Tandem nucleophilic addition/fragmentation reactions and synthetic versatility of vinylogous acyl triflates

Article abstract of DOI:10.1021/ja0608085

A thorough analysis of the chemistry of vinylogous acyl triflates provides insight into important chemical processes and opens new directions in synthetic technology. Tandem nucleophilic addition/C-C bond cleaving fragmentation reactions of cyclic vinylogous acyl triflates 1 yield a variety of acyclic acetylenic compounds. Full details are disclosed herein. A wide array of nucleophiles, such as organolithium and Grignard reagents, lithium enolates and their analogues, hydride reagents, and lithium amides, are applied. The respective reactions produce ketones 2, 1,3-diketones and their analogues 3, alcohols 4, and amides 5. The present reactions are proposed to proceed through a 1,2-addition of the nucleophile to the carbonyl group of starting triflates 1 to form tetrahedral alkoxide intermediates C, followed by Grob-type fragmentation, which effects C-C bond cleavage to yield acyclic acetylenic compounds 2-5 and 7. The potent nucleofugacity of the triflate moiety is channeled through the σ-bond framework of 1, providing direct access to the fragmentation pathway without denying other typical reactions of cyclic vinylogous esters. The synthetic versatility of vinylogous acyl triflates, including functionalization reactions of the cyclic enone core (1 → 6 or 8), is also illustrated.

Full text of DOI:10.1021/ja0608085

Published on Web 04/20/2006
Tandem Nucleophilic Addition/Fragmentation Reactions and
Synthetic Versatility of Vinylogous Acyl Triflates
Shin Kamijo and Gregory B. Dudley*
Contribution from the Department of Chemistry and Biochemistry, Florida State UniVersity,
Tallahassee, Florida 32306-4390
Received February 2, 2006; E-mail: gdudley@chem.fsu.edu
Abstract: A thorough analysis of the chemistry of vinylogous acyl triflates provides insight into important
chemical processes and opens new directions in synthetic technology. Tandem nucleophilic addition/C-C
bond cleaving fragmentation reactions of cyclic vinylogous acyl triflates 1 yield a variety of acyclic acetylenic
compounds. Full details are disclosed herein. A wide array of nucleophiles, such as organolithium and
Grignard reagents, lithium enolates and their analogues, hydride reagents, and lithium amides, are applied.
The respective reactions produce ketones 2, 1,3-diketones and their analogues 3, alcohols 4, and amides
5. The present reactions are proposed to proceed through a 1,2-addition of the nucleophile to the carbonyl
group of starting triflates 1 to form tetrahedral alkoxide intermediates C, followed by Grob-type fragmentation,
which effects C-C bond cleavage to yield acyclic acetylenic compounds 2-5 and 7. The potent
nucleofugacity of the triflate moiety is channeled through the σ-bond framework of 1, providing direct access
to the fragmentation pathway without denying other typical reactions of cyclic vinylogous esters. The synthetic
versatility of vinylogous acyl triflates, including functionalization reactions of the cyclic enone core (1 f 6
or 8), is also illustrated.
site.7,8 Ring opening metathesis is another poignant example of
C-C bond cleavage in synthetic chemistry.9 Judicious use of
Introduction
Carbon-carbon bond formation is a major focus of research
in organic synthesis. Tools for making such bonds are indis-
pensable for the construction of complex molecules, and intense
efforts are continuously directed toward developing novel and
selective bond forming reactions. In contrast, C-C bond
cleavage reactions receive less attention. Nonetheless, such bond
cleavage reactions often emerge as ideal methods for the
construction of new materials and complex molecules. The
reverse processes of several C-C bond forming transformations,
such as aldol,1 Diels-Alder,2 and Michael reactions,3 have found
utility in C-C bond cleavage. The Cope rearrangement4 and
oxidative cleavage of olefins5 and diols6 are also representative
examples. Recent advances in transition metal chemistry have
provided a variety of C-C bond cleaving methods, although
substrates are often restricted either to highly strained molecules
such as cyclopropanes and cyclobutanes or to properly designed
molecules possessing a coordinating group around the reaction
such bond cleavage reactions can reveal frameworks that are
otherwise difficult to prepare.10
Nearly 40 years have passed since Eschenmoser11 and
Tanabe12 independently reported the ring opening reaction of
epoxy-hydrazones to yield tethered alkynyl ketones (eq 1). The
key step in the Eschenmoser-Tanabe process (A f P) is
classified as a fragmentation, according to the criteria outlined
by Grob.13,14 Epoxy-hydrazones S are generally prepared by the
condensation of tosylhydrazide with an appropriate cyclic enone
(7) Hudlicky, T.; Reed, J. E. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 899-970.
(8) For reviews, see: (a) Jun, C.-H. Chem. Soc. ReV. 2004, 33, 610 and
references therein. (b) Murakami, M.; Ito, Y. In ActiVation of UnreactiVe
Bonds and Organic Synthesis; Murai, S., Ed.; Springer: Berlin, 1999; pp
97-129. (c) Jennings, P. W.; Johnson, L. L. Chem. ReV. 1994, 94, 2241.
(d) Tsuji, J. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-i., Ed.; Wiley: New York, 2002; Vol. 2, pp 2643-
2653.
(9) (a) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim,
2003. (b) Grubbs, R. H. Tetrahedron 2004, 60, 7117. (c) Buchmeiser, M.
R. Chem. ReV. 2000, 100, 1565.
(10) Recent examples: (a) Salamone, S. G.; Dudley, G. B. Org. Lett. 2005, 7,
4443. (b) Pfeiffer, M. W. B.; Phillips, A. J. J. Am. Chem. Soc. 2005, 127,
5334.
(11) (a) Eschenmoser, A.; Felix, D.; Ohloff, G. HelV. Chim. Acta 1967, 50,
708. (b) Felix, D.; Shreiber, J.; Ohloff, G.; Eschenmoser, A. HelV. Chim.
