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Indium Triflate-Catalyzed Stereoselective Tandem Intramolecular Conjugate Addition of Secondary Amines to α,β-Bisenones

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Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x We report an indium triflate-catalyzed stereoselective intramolecular tandem conjugate addition of secondary amines to α,β-bisenones to afford a 1,2,3-trisubstituted sixmembered ring bearing diketone substituents in good to excellent yields at room temperature. Various kinds of α,βbisenones and amines were employed to expand the scope of this chemistry. Intramolecular trapping of indium-enolate by the tethered electrophiles resulted in the stereoselective formation of three contiguous stereogenic centers. Development of new synthetic methods for the selective formation of complex molecules under mild reaction conditions is an active research field.1 Catalytic tandem conjugate addition strategies are a powerful method for stereoselective carbon– carbon bond formation and the construction of cyclic chiral building blocks in natural products synthesis.1-3 In particular, the addition of nucleophiles to α,β-unsaturated carbonyls, followed by intramolecular trapping of the resultant enolate with a pendent electrophile has been studied extensively for the construction of cyclic systems. This strategy permits the stereoselective formation of multiple bonds in a single step without isolation of the intermediates.4,5 Lewis acid-catalyzed reactions are of great interest because of their unique reactivity and selectivity under mild conditions.6 A wide variety of reactions using Lewis acids have been developed and applied to the synthesis of natural and unnatural compounds. Traditionally, Lewis acids such as AlCl3, BF3, TiCl4, and SnCl4 were employed; however, more than one equivalent of the Lewis acid is required in many cases. For Lewis acid-catalyzed processes, the role of the metal salt in carbon–carbon bond formation and other transformations is well established [6]. The disadvantage of most metal salts used as Lewis acids for organic transformations is that they are moisture sensitive and must be used under strictly anhydrous conditions. Kobayashi et al.7 categorized many metal salts on the basis of their relative stabilities in water and made correlations between the catalytic activities of metal salts in water by their “hydrolysis constants” and “exchange rate constants” for the substitution of inner-sphere water ligands. Finally, high “hydrolysis constants” and “exchange rate constants” of lanthanide, copper, zinc, cadmium, and indium salts make them highly soluble in water. During the last decade and particularly after the review by Cintas,8 indium(III)-based carbon–carbon bond formations and

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other transformations have gained significant attention.9 The recent surge of interest in moisture-stable metal triflates6b,10 has shown In(OTf)3 as a promising catalyst for various organic reactions.11 During the last decade, several research groups have developed various catalytic conjugate addition strategies using organocatalysts or transition metal catalysts.12 In particular, conjugate addition of carbon nucleophiles such as organosilicon,12g organozirconium,13 organozinc,14 and 15 organoboron reagents using transition metals has been extensively studied. Among them, tandem intramolecular conjugate addition using organozirconium/Rh,12h 12f,i 16 organoboron/Rh, and organozinc/Cu has received significant interest. Similar transformations of α,β-bisenones into cyclic products with organocatalysts is known as the Rauhut-Currier reaction.12c, 17 Herein, we report that changing the nucleophilic catalyst in the Rauhut-Currier reaction for a Lewis acid catalyst and addition of an amine nucleophile affords a different cyclic product (Scheme 1).

Scheme 1. Comparison of the Rauhut-Currier Reaction and This Work. 70

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To the best of our knowledge, this is the first example of an indium enolate trapping process for the stereoselective construction 1,2,3-trisubstituted six membered cyclic compounds. We present herein novel and promising indium triflate-catalyzed stereoselective intramolecular tandem conjugate additions of nitrogen nucleophiles to α,β-bisenones, which were synthesized by reported methods.4g, 4i,18 Initially, we examined the conjugate addition of pyrrolidine (2a) to (2E, 7E)-1,9-diphenylnona-2,7-diene-1,9-dione (1a) as a model, and assessed its reactivity with various metal triflate catalysts (Scheme 2). From the background reaction without [journal], [year], [vol], 00–00 | 1

ChemComm Accepted Manuscript

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Bodakuntla Thirupathaiaha and SungYong Seo*a

ChemComm

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DOI: 10.1039/C4CC10016F

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Scheme 2. Addition of Pyrrolidine (2a) to α,β-Bisenone (1a).

