Gold(I)-Catalyzed Cascade Hydroarylation/Cycloaromatization to Indolizines via Pyridine Ring Construction

Article abstract of DOI:10.1021/acs.joc.6b00346

An efficient and atom-economic method for the synthesis of multisubstituted indolizines via gold-catalyzed cascade hydroarylation/cycloaromatization reaction of α-(N-pyrrolyl)ketones with alkynes is described. The reaction is realized through the construction of the pyridine ring of indolizines, which allows the regioselective incorporation of a wide range of functionalities on the pyridine unit.

Full text of DOI:10.1021/acs.joc.6b00346

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Article
Gold(I)-Catalyzed Cascade Hydroarylation/Cycloaromatization
to Indolizines via Pyridine Ring Construction
Xiangdong Li, Xin Xie, and Yuanhong Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00346 • Publication Date (Web): 01 Apr 2016
Downloaded from http://pubs.acs.org on April 3, 2016
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Gold(I)ꢀCatalyzed Cascade Hydroarylation/Cycloaromatization to Indolizines via
Pyridine Ring Construction
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Xiangdong Li, Xin Xie and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry
，
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Lu, Shanghai 200032, People’s Republic of China
Fax: (+86) 021-64166128, E-mail: yhliu@sioc.ac.cn
R3
R3
cat. LAu+
80 oC, in toluene
R4
R4
R1
O
N
R1
N
R2
R2
26 examples
up to 91% yield
regioselective
functional group tolerance
gram scale
hydroarylation / cycloaromatization
Abstract: An efficient and atomꢀeconomic method for the synthesis of multiꢀsubstituted
indolizines via goldꢀcatalyzed cascade hydroarylation/cycloaromatization reaction of
αꢀ(Nꢀpyrrolyl)ketones with alkynes is described. The reaction is realized through the
construction of the pyridine ring of indolizines, which allows the regioselective
incorporation of a wide range of functionalities on the pyridine unit.
INTRODUCTION
Indolizines, which consist of a πꢀexcessive pyrrole and a πꢀdeficient pyridine ring, are
known to possess a variety of important biological activities,1 such as antibacterial,1b
antiviral,1c antiꢀinflammatory1d and central nervous system (CNS) depressant activity1e etc.
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They are also widely employed in the field of materials science2 such as organic light
emitting devices (OLEDs),2a biological markers2b and dyes.2c Consequently, the
development of efficient methods for the construction of indolizines has gained much
attention. Traditional synthetic methods to indolizines include Scholtz reaction,3
Tschitschibabin reaction,4 1,3ꢀdipolar5 or 1,5ꢀdipolar6 cycloadditions of pyridinium or
related ylides with activated alkynes or alkenes. Recent published reports involve
transitionꢀmetalꢀcatalyzed cycloisomerization of alkynyl or propargyl pyridine derivatives,7
transannulations of pyridotriazoles with alkynes,8 oxidative crossꢀcoupling/cyclization of
alkenes and pyridine derivatives,9 etc.10 Although much progress has been achieved, most
of these methods rely on the construction of the pyrrole ring of indolizines and lack a direct
substituent variation on the pyridine ring.11 Additionally, in some cases, they often involve
elaborately designed starting materials and suffer from limited substrate availability.
Therefore, a straightforward, convenient, and regioselective route to multipleꢀsubstituted
indolizines using common chemical materials is highly attractive.
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Alkynes have been recognized as versatile starting materials in synthetic chemistry
because of their low cost and ready availability. Goldꢀcatalyzed transformations of alkynes
have received great attention over the years due to their high selectivity and efficiency,
mild reaction conditions and functional group compatibility.12 In particular, goldꢀcatalyzed
hydrofunctionalization of alkynes via direct addition of a nucleophile to triple bonds is a
powerful and atomꢀeconomical protocol for the formation of CꢀC and CꢀX bonds.13
Recently, we realized that heterocycles could be conveniently constructed by
goldꢀcatalyzed reactions of alkynes with bifunctional compounds containing both
nucleophilic and electrophilic groups initialized by hydrofunctionalization (Scheme 1, eq
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1). Along this line, pyrroles have been synthesized by a goldꢀcatalyzed
hydroamination/cycloaromatization reaction of αꢀamino ketones with alkynes (Scheme 1,
eq 2).14 This strategy offers a convergent and oneꢀstep approach to heterocycles from
alkynes. Herein, we report another successful example based on the above strategy for the
synthesis of multipleꢀsubstituted indolizines from αꢀ(Nꢀpyrrolyl)ketones and alkynes, which
involves a goldꢀcatalyzed intermolecular hydroarylation/cycloaromatization cascade
(Scheme 1, eq 3). To the best of our knowledge, the construction of indolizines from simple
alkynes by intermolecular hydroarylation has not been reported.
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Scheme 1. GoldꢀCatalyzed Route to Heterocycles
gold-catalyzed reactions of alkynes with bifunctional molecules to heterocycles
E+
E+
Nu
E
Au+L
(1)
hydrofunctionalization
/ cyclization
Nu
NuH
our previous work: hydroamination / cycloaromatization to pyrroles
R1 R4
O
cat. LAu+
H
N
R3
R4
(2)
(3)
R3
+
R1
R2
N
R2
this work: hydroarylation / cycloaromatization to indolizines
R3
R4
O
cat. LAu+
+
N
R3
R4
R1
R2
N
R2
R1
RESULTS AND DISCUSSION
Compared with the goldꢀcatalyzed intramolecular hydroarylation of alkynes with
pyrroles,15 few applications with limited substrate scope have been reported for the
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intermolecular variant,16ꢀ17 possibly due to the following reasons: i) Pyrrole possesses
multiple nucleophilic sites, although pyrrole is known to undergo substitution
predominantly at the αꢀposition, the βꢀsubstitution can compete depending on the nature of
the substituents on nitrogen and the substitution pattern on pyrrole ring.18 ii)
Doubleꢀhydroarylation with two alkynes might occur at different reaction sites of
pyrrole.18a iii) In addition, double addition of pyrroles to acetylene to give the
bis(pyrrolyl)alkane products might take place under goldꢀcatalysis.16bꢀc All these challenges
make the intermolecular hydroarylation of pyrroles with high selectivity a formidable task.
We envisioned that employing an appropriate substituted pyrrole as the substrate may
improve the selectivity of the intermolecular hydroarylation, since the hydroarylation at
other positions of pyrrole or second hydroarylation might be inhibited by steric hindrance
of the existing substituents on the pyrrole ring. To validate our hypothesis,
αꢀ(Nꢀpyrrolyl)ketone 1a bearing two substituents at the Cꢀ2 and Cꢀ4 position on the pyrrole
ring was chosen as a model substrate for optimization of the reaction conditions (Table 1).
We were delighted to find that Echavarren’s catalyst (catalyst A, 5 mol %) bearing a bulky
biarylphosphine ligand (Johnphos) catalyzed the desired reaction of 1a with
phenylacetylene efficiently and regioselectively to afford 1,3,6,8ꢀtetraphenylindolizine 2a
in 84% yield, accompanied by 12% of 2ꢀvinylated indolizine 3a in toluene at 80 oC for 3 h
(Table 1, entry 1). 3a might be formed via double hydroarylation of 1a at its Cꢀ3 and Cꢀ5
position followed by cyclization, or through the hydroarylation of indolizine 2a with the
alkyne. In fact, reaction of 2a with phenylacetylene under the reaction conditions shown in
entry 1 did not afford 3a, which reveals that 3a was formed through the double
hydroarylation pathway. To minimize the formation of the overꢀalkenylated product 3a,
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gold catalysts with different ligands or counter anions were examined. The use of cationic
5
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gold(I)ꢀcarbene
complex
of
IPrAuCl/AgSbF6
(IPr
=
7
8
9
2,6ꢀbis(diisopropylphenyl)imidazolꢀ2ꢀylidene) gave a lower yield of 2a with increased
amount of 3a (Table 1, entry 2). Gratifyingly, the electronꢀneutral PPh3AuNTf2 turned out
to be more efficient to provide 2a in 90% yield with only 7% of 3a (Table 1, entry 3). Gold
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ꢀ
ꢀ
catalysts with different counter anions such as SbF6 , PF6 or OTsꢀ were less efficient (Table
1, entries 4ꢀ6). Performing the reaction in DCE also afforded 2a in high yield of 84%,
whereas only 68% of 2a was observed in CH3CN (Table 1, entries 7ꢀ8). Decreasing the
reaction temperature to 60 oC or lowering the catalyst loading to 2 mol% led to a prolonged
reaction time (Table 1, entries 9ꢀ10). The use of PPh3AuCl or AgNTf2 alone failed to
catalyze the reaction (Table 1, entries 11ꢀ12). Brønsted acid such as MsOH only provided
little amounts of the desired products (Table 1, entry 13).
