Semipinacol-type rearrangements of [3-(arylsulfonyl)bicyclo[1.1.0]butan-1-yl]alkanols

Article abstract of DOI:10.1021/acs.orglett.1c01004

Selective lithiation of arylsulfonylbicyclo[1.1.0]butanes at the bridgehead methine and addition to carbonyl compounds yield tertiary bicyclobutyl alcohols that form spiro[3.4]octanes and related heteroatom-containing spirocycles via an acid- or halogen-mediated semipinacol rearrangement. Further synthetic transformations at the carbonyl or arylsulfone positions, in general in high yield and good chemoselectivity, allow access to acetals, difluorides, amides, and methylenecyclobutene building blocks.

Full text of DOI:10.1021/acs.orglett.1c01004

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Letter
Semipinacol-Type Rearrangements of [3-
(Arylsulfonyl)bicyclo[1.1.0]butan-1-yl]alkanols
Michael J. Kerner and Peter Wipf*
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ABSTRACT: Selective lithiation of arylsulfonylbicyclo[1.1.0]-
butanes at the bridgehead methine and addition to carbonyl
compounds yield tertiary bicyclobutyl alcohols that form
spiro[3.4]octanes and related heteroatom-containing spirocycles
via an acid- or halogen-mediated semipinacol rearrangement.
Further synthetic transformations at the carbonyl or arylsulfone
positions, in general in high yield and good chemoselectivity, allow access to acetals, difluorides, amides, and methylenecyclobutene
building blocks.
hile bicyclo[1.1.0]butanes contain a relatively simple
fused cyclopropane scaffold, these compact carbocycles
the deprotonation of the vicinal methine C−H bond and allow
additions and substitutions with a broad range of electro-
philes.13,14 We sought to combine the ease of addition of these
metalated species to ketones 17 with a semipinacol-type ring
enlargement of tertiary alcohols 18, with the goal of generating
a new route to spirocyclic ketones 19 (Figure 1). Arylsulfonyl-
substituted cyclobutanes 19 could be further converted to
scaffolds 20, commonly encountered in natural products such
as trefolane A,15 astellatol,16 aplydactone,17 α-panasinsene,18
and maoecrystal M,19 yet still rarely used in pharmaceuticals
(e.g., UCB-118419720), and commercially available building
blocks.
W
have a unique reactivity profile that distinguishes them from
cyclopropanes by virtue of more than double the ring strain
(66.3 kcal/mol vs 27.0 kcal/mol for a single cyclopropane) as
well as a central C(1)−C(2) bond that has significantly more
π- than σ-bond character.1 The results of NMR studies are in
agreement with a calculated sp18 hybridization at C(1) and
C(2), i.e., a significant preponderance of a p orbital-like
electron distribution between the two carbon atoms.2
Substituent effects at these bridgehead carbons are therefore
more pronounced on bicyclo[1.1.0]butanes than on cyclo-
propanes, and arene rings or heteroatoms such as sulfur
strongly modulate stereoelectronic properties at all core carbon
atoms.3 For example, introduction of a phenylsulfone at C(1)
and a hydroxymethylene group at C(2) of bicyclo[1.1.0]-
butane opens the interflap angle by ∼3°, lengthens the C(1)−
C(2) bond distance by 0.02 Å, reduces its bond order by 35%,
and introduces a significant Mulliken atomic charge differential
across this core bond. The methine C(2) hydrogen also is
more readily deprotonated to generate the synthetically useful
3-(phenylsulfonyl)bicyclo[1.1.0]butyl carbanion.
