Photoinduced Fragmentation Borylation of Cyclic Alcohols and Hemiacetals

Article abstract of DOI:10.1021/acs.orglett.0c02513

A visible-light photoinduced fragmentation borylation of O-phthalimido cycloalkanols with bis(catecholato)diboron is described. Structurally diverse keto and formyloxy alkyl boronic esters are shown to be conveniently prepared by radical-mediated ring opening of cyclic alcohols and hemiacetals, respectively. The reactions proceed under mild conditions in the absence of additives or photocatalysts, display excellent functional group tolerance, and are shown to allow cleavage of 4-, 5-, 6-, and 7-membered ring substrates. The mechanism proceeds via sequential homolytic N-O and C-C bond cleavages, the latter of which involves β-scission of an alkoxy radical, generating a carbonyl and an alkyl radical that is trapped by the diboron reagent. Spectroscopic studies suggest direct photoexcitation of either the phthalimide or diboron substrates with blue light can initiate a radical chain mechanism.

Full text of DOI:10.1021/acs.orglett.0c02513

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Letter
Photoinduced Fragmentation Borylation of Cyclic Alcohols and
Hemiacetals
Chao Shu, Rudrakshula Madhavachary, Adam Noble,* and Varinder K. Aggarwal*
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ABSTRACT: A visible-light photoinduced fragmentation borylation of O-phthalimido cycloalkanols with bis(catecholato)diboron
is described. Structurally diverse keto and formyloxy alkyl boronic esters are shown to be conveniently prepared by radical-mediated
ring opening of cyclic alcohols and hemiacetals, respectively. The reactions proceed under mild conditions in the absence of
additives or photocatalysts, display excellent functional group tolerance, and are shown to allow cleavage of 4-, 5-, 6-, and 7-
membered ring substrates. The mechanism proceeds via sequential homolytic N−O and C−C bond cleavages, the latter of which
involves β-scission of an alkoxy radical, generating a carbonyl and an alkyl radical that is trapped by the diboron reagent.
Spectroscopic studies suggest direct photoexcitation of either the phthalimide or diboron substrates with blue light can initiate a
radical chain mechanism.
versatile organoboron compounds,12 the nature of substitution
reactions means they do not provide products of greater
arbon−carbon single bond cleavage reactions provide a
Cpowerful platform for diversification of organic mole-
cules. These methods allow nontraditional and often dramatic
structural changes, which can be beneficial for accessing new
chemical space in the search for compounds with novel
bioactivities.1 This is particularly attractive in carbocyclic and
heterocyclic ring systems, where fragmentation provides
structures vastly different to those of the parent substrates.
However, the inertness of C−C bonds makes this challenging,
especially for heterolytic cleavage pathways, which typically
require multiple activating groups,2 strained ring systems,3 or
directing groups.4 By contrast, homolytic C−C bond cleavage
can allow fragmentation of nonactivated and unstrained
cycloalkanes, for example, via β-scission of high energy
heteroatom-centered radicals (Figure 1a).5 Recent develop-
ments in visible-light photocatalysis have provided valuable
methods to achieve such deconstructive functionalizations of
cyclic alcohols6 and oximes7 under mild conditions.1b,8
functional complexity than that of the substrate. We
recognized the potential to expand on these radical borylations
by taking advantage of homolytic C−C bond cleavage via β-
scission of alkoxy radicals derived from readily available
cycloalkanols. In comparison to deoxygenative borylations,11
such a process would benefit from providing boronic ester
products that retain the oxygen functionality (Figure 1b).
