A high yielding procedure for preparation of mono-carboxylate surrogates of allenic dicarboxylates and diesters

Article abstract of DOI:10.1081/SCC-120012992

A high yielding procedure for preparation of various allenyl mono-carboxylates is presented.

Full text of DOI:10.1081/SCC-120012992

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A HIGH YIELDING PROCEDURE FOR PREPARATION
OF MONO-CARBOXYLATE SURROGATES OF ALLENIC
DICARBOXYLATES AND DIESTERS
a
a
Thomas R. R. Pettus & Richard H. Schlessinger
a
Department of Chemistry and Biochemistry , University of California at Santa Barbara ,
Santa Barbara, CA, 93106, U.S.A.
Published online: 16 Aug 2006.
To cite this article: Thomas R. R. Pettus & Richard H. Schlessinger (2002) A HIGH YIELDING PROCEDURE FOR PREPARATION OF
MONO-CARBOXYLATE SURROGATES OF ALLENIC DICARBOXYLATES AND DIESTERS, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 32:19, 3019-3025, DOI: 10.1081/SCC-120012992
To link to this article: http://dx.doi.org/10.1081/SCC-120012992
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 19, pp. 3019–3025, 2002
A HIGH YIELDING PROCEDURE
FOR PREPARATION OF
MONO-CARBOXYLATE SURROGATES
OF ALLENIC DICARBOXYLATES
AND DIESTERS
y
Thomas R. R. Pettus* andRichardH. Schlessinger
Department of Chemistry and Biochemistry,
University of California at Santa Barbara,
Santa Barbara, CA 93106, USA
ABSTRACT
A high yielding procedure for preparation of various allenyl
mono-carboxylates is presented.
Key Words: Allene; Thioester; Silylester; Mitsunobu
[
Allenyl dicarboxylates and their correspondingdiesters are readily
1]
[2]
[
3]
accessible five carbon synthons that have proven tremendously versatile.
[5]
[
4]
These systems undergo a myriad of reactions including [4þ2], [3þ2], and
[6]
[7]
[8]
[
2þ2]-cycloadditions, additions with radicals and soft nucleophiles, and
*
{
Correspondingauthor. E-mail: pettus@chem.ucsb.edu
Professor Schlessinger had been a member of the department of chemistry at the
University of Rochester for more than three decades. He passed away on December
1, 1998 at the age of 62 and will be remembered by his students as a colorful teacher
and demandingmentor.
1
3
019
DOI: 10.1081/SCC-120012992
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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3
020
PETTUS AND SCHLESSINGER
Figure 1.
[
9]
sundry metal mediated couplings. Recent reports of procedures for
dynamic kinetic resolution of allenyl carboxylates should significantly
[
10]
increase their applications in enantioselective syntheses as well.
However, differentiatingthe 1,3-dicarboxylate moieties in the adducts often
proves challenging. An obvious solution, using a mono-carboxylate surrogate
in these processes, has been largely ignored because of the difficulty associated
with preparation of a non-symmetric allenyl system.
The previous method (b, Fig. 1) for syntheses of mono-carboxylate
allene derivatives begins with a propargylic alcohol 8, which is converted to
a robust propargylic ether and then coupled as the corresponding acetylide
[
2a]
[11]
with a two-carbon fragment such as an epoxide
or a-diazoester.
The
couplingusually proceeds in less than 50% yield and examples employing
epoxides also require oxidation to an acid and conversion to an ester. The
resultingdeconjugated ynoate is then isomerized into an allenyl system upon
treatment with a catalytic quantity of Et N.
3
Our method (a, Fig. 1) begins instead with the homo-propargylic
alcohol 1. This is protected as an acid-labile ether. Formation of the
lithium acetylide and couplingwith aldehydes, in this instance formalde-
hyde, proceeds in a far greater yield (>80%), than the umpolung cou-
plings of procedure b. The resultingpropar gy lic alcohol can be displaced
with a variety of nucleophiles via a modified Mitsunobu reaction in good
yields. Jones oxidation of the labile homo-propargylic ether furnishes a
deconjugated ynoate that can be esterified and isomerized into the allenyl
system.
The differences between these processes may seem inconsequential,
however, allenes 7a–c (Sch. 1) illuminate the benefits of process (a).
Compounds 7a–c are not accessible by type (b) processes. The route to
these materials begins with 1, which is converted to the silyl ether 2 (94%)
by treatment with TBSCl and imidazole in CH Cl . Next, alkyne 2 is
2
2

