Selective cleavage and decarboxylation of β-keto esters derived from (trimethylsilyl)ethanol in the presence of β-keto esters derived from other alcohols

Article abstract of DOI:10.1055/s-2008-1078568

β-Keto[2-(trimethylsilyl)ethyl esters] are dealkoxycarbonylated at 50 °C by 0.75 equivalents of Bu₄N⁺F ^-·3H₂O in THF. This reaction proceeds chemoselectively in the presence of β-keto(methyl esters), β-keto(tert-butyl esters), β-keto(allyl esters), or β-keto(benzyl esters) as revealed in intermolecular competition experiments. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078568

LETTER
1865
Selective Cleavage and Decarboxylation of b-Keto Esters Derived from
(Trimethylsilyl)ethanol in the Presence of b-Keto Esters Derived from
Other Alcohols
S
elective Cleav
v
age and Deca
a
rboxylation of
b
-
K
Ketoesters nobloch, Reinhard Brückner*
Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität Freiburg, Albertstr. 21, 79104 Freiburg, Germany
Fax +49(761)2036100; E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de
Received 24 March 2008
the b-keto[(triphenylsilyl)ethyl ester] group incorporated
into the substrate 5,7 can be cleaved by Bu4N+F–·3H2O,
too, as we observed recently (Scheme 2). In these instan-
ces the ester cleavages proper were followed by an in situ
Abstract: b-Keto[2-(trimethylsilyl)ethyl esters] are dealkoxycar-
bonylated at 50 °C by 0.75 equivalents of Bu4N+F-·3H2O in THF.
This reaction proceeds chemoselectively in the presence of b-ke-
to(methyl esters), b-keto(tert-butyl esters), b-keto(allyl esters), or
b-keto(benzyl esters) as revealed in intermolecular competition ex- decarboxylation of the respective b-keto carboxylic acid
periments.
or corresponding b-keto carboxylate intermediate.
Key words: chemoselectivity, dealkoxycarbonylation, defunction-
alization, b-keto esters, ketones
α
Non
O
Non
a)
α
SiMe3
+
O
O
O
(ref. 7)
3
4
Thirty years ago CIBA-GEIGY reported that N-protected
amino acids can be condensed with 2-(trimethylsilyl)eth-
anol (1; ‘TMSE–OH’) and that the resulting (trimethylsi-
lyl)ethyl esters 2 (‘TMSE esters’) are cleaved at room
temperature by treatment with 2–10 equivalents of anhy-
drous tetraalkylammonium tetrafluoroborates in DMF
solution within 3–60 minutes (Scheme 1).1 Since then,
TMSE esters have been used as protecting groups repeat-
edly. The usual motivation is the desire to cleave TMSE
esters by the already mentioned or other fluoride sources2
without affecting other functionalities. In particular,
TMSE ester were cleaved in the presence of methyl es-
ters,3 tert-butyl esters,4 allyl esters,5 and benzyl esters.6
Arguably, Bu4N+F–·3H2O (1.2–6 equiv) is the most com-
mon reagent used for this purpose (r.t., 4–16 h).3–6
SiPh3
O
Me
O
Me
O
Me
Me
O
O
O
O
α
b)
O
α
(ref. 8)
α
α
OPMB
OPMB
O
O
O
Me3Si
+
O
5
6
Scheme 2 Dealkoxycarbonylations of b-keto(TMSE esters) prior to
the present study. Reagents and conditions: a) Bu4N+F–·3H2O (2.0
equiv), THF, r.t., 8 h; 98%; b) Bu4N+F–·3H2O (3.0 equiv), THF, r.t.,
10 h, 64%. Non = n-C9H19; PMB = 4-MeOC6H4CH2.
R(FGs protected)
The reactions depicted in Scheme 2 exemplify a previous-
ly unrecorded transformation: the one-pot cleavage and
decarboxylation – or dealkoxycarbonylation – of b-ke-
to(TMSE esters) providing C1-shortened ketones, for ex-
ample, compounds 4 or 6.
PG
OH
HO
+
N
SiMe3
H
1
O
a)
b)
R(FGs protected)
O
Investigating the scope and limitations of this process, we
examined three aspects (Scheme 3):
PG
N
SiMe3
H
O
• Do b-keto(TMSE esters) 7 in general dealkoxycarbony-
late in the presence of Bu4N+F–·3H2O and form C1-short-
ened ketones 8 thereby?