Table 1. Optimization of Reaction Conditions
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Ph
Ph
Ph
Ph
Ph
Ph
catalyst
O
+
+
N
solvent
N
N
Ph
1.2 equiv
Ph
Ph
Ph
Ph
Ph
Ph
9
1a
2a
3a
10
11
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yield(%)a
catalyst
(mol %)
temp
(oC)
time
entry
solvent
(h)
3a
2a
84
68
90
75
45
4
1
catalyst A (5)
toluene
toluene
toluene
toluene
toluene
toluene
80
80
80
80
80
80
3
12
17
7
2
IPrAuCl/AgSbF6 (5)
PPh3AuNTf2 (5)
10
3b
3
4
PPh3AuCl/AgSbF6 (5)
PPh3AuCl/AgPF6 (5)
PPh3AuCl/AgOTs (5)
14
14
14
5
5
2
6
0
7
PPh3AuNTf2 (5)
PPh3AuNTf2 (5)
PPh3AuNTf2 (5)
PPh3AuNTf2 (2)
PPh3AuCl (5)
AgNTf2 (5)
DCE
80
80
60
80
80
80
80
+
12
22
10
12
24
24
22
84
68
89
88
0
8
4
7
8
0
1
0
8
CH3CN
toluene
toluene
toluene
toluene
toluene
9
10
11
12
13
3
MsOH (20)
6
tBu
-
SbF6
tBu
P Au NCMe
catalyst A
aAll the reactions were carried out on 0.3 mmol scale. NMR yields determined by 1H NMR
b
of the crude reaction mixture using CH2Br2 as an internal standard. The isolated yields of
2a and 3a were 86% and 5%, respectively.
With optimized reaction conditions established (Table 1, entry 3), we next examined
the reaction scope (Table 2). First, the reactivity of terminal alkynes using 1a as the
reaction partner was investigated. In the cases of aryl substituted alkynes, a wide variety of
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functional groups on the aryl rings were tolerated well. For example, both of the
electronꢀwithdrawing (pꢀF, pꢀCl, pꢀCO2Et) and electronꢀdonating (pꢀMe, pꢀMeO, pꢀ
NHCbz, 3,4,5ꢀ(MeO)3) substituted aryl alkynes underwent the reaction smoothly to afford
the corresponding indolizines 2bꢀ2h in 81ꢀ91% yields. The electronic nature of the aryl
substituents had little influence on the reaction efficiency. Heteroarylꢀsubstituted alkyne
such as thienylꢀsubstituted one was also compatible in this reaction, furnishing 2i in 80%
yield. Notably, alkyne substituted with a 1ꢀcyclohexenyl group underwent the reaction well
to provide the desired 2j in 71% yield, implying the cationic Au(I) complexes activate the
alkyne preferentially. Employing ethynylcyclopropane provided the desired indolizine 2k
in 54% yield. Activated terminal alkyne such as ethyl propiolate was also suitable to afford
the expected 2l in moderate yield. The reaction could be extended successfully to activated
internal alkynes, for example, the use of alkynyl esters or ketone provided the
corresponding indolizines 2mꢀ2o in 63ꢀ85% yields.19 In addition, the reaction was also
applicable to heteroatom substituted alkynes such as alkynyl ether or ynamide, furnishing
2pꢀ2q in 40ꢀ41% yields, which are difficult to be prepared by other methods. In the cases of
2l, 2p, and 2q, some byproducts were also observed. These results are significant since
Cꢀ8ꢀO or Nꢀfunctionalized indolizines have been found to be potent sPLA2 inhibitor that
can be used in the treatment of septic shock, pancreatitis, gout, and other diseases.20 Our
method provided a convenient route to these functionalized indolizines. The structure of
indolizine was unambiguously confirmed by Xꢀray crystallographic analysis of 2f.21
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Table 2. Scope of the Alkynesa
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R1
Ph
Ph
Ph
R2
Ph
O
5 mol % PPh3AuNTf2
R1
1.2 equiv
R2
+
toluene, 80 oC
N
N
Ph
Ph
1a
2
10
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OMe
OMe
X
MeO
S
N
Ph
Ph
Ph
Ph
Ph
N
N
Ph
Ph
Ph
Ph
2h, 6 h, 86%
2i, 10 h, 80%
2a, X = H, 3 h, 86%b
2b, X = F, 10 h, 81%
2c, X = Cl, 10 h, 82%
Ph
Ph
Ph
2d, X = CO2Et, 10 h, 86%
2e, X = Me, 10 h, 85%
2f, X = OMe, 4 h, 91%c
2g, X = NHCbz, 10 h, 87%
N
N
Ph
Ph
Ph
2j, 10 h, 71%
2k, 14 h, 54%
Me
Ph
Ph
Ph
Ph
EtO2C
Ph
EtO2C
EtO2C
Ph
N
N
N
Ph
Ph
Ph
Ph
2l, 15 h, 44%
2m, 15 h, 77%
2n, 24 h, 63%
Ms
O
Ph
O
N
Ph
Ph
Ph
Ph
Ph
Bu
N
N
N
Ph
Ph
Ph
Ph
Ph
2p, 3 h, 40%d
2q, 36 h, 41%
2o, 16 h, 85%
aIsolated yields. 2ꢀVinylated product 3a was isolated in 5% yield. 2ꢀVinylated product
b
c
3f was isolated in 7% yield. d5 mol% catalyst A and 2 equiv of ethoxyethyne were used.
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Next, the scope of αꢀ(Nꢀpyrrolyl)ketones 1 using 1ꢀethynylꢀ4ꢀmethoxybenzene as the
reaction partner was examined (Table 3). We first examined the substituent effect (R1) on
the carbonyl group. Gratifyingly, substrates bearing an alkyl group, such as ethyl or
cyclopropyl on the carbonyl moiety reacted well, furnishing 2r and 2s in high yields of
81% and 82%, respectively. When R1 was a vinyl group such as a propenyl group, the
corresponding indolizine 2t was efficiently formed in 81% yield, while the vinyl group
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t
remained intact. Interestingly, alkynyl substituent with a bulky Bu group on the alkyne
terminus was proved to be well tolerated, providing alkynyl indolizine 2u in 88% yield. As
for the pyrrole moiety in αꢀ(Nꢀpyrrolyl)ketones, substrates derived from various
2,4ꢀdisubstituted pyrroles underwent facile cyclization to provide 2vꢀ2x in 55ꢀ86% yields.
Among them, more nucleophilic 2,4ꢀdimethyl pyrrole substrate led to a moderate yield of
the product 2x. Substrates derived from 2,3ꢀdisubstituted pyrrole or 2ꢀsubstituted pyrrole
afforded the corresponding indolizines 2yꢀ2z in moderate yields, possibly due to the
decreased regioselectivity in the hydroarylation step in these cases. It was also noted that
trace amounts of byproducts 3 were generally observed in above cases.
Table 3. Scope of the αꢀ(Nꢀpyrrolyl)ketonesa
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Ar
O
5 mol % PPh3AuNTf2
N
+ MeO
R2
N
R1
toluene, 80 oC
R2
R1
7
8
9
1.2 equiv
Ar = 4-MeOC6H4
1
2
10
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Ar
Ar
Ar
Ph
Ph
Ph
Ph
N
N
N
Ph
Ph
2r, 8 h, 81%
2s, 9 h, 82%
2t, 3 h, 81%
Ar
Ar
Ar
Ph
Ph
Ph
Ph
N
N
N
Ph
Ph
Bu
2u, 4 h, 88%
2v, 6 h, 78%
2w, 12 h, 86%
Ar
Ar
Ar
Ph
N
N
N
Ph
Ph
Ph
Ph
Ph
2x, 2 h, 55%b
2y, 22 h, 51%
2z, 4 h, 53%
aIsolated yields. b2ꢀVinylated product 3x was isolated in 13% yield.
A gram scale reaction was performed to demonstrate the practicality of our protocol.
The reaction of 1a with 1ꢀethynylꢀ4ꢀmethoxybenzene at 5 mmol scale using 2 mol % of
PPh3AuNTf2 provided indolizine product 2f in high yield of 90% (Scheme 2).
