Photoredox-Catalyzed Cyclobutane Synthesis by a Deboronative Radical Addition–Polar Cyclization Cascade

Article abstract of DOI:10.1002/anie.201813917

Photoredox-catalyzed methylcyclobutanations of alkylboronic esters are described. The reactions proceed through single-electron transfer induced deboronative radical addition to an electron-deficient alkene followed by single-electron reduction and polar

Full text of DOI:10.1002/anie.201813917

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Accepted Article
Title: Photoredox-Catalyzed Cyclobutane Synthesis via a Deboronative
Radical Addition–Polar Cyclization Cascade
Authors: Chao Shu, Adam Noble, and Varinder Kumar Aggarwal
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201813917
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10.1002/anie.201813917
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COMMUNICATION
Photoredox-Catalyzed Cyclobutane Synthesis via a Deboronative
Radical Addition–Polar Cyclization Cascade
Chao Shu, Adam Noble, and Varinder K. Aggarwal*
Abstract:
Photoredox-catalyzed
methylcyclobutanations
of
the reactions under rigorously anhydrous conditions. This was
attributed to the much slower rates of 4- and 6-exo-tet
cyclizations,[10] which resulted in competing protonation of the
intermediate carbanion. To prevent the formation of these
undesired Giese products, we sought an alternative radical
alkylboronic esters are described. The reactions proceed via single-
electron transfer induced deboronative radical addition to an electron-
deficient alkene followed by single-electron reduction and polar 4-exo-
tet cyclization with a pendant alkyl halide. Key to the success of the
methodology was the use of easily oxidizable arylboronate complexes. precursor that would enable radical generation under fully aprotic
Structurally diverse cyclobutanes are shown to be conveniently
prepared from readily available alkylboronic esters and a range of
haloalkyl alkenes. The mild reactions display excellent functional
group tolerance, and the radical addition–polar cyclization cascade
also enables the synthesis of 3-, 5-, 6-, and 7-membered rings.
conditions and considered boronic ester derivatives.[11]
Cyclobutanes are highly valuable structural motifs in the
chemical sciences. They have found prominence as synthetic
intermediates due to their high ring strain and are present in
numerous bioactive small molecules (Figure 1a).[1,2] In particular,
the spatially defined arrangement of substituents imparted by
their structural rigidity makes them attractive targets for drug
discovery.[3] Synthetic efforts towards these important small rings
have largely focused on [2+2] cycloadditions or ring expansion of
cyclopropane derivatives.[4] Alternative approaches involve 1,4-
cyclization reactions of functionalized alkyl (pseudo)halides,[4a]
such as via enolate alkylation or reductive coupling of a tethered
alkene.[5] We considered
a related approach utilizing a
photoredox-catalyzed radical addition–polar cyclization cascade
between a carboxylic acid and a haloalkyl alkene (Figure 1b, n =
2),[6] a process that represents an open-shell variant of Michael-
induced ring closure (MIRC) reactions.[7] This would allow a
fragment coupling-based cyclobutanation, in which a cyclobutane
ring could be incorporated into a complex molecule in a single
step, under mild conditions, by substitution of a carboxylic acid, or
another suitable radical precursor.[8]
We
recently
reported
a
photoredox-catalyzed
cyclopropanation and methylcyclopropanation of aliphatic
carboxylic acids 1 (Figure 1b, n = 1).[6a] The reaction proceeds via
a decarboxylative radical addition to a chloride-tethered alkene 2
followed by single-electron reduction and 3-exo-tet cyclization of
the resulting carbanion 3. While this protocol enabled the
formation of cyclopropanes and cyclopentanes, a limitation was
discovered during our attempts to generate 4- and 6-membered
rings. In these cases, the Giese-type protonated products 4 were
obtained instead of the cyclized products,[9] despite conducting
[*]
Dr. C. Shu, Dr. A. Noble, Prof. Dr. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: v.aggarwal@bristol.ac.uk
Figure 1. a) Bioactive cyclobutanes; b) Photoredox-catalyzed decarboxylative
radical addition–polar cyclization cascades; and c) Boronate complexes as alkyl
radical precursors. Reduction potentials are vs. SCE in MeCN. EWG = electron-
withdrawing group; PC = photocatalyst; SET = single-electron transfer; PMP =
4-methoxyphenyl.
Supporting information for this article is given via a link at the end of
the document.
