Enantioselective 1,2-addition of grignard reagents to aldehydes using chiral diamines

0040-4020/93 $6 oO+ 00 0 1993 PergamonPress L

Tetmhedron Vol 49, No 43. pi 97X-9158.1993 I’mted m Great Brltam

Enantioselective 1,2=Addition of Grignard Reagents to Aldehydes using Chiral Diamines

Makoto Nakajima,

Kiyoshi Tomioka,*l

and Kenji Koga

Faculty of Pharmaceuttcal Sctences. Umverslty of Tokyo. Hongo, Btmkyo-ku, Tokyo 113, Japan

(Recerved rn Japan 8 July 1993, accepted 16 August 1993)

AbatEnannoselechve 1.2~addmon of Gngnard reagents to aldehydes usmg chal dtamme 1.2 was exammed High ee (up to 75 %) of carbmol was acbeved by the reactton of arylmagneaum brotmde and benzakiehyde with chtral dtamme Uuhzmg 2,4,6-mmethylphenoxyahumnum drchlmde 6 as a coordmatmg agent to betuakIehyde, enanttoselechvlty of the addtaon of alkylmagnesium bronude was dramattcally mcmased (up to 70 46)

The fortnahon

of carbon-carbon bonds IS one of the most fundamental problems m orgamc chenustry

The

stereoselechve addmon of ackal nucleophles to prochmtl carbonyl compounds m the presence of &ml ad&hves 1s a conceptually elegant method for the synthesis of ophcally achve compounds from achual startmg mater&l The successful examples of &us type of asymmetnc reachon are employed by organ0hthmm and -magnesmm211, -zinc12 , or Mamum

compounds with clural bgands

We have

reported the design and synthesis of novel

clural diammes 1, 214a and their apphcahon to the enanhoselechve reachons l4 In order to eshmate the.lr ab&y of enantmdifferentition, enantioselechve 1,2-ad&Ion of Gngnard reagents to aldehydes was examined We herem descnbe the detad for our prehmmary commumcahons 14b$c Desrgn of enantroselectrveI ,2-a&non of organometalhc reagents

Coordmahon of organometalhc reagent with chval hdentate hgand creates a chual envuonment to control the stereochemistry of metal-induced reachons We have described the design and synthesis of novel chual pyrrohdme-based duumnes 1,2 with C2-symmetry 14a These dmnunes are supposed to form stable complexes 3 wth organometalhcsl5, which has an umque structure because of then lugh symmetry Conformahonally n@d aryl groups provide the well-defined

clural environment,

which IS expected to reahze high enantloface

hfferenhahon of carbonyl plane of aldehydes

1 Ar=Ph 2 Ar = 35Xylyl

R’CHO + R*Metal

-

H PH

1 or2

R’XR2

9751

9752

M

NAKAJWA

et al

Organohthmm and organomagnesmm compounds are the most rehable organometalhcs for 1,2-addmon to We first examined wide screening of 1,2-addition of organohthmm

aldehydes

and organomagnesmm

compounds to benzaldehyde with chtral dlamme 1 (Table 1) The aldehyde was added to a solution of the complex of an organometalhc and a dnumne at -78’C m toluene Usual work up gave the comqondmg and the ee was determmed by ophcal rotatton Lknme

carbmol

was easily recovered without any loss of optical punty by

simple tiltrahon as a hydrochlonde Just after acidic work up

Although organohduum reagents showed no

asymmetnc induction at all (Run 1, 2), organomagnesmm reagents gave slgmficant asymmetnc mductlons Among various reagents surveyed, phenyhnagnestum bromide was found to gave the best result (Run 7) Enantaoselectrve I &Addrtlon of Arymagnesrum Brormdes to Aldehydes usmg Chrral Dwmrnes Asymmetnc addition of arylmagnesmm bromides to various aldehydes at -1CKK m toluene usmg choral dtamme 1,2 were investigated (Table 2)

