Efficient and stereoselective synthesis of allylic ethers and alcohols

Article abstract of DOI:10.1021/ol062433y

(Chemical Equation Presented) A short and efficient synthesis of allylic TBS ethers and allylic alcohols has been developed, based upon a unique Kocienski-Julia olefination reaction. Allylic alcohols and allylic ethers are obtained in good to excellent yields and with high (E)-selectivity. The conditions are mild and the procedure is broadly applicable.

Full text of DOI:10.1021/ol062433y

ORGANIC
LETTERS
2006
Vol. 8, No. 26
5983-5986
Efficient and Stereoselective Synthesis
of Allylic Ethers and Alcohols
Jirˇ´ı Posp´ısˇil and Istva´n E. Marko´*
De´partement de Chimie, UniVersite´ catholique de LouVain, Baˆtiment LaVoisier,
Place Louis Pasteur 1, B-1348 LouVain-la-NeuVe, Belgium
marko@chim.ucl.ac.be
Received October 3, 2006
ABSTRACT
A short and efficient synthesis of allylic TBS ethers and allylic alcohols has been developed, based upon a unique Kocienski−Julia olefination
reaction. Allylic alcohols and allylic ethers are obtained in good to excellent yields and with high (E)-selectivity. The conditions are mild and
the procedure is broadly applicable.
Allylic alcohols are important building blocks in synthetic
organic chemistry, being easily transformed into useful
epoxides,1 R,â-unsaturated aldehydes,2 carboxylic acid de-
rivatives,3 and polyenes.4 Their synthesis usually entails the
reaction of an aldehyde 1 with a stabilized Wittig (2a) or
Horner-Wadsworth-Emmons (2b) reagent5 followed by the
subsequent reduction of the resulting R,â-unsaturated ester
3 (Scheme 1). Surprisingly, even though the transformation
To the best of our knowledge, the only way to transform
aldehydes into allylic alcohols in a single step involves the
use of the â-hydroxy phosphonium salt 5. When reacted with
aldehyde 1, in the presence of an excess of base, salt 5 affords
the desired allylic alcohol 4 (Scheme 2).7 Disappointingly,
this olefination reaction proceeds with poor to moderate
yields, presumably due to the low stability of the generated
phosphonium ylide.6b,c
(1) (a) Johnson, A. A.; Sharpless, K. B. ComprehensiVe Organic
Synthesis; Pergamon Press: Oxford, UK, 1990; Vol. 7. (b) Finn, M. G.;
Sharpless, K. B. Asymmetric synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1985; Vol. 5. (c) Burns, C. J.; Martin, C. A.; Sharpless,
K. B. J. Org. Chem. 1989, 54, 2826.
Scheme 1. Synthesis of Allylic Alcohols
(2) (a) Lee, D. G. Oxidation; Augustine, R. L., Ed.; Marcel Dekker: New
York, 1969; Vol 1. (b) Ball, S.; Goodwin, T. W.; Morton, R. A. Biochem.
J. 1948, 42, 516.
(3) Corey, E. J.; Gilman, N, W.; Ganem, B. E. J. Am. Chem. Soc. 1968,
90, 5616.
(4) Catalan, J.; Hopf, H.; Mlynek, C.; Klein, D.; Kilickiran, P. Chem.
Eur. J. 2005, 11, 3915.
(5) For an extensive review on phosphorus-based olefination methods,
see: Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863. For recent
examples see: (a) Christoph, G.; Hoppe, D. Org. Lett. 2002, 4, 2189.(b)
Ding, P.; Miller, M. J.; Chen, Y.; Helquist, P.; Oliver, A. J.; Wiest, O.
Org. Lett. 2004, 6, 1805.
(6) (a) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360. (b) Connon, S. J.; Blechert, S. Angew.
Chem., Int. Ed. 2003, 42, 1900.
(7) (a) Schlosser, M. Angew. Chem., Int. Ed. 1968, 7, 650. (b) Schlosser,
M.; Christmann, F. K.; Piskala, A.; Coffinet, D. Synlett 1971, 29. (c) Corey,
E. J.; Shirahama, H.; Yamamoto, H.; Terashima, S.; Venkateswarlu, A.;
Schaaf, T. K. J. Am. Chem. Soc. 1971, 93, 1490. (d) Maryanoff, B. E.;
Reitz, A. B.; Duhl-Emswiler, B. A. J. Am Chem. Soc. 1985, 107, 217.
of aldehydes into the corresponding allylic alcohols is often
encountered in total synthesis, this two-step sequence is still
classically employed. To reach the corresponding allylic
ethers, a third step is required.
Recently, the synthesis of allylic alcohols, ethers, and
halides was also accomplished via olefination/cross-metath-
esis protocol.6
10.1021/ol062433y CCC: $33.50
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Published on Web 11/29/2006

