Indium(III) chloride-catalyzed propargylation/amination/cycloisomerization tandem reaction: One-pot synthesis of highly substituted pyrroles from propargylic alcohols, 1,3-dicarbonyl compounds and primary amines

Article abstract of DOI:10.1002/adsc.200800473

A convenient one-pot propargylation/amination/cycloisomerization tandem process has been developed for the synthesis of highly substituted pyrroles derivatives from propargylic alcohols, 1,3-dicarbonyl compounds and primary amines using indium(III) chloride as a multifunctional catalyst. This method provides a flexible and rapid route to substituted pyrroles.

Full text of DOI:10.1002/adsc.200800473

FULL PAPERS
DOI: 10.1002/adsc.200800473
Indium
G
ACHTUNGTRENNUNG
Substituted Pyrroles from Propargylic Alcohols, 1,3-Dicarbonyl
Compounds and Primary Amines
Xiao-tao Liu,a Lei Huang,a Fei-jian Zheng,a and Zhuang-ping Zhana,*
a
Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, Fujian,
Peopleꢀs Republic of China
Fax : (+86)-592-218-0318; phone: (+86)-592-218-0318; e-mail: zpzhan@xmu.edu.cn
Received: July 29, 2008; Published online: November 19, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800473.
Abstract: A convenient one-pot propargylation/ami- method provides a flexible and rapid route to substi-
nation/cycloisomerization tandem process has been tuted pyrroles.
developed for the synthesis of highly substituted pyr-
roles derivatives from propargylic alcohols, 1,3-dicar- Keywords: 1,3-dicarbonyl compounds; indium
bonyl compounds and primary amines using indium- chloride; primary amines; propargylic alcohols; pyr-
ACHTUNGTRENNUNG(III) chloride as a multifunctional catalyst. This roles; tandem reactions
ACHTUNGTRENNUNG(III)
[8]
Introduction
the presence of [Cp*RuCl
ACHTNUGTNER(UNNG m2-SMe)2RuCp*Cl]/PtCl2
or CF3CO2H/Ru(II),[9] which lead to the synthesis of
The ever-increasing complexity of organic target mol- substituted pyrroles, have been reported. However,
ecules necessitates the introduction of new methods two or more catalysts are needed in these reactions.
for the efficient assembly of functionalized intermedi- To the best of our knowledge, there is no propargyla-
ates from simple precursors. An appealing strategy tion/amination/cycloisomerization tandem reaction
toward this end is the development of novel tandem for the synthesis of substituted pyrroles in the pres-
reactions whereby sequential transformations can be ence of a single catalyst reported in the literature. As
performed without isolation or purification of inter- the results of development on the transition metal-
mediates in a single-pot with minimal work-up.[1] Es- catalyzed propargylic substitution reaction in our
pecially, the finding and utilization of a single catalyst group,[10] herein, we wish to report a highly efficient
to promote several transformations in a selective propargylation/amination/cycloisomerization tandem
manner is a promising area of research.[2] Such direct reaction for the synthesis of substituted pyrroles di-
synthesis routes help to avoid side-product formation rectly from propargylic alcohols, 1,3-dicarbonyl com-
and loss of starting material as well as to reduce capi- pounds and primary amines using indium
tal investment and operation costs. ride as catalyst. The process is outlined in Scheme 1.
Transition metal-catalyzed cyclization reactions of Indium(III) chloride acts as a multifunctional catalyst
ACHTUNGTRENUN(NG III) chlo-
AHCTUNGTRENNUNG
unsaturated systems provide access to structural and effectively catalyzes the three reaction processes
motifs not accessible through their thermal counter- in a single reaction vessel. A wide range of secondary
parts. This is exemplified by the applications of transi- propargylic alcohols bearing not only terminal alkyne
tion metal-catalyzed cycloaddition or cycloisomeriza- groups but also internal alkyne groups can effectively
tion of acyclic precursors for the synthesis of substi- be employed and a number of functionalities, such as
tuted pyrroles.[3–7] The corresponding multicomponent chloro, cyano, bromo, ester, and methoxy, are tolerat-
coupling reactions proceeding directly from simple ed under the reaction conditions.
and readily available substrates are much less studied.
