Substrate-Controlled Divergent Synthesis of Enaminones and Pyrroles from Indolizines and Nitroso Compounds

Article abstract of DOI:10.1002/adsc.201900837

It is imperative to learn new synthetic transformations to succeed in drug discovery and development. We report the substrate-driven synthesis of β-enaminones and N-aryl pyrroles from indolizines and nitrosoarenes; aryl-substituted indolizines lead to β-enaminones in a regio- and diastereoselective manner, whereas alkyl-substituted indolizines produce tetrasubstituted pyrroles. All products contain a pyridine unit, the second most abundant ring (after phenyl) in the FDA Orange Book. In both cases, the reactions proceed at room temperature without any catalyst. Moreover, both types of products can be obtained in one pot from commercial materials as well as at a gram scale. It is worthy of note that the regioselectivity of the β-enaminones is inaccessible by the standard literature methods and their utility has been exemplified in the synthesis of diverse heterocycles. We have made every endeavor to put forward the corresponding reaction mechanisms based on thorough experimental work. (Figure presented.).

Full text of DOI:10.1002/adsc.201900837

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DOI: 10.1002/adsc.201900837
Substrate-Controlled Divergent Synthesis of Enaminones and
Pyrroles from Indolizines and Nitroso Compounds
María José González-Soriaa and Francisco Alonsoa,*
a
Instituto de Síntesis Orgánica (ISO) and Departamento de Química Orgánica, Facultad de Ciencias,
Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
E-mail: falonso@ua.es
Manuscript received: July 8, 2019; Revised manuscript received: August 26, 2019;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201900837
Abstract: It is imperative to learn new synthetic transformations to succeed in drug discovery and
development. We report the substrate-driven synthesis of β-enaminones and N-aryl pyrroles from indolizines
and nitrosoarenes; aryl-substituted indolizines lead to β-enaminones in a regio- and diastereoselective manner,
whereas alkyl-substituted indolizines produce tetrasubstituted pyrroles. All products contain a pyridine unit,
the second most abundant ring (after phenyl) in the FDA Orange Book. In both cases, the reactions proceed at
room temperature without any catalyst. Moreover, both types of products can be obtained in one pot from
commercial materials as well as at a gram scale. It is worthy of note that the regioselectivity of the β-
enaminones is inaccessible by the standard literature methods and their utility has been exemplified in the
synthesis of diverse heterocycles. We have made every endeavor to put forward the corresponding reaction
mechanisms based on thorough experimental work.
Keywords: enaminones; indolizines; nitroso compounds; nitrogen heterocycles; pyrroles
Introduction
Innovations in synthetic organic chemistry are crucial
to advance in drug discovery.[1] In this context, the
pyridine ring is the second most recurrent ring (after
phenyl) in the small-molecule drug list of the FDA
Orange Book, but is also present in manifold
agrochemicals.[2] The pyrrole ring[3a] can be found in
numerous natural products (e.g., lamellarin O, I)[3b] as
well as in the aforementioned list,[2a] albeit it is
relatively less frequent in drugs (Figure 1). Never-
theless, the best-selling pharmaceutical within the
recent past, atorvastatin (II, a cholesterol-lowering
agent), is comprised of a polysubstituted pyrrole
ring.[3b] The latter ring is represented in other best-
selling drugs, such as sunitinib (anticancer agent),[3c] or
in agrochemicals, such as the fungicides fenpiclonil
(III, Beret®) and fludioxonil (Celest®).[3d] The N-
arylated pyrroles IV[3e] and TDR37250 (V)[3f] have
been identified as powerful substances for the treat-
ment of leishmaniasis and malaria, respectively.
On the other hand, enaminones can be considered
push-pull olefins which merge the nucleophilic charac-
ter of the enamines with the electrophilic one of the
Figure 1. Biologically active pyrroles and enaminones.
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enones.[4] The enaminone moiety is part of the structure
of natural products, such as the glucose-lowering (À )-
multiflorin (VI),[5a] and of some synthetic compounds,
such as the anticonvulsant VII[5b] (with comparable
potency to that of diazepam) or the fluorinated
quinolone antibacterials (e.g., ciprofloxacin, VIII)[5c]
(Figure 1). In addition, enaminones are highly versatile
scaffolds in heterocyclic chemistry,[4a,d,6] particularly, in
the total synthesis of alkaloids.[4f]
Scheme 1. Synthesis of indolizines and heterocyclic chalcones
Enaminones are generally prepared through con-
densation and addition reactions, by acylation of
enamines or cleavage of heterocycles.[4a–c] Among
them, the condensation of primary or secondary amines
with 1,3-dicarbonyl compounds is surely the most
practiced method. However, the less nucleophilic
aromatic amines are more reluctant to react and
azeotropic removal of water is mandatory in order to
shift the equilibrium towards the enaminone. Some
alternative procedures mostly based on transition-metal
catalysis have emerged in the last years,[7] with those
involving the transmutation of heterocycles into
enaminones being uncommon.[7c]
catalyzed by CuNPs/C.
