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Azetidines with All-Carbon Quaternary Centers: Merging Relay

Catalysis with Strain Release Functionalization
Che-Ming Hsu, Heng-Bo Lin, Xin-Zhi Hou, Radyn Vanessa Phaz P. Tapales, Chen-Kuei Shih,
Shinje Miñoza, Yu-Syuan Tsai, Zong-Nan Tsai, Cheng-Lin Chan, and Hsuan-Hung Liao*
Cite This: J. Am. Chem. Soc. 2023, 145, 19049−19059 Read Online

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ABSTRACT: Given the importance and beneficial characteristics of

decorated azetidines in medicinal chemistry, efficient strategies for
their synthesis are highly sought after. Herein, we report a facile
synthesis of the elusive all-carbon quaternary-center-bearing
azetidines. By adopting a well-orchestrated polar-radical relay
strategy, ring strain release of bench-stable benzoylated 1-
azabicyclo[1.1.0]butane (ABB) can be harnessed for nickel-
catalyzed Suzuki Csp2−Csp3 cross-coupling with commercially
available boronic acids in broad scope (>50 examples), excellent
functional group tolerance, and gram-scale utility. Preliminary
mechanistic studies provided insights into the underlying mecha-
nism, wherein the ring opening of ABB with a catalytic quantity of
bromide accounts for the conversion of ABB into a redox-active azetidine, which subsequently engages in the cross-coupling reaction
through a radical pathway. The synergistic bromide and nickel catalysis could intriguingly be derived from a single nickel source
(NiBr2). Application of the method to modify natural products, biologically relevant molecules, and pharmaceuticals has been
successfully achieved as well as the synthesis of melanocortin-1 receptor (MC-1R) agonist and vesicular acetylcholine transporter
(VAChT) inhibitor analogues through bioisosteric replacements of piperidine with azetidine moieties, highlighting the potential of
the method in drug optimization studies. Aside from the synthesis of azetidines, we demonstrate the ancillary utility of our nickel
catalytic system toward the restricted Suzuki cross-coupling of tertiary alkyl bromides with aryl boronic acids to construct all-carbon
quaternary centers.

1. INTRODUCTION qualities, the potential of azetidine in medicinal chemistry

Azetidine has recently gained prominence in drug design and
development campaigns.1 This is due to its innate rigidity,
which reduced the entropic penalty of ligand binding, and to
its beneficial effects as a small alicyclic bioisostere in optimizing
the pharmacokinetic properties and metabolic stability of a
drug lead.1c−e Some identified active pharmaceutical ingre-
dients (APIs) possessing the azetidine scaffold are PF-
04418948,2 an orally active prostaglandin EP2 receptor
antagonist, and WO2012020130,3 a glycine transporter 1
(glyt1) inhibitor for central-nervous-system-related disorders
(Scheme 1A), both of which hold a C3 all-carbon quaternary
center. As a bioisostere,4 azetidine can replace pyrrolidine
(among other N-heterocycles) such as in the development of
transition state mimics for the inhibition of N-ribosyl
hydrolases and phosphorylases (Scheme 1A).4c The three-
dimensionality of azetidine building blocks also renders them
among the privileged scaffolds to represent untapped areas of
chemical space, enabling diversification and scaffold hopping
through an escape from the traditional flat (two-dimensional)
molecules that are long-standing norms in small- to high-
throughput screening libraries.4a,5 Despite these attractive
programs is still obstructed by its challenging synthesis,1a,6
especially for units with an all-carbon quaternary center.
Traditional protocols for the synthesis of congested
azetidines include intramolecular cyclization of alkylamines,6
reduction of β-lactams,6,7 [2+2] cycloaddition between imine
and alkenes,6,8 and ring expansion of aziridines.6 To note, these
methods generally have higher step counts and require
preinstallation of appended groups. Other practical approaches
hinge on the modular functionalization of azetidine motifs.
