Articles

https://doi.org/10.1038/s41557-021-00746-7

A ring expansion strategy towards diverse

azaheterocycles
Ruirui Li, Bo Li, Hongpeng Zhang, Cheng-Wei Ju , Ying Qin, Xiao-Song Xue
and Dongbing Zhao ✉

The development of innovative strategies for the synthesis of N-heterocyclic compounds is an important topic in organic syn-
thesis. Ring expansion methods to form large N-heterocycles often involve the cycloaddition of strained aza rings with π bonds.
However, in some cases such strategies suffer from some limitations owing to the difficulties in controlling the regioselec-
tivity and the accessibility of specific π-bond synthons. Here, we report the development of a general ring expansion strat-
egy that involves a formal cross-dimerization between three-membered aza heterocycles and three- and four-membered-ring
ketones through synergistic bimetallic catalysis. These formal cross-dimerizations of two different strained rings are efficient
and scalable, and provide a straightforward and broadly applicable means of assembling diverse N-heterocycles, such as
3-benzazepinones, dihydropyridinones and uracils, which are versatile units in numerous drugs and biologically active com-
pounds. Preliminary mechanistic studies revealed that the C–C bond of strained ring ketones is first cleaved by the Pd0 species
during the reaction.

N
itrogen heterocycles are inextricably woven into our daily
life for use as pharmaceuticals, agrochemicals, dyes and
plastics. More than half of all drugs approved by the US
Food and Drug Administration contain at least one N-heterocycle
(Fig. 1a)1,2. Thus, the development of innovative strategies for the
synthesis of N-heterocycles has been a core area of research in
organic synthesis3–6. Although substantial progress has been made
in preparing N-heterocycles by a myriad of synthetic methods, it
is worthwhile to contemplate possible retrosynthetic approaches to
construct them with an improved flexibility, efficiency, generality
and practicality.
As a class of partners, strained (three- and four-membered) rings
have been widely employed in a vast number of organic transforma-
tions due to their facile ring opening7–15. In particular, for decades
the cycloaddition of strained aza rings with π bonds, such as ole-
fins or alkynes, has been regarded as a powerful and straightfor-
ward ring expansion strategy to form larger aza-ring systems from
smaller rings (Fig. 1b). However, in some cases the product types
and scopes are somewhat limited due to the difficulties in control-
ling the regioselectivity of electronically or sterically unbiased π
bonds and the accessibility of specific π-bond synthons. For exam-
ple, even though the skeletal motifs of azepines, dihydropyridinones
and uracils are prevalent in countless natural products and synthetic
compounds with important biological and medicinal properties, as
shown in Fig. 1a16–20, the cycloaddition of strained aza rings with
π bonds is incapable of delivering such important skeletons. The
conventional approaches to prepare these N-heterocycles are often
inefficient and involve multistep synthesis. Recently, a few exam-
ples of ring expansion via the formal cross-dimerization of strained
(benzo)silacyclobutanes and other strained rings with a 100%
atom economy have dramatically expanded chemists’ toolbox, and
enabled the rapid construction of specific silacycles21–23, which often
require tedious multistep synthesis. Inspired by these pioneering
results, we wondered whether the formal cross-dimerization of two
strained rings could become a general ring expansion strategy for
N-heterocycle synthesis starting from strained aza rings. However,
ring expansion via the formal cross-dimerization of two strained
rings remains a formidable challenge for reactivity, selectivity and
reaction-pathway control due to their high reactivity. These reac-
tive rings often undergo homodimerization and/or decomposi-
tion as well as undesired mismatch reactions in most catalytic
systems. Hence, alternative general ring expansion methods for
N-heterocycle synthesis via the cross-dimerization of two different
strained rings would represent an important synthetic advancement
and is highly sought after.
Three-membered aza rings, the smallest N-heterocycles, have
been widely applied as intriguing building blocks in a myriad of
powerful transformations due to their intrinsic ring strain. In par-
ticular, the oxidative addition of three-membered aza rings, such
as the aziridines and diaziridinones, to late transition metal com-
plexes to generate the corresponding organometal species, which
contain an anionic amido group, as a key step has been impli-
cated in a number of metal-catalysed reactions24–36. However, the
C–C bond activation of three- or four-membered cyclic ketones
to generate a highly reactive organometallic intermediate, which
is driven by the release of its ring strain, has also been extensively
utilized in numerous downstream reactions7,10,14,37–44. To this end,
we envisioned a strategy in which both three-membered aza rings
and three- or four-membered strained cyclic ketones are inter-
twined by nucleophilic addition of the anionic amido group on
aza–organometal species to the three- and four-membered strained
cyclic ketones to join sequential diverse steps. This approach would
allow the formal cross-dimerization of three-membered aza rings
and three- or four-membered cyclic ketones to give access larger
N-heterocycles. The key challenge for such a strategy is to identify
the difference in reactivity between three-membered aza rings and
three- or four-membered cyclic ketones in the reaction by choosing
the proper catalytic systems, as both partners are highly suscepti-
ble to ring opening by transition metals. Here we describe an effi-
cient and scalable ring expansion strategy, which involves a formal

State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, China.
✉e-mail: dongbing.chem@nankai.edu.cn

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NaTuRe CHemisTRy Articles
a NH O O
Cl O Me
MeO N
OMe Cl O
N N OMe
HO NH
MeO Me
Ivabradine OMe Lennoxamine
HO OMe
Marketed drug Lorcaserin Natural product
Fenoldopam Marketed drug
Marketed drug OH MeO O
Me
O Me
O O O N F N
Me
OMe N NH2
N N F O N
N
OMe Me O HN

OMe CN
Piperlongumine Pirfenidone Setiptiline CF3 Elagolix COONa Alogliptin
Natural product Marketed drug Marketed drug Marketed drug Marketed drug

b c
C M C M
A N + A N + B AB
D Cycloaddition N D Cross-dimerization N
Well-known Unknown
Aza ring A π-bond Aza ring A Ring B Aza ring AB

d
R′
M LnM O
N X
X R N R′
R O R O O
X = C or N t
TM LA R Ts R Bu
3-membered aza rings N N
Ar N Ts
Synergistic catalysis
+ R′ R′ N O
Ln This work
O M O R t
Bu
M
Benzoazepinones Dihydropyridinones Uracils
O
n
n = 0, 1 n

3- or 4-membered ketones

Fig. 1 | Examples of important N-heterocycles and our reaction design. a, Natural products and pharmaceuticals derived from 3-benzazepines,
pyridinones and uracils. b, The well-known ring expansion strategy for N-heterocycle synthesis via the cycloaddition reaction of strained aza rings
with π bonds. c, Proposed ring expansion strategy to deliver larger N-heterocycles via the formal cross-dimerization of two different strained rings.
d, Our study on N-heterocycle synthesis via the formal cross-dimerization between three-membered azaheterocycles and three- or four-membered ring
ketones. M, metal; TM, transition metal; LA, Lewis acid.

