Synthetic strategies for the synthesis and transformation of substituted pyrrolinones as advanced intermediates for rhazinilam analogues

Article abstract of DOI:10.1002/ejoc.201402903

The biaryl core structure of rhazinilam with its fixed dihedral angle is a pivotal element for its unique in vitro cytotoxic activity. Most of the related natural products are oxidized versions of rhazinilam. Replacing the sensitive pyrrole ring by a pyrrolinone ring is the basis of our initial strategy towards rhazinilam analogues. With this goal, variants of the sequence crossed Mukaiyama aldol reaction followed by the Staudinger reaction were studied. Reacting a suitably substituted acetophenone with O-methyl O-trimethylsilyl ketene acetal gave pyrrolinones 8a and 8b in good to excellent yields. These intermediates could be transformed in four high-yielding steps into the pyrrolic precursors 7a-c containing all the atoms necessary for the construction of rings A, B, and C of rhazinilam. Our studies illustrate a lack of stability of these intermediates. Alternative synthetic approaches towards this central biaryl core structure are described.

Full text of DOI:10.1002/ejoc.201402903

FULL PAPER
DOI: 10.1002/ejoc.201402903
Synthetic Strategies for the Synthesis and Transformation of Substituted
Pyrrolinones as Advanced Intermediates for Rhazinilam Analogues
Inga Kholod,[a] Olivier Vallat,[b] Ana-Maria Buciumas,[c] Antonia Neels,[d][‡] and
Reinhard Neier*[a]
Dedicated to Pierre Vogel on the occasion of his 70th birthday
Keywords: Synthetic methods / Natural products / Aldol reactions / Fused-ring systems / Nitrogen heterocycles
The biaryl core structure of rhazinilam with its fixed dihedral
angle is a pivotal element for its unique in vitro cytotoxic
activity. Most of the related natural products are oxidized
versions of rhazinilam. Replacing the sensitive pyrrole ring
by a pyrrolinone ring is the basis of our initial strategy
towards rhazinilam analogues. With this goal, variants of the
sequence crossed Mukaiyama aldol reaction followed by the
Staudinger reaction were studied. Reacting a suitably substi-
tuted acetophenone with O-methyl O-trimethylsilyl ketene
acetal gave pyrrolinones 8a and 8b in good to excellent
yields. These intermediates could be transformed in four
high-yielding steps into the pyrrolic precursors 7a–c contain-
ing all the atoms necessary for the construction of rings A, B,
and C of rhazinilam. Our studies illustrate a lack of stability
of these intermediates. Alternative synthetic approaches
towards this central biaryl core structure are described.
Introduction
Since its discovery fifty years ago, (R)-(–)-rhazinilam (1)
and some of its congeners have been the subject of intense
studies because of their relatively simple but fascinating
structure and original in vitro cytotoxic activity (Fig-
ure 1).[1]
Transferring the knowledge from in vitro studies to in
vivo experiments has, however, proven to be almost imposs-
ible.[2] The SAR understanding of this promising spindle
toxin is clearly a scientific challenge, as testified by the in-
ability to design more active compounds. Despite a number
of previous efforts to obtain potent analogues, none have
succeeded in producing a more cytotoxic compound than
Figure 1. Bioactive (R)-(–)-rhazinilam (1) and some of its natural
occurring analogues.
[a] Institute of Chemistry, University of Neuchatel,
Av. Bellevaux 51, CP 158, 2009 Neuchatel, Switzerland
E-mail: Reinhard.Neier@unine.ch
http://www2.unine.ch/cho/page-7961.html
[b] Febex SA,
the natural product. Even worse, no analogues showed in
vivo activity. Three reasons have been proposed to account
for the in vivo inactivity of rhazinilam and its analogues:
lack of transport, solubility issues, or its biotransformation
by cytochromes.[3] Recent in-depth studies have ruled out
the first two factors. On the other hand it was found that
rhazinilam is easily oxidized and transformed into less
active, mostly inactive, metabolites. The combination of the
findings on the chemical reactivity, with the sensitivity of
rhazinilam towards oxidative metabolic transformations,
was used by our group as a guideline for proposing and
designing novel rhazinilam analogues (Scheme 1).
Route des Placettes, 1880 Bex/VD, Switzerland
E-mail: Olivier.Vallat@febex.ch
[c] R. Montavon SA,
Rue Dos l’Essert 52p, Case Postale 26, 2856 Boécourt,
Switzerland
E-mail: Ana-Maria.Buciumas@montavon.ch
[d] BENEFRI Crystallography Service, Institute of Chemistry,
University of Neuchâtel,
Av. Bellevaux 51, 2000 Neuchâtel, Switzerland
[‡] Present address: Center for X-ray Analytics, Empa - Swiss
Federal Laboratories for Materials Science and Technology,
Überlandstrasse 129, 8600 Dübendorf, Switzerland
E-mail: antonia.neels@empa.ch
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402903.
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Scheme 1. Synthetic pathway to pyrrole- and pyrrolinone-based analogues of rhazinilam.
Two approaches to the synthesis of rhazinilam analogues We mostly isolated polymeric materials, probably due to the
1a and 1b have been investigated by our group.[4] The start- high reactivity of the substituted phenylacetaldehyde ob-
ing point of our first approach is a convergent synthesis of tained after the crossed aldol reaction. To avoid this prob-
the phenyl-pyrrolic core of rhazinilam involving a tandem lem the nucleophile was modified by using O-alkylketene
Mukaiyama aldol-type condensation – Staudinger cycliza- O-silyl acetals of the type 12 instead of the silyl enol ether
tion sequence.[5] The key intermediate is 3-pyrrolin-2-one (Scheme 2).
8b, which can help to achieve two goals: facilitating the in-
troduction of the substituents needed for construction of
rings B and D, and reducing the sensitivity of the pyrrole
ring precursor (ring C). The second approach involves con-
struction of the biaryl core of 3 by a one-pot Ir-catalyzed
C–H borylation[6] followed by Suzuki coupling.[7]
Having key intermediate 8b and 3 in hand, the important
challenges are to find good and efficient methodologies to
introduce rings B and D.
Scheme 2. Mukaiyama reaction involving O-alkylketene O-silyl
acetals of type 12a–c as nucleophile and acetals 13a–c.
Results and Discussion
By using ketene-acetal 12a and acetal 13c it was possible
The first task was the elaboration of an efficient method- to isolate small amounts of the aldol product 14 as reported
ology for the synthesis of pyrrolinone-containing precursors by Mukaiyama in his previous work.[8] By using aldehydes
of type 8b. Once a reliable access to precursors of this type 15a–c instead of acetals 13a–c, considerably improved
was available, more advanced studies focused on introduc- yields of the products 16a–e were obtained (Scheme 3 and
ing the side chain needed for the creation of rings B and D Table 1).
via intermediates 7 and 11 (Scheme 1). To realize this goal,
The yields of aldol products 16a–d obtained under these
we embarked on a synthetic effort to prepare 3-pyrroline-2- optimized conditions were satisfactory to excellent. Only
one derivatives by using a Mukaiyama aldol addition reac- the Mukaiyama reaction between ketene acetal 12c and al-
tion followed by Staudinger reaction.
dehyde 15c was unsatisfactory. Compound 15c was difficult
In our initial trials we tried to use silyl enol ethers de- to obtain in anhydrous form, and the enolization of the β-
rived from phenylacetaldehyde as nucleophiles, however, we aldehydo ester occurs easily, diminishing the yield of prod-
were unable to control the reaction conditions sufficiently. uct obtained under the reaction conditions.
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Synthesis and Transformation of Substituted Pyrrolinones
try 2). The reaction was allowed to run for 2 h without sig-
nificant change in the yield.
The Staudinger reaction transforming the aldol products
17c and 17e into pyrrolidinones 18a and 18b occurred with-
out any problems, in good yields by using 1.5 equiv. of tri(n-
butyl)phosphine for 18a and triphenylphosphine for 18b
(Scheme 5).
Scheme 3. Mukaiyama reaction involving O-alkylketene O-silyl
acetals of type 12 as nucleophile and aldehydes 15a–c.
Table 1. Synthesis of aldol products 16a–e from O-alkylketene O-
silyl acetals 12a–c and aldehydes 15a–c.
Entry
Substrates
Product
Isolated yield [%]
1
2
3
4
5
12a
15a
15a
15a
15b
15c
16a
16b
16c
16d
16e
51
34
70
51
13
12b
12c
12c
12c
Scheme 5. Staudinger-type reductive cyclization. Conditions 1 for
18a: P(nBu)3, H2O, THF, room temp.; Conditions 2 for 18b: PPh3,
H2O, THF, room temp.
The isolation of 18b was very expedient because the
product is not soluble in tetrahydrofuran (THF). Simple fil-
tration allowed the pure product to be isolated. X-ray crys-
tallographic analysis of 18b revealed that all functional
groups are implicated in a dense network of hydrogen
bonds (Figure 2 and Table S1 in the Supporting Infor-
mation for details).
In view of these results, we decided to invert the roles of
the two fragments needed for the pyrrole synthesis
(Scheme 4 and Table 2).
Scheme 4. Mukaiyama reaction involving ketene acetal 10 as nu-
cleophile and phenylacetophenones 9a–e.
Table 2. Synthesis of aldol products 17a–e from ketene acetal 10
and phenylacetophenones 9a–e.
Entry
9
X
R
Isolated yield of 17 [%]
1
2
3
4
5
9a
9b
9c
9d
9e
Cl
H
H
H
NO2
NO2
20
87
74
48
80
Br
N3
Br
N3
We initially used 6 equiv. of TiCl4 and near stoichiomet-
ric amounts of 10. The reaction was initiated at –78 °C and
then warmed slowly to room temperature; under these con-
ditions, moderate yields of the condensation products 17a
and 17b were isolated.
Detailed studies indicated the formation of side products
and a corresponding reduction of the yield at temperatures
above –10 °C. The presence of large quantities of the strong
Lewis acid TiCl4, which had to be neutralized, rendered the
work-up more difficult and this led to lower yield. In a sys-
tematic study, the amount of TiCl4 was reduced from 6 to
0.5 equiv. The amount of ketene acetal was increased to
Figure 2. Packing diagram of compound 18b. Hydrogen bonds are
indicated by dashed lines.
The solubility of 18a in organic solvents was sufficient
3 equiv., and the reaction temperature was kept between and did not complicate further transformations. X-ray
–30 and –15 °C. Under these conditions, the reaction time analysis of 18a revealed that the molecules are associated
could be kept to just under 1 h, allowing the isolation of as dimers. A third hydrogen bond links these dimers to-
the products in excellent yields of up to 87% (Table 2, en- gether into a one-dimensional chain (Figure 3).
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Table 3. One-pot bocylation of 18b and tertiary alcohol elimi-
nation.
Entry Boc2O Solvent
[equiv.]
