A new convergent approach to α-branched alkynes

Article abstract of DOI:10.1055/s-2002-32956

A variety of α-branched alkynes can be easily assembled by a Knoevenagel type condensation of 4-unsubstituted isoxazolin-5-ones with aldehydes or ketones, followed by conjugate addition of an organometallic reagent and nitrosative cleavage of the heterocy

Full text of DOI:10.1055/s-2002-32956

LETTER
1257
A New Convergent Approach to -Branched Alkynes
New
Convergent
A
e
pproach to
l
-Bran
p
c
hed Alkyn
hes ine Renard, Hadi Rezaei, Samir Z. Zard*
Laboratoire de Synthèse Organique associé au CNRS, Ecole Polytechnique, 91128 Palaiseau, France
Fax +3(1)69333851; E-mail: zard@poly.polytechnique.fr
Received 7 June 2002
tones to give 4-alkylidene derivatives 2.3 Surprisingly, the
ability of such highly electrophilic condensation products
to act as acceptors for organometallic reagents has hardly
been examined in the past. The rare existing reports de-
scribe the addition of Grignard reagents to 4-arylidene de-
rivatives (2, R2 = Ar; R3 = H) obtained by condensation of
1 with aromatic aldehydes.4 We have now found that by
the appropriate selection of the organometallic reagent,
this conjugate addition acquires a much wider scope and
can be exploited for the preparation of -branched alkynes
with a range of interesting substitution patterns, including
quaternary centres which are difficult to prepare by more
traditional routes.
Abstract: A variety of -branched alkynes can be easily assembled
by a Knoevenagel type condensation of 4-unsubstituted isoxazolin-
5-ones with aldehydes or ketones, followed by conjugate addition
of an organometallic reagent and nitrosative cleavage of the hetero-
cyclic ring.
Key words: alkynes, isoxazolin-5-ones, Knoevenagel condensa-
tion, conjugate addition
Alkynes play a central role in organic synthesis. Their rich
and varied chemistry, highlighted by their amazing ability
to participate in a vast number of transition metal mediat-
ed transformations, has frequently been exploited in the
total synthesis of natural and unnatural products of all
types and complexities.1 Finding new, flexible methods
for creating the carbon-carbon triple bond remains there-
fore a worthwhile endeavour. We now describe a simple,
convergent strategy that allows access to -branched
alkynes including those with adjacent quaternary centres.
Our approach, outlined in Scheme 1, relies on the conju-
gate addition of an organometallic species to a 4-alky-
lidene-isoxazolin-5-one 2, followed by the nitrosative
cleavage of the heterocyclic ring to create the C-C triple
bond, a reaction we discovered a few years ago.2 A com-
bination of sodium nitrite, aqueous acetic acid, and fer-
rous sulfate is used to accomplish the second
transformation, the last reagent being required to generate
nitric oxide in the medium and thus suppress, through the
persistent radical effect, the unwanted formation of isox-
azolidinone dimers by radical-radical coupling.2a
Scheme 2 Conditions (i) Vinyl MgBr or allyl MgBr or ethynyl
MgBr–THF, –70 °C. (ii) NaNO2–FeSO4–AcOH–H2O, r.t.
Compound 2a, prepared quantitatively as one geometrical
isomer (presumably the one shown) by condensation of
commercially available 3-phenyl-isoxazolin-5-one with
benzaldehyde in the presence of a small amount of piperi-
dine, reacted smoothly with allyl, vinyl, and ethynyl mag-
nesium bromides to give the corresponding adducts 3a–c
and thence alkynes 4a–c upon nitrosative cleavage
(Scheme 2). Such enynes and diynes are useful substrates
in a number of transition metal mediated transformations.5
Both the organometallic reagents and the initial substitu-
tion pattern on the heterocyclic ring can be varied, as illus-
trated by the examples compiled in the Table (the yields
shown are for the two steps, since in most cases the adduct
from the reaction with the organometallic reagent was not
purified). We were pleased to find that organozinc re-
agents also underwent the addition smoothly. The much
greater tolerance of organozinc reagents with respect to
the presence of functional groups opens up many possibil-
ities for the synthesis of -branched yet usefully function-
4-Unsubstituted isoxazolinones 1 are known to undergo a
Knoevenagel type condensation with aldehydes and ke-
Scheme 1
Synlett 2002, No. 8, Print: 30 07 2002.
