One-pot synthesis of pyrrole-2-carboxylates and -carboxamides via an electrocyclization/oxidation sequence

Article abstract of DOI:10.1021/jo5021823

An electrocyclic ring closure is the key step of an efficient one-pot method for the synthesis of pyrrole-2-carboxylates and -carboxamides from chalcones and glycine esters or amides. The 3,4-dihydro-2H-pyrrole intermediates generated in situ are oxidized

Full text of DOI:10.1021/jo5021823

Note
pubs.acs.org/joc
One-Pot Synthesis of Pyrrole-2-carboxylates and -carboxamides via
an Electrocyclization/Oxidation Sequence
Dennis Imbri, Natalie Netz, Murat Kucukdisli, Lisa Marie Kammer, Philipp Jung, Annika Kretzschmann,
and Till Opatz*
Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, D-55128 Mainz, Germany
S
* Supporting Information
ABSTRACT: An electrocyclic ring closure is the key step of
an efficient one-pot method for the synthesis of pyrrole-2-
carboxylates and -carboxamides from chalcones and glycine
esters or amides. The 3,4-dihydro-2H-pyrrole intermediates
generated in situ are oxidized to the corresponding pyrroles by
stoichiometric oxidants or by catalytic copper(II) and air in
moderate to high yields. A wide range of functional groups are
tolerated, and further combination with an in situ bromination
gives access to polyfunctional pyrrole scaffolds.
yrroles are nitrogen-containing heterocycles of high
oxidants that have been used in this context are chloranil,40 Pd/
Pimportance due to their occurrence as common structural C,41,42 MnO2,43 CrO3,44 FeCl3,45 and DDQ.46,47 Generally,
motifs of natural products in alkaloids,1,2 porphyrins, chlorins,
these methods were applied to isolated dihydropyrroles. Here,
we report a one-pot synthesis of pyrrole-2-carboxylates48−55
and corrins. Since pyrrole-containing molecules often exhibit
pronounced bioactivities, such as antibacterial,3 antifungal,4
and -carboxamides from enones and glycine esters or amides
that is based on the oxidation of 3,4-dihydropyrrole
anti-inflammatory,5 or antitumor6 effects, there are also several
drugs possessing pyrrole units.7 Furthermore, pyrrole-2-
intermediates formed in a spontaneous 6π-electrocyclization.
As reported previously,56,57 3,4-dihydropyrrole-2-carbo-
carboxylates and -carboxamides are frequently used intermedi-
nitriles can be obtained by cyclocondensation22,23,40 of
ates in the total synthesis of natural products like the
lamellarins,8,9 or bromopyrrole alkaloids like hanishin or
aminoacetonitrile with chalcones. While the nitrile function
longamide B.10 Moreover, they are building blocks for the
can be used as a removable acceptor group, an ester function
would remain in the products instead but should allow the
preparation of the useful pyrrole-2-carboxylates. Ideally, air
should be used as the stoichiometric oxidant and condensation,
cyclization, and oxidation should be combined to a one-pot
sequence. In this case, a pyrrole-2-carboxylate would be
obtained from an enone and a glycine ester by loss of two
molecules of water. A similar cyclocondensation approach has
recently been used by Zu et al. to generate 3,4-disubstituted
pyrrole-2-carboxylates in a cascade reaction, but the scope of
this process is limited to products with an allylic 4-substituent
(Scheme 1).58
In our first attempt to react (E)-chalcone (1a) with glycine
ethyl ester hydrochloride (2a) in boiling pyridine, dihydro-
pyrrole 5a was isolated in 73% yield as a mixture of its
diastereomers (trans/cis = 4:1). Subsequent oxidation with
DDQ in toluene afforded pyrrole-2-carboxylate 6a in 65% yield
(48% overall yield, Scheme 2).
assembly of polycyclic heterocycles such as indolones and
pyrroloindolones.11 For various substituted pyrrole-2-carbox-
ylates, antimitotic and cytostatic effects have been reported.12
Moreover, pyrrole-2-carboxyl units formed via a four-electron
oxidation from L-proline play a vital role in the biosynthesis of
monopyrrolic natural products such as the antibiotics
prodigiosin, undecylprodigiosin, clorobiocin, coumermycin A1,
and pyoluteorin.13
Since the pioneering work of Knorr and Fischer, numerous
methods for the synthesis of the pyrrole-2-carboxylate motif
have been developed,14−23 including transition-metal-catalyzed
cycloaddition reactions of isocyanides and alkynes,24,25 and
cycloisomerization of functionalized intermediates, such as
dienyl azides,26 homopropargyl azides,27−29 alkynyl aziri-
dines,30−32 homopropargyl amines,33 2-amino-3-iodoacry-
lates,34,35 or vinyl diazomethanes.36 A particularly efficient
method for their synthesis is the Barton−Zard reaction37 of
ethyl isocyanoacetate with nitroolefins or the related Montforts
synthesis using α,β-unsaturated sulfones as the electrophilic
component.38 The Barton−Zard reaction even works on 9-
nitrophenanthrenes,39 but it only yields products devoid of a 5-
substituent. Other methods build up the five-membered ring
and adjust the oxidation stage by a dehydrogenation of a 4,5-,
3,4-, and 2,5-dihydropyrrole intermediate. The most common
Substitution of refluxing pyridine by combinations of various
solvents (1,4-dioxane, THF, toluene, AcOH, and N,N-
diethylaniline) with bases (triethylamine, DIPEA, DBU,
KOtBu, N,N-diethylaniline) gave inferior results in terms of
Received: September 22, 2014
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
Note
with alkyl substituted enones failed. Several products were
synthesized in a two-step procedure with isolation of the 3,4-
dihydro-2H-pyrrole intermediates that gave inferior results
compared to the one-pot procedure.
Scheme 1. Cyclocondensation Routes to Pyrrole-2-
carboxylates
As an alternative to DDQ, Cu2+ salts were investigated as
potential oxidants, which not only are cheaper and have a lower
toxicity but also may provide an easier workup. Finally, copper
could be used in catalytic amounts in combination with oxygen
or air as a stoichiometric oxidant.
First attempts with stoichiometric amounts of copper(II)
acetate (1.2 equiv), added to the solution of crude
dihydropyrrole 5a in pyridine, were carried out under
microwave irradiation to obtain pyrrole 6a (82% yield). The
addition of 1.2 equiv of copper(II)acetate to various crude
dihydropyrroles 5a−n prepared by either conventional or
microwave heating yielded pyrrole-2-carboxylates 6a−n in 47−
82% yield within an 8 h reaction time. A larger amount (2.0
equiv) of copper(II) acetate yielded pyrrole-2-carboxylates in
44−84% yield in less than 2 h.
Scheme 2. Two-Step Synthesis of Pyrrole-2-carboxylate 6a
To investigate the copper-catalyzed aerobic oxidation, copper
was first added from the beginning of the reaction sequence.
The addition of 1 mol % copper(II) acetate to the solution of
chalcone (1a) and 2a in pyridine led to incomplete conversion
after 32 h of stirring at reflux under air flow. Dihydropyrrole 5a
was consumed entirely, but chalcone was still present (TLC
and HPLC-MS), and the reproducibility of the procedure was
low. Therefore, the addition of catalytic amounts of copper to
the solution of crude dihydropyrrole 5a was investigated as an
alternative. CuCl and Cu(MeCN)4PF6 were similarly efficient
Cu sources so that the former salt was chosen due to its low
cost. Lowering the reaction temperature to 60−100 °C led to
significantly longer reaction times or complete stagnation of the
cyclization compared to boiling pyridine. While the addition of
K3PO4 or CsOPiv led to lower yields of pyrrole (36% and
25%), the addition of diethyl azodicarboxylate (DEAD) or
iron(III) chloride as cooxidants had no positive effect on the
yield (55% and 43%).59 After screening different copper
sources and ligands (N,N′-di-tert-butylethylenediamine, 2,2′-
bipyridine, 1,10-phenanthroline, N,N-dimethylglycine), the
highest yield (56%) was obtained with 10 mol % CuCl, air
flow, and without any added ligand. Thus, the ecologically
attractive copper-catalyzed one-pot procedure is feasible but
provides the desired compounds in moderate yields of 23−
56%. The results obtained with all three methods are
summarized in Table 1.
conversion and purity of the product, as judged by HPLC/MS
and TLC. In contrast to the analogous reaction with glycine
nitrile hydrochloride, microwave irradiation proved to be
feasible and reduced the reaction time from days to hours.
The high stability of glycine esters allows the use of a
stoichiometric amount instead of an excess of the amine
component. To test the compatibility of the cyclization
conditions with the oxidation reaction, various oxidants were
employed.
Adding N-bromosuccinimide (NBS) to the reaction mixture
after complete oxidation of dihydropyrrole 5a with DDQ
smoothly led to the brominated pyrrole 7 in 49% yield over
three consecutive steps (Scheme 3). Similarly, the crude
reaction mixture of the dihydropyrrole 5a was oxidized by air in
the presence of Cu(MeCN)4PF6 (10 mol %) and bipyridine
(10 mol %) prior to bromination with NBS. In the latter case,
bromopyrrole 7 was obtained in 56% yield.
The copper-mediated two-step, one-pot procedure also
proved to be effective for the synthesis of the pyrrole-2-
carboxamides. Cyclization of enones 1 with glycine amides 8
and subsequent oxidation with copper(II) acetate (1.2 or 2.0
equiv) gave pyrrole-2-carboxamides 9a−c in moderate yields
(Table 2).