Although many elegant developments have been disclosed,
most reports concentrate on heteroatom substitution,6a,9 while
strategies for carbo-functionalization remain exiguous (Scheme
1B). For example, azetidines with a C3 all-carbon quaternary
center can be accessed from the nucleophilic substitution of
Received: June 26, 2023
Published: August 17, 2023

© 2023 American Chemical Society https://doi.org/10.1021/jacs.3c06710

19049 J. Am. Chem. Soc. 2023, 145, 19049−19059
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Scheme 1. (A) Representative Drug Candidates and Bioisosteric Analogues of a Drug Lead Containing Azetidine with C3 All-
Carbon Quaternary Centers; (B) Modular Synthesis of the Title Motif; and (C) Research Design: Cross-Coupling Type
Arylation/Alkenylation of ABB for the Synthesis of Azetidines Bearing an All-Carbon Quaternary Center
appropriate leaving groups, such as alcohols10 and sulfonate,11
or from the functionalization of tertiary radicals generated from
carboxylic acids12 and redox-active esters13 via photocatalytic
or nickel-catalyzed strategies. Transition metal-mediated
arylations of exomethylenated azetidines are also feasible.14
Collectively, these approaches require functional group
interconversion (FGI) to prepare suitable azetidines tailored
for specific synthetic manipulations and a protecting group to
mask the basic nitrogen atom.
Recently, the judicious use of 1-azabicyclo[1.1.0]butanes
(ABBs) as a divergent and versatile intermediate to azetidines
proved practical in circumventing the aforementioned
concerns.15 The high ring strain of ABB and the presence of
the nucleophilic nitrogen atom and the acidic bridgehead
proton dictate its overall reactivity, making the central C−N σ-
bond ambiphilic. Although 3-addition with turbo-amides,16
thiols,6b,17 nitro,6b,18 and halogens16,19 to ABB via ring strain
release was accomplished, carbo-functionalizations are limited
to organometallic (M = Mg, Zn) alkylations and arylations.20
On the other hand, direct double functionalization of the 3-
position can be achieved through an umpolung approach via
lithiation of the acidic bridgehead proton.21,22 Aggarwal’s
seminal work on ABB chemistry utilized 3-lithiated ABBs
(ABB-Li) as nucleophiles (Scheme 1B) for additions to various
carbonyl groups with retention of the spring-loaded central σ-
bond.21 The preserved ring strain can then be harnessed as a
thermodynamic driving force for the latter synthetic manipu-
lations. As for the second C−C bond formation, Friedel−
Crafts arylation21b and semipinacol rearrangement21c could
afford azetidines possessing an all-carbon quaternary center.
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Alternatively, deboronative functionalization of homologated
azetidinyl boronic esters could also construct the target
azetidine framework.21d The development of new C−C bond
formation strategies employing the inherent ring strain of the
ABBs should be further probed.
In this study, we envisage expanding the current toolbox by
opening a milder, more robust, and straightforward strategy to
prepare azetidines with an all-carbon quaternary center. A
Suzuki cross-coupling-type modification of ABB would be
intriguing, being one of the most important processes in the
production of pharmaceuticals,23 and to our knowledge is not
yet reported. Nonetheless, one challenge to overcome is the
disinclination of tertiary electrophiles, in our case, the ABB,
toward Suzuki cross-coupling, which to date remained
restricted with only a few successful reports.24 Inspired by
the works of Fu24e,25 and Baran,26 and with our continuing
interest in nickel catalysis,27 we report a nickel-catalyzed
Suzuki Csp2−Csp3 cross-coupling of ABBs with aryl and
alkenyl boronic acids. We reckon that ABB can be captured by
a nickel catalyst through ring strain release and forge a new
Csp2−Csp3 bond. The demonstration of the developed
strategy for the derivatization of biologically relevant
compounds and drug entities and for the preparation of
bioisosteric derivatives of drug candidates is also endeavored.
2. RESULTS AND DISCUSSION
Our research was initiated with the telescoping synthesis of our
ABB substrates from the commercially available 2,3-dibromo-
propan-1-amine 1. Cheap n-BuLi proved useful for the in situ
generation of ABB-Li at −50 °C, affording various benzoyl
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ABBs 3 in up to 89% yield in the presence of appropriate mol %), LiBr (10 mol %), K2CO3 (2.0 equiv), and Boc2O (2.0
electrophilic pairs 2 (Scheme 2). Weinreb amides featuring equiv) in 1,4-dioxane/dimethylformamide (DMF) (9:1) under
one-pot conditions (entry 1). Further purification by column
Scheme 2. Telescoping Synthesis of Benzoyl ABB chromatography afforded 5a in a 97% isolated yield. In the
absence of LiBr, a modest decrease in the yield was observed
(entry 2). Screening of various nickel sources, such as Ni(cod)2
and Ni(acac)2 (entries 3 and 4), led to no product formation.
