One-pot two-step synthesis of 1-(ethoxycarbonyl)indolizines via pyridinium ylides

Article abstract of DOI:10.1002/ejoc.201300784

Pyridinium salts Py⁺-CH₂-EWG (EWG = CO₂Et, CONEt₂, CN, COMe, COPh) reacted with Michael acceptors Ar-CH=C(CO₂Et)(Acc) (Acc = CO₂Et, COMe, SO₂Me, CONH₂) at ambient temperature in the presence of base to give [3 + 2]-cycloadducts by stepwise [3 + 2]-cycloaddition of the intermediate pyridinium ylides. Treatment of the crude reaction mixtures with 1 equiv. of chloranil and atmospheric oxygen in the presence of sodium hydroxide gave 1-(ethoxycarbonyl)indolizines by dehydrogenation and elimination of the acceptor group (Acc). A good yield of indolizine was also obtained from Py ⁺-CH₂CN and iPr-CH=C(CO₂Et)₂, which indicates that this method is not restricted to aromatic Michael acceptors. Structurally related isoquinolinium salts react with Michael acceptors analogously to give pyrrolo[2,1-a]isoquinolines.

Full text of DOI:10.1002/ejoc.201300784

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FULL PAPER
DOI: 10.1002/ejoc.201300784
One-Pot Two-Step Synthesis of 1-(Ethoxycarbonyl)indolizines via Pyridinium
Ylides
Dominik S. Allgäuer[a] and Herbert Mayr*[a]
Keywords: Cycloaddition / Nitrogen heterocycles / Reaction mechanisms / Oxidation / Substituent effects
Pyridinium salts Py+-CH2-EWG (EWG = CO2Et, CONEt2,
CN, COMe, COPh) reacted with Michael acceptors Ar-
CH=C(CO2Et)(Acc) (Acc = CO2Et, COMe, SO2Me, CONH2)
at ambient temperature in the presence of base to give
[3+2]-cycloadducts by stepwise [3+2]-cycloaddition of the
intermediate pyridinium ylides. Treatment of the crude reac-
tion mixtures with 1 equiv. of chloranil and atmospheric oxy-
gen in the presence of sodium hydroxide gave 1-(ethoxy-
carbonyl)indolizines by dehydrogenation and elimination of
the acceptor group (Acc). A good yield of indolizine was also
obtained from Py+-CH2CN and iPr-CH=C(CO2Et)2, which in-
dicates that this method is not restricted to aromatic Michael
acceptors. Structurally related isoquinolinium salts react with
Michael acceptors analogously to give pyrrolo[2,1-a]isoquin-
olines.
Introduction
Since their discovery by Kröhnke in 1935,[1] the proper-
ties and reactions of pyridinium ylides have been intensively
studied.[2,3] In recent years, pyridinium ylides have attracted
a lot of attention, as they react with various electrophiles
to form a great variety of products,[4] including indoliz-
ines.[5] The indolizine scaffold has a broad pharmacological
profile, as it can act as calcium-channel blocker[6] or aro-
matase inhibitor,[7] and it is found in agents with antibi-
otic,[8] antitumor,[9] anti-inflammatory,[10] and antiviral ac-
tivities.[11] Moreover, several indolizines are potent, inex-
pensive, and easily modifiable fluorescent probes.[12]
Reactions of pyridinium ylides with benzylidene-ma-
lononitriles and other unsaturated nitriles have already been
reported.[4b–4f,4o] Cyclopropanes 3 have been obtained from
the reactions of pyridinium salts 1·H+X– with benzylidene-
malononitriles 2 and related compounds under basic condi-
tions (Scheme 1).[4f] At least one of the two acceptor groups
of the Michael acceptor has to be a cyano group, how-
ever.[4b,4d–4f] The corresponding reactions of isoquinolinium
salts 4·H+Br– with Michael acceptors 2 under basic condi-
tions produced pyrrolo[2,1-a]isoquinolines 5 after oxidative
work-up (Scheme 2).[4o]
Scheme 1. Cyclopropanation of benzylidene-malononitriles and re-
lated compounds 2 via pyridinium ylides.[4f]
The nitrile group was preserved in these products, while the
amide or the ester group was eliminated during the oxidat-
ive aromatization.
