Regiodivergent cyclobutanone cleavage: Switching selectivity with different Lewis acids

Article abstract of DOI:10.1002/chem.201406135

The exploitation of strain release in small rings as driving force to enable complex transformations is a powerful synthetic tool. Among them, cyclobutanones are particularly versatile substrates that can be elaborated in a wide variety of structurally diverse building blocks. Herein, Lewis acid catalyzed rearrangement reactions are presented that provide selective access to two structurally distinct polycyclic scaffolds, that is, indenylacetic acid derivatives and benzoxabicyclo[3.2.1]octan-3-ones. The choice of the Lewis acid fully controls the reaction pathway and the regioselectivity of the cyclobutanone C-C bond cleavage site.

Full text of DOI:10.1002/chem.201406135

DOI: 10.1002/chem.201406135
Communication
&
Lewis Acid Catalysis
Regiodivergent Cyclobutanone Cleavage: Switching Selectivity
with Different Lewis Acids
Laetitia Souillart and Nicolai Cramer*[a]
Abstract: The exploitation of strain release in small rings
as driving force to enable complex transformations is
a powerful synthetic tool. Among them, cyclobutanones
are particularly versatile substrates that can be elaborated
in a wide variety of structurally diverse building blocks.
Herein, Lewis acid catalyzed rearrangement reactions are
presented that provide selective access to two structurally
distinct polycyclic scaffolds, that is, indenylacetic acid de-
rivatives and benzoxabicyclo[3.2.1]octan-3-ones. The
choice of the Lewis acid fully controls the reaction path-
Scheme 1. Regiodivergent cyclobutanone CÀC bond cleavages.
way and the regioselectivity of the cyclobutanone CÀC
bond cleavage site.
a complete skeletal rearrangement were isolated in moderate
yields [Eq. (1)].
The exploitation of strain release in small rings as driving force
to enable synthetic transformations has received considerable
attention.[1] Among them, cyclobutane derivatives are versatile
substrates that can be elaborated in a wide variety of structur-
ally diverse building blocks.[2–6] Mostly, the site of the CÀC
bond cleavage is inherently substrate controlled. Recently, cat-
alytic asymmetric CÀC bond cleavages enabling a selection be-
tween the enantiotopic CÀC bonds have been reported.[7–9] On
the other hand, a regiodivergent cleavage of the proximal and
distal CÀC bond of a four-membered ring would enable access
to two structurally different products. For example, a regiodi-
vergent ring opening of benzocyclobutanones was achieved
by using transition-metal catalysts[10–12] or by a thermally in-
duced electrocyclic ring opening (Scheme 1).[13] Preferably,
such a reactivity switch can be triggered by two different cata-
lysts under otherwise identical reaction conditions.[14] Herein,
we report a Lewis acid catalyzed ring opening of cyclobuta-
nones. Depending on the nature of the Lewis acid, two com-
plementary reaction pathways are triggered, leading to two
different scaffolds as a result of either a proximal or distal CÀC
bond cleavage of the cyclobutanone.
Mechanistically, this intriguing transformation might be ra-
tionalized by the following pathways. Initial coordination of
the Lewis acid to the carbonyl group of the cyclobutanone can
trigger two reaction cascades, depending on the nature of the
Lewis acid used (Scheme 2). “Soft” metals trigger an enoliza-
tion reaction to give 4 (pathway I). Subsequent aldol addition
across the appended carbonyl group provides intermediate 5.
Under the reaction conditions, ionization would then lead to
benzylic carbenium ion 6, which in turn would be prone to
a strain-driven retro-Friedel–Crafts acylation, forming an olefin
and a highly reactive acylium cation 7. The reaction is termi-
nated by nucleophilic trapping of the acylium species, either
by water generated in the reaction or by an added nucleo-
phile, giving rise to indenylacetic acid derivative 2. In the com-
plementary reaction pathway II, the coordination of a “hard”
Lewis acid induces a heterolytic ring-opening reaction of the
cyclobutanone core, delivering 1,4-dipol 8. The propensity of
such a ring opening strongly depends on the substituents sta-
bilizing the arising benzylic carbenium ion.[15] This behavior is
known for strongly polarized donor–acceptor cyclobutanes
having either powerful donors, such as an alkoxy group[16] or
a Nicholas-type complexed alkyne,[17] that are able to sufficient-
ly stabilize the arising carbenium ion or an acidic malonate
pattern[18] to strongly stabilize the anion. Systems that would
Initially, cyclobutanone 1a was exposed to 20 mol%
Zn(OTf)2 and two distinct products 2a and 3a that underwent
[a] L. Souillart, Prof. Dr. N. Cramer
Laboratory of Asymmetric Catalysis and Synthesis
EPFL SB ISIC LCSA
BCH 4305, 1015 Lausanne (Switzerland)
Fax: (+41)21 693 97 00
E-mail: Nicolai.cramer@epfl.ch
Homepage: http://isic.epfl.ch/lcsa
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406135.