Employing NiCl2, however, gave the desired product 5a, albeit
in only 30% yield (entry 5). Substituting L1 with other
bipyridine ligands L2−L4 (entries 6−8) delivered 5a in 74−
80% yields. On the other hand, phosphine ligands, namely,
PPh3 and dycpe (entries 9 and 10), resulted in trace amounts
of 5a at most. Using Et3N as the base instead of K2CO3 (entry
different cyclic (aromatic/hetero/saturated) and acyclic 11) could also give the target product in a 79% yield. Changing
vectors, as well as one sulfinyl Weinreb amide, were all the mixed solvent to either DMF or 1,4-dioxane alone (entries
suitable (see the Supporting Information, Section 4). 12 and 13) diminished the reaction efficiency. Lastly,
2.1. Reaction Optimization. We then envisaged a ring- decreasing the temperature to 40 °C caused a drop in the
strain-driven functionalization of benzoyl ABB 3a and planned yield to 30% (entry 14).
to demonstrate this in a nickel-catalyzed Suzuki−Miyaura-type Other aryl boronic esters were also tested for compatibility
arylation with aryl boronic acid 4a (Table 1). After a with the developed reaction. Aryl neopentylglycolato boronic
meticulous survey on different reaction parameters, azetidine acid (Bneop) 4a-II was found applicable in lieu of aryl boronic
5a could be provided in 99% NMR yield after stirring for 12 h acid 4a under our reaction conditions, providing a 27% yield of
at 75 °C in the presence of NiBr2·diglyme (10 mol %), L1 (12 5a. Conversely, aryl boronic esters 4a-III and 4a-IV and aryl
boronate 4a-V did not afford the desired product. Therefore,
Table 1. Optimization of Reaction Conditionsa aryl boronic acid 4a is the best cross-coupling partner, where a
quantitative yield of 5a was acquired.
2.2. Substrate Scope. Having established the optimized
conditions, we began investigating the generality of our
method. Various aryl boronic acids (4a−4x) were first assessed
along with benzoyl ABB (3a) as a representative cross-coupling
entry variation from optimized condition yieldb
partner. All afforded the corresponding azetidine products 5a−
5x in good to excellent yields. Particularly, aryl boronic acids
1 none 99 (97)c
with electron-donating groups, such as tert-butyl (4b) and
2 without LiBr 90c
methoxy (4c) at the para-positions, participated in the reaction
3d Ni(cod)2 instead of NiBr2·diglyme 0
giving 96−98% yields, comparable to the electronically neutral
4d Ni(acac)2 instead of NiBr2·diglyme 0
product 5a. Other electron-rich groups, including p-methyl-
5d NiCl2 instead of NiBr2·diglyme 30
sulfide (4d) and p-morpholine (4e), also performed well as
6 L2 instead of L1 78
reaction partners. Aryl boronic acids with methoxy (4f) and
7 L3 instead of L1 80
dimethylamine (4g) at meta-positions also yielded azetidines
8 L4 instead of L1 74
5f and 5g in 72% and 55% yield.
