β-Keto esters derived from 2-(trimethylsilyl)ethanol: An orthogonal protective group for β-keto esters

PAPER

2229

b-Keto Esters Derived from 2-(Trimethylsilyl)ethanol: An Orthogonal

Protective Group for b-Keto Esters

b

-Keto Esters

D

v

erived from

a2-(TrimethylsilylK)ethanol nobloch, Reinhard Brückner*

Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität, Albertstr. 21, 79104 Freiburg, Germany

Fax +49(761)2036100; E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de

Received 8 May 2008

Continuing to explore b-keto ester differentiation, we re-

cently reported²that b-keto esters 4a–c derived from 2-

(trimethylsilyl)ethanol (‘TMS-ethanol’) can be deprotect-

ed/decarboxylated quantitatively in tetrahydrofuran solu-

Abstract: b-Keto esters derived from 2-(trimethylsilyl)ethanol un-

dergo cleavage and decarboxylation when treated with 0.75 equiv-

alents of tetrabutylammonium fluoride trihydrate in tetrahydrofuran

at 50 °C, while b-keto esters derived from methanol, tert-butyl al-

cohol, allyl alcohol, or benzyl alcohol stay intact. Conversely, tion by exposure to 0.75 equivalents of tetrabutyl-

ammonium fluoride trihydrate (50 °C, several h),³giving

methyl-, tert-butyl-, allyl-, or benzyl b-keto esters can be cleaved

and decarboxylated without the 2-(trimethylsilyl)ethyl b-keto esters

ketones 5a–c (Scheme 2). These conditions left analogous

being affected. Similarly, mixed bis(b-keto esters) derived from 2-

b-keto esters 7a–c derived from methanol, b-keto esters

(trimethylsilyl)ethanol and methanol, tert-butyl alcohol, allyl alco-

8a–c derived from tert-butyl alcohol, b-keto esters 9a–c

hol, or benzyl alcohol can be defunctionalized chemoselectively un-

der the same reaction conditions.

derived from allyl alcohol, and b-keto esters 10a–c de-

rived from benzyl alcohol (Scheme 2) almost untouched.

Key words: chemoselectivity, dealkoxycarbonylation, deprotec-

tion, b-keto esters, ketones

Me_n

OTMSE

either

Biph

Ph

Biph

without

O

An ongoing project requires the transformation of an un-

symmetric bis(b-keto ester) 1 into a chain-shortened b-hy-

droxy (w-1)-keto ester of generic structure 2 (Scheme 1).

This implies the need for ester differentiation – and more

processing thereafter – either at the bis(b-keto ester) stage

or in the bis(b-hydroxy ester) 3, which should be deriv-

able from 1 by the asymmetric hydrogenation of both b-

keto ester moieties. With regard to the feasibility of the

first approach, we discovered a while ago that b-keto es-

ters with an electron-donating substituent R¹can be hy-

drogenated asymmetrically without a b-keto ester with an

electron-withdrawing substituent R²being affected.¹

O

4a–c

5a–c

6a–c

in the presence of

Me_n

O R

or

Ph

without Biph

O

7a–c - 10a–c

5a–c

6a–c

..7: R = Me

8: R = t-Bu

9: R = Allyl

10: R = Bn

a

b

c

Me_nMe₀Me₁Me₂

O

R¹O

Scheme 2 Goal I of chemoselective b-keto ester deprotection/

decarboxylation reactions (upper reaction): defunctionalizing TMSE

b-keto esters 4 without analogous methyl-, tert-butyl-, benzyl-, or al-

lyl b-keto esters 7–10 being affected. Goal II: achieving the opposite

selectivities. [TMSE = (CH₂)₂TMS; Biph = p-PhC₆H₄(biphenyl-4-yl)]

1

R_{polyfunctional}

OR²

O

OH

O

2

R¹O

Here we provide full experimental details for these reac-

tions. In addition, we show that b-keto ester deprotec-

tions/decarboxylations with reversed chemoselectivities

are, in general, feasible, too: the mentioned methyl b-keto

esters 7a–c, tert-butyl b-keto esters 8a–c, allyl b-keto es-

ters 9a–c, and benzyl b-keto esters 10a–c were decarbox-

ylated to give ketones 6a–c without much of their 2-

(trimethylsilyl)ethyl b-keto ester (TMSE b-keto ester)

counterparts 7a–c being affected (Scheme 2). Moreover,

we present here the extension of these reactions from in-

termolecularly to intramolecularly competing deprotec-

tions/decarboxylations of two b-keto ester moieties.

OH

O

R¹O

OR²

3

Scheme 1

SYNTHESIS 2008, No. 14, pp 2229–2246

Advanced online publication: 02.07.2008

x

.x

x

.

2

0

8

DOI: 10.1055/s-2008-1067157; Art ID: C02108SS

2230

E. Knobloch, R. Brückner

PAPER

The b-keto ester substrates 4 and 7–10 of our study were

chosen because of two considerations:

O

X

O

1) We wanted to perform the dealkoxycarbonylation of

each TMSE b-keto ester 4a–c as an intermolecular com-

petition, i.e. starting from a mixture of a TMSE b-keto es-

ter 4 of a given methylation pattern (Me₀in all b-keto

esters labeled a, Me₁in series b, and Me₂in series c) and

another b-keto ester 7, 8, 9, or 10 with an equal number of

methyl groups. After treatment with tetrabutylammonium

fluoride trihydrate, any such experiment should technical-

ly (i.e., in the absence of side reactions) deliver a mixture

of up to four components, namely the two unconsumed b-

keto esters and the two resulting ketones. Ideally, one

should be able to distinguish all of them by ¹H NMR spec-

troscopy, and quantify their relative amounts by integra-

tion of non-interfering resonances.⁴For the outcome of

the competition experiments to be analyzable in this man-

ner, we regarded b-keto esters 4 and 7–10 and, by conse-

quence, the emerging ketones 5 and 6 too, to be

appropriate, because they were structurally confined to re-

sult in a minimum number of non-singlet resonances (let

alone severely split signals) in the aliphatic section of the

¹H NMR spectra. Accordingly, the b-keto esters selected

were (arylacetyl)acetic esters, and the ketones formed

therefrom were benzyl ketones.

2) The intended competition experiments would be mean-

ingful only if the participating b-keto esters 4 and 7–10

differed reactivity-wise for no other reason than the inher-

ent differences imposed by their non-uniform alkoxy

groups. Minimizing substituent effects on ester reactivity,

but trying to allow some small substituent effect to modify

¹H NMR shifts in the emerging ketones, we varied the

para substituent in the arylacetyl moiety somewhat: It was

a phenyl group in the b-keto esters 4 and a hydrogen atom

in the b-keto esters 7–10. As remote and modest as this

substituent variation may appear, the chemical shift effect

accompanying it sufficed for pertinent resonances of all

substrates and products to be differentiated.

Biph

OH

= Biph

13

11: X = OH

12: X = Cl

HO

a

b

d

c

TMS

14

2´

4

2

O

Biph

TMS

1´

O

4a

O

Biph

TMS

e

1´

O

4b

O

Biph

TMS

1´

O

4c

Scheme 3 Syntheses of TMSE b-keto esters 4a–c. Reagents and

conditions: (a) SOCl₂(11 equiv), DMF (10 mol%), toluene, 80 °C,

3 h; (b) Meldrum’s acid (1.0 equiv), py (3 equiv), CH₂Cl₂, 0 °C to r.t.,

18 h; (c) 14 (1.1 equiv), toluene, 85 °C, 3.5 h (97%, 3 steps); (d) NaH

(1.1 equiv), THF, 0 °C, 30 min; then MeI (1.1 equiv), r.t., 17 h (84%);

(e) 2 × [NaH (1.1 equiv), THF, 0 °C, 30 min; then MeI (1.1 equiv),

r.t., THF, 17–19 h] (69%).

O

OR

a

2

4

Ph

OH

O

15

..7a: R = Me

8a: R = t-Bu

9a: R = Allyl

10a: R = Bn

100%

97%

88%

93%

b

c

The TMSE b-keto esters 4a–c were obtained as shown in

Scheme 3. Biphenyl-4-ylacetic acid (11), prepared⁵by a

palladium/carbon-catalyzed Suzuki coupling between

phenylboronic acid and (p-bromophenyl)acetic acid, gave

acid chloride 12 when treated with thionyl chloride and

catalytic N,N-dimethylformamide (Scheme 3). Condensa-

tion of the crude product with Meldrum’s acid gave enol

13. Without prior purification, the latter was combined

with 2-(trimethylsilyl)ethanol (14) to provide, after purifi-

cation by flash chromatography on silica gel,⁶b-keto ester

OR

4

2

4

2

Ph

O

..7b: R = Me

8b: R = t-Bu

9b: R = Allyl

10b: R = Bn

79%

96%

82%

84%

..7c: R = Me

8c: R = t-Bu

9c: R = Allyl

10c: R = Bn

79%

75%

70%

69%

Scheme 4 Syntheses of the silicon-free b-keto esters 7a–c to 10a–

c. Reagents and conditions: (a) ROH (1.1 equiv), toluene, 80 °C, 3.5

4a in 97% overall yield (Scheme 3). This compound was h; (b) NaH (1.1 equiv), THF, 0 °C, 30 min, then r.t., MeI (1.1 equiv),

12 h; (e) 2 × [NaH (1.1 equiv), THF, 0 °C, 30 min, then r.t., MeI (1.1

a-methylated by successive treatments with sodium hy-

dride and iodomethane.⁷One such treatment delivered a-

equiv), THF, 12 h].

methyl-b-keto ester 4b in 84% yield and two such treat-

ments – without isolation of the intermediate, i.e. 4b –

The thus obtained b-keto esters 4 and 7–10 were then ex-

gave the a,a-dimethyl-b-keto ester 4c in 69% yield

posed to cleavage/decarboxylation conditions in intermo-

lecular competition experiments (Tables 1–4).

(Scheme 3).

The silicon-free b-keto esters 7a–c to 10a–c were access-

ed analogously from compound 15, a known⁸acylation

product of Meldrum’s acid (Scheme 4).

TMSE esters of carboxylic acids are known to be cleav-

able by two to ten equivalents of anhydrous tetraalkylam-

monium tetrafluoroborates in N,N-dimethylformamide

Synthesis 2008, No. 14, 2229–2246 © Thieme Stuttgart · New York

PAPER

b-Keto Esters Derived from 2-(Trimethylsilyl)ethanol

2231

solution within 3–60 minutes at room temperature.⁹Sev-

eral other fluoride sources also effect this kind of cleav-

age.¹⁰They are similarly used in over-stoichiometric

amounts. Given that, we were pleased to find that cleav-

age and decarboxylation of the TMSE b-keto ester 4a

could be brought about by distinctly substoichiometric

amounts of the hydrate tetrabutylammonium fluoride tri-

hydrate – provided, we worked in refluxing tetrahydrofu-

ran and let the reaction proceed sufficiently long.²The use

of 0.75 equivalents of this reagent furnished the desired

ketone 5a in 100% yield after two hours, 0.50 equivalents

gave 89% 5a after two hours, 0.25 equivalents gave 84%

after eight hours, and 0.10 equivalents gave 54% after 48

hours (in addition to 46% of re-isolated ester 4a). The fea-

Table 2 Intermolecularly Competing Dealkoxycarbonylations in

Mixtures of TMSE b-Keto Esters 4a–c^aand tert-Butyl b-Keto Esters

8a–c^b

Me_n

O

1

3

Biph

TMS

Biph

1´

O

TBAF·3H₂O

(0.75 equiv)

4a–c

5a–c

in the presence of

(almost) without

THF, 50 °C

Me_n

O

1´

1

Ph

3

Ph

O

6a–c

8a–c

sibility of the 4a→5a conversion with 25 mol% fluoride Entry 4, 5, 6, 8 Me_nTime (h) Yield or recovery (%)^c

anions – but not with less – implies that the trimethylsilyl

4

5

8

6

group is incorporated not solely in TMS–F but also in Si–

O bond containing species (plausibly TMS–OH and/or

TMS–O–TMS). We are unaware of a similarly efficient

fluoride-mediated cleavage of any simple TMSE ester.^9–14

1

2

3

a

b

c

Me₀3.5

Me₁1.5

Me₂1.5

0

98

95

0

93

89

103

We employed 0.75 equivalents of tetrabutylammonium

fluoride trihydrate at 50 °C in tetrahydrofuran for the stan-

dard decarboxylation of the TMSE b-keto esters in the

competition experiments we investigated. In the intermo-

lecular competition experiments, TMSE b-keto ester 4a or

one of its methylated congeners 4b or 4c was cleaved in

the presence of a second b-keto ester, one of esters 7–10,

with the same methylation pattern (Tables 1– 4). The in-

^aEnol content in CDCl₃: 4a, 10%; 4b, 9%.

^bEnol content in CDCl₃: 8a, 1%; 8b, 3%.

^cThe yields of the ketone products and of the recovered ester starting

materials were determined by ¹H NMR spectroscopy of samples in

CDCl₃(see Table 9 in the experimental section for the pertinent sig-

nals) after separation of the 4/5/6/8 mixture from side products by

flash chromatography (silica gel).⁶

Table 1 Intermolecularly Competing Dealkoxycarbonylations in

Mixtures of TMSE b-Keto Esters 4a–c^aand Methyl b-Keto Esters 7a–c^b

tramolecular competition experiments were conducted

with bis(b-keto esters) that each contain both a TMSE b-

keto ester moiety and another, different b-keto ester moi-

ety. Each TMSE b-keto ester unit subjected to our treat-

ment reacted very selectively and essentially to

completion within 1–3.5 hours.

Me_n

O

1

3

Biph

TMS

Biph

1´

O

5a–c

4a–c

TBAF·3H₂O

(0.75 equiv)

The intermolecularly competing dealkoxycarbonylations

of TMSE b-keto esters 4a–c of our study were realized by

exposing each of them as one constituent of a pair of b-

keto esters, as specified in Tables 1– 4, to fluoridolysis.

The starting quantity of each keto ester was 0.2 mmol.

Crude products were freed from side products by flash

chromatography on silica gel,⁶so that in each instance a

pure mixture of up to two b-keto esters and up to two ke-

tones was obtained. The mass of this mixture was deter-

mined, and the identities and proportions of the

constituents were determined by the assignment and inte-

gration of the non-superimposed signals in the 300-MHz

¹H NMR spectra of the mixtures. The relevant signals are

compiled in Table 9 in the experimental section.

in the presence of

(almost) without

THF, 50 °C

Me_n

O

1

3

Ph

1´

O

7a–c

6a–c

Entry 4, 5, 6, 7 Me_n

Time (h) Yield or recovery (%)^c

7

6

4

0

5

1

2

3

a

b

c

Me₀

Me₁

Me₂

3.5

1.5

98

97

5

0

100

99

88

99

^aEnol content in CDCl₃: 4a, 10%; 4b, 9%.

^bEnol contents in CDCl₃: 7a, 9%; 7b, 5%.

As suggested by the feasibility of chemoselective fluori-

dolysis of simple TMSE esters in substrates also contain-

^cThe yields of the ketone products and of the recovered ester starting

materials were determined by ¹H NMR spectroscopy of samples in

CDCl₃(see Table 9 in the experimental section for the pertinent sig-

nals) after separation of the 4/5/6/7 mixture from side products by

flash chromatography (silica gel).⁶

ing a simple methyl ester,¹¹a simple tert-butyl ester,¹²

a

simple allyl ester¹³or a simple benzyl ester moiety,¹⁴

TMSE b-keto esters can be cleaved/decarboxylated with

the same chemoselectivity in the presence of a methyl b-

keto ester (Table 1), tert-butyl b-keto ester (Table 2), allyl

b-keto ester (Table 3), or benzyl b-keto ester (Table 4).

Synthesis 2008, No. 14, 2229–2246 © Thieme Stuttgart · New York

2232

E. Knobloch, R. Brückner

PAPER

Table 3 Intermolecularly Competing Dealkoxycarbonylations in

Mixtures of TMSE b-Keto Esters 4a–c^aand Allyl b-Keto Esters 9a–c^b

Table 4 Intermolecularly Competing Dealkoxycarbonylations in

Mixtures of TMSE b-Keto Esters 4a–c^aand Benzyl b-Keto Esters

10a–c^b

Me_n

O

Me_n

1

3

Biph

TMS

Biph

1´

O

1

3

Biph

TMS

Biph

O

1´

O

4a–c

5a–c

TBAF·3H₂O

(0.75 equiv)

4a–c

5a–c

TBAF·3H₂O

(0.75 equiv)

in the presence of

(almost) without

THF, 50 °C

in the presence of

(almost) without

Me_n

THF, 50 °C

O

Me_n

1

3

Ph

1´

O

Ph

1

3

Ph

O

1´

O

6a–c

9a–c

6a–c

10a–c

Entry 4, 5, 6, 9 Me_nTime (h)

Yield or recovery (%)^c

Entry 4, 5, 6, 10 Me_nTime (h) Yield or recovery (%)^c

4

5

9

6

4

5

10

6

4

1

2

3

a

b

c

Me₀3.5

Me₁1.5

Me₂1.5

0

105

96

100

95

<5^d

0

1

2

3

a

b

c

Me₀

Me₁

Me₂

3.5

1.5

0

100

105

90

95

<5^d

0

102

96

0

100

0

^aEnol content in CDCl₃: 4a, 10%; 4b, 9%.

^bEnol content in CDCl₃: 9a, 9%; 9b, 5%.

^aEnol content in CDCl₃: 4a, 10%; 4b, 9%.

^bEnol content in CDCl₃: 10a, 8%; 10b, 9%.

^cThe yields of the ketone products and of the recovered ester starting

materials were determined by ¹H NMR spectroscopy of samples in

CDCl₃(see Table 9 in the experimental section for the pertinent sig-

nals) after separation of the 4/5/6/9 mixture from side products by

flash chromatography (silica gel).⁶

^cThe yields of the ketone products and of the recovered ester starting

materials were determined by ¹H NMR spectroscopy of samples in

CDCl₃(see Table 9 in the experimental section for the pertinent sig-

nals) after separation of the 4/5/6/10 mixture from side products by

flash chromatography (silica gel).⁶

^dThis value is meant to indicate that the presence of ketone 6 did not

follow unequivocally from the ¹H NMR spectrum.

