO₂C₆H₄

4-MeC₆H₄

4-MeOC₆H₄

2-Naph

4-Py

1

5

2.5

1

3c (10)

6

1d

1e

7

1

8

1f

2

3f (8)

3g (9)

9

1g

2

10

11

12

13

14

15

16

17

18

19

20

21

1h

1i

1:2.5

0.5

1

1j

2-Thienyl

Ph

1

1k

1l

1

CH₂

Ph

5

C(Me)₂

H

reflux

2

1m

1n

1o

Me

1

4m (17)

Me

10

Et

4n (5)

4o (7)

4p (9)

4q (36)

Pr

1p

1q

Bu

i-Pr

AcOH/4,

HCO₂H/6

AcOH/6,

HCO₂H/4

AcOH/6,

HCO₂H/4

AcOH/6,

HCO₂H/4

AcOH/6,

HCO₂H/4

AcOH/6,

HCO₂H/4

AcOH/6,

HCO₂H/4

AcOH/6,

HCO₂H/4

AcOH/6,

HCO₂H/4

AcOH/6,

HCO₂H/4

AcOH/6,

HCO₂H/4

AcOH/6,

HCO₂H/4

22

1a

1b

1c

1d

1e

1f

C(Me)₂

CH₂

Ph

1:2.5

reflux

7

5

3

2

5

8

1

5a (quant)

2a (93)

2b (80)

2c (89)

2d (86)

2e (88)

2f (89)

2g(48)

23^d

24^d

25^d

26^d

27^d

28^d

29^d

30^d

31^d

32^d

33^d

rt

4-FC₆H₄

4-ClC₆H₄

4-BrC₆H₄

4-NO₂C₆H₄

4-MeC₆H₄

4-MeOC₆H₄

2-Naph

4-Py

1g

1h

1i

2h (48)

2i (48)

2j (13)

2k (85)

1j

2-Thienyl

Ph

1k

5k (3)

34^d

35^d

36^d

1l

1m

1n

C(Me)₂

H

Me

Et

1:2.5

HCO₂H/10

AcOH/10

rt

5

1

2l (90)

2m (71)

2n (40)

4l (8)

4m (8)

4n (22)

6 h

AcOH/6,

HCO₂H/4

37^d

1n

C(Me)₂

Et

1:2.5

rt

1

2n (73)

4n (11)

38^d

39^d

40^d

41^d

1n

1o

1p

1q

C(Me)₂

Et

Pr

1:2.5

HCO₂H/10

rt

1

2n (74)

2o (59)

2p (61)

2q (19)

4n (14)

4o (13)

4p (14)

4q (72)

Bu

i-Pr

^aThe reaction of methylenebis(cyclohexanedione) 1 (0.5 mmol) was carried out in a solvent (10 mL).

^bMolar ratio.

^cIsolated yield based on 1.

^dThe reaction was conducted under argon.

With the desirable results for the synthesis of the spiro

compounds using tetreaketones in hand, we attempted the

reaction

using methylenebis(piperidinedione)s

methylenebis(cyclohexanedione)s 1 in order to synthesize new

intriguing azaspiro compounds (Scheme 2). In addition, to

6

instead of the

5

anticipate the production of the hexahydropyrano[3,2-c:5,6-

c']dipyridinediones, a similar dehydration was also investigated

cyclopropanes 4l-q except for 8d bearing an isopropyl

substituent (Entry 13).

Table 2

Oxidation of methylenebis(cyclohexanedione)s 1l-q with Mn(OAc)₃•2H₂O in various solvents^a

b

Entry

Substrate

X

R

1:Mn(OAc)₃

Solvent/mL

EtOH/10

benzene/10

toluene/10

DMF/10

Temp/°C

reflux

80

Time/min

Product yield/%^c

2n (11)

1

1n

C(Me)₂

Et

1:5

60

10

5

4n (23)

4n (36)

4n (22)

4n (64)

4n (46)

4n (68)

4n (73)

4n (77)

4l (55)

2

1n

Et

1:5

2n (26)

2n (39)

2n (11)

2n (24)

2n (9)

