One-pot Claisen rearrangement with n-butyl vinyl ether

Article abstract of DOI:10.1081/SCC-120002696

A protocol for one-pot Claisen rearrangement with n-butyl vinyl ether is described. Upon heating allylic alcohols with excess n-butyl vinyl ether with catalytic amount of Hg(OAc)₂ and NaOAc, Claisen rearrangement takes place through in situ formation of the requisite allyl vinyl ether.

Full text of DOI:10.1081/SCC-120002696

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ONE-POT CLAISEN REARRANGEMENT WITH N-BUTYL
VINYL ETHER
Hidetoshi Tokuyama a , Takaki Makido a b , Toshihiro Ueda a b & Tohru Fukuyama a b
a Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
b CREST, The Japan Science and Technology Corporation (JST), 7-3-1 Hongo, Bunkyo-ku,
Tokyo, 113-0033, Japan
Version of record first published: 16 Aug 2006.
To cite this article: Hidetoshi Tokuyama, Takaki Makido, Toshihiro Ueda & Tohru Fukuyama (2002): ONE-POT CLAISEN
REARRANGEMENT WITH N-BUTYL VINYL ETHER, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 32:6, 869-873
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SYNTHETIC COMMUNICATIONS, 32(6), 869–873 (2002)
ONE-POT CLAISEN REARRANGEMENT
WITH N-BUTYL VINYL ETHER
Hidetoshi Tokuyama, Takaki Makido,
Toshihiro Ueda, and Tohru Fukuyama
*
Graduate School of Pharmaceutical Sciences, The
University of Tokyo, CREST, The Japan Science and
Technology Corporation (JST), 7-3-1 Hongo,
Bunkyo-ku, Tokyo, 113-0033, Japan
ABSTRACT
A protocol for one-pot Claisen rearrangement with n-butyl
vinyl ether is described. Upon heating allylic alcohols with
excess n-butyl vinyl ether with catalytic amount of
Hg(OAc)2 and NaOAc, Claisen rearrangement takes place
through in situ formation of the requisite allyl vinyl ether.
The Claisen rearrangement of allyl vinyl ether is a convenient tool for
preparation of g,d-unsaturated aldehydes from allylic alcohols.1 In conven-
tional protocol, a two-step transformation, consisting of acid2 or mercury
acetate-catalyzed3 vinylation of allylic alcohols with a large excess of ethyl
vinyl ether and the subsequent thermolysis at high temperature, is
employed. Since the vinyl ether formation is an equilibrium process, the
reaction is usually slow and low yielding. Although this two-step transfor-
mation has been carried out in a one-pot procedure, use of a pressure-proof
*Corresponding author.
869
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

870
TOKUYAMA ET AL.
reaction vessel or a sealed tube was required due to the high volatility of
ethyl vinyl ether.2,4 To date, several modified protocols have been devel-
oped,5–8 but none of them seems to be practical enough for preparation of
a large quantity of g,d-unsaturated aldehydes. During the study of natural
products synthesis, we have found that one-pot transformation involv-
ing vinylation and Claisen rearrangement was quite effectively performed
in n-butyl vinyl ether at refluxing temperature. While n-butyl vinyl ether
has occasionally been used for vinyl ether formation,3a–9 to the best of our
knowledge, no examples of its application to one-pot Claisen rearrangement
has been reported. We report herein a highly practical protocol for
one-pot Claisen rearrangement with n-butyl vinyl ether, which is practically
suited for a large-scale preparation of g,d-unsaturated aldehydes (scheme).
Scheme.
Allylic alcohols were directly converted to the corresponding
g,d-unsaturated aldehydes in high overall yields by a quite simple procedure.
Thus, a mixture of allylic alcohol, five equivalents of n-butyl vinyl ether, and
catalytic Hg(OAc)2 (0.1 eq.) and NaOAc (0.1 eq.) was stirred at reflux for 10
to 40 h. The irreversible Claisen rearrangement of the vinyl ether at refluxing
temperature shifted the equilibrium of the reaction to vinyl ether side, allow-
ing us to reduce the amount of n-butyl vinyl ether down to five equivalents.
The other advantage of using n-butyl vinyl ether is that excess n-butyl vinyl
ether could easily be removed by concentration on a rotary evaporator.
As shown in the table, the protocol is applicable to a variety of allylic
alcohols. The reaction of secondary allylic alcohols bearing trans-
1,2-disubstituted olefins proceeded smoothly to furnish the desired aldehydes
in good yields (Entries 1–5). Due to low reactivity of vinyl ethers formed,
geraniol forming quarternary carbon center, styrene derivative giving decon-
jugated product, and a terminal olefin required prolonged reaction time
(Entries 6–9). For these relatively unreactive substrates, heating the mixture
up to 180ꢀC in a sealed tube (Condition B) shortened the reaction time.
The practical utility of this protocol has been proved by a large-scale
preparation of g,d-unsaturated aldehydes (table, Entry 1). A mixture
of allylic alcohol prepared from phenyl magnesium bromide (1.2 mol) and

