Organocerium Reagents

1.8 Organocerium Reagents TSUNEOIMAMOTO Chiba University, Japan 1.8.1

231

INTRODUCTION

1.8.2 ORGANOCERIUM REAGENTS 1.8.2.1 Generation ofOrganocerium Reagents 1.8.2.1.1 General comments 1.8.2.1.2 General procedure for the preparation ofanhydrous cerium chloride 1.8.2.1.3 General procedure for the generation of organocerium reagents 1.8.2.1.4 Reactions with ketones and similar compounds 1.8.2.2 Scope of the Reactivity 1.8.2.2.1 Thermal stability 1.8.2.2.2 Reactions with organic halides, nitro compounds and epoxides 1.8.2.3 Reactions with Carbonyl Compounds 1.8.2.4 Selective Addition to a,f3-Unsaturated Carbonyl Compounds 1.8.2.5 Addition to C-N 1T-Bonds 1.8.2.6 Synthetic Applications 1.8.2.6.1 Alkylcerium reagents 1.8.2.6.2 Allylcerium reagents 1.8.2.6.3 Alkenyl- and aryl-cerium reagents 1.8.2.6.4 Alkynylcerium reagents

232 232

232 232 233 233

233

233 233

234 235 236 237

237 239 240 242

1.8.3 CERIUM ENOLATES

243

1.8.4 GRIGNARD REAGENT/CERIUM CHLORIDE SYSTEMS

244

1.8.5 REFERENCES

248

1.8.1 INTRODUCTION Elements of the lanthanide series possess unique electronic and stereochemical properties due to their I-orbitals, and have great potential as reagents and catalysts in organic synthesis. l -4 During the 1970s and 1980s many synthetic reactions and procedures using lanthanide elements were reported, in conjunction with significant development in the chemistry of organolanthanides. Several review articles covering this field of chemistry have appeared. 5- 11 Of the 15 elements from lanthanum to lutetium, cerium has the highest natural abundance, and its major inorganic salts are commercially available at moderate prices. The present author and his coworkers have utilized this relatively inexpensive element in reactions which form carbon--carbon bonds, studying the generation and reactivities of organocerium reagents. The cerium reagents, which are prepared from organolithium compounds and cerium(III) halides, have been found to be extremely useful in organic synthesis, particularly in the preparation of alcohols by carbonyl addition reactions. They react with various carbonyl compounds to afford addition products in satisfactory yields, even though the substrates are susceptible to so-called abnormal reactions when using simple organolithiums or Grignard reagents. This chapter surveys the addition reactions of organocerium reagents to the C-X 'iT-bond. Emphasis is placed on the utility of cerium chloride methodology, and many examples of its practical applications 231

232

Nonstabilized Carbanion Equivalents

are given. Experimental procedures are also described in detail to enable readers to employ this method immediately in practical organic syntheses. Other organolanthanide reagents are covered in Chapter 1.10 in this volume, while selective carbonyl addition reactions promoted by samarium and ytterbium reagents are surveyed in Chapter 1.9.

1.8.2 ORGANOCERIUM REAGENTS

1.8.2.1 Generation of Organocerium Reagents Organocerium reagents are prepared in situ by the reaction of organolithium compounds with anhydrous cerium chloride or cerium iodide, as shown in equation (1).12-14 A variety of organolithium compounds can be employed, including alkyl-, allyl-, alkenyl- and alkynyl-lithiums, which are all converted to the corresponding cerium reagents. RLi

+ CeX3

THF (1) X=CI,I

No systematic studies on the structure of organocerium reagents have been made so far. Although some experimental results indicate that no free organolithium compounds are present in the reagents, the structure of the reagents has not yet been elucidated. The cerium reagents are presumed to be
1.8.2.1.1 General comments Organocerium reagents can be generated without difficulty, but the following suggestions will help to ensure success. Cerium chloride, rather than cerium iodide, is recommended because preparation of the iodide requires the handling of pyrophoric metallic cerium. 14 Anhydrous cerium chloride is commercially available from Aldrich, but can also be prepared in the laboratory by dehydration of cerium chloride heptahydrate using thionyl chloride,15 or by reduction of cerium(IV) oxide using HC02H/HCI followed by dehydration. 16 Heating the hydrate without additive in vacuo is a comparatively simple method and is satisfactory for the generation of organocerium reagents. Ethereal solvents such as tetrahydrofuran (THF) and dimethoxyethane (DME) are employed in the reactions, with THF generally being preferred. Usually, THF freshly distilled from potassium or sodium with benzophenone is used. Use of hot THF is not recommended, because on addition to cerium chloride a pebble-like material, which is not easily suspended, may be formed.