3

1n

Et

1:5

4

1n

Et

1:5

5

1n

Et

1:5

DMSO/10

MeCN/10

MeCN/1

80

5

6

1n

Et

1:5

reflux

50

60

120

5

7

1n

Et

1:5

2n (3)

8

1n

Et

1:3

reflux

2n (11)

2l (41)

9

1l

H

1:3

5

10

11

12

13

14

1m

1n

Me

Et

1:3

5

2m (20)

2n (11)

2o (11)

2p (10)

2q (trace)

4m (54)

4n (77)

4o (80)

4p (76)

4q (93)

1:3

5

1o

Pr

1:3

5

1p

Bu

1:3

5

1q

i-Pr

1:3

5

^aThe reaction of methylenebis(cyclohexanedione) 1 (0.5 mmol) was conducted in solvent.

^bMolar ratio.

^cIsolated yield based on 1.

(Scheme 3) because the hexahydroxanthenediones 5 were easily

Recently, Bayat et al. reported the synthesis of the 3,4,5,6,7,9-

synthesized by the acid-catalyzed dehydration of the tetraketones

1 (see Scheme 1 and Table 1, Entry 22).

hexahydro-1H-xanthene-1,8(2H)-diones, such as 5a, in the

presence of p-toluene sulfonic acid (p-TsOH).²⁰We also found a

similar synthesis using AcOH/HCO₂H (see Scheme 1 and Table

1, Entry 22). The application to the reaction using

methylenebis(piperidinedione)s 6 then intrigued us from the

synthetic viewpoint of the 3,4,6,7,8,10-hexahydro-1H-

pyrano[3,2-c:5,6-c']dipyridine-1,9(2H)-diones as an important

class of alkalids.²¹Although the reaction of 6a with p-TsOH was

conducted according to the literature,²⁰unfortunately, no reaction

occurred. On the other hand, methylenebis(piperidinedione) 6a

underwent the reaction based on our conditions to give the

desired pyranodipyridinedione 9a. The best yield of 9a was

achieved in AcOH/HCO₂H (1:4 v/v) at reflux temperature

(Scheme 3). Other methylenebis(piperidinedione)s 6b-e under

the same conditions also produced the corresponding

pyranodipyridinediones 9b-e in synthetically acceptable yields.

Methylenebis(piperidinedione) 6a was initially selected and

the reaction was evaluated in boiling AcOH (Scheme 2 and Table

3, Entry 1). Although the reaction was complicated, the

corresponding

tetrahydrospiro[furo[3,2-c]pyridine-2,3'-

piperidine]trione 7a was somehow isolated as a diastereomeric

mixture from the intractable mixture. All attempts to improve the

product yield of 7a failed (Entries 2-5). However, increasing the

addition of HCO₂H to the reaction culminated in the formation of

another crystalline product 8a (Entries 6-10). The NMR spectrum

of 8a showed a symmetrical structure pattern, and especially,

characteristic peaks (δ 52.7 and 39.7) assigned to the dispiro

cyclopropane ring appeared in the ¹³C MNR spectrum (see

supporting information). In addition, the COSY, HMQC, and

HMBC spectra also supported the dispiro cyclopropane structure

containing bis(piperidinedione), and finally, the structure of 8a

was determined by an X-ray single crystal analysis as

(6R,7S,13r)-2,9-dibenzyl-13-phenyl-2,9-

2.4. Mechanism for the formation of spiro and dispiro

compounds

The mechanism of the Mn(III)-based oxidation using 1,3-

dicarbonyl compounds was well-documented by Snider²²and

us.^2,3,23The reaction of tetracarbonyl compounds 1 could also be

understandable similar to that of the 1,3-dicarbonyl compounds.

