Synlett 2015; 26(12): 1732-1736
DOI: 10.1055/s-0034-1380691
letter
© Georg Thieme Verlag Stuttgart · New York

Rasta Resin-TBD-Catalyzed γ-Selective Morita–Baylis–Hillman Reactions of α,γ-Disubstituted Allenones

Shuang Ma
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of China   Email: phtoy@hku.hk
,
Yun-Chin Yang
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of China   Email: phtoy@hku.hk
,
Patrick H. Toy*
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of China   Email: phtoy@hku.hk
› Author Affiliations
Further Information

Publication History

Received: 10 March 2015

Accepted after revision: 06 April 2015

Publication Date:
20 May 2015 (online)

 


Abstract

Rasta resin-TBD (RR-TBD) was found to be an efficient organocatalyst for γ-selective Morita–Baylis–Hillman reactions between α,γ-disubstituted allenones and aryl aldehydes. In these reactions the heterogeneous nature of RR-TBD greatly facilitated product isolation since the catalyst could be separated simply by filtration.


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The Morita–Baylis–Hillman (MBH) reaction is a widely studied C–C bond-forming transformation between an electron-withdrawing-group-activated alkene and an electrophile, typically an aldehyde or related compound, that is catalyzed by a nucleophilic organocatalyst.[1] Generally MBH reactions are α-selective, with the new C–C bond formed at the alkene position adjacent to the activating group (Scheme [1,] A). However, with activated allene substrates, the new C–C bond can be formed at the γ-position (Scheme [1,] B).[2] Recently Selig and co-workers have reported examples of such γ-selective MBH reactions involving allenoates catalyzed by the organic superbase[3] 7-methyl-1,5,7-tri­azabicyclo[4.4.0]dec-5-ene (MTBD, 1, Figure [1] and Scheme [1,] C).[4] [5] [6] Contemporaneous to this research, we were developing a heterogeneous polystyrene-based rasta resin-supported analogue of MTBD (RR-TBD, 2, Figure [1]) as an organocatalyst.[7] [8] [9] Initially we studied the use of 2 in transesterification reactions such as biodiesel production,[10] [11] and once this research was completed, we next turned our attention to examining the utility of 2 as a nucleophilic catalyst. Since we had extensive prior experience in developing polymer-supported nucleophilic phosphine catalysts for MBH reactions,[12] we attempted to use 2 in similar reactions and settled on allenoate substrates. However, in light of the report by Selig et al.[5] and the fact that Shi and co-workers originally studied only α-substituted allenones, we changed our focus to γ-selective MBH reactions of α,γ-disubstituted allenones catalyzed by 2, and report our results herein.

Zoom Image
Scheme 1 MBH reaction variations
Zoom Image
Figure 1 MTBD (1), the rasta resin concept, and RR-TBD (2)

Polymer 2 was synthesized as previously reported starting from the initiator functionalized heterogenous core using a combination of styrene and 4-vinylbenzyl chloride (5:1 ratio) to install the functionalized grafts by a living radical polymerization process (Scheme [2, ]A).[10] The benzyl chloride groups of the grafts were subsequently treated with deprotonated 1,5,7-triazabicyclo[4.4.0]dec-5-ene to install the catalytic MTBD group analogues. The allenone substrates 3AD were prepared by olefination of in situ generated ketenes according to a literature procedure, starting from α-bromo ketones 4A,B via phosphonium salt intermediates 5A,B, in moderate overall yields (Scheme [2,] B).[13] [14]

Zoom Image
Scheme 2 Synthesis of polymer 2 and allenones 3AD

With allenones 3AD in hand, we first investigated the possibility of their participation in γ-selective MBH reactions catalyzed by 1. In the original report by Shi and co-workers, DMAP was used as the catalyst in reactions for which the solvent was DMSO.[2] We therefore applied similar reaction conditions in side-by-side reactions between 3A and 4-chlorobenzaldehyde (6a) catalyzed by either DMAP or 1, and observed that the later afforded higher yield of product 7Aa as a nearly 1:1 mixture of diastereomers than did the former (Table [1], entries 1 and 2). Changing the solvent to NMP and increasing the amount of allenone 3A relative to electrophile 6a led to further yield enhancement (Table [1], entries 3–5).[15] Unfortunately, when a 1:1 ratio of 3A to 6a was used, the reaction did not go to completion, and chromatographic purification of 7Aa was required. On the other hand, using a four-fold excess of the allenone substrate compared to the aldehyde was wasteful, made the product purification tedious, and resulted in only a slightly higher yield. Thus, we chose to use a 2:1 ratio of allenone to aldehyde in the subsequent reactions.

