One-pot AgOAc-mediated synthesis of polysubstituted pyrroles from primary amines and aldehydes: Application to the total synthesis of purpurone

Article abstract of DOI:10.1021/ol101644g

A simple and efficient method for the synthesis of 1,3,4-trisubstituted or 3,4-disubstituted pyrroles has been developed. The reaction represents the first time that pyrroles are synthesized directly from readily available aldehydes and amines (anilines)

Full text of DOI:10.1021/ol101644g

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4066-4069
One-Pot AgOAc-Mediated Synthesis of
Polysubstituted Pyrroles from Primary
Amines and Aldehydes: Application to
the Total Synthesis of Purpurone
Qingjiang Li,† Aili Fan,† Zhiyao Lu,† Yuxin Cui,† Wenhan Lin,† and
Yanxing Jia*,†,‡
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking UniVersity, 38 Xueyuan Road, Beijing 100191, China, and State Key
Laboratory of Drug Research, Shanghai Institute of Materia Media, Chinese Academy
of Sciences, Shanghai 201203, China
yxjia@bjmu.edu.cn
Received July 16, 2010
ABSTRACT
A simple and efficient method for the synthesis of 1,3,4-trisubstituted or 3,4-disubstituted pyrroles has been developed. The reaction represents
the first time that pyrroles are synthesized directly from readily available aldehydes and amines (anilines) as starting materials. This method
has been successfully applied to the rapid synthesis of purpurone.
The pyrrole nucleus is one of the most important hetero-
cycles since it is not only found in many natural products1
and bioactive molecules2 but also broadly used in material
science and supramolecular chemistry.3 Accordingly, a
variety of well-documented traditional and modern meth-
ods have been developed for the construction of pyrroles
and their derivatives.4,5 However, there are very few general
approaches that convert commercially available or readily
accessible materials in one step to polysubstituted pyrroles.
Therefore, a more flexible and general approach from simple
and easily accessible starting materials is still of critical
importance. It is also noteworthy that the 3,4-disubstituted
pyrrole system is probably the most difficult to obtain since
selective substitutions at one or more of the ꢀ-positions have
been a challenging goal in many synthetic programs.
Functionalizations of pyrrole-N systems also suffered from
a lack of selectivity and significant polymerization.6
† Peking University.
‡ State Key Laboratory of Drug Research.
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10.1021/ol101644g  2010 American Chemical Society
Published on Web 08/24/2010