The different reaction course for pyridinium and isoquin-
olinium ylides has been explained by the ab initio MO cal-
culations of Matsumura and co-workers.[3i] They showed
that the addition of pyridinium and isoquinolinium ylides
to alkylidene-malononitriles proceeds stepwise, and not in
a concerted manner. As cyclization of the intermediate be-
taine to give the [3+2]-cycloadduct leads to a greater loss
of aromaticity for the pyridinium ylides than for the iso-
quinolinium ylides, only the latter ylides undergo [3+2]-
cycloadditions with Michael acceptors 2. In contrast, the
betaines formed from pyridinium ylides undergo intramo-
lecular SN2 reactions that result in the formation of cyclo-
propanes and the elimination of pyridine.
The same pyrrolo[2,1-a]isoquinolines (i.e., 5) were ob-
tained from the reaction of isoquinolinium salt 4·H+Br–
with either of the two electrophiles 2 shown in Scheme 2.
[a] Department Chemie, Ludwig-Maximilians-Universität
München,
Butenandtstrasse 5–13 (Haus F), 81377 München, Germany
E-mail: Herbert.mayr@cup.uni-muenchen.de
Homepage: http://www.cup.uni-muenchen.de/oc/mayr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300784.
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D. S. Allgäuer, H. Mayr
FULL PAPER
Scheme 2. Reaction of isoquinolinium ylide 4 with benzylidene cyanoactetates and cyanoacetamides 2.[4o]
We now report that in contrast to cyano-substituted
Michael acceptors 2, benzylidene-malonates 6 undergo
[3+2]-cycloaddition with pyridinium ylides. Subsequent
oxidation provides a simple and straightforward access to
indolizines.
This investigation is part of our program to determine
the nucleophile-specific parameters N and sN by studying
the rates of reactions with benzylidene-malonates 6, which
have been introduced as reference electrophiles (–24 Ͻ E Ͻ
–17 for p-NMe2 to p-NO2)[13] for the characterization of
strong nucleophiles by the linear-free-energy relationship
given in Equation (1).[14]
logk20 °C = sN(N + E)
(1)
Results and Discussion
As most pyridinium (1) and isoquinolinium ylides (4) are
unstable compounds, we made no attempts to isolate them.
Instead we used their conjugate acids 1·H+X– or 4·H+Br–,
which were obtained by nucleophilic substitution from the
corresponding pyridines or from isoquinoline in THF in
moderate to high yields (Scheme 3).[3c,15]
Treatment of 1·H+X– or 4·H+Br– with a base in the pres-
ence of arylidene-malonates 6a–i or alkylidene-malonate 6j
(Table 1) gave ylides 1 and 4, which subsequently reacted
with Michael acceptors 6.
As shown by Table 2, entries 1–5 Michael adduct M-1a
was formed exclusively when an equimolar mixture of
1a·H+Br– and 6f was treated with an excess of HNMe2,
NEt3, or KOtBu in various solvents at ambient tempera-
ture. Analogous reactions with NEt3 (2 equiv.) in CH2Cl2
or Et2O/MeCN (2:1) at ambient temperature gave mixtures
of Michael adduct M-1a and [3+2]-cycloadduct C-1a
within 15 min (Table 2, entries 6 and 7). [3+2]-Cycloadduct
C-1a, contaminated by traces of 7a, was observed exclu-
Scheme 3. Synthesis of pyridinium 1·H+X– and isoquinolinium
salts 4·H+Br– used as precursors for pyridinium ylides 1 and isoqui-
nolinium ylide 4.
sively, when the mixture of 1a·H+Br– and 6f was combined terized by 2D NMR spectroscopy and HRMS (Scheme 4).