Initially, the one-pot procedure was investigated by adding
DDQ to the crude reaction mixture of the cyclocondensation to
dihydropyrrole 5a in pyridine to furnish pyrrole 6a. Using 2.0
equiv of DDQ gave a modest yield of 6a (32% yield), whereas
lowering the amount to 1.1 equiv afforded a higher yield (56%
yield). The addition of a stoichiometric amount of acetic acid
proved beneficial and not only led to the hitherto highest yield
(58%) but also reduced the formation of black, tarry oxidation
products. Unlike the cyclocondensation step, DDQ oxidation
under microwave irradiation was unsuccessful. With the
established method, a series of enones 1a−k and 1o were
transformed into the corresponding pyrrole-2-carboxylates 6a−
k and 6o in moderate to high yields. Glycine tert-butyl ester
(2b) could successfully be used, although dealkoxycarbonyla-
tion was observed under harsh microwave conditions. Perform-
ing the reaction under conventional heating in pyridine gave
the best results. An oxidation-sensitive 2-furyl moiety, as
present in substrate 1o, resulted in a low yield, and reactions
While tertiary amides could be reacted smoothly, glycine
amide did not even cyclize with enones under identical
conditions, presumably due to its insolubility. Secondary
amides could be transformed into the desired products
B
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Note
a
Table 1. Synthesis of Pyrrole-2-carboxylates 6a−s
entry
R1
R2
R3
(A) %
(B) %
(C) %
product
bc
82* , 84**
57*
,
1
2
Ph
Ph
Ph
Et
Et
58
55
56
60
89
61
74
54
56
28
61
56
37
45
23
23
38
6a
6b
6c
6d
6e
6f
2-Naph
d
3
3-NO2-C6H4
2,3-Cl2-C6H3
2-Br-C6H4
4-Cl-C6H4
Ph
Et
65*, 56**
4
Et
67*
56*
61*
5
2-Naph
Ph
Et
6
4-CN-C6H4
Et
d
7
4-MeO-C6H4
2-Cl-C6H4
4-F-C6H4
4-F-C6H4
Ph
Et
65* , 55**
6g
6h
6i
8
Et
61*
61*
55*
55**
46**
44**
47*
28
40
9
4-MeO-C6H4
3,4-(MeO)2-C6H3
Biphenyl-4-yl
4-NMe2-C6H4
4-OH-C6H4
Et
e
10
11
12
13
14
15
16
17
18
19
3,4-(MeO)2-C6H3
Et
37
e
6j
Ph
Et
29
6k
6l
Ph
Et
Ph
Et
6m
6n
6o
6p
6q
6r
6s
2-Br-4,5-(MeO)2-C6H2
3,4-(MeO)2-C6H3
Ph
3,4-(MeO)2-C6H3
2-Furyl
Et
b
Et
21
f
Ph
tBu
tBu
tBu
tBu
30
f
4-MeO-C6H4
2-Cl-C6H4
4-F-C6H4
4-F-C6H4
2-Furyl
40
f
57
3,4-(MeO)2-C6H3
19
a
Reaction conditions: enone (1.00 mmol), glycine ester (1.05 mmol), AcOH (1.00 mmol), pyridine (5−10 mL) at reflux, method A: DDQ (1.10
b
mmol); B*: Cu(OAc)2 (1.20 mmol); B**: Cu(OAc)2 (2.00 mmol); C: CuCl (10−20 mol %), air flow. Both cyclization and oxidation were
performed under microwave irradiation. After 1 h oxidation, an additional 0.3 equiv of Cu(OAc)2 was used. Cyclization was performed under
microwave irradiation. DEAD (20 mol %) and 1,10-phenanthroline (20 mol %) were added in the oxidation step. 1.5 equiv of 2b and 2.0 equiv of
c
d
e
f
DDQ were used.
a
Scheme 3. One-Pot Cyclization−Oxidation−Bromination
Sequence
Table 2. Pyrrole-2-carboxamides
entry
R1
R2
R3
R4
yield (%) product
b
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
i-Bu
i-Bu
H
Me
Me
H
46
55
59
43
9a
9a
9b
9c
c
b
c
4-MeO-C6H4
4-F-C6H4
Ph
H
Ph
Ph
H
n.r.
n.r.
Ph
Me
H
a
Reaction conditions: (i) enone (1.00 mmol), glycine amide (1.20
mmol), MS 3 Å, pyridine (4 mL) at 130 °C, microwave irradiation;
(ii) Cu(OAc)2 (1.20 or 2.00 mmol) at 130 °C, microwave irradiation.
depending on the length of the alkyl chain, which also governs
their solubility in hot pyridine (Table 2, entries 3 and 4
compared to entry 6).
b
c
Oxidation was performed with 1.20 equiv of Cu(OAc)2. Oxidation
was performed with 2.00 equiv of Cu(OAc)2.
In conclusion, our method permits a simple one-pot
synthesis of 3,5-disubstituted pyrrole-2-carboxylates or -carbox-
amides from enones and glycine esters or amides by
cyclocondensation, followed by oxidation of the dihydropyrrole
intermediates by DDQ or copper(II). Copper can also be used
in catalytic amounts in combination with air as a stoichiometric
oxidant, but lower yields and reaction rates are observed. A
wide range of substituents, such as chloro, bromo, fluoro, nitro,
cyano, dialkylamino, and hydroxyl groups, are tolerated. The
combination of the two-step sequence with an in situ
bromination allows the preparation of 3,5-disubstituted 4-
bromopyrrole-2-carboxylates.
EXPERIMENTAL SECTION
■
General Procedure for DDQ Oxidation (A). Unless otherwise
noted, the respective enone (1.00 mmol, 1.00 equiv) and ethyl or tert-
butyl glycine ester hydrochloride (1.05 mmol, 1.05 equiv) were
dissolved in pyridine (10 mL). Acetic acid (1.00 mmol, 60 μL, 1.00
equiv) was added, and the reaction mixture was stirred at 125 °C oil
bath temperature until complete conversion of the enone was
determined, as indicated by TLC or HPLC-MS (reaction time
indicated for each compound). After complete consumption of the
enone, DDQ (1.10 mmol, 250 mg, 1.10 equiv) was added in one
portion and the mixture was refluxed until complete conversion of the
dihydropyrrole was determined, as indicated by TLC or HPLC-MS.
C
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Note
Upon completion, the solvent was removed by azeotropic distillation
with toluene. The residue was purified by column chromatography on
silica gel to afford the particular pyrroles, with yields ranging from 19%
to 89%.
added after 1 h). Purification by flash column chromatography
(cyclohexane/EtOAc, 7:1) yielded 6a (238 mg, 82%) as a colorless
solid. According to general procedure B**, 1a and 2a were cyclized by
microwave-assisted reaction (2 h), followed by oxidation (30 min).
Purification by flash column chromatography (cyclohexane/EtOAc,
7:1) yielded 6a (245 mg, 84%) as a colorless solid. According to
general procedure C, 1a and 2a were cyclized by conventional heating
(21 h), followed by oxidation (19 h) with anhydrous copper(I)
chloride (10 mg, 10 mol %). Purification by flash column
chromatography (cyclohexane/EtOAc, 7:1) yielded 6a (162 mg,
56%) as a colorless solid. The data are in accordance with the
literature.50
General Procedure for Copper-Mediated Oxidation, 1.2
equiv* or 2.0 equiv** (B). Unless otherwise noted, the respective
enone (1.00 mmol, 1.00 equiv) and ethyl glycine ester hydrochloride
(1.05 mmol, 147 mg, 1.05 equiv) were dissolved in pyridine (5 mL).
Grained molecular sieve 3 Å (100 mg) was added, and the mixture was
stirred at 125 °C oil bath temperature until complete conversion of the
enone was determined, as indicated by TLC or HPLC-MS. Then,
Cu(OAc)2 (1.20 mmol, 218 mg, 1.2 equiv or 2.00 mmol, 363 mg, 2.00
equiv) was added in one portion and the mixture was refluxed until
complete conversion of the dihydropyrrole was determined, as
indicated by TLC or HPLC-MS. Upon completion of the oxidation,
the solvent was removed by azeotropic distillation with toluene. The
residue was dissolved in dichloromethane (60 mL) and subsequently
washed with a 0.1 M Na2-EDTA solution (3 × 30 mL) and brine (30
mL). The organic layer was dried over Na2SO4 and filtered. The
solvent was removed in vacuo, and the residue was purified by column
chromatography on silica gel to afford the particular pyrroles, with
yields ranging from 44% to 84%.
Ethyl 5-(Naphth-2-yl)-3-phenyl-1H-pyrrole-2-carboxylate
(6b). According to the general procedure A, 1b and 2a were cyclized
by conventional heating (25 h), followed by oxidation (45 h).
Purification by flash column chromatography (cyclohexane/EtOAc,
15:1) yielded 6b (187 mg, 55%) as a yellow solid: mp 156−160 °C; Rf
= 0.42 (silica gel, cyclohexane/EtOAc, 3:1); IR (ATR) ν (cm−1) =
3300, 3056, 2980, 1709, 1663, 1630, 1604, 1507, 1435, 1281; 1H NMR
(400 MHz, CDCl3) δ (ppm) = 9.58 (br s, 1H, NH), 8.07−8.03 (m,
1H, H-1″), 7.93−7.83 (m, 3H, Ar), 7.73 (dd, J = 8.5, 1.8 Hz, 1H, H-
3′), 7.66−7.62 (m, 2H, H-2′/6′), 7.56−7.46 (m, 2H, Ar), 7.44−7.39
(m, 2H, H-3′/5′), 7.37−7.31 (m, 1H, H-4′), 6.76 (d, J = 3.1 Hz, 1H,
General Procedure for Copper-Catalyzed Oxidation (C).