^dThis value is meant to indicate that the presence of ketone 6a did not

follow unequivocally from the ¹H NMR spectrum.

Specifically, all three TMSE b-keto esters 4a–c were con-

verted completely into the corresponding ketones 5a–c,

whereas the other components in the reaction mixtures,

their methyl b-keto ester counterparts 7a–c provided the

corresponding ketones 6a–c not at all or in only 5% yield

(Table 1). Similarly, TMSE b-keto esters 4a–c were

cleaved by tetrabutylammonium fluoride trihydrate com-

pletely – furnishing the corresponding ketones 5a–c in

89–98% yield – while the analogous tert-butyl b-keto es-

ters 8a–c in the reaction mixtures remained unchanged

(Table 2). Likewise, fluoridolysis of TMSE b-keto esters

4a–c gave the expected ketones 5a–c in quantitative

yields – in contrast to the allyl b-keto esters 9a–c present

in the mixtures, which stayed inert (Table 3). In the same

way, ketones 5a–c were obtained in ≥ 90% yield from

TMSE b-keto esters 4a–c and tetrabutylammonium fluo-

ride trihydrate in the presence of benzyl b-keto esters

10a–c, which, in contrast, were re-isolated in essentially

quantitative yields (Table 4).

deprotection of benzyl b-keto esters 10a–c proceeded

with excellent selectivities and yields (Table 8). Depro-

tection of the allyl b-keto esters 9a–c was slightly inferior

(Table 7). Up to 20% material losses occurred when tert-

butyl b-keto esters 8a–c (Table 6) or their methyl ana-

logues 7a–c (Table 5) were deprotected, but the chemose-

lectivity was invariably high.

A more detailed look at the results summarized in

Tables 5–8 reveals the following three points:

(a) The silicon-free b-keto esters 7–10 that we degraded

were never re-isolated, whereas ketones 6a–c were not all

obtained in 100% yield (Tables 5–8). This is illustrated by

the experiments summarized in Table 5, entry 1 (6a, 64%

yield), Table 6, entry 1 (6a, 83% yield), Table 6, entry 2

(6b, 87% yield), and Table 7, entry 2 (6b, 88% yield).

Nonetheless, eight b-keto ester cleavages led to the forma-

tion of the corresponding ketones 6a–c in ≥ 94% yield

(Tables 5–8).

Our experiments aimed at cleaving/decarboxylating

methyl b-keto esters 7a–c, tert-butyl b-keto esters 8a–c,

allyl b-keto esters 9a–c, and benzyl b-keto esters 10a–c

without affecting the concomitantly present analogous

TMSE b-keto esters 4a–c are summarized in Tables 5–8.

They reveal opposite, albeit sometimes lower substrate se-

lectivities than those shown in Tables 1– 4. In the pres-

ence of the TMSE b-keto ester analogues 4a–c, the

(b) In some instances, the silicon-containing TMSE b-

keto esters 4a–c were degraded partly, while their silicon-

free analogues disappeared completely. This is evidenced

by the experiments shown in Table 5, where 73–83% of

esters 4 remained, and Table 6, entry 2, where 72% of es-

ter 4b remained. However, in eight instances we retrieved

TMSE b-keto esters 4a–c in ≥ 89% yield, and in four of

these instances quantitatively.

Synthesis 2008, No. 14, 2229–2246 © Thieme Stuttgart · New York

PAPER

b-Keto Esters Derived from 2-(Trimethylsilyl)ethanol

2233

Table 5 Intermolecularly Competing Dealkoxycarbonylations in

Mixtures of Methyl b-Keto Esters 7a–c and TMSE b-Keto Esters 4a–c

Table 7 Intermolecularly Competing Dealkoxycarbonylations in

Mixtures of Allyl b-Keto Esters 9a–c and TMSE b-Keto Esters 4a–c

Me_n

O

1

3

Ph

1

3

Ph

1´

O

Pd(OAc)₂

(2.5 mol%),

Ph₃P (5.0 mol%)

6a–c

7a–c

PhSH (1.5 equiv),

Cs₂CO₃(0.5 equiv)

9a–c

6a–c

in the presence of

(almost) without

in the presence of

(almost) without

DMF, 85 °C

HNEt₃HCO₂

(2.0 equiv),

THF, r.t.

Me_n

O

1

O

3

Biph

TMS

Biph

1

1´

3

Biph

TMS

Biph

1´

O

4a–c

5a–c

4a–c

5a–c

Entry 4, 5, 6, 7 Me_nTime (h) Yield or recovery (%)^a

Entry 4, 5, 6, 9 Me_n

Time (h) Yield or recovery (%)^a

7

6

4

5

9

6

4

5

1

2

3

a

b

c

Me₀3.5

Me₁4.0

Me₂5.5

0

64

105

74

73

83

0

1

2

3

a

b

c

Me₀

Me₁

Me₂

2.5

6.0

0

100

91

100

0

88

94

^aThe yields of the ketone products and of the recovered ester starting

materials were determined by ¹H NMR spectroscopy of samples in

CDCl₃(see Table 9 in the experimental section for the pertinent sig-

nals) after separation of the 4/5/6/7 mixture from side products by

flash chromatography (silica gel).⁶

^aThe yields of the ketone products and of the recovered ester starting

materials were determined by ¹H NMR spectroscopy of samples in

CDCl₃(see Table 9 in the experimental section for the pertinent sig-

nals) after separation of the 4/5/6/9 mixture from side products by

flash chromatography (silica gel).⁶

Table 8 Intermolecularly Competing Dealkoxycarbonylations in

Mixtures of Benzyl b-Keto Esters 10a–c and TMSE b-Keto Esters

4a–c

Table 6 Intermolecularly Competing Dealkoxycarbonylations in

Mixtures of tert-Butyl b-Keto Esters 8a–c and TMSE b-Keto Esters

4a–c^a

Me_n

O

Ph

O

1´

1

3

1

3

Ph

1´

O

Pd/C (5 mol%),

₂(1 bar),

Et₃N (1.0 equiv)

H

6a–c

10a–c

8a–c

6a–c

Montmorillonite KSF,

in the presence of

(almost) without

in the presence of

(almost) without

EtOAc, r.t.

MeCN, 80 °C;

Et₃N (20 equiv),

r.t., 1 h

Me_n

O

1

3

1

3

Biph

TMS

Biph

TMS

Biph

1´

O

4a–c

5a–c

4a–c

Entry 4, 5, 6, 10 Me_nTime (h) Yield or recovery (%)^a

Entry 4, 5, 6, 8 Me_nTime (h) Yield or recovery (%)^b

10

6

4

5

8

6

4

5

1

2

3

a

b

c

Me₀

9

0

95

100

98

104

99

0

1

2

3

a

b

c

Me₀2.5

Me₁3.0

Me₂3.0

0

83

87

96

89

72

89

10

0

Me₁20

Me₂53

0

100

0

^aThe yields of the ketone products and of the recovered ester start-

ing materials were determined by ¹H NMR spectroscopy of samples

in CDCl₃(see Table 9 in the experimental section for the pertinent

signals) after separation of the 4/5/6/10 mixture from side products

by flash chromatography (silica gel).⁶

^aReagents and conditions: Montmorillonite KSF (300 mg/mmol 8a–

c).

^bThe yields of the ketone products and of the recovered ester starting

materials were determined by ¹H NMR spectroscopy of samples in

CDCl₃(see Table 9 in the experimental section for the pertinent sig-

nals) after separation of the 4/5/6/8 mixture from side products by

flash chromatography (silica gel).⁶

Synthesis 2008, No. 14, 2229–2246 © Thieme Stuttgart · New York

2234

E. Knobloch, R. Brückner

PAPER

(c) Ketone 5a formed in spite of our intentions from sili- Scheme 5). It is possible that ester derivatives of these

con-containing b-keto ester 4a in two experiments would have to be tolerated on the access route to these

(Tables 5 and 6, entries 1), albeit in low yields (9% and compounds (Scheme 6). We took care of this requirement

10%, respectively). In contrast, ten b-keto ester dealkoxy- by structural design – a hexamethylene spacer between

carbonylations furnished no ketones 5a–c along with the the keto ester moieties was deemed appropriate for dis-

desired ketones 6a–c (Tables 5–8).

couraging cyclization – and by creating both b-keto ester

moieties no earlier than in the ultimate step of our synthe-

ses (Scheme 6).

Methyl b-keto ester 7a could be deprotected under

Krapcho’s conditions, i.e. treatment with sodium chloride

in N,N-dimethylformamide at 110 °C¹⁵for five hours.

However, 81% of the concomitantly present TMSE b-

keto ester 4a did so too. Attempted demethylation of a

mixture of the same b-keto esters with lithium iodide in

N,N-dimethylformamide at 140 °C¹⁶gave a plethora of

products. A conversion of 100% of methyl b-keto ester 7a

into ketone 6a was induced by heating a mixture of b-keto

esters 7a and 4a, benzenethiol, and either cesium

carbonate¹⁷or potassium carbonate (Table 5). In both cas-

es, there was some undesired conversion of TMSE b-keto

ester 4a into ketone 5a (leading to 85:15 mixtures of these

components).

O

"8"

"1"

TMS

OR

5

O

16: R = Me

17: R = t-Bu

18: R = Allyl

19: R = Bn

either

or

O

1

8

1

8

TMS

OR

5

The chemoselective cleavage of simple tert-butyl esters

by anhydrous hydrogen chloride in trifluoroethanol in the

presence of an unaffected TMSE ester has been de-

scribed.⁹In spite of this, the same reagent cleaved and de-

carboxylated tert-butyl b-keto ester 8a and most of TMSE

b-keto ester 4a. Refluxing a simple tert-butyl ester in a

5

O

20: R = Me

24

21: R = t-Bu

22: R = Allyl

23: R = Bn

Scheme 5 Goal III of chemoselective b-keto ester deprotection/

suspension of silica gel in toluene should also be suitable decarboxylation reactions: defunctionalizing the TMSE b-keto ester

moiety of bis(b-keto esters) 16–19 without affecting concomitantly

present methyl-, tert-butyl-, benzyl-, or allyl b-keto ester groups

(left); Goal IV: achieving the opposite selectivities (right)

for cleaving the tert-butyl ester and not affecting a simple

TMSE ester,¹⁸but these conditions spared only 43% of

TMSE b-keto ester 4a and provided ketone 5a in 49%

yield on a timescale allowing the complete cleavage of

tert-butyl b-keto ester 5a. Our treatment of choice for the

hydrolysis of tert-butyl b-keto esters 8a–c in the presence

of TMSE b-keto esters 4a–c (Table 6) began with reflux-

ing the mixture in a suspension of activated (100 °C,

0.001 Torr, 4 h) Montmorillonite KSF in acetonitrile.¹⁹

Subsequently, triethylamine had to be added (at r.t.), be-

cause otherwise decarboxylation of the initially formed b-

keto carboxylic acid was incomplete.

Our syntheses of bis(b-keto esters) 16–19 started with

Schreiber’s end-group-differentiating ozonolysis²⁴of cy-

clooctene (25; Scheme 6).²⁵The resulting dimethoxyalde-

hyde 26 (£86% yield) was combined with the lithium

enolate of TMSE acetate (27) to give TMSE b-hydroxy

ester 28 (54% yield over two steps; Scheme 6). TMSE

acetate (27) was prepared from 2-(trimethylsilyl)ethanol

(14) and acetic anhydride by a variation of the published

26

procedure, i.e. by using Mg(ClO₄)₂

instead of

For the chemoselective cleavages of allyl b-keto esters

9a–c (Table 7) and benzyl b-keto esters 10a–c (Table 8)

in the presence of TMSE b-keto esters 4a–c, palladium

catalysis was exploited, and no exploratory experiments

were needed. Allyl b-keto esters 9a–c, admixed with

TMSE b-keto esters 4a–c, were de-allylated by reaction

with triethylammonium bicarbonate,²⁰catalytic palladi-

um(II) acetate, and catalytic triphenylphosphine, i.e. un-

der Tsuji’s conditions (Table 7).²¹Benzyl b-keto esters

10a–c – admixed with TMSE b-keto esters 4a–c – were

debenzylated selectively by hydrogenolysis (H₂, atmo-

spheric pressure, cat. Pd/C),²²under the proviso that tri-

ethylamine was present (Table 8).²³

Zn(ClO₄)₂·6H₂O²⁷as a condensation catalyst. Cleavage of

the acetal moiety of TMSE b-hydoxy ester 28 with Mont-

morillonite K10 in refluxing wet acetone (following a

general procedure by Li and Li²⁸) gave the multiply func-

tionalized aldehyde 29 in 87% yield (Scheme 6). Addition

of 2.2 equivalents of the lithium enolate of methyl-, tert-

butyl-, allyl-, or benzyl acetate provided the correspond-

ing bis(b-hydroxy ester) 30, 31, 32, or 33, respectively, in

44–56% yield (Scheme 6). Oxidation of both hydroxy

groups of each of these compounds with Dess–Martin

periodinane²⁹(DMP) afforded the desired bis(b-keto es-

ters) 16–19 in 55–82% yield (Scheme 6).

When we treated the bis(b-keto ester) 16 with 0.75 equiv-

alents tetrabutylammonium fluoride trihydrate at 50 °C in

tetrahydrofuran for two hours (Scheme 7), we isolated a

chemically homogeneous diketo ester after aqueous

workup and purification by filtration over a pad of silica

gel. As revealed by the appearance of methoxy singlets in

In the second part of our investigation, we studied the fea-

sibility of chemoselective cleavages/decarboxylations of

mixed bis(b-keto esters) 16–19 (Scheme 5). These feature

a TMSE b-keto ester moiety and a methyl-, tert-butyl-, al-

lyl-, or benzyl b-keto ester moiety (16–19, respectively,

Synthesis 2008, No. 14, 2229–2246 © Thieme Stuttgart · New York

PAPER

b-Keto Esters Derived from 2-(Trimethylsilyl)ethanol

2235

conditions (Scheme 7). Thus we obtained the tert-butyl-

containing b,w-diketo ester 21 (100% yield) and its allyl-

and benzyl-containing analogues 22 (99% yield) and 23

(81% yield), respectively, in good to excellent yields

(Scheme 7).

HO

TMS

14

25

a

b

O

RO

TMS

O

27

26 (impure)

O

16: R = Me

17: R = t-Bu

18: R = Allyl

19: R = Bn

c

O

TMS

OH

O

d

a

28

29

O

RO

O

TMS

20: R = Me

21: R = t-Bu

22: R = Allyl

23: R = Bn

100%

99%

OH

O

e

81%

Scheme 7 Reagents and conditions: (a) TBAF·3H₂O (0.75 equiv),

O

OH

THF, 50 °C, 2 h.

RO

O

As shown in Scheme 8, bis(b-keto esters) 16–19 were fi-

nally subjected to the demethylation, de-tert-butylation,

de-allylation, and debenzylation conditions, respectively,

that had served us best in the intermolecularly competing

b-keto ester cleavages/decarboxylations compiled in

Tables 5– 8. This was essentially unsuccessful as far dem-

ethylation was concerned, because it led to only 25% of

the b,w-diketo ester 24 after complete consumption of the

substrate and purification by flash chromatography on sil-

ica gel (Scheme 8).⁶The same b,w-diketo ester was ac-

cessed from bis(b-keto esters) 17–19 much more

efficiently: in 88% yield by the de-tert-butoxycarbonyla-

tion of bis(b-keto ester) 17, in 93% yield by the de-allyl-

30: R = Me

48%

44%

45%

56%

31: R = t-Bu

32: R = Allyl

33: R = Bn

f

O

RO

TMS

O

16: R = Me

17: R = t-Bu

18: R = Allyl

19: R = Bn

82%

62%

77%

55%

Scheme 6 The synthesis of bis(b-keto esters) 16–19. Reagents and

conditions: (a) O₃, CH₂Cl₂/MeOH (3:7), –78 °C, 20 min; then N₂, 30

min; then PTSA (10 mol%), –78 °C to r.t., 2 h; then Na₂CO₃(0.3

equiv), 30 min; then Me₂S (2.2 equiv), 17.5 h; £86% (Lit.^25a,b71%);

(b) Ac₂O (1.05 equiv), Mg(ClO₄)₂(1 mol%), 4 h; 94%; (c) 27 (1.0

equiv), LDA (1.15 equiv), THF, –78 °C, 1 h; then 26, 0.5 h; 54% (two

steps); (d) Montmorillonite K10 (180 mg/mmol 28), H₂O (16 equiv),

acetone, reflux, 50 min; 87%; (e) AcOR (2.2 equiv), LDA (2.2 equiv),

THF, –78 °C, 1 h; then 29, 0.5 h; (f) DMP (2.3 equiv), CH₂Cl₂, 0 °C;

then one of 30–33, 0 °C to r.t., 30 min.

O

R

O

TMS

O

16: R = Me 17: R = t-Bu 18: R = Allyl 19: R = Bn

a

25%

d

67%

b

88%

c

93%

O

TMS

the ¹H NMR spectrum (400 MHz, CDCl₃) at d = 3.69 for

the keto form and at d = 3.70 for the enol form, this prod-

uct was methyl diketo ester 20 (Scheme 7). Its yield being

100%, a completely selective degradation of the TMSE b-

keto ester terminus of the bis(b-keto ester) 16 had been re-

alized, and the methyl b-keto ester moiety had remained

unchanged. Cleavage of the TMSE ester moieties of

bis(b-keto esters) 17–19 and in situ decarboxylation of the

initially obtained b-keto acids occurred under the same

O

24

Scheme 8 Reagents and conditions: (a) 16, PhSH (1.5 equiv),

Cs₂CO₃(0.5 equiv), DMF, 85 °C, 5 h; 25%; (b) 17, Montmorillonite

KSF (300 mg/mmol 17), MeCN, reflux, 3.25 h; then r.t., Et₃N (20

equiv), 1.5 h; 88%; (c) Pd(OAc)₂(2.5 mol%), Ph₃P (5.0 mol%),

Et₃NH⁺HCO₂(2.0 equiv), THF, r.t., 5 min; then 18, 25 h; 93%; (d)

–

19, 5% Pd/C (10 mol% Pd), H₂(1 bar), Et₃N (2.0 equiv), EtOAc, r.t.,

31 h; 67%.

