Polysubstituted 2-Aminopyrrole Synthesis via Gold-Catalyzed Intermolecular Nitrene Transfer from Vinyl Azide to Ynamide: Reaction Scope and Mechanistic Insights

Article abstract of DOI:10.1021/acs.joc.5b02057

A gold-catalyzed intermolecular reaction of vinyl azides and ynamides is described. This process presents an efficient and mild approach to multisubstituted 2-aminopyrroles in good-to-excellent yields. Control experiments were carried out to distinguish the reactivity between vinyl azides and the corresponding 2H-azirines. A plausible reaction mechanism was also proposed according to previous reports and our preliminary mechanistic studies.

Full text of DOI:10.1021/acs.joc.5b02057

Article
pubs.acs.org/joc
Polysubstituted 2‑Aminopyrrole Synthesis via Gold-Catalyzed
Intermolecular Nitrene Transfer from Vinyl Azide to Ynamide:
Reaction Scope and Mechanistic Insights
Yufeng Wu,† Lei Zhu,‡ Yinghua Yu,‡ Xuesong Luo,§ and Xueliang Huang*,‡
†College of Chemistry and Chemical Engineering, Fuzhou University, Fuzhou, Fujian 350108, P. R. China
‡Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian Institute of Research on the Structure of Matter,
Chinese Academy of Sciences, Fuzhou, Fujian 350002, P. R. China
§School of Chemistry and Chemical Engineering, Shihezi University, Xinjiang Uygur Autonomous Region, 832000, P. R. China
S
* Supporting Information
ABSTRACT: A gold-catalyzed intermolecular reaction of vinyl
azides and ynamides is described. This process presents an
efficient and mild approach to multisubstituted 2-aminopyrroles
in good-to-excellent yields. Control experiments were carried out
to distinguish the reactivity between vinyl azides and the
corresponding 2H-azirines. A plausible reaction mechanism was
also proposed according to previous reports and our preliminary mechanistic studies.
Scheme 1. Gold-Catalyzed Reactions of Organic Azides with
Alkynes
INTRODUCTION
■
In the past decades, homogeneous gold catalysis has been
recognized as a convenient tool for assembling complex
functionalized structures from readily available, simple building
blocks through electrophilic activation of π systems.1 α-Oxo
gold carbene generated by alkyne oxidation is a reactive
intermediate. It can further react with various nucleophiles,
leading to useful molecules.2 Compared with α-oxo gold
carbenes, the studies on generation of azavinyl gold carbenes
are still far from fully explored.3 Recently, the research groups
of Zhang and Davies reported elegant works on the gold-
catalyzed intermolecular reaction of iminopyridium ylides with
ynamides, affording α,β-unsaturated amidines and substituted
oxazole, respectively.4 Alkynes and organic azides5 are
fundamental feedstocks, which are inexpensive and easily
accessible. In 2005, Toste and co-workers realized the first
gold-catalyzed intramolecular nitrene transfer by the reaction of
alkyne with tethered azide moiety, giving multiply substituted
pyrroles in an atom economic manner (Scheme 1a).6 This
strategy was further explored by the research groups of Zhang,7
Gagosz,8 and others9 (Scheme 1b). Intriguingly, the seemingly
simple concept of gold-catalyzed intermolecular reactions of
alkynes with organic azides leading to useful N-heterocycles by
nitrene transfer is still in its infancy.10−12
which has been proved to be a versatile reagent employed in a
variety of aza-heterocycle synthesis,15 could be considered as an
alkenyl nitrene precursor. Thus, it may fulfill the mission for the
simple concept on pyrrole synthesis by formal [2 + 3]
cycloaddition of alkyne and vinyl azide. With this consideration
in mind, and inspired by the seminal work of Toste and co-
workers (Scheme 1a), we sought to develop a straightforward
Pyrroles are important heterocycles that are embedded in a
broad range of natural products and pharmaceutical agents.13
Not surprisingly, recently people have witnessed the develop-
ment of myriad methods for their synthesis.14 From a synthetic
standpoint, the ability to assemble these heterocycles from
simple precursors in an atom- and step-economic manner
would be highly rewarding. Retrosynthetic cleavage of the C2−
N and C3−C4 bonds of the pyrrole core furnishes two
fragments, an alkynyl unit and a three-atom unit. Vinyl azide,
Received: September 3, 2015
Published: October 27, 2015
© 2015 American Chemical Society
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Scheme 2. Gold-Catalyzed Divergent Formal Cycloadditions of Ynamides with Vinyl Azides or 2H-Azirines
approach for multiply substituted pyrrole synthesis16,17 by gold-
catalyzed intermolecular reaction of alkyne and vinyl azide
(Scheme 1c). Recently, Liu and co-workers reported a
conceptually similar process for gold-catalyzed formal cyclo-
additions of ynamides with vinyl azides or 2H-azirines,10
yielding substituted pyrroles (Scheme 2a,b) and 1H-benzo[b]-
azepine derivertives (Scheme 2c), respectively (mostly R3 = H).
The divergent reaction modes and regioselectivity of the
corresponding products indicated that the pathway involving
gold carbene intermediate was less likely.
SbF6) as catalyst, the reaction of ynamide 1a with vinyl azide 2b
proceeded smoothly under relatively mild conditions (60 °C, in
DCE), affording pyrrole 3b in high yield (Table 1, entry 2).
Replacing ynamide 1a by 1b, which contains an oxazolidonyl
ring, led to nearly quantitative formation of pyrrole 3c. It is
Table 1. Effect of Reaction Parameters on the Gold-
a
Catalyzed Reaction of 1b and 2b
RESULTS AND DISCUSSION
■
As shown in Scheme 3a, in the presence of the Echavarren’s
catalyst [JohnPhosAu(MeCN)SbF6],18 the reaction of vinyl
time
(h)
yield
b
Scheme 3. Gold-Catalyzed Nitrene Transfers Using Vinyl
Azide or 2H-Azirine as Nitrene Precursors
entry
variation from the standard conditions
no change
(%)
1
2
2.5
2.5
2.5
10.5
9.5
15
98
80
74
37
10
42
25
98
55
96
93
81
95
17
98
ynamide 1a was tested instead of 1b
JohnPhosAuNTf2 was used as catalyst
Ph3PAuNTf2 was used as catalyst
L1AuNTf2 was used as catalyst
3
4
5
6
L2AuNTf2 was used as catalyst
7
IPrAuNTf2 was used as catalyst
tBuXPhosAu(MeCN)SbF6 was used as catalyst
IPrAu(PhCN)SbF6 was used as catalyst
IAdAu(PhCN)SbF6 was used as catalyst
the reaction was run in PhMe
16
8
2.5
16
9
10
11
12
13
14
15
2.5
2.5
2.5
2.5
24
the reaction was run in MeCN
the reaction was run in CHCl3
the reaction was run in THF
the reaction was run in 1,4-dioxane
2.5
azide 2a with ynamide19,20 1a indeed took place under
remarkably mild conditions, giving multisubstituted 2-amino-
pyrrole 3a in moderate yield. Noticing that vinyl azide 2a could
slowly convert to 2H-azirine 4a at room temperature, a control
experiment using 2H-azirine 4a as nitrene precursor was carried
out consequently.21,22 This led to our recent unexpected
discovery of gold-catalyzed pyrrole synthesis by formal
cycloaddition of 2H-azirines and ynamides (Scheme 3b).23
However, when 2H-azirine 4b was tested, higher temperature
and extended reaction time were required for the reaction to
reach full conversion (Scheme 3c). Combining these intriguing
observations with our initial hypothesis, we decided to explore
further the gold-catalyzed intermolecular nitrene transfer
reaction of vinyl azides with ynamides.
a
All the reactions were carried out in 0.3 mmol scale. The ratio of 1b
b
to 2b was 1:1.2. Pyrrole 3b was obtained.
