A one-pot coupling-addition-cyclocondensation sequence (CACS) to 2-substituted 3-acylpyrroles initiated by a copper-free alkynylation

Article abstract of DOI:10.1039/c3ob41269e

A novel three-component synthesis of 2-substituted 3-acylpyrroles can be initiated by a copper-free Pd-catalyzed alkynylation in a one-pot fashion. The reaction sequence proceeds under mild reaction conditions and in moderate to good yields with a broad s

Full text of DOI:10.1039/c3ob41269e

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A one-pot coupling–addition–cyclocondensation
sequence (CACS) to 2-substituted 3-acylpyrroles
Cite this: DOI: 10.1039/c3ob41269e
initiated by a copper-free alkynylation†
Jan Nordmann and Thomas J. J. Müller*
Received 19th June 2013,
Accepted 24th July 2013
A novel three-component synthesis of 2-substituted 3-acylpyrroles can be initiated by a copper-free
Pd-catalyzed alkynylation in a one-pot fashion. The reaction sequence proceeds under mild reaction con-
ditions and in moderate to good yields with a broad scope of diversity.
DOI: 10.1039/c3ob41269e
www.rsc.org/obc
we reasoned that a three-component synthesis of 2-substituted
3-acylpyrroles should be readily accessible. Furthermore, our
Introduction
Pyrroles1 are the basis of many pharmacologically active natural just recently developed copper-free catalytic alkynylation as an
products.2 In particular, 3-substituted derivatives are found in entry to ynones22 sets the stage for this endeavor and here we
a wide variety of medicinal and agrochemical applications, such report a novel consecutive one-pot three-component synthesis
as efficient inhibitors of histone deacetylase,3 HIV-1 transcrip- of 2-substituted 3-acylpyrroles.
tase,4 and COX-1/COX-2 cyclooxygenases.5 Furthermore, per-
substituted pyrroles are potent hypocholesterolemic agents
inhibiting HMG-CoA reductase, a key enzyme in the biosyn-
thesis of cholesterol.6 Besides a wide range of applications in
medicinal chemistry pyrroles are also found to be electroni-
cally polarizable and oxidizable building blocks for polymeric
and supramolecular structures for applications in nonlinear
optics.7
Results and discussion
The retrosynthetic analysis of functionalized 3-acylpyrroles 1
(Scheme 1) suggests the corresponding N-(2,2-diethoxyethyl)-
3-aminoalk-2-en-1-ones
2 as intermediates according to
Langer’s synthesis.11 These enaminones can be directly dis-
connected to alkynones 3 and aminoacetaldehyde diethylacetal
(4) via a retro-Michael step. The alkynones 3 stem from cataly-
tic alkynylation of acid chlorides 5 with terminal alkynes
6 (Scheme 1).
The most common methods rely on classical condensation
reactions, such as the Hantzsch,8 the Paal–Knorr,9 and the
Knorr pyrrole syntheses.10 In addition, many uni- and bimole-
cular pyrrole syntheses have been established.11–13 However, in
recent years multicomponent approaches have been developed
and promise very efficient, diversity oriented accesses to
this important class of heterocycle.14–16 Interestingly, only
very few examples of 2-substituted 3-acylpyrroles are known.
After the first example of a 3-trifluoracetyl pyrrole in 1992,17
it was not until 2005 that Langer established a general
route to 3-acylpyrroles.18 Most interestingly, in this approach
specifically substituted enaminones are directly transformed
into 2-substituted 3-acylpyrroles.
Recently, we scouted, identified and optimized a copper-free
Pd-catalyst system23 for an efficient alkynone formation
from acid chlorides 5 and terminal alkynes 6,22 which allows
for a very flexible choice of solvents and still retains the advan-
tages of the modified Sonogashira coupling.19 The copper-free
Based upon our catalytic access to ynones19 and their
one-pot transformation into enaminones20 and heterocycles21
Lehrstuhl für Organische Chemie, Institut für Organische Chemie und
Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße
1, D-40225 Düsseldorf, Germany. E-mail: ThomasJJ.Mueller@uni-duesseldorf.de;
Fax: +49 (0)2118114324; Tel: +49 (0)211 8112298
†Electronic supplementary information (ESI) available: Experimental details of
the syntheses and analytical details of the compounds 1. See DOI: 10.1039/
c3ob41269e
Scheme 1 Retrosynthetic analysis and multicomponent synthetic concept for a
coupling–addition–cyclocondensation synthesis of 2-substituted 3-acylpyrroles 1.
