Selective PdII-Catalyzed Acylation of Pyrrole with Aldehydes. Application to the Synthesis of Celastramycin Analogues and Tolmetin

Article abstract of DOI:10.1002/ejoc.202000444

The Pd^II-catalyzed C-2 acylation of pyrrole with aldehydes in the presence of TBHP as oxidant has been studied for the synthesis of di(hetero)aryl ketones. The use of 2-pyrimidine as directing group leads to 2-acylpyrroles in moderate to good yields, although 2,5-diacylpyrroles are obtained as by products. This side-reaction could be avoided using 3-methy-2-pyridine as directing group, obtaining selectively 2-acylpyrroles. The reaction has been extended to a series of aromatic and heteroaromatic aldehydes, obtaining the best results with electron rich aromatic aldehydes. The methodology has been applied in the synthesis of pyrrolomycin alkaloid Celastramycin analogues and for an improved synthesis of Tolmetin, a nonsteroidal anti-inflammatory drug.

Full text of DOI:10.1002/ejoc.202000444

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Selective Pd(II)-catalyzed Acylation of Pyrrole with Aldehydes.
Application to the Synthesis of Celastramycin analogues and
Tolmetin
Authors: Carlos Santiago, Ibon Rubio, Nuria Sotomayor, and Esther
Lete
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000444
Link to VoR: https://doi.org/10.1002/ejoc.202000444
01/2020

10.1002/ejoc.202000444
European Journal of Organic Chemistry
FULL PAPER
Selective Pd(II)-catalyzed Acylation of Pyrrole with Aldehydes.
Application to the Synthesis of Celastramycin analogues and
Tolmetin
Carlos Santiago,[a] Ibon Rubio, [a] Nuria Sotomayor[a]* and Esther Lete [a]*
[a]
Departamento de Química Orgánica II, Facultad de Ciencia y Tecnología
Universidad del País Vasco / Euskal Herriko Unibertsitatea UPV/EHU
Apdo. 644. 48080 Bilbao (Spain)
E-mail: nuria.sotomayor@ehu.es; esther.lete@ehu.es. https://www.ehu.eus/es/web/oms/home
Supporting information for this article is given via a link at the end of the document.
Abstract: The Pd(II)-catalyzed C-2 acylation of pyrrole with
aldehydes in the presence of TBHP as oxidant has been studied for
the synthesis of di(hetero)aryl ketones. The use of 2-pyrimidine as
directing group leads to 2-acylpyrroles in moderate to good yields,
although 2,5-diacylpyrroles are obtained as by products. This side-
reaction could be avoided using 3-methy-2-pyridine as directing
group, obtaining selectively 2-acylpyrroles. The reaction has been
extended to a series of aromatic and heteroaromatic aldehydes,
obtaining the best results with electron rich aromatic aldehydes. The
methodology has been applied in the synthesis of pyrrolomycin
alkaloid Celastramycin analogues and for an improved synthesis of
Tolmetin, a nonsteroidal anti-inflammatory drug.
Figure 1. Selected alkaloids and pharmaceuticals with 2-aroylpyrrole
framework.
Introduction
Di(hetero)aryl ketones are important motifs present in natural
products, pharmaceuticals or agrochemicals. In particular,
various natural and synthetic molecules containing 2-
aroylpyrrole cores have been extensively studied in the
development of antibacterial, anti-fungal, and anticancer
agents.[1] Pyrrolomycins[2] are a family of potent natural product
antibiotics with nanomolar activity against Gram-positive and
Gram-negative bacteria with the ability to target biofilms, which
confers them a great potential for the development of new
antimicrobial agents to face the antibiotic resistance problem.[3]
For example, Pyoluteorin (Figure 1), a pyrrolomycin alkaloid
isolated from several species of Pseudomonas, shows a broad
bioprofile, demonstrating antibiotic, antifungal and herbicidal
activity.[4] The alkaloid Celastramycin A (Figure 1) exhibits high
The development of efficient and catalytic methods to acylate
pryrroles at C-2 is of significant value. For example, catalytic
Friedel–Crafts acylation of heteroaromatics has been achieved
using metal triflates as catalysts, though the procedure has been
mainly applied to the synthesis of alkanoyl pyrroles.[10] More
recently, an organocatalytic Friedel-Crafts acylation of pyrroles
and
indoles
with
acyl
chlorides
using
1,5-
diazabicyclo[4.3.0]nonane (DBN) as a nucleophilic catalyst has
been developed.[11] Transition-metal catalyzed acylation of
(hetero)arenes via C-H bond activation is a good alternative to
access di(hetero)aryl ketones,[12] but the method has been
scarcely applied to pyrroles. A notable example is the palladium-
catalyzed regioselective acylation of pyrroles with arylnitriles,
which have proven successful even with N-H free pyrrole.[13]
In this context, the Pd(II)-catalyzed acylation of (hetero)arenes in
the presence of an oxidant has recently emerged as catalytic
alternative to classical acylation methods, reducing the
production of toxic metal waste. Different directing groups and
acyl sources are being studied for this purpose,[14] although
further development is required to face mainly selectivity
problems in order to be applied in the synthesis of more complex
molecules. Examples reported in the literature involve Pd(II)-
catalyzed acylation reactions of indole derivatives, where no
selectivity problems arise. Thus, C-2 selective acylation of
indoles has been described using 2–pyrimidine as a directing
group on nitrogen and -oxocarboxylic acids,[15] aldehydes,[16] -
diketones[17] and even toluene derivatives[18] as the acyl
surrogates (Scheme 1).
activity against
a
series of multiresistant bacteria and
mycobacteria and has also been identified as a potent innate
immune suppressor.[5] Tolmetin (Figure 1) is a nonsteroidal anti-
inflammatory drug (NSAID) used in the treatment of rheumatoid
arthritis, osteoarthrosis, pain, and ankylosing spondylitis.[6].
Therefore, the construction of 2-aroyl pyrroles has received
considerable attention.[7] However, classical methodologies
through Friedel-Crafts, Vilsmeier- Haack and Houben-Hoesch
type acylations are frequently not regioselective, and require the
use of stoichiometric quantities of Lewis or protic acids.[8]
However, more environmentally friendly Friedel-Crafts acylation
methods based on the use of solid catalysts have been applied
only to acetylation of pyrrole.[9]
1
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10.1002/ejoc.202000444
European Journal of Organic Chemistry
FULL PAPER
Scheme 2. Schematic mechanistic proposal
Results and Discussion
Scheme 1.
We started testing reaction conditions related to those reported
for the acylation of indoles with aldehydes,[16] using 2-pyrimidine
as directing group[22] (1a), Pd(OAc)2 as pre-catalyst in the
presence of TBHP as oxidant. Using toluene as solvent at 90 ºC,
the reaction took place obtaining ketone 3aa, though in a
moderate yield (53%), together with the diacylated product 4aa
(2%) (Table 1, entry 1). In the presence of acetic acid as additive,
a similar yield was obtained (Table 1, entry 2), while the
reactivity is almost completely lost when Pd(CH3CN)2Cl2 was
used a pre-catalysts (Table 1, entry 3). Lower conversions and
isolated yields of 3aa and were obtained when the solvent was
changed to dioxane, THF or DCE (Table 1, entries 4-6), always
isolating diketone 4aa as the minor product, and recovering
unreacted 1aa. We next studied the effect of the acid additive,
and we observed that the reactivity is almost completely shut
down when stronger acids, such as pTsOH or TFA were used,
recovering unreacted 1aa (Table 1, entries 7-8). The effect of
the acid additive has been shown to increase the reactivity by
generating more electrophilic palladium species and,
consequently, facilitating the C-H activation event. However, the
acid may also have a detrimental effect by protonation of the
substrate,[23] in accordance with the results obtained in the
presence of strong acids. Thus, a significant increase of the
reactivity was observed when less strongly acidic pivalic acid
was used as an additive (Table 1, entries 9-14). The reaction
was complete in only 3 hours at 90 ºC in the presence of 1 equiv.
of pivalic acid, although it also led to a significant increase in the
ratio of the formation of the diketone 4aa (Table 1, entry 9). It
was also necessary to use an excess of oxidant, as the use of
less TBHP led to a loss of reactivity, with a low conversion after
24 h (Table 1, entry 10). Finally, the effect of amount of acid
additive (0.5 or 0.75 equiv.) and the temperature (90 or 60 ºC)
were studied (Table 1, entries 11-14), obtaining full conversion
and a 71% isolated yield of 3aa (Table 1, entry 13), although
minor formation of 4aa could not be avoided reducing the
amount of benzaldehyde (2a) used (Table 1, entry 14).
This acylation reaction has been only scarcely applied to pyrrole,
and in this case the C2-acylated compound was obtained with a
modest yield (41%), together with the corresponding 2,5-
diacylated product in a significant amount (18%).[17] Diacylated
products have also been obtained using 2-pyridine as directing
group on pyrrole.[16a]The formation of diacylated products has
been observed as a side reaction also in related systems, such
as carbazoles.[19] Related protocols, as the ruthenium catalyzed
carbonylative direct arylation of pyrroles using the 2-pyrimidine
directing group have also been developed with high selectivity,
although yields obtained with pyrrole were moderate to good,
and generally lower than those obtained with indoles.[20] In this
context, in connection with our previous work on Pd(II)-catalyzed
C-H functionalization reactions,[21] we decided to study the
palladium catalyzed acylation of pyrroles 1 for the regioselective
formation of C-2 monoacylated pyrroles 3. For this purpose, we
selected first the 2-pyrimidine (1a, X = N) as directing group,
which has been successfully used in these reactions with indole,
but only one example has been reported with pyrrole.[17] Besides,
we decided to study the 3-methyl-2-pyridine as directing group
(1b, X = C-CH3). We reasoned that, once the monoacylated
compound 3b is formed, the presence of the C-3 substituent on
the directing group could result in a steric interaction with the
acyl group in C-2 that may prevent the adoption of the required
conformation to assist the second palladation, hampering the
formation of diacylated products. Although the nature of all the
intermediate species is not still clear, the generally accepted
mechanism for this type of reactions involves the chelation
assisted C-H activation to form a palladacycle I, that reacts with
an acyl radical generated in the presence of an oxidant form the
corresponding precursor (an aldehyde 2 in Scheme 2) to form
an intermediate Pd(III) or Pd(IV) intermediate. Reductive
elimination would give the acylated compound 3, regenerating
the active Pd(II) catalyst (Scheme 2). For this study, we decided
to use aldehydes 2 as the acyl radical source, due to their wide
availability and ease of generation in the presence of TBHP as
oxidant.[14
2
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10.1002/ejoc.202000444
European Journal of Organic Chemistry
FULL PAPER
Table 1. Acylation of 1a. Optimization of reaction conditions
Table 2. Acylation of 1a with aromatic aldehydes 2b-o
entry
1
2
Ar
t [h)]
1.5
3 [%][a]
4 [%][a]
entry
Additive.
solvent
T
[ºC]
t
[h]
3aa
4aa
[%][a]
[%][a]
2b
61
24
1
-
toluene
toluene
toluene
dioxane
THF
90
90
90
90
60
60
90
90
90
90
90
60
60
60
17
24
24
17
24
24
24
24
3
53[c]
51[c]
9[c]
2
2
AcOH[b]
AcOH[b]
AcOH[b]
AcOH[b]
AcOHb)
TsOH[b]
TFA[b]
9
2
3
4
2c
2d
2e
7
3
3
47
66
58
41
8
3[d]
4
2
41[c]
34[c]
48[c]
3[c]
6
<5[b]
5
3
6
DCE
10
-
5
6
7
8
2f
1.5
5
64
5
-
7
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
8
7[c]
-
2g
2h
2i
35[d]
22[d]
72
9
PivOH[b]
PivOH[b]
PivOH[f]
PivOH[f]
PivOH[g]
PivOH[g]
46
23
9
7
-
10[e]
11
12
13
14[h]
24
1.5
1.5
2
31[c]
66
17
10
16
8
2.5
8
69
71
9
2j
2.5
6
70
8
2.5
61
[a]Yield (%) of isolated pure compound. [b]1 equiv. [c]Unreacted 1a was
recovered. [d]Pd(CH3CN)2Cl2 (10 mol%) was used. [e]3 equiv. of TBHP were
used. [f]0.5 equiv. [g]0.75 equiv. [h]1.5 equiv. of PhCHO.