Both duunme 1,2 well medlated enanhoselechve

addlhon of

phenylmagnestum bromide and the selecttvthes are m good relattonshtp with the bulkmess of the aldehyde substttuent (Run l-4, 6-9) Carbmols of high ee (71 %, 75 %) were obtamed m the reaction of anaphthylmagnesmm

bromde with benzaldehyde usmg dtamme 1 or 2 (Run 5.10)

Smce Arylmagnesmm

Table 1 Asymmetnc 1,2-Addmon of R2Metai to RlCHO usmg Dmmme 1 Run

Rl

R2Meti

1

Ph

Bti

2

Ph

F%Ll

ee (%)

Conf

Yield (%)

-2 0

6

S

79

0

0

-

81

[U]~~:(‘&alzenc)

3

Ph

Bu2Mg

0

0

-

86

4

Ph

BuMgCl

+5 2

13

R

88

5

Ph

BuMgBr

+7 5

20

R

86

6

Bu

Ph2Mg

-9 5

25

S

75

7

Bu

PhMgBr

32

s

80

R1CHO/R2MgBr/Dunme=l/2

-119

5t3 0

Table 2 Asymmemc 1,2-Addmon of R*MgBr to RICH0 using Chtral Dtamme 1 or 2 at - 1WC Run

L#lganda

Rl

R2

[a]&)

ee (%)

Conf

Yteld (%)

Bu

Ph

- 14 3 (benzene)

38

S

73

1

‘pr

Ph

-22 6 (ether)

47

S

68

1

cHex

Ph

-12 7 (benzene)

4.5

S

76

1

tBu

Ph

-21 6 (ether)

60

S

82 92

1

1

2 3 4 5

lb

Ph

a-Nap

-84 4 (acetone)c

71

Sd

6

2

Bu

Ph

-13 7 (benzene)

36

S

87

7

2

‘pr

Ph

-20 0 (ether)

42

S

90

8

2

cHex

Ph

-15 6 (benzene)

55

s

68

9

2

tBu

Ph

-19 3 (ether)

55

S

77

10

2b

Ph

a-Nap

-88 0 (acetone)c

75

sd

94

a) R1CHO/R2MgBr/I)lamme=1/1 25/l 5 b) R1CHO/R2MgBr/Dmmme=V2 acetatem CgDg with Eu(hfc)j See expenmental sechon

5/3 0

c) [a]:&

d) NMR analysts

1 of the

1,2-Ad&tton of Gngnard reagents to aldehydes

Table 3 Asymmetnc 1,ZAddmon of a-Naphthyhnagnesmm Run

Temp.(“C)

[a]$&(*)(aCetone)

9753

Bromide to Benzaldehyde usmg 1 a

ee (8)

Yield (96)

A(AG#)(kcal/mol)b

1

-20

-45 7

38

59

040

2

-45

-65 3

55

94

0 56

3

-78

-76 0

64

96

0 58

-84 4

71

92

0 58

Ia) R1CHOIR2MgBr/Thmme=l/2 4 -100

I

5/3 0 b)d(dG3cRTln(S_enantomer/R~n~ho~r)

Table 4 Asymmemc 12-Addmon of a-Naphthylmagnewum Bromide to Benzaldehyde using 1 at -78’C Run

PhCHO/NapMgBr/Amme

[a]$&( ‘)(acetone) -51 5

ee (%)

Yield (%)

43

74

1

l/125/075

2

l/125/15

-71 4

60

81

3

l/25/3

-76 0

64

96

4

1 I2516

-76 2

64

98

reagents have been scarcely used m this type of asymmemc reachon without any assistance of other metals.*2aV 13a these results show the first successful asymmemc mduchon m 1,2-ad&on

of arylmagnesmm bronude to

aldehyde with chnal &amme The possible ongm of enantloface selection IS probably related to the stenc mteraction between the aryl group on the choral llgand and Rl on the aldehyde shown m Fig 1

