DBU-promoted Cascade Annulation of Nitroarylcyclopropane-1,1

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DBU-promoted Cascade Annulation of Nitroarylcyclopropane-1,1dicarbonitriles and 3-Aryl-2-cyanoacrylates: An Access to Highly Functionalized Cyclopenta[b]furan Derivatives Siran Qian, Zengyang Xie, Jiaming Liu, Mingshuang Li, Shan Wang, Naili Luo, and Cunde Wang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02325 • Publication Date (Web): 07 Nov 2018 Downloaded from http://pubs.acs.org on November 7, 2018

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The Journal of Organic Chemistry

DBU-promoted Cascade Annulation of Nitroarylcyclopropane-1,1-dicarbonitriles and 3-Aryl-2-cyanoacrylates: An Access to Highly Functionalized Cyclopenta[b]furan Derivatives Siran Qian,a,& Zengyang Xie,b,& Jiaming Liu,a Mingshuang Li,a Shan Wang,a Naili Luoa and Cunde Wang*a a

School of Chemistry and Chemical Engineering, Yangzhou University,180 Siwangting Street, Yangzhou 225002, P. R. China. Fax: +86-514-8797-5244; Tel: +86-514-8797-5568; E-mail: [email protected] b

College of Basic Medicine, Jining Medical University, Jining 272067, P. R. China.

&

These authors contributed equally to this work and should be considered co-first authors

A DBU-promoted cascade annulation of nitroarylcyclopropane-1,1-dicarbonitriles and

3-aryl-2-cyanoacrylates

cyclopenta[b]furan

for

derivatives

is

the

synthesis

described.

of

High

highly

functionalized

stereoselectivity,

fused

cyclopentane and furan can be established in a single reaction, highlighting the high efficiency and step-economy of this protocol. This reaction offers a novel and straightforward protocol to the synthesis of cyclopenta[b]furans featuring the [3 + 2] cycloadditions

of

nitroarylcyclopropane-1,1-dicarbonitriles

with

3-aryl-2-cyanoacrylates.

Keywords: donor–acceptor cyclopropane; nitroarylcyclopropane-1,1-dicarbonitrile; cyclopenta[b]furan; [3 + 2] cycloaddition; cyclization 1

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Donor-acceptor cyclopropanes (D-A cyclopropanes) have emerged as important synthons for the construction of complex architectures in organic chemistry due to their stereoelectronic factors and intrinsic ring strain.1 D-A cyclopropanes generate easily the stabilised dipoles which can participate in a variety of the annulations and cycloadditions with nucleophiles and electrophiles to these cyclic compounds.2 Moreover, for quite some time the annulations and cycloadditions of D-A cyclopropanes with all-carbon partners have proved to be powerfully synthetic tools to form carbocyclic compounds. In this light, D-A cyclopropanes have emerged to have a prominent role, in recent years remarkable progress has been acquired which led to the development of highly substituted 5-membered carbocycles synthesis, based on the [3 + 2] annulation of functionalized D–A cyclopropanes with alkenes, alkynes, allenes, enol ethers, and enamines.3 As new type of D-A cyclopropanes with three-carbon building blocks, these 1-cyanocyclopropane-1-carboxylate derivatives were used widely in the construction of heterocycles and carbocycles. Because the synergistic effects of the strain and high polarization of the ring, the cyclopropane ring may be cleaved into two 1,3-dipoles in various conditions for the preparation of very important molecular scaffolds, providing a method that was diversity oriented.4 Recently, we have demonstrated the utility of the base-mediated opening ring of 1-cyanocyclopropane-1-carboxylates for the synthesis of densely functionalized and architecturally complex compounds.5 Like 1-cyanocyclopropane-1-carboxylates, 2-aroyl-3-arylcyclopropane-1,1-dicarbonitriles as appropriate D–A cyclopropane candidates can also participate as dipoles in a variety of cycloaddition reactions via rapid ring opening under appropriate conditions.6 As a result of continuing efforts from our research group in this field, an new

[3 + 3] annulation reaction of

2-aroyl-3-arylcyclopropane-1,1-dicarbonitriles was disclosed for the synthesis of fully substituted benzenes.5c The following fully substituted anilines also were successfully prepared via [4 + 2] annulation of 2-aroyl-3-arylcyclopropane-1,1-dicarbonitriles with 3-aryl-2-cyanoacrylate mediated by DBU.7 However, when we further explored the generality of this reaction with a variety of 2-aroyl-3-nitrophenylcyclopropane 2


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-1,1-dicarbonitriles to the reaction conditions, quite unexpectedly, the corresponding fully

substituted

anilines

cyclopenta[b]furan-6-carboxylates

were were

not yielded

obtained, with

the

fused

complete

relative

stereoselectivity via simple DBU-mediated twice annulations. The pleasingly result promoted us to improve further the reaction conditions for the construction of cyclopenta[b]furan core. Functionalized cyclopenta[b]furans are important structural motifs of numerous biologically active natural products and synthetic pharmaceuticals (Figure 1).8-11 For example, (–)-rocaglamide (Scheme 1) is a potent inhibitor of P388 lymphocytic leukemia, a novel natural product isolated from Aglaiaelliptifolia Merr.8-11

Figure 1 Examples for cyclopenta[b]furan containing natural product and synthetic pharmaceuticals The cyclopenta[b]furan class of natural products also includes more complex polycyclic compounds incorporating further fused saturated or unsaturated rings. For instance, the marine alkaloid nakadomarin A9 contains a reduced pyridine and pyrrole core structure, whereas sessilifoliamide I10 can be seen as Stemona derived alkaloids, and the brazilide A,11 is characterized by core structures derived from furan-fused cyclopentanones and chromane, as well as the euphane triterpenes fused cyclopenta[b]furan core12 are a new class of natural products from Lantana Camara, and their simplified synthetic compounds including cyclopenta[b]furan core are used as potential inhibitors to treat thrombotic disorders.13 Synthetic GRL-06579A (Figure 1) is considered to be a powerful enzyme inhibitor and antiviral agents for treatment of HIV.14 Additionally, Strigolactones core structures derived from fused 3



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cyclopentanfuran are important plant hormones, involved in several crucial processes like seed germination, plant growth and shoot branching.15 Therefore, efficient synthesis methods for cyclopenta[b]furan system should be of great importance. In spite of the importance of the cyclopenta[b]furans, only a few methods were reported for the synthesis of these cyclopenta[b]furan derivatives. The existing methods include oxidative cyclization of o-cyclopentenylphenol derivatives,8b [2+2] cycloaddition oxidation sequence,16 Iodine-catalyzed reaction of indandione/indanone and

aldehydes,17

’-bifunctionalization

hypervalent-iodine-mediated of

-ketoesters

and

direct

-diketones,18

dehydrogenative lactonization

of

2-substituted indanone,19 triphenylphosphine-mediated annulation from dialkyl acetylenedicarboxylates,20 Nazarov reactions of 2-furyl vinyl ketones and related enones,21 cobalt-catalyzed domino reaction between 2-bromoaryl aldehyde and dimethyl itaconate,22 ring-closing metathesis/ atom-transfer ring closure strategy,23 acid catalyzed double cyclization,24 intramolecular carboxypalladation of alkynoic acids followed by intramolecular olefin insertion.25 Recently, Vitale and co-workers reported that few compounds containing cyclopenta[b]furan moiety were prepared through formal [3+2] cycloadditions of 2-nitrobenzofurans with vinylcyclopropanes in the presence of palladium(0) catalyst.26 Despite several synthetic strategies to this cyclopenta[b]furan moiety have been researched, to the best of our knowledge, no example of this kind of base-promoted [3+2]/[3+2] cycloaddition reaction has been reported.