9 PPh3 instead of L1 trace
Additionally, electron-withdrawing groups at the p-position
10 dcype instead of L1 trace
were examined in parallel. Groups such as aldehyde (4h),
11 Et3N instead of K2CO3 79
ketone (4i), ester (4j), and amide (4k) remained intact under
12 DMF instead of 1,4-dioxane/DMF (9:1) 24
our standard conditions, affording the elusive carbonyl-group-
13 1,4-dioxane instead of 1,4-dioxane/DMF (9:1) 34
containing azetidines 5h−5k in 77−93% yields. With the
14 40 °C 30
avoidance of strongly nucleophilic organometallic reagents (M
= Mg, Li) that are requisite in previously reported
protocols,17,20,21 an impressive tolerance to carbonyl groups
was observed. Cyano (4l) and sulfone (4m) moieties were also
incorporated into azetidine products 5l and 5m without any
deleterious effects on the reaction efficiency. 4-Trifluorome-
thylphenyl 4n and 4-fluorophenyl 4o boronic acids were also
tested, both of which provided azetidines 5n and 5o in 83%
yields. Other halogenated aryl boronic acids were also
tolerated; these are the p- and m-chlorinated (4p and 4q)
and p-brominated (4r) ones (67−86% yields). We then
a considered several disubstituted aryl boronic acids with
Reaction conditions: 3a (0.1 mmol, 1.0 equiv), 4a (0.2 mmol, 2.0
different functionalities. Examples are 3,4-dimethoxy (4s),
equiv), nickel catalyst (10 mol %), ligand (12 mol %), LiBr (10 mol
%), base (2.0 equiv), Boc2O (2.0 equiv) in solvent (1.0 mL, 0.1 M). 3,5-dimethoxy (4t), 3-fluoro-4-methyl (4u), and 3-fluoro-4-
b
Determined by 1H NMR using tetrachloroethane as internal phenyl (4v) aryl boronic acids, which pleasingly furnished the
standard. cIsolated yield after purification by silica gel column desired products 5s−5v in 73−88% yields. Pi-conjugated
chromatography. d Performed without LiBr. dcype: 1,2-bis- systems such as biphenyl (4w) and naphthyl (4x) similarly
(dicyclohexylphosphino)ethane. endured our standard conditions, affording azetidines 5w and
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Scheme 3. Substrate Scopea

a
Unless otherwise noted, the reaction conditions were conducted with 3 (0.1 mmol, 1.0 equiv), 4 (0.2 mmol, 2.0 equiv), NiBr2·diglyme (10 mol
%), L1 (12 mol %), LiBr (10 mol %), K2CO3 (2.0 equiv), and Boc2O (2.0 equiv) in 1,4-dioxane/DMF (9:1, 0.1 M), 75 °C, 12 h. All yields are of
purified products. bGram-scale synthesis (4.0 mmol scale).

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5x in satisfactory yields. Extension of the substrate scope to Scheme 4. Synthetic Application to Biorelevant Molecules
heterocyclic frameworks was also investigated. Boronic acids
with heteroaryls, such as 9-phenyl-9H-carbazole (4y) and furan
(4z), gave azetidines 5y and 5z in 84% and 31% yields. Other
Csp2-containing groups in the form of alkenyl boronic acid
derivatives also proved valuable, yielding azetidine scaffolds
with cyclohexene (5aa) and styrene (5ab) in 65% and 75%
yields. In general, functional groups with different stereo-
electronic properties at different positions on the aryl boronic
acids, as well as heteroaryls and alkenyls, were not detrimental
to the reaction.
Our attention was then shifted toward the 3-substituted ABB
component 3. Initially, substituent effects from both electron-
donating and -withdrawing groups attached at the p- and m-
positions of the benzoyl ABB were evaluated (3b−3f).
Inductively donating groups, such as p-methyl (3b) and p-
tert-butyl (3c), and methoxy (3d) as an electron-rich moiety
performed well, providing products 5ac−5ae in 63−86%
yields. Halogen-bearing azetidines, trifluoromethylated 5af and
chlorinated 5ag, were also furnished in 93% and 80% yields.
Additionally, an up-scale synthesis of azetidine 5ag seamlessly
managed to provide 1.2 g (82% yield), showcasing good
scalability. m-Methylated benzoyl ABB 3g was also inves-
tigated, which supplied the target azetidine 5ah in 84% yield.
In a similar manner, conjugated systems such as naphthyl 3h
and quinoline 3i were transformed efficiently to the desired
products 5ai and 5aj in 93% and 61% yields. 2-Furoyl ABB
(3j) and 2-thenoyl ABB (3k) were also viable reactants, giving
azetidines 5ak and 5al in 65% and 94% yields.
Aliphatic entities in the benzoyl ABBs were also examined.
For example, secondary cycloalkyl frameworks including
cyclohexane (3l) and tetrahydropyran (3m), as well as the
primary alkyls n-butyl (3n) and n-butylbenzene (3o), all
translated to their corresponding azetidines 5am−5ap (75−
92% yields). The compatibility of sulfonyl ABB (3p) to our a
Unless otherwise noted, the reaction conditions were conducted
reaction condition was also evaluated to scrutinize the with 3 (0.1 mmol, 1.0 equiv), 4 (0.2 mmol, 2.0 equiv), NiBr2·diglyme
tolerance of our method toward a non-carbon-centered 3- (10 mol %), L1 (12 mol %), LiBr (10 mol %), K2CO3 (2.0 equiv), and
substituted ABB. To our delight, the sulfoxide remained intact Boc2O (2.0 equiv) in 1,4-dioxane/DMF (9:1, 0.1 M), 75 °C, 12 h. All
with 37% yield (5aq). Overall, broad tolerance to various yields are of purified products.