Art Id.1437-2096,E;2002,0,08,1257,1260,ftx,en;D12802ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

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D. Renard et al.
LETTER
alised alkynes.6 The addition of allenylzinc reagent trimethylsilylalkyne portion of the molecule constitutes a
leading to alkyne 4n pictured in Scheme 3 is of special in- further testimony to the mildness of the nitrosative cleav-
terest because essentially one diastereoisomer was ob- age of the isoxazolinone ring.
tained, but of as yet undetermined relative stereo-
chemistry. Moreover, the survival of the relatively fragile
In the case of organometallic additions to 4-alkylidene-
isoxazolin-5-one 2 derived from aliphatic ketones, the
difficulties we encountered resulted from the acidity of
the -hydrogens and the ready formation of the corre-
sponding salts 6. Grignard reagents did not therefore add
well; however, the less basic organozinc and organocop-
per reagents proved satisfactory allowing the convenient
creation of quaternary centers (examples 4l and 4m). In
the case of aliphatic aldehydes, one further complication
appears to be the easy formation of bis-addition products
5.3 One notable exception is cyclopropane-carboxalde-
hyde whose derivative could be transformed cleanly into
alkyne 4i possessing a rare substitution pattern.
Despite some of the limitations we have so far observed
and which we are attempting to circumvent, this approach
to -branched alkynes is straightforward,8 quite flexible,
and provides structures only tediously accessible other-
wise. The 4-alkylidene-isoxazolin-5-ones represent in
fact practical synthetic equivalents of propargyl cations.
One further aspect worth underlining concerns the possi-
bility of controlling the absolute stereochemistry by using
chiral ligands in conjunction with the organozinc re-
agents.7
Scheme 3
Table Synthesis of -Branched Alkynes
4-Alkylidene isoxazolidin-5-one 2
Adduct 3 (Organo-metallic reagent)a
Alkyne 4 (yield %)
2d
3d (a)
4d (37%)
4e (66%)
2e
2f
3e (a)
3f (a)
4f (31%)
Synlett 2002, No. 8, 1257–1260 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
New Convergent Approach to -Branched Alkynes
1259
Table Synthesis of -Branched Alkynes (continued)
4-Alkylidene isoxazolidin-5-one 2
Adduct 3 (Organo-metallic reagent)a
Alkyne 4 (yield %)
2g
3g (b)
4g (35%)
4h (50%)
3h (c)
2h
3i (c)
4i (75%)
4j (50%)
2i
2j
2k
3j (c)
3k (d)
4k (56%)
2l
3l (e)
4l (33%)
2m
3m (f)
4m (35%)
a (a) CH2=CHCH2CH2MgBr; (b) iPrMgCl; (c) BrZnCH2CO2Et; (d) crotyl ZnBr; (e) allyl ZnBr; (f) PhCu (MgBr2).
Preparative Acetylenic Chemistry; Elsevier Science: New
York, 1992. (d) Modern Acetylene Chemistry; Stang, P. J.;
Diederich, F., Eds.; Wiley-VCH: Weinheim, 1995.
References
(1) (a) Ben-Efraim, D. A. In The Chemistry of the Carbon-
Carbon Triple Bond; Patai, S., Ed.; John Wiley & Sons:
Chichester, 1978, Chap. 18, 755–812. (b) Jäger, V. In
Methoden Orgischen Chemie (Houben–Weyl), Vol. 5/2a;
Georg Thieme Verlag: Stuttgart, 1977. (c) Brandsma, L.