2
Scheme 11 Reagents and conditions: a) protected amino acid, 1 (1.2
equiv), pyridine (2.0 equiv), DCC (1.1 equiv), MeCN, 0 °C, 6–16 h;
b) 2 in DMF, Bu4N+F– or Et4N+F– (2–10 equiv) in DMSO, 24 °C, 3–
60 min, then 0 °C, H2O. FG = functional group.
• Can the substitution pattern of the b-keto(TMSE esters)
7 be varied (a–c) such that ketones 8a–c are obtained,
which exhibit 0, 1, or 2 substituents at C-a?
• Are selective Bu4N+F–-induced dealkoxycarbonylations
of b-keto(TMSE esters) 7 possible in the presence of a b-
keto ester derived from methanol (9), tert-butanol (10), al-
lyl alcohol (11), or benzyl alcohol (12)?9,10
b-Keto[(trimethylsilyl)ethyl esters] [‘b-keto(TMSE es-
ters)’] – present in substrates 37 and 48 of Scheme 2 – or
SYNLETT 2008, No. 12, pp 1865–1869
x
x
.x
x
.
2
0
0
8
Advanced online publication: 02.07.2008
DOI: 10.1055/s-2008-1078568; Art ID: G10508ST
© Georg Thieme Verlag Stuttgart · New York

1866
E. Knobloch, R. Brückner
LETTER
The b-keto(TMSE esters) 7a–c were obtained as shown in
Scheme 4. 4-Phenylphenylacetic acid (16) was prepared
by a Pd/C-catalyzed11 Suzuki coupling12 between phenyl-
boronic acid and 4-bromophenylacetic acid as pub-
lished.13 Acid 16 was converted into acid chloride 17,14
which was condensed without purification with Mel-
drum’s acid. The resulting enol 18 was carried on one
more step without purification: by (trimethylsily)ethanol-
ysis and in situ decarboxylation. Purification by flash
chromatography on silica gel15 provided b-keto ester 7a in
79% overall yield.16 This compound was a-methylated by
successive treatments with NaH and MeI.17 The simple
succession of these treatments delivered 84% a-methyl-b-
keto ester 7b and the double succession (without working
up the intermediate, i. e. 7b) a,a-dimethyl-b-keto ester 7c
in 69% yield. The silicon-free b-keto esters 9a–c to 12a–c
were accessed by the same strategy.
Scheme 3 Scope and limitations of one-pot b-keto(TMSE ester)
cleavage–decarboxylation reactions. Biph = 4-PhC6H4 (biphenyl-4-yl)
Table 1 Cleavage and Decarboxylations of b-Keto(TMSE Ester) 7a
with Different Amounts of Bu4N+F–·3H2O
O
Biph
SiMe3
Biph
Bu4NF⋅3H2O,
OH
X
O
O
O
THF, 50 °C
7a
8a
O
B(OH)2
O
Br
15
Entry
Bu4N+F–·3H2O Time
Yield
(%)
a)
(equiv)
(h)
1.25
2
= Biph
14
1
2
3
4
5
1.0
94
100
89
16: X = OH
17: X = Cl
b)
0.75
0.5
O
O
O
c)
2
O
Biph
0.25
0.1
8
84
OH
18
a
8
–
a After 8 h the 1H NMR spectrum of the reaction mixture revealed the
presence of starting material and product in a 52:48 ratio.