Synthesis 2008, No. 14, 2229–2246 © Thieme Stuttgart · New York

2236

E. Knobloch, R. Brückner

PAPER

At 0 °C, py (1.0 mL, 1.0 g, 12 mmol, 3 equiv) was added dropwise

to Meldrum’s acid (607 mg, 4.2 mmol, 1.1 equiv) in CH₂Cl₂(6 mL),

and the mixture was stirred for 5 min. The crude acid chloride 11

was added over 10 min. The mixture was allowed to warm to r.t.

over 1 h. After stirring of the mixture for another 16 h, CH₂Cl₂(10

mL) was added and the mixture washed with 0.1 M aq HCl (2 × 20

mL) and brine (25 mL). Drying (Na₂SO₄) of the mixture and evap-

oration of the solvent under reduced pressure furnished the crude

acylation product 13.

oxycarbonylation of bis(b-keto ester) 18, and in 67% yield

by the debenzyloxycarbonylation of bis(b-keto ester) 19

(Scheme 8).

In summary, we have established that TMSE esters of b-

keto carboxylic acids can be cleaved and decarboxylated

with near-perfect selectivity in the presence of a methyl-,

tert-butyl-, allyl-, or benzyl b-keto ester. This was

achieved for b-keto ester moieties residing in different

molecules as well as in a single bis(b-keto ester) mole-

cule. Cleavage/decarboxylation of a methyl-, tert-butyl-,

allyl-, or benzyl b-keto ester unit in the presence of a

TMSE b-keto ester group generally did not proceed satis-

factorily when a methyl b-keto ester was involved. Selec-

tive de-tert-butoxycarbonylation in the presence of a

TMSE b-keto ester did, however, turn out to be efficient.

Allyl- and benzyl b-keto esters were cleaved/defunction-

alized in the presence of a TMSE b-keto ester even more

efficiently. Hence, TMSE esters of b-keto acids can be

employed as orthogonally protected b-keto acid deriva-

tives.

2-(Trimethylsilyl)ethanol (14; 0.60 mL, 0.50 g, 4.2 mmol,

1.1 equiv) was added to crude 13 in toluene (10 mL). The mixture

was stirred at 80 °C for 3.5 h. Evaporation of the solvent under re-

duced pressure and flash chromatography (silica gel, column dia-

meter 5.0 cm, cyclohexane–EtOAc, 15:1) furnished 4a.

Colorless oil; yield: 1.316 g (97%).

IR (film): 3030, 2955, 2345, 1745, 1720, 1650, 1520, 1490, 1410,

1315, 1250, 1180, 1060, 1010, 915, 860, 835, 745, 695 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 0.06 [s, Si(CH₃)₃(4a)], 0.06 [s,

Si(CH₃)₃(enol-4a)], 1.02 [m_c, 2¢-CH₂(4a and enol-4a)], 3.43 [s, 4-

CH₂(4a)], 3.56 [s, 4-CH₂(enol-4a)], 3.90 [s, 2-CH₂(4a)], 4.25 [m_c,

1¢-CH₂(4a and enol-4a)], 4.99 [m_c, 2-H (enol-4a)], 7.27–7.61 [m,

Ar²-H, Ar³-H, Ar⁵-H, Ar⁶-H, Ar^2¢-H, Ar^3¢-H, Ar^4¢-H, Ar^5¢-H, Ar^6¢-H

(4a and enol-4a)], 12.23 [s, 3-OH, (enol-4a)].

¹³C NMR (101 MHz, CDCl₃): d = –1.48 [s, Si(CH₃)₃(4a)], –1.46 [s,

Si(CH₃)₃(enol-4a)], 17.4 [C-2¢ (4a)], 17.5 [C-2¢¢ (enol-4a)], 41.1

[C-4 (enol-4a)], 48.6 [C-4 (4a)], 49.7 [C-2 (4a)], 62.4 [C-1¢ (enol-

4a)], 63.9 [C-1¢¢ (4a)], 90.5 [C-2 (enol-4a)], 127.1 [C-Ar^2¢, C-Ar^6¢

(4a)], 127.4 [C-Ar^4¢(4a)], 127.6 [C-Ar^3¢, C-Ar^5¢(4a)], 128.9 [C-Ar³,

C-Ar⁵(4a)], 130.05 [C-Ar⁴(4a)], 130.07 [C-Ar², C-Ar⁶(4a)], 140.4

and 140.7 [C-Ar¹, C-Ar^1¢(4a)], 167.3 [C-1 (4a)], 176.8 [C-3 (enol-

4a)], 200.5 [C-3 (4a)]

Products were purified by flash chromatography⁶on Macherey-

Nagel silica gel 60. ¹H and ¹³C NMR spectra were obtained on Varian

Mercury VX 300 or Bruker AM 400 spectrometers. As internal

standards, TMS (d = 0.00) was used for ¹H, and CDCl₃(d = 77.16³⁰)

was used for ¹³C NMR spectra of samples dissolved in CDCl₃. The

assignments of the ¹H and ¹³C NMR resonances refer to the labeling

according to IUPAC nomenclature, with primed numbers belonging

to the side chains. NMR spectroscopy was carried out by Dr. M.

Keller, combustion analyses were carried out by E. Hickl, and MS

was carried out by Dr. J. Wörth, all at the Institut für Organische

Chemie und Biochemie, Universität Freiburg. IR spectra were ob-

tained on an FTIR Perkin-Elmer Spectrum 1000. Melting points

were determined on a Dr. Tottoli apparatus (Büchi), and are uncor-

rected.

Anal. Calcd for C₂₁H₂₆O₃Si (354.5): C, 71.15; H, 7.39. Found: C,

70.90; H, 7.40.

2-(Trimethylsilyl)ethyl 4-(Biphenyl-4-yl)-2-methyl-3-oxo-

butanoate (4b)

NaH (79 mg, 3.3 mmol, 1.1 equiv) was added in one portion to a

soln of 4a (1.065 g, 3.000 mmol) in THF (5 mL) at 0 °C, and the

mixture was stirred until no evolution of H₂could be detected (30

min). At r.t., MeI (0.20 mL, 0.46 g, 3.3 mmol, 1.1 equiv) was added

dropwise and the mixture was stirred for another 19 h. Sat. aq

NH₄Cl (6 mL) and MTBE (5 mL) were added. Extraction with

MTBE (4 × 5 mL), drying of the combined extracts (Na₂SO₄), evap-

oration of the solvent under reduced pressure, and flash chromatog-

raphy (silica gel, column diameter 2 cm, cyclohexane–EtOAc, 15:1)

furnished 4b.

2-(Trimethylsilyl)ethyl 4-(Biphenyl-4-yl)-3-oxobutanoate (4a)

(Figure 1)

Ar⁶

4

2

2'

O

3

1

TMS

1'

Ar^6'

4a

O

Ar²

Ar⁴

Ar^2'

Ar^4'

Colorless oil; yield: 922 mg (84%).

IR (film): 3450, 3030, 2955, 2361, 1715, 1605, 1520, 1490, 1415,

1410, 1380, 1250, 1175, 1115, 1040, 1010, 915, 860, 335, 750, 695

cm^–1.

Ar⁶

4

2

2'

O

1

3

TMS

1'

Ar^6'

OH

O

Ar²

enol-4a

¹H NMR (400 MHz, CDCl₃): d = 0.04 [s, Si(CH₃)₃(4b)], 0.06 [s,

Si(CH₃)₃(enol-4b)], 0.99 [m_c, 2¢-H₂(4b)], 1.05 [m_c, 2¢-H₂(enol-

4b)],1.45 [d, J_2-CH3,2= 7.1 Hz, 2-CH₃(4b)], 1.86 [s, 2-CH₃(enol-

4b)], 3.65 [q, J_2,2-CH3= 7.1 Hz, 2-H (4b)], 3.68 [s, 4-CH₂(enol-4b)],

AB signal [d_A= 3.87, d_B= 3.89, J_AB= 15.6 Hz, 4-H₂(4b)], 4.21

[m_c, 1¢-H₂(4b)], 4.27 [m_c, 2¢-H₂(enol-4b)], 7.27–7.59 [m, Ar²-H,

Ar³-H, Ar⁵-H, Ar⁶-H, Ar^2¢-H, Ar^3¢-H, Ar^4¢-H, Ar^5¢-H, Ar^6¢-H (4b and

enol-4b)], 12.84 [t, ⁴J_3-OH,4= 1.0 Hz, 3-OH (enol-4b)].

¹³C NMR (101 MHz, CDCl₃): d = –1.5 [Si(CH₃)₃(4b)], 11.5 [2-CH₃

(enol-4b)], 13.0 [2-CH₃(4b)], 17.4 [C-2¢ (4b)], 17.5 [C-2¢ (enol-

4b)], 38.3 [C-4 (enol-4b)], 48.3 [C-4 (4b)], 52.2 [C-2 (4b)], 62.95

[C-1¢ (enol-4b)], 64.0 [C-1¢ (4b)], 127.1 [C-Ar^2¢, C-Ar^6¢(4b)], 127.4

[C-Ar^4¢(4b)], 127.5 [C-Ar^3¢, C-Ar^5¢(4b)], 128.9 [C-Ar³, C-Ar⁵

Ar⁴

Ar^2'

Ar^4'

Figure 1

SOCl₂(3.0 mL, 4.9 g, 41 mmol, 11 equiv) was added dropwise to a

suspension of biphenyl-4-ylacetic acid (11; 819 mg, 3.80 mmol) in

toluene (8 mL). DMF (0.04 mL, 0.04 g, 0.5 mmol, 0.1 equiv) was

added. The resulting soln was stirred for 1 h at r.t., for 2 h at 55 °C,

and for 30 min under reflux. After cooling of the mixture to r.t., the

solvent was removed under reduced pressure; this furnished the

crude acid chloride 12.

Synthesis 2008, No. 14, 2229–2246 © Thieme Stuttgart · New York

PAPER

b-Keto Esters Derived from 2-(Trimethylsilyl)ethanol

2237

(4b)], 130.1 [C-Ar², C-Ar⁶(4b)], 132.6 [C-Ar¹(4b)], 140.2 [C-Ar⁴

(4b)], 140.8 [C-Ar^1¢(4b)], 170.6 [C-1 (4b)], 203.3 [C-3 (4b)].

at 50 °C until conversion was completed as judged by TLC (1.5 h).

Brine (1.5 mL), H₂O (3 mL), and MTBE (3 mL) were added. Ex-

traction with MTBE (3 × 3 mL), drying of the combined extracts

(Na₂SO₄), evaporation of the solvent under reduced pressure, and

flash chromatography (silica gel, column diameter 2 cm, cyclohex-

ane–EtOAc, 15:1) furnished 5c.

Anal. Calcd for C₂₂H₂₈O₃Si (368.5): C, 71.70; H, 7.66. Found: C,

71.29; H, 7.55.

2-(Trimethylsilyl)ethyl 4-(Biphenyl-4-yl)-2,2-dimethyl-3-oxo-

butanoate (4c)

White solid; yield: 39 mg (82%); mp 52 °C.

NaH (54 mg, 2.2 mmol, 1.1 equiv) was added in one portion to a

soln of b-keto ester 4a (713 g, 2.00 mmol) in THF (15 mL) at 0 °C,

and the mixture was stirred until no evolution of H₂could be ob-

served (30 min). At r.t., MeI (0.14 mL, 0.32 g, 2.2 mmol, 1.1 equiv)

was added dropwise and the mixture was stirred for another 17 h.

The mixture was cooled to 0 °C again, and NaH (54 mg, 2.2 mmol,

1.1 equiv) was added in one portion; then the mixture was again

stirred until no evolution of H₂could be observed (30 min). At r.t.,

MeI (0.14 mL, 0.32 g, 2.2 mmol, 1.1 equiv) was added dropwise

and the mixture was stirred for another 19 h. NH₄Cl (6 mL) was

added. Extraction with MTBE (3 × 15 mL), drying of the combined

extracts (Na₂SO₄), evaporation of the solvent under reduced pres-

sure, and flash chromatography (silica gel, column diameter 3.5 cm,

cyclohexane–EtOAc, 50:1) furnished 4c.

IR (film): 2970, 2935, 2870, 1710, 1490, 1465, 1410, 1380, 1120,

1045, 1010, 865, 820, 750, 725, 690 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.12 (d, J_4,3= J_3-CH3,3= 6.9 Hz, 3-

CH₃, 4-H₃), 2.76 (sept, J_3,4= J_3,3-CH3= 6.9 Hz, 3-CH), 3.78 (s, 1-H₂),

7.25–7.59 (m, Ar²-H, Ar³-H, Ar⁴-H, Ar⁵-H, Ar⁶-H, Ar^2¢-H, Ar^3¢-H,

Ar^4¢-H, Ar^5¢-H, Ar^6¢-H).

¹³C NMR (75 MHz, CDCl₃): d = 18.6 (C-4, 3-CH₃), 40.5 (C-3), 47.4

(C-1), 127.3 (C-Ar^2¢, C-Ar^6¢), 127.4 (C-Ar^4¢), 127.5 (C-Ar^3¢, C-Ar^5¢),

129.0 (C-Ar³, C-Ar⁵), 130.1 (C-Ar², C-Ar⁶), 133.7 (C-Ar¹), 140.0

(C-Ar⁴), 141.0 (C-Ar^1¢), 212.0 (C-2).

HRMS (EI): m/z [M⁺] calcd for C₁₇H₁₈O₁: 238.1357; found:

238.1358.

White solid; yield: 750 mg (69%); mp 38–39 °C.

Methyl 3-Oxo-4-phenylbutanoate (7a)

MeOH (14 mg, 0.42 mmol, 1.1 equiv) was added to a soln of 15

(100 mg, 0.380 mmol) in toluene (2 mL). The mixture was stirred

at 80 °C for 3.5 h. Evaporation of the solvent under reduced pres-

sure, followed by flash chromatography (silica gel, column diame-

ter 2.0 cm, cyclohexane–EtOAc, 10:1) furnished 7a.

IR (film): 3030, 2955, 1715, 1520, 1490, 1465, 1410, 1390, 1365,

1250, 1155, 1045, 1010, 915, 860, 835, 745, 695 cm^–1.

¹H NMR (400.1 MHz, CDCl₃): d = 0.05 [s, Si(CH₃)₃], 0.99 (m_c, 2¢-

H₂), 1.45 [s, 2(CH₃)₂], 3.84 (s, 4-H₂), 4.23 (m_c, 1¢-H₂), 7.26–7.60

(m, Ar²-H, Ar³-H, Ar⁴-H, Ar⁵-H, Ar⁶-H, Ar^2¢-H Ar^3¢-H, Ar^4¢-H, Ar^5¢-

H, Ar^6¢-H).

¹³C NMR (101 MHz, CDCl₃): d = –1.5 [Si(CH₃)₃], 17.4 (C-2¢), 22.1

[(CH₃)₂-2], 44.4 (C-4), 56.0 (C-2), 64.0 (C-1¢), 127.2 (C-Ar^2¢, C-

Ar^6¢), 127.26 (C-Ar^3¢, C-Ar^5¢), 127.30 (C-Ar^4¢), 128.8 (C-Ar³, C-

Ar⁵), 130.0 (C-Ar², C-Ar⁶), 133.3 (C-Ar¹), 140.0 (C-Ar⁴), 140.9 (C-

Ar^1¢), 173.8 (C-1), 205.3 (C-3).

Colorless oil; yield: 73.1 mg [100%; cf. 79% (by alcoholysis in

MeOH)³¹; different synthesis³²].

¹H NMR (300 MHz, CDCl₃): d = 3.46 [s, 2-H₂(7a)], 3.51 [s, 4-H₂

(enol-7a)], 3.71 [s, 1¢-H₃(7a and enol-7a)], 3.83 [s, 4-H₂(7a)], 4.94

[s, 2-H (enol-7a)], 7.20–7.38 [m, Ar²-H, Ar³-H, Ar⁴-H, Ar⁵-H, Ar⁶-

H (7a and enol-7a)], 12.03 [s, 3-OH (enol-7a)].

Anal. Calcd for C₁₁H₁₂O₃(192.2): C, 68.74; H, 6.29. Found: C,

68.46; H, 6.36.

Anal. Calcd for C₂₃H₃₀O₃Si (382.6): C, 72.21; H, 7.90. Found: C,

71.94; H, 7.90.

Methyl 2-Methyl-3-oxo-4-phenylbutanoate (7b)

1-(Biphenyl-4-yl)butan-2-one (5b)

Ester 7b was prepared similarly to 4b as described above, starting

from 7a (385 mg, 2.00 mmol), NaH (53 mg, 2.20 mmol, 1.1 equiv),

and MeI (0.14 mL, 0.32 g, 2.2 mmol, 1.1 equiv) in THF (3 mL); pu-

rification of the residue by flash chromatography (silica gel, column

diameter 2.0 cm, cyclohexane–EtOAc, 15:1) furnished 7b.

TBAF·3H₂O (47 mg, 0.15 mmol, 0.75 equiv) in THF (0.5 mL) was

added dropwise to TMSE b-keto ester 4b (71 mg, 0.20 mmol) in

THF (1.5 mL) at 0 °C. The resulting mixture was stirred at 50 °C

until conversion was completed as judged by TLC (2 h). Brine

(1.5 mL), H₂O (3 mL), and MTBE (3 mL) were added. Extraction

with MTBE (3 × 3 mL), drying of the combined extracts (Na₂SO₄),

evaporation of the solvent under reduced pressure, and flash chro-

matography (silica gel, column diameter 2 cm, cyclohexane–

EtOAc, 10:1) furnished 5b.

Colorless oil; yield: 342 mg (79%).