Table 1 Screening of reaction conditions for the synthesis of 3a

4


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Entry

Base (eq.)

Solvent

T (oC)

t (h)

Yield (%)a

1

(-)

DCM

20

24

0

2

Et3N(1.0)

DCM

20

24

0

3

Et3N(1.0)

DCM

40

24

25

4

Piperidine(1.0)

DCM

40

24

11

5

DBU (1.0)

DCM

40

12

89

6

DABCO(1.0)

DCM

40

14

69

7

K2CO3(1.0)

DCM

40

12

trace

8

NaOH(1.0)

DCM

40

12

trace

9

DBU(1.0)

1,2-DCE

80

14

82

10

DBU(1.0)

THF

70

14

72

11

DBU (1.0)

toluene

110

14

78

12

DBU(1.0)

EtOH

80

16

65

13

DBU (1.0)

DMF

100

24

trace

14

DBU (1.25)

DCM

40

10

89

15

DBU (0.75)

DCM

40

14

83

14b

EtONa (1.0)

toluene

40

12

36

15b

Guanidine (1.0)

DCM

40

12

88

a

Isolated yields. bnitrogen atmosphere and dried solvent.

At the outset of our experiment, the reaction between 1a and 2a in the mole ratio 1.0:1.0 was chosen as the model reaction (Table 1). Firstly, the solution of substrates 1a and 2a in dichloromethane was stirred at 20 oC without any promoter for 24 h, the conceivable annulation product was not obtained (Table 1, entry 1). Then when the experiment was performed with the reaction between 1a and 2a using 1 equiv. Et3N as a basic promoter at 20 oC for 24 h (Table 1, entry 2), no annulation product was observed. Under otherwise identical conditions, the annulation product 3a was obtained in 25% yield when the reaction was carried out at 40 oC (Table 1, entry 3). The following various bases, piperidine, DBU, DABCO, K2CO3 and NaOH were employed respectively for basic promoters evaluation (entries 4–8). 5


It seems that


more basic organic amines were beneficial to the reaction. With the use of DBU and DABCO as the catalyst, the reaction worked at 40 oC for 12 or 14 h to give the product 3a in 89% and 69% yield (entries 5-6), respectively. Compared with Et3N, DBU displayed much better catalytic activity, greatly shortening the reaction time to 12 h to afford the product 3a (entry 5). With the use of inorganic amines such as K2CO3 or NaOH instead of amines as the basic promoter, only trace product was observed under otherwise identical conditions (entries 7–8). In an attempt to improve yield, different solvents were employed to escalate the reaction temperature. When 1,2-DCE, THF, toluene or EtOH were used respectively in the reaction at different reaction temperatures, the product 3a was obtained in good yields (entries 9-12), however, with the use of DMF as the solvent, the reaction worked at 100 oC to give only trace product 3a even when the reaction time was prolonged to for 24 h (entry 13), the results support the important role that the solvent and the reaction temperature may play in the transition state of this opening ring of D-A cyclopropanes, the higher temperature and the polar aprotic solvents were propitious to the formation of the product 3a. Increasing the DBU loading to 1.25 equiv did not have a significant improvement under otherwise identical conditions (entry 14). Lowering the DBU loading to 0.75 equiv still resulted in 3a in 83% yield, albeit requiring a reaction time of 14 h (entry 15). Additionally, the organic bases EtONa and guanidine were used in the cascade [3+2]/[3+2] cycloaddition under nitrogen atmosphere in dried toluene and dichloromethane respectively (entries 16-17), a modest 36% yield of 3a was obtained with 1 equiv of EtONa in dried toluene (entry 16), EtONa performed worse than the bases DBU and DABCO studied due to both its nucleophilic ability to carry on conjugate addition more readily with acrylates.27 Guanidine (1 equiv) gave a 88% yield of 3a in dried DCM under nitrogen (entry 17), which promoted to catalyze the reaction similarly to DBU. The best result was obtained in the mole ratio 1.0:1.0 for 1a/2a using DBU (1.0 equiv.) as the base at 40 °C in dichloromethane under reflux for 12 h, whereby the yield of product 3a reached 89 % (Table 1, entry 5).

6


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Table 2. Synthesis of 6,6a-dihydro-5H-cyclopenta[b]furan-6-carboxylatesa

Entry

R1

R2

R3

Yield(%)a

1

p-NO2

m-CH3O

p-CH3

89(3a)

2

p-NO2

p-CH3O

p-CH3

89(3b)

3

p-NO2

p-CH3O

p-Br

87(3c)

4

p-NO2

m-CH3O

p-Cl

88(3d)

5

p-NO2

p-CH3O

p-Cl

88(3e)

6

p-NO2

p-CH3O

m-CH3

89(3f)

7

p-NO2

m-Cl

p-OCH3

89(3g)

8

p-NO2

p-CH3O

p-CH3O

87(3h)

9

p-NO2

m-CH3

m-CH3O

90(3i)

10

p-NO2

m-CH3O

p-Br

90(3j)

11

p-NO2

m-CH3

p-CH3O

91(3k)

12

p-NO2

m-CH3O

3,4-OCH2CH2O

88(3l)

13c,d

p-NO2

m-CH3O

thiophen-2-yl

89(3m)

14c

p-NO2

p-CH3O

m-Cl

84(3n)

15

p-NO2

p-Br

p-CH3

86(3o)

16

p-NO2

m-CH3O

m-CH3

89(3p)

17c

o-NO2

p-CH3O

p-Br

85(3q)

18c

o-NO2

p-CH3O

p-Cl

83(3r)

a

Reaction conditions: D-A cyclopropanes 1a-f (1 mmol), acrylates 2a-i (1

mmol), DBU ( 152 mg, 1 mmol), DCM (15 mL), 40 oC, 12 h. bisolated yield. creaction time: 16 h. dUsing ethyl 2-cyano-3-(thiophen-2-yl)acrylate 7



as a substrate.