Scheme 2. General syntheses of enaminones and pyrroles.
dyes through
a
metal-free CÀ H site-selective
As regards pyrroles, multitude of efficient ap- alkenylation.[17b]
proaches to their synthesis have been devised,[8] mostly
We present herein a novel entry to β-enaminones
relying on transition-metal catalysis[8a,b] and multi- and polysubstituted pyrroles, which bear a pyridine
component reactions.[8c,9] Pd, Rh, Au, Ru and Cu moiety, from indolizines and nitroso compounds
catalysts have been the most applied transition metals (Scheme 2). Interestingly, the course of the reaction is
for this purpose, not only in MCRs but in intra- driven by the aromatic or aliphatic nature of the
molecular cyclizations[10] or intermolecular annulations substituent at the 3-position of the indolizine ring.
involving alkynes[11] or other substrates;[12] organo- Another remarkable common feature is that both
catalyzed procedures are also known.[13] As in the case transformations occur under ambient conditions with-
of the enaminones, the transformation of other hetero- out the need of a catalyst. The efficacy of the method
cycles into pyrroles is barely documented.[14] Due to and the applicability of the products synthesized,
the type of starting chemicals normally deployed for together with the reaction mechanisms, are also
pyrrole synthesis, the majority of the products end with tackled.
a carboxylate/carbonyl group attached to the ring. We
must also underline that the N-arylation of five-
membered nitrogen-containing amino heterocycles is Results and Discussion
known to be troublesome.[1a]
Synthesis of β-enaminones
In view on these antecedents, there is a certain
upsurge of interest in designing novel synthetic We first assessed the effect of the amino substituent at
strategies that impart functionalization and substitution the 1-position of the indolizine. For this purpose,
patterns to enaminones and pyrroles unreachable by indolizine 1 (derived from pyridine-2-carbaldehyde, a
other routes. By virtue of our current interest in the secondary amine and phenylacetylene) and nitrosoben-
application of copper nanoparticles[15] to multicompo- zene (2a) were deployed as the model substrates and
nent reactions,[15a] we published the solvent-controlled allowed to react at room temperature in ethanol
three-component synthesis of amino-substituted indoli- (Table 1, entries 1–5). The dibenzylamino-substituted
zines and the synthesis of heterocyclic chalcones from indolizine gave the highest conversion (Table 1, en-
pyridine-2-carbaldehyde derivatives, secondary amines try 3). A range of solvents was tested for this
and terminal alkynes catalyzed by copper nanoparticles indolizine derivative, concluding that acetonitrile was
on activated carbon (CuNPs/C) (Scheme 1).[16] The the best choice (Table 1, entry 7). The absence of
reactivity of the aforementioned indolizines has been solvent or presence of CuNPs/C (utilized for the
explored only recently: their heterogeneous catalytic synthesis of the indolzines) were detrimental to the
hydrogenation led to indolizidines in a chemo- and conversion (Table 1, entries 6 and 13, respectively).
diastereoselective manner,[17a] whereas an acid-base
With the optimized conditions in hand (Table 1,
treatment furnished a new family of solvatochromic entry 7), we tried to expand the procedure to other
substrates (Table 2). Nitrosobenzene (2a) was com-
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Table 1. Optimization of the enaminone synthesis.[a]
Entry
R1
R2
Solvent
Conv. [%][b]
1
2
3
4
5
6
7
8
(CH2)5
Bu
Bn
Bn
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
EtOH
EtOH
EtOH
EtOH
EtOH
–
MeCN
THF
PhMe
CH2Cl2
H2O
71
32
80
76
49
25[c]
90
36
49
42
15
24
45
Bu
Bn
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Figure 2. Plot displaying the evolution of the synthesis of the
enaminone 3aa from the indolizine 1a and nitrosobenzene
(2a).
9
10
11
12
13
CH3COCH3
MeCN[d]
[a] Reaction conditions: 1 (0.1 mmol), 2a (0.1 mmol), solvent
(1 mL), rt, overnight.
[b] Conversion into 3aa determined by GLC.
[c]
°
Reaction at 50 C.
