3-Chloro-propenyl Esters in Organic Synthesis: A

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A New Chromium-Catalysed Homoaldol Reaction ... aldol reaction, regioselectivity. Synthetic .... the homoaldol condensation.12 3-Halo-propenyl esters 4.
LETTER

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3-Chloro-propenyl Esters in Organic Synthesis: A New Chromium-Catalysed Homoaldol Reaction ANewChromium-Cat lysedHomoaldolReaction Lombardo,* Stefano Morganti, Sebastiano Licciulli, Claudio Trombini* Marco Università di Bologna, Dipartimento di Chimica ‘G. Ciamician’, via Selmi 2, 40126 Bologna, Italy Fax +39(51)2099456; E-mail: [email protected] Received 18 September 2002

addition of Cr(II) to allylic halides (Nozaki–Hiyama– Kishi, NHK reaction) or to acrolein acetals (Takai– Utimoto reaction).6

Abstract: Chromium(II) oxidatively adds to 3-halo-propenyl esters affording heterosubstituted allylchromium(III) reagents exploitable in the Nozaki–Hiyama–Kishi reaction. A catalytic cycle based on the Cr(III)–Mn(0) redox couple was applied, affording protected homoaldols as the major products, at 65 °C in acetonitrile as solvent.

Fürstner’s catalytic version4 of the NHK reaction was tested, using both 3-bromo and 3-chloro propenyl esters 4a–d.7 Trimethylsilyl chloride (TMSCl) was used as stoichiometric promoter and catalytic tetrabutylammonium iodide (TBAI) was found to be necessary when chlorides 4a and 4c,d were used. Organochromium species 7, likely consisting of a fluxional mixture of (E)-g-7, (Z)-g-7 and a7, added to aldehydes affording a and g-intermediates 8 and 9, which were silylated in situ to give 10 and 11, respectively (Scheme 3).

Key words: 3-halo-propenyl esters, catalytic Nozaki–Hiyama– Kishi reaction, heterosubstituted allylchromium complexes, homoaldol reaction, regioselectivity

Synthetic equivalents of the heterosubstituted allylic anion 1 offer a practical solution to the synthesis of homoaldols 2 and of alken-3,4-diols 3, respectively (Scheme 1).

Table 1 collects preliminary data obtained with a few 3halo-propenyl esters 4a–d, in acetonitrile as solvent. Following Fürstner’s protocols,4,8 cyclohexanecarboxaldehyde (1 mmol), 4 (1.5 equiv), TMSCl (1.2 equiv) and tetrabutylammonium iodide when required (runs 3–7, 0.2 equiv), were successively added to a premixed suspension of Mn powder (3 equiv) and CrCl3 (0.1 equiv) in acetonitrile (2 mL). After being stirred under the reaction conditions reported in Table 1, the reaction mixtures were quenched with water.

OH

OH OR

R'

R'CHO

R'CHO

RO

2

R'

1

3

OR

Scheme 1

Within this research framework, we recently proposed 3-halo-propenyl esters 4 as new precursors of 1, through oxidative addition of indium or zinc to the C–Br bond (Scheme 2). Based on organometallic species 5, two regioselective synthetic protocols operating under Grignard or Barbier conditions were developed, which afforded adducts 6 in good to excellent yields.1,2

The conspicuous formation of homoaldol derivatives 11 represented the most important difference observed using chromium with respect to indium and zinc. Assuming that the nucleophilic addition step occurs with allylic inversion through six-membered transition states, a-7 proved to be able to react with aldehydes, differently from its indium and zinc analogues.1,2 The role of solvent is crucial in determining the regioselectivity of the reaction; when N,N-dimethylformamide was replaced with acetonitrile, reaction rates increased but regioselectivity was reversed in favour of 10 (compare runs 7 and 8).