10
11
2k
2l
47[d]
40[d]
10
8
Once the reaction conditions were selected, we studied the
application of this procedure to a series of aldehydes 2b-2o with
different substitution patterns on the aromatic ring. As depicted
in Table 2, aromatic aldehydes bearing both electron
withdrawing and electron donating groups can be used for the
reaction. The use of p-alkyl substituted aldehydes 2b and 2c
gave the highest ratio of the corresponding diketones 4ab and
4ac (Table 2, entries 1 and 2). On the other hand, the presence
of halogens on the para position is well tolerated, giving
moderate to good yields on the corresponding ketones 3ad-af
(Table 2, entries 3-5) in shorter reaction times, and with minor
formation of the diketones 4. The best results were obtained
when electron donating groups are introduced in the aromatic
ring (Table 2, entries 8-9), although when an ortho-substituent
was present, the reaction was slower giving a lower yield of 3ak
and 3al, possibly due to a steric effect (Table 2, entries 10-11).
2-Naphthaldehyde 2o could also be used to obtain 3ao,
although together with a significant amount of the diketone 4ao
(Table 2, entry 14).
7
12
13
2m[c]
2n[c]
7
7
33[d]
14[d]
-
-
14
2o
1.5
51[d]
19
[a]Yield (%) of isolated pure compound. [b]Detected by 1H NMR but not isolated.
[c]Reaction temperature: 40 ºC. [d]Unreacted 1a was recovered.
On the other hand, the aldehydes bearing electron-withdrawing
groups gave sluggish reactions that required longer reaction
times and gave only low yields of the corresponding ketones 3
(Table 2, entries 6-7, 12-13). In these cases, the corresponding
diketones 4 were not detected. This reactivity pattern has also
been described in related palladium catalyzed radical acylation
reactions using aldehydes,[24] but it is opposite to the reactivity
observed when -diketones were used as acyl radical
precursors.[17] Although the change of the structure of the aroyl
3
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10.1002/ejoc.202000444
European Journal of Organic Chemistry
FULL PAPER
radical has a small effect on its polar character,[25] the observed
trend could be correlated to the nucleophilicity of the resulting
acyl radical. Thus the introduction of donating groups, mainly in
the p-position, would increase the nucleophilicity of the acyl
radical,[26] favoring the reaction with the electrophilic palladium
atom in intermediate I (Scheme 2). Besides, the electron
donating effect of the aroyl group could also stabilize the
resulting palladium intermediate.[24b]
Table 4. Acylation of 1b with aromatic aldehydes 2b-t
As has been shown, ketones 3 have been obtained as the major
compounds with moderate to good yields but, in most cases,
together with minor amounts of the corresponding diketones 4.
Although both products could be separated by chromatography,
we decided to explore the use of 3-methyl-2-pyridine as directing
group in order to avoid the formation of the diketones 4. Thus,
1b was reacted with benzaldehyde (2a), obtaining a moderate
yield of ketone 3ba, no detecting the formation of the
corresponding diketone (Table 3, entry 1). Therefore, the
reaction conditions were further optimized to improve the yield of
3ba (Table 3). An increase in the reaction temperature (Table 3,
entries 2-3) led to a significant increase of the yield of 3ba,
which was isolated in a 74%. The use of MW irradiation was
also explored (Table 3, entries 4-6) but although the reactions
were much faster, and full consumption of the staring material
was observed in 10-20 minutes, the isolated yields of 3ba were
lower. The use of less aldehyde (1 equiv) and oxidant (2 equiv)
gave lower yields. However, the reaction could be carried out
with similar efficiency using 1.5 equiv of benzaldehyde at 120 ºC
in toluene (Table 3, entry 7), although unreacted 1b was
recovered in this case. The change of the solvent did not
improve the isolated yields of 3ba (Table 3, entries 8-10).
entry
1
2
Ar
t [h]
3.5
3
Yield
[%][a]
2b
3bb
48[b]
2
3
4
5
6
7
2c
2d
2e
2f
3.5
3
3bc
3bd
3be
3bf
31[b]
53[b]
43[b]
44[b]
43b)
11[b]
3
3.5
3.5
7
2g
2h
3bg
3bh
8
2i
1.5
3.5
7
3bi
65
9
2j
3bj
62
Table 3. Acylation of 1b. Optimization of reaction conditions
10
11
2k
2p
3bk
3bp
39[b]
1.5
60[b]
entry
2a
[eq.]
TBHP
[eq.]
solvent
T [ºC]
t
[h]
3ba
12
13
14
2q
2r
2
3bq
3br
3bs
61
[%][a]
1.5
4.5
71
1
2
3
4
5
6
7
8
9
10
2
4
4
4
4
2
2
3
3
3
3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
C6H5Cl
DCE
60
2
47
2
90
2
67
2s
54[b]
2
120
90[b]
90[b]
110[b]
120
120
90
1.5
0.16
0.3
0.3
1
74
15
2t
1.5
3bt
78
2
56
[a]Yield (%) of isolated pure compound. [b]Unreacted 1b was recovered
1
35
1
50
We then extended the procedure to a series of aldehydes 2b-t
(Table 4). As expected, all reactions afforded selectively the
corresponding ketones 3bb-bt not detecting in any case the
formation of the diacylated compounds. The same trend of
reactivity for the aldehydes was observed, obtaining the best
results with electron rich aromatic rings (Table 4, entries 8-9, 11-
12). However, with the exception of 3bg (Table 4, entry 6), the
isolated yields of the ketones 3b were in the same range or
below the yields obtained for ketones 3a. In this case, the
procedure could be extended to the use of electron rich
1.5
1.5
1.5
1.5
74[c]
66
1
2.5
8
69
CH3CN
90
30[c]
[a]Yield (%) of isolated pure compound. [b]Microwave irradiation (250 W).
[c]Unreacted 1b was recovered (20-30%)
4
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10.1002/ejoc.202000444
European Journal of Organic Chemistry
FULL PAPER
heteroaromatic aldehydes 2r-2t, obtaining diheteroayl ketones
3br-bt with good yields (Table 4, entries 13-15).
Finally, the potential application of this acylation protocol in
medicinal chemistry and natural products synthesis has also
been demonstrated with the synthesis of Tolmetin, a non-
To test the applicability of these acylation reactions, it was first
necessary to remove both directing groups in an efficient
manner. Thus, the 2-pyrimidine directing group on 3aa could be
removed under previously described conditions[17] (Scheme 3),
obtaining 5a in excellent yield (90%). On the other hand, the 3-
methyl-2-pyridine group could also be removed in good yield
using the procedure described for removal of 2-pyridine
group.[16a]
steroidal anti-inflammatory drug. As shown on Scheme
5
Tolmetin could be easily obtained from C-2 p-toluoylpyrrole 3ab
in three steps. Deprotection and methylation of pyrrole was
accomplished in nearly quantitative yield. to obtain 8. The
carboxylic acid side chain was introduced as the final step of the
synthesis using the manganese-catalyzed intermolecular C-H
coupling protocol described by Yamaguchi.[31] Thus, coupling of
pyrrole 8 with triethyl methanetricarboxylate in the presence of
Mn(OAc)2, followed by hydrolysis and decarboxylation gave
Tolmetin (9) in a good overall yield starting from pyrrole. This
strategy effectively competes with or overcomes other reported
procedures for the synthesis of this drug. It is a catalytic
approach with atom-economy, which gives comparable or better
overall yields. In fact, various described routes involve as key
step a classical Friedel-Crafts aroylation of N-methylpyrrole
acetate, prepared in three steps by traditional methods,[32] or N-
methylpyrrole acetonitrile.[33] In the last case, it is noteworthy the
synthesis of the pyrrole acetonitrile intermediate by
photochemical generation of radicals. There is also one example
using an organocatalytic Friedel-Crafts reaction using p-
methyltoluoyl chloride and DBN as catalyst[11] but the overall
yield is lower (19.3% vs 28.6%). Alternatively, the
methylcarboxyl group has been introduced in the last step by a
radical process, after the Friedel-Crafts acylation.[34]
Scheme 3. Removal of the directing group
The prepared 2-acyl pyrroles 3 are advanced intermediates for
the synthesis of more elaborated compounds. Thus, the
compounds obtained could be derivatized to other potentially
interesting structures. As shown on Scheme 4, the directing
group could also be efficiently removed from 3ak to yield 5k in
high isolated yield. This pyrrole 5k has already been described
as an intermediate in the synthesis of Pyoluteorin (Figure 1).[4a]
Alternatively, the trichlorinated derivative 6 could be selectively
obtained in high yield (81 %) using NCS.[27] This compound has
been described to have activity as pesticide[28] and as glutamate
release inhibitor.[29] Besides, selective demethylation using AlCl3
afforded 7 in moderate yield. Both 6 and 7 could be considered
as Celastramycin analogues (Figure 1), structures that have
been recently identified to have interesting activity against
pulmonary arterial hypertension.[30]
Scheme 5. Synthesis of Tolmetin
Conclusion
In conclusion, the use of 2-pyrimidine as directing group allowed
the C-2 metalation of pyrrole with Pd(OAc)2 in toluene, which
could be acylated with aldehydes in the presence of TBHP as
oxidant. The presence of a moderately acidic additive, such as
pivalic acid increases the reactivity. The reaction has been
extended to a variety of aromatic aldehydes, bearing electron
rich and electron deficient aromatic rings. However, in most of
the cases, a minor amount of the corresponding diacylated
product was obtained. This side reaction could be avoided using
the 3-methyl-2-pyridinyl group as directing group, obtaining
selectively monoacylated pyrroles in moderate to good yields.
The so obtained acylated pyrroles have been used as
Scheme 4. Derivatization of 3ak
5
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10.1002/ejoc.202000444
European Journal of Organic Chemistry
FULL PAPER
fluorobenzaldehyde 2d (0.21 mL, 2 mmol) and TBHP (5.5 M in decane,
intermediates in the synthesis of celastramycin analogues and in
an improved synthesis of Tolmetin.