HO
SiMe3
d)
1
4
2'
2
Three equivalents of Bu4N+F–·3H2O were required for
cleaving and decarboxylating b-keto(TMSE ester) 7a at
room temperature. However, the reaction proceeded for
56 hours before we isolated 86% of the desired ketone 8a
but still retrieved 6% of unreacted substrate. Conducting
the same reaction at 50 °C, an equimolar amount of
Bu4N+F–·3H2O assured already a 94% yield of ketone 8a
after only 75 minutes (Table 1, entry 1). Substoichiomet-
ric amounts of Bu4N+F–·3H2O sufficed even for effecting
the reaction, too (Table 1, entries 2–4): 0.75 equivalents
thereof gave a perfect 100% yield after two hours, 0.5
equivalents gave 89% after 2 hours, and 0.25 equivalents
gave 84% after 8 hours. The amount of 10 mol% of
Bu4N+F–·3H2O effected ca. 50% cleavage and decarboxy-
lation of keto ester 7a within 8 hours (Table 1, entry 5). To
the best of our knowledge, these findings are unprecedent-
ed in fluoride-mediated cleavages of simple TMSE es-
ters.1–6 The first dealkoxycarbonylations of b-keto(TMSE
esters) 37 and 58 (cf. Scheme 1) did not anticipate these
modified conditions either. The feasibility of such 7a →
8a conversions with as little as 25 mol% fluoride anions
O
O
O
Biph
Biph
Biph
SiMe3
SiMe3
SiMe3
1'
O
O
O
O
7a
e)
O
7b
f)
O
7c
Scheme 4 Syntheses of b-keto(TMSE esters) 7a–c. Reagents and
conditions: a) 14 (1.1 equiv), 5% Pd/C (3 mol%), Na2CO3 (1.3 equiv),
H2O–i-PrOH (6:1); 92% (ref.13 85%); b) SOCl2 (11 equiv), DMF (10
mol%), toluene, 80 °C, 3 h; c) Meldrum’s acid (1.0 equiv), pyridine
(3 equiv), CH2Cl2, 0 °C to r.t., 18 h; d) 1 (1.1 equiv), toluene, 85 °C,
3.5 h; 86% (over the 3 steps); e) NaH (1.1 equiv), THF, 0 °C, 30 min;
then r.t., MeI (1.1 equiv), 12 h; 84%; f) 2 × [NaH (1.1 equiv), THF,
0 °C, 30 min; then r.t., MeI (1.1 equiv), THF, 12 h]; 69%.
Synlett 2008, No. 12, 1865–1869 © Thieme Stuttgart · New York

LETTER
Selective Cleavage and Decarboxylation of b-Keto Esters
1867
Table 3 Intermolecularly Competing Dealkoxycarbonylations in
Mixtures of b-Keto(TMSE esters) 7a–c and b-Keto(methyl esters)
9a–c
implies that the Me3Si group becomes incorporated not
solely in Me3Si–F but also – and sometimes mostly – in
Si–O bond containing species (presumably Me3Si–OH
and/or Me3Si–O–SiMe3).
Men
Men
O
Biph
SiMe3
1
3
Biph
The a-methylated b-keto(TMSE esters) 7b,c were
dealkoxycarbonylated at 50 °C by 0.75 equivalents of
Bu4N+F–·3H2O in THF within 90 minutes almost as effi-
ciently (Table 2, entries 2, 3) as the parent compound 7a
(Table 2, entry 1): Ketones 8b,c were isolated in 90% and
82% yield, respectively.
1'
O
O
O
7a–ca
8a–c
Bu4NF⋅3H2O
(0.75 equiv),
in the presence of
(almost) without
THF, 50 °C
Men
Men
O
1
3
Ph
Ph
Table 2 Cleavage and Decarboxylations of b-Keto(TMSE Esters)
7a–c with 0.75 Equivalents of Bu4N+F–·3H2O
1'
O
O
O
9a–cb
13a–c
Men
Men
Bu4NF⋅3H2O
(0.75 equiv),
O
Entry 7–9, 13
Men
Time
Yields (%)c
Biph
SiMe3
Biph
(h)
of re-isolated b-keto esters
and resulting ketones
O
O
O
THF, 50 °C
7a–c
8a–c
9
13
7
8
Substrate
Men
Me0
Me1
Me2
Time (h)
Yield (%)
1
2
3
a
b
c
Me0 3.5
Me1 1.5
Me2 1.5
0
0
0
98
100
99
97
88
99
5
7a
7b
7c
2
100
90
0
0
1.5
1.5
82
a Enol contents in CDCl3: 7a, 10%; 7b, 9%.
b Enol contents in CDCl3: 9a, 9%; 9b, 5%.