In order to confirm the versatility of 4 as precursors of organometallic reagents, we inspected the interaction of 4 with Cr(II) salts. Three recent review articles3–5 testify the rapidly accelerating interest in organochromium chemistry, with particular reference to carbonyl additions of allylic chromium complexes, generated by oxidative

OH M CH3COO

X

CH3COO

4 X = Br, Cl M = In, Zn

Scheme 2

Synlett 2003, No. 1, Print: 30 12 2002. Art Id.1437-2096,E;2003,0,1,0043,0046,ftx,en;G27702ST.pdf. © Georg Thieme Verlag Stuttgart · New York ISSN 0936-5214

MLn 5

1) R'CHO 2) K2CO3

R' 6 OH

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LETTER

M. Lombardo et al. CrLn RCOO

CrLn

O

E γ-7

α-7

L O Cr L

O R

R

O

Z γ-7

R'CHO 7 RCOO

X 4a-d OCr(III)

OCr(III) 2 Cr(II)

and/or

R'

8

OCOR

R' 9

OCOR

Mn(II)

TMSCl Cr(III)

Mn(0)

OTMS

OTMS

a: R = CH3, X = Cl b: R = CH3, X = Br c: R = CH3OCH2, X = Cl d: R = (CH3)3C, X = Cl

R'

and/or 10

OCOR

OCOR

R' 11

Scheme 3

Table 1

Chromium-Catalysed Reactions of 4 with Cyclohexanecarboxaldehyde in Acetonitrile. 10 Yield (%)a (syn/anti)b

11 Yield (%)a,c

Run

4

T (°C)

t (h)

Additives

1

4a

22

12

TMSCl

2

4a

22

20

TMSCl/TBAI (20%)

15 (1:1)

54

3

4a

0

20

TMSCl/TBAI (20%)

18 (1:1)

18

4

4b

22

12

TMSCl

19 (1:1)

44

5

4b

22

20

TMSCl/TBAI (20%)

10 (2:3)

33

6

4c

22

16

TMSCl/TBAI (20%)

23 (1:1)

26

7

4d

22

16

TMSCl/TBAI (20%)

5 (4:1)

40

8d

4d

22

16

TMSCl/TBAI (20%)

80 (3:2)

15

0

a

0

1

Products 10 and 11 were chromatographed as a mixture and relative ratios were determined by H NMR. Determined by GC-MS analysis of the crude reaction mixture. c Invariably present in a Z/E ratio > 98:2 (1H NMR). d Reaction carried out in anhydrous N,N-dimethylformamide. b

The following remarks derive from the results reported in Table 1:

iv) Homoaldol derivatives 11 are always formed in virtually pure Z-configuration.

i) Chlorides 4a,c,d were not reactive, unless a catalytic amount of tetrabutylammonium iodide (TBAI, runs 1–3) was used, likely forming in situ 3-iodo-propenyl esters; on the other hand, addition of TBAI had a negative effect on bromide 4b (runs 4–5).

v) Formation of adducts 10 is not diastereoselective, while simple E- and Z-crotyl chromium complexes are known to stereoconverge to anti homoallylic alcohols.8–10

ii) No regioselectivity was observed either when the reaction temperature was set at 0 °C (run 3) or when the methoxyacetate derivative 4c was used (run 6). iii) The regioselectivity in favour of 11 increases on moving to the sterically encumbered pivaloate 4d (run 7), most likely due to the much more congested reactive centre in (E) or (Z) g-7 with respect to a-7.

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Considering the appreciable dependence of regiochemistry on temperature (runs 2 and 3), we explored the reaction at 65 °C using 4a in the presence of TBAI, both with aldehydes and ketones. (Z)-g-Trimethylsilyloxy-enolesters 11 were invariably obtained as the major products, as demonstrated by the experiments reported in Table 2, thus allowing the synthesis of this family of homoaldol derivatives.11 Adducts 11 look like promising intermediates since they present two functional groups valuably protected as a silyl ether and a Z-enol acetate respectively,

© Thieme Stuttgart · New York

LETTER

A New Chromium-Catalysed Homoaldol Reaction

and because simple treatment with K2CO3 in methanol– water (9:1) quantitatively converts them into g-substituted g-lactols 12 (Scheme 4).

