A convenient triisobutylaluminium (TIBAL)-promoted Johnson-Claisen approach to γ,δ-unsaturated alcohols

Article abstract of DOI:10.1055/s-0029-1217382

Mixed ortho esters derived from allylic alcohols undergo methanol elimination in the presence of triisobutylaluminium (TIBAL) at room temperature to form mixed ketene acetals. TIBAL then promotes immediate Claisen rearrangement of these intermediates, and

Full text of DOI:10.1055/s-0029-1217382

LETTER
1749
A Convenient Triisobutylaluminium (TIBAL)-Promoted Johnson–Claisen
Approach to g,d-Unsaturated Alcohols
T
IBA
L
Johnson–C
e
laisen
r
earr
l
angem
l
ent y L. Cosgrove,a Ross P. McGeary*a,b
a
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia
School of Pharmacy, The University of Queensland, Brisbane, Queensland 4072, Australia
Fax +61(7)33463249; E-mail: r.mcgeary@uq.edu.au
b
Received 5 March 2009
acid catalysed method for the Johnson–Claisen rearrange-
ment in which the intermediate g,d-unsaturated ester 5 is
further reduced to the corresponding g,d-unsaturated alco-
hol. g,d-Unsaturated alcohols are useful intermediates in
Abstract: Mixed ortho esters derived from allylic alcohols undergo
methanol elimination in the presence of triisobutylaluminium
(TIBAL) at room temperature to form mixed ketene acetals. TIBAL
then promotes immediate Claisen rearrangement of these interme-
diates, and subsequent reduction of the ester products, to give unsat- natural product syntheses, particularly as precursors for
urated g,d-primary alcohols in a convenient, one-pot procedure.
molecular constructs containing tetrahydrofurans and
tetrahydropyrans.5–7
Key words: triisobutylaluminium, mixed ortho esters, ketene di-
methyl acetal, Johnson–Claisen rearrangement, g,d-unsaturated al-
cohols
As part of our studies on the Johnson–Claisen rearrange-
ment we recently reported a mild, solvent-free, uncata-
lysed, quantitative procedure for the synthesis of mixed
ortho esters (Equation 1).8
The Johnson–Claisen rearrangement is a valuable method
for the formation of new carbon–carbon bonds.1 The ef-
fectiveness of the approach can be attributed, at least in
part, to the execution of several steps in a one-pot proce-
dure. Typically, an allylic alcohol is heated in the pres-
ence of a large excess of ortho ester and a catalytic amount
of a weak protic acid at temperatures ranging from 140–
200 °C.1 The reaction sequence involves an allylic alcohol
1 condensing with an ortho ester 2 to form a mixed ortho
ester intermediate 3, which is generally not isolated. Sub-
sequent acid-catalysed alcohol elimination results in for-
mation of a mixed ketene acetal 4, which immediately
undergoes a Claisen rearrangement to give a g,d-unsatur-
ated ester 5 (Scheme 1).2 Despite the fact that this reaction
suffers from high reaction temperatures and prolonged re-
action times, the Johnson–Claisen rearrangement is regu-
larly employed in natural product syntheses, an extensive
review of which was recently reported by Langlois.1 Ad-
ditionally, an excellent discussion on the various Claisen
rearrangements can be found in the reviews of Ziegler3
and Castro.4
O
OH
O
O
O
O
r.t.
+
neat
R
R
1
6
3
Equation 1 Primary and secondary allylic alcohols react with ke-
tene dimethyl acetal to form mixed ortho esters at room temperature
without the need for solvent or catalyst8
Having developed an attractive route to mixed ortho es-
ters, we sought to develop a comparably mild method for
converting these into mixed ketene acetals and promoting
their subsequent Claisen rearrangement. TIBAL caught
our attention because it is a Lewis acid and reducing agent
which has previously been shown to promote methanol
elimination in dimethoxyalkanes.9 The [3,3]-sigmatropic
rearrangement of allyl vinyl ethers and the Ketal–Claisen
rearrangement are also known to be promoted by
TIBAL.10,11 As envisioned, we successfully converted a
mixed ortho ester derived from an allylic alcohol 3 into a
g,d-unsaturated alcohol 7 via TIBAL-mediated Johnson–
We wish to expand upon the versatility of this reaction
and we now report a one-pot, room temperature, Lewis
O
O
O
MeO
MeO
OH
O
O
H+
OMe
[3,3]
– MeOH
+
O
O
R
Δ
R
R
R
1
2
3
4
5
Scheme 1 The Johnson–Claisen rearrangement
SYNLETT 2009, No. 11, pp 1749–1752
x
x
.x
x
.2
0
0
9
Advanced online publication: 16.06.2009
DOI: 10.1055/s-0029-1217382; Art ID: D06609ST
© Georg Thieme Verlag Stuttgart · New York