Optimization of the Reaction Conditions. Pleasingly, by
employing a cationic gold complex (JohnPhosAu(MeCN)-
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worthwhile to mention that we did not observe any formation
of 2H-azirine 4b in the reaction mixture (vide infra). Upon
switching the counteranion to bis(trifluoromethanesulfonyl)-
3n) in high yields. Ynamide possessing an ortho substituent was
tolerated as well, and pyrrole 3o was isolated in high yield. In
addition, the ynamide derived from thiophenyl acetylene was
also suitable for this reaction (cf., 3p). Interestingly, the
reaction of cyclopropyl ynamide took place well, and pyrrole 3q
was obtained in 54% yield.
Scope of Vinyl Azides. Subsequently, an array of vinyl
azides 2 was surveyed under the standard conditions to react
with ynamide 1b. As shown in Table 3, vinyl azides bearing
−
imide (NTf2 ) in the catalyst, a slightly lower conversion of
ynamide 1b was observed (Table 1, entry 3). A brief screening
of the gold catalyst revealed that the catalysts bearing bulky
electron-rich phosphine ligands gave the best results, and the
reactions were complete in relatively short time while high
efficiency was maintained (Table 1, entries 3−6 and 8). The
catalyst IAdAu(PhCN)SbF6 could catalyze the reaction well
(Table 1, entry 10). Surprisingly, the reaction catalyzed by
IPrAu(PhCN)SbF6 was significantly slow (Table 1, entry 9).
To our delight, the current gold-catalyzed nitrene transfer was
compatible with a varietyof solvents, except tetrahydrofuran
(Table 1, entries 11−15).
Table 3. Reaction Scope of Vinyl Azides 2 with Ynamides
a
1b
Scope of Ynamides. With the optimal reaction conditions
established, the scope of the ynamides was investigated. As
shown in Table 2, changing the protecting groups of the amide
a
Table 2. Reaction Scope of Ynamides 1 with Vinyl Azide 2b
a
All the reactions were carried out in 0.3 mmol scale. The ratio of 1b
to 2 was 1:1.2.
electron-donating groups (methyl, methoxy) at the para
position of the phenyl ring reacted well with ynamide 1b,
giving the corresponding pyrroles in high yields (Table 3, 3r
and 3s). Similarly, substrates 2t, 2u, and 2v, bearing electron-
withdrawing groups, exhibited good reactivity, affording the
desired pyrroles 3t−3v in good-to-excellent yields. Again, vinyl
azide 2w containing a thiophenyl group could react with
ynamide 1b, furnishing pyrrole 3w in high yield, albeit slightly
longer reaction time was required. Furthermore, the structure
and regioselectivity were confirmed by single-crystal X-ray
analysis of pyrroles 3e and 3s.24
Elucidation of the Mechanism. It is well-known that vinyl
azide could transform to 2H-azirine upon heating.21b To verify
whether 2H-azirine 4b is a real intermediate for the nitrene
transfer, we monitored the reaction of ynamide 1b with a slight
1
excess (1.2 equiv) of vinyl azide 2b by H NMR spectroscopy.
a
All the reactions were carried out in 0.3 mmol scale. The ratio of 1 to
As depicted in Figure 1, the reaction is selective and highly
efficient. Again, we did not observe any formation of 2H-azirine
4b, and the excess amount of 2b remained intact. Additionally,
we performed a controlling experiment by using 2H-azirine 4b
as reaction partner instead of 2b. Surprisingly, the reaction of
4b with ynamide 1b was significantly slow. Even after extended
reaction time, low conversion of both starting materials was
observed (Scheme 4).
It should be noted that, slightly prior to our completion of
this work, Liu and co-workers reported a related gold-catalyzed
formal cycloaddition of ynamides with vinyl azides or 2H-
azirines.10 Nevertheless, under their standard conditions, 2H-
2b was 1:1.2.
moiety had no significant influence on the reaction efficiency
(cf. 3b and 3d). In general, a series of ynamides bearing both
electron-donating (methyl, ethyl, and methoxy, cf., 3e, 3g−3j)
and electron-withdrawing (chloro, bromo, and fluoro, cf., 3k−
3m) groups on the phenyl ring were compatible with the
reaction conditions, providing the desired products in
satisfactory yields. The ynamides containing methyl or chloro
group at the meta position of the phenyl ring reacted well with
2b, affording the corresponding 2-aminopyrroles (cf. 3f and
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diazabicycloundec-7-ene, which also possesses a CN double
bond inside the ring system, N/SN 15.29/0.70).27 However,
vinyl azide is a neutral molecule; the nucleophilicity of the azide
moiety may be further undermined by the adjacent double
bonds. Moreover, the three-member ring of 2H-azirine may
increase the reactivity of CN, thus making it more
nucleophilic than the corresponding vinyl azide 2. On the
other hand, 2H-azirine 4b bears an aliphatic group (the
inductive effect of the methyl group is electron-donating) on
the three-member ring; thus, the nitrogen atom is more
electron-releasing than the one in 4a (the resonance effect of
the phenyl group may reduce the nucleophilicity of the
nitrogen atom). Furthermore, considering that 4a is more
sterically hindered than 4b, one can easily assume that 2H-
azirine 4b could coordinate better to the bulky cationic gold
catalyst [JohnPhosAu(MeCN)SbF6] than 4a. In other words,
for the reaction of ynamide 1 with 2H-azirine 4b under
standard conditions, the large excess of 4b compared to gold
catalyst, may lead to partial poisoning of the gold catalyst.26 To
test this speculation, a control experiment was carried out. As
expected, under otherwise identical conditions, addition of 1.2
equiv of 2H-azirine 4b to the reaction of 1b and 2b led to a low
conversion of ynamide 1b (Scheme 6). These considerations
well-explained the distinct behaviors of vinyl azides and the
corresponding 2H-azirines as shown in Schemes 3 and 4.
1
Figure 1. H NMR monitoring of the reaction of ynamide 1b with
vinyl azide 2b.
Scheme 4. Gold-Catalyzed Reaction of Ynamide 1b with 2H-
Azirine 4b
Scheme 6. Reaction of Ynamide 1b of with Vinyl Azide 2b in
the Presence of 4b
azirine was proposed as the reactive intermediate for the
nitrene transfer based on their observation. However, when the
vinyl azide derived from styrene was tested under our standard
conditions, very low conversion of the ynamide was observed.25
Interestingly, with ynamide possessing an electron donating
group (MeO−) at the meta position of the phenyl ring, a
switched reaction mode was observed by Liu and co-workers
(from [2 + 3] to [4 + 3]).10 The regioselectivity of the product
further indicated the involvement of 2H-azirine as a reactive
intermediate. Thus, the ynamide 1r was prepared and subjected
to our optimal conditions; as depicted, the reaction of 1r with
vinyl azide 2b gave pyrrole 3rb ([2 + 3]) and 1H-
benzo[b]azepine 5rb ([4 + 3]) in 23% and 36% yields,
respectively (Scheme 5). On the basis of all the observation
from Liu10 and ourselves (Figure 1), we speculate that a
process involving the slow generation of 2H-azirine, which was
further consumed spontaneously, was possible.26
To identify the mechanism of this formal cycloaddition of
ynamides with vinyl azides, ynamide 1z bearing an n-Bu group
was prepared and subjected to the reaction with vinyl azide 2b.
Pyrrole 3z was isolated in 28% yield, but we could not verify the
formation of aza-triene 6a from the complicated reaction
mixture (Scheme 7a). Interestingly, upon altering the amide
moiety (Scheme 7b, from carbamate-substituted ynamide to
sulfonyl-substituted ynamide), from the reaction mixture of
ynamide 1aa with 2b, we could observe the formation of aza-
1
triene 6b by H NMR spectroscopy analysis, which may be
generated from the potential gold carbene intermediate.28,29
To further probe the involvements of gold carbene
intermediate, we envisioned that the introduction of a benzyl
group on the terminal position of the triple bond may facilitate
1,2-H insertion of the suspecting gold carbene intermediate.
Much to our delight, under the standard conditions, from the
reaction of ynamide 1ab with vinyl azide 2b, we could observe
the formation of pyrrole 3ab and dihydropyridine 7, which
were isolated in 7% and 8% yields, respectively (Scheme 8a).