IR (film): 1750, 1715, 1495, 1455, 1225, 1210, 1120, 1076, 1030,

915, 860, 740, 700 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.32 [d, J_2-CH3,2= 7.0 Hz, 2-CH₃

(7b)], 1.83 [s, 2-CH₃(enol-7b)], 3.64 [s, 4-CH₂(enol-7b)], super-

imposed by 3.64 [q, J_2,2-CH3= 7.0 Hz, 2-H (7b)], 3.70 [s, 1¢-CH₃(7b

and enol-7b)], 3.84 [s, 4-CH₂(7b)], 7.19–7.36 [m, Ar²-H, Ar³-H,

Ar⁴-H, Ar⁵-H, Ar⁶-H (7b and enol-7b)], 12.66 [s, 3-OH (enol-7b)].

¹³C NMR (63 MHz, CDCl₃): d = 13.0 [2-CH₃(7b)], 48.7 [C-4 (7b)],

51.8 [C-2 (7b)], 52.5 [C-1¢ (7b)], 127.3 [C-Ar⁴(7b)], 128.8 [C-Ar³,

C-Ar⁵(7b)], 129.6 [C-Ar², C-Ar⁶(7b)], 133.5 [C-Ar¹(7b)], 170.9

[C-1 (7b)], 203.2 [C-3 (7b)].

Off-white solid; yield: 44 mg (100%); mp 40 °C.

IR (film): 3030, 2975, 2920, 1710, 1565, 1490, 1450, 1410, 1340,

1165, 1110, 1040, 915, 865, 815, 745, 690, 645 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.06 (t, J_4,3= 7.2 Hz, 4-H₃), 2.51

(q, J_3,4= 7.2 Hz, 3-CH₂), 3.73 (s, 1-H₂), 7.26–7.43 (m, Ar²-H, Ar³-

H, Ar⁴-H, Ar⁵-H, Ar⁶-H, Ar^2¢-H, Ar^3¢-H, Ar^4¢-H, Ar^5¢-H, Ar^6¢-H).

¹³C NMR (75 MHz, CDCl₃): d = 8.0 (C-4), 35.6 (C-3), 49.6 (C-2),

127.2 (C-Ar^2¢, C-Ar^6¢), 127.5 (C-Ar^4¢), 127.6 (C-Ar^3¢, C-Ar^5¢), 129.0

(C-Ar³, C-Ar⁵), 130.0 (C-Ar², C-Ar⁶), 133.7 (C-Ar¹), 140.1 (C-Ar⁴),

141.0 (C-Ar^1¢), 209.0 (C-2).

Anal. Calcd for C₁₂H₁₄O₃(206.2): C, 69.89; H, 6.84. Found: C,

69.77; H, 6.76.

HRMS (EI): m/z [M⁺] calcd for C₁₆H₁₆O₁: 224.1204; found:

Methyl 2,2-Dimethyl-3-oxo-4-phenylbutanoate (7c)

Ester 7c was prepared similarly to 4c as described above, starting

from methyl b-keto ester 7a (393 mg, 2.00 mmol), NaH (54 mg,

2.2 mmol, 1.1 equiv), and MeI (0.14 mL, 0.32 g, 2.2 mmol, 1.1

equiv) in THF (15 mL); purification of the residue by flash chroma-

tography (silica gel, column diameter 3.5 cm, cyclohexane–EtOAc,

25:1) furnished 7c.

224.1201.

1-(Biphenyl-4-yl)-3-methylbutan-2-one (5c)

A 0.20 M soln of TBAF·3H₂O in THF (0.74 mL, 0.15 mmol, 0.75

equiv) was added dropwise to TMSE b-keto ester 4c (76 mg, 0.20

mmol) in THF (1.3 mL) at 0 °C. The resulting mixture was stirred

Synthesis 2008, No. 14, 2229–2246 © Thieme Stuttgart · New York

2238

E. Knobloch, R. Brückner

PAPER

Colorless oil; yield: 356 mg (79%).

tert-Butyl 2,2-Dimethyl-3-oxo-4-phenylbutanoate (8c)

Ester 8c was prepared similarly to 4c as described above, starting

from tert-butyl b-keto ester 8a (471 mg, 2.00 mmol), NaH (53 mg,

2.2 mmol, 1.1 equiv), and MeI (0.14 mL, 0.32 g, 2.2 mmol, 1.1

equiv) in THF (15 mL); purification of the residue by flash chroma-

tography (silica gel, column diameter 3.5 cm, cyclohexane–EtOAc,

30:1) furnished 8c.

IR (film): 1740, 1715, 1495, 1455, 1385, 1365, 1265, 1190, 1145,

910, 850, 740, 700 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.42 [s, 2-CH₃)₂], 3.70 (s, 1¢-H₃),

3.77 (s, 4-H₂), 7.16–7.34 (m, Ar²-H, Ar³-H, Ar⁴-H, Ar⁵-H, Ar⁶-H).

¹³C NMR (63 MHz, CDCl₃): d = 22.1 [2-(CH₃)₂], 44.8 (C-4), 52.5

(C-1¢), 55.9 (C-2), 127.0 (C-Ar⁴), 128.5 (C-Ar³, C-Ar⁵), 129.6 (C-

Ar², C-Ar⁶), 124.1 (C-Ar¹), 174.1 (C-1), 205.1 (C-3).

White solid; yield: 356 mg (75%); mp 36 °C.

IR (film): 3440, 3090, 3065, 3030, 2980, 935, 2360, 1735, 1715,

1605, 1495, 1465, 1455, 1385, 1370, 1270, 1140, 1075, 1045, 1000,

950, 875, 845, 735, 700 cm^–1.

Anal. Calcd for C₁₃H₁₆O₃(220.3): C, 70.89; H, 7.32. Found: C,

70.61; H, 7.24.

¹H NMR (400 MHz, CDCl₃): d = 1.39 [s, 1¢-(CH₃)₃], 1.48 [s, 2-

(CH₃)₂], 3.80 (s, 4-CH₂), 7.20–7.30 (m, Ar²-H, Ar³-H, Ar⁴-H, Ar⁵-

H, Ar⁶-H).

¹³C NMR (101 MHz, CDCl₃): d = 22.0 [2-(CH₃)₂], 27.9 [1¢-(CH₃)₃],

44.7 (C-4), 56.7 (C-2), 81.9 (C-1¢), 126.9 (C-Ar⁴), 128.5 (C-Ar³, C-

Ar⁵), 129.6 (C-Ar², C-Ar⁶), 134.3 (C-Ar¹), 172.8 (C-1), 205.5 (C-3).

tert-Butyl 3-Oxo-4-phenylbutanoate (8a)

Ester 8a was prepared similarly to 7a as described above, starting

from 15 (100 mg, 0.380 mmol) and t-BuOH (32 mg, 0.42 mmol, 1.1

equiv) in toluene (2 mL); purification of the residue by flash chro-

matography (silica gel, column diameter 2.0 cm, cyclohexane–

EtOAc, 10:1) furnished 8a.

White solid; yield: 86.4 mg [97%; cf. 82% (by alcoholysis in

t-BuOH)³¹; 98% (by alcoholysis in t-BuOH)³³]; mp 36 °C (Lit.³¹

36 °C).

Anal. Calcd for C₁₆H₂₂O₃(262.3): C, 73.25; H, 8.45. Found: C,

73.17; H, 8.55.

Allyl 3-Oxo-4-phenylbutanoate (9a)

IR (film): 3060, 3030, 29.80, 2930, 1735, 1715, 16.45, 1600, 14.95,

1475, 1455, 1410, 1395, 1370, 1320, 1250, 1145, 1095, 1060, 1030,

965, 915, 845, 735, 700 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 1.46 [s, 1¢-(CH₃)₃(8a)], 1.46 [s,

1¢-(CH₃)₃(enol-8a)], 3.37 [s, 4-H₂(8a)], 3.47 [s, 4-H₂(enol-8a)],

3.82 [s, 2-H₂(8a)], 4.82 [s, 2-H (enol-8a)], 7.20–7.36 (m, Ar²-H,

Ar³-H, Ar⁴-H, Ar⁵-H, Ar⁶-H), 12.28 [s, 3-OH (enol-8a)].

Ester 9a was prepared similarly to 7a as described above, starting

from 15 (878 mg, 3.35 mmol) and AllOH (0.30 mL, 0.26 g, 4.4

mmol, 1.1 equiv) in toluene (30 mL); purification of the residue by

flash chromatography (silica gel, column diameter 3.5 cm, cyclo-

hexane–EtOAc, 15:1) furnished 9a.

Colorless oil; yield: 646 mg (88%).

IR (film): 3445, 3090, 3065, 1010, 2940, 2360, 2345, 1745, 1720,

1650, 1600, 1495, 1455, 1410, 1360, 1315, 1275, 1225, 1150, 1095,

1060, 1030, 990, 915, 800, 740, 700 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 3.49 [s, 2-H₂(9a)], 3.53 [s, 4-H₂

¹³C NMR (101 MHz, CDCl₃): d = 28.1 [1¢-(CH₃)₃(8a)], 28.4 [1¢-

(CH₃)₃(enol-8a)], 41.5 [C-4 (enol-8a)], 49.7 [C-4 (8a)], 50.0 [C-2

(8a)], 81.0 [C-1¢ (enol-8a)], 82.1 [C-1¢ (8a)], 91.6 [C-2 (enol-8a)],

127.0 [C-Ar⁴(enol-8a)], 127.4 [C-Ar⁴(8a)], 128.7 [C-Ar³, C-Ar⁵

(enol-8a)], 128.9 [C-Ar³, C-Ar⁵(8a)], 129.4 [C-Ar², C-Ar⁶(enol-

8a)], 129.7 [C-Ar², C-Ar⁶8a)], 133.5 [C-Ar¹(8a)], 166.4 [C-1

(8a)], 200.9 [C-3 (8a)].

(enol-9a)], 3.84 [s, 4-H₂(9a)], 4.62 [ddd,

J_1¢,2¢= 5.8,

⁴J_1¢,3¢(E)= ⁴J_1¢,3¢(Z)= 1.4 Hz, 1¢-H₂(9a)], superimposed by 4.63–4.64

4

[m, 1¢-H₂(enol-9a)], 5.23 [t, J_2,4= 0.6 Hz, 2-H (enol-9a)], 5.25

[ddt, J_3¢(E),2¢= 10.4, J_{3¢(E),3¢(Z)}= ⁴J_3¢(E),_1¢= 1.3 Hz, 3¢(E)-H (enol-9a)],

superimposed by 5.27 [ddt, J_3¢(E),2¢= 10.4, J_{3¢(E),3¢(Z)}= ⁴J_3¢(E),1¢= 1.3

Hz, 3¢(E)-H (9a)], 5.33 [ddt, J_3¢(Z),2¢= 17.3, J_{3¢(Z),3¢(E)}= ⁴J_3¢(Z)1¢= 1.5

Hz, 3¢(Z)-H (enol-9a)], superimposed by 5.35 [ddt, J_3¢(Z),2¢= 17.3,

J_{3¢(Z),3¢(E)}= ⁴J_3¢(Z)1¢= 1.5 Hz, 3¢(Z)-H (9a)], 5.91 [ddt, J_2¢,3¢(Z)= 17.2,

J_2¢,3¢(Z)= 10.4, J_2¢,1¢= 5.8 Hz, 2¢-H (9a)], superimposed by 5.92 [ddt,

Anal. Calcd for C₁₄H₁₈O₃(234.3): C, 71.77; H, 7.74. Found: C,

71.75; H, 7.84.

tert-Butyl 2-Methyl-3-oxo-4-phenylbutanoate (8b)

Ester 8b was prepared similarly to 4b as described above, starting

from tert-butyl b-keto ester 8a (552 mg, 2.36 mmol), NaH (62 mg,

2.6 mmol, 1.1 equiv), and MeI (0.16 mL, 0.37 g, 2.6 mmol, 1.1

equiv) in THF (3 mL); purification of the residue by flash chroma-

tography (silica gel, column diameter 2.0 cm, cyclohexane–EtOAc,

15:1) furnished 8b.

J

_2¢,3¢(Z)= 17.2, J_2¢,3¢(Z)= 10.4, J_2¢,1¢= 5.8 Hz, 2¢-H (enol-9a)], 7.20–

7.38 [m, Ar²-H, Ar³-H, Ar⁴-H, Ar⁵-H, Ar⁶-H (9a and enol-9a)],

12.05 [s, 3-OH (enol-9a)].

¹³C NMR (101 MHz, CDCl₃): d = 41.5 [C-4 (enol-9a)], 48.2 [C-2

(9a)], 50.1 [C-4 (9a)], 64.8 [C-1¢ (enol-9a)], 66.0 [C-1¢ (9a)], 90.0

[C-2 (enol-9a)], 118.5 [C-3¢ (enol-9a)], 118.9 [C-3¢ (9a)], 127.1 [C-

Ar⁴(enol-9a)], 127.4 [C-Ar⁴(9a)], 128.7 [C-Ar³, C-Ar⁵(enol-9a)],

128.9 [C-Ar³, C-Ar⁵(9a)], 129.3 [C-Ar², C-Ar⁶(enol-9a)], 129.6

[C-Ar², C-Ar⁶(9a)], 131.6 [C-2¢ (9a)], 132.1 [C-2¢ (enol-9a)],

133.22 [C-Ar¹(9a)], 135.5 [C-Ar¹(enol-9a)], 166.77 [C-1 (9a)],

172.3 [C-1 (enol-9a)], 177.5 [C-3 (enol-9a)], 200.3 [C-3 (9a)].

Colorless oil; yield: 563 mg (96%).

IR (film): 3090, 3065, 3030, 2980, 2940, 1740, 1715, 1645, 1605,

1585, 1495, 1480, 1455, 1395, 1370, 1330, 1280, 1250, 1225, 1155,

1120, 1080, 1035, 1000, 900, 845, 755, 730, 700 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 1.28 [d, J_2-CH3,2= 7.1 Hz, 2-CH₃

(8b)], 1.47 [s, 1¢-(CH₃)₃, (8b)], 1.48 [s, 1¢-(CH₃)₃, (enol-8b)], 1.79

[s, 2-CH₃(enol-8b)], 3.56 [q, J_2,2-CH3= 7.1 Hz, 2-CH₃(8b)], 3.62 [s,

4-H₂(enol-8b)], AB signal [d_A= 3.84, d_B= 3.87, J_AB= 15.8 Hz, 4-

H₂(8b)], 7.20–7.36 [m, Ar²-H, Ar³-H, Ar⁴-H, Ar⁵-H, Ar⁶-H (8b and

enol-8b)], 12.90 [s, 3-OH (enol-8b)].

Anal. Calcd for C₁₃H₁₄O₃(218.2): C, 71.54; H, 6.47. Found: C,

71.39; H, 6.51.

Allyl 2-Methyl-3-oxo-4-phenylbutanoate (9b)

¹³C NMR (101 MHz, CDCl₃): d = 12.9 [2-CH₃(8b)], 27.9 [1¢-

(CH₃)₃(enol-8b)], 28.0 [1¢-(CH₃)₃(8b)], 48.7 [C-2 (8b)], 52.9 [C-4

(8b)], 82.0 [C-1¢ (8b)], 127.2 [C-Ar⁴(8b)], 128.8 [C-Ar³, C-Ar⁵

(8b)], 129.7 [C-Ar², C-Ar⁶(8b)], 133.7 [C-Ar¹(8b)], 169.6 [C-1

(8b)], 203.7 [C-3 (8b)].

Ester 9b was prepared similarly to 4b as described above, starting

from allyl b-keto ester 9a (453 mg, 2.07 mmol), NaH (55 mg,

2.2 mmol, 1.1 equiv), and MeI (0.14 mL, 0.32 g, 2.2 mmol, 1.1

equiv) in THF (3 mL); purification of the residue by flash chroma-

tography (silica gel, column diameter 2.0 cm, cyclohexane–EtOAc,

15:1) furnished 9b.

Anal. Calcd for C₁₅H₂₀O₃(248.3): C, 72.55; H, 8.12. Found: C,

72.23; H, 8.14.

Colorless oil; yield: 392 mg (82%).

Synthesis 2008, No. 14, 2229–2246 © Thieme Stuttgart · New York

PAPER

b-Keto Esters Derived from 2-(Trimethylsilyl)ethanol

2239

IR (film): 3065, 1010, 2940, 2735, 1745, 1715, 1650, 1600, 1495,

1455, 1375, 1330, 1240, 1190, 1090, 1030, 1000, 950, 850, 700

cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 1.33 [d, J_2-CH3,2= 7.1 Hz, 2-CH₃

(9b)], 1.86 [s, 2-CH₃(enol-9b)], 3.65 [s, 4-H₂(enol-9b)], superim-

posed by 3.66 [q, J_2,2-CH3= 7.2 Hz, 2-H (9b)], AB signal [d_A= 3.83,

d_B= 3.86 J_AB= 15.6 Hz, 4-H₂(9b)], 4.60 [ddd, J_1¢,2¢= 5.8 Hz,

⁴J_1¢,3¢(E)= ⁴J_1¢,3¢(Z)= 1.4 Hz, 1¢-H₂(9b)], 4.66 [ddd, J_1¢,2¢= 5.8 Hz,

⁴J_1¢,3¢(E)= ⁴J_1¢,3¢(Z)= 1.4 Hz, 1¢-H₂(enol-9b)], 5.24 [ddd,

¹H NMR (300 MHz, CDCl₃): d = 3.49 [s, 2-H₂(10a)], 3.51 [s, 4-H₂

(enol-10a)], 3.80 [s, 4-H₂(10a)], 4.97 [s, 2-H (enol-10a)], 5.15 [s,

1¢-H₂(10a und enol-10a)], 7.15–7.26 [m, Ar²-H, Ar³-H, Ar⁴-H, Ar⁵-

H, Ar⁶-H, Ar^2¢-H, Ar^3¢-H, Ar^4¢-H, Ar^5¢-H, Ar^6¢-H (10a und enol-

10a)], 12.04 [s, 3-OH (enol-10a)].