Acta 1971, 54, 2896.
(12) (a) Tanabe, M.; Crowe, D. F.; Dehn, R. L. Tetrahedron Lett. 1967, 3943.
(b) Tanabe, M.; Crowe, D. F.; Dehn, R. L.; Detre, G. Tetrahedron Lett.
1967, 3739.
(13) (a) Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. Engl. 1967, 6, 1.
(b) Grob, C. A. Angew. Chem., Int. Ed. Engl. 1969, 8, 535.
(14) For other reviews on the Grob-type fragmentations, see: (a) Weyerstahl,
P.; Marschall, H. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 6, pp 1041-1070. (b)
Hesse, M. In Ring Enlargement in Organic Chemistry; VCH: Weinheim,
1991; pp 163-198.
(1) (a) Mukaiyama, T. Org. Synth. 1982, 28, 203. (b) Heathcock, C. H. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 2, pp 133-238.
(2) (a) Rickborn, B. Org. Synth. 1998, 52, 1. (b) Sweger, R. W.; Czarnik, A.
W. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 5, pp 551-592.
(3) (a) Bergmann, E. D.; Ginsburg, D.; Pappo, R. Org. Synth. 1959, 10, 179.
(b) Jung, M. E. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 1-67.
(4) (a) Hill, R. K. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 785-826. (b) Lutz, R. P.
Chem. ReV. 1984, 84, 205-247.
(5) Lee, D. G.; Chen, T. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I. Eds.; Pergamon: Oxford, 1991; Vol. 7, pp 541-591.
(6) Shing, T. K. M. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, pp 703-717.
9
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J. AM. CHEM. SOC. 2006, 128, 6499-6507
6499

A R T I C L E S
Kamijo and Dudley
Scheme 1. Tandem Nucleophilic Addition/C-C Bond Cleaving
Fragmentation Reactions of Vinylogous Acyl Triflates 1
oxide in protic media (often methanol or acetic acid). The
multistep sequence from cyclic enone to acyclic acetylenic
ketone has received considerable attention through the years,
both as a synthetic strategy15 and as a pedagogical tool.16
Results and Discussion
Synthesis of Aryl Ketones Using Aryl Grignard and
Aryllithium Nucleophiles.18 Table 1 summarizes the results
of reactions between vinylogous acyl triflate 1a (derived from
2-methyl-1,3-cyclohexanedione: R ) Me, n ) 1 in eq 4) and
a variety of aryl Grignard and aryllithium reagents. When 1a
(1.1 equiv) was treated with phenylmagnesium bromide (Ph-
MgBr, 1.0 equiv) in THF at 0 °C for 10 min and then at room
temperature for 30 min, 1-phenyl-5-heptynone (2a) was obtained
in 80% yield (entry 1, average of two runs).20 Alternative
Equation 2 illustrates a common method for the synthesis of
cyclic enones.17 The presumed reaction intermediates, A and
B, are strikingly similar, yet they generally decompose by
distinct, unrelated mechanisms. Inducing species similar to B
to fragment under mild conditions in an aprotic solvent would
have important synthetic and mechanistic implications. We
sought to achieve a crossover in reaction pathways via inter-
mediate C, starting from cyclic vinylogous acyl triflates 1 (eq
3).
Initial success stemmed from the use of aryllithium and aryl
Grignard reagents as nucleophilic triggers (eq 4, Scheme 1).18
Optimization of the reaction conditions with regard to other
nucleophilic agents enabled us to extend the scope to include
alkyl-, alkynyl-, and vinyl-metal species, producing acetylenes
tethered to alkyl ketones, conjugated alkynyl ketones, and R,â-
unsaturated enones, respectively. Lithium enolates and their
analogues were also applicable in the tandem addition/
fragmentation reaction to form alkynes 3 bearing a 1,3-diketone-
type moiety (eq 5).19 Treatment of triflates 1 with excess
amounts of LiBHEt3 (Super-Hydride) promoted the reductive
ring opening reaction to afford alcohols 4 (eq 6). When triflates
1 were subjected to nitrogen nucleophiles, a similar reaction
took place to furnish corresponding amides 5 (eq 7). Herein,
we report full details of our ongoing studies, which include a
series of tandem nucleophilic addition/C-C bond cleaving
fragmentation reactions (Scheme 1), as well as the utility of
vinylogous acyl triflates 1 from a general synthetic perspective.
Representative synthetic transformations are demonstrated (vide
infra).
Table 1. Reaction of Triflate 1a with Various Aryl Grignard and
Aryllithium Reagentsa
entry
Ar-M
conditions
2
yield, %b
1
2
3
4
5
6
7
8
9
Ph-MgBr
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 to 60 °C
0 to 60 °C
-78 °C to rt
-78 °C to rt
-78 °C to rt
2a
2b
2c
2d
2e
2f
2a
2c
2d
80c
86
57
34
61
63
93c
78
57
(p-MeO)C6H4-MgBr
(m-MeO)C6H4-MgBr
(o-MeO)C6H4-MgBr
(p-Cl)C6H4-MgBr
(2-thienyl)-MgBr
Ph-Li
(m-MeO)C6H4-Li
(o-MeO)C6H4-Li
a Typical reaction procedure: a mixture of triflate 1a (0.55 mmol), Ar-M
(0.50 mmol), and THF (2 mL) was stirred at the temperatures shown in
Table 1 (reactions complete within 80 min). b Isolated yield. c Average of
two runs.
nucleofuges such as mesylate21 and bromide22 instead of triflate
did not give the desired product (2a). THF was the solvent of
choice for this initial study; reactions conducted under the same
conditions in DMPU gave 2a in ca. 50% yield and in toluene
produced only a trace amount of 2a with the formation of
2-methyl-3-phenyl-2-cyclohexenone (6a) in 66% yield. The
reaction of 1a with para-, meta-, and ortho-anisylmagnesium
bromides afforded 2b-d, respectively, in yields that increased
(15) For selected applications of the Eschenmoser-Tanabe fragmentation in
total synthesis, see: (a) Murakami, Y.; Shindo, M.; Shishido, K. Synlett
2005, 664. (b) Fehr, C.; Galindo, J.; Etter, O. Eur. J. Org. Chem. 2004,
1953. (c) Mander, L. N.; McLachlan, M. M. J. Am. Chem. Soc. 2003, 125,
2400. (d) Kocienski, P. J.; Ostrow, R. W. J. Org. Chem. 1976, 41, 398.