Oxidative homodimerization of enamino ketones or esters
for the synthesis of pyrrole has been described in the literature
under electrochemical conditions7 or by using Pb(OAc)4,8
Ce(IV),9 and PhI(OAc)210 as the oxidants (Scheme 1a). How-
indole using o-halo-aniline with aldehyde via an enamine
intermediate,15 we recently questioned whether the pyrrole
product could be obtained via oxidative homodimerization
of the enamine intermediate, formed in situ by reaction of
amine (aniline) and aldehyde, with an appropriate oxidant
(Scheme 1b). Herein, we demonstrate the first efficient and
direct approach to polysubstituted pyrroles from simple and
readily available amine (aniline) and aldehyde by using
AgOAc as the oxidant in a one-pot manner.
Scheme 1. (a) Homodimerization of the Enamino Ketones or
Esters and (b) Homodimerization of Enamines Formed in Situ
Drectly from Simple Amines and Aldehydes
To test this activation concept, reaction of 4-methoxya-
niline 1a with butylaldehyde 2a was initially attempted under
oxidative conditions [Pd(OAc)2 (5 mol %), Cu(OAc)2 (2
equiv), AgOAc (2 equiv)]. Gratifyingly, the pyrrole product
3a was obtained in 24% yield as the only detectable product.
A condition survey quickly revealed that Pd(OAc)2 and
Cu(OAc)2 were not necessary, and AgOAc (2 equiv) alone
could promote this reaction well (see Supporting Informa-
tion). In addition, the use of equivalent amounts of amine
and aldehyde was crucial for obtaining good yield (see
Scheme 2). A wide variety of reaction conditions (silver
ever, the substrates are limited to enamino ketones or esters,
and these must be prepared before use.7-10 The oxidative
homodimerization of aldehyde enamine has never been
reported.11 In fact, pure aldehyde enamines are rarely
employed in organic synthesis due to the limitations of their
preparation and the isolation restrictions.12
Scheme 2. Proposed Mechanism for the Transformations
Recently, oxidative coupling reactions have proven to be
excellent and efficient methods for formation of C-C
bonds.13,14 In connection with our work for preparation of
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of Pyrroles; Academic Press: London, 1977.
source oxidants, solvents, and additives) were also examined,
and some of the representative results are shown in Table 1.
AgOAc turned out to be the oxidant of choice, albeit Ag2CO3
was also capable of promoting the reaction but with lower
yield (entries 1-4). The solvent also played a very important
role in this reaction (entries 1 and 6-8). Further studies
indicated that the addition of a base such as pyridine or
NaOAc dramatically increased the yield of 3a (entries
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Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan,
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Org. Lett., Vol. 12, No. 18, 2010
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Table 1. Optimization of the Reaction Conditionsa
entry
oxidant
AgOAc
AgBF4
Ag2CO3
AgCO2CF3
solvent
THF
THF
THF
THF
additive yield (%)b
1
-
-
49
0
2
3c
4
-
-
-
-
-
21
0
5
6
7
8
Mn(OAc)3·2H2O THF
12
20
19
10
35
66
72
74
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
1,4-dioxane
ClCH2CH2Cl
DMF
THF
THF
-
9
L-proline
pyridine
NaOAc
NaOAc
10d
11
12e
THF
THF
a General reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), oxidant
(1.0 mmol), additive (1.0 mmol), solvent (2.5 mL), 60 °C, 8 h. b Yields
determined by GC analysis. c Ag2CO3 (1.0 equiv) was employed. d Pyridine
(0.25 mL) was employed. e rt for 0.5 h, then 60 °C for 8 h.
10-12), and it was proposed that the base would neutralize
the acid formed during the reaction (see Scheme 2).
Having established the optimal reaction conditions, the scope
of this reaction was examined with respect to the aldehydes
and amines. As illustrated in Figure 1, the transformation was
found to be very general. A diverse set of aldehydes are suitable
reaction partners (3a-3g). However, the reaction is quite
sensitive to the electronic contribution of substituents on the
benzene ring of anilines. Only anilines with electron-donating
and electron-neutral substituents provide the desired pyrroles
in reasonable yield (3h-3o). Steric hindrance at the 2-position
of anilines is tolerated well (3j, 3l, and 3m). In addition, all the
tested aliphatic amines, including sterically hindered cases, prove
to be suitable partners (3p-3u). Most notably, the desired
pyrrole is also formed by using NH3 as a reaction partner, albeit
in lower yield (25%) (3v).
With the successful synthesis of symmetric pyrroles,
attempts were next made to prepare asymmetric pyrroles by
reaction of amine with two different aldehydes. However,
no selectivity was observed. For example, reaction of
4-methoxyaniline 1a with heptanal 2d and methyl 6-oxo-
hexanoate 2e gave pyrroles 3d, 3e, and 3de in the yield of
20%, 14%, and 14%, respectively [eq 1].
Figure 1. Scope of the AgOAc-mediated oxidative coupling of
a
amine 1 and aldehyde 2. 2-Chloroethylamine hydrochloride was
b
used; AgOAc (3 equiv) and NaOAc (3 equiv) were employed. A
c
condenser was needed. An NH3 balloon was used.
Reaction of amine 1 with aldehyde 2 rapidly produces imine
4, which equilibrates to enamine 5. A one-electron oxidation
of a transient enamine species 5 with AgOAc generates an
R-imine radical cation 6. At this stage, 6 can undergo self-
coupling to give the diimine 7 (path a).7,8,11,16 Alternatively,
6 can also suffer attack by another enamine 5 resulting in a
(16) (a) Fritsch, J. M.; Weingarten, H.; Wilson, J. D. J. Am. Chem. Soc.
1970, 92, 4038–4046. (b) Weingarten, H.; Wager, J. S. J. Org. Chem. 1970,
A plausible mechanism for this multicomponent oxidative
coupling reaction was hypothesized as shown in Scheme 2.
35, 1750–1753
.
4068
Org. Lett., Vol. 12, No. 18, 2010