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We were particularly attracted to arylboronate complexes
generated from aryllithium reagents and pinacol boronic esters.[12]
These species offer a number of attractive features that would
benefit the proposed cyclobutanation, such as (i) they can be
generated and used in situ under strictly anhydrous conditions,
which should inhibit formation of the Giese products; (ii) the
electron-rich arylboronate complexes were expected to undergo
facile single-electron oxidation, and this was confirmed by
measurement of the reduction potential for arylboronate complex
5 of 0.31 V vs. SCE in MeCN (Figure 1C).[13] This value is
significantly lower than other commonly used boron-based alkyl
radical precursors, e.g., trifluoroborate salts,[14] cyclic triol
boronates,[14a] or nitrogen and phosphorus Lewis base
complexes,[15] which can also often suffer from either low solubility,
limited availability or limited substrate scope; (iii) pinacol boronic
esters are readily available. Herein, we describe a transition
metal-free photoredox-catalyzed generation of alkyl radicals from
arylboronate complexes. These species participate in radical
addition–polar cyclization cascades with halide-tethered alkenes
enabling the synthesis of a broad range of functionalized
cyclobutanes.
We began our investigation by studying the reaction of
cyclohexyl boronic acid pinacol ester (6) with iodide-tethered
enoate 7a (X = I, Table 1). Arylboronate complex 5 was generated
in situ by reaction of 6 with a slight excess of phenyllithium at 0 °C.
To the THF solution of 5 was then added enoate 7a and 2.0 mol%
of the organic photocatalyst 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-
dicyano-benzene (4CzIPN),[16] and the mixture was irradiated with
blue LEDs at RT for 20 h. Pleasingly, cyclobutane 8 was formed
in 45% yield with none of the undesired Giese product 9 (entry 1).
A significant improvement in yield was observed upon performing
a solvent switch from THF to MeCN after formation of boronate
complex 5, providing 8 in 70% yield (entry 2). Changing to alkyl
bromide 7b (X = Br) resulted in a slightly lower yield of 8, whereas
the corresponding chloride 7c (X = Cl) and tosylate 7d (X = OTs)
only gave Giese products 9c and 9d (entries 3–5). Evaluation of
a range of iridium, ruthenium, and organic photocatalysts did not
provide any improvements over 4CzIPN (see Supporting
Information). The catalyst loading was found to have a modest
effect on the yield, with 5 mol% proving optimal (entries 6–7). The
importance of anhydrous conditions was highlighted by the
complete reversal of selectivity from cyclobutane to Giese product
formation upon addition of water to the reaction (entry 8). Finally,
it was found that using DMSO as the solvent provided 8 in
similarly high yield to MeCN (entry 9). Control experiments
highlighted the importance of phenyllithium activation (entry 10),
and no product was observed in the absence of photocatalyst or
light (entries 11–12). Interestingly, replacement of arylboronate
complex 5 with the corresponding trifluoroborate (entry 13) or a
combination of 6 and DMAP (entry 14) failed to give either
cyclobutane 8 or the Giese product 9. Furthermore, submitting
enoate 7a to the optimized Giese reaction conditions reported by
Akita (with BF3K salt) and Ley (with Bpin and DMAP) resulted in
no cyclobutane formation.[13] These results highlight the benefits
on reactivity of using easily oxidized arylboronate complexes such
as 5.
Table 1. Optimization studies.[a]
Entry
1
4CzIPN mol%
Solvent
THF
X
% 8
45
70
62
0
% 9
0
2
2
2
2
2
1
5
5
5
5
0
5
5
5
I
2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
I
0
3
Br
0
4
Cl
50
55
0
5
OTs
0
6
I
I
I
I
I
I
I
I
I
65
75
0
7
8[b]
0
53
0
9
76
0
10[c]
11
12[d]
13[e]
14[f]
0
0
0
0
0
0
0
0
0
[a] All reactions were carried out using 6 (1.1 equiv) and PhLi (1.2 equiv),
followed by addition of 7 (0.20 mmol, 1.0 equiv) and photocatalyst (1–5
mol%) in solvent (0.05 M). Yields were determined after aqueous workup by
1H NMR analysis using an internal standard. [b] Reaction performed with the
addition of 5.0 equiv H2O. [c] Reaction performed without phenyllithium
activation. [d] Reaction performed in the dark. [e] Reaction performed using
potassium cyclohexyltrifluoroborate in place of arylboronate 5. [e] Reaction
performed using DMAP (2.0 equiv) in place of phenyllithium.
primary boronic esters could also be utilized (12–16).
