Synlett 2019; 30(03): 293-298
DOI: 10.1055/s-0037-1611706
letter
© Georg Thieme Verlag Stuttgart · New York

Molecular-Iodine-Promoted Synthesis of Dihydrobenzofuran-3,3-dicarbonitriles through a Novel Rearrangement

Nagaraju Medishetti
a   Fluoro & Agro Chemicals Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India
c   AcSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India   Email: krishnu@iict.res.in
,
Ashok Kale
a   Fluoro & Agro Chemicals Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India
c   AcSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India   Email: krishnu@iict.res.in
,
Jagadeesh Babu Nanubolu
b   Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India
,
a   Fluoro & Agro Chemicals Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India
c   AcSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India   Email: krishnu@iict.res.in
› Author Affiliations

We are grateful to SERB-DST, New Delhi, for financial support (Grant no. EEQ/20l6/000066). We gratefully acknowledge the help received from the Centre for NMR & Structural Chemistry and Analytical Chemistry & Mass Spectrometry, CSIR –IICT.
Further Information

Publication History

Received: 01 November 2018

Accepted after revision: 16 December 2018

Publication Date:
11 January 2019 (online)

 


CSIR-IICT Communication No. IICT/pubs./2018/203.

Abstract

The title compounds were synthesized from 5,5-dimethyl­cyclohexane-1,3-dione, benzaldehyde, and malononitrile promoted by molecular iodine in basic medium via 2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile, by a novel protocol. The protocol involves a novel rearrangement in which the 4H-chromene fragment dissociates to a cyclopropane moiety and rearranges to the five-membered compound 6,6-dimethyl-4-oxo-2-phenyl-4,5,6,7-tetrahydrobenzofuran-3,3(2H)-dicarbonitrile. Simple reaction conditions, excellent yields, and high compatibility are the advantages of this protocol.


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Furan scaffolds are an important class of heterocycles, widely found in many natural products and biologically ­active compounds.[1] Of these, dihydrofurans represent one of the important moieties found in many biologically interesting natural products,[2] such as (±)-kadsurinone,[3] (±)-denudatin,[4] (±)-obtusafuran,[5] (±)-liliflol B,[6] and (+)-conocarpan[7] (Figure [1]). (+)-Conocarpan was first isolated from the mangrove shrub Conocarpus erectus, and exhibits a broad spectrum of biological activities, including insecticidal,[8] anti­fungal,[9] and antitrypanosomal properties.[10] Furthermore, dihydrofurans are subunits of a range of biologically active compounds that are reported to act as anticancer agents,[11] antiangiogenic agents,[12] and cyclooxygenase, ­lipoxygenase, and platelet-aggregations inhibitors.[13] Finally, dihydrofurans can serve as important building blocks in organic synthesis, as they can be transformed into an array of highly functionalized tetrahydrofurans.[14]

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Figure 1 Dihydrofuran-ring-containing biologically active natural products

For these reasons, the development of synthetic routes to these compounds is an important task and many strategies have been reported for the synthesis of highly functionalized dihydrofurans. These include TMEDA-catalyzed synthesis from 1,3-diketones,[15] the Feist–Benary reaction,[16] domino reactions using 1,3-diketones,[17] DABCO-promoted reactions of pyridinium salts with enones,[18] [19] CAN-mediated oxidative cycloaddition of 1,3-dicarbonyls to conjugated compounds,[20] olefin metathesis,[21] Cu-catalyzed syntheses using olefins,[22] an ionic-liquid-promoted interrupted Feist–Benary reaction,[23] copper-catalyzed asymmetric cycloaddition,[24] and Pd-catalyzed coupling–cyclization of 2-(2′,3′-­allenyl)acetylacetates.[25] However, because most of these methods involve a metal catalyst, the development of ­simple and efficient methods with readily available starting materials is a continual aim of synthetic chemists.

With this background, and as part of our ongoing research program on the synthesis of bioactive molecules by multicomponent one-pot reactions,[26] we report the synthesis of 2-aryl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-3,3(2H)-dicarbonitrile (2) derivatives promoted by ­molecular iodine through an unexpected novel rearrangement involving C–C bond cleavage.

We were recently working on the synthesis of 2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (1a) and its derivatives, and their subsequent conversion into dihydrofuran compounds.[26a] In a continuation of this work, we treated compound 1a with molecular iodine (0.5 equiv), (diacetoxyiodo)benzene (­IBDA) (0.5 equiv), and triethylamine (2 equiv) in 1,2-dichloroethane (DCE) at reflux temperature, hoping to obtain product 3 (Scheme 2), as previously reported (Scheme 1).[27a]

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Scheme 1 Previous reports

Instead, and to our surprise, the dihydrobenzofuran 2a was obtained in 68% yield (Scheme [2]).

