Regioselective Transition-Metal-Free Oxidative Cyclobutanol Ring Expansion to 4-Tetralones

Article abstract of DOI:10.1021/acs.orglett.8b03619

A facile and transition-metal-free ring expansion of the cyclobutanol moiety to 4-tetralones fused to heteroaromatic systems is described. The oxidative ring expansion proceeds rapidly and regioselectively through mediation by N-bromosuccinimide and aceto

Full text of DOI:10.1021/acs.orglett.8b03619

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Regioselective Transition-Metal-Free Oxidative Cyclobutanol Ring
Expansion to 4‑Tetralones
Philipp Natho,† Mia Kapun,‡ Lewis A. T. Allen,† and Philip J. Parsons*,†
†Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, W12 0BZ, London, U.K.
‡School of Chemistry, University of Edinburgh, EH9 3FJ, Edinburgh, U.K.
S
* Supporting Information
ABSTRACT: A facile and transition-metal-free ring expansion of the
cyclobutanol moiety to 4-tetralones fused to heteroaromatic systems is
described. The oxidative ring expansion proceeds rapidly and
regioselectively through mediation by N-bromosuccinimide and acetoni-
trile in satisfactory to good yields. The preparation of precursors and the
ring expansion have proven to be scalable and are straightforward to carry
out.
he use of cyclobutanols as precursors to a series of γ-
Tfunctionalized butanones has recently attracted the
interest of the synthetic community. This has led to the
development of a vast array of γ-functionalization protocols,
including fluorination, chlorination, bromination, cyanation, or
selenylation through pioneering work by Zhu.1−8 All current
protocols for the introduction of functionality to the
cyclobutanol ring require the use of catalytic quantities of
transition metals such as silver(I) species or manganese(III)
acetate.
Interestingly, through the absence of a radical trapping agent
the protocol can be modified to achieve an oxidative
intramolecular ring opening and closure of cyclobutanol 1 to
1-tetralone 2 in one synthetic operation (Scheme 1).9 This
reaction proceeds regioselectively to the 1-tetralone 2 in 40%
yield.
Figure 1. Natural products containing the 4-tetralone motif.
ate for the formation of the 1-tetralone and 4-tetralone would
allow for the derivitization of natural products (e.g., regiomeric
Ribisin A) to be submitted for structure−activity relationship
studies.
Cyclobutanols have been shown to expand under halonium
ion mediation to the five-membered rings (Scheme 2). This
work had been pioneered by Fukumoto in 1996 (a) in which a
Scheme 2. Literature Precedent for Halonium Ion-Mediated
Cyclobutanol Ring Expansion
Scheme 1. Oxidative Ring Expansion to the 1-Tetralone by
Zhu
The conversion outlined in Scheme 1 has also been shown
to be effective under hypervalent iodine catalysis, resulting in
the formation of the 1-tetralone 2 in 47% yield.10 In contrast to
the two protocols existing for the construction of the 1-
tetralone 2, synthesis of the regioisomeric 4-tetralone from the
same cyclobutanol intermediate 1 has not yet been reported.
The formation of this motif would be of synthetic importance
due to the presence of this unique scaffold in natural products
such as Fortuneanoside K or of the Ribisin family, including
Ribisin A (Figure 1). The aforementioned compounds have
shown interesting biological properties, particularly tyrosinase
inhibition and stimulation of neurite outgrowth of NGF-
mediated PC12-cells.11,12 A common cyclobutanol intermedi-
Received: November 13, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03619
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Letter
cyclobutanol in the allylic position of an alkene 3 was
expanded to the cyclopentanone 4 with an iodine in the β-
position. This methodology was advanced by Paquette (1998)
(b), who prepared brominated spirocyclic compounds 6 from
dihydrofurans 5. Dake (2004) (c) replaced the dihydrofuran
moiety with tetrahydropyridines 7 to form the spirocycle 8 in
96% yield.13−15 Furthermore, modifications to the previous
work have recently been developed to include similar 1,2-
carbon migration sequences with concomitant trifluoromethy-
lation, arylation or arylsulfonylation under visible-light or
transition-metal-free induction.16−18
In all examples cited, expansion of the alkene-substituted
cyclobutanol to the five-membered ring is observed, with
concomitant functionalization of the alkene. Mechanistically, as
shown in Scheme 2, the formation of a halonium ion was
suggested, which induces an electronic shift of the carbon−
carbon σ-bond. We envisioned that a further in situ 1,2-carbon
migration with elimination of an equivalent of hydrogen
bromide should lead to the formation of the desired six-
membered ring and restore aromaticity in an overall 1,3-carbon
migration.