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Table 1 Optimization study for the preparation of (2-chlorophenyl)(2-phenyl-
1H-pyrrol-3-yl)methanone (1a)
Brønsted or Lewis acid
Entry (equivalents)
T
t
Yield of 1aa
1
2
3
Trifluoroacetic acid (TFA) (10.0) rt
4 h
6 h
23 h
11%
9%
5%
TFA (10.0)
0 °C
rt
TFA (5.0)
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
CH3COOH (10.0)
HCOOH (10.0)
Dichloroacetic acid (DCA) (10.0) rt
DCA (10.0)
DCA (10.0)
TMSOTf (1.0)
TMSOTf (1.0)
FeCl3 (0.2)
40 °C 24 h
40 °C 24 h
—
12%
5%
15%
9%
—
4.5 h
4 h
4 h
40 °C
30 °C
0 °C 24 h
rt
rt
24 h
24 h
18 h
23 h
—
—
pTolSO3H·H2O (PTSA·H2O) (2.5) rt
53%
33%
51%
62%
59%
59%
50%
Scheme 2 Model reaction for the optimization of the one-pot CACS synthesis
of the 3-acylpyrrole 1a.
MeSO3H (2.6)
MeSO3H (2.0)
MeSO3H (2.0)
MeSO3H (2.0)
MeSO3H (1.5)
MeSO3H (3.0)
rt
30 °C 17 h
40 °C 16 h
50 °C 23 h
40 °C 24 h
40 °C
4 h
catalyst system consists of 1 mol% of PdCl2 and 2 mol% di-
(1-adamantyl)-benzyl-phosphonium bromide (cataCXium®
ABn·HBr)24 in connection with reagent grade triethylamine as
a base providing quantitative conversion within 24 h at room
temperature depending on the substrate structures. Dichloro-
methane was chosen as a solvent for the complete reaction
sequence, as in the final step the acetal should be activated by
means of Brønsted or Lewis acid catalysis.
a All yields refer to isolated and purified products.
For the optimization of the novel coupling–addition–cyclo-
condensation sequence (CACS) a model system was chosen
(Scheme 2). Upon reacting one equivalent of 2-chlorobenzoyl
chloride (5a) and one equivalent of phenylacetylene (6a) under
copper-free alkynylation conditions at room temperature15 the
intermediate alkynone 3a was obtained within 2 h (monitored
by TLC). Then, 1.03 equivalents of aminoacetaldehyde diethyl-
acetal (4) were added to the reaction mixture and the alkynone
3a was quantitatively converted into the corresponding
β-enaminone 2a within 16 h at 40 °C (monitored by TLC). For
the optimization of the terminal cyclocondensation step
various Brønsted and Lewis acids were tested in the sequence
for furnishing the highest overall yields (Table 1).
First, Langer’s conditions of the cyclocondensation were
applied in the terminal reaction step at 0 °C and at room temp-
erature (Table 1, entries 1 and 2). According to TLC a full con-
version of the β-enaminone 2a was achieved at 0 °C after 6 h
and at room temperature after 4 h; however, the isolated yields
of the target compound 1a were only 9 and 11%, respectively.
Reducing the amount of trifluoroacetic acid (TFA) to 5 equi-
valents showed no improvement in yield, although a quantitative
conversion of 2a was first observed after 23 h (Table 1, entry 3).
