One-pot highly efficient synthesis of substituted pyrroles and N-bridgehead pyrroles by zinc-catalyzed multicomponent reaction

Article abstract of DOI:10.1039/c003885g

A convenient zinc(ii) chloride-catalyzed regioselective propargylation/amination/cycloisomerization process has been developed for the synthesis of substituted pyrrole derivatives from propargylic acetates, enoxysilanes and primary amines. Various aromati

Full text of DOI:10.1039/c003885g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
One-pot highly efficient synthesis of substituted pyrroles and N-bridgehead
pyrroles by zinc-catalyzed multicomponent reaction†
Xiao-tao Liu, Lu Hao, Min Lin, Li Chen and Zhuang-ping Zhan*
Received 5th March 2010, Accepted 21st April 2010
First published as an Advance Article on the web 18th May 2010
DOI: 10.1039/c003885g
A convenient zinc(II) chloride-catalyzed regioselective propargylation/amination/cycloisomerization
process has been developed for the synthesis of substituted pyrrole derivatives from propargylic
acetates, enoxysilanes and primary amines. Various aromatic and aliphatic propargylic acetates
participate well in the reaction, providing the propargylation/amination/cycloisomerization products
in good yields with complete regioselectivity. The one-pot multicomponent coupling reaction furnishes
substituted pyrroles in high yields by circumventing the intermediates’ isolation. Zinc(II) chloride acts
as a multifunctional catalyst and catalyzes three mechanistically distinct processes in a single-pot. The
protocol developed has been extended to the synthesis of N-bridgehead pyrroles containing polycyclic
fragments.
reactions direct from several readily available and easily diversified
Introduction
building blocks are much less studied.6 Hence, the development of
Substituted pyrroles represent indispensable structural motifs,
new, mild, and versatile synthetic methods to access functionalized
broadly found in biologically active natural products, as well as
molecular sensors.1 Moreover, N-bridgehead pyrroles containing
pyrroles has remained an ongoing challenge.
Substituted pyrroles are highly biologically active, and have
proven to display antimycobacterial activity7 and to inhibit
cytokine-mediated diseases.8 The intriguing molecular architec-
tures prompt us to study the feasibility of synthesizing substituted
pyrroles. To the best of our knowledge, no examples of the
synthesis of substituted pyrroles directly from propargylic acetates,
enoxysilanes and amines have ever been reported. Herein, as
the results of development on the transition metal-catalyzed
propargylic substitution reaction in our group,9 we wish to report
a highly efficient propargylation/amination/cycloisomerization
reaction for the synthesis of substituted pyrroles directly from
propargylic acetates, enoxysilanes and primary amines using
zinc(II) chloride as a multifunctional catalyst (Scheme 1).
polycyclic fragments and their partially or completely reduced
analogues constitute the basic skeleton of many alkaloids with well
recognized pharmacological properties.2 Accordingly, substantial
attention has been paid to developing efficient methods for the
synthesis of substituted pyrroles. The traditional routes to their
preparation are multistep reactions, as illustrated by the Paal–
Knorr cyclization of amines with pre-formed 1,4-diketones. As
an alternative, recent strategies for the synthesis of pyrroles
are mainly based on transition metal-catalyzed cycloaddition or
cycloisomerization of acyclic precursors, many of which provide
structures not easily generated by classical routes.3–5 Despite
numerous advances, the corresponding multicomponent coupling
Department of Chemistry, College of Chemistry and Chemical Engineering,
and State Key Laboratory for Physical Chemistry of Solid Surfaces,
Xiamen University, Xiamen 361005, Fujian, P. R. China. E-mail: zpzhan@
xmu.edu.cn
† Electronic supplementary information (ESI) available: General experi-
mental information and characterization data of all compounds. See DOI:
10.1039/c003885g
Results and discussion
We recently described a straightforward approach to the synthesis
of substituted furans from propargylic acetates and enoxysilanes.9c
The process, which proceeds in a one-pot manner, involves initial
Scheme 1 Synthesis of pyrroles from propargylic acetates, enoxysilanes and primary amines.
