Substituted furans from butenolides

A method of preparing alkoxy and acyloxy furans from butenolides comprising reacting a butenolide with an alkylating agent in the presence of a base to provide an alkylated or acylated furan ring containing intermediate, which in turn is reacted under metallating conditions with an organic electrophile to provide addition of the electrophile to the gamma position of the furan ring. Under the conditions of the reaction, it has been discovered that the butenolide ring will undergo rearrangement to provide the furan ring, forming the nucleus for synthesis of a wide variety of furan compounds.

BACKGROUND OF THE INVENTION 
This invention relates to preparation of substituted alkoxy and acyloxy 
furans using as starting materials butenolides. Prior to this invention 
there has been no reasonable synthetic method for the general preparation 
of alkoxy furans or acyloxy furans. Often such compounds have been 
painstakingly and meticulously isolated from natural sources. This is very 
expensive, time consuming and does not provide significant product yields. 
As those skilled in the art know and understand, furan compounds are those 
which contain at some point in the compound's structure the following 
common nucleus: 
##STR1## 
Such furan ring containing compounds are valuable presursors for the 
preparation of a wide variety of biologically active compounds. They can, 
for example, be successfully used as the starting point for preparation of 
complex butenolides, of other substituted furans, and they can be used for 
the making of such biologically active compounds, such as lycorine which 
is an anti-bacterial agent whose structure represents a challenge to 
present methods of synthesis, gibberelic acid, which is an important plant 
growth regulator that is not easily available from natural sources, and 
protoanemonin and its substituted derivatives, among others. In short, the 
number of desirable biologically active compounds which can be prepared 
using as a nucleus the furan moiety, is almost limitless. However, the 
effective utilization of furans as a precursor for preparation the 
numerous desirable biologically active compounds such as those listed 
above has met with only limited success and usage in the past. This is so 
primarily because of the difficulty of obtaining the furan starting 
materials. 
Accordingly, the primary object of this invention is to provide a synthesis 
process which allows for quick, easy, high yield preparation of furan 
compounds. 
Another object of this invention is to provide a synthetic process for 
furans which in turn can be used as building blocks for preparing a wide 
variety of biologically active compounds. 
Yet another object of this invention is to provide a synthetic process for 
furans which uses readily available butenolides as a starting material, 
which under the conditions of the reactions of this invention, undergo 
rearrangement to the furan ring. 
An even further object of this invention is to provide a process of 
alkylating butenolides to provide an alkylated furan intermediate which 
will quickly and easily add an electrophilic agent, under metallating 
conditions to provide a substituted furan. 
The method and manner of accomplishing these objects of this invention, as 
well as others, will become apparent from the detailed description of the 
invention, which follows. 
SUMMARY OF THE INVENTION 
A butenolide or substituted butenolide wherein the substituted moiety is a 
non-functionally substituted alkyl, alkenyl, alkynyl, or an aryl is 
reacted with an alkylating agent, such as a trialkyl chlorosilane, in the 
presence of a base and a suitable organic solvent, to provide an alkylated 
furan ring containing intermediate. The intermediate in turn is reacted 
under metallating conditions with an organic electrophile to provide 
addition of the electrophile to the furan ring at a position which 
corresponds to the gamma position of the original butenolide ring. 
DETAILED DESCRIPTION OF THE INVENTION 
In accordance with the first step of the process of this invention, a 
butenolide of the following formula is the starting material: 
##STR2## 
As can be seen, the starting butenolide may if desired be substituted at 
the alpha and beta position. It cannot, however, be substituted at the 
gamma position since after the subsequently described rearrangement to a 
furan, the electrophile is added at the gamma position of the starting 
butenolide. 
R and R' can be selected from the group consisting of hydrogen, and 
nonfunctionally substituted alkyls, alkenyls, alknyls and aryls. The R and 
R' moieties must be non-functionally substituted in order to prevent 
undesired side reactions from occurring on these side chain moieties, as 
opposed to undergoing the desired furan rearrangement. For example, it has 
been found that if either R or R' is substituted with the carbomethoxy 
group, the reaction fails. Preferably R and R' are C.sub.1 to C.sub.12 
substituents. 
The butenolide in the first step reaction is reacted with an alkylating 
agent which must be a trialkyl halosilane alkylating agent of the 
following formula: 
##STR3## 
X represents any halide. It is, however, most preferably chloride. A, B 
and C represent alkyl groups, preferably C.sub.1 to C.sub.12 alkyl groups 
either straight or branched chain. The most preferred trialkyl halosilane 
alkylating agent is butyl dimethylchlorosilane in which A and C are 
dimethyl groups and B represents tertiarybutyl group. Tertiary 
butyldimethylchlorosilane is the most preferred alkylating agent because 
of easy availability and the good results achieved when it is used as the 
alkylating agent. 
