Alkylaluminum derivatives as oxophiles in organic synthesis : structure and reactivity studies

100 Pages·1991·3.2 MB·English

by  Campbell, Curtis R.

ALKYLALUMINUM DERIVATIVES AS OXOPHILES IN ORGANIC
SYNTHESIS: STRUCTURE AND REACTIVITY STUDIES
BY
CURTIS R. CAMPBELL
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE
UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE
REQUIREMENTS FOR DEGREE OF DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
1991
To my parents, with thanks
for their never ending
support and encouragement
ACKNOWLEDGMENTS
The author would like to express his appreciation
to Professor Merle Battiste for the guidance provided
in this work, the late night philosophical
discussions, and the occasional "attitude adjustment."
My gratitude is also expressed to the other faculty
members that made life a little more interesting and
lively during my stay at UF. Special thanks go to
Professor Jim Deyrup who taught me many things in and
out of the classroom. A debt of gratitude is owed to
Dr. Radi Awartani for those "special lab skills" that
he has passed on to me. My appreciation is also
extended to Dr. Dave Powell and his staff for their
assistance and special handling of those "dissertation
making, gotta have 'em yesterday mass spectra".
"Merle's Perles," both past and present, deserve a
unigue thanks for the unigue outings and lab
conversations embarked upon. Finally, greatest thanks
and best wishes go to Kristen for just being there and
putting up with me.
111
TABLE OF CONTENTS
PAGE
ACKNOWLEDGMENTS 11*
ABSTRACT
CHAPTER I INTRODUCTION
±
CHAPTER II VINYL OXIRANE SYNTHESIS VIA THE
HORNER-WITTIG REACTION
14
CHAPTER III STRUCTURE AND REACTIVITY OF
ALUMINUM ENOLATES
33
CHAPTER IV ALKENE FORMATION VIA TRIMETHYL-
ALUMINUM ACTION OF KETONES
49
CHAPTER V SUMMARY
59
CHAPTER VI EXPERIMENTAL
61
General Experimental
.* .' 61
Apparatus and Technique !
62
Reagents and Solvents
.' .* 62
BIBLIOGRAPHY
88
BIOGRAPHICAL SKETCH
91
iv
Abstract of Dissertation Presented to the Graduate
School of the University of Florida in Partial
Fulfillment of the Requirements for the Degree of
Doctor of Philosophy
ALKYLALUMINUM DERIVATIVES AS OXOPHILES IN ORGANIC
SYNTHESIS: STRUCTURE AND REACTIVITY STUDIES
BY
Curtis R. Campbell
December 1991
Chairman: Merle A. Battiste
Major Department: Chemistry
A new synthetic approach for the more volatile
alpha-vinyl oxiranes required for subsequent studies
with organoaluminum reagents has been developed. This
the Horner-Wittig reaction of diphenylphosphinoyl-
methyl lithium with a, p-unsaturated ketones, e.g.
2-cyclohexen-l-one, is the key step in the sequence
producing stable crystalline intermediates, in
contrast to previous schemes in which volatile liquids
are realized at each stage. These solid intermediates
can then be stereoselectively epoxidized with MCPBA to
give a penultimate crystalline precursor to the
desired vinyl oxirane. Treatment of this 2,3-oxido
Horner-Wittig intermediate under basic conditions
results in the loss of the diphenylphosphinoyl group
as the water soluble phosphinous acid, thus
simplifying final workup and isolation of the volatile
vinyl oxiranes. The synthetic sequence as presented
proceeds with good to excellent yields.
The reaction of diethyl-carbo-tert-butoxymethyl-
alane (Rathke alane, RkeAl) with vinyl oxiranes has
been studied in order to determine the necessary
stoichiometry for optimum yields of the product
hydroxy ester. Several NMR studies were carried out
in an attempt to elucidate the structure of the RkeAl
in tetrahydrofuran (THF) solution. A mechanism for
the reaction of RkeAl with vinyl oxiranes is proposed
based on the reactivity and structural investigations.
Reactions of the RkeAl with aldehydes and ketones were
also demonstrated to proceed with good yields.
Structural variations of the ester moiety of the alane
were investigated in order to expand the reagent's
applicability to organic synthesis. Preliminary
studies on chiral induction via the RkeAl type
reaction are described.
Formation of alkenes through the thermal reaction
of trimethylaluminum with ketones, an overlooked
reaction, has been demonstrated. The possible
synthetic utility of this reaction may be seen in the
formation of 2-methylcamphene in one step from camphor
in high yield. Reaction conditions are described for