Previously, our group studied the preparation of
(bicyclo[1.1.0]butan-1-yl)alkylamines 1 and their thermal
and transition metal-catalyzed conversions to five-, six-, and
seven-membered heterocycles such as 2 and 3.1,4,5 Other
noteworthy discoveries in the field include enantioselective
routes to bicyclo[1.1.0]butanes 5, diastereoselective additions
to substituted cyclobutanes 7 and 10, and insertions to access
2,2-dihalobicyclo[1.1.1]pentanes 12 (Scheme 1).6 Very
recently, and independent of our concomitant studies, Gregson
et al. disclosed strain-release semipinacol rearrangements of
isoelectronic azabicyclo[1.1.0]butyl carbinols 14 toward
azetidines 157
1-(Phenylsulfonyl)bicyclo[1.1.0]butane (16) was prepared
as previously reported from sodium benzenesulfinate in 41%
overall yield.13 For the preparation of 23b and 23c, sulfonyl
chlorides 21b and 21c were alkylated with 4-bromobutene and
epoxidized with in situ-generated dimethyldioxirane to give γ,δ-
epoxysulfones 22b and 22c (Scheme 2). Intramolecular
epoxide opening, followed by mesylation of the primary
alcohol and treatment with n-BuLi, closed the second three-
membered ring and provided bicyclo[1.1.0]butanes 23b and
23c in moderate overall yields.21 Treatment with n-
butyllithium in THF at −78 °C followed by addition of
cyclobutanone 24 provided tertiary alcohols 25a−c in 65−88%
yield.14a
1
On the basis of H NMR studies that suggested that the
m o r e e l e c t r o n - r i c h p - m e t h o x y - s u b s t i t u t e d
sulfonylbicyclo[1.1.0]butane 25b rearranged more quickly
Received: March 23, 2021
Published: April 19, 2021
The sulfone substituent on the bicyclo[1.1.0]butane bridge-
head C(1)−C(2) bond in 16 was previously found to facilitate
https://doi.org/10.1021/acs.orglett.1c01004
© 2021 American Chemical Society
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Scheme 1. Cycloadditions of Bicyclo[1.1.0]butanes to
Heterocycles 2 and 3,5 Enantioselective Preparations of 5,8
and Syntheses of Cyclobutylphosphine Boranes 7,9 Pinacol
Boronates 10,10 Difluorinated Bicyclo[1.1.1]pentanes
12,11,12 and Azetidines 157
Scheme 2. Preparations of Bicyclo[1.1.0]butanes 23b and
23c from Sulfonyl Chlorides 21b and 21c, Followed by
Conversion to Cyclobutyl Alcohols 25a−c and Spirocycle
26b
Table 1. Optimization of Semipinacol Rearrangement of
a
25b to Spirocycle 26b
entry
acid (mol %)
solvent
time (h)
conversion (%)
1
2
3
4
5
6
7
8
AcOH (10)
TFA (10)
CSA (10)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
THF
12
12
12
12
1
0
11
83
100
100
91
99
9
MsOH (10)
MsOH (5)
MsOH (2.5)
MsOH (1)
MsOH (1)
MsOH (1)
MsOH (1)
MsOH (1)
BF3·OEt2 (10)
1
12
12
12
12
12
1
9
5
24
4
10
11
12
MeCN
toluene
CH2Cl2
85
a
All reactions were performed at room temperature at a concentration
of 0.05 M on a 0.1 mmol scale; the conversion was determined by LC-
MS using an internal standard (4-bromophenylacetic acid), and the
conversion was based on both starting material and product peak
integration.
atures (entries 1 and 2). In contrast, sulfonic acids such as
camphorsulfonic acid (CSA) and methanesulfonic acid
(MsOH) led to a stereoselective formation of 26b in >90%
conversion in CH2Cl2 even at 1 mol % loading after a 12 h
reaction time (entries 2−7). We noticed a significant solvent
dependence in this rearrangement, because methanol, THF,
acetonitrile, and toluene suppressed the conversion (entries 8−
11). Lewis acids such as BF3 etherate could be used in place of
MsOH but also led to the formation of side products that were
tentatively assigned as dehydrated derivatives of 25b. The
combination of LiNTf2 and Bu4NPF6 also led to the desired
rearrangement at room temperature but was not further
optimized for cost reasons.
