One pot regiospecific synthesis of polysubstituted pyrroles from benzylamines and ynones under metal free conditions

Article abstract of DOI:10.1039/c3cc43844a

A convenient one-pot weak base-promoted synthesis of polysubstituted pyrroles has been developed from benzylamines and ynones. This transformation involves the Michael addition reaction and intramolecular condensation, which features high regioselectivity, high efficiency, environmental friendliness and metal free. A series of polysubstituted pyrroles were provided in up to 91% yield for 27 examples.

Full text of DOI:10.1039/c3cc43844a

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“One pot” regiospecific synthesis of polysubstituted pyrroles from
benzylamines and ynones under metal free conditions
Jinhai Shen a, Guolin Cheng a and Xiuling Cui* a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A convenient “oneꢀpot” weak baseꢀpromoted synthesis of polysubstituted pyrroles has been developed
from benzylamines and ynones. This transformation involves Micheal addition reaction and
intramolecular condensation, which features with high regioselectivity, high efficiency, environmental
friendliness and metal free. Series of polysubstituted pyrroles were provided in up to 91% yield for 27
10 examples.
40 Guan8b and Palmieri8c have independently reported the synthesis
of polysubstituted pyrroles from nitroolefins and enaminones
without metal catalyst. Nitroolefin acted as a binucleophilic
synthon in these reactions and produced HNO2 as waste (a,
Scheme 1). In terms of green chemistry, an environmentally
45 friendly route to pyrroles with atom economy becomes highly
desired. We envision that a simple and versatile procesure to
pyrrole derivatives from benzylamines and α,βꢀ unsaturated
ynones could be developed since α,βꢀunsaturated yones are
bielectrophilic9 and Micheal addition reaction of benzylamines
50 with α,βꢀ unsaturated ynones and baseꢀcatalyzed condensation of
resultant Nꢀbenzyl enaminones can be combined in one pot
operation. In our continuing effort to develop heterocycleꢀ
forming protocols10, herein, we report a weak baseꢀpromoted
“oneꢀpot” synthesis of polysubstituted pyrroles from
55 benzylamines and ynones, which avoides transition metal as
catalyst under mild reaction conditions. Moreover, high atom
economy could be realized since only H2O was procucted as a
byporduct (b, Scheme 1).
Introduction
Substituted pyrrole is a privileged heretocycle and key skeleton in
many natural products, such as hemoglobin, vitamin B12,
chlorophylls, lukianols and tetrapentalones. Moreover, they exist
15 widely in pharmaceuticals (e. g. Atorvastatin), agrochemicals (e.
g. Fludioxonil) and novel advanced materials (e. g. Polypyrrole)
(Figure 1).1 Thus, great efforts have been devoted to construct
such a structure.
20 Figure 1. Three examples illustrating the importance of pyrrole skeleton
The Knorr,2 PaalꢀKnorr3 and Hantzch4 reactions are wellꢀ
documented as the traditional methods to build pyrrole rings.
Recently, transition metal catalyzed cyclizations5 and
multicomponent tandem coupling reactions6 have become
25 increasingly popular due to their high efficiency. For example,
Liang5c reported a Cu(I) catalyzed synthesis of polysubstituted
pyrroles from oxidative cyclization of enaminones and
alkynoates; Glorius5j described an aerobic synthesis of pyrroles
from imines by Pd(II)ꢀcatalyzed intramolecular CꢀH activation;
30 Milstein5k developed a direct protocol to pyrroles by Ruꢀ
catalyzed dehydrogenative coupling reaction of βꢀaminoalcohols
with secondary alcohols. However, the less expensive and more
available substrates are limited in most cases. And the transition
metals are requried, which causes potential contamination of the
35 products, that is particularly significant in the pharmaceutical
industry7.
60 Scheme 1. Synthesis of pyrroles from nitroolefins (a) and ynones (b)
which serve as a bielectrophilic synthon.
