Synthesis of functionalized α,α-disubstituted β/alkynyl esters from allenoates through an alkynylenolate intermediate

Article abstract of DOI:10.1021/ol801287t

(Chemical Equation Presented) Highly substituted α,α- disubstituted β-alkynyl esters are readily prepared from allenyl esters and either alkyl halide, acid chloride, or alkyl chloroformate, mediated by an amide base. This highly efficient and mild process

Full text of DOI:10.1021/ol801287t

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3713-3716
Synthesis of Functionalized
r,r-Disubstituted ꢀ-Alkynyl Esters from
Allenoates through an Alkynylenolate
Intermediate
Weibo Wang, Bo Xu,† and Gerald B. Hammond*,†
Department of Chemistry, UniVersity of LouisVille, LouisVille, Kentucky, 40292
gb.hammond@louisVille.edu
Received June 11, 2008
ABSTRACT
Highly substituted r,r-disubstituted ꢀ-alkynyl esters are readily prepared from allenyl esters and either alkyl halide, acid chloride, or alkyl
chloroformate, mediated by an amide base. This highly efficient and mild process tolerates various functional groups and provides r,r-
disubstituted ꢀ-alkynyl esters in good to excellent yields. This method is especially suitable for the synthesis of 1,n-enynes or 1,n-diynes
(n > 4). Electrophilic cyclization of 1,5-enyne gives a highly functionalized γ-iodolactone, whereas its platinum-catalyzed cycloisomerization
affords 1,3-cyclohexadiene.
Enolates are used pervasively throughout organic synthesis.
A comprehensive survey of GMP bulk reactions run in a
Scheme 1
.
Alkynylogation and Vinylogation As Extensions of
Enolates
research facility between 1985 and 2002 showed that 68%
of all C-C bond formations are carbanion based, and 44%
of these involved enolates.1 If a double or triple bond is
appended to the enolate precursor through conjugation, it
gives rise to the so-called extended enolates (Scheme 1).
Among these, the chemistry of dienolates has received the
most attention (Scheme 1, left).2-4 A highly attractive
† B. Xu and G.B. Hammond share senior authorship.
(1) Dugger, R. W.; Ragan, J. A.; Ripin, D. H. B. Org. Process Res.
DeV. 2005, 9, 253–258.
(2) For a selected review, see: Casiraghi, G.; Zanardi, F.; Appendino,
G.; Rassu, G. Chem. ReV. 2000, 100, 1929–1972
(3) Denmark, S. E.; Heemstra, J. R,.; Beutner, G. L. Angew. Chem.,
Int. Ed. 2005, 44, 4682
.
alternative, but as yet much less explored, is the reaction of
an enolate conjugated with a triple bond or allene moiety
(A or B in Scheme 1, right).5 Because there are two
nucleophilic centers in an extended enolate, regioselectivity
.
(4) (a) Kalesse, M. Natural Products Synthesis II Targets, Methods,
Concepts, 2005; Vol. 244. (b) For an early review on the ambiphilic nature
of allenyl enolates, see: Frederick, M. A.; Hulce, M. Tetrahedron 1997,
53, 10197–10227
.
10.1021/ol801287t CCC: $40.75
Published on Web 08/13/2008
2008 American Chemical Society