After identifying optimal conditions for the rearrangement of
25b in CH2Cl2 in the presence of 5 mol % MsOH, we explored
the scope of this reaction with diverse tertiary alcohol
substrates (Table 2). Addition of lithiated 23b to the
corresponding ketones occurred preferentially anti to the
substituents at position 2 or 3 of the cyclobutanone and
generated alcohols 25f−n in 60−92% yield as single
diastereomers (see the Supporting Information).
Figure 1. Semipinacol-type rearrangement of sulfonylbicyclo[1.1.0]-
butane alcohols 18 to spiroalkanes 19, and representative natural
products and pharmaceuticals with spiro[3.4]octane substructures.
under acidic conditions than analogues 25a and 25c, we
selected 25b for a survey of acidic conditions for the
semipinacol rearrangement to spiro[3.4]octan-5-one 26b
(Table 1). Carboxylic acids such as AcOH and TFA were
ineffective at catalyzing this conversion at ambient temper-
1
In agreement with our preliminary H NMR studies, there
was a notable reaction time difference between the electron-
deficient p-trifluoromethylphenyl sulfone 25c (Table 2, entry
3) and the electron-rich p-methoxyphenyl sulfone 25b (entry
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Table 2. continued
Table 2. Semipinacol Rearrangement of Tertiary Alcohols
25 to Spirocycles 26 [R = (p-MeO)PhSO2] in the Presence
of a Catalytic Acid
a
All reactions were performed in CH2Cl2 at room temperature in the
presence of 1 mol % MsOH on a 0.5 mmol scale unless indicated
b
otherwise; yields are based on the isolated compound. On a 5.0
mmol scale. On a 2.0 mmol scale. Two portions of 5 mol % MsOH
were added. On a 0.33 mmol scale. NR, no reaction.
c
d
e
2), with 25c requiring 3 h to produce 92% product 26c
compared to 70−80 min for 26b. There was a less significant
rate difference between phenylsulfone 25a (entry 1) and 25b.
The introduction of a heteroatom in cyclic carbinol 25
decreased the reactivity of the substrate. Oxetanol 25d
generated 74% of furanone 26d after reaction for 12.5 h
(entry 4). In contrast, Boc-protected azetidine 25e was inert
under the standard conditions with MsOH (entry 5).
Alternatively, aryl-substituted cyclobutanes 25f and 25g
rearranged smoothly to spirocycles 26f and 26g in 76% and
86% yield, respectively (entries 6 and 7, respectively). Alkyl
substituents at various positions on the cyclobutane also led to
semipinacol products 26h and 26j−26l in 84−95% yield
(entries 8 and 10−12, respectively). Amide and nitrile
substituents in 25i and 25n, however, showed significantly
slower conversions and lower yields to spirocycles 26i and 26n
(entries 9 and 14, respectively). In addition to the electron-
withdrawing effect of these substituents, we speculate that
these groups also provide additional sites for protonation, thus
preventing the acid from efficiently catalyzing the semipinacol
rearrangement. In support of this hypothesis, benzyl ether 25m
was spontaneously eliminated to give enone 26m in 84% yield
after 24 h (entry 13).
The configuration of spirocycle 26b and rearrangement
products 26c−n was assigned on the basis of an X-ray analysis
of phenylsulfone 26a (Figure 2). The carbonyl group of the
Figure 2. X-ray analysis of semipinacol rearrangement product 26a
(CCDC 2071902).