Recently, efficient sequential reactions of propargylic
alcohols, carbonyl compounds and primary amines in
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Scheme 1. Synthesis of highly substituted pyrroles from propargylic alcohols, 1,3-dicarbonyl compounds and primary amines.
Results and Discussion
reaction time from 24 h to 3.5 h (Table 1, entry 1 vs.
entry 10).
To extend the scope of the FeCl3- or Cu(OTf)2-cata-
With the identification of the optimal conditions in
CuACHTUNGTRENNUNG(OTf)2 as a single catalyst. Initially, propargylic al- ing the propargylation/amination/cycloisomerization
cohol 1a (0.5 mmol) was treated with 1,3-dicarbonyl products in good yields with complete regionselectivi-
compounds 2a (0.6 mmol) in the presence of 10 mol% ty. Among the propargylic alcohols that were exam-
FeCl3 in toluene, aniline 3a (0.6 mmol) was added di- ined, internal propargylic alcohol 1a (R2 =Ph) gave
rectly to the reaction after consumption of 1a and the most desirable result, providing the highly substi-
then the reaction mixture was heated to reflux for an tuted pyrroles in high to excellent yields (Table 2, en-
additional 24 h. The tandem reaction led not to the tries 1–7). Internal propargylic alcohols 1b and 1d
expected pyrrole 6aa, but to the intermediate g-alkyn- (R2 =TMS, n-Bu) gave desirable results (Table 2, en-
yl ketone 4a (Scheme 1). Gratifyingly, switching the tries 9 and 10, 13-15), although slightly longer reaction
catalyst to CuACHTUNGTRENNUNG(OTf)2 furnished the highly substituted times were required. Terminal propargylic alcohol 1c
pyrrole 6aa in 45% yield (Table 1, entry 4). To identi- (R2 =H) also participated in the reaction in moderate
fy suitable conditions for the tandem process,[11] the yields (Table 2, entries 11 and 12).[9,12] Unfortunately,
series of Lewis acids from Table 1 was screened. For- the primary aliphatic progargylic alcohol 1k (R1 =H;
tunately, indiumACHTUNGTRENNUNG
(III) chloride provided the best re- R2 =Ph) and secondary aliphatic progargylic alcohol
sults in comparison to other Lewis acids investigated 1l (R1 =CH3; R2 =Ph) failed to give highly substituted
and was effective in catalytic quantities (10 mol%) pyrroles (Table 2, entries 22 and 23). The experimen-
(Table 1, entry 1). The combination of AgOTf and tal results suggested a mechanism through the forma-
CuACHTUNGTRENNUNG(OTf)2 also produced the highly substituted pyrrole tion of a propargylic cation intermediate. The instabil-
6aa in 85% isolated yield (Table 1, entry 5), whereas ity of the propargylic cation intermediate made the
two catalysts were needed. Other catalysts such as sequential reaction less favorable. Propargylic alcohol
FeCl3, BiCl3, or HgACTHNUGTRENNUG(OAc)2 did not promote the reac- 1f possessing an electron-donating group at the aryl
tion. Furthermore, the propargylation/amination/cy- ring (R1 =4-MeO-C6H4) reacted smoothly with 1,3-di-
cloisomerization proceeded smoothly without exclu- carbonyl compound 2a and aniline 3a affording the
sion of moisture or air from the reaction mixture. The pyrrole 6fa in high yield (Table 2, entry 17). More-
choice of the solvent also played a crucial role. Fur- over, substrates 1e and 1i possessing strong electron-
ther optimization led to the discovery that toluene withdrawing groups at the aryl ring (R1 =4-MeOOC-
and 1,2-dichloroethane as solvent were able to facili- C6H4, 4-CN-C6H4) were also successfully employed in
tate the transformation. However, the use of toluene the reaction to give the pyrroles 6ea and 6ia in 79%
instead of 1,2-dichloroethane obviously reduced the and 66% isolated yields, respectively (Table 2, en-
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Table 1. Optimization of the formation of highly substituted pyrroles.[a]
Entry
Catalyst
Solvent
Time [h][b]
Isolated yield [%][c]
1
2
3
4
5
6
7
8
InCl3
InCl3
AgOTf
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH3CN
DCE
3.5
24
24
8
85
76[d]
0
45
85[e]
0
0
0
26
84
5
Cu
N
Cu(OTf)2/AgOTf
E
4
FeCl3
BiCl3
24
24
24
36
24
12
24
Hg
N
9
InCl3
InCl3
InCl3
InCl3
10
11
12
CH3NO2
C2H5OH
0
[a]
Reaction conditions: 10 mol% of catalyst, 1.0 equiv. of 1a (0.5 mmol), and 1.2 equiv. of 2a (0.6 mmol), solvent (2 mL), at
608C for 2 h, 1.2 equiv. of 3a (0.6 mmol) then added for the period of time indicated at reflux.
