Cu(ii)-catalyzed cyclization of α-diazo-β-oxoamides with amines leading to pyrrol-3(2H)-ones

Article abstract of DOI:10.1039/c2cc38473f

A novel Cu(ii)-catalyzed cyclization of α-diazo-β-oxoamides with amines has been developed, constituting a straightforward method to construct pyrrol-3(2H)-one rings. The intramolecular hydrogen bonding effect in α-diazo-β-oxoamides plays an essential role in this reaction. A plausible reaction mechanism involving divergent generation and subsequent [2 + 3] cyclization of ketene and α-diazoimine intermediates was proposed.

Full text of DOI:10.1039/c2cc38473f

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Cu(II)-catalyzed cyclization of a-diazo-b-oxoamides
with amines leading to pyrrol-3(2H)-ones†
Zikun Wang,a Xihe Bi,*bc Peiqiu Liao,b Xu Liua and Dewen Dong*ab
Cite this: Chem. Commun., 2013,
49, 1309
Received 25th November 2012,
Accepted 18th December 2012
DOI: 10.1039/c2cc38473f
www.rsc.org/chemcomm
A novel Cu(II)-catalyzed cyclization of a-diazo-b-oxoamides with
amines has been developed, constituting straightforward
a
method to construct pyrrol-3(2H)-one rings. The intramolecular
hydrogen bonding effect in a-diazo-b-oxoamides plays an essential
role in this reaction. A plausible reaction mechanism involving
divergent generation and subsequent [2 + 3] cyclization of ketene
and a-diazoimine intermediates was proposed.
The readily available a-diazocarbonyl compounds are distinguished
by their unique reactivity through the generation of carbenoid
species, induced thermally, photochemically, or by transition metal
catalysis.1 One important transformation of carbenoids is the Wolff
rearrangement to yield ketenes that are useful in [2 + 2] and [2 + 4]
cycloadditions, nucleophilic and rearrangement reactions.2 On the
other hand, the condensation of a-diazocarbonyls with amines
promoted by Lewis or Brønsted acids generates a-diazoimine inter-
mediates capable of undergoing further reactions such as 1,2-alkyl
Scheme 1 Cyclizations of a-diazo-b-oxoamides with amines in the presence of
different catalysts.
migration, 1,3-dipolar cycloaddition and ring-closure reactions.3,4 the Wolff rearrangement and the condensation.9 Also observed
However, to our knowledge, a reaction between ketenes and was the effect of intramolecular hydrogen bonding in the cycliza-
a-diazoimine intermediates remains unknown, probably due to tion of a-diazo-b-oxoamides essential for this cyclization reaction.
the difficulty of generating both of them in one reaction system.
Pyrrol-3(2H)-one belongs to a class of interesting heterocycles
We have previously realized the first catalytic Wolff 1,2,3-triazole extensively studied by Smith and Hirschmann et al. that consti-
synthesis via the cyclocondensation of a-diazo-b-oxoamides with tutes the key heterocyclic structural core in polypyrrolinone
amines due to the intramolecular hydrogen bonding effect nonpeptidomimetics.10 However, the construction of stable
(Scheme 1).5a,6 As part of our continuing interest in developing pyrrol-3(2H)-one rings is still challenging because of the keto–enol
new reactions based on functionalized b-oxoamides,5 we herein equilibrium with 3-hydroxyl pyrrole.11 So far, this difficulty has
wish to describe an unprecedented copper-catalyzed cyclization been addressed by use of a quaternary carbon centre or exocyclic
of a-diazo-b-oxoamides with amines that afforded pyrrol-3(2H)- double bond to block the 2-position of pyrrol-3(2H)-ones. Hitherto,
ones through formal [2 + 3] cycloaddition of in situ generated only a few synthetic methods are available, including (i) cyclo-
ketene and a-diazoimine intermediates (Scheme 1).7,8 Divalent condensations of a-amino esters with aldehydes,12 vicinal tricarbonyls
copper catalyst plays a dual role in this reaction by inducing both with enamines or amines,13 and amidines with acetylenic esters,14
(ii) [2 + 3] cycloaddition reaction of cyclopropenones with imines,15
a Changchun Institute of Applied Chemistry, Chinese Academy of Sciences,
(iii) hypervalent iodine reagent-mediated cyclization reaction of
enaminones,16 (iv) intramolecular alkylation reaction of 3-hydroxy-
pyrrole-2-carboxylates,17 and (v) ring-closure reactions.18 Invariably,
some of these methods suffer from serious drawbacks such as
multi-step operations, non-readily available reactants and/or lower
product yields. These shortcomings thus appeal the development
Changchun, 130022, China. E-mail: dwdong@ciac.jl.cn
b Department of Chemistry, Northeast Normal University, Changchun, 130024,
China. E-mail: bixh507@nenu.edu.cn
c State Key Laboratory of Elemento-organic Chemistry, Tianjin 300071, China
† Electronic supplementary information (ESI) available: Experimental procedures,
analytical data, and spectra copies of all compounds. CCDC 911645. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c2cc38473f of novel and efficient synthetic methods for pyrrol-3(2H)-ones.
