New Synthesis of Hydroxydienones - Wiley Online Library

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Aug 28, 2014 - &Synthetic Methods. New Synthesis of α'-Hydroxydienones. Rama Rao Tata, Carissa S. Hampton, Erich F. Altenhofer, Michael Topinka, ...

DOI: 10.1002/chem.201404638

Communication

& Synthetic Methods

New Synthesis of a’-Hydroxydienones Rama Rao Tata, Carissa S. Hampton, Erich F. Altenhofer, Michael Topinka, Weijiang Ying, Xuefeng Gao, and Michael Harmata*[a] nols in short order. Structures and yields of the products obtained in our studies are shown in Scheme 2.

Abstract: Herein, attempted oxidation of selected allenols with PCC affording a’-hydroxydienones rather than simple oxidation products is described. The formation of the products observed is rationalized via a series of sigmatropic shifts, followed by hydrolysis.

Recently, we reported the silver-catalyzed rearrangement of propargylic sulfinate esters, a process that rapidly gives the isomeric allenic sulfones in high yield.[1] Although there is a great deal of interesting chemistry already associated with allenic sulfones,[2] we were intrigued by the possibility of further exploring this class of compounds, given that we had such convenient access to them. To that end, we became interested in a Nazarov cyclization illustrated in Scheme 1.[3] We wondered whether compounds, such as 1, might spontaneously, or under the influence of a catalyst, undergo a Nazarov cyclization to give 3.[4] That the intermediate in such a process would likely be 2 was even more alluring, because one could imagine trapping such a species in a (4 + 3)-cycloaddition reaction.[5, 6]

Scheme 1. Possible Nazarov cyclization of allenyl vinyl ketone 1.

The synthesis of precursors to compounds represented by 1 is relatively straightforward, provided the substituents R3 and R4 are both alkyl. Thus, treatment of allene 4 a with nBuLi in THF at 78 8C gave the corresponding organolithium species.[7] This could be trapped with cinnamaldehyde to give 5 a in 95 % yield. Other electrophiles including saturated aldehydes, benzaldehydes, aliphatic ketones, and unsaturated ketones could also be used in this process to create a very large array of alle[a] R. R. Tata, C. S. Hampton, E. F. Altenhofer, M. Topinka, W. Ying, X. Gao, Prof. Dr. M. Harmata Department of Chemistry, University of Missouri-Columbia 601 S. College Ave., Columbia, MO 65211 (USA) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404638. Chem. Eur. J. 2014, 20, 13547 – 13550

Scheme 2. Synthesis of allenyl alcohols.

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 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication Table 2. Synthesis of a’-hydroxydienones.[a]

Table 1. Conversion of 5 a to a’-hydroxydienone 6 a.

Entry

Reagent

Solvent

T [8C]

Yield of 6 a [%]

1 2 3 4 5 6 7 8

PCC PCC/SiO2 PCC/Al2O3 PCC/NaOAc[b] PCC/4  MS PDC Collins reagent Jones reagent[c]

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 H2O/acetone

RT RT RT RT RT RT 0 8C!RT RT

58[a] 44 37 53 58 35 20 29

[a] In this case, work-up was filtration and did not include dilution with diethyl ether. [b] Sodium acetate (2.5 equiv). [b] K2Cr2O7 (1.1 equiv); H2SO4 (2.0 equiv), RT.

Our initial goal was to produce allenyl vinyl ketones. To that end, alcohol 5 a was treated with PCC in dichloromethane. Rather than simple oxidation, the hydroxyketone 6 a was obtained in 60 % yield. We considered this result important and pursued it. The synthetic utility of a’-hydroxyenones makes their preparation desirable.[8] For example, a’-hydroxyenones can be used as 1,4-bidentate templates in asymmetric Diels– Alder cycloaddition reactions,[9] as well as enantioselective conjugate radical reactions.[10] They can also be used in aza-Claisen annulation reactions.[11] Attempts to optimize the reaction with CrVI-based oxidants are shown in Table 1. The use of PCC on silica gel[12] or alumina[13] gave 6 a, but in yields lower than that afforded by PCC alone (Table 1, entries 2 and 3). Buffering the PCC with sodium acetate[14] or by using 4  molecular sieves[15] had essentially no effect on the yield of the reaction (Table 1, entries 4 and 5). Neither PDC, Collins reagent, nor Jones reagent was better than PCC in effecting the transformation. Thus, within the context of this limited optimization, the simple use of PCC gave the most satisfactory yield of product. With the best conditions for the transformation in hand, we applied it to the allenols 5 produced by the straightforward alkylation process shown earlier. The results are summarized in Table 2. Interestingly, all the products from secondary allenols, derived from aldehydes, were obtained as single stereoisomers. The stereochemistry of dienone 6 a, was established by NOESY as illustrated in Figure 1. The same procedure was used for 6 m and 6 aa. All other stereochemical assignments were made on the basis of analogy. Generally, the yields obtained in this process are moderate, with the exception of 6 n, for reasons that are unclear. These reactions appear clean by simple standard methods of analysis (e.g., TLC) but the mass balances tend to suggest side reactions.