employed as the solvent at room temperature (entry 6, Table
1). The superiority of acetonitrile in combination with NBS for
certain reactions has previously been observed in the
bromocyclization of 3-olefinic alcohols.19 Lowering the
reaction temperature to −35 °C (entry 7, Table 1) or an
increase to reflux (entry 8, Table 1) still led to formation of the
desired tetralone 9, but with decreased yields. We deduced
from the initial solvent screen that a solvent containing a nitrile
group is of essence for this reaction, which was further
confirmed by the successful ring expansion to tetralone 9 in
propionitrile (entry 9, Table 1). A change of the electrophile
from NBS to NIS, NCS, PhSeCl, or tribromoisocyanuric acid
(entries 10−13, Table 1) proved inferior. While no conversion
was detected with PhSeCl, reactions with NCS and NIS
proved sluggish and were accompanied by a complex mixture
of unidentifiable side products. The poor yields of products
observed in the NCS- or NIS-mediated cyclizations suggest a
difference in reaction mechanism compared to NBS. Variation
of the bromine source to tribromo-isocyanuric acid again led to
complete cessation of the reaction. Addition of further metal-
based oxidants (entries 14−15, Table 1) did not lead to yield
improvements of the desired product.
In order to investigate the aforementioned possibility and to
uncover the optimal reaction conditions, we selected cyclo-
butanol 1 as our model study and subjected it to a variety of
potential ring expansion conditions (Table 1) to generate the
desired 4-tetralone 9.
With optimal conditions in hand, we explored the scope of
substrates, which ring-expand under these conditions (Scheme
3).
Our initial aim was to exchange the heteroatom from oxygen
to sulfur, and to our delight we isolated the tetralone 11 in 49%
yield. In order to investigate our ring-expansion chemistry on
indoles, protection of the indolic nitrogen was required. Use of
N-methylindole-2-cyclobutanol only led to a complex mixture
of unidentifiable products. Our assumption was that the indole
was too electron-rich to allow the desired reaction to take
place. N-boc indole was then selected as a candidate for these
experiments due to the electron-withdrawing nature of the boc
group. However, the preparation of the cyclobutanol under the
metalation conditions failed to give the desired alcohol, but
formation of the cyclobutene 33 was observed as the major
product in 35% yield (Scheme 4). At this stage we are
uncertain if the ring expansion methodology is sufficiently
robust to tolerate the boc-protecting group.
In addition to these results, we evaluated the use of the tosyl
group in these studies. The desired N-tosyl indole was
prepared and exposed to n-butyllithium followed by cyclo-
butanone. This gave the desired cyclobutanol 12 in 44% yield.
The electron-withdrawing nature and stability of the tosyl
group finally led to successful conversion of the cyclobutanol
to the desired 4-tetralone 13 in 52% yield. This transformation
was notable for its rate acceleration compared to the
benzofuran and thiophene examples with complete conversion
of the starting material observed within 10 min. In this case
reaction of the cyclobutanol 12 with NBS in acetonitrile
proceeded more quickly than the other cases (1 and 10). This
is because the enamine moiety in the indole is highly
nucleophilic compared with the sulfur and oxygen analogues.
When monosubstituted thiophene or furan examples were
exposed to NBS in acetonitrile, bromination of the 5-position
was found to be favored over ring expansion. In order to
prevent monobromination of the ring, we elected to prepare
the bis-cyclobutanol 14 for a potential double ring expansion.
