Preparation of NH-pyrroles under superelectrophilic conditions by an Aza-Nazarov reaction cascade with indole as neutral leaving group: Experiment and theory

Article abstract of DOI:10.1002/ejoc.201200913

Aza-Nazarov reactions starting from 1-azapenta-1,4-dien-3-ones offer an attractive route to five-membered nitrogen heterocycles such as N-substituted pyrroles. It has now been discovered that N-indolinylhydrazone-derived 1-azapenta-1,4-dien-3-one 9a gives different products under conditions of varying acidity. Under strongly acidic conditions (2 equiv. of triflic acid, dilute solution, electrophilic conditions) it simply undergoes an aza-Nazarov reaction to give N-indolinylpyrrole 15a after workup with acetic anhydride. If, however, a large excess of triflic acid is used (7-10 equiv., concentrated solution, superelectrophilic conditions), 9a has been found to undergo an aza-Nazarov reaction cascade followed by N-N bond cleavage to give NH-pyrrole 10a and acetylated indole 8 as the final products (after workup with acetic anhydride). High-level quantum chemical calculations were used to explain this acid-concentration-dependent reaction cascade. The formation of the reaction products can be explained in terms of an electrocyclization reaction of the protonated starting material 9a and a subsequent N-N bond cleavage reaction involving either mono- or dicationic species under strongly acidic conditions. In an easy one-pot reaction sequence,1-azapenta-1,4-dien-3-ones 9a-i undergo aza-Nazarov reactions with subsequent acid-induced N-N bond cleavage in the presence of large excesses of triflic acid to give NH-pyrroles 10a-i and acetylated indole 8 (after acetic anhydride workup). Quantum chemical calculations were used to explain this acid-concentration-dependent reaction cascade.

Full text of DOI:10.1002/ejoc.201200913

Job/Unit: O20913
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Pages: 13
FULL PAPER
DOI: 10.1002/ejoc.201200913
1
Preparation of NH-Pyrroles under Superelectrophilic Conditions by an Aza-
Nazarov Reaction Cascade with Indole as Neutral Leaving Group: Experiment
and Theory
Rishikesh Narayan,[a,b] Constantin-Gabriel Daniliuc,[a] and Ernst-Ulrich Würthwein*[a]
Keywords: Nitrogen heterocycles / Superacidic systems / Electrocyclic reactions / Reaction mechanisms / Ab initio
6
calculations / Aza-Nazarov reaction
Aza-Nazarov reactions starting from 1-azapenta-1,4-dien-3-
ones offer an attractive route to five-membered nitrogen het-
erocycles such as N-substituted pyrroles. It has now been
discovered that N-indolinylhydrazone-derived 1-azapenta-
1,4-dien-3-one 9a gives different products under conditions
of varying acidity. Under strongly acidic conditions (2 equiv.
of triflic acid, dilute solution, “electrophilic” conditions) it
simply undergoes an aza-Nazarov reaction to give N-indolin-
ylpyrrole 15a after workup with acetic anhydride. If, how-
ever, a large excess of triflic acid is used (7–10 equiv., con-
centrated solution, “superelectrophilic” conditions), 9a has
been found to undergo an aza-Nazarov reaction cascade fol-
lowed by N–N bond cleavage to give NH-pyrrole 10a and
acetylated indole 8 as the final products (after workup with
acetic anhydride). High-level quantum chemical calculations
were used to explain this acid-concentration-dependent re-
action cascade. The formation of the reaction products can
be explained in terms of an electrocyclization reaction of the
protonated starting material 9a and a subsequent N–N bond
cleavage reaction involving either mono- or dicationic spe-
cies under strongly acidic conditions.
21
26
11
16
Introduction
The aza variant of the classical Nazarov reaction,[1] the
so called aza-Nazarov reaction,[2] is an attractive and ef-
ficient route for the synthesis of variably substituted five-
membered nitrogen heterocycles. Through extensive compu-
tational and experimental studies we were able to establish
the electronic and topological preconditions for successful
aza-Nazarov cyclization[3] and its variants for the synthesis
of nitrogen-containing aromatic and non-aromatic hetero-
cycles.[4] We discovered that 1-azapenta-1,4-dien-3-ones 1
(Scheme 1) generate 1-aza-3-hydroxypentadienyl cations 2
upon preferential protonation at their carbonyl oxygen
atoms with strong Brønsted acids and that cations 2 un-
dergo thermal conrotatory 4π-electrocyclization to form
pyrrolium cations 3.[3] These cations 3 then eliminate pro-
tons from their C-5 positions to form highly sensitive 3-
hydroxypyrroles 4, which can be trapped by acetic acid an-
hydride as the corresponding stable esters 5.
31
36
41
Scheme 1. Aza-Nazarov reaction for the synthesis of N-amino- and
N-alkoxypyrroles 5.
The last step of this cascade, the loss of the proton to
aromatize the system, is not necessarily required if another
leaving group is present in the molecule. As an immediate
46
51
56
extension of this study, we investigated systems
6
[a] Organisch-Chemisches Institut, Westfälische Wilhelms-
Universität,
(Scheme 2), in which the proton elimination was blocked by
double substitution at C-5. Compounds 6 underwent aza-
Nazarov reactions under strongly acidic conditions at ele-
vated temperatures to form non-aromatic 2H-pyrroles 7 af-
ter the elimination of indole as a neutral leaving group.[5]
In this case the indolinyl fragment may be considered to act
as a “large hydrogen atom” protecting the otherwise un-
stable imine functions in the 1-positions in the 1-azapenta-
Corrensstraße 40, 48149 Münster, Germany
Fax: +49-251-83-39772
E-mail: wurthwe@uni-muenster.de
Homepage: http://www.uni-muenster.de/Chemie/OC/research/
wue/euw.htm
[b] Graduate School of Chemistry, University of Münster,
Wilhelm-Klemm-Str. 10, 48149 Münster, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200913.
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R. Narayan, C.-G. Daniliuc, E.-U. Würthwein
FULL PAPER
1,4-dien-3-ones 6. The final products were isolated as the results of this recent study. Furthermore, we undertook, for
corresponding acetylated compounds 7 and 8 after treat- the first time, a detailed computational study of the mecha-
81
86
91
ment with acetic anhydride.
nism of this N–N bond fission reaction under the superelec-
trophilic reaction conditions employed here.
In this context it should be noted that pyrrole is a struc-
tural unit of great importance because it is found as a build-
ing block in many physiologically active natural products
such as heme, chlorophyll, and vitamin B12, among
others.[8] It has also been widely applied in the synthesis of
various pharmaceutical agents,[9] and also in the field of
material science[10] for conducting polymers,[11] molecular
optics,[12] etc. There is a wide range of methods[13] available
for their synthesis, but a large fraction of these methods
usually give N-substituted pyrroles.
Scheme 2. Synthesis of 2H-pyrroles 7 and 3-acetylindole (8)
through an aza-Nazarov reaction cascade involving indole as the
neutral leaving group.
61
66
71
76
The leaving group ability of indoline was further estab-
lished by us in AgNO3-induced cyclizations for a versatile
synthesis of annulated pyridine derivatives.[6]
Results and Discussion
One of the common problems associated with the synthe-
sis of pyrroles in general is the presence of the substituent
at the nitrogen atom of the pyrrole ring. Removal of this
substituent not only requires an extra synthetic step but
also sometimes harsh reaction conditions.[7] A direct syn-
thesis of NH-pyrroles is hence highly desirable. Our idea
was therefore that a substrate of type 9 might combine the
high electrocyclization tendency of a 1-azapenta-1,4-dien-3-
one skeleton with the leaving group ability of the indolinyl
group (Scheme 3). Under appropriate Brønsted acidic con-
ditions, such a compound of type 9 should form the corre-
sponding NH-pyrrole 10 as the final product through an
aza-Nazarov cyclization of the 1-azapenta-1,4-dien-3-one
part of the molecule and subsequent expulsion of the
indoline part as indole (Scheme 3). Finally, workup with
acetic anhydride would give 10 and 8. Here we describe our
The C-2 methyl-substituted precursors 9a–d were synthe-
sized in a two-step procedure starting from the commer-
cially available diacetyl and N-aminoindoline (Scheme 4).[5]
96
Scheme 4. Synthesis of the cyclization precursors 9a–d.
In the first step, α-ketohydrazone 11 was obtained in
58% yield by condensation of diacetyl with N-amino-
indoline in ethanol at room temperature. In the second step
the substituted vinyl moieties were introduced through 101
Scheme 3. Proposed reaction pathway.
aldol condensation variously with benzaldehyde or with
Scheme 5. Synthesis, substitution patterns, and yields of compounds 9e–i prepared by the Horner–Wadsworth–Emmons (HWE) ole-
fination procedure.
2
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Preparation of NH-Pyrroles under Superelectrophilic Conditions
substituted benzaldehydes to give the E-configured precur- compound 15a was isolated as the result of triple acylation:
sors 9a–d in excellent yields (73–93%). at the hydroxy group in C-3 position, at C-4 of the pyrrole,
For the synthesis of the C-2 phenyl-substituted precur- and at C-5 of the indolinyl subunit. The yield of this reac-
106 sors 9e–i, however, we took advantage of the procedure de- tion could be increased up to 70% when carried out at
veloped by us earlier for the synthesis of similar C-5 CF3- –30 °C.
136
substituted 1-azapenta-1,4-dien-3-ones 6 (Scheme 5).[5]
However, when the reaction was carried out under
Hydrazone 12 could be obtained by condensation of N- strongly acidic conditions [triflic acid (5 equiv.) in concen-
aminoindoline and commercially available ethyl phenylgly- trated reaction medium (5 mL of CH2Cl2 per mmol of 9a)],
111 oxalate in 52% yield. This ester 12 was converted into the 9a gave NH-pyrrole 10a after acylation with acetic anhy-
corresponding phosphonate 13 by treatment with deproton- dride (Scheme 7). The indole leaving group was also acet- 141
ated dimethyl methylphosphonate. Phosphonate 13 was ylated to form 3-acetylindole (8), which could be isolated.
then used in Horner–Wadsworth–Emmons olefinations[14]
with various substituted benzaldehydes to give the 1-aza-
116 penta-1,4-dien-3-ones 9e–i in moderate to good yields (55–
72%). In every case the configuration of the C=C bond was
found from the coupling constant in the 1H NMR spectrum
(ca. 16 Hz) to be E, and this was confirmed by single-crystal
X-ray analysis of compound 9h (Figure 1).