Scheme 2. Gram Scale Study
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OMe
5
6
7
Ph
Ph
Ph
8
9
O
2 mol % Ph3PAuNTf2
+
N
toluene, 80 oC, 12 h
Ph
10
11
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N
Ph
Ph
1a, 1.69 g
5 mmol scale
OMe
1.2 equiv
2f, 90%, 2.03 g
To gain mechanistic insights, we tried to isolate the possible reaction intermediates. To
our delight, Cꢀ5ꢀalkenylatedꢀpyrrole intermediate 4 was isolated in 74% yield by lowering
the reaction temperature to room temperature, along with Cꢀ3ꢀalkenylatedꢀpyrrole 5 in 11%
yield (Scheme 3). 4 cyclized smoothly in the presence of 5 mol % PPh3AuNTf2 to afford
indolizine 2m in 95% yield. However, in the absence of gold catalyst, formation of 2m was
not observed. These experiments indicated that the formation of Cꢀ5ꢀalkenylatedꢀpyrrole
intermediate 4 was the initial step in this cascade reaction, and cyclization of 4 to indolizine
was promoted by gold catalyst.
Scheme 3. Mechanistic Studies
1.2 equiv
Ph
Ph
CO2Et
+ 2m
Ph
Ph
CO2Et
O
5 mol % Ph3PAuNTf2
1a
EtO2C
O
+
N
N
toluene, rt, 37 h
Ph
Ph
9%
Ph
5, 11%
Ph
Ph
4, 74%
5 mol % Ph3PAuNTf2
toluene, 80 oC, 20 h
2m, 95%
4
4
2m
+
toluene, 80 oC, 20 h
96% recovery
0%
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Based on the above observations, we propose the following reaction mechanism for
this cascade reaction (Scheme 4). Initially, hydroarylation of 1 with terminal alkyne occurs
regioselectively at the αꢀposition of pyrrole ring to afford the alkenyl gold intermediate 6,
which undergoes the protodeauration to give the intermediate 7. Then nucleophilic attack of
the vinyl moiety in 7 to the carbonyl group followed by elimination of water leads to the
indolizine products 2. This process is also promoted by gold due to its Lewis acid property.
In addition, the alkene moiety which conjugates with the pyrrole in 7 is more nucleophilic
since the electrons on pyrrole ring can delocalize on to the alkene unit, thus triggering an
efficient ringꢀclosure. Alternatively, ringꢀclosure might occur directly from 6 followed by
deauration and dehydration.
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Scheme 4. Proposed Reaction Mechanism
R3
LAu+
R3
O
N
N
R1
R2
R3
R2
R1
1
2
dehydration
+ H2O
out-sphere attack
LAu+
R3
N
H+
LAu+
LAu
R3
gold-assisted
cyclization
O
O
R1
R2
R3
8
N
R1
R2
O
6
H+
N
R1
R2
7
CONCLUSION
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In summary, we have developed a new and efficient method for the synthesis of
multiꢀsubstituted indolizines based on goldꢀcatalyzed hydroarylation/cycloaromatization
reaction of αꢀ(Nꢀpyrrolyl)ketones with alkynes. A wide variety of the functional groups,
particularly, esters, ketones, alkoxy or amide groups can be easily elaborated into the
pyridine unit of the indolizine products. These results make the current method an attractive
alternative and/or complement to the existing methods in which the functionality is usually
incorporated into the pyrrole unit of the indolizines. Further studies to extend this chemistry
for the synthesis of other heterocycles are in progress in our laboratory.
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EXPERIMENTAL SECTION
General Methods. All reactions were carried out using standard Schlenk technique under
Argon unless noted. DCM and DCE were distilled from CaH2. Toluene and THF was
distilled from sodium and benzophenone. MeCN was dried using Innovative Technology
Solvent Purifier. Unless noted, all commercial reagents were used without further
23
purification. Ph3PAuCl22 and Ph3PAuNTf2 were prepared according to the published
method. 1,3ꢀBis(2,6ꢀdiꢀisopropylphenyl)ꢀimidazoleꢀ2ꢀylidenegold(I) chloride, AgSbF6 and
(acetonitrile)[(2ꢀbiphenyl)diꢀtertꢀbutylphosphine]gold(I) hexafluoroantimonate (catalyst A)
1
were purchased from Chemical Company. H NMR spectra was recorded at 400 or 600
13
1
MHz, C NMR spectra was recorded at 100 or 150 MHz. H NMR spectra was recorded
with tetramethylsilane (δ = 0.00 ppm) as internal reference; 13C NMR spectra was recorded
with CDCl3 (δ = 77.00 ppm) or C6D6 (δ = 128.06 ppm) as internal reference.
Highꢀresolution mass spectra was performed on a mass spectrometer with a TOF or LTQ
analyzer.
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Synthesis of NꢀH pyrroles sꢀ1a, sꢀ1b and sꢀ1c.
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Typical procedure for the synthesis of 2,4ꢀdiphenylꢀ1Hꢀpyrrole (sꢀ1a).
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To a solution of phenylacetylene (18.1 mL, 165 mmol) in THF (150 mL) was added
nꢀBuLi (2.5 M in hexane, 60 mL, 150 mmol) at ꢀ78 oC. After stirring for 30 min at the same
temperature, αꢀaminoacetophenone hydrochloride (8.58 g, 50.0 mol) was added, then the
resulting mixture was warmed up to room temperature and stirred for 1 h. After the starting
material was consumed, the mixture was quenched with water, extracted with ethyl acetate,
washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under the
reduced pressure and the residue was purified by a short column chromatography on silica
gel (eluent: dichloromethane ： methanol = 25:1) to afford the crude product
1ꢀaminoꢀ2,4ꢀdiphenylbutꢀ3ꢀynꢀ2ꢀol as an offꢀwhite solid.
To a solution of above crude alcohol in DCE (150 mL) was added catalyst A (77.2 mg,
o
0.1 mmol), and then the flask was immersed into an oil bath preheated at 80 C. After the
reaction was complete as monitored by thinꢀlayer chromatography (1 h), the mixture was
cooled down. Then anhydrous Na2SO4 was added to the reaction mixture to remove the
byꢀproduct water. Next, the mixture was filtered through a pad of celite, concentrated under
reduced pressure and the residue was purified by column chromatography on silica gel
(eluent: petroleum ether: dichloromethane = 1:1 to dichloromethane) to afford sꢀ1a (7.73 g,
71% overall yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.33 (bs, 1 H), 7.55 (d, J
= 7.2 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H), 7.34 (t, J = 7.6 Hz, 4H), 7.23ꢀ7.17 (m, 2H),
13
7.04ꢀ7.03 (m, 1H), 6.82ꢀ6.81 (m, 1H); C NMR (100 MHz, CDCl3) δ 135.4, 133.0, 132.4,
128.9, 128.7, 126.4, 126.4, 125.7, 125.1, 123.8, 115.7, 103.8. The spectroscopic data is in
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agreement with that previously reported.24
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2ꢀButylꢀ4ꢀphenylꢀ1Hꢀpyrrole (sꢀ1b). Column chromatography on silica gel (eluent:
petroleum ether: ethyl acetate = 30:1) afforded the title product in 57% overall yield (15
mmol scale, 1.71 g) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.58 (bs, 1H),
7.49ꢀ7.46 (m, 2H), 7.30ꢀ7.26 (m, 2H), 7.13ꢀ7.09 (m, 1H), 6.75ꢀ6.74 (m, 1H), 6.19ꢀ6.18 (m,
1H), 2.45 (t, J = 7.2 Hz, 2H), 1.55ꢀ1.48 (m, 2H), 1.36ꢀ1.27 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 136.0, 133.9, 128.5, 125.1, 124.8, 124.4, 112.8, 103.0, 31.5,
27.3, 22.3, 13.8; IR (film): 3326, 3059, 3029, 2958, 2931, 2862, 1687, 1604, 1524, 1493,
1449, 1378, 1265, 1182, 1124, 1072, 1032, 980, 926, 866, 794, 735, 696, 655 cmꢀ1; HRMS
(EI) calcd for C14H17N [M]+: 199.1361, found 199.1364.