Since TFA is a relatively strong acid (pKa (water) ∼ 0.23)25 other
carboxylic acids, such as acetic acid (pKa (water) ∼ 4.76),25
formic acid (pKa (water) ∼ 3.77),26 and dichloroacetic acid (pKa
(water) ∼ 1.29),25 were screened next (Table 1, entries 4–8). In
neither case could a substantial increase of the yield of com-
pound 1a be achieved. The attempted cyclocondensation with
acetic acid at 40 °C (oil bath) for 24 h eventually led to the
complete recovery of β-enaminone 2a (Table 1, entry 4). The
Scheme 3 Acid catalyzed hydrolysis of β-enaminone 2a to give the β-hydroxy
enone 7.
application of the Lewis acids trimethylsilyltriflate (TMSOTf)
and iron(III) chloride at 0 °C and at room temperature for 24 h
also proved to be unsuccessful (Table 1, entries 9–11).
When p-toluenesulfonic acid monohydrate (PTSA·H2O) was
employed in the final cyclisation step after 18 h at room temp-
erature, an overall yield of 53% of 1a was isolated (Table 1,
entry 12). However, as a drawback the chemically bound water
of PTSA caused a partial hydrolysis of the β-enaminone 2a to
give (Z)-1-(2-chlorophenyl)-3-hydroxy-3-phenylprop-2-en-1-one
(7) as a byproduct (Scheme 3).27
Therefore, methanesulfonic acid (MeSO3H), a similarly
strong acid as PTSA·H2O (pKa ∼ −1.9), was chosen.28 Upon
addition of 2 equivalents of MeSO3H in the final step at room
temperature for 24 h a 33% overall yield of 1a was isolated
after column chromatography (Table 1, entry 13). At slightly
elevated temperatures (30 or 40 °C oil bath) the isolated yields
of 1a could be raised to 51 and 62% (Table 1, entries 14 and
15). A further increase of the temperature did not give an
additional increase of yields (Table 1, entry 16). Finally the
employed equivalents of MeSO3H were varied. While
a
reduction to 1.5 equivalents had no particular changes in
yields (Table 1, entry 17), the addition of 3 equivalents of
MeSO3H let the reaction progress significantly faster; however,
only a 50% overall yield of compound 1a could be isolated
(Table 1, entry 18).
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Table 2 Variation of acid chloride 5 in the three-component CACS synthesis of
2-substituted 3-acylpyrroles 1a
3-Acylpyrrole
Entry Acid chloride 5
Alkyne 6
1 (yield)b
1
2
R1 = o-ClC6H4 (5a)
R2 = Ph (6a)
Scheme 4 Variation of acid chloride 5 and alkyne 6 in the three-component
CACS synthesis of 2-substituted 3-acylpyrroles 1.
1a (62%)c
With this optimized protocol of a copper-free coupling–
addition–cyclocondensation sequence (CACS) in hand we
investigated the scope and limitations for this novel one-pot
synthesis of 2-substituted 3-acylpyrroles 1 and the variations of
the acid chlorides 5 and the alkynes 6 were studied (Scheme 4,
Tables 2 and 3).
R1 = o-FC6H4 (5b)
6a
1b (50%)c
1c (20%)d
1d (11%)d
3
4
5
R1 = p-FC6H4 (5c)
R1 = p-MeC6H4 (5d)
R1 = m-MeC6H4 (5e)
6a
6a
6a
As previously reported the alkynone formation is strongly
dependent on the electronic nature of the acid chlorides 5;
therefore, the quantitative coupling proceeds in a range of
2–19 h.22 In addition to aroyl acid chlorides 5a–j also hetero-
aroyl chlorides 5k–n were successfully employed. With phenyl-
acetylene (6a) as an alkyne component the corresponding
3-acylpyrroles 1a–n were all isolated in moderate to excellent
yields (11–73%) (Table 2). Interestingly, the overall yields are
strongly dependent on the used aroyl chlorides 5. The yields of
1 dropped significantly to 11–30% (Table 2, entries 3, 4, and 7)
for electron-donating or slightly electron-withdrawing substitu-
ents in the para-position of the aroyl chloride. In contrast,
strongly electron-withdrawing groups resulted in higher yields
(Table 2, entries 8 and 9). The highest overall yields were
obtained for ortho-halo-substituted aroyl chlorides. Therefore,
it can be concluded that the electronic and stereoelectronic
effect of the acid chloride 5 is crucial in the terminal step
of the sequence, i.e. the acid catalyzed cyclocondensation.