Scheme 7. Reaction of 9a under strongly acidic conditions to form
NH-pyrrole 10a and 3-acetylindole (8).
It is evident that substrate 9a reacts selectively, giving two
different products (15a/10a) depending on the concentra-
tion of the acid in the medium. Whereas under “normal”
acidic conditions it gave the N-substituted pyrrole 15a as 146
the product (Scheme 6), under strongly acidic conditions
NH-pyrrole 10a was obtained as the exclusive product of
the reaction (Scheme 7). In order to study this acidity de-
pendence further and to establish the optimal reaction con-
ditions for the proposed reaction we carried out a series of 151
reactions (Table 1).
Figure 1. Molecular structure of azadienone 9h in the solid state
obtained by X-ray diffraction.
Table 1. Optimization attempts for the formation of NH-pyrrole
10a.
Entry
Acid
(equiv.)
Amount of CH2Cl2
(mL per mmol of 9a)
15a
10a
Yields [%]
121 Model Cyclization Reaction
1
2
3
4
5
2
3
5
7
10
50
20
5
5
5
42
10
–
–
–
–
Compound 9a was used as precursor for our model cycli-
29
34
45
35
zation reaction. When 9a was treated with triflic acid
(2 equiv.) in a highly diluted reaction medium (50 mL of
CH2Cl2 per mmol of substrate 9a) at –10 °C it gave the
126 corresponding N-substituted pyrrole 15a in 42% yield
(Scheme 6). These were exactly the conditions that had also
been used for the “aza-Nazarov cyclization” of 1-azapenta-
1,4-dien-3-ones 1.[3] Obviously, the expected 4π-electrocycl-
ization reaction takes place to form the rather unstable 3-
131 hydroxypyrrole 14a. After workup with acetic anhydride,
As the amount of acid was increased from 5 to 7 equiv.
the yield of 10a increased from 34 to 45% (Entries 3, 4).
Any further increase in the amount of acid, however, led to
a decrease in the yield (Entry 5). Under intermediate acidic 156
conditions (Entry 2) both the products could be isolated,
but in smaller yields. We were not able to identify the by-
products that were formed during the reaction and detected
by thin-layer chromatography. It should further be noted
that the treatment of compound 15a with a large excess of 161
triflic acid in small amounts of dichloromethane only led to
decomposition products. N–N Bond cleavage of this triply
acylated material under superelectrophilic conditions thus
does not seem to be possible.
After having identified the optimal reaction conditions 166
we started to explore the generality of this reaction se-
quence with respect to variation in the substitution pattern.
Scheme 6. Aza-Nazarov reaction of 9a in dilute triflic acid solution
to form the N-indoline-substituted pyrrole 15a.
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All the cyclization precursors 9a–i reacted under the
strongly acidic reaction conditions to give NH-pyrroles
171 10a–i (Scheme 8) in moderate to good yields (Table 2). In
view of the fact that the overall reaction sequence involves
two steps in one pot (i.e., cyclization followed by N–N bond
cleavage) the yields are satisfactory. Both alkyl and aryl
groups could be introduced at the C-2 position. At the C-5
176 position it was possible to incorporate aryl groups with
either electron-donating or electron-withdrawing groups at
their 2-, 3-, or 4-positions. Alkyl groups were not intro-
duced at the C-5 position. It is worth mentioning here that
diaryl-NH-pyrroles have been identified as p38 mitogen-ac-
181 tivated protein (MAP) kinases and COX-2-selective (cyclo-
oxygenase-2-selective) inhibitors.[15]
Figure 2. Molecular structure of pyrrole 10i in the solid state ob-
tained by X-ray diffraction.
Mechanistic Discussion
A detailed look at the two different products 10 and 15a
obtained by use either of a large or of a small excess, respec-
tively, of the strong triflic acid reveals that there are two 191
consecutive steps involved in this reaction (Scheme 9): the
ring closure reaction and the N–N bond cleavage. Whereas
the relatively normal acidic conditions (2 equiv. of acid in
50 mL of solvent) that lead to cyclic product 15a can be
regarded as simple “electrophilic” conditions, the strongly 196
acidic conditions (7 equiv. of triflic acid in 5 mL of solvent)
seem to be essential for the N–N bond cleavage to form 10a
and 8, indicating possible involvement of “superelectro-
philic solvation or activation”.[16]
Scheme 8. Optimized reaction conditions for the synthesis of NH-
pyrroles 10a–i.
Table 2. Substitution patterns and yields of the NH-pyrroles
10a–i.
Precursor
Product
R1
R2
Yield [%]
9a
9b
9c
9d
9e
9f
9g
9h
9i
10a
10b
10c
10d
10e
10f
10g
10h
10i
Me
Me
Me
Me
Ph
Ph
Ph
Ph
45
40
44
33
51
53
60
49
45
Extensive high-level quantum chemical calculations 201
2-BrC6H4
4-ClC6H4
4-MeC6H4
Ph
3-FC6H4
4-ClC6H4
4-MeC6H4
4-CF3C6H4
[SCS-MP2/6-311+G(d,p)//B3LYP/6-311+G(d,p)
+
ZPE
level of theory] were performed both for the gas phase and
for dichloromethane solutions [M062x/6-311+G(d,p)
CPCM model].[17–20] The inclusion of the solvent often has
a moderating effect, reducing the relative energy differences 206
of isomeric species. In the following discussion, the SCS-
MP2 relative energies are used. In the schemes, gas-phase
data are given in square brackets [ ] and the dichlorometh-
Ph
Ph
The NH-pyrroles 10 were easily identified by NMR spec- ane relative energies in parentheses ( ).
troscopy. The typical NH-proton peak at low field
The 1-azapenta-1,4-dien-3-one 9a was used as model 211
(Ͼ8.4 ppm) is a first useful indicator for the product substrate for the computational study. At first its proton-
186 formed. The single-crystal X-ray analysis of 10i also con- ation behavior in less concentrated acidic solution (“electro-
firms the structure of the product (Figure 2).
philic conditions”) was studied in order to identify the most
Scheme 9. Reactivity profile of the precursor 9a under acidic (“electrophilic”) and very strongly acidic (“superelectrophilic”) conditions.
4
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Preparation of NH-Pyrroles under Superelectrophilic Conditions
likely reactive species present in the mixture (Scheme 10). sponding pyrrolium cation. The bond rotation for the
216 There are at least three basic sites that might be protonated monocationic species 17a to form 17aU requires an acti-
under these reaction conditions present in the substrate: vation barrier of 9.5 kcalmol–1, whereas the subsequent cy-
namely the oxygen atom and the two nitrogen atoms. The clization step to give 19a requires 8.5 kcalmol–1 for acti-
gas-phase protonation energies for 9a suggest that the carb- vation. Overall, this monocationic cyclization was found to 236
onyl oxygen atom is the most basic site in the molecule, be exothermic by –13.9 kcalmol–1. The calculated acti-
221 giving the protonated species 17a, followed by protonation vation barriers are highly compatible with the reaction con-
at the two nitrogen atoms N2 (Erel = 5.3 kcalmol–1, 18) and ditions used (room temperature) and the properties of the
N1 (Erel = 6.9 kcalmol–1, 16). The calculations for the cor- transition states are consistent with our previous studies.[3]
responding dichloromethane solutions indicate smaller dif- Removal of the proton from the 5-position of the pyrrolium 241
ferences in basicity.
ion and subsequent triple reaction with acetic anhydride
would give compound 15a, which was isolated in the experi-
ments.
For comparison we also studied second protonations of
monocation 17a at either one of the two nitrogen atoms and 246
the subsequent electrocyclization reactions of the resulting
dications. Possibly due to a larger distance between the two
charges, the formation of the O,N2-dication 21 is predicted
to be favored over that of the O,N1-dication 20
(Scheme 12).
251
Scheme 10. Protonation behavior of the substrate 9a (kcalmol–1)
under electrophilic conditions. [SCS-MP2/6-311+G(d,p)//B3LYP/6-
311+G(d,p)+ZPE] (M062x/6-311+G(d,p) including dichlorometh-
ane solvent sphere (CPCM)).
226
Of the three protonation products, cation 17a is the only
possible intermediate that might be expected to undergo an
electrocyclization reaction under the reaction conditions
employed. As first step a bond rotation would be necessary
in order to obtain the active “U” conformation
231 (Scheme 11), followed by the cyclization to form the corre-
Scheme 12. Second protonation of cation 17a and subsequent ring
closure reaction (kcalmol–1). [SCS-MP2/6-311+G(d,p)//B3LYP/6-
311+G(d,p)+ZPE] (M062x/6-311+G(d,p) including dichlorometh-
ane solvent sphere (CPCM)).
The bond rotation in the dicationic species 21 requires a
considerably higher activation barrier of 26.9 kcalmol–1
(TS 21–21U), whereas the corresponding cyclization
(TS 21U–22) has
a calculated activation barrier of
12.0 kcalmol–1 (Scheme 12). NBO charges of the connect- 256
ing atoms in the transition state (N: –0.2923, C: 0.1634, C–
N distance: 1.9476 Å) and a rather low NICS(0) value of
–5.8 are indicative of a charge-controlled reaction. The di-
cationic cyclization to give 22 was calculated to be slightly
endothermic by 0.3 kcalmol–1. For dichloromethane solu- 261
tion, the calculations indicate that the compact tri-
cyclic product 22 benefits exceptionally from solvation
(–13.1 kcalmol–1), so from the kinetic and thermodynamic
points of view an electrocyclization of such a dication might
Scheme 11. Calculated cyclization reaction (kcalmol–1) of the
monocation 17a [SCS-MP2/6-311+G(d,p)//B3LYP/6-311+G(d,p)
+ZPE] (M062x/6-311+G(d,p) including dichloromethane solvent
sphere (CPCM)).