For comparison of the reactivity of vinyl azide 2 and 2H-
azirine 4, several factors need to be considered. For example,
according to Mayr’s nucleophilicity scale, azide anion (N/SN
20.50/0.59) exhibits better nucleophilicity than DBU (1,8-
Scheme 5. Gold-Catalyzed Reaction of Ynamide 1r with Vinyl Azide 2b
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Scheme 7. Reaction of Ynamide 1z or 1aa with Vinyl Azide 2b
Scheme 8. Reaction of Ynamide 1ab with Vinyl Azide 2b or 2H-Azirine 4a
Similarly, under our previous conditions,23 polysubstituted 2-
aminopyrridine 8 was isolated in 17% yield by the reaction of
ynamide 1ab with 2H-azirine 4a. The structure of 8 was
confirmed by X-ray crystallographic analysis (Scheme 8b).
From a mechanistic viewpoint, the generation of 7 or 8 may be
attributed to 1,2-H insertion of the gold carbene intermediate A
giving aza-triene B. A sequence of electrocyclization, isomer-
ization, or oxidation30 will lead to the formation of
dihydropyridine or 2-aminopyrridine. To further clarify the
existence of carbene intermediate A, we performed a
deuterium-labeling experiment.26,31 As depicted, in the
presence of 3 equiv of D2O, less than 15% deuterium
incorporation was observed in dihydropyridine 7. The small
deuterium incorporation in 7 cannot fully exclude the existence
of carbene intermediate and indicates that a nonmetal carbene
pathway for the generation of B from C/C′ is also possible.
Combining all the results obtained by Liu10 and us, a
plausible reaction mechanistic rationale for current nitrene
transfer is depicted in Scheme 9. The reaction of keteniminium
intermediate I with 2H-azirine 4, which may be generated in
situ in a very small amount from vinyl azide 2, gives zwitterions
intermediate II. Subsequent ring opening may produce gold
Scheme 9. Plausible Catalytic Cycles for the Pyrrole
Synthesis
carbene III.32 III may equilibrate to a more stabilized
intermediate III′.4b An intramolecular cyclization of III′ leads
to the formation of species IV, which contains an aza-
heterocycle backbone (pathway a, blue). Alternatively, a direct
ring closure of II would also give IV (pathway b, red).33
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dropwise via one of the dropping funnels over a period of 15 min. The
solution was stirred for an additional 10 min, and (1E)-1-
propenylbenzene (2.0 g, 16.9 mmol) was added via the other
dropping funnel over a period of 15 min. The resulting reaction
mixture was stirred for 12 h at ambient temperature and then poured
into water (50 mL) and extracted diethyl ether (50 mL × 3). The
combined organic extracts were washed with 5% aqueous solution of
sodium thiosulfate (100 mL) and water (100 mL) successively. The
combined organic layer was dried over magnesium sulfate anhydrous.
Then the solvent was removed under vacuum at ambient temperature
to yield the crude product as a pale-yellow oil (4.5 g) which is in
sufficient purity to be used for next step.
Sequential elimination of the gold catalyst and isomerization
would eventually afford substituted 2-aminopyrrole 3.
CONCLUSION
■
In summary, a gold-catalyzed polysubstituted pyrrole synthesis
by formal cycloaddition of ynamides with vinyl azides is
described. Although the precise mechanism is still not clear at
this stage, the current method for polysubstituted pyrrole
synthesis complements the studies of Liu10 and us.23
Mechanistic experiments suggest that 2H-azirine may be slowly
generated in situ and consumed spontaneously. Moreover, 2H-
azirine bearing an alkyl group on the three-membered ring (e.g.,
4b), especially when it is in large excess compared to the
catalyst, could partially poison the gold catalyst. Further studies
on gold-catalyzed aza-heterocycle synthesis via intermolecular
reactions of organic azides with alkynes are ongoing, and the
results will be reported in due course.
Note that for the preparation of 2s and 2w, 1 equiv of iodine
monochloride was employed and the starting temperature was −10
°C.
Step 2. A solution of alkyl azide (obtained from step 1, 15.7 mmol)
in dry diethyl ether (100 mL) was cooled by an ice bath, and to this
solution was added tBuOK (2.3 g, 20.4 mmol). After stirring for 4 h at
0 °C, the reaction mixture was washed with water (100 mL × 2). The
organic layer was dried over anhydrous MgSO4. Then the solvent was
removed under vacuum. The resulting residue was purified by column
chromatography on silica gel (petroleum ether), giving 2 as a pale-
yellow oil.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise indicated, all glassware
was dried by a heat gun before use and all reactions were performed
under an atmosphere of argon. All ynamides were synthesized
according to known procedures reported in the literature.23,34,35 All
solvents were distilled from appropriate drying agents prior to use.
Reaction progress was monitored by thin layer chromatography
(TLC). Visualization was achieved by ultraviolet light at 254 nm or by
staining using potassium permanganate. Flash column chromatography
was performed using silica gel 60 (200−300 mesh). Pressed KBr disks
for infrared spectra were recorded using a FT-IR spectrometer.
Wavelengths (ν) are reported in cm−1. Melting points were recorded
using a melting point thermometer. All 1H and 13C NMR spectra were
recorded in CDCl3, CD3CN, or DMSO-d6. Chemical shifts were given
in parts per million (ppm, δ), referenced to the peak of
tetramethylsilane, defined at δ = 0.00 (1H NMR); the solvent peak
of CDCl3, defined at δ = 77.0 (13C NMR); the peak of CD3CN,
defined at δ = 1.94 (1H NMR) or δ = 1.32 (13C NMR); or the peak of
DMSO-d6, defined at δ = 2.50 (1H NMR) or δ = 40.0 (13C NMR).
Coupling constants are quoted in Hz (J). 1H NMR spectroscopy
splitting patterns are designated as singlet (s), doublet (d), triplet (t),
quartet (q), pentet (p), septet (se), and octet (o). Splitting patterns
that could not be interpreted or easily visualized were designated as
multiplet (m) or broad (br). High-resolution mass spectra were
obtained using a high-resolution ESI-TOF mass spectrometer.
(E)-(1-Azidoprop-1-en-1-yl)benzene (2b).36a Compound 2b was
obtained as a yellow oil (1.86 g) in 78% yield: Rf = 0.85 (petroleum
ether); 1H NMR (400 MHz, CDCl3, TMS) δ 7.44−7.31 (m, 5H), 5.48
(q, J = 7.2 Hz, 1H), 1.72 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 137.3, 133.2, 128.8, 128.6, 128.4, 112.1, 13.8.
(E)-1-(1-Azidoprop-1-en-1-yl)-4-methylbenzene (2r). Compound
2r was obtained as a yellow oil (0.6 g) in 44% yield: Rf = 0.7
1
(petroleum ether); H NMR (400 MHz, CDCl3, TMS) δ 7.21−7.19
(m, 4H), 5.44 (q, J = 7.2 Hz, 1H), 2.37 (s, 3H), 1.70 (d, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 138.4, 137.3, 130.2, 129.1,
128.6, 111.7, 21.3, 13.8.
(E)-1-(1-Azidoprop-1-en-1-yl)-4-methoxybenzene (2s). Com-
pound 2s was obtained as a yellow oil (0.98 g) in 89% yield: Rf =
0.7 (petroleum ether); 1H NMR (400 MHz, CDCl3, TMS) δ 7.28 (d, J
= 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 5.45 (q, J = 7.2 Hz, 1H), 3.86
(s, 3H), 1.73 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
159.6, 137.0, 130.1, 125.6, 113.8, 111.5, 55.3, 13.8.
(E)-1-(1-Azidoprop-1-en-1-yl)-4-chlorobenzene (2t). Compound
2t was obtained as a yellow oil (0.55 g) in 47% yield: Rf = 0.8
(petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.0 Hz,
2H), 7.29 (d, J = 8.0 Hz, 2H), 5.52 (q, J = 7.2 Hz, 1H), 1.74 (d, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 136.3, 134.5, 131.7, 130.2,
128.7, 112.6, 13.8.