[d] In the presence of CuNPs/C (5 mol%).
Scheme 3. One-pot synthesis of the enaminone 3aa.
bined with indolizines bearing all sort of substituents
on the aryl ring at the 3-position (R1), i.e., electron-
neutral, electron-donating and electron-withdrawing the presence of the strong electron-releasing dimeth-
ones; the corresponding β-enaminones 3aa–3ea were ylaminophenyl group.
formed in moderate-to-good isolated yields. The out-
The kinetic profile corresponding to the reaction of
come for indolizines with additional substitution was the indolizine 1a with nitrosobenzene (2a) displays
uneven. For instance, the 5-methyl-substituted indoli- the highest conversion variation in the interval 4–8 h
zine 1f performed much better than the (meth- (Figure 2); the progress of the reaction is much slower
ylsulfonyl)phenyl counterpart (1g), which was more at the outset of the reaction and after 8 h. We also
°
reluctant to react and required warming at 50 C for attempted to reach the enaminone in one pot from the
improving the yield. The product 3ga was formed as a commercial starting materials pyridine-2-carbaldehyde,
mixture of regioisomers (ca. 1.5:1, NMR); fortunately, dibenzylamine and phenylacetylene, without the need
the major one could be isolated by column chromatog- to isolate the intermediate indolizine (Scheme 3); the
raphy. Similar behavior was observed for N,N-diben- moderate success of this approach might be due, in
zyl-3,5-diphenylindolizin-1-amine, which gave the part, to the interference of CuNPs/C in the second step
final product in very low conversion as a 2:1 of the sequence (see, Table 1, entry 13). It was,
regioisomeric ratio (not isolated). The procedure was however, gratifying to demonstrate that the enaminone
also successfully applied to the more complex indoli- 3aa could be synthesized with equal efficiency at a
zine 1h, furnishing the expected product 3ha with a gram scale (Scheme 4). Moreover, the lack of atom
double pyridinyl chalcone motif. Nitrosoarenes other
than nitrosobenzene were also tested (2b–2h); para-
substituted representative examples with electron-
donating, electron-withdrawing and halogen groups
gave rise the enaminones 3ab–3ae in moderate
isolated yields. Ortho-substituted nitrosobenzenes be-
haved likewise (2f–2h), though some by-product
formation was observed in the case of the cyano
derivative 3ag. As an exception, a β-alkyl-β-enami-
none could be also synthesized (3id), albeit only with
Scheme 4. Gram-scale synthesis of the enaminone 3aa.
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Table 2. Synthesis of enaminones 3.[a]
[a] Reaction conditions: 1 (0.3 mmol), 2 (0.3 mmol), MeCN (1 mL), rt, overnight; isolated yield in parentheses.
[b]
°
Reaction at 50 C; 3ga was obtained as a ca. 1.5:1 mixture of regioisomers.
economy associated with the release of dibenzylamine
could be overcome by subjecting the reaction crude to
acid-base work-up (2 M HCl and 2 M NaHCO3,
respectively); in this way, 80% of the original
dibenzylamine could be recovered, what substantially
decreased the E factor of the process.
It is noteworthy that all the β-enaminones were
obtained as single stereoisomers. The Z stereochemis-
try was unequivocally assigned by X-ray crystallo-
graphic analysis of the enaminone 3aa (Figure 3).[18]
The formation of an intramolecular hydrogen bond
with the participation of the carbonyl-group oxygen
and the NÀ H of the arylamino moiety is a common
1
feature to all the enaminones, also observable by H
NMR. The usefulness of the obtained enaminones as
bulding blocks for heterocyclic synthesis was exempli-
fied by transforming 3aa into the pyridinyl-containing
Figure 3. X-ray structure of the enaminone 3aa.
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Table 3. Reaction of the 1,3-dione 8 with aniline under differ-
ent conditions.[a]
Entry Catalyst
Conditions
3aa/3aa’ Ref.
[%][b]
1
2
3
4
5
6
Cu(OTf)2 (5 mol%)
Yb(OTf)3 (5 mol%)
–.
–.
neat, rt, 16 h
neat, rt, 60 min 0/85
–.
19a
19a
19a
19b
19c
19d
°
neat, 70 C, 16 h –.
H2O, rt, 16 h
–.
–.
0/65
Bi(CF3CO2)3 (5 mol%) H2O, rt, 3 h
Scheme 5. Transformation of the enaminone 3aa into different
heterocyclic compounds.
MK-10[c]
US, 16 h
[a] 1,3-Dione 8 (0.2 mmol), aniline (0.4 mmol).
