Synthesis of Multisubstituted Pyrroles from Enolizable Aldehydes and Primary Amines Promoted by Iodine

Article abstract of DOI:10.1021/acs.joc.9b00596

1,2,4-Trisubstituted pyrroles were synthesized from enolizable aliphatic aldehydes and primary aliphatic amines by using iodine as the dual Lewis acid/mild oxidant. In the presence of 3.0 equiv of TBHP, enolizable α,β-unsaturated aldehyde, for example, co

Full text of DOI:10.1021/acs.joc.9b00596

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Article
Synthesis of Multisubstituted Pyrroles from Enolizable
Aldehydes and Primary Amines Promoted by Iodine
Wenbo Huang, Shaomin Chen, Zhiyan Chen, Meie Yue, Minghao Li, and Yanlong Gu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00596 • Publication Date (Web): 16 Apr 2019
Downloaded from http://pubs.acs.org on April 16, 2019
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Synthesis of Multisubstituted Pyrroles from Enolizable Aldehydes and Primary
Amines Promoted by Iodine
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Wenbo Huang,a Shaomin Chen,a Zhiyan Chen,a Meie Yue,b Minghao Li,a* and Yanlong Gu a,c*
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a
Key Laboratory of Material Chemistry for Energy Conversion and Storage, Ministry of
Education, School of Chemistry and Chemical Engineering, Hubei Key Laboratory of Material
Chemistry and Service Failure, Huazhong University of Science and Technology, 430074,
Wuhan, China.
b
College of Chemistry and Molecular Engineering, Qingdao University of Science and
Technology, 266042, Qingdao, China.
c State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical
Physics, 730000, Lanzhou, China.
R2
CHO
Ar
Ar
CHO
Ar
Ar
I2 (30 mol%)
I2 (50 mol%), TBHP (3.0 equiv)
R1-NH2
I
R2
N
R1
Ar
CH3CN, 60 oC, 8 h
N
R1
PhMe, r.t. 8 h
R1-NH2: aliphatic amine
R1-NH2: aromatic amine
ABSTRACT: 1,2,4-Trisubstituted pyrroles were synthesized from enolizable aliphatic aldehydes
and primary aliphatic amines by using iodine as dual Lewis acid/mild oxidant. In the presence of
3.0 equivalent of TBHP, enolizable ,-unsaturated aldehyde, for example cocal, reacted with
aromatic primary amines to form C2-iodized N-arylpyrroles. An acetal-containing pyrrole was
successfully prepared from 4-aminobutyraldehyde diethyl acetal, which can be converted easily to
5,6,7,8-tetrahydroindolizine derivative.
Introduction
Pyrrole represents an important class of five-member nitrogen-containing naturally occurring
heterocycle.1 It is widely found in natural products,2 pharmaceutical concerning drugs3 and other
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biologically active utilization ways.4 Many pyrroles are also used in the synthesis of some
functional materials.5 The major route to access pyrroles relies heavily on chemical synthesis.
Traditionally, synthesis of pyrrole can be generally catalogued as classical Knorr reaction,6
Hantzsch reaction,7 and Paal-Knorr reaction.8 As pyrrole ring is an aromatic ring, some convergent
reaction strategies were also used to synthesize pyrroles, such as multicomponent reactions,9
tandem reactions,10 and transition-metal-catalyzed cyclizations.11 Recently, C-H bond activation
strategy has also been prove to be a suitable choice to construct pyrrole scaffold.12 Despite large
number of efforts have been dedicated into the synthesis of pyrrole skeleton, a practical way that
uses easily accessible starting materials, low-cost catalysts, and simple operation procedure is still
appealingly needed.
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Enolizable aliphatic aldehydes are easily available, and have often been used to construct
pyrrole scaffolds.13 Most of the synthetic protocols reported so far can be classified into the
following two approaches:14 (i) The aldehyde was used as 2C donor to construct pyrrole scaffold:
many nitrogen-containing counter-reagents, such as -amino carbonyl compounds,15 secondary
N-propargylamine,16 vinyl azides,17 cyclic 1,3-oxazolium-5-olates,18 and tosylmethylisocyanide
(TosMIC),19 have been used to react with enolizable aliphatic aldehydes, providing various
pyrrole derivatives; Some three-component reactions for synthesizing pyrroles were also
developed by using a primary amine as nitrogen source and the aliphatic aldehyde as 2C donor;20
(ii) The aldehyde was used as 4C donor to construct pyrrole scaffold: Scheidt et al21 used
hydrazine and some enolizable aliphatic aldehydes as precursors to synthesize N-acyl
3,4-disubstituted pyrroles via a Piloty-Robinson reaction; Jia et al22 reported a AgOAc-mediated
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oxidative coupling reaction of enolizable aliphatic aldehyde and primary amine, which produced
1,3,4-trisubstituted or 3,4-disubstituted pyrroles. While a diverse range of pyrrole derivatives were
synthesized by using the aldehyde as 2C donor, the reported protocols to use the aldehyde as 4C
donor produced only similar type of pyrrole products. However, the methods to construct pyrrole
ring using an aldehyde as a 4C donor avoided the use of complex molecule as substrate, the
operation procedure is also quite simple. To enrich the product diversity, a complementary method
that can provide new type pyrroles meanwhile uses the aldehyde as 4C donor is therefore still
needed. Herein, we report a new way for using the enolizable aliphatic aldehyde as 4C donor to
synthesize pyrrole derivative. We found that, by using iodine as catalyst, the aldehyde reacted
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R
CHO
R2
Aldehyde as 2C donor
O
H
N
H
N
R2
R1
R1
R2
R2
R
R
N
N
R1
R1
O
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Organ, J. Comb. Chem. 2008
Yan and Huang, JOC, 2014
O
N3
F3C
C6H5
R
N
R
R
Ar
or
Ar
O
F3C
C6H5
Harrity, OL, 2018
R2
N
Ar
N
N
H
H
O
Jiao, OL, 2012
O
O
EtO P
EtO
Br
O
R
OEt
R1 NH3 + R2
R
OEt
NO2
+ TosMIC
N
R1
N
H
Aleman, ChemCatChem, 2012
Shin, Org. Proc. Res. Dev. 2008
R
R2
R
R2
OH
R1 NH2 R1 NH2 +
+
NO2
HO
N
R1
N
R1
Beller, ACIE, 2013
Lykakis, JOC, 2018
Aldehyde as 4C donor
R
R
O
R
R
R
H2N NH2
R1 NH2
+
Ar
Cl
N
R
N
R1
N
R1
O
Ar
This work
Scheidt, JOC, 2007
Jia, OL, 2010
Fig. 1. Typical routes for pyrrole synthesis from enolizable aliphatic aldehydes.
readily with primary aliphatic amine, producing exclusively 1,2,4-trisubstituted pyrroles in good
to excellent yields. Iodine acted as dual catalyst/oxidant, and the primary aliphatic amine seemed
also not innocent in the catalytic mechanism.
Results and discussion
Initially, 2-phenylacetaldehyde 1a and n-butylamine 2a were mixed together in a mole ratio of 2/1.
o
The mixture was heated in acetonitrile at 60 C. We expect that a N-butyldiphenylpyrrole can be
formed. As shown in Table 1, no reaction occurred in the absence of catalyst (entry 1). Strong
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Lewis acids, such as AlCl3 and Sc(OTf)3, were proven to be unsuitable for initiating the reaction
as pyrrrole product can be hardly detected (entries 2 and 3). Attempts to use LiBr.H2O, a weak
Lewis acid, lead to recovery of unreacted starting materials (entry 4). p-Toluenesulfonic acid
(PTSA), a strong Brönsted acid, cannot initiate this reaction either (entry 5). To our surprise, a
1,2,4-trisubstitued pyrrole derivative 3a was isolated in 83% yield when 30 mol% of I2 was used
as catalyst (entry 6). It should be noted that such a reaction for converting enolizable aldehyde to
2,4-disubstituted pyrroles has not been reported before. Other iodine-containing species including
(diacetoxyiodo)benzene and N-iodosuccinimide (NIS), were then screened. It was found that
iodine was the best one for promoting the formation of 3a (entries 7 to 9). Various solvents were
then tested. Among the solvents used, CH3CN clearly stood out because it delivered the desired
product in the highest yield (entries 6, 10 to 13). In ethanol, the reaction proceeded also well.