c
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Table 1 Condition screening
Table 2 Cyclization of different a-diazo-b-oxoamides with aniline
Yielda (%)
Entry
1
R1
R2
2a
Yielda (%)
Entry [Cu]
T (1C)
Solvent
Time (h)
2aa
3a
1
2
3
4
5
6
7
8
9
1b
1c
1d
1e
1f
1g
1h
1i
Me
Me
Me
Me
Me
Me
Me
Me
n-Pr
2-MeC6H4
4-MeC6H4
2-MeOC6H4
4-MeOC6H4
2-ClC6H4
2ab
2ac
2ad
2ae
2af
2ag
2ah
2ai
72
78
63
78
60
77
71
70
73
1
2
3
4
CuCl2
90
90
90
90
90
90
90
60
110
90
90
90
90
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
EtOH
Toluene
H2O
8
7
7
6
5
4
4
10
4
5
42
54
76
81
83
0
16
13
Trace
Trace
Trace
0
0
21
0
CuSO4
Cu(OAc)2
Cu(acac)2
CuBr2
CuBr
4-ClC6H4
5
2,4-Me2C6H3
4-CF3C6H4
C6H5
6b
7b
8
CuI
0
0
1j
2aj
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
a
9
71
77
Trace
nr
Isolated yields.
10
11
12
13c
Trace
36
nr
10
20
15
Several aromatic amines bearing different substituents on the
phenyl ring were subjected to reactions with a-diazo-b-oxoamides
and afforded products 2ba–2bd in good to high yields. Similarly,
aliphatic amines such as n-butylamine, cyclopropylamine, allyl-
amine also displayed conformity to this cyclization by furnishing
the corresponding N-functionalized pyrrol-3(2H)-ones 2be–2bh in
moderate to good yields.
Ammonium acetate (NH4OAc) as the amine source was also
explored with regard to assembling N-unsubstituted pyrrol-
3(2H)-ones. Under slightly modified conditions, corresponding
N-unsubstituted pyrrol-3(2H)-ones such as 2ca and 2cb were
obtained in good yields (eqn (1)). The presence of 0.5 equivalent
of p-toluenesulfonic acid (TsOH) was pivotal for an efficient
transformation, which was ascribed to assisting the condensa-
tion of a-diazo-b-oxoamides 1 with ammonium acetate.4
Trace
43
a
b
c
Isolated yields. Unidentified mixture was formed. Tetrabutyl
ammonium bromide (TBAB) (10 mol%) was added.
Our procedure described in this communication provided a straight-
forward method to construct pyrrol-3(2H)-one rings with simulta-
neous formation of a quaternary carbon center at the 2-position.
Initial survey on reaction parameters, including copper catalyst,
temperature and solvent, was carried out with the reaction of a-diazo-
b-oxoamide 1a and aniline as a model. Some key results are summari-
zed in Table 1. At 90 1C in DMF, treatment of the model substrates
with CuSO4 and CuCl2 all resulted in a mixture of pyrrol-3(2H)-one 2aa
and 1,2,3-trizaole 3a, albeit the ratio of 2aa being a little higher (entries
1 and 2). The structure of 2aa was unambiguously confirmed by X-ray
diffraction (CCDC 911645). Other divalent copper salts such as
Cu(OAc)2, Cu(acac)2 and CuBr2 under the same conditions produced
2aa in high yields with only trace amount of 3a (entries 3–5). However,
CuBr2 was much more robust, offering 83% yield of the target within
5 h. On the contrary, cuprous catalysts such as CuBr and CuI under
identical conditions afforded unidentified mixtures (entries 6 and 7).