In a protic solvent, such as AcOH, the enol of tetraketone 1

diazadispiro[5.0.5⁷.1⁶]tridecane-1,5,8,12-tetraone (See supporting

information). Other methylenebis(piperidinedione)s 6b-e were

then allowed to react under the optimized conditions, giving the

corresponding diazadispiro cyclopropanes 8b-e (Entries 11-14)

though the yield was modest compared to that of the dispiro

underwent

a ligand-exchange reaction with Mn(OAc)₃to

preferentially produce the enolate complex A (Scheme 4, path a),

of which two hydroxycyclohexenone moieties should be

orthogonal through the methylene group and independently

6

Tetrahedron

oxidized with Mn(III), followed by cyclization between the

methine carbon and the nearest carbonyl oxygen of the other

hydroxycyclohexenone part (solid half arrow in step B),

corresponding dispiro cyclopropanes 4l-q were also produced in

poor yields except for the isopropyl 4q (Table 1, Entries 16, 18-

21 and 34-41). In the case of the reaction of 1q in a protic

solvent, the orthogonal enolate complex, such as A, might be

Table 3

a

Oxidation of methylenebis(piperidinedione)s 6a-e with Mn(OAc)₃

Entry

b

Substrate

R

Ph

Me

Et

R'

Bn

i-Pr

6:Mn(OAc)₃

Solvent/mL

AcOH/6

Temp/°C

Time/min

Product yield/%^c

7a (35)

7a (20)

nr^d

1

6a

1:2

reflux

1

2

6a

1:3

AcOH/6

reflux

3

6a

1:2

EtOH/6

reflux

30

21 h

30

4

6a

1:2

MeCN/6

reflux

rt

nr^d

5

6a

1:2

AcOH/4, HCO₂H/1

AcOH/2, HCO₂H/3

AcOH/1, HCO₂H/4

HCO₂H/5

c.m.^e

6

6a

1:2

rt

8a (33)

8a (40)

8a (23)

8a (36)

8a (33)

8b (16)

8c (25)

8d (71)

8e (48)

7

6a

1:2

rt

4

8

6a

1:2

rt

4

9

6a

1:3

AcOH/1, HCO₂H/4

rt

5

10

11

12

13

14

6a

1:2.5

1:2

50

rt

2

6b

5

6c

1:2

rt

4

6d

i-Pr

Ph

1:2

rt

7

6e

1:2

rt

5

^aThe reaction of methylenebis(piperidinedione) 6 (0.3 mmol) was carried out in a solvent (6 mL) under argon.

^bMolar ratio.

^cIsolated yield based on 6.

^dNo reaction.

^eComplex mixture.

selectively producing the spiro dihydrofurans 2 (path a). The

difficult to generate because of steric hindrance of the isopropyl

group, and therefore, the bridged parallel enolate complex, such

as C, should be exclusively formed, culminating in the dispiro

cyclopropane 4q (Table 1, Entry 41).

Although the reaction of the methylenebis(piperidinedione)s

6a-e were also understood according to the above mechanism,

the planar 4-hydroxy-5,6-dihydropyridin-2-one rings probably

tend to be arranged parallel by coordination of the oxygen-

centered Mn(III) complex through the enolate carbonyls in a

protic solvent at room temperature similar to C in Scheme 4, so

that the head-to-head coupling should be preferred and the

corresponding diazadispiro cyclopropanes 8a-e must be formed

in spite of the complexity of the reaction.

reaction of the alkyl-substituted 1m-p also afforded a small

amount of the dispiro cyclopropanes 4m-p under the acidic

conditions (Table 1, Entries 16, 18-20, 35-40). Probably, the

head-to-head coupling (C–C bond forming) somewhat involved

in the

step B (dashed half arrow shown in B) to produce the dispiro

cyclopropanes 4m-p. However, the head-to-head coupling must

be reversible under the conditions, and the head-to-tail coupling

(C–O bond coupling) predominantly proceeded (solid half arrow

shown in B) to form thermodynamically stable spiro

dihydrofuranes 2m-p except for the case of isopropyl-substituted

1q (vide infra). Treatment of 4n in AcOH at reflux temperature

for 5 min afforded 2n only in 3% yield together with 4n

unchanged (70% recovered). Therefore, the process from B to

2m-q via 4m-q might not contribute under the acidic conditions.