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Table 1 Reaction optimizationa
Isolated yield (%)c
Entry
Catalyst
Solvent
Time/hb
4a
5aa
1
2
3
4
5
6
7
8
ZnCl2
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
CH3CN
1.5
24
5
0
0
0
0
0
0
36
0
27
27
0
83
0
61
0
0
0
25
67
16
40
0
AgOTf
Cu(OTf)2
Cu(OAc)2
CuI
CuSO4
FeCl3
InCl3
BiCl3
AlCl3
SnCl4
Zn(OTf)2
BF3·Et2O
Bi(OTf)3
RuCl3·3H2O
HAuCl4·3H2O
Mg(ClO4)2
5% ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
24
24
24
12
1.5
12
12
24
24
12
12
24
24
24
12
10
10
12
12
10
12
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
0
0
36
29
0
0
0
34
39
42
0
0
5
20
38
0
0
0
46
34
38
0
0
17
0
DCE
CH3NO2
1,4-Dioxane
Toluene
p-Xylene
ZnCl2
0
a Reaction conditions: 10 mol% of catalyst, 1.0 equiv. of 1a (0.5 mmol), and 2.0 equiv. of 2a (1.0 mmol), solvent (2 mL) at 75 ◦C for 0.3 h, followed by the
addition of 2.0 equiv. of 3a (1.0 mmol). Amination/cycloisomerization proceeded at reflux. b Reaction time for amination/cycloisomerization at reflux.
c Isolated yield of pure product based on propargylic acetate 1a.
FeCl3-promoted nucleophilic substitution of propargylic acetates
with enoxysilanes in acetonitrile and subsequent cycloisomer-
ization of the resulting intermediate g-alkynyl ketone catalyzed
by PTSA in toluene. Encouraged by the successful synthesis of
substituted furans, we became interested in developing approaches
toward substituted pyrroles when a primary amine is introduced
into the reaction medium, and tested the multicomponent reaction
of propargylic acetate 1a, enoxysilane 2a and primary amine 3a.
Initially, treatment of a chlorobenzene solution of propargyl
ace◦tate 1a and 2.0 equiv. of enoxysilane 2a with 10 mol% FeCl3 at
75 C for 0.3 h, followed by the addition of 2.0 equiv. of aniline
3a and then heating to reflux for an additional 12 h, afforded the
desired substituted pyrrole 5aa in 25% yield along with uncyclized
g-alkynyl ketone 4a in 36% yield (Table 1, entry 7). To optimize
the reaction conditions, we first investigated a variety of Lewis
acids for their effectiveness at catalyzing this reaction. Fortunately,
zinc(II) chloride provided the best results in comparison to other
Lewis acids investigated and led to the formation of the desired
product with complete regioselectivity in high yield at reflux
after 1.5 h (Table 1, entry 1). Other Lewis acids, such as BiCl3,
AlCl3, BF3·Et2O or Bi(OTf)3, also produced some of the desired
substituted pyrrole 5aa, but the amination/cycloisomerization
of the intermediate g-alkynyl ketone 4a did not proceed to
completion even after 12 h at reflux (Table 1, entries 9, 10, 13 and
14). On the other hand, Cu(OTf)2 and InCl3 rapidly consumed
the starting propargylic acetate 1a and the intermediate 4a, but
produced the desired product only in moderate yield (Table 1,
entries 3 and 8). Other catalysts such as AgOTf, Cu(OAc)2,
CuI, CuSO4, SnCl4, Zn(OTf)2, RuCl3·3H2O, HAuCl4·3H2O or
Mg(ClO4)2 were unreactive (Table 1, entries 2, 4–6, 11, 12 and
15–17). Decreasing the catalyst loading to 5 mol% led to a longer
reaction time and gave a lower yield of 5aa (Table 1, entry
18). Furthermore, the reaction proceeded smoothly under “open-
flask” conditions without exclusion of moisture or air from the
reaction mixture. The choice of the solvent also played a crucial
role. Acetonitrile, 1,2-dichloroethane and toluene as solvents only
produced the desired product 5aa in low yields (Table 1, entries 19,
20 and 23). In other solvents, such as CH3NO2, 1,4-dioxane and
p-xylene, no cyclization products were observed (Table 1, entries
21, 22 and 24). However, employing chlorobenzene (PhCl) as the
solvent produced a further improvement and provided 5aa in 83%
yield (Table 1, entry 1).