After the optimal conditions were determined, various nitrophenylcyclopropanes 1a-f and acrylates 2a-i with different substituents were carefully investigated (Table 2). The results indicated that D-A cyclopropanes 1a-f and acrylates 2a-i bearing electron-withdrawing substituents or electron-donating substituents on the aromatic ring are suitable substrates, and the corresponding 3a-r were obtained with usually good to high yields. Substrate acrylates 2a-i at aromatic ring bearing chloro, bromo, methoxy or methyl did not have a remarkable influence on the reaction. Additionally, the substrate acrylates 2a-i with a heterocyclic core such as thiophene was also compatible substrates under the optimal reaction conditions and the corresponding product was obtained in excellent yield (Table 2, entry 13). Both electron-donating and electron withdrawing substituents on the aromatic aroyl group of D-A cyclopropanes 1a-f were well tolerated. The results revealed that a significant ortho site effect of the nitro group was observed. For example, the 2-nitro substituted on the nitrobenzene led to lower yields of the products compared with their 4-substituted counterparts even though the reaction time was prolonged to 16 h. However, the 3-nitro substituted on the nitrobenzene did not undergo annulation under the optimal reaction conditions. Meanwhile, when other electron-withdrawing groups such as p-CF3, m-nitro were used to replace the ortho- or para-nitro group of D-A cyclopropanes 1a-f, the reaction did not work either via cascade annulations, only gave the corresponding aniline derivates (See ESI).7 The relative configuration of 3h and 3p bearing an amine and a carboxylate contiguous substituents at C(2) and C(6), two cyano substituents at C(3) and C(6), three aryl contiguous substituents at C(4), C(5) and C(6a) of 5H-cyclopenta[b]furan core was determined by X-ray crystallography (Figure 2).28

8


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3h

3p

Figure 2 Molecular structures of 3h and 3p, non-hydrogen atoms are shown at the 30% probability level.

On the basis of the above-described results and our previous work on organic base-mediated opening-ring/closing ring reactions of D-A cyclopropane compounds, we propose the mechanism outlined in Scheme 1. First, DBU-mediated deprotonation of D-A cyclopropane affords a cyclopropan-1-ide [A], which undergoes opening ring to produce prop-2-en-1-ide [B].5a In view of nitro group as a strong electron-withdrawing group of prop-2-en-1-ide [B], in addition to induced effects, ortho or para-nitro group promotes the charge separation of anion [B] by conjugation effects. Charge-separated resonance structures do contribute very much to stabilize anion [B] via the resonance hybrids anion [C], [D] and [E]. The Micheal addition of substituted benzyl anion [C] to the double bond of the substrate acrylate gave the adduct [F]. Subsequently, the intramolecular nucleophilic addition of intermediate [F] to C2-carbonyl group of aroyl forms the intermediate nitrophenylcyclopentan-1-olate, following the addition to C5-cyano group transfers easily to the dicyclo intermediate [G] again.5b,5f The 2-amino-6,6a-dihydro-5H-cyclopenta[b]furan-6-carboxylates 3a-r are finally obtained through 1,5-H shift of the intermediate [G] in the presence of base DBU. Moreover, the above reactions are carried out under the optimized reaction conditions when the ortho or para-nitro group of D-A cyclopropanes is replaced by other analogously electron-withdrawing groups such as p-CF3 and m-nitro, the reactions do not afford the title cascade annulations, only gave the corresponding 9



Page 10 of 28

aniline derivates via [4 + 2] annulations promoted by DBU (See ESI).7 Additionally, to understand further the proposed mechanism, the nitroarylcyclopropane-1,1dicarbonitrile was replaced with 1-cyanocyclopropanecarbonate for the reaction with 3-aryl-2-cyanoacrylate,

the

result

showed

that

the

reaction

of

1-cyanocyclopropanecarbonate and 3-aryl-2-cyanoacrylate afforded the simple [3 + 2] cycloaddition to yield a highly functionalized cyclopentane (See ESI). According to the experimental results, the strongly electron-withdrawing ortho or para-nitro group of D-A cyclopropanes plays a very crucial role in the title reactions by synergetic conjugation effects and induced effects. NO2

O

DBU

Ar2

-H NC

CN NC

O2N

CN

CN [A]

[B]

Ar2

O

CN

O2N

Ar

O

Ar3

C

Ar3

CO2Et

O

DBUH

CN CN [E]

O2N

CN Ar2

NC

Ar2

O

[D]

CN O2N

O

O N

CN

CO2Et

Ar3

2

CN

CN

[C]

Ar2

O

Ar2

CN

N

NO2 O N 2

O

O

CN Ar2

DBUH HN [F]

Ar3

CO2Et

DBU H NC

O2N

[G]

CO2Et NC

O

CN Ar2

H2 N

Scheme 1 Proposed Reaction Mechanism

Conclusion In summary, we have demonstrated that a range of fused cyclopenta[b]furan-6carboxylates can be successfully obtained with complete relative stereoselectivity via a simple DBU-mediated cascade annulation of D-A nitroarylcyclopropane and 3-aryl-2-cyanoacrylates. 10


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The reaction is simply promoted by DBU giving the final products in good yields via domino sequence including ring opening of D-A nitroarylcyclopropane, regioselective Micheal addition, twice intramolecular nucleophilic addition and 1,5-H shift. The developed procedure offers several advantages, including good yields, operational simplicity,

mild

reaction

conditions

and

easily

available

substrates

D-A

nitroarylcyclopropanes and 3-aryl-2-cyanoacrylate, which makes it a useful practical process for the synthesis of these cyclopenta[b]furan-6-carboxylate derivatives.

Experimental Melting points were measured on a Mel-Tem capillary melting point apparatus and are uncorrected. 1H NMR spectra are recorded at 400 or 600 MHz and

13

C

NMR were recorded at 100 or 150 MHz in DMSO-d6 referenced to TMS. 1H NMR data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. Chemical shifts are reported in parts per million relative to TMS (1H, δ 0.00;

13

C, δ 0.00). High-resolution mass spectra analysis was

performed using ESI (electrospray ionization) and a TOF analyzer. IR spectra were reported in frequency of absorption (cm−1) with KBr pellet. All reactions were monitored by thin layer chromatography (TLC). For thin-layer chromatography (TLC), silica gel plates (HSGF 254) were used and compounds were visualized by irradiation with UV light. Flash column chromatography was performed using silica gel (230-400 mesh). Acrylates 2a-i and other reagents were purchased from commercial suppliers and purified by standard techniques. Procedure for preparation of nitrophenylcyclopropanes 1a-f The nitrophenylcyclopropanes 1a-f were synthesized following a literature procedure method as described.29