A strongly electron-withdrawing substituted enaminone is
obviously stronger polarized in the ground state. The enami-
nones 2 decompose more rapidly upon addition of methane-
sulfonic acid when more electron-rich acid chlorides 15 are
employed.
For the variation of the alkynes 6 the acid chloride com-
ponent 1j was kept constant (Table 3). The nature of the
alkyne affects the rate of the initial coupling.15 While the aro-
matic alkynes were fully consumed between 3 and 6 h (Table 3,
entries 1–7), the aliphatic alkynes required a longer reaction
time. Therefore, the coupling step was performed for
14–15.5 h, i.e. overnight (Table 3, entries 8 and 9). The corres-
ponding 2-substituted 3-acylpyrroles 1o–w were isolated in
moderate to good yields (Table 3). The electronic effect of the
substituents of the alkynes also affects the acid induced cyclo-
condensation reaction. While aliphatic substituents (Table 3,
entries 8 and 9) furnish moderate yields of 30 and 46%,
aromatic substituents give yields ranging from 21 to 69%
(Table 3, entries 1–7). Electron-donating substituents in the
para-position gave the same results as the electron neutral
phenyl substituent (Table 3, entries 1 and 2 and Table 2, entry
10). Although the cyano substituent furnished a yield of 65%
(Table 3, entry 3), the nitro substituent only gave rise to a
1e (20%)d
6
R1 = o-MeC6H4 (5f)
6a
1f (26%)d
1g (30%)d
1h (43%)d
7
8
9
R1 = Ph (5g)
6a
6a
6a
R1 = p-O2NC6H4 (5h)
R1 = 2-Cl-4-O2NC6H3 (5i)
1i (50%)c
1j (59%)c
10
11
R1 = 2,4-Cl2C6H3 (5j)
R1 = 2-Pyrid-5-yl (5k)
6a
6a
1k (43%)d
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Table 2 (Contd.)
Table 3 Variation of alkyne 6 in the three-component CACS synthesis of 2-sub-
stituted 3-acylpyrroles 1a
3-Acylpyrrole
Entry Acid chloride 5
Alkyne 6
1 (yield)b
3-Acylpyrrole
R1 = 2-Pyrid-3-yl (5l)
6a
Entry
1
Acid chloride 5
Alkyne 6
1 (yield)b
12
13
14
5j
R2 = p-tBuC6H4 (6b)
1l (57%)c
R1 = 2-Cl-6-Me-pyrid-3-yl (5m) 6a
1o (59%)c
2
3
4
5
5j
5j
5j
5j
R2 = p-MeC6H4 (6c)
R2 = p-NCC6H4 (6d)
R2 = p-O2NC6H4 (6e)
R2 = o-FC6H4 (6f)
1m (73%)c
1n (36%)c
R1 = 2-Thienyl (5n)
6a
1p (55%)c
1q (65%)d
1r (21%)d
a All reactions were carried out on a 2 mmol scale (c0(5) = c0(6) = 1.0
M). b All yields refer to isolated and purified products. c The coupling
step was performed at room temperature in 2–5 h. d The coupling
reaction was performed at room temperature in 18–19 h.
moderate yield of 21% (Table 3, entry 4). Obviously, side reac-
tions of the intermediate β-enaminone 2 occurred in this case
since an unidentified red product formed during column
chromatography could not be eluted from the column.
Upon upscaling to 20 mmol, we noticed that the coupling
reaction between acid chloride 5j and terminal alkyne 6a
proceeds with a catalyst loading of 0.25 mol% of PdCl2
and 0.5 mol% di-(1-adamantyl)-benzyl-phosphonium bromide
(cataCXium® ABn·HBr) within the same reaction time.