functionalities in the boronic acid and ABB modules was
realized. In contrast, substrates such as 4-bromoaryl 3g, 2- effectively in an 85% yield. Additionally, azetidines bearing the
bromo-4-methoxyaryl 3s, and styryl 3t ABBs failed to cross- anti-inflammatory motifs indomethacin (6h) and naproxen
couple with boronic acid 4a. Some unsuccessful (hetero)aryl (6i) were constructed with ease under our standard conditions
boronic acids also include 4-nitroaryl 4ak, 4-(N,N-diphenyl)- in 87% and 45% yields, respectively.
aryl 4al, 2-methylaryl 4am, 4-pyridinyl 4ao, and 3-quinolinyl 2.3.2. Bioisosteres. In drug development, structural revision
4ap. More of this is in the Supporting Information, Section 4. of drug leads is performed to optimize the drug metabolism
2.3. Synthetic Applications. 2.3.1. Modification of and pharmacokinetic (DMPK) properties. One important
Biorelevant Molecules. Motivated by the broad scope and technique toward this end is bioisosterism, which is the
tolerance to various sensitive functional groups, we examined alteration of a structural element with a distinct moiety with a
the potential of our protocol for the modular installation of similar biofunction.4,28 Azetidine is a known bioisostere to its
azetidinyl scaffolds in natural products, biologically active larger homologues, namely, pyrrolidine and piperidine.1c,4,29 As
compounds, and pharmaceutical agents (Scheme 4). Beginning such, we sought to prepare bioisosteric analogs of some known
with sesamol analogue 4ac, benzoyl ABB 3a was effectively drug candidates to highlight the potential of our methodology
cross-coupled to give azetidine 6a. The choleretic drug in drug optimization studies.
hymecromone was also derivatized (6b) in a satisfactory A vesicular acetylcholine transporter (VAChT) protein
67% yield. Interestingly, incorporation of the azetidine moiety inhibitor30 and a melanocortin-1 (MC-1R) receptor agonist31
into a proteogenic amino acid, particularly tyrosine (4ae), was were selected as model drug candidates. By modification of the
also successful, offering a 76% yield of 6c. Commercially piperidine rings in both models with azetidine, azetidine-
available pharmaceuticals were also diversified accordingly. VAChT inhibitor 8 and azetidine-MC-1R 9a are pursued
Clofibrate (6d), bezafibrate (6e), and fenofibrate (6f) (Scheme 5). We started our synthesis by preparing both
derivatives, which are lipid-lowering agents, were obtained in azetidine precursors 5a and 5ao on a large scale. Gratefully,
excellent yields (75−88%). The steroidal hormone estrone their syntheses were translated in gram scale without any loss
(4ai) was also shown to cross-couple with benzoyl ABB 3a in efficiency, delivering the products in 1.5 g (92%) for 5a and
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Scheme 5. Synthesis of Azetidine Analogues of Drug Candidates

a
Reaction conditions: TFA (16.0 equiv), CH2Cl2 (0.8 M), rt, 2 h. bCyclohexene oxide (1.0 equiv), H2O (3.0 M), rt, overnight. cTyrosine-Boc (1.1
equiv), EDC·HCl (1.5 equiv), HOAt (1.5 equiv), CH2Cl2/DMF (1:1, 0.3 M), Et3N (5.0 equiv), rt, overnight. dHistidine-Boc (1.1 equiv), EDC·
HCl (1.5 equiv), HOAt (1.5 equiv), CH2Cl2/DMF (1:1, 0.3 M), Et3N (5.0 equiv), rt, overnight.

Figure 1. Mechanistic studies. aIsolated yield; bNMR yield determined against tetrachloroethane as internal standard; cNiBr2·diglyme (10 mol %),
L1 (12 mol %), K2CO3 (2.0 equiv), and 1,4-dioxane/DMF (9:1, 0.1 M), 75 °C, 12 h.