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2ꢀCyclopropylꢀ4ꢀphenylꢀ1Hꢀpyrrole (sꢀ1c). Column chromatography on silica gel (eluent:
petroleum ether: ethyl acetate: dichloromethane = 60:1:20) afforded the title product in
60% overall yield (15 mmol scale, 1.65 g) as a light yellow oil. 1H NMR (400 MHz, CDCl3)
δ 7.87 (bs, 1H), 7.47 (d, J = 7.6 Hz, 2H), 7.31ꢀ7.28 (m, 2H), 7.17ꢀ7.11 (m, 1H), 6.84 (t, J =
2.0 Hz, 1H), 6.15 (t, J = 2.0 Hz, 1H), 1.78ꢀ1.72 (m, 1H), 0.83ꢀ0.78 (m, 2H), 0.64ꢀ0.60 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 135.9, 135.5, 128.5, 125.2, 124.9, 124.6, 112.9, 102.1,
8.1, 6.5; IR (film): 3416, 3076, 3004, 1686, 1602, 1526, 1479, 1450, 1421, 1358, 1181,
1156, 1117, 1072, 1046, 1021, 970, 928, 903, 874, 799, 762, 743, 693, 676, 609 cmꢀ1;
HRMS (ESI) calcd for C13H14N [M+H]+: 184.1121, found 184.1121.
2,4ꢀDimethylꢀ1Hꢀpyrrole (sꢀ1d) was commercially available, 2,3ꢀdiphenylꢀ1Hꢀpyrrole
(sꢀ1e)25 and 2ꢀphenylꢀ1Hꢀpyrrole (sꢀ1f)26 were prepared according to published methods.
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Synthesis of αꢀ(Nꢀpyrrolyl)ketones 1a, 1f, 1g, 1i and 1j.
Typical procedure for the synthesis of 2ꢀ(2,4ꢀdiphenylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ1ꢀphenylꢀethanꢀ
1ꢀone (1a).
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Under argon, to a solution of 2,4ꢀdiphenylꢀ1Hꢀpyrrole (2.19 g, 10.0 mmol) in DMF (40
o
mL) was added sodium hydride (60% w/w in mineral oil, 480 mg, 12.0 mmol) at 0 C.
After stirring for 30 min at the same temperature, 2ꢀbromoꢀNꢀmethoxyꢀNꢀmethylacetamide
(2.18 g, 12.0 mmol) was added, then the resulting mixture was warmed up to room
temperature and stirred at for 30 min. The mixture was quenched with water, extracted with
ethyl acetate, washed with brine and dried over anhydrous Na2SO4. The solvent was
evaporated under the reduced pressure and the residue was purified by a short column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate: dichloromethane =
3:1:1)
to
afford
the
crude
product
of
2ꢀ(2,4ꢀdiphenylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀNꢀmethoxyꢀNꢀmethylacetamide as an offꢀwhite solid.
To a solution of the above crude product in DCM (50 mL) was added dropwise phenyl
o
magnesium bromide (1.0 M in THF, 14.0 mL, 14.0 mmol) at ꢀ78 C.27 Then the resulting
o
mixture was warmed up to 0 C and stirred for 1 h. After the starting material was
consumed, the mixture was quenched with saturated NH4Cl solution, extracted with DCM,
washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under the
reduced pressure and the residue was purified by column chromatography on silica gel
(eluent: petroleum ether: ethyl acetate: dichloromethane = 50:1:20) to afford 1a (2.86 g,
85% overall yield) as a light yellow solid.
o
1
2ꢀ(2,4ꢀdiphenylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ1ꢀphenylethanꢀ1ꢀone (1a). M.p. 140ꢀ141 C. H
NMR (400 MHz, CDCl3) δ 7.85ꢀ7.83 (m, 2H), 7.59ꢀ7.52 (m, 3H), 7.44ꢀ7.41 (m, 2H),
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7.35ꢀ7.26 (m, 7H), 7.17ꢀ7.13 (m, 1 H), 7.00 (d, J = 2.0 Hz, 1 H), 6.59 (d, J = 2.0 Hz, 1 H),
5.28 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 193.8, 136.0, 135.4, 134.5, 133.9, 132.6, 128.9,
128.8, 128.6, 128.5, 127.9, 127.4, 125.5, 125.1, 125.0, 120.2, 107.1, 53.4; IR (film): 3059,
3032, 2925, 2338, 1955, 1889, 1814, 1698, 1602, 1580, 1524, 1485, 1450, 1422, 1402,
1350, 1300, 1211, 1182, 1160, 1074, 1057, 1012, 1000, 985, 929, 806, 751, 690, 667, 643,
616 cmꢀ1; HRMS (ESI) calcd for C24H20NO [M+H]+: 338.1539, found 338.1540.
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2ꢀ(2ꢀbutylꢀ4ꢀphenylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ1ꢀphenylethanꢀ1ꢀone
(1f).
Column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate: dichloromethane =
100:1:30) afforded the title product in 16% overall yield (8.5 mmol scale, 432 mg) as a
o
1
white solid. M.p. 90ꢀ91 C. H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.4 Hz, 2H),
7.63ꢀ7.59 (m, 1H), 7.50ꢀ7.47 (m, 4H), 7.31ꢀ7.27 (m, 2H), 7.14ꢀ7.10 (m, 1H), 6.83 (d, J =
1.6 Hz, 1H), 6.31 (s, 1H), 5.20 (s, 2H), 2.40 (t, J = 7.6 Hz, 2H), 1.67ꢀ1.59 (m, 2H),
13
1.42ꢀ1.33 (m, 2H), 0.90 (t, J = 7.6 Hz, 3H); C NMR (100 MHz, CDCl3) δ 193.4, 135.9,
135.0, 134.6, 133.9, 128.9, 128.4, 127.9, 125.1, 124.9, 124.0, 117.8, 104.3, 52.9, 30.5, 25.8,
22.5, 13.9; IR (film): 3062, 3033, 2956, 2928, 2870, 2337, 1698, 1603, 1580, 1523, 1493,
1449, 1416, 1380, 1350, 1300, 1264, 1213, 1182, 1098, 1072, 1054, 1027, 989, 931, 834,
792, 752, 734, 688, 636, 617 cmꢀ1; HRMS (ESI) calcd for C22H24NO [M+H]+: 318.1852,
found 318.1854.
2ꢀ(2ꢀCyclopropylꢀ4ꢀphenylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ1ꢀphenylethanꢀ1ꢀone
(1g).
Column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate: dichloromethane =
50:1:20) afforded the title product in 62% overall yield (8.65 mmol scale, 1.61 g) as a white
o
1
solid. M.p. 130ꢀ131 C. H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.2 Hz, 2H), 7.61ꢀ7.57
(m, 1H), 7.48ꢀ7.45 (m, 4H), 7.29ꢀ7.25 (m, 2H), 7.12ꢀ7.09 (m, 1H), 6.84 (s, 1H), 6.20 (s,
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1H), 5.33 (s, 2H), 1.54ꢀ1.47 (m, 1H), 0.75ꢀ0.70 (m, 2H), 0.63ꢀ0.59 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 193.5, 136.5, 135.8, 134.7, 133.8, 128.9, 128.4, 127.9, 125.1, 124.8, 123.6,
118.2, 104.0, 52.9, 6.6, 5.7; IR (film): 3055, 3004, 2927, 1698, 1601, 1580, 1527, 1450,
1411, 1389, 1352, 1265, 1215, 1183, 1140, 1067, 1052, 1027, 989, 889, 830, 799, 761, 730,
690, 646 cmꢀ1; HRMS (ESI) calcd for C21H20NO [M+H]+: 302.1539, found 302.1541.
2ꢀ(2,3ꢀDiphenylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ1ꢀphenylethanꢀ1ꢀone (1i). Column chromatography
on silica gel (eluent: petroleum ether: ethyl acetate: dichloromethane = 50:1:20) afforded
the title product in 83% overall yield (10.0 mmol scale, 2.80 g) as a white solid. M.p.
3
4
5
6
7
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o
1
138ꢀ139 C. H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.56ꢀ7.53 (m, 1H),
7.42ꢀ7.38 (m, 2H), 7.26ꢀ7.12 (m, 9H), 7.07ꢀ7.04 (m, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.55 (d,
13
J = 2.0 Hz, 1H), 5.16 (s, 2H); C NMR (100 MHz, CDCl3) δ 193.9, 136.3, 134.5, 133.8,
132.4, 131.0, 130.8, 128.8, 128.6, 127.9, 127.8, 127.8, 127.6, 125.0, 122.9, 122.3, 108.9,
53.2; IR (film): 3049, 3031, 2907, 1701, 1599, 1578, 1504, 1474, 1449, 1416, 1347, 1273,
1226, 1182, 1160, 1077, 1029, 1015, 999, 984, 957, 924, 912, 852, 825, 783, 751, 724, 700,
690, 673, 639, 625, 611 cmꢀ1; HRMS (ESI) calcd for C24H20NO [M+H]+: 338.1539, found
338.1542.