Table 1 MBH Reactions of 3A with 6a a

Entry

Catalyst

Solvent

3A/6a

Time (h)

Combined yield (%)

1

DMAP

DMSO

1:1

6

54

2

1

DMSO

1:1

6

67

3

1

NMP

1:1

5

71

4

1

NMP

2:1

4

85

5

1

NMP

4:1

4

89

a Reaction conditions: allenone 3A, aldehyde 6a (0.4 mmol), catalyst (0.08 mmol), and solvent (1.0 mL) were stirred at r.t. for the indicated time.

We next turned our attention to examining the catalyst 1 in a range of γ-selective MBH reactions using the optimized reaction conditions (Table [2]). When allenone 3A was reacted with other electron-withdrawing group substituted aldehydes 6b,c, high yields of products 7Ab and 7Ac were obtained in short reaction times (entries 2 and 3). Very high yield of 7Ad could be obtained even when unactivated benzaldehyde (6d) was used (entry 4). However, when electron-rich 4-methoxybenzaldehyde (6e) was used, only relatively low yield of the corresponding product 7Ae was obtained after a prolonged reaction (entry 5). Reactions using allenone 3B that bears a phenyl group at the γ-position took longer and afforded lower product yields than did reactions with 3A (entries 6 and 7), perhaps due to the steric hindrance. Phenyl ketone substrates 3C and 3D showed similar reactivity patterns (entries 8–14). In all cases, the product was obtained as a nearly 1:1 mixture of diastereomers.

Table 2 MBH Reactions of 3 with 6 Catalyzed by 1 or 2 a

Entry

3

6

R1

R2

R3

7

1

2

Time (h)

Combined yield (%)

Ratio (major/minor)

Time (h)

Combined yield (%)

Ratio (major/minor)

 1

3A

6a

Et

Me

Cl

7Aa

 4

85

57:43

24

72

56:44

 2

3A

6b

Et

Me

CN

7Ab

 1.5

92

50:50

12

80

52:48

 3

3A

6c

Et

Me

NO2

7Ac

 3

87

51:49

18

70

50:50

 4

3A

6d

Et

Me

H

7Ad

 7

87

52:48

48

50

54:46

 5

3A

6e

Et

Me

MeO

7Ae

18

64

56:44

60

11

50:50

 6

3B

6b

Et

Ph

CN

7Bb

 9

74

58:42

48

66

55:45

 7

3B

6a

Et

Ph

Cl

7Ba

12

66

52:48

84

19

52:48

 8

3C

6b

Ph

Me

CN

7Cb

 0.5

91

53:47

 6

81

50:50

 9

3C

6c

Ph

Me

NO2

7Cc

 1.5

95

55:45

10

81

51:49

10

3C

6a

Ph

Me

Cl

7Ca

 3

89

50:50

12

81

56:44

11

3C

6d

Ph

Me

H

7Cd

 5

79

59:41

48

64

55:45

12

3C

6e

Ph

Me

MeO

7Ce

10

48

50:50

48

40

54:46

13

3D

6b

Ph

Ph

CN

7Db

 6

74

60:40

20

69

58:42

14

3D

6a

Ph

Ph

Cl

7Da

 9

91

52:48

36

40

52:48

15b

3C

6b

Ph

Me

CN

7Cb

24

47

50:50

16c

3C

6a

Ph

Me

Cl

7Ca

24

33

50:50

17d

3C

6a

Ph

Me

Cl

7Ca

12

49

56:44

18e

3C

6a

Ph

Me

Cl

7Ca

12

 0

-

a Reaction conditions: allenone 3 (0.8 mmol), aldehyde 6 (0.4 mmol), 1 or 2 (0.08 mmol), and NMP (1.0 mL) were stirred at r.t. (with 1) or at 50 °C (with 2) for the indicated time.

b Reaction was carried out at r.t.

c Reaction was carried out using 8 at 50 °C.

d First reuse of 2.

e Second reuse of 2.