We initially chose (Z)ꢀ3ꢀ(benzylamino)ꢀ1,3ꢀdiphenylpropꢀ2ꢀ
enꢀ1ꢀone 1aa as a model substate to optimize the reaction
parameters. The solution of potassium hydroxide in DMSO was
65 recently reported as a “super base” in some baseꢀpromoted
Recently, some impressive procedures to pyrroles starting from
halogenated nitroolefins or nitroolefins and enaminones under
metal free conditions have emerged.8 For instance, Rueping,8a
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reactions.11 To our delight, 2,3,5ꢀtriphenylꢀ1Hꢀpyrrole 4aa was
obtained in 51% yield in such a “super base” system under air
(entry 1). The yield of 4aa could increase to 67% when the
reaction was carried out under N2 atmosphere (entry 2). Then
electronꢀdonating groups, such as methyl, methoxy, tertꢀbutyl,
chloro, trifluoromethyl and 3,4ꢀdimethoxy groups, afforded the
corresponding 2,3,5ꢀtriarylpyrroles in appreciable yields ( 75ꢀ
88 %, Table 2, entries 1ꢀ8). This reaction system was also applied
5
other DMSOꢀtailored heterogeneous base systems were tested. 40 to Nꢀalkyl benzylamines. The efficiency was effected by the
Combination of K3PO4/DMSO was found to be the most efficient
for this transformation at 120 ºC under N2 atmosphere (entries 3ꢀ
8). Organic bases were also tested, such as Et3N and DABCO. No
desired products were observed (entries 9ꢀ10). The yields were
steric hindrance. NꢀMethyl benzylamine gave higher yield (91%)
than Nꢀnbutyl benzylamine (55%) (entry 9 vs 10). However, Nꢀ
nbutyl enaminone could give 80% yield under the same reaction
conditions. The Nꢀaryl benzylamines was limited to this
10 slightly decreased using DMF or NMP as a solvent (entries 11ꢀ 45 transformation. These results indicated that the large bulk and
12). No product was observed in toluene, 1,4ꢀdioxane, H2O and tꢀ
amyl alcohol (entries 13ꢀ16). 91% Yield could be achieved when
the reaction temperature was increased to 140 ºC (entry 17).
Interestingly, considerable yields (78% and 84%) was obtained
low electronꢀdensity in N atom disfavored the Micheal addition
reaction. nꢀButylamine, allylamine, propargylamine, 1ꢀ
aminopropanꢀ2ꢀone and amino acid ester were tested and failed to
give the corresponding pyrrole products under the standard
15 when 20 mol% K3PO4 and 50 mol% K3PO4 was loaded (entries 50 reaction conditions.
18ꢀ19). As (Z)ꢀ3ꢀ(Benzylamino)ꢀ1,3ꢀ diphenylpropꢀ2ꢀenꢀ1ꢀone 3
Table 2 Reaction of 1,3ꢀdiphenylpropꢀ2ꢀynꢀ1ꢀone 3a with various
benzylamines 2a-2ja
could be easily obtained from benzylamine and 1,3ꢀdiphenylpropꢀ
2ꢀynꢀ1ꢀone, we attempted “one pot” tandem reaction starting
from benzylamine and 1,3ꢀdiphenylpropꢀ2ꢀynꢀ1ꢀone (see
20 supporting information). Fortunately, the overall yield of the
transformation was remarkable (88%, entry 20). In terms of green
chemistry and atom economy, “oneꢀpot” operation using
benzylamines and ynones as substrates was adopted.
Table 1 Screening reaction parameters for the cyclization a
Entry
2
R1
H
H
H
H
H
H
H
R2
H
4ꢀMe
2ꢀMe
4ꢀOMe
4ꢀtBu
4ꢀCl
4
Yield(%)b
88
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
4aa
4ba
4ca
4da
4ea
4fa
4ga
4ha
4ia
82
84
75
81
85
79
82
25
Temperature
Entry
Base
Solvent
Yield b (%)
4ꢀCF3
3,4ꢀOMe
H
(oC)
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
100
140
140
140
140
1 c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18 d
19 e
20 f
KOH
KOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
NMP
PhMe
Dioxane
H2O
t-amyl alcohol
DMSO
DMSO
DMSO
DMSO
51
57
54
trace
75
68
84
H
Me
nBu
91
10
2j
H
4ja
55c
NaOH
KOtBu
NaOEt
Cs2CO3
K3PO4
K2HPO4
Et3N
DABCO
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
a Reaction condition: Benzylamines 2a-2j (1 mmol), 1,3ꢀdiphenylpropꢀ2ꢀ
55 ynꢀ1ꢀone 3a (1 mmol), K3PO4 (1 mmol) and DMSO (2.0 mL) at a 140 ºC
under N2 atmosphere. b Isolated yields based on 1,3ꢀdiphenylpropꢀ2ꢀynꢀ1ꢀ
one 3a. c 80% yield was obtained from corresponding NꢀnButyl
enaminone.
no reaction
0
0
78
72
The scope of ynones 3 was investigated as well. As shown in
60 Table 3, both of the electronꢀdonating and electronꢀwithdrawing
groups on the 1ꢀaryl ring of the 1,3ꢀdiarylpropynones were well
tolerated and provided the corresponding pyrroles in desirable
yields (64ꢀ89%, entries 1ꢀ6). Moreover, steric hindrance did not
influence the transformation obviously (entry 1 vs 2). When R3
65 was 2ꢀthiophen, cyclohexyl and isopropyl, the reaction could
proceed smoothly and gave the corresponding polysubstituted
pyrroles in 87%, 91% and 40% yields, respectively (enties 7ꢀ9).
