Tandem one-pot synthesis of polysubstituted NH-pyrroles involving the palladium-catalyzed intramolecular oxidative amination of the zinc bromide complex of β-enamino esters

Article abstract of DOI:10.1021/jo501672c

The Pd-catalyzed oxidative olefin amination of the zinc bromide complex intermediate, formed by the sequential reaction of nitriles with a Reformatsky reagent and 1-alkynes, affords pyrrole derivatives in good to excellent yields. This tandem protocol pro

Full text of DOI:10.1021/jo501672c

Article
pubs.acs.org/joc
Tandem One-Pot Synthesis of Polysubstituted NH-Pyrroles Involving
the Palladium-Catalyzed Intramolecular Oxidative Amination of the
Zinc Bromide Complex of β‑Enamino Esters
Ju Hyun Kim, Suh Young Choi, Jean Bouffard, and Sang-gi Lee*
Department of Chemistry and Nano Science (BK 21 Plus), Ewha Womans University, 120-750 Seoul, Korea
S
* Supporting Information
ABSTRACT: The Pd-catalyzed oxidative olefin amination of the
zinc bromide complex intermediate, formed by the sequential
reaction of nitriles with a Reformatsky reagent and 1-alkynes,
affords pyrrole derivatives in good to excellent yields. This tandem
protocol provides a simple, efficient, and atom- and pot-
economical way to quickly build polysubstituted NH-pyrroles
starting from readily available reagents in a regiocontrolled
manner with a broad substrate scope and high functional group
tolerance. In contrast, the Pd-catalyzed oxidative olefin amination
of an isolated α-vinyl-β-enamino ester did not proceed effectively, but the reaction efficiency can be restored by addition of n-
BuZnBr or Zn(OAc)2, indicating the crucial role of the zinc complex in this transformation. The synthetic utility of this protocol
is exemplified by the rapid synthesis of pyrrolophenanthrenes and pyranopyrrolones through selective Pd- and Cu-catalyzed C−
C and C−O bond-forming reactions.
intermediate B may serve as a viable substrate for palladium-
catalyzed intramolecular oxidative aminations to provide
pyrroles 3, given that, under the reaction conditions, the
intermediate B may be in equilibrium with the unchelated
isomer B′, facilitating the cyclization step (Scheme 1). In a
preliminary communication, the intermediate B (R2 = o-Cl-Ph),
formed by tandem reaction of A with o-chlorophenyl acetylene,
was utilized as a common precursor for palladium catalyst-
controlled divergent synthesis of pyrrole and quinoline.9
Herein, we report the details and expand on our studies of
this simple protocol that provides an efficient and atom- and
pot-economic way to quickly build regiodefined pyrrole
frameworks. Furthermore, we also report for the first time
our important finding that the Pd-catalyzed oxidative olefin
amination of the isolated α-vinyl-β-enamino ester does not
proceed effectively, but that the reaction efficiency can be
restored by addition of Zn(OAc)2 or n-BuZnBr, indicating that
the use of zinc complex intermediate B is crucial for the
intramolecular oxidative olefin amination reaction. Finally, we
disclose here a new divergent conversion of a pyrrole having
chlorophenyl and ester functionalities to pyrrolophenathrene
and pyranopyrrolone derivatives, demonstrating the synthetic
utility of this tandem process.
INTRODUCTION
■
The pyrrole moiety is a widespread scaffold found in natural
products, biologically active compounds,1 as well as in dyes,
pigments, and other functional materials.2 This broad utility has
made pyrroles long-standing synthetic targets and has spurred
extensive efforts toward the development of efficient methods
to prepare this important heterocyclic compound.3 Recent
advances in transition-metal-catalyzed reactions have provided
new approaches for the construction of the pyrrole ring.4 For
example, the direct pyrrole-forming annulation using 1-alkynes
remained elusive until the discovery of silver-catalyzed alkyne-
isocyanide click reactions (Scheme 1a).5a,b Pd- or Pd/Cu-
catalyzed addition/cyclization/tautomerization cascades via
propargyl amines were also recently reported (Scheme
1b).5c,d In spite of these advances, many of the methods can
only provide N-substituted pyrroles, requiring an extra
synthetic step to remove the N-substituent for further synthetic
elaboration. Others offer a limited scope with respect to the
accessible substitution patterns about the pyrrole ring.6
Therefore, the development of an efficient and direct method
for the synthesis of regiocontrolled polysubstituted NH-
pyrroles starting from readily available reagents remains an
incomplete task.
During our continuing studies on the tandem use of the
Blaise reaction,7 we have found that the Blaise reaction
intermediate A, formed by reaction of nitriles 1 with
Reformatsky reagents, could react chemo- and regioselectively
with 1-alkynes to afford the corresponding α-vinylated β-
enamino esters. Mechanistic studies suggested that a zinc
bromide complex of α-vinylated β-enamino ester B was formed
as a second intermediate.8 We envisioned that the vinylated
RESULTS AND DISCUSSION
■
While large numbers of efficient transition-metal-catalyzed
intramolecular oxidative olefin aminations have been de-
Received: July 24, 2014
© XXXX American Chemical Society
A
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Scheme 1. Examples for the Syntheses of Pyrrole Rings Using 1-Alkyne Synthons, and Our Tandem Strategy for One-Pot
Synthesis of Polysubstituted NH-Pyrroles
a
Table 1. Optimization of the Reaction Conditions
b
entry
additive (equiv)
solvent
DMF
°C/h
yield (%)
1
2
3
4
5
6
Cu(OAc)2 (2.2)/AcOH (2.0)
Cu(OAc)2 (2.2)/AcOH (1.0)
Cu(OAc)2 (3.0)/AcOH (2.0)
Cu(OAc)2 (3.0)
90/4
85
70
88
52
48
37
48
DMF
90/4
DMF
90/1
DMF
110/4
110/3
110/3
90/24
90/12
110/12
110/12
110/24
110/24
Cu(OAc)2 (3.0)
DMSO
DMF/H2O
DMF
Cu(OAc)2 (3.0)
c
7
d
Cu(OAc)2 (2.2)/AcOH (2.0)
Cu(OAc)2 (2.2)/AcOH (2.0)
8
DMF
9
10
11
12
DMSO
DMSO
toluene
MeOH
15
<5
13
<5
AcONa (1.0)
pyridine (0.2)
Phen (0.2)
a
Reaction conditions: A solution of A-aa was prepared from 1a (2.29 mmol), Zn (4.59 mmol), ethyl bromoacetate (3.44 mmol), and 2a (2.52
b
mmol) in THF (0.7 mL). This solution was then diluted with the indicated solvent (6.0 mL), and Pd(OAc)2 and additives were added. Isolated
yields. Reaction under a N2 atmosphere. Reaction in the absence of Pd(OAc)2. Phen = phenanthroline.