0.72 mL,
4 mmol). After 3 h at 70 °C, purification by column
chromatography (silica gel, petroleum ether/Et2O 3/7) afforded 3ad as
white solid, whose data are coincidental to those reported[20] (177.0 mg,
66%). mp (CH2Cl2): 153-155 °C; IR (ATR):, 1645, 1602, 1570 cm-1; 1H
NMR (300 MHz, CDCl3): δ 6.35 (dd, J = 3.5, 3.0 Hz, 1H), 6.79 (dd, J =
3.6, 1.6 Hz, 1H), 7.06-7.12 (m, 3H), 7.71 (dd, J = 2.9, 1.6 Hz, 1H), 7.92-
7.97 (m, 2H), 8.59 (d, J = 4.8 Hz, 2H) ppm; 13C NMR (75.5 MHz, CDCl3):
δ 184.5, 165.4 (d, J = 25 3.5 Hz), 158.3, 156.7, 134.6, 132.1 (d, J = 9.1
Experimental Section
Acylation reactions of 1a with aldehydes. General procedure. Under
argon atmosphere, a sealable reaction tube equipped with a stirring bar
was charged with 1a (1 mmol), Pd(OAc)2 (0.1 mmol), PivOH (0.75 mmol)
and corresponding aldehyde 2a-o (2 mmol). Toluene was added (2 mL),
and the mixture was stirred for 2 min until solids were dissolved. Then,
TBHP (5.5 M in decane, 4 mmol) was added, the reaction tube was
sealed and the reaction mixture was stirred at 60 °C for 1.5-7 h. After
cooling to room temperature, the reaction mixture was filtered through
silica gel and the filtrate was concentrated under vacuum. The residue
was purified by column chromatography affording 3aa-ao and 4aa-ao.
(See SI for characterization of diacylated compounds 4).
Hz), 131.9, 128.0, 122.5, 118.5, 115.4 (d, J = 21.9 Hz), 110.5 ppm; 19
F
NMR (376 MHz, CDCl3): δ -106.41 ppm; MS (ESI+): m/z (rel intensity):
268 (MH+, 100), 123 (11). HRMS (ESI+): calcd. for C15H11FN3O [MH+]
268.0886; found, 268.0896.
(4-Chlorophenyl)[1-(pyrimidin-2-yl)-1H-pyrrol-2-yl]methanone (3ae).
Following the general procedure 1a (145.2 mg, 1 mmol) was treated with
Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg, 0.75 mmol), 4-
chlorobenzaldehyde 2e (281.1 mg, 2 mmol) and TBHP (5.5 M in decane,
0.72 mL,
4 mmol). After 3 h at 60 °C, purification by column
Phenyl[1-(pyrimidin-2-yl)-1H-pyrrol-2-yl]methanone (3aa) (Table 1,
entry 13). Following the general procedure, 1a (145.2 mg, 1 mmol) was
treated with Pd(OAc)2 (22.5 mg, 0.1mmol), PivOH (76.6 mg, 0.75 mmol),
benzaldehyde 2a (0.20 mL, 2 mmol) and TBHP (5.5 M in decane, 0.72
mL, 4 mmol). After 2 h at 60 °C, purification by column chromatography
(silica gel, petroleum ether/EtO2 4/6) afforded 3aa as a white solid whose
chromatography (silica gel, petroleum ether/AcOEt 8/2) afforded none
3ae as white solid (164.4 mg, 58%): mp (CH2Cl2): 134-136 °C; IR (ATR):
1645, 1573 cm-1; 1H NMR (300 MHz, CDCl3): δ 6.35 (t, J = 3.5 Hz, 1H),
6.79 (dd, J = 3.5, 1.5 Hz, 1H), 7.10 (d, J = 4.8 Hz, 1H), 7.39 (d, J = 8.4
Hz, 2H), 7.72 (dd, J = 3.5, 1.5 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 8.57 (d, J
= 4.8 Hz, 2H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 184.6, 158.2, 156.7,
138.7, 136.7, 131.8, 130.9, 128.5, 128.0, 122.5, 118.9, 110.6 ppm; MS
(ESI+): m/z (rel intensity): 286 (MH++2, 26), 284 (MH+, 100), 140 (2) 138
(6). HRMS (ESI+): calcd. for C15H11ClN3O [MH+] 284.0591; found,
284.0591.
data are coincidental to those reported[17] (179.7 mg, 71%): mp (CH2Cl2):
[17]
115-117°C (Lit.
105-107 ºC); IR (ATR): 1740, 1641, 1566 cm-1; 1H
NMR (300 MHz, CDCl3): δ 6.35 (t, J = 3.2 Hz, 1H), 6.80 (dd, J = 3.2 , 1.5
Hz, 1H), 7.07 (t, J = 4.9 Hz, 1H,), 7.41 (t, J = 7.3 Hz, 2H), 7.51 (t, J = 7.3
Hz, 1H), 7.71 (t, J = 1.5 Hz, 1H), 7.93 (d, J = 7.3 Hz, 2H), 8.57 (d, J = 4.9
Hz, 2H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 185.9, 158.2, 156.8, 138.3,
132.4, 132.2, 129.6, 128.2, 127.9, 122.5, 118.5, 110.4 ppm; MS (ESI+):
m/z (rel intensity): 250 (MH+, 100), 105 (1). HRMS (ESI+): calcd. for
C15H12N3O [MH+]: 250.0980; found: 250.0986.
(4-Bromophenyl)[1-(pyrimidin-2-yl)-1H-pyrrol-2-yl]methanone (3af).
Following the general procedure 1a (145.2 mg, 1mmol), Pd(OAc)2 was
treated with (22.5 mg, 0.1mmol), PivOH (76.6 mg, 0.75 mmol), 4-
bromobenzaldehyde 2f (281.1 mg, 2 mmol) and TBHP (5.5 M in decane,
0.72 mL, 4 mmol). After 1.5
h at 70 °C, purification by column
[1-(Pyrimidin-2-yl)-1H-pyrrol-2-yl](p-tolyl)methanone (3ab). Following
the general procedure 1a (145.2 mg, 1 mmol) was treated with Pd(OAc)2
(22.5 mg, 0.1 mmol), PivOH (76.6 mg, 0.75 mmol), 4-
methylbenzaldehyde 2b (0.22 mL, 2 mmol) and TBHP (5.5 M in decane,
chromatography (silica gel, petroleum ether/Et2O 6/4) afforded 3af as
white solid (211.0 mg, 64%): mp (CH2Cl2): 139-140 °C; IR (ATR): 1741,
1645, 1573 cm-1; 1H NMR (300 MHz, CDCl3): δ 6.34-6-36 (m, 1H), 6.79
(dd, J = 3.6 Hz, 1.6 Hz, 1H), 7.10 (t, J = 4.8 Hz, 1H), 7.55 (d, J = 8.5 Hz,
2H), 7.72 (dd, J = 2.9, 1.6 Hz, 1H), 7.78 (d, J = 8.5 Hz, 2H), 8.57 (d, J =
4.8 Hz, 2H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 184.8, 158.2, 156.6,
137.1, 131.8, 131.5, 131.1, 128.0, 127.3, 122.5, 118.5, 110.6 ppm; MS
(ESI+): m/z (rel intensity): 330 (MH++2,99), 328 (MH+, 100), 184 (4), 182
(4). HRMS (ESI+): calcd. for C15H11BrN3O [MH+] 328.0085; found,
328.0094.
0.72 mL, 4 mmol). After 1,5
h at 60 °C, purification by column
chromatography (silica gel, petroleum ether/Et2O 6/4) afforded 3ab as
white solid (160.7 mg, 61%): mp (CH2Cl2): 159-161 °C ; IR (ATR): 1641,
1570 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.40 (s, 3H), 6.35 (m, 1H), 6.79
(dd, J = 3.6, 1.6 Hz, 1H), 7.08 (t, J = 4.8 Hz, 1H), 7.23 (d, J = 8.1 Hz, 2H),
7.70 (dd, J = 2.9, 1.6 Hz, 1H), 7.85 (d, J = 8.1 Hz, 2H), 8.58 (d, J = 4.8
Hz, 2H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 186.7, 158.2, 156.9, 143.3,
135.6, 132.4, 129.8, 128.9, 127.6, 122.2, 118.4, 110.3, 21.7 ppm; MS
(ESI+) m/z (rel intensity): 264 (MH+, 100), 172(1), 119 (8). HRMS (ESI+):
calcd. for C16H14N3O [MH+] 264.1137; found, 264.1143.
4-[1-(Pyrimidin-2-yl)-1H-pyrrole-2-carbonyl]benzonitrile
(3ag).
Following the general procedure 1a (145.2 mg, 1 mmol) was treated with
Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg, 0.75 mmol), 4-
formylbenzonitrile 2g (262.3 mg, 2 mmol) and TBHP (5.5 M in decane,
[4-(tert-Butyl)phenyl][1-(pyrimidin-2-yl)-1H-pyrrol-2-yl]methanone
(3ac). Following the general procedure, 1a (145.2 mg, 1 mmol) was
treated with Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg, 0.75 mmol),
4-(tert-butyl)benzaldehyde 2c (0.33 mL, 2 mmol) and TBHP (5.5 M in
decane, 0.72 mL, 4 mmol). After 7 h at 60 °C, purification by column
chromatography (silica gel, petroleum ether/AcOEt 9/1) afforded 3ac as
white solid (144.8 mg, 47%). mp (CH2Cl2): 121-123 °C; IR (ATR): 1735,
1641, 1573 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.34 (s, 9H), 6.35 (m, 1H),
6.82 (dd, J = 3.6, 1.6 Hz, 1H), 7.10 (t, J = 4.8 Hz, 1H), 7.45-7.48 (m, 2H),
7.70 (dd, J = 2.9, 1.6 Hz, 1H), 7.90-7.93 (m, 2H), 8.60 (d, J = 4.8 Hz, 2H)
ppm; 13C NMR (75.5 MHz, CDCl3): δ 186.5, 158.2, 156.9, 156.2, 135.6,
132.4, 129.7, 127.8, 125.2, 122.4, 118.4, 110.3, 35.1, 31.2 ppm; MS
(ESI+): m/z (rel intensity): 306 (MH+, 100), 161 (1). HRMS (ESI+): calcd.
for C19H20N3O [MH+] 306.1606; found, 306.1614.
0.72 mL,
4 mmol). After 5 h at 60 °C, purification by column
chromatography (silica gel, petroleum ether/Et2O 3/7) afforded 3ag as
light brown solid (95.4 mg, 35%): mp (CH2Cl2): 176-178 °C; IR (ATR):
2230, 1645, 1570, cm-1; 1H NMR (300 MHz, CDCl3): δ 6.38-6.40 (m, 1H),
6.83 (dd, J = 3.7, 1.6 Hz, 1H), 7.13 (t, J = 4.8 Hz, 1H), 7.70-7.72 (m, 2H),
7.76 (dd, J = 2.9, 1.6 Hz, 1H), 7.96-7.98 (m, 2H), 8.58 (d, J = 4.8 Hz, 2H)
ppm; 13C NMR (75.5 MHz, CDCl3): δ 184.1, 158.6, 156.5, 141.9, 132.1,
131.4, 129.7, 129.0, 123.1, 118.7, 118.2, 115.5, 110.9 ppm; MS (ESI+):
m/z (rel intensity): 275 (MH+, 100), 130 (12). HRMS (ESI+): calcd. for
C16H11N4O [MH+] 275.0933; found, 275.0935.
