Rh(II) acetate catalyzed cyclopropanation of styrenes with enaldiazo esters: diastereoselective synthesis of enal-cyclopropanes

Accepted Manuscript Rh(II) acetate catalyzed cyclopropanation of styrenes with enaldiazo esters: Diastereoselective synthesis of enal-cyclopropanes Kuldeep Singh Rathore, Sreenivas Katukojvala PII: DOI: Reference:

S0040-4039(14)01662-1 http://dx.doi.org/10.1016/j.tetlet.2014.09.126 TETL 45220

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Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

19 August 2014 24 September 2014 28 September 2014

Please cite this article as: Rathore, K.S., Katukojvala, S., Rh(II) acetate catalyzed cyclopropanation of styrenes with enaldiazo esters: Diastereoselective synthesis of enal-cyclopropanes, Tetrahedron Letters (2014), doi: http:// dx.doi.org/10.1016/j.tetlet.2014.09.126

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Rh(II) acetate catalyzed cyclopropanation of styrenes with enaldiazo esters: Diastereoselective synthesis of enalcyclopropanes Kuldeep Singh Rathore and Sreenivas Katukojvala*

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Tetrahedron Letters j o ur n al h om e p a g e : w w w . e l s e v i er . c o m

Rh(II) acetate catalyzed cyclopropanation of styrenes with enaldiazo esters: Diastereoselective synthesis of enal-cyclopropanes Kuldeep Singh Rathorea and Sreenivas Katukojvalaa ∗ a

Department of Chemistry, Indian Institute of Science Education & Research, Bhopal, Madhya Pradesh- 462066, India

A R T IC LE IN F O

A B S TR A C T

Article history: Received Received in revised form Accepted Available online

An efficient Rh(II) acetate catalyzed highly diastereoselective cyclopropanation of styrenes with enaldiazo esters has been developed (upto >95:5 dr and 62-82% yield). The reaction is proposed to involve diacceptor electrophilic rhodium enalcarbenoids and constitutes the first direct synthesis of enal-cyclopropanes with an all carbon γ-quaternary stereocenter. 2009 Elsevier Ltd. All rights reserved.

Keywords: carbenes cyclopropanes diazo compounds enalcarbenoids enals

Catalytic generation of metal carbenes from α-diazocarbonyl compounds provides a unique strategy to explore the reactivity of highly unstable carbene intermediates in various difficult and selective synthetic transformations.1,2 The new discoveries from these strategies are stimulated by the availability of new classes of diazo substrates.1-3 In this context, recently we have designed a unique class of enaldiazo compounds 1 embedded with both enal and diazo moieties (eq. 1). These diazo compounds have been successfully used in the synthesis of indoles, carbazoles and pyrroles via the proposed rhodium enal-carbenoid 2 (M: Rh2(OAc)4). 3 In continuation to our studies on the synthetic applications of enaldiazo esters 3, herein we report a Rh(II) catalyzed highly diastereoselective cyclopropanation of styrenes via the enalcarbenoids 4 leading to the first direct synthesis of valuable enal-cyclopropanes 6, possessing an all carbon γ−quaternary stereocenter (eq. 1). 1,4,5 Cyclopropanes and enals are highly valuable substrates in organic synthesis for a variety of synthetic transformations including organocatalytic and metal catalyzed reactions. 6,7

The initial cyclopropanation studies were carried with enaldiazo ester 3a and 3-methylstyrene in presence of

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∗ Corresponding author. Tel.: +91-755-669-2327; e-mail: [email protected]

rhodium(II) acetate. When a 0.15 M solution of 3a (0.3 mmol, 1 equiv.) in dichloromethane (CH2 Cl2) was added slowly over 2 h to a CH2 Cl2 solution (2 ml) of 3-methylstyrene (0.36 mmol, 1.2 equiv.) and 1 mol% [Rh2(OAc)4] at room temperature, enalcyclopropane 7 was obtained in 20% yield with high diastereoselectivity (7a:7b 95:5). 8,9 The yield was improved to 65% when the addition was carried at 40 oC and continuing the reaction for an additional 4 h at the same temperature. Encouraged by this result, as shown in Table 1, optimization studies were carried. Either increase of diazo substrate or styrene resulted in diminished yields (entry 2, 3). Use of 2 mol% [Rh2(OAc)4] significantly increased the yield to 82% (entry 4) while maintaining the high diastereoselectivity. Increasing the addition time of diazo substrate did not improve the yield (entry 5). Among all the Rh(II) carboxylates tested, [Rh2(OAc)4] was superior in terms of yield and diastereoselectivity (entry 4-10). The reaction with chiral rhodium(II) catalysts [Rh2(S-DOSP)4 ] and [Rh2(S-PTAD)4] was sluggish which led to low yields due to incomplete conversion, diminished diastereoselectivity, and only <30% enantioselectivity (entry 9 and 10). These results indicate that increasing the steric bulk on the Rh(II) catalyst was not favorable for the cyclopropanation (entries 6, 7, 9 and 10). High reaction temperature gave reduced yields (entry 11, 12). The reaction was sluggish in toluene and led to decomposition of diazo compound at elevated temperature (entry 13). The optimal yield (82%) and diastereoselectivity (>95:5) was obtained with 1.2 equivalents of 3-methylstyrene, 2 mol % [Rh2(OAc)4] in low boiling CH2Cl2 solvent (entry 4).