However, owing to the formation of diethyl acetal of 1a, 3a was only isolated in 78% yield (entry
10). Further investigations revealed that the reaction was also affected by temperature. And it was
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found that 60 C was enough for ensuring a good yield of 3a (entries 6 and 14). The reaction
proceeded sluggishly when the amount of I2 was decreased to 10 mol% (entry 15). When the
reaction was performed in an inert atmosphere (with protection of argon), the yield reached only
9% (entry 16). This result implies that molecular oxygen was essential for ensuring completion of
the reaction. Therefore, the optimal reaction conditions were confirmed to be the followings: 1a
(0.6 mmol), 2a (0.3 mmol), acetonitrile as solvent (1 mL), 60 oC, and 8 h of reaction under air.
Table 1: Condition optimization for the model reaction.a
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Catalyst (30 mol%)
CHO
+
NH2
60 oC, 8 h
N
8
9
1a
2a
3a
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entry
1
catalyst
solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EtOH
yield (%)
―
0
2
AlCl3
Trace
Trace
0
3
Sc(OTf)3
4
LiBr.H2O
5
PTSA
Trace
83
6
I2
7
KI
20
8
PhI(OAc)2
Trace
45
9
NIS
I2
10
11
12
13
14b
15c
16d
78
I2
Toluene
DCE
51
I2
40
I2
DMSO
CH3CN
CH3CN
CH3CN
31
I2
36
I2
39
I2
9
a 1a (0.6 mmol), 2a (0.3 mmol), solvent (1 mL), 8 h, under air. b Reaction temperature: 40 oC. c Catalyst loading: 10
mol%. d The reaction was performed under inert atmosphere.
With the optimized reaction condition in hand, the scope of substrate with respect to the
aldehyde component was screened. As evidenced in Scheme 1, 2-phenylacetaldehyde derivatives
bearing ortho, meta or para substituent in the phenyl ring all participate in the reaction readily,
affording the pyrrole products in good to excellent yields (3b–3l). Compared with the
electron-deficient precursor, 2-phenylacetaldehyde possessing an electron-donating group in the
phenyl ring produced pyrroles in relatively higher yield (3k and 3l). Naphthalen-1-yl-acetaldehyde
also worked well, producing the expected pyrrole 3m in 62% yield. We also tried to use a linear
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aliphatic aldehdye, n-butyraldehyde, but failed. Substrate scope with respect to amine component
was then investigated. Primary aliphatic amines with long chain readily participated in the reaction
(3n and 3o). Aliphatic amines with a bulky group, for example tert-butylamine (3p) and
cyclohexylamine (3q), were also able to take part in this reaction. 3-Aminopropanol was proven to
be a viable substrate as well (3r). Aliphatic amines bearing an acetal group can also be used
successfully. Interestingly, although the acetal fragment is known to be susceptible toward acid, it
can be delivered into the product molecule without any structural damage (3s and 3t). It should be
noted that the presence of electrophilic acetal may facilitate the downstream conversions of the
pyrrole products. A N-propargylpyrrole 3u can be synthesized in 58% yield from propargylamine
and phenylacetaldehyde. Notably, literature survey stated that this kind of N-propargylpyrrole
derivative is useful intermediate for the synthesis of pyrrolo[1,2-]azepine derivative.23 To access
these pyrroles, a three-step method was used by using phenylacetylene and -aminoacetophenone
hydrochloride as starting materials.24 The present reaction offered thus a cost-effective and an
straightforward way to synthesize N-propargylpyrroles. 2-(3,4-Dimethoxyphenyl)ethylamine and
tryptamine were known to be able to react with an aldehyde to form Pictet-Spengler product.25 But,
under our conditions, these two amines can be converted to the corresponding pyrroles in 62% and
85% yields, respectively (3v and 3w). During the reaction, no Pictet-Spengler reaction product or
their downstream derivatives can be detected. We also attempted to use aniline in this
pyrrole-forming reaction, but failed. The reasons will be given later.
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Scheme 1. Substrate scope of the pyrrole synthesis.
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Ar
4
5
6
7
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9
I2 (30 mol%)
Ar
CHO
R
+
R
NH2
Ar
N
CH3CN, 60 oC, 8 h
R
R
3g
3h
R = F 71%
R = Cl 73%
R = Br 65%
R = I 70%
R
R
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R
3i
3j
3k
3l
N
N
R = Me 84%
R = OMe 85%
N
3b
3c
R = F 74%
R = Br 67%
3d
3e
3f
R = F 72%
R = Cl 78%
R = Br 70%
R
N
N
N
N
( )6
( )10
3p
75%
3o
80%
3m
3n
82%
62%
N
N
N
N
EtO
EtO
HO
OEt
OEt
3q
3s
82%
3r
56%
3t
71%
75%
H
MeO
MeO
N
N
N
N
3v
62%
3w
85%
3u
58%
To gain insights into this reaction, some control experiments were carried out. Firstly, 1a was
o
treated with I2 in the absence of amine. After 8 h of reaction at 60 C, only unreacted starting
material was recovered (Scheme 2, equation 1). Heating a mixture of 1a and 2a in the absence of
I2 gave no product (equation 2), When some radical scavengers, such as
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO, 2.0 equiv.) or 2,6-di-tert-butyl-4-methylphenol
(BHT, 2.0 equiv.), were added to the reaction system, the pyrrole product 3a was obtained in 69%
and 74% yields, respectively (equation 3). These results implies that this transformation may not
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involve a radical mechanism. In literature, 1a can be converted into an ,-unsaturated aldehyde
1b in the presence of a strong Lewis acid (e.g. FeCl3)26 or a strong organic base (e.g.
pyrrolidine).27 We also found that AlCl3 can catalyze the formation of 1b in the absence of 2a
(equation 4). But, I2 alone cannot catalyze the self-condensation of 1a. We also tried to isolate 1b
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Scheme 2. Some control experiments.
I2 (30 mol%)
CHO
(1)
no reaction
CH3CN, 60 oC, 8 h
1a
CHO
+
no reaction
NH2
(2)
(3)
CH3CN, 60 oC, 8 h
Standard conditions
1a
1a
2a
2a
CHO
+
NH2
3a
Additive (2.0 equiv.) Yield (%)
TEMPO
BHT
69
74
CHO
AlCl3 (10 mol%)
CH3CN, 60 oC, 8 h
CHO
(4)
(5)
1a
1b
33%
CHO
I2 (30 mol%)
+
NH2
N
CH3CN, 60 oC, 8 h
1b
CHO
1b
2a
3
a
8
9
%
NH2
2b
I2 (30 mol%)
(6)
+
CH3CN, 60 oC, 8 h
N
3x
90%
from the model reaction, but failed. However, we cannot totally exclude the possibility of forming
1b in the model reaction. Therefore, other experiments were done in order for us to get some
useful information. When 1b was allowed to react with 2a in the presence of 30 mol% of I2 at 60
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oC, 3a was obtained in 89% yield (equation 5). Interestingly, under the identical conditions, a
reaction between 1b and aniline occurred smoothly, giving a 1,2,4-triphenylpyrrole 3x in 90%
yield (equation 6).
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On the basis of the above-mentioned results and the previous literature’s reports,28 a plausible
mechanism was proposed and depicted in Scheme 3. Initially, a reaction of 1a and 2a occurred,
providing an imine intermediate I. The enamine form of I acted then as a nucleophile to react with
another molecule of 1a to generate an intermediate II.29 The enamine of II tautomerized to the
corresponding imine form. Hydrolysis of II may occur to form 1b and 2a. But, in the presence of
I2, the imine tautomer of II tended to be iodized to give an intermediate III via electrophilic
substitution path.30 Subsequently, III underwent an intramolecular quaternization and HI
elimination to afford the final product 3a.31 It should be mentioned that iodine can be regenerated
under an aerobic oxidative condition.32 Therefore, oxygen is necessary in this reaction. We also
suspected that a high nucleophilicity of the enamine form of the intermediate I should be the key
to initiating the reaction. When aromatic amine 2b was used, the generated intermediate may be
less nucleophilic. As a result, the reaction of 1a and 2b hardly proceeded. In other words, the
aliphatic amine played to some extent the role of a catalyst in the initial stage of the reaction,
ensuring a C-C bond forming reaction between two molecules of 1a proceeded. As both of the
aromatic and aliphatic amines can be used as the counter-reagents of ,-unsaturated aldehyde 1b
to synthesize pyrroles, we therefore deduced that the catalytic effect of amine ensured only the
self-condensation of 1a proceed well, but not critical for their downstream reactions.