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266 be feasible, provided that the reaction conditions allow such strongly acidic conditions for the N–N bond cleavage reac-
a second protonation. The large excess of triflic acid in a tion (for the possible involvement of a dication, see below).
small amount of the less polar solvent dichloromethane In contrast, deprotonation of 19a leads either to the N-
might provide such unusual “superelectrophilic” reaction indolinyl pyrrole 26 or to the high-energy zwitterion 25.
conditions. However, the cyclization by the monocationic
Finally we considered dication 22 as an intermediate for 306
271 pathway is clearly predicted to proceed more easily than the the N–N bond fission step (Scheme 14). Interestingly, re-
+
dicationic pathway.
moval of the Ha proton here also leads during the geome-
We next performed model calculations relating to the try optimization in a very exothermic reaction directly to
mechanism of the N–N bond cleavage reaction. We as- the N–N cleavage products, now in form of the positively
sumed that the removal of the proton from the carbon atom charged hydrogen-bonded aggregate 28. The two units of 311
276 next to the nitrogen atom N2 of the indoline moiety might the aggregate 28 would be expected to tautomerize readily
be the essential step, possibly promoted by the trifluoro- to their corresponding more stable forms, the 1H-pyrrole
methanesulfonate anion as base. We therefore analyzed the 30 and 1H-indole (29), which are the direct precursors of
relative acidities of the three monocationic species 19a, 23, the experimentally observed acetylated products 10a and 8,
and 24 (Scheme 13) and of the dicationic species 22 respectively. The high acidity of proton Ha in 22 is certainly 316
281 (Scheme 14, below) with respect to the removal of all pos- again related to the positive charge of the ammonium moi-
sible protons that might be abstracted in the course of the ety next to it (for details see Supporting Information).[21]
reaction. As can be seen from Scheme 13, the lowest in en-
ergy among the cyclic monocations is the species 19a, pro-
tonated at C-5 (the C-4 protonated isomer, not shown, is
286 higher in energy), which is the primary electrocyclization
product. It is followed by the pyrrole derivative 23, featur-
ing protonation at the indolinyl nitrogen atom with a rela-
tive energy of 9.2 kcalmol–1. As would be expected from
pyrrole chemistry, protonation at the pyrrole nitrogen atom
291 (species 24) is much less likely.
Scheme 14. N–N cleavage reaction of 19a upon protonation at ni-
trogen atom N2 to form dication 22 (kcalmol–1). [SCS-MP2/6-
311+G(d,p)//B3LYP/6-311+G(d,p)+ZPE] (M062x/6-311+G(d,p),
including dichloromethane solvent sphere (CPCM)).
In conclusion, reaction pathways for the N–N bond
cleavage reaction involving mono- and dicationic intermedi-
Scheme 13. Proton abstraction behavior (kcalmol–1) of the mono-
cationic species 19a, 23, and 24 [SCS-MP2/6-311+G(d,p)//B3LYP/
6-311+G(d,p)+ZPE] (M062x/6-311+G(d,p), including dichloro-
methane solvent sphere (CPCM)).
ates were derived from the calculations. The monocationic 321
route requires the intermediate formation of cation 23,
whereas the dicationic route starting from 22 implies double
protonation. With regard to the experimental observations
(the formation of the N-substituted product 15a when just
With regard to the N–N bond cleavage reaction, cation 2 equiv. of triflic acid were present, and cleavage of the N– 326
23 is the most interesting candidate: upon removal of the N bond to give 8 and 10a when a large excess of triflic acid
Ha+ proton the computational geometry optimization leads was used), the intermediacy of dicationic intermediates for
directly without any activation barrier to the hydrogen- the latter reaction seem to be an attractive explanation for
296 bonded pair 27 (Scheme 13) of cleavage products in a quite the diverse reactivity of the azadienone 9 under “electro-
exothermic reaction (the high-energy cation 24 behaves philic” and “superelectrophilic” conditions. In any case, the 331
similarly). The data suggest that the protonation at N2 to indolinyl moiety serves as redox-active neutral leaving
give species 23 requires more strongly acidic conditions group delivering a hydrogen atom to the pyrrole unit. Aro-
than the formation of cation 19a, which is lower in energy. matization of 2H-indole to 1H-indole contributes to the
301 This might be one explanation for the necessity of the very necessary exothermicity of the process.
6
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Preparation of NH-Pyrroles under Superelectrophilic Conditions
(1E,4E)-4-(Indolin-1-ylimino)-1-phenylpent-1-en-3-one (9a): Com-
pound 9a was prepared from 11 (0.606 g, 3 mmol) and benzalde-
hyde (0.35 mL, 3.3 mmol) by the general procedure. The compound
(0.8 g, 0.28 mmol, 93%) was obtained as a yellow solid (m.p. 151–
336 Conclusions
In summary, we have been able to demonstrate the effec-
tive use of indoline as a neutral leaving group for the one-
396
step synthesis of highly substituted NH-pyrrole derivatives 153 °C) after filtration and recrystallization from CH2Cl2/Et2O. 1H
NMR (300 MHz, CD2Cl2): δ = 2.21 (s, 3 H, CH3CN), 3.16 (t, J =
8.3 Hz, 2 H, NCH2CH2), 4.10 (t, J = 8.3 Hz, 2 H, NCH2CH2),
10a–i through an aza-Nazarov reaction pathway under am-
341 bient conditions. The cyclization precursors 9a–i are easily
available through two- or three-step reaction sequences
starting from commercially available compounds and 1-
aminoindoline. The behavior of the cyclization precursor 9
was found to be acidity-dependent. Whereas the N-substi-
346 tuted pyrrole 15a was obtained as the exclusive product un-
der electrophilic condition, NH-pyrroles 10 were formed as
the sole products under superelectrophilic conditions. High-
6.87–6.92 (m, 1 H, CHar), 7.10–7.13 (m, 1 H, CHar), 7.19–7.23 (m, 401
2 H, CHar), 7.27–7.32 (m, 3 H, CHar), 7.53–7.56 (m, 2 H, CHar),
7.60 (d, J = 16.0 Hz, 1 H, CHol), 7.98 (d, J = 16.0 Hz, 1 H,
CHol) ppm. 13C NMR (75 MHz, CD2Cl2): δ = 13.3 (CH3CN), 28.5
(NCH2CH2), 53.7 (NCH2CH2), 111.7 (CHar/ol), 122.0 (CHar/ol),
123.0 (CHar/ol), 125.3 (CHar/ol), 128.2 (CHar/ol), 128.5 (Cq), 128.6 406
(CHar/ol), 129.2 (CHar/ol), 130.1 (CHar/ol), 136.2 (Cq), 140.8
(CHar/ol), 143.4 (C ), 149.6 (C ), 188.2 (C=O) ppm. IR (neat): ν =
˜
q
q
level quantum chemical calculations were performed to in- 2363 (w), 2332 (w), 1645 (s), 1591 (s), 1551 (s), 1481 (w), 1449 (m),
1402 (s), 1364 (s), 1331 (m), 1300 (s), 1267 (m), 1217 (s), 1177 (s),
1067 (m), 1047 (w), 1032 (m), 1007 (m), 760 (m), 745 (s), 704 (w),
681 (m) cm–1. HRMS (ESI): calcd. for C19H18N2ONa 313.1317;
found 313.1311.
vestigate the reaction mechanism. The cyclization was
351 found to proceed through the typical aza-Nazarov reaction
pathway. Calculations indicate that mono- or diprotonation
is necessary for the N–N bond cleavage, underlining the im-
portance of strongly acidic conditions (“superelectrophilic
solvation”) for the N–N bond cleavage step in this synthesis
356 of such NH-pyrroles.
411
416
(1E,4E)-1-(2-Bromophenyl)-4-(indolin-1-ylimino)pent-1-en-3-one
(9b): Compound 9b was prepared from 11 (0.404 g, 2 mmol) and
2-bromobenzaldehyde (0.41 g, 2.1 mmol) by the general procedure.
The compound (0.65 g, 0.176 mmol, 88%) was obtained as a yellow
solid (m.p. 156–157 °C) after filtration and recrystallization from
CH2Cl2. 1H NMR (300 MHz, CD2Cl2): δ = 2.23 (s, 3 H, CH3CN),
3.18 (t, J = 8.2 Hz, 2 H, NCH2CH2), 4.13 (t, J = 8.2 Hz, 2 H,
NCH2CH2), 6.87–6.92 (m, 1 H, CHar), 7.10–7.17 (m, 4 H, CHar), 421
7.27–7.33 (m, 1 H, CHar), 7.55 (dd, J = 8.0, 1.2 Hz, 1 H, CHar),
7.69 (dd, J = 7.8, 1.7 Hz, 1 H, CHar), 7.85 (d, J = 15.9 Hz, 1 H,
CHol), 7.95 (d, J = 15.9 Hz, 1 H, CHol) ppm. 13C NMR (75 MHz,
CD2Cl2): δ = 13.3 (CH3CN), 28.5 (NCH2CH2), 53.7 (NCH2CH2),
111.7 (CHar/ol), 123.1 (CHar/ol), 124.9 (CHar/ol), 125.4 (CHar/ol), 426
125.9 (Cq), 128.1 (CHar/ol), 128.2 (CHar/ol), 128.24 (CHar/ol), 128.5
(Cq), 131.0 (CHar/ol), 133.7 (CHar/ol), 136.1 (Cq), 138.9 (CHar/ol),
Experimental Section
General: 1H and 13C NMR spectroscopy: TMS (1H, δ = 0.00 ppm)
and CDCl3 (13C, δ =77.0 ppm) were used as internal references.
When necessary, the experiments were carried out with complete
361
366
exclusion of moisture.
(E)-3-(Indolin-1-ylimino)butan-2-one (11): Diacetyl (0.78 mL,
0.77 g, 1 equiv.) was dissolved in abs. ethanol (20 mL) at 0 °C. N-
Aminoindoline (1.2 g, 1 equiv.) was added to this solution dropwise
with stirring. The color of the reaction mixture slowly changed
from yellow to red. A yellow precipitate was formed after approx.