(3) Avalos, M.; Babiano, R.; Cintas, P.; Jiménez, J. L.; Palacios, J. C. Chem. Soc. Rev. 1999, 28, 169. (4) Fürstner, A. Chem. Rev. 1999, 99, 991. (5) Wessjohann, L. A.; Scheid, G. Synthesis 1999, 1. (6) (a) Takai, K.; Nitta, K.; Utimoto, K. Tetrahedron Lett. 1988, 29, 5263. (b) Boeckman, R. K. Jr.; Hudack, R. A. Jr. J. Org. Chem. 1998, 63, 3524. (c) Takai, K.; Kataoka, Y.; Utimoto, K. Tetrahedron Lett. 1989, 30, 4389. (7) (a) 3-Halo-1-propenyl esters 4a–d were prepared according to Neuenschwander procedure: Neuenschwander, M.; Bigler, P.; Christen, K.; Iseli, R.; Kyburz, R.; Mühle, H. Helv. Chim. Acta 1978, 61, 2047. (b) The new compounds 4c and 4d have the following NMR spectra: (Z)-4c 1H NMR (200 MHz, CDCl3) d = 3.49 (s, 3 H, OCH3), 4.10 (dd, 2 H, 3 JH-H = 8.1 Hz, 4JH-H = 1.2 Hz, H-3), 4.18 (s, 2 H, CH2O), 5.23 (dt, 1 H, 3JH-H = 8.1 Hz, 3JH-H = 6.5 Hz, H-2), 7.26 (dt, 1 H, 3JH-H = 6.5 Hz, 4JH-H = 1.2 Hz, H-1); 13 C NMR (75 MHz, CDCl3) d = 36.2 (C-3), 59.3 (CH3O), 69.0 (CH2O), 110.1 (C-2), 135.8 (C-1), 166.6 (C=O). (E)-4c 1H NMR (300 MHz, CDCl3) d = 3.48 (s, 3 H, OCH3), 4.10 (dd, 2 H, 3 JH-H = 7.5 Hz, 4JH-H = 1.2 Hz, H-3), 4.13 (s, 2 H, CH2O), 5.68 (dt, 1 H, 3JH-H = 7.5 Hz, 3JH-H = 12.1 Hz, H-2), 7.46 (dt, 1 H, 3JH-H = 12.1 Hz, 4JH-H = 1.2 Hz, H-1); 13C NMR (75 MHz, CDCl3) d = 40.7 (C-3), 59.2 (CH3O), 69.0 (CH2O), 111.7 (C-2), 138.2 (C-1), 166.9 (C=O). (Z)-4d 1 H NMR (200 MHz, CDCl3) d = 1.29 [s, 9 H, (CH3)3], 4.21 (dd, 2 H, 3JH-H = 8.0 Hz, 4JH-H = 1.1 Hz, H-3), 5.18 (dt, 1 H, 3JH-H = 8.0 Hz, 3JH-H = 6.5 Hz, H-2), 7.22 (dt, 1 H, 3JH-H = 6.5 Hz, 4JH-H = 1.1 Hz, H-1); 13C NMR (75 MHz, CDCl3) d = 36.2 (C-3), 59.3 (CH3O), 69.0 (CH2O), 110.1 (C-2), 135.8 (C-1), 166.6 (C=O). (E)-4d 1H NMR (200 MHz, CDCl3) d = 1.26 [s, 9 H, (CH3)3], 4.11 (dd, 2 H, 3 JH-H = 8.0 Hz, 4JH-H = 1.1 Hz, H-3), 5.64 (dt, 1 H, 3JH3 3 H = 8.0 Hz, JH-H = 12.7 Hz, H-2), 7.43 (dt, 1 H, JH-H = 12.7 Hz, 4JH-H = 1.1 Hz, H-1); 13C NMR (75 MHz, CDCl3) d = 40.7 (C-3), 59.2 (CH3O), 69.0 (CH2O), 111.7 (C-2), 138.2 (C-1), 166.9 (C=O). (8) Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349. (9) Buse, C. T.; Heathcock, C. H. Tetrahedron Lett. 1978, 1685. (10) Hiyama, T.; Kimura, K.; Nozaki, H. Tetrahedron Lett. 1981, 22, 1037. (11) Typical Experimental Procedure (Table 2, Run 1). (Z)-4-Cyclohexyl-4-trimethylsilyloxy-but-1-en-1-yl acetate (11, R = c-C6H11). A flame dried 10 mL flask is charged under argon with freshly distilled CH3CN (2.5 mL), manganese powder (0.164 g, 3 mmol, ~50 mesh, 99.9% purity, Aldrich)and chromium(III) chloride (0.016 g, 0.1 mmol, 99% purity, Aldrich). The heterogeneous mixture is left unstirred for 15 min, then vigorously stirred for 30 min until the solution turns light blue, an evidence of chromium(II) chloride formation. 3-Chloro-propenyl acetate 4a (0.175 mL, 1.5 mmol), cyclohexanecarboxaldehyde (0.120 mL, 1 mmol), trimethylsilyl chloride (0.150 mL, 1.2 mmol, purified immediately before use by elution through a short column of basic alumina) and tetrabutylammonium iodide (0.075 g, 0.2 mmol) are sequentially added to the reaction mixture. The temperature is raised to 65 °C and stirring is continued vigorously for 2 h at 65 °C. The reaction mixture is cooled to room temperature and finally quenched with 5 mL of water. Inorganic salts are removed by filtration through Celite, the organic solvent is evaporated at reduced pressure and the aqueous layer is extracted with diethyl ether (3 ´ 10 mL). The combined organic layers are dried (Na2SO4) and evaporated at reduced pressure. Flashchromatography (cyclohexane–diethyl ether 95:5) of the residue furnishes a fraction containing (Z)-4-cyclohexyl-4trimethylsilyloxy-but-1-en-1-yl acetate and its regioadduct,