Scheme 3. Proposed mechanism for pyrrole synthesis.
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H
N
N
5
CHO
+
H2N
6
7
1a
2a
I
8
9
- H2O
1a
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N
H
N
N
3a
II
[O]
HI
I2
I
I
I
I
N
N
NH
N
III
IV
On the basis of these results, we also established a transformation of enolizable
,-unsaturated aldehyde to a 1,2,4-trisubstituted pyrrole. Although some methods have been
developed for pyrrole synthesis from ,,-unsaturated aldehydes33 or ketones,34 transformation of
an enolizable ,-unsaturated aldehyde to 1,2,4-trisubstituted pyrrole has not been reported yet.
We tried to use cocal, an easily available enolizable ,-unsaturated aldehyde, to react with
anilines. As shown in Scheme 4, in the presence of 0.5 equiv. of I2, anilines with either
electron-donating or moderately electron-withdrawing substituents reacted smoothly with cocal,
providing the corresponding pyrroles in moderate yields (3y–3ac). A 1,3-diphenylpyrrole 3ad can
be synthesized in 32% yield from 2-phenyl-2-butenal. Amino-substituted heterocycles, such as
2-aminopyridine, 1-methyl-1H-pyrazol-5-ylamine and 3-amino-1H-indazole, can also be used in
this reaction (3ae–3ag). But the reactions yields are less than 55%.
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Scheme 4. Pyrrole synthesis from ,,-unsaturated aldehydes and aromatic amines.
5
6
CHO
R2NH2
7
C6H5
R1 +
8
9
C6H5
C6H5
I2 (50 mol%)
I2 (50 mol%)
TBHP (3.0 equiv.)
R1
R1
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I
N
R2
N
R2
PhMe, r.t., 8 h
PhMe, r.t., 8 h
C6H5
C6H5
C6H5
C6H5
N
N
N
N
OMe
OMe
R
a
a
a
a
3y
3z
R = H 43%
R = F 48%
3ab
45%
3ac
50%
3ad
32%
a
a
3aa
R = Br 39%
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
N
I
N
N
N
R
N
N
N
N
NH
a
a
a
3ae
47%
3af
55%
3ag
35%
C6H5
C6H5
b
C6H5
3ah
3ai
3aj
3ak
3al
R = H 82%
R = Me 84%
R = F 73%
R = Cl 70%
b
b
I
I
I
N
N
N
b
b
t
R = Bu 85%
b
Cl
F
3am
3an
R = CO2Et 39%
R = OCF3 51%
F
b
b
b
b
3aq
65%
3ap
68%
3ao
88%
C6H5
C6H5
C6H5
I
N
I
N
I
N
N
Br
OMe
b
b
b
3ar
59%
3as
3at
30%
68%
a: Reaction condition: I2 (50 mol%), PhMe, r t, 8 h.
b: Reaction condition: I2 (50 mol%), TBHP (3.0 equiv), PhMe, r t, 8 h.
Surprisingly, C2-iodized pyrrole was isolated when TBHP was added with the hope of
enhancing the synthesis efficiency of pyrrole. Inspired by this observation, we added 3.0 equiv. of
TBHP into the reaction system. This led us to develop an efficient method to synthesize
C2-iodized N-arylpyrroles. All the electron-rich anilines worked well in this reaction. And the
corresponding C2-iodized pyrroles can be obtained in up to 88% yield. But, electron-poor aniline,
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for example, benzocaine, participated in the reaction reluctantly. The expected product 3am was
obtained only in 39% yield. 1-Aminonaphthalene can also be utilized successfully (3as).
3-Amino-6-methoxy-2-picoline can also be applied in this reaction, but the expected product can
be isolated only in 30% yield. It should be noted that the iodized pyrroles are useful because the
presence of iodo group offers a chance for further functionalization of the pyrrole ring.35
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Several control experiments were conducted to further study the reaction mechanism to
produce 2-iodine-substituted pyrrole derivative. In the absence of TBHP, the 2-iodine-substituted
pyrrole product 3ah could be formed in 83% yield via the reaction of 3y with I2 (Scheme 5a). In
the presence of 3.0 equivalents of an oxidant TBHP, the yield of 3ah could be improved to 94%
(Scheme 5b). When radical scavengers, such as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO,
3.0 equiv.) or 2,6-di-tert-butyl-4-methylphenol (BHT, 3.0 equiv.), were added to the reaction
system, 3ah was obtained in 71% and 75% yields, respectively (Scheme 5c). The reaction
proceeded even quite well in the presence of 5.0 equiv. of TEMPO. These results demonstrated
that this transformation may not involve a radical pathway.
Scheme 5. Mechanistic investigation by control experiments.
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C6H5
5
6
7
8
I2 (50 mol%)
N
3ah
(a)
PhMe, r. t, 8 h
Yield = 83%
3y
3y
9
I2 (50 mol%)
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TBHP (3.0 equiv.)
3ah
3ah
(b)
(c)
PhMe, r.t., 8 h
Yield = 94%
Standard conditions
3y
Additive (3.0 equiv.) Yield (%)
TEMPO
71
75
59
BHT
TEMPO (5.0 equiv.)
Based on our experimental results and the previous investigations, a plausible reaction
mechanism of generating 2-iodine-substituted pyrrole was proposed in Scheme 6. Firstly,
α,β-unsaturated aldehyde 1c reacted with 2b, providing an imine intermediate IV. Subsequently,
the imine intermediate IV was iodized to give an intermediate V via an electrophilic substitution.
Then, 3y was formed via a reaction sequence including an intramolecular quaternization and HI
elimination. Finally, the C-2 position of the pyrrole ring was iodized through electrophilic
substitution to give 2-iodine-substituted pyrrole 3ah. The eliminated HI was oxidized to I2 in the
presence of TBHP.
Scheme 6. A possible mechanism of this transformation
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NH2
CHO
N
-H2O
NH
6
+
C6H5
7
8
C6H5
C6H5
1c
2b
IV
9
I2
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ref 30
tBuOH
H2O
+
+
TBHP
I2
2HI
+
HI
(50%)
HI
C6H5
I2
C6H5
HI (50%)
I
N
N
N
I
C6H5
3ah
3y
V
A
Knoevenagel
reaction
product
4a,
formed
from
acetylacetone
and
2-(p-chlorophenyl)acetaldehyde, was also proven to be capable of synthesizing a pyrrole
derivative. As shown in Scheme 7, the reaction between 4a and aniline occurred smoothly with
the aid of 30 mol% of I2, generating a pyrrole derivative 5a in 67% yield. The formation of an
intermediate VI may be involved in the reaction mechanism. We also tried to synthesize 5a
starting from enolizable aliphatic aldehyde, acetylacetone and aniline, but failed.
Scheme 7. Synthesis of pyrrole derivative 5a from aniline and 4a.
O
O
NH2
I2 (30 mol%)
N
+
CH3CN, 60 oC, 8 h
Cl
O
Cl
4a
2b
5a
67%
HI
O2
O
O
I2
HN
N
Cl
Cl
VI
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Pyrrole derivative 3s contains both an electrophilic acetal moiety and a nucleophilic pyrrole
fragment. We thus suspected that 3s can be converted via an intramolecular reaction. As we
expected, an indol-3-yl-substituted 5,6,7,8-tetrahydroindolizine derivative 6a was obtained in 81%
yield by treating 3s with N-methylindole in the presence of 10 mol% of CuBr2 (Scheme 8). It
should be mentioned that indolizine was a privilege motif that widely existed in natural product
and other biological molecular.36
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Scheme 8. Synthesis of tetrahydroindolizine derivative from 3s.