cross-dimerization between three-membered azaheterocycles and
three- or four-membered-ring ketones, enabled by synergistic
bimetallic catalysis. This method provides a versatile and enantio-
specific protocol to rapidly assemble diverse N-heterocycles such as
3-benzazepinones, dihydropyridinones and uracils (Fig. 1d).
Results and discussion
Reaction development. We began by studying the formal dimer-
ization of sulfonylated aziridine 1a and benzocyclobutenone 2a to
develop straightforward access to 3-benzazepine scaffolds, which are
classically formed via intramolecular transformations that exhibit a
lack of flexibility45–51. Diverse ligands, solvents and transition metal
precatalysts were evaluated at 60 °C for 12 hours, as shown in the
Supplementary Tables 1–4. In general, Pd catalytic systems were
effective at producing cyclic product 3aa, albeit in poor yields due to
the high reactivity of both 1a and 2a. Many different side reactions
occurred under most of the reaction conditions and delivered vari-
ous by-products. Inspired by recent studies of synergistic catalysis
that involve a transition metal and Lewis acid, which have shown
potential in the development of new, previously unattainable chemi-
cal transformations, rate enhancements and/or selectivity control
of existing transformations52–56, we reasoned that the employment
of Pd–Lewis acid cooperative catalysis might ultimately tune the
reactivities of sulfonylated aziridine 1a and benzocyclobutenone
2a, inhibit the side reactions and improve the efficiency of the
ring-opening cross-dimerization. Following this idea, we further
screened a range of Lewis acid additives. Finally, ring expansion
smoothly occurred to produce 3-benzoazepinone 3aa with a high
yield under two optimized conditions, as shown in Table 1 (entries 1
and 2), identified as 10 mol% Pd(PtBu3)2, 10 mol% L1 and methylal-
uminium bis(2,6-di-t-butyl-4-methylphenoxide) (MAD, 0.5 equiv.),
with acetonitrile (CH3CN) as the solvent at 60 °C for 12 hours (con-
dition A) and 10 mol% Pd(PtBu3)2, 20 mol% L1 and triphenylborane
(BPh3) (0.5 equiv.) in the presence of CF3SO3Li (1.0 equiv.) under the
same solvent and temperature (condition B). The structure of 3aa
was confirmed by single-crystal X-ray diffraction (Supplementary
Table 11). A series of control experiments was subsequently carried
out to understand the role of each component. In the absence of the
Lewis acid additives, the yields of the reaction decreased (Table 1,
entries 3 and 4). No desired product was obtained without ligand L1
(entries 5 and 6). We reasoned that the coordination of ligand L1 to
the Pd centre during the reaction might be crucial to stabilize C–Pd
species and inhibit the undesired β-hydrogen elimination. Omitting
CF3SO3Li in condition B was unfavourable for the yield (Table 1,
entry 7). Unsurprisingly, the reaction did not occur in the absence
of the Pd0 catalyst (entries 8 and 9).
Reaction scope for the cross-dimerization of sulfonylated aziridi-
nes and benzocyclobutenones. With these two sets of optimal reac-
tion conditions in hand (conditions A and B), the scope of this formal
dimerization of sulfonylated aziridines 1 and benzocyclobutenones 2
was explored. As shown in Table 2, styrenyl aziridines that bare ortho-,
para- and meta-substituents on the aromatic ring could be employed
as coupling partners, and efficiently afforded the 3-benzoazepinones

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Articles
Table 1 | Control experiments for the screening of reaction
conditions
Ts
10 mol% Pd(PtBu3)2
10 mol% L1
N O
0.5 equiv. MAD
+ Ts group to measure the e.e. To our delight, our ring expansion
1 ml CH3CN,
60 °C, 12 h
O HPLC. X-ray crystallography of a single crystal of (R)-8a allowed
1a 2a
N
L1
N which confirms the complete stereoinversion at the benzylic carbon
Entry Reaction conditions
1 10 mol% Pd(P Bu3)2, 10 mol% L1,
t
0.5 equiv. MAD
2 10 mol% Pd(PtBu3)2, 20 mol% L1,
0.5 equiv. BPh3, 1.0 equiv. CF3SO3Li
3 10 mol% Pd(PtBu3)3, 10 mol% L1
4 10 mol% Pd(P Bu3)2, 20 mol% L1,
t
1.0 equiv. CF3SO3Li
5 10 mol% Pd(PtBu3)2, 0.5 equiv. MAD
6 10 mol% Pd(PtBu3)2, 0.5 equiv. BPh3,
1.0 equiv. CF3SO3Li
7 10 mol% Pd(PtBu3)2, 20 mol% L1,
0.5 equiv. BPh3
8 10 mol% L1, 0.5 equiv. MAD
9 20 mol% L1, 0.5 equiv. BPh3,
1.0 equiv. CF3SO3Li
Unless otherwise specified, all reactions were carried out using 1a (0.4 mmol, 2.0 equiv.) and 2a
(0.2 mmol, 1.0 equiv.), with 10 mol% Pd(PtBu3)2, 10 mol% L1 and MAD (0.5 equiv.) in CH3CN at
60 °C for 12 h. NR, no reaction. The CCDC number of compound 3aa is 2008377. aIsolated yields
after chromatography.
(Table 2, 3ba–3qa). Aziridines that bear electron-donating substit-
uents on the aromatic ring afforded higher yields than those with
electron-withdrawing groups (3ba–3fa versus 3ga–3ka). The yield
of the substrate that bore a substituent in the ortho-position on the
phenyl ring was slightly lower, presumably due to steric encumbrance
(Table 2, 3oa). The multisubstituted substrate also provided the cor-
responding product in a high yield (3qa). In addition to diverse
styrenyl aziridines, we were pleased to find that an unsubstituted
aziridine was a competent substrate to access 5-unsubstituted-3
-benzoazepinone (Table 2, 3ra). The effect of the substituent on the
N atom of aziridines was also investigated. The reaction of 2a with
N-methyl- and N-Boc-substituted 2-phenylaziridines gave little to
no conversion. Moreover, switching the tosyl (Ts) group on the N
atom of aziridine to other sulfonyls under conditions A or B led to a
decrease in the yields (Table 2, 3sa–3xa).
We further proceeded to explore this formal dimerization
reaction of various benzocyclobutenones 2 with 2-phenyl-1-
tosylaziridine 1a. Benzocyclobutenones that bear a substituent at any
position on the benzene ring successfully gave the corresponding
seven-membered benzoazepinones (3ab–3ak). The 3,4-disubstituted
substrates were still tolerated to provide the desired products
in good yields (3al and 3am). In addition to benzocyclobutones,
naphthalene cyclobutone worked well to deliver product 3an in 71%
yield. Benzocyclobutenones that bear methyl or dimethyl groups at
the C8 position both afforded the desired products in good yields
(3ao and 3ap), albeit with a 1:1 diastereoselectivity ratio (d.r.)
for product 3ao. Importantly, this method is compatible with an
array of functional groups, such as halo, nitro, alkoxycarbonyl and
methoxy substituents, either on the benzene ring of aziridines or
benzocyclobutones.
1008
NaTuRe CHemisTRy
Next, we explored the stereochemical outcome of the reaction
by applying enantioenriched aziridine (R)-1a (>99% e.e.) to the
cross-dimerization with benzocyclobutenone 2a to produce opti-
cally active compound (R)-3aa in 81% yield (Table 2). Owing to the
difficulty in chiral resolution for product (R)-3aa by chiral HPLC,
it was transformed into compound (R)-8a by deprotection of the
N Ts strategy resulted in >99% enantiospecificity by analysis with chiral
3aa
O us to unambiguously assign the absolute configuration to be R,
of aziridine (R)-1a. This fact strengthens the assumption that the
Yield (%)a oxidative addition of aziridine for C−N bond cleavage proceeds in
80 (condition A) a nucleophilic substitution (SN2) manner to form a stereoinverted
alkylpalladium species.
90 (condition B)
Development and reaction scope for the cross-dimerization of
sulfonylated aziridines and cyclopropenones. After the success
36 of the formal dimerization of benzocyclobutenones and aziridi-
51 nes, we proceeded to examine other types of strained rings, and
therefore provide a general ring expansion process to form other
NR N-heterocycles. Cyclopropenones possess an electrophilic car-
NR
bonyl unit and three-membered strained ring, and have drawn
much attention for the construction of complicated molecules57–59.
Although cycloadditions of cyclopropenones with π-unsaturated
53 bonds have been extensively investigated in synthetic methodol-
ogy60–66, their application in the formal dimerization of two strained
NR rings remains rather unexplored. We wondered whether cyclopro-
NR penones could be included in our catalytic cycle as an activated cou-
pling partner to react with sulfonylated aziridines 1. If successful,
this reaction would provide a direct and efficient route to access
dihydropyridinone motifs. Following this idea, we tested the reac-
tion of cyclopropenone 4a with sulfonylated aziridine 1a under the
optimized conditions (conditions A and B). Unfortunately, only
low yields of the desired dihydropyridinone 5aa were obtained due
to the competitive decarbonylation and dimerization of 4a. We
rationalized that the side reaction could be inhibited by tuning the
coordination environment around palladium and the Lewis acid
strength. Thus, various ligands and Lewis acids were re-evaluated
(Supplementary Tables 5–9). As discovered for the reaction of 1a
and 2a, the reaction is very sensitive to the reaction conditions, and
a lot of different by-products (as shown in Supplementary Section
3.2) were detected due to the high reactivities of 1a and 4a. Finally,
we found that the reaction occurred smoothly in 80% yield with the
use of synergistic Pd–Cu catalytic processes in the presence of L2
(20 mol%) in CH3CN at 25 °C for 24 hours.
We investigated the enantiospecificity of the cross-dimerization
of (R)-1a and 4a. To our delight, under the optimized conditions, the
reaction occurred with 99% enantiospecificity, which showed that
the reaction of aziridines 1 and cyclopropenone 4 would undergo
the same mechanism as the reaction of aziridines 1 and benzocy-
clobutenones 2. We next examined the scope of the aziridine cou-
pling partner under the modified conditions. We were pleased to
find that a large range of 2-arylaziridines could be utilized to react
with 4a and provide diverse dihydropyridinones in good yields
(Table 3, 5aa–5qa). For example, a wide variety of para-, meta- or
ortho-substituted 2-arylaziridines afforded the desired products in
good yields (5ba–5oa). Furthermore, the reaction is not limited to
styrenyl aziridines. Unsubstituted aziridines are also suitable sub-
strates, which enables access to 5-unsubstituted dihydropyridinones
(Table 3, 5ra and 5sa). The cyclopropenone substrate scope was
also investigated, with sulfonylated aziridine 1a as the other partner
(Table 3, 5ab). Various diarylcyclopropenones with a substituent at
the para- or meta-position of the phenyl ring proceeded smoothly
to afford the desired dihydropyridinones in satisfactory yields
(5ab–5af). Employment of ortho-substituted diarylcyclopropenones
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NaTuRe CHemisTRy Articles
Table 2 | Substrate scope for cross-dimerization of aziridines 1 and benzocyclobutenones 2

