CC BY ND NC 4.0 · SynOpen 2017; 01(01): 0068-0075
DOI: 10.1055/s-0036-1590969
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Diastereoselective [Cu(MeCN)4BF4/BF3·Et2O]-Catalyzed Cyclopropenation of Alkynes: Asymmetric Synthesis of β-Amino-α-cyclopropenyl Phosphonates

Haihong Gea, Shuang Liua, Yan Caia, Zenghui Gaoa, Siyi Dua, Zhiwei Miao*a, b, Guixian Xie*c
  • aState Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, P. R. of China   Email: miaozhiwei@nankai.edu.cn
  • bCollaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, P. R. of China
  • cCollege of Resources and Environment, Hunan Agricultural University, Changsha 410128, P. R. of China   Email: xieguixian@126.com
We thank the Committee of Science and Technology of Tianjin (15JCYBJC20700), the Tianjin Rural Work Committee (201604020) and State Key Laboratory of Elemento-Organic Chemistry in Nankai University for financial support.
Further Information

Publication History

Received: 31 May 2017

Accepted after revision: 06 July 2017

Publication Date:
03 August 2017 (online)

 

Abstract

The diastereospecific formation of β-amino-α-cyclopropenyl phosphonates has been achieved in moderate yields from the cyclopropenation of 1-alkynes with dialkyl α-diazophosphonates. The reaction was performed by using a combined catalyst consisting of Cu(MeCN)4BF4 and BF3·Et2O as additive in dichloromethane at 40 °C. A possible mechanism for the reaction has been proposed to explain the origin of the activation and the asymmetric induction. This method provides a versatile approach to β-amino-α-cyclopropenylphosphonates containing a quaternary stereogenic center with good efficiency and diastereoselectivity.


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Cyclopropenes are a unique class of the smallest ring compound with a double bond, and the combination of high strain and unsaturation renders cyclopropenes as versatile synthons in a wide variety of organic synthesis.[1] To enhance the synthetic potential of cyclopropenes further, the development of expeditious methods for their synthesis is highly desirable.[2] One of the most efficient catalytic asymmetric methods for their preparation involves the reaction of alkynes with diazo compounds using chiral copper(I),[3] iridium(II),[4] cobalt(II),[5] or rhodium(II)[6] catalysts. Diazo compounds are commonly used in formation of metallocarbenoids, which can subsequently undergo diverse chemical transformations.[7] In 1992, Doyle, Müller and co-workers reported the first cyclopropenation reactions of diazoacetates with terminal alkynes using [Rh2(5S-mepy)4] as a chiral catalyst.[8] Corey and co-workers also reported a significantly improved enantioselective cyclopropenation of ethyl diazoacetate with 1-alkynes using a new rhodium complex, Rh2(OAc)(DPTI)3, as a catalyst.[9] Although high levels of enantioselectivity (up to 99% ee) in cyclopropenations of terminal alkynes with aryldiazoacetates under catalysis by [Rh2(S-dosp)4] have been reported by Davies and co-workers,[10] stereoselective syntheses of the corresponding cyclopropenylphosphonates using such a strategy remain scarce.[11]

α-Diazophosphonates are phosphorus analogues of α-diazoacetates, and therefore could undergo a range of chemical transformations and the synthesis of varieties of functionalized phosphorous compounds.[12] In 2013, Charette and co-workers reported the first catalytic asymmetric synthesis of bis-acceptor cyclopropylphosphonates through the reaction of α-cyano diazophosphonates with allenes catalyzed by Rh2(S-IBAZ)4 under mild reaction conditions.[13] Cyclopropylphosphonates demonstrate a range of biological and biochemical properties.[14] By analogy with cyclopropylphosphonates,[15] the development of efficient methods for the preparation of cyclopropenephosphonates is attracting increasing attention. In particular, the presence of a quaternary stereocenter in a highly substituted cyclopropenephosphonate can lead to interaction with certain proteases and a resistance to proteolytic degradation.[14]

Recently, we reported novel α-diazophosphonyl compounds prepared from natural amino acids that be used to could perform combined C–H functionalization and O–H insertion to form tertiary β-alkoxy-substituted β-aminophosphonates (Scheme [1], Eq. 1).[16] As a natural extension of the combined C–H functionalization/O–H insertion reaction, we have developed a regioselective boron trifluoride-catalyzed C–H functionalization/S–H insertion reaction for the synthesis of N,S-acetals containing quaternary centers (Scheme [1], Eq. 2).[17] In a continuation of our interest in the chemistry of aminophosphorus derivatives,[18] we herein report the first example of the conversion of dialkyl α-diazophosphonates into cyclopropenylphosphonate derivatives catalyzed by tetrakis (acetonitrile)copper(I) tetrafluoroborate/boron trifluoride [Cu(MeCN)4BF4/BF3·Et2O] in a highly diastereoselective manner (Scheme [1], Eq. 3).