Furthermore, methanesulfonic acid was lowered from 2 to
1.5 equivalents. The overall yield of (2,4-dichlorophenyl)-
(2-phenyl-1H-pyrrol-3-yl)methanone (1j) on a 20 mmol scale
was found to be 57% (Scheme 5), almost identical to the yield
of the 2 mmol scale, but the latter with a higher catalyst
loading (Table 2, entry 10).
1s (69%)c
6
5j
R2 = m-FC6H4 (6g)
1t (33%)c
1u (39%)c
1v (30%)e
1w (46%)f
7
8
9
5j
5j
5j
R2 = p-FC6H4 (6h)
R2 = nBu (6i)
Conclusions
In conclusion we have developed a straightforward novel three-
component synthesis of 2-substituted 3-acylpyrroles in a
modular fashion. The sequence proceeds with easily available
starting materials, which are consequently used in a strictly
stoichiometric fashion, and under fairly mild reaction con-
ditions of all three steps of the one-pot sequence. Further-
more, upon upscaling, the amount of the catalyst for the
coupling step could be critically reduced into the 0.25 mol%
regime; hence, the cost expensive palladium source will not
R2 = Cyclopropyl (6g)
a All reactions were carried out on a 2 mmol scale (c0(5) = c0(6) = 1.0
have to be used in large quantities. Only the electron rich aroyl M). b All yields refer to isolated and purified products. c The coupling
chlorides furnish overall moderate yields. Nonetheless, with
these unparalleled mild reaction conditions and the overall
step was performed at room temperature in 3–4 h. d The coupling
reaction was performed at room temperature in 5–6 h. e The coupling
reaction was performed at room temperature in 15.5 h. f The coupling
efficient one-pot multistep synthesis in hand two points of reaction was performed at room temperature in 14 h.
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689 (s), 677 (m), 654 (m), 613 (w). Anal. calcd for C17H12FNO
(265.3): C 76.97, H 4.56, N 5.28; Found: C 76.77, H 4.75,
N 5.03.
Acknowledgements
Scheme 5 CACS synthesis of (2,4-dichlorophenyl)(2-phenyl-1H-pyrrol-3-yl)
methanone (6j) on a 20 mmol scale.
The authors cordially thank the Fonds der Chemischen Indus-
trie for financial support.
diversity could be readily explored. Now the stage is set for
further methodological extensions towards differently N-sub-
stituted aminoacetaldehyde diethylacetals in the Michael step,
which should furnish N-substituted 3-acylpyrrole analogues.
These studies are currently underway.
Notes and references
1 J. Bergman and T. Janosik, Five-Membered Heterocycles:
Pyrrole and Related Systems, in Modern Heterocyclic
Chemistry, ed. J. Alvarez-Builla, J. J. Vaquero and
J. Barluenga, Wiley-VCH, Weinheim, 2011, vol. 1, p. 269;
R. A. Jones, The Chemistry of Heterocyclic Compounds, John
Wiley & Sons. Inc., New York, 1992, vol. 48, part 2;
R. A. Jones and G. P. Bean, The chemistry of pyrroles,
Academic Press, London, 1977; A. Gossauer, Die Chemie der
Pyrrole, Springer Verlag, Berlin, 1974, vol. 47, p. 1098.
2 I. S. Young, P. D. Thornton and A. Thompson, Nat. Prod.
Rep., 2010, 27, 1801; M. d’Ischia, A. Napolitano and
A. Pezzella, Pyrroles and their Benzo Derivatives: Appli-
cations, in Comprehensive Heterocyclic Chemistry III,
Elsevier, Amsterdam, 2008, p. 353; C. T. Walsh, S. Garneau-
Tsodikova and A. R. Howard-Jones, Nat. Prod. Rep., 2006,
23, 517; J. T. Gupton, Top. Heterocyclic Chem., 2006, 2, 53;
H. Falk, The Chemistry of Linear Oligopyrroles and Bile
Pigments, Springer, New York, 1989; R. J. Sundberg,
Pyrroles and their Benzo Derivatives: (iii) Synthesis and
Applications, in Comprehensive Heterocyclic Chemistry, ed.