Furthermore, the functional group tolerance of the protocol was
highlighted by the successful synthesis of cyclobutanes bearing
methyl ester, nitrile, acetal, and carbazole groups. Application of
unactivated cyclic secondary boronic esters led to the
corresponding cyclobutanes in high yields (8 and 17–20),
including oxygen- and nitrogen-based heterocycles (19 and 20).
Boronic esters bearing carbamoyl-protected α-amino groups
provided access to cyclobutane-substituted piperidine 21 and
pyrrolidine 22, and
a
bicyclo[2.2.1]heptane (norbornane)
substrate gave the corresponding product 23 in excellent
diastereoselectivity. Acyclic secondary boronic esters were also
shown to be viable substrates (24–27). Furthermore, tertiary
boronic esters, including acyclic and cyclic, also underwent
cyclobutanation to give 28 and 29 in good yields.
To further demonstrate the utility of this deboronative
chemistry for the introduction of cyclobutanes into complex
molecules, we applied the optimized conditions to boronic esters
derived from natural products and drugs. For example, boronic
ester derivatives of the terpenes menthol and α-pinene provided
high yields of the corresponding cyclobutanes 30 and 31,
We next proceeded to explore the scope of the
cyclobutanation reaction with respect to the alkylboronic ester
substrate (Table 2). Primary benzylic and α-oxy boronic esters
were competent coupling partners, yielding cyclobutanes 10 and
11 in moderate to good yields. The more challenging unactivated
respectively,
with
the
latter
formed
in
excellent
diastereoselectivity. A derivative of the fibrate drug gemfibrozil
was prepared in excellent yield (32). Finally, the steroids
cholesterol and lithocholic acid reacted efficiently to give
cyclobutanes 33 (>20:1 d.r.) and 34 in good yields.
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Table 2. Alkyl boronic ester scope.[a]
[a] Reactions were carried out on a 0.40 mmol scale with respect to the alkene 7a. Yields are of isolated product after chromatographic purification. Diastereomeric
ratios were determined by 1H NMR analysis of the purified product.
We then proceeded to evaluate the scope of the reaction
with respect to the halide-tethered alkene using 4-piperidinyl
boronic ester 35 as a model substrate (Table 3). In addition to
methyl ester 7a, alkenes functionalized with benzyl esters and
thioesters could be utilized, to generate cyclobutanes 37 and 38,
respectively. Other electron-withdrawing groups that led to
successful cyclobutane formation included nitrile (39),
phenylsulfones (40) and pinacol boronic esters (41). Although the
yield is modest, the formation of boronic ester 41 represents an
interesting 2-carbon boron homologation, involving insertion of
both a methylene and a cyclobutane ring. In addition to
cyclobutanation, cyclopropanation was also possible by using
homoallylic halide substrates (n = 1). In this case, the high rate of
cyclopropane formation enabled the use of the homoallylic
pathway in which the arylboronate complexes undergo direct SE2
reaction with the Michael acceptor is unlikely.[12a]
Table 3. Halide-tethered alkene scope.[a]
chloride (X
= Cl) in place of the corresponding iodide.
Cyclopropanes functionalized with carboxylate ester (42), nitrile
(43), boronic ester (44), and aryl groups (45) could be prepared
in moderate to excellent yields. Substitution on the tether in the
haloalkyl alkene was also tolerated, with gem-dimethyl
cyclobutane 46 formed in high yield. Furthermore, extending the
tether enabled the synthesis of cyclopentane (47), cyclohexane
(48) and cycloheptane (49) products.
To probe the mechanism of the reaction, we conducted
several experiments to determine the intermediacy of radical and
anionic intermediates. The formation of alkyl radicals by single-
electron oxidation and deboronation was confirmed by the
isolation of hydroxylamine 50 upon reaction of TEMPO with
boronate complex 36 (Scheme 1a). Additionally, hexenyl
boronate complex 51 underwent radical cyclization prior to
reaction with 7a to give cyclopentane 52 instead of linear product
53 (Scheme 1b). This suggests that an alternative two-electron
[a] Reactions were carried out on a 0.40 mmol scale with respect to the alkene
substrate. Yields are of isolated product after chromatographic purification. [b]
Reactions performed using DMF as the solvent.