1ꢀPhenylꢀ2ꢀ(2ꢀphenylꢀ1Hꢀpyrrolꢀ1ꢀyl)ethanꢀ1ꢀone (1j). Column chromatography on
silica gel (eluent: petroleum ether: ethyl acetate: dichloromethane = 50:1:20) afforded the
title product in 72% overall yield (10.0 mmol scale, 1.87 g) as a colorless oil. 1H NMR (400
MHz, CDCl3) δ 7.86ꢀ7.83 (m, 2H), 7.59ꢀ7.54 (m, 1H), 7.45ꢀ7.41 (m, 2H), 7.33ꢀ7.20 (m,
5H), 6.72 (dd, J = 2.4, 1.6 Hz, 1H), 6.32ꢀ6.31 (m, 1H), 6.29ꢀ6.28 (m, 1H), 5.30 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ 194.0, 134.9, 134.5, 133.8, 132.8, 128.78, 128.76, 128.4, 127.8,
127.1, 123.5, 109.0, 108.8, 53.3; IR (film): 3059, 2925, 1961, 1892, 1816, 1698, 1597,
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1579, 1546, 1493, 1470, 1448, 1424, 1353, 1313, 1221, 1182, 1159, 1074, 1056, 1026, 999,
975, 917, 884, 847, 823, 788, 754, 714, 700, 687, 642, 608 cmꢀ1; HRMS (ESI) calcd for
C18H16NO [M+H]+: 262.1226, found 262.1228.
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Synthesis of αꢀ(Nꢀpyrrolyl)ketones 1b, 1c, 1d.
1) Synthesis of 2ꢀ(2,4ꢀdiphenylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀNꢀmethoxyꢀNꢀmethylꢀacetamide.
Under argon, to a solution of 2,4ꢀdiphenylꢀ1Hꢀpyrrole (877.2 mg, 4.0 mmol) in DMF
o
(20 mL) was added sodium hydride (60% w/w in mineral oil, 192 mg, 4.8 mmol) at 0 C.
After stirring for 30 min at the same temperature, 2ꢀbromoꢀNꢀmethoxyꢀNꢀmethylacetamide
(874 mg, 4.8 mmol) was added, then the resulting mixture was warmed up to room
temperature and stirred for 30 min. After the starting material was consumed, the mixture
was quenched with water, extracted with ethyl acetate, washed with brine and dried over
anhydrous Na2SO4. The solvent was evaporated under the reduced pressure and the residue
was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate:
dichloromethane = 10:1:5) to afford 2ꢀ(2,4ꢀdiphenylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀNꢀmethoxyꢀNꢀmethylꢀ
o
1
acetamide (1.14 g, 89% yield) as a white solid. M.p. 112ꢀ113 C. H NMR (400 MHz,
CDCl3) δ 7.53 (d, J = 8.4 Hz, 2H), 7.38ꢀ7.37 (m, 4H), 7.31ꢀ7.28 (m, 3H), 7.15ꢀ7.11 (m, 1H),
7.04 (d, J = 2.0 Hz, 1 H), 6.54 (d, J = 2.0 Hz, 1 H), 4.75 (s, 2H), 3.44 (s, 3H), 3.14 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 169.2, 135.8, 135.4, 132.6, 128.8, 128.4, 128.3, 127.2,
125.3, 124.9, 124.7, 120.2, 106.7, 61.1, 47.9, 32.3; IR (neat): 3062, 2966, 2936, 1672, 1602,
1579, 1522, 1489, 1478, 1455, 1443, 1422, 1385, 1317, 1250, 1211, 1173, 1160, 1119, 1095,
1076, 1058, 1035, 992, 959, 929, 917, 855, 814, 802, 780, 757, 749, 701, 685, 666, 639,
618, 606 cmꢀ1; HRMS (ESI) calcd for C20H21N2O2 [M+H]+: 321.1598, found 321.1600.
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2) Typical procedure for the synthesis of 1ꢀ(2,4ꢀdiphenylꢀ1Hꢀpyrrolꢀ1ꢀyl)butanꢀ2ꢀone
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(1b).
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Under
argon,
to
a
solution
of
2ꢀ(2,4ꢀdiphenylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀNꢀmethoxyꢀNꢀmethylꢀacetaꢀmide (1.46 g, 4.57 mmol) in
DCM (20 mL) was added dropwise ethyl magnesium bromide (3.0 M in Et2O, 2.13 mL,
6.40 mmol) at ꢀ78 oC. Then the resulting mixture was warmed up to 0 oC and stirred for 1 h.
After the starting material was consumed, the mixture was quenched with saturated NH4Cl
solution, extracted with DCM, washed with brine and dried over anhydrous Na2SO4. The
solvent was evaporated under the reduced pressure and the residue was purified by column
chromatography on silica gel (eluent: petroleum ether: dichloromethane = 1:1) to afford 1b
(1.07 g, 81% yield) as a white solid.
o
1
1ꢀ(2,4ꢀDiphenylꢀ1Hꢀpyrrolꢀ1ꢀyl)butanꢀ2ꢀone (1b). M.p. 86ꢀ87 C. H NMR (400
MHz, CDCl3) δ 7.54ꢀ7.52 (m, 2H), 7.40ꢀ7.29 (m, 7H), 7.20ꢀ7.15 (m, 1H), 6.94 (d, J = 2.0
Hz, 1 H), 6.56 (d, J = 2.0 Hz, 1 H), 4.62 (s, 2H), 2.22 (q, J = 7.2 Hz, 2 H), 0.96 (t, J = 7.6
Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 206.5, 135.9, 135.1, 132.3, 128.8, 128.60, 128.55,
127.5, 125.6, 125.2, 125.0, 119.8, 107.4, 56.2, 32.4, 7.2; IR (neat): 3051, 2978, 2941, 2913,
2882, 1881, 1817, 1728, 1602, 1579, 1564, 1526, 1486, 1474, 1453, 1414, 1366, 1244,
1214, 1155, 1111, 1073, 1042, 1011, 985, 929, 905, 802, 785, 755, 745, 692, 665, 639 cmꢀ1;
HRMS (ESI) calcd for C20H20NO [M+H]+: 290.1539, found 290.1543.
1ꢀCyclopropylꢀ2ꢀ(2,4ꢀdiphenylꢀ1Hꢀpyrrolꢀ1ꢀyl)ethanꢀ1ꢀone
(1c).
Cyclopropylꢀmagnesium bromide was used. Column chromatography on silica gel (eluent:
petroleum ether: ethyl acetate: dichloromethane = 20:1:4) afforded the title product in 36%
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yield (4.46 mmol scale, 489 mg) as a white solid. M.p. 90ꢀ91 C. H NMR (400 MHz,
CDCl3) δ 7.53 (d, J = 7.6 Hz, 2H), 7.39ꢀ7.29 (m, 7H), 7.19ꢀ7.14 (m, 1H), 7.00 (d, J = 2.0
Hz, 1 H), 6.57 (d, J = 1.6 Hz, 1 H), 4.73 (s, 2H), 1.71ꢀ1.65 (m, 1 H), 1.03ꢀ0.99 (m, 2 H),
0.86ꢀ0.81 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 206.2, 136.0, 135.1, 132.3, 128.8, 128.6,
128.5, 127.4, 125.6, 125.2, 125.0, 120.0, 107.3, 57.0, 17.4, 11.9; IR (neat): 3098, 3055,
3009, 2912, 2324, 2085, 1952, 1877, 1813, 1707, 1602, 1564, 1525, 1486, 1475, 1454,
1414, 1385, 1340, 1260, 1216, 1193, 1156, 1108, 1072, 1026, 964, 929, 893, 843, 803, 766,
752, 743, 692, 665, 645, 633, 617 cmꢀ1; HRMS (ESI) calcd for C21H20NO [M+H]+:
302.1539, found 302.1540.
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(E)ꢀ1ꢀ(2,4ꢀdiphenylꢀ1Hꢀpyrrolꢀ1ꢀyl)pentꢀ3ꢀenꢀ2ꢀone (1d). Allylmagnesium bromide
was used. In this case, double bond isomerization occurred to afford the α,βꢀunsaturated
ketone product 1d. Column chromatography on silica gel (eluent: petroleum ether: ethyl
acetate: dichloromethane = 50:1:10) afforded the title product in 40% yield (4.5 mmol scale,
548 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.55ꢀ7.53 (m, 2H), 7.39ꢀ7.28 (m,
7H), 7.18ꢀ7.14 (m, 1H), 6.97 (d, J = 2.0 Hz, 1 H), 6.90 (dq, J = 15.6, 6.8 Hz, 1 H), 6.58 (d,
J = 2.0 Hz, 1H), 5.99 (dq, J = 15.6, 1.6 Hz, 1 H), 4.75 (s, 2 H), 1.83 (dd, J = 6.8, 1.2 Hz, 3
13
H); C NMR (100 MHz, CDCl3) δ 194.2, 145.5, 136.0, 135.2, 132.4, 128.8, 128.6, 128.5,
127.4, 127.3, 125.6, 125.2, 125.0, 119.9, 107.3, 55.0, 18.5; IR (film): 3056, 3034, 2916,
1687, 1634, 1604, 1524, 1487, 1453, 1441, 1402, 1375, 1289, 1265, 1203, 1131, 1075,
1057, 1030, 1010, 968, 930, 808, 757, 732, 697, 668, 638, 617 cmꢀ1; HRMS (ESI) calcd for
C21H20NO [M+H]+: 302.1539, found 302.1541.