radical cation 8, which is then further oxidized by AgOAc
to produce 7 (path b).13 Finally, aromatization of 7 affords
pyrrole 3 and one mole of amine 1.
which was then transformed to purpurone 12 following a
literature protocol reported by Steglich.19b
In summary, we have developed a simple and efficient
method for the synthesis of 1,3,4-trisubstituted or 3,4-
disubstituted pyrroles using a AgOAc-mediated oxidative
coupling reaction in a one-pot manner. The reaction repre-
sents the first time that pyrroles are synthesized directly from
simple, readily available aldehydes and amines (anilines) as
starting materials. Its utility can be seen in the rapid total
synthesis of purpurone. Broadening of the scope of this
reaction and the synthesis of biologically important lamellarin
derivatives and related compounds20 are in progress in our
laboratory and will be reported in due course.
Shi recently reported that phenethylamines could be
converted to pyrroles under oxidation conditions.5h Since it
is known that diphenethylamine can be produced by deami-
nation of phenethylamine, we believe that this transformation
takes the same reaction pathway with us.
The utility of this new process is demonstrated by a rapid
total synthesis of purpurone, a potent ATP-citrate lyase
(ACL) inhibitor,17 which belongs to a group of biologically
very important marine natural products (Scheme 3).18,19
Acknowledgment. This research was supported by the
National Basic Research Program of China (973 Program,
NO. 2010CB833200), the State Key Laboratory of Drug
Research, the National Natural Science Foundation of China
(Nos. 20972007, 20802005, 30930109), and NCET.
Scheme 3. Synthesis of Purpurone
Supporting Information Available: Detailed experimen-
tal procedures, compound characterization, and copies of
spectral data. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL101644G
(18) For reviews on lamellarins, see: (a) Fan, H.; Peng, J.; Hamann,
M. T.; Hu, J.-F. Chem. ReV. 2008, 108, 264–287. (b) Banwell, M. G.;
Goodwin, T. E.; Ng, S.; Smith, J. A.; Wong, D. J. Eur. J. Org. Chem.
2006, 3043–3060.
Treatment of aldehyde 9 with amine 10 under our optimized
conditions provided the desired pyrrole 11 in 59% yield,
(19) (a) Heim, A.; Terpin, A.; Steglich, W. Angew. Chem., Int. Ed. 1997,
36, 155–156. (b) Steglich, W.; Peschko, C. Tetrahedron Lett. 2000, 41,
9477–9481. (c) Hamasaki, A.; Zimpleman, J. M.; Hwang, I.; Boger, D. L.
J. Am. Chem. Soc. 2005, 127, 10767–10770. (d) Fu¨rstner, A.; Domostoj,
M. M.; Scheiper, B. J. Am. Chem. Soc. 2006, 128, 8087–8094.
(20) Fan, G.; Li, Z.; Shen, S.; Zeng, Y.; Yang, Y.; Xu, M.; Bruhn, T.;
Bruhn, H.; Morschha¨user, J.; Bringmann, G.; Lin, W. Bioorg. Med. Chem.
2010, 18, 5466–5474.
(17) (a) Chan, G. W.; Francis, T.; Thureen, D. R.; Offen, P. H.; Pierce,
N. J.; Westley, J. W.; Johnson, R. K.; Faulkner, D. J. J. Org. Chem. 1993,
58, 2544–2546. (b) Berkhout, T. A.; Havekes, L. M.; Pearce, N. J.; Groot,
P. H. E. Biochem. J. 1990, 272, 181–186.
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