Iron-catalyzed carbonylative cyclization of γ,δ-unsaturated aromatic oxime esters to functionalized pyrrolines

Article abstract of DOI:10.1039/d0cc02784g

Herein, a new method of iron-catalyzed carbonylative cyclization of γ,δ-unsaturated aromatic oxime esters to functionalized pyrrolines has been developed. By using readily available substrates, 32 examples of functionalized pyrrolines were prepared in moderate to good yields. Notably, examples of reduction and cycloaddition reactions of the obtained product were given as well. This journal is

Full text of DOI:10.1039/d0cc02784g

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DOI: 10.1039/D0CC02784G
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Iron-Catalyzed Carbonylative Cyclization of γ,δ-Unsaturated
Aromatic Oxime Esters Toward Functionalized Pyrrolines
Youcan Zhang, Zhiping Yin, Hai Wang, and Xiao-Feng Wu*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
developed a series of iminyl radical-mediated carbonylation
reactions of oxime esters.9 In the carbonylative reaction ofN-
fluoro-sulfonamides, we found the sulfonamide group was
not possible to remove from the obtained products.10 This
disadvantage will definitely limit the further applications of
this procedure, besides the drawbacks from the substrates.
Hence, a new methodology from readily available starting
materials without the above discussed weaknesses is highly
demanded.
Herein, a new method on iron-catalyzed carbonylative cyclization
of γ,δ-unsaturated aromatic oxime esters to functionalized
pyrrolines has been developed. By using readily available
substrates, 32 examples of functionalized pyrrolines were prepared
in moderate to good yields. Notably, examples on reduction and
cycloaddition reactions of the obtained product were given as well.
Intramolecular amination of alkenes is a valuable and
powerful synthetic tool for preparing nitrogen-containing
heterocycles such as piperazine, pyrroline, oxazolidin-2-one,
pyridine, indoline, oxindole and lactam derivatives.1 Among
these heterocyclic units, pyrrolines are important
heterocyclic motifs in the fields of naturally occurring
products and bioactive compounds,2 such as the special
applications of β-homoprolines in
biology and
pharmacology.3 In this regard, unsaturated oxime esters as a
class of readily available and highly reactive substrates have
been successfully employed in constructing a series of
functionalized pyrrolines in the presence of metal or
photocatalyst under mild reaction conditions (Scheme 1a).4
Notably, Bower and co-workers reported their detailed
studies on palladium-catalyzed cyclization of unsaturated
oxime esters in 2015.4a The desired 1,2-carboamination
products were produced in good yields with alcohols and
organometallic reagents as the coupling partners. By
performing the reaction under CO atmosphere (1 bar), the
corresponding carbonylation products can be produced in an
effective manner as well. Several alternative synthetic
procedures relied on specific substrates, stoichiometric
Scheme 1. Functionalized pyrrolidines synthesis from
strong oxidants, or precious transition-metal catalyst have oxime esters.
been established as well.5-7
On the other hand, carbonylation is known as one of the
Considering the intramolecular amination of alkenes and
most effective methods to introduce carbonyl functional
the carbonylation of radicals,11 we become interested in
exploring a new method for the synthesize of functionalized
pyrrolines from γ, δ-unsaturated oxime esters. This strategy
may be achieved through transition-metal catalyzed O-N
bond activation of oxime esters to generate iminylradicals,4,12
followed by an intramolecular cyclization to obtain new
carbon radicals, which subsequently captured by CO and
group into the target molecules.8 Recently, our group has
a.Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Straße
29a, 18059 Rostock, Germany, E-mail: xiao-feng.wu@catalysis.de
Electronic Supplementary Information (ESI) available: [General comments, general
procedure, optimization details, analytic data and NMR spectrums]. See
DOI: 10.1039/x0xx00000x
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PhCF3 instead of DCE
THF instead of DCE
7
75
finally been converted into the corresponding products
(Scheme 1b).
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DOI: 10.1039/D0CC02784G
8
19
no ligand, L1 or L4 instead of L2
L3 or L5 instead of L2
In order to establish the catalyst system, we used 1-
phenylpent-4-en-1-one O-benzoyloxime 1a-1, MeOH (50 uL)
as the model substrate and nucleophile, respectively.