With optimal conditions in hand, the substrate scope of the zinc-
catalyzed propargylation/amination/cycloisomerization reaction
was examined. Typical results are shown in Table 2. To our
delight, propargylation/amination/cycloisomerization occurred
with a range of secondary aromatic propargylic acetates (R1 =
aryl), including phenyl (Table 2, entries 1–22) and phenyl rings
substituted with electron-withdrawing (Table 2, entries 23 and
24) or electron-donating (Table 2, entries 25 and 26) groups,
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Scheme 2 Synthesis of the pyrrole 6aa
affording the substituted pyrroles in good yields with complete
regioselectivity. Electron-rich propargylic acetates provided the
desired products in higher yields than electron-poor propargylic
acetates. Sterically encumbered ortho-substituted phenyl groups
(Table 2, entry 26) did not affect the course of the reaction.
Moreover, fused aromatic and heteroaromatic substrates were
also successfully employed in the reaction to give the pyrroles
5ia and 5ja in 79 and 83% isolated yields, respectively (Table 2,
entries 27 and 28). Among the propargylic acetates that were
examined, substrates containing a terminal alkynyl unit (R2 = H)
gave desirable results, providing the substituted pyrroles in high
yields (Table 2, entries 1–6). Substrates containing an internal
alkynyl unit (R2 = TMS, n-Bu, phenyl) also underwent smooth
reaction to give the substituted pyrroles, and required slightly
longer reaction times, but maintain high yields (Table 2, entries
7–28). The trimethylsilyl group was removed either in the course
of the reaction or during workup (Table 2, entries 7–9 and 27).
It should be noted that in all cases the reactions proceeded with
complete regioselectivity and functional groups such as bromo,
ester, and methoxy in the propargylic acetates were readily carried
through the reaction, allowing for the subsequent elaboration of
the products.
The reaction was not limited to secondary propargylic acetates.
For example, tertiary propargylic acetate 1k readily underwent
propargylation/amination/cycloisomerization to afford the sub-
stituted pyrrole 6aa in 61% yield through the formation of allenyl
isomer10 (Scheme 2).
We next turned to examine the scope of the enoxysilane com-
ponent of the reaction (Table 2), and the corresponding pyrroles
were obtained in good yields. Enoxysilanes 2a and 2b participate as
nucleophiles in the reaction without a noticeable difference. On the
other hand, increasing the steric nature of enoxysilane influenced
the efficiency of the reaction, cyclic enoxysilane 2c required slightly
prolonged reaction times.
reaction times, but maintain high yields. Additionally, symmet-
rical amine 3i also participated in zinc-catalyzed propargyla-
tion/amination/cycloisomerization, smoothly affording oligomer
5dj with complete regioselectivity (Scheme 3). This process has the
potential to access oligoaryls of well-defined conjugation lengths,
a class of compounds that show promise as new optoelectronic
materials.11
Under the above standard conditions, attempts to extend the
ZnCl2 system to the secondary aliphatic propargylic acetate
(R1 = alkyl) were not successful. We reasoned that the process
proceeded through a propargylic cation intermediate. Instability of
the propargylic cation intermediate made sequential reaction less
favorable. The polarity of the solvent could have a significant effect
on the outcome of the reaction. By further screening of solvents,
we were pleased to find that nitromethane was ideal, leading to
the rapid formation of the intermediate g-alkynyl ketone 4 which
could be directly used for the next amination/cycloisomerization,
without purification, to afford the substituted pyrroles in good
yields with complete regioselectivity (Table 3). Other solvents,
such as chlorobenzene, 1,2-dichloroethane, acetonitrile, and THF,
were less efficient or did not promote the reaction. For example,
propargylic acetate 1l (0.5 mmol) was treated with enoxysilane 2b
(1.0 mmol) in the presence of 10 mol% ZnCl2 in nitromethane.