Synthesis of αꢀ(Nꢀpyrrolyl)ketone 1e.
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Under argon, to a solution of 3,3ꢀdimethylbutꢀ1ꢀyne (530 mg, 6.45 mmol) in THF (10
5
6
o
mL) was added dropwise nꢀBuLi (2.5 M in hexane, 2.41 mL, 6.02 mmol) at 0 C, and the
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resulting mixture was stirred at 0 C for 30 min. Then, the in situ formed alkynyl lithium
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solution was added dropwise into the solution of the Weinreb amide (1.378 g, 4.3 mmol) in
DCM (30 mL) through a syringe at ꢀ78 oC. After that, the resulting mixture was warmed up
o
to 0 C and stirred for 1 h. The mixture was quenched with saturated NH4Cl solution,
extracted with DCM, washed with brine and dried over anhydrous Na2SO4. The solvent
was evaporated under the reduced pressure and the residue was purified by column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 20:1) to afford 1e
1
(0.909 g, 62% yield) as a light yellow oil. H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.6
Hz, 2H), 7.41ꢀ7.31 (m, 7H), 7.20ꢀ7.15 (m, 1H), 7.00 (d, J = 2.0 Hz, 1 H), 6.57 (d, J = 1.6
13
Hz, 1 H), 4.69 (s, 2H), 1.14 (s, 9 H); C NMR (100 MHz, CDCl3) δ 183.7, 135.9, 135.3,
132.3, 128.9, 128.59, 128.55, 127.5, 125.6, 125.3, 125.0, 120.0, 107.4, 106.6, 77.1, 57.6,
29.6, 27.7; IR (film): 3392, 3061, 3032, 2972, 2930, 2869, 2211, 1676, 1603, 1492, 1476,
1450, 1365, 1261, 1202, 1135, 1072, 1030, 918, 790, 757, 736, 697, 671, 640 cmꢀ1; HRMS
(ESI) calcd for C24H24NO [M+H]+: 342.1852, found 342.1852.
Synthesis of αꢀ(Nꢀpyrrolyl)ketone 1h.
1) Synthesis of precursor 1ꢀbromoꢀ2,4ꢀdiphenylbutꢀ3ꢀynꢀ2ꢀol.
Under argon, to a solution of ethynylbenzene (7.14 mL, 65.0 mmol) in THF (100 mL)
was added dropwise ethylmagnesium bromide (3.0 M in diethyl ether, 20 mL, 60 mmol) at
0
oC. Then the resulting mixture was stirred at 0 oC for 1 h. Then,
2ꢀbromoꢀ1ꢀphenylethanꢀ1ꢀone (9.95 g, 50 mmol) was added in one portion. The reaction
mixture was stirred at 0 oC for another 0.5 h. After the starting material was consumed, the
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mixture was quenched with saturated NH4Cl solution, extracted with ethyl acetate, washed
with brine and dried over anhydrous Na2SO4. The solvent was evaporated under the
reduced pressure and the residue was purified by column chromatography on silica gel
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(eluent: petroleum ether: ethyl acetate
=
60:1 to 20:1) to afford
1ꢀbromoꢀ2,4ꢀdiphenylbutꢀ3ꢀynꢀ2ꢀol (13.9 g, 92% yield) as a light yellow oil. 1H NMR (400
MHz, CDCl3) δ 7.73ꢀ7.70 (m, 2H), 7.51ꢀ7.49 (m, 2H), 7.42ꢀ7.29 (m, 6H), 3.79 (d, J = 10.4
13
Hz, 1H), 3.72 (d, J = 10.4 Hz, 1H), 3.20 (s, 1H); C NMR (100 MHz, CDCl3) δ 140.5,
131.8, 128.8, 128.6, 128.4, 128.2, 125.7, 121.8, 89.0, 86.6, 72.3, 44.9; IR (film): 3541,
3433, 3060, 3030, 2963, 2231, 1954, 1883, 1758, 1680, 1597, 1574, 1489, 1445, 1412,
1335, 1268, 1231, 1167, 1068, 1031, 999, 970, 917, 844, 755, 689, 668, 615 cmꢀ1; HRMS
(EI) calcd for C16H13OBr [M]+: 300.0150, found 300.0146.
2) Synthesis of 2ꢀ(2,4ꢀdimethylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ1ꢀphenylethanꢀ1ꢀone (1h).
Under argon, to a schlenk tube were added KOH (898 mg, 16 mmol), DMSO (20 mL)
and 2,4ꢀdimethylꢀ1Hꢀpyrrole (1.14 g, 12 mmol) sequentially. The resulting mixture was
stirred at room temperature for 1 h. Then, 1ꢀbromoꢀ2,4ꢀdiphenylbutꢀ3ꢀynꢀ2ꢀol (2.41 g, 8
mmol) in DMSO (5 mL) was added in one portion. The reaction mixture was stirred at
room temperature for another 3 h. Then the mixture was quenched with water, extracted
with ethyl acetate, washed with brine and dried over anhydrous Na2SO4. The solvent was
evaporated under the reduced pressure and the residue was purified by column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate: dichloromethane =
30:1:3) to afford 1h (1.11 g, 65% yield) as a white solid. In this reaction, the alkynyl group
1
was eliminated to furnish a ketone functionality. H NMR (400 MHz, CDCl3) δ 7.96ꢀ7.94
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(m, 2H), 7.63ꢀ7.59 (m, 1H), 7.51ꢀ7.47 (m, 2H), 6.31 (s, 1H), 5.82 (s, 1H), 5.14 (s, 2H), 2.08
5
6
13
(s, 3H), 2.07 (s, 3H); C NMR (100 MHz, CDCl3) δ 193.7, 134.7, 133.8, 128.9, 128.8,
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8
9
127.8, 118.8, 118.1, 109.0, 52.7, 11.8, 11.7; IR (film): 3059, 2970, 2925, 2859, 1688, 1596,
1579, 1515, 1448, 1413, 1389, 1359, 1343, 1304, 1225, 1198, 1185, 1157, 1136, 1102, 1077,
1030, 995, 978, 925, 829, 797, 773, 756, 727, 687, 626, 612 cmꢀ1; HRMS (ESI) calcd for
C14H16NO [M+H]+: 214.1226, found 214.1228.
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Synthesis of indolizines 2.
Typical procedure for the synthesis of 1,3,6,8ꢀtetraphenylindolizine (2a).
Under argon, to a Schlenk tube were added PPh3AuNTf2 (0.015 mmol, 11.1 mg),
αꢀ(Nꢀpyrrolyl)ketone 1a (0.3 mmol, 101.2 mg), toluene (3 mL) and phenylacetylene (0.36
o
mmol, 39.5 ꢁL). Then the Schlenk tube was immersed into an oil bath preheated at 80 C.
After the reaction was complete as monitored by thinꢀlayer chromatography (3 h), the
mixture was cooled down. The solvent was evaporated under the reduced pressure and the
residue was purified by column chromatography on silica gel (eluent: hexane: ethyl acetate
= 100:1) followed by recycling preparative HPLC to afford indolizine 2a in 86% yield
(108.6 mg) and 3a in 5% yield (7.7 mg)
.
1,3,6,8ꢀtetraphenylindolizine (2a). Yellow solid. M.p. 193ꢀ194 oC. 1H NMR (400 MHz,
C6D6) δ 8.48 (s, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.6 Hz, 2H), 7.21ꢀ6.92 (m, 18H);
13C NMR (100 MHz, C6D6) δ 139.3, 138.9, 137.4, 134.7, 132.8, 130.0, 129.4, 129.3, 129.2,
128.8, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 127.0, 126.7, 125.3, 125.3, 120.6, 119.3,
118.1, 117.8; IR (film): 3055, 3031, 2987, 1955, 1888, 1598, 1500, 1488, 1470, 1448, 1396,
1347, 1314, 1264, 1220, 1172, 1149, 1074, 1027, 949, 896, 829, 734, 696, 656, 606 cmꢀ1;
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HRMS (ESI) calcd for C32H24N [M+H]+: 422.1903, found 422.1899.