c
d
scribed,10 the use of N-zincated amines as nitrogen sources has
not been reported. To test the feasibility of our tandem
strategy, we first investigated the Pd(OAc)2-catalyzed oxidative
olefin amination of intermediate A-aa (R1 = Ph, R = Et, X = H),
formed by the sequential reaction of benzonitrile (1a) first with
the Reformatsky reagent generated in situ from ethyl α-
bromomoacetate and zinc, followed with phenylacetylene (2a)
(Table 1). To our delight, the intramolecular oxidative olefin
amination of A-aa could be achieved upon treatment with 10
mol % Pd(OAc)2, 2.2 equiv of Cu(OAc)2, and 2.0 equiv of
AcOH in DMF under air for 4 h at 90 °C to afford the desired
pyrrole 3a in 85% overall yield (Table 1, entry 1).11 Reducing
the amount of AcOH to 1.0 equiv decreased the yield of 3a to
70% (Table 1, entry 2). By contrast, increasing the amount of
the Cu(OAc)2 oxidant to 3.0 equiv slightly raised the yield to
88% and shortened the reaction time to 1 h (Table 1, entry 3).
In the absence of AcOH, the yield of 3a was substantially
depressed (Table 1, entries 4−6). Carrying out the reaction
under a nitrogen atmosphere dramatically decreased the yield
of 3a to only 48% after 24 h (Table 1, entry 7). A control
reaction in the absence of Pd(OAc)2 did not proceed, and no
trace of pyrrole 3a was detected by TLC (Table 1, entry 8).
Other reaction conditions, developed by Larock,12 Stahl,13 and
Stoltz,14 among others,15 for PdII-catalyzed aerobic oxidative
olefin aminations, such as Pd(OAc)2/DMSO, Pd(OAc)2/
NaOAc/DMSO, Pd(OAc)2/pyridine in toluene, and other
closely related variants, were not effective (Table 1, entries 9−
12). Moreover, under the standard reaction conditions (Table
1, entry 1), the isolated α-vinylated β-enamino ester 4a could
also afford pyrrole 3a, but only in a modest 30% yield (Scheme
2). These results suggest that the tandem reaction of N-
zincated intermediate A-aa may have some advantages for PdII-
catalyzed oxidative olefin amination. Additional empirical
evidence supports the unforeseen zinc additive effect: (i) A
similarly low yield (28%) of 3a was observed from the reaction
of 4a in the absence of AcOH. (ii) The reaction efficiency with
4a could be restored in the presence of Zn(OAc)2 (2.0 equiv)
to afford 3a in 73% yield. (iii) Pretreatment of 4a with 1.0 equiv
B
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successfully incorporated to result in the corresponding
pyrroles 3g and 3h in high yields. Formation of pyrrole 3i
from the aliphatic nitrile 1i having an olefinic moiety suggested
that the vinylene group is more reactive than the internal olefin
under oxidative olefin amination conditions.
Scheme 2. Zinc Additive Effect on the Oxidative Olefin
Amination of Isolated α-Vinylated β-Enamino Ester 4a
Variation of the Reformatsky reagent did not affect the
reaction efficiency, as shown for 3j bearing an isopropyl ester in
72% yield. The scope of the reaction with respect to alkynes
was also investigated with benzonitrile 1a. Aromatic alkynes
with electron-donating methyl (2b) or methoxy (2c) groups,
and electron-withdrawing fluorine (2d) and nitrile (2e)
substitutents, in addition to aliphatic 1-hexyne 2f (R2 = n-
Butyl) and 4-phenylbutyne (2g, R2 = PhCH2CH2) were all
successfully incorporated in the corresponding pyrroles 3k−3p
in comparably good yields. The 2,4-dialkylated pyrrole 3q could
also be synthesized in 64% yield using propionitrile (1j) and 1-
hexyne (2f).
When we investigated the present protocol with the 2-
halogenated phenylacetylenes 2h (X = Cl) and 2i (X = Br), it
was found that the regioselectivity of the vinylation largely
depended on the reaction temperature (Scheme 3). For
example, the tandem reaction of the Blaise reaction
intermediate with 2-chlorophenylacetylene 2h in THF at reflux
(80 °C bath temperature) for 2 h gave the two regioisomers 4h
and 4h′ in a 5 to 1 ratio, as determined by 1H NMR analysis of
of nBuZnBr, possibly generating intermediate A-aa, also
increased the yield of 3a to 75% under the standard reaction
conditions. The observed zinc additive effect appears consistent
with the formation of a zinc complex of the β-enamino ester
that may prevent the formation of inactive palladium
complexes.
Under optimized reaction conditions, a variety of pyrroles 3
can be synthesized in a tandem one-pot manner (Table 2).
Aromatic nitriles with methyl (1b and 1c), fluorine (1d), and
alkyne substituents (1e), as well as the heteroaromatic nitrile 1f,
were well tolerated and reacted with phenylacetylene 2a to give
the pyrroles 3b−3f in high yields (65−82%). Benzyl nitrile
(1g) and sterically demanding isovaleronitrile (1h) were also
a
Table 2. Tandem One-Pot Synthesis of Various Pyrroles
a
Reactions were carried out under the optimized conditions shown in entry 1 of Table 1. Isolated yields are shown.
C
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the pyrrole 3w, formed by the sequential reaction of 3-
phenylpropionitrile (1k) with a Reformatsky reagent and 1-
chloro-2-ethynylbenzene (2i), could be converted to pyrrolo-
phenathrenes 7a and 7b, and pyranopyrrolone 8, demonstrat-
ing the synthetic utility of our tandem protocol (Scheme 5).
Scheme 3. Effects of Temperature on the Regioselectivity of
Vinylation
Scheme 5. Divergent Transformations of 3w to 7 and 8 via
Selective C−C and C−O Bond Formations
the crude reaction mixture. Decreasing the reaction temper-
ature could suppress the formation of regioisomer 4h′.
Carrying out the vinylation at 30 °C for a prolonged reaction
time (28 h) allowed for the isolation of the regioisomerically
pure 4h.