N
C6H5
CuBr2 (10 mol%)
CH3CN, r t, 1 h
C6H5
C6H5
+
C6H5
N
N
EtO
N
OEt
3s
6a
81%
Conclusion
In summary, a range of 1,2,4-trisubstituted pyrrole derivatives were synthesized by using easily
accessible enolizable aldehyde and aliphatic primary amines as starting materials by using I2 as
catalyst. The amine component not only played a role of nitrogen source, it can also be used as an
activator to enhance the nucleophilicity of aldehyde by forming an enamine intermediate. With the
aid of the similar catalytic system, enolizable ,-unsaturated aldehydes reacted also smoothly
with aromatic primary amines, generating C2-iodized N-arylpyrroles. This study offered a
complementary method to the traditional protocols to construct pyrrole scaffolds using the
aliphatic aldehyde as 4C donor, enriching thus the product diversity of the pyrrole derivatives.
Experimental Sections
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Unless otherwise noted, all reagents were purchased from commercial suppliers and used without
further purification. The reactions were monitored by TLC with Haiyang GF-254 silica gel plates
(Qingdao Haiyang chemical industry Co. Ltd, Qingdao, China) using UV light or KMnO4 as
visualizing agents as needed. Flash column chromatography was performed using 200-300 mesh
silica gel at increased pressure. 1H NMR spectra and 13C NMR spectra were respectively recorded
on Brüker AV-400 spectrometers. Chemical shifts (δ) were expressed in ppm with TMS as the
internal standard, and coupling constants (J) were reported in Hz. High-resolution mass spectra
(HRMS) were obtained on Brüker Compass Data Analysis 4.0.
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Typical procedure for the synthesis of pyrrole derivatives from phenylacetaldehyde and
aliphatic amine. The reactions were conducted in a 10 mL of V-type flask equipped with triangle
magnetic stirring. In a typical reaction, 1a (0.60 mmol) was mixed with 2a (0.30 mmol), I2 (22.8
mg, 30 mol%) in acetonitrile (1.0 mL). The mixture was then stirred at 60 °C for 8 h. When the
reactions were completed, the mixture was cooled to room temperature. Then, the mixture was
washed with aqueous sodium thiosulfate, dried with sodium sulfate, and concentrated under
reduced pressure. The product was obtained by isolation with silica column chromatography
(eluting solution: petroleum ether / ethyl acetate = 40/1 (v/v)). Tests for substrate scope were all
performed with an analogous procedure.
Typical procedure for the synthesis of pyrrole derivatives from 5-methyl-2-phenyl-2-hexenal
and aromatic amine. The reactions were conducted in a 10 mL of V-type flask equipped with
triangle magnetic stirring. In a typical reaction, 5-methyl-2-phenyl-2-hexenal (0.30 mmol) was
mixed with aniline (0.36 mmol), I2 (50 mol%) in toluene (1.0 mL). The mixture was then stirred at
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room temperature for 8 h. When the reactions were completed, the mixture was washed with
aqueous sodium thiosulfate, dried with sodium sulfate, and concentrated under reduced pressure.
The organic residue was subjected to an isolation with silica column chromatography (eluting
solution: petroleum ether / ethyl acetate = 50/1 (v/v)). Tests for substrate scope were all performed
with an analogous procedure. In the synthesis procedure of 3ah to 3at, TPHP (3.0 equiv.) was
added. All the other operation procedures are the same with the above reactions.
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Procedure for large scale synthesis of 3ah. In a 50 mL of single-neck round bottom flask
equipped with magnetic stirring, 5-methyl-2-phenyl-2-hexenal (1.88 g, 10.0 mmol) was mixed
with aniline (1.12 g, 12.0 mmol), I2 (2.03 g, 5.0 mmol) and TBHP (3.86 g, 30.0 mmol) in toluene
(20.0 mL). The mixture was then stirred at room temperature for 8 h. When the reactions were
completed, the mixture was washed with aqueous sodium thiosulfate and brine, and then extracted
by ethyl acetate (20 mL × 3). The organic phase was combined and dried over anhydrous Na2SO4.
After removing the volatile component, the residue mixture was subjected to an isolation with
silica column chromatography (eluting solution: petroleum ether / ethyl acetate = 50/1 (v/v)).
Product 3ah was obtained in 71% yield (2.74 g).
Procedure for the synthesis of 1b. In a 50 mL of single-neck round bottom flask equipped with
magnetic stirring, 1a (2.40 g, 20.0 mmol) was mixed with AlCl3 (267.0 mg, 2.0 mmol) in
o
acetonitrile (30.0 mL). The mixture was then stirred at 60 C for 8 h. After reaction, the mixture
was cooled to room temperature, washed with brine (40 mL), and the aqueous phase was extracted
by ethyl acetate (20 mL × 3). The organic phase was combined and dried over anhydrous Na2SO4.
After removing the volatile component, the residue mixture was subjected to an isolation with
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silica column chromatography (eluting solution: petroleum ether / ethyl acetate = 30/1 (v/v)).
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Product 1b was obtained in 33% yield.
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Procedure for the synthesis of 4b.37 In
a
10 mL roundbottom flask,
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2-(4-chlorophenyl)acetaldehyde (154.0 mg, 1 mmol), acetyl acetone (100.0 mg, 1 mmol) and
piperidinium acetate (29.0 mg, 0.2 mmol) were mixed, and reaction mixture was shaken under
solvent-free conditions. The formation of aldehyde-acetyl acetone adduct was complete in about
10 min (monitored by TLC). The mixture was washed with brine (30 mL), and the aqueous phase
was extracted by ethyl acetate (20 mL × 3). The organic phase was combined and dried over
anhydrous Na2SO4. After removing the volatile component, the residue mixture was subjected to
an isolation with silica column chromatography (eluting solution: petroleum ether / ethyl acetate =
20/1 (v/v)). Product 4a was obtained in 65% yield.
Characterization data of compounds. 1-Butyl-2,4-diphenyl-1H-pyrrole (3a):38 white solid, mp:
59–61 oC, 83% yield (68.4 mg); 1H NMR: (400 MHz, DMSO-d6, 25 °C) δ = 7.55 (d, J = 7.3 Hz,
2H), 7.44 (d, J = 4.3 Hz, 4H), 7.38 (d, J = 1.8 Hz, 1H), 7.31 (dd, J = 13.6, 6.1 Hz, 3H), 7.13 – 7.09
(m, 1H), 6.51 (d, J = 1.8 Hz, 1H), 3.96 (t, J = 7.2 Hz, 2H), 1.62 – 1.53 (m, 2H), 1.14 (dd, J = 14.7,
7.4 Hz, 2H), 0.76 (t, J = 7.3 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6, 25 oC) δ = 135.5,
134.5, 133.0, 128.6, 128.5, 128.3, 127.0, 125.0, 124.3, 123.0, 119.9, 106.3, 46.5, 32.8, 19.2, 13.4
ppm.
1
1-Butyl-2,4-bis(2-fluorophenyl)-1H-pyrrole (3b): yellow oil, 74% yield (69.0 mg); H NMR
(400 MHz, CDCl3, TMS, 25 °C) δ = 7.56–7.48 (m, 1H), 7.33–7.27 (m, 2H), 7.22 (s, 1H), 7.19 (s,
1H), 7.17–7.07 (m, 2H), 7.06–7.02 (m, 2H), 6.50 (s, 1H), 3.77 (t, J = 7.3 Hz, 2H), 1.57 (dt, J =
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14.9, 7.5 Hz, 2H), 1.17–1.09 (m, 2H), 0.74 (t, J = 7.3 Hz, 3H) ppm. 13C{1H} NMR (100 MHz,
CDCl3, 25 oC) δ = 160.2 (d, J = 245.0 Hz), 159.7 (d, J = 245.0 Hz), 132.5 (d, J = 3.0 Hz), 129.8 (d,
J = 8.1 Hz), 128.3, 127.5 (d, J = 5.0 Hz), 126.3 (d, J = 8.6 Hz), 124.3 (d, J = 4.0 Hz), 124.2 (d, J =
4.0 Hz), 123.4 (d, J = 13.0 Hz), 121.9 (d, J = 11.0 Hz), 121.3 (d, J = 15.0 Hz), 117.8, 116.0 (d, J =
22.0 Hz), 115.9 (d, J = 22.0 Hz), 108.8 (d, J = 1.5 Hz), 47.5, 33.4, 19.9, 13.7 ppm. 19F NMR (377
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o
MHz, CDCl3, 25 C ) δ = -113.4, -115.2 ppm. IR (KBr) v: 2961, 2927, 2869, 1694, 1488, 1456,
1263, 1095, 1028, 800, 759 cm-1, HRMS (TOF, ESI): m/z calcd for C20H20F2N, [M + H]+
312.1564, found 312.1562.
