Ireland-Claisen rearrangement of secondary allyl acetate revisited: Inevitable C-silylation circumvented by one-pot application of excessive LDA/TMSCl and TBAF

Article abstract of DOI:10.1016/j.tetlet.2012.02.071

Yield lowering C-silylation was found to be inevitable in all the six tested examples of stoichiometric LDA/TMSCl promoted Ireland-Claisen rearrangement of secondary allyl acetates. In order to circumvent this problem, a higher yielding protocol was devis

Full text of DOI:10.1016/j.tetlet.2012.02.071

Tetrahedron Letters 53 (2012) 2177–2180
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Tetrahedron Letters
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Ireland-Claisen rearrangement of secondary allyl acetate revisited: inevitable
C-silylation circumvented by one-pot application of excessive LDA/TMSCl
and TBAF
⇑
Di Liu, Xiaoming Yu
State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Beijing Key Laboratory of Active Substance Discovery and Drugability Evaluation,
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Xiannongtan Street, Beijing 10050, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Yield lowering C-silylation was found to be inevitable in all the six tested examples of stoichiometric
LDA/TMSCl promoted Ireland-Claisen rearrangement of secondary allyl acetates. In order to circumvent
this problem, a higher yielding protocol was devised after the isolated by-products were found to be
excellent substrates for further rearrangement. Thus, excessive LDA/TMSCl was applied to achieve
Received 1 December 2011
Revised 10 February 2012
Accepted 14 February 2012
Available online 20 February 2012
complete 3,30-sigmatropic shift of the substrates, and the resulting mixtures of normal and
,d-unsaturated carboxylic acids was then desilylated by one-pot application of TBAF.
a-silylated
c
Keywords:
Ireland-Claisen rearrangement
Allyl acetate
Ó 2012 Elsevier Ltd. All rights reserved.
C-silylation
High yield
One-pot protocol
Ireland-Claisen rearrangement, the 3,30-sigmatropic shift of
O-silyl ketene acetal in situ formed from allyl esters, has been play-
ing active roles in organic synthesis over the decades since its first
report in 1972.1 While sharing with the other variants of
Claisen-type reactions the high stereo-specificity and step-
efficiency of transforming simple allylic alcohols into structurally
O
O
Li
R1
O
R1
O
*
LDA
+
TMSCl
R2
R4
R2
R4
*
R3
R3
1
more advanced
c,d-unsaturated carboxylic acids, Ireland-Claisen
path a
path b
O
-silylation
C
-silylation
rearrangement is favored in particular for its mild condition and
ease of substrate preparation.2,3 On paralleling to the fast accumu-
lation of enantioselective approaches to secondary allylic alcohols
in the recent years, Ireland-Claisen rearrangement of allyl acetates
has become a standard strategy to define a stereogenic center at
the b position of carboxylic acids (Path a, Scheme 1).4–20
On accompanying the large number of reportedly successful
applications of Ireland-Claisen rearrangement of allyl acetates,
there are also scattered reports showing that the overall yield of
this reaction could be significantly lowered by competitive
C-silylation (Path b, Scheme 1). Beaudry and Trauner4 recently
reported the isolation of a C-silylated by-product in 32% yield from
a reaction in THF. Frank et al.21 described a more extreme example
that exclusive C-silylation was observed under similar condition.
Kishi22 also noted a similar side reaction (not with allyl acetate)
in their total synthesis of (+)-ophiobolin and finally had to take a
tandem Brook/Claisen rearrangement as an alternative. Albeit
O
R1
SiMe3
COOH
OSiMe3
H
R1
O
R4
O
R1
R2
*
R4
R2
R4
∗
R2
R3
R3
R3
2
3
Scheme 1. Mechanism and possible side reaction of Ireland-Claisen rearrangement.
these records, this yield-deterring side reaction has received little
attention since focused investigations are still in absence in the lit-
erature. Herein we describe a more detailed study to address this
problem.
Simply because of the very limited number of literature records
of C-silylation occurring in the process of Ireland-Claisen rear-
rangement, it is well arguable that such side-reactions are merely
substrate-dependent instances. However, our experimental results
in the first stage of this study led to a quite different conclusion.
Hence, differently substituted racemic acyclic allyl acetates 1a–f
⇑
Corresponding author. Tel.: +86 10 63165259; fax: +86 10 63017757.
E-mail address: mingxyu@imm.ac.cn (X. Yu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.071