with KOtBu (1.1 equiv.) in THF (Table 2, entry 8) or with The ratio of the diastereoisomers was determined from the
NaOH (32% aq.) under biphasic conditions (Table 2, en- 1H NMR spectrum of the crude product, and the stereo-
try 9).
chemistry was assigned on basis of NOESY-correlation of
Although [3+2]-cycloadduct C-1a was a labile com- the protons at the 2-, 3-, and 10b-positions of the adduct.
pound that could not be purified, [3+2]-cycloadduct C-4a, From the configuration of the stereocenters, one can con-
from the reaction of 4a and 6f, was purified and charac- clude that the major diastereoisomer of C-4a shown is pref-
2
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Synthesis of 1-(Ethoxycarbonyl)indolizines
Table 1. Electrophilicity parameters E of arylidene (i.e., 6a–i) and erentially formed by an anti-2-endo approach of ylide 4a
alkylidene (i.e., 6j) malonates.[a]
and benzylidene-malonate 6f. The stereochemistry of the
minor diastereoisomers could not be assigned unambigu-
ously.
To find the best conditions for the conversion of [3+2]-
cycloadduct C-1a into indolizine 7a in CH2Cl2 at ambient
temperature, we tested different oxidants. Catalytic
amounts of Pd/C under an O2 atmosphere, di-tert-butyl hy-
droperoxide (4 equiv.), or N-chlorosuccinimide (4 equiv.)
did not promote the oxidation of C-1a into indolizine 7a
within 18 h at 20 °C (Table 3, entries 1–3). The formation
of indolizine 7a was observed when DDQ was used as an
oxidant (Table 3, entry 4). Chloranil gave a significantly
higher conversion into indolizine 7a (Table 3, entry 5).
When the amount of chloranil was reduced and the reaction
time was decreased from 18 to 3 h, a further increase in the
conversion to indolizine 7a was observed (Table 3, entry 6).
After a reaction time of 1 h, the conversion to 7a was the
same as after 3 h, but decreasing the reaction time further
led to a decrease in the conversion (Table 3, entries 7 and
8). Under all the conditions examined, the oxidation of C-
1a to 7a was accompanied by regeneration of 6f, which indi-
cates that the formation of C-1a by cyclization of betaine
B-1a must be a reversible process (Table 2). The existence
of the base-mediated equilibrium between Michael adduct
M-1a and [3+2]-cycloadduct C-1a was proved by the for-
[a] Generated by Knoevenagel condensation according to ref.[13,16]
mation of indolizine 7a when the solution obtained under
the conditions of Table 2, entry 2 was heated with MnO2 at
[b] E parameters taken from ref.[13]
Table 2. Base-induced reactions of pyridinium salts 1a·H+Br– with arylidene-malonate 6f at ambient temperature (B = betaine, M =
Michael adduct, C = [3+2]-cycloadduct).
Entry
Base
Equiv. base
Solvent
Conversion of 6f [%][a]
Ratio M-1a/C-1a[b]
1
2
3
4
5
6
7
8
9
HNMe2 (30% aq.)
NEt3
KOtBu
NEt3
NEt3
NEt3
NEt3
KOtBu
NaOH (32% aq.)
36
2.0
1.2
1.4
2.0
1.5
1.5
1.1
32
DMSO
DMSO
DMSO
MeOH
75[c]
40[c]
93[c]
78
88
92
Ͼ98:2
Ͼ98:2
Ͼ98:2
Ͼ98:2
Ͼ98:2
72:28
MeCN
CH2Cl2
Et2O/MeCN[d]
THF
86
34:66
Ͼ2:98
[e]
99
CH2Cl2
97[f]
Ͼ2:98
[a] From 1H NMR spectroscopy as the ratio: (M-1a + C-1a)/(6f + M-1a + C-1a). [b] From 1H NMR spectroscopy. [c] After aqueous
work-up. [d] Et2O/MeCN = 2:1. [e] Contaminated by traces of indolizine 7a. [f] After filtration through silica (n-pentane/EtOAc/NEt3,
5:1:1).