Unless otherwise noted, the respective enone (1.00 mmol, 1.00
equiv) and ethyl glycine ester hydrochloride (1.05 mmol, 147 mg, 1.05
equiv) were dissolved in pyridine (5 mL). Molecular sieve 3 Å (100
mg) was added, and the mixture was stirred at 125 °C oil bath
temperature until complete conversion of the enone was determined,
as indicated by TLC or HPLC-MS. Following, CuCl (10−20 mol %,
10−20 mg) was added in one portion and the mixture was refluxed
with air continuously passing through the reaction mixture until
complete conversion of the dihydropyrrole was determined, as
indicated by TLC or HPLC-MS. Purification and isolation as described
before. Pyrroles were isolated with yields ranging from 23% to 56%.
Optional Method for 3,4-Dihydro-2H-pyrrole Formation via
Microwave Irradiation. Unless otherwise noted, the respective
enone (1.00 mmol, 1.00 equiv) and ethyl glycine ester hydrochloride
(1.05 mmol, 147 mg, 1.05 equiv) were placed in a microwave vessel,
and pyridine (3 mL) was added. Molecular sieve 3 Å (100 mg) was
added, followed by sealing the vessel and heating to 130 °C for 60 min
(200 W, air cooling) in a microwave reactor. The reaction temperature
increased from 25 to 130 °C in 180 s and was maintained at 130 °C
for the rest of the period. An additional portion of ethyl glycine ester
hydrochloride (0.20 mmol, 27.9 mg, 0.20 equiv) was added, followed
by sealing the vessel and repeating the aforementioned procedure for
another 60 min. The aromatization reaction was performed in an oil
bath by adding the oxidant and proceeding as described before.
Alternatively, the oxidation can also be performed under microwave
irradiation. In this case, Cu(OAc)2 (1.20 mmol, 218 mg, 1.20 equiv)
was added to the reaction mixture, followed by sealing the vessel and
heating to 140 °C for 60 min (250 W, air cooling). The reaction
temperature increased from 25 to 140 °C in 180 s and was maintained
at 140 °C for the rest of the period. An additional portion of
Cu(OAc)2 (0.30 mmol, 55 mg, 0.30 equiv) was added, followed by
sealing the vessel and repeating the aforementioned method for
another 60 min. Purification and isolation were performed as described
before.
H-4), 4.30 (q, J = 7.1 Hz, 2H, CH2), 1.27 (t, J = 7.1 Hz, 3H, CH3); 13
C
NMR (100.6 MHz, CDCl3) δ (ppm) = 161.4 (CO), 135.5 (Cq),
135.2 (Cq), 133.7 (Cq), 133.6 (Cq), 133.0 (Cq), 129.7 (2C, C-2′/6′),
129.0, 128.5 (Cq), 128.2, 127.9, 127.8 (2C, C-3′/5′), 127.3 (C-4′),
126.9, 126.4, 123.2, 123.2, 119.0 (C-2), 110.6 (C-4), 60.6 (CH2), 14.4
(CH3); ESI-HRMS calcd for [C23H19NO2 + Na]+ 364.1313, found
364.1323. According to the general procedure B*, 1b and 2a were
cyclized by conventional heating (16 h), followed by oxidation (4 h).
Purification by flash column chromatography (cyclohexane/EtOAc,
15:1) yielded 6b (193 mg, 57%) as a yellow solid. According to
general procedure C, 1b and 2a were cyclized by conventional heating
(24 h), followed by oxidation (26 h) with anhydrous copper(I)
chloride (20 mg, 20 mol %). Purification by flash column
chromatography (cyclohexane/EtOAc, 7:1) yielded 6b (125 mg,
37%) as a yellow solid.
Ethyl 5-(4-Chlorophenyl)-3-(3-nitrophenyl)-1H-pyrrole-2-
carboxylate (6c). According to the general procedure A, 1c and 2a
were cyclized by conventional heating (53 h), followed by oxidation
(41 h). Purification by flash column chromatography (cyclohexane/
EtOAc, 8:1) yielded 6c (207 mg, 56%) as an orange solid: mp 179−
182 °C; Rf = 0.49 (silica gel, cyclohexane/EtOAc, 2:1); IR (ATR) ν
(cm−1) = 3309, 1667, 1608, 1588, 1572, 1529, 1514, 1483, 1427, 1283;
1H NMR (400 MHz, CDCl3) δ (ppm) = 9.48 (br s, 1H, NH), 8.48
(pseudo-t, J ≈ 2 Hz, 1H, H-2′), 8.19 (ddd, J = 8.3, 2.3, 1.1 Hz, 1H, H-
4′), 7.92 (ddd, J = 7.7, 1.7, 1.1 Hz, 1H, H-6′), 7.58−7.52 (m, 3H, H-
2″/6″/5′), 7.46−7.39 (m, 2H, H-3″/5″), 6.65 (d, J = 3.1 Hz, 1H, H-
4), 4.29 (q, J = 7.1 Hz, 2H, CH2), 1.25 (t, J = 7.1 Hz, 3H, CH3); 13
C
NMR (100.6 MHz, CDCl3) δ (ppm) = 160.9 (CO), 148.0 (C-3′),
136.7 (C-5), 135.7 (C-6′), 134.8 (C-1′), 134.3 (C-4″), 130.7 (C-1″),
129.5 (2C, C-3″/5″), 129.2 (C-3), 128.7 (C-5′), 126.2 (2C, C-2″/6″),
124.7 (C-2′), 122.1 (C-4′), 119.5 (C-2), 110.1 (C-4), 61.1 (CH2), 14.3
(CH3); ESI-HRMS calcd for [C19H15ClN2O4 + Na]+ 393.0618, found
393.0606. According to the general procedure B*, 1c and 2a were
cyclized by conventional heating (10 h), followed by oxidation (4 h).
Purification by flash column chromatography (cyclohexane/EtOAc,
8:1) yielded 6c (240 mg, 65%) as an orange solid. According to
general procedure B**, 1c and 2a were cyclized by microwave-assisted
reaction (2 h), followed by oxidation (1 h). Purification by flash
column chromatography (cyclohexane/EtOAc, 8:1) yielded 6c (207
mg, 56%) as an orange solid. According to general procedure C, 1c
and 2a were cyclized by conventional heating (24 h), followed by
oxidation (21 h) with anhydrous copper(I) chloride (20 mg, 20 mol
%). Purification by flash column chromatography (cyclohexane/
EtOAc, 8:1) yielded 6c (166 mg, 45%) as an orange solid.
Ethyl 3,5-Diphenyl-1H-pyrrole-2-carboxylate (6a).50 Accord-
ing to the general procedure A, 1a and 2a were cyclized by
conventional heating (29 h), followed by oxidation (66 h). Purification
by flash column chromatography (cyclohexane/EtOAc, 7:1) yielded 6a
1
(168 mg, 58%) as a colorless solid: mp 140−141 °C; H NMR (400
MHz, CDCl3) δ (ppm) = 9.43 (br s, 1H, NH), 7.65−7.58 (m, 4H),
7.50−7.29 (m, 6H), 6.64 (d, J = 3.1 Hz, 1H, H-4), 4.28 (q, J = 7.1 Hz,
2H, CH2), 1.26 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (100.6 MHz,
CDCl3) δ (ppm) = 161.5 (CO), 135.6, 135.3, 133.6, 131.2, 129.7,
129.1, 128.0, 127.8, 127.2, 125.0, 118.8 (C-2), 110.1 (C-4), 60.6
(CH2), 14.3 (CH3). According to the general procedure B*, 1a and 2a
were cyclized by microwave-assisted reaction (2 h), followed by
microwave-assisted oxidation (2 h) (additional 0.3 equiv of Cu(OAc)2
Ethyl 3-(2,3-Dichlorophenyl)-5-phenyl-1H-pyrrole-2-carbox-
ylate (6d). According to the general procedure A, 1d and 2a were
cyclized by conventional heating (23.5 h), followed by oxidation (69.5
D
dx.doi.org/10.1021/jo5021823 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
h) with DDQ (277 mg, 1.30 mmol, 1.3 equiv). Purification by flash
column chromatography (cyclohexane/EtOAc, 12:1) yielded 6d (214
mg, 60%) as a light yellow solid: mp 150−152 °C; Rf = 0.57 (silica gel,
cyclohexane/EtOAc, 2:1); IR (ATR) ν (cm−1) = 3309, 1667, 1572,
1477, 1438, 1427, 1413, 1283, 1260, 1211; 1H NMR (400 MHz,
CDCl3) δ (ppm) = 10.00 (br s, 1H, NH), 7.65 (d, J = 7.4 Hz, 2H, H-
2″/6″), 7.45 (dd, J = 8.0, 1.7 Hz, 1H, H-4′), 7.44−7.38 (m, 2H, H-3″/
5″), 7.35−7.31 (m, 1H, H-4″), 7.29 (dd, J = 7.8, 1.7 Hz, 1H, H-6′),
7.21 (pseudo-t, J ≈ 8 Hz, 1H, H-5′), 6.56 (d, J = 2.9 Hz, 1H, H-4),
4.16 (q, J = 7.1 Hz, 2H, CH2), 1.08 (t, J = 7.1 Hz, 3H, CH3); 13C
NMR (100.6 MHz, CDCl3) δ (ppm) = 161.4 (CO), 137.5 (C-1′),
135.9 (C-5), 132.9 (C-3′), 132.6 (C-2′), 131.1 (C-1″), 130.0 (C-6′),
129.6 (C-3), 129.3 (C-4′), 129.1 (2C, C-3″/5″), 128.1 (C-4″), 126.6
(C-5′), 125.0 (2C, C-2″/6″), 120.4 (C-2), 110.0 (C-4), 60.7 (CH2),
13.9 (CH3); ESI-HRMS calcd for [C19H15Cl2NO2 + Na]+ 382.0378,
found 382.0383. According to the general procedure B*, 1d and 2a
were cyclized by conventional heating (36 h), followed by oxidation (5
h). Purification by flash column chromatography (cyclohexane/EtOAc,
8:1) yielded 6d in (239 mg, 67%) as a light yellow solid. According to
general procedure C, 1d and 2a were cyclized by conventional heating
(48 h), followed by oxidation (24 h) with anhydrous copper(I)
chloride (20 mg, 20 mol %). Purification by flash column
chromatography (cyclohexane/EtOAc, 8:1) yielded 6d (81 mg,
23%) as a light yellow solid.
were cyclized by conventional heating (10 h), followed by oxidation (9
h). Purification by flash column chromatography (cyclohexane/EtOAc,
6:1) yielded 6f (191 mg, 61%) as a colorless solid. According to
general procedure C, 1 and 2a were cyclized by conventional heating
(21 h), followed by oxidation (8 h) with anhydrous copper(I) chloride
(20 mg, 20 mol %). Purification by flash column chromatography
(cyclohexane/EtOAc, 6:1) yielded 6 (120 mg, 38%) as a colorless
solid.
