Selective synthesis of trisubstituted pyrroles through the reactions of alkynyl Fischer carbene complexes with oxazolones

Article abstract of DOI:10.1039/c9ob02411e

An efficient and simple synthesis of novel trisubstituted 1H-pyrroles 4a-qvia 1,3-dipolar cycloaddition of Δ³-trifluoromethyloxazolones 2a-d with both chromium and tungsten alkynyl Fischer carbene complexes (1a-h) is described. An unexpected and unreported -CF₃ group elimination process was observed in the pyrrole structure. Our experimental and theoretical data suggested that the metal fragment may be responsible for this phenomenon. The dipolar cycloaddition proceeded efficiently to produce a single regioisomer, which was unambiguously established through NMR and single-crystal X-ray diffraction studies. Nevertheless, the reaction of alkynyl carbenes bearing an α,β,γ,δ-unsaturated moiety with excess oxazolone 2a produced a polycyclic compound 6 speculatively formed through a cascade reaction involving 1,6-, 1,4- and 1,2-nucleophilic addition steps.

Full text of DOI:10.1039/c9ob02411e

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Selective synthesis of trisubstituted pyrroles
through the reactions of alkynyl Fischer carbene
Cite this: DOI: 10.1039/c9ob02411e
complexes with oxazolones†
a
Julio López, a Iván Velazco-Cabral, a Eloy Rodríguez-deLeón,
Clarisa Villegas Gómez, a Francisco Delgado, b Joaquín Tamariz,
b
a
Ana Arrieta, c,d Fernando P. Cossío c,d and Miguel A. Vázquez
*
An efficient and simple synthesis of novel trisubstituted 1H-pyrroles 4a–q via 1,3-dipolar cycloaddition of
Δ3-trifluoromethyloxazolones 2a–d with both chromium and tungsten alkynyl Fischer carbene com-
plexes (1a–h) is described. An unexpected and unreported –CF3 group elimination process was observed
in the pyrrole structure. Our experimental and theoretical data suggested that the metal fragment may be
responsible for this phenomenon. The dipolar cycloaddition proceeded efficiently to produce a single
regioisomer, which was unambiguously established through NMR and single-crystal X-ray diffraction
studies. Nevertheless, the reaction of alkynyl carbenes bearing an α,β,γ,δ-unsaturated moiety with excess
oxazolone 2a produced a polycyclic compound 6 speculatively formed through a cascade reaction
involving 1,6-, 1,4- and 1,2-nucleophilic addition steps.
Received 7th November 2019,
Accepted 11th December 2019
DOI: 10.1039/c9ob02411e
rsc.li/obc
the formation of a variety of different bonds (C–Y; Y = C, O, N)
at the same time with good selectivities and yields.
Introduction
Since the introduction of Fischer carbene complexes in the
The reactivity of Fischer alkynyl carbenes with masked azo-
early 1960s, they have been used as reagents for organic chem- methine imines has been described in the literature. Choi
istry in a number of different ways.1 This enormous versatility et al. reported a [3 + 2] dipolar cycloaddition between carbenes
has been attributed to the metallic fragment, as it induces a and münchnones. The reaction was carried out in satisfactory
strong electrophilicity at the carbon atom (carbene) and as a yields and high selectivity to produce pentacarbonyl[(methoxy)
consequence the reactivity of its substituents increases (alkyl, (pyrrolyl)]metal compounds (Scheme 1a).10 Another interest-
alkenyl, etc.). Typical cycloaddition reactions, such as [4 + 2],2,3 ing study was reported by Merlic,11 where the pyrrole core was
[3 + 2],4 and [3 + 2 + 1]5 types have been studied extensively produced in good yields from the non-photochemical inser-
with Fischer carbene complexes comprising α,β-unsaturated
systems. The use of this methodology as a synthetic strategy
has allowed access to a range of important molecules in bio-
logical and medicinal chemistry research.6–9 Moreover, these
organometallic compounds have been employed in multicom-
ponent reactions (MCRs)7 and domino reactions,9 allowing for
aDepartament of Chemistry, University of Guanajuato, Noria Alta S/N,
36050 Guanajuato, Gto, Mexico. E-mail: mvazquez@ugto.mx
bDepartament of Organic Chemistry, National School of Biological Sciences-Instituto
Politécnico Nacional, Prol. Carpio y Plan de Ayala S/N, 11340 Ciudad de Mexico,
Mexico
cDepartament of Organic Chemistry I and Centro de Innovación en Química
Avanzada (ORFEO-CINQA). Universidad del País Vasco/Euskal Herriko Unibertsitatea
(UPV/EHU), Manuel Lardizabal Ibilbidea 3, 20018 San Sebastian/Donostia, Spain
dDonostia International Physics Center (DIPC), Manuel Lardizabal Ibilbidea 4,
20018 San Sebastian/Donostia, Spain
†Electronic supplementary information (ESI) available. CCDC 1912568, 1912115,
1912414, 1912422, 1912423, 1912569 and 1911540. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c9ob02411e
Scheme 1 Comparison of the reactivity of organometallic substrates in
the synthesis of pyrroles.
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tion of carbon monoxide at room temperature and subsequent
formation of münchnones as reactive intermediates in reac-
tions of acylamino chromium carbene complexes with various
alkynes (Scheme 1b). Unlike the first case, the latter studies
constitute the conventional method for obtaining pyrrole
scaffolds from Fischer alkynyl carbene complexes. Recently, we
reported the synthesis of N-benzyl-1H-pyrroles by a cascade
sequence, implying 1,4-addition/isomerization/ring closure/
demetallation processes of alkynyl Fischer carbene complexes
and α-imino glycine methyl esters (Scheme 1c).12
Our research with Fischer carbene complexes has demon-
strated the fascinating ability of these reactions to show unex-
pected behavior by merely changing the substituents and/or
reaction conditions.
Fig. 1 Single-crystal X-ray structure of 4a with ellipsoids drawn at the
50% probability level.
Here, as an extension of our interest in the synthesis of sub-
stituted pyrroles, reactivity and selectivity studies of Δ3-
trifluoromethyloxazolones with alkynyl Fischer carbenes are
reported.
Results and discussion
In order to investigate the reactivity of these compounds, we
applied a procedure similar to that previously reported,10
using the alkynyl Fischer carbene 1a 2 and Δ3-trifluoromethyl-
oxazolone 2a.13 We first tested the use of triethylamine as base
in THF (see section 7 of ESI†) at room temperature (Table 1,
entry 1). After 3 h, the transformation of 1a was complete. The
crude reaction mixture was analyzed employing 19F, 13C NMR
spectroscopy and GC-MS. Both techniques indicated that a (3 +
2) cycloaddition reaction had taken place. However, the -CF3
group was not detected. After purification by column chrom-
atography and complete characterization by NMR spec-
troscopy, HRMS and X-ray crystallography (Fig. 1), the loss of
the –CF3 group was confirmed and the obtained product was
established to be compound 4a (Scheme 2).
Scheme 2 Unpredicted behavior of the trifluoromethyl moiety during
the (3 + 2) cycloaddition process.
LDA) and catalysts (AgOAc, CuOAc) (Table 1). However, all of
the experiments led to product 4a. Consequently, the screen-
ing of the reaction conditions suggested that the transform-
ation of 1a and 2a proceeded most efficiently in the presence
of AgOAc (10 mol%) as catalyst (Table 1, entry 10). On the
other hand, oxidation product was also detected by CG-MS
analysis under these conditions (an ester 1a[ox] derived from
the Fischer carbene complex 1a).