(16) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry; Wiley:
New York, 2001; p 1347.
(17) (a) Woods, G. F.; Tucker, I. W. J. Am. Chem. Soc. 1948, 70, 2174. (b)
Zimmerman, H. E.; Nesterov, E. E. J. Am. Chem. Soc. 2003, 125, 5422.
(18) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2005, 127, 5028.
(19) Kamijo, S.; Dudley, G. B. Org. Lett. 2006, 8, 175.
(20) Related fragmentations have been reported, see: (a) Coke, J. L.; Williams,
H. J.; Natarajan, S. J. Org. Chem. 1977, 42, 2380. (b) Shimizu, M.; Ando,
R.; Kuwajima, I. J. Org. Chem. 1981, 46, 5246. (c) Shimizu, M.; Ando,
R.; Kuwajima, I. J. Org. Chem. 1984, 49, 1230.
(21) Lee, S.; Fuchs, P. L. Tetrahedron Lett. 1991, 32, 2861.
(22) Shih, C.; Swenton, J. S. J. Org. Chem. 1982, 47, 2825.
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Reactions of Vinylogous Acyl Triflates
A R T I C L E S
with decreasing steric bulk (entries 2-4). The para-chlorophenyl
adduct seemed to fragment slightly slower than the correspond-
ing para-methoxy adduct; therefore, the reaction mixture was
warmed to 60 °C to obtain the best yield of the product (2e,
entry 5; 61% yield). It thus appears that the electron donating
methoxy group on the aromatic ring promotes C-C bond
cleaving fragmentation more smoothly, possibly due to favorable
conjugation with the developing carbonyl group. The reaction
with 2-thienylmagnesium bromide furnished the expected het-
eroaromatic product 2f as well (entry 6; 63% yield).
We further examined the addition/C-C bond cleaving
fragmentation reaction employing aryllithium nucleophiles. The
more ionic lithium alkoxide intermediates (cf. C, M ) Li vs
MgX, eq 3) seemed to fragment more readily to furnish the
corresponding aryl ketones. In the case of phenyllithium (PhLi),
appreciable C-C bond cleavage occurred at 0 °C, with the
resulting ketone then being susceptible to overaddition. Initial
cooling of the reaction mixture to -78 °C suppressed undesired
reaction pathways, particularly the formation of the tertiary
alcohol impurity, and provided aryl ketone 2a in high yield
(entry 7; 93% yield, average of two runs). The meta- and ortho-
anisyllithiums afforded corresponding products 2b and 2c in
78 and 57% yields, respectively (entries 8 and 9)sdistinct
improvements over the corresponding Grignard reagents (cf.
entries 3 and 4).
afforded 2h in excellent yield. Seven- and five-membered cyclic
triflates 1d and 1e also furnished expected products 2i and 2j
in 79 and 61% yields, respectively (entries 3 and 4). Compound
2j, also known as capillon, is a natural product isolated from
the Japanese shrub Artemisia capillaries.23
Synthesis of Alkyl Ketones Using Alkyllithium and Alkyl
Grignard Nucleophiles. Although various arene nucleophiles
were applicable in the addition/fragmentation reaction described
in the previous section, analogous reactions using n-butyllithium
(n-BuLi) did not proceed with acceptable efficiency. After some
examination, we concluded that the n-BuLi addition to 1a is
sensitive to reagent quality and choice of solvent.24 Using a
fresh supply of n-BuLi, alkyl ketone 2k (R ) Me, R′ ) Bu, n
) 1 in eq 4) was obtained in 63% yield in THF under the same
reaction conditions applied in entry 7 of Table 1. Alternatively,
the inclusion of TMEDA25 in the reaction mixture seemed to
make the reaction more tolerant of minor impurities in the
n-BuLi reagent, but the optimal yield of 2k remained almost
the same (65% yield). After further tuning of the reaction
conditions, toluene emerged as the best solvent, providing
improvements in the yield, reproducibility, and efficiency of
the reaction. This finding was key to extending the scope of
effective nucleophiles to include the range of alkyllithium and
alkyl Grignard reagents illustrated in Table 3. Our recent
synthesis of (Z)-6-heneicosen-11-one, a sex attractant of the
Douglas fir tussock moth, features this tandem addition/C-C
bond cleaving fragmentation reaction conducted in toluene.26
We next probed the scope of triflates 1 for this addition/
fragmentation reaction using PhLi as the nucleophile (Table 2).
Table 3. Reaction of Triflate 1a with Various Alkyllithium and Alkyl
Table 2. Reaction of Various Triflates 1 with PhLia
Grignard Reagentsa
a Typical reaction procedure: triflate 1a (0.55 mmol), R-M (0.50 mmol),
and toluene (2 mL), -78 °C to room temperature within 50 min. b Isolated
yield. c The reaction mixture was warmed to 60 °C for 30 min after the
typical reaction procedure. d 2n was obtained in 65% yield in THF.
e Cleavage of the Me3Si group occurred during purification on silica gel,
and 2n was obtained as the final product.
a Triflate 1 (0.55 mmol), PhLi (0.50 mmol), and THF (2 mL), -78 to
60 °C within 80 min. b Isolated yield.
The treatment of triflate 1a (1.1 equiv) with n-BuLi (1.0
equiv) in toluene at -78 °C for 10 min, at 0 °C for 10 min, and
then at room temperature for 30 min gave the corresponding
alkyl ketone, 9-undecyn-5-one (2k), in 76% yield (entry 1).