1.8.2.1.2 General procedure for the preparation ofanhydrous cerium chloride Cerium chloride heptahydrate (560 mg, 1.5 mmol) is quickly ground to a fine powder in a mortar and placed in a 30 mL two-necked flask. The flask is immersed in an oil bath and heated gradually to 135140°C with evacuation (ca. 0.1 mmHg). After 1 h, a magnetic stirrer is placed in the flask and the cerium chloride is dried completely by stirring at the same temperature in vacuo for a further 1 h. The following procedure is recommended for the small-scale preparation of anhydrous cerium chloride. Cerium chloride heptahydrate (ca. 20 g) is placed in a round-bottomed flask connected to a dry ice trap. The flask is evacuated and heated to 100°C for 2 h. The resulting opaque solid is quickly pulverized in a mortar and is heated again, in vacuo at the same temperature, for 2 h with intermittent shaking. A stirrer is then placed in the flask, which is subsequently evacuated, and the bath temperature is raised to 135-140 ac. Drying is complete after 2-3 h of stirring. Anhydrous cerium chloride can be stored for long periods provided it is strictly protected from moisture. Cerium chloride is extremely hygroscopic; hence, it is recommended that it be dried in vacuo at ca. 140°C for 1-2 h before use.

Organocerium Reagents

233

1.8.2.1.3 General procedure for the generation oforganocerium reagents Cerium chloride heptahydrate (560 mg, 1.5 mmol) is dried by the procedure described above. While the flask is still hot, argon gas is introduced, after which the flask is cooled in an ice bath. Tetrahydrofuran (5 mL) is added all at once with vigorous stirring. The ice bath is removed and the suspension is stirred well for 2 h or more (usually overnight) under argon at room temperature. The flask is cooled to -78°C and an organolithium compound (1.5 mmol) is added with a syringe. Stirring for 0.5-2 h at the same temperature, or a somewhat higher temperature (-40 to -20°C), results in the formation of a yellow or red suspension, which is ready to use for reactions.

1.8.2.1.4 Reactions with ketones and similar compounds The addition reactions are usually carried out at -78°C, except for reactions of the Grignard reagent/cerium chloride system (Section 1.8.4), which are conducted at 0 °C. A substrate is added to the well-stirred organocerium reagent and the mixture is stirred until the reaction is complete. Work-up is carried out in the usual manner: quenching with dilute HCI or dilute AcOH and extraction with a suitable organic solvent. When the substrates are acid sensitive, work-up using tetramethylenediamine is recommended. I?

1.8.2.2 Scope of the Reactivity

1.8.2.2.1 Thermal stability The reagents are generally stable at low temperature (-78 to -20°C) and react readily with various carbonyl compounds to give the corresponding addition products in high yields. However, at temperatures above 0 °c, reagents with (3-hydrogens decompose; reactions with ketones provide reduction products (secondary alcohols and pinacol coupling products), as shown in Scheme 1. Other reagents, such as methyl- and phenyl-cerium reagents, are stable at around room temperature but decompose at about 60 °C.I3,14,18

-78 to-65 °C

R 1 =Et, Bun, BuS X = CI, I

0-50°C

o °C to r.t. Scheme 1

1.8.2.2.2 Reactions with organic halides, nitro compounds and epoxides The reactivities of organocerium reagents toward organic halides are in sharp contrast to the reactivities of alkyllithiums. No metal-halogen exchange occurs at -78°C; aryl bromides and iodides are quantitatively recovered unchanged after treatment with n-butyl- or t-butyl-cerium reagents. I8 ,I9 Alkyl iodides are also inert to prolonged treatment with organocerium reagents at the same temperature. Benzylic halides undergo reductive coupling to give 1,2-diphenylethane derivatives upon treatment with the n-butylcerium reagent. 18 Nitro compounds react immediately with organocerium reagents at -78°C to give many products,I9 while epoxides undergo ring opening followed by deoxygenation to yield substituted alkenes. 2o

