Nickel-catalyzed [3 + 2] cycloaddition of diynes with methyleneaziridines via C-C bond cleavage

Article abstract of DOI:10.1039/c3cc41061g

A Ni-catalyzed [3 + 2] cycloaddition via C-C bond cleavage of methyleneaziridines under mild conditions was developed. This reaction gave substituted pyrroles with excellent regioselectivity and a pendant alkyne unit, which is advantageous for further derivatization. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc41061g

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Nickel-catalyzed [3 + 2] cycloaddition of diynes with
methyleneaziridines via C–C bond cleavage†
Cite this: Chem. Commun., 2013,
49, 5073
Bin Pan, Chunxiang Wang, Dongping Wang, Fan Wu and Boshun Wan*
Received 7th February 2013,
Accepted 10th April 2013
DOI: 10.1039/c3cc41061g
www.rsc.org/chemcomm
A Ni-catalyzed [3 + 2] cycloaddition via C–C bond cleavage of methyl- less investigated. Alper and co-workers reported a palladium-catalyzed
eneaziridines under mild conditions was developed. This reaction gave carbonylation reaction5 of MAs which proceeded via N–C2 bond
substituted pyrroles with excellent regioselectivity and a pendant cleavage (Scheme 1, a). Later, Yamamoto and co-workers reported
alkyne unit, which is advantageous for further derivatization.
the palladium-catalyzed reactions of MAs with 2-acetylpyridines6a or
1,3-diketones,6b giving pyrrole derivatives in good yields (Scheme 1,
Cleavage of C–C s bonds by transition metals presents a b and c), which also involved N–C2 bond cleavage steps. Despite these
fundamental challenge1 attributed to the inertness of the C–C achievements, metal-catalyzed ring expansion reactions via C2–C3
s bond and the poor interaction of the orbitals of the C–C s bond cleavage of MAs have not been reported.
bond with transition metals. Strained rings as substrates offer a
feasible approach for C–C s bond activation.
We have recently reported the [2 + 2 + 2] cycloaddition reactions of
diynes with nitriles or oximes to give pyridine derivatives.7 As a
Methyleneaziridines (MAs), a class of highly strained heterocycle continuation of our interest in the metal-catalyzed cycloaddtion
derived aziridines bearing an exocyclic alkene group (Scheme 1),2 reactions of diynes, we turned our attention to the reaction of diynes
have drawn less attention in organic synthesis than other three- and MAs. It is well-known that Ni(0) can catalyze the carbon–carbon
membered rings.3 Although the ring-opening couplings of MAs bond cleavage of methylenecyclopropanes in coupling reactions,3d–f
with strong electrophiles and organometallics have been studied,4 including [3 + 2 + 2] cycloaddition reactions.8 Given the structural
the metal-catalyzed ring expansion reactions of MAs have been similarity between methylenecyclopropanes and MAs, we surmised
that Ni(0) might also activate the C2–C3 bond of MAs to undergo
coupling with diynes to give [3 + 2 + 2] cycloaddition products.
Surprisingly, such a [3 + 2 + 2] cycloaddition product was not obtained
after extensive screening. In contrast, only [3 + 2] selectivity occurred
and a series of substituted pyrroles were obtained (Scheme 1, d).9 To
the best of our knowledge, this is the first example of metal-catalyzed
cycloaddition of MAs via the C2–C3 bond cleavage.
Our initial attempts to explore the viability of the cycloaddition
reaction using 1-benzyl-2-methyleneaziridine (1a) and diyne (2a) as
model compounds were conducted in the presence of several Ni(0)
catalysts (Table 1). When Ni(cod)2 (10 mol%) and N-heterocyclic
carbene (NHC) SIPr (10 mol%) were used as catalysts,10 a formal
[3 + 2] cycloaddition reaction took place at room temperature to afford
pyrrole 3aa in 27% yield (entry 1). Further attempts using IPr, SIMes
or PPh3 as a ligand, which has been successfully applied in other
cycloadditions,11 were completely futile (entries 2–4). Given that Ni(0)
Scheme 1 Metal-catalyzed ring expansion reactions of methyleneaziridines.