cyclopentanone and the sulfone moiety were found to be in a
syn position across the cyclobutane ring, suggesting that the
1,2-shift in the ring expansion occurs suprafacially across the
bicyclo[1.1.0]butane, placing the tertiary alcohol into an endo
position and into the vicinity of the sulfone (Figure 3). The
rearrangement-initiating proton transfer from the catalytic acid
would thus occur from the large solvent-exposed exo
hemisphere of the bicyclobutane, in agreement with related
intermolecular, kinetically controlled additions.9,10
While (bicyclo[1.1.0]butan-1-yl)cyclopentan-1-ol 27a and
larger cycloalkanols such as 27b and 27c failed to undergo the
semipinacol rearrangement in the presence of MsOH, these
substrates were converted in 80−84% yield to cyclohexanone
28a, cycloheptanone 28b, and cyclononanone 28c with 1.1−
2.3 equiv of NBS (Scheme 3). While side products were not
isolated in all cases, LC-MS and 1H NMR analyses of some of
these reactions suggested the formation of dehydrated (alkene)
byproducts with >4-membered cycloalkanols and MsOH or
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Scheme 4. Selective Fluorination, Beckman Rearrangement,
Acetalization, Reduction, and Methenylations of Spirocycles
26d, 26f, and 26h
Figure 3. Mechanistic overview for supra- and antarafacial semi-
pinacol rearrangements of bicyclo[1.1.0]butane 25a. The exclusive
formation of syn product 26a eliminates the antarafacial (a1) pathway
in favor of a suprafacial (s1) shift, possibly with a concomitant
intramolecular proton transfer from the alcohol to the sulfone oxygen.
Scheme 3. Semipinacol-Type Rearrangements of
Bicyclo[1.1.0]butanes 27a−c, 26e,and 26m with NBS
In conclusion, we were able to extend the use of
sulfonylbicyclo[1.1.0]butanes to the formation of spiro[3.4]-
octanes and related heteroatom-containing spirocycles via the
acid- and halogen-mediated semipinacol rearrangement of
intermediate (bicyclo[1.1.0]butan-1-yl)alkanols. The resulting
products could be synthetically manipulated at the carbonyl or
arylsulfone positions, in general with high yield and in good
chemoselectivity.
Beyond showcasing a novel synthetic strategy, this approach
should readily lend itself to the preparation of new spiro[3.4]-
octanes for future use as synthetic building blocks, as well as
investigations of their biological properties.
other acids, such as Amberlyst 15. Presumably, the tertiary
alcohol may be protonated by MsOH, leading to an essentially
irreversible elimination instead of undergoing the desired
semipinacol ring expansion. Gratifyingly, the NBS conditions
also allowed the preparation of rearrangement products 28e
and 28m from Boc-azetidine 25e and benzyl ether 25m, which
is remarkable because these substrates had previously remained
inert or, in the case of 25m, had led to elimination product
26m under acidic conditions.
The spirocyclic ketone products could be further converted
in high yields to difluoroalkanes and lactams (Scheme 4).
Treatment of 26d with Deoxo-fluor22 provided difluoride 29 in
69% yield. Lactam 30 was obtained in 86% overall yield from
26f after Beckman rearrangement of the intermediate oxime.
Most significantly, after acetalization of ketone 26h, removal of
the sulfone in 31 was feasible by lithium in naphthalene
reduction23 to give cyclobutene 32. Alternatively, methylena-
tion24 of sulfone 31 generated methylenecyclobutane 33,
which was converted to ketone 34 in 99% yield by acetal
hydrolysis with catalytic amounts of CAN in a sodium borate
buffer.25
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01004.
1
Experimental details and H and 13C NMR spectra for
new synthetic intermediates and products (PDF)
Accession Codes
CCDC 2071902 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
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.
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(25) Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.-M.; Quesnel, Y.;
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AUTHOR INFORMATION
Corresponding Author
■
Peter Wipf − Department of Chemistry, University of
Pittsburgh, Pittsburgh, Pennsylvania 15260, United States;
orcid.org/0000-0001-7693-5863; Email: pwipf@
pitt.edu
Author
Michael J. Kerner − Department of Chemistry, University of
Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01004
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Boehringer-Ingelheim Pharmaceuticals
(Ridgefield, CT) for discretionary funding supporting this
research and S. J. Geib (University of Pittsburgh) for
determining the X-ray structure of 26a.
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