(2S,3R/2R,3S)-2-(3-methoxybenzoyl)-3-(4-nitrophenyl)cyclopropane -1,1-dicarbonitrile (1a) Bright yellow solid, 812 mg, yield: 78%; m.p. 195.5-196.0 oC (EA/PE); IR (KBr, 11



cm-1): 3440, 2972, 2930, 2730, 2672, 2431, 2202, 1680, 1550, 1436, 1332, 1267, 1107, 1021; 1H NMR (600 MHz, DMSO-d6) δ (ppm): 8.30 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 7.2 Hz, 1H), 7.76 (s, 1H), 7.56 (dd, J = 8.4 and 7.2 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 5.20 (d, J = 8.4 Hz, 1H), 4.27 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ (ppm): 189.7, 159.6, 147.8, 138.2, 136.6, 130.7, 130.2, 123.5, 121.7, 120.8, 113.6, 112.5, 112.4, 55.6, 37.5, 34.8, 15.6; HR-MS (ESI) calcd. for C19H13N3NaO4 [(M+Na)+]: 370.0804; Found: 370.0802. (2S,3R/2R,3S)-2-(4-methoxybenzoyl)-3-(4-nitrophenyl)cyclopropane -1,1-dicarbonitrile (1b) Bright yellow solid, 844 mg, yield: 81%; m.p. 211.5-212.0 oC (EA/PE); IR (KBr, cm-1): 3432, 2980, 2932, 2730, 2672, 2422, 2209, 1686, 1552, 1450, 1332, 1289, 1092, 1008; 1H NMR (600 MHz, DMSO-d6) δ (ppm): 8.30 (d, J = 7.8 Hz, 2H), 8.29 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 9.0 Hz, 2H), 7.17 (d, J = 9.0 Hz, 2H), 5.16 (d, J = 8.4 Hz, 1H), 4.25 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ (ppm): 187.8, 164.5, 147.8, 138.3, 131.8, 130.7, 128.2, 123.5, 114.3, 112.6, 112.5, 55.8, 37.2, 34.5, 15.3; HR-MS (ESI) calcd. for C19H13N3NaO4 [(M+Na)+]: 370.0804; Found: 370.0794. (2S,3R/2R,3S)-2-(3-chlorobenzoyl)-3-(4-nitrophenyl)cyclopropane-1,1dicarbonitrile (1c) Bright yellow solid, 876 mg, yield: 83%; m.p. 216.5-217.5 oC (EA/PE); IR (KBr, cm-1): 3428, 3130, 2980, 2922, 2730, 2674, 2426, 2221, 1682, 1555, 1438, 1330, 1270, 1096, 1001; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.43 (s, 1H), 8.30 (d, J = 8.0 Hz, 2H), 8.20 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 7.6 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 5.21 (d, J = 8.0 Hz, 1H), 4.25 (d, J = 8.0 Hz, 1H); 13

C{1H} NMR (100 MHz, DMSO-d6) δ (ppm): 189.7, 148.3, 138.7, 137.7, 134.7,

134.4, 131.3, 131.2, 129.6, 128.1, 123.9, 113.0, 112.1, 38.2, 34.8, 16.7; HR-MS (ESI) calcd. for C18H10ClN3NaO3 [(M+Na)+]: 374.0308; Found: 374.0302. (2S,3R/2R,3S)-2-(3-mehtylbenzoyl)-3-(4-nitrophenyl)cyclopropane-1,1dicarbonitrile (1d) Bright yellow solid, 756 mg, yield: 76%; m.p. 149.0-149.5 oC (EA/PE); IR (KBr, 12


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cm-1): 3420, 3132, 2980, 2920, 2734, 2670, 2420, 2220, 1679, 1550, 1440, 1332, 1272, 1090, 898; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.73 (s, 1H), 8.43 (d, J = 8.0 Hz, 2H), 8.31 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 7.6 Hz, 1H), 8.03 (d, J = 8.0 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 5.18 (d, J = 8.0 Hz, 1H), 4.27 (d, J = 8.0 Hz, 1H), 2.45 (s, 3H);

13

C{1H} NMR (100 MHz, DMSO-d6) δ (ppm): 193.1, 138.3, 137.0, 134.2,

132.9, 130.0, 129.9, 129.1, 128.7, 126.8, 117.9, 112.9，112.1, 32.5, 31.3, 21.4, 16.1; HR-MS (ESI) calcd. for C19H13N3NaO3 [(M+Na)+]: 354.0855; Found: 354.0851. (2S,3R/2R,3S)-2-(4-bromobenzoyl)-3-(4-nitrophenyl)cyclopropane-1,1dicarbonitrile (1e) Bright yellow solid, 975 mg, yield: 82%; m.p. 247.2-247.0 oC (EA/PE); IR (KBr, cm-1): 3430, 2977, 2930, 2728, 2676, 2425, 2202, 1680, 1550, 1442, 1330, 1287, 1082, 998; 1H NMR (600 MHz, DMSO-d6) δ (ppm): 8.30 (d, J = 8.4 Hz, 2H), 8.23 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 9.0 Hz, 2H), 7.87 (d, J = 9.0 Hz, 2H), 5.17 (d, J = 8.4 Hz, 1H), 4.26 (d, J = 8.4 Hz, 1H); 13C{1H} NMR (150 MHz, DMSO-d6) δ (ppm): 189.4, 147.8, 138.3, 134.5, 132.0, 131.1, 130.7, 129.1, 123.4, 112.5, 112.4, 37.6, 34.5, 15.9; HR-MS (ESI) calcd. for C18H10BrN3NaO3 [(M+Na)+]: 417.9803; Found: 417.9801. (2S,3R/2R,3S)-2-(4-methoxybenzoyl)-3-(2-nitrophenyl)cyclopropane -1,1-dicarbonitrile (1f) Bright yellow solid, 761 mg, yield: 73%; m.p. 210.3-211.3 oC (EA/PE); IR (KBr, cm-1): 3387, 2976, 2920, 2720, 2670, 2426, 2220, 1675, 1532, 1450, 1311, 1265, 1090, 898; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.30 (d, J = 7.2 Hz, 2H), 8.28 (t, J = 8.4 Hz, 1H), 7.89 (d, J = 6.6 Hz, 2H), 7.78-7.76 (m, 1H), 7.17 (d, J = 9.0 Hz, 2H), 5.13 (d, J = 8.4 Hz, 1H), 4.27 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H);

13

C{1H} NMR (100

MHz, DMSO-d6) δ (ppm): 187.9, 164.5, 148.9, 134.4, 131.9, 131.8, 130.9, 128.3, 126.3, 125.5, 114.3, 112.9, 112.7, 55.8, 36.6, 35.0, 15.5; HR-MS (ESI) calcd. for C19H13N3NaO4 [(M+Na)+]: 370.0804; Found: 370.0801. General procedure for preparation of 4-nitrophenyl-6,6a-dihydro-5Hcyclopenta[b]furan-6-carboxylate 3a-r 13



To the mixture of nitrophenylcyclopropanes 1a-f (1.0 mmol), and ethyl 2-cyano-3-phenylacrylates 2a-i (1.0 mmol) in dichloromethane (15 mL) was added DBU (152 mg, 1.0 mmol), and the resulting mixture was slowly warmed up to 40 oC and stirred sequentially for ca 12 h until full conversion of the nitrophenylcyclopropanes was achieved (monitored by TLC, Hexanes/EtOAc, 3/1). Upon completion, the reaction mixture was diluted with 10 mL of H2O and extracted with dichloromethane (10 mL X 2). The combined organic layers were washed with water (10 mL) and brine (10 mL), and dried over anhydrous sodium sulphate, and concentrated under reduced pressure to yield a crude product. The crude product was puriﬁed by column chromatography (EtOAc/hexanes, 1/5, silica gel) to provide the desired products 3a-r.