Reaction time for propargylation/amination/cycloisomerization.
Isolated yield of pure product based on propargylic alcohol 1a.
5 mol% InCl3.
[b]
[c]
[d]
[e]
Reaction conditions: 5 mol% of Cu
ACHTUNGRTEN(NUNG OTf)2, 1.0 equiv. of 1a (0.5 mmol), and 1.2 equiv. of 2a (0.6 mmol), toluene (2 mL), at
608C for 2 h. 1.2 equiv. of 3a (0.6 mmol) and 10 mol% of AgOTf then added for an additional 2 h at reflux.
tries 16 and 20). Obviously, electron-rich propargylic (Table 2, entries 5, 6, 10 and 15) in good yields with
alcohols provided the desired products in higher complete chemoselectivity.
yields than electron-poor propargylic alcohols. Addi-
We next investigated the scope of the primary
tionally, propargylic alcohol 1j (R1 =2-thienyl; R2 = amines 3. The typical results are depicted in Table 3.
Ph) also participated to give the product in 86% iso- Aromatic (Table 3, entries 1, 2, 8, 9 and 13) and ali-
lated yield (Table 2, entry 21). It should be noted that phatic primary amines (Table 3, entries 3–5, 10, 11
functional groups such as chloro, cyano, bromo, ester, and 14) could be efficiently incorporated into the pyr-
and methoxy in the propargylic alcohols were readily role framework. The reaction proceeded smoothly
carried through the tandem reaction, allowing for the when the aryl groups of the primary amines were sub-
subsequent elaboration of the products. The reaction stituted with electron-donating (Table 3, entries 1 and
proceeded smoothly under mild conditions and air 2) and electron-withdrawing groups (Table 3, entries 8
was tolerated.
and 9). Aliphatic primary amines required slightly
A variety of 1,3-dicarbonyl compounds 2 was also longer reaction times, but maintained high yields. Un-
employed to examine the generality of the method. fortunately, the optically active primary amine 3g
For example, b-keto esters (Table 2, entries 1–3, 9, could not afford the desired product under the same
11, 13, 16–21) and b-diketones (Table 2, entries 4–7, reaction conditions, possibly due to the steric bulki-
10, 12, 14 and 15) were treated with propargylic alco- ness of 3g. Further screening of various catalysts led
hols 1 and aniline 3a, and the corresponding highly to the discovery that the use of the combination of
substituted pyrroles were obtained in moderate to CuACTHNUGTRENUNG(OTf)2 and AgOTf was ideal, providing the desired
good yields. While increasing the steric nature of the pyrrole 6kg in 86% isolated yield (Table 3, entry 7),
b-keto esters and b-diketones also influenced the ef- with the stereogenic centre in the initial amine not
ficiency of the reaction, 2c and 2g required pro- being affected during the transformation. However,
longed reaction times for better conversation the trimethylsilyl group could not be tolerated under
(Table 2, entries 3 and 7). However, on using diethyl this condition and had fallen off during work-up. No-
malonate 2h, no pyrrole was observed (Table 2, tably, an amide also participated in the reaction,
entry 8). Remarkably, non-symmetrical diketones albeit in somewhat lower yield (Table 3, entry 12).
also reacted rapidly with propargylic alcohols and Propargylic alcohol 1m (R1 =1-naphthyl) readily un-
aniline affording the highly substituted pyrroles derwent the propargylation/amination/cycloisomeriza-
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tion to afford the highly substituted pyrroles 6ma and enamino esters or ketones that might be the key inter-
6mb in good yields with complete regioselectivity mediates for the transformation, were produced
(Table 3, entries 13 and 14).
