tions since the 1990s.3 A key issue in their studies was the
requirement for electron-withdrawing substituents on a six-
membered oxonium ion-bearing ring, as cyclopentanols did
not ring expand in their absence. Although it was expected
in our case that reactions proceeding through iminium ion
intermediates would be less facile compared to the oxonium
species, the possible efficiency of the construction of the
desired azaspirocyclic compounds outweighed this risk. Even
so, our initial studies utilized cyclobutanol substrates, as relief
of ring strain should promote the expansion of the cyclo-
butanol to the cyclopentanone.4
After the exploration of other (unsuccessful) options, the
requisite hydroxyiminium ion intermediates were generated
by the protonation of p-toluenesulfonyl enamides of general
structure 1. These compounds were constructed in the
following manner (Scheme 1).3,5 The N-p-toluenesulfonyl
c. The use of a very low reaction temperature (-100 °C)
and addition of magnesium bromide-etherate was sometimes
necessary for improved yields (74-89%). Alternate additives
such as HMPA, zinc (II) chloride, or cerium (III) chloride
did not improve the reaction yields.
Subjecting cyclobutanols 1a-c to the action of acid
resulted in smooth expansion to cyclopentanones 4 and 5
(Table 1). Unlike Paquette’s semipinacol reactions through
Table 1. Semipinacol-Type Ring Expansion of Cyclobutanols
1
Scheme 1
entry
SMa
acidb
T (°C)
t (h)
yield (%)c
ratio 4:5c
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1b
1c
1c
1c
CSA
HCl
CSA
CSA
CSA
CSA
HCl
HCl
45
25
25
45
45
45
25
0
13
2
24
6
13
144
11
48
73
67
13
17
81
89
93
93
n/a
n/a
nd
2:1
2.8:1
4.5:1
11:1
14:1
a SM ) starting material. b CSA ) camphorsulfonic acid (1.2 equiv) in
dichloromethane; HCl ) hydrochloric acid (1.1 equiv) in dichloromethane.
c Ratios are determined by 1H NMR integration and GC analysis of the
product mixture; n/a ) not applicable; nd ) not determined.
oxonium ion intermediates, these reactions were sluggish
using 1.2 equiv of camphorsulfonic acid as a promoter at
room temperature (entry 3), and therefore heating to 45 °C
for 13 h was required for good conversions (compare entries
lactams 2a-c6 were converted to their corresponding enol
triflates under standard conditions. These were converted to
vinylstannanes 3a-c by palladium(0)-catalyzed cross-
coupling using hexamethyldistannane.7 The yields of the
vinylstannanes were highest when the reaction was run at
room temperature in THF for roughly 7 h. Shorter or longer
reaction times resulted in lower isolated yields of 3a-c. Tin-
lithium exchange of 3a-c using methyllithium was followed
by quenching with cyclobutanone to give cyclobutanols 1a-
1
1, 4, and 5). By following the reaction using H NMR
spectroscopy, we have since found that hydrochloric acid
can promote this reaction at lower temperatures (entries 2,
7, and 8). The diastereoselectivity of the ring expansion
reactions were moderately low (2:1 to 4.5:1) when the
reaction was performed at 45 °C (entries 4-6) but improved
significantly at lower temperatures (entries 7 and 8). The
structures of 4b and 5b have been assigned by construction
through an alternate path.8 The structures of 4c and 5c, which
are inseparable by column chromatography, are assigned by
mechanistic analogy to 4b and 5b.
Although the examination of more substrates is necessary
to determine the generality of this process, these results are
consistent with the mechanistic rationale proposed by
Paquette (Scheme 2).3a The stereoselectivities of these
reactions (shown here for 1b) are thought to derive through
transition states in which the substituents are pseudoequa-
torial. The diastereomeric transition states differ depending
(3) (a) Paquette, L. A.; Lanter, J. C.; Johnston, J. N. J. Org. Chem. 1997,
62, 1702. (b) Paquette, L. A.; Kinney, M. A.; Dullweber, U. J. Org. Chem.
1997, 62, 1713 and references within.
(4) (a) Hirst, G. C.; Johnson, Jr, T. O.; Overman, L. E. J. Am. Chem.
Soc. 1993, 115, 2992. (b) Trost, B. M.; Chen, D. W. C. J. Am. Chem. Soc.
1996, 118, 12541.
(5) All previously unreported compounds have been fully characterized
spectroscopically (1H and 13C NMR, IR, HRMS).
(6) 2a and 2b were made by treating the parent lactams with BuLi and
TsCl. 2b: Herdeis, C. Synthesis 1986 232. 2c was made by the copper-
catalyzed conjugate addition of PhMgBr to ∆3,4-N-p-toluenesulfonyl-2-
oxopiperidene: Nagashima, H.; Ozaki, N.; Washiyama, M.; Itoh, K.
Tetrahedron Lett. 1985, 26, 657. The details of the construction of 1a-c
will be published elsewhere.
(7) Luker, T.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997, 62,
8131.
(8) The details of this chemical correlation will be published elsewhere.
2110
Org. Lett., Vol. 3, No. 13, 2001