MeOTf-Mediated Annulation of Alkylnitriles and Arylalkynes Leading to Polysubstituted NH-Pyrroles

Article abstract of DOI:10.1021/acs.joc.7b01845

A metal-free multicomponent domino reaction for the highly regioselective synthesis of tetrasubstituted NH-pyrroles from readily available alkylnitriles, arylalkynes, and MeOTf has been developed. A variety of NH-pyrroles were obtained in moderate to good yields under mild conditions. In addition, the reactions using diarylalkynes with electron-rich aryl groups were found to afford isoquinolines.

Full text of DOI:10.1021/acs.joc.7b01845

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Article
MeOTf-Mediated Annulation of Alkylnitriles and
Arylalkynes Leading to Polysubstituted NH-Pyrroles
Yu Liu, Xiangli Yi, Xuewei Luo, and Chanjuan Xi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01845 • Publication Date (Web): 17 Oct 2017
Downloaded from http://pubs.acs.org on October 17, 2017
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MeOTfꢀMediated Annulation of Alkylnitriles and Arylalkynes Leadꢀ
ing to Polysubstituted NHꢀPyrroles
Yu Liu,† Xiangli Yi,† Xuewei Luo,† Chanjuan Xi*,†‡
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†MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua Uniꢀ
versity, Beijing 100084, China
‡State Key Laboratory of ElementoꢀOrganic Chemistry, Nankai University, Tianjin 300071, China
Supporting Information
ABSTRACT: A metalꢀfree multicomponent domino reaction for the highly regioselective synthesis of tetrasubstituted NHꢀpyrroles
from readily available alkylnitriles, arylalkynes, and MeOTf has been developed. A variety of NHꢀpyrroles were obtained in modꢀ
erate to good yields under mild conditions. In addition, the reactions using diarylalkynes with electronꢀrich aryl groups were found
to
afford
isoquinolines.
INTRODUCTION
process, MeOTf as an electrophile reacts with arylnitrile to
give the Nꢀmethylnitirilium A, which is a highly reactive speꢀ
cies and can react with alkynes to afford intermediate B. The
intermediate B undergoes a FriedelꢀCrafts reaction to form
indenone imine C (Scheme 1). We are curious about the reacꢀ
tion of alkylnitriles, which lacks an aryl ring for the ring cloꢀ
sure and may lead to a different ring formation process. To our
delight, reaction of alkylnitriles, alkynes, and MeOTf indeed
afforded tetrasubstituted NHꢀpyrroles D (Scheme 1).
Pyrrole is an important organic skeleton that exists in
many useful compounds such as pharmaceuticals, natural
products, and functional materials.1 Thus, a variety of reacꢀ
tions have been created for the synthesis of the pyrroles.2, Beꢀ
sides the classical methods such as PaalꢀKnorr pyrrole syntheꢀ
sis and Hantzsch pyrrole synthesis,2a,2b a number of efficient
synthetic methodologies have been documented in recent
years under the promotion of transition metals.3,4 From the
viewpoint of sustainable chemistry, the development of metalꢀ
free pathways using readily accessible starting materials under
mild conditions toward polysubstituted NHꢀpyrroles are more
attractive, especially for the drug screen.5 Consequently, it is
still highly desirable to further explore this topic, of particular
interest is pyrroles containing a Cꢀ2 carbonyl group, which are
of great synthetic significance as biologically active moleꢀ
cules,6 and building blocks in organic synthesis,7 although
many transition metalꢀmediated formations of substituted pyrꢀ
roles have been developed.8 As a part of our ongoing projects
on alkyltriflateꢀmediated annulation,9 herein, we report a oneꢀ
pot procedure for the regioselective synthesis of tetrasubstitutꢀ
ed NHꢀpyrroles containg a Cꢀ2 keto group via a methyltriflate
(MeOTf)ꢀtriggered domino reaction of alkylnitrile and arꢀ
ylalkynes under mild conditions.
R1
N
MeOTf
R1
Me
A
N
R2
R3
R3
R2
R1
R1
C
NMe
R2
NMe
R2
R1 = Aryl
ref. 9a
R1 = Alkyl
NMe
R1
N
H
This work
R3
R3
B
C
D
Scheme 1. MeOTfꢀinduced Reaction of Nitriles and Alkynes
RESULTS AND DISCUSSION
Initially, butyronitrile 1a, 1ꢀphenylꢀ1ꢀpropyne 2a and Meꢀ
OTf were chosen as model substrates to optimize the reaction
conditions. As shown in Table 1, we first tested a reaction in
Recently, we have reported MeOTfꢀinducted annulation of
arylnitriles and aromatic alkynes leading to indenones.9a In this
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dichloroethane (DCE) at 60 oC for 24 h with 1:1:1 ratio of the
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three substrates (entry 1) and 2ꢀacylpyrrole 3aa was obtained
as a product in 25% yield after work up. A part of 2a remained,
which is probably because the reaction of 2a to afford 3aa
entails two equivalents of butyronitrile and MeOTf. Therefore,
two equivalents of butyronitrile 1a and MeOTf were used and
3aa was obtained in 87% yield (entry 2). Temperature screenꢀ
ing experiments (entries 2ꢀ5) revealed that the best reaction
o
temperature was 60 C (entry 2). Furthermore, different reacꢀ
tion times were examined (entries 2, 6ꢀ8), and 24 h was found
to be most suitable for this reaction (entry 2). When the reacꢀ
tion was treated in CHCl3, CCl4, and nꢀhexane, only trace
amount of the product was observed (entries 9ꢀ11). Furtherꢀ
more, other methyl cation sources such as dimethyl sulfate,
dimethyl carbonate, and methyl 4ꢀ(methyl)benzenesulfonate
were used and the reactions did not proceed (entries 12ꢀ14).
On the basis of above results, the optimal conditions are
shown in entry 2.
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Scheme 2. Substrate Scope of Alkylnitriles. Reaction condition:
0.6 mmol 1, 0.3 mmol 2a, 0.6 mmol MeOTf, 0.5 mL solvent,
under N2, in a sealed tube. All chemical isolated yields are calcuꢀ
lated on the basis of 2a.
Then, the substrate scope of alkynes for the synthesis of 2ꢀ
acylpyrroles was also investigated (Scheme 3). First, we tried
different alkylarylacetylenes (2bꢀ2j). The reaction of 1a with
pentꢀ1ꢀynꢀ1ꢀylbenzene 2b or hexꢀ1ꢀynꢀ1ꢀylbenzene 2c and Meꢀ
OTf afforded the desired product 3ab or 3ac in 65% and 68%
yield, respectively. The substrates with methyl group at the paraꢀ
position of the phenyl reacted smoothly to give desired pyrrole
3ad in 67% yield. However, the reaction did not proceed with
substrate 2e bearing a methoxyl group at the paraꢀposition of the
phenyl. Halogen substitution such as bromine, fluorine, and chloꢀ
rine on the paraꢀposition of the phenyl led to higher yields (75%
for 3af, 78% for 3ag, and 68% for 3ah). Gratifyingly, crystal of
3af was suitable for a single crystal analysis, and its structure was
fully characterized by Xꢀray diffraction analysis. The structure of
3af clearly shows the formation of substituted pyrrole with aroꢀ
matic groups neighbouring to acyl group on the pyrroles. When
the phenyl in the substrate 2i was substituted by trifluoromethyl,
the reaction became unproductive. Next, arylalkynes with meta-
chlorine (2j) and orthoꢀchlorine (2k) were used, the reaction
could also proceed well and the desired pyrroles (3aj, 3ak, 3bj,
and 3bk) were obtained in 52%, 61%, 50%, and 56% yield, reꢀ
spectively. Additionally, unsymmetrical diarylacetylenes (2lꢀ2p)
were also found to regioselectively furnish the corresponding
products in good yields. The reactions with diarylacetylenes such
Table 1. Optimization of the Reactiona
as
1ꢀbromoꢀ4ꢀ(pꢀtolylethynyl)benzene
2l,
1ꢀchloroꢀ4ꢀ(pꢀ
aReaction condition: 0.3 mmol 2a, 0.5 mL solvent, under N2, in
tolylethynyl)benzene 2m, 1ꢀfluoroꢀ4ꢀ(pꢀtolylethynyl)benzene 2n,
1ꢀmethylꢀ4ꢀ((4ꢀ(trifluoromethyl)phenyl)ethynyl)benzene 2o, and
1ꢀ(phenylethynyl)ꢀ4ꢀ(trifluoromethyl)benzene 2p were treated
and the products were obtained in modrate yields (65% for 3al,
70% for 3am, 58% for 3an, 41% for 3ao, 40% for 3ap) with subꢀ
stituents on high regioselectivity, respectively. It is noteworthy
that no other products were obtained. The structure of 3bm was
further confirmed by its Xꢀray diffraction analysis, which conꢀ
firmed that the phenyl with more electronꢀdonating methyl neighꢀ
bored to an acyl group on the pyrrole. Next, when dialkylꢀ
substituted alkynes such as 4ꢀoctyne and 5ꢀdecyne were employed
in this reaction and the desired products were not observed. Furꢀ
thermore, when 1,2ꢀbis(4ꢀchlorophenyl)ethyne 2q and 1,2ꢀbis(4ꢀ
fluorophenyl)ethyne 2r were employed, only trace pyrrole 3aq
and 3ar were observed by GCꢀMS. The starting materials reꢀ
mained. Notably, when 1,2ꢀdiphenylethyne 2s and 1,2ꢀdiꢀpꢀ
tolylethyne 2t were employed under the same reaction condition,
the expected pyrroles were observed by GCꢀMS in trace but an
amount of isoquinolines 4 were obtained. The reaction conditions
were further optimized and we found that the reactions were treatꢀ
ed at 130 oC and the isoquinolines 4 were obtained in good yields.