Zoom Image
Scheme 1 Previous and proposed work

We began our investigations by studying the reaction of diethyl α-diazophosphonate 1a [16] with phenylacetylene 2a in the presence of catalyst in dichloromethane at 25 °C (Table [1]). The results revealed that transition-metal catalysts such as Rh2(OAc)4 and Hg(OTf)2 did not decompose 1a in the presence of 2a (entries 1 and 2). The other catalysts tested (e.g., CuOTf, AgOTf, and Cu(MeCN)4PF6) could be used to promote the reaction, resulting in low yields of product with moderate diastereoselectivities (entries 3–5). To our delight Cu(MeCN)4BF4 catalyzed the decomposition of 1a, and diethyl(2-(phenyl-cycloprop-2-enyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)phosphonate (3a) was obtained with good diastereoselectivity (dr = 12:1) in 29% yield (entry 6). In addition, a 1,2-hydrogen migration by-product (Z)-diethyl(2-(1,3-dioxoisoindolin-2-yl)prop-1-en-1-yl) phosphonate (4a) was obtained in 9% yield. The molecular structure of 3a was determined based on 1H, 31P, 13C NMR, and 2D NMR spectroscopy and mass spectrometry.[19] This result encouraged us to choose Cu(MeCN)4BF4 as the catalyst for further optimization of the reaction conditions. To improve the reactivity and diastereoselectivity, the effects of different additives and solvents were investigated.

Initially, additives were evaluated to study the diastereo­selectivity of this transformation. As shown in Table [1], both the diastereoselectivity and the ratio of the two products 3a and 4a was affected dramatically by the additive. In the presence of Cu(MeCN)4BF4 as the catalyst (5 mol%) and BF3·Et2O (20 mol%) as the additive in dichloromethane, the reaction proceeded with an increased combined yield and good diastereoselectivity (dr = 12:1) (entry 7). Furthermore, we found that high temperatures favored this reaction. When the reaction was carried out at 40 °C, the desired product 3a could be obtained in 66% yield (entry 8). After screening BF3·Et2O, it was found that acetone, CH3CN, DMF, and iodine did not give superior results in terms of either reactivity or stereoselectivity (entries 9–12).

Table 1 Optimization of the Reaction Conditionsa

Entry

Catalysts

Additive

Solvent

(3a:4a) ratiob

Overall yield (%)c

Yield 3a (%)d

dr e

1

Rh2(OAc)4

CH2Cl2

N.R.

N.R.

2

Hg(OTf)2

CH2Cl2

N.R.

N.R.

3

CuOTf

CH2Cl2

63:37

<10

<10

8:1

4

AgOTf

CH2Cl2

57:43

<10

<10

10:1

5

Cu(MeCN)4PF6

CH2Cl2

60:40

23

14

12:1

6

Cu(MeCN)4BF4

CH2Cl2

77:23

38

29

12:1

7

Cu(MeCN)4BF4

BF3·Et2O

CH2Cl2

78:22

42

33

12:1

8f

Cu(MeCN)4BF4

BF3·Et2O

CH2Cl2

82:18

81

66

12:1

9

Cu(MeCN)4BF4

CH3COCH3

CH2Cl2

75:25

28

21

10:1

10

Cu(MeCN)4BF4

CH3CN

CH2Cl2

70:30

33

23

>25:1

11

Cu(MeCN)4BF4

DMF

CH2Cl2

78:22

25

20

15:1

12

Cu(MeCN)4BF4

iodine

CH2Cl2

64:36

40

26

13:1

13f

Cu(MeCN)4BF4

BF3·Et2O

toluene

76:24

38

29

16:1

14f

Cu(MeCN)4BF4

BF3·Et2O

THF

80:20

47

38

15:1

15f

Cu(MeCN)4BF4

BF3·Et2O

DMEg

78:22

42

33

10:1

16f

Cu(MeCN)4BF4

BF3·Et2O

1,2-dichloroethane

82:18

42

34

12:1

17f,h

Cu(MeCN)4BF4

BF3·Et2O

CH2Cl2

68:32

44

30

8:1

18f,i

Cu(MeCN)4BF4

BF3·Et2O

CH2Cl2

66:34

51

34

10:1

a Unless otherwise specified, all reactions were carried out using α-diazophosphonate 1a (0.28 mmol, 1 equiv) and phenylacetylene 2a (1.40 mmol, 5 equiv) in the specified solvent (6 mL) with 5 mol% catalyst and 20 mol% additive at 25 °C for 3.5 h (addition over 1.5 h, then a further 2 h).

b The product ratio was determined by 31P NMR spectroscopic analysis of the crude product.

c Overall yield of the mixture of 3a and 4a after silica gel chromatograph.

d Yield of isolated product.

e Diastereomeric ratio (dr) based on 31P NMR spectroscopic analysis of the isolated product 3a.

f Reaction temperature 40 °C.

g DME = dimethoxyethane.

h 2 mol% Cu(MeCN)4BF4 and 10 mol% BF3·Et2O were used.

i 10 mol% Cu(MeCN)4BF4 and 30 mol% BF3·Et2O were used.