Ethyl 5-(4-Fluorophenyl)-3-(4-methoxyphenyl)-1H-pyrrole-
2-carboxylate (6g). According to the general procedure A, 1g and
2a were cyclized by conventional heating (24 h), followed by oxidation
(63 h). Purification by flash column chromatography (cyclohexane/
EtOAc, 6:1) yielded 6g (252 mg, 74%) as a colorless solid: mp 177−
179 °C; Rf = 0.43 (silica gel, cyclohexane/EtOAc, 2:1); IR (ATR) ν
(cm−1) = 3329, 1664, 1611, 1600, 1577, 1570, 1532, 1506, 1477, 1292;
1H NMR (400 MHz, CDCl3) δ (ppm) = 9.24 (br s, 1H, NH), 7.63−
7.48 (m, 4H, H-2′/6′/2″/6″), 7.20−7.06 (m, 2H, H-3″/5″), 6.97−
6.89 (m, 2H, H-3′/5′), 6.53 (d, J = 3.1 Hz, 1H, H-4), 4.29 (q, J = 7.1
Hz, 2H, CH2), 3.85 (s, 3H, OCH3), 1.28 (t, J = 7.1 Hz, 3H, CH3); 13
NMR (100.6 MHz, CDCl3) δ (ppm) = 162.6 (d, JC,F = 248.2 Hz, C-
C
1
4″), 161.3 (CO), 159.1 (C-4′), 134.5 (C-5), 133.5 (C-3), 130.8 (2C,
C-2′/6′), 127.6 (d, 4JC,F = 3.4 Hz, C-1″), 127.4 (C-1′), 126.7 (d, 3JC,F
=
2
8.2 Hz, 2C, C-2″/6″), 118.5 (C-2), 116.3 (d, JC,F = 22.0 Hz, 2C, C-
3″/5″), 113.3 (2C, C-3′/5′), 109.8 (C-4), 60.6 (CH2), 55.4 (OCH3),
14.5 (CH3); ESI-HRMS calcd for [C20H18FNO3 + H]+ 340.1349,
found 340.1338. According to the general procedure B*, 1g and 2a
were cyclized by microwave-assisted cyclization (2.5 h), followed by
oxidation (8 h). Purification by flash column chromatography
(cyclohexane/EtOAc, 6:1) yielded 6g (220 mg, 65%) as a colorless
solid. According to general procedure B**, 1g and 2a were cyclized by
conventional heating (24 h), followed by oxidation (1 h). Purification
by flash column chromatography (cyclohexane/EtOAc, 6:1) yielded
6g (185 mg, 55%) as a colorless solid.
Ethyl 3-(2-Bromophenyl)-5-(naphth-2-yl)-1H-pyrrole-2-car-
boxylate (6e). According to the general procedure A, 1e and 2a
were cyclized by conventional heating (28.5 h), followed by oxidation
(29 h). Purification by flash column chromatography (cyclohexane/
EtOAc, 10:1) yielded 6e (375 mg, 89%) as a colorless solid: mp 144−
145 °C; Rf = 0.21 (silica gel, cyclohexane/EtOAc, 12:1); IR (ATR) ν
(cm−1) = 3294, 1668, 1479, 1443, 1277; 1H NMR (400 MHz, CDCl3)
δ (ppm) = 9.69 (br s, 1H, NH), 8.06−8.04 (m, 1H, H-1″), 7.92 (d, J =
8.5 Hz, 1H, H-4″), 7.88−7.85 (m, 1H, H-8″), 7.85−7.82 (m, 1H, H-
5″), 7.74 (dd, J = 8.5, 1.8 Hz, 1H, H-3″), 7.66 (dd, J = 8.0, 1.2 Hz, 1H,
H-3′), 7.54−7.50 (m, 1H, H-6″), 7.50−7.45 (m, 1H, H-7″), 7.41 (dd, J
= 7.6, 1.8 Hz, 1H, H-6′), 7.34 (ddd, J = 8.0, 7.5, 1.2 Hz, 1H, H-5′),
7.21 (ddd, J = 8.0, 7.5, 1.8 Hz, 1H, H-4′), 6.69 (d, J = 3.0 Hz, 1H, H-
Ethyl 3-(2-Chlorophenyl)-5-(4-fluorophenyl)-1H-pyrrole-2-
carboxylate (6h). According to the general procedure A, 1h and
2a were cyclized by conventional heating (28 h), followed by oxidation
(28.5 h). Purification by flash column chromatography (cyclohexane/
EtOAc, 8:1) yielded 6h (185 mg, 54%) as a yellow solid: mp 129−131
°C; Rf = 0.57 (silica gel, cyclohexane/EtOAc, 2:1); IR (ATR) ν (cm−1)
4), 4.18 (q, J = 7.1 Hz, 2H, CH2), 1.09 (t, J = 7.1 Hz, 3H, CH3); 13
C
NMR (100.6 MHz, CDCl3) δ (ppm) = 161.3 (CO), 137.2 (C-1′),
135.3 (C-5), 133.6 (C-2″), 133.0 (C-4a″), 132.4 (C-3′), 131.9 (C-6′),
131.8 (C-3), 129.0 (C-4″), 128.8 (C-4′), 128.5 (C-8a″), 128.2 (C-8″),
127.9 (C-5″), 126.9 (C-6″), 126.7 (C-5′), 126.4 (C-7″), 124.4 (C-2′),
123.3 (C-1″), 123.2 (C-3″), 120.6 (C-2), 110.8 (C-4), 60.6 (CH2),
14.1 (CH3); ESI-HRMS calcd for [C23H18(79Br)NO2 + Na]+
442.0419, found 442.0424. According to the general procedure B*,
1e and 2a were cyclized by conventional heating (36 h), followed by
oxidation (5 h). Purification by flash column chromatography
(cyclohexane/EtOAc, 8:1) yielded 6e (234 mg, 56%) as a colorless
solid. According to general procedure C, 1e and 2a were cyclized by
conventional heating (30 h), followed by oxidation (24 h) with
anhydrous copper(I) chloride (20 mg, 20 mol %). Purification by flash
column chromatography (cyclohexane/EtOAc, 8:1) yielded 6e (95
mg, 23%) as a colorless solid.
1
= 3302, 1670, 1479, 1450, 1292, 1266, 1233, 1213, 1162, 1138; H
NMR (400 MHz, CDCl3) δ (ppm) = 9.81 (br s, 1H, NH), 7.68−7.55
(m, 2H, H-2″/6″), 7.47−7.42 (m, 1H, H-6′), 7.40−7.35 (m, 1H, H-
3′), 7.30−7.25 (m, 2H, H-4′/5′), 7.14−7.07 (m, 2H, H-3″/5″), 6.51
(d, J = 3.0 Hz, 1H, H-4), 4.15 (q, J = 7.1 Hz, 2H, CH2), 1.08 (t, J = 7.1
Hz, 3H, CH3); 13C NMR (100.6 MHz, CDCl3) δ (ppm) = 162.5 (d,
1JC,F = 248.0 Hz, C-4″), 161.5 (CO), 135.0 (C-1′), 134.8 (C-5),
134.0 (C-2′), 131.9 (C-3′), 129.9 (C-3), 129.2 (C-6′), 128.6 (C-5′),
127.6 (d, 4JC,F = 3.4 Hz, C-1″), 126.8 (d, 3JC,F = 8.1 Hz, 2C, C-2″/6″),
2
126.1 (C-4′), 120.5 (C-2), 116.1 (d, JC,F = 21.9 Hz, 2C, C-3″/5″),
110.2 (C-4), 60.6 (CH2), 14.0 (CH3); ESI-HRMS calcd for
[C19H15ClFNO2 + Na]+ 366.0673, found 366.0673. According to
the general procedure B*, 1h and 2a were cyclized by conventional
heating (46 h), followed by oxidation (17 h). Purification by flash
column chromatography (cyclohexane/EtOAc, 8:1) yielded 6h (208
mg, 61%) as a yellow solid. According to general procedure C, 1h and
2a were cyclized by conventional heating (29 h), followed by oxidation
(29 h) with anhydrous copper(I) chloride (20 mg, 20 mol %).
Purification by flash column chromatography (cyclohexane/EtOAc,
8:1) yielded 6h (97 mg, 28%) as a yellow solid.
