Silver-catalysed hydroamination: Synthesis of functionalised pyrroles

Article abstract of DOI:10.1016/j.tetlet.2004.07.019

It has been shown that functionalised pyrroles can be efficiently prepared using a two-step sequence. This sequence involves the propargylation of secondary enaminones using n-BuLi and propargyl bromide, followed by intramolecular hydroamination catalysed by silver nitrate. The hydroamination can be carried out at room temperature (overnight) or in a domestic microwave oven (60 s).

Full text of DOI:10.1016/j.tetlet.2004.07.019

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6787–6789
Silver-catalysed hydroamination: synthesis of functionalised
pyrroles
Ross S. Robinson, Martin C. Dovey* and David Gravestock
Warren Research Laboratory, School of Chemistry, University of KwaZulu-Natal, Corner of Golf and Ridge Roads,
Private BagX01, Scottsville, Pietermaritzburg3209, South Africa
Received 2 June 2004; revised 29 June 2004; accepted 6July 2004
Available online 29 July 2004
Abstract—It has been shown that functionalised pyrroles can be efficiently prepared using a two-step sequence. This sequence
involves the propargylation of secondary enaminones using n-BuLi and propargyl bromide, followed by intramolecular hydro-
amination catalysed by silver nitrate. The hydroamination can be carried out at room temperature (overnight) or in a domestic
microwave oven (60s).
Ó 2004 Elsevier Ltd. All rights reserved.
Z
Hydroamination of unactivated carbon–carbon multiple
bonds is an active area of research in catalysis and or-
ganic synthesis and, as a result, has been reviewed exten-
sively in the literature in recent times.1 The vast majority
of work is concerned with the preparation of highly effi-
cient transition metal catalysts that are used to convert
simple amines to imines, enamines and alkylated amines.
These compounds constitute important bulk and fine
chemicals.1 Hydroamination has also been used as a
key step in several total syntheses although to a lesser
extent.2
Br
R
N
H
N
R
Z
AgNO3, one pot
1
2
Z = COMe, CO2Et
R = Me, Bu, Cy, Bn, Ph
Scheme 1.
be synthetically useful. In addition, insufficient under-
standing of the mechanism in operation has led to little
success in optimising these yields.
Hydroamination can be accomplished by amine or car-
bon–carbon multiple bond activation. Both strategies
employ metals to affect the activation.1 The most com-
monly used metals for this purpose are lanthanides, acti-
nides and those belonging to groups 4 and 10.1 Silver,
and other group 11 metals, have received far less atten-
tion and only a handful of methods have been published
using silver as a hydroamination catalyst.3
After further investigation, the following mechanism is
proposed for this transformation (Scheme 2). Co-ordi-
nation between the silver ion and the carbon–carbon
triple bond of propargyl bromide facilitates hydroami-
nation and gives rise to enamine 4. Enamine 4, a tertiary
enaminone, undergoes cyclisation in typical fashion5 to
give cyclic enamine 5. Rearrangement of cyclic enamine
5 affords the thermodynamically more stable pyrrole 2.
Based on this proposed mechanism, it is suspected that
the reason for the low yields observed for this reaction
is that there are many potential reaction pathways sub-
sequent to the initial hydroamination.
We have recently reported a novel one-pot synthesis of
functionalised pyrroles 2 via the silver-mediated reaction
of secondary vinylogous amides or carbamates 1 with
propargyl bromide (Scheme 1).4 This reaction, although
facile, does not generate high enough yields (ꢀ25%) to
It was believed that performing a C-propargylation
of vinylogous amides and carbamates 1, followed by
silver-mediated hydroamination, would provide an
improvement in overall yields (Scheme 3).
Keywords: Amination; Pyrroles; Silver and compounds; Microwave
heating.
*
Corresponding author. Tel.: +27-33-260-5659; fax: +27-33-260-
5009; e-mail: robinsonr@ukzn.ac.za
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.019