1750
K. L. Cosgrove, R. P. McGeary
LETTER
Claisen rearrangement. Further reduction of the interme- rangement. We are pleased to report a TIBAL-catalysed
diate g,d-unsaturated ester 5 was accomplished by the ac- Johnson–Claisen rearrangement using a one-pot proce-
tion of TIBAL, along with subsequent addition of DIBAL. dure that has been applied to a variety of allylic alcohols
To the best of our knowledge there are no reports in the lit- (Table 1).
erature of TIBAL promoting the Johnson–Claisen rear-
Table 1 Reaction of Various Mixed Ortho Esters with TIBAL to Yield g,d-Unsaturated Primary Alcohols
OH
O
O
O
O
O
TIBAL
TIBAL
[3,3]
TIBAL/DIBAL
O
O
r.t.
– MeOH
R
R
R
R
3
4
5
7
Entry
Substrate
Product
Ratio Z/Ea
Yield (%)b
70
OH
O
O
O
1
2
14:86
9
8
OH
O
O
O
15:85
17:83
79
77
11
10
OH
O
O
O
3
4
5
13
15
17
12
14
O
O
1
23c
O
OH
OH
O
O
O
14:86
75
16
OH
O
O
O
6
7
15:85
16:84
67
71
O
O
19
21
18
20
OH
O
O
O
Synlett 2009, No. 11, 1749–1752 © Thieme Stuttgart · New York

LETTER
TIBAL Johnson–Claisen rearrangement
1751
Table 1 Reaction of Various Mixed Ortho Esters with TIBAL to Yield g,d-Unsaturated Primary Alcohols (continued)
OH
O
O
O
O
O
TIBAL
TIBAL
[3,3]
TIBAL/DIBAL
O
O
r.t.
– MeOH
R
R
R
R
3
4
5
7
Entry
Substrate
Product
Ratio Z/Ea
Yield (%)b
OH
O
O
O
8
92:8
64
Br
O
Br
23
25
22
O
O
O
OH
O
9
N/A
N/A
52
54
24
26
OH
O
O
10
O
27
29
OH
O
O
1112
43:57d
81
O
28
a The E/Z ratio was measured by 1H NMR spectroscopy.
b Isolated uncorrected yields.
c Lower yield due to evaporative losses.
d The E/Z ratio was measured by GCMS.
Isolated yields of the product unsaturated alcohols 7 range ment. The reaction conditions are compatible with the
from moderate for mixed ortho esters derived from prima- presence of other functional groups: an additional double
ry alcohols, to good through to excellent for mixed ortho bond (26 and 28), an aromatic methyl ether 18, a vinyl
esters derived from secondary and tertiary alcohols. The bromide 22 and, quite surprisingly, a benzyl ether 24 are
variation in yields can be explained by the bulky TIBAL all stable to TIBAL. TIBAL is regularly employed to re-
coordinating to the least hindered ortho ester oxygen, ductively cleave benzyl ethers of carbohydrates, with the
which in the case of mixed ortho esters derived from sec- reaction typically being performed at 50 °C.13 Even
ondary and tertiary alcohols, is the methoxy oxygen, mak- though the addition of TIBAL to mixed ortho esters is
ing methanol elimination the favoured pathway and exothermic, the reaction products of substrate 24 in their
thereby promoting ketene acetal formation. In contrast, entirety consisted of rearranged alcohol 25 and some re-
mixed ortho esters derived from primary alcohols are less covered starting material, with no detectable trace of de-
hindered at the allylic oxygen. This is demonstrated for benzylated alcohol.
primary alcohol derivatives 24 and 26 which gave reac-
tion yields of 52% and 54%, respectively, indicating that
there is an almost equal likelihood of TIBAL coordinating
to either the methoxy oxygen or the allylic oxygen, result-
ing in either ketene acetal formation and subsequent rear-
rangement, or ortho ester elimination to regenerate the
starting allylic alcohol.
Mixed ortho esters derived from acyclic secondary allylic
alcohols predominantly lead to the E-isomer on rearrange-
ment as shown in entries 1–3 and 5–7. Interestingly, the
mixed ortho ester derived from the tertiary alcohol 28
gave a 43:57 Z/E mixture of reaction products; the lower
than expected yield of the E-isomer can be attributed to
the presence of an unfavourable 1,3-diaxial interaction be-
Mixed ortho esters derived from allylic alcohols possess- tween the methoxy group and the methyl group in the
ing mono-, di- and tri-substituted alkenes, together with chair-like transition-state, which leads to the E-isomer of
both cis and trans-alkenes were all capable of rearrange-
Synlett 2009, No. 11, 1749–1752 © Thieme Stuttgart · New York