Ethyl (5R,6R,6aS/5S,6S,6aR)-2-amino-3,6-dicyano-6a-(3-methoxyphenyl)-4-(4nitrophenyl)-5-(p-tolyl)-6,6a-dihydro-5H-cyclopenta[b]furan-6-carboxylate (3a) Bright yellow solid, 501 mg, yield: 89 %; m.p. 202.2-203.2 oC (EA/PE); IR (KBr, cm-1): 3410, 3320, 3170, 2999, 2206, 1554, 1513, 1442, 1337, 1237, 1109, 1023, 896, 786; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.19 (s, 2H), 8.10 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.43 (dd, J = 7.6 Hz, 1H), 7.07 (d, J = 6.1 Hz, 3H), 7.05 – 6.94 (m, 3H), 6.89 (s, 1H), 5.49 (s, 1H), 3.98 (s, 2H), 3.77 (s, 3H), 2.20 (s, 3H), 1.07 (t, J = 6.7 Hz, 3H);

13

C{1H} NMR (100 MHz, DMSO-d6) δ (ppm): 175.3, 163.3,

159.8, 145.5, 142.9, 141.6, 137.8, 135.4, 132.7, 130.6, 129.1, 129.0, 123.6, 118.2, 116.0, 115.8, 115.2, 115.0, 112.3, 99.8, 66.6, 63.7, 59.1, 57.5, 55.6, 21.0, 14.0; HR-MS (ESI) calcd. for C32H26N4NaO6 [(M+Na)+]: 585.1750; Found: 585.1748. Ethyl (5R,6R,6aS/5S,6S,6aR)-2-amino-3,6-dicyano-6a-(4-methoxyphenyl)-4-(4nitrophenyl)-5-(p-tolyl)-6,6a-dihydro-5H-cyclopenta[b]furan-6-carboxylate (3b) Bright yellow solid, 501 mg, yield: 89 %; m.p. 197.1-197.6 oC (EA/PE); IR (KBr, cm-1): 3409, 3322, 3221, 3170, 2994, 2929, 2206, 1553, 1513, 1441, 1337, 1236, 1107, 1023, 851, 786; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.19 (s, 2H), 8.10 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 7.0 Hz, 1H), 7.07 (s, 3H), 7.05 – 6.95 (m, 3H), 6.90 (s, 1H), 5.49 (s, 1H), 3.98-3.95 (m, 2H), 3.77 (s, 3H), 2.20 (s, 3H), 1.08 (t, J = 6.6 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm): 175.4, 163.3, 14


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159.8, 145.5, 143.0, 141.6, 137.8, 135.4, 132.7, 130.5, 129.1, 128.8, 123.6, 123.5, 116.0, 115.8, 115.1, 112.3, 99.8, 66.6, 63.7, 59.1, 57.5, 55.7, 20.9, 14.1; HR-MS (ESI) calcd. for C32H26N4NaO6 [(M+Na)+]: 585.1750; Found: 585.1745. Ethyl (5R,6R,6aS/5S,6S,6aR)-2-amino-5-(4-bromophenyl)-3,6-dicyano-6a-(4methoxyphenyl)-4-(4-nitrophenyl)-6,6a-dihydro-5H-cyclopenta[b]furan-6-carbox ylate (3c) Bright yellow solid, 546 mg, yield: 87%; m.p. 222.3-223.3 oC (EA/PE); IR (KBr, cm-1): 3403, 3325, 3177, 2998, 2202, 1743, 1634, 1553, 1512, 1429, 1332, 1227, 1107, 1021; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.17 (s, 2H), 8.11 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 5.49 (s, 1H), 4.00 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 1.10 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm): 175.4, 163.2, 160.8, 145.5, 143.6, 141.3, 135.2, 133.1, 132.7, 131.7, 131.2, 129.3, 128.8, 127.8, 127.3, 125.4, 123.7, 123.5, 122.0, 115.8, 115.1, 114.8, 114.6, 100.0, 66.4, 63.8, 58.6, 57.6, 55.6, 14.1; HR-MS (ESI) calcd. for C31H23BrN4NaO6 [(M+Na)+]: 649.0699; Found: 649.0706. Ethyl (5R,6R,6aS/5S,6S,6aR)-2-amino-5-(4-chlorophenyl)-3,6-dicyano-6a-(3methoxyphenyl)-4-(4-nitrophenyl)-6,6a-dihydro-5H-cyclopenta[b]furan-6-carbox ylate (3d) Bright yellow solid, 513 mg, yield: 88%; m.p. 191.5-192.2 oC (EA/PE); IR (KBr, cm-1): 3364, 3178, 2930, 2838, 2202, 1742, 1634, 1558, 1502, 1446, 1377, 1249, 1106, 1025; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.22 (s, 2H), 8.11 (s, 2H), 7.60 (s, 2H), 7.44 (s, 1H), 7.31 (s, 2H), 7.22 (s, 2H), 7.11 (s, 1H), 7.02 (s, 1H), 6.91 (s, 1H), 5.60 (s, 1H), 4.01 (s, 2H), 3.78 (s, 3H), 1.09 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm): 175.4, 163.1, 159.9, 145.6, 143.3, 141.2, 135.3, 134.8, 133.3, 132.8, 132.4, 131.0, 129.3, 128.8, 128.3, 123.7, 118.3, 115.7, 115.3, 114.9, 112.3, 99.8, 66.4, 63.8, 58.7, 57.6, 55.7, 14.1; HR-MS (ESI) calcd. for C31H23ClN4NaO6 [(M+Na)+]: 605.1204; Found: 605.1205. Ethyl (5R,6R,6aS/5S,6S,6aR)-2-amino-5-(4-chlorophenyl)-3,6-dicyano-6a-(4methoxyphenyl)-4-(4-nitrophenyl)-6,6a-dihydro-5H-cyclopenta[b]furan-6-carbox 15



ylate (3e) Bright yellow solid, 513 mg, yield: 88%; m.p. 204.5-205.7 oC (EA/PE); IR (KBr, cm-1): 3385, 3168, 2933, 2835, 2201, 1742, 1635, 1549, 1443, 1369, 1248, 1106, 1029; 1