On the other hand, in a polar aprotic solvent, such as MeCN, the

3. Conclusion

The efficient and convenient syntheses of the spiro

dihydrofurans 2a-p and dispiro cyclopropanes 4l-q were realized

by the Mn(III)-based oxidation of tetracarbonyl compounds such

as the 2,2’-methylenebis(cyclohexane-1,3-dione) derivatives 1a-

q. The reaction in a protic solvent at room temperature mainly

produced the spiro dihydrofurans 2a-p, while the dispiro

cyclopropanes 4l-q were selectively produced in an aprotic polar

solvent at reflux temperature. A similar reaction of the

methylenebis(piperidinedione)s 6a-e in a protic solvent at room

temperature preferentially generated the corresponding

diazadispiro cyclopropanes 8a-e. The interpretation for the

selective production of the spiro 2 and dispiro compounds 4 and

8 was also given based on the intermediate Mn(III)-enolate

complex formation (Scheme 4). In addition, we demonstrated the

synthesis of the hexahydropyrano[3,2-c:5,6-c']dipyridinediones

9a-e, which would contribute to the synthesis of a new type of

alkaloid.²⁴

oxidant

Mn(OAc)₃•2H₂O

and

the

methylenebis(cyclohexanedione)s 1a-k did not dissolve in

MeCN, but bridged the enolate complex C (R = alkyl and H), of

which two hydroxycyclohexenone moieties, which should be

arranged parallel by coordination of the Mn(III), gradually

formed (Scheme 4, path b). Once the enolate complex C was

formed, it must undergo a single-electron-transfer oxidation

(SETO) followed by predominant cyclization (head-to-head

coupling) between the nearest methine carbons (solid half arrow

in step D), resulting in the dispiro cyclopropanes 4 (path b).

Since the spiro dihydrofurans 2l-p also produced in low yields,

the head-to-tail coupling (C–O bond forming) might somewhat

occur under the polar aprotic conditions (dashed half arrow in

step D). In addition, the bridged enolate complex C might

somewhat generate under the acidic conditions because the

7

The solvents were commercially-available first-grade and used as

received.

4. Experimental section

4.1. Measurements

4.3. Reaction of methylenebis(cyclohexanedione)s 1a-q in

AcOH.

Melting points were taken using a MP-J3 Yanagimoto

micromelting point apparatus and are uncorrected. The IR spectra

were measured in CHCl₃or KBr using a Shimadzu 8400 and in

neat or CHCl₃using an IRAffinity-1S FT IR spectrometer with

MIRacle 10 ATR accessary. All the IR data were expressed in

cm⁻¹. The NMR spectra were recorded using a JNM ECX 500

Methylenebis(cyclohexanedione) 1 (0.5 mmol) in AcOH (10

mL) was heated at 110 °C to dissolve 1, and Mn(OAc)₃•2H₂O

(1.25 mmol) was added. The mixture was heated under reflux

until the Mn(III) oxidant was completely consumed and the

brown color of Mn(III) turned transparent. The existence of the

Mn(III) was monitored by iodine-starch paper and each reaction

time is listed in Table 1. After completion of the reaction, 2M

HCl (10 mL) was added and the aqueous mixture was extracted

with CHCl₃(10 mL × 5). The combined extracts were washed

with water (10 mL), a saturated aqueous solution of NaHCO₃(10

mL), brine (10 mL), dried over anhydrous MgSO₄(3 g), then

concentrated to dryness. The residue was separated by column

chromatography on silica gel eluting with 10% EtOAc/CHCl₃,

mainly giving the corresponding spiro dihydrofuran 2 together

with a small amount of isomeric spiro dihydrofuran 3 and dispiro

cyclopropane 4 in some cases (see Table 1).

1

FT-NMR spectrometer at 500 MHz for the H and at 125 MHz

for ¹³C, with tetramethylsilane as the internal standard. The

chemical shifts are reported as δ values (ppm) and the coupling

constants in Hz. The following abbreviations are used for the

multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m,

1

multiplet; and brs, broad singlet for the H NMR spectra. The EI

MS spectra were obtained by a Shimadzu QP-5050A gas

chromatograph-mass spectrometer at the ionizing voltage of 70

eV. The high-resolution mass spectra using a JEOL JMS-700

MStation and the elemental analyses using a J-SCIENCE LAB

JM10 for the products were performed at the Instrumental

Analysis Center, Kumamoto University, Kumamoto, Japan. The

X-ray analysis was performed by a Rigaku RAXIS-RAPID

Imaging Plate diffractometer with graphite monochromated Mo-

Kα radiation, and the structure was solved by direct methods and

expanded using Fourier techniques.