[b] Conversion into 3aa and 3aa’ determined by GLC.
[c] Montmorillonite K-10 (60 mg).
isoxazole 4, pyrazoles 5 and 6, and indole 7
(Scheme 5).
As said in the introduction, β-enaminones are
readily accessible by the condensation of primary or
secondary amines with 1,3-dicarbonyl compounds; this
path is particularly effective for symmetrically sub-
stituted diketones. However, for unsymmetrical sub-
strates, and when coordinating fragments are present,
other factors go into play which might condition both
the conversion and regioselectivity of the reaction. In
this context, and in order to validate our procedure, the
unsymmetrical 1,3-dione 8 was synthesized and sub-
jected to some of the available literature methods for
enaminone synthesis (Table 3). For instance, Cu(OTf)2,
which proved to be a good catalyst for the condensa-
tion of acetylacetone with aniline (78% yield),[19a]
completely failed in the test reaction (Table 3, entry 1);
this behavior could be explained in terms of copper
complexation with the pyridinylcarbonyl unit of 8.[20]
Table 4. Optimization of the pyrrole synthesis.[a]
Entry
Solvent
Conversion [%][b]
1
2
3
4
5
6
7
8
9
neat[c]
EtOH
MeCN
THF
57
96
93
90
95
91
85
0
PhMe
CH2Cl2
CH3COCH3
H2O[c]
EtOH[d]
59
In contrast, good conversion was attained with
[19a]
Yb(OTf)2
albeit towards the opposite regioisomer
[a] Reaction conditions: 1i (0.1 mmol), 2a (0.1 mmol), solvent
3aa’ (Table 3, entry 2). The reaction was unproductive
in the absence of catalyst (Table 3, entries 3 and 4)[19b]
or with Bi(CF3CO2)3 (Table 3, entry 5),[19c] whereas
montmorillonite K-10 under ultrasounds[19d] also
formed the product 3aa’ in moderate conversion
(Table 3, entry 6). It is clear that the condensation route
(1.0 mL), rt, overnight.
[b] Conversion determined by GLC.
[c]
°
Reaction at 50 C.
[d] In the presence of CuNPs/C (5 mol%).
is not valid for the target enaminone 3aa: the Synthesis of Pyrroles
picolinoyl carbonyl group undergoes preferentially the
nucleophilic attack of aniline because of the larger Indolizine 1i and nitrosobenzene (2a) were used as the
electrophilicity of the former compared to that of the model substrates to optimize the reaction conditions in
benzoyl carbonyl and, hence, this fact reinforces the the pyrrole synthesis (Table 4). Practically, every
utility of our strategy.
organic solvent tested was adequate to accomplish this
transformation, providing conversions above 85% for
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9ia (Table 4, entries 2–7). On the contrary, the absence yields for the N-arylated pyrroles 9ib–9if. It is
of solvent or presence of water had an adverse effect, worthwhile mentioning that product 9if is an axially
decreasing the conversion or impeding the reaction, chiral pyrrole, with the free rotation through the CÀ N
respectively (Table 4, entries 1 and 8). Ethanol was bond at room temperature being suppressed by the
considered the solvent of choice because of being a ortho-tolyl substituent. Axially chiral arylpyrroles can
recommended solvent[21] and achieving the highest be found in bioactive natural products as well as in
conversion (Table 4, entry 2). To our delight, the chiral ligands and catalysts.[22]
reaction proceeded under ambient conditions and, as
The reaction profile for the pyrrole synthesis
occurred in the case of the β-enaminones, the presence notably differed from that of the enaminone synthesis:
of CuNPs/C exerted a negative effect on the con- a high conversion (80%) was reached after only 1 h at
version (Table 4, entry 9).
room temperature, continuing to completeness after 6 h
These mild and green conditions were extended to (Figure 4). An effective one-pot synthesis of pyrrole
an array of indolizines and nitroso compounds 9ia from commercial substances was shown to be
(Table 5). First, the amino group at the 1-position of plausible following a multicomponent synthesis of the
the indolizine was varied: the expected pyrroles were indolizine and nitroso compound addition sequence
produced in good-to-excellent isolated yields for (Scheme 6). CuI is recommended as catalyst instead of
dibenzyl, dialkyl, cyclic, alkylaryl, alkylbenzyl and CuNPs/C in order to improve the yield of the
chiral amino groups (9ia–9na). Pyrroles with a intermediate 3-alkylindolizine. Furthermore, the sim-
substituted pyridinyl, different alkyl chain length or plicity of the experimental operation and satisfactory
functionalized alkyl chain were also accessible by this reproducibility allowed the gram-scale synthesis of the
way but with relatively lower yields (9oa–9sa), in the indole 9ia (Scheme 7). The structure of the pyrroles 9
latter case because of some by-product formation. was confirmed by X-ray crystallographic examination
Finally, the N-aryl substituent could be modified by the of the derivative 9ia (Figure 5).[18] The perpendicular
choice of the nitrosoarene, recording moderate-to-good arrangement of the N-phenyl group with respect to the
Table 5. Synthesis the pyrroles 9.[a]
[a] Reaction conditions: 1 (0.3 mmol), ArNO (0.3 mmol), EtOH (1.0 mL), rt, overnight; isolated yield in parentheses.