R
R O 10 mol% Pd(PtBu3)2, 10–20 mol% L1,
O
0.5 equiv. MAD or BPh3, 0–1.0 equiv. CF3SO3Li
N + Ar Ar N R
1
R N
1 ml CH 3CN, 60 °C, 12 h N
R R2 R1 O
R2 L1
1 2 3

Sulfonylated aziridines
Ph 4-MeC6H4 4-tBuC6H4 4-PhC6H4 4-OMeC6H4 4-OAcC6H4 4-FC6H4

N Ts N Ts N Ts N Ts N Ts N Ts N Ts

O O O O O O O
3aa, 80%a 3ba, 77%a 3ca, 83%a 3da, 90%a 3ea, 80%a 3fa, 75%a 3ga, 75%a

4-ClC6H4 4-CF3C6H4 4-CO2MeC6H4 4-NO2C6H4 3-MeC6H4 3-OMeC6H4

N Ts N Ts N Ts N Ts N Ts N Ts

O O O O O O
3ha, 75%b 3ia, 53%b 3ja, 63%a 3ka, 30%b 3la, 75%a 3ma, 64%a
3-FC6H4 2-MeC6H4 2-Naphthyl 3,5-DiMeC6H3 Ph

N Ts O O
N Ts N Ts N Ts N Ts N S
Me
O
O O O O O
3na, 47%b 3oa, 63%a 3pa, 68%b 3qa, 90%a 3ra, 65%c 3sa, 53%a
Ph Ph Ph
Ph Ph
O O O O O
O O O O O
N S N S N S
N S N S
Cl Me
O O O
O O
a a
3ta, 30% NO2 3ua, 64% OMe 3va, 52%b 3wa, 53%a 3xa, 57%a

Benzocyclobutenones
Ph BnO Ph Ph Ph Ph
MeO
Me MeO

N Ts N Ts N Ts N Ts N Ts
Me
O O O O O
3ab, 78%a 3ac, 69%d 3ad, 87%b 3ae, 62%a 3af, 83%a
Ph Ph
Ph Ph Ph

N Ts N Ts
N Ts N Ts N Ts
MeO Cl F O O
O O O Me F
a
3ag, 83% 3ah, 64%b 3ai, 67%a 3aj, 78%a 3ak, 50%b
Ph Ph Ph
Ph Ph
MeO
O N Ts N Ts N Ts
N Ts N Ts
MeO O Me
O O O
O O Me Me
3al, 80%a 3am, 56%a 3an, 71% a
3ao, 61% (d.r. = 1:1) b
3ap, 78% a

Stereochemical outcome
Pd(PtBu3)2 (0.02 mmol, 10 mol%)
Ts
MAD (0.1 mmol, 0.5 equiv.) SmI2
N O
L1 (0.02 mmol, 10 mol%) (0.1 M in THF, 4.0 equiv.)
+
CH3CN (1 ml), 60 °C, 12 h THF, 0 °C, 1 h
N Ts NH

O O
(R)-1a (>99% e.e.) 2a (R)-8a, 90%
(R)-3aa, 81%
0.4 mmol 0.2 mmol (>99% e.e.)