Initially, the reaction was performed with FePC (Iron(II)
phthalocyanine)as the catalystin DCE under 50 bar of CO at
100 °C. The desired product 2aawas produced in 67% (Table
1, entry 1). However, only trace amount of 2aa could be
detected when Fe(OTf)3 or Cu(OTf)2 with 1,10-Phen·HCl·H2O
was tested as the catalytic system (Table 1, entry 2). FeF3 as an
iron precursor was tested as well, 38% of the target product
was formed (Table 1, entry 3). No desired molecule was
observed in the absence of an iron catalyst (Table 1, entry 4).
Satisfactorily, 80% of methyl 2-(5-phenyl-3,4-dihydro-2H-
pyrrol-2-yl)acetate 2aa was determined with Fe(acac)3 and
1,10-Phen·HCl·H2O as the catalytic system (Table 1, entry 5).
Then some other solvents were examined, including MeCN,
PhCF3 and THF, no improved results were obtained (Table 1,
entries 6-8). Different ligands were subsequently tested,
which indicated that the ligand had a dramatic effecton this
reaction, and 1,10-Phen·HCl·H2O was found to be the best
than the other tested ligands (Table 1, entries 9-11). Only
traces of product 2aa was found in the absence of ligand. As
carboxylic acid mightbe the byproduct, 1.2 equiv. of HOAc as
additives was tested and little influence was obtained (Table
1, entry 12). However, adding 1.2 equiv. of pyridine led to the
yield of 2aa diminished to 46% (Table 1, entry 13). And no
desired product could be detected when other organic base
(Et3N) or inorganic base (Na2CO3) was added (Table 1, entry
14). Finally, lowing the temperature to 80 °C, the pressure of
CO to 40 bar or the loading of ligand to 5 mol% lead to a
slightly decreased yield of the final product (Table 1, entries
15-17).
9
trace
n.d.
38
10
11
L6 instead of L2
added 1.2 equiv. HOAc
12
13
14
15
16
17
81
added 1.2 equiv. pyridine
added 1.2 equiv. Et3N or Na2CO3
80 oC instead of 100 oC
46
n.d.
74
CO 40 bar instead of 50 bar
L2 5 mol% instead of 10 mol%
73
75
aReaction conditions: 1a-1 (0.1 mmol), MeOH (50 uL), catalysts (5mol%),
ligands (10 mol%) in solvent (1 mL) at 100 oC for 20 h under CO (50 bar).
bYields were determined by GC-FID analysis using n-hexadecane as
internal standard. cIsolated yield (1a-1 0.2 mmol scale). n.d.= no
detection. FePC = iron(II) phthalocyanine. THF = tetrahydrofuran. DCE
= 1,2-dichloroethane.
Additionally, different leaving groups (LG) of the oxime
esters 1a substrates were also examined (Table 2). The yield
of 2aa dramatical decreased when OAc was used as the
leaving group instead of OBz. Other aryl or heterocyclic
substituted leaving groups were checked and no better
results were obtained under the optimalreaction conditions.
Table 2. Optimization of oxime ester leaving groups.a
entry
yieldb (%)
LG
OBz (1a-1)
OAc (1a-2)
OBz5F (1a-3)
1
80
12
Table 1. Optimization of reaction conditions.a
2
3
4
78
46
(1a-4)
(1a-5)
5
72
68
6
(1a-6)
aReaction conditions: 1a (0.1 mmol), MeOH (50 uL), Fe(acac)3 (5 mol%),
1,10-Phen·HCl·H2O (10 mol%) in DCE (1 mL) at 100 oC for 20 h under CO
(50 bar). bYields were determined by GC-FID analysis using n-
hexadecane as internal standard.
Having established the optimized reaction conditions, we
started to explore the substrate scope of this reaction with
different alcohols and unsaturated aromatic oxime esters.
Firstly, a series of alcohols were reacted with oxime esters 1a-
1 (Scheme 2). Some low boiling point primary alkyl alcohols
like methanol, ethanol, propanol, and n-butanol were all
reacted well with oxime esters 1a-1 to form the desired
products 2aa-2ad in 56%-72% yields. Even isopropanol as
secondary alcohol and t-butanol as sterically hindered
tertiary alcohol were also smoothly converted into the target
variations from the standard conditions
entry
yieldb (%)
FePC instead of Fe(acac)3 and ligand
Fe(OTf)3 or Cu(OTf)2 instead of Fe(acac)3
FeF3 instead of Fe(acac)3
no Fe(acac)3
1
67
trace
38
2
3
4
5
6
n.d.
