An Unprecedented Organocascade Synthesis of Functionalized Bicyclic Nitrones from 2-Aminomalonate Derived Nucleophiles and 1-Nitro-1,3-Enynes via Allenes Formation and Subsequent Rearrangement

Article abstract of DOI:10.1002/adsc.201801161

An efficient organocatalytic cascade reaction for synthesising functionalized bicyclic nitrones is reported. The reaction of dielectrophilic ethyl 2-(nitromethylene)-4-arylbut-3-ynoate and (E)-diethyl 2-((2-hydroxybenzylidene)-amino)malonates to give a un

Full text of DOI:10.1002/adsc.201801161

Title: An Unprecedented Organocascade Synthesis of Functionalized
Bicyclic Nitrones from 2-Aminomalonate Derived Nucleophiles
and 1-Nitro-1,3-Enynes via Allenes Formation and Subsequent
Rearrangement
Authors: Kwunmin Chen, Wan-Wun Huang, and Ramani
Gurubrahamam
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10.1002/adsc.201801161
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
An Unprecedented Organocascade Synthesis of Functionalized
Bicyclic Nitrones from 2-Aminomalonate Derived Nucleophiles
and 1-Nitro-1,3-Enynes via Allenes Formation and Subsequent
Rearrangement
Wan-Yun Huanga, Ramani Gurubrahamama, and Kwunmin Chena*
a Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan 11677
Fax: (+886)-2-2932-4249; phone: (+886)-2-7734-6124; e-mail: kchen@ntnu.edu.tw
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An efficient organocatalytic cascade reaction for
synthesising functionalized bicyclic nitrones is reported. The
reaction of dielectrophilic ethyl 2-(nitromethylene)-4-
arylbut-3-ynoate and (E)-diethyl 2-((2-hydroxybenzylidene)-
amino)malonates to give a unique nitrone scaffold in the
presence of a catalytic amount of DABCO is described. The
working mechanism was proposed to proceed with allene
formation followed by intramolecular cyclization and the
rearrangement of an oxygen atom in the nitro group. A broad
range of substrates was accessed in this facile chemical
transformation, in which the bicyclic nitrones were isolated
in moderate to good yields (19% to 79%) with excellent
diastereoselectivity (>20:1 dr).
Bicyclic nitrones
Keywords:, 1-Nitro-1,3-Enynes, Allene, Rearrangement,
Introduction
Nitrogen-containing substances are of significant
importance in organic synthesis because these
compounds are valuable intermediates in the synthesis
of diverse naturally occurring complex molecules and
potential medicinal applications.[1,2] Distinct among
these functional groups, the nitrone group has served
as an essential moiety in the synthesis of nitrogenous
heterocycles and has demonstrated its synthetic utility,
including for 1,3-dipolar cycloadditions.[3] Although
various approaches have been established for
synthesising nitrones under both metal-mediated[4]
and metal-free[5] reaction conditions starting from
secondary amines,[6] hydroxyamines,[7]
imines,[8]
oximes,[9] nitroalkanes,[10] etc., general strategies
remain elusive. On the other hand, the development of
organocascade reactions has emerged as an efficient
organic synthetic strategy to construct complex
chemical scaffolds.[11] The use of conjugate nitro-1,3-
enynes and related derivatives in this protocol has
received much attention in recent years, including 2-
nitro-1,3-enynes (1),[12] 1-nitro-1,3-enynes (2)[13] and Figure 1. Structures of various nitroenynes 1-4 and their
alkyne-tethered nitroalkenes (3).[14] Numerous
synthetic applications.
chemical scaffolds that include nitrochromans
(Xu),[12a] pyrano-annulated derivatives
1
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10.1002/adsc.201801161
Advanced Synthesis & Catalysis
(Chen,[12b,c] Samanta,[12d] Singh[12e]), substituted 19% yield of 6a was achieved (Table 1, entry 8).
pyrrole/thiophenes
(Punniyamurthy),[12f-h] Presumably, this could be attributed to the lack of
tetrahydrofuranyl ethers (Krause, Alexakis),[13a] formation and stabilization of zwitterionic product 6a
spirooxindole (Zhou),[13b] pyrano-annulated pyrazoles in nonpolar solvents than it is in polar solvents.