With the optimum combination of Cu(MeCN)4BF4 catalyst and BF3·Et2O additive, we next carried out the reaction in different solvents to determine the best solvent for this reaction. Toluene, THF, DME, and 1,2-dichloroethane all provided lower yields of the desired products 3a and 4a with moderate diastereoselectivities (Table [1], entries 13–16). This screening therefore identified CH2Cl2 as the optimal solvent for this reaction. Furthermore, a decrease in the catalyst loading to 2 mol% Cu(MeCN)4BF4 and 10 mol% BF3·Et2O led to a decrease in both yield and diastereoselectivity (entry 17). A similar result was obtained when the reaction was performed in CH2Cl2 with increased catalyst loading to 10 mol% Cu(MeCN)4BF4 and 30 mol% BF3·Et2O (entry 18). Thus, the optimal reaction conditions for this transformation were determined to be 0.28 mmol α-diazo phosphonate 1a, 5.0 equivalents of phenylacetylene 2a, 5 mol% Cu(MeCN)4BF4 and 20 mol% BF3·Et2O as co-catalyst in 6 mL CH2Cl2 as solvent at 40 °C.

Under the optimal reaction conditions, the substrate scope of this reaction was investigated (Table [2]). The impact of different groups on the β-position of dialkyl α-diazophosphonates 1 was evaluated. α-Diazophosphonates 1ae with different substituents in the β-position, such as methyl, benzyl, isobutyl, ethyl, and 4-acetoxybenzyl groups, afforded moderate yields of the β-amino-α-cyclopropenylphosphonates 3ae and the 1,2-hydride migration products 4ae (entries 1–5). It is worth noting that diethyl α-diazophosphonate 1f, derived from methionine, did not undergo reaction to give the desired products, probably due to the fact that the sulfur atom coordinates with the copper(I) and hinders the reaction (entry 6). Instead, the starting material 1f decomposed under the reaction conditions. In addition to phenylacetylene, 3-methylphenyl acetylene and 4-methylphenylacetylene were also examined in the cyclopropenation reaction with carbenoids derived from dialkyl α-diazophosphonates 1b and 1g. Electron-rich phenylacetylene derivatives, substituted either at the meta-, or para-position, all provided good yields and diastereoselectivities of the corresponding β-amino-α-cyclopropenylphosphonates (entries 7 and 8). Chiral cyclopropene derivatives 3i and 3j from reactions of aromatic alkynes containing both electron-withdrawing and -donating groups at the para-position could also be obtained in poor yields but with good dia­stereoselectivities (entries 9 and 10). The cyclopropenation could also be conducted on the internal alkyne prop-1-ynyl-benzene 2f with excellent diastereoselectivity (>30:1), albeit in diminished yield (11%), presumably due to the steric effect (entry 11).

To assess the effects of the substrate on product selectivity, we set out to study the reactions of a series of dialkyl α-diazophosphonates 1hl under Cu(MeCN)4BF4/BF3·Et2O catalysis. When the steric bulk of the R2 group was increased from methyl to isopropyl or n-butyl, similar yields were obtained. These results showed that the size of the R2 group on the α-diazophosphonates 1 has almost no influence on reactivity in this cyclopropenation reaction (Table [2], entries 12–16). The method was successful for alkynes that are conjugated to an arene. However, cyclopropene products were not obtained when diethyl α-diazophosphonate 1a was reacted with (triisopropyl)silylacetylene or 1-hexyne.

Table 2 Scope of the Reactiona

Entry

Product

R1

R2

R3

R4

3/4 Ratiob

Overall yield (%)c

Yield 3 (%)d

dr e

1

3a

CH3 (1a)

CH2CH3

H (2a)

H

82:18

81

66

12:1

2

3b

CH2C6H5 (1b)

CH2CH3

H (2a)

H

78:22

74

58

>30:1

3

3c

CH2CH(CH3)2 (1c)

CH2CH3

H (2a)

H

83:17

67

56

16:1

4

3d

CH2CH3 (1d)

CH2CH3

H (2a)

H

81:19

74

60

8:1

5

3e

p-AcOC6H4 (1e)

CH2CH3

H (2a)

H

84:16

64

54

>30:1

6

3f

CH2CH2SCH3 (1f)

CH2CH3

H (2a)

H

N.R.

7

3g

CH2C6H5 (1b)

CH2CH3

3-CH3 (2b)

H

81:19

76

62

12:1

8

3h

CH2C6H5 (1g)

n-Bu

4-CH3 (2c)

H

82:18

78

64

12:1

9

3i

CH3 (1a)

CH2CH3

4-F (2d)

H

61:39

31

19

30:1

10

3j

CH2C6H5 (1b)

CH2CH3

4-OMe (2e)

H

45:55

55

25

31:1

11

3k

CH3 (1a)

CH2CH3

H (2f)

CH3

33:67

33

11

>30:1

12

3l

CH3 (1h)

CH3

H (2a)

H

86:14

64

55

15:1

13

3m

CH2C6H5 (1i)

CH3

H (2a)