through amination of the g-alkynyl ketones. Firstly,
Accordingly, we hoped to extend the application of we employed NH4OAc or NH4Cl as sources of the N-
this method to the synthesis of N-H pyrroles. The b- H unit of the pyrrole. Unfortunately, none of the de-
Table 2. Synthesis of highly substituted pyrroles 6 from propargylic alcohols 1, 1,3-dicarbonyl compounds 2 and primary
amine 3a.[a]
Entry Propargylic alcohol
1,3-Dicarbonyl
compound
Product
Time [h][b] Isolated
yield [%][c]
1
2a: R3 =CH3; R4 =OEt 6aa
3.5
3.5
5
85
2b: R3 =CH3;
2
3
6ab
84
65
78
93
89
R4 =OCH
ACTHNUGTRENNUG(CH3)2
2c: R3 =CH3;
R4 =OC
(CH3)3
6ac
6ad
6ae
6af
AHCTUNGTRENNUNG
4
2d: R3 =R4 =CH3
3.5
3
1a: R1 =Ph; R2 =Ph
5
6
7
2e: R3 =CH3; R4 =Ph
2f: R3 =CH3;
3
R4 =4-Cl-C6H4
2g: R3 =R4 =Ph
6ag
24
70
0
8
2h: R3 =OEt; R4 =OEt –
24
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Table 2. (Continued)
Entry Propargylic alcohol
1,3-Dicarbonyl
compound
Product
Time [h][b] Isolated
yield [%][c]
9
2b: R3 =CH3; R4 =OEt 6ba
5
4
6
6
6
6
6
83
89
46
42
72
69
81
1b: R1 =Ph; R2 =TMS
10
2e: R3 =CH3; R4 =Ph
6bb
11
2a: R3 =CH3; R4 =OEt 6ca
1c: R1 =Ph; R2 =H
12
2d: R3 =R4 =CH3
6cb
13
2a: R3 =CH3; R4 =OEt 6da
14
15
1d: R1 =Ph; R2 =n-Bu
2d: R3 =R4 =CH3
6db
6dc
2e: R3 =CH3; R4 =Ph
16
17
1e: R1 =4-MeOOC-C6H4; R2 =Ph 2a: R3 =CH3; R4 =OEt 6ea
4
3
79
89
1f: R1 =4-MeO-C6H4; R2 =Ph
2a: R3 =CH3; R4 =OEt 6fa
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Table 2. (Continued)
Entry Propargylic alcohol
1,3-Dicarbonyl
compound
Product
Time [h][b] Isolated
yield [%][c]
18
19
1g: R1 =4-Br-C6H4; R2 =TMS
2a: R3 =CH3; R4 =OEt 6ga
5.5
80
70
1h: R1 =4-Cl-C6H4; R2 =n-Bu
2a: R3 =CH3; R4 =OEt 6ha
6
20
21
1i: R1 =4-CN-C6H4; R2 =Ph
2a: R3 =CH3; R4 =OEt 6ia
6
66
86
1j: R1 =2-thienyl; R2 =Ph
2a: R3 =CH3; R4 =OEt 6ja
3.5
22
23
1k: R1 =H; R2 =Ph
1l: R1 =CH3; R2 =Ph
2a: R3 =CH3; R4 =OEt
2a: R3 =CH3; R4 =OEt
–
–
24
24
0
0
[a]
Reaction conditions: 10 mol% of InCl3, 1.0 equiv. of 1 (0.5 mmol), and 1.2 equiv. of 2 (0.6 mmol), toluene (2 mL), at 608C
for 2 h or for 3 h (for substrates 1b, 1d, 1g and 1h), or at 708C for 5 h (for substrate 1c), followed by the addition of
1.2 equiv. of 3a (0.6 mmol). The amination/cycloisomerization proceeded under reflux for 1-22 h. See Supporting Informa-
tion for details.
Reaction time for propargylation/amination/cycloisomerization.
Isolated yield of pure product based on propargylic alcohols 1.