A

mixture of 2,2'-(phenylmethylene)bis(3-hydroxy-5,5-

dimethylcyclohex-2-en-1-one) (1a) (0.5 mmol, 0.184 g) and

Mn(OAc)₃•2H₂O (1.25 mmol, 0.284 g) was heated under reflux

in AcOH/HCO₂H (10 mL, 3:2 v/v) for 7 min. After the work-up

described

above,

3,3,6,6-tetramethyl-9-phenyl-3,4,5,6,7,9-

4.2. Materials.

hexahydro-1H-xanthene-1,8(2H)-dione (5a) was obtained in

quantitative yield (0.175 g) instead of 2a (Table 1, Entry 22). The

reaction in the absence of Mn(OAc)₃•2H₂O gave the same result.

Manganese(II) acetate tetrahydrate, Mn(OAc)₂•4H₂O, was

purchased from Wako Pure Chemical Ind., Ltd. Dimedone and

1,3-cyclohexanedione were purchased from Tokyo Kasei Co.,

Ltd. Methylenebis(cyclohexanedione)s 1a-q were prepared by

condensation of 1,3-cyclohexanedione with the corresponding

commercially available aldehyde in the presence of piperidine

(See supporting information).²⁵Methylenebis(piperidinedione)s

6a-e were prepared by condensation of 1-benzyl- and 1-

4.4. Reaction of methylenebis(cyclohexanedione)s 1a-q using

HCO₂H.

AcOH (6 mL) and HCO₂H (4 mL) were added to a 50-mL

round-bottomed flask and degassed under reduced pressure for

10 min using an ultrasonicator for exchange in an argon

atmosphere. Methylenebis(cyclohexanedione) 1 (0.5 mmol) and

Mn(OAc)₃•2H₂O (1.25 mmol) were added to the degassed

solution and the mixture was stirred at room temperature under

an argon atmosphere until the brown color of Mn(III) turned

transparent (normally 5 min, see Table 1, Entries 23-33). After

finishing the reaction, the usual work-up described above was

performed. The specific details of the new compound 2h are

isopropyl-piperidine-2,4-diones

with

the

corresponding

commercially available aldehyde in the presence of piperidine

(See supporting information).²⁶Manganese(III) acetate dihydrate,

Mn(OAc)₃•2H₂O, was synthesized according to our modified

method.¹²Flash column chromatography was performed on silica

gel 60N (40-50 mm), which was purchased from Kanto Chemical

Co., Inc., and preparative thin layer chromatography (TLC) on

Wakogel B-10 and B-5F from Wako Pure Chemical Ind., Ltd.

8

Tetrahedron

given below and the other new and known compounds are

= 14.3 Hz, CH₂), 2.51 (2H, d, J = 14.0 Hz, CH₂), 1.75 (2H, q, J =

described in the Supporting Information.

7.0 Hz, >CH-CH₂-CH₂CH₃), 1.45 (2H, sext, J = 7.5 Hz, CH₂-

CH₂-CH₃), 1.11 (6H, s, Me×2), 1.04 (6H, s, Me×2), 0.95 (3H, t, J

= 7.5 Hz, CH₂-CH₂-CH₃); ¹³C NMR (CDCl₃) δ 201.0 (C=O×2),

199.9 (C=O×2), 58.2 (2C) (C-6, C-7), 55.3 (CH₂×2), 54.2

(CH₂×2), 44.2 (C-13), 30.9 (2C) (C-3, C-10), 28.9 (Me×2), 27.8

(Me×2), 25.5 (CH₂), 22.7 (CH₂), 13.8 (CH₃-CH₂-). Anal. Calcd

for C₂₀H₂₈O₄: C, 72.26; H, 8.49. Found: C, 72.09; H, 8.70.