2178
D. Liu, X. Yu / Tetrahedron Letters 53 (2012) 2177–2180
Table 1
1/1 mixture of HMPA/THF or CPME did not result in significant
improvement (entry 2 and 3). Use of KHMDS instead of LDA, how-
ever, appeared to be more effective since the yield of 2a was in-
creased for approximately 20% and that of the by-product 3a
decreased for 14% (entry 4 vs 1), but C-silylation still dominated, sug-
gesting that simple adjustment of reaction conditions may not neces-
sarily solve the problem.
Upon realizing that more reliable protocols are in need to pre-
vent the interference of C-silylation, we noticed an interesting
example reported earlier by Enev et al. (Scheme 2).24 In this study,
a type of unusual allyl acetates were treated with excessive lithium
Stoichiometric LDA/TMSCl effected Ireland-Claisen rearrangement of secondary allyl
acetates in THF
O
O
O
LDA (1.2 eq)
SiMe3
R1
O
OH
Me
R1
O
TMSCl (1.2 eq)
+
R1
R2
Me
R2
Me
THF, -78 °C then rt
R2
R3
R3
R3
1
2
3
Entry
Ester
R1
R2
R3
Product
Yield (%)
2
3
2/3
N-isopropylcyclohexylamide (LICA) and TMSCl, and finally gave
silyl carboxylic acids as single products (Scheme 2). Although there
is no direct evidence, -silylacetates were believed to be the inter-
a-
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
H
Ph
H
H
H
Me
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
16/54
13/50
46/42
29/40
45/30
25/50
H
Me
H
C6H11
C6H11
Ph
a
mediates. Therefore the one-pot sequence depicted in Scheme 3
was proposed. It was expected that, along with the normal fashion
of rearrangement giving acid 2, C-silylation product 3 would un-
dergo a second round of deprotonation and O-silylation in the
Me
H
Ph
H
a
CH2CH2CH2CH2
a
R2 + R3 = CH2CH2CH2CH2.
presence of excessive LDA and TMSCl to deliver
a-silyl-acid 4.
Because C–Si bonds are labile on exposure to fluorine anion,24–27
application of TBAF in the work-up stage would help to bring up
2 as the single final product. However, the transformation of 3 into
2 was to be testified because it was still questionable whether
compound 3 was prone to additional C-silylation, without men-
tioning that Enev’s substrates appeared to be too unusual.
were treated with LDA (1.2 equiv) and TMSCl (1.2 equiv) in THF at
ꢀ78 °C, and then stirred at room temperature for 2 h. After deter-
mining the yield of both expected carboxylic acids 2a–f and unex-
pected
a-silylacetates 3a–f by chromatographic isolation of the
products (table 1), we noticed that C-silylation in fact dominated
in four of the six reactions (Table 1, entry 1, 2,4, and 6) and contrib-
uted nearly half of the products in other two (entry 3 and 5). These
data, in combination with the previous reports,4,21,22 clearly sug-
gested that such C-silylation could not be simply referred as an
occasionally encountered incidence but an inevitable side reaction,
and improved reaction conditions are to be sought.
The previously isolated
a-trimethylsilyl acetates, 3a–f, were
treated with 1.2 equiv of LDA and 1.2 equiv of TMSCl at ꢀ78 °C in
THF and stirred at room temperature or slightly above for 30 h (Ta-
ble 3). To our delight, the rearrangement products, 4a–f, were iso-
lated in 70–83% yield without the detection of by-products,
implying that the presence of a silyl group at the
a-position of
the substrate completely blocked further C-silylation. More
impressively, steric repulsions were well tolerated since 3,3-disub-
stituted allyl substrates were able to give more than 70% yields
(Table 3, entry 3 and 5). Subsequent treatment of 4a–f with
1.5 equiv of TBAF in THF readily afforded 2a–f in excellent yields
(Table 3).
With these encouraging results obtained, we set out to testify
the one-pot protocol described in Scheme 3. Compounds 1a–k
(1 equiv) and TMSCl (2.5 equiv) were successively added to a solu-
tion of LDA (3 equiv) in dry THF at ꢀ78 °C. The reaction mixture
was then stirred for 30 h at the indicated temperature (Table 4)
Metal enolates existing as separated ion pairs are believed to
favor O-alkylation upon the exposure to electrophiles. Polar
solvents12–18 and non-lithium derived bases, such as KHMDS,19,20
are therefore often adopted to increase the proportion of O-silylation
in the generation of enol silyl ethers. More interestingly, Okabayashi
et al.23 reported that utilization of cyclopentyl methyl ether (CPME)
instead of THF dramatically enhanced O-silylation. In order to
examine the effectiveness of these conditions, compound 1a was
subjected to a different set of experiments using stoichiometric
amount of LDA and TMSCl. Unfortunately, data listed in
Table 2 showed that the change of reaction media from THF into
Table 2
Ireland-Claisen rearrangement of 1a under simply adjusted reaction conditions
O
O
O
LDA (1.2 eq)
SiMe3
O
OH
Me
O
TMSCl (1.2 eq)
+
Ph
Me
1a
Ph
Ph
Me
3a
THF, -78 °C then rt
2a
Entry
Solvent
Base
Yield (%)
2a
3a
1
2
3
4
THF
LDA
LDA
LDA
16
19
24
35
54
49
50
40
THF/HMPA
CPME
THF
KHMDS
O
1. 4equiv. LICA
Me
Me
H
2. 3.5 equiv. TMSCl
3. -80 °C to -10 °C
H
O
L3Si*
L3Si*
or
COOH
TMS
COOH
H TMS
∗
L3Si
Me
Scheme 2.
H
a
-Silylacetate mediated Ireland-Claisen rearrangement reported by Enev.