1
2,4-Bis(2-bromophenyl)-1-butyl-1H-pyrrole (3c): brown oil, 67% yield (86.4 mg); H NMR
(400 MHz, CDCl3, TMS, 25 °C) δ = 7.68 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.51 (dd, J
= 7.7, 1.2 Hz, 1H), 7.41 (dd, J = 7.4, 1.5 Hz, 1H), 7.36 (t, J = 7.3 Hz, 1H), 7.27 (dd, J = 13.3, 6.2
Hz, 2H), 7.22 (d, J = 1.6 Hz, 1H), 7.06 – 7.00 (m, 1H), 6.46 (d, J = 1.6 Hz, 1H), 3.76 (t, J = 7.2 Hz,
13
2H), 1.61 – 1.57 (m, 2H), 1.19 (dt, J = 14.7, 7.4 Hz, 2H), 0.81 (t, J = 7.3 Hz, 3H) ppm. C{1H}
NMR (100 MHz, CDCl3, 25 oC) δ = 136.7, 134.7, 133.8, 133.2, 133.0, 132.2, 130.6, 129.7, 127.4,
127.2, 126.8, 125.9, 122.2, 121.9, 121.0, 110.4, 47.3, 33.4, 19.9, 13.7 ppm. IR (KBr) v: 2958,
2928, 2869, 1702, 1463, 1434, 1024, 753 cm-1, HRMS (TOF, ESI): m/z calcd for C20H20Br2N, [M
+ H]+ 431.9962, 431.9945.
1
1-Butyl-2,4-bis(3-fluorophenyl)-1H-pyrrole (3d): brown oil, 72% yield (67.1 mg); H NMR
(400 MHz, CDCl3, TMS, 25 °C) δ = 7.37 (dd, J = 14.2, 7.8 Hz, 1H), 7.29 – 7.26 (m, 2H), 7.19 (t,
J = 9.5 Hz, 2H), 7.11 (d, J = 9.8 Hz, 1H), 7.07 – 7.05 (m, 1H), 7.04 – 6.99 (m, 1H), 6.87 – 6.82 (m,
1H), 6.47 (d, J = 1.1 Hz, 1H), 3.94 (t, J = 7.3 Hz, 2H), 1.66 (dt, J = 14.9, 7.4 Hz, 2H), 1.24 (dt, J =
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14.9, 7.3 Hz, 2H), 0.85 (t, J = 7.3 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3, 25 C) δ =
163.5 (d, J = 242.0 Hz), 162.9 (d, J = 245.0 Hz), 138.0 (d, J = 8.4 Hz), 135.4 (d, J = 8.1 Hz),
134.4, 129.7 (d, J = 9.0 Hz), 124.6 (d, J = 2.7 Hz), 120.6 (d, J = 2.5 Hz), 119.8, 115.8 (d, J = 22.0
Hz), 114.2 (d, J = 21.0 Hz), 112.2 (d, J = 21.0 Hz), 111.7 (d, J = 21.9 Hz), 107.4, 47.4, 33.6, 19.9,
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13.7 ppm. 19F NMR (377 MHz, CDCl3, 25 C ) δ = -112.8, -113.8 ppm. IR (KBr) v: 3078, 2962,
o
2934, 2872, 1692, 1588, 1487, 1444, 1268, 789 cm-1, HRMS (TOF, ESI): m/z calcd for
C20H20F2N, [M + H]+ 312.1564, found 312.1562.
1
1-Butyl-2,4-bis(3-chlorophenyl)-1H-pyrrole (3e): brown oil, 78% yield (80.2 mg); H NMR
(400 MHz, CDCl3, TMS, 25 °C) δ = 7.50 (s, 1H), 7.43 – 7.36 (m, 2H), 7.36 – 7.30 (m, 2H), 7.30 –
7.24 (m, 2H), 7.13 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 1.4 Hz, 1H), 6.46 (d, J = 1.5 Hz, 1H), 3.93 (t, J
= 7.3 Hz, 2H), 1.67 (dt, J = 14.9, 7.4 Hz, 2H), 1.25 (dt, J = 14.8, 7.5 Hz, 2H), 0.85 (t, J = 7.3 Hz,
3H) ppm. C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 137.6, 135.1, 134.6, 134.5, 134.3, 130.0,
129.8, 128.9, 127.4, 127.0, 125.5, 125.0, 123.3, 123.1, 119.8, 107.4, 47.4, 33.6, 19.9, 13.7 ppm. IR
(KBr) v: 3071, 2960, 2928, 2856, 1698, 1569, 1419, 1256, 1078, 792, 694 cm-1, HRMS (TOF,
ESI): m/z calcd for C20H20Cl2N, [M + H]+ 344.0973, found 344.0973.
13
o
1
2,4-Bis(3-bromophenyl)-1-butyl-1H-pyrrole (3f): brown oil, 70% yield (90.3 mg); H NMR
(400 MHz, CDCl3, TMS, 25 °C) δ = 7.66 (s, 1H), 7.56 (s, 1H), 7.44 (dd, J = 11.1, 8.7 Hz, 2H),
7.34 – 7.28 (m, 2H), 7.27 – 7.24 (m, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.06 (s, 1H), 6.45 (s, 1H), 3.92
(t, J = 7.3 Hz, 2H), 1.66 (dt, J = 14.9, 7.4 Hz, 2H), 1.25 – 1.19 (dt, 2H), 0.85 (t, J = 7.2 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 137.8, 135.3, 134.1, 131.8, 130.3, 130.1, 128.4,
o
127.9, 127.4, 123.5, 123.1, 123.0, 122.6, 119.8, 107.4, 47.3, 33.6, 19.9, 13.7 ppm. IR (KBr) v:
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3067, 2959, 2930, 2869, 1694, 1565, 1416, 1250, 1072, 789, 688 cm-1, HRMS (TOF, ESI): m/z
calcd for C20H20Br2N, [M + H]+ 431.9962, found 431.9959.
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1-Butyl-2,4-bis(4-fluorophenyl)-1H-pyrrole (3g): yellow oil, 71% yield (66.2 mg); H NMR
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(400 MHz, CDCl3, TMS, 25 °C) δ = 7.47 (dd, J = 8.3, 5.5 Hz, 2H), 7.36 (dd, J = 8.2, 5.5 Hz, 2H),
7.11 (t, J = 8.5 Hz, 2H), 7.02 (dd, J = 14.9, 5.9 Hz, 3H), 6.38 (s, 1H), 3.89 (t, J = 7.4 Hz, 2H), 1.65
(dt, J = 14.9, 7.4 Hz, 2H), 1.26 – 1.21 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz,
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CDCl3, 25 C) δ = 134.4, 131.7, (d, J = 30.0 Hz), 130.8 (d, J = 7.9 Hz), 130.7 (d, J = 239.0 Hz),
126.4 (d, J = 7.7 Hz), 123.5, 118.4, 115.7 (d, J = 4.0 Hz), 115.4 (d, J = 3.0 Hz), 106.8, 47.2, 33.7,
20.0, 13.8 ppm. 19F NMR (377 MHz, CDCl3, 25 oC ) δ =-114.67 – -114.93 (m), -117.89 – -118.15
(m) ppm. IR (KBr) v: 3077, 2960, 2931, 1693, 1603, 1508, 1232, 1159, 839 cm-1, HRMS (TOF,
ESI): m/z calcd for C20H20F2N, [M + H]+ 312.1564, found 312.1561.