Nonstabilized Carbanion Equivalents

234

1.8.2.3 Reactions with Carbonyl Compounds Organocerium reagents react readily with various ketones at low temperature to give the addition products in good to high yields. 12-14,21 Some representative results are shown in Table 1,12,13 together with the results obtained on using the corresponding organolithiums alone. Table 1 The Reaction of Organocerium Reagents with Ketones Ketone

Reagent

Product

Yield (%)a

(PhCH2)2CO (PhCH2)2CO (PhCH2)2CO

BunCeCl2 ButCeC12 HC=CCeCI2

(PhCH2)2C(OH)Bun (PhCH2)2C(OH)But (PhCH2)2C(OH)C=CH

96 (33) 65 (trace) 95 (60)

PhC=CCeCI2

~

89 (30)

0=0

roo roo ~I

~I

COMe

P-IC6H4COMe P-BrC6H4COMe P-BrC6H4COCH2Br P-NCC6H4COMe m-02NC6H4COMe

Ph

(XJBU OH

BunCeC12

n

88 (trace)

OH

H 2C=C(Me)CeCI2

OJ( OH Bun

BunCeC12

BunCeCl2 BunCeCl2 PhC=CCeCI2 BunCeCl2 BunCeCl2

P-IC6H4C(OH)(Me)Bun p-BrC6H4C(OH)(Me)Bu n P-BrC6H4C(OH)(CH2Br)C=CPh p-NCC6H4C(OH)(Me)Bu n Complex mixture

88 (12)

57 «10) 93 (trace) 96 (43) 95 (trace) 48

Ph

Ph

~ ~COPh

~

BunCeCl2

C6H 11

~OH

I Ph H ll C 6 Bun

93

Ph Ph

~ OCOPh

BunCeCl2

Vr°H Ph

52

Bun

a The figures in parentheses indicate the yields obtained by use of the lithium reagent alone.

It is noteworthy that the reagents are only weakly basic and react even with readily enolizable ketones in moderate to good yields. Another important fact is that selective carbonyl addition occurs in the presence of carbon-halogen bonds. The chemoselectivity between aldehydes and ketones has been studied by Kauffmann et al. 22 Cerium reagents exhibit moderate aldehyde selectivities, although these are much lower than those of the organometallic reagents of titanium, zirconium and chromium (Scheme 2).23-26

Organocerium Reagents

n-C H 6

Ao 13

0

+

H

Et

235 EtxEt

RCeX2

~ Et - - -....

+

R

OH

MeCeC12

79

21

MeCeI2

87

13

90

10

n

Bu CeI2 Scheme 2

Stereoselectivities have been studied by several research groups. In the case of a-heterosubstituted carbonyl compounds, both chelation control and nonchelation control have been observed, depending on the reagents and substrates (Section 1.8.2.6).

1.8.2.4 Selective Addition to a,~-Unsaturated Carbonyl Compounds Organocerium reagents react with a,~-unsaturated carbonyl compounds to give 1,2-addition products in good to high yields (equation 2).27,28 THF

R2 R

OH

(2)

Rl~R3

-78°C

The reactions of (E)- and (Z)-I-(4'-methoxyphenyl)-3-phenyl-2-propen-l-ones (la and Ib; Scheme 3) are representative examples. The 1,2-selectivities are generally higher than those of the corresponding lithium reagents and Grignard reagents (Table 2);28 however, the selectivity can be severely eroded by steric effects, as exemplified by the reactions of an isopropylcerium reagent. The reactions of (Z)-PhCH==CHCOC6H4-p-OMe with cerium reagents provide (Z)-allyl alcohols in excellent yields, suggesting that the addition reactions proceed almost exclusively through a polar pathway. Another notable difference between cerium and lithium reagents has been observed in the reaction of a stabilized carbanion with cyclohex-2-enone. The reaction with a-cyanobenzyllithium is known to be thermodynamically controlled; thus, the initially formed 1,2-adduct dissociates to the starting carbanion and a-enone, which in tum are gradually converted to the thermodynamically stable 1,4-adduct. 29 In contrast, the corresponding cerium reagent affords the 1,2-adduct exclusively in good yield, regardless of reaction time (Scheme 4 and Table 3).28 Trivalent cerium is strongly oxophilic and intercepts the intermediate 1,2-adduct by virtue of its strong bonding to the alkoxide oxygen, thus suppressing the reverse reaction. Ph

Ph

Ph

R ~

RM

+

~

0

~

OMe

RM

?? ~

Ph

OMe

(3)

(2a)

~

0

~

OM'e

(la)

Ph

??