alkene isolation for several ketones. A mechanism for
the formation of these alkenes is offered.
VI
CHAPTER I
INTRODUCTION
The field of organometallic chemistry has
undergone a tremendous surge in popularity in research
over the last guarter century. One of the main goals
of this research has been the development and
application of organometals as synthetic reagents for
selective organic transformations. In particular,
investigations into the application and scope of
organoaluminum compounds has garnered significant
interest due to their application in natural product
synthesis and their somewhat unigue properties. 1 As
early as 1955 aluminum alkyl species were noted to
exhibit unusual behavior. 2 Aluminum alkyIs, R A1,
3
react with carbonyl compounds in an analogous fashion
to that of Grignard reagents; however, only a single
aluminum-carbon bond reacts in an additive fashion,
leaving the remaining two alkyl substituents
deactivated. This deactivation is associated with
bond formation in the product between aluminum and the
oxygen atom of the former carbonyl group, but the
precise reasons for the greatly reduced reactivity of
the remaining aluminum bound alkyls is still open to
speculation.
In general, organometallic compounds may act as
either a Lewis acid or as a nucleophile in their
reactions with carbonyl compounds and oxiranes. From
an antithetic standpoint oxiranes are seen to have
greater synthetic potential than carbonyl compounds
owing to their greater flexibility as starting
materials for advanced syntheses since two
carboncenters are available for substitution, rather
than one. In addition two different pathways are
available for the reaction of saturated oxiranes with
organometals: direct addition resulting in two
1)
possible isomeric alcohols; 2) rearrangement to either
the aldehyde or ketone and subseguent addition to the
resulting carbonyl group. The pathway taken can be
dependent on the metal atom involved and the
structural (steric) environment of the oxirane sites.
For example, nucleophilic ring opening at the least
hindered site of an epoxide is generally the main
reaction seen with alkyl cuprates, 3 whereas
trialkylaluminums yield predominantly the addition
product resulting from ring opening and addition to
the more substituted site. 4 Also seen in some of
these reactions are products resulting from
rearrangement and subsequent addition. Reactions
involving trialkylaluminum reagents appear to be
.
sensitive to the choice of reaction solvent and
conditions as demonstrated by the reaction of styrene
oxide with trimethylaluminum as shown in Figure 1-1. 5
(CH A1
3)3
-OH
35°C
Ph
(C H CH
2 5) 2 3
53%
(CH A1
3) 3 CH
3
35°C
OH
C H
6 14 ph
86%
Figure 1-1
An additional illustration of the condition dependent
reactions of trimethylaluminum is presented later in
this work (Chapter IV)
A common nucleophilic addition to epoxides is
through the malonic ester synthesis. The resulting
product, a hydroxy ester, can be further manipulated
enroute to a desired target molecule. A major problem
associated with this approach is the rather harsh
conditions necessary for the reaction to proceed, e.g.
refluxing, alkaline ethanol solution. In order to
alleviate this situation, a concentrated research
s
effort has been dedicated to the exploitation of metal
mediated enolate/anion transfer reagents. Work
throughout the field has been focused in the two main
areas of reactivity and selectivity. Prostaglandin
synthesis is itself a very active area of chemical
research. It follows that a breakthrough in metal
mediated anion addition could likely evolve from this
field. Fried demonstrated a useful synthetic approach
Et AlC:=CR
2
R - -C H -CHC H
6 13 ; 5 11
OCH Ph
2
Figure 1-2
shown in Figure 1-2 involving the opening of cyclic
oxiranes with various alanes while working in the area
of prostaglandin synthesis. 6 These reagents were
prepared in toluene by addition of diethylchloroalane
(Et2AlCl) to various lithium acetylides to give the
alkynylaluminums 2. Yields of these reactions ranged
from 30-80% of the anticipated trans-cycloalkanols. 6
Somewhat later (1976) Danishefsky demonstrated
the first examples of the reaction of an aluminum
ester enolate with oxiranes. 7 This acetate eguivalent
was prepared in an analogous way to that of Fried'