o
1-Butyl-2,4-bis(4-chlorophenyl)-1H-pyrrole (3h): yellow solid, mp: 70–72 C, 73% yield (75.1
mg); 1H NMR (400 MHz, CDCl3, TMS, 25 °C) δ = 7.37 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.5 Hz,
2H), 7.26 (s, 1H), 7.21 (dd, J = 17.0, 8.6 Hz, 3H), 6.97 (d, J = 1.5 Hz, 1H), 6.34 (d, J = 1.5 Hz,
1H), 3.83 (t, J = 7.3 Hz, 2H), 1.62 – 1.52 (m, 2H), 1.20 – 1.14 (m, 2H), 0.77 (t, J = 7.4 Hz, 3H)
ppm. 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ = 134.5, 134.2, 133.3, 131.8, 131.0, 130.2, 129.7,
128.9, 126.2, 123.4, 119.2, 107.0, 47.3, 33.7, 20.0, 13.8 ppm. IR (KBr) v: 3093, 2960, 2929, 2869,
1689, 1593, 1490, 1402, 1093, 830 cm-1, HRMS (TOF, ESI): m/z calcd for C20H20Cl2N, [M + H]+
344.0973, found 344.0972.
o
2,4-Bis(4-bromophenyl)-1-butyl-1H-pyrrole (3i): white solid, mp: 78–80 C, 65% yield (83.8
mg); 1H NMR (400 MHz, CDCl3, TMS, 25 °C) δ = 7.54 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.2 Hz,
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2H), 7.38 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 7.05 (s, 1H), 6.42 (s, 1H), 3.91 (t, J = 7.3
Hz, 2H), 1.71 – 1.59 (m, 2H), 1.24 (dd, J = 14.9, 7.1 Hz, 2H), 0.85 (t, J = 7.3 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3, 25 oC) δ = 134.5, 134.4, 132.1, 131.7, 131.6, 130.4, 126.4, 123.3, 121.4,
119.2, 118.9, 106.9, 47.2, 33.5, 19.8, 13.6 ppm. IR (KBr) v: 3085, 2958, 2927, 2869, 1685, 1485,
1398, 1072, 1010, 825 cm-1, HRMS (TOF, ESI): m/z calcd for C20H20Br2N, [M + H]+ 431.9962,
found 431.9958.
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1-Butyl-2,4-bis(4-iodophenyl)-1H-pyrrole (3j): brown solid, mp: 75–77 C, 70% yield (110.4
mg); 1H NMR (400 MHz, CDCl3, TMS, 25 °C) δ = 7.74 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.2 Hz,
2H), 7.26 (d, J = 5.2 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 1.3 Hz, 1H), 6.42 (d, J = 1.4
Hz, 1H), 3.91 (t, J = 7.4 Hz, 2H), 1.69 – 1.61 (m, 2H), 1.25 – 1.19 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H)
ppm. 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ = 137.8, 137.7, 135.2, 134.6, 132.8, 130.7, 126.9,
123.5, 119.5, 107.0, 92.9, 90.0, 47.4, 33.7, 20.0, 13.8 ppm. IR (KBr) v: 2957, 2924, 2854, 1680,
1461, 1378, 1059, 821 cm-1, HRMS (TOF, ESI): m/z calcd for C20H20I2N, [M + H]+ 527.9685,
found 527.9687.
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1-Butyl-2,4-di-p-tolyl-1H-pyrrole (3k): yellow oil, 84% yield (76.3 mg); H NMR (400 MHz,
CDCl3, TMS, 25 °C) δ = 7.43 (d, J = 7.6 Hz, 2H), 7.30 (d, J = 7.7 Hz, 2H), 7.21 (d, J = 7.7 Hz,
2H), 7.14 (d, J = 7.7 Hz, 2H), 7.01 (s, 1H), 6.42 (s, 1H), 3.91 (t, J = 7.4 Hz, 2H), 2.39 (s, 3H), 2.33
(s, 3H), 1.71 – 1.64 (m, 2H), 1.26 – 1.22 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H) ppm. 13C{1H} NMR
(100 MHz, CDCl3, 25 oC) δ = 136.9, 135.4, 134.9, 133.1, 130.7, 129.4, 129.2, 129.0, 125.0, 124.2,
118.2, 106.4, 47.1, 33.7, 21.4, 21.2, 20.0, 13.8 ppm. IR (KBr) v: 3029, 2959, 2928, 2869, 1694,
1610, 1410, 1178, 820 cm-1, HRMS (TOF, ESI): m/z calcd for C22H26N, [M + H]+ 304.2065,
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1-Butyl-2,4-bis(4-methoxyphenyl)-1H-pyrrole (3l): yellow oil, 85% yield (85.4 mg); H NMR
(400 MHz, CDCl3, TMS, 25 °C) δ = 7.45 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H), 6.94 (d, J =
7.4 Hz, 3H), 6.88 (d, J = 8.5 Hz, 2H), 6.35 (d, J = 1.5 Hz, 1H), 3.89 (t, J = 7.3 Hz, 2H), 3.84 (s,
3H), 3.81 (s, 3H), 1.70 – 1.62 (m, 2H), 1.29 – 1.20 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H) ppm. 13C{1H}
NMR (100 MHz, CDCl3, 25 oC) δ = 158.9, 157.7, 135.1, 130.4, 129.5, 128.9, 126.1, 123.9, 117.5,
114.2, 113.9, 106.1, 55.4, 47.0, 33.7, 20.0, 13.8 ppm. IR (KBr) v: 3075, 2959, 2932, 2870, 2839,
1688, 1606, 1511, 1254, 1175, 1032, 835 cm-1, HRMS (TOF, ESI): m/z calcd for C22H26NO2, [M
+ H]+ 336.1964, found 336.1962.
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1-Butyl-2,4-di(naphthalen-1-yl)-1H-pyrrole (3m): yellow oil, 62% yield (69.7 mg); H NMR:
(400 MHz, DMSO-d6, 25 °C) δ = 8.54 (d, J = 8.5 Hz, 1H), 8.08 – 8.02 (m, 2H), 8.01 –7.96 (m,
1H), 7.91 – 7.82 (m, 2H), 7.68 –7.63 (m, 2H), 7.63 –7.53 (m, 6H), 7.39 (d, J = 1.6 Hz, 1H), 6.51
(d, J = 1.7 Hz, 1H), 3.81 (t, J = 7.3 H, 2H), 1.53 – 1.44 (m, 2H), 1.08 (m, 2H), 0.65 (t, J = 7.3 Hz,
3H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6, 25 C) δ = 134.2, 133.8, 133.3, 132.6, 131.1,
o
131.0, 130.5, 128.7, 128.3, 126.6, 126.1, 126.0, 125.9, 125.8, 125.6, 125.5, 125.4, 121.5, 121.3,
111.1, 46.4, 32.7, 19.0, 13.2 ppm. IR (KBr) v: 3050, 2957, 2927, 2867, 1703, 1593, 1461, 1389,
1022, 798, 777 cm-1, HRMS (TOF, ESI): m/z calcd for C28H26N, [M + H]+ 376.2065, found
376.2067.
1-Dodecyl-2,4-diphenyl-1H-pyrrole (3n): yellow oil, 82% yield (95.2 mg); 1H NMR (400 MHz,
CDCl3, TMS, 25 °C) δ = 7.54 (d, J = 7.8 Hz, 2H), 7.41 (d, J = 4.0 Hz, 3H), 7.33 (t, J = 7.4 Hz,
3H), 7.25 (d, J = 7.0 Hz, 1H), 7.16 (t, J = 7.0 Hz, 1H), 7.07 (s, 1H), 6.48 (s, 1H), 3.92 (t, J = 7.4
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Hz, 2H), 1.68 (d, J = 6.4 Hz, 2H), 1.24 – 1.20(m, 18H), 0.88 (t, J = 6.5 Hz, 3H) ppm. 13C{1H}
NMR (100 MHz, CDCl3, 25 oC) δ = 135.8, 135.4, 133.5, 129.0, 128.6, 128.4, 128.1, 127.1, 125.4,
124.9, 118.7, 106.7, 47.4, 31.9, 31.5, 29.6, 29.5, 29.4, 29.3, 29.1, 26.6, 22.7, 14.2 ppm. IR (KBr) v:
3063, 2925, 2854, 1683, 1579, 1451, 1411, 764, 697 cm-1, HRMS (TOF, ESI): m/z calcd for
C28H38N, [M + H]+ 388.3004, found 388.3002.