All the configurational

bias of thus

asymmetnc addmon can be explamed Hrlthout exception

In order to elucidate the reactlon mechamsm, reactlon com-htions such as temperature (Table 3) and molar ratio of reactant (Table 4) were exammed As shown m Table 3, nearly constant A(AG*) (0 58 kcal/mol, 2 4 kJ/mol), realizing m the temperature rangmg from -100 to -45-C, implies the involvement of a single active species in this asymmemc addition

No significant change of ee was observed by mcreasmg the ratio of Gngnard reagent and dlamme to aldehyde (Table 4, Run 2-4) These results suggest the monomenc structure sumlar to 4 to be an actual acme spectes

..e. Ar m

Rg 1

HO ,lY

H R2

M NAKAJIMAet al

9754

Enantroselecttve 1 &Addatron of Alkylmagnesrum Bromdes to Akiehydes wrthChu-al Dtamtnes In the Presence of Metal Haltdes

Although arylmagnesmm bronudes showed sahsfactory enanhoselectlvrty, alkyhnagnesmm bromide gave no promismg ee m tlus system We then used a new approach to mcrease enan~oselectlvlty utlhzmg Lewis acid to control the geometry of the coordmatlon 16 As a metal hahde IS supposed to coordmate wtth an aldehyde occupymg the position syn to aldehyde hydrogen (ii), the coordinating site of the magnesium atom of the Gngnard reagent should be restncted to antr, which IS expected to provide more effective stenc mteractlon between RI on the aldehyde and the a@ groups on choral dmmmes

The chnal complex of butylmagnesmm

bromde and 1 was added to the complex of benzaldehyde and phenoxymagnestum bromide in toluene Among various phenols surveyed, 2,4,6-mmethylphenoxymagnesmm enanttoselecttvq

bromide 17 exhibits a profound effect on the

As shown in Table 5, enanttoselechvlty was improved up to 43 % upon an addihon of the

metal hahde (Run 6) Replacement of magnesium with the more coordmatable aluminum (6, prepared m situ from 2,4,6trunethylphenol and ethylalummum d~chlonde) afforded carbmol m 56 % ee (Run 7) ‘flus IS m dramatic contrast to the enanhoselechvIty of 20 96 ee whtch IS obtamed in the reactton wtthout the metal hahde (Run 1) Usmg thus new system, asymmemc ad&hon of various alkylmagnestum bromides were exammed at -1oo’C (Table 6) In the reachon of pentyl- and hexyl-magnesium bromide. with d~amme 2, correspondmg carbmols were obtamed in 65 and 70 46 ee (Run 10.11) Tlus effect of atyloxymetal halides on the enanhoselechve n?achon may hold great promtse m development of the new asymmemc Eachon of organometalhcs with carbonyl compounds

l .MX”OAr R’ A l-i o.N

6

5

Table 5 Asymmetric 1,2-Atihon of Butyhnagnesium Brom& to Benzaldehyde wtth 1 m thepresence of Phenoxymetal Hahde at -78% Run

AroMxn

1

none

2

PhOMgBr

3

[a 25CH==) +7 5

ee (96)

Meld (%)

20

86

+lO 1

28

86

2-MeOPhOMgBr

+6 5

17

62

4

3,5Me2PhOMgBr

+6 2

17

80

5

2,6-tBu2-4~MePhOMgBr

+8.4

23

93

6

2,4,6-Me3PhOMgBr

+15 6

43

58

+19 8

56

61

2,4,6-Me3PhOAlCl2 7 IphcHo/hietal hsll&/¶HgBr/Dlamlnc=l/ll/l l/l 2

1,ZAddmon of Grlgnard reagents to aldehydes

9755

Table 6 Asymmetnc 1,ZAddmon of Alkyhnagnesmm Brormde to Benzaldehyde m the presence of 2,4,6-Tnmethylphenoxyalnunum D~chlonde at -1WC Run

ilganda

ee (%)b

Yield (46)