After establishing the optimal conditions for tandem
vinylation reaction with 2-halogenated phenylacetylenes, the
intermediate A-ah (X = Cl) was subjected to the standard
oxidative olefin amination reaction conditions to afford the
corresponding pyrrole 3r in 62% yield. Under the same reaction
conditions, however, the intermediate A-ai (X = Br) bearing an
aryl bromide afforded a mixture of pyrrole 3s (40%) and the
undesired quinoline 5 (13%) (Scheme 4). Formation of
quinoline 5 suggests that the rate of reoxidation of Pd(0),
generated during the catalytic cycle, to Pd(II) competes with
that of its oxidative addition to the Ar−Br bond, funnelling the
intermediate through a Buchwald−Hartwig aryl amination
reaction pathway.16 Under optimized reaction conditions, a
variety of pyrroles (3t−3z) having an o-chlorophenyl
substituent at the 3-position were successfully synthesized in
good yields.9,17
These classes of compounds were shown to have anticancer
potency, as well as interesting photoconducting and optoelec-
tronic properties.18 After N-methylation of 3w, affording S1,
the C−H at the 2-position was directly arylated with
bromobenzenes under the action of a palladium catalyst to
afford 6a (87%) and 6b (97%) in high yields. These
compounds served as common starting materials for selective
C−C and C−O coupling reactions leading to 7 and 8,
respectively. Thus, a palladium-catalyzed intramolecular C−H
bond arylation of 6a and 6b afforded the corresponding
pyrrolophenathrene derivatives 7a (81%) and 7b (78%) in high
yields.19 Alternatively, a CuTC-mediated C−O coupling,20
following hydrolysis of the ester group of 6a giving
corresponding carboxylic acid (S2), allowed access to
pyranopyrrolone 8 in a 95% overall yield over two steps.
The o-chlorophenyl and ester functionalities offered synthetic
handles for further elaboration of these pyrroles. For example,
Scheme 4. Tandem Synthesis of Pyrroles with 2-Halogenated Phenylacetylenes
D
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Scheme 6. Proposed Mechanism for the Formation of Pyrrole 3
Our mechanistic proposal for the formation of pyrrole 3 is
outlined in Scheme 6. To facilitate the oxidative ring formation,
the N-zincated nitrogen atom and olefin can adopt a more
suitable geometry through the unchelated isomer B, which may
be in equilibrium with A under the reaction conditions via
enamine−imine tautomerization. One possible catalytic reac-
tion pathway is a 5-endo-trig aminopalladation/β-H elimination
cascade route (pathway a in Scheme 6). The transformation
begins with a direct ligand substitution of Pd(OAc)2, resulting
in aminopalladate complex C and/or formation of palladium
complex C′. A 5-endo-trig cyclization through either a syn-
aminopalladation of C or an anti-aminopalladation of C′ gives
the intermediate D,21 and subsequent β-H elimination affords
pyrrole 3. The resulting palladium hydride is then reoxidized
back to Pd(OAc)2 by Cu(OAc)2 and O2/AcOH.22 Another
possible catalytic pathway that cannot be ruled out is γ-
nucleophilic substitution, forming the γ-C-palladate E (pathway
b in Scheme 6). Extrusion of AcOH from E, affording F,
followed by reductive elimination, results in intermediate G,
which isomerizes quickly to give product 3.
uncovered. The synthetic utility of the present protocol has
been demonstrated through the divergent transformation of a
pyrrole bearing 2-chlorophenyl and ester functionalities into
pyrrolophenathrenes and a pyranopyrrolone via C−C and C−
O bond formations. Given these advantages, this procedure
may hold considerable promise in drug discovery and in the
development of functional materials.
EXPERIMENTAL SECTION
■
General Methods. THF was distilled from sodium benzophenone
ketyl prior to use. Anhydrous DMF and other reagents were purchased
and used directly without further purification. The nitriles bearing
alkyne (1e) and olefin moieties (1i) were synthesized according to the
reported procedures.23 1-Chloro-2-ethynylbenzene (2i) was synthe-
sized according to the reported procedures.24 The NMR spectra were
1
recorded at 300 MHz for H, and 75.5 or 63.0 MHz for 13C. HRMS
data were obtained by electron ionization with a magnetic sector-
electronic sector double focusing mass analyzer.
General Procedure for Tandem Synthesis of Pyrroles 3. To a
stirred suspension of commercial zinc dust (300 mg, 4.59 mmol) in
THF (0.7 mL) at reflux was added a solution of methanesulfonic acid
in THF (1.0 M, 0.15 mL). After 5 min of stirring, the nitrile (2.29
mmol) was added at once. While maintaining the THF at reflux, alkyl
bromoacetate 1 (3.44 mmol) was added over 1 h using a syringe
pump, and the resulting reaction mixture was stirred for an additional
1 h. To this reaction mixture was added 1-alkyne 2 (2.52 mmol), and
the mixture was stirred for 1.5−2 h (followed by TLC). After cooling
to room temperature, the reaction mixture was diluted with DMF (6.0
mL), and then palladium(II) acetate (52 mg, 0.23 mmol), copper(II)
acetate (917 mg, 5.05 mmol), and acetic acid (0.26 mL, 4.59 mmol) in
DMF (6 mL) were added. The resulting mixture was heated in a
preheated oil bath at 90 °C under air until the vinylated intermediate
was entirely consumed, as monitored by TLC. The reaction mixture
was allowed to cool to room temperature, quenched with saturated
aqueous Na2CO3 (3 mL), and then diluted with saturated aqueous
CONCLUSION
■
We have developed a novel tandem palladium-catalyzed
intramolecular oxidative olefin amination of the zinc bromide
complex of α-vinylated β-enamino esters, which are formed by
the sequential reaction of nitriles with a Reformatsky reagent
and 1-alkynes, to afford 2,3,4-trisubstituted NH-pyrroles in
good yields for a diverse range of substrates. This protocol
provides a simple, efficient, and atom- and pot-economical way
for the regioselective assembly of pyrrole rings. Unforeseen zinc
additive effects on the PdII-catalyzed oxidative olefin amination
of isolated α-vinylated β-enamino esters have also been
E
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NH4Cl (50 mL). The organic compounds were extracted with ethyl
acetate (30 mL × 3), and the combined organic layers were dried over
anhydrous sodium sulfate, filtered, and concentrated under reduced
pressure. The residue was purified by chromatography on silica gel to
afford the corresponding NH-pyrroles 3.
ppm. HRMS (EI) Calcd m/z for C17H21NO2 [M]+: 271.1572. Found:
271.1571.
Ethyl 4-Phenyl-2-[(4E)-5-phenylpent-4-en-1-yl]-1H-pyrrole-3-
carboxylate (3i). Yield: 77% (635 mg); Eluents: n-hexane/EtOAc =
5/1; viscous brown liquid; 1H NMR (300 MHz, CDCl3) δ 1.11 (t, J =
7.1 Hz, 3H), 1.77−1.86 (m, 2H), 2.34−2.42 (m, 2H), 2.90 (t, J = 7.3
Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 6.35 (d, J = 2.4 Hz, 1H), 6.52 (d, J
= 11.6 Hz, 1H), 7.23−7.32 (m, 5H), 7.33−7.37 (m, 5H), 7.87 (brs,
1H) ppm; 13C NMR (75 MHz, CDCl3) δ 14.1, 27.1, 27.8, 29.7, 59.4,
109.5, 115.7(115.67), 115.7(115.73), 126.2, 126.8, 127.1, 127.6, 128.4,
128.9, 129.4, 132.5, 136.0, 137.6, 140.0, 165.8 ppm. HRMS (EI) Calcd
m/z for C24H25NO2 [M]+: 359.1885. Found: 359.1884.