H NMR (400 MHz, DMSO-d6) δ (ppm): 9.18 (s, 2H), 8.12 (d, J = 7.8 Hz, 2H), 7.56

(d, J = 7.9 Hz, 2H), 7.33 (s, 4H), 7.20 (d, J = 7.3 Hz, 2H), 7.06 (d, J = 7.8 Hz, 2H), 5.52 (s, 1H), 4.01 (d, J = 6.6 Hz, 2H), 3.79 (s, 3H), 1.11 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm): 175.4, 163.2, 160.8, 145.5, 143.6, 141.3, 134.8, 133.3, 132.6, 129.0, 128.6, 127.6, 125.4, 123.6, 115.9, 115.1, 114.9, 114.7, 100.0, 66.5, 63.8, 58.5, 57.6, 55.7, 14.0; HR-MS (ESI) calcd. for C31H23ClN4NaO6 [(M+Na)+]: 605.1204; Found: 605.1219. Ethyl (5R,6R,6aS/5S,6S,6aR)-2-amino-3,6-dicyano-6a-(4-methoxyphenyl)-4-(4nitrophenyl)-5-(m-tolyl)-6,6a-dihydro-5H-cyclopenta[b]furan-6-carboxylate (3f) Bright yellow solid, 501 mg, yield: 89%; m.p. 218.4-219.2 oC (EA/PE); IR (KBr, cm-1): 3402, 3328, 3176, 2995, 2212, 1753, 1643, 1508, 1429, 1335, 1234, 1101, 1022; 1


(d, J = 8.6 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.13-6.96 (m, 5H), 6.92 (d, J = 7.5 Hz, 1H), 5.40 (s, 1H), 4.07 – 3.87 (m, 2H), 3.78 (s, 3H), 2.16 (s, 3H), 1.10 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm): 180.1, 168.1, 165.5, 150.1, 148.1, 146.4, 142.24, 140.5, 136.2, 133., 133.7, 133.0, 132.6, 132.3, 130.3, 128.2, 120.7, 120.2, 119.9 119.4, 104.8, 71.4, 68.4, 63.9, 62.3, 60.5, 26.1, 18.8; HR-MS (ESI) calcd. for C32H26N4NaO6 [(M+Na)+]: 585.1750; Found: 585.1761. Ethyl (5R,6R,6aS/5S,6S,6aR)-2-amino-6a-(3-chlorophenyl)-3,6-dicyano-5-(4methoxyphenyl)-4-(4-nitrophenyl)-6,6a-dihydro-5H-cyclopenta[b]furan-6-carbox ylate (3g) Bright yellow solid, 519 mg, yield: 89%; m.p. 158.6-159.6 oC (EA/PE); IR (KBr, cm-1): 3394, 3179, 2945, 2208, 1548, 1356, 1248, 1108, 1021, 886, 789, 506; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.17 (s, 2H), 8.11 (s, 2H), 7.56 (s, 2H), 7.32 (s, 4H), 7.20 (s, 2H), 7.06 (s, 2H), 5.51 (s, 1H), 4.01 (s, 2H), 3.79 (s, 3H), 1.11 (s, 3H); 13


141.3, 134.8, 133.3, 132.6, 129.0, 128.6, 127.6, 125.4, 123.6, 115.9, 115.1, 114.9, 16


Page 16 of 28

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114.7, 100.0, 66.5, 63.8, 58.5, 57.6, 55.7, 14.0; HR-MS (ESI) calcd. for C31H23ClN4NaO6 [(M+Na)+]: 605.1204; Found: 605.1201. Ethyl (5R,6R,6aS/5S,6S,6aR)-2-amino-3,6-dicyano-5,6a-bis(4-methoxyphenyl)-4(4-nitrophenyl)-6,6a-dihydro-5H-cyclopenta[b]furan-6-carboxylate (3h) Bright yellow solid, 503 mg, yield: 87%; m.p. 197.1-197.8 oC (EA/PE); IR (KBr, cm-1): 3426, 3306, 3221, 3170, 2925, 2211, 1744, 1635, 1549, 1432, 1330, 1239, 1106, 1029; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.14 (s, 2H), 8.09 (s, 2H), 7.53 (s, 2H), 7.30 (s, 2H), 7.07 (d, J = 9.0 Hz, 4H), 6.79 (s, 2H), 5.40 (s, 1H), 3.99 (s, 2H), 3.78 (s, 3H), 3.67 (s, 3H), 1.10 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm): 175.4, 163.4, 160.7, 159.2, 145.4, 143.1, 141.7, 131.9, 129.0, 127.5, 125.5, 123.5, 116.0, 115.7, 115.3, 114.7, 113.9, 99.9, 66.8, 63.6, 58.7, 57.5, 55.7, 55.3, 14.0; HR-MS (ESI) calcd. for C32H26N4NaO7 [(M+Na)+]: 601.1699; Found: 601.1701. Ethyl (5R,6R,6aS/5S,6S,6aR)-2-amino-3,6-dicyano-5-(3-methoxyphenyl)-4-(4nitrophenyl)-6a-(m-tolyl)-6,6a-dihydro-5H-cyclopenta[b]furan-6-carboxylate (3i) Bright yellow solid, 506 mg, yield: 90%; m.p. 183.5-184.3 oC (EA/PE); IR (KBr, cm-1): 3412, 3307, 3217, 3172, 2926, 2201, 1753, 1643, 1558, 1509, 1446, 1334, 1237, 1105, 1032; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.15 (s, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.40 (dd, J = 7.9 Hz, 1H), 7.05 (d, J = 6.2 Hz, 2H), 7.03-6.93 (m, 3H), 6.90 (d, J = 7.2 Hz, 1H), 6.85 (s, 1H), 5.45 (s, 1H), 4.08 – 3.84 (m, 2H), 3.73 (s, 3H), 2.13 (s, 3H), 1.04 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ (ppm): 174.9, 162.8, 159.4, 145.0, 142.6, 141.2, 137.0, 135.2, 135.0, 131.0, 130.2, 128.7, 128.4, 127.8, 127.3, 123.1, 117.8, 115.4, 114.7, 114.5, 111.8, 99.4, 66.1, 63.2, 58.8, 57.1, 26.3, 20.9, 13.5; HR-MS (ESI) calcd. for C32H26N4NaO6 [(M+Na)+]: 585.1750; Found: 585.1747. Ethyl (5R,6R,6aS/5S,6S,6aR)-2-amino-5-(4-bromophenyl)-3,6-dicyano-6a-(3methoxyphenyl)-4-(4-nitrophenyl)-6,6a-dihydro-5H-cyclopenta[b]furan-6-carbox ylate (3j) Bright yellow solid, 565 mg, yield: 90%; m.p. 163.1-164.0 oC (EA/PE); IR (KBr, cm-1): 3398, 3182, 2926, 2207, 1743, 1642, 1588, 1369, 1242, 1107, 1028; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.21 (s, 2H), 8.10 (s, 2H), 7.58 (s, 2H), 7.44 (s, 3H), 17