rapid rearrangement, affording olefin 10. Similarly, â-alkyl-
oxy and â-acyloxy sulfones11 suffer a rapid â-elimination,
yielding the corresponding vinyl sulfones. Therefore, we
envisioned that â-trialkylsilyloxy sulfones 13, bearing a poor
silyloxy leaving group, might be good reagents for the
desired transformation. The â-elimination process might be
sufficiently slowed down to enable the desired olefination
reaction to proceed competitively.
Scheme 2. One-Step Transformation of Aldehydes to Allylic
Alcohols
To test our hypothesis, the coupling of sulfones 13a (PG
) TMS) and 13b (PG ) TBS) with benzaldehyde was
attempted (Table 1).
As a part of our ongoing research program aimed at the
development of novel modifications of the Julia olefination
reaction,8,9 a short and efficient synthesis of allylic ethers and
alcohols was targeted. To fulfill this goal, the Kocienski-Julia
variant10 was selected as the desired sequence (Scheme 3).
Table 1. Optimization of the Olefination Reaction
Scheme 3. The Kocienski-Julia Reaction
entry
sulfone
method
base
yielda
E/Zb
1
2
3
4
5
6
7
8
13a
13a
13a
13a
13a
13b
13b
13b
A
B
C
C
C
C
C
C
LiN(TMS)2
LiN(TMS)2
LiN(TMS)2
NaN(TMS)2
KN(TMS)2
LiN(TMS)2
NaN(TMS)2
KN(TMS)2
deg
n/a
40%
45%
35%
28%
81%
79%
83%
52/48
62/38
72/28
81/19
67/23
89/11
98/2
a Overall yields refer to pure, isolated products. b Determined by capillary
GC. TMS ) trimethylsilyl.
From a retrosynthetic point of view, allylic alcohol 4 can
be divided into sulfone 13 and aldehyde 1 (Scheme 4).
Initially, the Li anion of 13a was generated at low
temperature and the aldehyde was added after 10 min (Table
1, entry 1). In this case, only degradation of the sulfone 13a
was observed. It was thought that this decomposition was
due to the low stability of the sulfonyl anion. Hence, Barbier-
type conditions, in which the anion R to the sulfone is
generated in the presence of an aldehyde, were employed.
Gratifyingly, the desired product 15 could be isolated in 40%
yield. However, the E/Z-selectivity was extremely poor
(Table 1, entry 2). It was also observed that the slow addition
of the base to the reaction mixture led to a slight increase in
both the yield and the selectivity of this process (Table 1,
entry 3).
Scheme 4. Retrosynthetic Approach to Allyl Alcohols
Unfortunately, â-hydroxy sulfones 7 cannot be directly
employed. Indeed, when treated with a base, they undergo a
(8) For a recent review on the Julia reaction, see: Dumeunier, R.; Marko´,
I. E. Modern Carbonyl Olefination; Takeda, T., Ed.; Wiley-VCH: Weinheim,
Germany, 2004; pp 104-150.
(9) (a) Posp´ısˇil, J.; Posp´ısˇil, T.; Marko´, I. E. Collect. Czech. Chem.
Commun. 2005, 70, 1953. (b) Posp´ısˇil, J.; Posp´ısˇil, T.; Marko´, I. E. Org.
Lett. 2005, 7, 2373. (c) Marko´, I. E.; Murphy, F.; Kumps, L.; Ates, A.;
Touillaux, R.; Craig, D.; Carballares, S.; Dolan, S. Tetrahedron 2001, 57,
2609. (d) Marko´, I. E.; Murphy, F.; Dolan, S. Tetrahedron Lett. 1996, 37,
2089.
Next, it was decided to evaluate the influence of the nature
of the cation associated with the base. As can be seen in
Table 1 (entries 4 and 5), the use of NaNTMS2 and KNTMS2
(11) (a) Abel, S.; Faber, D.; Hu¨ter, O.; Giese, B. Synthesis 1999, 188.
(b) Keck, G. E.; Savin, A. K.; Weglarz, M. A.; Cressman, E. N. K.
Tetrahedron Lett. 1996, 37, 3291. (c) Tanner, D.; Somfai, P. Tetrahedron
1987, 43, 4395.
(10) (a) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
(b) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998,
26.
5984
Org. Lett., Vol. 8, No. 26, 2006