(E)-1-(1-Azidoprop-1-en-1-yl)-4-bromobenzene (2u). Compound
2u was obtained as a yellow oil (0.6 g) in 72% yield: Rf = 0.8
(petroleum ether; 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.4 Hz,
2H), 7.21 (d, J = 8.4 Hz, 2H), 5.50 (q, J = 7.2 Hz, 1H), 1.72 (d, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 136.3, 132.2, 131.6, 130.4,
122.7, 112.6, 13.8.
3-(Thiophen-2-ylethynyl)oxazolidin-2-one (1o).34d Compound 1o
was obtained as a yellow solid (0.164 g) in 36% yield: Rf = 0.4
1
(petroleum ether:ethyl acetate = 3:1); mp 101−103 °C; H NMR
(400 MHz, CDCl3, TMS) δ 7.30−7.27 (m, 1H), 7.243−7.236 (m,
1H), 6.99−6.97 (m, 1H), 4.49 (t, J = 8.0 Hz, 2H), 4.00 (t, J = 8.0 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 155.7, 133.2, 128.0, 127.0,
121.9, 82.3, 64.6, 63.1, 46.9; IR (KBr) ν 3102, 2260, 1756, 1475, 1445,
1397, 1208, 1145; HRMS-(ESI) (m/z) [M + H]+ calcd for C9H
8NO2S 194.0276, found 194.0269.
(E)-1-(1-Azidoprop-1-en-1-yl)-3-bromobenzene (2v). Compound
2v was obtained as a yellow oil (0.5 g) in 82% yield: Rf = 0.83
1
(petroleum ether); H NMR (400 MHz, CDCl3, TMS) δ 7.53−7.51
(m, 2H), 7.33−7.27 (m, 2H), 5.54 (q, J = 7.2 Hz, 1H), 1.76 (d, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 136.0, 135.4, 131.8, 131.6,
129.9, 127.4, 122.4, 112.9, 13.8.
1-Methyl-4-((5-phenylpent-3-yn-2-yl)sulfonyl)benzene
(1ab).34b,35 Compound 1ab was obtained as a colorless oil or white
solid (2.25 g) in 73% yield: Rf = 0.4 (petroleum ether:ethyl acetate =
1
(E)-2-(1-Azidoprop-1-en-1-yl)thiophene (2w). Compound 2w was
obtained as a yellow oil (0.6 g) in 43% yield: Rf = 0.78 (petroleum
ether); 1H NMR (400 MHz, CDCl3) δ 7.38 (dd, J1 = 5.2 Hz, J2 = 0.8
Hz, 1H), 7.20−7.19 (m, 1H), 7.10−7.08 (m, 1H), 5.57 (q, J = 7.2 Hz,
1H), 1.96 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 135.6,
131.7, 127.3, 127.0, 126.3, 112.3, 14.1.
10:1); H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J = 8.0 Hz, 2H),
7.47 (d, J = 8.0 Hz, 2H), 7.34−7.30 (m, 2H), 7.26−7.22 (m, 3H), 3.69
(s, 2H), 3.02 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
δ 144.9, 136.9, 132.3, 130.0, 128.4, 127.7, 127.5, 126.5, 76.8, 66.5, 23.6,
21.1; IR (KBr) ν 3068, 3030, 2928, 2255, 2055, 1689, 1599, 1492,
1362, 1173; HRMS-(ESI) (m/z) [M + H]+ calcd for C17H18NO2S
300.1058, found 300.1057.
Transformation of Vinyl Azide to 1,2,3-Triazole.37 CuTC
(28.6 mg, 0.15 mmol) was added to a solution of 2 (0.5 mmol) and
phenylacetylene (0.11 mL, 1.0 mmol) in toluene (2 mL). The reaction
mixture was then stirred for 2.0 h at 25 °C until the disappearance of
2, as indicated by TLC. The resulting mixture was concentrated and
taken up by dichloromethane (3 × 15 mL). The organic layer was
Procedure for Preparation of Vinyl Azide.36a Step 1. A slurry
of sodium azide (3.58 g, 22 mmol) in acetonitrile (50 mL) was placed
in a 100 mL three-neck round-bottom flask, which was fitted with two
50 mL pressure-equalizing dropping funnels. This flask was cooled by
an ice bath, and iodine monochloride (2.75 g, 42.4 mmol) was added
11412
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J. Org. Chem. 2015, 80, 11407−11416

The Journal of Organic Chemistry
Article
washed with brine (3 × 40 mL), dried over MgSO4, and concentrated.
Purification of the crude product with flash column chromatography
gave triazole.
(E)-4-Phenyl-1-(1-(p-tolyl)prop-1-en-1-yl)-1H-1,2,3-triazole (2rc).
Compound 2rc was obtained as a white solid (106.2 mg) in 95%
yield: Rf = 0.4 (petroleum ether:ethyl acetate = 12:1); mp 81−83 °C;
1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.6 Hz, 2H, Ar), 7.44 (s,
1H, Ar), 7.28−7.24 (m, 2H, Ar), 7.19−7.07 (m, 5H, Ar), 6.41 (q, J =
7.2 Hz, 1H, CH), 2.29 (s, 3H, CH3), 1.78 (d, J = 7.2 Hz, 3H, CH3);
13C NMR (100 MHz, CDCl3) δ 147.1, 139.1, 136.0, 130.34, 130.26,
(MeCN)SbF6] (7.0 mg, 3 mol %). The tube was evacuated and
backfilled with argon, and this procedure was repeated three times. To
this mixture was added dry 1,2-dichloroethane (1 mL). The reaction
was complete after stirring at 60 °C for 2.5 h, and the resulting mixture
was purified by column chromatography on silica gel, providing 3c as a
white solid (98% yield).
3-(4-Methyl-3,5-diphenyl-1H-pyrrol-2-yl)oxazolidin-2-one (3c).
[1b] = 0.3 M. Compound 3c was obtained as a white solid (93.5
mg) in 98% yield: Rf = 0.28 (petroleum ether:ethyl acetate = 3:1); mp
1
162−164 °C; H NMR (400 MHz, CDCl3, TMS) δ 9.93 (s, 1H),
129.4, 129.2, 128.6, 127.9, 125.5, 120.3, 119.2, 21.2, 13.8; IR (KBr) ν
3127, 2918, 1417, 1038, 821, 769, 697, 502; HRMS-(ESI) (m/z) [M +
H]+ calcd for C18H 18N3 276.1501, found 276.1490.
7.23−7.18 (m, 4H), 7.34−7.22 (m, 5H), 7.11 (s, 1H), 4.34 (t, J = 8.0
Hz, 2H), 3.60 (t, J = 8.0 Hz, 2H), 2.08 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 158.5, 134.4, 132.8, 129.8, 128.3, 126.5, 126.21, 126.18,
125.8, 121.1, 119.4, 119.2, 114.1, 62.9, 47.1, 11.2; IR (KBr) ν 3287,
1729, 1592, 1502, 1223, 1145, 1026, 776, 759, 699; HRMS-(EI) (m/z)
[M + H]+ calcd for C20H19N2O2 319.1447, found 319.1439.
(E)-1-(1-(4-Methoxyphenyl)prop-1-en-1-yl)-4-phenyl-1H-1,2,3-tri-
azole (2sc). Compound 2sc was obtained as a white solid (120 mg) in
95% yield: Rf = 0.57 (petroleum ether:ethyl acetate = 5:1); mp 84−86
1
°C; H NMR (400 MHz, CDCl3) δ 7.69−7.67 (m, 2H, Ar), 7.47 (s,
N-(4-Methyl-3,5-diphenyl-1H-pyrrol-2-yl)-N-phenylmethanesul-
fonamide (3d). [1c] = 0.3 M. Compound 3d was obtained as a pale
yellow solid (107.6 mg) in 89% yield: Rf = 0.37 (petroleum ether:ethyl
1H, Ar), 7.28−7.24 (m, 2H, Ar), 7.20−7.16 (m, 1H, Ar), 7.11 (d, J =
8.8 Hz, 2H, Ar), 6.84 (d, J = 8.8 Hz, 2H, Ar), 6.37 (q, J = 7.2 Hz, 1H,
CH), 3.72 (s, 3H, OCH3), 1.77 (d, J = 7.2 Hz, 3H, CH3C); 13C NMR
(100 MHz, CDCl3) δ 160.0, 147.0, 135.7, 130.6, 130.3, 128.6, 128.0,
125.5, 125.4, 119.9, 119.3, 114.1, 55.2, 13.8; IR (KBr) ν 3125, 2921,
1609, 1512, 1248, 1178, 1028, 834, 762, 692; HRMS-(ESI) (m/z) [M
+ H]+ calcd for C18H18N3O 292.1450, found 292.1444.