For 3ꢀaryl ring of the 1,3ꢀdiarylpropynones, steric hindrance had
a significant impact on the yield. Ortho methyl substituted
70 substrate gave lower yield than corresponding substrates with
paraꢀ and meta- methyl (entry 12 vs 10, 11). A number of
electronꢀdonating and electronꢀwithdrawing groups, including
methoxyꢀ, chloroꢀ and fluoroꢀ in the 3ꢀaryl ring of the 1,3ꢀ
diarylpropynones were tolerant and furnished in good yields
75 (entries 13–15). In addition, good yields was obtained when R4
was aliphatic groups (entries 16ꢀ17).
no reaction
no reaction
no reaction
no reaction
91
78
84
88
a Reaction conditions: 1aa (0.5 mmol), base (0.5 mmol) and solvent (2.0
mL) under N2 atmosphere. b Isolated yield based on 1aa. c Under air. d 0.2
eq K3PO4 was used. e 0.5 eq K3PO4 was used. f Benzylamine and 1,3ꢀ
diphenylpropꢀ2ꢀynꢀ1ꢀone as substrates.
30
With the optimized reaction conditions in the hand (1 equiv of
K3PO4, DMSO as base and solvent, respectively, at 140 ºC), we
subsequently investigated the substrate scope of this “oneꢀpot”
transformation. The results of the reaction of 1,3ꢀdiphenylpropꢀ2ꢀ
ynꢀ1ꢀone 3a with various benzylamines 2a-2j were summarized
35 in Table 2. Benzylamines with both electronꢀwithdrawing and
2
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Table 3 Reactions of benzylamine 2a with various ynones 3a-3ha
25 Science and Technology of Xiamen City (3502z201014) and
Fundamental Research Funds of Huaqiao University.
Notes and references
a
Engineering Research Center of Molecular Medicine, Ministry of
Education, Key Laboratory of Xiamen Marine and Gene Drugs, Institutes
30 of Molecular Medicine and School of Biomedical Sciences, Huaqiao
University, Xiamen, 361021
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
35 1. (a) A. Gossauer, Die Chemie der Pyrrole, Springer Verlag, Berlin,
1974; (b) A. F. Pozharskii, A. T. Soldatenkov and A. R. Katritzky,
Heterocycles in life and society. An introduction to heterocyclic
chemistry and biochemistry and the role of heterocycles in science,
technology, medicine and agriculture, John Wiley & Sons, 1997; (c)
Yield
(%)b
89
86
82
81
64
85
87
91
40
88
81
49
83
70
82
74
70
Entry
3
R3
R4
4
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
2ꢀMeC6H4ꢀ
4ꢀMe C6H4ꢀ
3ꢀMeOC6H4ꢀ
4ꢀtBuC6H4ꢀ
4ꢀClC6H4ꢀ
4ꢀFC6H4ꢀ
Thiophenꢀ2ꢀ
Cyclohexylꢀ
isopropylꢀ
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
4aj
4ak
4al
4am
4an
4ao
4ap
4aq
4ar
40
B. A. Trofimov, L. N. Sobenina, A. P. Demenev and A. b. I.
Mikhaleva, Chem. Rev., 2004, 104, 2481; (d) F. Bellina and R. Rossi,
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4ꢀMeC6H4ꢀ
3ꢀMeC6H4ꢀ
2ꢀMeC6H4ꢀ
4ꢀMeOC6H4ꢀ
4ꢀClC6H4ꢀ
4ꢀFC6H4ꢀ
nBu
Ph
Ph
Ph
Ph
Ph
Ph
Ph
50
55
60
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tBu
a Reaction condition: Benzylamine 2a (1 mmol), ynone 3 (1 mmol),
K3PO4 (1 mmol), DMSO (2.0 mL) at 140 ℃ under N2 atmosphere. b
Isolated yields based on ynone 3.
5
To prove the practicality of this “oneꢀpot” reaction system, a
gramꢀscale synthesis of the 2,3,5ꢀtriphenylꢀ1Hꢀpyrrole 4aa was
performed. The result was shown in Scheme 2. When 1.03g 1,3ꢀ
10 diphenylpropꢀ2ꢀynꢀ1ꢀone 3a and 0.54g benzylamine 2a were
loaded, 1.27g pyrrole 4aa was obtained (86% yield). Metalꢀfree
and high effciency make this reaction possess extensive synthesis
application, especially in the pharmaceutical industry.
65
70
75
7. (a) F.ꢀX. Felpin, T. Ayad and S. Mitra, Eur. J. Org. Chem., 2006, 2679;
(b) J. Mao, Q. Hua, G. Xie, J. Guo, Z. Yao, D. ShiandS. Jia, Adv.
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15 Scheme 2. Gramꢀscale synthesis of 2, 3, 5ꢀtriphenylꢀ1Hꢀpyrrole 4aa
In conclusion, we have developed an efficient, facile and practical
oneꢀpot procedure for the polysubstituted pyrroles. This
transformation features with easy accessibility of starting
materials, good functional group tolerance and transition metal
20 free. A wide variety of polyꢀsubstituted pyrroles were obtained in
good to excellent yields in an environmentally benign manner.
10. G. Cheng and X. Cui, Org. Lett., 2013, 15, 1480.
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Acknowledgment
This work was supported by NSF of China (21202048), Program
for Minjiang Scholar (10BS216), Science Research Item of
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