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using the catalyst and LiCl, no product was found (entry 1, Table 1). Then, as an initial control experiment, we conducted the conjugate addition in the absence of a catalyst. Surprisingly, treatment of 1a and 2a with LiCl in THF afforded 2-(2-benzoyl3-(pyrrolidin-1-yl)cyclohexyl)-1-phenylethanone (3a) in 45% yield (entry 2, Table 1). Interestingly, formation of the RauhutCurrier product and eliminated product were not observed. Based on this result, we envisioned that addition of a Lewis acid catalyst would activate α,β-bisenone resulting in enhanced reactivity. A rapid screen of a series of moisture-stable metal triflates highlighted indium triflate as an active catalyst to afford 3a as the sole product (entry 6, Table 1). Note that predominantly one diastereomer was observed in the crude 1H NMR spectrum analysis and determining the diastereomeric ratio was hard due to the difficulty in separation of minor diastereomer.

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Having determined THF as the optimal solvent, we next examined the role of additive, LiCl. Unexpectedly, no product was obtained without LiCl (entry 2, Table 3). Addition of 1 and 3 equiv. of LiCl afforded good yields (entries 3 and 4, Table 3), while 2 equiv. was determined as the optimal amount. We next explored the effect of the cation and anion in LiCl by changing the cation and anion. Interestingly, changing the cation from Li+ to Na+ and K+ resulted in no product (entries 5 and 6, Table 3). Furthermore, variation of the anion to F− and BF4−resulted in no product (entries 7 and 10, Table 3), while Br− and I− afforded low yields (entries 8 and 9, Table 3). Based on these findings, the LiCl additive likely plays a significant role in the reactivity and conversion partially due to its ionic size.19 Two potential roles for LiCl are (1) preventing the metal to aggregate which decreased the reactivity20 and (2) inducing the formation of indium-chlorobridging complex.21 Table 3. Effect of Additivesa

Table 1. Screening Various Metal Triflate Catalystsa

Catalystb

1

In(OTf)3

Additive (equiv.) LiCl (2)

THF

92

2

In(OTf)3

LiCl (0)

THF

trace

3

In(OTf)3

LiCl (1)

THF

77

4

In(OTf)3

LiCl (3)

THF

85

5

In(OTf)3

NaCl (2)

THF

trace

Solvent

Yield (%)c

6

In(OTf)3

KCl (2)

THF

trace

Entry

Catalystb

LiCl

Solvent

Yield (%)c

7

In(OTf)3

LiF (2)

THF

trace

1

None

None

THF

trace

8

In(OTf)3

LiBr (2)

THF

32

2

None

2 equiv.

THF

45

9

In(OTf)3

LiI (2)

THF

37

10

In(OTf)3

LiBF4 (2)

THF

trace

3

Sc(OTf)3

2 equiv.

THF

75

4

La(OTf)3

2 equiv.

THF

86

5

Cu(OTf)3

2 equiv.

THF

87

6

In(OTf)3

2 equiv.

THF

92

a

Reaction conditions: α,β -bisenone 1a (1 mmol), pyrrolidine 2a (1.1 mmol), additive (as indicated) in THF (5 mL) stirred at room temperature for 6 h, unless otherwise stated. b 5 mol%. c Isolated yields

a Reaction conditions: α,β -bisenone 1a (1 mmol), pyrrolidine 2a (1.1 mmol), LiCl (2 mmol) in THF (5 mL) stirred at room temperature for 6 h, unless otherwise stated. b 5 mol%. c Isolated yields

20

Entry

After identifying a suitable catalyst, a solvent screen was conducted to improve conversion and product yield. Use of more nonpolar solvents, including CH2Cl2, Et2O, and toluene, led to much lower reactivities (entries 2-4, Table 2), while the more polar solvent CH3CN showed only moderate reactivity (70% yield; entry 5, Table2). Table 2. Screening the Solventa b

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Entry

Catalyst

LiCl

Solvent

1

In(OTf)3

2 equiv.

THF

92

2

In(OTf)3

2 equiv.

CH2Cl2

28

3

In(OTf)3

2 equiv.

Et2O

29

4

In(OTf)3

2 equiv.

Toluene

45

5

In(OTf)3

2 equiv.