Mild heating proved to be optimal in the case of triflate 1b
(derived from 1,3-cyclohexanedione), which gave rise to ketone
2g (entry 1; 65% yield). When this reaction was quenched at
room temperature, a large amount of 3-phenyl-2-cyclohexenone
6b (50% yield) was obtained along with the desired product 2g
(26% yield). Triflate 1c, which bears a geminal dimethyl group,
(23) Harada, R. Nippon Kagaku Kaishi 1956, 77, 990, ibid, Chem. Abstr. 1957,
51, 18489. (b) Harada, R. Nippon Kagaku Kaishi 1956, 77, 1036, ibid,
Chem. Abstr. 1959, 53, 21773.
(24) Impurities in aged stock solutions of n-BuLi, such as LiOH and n-BuOLi,
may cause decomposition of 1a or may alter the aggregation properties of
the nucleophile. TMEDA seemed to abrogate this effect.
(25) Collum, D. B. Acc. Chem. Res. 1992, 25, 448.
(26) Jones, D. M.; Kamijo, S.; Dudley, G. B. Synlett 2006, 936.
9
J. AM. CHEM. SOC. VOL. 128, NO. 19, 2006 6501

A R T I C L E S
Kamijo and Dudley
Yields suffered when we screened aggressively reactive and
hindered alkyllithium reagents such as i-PrLi and t-BuLi (entries
2 and 3). Conversely, nucleophilic reagents derived from
relatively stabilized carbanions were more effective. For ex-
ample, the addition of MeLi and (trimethylsilyl)methyllithi-
um27,28 afforded the same product (2n), with the latter reaction
providing a higher yield (entries 4 and 5). Interestingly, the
reaction of 1a with MeLi took place even in THF, and almost
the same yield of 2n was observed (65% yield).18 The pyri-
dine-29 and dithiane-containing30 organolithium reagents gave
the alkyl ketones 2o and 2p, respectively, in good yields (entries
6 and 7). The reaction employing alkyl Grignard reagents, such
as n-BuMgCl and PhCH2MgCl, proceeded smoothly in toluene
to furnish the corresponding products 2k and 2q, although mild
heating was essential to complete the fragmentation (entries 8
and 9).
alkyl ketone 2u in only 14% yield along with the formation of
cyclopentenone derivative 6c in 33% yield (entry 4).
Synthesis of r,â-Unsaturated Ketones Using Alkynyl and
Vinyllithium Nucleophiles. The next series of experiments was
designed to verify that alkynyl- and vinyllithium reagents are
suitable for the synthesis of R,â-unsaturated ketones (Table 5).
The reaction between triflate 1a and alkynyllithiums generated
from phenylacetylene and (trimethylsilyl)acetylene gave the
corresponding alkynyl ketones 2v and 2w in moderate yields
(entries 1 and 2). Treatment of 1a with the vinyllithium species
derived from dihydropyran31 afforded the expected conjugated
enone 2x in 64% yield (entry 3). These results indicate that not
only aryl- and alkyllithium reagents but also alkynyl- and
vinyllithium species are applicable in this process.
Table 5. Reaction of Triflate 1a with Alkynyl and Vinyllithium
Reagentsa
We then carried out the present tandem addition/fragmentation
reaction using a variety of vinylogous acyl triflates 1 and n-BuLi
(Table 4). 1,3-Cyclohexanedione-derived triflate 1b afforded 2r
Table 4. Reaction of Various Triflates 1 with n-BuLia
a Triflate 1a (0.55 mmol), R-Li (0.50 mmol), and THF (2 mL), -78 °C
to room temperature within 50 min. b Isolated yield. c Terminal acetylene
(0.60 mmol) was treated with n-BuLi (0.50 mmol) in THF at -78 °C for
30 min to generate the alkynyllithium species. d 3,4-Dihydro-2H-pyran (0.60
mmol) was treated with t-BuLi (0.50 mmol) in THF at -78 °C for 10 min
and then at room temperature for 20 min to generate the vinyllithium species.
The mechanistic pathway for the present tandem nucleophilic
addition/C-C bond cleaving fragmentation reactions of vinyl-
ogous acyl triflates 1 using various carbanionic metal reagents
is proposed as depicted in Scheme 2. Initially, alkoxide
intermediate C1 is formed by 1,2-addition of the carbanion
species. Subsequent collapse of the tetrahedral intermediate C1
via C-C bond cleavage (Grob-type fragmentation)13,14 would
produce ketones 2. The formation of cyclic enone side products
6a-c in some cases would strongly suggest the intervention of
intermediate C1 in the reaction process. We assume a similar
fragmentation pathway as proposed for the Eschenmoser-
Tanabe sequence,11,12 except that it operates under distinctly
different (and in many cases more efficient) conditions.
a Triflate 1a (0.55 mmol), n-BuLi (0.50 mmol), and toluene (2 mL),
-78 °C to room temperature within 50 min. b Isolated yield. c The reaction
mixture was warmed to 60 °C for 30 min after the typical reaction procedure,
and 6c was obtained in 33% yield.
Scheme 2. Proposed Mechanistic Pathway for the Tandem
Carbanion Addition/C-C Bond Cleaving Fragmentation of
Vinylogous Acyl Triflates 1
in 63% yield (entry 1). Triflate 1f, bearing a geminal dimethyl
substituent adjacent to the carbonyl group, gave 2s in moderate
yield (entry 2). Seven-membered triflate 1d furnished 2t in
allowable yield (entry 3). On the other hand, five-membered
triflate 1e, derived from 2-methyl-1,3-cyclopentanedione, gave
(27) Reactions of (trimethylsilyl)methyllithium with enol ethers of 1,3-cyclo-
hexanedione derivatives have been reported, see: (a) Horiguchi, Y.;
Kataoka, Y.; Kuwajima, I. Tetrahedron Lett. 1989, 30, 3327. (b) Furukawa,
T.; Morihira, K.; Horiguchi, Y.; Kuwajima, I. Tetrahedron 1992, 48, 6975.