The representative results are summarized in Scheme 4. When
1,2ꢀbis(4ꢀfluorophenyl)ethyne was used and the reaction failed to
give any product. The 1,2ꢀbis(4ꢀfluorophenyl)ethyne still reꢀ
mained. Notably, when diarylacetylenes such
a sealed tube. All chemical yields are calculated on the basis of
c
2a. bNMR yield, isolated yield was given in parenthesis. Dimeꢀ
thyl sulfate was used. dMethyl 4ꢀ(methyl)benzenesulfonate was
used.
With the optimized conditions, we initially tried various alꢀ
kylnitriles as substrates (Scheme 2). Unbranched alkylnitriles,
including butyronitrile 1a, acetonitrile 1b, nꢀpentanenitrile 1c,
and 3ꢀphenylpropanenitrile reacted with 1ꢀphenylꢀ1ꢀpropyne 2a
afforded 2ꢀacylpyrroles 3aa, 3ba, 3ca, and 3da in 78%, 60%,
68%, and 60% yield, respectively. The use of branched alkylniꢀ
trile such as isobutyronitrile 1e led to 3ea in 48% yield, which
might have resulted from greater steric hinderance. Moreover,
when alkylnitriles with a ring structure, like cyclopropanecarboniꢀ
trile 1f and cyclopentanecarbonitrile 1g were employed, the correꢀ
sponding products could also be obtained (45% yield for 3fa and
40% yield for 3ga). Unfortunately, when phenylacetonitrile 1h,
pivalonitrile 1i, and cyclohexanecarbonitrile 1j were used in this
reaction, only trace amount of the corresponding products were
observed in GCꢀMS.
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as 2l and 2n were employed under the same condition and a mixꢀ
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ture of products (including pyrroles as major and isoquinolines as
minor) were observed. Furthermore, 1,2ꢀdiꢀmꢀtolylethyne 2u was
used and a mixture of two products 4au (49%) and 4au′ (29%)
were obtained. Notably, the two isomers could be easily seperated
by flash chromatography on silica gel. When 1,2ꢀdiꢀoꢀtolylethyne
2v and 1,2ꢀbis(4ꢀmethoxyphenyl)ethyne 2w were employed and
the reactions failed to give the corresponding isoquinolines. Overꢀ
all, for the formation of isoquinolines 4, the diarylalkynes are
limited to the without or electrodonating group in the phenyl ring.
When deuterated acetonitrile 1k was used and the product 4ks
was obtained in 65% isolated yield, which points further the reacꢀ
tion pathway.
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R4
R4
R4
R1
MeOTf
R1
N
+
DCE, 130 oC, 24 h
N
1
2
4
iPr
Pr
Me
Bn
N
N
N
N
4as, 70%
4bs, 67%
Me
4ds, 72%
4es, 40%
Me
F
Pr
Me
F
Me
N
N
N
N
Me
Me
4fs, 45%
4at,
4bt,
4br,
0%
75%
71%
Me
Me
Me
Pr
+
CD3
Pr
N
N
N
Me
4au', 29%
4au, 49%
4ks, 65%
Scheme
4
Substrate Scope of Alkylnitriles with 1,2ꢀ
1,2ꢀDiꢀpꢀtolylethyne, and 1,2ꢀDiꢀmꢀ
Diphenylethyne,
tolylethyne. Reaction condition: 0.3 mmol 1, 0.3 mmol 2, 0.3
mmol MeOTf, 0.5 mL solvent, under N2, in a sealed tube. All
chemical isolated yields are calculated on the basis of 2.
To further understand this reaction, we tried the reaction of
acetonitrile
1b, 1ꢀmethylꢀ4ꢀ((4ꢀ(trifluoromethyl)phenyl)ꢀ
ethynyl)benzene 2o and EtOTf (Scheme 5, a). Compound 5
was obtained in 40% isolated yield, and no acylated product
was observed. In addition, when deuterated acetonitrile 1k was
used and the product 3'ka was obtained in GCꢀMS. As a reꢀ
sult, we finally got a product 6 with only one fullyꢀdeuterated
methyl group in 65% isolated yield after hydrolysis (Scheme
5, b), which may have resulted from the fast exchange beꢀ
tween hydrogen and deuterium during the work up.
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Scheme 3. Substrate Scope of Arylalkynes. Reaction condition:
0.6 mmol 1, 0.3 mmol 2, 0.6 mmol MeOTf, 0.5 mL solvent, under
N2, in a sealed tube. All chemical isolated yields are calculated on
the basis of 2.aReaction Temperature at 80 oC
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General Information. All the reactions were carried out in
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ovenꢀdried sealed tube with Teflonꢀlined septum under N2
atmosphere. Unless indicated, all materials were obtained
from commercial sources and used as received. DCE was
dried by activated 4Å molecular sieve. Column chromatogꢀ
raphy was performed on silica gel (particle size 200ꢀ300
1
mesh). H NMR and 13C NMR spectra were recorded on 300
MHz or 400 MHz at ambient temperature with CDCl3 as the
solvent. Chemical shifts (δ) were given in ppm, referenced to
the residual proton resonance of CDCl3 (7.26), to the carbon
resonance of CDCl3 (77.16). Coupling constants (J) were givꢀ
en in Hertz (Hz). The term m, q, t, d, s referred to multiplet,
quartet, triplet, doublet, singlet. The reaction progress was
monitored by GCꢀMS if applicable. The melting points were
measured on Xꢀ4 digital melting point apparatus and were
uncorrected. HRMS were obtained with ESI in positive ion
mode on ITꢀTOF instrument.
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Scheme 5. Mechanistic Experiments
On the basis of above results and reported lecture,9a we
proposed a plausible mechanism as shown in Scheme 6. First,
methylation of alkylnitrile by MeOTf gives nitrilium 7, which
adds to alkyne to form an alkenyl carbocation 8. Then, 1,5ꢀH
shift could occur leading to intermediate 9, which could unꢀ
dergo electrophilic annulation, elimination and isomerization
to form pyrrole 12 via intermediate 10 and 11. Subsequently,
the pyrrole 12 reacts with another molecule of the nitrilium 7
via electrophilic substitution to give 14, which leads to the
final product 3 after hydrolysis. When R1 is phenyl or pꢀtolyl
or mꢀtolyl on the intermediate 9, FriedelꢀCrafts reaction takes
place with priority, which is followed by isomerization to lead
to isoquinoline 4. This is consistent with the fact that Friedelꢀ
Crafts reaction is favored on electronꢀrich aryl rings.