Time
[h]
Ratio [%]
Yield
[%]
19
8b
20
1
2
3
4
1
2.1
3
DMF
THF
DMF
THF
1
24
2
75
–
–
25
98
–
–
2
100
100
–
98
93
3
2
–
–
82–98
this reaction in N,N-dimethylformamide (DMF) because of
the low solubility of 18b. However, by using THF as sol-
vent, the reaction was found to proceed with the same effi-
ciency and it simplified purification. This study suggests
that the first step is N-Boc protection followed by O-Boc
protection. Elimination with the help of the third equivalent
of Boc2O produced aromatic compound 20 (Scheme 6).
To introduce the four-carbon side chain, the pyrrolinone
was first silylated to form 21a and 21b (Scheme 7).[10] We
were able to purify 21b by flash chromatography on silica
gel but 21a was not stable under these conditions and was
instead purified by distillation to prevent hydrolysis. The
side chain was introduced by using aldehyde 22a–d as elec-
trophile and BF3 etherate as catalyst.[11] Aldehyde 22a was
obtained by using a previously described procedure,[12]
whereas compounds 22b–d were prepared by hydrolysis and
esterification of γ-butyrolactone followed by Swern oxi-
dation.
Figure 3. Packing diagram of compound 18a. Hydrogen bonds are
indicated by dashed lines.
Whereas 18b makes six hydrogen bonds per molecule, the
absence of the nitro group in 18a reduces this number of
hydrogen bonds to four. In the crystals, 18b forms sheets,
whereas 18a forms one-dimensional chains, which probably
contributes to the difference in solubility.
The elimination of the tertiary alcohol was more difficult
than anticipated. The alcohol reacted only sluggishly, if at
all, with many of the reagents tried. Part of the problem
was the low solubility of 18b. However, treating 18b with
2 equiv. Boc-anhydride in the presence of 4-(dimeth-
ylamino)pyridine (DMAP) using THF as a solvent, intro-
duced the Boc-protecting group on the lactam nitrogen and
effected at the same time the elimination of the tertiary
alcohol in almost quantitative yield to give the product 8b
(Scheme 6).[9] This one-pot procedure was an elegant solu-
tion to the problem of solubility and associated low reactiv-
ity. A systematic study of this reaction revealed that three
different products could be isolated with satisfactory selec-
tivity by changing the amount of Boc2O (Table 3).
Scheme 6. One-pot Boc-protection and tertiary alcohol elimi-
nation.
Scheme 7. Synthesis of advanced precursor 7b.
With one equivalent of Boc2O, a mixture of 19 and 8b
The aldol products 23a–d were obtained in 84 to 94%
was isolated (conditions were not optimized). When 18b yield starting from 21b. The diastereoselectivity of the reac-
was treated with 3 equiv. Boc2O, pyrrolic tautomer 20 was tion controlling the two newly formed chiral centers was
isolated in almost quantitative yield. We initially conducted low. In the next step, alcohols 23a–c were oxidized by using
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Synthesis and Transformation of Substituted Pyrrolinones
pyridinium dichromate (PDC) in the presence of molecular formed into the corresponding triflate derivatives and then
sieves (Table 4).
reduced by Pd0-catalyzed reductive elimination. Taking into
account that the α-ketopyrrole are more stable and less sen-
sitive than the pyrrolinone, four different triflate derivatives
25a–d were prepared in good to moderate yields
(Scheme 9).
Table 4. Oxidation of alcohols 23a–c with pyridinium dichromate
(PDC).
Entry
R
PDC
[equiv.]
Conc. Temp. Time MS 4 Å Yield
[m]
[°C]
[h]
[g]
[%]
1
2
3
4
5
6
7
Me
Me
Et
Et
Et
Et
Bz
3.4
2.5
1.8
1.1
1.1
2
2.4 10–2
1.6 10–2
1.6 10–2
1.6 10–2
1.4 10–2
9 10–3
r.t.
r.t.
r.t.
0
0
0
1
3
3
3
6
7
7
2
2
2
2.5
2
2
23
76
43
35
45
77
78
2
1 10–2
0
2
The synthetic sequence towards the first advanced inter-
mediate developed in our group is summarized in Scheme 7.
The resulting compound 7b contains all the carbons re-
quired to form the nine-membered lactam ring B. However,
this intermediate has proven to be very sensitive to pH
changes due to the acidic proton at C-5 of 3-pyrrolin-2-one
ring. This proton can easily be deprotonated due to the
keto-enol equilibrium between the pyrrolinone and the aro-
matic hydroxy-pyrrole tautomeric form (Figure 4).
Scheme 9. Preparation of triflate derivatives 25a–d.
The use of 2,6-lutidine as base for the nonsubstituted
pyrrolinones 8a and 8b gave the corresponding triflate 25a
and 25b in good yield. However, in the presence of the side
chain, this base gave only moderate yield of 25c. The use
of Et3N instead improved the reaction and gave 25d in good
yield.
We observed for all compounds 25a–d an unusual 6J cou-
pling in the 1H NMR spectra between H-3 and the fluorines
1
of the triflate group (Figure 5). The H NMR signal of H-
3 appeared as a doublet of quadruplets. The coupling con-
4
stant of the doublet is a classical J for pyrrole rings be-
Figure 4. Keto-enol equilibrium in 3-pyrrolin-2-ones.
tween H-3 and H-5 with a typical coupling constant of
The ease of tautomerization makes this position particu- 2.3 Hz. The coupling constant of the quadruplet is much
larly sensitive to unwanted side reactions. All efforts to sap- smaller (0.8 Hz) and is correlated with the coupling con-
onify or to reduce these intermediates and thereby increase stant of the doublet (0.7 Hz) observed in 19F NMR spec-
their stability have either been inconclusive or have failed. troscopy. X-ray analysis of derivative 25a showed the tri-
We summarize in the following our efforts.
fluoromethyl group to be in the vicinity of the pyrrolic
The hydrolysis of 7b under basic conditions gave the cor- hydrogen, reinforcing the argument of a through-space in-
responding acid 24 but only in moderate yield (Scheme 8). teraction (Figures S1 and S2 in the Supporting Infor-
We were not able to improve this result by changing the mation).
parameters of this procedure. The best conditions for basic
hydrolysis found were the treatment of 7b with an excess of
aqueous sodium hydroxide and MeOH at room tempera-
ture. The hydrolysis under acidic conditions was even less
convincing. Other procedures such as enzymatic hydrolysis
or hydrogenation of 7c were tried in an attempt to optimize
this step but without success.
Scheme 8. Hydrolysis of intermediate 7b.
In a second approach we tried to reduce pyrrolinone 7b
to the pyrrole ring. For this purpose, a two-step procedure
was developed in which the pyrrolinones were first trans- the fluorine atoms of the triflate group.
1
6
Figure 5. H NMR spectrum of 25b: J coupling between H-3 and
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The reduction of 25d using Et3SiH in the presence of
To realize this strategy, the corresponding iodoacrylate
Pd(OAc)2 and 1,1Ј-bis(diphenylphosphino)ferrocene (dppf) 33 and the pentafluorophenyl ester 35 were prepared ac-
as catalyst afforded the expected pyrrole in good yield cordingly to a previously described procedure.[14] Synthesis
(Scheme 10). This reduction was very fast at room tempera- of these acrylates started with commercially available γ-
ture (less than 1 min) and lower temperatures were required butyrolactone 27, which was converted into the Weinreb
to control the reaction. Finally, deprotection of the Boc amide 28 according to the procedure described by Fukuda
group under standard conditions using trifluoroacetic acid et al.[15] in 90% yield over the two steps (Scheme 12). Reac-
(TFA) in CH2Cl2 gave the advanced intermediate 6 in 88% tion of amide 28 with ethylmagnesium bromide afforded
yield. However, introducing the additional carbon atoms alkynone 29[16] in nearly quantitative yield. Compound 29
needed for the introduction of the D-ring proved difficult.
underwent a Wadsworth–Horner–Emmons (WHE)[13,17]
olefination to give the unsaturated ester 30 as a 60:40 mix-
ture of E/Z isomers in excellent yield. After desilylation of
30 with tetrabutylammonium fluoride (TBAF), treatment
of the resulting alcohol 31 with tosyl chloride produced to-
syl acrylate 32[18] in 78% yield over the two steps. Finally,
32 was converted into the desired iodo acrylate 33[19] in ex-
cellent 67% overall yield over seven steps starting from the
commercial lactone 27.
Scheme 10. Preparation of precursor 6 by Pd0-catalyzed reductive
elimination.
The structure of 31 was determined by spectral analyses,
and the stereochemistry was confirmed by NOE experi-
ments (Figure 6).
Thus, alternative strategies that either avoided or reduced
the problem of stability of substituted 3-pyrrolin-2-one were
needed. We wondered whether inverting the proposed se-
quence by constructing the D-ring first might bring a solu-
tion to the observed problem.
A strategy that introduced a side chain containing all the
carbon atoms of ring D and the appropriate functionality
for the ring closure and the introduction of ring B on the
3-pyrrolin-2-one ring was chosen. Intramolecular Michael
addition reactions have been successfully applied[13] in ear-
lier syntheses of Rhazinilam. The activation of the pyrrole
26 through the O-silyl group in the 2-position should facili-
tate the ring-closing process (Scheme 11).
Figure 6. NOE experiments of (E)-31 and (Z)-31.
In parallel, alcohol 31 was oxidized with Jones’ rea-
gent[20] (1.9 m, acetone/H2O, 0 °C) to provide acid 34 in
81% yield. Activation of acid 34 using pentafluorophenol
and N,NЈ-dicyclohexylcarbodiimide provided the penta-
fluorophenylethyl ester 35[21] in moderate yield. The acti-
vated acrylate 35 could be obtained from the commercially
available γ-butyrolactone 27 in seven-steps and in 31%
overall yield.
Our previous studies demonstrated that the nucleophilic-
ity of the 3-pyrrolin-2-one substrate is not sufficiently high
for an optimal further transformation through N-alkyl-
ation.[14] We envisaged the use of more nucleophilic aryl-
pyrrole 40 (Scheme 13). The synthesis started with pyrrole
Scheme 11. Retrosynthetic pathway to formation of the D-ring
through intramolecular Michael addition reaction.
Scheme 12. Synthesis of acrylates 33 and 35.
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Synthesis and Transformation of Substituted Pyrrolinones
36 containing a temporary blocking group at C2 position. porting Information). Removal of the Boc group under
In most of the reported rhazinilam syntheses[4b,22] a carb- thermal conditions[23,24] furnished 39 in quantitative yield.
oxymethyl group at the C2 position of the pyrrole ring had
Having sufficient quantities of the required aryl-pyrrole
to be used as temporary protecting group. This protection 39 available, we tested the alkylation reaction with the cor-
probably prevents competing oxidative pyrrole dimerization responding olefin (Table 5).
reactions.