c Determined 1H NMR spectroscopically in CDCl319 after separation
of the 7/8/9/13 mixture from side products by flash chromatography
on silica gel.15
The dealkoxycarbonylation procedure adopted in the ex-
periments of Table 2 was then applied to pairs of b-keto
esters (Tables 3– 6), one of them invariably being a b-ke-
to(TMSE ester) 7. All b-keto esters, which we exposed ‘in
competition’ to the action of Bu4N+F–·3H2O18 differed by
their alkoxy groups but was identically a-methylated. The
starting quantity of each keto ester was 0.2 mmol. Crude
products were freed from side products by flash chroma-
tography on silica gel15 so that in each instance a pure
mixture of up to two b-keto esters and up to two ketones
was obtained. Its mass was determined and the kind and
proportion of its constituents inferred by the assignment
and integration of baseline-separated signals in its 300
MHz 1H NMR spectrum.19 The error margin for any yield
calculated from these data9 is estimated to be £ 5%. This
assessment is tantamount to accepting that the combined
yields of a given substrate/product pair may be up to
10% off the expected mass balance (100%) in the ab-
sence of side reactions and losses during the isolation pro-
cedure. Reassuringly, the yields presented in Tables 3– 6
stay within these margins.
Table 4 Intermolecularly Competing Dealkoxycarbonylations in
Mixtures of b-Keto(TMSE esters) 7a–c and b-Keto(tert-butyl esters)
10a–c
Men
Men
O
1
3
Biph
SiMe3
Biph
1'
O
O
O
7a–ca
Bu4NF⋅3H2O
(0.75 equiv),
8a–c
in the presence of
(almost) without
THF, 50 °C
Men
Men
O
1'
1
Ph
3
Ph
O
O
O
10a–cb
13a–c
Entry 7, 8, 10, 13
Men
Time
(h)
Yields (%)c
of re-isolated b-keto esters
and resulting ketones
7
8
10
13
In complete agreement with a number of chemoselective
cleavages of simple TMSE esters with Bu4N+F–·3H2O
performed in substrates containing additionally a simple
methyl ester,3 tert-butyl ester,4 allyl ester,5 or benzyl es-
ter,6 the results of Tables 3– 6 document that b-ke-
to(TMSE esters) can be cleaved and decarboxylated by
Bu4N+F–·3H2O as chemoselectively if a b-keto(methyl es-
ter), a b-keto(tert-butyl ester), a b-keto(allyl ester), or a b-
keto(benzyl ester) is present concomitantly.
1
2
3
a
b
c
Me0
Me1
Me2
3.5
1.5
1.5
0
0
0
98 98
100 95
99 103
0
0
0
a Enol contents in CDCl3: 7a, 10%; 7b, 9%.
b Enol contents in CDCl3: 10a, 1%; 10b, 3%.
c Determined 1H NMR spectroscopically in CDCl319 after separation
of the 7/8/10/13 mixture from side products by flash chromatography
on silica gel.15
In more detail, each of the b-keto(TMSE esters) 7a–c was
converted completely into the corresponding ketone 7a,
Synlett 2008, No. 12, 1865–1869 © Thieme Stuttgart · New York

1868
E. Knobloch, R. Brückner
LETTER
Table 5 Intermolecularly Competing Dealkoxycarbonylations in
Mixtures of b-Keto(TMSE Esters) 7a–c and b-Keto(allyl Esters)
11a–c
Table 6 Intermolecularly Competing Dealkoxycarbonylations in
Mixtures of b-Keto(TMSE Esters) 7a–c and b-Keto(benzyl Esters)
12a–c
Men
Men
Men
Men
O
O
Biph
SiMe3
1
3
Biph
SiMe3
1
3
Biph
Biph
1'
1'
O
O
O
O
O
O
7a–ca
7a–ca
8a–c
8a–c
Bu4NF⋅3H2O
Bu4NF⋅3H2O
(0.75 equiv),
(0.75 equiv),
in the presence of
(almost) without
in the presence of
(almost) without
THF, 50 °C
THF, 50 °C
Men
Men
Men
Men
O
O
Ph
1
3
1
3
Ph
Ph
Ph
Ph
1'
1'
O
O
O
O
O
O
11a–cb
12a–cb
13a–c
13a–c
Yields (%)c
Entry 7, 8, 11, 13 Men
Time
Yields (%)c
Entry 7, 8, 12, 13 Men
Time
(h)
of re-isolated b-keto esters
and resulting ketones
(h)
of re-isolated b-keto esters
and resulting ketones
11
13
7
8
12
13
7
8
1
2
3
a
b
c
Me0
Me1
Me2
3.5
1.5
1.5
0
98
98 <5d
1
2
3
a
b
c
Me0
Me1
Me2
3.5
1.5
1.5
0
0
0
100 95
105 95
90 100
<5d
0
0
0
100
95
0
0
99 103
0
a Enol contents in CDCl3: 7a, 10%; 7b, 9%.