2

Tetrahedron

Table 1. Optimization of cyclopropanationa,8

Table 2. Substrate scope of cyclopropanationa,b,8

entry

Rh2 Ln (mol%)

3a/ styrene

T (oC) /Solvent

Yield %b

1

Rh2 (OAc)4 (1)

1/1.2

40/CH2Cl2

65 (>95:5)

(7a:7b)

2

Rh2 (OAc)4 (1)

1/2.0

40/CH2Cl2

38 (>95:5)

3

Rh2 (OAc)4 (2)

1.5/1

40/CH2Cl2

51 (>95:5)

4

Rh2 (OAc)4 (2)

1/1.2

40/CH2Cl2

82 (>95:5)

5c

Rh2 (OAc)4 (2)

1/1.2

40/CH2Cl2

79 (>95:5)

6

Rh2 (OOct)4 (2)

1/1.2

40/CH2Cl2

31 (>95:5)

7

Rh2 (esp)2 (2)

1/1.2

40/CH2Cl2

43 (>95:5)

8

Rh2 (TFA)4 (2)

1/1.2

40/CH2Cl2

14 (nd)

9d

[Rh2(R-DOSP)4] (2)

1/1.2

40/CH2Cl2

28 (92:8)

10

e

[Rh2(S-PTAD)4] (2)

1/1.2

40/CH2Cl2

32 (95:5)

11

Rh2 (OAc)4 (2)

1/1.2

60/CHCl3

26 (nd)

12

Rh2 (OAc)4 (2)

1/1.2

60/C2 H4 Cl 2

<5 (nd)

13

Rh2 (OAc)4 (2)

1/1.2

50/toluene

<5 (nd)

a

Reaction conditions: Reaction was carried with 0.3 mmol of 3a; 0.15 M solution of 3a was added with a flow rate of 1 ml/h to a solution of 3-methylstyrene and Rh(II) at temperature (T) and continued for an additional 4 h at same temperature. b Isolated yield. c 3a addition rate 0.5 ml/h. d29% ee of 7a. e16% ee of 7a. nd: not determined.

With the optimized conditions, the generality of the cyclopropanation was tested with enaldiazo esters 3 and styrenes 8 (Table 2). Both enaldiazo esters 3a and 3b participated efficiently in the cyclopropanation leading to good yields of cyclopropylenals 9-23 (62-82%). With respect to styrenes, neutral and electron deficient styrenes gave good diastereoselectivities for cyclopropanes 9-17. However, electron rich 4-methoxystyrene gave low diastereoselectivity of enalcyclopropane 18 (dr 68:32) and 19 (dr 72:28). The sterically crowded disubstituted α-methylstyrene gave diminished diastereoselectivity of 20 (dr 88:22) and 21 (dr 89:21). Cyclopropanation of aliphatic olefins (eg. 1-octene, cyclohexene) was not successful. Interestingly, reaction with 1,2-disubstituted styrene derivatives cis and trans stilbene resulted in only decomposition of the diazo compound. In contrast, the cyclopropanation of indene proceeded very smoothly and produced tricyclic enals 22 and 23 in high yields and high diastereoselectivity (dr >95:5). In summary we have demonstrated the synthetic utility of enaldiazo esters and enalcarbenoids in the Rh(II) acetate catalyzed highly diastereoselective cyclopropanation of styrenes. This methodology offers the direct synthesis of valuable enalcyclopropanes with an all carbon γ-quaternary stereocenter. Further studies are ongoing towards the mechanistic aspects and applications of the cyclopropanation reaction.

a

Reaction conditions: Reaction carried with 0.3 mmol of 3; 0.15 M solution of 3 was added with a flow rate of 1 ml/h to a solution of 8 (0.36 mmol) and 2 mol% [Rh2(OAc)4 ] at 40 oC and continued for an additional 4 h at the same temperature. bYield and diastereomeric ratio corresponds to isolated products.

Acknowledgments We are grateful for the financial support from IISER Bhopal and the Department of Science and Technology (DST-SERB). We also thank CSIR for a research fellowship to KSR. References and notes 1.

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Supplementary Material Experimental procedures, characterization data and NMR spectra are available. .

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