80 (72)c
-
MeCN instead of DCE
66
2 | J. Name. , 2012, 00, 1-3
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products 2ae and 2af in 50% and 17% yields, respectively. possibly due to the competitive conversion of 5-exo-trig
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14
Additionally, a series of halogen-substituted aliphatic cyclization13 and 1,5 H-atom transfer (HAT) during the
DOI: 10.1039/D0CC02784G
alcohols can be applied as well and gave the corresponding reaction. To further explore the applicability of this
products 2ag-2aj in moderate yields. Furthermore, alcohols procedure, we used substrates 1t and 1u to inspect the
with a terminalalkenyl unit were also tolerated, affording the carbonylation of secondary and tertiary carbon radicals,
desired products 2ak and 2al in 51% and 48% yields, respectively. Delightfully, 50% of methyl 2-(5-phenyl-3,4-
respectively. Notably, benzylalkohol and furfurylalkohol as dihydro-2H-pyrrol-2-yl)propanoate 2tacan be prepared from
high boiling point alcohols can also be applied, the desired carbonylation of the corresponding secondary radical
carbonylation products 2am and 2an were provided in intermediate. However, the tertiary radicalintermediate was
moderate to good yields. To further explore the synthetic only converted into the elimination products, which were
value of this protocol, a 1.0 mmol scale reaction of 1a-1 with detected by GC-MS. Unfortunately, the oxime esters with
methanolwas carried out under the best reaction conditions, furan (1o), different carbon chain lengths (1v 1-phenylhex-5-
the corresponding product 2aawas delivered in 65% isolated en-1-one O-benzoyloxime, and 1w 1-phenylbut-3-en-1-one O-
yield.
benzoyl oxime) or alkyl oxime ester (1x hex-5-en-2-one O-
benzoyloxime)were failed to give the desired products.
Scheme 2. Scope of alcohols.a
Scheme 3. Scope of O-benzoyloximes.a
aReaction conditions: 1 (0.2 mmol), ROH (0.1 mL), Fe(acac)3 (5 mol%), 1,10-
Phen·HCl·H2O (10 mol%) in DCE (2 mL) at 100 oC for 20 h under CO (50
bar), isolated yield. b1a-1 (1.0 mmol), MeOH (0.5 mL), DCE (7 mL). cROH (2
equiv.).
Subsequently, a range of aromatic and heteroaromatic
oxime esters were prepared and investigated (Scheme 3). In
general, both electron-withdrawing and donating
substituents on different positions of the aromatic ring were
all smoothly transformed, supplying the corresponding
products 2ba-2ia in moderate yields. Perfluorinated
substrate 1j 1-(perfluorophenyl)pent-4-en-1-one O-benzoyl
oxime was also converted into the corresponding product
2ja. Other substrates including 1-naphthalene, 2-
naphthalene and thiophene, even adamantane substituted
O-benzoyl oximes can all be applied and gave moderate
yields of the corresponding products. Moreover, a panel of
substrates with different alkyl chain units on the α position
of O-benzoyl oximes afforded the corresponding products
2pa-2sa in moderate yields. Relatively low yield formed 2ra,
aReaction conditions: 1 (0.2 mmol), ROH (0.1 mL), Fe(acac)3 (5 mol%),
1,10-Phen·HCl·H2O (10 mol%) in DCE (2 mL) at100 oC for 20 h under CO
(50 bar), isolated yield.
Moreover, the obtained product 2aacan be easily reduced
to 3 in high yield by a PtO2-catalyzed hydrogenation reaction
in MeOH under 30 bar hydrogen (Scheme 4, eq 1).4a
Additionally, by using triethylamine as the base, a cyclization
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J. Name. , 2013, 00, 1-3 | 3
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reaction between 2aa and N-hydroxybenzimidoyl chloride
can occur at room temperature (Scheme 4, eq 2). The
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Conflicts of interest
There are no conflicts to declare.
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