b Enol contents in CDCl3: 11a, 9%; 11b, 5%.
a Enol contents in CDCl3: 7a, 10%; 7b, 9%
b Enol contents in CDCl3: 12a, 8%; 12b, 9%
c Determined 1H NMR spectroscopically in CDCl319 after separation
of the 7/8/11/13 mixture from side products by flash chromatography
on silica gel.15
c Determined 1H NMR spectroscopically in CDCl319 after separation
of the 7/8/12/13 mixture from side products by flash chromatography
on silica gel;15,
d This value is meant to indicate that the presence of ketone 13 did not
follow unequivocally from the 1H NMR spectrum.
d This value is meant to indicate that the presence of ketone 13a did
not follow unequivocally from the 1H NMR spectrum
7b, or 7c, whereas their b-keto(methyl ester) counterparts
9a–c provided the underlying ketone 9a, 9b, or 9c not all
or in only 5% yield (Table 3). Similarly, the b-keto(TMSE
esters) 7a–c were defunctionalized by Bu4N+F–·3H2O
completely – rendering the corresponding ketones 8a–c in
89–98% yield – while the analogous b-keto(tert-butyl es-
ters) 10a–c stayed untouched (Table 4). Likewise, the b-
keto(TMSE esters) 7a–c and Bu4N+F–·3H2O provided the
expected ketones 8a–c in quantitative yields – in contrast
to the b-keto(allyl esters) 11a–c, which remained inert
(Table 5). Finally, ketones 8a–c formed from b-ke-
to(TMSE esters) 7a–c and Bu4N+F–·3H2O in ≥ 90% yield
whereas the equally present b-keto(benzyl esters) 12a–c
were retrieved in essentially quantitative yields (Table 6).
References and Notes
(1) Sieber, P. Helv. Chim. Acta 1977, 60, 2711.
(2) Wuts, P. G.; Greene, T. W. Protective Groups in Organic
Synthesis, 4th ed.; John Wiley and Sons: New York, 2007,
576.
(3) Chemoselective deprotection of TMSE esters besides
methyl esters (representative examples): (a) Jung, M.;
Miller, M. J. Tetrahedron Lett. 1985, 26, 977. (b) Bailey,
S.; Teerawutgulrag, A.; Thomas, E. J. J. Chem. Soc., Chem.
Commun. 1995, 2521. (c) Travins, J. M.; Etzkorn, F. A.
J. Org. Chem. 1997, 62, 8387. (d) Hu, T.; Panek, J. S. J. Am.
Chem. Soc. 2002, 124, 11368. (e) Tripp, J. C.; Schiesser, C.
H.; Curran, D. P. J. Am. Chem. Soc. 2005, 127, 5518.
(f) Bailey, S.; Helliwell, M.; Teerawutgulrag, A.; Thomas,
E. J. Org. Biomol. Chem. 2005, 3, 3654.
In summary, we have shown how b-keto(TMSE esters)
can be dealkoxycarbonylated chemoselectively in the
presence of a b-keto(methyl ester), a b-keto(tert-butyl es-
ter), a b-keto(allyl ester), or a b-keto(benzyl ester).
Whether, in an extension of the present findings, one may
regard b-keto(TMSE esters) as orthogonally protected b-
keto esters vs. b-keto esters derived from methanol, tert-
butanol, allyl alcohol, or benzyl alcohol, is a matter of cur-
rent study in our laboratory. This additional attribute
would be justified if the latter b-keto esters can be
dealkoxycarbonylated under conditions, which leave a b-
keto(TMSE ester) intact.
(4) Chemoselective deprotection of TMSE esters besides tert-
butyl esters (representative examples): (a) Liu, G.; Xin, Z.;
Liang, H.; Abad-Zapatero, C.; Hayduk, P. J.; Janowick, D.
A.; Szczepankiewicz, B. G.; Pei, Z.; Hutchins, C. W.;
Ballaron, S. J.; Stashko, M. A.; Lubben, T. H.; Berg, C. E.;
Rondinone, C. M.; Trevillyan, J. M.; Jirousek, M. R. J. Med.