1
acetate = 5:1); mp 168−169 °C; H NMR (400 MHz, CDCl3, TMS)
δ 8.57 (s, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.43 (t, J = 8.0 Hz, 2H),
7.43−7.30 (m, 5H), 7.25−7.18 (m, 4H), 7.15−7.13 (m, 2H), 2.76 (s,
3H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 142.0, 134.1,
132.7, 129.9, 129.2, 128.7, 128.23, 128.18, 126.93, 126.90, 126.7,
126.0, 124.2, 123.7, 122.5, 115.0, 40.3, 11.2; IR (KBr) ν 3347, 3297,
1587, 1492, 1347, 1148, 963, 779, 697, 545; HRMS-(EI) (m/z) [M +
H]+ calcd for C24H23N2O2S 403.1480, found 403.1472.
(E)-1-(1-(4-Chlorophenyl)prop-1-en-1-yl)-4-phenyl-1H-1,2,3-tria-
zole (2tc). Compound 2tc was obtained as a white solid (193.4 mg) in
82% yield: Rf = 0.45 (petroleum ether:ethyl acetate = 8:1); mp 74−76
°C; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.2 Hz, 2H, Ar), 7.62
(s, 1H, Ar), 7.43−7.37 (m, 4H, Ar), 7.33−7.29 (m, 1H, Ar), 7.24 (d, J
= 8.4 Hz, 2H, Ar), 6.53 (q, J = 7.2 Hz, 1H, CH), 1.89 (d, J = 7.2 Hz,
3H, CH3); 13C NMR (100 MHz, CDCl3) δ 147.2, 135.1, 135.0, 131.6,
130.6, 130.1, 129.0, 128.7, 128.1, 125.5, 121.5, 119.1, 13.8; IR (KBr) ν
3122, 1494, 1415, 1091, 1036, 1013, 879, 826, 766, 694, 525, 500;
HRMS-(ESI) (m/z) [M + H]+ calcd for C17H15ClN3 296.0955, found
296.0947.
N-Methyl-N-(4-methyl-5-phenyl-3-(p-tolyl)-1H-pyrrol-2-yl)-
methanesulfonamide (3e). [1d] = 0.3 M. Compound 3e was
obtained as a white solid (76.0 mg) in 72% yield: Rf = 0.40 (petroleum
1
ether:ethyl acetate = 4:1); mp 194−195 °C; H NMR (400 MHz,
CDCl3, TMS) δ 8.35 (s, 1H), 7.46−7.39 (m, 4H), 7.29−7.23 (m, 5H),
3.26 (s, 3H), 2.60 (s, 3H), 2.40 (s, 3H), 2.12 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 136.6, 132.8, 131.4, 129.7, 129.2, 128.7, 127.0, 126.8,
126.6, 124.1, 122.1, 114.8, 39.5, 38.0, 21.2, 11.2; IR (KBr) ν 3372,
1507, 1332, 1140, 976, 874, 821, 764, 697, 517; HRMS-(EI) (m/z) [M
+ H]+ calcd for C20H23N2O2S 355.1480, found 355.1472.
(E)-1-(1-(4-Bromophenyl)prop-1-en-1-yl)-4-phenyl-1H-1,2,3-tria-
zole (2uc). Compound 2uc was obtained as a white solid (114.3 mg)
in 84% yield: Rf = 0.3 (petroleum ether:ethyl acetate = 10:1); mp 87−
N-Methyl-N-(4-methyl-5-phenyl-3-(m-tolyl)-1H-pyrrol-2-yl)-
methanesulfonamide (3f). [1e] = 0.3 M. Compound 3f was obtained
as a white solid (77.3 mg) in 73% yield: Rf = 0.41 (petroleum
1
89 °C; H NMR (400 MHz, CDCl3) δ 7.70−7.67 (m, 2H), 7.49 (s,
1H), 7.46 (d, J = 8.8 Hz, 2H), 7.29−7.25 (m, 2H), 7.21−7.16 (m,
1H), 7.06 (d, J = 8.8 Hz, 2H), 6.41 (q, J = 7.2 Hz, 1H), 1.77(d, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 147.2, 135.0, 132.0, 131.9,
130.9, 130.1, 128.7, 128.1, 125.5, 123.3, 121.5, 119.1, 13.8; IR (KBr) ν
3122, 1489, 1412, 1073, 841, 821, 764, 692, 520, 492; HRMS-(ESI)
(m/z) [M + H]+ calcd for C17H15BrN3 340.0449, found 340.0443.
(E)-1-(1-(3-Bromophenyl)prop-1-en-1-yl)-4-phenyl-1H-1,2,3-tria-
zole (2vc). Compound 2vc was obtained as a white solid (122.5 mg)
in 90% yield: Rf = 0.3 (petroleum ether:ethyl acetate = 10:1); mp
1
ether:ethyl acetate = 4:1); mp 125−127 °C; H NMR (400 MHz,
CDCl3, TMS) δ 8.37 (s, 1H), 7.46−7.40 (m, 4H), 7.33−7.28 (m, 2H),
7.16−7.13 (m, 3H), 3.26 (s, 3H), 2.59 (s, 3H), 2.40 (s, 3H), 2.13 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 138.0, 134.4, 132.7, 130.5,
128.7, 128.4, 127.7, 127.0, 126.9, 126.8, 126.6, 124.1, 122.3, 114.7,
39.6, 38.0, 21.5, 11.2; IR (KBr) ν 3362, 1332, 1140, 971, 884, 796, 766,
697, 512; HRMS-(EI) (m/z) [M + H]+ calcd for C20H23N2O2S
355.1480, found 355.1472.
1
116−117 °C; H NMR (400 MHz, CDCl3) δ 7.83−7.81 (m, 2H),
3-(4-Methyl-5-phenyl-3-(p-tolyl)-1H-pyrrol-2-yl)oxazolidin-2-one
(3g). [1f] = 0.3 M. Compound 3g was obtained as a white solid (94.3
mg) in 95% yield: Rf = 0.46 (petroleum ether:ethyl acetate = 3:1); mp
7.62 (s, 1H), 7.58−7.56 (m, 1H), 7.484−7.480 (m, 1H), 7.42−7.38
(m, 2H), 7.35−7.31 (m, 2H), 7.25−7.23 (m, 1H), 6.55 (q, J = 7.2 Hz,
1H), 1.91 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 147.3,
135.2, 134.7, 132.2, 132.1, 130.3, 130.1, 128.7, 128.1, 127.9, 125.6,
122.7, 122.1, 119.1, 13.8; IR (KBr) ν 3135, 1457, 1417, 1076, 1033,
816, 786, 764, 749, 692; HRMS-(ESI) (m/z) [M + H]+ calcd for
C17H15BrN3 340.0449, found 340.0442.
1
159−161 °C; H NMR (400 MHz, CDCl3, TMS) δ 9.79 (s, 1H),
7.27−7.15 (m, 9H), 4.34 (t, J = 7.6 Hz, 2H), 3.59 (t, J = 7.6 Hz, 2H),
2.41 (s, 3H), 2.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.8,
136.3, 133.0, 131.4, 130.0, 129.0, 128.4, 126.5, 125.9, 125.3, 121.8,
117.6, 114.3, 62.9, 46.6, 21.2, 11.1; IR (KBr) ν 3267, 1746, 1719, 1592,
1512, 1235, 1145, 826, 762; HRMS-(EI) (m/z) [M + H]+ calcd for
C21H21N2O2 333.1603, found 333.1596.