~

R HO

~ ~

OMe

(lb)

+ OMe

(2b)

R =Me, Bu, Ph, I¥; M =CeC12, Li, MgBr Scheme 3

(2a)

+

(3)

Nonstabilized Carbanion Equivalents

236

Table 2 Reaction of Organocerium, Organolithium or Grignard Reagents with (E)- or (Z)-PhCH=CHCOC6J4-0Me-p

a

ConditionsB Time (min)

Substrate

Reagent

Solvent

(la)

MeCeCl2 MeLi MeMgBr BuCeCl2 BuLi BuMgBr PhCeCl2 PhLi PnMgBr PfC.eC12 PfLi FtMgCI

(lb)

MeCeCl2 MeLi MeMgBr BuCeCl2 BuLi BuMgBr PhCeCl2 PhLi PhMgBr

THF-ether (12: 1) THF-ether (5: 1) THF THF-hexane (8:1) THF-hexane (2:1) THF THF-ether (8: 1) THF-ether (3: 1) THF THF-hexane (4:1) THF-hexane (3:1) THF THF-ether (12: 1) THF-ether (5: 1) THF THF-hexane (8:1) THF-hexane (2:1) THF THF-ether (8: 1) THF-ether (3: 1) THF

All reactions were carried out at -78

30 30 30 30 30 30 30 30 30 30 30 30 60 60 60 60 60 60 90 90 90

(2a)

Yield ofproducts (%)b

98 65 38 50 36 10 90 85 14 42 39

44

Trace Trace

26

Trace Trace

20

Trace Trace

25

(2 b)

(3)

0 0 0 0 0 0 0 0 0 0 0 0 97 96 20 97 70 25 93 90 20

Trace

17 65 43 50 76 4 10 78 35 57 51

Trace Trace

38

Trace

20 50 4 4 45

°e. b Isolated yield.

o

6

+

CN

CN

Scheme 4 Table 3 M Li Li Li CeCl2 CeCl2 CeCl2 a All

ConditionsB Temperature CC) Time (min)

-70 -70 -70 -78 -78 -78

Yield(%) 1,2-Addition 1,4-Addition

1

29 21

4

61

15 180 15 240

o

60

62

36 49 90

o o o

Ref

29 29 29 28 28 28

reactions carried out using THF as solvent.

1.8.2.5 Addition to C-N 1T-Bonds The reaction of cerium reagents with imines and nitriles which possess a-hydrogens has been studied by Wada et al. 3o Available data indicate that the reagents do not effectively add to these substrates, although the results are better than with alkyllithiums themselves. A modification of the procedure improves the yields of addition products. Thus, addition of the organocerium or organolithium reagent to an

Organocerium Reagents

237

admixture of cerium chloride and imine or nitrile at -78°C affords the adducts in acceptable yields, as exemplified in equation (4).30 i,CeC13 ii, BuDCeClz

ptt~N~Ph

(4)

92%

It has been reported by Denmark et ale that aldehyde hydrazones react smoothly with organocerium reagents to give addition products in good to high yields (Section 1.8.2.6).31

1.8.2.6 Synthetic Applications 1.8.2.6.1 Alkylcerium reagents Mash has recently employed a methylcerium reagent in the synthesis of (-)-chokol A.32 The reagent reacts with the readily enolizable cyclopentanone derivative (4) to give (-)-chokol A in 80% yield, as shown in Scheme 5.

H)( __

o

o

&-

6--

U-

f

12 steps

r -:;.

80%

OH (4)

OH

(-)-Chokol A

i, MeCeCl2 (5 equiv.), THF, -78°C, 2 h

SchemeS

Corey and Ha have successfully employed a cerium reagent at the crucial step in the total synthesis of venustatriol, as illustrated in Scheme 6. 33 0 0 H

0

CHO -78°C, 10 min, then 0 °C, 2 h

+

CeCl2

H

85%

0"-../0 OH

0 0 H

0

3 steps

H

0

o

o

H

""'"

OH

Venustatriol

Scheme 6

OH

Nonstabilized Carbanion Equivalents

238

In a total synthesis of (-)-bactobolin, Garigipati and Weinreb used a dichloromethylcerium reagent. 34 The intermediate product (5) was isolated in 54% yield as a single isomer, as shown in Scheme 7. Dichloromethyllithium alone in this reaction afforded intractable material.