(4-Nitrophenyl)[1-(pyrimidin-2-yl)-1H-pyrrol-2-yl]methanone
(3ah):
Following the general procedure 1a (145.2 mg, 1 mmol) was treated with
Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg, 0.75 mmol), 4-
nitrobenzaldehyde 2h (302.2 mg, 2 mmol) and TBHP (5.5 M in decane,
(4-Fluorophenyl)[1-(pyrimidin-2-yl)-1H-pyrrol-2-yl]methanone (3ad).
Following the general procedure 1a (145.2 mg, 1 mmol) was treated with
Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg, 0.75 mmol), 4-
0.72 mL,
4 mmol). After 7 h at 60 °C, purification by column
chromatography (silica gel, petroleum ether/AcOEt 7/3) afforded 3ah as
yellow solid (58.8 mg, 22%). mp (CH2Cl2): 173-174 °C; IR (ATR): 1649,
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000444
European Journal of Organic Chemistry
FULL PAPER
1570, cm-1; 1H NMR (300 MHz, DMSO-d6): δ 6.48-6.50 (m, 1H), 6.95 (dd,
J = 3.7, 1.6 Hz, 1H), 7.42 (t, J = 4.9 Hz, 1H), 7.85 (dd, J = 2.8, 1.6 Hz,
1H), 7.99-8.02 (m, 2H), 8.31-8.34 (m, 2H), 8.75 (d, J = 4.9 Hz, 2H) ppm;
13C NMR (75.5 MHz, CDCl3): δ 183.8, 158.3, 156.5, 149.8, 143.6, 131.4,
130.2, 128.7, 123.4, 123.3, 118.7, 111.0 ppm; MS (ESI+): m/z (rel
intensity): 295 (MH+, 100), 150 (7). HRMS (ESI+): calcd. for C15H11N4O3
[MH+] 295.0831; found, 295.0835.
ppm; MS (ESI+): m/z (rel intensity): 310 (MH+, 100), 172 (31). HRMS
(ESI+): Calcd. for C17H16N3O3 [MH+] 310.1192; found, 310.1196.
[1-(Pyrimidin-2-yl)-1H-pyrrol-2-yl[[4-
(trifluoromethyl)phenyl]methanone (3am). Following the general
procedure 1a (145.2 mg, 1 mmol) was treated with Pd(OAc)2 (22.5 mg,
0.1 mmol), PivOH (76.6 mg, 0.75 mmol), 4-(trifluoromethyl)benzaldehyde
2m (0.27 mL, 2 mmol) and TBHP (5.5 M in decane, 0.72 mL, 4 mmol).
After 7 h at 40 °C, purification by column chromatography (silica gel,
petroleum ether/Et2O 3/7) afforded 3am as white solid (105.8 mg, 33%):
mp (CH2Cl2): 103-104 °C; IR (ATR): 1649, 1570 cm-1; 1H NMR (300 MHz,
CDCl3): δ 6.38 (s, 1H), 6.83 (d, J = 1.7 Hz, 1H), 7.13 (t, J = 4.8 Hz, 1H),
7.69 (d, J = 8.0 Hz, 2H), 7.74-7.76 (m, 1H), 8.01 (d, J = 8.0 Hz, 2H), 8.60
(d, J = 4.8 Hz, 2H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 184.6, 158.3,
156.6, 141.3, 133.6 (q, J = 32.5 Hz), 131.7, 130.3, 129.8, 128.5, 125.2 (q,
J = 3.8 Hz), 123.7 (q, J = 271.1 Hz), 118.7, 110.8 ppm; 19F NMR (376
MHz, CDCl3): δ -62.9 ppm; MS (ESI+): m/z (rel intensity): 318 (MH+, 100),
173 (4). HRMS (ESI+): Calcd. for C16H11F3N3O [MH+] 318.0854; found,
318.0861.
(3,5-Dimethoxyphenyl)[1-(pyrimidin-2-yl)-1H-pyrrol-2-yl]methanone
(3ai). Following the general procedure 1a (145.2 mg, 1 mmol), was
treated with Pd(OAc)2 (22.5 mg, 0.1mmol), PivOH (76.6 mg, 0.75 mmol),
3,5-dimetoxibenzaldehyde 2i (332.3 mg, 2 mmol) and TBHP (5.5 M in
decane, 0.72 mL, 4 mmol). After 2.5 h at 60 °C, purification by column
chromatography (silica gel, petroleum ether/AcOEt 7/3) afforded 3ai as
white solid (222.8 mg, 72%): mp (CH2Cl2): 107-109 °C ; IR (ATR): 1737,
1595 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.77 (s, 6H), 6.34 (t, J = 3.2 Hz,
1H), 6.58 (t, J = 2.3 Hz, 1H), 6.81 (dd, J = 3.5, 1.5 Hz, 1H), 7.04-7.07 (m,
3H), 7.69 (dd, J = 3.1 Hz, 1.5 Hz, 1H), 8.58 (d, J = 4.8 Hz, 2H) ppm; 13
C
NMR (75.5 MHz, CDCl3): δ 185.3, 160.5, 158.3, 156.8, 140.1, 132.0,
128.0, 122.7, 118.5, 110.4, 107.4, 106.2, 55.6 ppm; MS (ESI+): m/z (rel
intensity): 310 (MH+, 100), 165 (1). HRMS (ESI+): Calcd. for C17H16N3O3
[MH+] 310.1192; found. 310.1201.
[3,5-bis(Trifluoromethyl)phenyl][1-(pyrimidin-2-yl)-1H-pyrrol-2-
yl]methanone (3an). Following the general procedure 1a (145.2 mg, 1
mmol) was treated with Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg,
0.75 mmol), 3,5-bis(trifluoromethyl)benzaldehyde 3n (0.33 mL, 2 mmol)
and TBHP (5.5 M in decane, 0.72 mL, 4 mmol). After 7 h at 40 °C,
purification by column chromatography (silica gel, petroleum ether/Et2O
3/7) afforded 3an as light-brown solid (52.9 mg, 14%): mp (CH2Cl2): 96-
98 °C; IR (ATR): 1656, 1573 cm-1; 1H NMR (300 MHz, CDCl3): δ 6.43 (s,
1H), 6.87 (s, 1H), 7.18 (t, J = 4.3 Hz, 1H), 7.82 (s, 1H), 8.04 (s, 1H), 8.38
(s, 2H), 8.62 (d, J = 4.6 Hz, 2H) ppm; 13C NMR (75.5 MHz, CDCl3): δ
182.3, 158.3, 156.5, 140.1, 131.9 (q, J = 33.9 Hz), 130.8, 129.4 (q, J =
3.2 Hz), 129.4, 125.5 (q, J = 3.65 Hz), 123.6, 122.9 (q, J = 271.6 Hz),
118.8, 111.0 ppm; 19F NMR (376 MHz, CDCl3): δ -62.9 ppm; MS (ESI+):
m/z (rel intensity): 386 (MH+, 100), 241 (1). HRMS (ESI+): calcd. for
C17H10F6N3O [MH+] 386.0728; found, 386.0728.
[1-(Pyrimidin-2-yl)-1H-pyrrol-2-yl](3,4,5-
trimethoxyphenyl)methanone (3aj). Following the general procedure
1a (145.2 mg, 1 mmol) was treated with Pd(OAc)2 (22.5 mg, 0.1 mmol),
PivOH (76.6 mg, 0.75 mmol), 3,4,5-trimethoxybenzaldehyde 3j (392.4
mg, 2 mmol) and TBHP (5.5 M in decane, 0.72 mL, 4 mmol). After 2,5 h
at 60 °C, purification by column chromatography (silica gel, petroleum
ether/AcOEt 6/4) afforded 3aj as yellow solid (237.9 mg, 70%): mp
(CH2Cl2): 124-126 °C ; IR (ATR): 1741, 1577 cm-1; 1H NMR (300 MHz,
CDCl3): δ 3.81 (s, 6H), 3.87 (s, 3H), 6.32 (dd, J = 3.5, 2.9 Hz, 1H), 6.81
(dd, J = 3.5, 1.6 Hz, 1H), 7.08 (t, J = 4.8 Hz, 1H), 7.20 (s, 2H), 7.68 (dd, J
= 2.9, 1.6 Hz, 1H), 8.57 (d, J = 4.8 Hz, 2H) ppm; 13C{1H} NMR (75.5 MHz,
CDCl3): δ 184.7, 158.2, 156.8, 152.8, 141.9, 133.2, 131.9, 127.9, 122.2,
118.2, 110.4, 107.1, 60.9, 56.2 ppm; MS (ESI+): m/z (rel intensity): 340
(MH+, 100), 172 (1). HRMS (ESI+): calcd. for C18H18N3O4 [MH+]
340.1297; found, 340.1310.
Naphthalen-2-yl[1-(pyrimidin-2-yl)-1H-pyrrol-2-yl]methanone (3ao).
Following the general procedure 1a (145.2 mg, 1 mmol) was treated with
Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg, 0.75 mmol), 2-
naphthaldehyde 2o (312.4 mg, 2 mmol) and TBHP (5.5 M in decane,
(2,6-Dimethoxyphenyl)[1-(pyrimidin-2-yl)-1H-pyrrol-2-yl]methanone
(3ak). Following the general procedure 1a (145.2 mg, 1 mmol) was
treated with Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg, 0.75 mmol),
2,6-dimetoxibenzaldehyde 2k (332.3 mg, 2 mmol) and TBHP (5.5 M in
decane, 0.72 mL, 4 mmol). After 6 h at 90 °C, purification by column
chromatography (silica gel, petroleum ether/Et2O 3/7) afforded 3ak as
yellow solid (143.9 mg, 47%): mp (CH2Cl2): 156-158 °C; IR (ATR): 1649,
1591cm-1; 1H NMR (300 MHz, CDCl3): δ 3.74 (s, 6H), 6.27 (dd, J = 3.8,
2.9 Hz, 1H), 6.55 (d, J = 8.4 Hz, 2H), 6.76 (dd, J = 3.8, 1.7 Hz, 1H), 7.20
(t, J = 4.8 Hz, 1H), 7.26 (t, J = 8.4 Hz, 1H), 7.49 (dd, J = 2.9, 1.7 Hz, 1H),
8.71 (d, J = 4.8 Hz, 2H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 182.5,
158.2, 158.1, 157.8, 134.1, 130.7, 129.9, 123.9, 119.1, 119.0, 110.3,
104.1, 56.1 ppm; MS (ESI+): m/z (rel intensity): 310 (MH+, 20), 172 (100),
158 (20), 98 (50). HRMS (ESI+): calcd. for C17H16N3O3 [MH+] 310.1192;
found, 310.1185.