Having established the general utility of 1 as a catalyst for the reactions of interest, we next used 2 in an identical set of reactions (Table [2]). Since we anticipated that the heterogeneous nature of 2 would lead to less efficient reactions, we performed these reactions at 50 °C rather than at room temperature. Even at this elevated temperature reaction times were much longer using 2 as the catalyst than those with 1 and product yields were slightly lower (entries 1–14). When a reaction between 3C and 6b was performed using 2 at room temperature, only 47% yield of 7Cb was obtained after 24 hours, compared to 81% yield of 7Cb after six hours at 50 °C (entry 15 vs. entry 8). Gratifyingly, when we used a macroporous polystyrene-supported TBD (PS-TBD­, 8) in which the catalytic groups are located on the interior of a heterogeneous polymer bead,[16] [17] much lower product yield of 7Ca was obtained after a much longer reaction time (entry 16 vs. entry 10). This supports the notion that placing the catalytic groups on flexible grafts makes them more accessible to the substrate molecules and more efficient compared to having them located on the interior of a polystyrene bead, as we have observed in our previous studies.[9] Unfortunately, we observed that polymer 2 was not an effective catalyst when reused (entries 17 and 18), and at this time the reasons for this are unclear. Reactivation of the catalytic groups by washing the polymer with a base did not improve the situation.

In summary, we have found that both 1 and our previously reported polymer 2 based on the rasta resin architecture are able to effectively catalyze γ-selective MBH reactions between α,γ-disubstituted allenones and aryl aldehydes. Superbase 1 was found to be a more efficient catalyst than the previously used DMAP, and while 2 was not reusable in these reactions, it did prove to be a more efficient catalyst than did a more traditional polystyrene-supported analogue. Importantly, the heterogeneous nature of 2 did facilitate product purification when it was used. We are currently examining other applications for 2 and will report the results of these studies shortly.


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Acknowledgment

This research was supported financially by the University of Hong Kong and the Research Grants Council of the Hong Kong S. A. R., P. R. of China (Project No. HKU 705510P).