The butenolide and the alkylating agent are reacted together in the 
presence of a base and a substantially inert solvent. The solvent maybe 
any anhydrous inert solvent such as ether and tetrahydrofuran or 
dimethoxyethane, commonly referred to as glyme. The purpose of the base is 
to remove a proton from the gamma position of butenolide ring. Suitable 
bases are well known and the work-up for such bases is well known in the 
art. Bases which will work in the reaction of this invention are 
preferably the dialkylamide bases which are formed by the reaction of 
alkyl lithiums and dialkyl amines. Preferably the alkyl group is C.sub.2 
or greater. For example, tertiarybutyllithium with a compound such as 
disopropyl amine may be dissolved in tetrohydrofuran (THF) and 
hexamethylphosphoric triamide (HMPA) to provide a base such as 
di-isopropyl lithium amide represented by the following formula: 
EQU i-Pr.sub.2 N Li 
Preparation of the bases suitable for reaction in this invention is well 
known and will not be described in detail. For further reference to the 
preparation of bases, see for example J. American Chemical Society, 89 
(1967) at pages 2500 through 2503 which is incorporated herein by 
reference. 
Since the reaction ingredients for this reaction are highly reactive, it is 
preferable, and in most cases essential that the reaction be conducted in 
an inert atmosphere such as an argon or nitrogen atmosphere. Any oxygen 
which is present will react with the base and the intermediate carbanion 
which is formed. It is for this reason that the system is flushed with an 
inert gas. 
The reaction of the butenolide and the preferred trialkylchlorosilane 
alkylating agent, in the presence of a base will provide addition of the 
alkylating agent on the butenolide ring and rearrangement to a furan ring. 
The resulting intermediate compound has the following formula. 
##STR4## 
It has been found most desirable and efficient when equimolar quantities of 
all reactants are employed. Reaction temperatures likewise are not 
critical, although it has been found desirable to react at room 
temperature, or lower. Pressure does not appear to be a controlling 
factor. Atmospheric pressure works satisfactorily. 
As can be seen from the structural formula presented for the alkylated 
compound, there is a rearrangement from the butenolide ring formation in 
the initial starting reactant to the furan ring arrangement. The 
intermediate alkylated compound is next reacted, under metallating 
conditions, with an organic electrophile in order to add the organic 
electrophilic agent to the furan ring at the gamma position. 
Again, metallating conditions are well known to those skilled in the art of 
organic synthesis and need not be detailed herein any further than is 
specifically detailed in the examples. However, basically the metallation 
is accomplished by reacting the desired organic electrophilic agent with 
the intermediate alkylated compound in the presence of an alkyl lithium 
compound. A suitable alkyl lithium compound is tertiarybutyllithium. 
Preferably the reaction is conducted in the presence of ether. 
In the metallating reaction wherein the trialkyl silyl substituted furan is 
reacted with an organic electro-philic reagent, the suitable electrophile 
is almost limitless. It can be any preselected organic compound which is 
desired for addition at the gamma position of the furan ring. The exact 
electrophile used will, of course, depend upon the furan which one is 
synthesizing. The reaction can be represented by the following formula: 
##STR5## 
In the above reaction the electrophile is represented by E. 
The suitable electrophilic agents and conditions for the reaction are 
specified in the examples below. There is no criticality to reaction 
conditions, but generally it is preferred that the equal molar quantities 
of the reactants be employed, that the reaction be conducted under an 
inert atmosphere, and that ambient temperatures or sub-ambient conditions 
be employed. Atmospheric pressure is very satisfactory. 
As heretofore mentioned, there is no criticality with regard to the 
electrophilic addition compound being used, its precise structure being 
chosen by the desired structure selected for addition to the furan ring. 
Generally, however, both substituted and unsubstituted, straight chain, 
branched chain and cyclic compounds may be used as well as aromatics, both 
substituted and unsubstituted. Examples of suitable electrophiles include: 
disulphides, alkylhalides, aldehydes, ketones, acid chlorides, 
halosilanes, and epoxides. After the electrophilic agent has been added to 
metallated furan, the silane moiety may be removed if desired by the 
addition of a dilute aqueous acid such as p-toluene sulfonic acid in 
aqueous THF. Such removal reactions again are likewise well known and for 
a general description thereof see J. American Chem. Soc. 94, (1972) at 
pages 6190 through 6192 which are incorporated herein by reference. The 
removal procedure is also explained further in the examples.