A. R. Katritzky and C. W. Rees, Pergamon, Oxford, 1984,
vol. 4, p. 313.
Experimental
Typical procedure for the three-component synthesis of
(2-chlorophenyl)(2-phenyl-1H-pyrrol-3-yl)methanone (1b)
Palladium(II) chloride (3.5 mg, 0.02 mmol, 1.0 mol%) and di-
(1-adamantyl)benzylphosphonium hydrobromide (18.9 mg,
0.04 mmol, 2.0 mol%) were placed in a dry Schlenk tube under
an argon atmosphere and dry dichloromethane (2 mL) was
added. 2-Fluorobenzoyl chloride (5b) (360 mg, 2.00 mmol),
phenylacetylene (6a) (209 mg, 2.00 mmol), and reagent grade
triethylamine (0.30 mL, 2.15 mmol) were added to the
mixture, and stirring at room temperature was continued
for 2 h until complete conversion (monitored by TLC). Then,
aminoacetaldehyde diethylacetal (4) (281 mg, 2.07 mmol) was
added and the reaction mixture was stirred for 16 h at 40 °C
(oil bath). Then, the reaction mixture was allowed to cool to
room temperature and methanesulfonic acid (401 mg,
4.13 mmol) was successively added. After stirring for 24 h
at 40 °C (oil bath) the reaction mixture was allowed to cool to
room temperature. The solvents were removed in vacuo and
the residue was purified by flash chromatography on silica gel
(n hexane–ethyl acetate 4 : 1) to give compound 1b as a brown-
ish red solid (265 mg, 50% yield). M.p. 118 °C; 1H NMR
(600 MHz, DMSO-d6, rt): δ = 6.33 (t, J = 2.6 Hz, 1 H), 6.90 (t, J =
2.7 Hz, 1 H), 7.08–7.12 (m, 1 H), 7.15 (t, J = 7.4 Hz, 1 H),
7.25–7.31 (m, 3 H), 7.37–7.43 (m, 2 H), 7.44–7.47 (m, 2 H),
11.87 (s, 1 H). 13C NMR (150 MHz, DMSO-d6, rt): δ = 112.4
3 A. Mai, S. Massa, I. Cerbara, S. Valente, R. Ragno,
P. Bottoni, R. Scatena, P. Loidl and G. Brosch, J. Med.
Chem., 2004, 47, 1098.
4 T. Antonucci, J. S. Warmus, J. C. Hodges and D. G. Nickell,
Antiviral Chem. Chemother., 1995, 6, 98.
5 G. Dannhardt, W. Kiefer, G. Krämer, S. Maehrlein, U. Nowe
and B. Fiebich, Eur. J. Med. Chem., 2000, 35, 499.
6 J. M. Holub, K. O’Toole-Colin, A. Getzel, A. Argenti,
M. A. Evans, D. C. Smith, G. A. Dalglish, S. Rifat,
D. L. Wilson, B. M. Taylor, U. Miott, J. Glersaye, K. Suet
Lam, B. J. McCranor, J. D. Berkowitz, R. B. Miller,
J. R. Lukens, K. Krumpe, J. T. Gupton and B. S. Burnham,
Molecules, 2004, 9, 134.
7 S. Venkatraman, R. Kumar, J. Sankar, T. K. Chandrashekar,
K. Sendhil, C. Vijayan, A. Kelling and M. O. Senge,
Chem.–Eur. J., 2004, 10, 1423; A. Facchetti, A. Abbotto,
L. Beverina, M. E. van der Boom, P. Dutta, G. Evmenenko,
G. A. Pagani and T. J. Marks, Chem. Mater., 2003, 15, 1064.
8 A. Hantzsch, Chem. Ber., 1890, 21(1), 1474; M. W. Roomi
and S. F. MacDonald, Can. J. Chem., 1970, 4, 1689.