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Table 1. Optimizations for a selective pathway switch between indenyl
carboxylic acid 2a and bicyclic ketone 3a.[a]
Entry
Lewis acid
Yield of 2a [%][b]
Yield of 3a [%][b]
1
2
3
4
5
6
7
Cu(OTf)2
Zn(OTf)2
ZnCl2
FeCl3
TiCl4
85 (80)
0
30
67 (64)
55
62
30
33
0
0
0
Sc(OTf)3
SnCl4
80 (72)
95 (92)
0
[a] Reaction conditions: 1a (0.05 mmol) and Lewis acid (1.00 mmol) in di-
1
oxane (0.25m) at 1108C for 12 h; [b] determined by H NMR spectroscopy
(isolated yield).
Scheme 2. Proposed mechanistic rationale for the regiodivergent CÀC cleav-
age of cyclobutanones 1.
open to simple ketone enolates and benzylic cations are much
less prone to ring opening.[19] Intramolecular cyclization of 8
with the carbonyl oxygen atom would provide oxycarbenium
ion 9. In turn, 9 undergoes an intramolecular aldol cyclization,
leading to the benzoxabicyclo[3.2.1]octan-3-one scaffold 3,
which overall can be viewed as a formal [4+2] cycloaddition. It
would be highly desirable to selectively address either path-
way by proper choice of the catalyst and the reaction condi-
tions. Herein, we report the use of different Lewis acids to se-
lectively trigger and switch between these two reaction path-
ways.[20,21]
Scheme 3. Scope of the synthesis of bicyclic ketones 3. Conditions:
1 (0.10 mmol) and SnCl4 (0.02 mmol) in dioxane (0.25m) at 1108C for 12 h;
[a] ZnCl2 instead of SnCl4.
The evaluation of the reaction conditions was initially per-
formed on cyclobutanone 1a as a model substrate, primarily
examining the behavior of different Lewis acids on the selectiv-
ity (Table 1). In summary, copper(II) triflate as a soft Lewis acid
was found to be an excellent catalyst for the aldol-addition
pathway I, leading selectively to indenyl carboxylic acid 2a in
80% isolated yield (entry 1). In contrast, zinc(II) triflate and
zinc(II) chloride were both not selective and lead to a mixture
of the products 2a and 3a, indicating that both pathways
were operative (entries 2 and 3). On the other hand, both
iron(III) chloride and titanium(IV) chloride exclusively gave rise
to bicyclic ketone 3a, albeit in moderate yields (entries 4 and
5). Scandium(III) triflate displayed an improved reactivity by se-
lectively affording 3a in a higher yield (entry 6). Finally, tin(IV)
chloride was found to be the best catalyst, resulting in the for-
mation of 3a in 92% isolated yield (entry 7).[22]
cleavage pathway initiating the formation of benzoxabicy-
clo[3.2.1]octan-3-one 3 was exploited (Scheme 3). The nature
of the rearranged product was confirmed by X-ray crystallogra-
phy of product 3b (Figure 1). The electronic properties of the
aromatic tether can be varied and both electron-withdrawing
and -donating groups (3c and 3d) are well tolerated to pro-
vide the oxabicyclooctanones 3 in reliably high yields. Besides
aromatic substituents R’, which provide a good stabilization of
intermediate 8 via a dibenzylic carbenium ion, 3-alkyl-substitut-
ed cyclobutanones 1e–h are also competent substrates. This is
worth noting, because the intermediate carbenium ions are
less stabilized, which might impact the ring-opening rates sig-
nificantly. Pleasingly, this substrate type still efficiently rear-
ranged into ketones 3e–h. However, substrates having an al-
dehyde moiety instead of a ketone are not competent sub-
strates, owing to their higher carbonyl electrophilicity.
Having established two sets of conditions to selectively trig-
ger both rearrangement pathways, we next investigated the
generality and limitations of the two transformations. First, the
Next, we turned our attention towards the second rear-
rangement pathway, exploiting the formation of indenylacetic
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Scheme 5. Stepwise formation of carboxylic acid 2j supports proposed aldol
intermediate 5j.
is a transient intermediate in the reaction. Furthermore, this
suggests that the high reaction temperature is required for the
ionization or the retro-Friedel–Crafts step. On the other hand,
an increased reaction temperature of 1308C led to significant
product degradation, thus leaving a rather narrow optimal
temperature window. Moreover, submission of 5a to tin(IV)
chloride in refluxing dioxane only lead to the formation of in-
denyl acetic acid 2a, indicating that the steps after the aldoli-
zation are independent of the hard or soft nature of the Lewis
acid.
With this additional information on the mechanism in hand
(Scheme 6), we further explored trapping the acylium ion spe-
Figure 1. X-ray crystal structure of ketone 3b.