(c) Foote, K. M.; Hayes, C. J.; John, M. P.; Pattenden, G. Org. Biomol.
Chem. 2003, 1, 3917.
Synthesis of Tertiary Alcohols via Double Addition of
Alkyllithium Nucleophiles. Encouraged by the success of the
ketone synthesis via the reaction between cyclic vinylogous acyl
triflates 1 and various organolithium reagents, we investigated
the formation of acyclic alkynols 7 using excess amounts of
(28) Cleavage of the Me3Si group occurred during purification.
(29) (a) Beumel, O. F., Jr.; Smith, W. N.; Rybalka, B. Synthesis 1974, 43. (b)
Roussel, R.; Guerrero, M. O. D.; Galin, J. C. Macromolecules 1986, 19,
291.
(30) Wakefield, B. J. Organolithium Methods; Academic Press: London, 1988.
(31) Barriault, L.; Thomas, J. D. O.; Cle´ment, R. J. Org. Chem. 2003, 68, 2317.
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Reactions of Vinylogous Acyl Triflates
A R T I C L E S
Table 6. Reaction of Triflate 1a with Lithium Enolates and Their
organolithium reagents (eq 8). When triflate 1a was subjected
to 2.2 equiv of MeLi in toluene (-78 °C to room temperature
within 50 min), the double addition of MeLi took place as
expected to afford alkynol 7a in 55% yield. In the case of
n-BuLi, the corresponding alkynol 7b was obtained in 77%
yield. In addition to providing alkynols 7 in one step, these
results indicate that lithium alkoxide intermediate C1 (with its
pendant vinyl triflate) is compatible with excess amounts of
alkyllithium reagents.
Analoguesa
Synthesis of 1,3-Diketones Using Lithium Enolate Nu-
cleophiles.19 Whereas alkyllithium and Grignard reagents typi-
cally add in a 1,2-fashion to unsaturated ketones, enolates and
other stabilized carbanions are more likely to react in a 1,4-
manner (Michael reaction pathway). Nonetheless, the cross-
coupling reaction of 1 with lithium enolates and their analogues
proceeded to give 1,3-diketone-type compounds tethered to
alkynes 3 (eq 5, Scheme 1). This reaction may be viewed as a
direct mechanistic analogue of the Claisen condensation,32 using
a vinylogous carboxylic acid ester as a starting material.
Table 6 summarizes the results of reaction between vinylo-
gous acyl triflate 1a (derived from 2-methyl-1,3-cyclohexanedi-
one) and a variety of lithium enolates and their analogues. When
1a (1.0 equiv) was treated with the lithium enolate of acetophe-
none (2.2 equiv) in THF between -78 and 60 °C within 80
min, the corresponding alkynyl-1,3-diketone 3a33 was obtained
in 85% yield (entry 1). The mild heating (to 60 °C) was
necessary for best results. Reaction stoichiometry had a
significant effect on the yield of 3a. The reaction of triflate 1a
with a slight excess amount of the lithium enolate (1.2 equiv)
gave 3a in 56% yield along with recovered 1a. This stoichio-
metric requirement suggests that the relatively acidic dicarbonyl
product (3) consumes 1 equiv of base as it forms, which is
consistent with the traditional Claisen condensation. Among the
various solvents tested, the present Claisen-type addition/
fragmentation reaction proceeded most efficiently in THF.
Inclusion of DMPU as a cosolvent was detrimental to the yield
of 3a, and the overall transformation was slower in toluene.
The lithium enolate derived from acetone reacted with 1a to
give diketone 3b in moderate yield (entry 2). The ethyl acetate
enolate produced ketoester 3c in 88% yield (entry 3). Lithiated
dimethyl sulfone reacted with 1a to furnish â-ketosulfone 3d
in moderate yield along with a small amount of the diyne 3d′
(entry 4). Similar reactions using dimethyl methylphosphonate
and acetonitrile provided the corresponding products 3e and 3f
in low yields (entries 5 and 6, unoptimized).
a Typical reaction procedure: triflate 1a (0.50 mmol), lithium enolate
(1.1 mmol; generated by the treatment of 1.2 equiv of prenucleophile with
1.1 mmol of LiHMDS), and THF (2 mL), -78 to 60 °C within 80 min.
b Isolated yield. c n-BuLi was used instead of LiHMDS. d Diyne 3d′ was
obtained in 8.4% yield.
acetophenone (Table 7). Triflate 1b afforded the corresponding
diketone 3g in excellent yield (entry 1). The six-membered
triflates 1f, 1c, and 1g bearing a geminal dimethyl group were
next examined. The reaction of 1f, which bears a sterically
congested quaternary center alpha to the carbonyl group,
resulted in decomposition; no desired product 3h was detectable
(entry 2). On the other hand, the triflates such as 1c and 1g, in
which the carbonyl groups are progressively less hindered,
furnished the corresponding products 3i and 3j in 45 and 79%
yields, respectively (entries 3 and 4). Accordingly, the reaction
appears to be sensitive to steric influences around the initial
1,2-addition.34 The seven-membered cyclic triflate 1d gave the
desired product 3k in high yield (entry 5).
We then explored the Claisen-type addition/fragmentation
reaction using various triflates 1 and the lithium enolate of
A plausible mechanistic pathway for the Claisen-type addi-
tion/C-C bond cleaving fragmentation reaction of vinylogous
(32) For reviews on the Claisen condensation, see: (a) Davis, B. R.; Garratt, P.
J. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 2, pp 795-863. (b) Hauser, C. R.; Hudson,
D. E. Org. React. 1942, 1, 266. (c) Hauser, C. R.; Swamer, F. W.; Adams,
J. T. Org. React. 1954, 8, 59. For a review on the Dieckman condensation,
see: (d) Schaefer, J. P.; Bloomfield, J. J. Org. React. 1967, 15, 1.