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1-Octyl-2,4-diphenyl-1H-pyrrole (3o): yellow oil, 80% yield (79.4 mg); H NMR: (400 MHz,
DMSO-d6, 25 °C) δ = 7.55 (d, J = 7.4 Hz, 2H), 7.43 (d, J = 4.3 Hz, 4H), 7.36 (d, J = 1.4 Hz, 1H),
7.31 (dd, J = 14.8, 7.4 Hz, 3H), 7.11 (t, J = 7.3 Hz, 1H), 6.51 (d, J = 1.5 Hz, 1H), 3.94 (t, J = 7.1
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Hz, 2H), 1.60 –1.50 (m, 2H), 1.22 – 1.09 (m, 10H), 0.80 (t, J = 7.0 Hz, 3H) ppm. C{1H} NMR
o
(100 MHz, DMSO-d6, 25 C) δ = 135.5, 134.5, 133.1, 128.6, 128.5, 128.3, 126.9, 125.0, 124.3,
123.0, 119.9, 106.3, 46.7, 31.1, 30.6, 28.5, 28.3, 25.8, 22.0, 13.9 ppm. IR (KBr) v: 3063, 2955,
2926, 2855, 1694, 1450, 1409, 1261, 763, 697 cm-1, HRMS (TOF, ESI): m/z calcd for C24H30N,
[M + H]+ 332.2378, found 332.2377.
1-(tert-Butyl)-2,4-diphenyl-1H-pyrrole (3p):39 White solid , mp: 101–103 °C, 75% yield (61.8
mg); 1H NMR (400 MHz, CDCl3, TMS, 25 °C) δ = 7.52 (d, J = 7.8 Hz, 2H), 7.43 (d, J = 3.3 Hz,
2H), 7.37 – 7.27 (m, 5H), 7.21 (d, J = 0.8 Hz, 1H), 7.13 (t, J = 7.3 Hz, 1H), 6.34 (s, 1H), 1.46 (s,
13
o
9H) ppm. C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 137.1, 136.0, 135.2, 131.9, 128.7, 128.5,
127.8, 127.6, 125.3, 124.9, 115.8, 110.0, 57.6, 32.0 ppm.
1-Cyclohexyl-2,4-diphenyl-1H-pyrrole (3q):39 White solid, mp: 83–85 °C, 82% yield (74.0 mg);
1H NMR (400 MHz, CDCl3, TMS, 25 °C) δ = 7.54 (d, J = 7.4 Hz, 2H), 7.44 – 7.37 (m, 4H), 7.32
(t, J = 6.9 Hz, 3H), 7.19 – 7.10 (m, 2H), 6.44 (s, 1H), 4.01 (t, J = 11.6 Hz, 1H), 2.03 (d, J = 11.6
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Hz, 2H), 1.83 (d, J = 11.1 Hz, 2H), 1.70 (d, J = 10.3 Hz, 2H), 1.33 – 1.17 (m, 4H) ppm. 13C{1H}
NMR (100 MHz, CDCl3, 25 oC) δ = 135.9, 135.0, 133.6, 129.2, 128.6, 128.5, 127.1, 125.3, 124.9,
124.3, 115.1, 106.3, 55.5, 35.0, 25.9, 25.5 ppm.
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1-3-(2,4-Diphenyl-1H-pyrrol-1-yl)propan-1-ol (3r): yellow oil, 75% yield (62.3 mg); 1H NMR:
(400 MHz, DMSO-d6, 25 °C) δ = 7.61 (d, J = 7.6 Hz, 2H), 7.50 (q, J = 7.8 Hz, 4H), 7.44 (d, J =
1.5 Hz, 1H), 7.37 (t, J = 7.7 Hz, 3H), 7.17 (t, J = 7.3 Hz, 1H), 6.58 (d, J = 1.3 Hz, 1H), 4.60 (t, J =
4.8 Hz, 1H), 4.09 (t, J = 7.2 Hz, 2H), 3.39 – 3.38 (m, 2H), 1.87 – 1.79 (m, 2H) ppm. 13C{1H}
o
NMR (100 MHz, DMSO-d6, 25 C) δ = 136.0, 135.0, 133.4, 129.0, 128.7, 127.4, 125.5, 124.8,
123.5, 120.4, 106.9, 58.2, 44.5, 34.3 ppm. IR (KBr) v: 3390, 3061, 2930, 2874, 1699, 1450, 1401,
1052, 763, 699 cm-1, HRMS (TOF, ESI): m/z calcd for C19H20NO, [M + H]+ 278.1545, found
278.1543.
1-(4,4-Diethoxybutyl)-2,4-diphenyl-1H-pyrrole (3s): yellow oil, 56% yield (60.9 mg); 1H NMR
(400 MHz, CDCl3, TMS, 25 °C) δ = 7.54 (d, J = 7.7 Hz, 2H), 7.41 (d, J = 3.7 Hz, 4H), 7.33 (t, J =
7.1 Hz, 3H), 7.16 (t, J = 6.9 Hz, 1H), 7.07 (s, 1H), 6.48 (s, 1H), 4.35 (t, J = 5.3 Hz, 1H), 3.98 (t, J
= 7.2 Hz, 2H), 3.60 – 3.51 (m, 2H), 3.44 – 3.35 (m, 2H), 1.81 – 1.71 (m, 2H), 1.56 – 1.49 (m, 2H),
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1.15 (t, J = 6.9 Hz, 6H) ppm. 13C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 135.8, 135.5, 133.5,
129.1, 128.7, 128.6, 127.3, 125.5, 125.1, 124.4, 118.8, 107.0, 102.5, 61.3, 47.3, 30.8, 26.8, 15.4
ppm. IR (KBr) v: 3063, 2974, 2928, 2878, 1696, 1449, 1375, 1125, 1062, 698 cm-1, HRMS (TOF,
ESI): m/z calcd for C24H30NO2, [M + H]+ 364.2277, found 364.2260.
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(2,2-Diethoxyethyl)-2,4-diphenyl-1H-pyrrole (3t): yellow oil, 71% yield (71.3 mg); H NMR
(400 MHz, CDCl3, TMS, 25 °C) δ = 7.54 (d, J = 7.4 Hz, 2H), 7.46 (d, J = 7.1 Hz, 2H), 7.43 – 7.39
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(m, 2H), 7.36 – 7.32 (m, 3H), 7.20 – 7.15 (m, 2H), 6.50 (d, J = 1.3 Hz, 1H), 4.52 (t, J = 5.2 Hz,
1H), 4.06 (d, J = 5.2 Hz, 2H), 3.59 (td, J = 14.2, 7.0 Hz, 2H), 3.34 (td, J = 14.1, 7.0 Hz, 2H), 1.13
(t, J = 7.0 Hz, 6H) ppm. 13C{1H} NMR (100 MHz, CDCl3, 25 oC) δ = 135.9, 135.8, 133.2, 129.3,
128.8, 128.6, 127.4, 125.6, 125.1, 124.5, 120.0, 107.2, 102.5, 63.6, 50.5, 15.3 ppm. IR (KBr) v:
3058, 2969, 2928, 2871, 1674, 1463, 778, 695 cm-1, HRMS (TOF, ESI): m/z calcd for C22H26NO2,
[M + H]+ 336.1964, found 336.1948.
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2,4-Diphenyl-1-(prop-2-yn-1-yl)-1H-pyrrole (3u):40 yellow oil, 58% yield (44.7 mg); H NMR
(400 MHz, CDCl3, TMS, 25 °C) δ = 7.55 (d, J = 7.7 Hz, 2H), 7.50 (d, J = 7.4 Hz, 2H), 7.44 (t, J =
7.5 Hz, 2H), 7.35 (t, J = 7.6 Hz, 3H), 7.25 (s, 1H), 7.19 (t, J = 7.2 Hz, 1H), 6.53 (s, 1H), 4.69 (d, J
o
= 2.1 Hz, 2H), 2.45 (s, 1H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6, 25 C) δ = 135.1, 134.5,
132., 128.7, 128.6, 128.0, 127.2, 125.4, 124.4, 123.7, 120.2, 106.8, 79.9, 76.0, 36.8 ppm.