Ethyl 3-(4-Cyanophenyl)-5-phenyl-1H-pyrrole-2-carboxylate
(6f). According to the general procedure A, 1f and 2a were cyclized by
conventional heating (23 h), followed by oxidation (22 h). Purification
by flash column chromatography (cyclohexane/EtOAc, 6:1) yielded 6f
(192 mg, 61%) as a colorless solid: mp 200−204 °C; Rf = 0.37 (silica
gel, cyclohexane/EtOAc, 2:1); IR (ATR) ν (cm−1) = 3319, 3285,
2222, 1658, 1607, 1471, 1460, 1443, 1290, 1260; 1H NMR (400 MHz,
CDCl3) δ (ppm) = 9.56 (br s, 1H, NH), 7.73−7.69 (m, 2H, H-3′/5′),
7.69−7.64 (m, 2H, H-2′/6′), 7.65−7.58 (m, 2H, H-2″/6″), 7.53−7.47
(m, 2H, H-3″/5″), 7.39−7.32 (m, 1H, H-4″), 6.62 (d, J = 3.0 Hz, 1H,
Ethyl 3-(4-Methoxyphenyl)-5-phenyl-1H-pyrrole-2-carboxy-
late (6i).50 According to the general procedure A, 1i and 2a were
cyclized by conventional heating (25.5 h), followed by oxidation (30
h). Purification by flash column chromatography (cyclohexane/EtOAc,
6:1) yielded 6i (179 mg, 56%) as a yellow solid: mp 134−137 °C
(Lit.43: 132−133 °C); Rf = 0.44 (silica gel, cyclohexane/EtOAc, 2:1);
IR (ATR) ν (cm−1) = 3308, 1707, 1661, 1608, 1601, 1573, 1528, 1460,
H-4), 4.29 (q, J = 7.1 Hz, 2H, CH2), 1.27 (t, J = 7.1 Hz, 3H, CH3); 13
C
NMR (100.6 MHz, CDCl3) δ (ppm) = 160.9 (CO), 140.1 (C-1′),
136.0 (C-5), 131.6 (2C, C-3′/5′), 131.4 (C-1″), 130.7 (C-3), 130.3
(2C, C-2′/6′), 129.3 (2C, C-3″/5″), 128.4 (C-4″), 125.0 (2C, C-2″/
6″), 119.3 (CN), 119.1 (C-2), 110.7 (C-4′), 109.8 (C-4), 60.9 (CH2),
14.4 (CH3); ESI-HRMS calcd for [C20H16N2O2 + Na]+ 339.1109,
found 339.1111. According to the general procedure B*, 1f and 2a
1
1290, 1266; H NMR (400 MHz, CDCl3) δ (ppm) = 9.37 (br s, 1H,
NH), 7.64−7.58 (m, 2H, Ar), 7.58−7.54 (m, 2H, Ar), 7.47−7.40 (m,
2H, H-3″/5″), 7.36−7.30 (m, 1H, H-4″), 6.97−6.89 (m, 2H, H-3′/5′),
6.60 (d, J = 3.1 Hz, 1H, H-4), 4.29 (q, J = 7.1 Hz, 2H, CH2), 3.86 (s,
E
dx.doi.org/10.1021/jo5021823 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
3H, OCH3), 1.29 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (100.6 MHz,
CDCl3) δ (ppm) = 161.3 (Cq), 159.0 (Cq), 135.4 (Cq), 133.4 (Cq),
131.2 (Cq), 130.8 (2C), 129.2 (2C), 128.0 (Cq), 127.6, 124.9 (2C),
118.4 (C-2), 113.3 (2C), 109.9 (C-4), 60.5 (CH2), 55.4 (OCH3),
14.5(CH3).43 ESI-HRMS calcd for [C20H19NO3 + Na]+ 344.1263,
found 344.1264. The data are in accordance with the literature.
According to the general procedure B*, 1i and 2a were cyclized by
conventional heating (30 h), followed by oxidation (4 h). Purification
by flash column chromatography (cyclohexane/EtOAc, 6:1) yielded 6i
(193 mg, 61%) as a yellow solid. According to general procedure C, 1i
and 2a were cyclized by conventional heating (24 h), followed by
oxidation (8 h) with anhydrous copper(I) chloride (20 mg, 20 mol %).
Purification by flash column chromatography (cyclohexane/EtOAc,
6:1) yielded 6i (127 mg, 40%) as a yellow solid.
Ethyl 3,5-Bis(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxy-
late (6j). According to the general procedure A, 1j and 2a were
cyclized by conventional heating (24 h), followed by oxidation (24 h).
Purification by flash column chromatography (cyclohexane/EtOAc,
3:1) yielded 6j (113 mg, 28%) as a yellow foam: Rf = 0.18 (silica gel,
cyclohexane/EtOAc, 2:1); IR (ATR) ν (cm−1) = 3322, 2835, 1680,
1509, 1436, 1244, 1107, 1023, 802, 763; 1H NMR (400 MHz, CDCl3)
δ (ppm) = 9.26 (br s, 1H, NH), 7.19 (d, J = 1.9 Hz, 1H, H-2′), 7.17
(dd, J = 8.1, 1.9 Hz, 1H, H-6′), 7.16 (dd, J = 8.2, 2.0 Hz, 1H, H-6″),
7.08 (d, J = 2.0 Hz, 1H, H-2″), 6.92 (d, J = 8.2, 1H, H-5″), 6.90 (d, J =
8.1 Hz, 1H, H-5′), 6.51 (d, J = 3.1, 1H, H-4), 4.28 (q, J = 7.1 Hz, 2H,
CH2), 3.95 (s, 3H, OCH3-4″), 3.92 (s, 3H, OCH3), 3.92 (s, 3H,
OCH3), 3.92 (s, 3H, OCH3), 1.27 (t, J = 7.1 Hz, 3H, CH3); 13C NMR
(100.6 MHz, CDCl3) δ (ppm) = 161.4 (CO), 149.5 (C-3″), 149.2
(C-4″), 148.4 (C-3′), 148.2 (C-4′), 135.7 (C-5), 133.5 (C-3), 127.9
(C-1′), 124.3 (C-1″), 122.0 (C-6′), 118.0 (C-2), 117.5 (C-6″), 113.2
(C-2′), 111.7 (C-5″), 110.6 (C-5′), 109.3 (C-4), 108.5 (C-2″), 60.4
(CH2), 56.2 (OCH3), 56.1 (2C, OCH3), 56.0 (OCH3), 14.6 (CH3);
ESI-HRMS calcd for [C23H25NO6 + Na]+ 434.1580, found 434.1560.
According to the general procedure B*, 1j and 2a were cyclized by
conventional heating (36 h), followed by oxidation (2 h). Purification
by flash column chromatography (cyclohexane/EtOAc, 2:1) yielded 6j
(226 mg, 57%) as a yellow foam. According to general procedure C, 1j
and 2a were cyclized by conventional heating (36 h), followed by
oxidation (9 h) with anhydrous copper(I) chloride (20 mg, 20 mol %)
with addition of diethyl azodicarboxylate (92 μL, 20 mol %, 40% in
toluene) and 1,10-phenanthroline (36 mg, 20 mol %). Purification by
flash column chromatography (cyclohexane/EtOAc, 2:1) yielded 6j
(152 mg, 37%) as a yellow foam.
Ethyl 3-(Biphenyl-4-yl)-5-phenyl-1H-pyrrole-2-carboxylate
(6k). According to the general procedure A, 1k and 2a were cyclized
by conventional heating (24 h), followed by oxidation (48 h)
(additional 0.27 equiv of DDQ added after 24 h). Purification by flash
column chromatography (cyclohexane/EtOAc, 10:1) yielded 6k (225
mg, 61%) as a light brown solid: mp: 197−200 °C; Rf = 0.52 (silica gel,
cyclohexane/EtOAc, 2:1); IR (ATR) ν (cm−1) = 3310, 1654, 1443,
1291, 1265, 1134, 1033, 816, 761, 694; 1H NMR (400 MHz, CDCl3) δ
(ppm) = 9.39 (br s, 1H, NH), 7.75−7.58 (m, 8H, H-2′/3′/5′/6′/2″/
6″/2‴/6‴), 7.51−7.40 (m, 4H, H-3″/5″/3‴/5‴), 7.40−7.30 (m, 2H,
H-4″/4‴), 6.69 (d, J = 3.0 Hz, 1H, H-4), 4.32 (q, J = 7.1 Hz, 2H,
CH2), 1.30 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (100.6 MHz, CDCl3)
δ (ppm) = 161.3 (CO), 141.2 (C-1″), 140.0 (C-4′), 135.6 (C-5),
134.2 (C-1′), 133.2 (C-3), 131.2 (C-1‴), 130.1 (2C, C-2′/6′), 129.2
(2C, C-3‴/5‴), 128.9 (2C, C-3″/5″), 128.1 (C-4‴), 127.3 (C-4″),
127.2 (2C, C-3′/5′), 126.6 (2C, C-2″/6″), 124.9 (2C, C-2‴/6‴),
118.7 (C-2), 110.0 (C-4), 60.6 (CH2), 14.5 (CH3); ESI-HRMS calcd
for [C25H21NO2 + H]+ 368.1651, found 368.1654. According to the
general procedure B**, 1k and 2a were cyclized by conventional
heating (8 h), followed by oxidation (1 h). Purification by flash
column chromatography (cyclohexane/EtOAc, 8:1) yielded 6k (200
mg, 55%) as a light brown solid. According to general procedure C, 1k
and 2a were cyclized by conventional heating (36 h), followed by
oxidation (22 h) with anhydrous copper(I) chloride (20 mg, 20 mol
%) with addition of diethyl azodicarboxylate (92 μL, 20 mol %, 40% in
toluene) and 1,10-phenanthroline (36 mg, 20 mol %). Purification by
flash column chromatography (cyclohexane/EtOAc, 8:1) yielded 6k
(106 mg, 29%) as a light brown solid.