1 h of stirring. Stirring was then continued overnight. The yellow
precipitate was filtered off and dried to give 11 in 58% yield as a
yellow solid (m.p. 110–112 °C). The compound was found to be of
high purity by 1H NMR and was used for the next step without
143.0 (C ), 149.4 (C ), 187.7 (C=O) ppm. IR (neat): ν = 3082 (w),
˜
q
q
3051 (w), 3011 (w), 2930 (w), 2853 (w), 1647 (s), 1599 (s), 1551 (s),
1481 (s), 1464 (m), 1437 (m), 1369 (s), 1331 (m), 1319 (s), 1300 (m), 431
1285 (s), 1260 (m), 1213 (m), 1171 (s), 1152 (m), 1070 (m), 1042
(m), 1022 (m), 1013 (m), 980 (m), 766 (m), 745 (s), 727 (s), 716 (w),
704 (s) cm–1. HRMS (ESI): calcd. for C19H17BrN2ONa 391.0422;
found 391.0416. C19H17BrN2O (369.26): calcd. C 61.80, H 4.64, N
371 further purification. 1H NMR (400 MHz, CDCl3): δ = 2.12 (s, 3
H, CH3CN), 2.40 (s, 3 H, CH3CO), 3.17 (t, J = 8.4 Hz, 2 H,
NCH2CH2), 4.06 (t, J = 8.4 Hz, 2 H, NCH2CH2), 6.90 (td, J = 7.2,
1.2 Hz, 1 H, CHar), 7.09–7.12 (m, 2 H, CHar), 7.13–7.16 (m, 1 H,
CHar) ppm. 13C NMR (100 MHz, CDCl3): δ = 12.7 (CH3CN), 24.8
7.59; found C 61.07, H 4.69, N 7.63.
436
(1E,4E)-1-(4-Chlorophenyl)-4-(indolin-1-ylimino)pent-1-en-3-one
(9c): Compound 9c was prepared from 11 (0.404 g, 2 mmol) and 4-
chlorobenzaldehyde (0.295 g, 2.1 mmol) by the general procedure.
The compound (0.47 g, 1.46 mmol, 73%) was obtained as a yellow
solid (m.p. 170–171 °C) after filtration and recrystallization from
CH2Cl2. 1H NMR (300 MHz, CD2Cl2): δ = 2.22 (s, 3 H, CH3CN),
3.18 (t, J = 8.3 Hz, 2 H, NCH2CH2), 4.12 (t, J = 8.2 Hz, 2 H,
NCH2CH2), 6.88–6.93 (m, 1 H, CHar), 7.11–7.19 (m, 3 H, CHar),
7.29 (d, J = 8.4 Hz, 2 H, CHar), 7.48 (d, J = 8.4 Hz, 2 H, CHar),
7.50 (d, J = 16.1 Hz, 1 H, CHol), 7.97 (d, J = 16.1 Hz, 1 H,
CHol) ppm. 13C NMR (75 MHz, CD2Cl2): δ = 13.3 (CH3CN), 28.5
(NCH2CH2), 53.7 (NCH2CH2), 111.7 (CHar/ol), 122.6 (CHar/ol),
123.1 (CHar/ol), 125.4 (CHar/ol), 128.3 (CHar/ol), 128.5 (Cq), 129.4
(CHar/ol), 129.8 (CHar/ol), 134.8 (Cq), 135.7 (Cq), 139.2 (CHar/ol),
376
(CH3CO), 28.2 (NCH2CH2), 53.0 (NCH2CH2), 111.5 (CHar), 122.6
(CHar), 124.9 (CHar), 127.5 (Cq), 127.9 (CHar), 142.4 (Cq), 149.2
(C , CH CN), 198.7 (C , CH CO) ppm. IR (neat): ν = 3055 (w),
˜
q
3
q
3
441
446
451
456
2974 (w), 2932 (w), 2858 (w), 1665 (s), 1605 (s), 1570 (s), 1481 (m),
1443 (s), 1350 (m), 1290 (s), 1196 (w), 1165 (s), 1115 (s), 974 (m),
835 (s), 775 (m), 756 (w), 669 (s), 621 (m) cm–1. HRMS (ESI):
calcd. for C12H14N2ONa 225.1004; found 225.0998.
381
General Procedure for the Preparation of (1E,4E)-4-(Indolin-1-yl-
imino)-1-arylpent-1-en-3-ones 9a–d: Compounds 9a–d were pre-
pared through base-catalyzed aldol condensations. α-Ketohydra-
386 zone 11 (1 equiv.) was dissolved in methanol (2 mLmmol–1). KOH
(30% in methanol) was added to this solution, followed by the
addition of the appropriate aldehyde (1.1 equiv.). Usually the for-
mation of a precipitate was observed after a few hours. The reac-
tion mixture was stirred overnight at room temperature. The pre-
143.2 (C ), 149.5 (C ), 187.9 (C=O) ppm. IR (neat): ν = 3088 (w),
˜
q
q
3019 (w), 1643 (s), 1587 (s), 1549 (vs), 1489 (s), 1481 (m), 1462 (m),
1441 (s), 1429 (s), 1406 (m), 1331 (m), 1298 (vs), 1285 (m), 1267
(vs), 1217 (vs), 1204 (vs), 1175 (s), 1090 (s), 1063 (vs), 1045 (m),
1026 (m), 1011 (s), 961 (s), 945 (m), 926 (m), 824 (m), 814 (s), 800
(m), 766 (s), 741 (s), 716 (s), 704 (m), 685 (m) cm–1. HRMS (ESI):
391
cipitate was then filtered off and washed with ice-cold methanol to
remove impurities. The crude product was purified through
recrystallization.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20913
/KAP1
Date: 10-09-12 12:01:02
Pages: 13
R. Narayan, C.-G. Daniliuc, E.-U. Würthwein
FULL PAPER
calcd. for C1 9 H1 7 ClN2 ONa 347.0927; found 347.0922.
C19H17ClN2O (324.81): calcd. C 70.26, H 5.28, N 8.62; found C
69.22, H 5.44, N 8.52.
(1E,3E)-4-(3-Fluorophenyl)-1-(indolin-1-ylimino)-1-phenylbut-3-en-
2-one (9f): Compound 9f was produced from 13 (0.372 g, 1 mmol)
and 3-fluorobenzaldehyde (0.14 g, 1.1 mmol) by the general pro-
cedure, being obtained (0.21 g, 0.58 mmol, 58%) as a yellow solid 521
(m.p. 142–143 °C) after recrystallization. 1H NMR (300 MHz,
CDCl3): δ = 2.94 (t, J = 8.2 Hz, 2 H, NCH2CH2), 3.24 (t, J =
8.2 Hz, 2 H, NCH2CH2), 6.94 (td, J = 7.3, 1.1 Hz, 1 H, CHar),
6.98–7.03 (m, 1 H, CHar), 7.06–7.09 (m, 1 H, CHar), 7.22–7.26 (m,
3 H, CHar), 7.30–7.36 (m, 7 H, CHar), 7.57 (d, J = 16.0 Hz, 1 H, 526
CHol), 8.10 (d, J = 16.0 Hz, 1 H, CHol) ppm. 13C NMR (75 MHz,
CDCl3): δ = 28.0 (NCH2CH2), 53.5 (NCH2CH2), 111.3 (CHar/ol),
(1E,4E)-4-(Indolin-1-ylimino)-1-(p-tolyl)pent-1-en-3-one (9d): Com-
pound 9d was prepared from 11 (0.404 g, 2 mmol) and 4-methyl-
benzaldehyde (0.24 g, 2 mmol) by the general procedure. The com-
pound (0.515 g, 0.17 mmol, 85%) was obtained as a yellow solid
(m.p. 93–95 °C) after filtration and recrystallization from meth-
anol. 1H NMR (300 MHz, CD2Cl2): δ = 2.19 (s, 3 H, CH3CN),
2.28 (s, 3 H, CH3Ph), 3.14 (t, J = 8.2 Hz, 2 H, NCH2CH2), 4.07
(t, J = 8.2 Hz, 2 H, NCH2CH2), 6.86–6.90 (m, 1 H, CHar), 7.07–
7.11 (m, 1 H, CHar), 7.13 (d, J = 8.1 Hz, 2 H, CHar), 7.16–7.18 (m,
2 H, CHar), 7.50 (d, J = 8.1 Hz, 2 H, CHar), 7.52 (d, J = 16.0 Hz,
1 H, CHol), 7.93 (d, J = 16.0 Hz, 1 H, CHol) ppm. 13C NMR
(75 MHz, CD2Cl2): δ = 13.4 (CH3CN), 21.6 (CH3Ph), 28.5
(NCH2CH2), 53.7 (NCH2CH2), 111.8 (CHar/ol), 120.9 (CHar/ol),
122.9 (CHar/ol), 125.3 (CHar/ol), 128.2 (CHar/ol), 128.5 (Cq), 128.6
(CHar/ol), 129.9 (CHar/ol), 133.4 (Cq), 140.7 (Cq), 140.9 (CHar/ol),
461
466
471
476
481
2
2
114.3 (d, J = 21.7 Hz, CHar), 116.5 (d, J = 21.7 Hz, CHar), 121.6
(CHar/ol), 123.4 (CHar/ol), 124.3 (d, 4J = 2.8 Hz, CHar), 125.2
(CHar/ol), 127.6 (CHar/ol), 128.2 (CHar/ol), 128.3 (CHar/ol), 128.6 531
3
(CHar/ol), 130.3 (d, J = 8.4 Hz, CHar), 130.8 (Cq), 130.4 (CHar/ol),
134.4 (Cq), 138.1 (d, 3J = 7.6 Hz, Cq), 139.5 (Cq), 139.5, 141.4 (Cq),
147.8 (Cq), 163.0 (d, 1J = 246.1 Hz, CFar), 187.2 (C=O) ppm. IR
(neat): ν = 3444 (w), 3376 (w), 3228 (w), 2356 (w), 2143 (w), 2133
˜
(w), 1638 (s), 1611 (s), 1554 (s), 1494 (m), 1333 (m), 1329 (s), 1269
(s), 1241 (m), 1172 (m), 1115 (m), 1102 (m), 1091 (s), 1065 (s), 1011
(m), 975 (s), 892 (s), 757 (m), 716 (m), 702 (m), 697 (m), 668
(m) cm–1. HRMS (ESI): calcd. for C24H19FN2ONa 393.1379;
found 393.1374.