H

88:12

75

66

>30:1

14

3n

CH2C6H5 (1j)

i-Pr

H (2a)

H

82:18

73

60

12:1

15

3o

CH3 (1k)

n-Bu

H (2a)

H

87:13

77

67

21:1

16

3p

CH2C6H5 (1l)

n-Bu

H (2a)

H

82:18

73

60

>30:1

a Reaction conditions: α-diazophosphonate 1 (0.28 mmol) and 2 (1.40 mmol, 5 equiv) in CH2Cl2 (6 mL) at 40 °C in the presence of 5 mol% Cu(MeCN)4BF4 and 20 mol% BF3·Et2O for 3.5 h (addition over 1.5 h, then a further 2 h).

b The product ratio was based on 31P NMR spectroscopic analysis of the crude product.

c Overall yield of the mixture of 3 and 4 after silica gel chromatography.

d Yield of isolated product.

e Diastereomeric ratio (dr) based on 31P NMR spectroscopic analysis of the isolated product 3a.

A stepwise mechanism for the formation of the cyclopropenylphosphonates is outlined in Scheme [2]. Firstly, α-diazophosphonate 1 releases N2 under the influence of the Cu catalyst on heating, affording Cu-carbenoid A.[20] The role of the strong Lewis acids (BF3·Et2O) could be to coordinate to the copper to give metallocarbenoid B in order to make the α-diazo position more electron deficient. Carbenoid B is then trapped by the triple bond of ethynylbenzene to give vinyl cation C. Subsequent cleavage of the C–Cu bond of intermediate C with delivery of the electrons to the vinyl cation leads to cyclopropenyl phosphonate 3 with simultaneous regeneration of the Cu(I) catalyst and BF3·Et2O. Intermediate B may also be transformed into by-product 4 through loss of Cu(MeCN)4BF4 and BF3·Et2O before the attack of phenylacetylene 2a.

The diastereoselectivity observed in generating the cyclopropenyl phosphonates implies that conformational factors may play a role in the cyclopropenation process. In fact, the stereoselectivity can be attributed to steric hindrance between the phosphonate group and the R1 group, with attack occurring on the back face of the carbenoid preferentially. In forming intermediate C, the terminal alkyne carbon is involved in C–C bond formation with the carbenoid carbon, while positive charge build-up occurs at the internal sp-carbon. Furthermore, the second C–C bond forms with inversion of the carbenoid center. This model is partly consistent with the observed sense of asymmetric induction, but there are a few anomalies. For instance, isopropyl phosphonate 1j leads to lower dr than methyl phosphonate 1i (Table [2], entries 13 and 14).

Zoom Image
Scheme 2 Proposed reaction mechanism

In conclusion, we have developed a Cu(MeCN)4BF4/BF3·Et2O-catalyzed cyclopropenation of 1-alkynes with dialkyl α-diazophosphonates to synthesize β-amino-α-cyclopropenyl phosphonates in moderate yields with good to excellent diastereoselectivities. The observed sense of asymmetric induction is rationalized by invoking steric hindrance between the phosphonate group and the R1 group of the α-diazophosphonate. The present catalytic protocol provides attractive and easy access to β-amino-α-cyclopropenyl phosphonates containing a quaternary stereogenic center. Further studies to explore the enantio­selective synthesis of cyclopropenyl phosphonates are in progress in our laboratory.

All reactions and manipulations were performed using standard Schlenk techniques. Solvents were dried and distilled prior to use according to standard methods. Unless otherwise indicated, all materials were obtained from commercial sources, and used as purchased without dehydration. Flash column chromatography was performed on silica gel (particle size 10–40 μm, Ocean Chemical Factory of Qingdao­, China). Nitrogen gas (99.999%) was purchased from Boc Gas Inc. 1H NMR, 13C NMR, and 31P NMR spectra were recorded in CDCl3 with Bruker 400 MHz spectrometers, TMS served as internal standard (δ = 0 ppm) for 1H NMR and 13C NMR, H3PO4 served as internal standard (δ = 0 ppm) for 31P NMR. Mass spectra were recorded with a LCQ advantage spectrometer with ESI resource. HRMS were recorded with a PEXII and ZAB-HS spectrometer.


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Preparation of 3 and 4; General Procedure

In an oven-dried Schlenk tube, [Cu(MeCN)4]BF4 (0.014 mmol) and BF3·Et2O (0.056 mmol) were dissolved in freshly distilled CH2Cl2 (4 mL) under nitrogen, the requisite phenylacetylene 2 (1.4 mmol) was added and the solution was stirred for 30 min at 25 °C. α-Diazophosphonate 1 (0.28 mmol) dissolved in CH2Cl2 (2 mL) was then added to the reaction mixture dropwise over a period of 1.5 h by using a syringe pump. When the addition was complete, the reaction mixture was stirred for a further 2 h at 40 °C. The solvent was then removed under reduced pressure and the crude residue was purified by silica gel chromatography, eluting with CH2Cl2/EtOAc (15:1) to afford the corresponding products 3 and 4.