Unless otherwise specified, percentages denote isolated yields after chromatography. The ratio of the d.r. was analysed by crude 1H NMR analysis. The CCDC number of compound (R)-8a is 2010994. The
e.e. was determined by chiral HPLC. aThe reaction was performed under optimized condition A: aziridines 1 (0.4 mmol, 2.0 equiv.), benzocyclobutenones 2 (0.2 mmol, 1.0 equiv.), Pd(PtBu3)2 (0.02 mmol,
10 mol%), MAD (0.1 mmol, 0.5 equiv.) and L1 (0.02 mmol, 10 mol%) in CH3CN (1 ml) at 60 °C for 12 h. bThe reaction was performed under optimized condition B: aziridines 1 (0.4 mmol, 2.0 equiv.),
benzocyclobutenones 2 (0.2 mmol, 1.0 equiv.), Pd(PtBu3)2 (0.02 mmol, 10 mol%), BPh3 (0.1 mmol, 0.5 equiv.), L1 (0.04 mmol, 20 mol%) and CF3SO3Li (0.2 mmol, 1.0 equiv.) in CH3CN (1 ml) at 60 °C for 12 h.
c
The reaction was conducted under optimized condition B with a slight modification: sulfonylated aziridine 1r (0.4 mmol, 2.0 equiv.), benzocyclobutenone 2a (0.2 mmol, 1.0 equiv.), Pd(PtBu3)2 (0.02 mmol,
10 mol%), BPh3 (0.1 mmol, 0.5 equiv.), 4,5-diazafluoren-9-one (0.04 mmol, 20 mol%) as the ligand and NaOAc (0.04 mmol, 20 mol%) in CH3CN (1 ml) at 60 °C for 12 h. dThe reaction was conducted under
optimized condition A with a slight modification: MAD (0.2 mmol, 1.0 equiv.) was used during the reaction.

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Articles NaTuRe CHemisTRy

Table 3 | Substrate scope for ring expansion via formal dimerization of aziridines 1 and cyclopropenones 4

10 mol% Pd(PtBu3)2 Ts
Ts O MeO OMe
20 mol% CuBr, 20 mol% L2 N
N + R O
CH3CN, 25 °C, 24 h
R R1 R2 N N
R2 R1
1 4 5 L2
Sulfonylated aziridines
Ts Ts Ts Ts Ts
N N N N N
Ph O 4-MeC6H4 O 4-tBuC6H4 O 4-PhC6H4 O 4-OMeC6H4 O

Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph
(R)-5aa, 80%, >99% ee 5ba, 81% 5ca, 64% 5da, 78% 5ea, 91%
Ts Ts Ts Ts Ts
N N N N N
4-OAcC6H4 O 4-FC6H4 O 4-ClC6H4 O 4-CF3C6H4 O 4-CO2MeC6H4 O

Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph
5fa, 83% 5ga, 48% 5ha, 57% 5ia, 65% 5ja, 71%
Ts Ts Ts Ts Ts
N N N N N
4-NO2C6H4 O 3-MeC6H4 O 3-OMeC6H4 O 3-FC6H4 O 2-MeC6H4 O

Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph
5ka, 53% 5la, 90% 5ma, 40% 5na, 56% 5oa, 44%

Ts Ts Ts Ns
N N N N
2-Np O 3,5-DiMeC6H3 O O O

Ph Ph Ph Ph Ph Ph Ph Ph
5pa, 82% 5qa, 75% 5ra, 67%a 5sa, 57%a
Cyclopropenones
Ts Ts Ts Ts
Ts
N N N N
N
Ph O Ph O Ph O Ph O
Ph O

Me Me
t t
MeO OMe Bu Bu Me Me F F
5ab, 76% 5ac, 84% 5ad, 80% 5ae, 70%b 5af, 70%c
Ts
Ts
N
N Ts Ts Ts
Ph O
Ph O N N N
MeO OMe
F F Ph O Ph O Ph O
Me Me
MeO OMe
Ph Me Me Me

MeO OMe

5ag, 30% (d.r. = 1:1)d 5ah, 70% (d.r. = 1.5:1)d 5ai, 46%e 5aj, 66%f 5ak, 73%g

Unless otherwise specified, all the reactions were carried out using aziridine 1 (0.3 mmol, 1.5 equiv.) and cyclopropenone 4 (0.2 mmol, 1.0 equiv.), Pd(PtBu3)2 (10 mol%), CuBr (20 mol%) and L2 (20 mol%) in
CH3CN (0.5 ml) at 25 °C for 24 h. Isolated yields after chromatography are shown. The d.r. was analysed by crude 1H NMR spectroscopy. The CCDC number of compound 5sa is 2008376. aDichloromethane
(1 ml) was used as the solvent. b70 °C. c40 °C. dThe reaction was carried out in the presence of Pd(PtBu3)2 (10 mol%), MAD (0.04 mmol, 0.2 equiv.) and L2 (0.02 mmol, 10 mol%) at 60 °C for 12 h. e2,2′-
Bipyridyl (20 mol%) was used as the ligand and without CuBr; the solvent was a mixture of CH3CN and dichloromethane (0.5 ml, 4/1). fA mixture of 4,4′-di-t-butylbipyridine (20 mol%) and biphenyl-2-
yldiphenylphosphine (20 mol%) as well as CuCl (20 mol%) was used. gA mixture of 4,4′-di-t-butylbipyridine (20 mol%), CuBr (20 mol%) and biphenyl-2-yldiphenylphosphine (20 mol%) was used.

as the coupling partners led to the desired products with a weak d.r. N−N bond of three-membered di-t-butyldiaziridinone by a transi-
(Table 3, 5ag and 5ah). The hindrance of the ortho-position means tion metal is well-known and widely utilized in many cycloaddition
that both atropisomerism and central chirality exist simultaneously reactions due to its high ring strain67,68. Along this line, we won-
in these structures. For unsymmetrically disubstituted cyclopro- dered whether the cross-dimerization of di-t-butyldiaziridinone 6
penone, dihydropyridinone was also obtained, with 46% yield and and strained cyclic ketones (2 or 4) would also happen by a tran-
specific regioselectivity (Table 3, 5ai). Additionally, dialkylcyclopro- sition metal and Lewis acid cooperative catalysis. After extensive
penones were suitable for this reaction (5aj and 5ak). Notably, the screening (Supplementary Table 10), we found that the reaction of
structure of the product was clearly confirmed by X-ray analysis of cyclopropenone 4a with di-t-butyldiaziridinone 6 under the Pd/Cu
a single crystal of 5sa (Table 3). synergistic system smoothly proceeded to yield 5,6-diaryluracil 7a
in 98% yield. Under these optimized conditions, we next examined
Development and reaction scope for the cross-dimerization of the substrate scope of cyclopropenones, and the results are shown
di-t-butyldiaziridinone and cyclopropenones. In addition to in Table 4. Symmetrical diarylcyclopropenones bearing differ-
reactions with sulfonylated aziridines, oxidative cleavage of the ent groups such as –F, –Br and –CF3 at the ortho-, meta- and para

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NaTuRe CHemisTRy Articles
Table 4 | Substrate scope for formal dimerization of cyclopropenones 4 and di-t-butyldiaziridinone 6

O
O O PdCl2 (1 mol%), CuCl (20 mol%) t
Bu R1
P(OPh)3 (1 mol%) N
+
N N PhMe, 30 °C, 24 h
R1 R2 t
Bu t
Bu O N R2
tBu