536
143.6 (C ), 149.7 (C ), 188.2 (C=O) ppm. IR (neat): ν = 2361 (w),
˜
q
q
2340 (w), 1665 (s), 1647 (s), 1605 (s), 1595 (s), 1558 (s), 1481 (m),
1329 (m), 1296 (s), 1261 (s), 1221 (w), 1206 (w), 1167 (m), 1115
(m), 1067 (s), 1028 (s), 1005 (m), 829 (m), 810 (m), 741 (s) cm–1.
HRMS (ESI): calcd. for C20H20N2ONa 327.1473; found 327.1468.
(1E,3E)-4-(4-Chlorophenyl)-1-(indolin-1-ylimino)-1-phenylbut-3-en- 541
2-one (9g): Compound 9g was produced from 13 (0.372 g, 1 mmol)
and 4-chlorobenzaldehyde (0.155 g, 1.1 mmol) by the general pro-
cedure, being obtained (0.227 g, 0.59 mmol, 59%) as a yellow solid
(m.p. 137–139 °C) after recrystallization. 1H NMR (300 MHz,
CDCl3): δ = 2.94 (t, J = 8.2 Hz, 2 H, NCH2CH2), 3.23 (t, J = 546
8.2 Hz, 2 H, NCH2CH2), 6.93 (td, J = 7.3, 1.1 Hz, 1 H, CHar), 7.07
(d, J = 7.3 Hz, 1 H, CHar), 7.21–7.24 (m, 3 H, CHar), 7.29–7.32
(m, 6 H, CHar), 7.50 (d, J = 8.4 Hz, 2 H, CHar), 7.56 (d, J =
16.0 Hz, 1 H, CHol), 8.07 (d, J = 16.0 Hz, 1 H, CHol) ppm. 13C
NMR (75 MHz, CDCl3): δ = 28.0 (NCH2CH2), 53.5 (NCH2CH2), 551
111.2 (CHar/ol), 122.6 (CHar/ol), 123.4 (CHar/ol), 125.2 (CHar/ol),
127.6 (CHar/ol), 128.1 (CHar/ol), 128.3 (CHar/ol), 128.6 (CHar/ol),
129.1 (CHar/ol), 129.4 (CHar/ol), 130.4 (Cq), 134.4 (Cq), 134.5 (Cq),
135.5 (Cq), 139.5 (CHar/ol), 141.5 (Cq), 147.9 (Cq), 187.2
C
20H20N2O (304.39): calcd. C 78.92, H 6.62, N 9.20; found C
78.56, H 6.56, N 9.24.
General Procedure for the Preparation of Compounds 9e–i: tBuOK
(1 equiv.) was placed in a dry Schlenk flask and dissolved in abs.
THF (10 mLmmol–1). Ketophosphonate 13 (1 equiv.) was then
added as a solution in THF (2 mLmmol–1). This reaction mixture
was stirred at room temp. for one hour, followed by the addition
of the appropriate aldehyde (1.1 equiv.) dissolved in THF. The pro-
gress of the reaction was monitored by TLC. After the completion
of the reaction, the solvent was evaporated in vacuo. The residue
was dissolved in CH2Cl2, washed with brine, dried with MgSO4,
and concentrated to afford the crude product. The product was
purified by recrystallization from CH2Cl2.
486
491
The products were found to be extremely susceptible to decomposi-
tion in the presence of acidic impurities, so column chromatog-
raphy could not be used for purification. However, the compounds
could be purified by recrystallization from CH2Cl2 and were found
(C=O) ppm. IR (neat): ν = 3455 (w), 3387 (w), 2361 (w), 2280 (w),
556
˜
2154 (w), 1640 (s), 1610 (s), 1537 (s), 1521 (m), 1427 (m), 1352 (s),
1287 (s), 1242 (m), 1173 (m), 1116 (m), 1105 (m), 1087 (s), 1065
(s), 1031 (m), 957 (s), 834 (s), 750 (m), 734 (m), 656 (m), 633
(m) cm–1. HRMS (ESI): calcd. for C24H19ClN2ONa 409.1084;
found 409.1078.
496
1
to be of high purity by H NMR spectroscopy.
561
(1E,3E)-1-(Indolin-1-ylimino)-1,4-diphenylbut-3-en-2-one (9e):
Compound 9e was obtained from 13 (0.372 g, 1 mmol) and benzal-
dehyde (0.11 mL, 1.1 mmol) by the general procedure. Subsequent
recrystallization gave 9e (0.25 g, 0.72 mmol, 72%) as a yellow solid
(1E,3E)-1-(Indolin-1-ylimino)-1-phenyl-4-(p-tolyl)but-3-en-2-one
(9h): Compound 9h was produced from 13 (0.372 g, 1.0 mmol) and
4-methylbenzaldehyde (0.132 g, 1.1 mmol) by the general pro-
cedure, being obtained (0.2 g, 0.55 mmol, 55%) as a yellow solid
501
506
511
516
1
(m.p. 127–128 °C). H NMR (300 MHz, CDCl3): δ = 2.93 (t, J =
8.2 Hz, 2 H, NCH2CH2), 3.22 (t, J = 8.2 Hz, 2 H, NCH2CH2), (m.p. 122–123 °C) after recrystallization. 1H NMR (300 MHz,
6.92 (td, J = 7.4, 0.7 Hz, 1 H, CHar), 7.06 (d, J = 7.3 Hz, 1 H, CD2Cl2): δ = 2.30 (s, 3 H, CH3Ph), 2.90 (t, J = 8.2 Hz, 2 H,
CHar), 7.22–7.26 (m, 3 H, CHar), 7.30–7.36 (m, 7 H, CHar), 7.59 NCH2CH2), 3.19 (t, J = 8.2 Hz, 2 H, NCH2CH2), 6.90 (td, J = 7.4,
1.1 Hz, 1 H, CHar), 7.07–7.08 (m, 1 H, CHar), 7.16 (d, J = 8.0 Hz,
1 H, CHar), 7.21–7.23 (m, 3 H, CHar), 7.30–7.35 (m, 4 H, CHar),
= 26.9 (NCH2CH2), 52.4 (NCH2CH2), 110.2 (CHar/ol), 121.0 7.50 (d, J = 8.0 Hz, 2 H, CHar), 7.54 (d, J = 16.0 Hz, 1 H, CHol),
(CHar/ol), 122.1 (CHar/ol), 124.1 (CHar/ol), 126.5 (CHar/ol), 127.1 8.09 (d, J = 16.0 Hz, 1 H, CHol) ppm. 13C NMR (75 MHz,
(CHar/ol), 127.21 (CHar/ol), 127.22 (CHar/ol), 127.5 (CHar/ol), 127.8 CD2Cl2): δ = 21.6 (CH3Ph), 28.4 (NCH2CH2), 53.8 (NCH2CH2),
566
571
576
(d, J = 7.3 Hz, 2 H, CHar), 7.63 (d, J = 16.0 Hz, 1 H, CHol), 8.12
(d, J = 16.0 Hz, 1 H, CHol) ppm. 13C NMR (75 MHz, CDCl3): δ
(CHar/ol), 128.7 (Cq), 129.3 (CHar/ol), 133.5 (Cq), 134.8 (Cq), 139.9
(CHar/ol), 140.5 (C ), 146.9 (C ), 187.4 (C=O) ppm. IR (neat): ν =
3458 (m), 3421 (m), 2359 (w), 2180 (w), 2154 (w), 1653 (s), 1607
111.5 (CHar/ol), 121.6 (CHar/ol), 123.4 (CHar/ol), 125.5 (CHar/ol),
127.8 (CHar/ol), 128.3 (CHar/ol), 128.6 (CHar/ol), 128.8 (CHar/ol),
128.9 (Cq), 129.9 (CHar/ol), 130.9 (CHar/ol), 133.4 (Cq), 135.4 (Cq),
˜
q
q
(s), 1547 (s), 1481 (m), 1325 (m), 1302 (s), 1269 (s), 1240 (m), 1163 140.7 (Cq), 140.8 (CHar/ol), 141.7 (Cq), 148.4 (Cq), 187.7
(m), 1126 (m), 1115 (m), 1103 (s), 1065 (s), 1011 (m), 957 (s), 829 (C=O) ppm. IR (neat): ν = 3443 (w), 3381 (w), 2367 (w), 21940
˜
(s), 750 (m), 716 (m), 696 (m) cm–1. HRMS (ESI): calcd. for
C24H20N2OH: 353.1654; found 353.1648.
(w), 2156 (w), 1647 (s), 1607 (s), 1556 (s), 1471 (m), 1355 (s), 1299
(s), 1269 (s), 1243 (m), 1223 (m), 1213 (s), 1136 (m), 1120 (m), 1103
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20913
/KAP1
Date: 10-09-12 12:01:02
Pages: 13
Preparation of NH-Pyrroles under Superelectrophilic Conditions
581
(s), 1034 (s), 1021 (m), 959 (s), 839 (s), 750 (m), 733 (m), 696 (Cq), 118.7 (Cq), 128.7 (CHar), 128.8 (CHar), 129.7 (CHar), 133.0
(m) cm–1. HRMS (ESI): calcd. for C25H22N2ONa 389.1630; found
389.1635. C25H22N2O (366.46): calcd. C 81.94, H 6.05, N 7.64;
found C 81.97, H 5.82, N 7.84.