The bis-cyclobutanol 14 was prepared under bis-metalation
conditions with activation through TMEDA and then
subjected to 1 equiv of NBS in acetonitrile. Under these
conditions, only one of the cyclobutanol rings was observed to
a
Table 1. Optimization of Reaction Conditions
entry
conditions
solvent
yield [%]
1
2
3
4
5
6
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NCS
NIS
iPrOH, propylene oxide
THF
DCM
DMF
Et3N
MeCN
MeCN
MeCN
EtCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
−
−
−
−
−
63
10
40
27
7
b
7
8
c
9
10
11
12
13
14
3
PhSeCl
(BrNCO)3
NBS, K2S2O8
NBS, Mn(OAc)3·2H2O
−
−
48
−
d
e
f
15
a
Conditions: alcohol (1.0 equiv), electrophile (1.15 equiv), solvent
b
c
d
(0.05−0.1 M), 0 °C to rt. −35 °C. 0 °C to reflux. 0.35 equiv of
(BrNCO)3. Addition of 2.1 equiv of K2S2O8. Addition of 1.2 equiv
e
f
of Mn(OAc)3·2H2O.
To test our hypothesis, we decided to subject alcohol 1 to
conditions used by Paquette and Dake (entry 1, Table 1).
Surprisingly, however, no conversion was detected, and no
expansion to the five- or six-membered ring could be observed.
Equally, when THF, DCM, DMF, or triethylamine (entries 2−
5, Table 1) were employed as the solvent, only starting
material could be isolated. To our delight the desired tetralone
9 could be isolated in 63% yield, when acetonitrile was
B
DOI: 10.1021/acs.orglett.8b03619
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Letter
a
Scheme 3. Scope Evaluation of NBS-Mediated Ring Expansion
a
b
Conditions: alcohol (1.0 equiv), NBS (1.15 equiv), MeCN (0.05−0.1 M), 0 °C to rt. This reaction was also performed at a 1.5 mmol scale to
yield the tetralone in 53% yield.
the desired diketone. We rationalized that the thiophene ring
after the first ring expansion is much less electron-rich due to
conjugation with the newly formed ketone in the fused
cyclohexanone. The thiophene ring is hence considerably less
reactive to bromination followed by ring expansion.
Scheme 4. Cyclobutene Formation after Metalation of 32
and Addition to Cyclobutanone
After variation of the heteroaromatic moiety, we decided to
investigate substituted cyclobutanols. 3-Phenylcyclobutanone
was prepared according to conditions developed by Haufe,20
and the corresponding heteroaromatic-containing cyclobuta-
nols were prepared through standard lithiation and addition
conditions and subsequently subjected to ring expansion
conditions. To our delight it was found that all examples (16,
18, and 20) expanded to the expected tetralones (17, 19, and
21) in notably fast rates. The structure of tetralone 17 was
confirmed by X-ray crystallography (Figure 2).
expand as expected to yield 15 in 48% yield. We then reacted
the bis-cyclobutanol 14 with 2 equiv of NBS in acetonitrile. To
our initial surprise, again only one of the cyclobutanol groups
underwent ring expansion. Addition of 4 equiv of NBS to the
diol 14 at room temperature and above (reflux) failed to
expand the second cyclobutanol ring. Isolation of the mono
ring-expanded cyclobutanol 15, followed by addition of an
additional 2 equiv of NBS in acetonitrile, also did not provide
C
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for the aromatic part to be heteroaromatic, potentially due to
the stabilizing nature for the tertiary radical. Formation of this
radical induces expansion (c) to the five-membered ring
forming a spirocyclic intermediate 35, also possessing a tertiary
radical. This is easily oxidized to the ketone by single electron
transfer (d) to the succinimide and ring-expands further
eliminating acetonitrile, as well as a bromide ion (e) generating
intermediate 37. Aromaticity is restored by abstraction of a
proton by bromide (f) yielding the observed tetralone 9. The
progression through a five-membered intermediate could
explain the regioselectivity observed in examples with
disubstituted cyclobutanol rings, in which the carbon
containing the substituent would migrate over the unsub-
stituted carbon due to the higher migratory aptitude.
Figure 2. X-ray crystal structure of tetralone 17.
We then proceeded to investigate fused cyclobutanone
systems and prepared bicyclo[3.2.0]heptanone21 and the
corresponding alcohols. To our delight, the benzofuran and
benzothiophene examples 22 and 24 expanded within 15 min
and with good yields. The rapid conversion to the tetracycle
can be attributed to the release of ring strain of the fused
system when expansion occurs. Notably, only the β,γ-
substituted tetracycles 23 and 25 were formed, without the
α,β-substituted products.