4.4.1. 4',4',6,6-Tetramethyl-3-(naphthalen-2-yl)-3,5,6,7-

tetrahydro-4H-spiro[benzofuran-2,1'-cyclohexane]-2',4,6'-trione

4.6. Reaction of methylenebis(piperidinedione)s 6a-e.

3,3'-(Phenylmethylene)bis(1-benzyl-4-hydroxy-5,6-

dihydropyridin-2(1H)-one) (6a) (0.3 mmol, 0.148 g) was

dissolved in AcOH (6 mL) at 110 °C and Mn(OAc)₃•2H₂O (0.6

mmol, 0.161 g) was added. The mixture was heated under reflux

for 1 min. The work-up procedure mentioned above was

performed and the crude product was separated by column

chromatography on silica gel eluting with 2% MeOH/CH₂Cl₂,

(2h).

Yield (79%); colorless microcrystals (from EtOH); mp 279-

280 °C; R_f= 0.55 (EtOAc/CHCl₃1:9 v/v); IR (KBr) ν 1769

(C=O), 1697 (C=O); ¹H NMR (CDCl₃) δ 7.81−7.78 (2Η, m,

naph-Η), 7.78 (1H, d, J = 8.4 Hz, naph-H-4), 7.69 (1H, br, s,

naph-H-1), 7.50-7.46 (2H, m, naph-H), 7.20 (1H, dd, J = 8.4, 1.5

Hz, naph-H-3), 4.62 (1H, s, H-3), 3.16 (1H, d, J = 14.8 Hz, H-5’-

a), 2.71 (2H, s, H-7), 2.56 (1H, dd, J = 14.8, 2.6 Hz, H-5’-b),

2.23 (1H, d, J = 16.2 Hz, H-5-a), 2.15 (1H, d, J = 16.2 Hz, H-5-

b), 2.07 (1H, dd, J = 14.3, 2.9 Hz, H-3’-a), 1.99 (1H, d, J = 14.3

Hz, H-3’-b), 1.17 (6H, s, Me-6), 1.09 (3H, s, 4’-Me), 0.82 (3H, s,

4’-Me); ¹³C NMR (CDCl₃) δ 199.4, 198.9 (C-2’, C-6’), 193.3 (C-

4), 176.8 (C-7a), 133.7, 133.3, 133.2 (arom C), 129.2, 128.2,

128.0, 127.8, 126.6 (2C), 125.8 (arom CH), 113.9 (C-3a), 104.1

(C-2), 55.2 (C-3), 53.9 (C-5’), 51.2 (C-5), 50.1 (C-3’), 37.4 (C-

7), 34.4 (C-6), 30.7 (C-4’), 30.6 (Me), 29.0 (Me), 28.5 (Me), 26.4

(Me). FAB HRMS (acetone-NBA): calcd for C₂₇H₂₉O₄417.2066

(M+H). Found 417.2072.

affording

1',5-dibenzyl-3-phenyl-3,5,6,7-tetrahydro-4H-

spiro[furo[3,2-c]pyridine-2,3'-piperidine]-2',4,4'-trione (7a) in

35% yield (0.052 g) as a diastereomeric mixture.

4.6.1. 1',5-Dibenzyl-3-phenyl-3,5,6,7-tetrahydro-4H-

spiro[furo[3,2-c]pyridine-2,3'-piperidine]-2',4,4'-trione (7a).

Yield (35%); R_f= 0.21 (1:49 MeOH/CH₂Cl₂v/v);

Amorphous solid; IR (neat) ν 1740 (C=O), 1649 (O=C–C=C); ¹H

NMR (CDCl₃) δ 7.57-7.15 (13H, m, arom H), 6.68-6.66 (2H, m,

arom H), 4.85-4.61 (4H, m, N-CH₂-Ph), 4.51 (1H, s, Ph-CH<),

3.77-3.18 (4H, m, -CH₂-), 2.93-2.85, 2.69-2.20, 1.82-1.73 (4H,

m, -CH₂-); ¹³C NMR (CDCl₃) δ 197.6 (C-4’), 184.4 (C-2’), 168.7

(C-4), 163.6 (C-7a), 137.6, 135.5, 135.1 (arom C) 129.0 (2C),

128.7 (2C), 128.6 (2C), 128.5 (2C), 128.48 , 128.46 (2C), 128.2

(2C), 128.0, 127.7 (arom CH), 96.8 (>C=), 91.1 (C-2), 52.2 (N-

CH₂-Ph), 51.5 (C-3), 50.3 (N-CH₂-Ph), 45.9, 39.4, 35.0, 33.9 (-

CH₂-). FAB HRMS (acetone/NBA): calcd for C₃₁H₂₉N₂O₄

493.2127 (M+H). Found 493.2125.