OTMS

K2CO3

OCOR

R'

R'

MeOH/H2O (9:1)

11

O

OH 12

Scheme 4 Table 2 Chromium-Catalysed Additions of 4a to Carbonyl Compounds in the Presence of TBAI in Acetonitrile at 65 °C for 2 h. 10+11 11/10b a Overall Yield (%)

Run

Carbonyl compound

1

Cyclohexanecarboxaldehyde 66

90:10

2

3-Phenylpropanal

64

83:17

3

Hexanal

72

83:17

4

Benzyloxyacetaldehyde

53

90:10

5

Cinnamaldehyde

50

74:26

6

Benzaldehyde

61

82:18

7

2-Naphthaldehyde

53

72:28

8

Cyclohexanone

55

91:9

9

Acetophenone

55

73:27

a

Determined as a purified mixture of 10 and 11, not separable by flash-chromatography. Conversely, the corresponding deprotected products, i.e. 1-alken-3,4-diols and g-lactols, obtained after alkaline hydrolysis (K2CO3 in MeOH–H2O 9:1), are easily separated by flashchromatography. b Determined by 1H NMR analysis of the crude reaction mixture. Major products 11 were invariably present in a Z/E ratio > 98:2, while minor products 10 were obtained as ~ 1:1 syn/anti mixtures.

In conclusion, a new synthetic application of 3-halo-propenyl esters 4 is reported, consisting of a novel version of the homoaldol condensation.12 3-Halo-propenyl esters 4 were recently highlighted both for the very easy preparation by 1,4-haloacylation of propenal,7 and for a few practical syntheses of alk-1-en-3,4-diols.1,2 The present chromium-catalysed addition of 4 to carbonyl compounds complements the previous methods based on the use of indium and zinc, since the regioselectivity reversal in favour of the homoaldol derivative 11 is now achieved.

Acknowledgement This work was supported by MURST–Rome (National Project ‘Stereoselezione in Sintesi Organica. Metodologie e Applicazioni’) and University of Bologna (funds for selected topics).