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D. S. Allgäuer, H. Mayr
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Scheme 4. Formation of [3+2]-cycloadduct C-4a.
Table 3. Oxidant-screening for the formation of indolizine 7a.
Entry
Oxidant
Equivalents
t [h]
Conversion [%]
[a]
1
2
3
4
5
6
7
8
Pd-C/O2
18
18
18
18
18
3
0[b]
DTBPO/air[c]
NCS/air[d]
4.0
4.0
1.4
2.0
1.0
1.0
1.0
0[b]
0[b]
DDQ/air[e]
chloranil/air
chloranil/air
chloranil/air
chloranil/air
54[f, g]
69[f, g]
74[f]
74[f]
65[f]
1
0.5
[a] Under an O2 atmosphere. [b] By TLC. [c] DTBPO = di-tert-butyl peroxide. [d] NCS = N-chlorosuccinimide. [e] DDQ = 2,3-dichloro-
1
5,6-dicyano-1,4-benzoquinone. [f] From H NMR spectroscopy as the ratio: 7a/(6f + 7a). [g] After filtration through silica with CH2Cl2.
100 °C for 3 h in DMSO (for details, see Supporting Infor- Table 4. Direct oxidation of [3+2]-cycloadduct C-4a with chloranil
into indolizine 8a under various conditions.
mation).
To clarify why 1 equiv. of chloranil is sufficient to pro-
mote the full oxidation of [3+2]-cycloadduct C-1a into
indolizine 7a (Table 3, entries 6–8), isolated [3+2]-cycload-
duct C-4a (Table 4) was treated with 1 equiv. of chloranil
under different conditions. When the reaction with
chloranil was performed under a nitrogen atmosphere, only
21% of C-4a was converted into indolizine 8a (Table 4, en-
Entry Atmosphere Additive
Conversion [%][a]
try 1), whereas in an open flask, the oxidation of C-4a with
1 equiv. of chloranil gave a 58% conversion of C-4a into 8a
(Table 4, entry 2). Addition of a small amount of NaOH
(32% aq.) to the reaction mixture significantly lowered the
conversion of C-4a into indolizine 8a (Table 4, entry 3).
When CH2Cl2 was stirred with NaOH (32% aq.) for 1 h,
the aqueous layer was subsequently removed, and the
CH2Cl2 was dried with Na2SO4 before dissolving C-4a and
chloranil, complete conversion of C-4a into 8a was achieved
(Table 4, entry 4). These experiments show that air and
traces of anhydrous hydroxide are favorable to promote the
oxidation of the [3+2]-cycloadduct into the indolizine.
1
2
3
4
N2
air
air
air
–
–
21
58
17
NaOH (32% aq.)
NaOH[b]
quant.
[a] Determined by 1H NMR spectroscopy. [b] CH2Cl2 was stirred
with NaOH (32% aq.) for 1 h; the aqueous layer was removed;
CH2Cl2 was dried with Na2SO4; then C-4a and chloranil were dis-
solved.
A mechanism for the conversion of [3+2]-cycloadduct
C-1a into indolizine 7a that requires only 1 equiv. of
4
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Synthesis of 1-(Ethoxycarbonyl)indolizines
Scheme 5. Proposed mechanism for the formation of indolizine 7a.