Having improved the methodology of this reaction, we then
turned our attention to the analysis of the effect of incorporat-
ing different functional groups (R1) into the alkynyl Fischer
carbene Cr(0). As shown in Table 2, the corresponding pro-
ducts were obtained in good yields when aromatic groups were
attached next to the alkyne functionality. However, the use of
alkyl groups at this position lowered the yield. This may be
attributed to the instability of these Fischer carbenes at room
temperature and in solution (4f). When W(0) was used as the
metal in the carbene complex, a decrease in the yield was
observed for the synthesis of 4a–c (Table 2).
In addition, alternative amino acids were used to prepare
the oxazolone derivatives [phenylalanine (2b), trifluoro acetyl
tyrosine (2c), and alanine (2d)]. The compounds 4h–q were
obtained with lower yields (Table 3) than those obtained using
oxazolone 2a. All reaction mixtures were monitored by GC-MS,
corroborating that only one regioisomer was produced by this
process, along with the oxidized carbene (1a[ox]). Further
structural support for the proposed regioisomer was provided
Subsequently, we explored a range of different reaction con-
ditions by testing other appropriate solvents (CH3CN, CH2Cl2,
dioxane), temperatures (reflux, −70 °C), bases (DIPEA, DBU,
Table 1 Screening of the reaction conditions
Entrya Solvent
Base
T (°C)
t (min) Catalyst Yieldb (%)
1
2
3
4
5
6
7
8
THF
CH3CN
CH2Cl2
Et3N
Et3N
Et3N
rt
rt
rt
rt
180
180
180
180
—
—
—
—
—
—
—
—
80
68
70
56
75
44
70
62
70
88
68
Dioxane Et3N
THF
THF
THF
THF
THF
THF
THF
Et3N
LDA
DIPEA rt
DBU rt
DIPEA rt
Et3N
Et3N
Reflux 180
−70
120
180
180
180
20
9
10
11
—
AgOAc
CuOAc
rt
rt
20
a All the reactions were carried out under the following conditions:
1.0 mmol of 1a, 1.1 mmol of 2a, base (1.1 mmol), catalyst (10 mol%)
in solvent (10 mL). b Yield of the isolated product.
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Table 2 Scope of the methodology for the synthesis of pyrroles 4a–g and 5 using different
alkynyl Fischer carbenesa
a 1.0 mmol of 1a–g, 1.1 mmol of 2b–d, Et3N, AgOAc (10 mol%), THF (10 mL), rt, 20 min.
by resonance structures A–F (Scheme 3); furthermore, when a
Lewis acid catalyst is used, a highly stabilized 1,3-dipole is
formed (D–F, Scheme 3).
Table 3 Results of the synthesis of pyrroles 4h–r using various
oxazolonesa
DFT calculations were performed in order to gain more
information about the structure and reactivity of species A–C
and D–F. First, we optimized the structure of intermediate ABC
bound to protonated trimethylamine, a computational model
of the salt produced after the addition of triethylamine in
THF.
These calculations were performed at the B3LYP-D3
(SCRF=THF)/6-31(d) level of theory. In addition, we computed
the structures and energies of the complex DEF, in which the
silver cation stemming from silver acetate is bound to the
nitrogen atom of the deprotonated 2a (Scheme 4) or, alterna-
tively, to the carbon atom contiguous to the trifluoromethyl
group. These latter intermediates are denoted as complexes
DEF and DEF′ in Scheme 4, respectively, and were computed
using the LANL2DZ effective core potential and basis set for
the Ag(I) center (see the Computational methods section and
the ESI† for additional details). In these complexes three dis-
crete molecules of THF were added in order to saturate the
coordination sphere of the metallic center. According to the
data compiled in Scheme 4, formation of complexes ABC, DEF
and DEF′ is energetically favored in terms of total energies, but
endergonic when Gibbs free energies are considered. The
thermodynamically preferred process is the transformation of
a 1.0 mmol of 1a–g, 1.1 mmol of 2a, 1.1 mmol of Et3N, AgOAc
(10 mol%), THF (10 mL), rt, 20 min.
by NOE NMR experiments, GC-MS and HRMS, while the struc- 2a into the N⋯Ag DEF complex, which is very close to the
tures of 4c, 4d and 4h were confirmed unambiguously by C⋯Ag analogue DEF′. In addition, the N⋯Ag DEF complex is
single-crystal X-ray diffraction analysis (Fig. 2). Signals at δ the closest one to free-energy thermoneutrality. The chief geo-
1
8.5–9.0 (NH) and 7.4–7.8 (H-2) ppm in the H NMR spectrum metric and electronic features of ABC and DEF are compiled in
clearly revealed the formation of the pyrrole ring and the dis- Fig. 4. Our calculations show the presence of loose dipoles in
appearance of the –CF3 group. The electronic effect on the which the 1,3-oxazole unit has a collective charge close to −0.9
reactivity and regioselectivity can be explained by stabilization a.u. In ABC there is a strong hydrogen bond between the 1,3-
of the oxazole enolate structure (C and F, Scheme 3). The solid- oxazole moiety and the protonated trimethylamine unit. This
state structure of oxazolone 2a was determined (Fig. 3) and a situation is similar to that shown by complex DEF. Calculation
proton was definitively located at the C-2 position. As dis- of the bond orders of both complexes revealed a 1,3-oxazole
cussed in the literature,14 the pKa value of this proton likely unit that contributes 40% to the ABC and DEF units as the C
permits the formation of a carbanion, which can be stabilized and F mesomeric forms shown in Scheme 3. The combined
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Fig. 2 ORTEP representations of pyrrole derivatives 4c, 4d and 4h with ellipsoids drawn at the 50% probability level.
Scheme 3 Mesomeric structures of likely products of the reaction of 2a under two different sets of conditions.
Fig. 3 ORTEP representation of oxazolone derivative 2a with ellipsoids
drawn at the 50% probability level.
contributions of the 1,3-dipole forms A,D and B,E represent
60% of the resonance contributions, thus revealing a signifi-
cant azomethine ylide character that, in turn, determines the
reactivity of these intermediates. Next, we studied the inter-
action of dipolar molecules ABC and DEF with alkynyl Fischer
carbene 1i, a methoxy analogue of 1a (Scheme 2). In the case
Scheme 4 DFT results (B3LYP-D3(SCRF=THF)/6-31G(d)&LanL2DZ level
of theory, see text) concerning the formation of zwitterionic species
ABC, DEF and DEF’.
of intermediate ABC, our calculations identified a concerted
(3 + 2) cycloaddition after its interaction with 1i (Scheme 5).
The saddle point TS1-H (Fig. 5) corresponds to a [π4s + π2s]
topology, with an activation energy of ca. 20 kcal mol−1. This
1,3-dipolar reaction also involves a proton transfer from the
protonated trimethylamine group to the cycloadduct INT1-H.