(Enders),[13c] and spiropyrazolones (Schoenebeck, Etherated solvents, such as 1,4-dioxane and THF
Enders)[14] were prepared using these electron were not suitable for this reaction as they provide 6a
deficient enynes under either organocatalytic reaction with only in 24% and 18% yield, respectively (Table
conditions or sequential organocatalysis and metal 1, entries 9 and 10). Then, polar solvents such as ethyl
catalysis (Figure 1).
acetate (EA) and acetonitrile were investigated;
In continuation of our efforts on organocatalytic unfortunately, the low yields of products 6a and 7a
reactions on electron deficient alkynes,[12b-c, 15], herein, were revealed (Table1, entries 11 and 12).
we report an unprecedented example for synthesis of
Table 1. Screening of temperature, organocatalyst and
functionalized bicyclic nitrones 6 from dielectrophilic
ethyl 2-(nitromethylene)-4-arylbut-3-ynoate 4 and 2-
solvent in organocascade synthesisa
aminomalonate
derived
(E)-diethyl
5.
2-((2-
The
hydroxybenzylidene)amino)malonates
organocascade process was believed to proceed via
conjugate addition, in situ generation of allenes[16] and
subsequent rearrangement.[17]
6a
Yield
[%]b
53
42
57
58
12
28
11
19
24
18
17
16
diethyl
7a
Yield
[%]b,c
17
14
12
9
30
9
31
20
9
19
18
12
(2-(2-
Results and Discussion
temp.
(oC)
entry
cat.
Solvent
We initiated the study by using ethyl 2-
(nitromethylene)-4-phenylbut-3-ynoate (4a)[18] and
(E)-diethyl 2-((2-hydroxy-benzylidene)amino)malon
ates 5a in the presence of a Brønsted base (DABCO:
1,4-diazabicyclo[2.2.2]octane). The reaction was
carried out to yield two products at ambient
temperature in CHCl3. The minor product was
identified as an imine derived enyne 7a, while the
major product was characterized as a unique scaffold
of hexahydropyrrolo[3,4-b]pyrrole 1-oxide 6a (Table
1, entry 1). The chemical structures of both products
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
CCl4
Toluene
1,4-dioxane
THF
1
2
3
4
5
6
7
8
9
10
11
12
aTo
DABCO rt (18.1)
DABCO
DABCO
DABCO
N-MM
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
30
40
50
50
50
50
50
50
50
50
50
1
were initially assigned by H-NMR, 13C-NMR and
EA
CH3CN
HRMS analyses.[19] The unique chemical structure of
the nitrone product 6a is intriguing, as the reaction
proceeded with multi-transformations. To improve the
chemical outcome of this transformation, we tried to
examine the reaction temperature factor, which was
gradually increased from 30 to 50 oC (Table 1, entries
2-4). Fortunately, we were able to minimize the
formation of side product 7a (9% yield) at higher
a
stirred
solution
of
hydroxyphenyl(imino))malonate 5a (0.1 mmol), catalyst (20
mol%) and CHPh3 (as an internal standard, 1.0 equiv.) was added
enynoate 4a slowly at 50 oC. The reaction was monitored by
TLC, after enynoate 4a was fully consumed, the reaction was
quenched with H2O.
bIsolated yield.
cDuring the optimization of the reaction conditions, a side
reaction product was isolated and characterized. The chemical
structure of the side product was temporarily assigned (7a). The
reaction was believed to proceed through the addition/elimination
reaction.
o
reaction temperature (50 C). Furthermore, the yield
of five-membered bicyclic pyrrole scaffold 6a was
also increased to 58% (Table 1, entry 4). Then, we
turned our attention to screen the utility of various
Brønsted bases in the reaction. The amine base, N-
methyl morpholine (N-MM) has afforded inferior
result as the desired product 6a was observed only in
12% yield, besides addition/elimination product 7a in
30% yield (Table 1, entry 5). Other organic bases
including imidazole, DMAP, Et3N, DIPEA, and DBU
failed to provide the desired product 6a, and the
production of 7a was dominated instead. Based on
these results, we made an attempt to improve the yield
of 6a by optimizing the reaction solvent. Other
chlorinated solvents, such as CH2Cl2 and CCl4 failed
to improve the chemical yield of 6a, and the yields
were dropped to 28% and 11%, respectively (Table 1,
entries 6 and 7). The applicability of nonpolar
solvents such as toluene were evaluated, and only a
DABCO: 1,4-Diazabicyclo[2.2.2]octane; N-MM: N-methyl
morpholine; THF: Tetrahydrofuran; EA: Ethyl acetate.