References (1) Lombardo, M.; Girotti, R.; Morganti, S.; Trombini, C. Org. Lett. 2001, 3, 2981. (2) Lombardo, M.; Girotti, R.; Morganti, S.; Trombini, C. Chem. Commun. 2001, 2310.

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M. Lombardo et al. 4-cyclohexyl-4-trimethylsilyloxy-but-1-en-3-yl acetate (0.187 g, 0.66 mmol, 66%), in a 9:1 ratio. Title compound: 1 H NMR (300 MHz, CDCl3): d = 0.11 [s, 9 H, (CH3)3Si], 0.85–1.40 (m, 6 H), 1.57–1.88 (m, 5 H), 2.15 (s, 3 H, CH3CO), 2.32 (br dd, 1 H, 3JH-H = 7.5 Hz, 3JH-H = 5.8 Hz, H3), 3.44 (dt, 1 H, 3JH-H = 3JH-H = 5.8 Hz, H-4), 4.95 (dt, 1 H, 3 JH-H = 6.5 Hz, 3JH-H = 7.5 Hz, H-2), 7.08 (dt, 1 H, 3JH-H = 6.5 Hz, 4JH-H = 1.4 Hz, H-1); 13C NMR (50 MHz, CDCl3): d = 0.36, (Me3Si), 20.6 (CH3CO), 26.2, 26.3, 26.5, 28.2, 29.4, 29.5, 42.7 (C-3), 76.1 (C-4), 110.4 (C-2), 135.0 (C-1), 167.8 (C=O); MS (EI): m/z (%) = 185(100), 172(7), 158(3), 129(9), 117(10), 103(67), 95(69), 75(25), 73(78), 55(8). HRMS: m/z calcd for C15H28O3Si 284.1808; found 284.1811. 5-Cyclohexyl-tetrahydrofuran-2-ol (12, R = cC6H11). Potassium carbonate (0.210 g, 1.5 mmol) is added to the previously reported 9:1 mixture of regioadducts (0.140 g, 0.5 mmol) dissolved in CH3OH–H2O (5 mL, 9:1) and the heterogeneous reaction mixture is vigorously stirred at room temperature for 8 h. Water is added (5 mL), CH3OH is

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evaporated at reduced pressure and the aqueous layer is extracted with diethyl ether (3 ´ 15 mL). The combined organic layers are dried (Na2SO4) and evaporated at reduced pressure. Purification by flash-chromatography (cyclohexane–diethyl ether 8:2) allows separation of the corresponding g-lactol (0.076 g, 0.44 mmol, 99%), present as a 3:2 mixture of anomers, and 4-cyclohexyl-1-buten-3,4diol (0.009 g, 0.05 mmol, 100%), identical to an authentic specimen obtained in previous work.1,2 Title compound: 1 H NMR (300 MHz, CDCl3): d = 0.80–2.10 (m, 30 H), 2.44 (d, 1 H, J = 3.0 Hz, OH), 2.62 (d, 1 H, J = 3.0 Hz, OH), 3.69 (br q, 1 H, J ~ 7.5 Hz, H-5), 3.94 (br q, 1 H, J = ca. 6.85 Hz, H-5), 5.44–5.48 (m, 1H, H-2), 5.52–5.57 (m, 1 H, H-2). 13 C NMR (50 MHz, CDCl3): d = 25.8, 25.9, 26.0, 26.5, 26.9, 27.0, 28.9, 29.0, 29.5, 29.7, 30.2, 33.1, 33.9, 42.7, 44.1, 82.7 (C-5), 85.7 (C-5), 97.9 (C-2), 98.3 (C-2). (12) (a) Martins, E. O.; Gleason, J. L. Org. Lett. 1999, 1, 1643. (b) Hoppe, D.; Thomas, H. Angew. Chem., Int. Ed. Engl. 1997, 36, 2282. (c) Hoppe, D. Angew. Chem., Int. Ed. Engl. 1984, 23, 932.

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