Nucleophilic substitution of the tosyl group by the po-
tassium salt of pyrrole 39 was unsuccessful. The N-alkyl-
ated pyrrole 2 was isolated in moderate yield by using the
sodium salt of the pyrrole precursor. Gratifyingly N-alkyl-
ation of pyrrole 39 preceded smoothly and quantitatively
by using iodo-alkyl 33 as electrophile and NaH as base. The
structure of 2 was determined by spectral analyses, and the
stereochemistry was confirmed by NOE experiments (Fig-
ure 7).
Scheme 13. Synthesis of biaryl 39.
The key structural elements of 39 could be directly in-
stalled starting from a simple pyrrole nucleus by a metal-
catalyzed C–H bond arylation to produce the heterobiaryl
framework.
Figure 7. NOE experiments with (E)-2.
Unfortunately, all our attempts to obtain the cyclic ad-
duct 40 from acrylate 2 by using aluminum chloride in di-
ethyl ether or nitromethane failed (Scheme 14).
The IrI-catalyzed C–H borylation, developed by the
groups of Smith–Malezcka and Hartwig–Miyaura,[6] was
adopted to furnish the desired pyrrole nucleus, which was
followed by a Suzuki coupling. The tert-butylcarboxy (Boc)
group is known to be a protector and director for Ir-cata-
lyzed borylations.[23] Pyrrole 36 was converted into N-Boc-
pyrrole 4 in excellent yield. Compound 4 underwent an Ir-
catalyzed borylation under Smith–Malezcka conditions to
give 4-borylated pyrrole 38 in 72% yield with complete re-
gioselectivity at C-4. The Pd-catalyzed Suzuki cross-cou-
pling reaction of 38 with 2-bromo-nitrobenzene 5 was
achieved quantitatively by following the procedure de-
scribed by Morrison and co-workers.[7] Alternatively, biaryl
Scheme 14. Attempts to cyclize acrylate 2 into tetrahydroindolizine
40.
The presence of both a methyl ester substituent on the
3 could be obtained in 96% yield by one-pot IrI-catalyzed pyrrole ring and a 2-nitro group on the phenyl ring deacti-
C–H borylation and Suzuki coupling on 4 (see in the Sup- vates the pyrrole ring sufficiently, preventing the Michael
Table 5. N-Alkylation of pyrrole 39.
Entry
Electrophile
Base
Solvent
Temp. [°C]
Time [h]
Yield [%]
[a]
1
2
3
32
32
33
KHMDS
NaH
NaH
THF
DMF
DMF
85
0–20
0–20
20
20
6
–
63[b]
quant.
[a] Only starting materials were recovered. [b] According to NMR spectroscopic analysis.
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addition from occurring. The synthesis of a more nucleo-
philic pyrrole was a logical solution that could overcome
this problem. Therefore we decided not to pursue this ap-
proach further.
Conclusions
We have described the evolution of our synthetic strate-
gies towards the preparation of advanced intermediates of
pyrrole- and pyrrolinone-based analogues of rhazinilam, a
potent mitotic spindle toxin. The retrosynthetic approach
focused on the synthesis of the heterobiarylic core, at-
taching the chains and functional groups needed for the
formation of rings C and D in a later stage. Building on the
known sensitivity of pyrrole rings lacking electronic or ste-
ric stabilization, the synthetic intermediates were designed
to contain at least one stabilizing element: either the well-
known methoxycarbonyl ester group or the novel pyrroli-
none element. Each successive generation of our synthetic
approaches implemented new chemistry or modified exi-
sting methods, broadening the substrate scope. The focus
on stable and resistant pyrrole derivatives facilitated the iso-
lation but posed its own unique challenges for the later-
stage transformations. The reported approaches make ad-
vanced intermediates readily available through two efficient
and flexible syntheses. The most promising approach to the
desired rhazinilam analogues is based on the elegant tan-
dem Mukaiyama–Staudinger reaction sequence.
Given the poor nucleophilic nature of 3-pyrrolin-2-one
substrate, it was decided to investigate the N-acylation in-
stead of the N-alkylation on the model series involving ste-
rically less demanding substrates (Scheme 15). N-Acylation
of sterically hindered chiral cyclic amides has previously
been described, and oxazolidinones especially have at-
tracted much interest because of their use as chiral auxilia-
ries.[25] Similar 3-pyrrolin-2-ones have been N-acylated by
using an nBuLi protocol with electrophiles such as acid
chlorides[26] and pentafluorophenyl (Pfp) esters.[27]
Studies on the further transformations disclosed a dis-
turbing tendency of these advanced intermediates to un-
dergo a panoply of uncharacterized side reactions. This
statement is especially true for the intermediates of type 7
containing the pyrrolinone unit. This, from the synthetic
standpoint, obstructive inclination for oxidative side reac-
tions has a significance in the context of the metabolism of
the natural product. (–)-Leuconolam and (+)-epi-leu-
conolam are products obtained through oxidative pathways
from (–)-rhazinilam. Both products are known to be inac-
tive in vivo. No plausible proposal for this remarkable dif-
ference in the biological effect compared with rhazinilam
has been proposed so far. Our synthetic observation on the
lack of stability of the pyrrolinone class of derivatives may
be relevant in this context. The observed chemical instabil-
ity of compounds of this type under hydrolytic conditions
and in the presence of oxygen might be the reason for the
inactivity of (–)-leuconolam and (+)-epi-leuconolam. This
important message is taken into consideration in our ongo-
ing studies, which are focused on the preparation of newly
designed analogues of rhazinilam.
Scheme 15. Retrosynthetic pathways for the preparation of 11
through N-acylation of 3-pyrrolin-2-one 42.
Two retrosynthetic pathways were envisaged and experi-
mentally tested. The N-acylation could be successfully exe-
cuted by using activated esters derived from levulinic acid,
but attempts to extend the chain were not successful (see
the Supporting Information for more details).
Treating the more complex aryl-3-pyrrolin-2-one 42 with
the activated acrylate 35, which was specifically synthesized
for this purpose, and nBuLi under low temperature was suc-
cessful (Scheme 16). Compound 11 was easily silylated by
using tert-butyldimethylsilyl trifluoromethanesulfonate and
2,6-lutidine to give the pyrrole 26 in good yield. Compound
11 and 26 contain all essential elements needed for the con-
struction of the Rhazinilam skeleton through a simple ho-
mologation step.[13,28]
Experimental Section
Materials and Methods: All chemicals were used as received unless
otherwise noted. Reagent-grade solvents were distilled prior to use.
Scheme 16. Preparation of precursors 11 and 26 by N-acylation of 3-pyrrolin-2-one 42.
7872
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 7865–7877

Synthesis and Transformation of Substituted Pyrrolinones
All reported NMR spectra were recorded in appropriated solvent Methyl 4-Azido-3-hydroxy-3-phenylbutyrate (17c): Yield 74%. 1H
(Cambridge Isotope Laboratories) at 298 K either with a Bruker NMR (400 MHz, CDCl3): δ = 7.48–7.43 (m, 2 H), 7.41–7.36 (m, 2
Avance-400 spectrometer at 400 (1H NMR) or 100 (13C NMR) H), 7.33–7.29 (m, 1 H), 4.64 (d, J ≈ 1.4 Hz, 1 H), 3.62 (s, 3 H),
MHz or with a Varian Gemini XL-200 spectrometer at 200 (1H 3.51 and 3.27 [AB system, J = 12.7 Hz, (B part)ϫd, J = 1.3 Hz, 2
NMR) and 50 (13C NMR) MHz. Chemical shifts are reported as H], 3.10 and 3.00 (AB system, J = 16.2 Hz, 2 H) ppm. 13C NMR
δ values relative to TMS, defined as CDCl3, δ = 7.26 ppm; CD3OD, (100 MHz, CDCl3): δ = 173.0, 142.7, 128.6, 127.8, 125.0, 75.7, 60.7,
1
δ = 4.87 ppm; DMSO, δ = 3.33 ppm for H NMR and CDCl3, δ = 52.0, 41.2 ppm. IR (KBr): ν = 3522, 3435, 3024, 2987, 2962, 2918,
˜
77.00 ppm; CD3OD, δ = 49.00 ppm; DMSO, δ = 39.52 ppm for 13
C
2852, 2473, 2097, 1721, 1697, 1434, 1356, 1297, 1286, 1217, 1161,
NMR spectroscopy. H NMR spectroscopic data are recorded as 1006, 700, 587 cm–1. ESI-MS: m/z = 258.1 [M + Na]+. C11H13N3O3
follows: chemical shift (δ) [multiplicity, coupling constant(s) J (Hz), (235.24): calcd. C 56.16, H 5.57, N 17.86; found C 55.69, H 5.57,
number of protons] where multiplicity is defined as: s singlet, d N 17.81.
1
doublet, t triplet, q quartet, quint quintet, br. broad, m multiplet
or combinations of the above. The symbol “≈” denotes for the
average value of J varying from 0.2 to 0.4 Hz. Infrared spectra were
obtained with a Perkin–Elmer Spectrum One version B FTIR unit
using KBr pressed films or KBr disks. Mass spectra were obtained
with a ThermoFinnigan PolarisQ instrument by EI (70 eV) or with
a ThermoFinnigan LCQ instrument by the ESI or APCI technique.
HRMS were recorded with a Bruker BioAPEX II Daltonics instru-
ment. Flash column chromatography was performed on silica gel
(Kieselgel 60, 230–400 mesh ASTM). TLC analyses were per-
formed on silica gel plates (0.2 mm) 60 F254 (Merck). Detection
was first by UV (254 nm) then charring with a basic aqueous solu-
tion of KMnO4. The isomer ratios were determined by gas
Methyl 4-Azido-3-hydroxy-3-(2-nitrophenyl)butyrate (17e): Yield
80%. H NMR (400 MHz, CDCl3): δ = 7.43–7.56 (m, 4 H), 4.86
1
(s, 1 H), 3.67 (s, 3 H), 3.82 and 3.59 (AB system, J = 12.8 Hz, 2
H), 3.18 and 3.08 (AB system, J = 16.7 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 173.0, 150.7, 134.8, 131.4, 129.7, 128.3,
124.7, 76.4, 59.4, 52.8, 41.2 ppm. IR (KBr): ν = 3600–2800 (br.),
˜
3445, 3075, 3009, 2959, 2924, 2853, 2198, 2109, 1716, 1532, 1436,
1419, 1365, 1303, 1276, 1244, 1200, 1168, 1044, 1008, 950, 911,
771, 554 cm–1. ESI-MS: m/z = 303.0 [M + Na]+. C11H12N4O5
(280.24): calcd. C 47.15, H 4.32, N 19.99; found C 47.15, H 4.39,
N 19.76.