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Figure 4. Plot displaying the evolution of the synthesis of the
pyrrole 9ia from the indolizine 1a and nitrosobenzene (2a).
Figure 5. X-ray structure the pyrrole 9ia.
Synthesis of β-Enaminones
First, a series of labelling experiments was carried out.
The starting indolizine 1a-[D] was synthesized from
pyridine-2-carbaldehyde, deuterated dibenzylamine
and deuterated terminal alkyne. Then, it was subjected
to the standard conditions showing a total loss of D in
the β-enaminone 3aa (Scheme 8a, Figures S3 and S4).
Another experiment consisted in the synthesis of 3aa
in a mixture of deuterated solvents, CD3CNÀ D2O
(1:0.4), observing the incorporation of D into the final
Scheme 6. One-pot synthesis of the pyrrole 9ia.
1
product (by H NMR of the reaction crude) but mainly
Scheme 7. Gram-scale synthesis of the pyrrole 9ia.
pyrrole ring accounts for the symmetry break when
introducing an ortho-methyl group on that phenyl and
the consequent manifestation of atropoisomerism.
Aliphatic nitroso compounds were found to be
difficult to prepare in pure form and rather unreactive
under the standard reaction conditions for the synthesis
of β-enaminones and pyrroles.
Reaction Mechanisms
Different studies were carried out in order to get an
insight into the reaction mechanism for the formation
of the two products, the β-enaminones and the
pyrroles.
Scheme 8. Labeling experiments in the synthesis of 3aa.
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at the nitrogen atom of the amine (98% D, Scheme 8b,
Figure S5). The last experiment was carried out under
the standard conditions, but adding a small amount of
18
labeled water (H2 O, Scheme 8c, Figure S6); the
incorporation of 18O into the final structure was
virtually zero. These results suggest that the 2-H in 1a
is exchangeable for water protons (e.g., air or solvent
humidity) and that the O of the β-enaminone could
come from the nitroso compound.
The radical traps 2,2,6,6-tetramethylpiperidine-1-
oxyl (TEMPO) and 2,6-di-tert-butylphenol (2,6-
DTBP), 1equiv. each, were added under the standard
conditions in order to prove any participation of
radicals in the reaction mechanism; they did not alter
the outcome of the processes as the final product was
obtained in good conversions and the radical traps
were recovered unchanged (Scheme 9). Those results
are in concordance with an ionic reaction pathway.
Figure 6. Reaction profiles for the synthesis of 3aa under
different atmospheres.
Scheme 10. Resonance structures for indolizines 1.
Scheme 9. Synthesis of 3aa in the presence of radical traps.
The effect of the atmosphere was found to be
highly revealing in the synthesis of β-enaminones
(Figure 6). Neither the use of molecular oxygen nor an
inert atmosphere (using dry MeCN) were beneficial for
the reaction rate. Conversely, the reaction was accel-
erated by air in MeCN or in the presence of water,
being almost complete after 2 h in the latter case. It
can be deduced that the air humidity and water act as
proton sources favoring the process, whereas the lower
rate attained with O2 seems to support the fact that it
has not structural contribution to the product.
It is known that the C1 and C3 of the indolizine
nucleus are activated toward electrophiles in terms of
resonance stability.[23] We believe that indolizines
bearing an aromatic 3-substituent could preferentially
react with ArNO through the C3, due to better charge
stabilization and, maybe, π-π interactions, whereas the
reaction might take place through C1 in the case of 3-
alkyl substituted indolizines (Scheme 10).
With all these results in hand, the following
reaction mechanism (exemplified for indolizine 1a)
was envisaged for the formation of the β-enaminones 3
(Scheme 11). First, nitrosobenzene could act as an
electrophile to form a CÀ N bond at the 3 position.
Scheme 11. Proposed mechanism for the formation of the β-
enaminones 3.