Supporting Information

  • References and Notes

  • 5 Selig P, Turočkin A, Raven W. Synlett 2013; 24: 2535
  • 6 For a report regarding the conversion of the alcohol products of these reactions into the corresponding acetates and carbonates, see: Selig P, Nghiem T.-L. Synlett 2015; 26: 907
  • 7 For a review regarding organic polymer supports in organic chemistry, see: Lu J, Toy PH. Chem. Rev. 2009; 109: 815
  • 10 Yang Y.-C, Leung DY. C, Toy PH. Synlett 2013; 24: 1870
  • 11 For another report regarding the use of RR-TBD as a catalyst, see: Bonollo S, Lanari D, Angelini T, Pizzo F, Marrocchi A, Vaccaro L. J. Catal. 2012; 285: 216
  • 13 Lang RW, Hansen H.-J. Org. Synth. 1984; 62: 202
  • 14 General Procedure for the Synthesis of Allenones 3A–D: α-Bromo ketone 4A or 4B (20.0 mmol), Ph3P (6.29 g, 24.0 mmol), and benzene (100 mL) were added to a 250-mL round-bottomed flask equipped with a magnetic stirrer and a condenser. The reaction flask was immersed in an oil bath, and the reaction mixture was refluxed for 2 d. After cooling to r.t., the solvent was removed under reduced pressure to afford the crude phosphonium salt 5A or 5B as a viscous oil. The crude salt dissolved in CHCl3 (65 mL) was transferred to a 100-mL round-bottomed flask equipped with a magnetic stirrer. The reaction mixture was cooled to 0 °C with an ice-water bath and then Et3N (6.1 mL, 44 mmol) was added dropwise. The ice-water bath was removed, and the reaction mixture was then stirred at r.t. for 3 h. The reaction mixture was cooled to 0 °C and the appropriate acid chloride (18.0 mmol) was added dropwise. After 1 h, the reaction mixture was warmed to r.t. and stirred for a further 10 h. The reaction mixture was transferred to a separation funnel and H2O (100 mL) was added. The organic layer was separated and washed with brine (50 mL) and then dried over MgSO4. The solvent was removed under reduced pressure to afford a yellow oil which was then purified by silica gel column chromatography using a mixture of CH2Cl2 and hexane as the eluent. 4-Methylhepta-4,5-dien-3-one (3A): 1H NMR (400 MHz, CDCl3): δ = 5.43–5.50 (m, 1 H), 2.59–2.71 (m, 2 H), 1.79 (d, J = 7.3 Hz, 3 H), 1.76 (d, J = 2.7 Hz, 3 H), 1.07 (t, J = 7.3 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 212.29, 202.88, 159.50, 138.13, 91.70, 88.92, 32.10, 13.49, 13.39, 8.99. HRMS: m/z calcd for C8H12O: 124.0883; found: 124.0881.
  • 15 General Procedure for the MBH Reactions: Allenone 3AD (0.8 mmol), aldehyde 6ae (0.4 mmol), NMP (1.0 mL), and 1, 2 or 8 (0.08 mmol) were added to a 10-mL round-bottomed flask equipped with a magnetic stirrer. The reaction mixture was stirred either at r.t. (when 1 was used as the catalyst) or at 50 °C (when 2 or 8 was used as the catalyst) for the reaction times indicated in Table 2. When 1 was used as the catalyst, solid NH4Cl (0.006 g, 0.1 mmol) was added to the reaction mixture to quench the reaction. The reaction mixture was then transferred to a separation funnel, and then H2O (30 mL) and EtOAc (15 mL) were added. The organic layer was separated, washed with brine (30 mL), and dried over MgSO4. The solvent was evaporated under reduced pressure to afford an oil, which was purified by silica gel column chromatography using a mixture of EtOAc and hexane as the eluent. When 2 was used as the catalyst, the reaction mixture was merely filtered, and the crude product was purified by silica gel column chromatography. 7-(4-Chlorophenyl)-7-hydroxy-4,6-dimethylhepta-4,5-dien-3-one (7Aa): 1H NMR (400 MHz, CDCl3): δ = 7.29–7.37 (m, 4 H, CHAr, major + minor), 5.26 (s, 1 H, CHOH, major), 5.24 (s, 1 H, CHOH, minor), 2.50–2.64 (m, 2 H, COCH 2CH3, major + minor), 2.43 (br s, 1 H, OH, major), 2.37 (s, 1 H, OH, minor), 1.78 [s, 3 H, (CH 3)CCOEt, major + minor], 1.74 [s, 3 H, (CH 3)CCHOH, major + minor], 1.05 (t, J = 7.4 Hz, 3 H, CH2CH 3, major + minor). 13C NMR (major diastereomer, 101 MHz, CDCl3): δ = 208.73 (s, =C=), 202.80 (s, COEt), 140.12 (s, C ArCHOH), 133.73 (s, CArCl), 128.62 (s, CArH), 127.67 (s, CArH), 106.43 (s, CCHOH), 105.04 (s, CCOEt), 74.48 (s, CHOH), 32.43 (s, CH2CH3), 8.92 (s, CH2 CH3). The signals for (CH3)CCHOH and (CH3)CCO (14.43, 14.20, 13.81) were not assigned due to overlapping signals. 13C NMR (minor diastereomer, 101 MHz, CDCl3): δ = 208.67 (s, =C=), 202.86 (s, COEt), 140.09 (s, C ArCHOH), 133.80 (s, CArCl), 128.67 (s, CArH), 127.74 (s, CArH), 106.42 (s, CCHOH), 105.32 (s, CCOEt), 74.39 (s, CHOH), 32.43 (s, CH2CH3), 8.88 (s, CH2 CH3). HRMS: m/z calcd for C15H17Cl1O2: 264.0912; found: 264.0724.
  • 16 See reference 10 for details and a cartoon illustrating the structure of 8. The polystyrene support used in 8 is commercially available and is the typical material used in polystyrene-supported reagents and catalysts.