0.72 mL, 4 mmol). After 1,5
h at 60 °C, purification by column
chromatography (silica gel, petroleum ether/Et2O 1/1) afforded 3ao as
white solid (152.2 mg, 51%): mp (CH2Cl2): 110-112 °C; IR (ATR): 3052,
2999, 1739, 1641, 1573, 1530, 1444 cm1-; 1H NMR (500 MHz, CDCl3): δ
= 6.39-6.41 (m, 1H), 6.88-6.89 (m, 1H), 7.02 (t, J = 4.7 Hz, 1H), 7.51-755
(m, 2H), 7.78 (d, J = 1.1 Hz, 1H), 7.85-7.91 (m, 3H), 8.04 (d, J = 8.4 Hz,
1H), 8.47 (s, 1H), 8.55 (d, J = 4.7 Hz, 2H) ppm; 13C NMR (125 MHz,
CDCl3): δ 186.0, 158.2, 156.8, 135.7, 135.35, 132.4, 131.3, 129.5, 128.2,
128.2, 127.8, 126.4, 125.4, 122.5, 118.4, 110.5 ppm; MS (ESI+): m/z (rel
intensity): 300 (MH+, 100), 155 (3). HRMS (ESI+): calcd. for C19H14N3O
[MH+] 300.1137; found, 300.1141.
Acylation reactions of 1b with aldehydes. General procedure. Under
argon atmosphere, a sealable reaction tube equipped with a stirring bar
was charged with 1b (1 mmol), Pd(OAc)2 (0.1 mmol), PivOH (0.75 mmol)
and corresponding benzaldehyde 2a-t (2 mmol). Toluene was added (2
mL), mixture was stirred for 2 min until solids were dissolved. Then,
TBHP (5.5 M in decane, 4 mmol) was added, reaction tube was sealed
and the reaction mixture was stirred at 120 °C for 1.5-7 h. After cooling to
room temperature, AcOEt (15mL) was added to reaction mixture and
organic phase was washed with an aqueous solution of NaOH 2M (3 ×
20 mL) the combined aqueous phase was extracted with AcOEt (2 × 15
mL). The combined organic phase was dried over Na2SO4 and the
solvent was evaporated under reduced pressure. The residue was
purified by column chromatography affording 3ba-3bt.
(2,4-Dimethoxyphenyl)[1-(pyrimidin-2-yl)-1H-pyrrol-2-yl]methanone
(3al). Following the general procedure 1a (145.2 mg, 1 mmol) was
treated with Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg, 0.75 mmol),
2,4-dimetoxibenzaldehyde 2l (332.3 mg, 2 mmol) and TBHP (5.5 M in
decane, 0.72 mL, 4 mmol). After 7 h at 60 °C, purification by column
chromatography (silica gel, petroleum ether/AcOEt 6/4) afforded 3al as
yellow solid (124.1 mg, 40%): mp (CH2Cl2): 137-138 °C; IR (ATR): 1602,
1570, 1441 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.69 (s, 3H), 3.79 (s, 3H),
6.27 (dd, J = 3.5, 3.1 Hz, 1H), 6.37 (d, J = 2.3 Hz, 1H), 6.43 (dd, J = 8.6,
2.3 Hz, 1H), 6.70 (dd, J = 3.6, 1.7 Hz, 1H), 7.05 (t, J = 4.8 Hz, 1H), 7.58
(dd, J = 3.1, 1.7 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 8.54 (d, J = 4.8 Hz, 2H)
ppm; 13C NMR (75.5 MHz, CDCl3): δ 181.9, 161.6, 160, 158.0, 157.0,
134.3, 133.4, 127.1, 121.8, 121.5, 118.4, 110.1, 102.0, 98.7, 55.8, 55.5
[1-(3-Methylpyridin-2-yl)-1H-pyrrol-2-yl](phenyl)methanone
(3ba).
(Table 3, entry 3) Following the general procedure 1b (158.2 mg, 1
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000444
European Journal of Organic Chemistry
FULL PAPER
mmol) was treated with Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg,
0.75 mmol), benzaldehyde 2a (0.20 mL, 2 mmol) and TBHP (5.5 M in
decane, 0.72 mL, 4 mmol). After 1.5 h at 120 ºC, purification by column
chromatography (silica gel, petroleum ether/ AcOEt 7/3) afforded 3ba as
a yellow oil (202.5 mg, 74%): IR (ATR): 1739, 1634 cm-1; 1H NMR (300
MHz, CDCl3): δ 2.10 (s, 3H), 6.37 (dd, J = 3.9, 2.6 Hz, 1H), 6.90 (dd, J =
3.9, 1.6 Hz, 1H), 7.10 (dd, J = 2.6, 1.6, 1H), 7.20-7.25 (m, 1H), 7.40 (dd,
J = 8.2, 6.6 Hz, 2H), 7.43-7.54 (m, 1H), 7.56-7.64 (m, 1H), 7.79-7.91 (m,
2H), 8.33-8.38 (m, 1H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 184.6, 152.4,
146.4, 139.4, 138.7, 131.9, 131.7, 130.0, 129.6, 129.4, 128.2, 123.7,
122.2, 109.8, 17.3 ppm; MS (ESI+): m/z (rel intensity): 263 (MH+, 100),
106 (2), 105 (33). HRMS (ESI+): calcd. for C17H15N2O [MH+] 263.1184;
found, 263.1198.
chromatography (silica gel, petroleum ether/AcOEt 7/3) afforded 3be as
white solid (128.6 mg, 43%): mp (CH2Cl2): 99-102 °C; IR (ATR): 1739,
1631, cm-1; 1H NMR (300 MHz, CDCl3): δ 2.12 (s, 3H), 6.40 (dd, J = 3.9,
2.7 Hz, 1H), 6.89 (dd, J = 3.9, 1.6 Hz, 1H), 7.13 (dd, J = 2.7, 1.6 Hz, 1H),
7.29 (dd, J = 7.6, 4.8Hz, 1H), 7.41 (d, J = 8.6 Hz, 2H), 7.65 (dd, J = 7.6,
1.2 Hz, 1H), 7.80 (d, J = 8.6 Hz, 2H), 8.37 (dd, J = 4.8, 1.2 Hz, 1H) ppm;
13C NMR (75.5 MHz, CDCl3): δ 183.3, 152.2, 146.4, 139.5, 138.1, 137.0,
131.3, 130.8, 130.0, 129.9, 128.5, 123.8, 122.1, 110.1, 17.2 ppm; MS
(ESI+): m/z (rel intensity): 299 (MH++2, 29), 297 (MH+, 100), 271 (1), 141
(5), 139 (17). HRMS (ESI+): calcd. for C17H14ClN2O [MH+] 297.0795;
found, 297.0802.
(4-Bromophenyl)[1-(3-methylpyridin-2-yl)-1H-pyrrol-2-yl]methanone
(3bf). Following the general procedure 1b (158.2 mg, 1 mmol) was
treated with Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg, 0.75 mmol),
4-bromobenzaldehyde 2f (370.0 mg, 2 mmol) and TBHP (5.5 M in
decane, 0.72 mL, 4 mmol). After 3.5 h at 120 °C, purification by column
chromatography (silica gel, petroleum ether/AcOEt 7/3) afforded 3bf as
white solid (149.2mg, 44 %): mp (CH2Cl2): 109-111 °C; IR (ATR): 1739
cm-1; 1H NMR (500 MHz, CDCl3): δ 2.11 (s, 3H), 6.40 (dd, J = 3.8, 2.7 Hz,
1H), 6.89 (dd, J = 3.8, 1.5 Hz, 1H), 7.10–7.16 (m, 1H), 7.29 (dd, J = 7.6,
4.8 Hz, 1H),7.57 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 7.5 Hz, 1H), 7.73 (d, J =
8.4 Hz, 2H), 8.37 (d, J = 3.8 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ
183.4, 152.2, 146.4, 139.5, 137.5, 131.4, 131.3, 130.9, 130.1, 129.9,
126.7, 123.8, 122.2, 110.1, 17.4 ppm; MS (ESI+): m/z (rel intensity):
343(MH+ +2, 99), 341 (MH+, 100), 185 (9), 183 (10). HRMS (ESI+): calcd.
for C17H14BrN2O [MH+] 341.0290; found, 341.0293.
1-(3-Methylpyridin-2-yl)-1H-pyrrol-2-yl](p-tolyl)methanone
(3bb).
Following the general procedure 1b (158.2 mg, 1 mmol) was treated with
Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg, 0.75 mmol), 4-
methylbenzaldehyde 2b (0,24 mL, 2 mmol) and TBHP (5.5 M in decane,
0.72 mL, 4 mmol). After 3.5 h at 120 °C, purification by column
chromatography (silica gel, petroleum ether /AcOEt 7/3) afforded 3bb as
yellow oil (132.6 mg, 48 %): IR (ATR): 1739, 1458 cm-1; 1H NMR (500
MHz, CDCl3) δ 2.14 (s, 3H), 2.44 (s, 3H), 6.41 (dd, J = 3.9, 2.7 Hz, 1H),
6.94 (dd, J = 3.9, 1.6 Hz, 1H), 7.13 (dd, J = 2.7, 1.6 Hz, 1H), 7.27 (d, J
=8.1 Hz, 2H), 7.30-7.34 (m, 1H), 7.67 (dd, J = 7.5,1.2 Hz, 1H), 7.80 (d, J
= 8.1 Hz, 2H), 8.41 (dd, J = 4.7, 1.2 Hz, 1H) ppm; 13C NMR (125 MHz,
CDCl3): δ 184.5, 152.4, 146.4, 142.5, 139.4, 136.0, 131.8, 130.1, 129.6,
129.3, 128.8, 123.6, 121.8, 109.8, 21.6, 17.3 ppm; MS (ESI+): m/z (rel
intensity): 277 (MH+, 100), 119 (37). HRMS (ESI+): calcd. for C18H17N2O
[MH+] 277.1341; found, 277.1350.
4-[1-(3-Methylpyridin-2-yl)-1H-pyrrole-2-carbonyl]benzonitrile (3bg).
Following the general procedure 1b (158.2 mg, 1 mmol) was treated with
Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg, 0.75 mmol), 4-
formylbenzonitrile 2g (262.2 mg; 2 mmol) and TBHP (5.5 M in decane,
0.72 mL, 4 mmol). After 3.5 h at 120 °C, purification by column
chromatography (silica gel, petroleum ether/AcOEt 7/3) afforded 3bg as
yellow solid (124.4 mg, 43%): mp (CH2Cl2): 112-115 °C; IR (ATR): 2230,
1739, 1634 cm-1; 1H NMR (500 MHz, CDCl3) δ 2.11 (s, 3H), 6.41 (dd, J =
4.0, 2.7 Hz, 1H), 6.87 (dd, J = 4.0, 1.5 Hz, 1H), 7.16 (dd, J = 2.7, 1.6 Hz,
1H), 7.30 (dd, J = 7.5, 4.8 Hz, 1H), 7.67 (dd, J = 7.5,1.0 Hz, 1H), 7.72 (d,
J = 8.4 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 8.36 (dd, J = 4.8, 1.0 Hz, 1H)
ppm; 13C NMR (125 MHz, CDCl3): δ 182.6, 151.9, 146.5, 142.4, 139.6,
132.1, 131.0, 130.7, 130.1, 129.7, 124.0, 122.9, 118.2, 115.1, 110.4,
17.2, ppm; MS (ESI+): m/z (rel intensity): 288 (MH+, 100), 130 (6). HRMS
(ESI+): calcd. for C18H14N3O [MH+] 288.1137; found, 288.1141.