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Support for the proposed radical–polar crossover, with
subsequent SN2 4-exo-tet cyclization of the resulting carbanion,
was provided upon performing the reaction between arylboronate
36 and iodide 7a in the presence of H2O as a proton source (see
Table in Scheme 1c). With MeCN as the solvent, addition of 5.0
equiv of H2O resulted in a 60% yield of Giese product 54 and none
of cyclobutane 20 (entries 1 and 2). This confirms that 20 is
(SET) between the excited state photocatalyst (4CzIPN*, E1/2
[PC*/PC•–] = 1.35 V vs. SCE in MeCN)[20b] and arylboronate
complex 5 (Ep/2 = 0.31 V vs. SCE in MeCN) generates alkyl radical
55 and phenylboronic acid pinacol ester (56). Addition of radical
55 to alkene 7a leads to the stabilized radical 57. SET with the
reduced state of the photocatalyst (PC•–, E1/2 [PC/PC•–] = –1.21 V
vs. SCE in MeCN for 4CzIPN) then gives anion 58 prior to polar
generated via a polar (SN2), rather than a radical (SH2), cyclization, 4-exo-tet cyclization to yield the cyclobutane product 8 (path A).
where the presence of H2O results in protonation of the of the
intermediate carbanion outcompeting 4-exo-tet cyclization.
Intriguingly, when the same reaction was performed in DMSO,
only cyclobutane 20 was isolated and Giese product 54 was not
observed (entries 3 and 4). This remarkable switch in selectivity
seemed to suggest a change in cyclization mechanism from SN2
in MeCN to SH2 in DMSO. However, the poor mass recovery (40%
vs. 76%) in the reaction with added H2O promoted further
investigations. Reducing the reaction time to 1 h resulted in a
mixture of 20 and 54 in 34% and 20% yield, respectively (entry 5),
proving that 54 is unstable under the reaction conditions. These
results indicate that an SN2 cyclization occurs in both MeCN and
DMSO. However, the formation of cyclobutane 20 in wet DMSO
appears to be a result of an SH2 cyclization, which was further
supported by the observation that the yield of 20 did not decrease
upon increasing the concentration of H2O.[13]
In the presence of a proton source, 58 is intercepted to give Giese
product 9a. In reactions performed in DMSO, an alternative
pathway involving SH2 cyclization of radical 57 to form
cyclobutane 8 is also operative (path B), with SET between PC•–
and an iodine radical completing the catalytic cycle.
Scheme 2. Proposed mechanism.
In conclusion, we have described the first application of
alkylboronate complexes generated from pinacol boronic esters
and phenyllithium in photoredox-catalyzed deboronative
transformations. The low reduction potential of these complexes
allows facile single-electron oxidation to generate non-stabilized
alkyl radicals, including primary radicals, under mild conditions.
Their synthetic utility has been demonstrated in radical addition–
polar cyclization cascades with halide-tethered alkenes, providing
access to structurally diverse cyclobutanes. A broad substrate
scope was demonstrated and the method was readily extended
to the formation of other ring systems. Given the wide availability
of alkylboronic esters, this new radical deboronation strategy
could find wide application in other photoredox-catalyzed
transformations.
Acknowledgements
We thank EPSRC (EP/I038071/1) and H2020 ERC (670668) for
financial support. We thank Dr. Alastair Lennox for measuring the
reduction potential of 5.
Scheme 1. Mechanistic studies. [a] 36 was prepared in situ from 35 (1.0 equiv)
and PhLi (1.1 equiv). [b] 51 was prepared in situ from hex-1-en-6-yl boronic acid
pinacol ester (1.1 equiv) and PhLi (1.2 equiv). [c] Using 1.1 equiv of 36 prepared
in situ from 35 (1.1 equiv) and PhLi (1.2 equiv).
Keywords: Photoredox catalysis • cyclobutanes • boronic esters
• radical–polar crossover • cascade
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Entry for the Table of Contents
COMMUNICATION
Arylboronate complexes formed from
alkylboronic esters and phenyllithium
were found to undergo facile single-
electron oxidation to form alkyl
radicals. The novel use of these
complexes as radical precursors
C. Shu, A. Noble, V. K. Aggarwal*
Page No. – Page No.
Photoredox-Catalyzed Cyclobutane
Synthesis via a Deboronative Radical
Addition–Polar Cyclization Cascade
enabled the development of
a
photoredox-catalyzed cyclobutane
synthesis proceeding through
a
radical–polar crossover mechanism.
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