Page 18 of 28

7.11 (s, 3H), 6.99 (s, 1H), 6.88 (s, 1H), 5.57 (s, 1H), 3.99 (s, 2H), 3.77 (s, 3H), 1.07 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm): 175.4, 163.1, 159.8, 145.6, 143.3, 141.2, 135.2, 132.9, 131.5, 130.7, 129.0, 123.6, 122.0, 118.2, 115.7, 115.3, 114.9, 112.3, 99.8, 66.3, 63.9, 58.8, 57.5, 55.6, 14.0; HR-MS (ESI) calcd. for C31H23BrN4NaO6 [(M+Na)+]: 649.0699; Found: 649.0693. Ethyl (5R,6R,6aS/5S,6S,6aR)-2-amino-3,6-dicyano-5-(4-methoxyphenyl)-4-(4nitrophenyl)-6a-(m-tolyl)-6,6a-dihydro-5H-cyclopenta[b]furan-6-carboxylate (3k) Bright yellow solid, 512 mg, yield: 91%; m.p. 197.0-197.8oC(EA/PE); IR (KBr, cm-1): 3410, 3318, 3170, 2996, 2935, 2208, 1554, 1512, 1441, 1336, 1236, 1107, 1023, 971, 893, 749, 462; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.18 (s, 2H), 8.09 (d, J = 7.1 Hz, 2H), 7.54 (d, J = 7.1 Hz, 2H), 7.42 (s, 1H), 7.25-6.89 (m, 6H), 6.88 (s, 1H), 5.48 (s, 1H), 3.97 (s, 2H), 3.76 (s, 3H), 2.18 (s, 3H), 1.06 (s, 3H);

13

C{1H} NMR (100

MHz, DMSO-d6) δ (ppm): 175.3, 163.3, 159.8, 145.5, 142.9, 141.6, 137.8, 135.4, 132.7, 130.7, 130.6, 129.1, 129.0, 123.6, 118.2, 116.0, 115.8, 115.2, 115.0, 112.3, 99.8, 66.6, 63.7, 59.1, 57.4, 55.6, 21.0, 14.0; HR-MS (ESI) calcd. for C32H26N4NaO6 [(M+Na)+]: 585.1750; Found: 585.1753. Ethyl (5R,6R,6aS/5S,6S,6aR)-2-amino-3,6-dicyano-5-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)-6a-(3-methoxyphenyl)-4-(4-nitrophenyl)-6,6a-dihydro-5H-cyclopenta [b]furan-6-carboxylate (3l) Bright yellow solid, 534 mg, yield: 88%; m.p. 159.1-159.8 oC (EA/PE); IR (KBr, cm-1): 3356, 3179, 2934, 2205, 1747, 1647, 1566, 1509, 1444, 1387, 1338, 1290, 1242, 1113, 1057, 1031; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.17 (s, 2H), 8.12 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 7.42 (dd, J = 8.1 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 7.7 Hz, 1H), 6.85 (s, 1H), 6.68 (d, J = 8.5 Hz, 2H), 6.59 (d, J = 8.6 Hz, 1H), 5.40 (s, 1H), 4.15 (s, 4H), 3.98 (q, J = 5.2 Hz, 2H), 3.76 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm): 175.3, 163.3, 159.8, 145.5, 143.5, 143.0, 142.8, 141.6, 135.4, 130.7, 128.9, 128.5, 123.7, 123.6, 119.3, 118.2, 117.0, 115.9, 115.8, 115.2, 115.1, 112.3, 99.7, 66.5, 64.3, 63.7, 58.7, 57.4, 55.6, 55.3, 14.0; HR-MS (ESI) calcd. for C33H26N4NaO8 [(M+Na)+]: 629.1648; Found: 18


Page 19 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


629.1645. Ethyl (5R,6R,6aS/5S,6S,6aR)-2-amino-3,6-dicyano-6a-(3-methoxyphenyl)-4-(4nitrophenyl)-5-(thiophen-2-yl)-6,6a-dihydro-5H-cyclopenta[b]furan-6-carboxylat e (3m) Bright yellow solid, 494 mg, yield: 89%; m.p. 127.6-128.2 oC (EA/PE); IR (KBr, cm-1): 3451, 3339, 3160, 2942, 2838, 2205, 1731, 1636, 1594, 1560, 1518, 1340, 1254, 1110, 1026; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.21 (s, 2H), 8.13 (s, 2H), 7.60 (s, 2H), 7.41 (s, 2H), 7.09 (s, 1H), 6.97 (s, 1H), 6.87 (s, 2H), 6.79 (s, 1H), 5.80 (s, 1H), 4.00 (s, 2H), 3.76 (s, 3H), 1.08 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm): 175.2, 163.1, 159.9, 145.7, 142.7, 141.5, 138.0, 135.0, 130.8, 129.6, 129.0, 127.4, 127.2, 123.5, 118.2, 115.7, 115.6, 115.3, 115.0, 112.2, 99.3, 67.1, 63.9, 57.2, 55.6, 55.0, 14.0; HR-MS (ESI) calcd. for C29H22N4NaO6S [(M+Na)+]: 577.1158; Found: 577.1152. Ethyl (5R,6R,6aS/5S,6S,6aR)-2-amino-5-(3-chlorophenyl)-3,6-dicyano-6a-(4methoxyphenyl)-4-(4-nitrophenyl)-6,6a-dihydro-5H-cyclopenta[b]furan-6-carbox ylate (3n) Bright yellow solid, 490 mg, yield: 84%; m.p. 184.6-185.8 oC (EA/PE); IR (KBr, cm-1): 3429, 3326, 3179, 2985, 2204, 1753, 1634, 1558, 1508, 1323, 1231, 1100, 1019; 1