4-Hydroxy-4-(2-nitrophenyl)pyrrolidin-2-one (18b): PPh3 (1.4 g,
5.4 mmol) was added to a solution of azido 17e (3.6 mmol) in THF
(15 mL). Water (1%, 0.15 mL) was added and the mixture was
stirred at room temperature for 3 d. The solution was concentrated
and MeOH (10 mL) was added. The mixture was stirred and heated
to reflux for 30 min, then the suspension was cooled to –20 °C over-
night, filtered, and the white powder was washed with EtOAc and
dried to afford 18b (80% yield). 1H NMR (400 MHz, [D6]DMSO):
δ = 7.79 (br. s, 1 H), 7.49–7.67 (m, 4 H), 6.08 (s, 1 H), 3.66 and
3.46 (AB system, J = 10.7 Hz, 2 H), 2.97 and 2.42 (AB system, J
= 16.6 Hz, 2 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 174.7,
151.0, 137.8, 132.1, 129.6, 128.3, 124.8, 77.2, 56.3, 46.5 ppm. IR
chromatography (Agilent 6850 Series chromatograph) on
a
high-resolution gas chromatography HP-5 column
(30 mϫ0.32 mmϫ0.25 μm) and the configuration was assigned by
comparison of the retention time with the reported values. The
following temperature programs were employed: (1) 100 °C (3 min),
15 °C/min to 280 °C, 280 °C (4 min); (2) 220 °C (2 min), 5 °C/min
to 300 °C, 300 °C (10 min).
CCDC-813048 (for 18a), -813047 (for 18b), -813045 (for 20), and
-813046 (for 25a) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(KBr): ν = 3500–2800 (br.), 3402, 3225, 1672, 1526, 1481, 1440,
˜
1406, 1373, 1321, 1284, 1104, 781, 752, 725, 712, 645, 632 cm–1.
ESI-MS: m/z = 688.7 [3M + Na]+, 466.9 [2M + Na]+. C10H10N2O4
(222.20): calcd. C 54.06, H 4.54, N 12.61; found C 54.00, H 4.63,
N 12.50.
(1-Methoxyvinyloxy)trimethylsilane (10). A solution of LHMDS
(1 m in THF, 16.20 mL, 16.2 mmol) was diluted in anhydrous THF
(10 mL) and cooled to –78 °C, and a solution of methyl acetate
(1.00 g, 13.5 mmol) in THF (6 mL) was added dropwise. After
30 min, TMSCl (1.75 g, 16.2 mmol) was added and the resulting
mixture was stirred for 1.5 h at –78 °C. The solvent was evaporated
and the salts were precipitated with pentane. The solution was fil-
tered through Celite and the solvent was evaporated. The crude
product was purified by distillation (P = 45 Torr, T = 48–50 °C) to
tert-Butyl 4-(2-Nitrophenyl)-2oxo-2,5-dihydropyrrole-1-carboxylate
(8b): DMAP (22.7 mg, 0.18 mmol) and Boc2O (206 mg, 0.95 mmol)
were added to a suspension of lactam 18–b (0.45 mmol) in anhy-
drous THF (10 mL) under argon. The solution became clear imme-
diately. The solution was stirred at room temperature for a mini-
mum of 2 h. After removal of the solvent, the residue was purified
by flash chromatography (silica gel; MeOH/CH2Cl2, 1%) to afford
1
give a pure 9 (1.81 g, 92%) as a colorless oil. H NMR (200 MHz,
1
CDCl3): δ = 3.54 (s, 3 H), 3.21 and 3.11 (2ϫ d, J = 2.6 Hz, 2 H),
0.22 (s, 9 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 162.1, 59.9,
55.1, 2.5 ppm.
8b (98%) as a white solid. H NMR (400 MHz, CDCl3): δ = 8.10
(dd, J = 8.1, 1.3 Hz, 1 H), 7.72 (dt, J = 7.6, 1.3 Hz, 1 H), 7.63 (td,
J = 8.1, 7.6, 1.5 Hz, 1 H), 7.41 (dd, J = 7.6, 1.5 Hz, 1 H), 6.13 (t,
J = 1.6 Hz, 1 H), 4.55 (d, J = 1.6 Hz, 2 H), 1.56 (s, 9 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 168.0, 155.3, 149.2, 147.4, 133.7,
General Procedure for 17c,e: A solution of 9c,e (2.4 mmol) in anhy-
drous CH2Cl2 (15 mL) was added to a solution of keten acetal 10
(7.3 mmol) in anhydrous CH2Cl2 (15 mL) at –30 °C under argon.
A solution of TiCl4 (1.2 mmol), freshly distilled from polyvinylpyr-
idine, in anhydrous CH2Cl2 (4 mL) was added slowly. The solution
became red immediately and then dark-red. The reaction mixture
was stirred at –30 °C for 15 min and then at –15 °C for 30 min. The
130.7, 130.3, 128.3, 125.0, 124.9, 83.3, 53.0, 28.1 ppm. IR (KBr): ν
˜
= 3359, 3081, 2984, 2971, 2933, 2857, 1780, 1524, 1365, 1356, 1344,
1323, 1288, 1256, 1153, 1072, 846 cm–1. ESI-MS: m/z = 303.1 [M –
H]–. C11H12N4O5 (280.24): calcd. C 59.21, H 5.30, N 9.21; found
C 59.23, H 5.39, N 9.11.
cold mixture was poured into an aqueous solution of NaOH (2 n, tert-Butyl 4-Hydroxy-4-(2-nitrophenyl)-2-oxopyrrolidine-1-carboxyl-
2.4 mL) and was extracted with chloroform. The combined organic ate (19): DMAP (0.023 g, 0.2 mmol) and Boc2O (0.1 mg, 0.5 mmol)
layers were washed with brine, dried with MgSO4, filtered, and con- were added to a solution of 4-hydroxy-4-(2-nitrophenyl)pyrrol-
centrated. Purification of the residue by flash chromatography (sil- idine-2-one (18b; 0.10 g, 0.5 mmol) in DMF (2 mL) under Ar. After
ica gel; CH2Cl2) followed by crystallization (diethyl ether/hexane) 24 h at room temp., the solvent was evaporated and the crude prod-
afforded 17c,e as a white solid.
uct was purified by chromatography (EtOAc/CH2Cl2, 8:2). 1H
Eur. J. Org. Chem. 2014, 7865–7877
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7873

R. Neier et al.
NMR (200 MHz, CD3OD): δ = 7.65–7.47 (m, 4 H), 4.11 and 5.05 1.71–1.65 (m, 1 H), 1.57 (s, 9 H), 1.50–1.42 (m, 1 H), 1.19 (t, J =
FULL PAPER
(2ϫ d AB system, J = 12.6 Hz, 2 H), 3.43 and 2.75 (1ϫ d and 1ϫ
dd AB system, J = 17.0, 0.9 Hz, 2 H), 1.54 (s, 9 H) ppm.
7.2 Hz, 3 H) ppm; δ (isomer 2) = 8.14 (dd, J = 8.2, 1.2 Hz, 1 H),
7.73 (dt, J = 7.6, 1.3 Hz, 1 H), 7.64 (ddd, J = 8.2, 7.5, 1.5 Hz, 1
H), 7.53 (dd, J = 7.6, 1.4 Hz, 1 H), 6.05 (d, J = 1.3 Hz, 1 H), 5.09
(t, J = 1.2 Hz, 1 H), 4.40–4.20 (br. s, 1 H, OH), 4.02 (q, J = 7.1 Hz,
2 H), 3.93 (m, 1 H), 2.34 (m, 2 H), 1.57 (s, 9 H), 1.52–1.44 (m, 1
H), 1.26–1.20 (m, 1 H), 1.16 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ (isomer 1) = 173.9, 168.2, 159.0, 149.5, 148.0,
133.6, 131.3, 130.5, 129.3, 125.9, 124.9, 83.8, 70.5, 65.9, 60.7, 31.4,
28.1, 26.4, 14.1 ppm; δ (isomer 2) = 173.1, 167.9, 157.9, 150.8,
147.1, 134.0, 131.7, 130.7, 128.7, 125.5, 125.0, 84.2, 69.1, 60.3, 30.6,
tert-Butyl 2-(tert-Butoxycarbonyloxy)-4-(2-nitrophenyl)-1H-pyrrole-
1-carboxylate (20): DMAP (0.023 g, 0.2 mmol) and Boc2O (0.30 g,
1.4 mmol) were added to a suspension of 4-hydroxy-4-(2-ni-
trophenyl)pyrrolidine-2-one (18b; 0.10 g, 0.5 mmol) in anhydrous
THF (3 mL) under Ar. The solution became clear. After 1 h at
room temp., the solvent was evaporated and the crude product was
purified by chromatography (hexane/EtOAc, 7:3) to give 20
1
(169 mg, 93%) as a white solid. H NMR (400 MHz, CDCl3): δ =
28.6, 26.9, 14.1 ppm. IR (KBr): ν = 3468, 3102, 2982, 2934, 1777,
˜
7.76 (ddd, J = 8.1, 1.3, 0.5 Hz, 1 H), 7.64 (ddd, J = 7.8, 7.1, 1.3 Hz,
1 H), 7.60 (ddd, J = 7.8, 1.8, 0.5 Hz, 1 H), 7.49 (ddd, J = 8.1, 7.1,
1.8 Hz, 1 H), 7.16 (d, J = 2.3 Hz, 1 H), 5.97 (d, J = 2.3 Hz, 1 H),
1.62 (s, 9 H), 1.55 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 151.2, 149.6, 147.7 and 137.9, 132.2, 131.1, 128.2, 128.0, 123.6,
119.3, 114.5, 100.6, 85.2, 84.7, 27.1, 26.8 ppm. ESI-MS: m/z =
426.9 [M + Na]+. C20H24N2O7 (404.42): calcd. C 59.40, H 5.98, N
6.93; found C 59.66, H 6.16, N 6.89.
1733, 1605, 1572, 1528, 1478, 1443, 1371, 1350, 1323, 1256, 1229,
1156, 1077, 965, 869, 845, 789, 773, 759, 716, 690, 641, 530 cm–1.
ESI-MS: m/z = 457.0 [M + Na]+. HRMS (ESI): m/z calcd. for
C21H26N2O8 [M + Na]+ 457.1587; found 457.1584.
tert-Butyl 2-(4-Ethoxy-4-oxobutanoyl)-3-(2-nitrophenyl)-5-oxo-2,5-
dihydro-1H-pyrrole-1-carboxylate (7b): To a solution of aldol prod-
uct 23b (0.52 mmol) in anhydrous CH2Cl2 (60 mL) was added MS
4 Å (2 g) and pyridinium dichromate (PDC) (1.04 mmol) at 0 °C.