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Diethyl(1-(phenylcycloprop-2-enyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)phosphonate (3a)

Yield: 0.085 g (66%); pale-yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.61 (dd, J = 5.2, 3.2 Hz, 2 H), 7.56 (dd, J = 5.3, 3.1 Hz, 2 H), 7.49 (d, J = 7.1 Hz, 2 H), 7.16–7.25 (m, 3 H), 7.01 (d, J = 4.1 Hz, 1 H), 5.17–5.27 (m, 1 H, CH), 4.11 (dd, J = 12.8, 5.7 Hz, 4 H), 1.70 (d, J = 7.2 Hz, 3 H), 1.30 (td, J = 7.0, 4.2 Hz, 6 H).

13C NMR (101 MHz, CDCl3): δ = 168.35, 133.57, 131.51, 129.77, 129.59, 128.30, 125.48, 122.71, 116.00, 97.61, 62.02, 61.88, 47.44 (d, J = 36.5 Hz), 30.15, 28.17, 16.16.

31P NMR (162 MHz, CDCl3): δ = 26.86.

HRMS (ESI): m/z [M + H]+ calcd for C23H24NO5P: 426.1426; found: 426.1470.


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Diethyl(1-(phenylcycloprop-2-enyl)-2-(1,3-dioxoisoindolin-2-yl)-2-phenylethyl)phosphonate (3b)

Yield: 0.086 g (58%); pale-yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.49 (d, J = 6.5 Hz, 5 H), 7.11–7.28 (m, 7 H), 7.09 (d, J = 4.0 Hz, 2 H), 5.43 (d, J = 11.0 Hz, 1 H), 4.17 (dd, J = 15.5, 7.7 Hz, 4 H), 3.06–3.83 (m, 2 H), 3.51 (dd, J = 14.2, 4.0 Hz), 1.32–1.38 (m, 6 H).

13C NMR (101 MHz, CDCl3): δ = 137.33, 133.40, 132.40, 128.71, 128.58, 127.66, 127.30, 125.21, 124.36, 122.66, 121.58, 114.55, 96.66, 61.04, 52.60 (d, J = 45.4 Hz), 33.87, 28.68, 15.44.

31P NMR (162 MHz, CDCl3): δ = 26.57.

HRMS (ESI): m/z [M + H]+ calcd for C29H28NO5P: 502.1739; found: 502.1783.


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Diethyl(1-(phenylcycloprop-2-enyl)-2-(1,3-dioxoisoindolin-2-yl)-3-methylbutyl)phosphonate (3c)

Yield: 0.078 g (56%); pale-yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.50–7.60 (m, 4 H), 7.43 (d, J = 6.7 Hz, 2 H), 7.08–7.23 (m, 3 H), 6.97 (d, J = 4.2 Hz, 1 H), 5.17 (d, J = 12.2 Hz, 1 H), 4.31 (t, J = 6.7 Hz, 1 H), 4.04–4.15 (m, 4 H), 2.50 (t, J = 13.3 Hz, 1 H), 2.34 (t, J = 7.4 Hz, 1 H), 1.73 (dd, J = 13.2, 9.3 Hz, 3 H), 1.44 (dd, J = 15.4, 7.6 Hz, 3 H), 0.88–0.93 (m, 6 H).

13C NMR (101 MHz, CDCl3): δ = 168.65, 133.52, 129.68, 129.47, 128.85, 128.26, 125.45, 122.68, 115.62, 97.48, 65.58, 61.97, 50.16 (d, J = 36.2 Hz), 37.45, 29.71, 25.44, 23.59, 22.70, 21.11, 16.48, 14.13, 13.74.

31P NMR (162 MHz, CDCl3): δ = 26.80.

HRMS (ESI): m/z [M + H]+ calcd for C26H30NO5P: 468.1895; found: 468.1924.


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Diethyl(1-(phenylcycloprop-2-enyl)-2-(1,3-dioxoisoindolin-2-yl)propyl)phosphonate (3d)

Yield: 0.079 g (60%); pale-yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.54–7.64 (m, 4 H), 7.47 (d, J = 6.7 Hz, 2 H), 7.15–7.24 (m, 3 H), 6.99 (d, J = 4.2 Hz, 1 H), 4.92–5.03 (m, 1 H), 4.10 (ddd, J = 14.5, 11.7, 7.1 Hz, 4 H), 2.35–2.42 (m, 1 H), 2.06–2.14 (m, 1 H), 1.34–1.49 (m, 3 H), 0.87 (dd, J = 15.3, 7.9 Hz, 6 H).

13C NMR (101 MHz, CDCl3): δ = 168.66, 133.56, 131.39, 129.72, 129.52, 128.29, 125.55, 122.71, 115.64, 97.64, 61.97, 53.99 (d, J = 36.1 Hz), 22.71, 22.11, 14.14, 11.20.

31P NMR (162 MHz, CDCl3): δ = 26.94.

HRMS (ESI): m/z [M + H]+ calcd for C24H26NO5P: 440.1582; found: 440.1619.