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Scheme 2 Synthesis of 6,6-dimethyl-4-oxo-2-phenyl-4,5,6,7-tetra­hydrobenzofuran-3,3(2H)- dicarbonitrile (2a)

The structure of the product 2a was established by spectral analyses, and the structure of a representative ­derivative 2c (see below) was confirmed by X-Ray crystallographic analysis (Figure [2]).[28]

Zoom Image
Figure 2 ORTEP diagram of compound 2c. Displacement thermal ­ellipsoids are drawn at the 30% probability level and H atoms are shown as small spheres of arbitrary radius.

Amazed by the formation of 2a, instead of the expected product 3,[27a] which was contrary to our previous report,[26a] we attempted to improve the yield of 2a. In this context, we conducted our experimental studies by employing IBDA and molecular iodine independently in basic medium to ­examine the role of each reagent, to establish the yield-­improvement factors, and to identify the reaction pathway. Accordingly, we treated compound 1a with IBDA and Et3N in refluxing 1,2-dichloroethane (Scheme [3]). Interestingly, the outcome of the study showed the formation of products 2 and 4 [27a] (Table [1], entries 1–3). We then conducted studies employing only IBDA under similar reaction conditions and we obtained similar results (entries 4 and 5). Surprisingly, when we used molecular iodine and Et3N in DCE at reflux temperature, we obtained product 2a exclusively in 63% yield. Excited over the exclusive formation of 2a, we ­examined the effects of varying the mole ratios of I2 and Et3N in the attempt to improve the yield of 2a (entries 6–12). The best results were obtained with one equivalent of I2 and two equivalents of Et3N (entry 11). Further experiments with I2 alone also gave 2a exclusively, albeit in low yields (entries 13–16). Additionally, studies were conducted by employing other bases, such as DMAP, DIPEA, piperidine, DBU, and DABCO to examine the possibility of increasing the yield of compound 2a. Of these bases, DMAP and DIPEA gave similar results to those obtained with I2 and Et3N, whereas DBU, DABCO, and piperidine gave 2a in moderate yields (entries 18–22). Next, we examined the effects of various solvents (entries 23–31) and found that toluene and DCE gave the best results (entries 11 and 31).

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Scheme 3

Table 1 Optimization of the Reaction Conditionsa

Entry

Reagent(s) (equiv)

Temp (oC)

Time (h)

Solvent

Yielda (%) of 2a

 1

IBDA (1) + Et3N (1)

reflux

2

DCE

53 (10)

 2

IBDA (1) + Et3N (1.5)

reflux

2

DCE

57 (26)

 3

IBDA (1.5) + Et3N (1.5)

reflux

2

DCE

57 (38)

 4

IBDA (1)

reflux

2

DCE

40 (20)

 5

IBDA (1.5)

reflux

2

DCE

56 (24)

 6

I2 (0.5) + Et3N (0.5)

reflux

2

DCE

58 (0)

 7

I2 (1) + Et3N (0.5)

reflux

2

DCE

63 (0)

 8

I2 (1) + Et3N (1)

reflux

2

DCE

71 (0)

 9
10

I2 (1) + Et3N (1.5)
I2 (1.5) + Et3N (1.5)

Reflux
reflux

2
2

DCE

76 (0)
76 (0)

11

I 2 (1) + Et3N (2)

reflux

2

DCE

80 (0)

12

I2 (1) + Et3N (2.5)

reflux

2

DCE

80 (0)

13

I2 (0.5)

reflux

2

DCE

28 (0)

14

I2 (0.8)

reflux

2

DCE

39 (0)

15

I2 (1)

reflux

2

DCE

51 (0)

16

I2 (1.5)

reflux

2

DCE

56 (0)

17

PhIO (1) + Et3N

reflux

2

DCE

20 (0)

18

I2 (1) + DBU (2)

reflux

2

DCE

41 (0)

19

I2 (1) + DABCO (2)

reflux

2

DCE

53 (0)

20

I2 (1) + DIPEA (2)

reflux

2

DCE

71 (0)

21

I2 (1) + piperidine (2)

reflux

2

DCE

63 (0)

22

I2 (1) + DMAP (2)

reflux

2

DCE

73 (0)