D. Liu, X. Yu / Tetrahedron Letters 53 (2012) 2177–2180
2179
OSiMe3
O
COOH
R4
R1
O
R1
O
LDA, TMSCl
3,3'-shift
R1
R2
R2
R4
R2
R4
R3
R3
R3
1
2
LDA, TMSCl
TBAF
OSiMe3
O
Me3Si
R1
COOH
SiMe3
SiMe3
R1
O
R1
O
LDA, TMSCl
3,3'-shift
R4
R2
R4
R2
R4
R2
R3
R3
R3
3
4
Scheme 3. Proposed one-pot protocol of Ireland-Claisen rearrangement.
Table 3
Ireland-Claisen rearrangement of secondary allyl
a
-trimethylsilylacetates and
a
-desilylation of the resulting
a-trimethylsilyl carboxylic acids
O
O
O
Me3Si
SiMe3
LDA (1.2 eq)
R1
O
OH
OH
TMSCl (1.2eq)
TBAF (1.5 eq)
THF, rt, 8h
R1
R2
R1
R2
R2
THF
R3
R3
R3
4
2
3
Entry
Ester
R1
R2
R3
Product 4e
Yield (%) 4
Product 2
Yield (%) 2
1b
2b
3c
4d
5b
6b
3a
3b
3c
3d
3e
3f
H
H
Me
H
Me
H
Ph
H
H
H
Me
4a
4b
4c
4d
4e
4f
79
76
70
83
81
80
2a
2b
2c
2d
2e
2f
95
92
90
95
96
89
C6H11
C6H11
Ph
Ph
H
a
CH2CH2CH2CH2
a
b
c
R2 + R3 = CH2CH2CH2CH2.
ꢀ78 °C then 33 °C for 30 h.
ꢀ78 °C then 37 °C for 35 h.
ꢀ78 °C then 25 °C for 30 h.
d
e
All the products except 4b appeared to be single diastereomer.28
Table 4
Ireland-Claisen rearrangement of secondary ally acetates following the proposed one-pot protocol
O
O
O
O
Me3Si
LDA (3.0 eq)
R1
O
OH
R4
OH
OH
TMSCl (2.5 eq)
TBAF (3.8 eq)
R1
R2
R1
R2
R1
R2
+
R4
R2
R4
R4
THF, rt, 8h
THF
R3
R3
R3
R3
1
2
2
4
Entry
Ester
R1
R2
R3
R4
Yielda (%) 2
Yieldb (%) 2/4
1c
2c
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
Me
H
Me
H
H
H
H
H
Ph
H
H
H
Me
H
Me
Me
Me
Me
Me
Me
i-Pr
Ph
80
80
74
88
81
84
78
79
82
77
86
26/50
29/49f
41/39
25/46
40/36
30/63
16/56f
28/51f
29/43f
20/38f
16/58f
C6H11
C6H11
Ph
3d
4e
5c
Ph
6c
CH2CH2CH2CH2
Ph
Ph
p-F-Ph
p-OMe-Ph
Ph
7e
H
H
H
H
H
8e
9e
Me
Me
Et
10e
11e
1j
1k
H
a
b
c
d
e
f
Overall yield of the one-pot protocol.
Determined by isolation of 2 and 4 without TBAF treatment.
ꢀ78 °C then 33 °C for 30 h.
ꢀ78 °C then 37 °C for 35 h.
ꢀ78 °C then 25 °C for 30 h.
Combined yield of two diastereomers.28