ONE-POT CLAISEN REARRANGEMENT
871
Table One-Pot Claisen Rearrangement Using n-Butyl Vinyl Ether
2-pentenal (0.82 mol), n-butyl vinyl ether (420 ml, 5 eq.), Hg(OAc)2 (26.0 g),
and NaOAc (6.7 g) was stirred at reflux for 10 h, followed by a treatment
with NaSH. After an aqueous work-up, distillation gave the desired alde-
hyde (111 g) in 72% overall yield from the starting aldehyde.

872
TOKUYAMA ET AL.
In conclusion, we have developed a one-pot protocol for the in situ
generation of allyl vinyl ether to effect direct Claisen rearrangement using
inexpensive and commercially available n-butyl vinyl ether. The process may
find a widespread use in organic synthesis.
EXPERIMENTAL
A Typical Procedure for One-Pot Claisen Rearrangement.
Preparation of 3-Ethyl-5-phenyl-4-pentenal
1-Phenyl-2-penten-1-ol was prepared by addition of phenylmagnesium
bromide (0.89 M in THF, 9.0 ml, 8.02 mmol) to 2-pentenal (500 mg,
5.94 mmol). After conventional aqueous work-up, the crude material was
directly subjected to the one-pot Claisen rearrangement. To the solution of
the crude allylic alcohol in n-butyl vinyl ether (4.11 ml, 31.8 mmol) were
added Hg(OAc)2 (202 mg, 0.635 mmol) and NaOAc (52.9 mg, 0.635 mmol).
The resulting suspension was stirred at reflux for 10 h. After treatment with
NaSHꢁnH2O (55.9 mg) at room temperature for an hour, the reaction mix-
ture was extracted with EtOAc. The organic extract was washed with brine,
dried over MgSO4, filtered through a pad of CeliteÕ, and concentrated.
Purification by flash column chromatography on silica gel (hexanes to
2.5% EtOAc in hexanes, gradient) gave 3-ethyl-5-phenyl-4-pentenyl alde-
hyde (0.89 g, 79%, 2 steps) as a colorless oil; IR (film, cmꢂ1): 3425, 2963,
1
2723, 2361, 1724, 1598, 1449, 968, 748; H NMR (400 MHz, CDCl3) d 0.95
(t, J ¼ 14.8 Hz, 1H), 1.38–1.61 (m, 2H), 2.45–2.56 (m, 2H), 2.66–2.75 (m,
1H), 6.06 (dt, J ¼ 7.3, 15.9 Hz, 1H), 6.44 (d, J ¼ 15.9 Hz, 1H), 7.19–7.35 (m,
5H), 9.75 (t, J ¼ 4.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 11.6, 28.0, 39.4,
49.7, 126.0, 127.0, 129.0, 131.0, 132.0, 137.0, 202. Anal. Calcd for C13H16O:
C; 82.94, H; 8.57. Found: C; 82.72, H; 8.58.
ACKNOWLEDGMENT
The authors thank Mr. Takeshi Kuboyama for an experimental data
of the large-scale reaction.
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ONE-POT CLAISEN REARRANGEMENT
873
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Received in Japan February 22, 2001