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7
8
1
1,3,6,8ꢀtetraphenylꢀ2ꢀ(1ꢀphenylvinyl)indolizine (3a). Yellow sticky oil. H NMR (400
MHz, C6D6) δ 8.39 (d, J = 1.2 Hz, 1H), 7.41 (d, J = 7.2 Hz, 2H), 7.33ꢀ7.30 (m, 4H),
7.21ꢀ6.86 (m, 17H), 6.80ꢀ6.79 (m, 3H), 5.66 (d, J = 1.2 Hz, 1H), 5.23 (d, J = 1.2 Hz, 1H);
13C NMR (100 MHz, C6D6) δ 143.0, 142.0, 139.1, 138.9, 136.2, 134.8, 131.9, 131.2, 130.6,
129.6, 129.30, 129.27, 129.1, 128.2, 127.9, 127.6, 127.5, 127.4, 127.2, 127.1, 126.99,
126.96, 125.29, 125.26, 124.7, 120.9, 119.3, 118.7, 117.1; IR (film): 3057, 3028, 2961,
2924, 2854, 1975, 1953, 1888, 1739, 1658, 1600, 1577, 1493, 1470, 1446, 1396, 1312,
1261, 1179, 1075, 1026, 802, 761, 736, 696 cmꢀ1; HRMS (ESI) calcd for C40H30N [M+H]+:
524.2373, found 524.2370.
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8ꢀ(4ꢀFluorophenyl)ꢀ1,3,6ꢀtriphenylindolizine (2b). PPh3AuNTf2 (0.015 mmol, 11.1
mg), 1a (0.3 mmol, 101.2 mg), 1ꢀethynylꢀ4ꢀfluorobenzene (0.36 mmol, 43.2 mg) and 3 mL
toluene were stirred at 80 oC for 10 h. Column chromatography on silica gel (eluent: hexane:
ethyl acetate: dichloromethane = 50:1:5) followed by recycling preparative HPLC afforded
the title product in 81% yield (106.4 mg) as a yellow solid. M.p. 205ꢀ207 oC. 1H NMR (400
MHz, C6D6) δ 8.47 (d, J = 1.2 Hz, 1H), 7.46 (d, J = 7.2 Hz, 2H), 7.30 (d, J = 6.8 Hz, 2H),
7.21ꢀ6.94 (m, 14H), 6.86 (d, J = 1.2 Hz, 1H), 6.60 (t, J = 8.4 Hz, 2H); 13C NMR (100 MHz,
1
4
C6D6) δ 162.6 (d, JCꢀF = 246.1 Hz), 138.8, 137.2, 135.2 (d, JCꢀF = 4.0 Hz), 133.6, 132.7,
3
130.9 (d, JCꢀF = 8.2 Hz), 130.1, 129.4, 129.3, 128.8, 127.8, 127.52, 127.48, 127.0, 126.7,
2
125.5, 125.3, 120.4, 119.4, 118.0, 117.7, 114.6 (d, JCꢀF = 21.7 Hz); IR (film): 3054, 3031,
1951, 1879, 1682, 1598, 1536, 1502, 1469, 1447, 1417, 1396, 1347, 1314, 1266, 1220,
1174, 1155, 1095, 1075, 1028, 1014, 969, 949, 912, 867, 855, 831, 798, 758, 741, 696, 659,
645, 631, 612 cmꢀ1; HRMS (ESI) calcd for C32H23FN [M+H]+: 440.1809, found 440.1805.
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8ꢀ(4ꢀChlorophenyl)ꢀ1,3,6ꢀtriphenylindolizine (2c). PPh3AuNTf2 (0.015 mmol, 11.1
mg), 1a (0.3 mmol, 101.2 mg), 1ꢀchloroꢀ4ꢀethynylbenzene (0.36 mmol, 49.2 mg) and 3 mL
toluene were stirred at 80 oC for 10 h. Column chromatography on silica gel (eluent: hexane:
ethyl acetate: dichloromethane = 50:1:5) followed by recycling preparative HPLC afforded
the title product in 82% yield (111.9 mg) as a yellow solid. M.p. 210ꢀ212 oC. 1H NMR (400
MHz, C6D6) δ 8.46 (d, J = 1.6 Hz, 1H), 7.45 (d, J = 7.2 Hz, 2H), 7.29 (d, J = 6.8 Hz, 2H),
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13
7.21ꢀ7.07 (m, 6H), 7.01ꢀ6.83 (m, 11H); C NMR (100 MHz, C6D6) δ 138.7, 137.6, 137.0,
133.36, 133.35, 132.6, 130.5, 130.0, 129.5, 129.3, 128.8, 127.9, 127.8, 127.5, 127.3, 127.0,
126.7, 125.6, 125.3, 120.4, 119.5, 118.0, 117.7; IR (film): 3050, 3032, 1679, 1597, 1574,
1487, 1447, 1415, 1348, 1314, 1266, 1252, 1174, 1148, 1089, 1015, 966, 948, 911, 827,
759, 742, 695, 658 cmꢀ1; HRMS (ESI) calcd for C32H23ClN [M+H]+: 456.1514, found
456.1511.
Ethyl 4ꢀ(1,3,6ꢀtriphenylindolizinꢀ8ꢀyl)benzoate (2d). PPh3AuNTf2 (0.015 mmol, 11.1
mg), 1a (0.3 mmol, 101.2 mg), ethyl 4ꢀethynylbenzoate (0.36 mmol, 62.7 mg) and 3 mL
o
toluene were stirred at 80 C for 10 h. Column chromatography on silica gel (eluent:
petroleum ether: ethyl acetate = 30:1) afforded the title product in 86% yield (128.0 mg) as
a yellow oil, which solidified upon standing. 1H NMR (400 MHz, C6D6) δ 8.48 (d, J = 1.6
Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.48ꢀ7.46 (m, 2H), 7.30ꢀ7.28 (m, 2H), 7.23ꢀ7.09 (m, 8H),
7.04ꢀ7.00 (m, 3H), 6.93ꢀ6.88 (m, 4H), 4.11 (q, J = 7.2 Hz, 2H), 1.00 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, C6D6) δ 166.2, 143.7, 138.6, 137.0, 133.6, 132.6, 129.9, 129.7, 129.5,
129.3, 129.24, 129.17, 128.8, 127.8, 127.6, 127.5, 127.1, 127.0, 126.8, 125.6, 125.2, 120.8,
119.8, 118.1, 117.8, 60.8, 14.3; IR (film): 3056, 3029, 2980, 2929, 2854, 2120, 1952, 1885,
1810, 1710, 1600, 1467, 1446, 1397, 1367, 1309, 1269, 1176, 1101, 1020, 949, 913, 845,
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758, 736, 697, 656, 614 cmꢀ1; HRMS (ESI) calcd for C35H28NO2 [M+H]+: 494.2115, found
494.2109.
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1,3,6ꢀTriphenylꢀ8ꢀ(pꢀtolyl)indolizine (2e). PPh3AuNTf2 (0.015 mmol, 11.1 mg), 1a (0.3
mmol, 101.2 mg), 1ꢀethynylꢀ4ꢀmethylbenzene (0.36 mmol, 41.8 mg) and 3 mL toluene
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60
o
were stirred at 80 C for 10 h. Column chromatography on silica gel (eluent: hexane: ethyl
acetate = 100:1) followed by recycling preparative HPLC afforded the title product in 85%
o
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yield (110.7 mg) as a yellow solid. M.p. 173ꢀ174 C. H NMR (400 MHz, C6D6) δ 8.48 (s,
1H), 7.47 (d, J = 7.6 Hz, 2H), 7.30 (d, J = 7.2 Hz, 2H), 7.21ꢀ6.96 (m, 15H), 6.78 (d, J = 7.6
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Hz, 2H), 2.09 (s, 3H); C NMR (100 MHz, C6D6) δ 139.0, 137.5, 136.8, 136.5, 134.8,
132.9, 130.1, 129.4, 129.2, 128.8, 128.5, 127.6, 127.4, 127.0, 126.6, 125.4, 125.1, 120.4,
119.2, 118.1, 117.8, 21.2; IR (film): 3050, 3028, 2920, 2862, 1951, 1887, 1802, 1674, 1598,
1537, 1501, 1485, 1468, 1447, 1416, 1397, 1346, 1314, 1264, 1221, 1174, 1147, 1111, 1073,
1029, 973, 949, 911, 854, 815, 757, 737, 695, 659, 634, 613 cmꢀ1; HRMS (ESI) calcd for
C33H26N [M+H]+: 436.2060, found 436.2055.