4 6 7

F Me t
Bu
O O O O O
t t t tBu
Bu Ph Bu Bu tBu
N N N Me N N
Me
O N Ph O N O N O N O N
t t tBu t
Bu Bu Bu t
Bu
F Me t
Bu
7a, 98% 7b, 97% (d.r. = 2:1) 7c, 95%a 7d, 87% 7e, 88%

CF3 Br F
O O O O O O
tBu tBu tBu tBu tBu tBu
Ph Me Ph
N N N N N N
and
O N O N O N O N Me O N Ph O N H
t t t t t t
Bu Bu Bu Bu Bu Bu
CF3 Br F
7f, 96% 7g, 38% 7h, 85% 7i and 7i′, 82% (1:1)b 7j, 60%c

Unless otherwise specified, all the reactions were carried out using cyclopropenone 4 (0.2 mmol, 1.0 equiv.) and di-t-butyldiaziridinone 6 (0.3 mmol, 1.5 equiv.), PdCl2 (1 mol%), CuCl (20 mol%) and P(OPh)3
(1 mol%) in toluene at 30 °C for 24 h. Isolated yields after chromatography are shown. The CCDC number of compound 7a is 2008375. aThe reaction was carried out at 0 °C for 24 h. bThe reaction was
carried out in the presence of Pd(PPh3)4 (5 mol%) and CuCl (20 mol%) in PhMe (1 ml) at 25 °C for 12 h. The ratio of 7i and 7i′ was calculated by the isolated yields of both isomers. cThe reaction was carried
out at –10 °C for 24 h.

positions of the benzene ring were all coupled with good-to–excel- made available in two steps (Fig. 2d). The literature method to access
lent yields to give diverse aryluracils (7b–7h). In addition to the use 8d involves a linear four-step reaction from 2-(3-methoxyphenyl)
of diarylcyclopropenones, this transformation can be extended to acetic acid73. Furthermore, the union of 2m and 1r, followed by
unsymmetrically disubstituted cyclopropenone and terminal aryl- the deprotective treatments, delivered 3-benzazepin-2-one 8e in
cyclopropenone (7i and 7j), thus broadening the application of the 41% overall yield, which is the key precursor for the synthesis of
current methodology. the natural products lennoxamine and chilenine (Fig. 2e)74. This
compound was formerly accessed by a route that included a chloro-
Synthetic utilities. As claimed earlier, 3-benzazepines at various formylation reaction, coupling with aminoacetaldehyde dimethylac-
oxidation levels are one of the privileged skeletons in drug discovery. etal, a Pomeranz–Fritsch-type cyclization and hydrogenation of the
However, the conventional approaches to prepare 3-benzazepines double bond74. Furthermore, we investigated the synthetic utility of
are often inefficient and involve multistep synthesis. Our ring expan- the dihydropyridinones by conducting four additional downstream
sion approach provides a convenient route to shorten the synthesis of transformations with our product 5ra (Fig. 2f). First, the protect-
complex pharmaceutical agents and natural products. For example, ing group (Ts) of 5ra was easily removed to yield 10 using SmI2.
removal of the Ts group in our product 3aa by treatment with SmI2 5ra also smoothly underwent reduction in the presence of diisobu-
in THF allowed us to access tetrahydro-2H-3-benzazepin-2-one tylaluminium hydride (DIBAL-H) to yield compound 11 with 66%
8a in 90% yield, previously prepared in five steps with 29% yield yield, which was further transformed to free tetrahydropyridine 12
(Fig. 2a)46. Furthermore, the reduction of compound 8a directly led in 60% yield by an additional deprotection step (Ts group removal).
to the NMDA (N-methyl-d-aspartate antagonist) 9a in 84% yield Further investigation showed that treatment of 5ra with LiAlH4 led
(Fig. 2a). As a comparison, the previous approach for compound 9a to ring opening and reduction of the carbonyl group to deliver com-
required nine linear steps in 3.6% yield from 2-bromobenzaldehyde49. pound 13. Additionally, we demonstrated that the protecting group
In the second case, the ring expansion method reported here (tBu) on the product uracil 7a was easily cleaved to give unprotected
was utilized in the formal synthesis of (R)-SKF 38393, which is a uracil 14 in 96% yield (Fig. 2g).
dopamine receptor agonist and antagonist (Fig. 2b)69. A three-step
manipulation that involves the cross-dimerization of aziridine Mechanistic studies. Next, both experimental and computational
(R)-1a (>99% e.e.) and benzocyclobutenone 2l, removal of the Ts studies were carried out to investigate the reaction pathway, with
group and reduction furnished compound (R)-9b, a key precursor the key question as to which strained ring would be first cleaved
of (R)-SKF 38393, in 84% yield with 97% e.e. The previous synthe- by the Pd0 species during this reaction. Taking the model reaction
sis of this precursor of the SKF 38393 enantiomer required seven of 1a and 2a as an example, two pathways, following either a Pd0/ii
steps from (E)-1,2-dimethoxy-4-(2-nitrovinyl)benzene, with an cycle or a Pd0/ii/iv cycle, are proposed (Fig. 3a). Path A involves
18% overall yield70. The third example involves the formal synthesis an oxidative addition of aziridine 1a to the Pd0 catalyst in an SN2
of the marketed drug ivabradine71. One key structural motif is the fashion, which accesses either a zwitterion complex or an azam-
7,8-dimethoxy-1,3,4,5-tetrahydrobenzo[d]azepinone moiety 8c, etallacyclobutane intermediate A. Subsequent nucleophilic addi-
which was easily synthesized by the cross-dimerization of 1r and 2l tion of intermediate A to the C=O bond of the strained cyclic
in 53% yield (Fig. 2c). The existing route prepared the key moiety ketone 2a affords the six-membered palladacycle B, which further
8c in five steps with 39% yield from 2-(3,4-dimethoxyphenyl)ethan- undergoes site-selective β-carbon elimination to cleave the C–C
1-amine72. Analogously, through our protocol, the key intermediate bond and access intermediate C. 3-Benzazepinone 3aa is then
8d in the synthesis of the H3 receptor antagonist GSK189254 was generated by reductive elimination. Alternatively, the reaction

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Articles NaTuRe CHemisTRy

a Ts H H
O N O N N
SmI2
CHO
(0.1 M in THF, 4.0 equiv.) BH3 in THF (6.0 equiv.) 9 steps, 3.6% yield

THF, 0 °C, 1 h THF, 80 °C, 24 h Previous route

Br

COOH
3aa O 8a, 90% 9a, 84%
NMDA antagonist
5 steps, 29% yield

Previous route
Ts H H
Pd(Pt Bu3)2 (10 mol%) O
b N N N
Ts MAD (0.5 equiv.)
MeO O
L1 (10 mol%) (1) SmI2 Ref. 69
+ N
CH3CN, 60 °C, 12 h (2) BH3/THF
MeO Ph

2l (R)-1a (>99% e.e.)