1ꢀ(Hexꢀ1ꢀynꢀ1ꢀyl)ꢀ4ꢀmethylbenzene 2d, 1ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)ꢀ
4ꢀmethoxybenzene 2e, 1ꢀbromoꢀ4ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)benzene 2f,
1ꢀfluoroꢀ4ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)benzene 2g, 1ꢀchloroꢀ4ꢀ(hexꢀ1ꢀynꢀ
1ꢀyl)benzene
2h,
1ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)ꢀ4ꢀ
(trifluoromethyl)benzene
2i,
1ꢀchloroꢀ3ꢀ(hexꢀ1ꢀynꢀ1ꢀ
yl)benzene 2j, 1ꢀchloroꢀ2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)benzene 2k, 1ꢀ
bromoꢀ4ꢀ(pꢀtolylethynyl)benzene 2l, 1ꢀchloroꢀ4ꢀ(pꢀ
tolylethynyl)benzene 2m, 1ꢀfluoroꢀ4ꢀ(pꢀtolylethynyl)benzene
2n, 1ꢀmethylꢀ4ꢀ((4ꢀ(trifluoromethyl)phenyl)ethynyl)benzene
2o, 1ꢀ(phenylethynyl)ꢀ4ꢀ(trifluoromethyl)benzene 2p, 1,2ꢀdiꢀ
mꢀtolylethyne 2u, 1,2ꢀdiꢀoꢀtolylethyne 2v, and 1,2ꢀbis(4ꢀ
methoxyphenyl)ethyne 2w were prepared according to literaꢀ
ture reported10.
General procedure for the synthesis of product 3
An ovenꢀdried sealed tube was charged with the mixture of
alkylnitriles 1 (0.60 mmol), MeOTf (0.60 mmol, 69 µL), aroꢀ
matic alkyne 2 (0.3 mmol), then stirred in dichloroethane (0.5
mL) at 60 oC under nitrogen atmosphere for 24 h. The reaction
mixture and sodium acetate (0.5 g, 6.1 mmol) in water (3 mL)
o
were heated to 115 C and refluxed for 15 min.11 Then, the
reaction was cooled to room temperature and extracted with
dichloromethane for 3 times, dried over Na2SO4, evaporated
and purified by 200ꢀ300 mesh silica gel (particle size 200ꢀ300
mesh) (petroleum ether/ethyl acetate: 10/1) to provide the
hopeful substance.
1-(4-Methyl-3-phenyl-5-propyl-1H-pyrrol-2-yl)butan-1-one
o
(3aa): Faint yellow solid, 63 mg (78% yield), mp: 72ꢀ74 C;
1H NMR (CDCl3, 400 MHz): δ 9.26 (s, 1H), 7.44 – 7.34 (m,
3H), 7.28 (dd, J = 8.1, 1.4 Hz, 2H), 2.62 – 2.55 (m, 2H), 2.12
(d, J = 7.7 Hz, 2H), 1.80 (s, 3H), 1.67 (d, J = 7.6 Hz, 2H), 1.46
(dd, J = 15.0, 7.4 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H), 0.66 (t, J =
7.4 Hz, 3H). 13C NMR (CDCl3, 101MHz): δ 191.0, 136.5,
135.9, 132.5, 130.3, 128.2, 127.3, 117.7, 40.8, 28.3, 22.5, 18.9,
14.1, 13.9, 9.4. IR (neat) νmax cmꢀ1 1613 (C=O); GCꢀMS:
269.2. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C18H24NO
270.1852; found: 270.1850.
Scheme 6. Proposed Reaction Mechanisms
CONCLUSION
1-(4, 5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)ethanone (3ba):
In conclusion, we present a MeOTfꢀinduced, highly regioseꢀ
lective, and metalꢀfree method for the synthesis of a series of
multiply substituted pyrroles under mild condition. This route
provides a practical and convenient method for the synthesis
of multiply substituted 2ꢀacylpyrroles from readily starting
materials in a oneꢀpot reaction. Moreover, the reactions using
diarylalkynes with electronꢀrich aryl groups were found to
afford isoquinolines in good yields.
o
1
Faint yellow solid, 38 mg (60% yield); mp: 141ꢀ143 C. H
NMR(CDCl3, 400 MHz): δ 9.21 (s, 1H), 7.42 (t, J = 7.2 Hz,
2H), 7.37 (d, J = 6.9 Hz, 1H), 7.28 ꢀ 7.26 (m, 2H), 2.26 (s,
3H), 1.89( s, 3H), 1.80 (s, 3H); 13C NMR (CDCl3, 101 MHz):
δ 187.7, 136.2, 133.1, 130.3, 128.4, 127.5, 118.1, 27.3, 11.7,
9.3. IR (neat) νmax cmꢀ1 1615 (C=O); GCꢀMS: 213.1. HRMS
(ESIꢀTOF) m/z: [M+H]+ calcd for C14H16NO 214.1226; found:
214.1238.
1-(5-Butyl-4-methyl-3-phenyl-1H-pyrrol-2-yl)pentan-1-one
o
(3ca): Faint yellow solid, 61 mg (68% yield) , mp: 65ꢀ67 C;
EXPERIMENTAL SECTION
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1H NMR (CDCl3, 600 MHz) : δ 9.69 (s, 1H), 7.41 (t, J = 7.4
1-(4-Butyl-3-phenyl-5-propyl-1H-pyrrol-2-yl) butan-1-one
o
1
1
2
3
4
5
6
7
8
Hz, 2H), 7.37 – 7.34 (m, 1H), 7.29 – 7.26 (m, 2H), 2.64 – 2.59
(m, 2H), 2.19 – 2.14 (m, 2H), 1.80 (s, 3H), 1.62 (dt, J = 15.4,
7.6 Hz, 2H), 1.46 – 1.36 (m, 4H), 1.03 (dd, J = 14.9, 7.4 Hz,
2H), 0.94 (t, J = 7.4 Hz, 3H), 0.69 (t, J = 7.4 Hz, 3H).13C
NMR (CDCl3, 101 MHz): δ 191.2, 136.6, 136.3, 132.6, 128.2,
127.3, 117.6, 38.7, 31.4, 27.5, 26.1, 22.6, 22.5, 14.0, 13.8, 9.4,
55.6. IR (neat) νmax cmꢀ1 1614 (C=O); GCꢀMS: 297.2.
HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C20H28NO 298.2165;
found: 298.2170.
(3ac): Yellow solid, 63 mg (68% yield) , mp: 56ꢀ58 C; H
NMR (CDCl3, 400 MHz): δ 9.35 (s, 1H), 7.43 – 7.35 (m, 3H),
7.29ꢀ7.26 (m, 2H), 2.59 (t, J = 7.4 Hz, 2H), 2.20 (t, J = 7.3 Hz,
2H), 2.12 – 2.05 (m, 2H), 1.69 (dd, J = 14.6, 7.3 Hz, 2H), 1.45
(dd, J = 14.4, 7.1 Hz, 2H), 1.27 – 1.18 (m, 4H), 1.00 (t, J = 7.3,
1.0 Hz, 3H), 0.74 (t, J = 6.7 Hz, 3H), 0.64 (t, J = 7.3, 1.1 Hz,
3H). 13C NMR (CDCl3, 101 MHz): δ 191.0, 136.5, 135.8,
132.3, 130.3, 128.1, 127.5, 127.22 ꢀ127.3, 123.2, 40.8, 33.7,
28.3, 23.8, 22.8, 22.6, 18.9, 14.2, 13.9. IR (neat) νmax cmꢀ1
1612 (C=O); GCꢀMS: 311.2. HRMS (ESIꢀTOF) m/z: [M+H]+
calcd for C21H30NO 312.2322; found: 312.2324.
9
1-(4-Methyl-5-phenethyl-3-phenyl-1H-pyrrol-2-yl)-3-
phenylpropan-1-one(3da): Yellow solid, 71 mg (60% yield) ,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
1
mp: 158ꢀ160 C; H NMR (CDCl3, 400 MHz): δ 9.77 (s, 1H),
7.45 – 7.34 (m, 3H), 7.30 – 7.19 (m, 5H), 7.13 (ddd, J = 14.0,
8.4, 4.1 Hz, 5H), 6.81 (d, J = 7.1 Hz, 2H), 2.94 (s, 4H), 2.81 –
2.73 (m, 2H), 2.56 – 2.48 (m, 2H), 1.69 (d, J = 1.3 Hz, 3H).