(2) (a) Boivin, J.; Elkaim, L. P. G.; Ferro, P. G.; Zard, S. Z.
Tetrahedron Lett. 1991, 32, 5321. (b) Boivin, J.; Huppé, S.;
Zard, S. Z. Tetrahedron Lett. 1995, 36, 5737. (c) Boivin, J.;
Synlett 2002, No. 8, 1257–1260 ISSN 0936-5214 © Thieme Stuttgart · New York

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D. Renard et al.
LETTER
Huppé, S.; Zard, S. Z. Tetrahedron Lett. 1996, 37, 8735.
(d) Boutillier, P.; Zard, S. Z. Chem. Commun. 2001, 1304.
(e) Huppé, S.; Rezaei, H.; Zard, S. Z. Chem. Commun. 2001,
1894. (f) Zard, S. Z. Chem. Commun. 2002, in press.
over MgSO4 and concentrated under reduced pressure. The
nearly pure 3j,k were used directly in step (C). (c)Addition
of allenylzinc (compound 3n): To a cooled (–70 °C) solution
of trimethylsilyl-3-phenoxyprop-1-yne (5 mmol) in dry THF
(20 mL) was added dropwise a solution of sec-butyllithium
[1.3 N] (5.1 mmol, 3.9 mL). After 10 min at –70 °C, a
solution of ZnBr2 (1 M; 5.1 mmol) was added dropwise.
After warming to –30 °C, isoxazolinone 2a was added and
the temperature allowed to rise to r.t. At the end of the
reaction (monitored by TLC), the mixture was hydrolyzed
using the same work-up as in the preceding procedure.
Compound 3n thus obtained was used as such in step (C).
(d) Addition of Reformatsky’s reagent (compounds 3h,i) :
1,2-Dibromoethane (0.2 mL) was added to zinc dust (15
mmol) in dry THF (10 mL) while heating to reflux under
nitrogen. After 2 min at reflux, the mixture was cooled down
to r.t., TMSCl (0.2 mL) was added, and the solution refluxed
again for 10 min. To this mixture, cooled down to r.t., was
added dropwise ethyl bromoacetate (5.5 mmol). After
stirring 15 min at r.t., the resulting Reformatsky’s reagent
was added to a cold (–10 °C) solution of isoxazolinone 2h or
2i (5 mmol) in THF (10 mL) then the temperature was
allowed to increase to r.t. At the end of reaction (monitored
by TLC) the mixture was hydrolyzed using again the same
work-up as for 2j and 2k. The nearly pure 3h,i were used
directly in step (C). (e)Addition of phenyl copper reagent
(compound 3m): To a suspension of copper bromide-
dimethyl sulfide (6 mmol) under nitrogen in dry THF (20
mL) was added dropwise at –50 °C a solution of
(3) (a) Lang, S. A.; Lin, Y.-I. In Comprehensive Heterocyclic
Chemistry, Vol. 6; Katritzky, A. R.; Rees, C. W., Eds.;
Pergamon Press: Oxford, 1984, 103–105. (b) Boulton, A. J.;
Katritzky, A. R. Tetrahedron 1961, 12, 41. (c) Wollweber,
H. G.; Wentrup, C. J. Org. Chem. 1985, 50, 2041; and
references cited there.
(4) (a) Mustafa, A.; Asker, W.; Harhash, A. H.; Kassab, N. A.
L.; Elnagdi, M. H. Tetrahedron 1964, 20, 1133.
(b) Mustafa, A.; Asker, W.; Harhash, A. H.; Kassab, N. A.
L. Tetrahedron 1963, 19, 1577.
(5) Aubert, C.; Buisine, O.; Malacria, M. Chem. Rev. 2002, 102,
813; and references cited there.
(6) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117.
(7) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757.