To further improve the chemical yield of nitrone 6a,
the adjustment of the amount of enynoate 4a and the
catalyst was studied. In the presence of 1.5 equiv. of
enynoate 4a and DABCO (30 mol%), 64% yield of
the major product 6a was obtained along with 2% of
the side product 7a (Table 2, entry 1). Comparable
results were observed when either 1.8 or 2.0 equiv. of
enynoate 4a was used (Table 2, entries 2 and 3). The
maximum chemical yield of nitrone 6a was achieved
when 1.8 equiv. of nitro enyne 4a and 20 mol% of
DABCO was introduced, which minimizes the
2
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10.1002/adsc.201801161
Advanced Synthesis & Catalysis
formation of addition/elimination side product 7a yields, which is interesting in this sequential
(Table 2, entry 4). Next, an attempt was studied to transformation. The heteroaryl substituent of
decrease the loading of organocatalyst (10 mol% and thiophene was subjected to the reaction, and
5 mol%), however, this led significant decrement in satisfactory results were obtained (6o: 57%). Finally,
formation of bicyclic nitrone 6a (Table 2, entries 5 if the reaction was carried out in the absence of an
and 6).
ortho-hydroxy group in iminomalonate 5b ((E)-
diethyl 2-(benzylidene)amino)malonate), the reaction
failed to proceed well and only a 33% yield of nitrone
6p was produced (compared with that of 6a). This
result may indicate the crucial role of ortho-hydroxy
group which increases the electrophilicity of imine
through intramolecular hydrogen bonding and further
Table 2. Optimization of the reaction conditionsa
facilitates
the
intramolecular
Mannich-type
cyclization (see mechanism in Scheme 1).
Table 3. Substrate scope.a
4a
(equiv.)
1.5
1.8
2.0
1.8
1.8
1.8
DABCO
(mol%)
30
6a
7a
entry
Yield [%]b
Yield [%]c
1
2
3
4
5
6
64
68
62
75
54
40
2
3
2
2
2
2
30
30
20
10
5
aA solution of diethyl (2-(2-hydroxyphenyl(imino))malonate 5a
(0.10 mmol) and DABCO in CHCl3 (600 μL) was slowly added
o
to a stirred solution of enynoate 4a in CHCl3 (400 μL) at 50 C.
1
The reaction was monitored by crude H-NMR, after malonate
derivative 5a was fully consumed, the reaction was quenched
with H2O.
bIsolated yield.
cDetermined by crude 1H-NMR using CHPh3 as internal
standard.
DABCO: 1,4-Diazabicyclo[2.2.2]octane
With the optimal reaction conditions in hand, we
surveyed the influence of different substituents in this
sequential transformation (Table 3). The chemical
yields remained the same (79% to 58%) when the 2-
ester group in the nitro enynoate 4 was replaced with
isopropyl (6b), t-butyl (6c), allyl (6d), or benzyl (6e),
indicating that the steric hindrance exerts limited
influence on the conjunction centre of the bicyclic
system. However, steric hindrance is crucial for aryl
substituents in nitro enynoates 4. The chemical yield
of nitrone 6f dropped to 19% when the 2-methyl
phenyl group was present, while 28% of the
addition/elimination product 7f was also isolated.
This result may be due to the significant steric
repulsion between the 2-methyl group and the
functionalities in close proximity. The chemical
yields rebounded to 73% and 68% yield (6g and 6h,
respectively) when the methyl substituent was at
either the meta or para position in the aryl group.
Similar results were observed when the t-butyl and
methoxy groups were examined (67% of 6i and 76%
of 6j). The chemical yields decreased (46-55% for
6k-6m) when meta or para-halo substituents were
used in the aryl group of 4. The strong electron-
withdrawing group of 4-CF3C6H4 failed to perform
well in the nitrone product formation, and only a 23%
yield of 6n was obtained. The general scenario is that
the electron-donating group provides better chemical
aAll reactions were carried out with amino malonate
derivative 5 (0.10 mmol, 1 equiv.) and enynoate 4 (0.18
mmol, 1.8 equiv.) under DABCO (20 mol%) catalysis in
CHCl3 at 50 oC.