chloranil is proposed in Scheme 5. Chloranil abstracts a hy-
As cyano-substituted ylide 1c gave the best results, cy-
dride from the 8a-position of C-1a to give pyridinium ion ano-substituted ylides were used to investigate substituent
9. One ester group of 9 is subsequently hydrolyzed by traces effects in the pyridine ring (Scheme 6, entries 6–8). A 3-
of hydroxide to give intermediate 10, which decarboxylates chloro substituent (in 1f) was tolerated and led regioselec-
in a Grob-type fragmentation[17] to give 2,3-dihydroindoliz- tively to indolizine 7f with chlorine in the 6-position, as
1
ine 11. Oxidation of the initially generated hydrochloranil shown by the dd (3J = 1.8 and 0.9 Hz) of 5-H in the H
anion (redox potential of hydrochloranil –0.71 V in CH2Cl2 NMR spectrum (Scheme 6, entry 6). In contrast, a strong
at 25 °C)[18] with oxygen (redox potential +0.65 V)[19] regen- electron donor such as the 4-NMe2 substituent in ylide 1g
erates chloranil and produces a hydroperoxide anion that resulted in a reduced yield of indolizine 7g (Scheme 6, en-
might also attack the ethyl ester. Hydride abstraction from try 7). Probably, the decreased electrophilicity of the pyrid-
dihydroindolizine 11 by chloranil forms pyridinium ion 12, inium ring retarded the cyclization of betaine B-1g to give
which loses a proton to form indolizine 7a and dihydro- [3+2]-cycloadduct C-1g (see Table 2). The reaction of iso-
chloranil (whose formation was verified by GC–MS). Di- quinolinium ylide 4h with benzylidene malonate 6f resulted
rect oxidation of dihydroindolizine 11 into indolizine 7a by in an almost quantitative formation of indolizine 8a
air seems unlikely, as the closely related dihydroindolizines (Scheme 6, entry 8), which can be explained by the smaller
derived from cyanoacetamides 2 and isoquinolinium ylides loss of aromaticity in the cyclization step.
4 are air-stable.[4o]
To rationalize the low yield of indolizine 7e, we examined
As shown in Scheme 6, indolizines can be analogously the reactions of benzoyl-substituted ylide 1e more closely.
synthesized from other pyridinium and isoquinolinium When 1e·H+Br– was combined with benzylidene-malonate
ylides. Exchanging the ester group in 1a for an N,N-dieth- 6a in EtOH at 20 °C in the presence of NEt3, debenzoylated
ylamido group (in 1b) or an acetyl group (in 1d) led to pyridinium salt 13a was formed in 99% yield (Scheme 7).
slightly decreased yields of the corresponding indolizines This product was unambiguously identified by NMR spec-
(i.e., 7b and 7d), while a cyano substituent led to indolizine troscopy, high-resolution mass spectrometry, and elemental
7c in a higher isolated yield (Scheme 6, entries 1–4). With analysis (see Supporting Information). Its formation may
benzoyl-substituted ylide 1e, indolizine formation was only be explained by the mechanism shown in Scheme 7. The
observed when p-nitro-substituted benzylidene-malonate 6a initially generated ylide (i.e., 1e) undergoes a 1,4-addition
was used as the electrophile, and even then, indolizine 7e to Michael acceptor 6a to form betaine B-1e. This interme-
was only observed in low conversion (Scheme 6, entry 5). diate is protonated by HNEt3+Br– to give Michael adduct
The reason for this behavior will be discussed below.
M-1e. Obviously, nucleophilic attack by ethoxide and elimi-
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Scheme 6. Dependence of indolizine formation on the stabilization of ylides 1 and 2.
nation of the benzoyl group (the formation of ethyl benzo- the reaction of ylide 1e with p-methylbenzylidene-malonate
ate was detected by GC–MS) is faster than the generation 6f.
of [3+2]-cycloadduct C-1e by cyclization of betaine B-1e.
An easier cyclization step, as had previously been ob-
This process seems to be general, as debenzoylated pyridin- served in the isoquinolinium series, was now also found
ium salt 13b was obtained under the same conditions from with benzoyl-substituted ylides, and a good yield of [3+2]-
Scheme 7. Reaction of salt 1e·H+Br– with benzylidene-malonates 6 in ethanol, and proposed mechanism for the formation of salts 13.