4.5. Predominant production of dispiro cyclopropanes in

MeCN.

Methylenebis(cyclohexanedione) 1 (0.5 mmol) was dissolved

in MeCN (1 mL) at 70 °C and Mn(OAc)₃•2H₂O (1.25 mmol) was

added. The mixture was heated under reflux for 5 min. After

cooling, 2M HCl (5 mL) was added to the reaction mixture and

the aqueous solution was extracted with CHCl₃(5 mL × 5). The

combined extracts were washed with water (10 mL), a saturated

aqueous solution of NaHCO₃(10 mL), brine (10 mL), dried over

anhydrous MgSO₄(3 g), then concentrated to dryness. The

residue was separated by column chromatography on silica gel

eluting with 2% EtOAc/CHCl₃, mainly giving the corresponding

dispiro cyclopropane 4 together with a small amount of the spiro

dihydrofuran 2 (see Table 2). The specific details of the new

compound 4o are given below, and the other new and known

compounds are described in the Supporting Information.

The reaction in AcOH/HCO₂H was as follows. AcOH (1 mL)

and HCO₂H (4 mL) were added to a 30-mL round-bottomed flask

and degassed under reduced pressure for exchange with an argon

atmosphere. Methylenebis(piperidinedione) 6 (0.3 mmol) was

dissolved in the AcOH/HCO₂H and Mn(OAc)₃•2H₂O (0.6 mmol)

was added. The mixture was stirred at room temperature under an

argon atmosphere until the Mn(III) was completely consumed

(see Table 3, Entries 5-14). After the usual work-up, the crude

product was separated by column chromatography on silica gel

eluting with 4% EtOAc/CHCl₃, affording the diazadispiro

cyclopropane 8a.

4.5.1.

3,3,10,10-Tetramethyl-13-

propyldispiro[5.0.5⁷.1⁶]tridecane-1,5,8,12-tetraone (4o).

4.6.2.

(6R,7S,13r)-2,9-Dibenzyl-13-phenyl-2,9-

diazadispiro[5.0.5⁷.1⁶]tridecane-1,5,8,12-tetraone (8a).

Ph

O

¹³O

12

5

11

4

7

6

N

1

N

10

8

3

O O

Yield (80%); colorless microcrystals (from EtOH); mp 153

°C; R_f= 0.33 (EtOAc/CHCl₃1:50 v/v); IR (KBr) ν 1701 (C=O);

¹H NMR (CDCl₃) δ 2.64 (2H, d, J = 14.0 Hz, CH₂), 2.59 (2H, d,

J = 14.3 Hz, CH₂), 2.57 (1H, t, J = 6.9 Hz, H-13), 2.56 (2H, d, J

2

9

Bn

8a

Figure 1. X-Ray Crystal Structure of 8a

9

6.5, 4.1 Hz, H-3, H-7), 2.63 (1H, ddd, J = 17.7, 12.2, 6.5 Hz, H-

Yield (40%); R_f= 0.39 (1:49 EtOAc/CHCl₃v/v); colorless

microcrystals (from EtOH); mp 213.6-214.9 °C; IR (neat) ν 1734

(C=O), 1709 (C=O), 1655 (C=O); H NMR (CDCl₃) δ 7.55-7.53

4 or H-6), 2.62 (1H, ddd, J = 17.7, 12.2, 6.5 Hz, H-4 or H-6),

2.46 (1H, ddd, J = 17.7, 5.2, 4.1 Hz, H-4 or H-6), 2.45 (1H, ddd,

J = 17.7, 5.2, 4.1 Hz, H-4 or H-6); ¹³C NMR (125 MHz, CDCl₃)

δ 165.1 (2C) (C-1, C-9), 154.1 (2C) (C-4a, C-5a), 144.9, 137.4

(2C) (arom C), 128.6 (2C), 128.5 (4C), 128.1 (2C), 127.8 (4C),

127.2 (2C), 126.3 (arom CH), 109.9 (2C) (C-9a, C-10a), 49.6

(2C) (N-CH₂-Ph), 42.7 (2C) (C-3, C-7), 34.1 (Ph-CH<), 25.7

(2C) (C-4, C-6). Anal. Calcd for C₃₁H₂₈N₂O₃: C, 78.13; H, 5.92;

N, 5.88. Found: C, 77.94; H, 5.99; N, 5.88.