We have attempted to profile a reasonable mechanism
by using high resolution mass spectrometry to
identify the reaction intermediates. An aliquot of the
reaction mixture was taken out after 3 min and
submitted for analysis. Three significant m/z peaks
were revealed, m/z = 525.1872, 547.1693, and
637.2868. The ambiguous m/z values of 525.1872
([524.1795+H]+) and 547.1693 ([524.1795+Na]+),
might either come from the allene intermediate or
final product because these two species have the same
exact mass. The intermediate after nucleophilic attack
3
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10.1002/adsc.201801161
Advanced Synthesis & Catalysis
by DABCO was detected, with its m/z equals to elimination of one molecule of nitrous acid and
637.2868 (Figure 2).
protonation.
Conclusion
In conclusion, we demonstrated a feasible strategy to
obtain a unique skeleton of bicyclic nitrones 6 by
treatment of 1-nitro-1,3-enynes
aminomalonate-derived nucleophiles
4
with 2-
in the
5
Figure 2. Intermediate identification by HRMS.
presence of DABCO (20 mol%). All reactions could
be completed within 4 h, and afforded the products
with moderate to good yields (19-79%) with excellent
diastereoselectivity. The highest yield was obtained
when aryl of the enynoate 4 contains the electron-
donating group. A possible mechanism for the
formation of bicyclic nitrone 6 was proposed that
proceed by sequential conjugate addition, alkynoate
isomerization to allenoate,[21] cyclization, Mannich-
type reaction, rearrangement of the oxygen atom of
the nitro group, and deprotonation. Further study of
related 1,3-enynes is underway in our laboratory.
Experimental Section
Diethyl (2-(2-hydroxyphenyl(imino))malonate 5 (0.10
mmol) and DABCO (20 mol%) in CHCl3 (600 μL)
were slowly added to a stirred solution of nitro 1,3-
enynoate 4 (0.18 mol) and CHPh3 (1.0 equiv.) in
CHCl3 (400 μL) at 50 oC. The reaction was monitored
1
by crude H-NMR spectrum analysis. After complete
consumption of the malonate derivative 5, the
reaction was quenched with H2O and extracted with
CH2Cl2. The organic phases were collected, dried
over MgSO4 and evaporated to obtain the crude
residue. The crude product was purified by flash
column chromatography using EtOAC/hexanes as
eluent to yield the corresponding nitrones 6.
Scheme 1. Proposed reaction mechanism.
Acknowledgements
We thank the Ministry of Science and Technology of
the Republic of China (MOST 106-2113-M-003-013)
for financial support of this work.
A plausible mechanism is depicted in Scheme 1. The
enynoate 4a was attacked by the deprotonated
iminomalonate 8 through conjugate addition to give
propargylic anion intermediate B, which has a
resonance form of allenic anion intermediate C. An
active allenoate E could be formed after facile
protonation of C (route b).[20] The allenoate E would
participate in favoured 5-endo-dig cyclization via
nucleophilic addition of the proximal oxygen atom of
the nitro group to give F, which contains a five
membered-ring. A bicyclic intermediate G could be
obtained via an intramolecular Mannich-type reaction
of F. The bicyclic ring opening reaction could occur
by the addition of DABCO to form H, which would
be re-cyclized to give intermediate I (detected by
HRMS). Subsequent deprotonation step to afford the
bicyclic nitrone product 6.[19] The side product 7a was
also observed in the reaction, which could be formed
from intermediate B (route a) upon sequential
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Advanced Synthesis & Catalysis
FULL PAPER
An Unprecedented Organocascade Synthesis of
Functionalized Bicyclic Nitrones from 2-
Aminomalonate Derived Nucleophiles and 1-Nitro-
1,3-Enynes via Allenes Formation and Subsequent
Rearrangement
Adv. Synth. Catal. 2018, Volume, Page – Page
Wa-Yun Huang, Ramani Gurubrahamam, and
Kwunmin Chen
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