Ethyl 2,4-Diphenyl-1H-pyrrole-3-carboxylate (3a) [CAS: 63324-
78-7]. Yield: 85% (568 mg); Eluents: n-hexane/EtOAc = 5/1 to 3/1;
brown solid; mp: 48−50 °C (lit:25 viscous oil); H NMR (300 MHz,
1
CDCl3) δ 0.91 (t, J = 7.1 Hz, 3H), 3.94 (q, J = 7.1 Hz, 2H), 6.45 (d, J
= 2.6 Hz, 1H), 7.22−7.39 (m, 10H), 9.00 (brs, 1H) ppm; 13C NMR
(75 MHz, CDCl3) δ 13.7, 60.0, 110.6, 117.7, 126.3, 127.3, 127.8,
127.9, 128.1, 128.7, 129.0, 132.4, 135.5, 137.0, 166.3 ppm.
Propan-2-yl 2,4-Diphenyl-1H-pyrrole-3-carboxylate (3j). Yield:
72% (504 mg); Eluents: n-hexane/EtOAc = 5/1 to 3/1; yellow
solid; mp: 40−42 °C; 1H NMR (300 MHz, CDCl3) δ 0.98 (d, J = 6.2
Hz, 6H), 4.90−4.98 (m, 1H), 6.62 (d, J = 2.4 Hz, 1H), 7.23−7.48 (m,
10H), 8.69 (brs, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 21.6, 67.5,
111.6, 117.4, 126.4, 127.6, 127.9, 128.1, 128.2, 128.9, 129.2, 130.8,
132.5, 135.6, 136.7, 165.6 ppm. HRMS (EI) Calcd m/z for
C20H19NO2 [M]+: 305.1416. Found: 305.1414.
Ethyl 2-(4-Methylphenyl)-4-phenyl-1H-pyrrole-3-carboxylate
(3b). Yield: 78% (546 mg); Eluents: n-hexane/EtOAc = 5/1 to 3/1;
1
pale yellow solid; mp: 108−110 °C; H NMR (300 MHz, CDCl3) δ
0.96 (t, J = 7.1 Hz, 3H), 2.33 (s, 3H), 4.01 (q, J = 7.1 Hz, 2H), 6.59 (d,
J = 2.6 Hz, 1H), 7.08−7.46 (m, 9H), 8.69 (brs, 1H) ppm ;13C NMR
(75 MHz, CDCl3) δ 13.8, 21.4, 60.0, 110.7, 117.3, 126.4, 127.6, 127.8,
128.7, 128.9, 129.1, 129.6, 135.7, 137.3, 138.0, 166.1 ppm. HRMS (EI)
Calcd m/z for C20H19NO2 [M]+: 305.1416. Found: 305.1414.
Ethyl 2-(3-Methylphenyl)-4-phenyl-1H-pyrrole-3-carboxylate
(3c). Yield: 82% (574 mg); Eluents: n-hexane/EtOAc = 5/1 to 3/1;
brown solid; mp: 80−82 °C; 1H NMR (300 MHz, CDCl3) δ 0.96 (t, J
= 7.1 Hz, 3H), 2.32 (s, 3H), 4.02 (q, J = 7.1 Hz, 2H), 6.60 (d, J = 2.4
Hz, 1H), 7.0−7.5 (m, 9H), 8.71 (brs, 1H) ppm; 13C NMR (75 MHz,
CDCl3) δ 13.8, 21.5, 60.0, 110.9, 117.4, 126.0, 126.4, 127.6, 127.9,
128.1, 128.9, 129.1, 129.4, 132.4, 135.6, 137.2, 137.8, 166.1 ppm.
HRMS Calcd m/z for C20H19NO2 [M]+: 305.1416. Found: 305.1417.
Ethyl 2-(4-Fluorophenyl)-4-phenyl-1H-pyrrole-3-carboxylate
(3d). Yield: 65% (462 mg); Eluents: n-hexane/EtOAc = 5/1 to 3/1;
Ethyl 4-(4-Methylphenyl)-2-phenyl-1H-pyrrole-3-carboxylate
(3k). Yield: 77% (539 mg); Eluents: n-hexane/EtOAc = 5/1 to 3/1;
1
brown solid; mp: 126−128 °C; H NMR (300 MHz, CDCl3) δ 0.97
(t, J = 7.1 Hz, 3H), 2.35 (s, 3H), 4.02 (q, J = 7.1 Hz, 2H), 6.61 (d, J =
2.6 Hz, 1H), 7.14 (d, J = 7.9 Hz, 2H), 7.27−7.37 (m, 5H), 7.44−7.47
(m, 2H), 8.66 (brs, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 13.9,
21.3, 60.0, 111.0, 117.3, 127.6, 128.1, 128.2, 128.6, 128.8, 128.9, 132.5,
132.6, 136.0, 136.9, 166.1 ppm. HRMS (EI) Calcd m/z for
C20H19NO2 [M]+: 305.1416. Found: 305.1412.
Ethyl 4-(4-Methoxyphenyl)-2-phenyl-1H-pyrrole-3-carboxylate
1
pale yellow solid; mp: 104−106 °C; H NMR (300 MHz, CDCl3) δ
(3l). Yield: 61% (450 mg); Eluents: n-hexane/EtOAc = 5/1; yellow
1
0.95 (t, J = 7.1 Hz, 3H), 3.98 (q, J = 7.1 Hz, 2H), 6.58 (d, J = 2.6 Hz,
1H), 7.00 (t, J = 8.7 Hz, 2H), 7.22−7.43 (m, 7H), 8.83 (brs, 1H) ppm;
13C NMR (75 MHz, CDCl3) δ 13.8, 60.0, 110.8, 115.1(d, J = 21.9 Hz),
solid; mp: 112−114 °C; H NMR (300 MHz, CDCl3) δ 1.00 (t, J =
7.1 Hz, 3H), 3.82 (s, 3H), 4.05 (q, J = 7.1 Hz, 2H), 6.70 (d, J = 2.6 Hz,
1H), 6.88−6.92 (m, 2H), 7.34−7.41 (m, 5H), 7.45−7.52 (m, 2H),
8.54 (brs, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 13.9, 55.3, 59.9,
110.8, 113.3, 117.2, 127.3, 128.0 (127.99), 128.0 (128.03), 128.2,
128.8, 130.2, 132.6, 137.0, 158.4, 166.1 ppm. HRMS (EI) Calcd m/z
for C20H19NO3 [M]+: 321.1365. Found: 321.1364.