MeO OMe MeO OMe HO OH
(R)-3al, 82% (R)-9b (97% e.e.), 84% (R)-SKF 38393
MeO NO2
D1/D5 receptor partial agonist
7 steps, 18% yield
MeO Previous route O
MeO
Ts Me
c N O O
N N
MeO O
MeO SmI2 MeO Ref. 71 MeO
NTs NH
Condition Ba
MeO MeO MeO Ivabradine
2l 3rl, 53% 8c, 92% Marketed drug

MeO NH2 MeO OMe

5 steps, 39% yield

MeO Previous route

Ts
d O N O O O
MeO SmI2 MeO Ref. 73 N
O
NTs NH
Condition Ab
MeO
NHMe GSK189254
2g 3rg, 46% 8d, 65%
H3 receptor antagonist
MeO
COOH 4 steps, 44% yield
O O
Previous route N
e Ts O OMe
N O O
O
O SmI2 Ref. 74 Lennoxamine
O O
NTs NH OMe
Condition Ab O
O O O O
N
2m 3rm, 47% 8e, 88% O OMe
O
COOH
4 steps, 54% yield O OH

O Previous route Chilenine OMe

f 5ra g
O O
4.0 equiv. 4.0 equiv. 2.0 equiv.
PhOH/HBr t
Bu Ph
O SmI2 DIBAL-H
TsHN
LiAlH4 N CH3SO3H/hexane = 1/10
HN
Ph
Ph Ph
Ph OH 65 °C
NH O N Ph O N Ph
N NH H
Ph Ts tBu
Ph
Ph Ph Ph
10, 84% 11, 66% 12, 60% 13, 56% 7a 14, 96%

Fig. 2 | Synthetic applications. a, The cross-dimerization product 3aa obtained by our method was easily transformed into the NMDA antagonist 9a by
deprotection and subsequent reduction. In contrast, 8a and 9a were previously synthesized in five steps in 29% yield46 and nine steps in 3.6% yield49,
respectively. b, Synthesis of (R)-9b, a key intermediate of (R)-SKF 38393, by the cross-dimerization of 1r and 2l, and subsequent deprotection and
reduction. (R)-9b was previously obtained in seven steps in 18% yield70. c, The formal synthesis of the marketed drug ivabradine by cross-dimerization
of 1r and 2l and deprotection to deliver the key moiety 8c in 49% overall yield. 8c was previously synthesized in five steps in 39% yield72. d, 8d, a key
intermediate for the synthesis of the H3 receptor antagonist GSK189254, was efficiently synthesized using the reported strategy. Previously, 8d was
synthesized by a linear four-step reaction73. e, A key intermediate 8e to produce lennoxamine and chilenine was obtained by our method. 8e was
formerly accessed by a non-catalytic four-step route74. f, Conversion of dihydropyridinone 5ra into diverse building blocks shows the versatility of 5ra.
g, Deprotection of the tBu group on the uracil 7a shows the practicality of our product. aThe reaction was conducted under condition B with a slight
modification, namely, 2,2′-bis(2-oxazoline) (0.2 equiv.) as the ligand and NaOAc (0.2 equiv.) instead of CF3SO3Li at 100 °C for 12 h. bThe reaction
was conducted under condition A with a slight modification, with 2,2′-bis(2-oxazoline) (0.2 equiv.) as the ligand. For the experimental details, see
Supplementary Section 7.

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NaTuRe CHemisTRy Articles
a Ts PdLn O LA
N
1a Ph 2a Ln Ph C–C cleavage
Ph Pd
NTs O
SN2-type oxidative Ts Nucleophilic addition N β-Carbon elimination
addition LnPd N
Ts O
C–N cleavage B
Path A: Pd 0/PdII cycle
Ph A
N Ts
Pd0Ln Reductive elimination 3aa

Pd
Path B: Pd 0/PdII /PdIV cycle Ln
Ph
C
C–C cleavage SN2-type oxidative LA
oxidative addition O addition O Nucleophilic addition
Pd
Pd Ts C–N cleavage Reductive acylation
O LA Ln
N NTs
Ph
D 1a E
2a
Ph
b OMe e
Ts
N 1a O Ph
Pd Ts 0.5 equiv. MAD
Pd2(dba)3 C
Ph N C 1.0 equiv. L1
Ts N Me + N
MeO + OMe
N N Ts
MeO N Pd N CH3CN, 60 °C
Me Me Ph
t
Bu O
Me
N N Ph tBu [Pd]-2a 1a 3aa, 38%
[Pd]-1a
c O
10 mol% [Pd]-2a
2a O
f 0.5 equiv. MAD
Ph
Ts O
C6D6, r.t., 7 h Pd 10 mol% L1
C N +
+ C N Me CH3CN, 60 °C
N Ts

Me Me N Ph
tBu Me Me O
tBu
Pd CN tBu
1a 2a 3aa, 59%
Me
2
[Pd]-2a g

d OMe
O Ph
Pd Ts 1.0 equiv. L1
C CH3CN
O C N Me
0.5 equiv. MAD + N
N N Ts
N + NR r.t.
Ts CH3CN, 60 °C Me Ph
Me Without LA
MeO N Pd N tBu
O
Me
tBu
[Pd]-2a 1a 3aa, 40%
[Pd]-1a Ph 2a

Fig. 3 | Mechanistic studies. a, Two proposed pathways for the cross-dimerization of 1a and 2a. Path A begins with an SN2-type oxidative addition of
the C–N bond in aziridine to the Pd0 catalyst. It features a Pd0/Pdii cycle that involves the oxidative addition of the C–N bond, nucleophilic addition,
β-carbon elimination and reductive elimination. In contrast, the proposed path B would undergo a Pd0/ii/iv cycle, triggered by a C–C cleavage from
benzocyclobutenone. b, Preparation of the four-membered aza–palladacyclobutane complex [Pd]-1a via C–N bond cleavage from aziridine 1a.
c, Preparation of the five-membered palladacycle [Pd]-2a via C–C cleavage from benzocyclobutenone 2a. d, Stoichiometric experiment with [Pd]-1a
and benzocyclobutenone 2a. e, Stoichiometric experiment with [Pd]-2a and aziridine 1a. f, The reaction of 1a and 2a by the employment of 10 mol%
[Pd]-2a as the catalyst in the presence of MAD (0.5 equiv.) and L1 (10 mol%) at 60 °C in CH3CN. g, Stoichiometric experiment with [Pd]-2a and
aziridine 1a in the absence of a Lewis acid at room temperature. dba, dibenzylideneacetone; r.t., room temperature.