13C NMR (CDCl3, 101 MHz): δ 189.9, 141.3, 140.9, 136.4,
135.6, 132.8, 130.2, 128.4 (dd, J = 27.4, 11.2 Hz), 127.4 (d,
J = 9.5 Hz), 126.4, 125.8, 118.3, 40.3, 35.7, 31.3, 28.4, 9.2.
IR (neat) νmax cmꢀ1 1603 (C=O); GCꢀMS: 393.2. HRMS (ESIꢀ
TOF) m/z: [M+H]+ calcd for C28H28NO 394.2165; found:
394.2160.
1-(4-Butyl-5-propyl-3-(p-tolyl)-1H-pyrrol-2-yl)butan-1-one
o
1
(3ad): Yellow solid, 65 mg (67% yield) , mp: 66ꢀ68 C; H
NMR (CDCl3, 400 MHz): δ 9.37 (s, 1H), 7.20 (d, J = 7.7 Hz,
2H), 7.15 (d, J = 7.9 Hz, 2H), 2.61 – 2.56 (m, 2H), 2.41 (s,
3H), 2.22 – 2.17 (m, 2H), 2.10 (t, J = 7.5 Hz, 2H), 1.68 (dd, J
= 15.2, 7.5 Hz, 2H), 1.50 – 1.43 (m, 2H), 1.26 – 1.20 (m, 2H),
1.17 (dd, J = 14.4, 7.2 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H), 0.76
(t, J = 7.3 Hz, 3H), 0.66 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3,
101 MHz): 13C NMR (151 MHz, CHLOROFORMꢀD) δ 191.1,
136.86 (s), 133.4, 132.3, 130.2, 128.8, 127.6, 123.2, 40.7, 33.7,
28.3, 23.9, 22.8, 22.6, 21.4, 18.9, 14.2, 13.9. IR (neat) νmax cmꢀ
1-(5-Isopropyl-4-methyl-3-phenyl-1H-pyrrol-2-yl)-2-
methylpropan-1-one (3ea): Faint yellow solid, 39 mg (48%
1
1612 (C=O); GCꢀMS: 325.2. HRMS (ESIꢀTOF) m/z:
[M+H]+ calcd for C22H32NO 326.2478; found: 326.2486.
1-(3-(4-Bromophenyl)-4-butyl-5-propyl-1H-pyrrol-2-
o
yield) , mp: 132ꢀ134 C; 1H NMR (CDCl3, 400 MHz) : δ 9.22
(s, 1H), 7.38 (m, 3H), 7.30ꢀ7.28 (m, 2H), 3.07(m, 1H), 2.63
(m, 1H), 1.80 (s, 3H), 1.30 (d, J = 7.1 Hz, 6H), 0.90 (d, J = 6.6
Hz, 6H). 13C NMR (CDCl3, 101 MHz): δ 195.5, 141.0, 136.4,
132.3, 130.2, 128.2, 127.3, 116.7, 34.7, 26.0, 21.8, 19.4, 9.3.
IR (neat) νmax cmꢀ1 1609 (C=O); GCꢀMS: 269.2. HRMS (ESIꢀ
TOF) m/z: [M+H]+ calcd for C18H24NO 270.1852; found:
270.1860.
yl)butan-1-one (3af): Yellow solid, 85 mg (75% yield), mp:
121ꢀ123 oC; 1H NMR (CDCl3, 400 MHz): δ 9.83 (s, 1H), 7.55
(dd, J = 8.1, 1.2 Hz, 2H), 7.20 – 7.14 (m, 2H), 2.60 (t, J = 7.6
Hz, 2H), 2.19 (t, J = 7.2 Hz, 2H), 2.10 (t, J = 7.3 Hz, 2H), 1.68
(dt, J = 14.6, 7.3 Hz, 2H), 1.47 (dd, J = 14.6, 7.3 Hz, 2H), 1.25
– 1.14 (m, 4H), 1.02 – 0.95 (m, 3H), 0.77 (t, J = 6.6 Hz, 3H),
0.70 (t, J = 6.9 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 190.7,
136.3, 135.7, 132.1, 131.3, 130.7, 127.5, 123.1, 121.5, 40.9,
33.7, 28.2, 23.8, 22.9, 22.6, 18.7, 14.2, 13.9. IR (neat) νmax cmꢀ
Cyclopropyl(5-cyclopropyl-4-methyl-3-phenyl-1H-pyrrol-2-
yl)methanone (3fa): Yellow solid, 36 mg (45% yield) , mp:
160ꢀ162 oC; 1H NMR (CDCl3, 400 MHz): δ 8.81 (s, 1H), 7.40ꢀ
7.30 (m, 5H), 1.92 (s, 3H), 1.87 – 1.81 (m, 1H), 1.66 – 1.62 (m,
1H), 1.02ꢀ1.01 (m, 2H), 0.96ꢀ0.94 (m, 2H), 0.73ꢀ0.72 (m, 2H),
0.55ꢀ0.54 (m, 2H); 13C NMR (CDCl3, 101 MHz): δ 190.3,
136.0, 135.9, 132.4, 130.7, 128.2, 127.3, 118.8, 18.2, 10.9, 9.5，
1
1611 (C=O); GCꢀMS: 389.1. HRMS (ESIꢀTOF) m/z:
[M+H]+ calcd for C21H29BrNO 390.1427; found: 390.1432.
1-(4-Butyl-3-(4-fluorophenyl)-5-propyl-1H-pyrrol-2-
yl)butan-1-one (3ag): Yellow solid, 67 mg (68% yield), mp:
1
81ꢀ83 oC; H NMR (CDCl3, 400 MHz): δ 9.84 (s, 1H), 7.28 –
7.3，6.6. IR (neat) νmax cmꢀ1 1598 (C=O); GCꢀMS: 265.1.
HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C18H20NO 266.1539;
found: 266.1541.
7.23 (m, 2H), 7.11 (t, J = 8.7 Hz, 2H), 2.63 – 2.57 (m, 2H),
2.21 – 2.16 (m, 2H), 2.11 – 2.07 (m, 2H), 1.69 (dd, J = 15.3,
7.5 Hz, 2H), 1.51 – 1.45 (m, 2H), 1.24 – 1.13 (m, 4H), 0.99 (t,
J = 7.3 Hz, 3H), 0.76 (t, J = 7.2 Hz, 3H), 0.69 (t, J = 7.4 Hz,
3H). 13C NMR (CDCl3, 101 MHz): δ 190.7, 163.1, 161.5,
136.2, 132.5, 131.9, 131.8, 131.0, 127.7, 123.2, 115.2, 115.1,
40.9, 33.7, 28.2, 23.8, 22.9, 22.6, 18.7, 14.2, 14.0, 13.9. IR
(neat) νmax cmꢀ1 1609 (C=O); GCꢀMS: 329.2. HRMS (ESIꢀ
TOF) m/z: [M+H]+ calcd for C21H29FNO 330.2228; found:
330.2233.
1-(4-Butyl-3-(4-chlorophenyl)-5-propyl-1H-pyrrol-2-
yl)butan-1-one (3ah): Yellow solid, 80 mg (78% yield), mp:
94ꢀ96 oC; 1H NMR (CDCl3, 400 MHz): δ 9.83 (s, 1H), 7.39 (d,
J = 8.4 Hz, 2H), 7.25 – 7.21 (m, 2H), 2.63 – 2.56 (m, 2H),
2.22 – 2.16 (m, 2H), 2.10 (t, J = 7.4 Hz, 2H), 1.69 (dd, J =
15.2, 7.5 Hz, 2H), 1.49 (dd, J = 14.8, 7.4 Hz, 2H), 1.20 (ddd, J
= 21.4, 11.5, 5.3 Hz, 4H), 0.99 (t, J = 7.4 Hz, 3H), 0.76 (t, J =
7.1 Hz, 3H), 0.70 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 101
MHz): δ 190.7, 136.3, 135.2, 133.3, 131.7, 130.7, 128.4,
127.6, 123.1, 40.9, 33.7, 28.2, 23.8, 22.9, 22.6, 18.7, 14.2,
13.9. IR (neat) νmax cmꢀ1 1611 (C=O); GCꢀMS: 345.2. HRMS
(ESIꢀTOF) m/z: [M+H]+ calcd for C21H29ClNO 346.1932;
found: 346.1933.