Upon reaction completion, nitromethane was removed in vacuo,
followed by the addition of chlorobenzene (2 mL) and amine
3a (1.0 mmol). The reaction was heated to reflux for 3 h.
The desired product 5la was gained in 72% yield. The other
results are depicted in Table 3. Similar yields and diversity
can be attained in this process as observed with the secondary
aromatic propargylic acetates. Methyl and pentyl substituents at
the propargylic position (Table 3, entries 1–3) are well tolerated
and can be incorporated into the pyrroles. Unfortunately, the
primary aliphatic propargylic acetate 1n (R1 = H; R2 = Ph) failed
to give substituted pyrrole (Table 3, entry 4).
With respect to the amines, the ZnCl2-catalyzed multicom-
ponent reaction is quite general. Aromatic (Table 2, entries 1–
4, 6–8, 10, 13–18, and 21–28) and aliphatic primary amines
(Table 2, entries 5, 9, 11, 12, and 19–20) could be efficiently
incorporated into the pyrrole framework. The reaction proceeded
smoothly when the aryl group of the primary amines were
substituted with electron-donating (Table 2, entries 3, 10, 17
and 21) and electron-withdrawing groups (Table 2, entries 4, 13,
18 and 22). Aliphatic primary amines required slightly longer
In the hope of extending the application of this method to
the synthesis of the N–H pyrrole, we examined the effect of
variation of ammonia source, which we thought would readily
allow for the reaction. Firstly, we employed NH4OAc, NH4Cl and
ammonium carbamate as sources of the N–H unit of the pyrrole.
Unfortunately, these variations did not deliver the desired N–H
pyrrole. We were pleased to find that the 2-chloroethyl moiety
is a versatile protecting group for the pyrrole nitrogen atom.12
Deprotection of the N-(2-chloroethyl)pyrrole is accomplished by
Scheme 3 Synthesis of the oligomer 5dj.
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Table 2 Synthesis of substituted pyrroles 5 from secondary aromatic propargylic acetates 1, enoxysilanes 2 and primary amines 3a
Propargylic acetate 1
R1; R2
Enoxysilane 2
R3; R4
Amine 3
R5
Entry
1
Product 5
Time/hb
1.5
Yield (%)c
83
1a: Ph; H
2a: Ph; H
3a: Ph-
5aa
2
3
1a: Ph; H
1a: Ph; H
2c: -(CH2)4-
2a: Ph; H
3a:Ph-
5ab
5ac
2
78
84
3b: 4-MePh-
1.5
4
5
1a: Ph; H
1a: Ph; H
2a: Ph; H
2a:Ph; H
3c: 4-ClPh-
3d: n-C8H17-
5ad
5ae
1.5
2.5
81
80
6
7
1a: Ph; H
2b: Me; H
2b: Me; H
3a:Ph-
3a:Ph-
5af
1.5
3
86
77
1b: Ph; TMS
5ba
8
9
1b: Ph; TMS
1b: Ph; TMS
2c: -(CH2)4-
2c: -(CH2)4-
3a:Ph-
5bb
5bc
3.5
3.5
73
72
3e: PhCH2-
10
11
1c: Ph; n-Bu
1c: Ph; n-Bu
2a: Ph; H
2a: Ph; H
3b: 4-MePh-
3d: n-C8H17-
5ca
5cb
3
86
80
12
12
13
1c: Ph; n-Bu
1h: Ph; n- Bu
2a: Ph; H
2b: Me; H
3e: PhCH2-
3f: 2-BrPh-
5cc
5cd
10
5
83
82
14
15
1d: Ph; Ph
1d: Ph; Ph
2a: Ph; H
2b: Me; H
3a: Ph-
3a: Ph-
5da
5db
3
3
87
91
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Table 2 (Contd.)