Ring opening involving the resonance of the dibenzy- mediate. Alternatively, the latter intermediate could be
lamino group followed by intramolecular 5-exo-dig obtained via a [3+2] cycloaddition reaction. Dibenzyl-
cyclization would furnish a dihydroisoxazole inter- amine elimination followed by isoxazole ring opening
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would provide the corresponding β-enaminone. The
redox step necessary for the NÀ O bond cleavage is the
most intriguing step in the postulated mechanism. The
likelihood of dibenzylamine acting as reducing agent
should not be totally disregarded, although despite
being a readily oxidizable amine,[24] the corresponding
imine has been detected as a minor byproduct. Another
proposal consists in dibenzylamine or water promoting
the NÀ O bond cleavage. The fact that water accelerates
the reaction could be related to water acting as a proton
source (as two new NÀ H bonds are formed) and
cleaving the NÀ O bond. Taking into account that
nitrosoarenes may exist as dimeric species, an analo-
gous alternative reaction mechanism has been pro-
posed involving these dimers (Scheme S1). The 2-D/H
exchange observed (Scheme 8a) could be explained
through protonation-deprotonation processes of some
of the intermediates and enamine-imine or enol-keto
tautomerism.
Figure 7. Reaction profiles for the synthesis of 9ia under
different atmospheres.
Synthesis of Pyrroles
A similar deuterium labeling strategy to that utilized
for the enaminones was implemented for pyrroles
Scheme 13. Effect of the addition of an external secondary
though with different results. For instance, most of the amine in the synthesis of the pyrroles.
deuterium content in 1i-[D] was retained in the product
9ia under the standard conditions (Scheme 12a,
Figures S7 and S8), and a marginal deuterium incorpo- presence of 3 equiv. of an external secondary amine,
ration was noted when the reaction of 1i was such as N-methylaniline, the corresponding amino
conducted in CD3CD2OD (Scheme 12b). As happened substituent was integrated into the pyrrole as also
in the case of the enaminones, the reaction was faster occurred with the dibenzylamino group, thus corrobo-
in air than in oxygen, though the presence of water did rating what hypothesized above (Scheme 13).
not have the pronounced positive effect observed for
the former (Figure 7, Figure S9).
Several reactions were also performed to explore
the feasibility of the β-enaminone being the intermedi-
Comparing the structure of the starting indolizine ate in the formation of the pyrroles 9 (Scheme S2).
with that of the final pyrrole, it is obvious that the The reaction of the unique β-alkyl-β-enaminone we
dibenzylamino substituent has experienced migration. obtained (3id) with dibenzylamine did not produce the
Apparently, this substituent is lost during the reaction expected pyrrole (Scheme S2a); this was somewhat
and reincorporated again into the final structure. expected as the precursor indolizine of 3id did not
Indeed, when the reaction was carried out in the furnish the corresponding pyrrole at all. The β-
enaminones 11 and 12 were also synthesized as
potential intermediates in the route to pyrrole 9ia.
However, under the standard conditions, neither 11
with dibenzylamine nor 12 with nitrosobenzene led to
the pyrrole 9ia (Schemes S2b and S2c).
A retrosynthetic analysis of pyrrole 9ia gives two
potential precursors with their tautomeric forms
(Scheme 14). In-situ NMR analysis during the first
hour of reaction of the indolizine 1i with nitro-
sobenzene (2a), at room temperature in CD3CN,
disclosed the presence of a significant signal at
188.8 ppm in the 13C NMR spectrum (Figure S10).
This signal could be attributed to a doubly conjugated
carbonyl group, which might be bonded to a pyridinyl
unit and to a carbon-carbon double bond, in conformity
with the disconnection b.
Scheme 12. Labeling experiments in the synthesis of 9ia.
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Figure 8. Structures and MS fragmentation proposed for some
potential intermediates in the pyrrole synthesis.
Scheme 14. Potential precursors of the pyrrole 9ia.
Scheme 15. Labeling experiment in the synthesis of the inter-
mediate of pyrrole 9ia.
The reaction between indolizine 1i and nitro-
sobenzene (2a) was also analyzed by GC-MS and
HRMS/Q-TOF after 10 min (Figures S11 and S12).