(33) 1,3-Diketones 3a, 3b, 3g, and 3i-k exist predominantly in the enol form
in CDCl3. See Supporting Information for details.
(34) The reactions of enolates derived from more hindered esters such as ethyl
valerate and ethyl isobutyrate with triflate 1a did not proceed well. In the
former case, we could detect the corresponding product in the crude mixture
by mass spectrometry (ESI, C14H2203Na; M+ ) 261.1); however, the yield
was quite low, and we could not isolate the desired product in acceptable
purity. In the latter case, the reaction resulted in the decomposition of triflate
1a, and a significant amount of ethyl isobutyrate was recovered.
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A R T I C L E S
Kamijo and Dudley
Table 7. Reaction of Various Triflates 1 with Lithium Enolate of
that utilization of a reducing agent would bring about the
formation of aldehydes. Unfortunately, intensive investigations
using a combination of vinylogous acyl triflate 1a and equimolar
amounts of various hydride sources resulted in failure; in most
of cases, a complex mixture of compounds was formed, which
included a small amount of aldehydes as determined by 1H NMR
analysis of the crude mixtures. On the basis of these results,
we treated triflate 1a (R ) Me, n ) 1) with excess hydride
reagent to obtain alcohol 4a (eq 6, Scheme 1). The results of
the effect of reducing agents are listed in Table 8. When 1a
(1.0 equiv) was treated with a very strong hydride donor,
LiBHEt3 (Super-Hydride, 2.2 equiv), in THF at -78 to 60 °C
within 80 min, the expected alcohol, 5-pentyn-1-ol (4a), was
obtained in 65% yield (entry 1). LiBH(s-Bu)3 (L-Selectride)
gave a moderate yield of 4a (entry 2). Other hydride sources,
such as LiBH4, NaBH4, and LiAlH4, were far less effective for
the formation of 4a, yielding cyclohexenol 9a as a major product
(entries 3-5). Interestingly, (i-Bu)2AlH (DIBALH) produced
9a solely in almost quantitative yield (entry 6).36 Returning to
LiBHEt3 as the hydride source, we determined that mild heating
was not necessary, and the optimal yield of 4a was obtained
when the reaction was quenched at room temperature (entry 7;
73% yield). Analogous reducing agents, such as NaBHEt3 and
KBHEt3, also afforded 4a in good yield as a single product
(entries 8 and 9).
Acetophenonea
a Triflate 1 (0.50 mmol), lithium enolate of acetophenone (1.1 mmol),
and THF (2 mL), -78 to 60 °C within 80 min. b Isolated yield.
Table 8. Reactivity of Reducing Agent To Promote the Reductive
Ring Opening Reaction of Triflate 1aa
acyl triflates 1 is shown in Scheme 3.35 1,2-Addition of the
lithium enolate to the carbonyl group of 1 generates tetrahedral
aldolate intermediate C2. Steric congestion around the reacting
site would retard this addition process, and the prolonged
exposure of triflates 1 to the reaction conditions would lead to
their decomposition. The Grob-type fragmentation13,14 effects
C-C bond cleavage along with extrusion of LiOTf to give 1,3-
diketone products 3. In the reaction mixture, however, a second
equivalent of the enolate abstracts a proton from the newly
formed active methylene moiety of 3 to furnish enolate
intermediate 3′, which yields 3 upon aqueous workup.
yield, %b
entry
reducing agent
4a
9a
1
2
3
4
5
6
LiBHEt3
LiBH(s-Bu)3
LiBH4
NaBH4
LiAlH4
(i-Bu)2AlH
LiBHEt3
NaBHEt3
KBHEt3
65c
42
9
4
4
0
0
62
72
12
99c
0
0
Scheme 3. Proposed Mechanistic Pathway for the Claisen-Type
Tandem Addition/C-C Bond Cleaving Fragmentation of
Vinylogous Acyl Triflates 1
7d
8d
9d
73
55
67
0
0
a Typical reaction procedure: triflate 1a (0.50 mmol), reducing agent
(1.1 mmol), and THF (2 mL), -78 to 60 °C within 80 min. b Estimated
yield based on 1H NMR unless otherwise noted. c Isolated yield. d The
reaction was quenched at room temperature.
Table 9 reflects efforts to determine the scope and limitations
of this reductive ring opening reaction of triflates 1, using
LiBHEt3. Treatment of 1a with LiBHEt3 afforded 4a in 73%
yield as mentioned previously (entry 1). The phenyl substituted
triflate 1h furnished the corresponding alcohol 4b in 62% yield
(entry 2), but the reaction of the triflate 1b (derived from 1,3-
cyclohexanedione) did not afford alcohol 4c (entry 3). Triflates
1f and 1g, bearing a geminal dimethyl substituent adjacent to
either the carbonyl group or the enol triflate moiety, gave the
corresponding products 4d and 4f in moderate yields, respec-
Synthesis of Alcohols Using Nucleophilic Hydride Re-
agents. Having realized successful addition/fragmentation of
vinylogous acyl triflates using a range of stabilized and
unstabilized carbon nucleophiles, we then turned our attention
to non-carbon reagents, starting with hydrides. We anticipated
(36) Similar reductions have been reported, see: (a) Yamano, Y.; Mimuro, M.;
Ito, M. J. Chem. Soc., Perkin Trans. 1 1997, 2713. (b) von Zezschwitz, P.;
Petry, F.; de Meijere, A. Chem.sEur. J. 2001, 7, 4035-4046. (c) Mart´ınez,
A. G.; Alvarez, R. M.; Casado, M. M.; Subramanian, L. R.; Hanack, M.
Tetrahedron 1987, 43, 275.
(35) A further mechanistic discussion can be found in our earlier paper; see ref
19.
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Reactions of Vinylogous Acyl Triflates
A R T I C L E S
tively, although it was necessary to warm the reaction mixture
to 60 °C after the typical procedure to facilitate the transforma-
tion (entries 4 and 6). In the case of 1c, the desired product 4e
was formed in only modest yield (entry 5). The seven-membered
cyclic triflate 1d furnished 4g in 63% yield (entry 7).