    • For research involving similar polystyrene-supported TBD reagents and catalysts, see:
    • 17a Fringuelli F, Pizzo F, Vittoriani C, Vaccaro L. Chem. Commun. 2004; 2756
    • 17b Fringuelli F, Pizzo F, Vittoriani C, Vaccaro L. Eur. J. Org. Chem. 2006; 1231
    • 17c Lanari D, Ballini R, Bonollo S, Palmieri A, Pizzo F, Vaccaro L. Green Chem. 2011; 13: 3181
    • 17d Lanari D, Ballini R, Palmieri A, Pizzo F, Vaccaro L. Eur. J. Org. Chem. 2011; 2874
    • 17e Alonzi M, Bracciale MP, Broggi A, Lanari D, Marrocchi A, Santarelli ML, Vaccaro L. J. Catal. 2014; 309: 260

  • References and Notes

  • 5 Selig P, Turočkin A, Raven W. Synlett 2013; 24: 2535
  • 6 For a report regarding the conversion of the alcohol products of these reactions into the corresponding acetates and carbonates, see: Selig P, Nghiem T.-L. Synlett 2015; 26: 907
  • 7 For a review regarding organic polymer supports in organic chemistry, see: Lu J, Toy PH. Chem. Rev. 2009; 109: 815
  • 10 Yang Y.-C, Leung DY. C, Toy PH. Synlett 2013; 24: 1870
  • 11 For another report regarding the use of RR-TBD as a catalyst, see: Bonollo S, Lanari D, Angelini T, Pizzo F, Marrocchi A, Vaccaro L. J. Catal. 2012; 285: 216
  • 13 Lang RW, Hansen H.-J. Org. Synth. 1984; 62: 202
  • 14 General Procedure for the Synthesis of Allenones 3A–D: α-Bromo ketone 4A or 4B (20.0 mmol), Ph3P (6.29 g, 24.0 mmol), and benzene (100 mL) were added to a 250-mL round-bottomed flask equipped with a magnetic stirrer and a condenser. The reaction flask was immersed in an oil bath, and the reaction mixture was refluxed for 2 d. After cooling to r.t., the solvent was removed under reduced pressure to afford the crude phosphonium salt 5A or 5B as a viscous oil. The crude salt dissolved in CHCl3 (65 mL) was transferred to a 100-mL round-bottomed flask equipped with a magnetic stirrer. The reaction mixture was cooled to 0 °C with an ice-water bath and then Et3N (6.1 mL, 44 mmol) was added dropwise. The ice-water bath was removed, and the reaction mixture was then stirred at r.t. for 3 h. The reaction mixture was cooled to 0 °C and the appropriate acid chloride (18.0 mmol) was added dropwise. After 1 h, the reaction mixture was warmed to r.t. and stirred for a further 10 h. The reaction mixture was transferred to a separation funnel and H2O (100 mL) was added. The organic layer was separated and washed with brine (50 mL) and then dried over MgSO4. The solvent was removed under reduced pressure to afford a yellow oil which was then purified by silica gel column chromatography using a mixture of CH2Cl2 and hexane as the eluent. 4-Methylhepta-4,5-dien-3-one (3A): 1H NMR (400 MHz, CDCl3): δ = 5.43–5.50 (m, 1 H), 2.59–2.71 (m, 2 H), 1.79 (d, J = 7.3 Hz, 3 H), 1.76 (d, J = 2.7 Hz, 3 H), 1.07 (t, J = 7.3 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 212.29, 202.88, 159.50, 138.13, 91.70, 88.92, 32.10, 13.49, 13.39, 8.99. HRMS: m/z calcd for C8H12O: 124.0883; found: 124.0881.