¹³C NMR (101 MHz, CDCl₃): d = 41.5 [C-4 (enol-10a)], 48.3 [C-4

(10a)], 50.1 [C-2 (10a)], 65.9 [C-1¢ (enol-10a)], 67.24 [C-1¢ (10a)],

90.1 [C-2 (enol-10a)], 127.5 and 128.6 (C-Ar⁴, C-Ar^4¢(10a), 128.5,

128.7, 129.0 and 129.6 [C-Ar³, C-Ar⁵, C-Ar², C-Ar⁶, C-Ar^3¢, C-Ar^5¢,

C-Ar^2¢, C-Ar^6¢(10a)], 133.2 and 135.3 [C-Ar¹, C-Ar^1¢(10a)], 167.0

[C-1 (10a)], 172.4 [C-1 (enol-10a)], 177.6 [C-3 (enol-10a)], 200.3

[C-3 (10a)].

J

_3¢(E),2¢= 10.4, J_{3¢(E),3¢(Z)}= ⁴J_3¢(E),1¢= 1.5 Hz, 3¢-H(E) (enol-9b)], su-

perimposed by 5.26 [ddd, J_3¢(E),2¢= 10.4, J_{3¢(E),3¢(Z)}= ⁴J_3¢(E),1¢= 1.5 Hz,

3¢-H(E) (9b)], 5.32 [ddd, J_3¢(Z),2¢= 17.2, J_{3¢(Z),3¢(E)}= ⁴J_3¢(Z),1¢= 1.5 Hz,

3¢-H(Z) (9b)], superimposed by 5.33 [ddd,

J_3¢(Z),2¢= 17.2,

Anal. Calcd for C₁₇H₁₆O₃(268.3): C, 76.10; H, 6.01. Found: C,

75.92; H, 6.01.

J_{3¢(Z),3¢(E)}= ⁴J_3¢(Z),1¢= 1.5 Hz, 3¢-H(Z) (enol-9b)], 5.89 [ddt,

J_2¢,3¢(Z)= 17.2, J_2¢,3¢(Z)= 10.5, J_2¢,1¢= 5.8 Hz, 2¢-H (9b)], superim-

posed by 5.96 [ddt, J_2¢,3¢(Z)= 17.2, J_2¢,3¢(Z)= 10.5, J_2¢,1¢= 5.8 Hz, 2¢-H

(enol-9b)], 7.19–7.35 [m, Ar²-H, Ar³-H, Ar⁴-H, Ar⁵-H, Ar⁶-H (9b

and enol-9b)], 12.66 [t, ⁴J_3-OH,4= 1.1 Hz, 3-OH (enol-9b)].

Benzyl 2-Methyl-3-oxo-4-phenylbutanoate (10b)

Ester 10b was prepared similarly to 4b as described above, starting

from benzyl b-keto ester 10a (547 mg, 2.04 mmol), NaH (54 mg,

2.20 mmol, 1.1 equiv), and MeI (0.14 mL, 0.32 g, 2.2 mmol, 1.1

equiv) in THF (3 mL); purification of the residue by flash chroma-

tography (silica gel, column diameter 3.5 cm, cyclohexane–EtOAc,

30:1) furnished 10b.

¹³C NMR (101 MHz, CDCl₃): d = 11.4 [2-CH₃(enol-9b)], 12.9 [2-

CH₃(9b)], 38.6 [C-4 (enol-9b)], 48.7 [C-2 (9b)], 51.8 [C-4 (9b)],

65.1 [C-1¢ (enol-9b)], 66.0 [C-1¢ (9b)], 118.1 [C-3¢ (enol-9b)],

119.0 [C-3¢ (9b)], 126.8 [C-Ar⁴(enol-9b)], 127.3 [C-Ar⁴(9b)],

128.7 [C-Ar³, C-Ar⁵(enol-9b)], 128.7 [C-Ar², C-Ar⁶(enol-9b)],

128.8 [C-Ar³, C-Ar⁵(9b)], 129.7 [C-Ar², C-Ar⁶(9b)], 131.6 [C-2¢

(9b)], 132.2 [C-2¢ (enol-9b)], 133.46 [C-Ar¹(9b)], 170.1 [C-1

(9b)], 203.1 [C-3 (9b)].

Colorless oil; yield: 474 mg (84%).

IR (film): 3090, 3065, 3030, 2985, 2940, 1745, 1716, 1650, 1605,

1585, 1495, 1455, 1380, 1330, 1235, 1175, 1115, 1080, 1030, 1000,

955, 915, 850, 825, 740, 700 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 1.34 [d, J_2-CH3,2= 7.2 Hz, 2-CH₃

(10b)], 1.87 [s, 2-CH₃(enol-10b)], 3.65 [s, 4-CH₂(enol-10b)], su-

perimposed by 3.68 [q, J_2,2-CH3= 7.2 Hz, 2-H (10b)], AB signal

(d_A= 3.77, d_B= 3.82, J_AB= 15.7 Hz, 4-H₂), 5.15 [s, 1¢-CH₂(10b)],

5.21 [s, 1¢-CH₂(enol-10b)], 7.11–7.40 [m, Ar²-H, Ar³-H, Ar⁴-H,

Ar⁵-H, Ar⁶-H, Ar^2¢-H, Ar^3¢-H, Ar^4¢-H, Ar^5¢-H, Ar^6¢-H (10b and enol-

10b)], 12.68 [t, J_3-OH,4= 1.1 Hz, 3-OH (enol-10b)].

¹³C NMR (101 MHz, CDCl₃): d = 11.4 [2-CH₃(enol-10b)], 12.9 [2-

CH₃(10b)], 38.7 [CH₃-2 (10b)], 48.7 [C-4 (10b)], 51.9 [C-2 (10b)],

66.2 [C-1¢ (enol-10b)], 67.2 [C-1¢ (10b)], 127.3 [C-Ar⁴(10b)],

128.4 [C-Ar^3¢, C-Ar^5¢(10b)], 128.6 [C-Ar^4¢(10b)], 128.7 and 128.8

[C-Ar³, C-Ar⁵, C-Ar^2¢, C-Ar^6¢(10b)], 129.6 [C-Ar², C-Ar⁶(10b)],

133.4 [C-Ar¹(10b)], 135.4 [C-Ar^1¢(10b)], 170.2 [C-1 (10b)], 203.1

[C-3 (10b)].

Anal. Calcd for C₁₄H₁₆O₃(232.3): C, 72.39; H, 6.94. Found: C,

72.15; H, 6.97.

Allyl 2,2-Dimethyl-3-oxo-4-phenylbutanoate (9c)

Ester 9c was prepared similarly to 4c as described above, starting

from allyl b-keto ester 9a (435 mg, 2.00 mmol), NaH (54 mg,

2.2 mmol, 1.1 equiv), and MeI (0.14 mL, 0.32 g, 2.2 mmol, 1.1

equiv) in THF (15 mL); purification of the residue by flash chroma-

tography (silica gel, column diameter 3.5 cm, cyclohexane–EtOAc,

25:1) furnished 9c.

Colorless oil; yield: 344 mg (70%).

IR (film): 1715, 1650, 1595, 1390, 1325, 1265, 1150, 1045, 985,

913, 740, 700 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.47 [s, 2-(CH₃)₂], 3.78 (s, 4-H₂),

4

4.60 (ddd, J_1¢,2¢= 5.9 Hz, J_1¢,3¢(E)= ⁴J_1¢,3¢(Z)= 1.5 Hz, 1¢-H₂), 5.85

Anal. Calcd for C₁₈H₁₈O₃(282.3): C, 76.10; H, 6.01. Found: C,

76.02; H, 6.42.

[ddd, J_3¢(E),2¢= 10.4, J_{3¢(E),3¢(Z)}= ⁴J_3¢(E),1¢= 1.2 Hz, 3¢-H(E)], 5.29

[ddd, J_3¢(Z),2¢= 17.1, J_{3¢(Z),3¢(Z)}= ⁴J_3¢(Z),1¢= 1.3 Hz, 3¢-H(Z)], 5.89 (ddt,

J_2¢,3¢(Z)= 17.1, J_2¢,3¢(Z)= 10.4, J_2¢,1¢= 5.7 Hz, 2¢-H), 7.16–7.34 (m,

Ar²-H, Ar³-H, Ar⁴-H, Ar⁵-H, Ar⁶-H).

Benzyl 2,2-Dimethyl-3-oxo-4-phenylbutanoate (10c)

Ester 10c was prepared similarly to 4c as described above, starting

from benzyl b-keto ester 10a (536 mg, 2.00 mmol), NaH (53 mg,

2.2 mmol, 1.1 equiv), and MeI (0.14 mL, 0.32 g, 2.2 mmol, 1.1

equiv) in THF (15 mL); purification of the residue by flash chroma-

tography (silica gel, column diameter 3.5 cm, cyclohexane–EtOAc,

25:1) furnished 10c.

¹³C NMR (101 MHz, CDCl₃): d = 22.9 [2-(CH₃)₂], 44.8 (C-4), 56.0

(C-2), 66.1 (C-1¢), 119.1 (C-3¢), 127.0 (C-Ar⁴), 128.5 (C-Ar³, C-

Ar⁵), 129.6 (C-Ar², C-Ar⁶), 131.5 (C-2¢), 134.1 (C-Ar¹), 173.3 (C-

1), 205.0 (C-3).

Anal. Calcd for C₁₅H₁₈O₃(246.3): C, 73.15; H, 7.37. Found: C,

72.85; H, 7.36.

Colorless oil; yield: 411 mg (69%).

IR (film): 3035, 2935, 2760, 1715, 1500, 1455, 1390, 1370, 1260,

1155, 1045, 1000, 915, 745, 700 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 1.44 [s, 2-(CH₃)₂], 3.70 (s, 4-H₂),

5.15 (s, 1¢-H₂), 7.05–7.31 (m, Ar²-H, Ar³-H, Ar⁴-H, Ar⁵-H, Ar⁶-H,

Ar^2¢-H, Ar^3¢-H, Ar^4¢-H, Ar^5¢-H, Ar^6¢-H).

¹³C NMR (101 MHz, CDCl₃): d = 22.1 [2-C(CH₃)₂], 44.8 (C-4),

56.0 (C-2), 67.2 (C-1¢), 127.0 (C-Ar⁴), 128.4 (C-Ar^3¢, C-Ar^5¢), 128.5

(C-Ar³, C-Ar⁵), 128.6 (C-Ar^4¢), 128.7 (C-Ar^2¢, C-Ar^6¢), 129.6 (C-

Ar², C-Ar⁶), 134.0 (C-Ar¹), 135.4 (C-Ar^1¢), 173.4 (C-1), 205.0 (C-

3).

Benzyl 3-Oxo-4-phenylbutanoate (10a)

Ester 10a was prepared similarly to 7a as described above, starting

from 15 (878 mg, 3.35 mmol) and BnOH (0.38 mL, 0.40 g, 3.7

mmol, 1.1 equiv) in toluene (30 mL); purification of the residue by

flash chromatography (silica gel, column diameter 3.5 cm, cyclo-

hexane–EtOAc, 15:1) furnished 10a.

White solid; yield: 840 mg [93%, cf. 74% (by alcoholysis in

BnOH)³¹]; mp 28 °C.

IR (film): 3060, 3030, 2930, 1745, 1720, 1645, 1600, 1585, 1445,

1455, 1410, 1375, 1310, 1260, 1215, 1150, 1095, 1060, 1030, 1000,

910, 735, 695 cm^–1.

Anal. Calcd for C₁₉H₂₀O₃(296.4): C, 77.00; H, 6.80. Found: C,

76.76; H, 6.69.

Synthesis 2008, No. 14, 2229–2246 © Thieme Stuttgart · New York

2240

E. Knobloch, R. Brückner

PAPER

O

OH

3

5

7

1'

11

9

12

10

Me₃Si

O

keto-enol_TMSE-16

1

O

1''

2'

2

6

8

4

O

5

7

9

11

1'

10

12

Me₃Si

1

3

diketo-16

1''

2'

2

6

8

4

O

5

9

11

1'

7

12

Me₃Si

O

keto_TMSE-enol-16m

1

3

O

10

1''

2

8

2'

4

6

OH

O

Figure 2

Methyl 2-(Trimethylsilyl)ethyl 3,10-Dioxododecanedioate (16)

(Figure 2)

ists as a mixture with enol tautomers: diketo-17/keto-enol_TMSE-17/

keto_TMSE-enol-17, 87:8:5.

Bis(b-hydroxy ester) 30 (75 mg, 0.20 mmol) in CH₂Cl₂(2 mL) was

added dropwise over 5 min to a mixture of DMP (187 mg, 0.44

mmol, 2.2 equiv) in CH₂Cl₂(2 mL) at 0 °C. After stirring of the

mixture at r.t. for 30 min, sat. aq Na₂S₂O₃(3 mL), sat. aq NaHCO₃

(3 mL), and MTBE (3 mL) were added. Extraction with MTBE (3

× 3 mL), washing with brine (2 × 5 mL), drying of the combined ex-

tracts (MgSO₄), evaporation of the solvent under reduced pressure,

and flash chromatography (silica gel, column diameter 2 cm, cyclo-

hexane–EtOAc, 7:1) furnished 16, which exists as a mixture with

enol tautomers: diketo-16/keto-enol_TMSE-16/keto_TMSE-enol-16,

85:7:8 (Figure 2).

Colorless oil; yield: 46 mg (62%).

IR (film): 2935, 2860, 1740, 1715, 1645, 1460, 1410, 1370, 1320,

1250, 1160, 1065, 950, 915, 860, 840, 745, 700 cm^–1.

¹H NMR (400 MHz, CDCl₃): d (17) = 0.04 [s, 2¢-Si(CH₃)₃], 1.01

(m_c, 2¢-CH₂), 1.28–1.31 (m, 6-CH₂, 7-CH₂), 1.46 [s, 1¢¢-(CH₃)₃],

1.55–1.62 (m, 5-CH₂, 8-CH₂), 2.51 (t, J_4,5= 7.5 Hz, 4- or 9-CH₂),

superimposed by 2.52 (t, J_9,8= 7.3 Hz, 4- or 9-CH₂), 3.32 (s, 11-H₂),

3.39 (s, 2-H₂), 4.22 (m_c, 1¢-H₂); d (keto-enol_TMSE-17 and keto_TMSE

-

enol-17) = 0.04 [s, 2¢-Si(CH₃)₃(keto-enol_TMSE-17)], 1.48 [s, 1¢¢-

(CH₃)₃(keto_TMSE-enol-17)], 2.17 [m_C, 4¢-CH₂, 9¢-CH₂(keto-

enol_TMSE-17 and keto_TMSE-enol-17)], 4.87 [s, 2-H (keto_TMSE-enol-

17)], 4.94 [s, 11-H (keto-enol_TMSE-17)], 12.12 [s, 3-OH (keto-

enol_TMSE-17)], 12.22 [s, 10-OH (keto_TMSE-enol-17)] (Unlisted sig-

nals of the minor tautomers keto-enol_TMSE-17 and keto_TMSE-enol-17

are overlapped by signals of the major tautomer diketo-17).

Colorless oil; yield: 61 mg (82%).

IR (film): 2955, 2860, 1745, 1715, 1630, 1440, 1410, 1375, 1320,

1250, 1170, 1065, 915, 860, 840, 745, 700, 655 cm^–1.

¹H NMR (400 MHz, CDCl₃): d (16) = 0.03 [s, 2¢-Si(CH₃)₃], 0.99

(m_c, 2¢-CH₂), 1.27–1.31 (m, 6-CH₂, 7-CH₂), 1.57 (m_c, 5-CH₂, 8-

CH₂), 2.52 (t, J_4,5= 7.3, J_9,8= 7.3 Hz, 4-CH₂, 9-CH₂), 3.39 (s, 2-H₂),

¹³C NMR (101 MHz, CDCl₃): d = –1.5 [Si(CH₃)₃(diketo-17)], –1.4

[Si(CH₃)₃(keto-enol_TMSE-17)], 17.4 [C-2¢ (diketo-17)], 23.3 [C-5,

C-8 (diketo-17)], 28.1 [1¢¢-(CH₃)₃(diketo-17)], 28.4 [1¢¢-(CH₃)₃(ke-

to_TMSE-enol-17)], 28.8 [C-6 (diketo-17)], 28.8 [C-7 (diketo-17)],

35.1 [C-4, C-9 (keto-enol_TMSE-17 and keto_TMSE-enol-17)], 42.8 and

43.0 [C-4, C-9 (diketo-17)], 49.5 [C-2 (diketo-17)], 50.7 [C-11

(diketo-17)], 63.8 [C-1¢ (diketo-17)], 82.0 [C-1¢¢ (diketo-17)], 89.3

[C-2 (keto-enol_TMSE-17)], 90.5 [C-11 (keto_TMSE-enol-17)], 166.6

[C-12 (diketo-17)], 167.5 [C-1 (diketo-17)], 202.9 [C-3 (diketo-

17)], 203.3 [C-10 (diketo-17)].

3.43 (s, 11-H₂), 3.72 (s, 1¢¢-H₃), 4.21 (m_c, 1¢-H₂); d (keto-enol_TMSE

-

16 and keto_TMSE-enol-16) = 0.04 [s, 2¢-Si(CH₃)₃(keto-enol_TMSE

16)], 2.17 [m_C, 4¢-CH₂, 9¢-CH₂(keto-enol_TMSE-16 and enol-keto-

16)], 2.71 [s, 1¢¢-H₃(keto_TMSE-enol-16)], 4.93 [s, 2-H (keto-

enol_TMSE-16)], 4.97 [s, 11-H (keto_TMSE-enol-16)], 12.12 [s, 3-OH

(keto-enol_TMSE-16)], 12.00 [s, 10-OH (keto_TMSE-enol-16)] (unlisted

signals of the minor tautomers keto-enol_TMSE-16 and keto_TMSE-enol-

16 are overlapped by signals of the major tautomer diketo-16).