In our previously reported radical borylations, we demon-
strated that these reactions proceed under catalyst- and
additive-free conditions by taking advantage of photoinduced
electron-transfer (PET) reactions of electron donor−acceptor
(EDA) complexes formed between the substrate and bis-
(catecholato)diboron [B2(cat)2].9a,10a,13 Therefore, we rea-
Received: July 31, 2020
We and others recently reported a range of radical-mediated
borylation reactions that allow access to alkyl boronic esters by
substitution of native functional groups, including carboxylic
acids,9 amines,10 and alcohols.11 While these are useful
methods for transforming feedstock chemicals into highly
https://dx.doi.org/10.1021/acs.orglett.0c02513
© XXXX American Chemical Society
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A

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We began our investigation by studying the reaction of O-
phthalimido 1-methylcyclopentanol 1a with B2(cat)2 (Table
1). Pleasingly, irradiation of an N,N-dimethylacetamide
a
Table 1. Optimization Studies
entry
deviation from standard conditions
yield (%)
1
2
3
4
5
6
7
8
None
90
92
83
0
1.2 equiv of B2(cat)2
1.0 equiv of B2(cat)2
B2(pin)2 instead of B2(cat)2
B2(NMe2)2 instead of B2(cat)2
B2(OH)2 instead of B2(cat)2
DMF as solvent
MeCN as solvent
EtOAc as solvent
THF as solvent
0
50
70
38
45
0
9
10
11
12
No light
Under air
19
0
a
Reactions were performed on a 0.10 mmol scale and irradiated with
a 40 W Kessil lamp. Yields were determined by 1H NMR using diethyl
phthalate as an internal standard.
(DMAc) solution of 1a and 1.5 equiv of B2(cat)2 with blue
LEDs at rt for 20 h yielded the desired δ-keto boronic ester 2
in 90% yield (entry 1). To facilitate isolation of the boronic
ester product, the initially formed catechol boronic ester was
converted to the stable pinacol boronic ester by in situ
transesterification with pinacol. The amount of B2(cat)2 could
be lowered to 1.2 equiv without reduction in efficiency (entries
2 and 3). The important role of the catechol ligand on the
diboron reagent was highlighted through the unsuccessful
reactions with bis(pinacolato)diboron (B2pin2) and
B2(NMe2)4 (entries 4 and 5). Interestingly, a moderate yield
of 2 could also be obtained using tetrahydroxydiboron
[B2(OH)4] (entry 6). Evaluation of various solvents indicated
that higher yields were achieved with more Lewis basic
solvents, such as DMAc and DMF (entries 7−10). The use of
Lewis basic solvents has been reported to promote EDA
complex formation with B2(cat)2,10c facilitate homolytic
substitution of B2(cat)2 by alkyl radicals, and stabilize chain
propagating boryl radical intermediates.19 A control reaction
performed in the dark showed that an inefficient thermal
reaction was also operative (entry 11), which is in agreement
with previously reported decarboxylative and deaminative
borylations with B2(cat)2.9a,10 Finally, the reaction was found
to be sensitive to oxygen, as no product formed if the reaction
was run open to air (entry 12).
Figure 1. Radical-mediated ring-opening functionalizations of cyclo-
alkanes.
soned that O-activated cycloalkanols could form EDA
complexes with B2(cat)2 to initiate fragmentation borylations
under similar conditions. Previous reports by the groups of
Guo and Zuo demonstrated the feasibility of photoinduced
fragmentation borylations of oxime esters,14 including under
catalyst-free conditions; however, they were limited to ring
opening of strained cyclobutanes. To date, reports of
fragmentation borylations of cycloalkanol derivatives have
relied on the use of hazardous peroxide substrates under
copper catalysis.15 To access alkoxy radicals under photo-
induced, catalyst-free conditions, we selected O-phthalimido
cycloalkanols 1 as radical precursors (Figure 1c),16 as these
species are easily prepared and stable and we have previously
shown that the phthalimide moiety forms complexes with
B2(cat)2.9a The use of these reagents as alkoxy radical
precursors under visible-light photocatalysis was pioneered
by the groups of Chen and Meggers in 2016, both of which
involved 1,5-hydrogen atom transfer reactions and trapping of
the resulting alkyl radicals with various alkenes.17 Their
application was subsequently extended to β-scission reac-
tions.18 Interestingly, all of these reports utilized the O-
phthalimido substrates in overall reductive transformations
that required superstoichiometric quantities of Hantzsch ester
as the reductant. To the best of our knowledge, there are no
reports of their use in redox neutral photoinduced alkoxy
radical-mediated reactions, nor are there examples of trapping
the intermediate alkyl radicals with heteroatom-based reagents.