[b]
[c]
sired product was observed even in the presence of 20 cohols allowing for the synthesis of oligomers contain-
mol% of InCl3 at reflux for 12 h (Table 3, entry 6). ing two pyrrole moieties. For example, symmetrical
We then began searching for an appropriate ammonia propargylic alcohol 1n underwent indium-catalyzed
source, which we thought would readily allow for the propargylation/amination/cycloisomerization to afford
propargylation/amination/cycloisomerization tandem the oligomer 6ra in 63% isolated yield with complete
reaction. We were pleased to find that ammonium regioselectivity (Scheme 3). This process has the po-
carbamate[13] gave the desirable result in the tandem tential to access oligoaryls of well-defined conjugation
reaction. For example, treatment of propargylic alco- lengths, a class of compounds that show promise as
hols 1 with 1,3-dicarbonyl compounds 2 in toluene fol- new optoelectronic materials.[15]
lowed by amination with ammonium carbamate pro-
On the basis of these data, we propose the process
ceeded uneventfully to give the b-enamino esters 5 detailed in Scheme 4 as the most likely mechanism
(Scheme 1). The next step, a sequential cycloisomeri- for this transformation.[16] Firstly, the ionization of
zation of b-enamino esters 5, gave the N-H pyrroles 6 propargylic alcohol 1 would lead to propargylic cation
(Scheme 2).[14]
8 and subsequent nucleophilic attack of the enol 7
Additionally, the indium-catalyzed tandem reaction gives g-alkynyl ketone 4. Reaction of 4 and amine
also proceeded well with symmetrical propargylic al- produces the b-enamino ester or ketone 5. Coordina-
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tion of cationic indiumACTHNUTRGENNUG(III) to the alkyne forms the p- the indiumACHUTNGTREN(NUGN III)-alkyne complex 11 would generate
alkyne indium complex 11 and enhances the electro- the alkenyl-indium derivative 12. Protonolysis of 12
philicity of the alkyne. Subsequent 5-exo-dig nucleo- completes the catalytic cycle to afford dihydropyrrole
philic attack of the amino group on the b-carbon of 13, which then undergoes isomerization to pyrrole 6.
Table 3. Synthesis of highly substituted pyrroles 6 from propargylic alcohols 1, 1,3-dicarbonyl compound 2a and primary
amines 3.[a]
Entry Propargylic
alcohol
Primary amine
Product
Time Isolated
[h][b] yield [%][c]
1
3a 4-Me-C6H4NH2
6ka
5
85
2
3
3b 2-MeO-C6H4NH2
6kb
6kc
5
6
86
82
3c C6H5CH2NH2
1b: R1 =Ph; R2 =TMS
4
3d 4-MeO-C6H4CH2NH2 6kd
6
85
5
3e CH
(CH2)6CH2NH2
6ke
6
80
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Table 3. (Continued)
Entry Propargylic
alcohol
Primary amine
Product
Time Isolated
[h][b]
yield [%][c]
6
7
3f NH4OAc or NH4Cl
6kf
15
0
3g
6kg
5
5
0 (86)[d]
1b: R1 =Ph; R2 =TMS
8
3h 4-Cl-C6H4NH2
6kh
81
9
3i
4-EtOOC-C6H4NH2
6ki
7
76
10
3d 4-MeO-C6H4CH2NH2 6la
6
57
1c: R1 =Ph; R2 =H
11
3e CH
(CH2)6CH2NH2
6lb
6
47
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Time Isolated
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Table 3. (Continued)
Entry Propargylic
alcohol
Primary amine
Product
[h][b]
yield [%][c]
12
13
1c: R1 =Ph; R2 =H
3h
6lc
17
36
3a PhNH2
6ma
6mb
5
84
83
1m: R1 =1-naphthyl; R2 =TMS
14
3e CH
G
5.5
[a]
Reaction conditions: 10 mol% of InCl3, 1.0 equiv. of 1 (0.5 mmol), and 1.2 equiv. of 2a (0.6 mmol), toluene (2 mL), at
608C for 3 h, or at 708C for 5 h (for substrate 1c), followed by the addition of 1.2 equiv. of 3 (0.6 mmol). The amination/
cycloisomerization proceeded under refluxing for 2–12 h at refulx. See Supporting Information for details.