¹³C NMR (101 MHz, CDCl₃): d = –1.47 [Si(CH₃)₃(diketo-16)],

–1.45 [Si(CH₃)₃(keto-enol_TMSE-16)], 17.4 [C-2¢ (diketo-16)], 23.2

[C-5, C-8 (diketo-16)], 28.8 [C-6, C-7 (diketo-16)], 34.5 [C-4, C-9

(keto-enol_TMSE-16 and keto_TMSE-enol-16)], 42.9 [C-4, C-9 (diketo-

16)], 49.1 [C-11 (diketo-16)], 49.2 [C-2 (diketo-16)], 51.1 [C-1¢¢

(keto_TMSE-enol-16)], 52.4 [C-1¢¢ (diketo-16)], 63.8 [C-1¢ (diketo-

Anal. Calcd for C₂₁H₃₈O₆Si (414.6): C, 60.84; H, 9.24. Found: C,

60.83; H, 9.08.

Allyl 2-(Trimethylsilyl)ethyl 3,10-Dioxododecanedioate (18)

Ester 18 was prepared similarly to 16 as described above, starting

from bis(b-hydroxy ester) 32 (80 mg, 0.20 mmol) in CH₂Cl₂(2 mL)

and DMP (200 mg, 0.47 mmol, 2.3 equiv) in CH₂Cl₂(2 mL); puri-

fication of the residue by flash chromatography (silica gel, column

diameter 2.0 cm, cyclohexane–EtOAc, 7:1) furnished 18, which ex-

ists as a mixture with enol tautomers: diketo-18/keto-enol_TMSE-18/

keto_TMSE-enol-18, 87:7:8.

16)], 88.9 [C-11 (keto_TMSE-enol-16)], 89.3 [C-2 (keto-enol_TMSE

-

16)], 167.4 [C-1 (diketo-16)], 167.7 [C-12 (diketo-16)], 202.7 [C-

10 (diketo-16)], 202.9 [C-3 (diketo-16)].

Anal. Calcd for C₁₈H₃₂O₆Si (390.2): C, 58.03; H, 8.66. Found: C,

58.22; H, 8.61.

Colorless oil; yield: 61 mg (77%).

tert-Butyl 2-(Trimethylsilyl)ethyl 3,10-Dioxododecanedioate

(17)

IR (film): 2950, 2860, 1745, 1720, 1650, 1410, 1365, 1315, 1250,

1170, 1060, 990, 915, 860, 840, 745, 700, 665 cm^–1.

Ester 17 was prepared similarly to 16 as described above, starting

from bis(b-hydroxy ester) 31 (76 mg, 0.18 mmol) in CH₂Cl₂(2 mL)

and DMP (180 mg, 0.42 mmol, 2.3 equiv) in CH₂Cl₂(2 mL); puri-

fication of the residue by flash chromatography (silica gel, column

diameter 2.0 cm, cyclohexane–EtOAc, 7:1) furnished 17, which ex-

¹H NMR (400 MHz, CDCl₃): d (18) = 0.04 [s, 2¢-Si(CH₃)₃], 1.0 (m_c,

2¢-CH₂), 1.28–1.31 (m, 6-CH₂, 7-CH₂), 1.55–1.63 (m, 5-CH₂, 8-

CH₂), 2.52 (t, Hz, 4- or 9-CH₂), superimposed by 2.53 (t, J_9,8= 7.3

Hz, 4- or 9-CH₂), 3.40 (s, 2-H₂), 3.45 (s, 11-H₂), 4.22 (m_c, 1¢-H₂),

4.63 (ddd, J_1¢¢,2¢¢= 5.8, ⁴J_{1¢¢,3¢¢(E)}= J_{1¢¢,3¢¢(Z)}= 1.4 Hz, 1¢¢-H₂), 5.26 [ddt,

PAPER

_{3¢¢(E),2¢¢}= 10.5, J_{3¢¢(E),3¢¢(Z)}= 1.3, J_{3¢¢(E),1¢¢}= 1.3 Hz, 3¢¢-H(E)], 5.34

b-Keto Esters Derived from 2-(Trimethylsilyl)ethanol

2241

2

J

Methyl 3,10-Dioxoundecanoate (20) (Figure 3)

2

[ddt, J_3¢(Z),2¢¢= 17.2, J_{3¢¢(Z),3¢¢(E)}= 1.5, J_{3¢¢(Z),1¢¢}= 1.5 Hz, 3¢¢-H(Z)],

5.91 (ddt, J_{2¢¢,3¢¢(Z)}= 17.2, J_{2¢¢,3¢¢(E)}= 10.4, J_2¢¢,1¢¢= 5.8 Hz, 2¢¢-H); d

(keto-enol_TMSE-18 and keto_TMSE-enol-18) = 0.05 [s, 2¢-Si(CH₃)₃(ke-

to-enol_TMSE-18)], 2.17 [m_C, 4¢-CH₂, 9¢-CH₂(keto-enol_TMSE-18 and

keto_TMSE-enol-18)], 4.94 [s, 2-H (keto-enol_TMSE-18)], 5.01 [s, 11-H

O

4

6

2

8

O

3

1

20

10

1'

11

9

5

7

O

2

(keto_TMSE-enol-18)], 5.24 [ddt, J_{3¢¢(E),2¢¢}= 10.5, J_{3¢¢(E),3¢¢(Z)}= 1.3,

J

_{3¢¢(Z),1¢¢}= 1.3 Hz, 3¢¢-H(E) (keto_TMSE-enol-18)], 5.33 [ddt,

2

O

_{3¢¢(Z),2¢¢}= 17.2 Hz, J_{3¢¢(Z),3¢¢(E)}= 1.5, J_{3¢¢(Z),1¢¢}= 1.5 Hz, 3¢¢-H(Z)

6

4

2

8

(keto_TMSE-enol-18)], 12.12 [s, 3-OH (keto-enol_TMSE-18)], 5.98 [ddt,

J_{2¢¢,3¢¢(Z)}= 17.2, J_{2¢¢,3¢¢(E)}= 10.4, J_2¢¢,1¢¢= 5.8 Hz, 2¢¢-H (enol-18)],

12.00 [s, 10-OH (keto_TMSE-enol-18)], 12.12 [s, 3-OH (keto-

enol_TMSE-18)] (unlisted signals of the minor tautomers keto-

enol_TMSE-18 and keto_TMSE-enol-18 are overlapped by signals of the

major tautomer diketo-18).

1

enol-20

10

1'

11

3

5

9

7

OH

O

Figure 3

A 0.19 M soln of TBAF·3H₂O in THF (0.21 mL, 39 mmol, 0.75

equiv) was added dropwise to bis(b-keto ester) 16 (23 mg, 52 mmol)

in THF (1.0 mL) at 0 °C. The resulting mixture was stirred at 50 °C

for 2 h. After warming to r.t., the mixture was filtered (Macherey-

Nagel silica gel 60). Evaporation of the solvent furnished 20, which

exists as a mixture with the minor tautomer enol-20 (20/enol-20,

92:8) (Figure 3).

¹³C NMR (101 MHz, CDCl₃): d = –1.5 [Si(CH₃)₃(diketo-18)], 17.4

[C-2¢ (diketo-18)], 23.3 [C-5, C-8 (diketo-18)], 28.8 [C-6, C-7

(diketo-18)], 35.0 [C-4 (keto-enol_TMSE-18)], 35.1 [C-9 (keto_TMSE

-

enol-18)], 42.96 [C-4 (diketo-18)], 42.98 [C-9 (diketo-18)], 49.3

[C-11 (diketo-18)], 49.5 [C-2 (diketo-18)], 62.3 [C-1¢ (keto-

enol_TMSE-18)], 63.8 [C-1¢ (diketo-18)], 64.7 [C-1¢¢ (keto_TMSE-enol-

18)], 66.0 [C-1¢¢ (diketo-18)], 89.0 [C-11 (keto_TMSE-enol-18)], 89.3

[C-2 (keto-enol_TMSE-18)], 118.3 [C-3¢¢ (keto_TMSE-enol-18)], 119.0

[C-3¢¢ (diketo-18)], 131.7 [C-2¢¢ (diketo-18)], 167.0 [C-12 (diketo-

18)], 167.5 [C-1 (diketo-18)], 202.6 [C-10 (diketo-918)], 202.9 [C-

3 (diketo-18)].

Off-white solid; yield: 11.8 mg (100%); mp 47–48 °C.

IR (film): 2930, 2855, 1750, 1715, 1655, 1440, 1410, 1360, 1320,

1255, 1170, 1105, 1000, 915, 745, 655 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 1.21–1.28 [m, 6-H₂, 7-H₂(20 and

enol-20)], 1.49–1.59 [m, 5-H₂, 8-H₂(20 and enol-20)], 2.09 [s, 11-

H₃(20 and enol-20)], 2.15 [t, J_4,5= 7.8 Hz, 4-H₂(enol-20)], 2.37 [t,

J_4,5= 7.4 Hz, 4-H₂(20)], 2.49 [t, J_9,8= 7.5 Hz, 9-H₂(20 and enol-

20)], 3.40 [s, 2-H₂(20)], 3.69 [s, 1¢¢-H₃(enol-20)], 3.70 [s, 1¢-H₃

(20)], 4.94 [s, 2-H₂(enol-20)], 11.97 [s, 3-OH (enol-20)].

¹³C NMR (101 MHz, CDCl₃): d = 23.3 and 23.6 [C-5, C-8 (20)],

28.8 [C-6 (20)], 28.9 [C-7 (20)], 30.0 [C-11 (20)], 35.0 [C-4 (enol-

20)], 43.0 [C-9 (20)], 43.7 [C-4 (20)], 49.1 [C-2 (20)], 51.2 [C-1¢

(enol-20)], 52.4 [C-1¢ (20)], 88.9 [C-2 (enol-20)], 167.7 [C-3 (20)],

202.7 [C-10 (20)], 209.1 [C-3 (20)].

Anal. Calcd for C₂₀H₃₄O₆Si (398.6): C, 60.27; H, 8.60. Found: C,

60.20; H, 8.50.

Benzyl 2-(Trimethylsilyl)ethyl 3,10-Dioxododecanedioate (19)

Ester 19 was prepared similarly to 16 as described above, starting

from bis(b-hydroxy ester) 33 (95 mg, 0.21 mmol) in CH₂Cl₂(2 mL)

and DMP (207 mg, 0.48 mmol, 2.3 equiv) in CH₂Cl₂(2 mL); puri-

fication of the residue by flash chromatography (silica gel, column

diameter 2.0 cm, cyclohexane–EtOAc, 9:1) furnished 19, which ex-

ists as a mixture with enol tautomers: diketo-19/keto-enol_TMSE-19/

keto_TMSE-enol-19, 83:8:9.

Anal. Calcd for C₁₂H₂₀O₄(228.3): C, 63.14; H, 8.83. Found: C,

63.00; H, 8.45.

Colorless oil; yield: 52 mg (55%).

IR (film): 2950, 2860, 1745, 1715, 1640, 1500, 1455, 1410, 1375,

1310, 1250, 1170, 1065, 975, 915, 860, 840, 745, 700, 655 cm^–1.

tert-Butyl 3,10-Dioxoundecanoate (21)

Ester 21 was prepared similarly to 20 as described above, starting

from bis(b-keto ester) 17 (20 mg, 48 mmol) and 0.17 M TBAF·3H₂O

in THF (0.21 mL, 36 mmol, 0.75 equiv) in THF (1.8 mL). Filtration

(Macherey-Nagel silica gel 60) furnished 21, which exists as a mix-

ture with the minor tautomer enol-21 (21/enol-21, 95:5).

H NMR (400 MHz, CDCl₃): d (19) = 0.04 [s, 2¢-Si(CH₃)₃], 1.01

(m_c, 2¢-CH₂), 1.24–1.28 (m, 6-CH₂, 7-CH₂), 1.53–1.61 (m, 5-CH₂,

8-CH₂), 2.51 (m_c, 4-CH₂, 9-CH₂), 3.40 (s, 2-H₂), 3.47 (s, 11-H₂),

4.22 (m_c, 1¢-H₂), 5.17 (s, 1¢¢-H₂), 7.36 (s, 3¢¢-H, 4¢¢-H, 5¢¢-H, 6¢¢-H,

7¢¢-H); d (keto-enol_TMSE-19 and keto_TMSE-enol-19) = 0.05 [s, 2¢-

Si(CH₃)₃(keto-enol_TMSE-19)], 2.17 [m_C, 4¢-CH₂, 9¢-CH₂(keto-

Colorless oil; yield: 13.0 mg (100%).

enol_TMSE-19 and keto-enol_TMSE-19)], 4.94 [s, 11-H (keto-enol_TMSE

-

IR (film): 2930, 2855, 1715, 1640, 1460, 1410, 1370, 1320, 1255,

1155, 1115, 955, 915, 840, 745, 655 cm^–1.

19)], 5.03 [s, 2-H (keto_TMSE-enol-19)], 12.00 [s, 10-OH (keto_TMSE

enol-19)], 12.13 [s, 3-OH (keto-enol_TMSE-19)] (unlisted signals of

the minor tautomers keto-enol_TMSE-19 and keto_TMSE-enol-19 are

overlapped by signals of the major tautomer diketo-19).

¹³C NMR (101 MHz, CDCl₃): d = –1.5 [Si(CH₃)₃(19)], 17.4 [C-

2¢(19)], 23.2 [C-5 (19)], 26.1 [C-8 (19)], 28.8 [C-6 (19)], 29.8 [C-7

(19)], 42.96 and 43.00 [C-4, C-9 (19)], 49.3 [C-11 (19)], 49.5 [C-2

(19)], 63.8 [C-1¢ (19)], 67.2 [C-1¢¢ (19)], 128.5 [C-3¢¢, C-4¢¢ (19)],

128.6 [C-7¢¢ (19)], 128.7 [C-5¢¢, C-6¢¢ (19)], 135.4 [C-2¢¢ (19)], 167.1

[C-12 (19)], 167.5 [C-1 (19)], 202.6 [C-10 (19)], 202.9 [C-3 (19)].

¹H NMR (400 MHz, CDCl₃): d = 1.25–1.31 [m, 6-H₂, 7-H₂(21 and

enol-21)], 1.47 [s, 1¢-(CH₃)₃(21)],1.48 [s, 1¢-(CH₃)₃(enol-21)],

1.55–1.62 [m, 5-H₂, 8-H₂(21 and enol-21)], 2.13 [s, 11-H₃(21 and

enol-21)], superimposed by 2.14 [t, J_4,5= 7.6 Hz, 4-H₂(enol-21)],

2.41 [t, J_4,5= 7.3 Hz, 4-H₂(21)], 2.51 [t, J_9,8= 7.3 Hz, 9-H₂(21 and

enol-21)], 3.33 [s, 2-H₂(21)], 4.87 [s, 2-H₂(enol-21)], 11.97 [s, 3-

OH (enol-21)].

¹³C NMR (101 MHz, CDCl₃): d = 23.3 and 23.7 [C-5, C-8 (21)],

28.1 [1¢-(CH₃)₃(21)], 28.9 and 29.0 [C-6, C-7 (21)], 30.0 [C-11

(21)], 42.9 [C-9 (21)], 43.7 [C-4 (21)], 50.8 [C-2 (21)], 82.0 [C-1¢

(21)], 166.6 [C-3 (21)], 203.4 [C-10 (21)], 209.1 [C-3 (21)].

Anal. Calcd for C₂₄H₃₆O₆Si (466.3): C, 64.25; H, 8.09. Found: C,

64.37; H, 8.14.

Anal. Calcd for C₁₅H₂₆O₄(270.4): C, 66.64; H, 9.69. Found: C,

66.80; H, 9.72.

2242

E. Knobloch, R. Brückner

PAPER

Allyl 3,10-Dioxoundecanoate (22)

mixture was stirred at 85 °C for 5 h. H₂O (3 mL) and MTBE (3 mL)

were added. Extraction with MTBE (3 × 3 mL), drying (MgSO₄),

evaporation of the solvent under reduced pressure, and flash chro-

matography (silica gel, column diameter 1.0 cm, cyclohexane–

EtOAc, 4:1) furnished 24.

Ester 22 was prepared similarly to 20 as described above, starting

from bis(b-keto ester) 18 (21 mg, 53 mmol) and 0.17 M TBAF·3H₂O

in THF (0.22 mL, 39 mmol, 0.75 equiv) in THF (1.8 mL). Filtration

(Macherey-Nagel silica gel 60) furnished 22, which exists as a mix-

ture with the minor tautomer enol-22 (22/enol-22, 92:8).

Colorless oil; yield: 3.5 mg (25%).

Colorless oil; yield: 13.3 mg (99%).

From bis(b-keto ester) 17: Bis(b-keto ester) 17 (15 mg, 36 mmol) in

MeCN (0.7 mL) was added dropwise to a suspension of activated

montmorillonite KSF (19 mg) in MeCN (0.8 mL). The resulting

mixture was stirred under reflux for 3.25 h. At r.t., Et₃N (0.05 mL,

0.05 g, 0.7 mmol, 20 equiv) was added dropwise and the mixture

was stirred for another 1.5 h. Filtration of the mixture and evapora-

tion of the solvent under reduced pressure furnished 24.

IR (film): 2930, 2855, 1745, 1720, 1650, 1460, 410, 1365, 1310,

1225, 1170, 1100, 990, 910, 740, 650 cm^–1.

¹H NMR (400.1 MHz, CDCl₃): d = 1.25–1.31 [m, 6-H₂, 7-H₂(22

and enol-22)], 1.68 [m_C, 5-H₂, 8-H₂(22 and enol-22)], 2.12 (s, 11-

H₃(22 and enol-22)], 2.18 [t, J_4,5= 7.7 Hz, 4-H₂(enol-22)], 2.41 [t,

J_9,8= 7.4 Hz, 9-H₂(22 and enol-22)], 2.53 [t, J_4,5= 7.5 Hz, 4-H₂

(22)], 3.46 [s, 2-H₂(22)], 4.63 [ddd,

J

_1¢,2¢= 5.8,

Colorless oil; yield: 10 mg (88%).