Chem. Eur. J. 2014, 20, 13547 – 13550

www.chemeurj.org

13548

Entry

Allenol

1

Product

t [h]

Yield [%]

5a

1

60

2

5b

1

55

3

5c

1

39

4

5d

1

57

5

5e

1

33

6

5h

1

78

7

5i

1

74

8

5j

1

65

9

5k

1

73

10

5l

1

66

11

5m

1

74

12

5n

3.5

96

13

5o

3.5

75

14

5p

10

39[b]

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication Table 2. (Continued)

Entry

Allenol

15

Product

t [h]

Yield [%]

Figure 1. NOE correlations for 6 a.

5r

5

61[c]

16

5s

1

64[d]

17

5t

5

66[e,f]

A prime candidate is oxidative cleavage of the products, though we have no evidence for this process to date.[16] Further investigation will be needed to clarify the matter. Although products derived from secondary allenols were formed as single isomers, those obtained from tertiary systems that lacked symmetry were often formed as nearly 1:1 mixtures of diastereomers (exception: Table 1, entry 17). We propose a mechanism for this process that is shown in Scheme 3 for the conversion of 5 a to 6 a. Formation of the

18

5u

2.5

55

19

5v

1

79

20

5w

1

23[f]

21

5x

1

50

22

5y

1

47[f]

23

5z

5

65

24

5 aa

0.67

42[f]

25

5 bb

1

26[f]

26

5 cc

5

53[g]

27

5 dd

2.5

58[h]

[a] The PCC oxidation used in these examples included standard dilution with ether followed by filtration. [b] Z/E 2:1, assignment based on proton chemical shifts, see the Supporting Information. [c] Z/E = 1.5:1, assignment based on proton chemical shifts, see the Supporting Information. [d] Z/E = 1.4:1, determined NOESY on purified product mixture, see the Supporting Information. [e] d.r. = 3:1. [f] No dilution with ether before filtration. [g] Ar = 2,4,6-triisopropylphenyl. [h] Ar = 2-naphthyl.

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Scheme 3. Proposed mechanism for the oxidative rearrangement of allenols.

chromate ester 7 is followed by a (3,3)-sigmatropic rearrangement to give 9. Assuming there is no isomerization along the way, this implies a transition structure represented by 8, in which the styryl substituent occupies a pseudoaxial position in a chairlike six-membered ring transition state. An alternative, in which this group is pseudoaxial, is possible, but would require subsequent isomerization of the product to the stereochemistry observed in the products. The product of the rearrangement is a chromium enolate (9), which undergoes a (2,3)-sigmatropic rearrangement to produce the chromate ester 10, which hydrolyzes to afford the a’-hydroxydienone product. Aspects of the mechanistic proposal have precedent. Oxidative rearrangements of allylic and propargylic alcohols in the presence of PCC/PDC are known.[17] Further, allenols are known to undergo rearrangements in the presence of a number of reagents, though this area is still emerging.[18] The stereochemical features of the transition state and the existence and fate of intermediates leading to 10 remain putative. We are examining other oxidations of allenols of this type. For example, the reaction of 5 a with DMSO and acetic anhydride gave 13 in 43 % unoptimized yield.[19] We imagine this process proceeding through acetate 11 through attack by 13549

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Communication

[4] [5]

[6] Scheme 4. Proposed mechanism for the reaction of 5 a with DMSO/Ac2O. [7]

DMSO to give, after deprotonation, the intermediate 12. Rearrangement of this intermediate would give 13 directly (Scheme 4). Although more work is needed on this process, it does represent a new way of producing quaternary carbons.[20] In summary, we have discovered a new synthesis of a’-hydroxydienones derived from readily available allenols. Further improvements on the methodology, studies of new allenol rearrangements, explorations of the chemistry of the products, and applications to organic synthesis are under investigation. Results will be reported in due course.

[8] [9] [10] [11] [12] [13] [14] [15]

Acknowledgements This work was supported by the National Science Foundation and the Department of Chemistry at the University of MissouriColumbia. W.Y. was supported by a grant from the U.S. Department of Energy (DE-SC0002040).

[16] [17]

[18]

Keywords: allenes · hydroxyketones · oxidation rearrangement · sigmatropic rearrangement · sulfones

·

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[19] [20]

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Received: July 29, 2014 Published online on August 28, 2014

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