α-tosyloxyketones: Convenient [4+3] cycloaddition precursors

Article abstract of DOI:10.1055/s-2002-20474

A concise, simple two-step method for the preparation of [4+3] cycloadducts from ketones using Koser's reagent and trifuoroethanol-triethylamine has been developed. This sequence affords yields similar to those obtained using the α-halo and α-mesyloxyketo

Full text of DOI:10.1055/s-2002-20474

LETTER
489
-Tosyloxyketones: Convenient [4+3] Cycloaddition Precursors
S
-Tosyloxyke
t
c
ones: Conv
o
enient [4+3]
t
Cycloa
t
ddition Precu
T
r
sors . Handy,* Maurice Okello
Department of Chemistry, State University of New York at Binghamton, Vestal Parkway East, Binghamton, NY 13902-6000
Fax +1(607)7774478; E-mail: shandy@binghamton.edu
Received 16 November 2001
Table 1 Preparation of -Tosyloxyketones
Abstract: A concise, simple two-step method for the preparation of
Yielda
89%
[4+3] cycloadducts from ketones using Koser's reagent and trifluo-
roethanol–triethylamine has been developed. This sequence affords
yields similar to those obtained using the -halo and -mesyloxyke-
tones, but with the advantages of simplicity in preparation and sta-
bility of the intermediates.
Entry
1
Ketone
Product
O
O
Ts
Ts
Key words: cycloaddition, ketones, cations, sonication, sulfonyl
2
3
82%
94%
O
O
The [4+3] cycloaddition of dienes with allylic cations has
a long and versatile synthetic history.1 Of the numerous
sources of the cation for this reaction (allylic halides, al-
lylic alcohols, haloenamines, haloketones), those which
undergo base-induced solvolysis are the most heavily em-
ployed. In particular, -haloketones have been used to
great advantage in a variety of synthetic efforts. Neverthe-
less, they suffer from two significant limitations: difficul-
ty in preparation and limited stability. Thus, direct
chlorination or bromination of ketones typically results in
significant amounts of over halogenation. The usual solu-
tion to this situation is halogenation of a preformed eno-
late or enolate equivalent (silyl enol ether), although even
then over-halogenation can still occur.2
O
O
Ts
a Yields of product isolated by trituration.
with sonication affords the desired -tosyloxy ketones in
generally good yields.5 The resulting products can be
readily isolated either by chromatography or, more conve-
niently, by trituration with hexanes to remove the iodo-
benzene by-product.6,7 In our hands, these
-
A less common alternative that avoids the complications
encountered with halogenation is to employ -mesylox-
yketones.3 These substrates are prepared from the corre-
sponding -hydroxy ketone. As such, over-mesylation is
not an issue. But, since the starting hydroxyketones are
rarely commercially available, this method of oxyallyl
cation generation typically requires a minimum of two
steps. Even after preparing the -mesyloxyketone, their
stability is sufficiently limited to preclude purification by
either distillation or chromatography. As a result, they
generally are prepared and then used directly in the [4+3]
reaction. This can lead to diminished yields and increased
side-products depending upon the efficiency of the mesy-
lation step.
tosyloxyketones were stable for several days at room tem-
perature and for several weeks in the refrigerator. As such,
they offer benefits over existing oxyallyl cation precur-
sors.
Despite the ease of preparation, the question remained as
to how they would compare to other [4+3] precursors. In
the event, -tosyloxyketone 1 (X = OTs) was treated with
furan under Föhlisch conditions to afford the anticipated
[4+3] cycloadduct in 60% yield after 4 hours.8 A compar-
ison of this result with that reported for other oxyallyl cat-
ion precursors is seen in Table 2. From this data, it can be
seen that the tosyloxyketone not only works in the [4+3]
reaction, but does so with similar rates and yields as the
chloro and bromo precursors.
A noteworthy absence from this list of potential oxyallyl-
cation precursors is -tosyloxyketones.4 One would ex-
pect that they should maintain similar reactivity to the me-
sylates, but with improved stability. More importantly,
they can be prepared directly from the parent ketones, as
seen in Table 1. Using a method reported by Tuncay,
treatment of ketones with Koser’s reagent in acetonitrile
Based on this encouraging result, the scope and limita-
tions of this reaction were explored. As seen in Table 3,
tosyloxyketones derived from cyclohexanone, cyclopen-
tanone, and 3-pentanone all afforded good yields of the
[4+3] cycloadducts with furan under the trifluoroethanol–
triethylamine conditions.10,11 An attempt using a solution
of lithium perchlorate in diethyl ether as the solvent (entry
2) showed no particular advantage, although this solvent
has been used to advantage in previous reports.12 All of
these reactions were performed with tosyloxyketones that
had been purified by chromatography. Similar results
Synlett 2002, No. 3, 04 03 2002. Article Identifier:
1437-2096,E;2002,0,03,0489,0491,ftx,en;S07901ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