Propargylic acetate 1
Enoxysilane 2
R3; R4
Amine 3
R5
Entry
16
R1; R2
Product 5
Time/hb
5
Yield (%)c
86
1d: Ph; Ph
2c: -(CH2)4-
3a: Ph-
5dc
17
18
1d: Ph; Ph
1d: Ph; Ph
2a: Ph; H
2a: Ph; H
3b: 4-MePh-
3c: 4-ClPh-
5dd
5de
3
90
85
3.5
19
1d: Ph; Ph
2a: Ph; H
3d: n-C8H17-
5df
12
80
20
21
22
1d: Ph; Ph
1d: Ph; Ph
1d: Ph; Ph
2a: Ph; H
2a: Ph; H
2a: Ph; H
3e: PhCH2
5dg
5dh
5di
10
3
83
86
76
3g: 2-MeOPh-
3h: 4-COOEtPh-
4
23
24
1e: 4-BrPh; n-Bu
2a: Ph; H
2a: Ph; H
3a: Ph-
3a: Ph-
5ea
5fa
3.5
4
81
77
1f: 4-COOMePh; n-Bu
25
1g: 4-MeOPh; Ph
2a: Ph; H
3a: Ph-
5ga
2.5
91
26
27
1h: 2-MeOPh; n-Bu
1i: 1-Naphthyl; TMS
2a: Ph; H
2a: Ph; H
3a: Ph-
3a: Ph-
5ha
5ia
3
4
89
79
28
1j: 2-Thienyl; n-Bu
2a: Ph; H
3a: Ph-
5ja
3.5
83
a Reaction conditions: 10 mol% of ZnCl2, 1.0 equiv. of 1 (0.5 mmol), and 2.0 equiv. of 2 (1.0 mmol), chlorobenzene (2 mL) at 75 ◦C for 0.3 h, followed by the
addition of 2.0 equiv. of 3 (1.0 mmol). Amination/cycloisomerization proceeded at reflux for 1.5–12 h. b Reaction time for amination/cycloisomerization
at reflux. c Isolated yield of pure products based on propargylic acetates 1.
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Table 3 Synthesis of substituted pyrroles 5 from secondary aliphatic propargylic acetates 1, enoxysilanes 2 and primary amines 3a
Propargylic acetate 1
R1; R2
Enoxysilane 2
R3; R4
Amine 3
R5
Entry
1
Product 5
Time/hb
3
Yield (%)c
72
1l: n-pent; Ph
2b: CH3; H
3a: Ph-
5la
2
1l: n-pent; Ph
2a: Ph; H
3d: n-C8H17-
5lb
10
63
3
4
1m: CH3; Ph
1n: H; Ph
2a: Ph; H
2a: Ph; H
3a: Ph-
3a: Ph-
5ma
5na
3
71
0
12
a Reaction conditions: 10 mol% of ZnCl2, 1.0 equiv. of 1 (0.5 mmol), and 2.0 equiv. of 2 (1.0 mmol), CH3NO2 (2 mL) at r.t. for 1 h. Upon reaction completion,
nitromethane was removed in vacuo, followed by the addition of chlorobenzene (2 mL) and 2.0 equiv. of 3 (1.0 mmol). Amination/cycloisomerization
proceeded at reflux for 3–12 h. b Reaction time for amination/cycloisomerization at reflux. c Isolated yield of pure products based on propargylic acetates 1.
means of efficient three-step, one-pot sequences via the N-vinyl
compound and subsequent degradation of the N-(1-hydroxyethyl)
compound obtained therefrom. The N–H pyrrole 7aa was afforded
in 41% yield over two steps (Scheme 4).
this synthetic scheme allows for facile analogue synthesis by
appropriate choice of the initial substrates.
Conclusions
N-Bridgehead pyrroles are found in various alkaloids such
as mitomycins, mytomicines and vincetene.13 The preparation of
complex polycyclic heterocycles is an important synthetic goal
owing to the use of these molecules as potential pharmaceuticals.
