fragmentations likely reflects a higher enthalpic barrier to
forming the alkyne π-bond as compared to alkenes or even
allenes.11 Alkynogenic fragmentations require either an ex-
ceedingly high temperature12 or an exceptionally strong
nucleofuge,13 namely molecular nitrogen14 or triflate.15,16
homopropargyl alcohols and amines.19 It also improved
the prospects of generating active carbanion nucleophiles
tethered to the VAT substrate (Scheme 1), so as to enable
cyclization and ring-expansion pathways.20
Table 1. Optimization of the Reductive VAT Ring Expansion
Scheme 1. Ring Expansion Strategy for the Synthesis of
Medium-Ring Cycloalkynones
concn
(M)
yieldb
(%)
entry
R-M
solventa
THF
1
n-BuLi
t-BuMgClc
n-BuLi
n-BuLi
n-BuLi
n-BuLi
t-BuLic
n-BuLi
n-BuLi
n-BuLi
n-BuLi
0.07
0.06
0.07
0.1
0
0
2
THF
3
Toluene
0
The central hypothesis of the present study is that
reductive cyclization of vinylogous acyl triflates (VATs) will
trigger ring-expanding fragmentation to produce medium-
sized cycloalkynes (Scheme 1) and that this process can be
initiatied by halogen-metal exchange in the presence of
VAT functionality. We have used VAT fragmentation to
produce acyclic alkynyl ketones, but our methodology had
been limited to aryl nucleophiles10c and stabilized carba-
nions.17 More reactive alkyllithium and Grignard reagents,
such as could be employed for halogen-metal exchange with
aryl iodides, induced decomposition of the VAT substrates.
As the study evolved, however, we came to realize that
nucleophilic 1,2-addition is easier to control;or rather, that
VAT decomposition is suppressed;using toluene as the
solvent.18 This observation facilitated expansion of the
methodology to heterocyclic VATs, providing access to
4
THF/HMPA
Et2O/HMPA
toluene/HMPA
toluene/HMPA
toluene/HMPA
toluene/HMPA
toluene/HMPA
toluene/HMPA
22
25
36d
0
5
0.1
6
0.1
7
0.1
8
0.03
0.025
0.01
0.005
44
51
62
83
9
10
11
a 3.0 equiv of HMPA in entries 4-11. b Isolated yield of pure
material; see Supporting Information for details. c 2.0 equiv. d Changing
the initial temperature to either -40 or -100 °C led to inferior results.
Experiments designed to provide evidence in support of
our central hypothesis are recounted in Table 1. We chose
benzocyclononyne 2 as the initial target and 2-iodobenzyl-
VAT 1 as the prototype substrate for method development.
As expected, treatment of 1 with either n-BuLi or t-BuMgCl
in THF resulted in decomposition of the substrate with no
evidence of cycloalkyne formation (entries 1 and 2). How-
ever, switching the solvent to toluene provided no measur-
able improvement (entry 3). The first promising results were
obtained when HMPA (3.0 equiv) was added.21 Entries 4-6
reveal that toluene is indeed preferable to ethereal solvents,
although t-BuLi continued to induce general decomposition
(11) Using an elegant combination of theory and experiment,
Williams recently described fragmentation reactions that preferentially
generate allenes over alkynes. For more information and applications in
synthesis, see: (a) Kolakowski, R. V.; Manpadi, M.; Zhang, Y.; Emge,
T. J.; Williams, L. J. J. Am. Chem. Soc. 2009, 131, 12910–12911.
(b) Saget, T.; Cramer, N. Angew. Chem., Int. Ed. 2010, 49, 8962–8965.
(12) Coke, J. L.; Williams, H. J.; Natarajan, S. J. Org. Chem. 1977,
42, 2380–2382.
(13) Lepore, S. D.; Mondal, D. Tetrahedron 2007, 63, 5103–5122.
(14) (a) Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta
1967, 50, 708–713. (b) Tanabe, M.; Crowe, D. F.; Dehn, R. L. Tetra-
hedron Lett. 1967, 3943–3946. (c) Tanabe, M.; Crowe, D. F.; Dehn,
R. L.; Detre, G. Tetrahedron Lett. 1967, 3739–3743. (d) Felix, D.;
Shreiber, J.; Ohloff, G.; Eschenmoser, A. Helv. Chim. Acta 1971, 54,
2896–2912. (e) Draghici, C.; Brewer, M. J. Am. Chem. Soc. 2008, 130,
3766–3767. (f) Draghici, C.; Huang, Q.; Brewer, M. J. Org. Chem. 2009,
74, 8410–8413. (g) Bayir, A.; Draghici, C.; Brewer, M. J. Org. Chem.
2010, 75, 296–302. (h) Dias-Jurberg, I.; Gagosz, F.; Zard, S. Z. Org. Lett.
2010, 12, 416–419.
(15) See ref 10c and (a) Fleming, I.; Ramarao, C. Org. Biomol. Chem.
2004, 2, 1504–1510. (b) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc.
2006, 128, 6499–6507. (c) Murphy, J. A.; Mahesh, M.; McPheators, G.;
Anand, R. V.; McGuire, T. M.; Carling, R.; Kennedy, A. R. Org. Lett.
2007, 9, 3233–3236. For related examples involving a selenium-derived
nucleofuge, see:(d) Shimizu, M.; Ando, R.; Kuwajima, I. J. Org. Chem.
1981, 46, 5246–5248. (e) Shimizu, M.; Ando, R.; Kuwajima, I. J. Org.
Chem. 1984, 49, 1230–1238.
(19) (a) Tummatorn, J.; Dudley, G. B. J. Am. Chem. Soc. 2008, 130,
5050–5051. (b) Tummatorn, J.; Dudley, G. B. Org. Lett. 2011, 13, 158–160.
(20) Note that Tanabe generated 5-cyclodecynone, albeit in modest
overall yield, using what we now call the Eschenmoser-Tanabe strategy;
this result was both encouraging and motivating with respect to devel-
oping new reductive ring expansions of iodoaryl- and iodovinyl-tethered
VATs. See ref 14b for details, and for a related example, see: Gordon,
D. M.; Danishefsky, S. J.; Schulte, G. K. J. Org. Chem. 1992, 57, 7052–
7055.
(16) Use of carbon dioxide as an electrofuge has also been used to
drive alkyne formation; see refs 10a, 10b, 14h, and 15a.
(17) (a) Kamijo, S.; Dudley, G. B. Org. Lett. 2006, 8, 175–177.
(b) Jones, D. M.; Lisboa, M. P.; Kamijo, S.; Dudley, G. B. J. Org.
Chem. 2010, 75, 3260–3267.
(21) The 1H NMR spectrum of 2 displays unusually broad resonance
signals suggestive of a complex mixture of conformational isomers (see
p S27 of the Supporting Information for a copy of the spectrum).
(18) Jones, D. M.; Kamijo, S.; Dudley, G. B. Synlett 2006, 936–938.
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