⁴J_1¢,3¢(E)= J_1¢,3¢(Z)= 1.4 Hz, 1¢-H₂(22 and enol-22)], 5.06 [s, 2-H

(enol-22)] 5.24 [ddt, J_3¢(E),2¢= 10.5, ²J_{3¢(E),3¢(Z)}= 1.3, J_3¢(Z),1¢= 1.3 Hz,

3¢-H(E) (enol-22)], superimposed by 5.25 [ddt, J_3¢(E),2¢= 10.5,

From bis(b-keto ester) 18: A 0.5 M soln of Et₃NH⁺HCO₂^–in THF

(0.19 mL, 75 mmol, 2.0 equiv) was added to 0.015 M Pd(OAc)₂in

THF (60 mL, 0.9 mmol, 2.5 mol%) and 0.03 M Ph₃P in THF (60 mL,

1.9 mmol, 5.0 mol%) in THF (0.8 mL) at r.t. Bis(b-keto ester) 18 (15

mg, 38 mmol) in THF (1 mL) was added dropwise and the resulting

mixture was stirred for 25 h. Evaporation of the solvent under re-

duced pressure, followed by flash chromatography (silica gel, col-

umn diameter 2.0 cm, cyclohexane–EtOAc, 7:1) furnished 24.

²J_{3¢(E),3¢(Z)}= 1.3,

J_3¢(E),1¢= 1.3 Hz, 3¢-H(E) (22)], 5.30 [ddt,

2

J

_3¢(Z),2¢= 17.2, J_{3¢(Z),3¢(E)}= 1.5, J_3¢(Z),1¢= 1.5 Hz, 3¢-H(Z) (enol-22)],

2

superimposed by 5.33 [ddt,

J_3¢(Z),2¢= 17.2, J_{3¢(Z),3¢(E)}= 1.5,

J

_3¢(Z),1¢= 1.5 Hz, 3¢-H(Z) (22)], 5.92 [ddt, J_2¢,3¢(Z)= 17.2,

J_2¢,3¢(E)= 10.4, J_2¢,1¢= 5.8 Hz, 2¢-H (22)], superimposed by 5.98 [ddt,

J_2¢,3¢(Z)= 17.2, J_2¢,3¢(E)= 10.4, J_2¢,1¢= 5.8 Hz, 2¢-H (enol-22)], 11.99

[s, 3-OH (enol-22)].

Colorless oil; yield: 11 mg (93%).

¹³C NMR (100.6 MHz, CDCl₃): d = 23.3 and 23.6 [C-5, C-8 (22 and

enol-22)], 28.8and 28.9 [C-6, C-7 (22 and enol-22)], 30.0 [C-11 (22

and enol-22)], 36.0 [C-4 (enol-22)], 43.0 [C-4 (22)], 43.7 [C-9 (22

and enol-22)], 49.2 [C-2 (22)], 64.1 [C-1¢(enol-22)], 66.01 [C-1¢

(22)], 88.9 [C-2 (enol-22)], 118.3 [C-3¢ (enol-22)], 119.0 [C-3¢

(22)], 131.7 [C-2¢ (22)], 167.0 [C-1 (22)], 202.6 [C-3 (22)], 209.1

[C-10 (22 and enol-22)].

From bis(b-keto ester) 19: Pd/C (5%, 1.0 mg, 10 mol% Pd) was

added to bis(b-keto ester) 19 (19.4 mg, 43 mmol) and Et₃N (0.02

mL, 0.01 g, 0.1 mmol, 2 equiv) in EtOAc (0.4 mL). The resulting

mixture was stirred under a H₂atmosphere (1 bar) for 31 h. The

mixture was filtered (silica gel). Evaporation of the solvent under

reduced pressure, followed by flash chromatography (silica gel, col-

umn diameter 1.0 cm, cyclohexane–EtOAc, 4:1) furnished 24.

Colorless oil; yield: 9.0 mg (67%).

Anal. Calcd for C₁₄H₂₂O₄(254.3): C, 66.12; H, 8.72. Found: C,

66.04; H, 8.85.

Ester 24 exists as a mixture with the minor tautomer enol-24 (24/

enol-24, 92:8).

Benzyl 3,10-Dioxoundecanoate (23)

IR (film): 2935, 2860, 1740, 1715, 1640, 1460, 1410, 1365, 1310,

1250, 1170, 1065, 915, 860, 840, 745, 700, 655 cm^–1.

Ester 23 was prepared similarly to 20 as described above, starting

from bis(b-keto ester) 19 (29 mg, 64 mmol) and 0.10 M TBAF·3H₂O

in THF (0.48 mL, 48 mmol, 0.75 equiv) in THF (1.8 mL). Filtration

over silica gel furnished 23, which exists as a mixture with the mi-

nor tautomer enol-23 (23/enol-23, 91:9).

¹H NMR (400 MHz, CDCl₃): d = 0.04 [s, Si(CH₃)₃(24)], 0.05 [s,

Si(CH₃)₃(enol-24)], 1.0 (m_c, 1¢-H₂(24 and enol-24)], 1.27–1.31 [m,

6-H₂, 7-H₂(24 and enol-24)], 1.57 [m_c, 6-H₂, 7-H₂(24 and enol-

24)], 2.12 [s, 11-H₃(24 and enol-24)], 2.18 [t, J_4,5= 7.7 Hz, 4-H₂

(enol-24)], 2.41 [t, J_9,8= 7.5 Hz, 9-H₂(24 and enol-24)], 2.53 [t,

J_4,5= 7.3 Hz, 4-H₂(24)], 3.40 [s, 2-H₂(24)], 4.22 [m_c, 1¢-H₂(24 and

enol-24)], 4.94 [s, 2-H₂(enol-24)], 12.13 [s, 3-OH (enol-24)].

Off-white solid; yield: 16 mg (81%); mp 34–35 °C.

IR (film): 2930, 2855, 1745, 1715, 1455, 1410, 1375, 1260, 1170,

1105, 1000, 910, 740, 650 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 1.24–1.27 [m, 6-H₂, 7-H₂(23 and

enol-23)], 1.57 [m_c, 6-H₂, 7-H₂(23 and enol-23)], 2.12 [s, 11-H₃(23

and enol-23)], 2.18 [t, J_4,5= 7.6 Hz, 4-H₂(enol-23)], 2.40 [t,

¹³C NMR (101 MHz, CDCl₃): d = –1.5 [Si(CH₃)₃(24)], –1.4

[Si(CH₃)₃(enol-24)], 17.4 [C-2¢ (24)], 23.3 and 23.7 [C-5, C-8

(24)], 28.8 and 29.0 [C-6, C-7 (24)], 30.0 [C-11 (24)], 35.0 [C-4

(enol-24)], 43.0 [C-4 (24)], 43.7 [C-9 (24)], 49.6 [C-2 (24)], 63.8

[C-1¢ (24)], 89.3 [C-2 (enol-24)], 167.5 [C-1 (24)], 202.9 [C-3 (24)],

209.1 [C-1¢ (24 and enol-24)].

J

_9,8= 7.4 Hz, 9-H₂(23 and enol-23)], 2.50 [t, J_4,5= 7.3 Hz, 4-H₂

(23)], 3.47 [s, 2-H₂(23)], 5.03 [s, 2-H₂(enol-23)], 5.17 [s, 1¢-H₂

(enol-23)], 7.31–7.39 [m, Ar²-H, Ar²-H, Ar³-H, Ar⁴-H, Ar⁵-H, Ar⁶-

H (23 and enol-23)], 12.00 [s, 3-OH (enol-23)].

¹³C NMR (101 MHz, CDCl₃): d = 23.3 and 23.6 [C-5, C-8 (23)],

28.8 and 28.9 [C-6, C-7 (23)], 30.0 [C-11 (23)], 43.0 [C-4 (23)],

43.7 [C-9 (23)], 49.3 [C-2 (23)], 67.2 [C-1¢ (23)], 89.0 [C-2 (enol-

23)], 128.5 [C-Ar², C-Ar⁶(23)], 128.6 [C-Ar⁴(23)], 128.7 [C-Ar³,

C-Ar⁵(23)], 135.4 [C-Ar¹(23)], 167.2 [C-1 (23)], 202.6 [C-3 (23)],

209.1 [C-10 (23 and enol-23)].

Anal. Calcd for C₁₆H₃₀O₄Si: (314.5): C, 61.11; H, 9.61. Found: C,

61.20; H, 9.59.

8,8-Dimethoxyoctanal (26)²⁰

O₃was bubbled through a soln of cyclooctene (3.9 mL, 3.3 g, 30

mmol) in CH₂Cl₂–MeOH (70 mL/30 mL) at –78 °C until it turned

pale blue (ca. 20 min). N₂was bubbled into the soln to remove the

excess O₃(ca. 30 min). PTSA (571 mg, 3.00 mmol, 1.0 equiv) was

added and the reaction mixture was warmed to r.t. over 2 h and

stirred at r.t. for another 2 h. Na₂CO₃(833 g, 7.80 mmol, 0.26 equiv)

was added, and after 30 min Me₂S (4.8 mL, 4.1 g, 66 mmol, 2.2

equiv) was added. After stirring of the mixture for another 18 h,

H₂O (100 mL) and MTBE (100 mL) were added. Extraction with

MTBE (2 × 100 mL), washing of the combined organic layers with

brine (2 × 100 mL), drying of the combined extracts (MgSO₄),

Anal. Calcd for C₁₈H₂₄O₄(304.4): C, 71.03; H, 7.95. Found: C,

70.85; H, 7.94.

2-(Trimethylsilyl)ethyl 3,10-Dioxoundecanoate (24)

From bis(b-keto ester) 16: Cs₂CO₃(9 mg, 23 mmol, 0.5 equiv) and

0.4 M PhSH in DMF (0.17 mL, 68 mmol, 1.5 equiv) were added to

bis(b-keto ester) 16 (20 mg, 45 mmol) in DMF (1 mL). The resulting

PAPER

b-Keto Esters Derived from 2-(Trimethylsilyl)ethanol

2243

evaporation of the solvent under reduced pressure, and distillation

(72 °C/0.1 mbar) afforded impure 26.

Anal. Calcd for C₁₇H₃₆O₅Si (366.3): C, 58.58; H, 10.41. Found: C,

58.65; H, 10.53.

Colorless oil; yield: 4.842 g (£86%).

2-(Trimethylsilyl)ethyl 3-Hydroxy-10-oxodecanoate (29)

Montmorillonite K10 (760 mg) was added to a soln of dimethyl

acetal 28 (1.460 g, 4.189 mmol) in acetone (50 mL) and H₂O (1.2

mL, 1.2 g, 66 mmol, 18 equiv). The mixture was heated for 50 min

to reflux. After cooling to r.t., the mixture was filtered over Celite.

Evaporation of the solvent under reduced pressure, followed by

flash chromatography (silica gel, column diameter 3.5 cm, cyclo-

hexane–EtOAc, 9:1) furnished 29. This compound was processed

further without delay.

IR (film): 2940, 2860, 2720, 1725, 1465, 1410, 1385, 1365, 1190,

1130, 1055, 950, 725 cm^–1.

¹H NMR (300 MHz, CDCl₃, contaminated): d = 1.27 (m_c, 4-H₂, 5-

H₂, 6-H₂), 1.49–1.59 (m, 2-H₂, 7-H₂), 2.35 (td, J_2,3= 7.3, J_2,1= 1.9

Hz, 2-H₂), 3.24 [s, 8-(OCH₃)₂], 4.28 (t, J_8,7= 5.7 Hz, 8-H), 9.69 (t,

J_1,2= 1.8 Hz, 1-H).

¹³C NMR (101 MHz, CDCl₃): d = 22.1 (C-3), 24.5 (C-6), 29.2 and

29.3 (C-5, C-4), 32.5 (C-7), 44.0 (C-2), 52.8 [8-(OCH₃)₂], 104.2 (C-

8), 202.9 (C-1).

Colorless oil; yield: 1.098 g (87%).

IR (film): 3460, 2935, 2860, 2720, 1730, 1455, 1415, 1350, 1250,

1170, 1105, 1040, 975, 935, 860, 840, 765, 725, 695, 665, 610 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.04 [s, 2¢-Si(CH₃)₃], 0.99 (m_c, 2¢-

CH₂), 1.25–1.65 (m, 4-CH₂, 5-CH₂, 6-CH₂, 7-CH₂, 8-CH₂), AB sig-

nal (d_A= 2.33, d_B= 2.43, J_AB= 16.4 Hz, additionally split by

J_A,3= 8.8, J_B,3= 3.2 Hz, 2-H₂), superimposed by by 2.37 (tt,

2-(Trimethylsilyl)ethyl Acetate (27)²⁷

2-(Trimethylsilyl)ethanol (13; 3.6 mL, 3.0 g, 25 mmol) was added

dropwise to a soln of Mg(ClO₄) (56 mg, 1 mol%) in Ac₂O (2.5 mL,

2.7 g, 26 mmol, 1.05 equiv). The mixture was stirred at r.t. for 4 h.

Sat. aq NaHCO₃(12 mL) and MTBE (9 mL) were added. Extraction

with MTBE (3 × 9 mL), washing of the combined organic layers

with sat. aq NaHCO₃(2 × 6 mL), drying of the combined extracts

(MgSO₄), and evaporation of the solvent under reduced pressure

furnished 27.

J_9,8= 7.2, J_9,10= 2.0 Hz, 9-H₂), 2.92 (s, 3-OH), 3.93 (m_c, 3-H), 4.16

(m_c, 1¢-CH₂), 9.71 (t, J_10,9= 1.9 Hz, 10-H),.

¹³C NMR (101 MHz, CDCl₃): d = –1.4 [Si(CH₃)₃], 17.4 (C-2¢), 22.1

(C-8), 25.4 (C-5), 29.2 and 29.3 (C-6, C-7), 36.5 (C-4), 41.5 (C-2),

43.9 (C-9), 63.1 (C-1¢), 68.0 (C-3), 173.4 (C-1), 202.9 (C-10).

Colorless oil; yield: 3.77 g (94%)].

¹H NMR (300 MHz, CDCl₃): d = 0.04 [s, Si(CH₃)₃], 0.98 (m_c, 2¢-

H₂), 2.03 (s, 2-H₃), 4.15 (m_c, 1¢-H₂).

Methyl 2-(Trimethylsilyl)ethyl 3,10-Dihydroxydodecanedioate

(30)

2-(Trimethylsilyl)ethyl 3-Hydroxy-10,10-dimethoxydecanoate

(28) (Figure 4)

A 2.3 M soln of n-BuLi in n-hexane (1.30 mL, 3.07 mmol, 2.3

equiv) was added dropwise to i-Pr₂NH (0.45 mL, 3.2 mmol, 2.4

equiv) in THF (7 mL) at –78 °C. The mixture was stirred for 1 h.

MeOAc (213 mg, 2.8 mmol, 2.2 equiv) in THF (3 mL) was added

dropwise over 10 min and the mixture was stirred for another 1 h.

Aldehyde 29 (403 mg, 1.33 mmol) in THF (3 mL) was added drop-

wise, and after stirring of the mixture for 50 min, the reaction was

stopped by the addition of sat. aq NH₄Cl (6 mL). Extraction with

MTBE (3 × 10 mL), washing of the combined organic layers with

brine (2 × 10 mL), drying (MgSO₄), evaporation of the solvent un-

der reduced pressure, and flash chromatography (silica gel, column

diameter 3.5 cm, cyclohexane–EtOAc, 2:1) furnished 30.

O

OH

1'

TMS

O

10

3

1

28

O

2'

O

Figure 4

A 2.3 M soln of n-BuLi in n-hexane (0.64 mL, 15 mmol, 1.1 equiv)

was added dropwise to i-Pr₂NH (0.22 mL, 0.16 g, 15 mmol, 1.15

equiv) in THF (3 mL) at –78 °C. The mixture was stirred for 1 h.

TMSE acetate 27 (326 mg, 13.5 mmol, 1.0 equiv) in THF (2 mL)

was added dropwise over 10 min and the mixture was stirred for an-

other 1 h. 8,8-Dimethoxyoctanal (26; 260 mg, 13.5 mmol) in THF

(2 mL) was added dropwise. After stirring of the mixture for 30 min,

the reaction was stopped by the addition of 0.2 M aq HCl (4 mL)

and MTBE (6 mL). Extraction with MTBE (3 × 6 mL), washing of

the combined organic layers with brine (2 × 6 mL), drying

(MgSO₄), evaporation of the solvent under reduced pressure, and

flash chromatography (silica gel, column diameter 3.5 cm, cyclo-

hexane–EtOAc, 4:1) furnished 28.

White solid: 272 mg (48%); mp 34 °C.

IR (film): 3450, 2930, 2860, 1730, 1440, 1415, 1250, 1175, 1045,

980, 915, 860, 840, 745, 700, 640 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 0.04 [s, Si(CH₃)₃], 1.00 (m_c, 2¢-

H₂), 1.32–1.62 (m, 4-H₂, 5-H₂, 6-H₂, 7-H₂, 8-H₂, 9-H₂), AB signal

(d_A= 2.36, d_B= 2.50, J_AB= 16.4 Hz, additionally split by J_A,3= 9.0

and J_B,3= 3.2 Hz, 2-H₂), superimposed by by AB signal (d_A= 2.40,

d_B= 2.55, J_AB= 16.4 Hz, additionally split by J_A,10= 9.0 and

J_B,10= 3.2 Hz, 11-H₂), 2.85 (d, J_3-OH,3= 4.0 Hz, 3-OH), 2.96 (d, J_10-

_OH,10= 3.9 Hz, 10-OH), 3.71 (s, 1¢¢-H₃), 3.99 (m_c, 3-H, 10-H), 4.20

(m_c, 1¢-H₂).

¹³C NMR (101 MHz, CDCl₃): d = –1.4 [Si(CH₃)₃], 17.4 (C-2¢), 25.5

(C-5, C-8), 29.5 (C-6, C-7), 36.5 and 36.6 (C-4, C-9), 41.2 (C-11)

41.5 (C-2), 51.8(C-1¢¢), 63.04 (C-1¢), 68.06 and 68.07 (C-3, C-10),

173.4 (C-1), 173.6 (C-12).

Colorless oil; yield: 297 mg (54%, over 2 steps from cyclooctene).