6
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Synthesis of 1-(Ethoxycarbonyl)indolizines
Scheme 8. Reaction of 4b·H+Br– with benzylidene-malonate 6a in DMSO at 20 °C.
cycloadduct C-4b was obtained when isoquinolinium salt group in the 2-position, as does the calcium-channel
4b·H+Br– was combined with benzylidene-malonate 6a in blocker fantofarone.[6]
DMSO under basic conditions (Scheme 8). The dia-
Indolizine 7l was not only obtained as described in
stereomeric ratio was determined from the H NMR spec- Table 5, but also when pyridinium bromide 1c·H+Br– was
trum of the crude product. Recrystallization of C-4b from combined with Michael acceptors 14a or 14b under the
EtOH resulted in the formation of needle-shaped and pris- conditions described above, followed by oxidation with
matic crystals, which were separated for analysis (see Sup- chloranil (1 equiv.) in air (Scheme 9). The yield of 7l de-
porting Information). The needle-shaped crystals were com- creased from 34 to 22% when 2 equiv. of chloranil was used
posed of all three diastereoisomers, whereas the prismatic for the oxidation of [3+2]-cycloadduct 15b. Indolizine 7q
1
1
crystals were composed of a single diastereoisomer (by H was obtained from pyridinium bromide 1c·H+Br– and 14c
NMR spectroscopy). Solutions of this single diastereoiso- under the same conditions.
mer in CDCl3 slowly isomerized to give a mixture of three
While the selective formation of 7l from 15a, i.e., the
diastereoisomers, which prevented an unambiguous assign- preferential elimination of the acetyl group over the ethoxy-
ment of the stereochemistry. The isomerization may be due carbonyl group, can be explained by the mechanism de-
to a deprotonation of the proton α to the benzoyl group or scribed in Scheme 5 (nucleophilic attack at COCH3 is
reversible opening of the pyrrolidine ring of C-4b.
easier than that at CO2Et), the preferential cleavage of the
As shown in Table 5, the indolizine synthesis presented SO2Me group can be explained by the high nucleofugality
in this work tolerates strongly electron-withdrawing and of this group, which has recently been quantified
electron-donating groups on the phenyl ring of the electro- (Scheme 10).[20]
phile. The most electrophilic and the least electrophilic aryl-
The preferential cleavage of the formamido group over
idene-malonates tested (i.e., 6a and 6i, respectively) gave the the ethoxycarbonyl group, which has previously been ob-
corresponding indolizines (i.e., 7h and 7o) in lower yields served in the isoquinolinium series,[4o] may be explained by
(Table 5, entries 1 and 9). It was even possible to replace the elimination of isocyanic acid, as shown in Scheme 11.[21]
the aryl ring in the arylidene-malonates by an isopropyl
In agreement with literature reports,[4o] the leaving-group
group (in 6j) and obtain 83% of the corresponding indoliz- abilities of different electron-withdrawing substituents in
ine (i.e., 7p; Table 5, entry 10). Product 7p has an isopropyl the oxidative aromatizations of the [3+2]-cycloadducts to
Table 5. Formation of indolizines 7c,h–p from pyridinium salt 1c·H+Br– and Michael acceptors 6a–j.
Entry
Reactant
R
Product
Yield [%]
1
2
3
4
5
6
7
8
9
10
6a
6b
6c
6d
6e
6f
C6H4-p-NO2
C6H4-p-CN
C6H4-p-Br
C6H4-m-Cl
C6H5
C6H4-p-Me
C6H4-p-OMe
C6H4-p-NMe2
juloldin-9-yl
CH(CH3)2
7h
7i
48
82
81
77
69
74
78
80
53
83
7j
7k
7l
7c
7m
7n
7o
7p
6g
6h
6i
6j
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Scheme 9. Reaction of 1c·H+Br– with 14a–c to give indolizine 7l and 7q.
The preliminary results shown in Scheme 12 illustrate
that less activated Michael acceptors like ethyl methacrylate
could also be used for this reaction sequence, although the
isolated yields of indolizine 18 were low.
Conclusions
Scheme 10. Elimination of the –SO2Me group during the formation
of indolizine 7l.