In contrast with the results shown above, reaction between
Neutral intermediate INT2-H decarboxylates via a concerted the N⋯Ag dipolar complex DEF and electrophilic reactant 1i
retro-(4 + 2) cycloreversion process. The corresponding tran- is not concerted, but stepwise. According to our calculations,
sition structure TS3 (Fig. 5) also shows a [π4s + π2s] topology the first step consists of a Michael addition between the
and leads to 1H-pyrrole 4r, thus completing a strongly exother- nucleophilic species E and the β-sp-hybridized carbon atom
mic process with respect to reactants ABC and 1i. It is interest- of 1i (Schemes 3 and 5). The structure of transition structure
ing to note that a similar (3 + 2) cycloaddition process followed TS1-Ag shows two different C⋯C distances, the largest being
by decarboxylation has been reported in the chemical syn- 3.21 Å (Fig. 5). The activation energy associated with this step
thesis of atorvastatin.15,16
was calculated to be ca. 10 kcal mol−1 lower than that found
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Fig. 4 Optimized structures (B3LYP-D3(SCRF=THF)/6-31G(d)&LanL2DZ
level of theory, see text) of zwitterionic species ABC and DEF. Bond dis-
tances (bold numbers) are given in Å. Wiberg bond orders (in parenth-
eses) are given in atomic units (a. u.). Σq stands for the sum of NBO
charges of the anionic part of ABC and DEF species, in a.u. The approxi-
mate ratios of the different resonance forms, computed from the NBO
analysis of the bond orders, are given in %. Hydrogen atoms of THF
ligands around the Ag(I) center have been omitted for clarity.
Scheme 5 Formation of 5-trifluoromethyl-1H-pyrrole 4r according to
DFT results (B3LYP-D3(SCRF=THF)/6-31G(d)&LanL2DZ level of theory).
Numbers in parenthesis and square brackets are the relative total and
for the concerted (3 + 2) cycloaddition via TS1-H (Scheme 5),
which suggests that reaction via metallated TS1-Ag is kineti-
cally favored. The aforementioned Michael addition leads to
an allene-oxazol-5(4H)-one intermediate INT1-Ag, which is
Gibbs (298 K) energies, respectively, in kcal mol−1
.
almost isoenergetic with respect to the reactants. This inter- triethylamine and silver acetate, pyrrole 4r is the first
mediate performs an intramolecular cyclization in which the cycloadduct.
nucleophilic allenyl moiety reacts via
a
Mannich-like
Aiming to gain further insight into this reactivity, the reac-
addition to the CvN bond to form bicyclic compound INT2- tion between dimethyl acetylenedicarboxylate (DMAD) and
Ag, which can be considered the N-metallated analogue of oxazolone 2a was carried out employing previously reported
the INT2-H cycloadduct. However, INT2-Ag was shown to be reaction conditions.17,18 The synthesis proceeded efficiently
unstable and, upon optimization, decarboxylated to yield and the expected product was obtained (Table 2, compound 5).
pyrrole 4r-Ag by a highly exothermic barrierless process. The The 13C NMR spectrum showed that the –CF3 group was still
activation energy associated with the second step of the present [(120.4 ppm (J = 40 Hz) and 119.9 ppm (J = 267 Hz)].
formal (3 + 2)/decarboxylation process is ca. 11 kcal mol−1
,
These results allowed us to confirm the effect that the metal
saddle point TS2-Ag (see its structure in Fig. 5) being the only exerts on this reaction. Literature results reveal only rare
transition structure associated with the second part of this examples where the –CF3 group undergoes an SN2 reaction,
stepwise process. Therefore, our calculations show that in the leading to elimination of fluoride,19–21 or displacement of
reaction between 2a and 1i in THF and in the presence of the trifluoromethyl carbanion.22 In addition, the hydrolysis
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Fig. 5 Optimized structures (B3LYP-D3(SCRF=THF)/6-31G(d)&LanL2DZ level of theory) of transition structures TS1-H (see Scheme 5). Bond dis-
tances are given in Å. The hydrogen atoms of the three THF ligands of saddle point TS1-Ag have been omitted for clarity.
of 2-difluoromethylpyrroles has also been studied, whereby would start. However, all our attempts to computationally
the electronic effects of the substituents on the pyrrole ring locate this intermediate met with no success. We then con-
were found to be important in order to obtain the desired sidered two possible 1,2-additions of one molecule of water
formyl derivatives.23 Considering the outcome of –CF3 loss, to 4r. Attempts to locate the transition structure leading to
further analysis and experiments were carried out in the adduct INT4 were also unsuccessful. However, we were able
search for a plausible explanation of this behavior. The to optimize saddle point TS4 that connects 4r with INT5. The
model reaction of 1a with 2a was thus performed in D2O (1 geometric features of this latter transition structure showed a
equiv.), leading deuteration of C2 position in 4g and loss of relatively synchronous formation of C–H and O–H bonds and
the –CF3 group (Table 2). Moreover, the analysis of the crude a weaker C–Cr bond (Fig. 6). The five-membered cyclic struc-
reaction mixture by 13C NMR spectroscopy after 4 h at room ture of TS4 could be relaxed by incorporating an additional
temperature showed a single signal around 211.0 ppm water molecule, thus yielding transition structure TS4′, which
accompanied by the disappearance of the signals corres- was readily located and characterized. This latter saddle
ponding to the carbonyl [(∼214.0 ppm) cis and (∼220.0 ppm) point is associated with an activation energy ca. 10 kcal
trans] and MvC (∼350.0 ppm) carbon nuclei. Likewise, when mol−1 lower than that calculated for TS4, thus showing that
the –CF3 group in 2a was monitored by 19F NMR spec- the presence of water microclusters accelerates this addition
troscopy, the chemical shift of the signal changed from step. From INT5 we located the transition structure TS5
−78.69 ppm to −75.89 ppm (crude reaction) (see ESI†). These leading to intermediate INT4, which is almost isoenergetic
results indicated the possibility of the formation of a with 4r (Scheme 6). The geometry of TS5, shown in Fig. 6,
complex between the metal fragment and the –CF3 group. corresponds to a suprafacial [1,4] sigmatropic shift and
Considering the evidence presented above, a mechanistic shows a weak C⋯Cr interaction that is even weaker in INT4
proposal is depicted in Scheme 6, in which 2-unsubstituted in which the Cr(CO)5 complex is not covalently bound to the
1H-pyrrole 4s, the methoxy analogue of 4a, is formed from 1H-pyrrole unit. From INT4, the 2-unsubstituted intermedi-
cycloadduct 4r.
ate INT6 is formed via transition structure TS6 (Scheme 6).
In principle, a water molecule could add to the carbene The geometric features of this latter stationary point show
moiety of 4r to form adduct INT3, from which the process the cleavage of the HC⋯CF3 bond (Fig. 6) and a weak inter-
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action between the trifluoromethyl moiety and the hydroxy
group of the enol group attached to the 1H-pyrrole and Cr
(CO)5 moieties. Intermediate INT6 consists of a very polar tri-
fluoromethyl carbanion, the Cr(CO)5 complex and a proto-
nated ester group. Therefore, this latter intermediate evolves
downhill towards 1H-pyrrole 4s and a loosely bound fluoro-
form-Cr(CO)5 complex. The overall 4r + H2O → 4s + CHF3
+
Cr(CO)5 process is predicted to be exothermic (Scheme 6), in
good agreement with the experimental results. In addition,
this mechanistic proposal, emerging from DFT calculations,
is compatible with the deuteration pattern obtained in a
closely related system (vide supra), as well as with the partici-
pation of the Cr(CO)5 moiety in the detrifluoromethylation
process.
Finally, a highly interesting reaction outcome was observed
when the set of conditions described above was applied to the
carbene 1h and Δ3-trifluoromethyloxazolone 2a. The new poly-
cyclic compound 6 was isolated, its connectivity and structure
confirmed by a combination of techniques (NMR, HRMS and
X-ray) (Fig. 7).