The presence of a peak of m/z 278 was confirmed by vide one of the pyrrole precursors in Figure 8 (A).
both techniques; this peak diminished in intensity with There is little chance that the rupture of the NÀ O bond
the reaction course and disappeared after completion is promoted by nucleophilic attack of Bn2NÀ or EtOÀ
of the reaction, thus evidencing its role as a reaction on the N atom, as this would entail (a) the participation
intermediate. Several structures match the m/z 278 and of two equivalents of nitrosobenzene, (b) the formation
some of the fragmentations observed (Figure 8, A and of the respective hydrazine or hydroxylamine deriva-
B). This very important finding demonstrates that the tives (not detected) and (c) the difficulty to explain the
nitroso compound-derived fragment is incorporated reaction in non-nucleophilic solvents or in the absence
first and the dibenzylamino group second, prior to the of solvent (Table 4). Michael addition of dibenzyl-
ring closure. A broad peak at longer retention time was amine to A would generate C, the tautomer of which
also observed by GC-MS; although the molecular ion (D) could suffer intramolecular condensation and
was not brought into view, the average fragmentation aromatization to the final pyrrole. The release of water
points to structures that might be the immediate from the suggested intramolecular condensation is in
precursors of the pyrroles 9 (Figure 8, C–E).
agreement with the reaction slowing down in a mixture
The same labeling procedure as for the β-enami- of EtOH/H2O (Figure 7).
nones was applied in the synthesis of pyrroles in order
Although the accuracy of some of the steps of the
to ascertain the origin of the oxygen atom in the reaction mechanism depicted in Scheme 16 is arguable,
postulated intermediate (Scheme 15). However, no we believe that the reaction sequence established based
incorporation of 18O was observed in the corresponding on experimentation is reasonable, that is to say: (a)
GC-MS spectrum (Figure S13), again pointing to nitro- reaction of the indolizine with nitrosobenzene, (b)
sobenzene as the probable source of oxygen.
elimination of dibenzylamine, (c) cleavage of the NÀ O
On the basis of the above results, a tentative bond, (d) reincorporation of dibenzylamine, (d) intra-
reaction mechanism has been set forth considering that molecular cyclization and (e) aromatization.
the source of oxygen is the nitroso compound
(Scheme 16). The indolizine reacts through its 1
position with nitrosobenzene to form a CÀ N and/or
Conclusion
CÀ O bond, followed by intramolecular displacement Concluding this study, we can say that 1-amino-
of dibenzylamide ion. This ion (or less probably, the indolizines are versatile compounds that, under sub-
ethoxide ion) could deprotonate the pseudo-benzylic H strate control, can be transformed into β-enaminones or
of the resulting intermediate to give a 1,3-dienol tetrasubstituted pyrroles by reaction with nitrosoarenes;
structure. Intermolecular delivery of the anilino moiety 3-aryl-substituted indolizines give rise to β-enaminones
(PhNH), accompanied by deprotonation, would pro- (35–88% yield), whereas the 3-alkyl-substituted coun-
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Scheme 16. Proposed mechanism for the formation of the pyrrole 9ia.
terparts give rise to pyrroles (33–96% yield), all Experimental Section
containing a pyridinyl fragment. Both reactions have
some notable characteristics in common, namely: (a)
General
Melting points were obtained with a Reichert Thermovar apparatus
they proceed in the absence of catalyst, (b) at room
temperature, (c) in air, (d) they can be implemented in
one pot from commercial chemicals, without the need
to isolate the intermediate indolizine, and (e) the
experimental is adaptable to gram-scale synthesis.
Unconventional reaction pathways have been de-
lineated to rationalize the formation of these products.
Furthermore, the β-enaminones are produced stereo-
selectively with a regioselectivity unattainable by the
previously reported experimental operations. There is
no room for doubt about the usefulness of this type of
compounds, as illustrated in the synthesis of various
and are uncorrected. Infrared analysis was performed with a Jasco
4100LE (Pike MIRacle ATR) spectrophotometer; wavenumbers
(ῦ) are given in cmÀ 1. NMR spectra were recorded on Bruker
1
Avance 300 and 400 spectrometers (300 and 400 MHz for H
NMR; 75 and 101 MHz for 13C NMR); chemical shifts are given
in (δ) parts per million and coupling constants (J) in Hertz. Mass
spectra (EI) were obtained at 70 eV on an Agilent 5763 GC-MS
apparatus; fragment ions in m/z with relative intensities (%) in
parentheses. HRMS analyses were also carried out in the electron
impact mode (EI) at 70 eV using an Agilent 7200 spectrometer
with a quadrupole analyzer or with a LC-ESI-TOF system. The
purity of volatile compounds and the chromatographic analyses
nitrogen heterocycles. Equally appealing is the struc- (GLC) were determined with a Youling 6100 instrument equipped
with a flame ionization detector and a 30 m capillary column
(0.32 mm diameter, 0.25 μm film thickness), using nitrogen
ture of the pyrroles, which are N-arylated and
uncommonly functionalized with an amino group[25]
and a pyridinyl segment that might make them suitable
as ligands in catalysis. This approach to N-aryl
pyrroles overcomes the hurdles encountered in the
pyrrole N-arylation when amino or heterocyclic sub-
stituents are present.[1a] Drug-discovery projects at the
individual compound synthesis demand robust, scal-
able and safe methods; therefore, the fascinating
heterocycle transmutation presented in this survey can
be also incorporated in a synthetic toolkit that can pave
the way for the discovery of new and more efficient
drugs, given the significance in this field of pyridines,
β-enaminones and pyrroles.