C12CHLi/CeC13 Et2 0, -100 °C

.

6 steps

H 2N

0

NH

= ~

..

54%

o

I ~ I

H

(5)

SES: Me3SiCH2CH2S02

0

HOi --H

(-)-Bactobolin

Scheme 7

The stereochemistry in the reactions mentioned above is consistent with a chelation-controlled addition of the organocerium reagents. On the other hand, nonchelation-controlled addition of alkylcerium reagents to carbonyl components has also been observed, as shown in Scheme 8. 35 ,36

(

0

~ OBn

90%

0

yYs OBn

s~

ii 83%

~

+

"

"

OBn 87

OBn 13

~s~ ",

",OH

S

+

OBn

86

9Ys~ ",

S

OBn

14

o

i, Bu CeC12, THF, -78°C; ii, WCeC12, THF, -78 to -60 °c SchemeS

Johnson and Tait prepared a trimethylsilylmethylcerium reagent and examined its reaction with carbonyl compounds. I7 The reagent adds to aldehydes and ketones including many readily enolizable ones to afford 2-hydroxysilanes. This modified Peterson reagent gives vastly superior yields in comparison with trimethylsilylmethyllithium. An example is shown in Scheme 9.

0=>=0

Me3SiCH2CeC12 THF

-78°C 83%

50% aq. HF,

~OH

~siMe3

MeCN,r.t. 87%

Scheme 9

The same reagent reacts with acyl chlorides to afford 1,3-bis(trimethylsilyl)-2-propanol derivatives, which efficiently undergo a trimethylchlorosilane-promoted Peterson reaction to afford allysilanes in high overall yields (equation 5).37 (5) 72-90%

Organocerium Reagents

239

Recently, Mudryk and Cohen have found that reactions of lactones with organocerium reagents provide lactols in good yields, as exemplified in Scheme 10.38 This reaction leads to an efficient one-pot synthesis of spiroketals, as illustrated in Scheme 11.38

f\vBun ~cI"OH Scheme 10 i,CeC13 radical anion

ii,~ Et

Li~OLi

0

o.

EtJ)(J 60%

i.~

~oAo

o 76% i,

o

1\

oAoA o

o Scheme 11

Denmark et ale have recently reported that aldehyde SAMP-hydrazones react with various alkylcerium reagents in good yields and with high diastereoselectivities. 31 The method can be applied to the synthesis of optically active primary amines, as exemplified in Scheme 12.

.0

~ '~OMe H

i-iii 45%

V'NH

2

96%ee

i, MeCeCI2, THF; ii, MeOH; iii, H2 (375 psi = 2.59 MPa), Raney nickel, 60°C

Scheme 12

1.8.2.6.2 Allylcerium reagents Cohen et ale have extensively studied the generation and reactivities of allylcerium reagents. 39,40 Allylcerium reagents react with a,J3-unsaturated carbonyl compounds in a 1,2-selective fashion. It is particularly noteworthy that unsymmetrical allylcerium reagents react with aldehydes or enals mainly at the least-substituted terminus, as opposed to other allylorganometallics such as allyltitanium reagents. An example is shown in Scheme 13. 39 Another prominent feature is that the reaction at -78°C provides (Z)-alkenes, while at -40 °C (E)-alkenes are formed. Allylcerium reagents have been successfully employed in an economical synthesis of

240

Nonstabilized Carbanion Equivalents

OH +

ii, MeCH=CHCHO, -78°C

HO MX n = CeCl3 MX n = Ti(Off)4

82%

95

5

90%

10

90

Scheme 13

some pheromones. Typical examples, which illustrate these characteristic reactivities, are shown in Schemes 14 and 15.40 SPh

OH

i-iii

~

#

72% H2C

SPh

iv

#

98%

=CHCHO ,-78°C

OH ~

65%

i, ii -400C

H2C = CHCHO , -78°C

OH

48%

i, lithiump,p'-di-t-butylbiphenylide (LDBB) or lithium 1-(dimethylamino)naphthalenide (LDMAN),