Ethyl 3-[4-(Dimethylamino)phenyl]-5-phenyl-1H-pyrrole-2-
carboxylate (6l).23 According to the general procedure B**, 1l
and 2a were cyclized by conventional heating (12 h), followed by
oxidation (1 h). Purification by flash column chromatography
(cyclohexane/EtOAc, 6:1) yielded 6l (151 mg, 46%) as a yellow
solid: mp 130−133 °C; Rf = 0.39 (silica gel, cyclohexane/EtOAc, 2:1);
1H NMR (400 MHz, CDCl3) δ (ppm) = 9.30 (br s, 1H, NH), 7.64−
7.58 (m, 2H, H-2′/6′), 7.58−7.52 (m, 2H, H-3″/5″), 7.46−7.39 (m,
2H, H-2″/6″), 7.36−7.29 (m, 1H, H-4″), 6.82−6.75 (m, 2H, H-3′/5′),
6.61 (d, J = 3.1 Hz, 1H, H-4), 4.31 (q, J = 7.1 Hz, 2H, CH2), 3.00 [s,
6H, N(CH3)2], 1.32 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (100.6 MHz,
CDCl3) δ (ppm) = 161.3 (CO), 149.8, 135.2, 134.0, 131.3, 130.3
(2C), 129.0 (2C), 127.8, 124.7 (2C), 123.0, 118.0 (C-2), 111.9 (2C),
109.6 (C-4), 60.3 (CH2), 40.7 (2C, N-CH3), 14.4 (CH3). The data are
in accordance with the literature.23
Ethyl 3-(4-Hydroxyphenyl)-5-phenyl-1H-pyrrole-2-carboxy-
late (6m).43 According to the general procedure B**, 1m and 2a
were cyclized by conventional heating (18 h), followed by oxidation (1
h). Purification by flash column chromatography (cyclohexane/EtOAc,
3:1) yielded 6m (135 mg, 44%) as a light yellow solid: mp 204−206
1
°C; Rf = 0.27 (silica gel, cyclohexane/EtOAc, 2:1); H NMR (400
MHz, CDCl3) δ (ppm) = 9.25 (br s, 1H, NH), 7.62−7.56 (m, 2H, H-
2″/6″), 7.53−7.48 (m, 2H, H-2′/6′), 7.47−7.40 (m, 2H, H-3″/5″),
7.36−7.29 (m, 1H, H-4″), 6.89−6.82 (m, 2H, H-3′/5′), 6.59 (d, J =
3.0 Hz, 1H, H-4), 4.92 (br s, 1H, OH), 4.30 (q, J = 7.1 Hz, 2H, CH2),
1.29 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (100.6 MHz, CDCl3) δ
(ppm) = 161.2 (CO), 154.8, 135.3, 133.3, 131.1, 130.8 (2C), 129.1
(2C), 127.9, 127.6, 124.7 (2C), 118.2 (C-2), 114.6 (2C), 109.7 (C-4),
60.4 (CH2), 14.3 (CH3). The data are in accordance with the
literature.43
Ethyl 3-(2-Bromo-4,5-dimethoxyphenyl)-5-(3,4-dimethoxy-
phenyl)-1H-pyrrole-2-carboxylate (6n). According to the general
procedure B*, 1n (203 mg, 0.50 mmol) and 2a (74 mg, 0.53 mmol,
1.05 equiv) were cyclized by conventional heating (6 h), followed by
oxidation (2 h). Purification by flash column chromatography
(cyclohexane/EtOAc, 2:1) yielded 6n (114 mg, 47%) as a light
brown foam: Rf = 0.20 (silica gel, cyclohexane/EtOAc, 2:1); IR (ATR)
ν (cm−1) = 3313, 2837, 1669, 1504, 1435, 1249, 1208, 1022, 782, 766;
1H NMR (400 MHz, CDCl3) δ (ppm) = 9.29 (br s, 1H, NH), 7.16
(dd, J = 8.3, 2.1 Hz, 1H, H-6″), 7.10 (s, 1H, H-3′), 7.08 (d, J = 2.1 Hz,
1H, H-2″), 6.92 (d, J = 8.3, 1H, H-5″), 6.89 (s, 1H, H-6′), 6.46 (d, J =
3.0, 1H, H-4), 4.19 (q, J = 7.1 Hz, 2H, CH2), 3.95 (s, 3H, OCH3-4″),
3.92 (s, 3H, OCH3-4′), 3.91 (s, 3H, OCH3-3″), 3.86 (s, 3H, OCH3-
5′), 1.14 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (100.6 MHz, CDCl3) δ
(ppm) = 161.3 (CO), 149.5 (C-3″), 149.2 (C-4″), 148.7 (C-4′),
147.7 (C-5′), 135.4 (C-5), 131.6 (C-3), 129.1 (C-1′), 124.3 (C-1″),
119.8 (C-2), 117.5 (C-6″), 115.2 (C-3′), 114.5 (C-6′), 114.4 (C-2′),
111.7 (C-5″), 109.8 (C-4), 108.4 (C-2″), 60.4 (CH2), 56.3 (OCH3),
56.2 (2C, OCH3), 56.1 (OCH3), 14.3 (CH3); ESI-HRMS calcd for
[C23H24(79Br)NO6 + Na]+ 512.0685, found 512.0695.
Ethyl 3-(3,4-Dimethoxyphenyl)-5-(furan-2-yl)-1H-pyrrole-2-
carboxylate (6o). According to the general procedure A, 1o and
2a were cyclized by microwave-assisted reaction (2 h, 150 °C, 120 W),
followed by microwave-assisted oxidation (2 h, 150 °C, 120 W).
Purification by flash column chromatography (cyclohexane/EtOAc,
7:1) yielded 6 (71 mg, 21%) as a yellow oil: Rf = 0.32 (silica gel,
cyclohexane/EtOAc, 2:1); IR (ATR) ν (cm−1) = 3301, 2931, 1665,
1523, 1438, 1241, 1113, 1024, 802, 729; 1H NMR (400 MHz, CDCl3)
δ (ppm) = 9.38 (br s, 1H, NH), 7.44 (dd, J = 1.8, 0.7 Hz, 1H, H-5″),
7.19 (d, J = 2.0 Hz, 1H, H-2′), 7.18 (dd, J = 8.2, 2.0 Hz, 1H, H-6′),
6.89 (d, J = 8.2 Hz, 1H, H-5′), 6.57 (dd, J = 3.4, 0.7 Hz, 1H, H-3″),
6.52 (d, J = 3.0 Hz, 1H, H-4), 6.48 (dd, J = 3.4, 1.8, 1H, H-4″), 4.29
(q, J = 7.1 Hz, 2H, CH2), 3.92 (s, 3H, OCH3), 3.91 (s, 3H, OCH3),
1.29 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (100.6 MHz, CDCl3) δ
(ppm) = 161.0 (CO), 148.5 (C-4′), 148.2 (C-3′), 146.6 (C-2″),
142.0 (C-5″), 133.3 (C-3), 127.5 (C-1′), 126.9 (C-5), 122.0 (C-6′),
117.7 (C-2), 113.2 (C-2′), 111.9 (C-4″), 110.6 (C-5′), 108.8 (C-4),
F
dx.doi.org/10.1021/jo5021823 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
105.7 (C-3″), 60.5 (CH2), 56.0 (2C, OCH3), 14.5 (CH3); ESI-HRMS
calcd for [C19H19NO5 + Na]+ 364.1161, found 364.1174.
4″), 110.5 (C-5′), 108.7 (C-4), 105.3 (C-3″), 81.2 (C(CH3)3), 55.9
(2C, OCH3), 28.4 (3C, CH3); ESI-HRMS calcd for [C21H23NO5 +
Na]+ 392.1474, found 392.1479.
tert-Butyl 3,5-Diphenyl-1H-pyrrole-2-carboxylate (6p). Ac-
cording to the general procedure A, 1a and 2b (251 mg, 1.50 mmol,
1.5 equiv) were cyclized by conventional heating (17 h), followed by
oxidation (96 h) with DDQ (454 mg, 2.00 mmol, 2.0 equiv).
Purification by flash column chromatography (cyclohexane/EtOAc,
6:1) yielded 6p (94 mg, 30%) as a purple oil: Rf = 0.40 (silica gel,
cyclohexane/EtOAc, 4:1); IR (ATR) ν (cm−1) = 3306, 2977, 1657,
1432, 1270, 1253, 1164, 1129, 757, 692; 1H NMR (400 MHz, CDCl3)
δ (ppm) = 9.50 (br s, 1H, NH), 7.66−7.57 (m, 4H, H-2′/6′/2″/6″),
7.49−7.38 (m, 4H, H-3′/5′/3″/5″), 7.38−7.30 (m, 2H, H-4′/4″), 6.63
(d, J = 3.0 Hz, 1H, H-4), 1.48 (s, 9H, CH3); 13C NMR (100.6 MHz,
CDCl3) δ (ppm) = 161.1 (CO), 135.7 (C-1″), 134.9 (C-5), 132.7
(C-3), 131.3 (C-1′), 129.8 (2C, C-2′/6′), 129.1 (2C, C-3′/5′), 127.8
(C-4″), 127.7 (2C, C-3″/5″), 127.0 (C-4′), 124.8 (2C, C-2″/6″),
120.3 (C-2), 109.9 (C-4), 81.4 (C(CH3)3), 28.4 (3C, CH3); ESI-
HRMS calcd for [C21H21NO2 + Na]+ 342.1470, found 342.1473.
tert-Butyl 5-(4-Fluorophenyl)-3-(4-methoxyphenyl)-1H-pyr-
role-2-carboxylate (6q). According to the general procedure A, 1g
and 2b (251 mg, 1.50 mmol, 1.5 equiv) were cyclized by conventional
heating (21.5 h), followed by oxidation (72 h) with DDQ (454 mg,
2.00 mmol, 2.0 equiv). Purification by flash column chromatography
(cyclohexane/EtOAc, 6:1) yielded 6q (145 mg, 40%) as a light yellow
solid: mp 121−123 °C; Rf = 0.22 (silica gel, cyclohexane/EtOAc, 6:1);
IR (ATR) ν (cm−1) = 3352, 2931, 1660, 1504, 1444, 1244, 1161, 1129,
Ethyl 4-Bromo-3,5-diphenyl-1H-pyrrole-2-carboxylate 7.