The progress of the reaction was monitored by TLC until the start-
ing material disappeared (ca. 6 h). The mixture was then filtered
through a pad of Celite and silica gel and, after concentration, the
residue was purified by flash chromatography (silica gel; CH2Cl2/
Et2O, 30%) to afford the products 7b (77% yield) as a slightly yel-
low paste. 1H NMR (400 MHz, CDCl3): δ = 8.15 (dd, J = 8.1,
1.4 Hz, 1 H), 7.70 (dt, J = 7.5, 1.4 Hz, 1 H), 7.63 (td, J = 8.0, 7.6,
1.5 Hz, 1 H), 7.34 (dd, J = 7.5, 1.5 Hz, 1 H), 6.20 (d, J = 1.7 Hz,
1 H), 5.44 (d, J = 1.7 Hz, 1 H), 4.05 (q, J = 7.1 Hz, 2 H), 2.84 [(A
part of AB system)ϫt, J ≈ 19.0 Hz, 1 H], 2.55 [(B part of AB
system)ϫdd, J ≈ 19.0, 7.1, 5.7 Hz, 1 H], 2.41 and 2.40 [(AB sys-
tem)ϫdd, J ≈ 17.2, 7.1, 5.7 Hz, 2 H], 1.55 (s, 9 H), 1.19 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 201.4, 171.8,
167.3, 153.8, 148.7, 147.2, 133.8, 131.3, 131.1, 126.7, 125.8, 125.2,
General Procedure for 21a–b: 2,6-Lutidine (0.2 mL) and TBSOTf
(127 mg, 0.48 mmol) were added at room temperature under argon
to a solution of pyrrolidinone 8a–b (0.48 mmol) in anhydrous
CH2Cl2 (5 mL), and the mixture was stirred for 1 h. After removal
of the solvent, purification of the residual oil by filtration through
silica gel (EtOAc/hexane, 20%) afforded silyl enol 21a–b as an
orange oil.
tert-Butyl 2-(tert-Butyldimethylsilanyloxy)-4-phenylpyrrole-1-carb-
1
oxylate (21a): Yield 62%. H NMR (400 MHz, CDCl3): δ = 7.50
(m, 2 H), 7.36 (m, 2 H), 7.23 (m, 1 H), 7.04 (d, J = 2.3 Hz, 1 H),
5.63 (d, J = 2.3 Hz, 1 H), 1.63 (s, 9 H), 1.06 (s, 9 H), 0.31 (s, 6
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.1, 144.1, 134.6,
128.5, 126.2, 125.0, 123.3, 108.6, 91.2, 83.0, 28.1, 25.7, 18.4,
–4.7 ppm. IR (KBr): ν = 2955, 2931, 2859, 1757, 1595, 1575, 1552,
˜
1473, 1452, 1386, 1369, 1353, 1301, 1288, 1255, 1210, 1162, 1113,
84.7, 71.9, 60.7, 32.9, 27.9, 27.1, 14.1 ppm. IR (KBr): ν = 3102,
˜
895, 841, 785 cm–1.
2982, 2930, 1787, 1728, 1635, 1605, 1572, 1530, 1396, 1371, 1348,
1329, 1258, 1208, 1155, 1126, 1070, 843, 755 cm–1. ESI-MS: m/z =
454.9 [M + Na]+. HRMS (ESI): m/z calcd. for C21H24N2O8 [M +
Na]+ 455.1430; found 455.1427.
tert-Butyl 2-(tert-Butyldimethylsilanyloxy)-4-(2-nitrophenyl)pyrrole-
1
1-carboxylate (21b): Yield 98%. H NMR (400 MHz, CDCl3): δ =
7.69 (dd, J = 8.1, 1.2 Hz, 1 H), 7.53 (td, J = 7.8, 6.9, 1.3 Hz, 1 H),
7.50 (dd, J = 7.8, 2.0 Hz, 1 H), 7.37 (ddd, J = 8.1, 6.9, 1.9 Hz, 1
H), 6.91 (d, J = 2.3 Hz, 1 H), 5.31 (d, J = 2.3 Hz, 1 H), 1.61 (s, 9
H), 1.02 (s, 9 H), 0.27 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 149.1, 147.8, 144.0, 131.8, 130.8, 129.3, 127.2, 123.6, 118.7,
4-[1-(tert-Butoxycarbonyl)-3-(2-nitrophenyl)-5-oxo-2,5-dihydro-
1H-pyrrol-2-yl]-4-oxobutanoic Acid (24): To a solution of tert-butyl
2-(4-ethoxy-4-oxobutanoyl)-3-(2-nitrophenyl)-5-oxo-2,5-dihydro-
1H-pyrrole-1-carboxylate (7b; 0.70 g, 1.6 mmol) was added a solu-
tion of NaOH 50% (3 mL). The solution became red and then
dark-brown. After 1 h, the reaction mixture was diluted with Et2O,
the phases were separated, and the aqueous phase was acidified
with HCl (3.5N) to pH ca. 1 and extracted three times with Et2O.
The combined organic phases were dried with MgSO4, filtered, and
concentrated. The crude product was purified by chromatography
(CH2Cl2/MeOH, 95:5) to afford the acid 24 (40%) as a brown solid.
1H NMR (400 MHz, CDCl3): δ = 8.15 (dd, J = 8.0, 1.4 Hz, 1 H),
7.68 (dt, J = 7.4, 1.5 Hz, 1 H), 7.63 (ddd, J = 8.0, 7.6, 1.6 Hz, 1
H), 7.29 (dd, J = 7.5, 1.6 Hz, 1 H), 6.22 (d, J = 1.7 Hz, 1 H), 5.46
(d, J = 1.7 Hz, 1 H), 1.55 (s, 9 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 201.1, 177.1, 167.3, 153.9, 148.7, 147.2, 133.9, 131.3,
131.3, 126.5, 125.8, 125.3, 84.8, 71.6, 32.7, 27.9, 26.7 ppm. IR
111.1, 92.4, 83.5, 28.1, 25.7, 18.4, –4.8 ppm. IR (KBr): ν = 2955,
˜
2931, 2859, 1761, 1736, 1595, 1553, 1530, 1386, 1370, 1351, 1257,
1160, 1118, 896, 842, 785 cm–1.
tert-Butyl 2-(3-Ethoxycarbonylpropionyl)-3-(2-nitrophenyl)-5-oxo-
2,5-dihydropyrrole-1-carboxylate (23b): To a solution of silyl enol
21b (2.3 mmol) in anhydrous CH2Cl2 (20 mL) at –78 °C and under
argon were added aldehyde 22b (3.0 mmol) and dropwise BF3·OEt2
(2.3 mmol). The color of the solution changed from yellow to pale-
yellow. The mixture was stirred at –78 °C for 1 h, then the reaction
was quenched at –78 °C with a saturated aqueous solution of
NaHCO3 (15 mL) and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were washed with brine,
dried with MgSO4, filtered and concentrated. Purification of the
residue by flash chromatography (silica gel; EtOAc/Et2O, 30%) af-
forded the aldol products 23b (93% yield) as a white solid.
1H NMR (400 MHz, CDCl3): δ (isomer 1) = 8.05 (dd, J = 8.1,
1.2 Hz, 1 H), 7.69 (dt, J = 7.6, 1.3 Hz, 1 H), 7.59 (ddd, J = 8.1,
7.5, 1.5 Hz, 1 H), 7.47 (dd, J = 7.7, 1.4 Hz, 1 H), 6.21 (d, J =
(KBr): ν = 3276, 3104, 2981, 2932, 1784, 1726, 1605, 1572, 1529,
˜
1478, 1458, 1396, 1370, 1347, 1258, 1154, 1129, 1074, 871, 844,
788, 756, 691 cm–1. ESI-MS: m/z = 403.1 [M – H]–.
tert-Butyl 2-(4-Ethoxy-4-oxobutanoyl)-3-(2-nitrophenyl)-5-(trifluor-
1.2 Hz, 1 H), 5.15 (dd, J = 3.8, 1.2 Hz, 1 H), 4.12 (m, 1 H), 4.05 omethylsulfonyloxy)-1H-pyrrole-1-carboxylate (25d): To a solution
(q, J = 7.2 Hz, 2 H), 2.78 (d, J = 5.7 Hz, 1 H, OH), 2.35 (m, 2 H), of pyrrolinone 7b or 8a–b (3.52 mmol) in anhydrous CH2Cl2
7874
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 7865–7877

Synthesis and Transformation of Substituted Pyrrolinones
(80 mL) was added Et3N (7.04 mmol) followed by Tf2O
(4.93 mmol) at –10 °C. The reaction was monitored by TLC until
complete disappearance of the starting material was observed, then
it was quenched with a saturated solution of NaHCO3 (40 mL).
The organic phase was washed with brine, dried with MgSO4, fil-
tered, and concentrated. Purification of the residue by flash
chromatography (silica gel; EtOAc/hexane, 40%) afforded triflate
25d (71% yield) as a slightly orange oil. 1H NMR (400 MHz,
1-tert-Butyl 2-Methyl 4-(2-Nitrophenyl)-1H-pyrrole-1,2-dicarboxyl-
ate (3). Method A: In an over-dried glass microwave flask, the solid
starting materials N-(Boc)pyrrole pinacol boronate 38 (450 mg,
1.28 mmol), 2-bromo-nitrobenzene 5 (216 mg, 1.07 mmol), palla-
dium acetate (12 mg, 0.05 mmol), 2-dicyclohexyl-phosphino-2Ј,6Ј-
dimethoxybiphenyl (44 mg, 0.11 mmol), and K3PO4 (453 mg,
2.14 mmol) were combined. The vial was sealed with a Teflon®-
coated screwcap, a needle was inserted through the cap and the vial
CDCl3): δ = 8.02 (ddd, J = 8.1, 1.4, 0.3 Hz, 1 H), 7.65 (td, J = 7.5, was then evacuated and backfilled with argon. The solvent system
1.4 Hz, 1 H), 7.57 (ddd, J = 8.1, 7.5, 1.6 Hz, 1 H), 7.43 (ddd, J = (2.56 mL, 2.0 mL/mmol 2-bromo-nitrobenzene), consisting of de-
7.5, 1.6, 0.3 Hz, 1 H), 5.99 (m, 1 H), 4.02 (q, J = 7.2 Hz, 2 H),
gassed n-butanol (1.83 mL) and degassed deionized water
2.58–2.54 (m, 2 H), 2,48–2.45 (m, 2 H), 1.60 (s, 9 H), 1.16 (t, J = (0.73 mL) in the ratio of 2.5:1 was added. The resulting mixture
7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 190.0, 172.0,
148.9, 146.2, 135.1, 133.0, 132.8, 129.9, 127.9, 126.7, 124.5, 124.5,
118.6 [q, JC,F = 321.1 Hz, CF3], 101.9, 88.1, 60.5, 36.3, 28.1, 27.3,
14.1 ppm. ESI-MS: m/z = 586.8 [M + Na]+.
was heated at 35 °C for 16 h. The crude reaction mixture was then
filtered through a plug of silica gel (eluting with 35 mL of EtOAc)
and concentrated in vacuo. The crude material so obtained was
purified by flash chromatography on silica gel (petroleum ether and
then petroleum ether/EtOAc gradually to 90:10) to provide the de-
sired Boc-protected phenylpyrrole 3 (380 mg, 100%) as a yellow
oil.