The well-known reactivity of nucleophiles towards 1,4-
unsaturated systems is one of the most important strategies
for constructing carbon–carbon bonds. Indeed, this type of
reactivity has recently been applied to α,β,γ,δ-unsaturated
carbonyl systems.24 A number of experimental and theore-
tical studies have been carried out with organic com-
pounds, wherein the selectivity (1,2-, 1,4-, and 1,6-addition),
reactivity (catalyzed or uncatalyzed addition) and yields
were discussed.25 In the same way, a number of reports of
Scheme 6 Mechanism of the formation of 1H-pyrrole 4s according to
DFT results (B3LYP-D3(SCRF=THF)/6-31G(d)&LanL2DZ level of theory).
Numbers in parentheses and square brackets are the relative total and
Gibbs free (298 K) energies, respectively, in kcal mol−1
.
Fig. 6 Optimized structures (B3LYP-D3(SCRF=THF)/6-31G(d)&LanL2DZ level of theory) of transition structures TS3 (see Fig. 5). Bond distances are
given in Å.
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nucleophilic addition towards Fischer carbene complexes
have been published;7,26 for instance, Aumann et al.27
reported a regioselective cyclohexadiene annulation using
enamines and a pyran-2-ylidene carbene Fischer complex,
whereby the 1,6-addition of the enamine was the initial
step.
Another interesting report was published by Barluenga
et al.,28 where sterically demanding groups attached to the
carbene carbon of the complex were used to regioselectively
produce the 1,6-addition product. However, to the best of our
knowledge, the reactivity of Fischer carbene complex observed
here has not been previously reported. A preliminary investi-
gation of the effects of changing the reaction conditions was
conducted in order to understand the reactivity of this system
(Table 4). Thereby, we noted the need for 2.1 equiv. of oxazo-
lone 2a to complete the reaction (Table 4, entry 1), and the
yield did not markedly improve when the amount of 2a was
increased (Table 4, entry 2). The yield decreased when the reac-
tion was carried out at −70 °C (Table 1, entry 4), leading to the
recovery of oxidized carbene complex along with oxazolone 2a.
Based on these reactions, the best yield was found to be
40–42% (Table 4, entries 1 and 2) despite the use of a catalyst
(Table 4, entries 5–9).
Fig. 7 ORTEP representation of 6 with ellipsoids drawn at the 50%
probability level.
Table 4 Analysis of the effect of reaction conditions in the synthesis of 6
Entrya
Base
T (°C)
t (min)
Catalystc
Yield (%)
1
Et3N
Et3N
Et3N
LDA
Et3N
Et3N
Et3N
Et3N
Et3N
rt
rt
Reflux
−70
rt
−70
rt
−70
−70
180
180
180
120
20
90
90
—
—
—
—
AgOAc
AgOAc
CuOAc
CuOAc
CuBr
40
42
20
15
35
32
37
36
32
2b
3
4
5c
6c
7c
8c
9c
A plausible mechanism is depicted in Scheme 7, wherein
the initial step is a nucleophilic 1,6-addition. At this stage, as
discussed above (Scheme 3), deprotonated structure A leads to
the intermediate H, which is congruent with reported organic
analogues.29 Then, H suffers a 1,4-nucleophilic attack to gene-
90
90
a 1.0 mmol of 1h, 2.1 mmol of 2a, 2.1 mmol of Et3N, THF (10 mL).
b 1.0 mmol of 1h, 4.0 mmol of 2a, 2.1 mmol of base, THF (10 mL).
c Catalyst (20 mol%).
Scheme 7 Proposed mechanism of formation of 6 from Fischer carbene complexes.
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rate J, and after N-addition to the carbenic carbon, the (CO)5Cr added. Then 3.9 mmol (3.0 equiv., ρ = 1.511 g mL−1) of tri-
group experiences a [1,3] shift as previously described30 to fluoroacetic anhydride was incorporated dropwise and the
produce 6 by reductive elimination of L. Finally, compound 6 mixture was stirred for 4 h at room temperature. After this
is transformed efficiently into 7 when exposed to acid medium time, the reaction crude was poured into a separation funnel,
(silica gel/CHCl3).
washed with a saturated solution of NaHCO3 (3 × 15 mL) and
then extracted with CH2Cl2. The organic fractions were evapor-
ated under reduced pressure and the pure compounds 2a–d
were recuperated as viscous liquids.
Conclusions
4-Phenyl-2-(trifluoromethyl)oxazol-5(2H)-one (2a).31 Yield:
95%; yellow solid. 1H NMR (500 MHz, CDCl3) δ: 8.42 (d,
In this study, the unusual reactivity of fluorinated oxazolidi-
nones 2a–d towards alkynyl Fischer carbenes 1a–g is presented
and discussed with relation to the regioselective synthesis of
pyrrole derivatives 4a–q. This methodology demonstrated good
efficiency and wide applicability to a variety of molecular
scaffolds. According to isotopic labeling experiments (4g) and
cycloadditions performed with an organic analogue of car-
benes (5), the presence of the metal fragment is crucial for the
loss of the –CF3 moiety. At the same time, an interesting
cascade process involving 1,4-, 1,6- and 1,2-nucleophilic
addition steps, observed for carbene 1h, is a rare example of
the preparation of a bicyclic pyrroloxazolone framework (6),
which enhances the value of the Fischer-carbene-mediated
protocol.
3
3JH–H = 5.0 Hz, 2H, H-6,6′), 7.64 (t, JH–H = 7.5 Hz, 1H, H-8),
3
3
7.53 (t, JH–H = 7.8 Hz, 2H, H-7,7′), 6.25 (q, JH–F = 5.0 Hz, 1H,
H-1). 13C NMR (125 MHz (CDCl3) δ: 162.7 (CvO), 160.6 (C-3),
133.9 (C-8), 129.1 (C-6) 129.0 (C-7), 127.2 (C-5), 120.4 (q, 1JC–F
280.0 Hz, C-2), 92.4 (q, 1JC–C = 91.5 Hz, C-1). CCDC 1912568.†
=
4-Benzyl-2-(trifluoromethyl)oxazol-5(2H)-one (2b).31 Yield:
60%; yellow liquid. 1H NMR (500 MHz, CDCl3) δ: 7.25–7.20 (m,
2
5H, H-7–9, 7′,8′), 5.99–5.96 (m, 1H, H-1), 3.96–3.89 (dd, JH–H
=
5.0 Hz, 2H, H-5). 13C NMR (125 MHz, CDCl3) δ: 162.7 (CvO),
160.6 (C-3), 133.5 (C-6), 129.8 (C-7, 7′) 129.6 (C-8, 8′), 127.2
2
1
(C-9), 120.4 (q, JC–F = 280.0 Hz, C-2), 92.4 (q, JC–C = 91.5 Hz,
C-1), 34.8 (C-5).
4-((5-Oxo-2-(trifluoromethyl)-2,5-dihydrooxazol-4-yl)methyl)
phenyl 2,2,2-trifluoroacetate (2c).31 Yield: 89%; orange liquid.
3
1H NMR (500 MHz, CDCl3) δ: 7.35 (d, JH–H = 10.0 Hz, 2H,
3
H-8,8′), 7.15 (d, JH–H = 10.0 Hz, 2H, H-7,7′), 6.06–6.03 (m, 1H,
Experimental section
Chemistry
H-1), 4.03–3.96 (m, 1H, H-5). 13C NMR (125 MHz (CDCl3) δ:
166.9 (CvO), 163.0 (C-3), 148.9 (C-9), 131.7 (C-6), 130.9
(C-8, 8′), 121.1 (C-7, 7′), 117.5 (q, 2JC–F = 283.7 Hz, C-2), 93.2 (q,
1JC–C = 70.0 Hz, C-1), 33.8 (C-5).