1.1 g (73%) for 5ao under our standard conditions (see
Supporting Information, Section 5). The azetidine-VAChT
analogue 7 was then prepared from the simple deprotection of
19054
the Boc group of 3a and subsequent nucleophilic ring opening
of cyclohexene oxide with an overall 47% yield (over three
steps). Similarly, azetidine 5ao was deprotected and,
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consequently, used for the amidation of Boc-protected O-
methyltyrosine. Removal of the Boc group and the formation
of a dipeptide intermediate through the introduction of Boc-
protected histidine obtains the skeleton of the target molecule.
To complete the synthesis of azetidine-MC-1R 9a, another
round of Boc deprotection was performed, resulting in an
overall 10% yield (over six steps). Prior to this, the phenyl
analogue of azetidine-MC-1R 9b was also prepared to test out
the planned synthesis route, which supplied the analogue in an
overall 23% yield (over six steps). Moreover, these
demonstrations underscore the capacity of our protocol in
bioisosteric replacements, offering a facile approach toward
azetidines with an all-carbon quaternary center. This platform
effectively expands the current synthetic toolbox for medicinal
chemists, with potential for not only bioisostere strategies but
also extension to library preparation (especially when seeking
structural novelty) and to scaffold hopping. Noteworthily,
good scalability and operational simplicity are added bonuses.
2.4. Mechanistic Studies. To elucidate the underlying
mechanism of the title reaction, a series of experiments was
performed (Figure 1). First, in the presence of 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO, 2.0 equiv) as a radical
scavenger under our standard conditions, no desirable
formation of product 3a was realized. Azetidine-TEMPO
adduct 10 was instead isolated in a 67% yield. Subjecting the
reaction further to electron paramagnetic resonance (EPR)
studies with the spin-trapping agent phenyl tert-butyl nitrone
(PBN) also led to the detection of intermediate 11. Both
results correlate to a nickel-catalyzed reaction that progressed
via a radical pathway with the tertiary azetidinyl radical as a key
intermediate (Figure 1A). To further probe the genesis of the
putative radical species, we conducted cyclic voltammetry
(CV) analyses of both NiBr2 and 3a. The results of 3a and
Boc-activated ABB 3a′ showed reversible reduction peaks at
−2.45 and −2.39 V versus ferrocene+/0 (Fc+/0) in 1,4-
dioxane/DMF (9:1) (Figure 1B). This indicates that the
reduction potential of both Ni(II) dibromide (E1/2[Ni(II)/Ni(I)]
= −1.62 V vs Fc+/0) and Ni(I) bromide (E1/2[Ni(I)/Ni(0)] =
−2.11 V vs Fc+/0) is thermodynamically incapable of
initiating a radical pathway to relieve the ring strain of 3a via
a single-electron reduction process. This led us to propose that
a polar mechanism commences the ring opening of benzoyl
ABB 3a. We hypothesize that the ring strain of 3a was instead
alleviated through an SN2-type process with a bromide.18,19
The resulting brominated azetidine then serves as a redox-
active species that participates in the following Suzuki-type
cross-coupling after a single electron transfer (SET) event. To
confirm our notion, halide-free nickel complexes, such as
Ni(cod)2 and Ni(OTf)2, were subjected to our standard
conditions (Figure 1C). Essentially, no cross-coupled product
was detected. Yields conversely increased amid halides, even in
low quantities, sourced from either the halide-containing nickel
precatalyst or the additive.32 Having determined the halide as a
crucial reagent, halogenated azetidines were tested as starting
materials to verify their intermediary role in the underlying
reaction pathway. In lieu of benzoyl ABB 3a, 3-brominated
azetidine 12a delivered product 3a in 88% yield, a strikingly
similar yield when compared to our standard conditions. Using
chlorinated 12b and iodinated azetidines 12c, compound 3a
was also produced in 70% and 29% yields. Performing a CV
analysis for each halogenated azetidine 12a−12c further
revealed reduction potentials lower than that of 3a and 3a′
(Figure 1D). In this case, the Ni(I) complex is thermodynami-
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cally capable of initiating a radical reaction via single-electron
reduction of 12, which can be attributed to the activation of
the C−X bond by the adjacent benzoyl moiety.33
Based on these studies, we propose a novel polar-radical
relay mechanism through the mergence of bromide and nickel
catalysts (Scheme 6).34 Reductive elimination of the Ni(II)
Scheme 6. Proposed Reaction Mechanism
precatalyst initially liberates Ni(0) and a diaryl homocoupled
product as identified in our GCMS assay (see Supporting
Information, Section 6.5). The comproportionation of Ni(0)
and Ni(II) species then forms the active Ni(I)-Br complex I,24e,35
which kicks off the catalytic cycle. Transmetalation of aryl
boronic acid 4 with Ni(I)-Br I affords aryl-Ni(I) complex II. In
parallel, catalytic amounts of bromide, either from NiBr2·
diglyme or LiBr, relieve the ring strain of Boc-activated benzoyl
ABB 3′ via a polar pathway, forming in situ the redox-active
species 12a. Reduction of intermediate 12a by aryl-Ni(I)
complex II further leads to azetidinyl radical 12a′, while
concomitantly liberating Ni(II)-bromide complex III. Recombi-
nation of the azetidinyl radical 12a′ to Ni(II) complex III
furnishes Ni(III) intermediate IV. Facile decomposition via
reductive elimination then affords the desired C3 all-carbon
quaternary-center-containing azetidine 5 along with the
regeneration of the active Ni(I) species I, thereby concluding
the catalytic cycle in an elegant fashion.