is a major concern in the reaction of extended enolates with
electrophiles.
palladium catalyst (Scheme 3, middle).10 Another method
to make 2 is by coupling an alkynyl halide with an R,R-
disubstituted ester (Scheme 3, bottom), but only a few active
alkynyl halides can be used (X ) Ph, Cl).11-13 2 can also
be prepared from sulfonylallenes but only in an intramo-
lecular fashion.14
We have demonstrated in the past that both allenoates and
propargylic esters can be suitable precursors of an alkynyle-
nolate anion.6 If allenoate 1 is treated with a strong enough
base, the deprotonation of the γ-hydrogen atom of 1 will
occur, furnishing the alkynylenolate anion (Scheme 2).
Because allenoates can be prepared easily using a standard
methodology,15,16 in this report we have only used allenoates
1 as precursors of alkynylenolates and investigated their
reactions with alkyl halides or acid chlorides.
Recently, we reported a thermodynamically favored aldol
reaction of propargylic or allenyl esters, through a common
alkynylenolate intermediate (A in Scheme 1), which led to
the regioselective synthesis of carbinol allenoates (exclusive
γ-selectivity).6 As an ongoing exploration of this chemistry,
herein we report the reaction of alkynylenolate, prepared
from 1, with other electrophiles like alkyl halides or acid
chlorides, to give exclusively the R-product 2 (Scheme 2).
Scheme 2. Allenoates Are Precursors of Alkynylenolates
We began by examining the influence of different bases
and temperatures in the reaction of allenoate 1a with allyl
bromide. The results are summarized in Table 1.
Table 1. Optimization of Synthesis of R,R-Disubstituted
ꢀ-Alkynyl Estersa
entry
base/equiv
TBAF/2
temp
yieldb
This discovery has led to a one-step synthesis of highly
functionalized R,R-disubstituted ꢀ-alkynyl esters 2 from the
readily available allenoate 1.
Functionalized R,R-disubstituted ꢀ-alkynyl esters 2 are
important synthetic synthons and targets.7,8 There are several
reported methods to make them, but most of them have
limited scope. For example, Lepore and co-workers reported
a method for the conversion of conjugated R-alkynyl esters
to R,R-disubstituted (i.e., R2dR4 in 2) ꢀ-alkynylesters using
2 equiv of LDA/HMPA at -98 °C (Scheme 3, top).9
1
2
3
4
5
0 °C, rt
0 °C, rt
0 °C, rt
-78 °C, rt
-78 °C, rt
no reaction
no reaction
72%
71%
88%
DBU/1.5
t-BuOK/1.5
LDA(HMPA)/1.5(3)
LDA/1.5
a Reaction condition: allenoate (0.5 mmol), allyl bromide (0.75 mmol),
LDA (0.75 mmol), THF (2 mL). b Yields of isolated compound. LDA )
lithium diisopropyl amide, DBU ) 1,8-diazabicyclo[5,4,0]undec-7-ene,
HMPA ) hexamethyl phosphoramide.
When we used TBAFsthe base of choice in our reported
alkynylogous aldol reaction (reaction of an alkynylenolate
with an aldehyde)6sno reaction occurred. An organic base
like DBU did not mediate this reaction either. We believe
that this is due to the fact that DBU and TBAF are
nucleophilic bases and may displace allyl bromide, so we
used a hindered, less nucleophilic base. To our delight, the
reaction proceeded in excellent yield (88%) using LDA, one
of the most frequently used amide bases in synthetic organic
chemistry (Table 1, entry 5). By using LDA in the presence
of HMPA, a common combination in enolate chemistry, only
a moderate yield (71%) was obtained (Table 1, entry 4).
Similarly, in the presence of t-BuOK, we also got a similar
lower yield (72%) (Table 1, entry 3).
Scheme 3. Literature Methods for the Preparation of
R,R-Disubstituted ꢀ-Alkynyl Esters
Next, we investigated the scope of this reaction by
examining various types of halides and substituted allenoates
under the optimized conditions found above (Table 2). These
reactions proceeded smoothly, and R,R-disubstituted ꢀ-alky-
nyl esters 2 were obtained in good to excellent yields.
Reaction of 1a with reactive alkyl halides like allyl bromide
or propargyl bromide gave better yields (Table 2, entries
Alper and Nanayakkara obtained 2 through the reaction
of allenoates with vinyl oxiranes in the presence of a
3714
Org. Lett., Vol. 10, No. 17, 2008