Method I: According to general procedure A, 1a and 2a were placed
in a microwave vessel, dissolved in pyridine (3 mL), and cyclized via
microwave-assisted cyclization (2 h). After dilution with pyridine (7
mL) and adding DDQ (250 mg, 1.10 mmol, 1.1 equiv) in acetic acid
(4 mL), the reaction mixture was refluxed for 20 h. The crude reaction
mixture was subjected to bromination at ambient temperature by the
addition of NBS (187 mg, 1.05 mmol, 1.05 equiv), and additional NBS
(100 mg, 0.5 equiv) was added after 24 h, followed by stirring for
another 5 h. Purification by flash column chromatography (cyclo-
hexane/EtOAc, 6:1) yielded 7 (181 mg, 49%) as a colorless solid: mp
145−148 °C; Rf = 0.28 (silica gel, cyclohexane/EtOAc, 6:1); IR
(ATR) ν (cm−1) = 3282, 2979, 1670, 1434, 1289, 1264, 1165, 1024,
1
762, 694; H NMR (400 MHz, CDCl3) δ (ppm) = 9.30 (br s, 1H,
NH), 7.78−7.72 (m, 2H, H-2″/6″), 7.54−7.46 (m, 2H, H-3″/5″),
7.46−7.33 (m, 6H, H-4″/Ph′), 4.18 (q, J = 7.1 Hz, 2H, CH2), 1.13 (t, J
= 7.1 Hz, 3H, CH3); 13C NMR (100.6 MHz, CDCl3) δ (ppm) = 160.8
(CO), 133.4 (Cq), 133.1 (C-5), 132.3 (Cq), 130.8 (2C, C-2′/6′),
130.7 (C-1″), 129.0 (2C, C-3″/5″), 128.8 (C-4″), 127.73 (C-4′),
127.72 (2C, C-2″/6″), 127.6 (2C, C-3′/5′), 119.3 (C-2), 99.0 (C-4),
60.8 (CH2), 14.1 (CH3); ESI-HRMS calcd for [C19H16(79Br)NO2 +
Na]+ 392.0262, found 392.0267. Method II: 1a and 2a were subjected
to microwave-assisted cyclization (1 h), followed by oxidation via
anhydrous [Cu(MeCN)4]PF6 (38 mg, 10 mol %) with addition of
2,2′-bipyridine (16 mg, 10 mol %) (with air continuously passing
through the reaction mixture for copper) for 13 h. To the crude
reaction mixture was added NBS (187 mg, 1.05 mmol, 1.05 equiv).
After stirring for 5 h at ambient temperature, purification by flash
column chromatography (cyclohexane/EtOAc, 6:1) yielded 7 (208
mg, 56%) as a colorless solid.
General Procedure for the Synthesis of Pyrrole-2-carbox-
amides 9. Unless otherwise noted, the respective enone (1.00 mmol,
1.00 equiv) and amide (1.20 mmol, 1.20 equiv) were placed in a
microwave vessel and dissolved in pyridine (4 mL). Molecular sieve 3
Å (100 mg) was added, followed by sealing the vessel and heating to
130 °C for 60 min at 200 W in a microwave reactor. The reaction
temperature increased from 25 to 130 °C in 180 s and was maintained
at 130 °C for the rest of the period (until complete conversion of the
enone was determined, as indicated by TLC or HPLC-MS, 1−2 h).
Then, Cu(OAc)2 (1.20 mmol, 218 mg, 1.20 equiv or 2.00 mmol, 363
mg, 2.00 equiv) was introduced in one portion and the mixture was
heated under the same microwave conditions until complete
conversion of the dihydropyrrole was determined (1−2 h), as
indicated by TLC or HPLC-MS. Upon completion, the solvent was
removed by azeotropic distillation with toluene. The residue was
dissolved in dichloromethane (60 mL) and subsequently washed with
a 0.1 M Na2-EDTA solution (3 × 30 mL) and brine (30 mL). The
organic phase was dried over Na2SO4 and filtered. The solvent was
removed in vacuo, and the resiude was purified by column
chromatography on silica gel.
N,N-Dimethyl-3,5-diphenyl-1H-pyrrole-2-carboxamide (9a).
The general procedure was applied using 2a, 2-amino-N,N-
dimethylacetamide hydrochloride (8a), and Cu(OAc)2 (1.20 mmol,
218 mg, 1.20 equiv). After cyclization (2 h) and oxidation (2 h),
purification of the crude reaction mixture by flash column
chromatography (cyclohexane/EtOAc, 3:1) yielded 9a (133 mg,
46%) as a colorless solid: mp 155−156 °C; Rf = 0.16 (silica gel,
cyclohexane/EtOAc, 3:1); IR (ATR) ν (cm−1) = 3145, 3062, 3025,
2929, 1650, 1595, 1491, 1274, 760, 696; 1H NMR (400 MHz, DMSO-
d6) δ (ppm) = 11.78 (d, J = 2.8 Hz, 1H, NH), 7.80−7.73 (m, 2H, H-
2″/6″), 7.43−7.32 (m, 6H, H-2′/6′/3′/5′/3″/5″), 7.27−7.17 (m, 2H,
H-4′/4″), 6.84 (d, J = 2.8 Hz, 1H, H-4), 2.95 (s, 3H, CH3), 2.64 (s,
3H, CH3); 13C NMR (100.6 MHz, DMSO-d6) δ (ppm) = 164.4 (C
O), 135.4 (C-1′), 132.3 (C-5), 131.9 (C-1″), 128.7 (2C, CPh), 128.6
(2C, CPh), 126.43 (2C, CPh), 126.36 (C-4″), 126.0 (C-4′), 124.2 (C-3),
124.0 (2C, C-2″/6″), 123.3 (C-2), 105.3 (C-4), 37.7 (CH3), 34.4
(CH3); ESI-HRMS calcd for [C19H18N2O + H]+ 291.1497, found
1
1040, 805; H NMR (400 MHz, CDCl3) δ (ppm) = 9.18 (br s, 1H,
NH), 7.56−7.48 (m, 4H, H-2″/6″/H-3′/H-6″), 7.15−7.08 (m, 2H, H-
4′/5′), 6.95−6.90 (m, 2H, H-3″/5″) 6.49 (d, J = 3.0 Hz, 1H, H-4),
3.85 (s, 3H, OCH3), 1.48 (s, 9H, CH3); 13C NMR (100.6 MHz,
1
CDCl3) δ (ppm) = 162.5 (d, JC,F = 248 Hz, C-4″), 160.1 (CO),
158.9 (C-4′), 133.9 (C-5), 132.5 (C-3), 130.8 (2C, C-2′/6′), 127.9 (C-
1′), 127.8 (d, 4JC,F = 3.3 Hz, C-1″), 126.6 (d, 2C, 3JC,F = 8.1 Hz, C-2″/
6″), 120.0 (C-2), 116.2 (d, 2C, 2JC,F = 22 Hz, C-3″/5″), 113.2 (2C, C-
3′/5′), 109.7 (C-4), 81.4 (C(CH3)3), 55.4 (OCH3), 28.0 (3C, CH3);
ESI-HRMS calcd for [C22H22FNO3 + Na]+ 390.1481, found 390.1488.
tert-Butyl 3-(2-Chlorophenyl)-5-(4-fluorophenyl)-1H-pyr-
role-2-carboxylate (6r). According to the general procedure A, 1h
(108 mg, 0.40 mmol) and 2b (104 mg, 0.6 mmol, 1.5 equiv) were
cyclized by conventional heating (17.5 h), followed by oxidation (72
h) with DDQ (182 mg, 0.80 mmol, 2.0 equiv). Purification by flash
column chromatography (cyclohexane/EtOAc, 6:1) yielded 6r (84
mg, 57%) as a light purple solid: mp 127−129 °C; Rf = 0.37 (silica gel,
cyclohexane/EtOAc, 6:1); IR (ATR) ν (cm−1) = 3273, 2978, 1660,
1444, 1303, 1158, 1136, 838, 817, 757; 1H NMR (400 MHz, CDCl3) δ
(ppm) = 9.58 (br s, 1H, NH), 7.59−7.51 (m, 2H, H-2″/6″), 7.46−
7.40 (m, 1H, H-3′), 7.37−7.31 (m, 1H, H-6″), 7.29−7.22 (m, 2H, H-
4′/5′), 7.13−7.06 (m, 2H, H-3″/5″) 6.46 (d, J = 3.0 Hz, 1H, H-4),
1.29 (s, 9H, CH3); 13C NMR (100.6 MHz, CDCl3) δ (ppm) = 162.4
1
(d, JC,F = 248 Hz, C-4″), 161.0 (CO), 135.6 (C-2′), 134.1 (C-5),
134.1 (C-1′), 131.8 (C-6′), 129.1 (C-3′), 129.0 (C-3), 128.4 (C-4′),
127.8 (d, 4JC,F = 3.0 Hz, C-1″), 126.6 (d, 2C, 3JC,F = 8.1 Hz, C-2″/6″),
126.1 (C-5′), 122.0 (C-2), 116.2 (d, 2C, 2JC,F = 22 Hz, C-3″/5″), 109.9
(C-4), 81.1 (C(CH3)3), 28.0 (3C, CH3); ESI-HRMS calcd for
[C21H19FClNO2 + Na]+ 394.0986, found 394.0990.