The organometallic reactions were carried out under nitrogen.
The THF was purchased in TEDIA (http://www.T2-P2.com,
#TS2123-001, with 0.02% of water). On the other hand, the
Et2O was acquired in Merck (#296082) and was distilled
over Na. Likewise, dichloromethane (Sigma-Aldrich, #34859)
was distilled over CaCl2. The products were purified by column
chromatography on silica gel (MN Kieselgel 60, 230–400 mesh).
Mixtures of ethyl acetate and hexane were used as eluents.
Analytical TLC was employed on aluminum sheets (silica gel 60
F/UV254) with visualization carried out with UV light and
4-Methyl-2-(trifluoromethyl)oxazol-5(2H)-one (2d).31 Yield:
95%; orange liquid. 1H NMR (500 MHz, CDCl3) δ: 6.02–6.00
(m, 1H, H-1), 2.33 (s, 1H, H-5). 13C NMR (125 MHz (CDCl3) δ:
2
166.0 (CvO), 163.7 (C-3), 120.0 (q, JC–F = 280.0 Hz, C-2), 93.2
(q, 1JC–C = 70.0 Hz, C-1), 14.2 (C-5).
General method for the synthesis of pyrroles 4a–g and 4h–q
In a 100 mL dried round-bottom flask provided with a stirring
bar, 0.9 mmol (1.1 equiv.) of the corresponding oxazolone
2a–d and 0.095 mmol of AgOAc (10 mol%) were added and
this mixture was purged for 5 min under a nitrogen flow.
Later, 40 mL of THF (TEDIA, http://www.T2-P2.com, #TS2123-
001, with 0.02% of water) were added into the container and
0.9 mmol of Et3N (0.5% water, Sigma-Aldrich #T0886) was
finally incorporated into the mixture, which was then stirred
for a further 30 min at room temperature. Meanwhile, in a sep-
arate flask, 0.86 mmol (1.0 equiv.) of the corresponding
alkynyl Fischer carbene 1a–h was dissolved in 10 mL of THF
and maintained under an inert atmosphere. Once the required
reaction time, the solution of the carbene was slowly trans-
ferred via cannula into the flask with the oxazolone and then
allowed to react for 20–180 min, as judged by TLC monitoring.
For 4g, the D2O was added to the mixture of reaction using
5 ml anhydrous THF. The crude reaction mixture was purified
iodine. Melting points were determined on
a
digital
Electrothermal 90100 melting point apparatus and are uncor-
rected. 1H and 13C NMR spectra (CDCl3, DMSO-d6) were
recorded with a Varian Gemini 300 MHz, a Varian VNMR
System 500 MHz, a Bruker Ascend 400 MHz, or a Bruker
Ultrashield 500 MHz spectrometer. All chemical shifts are
reported in ppm relative to Me4Si and CHCl3 used as the
internal standard. IR spectra were recorded on potassium
bromide plates with a PerkinElmer Spectrum 100 FT-IR spectro-
photometer. High-resolution mass spectra (HRMS) were deter-
mined with electrospray ionization on a Bruker micrOTOF-Q II
or electronebulization ionization on a Bruker QTOF mass
spectrometer. X-ray data were collected on Oxford Diffraction
Gemini “A” diffractometer with a CCD area detector.
General method for the synthesis of oxazolones 2a–d
In a 25 mL round-bottom flask containing a stirring bar, by column chromatography (silica gel, 9 : 1 Hex : AcOEt) and
1.3 mmol (1.0 equiv.) of the appropriate amino acid was isolated products were recovered under reduced pressure.
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Ethyl 4,5-diphenyl-1H-pyrrole-3-carboxylate (4a).32 Yield: 59.4 (C-16), 21.2 (C-14), 14.2 (C-17). HRMS (ESI+): m/z calcd for
88%; white crystals; mp: 203–205 °C. IR (ν cm−1) 3327 (N–H), C20H19NO2 [M + Na]+ 328.1313, found 328.1319.
1685 (CvO). 1H NMR (500 MHz, CDCl3) δ: 8.67 (s, 1H, H-1),
Ethyl 4-cyclopropyl-5-phenyl-1H-pyrrole-3-carboxylate (4f).
3
1
7.52 (d, JH–H = 5.0 Hz, 1H, H-2), 7.29–7.13 (m, 10H, Ph-H), Yield: 72%; white solid; mp: 114–115 °C. H NMR (400 MHz,
3
3
3
4.13 (q, JH–H = 7.5 Hz, 2H, H-15), 1.14 (t, JH–H = 7.5 Hz, 3H, CDCl3) δ: 8.34 (s, 1H, H-1), 7.50 (d, JH–H = 7.6 Hz, 2H, H-7,7′),
H-16). 13C NMR (125 MHz, CDCl3) δ: 164.7 (C-14), 134.9 (C-10), 7.42 (d, JH–H = 3.0 Hz, 1H, H-2), 7.40 (t, JH–H = 7.6 Hz, 2H,
3
3
132.0 (C-6), 130.8 (C-8), 130.1 (C-12), 128.5 (C-9), 127.6 (C-7), H-8,8′), 7.30 (t, 3JH–H = 7.6 Hz, 1H, H-9), 4.31 (q, 3JH–H = 7.0 Hz,
3
3
127.0 (C-13), 126.9 (C-11), 126.5 (C-2), 124.2 (C-4), 122.8 (C-5), 2H, H-11), 1.96 (q, JH–H = 5.6 Hz, 1H, H-10), 1.37 (t, JH–H
=
116.4 (C-3), 59.5 (C-15), 14.1 (C-16). HRMS (ESI+): m/z calcd 7.0 Hz, 3H, H-15), 0.82 (q, JH–H = 5.6 Hz, 2H, H-11), 0.24 (q,
3
for C19H17NO2 [M + Na]+ 314.1157, found 314.1159. CCDC 3JH–H = 5.6 Hz, H-12). 13C NMR (100 MHz, CDCl3) δ: 165.0
1912115.†
(C-13), 132.5 (C-6), 131.5 (C-5), 128.2 (C-7), 127.3 (C-8), 126.5
Ethyl 4-(2-methoxyphenyl)-5-phenyl-1H-pyrrole-3-carboxylate (C-9), 123.8 (C-2) 122.9 (C-4), 117.8 (C-3), 59.5 (C-14), 14.5
(4b). Yield: 80%; colorless crystals; mp: 171–172 °C. IR (C-15), 8.45 (C-11,12), 7.21 (C-10).