Chem. 2003, 46, 3437. (b) Seebach, D.; Kimmerlin, T.;
Šebasta, R.; Campo, M. A.; Beck, A. K. Tetrahedron 2004,
60, 7455.
(5) Chemoselective deprotection of TMSE esters besides allyl
esters (representative examples): (a) Scheidt, K. A.; Chen,
H.; Follows, B. C.; Chemler, S. R.; Coffey, D. S.; Roush, W.
R. J. Org. Chem. 1998, 63, 6436. (b) Bourne, G. T.;
Meutermans, W. D. F.; Alewood, P. F.; McGeary, R. P.;
Synlett 2008, No. 12, 1865–1869 © Thieme Stuttgart · New York

LETTER
Selective Cleavage and Decarboxylation of b-Keto Esters
1869
Scanlon, M.; Watson, A. A.; Smythe, M. L. J. Org. Chem.
1999, 64, 3095.
(6) Chemoselective deprotection of TMSE esters besides benzyl
esters (representative examples): (a) Cuenoud, B.;
Schepartz, A. Tetrahedron 1991, 47, 2535. (b) Dietrich, A.;
Wrobel, J. Tetrahedron Lett. 1993, 34, 3543.
4.2 mmol, 1.1 equiv) was added within 5 min. The mixture
was stirred at 80 °C for 3.5 h. Evaporation of the solvent
under reduced pressure and flash chromatography on SiO2
(see ref. 15; eluent: cyclohexane–EtOAc, 15:1) provided a
mixture of the two tautomers of 2-(trimethylsilyl)ethyl
4-(4-phenylphenyl)-3-oxobutanoate (7a; 1.324 g, 94%) as a
faintly yellow oil. 1H NMR (400.1 MHz, CDCl3; 90:10
mixture of keto and enol tautomer): d = 0.06 [s, Si(CH3)3
(7a)], 0.06 [s, Si(CH3)3 (enol-7a)], 1.02 [mc, 2¢-H2 (7a and
enol-7a)], 3.43 [s, 4-H2 (7a)], 3.56 [s, 4-H2 (enol-7a)], 3.90
[s, 2-H2 (7a)], 4.25 [mc, 1¢-H2 (7a and enol-7a)], 4.99 [mc, 2-
H (enol-7a)], 7.27–7.61 [m, Ar-H (7a and enol-7a)], 12.23
[s, 3-OH (enol-7a)]. Anal. Calcd (%) for C21H26O3Si
(354.5): C, 71.15; H, 7.39. Found: C, 70.90; H, 7.40.
(17) Reaction conditions were gleaned from a protocol by:
Hogan, F.; Herald, D. L.; Petit, G. R. J. Org. Chem. 2003, 69,
4019.
(c) Sundaramoorthi, R.; Siedem, C.; Vu, C. B.; Dalgarno, D.
C.; Laird, E. C.; Botfield, M. C.; Combs, A. B.; Adams, S.
E.; Yuan, R. W.; Weigele, M.; Narula, S. S. Bioorg. Med.
Chem. Lett. 2001, 11, 1665. (d) Venturi, F.; Venturi, C.;
Liguori, F.; Cacciarini, M.; Montalbano, M.; Nativi, C.
J. Org. Chem. 2004, 69, 6153.
(7) Kramer, R. Dissertation; Universität Freiburg: Germany,
2007, 279–280.
(8) Tricotet, T.; Brückner, R. Eur. J. Org. Chem. 2007, 1069.
(9) After treatment with Bu4N+F–·3H2O, any such experiment
could ‘rightfully’ (i. e., in the absence of side reactions)
deliver a mixture of up to four components, namely the
unconsumed b-keto esters and the resulting ketones. We
distinguished them by 1H NMR spectroscopy (ref. 10) and
quantified their relative amounts by integration of non-
superimposed resonances. In addition, we determined the
absolute amounts (i. e., absolute yields) of these species by
weighing the respective mixture. Thereupon, the mole
fraction of each component, its molecular weight, and the
gram amount of the mixture allowed for the yields listed in
Tables 3– 6 to be calculated.