117.6, 126.5, 127.7, 127.8, 128.6 (d, J = 3.0 Hz), 129.1, 130.8 (d, J =
8.3 Hz), 135.4, 136.2, 162.6 (d, J = 247.6 Hz), 166.0 ppm. HRMS (EI)
Calcd m/z for C19H16FNO2 [M]+: 309.1165. Found: 309.1167
Ethyl 4-Phenyl-2-[4-(phenylethynyl)phenyl]-1H-pyrrole-3-carbox-
ylate (3e). Yield: 65% (584 mg); Eluents: n-hexane/EtOAc = 5/1;
Ethyl 4-(4-Fluorophenyl)-2-phenyl-1H-pyrrole-3-carboxylate
1
(3m). Yield: 83% (589 mg); Eluents: n-hexane/EtOAc = 5/1 to 2/
light yellow solid; mp: 158−161 °C; H NMR (300 MHz, CDCl3) δ
1
1; viscous brown liquid; H NMR (300 MHz, CDCl3) δ 0.99 (t, J =
1.03 (t, J = 7.1 Hz, 3H), 4.10 (q, J = 7.1 Hz, 2H), 6.84 (d, J = 2.6 Hz,
1H), 7.26−7.31 (m, 1H), 7.36−7.42 (m, 5H), 7.43−7.46 (m 2H),
7.50−7.53 (m, 2H), 7.54−7.59 (m, 4H), 8.76 (brs, 1H) ppm; 13C
NMR (75 MHz, CDCl3) δ 13.9, 60.2, 89.3, 90.6, 111.7, 118.0, 123.1,
123.3, 126.7, 128.0, 128.2, 128.5, 128.7, 129.1, 131.6, 131.8, 132.2,
135.3, 136.1, 165.8 ppm. HRMS (EI) Calcd m/z for C27H21NO2
[M]+: 391.1572. Found: 391.1572.
7.1 Hz, 3H), 4.05 (q, J = 7.1 Hz, 2H), 6.72 (d, J = 1.6 Hz, 1H), 7.03 (t,
J = 8.6 Hz, 2H), 7.30−7.41 (m, 5H), 7.50−7.53 (m, 2H), 8.55 (brs,
1H) ppm; 13C NMR (75 MHz, CDCl3) δ 13.9, 60.0, 111.1, 114.5 (d, J
= 21.1 Hz), 117.3, 127.0, 128.3 (128.31), 128.3 (128.33), 128.9, 130.7
(d, J = 8.3 Hz), 131.5 (d, J = 3.0 Hz), 132.5, 137.3, 162.0 (d, J = 244.6
Hz), 165.7 ppm. HRMS (EI) Calcd m/z for C19H16FNO2 [M]+:
309.1165. Found: 309.1166.
Ethyl 2-(Furan-2-yl)-4-phenyl-1H-pyrrole-3-carboxylate (3f)25
[CAS: 319905-68-5]. Yield: 70% (452 mg); Eluents: n-hexane/
Ethyl 4-(4-Cyanophenyl)-2-phenyl-1H-pyrrole-3-carboxylate
1
(3n). Yield: 66% (479 mg); Eluents: n-hexane/EtOAc = 5/1 to 3/1;
EtOAc = 5/1 to 3/1; viscous brown liquid; H NMR (300 MHz,
1
light yellow solid; mp: 130−132 °C; H NMR (300 MHz, CDCl3) δ
CDCl3) δ 1.06 (t, J = 7.1 Hz, 3H), 4.15 (q, J = 7.1 Hz, 2H), 6.48 (dd, J
= 3.5, 1.6 Hz, 1H), 6.72 (d, J = 2.6 Hz, 1H), 7.24−7.38 (m, 7H), 9.06
(brs, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 14.0, 60.0, 109.8,
112.2, 117.5, 126.5, 127.7, 128.0, 128.1,129.3, 135.6, 141.5, 146.1,
165.4 ppm.
1.00 (t, J = 7.1 Hz, 3H), 4.06 (q, J = 7.1 Hz, 2H), 6.81 (d, J = 2.6 Hz,
1H), 7.39−7.41 (m, 3H), 7.51−7.54 (m, 4H), 7.60−7.63 (m, 2H),
8.79 (brs, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 13.8, 60.2, 109.8,
110.8, 118.1, 119.5, 126.2, 128.3, 128.6, 129.0, 129.7, 131.7, 132.1,
138.1, 140.6, 165.4 ppm. HRMS (EI) Calcd m/z for C20H16N2O2
[M]+: 316.1212. Found: 316.1212.
Ethyl 2-Benzyl-4-phenyl-1H-pyrrole-3-carboxylate (3g) [CAS:
856118-83-7]. Yield: 79% (553 mg); Eluents: n-hexane/EtOAc = 5/
1; brown solid; mp: 88−90 °C (lit:26b 94−95 °C); H NMR (300
1
Ethyl 4-Butyl-2-phenyl-1H-pyrrole-3-carboxylate (3o). Yield: 73%
(454 mg); Eluents: n-hexane/EtOAc = 7/1 to 5/1; brown solid; mp:
MHz, CDCl3) δ 1.12 (t, J = 7.1 Hz, 3H), 4.15 (q, J = 7.1 Hz, 2H), 4.33
(s, 2H), 6.50 (d, J = 2.3 Hz, 1H), 7.24−7.40 (m, 10H), 8.10 (brs, 1H)
ppm; 13C NMR (75 MHz, CDCl3) δ 14.2, 34.1, 59.6, 110.1, 116.1,
126.4, 127.0, 127.4, 127.6, 129.0, 129.3, 129.5, 135.8, 138.0, 138.3,
165.7 ppm.
1
74−76 °C; H NMR (300 MHz, CDCl3) δ 0.95 (t, J = 7.3 Hz, 3H),
1.16 (t, J = 7.1 Hz, 3H), 1.35−1.47 (m, 2H), 1.55−1.65 (m, 2H),
2.70−2.80 (m, 2H), 4.15 (q, J = 7.1 Hz, 2H), 6.54 (d, J = 2.4 Hz, 1H),
7.29−7.39 (m, 3H), 7.44−7.48 (m, 2H), 8.25 (brs, 1H) ppm; 13C
NMR (75 MHz, CDCl3) δ 14.0, 14.1, 22.8, 26.6, 32.7, 59.4, 110.5,
116.2, 127.6, 127.7, 127.9, 129.1, 133.1, 137.6, 166.1 ppm. HRMS (EI)
Calcd m/z for C17H21NO2 [M]+: 271.1572. Found: 271.1570.