Having successfully developed the Zn(II)-catalyzed propargyla-
tion/amination/cycloisomerization reaction, we turned to the
application of this methodology in the synthesis of N-bridgehead
pyrroles containing polycyclic fragments. To begin the synthetic
sequence, terminal propargylic acetates 1 reacted with enoxysi-
lanes 2 to give the g-alkynyl ketones 4. Subsequent Sonogashira
coupling of adducts 4 with amines 3 set the stage for zinc-catalyzed
intramolecular amination/5-exo-dig-cycloisomerization to afford
N-bridgehead pyrroles 8 (Scheme 5). The modular design of
In summary, we have developed an air- and moisture-
tolerant zinc-catalyzed regioselective propargylation/amination/
cycloisomerization reaction of propargylic acetates, enoxysilanes
and primary amines in a single-pot. Zinc(II) chloride, working as a
multifunctional catalyst, catalyzes three mechanistically distinct
processes in a single-pot under the same conditions. A wide
range of aromatic propargylic acetates bearing terminal or internal
alkyne groups are readily available and a number of functionalities
are tolerated. Additionally, the secondary aliphatic propargylic
acetates also could be efficiently incorporated into the pyrrole
framework. The broad scope, mild reaction conditions, and
experimental ease of this transformation have made it a valuable
Scheme 4 Synthesis of the N–H pyrrole 7aa.
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Scheme 5 Synthesis of the N-bridgehead pyrroles 8.
alternative to current available transformations. The protocol
developed has been extended to the synthesis of N-bridgehead
pyrroles containing polycyclic fragments. Further development
on this methodology is currently underway in our laboratories.
combined organic layers were dried over MgSO4 and filtered. The
filtrate was concentrated in vacuo, and then the residue was purified
by silica gel column chromatography (EtOAc–hexane = 1 : 100) to
afford the corresponding substituted pyrroles.
General procedure for the synthesis of substituted pyrrole 5dj
Experimental
To a 10 mL flask, propargylic acetate 1d (1.0 mmol), enoxysilane 2b
(2.0 mmol), chlorobenzene (4.0 mL) and ZnCl2 (0.20 mmol) were
successively added. The reaction was allowed to stir at 75 ◦C for
0.3 h, followed by the addition of primary amine 3i (0.4 mmol).
The reaction mixture was heated to reflux temperature for an
additional 10 h until completion by TLC. Upon cooling to room
temperature, the reaction mixture was then quenched with 1 M
HCl (2 mL), the organic and aqueous layers were separated,
and the aqueous layer was extracted with Et2O (3 ¥ 5 mL). The
combined organic layers were dried over MgSO4 and filtered. The
filtrate was concentrated in vacuo, and then the residue was purified
by silica gel column chromatography (EtOAc–hexane = 1 : 100) to
afford the substituted pyrrole.
General experimental
Propargylic acetates 1 and enoxysilanes 2 were prepared according
to published procedures. All other compounds are commercially
available and were used without further purification. Infrared spec-
tra were recorded on a Nicolet AVATER FTIR360 spectrometer.
NMR spectra were recorded on a Bruker AVANCE DPX-400
instrument at 400 MHz (1H) or 100 MHz (13C). The chemical
shift values (d) are given in parts per million (ppm) and are
referred to the residual peak of the deuterated solvent (CDCl3).
MS measurements were performed on Bruker Reflex III mass
spectrometer. Elemental analyses were performed with a Perkin–
Elmer 2400 microanalyser. Flash chromatography was performed
with QingDao silica gel (300–400 mesh).
General procedure for the synthesis of substituted pyrroles
(5la–5ma)
General procedure for the synthesis of substituted pyrroles (5aa,
5ac–5ae, 5ca–5cd, 5db, 5dc, 5de, 5dg–5fa, 5ha–5ja, 6aa)
To a 10 mL flask, propargylic acetates 1 (0.5 mmol), enoxysilanes
2 (1.0 mmol), nitromethane (2.0 mL) and ZnCl2 (0.05 mmol)
were successively added. The reaction was allowed to stir at
r.t. for 1 h, nitromethane was removed in vacuo, followed by
the addition of chlorobenzene (2 mL) and amine 3 (1.0 mmol).