2180
D. Liu, X. Yu / Tetrahedron Letters 53 (2012) 2177–2180
before solid TBAF (3.8 equiv) was added and stirring was continued
for additional 8 h. After regular aqueous work-up of the reaction,
we delightfully found that the overall isolated yield of the final
products 2a–k, obtained by following this one-pot protocol were
enormously higher (74–88% vs 16–46%) even without further opti-
mization. In a paralleling set of experiments without the applica-
tion of TBAF, 4a–k and 2a–k were separated to confirm the
intermediacy of the former, and their yields were listed in Table 4.
References and notes
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These results clearly evidenced that the
a-trimethylsilylacetate 3
mediated pathway contributed more than half of the final
products.
Obviously, the differences between this newly devised protocol
and the conventional ones are minor and all advantageous aspects
of Ireland-Claisen rearrangement, such as easily available reagents
and mild conditions, are well retained. Although there are limits,
for example, the use of silyl-protecting group needs to be carefully
considered, and substrates other than acetates are not recom-
mended because it might cause more complicated stereochemistry
outcomes referring the a-position of the final products, this proce-
dure is particularly useful in large scale Ireland-Claisen rearrange-
ment of ally acetates.
In summary, we presented the first focused study addressing
the issue of undesired C-silylation in the Ireland-Claisen rearrange-
ment of allyl acetates. Our data suggested that, despite the inade-
quate notification in the literature, this yield detrimental side
reaction is nearly inevitable in THF when stoichiometric reagents
are used. Simple adjustment of reaction condition, for example,
change of solvent or base, proved to be ineffective. A highly effec-
tive one-pot protocol was therefore developed, so that the final
products could be obtained in substantially higher yields.
24. Enev, V.; Stojanova, D.; Bienz, S. Helv. Chim. Acta 1996, 79, 391–404.
25. Nahm, M. R.; Xin, L.; Potnick, J. R.; Yates, C. M.; White, P. S.; Johnson, J. S. Angew.
Chem., Int. Ed. 2005, 44, 2377–2379.
26. Trost, B. M.; Papillon, J. P. N.; Nussbaumer, T. J. Am. Chem. Soc. 2005, 127,
17921–17937.
27. Iguchi, M.; Doi, H.; Hata, S.; Tomioka, K. Chem. Pharm. Bull. 2004, 52, 125–129.
28. Isolated compound 4a and 4c–f were suggested to be single diastereomers by
1HNMR. The stereochemistry of 4a was assigned as below based on a ROESY
study (see Supplementary data). Unfortunately, such stereospecificity was not
observed in the cases of 4b and 4g–k.
Acknowledgment
This project received financially support from the Chinese Nat-
ural Science Foundation (30672530).
H
HOOC
Me3Si
H
Supplementary data
4a
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.02.071.