1
(ν cm−1) 3281 (N–H), 1692 (CvO). H NMR (500 MHz, CDCl3)
Ethyl 4,5-diphenyl-1H-pyrrole-3-carboxylate-2-d (4g). Yield:
δ: 8.68 (s, 1H, H-1), 7.52 (d, JH–H = 3.0 Hz, 1H, H-2), 7.27–7.09 80%; colorless crystals; mp: 202–204 °C. IR (ν cm−1) 3327
(m, 7H, CH Ar), 6.91–6.86 (m, 2H, CH Ar) 4.10 (q, JH–H
3
3
1
=
(N–H), 1685 (CvO). H NMR (500 MHz, CDCl3) δ: 8.52 (s, 1H,
3
3
7.0 Hz, 2H, H-18), 3.61 (s, 3H, H-16), 1.09 (t, JH–H = 7.0 Hz, H-1), 7.25–7.14 (m, 10H, H-1, Ph-H), 4.15 (q, JH–H = 5.0 Hz,
3H, H-19). 13C NMR (125 MHz, CDCl3) δ: 164.7 (C-17), 157.9 2H, H-15), 1.15 (t, JH–H = 5.0 Hz, 3H, H-16). 13C NMR
3
(C-11), 132.4 (C-6), 132.0 (C-15), 130.1 (C-13), 128.4 (C-8), 128.3 (125 MHz, CDCl3) δ: 164.7 (C-14), 134.9 (C-10), 132.0 (C-6),
(C-9), 126.7 (C-10), 126.3 (C-7), 124.3 (C-3), 123.9 (C-14), 120.2 130.8 (C-8), 130.1 (C-12), 128.5 (C-9), 127.6 (C-7), 127.0 (C-13)
(C-12), 118.6 (C-4), 117.3 (C-5), 110.7 (C-2), 59.3 (C-18), 55.4 (C-11), 126.9 (C-2), 126.5 (C-4), 124.2 (C-5), 122.8 (C-3), 116.4,
(C-16), 14.1 (C-19). HRMS (ESI+): m/z calcd for C20H19NO3 59.5 (C-15), 14.1 (C-16). HRMS (ESI+): m/z calcd for
[M + Na]+ 344.1263, found 344.1269. CCDC 1912414.†
C19H16DNO2 292.1322, found 292.1338.
Ethyl 4-(4-methoxyphenyl)-5-phenyl-1H-pyrrole-3-carboxylate
Ethyl 5-benzyl-4-phenyl-1H-pyrrole-3-carboxylate (4h). Yield:
1
(4c). Yield: 87%; brown solid; mp: 188–190 °C. IR (ν cm−1
)
50%; white solid; mp: 126–127 °C. H NMR (400 MHz, CDCl3)
3304 (N–H), 1683 (CvO). 1H NMR (500 MHz, CDCl3) δ: 8.68 (s, δ: 1.16 (t, JH–H = 7.1 Hz, 3H, H-13), 3.9 (s, 2H, H-6) 4.14 (c,
3
3
1H, H-1), 7.52 (d, JH–H = 5.0 Hz, 1H, H-2), 7.11–7.09 (m, 7H, 3JH–H = 7.1 Hz 2H, H-12), 8.18 (s, 1H, H-1), 7.20–737 (m, 5H,
3
CH Ar), 6.91–6.86 (m, 2H, CH Ar), 4.10 (q, JH–H = 7.5 Hz, 2H, H-2, H-9,9′ and H-16,16′), 7.17–7.30 (m, 4H, H-10, H-15,15′,
3
3
H-16), 3.64 (s, 3H, H-14), 1.09 (t, JH–H = 7.5 Hz, 3H, H-17). H-17),7.12 (d, JH–H = 7.6 Hz, 2H, H-8,8′) 13C NMR (100 MHz,
13C NMR (125 MHz, CDCl3) δ: 164.7 (C-15), 157.9 (C-13), 132.4 CDCl3) δ: 164.8 (C-11), 139.0 (C-7), 134.9 (C-14), 130.5
(C-6), 132.0 (C-9), 130.1 (C-10), 128.4 (C-14), 126.7 (C-8), 126.3 (C-16,16′) 129.1 (C-5), 128.8 (C-15,15′), 128.5 (C-8,8′), 127.6
(C-7), 124.0 (C-3), 120.2 (C-12), 118.5 (C-4), 117.2 (C-5), 110.7 (C-9,9′), 126.6 (C-17), 126.4 (C-10), 123.5 (C-2), 123.2 (C-4),
(C-2), 59.3 (C-16), 55.4 (C-14), 14.1 (C-17). HRMS (ESI+): m/z 114.8 (C-3), 59.3 (C-12), 14.2 (C-13). HRMS (ESI+): m/z calcd for
calcd for C20H19NO3 [M + Na]+ 344.1263, found 344.1270. C20H19NO2 [M
CCDC 1912422.† 1912569.†
Ethyl 5-benzyl-4-(2-methoxyphenyl)-1H-pyrrole-3-carboxylate
+
Na]+ 328.1313, found 328.1319. CCDC
Ethyl
5-phenyl-4-(thiophen-3-yl)-1H-pyrrole-3-carboxylate
(4d). Yield: 90%; brown crystals; mp: 178–179 °C. IR (ν cm−1
)
(4i). Yield: 48%; brown solid; mp: 190–192 °C. IR (ν cm−1
)
3327 (N–H), 1681 (CvO). 1H NMR (500 MHz, CDCl3) δ: 8.72 (s, 3304 (N–H), 1683 (CvO). 1H NMR (400 MHz, CDCl3) δ: 8.29 (s,
1H, H-1), 7.50 (d, JH–H = 5.0 Hz, 1H, H-2), 7.27–7.17 (m, 6H, 1H, 1-H), 7.38–6.93 (m, 9H, H-8,8′,9,9′,10, H-13 to H-16), 4.06
3
2
3
3
H-7, H-8, H-9 and H-14), 7.10 (dd, JH–H = 1.0 Hz, 1H, H-12), (q, JH–H = 7.0 Hz, 2H, H-19), 3.80 (d, JH–H = 5.2 Hz, 2H, H-6),
7.05 (dd, JH–H = 1.0 Hz, H-13), 4.17 (q, J = 7.5 Hz, 2H, H-15), 3.71 (s, 3H, H-17), 1.07 (t, JH–H = 7.0 3H, Hz, H-20). 13C NMR
2
3
1.20 (t, JH–H = 7.5 Hz, 3H, H-16). 13C NMR (125 MHz, CDCl3) (100 MHz, CDCl3) δ: 165.1 (C-18), 157.7 (C-12), 139.1 (C-7),
3
δ: 164.7 (C-14), 134.2 (C-10), 132.1 (C-6), 130.8 (C-9), 130.5 129.4 (C-5), 128.7 (C-8), 128.6 (C-6), 126.4 (C-10), 124.1 (C-4),
(C-8), 128.5 (C-12), 127.1 (C-13), 124.3 (C-7), 123.9 (C-11), 123.8 123.2 (C-2), 118.6 (C-14), 115.6 (C-3), 59.3 (C-19), 55.3 (C-17),
(C-2), 117.2 (C-3), 116.4 (C-4), 59.5 (C-15), 14.2 (C-16). HRMS 32.0 (C-6), 14.0 (C-20). HRMS (ESI+): m/z calcd for C21H21NO3
(ESI+): m/z calcd for C17H15NO2S [M + Na]+ 320.0721, found [M + Na]+ 358.1419, found 358.1441.