Reaction time for propargylation/amination/cycloisomerization.
Isolated yield of pure product based on propargylic alcohols 1.
Reaction conditions: 5 mol% of CuACTHNUTRGENUG(N OTf)2, 1.0 equiv. of 1b (0.5 mmol), and 1.2 equiv. of 2a (0.6 mmol), toluene (2 mL), at
[b]
[c]
[d]
608C for 3 h; 1.2 equiv. of 3g (0.6 mmol) and 10 mol% of AgOTf then added for an additional 2 h at reflux. See Support-
ing Information for details.
Scheme 2. Synthesis of the N-H pyrroles.
Conclusions
dicarbonyl compounds and primary amines in a
single-pot. A wide range of secondary propargylic al-
In summary, we have developed a mild, general, and cohols bearing terminal alkyne groups or internal
efficient procedure for the synthesis of highly substi- alkyne groups are readily available and a number of
tuted pyrroles directly from propargylic alcohols, 1,3- functionalities are tolerated. Operational simplicity
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IndiumACHTUNGTRENNUNG(III) Chloride-Catalyzed Propargylation/Amination/Cycloisomerization Tandem Reaction
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Scheme 3. Synthesis of the highly substituted pyrrole 6ra.
Scheme 4. Proposed mecahnism for the indium-catalyzed propargylation/amination/cycloisomerization reaction.
InCl3 (0.05 mmol) were successively added. The reaction
and minimal waste generation of this process should
mixture was allowed to stir at 608C or at 708C, and was
monitored periodically by TLC, until completion, followed
be beneficial for its large-scale applications. This
method provides a flexible and rapid route to the
by the addition of primary amines 3 (0.6 mmol). The reac-
preparation of highly substituted pyrroles and makes
tion mixture was heated to reflux temperature for an addi-
it a valuable alternative to currently available trans-
formation. Further applications and studies on the
mechanism of the indiumACTHNUTRGNE(NUG III)-catalyzed tandem reac-
tional 2–22 h until completion by TLC. Upon cooling to
room temperature, the reaction mixture was then quenched
with 1M HCl (2 mL), the organic and aqueous layers were
tion are ongoing in our laboratories and will be re- separated, and the aqueous layer was extracted with Et2O
(3ꢂ5 mL). The combined organic layers were dried over
MgSO4 and filtered. The filtrate was concentrated under
vacuum, and then the residue was purified by silica gel
column chromatography (EtOAc/hexane) to afford corre-
sponding highly substituted pyrroles 6.
ported in due course.
Experimental Section
General Procedure for the Synthesis of Highly
Substituted Pyrroles
Supporting Information
To a 10-mL flask, propargylic alcohols 1 (0.5 mmol), 1,3-di-
carbonyl compounds 2 (0.6 mmol), toluene (2.0 mL) and
General experimental information and characterization data
of all compounds are given in the Supporting Infromation.
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[9] V. Cadierno, J. Gimeno, N. Nebra, Chem. Eur. J. 2007,
13, 9973–9981.
Acknowledgements
[10] a) Z.-P. Zhan, J.-L. Yu, H.-J. Liu, Y.-Y. Cui, R.-F. Yang,
W.-Z. Yang, J.-P. Li, J. Org. Chem. 2006, 71, 8298–
8301; b) Z.-P. Zhan, W.-Z. Yang, R.-F. Yang, J.-L. Yu,
H.-J. Liu, Chem. Commun. 2006, 3352–3354; c) Z.-P.
Zhan, S.-P. Wang, X.-B. Cai, H.-J. Liu, J.-L. Yu, Y.-Y.
Cui, Adv. Synth. Catal. 2007, 349, 2097–2102; d) Z.-P.
Zhan, X.-B. Cai, S.-P. Wang, J.-L. Yu, H.-J. Liu, Y.-Y.
Cui, J. Org. Chem. 2007, 72, 9838–9841.
The research was financially supported by the National Natu-
ral Science Foundation of China (Nos. 20772098 and
30572250) and the Program for New Century Excellent Tal-
ents in Fujian Province University.
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Adv. Synth. Catal. 2008, 350, 2778 – 2788