1

1

Me

+4 7 (c-pentane)

11

63

2

1

Et

+14 3 (chloroform)

31

68

3

1

Pr

+lO 4 (benzene)

23

74

4

1

Bu

+218 (benzene)

61

69

5

1

Pen

+20 7 (c-pentane)

59c

90

6

1

Hex

+13 0 (benzene)

4oc

59

7

2

Et

+ 14 9 (chloroform)

33

65

R

[aID(“)

8

2

Pr

+I0 1 (benzene)

22

57

9

2

Bu

+19 4 (benzene)

54

79

10

2

Pen

+21 9 (c-pentane)

65c

59

+22 6 (benzene)

7oc

71

11 2 Hex Ia) PhCHO/Metd hahde/RMgBr/Dwnme=l/l

l/l 4/l 6 b) All the absolute configurations of carbmols are R

c) IH-NMR analyas of 16 MTPA ester

Experimental

Section

Ophcal rotaUons were taken with a JASCO DIP-370 dqqal polanmeter IR spectra were taken with a JASCO IRA- 1 infrared spectrometer and expressed m cm- 1 NMR spectra were taken m CDC13 with a JEOL FX-100 spectrometer at lOOMHz, or a Hitachi R-24B spectrometer at 60 MHz

Chemical sluft values are

expressed m ppm relanve to internal tetrametbylsdane

MS were taken with a JBOL DX-300 mass spectrometer All the dned solvents were chshlled Just before use from sodium benzophenone ketyl Choral Qammes were prepared according to the reported procedure 14a a-Naphthylmagnesmm bromide was prepared from anaphthylbrotmde

with Mg metal m benzene-ether

(2/l)

Other Gngnard reagents were prepared from

correspondmg bmtmde with Mg metal m ether Dtbutylmagnesmm and diphenylmagnesmm were prepared from corresponding Gngnard reagent with dloxane m ether and then supematant were used

Phenoxymagnesmm bromide m toluene 2,4,6Qchlonde was prepared from 2,4,6-tnmethylphenol and ethylahumnum Qchlonde

bromides were prepared from correspondmg Tnmethylphenoxyahunmum

phenols and butylmagnesmm

m toluene The products of asymmemc reaction were identified by NMR, IR, MS and their optical punties were determined by optical rotanon otherwise noaced The maxfmum opt& rotations used here for PbRC*HOH are as follows, R Me1 8 ([a]~0 -43 1*

Cc=7

cyclopentane) for S ), Et19 ([CZ]D+45 45’ (c=5, chloroform) for R ), Pr20 C[a]k7+45 9’ (c=6 1, benzene)

19,

for

R ), lPr21([a];’ +47 7’ (c=7, ether) for R ), Bug ([a]Z: -35 7’ (c=3, benzene) for S ), tBu21 ([a];’ -36 2’ (c=9, ether) for S ), Pen22 ([a];’ +2 86’ (c=5 7. cyclopentane) for R ), cHex21 ([a];* -28 3’ (c=3, benzene) for S ), a-Nap23 ([a]::, +8 1 2’ (c= 1, acetone) for R )

M NAKAJIMA et al

9756

Representative Procedures of Asymmetnc Remon a-Naphthylphenylcarbrnol (Table 2, Run 10)

A solution of a-naphthylmagnenum

bromide (2 0 mmol) 1n benzene-ether (2 1, 3 ml) was added to a

solution of 2 (1 4 g, 2 4 mmol) m toluene (100 ml) at -78°C After 30 mm shmng at the same temperature, the mixture was cooled to -1WC and a solution of benzaldehyde (85 mg, 0 8 mmol) m toluene (5 ml) was added The mixture was stmed at -1WC for 1 h and quenched with 5 8 HCl Ether (100 ml) was added to the reaction nuxture and stirred for 2 h at room temperature