To test our hypothesis that the rate increase of the
disubstituted examples 22 and 24 was driven by release of
ring strain, we decided to prepare the corresponding
heteroaromatic-containing alcohols of trans-3-(benzyloxy)-
methyl-2-phenylcyclobutanone.22 When the disubstituted
cyclobutanol precursors 26, 28, and 30 were used, the same
selectivity for the β,γ-substitution pattern was observed to yield
tetralones 27, 29, and 31 respectively, however with a
concomitant drop in yield.
During review, an alternative mechanism was suggested
based on previous proposals in the metal-mediated formation
of tetralones (Scheme 6).23−25 This pathway involves the
Scheme 6. Mechanism for the NBS-Mediated Ring
Expansion Involving a Hypobromite Species
In order to probe the mechanism of these transformations
we investigated the addition of the free radical TEMPO to
benzofuranyl cyclobutanol 1 reaction with NBS. No reaction
was observed under these conditions. In addition, a
heteroatom in the aromatic ring system adjacent to the
cyclobutanol is an essential requirement for successful ring
expansion, since nuclear bromination of the aromatic ring
instead of ring expansion was observed in corresponding
cyclobutanol derivatives of anisole.
formation of a hypobromite 38, followed by homolysis to an
oxygen-centered radical 39 and carbon−carbon bond cleavage
to a high-energy primary radical 40. This mechanistic proposal
would eventually form the same intermediate 37 after single
electron transfer. Further investigations on the true nature of
the mechanism and the intermediates involved are currently
underway.
Based on initial mechanistic studies we propose the
mechanism shown in Scheme 5. As demonstrated from the
In summary we have developed the first ring expansion of
cyclobutanols to 4-tetralones on heteroaromatic systems. NBS-
acetonitrile has been found to be the reagent combination of
choice with mild reaction conditions and commercial
availability of the reagents. Due to the facile preparation of
the cyclobutanol precursors through metalation and addition
conditions, this methodology provides a mild and rapid entry
to 4-tetralones omitting the use of transition metals and harsh
Lewis acid required for Friedel−Craft protocols. The
regioselectivity was confirmed through X-ray crystallography,
and preliminary mechanistic studies suggest the involvement of
acetonitrile in the reaction and a spirocyclic intermediate.
Applications of this novel methodology to natural product
synthesis are currently ongoing in our laboratories
Scheme 5. Suggested Mechanism for the NBS-Mediated
Ring Expansion
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03619.
solvent screen, this reaction is specific to solvents containing a
nitrile group. Furthermore, the reaction is believed to have a
radical character, which was supported by the cessation of the
reaction, following addition of TEMPO to the mixture. It is
suggested that the bromine radical adds to acetonitrile forming
an iminyl radical (a) which adds to the 3-position generating a
stabilized tertiary radical 34 (b). It was found to be essential
Experimental procedures and spectra (PDF)
Accession Codes
CCDC 1878598 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
D
DOI: 10.1021/acs.orglett.8b03619
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(22) Brown, R. C. D.; Bataille, C. J. R.; Bruton, G.; Hinks, J. D.;
Swain, N. A. J. Org. Chem. 2001, 66, 6719−6728.
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(24) Wu, X.; Wu, S.; Zhu, C. Tetrahedron Lett. 2018, 59, 1328−
1336.
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(25) Yu, J.; Wang, D.; Xu, Y.; Wu, Z.; Zhu, C. Adv. Synth. Catal.
2018, 360, 744−750.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: p.parsons@imperial.ac.uk.
ORCID
Philip J. Parsons: 0000-0002-9158-4034
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge an Imperial College
President’s scholarship (to P.N.). Drs. Alfred and Isabel
Bader are gratefully acknowledged for their very generous
support of this work. We thank Peter Haycock and Dr. Lisa
Haigh (Imperial College London) for NMR and mass
spectrometric analysis, respectively. We also thank Dr. Jon
Wilden (University College London) for his interest in this
work. We sincerely thank Dr. Jeremy Cockcroft (University
College London) for the X-ray analysis of compound 17.
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DOI: 10.1021/acs.orglett.8b03619
Org. Lett. XXXX, XXX, XXX−XXX