A new synthesis of highly functionalized cyclohexenes via a vinylogous Ferrier-Petasis cyclization reaction

Article abstract of DOI:10.1016/j.tet.2017.10.055

Research on the O→C rearrangement reaction shows that alkoxydienes undergo a smooth rearrangement in a vinylogous manner with a catalytic amount of titanium (IV) chloride, which leads to highly substituted cyclohexenes a particularly useful starting mater

Full text of DOI:10.1016/j.tet.2017.10.055

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Accepted Manuscript
A new synthesis of highly functionalized cyclohexenes via a vinylogous Ferrier-
Petasis cyclization reaction
Anna Domżalska, Elżbieta Maziarz (Pluta), Bartłomiej Furman
PII:
S0040-4020(17)31092-X
10.1016/j.tet.2017.10.055
TET 29058
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 August 2017
Revised Date: 16 October 2017
Accepted Date: 20 October 2017
Please cite this article as: Domżalska A, Maziarz (Pluta) Elż, Furman Bartł, A new synthesis of highly
functionalized cyclohexenes via a vinylogous Ferrier-Petasis cyclization reaction, Tetrahedron (2017),
doi: 10.1016/j.tet.2017.10.055.
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ACCEPTED MANUSCRIPT
A new synthesis of highly functionalized cyclohexenes via a vinylogous Ferrier-
Petasis cyclization reaction
Anna Domżalska, Elżbieta Maziarz (Pluta), Bartłomiej Furman*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-
224 Warsaw, Poland
* Corresponding author. Tel.:+48 22 3432053; fax: +48 22 6326681.
E-mail address: furbar@icho.edu.pl (B. Furman).
Dedicated to prof. Marek Chmielewski on his 75th Birthday.
Research on the O→C rearrangement reaction shows that alkoxydienes undergo a
smooth rearrangement in a vinylogous manner with a catalytic amount of titanium (IV)
chloride, which leads to highly substituted cyclohexenes a particularly useful starting material
in the synthesis of cyclohexane containing products.
Keywords: Vinylogous Ferrier reaction; 1,5-rearrangement; O-1,3-alkoxydienes
INTRODUCTION
Vinylogy can be defined as the transmission of electronic effects through a
conjugated system. The SN’ reaction is probably the best-known example of a double bond
acting as an electron-conducting channel between two reacting termini. Many other polar
reactions have been modified in a vinylogous manner, including the Claisen and benzoin
condensations, the aldol and Mannich reactions, and the electrophilic addition to double
bonds.1
The Lewis acid-promoted [1,3] O-to-C rearrangement of vinyl ethers and acetals is
one of the fundamental reactions in organic synthesis.2 This transformation is believed, in
general, to proceed via ionic cleavage, forming an ion pair (an enolate and a carbocationic
species), followed by their recombination (Scheme 1).3,4
Scheme 1. The [1,3] O→C rearrangement of vinyl ethers.
The intramolecular transformation, where cyclic vinyl ethers undergo
a
1

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fragmentation/aldol-type recombination sequence, generating a carbocycle, is known as the
Ferrier-Petasis rearrangement5 (Scheme 1, eq 1). Recently, such reactions have found
widespread applications in complex natural product synthesis.6,7 In contrast, little attention
has been given to the O-1,3-dienyl version of the Ferrier reaction, where regiochemistry
could be an issue.8 Very recently, Tayama9 has demonstrated that the Ferrier reaction of O-
1,3-dienyl acetals in the presence of bulky aluminium complexes proceeds with high α-
regioselectivity ([1,3] rearrangement) to afford the corresponding α-alkenyl-substituted β-
alkoxy aldehydes, whereas the use of other Lewis acids led to the formation of the α- and γ-
regioisomers with the former predominant. In the present work, we hypothesized that in O-
1,3-dienyl ethers 2,a vinylogous Ferrier-Petasis cyclization to the corresponding 6-membered
carbocyclic products via a 6 – endo-trig pathway should be preferred as it would proceed via
a stabilized carbocation (Scheme 2, eq 2).
Scheme 2. The Ferrier-Petasis reaction of vinyl ethers 1 and O-1,3-alkoxydienes 2.
RESULTS AND DISCUSSION
In order to test our hypothesis, we synthesized a series of three α,β-unsaturated
aldehydes with phenyl (4c), 4-methylphenyl (4b) and 4-methoxyphenyl (4a) groups in two
steps from 3,4-dihydropyran (DHP) (Scheme 3).
Scheme 3. The synthesis of α,β-unsaturated aldehydes 5.
2

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The first step was the Heck coupling of aryl iodides with 3,4-dihydro-2H-pyran which
facilitated the regioselective synthesis of arylated cyclic enol ethers 4a-c. Good yields were
10
obtained using 10 mol% of Pd(OAc)2 in the presence of Et3N in DHP at 140 °C.
The formylation of 4 under the classical Vilsmeier-Haack reaction conditions
employing phosphorus oxychloride gave the expected α,β-unsaturated aldehydes 5a-c
selectively11 We did not observe products of the electron-rich arene formylation. While the
synthesis of aldehydes 5 proved to be straightforward, their chromatographic purification was
quite difficult, therefore they were used in the next step without further purification.
In the next step, aldehydes 5a-c were transformed into olefins 2a-p using the Wittig
reaction. The expected olefins were obtained in moderate to good yields after optimization
(Scheme 4).12
Scheme 4. The Synthesis of O-1,3-Alkoxydienes 2.
With a variety of O-dienyl ethers in hand, our interest was directed toward the regio-
and stereochemistry in the Lewis acid-promoted Ferrier reaction. Therefore, vinyl ethers 2a,
3