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(2-(Diethoxyphosphoryl)-1-(1,3-dioxoisoindolin-2-yl)-2-(phenylcycloprop-2-enyl)ethyl)phenyl Acetate (3e)

Yield: 0.087 g (54%); pale-yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.42–7.49 (m, 5 H), 7.14–7.21 (m, 4 H), 6.96–7.11 (m, 2 H), 6.82–6.86 (m, 2 H), 5.35–5.42 (m, 1 H), 4.13 (dt, J = 7.1, 4.7 Hz, 4 H), 3.07–3.94 (m, 1 H), 3.69 (dd, J = 14.2, 12.6 Hz, 1 H), 3.47 (dd, J = 14.4, 4.2 Hz, 1 H), 2.20 (s, 3 H), 1.32 (dd, J = 7.0, 3.5 Hz, 6 H).

13C NMR (101 MHz, CDCl3): δ = 169.37, 149.05, 135.95, 133.67, 133.50, 130.69, 129.75, 129.64, 128.95, 128.33, 125.27, 122.68, 121.36, 115.53, 97.54, 62.07, 53.44 (d, J = 36.9 Hz), 34.38, 29.72, 21.10, 16.54.

31P NMR (162 MHz, CDCl3): δ = 26.52.

HRMS (ESI): m/z [M + H]+ calcd for C31H30NO7P: 560.1793; found: 560.1838.


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Diethyl(1-(2-m-tolylcycloprop-2-enyl)-2-(1,3-dioxoisoindolin-2-yl)-2-phenylethyl)phosphonate (3g)

Yield: 0.095 g (62%); pale-yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.47 (s, 4 H), 7.24 (s, 2 H), 7.11–7.20 (m, 4 H), 7.02–7.09 (m, 3 H), 6.94 (d, J = 7.7 Hz, 1 H), 5.35–5.45 (m, 1 H), 4.09–4.19 (m, 4 H), 3.61–3.70 (m, 1 H), 3.47 (dd, J = 14.2, 4.2 Hz, 1 H), 2.18 (s, 3 H), 1.33 (td, J = 7.0, 3.5 Hz, 6 H).

13C NMR (101 MHz, CDCl3): δ = 138.36, 137.91, 133.38, 130.41, 130.35, 128.70, 128.32, 128.26, 126.90, 126.23, 125.20, 123.70, 122.55, 115.48, 97.31, 62.03, 53.54 (d, J = 37.3 Hz), 34.96, 29.71, 21.05, 16.52.

31P NMR (162 MHz, CDCl3): δ = 26.79.

HRMS (ESI): m/z [M + H]+ calcd for C30H30NO5P: 516.1895; found: 516.1912.


#

Dibutyl(1-(2-p-tolylcycloprop-2-enyl)-2-(1,3-dioxoisoindolin-2-yl)-2-phenylethyl)phosphonate (3h)

Yield: 0.108 g (64%); pale-yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.49 (s, 4 H), 7.13–7.27 (m, 5 H), 7.07 (dt, J = 10.2, 5.8 Hz, 3 H), 6.96 (d, J = 7.4 Hz, 1 H), 5.43 (d, J = 12.3 Hz, 1 H), 4.00–4.18 (m, 4 H), 3.64–3.74 (m, 1 H), 3.51 (dd, J = 14.3, 4.1 Hz, 1 H), 2.37 (t, J = 7.4 Hz, 1 H), 2.21 (s, 3 H), 1.35–1.52 (m, 8 H), 0.94 (t, J = 7.2 Hz, 6 H).

13C NMR (101 MHz, CDCl3): δ = 171.20, 138.37, 137.87, 133.36, 130.93, 130.36, 128.85, 128.68, 128.31, 128.21, 126.90, 126.21, 122.54, 97.22, 65.80, 60.42, 53.53 (d, J = 37.2 Hz), 34.97, 32.66, 31.93, 29.70, 22.70, 21.07, 18.79, 14.20, 13.65.

31P NMR (162 MHz, CDCl3): δ = 26.74.

HRMS (ESI): m/z [M + H]+ calcd for C34H38NO5P: 572.2521; found: 572.2569.


#

Diethyl(1-(4-fluorophenylcycloprop-2-enyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)phosphonate (3i)

Yield: 0.019 g (19%); pale-yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.50–7.56 (m, 4 H), 7.41 (dd, J , 7.41 (dd Hz, 2 H), 6.82–6.89 (m, 3 H), 5.11 (d, J = 7.1 Hz, 1 H), 3.97–4.05 (m, 4 H), 1.60 (d, J , 1.6 Hz, 3 H), 1.18–1.24 (m, 6 H).

13C NMR (101 MHz, CDCl3): δ = 168.30, 133.67, 131.86, 131.78, 131.51, 122.74, 115.57 (d, J 168.30 Hz), 97.17, 61.96 (dd, J = 18.1, 6.9 Hz), 47.39 (d, J z), 47 Hz), 30.20, 28.23, 16.42.

31P NMR (162 MHz, CDCl3): δ = 26.56.