The following samples will serve to illustrate the synthesis and scope of 
the invention but are not intended as limiting. 
EXAMPLES 1 THROUGH 9 
In each of the following examples butenolide was reacted with an alkylating 
agent which comprised a trialkylchlorosilane, namely, dimethyl tertiary 
butylchlorosilane in tetrahydrofuran solvent in the presence of i-Pr.sub.2 
N base and hexamethyl phosphoric triamide to provide an 85% yield of an 
intermediate furan oxy silane of the formula: 
##STR6## 
The equation for the reaction is as follows: 
##STR7## 
The amounts of each ingredient were equal molar amounts and are listed in 
Table I below. The reaction was run at atmospheric pressure, under a 
nitrogen atmosphere. Cooling of the reaction ingredients was by a dry 
ice-acetone bath. 
TABLE I 
______________________________________ 
tert-Butyl, 
dimethyl 
.DELTA. 
Butenolide 
BuLi i-Pr.sub.2 NH 
HMPA silyloxy furan. 
______________________________________ 
MW 84 2.45W 101 179 151 
GMS 1.0 1.44 2.33 2.0 
M1 5.31 2.00 2.26 
Moles 12 13 14.3 13 13.2 
______________________________________ 
The reaction was conducted at -78.degree. C. initially and allowed to 
gradually warm to 0.degree. C. The ingredients were added in the following 
manner. The butenolide was added to the tetrahydrofuran solvent which in 
turn was added to the Lithium-diisopropyl-amide-HMPA complex at 
-78.degree. C. over a ten minute period. Stirring continued for 20 minutes 
and then the tertiary butyldimethylchlorosilane alkylating agent was added 
rapidly. Stirring continued for an additional ten minutes at -78.degree. 
C. and then for an additional 60 minutes at 0.degree. C. After the 60 
minutes of continual stirring at 0.degree. C., the reaction mixture was 
poured into approximately 200 milliliters of hexane. The organic layer 
which separated was washed twice with 50 milliliters of water and once 
with a 25 milliliter of brine solution, followed by drying with sodium 
sulfate. It was thereafter filtered and roto-evaporated. Chromotography 
analysis was conducted to reveal an 85% yield of the desired furan ring 
containing compound. 
Thereafter, the separated intermediate was utilized in the second step 
reaction procedure for reacting with an electrophile in the presence of a 
metallating agent to provide the substituted furan. 
The amount of each ingredient was in accordance with Table II below. The 
product of Example 1 is a substituted analog of protonanemonin, which is 
known to possess physiological activity according to J. Med. Chemistry, 
11, 1176. 
__________________________________________________________________________ 
Amount of 
Alkylated Amount of 
Furan 
Ex. 
Intermediate 
t-BuLi 
E E Product Yield 
__________________________________________________________________________ 
1. 1.082 gms 
.36ml. 
6-methyl-5-heptene-2-one 
0.5 gms 
1.11 gms 
70% 
2. 0.99 3.3 
##STR8## .600 .97 gms 61% 
3. 0.99 3.3 
##STR9## .38 .62 45% 
4. 0.99 3.3 
##STR10## .50 .65 44% 
5. 0.99 3.3 
##STR11## 1.55 2.06 81% 
6. 0.99 3.3 ClCO.sub.2 Et .53 .94 70% 
7. 0.99 3.3 PhSSPh 1.09 1.22 80% 
8. 0.99 3.3 CH.sub.3 I .75 .69 65% 
9. 0.99 3.3 ClSi(CH.sub.3).sub.3 
.61 1.24 92% 
__________________________________________________________________________ 
In conducting the second step reaction the procedure was as follows: The 
tertiary butylithium was added to the tertiary butyl dimethylsiloxyfuran 
at -50.degree. C. It was allowed to warm to -40.degree. C. and then 
stirred for 60 minutes. Thereafter, it was cooled to -60.degree. C. and 
the electrophile, dissolved in ether was added. It was allowed to warm 
slowly to 0.degree. C. and then quenched with one normal hydrocholoric 
acid. The dilute ether layer was washed once with 15 milliliters of one 
normal hydrochloric acid, and once with a brine solution. It was 
thereafter dried with sodium sulfate, filtered and roto-evaporated. 
Chromatographic analysis of the product was then conducted in order to 
determine the percent yield of the desired furan product. Percents are 
reported in Table II under the heading "Yield". 
As can be seen, complex furan products have been provided at the lowest 
yield level of 44% and at the highest yield level (see example 9) of 92%. 
Thus, the invention has provided for a simple effective synthetic route 
for converting butenolide compounds to complex furans. Moreover, the 
reaction is a simple two-step reaction with a minimum of complex 
procedures involved.