Organic Letters
Letter
Due to our group’s interest in the development and
exploitation of molecular rearrangement reactions and syn-
thesis of strained ring-containing molecules, we sought to take
advantage of the Favorskii rearrangement mechanism to create
highly substituted cyclopropanes. Previously, Trost et al.
observed that treating a spirocyclic α,α-dibromocyclobutanone
under basic conditions resulted in a majority of the rearranged
cyclopropyl ester instead of the desired ring-opened product
(Figure 1D).7 While this ring-contraction result has been
observed in several instances, no comprehensive studies have
been conducted to evaluate the full scope and capabilities of
this transformation.8 With this precedent, our goal was to
conduct the quasi-Favorskii rearrangement on a tertiary
alcohol obtained by organometallic addition to an α,α-
dichlorocyclobutanone. This combination of reactions signifi-
cantly increases the complexity and substitution around the
final cyclopropane ring, as a fully substituted stereocenter is
formed (Figure 1E). Additionally, the motivation behind this
study was to synthesize highly substituted cyclopropane rings
without transition metal catalysts or the requirement of
directing groups.
precursor, displayed varying levels of success with yields
ranging from 10% to 89% (Scheme 1, 2d vs 2h, Condition
A).10 For olefins with poor reactivity in the first method, a
second method relying on agitation via sonication and
trichloroacetyl chloride as a ketene precursor was employed
(Scheme 1: Condition B).11 With this method, the yield of 2d
was improved (10% to 69%) and a wider variety of α,α-
dichlorocyclobutanones were obtained in good yield (Scheme
1, 2e−g, 2i). In most cases, the reaction proceeded with high
regio- and diastereoselectivity as expected.12 For compound
2c, an inseparable 5:1 mixture of diastereomers was formed
where the major product is presumed to be the one in which
the ketene adds to the face opposite of the bulky benzyl group.
Interestingly, compound 2e was isolated as an inseparable
mixture of regioisomers in approximately a 1:1.1 ratio
1
determined by H NMR integrations.
With an assortment of α,α-dichlorocyclobutanones in hand,
the next step was to convert the carbonyl functionality to the
corresponding tertiary alcohol through a C−C bond forming
reaction. To our surprise, the addition of carbon-centered
nucleophiles to cyclobutanones with one or two α-chlorine
atoms was relatively unexplored in the literature.13 Initial
experiments showed that reactions of these ketones with
Grignard reagents were unsuccessful or provided only low to
moderate yield of the expected tertiary alcohol (Scheme 2, 4a,
4f; Condition B). These results are presumed to be a
consequence of the basic nature of the Grignard reagent and
availability of easily removable protons on the α,α-dichlor-
ocyclobutanone. Instead of direct Grignard addition, it was
found that transmetalation of a Grignard or organolithium to
an organocerium reagent was needed for the reaction to occur
(Scheme 2; Condition A). To conduct the transmetalation,
CeCl3·7H2O was dried under heat and vacuum overnight
before forming a suspension in THF and incorporating the
corresponding Mg or Li organometal (see Supporting
Information).14 By replacing the Grignard reagent with an
organocerium, the yield of alcohol 4a increased from 58% to
71% and the yield of alcohol 4f drastically improved from 11%
to 73%. The importance of the transmetalation on the reaction
outcome was observed, and the remaining tertiary alcohols
were formed via organocerium addition. The relative stereo-
chemistry for the tertiary alcohols depicted in Scheme 2 was
determined based on previous literature examples of similar
additions to nonhalogenated cyclobutanones.15
For the first step, a diverse set of α,α-dichlorocyclobuta-
nones were synthesized through one of two methods utilizing a
Staudinger [2 + 2] ketene cycloaddition reaction between
olefins and in situ generated dichloroketene (Scheme 1).9 The
first method, using dichloroacetyl chloride as a ketene
Scheme 1. Staudinger Ketene [2 + 2] Cycloaddition of
Olefins
To increase the substrate scope of this addition reaction, a
variety of organocerium reagents were added to the α,α-
dichlorocyclobutanones in good to excellent yield (Scheme
2). Organometals with different substitution patterns and
electronic properties were used. The organocerium addition
tolerated ortho-, meta-, and para-substituents (Scheme 2, 4a−b,
4j−k, 4n−4q), heterocycles (Scheme 2, 4e, 4g), electron-
withdrawing groups (Scheme 2, 4o), electron-donating groups
(Scheme 2, 4b, 4j, 4q), aliphatic substrates (Scheme 2, 4c, 4h,
4l), and protecting groups (Scheme 2, 4i−4j, 4k). To
demonstrate the scalability of this nucleophilic addition,
formation of alcohol 4a was conducted on a 5.0 mmol scale
and an improvement in yield (71% to 76%) was observed
(Scheme 2). From an indene backbone, substitutions made to
the β-position of the carbonyl did not have an effect on the
outcome of the addition step (Scheme 1, 4a vs 4d).
Additionally, the bulky benzyl group on 2c did not hinder
thiophene addition to produce tertiary alcohol 4e in 72% yield.
Interestingly, compound 4e was isolated as a single
a
Reaction condition A: olefin (1.0 equiv) and dichloroacetyl chloride
(1.2 equiv) were dissolved in hexanes at room temperature (22 °C).
The solution was heated to reflux. NEt3 (1.2 equiv) in hexanes was
added dropwise over 0.5−1 h, and the solution was refluxed
b
overnight. Reaction condition B: A solution of olefin (1.0 equiv)
and Zn powder (2.5 equiv) in Et2O was cooled to 0 °C, and
sonication was applied. Trichloroacetyl chloride (1.5 equiv) was
added dropwise over 0.5−1 h. The temperature was maintained under
10 °C, and the solution was sonicated for a total of 2 h.
B
Org. Lett. XXXX, XXX, XXX−XXX