HRMS (ESI): m/z [M + H]+ calcd for C23H24FNO5P: 444.1371; found: 444.1378.


#

Diethyl(1-(4-methoxyphenylcycloprop-2-enyl)-2-(1,3-dioxoisoindolin-2-yl)-2-phenylethyl)phosphonate (3j)

Yield: 0.030 g (25%); pale-yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.40–7.48 (m, 5 H), 7.13–7.19 (m, 4 H), 7.09–7.10 (m, 1 H),7.05 (t, J (t,  Hz, 1 H), 6.89 (d, J (d,  Hz, 1 H), 6.71–6.79 (m, 2 H), 5.38 (d, J (d, ( Hz, 1 H), 4.12 (dd, J (dd, (400 M Hz, 4 H), 3.72 (s, 3 H), 3.62–3.69 (m, 1 H), 3.44–3.53 (m, 1 H), 1.29–1.34 (m, 6 H).

13C NMR (101 MHz, CDCl3): δ = 160.63, 138.46, 133.38, 131.44, 128.70, 128.29, 126.19, 122.61, 118.09, 115.03, 113.88, 94.80, 61.97, 55.23, 53.68 (d, J J60.63 Hz), 34.99, 29.39, 27.40, 16.52, 16.45.

31P NMR (162 MHz, CDCl3): δ = 26.93.

HRMS (ESI): m/z [M + H]+ calcd for C30H31NO6P: 532.1884; found: 532.1882.


#

Diethyl(1-(2-methyl-3-phenylcycloprop-2-enyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)phosphonate (3k)

Yield: 0.011 g (11%); pale-yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.85–7.87 (m, 2 H), 7.72–7.74 (m, 2 H), 7.58–7.60 (m, 1 H), 7.52–7.54 (m, 1 H), 7.36 (d, J J 7.3 Hz, 1 H), 7.05–7.16 (m, 2 H), 4.98–5.20 (m, 1 H), 4.05–4.15 (m, 4 H), 2.05 (s, 3 H), 1.70 (dd, J , 1.70 (dd, Hz, 3 H), 1.24–1.29 (m, 6 H).

13C NMR (101 MHz, CDCl3): δ = 167.37, 134.11, 133.43, 131.67, 129.14, 128.25, 128.15, 123.49, 122.63, 108.45, 108.05 61.41, 47.60 (d, J J47.60 Hz), 29.69, 21.03, 16.58, 15.16, 14.19.

31P NMR (162 MHz, CDCl3): δ = 27.73.

HRMS (ESI): m/z [M + H]+ calcd for C24H26NO5P: 440.1621; found: 440.1613.


#

Dimethyl(1-(phenylcycloprop-2-enyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)phosphonate (3l)

Yield: 0.066 g (55%); pale-yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.54–7.65 (m, 4 H), 7.48 (d, J = 6.7 Hz, 2 H), 7.17–7.26 (m, 3 H), 7.03 (d, J = 4.2 Hz, 1 H), 5.16–5.25 (m, 1 H), 3.77 (dd, J = 10.6, 5.5 Hz, 6 H), 1.72 (d, J = 7.2 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 168.34, 133.58, 131.46, 129.76, 129.69, 128.38, 125.26, 122.73, 115.73, 97.37, 52.84, 52.70, 47.40 (d, J = 37.1 Hz), 16.07.

31P NMR (162 MHz, CDCl3): δ = 29.30.

HRMS (ESI): m/z [M + H]+ calcd for C21H20NO5P: 398.1113; found: 398.1148.


#

Dimethyl(1-(phenyl-cycloprop-2-enyl)-2-(1,3-dioxoisoindolin-2-yl)-2-phenyl-ethyl)phosphonate (3m)

Yield: 0.093 g (66%); pale-yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.45–7.51 (m, 5 H), 7.13–7.24 (m, 7 H), 7.08 (dd, J = 12.8, 5.7 Hz, 2 H), 5.39 (ddd, J = 12.4, 4.3, 2.6 Hz, 1 H), 3.79–3.84(m, 6 H), 3.61–3.74 (m, 2 H), 3.46–3.50 (m, 1 H).

13C NMR (101 MHz, CDCl3): δ = 138.16, 133.49, 129.76, 129.73, 129.63, 128.70, 128.42, 128.35, 126.29, 125.10, 123.48, 122.66, 115.33, 97.46, 53.44 (d, J = 37.0 Hz), 34.94.

31P NMR (162 MHz, CDCl3): δ = 29.11.

HRMS (ESI): m/z [M + H]+ calcd for C27H24NO5P: 474.1426; found: 474.1468.


#

Diisopropyl(1-(phenylcycloprop-2-enyl)-2-(1,3-dioxoisoindolin-2-yl)-2-phenylethyl)phosphonate (3n)

Yield: 0.094 g (60%); pale-yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.70 (dd, J = 26.3, 19.1 Hz, 6 H), 7.37–7.51 (m, 3 H), 7.21 (d, J = 4.3 Hz, 1 H), 7.00–7.09 (m, 4 H), 5.44 (d, J = 8.9 Hz, 1 H), 4.52 (ddd, J = 13.4, 11.0, 6.2 Hz, 2 H), 2.74–3.25(m, 2 H), 2.55 (dd, J = 14.0, 4.2 Hz, 1 H), 1.19 (d, J = 6.2 Hz, 6 H), 1.03 (dd, J = 16.5, 6.2 Hz, 6 H).