(E)-4-Phenyl-1-(1-(thiophen-2-yl)prop-1-en-1-yl)-1H-1,2,3-tria-
zole (2wc). Compound 2wc was obtained as a white solid (82.3 mg)
in 99% yield: Rf = 0.3 (petroleum ether:ethyl acetate = 10:1); mp
115−117 °C; 1H NMR (400 MHz, CDCl3) δ 7.75−7.73 (m, 2H, Ar),
7.66 (s, 1H, Ar), 7.37−7.36 (m, 1H, Ar), 7.33−7.29 (m, 2H, Ar),
7.24−7.21 (m, 1H, Ar), 7.01−6.96 (m, 2H, Ar), 6.40 (q, J = 7.6 Hz,
1H, CH), 1.94 (d, J = 7.6 Hz, 3H, CH3); 13C NMR (100 MHz,
CDCl3) δ 147.2, 134.7, 130.4, 130.3, 129.1, 128.7, 128.1, 127.7, 127.1,
125.6, 123.5, 119.7, 14.2; IR (KBr) ν 3147, 3093, 1412, 1230, 1073,
1036, 771, 729, 697; HRMS-(ESI) (m/z) [M + H]+ calcd for
C15H14N3S 268.0908, found 268.0903.
3-(3-(4-Methoxyphenyl)-4-methyl-5-phenyl-1H-pyrrol-2-yl)-
oxazolidin-2-one (3h). [1g] = 0.3 M. Compound 3h was obtained as
a pale yellow solid (88.7 mg) in 85% yield: Rf = 0.22 (petroleum
1
ether:ethyl acetate = 3:1); mp 150−152 °C; H NMR (400 MHz,
CDCl3, TMS) δ 9.83 (s, 1H), 7.32−7.23 (m, 6H), 7.12 (s, 1H), 6.96
(d, J = 8.0 Hz, 2H), 4.33 (t, J = 8.0 Hz, 2H), 3.86 (s, 3H), 3.60 (t, J =
8.0 Hz, 2H), 2.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.4,
158.2, 133.0, 131.0, 128.8, 128.7, 128.3, 127.5, 127.2, 126.7, 126.4,
125.8, 125.6, 121.3, 118.2, 114.5, 114.3, 113.7, 62.9, 55.2, 46.9, 11.1; IR
(KBr) ν 3275, 1744, 1512, 1243, 1038, 839, 764; HRMS-(EI) (m/z)
[M + H]+ calcd for C21H21N2O3 349.1552, found 349.1544.
Procedure for the Construction of Pyrrole 3c. A dry Schlenk
tube was charged with ynamide 1b (56.2 mg, 0.3 mmol), vinyl azide
2b (57.3 mg, 0.36 mmol, 1.2 equiv), and gold catalyst [JohnPhosAu-
11413
DOI: 10.1021/acs.joc.5b02057
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The Journal of Organic Chemistry
Article
N-(3-(4-Methoxyphenyl)-4-methyl-5-phenyl-1H-pyrrol-2-yl)-N-
methylmethanesulfonamide (3i). [1h] = 0.3 M. Compound 3i was
obtained as a pale yellow (64 mg) in 64% yield: Rf = 0.4 (petroleum
ether:ethyl acetate = 3:1); mp 75−77 °C; 1H NMR (400 MHz,
CDCl3, TMS) δ 9.88 (s, 1H), 7.48−7.20 (m, 9H), 4.34−4.27 (m, 2H),
3.58−3.44 (m, 2H), 1.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
156.7, 135.6, 133.7, 133.4, 133.0, 129.3, 128.9, 128.5, 126.4, 126.2,
125.8, 124.0, 115.1, 112.1, 62.7, 45.5, 10.8; IR (KBr) ν 3270, 1744,
1602, 1492, 1228, 1148, 1083, 1031, 759, 697; HRMS-(EI) (m/z) [M
+ H]+ calcd for C20H18ClN2O2 353.1057, found 353.1049.
1
ether:ethyl acetate = 3:1); mp 149−151 °C; H NMR (400 MHz,
CDCl3, TMS) δ 8.37 (s, 1H), 7.46−7.39 (m, 4H), 7.29−7.25 (m, 3H),
6.97 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 3.26 (s, 3H), 2.61 (s, 3H), 2.11
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.5, 132.8, 130.9, 128.7,
126.9, 126.8, 126.7, 126.5, 124.1, 121.8, 114.8, 113.9, 55.2, 39.5, 38.0,
11.1; IR (KBr) ν 3369, 3319, 1507, 1342, 1248, 1150, 978, 836, 766,
697, 520; HRMS-(EI) (m/z) [M + H]+ calcd for C20H23N2O3S
371.1429, found 371.1422.
3-(4-Methyl-5-phenyl-3-(thiophen-2-yl)-1H-pyrrol-2-yl)-
oxazolidin-2-one (3p). [1o] = 0.3 M. Compound 3p was obtained as
a gray solid (73.4 mg) in 75% yield: Rf = 0.25 (petroleum ether:ethyl
1
acetate = 5:2); mp 139−140 °C; H NMR (400 MHz, CDCl3, TMS)
3-(3-(4-Ethylphenyl)-4-methyl-5-phenyl-1H-pyrrol-2-yl)-
oxazolidin-2-one (3j). [1i] = 0.3 M. Compound 3j was obtained as a
pale yellow solid (87.6 mg) in 84% yield: Rf = 0.28 (petroleum
ether:ethyl acetate = 3:1); mp 97−99 °C; 1H NMR (400 MHz,
CDCl3, TMS) δ 9.78 (s, 1H), 7.34−7.26 (m, 8H), 7.18 (s, 1H), 4.36
(t, J = 8.0 Hz, 2H), 3.62 (t, J = 8.0 Hz, 2H), 2.74 (q, J = 8.0 Hz, 2H),
2.11 (s, 3H), 1.33 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
157.7, 142.6, 133.0, 131.6, 130.1, 128.5 127.7, 126.5, 125.9, 125.2,
122.0, 117.4, 114.4, 62.9, 46.6, 28.5, 15.4, 11.1; IR (KBr) ν 3280, 1739,
1594, 1509, 1230, 1145, 1078, 839, 762, 697; HRMS-(EI) (m/z) [M +
H]+ calcd for C22H23N2O2 347.1760, found 347.1750.
δ 9.69 (s, 1H), 7.39−7.36 (m, 5H), 7.25 (s, 1H), 7.12−7.10 (m, 1H),
7.03−7.02 (m, 1H), 4.42 (t, J = 8.0 Hz, 2H), 3.76 (d, J = 8.0 Hz, 2H),
2.15 (s, 3H); 13C NMR (100 MHz, DMSO) δ 156.8, 135.5, 132.5,
128.6, 127.3, 126.9, 126.5, 126.3, 124.3, 124.2, 122.1, 113.5, 112.8,
62.6, 47.4, 11.8; IR (KBr) ν 3262, 1744, 1602, 1512, 1477, 1228, 1140,
1033, 762, 697; HRMS-(EI) (m/z) [M + H]+ calcd for C18H17N2O2S
325.1011, found 325.1004.
N-(3-Cyclopropyl-4-methyl-5-phenyl-1H-pyrrol-2-yl)-N-methyl-
methanesulfonamide (3q). [1p] = 0.3 M. Compound 3q was
obtained as a white solid (49.4 mg) in 54% yield: Rf = 0.38 (petroleum
1
ether:ethyl acetate = 2:1); mp 153−154 °C; H NMR (400 MHz,
3-(3-(4-Chlorophenyl)-4-methyl-5-phenyl-1H-pyrrol-2-yl)-
oxazolidin-2-one (3k). [1j] = 0.1 M. Compound 3k was obtained as a
white solid (112 mg) in 99% yield: Rf = 0.3 (petroleum ether:ethyl
acetate = 3:1); mp 170−172 °C; 1H NMR (400 MHz, CDCl3, TMS)
δ 9.93 (s, 1H), 7.39 (d, J = 7.6 Hz, 2H), 7.33 (d, J = 7.6 Hz, 2H),
7.25−7.11 (m, 5H), 4.37 (t, J = 7.2 Hz, 2H), 3.62 (t, J = 7.2 Hz, 2H),
2.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.3, 132.9, 132.7,
132.6, 131.1, 128.6, 128.4, 126.5, 126.2, 126.1, 121.4, 117.7, 114.0,
63.0, 47.1, 11.1; IR (KBr) ν 3374, 1736, 1494, 1233, 1143, 1033, 834,
769, 699; HRMS-(EI) (m/z) [M + H]+ calcd for C20H18ClN2O2
353.1057, found 353.1050.