species is significantly important in this reaction, we then examined
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan
Road, Dalian 116023, China. E-mail: bswan@dicp.ac.cn; Fax: +86-411-84379223;
Tel: +86-411-84379260
different nickel(0) sources. Unfortunately, in situ generated Ni(0) by
the reduction of Ni(II) salts failed (entries 5–7). Interestingly, the
optimal conditions were eventually obtained using Ni(cod)2 as a
catalyst without other ligands. Screening of the solvent showed that
the reaction proceeded well in 1,4-dioxane giving the desired products
3aa in 60% yield.12 The identity of 3 was unambiguously secured
† Electronic supplementary information (ESI) available: General experimental
procedures, characterization data, 1H and 13C NMR spectra and X-ray crystal-
lographic analysis of compound 3da. CCDC 923335. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c3cc41061g
c
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Table 1 Optimization of reaction conditionsa
The aliphatic Cy-substituted methyleneaziridine gave a lower yield
(3ga) than benzyl-substituted methyleneaziridines (3aa–3fa, entries
1–6). The dimerization of diyne more likely happened under these
conditions than in other cases. Subsequently, the scope of diynes
was investigated. Not only malonate-(2a, 2c, 2d, 2i), but also oxygen-
(2e, 2j), tosylamide- (2f) and CH2-linked (2b) 1,6-diynes could
undergo this coupling. The different ester moieties of the malo-
nate-diynes (2a, 2c, 2d) significantly influenced the yields and the
diethyl malonate-diyne 2c gave better yield. It is noteworthy that
unlike CH2-linked 1,6-diyne 2b gave the product in best yield;
the reaction turned out to be messy when a tosylamide linker
(2f, entry 13) was employed, only giving a trace amount of the
corresponding pyrrole (3af). Unfortunately, terminal 1,6-diynes
(2g, 2h) were also not suitable partners for 1a, and no desired
products were generated due to the rapid diyne dimerization. It
seems that the length of the linker plays a significant role, as no
desired product was detected in the reaction of 1,7-diyne 2k under
the standard conditions (entry 18, versus entry 8). Importantly, when
TMS-protected unsymmetrical 1,6-diynes (2i, 2j) were applied in the
reaction, the corresponding cycloadducts were obtained in moderate
yield with excellent regioselectivity, where a less hindered alkyne unit
participated in the reaction. The steric hindrance of the trimethylsilyl
moiety somewhat inhibited the dimerization of 2j (entry 17), thus
giving better yield than its methyl-substituted analogue 2e (entry 12).
To clarify the effects of the two alkynyl moieties and to under-
stand the mechanism of this process, the reactions of diyne (2a),
eneyne (2l) and monalkyne (2m) with 1a were examined under
optimized conditions (Scheme 2). The reaction of 1,6-eneyne (2l)
only gave a trace amount of the desired product 3ak. In contrast, no
desired product was detected when monalkyne 2m was employed in
the reaction with 1a. These results suggested that (1) the free alkyne
unit on the diyne was crucial to the reactivity, which may play an
intramolecular stabilizing role. (2) The contribution of alkenyl for
similar stabilization was smaller than that of alkynyl.
Entry
Catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
Ni(cod)2/SIPrc
Ni(cod)2/IPrd
Ni(cod)2/SIMese
Ni(cod)2/PPh3
NiCl2/Zn/SIPr
Ni(acac)2/Zn/SIPr
(DME)NiBr2/Zn
(DME)NiBr2/Zn
Ni(cod)2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1,4-Dioxane
27
0
0
0
0
0
0
21
49
60
7
8f
9
10
Ni(cod)2
a
Reaction conditions: 1a (0.5 mmol), 2a (0.2 mmol), 10 mol% catalyst
b
c
and 10 mol% ligand in 1 mL solvent. Isolated yield. SIPr = 1,3-bis-
d
(2,6-diisopropylphenyl)imidazolidin-2-ylidene. IPr
=
1,3-bis(2,6-di-
= 1,3-bis(2,4,6-trimethyl-
e
isopropylphenyl)imidazol-2-ylidene. SIMes
f
phenyl)imidazolidin-2-ylidene. At 60 1C.
by X-ray crystallographic analysis of 3da13 which confirmed the
connectivity and the cleavage of the C2–C3 bond in MAs.