13C NMR (101 MHz, CDCl3): δ = 153.59, 140.51, 137.65, 133.50, 129.97, 128.85, 128.09.127.98, 127.57, 126.44, 126.29, 123.42, 116.36, 100.21, 70.03 (d, J = 7.4 Hz), 52.71 (d, J = 25.3 Hz), 35.70, 29.71, 23.78.

31P NMR (162 MHz, CDCl3): δ = 24.92.

HRMS (ESI): m/z [M + H]+ calcd for C31H32NO5P: 530.2052; found: 530.2091.


#

Dibutyl(1-(phenylcycloprop-2-enyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)phosphonate (3o)

Yield: 0.096 g (67%); pale-yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.57–7.62 (m, 2 H), 7.52–7.56 (m, 2 H), 7.45 (d, J = 6.8 Hz, 2 H), 7.14–7.23 (m, 3 H), 6.98 (d, J = 4.1 Hz, 1 H), 5.21 (dt, J = 6.9, 5.1 Hz, 1 H), 3.98–4.05 (m, 4 H), 1.70 (d, J = 7.2 Hz, 3 H), 1.56–1.64 (m, 4 H), 1.36 (dd, J = 7.3, 4.6 Hz, 4 H), 0.87–0.92 (m, 6 H).

13C NMR (101 MHz, CDCl3): δ = 168.30, 133.51, 131.50, 129.76, 129.52, 128.23, 125.49, 122.67, 116.09, 97.56, 65.58, 47.49 (d, J = 36.9 Hz), 32.70, 32.41, 18.71, 16.17, 13.58.

31P NMR (162 MHz, CDCl3): δ = 26.73.

HRMS (ESI): m/z [M + H]+ calcd for C27H32NO5P: 482.2052; found: 482.2094.


#

Dibutyl(1-(phenylcycloprop-2-enyl)-2-(1,3-dioxoisoindolin-2-yl)-2-phenylethyl)phosphonate (3p)

Yield: 0.099 g (60%); pale-yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.45 (d, J = 8.2 Hz, 5 H), 7.11–7.21 (m, 7 H), 7.05 (d, J = 4.0 Hz, 2 H), 5.36–5.46 (m, 1 H), 4.07 (tt, J = 13.4, 6.7 Hz, 4 H), 3.80 (ddd, J = 31.7, 18.3, 9.8 Hz, 2 H), 3.50 (dd, J = 14.3, 4.1 Hz, 1 H), 1.61–1.68 (m, 4 H), 1.39 (dd, J = 11.2, 4.0 Hz, 4 H), 0.91 (td, J = 7.3, 1.4 Hz, 6 H).

13C NMR (101 MHz, CDCl3): δ = 138.38, 133.43, 129.75, 129.59, 128.68, 128.33, 128.30, 126.23, 125.36, 123.68, 122.62, 115.62, 97.59, 65.74, 53.60 (d, J = 37.3 Hz), 35.02, 32.66, 29.68, 18.78, 13.66.

31P NMR (162 MHz, CDCl3): δ = 26.53.

HRMS (ESI): m/z [M + H]+ calcd for C33H36NO5P: 558.2365; found: 558.2412.


#

(Z)-Diethyl(2-(1,3-dioxoisoindolin-2-yl)prop-1-en-1-yl)phosphonate (4a)

Yield: 0.014 g (15%); white solid; mp 140–143 °C.

1H NMR (400 MHz, CDCl3): δ = 7.87–7.94 (m, 2 H, Ph), 7.69–7.80 (m, 2 H, Ph), 5.96 (dd, J = 10.4, 1.2 Hz, 1 H, CH), 3.98–4.13 (m, 4 H, 2 °CH2), 2.25 (s, 3 H, CH3), 1.28 (t, J = 7.1 Hz, 6 H, 2CH3).

13C NMR (101 MHz, CDCl3): δ = 166.63 (C=O), 146.83 (CN), 134.11, 132.28, 123.71 (Ph), 118.32 (d, J = 186.2 Hz, CP), 62.08 (d, J = 5.3 Hz, OCH2), 24.56 (d, J = 17 Hz, CH3), 16.27 (d, J = 6.6 Hz, CH3).

31P NMR (162 MHz, CDCl3): δ = 11.34 (s).

HRMS (ESI): m/z [M + Na]+ calcd for C15H18NO5PNa: 346.0815; found: 346.0815.


#
#

Supporting Information

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    • 1g Banning JE. Prosser AR. Rubin M. Org. Lett. 2010; 12: 1488
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Zoom Image
Scheme 1 Previous and proposed work
Zoom Image
Scheme 2 Proposed reaction mechanism