Ethyl 4-[3-(2-Nitrophenyl)-1H-pyrrol-2-yl]-4-oxobutanoate
(6):
Compound 25d (1.37 g, 2.43 mmol) was dissolved in DMF
(15 mL), then Pd(OAc)2 (27.3 mg, 0.12 mmol) and dppf (67.3 mg,
0.12 mmol) were added and the temperature was decreased to
–10 °C. Et3SiH (0.96 mL, 6.08 mmol) was then added and the mix-
ture was stirred at this temperature for 30–40 min (reaction fol-
lowed by 1H NMR spectroscopic analysis). The solution was di-
luted with diethyl ether and first washed with water, then with a
saturated solution of NaHCO3 and finally with brine. The organic
phase was dried with MgSO4, filtered, and concentrated. Purifica-
tion of the residue by flash chromatography (silica gel; Et2O/hex-
ane, 50%) afforded the reduced product, yield 649 mg (64%). 1H
NMR (400 MHz, CDCl3): δ = 7.95 (dd, J = 8.1, 1.3 Hz, 1 H), 7.60
(dt, J = 7.6, 1.4 Hz, 1 H), 7.51 (ddd, J = 8.1, 7.5, 1.5 Hz, 1 H),
7.42 (dd, J = 7.6, 1.5 Hz, 1 H), 7.29 (d, J = 3.3 Hz, 1 H), 6.16 (d,
J = 3.2 Hz, 1 H), 4.06 (q, J = 7.1 Hz, 2 H), 2.86 (t, J ≈ 7.2 Hz, 2
H), 2.55 (t, J ≈ 7.2 Hz, 2 H), 1.61 (s, 9 H), 1.20 (t, J = 7.1 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 193.8, 172.4, 149.3,
148.3, 133.9, 132.3, 130.2, 128.9, 128.7, 127.0, 124.1, 123.7, 112.2,
Method B. One-Pot Synthesis from Pyrrole 4: A glass microwave
flask was initially charged with [Ir(OMe)(COD)]2 (20 mg,
0.03 mmol, 3 mol-% Ir) and 4,4Ј-di-tert-butyl-2,2Ј-bipyridine
(16 mg, 0.06 mmol, 3 mol-%). The vial was sealed with a Teflon®-
coated screwcap, a needle was inserted through the cap and the
vial was then evacuated and backfilled with argon. Anhydrous and
degassed hexane (3 mL) was added at room temperature. To the
resulting mixture was added dropwise pinacolborane (0.35 mL,
2.40 mmol) followed by pyrrole 4 (450 mg, 2.00 mmol). The re-
sulting mixture was heated at 80 °C for 6 h, and then stirred at
room temperature overnight. The screwcap was removed and the
solid starting materials were added to a crude mixture of 2-bromo-
nitrobenzene 5 (403 mg, 2.00 mmol), palladium acetate (19 mg,
0.04 mmol), SPhos (68 mg, 0.08 mmol), and K3PO4 (706 mg,
1.66 mmol). The vial was sealed with a Teflon®-coated screwcap, a
needle was inserted through the cap and the vial was then evacu-
ated and backfilled with argon. The solvent system (2.56 mL,
1.0 mL/mmol 2-bromo-nitrobenzene), consisting of degassed n-bu-
tanol (1.83 mL) and degassed deionized water (0.73 mL) in a ratio
of 2.5:1 was added. The resulting mixture was heated at 35 °C for
16 h. The crude reaction mixture was then filtered through a plug
of silica gel (eluting with 30 mL of EtOAc) and concentrated in
vacuo. The crude material so obtained was purified by flash
chromatography on silica gel (petroleum ether and then petroleum
ether/EtOAc gradually to 90:10) to give the desired Boc-protected
phenylpyrrole 3 (661 mg, 96% starting from pyrrole 4) as a yellow
oil. Rf = 0.30 (petroleum ether/EtOAc, 80:20). 1H NMR (400 MHz,
[D6]acetone): δ = 7.87 (dd, J = 8.1, 1.0 Hz, 1 H), 7.72 (ddd, J =
7.9, 6.9, 1.2 Hz, 1 H), 7.68 (dd, J = 7.7, 1.8 Hz, 1 H), 7.60 (d, J =
1.9 Hz, 1 H), 7.59 (ddd, J = 8.0, 6.9, 1.9 Hz, 1 H), 6.90 (d, J =
1.9 Hz, 1 H), 3.84 (s, 3 H), 1.60 (s, 9 H) ppm. 13C NMR (100 MHz,
[D6]acetone): δ = 161.4, 150.1, 148.9, 133.2, 132.3, 129.4, 128.0,
126.8, 125.2, 124.6, 121.8, 119.9, 86.3, 52.4, 27.7 ppm. IR (KBr,
85.6, 60.4, 38.0, 28.6, 27.7, 14.1 ppm. IR (KBr): ν = 3149, 3071,
˜
2983, 2937, 1740, 1681, 1615, 1563, 1530, 1492, 1478, 1459, 1436,
1413, 1372, 1345, 1280, 1260, 1215, 1149, 1071, 1038, 995, 943,
931, 877, 851, 844, 787, 752, 703, 651, 605 cm–1. ESI-MS: m/z =
454.9 [M + K]+, 438.9 [M + Na]+. HRMS (ESI): m/z calcd. for
C21H24N2O7 [M + Na]+ 439.1481; found 439.1475.
The resulting reduced product (374 mg, 0.90 mmol) was dissolved
in CH2Cl2 (10 mL) and TFA (2 mL) was added to the mixture at
room temperature. The progress of the reaction was followed by
1H NMR spectroscopy. After 20 min, the mixture was treated with
a saturated solution of NaHCO3 (10 mL) and the organic phase
was washed with brine, dried with MgSO4, filtered, and concen-
trated to give the pure product 6, yield 251 mg (88%). 1H NMR
(400 MHz, CDCl3): δ = 9.73 (s, 1 H), 7.95 (dd, J = 8.1, 1.3 Hz, 1
H), 7.64 (dt, J = 7.5, 1.4 Hz, 1 H), 7.55 (dϫtripletoid, J = 8.1, 7.5,
1.6 Hz, 1 H), 7.50 (dd, J = 7.5, 1.6 Hz, 1 H), 7.02 (tripletoid, J =
3.0, 2.6 Hz, 1 H), 6.20 (t, J = 2.7 Hz, 1 H), 4.07 (q, J = 7.1 Hz, 2
H), 2.57–2.51 (m, 4 H), 1.20 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 188.5, 172.7, 149.7, 132.8, 132.3, 130.9,
128.9, 128.8, 125.8, 124.0, 123.0, 112.8, 60.5, 33.7, 28.0, 14.1 ppm.
film): ν = 3134, 2983, 2954, 1732, 1613, 1569, 1529, 1459, 1436,
˜
1395, 1371, 1344, 1284, 1246, 1155, 1078, 1037, 954, 929, 849, 802,
776, 748, 704, 648, 634, 596, 527 cm–1. MS-ESI: m/z = 369.3 (100)
[M + Na]+, 269.2 (17) [M – 77]. HRMS (ESI): m/z calcd. for
C17H18N2O6 [M + Na]+ 369.10626; found 369.10566.
IR (KBr): ν = 3289, 3130, 3115, 2975, 2929, 2903, 2868, 2610, 2554,
˜
1998, 1964, 1886, 1847, 1734, 1629, 1571, 1529, 1494, 1481, 1412,
1372, 1353, 1308, 1291, 1276, 1259, 1221, 1202, 1183, 1162, 1121,
1100, 1075, 1032, 1012, 976, 965, 938, 896, 884, 852, 791, 771, 758,
Methyl 4-(2-Nitrophenyl)-1H-pyrrole-2-carboxylate (39): Under ar-
gon,
0.95 mmol) in anhydrous DMF (3 mL) was heated at 120 °C for
= 339.1 3 h. The reaction mixture was cooled to room temperature and
a solution of Boc-protected phenylpyrrole 3 (330 mg,
715, 701, 647, 621, 588, 529 cm–1. ESI-MS: m/z
[M + Na]+. HRMS (ESI): m/z calcd. for C16H16N2O5 [M + Na]+
poured into water (100 mL). The aqueous layer was extracted with
339.0957; found 339.0952.
EtOAc (3ϫ 60 mL) and the combined organic extracts were
Eur. J. Org. Chem. 2014, 7865–7877
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7875

R. Neier et al.
FULL PAPER
washed with water (2ϫ 50 mL), brine (60 mL), dried with MgSO4,
filtered, and the solvents evaporated. The residue was purified by
flash chromatography on silica gel (petroleum ether/EtOAc, 90:10
action was quenched with saturated aqueous NaHCO3 (30 mL).
The organic and aqueous layers were separated and the organic
layer was washed with brine (20 mL), dried with MgSO4, filtered,
to 70:30) to afford the deprotected phenylpyrrole 39 (243 mg, and the solvents evaporated. Deprotected pyrrolinone 42 (131 mg,
100%) as a yellow solid. Rf = 0.15 (petroleum ether/EtOAc, 80:20). 98%) was recovered as a yellow solid. 1H NMR (400 MHz,
1H NMR (400 MHz, [D6]acetone): δ = 11.28 (br. s, 1 H, NH), 7.75
(dd, J = 7.9, 0.9 Hz, 1 H), 7.68 (dd, J = 7.6, 1.8 Hz, 1 H), 7.65
CD3OD): δ = 8.03 (dd, J = 8.1, 1.3 Hz, 1 H), 7.76 (td, J = 7.5,
1.3 Hz, 1 H), 7.66 (td, J = 7.5, 1.3 Hz, 1 H), 7.59 (dd, J = 7.6,
(ddd, J = 7.8, 6.6, 1.2 Hz, 1 H), 7.49 (ddd, J = 8.1, 6.8, 1.9 Hz, 1 1.5 Hz, 1 H), 6.12 (t, J = 1.6 Hz, 1 H), 4.35 (d, J = 1.6 Hz, 2
H), 7.30 (dd, J = 3.0, 1.8 Hz, 1 H), 6.93 (t, J = 1.9 Hz, 1 H), 3.81
H) ppm. 13C NMR (100 MHz, CD3OD): δ = 176.0, 158.3, 149.6,
(s, 3 H) ppm. 13C NMR (100 MHz, [D6]acetone): δ = 161.5, 150.3, 134.4, 131.6, 131.6, 129.4, 126.6, 125.3, 51.6 ppm. MS (ESI): m/z
132.7, 131.7, 129.1, 128.3, 124.5, 124.1, 123.1, 121.1, 114.6, (%) = 227.2 (100) [M + Na]+. HRMS (ESI): m/z calcd. for
51.6 ppm. IR (KBr): ν = 3282, 3128, 2956, 2925, 2855, 1967, 1926,
C10H8N2O3 [M + Na]+ 227.04326; found. 227.04317.