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MONO-CARBOXYLATE SURROGATES
3021
Scheme 1. Procedure a.
deprotonated with n-BuLi. The correspondinglithium acetylide smoothly
adds to formaldehyde bubbled into the pot by cracking para-formaldehyde
[
12]
in a separate flask under a nitrogen stream. This combination
results in the formation of the propargylic alcohol 3 (93%), which is
displaced in good yields (82–93%) using a modified Mitsunobu pro-
[
13]
cedure.
t-BuCOSH,
Trimethylacetic acid, as well as the thio-acids CH COSH and
3
[14]
all smoothly couple under these conditions affording 4a–c,
respectively. Submittingthe respective products, which contain an acid-
labile ether, to Jones conditions causes both deprotection and oxidation.
The resultingcarboxylic acids 5a–c are readily purified by base extraction
into an aqueous phase followed by acidification and extraction into an
organic phase. Each acid is produced in >90% yield. The acids are
poised for conversion to any number of ester derivatives. However, we
had a need for a very labile ester derivative and chose to silylate 5a–c.
Treatment of each with a 1 : 1 equiv admixture of TMSCl–HMDS provides
ꢀ
4
6a–c, each respectively in >90% after Kugelrohr distillation (10 torr).
Submission of the pertinent silyl ester (0.05 M in CH Cl ) to a catalytic
2
2
quantity of Et N (0.2 equiv) affords the desired allene monoester (cf. 7a–c)
3
in essentially quantitative yield. These allenes can be stored indefinitely
ꢁ
at ꢀ78 C. It is hoped that the procedure developed for the synthesis of
7a–c may expand the future prospects for allene mono-carboxylates in
synthesis.

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022
PETTUS AND SCHLESSINGER
EXPERIMENTAL
Compound2: To a solution of alcohol (1 equiv 1 M in CH Cl ) at 0 C
ꢁ
2
2
under nitrogen was added imidazole (1.1 equiv) and t-butyldimethylsilyl
chloride (1.1 equiv) and a catalytic quantity of DMAP. The reaction was
ꢁ
ꢁ
stirred at 0 C for 1 h and slowly warmed to r.t. After stirringat 25 C for 4 h,
the reaction was diluted with ether/hexanes (4 : 1) and filtered through celite.
The solvent was evaporated and the material was purified by distillation
ꢁ
1
(
(
(
45 C, 2 torr, 94%) to give the TBS ether as a colorless oil. H-NMR
300 MHz, CDCl ) ꢀ 3.76 (m, 2H), 2.42 (m, 2H), 1.98 (m, 1H), 0.92
3
s, 9H), 0.08 (s, 6H).
Compound3: To a solution of alkyne (1 equiv, 1 M in Et O) at ꢀ78 C
ꢁ
2
under nitrogen was added n-BuLi (1.1 equiv, 1.54 M). The contents were
ꢁ
warmed to 0 C and stirred for 1 h. A nitrogen stream was passed through
a separate round bottom flask containingexcess solid (CH O) heated to
2
n
ꢁ
150 C, through a clean glass tube, and bubbled into the Et O solution of the
lithium acetylide at 0 C until the Et O solution turned cloudy. The reaction
2
ꢁ
2
was diluted with ether and quenched with 5% aqueous citric acid solution.
The organic layer was separated, dried over Na SO and filtered through
celite. After removal of solvent, the material was purified by distillation
2
4
ꢁ
(
110 C, 0.2 torr, 87%) to give the propargyl alcohol as a colorless oil.
H-NMR (300 MHz, CDCl ) ꢀ 4.23 (m, 2H), 3.75 (m, 2H), 2.47 (m, 2H),
1
3
1
.7 (br m, 1H), 0.97 (s, 9H), 0.07 (s, 6H).
Compounds 4a–c: To a stirred solution of PPh (2 equiv) 0.5 M in
3
ꢁ
THF at 0 C was added DIPAD (2 equiv). A white precipitate resulted
ꢁ
after stirringfor 1 h at 0 C. The propargyl alcohol was added neat
(
1 equiv) and followed by the addition of the appropriate acid (2 equiv).
After stirringfor 4 h, the volatiles were removed and the residue was taken
up in (hexanes : Et O, 4 : 1), washed with aqueous NaHCO , filtered
2
3
through celite and the volatiles were removed. This process was continued
until no solids remained. Dryingand evaporation igv es the respective
ester as a yellow oil. The S or O ester could be used directly in subsequent
1
Jones oxidation without purification. Compound4a:
(
9
87% H-NMR
300 MHz, CDCl ) ꢀ 4.61 (t, 2H), 3.73 (t, 2H), 2.45 (m, 2H), 1.22 (s,
3
1
H), 0.97 (s, 9H), 0.09 (s, 6H). Compound4b: 82% H-NMR (300 MHz,
CDCl ) ꢀ 3.72 (m, 2H), 3.68 (t, 2H), 2.47 (m, 2H), 2.42 (s, 3H), 0.97
3
1
(
s, 9H), 0.08 (s, 6H). Compound4c: 93% H-NMR (300 MHz, CDCl ) ꢀ
3
3
(
.72 (m, 2H), 3.63 (m, 2H), 2.41 (m, 2H), 1.32 (s, 9H), 0.97 (s, 9H), 0.08
s, 6H).
Compounds 5a–c: To a stirred solution of the TBS–ether (1 equiv) in
ꢁ
acetone (0.25 M solution) at ꢀ78 C was added Jones reagent (4 equiv of an
ꢁ
8
M solution). The reaction was permitted to warm to 25 C and stirring