(Cq ), 133.4 (Cq ), 133.5 (Cq ), 170.1 (OCOCH3 ), 194.1
(COCH ) ppm. IR (neat): ν = 3366 (w), 2974 (w), 2893 (w), 1757
˜
3
(s), 1638 (s), 1616 (s), 1456 (m), 1381 (s), 1285 (m), 1204 (m), 1088 646
(m), 1047 (m), 955 (s), 905 (s), 880 (m), 770 (m), 698 (s) cm–1
HRMS (ESI): calcd. for C15H15NO3Na 280.0950; found 280.0944.
.
X-ray Crystal Structure Analysis of 9h:[22] Formula C25H22N2O,
586 MW = 366.45, yellow crystal 0.30 ϫ 0.25 ϫ 0.22 mm3, a =
8.6032(3) Å, b = 9.8533(3) Å, c = 12.1841(5) Å, α = 74.374(1), β =
75.679(1), γ = 78.234(1), V = 953.27(6) Å3, ρcalcd. = 1.277 gcm–3, μ
= 0.611 mm–1, empirical absorption correction (0.838 Յ T Յ
3-Acetoxy-4-acetyl-5-(2-bromophenyl)-2-methyl-1H-pyrrole (10b):
Compound 10b was obtained from 9b (0.31 g, 1 mmol) by the gene-
ral procedure. Subsequent chromatographic purification (Et2O/
pentane 1:1) gave 10b (0.1 g, 0.38 mmol, 38%) as a yellow solid
(m.p. 114–116 °C). 1H NMR (400 MHz, CD2Cl2): δ = 1.84 (s, 3 H,
CH3CN), 2.01 (s, 3 H, CH3COO), 2.18 (s, 3 H, CH3CO), 7.19–7.24
(m, 1 H, CHar), 7.28–7.31 (m, 2 H, CHar), 7.57–7.59 (m, 1 H,
651
¯
0.877), Z = 2, triclinic, space group P1 (No. 2), λ = 1.54178 Å, T
591 = 223(2) K, ω and j scans, 10163 reflections collected (Ϯh, Ϯk,
Ϯl), [(sin θ)/λ] = 0.60 Å–1, 3206 independent (Rint = 0.041) and
2290 observed reflections [IϾ2σ(I)], 254 refined parameters, R =
2
0.041, Rw = 0.110, max. (min.) residual electron density 0.18 (–
CHar), 8.43 (s, 1 H, NH) ppm. 13C NMR (100 MHz, CD2Cl2): δ = 656
9.3 (CH3CN), 20.9 (CH3COO), 29.5 (CH3CO), 116.1 (Cq), 118.6
(Cq), 125.0 (Cq), 127.8 (CHar), 131.0 (CHar), 131.4 (Cq), 132.9
(CHar), 133.3 (CHar), 134.6 (Cq), 169.9 (OCOCH3), 193.1
0.17) eÅ–3, hydrogen atoms calculated and refined as riding atoms.
596
(1E,3E)-1-(Indolin-1-ylimino)-1-phenyl-4-[4-(trifluoromethyl)-
phenyl]but-3-en-2-one (9i): Compound 9i was produced from 13
(0.372 g, 1 mmol) and 4-(trifluoromethyl)benzaldehyde (0.19 g,
1.1 mmol) by the general procedure, being obtained (0.28 g,
0.67 mmol, 67 %) as a yellow solid (m.p. 144–146 °C) after
(COCH ) ppm. IR (neat): ν = 3285 (w), 1763 (s), 1651 (s), 1647 (s),
˜
3
1612 (s), 1421 (m), 1401 (s), 1368 (s), 1364 (m), 1283 (m), 1207 (s), 661
1164 (s), 1150 (m), 1112 (m), 1015 (s), 975 (m), 921 (s), 847 (m),
756 (m), 665 (s), 633 (m), 607 (m) cm–1. HRMS (ESI): calcd. for
C15H14BrNO3Na 358.0055; found 358.0060.
601 recrystallization. 1H NMR (300 MHz, CD2Cl2): δ = 2.90 (t, J =
8.5 Hz, 2 H, NCH2CH2), 3.23 (t, J = 8.5 Hz, 2 H, NCH2CH2),
6.93 (td, J = 7.4, 1.1 Hz, 1 H, CHar), 7.07–7.09 (m, 1 H, CHar),
3-Acetoxy-4-acetyl-5-(4-chlorophenyl)-2-methyl-1H-pyrrole (10c):
7.22–7.24 (m, 3 H, CHar), 7.33–7.35 (m, 4 H, CHar), 7.59 (d, J = Compound 10c was obtained from 9c (0.324 g, 1 mmol) by the ge-
666
16.0 Hz, 1 H, CHol), 7.61 (d, J = 8.4 Hz, 2 H, CHar), 7.72 (d, J =
neral procedure. Subsequent chromatographic purification (Et2O/
pentane 1.5:1) gave 10c (0.11 g, 0.38 mmol, 38%) as a yellow solid
606
8.4 Hz, 2 H, CHar), 8.22 (d, J = 16.0 Hz, 1 H, CHol) ppm. 13C
NMR (75 MHz, CD2Cl2): δ = 28.3 (NCH2CH2), 53.8 (NCH2CH2), (m.p. 172–174 °C). 1H NMR (400 MHz, CD2Cl2): δ = 1.95 (s, 3 H,
111.5 (CHar/ol), 123.7 (CHar/ol), 124.1 (q, 1J = 271.9 Hz, CF3), 125.2 CH3CN), 2.0 (s, 3 H, CH3COO), 2.18 (s, 3 H, CH3CO), 7.22–7.23
3
(CHar/ol), 125.6 (CHar/ol), 126.1 (q, JC,F = 3.8 Hz, 2ϫ CHo-ar),
(m, 4 H, CHar), 8.66 (s, 1 H, NH) ppm. 13C NMR (100 MHz, 671
127.8 (CHar/ol), 128.4 (CHar/ol), 128.7 (CHar/ol), 128.9 (CHar/ol), CD2Cl2): δ = 9.3 (CH3CN), 20.9 (CH3COO), 30.1 (CH3CO), 115.3
611 129.0 (Cq), 130.7 (q, 2JC,F = 32.7 Hz, 2ϫCHm-ar), 135.0 (Cq), 138.7
(CHar/ol), 139.88 (Cq), 139.9 (Cq), 141.4 (Cq), 148.2 (C=N), 187.2
(Cq), 119.0 (Cq), 128.8 (CHar), 130.9 (CHar), 131.4 (Cq), 131.8 (Cq),
133.4 (Cq), 134.7 (Cq), 170.0 (OCOCH3), 193.9 (COCH3) ppm. IR
(C=O) ppm. IR (neat): ν = 3436 (w), 3424 (w), 2367 (w), 2178 (w),
(neat): ν = 3271 (w), 1757 (s), 1651 (s), 1638 (s), 1616 (s), 1416 (m),
˜
˜
2153 (w), 1646 (s), 1609 (s), 1587 (s), 1501 (m), 1346 (m), 1322 (s),
1396 (s), 1368 (s), 1354 (m), 1279 (m), 1200 (s), 1146 (s), 1105 (m), 676
1269 (s), 1234 (m), 1263 (m), 1123 (m), 1120 (m), 1097 (s), 1065 1090 (m), 1015 (s), 955 (m), 905 (s), 837 (m), 716 (m), 660 (s) cm–1.
616
(s), 1021 (m), 989 (s), 839 (s), 750 (m), 716 (m), 696 (m), 657 (m),
HRMS (ESI): calcd. for C15H14ClNO3Na 314.0560; found
639 (m) cm–1. HRMS (ESI): calcd. for C25H19F3N2ONa 443.1347; 314.0554.
found 443.1342. C25H19F3N2O (420.43): calcd. C 71.42, H 4.56, N
3-Acetoxy-4-acetyl-2-methyl-5-(p-tolyl)-1H-pyrrole (10d): Com-
6.66; found C 71.10, H 4.51, N 6.55.
pound 10d was obtained from 9d (0.304 g, 1 mmol) by the general
procedure. Subsequent chromatographic purification (Et2O/pent-
ane 1.5:1) gave 10d (0.12 g, 0.33 mmol, 33%) as an off-white solid
(m.p. 108–109 °C). 1H NMR (300 MHz, CD2Cl2): δ = 1.95 (s, 3 H,
CH3CN), 1.96 (s, 3 H, CH3COO), 2.17 (s, 3 H, CH3CO), 2.28 (s,
3 H, CH3Ph), 7.11 (d, J = 7.9 Hz, 2ϫH, CHar), 7.20 (d, J = 7.9 Hz,
681
686
691
696
General Procedure for the Synthesis of NH-Pyrroles 10a–i: Dry
621 CH2Cl2 (5 mL per mmol of the substrate) was placed in a dry
Schlenk flask and cooled to –10 °C (ice/salt mixture). Triflic acid
(7 equiv.) was added, followed by the slow addition of the appropri-
ate 1-azapenta-1,4-dien-3-one 9a–i (1 equiv.) as a solution in
CH2Cl2 (2 mL per mmol of the substrate). The reaction mixture 2 H, CHar), 8.42 (s, 1 H, NH) ppm. 13C NMR (75 MHz, CD2Cl2):
626
was allowed to warm to room temp. and stirred for at least 1 h.
After that the reaction mixture was cooled to –10 °C, followed by
the dropwise addition of acetic anhydride (1 mL). The mixture was
δ = 9.2 (CH3CN), 20.9 (CH3COO), 21.3 (CH3Ctol), 30.0 (CH3CO),
114.9 (Cq), 118.3 (Cq), 129.4 (CHar), 129.5 (CHar), 130.1 (Cq), 133.4
(Cq ), 133.7 (Cq ), 139.0 (Cq ), 170.1 (OCOCH3 ), 194.0
stirred for a further 30 min before quenching with satd. aq. (COCH ) ppm. IR (neat): ν = 3369 (w), 2975 (w), 2893 (w), 1763
˜
3
NaHCO3. After that the solution was diluted with CH2Cl2 (20–
30 mL) and washed twice with water. The organic phase was then
dried with MgSO4, filtered, and concentrated in vacuo to obtain
the crude product. The product was purified by silica gel column
chromatography (diethyl ether/pentane).