Cyclopentyl(5-cyclopentyl-4-methyl-3-phenyl-1H-pyrrol-2-
yl)methanone (3ga)：Yellow solid, 39 mg (40% yield) , mp:
144ꢀ146 oC; 1H NMR (CDCl3, 400 MHz) : δ 9.07 (s, 1H), 7.37
(m, 3H), 7.31 – 7.26 (m, 2H), 3.16 – 3.06 (m, 1H), 2.79 (t, J =
7.7 Hz, 1H), 2.12 – 2.04 (m, 2H), 1.81 (s, 5H), 1.64 (m, 8H),
1.43 (m, 2H), 1.31 – 1.26 (m, 2H). 13C NMR (CDCl3, 101
MHz): δ 194.3, 138.7, 136.4, 132.4, 130.4, 128.1, 127.3, 126.9,
117.5, 45.9, 37.4, 32.5, 30.8, 26.5, 25.5, 9.6. IR (neat) νmax cmꢀ
1
1609 (C=O); GCꢀMS: 321.2. HRMS (ESIꢀTOF) m/z:
[M+H]+ calcd for C22H28NO 322.2165; found: 322.2170.
1-(3-Phenyl-4,5-dipropyl-1H-pyrrol-2-yl)butan-1-one (3ab):
o
1
Yellow solid, 57.6mg (65% yield) , mp: 76ꢀ78 C; H NMR
(CDCl3, 400 MHz): δ 9.41 (s, 1H), 7.44 – 7.36 (m, 3H), 7.32 –
7.27 (m, 2H), 2.65 – 2.55 (m, 2H), 2.27 – 2.19 (m, 2H), 2.08 (t,
J = 7.5 Hz, 2H), 1.69 (d, J = 7.7 Hz, 2H), 1.46 (d, J = 7.5 Hz,
2H), 1.25 (m, 2H), 0.99 (d, J = 7.3 Hz, 3H), 0.89ꢀ0.87 (m, 3H),
0.65 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 190.0,
135.5, 134.6, 131.0, 129.3, 127.2, 126.4 (d, J = 17.4 Hz),
123.7, 39.8, 27.2, 21.9, 17.8, 16.4, 15.3, 13.21 12.4. IR (neat)
ν
max cmꢀ1 1612 (C=O); GCꢀMS: 297.2. HRMS (ESIꢀTOF) m/z:
[M+H]+ calcd for C20H28NO 298.2165; found: 298.2171.
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1-(4-Butyl-3-(2-chlorophenyl)-5-propyl-1H-pyrrol-2-
yl)butan-1-one (3aj)：Yellow oil, 53.7mg (52% yield); H
GCꢀMS: 289.1. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for
C17H21ClNO 290.1306; found: 290.1312.
1-(4-(4-Bromophenyl)-5-propyl-3-(p-tolyl)-1H-pyrrol-2-
1
1
2
3
4
5
6
7
8
NMR (CDCl3, 400 MHz): δ 9.22 (s, 1H), 7.41 – 7.29 (m, 3H),
7.23 – 7.17 (m, 1H), 2.62 – 2.54 (m, 2H), 2.22 – 2.15 (m, 2H),
2.08 (t, J = 7.5 Hz, 2H), 1.68 (dd, J = 15.2, 7.5 Hz, 2H), 1.52 –
1.43 (m, 2H), 1.26 – 1.17 (m, 4H), 1.00 (t, J = 7.3 Hz, 3H),
0.76 (t, J = 7.1 Hz, 3H), 0.69 (t, J = 7.4 Hz, 3H). 13C NMR
(CDCl3, 101 MHz): δ 190.7, 138.5, 135.9, 134.0, 131.7, 130.4,
129.4, 128.7, 128.4, 127.5, 123.1, 40.9, 33.6, 28.2, 23.8, 22.7,
22.5, 18.8, 14.2, 13.9, 14.0. IR (neat) νmax cmꢀ1 1616 (C=O);
GCꢀMS: 345.2. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for
C21H29ClNO 346.1932; found: 346.1937.
yl)butan-1-one (3al): Yellow solid, 83 mg (65% yield), mp:
190ꢀ192 oC; 1H NMR (CDCl3, 400 MHz): δ 9.84 (s, 1H), 7.17
– 7.12 (m, 2H), 7.11 – 7.03 (m, 4H), 6.97 – 6.92 (m, 2H), 2.67
– 2.59 (m, 2H), 2.34 (s, 3H), 2.24 – 2.17 (m, 2H), 1.65 (dt, J =
15.2, 7.4 Hz, 2H), 1.51 (ddd, J = 14.7, 7.5, 1.4 Hz, 2H), 0.91 (t,
J = 7.3 Hz, 3H), 0.70 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3,
101 MHz): δ 191.8, 137.0, 133.4, 132.3, 131.9, 131.6, 130.6,
128.8, 128.10, 123.7, 40.9, 28.4, 22.9, 21.4, 18.7, 14.00. IR
(neat) νmax cmꢀ1 1611 (C=O); GCꢀMS: 423.1. HRMS (ESIꢀ
TOF) m/z: [M+H]+ calcd for C24H27BrNO 424.1271; found:
424.1279.
9
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(4-Butyl-3-(2-chlorophenyl)-5-propyl-1H-pyrrol-2-yl) bu-
1
tan-1-one (3ak): Yellow oil, 63.2 mg (61% yield); H NMR
1-(4-(4-Chlorophenyl)-5-propyl-3-(p-tolyl)-1H-pyrrol-2-
yl)butan-1-one (3am): Yellow solid, 80 mg (70% yield), mp:
(CDCl3, 400 MHz): δ 9.62 (s, 1H), 7.51 – 7.46 (m, 1H), 7.36 –
7.28 (m, 3H), 2.64 – 2.58 (m, 2H), 2.22 – 1.99 (m, 4H), 1.69
(dd, J = 15.2, 7.5 Hz, 2H), 1.48 (dt, J = 15.1, 7.4 Hz, 2H), 1.27
– 1.11 (m, 4H), 0.99 (t, J = 7.3 Hz, 3H), 0.74 (t, J = 7.1 Hz,
3H), 0.66 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ
190.5, 136.2, 135.7, 134.7, 132.3, 129.6, 129.1, 128.6, 127.3,
126.6, 123.1, 40.3, 33.1, 28.2, 24.1, 22.8, 22.5, 18.4, 14.1,
14.0, 13.9. IR (neat) νmax cmꢀ1 1614 (C=O); GCꢀMS: 345.2.
HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C21H29ClNO
346.1932; found: 346.1940.
1
180ꢀ182 oC; H NMR (CDCl3, 400 MHz): δ 9.68 (s, 1H), 7.30
(d, J = 8.4 Hz, 2H), 7.07 (d, J = 4.2 Hz, 4H), 6.88 (d, J = 8.0
Hz, 2H), 2.66 – 2.58 (m, 2H), 2.34 (s, 3H), 2.20 (t, J = 7.4 Hz,
2H), 1.62 (m, 2H), 1.50 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H), 0.69
(t, J = 7.3 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 191.8,
137.1, 136.1, 133.9, 132.2, 131.9, 131.1, 130.6, 128.8, 128.0,
123.7, 120.2, 40.9, 28.4, 22.9, 21.4, 18.7, 14.00. IR (neat) νmax
cmꢀ1 1611(C=O); GCꢀMS: 379.2. HRMS (ESIꢀTOF) m/z:
[M+H]+ calcd for C24H27ClNO 380.1776; found: 380.1783.