The reaction temperature also remarkably influenced the yield of
products. For instance, when the reaction temperature was reduced to
60 1C, poor yield of triazole 3a (21%) was obtained without formation
of 2aa (entry 8), while a higher temperature of 110 1C exclusively
generated 2aa in 71% yield (entry 9). Further, solvent screening
disclosed that except for DMSO (entry 10), other solvents such as
toluene, EtOH and H2O were inappropriate (entries 11–13). The poor
solubility of substrate 1a in these solvents may account for these
observations. As a result, the reaction conditions listed in entry 5 were
optimal and hence selected for further investigation.
(1)
Further, in order to probe the effect of the intramolecular
hydrogen bonding in a-diazo-b-oxoamides 1 several a-diazocarbonyl
In the presence of a catalytic amount of CuBr2 (10 mol%), a range
of a-diazo-b-oxoamides with varying R1 and R2 groups were prepared
and utilized in the cyclization reaction with aniline. As shown in
Table 2, these substrates all smoothly reacted with aniline to give
corresponding pyrrol-3(2H)-ones 2ab–2aj in moderate to good yields.
It is worth noting that the electronic effect of the substituent on the
phenyl ring (R2) played no significant role in the reactions.
The scope of the amines was examined in the reaction with
a-diazo-b-oxoamide 1a and the results are summarized in Scheme 2. Scheme 2 Cyclization of a-diazo-b-oxoamide 1a with different amines.
c
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Although a-diazocarbonyl compounds have been widely
studied over hundred years,1,3 the reaction described in this
communication represents an unprecedented reaction pattern
in the chemistry of a-diazocarbonyls.
Financial support by National Natural Science Foundation of
China (21172211, 21172029), ‘‘Hundred Talents Program’’ of the
Chinese Academy of Sciences, and Fundamental Research Funds
for the Central Universities (11CXPY005) is acknowledged.
Notes and references
Scheme 3 Probing the effect of hydrogen bonding.
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Scheme 4 A plausible reaction mechanism.
compounds (S1–S4) were prepared and subjected to the standard
reaction conditions (Scheme 3). Interestingly, we observed that
a-diazocarbonyl S1 was unreactive and compounds S2 and S3
resulted in an unidentified mixture, while that compound S4 afforded
an unexpected isatin derivative S4-a in 61% yield, for which a copper
carbenoid aromatic C–H insertion might be involved.6,9 These obser-
vations are consistent with our previous study5a in that the intra-
molecular hydrogen effect in a-diazo-b-oxoamides 1 is also necessary
in the current Cu(II)-catalyzed cyclization, probably aiding the genera-
tion of the a-diazoimine intermediate under the catalytic conditions.
Two possible reactive precursors, a-diazo-b-imine and ketene,
can be generated through retrosynthetic disconnection of pyrrol-
3(2H)-one 2aa. Consequently, a Lewis acid-catalyzed condensation
and a Cu–carbene pathway should take place simultaneously in
the cyclization of a-diazo-b-oxoamide 1a with aniline; otherwise
2aa would be difficult to be formed. On the basis of the above
results and analysis, a plausible reaction mechanism is proposed
and depicted in Scheme 4. Firstly, condensation of 1a with aniline 12 A. B. Smith III, M. C. Guzman, P. A. Sprengeler, T. P. Keenan,
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catalyst, to generate intermediate i that tautomerizes to i0.
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tion of 1a with CuBr2 followed by the subsequent loss of N2 and
further transformation of this intermediate into ketene iii through
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15 M. A.-M. Gomaa, J. Chem. Soc., Perkin Trans. 1, 2002, 341.
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intermediates iii and i0 occurs leading to pyrrol-3(2H)-one 2aa.19
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18 (a) A. V. Dobrydnev, T. A. Volovnenko, Y. M. Volovenko,
concerted or stepwise, still remains unclear at the present time.
In conclusion, a novel Cu(II)-catalyzed cyclization of a-diazo-
b-oxoamides with amines has been developed, providing a
straightforward method to construct pyrrol-3(2H)-one rings.
G. V. Palamarchuk and O. V. Shishkin, Monatsh. Chem., 2012,
´
143, 779; (b) N. Gouault, M. Le Roch, C. Cornee, M. David and
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philes, see: Y. Zhang and J. Wang, Chem. Commun., 2009, 5350.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 1309--1311 1311