Scheme 6. Synthesis of indenyl esters 10 by trapping of reactive intermedi-
ates with added nucleophiles. Conditions: 1 (0.10 mmol) and ZnCl2
(0.02 mmol) in dioxane (1m) at 1108C for 16 h; [a] Cu(OTf)2 instead of ZnCl2.
Scheme 4. Scope of the synthesis of indenyl derivatives 2. Conditions:
1 (0.10 mmol) and Cu(OTf)2 (0.02 mmol) in dioxane (1m) at 1108C for 16 h;
[a] ZnCl2 instead of Cu(OTf)2.
cies with external nucleophiles that are added to the reaction
mixture. For example, the corresponding indenyl esters 10
were directly obtained by adding the corresponding alcohol.
To suppress the formation of the carboxylic acid by-product 2,
formed by the reaction with generated water, orthoformates
were added as water scavengers. In this respect, several alco-
hols were well suited. Particularly, simple primary alcohols such
as methanol, ethanol, or propanol deliver the corresponding
esters in good yields. The more sterically hindered isopropanol
afforded the isopropyl ester, albeit in a lower yield. Similar to
the scope without added nucleophiles, this variant is tolerant
to a wide scope of substrates with different steric and elec-
tronic substrate variations.
acids 2 (Scheme 4). With catalytic amounts of copper(II) triflate
as Lewis acid, cyclobutanones 1 bearing a ketone moiety rear-
ranged smoothly into indenylacetic acids 2 bearing a trisubsti-
tuted double bond. The reaction is not influenced by electron-
ic modifications of the aromatic tether (2c and 2d). The use of
aldehyde-containing substrates 1 (R2 =H) enabled the use of
zinc(II) chloride, providing equally good reactivities and yields
(3i–m). Different substituents on the cyclobutanone ring in-
cluding esters are well tolerated and carboxylic acids 2 were
obtained in good yields. Modifications of the electronic proper-
ties of the aromatic moiety did not influence the selectivity, al-
though a meta-chlorine substituent (2n) diminished the yield.
To gain valuable insights on the rearrangement process, we
tried to identify reactive intermediates. Indeed, the expected
intermediate aldol product 5j could be isolated as a single dia-
stereomer in moderate yield by lowering the reaction tempera-
ture to 908C (Scheme 5). Resubmission of 5j to the standard
reaction conditions formed indenylacetic acid, proving that 5j
In summary, we have demonstrated that the inherent ring
strain of cyclobutanone can be exploited with Lewis acid cata-
lysts, giving access to rearranged and synthetically valuable
building blocks. One of the most prominent features is the
switch of the reaction pathways of enolization or ionization by
proper choice of the Lewis acid, allowing a regiodivergent
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Further work aims at introducing enantiocontrol in the cleav-
age reaction.
Experimental Section
Indenylacetic acid 2a
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Cyclobutanone 1a (26.4 mg, 0.100 mmol) and copper(II) triflate
(7.2 mg, 0.020 mmol) were weighed in an oven-dried vial equipped
with a magnetic stir bar, capped with a septum, and purged with
nitrogen. Then, dry dioxane (0.1 mL) was added. The mixture was
stirred for 20 min at 238C and subsequently heated to 1108C. After
16 h, the reaction mixture was cooled to 238C and purified by
silica-gel column chromatography eluting with pentane/ethyl ace-
tate (4:1). Indenyl carboxylic acid 2a was isolated as colorless oil in
80% yield (21 mg).
Benzoxabicyclo[3.2.1]octan-3-one 3a
Cyclobutanone 1a (26.4 mg, 0.100 mmol) was weighed in an oven-
dried vial equipped with
a magnetic stir bar, capped with
a septum, and purged with nitrogen. Dry dioxane (0.4 mL) and
tin(IV) chloride (2.3 mL, 0.020 mmol) were added. The mixture was
stirred for 20 min at 238C and subsequently heated to 1108C. After
16 h, the reaction mixture was cooled to 238C and purified by
silica-gel column chromatography eluting with pentane/ethyl ace-
tate (10:1). Benzoxabicyclo[3.2.1]octan-3-one 3a was isolated as
white solid in 92% yield (24 mg).
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Acknowledgements
This work is supported by the European Research Council
under the European Community’s Seventh Framework Pro-
gram (FP7 2007–2013)/ERC Grant agreement no 257891. We
thank Dr. R. Scopelliti for X-ray crystallographic analysis of 3b.
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Keywords: cyclobutanones · Lewis acids · rearrangement ·
regiodivergence · ring-opening reactions
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[22] Preliminary attempts for an asymmetric reaction were either hampered
by sluggish reactivity or non-existing enantiodiscrimination using chiral
ligands (CuII BOX/PyBOX complexes or TRIP as a chiral Bronsted acid).
Received: October 18, 2014
Published online on December 4, 2014
Chem. Eur. J. 2015, 21, 1863 – 1867
www.chemeurj.org
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