CH3CN

70

Yield (%)

a Reaction conditions: α,β-bisenone 1a (1 mmol), pyrrolidine 2a (1.1 mmol), LiCl (2 mmol) in solvent (5 mL) stirred at room temperature for 6

2 | Journal Name, [year], [vol], 00–00

In order to elucidate the mechanism and expand the utility of this reaction, the relative configuration of 2-(2-benzoyl-3(pyrrolidin-1-yl)cyclohexyl)-1-phenylethanone (3a) needs to be determined. The relative configuration was assigned by 1H NMR and NOESY experiments. The orientation of the C-1 proton showed significant NOESY correlations with the C-3 proton, confirming that the stereochemistry of the C-1 proton was syn to the C-3 proton, as shown in Figure 1. No correlation was observed between the C-1 and C-2 protons, confirming that the stereochemistry of the C-1 proton was anti to that of the C-2 proton.

Figure 1. NOESY Correlations of 3a.

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Entry

amine (2)

-bisenones (1)

product (3)

time (h) yield (%)b

yield of elim. product(%)c

O

O

O

O

1

N H 1a

6

92

0

6

78

0

10

N

2a

3a

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O

O

O

O

2

N H

N

15 1a O

2b O

3

3b

O

O

N H

N

O

4

82

0

6

73

2

6

72

9

O

1a

2c

O

3c

O

O

O

4

N H 1b

20

N

2a

3d O

O

O

O

5

N H

N

25 1b

2b

3e O

O

O

6

1b

O

O

N H

N O

2c

4

67

8

Cl

6

92

0

Cl

6

86

0

Cl

6

82

0

6

85

0

6

91

0

6

80

0

6

32

13

6

49

4

3f O

O

O

O

7 Cl

Cl 1c

N H

Cl

30

a Reaction conditions: α,β-bisenone (1 mmol), secondary amine (1.1 mmol), LiCl (2.0 mmol), and In(OTf)3 (5 mol%) in THF (5 mL) at rt for the indicated time. b Isolated yields. c Isolated yield of the eliminated product.

After investigating the model reaction in Scheme 2 under optimized reaction conditions, the scope of this novel catalytic protocol was extended to the tandem intramolecular conjugateaddition of different nitrogen nucleophiles to various α,β-bisenones containing phenyl, 4-methylphenyl, 4-chlorophenyl, and 2-thienyl groups. As shown in Table 4, 1,2,3-trisubstituted cyclohexanes were obtained with high stereoselectivity in good to excellent yields at room temperature. As shown in Table 4, the aromatic substituents had some effect on the conversion and reactivity. In this transformation, no Rauhut-Currier reaction product was observed, but some substrates showed the eliminated product as shown in Scheme 2. The electrophilicity of α,β-bisenones seems to play a significant role; electron-poor (entries 7-9, Table 4) showed higher yields than the electron-rich ones (entries 4-6, Table 4). Furthermore, phenyl-substituted (entries 1-3, Table 4) and 2-thienyl-substituted α,β-bisenones (entries 10-12, Table 4) also gave good to excellent yields. Next, various secondary amines including symmetrical and unsymmetrical amines were evaluated using substrate 1a (entries 1-3 and 13-15, Table 4). Amine nucleophilicity likely plays a role as suggested by the isolated yields, but no clear relationship was observed. Based on these findings, we concluded that amine nucleophilicity22 may affect the conversion and reactivity.

N

2a

3g O

O

O

O

8 Cl

Cl 1c

N H

Cl

N

2b

3h O

O

O

O

O

9 Cl

Cl 1c

N H

Cl

N O

2c

3i O

O

O

O S

10 S

S 1d

N H

S

N

2a

3j O

O

O

O

S

11 S

S 1d

N H

S

N

2b

3k O

O

O

O

O

S

12 S

S

N H

S

N

O

1d O

2c

3l

N H

13

1a O

3m

O

O

O N H 1a

Scheme 3. Proposed Catalytic Cycle for Tandem Intramolecular Conjugate Addition

N

2d

14

O

O

O

N

35

2e

3n O O

O

O

NH

15

4

56

3

N

1a

2f

3o

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A plausible mechanism for the tandem intramolecular conjugate addition is shown in Scheme 3 and may explain the observed stereoselectivity of this reaction. Although the constitution of M is required to fully elucidate the catalytic pathway operative here, the complexities of M place this beyond the scope of a communication. Conjugate addition of the nucleophile (NuH) to α,β-bisenones furnishes zwitterionic enolate Journal Name, [year], [vol], 00–00 | 3

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Table 4. Synthesis of 1,2,3- Trisubstituted Six Membered Compounds.a