The scope of substrates was explored under the optimal condi-
tions, and the results are summarized in Table 2. Electron-donating
and electron-withdrawing groups on the benzyl moiety of 1 are
compatible, providing the desired products in moderate yields
(entries 2–6). Methyleneaziridines with an electron-donating –OMe
group (1d–1f, entries 4–6) afforded the corresponding products in
better yields compared to those with an electron-withdrawing –Cl
group (1c, entry 3). And, the steric effect may be the primary reason
leading to the different yields of 3da–3fa (3da o 3ea o 3fa).
Table 2 [3 + 2] cycloaddition of MAs 1 with diynes 2a
Based on the above results, a plausible mechanism is depicted in
Scheme 3. Typically, such a cyclization begins with oxidative cou-
pling between Ni(0) and p-electron donors.14 In this case, oxidative
addition would first afford a spirocyclic Ni(II) intermediate A or B,
which is stabilized by a proximal alkyne unit. Intermediate B is more
favored than A as a result of the relatively minor interaction between
the alkyne substituent and the aziridine moiety. Metalacycle B then
undergoes b-carbon elimination to give a six-membered nicklacycle
C. Eventually, reductive elimination occurs to give 2-methylene-2,5-
dihydro-1H-pyrrole 4 and regenerates the catalyst. Product 4 should
Entry 1 (R)
X
R1 R2
3 yield (%)
1
2
3
1a (Bn)
1b (4-MeC6H4CH2)
1c (4-ClC6H4CH2)
2a [C(CO2Me)2] Me Me
2a
2a
3aa (60)
3ba (64)
3ca (45)
3da (51)
3ea (58)
3fa (62)
3ga (40)
3fb (81)
3ab (75)
3ac (72)
3ad (65)b
3ae (33)
3af (5)
Me Me
Me Me
Me Me
Me Me
Me Me
Me Me
Me Me
Me Me
Me Me
4
5
6
1d (2-OMeC6H4CH2) 2a
1e (3-OMeC6H4CH2) 2a
1f (4-OMeC6H4CH2) 2a
7
8
1g (Cy)
1f
2a
2b (CH2)
2b
2c [C(CO2Et)2]
2d [C(CO2Bn)2] Me Me
2e (O)
2f (NTs)
2g [C(CO2Me)2]
2h [C(CO2Me)2]
2i [C(CO2Me)2] Me TMS 3ai (57)
2j (O)
2k (CH2CH2)
9
1a
1a
1a
1a
1a
1a
1a
1a
10
11
12
13
14
15
16
17
18
Me Me
Me Me
H
H
H
Me
3ag (0)c
3ah (0)c
1a
1a
Me TMS 3aj (50)
Me Me
3ak (0)c
a
Reaction conditions: 1 (0.5 mmol), 2 (0.2 mmol), 10 mol% Ni(cod)2 in
b
c
1 mL 1,4-dioxane. At 60 1C. Product could not be detected by GC-MS
of the crude mixture.
Scheme 2 Control experiments.
c
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the possible C–N cleavage of intermediate B to D also existed in
this reaction, it would be difficult to explain that product 5 was
not observed.
In summary, we have developed a Ni-catalyzed [3 + 2] cycloaddi-
tion of methyleneaziridines with diynes to give pyrroles with a free
alkyne unit under mild conditions. This investigation includes a
significant indirect C–C bond activation of three-member azacycles
and represents an alternative strategy for the ring-enlargement of
methyleneaziridines compared with previous C–N bond cleavage.5,6
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cleavage of the methyleneaziridines makes it possible to promote
metal-catalyzed cycloaddition of this three-membered azacycle with
other substrates to give a structure various heterocycles. Further
studies on the mechanism and expanding this strategy to other
reactions are underway.
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Financial support from the National Natural Science Founda-
tion of China (21172218) is gratefully acknowledged.
Notes and references
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13 For molecular structure of 3da (ORTEP drawing), please see the ESI†.
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Chem. Commun., 2013, 49, 5073--5075 5075