6788
R. S. Robinson et al. / Tetrahedron Letters 45 (2004) 6787–6789
Z
R
Z
R
N
H
N
Z
Z
N
R
N
Br
R
Br
Ag
3
2
4
5
Scheme 2.
1. Base
R
R
N
H
N
H
Z
Z
2. Br
6
1
Ag
Z
Z
R
N
H
N
N
R
Z
R
2
5
7
Scheme 3.
This new strategy has been investigated and has given
some interesting results. It is possible to C-propargylate
vinylogous amides (1, Z = COMe) using propargyl bro-
mide and either sodium hydride or n-butyllithium as
base. As expected, the Z-configuration of the vinylogous
amide starting materials is preserved during this reac-
tion. This is evident from the downfield shifts of the
Propargyl compounds 6 (Z = COMe) are, indeed, con-
verted to pyrroles 2 by a catalytic amount (0.2equiv)
of silver nitrate in acetonitrile. The mechanism in oper-
ation is assumed to involve activation of the triple bond
by the silver ion 7, affecting hydroamination and afford-
ing cyclic intermediate 5. This initial step is followed by
rearrangement to afford pyrrole 2. This mechanism is
consistent with the generally accepted mechanism of
nucleophilic addition to metal-activated carbon–carbon
multiple bonds.7 It should be noted that this procedure
is analogous to the gold-catalysed preparation of similar
pyrroles reported by Arcadi et al.8
1
N–H protons in the H NMR spectra of these com-
pounds, suggesting hydrogen bonding, and has been
confirmed by NOE experiments. The propargyl com-
pounds 6 are stable enough to be purified by column
chromatography but must be used shortly thereafter.
Yields for this conversion are modest (Table 1) but it
is anticipated that improvements can be made in future
as a large portion of starting material is recovered. It is
possible that this is due to abstraction of the relatively
acidic terminal acetylenic proton (pKa ꢀ25) of propargyl
bromide by the initially formed vinylogous amide anion.
Vinylogous carbamates (1, Z = CO2Et), on the other
hand, do not undergo C-propargylation in the same
manner. A variety of bases (NaH, n-BuLi, LDA,
LHMDS) and solvents (THF, diethyl ether) have been
employed with little success.
An interesting observation is the direct conversion of 1g
to 2g without isolation of the intermediate propargyl
compound 6g. This is presumed to be the result of
hydroamination catalysed by the small excess of n-butyl-
lithium (activation of the amine).9 The reason for this to
be restricted to the benzyl group is not clear. The
remainder of the results reveal that slightly better yields
of 6 are achieved using n-butyllithium instead of sodium
hydride. Yields of 6 and 2 are unaffected by the steric
bulk of the alkyl groups attached to nitrogen, however,
yields are markedly lower for the aromatic analogue.
This observation is unsurprising.
Table 1. Synthesis of pyrroles 2 from vinylogous amides 1 via
hydroamination
A further investigation was carried out to determine the
effects of microwave irradiation on the hydroamination
reaction (Table 2). The reaction mixtures were subjected
to microwave irradiation in a sealed tube using a domes-
tic microwave oven (700W). Yields are typically of the
same order as those obtained at room temperature,
however, reaction times are dramatically reduced from
16–20h to 1min.
Entry
R
Yield 1 (%)6 Base
Yield 6 (%) Yield 2 (%)
a
b
c
d
e
f
Me
Me
80
80
n-BuLi 55
NaH
93
4693
n-Bu 76
n-BuLi 51
n-BuLi 52
95
87
Cy
88
6––
t-Bu
Ph
––
––
94
95
n-BuLi 21
n-BuLi ––
75
43a
g
Bn
In conclusion, we have developed a mild, efficient means
of preparing functionalised pyrroles, from readily avail-
a 2g was obtained directly from 1g.

R. S. Robinson et al. / Tetrahedron Letters 45 (2004) 6787–6789
6789
Herdtweck, Y. K.; Pleier, A.-K.; Walter, E.; Yan, Y. K.
Table 2. Microwave enhanced hydroamination
Organometallics 2000, 19, 170–183; (d) Muller, T. E.; Beller,
M. Chem. Rev. 1998, 98, 675–703.
¨
Entry
R
Yield 2 (%)
a
c
d
f
Me
n-Bu
Cy
93
91
96
78
2. (a) Trost, B. M.; Tang, W. J. Am. Chem. Soc. 2002, 124,
14542–14543; (b) Arredondo, V. M.; Tian, S.; McDonald,
F. E.; Marks, T. J. J. Am. Chem. Soc. 1999, 121, 3633–3639.
3. (a) Arseniyadas, S.; Sartoretti, J. Tetrahedron Lett. 1985,
26, 729–732; (b) Lathbury, D.; Gallagher, T. J. Chem. Soc.
Chem. Commun. 1986, 114–115; (c) Kinsman, R.; Lathbury,
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Ph
able starting materials, using an inexpensive catalyst sys-
tem. The practical value of this method is increased by
the fact that the reaction time can be significantly re-
duced using microwave irradiation. We are currently
investigating the potential of employing this procedure
to prepare N-bridgehead pyrroles and applying this
methodology to the total synthesis of pyrrolizidine and
indolizidine alkaloids.
(f) Muller, T. E.; Pleier, A.-K. J. Chem. Soc., Dalton Trans.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2004.07.019.
7. Harding, K. E.; Tiner, T. H. Electrophilic Heteroatom
Cyclizations In Comprehensive Organic Synthesis;
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References and notes
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¨