In contrast to arylidene-malononitriles and other cyano-
substituted Michael acceptors, which are cyclopropanated
by pyridinium ylides 1, arylidene-malonates 6 undergo step-
wise [3+2]-cycloaddition with pyridinium ylides 1 to give
Scheme 11. Cleavage of the formamido group in the formation of indolizine 7q.
give indolizines can roughly be ordered: CN[4o] Ͻ CO2Me [3+2]-cycloadducts C-1. Under certain conditions, interme-
≈ CO2Et Ͻ COMe, SO2Me, CONH2.
diate Michael adducts M-1 can be observed. In the presence
of air and sodium hydroxide, only 1 equiv. of chloranil is
needed to convert [3+2]-cycloadducts C-1 into indolizines
7 by hydride abstraction and degradation of the ethoxy-
carbonyl group. Michael acceptors 14a–c, in which one es-
ter group of the benzylidene-malonates (i.e., 6) is replaced
by an acetyl, methylsulfonyl, or amidocarbonyl group, be-
have similarly, and yield the same indolizines (i.e., 7), be-
cause the latter groups are eliminated faster than are alk-
oxycarbonyl groups. As isoquinolinium ylides react analo-
gously, the sequence of [3+2]-cycloaddition and oxidation
provides a simple one-pot synthesis of indolizines 7 and
benzindolizines 5 from readily accessible pyridinium salts
Scheme 12. Reaction of 1e·H+Br– and ethyl methacrylate to give
indolizine 18.
8
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Synthesis of 1-(Ethoxycarbonyl)indolizines
Py+-CH2-EWG or isoquinolinium salts IQ+-CH2-EWG and
a variety of Michael acceptors.
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Experimental Section
General Procedure for the Synthesis of Indolizines 5 and 7: Michael
acceptor 6a–j or 13a–c (1 equiv.) and salt 1a–h·H+X– or 4a·H+Br–
(1–2 equiv.) were suspended in dichloromethane (CH2Cl2, 0.1 m),
and NaOH (32% aq.; 1 mL) was added with vigorous stirring at
room temperature. The suspension was stirred until the Michael
acceptor was completely consumed (monitored by TLC; 15 min–
1 h). Then water (30 mL) was added, and the mixture was extracted
with CH2Cl2 (3ϫ 5 mL). The combined organic extracts were dried
with Na2SO4. Chloranil (1 equiv.) was added, and the solution was
stirred at room temperature for 30 min–3 h. The solvent was evapo-
rated, and the residue was subjected to column chromatography (n-
pentane/EtOAc, 15:1–3:1, depending on Rf). The resulting solids
were dissolved in CHCl3, and insoluble precipitates were removed
by filtration. After evaporation, the products were further purified
by recrystallization from Et2O.
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Supporting Information (see footnote on the first page of this arti-
cle): Synthetic procedures, product characterization, and copies of
NMR spectra.
Acknowledgments
The authors thank the Deutsche Forschungsgemeinschaft (DFG)
(SFB 749, project B1) for financial support. The authors are grate-
ful to Nathalie Hampel for the preparation of some of the indoliz-
ines. Dr. Jörg Bartl and Dr. Armin Ofial are thanked for their help
during the preparation of the manuscript.
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D. S. Allgäuer, H. Mayr
FULL PAPER
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Received: May 27, 2013
Published Online: ᭿
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Job/Unit: O30784
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Date: 12-08-13 11:38:45
Pages: 11
Synthesis of 1-(Ethoxycarbonyl)indolizines
Pyridinium Ylides
D. S. Allgäuer, H. Mayr* ................ 1–11
One-Pot Two-Step Synthesis of 1-(Ethoxy-
carbonyl)indolizines via Pyridinium Ylides
Pyridinium salts reacted with Michael ac-
ceptors in the presence of base to generate
[3+2]-cycloadducts at ambient tempera-
ture. Hydroxide-induced oxidation of the
crude [3+2]-cycloadducts with chloranil
(1 equiv.) and atmospheric oxygen yielded
1-ethoxycarbonyl-substituted indolizines.
Keywords: Cycloaddition / Nitrogen hetero-
cycles / Reaction mechanisms / Oxidation /
Substituent effects
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