-60 °C; ii, CeC13, -78 °C; iii, H 2C=CHCHO; iv, Bun3P/PhSSPh Scheme 14

i-iii

SPh

78%

81%

79%

SPh

JyLi

iv

Br

HO

i, v, iii, vi

PhS

56%

OAc (Z):(E)

=98:2

i, LDBB; ii, Ti(Off)4; iii, CH20; iv, Ph3P/CBr4, MeCN; v, CeCI3; vi, AC20/pyridine

Scheme 15

1.8.2.6.3 Alkenyl- and aryl-cerium reagents Suzuki et ale found that a-trimethylsilylvinylcerium reagents add to readily enolizable ~,'Y-enones. The method has been employed in the synthesis of (-)-eldanolide, as shown in Scheme 16.41 Paquette and his coworkers have employed alkenylcerium reagents in the efficient stereoselective synthesis of polycyclic molecules. 42,43 A typical example is illustrated in Scheme 17. ~,'Y-Enone (6) reacts with alkenylcerium reagent (7) with high diastereoselectivity to give adducts (8) and (9) in a ratio of 95:5. The major product (8) undergoes an oxy-Cope rearrangement, creating two chiral centers with high stereoselectivity to furnish (10).

Organocerium Reagents

241

o EtO~O

91%

EtO~O i, H2C=C(SiMe3)CeC12, THF-Et2Q-hexane (4:1:1), -78°C, 0.5 h Scheme 16

Me~ OSiButMe2 f

~

+

o

(6)

THF, -78°C, 2 h 56%

(7)

MeS

MeS OH

+ III IIII

"'"

(9) 5

(8)

95

(8) 68%

Scheme 17

A notably stereoselective reaction of an arylcerium reagent has been reported by Terashima et al. 44 As shown in Scheme 18, the cerium reagent provides adducts (11) and (12) in a ratio of 16:1 in 95% combined yield. In contrast, the organolithium reagent gives a lower and reversed stereoselectivity. OBn

MOMO

OMOM

M~ButSiO~

~

OBn

M~

OBn

+ MOMO

OBn

{

MeOCONMe 0

{ HO

(11)

M CeC12 Li

Conditions

THF,-78°C THF,O°C EtherrrHF (4:1),0 °C Ether,O°C Scheme 18

Yield (%)

95 56 74 77

OBn (12)

(11):(12)

94:6 12:88 11:89 34:66

242

Nonstabilized Carbanion Equivalents

Recently, a new method for synthesizing coumarin derivatives has exploited the properties of arylcerium reagents, as illustrated in Scheme 19.45 Interestingly, the bulky arylcerium reagent (13) adds to the easily enolizable t-butyl acetoacetate in satisfactory yield. B i r r , CeCl2

~

THF,-78°C

0

+ ~C02But

O~OMe (13)

20% HCl, MeOH

Br

o 78% overall yield

Scheme 19

An example of the reaction of an alkenylcerium reagent with a cyclopentanone derivative has been reported. As shown in Scheme 20, the (E)-cerium reagent adds to the ketone to provide a single adduct in modest yield. 46 However, the (Z)-cerium reagent did not react, presumably due to steric effects.

o

aN/'.....CN I

Me

+

41%

Cl2Ce

~

SiMe2Ph (£):(Z) 50:50

Scheme 20

1.8.2.6.4 Alkynylcerium reagents The trimethylsilylethynylcerium reagent, which was initially prepared by Terashima et al., is useful for adding ethynyl groups to carbonyl moieties. 47 This method was successfully employed in the preparation of daunomycinone and related compounds. 47- 51 Illustrative examples are shown in Scheme 21.49 0

SiMe3

OH 0

R

0

OH

Me3Si

==

0

CeC12

OH OH

R = H, -78°C, 77% R=MeO,66%

R

R

0

OH

o

OH

Scheme 21

OH

0

OH

-----.. -----..

Organocerium Reagents

243

The utility of this reagent has been demonstrated by Tamura et ale in its reaction with the readily ~nol­ izable ketone (14).52,53 The ethynylation of the ketone proceeds smoothly with the cerium reagent, as shown in Scheme 22; in sharp contrast, the corresponding lithium reagent provides the desired adduct (15) in only 11 % yield.