2.5. Arylation of Non-Azetidine Tertiary Bromides.
With the affinity of tertiary 3-bromoazetidine 12a for Suzuki
cross-coupling with phenyl boronic acids, we tested the
applicability of our Ni-catalytic system for the arylation of
other aliphatic tertiary bromides that are often restricted
(Scheme 7). This campaign gratifyingly furnished the arylation
of several tertiary bromides, such as cyclobutanes 14a and 14aa
without any reoptimization of the reaction conditions. Cyano-
14b and benzoyl- 14c containing cyclobutanes were also
tolerated under our conditions. The arylation of cyclopropane
13d and 1,3-diketone 13e were also provided (14d and 14e),
albeit in lower yields. Intriguingly, cyclopentane 14f was not
furnished, despite being structurally similar to 14aa and 14d.
This might be due in part to the better stability of the
cyclopentyl radical compared to the radicals derived from the
strained bromides cyclobutane 13a and cyclopropane 13d12a
and to the higher reduction potential of cyclopentyl bromide
13f (−2.05 V versus ferrocene+/0 (Fc+/0); see Supporting
Information, Section 6.3) relative to cyclobutyl bromide 13a.
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J. Am. Chem. Soc. 2023, 145, 19049−19059
Journal of the American Chemical Society
Scheme 7. Arylation of Non-Azetidine Tertiary Bromidesa
a
Unless otherwise noted, the reaction conditions were conducted
with 13 (0.1 mmol, 1.0 equiv), 4 (0.2 mmol, 2.0 equiv), NiBr2·
diglyme (10 mol %), L1 (12 mol %), and K2CO3 (2.0 equiv) in 1,4-
dioxane/DMF (9:1, 0.1 M), 75 °C, 12 h. All yields are of purified
products.
Aside from this, ketone 13g remained inert under standard
conditions, suggesting that the additional ketone moiety, as
seen in 1,3-diketone 13e, is essential. The nature of the
substrates amenable to this arylation tactic as well as the
evaluation of its scope will have to be investigated in due
course. This method provides a milder avenue to access all-
carbon quaternary centers in small alicyclic rings using tertiary
bromides that are often regarded as challenging electro-
philes,24e in lieu of existing methods that recourse to tertiary
nucleophiles, such as in the α-arylation of cycloalkyl esters36
and nitriles.37 For the other unsuccessful entries, see the
Supporting Information, Section 4. Nevertheless, we believe
these results provide a significant step toward the Suzuki cross-
coupling at tertiary alkyl bromides to construct all-carbon
quaternary centers, especially for small, strained rings.