The preclpltate of 2 HCl was filtered, washed with water and

ether, dned, and converted with NaOH back to unaltered (R&)-2 (1 3 g, 93 %) The water layer of ongmal filtrate was extracted with ether and the combined organic layer was washed successively with 10 % HCl, satd NaHC03, brine, and dned over MgS04 Punficatlon with S102 column chromatography (hexanedlchloromethane, l/l) afforded (S)-a-naphthylphenylcarbinol (0 18 g, 94 %) , [a&88 IR (CC14) 3300

0’ (c=l 66, acetone)

IH-NMR (60M, CDC13) 6 2 30 (lH, s, OH), 6 45 (lH, s, CH), 7 3-8 1 (12H, m, Ar)

MS

m/z 234 (M+) Tnethylamme (0 35 ml) and acehc anhydnde (0 1 ml) was added to a solution of above carb1nol (19 mg) 1n methylene chlonde (5 ml) and the whole was stured for 8 h at room temperature The reachon mixture was diluted with methylene chlonde and washed with 10 % HCl, satd NaHC03, brme, and dned over MgS04 Punficatlon with S102 column chromatography (hexane-benzene, l/l) afforded (S)-a-naphthylphenylcarb1nol acetate (19 mg, 83 %) , [a12’ 435 -38 1” (c=l 47, acetone)

IR (CC4)

1740 IH-NMR (60M, CDC13) 6 1 83

(3H, s, CH3), 6 9-8 2 (13H, m, Ar) MS m/z 276 (M+) Enantlomenc excess was determined by 1H-NMR with a chmtl shift reagent (benzene-d6, Eu(hfc)g, peaks of CH3) to be 75 % ee Hexylphenylcarbmol (Table 6, Run 11)

A solutton of benzaldehyde (57 mg, 0.54 mmol) 1n toluene (1 ml) was added to a solution of 2,4,6tnmethylphenoxyalumlnum

dichloride, prepared 1n situ by treatment of 2,4,6_tnmethylphenol

(88 mg, 0 65

mmol) with ethylalumlnum dichlonde (0 59 mmol) 1n toluene (20 ml) for 30 mm at -78-C After 30 mm samng, a solution of hexylmagneslum bromide (0 75 mmol) and 2 (0 5Og, 0.85 mmol) in ether-toluene (1 10, 5 ml), prematured for 30 mm at -78-C, was added to the above solution at -1WC

After 1 h sumng at -1WC the

rmxture was quenched with 5 % HCl Ether (20 ml) was added to the mixture and the whole was steed for 1 h at room temperature

The precipitate of 2 HCl was filtered, washed with water and ether, dried, and converted

with NaOH back to unaltered (RR)-2 (0 45 g, 90 8)

The water layer of onglnal filtrate was extracted with

ether and the combined orgamc layer was washed successively with 10 8 HCI, 15 % NaOH, bnne, and dned over MgS04 Punficafion with S102 column chromatography (hexane-dichloromethane, l/l) following bulb to bulb dlstlllatlon afforded (S)-hexylphenylcarb1nol (73 mg, 71 %) , [a];‘-22 6’ (c=3 01, benzene) IR (neat) 3400 lH-NMR (60M, CDC13) 6 0 9-2 2 (13H, m, CH2 & CH3), 4 70 (lH, t, J=6Hz, CH), 7 30 (5H, s, Ar) MS m/z 192 (M+) Enantlomenc excess was determined by 1H-NMR of 1ts MTPA ester to be 70 96 ee IH-NMR( IOOM, CDC13) 6 3 44 (R), 3 53 (S) (11t24, 6 3 45(R), 3 53(S))

( Present Address The Institute of Scientific and Industnal Research, Osaka Umvers1ty, Ibarak1, Osaka 567, Japan

9757

1,2-Addmon of Gngnard reagents to aldehydes

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