1-(4-(4-Fluorophenyl)-5-propyl-3-(p-tolyl)-1H-pyrrol-2-
yl)butan-1-one (3an): Yellow solid, 63 mg (58% yield), mp:
1-(4-Butyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)
ethanone
o 1
(3bc): Yellow solid, 51 mg (67% yield), mp: 109ꢀ111 C; H
NMR (CDCl3, 400 MHz): δ 9.51 (s, 1H), 7.41ꢀ7.37 (m, 3H),
7.28ꢀ7.26 (m, 2H), 3.28 (s, 3H), 2.22ꢀ2.19 (m, 2H), 1.85 (s,
3H), 1.27ꢀ1.22 (m,2H), 1.17ꢀ1.15 (m,2H), 0.76 (t, J = 6.7 Hz,
3H). 13C NMR (CDCl3, 101 MHz): δ 187.7, 136.3, 133.1,
131.7, 128.2, 127.6, 127.4, 123.5, 33.3, 27.3, 23.9, 22.5, 13.9,
11.7. IR (neat) νmax cmꢀ1 1617 (C=O); GCꢀMS: 255.2. HRMS
(ESIꢀTOF) m/z: [M+H]+ calcd for C17H22NO 256.1696; found:
256.1701.
1
138ꢀ140 oC; H NMR (CDCl3, 400 MHz): δ 9.89 (s, 1H), 7.09
– 7.05 (m, 4H), 6.98 (ddd, J = 8.1, 3.7, 1.4 Hz, 2H), 6.90 –
6.86 (m, 2H), 2.65 – 2.60 (m, 2H), 2.34 (s, 3H), 2.24 – 2.20 (m,
2H), 1.65 (dd, J = 15.3, 7.6 Hz, 2H), 1.52 (td, J = 7.8, 0.8 Hz,
2H), 0.91 (t, J = 7.3 Hz, 3H), 0.70 (t, J = 7.4 Hz, 3H). 13C
NMR (CDCl3, 101 MHz): δ 191.8, 162.2, 160.6, 136.9, 136.3,
132.4, 131.84 (d, J = 7.7 Hz), 131.4, 130.8, 130.6, 128.8,
127.9, 123.9, 114.87 (d, J = 21.3 Hz), 40.9, 28.4, 22.9, 21.4,
18.7, 14.1, 13.9. IR (neat) νmax cmꢀ1 1609 (C=O); GCꢀMS:
363.2. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C24H27FNO
364.2071; found: 364.2077.
(4-Butyl-5-cyclopentyl-3-phenyl-1H-pyrrol-2-
yl)(cyclopentyl)methanone (3gc)：Yellow solid, 44 mg (40%
o
yield) , mp: 88ꢀ90 C; 1H NMR (CDCl3, 400 MHz): δ 9.04 (s,
1H), 7.41 – 7.33 (m, 3H), 7.31 – 7.27 (m, 2H), 3.15 – 3.06 (m,
1H), 2.72 (m, 1H), 2.25 – 2.18 (m, 2H), 2.12 – 2.02 (m, 2H),
1.86 – 1.80 (m, 2H), 1.74 – 1.56 (m, 8H), 1.45 – 1.37 (m, 2H),
1.30 – 1.21 (m, 4H), 1.18 – 1.10 (m, 2H), 0.74 (t, J = 7.2 Hz,
3H). 13C NMR (CDCl3, 101 MHz): δ 194.3, 138.8, 136.4,
131.9, 130.4, 127.9, 127.3, 123.2, 45.9, 37.1, 33.9, 33.3, 30.8,
26.4, 25.6, 23.9, 22.6, 13.9. IR (neat) νmax cmꢀ1 1611 (C=O);
GCꢀMS: 363.3. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for
C25H34NO 364.2635; found: 364.2641.
1-(5-Propyl-3-(p-tolyl)-4-(4-(trifluoromethyl) phenyl)-1H-
pyrrol-2-yl) butan-1-one (3ao): Yellow solid, 51 mg (41%
o
yield), mp: 178ꢀ180 C; 1H NMR (CDCl3, 400 MHz): δ 7.43
(d, J = 8.3 Hz, 2H), 7.26 (s, 1H), 7.08 (d, J = 3.2 Hz, 6H), 2.68
– 2.62 (m, 2H), 2.35 (s, 3H), 2.21 (t, J = 7.4 Hz, 2H), 1.66 (dd,
J = 15.3, 7.6 Hz, 2H), 1.51 (dd, J = 14.8, 7.4 Hz, 2H), 0.93 (t,
J = 7.3 Hz, 3H), 0.70 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3,
101 MHz): δ 191.9, 138.8, 137.2, 136.1, 131.1, 130.5 (d, J =
16.6 Hz), 128.9, 128.1, 124.91 (d, J = 3.6 Hz), 123.5, 41.0,
28.4, 22.9, 21.4, 18.7, 13.99 (d, J = 15.9 Hz). IR (neat) νmax
cmꢀ1 1608 (C=O); GCꢀMS: 413.2. HRMS (ESIꢀTOF) m/z:
[M+H]+ calcd for C25H27F3NO 414.2039; found: 414.2039.
1-(4-Butyl-3-(3-chlorophenyl)-5-methyl-1H-pyrrol-2-
1
yl)ethanone (3bi): Yellow oil, 52 mg (50% yield); H NMR
(CDCl3, 400 MHz):δ 9.57 (s, 1H), 7.35 (dd, J = 3.5, 1.5 Hz,
2H), 7.28 (t, J = 4.8 Hz, 1H), 7.23 – 7.16 (m, 1H), 2.27 (s, 3H),
2.19 (d, J = 8.2 Hz, 2H), 1.88 (d, J = 2.0 Hz, 3H), 1.30 – 1.19
(m, 4H), 0.78 (t, J = 7.1 Hz, 3H).13C NMR (CDCl3, 101 MHz):
δ 187.5, 138.3, 134.1, 132.0, 131.2, 131.3, 129.5, 128.7, 127.6,
127.5, 123.4, 33.3, 27.4, 23.8, 22.4, 13.9, 11.69. IR (neat)
νmax cmꢀ1 1617 (C=O); GCꢀMS: 289.1. HRMS (ESIꢀTOF)
m/z: [M+H]+ calcd for C17H21ClNO 290.1306; found: 290.1310.
1-(4-Butyl-3-(2-chlorophenyl)-5-methyl-1H-pyrrol-2-
1-(4-(4-Chlorophenyl)-5-methyl-3-(p-tolyl)-1H-pyrrol-2-
yl)ethanone (3bm): Yellow solid, 63 mg (65% yield), mp:
1
170ꢀ172 oC; H NMR (CDCl3, 400 MHz):δ 9.71 (s, 1H), 7.17ꢀ
7.14 (m, 2H), 7.12ꢀ7.05 (m, 4H), 6.96ꢀ6.92 (m, 2H), 2.35ꢀ
2.32(s, 6H), 1.96 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ
188.6, 137.3, 133.1, 132.1, 131.9, 131.8, 131.4, 130.6, 129.0,
128.3, 128.2, 123.7, 27.6, 21.4, 12.4. IR (neat) νmax cmꢀ1 1617
(C=O); GCꢀMS: 323.1. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd
for C20H19ClNO 324.1150; found: 324.1153.
1-(4-(4-Bromophenyl)-5-methyl-3-(p-tolyl)-1H-pyrrol-2-
yl)ethanone (3bl): Yellow solid, 66 mg (60% yield), mp: 179ꢀ
181 oC; 1H NMR (CDCl3, 400 MHz): δ 9.62 (s, 1H), 7.33ꢀ7.29
(m, 2H), 7.12ꢀ7.04 (m, 4H), 6.90ꢀ6.86 (m, 2H), 2.35ꢀ2.32(s,
6H), 1.95ꢀ1.94(s, 3H). 13C NMR (CDCl3, 101 MHz): δ 188.6,
yl)ethanone (3bj): Yellow solid, 48.5 mg (56% yield), mp:
133ꢀ135 oC; 1H NMR (CDCl3, 400 MHz): δ 9.74 (s, 1H), 7.49
(dd, J = 5.6, 3.4 Hz, 1H), 7.34 – 7.25 (m, 3H), 2.29 (s, 3H),
2.23 – 2.08 (m, 2H), 1.85 (d, J = 1.3 Hz, 3H), 1.23 (dd, J = 7.2,
4.3 Hz, 2H), 1.16 (dd, J = 14.7, 6.9 Hz, 2H), 0.76 (dd, J = 7.6,
6.5 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 187.4, 135.5,
134.7, 132.1, 129.7, 129.4, 129.2, 127.4, 126.7, 123.3, 32.8,
26.5, 24.1, 22.4, 13.9, 11.8. IR (neat) νmax cmꢀ1 1619 (C=O);
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J = 7.6 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.24 (dd, J = 11.8,
137.3, 133.6, 132.1, 131.7, 131.2, 130.6, 129.1, 128.2, 123.7,
120.2, 27.6, 21.4, 12.4. IR (neat) νmax cmꢀ1 1619 (C=O); GCꢀ
MS: 367.1. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for
C20H19BrNO 368.0645; found: 368.0653.