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MONO-CARBOXYLATE SURROGATES
3023
was continued for 2 h. Upon completion by TLC analysis, isopropyl alco-
hol (1 equiv) was added slowly. After stirringfor an additional 20 min, the
reaction was diluted with ether and solids were removed by filtration
through celite. Volatiles were removed at reduced pressure and the residue
was dissolved in ether. After basification with saturated aqueous NaHCO3,
the organic phase was separated and discarded. The aqueous solution was
acidified with solid citric acid. After extraction with ether, the organic
layer was dried and the volatiles removed to give a crystalline white
1
solid. Compound5a: 93% H-NMR (300 MHz, CDCl ) ꢀ 7.5–5.0 (br,
3
1
H), 4.71 (s, 2H), 3.48 (s, 2H), 1.22 (s, 9H). Compound5b: 95% H-
1
NMR (300 MHz, CDCl ) ꢀ 7.5–6.5 (br, 1H), 3.70 (s, 2H), 3.59 (s, 2H),
3
1
2
.39 (s, 3H). Compound5c: 94% H-NMR (300 MHz, CDCl ) ꢀ 7.5–4.0
3
(
br, 1H), 3.70 (s, 2H), 3.65 (s, 2H), 1.22 (s, 9H).
Compounds 6a–c: To a stirred solution of the acid (1 equiv 1 M in
ꢁ
CH Cl ) at 0 C was added HMDS (1.1 equiv); followed by the slow addi-
2
2
ꢁ
tion of TMSCl (1.1 equiv). The reaction was permitted to warm to 25 C
and stirringwas continued for 6 h. The reaction was then diluted with
ether and the solids were removed by filtration through celite. Once the
volatiles were removed, the cloudy material was purified by distillation
(
1
92% H-NMR
0.01 torr) affordingcolorless oils.
Compound6a:
(
9
3
300 MHz, CDCl ) ꢀ 4.77 (s, 2H), 3.36 (s, 2H), 1.43 (s, 9H), 0.42 (s,
3
1
H). Compound6b: 94% H-NMR (300 MHz, CDCl ) ꢀ 3.70 (s, 2H),
3
1
.33 (s, 2H), 2.46 (s, 3H), 0.42 (s, 9H). Compound6c: 92% H-NMR
(
300 MHz, CDCl ) ꢀ 3.70 (s, 2H), 3.38 (s, 2H), 1.28 (s, 9H), 0.42 (s, 9H).
3
Compounds 7a–c: To a stirred solution of the TMS-ester 0.5 M in
ꢁ
ꢁ
CH Cl at 0 C was added Et N (0.2 equiv) and the reaction stirred at 0 C
2
2
3
for 6 h. The volatiles (Et N) were removed, a crystal of Rose Bengal was
3
ꢁ
added for stabilization and the material was stored at ꢀ78 C for use in
1
subsequent reactions. Compound7a: >98% H-NMR (300 MHz, CDCl )
3
ꢀ
5.73 (m, 2H), 4.65 (m, 2H), 1.25 (s, 3H), 0.38 (s, 9H). Compound7b: >98%
1
H-NMR (300 MHz, CDCl ) ꢀ 5.71 (m, 2H), 3.61 (m, 2H), 2.44 (s, 3H), 0.41
3
1
(
s, 9H). Compound7c: >98% H-NMR (300 MHz, CDCl ) ꢀ 5.71 (m, 2H),
3
3.54 (m, 2H), 1.27 (s, 9H), 0.41 (s, 9H).
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¨
¨
Received in the USA September 14, 2001

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