(8) Typical experimental procedures: (A) Condensation of
isoxazolinones 1 with aldehydes and ketones: To a solution
of the isoxazolin-5-one (10 mmol) in propan-2-ol (20 mL) in
a 100 mL round bottom flask were added the corresponding
aldehyde (1.2 equiv) or ketone (2 equiv) and a catalytic
amount of piperidine (ca. 0.2 mL). The resulting solution
was then stirred to 50 °C in the case of aldehydes or to reflux
in the case of ketones. When TLC showed complete
consumption of the isoxazolinone, most of the solvent was
removed under partial vacuum. In the case of aldehydes, the
products generally precipitated and were isolated by a
filtration and washed with petroleum ether. In the other
cases, an oil was obtained which was washed with a little
petroleum ether–Et2O, 80:20, dried, and used as such in next
step.
phenylmagnesium bromide (5.5 mmol). After stirring 15
min at –50 °C, isoxazolinone 2m (5 mmol) was added and
the reaction mixture was stirred while keeping the
temperature below –40 °C until the TLC showed no starting
material. The medium was then hydrolyzed at –60 °C with
dilute HCl (0.2 M; 40 mL) and the aqueous layer extracted
with ether (2 30 mL). The combined organic layers were
washed with a solution of citric acid (0.1 M; 2 20 mL),
brine (20 mL), and dried over MgSO4. After concentrating
under vacuum, the crude product was further purified by
filtration on a silica pad and used directly in step C.
(C) Synthesis of alkynes 4a–n: To a suspension of ferrous
sulfate (5.56 g, 20 mmol, 5.5 equiv) in acetic acid (15 mL)
was added half of a solution of sodium nitrite (2.1 g, 35
mmol, 10 equiv) in water (10 mL) under an inert atmosphere
(all solutions must also be thoroughly degassed beforehand).
The remainder was added simultaneously with a solution of
the isoxazolinone 3 (3.5 mmol) in degassed acid acetic (15
mL) over 30 minutes at 25 °C. The set-up was then flushed
with nitrogen for 30 minutes; water (150 mL) was added and
the reaction mixture extracted with CH2Cl2 (3 15 mL). The
organic extracts were then washed with dilute HCl (0.5 M),
saturated NaHCO3, and dried over NaHCO3 (with stirring)
for 45 minutes. Concentration and purification by
(B) Addition of organometallic reagents to alkylidene
isoxazolinone 2. (a)Addition of Grignard reagents
(compounds 3a–g): To a solution of the alkylidene
isoxazolinone 2 (5 mmol) in dry THF (15 mL) cooled to –70
°C was added a solution of the Grignard reagent (5 mmol).
After stirring for 15 min. at –70 °C, the mixture was allowed
to warm to r.t. then hydrolyzed with dilute HCl (0.2 M; 40
mL). The aqueous layer was extracted with Et2O (2 30 mL)
and the combined organic layers were washed with brine (20
mL), dried over MgSO4, and concentrated under reduced
pressure. The nearly pure products 3a–g were used directly
in step (C). (b)Addition of organozinc reagents (compounds
3k,l): To a cooled (–10 °C) solution of crotyl or allyl
magnesium bromide (5.2 mmol) in dry THF (15 mL) was
added under nitrogen a solution of ZnBr2 (1 M/THF). The
mixture was cooled to –70 °C and the alkylidene
isoxazolinone 2j or 2k (5 mmol) was added all at once. The
mixture was allowed to warm to r.t. and when TLC showed
that no starting material was left, dilute HCl (0.2 M; 40 mL)
was added and the aqueous layer extracted with Et2O (2 30
mL). The combined organic layers were washed with a
solution of citric acid (0.1 M; 20 mL), brine (20 mL), dried
chromatography of the residue provided alkynes 4 in the
stated yields.
Synlett 2002, No. 8, 1257–1260 ISSN 0936-5214 © Thieme Stuttgart · New York