tert-Butyl 3-(3,4-Dimethoxyphenyl)-5-(furan-2-yl)-1H-pyr-
role-2-carboxylate (6s). According to the general procedure A, 1o
and 2b were cyclized by conventional heating (48 h), followed by
oxidation (30 h). Purification by flash column chromatography
(cyclohexane/EtOAc, 4:1) yielded 6s (69 mg, 19%) as a yellow oil:
Rf = 0.35 (silica gel, cyclohexane/EtOAc, 4:1); IR (ATR) ν (cm−1) =
1
3307, 2933, 1672, 1438, 1241, 1164, 1153, 1026, 803, 728; H NMR
(400 MHz, CDCl3) δ (ppm) = 9.34 (br s, 1H, NH), 7.41 (dd, J = 1.8,
0.7 Hz, 1H, H-5″), 7.12 (dd, J = 8.2, 2.0 Hz, 1H, H-6′), 7.10 (d, J = 2.0
Hz, 1H, H-2′), 6.88 (d, J = 8.2 Hz, 1H, H-5′), 6.53 (dd, J = 3.4, 0.7 Hz,
1H, H-3″), 6.47 (d, J = 3.0 Hz, 1H, H-4), 6.45 (dd, J = 3.4, 1.8, 1H, H-
4″), 3.91 (s, 3H, OCH3-3′), 3.89 (s, 3H, OCH3-4′), 1.47 (s, 9H, CH3);
13C NMR (100.6 MHz, CDCl3) δ (ppm) = 160.5 (CO), 148.2 (C-
4′), 148.1 (C-3′), 146.7 (C-2″), 141.8 (C-5″), 132.5 (C-3), 128.0 (C-
1′), 126.3 (C-5), 122.1 (C-6′), 119.2 (C-2), 113.2 (C-2′), 111.8 (C-
G
dx.doi.org/10.1021/jo5021823 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
291.1503. The general procedure was applied using 2a, 8a, and
Cu(OAc)2 (2.00 mmol, 363 mg, 2.00 equiv). After cyclization (2 h)
and oxidation (2 h), purification of the crude reaction mixture by flash
column chromatography (cyclohexane/EtOAc, 3:1) yielded 9a (160
mg, 55%) as a colorless solid.
(3) Carter, G. A.; Dawson, G. W.; Garraway, J. L. Pestic. Sci. 1975, 6,
43.
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Ciacci, A.; Manetti, F.; Artico, M. J. Med. Chem. 2002, 45, 2720.
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Free Radical Biol. Med. 2004, 37, 1895.
N-Isobutyl-3,5-diphenyl-1H-pyrrole-2-carboxamide (9b).
The general procedure was applied using 1a, 2-amino-N-isobutyl-
acetamide hydrochloride (8b), and Cu(OAc)2 (1.20 mmol, 218 mg,
1.20 equiv). After cyclization (1 h) and oxidation (2 h), purification of
the crude reaction mixture by flash column chromatography
(cyclohexane/EtOAc, 4:1) yielded 9b (189 mg, 59%) as a colorless
solid: mp 143−144 °C; Rf = 0.18 (silica gel, cyclohexane/EtOAc, 4:1);
IR (ATR) ν (cm−1) = 3420, 3240, 3062, 2958, 1630, 1533, 1491, 1267,
817, 760, 701; 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 11.60 (d, J
= 2.8 Hz, 1H, NH), 7.84−7.77 (m, 2H, H-2″/6″), 7.54−7.47 (m, 2H,
H-2′/6′), 7.45−7.32 (m, 4H, H-3′/5′, H-3″/5″), 7.35−7.20 (m, 3H,
C(O)NH/H-4′/H-4″), 6.69 (d, J = 2.8 Hz, 1H, H-4), 3.02 (dd, J =
6.7, 5.8 Hz, 2H, CH2), 1.69 (n, J = 6.7 Hz, 1H, CH), 0.82 (d, J = 6.7
Hz, 6H, CH3); 13C NMR (100.6 MHz, DMSO-d6) δ (ppm) = 161.1
(CO), 135.7 (C-1′), 132.7 (C-5), 131.6 (C-1″), 128.8 (2C, C-2′/6′),
128.7 (2C, C-3″/5″), 128.1 (2C, C-3′/5′), 127.3 (C-3), 126.7 (C-4″),
126.4 (C-4′), 124.6 (2C, C-2″/6″), 123.6 (C-2), 108.3 (C-4), 46.3
(CH2), 28.1 (CH), 20.2 (2C, CH3); ESI-HRMS calcd for [C21H22N2O
+ H]+ 319.1810, found 319.1800.
(6) Gupton, J. T. In Heterocyclic Antitumor Antibiotics; Lee, M., Ed.;
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Petrich, S. A.; Du, K. X.; Bruce, M. A.; Vu, P.; Vargas, M.; Keertikar, K.
M.; Hosein, K. N.; Jones, C. R.; Sikorski, J. A. Tetrahedron 1998, 54,
5075.
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2014, 79, 529.
(10) Cheng, G.; Wang, X.; Bao, H.; Cheng, C.; Liu, N.; Hu, Y. Org.
Lett. 2012, 14, 1062.
(11) Giacometti, R. D.; Ramtohul, Y. K. Synlett 2009, 2010.
(12) Banwell, M. G.; Hamel, E.; Hockless, D. C. R.; Verdier-Pinard,
P.; Willis, A. C.; Wong, D. J. Biorg. Med. Chem. 2006, 14, 4627.
(13) Walsh, C. T.; Garneau-Tsodikova, S.; Howard-Jones, A. R. Nat.
Prod. Rep. 2006, 23, 517.
(14) Hombrecher, H. K.; Horter, G. Synthesis 1990, 389.
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(16) Walizei, G. H.; Breitmaier, E. Synthesis 1989, 337.
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5-(4-Fluorophenyl)-N-isobutyl-3-(4-methoxyphenyl)-1H-pyr-
role-2-carboxamide (9c). The general procedure was applied using
1g, 8b, and Cu(OAc)2 (1.20 mmol, 218 mg, 1.20 equiv). After
cyclization (2 h) and oxidation (1 h), purification of the crude reaction
mixture by flash column chromatography (cyclohexane/EtOAc, 4:1)
yielded 9c (156 mg, 43%) as a colorless solid: mp 175−176 °C (dec.);
Rf = 0.10 (silica gel, cyclohexane/EtOAc, 5:1); IR (ATR) ν (cm−1) =
1
3414, 3245, 2959, 2872, 1627, 1529, 1502, 1248, 837, 812; H NMR
(400 MHz, DMSO-d6) δ (ppm) = 11.53 (d, J = 2.8 Hz, 1H, NH),
7.88−7.79 (m, 2H, H-2″/6″), 7.47−7.38 (m, 2H, H-2′/6′), 7.28−7.18
(m, 2H, H-3″/5″), 7.11 (t, J = 5.8 Hz, C(O)NH), 6.98−6.21 (m,
2H, H-3′/5′), 6.61 (d, J = 2.8 Hz, 1H, H-4), 3.77 (s, 3H, OCH3), 3.01
(dd, J = 6.7, 5.8 Hz, 2H, CH2), 1.68 (n, J = 6.7 Hz, 1H, CH), 0.81 (d, J
= 6.7 Hz, 6H, CH3); 13C NMR (100.6 MHz, DMSO-d6) δ (ppm) =
1
161.13 (d, JC,F = 243.6 Hz, C-4″), 161.08 (CO), 158.1 (C-4′),
131.8 (C-5), 130.0 (2C, C-2′/6′), 128.4 (d, 4JC,F = 3.4 Hz, C-1″), 127.9
(C-1′), 127.2 (C-3), 126.6 (d, 3JC,F = 8.0 Hz, 2C, C-2″/6″), 123.2 (C-
2), 115.5 (d, 2JC,F = 21.7 Hz, 2C, C-3″/5″), 113.6 (2C, C-3′/5′), 108.4
(C-4), 55.1 (OCH3), 46.2 (CH2), 28.1 (CH), 20.2 (2C, CH3); ESI-
HRMS calcd for [C22H23N2O2F + H]+ 367.1822, found 367.1830.
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ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR spectra of all synthesized compounds, COSY,
HSQC and HMBC spectra of all new compounds, as well as
the crystallographic data (.cif) for compounds 6c and 9c. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(32) Du, X.; Xie, X.; Liu, Y. J. Org. Chem. 2010, 75, 510.
(33) Agarwal, S.; Knolker, H.-J. Org. Biomol. Chem. 2004, 2, 3060.
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(34) Queiroz, M.-J. R. P.; Begouin, A.; Pereira, G.; Ferreira, P. M. T.
Tetrahedron 2008, 64, 10714.
AUTHOR INFORMATION
Corresponding Author
*E-mail: opatz@uni-mainz.de (T.O.).
Notes
■
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We thank Dr. J. C. Liermann (Mainz) for NMR spectroscopy
and Dr. D. Schollmeyer (Mainz) for X-ray crystallography.
■
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I
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