(d, J = 7.0 Hz, 2H), 7.42-7.15 (m, 5H), 7.10 (s, 1H), 7.05 (s, 2H), 5.52 (s, 1H), 3.99 (s, 2H), 3.78 (s, 3H), 1.10 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm): 175.4, 163.2, 160.8, 145.5, 143.8, 141.3, 138.2, 132.9, 130.8, 130.3, 129.5, 129.0, 128.6, 127.5, 125.3, 123.6, 115.8, 115.0, 114.7, 99.9, 66.4, 63.9, 58.6, 57.5, 55.7, 14.0; HR-MS (ESI) calcd. for C31H23ClN4NaO6 [(M+Na)+]: 605.1204; Found: 605.1212. Ethyl (5R,6R,6aS/5S,6S,6aR)-2-amino-6a-(4-bromophenyl)-3,6-dicyano-4-(4nitrophenyl)-5-(p-tolyl)-6,6a-dihydro-5H-cyclopenta[b]furan-6-carboxylate (3o) Bright yellow solid, 526 mg, yield: 86%; m.p. 195.1-195.9 oC (EA/PE); IR (KBr, cm-1): 3384, 3222, 3153, 2926, 2837, 2200, 1743, 1636, 1526, 1450, 1343, 1287, 1162, 1106; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.20 (s, 2H), 8.10 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.05-7.02 19



(m, 4H), 5.44 (s, 1H), 3.99 (q, J= 6.8, 2H), 2.19 (s, 3H), 1.08 (t, J = 7.0 Hz, 3H); 13


137.8, 133.3, 132.5, 130.6, 129.2, 128.3, 123.9, 123.5, 116.3, 115.7, 114.9, 99.5, 66.6, 63.9, 59.0, 57.3, 21.0, 14.0; HR-MS (ESI) calcd. for C31H23BrN4NaO5 [(M+Na)+]: 633.0750; Found: 633.0749. Ethyl (5R,6R,6aS/5S,6S,6aR)-2-amino-3,6-dicyano-6a-(3-methoxyphenyl)-4-(4nitrophenyl)-5-(m-tolyl)-6,6a-dihydro-5H-cyclopenta[b]furan-6-carboxylate (3p) Bright yellow solid, 501 mg, yield: 89%; m.p. 170.3-171.4 oC (EA/PE); IR (KBr, cm-1): 3408, 3309, 3171, 2995, 2202, 1742, 1633, 1552, 1510, 1444, 1336, 1234, 1107, 1020; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.18 (s, 2H), 8.09 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.43 (dd, J = 8.0 Hz, 1H), 7.09 (dd, J = 8.3, 4.8 Hz, 2H), 7.06 – 7.00 (m, 2H), 6.98 (d, J = 7.8 Hz, 1H), 6.93 (d, J = 7.5 Hz, 1H), 6.88 (s, 1H), 5.47 (s, 1H), 4.05 – 3.90 (m, 2H), 3.77 (s, 3H), 2.16 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H); 13


141.6, 137.5, 135.7, 135.4, 131.4, 130.7, 129.1, 128.9, 128.3, 127.8, 123.5, 118.2, 115.9, 115.8, 115.2, 115.0, 112.3, 99.9, 66.6, 63.7, 59.3, 57.5, 55.6, 26.7, 14.0; HR-MS (ESI) calcd. for C32H26N4NaO6 [(M+Na)+]: 585.1750; Found: 585.1737. Ethyl (5R,6R,6aS/5S,6S,6aR)-2-amino-5-(4-bromophenyl)-3,6-dicyano-6a-(4methoxyphenyl)-4-(2-nitrophenyl)-6,6a-dihydro-5H-cyclopenta[b]furan-6-carbox ylate (3q) Bright yellow solid, 533 mg, yield: 85%; m.p. 172.6-173.3 oC (EA/PE); IR (KBr, cm-1): 3358, 3230, 3184, 2919, 2846, 2208, 1732, 1652, 1517, 1452, 1346, 1298, 1171, 1102, 1017; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.09 (s, 2H), 7.87 (s, 1H), 7.80 (s, 2H), 7.51 (s, 3H), 7.35 (s, 2H), 7.11 (s, 2H), 6.89 (s, 2H), 5.07 (s, 1H), 3.98 (s, 2H), 3.82 (s, 3H), 1.08 (s, 3H);

13

C{1H} NMR (100 MHz, DMSO-d6) δ (ppm): 174.6,

163.1, 160.9, 147.1, 134.1, 132.9, 131.4, 129.4, 129.0, 127.7, 125.5, 124.7, 122.3, 115.3, 114.7, 114.3, 99.7, 67.9, 63.8, 55.7, 55.3, 14.0; HR-MS (ESI) calcd. for C31H23BrN4NaO6 [(M+Na)+]: 649.0699; Found: 649.0697. Ethyl (5R,6R,6aS/5S,6S,6aR)-2-amino-5-(4-chlorophenyl)-3,6-dicyano-6a-(4methoxyphenyl)-4-(2-nitrophenyl)-6,6a-dihydro-5H-cyclopenta[b]furan-6-carbox 20


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ylate (3r) Bright yellow solid, 484 mg, yield: 83%; m.p. 187.6-188.2 oC (EA/PE); IR (KBr, cm-1): 3376, 3236, 3165, 2935, 2846, 2203, 1731, 1654, 1528, 1458, 1341, 1286, 1169, 1102; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.09 (s, 2H), 7.81 (s, 3H), 7.52 (s, 3H), 7.23 (s, 2H), 7.12 (s, 2H), 6.97 (s, 2H), 5.10 (s, 1H), 3.99 (s, 2H), 3.83 (s, 3H), 1.09 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm): 174.6, 163.1, 160.9, 147.1, 143.8, 134.20, 133.6, 132.9, 132.7, 129.4, 129.0, 128.5, 127.7, 125.4, 124.7, 115.3, 114.7, 114.4, 99.7, 67.8, 63.8, 58.4, 55.7, 14.0; HR-MS (ESI) calcd. for C31H23ClN4NaO6 [(M+Na)+]: 605.1204; Found: 605.1206.

Associated Content * Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc. 1

H NMR and 13C NMR Spectra of all the products and X-ray Structure of 3h and 3p.

Acknowledgements Financial support of this research by the National Natural Science Foundation of China (NNSFC 21173181) is gratefully acknowledged by authors. A project was funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions and the Top-notch Academic Programs Project of Jiangsu Higher Education Institutions (PPZY2015B112).

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cyclopenta[b]benzofurans, Synlett 2018, 29, 928-932. 27 (a) Wu, J. S.; Zhang, X.; Zhang, Y. L.; Xie, J. W. Synthesis and antifungal activities of novel polyheterocyclic spirooxindole derivatives, Org. Biomol. Chem. 2015, 13, 4967-4975; (b) Gowrisankar, S.; Park, D. Y.; Kim, J. N. Synthesis of 2,3,4-trisubstituted 2,5-dihydrofuran derivatives, Bull. Korean Chem. Soc. 2005, 26, 1826-1828. 28 CCDC 1588435 (for 3h), and 1570783 (for 3p) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre. 29 Wang, Q.; Song, X.; Chen, J.; Yan, C. Pyridinium ylide-assisted one-pot two-step tandem synthesis of polysubstituted cyclopropanes, J. Comb. Chem. 2009, 11, 1007–1010.

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DBU-promoted Cascade Annulation of Nitroarylcyclopropane-1,1

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