490
S. T. Handy, M. Okello
LETTER
Table 2 [4+3] Reactions with Cyclohexanones
Table 4 [4+3] Reactions with Cyclopentadienea
O
Yieldb
51%c
O
O
Entry
1
Ketone
Product
X
O
Ts
Et3N, CF3CH2OH
1
O
Yielda
60%
84%
70%
O
O
O
Entry
1
X
Time
4 h
2
3
59%d
70%e
O
Ts
Br
Cl
Ts
2b
3 d
3c
3 d
a Isolated yield.
O
b Data from ref.8
c Data from ref.9
Ts
were obtained with tosyloxyketones that were isolated by
simple trituration of the crude product from the reaction
with Koser’s salt. As a result, both steps could be carried
out with only a single chromatographic purification after
the [4+3] reaction.
a Reactions performed 0.5 M in a 1:1 v/v mixture of furan and triflu-
oroethanol with 1.8 equiv of triethylamine.
b Isolated yield over the two steps.
c 12:1 ratio of endo:exo isomers by 1H NMR.
d 5:1 ratio of endo:exo isomers by 1H NMR.
e 2.5:1 ratio of , -dimethyl: , -dimethyl isomers by 1H NMR.
Attempts using cyclopentadiene as the diene also afforded
good results (Table 4).11 These reactions were more rapid,
being complete in under 60 minutes at 0 °C. Unfortunate-
ly, attempts to extend these reaction conditions to less re-
active dienes such as cyclohexadiene or trans-piperylene
afforded very modest results which is in keeping with
general observations for the [4+3] cycloaddition of -halo
ketones.1 As such, the tosyloxy systems offer the advan-
tages of enhanced stability and simplicity of preparation,
but do not appear to afford any reactivity advantages.
Table 3 [4+3] Reactions with Furana
Entry
1
Ketone
Product
Yieldb
In conclusion, we have developed a new method for the
preparation of [4+3] cycloadducts in only two steps start-
ing from simple, readily available ketones. The overall
yields have not been highly optimized, but are still com-
petitive with other methods currently available. In partic-
ular, taking advantage of the ease with which the
sonication conditions can be employed, this modification
of standard oxyallyl cation precursors should find consid-
erable utility in organic synthesis.
60%
(33%)
O
O
Ts
2
(35)c
O
3
70%
(30%)
O
O
O
Ts
Acknowledgement
O
O
The authors thank the State University of New York at Binghamton
and the Research Foundation for financial support of this work.
4
57%
O
(47%)d
Ts
References
(1) For general reviews of [4+3] reactions, see: (a) Rigby, J. H.;
Pigge, F. C. Organic Reactions, Vol. 51; John Wiley &
Sons, Inc.: New York, 1997, 351–478. (b) Cha, J. K.; Oh, J.
Curr. Org. Chem. 1998, 2, 217. (c) Harmata, M.
a Reactions performed 0.5 M in a 1:1 v/v mixture of furan and triflu-
oroethanol with 1.8 equiv of triethylamine.
b Isolated Yield. Yields in parentheses are overall yields for the 2
steps with isolation of the -tosyloxyketone by trituration with
hexanes.
Tetrahedron 1997, 53, 6235.
(2) For a discussion of various methods for the halogenation of
ketones, see: House, H. O. Modern Synthetic Reactions, 2nd
Ed.; W. J. Benjamin Inc.: Menlo Park, CA, 1972, 459–478.
(3) This alternative has been most extensively explored by
Föhlisch and co-workers. For examples, see: Föhlisch, B.;
c Reaction performed 0.5 M in a 1:1 v/v mixture of furan and 1 M
LiClO4–Et2O with 1.8 equiv of triethylamine.
d 21:1 mixture of the , -dimethyl and the , -dimethyl isomers by
1H NMR.
Synlett 2002, No. 3, 489–491 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