2
(CH), 115.6 (d, JC–F = 21.6 Hz, CH), 119.0 (CH), 120.6 (Cquat),
3
124.0 (d, JC–F = 3.1 Hz, CH), 127.7 (2 CH), 127.8 (CH), 128.9
(2 CH), 129.6 (d, 2JC–F = 15.5 Hz, Cquat), 129.8 (d, 3JC–F = 3.2 Hz,
4
CH), 131.7 (Cquat), 131.9 (d, JC–F = 8.3 Hz, CH), 137.4 (Cquat),
1
158.8 (d, JC–F = 247.8 Hz, Cquat), 187.3 (Cquat). EI+MS
(m/z (%)): 265.1 ([M+], 67), 170.1 ([M+ − C6H4F], 100), 142.1
([M+
([M+
−
−
C7H4FO], 8), 123.0 ([M+
−
C10H8N], 9), 115.1
C8H6FNO], 59), 95.0 ([M+
−
C11H8NO], 23).
IR (diamond): ˜ν [cm−1] = 3233 (ν (N–H), m), 3109 (w), 2988 (m),
2972 (m), 2901 (m), 2795 (w), 1620 (s), 1609 (ν (CvO), s),
1578 (w), 1558 (w), 1474 (s), 1452 (s), 1431 (s), 1396 (s),
1362 (w), 1306 (m), 1290 (w), 1267 (w), 1225 (m), 1211 (w),
1177 (w), 1152 (w), 1101 (m), 1076 (m), 1057 (m), 999 (w),
901 (m), 885 (s), 812 (m), 787 (w), 756 (s), 739 (w), 721 (m),
9 C. Paal, Chem. Ber., 1885, 18, 367; L. Knorr, Chem. Ber.,
1885, 18, 299.
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10 L. Knorr, Chem. Ber., 1884, 17, 1635; L. Knorr, Justus Liebigs 17 E. Okada, R. Masuda, M. Hojo and R. Inoue, Synthesis,
Ann. Chem., 1886, 236, 290; L. Knorr and H. Lange, Chem.
Ber., 1902, 35, 2998.
1992, 533.
18 E. Bellur and P. Langer, Tetrahedron Lett., 2006, 47, 2151;
E. Bellur, M. A. Yawer, I. Hussain, A. Riahi, O. Fatunsin
and C. Fischer, Synthesis, 2009, 227.
19 A. S. Karpov and T. J. J. Müller, Org. Lett., 2003, 5, 3451;
D. M. D’Souza and T. J. J. Müller, Nat. Protoc., 2008, 3,
1660.
11 For an overview: J. Bergman and T. Janosik, Pyrroles and
their Benzo Derivatives: Synthesis, in Comprehensive Hetero-
cyclic Chemistry III, Elsevier, Amsterdam, 2008, p. 269.
12 For an example of a unimolecular pyrrole synthesis see e.g.:
S. Cacchi, G. Fabrizi and E. Filisti, Org. Lett., 2008, 10,
2629.
20 A. S. Karpov and T. J. J. Müller, Synthesis, 2003, 2815.
13 For examples of bimolecular pyrrole syntheses see: 21 For reviews, see: T. J. J. Müller, Top. Heterocycl. Chem.,
S. Chiba, Y.-F. Wang, G. Lapointe and K. Narasaka, Org.
Lett., 2008, 10, 313; J. T. Binder and S. F. Kirsch, Org. Lett.,
2006, 8, 2151; G. Minetto, L. F. Raveglia, A. Sega and
M. Taddei, Eur. J. Org. Chem., 2005, 5277; O. V. Larionov
and A. de Meijere, Angew. Chem., Int. Ed., 2005, 44, 5664.
2010, 25, 25; B. Willy and T. J. J. Müller, Curr. Org. Chem.,
2009, 13, 1777; B. Willy and T. J. J. Müller, ARKIVOC, 2008,
Part I, 195; D. M. D’Souza and T. J. J. Müller, Chem. Soc.
Rev., 2007, 36, 1095; T. J. J. Müller, Targets Heterocycl. Syst.,
2006, 10, 54.