Herein, we report that O-phthalimido cycloalkanols and
hemiacetals undergo photoinduced fragmentation borylations
with B2(cat)2 to provide acyclic keto and formyloxy alkyl
boronic esters, without the need for catalysts or other
additives.
With the optimum conditions in hand, we first examined the
scope of the fragmentation borylation of O-phthalimido
cycloalkanols, which are easily prepared from readily available
cyclic alcohols (Scheme 1).20 A broad range of functionalized
1-alkyl cyclobutanols were efficiently borylated, providing
acyclic δ-keto boronic esters 3−25. The mild conditions
tolerated aryl (13−17), heteroaryl (18−20), and alkyl
carboxylate esters (21−25), as well as various useful synthetic
handles, including alkyl tosylates (11), bromides (12, 23), and
aryl halides (15, 16). Various cyclopentanols were also
B
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a
Scheme 1. Cycloalkanol Fragmentation Borylation Scope
a
Reactions were carried out on a 0.10−0.50 mmol scale. Yields are of isolated products after chromatographic purification. The regioisomeric ratios
b
1
(r.r.) and diastereomer ratios (r.r.) were determined by H NMR analysis of the purified product. Yields in parentheses were obtained on a 3.5
mmol scale.
borylated in high yield (26−31), including those with
additional substituents, which provided mixtures of re-
gioisomers (28, 29). This ring-opening strategy was also
successfully applied to bridged bicycles, which regioselectively
generated the secondary boronic esters 30 and 31 in good
yields. Pleasingly, the 5,5-fused bicyclic product 31 was formed
with complete diastereoselectivity, which highlights the
potential utility of this method in the stereoselective synthesis
of complex molecular architectures. Interestingly, a secondary
cyclopentanol provided the corresponding aldehyde 32, albeit
in low yield. This example is notable given the lower
thermodynamic driving force for fragmentation due to the
formation of a weaker carbonyl bond, and also the known
instability of aliphatic aldehydes in the presence of B2(cat)2.21
The borylation protocol was also suitable for ring opening of
O-phthalimido cyclohexanols (33−36) and cycloheptanols
(37), although lower yields were obtained compared to the
more strained 4- and 5-membered ring substrates. The
successful borylation of these larger ring substrates contrasts
the reactivity previously observed by Wang and co-workers,
who reported them to be inert to their Hantzsch ester-
mediated fragmentation alkynylation and alkenylation con-
ditions.18b Finally, the synthetic utility of this photoinduced
fragmentation borylation reaction was demonstrated by
synthesizing boronic ester 6 in high yield on a preparative
scale (3.5 mmol), and through successful derivatizations of the
boronic ester group, including hydrolysis, fluorination, and
arylation.20
The scope of the fragmentation borylation was then
extended to O-phthalimido cyclic hemiacetals (Scheme
2a).18b Both tetrahydrofuran and tetrahydropyran derivatives
were successfully borylated to provide γ- and δ-formyloxy
boronic esters, respectively, in moderate to good yields (38−
46). Substitution adjacent to the oxygen of the cyclic ether was
tolerated, including alkyl (39), aryl (40, 42), and protected
alcohol groups (43−45). In addition, a glucal derivative was
successfully borylated in good yield to provide the densely
functionalized boronic ester 46, which bears three contiguous
stereocenters and may serve as a versatile building block in
synthetic chemistry. We also investigated a one-pot activation/
fragmentation borylation sequence to enable direct access to
formyloxy boronic esters from cyclic enol ethers (Scheme 2b).
Sequential treatment of 3,4-dihydro-2H-pyran in acetonitrile
with N-hydroxyphthalimide and triphenylphosphine hydro-
bromide, followed by B2(cat)2 and DMAc and subsequent
blue-light irradiation, provided boronic ester 41 in 44% yield,
which is comparable to that obtained from the isolated O-
phthalimido substrate (51%, Scheme 2a).