Ethyl 2-Phenyl-4-(2-phenylethyl)-1H-pyrrole-3-carboxylate (3p).
Yield: 63% (462 mg); Eluents: n-hexane/EtOAc = 5/1 to 3/1; brown
Ethyl 2-(2-Methylpropyl)-4-phenyl-1H-pyrrole-3-carboxylate
(3h). Yield: 70% (436 mg); Eluents: n-hexane/EtOAc = 5/1; viscous
brown liquid; 1H NMR (300 MHz, CDCl3) δ 0.94 (d, J = 6.6 Hz, 6H),
1.15 (t, J = 7.1 Hz, 3H), 1.93−2.06 (m, 1H), 2.78 (d, J = 7.2 Hz, 2H),
4.15 (q, J = 7.1 Hz, 2H), 6.55 (d, J = 2.3 Hz, 1H), 7.21−7.42 (m, 5H),
8.35 (brs, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 14.2, 22.6, 29.4,
37.0, 59.5, 110.1, 115.7, 126.2, 127.2, 127.6, 129.4, 136.1, 139.8, 165.9
1
solid; mp: 78−80 °C; H NMR (300 MHz, CDCl3) δ 1.14 (t, J = 7.1
Hz, 3H), 2.89−2.95 (m, 2H), 3.00−3.07 (m, 2H), 4.13 (q, J = 7.1 Hz,
F
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1
2H), 6.43 (d, J = 2.2 Hz, 1H), 7.15−7.20 (m, 1H), 7.22−7.37 (m,
7H), 7.42−7.45 (m, 2H), 8.36 (brs, 1H) ppm; 13C NMR (75 MHz,
CDCl3) δ 14.2, 28.9, 37.1, 59.5, 110.6, 116.5, 125.7, 126.7, 127.9,
128.3, 128.6, 129.2, 133.1, 137.8, 142.7, 165.8 ppm. HRMS (EI) Calcd
m/z for C21H21NO2 [M]+: 319.1572. Found: 319.1569.
hexane/EtOAc = 10/1; white solid; mp: 96−98 °C; H NMR (300
MHz, CDCl3) δ 1.00 (t, J = 7.1 Hz, 3H), 3.04−3.21 (m, 2H), 3.12 (s,
3H), 3.38−3.45 (m, 2H), 4.06 (dq, J = 10.6, 7.1 Hz, 1H), 4.17 (dq, J =
10.6, 7.1 Hz, 1H), 7.08−7.17 (m, 5H), 7.25−7.37 (m, 9H) ppm; 13C
NMR (75 MHz, CDCl3) δ 13.8, 28.3, 31.5, 36.2, 59.1, 111.2, 121.2,
125.8, 126.3, 127.6 (127.55), 127.6 (127.60), 128.1, 128.5 (128. 45),
128.5 (128.50), 128.9, 130.7, 131.6, 131.9, 132.5, 135.5, 136.2, 139.6,
141.5, 165.3 ppm. HRMS (EI) Calcd m/z for C28H26ClNO2 [M]+:
443.1652. Found: 443.1653.
Ethyl 4-Butyl-2-ethyl-1H-pyrrole-3-carboxylate (3q) [CAS:
594864-19-4]. Yield: 64% (328 mg); Eluents: n-hexane/EtOAc = 7/
1
1; brown solid; mp: 54−56 °C; H NMR (300 MHz, CDCl3) δ 0.92
(t, J = 7.3 Hz, 3H), 1.22 (t, J = 7.5 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H),
1.33−1.44 (m, 2H), 1.50−1.60 (m, 2H), 2.59−2.73 (m, 2H), 2.93 (q, J
= 7.5 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H), 6.36 (d, J = 2.0 Hz, 1H), 8.56
(brs, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 13.6, 14.1, 14.5, 21.4,
22.8, 26.8, 32.8, 59.2, 109.1, 113.9, 126.9, 142.0, 166.4 ppm.
Ethyl 4-(2-Chlorophenyl)-5-(4-cyanophenyl)-2-(2-phenylethyl)-1-
methyl-1H-pyrrole-3-carboxylate (6b). Yield: 97% (455 mg);
Eluents: n-hexane/EtOAc = 5/1; pale yellow solid; mp: 124−126
1
°C; H NMR (300 MHz, CDCl3) δ 0.94 (t, J = 7.1 Hz, 3H), 3.00−
Ethyl 4-(2-Bromophenyl)-2-phenyl-1H-pyrrole-3-carboxylate (3s).
3.13 (m, 2H), 3.07 (s, 3H), 3.27−3.41 (m, 2H), 4.00 (dq, J = 10.7, 7.1
Hz, 1H), 4.09 (dq, J = 10.7, 7.1 Hz, 1H), 7.02 (dd, J = 7.5, 1.8 Hz,
1H), 7.07 (dd, J = 7.2, 1.0 Hz, 1H), 7.10−7.19 (m, 5H), 7.22−7.34
(m, 4H), 7.49 (d, J = 8.3 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3)
δ 13.8, 28.3, 31.8, 36.0, 59.3, 110.9, 111.9, 118.7, 122.6, 126.0, 126.4,
128.2, 128.5, 128.7, 128.9, 129.9, 130.9, 131.9, 132.3, 135.3, 135.4,
136.4, 140.9, 141.3, 164.9 ppm. HRMS (EI) Calcd m/z for
C29H25ClN2O2 [M]+: 468.1605. Found: 468.1602.
Yield: 40% (170 mg); Eluents: n-hexane/EtOAc = 5/1 to 3/1; brown
1
solid; mp: 170−172 °C; H NMR (300 MHz, CDCl3) δ 0.84 (t, J =
7.1 Hz, 3H), 3.92 (q, J = 7.1 Hz, 2H), 6.55 (d, J = 2.3 Hz, 1H), 7.10−
7.15 (m, 1H), 7.23−7.35 (m, 5H), 7.49−7.52 (m, 2H), 7.58 (d, J = 7.9
Hz, 1H), 8.83 (brs, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 13.6,
59.8, 111.6, 118.0, 125.2, 126.5, 126.8, 128.1, 128.2, 129.1, 131.8,
132.2, 137.1, 137.5, 165.4 ppm. HRMS (EI) Calcd m/z for
C19H16BrNO2 [M]+: 369.0364. Found: 369.0365.