3. CONCLUSION
In conclusion, we developed an operationally straightforward,
one-pot methodology for the facile synthesis of 3,3-dicarbo-
funcationalized azetidines through a novel polar-radical relay
strategy, involving the ring strain release and nickel-catalyzed
Suzuki Csp2−Csp3 cross-coupling of 1-azabicyclo[1.1.0]-
butanes with boronic acids. Mechanistic studies revealed an
intricately harmonized in situ ring opening of ABB with
catalytic amounts of bromide, which accounts for the
conversion of ABB into a redox-active azetidine that is
predisposed to radical Suzuki cross-coupling reaction as
facilitated by an appropriate nickel catalyst. Interestingly, the
synergy of bromide and nickel as catalysts could stem from a
single nickel source (NiBr2) or can be improved with the
addition of LiBr as additive. Broad substrate scope, including
the modular installation of azetidine moieties into natural
products, bioactive compounds, and pharmaceuticals were
leveraged. The mild reaction conditions enabled excellent
functional group tolerance for both ABB and boronic acid
components, encompassing various (hetero)aromatic, satu-
rated cyclic, and acyclic motifs with opposing electronic
substituents. Streamlined construction of sp3-rich azetidine
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pubs.acs.org/JACS Article
fragments, specifically bearing the elusive C3 all-carbon
quaternary center, without prior FGI is proffered while being
amenable to gram-scale synthesis without any loss in reaction
efficiency. The successful derivatization of vesicular acetylcho-
line transporter inhibitor and melanocortin-1 receptor agonist
by employing azetidine as nonclassical bioisosteric replacement
to the piperidinyl ring also highlights the potential of the
current methodology for drug hits and lead optimization
campaigns. Ultimately, as the azetidine scaffold is of increasing
value in medicinal chemistry even beyond the realm of
bioisosterism, we believe that this protocol will find
applications in both industrial and academic fields, especially
when seeking to prepare or install azetidine-containing
building blocks for use in therapeutic discovery programs.
Lastly, the preliminary extension of our nickel catalytic system
toward the arylation of non-azetidine tertiary bromides to
prepare all-carbon quaternary centers is described.
■
*
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.3c06710.
EPR data (ZIP)
NMR raw data (ZIP)
Detailed optimization data, experimental procedures,
characterization data of all compounds, including novel
ones (PDF)
Accession Codes
CCDC 2165260 and 2169395 contain 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
■ AUTHOR INFORMATION
Corresponding Author
Hsuan-Hung Liao − Department of Chemistry and Green
Hydrogen Research Center, National Sun Yat-sen University,
Kaohsiung 80424, Taiwan (R.O.C.); orcid.org/0000-
0001-7825-2425; Email: hsuan-hung.liao@
mail.nsysu.edu.tw
Authors
Che-Ming Hsu − Department of Chemistry, National Sun
Yat-sen University, Kaohsiung 80424, Taiwan (R.O.C.)
Heng-Bo Lin − Department of Chemistry, National Sun Yat-
sen University, Kaohsiung 80424, Taiwan (R.O.C.)
Xin-Zhi Hou − Department of Chemistry, National Sun Yat-
sen University, Kaohsiung 80424, Taiwan (R.O.C.)
Radyn Vanessa Phaz P. Tapales − Department of Chemistry,
National Sun Yat-sen University, Kaohsiung 80424, Taiwan
(R.O.C.); orcid.org/0009-0003-2082-1615
Chen-Kuei Shih − Department of Chemistry, National Sun
Yat-sen University, Kaohsiung 80424, Taiwan (R.O.C.)
Shinje Miñoza − Department of Chemistry, National Sun Yat-
sen University, Kaohsiung 80424, Taiwan (R.O.C.)
Yu-Syuan Tsai − Department of Chemistry, National Sun Yat-
sen University, Kaohsiung 80424, Taiwan (R.O.C.)
Zong-Nan Tsai − Department of Chemistry, National Sun
Yat-sen University, Kaohsiung 80424, Taiwan (R.O.C.)
https://doi.org/10.1021/jacs.3c06710
J. Am. Chem. Soc. 2023, 145, 19049−19059
Journal of the American Chemical Society
Cheng-Lin Chan − Department of Chemistry, National Sun
Yat-sen University, Kaohsiung 80424, Taiwan (R.O.C.)
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.3c06710
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
This work was supported by the Young Scholar Fellowship
Program of the Ministry of Science and Technology (MOST
111-2636-M-110-011) and Yushan Young Scholar Program of
the Ministry of Education of Taiwan. The authors thank Dr.
Phillip S. Grant (University of Sydney, Australia) and Dr.
Gregory Perry (University of Southampton, United Kingdom)
for proofreading our manuscript.
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19059 https://doi.org/10.1021/jacs.3c06710
J. Am. Chem. Soc. 2023, 145, 19049−19059