1

(2H, m, arom H), 7.32-7.22 (13H, m, arom H), 4.93 (2H, d, J =

14.0 Hz, N-CH₂-Ph), 4.52 (2H, d, J = 14.0 Hz, N-CH₂-Ph), 3.75

(1H, s, Ph-CH<), 3.527 (1H, ddd, J = 13.7, 6.1, 5.9 Hz, H-3 or H-

10), 3.526 (1H, ddd, J = 13.7, 6.1, 5.9 Hz, H-3 or H-10), 3.38

(2H, ddd, J = 13.7, 5.7, 5.4 Hz, H-3, H-10), 2.64 (2H, ddd, J =

18.8, 6.1, 5.7 Hz, H-4, H-11), 2.547 (1H, ddd, J = 18.8, 5.9, 5.4

Hz, H-4 or H-11), 2.546 (1H, ddd, J = 18.8, 5.9, 5.4 Hz, H-4 or

H-11); ¹³C NMR (CDCl₃) δ 201.4 (2C) (C-5, C-12), 163.8 (2C)

(C-1, C-8), 136.3 (2C), 131.3 (arom C), 130.0 (3C), 128.7 (3C),

128.4 (5C), 128.03, 127.80, 127.76 (2C) (arom CH), 52.7 (2C)

(C-6, C-7), 50.0 (2C) (N-CH₂-Ph), 40.9 (2C) (C-3, C-10), 39,7

(Ph-CH<), 38.4 (2C) (C-4, C-11). Anal. Calcd for C₃₁H₂₈N₂O₄:

C, 75.59; H, 5.73; N, 5.69. Found: C, 75.52; H, 5.87; N, 5.73. X-

ray crystallographic data of 8a: empirical formula C₃₁H₂₈N₂O₄;

formula weight 492.57; colorless platelet crystal; crystal

dimensions 0.54 × 0.38 × 0.18 mm; monoclinic; space group

P2₁/c (# 14); a = 11.475(1), b = 22.139(3), c = 10.259(1) Å, β =

100.772(2)°, V = 2560.3(5) Å³, Z = 4; D_calcd= 1.278 g/cm³;

F(000) = 1040.00; µ(MoKα) = 0.848 cm^-1; 2θ_max= 54.9°; No. of

reflections measured 24626; No. of observations 5830; No. of

variables 334; Reflection/parameter ratio was 17.46; R = 0.1096;

R_w= 0.1840; GOF = 1.086. X-ray coordinates were deposited

with the Cambridge Crystallographic Data Centre: CCDC

1987107.

Acknowledgments

This research was supported by a Grant-in-Aid for Scientific

Research (C), No. 25410049, from the Japan Society for the

Promotion of Science. We also acknowledge Nissan Chemical

Corporation for the financial support.

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40%

EtOAc/hexane,

giving

(39.5

the

mg,

corresponding

83%). Other

pyranodipyridinedione

9a

–

,

methylenebis(piperidinedione)s 6b-e underwent the same

reaction to produce the corresponding pyranodipyridinediones

9b-e. The specific details of 9a are given below and the other

new compounds 9b-e are described in the Supporting

Information.

,

–

-

4.7.1.

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,

pyrano[3,2-c:5,6-c']dipyridine-1,9(2H)-dione (9a).

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Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships

that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered

as potential competing interests:

Article Doi

Selective synthesis of spiro and dispiro compounds using Mn(III)-based oxidation of tetracarbonyl compounds

DOI: 10.1016/j.tet.2020.131165

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Article abstract of DOI:10.1016/j.tet.2020.131165

Full text of DOI:10.1016/j.tet.2020.131165

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