N-(4,5-Diphenyl-3-(4-propylphenyl)-1H-pyrrol-2-yl)-N-methylme-
thanesulfonamide (3l). [1l] = 0.1 M. Compound 3l was obtained as a
white solid (110.5 mg) in 93% yield: Rf = 0.28 (petroleum ether:ethyl
acetate = 3:1); mp 196−197 °C; 1H NMR (400 MHz, CDCl3, TMS)
δ 9.57 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.15−7.17 (m, 6H), 713−7.11
(m, 1H), 4.30 (t, J = 7.6 Hz, 2H), 3.52 (t, J = 7.6 Hz, 2H), 2.00 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 158.6, 133.4, 132.6, 131.5,
131.3, 128.3, 126.6, 126.5, 126.0, 120.9, 120.6, 118.5, 113.9, 63.0, 47.3,
11.1; IR (KBr) ν 3367, 3284, 1736, 1602, 1497, 1233, 1143, 1073,
1033, 764, 697; HRMS-(EI) (m/z) [M + H]+ calcd for C20H18BrN2O2
397.0552, found 397.0544.
CDCl3, TMS) δ 8.27 (s, 1H), 7.35−7.23 (m, 5H), 3.30 (s, 3H), 3.01
(s, 3H), 2.20 (s, 3H), 1.55−1.52 (m, 1H), 0.86−0.84 (m, 2H), 0.63−
0.62 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 132.8, 128.5, 126.8,
126.5, 126.3, 124.7, 119.8, 119.7, 128.3, 116.2, 38.51, 38.46, 10.7, 6.0,
5.2; IR (KBr) ν 3369, 1604, 1589, 1335, 1143, 1016, 956, 859, 766,
702, 517; HRMS-(EI) (m/z) [M + H]+ calcd for C16H21N2O2S
305.1324, found 305.1317.
3-(4-Methyl-3-phenyl-5-(p-tolyl)-1H-pyrrol-2-yl)oxazolidin-2-one
(3r). [1b] = 0.3 M. Compound 3r was obtained as a white solid (88.7
mg) in 89% yield: Rf = 0.31 (petroleum ether:ethyl acetate = 3:1); mp
175−176 °C; 1H NMR (400 MHz, CDCl3) δ 9.48 (s, 1H), 7.43−7.29
(m, 7H), 7.21−7.19 (m, 2H), 4.34 (t, J = 8.0 Hz, 2H), 3.57 (s, 2H),
2.38 (s, 3H), 2.11 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.1,
135.6, 134.6, 130.1, 130.0, 129.1, 128.2, 126.5, 125.9, 121.2, 118.4,
113.7, 62.9, 46.9, 21.0, 11.1; IR (KBr) ν 3225, 2921, 1741, 1504, 1230,
1148, 1083, 821, 702; HRMS-(EI) (m/z) [M + H]+ calcd for
C21H21N2O2 333.1603, found 333.1594.
N-(3-(2-Chlorophenyl)-4,5-diphenyl-1H-pyrrol-2-yl)-N-methylme-
thanesulfonamide (3s). [1r] = 0.1 M. Compound 3s was obtained as
a white solid (88.1 mg) in 84% yield: Rf = 0.21 (petroleum ether:ethyl
acetate = 3:1); mp 204−205 °C; 1H NMR (400 MHz, CDCl3) δ 9.69
(s, 1H), 7.36−7.32 (m, 4H), 7.25−7.22 (m, 1H), 7.07 (d, J = 8.0 Hz,
2H), 6.70 (d, J = 8.0 Hz, 2H), 4.26 (t, J = 8.0 Hz, 2H), 3.64 (s, 3H),
3.52 (t, J = 8.0 Hz, 2H), 1.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
158.1, 157.9, 134.6, 129.9, 128.3, 128.0, 126.5, 125.72, 125.68, 120.9,
118.2, 113.9, 113.2, 62.9, 55.2, 46.9, 11.1; IR (KBr) ν 3282, 2928,
1736, 1604, 1509, 1253, 1145, 1033, 831; HRMS-(EI) (m/z) [M +
H]+ calcd for C21H21N2O3 349.1552, found 349.1544.
3-(3-(4-Fluorophenyl)-4-methyl-5-phenyl-1H-pyrrol-2-yl)-
oxazolidin-2-one (3m). [1l] = 0.1 M. Compound 3m was obtained as
a pale yellow solid (120.7 mg) in 99% yield: Rf = 0.29 (petroleum
1
ether:ethyl acetate = 3:1); mp 177−178 °C; H NMR (400 MHz,
CDCl3, TMS) δ 9.93 (s, 1H), 7.38−7.34 (m, 2H), 7.20−7.10 (m, 7H),
4.37 (t, J = 8.0 Hz, 2H), 3.62 (t, J = 8.0 Hz, 2H), 2.04 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 161.7 (d, JC−F = 243.5 Hz), 158.7, 132.7,
131.2 (d, JC−F = 7.7 Hz), 130.2, 128.2, 126.5, 125.9, 120.8, 118.9, 115.3
(d, JC−F = 21.1 Hz), 114.0, 63.0, 47.3, 11.1; 19F NMR (376.5 MHz,
CDCl3) δ −115.7; IR (KBr) ν 3312, 3277, 1746, 1604, 1509, 1235,
1148, 849, 759, 699; HRMS-(EI) (m/z) [M + H]+ calcd for
C20H18FN2O2 337.1352, found 337.1347.
N-(4,5-Diphenyl-3-(thiophen-2-yl)-1H-pyrrol-2-yl)-N-methylme-
thanesulfonamide (3t). [1s] = 0.3 M. Compound 3t was obtained as
a white solid (109 mg) in 89% yield: Rf = 0.41 (petroleum ether:ethyl
acetate = 5:1); mp 187−188 °C; 1H NMR (400 MHz, CDCl3) δ 9.65
(s, 1H), 7.37−7.27 (m, 5H), 7.25−7.19 (m, 4H), 4.27 (t, J = 8.0 Hz,
2H), 3.49 (t, J = 8.0 Hz, 2H), 1.99 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 158.7, 134.0, 131.5, 131.2, 129.6, 128.44, 128.40, 127.5,
126.7, 125.1, 121.2, 119.8, 114.5, 63.1, 47.1, 11.2; IR (KBr) ν 3272,
1732, 1604, 1497, 1233, 1150, 1088, 826, 762, 704; HRMS-(EI) (m/z)
[M + H]+ calcd for C20H18ClN2O2 353.1057, found 353.1050.
3-(5-(3-Bromophenyl)-4-methyl-3-phenyl-1H-pyrrol-2-yl)-
oxazolidin-2-one (3u). [1t] = 0.3 M. Compound 3u was obtained as a
white solid (102.2 mg) in 86% yield: Rf = 0.28 (petroleum ether:ethyl
3-(3-(3-Chlorophenyl)-4-methyl-5-phenyl-1H-pyrrol-2-yl)-
oxazolidin-2-one (3n). [1m] = 0.3 M. Compound 3n was obtained as
a white solid (88.1 mg) in 83% yield: Rf = 0.24 (petroleum ether:ethyl
1
acetate = 3:1); mp 147−148 °C; H NMR (400 MHz, DMSO) δ
11.46 (s, 1H), 7.51−7.45 (m, 5H), 7.34−7.28 (m, 4H), 4.38 (t, J = 7.6
Hz, 2H), 3.76 (t, J = 7.6 Hz, 2H), 2.15 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 157.1, 136.5, 133.0, 132.7, 130.2, 128.6, 128.3, 127.4, 126.6,
126.20, 126.16, 126.0, 122.3, 119.1, 112.9, 62.5, 47.8, 11.4; IR (KBr) ν
3245, 1721, 1594, 1492, 1215, 1143, 1081, 1028, 766, 694; HRMS-
(EI) (m/z) [M + H]+ calcd for C20H18ClN2O2 353.1057, found
353.1049.