1-3) than with unreactive alkyl halides (Table 2, entries
4-9). Reaction of an unconventional alkyl halide like
MOMCl gave an excellent yield of 2j (Table 2, entry 10).
The reaction with a secondary alkyl halide proceeded well
(Table 2, entry 5) and so did the reactions with acid chloride
and alkyl chloroformate (Table 2, entries 11-12). Reactions
of aryl-substituted allenoates, such as 1b and 1c, worked
nicely (Table 2, entries 13-15). However, the yields for the
reaction of 1d with allyl bromide or propargyl bromide were
modest, perhaps due to the instability of 1d17 (Table 2, entries
16 and 17).
Table 2. Synthesis of R,R-Disubstituted ꢀ-Alkynyl Estersa
The cycloisomerization of 1,n-enynes and 1,n-diynes is
currently a highly competititive field in organic synthetic
chemistry, with numerous applications appearing increasingly
often in the literature.18 Our method is especially suitable
for the synthesis of hitherto inaccessible functionalized 1,n-
enynes and 1,n-diynes (n > 4). For example, 1,5-enynes (2a,
2m, 2o, 2p), 1,6-enynes (2 g, 2n), and 1,5-diynes (2b, 2c,
2q) can be prepared in high yields in a single step.
We have explored the reaction of R,γ-unsubstituted
allenoate (1e) with allyl bromide; in this case, the reaction
could not be stopped to give the monosubstituted product.
Instead, it gave the disubstituted product 2r (eq 1).
Scheme 4 illustrates our proposed mechanism for the
formation of 2r. First, deprotonation of 1e gives alkynyle-
nolate A, which then reacts with allyl bromide to afford 3.
(5) (a) Blagoev, B.; Jordanov, B.; Ivanoff, D. Bull. Soc. Chim. Fr. 1967,
4657–4659. (b) Himbert, G. J. Chem. Res. (S) 1979, 88–89. (c) Petasis,
N. A.; Teets, K. A. J. Am. Chem. Soc. 1992, 114, 10328–10334. (d) Lepore,
S. D.; He, Y.; Damisse, P. J. Org. Chem. 2004, 69, 9171–9175. (e)
Denichoux, A.; Ferreira, F.; Chemla, F. Org. Lett. 2004, 6, 3509–3512.
(6) Xu, B.; Hammond, G. B. Angew. Chem., Int. Ed. 2008, 47, 689–
692.
(7) Diederich, F.; Stang, P.; Tykwinski, R. R. Acetylene chemistry:
chemistry, biology, and material science; Wiley-VCH: Weinheim, 2005, p
59.
(8) Just, Z. W.; Larock, R. C. J. Org. Chem. 2008, 73, 2662–2667.
(9) Lepore, S. D.; He, Y. J. Org. Chem. 2005, 70, 4546–4548.
(10) Nanayakkara, P.; Alper, H. J. Org. Chem. 2004, 69, 4686–4691.
(11) Kende, A. S.; Fludzinski, P.; Hill, J. H. J. Am. Chem. Soc. 1984,
106, 3551–62.
(12) Lin, G.-Y.; Yang, C.-Y.; Liu, R.-S. J. Org. Chem. 2007, 72, 6753–
6757.
(13) Sun, J.; Conley, M. P.; Zhang, L.; Kozmin, S. A. J. Am. Chem.
Soc. 2006, 128, 9705–9710.
(14) For a recent example of alkynyl-substituted cyclization products
from sulfonylallene derivatives by base treatment, see: Kitagaki, S.;
Teramoto, S.; Mukai, C. Org. Lett. 2007, 9, 2549–2552, and references
cited therein.
(15) Lang, R. W.; Hansen, H.-J. Org. Synth., Coll. Vol. 7 1990, 232.
(16) For selected recent papers on allenoates, see:(a) Elsner, P.; Bernardi,
L.; Dela Salla, G.; Overgaard, J.; Jorgensen, K. A. J. Am. Chem. Soc. 2008,
130, 4897–4905. (b) Singh, L.; Ishar, M. P. S.; Elango, M.; Subramaniam,
V.; Gupta, V.; Kanwal, P. J. Org. Chem. 2008, 73, 2224–2233. (c) Shi,
M.; Tang, X.-Y.; Yang, Y.-H. Org. Lett. 2007, 9, 4017–4020. (d) Cowen,
B. J.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 10988–10989. (e) Li, C.-
Y.; Sun, X.-L.; Jing, Q.; Tang, Y. Chem. Commun. 2006, 2980–2982. (f)
Klein, A.; Miesch, M. Synthesis 2006, 2613–2617.
a Reaction condition: allenoate 1 (0.5 mmol), R4-X (0.75 mmol), LDA
(0.75 mmol). b Yields of isolated compound (LDA ) lithium diisopropyl
amide).
(17) 1d decomposes at room temperature within one day.
(18) For a recent review: Michelet, V.; Toullec, P. Y.; Genet, J.-P.
Angew. Chem., Int. Ed. 2008, 47, 4268-4315 and references cited therein.
Org. Lett., Vol. 10, No. 17, 2008
3715

Scheme 4
.
Proposed Mechanism for the Formation of 2r
Scheme 5. Synthetic Transformations of 2a
Intermediate 3 may isomerize to the corresponding allene,
but in basic media, deprotonation of 3, or its corresponding
allene, will furnish alkynylenolate C. Finally, the reaction
of C with another molecule of allyl bromide affords 2r.
With a very easy and high-yielding synthesis of R,R-
disubstituted ꢀ-alkynyl esters 2, we decided to explore their
synthetic potential (Scheme 5). Electrophilic cyclization of
3-alkynoate esters has been reported by Larock and co-
workers very recently.8 Using similar conditions, 1,5-enyne
2a undergoes a highly efficient and mild I2-mediated elec-
trophilic cyclization7 to afford the functionalized γ-lactone
4 in excellent yield. Furthermore, 2a cycloisomerizes readily,
at ambient temperature, using PtCl2 as catalyst, to afford 1,3-
cyclohexadiene 5 (Scheme 5, yield not optimized).13
In summary, we have developed a one-step, extremely
efficient approach to various highly functionalized, substi-
tuted R,R-disubstituted ꢀ-alkynyl esters 2, through the
reaction of allenyl esters with various types of organic
halides. These reactions are run under mild conditions and
tolerate a number of functional groups. The broader implica-
tions of this reaction in organic synthesis, including its
asymmetric variant, are currently under investigation.
Acknowledgment. We are grateful to the National Science
Foundation for financial support (CHE-0809683).
Supporting Information Available: Experimental pro-
cedures and NMR spectra for 1 and 2. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL801287T
3716
Org. Lett., Vol. 10, No. 17, 2008