˜
1697, 1608, 1568, 1516, 1438, 1393, 1367, 1309, 1292, 1251, 1217,
1174, 1151, 1048, 992, 943, 929, 854, 834, 807, 764, 741, 703, 648,
611, 543, 503, 459, 438, 419 cm–1. MS-ESI: m/z = 245.3 (100) [M –
H]–. HRMS (ESI): m/z calcd. for C12H10N2O4 [M + Na]+
269.05383; found 269.05355.
Ethyl (E/Z)-3-Ethyl-6-[4-(2-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyr-
rol-1-yl]-6-oxohex-2-enoate (11): To a solution of pyrrolinone 42
(50 mg, 0.25 mmol) in anhydrous THF (3.0 mL) was added drop-
wise BuLi (2.0 m in cyclohexane, 0.13 mL, 0.25 mmol) at –55 °C
and under argon. After 10 min at –54 °C, a solution of activated
Methyl (E/Z)-1-(6-Ethoxy-4-ethyl-6-oxohex-4-enyl)-4-(2-nitrophen- ester 35 (98 mg, 0.27 mmol) in anhydrous THF (2.0 mL) was added
yl)-1H-pyrrole-2-carboxylate (2): To a solution of phenylpyrrole 39
(20 g, 0.08 mmol) in anhydrous DMF (0.3 mL) at 0 °C was added
95% NaH (2 mg, 0.09 mmol) under argon. After 10 min at 0 °C,
the solution was stirred at room temperature for 1 h. The mixture
was cooled to 0 °C, and a solution of iodo acrylate 33 (26 mg,
dropwise over 15 min. The mixture was stirred for an additional
5 min. Over this 30 min period, the temperature had been allowed
to reach –45 °C. The mixture was quenched with AcOH (0.1 mL)
and evaporated with 5 mL of silica. The product was purified by
column chromatography on silica gel (cyclohexane/EtOAc, 70:30
0.09 mmol) in anhydrous DMF (0.1 mL) was added dropwise. The to 50:50) to afford an E/Z mixture (70:30) of 11 (43 mg, 45%) as
flask containing 39 was rinsed with additional anhydrous DMF
(0.2 mL) and the resulting solution was stirred at room temperature
for 6 h, and then poured into water (20 mL) and extracted with
EtOAc (3ϫ 10 mL). The combined organic extracts were washed
with water (2ϫ 10 mL), brine (15 mL), dried with MgSO4, filtered,
and concentrated. The product was purified by column chromatog-
raphy (petroleum ether and then petroleum ether/EtOAc, 90:10) to
afford an E/Z mixture (70:30) of 2 (36 mg, 100%) as a yellowish
an orange oil. Rf = 0.45 (petroleum ether/EtOAc, 50:50). 1H NMR
(400 MHz, CDCl3): δ [(E)-11] = 8.11–8.08 (m, 1 H), 7.73 (td, J =
7.3, 2.4 Hz, 1 H), 7.67–7.62 (m, 1 H), 7.41 (dd, J = 7.2, 2.3 Hz, 1
H), 6.15 (t, J = 1.5 Hz, 1 H), 5.71 (s, 1 H), 4.64 (d, J = 1.5 Hz, 2
H), 4.15 (q, J = 7.1 Hz, 2 H), 3.21–3.13 (m, 2 H), 2.68 (q, J =
7.5 Hz, 2 H), 2.23 (td, J = 7.6, 0.8 Hz, 2 H), 1.28 (t, J = 7.1 Hz, 3
H), 1.12 (t, J = 7.5 Hz, 3 H) ppm; δ [(Z)-11] = 8.11–8.08 (m, 1 H),
7.73 (td, J = 7.3, 2.4 Hz, 1 H), 7.67–7.62 (m, 1 H), 7.41 (dd, J =
oil. Rf = 0.33 (petroleum ether/EtOAc, 80:20). GC: tR = 21.27 [(E)- 7.2, 2.3 Hz, 1 H), 6.13 (t, J = 1.5 Hz, 1 H), 5.69 (s, 1 H), 4.64 (d,
2], 20.55 [(Z)-2] min. 1H NMR (400 MHz, [D6]acetone): δ [(E)-2]
J = 1.5 Hz, 2 H), 4.14 (q, J = 7.1 Hz, 2 H), 3.21–3.13 (m, 2 H),
= 7.75 (dd, J = 7.9, 2.4 Hz, 1 H), 7.68–7.62 (m, 2 H), 7.49 (ddd, J 2.97 (app. t, J = 7.9 Hz, 2 H), 2.26 (q, J = 7.3 Hz, 2 H), 1.27 (t, J
= 8.8, 8.1, 4.3 Hz, 1 H), 7.35 (d, J = 2.1 Hz, 1 H), 6.99 (d, J =
= 7.1 Hz, 3 H), 1.11 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (100 MHz,
2.1 Hz, 1 H), 5.63 (s, 1 H), 4.45 (t, J = 7.1 Hz, 2 H), 4.08 (q, J = CDCl3): δ [(E)-11] = 171.8, 168.7, 166.3, 163.5, 156.8, 147.6, 133.6,
7.1 Hz, 2 H), 3.81 (s, 3 H), 2.64 (q, J = 7.5 Hz, 2 H), 2.23 (app. t, 130.9, 130.1, 128.0, 125.1, 124.5, 115.5, 59.6, 52.3, 34.7, 31.8, 25.5,
J = 7.5 Hz, 2 H), 2.00 (app. quint, J = 7.3 Hz, 2 H), 1.21 (t, J = 14.3, 13.0 ppm; δ [(Z)-11] = 172.2, 168.7, 166.4, 163.5, 156.5, 147.6,
7.1 Hz, 3 H), 1.03 (t, J = 7.5 Hz, 3 H) ppm; δ [(Z)-2] = 7.75 (dd, J 133.5, 130.8, 130.1, 128.1, 125.0, 124.6, 115.6, 59.6, 52.3, 35.4, 31.4,
= 7.9, 2.4 Hz, 1 H), 7.68–7.62 (m, 2 H), 7.49 (ddd, J = 8.8, 8.1, 26.9, 14.3, 11.9 ppm. IR (KBr, film): ν = 3079, 2979, 2924, 1744,
˜
4.3 Hz, 1 H), 7.37 (d, J = 2.1 Hz, 1 H), 6.98 (d, J = 2.1 Hz, 1 H), 1713, 1683, 1646, 1601, 1570, 1531, 1478, 1446, 1373, 1349, 1319,
5.66 (s, 1 H), 4.44 (t, J = 7.2 Hz, 2 H), 4.10 (q, J = 7.0 Hz, 2 H), 1259, 1239, 1208, 1190, 1172, 1152, 1085, 1048, 984, 897, 882, 866,
3.80 (s, 3 H), 2.67 (app. t, J = 7.7 Hz, 2 H), 2.22 (dq, J = 7.5, 796, 755, 726, 697, 688, 646, 629, 574, 533 cm–1. HPLC-MS (EI,
1.2 Hz, 2 H), 1.97 (app. quint, J = 7.4 Hz, 2 H), 1.22 (t, J = 7.1 Hz, 70 eV): tR = 6.94 [(E)-11], 7.08 [(Z)-11] min; m/z (%) = 425.1 (11)
1
3 H), 1.05 (t, J = 7.4 Hz, 3 H) ppm. H NOE diff: (E)-2: irrad H16 [M + K]+, 409.2 (100) [M + Na]+, 387.2 (14) [M + H]+. HRMS
(5.63 ppm)Ǟenhanced H14 (2.23 ppm) and H13 (2.00 ppm). 13C
(ESI): m/z calcd. for C20H22N2O6 [M + Na]+ 409.13756; found
NMR (100 MHz, [D6]acetone): δ [(E)-2] = 166.4, 165.1, 161.6, 409.13695.
150.2, 132.7, 131.6, 128.9, 128.6, 128.3, 124.2, 123.3, 119.0, 117.5,
116.0, 59.8, 51.5, 49.5, 35.2, 30.2, 25.3, 14.6, 13.3 ppm; δ [(Z)-2] =
Ethyl
(E/Z)-6-{2-[(tert-Butyldimethylsilyl)oxy]-4-(2-nitrophenyl)-
1H-pyrrol-1-yl}-3-ethyl-6-oxohex-2-enoate (26): To a stirred solu-
tion of pyrrolinone 11 (40 mg, 0.11 mmol) in anhydrous CH2Cl2
(1 mL) at room temperature and under argon was added 2,6-luti-
dine (0.04 g, 0.31 mmol) followed by TBSOTf (0.02 mL,
0.11 mmol). The reaction mixture was stirred at room temperature
for 15 min (reaction progress monitored by TLC) then concen-
trated in vacuo. The residue was purified by flash chromatography
on silica gel (cyclohexane/EtOAc, 90:10) to afford an E/Z mixture
(60:40) of 26 (36 mg, 69%) as a yellow oil. Rf = 0.39 (cyclohexane/
EtOAc, 90:10). 1H NMR (400 MHz, CDCl3): δ [(E)-26] = 7.70
(ddd, J = 8.0, 4.2, 1.2 Hz, 1 H), 7.54 (ddd, J = 7.8, 2.7, 1.2 Hz, 1
H), 7.51–7.47 [m (partially solved), J = 7.8, 4.2 Hz, 1 H], 7.40–7.35
[m (partially solved), J = 8.0 Hz, 1 H], 7.17 (d, J = 2.3 Hz, 1 H),
5.66 (s, 1 H), 5.28 (d, J = 2.3 Hz, 1 H), 4.15 (q, J = 7.2 Hz, 2 H),
166.4, 164.9, 161.6, 150.2, 132.7, 131.6, 128.9, 128.6, 128.2, 124.2,
123.3, 118.9, 117.4, 115.8, 60.0, 51.5, 49.9, 31.5, 30.9, 29.6, 14.3,
12.3 ppm. IR (KBr, film): ν = 3065, 2956, 2874, 1713, 1645, 1609,
˜
1563, 1531, 1495, 1476, 1446, 1394, 1368, 1259, 1206, 1148, 1105,
1038, 959, 933, 853, 812, 779, 749, 696, 674, 651, 561, 509,
445 cm–1. MS-ESI: m/z = 437.5 (100) [M + Na]+, 453.3 (13) [M +
K]+. HRMS (ESI): m/z calcd. for C22H26N2O6 [M + Na]+
437.16886; found 437.16802.
4-(2-Nitrophenyl)-1H-pyrrol-2(5H)-one (42): Trifluoroacetic acid
(1.60 mL) was added dropwise to a solution of Boc-protected pyr-
rolinone 8b (200 mg, 0.66 mmol) in anhydrous CH2Cl2 (8.0 mL) at
room temperature. The mixture was stirred at room temperature
for 40 min (reaction progress monitored by TLC) and then the re-
7876
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 7865–7877

Synthesis and Transformation of Substituted Pyrrolinones
[6] a) J.-Y. Cho, M. K. Tse, D. Holmes, R. E. Maleczka Jr., M. R.