1
acetate = 3:1); mp 168−169 °C; H NMR (400 MHz, CDCl3, TMS)
δ 10.09 (s, 1H), 7.37−7.33 (m, 2H), 7.29−7.23 (m, 3H), 7.14 (d, J =
8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 4.26 (t, J = 8.0 Hz, 2H), 3.53 (t,
J = 8.0 Hz, 2H), 1.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.8,
133.9, 131.6, 131.3, 129.5, 128.4, 127.8, 126.7, 125.2, 121.0, 120.2,
119.5, 114.5, 63.1, 47.2, 11.3; IR (KBr) ν 3262, 1736, 1497, 1238,
(S)-3-(3-(2-Chlorophenyl)-4-methyl-5-phenyl-1H-pyrrol-2-yl)-
oxazolidin-2-one (3o). [1n] = 0.3 M. Compound 3o was obtained as
a white solid (100.3 mg) in 95% yield: Rf = 0.23 (petroleum
11414
DOI: 10.1021/acs.joc.5b02057
J. Org. Chem. 2015, 80, 11407−11416

The Journal of Organic Chemistry
Article
1148, 1086, 1071, 826, 759, 724; HRMS-(EI) (m/z) [M + H]+ calcd
for C20H18BrN2O2 397.0552, found 397.0547.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02057.
■
S
N-(3-Cyclopropyl-4, 5-diphenyl-1H-pyrrol-2-yl)-N-methylmetha-
nesulfonamide (3v). [1u] = 0.1 M. Compound 3v was obtained as
a white solid (106 mg) in 97% yield: Rf = 0.43 (petroleum ether:ethyl
acetate = 5:1); mp 139−140 °C; 1H NMR (400 MHz, CDCl3, TMS)
δ 9.90 (s, 1H), 7.34−7.23 (m, 6H), 7.17−7.14 (m, 1H), 6.97 (s, 2H),
4.27 (d, J = 8.0 Hz, 2H), 3.52 (t, J = 8.0 Hz, 2H), 1.97 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 158.3, 134.9, 134.1, 130.00, 129.94, 129.0,
128.7, 128.3, 126.7, 124.7, 124.1, 122.5, 122.0, 119.0, 115.2, 63.0, 46.9,
11.2; IR (KBr) ν 3262, 1741, 1587, 1497, 1228, 1145, 1083, 705;
HRMS-(EI) (m/z) [M + H]+ calcd for C20H17BrN2O2 397.0552,
found 397.0544.
Mechanistic experiments; H and 13C NMR spectra for
1
all described compounds; and crystal structures of
compounds 3e, 8, 3s, 2uc, and 2vc (PDF)
Crystal data of compounds 2uc, 2vc, 3e, 3s, and 8 in CIF
format (ZIP)
AUTHOR INFORMATION
Corresponding Author
*Fax: 86-591-63173587. E-mail: huangxl@fjirsm.ac.cn.
Author Contributions
■
3-(4-Methyl-3-phenyl-5-(thiophen-2-yl)-1H-pyrrol-2-yl)-
oxazolidin-2-one (3w). Compound 3w was obtained as a pale yellow
solid (79 mg) in 62% yield: Rf = 0.27 (petroleum ether:ethyl acetate =
1
3:1); mp 158−159 °C; H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H),
7.45−7.37 (m, 5H), 7.12−6.93 (m, 3H), 4.36 (t, J = 8.0 Hz, 2H), 3.62
(t, J = 8.0 Hz, 2H), 2.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
158.2, 134.9, 134.2, 129.9, 128.2, 127.0, 126.6, 122.6, 122.0, 121.2,
120.5, 118.4, 114.8, 62.9, 46.9, 10.8; IR (KBr) ν 3277, 1736, 1609,
1502, 1230, 1145, 1083, 1031, 774, 709; HRMS-(EI) (m/z) [M + H]+
calcd for C18H17N2O2S 325.1011, found 325.1004.
Y.W., L.Z., and Y.Y. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Grant No. 21402197, 21502190) and Fujian Institute of
Research on the Structure of Matter, Chinese Academy of
Sciences for financial support. We thank Prof. Lutz Ackermann
from the Georg-August-University Gottingen for his insightful
suggestion on the mechanistic studies during his visit of our
institute in April.
3-(3-Butyl-4-methyl-5-phenyl-1H-pyrrol-2-yl)oxazolidin-2-one
(3z). Compound 3z was obtained as a white solid (26 mg) in 28%
yield: Rf = 0.4 (petroleum ether:ethyl acetate = 10:1); mp 124−125
°C; 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 7.21−7.17 (m, 2H),
7.07−7.05 (m, 3H), 4.44 (t, J = 8.0 Hz, 2H), 3.90 (t, J = 8.0 Hz, 2H),
2.30 (t, J = 7.2 Hz, 2H), 1.93 (s, 3H), 1.45−1.28 (m, 4H), 0.88 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.1, 133.2, 128.2,
126.4, 126.1, 125.6, 120.4, 118.8, 114.4, 62.7, 48.1, 33.0, 23.9, 22.9,
14.0, 10.4; IR (KBr) ν 3217, 2955, 2928, 2856, 1726, 1599, 1475,
1238, 1033, 764, 697; HRMS-(ESI) (m/z) [M + H]+ calcd for
C18H23N2O2 299.1760, found 299.1759.
N-(3-Benzyl-4-methyl-5-phenyl-1H-pyrrol-2-yl)-N,4-dimethylben-
zenesulfonamide (3ab). Compound 3ab was obtained as a pale
yellow solid (14 mg) in 7% yield: Rf = 0.25 (petroleum ether:ethyl
acetate = 10:1); 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.57 (d,
J = 8.0 Hz, 2H), 7.32−7.31 (m, 3H), 7.18−7.17 (m, 3H), 7.14−7.10
(m, 2H), 7.06−7.03 (m, 2H), 6.88 (d, J = 8.0 Hz, 2H), 3.23 (s, 2H),
3.04 (s, 3H), 2.36 (s, 3H), 1.88 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 143.8, 140.4, 135.3, 133.0, 129.9, 129.6, 128.7, 128.1, 128.0, 127.6,
126.6, 126.3, 125.6, 125.1, 118.3, 115.5, 39.2, 29.3, 21.6, 10.7; HRMS-
(ESI) (m/z) [M + H]+ calcd for C26H27N2O2S 431.1793, found
431.1792.
N,4-Dimethyl-N-(5-methyl-4,6-diphenyl-3,4-dihydropyridin-2-yl)-
benzenesulfonamide (7). Compound 7 was obtained as a white solid
(16 mg) in 8% yield: Rf = 0.5 (petroleum ether:ethyl acetate = 10:1);
1H NMR (400 MHz, CD3CN) δ 7.50 (d, J = 8.0 Hz, 2H), 7.41−7.35
(m, 4H), 7.31−7.25 (m, 4H), 7.22 (d, J = 8.0 Hz, 2H), 7.08−7.06 (m,
2H), 3.50 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 3.27 (dd, J1 = 16.8 Hz, J2
= 2.4 Hz, 1H), 3.12 (s, 3H), 2.68 (dd, J1 = 16.8 Hz, J2 = 8.8 Hz, 1H),
2.36 (s, 3H), 1.73 (s, 3H); 13C NMR (100 MHz, CD3CN) δ 154.6,
145.4, 141.70, 141.66, 140.2, 136.6, 130.8, 130.0, 129.7, 128.7, 128.5,
128.1, 127.9, 127.8, 120.8, 118.3, 44.0, 35.3, 34.9, 21.5, 18.5; HRMS-
(ESI) (m/z) [M + H]+ calcd for C26H27N2O2S 431.1793, found
431.1792.
̈
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