  • 15 General Procedure for the MBH Reactions: Allenone 3AD (0.8 mmol), aldehyde 6ae (0.4 mmol), NMP (1.0 mL), and 1, 2 or 8 (0.08 mmol) were added to a 10-mL round-bottomed flask equipped with a magnetic stirrer. The reaction mixture was stirred either at r.t. (when 1 was used as the catalyst) or at 50 °C (when 2 or 8 was used as the catalyst) for the reaction times indicated in Table 2. When 1 was used as the catalyst, solid NH4Cl (0.006 g, 0.1 mmol) was added to the reaction mixture to quench the reaction. The reaction mixture was then transferred to a separation funnel, and then H2O (30 mL) and EtOAc (15 mL) were added. The organic layer was separated, washed with brine (30 mL), and dried over MgSO4. The solvent was evaporated under reduced pressure to afford an oil, which was purified by silica gel column chromatography using a mixture of EtOAc and hexane as the eluent. When 2 was used as the catalyst, the reaction mixture was merely filtered, and the crude product was purified by silica gel column chromatography. 7-(4-Chlorophenyl)-7-hydroxy-4,6-dimethylhepta-4,5-dien-3-one (7Aa): 1H NMR (400 MHz, CDCl3): δ = 7.29–7.37 (m, 4 H, CHAr, major + minor), 5.26 (s, 1 H, CHOH, major), 5.24 (s, 1 H, CHOH, minor), 2.50–2.64 (m, 2 H, COCH 2CH3, major + minor), 2.43 (br s, 1 H, OH, major), 2.37 (s, 1 H, OH, minor), 1.78 [s, 3 H, (CH 3)CCOEt, major + minor], 1.74 [s, 3 H, (CH 3)CCHOH, major + minor], 1.05 (t, J = 7.4 Hz, 3 H, CH2CH 3, major + minor). 13C NMR (major diastereomer, 101 MHz, CDCl3): δ = 208.73 (s, =C=), 202.80 (s, COEt), 140.12 (s, C ArCHOH), 133.73 (s, CArCl), 128.62 (s, CArH), 127.67 (s, CArH), 106.43 (s, CCHOH), 105.04 (s, CCOEt), 74.48 (s, CHOH), 32.43 (s, CH2CH3), 8.92 (s, CH2 CH3). The signals for (CH3)CCHOH and (CH3)CCO (14.43, 14.20, 13.81) were not assigned due to overlapping signals. 13C NMR (minor diastereomer, 101 MHz, CDCl3): δ = 208.67 (s, =C=), 202.86 (s, COEt), 140.09 (s, C ArCHOH), 133.80 (s, CArCl), 128.67 (s, CArH), 127.74 (s, CArH), 106.42 (s, CCHOH), 105.32 (s, CCOEt), 74.39 (s, CHOH), 32.43 (s, CH2CH3), 8.88 (s, CH2 CH3). HRMS: m/z calcd for C15H17Cl1O2: 264.0912; found: 264.0724.
  • 16 See reference 10 for details and a cartoon illustrating the structure of 8. The polystyrene support used in 8 is commercially available and is the typical material used in polystyrene-supported reagents and catalysts.

    • For research involving similar polystyrene-supported TBD reagents and catalysts, see:
    • 17a Fringuelli F, Pizzo F, Vittoriani C, Vaccaro L. Chem. Commun. 2004; 2756
    • 17b Fringuelli F, Pizzo F, Vittoriani C, Vaccaro L. Eur. J. Org. Chem. 2006; 1231
    • 17c Lanari D, Ballini R, Bonollo S, Palmieri A, Pizzo F, Vaccaro L. Green Chem. 2011; 13: 3181
    • 17d Lanari D, Ballini R, Palmieri A, Pizzo F, Vaccaro L. Eur. J. Org. Chem. 2011; 2874
    • 17e Alonzi M, Bracciale MP, Broggi A, Lanari D, Marrocchi A, Santarelli ML, Vaccaro L. J. Catal. 2014; 309: 260

Zoom Image
Scheme 1 MBH reaction variations
Zoom Image
Figure 1 MTBD (1), the rasta resin concept, and RR-TBD (2)
Zoom Image
Scheme 2 Synthesis of polymer 2 and allenones 3AD