The success of this fragmentation borylation reaction is
intriguing given the potential alternative mechanistic pathways
C
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a
Scheme 2. Cyclic Hemiacetal Fragmentation Borylation
a
Reactions were carried out on a 0.10−0.50 mmol scale. Yields are of
isolated products after chromatographic purification.
of the postulated phthalimide radical anion intermediate 47
(Figure 2a). For formation of the desired alkoxy radical 48,
homolytic cleavage of the N−O bond of the O-phthalimido
group in 47 must occur. However, in the case of substrates
derived from hemiacetals (X = O), prior work by the group of
Sammis has shown that radical anions 47 undergo preferential
intramolecular elimination to form carbonyls 49 and
phthalimide radical anion 50.22 This pathway was also
investigated by Chen,17a who concluded that protonation of
radical anion 47, or coordination to tin, was required for
successful alkoxy radical formation. As our fragmentation
borylation reactions proceed under aprotic conditions, we
postulate that a key boron−oxygen interaction prevents
undesired elimination of 47, thus favoring alkoxy radical
formation. Another competing pathway is the direct O-
borylation of alkoxy radicals 48 to form borate esters 51, a
process that has been widely exploited for the generation of
alkyl radicals from catechol boronic esters.23 As this process is
facile, O-borylation becomes competitive if β-scission of 48 is
slow. Indirect evidence for this was provided by the lower
yields obtained when the reactions were performed at higher
concentration,20 and the observation of cycloalkanol side
products formed after hydrolysis of borates 51 during workup.
Based on these observations, and additional competition
experiments, spectroscopic studies, and quantum yield
measurements,20 we propose the mechanism shown in Figure
2b. Surprisingly, UV/vis analysis of DMAc solutions of 1a and
B2(cat)2 did not support the formation of an EDA complex.
However, the absorbance spectra of both species extended to
450 nm; therefore, a radical chain process could be initiated by
photoexcitation of either 1a or DMAc·B2(cat)2 complex 52.9a
This initiation generates the DMAc-stabilized boryl radical 53
and O-borylated phthalimide radical 54, both of which are
chain propagating species. Subsequent homolytic N−O bond
Figure 2. Potential competing pathways and proposed mechanism.
cleavage of 54 and rapid β-scission of alkoxy radical 56 form
the keto-substituted alkyl radical 57 and the phthalimide-
B(cat) byproduct 55. Borylation of 57 with B2(cat)2 proceeds
via a two-step process involving initial formation of radical
complex 58, with subsequent B−B bond cleavage facilitated by
complexation with DMAc to form 59.19 This provides the
boronic ester product 60 and DMAc-stabilized boryl radical
53. Chain propagation to generate 54 could occur via SET and
boron transfer,10c or via boryl radical addition to phthalimide
1a, analogous to tin radical-mediated reactions of N-
alkoxyphthalimides.16
In conclusion, we have developed the first photoinduced
catalyst- and additive-free C−C bond cleavage/borylation of
O-activated cyclic alcohols and hemiacetals. This was achieved
using readily available O-phthalimido cycloalkanols, which
efficiently reacted with B2(cat)2 in a photoinitiated radical
chain mechanism. This borylation reaction benefits from
providing distally difunctionalized products, wherein structural
reorganization of cyclic alcohols enables retention of the
oxygen functionality, therefore providing keto and formyloxy
alkyl boronic esters. Given the mild conditions, and the ready
availability of cyclic alcohols and hemiacetals from feedstock
chemicals, this new radical borylation strategy could find wide
application for the preparation of synthetically and biologically
important boron-containing molecules.
D
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02513.
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Experimental procedures and characterization data for
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Varinder K. Aggarwal − School of Chemistry, University of
Bristol, Bristol BS8 1TS, U.K.; orcid.org/0000-0003-0344-
6430; Email: v.aggarwal@bristol.ac.uk
Adam Noble − School of Chemistry, University of Bristol, Bristol
BS8 1TS, U.K.; orcid.org/0000-0001-9203-7828;
Email: a.noble@bristol.ac.uk
Authors
Chao Shu − School of Chemistry, University of Bristol, Bristol
BS8 1TS, U.K.
Rudrakshula Madhavachary − School of Chemistry, University
of Bristol, Bristol BS8 1TS, U.K.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02513
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC (EP/R004978/1) for financial support.
Dr. R. Madhavachary thanks the EU for an H2020 Marie
Skłodowska-Curie Fellowship (Grant No. 794053).
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