14 For reviews, see e.g.: V. Estevez, M. Villacampa and 22 J. Nordmann, N. Breuer and T. J. J. Müller, Eur. J. Org.
J. C. Menendez, Chem. Soc. Rev., 2010, 39, 4402; G. Balme,
Angew. Chem., Int. Ed., 2004, 43, 6238.
Chem., 2013, 4303.
23 For examples of copper-free Sonogashira-couplings see:
D. A. Alonso, C. Nájera and M. C. Pacheco, J. Org. Chem.,
2004, 69, 1615; P. R. Likhar, M. S. Subhas, M. Roy, S. Roy
and M. L. Kantam, Helv. Chim. Acta, 2008, 91, 259;
F. C. Fuchs, G. A. Eller and W. Holzer, Molecules, 2009, 14,
3814; R. Chinchilla and C. Nájera, Chem. Soc. Rev., 2011,
40, 5084; S. Atobe, H. Masuno, M. Sonoda, Y. Suzuki,
H. Shinohara, S. Shibata and A. Ogawa, Tetrahedron Lett.,
2012, 53, 1764.
15 For selected examples of multicomponent pyrrole synth-
eses see: A. A. Fesenko and A. D. Shutalev, J. Org. Chem.,
2013, 78, 1190; B. Das, N. Bhunia and M. Lingaiah,
Synthesis, 2011, 3471; S. Maiti, S. Biswas and U. Jana,
J. Org. Chem., 2010, 75, 1674; B. Das, G. C. Reddy,
P. Balasubramanyam and B. Veeranjaneyulu, Synthesis,
2010, 1625; P. Fontaine, G. Masson and J. Zhu, Org. Lett.,
2009, 11, 1555; I. Yavari and E. Kowsari, Synlett, 2008, 897;
D. J. St. Cyr, N. Martin and B. A. Arndtsen, Org. Lett., 2007, 24 For a seminal work and a review on Beller’s ligand
9, 449; D. Tejedor, D. González-Cruz, F. García-Tellado,
J. J. Marrero-Tellado and M. L. Rodríguez, J. Am. Chem.
Soc., 2004, 126, 8390; R. Dhawan and B. A. Arndtsen, J. Am.
Chem. Soc., 2004, 126, 468. For reviews, see e.g.: M. Viciano-
Chumillas, S. Tanase and L. J. de Jongh, Eur. J. Inorg.
Chem., 2010, 22, 3403; S. Trofimenko, Polyhedron, 2004, 23,
cataCXium® ABn·HBr, see e.g.: A. Zapf, A. Ehrentraut and
M. Beller, Angew. Chem., Int. Ed., 2000, 39, 4153;
C. A. Fleckenstein and H. Plenio, Chem. Soc. Rev., 2010, 39,
694; For examples of alkynylations see: A. Kollhofer,
T. Pullmann and H. Plenio, Angew. Chem., Int. Ed., 2003,
42, 1056; H. Plenio, Angew. Chem., Int. Ed., 2008, 47, 6954.
197; M. D. Ward, J. A. McCleverty and J. C. Jeffrey, Coord. 25 J. F. J. Dippy, S. R. C. Hughes and A. Rozanski, J. Am. Chem.
Chem. Rev., 2001, 222, 251; R. Mukherjee, Coord. Chem. Soc., 1959, 81, 2492.
Rev., 2000, 203, 151; S. Trofimenko, Chem. Rev., 1972, 72, 26 H. C. Brown, et al., in Determination of Organic Structures
497.
by Physical Methods, ed. E. A. Braude and F. C. Nachod,
16 For multicomponent pyrrole syntheses from our group,
Academic Press, New York, 1955.
see: E. Merkul, C. Boersch, W. Frank and T. J. J. Müller, 27 Product was identified with the help of recorded mass- and
Org. Lett., 2009, 11, 2269; R. U. Braun, K. Zeitler and
T. J. J. Müller, Org. Lett., 2001, 3, 3297.
NMR-spectra.
28 J. P. Guthrie, Can. J. Chem., 1978, 56, 2342.
Org. Biomol. Chem.
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