1752
K. L. Cosgrove, R. P. McGeary
LETTER
(10) Han, T.; Zhenjun, Y. L.; Zhang, L.; Zhang, L. Synlett 2008,
1985.
29. There are no steric impediments in the alternate boat-
like transition-state leading to the Z-isomer of 29.
(11) Rychnovsky, S. D.; Lee, J. L. J. Org. Chem. 1995, 60, 4318.
(12) Mixed ortho esters derived from tertiary alcohols cannot be
synthesised by the standard method which we employ.8
Ketene dimethyl acetal (3.17 mL, 33 mmol) and propionic
acid (~0.1 mL) were added to linalool (4 mL, 22 mmol; entry
11) and stirred at r.t. for 1.5 h. Distillation of the crude
reaction mixture allowed isolation of the mixed ortho ester
28 as a clear liquid (1.5 g, 28%).
In conclusion, we have developed a straightforward, room
temperature procedure14 for the Johnson–Claisen rear-
rangement. This method avoids the vigorous reaction con-
ditions of the standard method, whilst adding the further
step of reducing the ester to the alcohol. The synthesis of
a mixed ortho ester followed by ketene acetal formation,
rearrangement and subsequent reduction of the ester to the
alcohol, all occur in the one-pot to afford a g,d-unsaturat-
ed primary alcohol. We believe this method is a useful al-
ternative to the standard Johnson–Claisen conditions.
(13) Lecourt, T.; Alexandre, H.; Pearce, A. J.; Sollogoub, M.;
Sinay, P. Chem. Eur. J. 2004, 10, 2960.
(14) In a typical experiment, ketene dimethyl acetal (3 mmol per
hydroxyl group) was added cautiously to the anhyd allylic
alcohol (1 mmol) and stirred rapidly at r.t. under argon for
~2 h. Excess ketene dimethyl acetal was removed in vacuo,
giving the pure mixed ortho ester in quantitative yield.8 To
the same vessel, TIBAL (6 equiv, 1 M solution in toluene)
was added at r.t. under argon over ~2 min. The reaction
immediately became exothermic and was typically allowed
to stir at r.t. overnight, however, the reaction was usually
complete after ~6 h. DIBAL (1–2 equiv, 1 M in toluene) was
added and the reaction was stirred for 2 h to reduce any
remaining traces of ester. The reaction was quenched at
–78 °C by the cautious addition of 5% HCl and then
allowing the reaction to warm to room temperature. The
aqueous layer was extracted with Et2O (3 × 40 mL) and the
combined organic fractions were dried (Na2SO4), filtered
and evaporated to give the crude product as a yellow oil (we
found that the HCl quench worked better than aqueous
NaOH10,11 or aqueous sodium citrate solution9 as it avoided
formation of solid aluminum salts). Silica column chroma-
tography was required to separate residual starting alcohol
from the rearranged g,d-unsaturated primary alcohol. All
new compounds were characterised by 1H and 13C NMR
and/or by HRMS and elemental analysis. The spectroscopic
data can be found in the supplementary information.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
References and Notes
(1) Langlois, Y. In The Claisen Rearrangement - Methods and
Applications, 1st ed.; Hiersemann, M.; Nubbemeyer, U.,
Eds.; Wiley-VCH Verlag: Weinheim, 2007, 301.
(2) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom,
T. J.; Li, T.-T.; Faulkner, D. J.; Peterson, M. R. J. Am. Chem.
Soc. 1970, 92, 741.
(3) Ziegler, F. E. Chem. Rev. 1988, 88, 1423.
(4) Castro, A. M. M. Chem. Rev. 2004, 104, 2939.
(5) Coulombel, L.; Duñach, E. Green Chem. 2004, 6, 499.
(6) Franck, X.; Figadère, B.; Cavé, A. Tetrahedron Lett. 1997,
38, 1413.
(7) Srikrishna, A.; Lakshmi, B. V.; Sudhakar, A. V. S.
Tetrahedron Lett. 2007, 48, 7610.
(8) Cosgrove, K. L.; McGeary, R. P. Synlett 2008, 2425.
(9) Cabrera, G.; Fiaschi, R.; Napolitano, E. Tetrahedron Lett.
2001, 42, 5867.
Synlett 2009, No. 11, 1749–1752 © Thieme Stuttgart · New York