further improved the control of the double bond geometry,
affording the olefin 15 with an E/Z ratio of up to 81:19,
though at the expense of the yield that plummeted down to
28% (Table 1, entry 5).
Table 2. Preparation of TBS Allyl Ethers 14
At this stage, it was realized that the low stability of the
TMS ether function under the reaction conditions was
responsible for the formation of only modest amounts of the
desired allylsilyl ether 15. Therefore, sulfone 13b bearing a
more robust TBS group was employed (Table 1, entries
6-8). Much to our delight, a dramatic enhancement in the
yield of 14a was observed. Furthermore, the influence of
the counter cation on the geometry of the double bond present
in 14a was also improved, leading ultimately to 14a in 83%
yield and with an E/Z ratio of 98:2.
The synthesis of sulfones 13a and 13b is depicted in
Scheme 5. Having devised suitable reaction conditions to
Scheme 5. Synthesis of the Sulfones 13a and 13b
effect this allylic TBS ether preparation, its scope and
limitations were explored. A selection of pertinent results
are depicted in Table 2.
a Overall yields refer to pure, isolated products. b Determined by 1H NMR
spectroscopy. DME ) dimethoxy ether; TBS ) tert-butyldimethylsilyl.
It was observed that aryl (Table 2, entry 1), R,â-
unsaturated (Table 2, entries 3 and 5), and alkyl aldehydes
(Table 2, entries 6-13) react smoothly with sulfone 13b,
yielding the desired TBS protected allylic alcohols 14a-j
in good to excellent yields. It is noteworthy that, in essentially
all cases, a remarkably high control of the E/Z alkene gemetry
could be exercised, favoring largely the (E)-isomer. For
aliphatic aldehydes, the selectivity for the trans-olefin
increased as the steric bulk of the alkyl substituent became
larger (Table 2, entries 8-10). To further improve the E/Z
ratio, THF was replaced by DME.8b In full accord with
previous results described by Kocienski et al., it was observed
that the use of DME led to the corresponding allylic ethers
in higher stereoisomeric purity, though in somewhat lower
yields (Table 2, entries 1-4, 6, and 7).
aliphatic substrates (Scheme 6). Thus, the anion generated
from sulfone 13b was allowed to react with a 1:1 mixture
of aldehyde 1a and ketone 19a and with an equimolar amount
of 1e and 19b. In both cases, the expected ethers 14a and
14e were isolated as the only products of the reaction along
with the recovered starting ketones 19a and 19b. To
understand the origin of this excellent chemoselectivity, a
control reaction between sulfone 13b and ketone 19a, under
the same reaction conditions, was attempted. Surprisingly,
no olefination product was observed and the ketone 19a was
recovered in 92% yield. On the other hand, sulfone 13b was
completely decomposed under these conditions. We speculate
that this degradation was due to the low stability of the
generated organo potassium species at the higher tempera-
tures required for addition on the ketone function.12
Importantly, various functionalities, including esters, TBS
ethers, and benzyl ethers (Table 2, entries 11-13), are
tolerated under the reaction conditions.
Several synthetic ventures currently ongoing in our labora-
tory require the chemoselective Julia olefination of an alde-
hyde function in the presence of a ketone. Therefore, we won-
dered if a ketone group would also be tolerated under these
reaction conditions. Hence, a set of competitive experiments
was designed involving a combination of aromatic and
Finally, we have developed a simple and efficient one-
pot synthesis of allylic alcohols 4 starting from aldehydes
and employing the sulfone 13b (Scheme 7). Hence, addition
of an excess of the HF Pyr complex to the crude reaction
(12) For the stability of PT-SO2-CH2-Li species, see ref 10a.
Org. Lett., Vol. 8, No. 26, 2006
5985

Scheme 6. Competition Experiments between Aldehydes and
Scheme 7. One-Pot Olefination/Deprotection Preparation of
Ketones
Allyl Alcohols
Additionally, this reaction can be further extended into the
one-pot synthesis of allylic alcohols. A variety of functions
and protecting groups are also tolerated.
Acknowledgment. Financial support of this work by the
Universite´ catholique de Louvain, Rhodia Ltd. (studentship
to J.P.) and SHIMADZU Benelux (financial support for the
acquisition of a FTIR-8400S spectrometer) is gratefully
acknowledged.
mixture obtained by condensing 13b with 1a and 1e results
in the smooth deprotection of the TBS group, affording the
desired allylic alcohols 4a and 4b in high yields and excellent
stereochemical purity.
In summary, we have uncovered a novel, highly stereo-
selective method for the synthesis of allyl TBS ethers and
allylic alcohols. Under our conditions, aryl, R,â-unsaturated,
and alkyl aldehydes can be easily transformed, via a one-
step procedure, into the corresponding TBS allyl ethers.
Supporting Information Available: Spectroscopic and
analytical data for all new compounds, as well as experi-
mental procedures. This material is available free of charge
Via the Internet at http://pubs.acs.org.
OL062433Y
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Org. Lett., Vol. 8, No. 26, 2006