Smith III, Science 2002, 295, 305–308; b) T. Ishiyama, J. Tak-
agi, K. Ishida, N. Miyaura, N. R. Anastasi, J. F. Hartwig, J.
Am. Chem. Soc. 2002, 124, 390–391; c) J. Takagi, K. Sato, J. F.
Hartwig, T. Ishiyama, N. Miyaura, Tetrahedron Lett. 2002, 43,
5649–5651.
3.13–3.08 (m, 2 H), 2.66 (q, J = 7.5 Hz, 2 H), 2.62 (dd, J = 7.7,
6.4 Hz, 2 H), 1.28 (t, J = 7.2 Hz, 3 H), 1.11 (t, J = 7.5 Hz, 3 H),
1.00 (s, 9 H), 0.32 (s, 6 H) ppm; δ [(Z)-26] = 7.70 (ddd, J = 8.0,
4.2, 1.2 Hz, 1 H), 7.54 (ddd, J = 7.8, 2.7, 1.2 Hz, 1 H), 7.51–7.47
[m (partially solved), J = 7.8, 4.2 Hz, 1 H], 7.40–7.35 [m (partially
solved), J = 8.0 Hz, 1 H], 7.20 (d, J = 2.3 Hz, 1 H), 5.71 (s, 1 H),
5.25 (d, J = 2.3 Hz, 1 H), 4.13 (q, J = 7.1 Hz, 2 H), 3.13–3.08 (m,
2 H), 2.96 (dd, J = 9.0, 6.7 Hz, 2 H), 2.23 (qd, J = 7.4, 1.3 Hz, 2
H), 1.26 (t, J = 7.1 Hz, 3 H), 1.10 (t, J = 7.4 Hz, 3 H), 0.95 (s, 9
H), 0.28 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ [(E)-26] =
169.9, 166.1, 163.4, 149.0, 143.0, 132.1, 130.8, 129.0, 127.7, 123.8,
120.4, 115.6, 109.7, 91.8, 59.6, 35.3, 31.7, 25.7, 25.6, 18.3, 14.3,
13.0 ppm; δ [(Z)-26] = 170.4, 166.2, 163.8, 149.1, 143.1, 132.0,
130.8, 129.2, 127.5, 123.7, 120.1, 115.6, 109.7, 91.5, 59.7, 36.4, 31.8,
27.1, 25.7, 18.1, 14.1, 12.0 ppm. MS-ESI: m/z (%) = 539.4 (7) [M
+ K]+, 423.5 (100) [M + Na]+, 501.5 (8) [M + H]+. HRMS (ESI):
[7] M. D. Morrison, J. J. Hanthorn, D. A. Pratt, Org. Lett. 2009,
11, 1051–1054.
[8] a) T. Mukaiyama, Challenges in Synthetic Organic Chemistry,
Oxford, UK, New York, 1990; b) T. Mukaiyama, M. Murak-
ami, Synthesis 1987, 1043–1054.
[9] For selected syntheses of Boc-protected ureas and carbamates
under reported conditions, see: a) H.-J. Knölker, T. Braxmeier,
Tetrahedron Lett. 1996, 37, 5861–5864; b) H.-J. Knölker, T.
Braxmeier, G. Schlechtingen, Angew. Chem. Int. Ed. Engl. 1995,
34, 2497–2500; Angew. Chem. 1995, 107, 2746; c) H.-J. Knolker,
T. Braxmeier, Tetrahedron Lett. 1998, 39, 9407–9410.
[10] a) P. A. Jacobi, R. W. DeSimone, I. Ghosh, J. Guo, S. H.
Leung, D. Pippin, J. Org. Chem. 2000, 65, 8478–8489; b) G.
Rassu, G. Casiraghi, P. Spanu, L. Pinna, G. G. Fava, M. B.
Ferrari, G. Pelosi, Tetrahedron: Asymmetry 1992, 3, 1035–1048.
[11] a) W.-R. Li, S. T. Lin, N.-M. Hsu, M.-S. Chern, J. Org. Chem.
2002, 67, 4702–4706; b) I. Baussanne, J. Royer, Tetrahedron
Lett. 1996, 37, 1213–1216; c) F. Zanardi, L. Battistini, G.
Rassu, M. Cornia, G. Casiraghi, J. Chem. Soc. Perkin Trans. 1
1995, 2471–2475.
m/z calcd. for C26H36N2O6Si [M
523.22399.
+
Na]+ 523.22403; found
Supporting Information (see footnote on the first page of this arti-
cle): X-ray crystallographic analysis of 18b and 25a, studies on N-
acylation of 1H-pyrrol-2(5H)-one, detailed experimental pro-
cedures, full characterization, and copies of 1H and 13C NMR spec-
tra of newly reported compounds.
[12] M. A. Drinan, T. D. Lash, J. Heterocycl. Chem. 1994, 31, 255–
257.
[13] M. G. Banwell, D. A. S. Beck, A. C. Willis, ARKIVOC
(Gainesville, FL, U.S.) 2006, 163–174.
[14] I. Kholod, O. Vallat, A.-M. Buciumas, R. Neier, ARKIVOC
(Gainesville, FL, U.S.) 2014, 256–273.
[15] a) Y.-i. Fukuda, M. Shindo, K. Shishido, Org. Lett. 2003, 5,
749–751; b) T. Shimizu, K. Osako, T. Nakata, Tetrahedron Lett.
1997, 38, 2685–2688.
[16] K. Kiewel, Z. Luo, G. A. Sulikowski, Org. Lett. 2005, 7, 5163–
5165.
Acknowledgments
The authors thank Dr. Armelle Vallat, University of Neuchâtel for
MS measurements and Dr. Julien Furrer and Professor Claudio
Dalvit, University of Neuchâtel for NMR measurements and dis-
cussions. Financial support by the University of Neuchâtel is grate-
fully acknowledged.
[17] W. S. Wadsworth Jr., W. D. Emmons, J. Am. Chem. Soc. 1961,
83, 1733–1738.
[1] a) O. Baudoin, F. Claveau, S. Thoret, A. Herrbach, D. Guen-
ard, F. Gueritte, Bioorg. Med. Chem. 2002, 10, 3395–3400; b)
O. Baudoin, D. Guenard, F. Gueritte, Mini-Rev. Org. Chem.
2004, 1, 333–341; c) B. David, T. Sevenet, M. Morgat, D. Guen-
ard, A. Moisand, Y. Tollon, O. Thoison, M. Wright, Cell Motil.
Cytoskeleton 1994, 28, 317–326; d) O. Thoison, D. Guenard,
T. Sevenet, C. Kan-Fan, J. C. Quirion, H. P. Husson, J. R. De-
verre, K. C. Chan, P. Potier, C. R. Acad. Sci., Ser. II 1987, 304,
157–160.
[18] A. L. Bowie Jr., D. Trauner, J. Org. Chem. 2009, 74, 1581–1586.
[19] Y. Deng, R. G. Salomon, J. Org. Chem. 1998, 63, 3504–3507.
[20] a) K. Bowden, I. M. Heilbron, E. R. H. Jones, B. C. L. Wee-
don, J. Chem. Soc. 1946, 39–45; b) T. Hu, J. S. Panek, J. Am.
Chem. Soc. 2002, 124, 11368–11378.
[21] R. Vallinayagam, H. Bertschy, Y. Berger, V. Wenger, R. Neier,
Synthesis 2007, 3731–3735.
[22] I. Kholod, R. Neier, Targets in Heterocyclic Systems (Eds.:
O. A. Attanasi, D. Spinelli), RSC, Cambridge, UK, 2009, vol.
13, p. 252–272.
[23] V. A. Kallepalli, F. Shi, S. Paul, E. N. Onyeozili, R. E. Ma-
leczka, M. R. Smith, J. Org. Chem. 2009, 74, 9199–9201.
[24] a) E. M. Beck, R. Hatley, M. J. Gaunt, Angew. Chem. Int. Ed.
2008, 47, 3004–3007; Angew. Chem. 2008, 120, 3046; b) V. H.
Rawal, M. P. Cava, Tetrahedron Lett. 1985, 26, 6141–6142.
[25] a) D. J. Ager, I. Prakash, D. R. Schaad, Aldrichim. Acta 1997,
30, 3–12; b) D. A. Evans, J. Bartroli, T. L. Shih, J. Am. Chem.
Soc. 1981, 103, 2127–2109.
[26] S. G. Davies, D. J. Dixon, G. J. M. Doisneau, J. C. Prodger,
H. J. Sanganee, Tetrahedron: Asymmetry 2002, 13, 647–658.
[27] a) M. B. Andrus, W. Li, R. F. Keyes, J. Org. Chem. 1997, 62,
5542–5549; b) M. Hosseini, H. Kringelum, A. Murray, J. E.
Tonder, Org. Lett. 2006, 8, 2103–2106; c) Y. Jin, Y. Liu, Z.
Wang, S. Kwong, Z. Xu, T. Ye, Org. Lett. 2010, 12, 1100–1103.
[28] M. G. Banwell, A. J. Edwards, K. A. Jolliffe, J. A. Smith, E.
Hamel, P. Verdier-Pinard, Org. Biomol. Chem. 2003, 1, 296–
305.
[2] O. Baudoin, F. Gueritte, Stud. Nat. Prod. Chem. 2003, 29, 355–
417.
[3] A. Decor, B. Monse, M.-T. Martin, A. Chiaroni, S. Thoret, D.
Guenard, F. Gueritte, O. Baudoin, Bioorg. Med. Chem. 2006,
14, 2314–2332.
[4] For recent syntheses of rhazinilam and its analogues, see: a) Z.
Gu, A. Zakarian, Org. Lett. 2010, 12, 4224–4227; b) I. Kholod,
O. Vallat, A.-M. Buciumas, R. Neier, Heterocycles 2011, 82,
917–948; c) L. McMurray, E. M. Beck, M. J. Gaunt, Angew.
Chem. Int. Ed. 2012, 51, 9288–9291; d) K. Sugimoto, K.
Toyoshima, S. Nonaka, K. Kotaki, H. Ueda, H. Tokuyama,
Angew. Chem. Int. Ed. 2013, 52, 7168–7171.
[5] a) A. Meunier, R. Neier, Synthesis 1988, 381–383; b) H. Bert-
schy, A. Meunier, R. Neier, Angew. Chem. 1990, 102, 828–830;
c) A. R. Chaperon, T. M. Engeloch, R. Neier, Angew. Chem.
Int. Ed. 1998, 37, 358–360; Angew. Chem. 1998, 110, 369; d) R.
Neier, C. Soldermann-Pissot, Eur. Pat. Appl. EP 1357110 A1,
October 29, 2003; e) O. Vallat, Doctoral Thesis, Université
de Neuchâtel, Switzerland, 2004; f) A.-M. Buciumas, Doctoral
Thesis, Université de Neuchâtel, Switzerland, 2008.
Received: July 10, 2014
Published Online: October 30, 2014
Eur. J. Org. Chem. 2014, 7865–7877
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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