lecular attack of the alkoxide moiety would provide the
desired lactone and regenerate the NHC catalyst. Alterna-
tively, intermediate II could undergo an alkoxide-induced
elimination of the NHC to furnish a hydroxy-ketene which
would then cyclize to the lactone. Toward the achievement
of this catalytic sequence, the ability of NHCs to promote
the unprecedented ring opening of strain-free, unstabilized
systems was of particular concern. Indeed, the failure to
eliminate simple alkoxides from Breslow intermediates
related to I was recently underscored by Scheidt and co-
workers during their synthesis of coumarins.2h
withdrawing aryl group provided the desired product in
moderate yield (entry 4). The use of imidazolium catalyst 5
did not provide any of the expected lactone but instead slowly
gave rise to small amounts of the presumed benzoin product
(entry 5). In sharp contrast, imidazolinium catalyst 6 led to
a clean and quantitative conversion to the somewhat volatile
lactone (entry 6). A reduction in the catalytic loading was
accomplished through simultaneous increase of the concen-
tration, with no detrimental effect on the yield (entry 7).
Intrigued by the dramatically different outcomes obtained
with catalysts 5 and 6, we decided to test imidazolium 7
and imidazolinium 8 to determine whether this discrepancy
was due to steric or electronic factors. The results shown in
entries 5-9 clearly rule out the difference as arising from
steric factors. Along with the results from entries 3 and 4, it
further demonstrates that electronic factors play a major role
in this reaction. The conditions from entry 7, using imida-
zolinium catalyst 6, were chosen to study the scope of the
reaction. Interestingly, imidazolinium-catalyzed transforma-
tions of aldehydes have received very little attention thus
far. To the best of our knowledge, there is only one other
example of a reaction proceeding through an imidazolinium-
derived Breslow intermediate.4
We began our explorations with tetrahydrofurfural as a
model substrate and various NHC precatalysts (Figure 1).
We then examined the synthesis of a variety of function-
alized lactones, as shown in Table 2. Tetrahydrofuran
derivatives with substituents at the 3, 4, and 5 position all
provided the corresponding monosubstituted lactones very
efficiently (entries 2-6).5 Of note, the use of benzyl or
trialkylsilyl protecting groups was well tolerated (entries 2
and 3). Specifically, no side-products originating from a
possible 1,2-silyl transfer were detected in entry 3. Both
trans- and cis-fused bicyclic tetrahydrofuran derivatives
smoothly afforded bicyclic lactones (entries 7 and 8), making
this process particularly interesting in a synthetic context.
This new lactonization reaction is not limited to the
synthesis of six-membered lactones. Oxetane 2-carboxalde-
hydes, readily accessed from ketones and allylic alcohols in
two steps,6 undergo a ring expansion to form γ-butyrolactone
derivatives in high yield (entry 9). It is also possible to form
seven-membered lactones through the use of tetrahydropyran-
2-carboxaldehydes, albeit in reduced yield (entry 10). In this
case, only trace amounts of impurities were observed in the
crude reaction mixture following workup, suggesting the
formation of water-soluble or polymeric side products. This
last example is quite striking in that the closure of the
Figure 1. Precatalysts screened for the synthesis of lactones.
In contrast to the redox esterification of epoxy aldehydes,3a
we found that the use of thiazolium-derived catalysts led to
complex reaction mixtures (Table 1, entries 1 and 2).
Table 1. Reaction Optimizationa
catalytic concentration
entry catalyst loading( ×)
(M)
time (h) yieldb (%)
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
6
8
7
50
50
50
50
50
50
10
10
50
0.02
0.02
0.02
0.02
0.02
0.02
0.5
5
5
5
5
5
5
38
<5
42
<5
82
78
35
<5
(3) (a) Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126–
8127. (b) Sohn, S. S.; Bode, J. W. Angew. Chem., Int. Ed. 2006, 45, 6021–
6024. (c) Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios, R.; Co´rdova, A. Angew.
Chem., Int. Ed. 2007, 46, 778–781. (d) Li, G.-Q.; Li, Y.; Dai, L.-X.; You,
S.-L. Org. Lett. 2007, 9, 3519–3521. (e) Zhao, G.-L.; Co´rdova, A.
Tetrahedron Lett. 2007, 48, 5976–5980. (f) Vora, H. U.; Rovis, T. J. Am.
Chem. Soc. 2007, 129, 13796–13797. (g) Bode, J. W.; Sohn, S. S. J. Am.
Chem. Soc. 2007, 129, 13798–13799. (h) Alcaide, B.; Almendros, P.;
Cabrero, G.; Ruiz, M. P. Chem. Commun. 2007, 4788–4790. (i) Li, G.-Q.;
Li, Y.; Dai, L.-X.; You, S.-L. AdV. Synth. Catal. 2008, 350, 1258–1262. (j)
Ibrahem, I.; Zhao, G.-L.; Rios, R.; Vesely, J.; Sunde´n, H.; Dziedzic, P.;
Co´rdova, A. Chem.sEur. J. 2008, 14, 7867–7879. (k) Du, D.; Wang, Z.
Eur. J. Org. Chem. 2008, 4949–4954. (l) Vora, H. U.; Moncecchi, J. R.;
Epstein, O.; Rovis, T. J. Org. Chem. 2008, 73, 9727–9731.
5
13
17
4
0.5
0.02
a All reactions were performed on a 0.4-0.6 mmol scale; DBU )
1,8-diazabicyclo[5.4.0]undec-7-ene. b Yield of pure, isolated product.
(4) Matsumoto, Y.; Tomioka, K. Tetrahedron Lett. 2006, 5843–5846.
(5) No reaction was observed when 2-alkyloxacycloalkane-2-carboxal-
dehydes were used.
(6) Adam, W.; Stegmann, V. R. Synthesis 2001, 1203–1214.
Similarly, triazolium catalyst 3 afforded trace amounts of
the lactone, along with many unidentified side products (entry
3). Remarkably, triazolium catalyst 4 bearing an electron-
892
Org. Lett., Vol. 11, No. 4, 2009