We then conducted the reaction between cyclohexenol 9a and
excess amounts of LiBHEt3 to confirm the possible intervention
of alkoxybononate C3 during the transformation to afford
alcohol 4a. Indeed, the expected alcohol was obtained in 70%
yield (eq 9), which corresponds to the result obtained in entry
1 of Table 9.
Table 9. Reductive Ring Opening Reaction of Triflate 1 Using
a
LiBHEt3
Synthesis of Amides Using Lithium Amide Nucleophiles.
Along with the development of tandem addition/C-C bond
cleaving fragmentation reactions employing a range of orga-
nometallic and hydride nucleophiles, we became interested in
the potential application of heteroatom nucleophiles, which
would afford products at the carboxylic acid oxidation level.
After screening several possible classes of reagents, the ami-
dative ring opening reaction of vinylogous acyl triflates 1
emerged as the most promising choice (eq 7, Scheme 1).
Reaction of triflate 1a (1.0 equiv; R ) Me, n ) 1) with the
lithium amide generated from PrNH2 (2.4 equiv) and n-BuLi
(2.2 equiv) in THF gave the desired ring opened product,
N-propyl-5-heptynamide (5a), in 91% yield (entry 1). The same
reaction in toluene was less efficient (73% yield). Conducting
the reaction in THF using 1.2 equiv of PrNH2 and 1.1 equiv of
n-BuLi resulted in a small but distinct decrease in the yield of
5a (80 vs 91% with excess lithium amide). We then surveyed
the amidative ring opening reaction of triflate 1a with a variety
of lithium amides (Table 10). Typical alkylamines, such as
PrNH2 and i-PrNH2, afforded the corresponding products 5a
and 5b, respectively, in high yields (entries 1 and 2), whereas
the bulkier t-BuNH2 gave 5c in moderate yield (entry 3).
a Typical reaction procedure: triflate 1a (0.50 mmol), LiBHEt3 (1.1
mmol), and THF (2 mL), -78 °C to room temperature within 50 min.
b Isolated yield. c The reaction mixture was heated to 60 °C for 30 min
after the typical reaction procedure. d Complex mixture was formed under
the typical reaction conditions, and decomposition occurred when the
reaction was warmed to 60 °C.
Table 10. Amidative Ring Opening Reaction of Triflate 1a Using
Various Lithium Amidesa
The proposed mechanistic pathway for the reductive ring
opening reaction of vinylogous acyl triflates 1 parallels that
proposed in Scheme 2 for carbanionic nucleophiles, except for
the role of excess hydride (Scheme 4). Initially, alkoxyboronate
intermediate C3 presumably forms by 1,2-reduction of 1 with
LiBHEt3, and subsequent C-C bond cleaving fragmentation
(Grob-type fragmentation)13,14 would produce intermediate
aldehydes. The remaining LiBHEt3 reacts with these aldehydes
to give intermediate D, and aqueous workup furnishes alcohols
4 as a final product. We assume that our inability to isolate the
intermediate aldehydes in good yield results from their inherent
instability to the reaction conditions as compared to the
corresponding acetylenic ketones.
entry
RNH2
5
yield, %b
1
2
3
4
5
6
7
8
PrNH2
i-PrNH2
t-BuNH2
PhCH2NH2
PhNH2
(p-MeO)C6H4NH2
(p-CF3)C6H4NH2
LiNH2
5a
5b
5c
5d
5e
5f
91
87
49
91
79
82
77
5g
5h
c
d
-
Scheme 4. Proposed Mechanistic Pathway for the Reductive Ring
Opening Reaction of Vinylogous Acyl Triflates 1
a Triflate 1a (0.50 mmol), RNH2 (1.2 mmol; pretreated with 1.1 mmol
of n-BuLi), and THF (2 mL), -78 to 60 °C within 80 min. b Isolated yield.
c LiNH2 was purchased and used as received. d Significant recovery of 1a
was observed.
Benzylamine furnished 5d in high yield (entry 4). Anilines
produced the respective amide products 5e-g in good yields
(entries 5-7), irrespective of the electronic nature of substituents
on the aromatic ring. No reaction was observed between triflate
1a and lithium amide (LiNH2) (entry 8). Thus far, only primary
amines have functioned effectively in this tandem addition/
fragmentation reaction, whereas secondary amines such as Pr2-
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J. AM. CHEM. SOC. VOL. 128, NO. 19, 2006 6505

A R T I C L E S
Kamijo and Dudley
Scheme 5. Proposed Mechanistic Pathway for the Amidative Ring
Opening Reaction of Vinylogous Acyl Triflates 1
NH, (i-Pr)2NH, and Ph2NH resulted mainly in the decomposition
of the starting triflate 1a.
We next examined the amidative ring opening reaction
utilizing a variety of triflates 1 and the lithium amide of PhNH2
(Table 11). Phenyl-substituted triflate 1h afforded the corre-
sponding amide 5i in high yield (entry 1). Triflate 1b derived
from 1,3-cyclohexanedione furnished 5j in 58% yield (entry
2). The six-membered triflate 1f, bearing a geminal dimethyl
substituent adjacent to the carbonyl group, gave 5k in very low
yield (entry 2). This result again suggests that the transformation
is sensitive to the steric demands of substrates. Seven-membered
triflate 1d produced the expected product 5l in high yield (entry
4). Five-membered triflate 1e afforded amide 5m in only 20%
yield (entry 5).
starting material in diverse synthetic directions.38,39 We therefore
evaluated the synthetic utility and versatility of cyclic vinylogous
acyl triflates 1 through selective functionalization of the enone
core. One straightforward transformation that illustrated the
versatility of 1a was the synthesis of cyclohexenone derivatives
6 using Grignard reagents as depicted in eq 10.17 1,2-Addition
of a nucleophilic Grignard reagent to the carbonyl group of
triflate 1a formed an intermediate tentatively assigned as alcohol
C1′ upon aqueous workup.40 This material was subjected to
chromatographic purification on silica gel to furnish cyclohex-
enones 6. Treatment of 1a with PhMgBr in toluene at -78 °C
for 10 min and then at 0 °C for 10 min gave 6a in 91% yield
after chromatography. The reaction between 1a and MeMgBr
produced 6d in good yield as well.