[4-(tert-Butyl)phenyl][1-(3-methylpyridin-2-yl)-1H-pyrrol-2-
yl]methanone (3bc). Following the general procedure 1b (158.2 mg, 1
mmol) was treated with Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg,
0.75 mmol), 4-(tert-butyl)benzaldehyde 2c (0.33 mL; 2 mmol) and TBHP
(5.5 M in decane, 0.72 mL, 4 mmol). After 3,5 h at 120 °C, purification by
column chromatography (silica gel, petroleum ether/AcOEt 7/3) afforded
3bc as brown solid (100 mg, 31%): IR (ATR) = 1741, 1454 cm-1; mp
(CH2Cl2): 75-79 °C; 1H NMR (500 MHz, CDCl3): δ 1.35 (s, 9H), 2.12 (s,
3H), 6.39 (dd, J = 3.9, 2.7 Hz, 1H), 6.95 (dd, J = 3.9, 1.6 Hz, 1H), 7.12
(dd, J = 2.7, 1.6Hz, 1H), 7.24-7.32 (m, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.64
(dd, J = 7.5, 1.2Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 8.38 (dd, J = 4.8, 1.2
Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ 184.4, 155.4, 152.4, 146.3,
139.4, 135.9, 131.8, 130.0, 129.4, 129.2, 125.1, 123.6, 121.8, 109.8,
35.0, 31.2, 17.2 ppm; MS (ESI+): m/z (rel intensity): 319 (MH+, 100), 162
(1), 161 (7). HRMS (ESI+): calcd. for C21H23N2O [MH+] 319.1810; found,
319.1819.
[1-(3-Methylpyridin-2-yl)-1H-pyrrol-2-yl](4-nitrophenyl)methanone
(3bh). Following the general procedure 1b (158.2 mg, 1 mmol) was
treated with Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg, 0.75 mmol),
4-nitrobenzaldehyde 2h (302.2 mg, 2 mmol) and TBHP (5.5 M in decane,
(4-Fluorophenyl)[1-(3-methylpyridin-2-yl)-1H-pyrrol-2-yl]methanone
(3bd): Following the general procedure 1b (158.2 mg, 1 mmol) was
treated with Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg, 0.75 mmol),
4-fluorobenzaldehyde 2d (0.21 mL, 2 mmol) and TBHP (5.5 M in decane,
0.72 mL,
4 mmol). After 7 h at 120 °C, purification by column
chromatography (silica gel, petroleum ether/AcOEt 7/3) afforded as
yellow oil 3bh (32.4 mg, 11%): IR (ATR): 1745, 1637 cm-1; 1H NMR (300
MHz, CDCl3): δ 2.16 (s, 3H), 6.46 (dd, J = 4.0, 2.6 Hz, 1H), 6.92 (dd, J =
4.0, 1.6 Hz, 1H), 7.20 (dd, J = 2.6, 1.6 Hz, 1H), 7.35 (dd, J = 7.6, 4.8 Hz,
1H), 7.71 (ddd, J = 7.6, 1.8, 0.8 Hz, 1H), 7.94-8.08 (m, 2H), 8.20-8.35 (m,
2H), 8.41 (ddd, J = 4.8, 1.8, 0.7 Hz, 1H), ppm; 13C NMR (75.5 MHz,
CDCl3): δ 182.4, 151.9, 149.6, 146.50, 144.0, 139.6, 130.9, 130.9, 130.2,
130.1, 124.1, 123.4, 123.1, 110.5, 17.18 ppm; MS (ESI+): m/z (rel
intensity): 308 (MH+, 100), 274 (1), 150 (3). HRMS (ESI+): calcd. for
C17H14N3O3 [MH+] 308.1035; found, 308.1033.
0.72 mL,
4 mmol). After 3 h at 120 °C, purification by column
chromatography (silica gel, petroleum ether/AcOEt 7/3) afforded 3bd as
white solid (148.7 mg, 53%): mp (CH2Cl2): 76-78 °C; IR (ATR): 1634,
1595, cm-1; 1H NMR (500 MHz, CDCl3): δ 2.12 (s, 3H), 6.39 (d, J = 2.9
Hz, 1H), 6.89 (d, J = 3.8 Hz, 1H), 7.09-7.12 (m, 3H), 7.26-7.29 (m, 1H),
7.64 (d, J = 7.6 Hz, 1H), 7.96-7.82 (m, 2H), 8.37 (d, J = 4.8 Hz, 1H) ppm;
13C NMR (125 MHz, CDCl3): δ 183.2, 165.1 (d, J = 253.2 Hz), 152.2,
146.4, 139.5, 134.9 (d, J = 3.4 Hz) , 131.8 (d, J = 9.0 Hz), 131.4, 130.0,
129.7, 123.8, 122.0, 115.2 (d, J = 21.7 Hz), 110.0, 17.2 ppm; MS (ESI+):
m/z (rel intensity): 281 (MH+, 100), 265 (<1), 243 (1), 123 (21). HRMS
(ESI+): calcd. for C17H14FN2O [MH+] 281.1090; found, 281.1092.
(3,5-Dimethoxyphenyl)[1-(3-methylpyridin-2-yl)-1H-pyrrol-2-
yl]methanone (3bi). Following the general procedure 1b (158.2 mg, 1
mmol) was treated with Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg,
0.75 mmol), 3,5-dimethoxybenzaldehyde 2i (332.2, 2 mmol) and TBHP
(5.5 M in decane, 0.72 mL, 4 mmol). After 1.5 h at 120 °C, purification by
column chromatography (silica gel, petroleum ether/AcOEt 7/3) afforded
3bi as yellow oil (209.2 mg, 65%): IR (ATR): 1727, 1627 cm-1; 1H NMR
(300 MHz, CDCl3) δ 2.11 (s, 3H), 3.78 (s, 6H), 6.38 (dd, J = 3.9, 2.6 Hz,
(4-Chlorophenyl)[1-(3-methylpyridin-2-yl)-1H-pyrrol-2-yl]methanone
(3be). Following the general procedure 3 1b (158.2 mg, 1 mmol) was
treated with Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg, 0.75 mmol),
4-chlorobenzaldehyde 2e (281.2 mg; 2 mmol) and TBHP (5.5 M in
decane, 0.72 mL, 4 mmol). After 3 h at 120 °C, purification by column
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000444
European Journal of Organic Chemistry
FULL PAPER
1H), 6.61 (t, J = 2.3 Hz, 1H), 6.98 (dd, J = 3.9, 1.6 Hz, 1H), 7.00 (d, J =
2.3 Hz, 2H), 7.11 (dd, J = 2.7, 1.6 Hz, 1H), 7.27 (dd, J = 7.5, 4.8 Hz, 1H),
7.63 (ddd, J = 7.5, 1.8, 0.8 Hz, 1H), 8.36 (ddd, J = 4.8, 1.8, 0.7 Hz, 1H)
ppm;13C NMR (75 MHz, CDCl3): δ 184.1, 160.5, 152.3, 146.3, 140.4,
139.4, 131.5, 130.1, 129.7, 123.7, 122.2, 110.0, 107.2, 104.5, 55.5, 17.2
ppm; MS (ESI+): m/z (rel intensity): 323 (MH+, 100), 165 (18). HRMS
(ESI+): calcd. for C19H19N2O3 [MH+] 323.1396; found, 323.1406.
J = 7.6, 1.8, 1.0 Hz, 1H), 8.40 (dd, J = 4.8, 1.8 Hz, 1H) ppm; 13C NMR
(75 MHz, CDCl3): δ 184.3, 158.6, 152.4, 146.4, 140.0, 139.4, 136.7,
131.6, 130.1, 129.6, 129.3, 128.7, 128.1, 127.5, 123.7, 122.4, 122.3,
119.3, 114.9, 110.0, 70.1, 17.3 ppm; MS (ESI+): m/z (rel intensity): 369
(MH+, 100), 211 (6). HRMS (ESI+): calcd. for C24H21N2O2 [MH+]
369.1603; found, 369.1602.
[1-(tert-Butyl)-1H-pyrrol-3-yl][1-(3-methylpyridin-2-yl)-1H-pyrrol-2-
yl]methanone (3br). Following the general procedure 1b (158.2 mg, 1
mmol) was treated with Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg,
0.75 mmol), 1-(tert-butyl)-1H-pyrrole-3-carbaldehyde 3r (226.8 mg, 1.5
mmol) and TBHP (5.5 M in decane, 0.54 mL, 3 mmol). After 1.5 h at
120 °C, purification by column chromatography (silica gel, petroleum
ether/AcOEt 8/2) afforded 3br as white solid (216.7 mg, 71 %): mp
(CH2Cl2): 133-134 °C; IR (ATR): 1612, 1526, cm-1; 1H NMR (300 MHz,
CDCl3): δ 1.51 (s, 9H), 2.10 (s, 3H), 6.34 (dd, J = 3.8, 2.7 Hz, 1H), 6.66
(dd, J = 2.9, 1.8 Hz, 1H), 6.79 (t, J = 2.9 Hz, 1H), 7.00 (dd, J = 2.7, 1.6
Hz, 1H), 7.04 (dd, J = 3.8, 1.5 Hz, 1H), 7.21 (dd, J = 7.6, 4.8 Hz, 1H),
7.49 (t, J = 1.8 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 8.38-8.26 (m, 1H) ppm;
13C NMR (75.5 MHz, CDCl3): δ 179.1, 152.8, 146.1, 139.2, 133.0, 130.2,
127.7, 124.0, 123.8, 123.4, 118.9, 118.5, 110.0, 109.4, 55.7, 30.6, 17.4
ppm; MS (ESI+): m/z (rel intensity): 308 (MH+, 100), 185 (33), 150 (5).
HRMS (ESI+): calcd. for C19H22N3O [MH+] 308.1763; found, 308.1764.
[1-(3-Methylpyridin-2-yl)-1H-pyrrol-2-yl](3,4,5-
trimethoxyphenyl)methanone (3bj). Following the general procedure
1b (158.2 mg, 1 mmol) was treated with Pd(OAc)2 (22.5 mg, 0.1 mmol),
PivOH (76.6 mg, 0.75 mmol), 3,4,5-trimethoxybenzaldehyde 3j (392.4
mg, 2 mmol) and TBHP (5.5 M in decane, 0.72 mL, 4 mmol). After 3.5 h
at 120 °C, purification by column chromatography (silica gel, petroleum
ether/AcOEt 7/3) afforded 3bj as yellow oil (217.9 mg, 62%): IR (ATR):
1726, 1630 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.07 (s, 3H), 3.80 (s, 6H),
3.84 (s, 3H), 6.32 (dd, J = 3.9, 2.8 Hz, 1H), 6.91 (dd, J =3.9, 1.4 Hz, 1H),
7.03-7.08 (m, 1H), 7.10 (s, 2H), 7.20 (dd, J = 7.0, 3.5 Hz, 1H), 7.57 (d, J
= 7.0Hz, 1H), 8.28 (d, J = 3.5 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3): δ
183.5, 152.7, 152.2, 146.2, 141.5, 139.4, 133.6, 131.4, 130.0, 129.4,
123.7, 121.5, 109.7, 107.0, 60.8, 56.2, 17.3 ppm; MS (ESI+): m/z (rel
intensity): 353 (MH+, 100), 195 (10). HRMS (ESI+): calcd. for C20H21N2O4
[MH+] 353.1501; found, 353.1508.