Et0 Cn° 2

==

Me3Si CeC12 THF, -78°C, 2 h

OH

Et02C (14) (15)

Scheme 22

Some other alkynylcerium reagents have been generated and used for the synthesis of alkynyl alcohols and related compounds in good yields. 54-56 An example is illustrated in Scheme 23.

CHO

+

67%

OMPM

HO

HO

o OMPM

OMPM Scheme 23

1.8.3 CERIUM ENOLATES Cerium enolates are generated by the reaction of lithium enolates with anhydrous cerium chloride in THF.57 The cerium enolates react readily with various aldehydes and ketones at -78°C (Scheme 24). The yields are generally higher than in reactions of lithium enolates. This is presumably due to the relative stabilities of the adducts, that of the cerium reagent being greater by virtue of coordination to the more oxophilic cerium atom. The stereochemistry of the products is almost the same as in the case of lithium enolates, as shown in Table 4. The reaction is assumed to proceed through a six-membered, chair-like transition state, as with lithium enolates. A synthetic application of this cerium chloride methodology has been reported by Nagasawa et al., as shown in Scheme 25. 58 It is noteworthy that aldol reaction of the cerium enolate proceeds in high yields, even though the acceptor carbonyl group is sterically crowded and is readily enolized by lithium enolates. Fukuzawa et ale found that reduction of a-halo ketones followed by aldol reaction with aldehydes or ketones is promoted by CeI3, CeC13/NaI or CeC13/SnC12. 59,60 These reactions are carried out at room

o

Rl~R2

i, LDA

ii, CeCl3

OCeCI

I

22

Rl~R

R3COR4

0 Jl RX R Rl~ 'I -OH 3

R2 Scheme 24

4

Nonstabilized Carbanion Equivalents

244

Table 4 Enolized ketone

Acceptor carbonyl compound

Reagent

Yield (%)

Threo:erythro

PhCOCH2Me

MeCOCH2Me MeCOCH2Me

LDA-CeCh LDA

62 11

40:60 37:63

LDA-CeCh LDA

93 63

20:80 20:80

LDA-CeCh LDA

94 60

91:9 91:9

LDA-CeCh LDA

91 26

93:7 88:12

CHO

PhCHO PhCHO

COEt

CHO

C):):COMe ~ HO Cl

~ ~

OMOM C02But

I

+

OCeC12

==<

THF,-78°C 96%

OBut

20% HCI/MeOH

Cl

95%

OMOM

0

0

Scheme 25

temperature. Use of CeCl3 provides a,J3-unsaturated carbonyl compounds, while methods using CeCI3/NaI or CeCI3/SnCI2 afford exclusively J3-hydroxy ketones, as shown in Scheme 26.

70-98%

30-97%

Scheme 26

1.8.4 GRIGNARD REAGENT/CERIUM CHLORIDE SYSTEMS The addition of Grignard reagents to C-X 1T-bonds is undoubtedly one of the most fundamental and versatile reactions in synthetic organic chemistry. Nevertheless, it is also well recognized that these reactions are often accompanied by undesirable side reactions such as enolization, reduction, condensation, conjugate addition and pinacol coupling. In some cases, such abnormal reactions prevail over the 'normal addition reaction' , resulting in poor yields of the desired products.

Table 5 Reactions of Carbony.l Compounds with Grignard Reagents in the Presence of Cerium Chloride or w

Carbonylcontpound

Reagent

Method

Product(s)

Et3CCOMe Et3CCOMe

MeMgBr/CeCl3 MeMgBr

A

Et3CC(OH)Me2 Et3CC(OH)Me2

MeMgBr/CeCl3 MeMgBr

A

~OH

EtMgCl/CeCI3 EtMgCI

A

WEt

A

cO

J COMe

roo ~I

OH

0

06

H

WMgCl/CeCI3 WMgCI

MgBr/CeCl3

A

~

PhCOMe

MgBr

Table 5 (continued) Carbonyl COinpound

Reagent

Method

WMgCl/CeCI3 WMgCI

B

WMgCl/CeCI3 WMgCI

B

WMgCl/CeCI3 WMgCI

A

ButMgCl/CeCI3 ButMgCI

A

4T

Me2C=CH(CH2)2MgBr/CeCI3 Me2C=CH(CH2)2MgBr

Bb

PhCOCH2Br PhCOCH2Br PhCH=CHCOPh PhCH=CHCOPh PhCH=CHCOPh PhCH=CHCOPh PhCH=CHCOPh (Z)-PhCH=CHCOPh (Z)-PhCH=CHCOPh