-Tosyloxyketones: Convenient [4+3] Cycloaddition Precursors
491
Herrscher, I. Chem Ber. 1986, 119, 524; and further papers
from this group.
brown solution. After removal of the volatiles in vacuo, the
residue was dissolved in methylene chloride (15 mL) and
washed with saturated aqueous NaHCO3 (3 5 mL). The
organic layer was dried with magnesium sulfate and
concentrated in vacuo. The residue was then triturated with
minimal hexane (2 mL) at ice-bath temperatures to afford
0.375 g (89%) of a pale yellow solid.
(4) One similar variation that has been reported is the use of
-
keto trifluoromethanesulfones. This option has been used in
a number of intramolecular cycloadditions reported by the
Harmata and co-workers. For examples, see: Harmata, M.
Acc. Chem. Res. 2001, 34, 595.
(5) (a) Tuncay, A.; Dustman, J. A.; Fisher, G.; Tuncay, C. I.;
Suslick, K. S. Tetrahedron Lett. 1992, 33, 7647. (b) For a
review of the use and preparation of -tosyloxy and
mesyloxy ketones, see: Moriarty, R. M.; Prakash, O.
Organic Reactions, Vol. 54; John Wiley & Sons, Inc.: New
York, 1999, 273–418.
(6) We have noted that chromatographic purification of the
tosyloxyketones is generally unnecessary. Trituration with
hexanes is sufficient to remove virtually all of the
iodobenzene by-product and afford the products as white,
crystalline solids with melting points identical to those
reported in the literature. Further, in our studies using a
standard sonication cleaning bath, the yield of the reaction is
very dependent upon the location in the bath (and thus, the
strength of the sonication). Optimization in terms of the
location of the flask may be necessary to reproduce the
yields reported here and in ref.5
(7) Representative Procedure: To 0.650 g (1.67 mmol) of
[hydroxy(tosyloxy)iodo]benzene in a dry round-bottom
flask under argon were added 2 mL of cyclohexanone and 15
mL of acetonitrile. The flask was placed in an ultrasound
cleaning bath filled with warm (55 °C) water to a depth of 2
inches. The reaction mixture was sonicated for 15 minutes,
during which time the suspension cleared to a yellowish-
(8) For the first report of these now-standard conditions, see:
Föhlisch, B.; Gehrlach, E.; Herter, R. Angew. Chem. Int. Ed.
Engl. 1982, 21, 137.
(9) Jin, S.; Choi, J.-R.; Oh, J.; Lee, D.; Cha, J. K. J. Am. Chem.
Soc. 1995, 117, 10914.
(10) Representative Procedure: To 0.1928 g (0.7194 mmol) of
2-tosyloxycyclohexanone in 0.72 mL of furan was added
0.72 mL of 2,2,-trifluoroethanol at 0 °C under argon. The
mixture was stirred and 187 L (1.35 mmol) of triethylamine
was added slowly and the reaction was allowed to warm to
room temperature. After 4 hours, TLC indicated complete
consumption of starting material. The reaction mixture was
diluted with water (10 mL) and extracted with diethyl ether
(5 5 mL). The combined organics were washed with
saturated aqueous NaHCO3, dried with magnesium sulfate,
and concentrated in vacuo. The resulting residue was
purified by chromatography (elution with 1:4 ethyl acetate–
hexanes) to afford 70.8 mg (60%) of the cycloadduct as a
pale yellow solid.
(11) All compounds exhibited spectroscopic data consistent with
that reported in the literature.
(12) For the first report using these conditions, see: Herter, R.;
Föhlisch, B. Synthesis 1982, 976.
Synlett 2002, No. 3, 489–491 ISSN 0936-5214 © Thieme Stuttgart · New York