°
°
(2 mL/min) as carrier gas, Tinjector =270 C, Tcolumn =80 C (3 min)
°
°
and 80–270 C (20 C/min); retention times (tR) are given in min.
Analytical thin-layer chromatography (TLC) was carried out on
TLC plastic sheets with silica gel 60 F254 (Merck). Column and
preparative chromatography were performed using silica gel 60 of
40–60 microns and P/UV254, respectively (hexane/EtOAc as
eluent).
Bn2ND was prepared by mixing Bn2NH (1 mmol) with D2O
(1 mL) and stirring overnight at room temperature. After this
time, the crude was extracted with Et2O and the solvent was
evaporated. The deuterated amine was used without any further
purification. The deuterated alkynes (PhC�CD and BuC�CD)
were prepared by suspending CuNPs/C (0.5 mol%) in D2O
(1 mL) followed by the addition of the terminal alkyne
°
(1 mmol); the resulting mixture was stirred at 70 C overnight.
Then, the product was filtered and extracted with Et2O. The
deuterated alkyne was used without any further purification.
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Selected X-ray crystallographic data for 3aa: C20H16N2O,
M=300.35, monoclinic, space group P 21/c, yellow plates, a=
11.5001(16), b=11.1411(15), c=12.4298(17) Å, T=295(1),
Z=4, R=0.0386, GOF=1.010.
General Procedure for the Synthesis of the Indoli-
zines 1
The indolizines 1 were prepared from pyridine-2-carbaldehydes,
secondary amines and terminal alkynes using two methods: the
aldehyde (2 mmol), amine (2 mmol) and alkyne (2 mmol) were
added to a reactor tube containing (a) CuNPs/C (80 mg, ca.
0.5 mol%) and dichloromethane (2.0 mL) for the indolizines
1a–1g,[16] or (b) CuI (38 mg, 10 mol%) under solvent-free
conditions for the indolizines 1i–1s. The reaction mixture was
Selected X-ray crystallographic data for 9ia: C32H31N3, M=
457.60, monoclinic, space group C c, colorless plates, a=
16.960(3), b=8.7394(13), c=17.960(3) Å, T=295(1), Z=4,
R=0.0451, GOF=1.023.
°
warmed to 70 C without the exclusion of air and monitored by
Acknowledgements
TLC and/or GLC until total or steady conversion of the starting
materials. The solvent was removed in vacuum; EtOAc (2 mL)
was added to the resulting mixture followed by filtration
through Celite and washing with additional EtOAc (4 mL). The
reaction crude obtained after evaporation of the solvent was
purified by column chromatography (silica gel, hexane/EtOAc)
to give the corresponding indolizine 1. Indolizine 1h was
synthesized following our reported procedure,[17b] by stirring the
indolizine 1a (1.94 g, 5 mmol) in HOAc (5 mL) at room
temperature for 6 h, followed by basification with saturated
NaHCO3, extraction with EtOAc (3×20 mL) and solvent
evaporation. The reaction crude was purified by column
chromatography (silica gel, hexane/EtOAc) to give the pure
indolizine 1h. Deuterated indolizines 1a-[D] (78% D) and 1i-
[D] (72% D) were prepared following the general procedure but
starting from pyridine-2-carbaldehyde, Bn2ND, and PhC�CD or
BuC�CD, respectively, in D2O.
This work was generously supported by the the Spanish
Ministerio de Ciencia, Innovación y Universidades (MICIU;
grant no. CTQ2017-88171-P), the Generalitat Valenciana (GV;
grant no. AICO/2017/007), and the Instituto de Síntesis
Orgánica (ISO). M.J.G.-S. is grateful to the ISO for a pre-
doctoral grant (contract no. I-PAS-11/16).
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Substrate-Controlled Divergent Synthesis of Enaminones and
Pyrroles from Indolizines and Nitroso Compounds
Adv. Synth. Catal. 2019, 361, 1–14
Dr. M. J. González-Soria, Prof. Dr. F. Alonso*