The reaction mixture was heated to reflux temperature for an
additional 3–10 h until completion by TLC. Upon cooling to
room temperature, the reaction mixture was then quenched with
1 M HCl (2 mL), the organic and aqueous layers were separated,
and the aqueous layer was extracted with Et2O (3 ¥ 5 mL). The
To a 10 mL flask, propargylic acetates 1 (0.5 mmol), enoxysilanes 2
(1.0 mmol), chlorobenzene (2.0 mL) and ZnCl2 (0.05 mmol) were
successively added. The reaction was allowed to stir at 75 ◦C for
0.3 h, followed by the addition of primary amines 3 (1.0 mmol).
The reaction mixture was heated to reflux temperature for an
additional 1.5–12 h until completion by TLC. Upon cooling to
room temperature, the reaction mixture was then quenched with
1 M HCl (2 mL), the organic and aqueous layers were separated,
and the aqueous layer was extracted with Et2O (3 ¥ 5 mL). The
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combined organic layers were dried over MgSO4 and filtered. The
filtrate was concentrated in vacuo, and then the residue was purified
by silica gel column chromatography (EtOAc–hexane = 1 : 100) to
afford the corresponding substituted pyrroles.
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General procedure for the synthesis of substituted pyrroles (7aa)
Sodium hydride in mineral oil (60%, 24 mg, 0.6 mmol) was added
to a stirred solution of 5dk (0.186 g, 0.5 mmol) in dry acetonitrile
(3.0 mL) maintained in a nitrogen atmosphere. The solution was
heated at 50 ◦C for 2 h and 6 M hydrochloric acid (0.84 mL,
5 mmol) was added dropwise. After an additional 6 h, a solution
of sodium acetate (494 mg, 6 mmol) in water (1.0 mL) was added
and the solution was heated at reflux temperature for 0.5 h. Upon
cooling to room temperature, the solution was extracted with ether
(3 ¥ 5 mL). The combined organic layers were dried over MgSO4
and filtered. The filtrate was concentrated in vacuo, and then the
residue was purified by silica gel column chromatography (EtOAc–
hexane = 1 : 10) to afford N–H pyrrole 7aa.
General procedure for the synthesis of N-bridgehead pyrroles
(8aa–8ea)
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A. The synthesis of the c-alkynyl ketone 4. To a 10 mL flask,
propargylic acetates 1 (0.5 mmol), enoxysilanes 2 (1.0 mmol),
chlorobenzene (2.0 mL) and ZnCl2 (0.05 mmol) were successively
added. The reaction was allowed to stir at 75 ◦C for 0.3 h. The
solvent was removed under reduced pressure by an aspirator, and
then the residue was purified by silica gel column chromatography
(EtOAc–hexane = 1 : 20) to afford the g-alkynyl ketone 4.
B. The synthesis of N-bridgehead pyrroles 8. To a stirred solu-
tion of Pd(PPh3)4 (0.025 mmol), CuI (0.025 mmol) in anhydrous
Et3N (3 mL), amines 3 (0.5 mmol) and the g-alkynyl ketone
4 (0.5 mmol) in Et3N (2 mL) and THF (1 mL) were added.
The reaction mixture was heated at reflux temperature under
argon atmosphere for 2 h and then the solvent was removed
under reduced pressure, followed by the addition of chlorobenzene
(2.0 mL) and ZnCl2 (0.05 mmol). The reaction was stirred at reflux
until completion by TLC. Upon cooling to room temperature,
the reaction mixture was then quenched with 1 M HCl (2 mL),
the organic and aqueous layers were separated, and the aqueous
layer was extracted with Et2O (3 ¥ 5 mL). The combined organic
layers were dried over MgSO4 and filtered. The filtrate was
concentrated in vacuo, and then the residue was purified by silica
gel column chromatography (EtOAc–hexane = 1 : 100) to afford
the corresponding N-bridgehead pyrroles.
Acknowledgements
The research was financially supported by the National Natural
Science Foundation of China (No. 20772098) and the Program for
New Century Excellent Talents in Fujian Province University.
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10 An alternative pathway involves trapping of the allenyl cation by
enoxysilane, to give allenyl isomer, and subsequent amination/
cycloisomerization to pyrrole 6aa. see: ref. 9c.
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