8ꢀ(4ꢀMethoxyphenyl)ꢀ1,3,6ꢀtriphenylindolizine (2f). PPh3AuNTf2 (0.015 mmol, 11.1
mg), 1a (0.3 mmol, 101.2 mg), 1ꢀethynylꢀ4ꢀmethoxybenzene (0.36 mmol, 47.6 mg) and 3
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mL toluene were stirred at 80 C for 4 h. Column chromatography on silica gel (eluent:
petroleum ether: ethyl acetate: dichloromethane = 100:1:2 to 50:1:2) afforded 2f in 91%
yield (123.9 mg) and 3f in 7% yield (13.1 mg). For characterization data of 2f: yellow solid.
M.p. 155ꢀ156 oC. 1H NMR (400 MHz, C6D6) δ 8.49 (d, J = 1.2 Hz, 1H), 7.50ꢀ7.48 (m, 2H),
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7.34ꢀ7.33 (m, 2H), 7.22ꢀ6.95 (m, 15H), 6.58ꢀ6.56 (m, 2H), 3.29 (s, 3H); C NMR (100
MHz, C6D6) δ 159.6, 139.0, 137.5, 134.5, 132.8, 131.7, 130.4, 130.1, 129.4, 129.2, 128.8,
127.9, 127.6, 127.42, 127.36, 127.0, 126.6, 125.4, 125.1, 120.2, 119.0, 118.1, 117.7, 113.4,
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54.9; IR (film): 3055, 3029, 2930, 2834, 2540, 2314, 1953, 1885, 1814, 1746, 1600, 1575,
1536, 1504, 1464, 1443, 1418, 1398, 1370, 1343, 1314, 1289, 1264, 1244, 1221, 1175,
1144, 1108, 1095, 1073, 1030, 1001, 973, 949, 912, 865, 830, 782, 758, 736, 696, 659, 645,
631, 613 cmꢀ1; HRMS (ESI) calcd for C33H26NO [M+H]+: 452.2009, found 452.2002.
8ꢀ(4ꢀMethoxyphenyl)ꢀ2ꢀ(1ꢀ(4ꢀmethoxyphenyl)vinyl)ꢀ1,3,6ꢀtriphenylindolizine (3f).
Yellow solid. M.p. 126ꢀ127 oC. 1H NMR (400 MHz, C6D6) δ 8.45 (d, J = 1.6 Hz, 1H), 7.50
(d, J = 7.2 Hz, 2H), 7.36 (d, J = 6.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 7.15ꢀ7.07 (m, 10H),
7.02ꢀ6.98 (m, 1H), 6.85ꢀ6.79 (m, 3H), 6.61 (d, J = 8.4 Hz, 2H), 6.51 (d, J = 8.8 Hz, 2H),
5.65 (d, J = 1.2 Hz, 1H), 5.19 (d, J = 1.2 Hz, 1H), 3.30 (s, 3H), 3.18 (s, 3H); 13C NMR (100
MHz, C6D6) δ 159.43, 159.37, 142.3, 139.0, 136.5, 134.5, 134.4, 132.0, 131.5, 131.2, 130.6,
130.4, 129.8, 129.3, 129.1, 128.2, 128.0, 127.4, 127.0, 126.9, 125.3, 125.1, 124.5, 120.5,
119.0, 117.1, 116.8, 113.6, 113.3, 54.9, 54.6; IR (film): 3053, 2955, 2836, 2304, 1952, 1888,
1603, 1574, 1506, 1463, 1443, 1397, 1354, 1299, 1264, 1244, 1174, 1109, 1093, 1073,
1031, 987, 973, 895, 833, 804, 783, 759, 733, 698, 627 cmꢀ1; HRMS (ESI) calcd for
C42H34NO2 [M+H]+: 584.2584, found 584.2577.
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Benzyl (4ꢀ(1,3,6ꢀtriphenylindolizinꢀ8ꢀyl)phenyl)carbamate (2g). PPh3AuNTf2 (0.015
mmol, 11.1 mg), 1a (0.3 mmol, 101.2 mg), benzyl (4ꢀethynylphenyl)carbamate (0.36 mmol,
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90.5 mg) and 3 mL toluene were stirred at 80 C for 10 h. Column chromatography on
silica gel (eluent: petroleum ether: ethyl acetate: dichloromethane = 40:1:20) afforded the
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title product in 87% yield (149.7 mg) as a yellow solid. M.p. 171ꢀ172 C. H NMR (600
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MHz, C6D6, 70 C) δ 8.47 (s, 1H), 7.50 (d, J = 5.2 Hz, 2H), 7.37 (d, J = 5.2 Hz, 2H),
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7.24ꢀ7.22 (m, 4H), 7.18ꢀ7.06 (m, 13H), 7.00ꢀ6.94 (m, 5H), 6.20 (bs, 1H), 5.06 (s, 2H); C
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NMR (150 MHz, C6D6, 70 C) δ 153.4, 139.0, 137.8, 137.5, 137.0, 134.5, 134.4, 133.0,
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130.3, 129.9, 129.4, 129.2, 128.9, 128.7, 128.6, 128.4, 127.9, 127.7, 127.5, 127.4, 127.0,
126.7, 125.5, 125.4, 120.4, 119.3, 118.3, 117.8, 67.1; IR (film): 3419, 3054, 3033, 1734,
1599, 1517, 1467, 1447, 1414, 1399, 1343, 1313, 1264, 1207, 1183, 1143, 1051, 1028,
1017, 949, 913, 896, 868, 834, 761, 733, 697, 611 cmꢀ1; HRMS (DART) calcd for
C40H31N2O2 [M+H]+: 571.2380, found 571.2368.
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1,3,6ꢀTriphenylꢀ8ꢀ(3,4,5ꢀtrimethoxyphenyl)indolizine (2h). PPh3AuNTf2 (0.015 mmol,
11.1 mg), 1a (0.3 mmol, 101.2 mg), 5ꢀethynylꢀ1,2,3ꢀtrimethoxybenzene (0.36 mmol, 69.2
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mg) and 3 mL toluene were stirred at 80 C for 6 h. Column chromatography on silica gel
(eluent: hexane: ethyl acetate: dichloromethane = 20:1:4) afforded the title product in 86%
yield (131.5 mg) as a light yellow oil, which solidified upon standing. 1H NMR (400 MHz,
C6D6) δ 8.56 (d, J = 1.2 Hz, 1H), 7.52 (d, J = 7.6 Hz, 2H), 7.39 (d, J = 7.2 Hz, 2H),
7.25ꢀ7.08 (m, 10H), 6.99 (t, J = 7.2 Hz, 2H), 6.93ꢀ6.89 (m, 1H), 6.46 (s, 2H), 3.88 (s, 3H),
3.30 (s, 6H); 13C NMR (100 MHz, C6D6) δ 153.7, 139.1, 138.9, 137.8, 135.0, 134.5, 132.8,
129.8, 129.5, 129.3, 128.8, 127.8, 127.6, 127.5, 127.4, 127.0, 126.8, 125.43, 125.41, 120.2,
119.3, 118.1, 117.8, 107.5, 60.7, 55.7; IR (film): 3056, 2997, 2937, 2829, 2303, 1960, 1881,
1819, 1599, 1582, 1498, 1464, 1452, 1416, 1398, 1373, 1353, 1322, 1265, 1237, 1209,
1176, 1125, 1073, 1028, 1007, 958, 926, 835, 760, 733, 698, 665, 624, 608 cmꢀ1; HRMS
(ESI) calcd for C35H30NO3 [M+H]+: 512.2220, found 512.2214.
1,3,6ꢀTriphenylꢀ8ꢀ(thiophenꢀ2ꢀyl)indolizine (2i). PPh3AuNTf2 (0.015 mmol, 11.1 mg),
1a (0.3 mmol, 101.2 mg), 2ꢀethynylthiophene (0.36 mmol, 38.9 mg) and 3 mL toluene were
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stirred at 80 C for 10 h. Column chromatography on silica gel (eluent: hexane: ethyl
acetate = 50:1) followed by recycling preparative HPLC afforded the title product in 80%
yield (102.2 mg) as a yellow sticky oil. 1H NMR (400 MHz, C6D6) δ 8.41 (d, J = 1.2 Hz,
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