(18) General Procedure for the Execution of the Competition
Experiments Listed in Tables 3–6
At 0 °C Bu4N+F–·3H2O (47 mg, 0.15 mmol, 0.75 equiv) in
THF (0.5 mL) was added dropwise to a mixture of one of the
b-keto(TMSE esters) 7a–c (0.20 mmol) and another b-keto
ester 9a–c to 12a-c (0.20 mmol) in THF (1.5 mL). The
resulting mixture was stirred at 50 °C until conversion was
complete as judged by TLC. Brine (1.5 mL), H2O (3 mL),
and t-BuOMe (3 mL) were added. Extraction with t-BuOMe
(3 × 3 mL), drying of the combined extracts with Na2SO4,
evaporation of the solvent under reduced pressure, and flash
chromatography on SiO2 (ref. 15; eluent: cyclohexane–
EtOAc) furnished a mixture of unreacted b-keto ester(s) and
newly formed ketone(s) devoid of any byproducts. The yield
of each component was determined as described in refs. 9
and 19.
(10) As remote and modest as the aryl group variation in the
resulting ketones 8a–c vs. 13a–c may appear, the chemical
shift effect accompanying it sufficed for differentiating,
among others, the following resonances: d3-H3 = 2.20 in 8a
vs. 2.15 in 13a; d3-H = 2.51 in 8b vs. 2.47 in 13b; d1-H
=
2
2
3.78 in 8c vs. 3.74 in 13c. The b-keto esters were
distinguished from the ketone(s) by their alkoxy resonances.
(11) Felpin, F.-X.; Ayad, T.; Mitra, S. Eur. J. Org. Chem. 2006,
2679.
(19) The mole fractions of the b-keto ester and ketone
constituents of each mixture isolated from one of the
experiments summarized in Tables 3– 6 were inferred from
the integral ratios over the following 1H NMR resonances
(300 MHz, CDCl3): 7a: d = 4.22 (mc, 1¢-H2); 7b: d = 4.20
(mc, 1¢-H2); 7c: d = 4.21 (mc, 1¢H2); 8a: d = 2.20 (s, 3-H3);
8b: d = 2.51 (q, J3,4 = 7.2 Hz, 3-H2); 8c: d = 3.78 (s, 1-H2);
9a: d = 3.64 (s, 1¢-H3); 9b,c: d = 3.70 (s, 1¢-H3); 10a–c:
d = 1.46 [s, 1¢-(CH3)3]; 11a: d = 4.61 (ddd, J1¢,2¢ = 5.8 Hz,
4J1¢,3¢(E) = 4J1¢,3¢(Z) = 1.4 Hz, 1¢-H2); 11b,c: d = 4.60 (ddd,
(12) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002,
58, 9633. (c) Chemler, S. R.; Trauner, D.; Danishefsky, S. J.
Angew. Chem. Int. Ed. 2001, 40, 4544; Angew. Chem. 2001,
113, 4676. (d) Miyaura, N. In Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed.; de Meijere, A.; Diederich, F.,
Eds.; Wiley-VCH: Weinheim, 2004, 41–124. (e) Bellina,
F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419.
J
1¢,2¢ = 5.8 Hz, 4J1¢,3¢(E) = 4J1¢,3¢(Z) = 1.4 Hz, 1¢-H2); 12a,c:
(13) Gala, D.; Stamford, A.; Jenkins, J.; Kugelman, M. Org.
Process Res. Dev. 1997, 1, 163.
d = 5.15 (s, 1¢-H2); 12b: d = 5.14 (s, 1¢-H2); 13a: d = 2.15 (s,
3-H3); 13b: d = 2.47 (q, J3,4 = 7.3 Hz, 3-H2); 13c: d = 3.74 (s,
1-H2). The b-keto ester signals compiled above coincide for
the respective keto and enol tautomers if the substitution
pattern a is realized and for compound 10b; the enol
resonances corresponding to the signals specified for keto
tautomers 7b, 9b, 11b, and 12c are shifted downfield by 0.06
ppm.
(14) All new compounds gave satisfactory 1H NMR and 13
C
NMR spectra and provided correct combustion analyses (C
and H 0.4%).
(15) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923.
(16) The crude acylation product 18 (1.3 g, 3.8 mmol) was
dissolved in toluene (10 mL). Alcohol 1 (0.60 mL, 0.50 g,
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