H2C=CHMgBr/CeCI3 H2C=CHMgBr PhMgBr/CeCI3 PhMgBr/CeCI3 PhMgBr/CeC13 MeMgBr/CeCI3 MeMgBr PhMgBr/CeC13 PhMgBr

0=0 0=0 W2CO

W2CO

But-O=0

Product(s)

OR

,

O
W 3COH, W 2CHOH W 3COH, W 2CHOH But

-o

0H

')

o

Bu

I.......,,

OH A A

AC BC A A

PhC(OH)(CH2Br)C PhC(OH)(CH2Br)C PhCH=CHC(OH)Ph PhCH=CHC(OH)Ph PhCH=CHC(OH)Ph PhCH=CHC(OH)M PhCH=CHC(OH)M PhCH=CHC(OH)Ph PhCH=CHC(OH)Ph

Table 5 (continued)

Carbonyl compound

Reagent

Method

Product(s)

0°

J>tMgCVCeCI3 J>tMgCI

A

Q<0~,

PhCH2C02Me PhCH2C02Me PhCH=CHC02Et PhCH=CHC02Et PhCH2CONMe2 PhCH2CONMe2

J>tMgCVCeCI3 J>tMgCI H2C=CHMgBr/CeCI3 H2C=CHMgBr BunMgBr/CeC13 BunMgBr

A

B Bf

Prl

N

PhCH2C(OH)J>t2 PhCH2C(OH)J>t2 PhCH=CHC(OH)(CH=CH2)2, PhCH PhCH=CHC(OH)(CH=CH2)2, PhC PhCH2COBun PhCH2COBun

a All reactions are carried out in THF at 0 °C with a molar ratio of 1:1.5:1.5 (carbonyl compound:Grignard reagent:CeCI3) unless otherwise state reagent:CeCI3). C Molar ratio 1:1.5:2.5 (carbonyl compound:Grignard reagent:CeCI3). d (Z):(E) = 91:9. e (Z):(E) = 60:40. fMolar ratio 1:3:3 (a

Nonstabilized Carbanion Equivalents

248

It has been found that use of cerium chloride as an additive effectively suppresses abnonnal reactions, resulting in the formation of normal addition products in significantly improved yields. 61 ,62 The reactions are usually carried out by one of the following two methods. (i) The Grignard reagent is added to the suspension of cerium chloride in THF at 0 °C, the mixture is stirred well for 1-2 h at the same temperature and finally the substrate is added (method A). As vinylic Grignard reagents decompose rapidly on treatment with cerium chloride at 0 °C, reactions using these reagents should be carried out at a lower temperature. (ii) The Grignard reagent is added at 0 °C to the mixture of substrate and cerium chloride in THF that has previously been stirred well for 1 h at room temperature (method B). Representative examples of the reactions of various carbonyl compounds with Grignard reagents under these conditions are listed in Table 5. 62 It is emphasized that enolization, aldol reaction, ester condensation, reduction and 1,4-addition are remarkably suppressed by the use of cerium chloride. Various tertiary alcohols, which are difficult to prepare by the conventional Grignard reaction, can be synthesized by this method. The Grignard reagent/cerium chloride system has been applied to practical organic syntheses. 63-69 A typical example is shown in Scheme 27. 63 In sharp contrast to the reaction in the presence of cerium chloride, the Grignard reagent alone affords only a 2% yield of the adduct.

~ MgBr/CeC1

3

76%

o

OH

Scheme 27

Recently this method has been successfully applied to the preparation of substituted allylsilanes from esters. A variety of allylsilanes with other functional groups have been synthesized in good yields, as shown in Scheme 28. 70,71 SiMe3

Rl

-h OH

silica gel

SiMe3

R 1 = Me3SiCH2' Cl(CH2)n (n = 1, 3), (MeO)2CH(CH2)n (n = 0, 1, 3,4), PhCH=CH, etc.; R 2 = Me or Et Scheme 28

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