1-(3,4-Dimethoxyphenethyl)-2,4-diphenyl-1H-pyrrole (3v): yellow oil, 62% yield (71.2 mg); 1H
NMR (400 MHz, CDCl3, TMS, 25 °C) δ = 7.51 (d, J = 7.6 Hz, 2H), 7.40 – 7.30 (m, 5H), 7.27 (d,
J = 7.4 Hz, 2H), 7.17 (t, J = 7.1 Hz, 1H), 7.02 (s, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.51 (d, J = 7.9 Hz,
1H), 6.46 (s, 1H), 6.34 (s, 1H), 4.15 (t, J = 7.1 Hz, 2H), 3.83 (s, 3H), 3.71 (s, 3H), 2.85 (t, J = 7.0
o
Hz, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 149.0, 147.9, 135.8, 135.7, 133.4,
130.9, 129.2, 128.8, 128.5, 127.3, 125.6, 125.1, 124.5, 120.8, 118.8, 112.0, 111.4, 107.0, 56.1,
55.8, 49.2, 37.7 ppm. IR (KBr) v: 3060, 2931, 2836, 1692, 1600, 1515, 1452, 1262, 1236, 1028,
760, 731 cm-1, HRMS (TOF, ESI): m/z calcd for C26H26NO2, [M + H]+ 384.1964, found 384.1963.
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3-(2-(2,4-Diphenyl-1H-pyrrol-1-yl)ethyl)-1H-indole (3w): yellow oil, 85% yield (92.3 mg); H
NMR (400 MHz, CDCl3, TMS, 25 °C) δ = 7.93 (s, 1H), 7.53 (d, J = 7.4 Hz, 2H), 7.41 – 7.30 (m,
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2H), 3.10 (t, J = 7.5 Hz, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3, 25 C) δ = 136.2, 135.8,
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135.4, 133.3, 129.1, 128.7, 128.6, 128.5, 127.2, 127.1, 125.4, 124.9, 124.2, 122.1, 119.5, 118.8,
118.5, 112.3, 111.1, 106.9, 48.0, 27.6 ppm. IR (KBr) v: 3421, 3056, 2925, 2853, 1675, 1602, 1454,
1195, 744, 698 cm-1, HRMS (TOF, ESI): m/z calcd for C26H23N2, [M + H]+ 363.1861, found
363.1862.
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(Z)-2,4-diphenylbut-2-enal (1b):41 yellow oil, 33% yield (732.6 mg); H NMR: (400 MHz,
DMSO-d6, 25 °C) δ = 9.66 (s, 1H), 7.46 (t, J = 7.2 Hz, 2H), 7.40 (d, J = 7.2 Hz, 1H), 7.33 (t, J =
7.3 Hz, 2H), 7.23 (dd, J = 16.4, 7.3 Hz, 5H), 7.08 (t, J = 7.6 Hz, 1H), 3.65 (d, J = 7.5 Hz, 2H).
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13C{1H} NMR (100 MHz, DMSO-d6, 25 C) δ = 194.1, 154.1, 143.4, 138.2, 132.4, 129.4, 128.8,
128.5, 128.2, 127.9, 126.6, 35.1 ppm.
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1,2,4-Triphenyl-1H-pyrrole (3x):42 White solid, 150–152 C, 90% yield (79.6 mg); 1H NMR:
(400 MHz, DMSO-d6, 25 °C) δ = 7.67 (d, J = 7.5 Hz, 2H), 7.59 (s, 1H), 7.42 (t, J = 7.4 Hz, 2H),
7.35 (dd, J = 9.2, 5.3 Hz, 3H), 7.24 (td, J = 14.2, 9.4 Hz, 5H), 7.16 (t, J = 7.7 Hz, 3H), 6.88 (s, 1H)
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ppm. 13C{1H} NMR (100 MHz, DMSO-d6, 25 C) δ = 140.3, 135.3, 134.4, 132.8, 129.7, 129.1,
128.7, 128.3, 127.5, 127.0, 126.1,126.0, 125.2, 125.1, 122.2, 109.1 ppm.
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2-Isopropyl-1,4-diphenyl-1H-pyrrole (3y): colourless oil, 43% yield (33.6 mg); H NMR: (400
MHz, DMSO-d6, 25 °C) δ = 7.56 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 7.4 Hz, 2H), 7.43 (t, J = 8.3 Hz,
3H), 7.30 (t, J = 7.6 Hz, 2H), 7.24 (d, J = 1.3 Hz, 1H), 7.11 (t, J = 7.3 Hz, 1H), 6.44 (s, 1H), 2.92
(dt, J = 13.4, 6.7 Hz, 1H), 1.09 (d, J = 6.7 Hz, 6H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6, 25
oC) δ = 141.1, 139.8, 135.4, 129.4, 128.6, 127.5, 126.1, 125.1, 124.4, 123.2, 118.6, 102.5, 24.9,
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23.0 ppm. IR (KBr) v: 3064, 2964, 2929, 2872, 1716, 1598, 1496, 1385, 1027, 753, 696 cm-1,
HRMS (TOF, ESI): m/z calcd for C19H20N, [M + H]+ 262.1596, found 262.1593.
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1-(4-Fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrole (3z): colourless oil, 48% yield (40.1 mg);
1H NMR: (400 MHz, DMSO-d6, 25 °C) δ = 7.56 (d, J = 7.6 Hz, 2H), 7.48 (dd, J = 8.5, 5.0 Hz,
2H), 7.36 (t, J = 8.7 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.24 (d, J = 1.2 Hz, 1H), 7.12 (t, J = 7.3 Hz,
1H), 6.43 (s, 1H), 2.86 (dt, J = 13.5, 6.7 Hz, 1H), 1.09 (d, J = 6.8 Hz, 6H) ppm. 13C{1H} NMR
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(100 MHz, DMSO-d6, 25 C) δ = 161.1 (d, J = 243.0 Hz), 141.2, 136.1 (d, J = 3.0 Hz), 135.4,
128.6, 128.4 (d, J = 8.0 Hz), 125.2, 124.4, 123.2, 118.8, 116.1 (d, J = 22.0 Hz), 102.4, 24.9, 23.0
ppm. 19F NMR (377 MHz, DMSO-d6, 25 °C, 25 oC ) δ = -114.49 – -114.72 (m). IR (KBr) v: 2965,
2929, 2872, 1716, 1511, 1223, 1025, 799 cm-1, HRMS (TOF, ESI): m/z calcd for C19H19FN, [M +
H]+ 280.1502, found 280.1498.
1-(4-Bromophenyl)-2-isopropyl-4-phenyl-1H-pyrrole (3aa): yellow oil, 39% yield (39.6 mg);
1H NMR: (400 MHz, DMSO-d6, 25 °C) δ = 7.72 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 7.5 Hz, 2H),
7.41 (d, J = 8.5 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.27 (s, 1H), 7.13 (t, J = 7.3 Hz, 1H), 6.46 (s,
1H), 2.92 (dt, J = 13.4, 6.6 Hz, 1H), 1.10 (d, J = 6.7 Hz, 6H) ppm. 13C{1H} NMR (100 MHz,
DMSO-d6, 25 oC) δ = 141.1, 139.0, 135.2, 132.4, 128.6, 128.2, 125.3, 124.5, 123.6, 120.3, 118.6,
102.9, 24.9, 23.0 ppm. IR (KBr) v: 3082, 2964, 2929, 2871, 1717, 1491, 1383, 1071, 798 cm-1,
HRMS (TOF, ESI): m/z calcd for C19H19BrN, [M + H]+ 340.0701, found 340.0702.
1-1-(2,3-Dimethylphenyl)-2-isopropyl-4-phenyl-1H-pyrrole (3ab): brown oil, 45% yield (39.0
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mg); H NMR (400 MHz, CDCl3, TMS, 25 °C) δ = 7.54 (d, J = 7.8 Hz, 2H), 7.31 (t, J = 7.5 Hz,
2H), 7.25 – 7.21 (m, 1H), 7.19 – 7.10 (m, 3H), 6.86 (s, 1H), 6.38 (s, 1H), 2.53 (dt, J = 13.5, 6.7 Hz,
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