(s), 1640 (s), 1616 (s), 1532 (m), 1498 (s), 1387 (s), 1355 (m), 1204
(m), 1118 (m), 1098 (m), 1047 (m), 976 (s), 943 (m), 933 (s), 927
(m), 889 (m), 850 (m), 787 (m), 698 (s) cm–1. HRMS (ESI): calcd.
for C16H17NO3Na 294.1106; found 294.1101. C16H17NO3 (271.32):
calcd. C 70.83, H 6.32, N 5.16; found C 70.63, H 6.29, N 5.06.
631
3-Acetoxy-4-acetyl-2-methyl-5-phenyl-1H-pyrrole (10a): Compound
10a was obtained from 9a (0.29 g, 1 mmol) by the general pro-
cedure. Subsequent chromatographic purification (Et2O/pentane
1.5:1) gave 10a (0.115 g, 0.45 mmol, 45%) as a white solid (m.p.
3-Acetoxy-4-acetyl-2,5-diphenyl-1H-pyrrole (10e): Compound 10e
was obtained from 9e (0.15 g, 0.43 mmol) by the general procedure.
Subsequent chromatographic purification (Et2O/pentane 2:1) gave
10e (0.07 g, 0.52 mmol, 52 %) as an off-white solid (m.p. 128–
636
641
95–97 °C). 1H NMR (400 MHz, CD2Cl2): δ = 1.95 (s, 3 H, 129 °C). 1H NMR [300 MHz, (CD3)2CO]: δ = 1.90 (s, 3 H,
CH3CN), 1.96 (s, 3 H, CH3COO), 2.16 (s, 3 H, CH3CO), 7.27– CH3CN), 2.18 (s, 3 H, CH3COO), 7.11–7.16 (m, 1 H, CHar), 7.25–
7.31 (m, 5 H, CHar), 8.58 (s, 1 H, NH) ppm. 13C NMR (100 MHz, 7.35 (m, 5 H, CHar), 7.44–7.47 (m, 2 H, CHar), 7.56–7.59 (m, 2 H,
701
CD2Cl2): δ = 9.3 (CH3CN), 20.9 (CH3COO), 30.1 (CH3CO), 115.1
CHar), 10.67 (br. s, 1 H, NH) ppm. 13C NMR (75 MHz, acetone
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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R. Narayan, C.-G. Daniliuc, E.-U. Würthwein
0.43 mmol) by the general procedure. Subsequent chromatographic
FULL PAPER
D6): δ = 21.0 (CH3COO), 30.1 (CH3CO), 117.1 (Cq), 122.2 (Cq),
706
711
126.2 (CHar), 127.7 (CHar), 129.1 (CHar), 129.5 (CHar), 129.6 purification (Et2O) gave 10i (0.11 g, 0.38 mmol, 38%) as an off-
(CHar), 130.7 (CHar), 131.2 (Cq), 133.5 (Cq), 134.5 (Cq), 135.7 (Cq), white solid (m.p. 192–194 °C). H NMR (400 MHz, CD2Cl2): δ =
1
169.9 (OCOCH ), 193.3 (COCH ) ppm. IR (neat): ν = 3150 (m),
2.05 (s, 3 H, CH3COO), 2.21 (s, 3 H, CH3CO), 7.21–7.25 (m, 1 H,
771
776
˜
3
3
3130 (m), 3032 (m), 1753 (s), 1622 (s), 1489 (s), 1460 (m), 1433 (s), CHar), 7.34 (t, J = 7.7 Hz, 2 H, CHar), 7.42–7.44 (m, 2 H, CHar),
1358 (m), 1315 (s), 1263 (m), 1207 (vs), 1163 (m), 1148 (m), 1059 7.54 (t, J = 8.1 Hz, 2 H, CHar), 7.60 (t, J = 8.1 Hz, 2 H, CHar),
(m), 1015 (s), 964 (m), 916 (m), 901 (s), 851 (s), 781 (s), 764 (vs),
8.69 (s, 1 H, NH) ppm. 13C NMR (100 MHz, CD2Cl2): δ = 21.1
1
746 (m), 694 (vs), 665 (m), 635 (m) cm–1. HRMS (ESI): calcd. for (CH3COO), 30.3 (CH3CO), 117.6 (Cq), 122.8 (Cq), 124.6 (q, JC,F
C20H17NO3Na 342.1106; found 342.1101.
= 272 Hz, CF3), 126.0 (q, 3JC,F = 3.8 Hz, 2ϫCHo-ar), 125.8 (CHar),
125.82 (Cq), 128.0 (CHar), 129.5 (CHar), 129.8 (CHar), 130.1 (Cq),
3-Acetoxy-4-acetyl-5-(3-fluorophenyl)-2-phenyl-1H-pyrrole (10f):
Compound 10f was obtained from 9f (0.125 g, 0.32 mmol) by the
general procedure. Subsequent chromatographic purification
(Et2O/pentane 1.2:1) gave 10f (0.057 g, 0.17 mmol, 53%) as a yel-
low solid (m.p. 99–101 °C). 1H NMR (300 MHz, CDCl3): δ = 2.07
(s, 3 H, CH3COO), 2.26 (s, 3 H, CH3CO), 7.03–7.09 (m, 1 H,
CHar), 7.12–7.15 (m, 1 H, CHar), 7.19–7.24 (m, 2 H, CHar), 7.31–
7.35 (m, 3 H, CHar), 7.41–7.43 (m, 2 H, CHar), 8.42 (s, 1 H,
NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.0 (CH3COO), 30.0
2
131.0 (q, JC,F = 32.7 Hz, 2ϫCHm-ar), 132.9 (CHar), 133.7 (Cq),
136.1 (C ), 170.0 (OCOCH ), 193.9 (COCH ) ppm. IR (neat): ν =
˜
q
3
3
716
721
726
3258 (m), 3055 (m), 1744 (s), 1655 (s), 1616 (m), 1501 (m), 1460
(m), 1422 (m), 1364 (m), 1327 (s), 1260 (m), 1223 (s), 1169 (s), 1150 781
(s), 1117 (s), 1107 (s), 1065 (s), 1057 (s), 1032 (m), 1018 (s), 957
(m), 908 (m), 860 (s), 843 (s), 816 (m), 762 (s), 737 (m), 716 (m),
679 (s), 660 (m), 610 (m) cm–1 . HRMS (ESI): calcd. for
C21H16F3NO3Na 410.0980; found 410.0974. C21H16F3NO3
2
(387.36): calcd. C 65.12, H 4.16, N 3.62; found C 64.92, H 4.09, N
3.52.
786
(CH3CO), 115.9 (Cq), 116.1 (d, JC,F = 21.0 Hz, CHar), 116.4 (d,
2JC,F = 21.0 Hz, CHar), 122.1 (Cq), 125.2 (d, 4JC,F = 3.0 Hz, CHar),
125.4 (CHar), 127.6 (CHar), 129.0 (CHar), 129.4 (Cq), 130.3 (d, 3JC,F
X-ray Crystal Structure Analysis of 10i:[22] Formula C21H16F3NO3,
MW = 387.35, pale yellow crystal 0.20 ϫ 0.10 ϫ 0.03 mm3, a =
12.6476(5) Å, b = 13.9398(6) Å, c = 10.4166(4) Å, α = 90.000, β =
94.751(3), γ = 90.000, V = 1830.19(13) Å3, ρcalcd. = 1.406 gcm–3, μ
= 0.114 mm–1, empirical absorption correction (0.978Յ TՅ 0.997),
Z = 4, monoclinic, space group P21/c (No. 14), λ = 0.71073 Å, T
= 223(2) K, ω and j scans, 16701 reflections collected (Ϯh, Ϯk,
Ϯl), [(sin θ)/λ] = 0.59 Å–1, 3194 independent (Rint = 0.084) and
2171 observed reflections [IϾ2σ(I)], 259 refined parameters, R =
3
= 8.5 Hz, CHar), 133.1 (Cq), 133.2 (Cq), 134.1 (d, JC,F = 8.2 Hz,
1
Cq), 162.6 (d, JC,F = 247.9 Hz, CFar), 169.9 (OCOCH3), 194.0
(COCH3) ppm. HRMS (ESI): calcd. for C20H16FNO3Na 360.1012;
found 360.1006.
791
796
3-Acetoxy-4-acetyl-5-(4-chlorophenyl)-2-phenyl-1H-pyrrole (10g):
Compound 10g was obtained from 9g (0.11 g, 0.28 mmol) by the
general procedure. Subsequent chromatographic purification
(Et2O/pentane 1:1) gave 10g (0.06 g, 0.16 mmol, 60%) as a white
731
736
741
746
1
solid (m.p. 183–185 °C). H NMR [300 MHz, (CD3)2SO]: δ = 2.07
2
0.067, Rw = 0.134, max (min) residual electron density 0.19
(s, 3 H, CH3COO), 2.31 (s, 3 H, CH3CO), 7.26–7.31 (m, 1 H,
CHar), 7.41–7.46 (m, 2 H, CHar), 7.53–7.64 (m, 6 H, CHar), 11.92
(s, 1 H, NH) ppm. 13C NMR [75 MHz, (CD3)2SO]: δ = 20.7
(CH3COO), 29.8 (CH3CO), 115.7 (Cq), 121.3 (Cq), 125.3 (CHar),
126.9 (CHar), 128.1 (CHar), 128.7 (CHar), 129.7 (CHar), 130.7 (Cq),
131.6 (Cq), 132.9 (Cq), 133.1 (Cq), 133.3 (Cq), 169.4 (OCOCH3),
(–0.20) e Å–3, hydrogen atoms calculated and refined as riding
atoms.