Synthesis of Pyrrolophenanthrene Derivatives 7a and 7b. Pyrrole
6 (0.30 mmol), PdCl2 (11 mg, 0.06 mmol), and PCy3 (34 mg, 0.12
mmol) were introduced in a thick-wall Pyrex pressure tube, equipped
with a magnetic stirring bar. DBU (0.14 mL, 0.90 mmol) and DMF (5
mL) were added, and then the solution was purged with a nitrogen
stream for 5 min. The sealed tube was placed in a preheated oil bath at
160 °C, and the reaction mixture was stirred for 6 h. After cooling to
room temperature, the suspension was filtered through Celite and
washed with CH2Cl2 (30 mL), and then the filtrate was concentrated
in a reduced pressure. The residue was purified by chromatography on
silica gel to afford the pyrrolophenanthrene derivatives 7.
Ethyl 1-Methyl-2-(2-phenylethyl)-1H-dibenzo[e,g]indole-3-
carboxylate (7a). Yield: 81% (99 mg); Eluents: n-hexane/EtOAc =
7/1; pale yellow solid; mp: 108−110 °C; 1H NMR (300 MHz,
CDCl3) δ 1.43 (t, J = 7.1 Hz, 3H), 2.94−2.99 (m, 2H), 3.24−3.29 (m,
2H), 3.83 (s, 3H), 4.47 (q, J = 7.1 Hz, 2H), 7.12−7.18 (m, 2H), 7.19−
7.29 (m, 3H), 7.48−7.59 (m, 4H), 8.26−8.34 (m, 1H), 8.60−8.69 (m,
2H), 8.70−8.78 (m, 1H) ppm; 13C NMR (63 MHz, CDCl3) δ 14.5,
27.8, 34.8, 36.3, 60.6, 60.6, 108.8, 119.1, 121.4, 123.2, 123.8, 124.0,
124.4, 124.6, 125.6, 126.2, 126.4, 127.8, 127.9, 128.5, 128.6, 129.0,
129.4, 140.9, 142.6, 167.6 ppm. HRMS (EI) Calcd m/z for
C28H25NO2 [M]+: 407.1885. Found: 407.1887.
Ethyl (Z)-2-Aminophenylmethylidene-3-(o-chlorophenyl)-3-bute-
noate (4h). Eluents: n-hexane/EtOAc = 7/1; yellow solid; mp: 72−74
°C; 1H NMR (300 MHz, CDCl3) δ 1.03 (t, J = 7.1 Hz, 3H), 4.06 (q, J
= 7.1 Hz, 2H), 5.14 (d, J = 1.6 Hz, 1H), 5.33 (d, J = 1.6 Hz, 1H),
6.97−7.06 (m, 3H), 7.19−7.31 (m, 6H); 13C NMR (75 MHz, CDCl3)
δ 14.0, 59.3, 99.4, 123.3, 126.0, 127.2, 127.7, 128.2, 128.7, 129.9, 130.1,
132.0, 138.7, 141.2, 142.3, 160.3, 170.0 ppm. HRMS (EI) Calcd m/z
for C19H18ClNO2 [M]+: 327.1026. Found:327.1023.
Ethyl (Z)-2-Aminophenylmethylidene-4-(o-chlorophenyl)-3-bute-
noate (4h′). Eluents: n-hexane/EtOAc = 7/1; yellow liquid; 1H NMR
(300 MHz, CDCl3) δ 1.44 (t, J = 7.1 Hz, 3H), 4.33 (q, J = 7.1 Hz,
2H), 6.55 (d, J = 16.3 Hz, 1H), 6.96−7.05 (m, 2H), 7.08−7.10 (m,
1H), 7.10 (d, J = 16.3 Hz, 1H), 7.21−7.27 (m, 1H), 7.39−7.47 (m,
5H); 13C NMR (75 MHz, CDCl3) δ 14.5, 60.1, 96.6, 121.3, 125.1,
126.6 (126.60), 126.6 (126.64), 127.6, 128.6, 128.8, 129.6, 129.7,
132.5, 137.6, 138.2, 162.5, 170.3 ppm. HRMS (EI) Calcd m/z for
C19H18ClNO2 [M]+: 327.1026. Found:327.1024.
Procedures for the Synthesis of Pyrrolophenanthrene 7 and
Pyranopyrrolone 8. Synthesis of N-Methylated Pyrrole S1. To a
solution of the pyrrole 3t (1.77 g, 5.00 mmol) in DMF (6.0 mL) was
added NaH (144 mg, 6.00 mmol) at 0 °C. After stirring for 10 min,
iodomethane (0.38 mL, 6.0 mmol) was added, and the reaction
mixture was stirred at room temperature for an additional 2 h. The
reaction was quenched by the addition of H2O and extracted with
ethyl acetate (50 mL × 3). The combined organic layers were dried
over anhydrous sodium sulfate, filtered, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy on silica gel (n-Hexane/EtOAc = 7/1) to afford N-methylated
pyrrole S1 as a pale yellow solid (1.34g, 73% yield). Yield: 73% (1.34
g); Eluents: n-hexane/EtOAc = 7/1; pale yellow solid; mp: 40−42 °C;
1H NMR (300 MHz, CDCl3) δ 0.99 (t, J = 7.1 Hz, 3H), 2.92−2.98
(m, 2H), 3.19−3.24 (m, 2H), 3.22 (s, 3H), 4.07 (q, J = 7.1 Hz, 2H),
6.36 (s, 1H), 7.13−7.28 (m, 8H), 7.37−7.40 (m, 1H) ppm; 13C NMR
(75 MHz, CDCl3) δ 13.9, 28.0, 33.5, 36.1, 59.2, 111.5, 121.0, 122.8,
126.0, 126.2, 127.8, 128.5, 128.8, 128.9, 131.7, 134.7, 135.9, 139.5,
141.5, 165.2 ppm. HRMS (EI) Calcd m/z for C22H22ClNO2 [M]+:
367.1339. Found: 367.1340.
Ethyl 7-Cyano-1-methyl-2-(2-phenylethyl)-1H-dibenzo[e,g]-
indole-3-carboxylate (7b). Yield: 78% (101 mg); Eluents: n-
1
hexane/EtOAc = 3/1; white solid; mp: 148−150 °C; H NMR (300
MHz, CDCl3) δ 1.46 (t, J = 7.1 Hz, 3H), 2.97−3.03 (m, 2H), 3.27−
3.34 (m, 2H), 3.81 (s, 3H), 4.51 (q, J = 7.1 Hz, 2H), 7.12−7.18 (m,
2H), 7.22−7.31 (m, 3H), 7.53−7.65 (m, 3H), 8.28 (d, J = 8.8 Hz,
1H), 8.49 (d, J = 7.7 Hz, 1H), 8.62 (dd, J = 8.2, 1.3 Hz, 1H), 8.91 (d, J
= 1.4 Hz, 1H) ppm; 13C NMR (63 MHz, CDCl3) δ 14.5, 28.1, 35.1,
36.4, 61.0, 107.1, 109.6, 119.8, 121.6, 121.9, 123.1, 125.5, 125.8, 125.9,
126.7, 127.6, 127.8 (127.78), 127.8 (127.84), 127.9, 128.6, 128.8,
128.9, 129.1, 140.6, 144.2, 167.3 ppm. HRMS (EI) Calcd m/z for
C29H24N2O2 [M]+: 432.1838. Found: 432.1837.