(2,6-Dimethoxyphenyl)[1-(3-methylpyridin-2-yl)-1H-pyrrol-2-
yl]methanone (3bk). Following the general procedure 1b (158.2 mg, 1
mmol) was treated with Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg,
0.75 mmol), 2,6-dimethoxybenzaldehyde 2k (332.2, 2 mmol) and TBHP
(5.5 M in decane, 0.72 mL, 4 mmol). After 7 h at 120 °C, purification by
column chromatography (silica gel, petroleum ether/AcOEt 7/3) afforded
3bk as yellow oil (126.0 mg, 39%). IR (ATR): 1641 1595 cm-1; 1H NMR
(300 MHz, CDCl3) δ 2.15 (s, 3H); 3.71 (s, 6H), 6.31 (dd, J = 3.9, 2.6 Hz,
1H), 6.57 (d, J = 8.4 Hz, 2H), 6.65 (dd, J = 3.9, 1.7 Hz, 1H), 7.05 (dd, J =
2.6, 1.7 Hz, 1H), 7.33-7.22 (m, 2H), 7.66-7.61 (m, 1H), 8.41 (ddd, J = 4.8,
1.8, 0.7 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3): δ 182.9, 157.7, 152.5,
146.1, 139.1, 133.5, 131.1, 130.3, 129.3, 123.7, 121.8, 118.9, 109.9,
103.9, 55.8, 16.7 ppm; MS (ESI+): m/z (rel intensity): 323 (MH+, 100), 185
(50), 165 (24). HRMS (ESI+): calcd. for C19H19N2O3 [MH+]: 323.1396;
found, 323.1398.
(1-Methyl-1H-pyrrol-2-yl)[1-(3-methylpyridin-2-yl)-1H-pyrrol-2-
yl]methanone (3bs). Following the general procedure 1b (158.2 mg, 1
mmol) was treated with Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg,
0.75 mmol), 1-methyl-1H-pyrrole-2-carbaldehyde 2s (0.20 mL, 2 mmol)
and TBHP (5.5 M in decane, 0.72 mL, 4 mmol). After 4.5 h at 85 °C,
purification by column chromatography (silica gel, petroleum ether/AcOEt
7/3) afforded 3bs as a brown solid (142.0 mg, 54 %): mp (CH2Cl2): 108-
111°C; IR (ATR): 1739, 1609 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.12 (s,
3H), 3.81 (s, 3H), 6.14 (dd, J = 4.0, 2.4 Hz, 1H), 6.36 (dd, J = 3.8, 2.7 Hz,
1H), 6.81 (d, J = 2.4 Hz, 1H), 6.97-7.01 (m, 2H), 7.05 (dd, J = 2.7, 1.6 Hz,
1H), 7.25 (dd, J = 7.5, 4.9 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 8.38 (dd, J =
4.9, 1.8 Hz, 1H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 175.1, 152.4, 146.4,
139.5, 133.0, 130.8, 130.4, 129.7, 128.3, 123.5, 120.5, 120.0, 109.4,
107.8, 36.7, 17.3 ppm; MS (ESI+): m/z (rel intensity): 266 (MH+, 14), 185
(100), 108 (1). HRMS (ESI+): calcd. for C16H16N3O [MH+]: 266.1293;
found, 266.1297.
(4-Methoxyphenyl)[1-(3-methylpyridin-2-yl)-1H-pyrrol-2-
yl]methanone (3bp). Following the general procedure 1b (158.2 mg, 1
mmol) was treated with Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg,
0.75 mmol), 4-methoxybenzaldehyde 2p (0.24 mL, 2 mmol) and TBHP
(5.5 M in decane, 0.72 mL, 4 mmol). After 1,5 h at 120 °C, purification by
column chromatography (silica gel, petroleum ether/AcOEt 7/3) afforded
3bp as yellow solid (174.9 mg, 60%): mp (CH2Cl2): 109-111 °C; IR
(ATR): 3009., 2991, 1735, 1627, 1595, 1451, 1408 cm1-; 1H NMR (300
MHz, CDCl3): δ 2.09 (s, 3H), 3.80 (s, 3H), 6.36 (dd, J = 3.9, 2.7 Hz, 1H),
6.86-6.94 (m, 3H), 7.08 (dd, J = 2.7, 1.6 Hz, 1H), 7.23 (dd, J = 7.6, 4.6
Hz, 1H), 7.55-7.64 (m, 1H), 7.80-7.92 (m, 2H), 8.34 (dd, J = 4.6, 1.4 Hz,
1H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 183.6, 162.8, 152.4, 146.3,
139.4, 131.8, 131.6, 131.2, 130.0, 129.0, 123.6, 121.4, 113.5, 109.7,
55.5, 17.3 ppm; MS (ESI+): m/z (rel intensity): 293 (MH+, 100), 185 (2),
136 (2), 135 (29). HRMS (ESI+): calcd. for C18H17N2O2 [MH+] 293.1290;
found, 293.1293.
Furan-3-yl[1-(3-methylpyridin-2-yl)-1H-pyrrol-2-yl]methanone (3bt).
Following the general procedure 1b (158.2 mg, 1 mmol) was treated with
Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg, 0.75 mmol), furan-3-
carbaldehyde 2t (0.17 mL, 2 mmol) and TBHP (5.5 M in decane, 0.72 mL,
4 mmol). After 1.5 h at 120 °C, purification by column chromatography
(silica gel, petroleum ether : AcOEt 7:3) afforded 3bt as a brown-red oil
(196.7 mg, 78 %): IR (ATR): 1627, 1454 cm-1; 1H NMR (300 MHz,
CDCl3): δ 2.07 (s, 3H), 6.36 (dd, J = 3.7, 2.8 Hz, 1H), 6.76 (m, 1H), 7.08
– 7.04 (m, 2H), 7.24 (dd, J = 7.6, 4.8 Hz, 1H), 7.40 (t, J = 1.7 Hz, 1H),
7.61 (dd, J = 7.6, 1.0 Hz, 1H), 8.01 (t, J = 1.1 Hz, 1H), 8.33 (dd, J = 4.9,
1.8 Hz, 1H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 177.22, 152.2, 146.7,
146.3, 143.6, 139.4, 132.2, 130.2, 129.3, 126.8, 123.8, 119.7, 110.1,
110.0, 17.2 ppm; MS (ESI+): m/z (rel intensity): 253 (MH+, 100), 95 (16).
HRMS (ESI+): calcd. for C15H13N2O2 [MH+] 253.0977; found, 253.0982.
Removal of the 2-Pyrimidyl Directing Group. General procedure.
Under argon atmosphere, a solution of 3aa, 3ab or 3ak (1 mmol) and
NaOEt (3 mmol) in DMSO (5 mL) was stirred at 100 °C for 2.5-3.5 h. The
reaction was allowed to cool down, and EtOAc (10 mL) and H2O (15 mL)
were added. The aqueous layer was extracted with EtOAc (3 × 15 mL).
The combined organic layer were washed with H2O (3 × 10 mL) and
dried over Na2SO4. The solvent was removed under reduced pressure
and the crude product was purified by column chromatography affording
5a,b,k.
[3-(Benzyloxy)phenyl][1-(3-methylpyridin-2-yl)-1H-pyrrol-2-
yl]methanone (3bq). Following the general procedure 1b (158.2 mg, 1
mmol) was treated with Pd(OAc)2 (22.5 mg, 0.1 mmol), PivOH (76.6 mg,
0.75 mmol), 3-(benzyloxy)benzaldehyde 3q (424.5 mg, 2 mmol) and
TBHP (5.5 M in decane, 0.72 mL, 4 mmol). After 2 h at 120 °C,
purification by column chromatography (silica gel, petroleum ether/AcOEt
7/3) afforded as yellow oil 3bq (224.2 mg, 61%): IR (ATR): 1645, 1595
cm-1; 1H NMR (500 MHz, CDCl3) δ 2.13 (s, 3H), 5.11 (s, 2H), 6.40 (dd, J
= 4.0, 2.6 Hz, 1H), 6.91 (dd, J = 4.0, 1.6 Hz, 1H), 7.14 (dd, J = 2.6, 1.6
Hz, 1H), 7.18 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 7.28 (dd, J = 7.6, 4.8 Hz,
1H), 7.41-7.31 (m, 4H), 7.46-7.42 (m, 2H), 7.51-7.53 (m, 2H), 7.64 (ddd,
Phenyl(1H-pyrrol-2-yl)methanone (5a). Following the general
procedure 3aa (249.6 mg, 1 mmol) was treated with NaOEt (204.3 mg, 3
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000444
European Journal of Organic Chemistry
FULL PAPER
mmol) in DMSO (5 mL). After 2,5 h at 100 °C, purification by column
chromatography (silica gel, petroleum ether/AcOEt 7/3) afforded 5a as a
white solid, whose data are coincidental to those reported[13] (153.6 mg,
90%): mp (CH2Cl2): 76-78 °C (Lit.[13] 77-78 ºC); IR (ATR): 3282, 1609 cm-
1; 1H NMR (300 MHz, CDCl3): δ 6.35-6.38 (m, 1H), 6.92 (ddd, J = 3.8, 2.4,
1.3 Hz, 1H), 7.19 (td, J = 2.4, 1.3 Hz, 1H), 7.43-7.52 (m, 2H), 7.56-7.61
(m, 1H), 7.92-7.96 (m, 2H), 10.53 (br s, 1H) ppm; 13C NMR (75.5 MHz,
CDCl3): δ 186.1, 138.5, 131.8, 131.2, 129.0, 128.3, 125.8, 119.9, 111.0
ppm; MS (ESI+): m/z (rel intensity): 172 (MH+, 100), 105 (45). HRMS
(ESI+): Calcd. for C11H10NO [MH+] 172.0762; found, 172.0767.