320.0724. CCDC 1912423.†
Ethyl 5-benzyl-4-(4-methoxyphenyl)-1H-pyrrole-3-carboxylate
Ethyl 5-phenyl-4-(4-tolyl)-1H-pyrrole-3-carboxylate (4e). Yield: (4j). Yield: 32%; white solid; mp: 192–193 °C. IR (ν cm−1) 3304
80%; colorless crystals; mp: 206–208 °C. IR (ν cm−1) 3335 (N–H), 1683 (CvO). H NMR (500 MHz, CDCl3) δ: 8.20 (s, 1H,
1
1
(N–H), 1693 (CvO). H NMR (500 MHz, CDCl3) δ: 8.66 (s, 1H, H-1), 7.26 (s, 1H, H-2), 7.21–7.13 (m, 5H, H-8–10), 7.03 (d,
3
3
H-1), 7.49 (d, JH–H = 4.0 Hz, 1H, H-2), 7.25–7.14 (m, 7H, CH 3JH–H = 10.0 Hz, 2H, H-12), 6.83 (d, JH–H = 10.0 Hz, 2H, H-13),
3
3
3
Ar), 7.09 (d, JH–H = 10.0 Hz, 2H, H-11,11′), 4.13 (q, JH–H = 7.5 4.05 (q, JH–H = 10.0 Hz, 2H, H-17), 3.79 (s, 2H, H-6), 3.73 (s,
Hz, 2H, H-16), 2.34 (s, 3H, H-14), 1.14 (t, JH–H = 7.5 Hz, 3H, 3H, H-15), 1.09 (t, JH–H = 10.0 Hz, 3H, H-18). 13C NMR
H-17). 13C NMR (125 MHz, CDCl3) δ: 164.6 (C-15), 136.0 (C-10), (100 MHz, CDCl3) δ: 164.9 (C-16), 158.2 (C-14), 139.0 (C-7),
132.2 (C-13), 131.7 (C-6), 130.6 (C-12), 130.0 (C-3), 128.4 (C-8), 131.4 (C-12), 128.9 (C-5), 128.6 (C-8), 128.4 (C-9), 127.1 (C-11),
127.0 (C-7), 126.8 (C-9), 124.1 (C-2), 122.8 (C-4), 116.3 (C-5), 126.5 (C-10), 123.4 (C-2), 122.7 (C-4), 114.6 (C-3), 113.0 (C-13),
3
3
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59.3 (C-17), 55.1 (C-15), 31.7 (C-6), 14.2 (C-18). HRMS (ESI+): 129.7 (C-12), 129.4 (C-13), 128.3 (C-5), 127.4 (C-9), 123.3 (C-4),
m/z calcd for C21H21NO3 [M + Na]+ 358.1419, found 358.1440.
122.8 (CF3), 115.6 (C-3), 59.4 (C-18), 29.6 (C-6), 21.2 (C-16),
Ethyl 5-benzyl-4-(thiophen-3-yl)-1H-pyrrole-3-carboxylate (4k). 14.0 (C-19). HRMS (ESI+): m/z calcd for C20H19NO2 [M + Na]+
1
Yield: 45%; white solid; mp: 178–179 °C. H NMR (500 MHz, 328.1313, found 328.1319.
CDCl3) δ: 8.06 (s, 1H, H-1), 7.29 (s, 1H, H-2), 7.27–7.17 (m, 6H,
Ethyl 5-methyl-4-phenyl-1H-pyrrole-3-carboxylate (4p).33 Yield:
2
H-7, H-8, H-9 and H-14), 7.10 (dd, JH–H = 1.0 Hz, 1H, H-12), 60%; white solid; mp: 134–138 °C. IR (ν cm−1) 3304 (N–H),
2
3
7.05 (dd, JH–H = 1.0 Hz, H-13), 4.10 (q, JH–H = 10.0 Hz, 2H, 1683 (CvO). 1H NMR (500 MHz, CDCl3) δ: 8.22 (s, 1H, H-1),
3
3
H-16), 3.88 (s, 2H, H-6), 3.79 (s, 2H, H-6), 1.14 (t, JH–H = 10.0 7.29–7.19 (m, 6H, H-2,8–10), 4.08 (q, JH–H = 10.0 Hz, 2H,
Hz, 3H, H-17). 13C NMR (100 MHz, CDCl3) δ: 164.9 (C-15), H-12), 2.11 (s, 3H, H-6), 1.09 (t, JH–H = 5.0 Hz, 3H, H-13).
3
158.2 (C-14), 139.0 (C-7), 131.4 (C-12), 128.9 (C-5), 128.6 (C-8), 13C NMR (125 MHz, CDCl3) δ: 164.9 (C-11), 135.2 (C-7), 130.4
128.4 (C-9), 127.1 (C-11), 126.5 (C-10), 123.4 (C-2), 122.7 (C-4), (C-9), 127.4 (C-8), 126.1 (C-2), 122.7 (C-4), 122.3 (C-5), 123.3
114.6 (C-3), 113.0 (C-13), 59.3 (C-17), 55.1 (C-15), 31.7 (C-6), (C-4), 114.8 (C-3), 59.7 (C-12), 14.0 (C-13), 11.4 (C-6).
14.2 (C-17). HRMS (ESI+): m/z calcd for C18H17NO2S [M + Na]+
Ethyl 4-(4-methoxyphenyl)-5-methyl-1H-pyrrole-3-carboxylate
334.0878, found 334.0901.
(4q).34 Yield: 55%; white solid; mp: 116–119 °C. 1H NMR
3
Ethyl 5-benzyl-4-(p-tolyl)-1H-pyrrole-3-carboxylate (4l). Yield: (500 MHz, CDCl3) δ: 8.61 (s, 1H, H-1), 7.15 (d, JH–H = 10.0 Hz,
60%; white solid; mp: 206–208 °C; IR (ν cm−1) 3335 (N–H), 2H, H-8), 7.07 (d, JH–H = 10.0 Hz, 2H, H-2), 6.82 (s, 1H, H-2),
3
1
3
1693 (CvO). H NMR (500 MHz, CDCl3), δ: 7.99 (s, 1H, H-1), 4.05 (q, JH–H = 10.0 Hz, 2H, H-12), 3.74 (s, 3H, H-10′), 1.18 (t,
3
7.27 (s, 1H, H-2), 7.23–7.14 (m, 5H, H-8–10), 7.10 (d, JH–H
=
3JH–H = 5.0 Hz, 3H, H-13). 13C NMR (125 MHz, CDCl3) δ: 164.9
3
5.0 Hz, 2H, H-12), 7.05 (d, JH–H = 5.0 Hz, 2H, H-13), 4.07 (c, (C-12), 158.0 (C-10), 135.2 (C-7), 130.4 (C-9), 127.4 (C-8), 126.1
3JH–H = 5.0 Hz, 2H, H-17), 3.82 (s, 2H, H-6), 2.29 (s, 3H, (C-2), 122.7 (C-7), 122.3 (C-5), 123.3 (C-5), 114.8 (C-3), 59.7
3
H-15), 1.10 (t, JH–H
=
10.0 Hz, 3H, H-18). 13C NMR (C-12), 14.0 (C-13), 11.4 (C-6). HRMS (ESI+): m/z calcd for
(125 MHz, CDCl3) δ: 164.8 (C-16), 139.1 (C-7), 135.8 (C-14), C15H17NO3 [M + Na]+ 282.1106, found 282.1103.
131.7 (C-11), 130.3 (C-13), 128.9 (C-10), 128.6 (C-8), 128.4
Dimethyl-2-phenyl-5-(trifluoromethyl)-1H-pyrrole-3,4-dicarb-
(C-9), 128.3 (C-12), 126.5 (C-2), 123.4 (C-5), 123.1 (C-4), 114.6 oxylate (5).35 Yield: 40%; white solid. 1H NMR (400 MHz,
(C-3), 59.2 (C-17), 31.7 (C-6), 21.1 (C-15), 14.2 (C-18). HRMS CDCl3) δ: 9.75 (s, 1H, H-1), 7.46–7.35 (m, 5H, H-7, 7′, H-8,8′ and
(ESI+): m/z calcd for C21H21NO2 [M + Na]+ 342.1470, found H-9), 3.85 (s, 3H, H-11), 3.70 (s, 3H, H-13). 13C NMR (100 MHz,
342.1491.