1
2
3
4.8 Hz, 2H), 7.19 – 7.15 (m, 1H), 7.06 (d, J = 7.2 Hz, 2H),4.50
(s, 2H), 3.50ꢀ3.47 (m, 1H) , (d, J = 6.8 Hz, 6H). 13C NMR
(CDCl3, 101MHz): δ 158.7, 151.5, 140.2, 136.1, 129.4, 128.7,
128.2, 128.1, 126.2, 126.0, 124.1, 123.8, 33.0, 31.4, 22.6. GCꢀ
MS: 261.2.
4
5
6
7
8
9
1-(4-(4-Fluorophenyl)-5-methyl-3-(p-tolyl)-1H-pyrrol-2-
yl)ethanone (3bn): Yellow solid, 44 mg (48% yield), mp: 159ꢀ
161 oC; 1H NMR (CDCl3, 400 MHz):δ 9.66 (s, 1H), 7.11ꢀ7.07
(m, 4H), 6.99ꢀ6.95 (m, 2H), 6.90ꢀ6.86 (m, 2H), 2.34 (s, 3H),
2.32(s, 3H), 1.96(s, 3H). 13C NMR (CDCl3, 101 MHz): δ 188.6,
137.2, 132.3, 132.0, 131.8, 131.7, 131.6, 130.6, 129.0, 128.1,
124.0, 115.1, 114.9 27.6, 21.4, 12.3. IR (neat) νmax cmꢀ1 1608
(C=O); GCꢀMS: 307.1. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd
for C20H19FNO 308.1451; found: 308.1455.
4-Benzyl-3-cyclopropylisoquinoline (4fs): Faint yellow oil,
1
35 mg (45% yield); H NMR (CDCl3, 400 MHz): δ 9.08 (s,
1H), 7.91ꢀ7.86 (dd, J = 12.0, 8.4 Hz, 2H), 7.58 (t, J = 7.0 Hz,
1H), 7.46 (t, J = 7.1 Hz, 1H),7.27ꢀ7.23 (m, 2H), 7.19ꢀ7.15 (m,
3H), 4.61 (s, 2H), 2.29ꢀ2.27 (t, J = 4.9 Hz, 1H) , 1.20ꢀ1.81 (dt,
J = 4.8, 3.1 Hz, 2H) , 0.98ꢀ0.95 (m, 2H). 13C NMR (CDCl3,
101MHz): δ 153.8, 151.2, 140.1, 135.8, 130.5, 128.7, 128.3,
127.1, 126.2, 125.6 (d, J = 21.8 Hz), 125.4, 123.2, 33.1, 14.1,
9.11. GCꢀMS: 259.1. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for
C19H18N 260.1434; found: 260.1441.
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1-(3-Phenyl-5-propyl-4-(4-(trifluoromethyl)phenyl)-1H-
pyrrol-2-yl)butan-1-one (3ap): Yellow solid, 44.1 mg (40%
o
1
yield) , mp:161ꢀ163 C; H NMR (CDCl3, 400 MHz): δ 9.72
(s, 1H), 7.42 (s, 2H), 7.32 – 7.27 (m, 3H), 7.20 (m, 2H), 7.12
(d, J = 8.1 Hz, 2H), 2.69 – 2.62 (m, 2H), 2.22 – 2.15 (m, 2H),
1.67 (m, 2H), 1.50 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H), 0.68 (t, J
= 7.4 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 191.8, 138.6,
136.3, 135.3, 131.0, 130.8, 130.4, 128.2, 127.6, 124.9, 123.5,
41.1, 28.4, 22.9, 18.6, 13.99 (d, J = 18.4 Hz). IR (neat) νmax
cmꢀ1 1608 (C=O); GCꢀMS: 399.2. HRMS (ESIꢀTOF) m/z:
[M+H]+ calcd for C24H25F3NO 400.1883; found: 400.1880.
7-Methyl-4-(4-methylbenzyl)-3-propylisoquinoline
(4at):
Faint yellow oil, 65 mg (75% yield); 1H NMR (CDCl3, 400
MHz): δ 9.08 (s, 1H), 7.76 – 7.69 (m, 2H), 7.41 (dd, J = 8.7,
1.7 Hz, 1H), 7.03 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H),
4.41 (s, 2H), 2.96 – 2.91 (m, 2H), 2.50 (s, 3H), 2.28 (s, 3H),
1.76 (d, J = 7.8 Hz, 2H), 0.98 (t, J = 7.3 Hz, 3H). 13C NMR
(CDCl3, 101MHz): δ 153.5, 150.5, 137.1, 135.7, 134.4, 132.7,
129.3, 128.0, 127.7, 126.9, 125.6, 123.6, 37.7, 33.0, 23.6, 21.5,
21.1, 14.4. GCꢀMS: 289.2. HRMS (ESIꢀTOF) m/z: [M+H]+
calcd for C21H24N 290.1903; found: 290.1907.
General procedure for the synthesis of product 4
An ovenꢀdried sealed tube was charged with the mixture of
alkylnitriles 1 (0.3 mmol), MeOTf (0.3 mmol, 34 µL), aroꢀ
matic alkyne 3 (0.3 mmol), then stirred in dichloroethane (0.5
mL) at 130 oC under nitrogen atmosphere for 24 h. After comꢀ
pletion, the rough was subjected to 200ꢀ300 mesh neutral aluꢀ
minium oxide column chromatography (petroleum ether/ethyl
acetate: 10/1) to provide the hopeful substance.
3,7-Dimethyl-4-(4-methylbenzyl) isoquinoline (4bt): Faint
yellow oil, 56 mg (71% yield); 1H NMR (CDCl3, 400 MHz): δ
9.04 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.70 (s, 1H), 7.47 – 7.42
(m, 1H), 7.03 (d, J = 7.9 Hz, 2H), 6.94 (d, J = 7.9 Hz, 2H),
4.38 (s, 2H), 2.68 (s, 3H), 2.50 (s, 3H), 2.28 (s, 3H). 13C NMR
(CDCl3, 101MHz): δ 150.2, 149.6, 136.5, 135.7 (d, J = 4.8 Hz),
134.3, 132.8, 129.4, 128.0, 127.8, 127.0, 126.2, 123.2, 33.4,
22.6, 21.6, 21.1. GCꢀMS: 261.2. HRMS (ESIꢀTOF) m/z:
[M+H]+ calcd for C19H20N 262.1590; found: 262.1595.
4-Benzyl-3-propylisoquinoline (4as): Faint yellow oil, 54.8
1
mg (70% yield); H NMR (CDCl3, 400 MHz): δ 9.17 (s, 1H),
d-4-Benzyl-3-methylisoquinoline (4ks)：Faint yellow oil,
45.6 mg (65% yield); 1H NMR (CDCl3, 400 MHz): δ 9.13 (s,
1H), 7.94 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.60
(m, 1H), 7.50 (m, 1H), 7.25 – 7.20 (m, 2H), 7.16 (t, J = 7.3 Hz,
1H), 7.06 (d, J = 7.3 Hz, 2H), 4.44 (s, 2H). 13C NMR (CDCl3,
101MHz): δ 150.8, 139.4, 135.9, 130.6, 128.9, 128.22 (d, J =
15.9 Hz), 127.5, 126.52 – 125.86 (m), 123.3, 33.7. GCꢀMS:
236.1. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C17H13D3N
237.1466, found: 237.1475.
7.93 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.57 (t, J =
7.7 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.19 (dd, J = 19.1, 7.3
Hz, 3H), 7.06 (d, J = 7.5 Hz, 2H), 4.47 (s, 2H), 3.00 – 2.93 (m,
2H), 1.76 (dt, J = 14.9, 7.5 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H).