IR (film): 3450, 2935, 2860, 2830, 2345, 1732, 1460, 1385, 1360,

1150, 1170, 1130, 1060, 945, 860, 740, 760, 695, 665 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 0.04 [s, 2¢-Si(CH₃)₃], 0.99 (m_c, 2¢-

CH₂), 1.31–1.61 (m, 4-CH₂, 5-CH₂, 6-CH₂, 7-CH₂, 8-CH₂, 9-CH₂),

AB signal (d_A= 2.37, d_B= 2.47, J_AB= 16.4 Hz, additionally split

by J_A,3= 9.0, J_B,3= 3.1 Hz, 2-H₂), 2.95 (d, J_3-OH,3= 4.1 Hz, 3-OH),

3.31 [s, 10-(OCH₃)₂], 4.0 (m_c, 3-H), 4.20 (m_c, 1¢-CH₂), 4.35 (t,

J_10,9= 5.7 Hz, 10-H).

¹³C NMR (101 MHz, CDCl₃): d = –1.4 [Si(CH₃)₃], 17.4 (C-2¢), 24.6

and 25.5 (C-5, C-8), 29.47 and 29.52 (C-6, C-7), 32.6 (C-9), 36.6

(C-4), 41.5 (C-2), 52.7 [(10-(OCH₃)₂], 63.1 (C-1¢), 68.1 (C-3),

104.7 (C-10), 173.4 (C-1).

Anal. Calcd for C₁₈H₃₆O₆Si (394.3): C, 63.68; H, 8.96. Found: C,

63.78; H, 8.91.

tert-Butyl 2-(Trimethylsilyl)ethyl 3,10-Dihydroxydodecanedio-

ate (31)

Ester 31 was prepared analogously to 30 as described above, start-

ing from i-Pr₂NH (0.15 mL, 1.1 mmol, 2.3 equiv) in THF (1.5 mL),

2.3 M n-BuLi in n-hexane (0.43 mL, 1.0 mmol, 2.2 equiv), t-

BuOAc (117 mg, 1.0 mmol, 2.2 equiv) in THF (1 mL), and alde-

hyde 29 (139 mg, 0.46 mmol) in THF (1 mL), except that the mix-

2244

E. Knobloch, R. Brückner

PAPER

ture was stirred for 30 min after addition of aldehyde 29;

purification of the residue by flash chromatography (silica gel, col-

umn diameter 2.0 cm, cyclohexane–EtOAc, 3:1) furnished 31.

¹H NMR (400 MHz, CDCl₃): d = 0.04 [s, Si(CH₃)₃], 1.00 (m_c, 2¢-

H₂), 1.25–1.58 (m, 4-H₂, 5-H₂, 6-H₂, 7-H₂, 8-H₂, 9-H₂), AB signal

(d_A= 2.36, d_B= 2.47 J_AB= 16.4 Hz, additionally split by J_A,3= 9.0

and J_B,3= 3.2 Hz, 2-H₂), B-moiety overlapped by AB signal

(d_A= 2.46, d_B= 2.55, J_AB= 16.4 Hz, additionally split by J_A,10= 9.0

and J_B,10= 3.2 Hz, 11-H₂), 2.83 (d, J_3-OH,3= 4.0 Hz, 3-OH), 2.95 (d,

J_10-OH,10= 3.9 Hz, 10-OH), 4.00 (m_c, 3-H, 10-H), 4.20 (m_c, 1¢-H₂),

5.15 (s, 1¢¢-H₂), 7.35 (m_c, 2¢¢-H, 3¢¢-H, 4¢¢-H, 5¢¢-H, 6¢¢-H, 7¢¢-H).

¹³C NMR (101 MHz, CDCl₃): d = –1.4 [Si(CH₃)₃], 17.4 (C-2¢), 25.5

(C-5, C-8), 29.5 (C-6, C-7), 36.5 and 36.6 (C-4, C-9), 41.4 (C-11),

41.5 (C-2), 63.1 (C-1¢), 65.4 (C-1¢¢), 68.1 (C-3, C-10), 118.7 (C-3¢¢),

131.7 (C-2¢¢), 172.8 (C-12), 173.4 (C-1).

Pale yellow oil; yield: 85 mg (44%).

¹H NMR (300 MHz, CDCl₃): d = 0.05 [s, Si(CH₃)₃], 1.00 (m_c, 2¢-

H₂), 1.29–1.58 (m, 4-H₂, 5-H₂, 6-H₂, 7-H₂, 8-H₂, 9-H₂), superim-

posed by 1.46 [s, 1¢¢-CH₃)₃], AB signal (d_A= 2.30, d_B= 2.41

J_AB= 16.4 Hz, additionally split by J_A,10= 8.8 and J_B,10= 3.1 Hz,

10-H₂), superimposed by by AB signal (d_A= 2.36, d_B= 2.47

J

_AB= 17.5 Hz, additionally split by J_A,3= 8.8 and J_B,3= 3.2 Hz, 2-

H₂), 2.94 (d, J_3-OH,3= 3.8 Hz, 3-OH), 3.05 (d, J_10-OH,10= 3.8 Hz, 10-

OH), 3.96 (m_c, 3-H, 10-H), 4.20 (m_c, 1¢-H₂).

¹³C NMR (101 MHz, CDCl₃): d = –1.4 [Si(CH₃)₃], 17.4 (C-2¢), 25.5

(C-5, C-8), 28.2 [1¢-(CH₃)₃], 29.52 and 29.54 (C-6, C-7), 36.5 and

36.6 (C-4, C-9), 41.5 (C-2), 42.4 (C-11), 63.0 (C-1¢), 68.1 (C-3),

68.2 (C-10), 81.8 (C-1¢¢), 172.7 (C-12), 173.4 (C-1).

Anal. Calcd for C₂₄H₄₀O₆Si (470.3): C, 57.41; H, 9.64. Found: C,

59.69; H, 9.35.

Competition Experiments Listed in Tables 1–4; General Proce-

dure

Anal. Calcd for C₂₁H₄₂O₆Si (418.6): C, 60.25; H, 10.11. Found: C,

60.16; H, 10.14.

TBAF·3H₂O (47 mg, 0.15 mmol, 0.75 equiv) in THF (0.5 mL) was

added dropwise to a mixture of one of the TMSE b-keto esters 4a–

c (0.20 mmol) and another b-keto ester 7–10a–c (0.20 mmol) in

THF (1.5 mL) at 0 °C. The resulting mixture was stirred at 50 °C

until conversion was completed as judged by TLC. Brine (1.5 mL),

H₂O (3 mL), and MTBE (3 mL) were added. Extraction with MTBE

(3 × 3 mL), drying of the combined extracts (Na₂SO₄), evaporation

of the solvent under reduced pressure, and flash chromatography

(silica gel, cyclohexane–EtOAc) furnished a mixture of unchanged

b-keto ester(s) and newly formed ketone product(s) devoid of any

byproducts. The yield of each component was determined as de-

scribed in ref.⁴and shown in Table 9, which also lists the pertinent

characteristic ¹H NMR shifts.

Allyl 2-(Trimethylsilyl)ethyl 3,10-Dihydroxydodecanedioate

(32)

Ester 32 was prepared analogously to 30 as described above, start-

ing from i-Pr₂NH (0.15 mL, 1.1 mmol, 2.3 equiv) in THF (1.5 mL),

2.3 M n-BuLi in n-hexane (0.43 mL, 1.0 mmol, 2.2 equiv), AllOAc

(92 mg, 1.0 mmol, 2.2 equiv) in THF (1.5 mL) and aldehyde 29 (139

mg, 0.46 mmol) in THF (1 mL), except that the mixture was stirred

for 30 min after addition of aldehyde 29; purification of the residue

by flash chromatography (silica gel, column diameter 2.0 cm, cy-

clohexane–EtOAc, 2:1) furnished 32.

Pale yellow oil; yield: 83 mg (45%).

Competition Experiments Listed in Table 5; General Procedure

Cs₂CO₃(33 mg, 0.10 mmol, 0.5 equiv) and PhSH (0.03 mL, 0.03 g,

0.30 mmol, 1.5 equiv) were added to a mixture of one of the methyl

b-keto esters 7a–c (0.20 mmol) and the corresponding TMSE b-

keto ester 4a–c (0.20 mmol) in DMF (1.5 mL). The resulting mix-

ture was stirred at 85 °C until conversion was completed as judged

by TLC. H₂O (5 mL) and MTBE (3 mL) were added. Extraction

with MTBE (3 × 3 mL), drying of the combined extracts (Na₂SO₄),

evaporation of the solvent under reduced pressure, and flash chro-

matography (silica gel, cyclohexane–EtOAc) furnished a mixture of

unchanged b-keto ester(s) and newly formed ketone product(s) de-

void of any byproducts. The yield of each component was deter-

mined as described in ref.⁴and Table 9.

IR (film): 3450, 2930, 2860, 1730, 1415, 1385, 1250, 1175, 1045,

990, 915, 860, 840, 745, 700 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 0.04 [s, Si(CH₃)₃], 1.00 (m_c, 2¢-

H₂), 1.33–1.60 (m, 4-H₂, 5-H₂, 6-H₂, 7-H₂, 8-H₂, 9-H₂), AB signal

(d_A= 2.37, d_B= 2.47, J_AB= 16.4 additionally split by J_A,3= 9.0,

J_B,3= 3.1 Hz, 2-H₂), B-moiety overlapped by AB signal (d_A= 2.43,

d_B= 2.53, J_AB= 16.4 Hz, additionally split by J_A,10= 9.0, J_B,10= 3.2

Hz, 10-H₂), 2.84 (s, 10-OH), 2.95 (s, 3-OH), 4.00 (m_c, 3-H, 10-H),

4

4.20 (m_c, 1¢-H₂), 4.62 (ddd, J_1¢¢,2¢¢= 5.6 Hz, J_{1¢¢,3¢¢(E)}= J_{1¢¢,3¢¢(Z)}= 1.4

2

Hz, 1¢¢-H₂), 5.25 [ddt,

J

_{3¢¢(Z),2¢¢}= 10.5 Hz, J_{3¢¢(Z),3¢¢(E)}= 1.3,

J

_{3¢¢(Z),1¢¢}= 1.3 Hz, 3¢¢-H(Z)], 5.33 [ddt,

J

_{3¢¢(E),2¢¢}= 17.2 Hz,

²J_{3¢¢(E),3¢¢(Z)}= 1.5,

J_{3¢¢(E),1¢¢}= 1.5 Hz, 3¢¢-H(E)], 5.92 (ddt,

J

_{2¢¢,3¢¢(E)}= 17.2, J_{2¢¢,3¢¢(Z)}= 10.4, J_2¢¢,1¢¢= 5.8 Hz, 2¢¢-H).

Competition Experiments Listed in Table 6; General Procedure

A mixture of one of the tert-butyl b-keto esters 8a–c (0.20 mmol)

and the corresponding TMSE b-keto ester 4a–c (0.20 mmol) in

MeCN (0.5 mL) was added dropwise to a suspension of Montmoril-

lonite KSF (40 mg) in MeCN (1.5 mL). The resulting mixture was

stirred under reflux until conversion was completed as judged by

TLC. At r.t., Et₃N (0.26 mL, 4.0 mmol, 20 equiv) was added drop-

wise and the mixture was stirred for another 1 h. Filtration of the

mixture, evaporation of the solvent under reduced pressure, and

flash chromatography (silica gel, cyclohexane–EtOAc) furnished a

mixture of unchanged b-keto ester(s) and newly formed ketone

product(s) devoid of any byproducts. The yield of each component

was determined as described in ref.⁴and Table 9.

¹³C NMR (101 MHz, CDCl₃): d = –1.4 [Si(CH₃)₃], 17.4 (C-2¢), 25.5

(C-5, C-8), 29.5 (C-6, C-7), 36.5 and 36.6 (C-4, C-9), 41.4 (C-11),

41.5 (C-2), 63.1 (C-1¢), 65.4 (C-1¢¢), 68.1 (C-3, C-10), 118.7 (C-3¢¢),

131.7 (C-2¢¢), 172.8 (C-12), 173.4 (C-1).

Anal. Calcd for C₂₀H₃₈O₆Si (420.3): C, 59.67; H, 9.51. Found: C,

59.52; H, 5.54.

Benzyl 2-(Trimethylsilyl)ethyl 3,10-Dihydroxydodecanedioate

(33)

Ester 33 was prepared analogously to 30 as described above, start-

ing from i-Pr₂NH (0.09 mL, 0.06 g, 0.7 mmol, 2.3 equiv) in THF (1

mL), 2.3 M n-BuLi in n-hexane (0.28 mL, 0.67 mmol, 2.2 equiv),

BnOAc (87 mg, 0.57 mmol, 2.0 equiv) in THF (1 mL) and aldehyde

29 (84 mg, 0.28 mmol) in THF (1 mL), except that the mixture was

stirred for 30 min after addition of aldehyde 29; purification of the

residue by flash chromatography (silica gel, column diameter 2.0

cm, cyclohexane–EtOAc, 2:1) furnished 33.

Competition Experiments Listed in Table 7; General Procedure

A 2.0 M soln of Et₃NH⁺HCO₂^–in THF²⁰(0.25 mL, 0.40 mmol, 2.0

equiv) was added to 0.016 M Pd(OAc)₂in THF (0.30 mL, 5.0 mmol,

2.5 mol%) and 0.068 M Ph₃P in THF (0.14 mL, 10 mmol, 5.0 mol%)

in THF (0.8 mL) at r.t. A mixture of one of the allyl b-keto esters

9a–c (0.20 mmol) and one of the TMSE b-keto esters 4a–c (0.2

mmol) in THF (1 mL) was added dropwise and the resulting mix-

ture was stirred until conversion was completed as judged by TLC.

Pale yellow oil; yield: 74 mg (56%).

IR (film): 3455, 2935, 2860, 1735, 1500, 1455, 1385, 1350, 1250,

1170, 1140, 1065, 970, 860, 835, 755, 700 cm^–1.

PAPER

b-Keto Esters Derived from 2-(Trimethylsilyl)ethanol

2245

Table 9 Analytically Relevant ¹H NMR Shifts (300 MHz, CDCl₃) of the b-Keto Ester Substrates and the Emerging Ketone(s) of the Inter-

molecularly Competing Deprotection/Decarboxylation Experiments Presented in Tables 1–8^a

Remaining b-keto ester

Newly formed ketone

4

7

8

9

10

5

6

d_1¢-H

d_{1¢-(CH )}

d_1¢-H

d_3-Hfor a and c, d_3-H₂for b

3

2

3 3

2

a^b

b^c

c

4.22 (m_c)

4.20 (m_c)

4.21 (m_c)

3.64 (s)

3.70 (s)

1.46 (s)

4.61 (ddd)

4.60 (ddd)

5.15 (s)

5.14 (s)

5.15 (s)

2.20 (s)

2.51 (q)

3.78 (s)

2.15 (s)

2.47 (q)

3.74 (s)

^aNumbering of the protons: see Tables 1–8. The mole fractions of the b-keto ester and ketone constituents of the mixture isolated from each of

these experiments were inferred from the integral ratios over the resonances shown here.

^bAll chemical shifts listed in this line for b-keto esters are identical for the respective keto and enol tautomers.

^cThe chemical shift values listed in this line for b-keto esters 4, 7, 9, and 10 refer to the respective keto forms; the signal of the tautomeric enol

was shifted downfield by 0.06 ppm. In contrast, the resonances of the t-Bu group of the keto and the enol tautomer of b-keto ester 8 coincide.

Evaporation of the solvent under reduced pressure and flash chro-

matography (silica gel, cyclohexane–EtOAc) furnished a mixture of

unchanged b-keto ester(s) and newly formed ketone product(s) de-

void of any byproducts. The yield of each component was deter-

mined as described in ref.⁴and Table 9.

(11) For representative examples of chemoselective

deprotections of TMSE esters besides methyl esters, see

footnote 3 in ref. 2.

(12) For representative examples of chemoselective

deprotections of TMSE esters besides tert-butyl esters, see

footnote 4 in ref. 2.

Competition Experiments Listed in Table 8; General Procedure

Pd/C (5%, 2.2 mg, 5 mol% Pd) was added to a mixture of one of the

benzyl b-keto esters 10a–c (0.2 mmol), one of the TMSE b-keto es-

ters 4a–c (0.2 mmol), and Et₃N (0.03 mL, 0.03 g, 0.02 mmol,

1.0 equiv) in EtOAc (2 mL). The resulting mixture was stirred un-

der a H₂atmosphere (1 bar) until conversion was completed as

judged by TLC. The mixture was filtered over Macherey-Nagel sil-

ica gel 60. Evaporation of the solvent under reduced pressure fur-

nished a mixture of unchanged b-keto ester(s) and newly formed

ketone product(s) devoid of any byproducts. The yield of each com-

ponent was determined as described in ref.⁴and Table 9.

(13) For representative examples of chemoselective

deprotections of TMSE esters besides allyl esters, see

footnote 5 in ref. 2.

(14) For representative examples of chemoselective

deprotections of TMSE esters besides benzyl esters, see

footnote 6 in ref. 2.

(15) Krapcho, A. P.; Lovey, A. J. Tetrahedron Lett. 1973, 12,

957.

(16) Barbieri, G.; Seoane, G.; Trabalzo, J.-L.; Riva, A.;

Umpierrez, F.; Radesca, L.; Tubio, R.; Kwart, L. D.;

Hudlicky, T. J. Nat. Prod. 1987, 50, 646.

(17) Keinan, E.; Eren, D. J. Org. Chem. 1986, 51, 3165.

(18) Jackson, R. W. Tetrahedron Lett. 2001, 42, 5163.

(19) Reddy, B. V. S.; Rao, K. S.; Harikishan, K.; Yadav, J. S.

Synlett 2002, 826.

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(20) THF solutions of Et₃NH⁺HCO₂^–were prepared from Et₃N

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E. Knobloch, R. Brückner

PAPER

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Article Doi

β-Keto esters derived from 2-(trimethylsilyl)ethanol: An orthogonal protective group for β-keto esters

DOI: 10.1055/s-2008-1067157

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