23

I2 (1) + Et3N (2)

reflux

2

CH2Cl2

npb

24

I2 (1) + Et3N (2)

reflux

2

MeCN

78 (0)

25

I2 (1) + Et3N (2)

reflux

2

1,4-dioxane

76 (0)

26

I2 (1) + Et3N (2)

110

2

DMF

np

27

I2 (1) + Et3N (2)

reflux

2

H2O

np

28

I2 (1) + Et3N (2)

reflux

2

MeOH

np

29

I2 (1) + Et3N (2)

reflux

2

EtOH

np

30

I2 (1) + Et3N (2)

reflux

2

xylene

80 (0)

31

I 2 (1) + Et3N (2)

reflux

2

toluene

80 (0)

a Yields of byproduct 4 are given in parentheses.

b np = no product.

Having established the optimum conditions for the formation of the product 2a in excellent yield, we examined the scope of this protocol by treating ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate, 5-acetyl-2-amino-6-methyl-4-phenyl-4H-pyran-3-carbonitrile, 2-amino-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile, ethyl 2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate, and 2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carboxamide independently with molecular iodine and triethylamine under the optimized conditions. Of these compounds, only 2-amino-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile gave the desired product 2o in 77% yield. In contrast, the reaction of the other derivatives did not produce any product, and subjecting them to reflux conditions in high-boiling solvents such as toluene resulted in multiple unidentifiable spots on TLC. Next we examined, the scope of this protocol by examining the reactions under the optimized conditions of 1 prepared from simple, electron-rich, electron-deficient, heterocyclic, bicyclic, or aliphatic aldehydes (Scheme [4]).[29] To our satisfaction, this protocol gave the corresponding products 2. Compounds with electron-withdrawing groups gave better yields than those with electron-donating groups. The reaction of 1a was also conducted on a 5 g scale, and product 2a was obtained in 82% yield. An aliphatic aldehyde analogue of 1 did not give the desired product, and the starting material was recovered.

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Scheme 4 Substrate scope. Reaction conditions: 1 (1.02 mmol), I2 (1.02 mmol), Et3N (2.04 mmol), DCE (20 mL), reflux. Isolated yields are reported.

Finally, we attempted the synthesis of 2a by a one-pot multicomponent reaction from dimedone (5), benzaldehyde (6), and malononitrile (7) in toluene at the reflux ­temperature for one hour followed by addition of I2 (1 equiv) and Et3N (2 equiv) (Scheme [5]). Interestingly, product 2a was obtained in a similar yield to that obtained from 1a (see Scheme [4]).

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Scheme 5 One-pot synthesis of 6,6-dimethyl-4-oxo-2-phenyl-4,5,6,7-tetrahydrobenzofuran-3,3(2H)-dicarbonitrile (2a)

On the basis of previous reports,[27] we propose the mechanism shown in Scheme [6]. Initially, the chromene 1a reacts with I2 in the presence of Et3N to give intermediate A. Next, abstraction of the imine proton by the base and polarization of the imine toward simultaneous ring and C–O bond dissociation, followed by attack of the π-electrons at the electrophilic carbon attached to iodine, leads to formation of the cyclopropane moiety B (which could not be isolated). Then, attack of the iodide ion at the carbon attached to the phenyl group and subsequent ring opening by breaking of a C–C bond and formation of a new C–O bond, through a novel and unexpected rearrangement, leads to the desired product 2a.

Zoom Image
Scheme 6 Possible mechanism

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Supporting Information



Zoom Image
Figure 1 Dihydrofuran-ring-containing biologically active natural products
Zoom Image
Scheme 1 Previous reports
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Scheme 2 Synthesis of 6,6-dimethyl-4-oxo-2-phenyl-4,5,6,7-tetra­hydrobenzofuran-3,3(2H)- dicarbonitrile (2a)
Zoom Image
Figure 2 ORTEP diagram of compound 2c. Displacement thermal ­ellipsoids are drawn at the 30% probability level and H atoms are shown as small spheres of arbitrary radius.
Zoom Image
Scheme 3
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Scheme 4 Substrate scope. Reaction conditions: 1 (1.02 mmol), I2 (1.02 mmol), Et3N (2.04 mmol), DCE (20 mL), reflux. Isolated yields are reported.
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Scheme 5 One-pot synthesis of 6,6-dimethyl-4-oxo-2-phenyl-4,5,6,7-tetrahydrobenzofuran-3,3(2H)-dicarbonitrile (2a)
Zoom Image
Scheme 6 Possible mechanism