CDCl3) δ: 164.5 (C-13), 163.5 (C-11), 136.1 (C-6), 129.4 (C-9),
1
5-Benzyl-4-(tert-butyl)-1H-pyrrole-3-carbaldehyde (4m). Yield: 129.3 (C-8), 128.5 (C-7), 120.4 (q, JC–F = 40.0 Hz, C-2), 119.9 (q,
38%; white solid. 1H NMR (500 MHz, CDCl3) δ: 9.95 (s, 1H, 2JC–F = 267.0 Hz, C-14), 114.0 (C-3), 52.5 (C-11), 52.0 (C-13).
H-13), 8.53 (s, 1H, H-1), 7.20–7.04 (m, 5H, H-2,8,9,10), 4.17 (s,
Synthesis of bicyclic compounds 6 and 7
2H, H-6), 0.17 (s, 9H, H-12). 13C NMR (125 MHz, CDCl3) δ:
187.0 (C-13), 141.2 (C-7), 136.1 (C-5), 129.2 (C-8), 128.9 (C-9), Following the general procedure for the synthesis of pyrroles 4,
127.4 (C-10), 127.2 (C-2), 126.0 (C-4), 128.3 (C-12), 126.5 (C-2), compound 6 was obtained in the absence of a catalyst after
123.4 (C-5), 123.1 (C-4), 125.0 (C-3), 32.9 (C-6), 0.90 (C-11), 0.89 180 min of reaction when 1.0 mmol of 1h and 2.1 mmol of
(C-12). HRMS (ESI+): m/z calcd for C18H23NO2 [M + Na]+ oxazolone 2a were combined. Compound 7 was isolated from
308.1626, found 308.1621
the chloroform-based mixture of 6 stirred for 2 h at room
Ethyl 4-phenyl-5-(4-(2,2,2-trifluoroacetoxy)benzyl)-1H-pyrrole- temperature in presence of SiO2.
3-carboxylate (4n). Yield: 45%; white solid; mp: 205–206 °C.
(Z)-5-Ethoxy-7-(2-(5-oxo-4-phenyl-2-(trifluoromethyl)-2,5-
1H NMR (500 MHz, CDCl3) δ: 8.47 (s, 1H, H-1), 7.22–7.14 (m, dihydrooxazol-2-yl)cyclohexylidene)-3-phenyl-7a-(trifluoro-
3
6H, H-2,13–15), 6.77 (d, JH–H = 5.0 Hz, 2H, H-9), 6.57 (d, methyl)-7,7a-dihydropyrrolo[2,1-b]oxazol-2(3H)-one (6). Yield:
3JH–H = 10.0 Hz, 2H, H-8), 4.01 (m, 2H, H-17), 3.64 (s, 2H, H-6), 40%; yellow crystals; mp: 203–205 °C. 1H NMR (500 MHz,
3
1.01 (t, JH–H = 10.0 Hz, 3H, H-18). 13C NMR (125 MHz, CDCl3) CDCl3) δ: 8.47 (d, J = 5.0 Hz, 2H, H-26), 7.67–7.35 (m, 8H,
δ: 171.7 (C-11), 165.9 (C-16), 154.7 (C-10), 134.9 (C-7), 130.5 H-27, 28, 10–12), 4.90 (s, 1H, H-2), 4.83 (s, 1H, H-7),
(C-12), 130.4 (C-8), 129.8 (C-15), 129.4 (C-13), 127.5 (C-5), 126.3 4.00–3.96 (q, J = 5.0 Hz, 2H, H-29), 2.29 (d, J = 10.0 Hz, 1H,
(C-2), 123.9 (C-4), 122.7 (CF3), 115.5 (C-9), 60.6 (C-17), 22.6 H-15), 2.09–2.02 (m, 2H, H-19), 1.92–1.68 (m, 4H, H-16,17),
(C-6), 14.0 (C-18). HRMS (ESI+): m/z calcd for C20H22NNaO4 1.41–1.33 (m, 2H, H-18), 1.30 (t, J = 5.0 Hz, 3H, H-30).
[M + Na]+ 420.1399, found 420.1402
13C NMR (125 MHz, CDCl3) δ: 169.9 (C-3), 162.3 (C-22),
Ethyl 4-(p-tolyl)-5-(4-(2,2,2-trifluoroacetoxy)benzyl)-1H-pyrrole- 133.6 (C-8), 132.0 (C-23), 131.5 (C-14), 131.2 (C-6), 131.0 (C-9),
3-carboxylate (4o). Yield: 30%; white solid; mp: 196–197 °C. [129.1, 129.0, 128.5, 128.4, 127.9, 127.6, 126.8 (C-Ph)], 126.8
3
1H NMR (500 MHz, CDCl3) δ: 8.04 (s, 1H, H-1), 7.45 (d, JH–H
=
(C-20), 82.5 (C-5), 66.7 (C-29), 61.7 (C-7), 30.8 (C-18), 30.1
3
5.0 Hz, 1H, H-2), 7.28 (d, JH–H = 5.0 Hz, 2H, H-13), 7.09 (d, (C-19), 27.7 (C-15), 26.2 (C-17), 22.0 (C-16), 14.2 (C-30). CCDC
3JH–H = 10.0 Hz, 2H, H-9), 6.90 (d, JH–H = 10.0 Hz, 2H, H-14), 1911540.†
3
3
3
6.68 (d, JH–H = 10.0 Hz, 2H, H-9), 4.07 (q, JH–H = 5.0 Hz, 2H,
(Z)-7-(2-(5-Oxo-4-phenyl-2-(trifluoromethyl)-2,5-dihydroox-
azol-2-yl)cyclohexylidene)-3-phenyl-7a-(trifluoromethyl)dihydro-
3
H-18), 3.74 (s, 2H, H-6), 2.29 (s, 3H, H-16), 1.10 (t, JH–H
=
5.0 Hz, 3H, H-19). 13C NMR (125 MHz, CDCl3) δ: 165.0 (C-11), pyrrolo[2,1-b]oxazole-2,5(3H,6H)-dione (7). Yield: 40%; white
154.4 (C-17), 135.9 (C-10), 131.7 (C-7), 130.8 (C-15), 130.3 (C-8), solid; mp: 181–182 °C. IR (ν cm−1) 3327 (N–H), 1685 (CvO).
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1H NMR (500 MHz, CDCl3) δ: 8.48 (d, J = 5.0 Hz, 2H, H-26),
7.69–7.35 (m, 8H, H-27,28,10–12), 5.64 (s, 1H, H-2), 3.40 (dd,
2JH–H = 20.0, 2H, H-7), 2.28–2.17 (m, 2H, H-15), 2.06–2.01 (m,
2H, H-19), 1.75–1.71 (m, 2H, H-16), 1.58–1.56 (m, 2H, H-17),
1.39–1.36 (m, 2H, H-18). 13C NMR (125 MHz, CDCl3) δ: 174.3
(C-3), 167.9 (C-8), 162.5 (C-22), 160.1 (C-23), 143.2 (C-9), 134.1
(C-14), 131.7 (C-6), [129.2, 129.1, 128.7, 128.6, 125.8 (C-Ph)],
127.2 (CF3-21), 121.8 (CF3-13), 57.1 (C-2), 40.5 (C-9), 37.1 (C-7),
30.3 (C-18), 28.1 (C-15), 26.7 (C-17), 21.7 (C-16). HRMS (ESI+):
m/z calcd for C29H22F6N2O5 [M + Na]+ 615.1331, found
615.1332.
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