3-Acetoxy-4-acetyl-1-(5-acetylindolin-1-yl)-2-methyl-5-phenyl-1H-
pyrrole (15a): Compound 15a was obtained from the precursor 9a
exactly according to the procedure of Würthwein et al.[3] Dry
CH2Cl2 (50 mL) was placed in a dry Schlenk flask and cooled to
–10 °C (ice/salt mixture). Triflic acid (0.18 mL, 2 equiv.) was added,
followed by the slow addition of the 1-azapenta-1,4-dien-3-one 9a
(0.29 g, 1 mmol, 1 equiv.) as a solution in CH2Cl2 (2 mL). The pro-
gress of the reaction was monitored by TLC. Immediately after all
the starting material had been consumed (as indicated by TLC),
the reaction mixture was cooled to –10 °C, followed by the drop-
wise addition of acetic anhydride (1 mL). The mixture was stirred
for another 30 min before quenching with satd. aq. NaHCO3. The
organic phase was then washed twice with water, dried with
MgSO4, filtered, and concentrated in vacuo to afford the crude
product. The product was purified by silica gel column chromatog-
raphy (diethyl ether/pentane 3:1). Pyrrole 15a was obtained in 42%
801
806
811
816
821
192.6 (COCH ) ppm. IR (neat): ν = 3238 (m), 3051 (m), 2361 (w),
˜
3
2334 (w), 1742 (s), 1651 (s), 1612 (s), 1483 (m), 1456 (s), 1422 (m),
1369 (s), 1354 (m), 1310 (s), 1260 (m), 1225 (m), 1148 (s), 1086 (s),
1059 (m), 1013 (m), 955 (s), 910 (m), 845 (m), 812 (m), 760 (m),
702 (s), 677 (m) cm–1. HRMS (ESI): calcd. for C20H16ClNO3Na
376.0716; found 376.0711.
3-Acetoxy-4-acetyl-2-phenyl-5-(p-tolyl)-1H-pyrrole (10h): Com-
pound 10h was obtained from 9h (0.2 g, 0.55 mmol) by the general
procedure. Subsequent chromatographic purification (Et2O/pent-
ane 1:1) gave 10h (0.08 g, 0.45 mmol, 45%) as a yellow solid (m.p.
113–115 °C). 1H NMR (300 MHz, CD2Cl2): δ = 1.96 (s, 3 H,
CH3COO), 2.19 (s, 3 H, CH3CO), 2.31 (s, 3 H, CH3Ph), 7.16–7.22
(m, 3 H, CHar), 7.28–7.30 (m, 2 H, CHar), 7.32–7.34 (m, 2 H,
CHar), 7.41–7.44 (m, 2 H, CHar), 8.62 (s, 1 H, NH) ppm. 13C NMR
(75 MHz, CD2Cl2): δ = 21.2 (CH3COO), 21.4 (CH3Ctol), 30.2
(CH3CO), 116.5 (Cq), 121.6 (Cq), 125.5 (CHar), 127.6 (CHar), 129.4
(CHar), 129.6 (CHar), 129.7 (CHar), 129.7 (Cq), 130.1 (Cq), 133.7
(Cq ), 135. 6 (Cq ), 139.7 (Cq ), 170.1 (OCOCH3 ), 194.3
751
756
761
1
yield as a pale yellow solid (m.p. 76–78 °C). H NMR (300 MHz,
CDCl3): δ = 1.83 (s, 3 H, CH3), 1.83 (s, 3 H, CH3CN), 2.28 (s, 3
H, CH3COO), 2.45 (s, 3 H, CH3CO), 2.76–2.85 (m, 1 H, CHЈH),
3.00–3.07 (m, 1 H, NCHЈH), 3.54–3.60 (m, 1 H, NCHЈH), 3.69–
3.76 (m, 1 H, NCHЈH), 6.30 (d, J = 8.2 Hz, CHar), 7.23–7.32 (m,
5 H, CHar), 7.64 (s, 1 H, CHar), 7.70 (dd, J = 8.2, 1.6 Hz,
CHar) ppm. 13C NMR (75 MHz, CDCl3): δ = 8.6 (CH3CN), 20.8
(CH3COO), 26.3 (CH3), 27.0 (CH2), 30.1 (CH3CO), 54.9 (NCH2),
106.6 (CHar), 114.6 (Cq), 119.5 (Cq), 125.5 (CHar), 126.3 (CHar),
128.3 (CHar), 129.2 (CHar), 130.5 (CHar), 132.2 (Cq), 136.4 (Cq),
(COCH ) ppm. IR (neat): ν = 3145 (m), 3233 (m), 3045 (m), 1653
˜
3
(s), 1627 (s), 1498 (s), 1446 (m), 1425 (s), 1378 (m), 1315 (s), 1253
(m), 1211 (vs), 1183 (m), 1168 (m), 1079 (m), 1035 (s), 987 (m), 906
(m), 887 (s), 855 (s), 791 (s), 774 (vs), 745 (m), 657 (vs), 633 (m),
623 (m) cm–1. HRMS (ESI): calcd. for C21H19NO3Na 356.1263;
found 356.1257. C21H19NO3 (333.39): calcd. C 75.66, H 5.74, N
4.20; found C 75.67, H 5.40, N 4.08.
1 5 3 . 9 ( Cq ) , 1 6 9. 7 ( OCOCH3 ), 193. 5 ( COCH3 ), 196. 4 826
(COCH3) ppm. HRMS (ESI): calcd. for C25H24N2O4Na 439.1634;
766
3-Acetoxy-4-acetyl-2-phenyl-5-[4-(trifluoromethyl)phenyl]-1H- found 439.1629. C25H24N2O4 (416.48): calcd. C 72.10, H 5.81, N
pyrrole (10i): Compound 10i was obtained from 9i (0.180 g, 6.73; found C 71.89, H 5.68, N 6.78.
10
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Eur. J. Org. Chem. 0000, 0–0

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Date: 10-09-12 12:01:02
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Preparation of NH-Pyrroles under Superelectrophilic Conditions
Perovic-Ottstadt, H. C. Schroeder, Bioorg. Med. Chem. 2006,
Supporting Information (see footnote on the first page of this arti-
cle): Spectral characteristics of the synthesized compounds, 1H and
13C spectra for the new compounds, Cartesian coordinates and
SCS-MP2/6-311+G(d,p)//B3LYP/6-311+G(d,p)+ZPE energies for
the calculated structures, and thermal ellipsoid plots for the crystal
structures (50% ellipsoid probabilities).
14, 17–24; c) P. Lewer, E. L. Chapin, P. R. Graupner, J. R. Gil-
bert, C. Peacock, J. Nat. Prod. 2003, 66, 143–145; d) A.
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R. Rossi, Tetrahedron 2006, 62, 7213–7256.
896
901
831
[9]
For selected examples, see: a) B. R. Clark, R. J. Capon, E. La-
cey, S. Tennant, J. H. Gill, Org. Lett. 2006, 8, 701–704; b) H. B.
Bode, H. Irschik, S. C. Wenzel, H. Reichenbach, R. Mueller,
G. Hoefle, J. Nat. Prod. 2003, 66, 1203–1206.
836 Acknowledgments
This work was supported by the NRW Graduate School of Chemis-
try Münster, the Deutsche Forschungsgemeinschaft (DFG), and
the Fonds der Chemischen Industrie. We thank Dr. N. Ghavtadze
(University of Chicago) for helpful discussions.
[10]
906
911
a) D. Curran, J. Grimshaw, S. D. Perera, Chem. Soc. Rev. 1991,
20, 391–404. For selected examples, see: b) K. Ogawa, S. C.
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etti, A. Abbotto, L. Beverina, M. E. van der Boom, P. Dutta,
G. Evmenenko, G. A. Pagani, T. J. Marks, Chem. Mater. 2003,
15, 1064–1072.
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851
856
861
866
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876
881
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jected to frequency analyses. In the discussion, E (0 K) energies
containing zero-point corrections are used. The vibration re-
lated to the imaginary frequency corresponds to the nuclear
motion along the reaction coordinate under study. Intrinsic re-
action coordinate (IRC) calculations were performed in order
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Date: 10-09-12 12:01:02
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R. Narayan, C.-G. Daniliuc, E.-U. Würthwein
FULL PAPER
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may be obtained from E.-U. W. on request.
991
996
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[22] Data sets were collected with Nonius KappaCCD diffractome-
ters, equipped with a rotating anode generator. Programs used:
data collection COLLECT (Nonius B.V., 1998), data reduction
Denzo-SMN (Z. Otwinowski, W. Minor, Methods Enzymol.
1997, 276, 307–326), absorption correction, Denzo (Z. Ot-
winowski, D. Borek, W. Majewski, W. Minor, Acta Crystallogr.
2003, A59, 228–234), structure solution SHELXS-97 (G. M.
Sheldrick, Acta Crystallogr. 1990, A46, 467–473), structure re- 1001
finement SHELXL-97 (G. M. Sheldrick, Acta Crystallogr.
2008, A64, 112–122), graphics SCHAKAL (E. Keller, Uni-
versität Freiburg, 1997). CCDC-900199 (9h), and -900200 (10i)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge 1006
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_r-
equest/cif.
Received: July 10, 2012
Published Online: ᭿
12
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20913
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Date: 10-09-12 12:01:02
Pages: 13
Preparation of NH-Pyrroles under Superelectrophilic Conditions
1011
Aza-Nazarov Reaction
R. Narayan, C.-G. Daniliuc,
E.-U. Würthwein* ........................... 1–13
Preparation of NH-Pyrroles under Super-
electrophilic Conditions by an Aza-Naza-
rov Reaction Cascade with Indole as Neu-
tral Leaving Group: Experiment and The-
ory
1016 In an easy one-pot reaction sequence,
give NH-pyrroles 10a–i and acetylated in-
dole 8 (after acetic anhydride workup).
Quantum chemical calculations were used
to explain this acid-concentration-depen-
dent reaction cascade.
1-azapenta-1,4-dien-3-ones 9a–i undergo
aza-Nazarov reactions with subsequent
1021 acid-induced N–N bond cleavage in the
presence of large excesses of triflic acid to
Keywords: Nitrogen heterocycles / Super-
acidic systems / Electrocyclic reactions /
Reaction mechanisms / Ab initio
1026
calculations / Aza-Nazarov reaction
Eur. J. Org. Chem. 0000, 0–0
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