(3-Chloro-2-hydroxy-6-methoxyphenyl)(4,5-dichloro-1H-pyrrol-2-
yl)methanone (7). A solution of 6 (121.0 mg, 0.36 mmol) in dry
dichloromethane (4 mL) was added dropwise via syringe to a stirred
suspension of AlCl3 (964.4 mg, 7.23 mmol) in dichloromethane (4 mL) in
ice bath. The reaction mixture was stirred for 24 hours at room
temperature. Aqueous 5% sulfuric acid on ice was added to quench the
reaction mixture, the organic phase was collected and the aqueous
phase was extracted with diethyl ether (2 × 20 mL). The combined
extracts were dried over Na2SO4 and evaporated. The residue was
purified by column chromatography (silica gel, petroleum ether/AcOEt
8/2) affording 7 as white solid (64.5 mg, 56%): mp (CH2Cl2): 180-182 ºC;
1
IR (ATR,): 3518, 3246, 1587 cm-1; H NMR (300 MHz, Acetone-d6): 3.77
(1H-Pyrrol-2-yl)(p-tolyl)methanone (5b). Following the general
procedure 3ab (287.0 mg, 1.09 mmol) was treated with NaOEt (222.1 mg,
3.27 mmol) in DMSO (10 mL). After 3 h at 100 °C, purification by column
chromatography (silica gel, petroleum ether/AcOEt 7/3) afforded 5b as
white solid whose data are coincidental to those reported[13] (191.3 mg,
95%): mp (CH2Cl2): 120-122°C (Lit.[13] 118-119 ºC); IR (ATR) 3429, 1733,
1612 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.47 (s, 3H), 6.36 (dt, J = 3.8,
2.5 Hz, 1H), 6.94 (ddd, J = 3.8, 2.5, 1.4 Hz, 1H), 7.19 (td, J = 2.7, 1.4 Hz,
1H), 7.32 (d, J = 8.0 Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H), 10.54 (s, 1H) ppm;
13C NMR (75.5 MHz, CDCl3): δ 184.8, 142.5, 135.8, 131.3, 129.2, 129.0,
125.5, 119.5, 110.9, 21.6 ppm; MS (ESI+): m/z (rel intensity): 186 (MH+,
89), 119 (29), 94 (8). HRMS (ESI+): calcd. for C12H12NO [MH+] 186.0919;
found, 186.0914.
(s, 3H), 6.65 (s, 1H), 6.70 (d, J = 8.9 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H),
8.71 (br s, 1H), 12.00 (br s, 1H) ppm; 13C NMR (75.5 MHz, Acetone-d6):
δ 180.7, 157.0, 151.2, 131.0, 130.8, 120.1, 117.0, 116.7, 113.2, 110.8,
104.2, 55.5 ppm; MS (ESI+): m/z (rel intensity): 326 (MH++ 6, 2), 324
(MH++ 4, 23), 322 (MH++ 2, 99), 320 (MH+, 100), 187 (18), 185 (77);
HRMS (ESI+): calcd. for C12H9Cl3NO3 [MH+] 319.9651; found: 319.9648.
(1-Methyl-1H-pyrrol-2-yl)(p-tolyl)methanone (8) A solution of 5b (166.5
mg, 0.9 mmol) in dry dimethylformamide (3 mL) was added dropwise to a
stirred suspension of NaH (60% in mineral oil, 39.6 mg, 0.99 mmol) in
anhydrous DMF (3 mL). Then, CH3I (0.07 mL, 1.8 mmol) was added and
after 3.5 h at room temperature the reaction was quenched with water
(20 mL). The aqueous phase was extracted with Et2O (3 × 15 mL), and
the combined organic phase was washed with water (2 × 15 mL), dried
over Na2SO4 and evaporated in vacuo. The residue was purified by
column chromatography (silica gel, petroleum ether/AcOEt 9/1) affording
6 as colorless oil, whose data are coincidental to those reported[13] (177
mg, 99%): IR (ATR,): 1736, 1623 cm-1; 1H NMR (300 MHz, CDCl3): δ
2.43 (s, 3H), 4.03 (s, 3H), 6.16 (dd, J = 4.1, 2.5 Hz, 1H), 6.76 (dd, J = 4.1,
1.7 Hz, 1H), 6.90 (t, J = 2.1 Hz, 1H), 7.26 (d, J = 7.9 Hz, 2H), 7.76 (d, J =
8.1 Hz, 2H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 186.0, 141.9, 137.2,
131.2, 130.6, 129.4, 128.8, 122.4, 108.0, 37.3, 21.5 ppm; MS (ESI+): m/z
(rel intensity): 200 (MH+, 100), 119 (77). HRMS (ESI+): calcd. for
C13H14NO [MH+] 200.1075; found: 200.1066.
(2,6-Dimethoxyphenyl)(1H-pyrrol-2-yl)methanone (5k). Following the
general procedure 3ak (347.1 mg, 1.12 mmol) was treated with NaOEt
(229.1 mg, 3.37 mmol) in DMSO (10 mL). After 3.5 h at 100 °C,
purification by column chromatography (silica gel, petroleum ether/AcOEt
7/3) afforded 7k as orange solid, whose data are coincidental to those
reported[4a] (234.6 mg, 91%): mp (CH2Cl2):192-194 °C; IR (ATR): 3278,
1623, 1595 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.75 (s, 6H), 6.24 (dt, J =
3.8, 2.4 Hz, 1H), 6.57 (ddd, J = 3.8, 2.4, 1.4 Hz, 1H), 6.63 (d, J = 8.4 Hz,
2H), 7.10 (td, J = 2.7, 1.4 Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 10.00 (br s,
1H) ppm; 13C NMR (75.5 MHz, CDCl3): δ 183.9, 157.8, 133.4, 130.7,
125.4, 119.2, 118.0, 110.7, 104.1, 56.0 ppm; MS (ESI+): m/z (rel
intensity): 254 (MNa+, 100), 232 (MH+, 2), 165 (7). HRMS (ESI+): calcd.
for C13H13NNaO3 [MNa+] 254.0793; found, 254.0785.
Synthesis of 2-[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetic
acid (Tolmetin, 9). Under argon atmosphere, a solution of 6 (154.4 mg,
0.80 mmol), Mn(OAc)2·4H2O (4.9 mg, 0.02 mmol), triphenylphosphine
(10.5 mg, 0.05 mmol), NaIO4 (102.3 mg, 0.48 mmol), NaOAc (65.6 g,
0.80 mmol) and tri(ethoxycarbonyl)methane (0.08 mL, 0.4 mmol) in dry
acetic acid (1 mL) was stirred at 70 °C for 24 h. After cooling the reaction
mixture to room temperature, the mixture was added Me2S (1 mL) and
passed through a short pad of Celite (EtOAc) and the filtrate was
evaporated under reduced pressure. KOH (2.5 M in water, 10 mL) and
1,4-dioxane (2 mL) were added and the reaction mixture was stirred at
110 °C for 24 h. After cooling the reaction mixture to room temperature,
the mixture was evaporated under reduced pressure. The residue was
extracted with EtOAc (2 × 15 mL). The water layer was poured into HCl
(1.0 M, 20 mL) and extracted with EtOAc (2 × 15 mL). The organic layer
was washed with water, dried over anhydrous Na2SO4, evaporated under
reduced pressure and the crude product was purified by column
chromatography (silica gel, petroleum ether/AcOEt 6/4) affording 7 as a
white solid, whose data are coincidental to those reported[30a] (57.4 mg,
56%): mp (CH2Cl2) = 154-155 °C (Lit.[30a] 160-161 ºC); IR (ATR) 3225,
1739, 1619 cm-1; 1H NMR (300 MHz, acetone-d6): δ 2.42 (s, 3H), 3.84 (s,
2H), 3.95 (s, 3H), 6.15 (d, J = 4.0 Hz, 1H), 6.63 (d, J = 4.0 Hz, 1H), 7.31
(d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H) ppm; 13C NMR (75.5 MHz,
acetone-d6): δ 184.9, 170.2, 141.6, 137.7, 135.9, 131.0, 129.2, 128.6,
121.5, 109.2, 32.5, 31.9, 20.6 ppm; MS (ESI+): m/z (rel intensity): 258
(MH+, 100), 236 (54), 119 (54). HRMS (ESI+): calcd. for C15H16NO3 [MH+]
258.1130; found: 258.1120
Deprotection of 3ba. Methyl trifluoromethanesulfonate (0.07 mL, 0.62
mmol) was added dropwise to a solution of 3ba (131.9 mg, 0.50 mmol) in
dry CH2Cl2 (7 mL) at 0 °C, and the resulting solution was stirred for 24 h
at room temperature. Then, the solvent was removed under vacuum, and
the residue was dissolved in MeOH (10 mL). A 2 M aq. NaOH solution (6
mL) was added. The resulting solution was stirred at 60 °C for 24 h. The
solvents were removed, and the resulting residue was extracted with
EtOAc (2 × 20 mL). The combined organic layers were washed with H2O
(2 × 15mL), dried over Na2SO4, and concentrated in vacuo. Purification
by flash chromatography afforded 5a as a white solid (58.0 mg, 68 %).
(3-Chloro-2,6-dimethoxyphenyl)(4,5-dichloro-1H-pyrrol-2-
yl)methanone (6). To a stirred solution of 5k (113.5 mg, 0.49 mmol) in
acetonitrile (6 mL), NCS (164.2 mg, 1.23 mmol) was added and the
resulting solution was stirred 24 h at 50 °C. Then, the solvent was
evaporated, and the residue was partitioned between water (100 mL) and
diethyl ether (100 mL). The aqueous layer was separated and extracted
with diethyl ether (2 × 50 ml). The combined extracts were washed with
water (20 mL), dried over Na2SO4 and evaporated. The residue was
purified by column chromatography (silica gel, petroleum ether/AcOEt
9/1) affording 6 as light brown solid (132.6 mg, 81%): mp (CH2Cl2): 171-
173 ºC; IR (ATR,): 3219, 1729, 1627 cm-1; 1H NMR (300 MHz, CDCl3):
3.77 (s, 3H), 3.85 (s, 3H), 6.50 (d, J = 2.4 Hz, 1H), 6.72 (d, J = 8.9 Hz,
1H), 7.42 (d, J = 8.9 Hz, 1H), 10.60 (br s, 1H) ppm; 13C NMR (75.5 MHz,
CDCl3): δ 181.1, 156.4, 153.9, 131.7, 129.8, 123.3, 122.3, 119.7, 119.0,
112.3, 107.9, 62.6, 56.2 ppm; MS (ESI+): m/z (rel intensity): 340 (MH++ 6,
1), 338 (MH++ 4, 13), 336 (MH++ 2, 52), 334 (MH+, 53), 201 (24), 199
(110); HRMS (ESI+): calcd. for C13H11Cl3NO3 [MH+] 333.9805; found:
333.9803.
10
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10.1002/ejoc.202000444
European Journal of Organic Chemistry
FULL PAPER
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Acknowledgements
Ministerio de Economía y Competitividad (CTQ2016-74881-P),
Gobierno Vasco (IT1045-16) and Universidad del País
Vasco/Euskal Herriko Unibertsitatea UPV/EHU are gratefully
acknowledged for their financial support. Technical and human
support provided by Servicios Generales de Investigación
SGIker (UPV/EHU, MINECO, GV/EJ, ERDF and ESF) is also
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Keywords: C-H activation • Palladium • Acylation Synthetic
methods • Heterocycles
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European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Key Topic: C-H Acylation
The oxidative C-H acylation of pyrrole with aldehydes has been carried out avoiding the formation of diacylated compounds. This
acylation protocol has been applied as the key step for improved syntheses of Celastramycin analogues and non-steroidal anti-
inflammatory drug Tolemtin,
12
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