13C NMR (CDCl3, 101MHz): δ 154.4, 151.2, 140.1, 136.1,
130.5, 129.6, 129.3, 128.6, 128.5, 128.4, 128.3,128.2,128.1，
127.4, 126.2, 126.0, 125.4, 123.7, 37.8, 33.4, 23.5, 14.4. GCꢀ
MS: 261.2. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C19H20N
262.1590; found: 262.1589.
4-Benzyl-3-methylisoquinoline (4bs):12 Faint yellow oil, 47
6-Methyl-4-(3-methylbenzyl)-3-propylisoquinoline(4au):
Yellow oil, 42.4 mg (49% yield); 1H NMR (CDCl3, 400 MHz):
δ 9.10 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.63 (s, 1H), 7.33 (dd,
J = 8.3, 1.2 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.99 (s, 1H),
6.90 (s, 1H), 6.85 (d, J = 7.6 Hz, 1H), 4.40 (s, 2H), 2.95 – 2.87
(m, 2H), 2.46 (s, 3H), 2.26 (s, 3H), 1.75 (dd, J = 15.4, 7.6 Hz,
2H), 0.97 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3, 101MHz): δ
154.5, 150.7, 140.7, 140.1, 138.2, 136.4, 128.9, 128.5, 128.15
(d, J = 18.5 Hz), 126.9, 125.9, 125.2, 124.9, 122.6, 37.8, 33.2,
23.5, 22.6, 21.5, 14.4. GCꢀMS: 289.2. HRMS (ESIꢀTOF) m/z:
[M+H]+ calcd for C21H24N [M+H]+ 290.1903; found: 290.1912.
5-Methyl-4-(3-methylbenzyl)-3-propylisoquinoline(4au′):
Yellow oil, 25.1 mg (29% yield); 1H NMR (CDCl3, 400 MHz):
δ 9.40 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.45 (dd, J = 8.5, 7.0
Hz, 1H), 7.27 (d, J = 7.0 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H),
6.97 (d, J = 7.4 Hz, 1H), 6.89 (s, 1H), 6.83 (d, J = 7.5 Hz, 1H),
4.43 (s, 2H), 2.78 (s, 3H), 2.25 (s, 3H), 1.77 (d, J = 7.8 Hz,
1
mg (67% yield); H NMR (CDCl3, 400 MHz): δ 9.14 (s, 1H),
7.94 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.60 (ddd, J
= 8.3, 6.9, 1.1 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.23 (dd, J =
11.6, 4.5 Hz, 2H), 7.17 (d, J = 7.2 Hz, 1H), 7.06 (d, J = 7.3 Hz,
2H), 4.44 (s, 2H), 2.71 (s, 3H). 13C NMR (CDCl3, 101MHz): δ
150.9, 150.6, 139.4, 135.9, 130.6, 128.7, 128.3, 128.1, 127.5,
126.3, 126.1, 126.0, 123.3, 33.7, 22.8. GCꢀMS: 233.1.
4-Benzyl-3-phenethylisoquinoline(4ds): yellow oil, 69 mg
(72% yield); 1H NMR (CDCl3, 400 MHz): δ 9.22 (s, 1H), 7.95
(d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.63 – 7.56 (m,
1H), 7.52 (d, J = 7.4 Hz, 1H), 7.26 – 7.12 (m, 8H), 7.02 (d, J =
7.8 Hz, 2H), 4.36 (s, 2H), 3.31 – 3.23 (m, 2H), 3.07 – 2.98 (m,
2H). 13C NMR (CDCl3, 101MHz): δ 151.3, 142.0, 139.9, 136.0,
130.5, 128.8 – 128.4 (m), 128.1(d, J = 11.3 Hz), 127.4, 126.0
(dd, J = 28.2, 11.8 Hz), 123.6, 37.8, 36.3, 33.2. GCꢀMS: 323.1.
HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C24H22N 324.1747;
found: 324.1750.
2H), 0.99 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3, 101MHz):
δ
4-Benzyl-3-isopropylisoquinoline (4es):13 Faint yellow oil,
154.1, 147.8, 140.2, 138.2, 136.4, 135.8, 130.2, 128.9,
128.5, 126.92 (d, J = 8.5 Hz), 126.4, 125.8, 125.2, 122.1,
37.8, 33.5, 23.5, 21.5, 18.8, 14.4. GCꢀMS: 289.2. HRMS
1
31 mg (40% yield); H NMR (CDCl3, 400 MHz): δ 9.23 (s,
1H), 7.94 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.59 (t,
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(ESIꢀTOF) m/z: [M+H]+ calcd for C21H24N 290.1903; found:
2000, 65, 3587. (d) Minetto, G.; Raveglia, L. F.; Sega, A.; Taddei,
1
2
3
4
5
6
7
8
M. Eur. J. Org. Chem. 2005, 5277. (e) Liao, Q.; Zhang, L.; Wang,
F.; Li, S.; Xi, C. Eur. J. Org. Chem. 2010, 5426. (f) Zhou, Y.;
Yan, X.; Chen, C.; Xi, C. Organometallics 2013, 32, 6182. (g)
Dhinakaran, I.; Padmini, V.; Bhuvanesh, N. ACS Comb. Sci.
2016, 18, 236.
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Voituriez, A. Chem. Soc. Rev. 2012, 41, 4884. (f) Estevez, V.;
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290.1910.
A procedure for the synthesis of 2, 5-dimethyl-3-(p-tolyl)-4-(4-
(trifluoromethyl)phenyl)-1H-pyrrole (5): An ovenꢀdried sealed
tube was charged with the mixture of acetonitrile 1b (0.3
mmol, 16 ꢁL), CH3CH2OTf (0.3 mmol, 39 µL), 1ꢀmethylꢀ4ꢀ
((4ꢀ(trifluoromethyl)phenyl)ethynyl)benzene 2o (0.3 mmol, 78
o
mg), then stirred in dichloroethane (0.5 mL) at 80 C under
nitrogen for 24 h. After completion, the rough was subjected
to 200ꢀ300 mesh silica gel column chromatography (petroleꢀ
um ether/ethyl acetate: 20/1) to provide title compound 5. Yelꢀ
9
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17
18
19
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21
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23
24
25
26
27
28
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31
32
33
34
35
36
37
38
39
40
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45
46
47
48
49
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52
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58
59
60
1
low oil, 39.5 mg (40% yield); H NMR (CDCl3, 400 MHz):δ
7.81 (s, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H),
7.06 (d, J = 7.9 Hz, 2H), 6.95 (d, J = 7.9 Hz, 2H), 2.32 (d, J =
4.5 Hz, 6H), 2.29 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ
140.3, 135.1, 132.7, 130.10 (d, J = 3.4 Hz), 128.9, 124.8,
123.7, 123.3, 120.5, 21.3, 12.1, 11.9. GCꢀMS: 329.1. HRMS
(ESIꢀTOF) m/z: [M+H]+ calcd for C20H19F3N 330.1464; found:
330.1471.
dꢀ1ꢀ(4,5ꢀDimethylꢀ3ꢀphenylꢀ1Hꢀpyrrolꢀ2ꢀyl)ethanone (6):
Yellow solid, 39.5 mg (61% yield), mp: 150ꢀ152 oC; H NMR
1
(CDCl3, 400 MHz): δ 9.59 (s, 1H), 7.45 – 7.36 (m, 3H), 7.29 –
7.25 (m, 2H), 1.90 (s, 3H), 1.80 (s, 3H). 13C NMR (CDCl3, 101
MHz): δ 187.8, 136.3, 133.2, 130.2, 128.3, 127.4, 118.1, 27.3,
9.3.IR (neat) νmax cmꢀ1 1619 (C=O); GCꢀMS: 216.1. HRMS
(ESIꢀTOF) m/z: [M+H]+ calcd for C14H13D3NO 217.1415;
found: 217.1423.
ASSOCIATED CONTENT
Supporting Information
Full NMR spectra for all products. The Xꢀray structure of comꢀ
pounds 3af and 3bm as well as their crystallographic data. These
materials are available free of charge on the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: cjxi@tsinghua.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the National Natural Science Founꢀ
dation of China (Nos 21472106 and 91645120) and the National
Key Basic Research Program of China (973 program)
(2012CB933402).
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