Table 11. Amidative Ring Opening Reaction of Various Triflates 1
Using PhNHLia
a Triflate 1 (0.50 mmol), PhNH2 (1.2 mmol; pretreated with 1.1 mmol
of n-BuLi), and THF (2 mL), -78 to 60 °C within 80 min. b Isolated yield.
The mechanistic pathway for the present amidative ring
opening reaction of vinylogous acyl triflates 1 with lithium
amides can be proposed as shown in Scheme 5. The lithium
amide adds to the carbonyl group of triflates 1 in a 1,2-fashion
to form tetrahedral hemiaminal-type intermediate C4.37 Steric
congestion around the reacting site would retard this process,
and the prolonged exposure of triflates 1 under the reaction
conditions would lead to their decomposition. Similarly, amides
that function better as basic reagents than as nucleophiles (i.e.,
LDA) may abstract the acidic R-proton of 1 rather than proceed
along the desired addition/fragmentation pathway. Subsequent
C-C bond cleavage of C4 via the Grob-type fragmentation13,14
furnishes amides 5. In the reaction mixture, however, amide 5
may be subject to lithiation to afford 5′, which explains the
benefit of using excess amide reactants to obtain an optimal
yield of 5 upon workup.
Alkylation of the enone core of vinylogous acyl triflate 1a
provides substituted triflates 8 (eq 11). This alkylation, in
conjunction with addition and hydrolysis reactions analogous
to those presented in eq 10, recalls the Stork-Danheiser
alkylation strategy.41 Deprotonation of 1a was accomplished by
LiHMDS in a mixture of THF and DMPU at -78 °C. Treatment
of the derived lithium enolate with allyl iodide gave allylated
triflate 8a in 59% yield, whereas alkylation with ethyl iodoac-
etate afforded 8b in 78% yield. The success of these reactions
illustrates the durability of the triflate moiety in the face of
transformations that are designed to impact other functionalities
within the starting materials.
(38) (a) Schreiber, S. L. Science 2000, 287, 1964. (b) Burke, M. D.; Schreiber,
S. L. Angew. Chem., Int. Ed. 2004, 43, 46. (c) Spring, D. R. Org. Biomol.
Chem. 2003, 1, 3867.
(39) For reviews on combinatorial chemistry, see: (a) A Practical Guide to
Combinatorial Chemistry; Czarnik, A. W., DeWitt, S. H.; Eds.; American
Chemical Society: Washington, DC, 1997. (b) Obrecht, D.; Villalgordo,
J. M. Solid-Supported Combinatorial and Parallel Synthesis of Small
Molecular-Weight Compound Libraries; Pergamon: Oxford, 1998. (c)
Combinatorial Chemistry and Molecular DiVersity in Drug DiscoVery;
Gordon, E. M., Kerwin, J. F., Jr., Eds.; Wiley: New York, 1998.
(40) 1H NMR data consistent with metastable intermediate C1′ were routinely
observed during spectroscopic analysis of the crude reaction mixtures.
(41) Stork, G.; Danheiser, R. L. J. Org. Chem. 1973, 38, 1775.
Synthetic Versatility of Vinylogous Acyl Triflates. Vinyl-
ogous acyl triflates embody multiple modes of potential
reactivity, which allows one, in principle, to elaborate this single
(37) Zhao, P.; Condo, A.; Keresztes, I.; Collum, D. B. J. Am. Chem. Soc. 2004,
126, 3113.
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Reactions of Vinylogous Acyl Triflates
A R T I C L E S
Danheiser alkylation strategy. The diverse range of product
classes (2-8) available in one step from cyclic vinylogous acyl
triflates creates opportunities for building compound libraries
for high-throughput screening. In addition, all of the tandem
reactions proceeded under mild conditions by simple and unified
experimental operations, and the starting triflates 1 were easily
prepared in one step from the corresponding cyclic diketones.
Acknowledgment. This research was supported by a grant
from the James and Ester King Biomedical Research Program,
the Florida Department of Health, the Donors of the American
Chemical Society Petroleum Research Fund, an award from the
Research Corporation, and by the FSU Department of Chemistry
and Biochemistry. S.K. is a recipient of the Postdoctoral
Fellowship for Research Abroad (2004) from the Japan Society
for the Promotion of Science (JSPS). We are profoundly grateful
to all of these agencies for their support. We thank Dr. Joseph
Vaughn for assistance with the NMR facilities, Dr. Umesh Goli
for providing the mass spectrometry data, and the Krafft Lab
for access to their FT-IR instrument.
Conclusion
We have developed facile C-C bond cleaving fragmentation
reactions induced by the addition of nucleophiles to cyclic
vinylogous acyl triflates 1 to produce acyclic acetylenic
compounds. A variety of reactants such as organolithium and
Grignard reagents, lithium enolates, LiBHEt3, and lithium
amides yield a wide array of ketones 2, 1,3-diketones and their
analogues 3, alcohols 4, and amides 5, respectively, as final
products. This tandem reaction was successfully extended to
prepare acetylenes 7 tethered to tertiary alcohols by adjusting
the stoichiometry of the organolithium reagents. Moreover, we
demonstrated the synthetic versatility of vinylogous acyl triflates
1 by functionalizing their common cyclic enone core. Enolate
alkylation of the vinylogous acyl triflate (1 f 8) and the
addition/hydrolysis reactions (1 f 6) proceeded by analogy to
reactions of other vinylogous esters popularized by the Stork-
Supporting Information Available: Experimental procedures,
characterization data, and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
JA0608085
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