can be initiated by the oxidative C–C bond cleavage of benzocy- [Pd]-1a, which bears ligand L2, and the five-membered pallada-
clobutenone 2a to give a five-membered palladacycle D (path B in cycle [Pd]-2a which bears two isocyanide ligands, were prepared
Fig. 3a), which would undergo a further oxidative addition of aziri- via oxidative addition of an aziridine C–N bond or a benzocy-
dine 1a by an SN2 mechanism, subsequent nucleophilic addition clobutenone C–C bond (Fig. 3b,c). Notably, only one regioiso-
of the C=O group and reductive acylation to give intermediate mer was observed during the reaction, as the oxidative addition
C, followed by reductive elimination to deliver the final product occurred exclusively at the sterically hindered C–N bond or the
3aa and regenerate the Pd0 catalyst. Thus, the Pdiv intermediate C(aryl)–C(carbonyl) bond. These results are consistent with the
E is involved in path B. The role of the Lewis acid is proposed to regioselectivity and stereoselectivity of the reaction. Next, we
be twofold: first, it could facilitate C–C or C–N bond cleavage by performed a stoichiometric reaction between the aza–palladacy-
coordinating to the carbonyl or sulfonate group on substrate 1a or clobutane complex [Pd]-1a (1.0 equiv.) and benzocyclobutenone
2a. Second, the Lewis acid could also accelerate the nucleophilic 2a (1.0 equiv.) in the presence of MAD (0.5 equiv.) in CH3CN
addition of the anionic amido group on aza–organometal species at 60 °C, and no product 3aa was detected during the reaction
A or E to the carbonyl groups. We then conducted the follow- (Fig. 3d). In contrast, benzazepinone 3aa was obtained in 38%
ing experiments to differentiate the two possible pathways. First, yield when the five-membered palladacycle [Pd]-2a (1.0 equiv.)
following the literatures21,27, the aza–palladacyclobutane complex was heated with aziridine 1a (2.0 equiv.) in the presence of MAD

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Articles NaTuRe CHemisTRy
Free energy (kcal mo l–1)

Path A Ph (tBu)3P
Path B Ph
Pd
Path B (MAD)
Ts (tBu)3P Pd NTs
N O
O TS-BC
L1 N
47.6
O Ph H Ts
Pd PtBu3 TS-BC
Pd L1 Ph
t
P( Bu)3 Pd
P(tBu)3 TS-AB
36.1 O
TS-1 TS-A
2a N
Ph L1
TS-A Ts (tBu)3P
(tBu)3P NTs TS-2 Ph
28.1 Pd B Pd
25.9
PtBu3 PtBu3 21.8
A
TS-1 20.3 TS-3
1a N
25.6 24.6 Ts
TS-2-MAD INT-2
PtBu 3 L1 1a INT-3
21.8 21.8 O
12.9
ArO Ts PtBu3 TS-5
TS-1-MAD PtBu3 TS-4
2a ArO Al O O N 9.9
17.4 14.2
S Ph O L1
Me N p-tol PtBu3
N
INT-1 L1 Pd NTs
ArO OAr Ph H N
5.1 O Ph O Pd(PtBu3)2
Al
Pd(PtBu3)2 N TS-3 N
Me O L1 Pd INT-4
L1 Pd
0.0 N –1.1
Pd N
P(tBu)3 Ts TS-2-MAD TS-4
TS-1-MAD N
NTs (tBu)3P Ph 3aa
NTs –30.2
L1 Ph H O Pd
Ph Ph O
O
Pd N N
N
L1 Pd L1 Pd
O L1 Pd N
N
Ts
N N
INT-1 TS-2 INT-2 INT-3 INT-4 O

Fig. 4 | DFT calculations. The computed free energy profiles for two possible pathways in the formal cross-dimerization reaction of 1a with 2a (path
A: cyan line; path B: grey line). Level of theory: SMD(CH3CN)-PWPB95-D3(BJ)/def2-TZVPP//SMD(CH3CN)-B3LYP-D3(BJ)/SDD(Pd)-6-31G(d).
Computational details are provided in Supplementary Information section 10. The profiles start with Pd(PtBu3)2 and indicate that the oxidative cleavage
of C–C bond on benzocyclobutenone is more energetically favourable as the first step, which is consistent with the proposed path B. In contrast, the
requirement of a rather high energy barrier for β-carbon elimination step in the Pd0/ii catalytic cycle decreases the possibility of path A (cyan line). The
further computational results explained the role of MAD in improving the reactivity and efficiency of this reaction, which is to lower the activation energy
for both the C–C bond cleavage of benzocyclobutenone and C–N bond cleavage of aziridine (red line). TS-A, TS-AB and TS-BC are the transition states for
path A. All energies are in kcal mol–1.

(0.5 equiv.) and the N,N′-ligand L1 (1.0 equiv.) at 60 °C in CH3CN the favourable pathway (path B), from Pd(PtBu3)2, the regioselec-
(Fig. 3e). Moreover, we confirmed that the five-membered pal- tive oxidative cleavage of the C(aryl)–C(carbonyl) bond on ben-
ladacycle [Pd]-2a catalyst is capable of triggering the reaction of zocyclobutenone 2a followed by a tBu3P/N,N′-ligand L1 exchange
1a and 2a to obtain product 3aa in 59% yield (Fig. 3f). These leads to the five-membered palladacycle intermediate INT-1 via
results strongly support the Pd0/ii/iv pathway (path B), in which the monoligated three-membered ring transition state TS-1. This
the oxidative addition of benzocyclobutenone 2a occurs as the initial oxidative addition from Pd(PtBu3)2 to give INT-1 is ender-
first step. In addition, we found that the stoichiometric reaction gonic by 5.1 kcal mol–1, which demands a barrier of 25.6 kcal mol–1.
of [Pd]-2a with aziridine 1a works efficiently to deliver 3aa in The subsequent oxidative addition of aziridine 1a to give INT-1
40% yield in the absence of MAD at room temperature (Fig. 3g). occurs in an SN2 fashion via transition state TS-2, which generates
This result indicates that the C–C bond cleavage of benzocy- the zwitterionic Pd(iv) intermediate INT-2, which bears an anionic
clobutenone 2a might be the rate-limiting step and that the Lewis amido group. Then, the anionic amido group on INT-2 would
acid additive in the reaction could be bound to the C=O group to attack the carbon atom of the carbonyl group via TS-3 to gener-
lower the activation energies for C–C bond activation. ate the zwitterion complex INT-3 with C–N bond formation, which
The two possible pathways (A and B in Fig. 3a) were studied further undergoes the reductive acylation via TS-4 and subsequent
using density functional theory (DFT) calculations (Fig. 4 and N,N′-ligand/tBu3P exchange to give intermediate INT-4. The final
Supplementary Figs. 3 and 8). The computed free-energy profiles reductive elimination through TS-5 produces the observed formal
indicate that the Pd0/ii/iv catalytic cycle (path B) is more energetically cross-dimerization product 3aa and regenerates the active catalyst
favourable than the Pd0/ii catalytic cycle (path A), which is consistent Pd(PtBu3)2. Further DFT studies revealed that the use of MAD as
with the aforementioned stoichiometric experiments. The reaction the additive indeed lowers the activation energy for both the C–C
between zwitterion complex A and benzocyclobutenone 2a to pro- bond cleavage of benzocyclobutenone 2a and the C–N bond cleav-
duce INT-4 in the Pd0/ii catalytic cycle (path A), which involves the age of aziridine 1a by coordination to the carbonyl group or sulfo-
initial oxidative addition with aziridine 1a (Supplementary Figs. 1, nyl group to generate transition states TS-1-MAD and TS-2-MAD,
2 and 4), requires a barrier of 27.3 kcal mol–1, which is 6.5 kcal mol–1 respectively (Supplementary Fig. 2 and 10). Notably, the conformers
higher than that for the reaction between the five-membered pal- and number of ligands for all the intermediates and transition states
ladacycle INT-1 and aziridine 1a to deliver INT-4 (27.3 kcal mol–1 were carefully considered, and the unfavourable ones are presented
versus 20.8 kcal mol–1) in the Pd0/ii/iv catalytic cycle (path B). In in Supplementary Figs. 4–7 and 9.