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I, and reaction with LiCl and In(OTf)3 would afford metal enolate II, which can then undergo intramolecular cyclization on the pendent enone. Cyclization of II likely occurs via a chelated sixmembered transition state III affording 1,2,3-trisubstituted intermediate IV with an all-equatorial orientation. Finally, insertion of another substrate releases V and affords the final product VI after tautomerization. In this study, only cyclized product trapped by indium enolate was observed without forming the uncyclized 1,4-adduct. This result indicates that conjugate addition of the nucleophile to α, β-bisenone was slower than intramolecular enolate trapping. In summary, we have developed a novel and effective catalytic pathway for the construction of highly stereoselective 1,2,3trisubstituted six-membered rings bearing diketone substituents under mild reaction conditions. This indium-catalyzed tandem intramolecular conjugate addition of secondary amines to α,βbisenones affords products in high stereoselectivity without the need for conformationally predisposed substrates and affords products in good to excellent yields. Further investigation of an enantioselective variant of this reaction, transformation of these cyclic products into more complex compounds, and exploration of detailed reaction mechanism are the subject of a forthcoming report.

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Notes and references 25

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a

Department of Chemistry,Pukyong National University, Busan, Republic of Korea, 608-737.; E-mail:[email protected] † Electronic Supplementary Information (ESI) available: Complete experimental procedures, characterization data, and spectral data. See DOI: 10.1039/b000000x/ ‡ This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2012R1A1A1007364). Mr. P. Kim and Ms. S. Son are gratefully acknowledged for the initial study of this research. 1 For reviews see: (a) L. F. Tietze, Chem. Rev. 1996, 96, 115.; (b) S. E. Denmark, A. Thorarensen, Chem. Rev. 1996, 96, 137.; (c) P. J. Parsons, C. S. Penkett, A. J. Shell, Chem. Rev. 1996, 96, 195.; (d) N. Krause, A. Hoffmann-Roder, Synthesis 2001, 171.; (e) K. Fagnou, M. Lauten, Chem. Rev. 2003, 103, 169.; (f) H-C. Guo, J-A. Ma, Angew. Chem. Int. Ed. 2006, 45, 354.; (g) D. Enders, C. Grondal, M.R. M. Hüttl, Angew. Chem. Int. Ed. 2007, 46, 1570. 2 (a) M. Ono, K. Nishimura, H. Tsubouchi, Y. Nagaoka, K. Tomioka, J. Org. Chem. 2001, 66, 8199.; (b) M. L. Lanier, A. C. Kasper, H. Kim, J. Hong, Org. Lett. 2014, 16, 2406. 3 (a) H.-G. Schmaltz, in Comprehensive Organic Synthesis, Vol. 4 (Eds. B. M. Trost, I. Flemming), Pergamon, Oxford, 1991, Chapter 1.5; (b) P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis, Pergamon, Oxford, 1992; (c) T. L. Ho, Tandem Reactions in Organic Synthesis, Wiley, New York, 1992. 4 For addition of nucleophiles α,β-unsaturated carbonyl system: (a) P. G. Klimko, D. A. Singleton, J. Org. Chem. 1992, 57, 1733.; (b) T. Uyehara, N. Shida, Y. Yamamoto, J. Org. Chem. 1992, 57, 3139.; (c) J. G. Urones, N. M. Garrido, D. Díez, S. H. Dominguez, S. G. Davies, Tetrahedron: Asymmetry 1999, 10, 1637.; (d) E. Richards, P. J. Murphy, F. Dinon, S. Fratucello, P. M. Brown, T. Gelbrich, M. B. Hursthouse, Tetrahedron 2001, 57, 7771.; (e) J. Yang, D. F.Cauble, A. J. Berro, N. L. Bauld, M. J. Krische, J. Org. Chem. 2004, 69, 7979.; (f) S. G. Davies, D. Díez, S. H. Dominguez, N. M. Garrido, D. Kruchinin, P. D. Price, A. D. Smith, Org. Biomol. Chem., 2005, 3, 1284.; (g) A. G. Csákÿ, G. Herrán, M. C. Murcia, Chem. Soc. Rev. 2010, 39, 4080.; (h) D. Belmessieri, L. C. Morrill, C. Simal, A. M. Z. Slawin, A. D. Smith, J. Am. Chem. Soc. 2011, 133, 2714. and references cited therein.

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ChemComm Accepted Manuscript

DOI: 10.1039/C4CC10016F

Indium triflate-catalyzed stereoselective tandem intramolecular conjugate addition of secondary amines to α,β-bisenones.

We report an indium triflate-catalyzed stereoselective intramolecular tandem conjugate addition of secondary amines to α,β-bisenones to afford a 1,2,3...
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