Synthesis of 4-(2-Chlorophenyl)-1-methyl-5-phenyl-2-phenyl-
ethyl-1H-pyrrole-3-carboxylic Acid (S2). To a solution of pyrrole 6a
(444 mg, 1.0 mmol) in EtOH (20 mL) was added NaOH (280 mg, 7
mmol), and the mixture was stirred at reflux for 20 h. After removal of
ethanol in vacuo, the residue was diluted in water (5 mL). After
cooling to 0 °C, the resulting solution was acidified to pH < 3 with 6.0
N HCl and extracted with CH2Cl2 (30 mL × 3). The combined
organic layers were dried over anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure. The residue was purified by
recrystallization (CH2Cl2/n-hexane) to afford the pyrrole S2 as a white
Synthesis of Pentasubstituted Pyrroles 6a, 6b. A mixture solution
of bromobenzene (1.00 mmol), N-methylated pyrrole S1 (1.00
mmol), KOAc (196 mg, 2.00 mmol), and Pd(OAc)2 (11 mg, 0.05
mmol) in DMAc (3.0 mL) placed in a Schlenk tube was heated at 150
°C for 5 h. The reaction was quenched with H2O at room temperature
and extracted with ethyl acetate (30 mL × 3), and the combined
organic layers were dried over anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure. The residue was purified by
chromatography on silica gel to afford pyrroles 6.
1
solid. Yield: 99% (412 mg); white solid; mp: 202−204 °C; H NMR
(300 MHz, CDCl3) δ 2.92−3.0 (m, 2H), 3.07 (s, 3H), 3.32 (t, J = 7.4
Hz, 2H), 7.03−7.13 (m, 5H), 7.15−7.32 (m, 9H) ppm; 13C NMR (75
MHz, CDCl3) δ 28.6, 31.7, 36.2, 110.3, 121.6, 125.8, 126.2, 127.7,
127.8, 128.1, 128.5, 128.8, 129.0, 130.8, 131.5, 132.4, 132.6, 135.4,
Ethyl 4-(2-Chlorophenyl)-1-methyl-2-(2-phenylethyl)-5-phenyl-
1H-pyrrole-3-carboxylate (6a). Yield: 87% (386 mg); Eluents: n-
G
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135.6, 141.1, 141.6, 170.1 ppm. HRMS (EI) Calcd m/z for
C26H22ClNO2 [M]+: 415.1339. Found: 415.1340.
(k) Lee, C. F.; Yang, L. M.; Hwu, T. Y.; Feng, A. S.; Tseng, J. C.; Luh,
T. Y. J. Am. Chem. Soc. 2000, 122, 4992.
Synthesis of 2-Methyl-1-phenyl-3-(2-phenylethyl)chromeno[3,4-
c]pyrrol-4(2H)-one (8). Pyrrole S2 (125 mg, 0.30 mmol) and
copper(I)-thiophene-2-carboxylate (127 mg, 0.60 mmol) in DMF (3
mL) were introduced in a pressure tube, equipped with a magnetic
stirring bar. The pressure tube was placed in a preheated oil bath at
160 °C, and then the reaction mixture was stirred for 15 h. After it
cooled down to room temperature, the reaction was quenched with
saturated aqueous NH4Cl (30 mL) solution, and the mixture was
extracted with ethyl acetate (30 mL × 3). The combined organic layers
were dried over anhydrous sodium sulfate, filtered, and concentrated
under reduced pressure. The residue was purified by chromatography
on silica gel to afford pyranopyrrolone derivative 8 as a pale yellow
(3) (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
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(4) For recent selected reports, see: (a) Chen, G.-Q.; Zhang, X.-N.;
Wei, Y.; Tang, X.-Y.; Shi, M. Angew. Chem., Int. Ed. 2014, 53, 8492.
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(e) Michlik, S.; Kempe, R. Nat. Chem. 2013, 5, 140. (f) Zhang, M.;
Fang, X.; Neumann, H.; Beller, M. J. Am. Chem. Soc. 2013, 135.
(g) Lian, Y.; Huber, T.; Hesp, K. D.; Bergman, R. G.; Ellman, J. A.
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Davies, H. M. L. J. Am. Chem. Soc. 2013, 135, 4716. (l) Kim, C.-E.;
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Chem., Int. Ed. 2013, 52, 6958. (b) Liu, J.; Fang, Z.; Zhang, Q.; Liu, Q.;
Bi, X. Angew. Chem., Int. Ed. 2013, 52, 6953. (c) Trost, B. M.; Lumb, J.-
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1
solid. Yield: 95% (108 mg); pale yellow solid; mp: 146−148 °C; H
NMR (300 MHz, CDCl3) δ 2.92 (s, 3H), 3.05 (t, J = 7.2 Hz, 2H), 3.42
(t, J = 7.2 Hz, 2H), 6.82−6.91 (m, 1H), 7.02−7.14 (m, 3H), 7.16−
7.28 (m, 5H), 7.31−7.39 (m, 2H), 7.48−7.57 (m, 3H) ppm; 13C
NMR (75 MHz, CDCl3) δ 28.1, 31.3, 36.1, 104.9, 116.8, 117.4, 117.9,
122.6, 123.5, 126.4, 126.9, 127.0, 128.5, 128.9, 129.3, 131.3, 131.9,
138.8, 141.0, 151.5, 159.7 ppm. HRMS (EI) Calcd m/z for
C26H21NO2 [M]+: 379.1572. Found: 379.1568.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Boersch, C.; Frank, W.; Muller, T. J. J. Org. Lett. 2009, 11, 2269.
(6) For selected papers, see: (a) Narayan, R.; Daniliuc, C.-G.;
̈
AUTHOR INFORMATION
■
Wurthwein, E.-U. Eur. J. Org. Chem. 2012, 6021. (b) Tang, Q.; Zhang,
̈
Corresponding Author
*E-mail: sanggi@ewha.ac.kr (S.-g.L.).
C.; Luo, M. J. Am. Chem. Soc. 2008, 130, 5840. (c) Zhang, M.; Fang,
X.; Neumann, H.; Beller, M. J. Am. Chem. Soc. 2013, 135, 11384.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge the financial support for this work
from the Korea Research Foundation (NRF-2011-0016344).
We thank Dr. Sung Hong Kim at the Daegu Center of the
Korea Basic Science Institute for mass spectral analysis.
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