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NaTuRe CHemisTRy
Conclusions. In conclusion, we have described a synthetically use-
ful and mechanistically intriguing ring expansion strategy in which
two different strained rings can be cross-dimerized by intertwin-
ing the strain-release-driven oxidative C–C bond cleavage and
C–N bond cleavage, which opens up a substantial chemical space
for N-heterocycle synthesis in a stereospecific manner. The use
of synergistic bimetallic catalysis is critical to the success of the
transformation; the Lewis acid acted as a linchpin that facilitated
the C–C bond cleavage and nucleophilic addition of the anionic
amido group to the carbonyl unit. The methodology enables the
modular and robust synthesis of 3-benzazepinones, dihydro-
pyridinones and uracils, which are versatile units in numerous
drugs and biologically active compounds. This process reveals a
general N-heterocycle synthesis strategy that involves a formal
cross-dimerization between three-membered azaheterocycles and
three- and four-membered-ring ketones. It is anticipated that this
ring expansion method will open up new retrosynthetic approaches
to complex molecule synthesis by the transition-metal-catalysed
formal cross-dimerization of two different cyclic compounds.
Online content
Any methods, additional references, Nature Research report-
ing summaries, source data, extended data, supplementary infor-
mation, acknowledgements, peer review information; details of
author contributions and competing interests; and statements of
data and code availability are available at https://doi.org/10.1038/
s41557-021-00746-7.
Received: 6 June 2020; Accepted: 1 June 2021;
Published online: 19 July 2021
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Methods
General condition A for the cross-dimerization of aziridines 1 and
benzocyclobutenones 2. In an N2-filled glove box, an oven-dried 25 ml Schlenk
tube equipped with a Teflon-coated magnetic stir bar was charged successively with
aziridines 1 (0.4 mmol, 2.0 equiv.), MAD (0.1 mmol, 0.5 equiv.), L1 (0.02 mmol,
10 mol%), Pd(PtBu3)2 (0.02 mmol, 10 mol%) and benzocyclobutenones 2 (0.2 mmol,
1.0 equiv.) (if the compound is an oil, then it is injected into the reaction after
adding the solvent) and CH3CN (1 ml). The tube was then sealed with a Teflon
screw cap, moved out of the glove box and placed on a hotplate preheated to
60 °C with vigorous stirring. After 12 h, the reaction mixture was cooled to room
temperature and the solvent evaporated under vacuum to give the crude product.
The resulting residue was purified by column chromatography on silica gel to
afford the corresponding 3-benzazepinones 3.
General condition B for the cross-dimerization of aziridines 1 and
benzocyclobutenones 2. In a N2-filled glove box, an oven-dried 25 ml Schlenk
tube equipped with a Teflon-coated magnetic stir bar was charged successively
with aziridines 1 (0.4 mmol, 2.0 equiv.), BPh3 (0.1 mmol, 0.5 equiv.), L1 (0.04 mmol,
20 mol%), CF3SO3Li (0.2 mmol, 1.0 equiv.), Pd(PtBu3)2 (0.02 mmol, 10 mol%),
benzocyclobutenones 2 (0.2 mmol, 1.0 equiv.) (if the compound is an oil, then it is
injected into the reaction after adding the solvent) and CH3CN (1 ml). The tube
was then sealed with a Teflon screw cap, moved out of the glove box and placed
on a hotplate preheated to 60 °C with vigorous stirring. After 12 h, the reaction
mixture was cooled to room temperature and the solvent evaporated, and then the
residue was purified by column chromatography to give the desired product 3.
General procedure for the cross-dimerization of aziridines 1 and
cyclopropenones 4. In a N2-filled glove box, an oven-dried 25 ml Schlenk tube
equipped with a Teflon-coated magnetic stir bar was charged successively with
sulfonylated aziridines 1 (0.3 mmol, 1.5 equiv.), CuBr (0.04 mmol, 20 mol%),
L2 (0.04 mmol, 20 mol%), Pd(PtBu3)2 (0.02 mmol, 10 mol%), cyclopropenones
4 (0.2 mmol, 1.0 equiv.) and CH3CN (0.5 ml). The tube was then sealed with a
Teflon screw cap, moved out of the glove box and placed on a hotplate preheated
to 25 °C with vigorous stirring. After 24 h, the reaction mixture was cooled to
room temperature and the solvent was evaporated under vacuum to give the
crude product. The resulting residue was purified by silica gel flash column
chromatography to afford the corresponding dihydropyridinones 5.
General procedure for the cross-dimerization of cyclopropenones 4 and
di-t-butyldiaziridinone 6. In a N2-filled glove box, an oven-dried 25 mL Schlenk
tube equipped with a Teflon-coated magnetic stir bar was charged successively
with cyclopropenones 4 (0.2 mmol, 1.0 equiv.), CuCl (0.04 mmol, 20 mol%),
Nature Chemistry | www.nature.com/naturechemistry
Articles
P(OPh)3 (0.002 mmol, 1 mol%), PdCl2 (0.002 mmol, 1 mol%), PhMe (1 ml) and
di-t-butyldiaziridinone 6 (0.3 mmol, 1.5 equiv.). The tube then was sealed with a
Teflon screw cap, moved out of the glovebox and placed on a hotplate preheated
to 30 °C with vigorous stirring. After 24 h, the reaction mixture was cooled to
room temperature and the solvent was evaporated under vacuum to give the crude
product. The resulting residue was purified by column chromatography on silica
gel to afford the corresponding uracils 7.
Data availability
All the data generated or analysed during this study are included in this article
and its Supplementary Information. Crystallographic data have been deposited at
the Cambridge Crystallographic Data Centre (CCDC) as CCDC 2008377 (3aa),
2008376 (5sa), 2008375 (7a) and 2010994 ((R)-8a) and can be obtained free of
charge from the CCDC via www.ccdc.cam.ac.uk/getstructures.
Acknowledgements
We are grateful for the financial support from the National Natural Science Foundation
of China (22022103, 21871146 and 22071114), the National Key Research and
Development Program of China (2019YFA0210500), the 1000-Talent Youth Program
(020/BF180181), the Natural Science Foundation of Tianjin (18JCYBJC20400) and the
Fundamental Research Funds for the Central Universities and Nankai University.
Author contributions
R.L., H.Z., C.-W.J. and Y.Q. performed the experiments. B.L. and X.-S.X. conducted the
DFT calculations. D.Z. developed the concept, directed the project and wrote the paper.
All the authors approved the final version of the manuscript.
Competing interests
The authors declare no competing interests.
Additional information
Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s41557-021-00746-7.
Correspondence and requests for materials should be addressed to D.Z.
Peer review information Nature Chemistry thanks Matthew Grayson, Masahiro
Murakami and the other, anonymous, reviewer(s) for their contribution to the peer
review of this work.
Reprints and permissions information is available at www.nature.com/reprints.