Gold-catalysed rearrangement of O-vinyl oximes for the synthesis of highly substituted pyrroles

Article abstract of DOI:10.1039/c0cc04372a

O-Vinyl oximes were synthesised from the reaction of oximes with activated alkynes and subsequently rearranged using gold catalysis to afford highly substituted pyrroles in an efficient and regiocontrolled process. Additionally, pyrroles were formed direc

Full text of DOI:10.1039/c0cc04372a

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COMMUNICATION
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Gold-catalysed rearrangement of O-vinyl oximes for the synthesis
of highly substituted pyrrolesw
Simbarashe Ngwerume and Jason E. Camp*
Received 12th October 2010, Accepted 23rd November 2010
DOI: 10.1039/c0cc04372a
O-Vinyl oximes were synthesised from the reaction of oximes
with activated alkynes and subsequently rearranged using gold
catalysis to afford highly substituted pyrroles in an efficient and
regiocontrolled process. Additionally, pyrroles were formed
directly from oximes and activated alkynes in a multifaceted
catalysis process.
synthesis, catalytic variants seeking to improve the yield and
selectivity whilst removing the need for strongly basic con-
ditions have been developed. For example, earlier this year
Anderson et al. described an iridium-catalysed isomerisation
of O-allyl oximes under reductive conditions that afforded
4-methyl-5-unsubstituted pyrroles.6 Recently, we reported a
nucleophilic catalysis method for the regioselective synthesis
of pyrroles from oximes and activated alkynes.7 This one-
pot procedure relies on a two-stage microwave process to
initially form the O-vinyl oxime in situ, followed by thermal
rearrangement.8 In an effort to lower the reaction temperature,
improve the yield and increase the substrate scope of the
nucleophilic catalysis/thermal rearrangement protocol, we
examined a novel method using noble metal catalysis. A
number of synthetically useful reactions involving oximes have
employed gold catalysis,9 though not for their intermolecular
addition to alkynes.10 This communication describes the
unprecedented gold-catalysed rearrangement of vinyl oximes
to pyrroles as well as a one-pot procedure for the direct
formation of pyrroles from oximes and activated alkynes.
Our initial investigations were aimed at the synthesis of the
requisite O-vinyl oximes using nucleophilic catalysis. Thus,
O-vinyl oximes 4a–5e were synthesised by the reaction of oximes
1 with electron deficient alkynes 2 or 3 using the nucleophilic
catalyst DABCO under our previously reported conditions
(Scheme 1).7,11 The oximes were used as diastereomeric mixtures
in the subsequent transformations.
The mild and selective synthesis of pyrroles using metal
catalysis has received considerable research interest in recent
years due to the prevalence of nitrogen-containing hetero-
cycles in pharmaceuticals, agro-chemicals and biologically
active natural products.1 One procedure for the convergent
synthesis of pyrroles is the reaction of oximes2 with alkynes
under thermal superbasic conditions (DMSO/LiOH), the
Trofimov reaction (Fig. 1).3,4 Importantly, this reaction allows
for the direct formation of both a C–C and C–N bond from
unactivated alkynes. This powerful transformation is under-
utilised due to the harsh reaction conditions that result in poor
yields and low levels of product chemo-/regioselectivity.5
However, due to the potential of the Trofimov reaction in
Fig. 1 Synthesis of pyrroles via the Trofimov reaction and via
rearrangement of substituted oximes.
School of Chemistry, University of Nottingham, Nottingham,
NG7 2RD, UK. E-mail: jason.camp@nottingham.ac.uk;
Tel: +44 (0)11 5846 8464
w Electronic supplementary information (ESI) available: Experimental
details and full spectroscopic data for all novel compounds. See DOI:
10.1039/c0cc04372a
Scheme 1 Synthesis of O-vinyl oximes via nucleophilic catalysis.
Chem. Commun., 2011, 47, 1857–1859 1857
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Table 1 Optimisation of the noble metal-catalysed rearrangement of
O-vinyl oximes
Entry
Catalyst
Time/min
Yield (%)
1
2
3
4
5
6
7
8
9
10
Ph3PAuCl, AgOTf
Ph3PAuCl, AgOTf
Ph3PAuCl, AgBF4
Ph3PAuCl, AgBF4
PtCl4
AuCl3
Au(I)b
None
10
40
10
40
10
10
10
40
40
40
10a
52
13a
68
NR
NR
NR
NR
NR
NR
PPh3
AgBF4
a
b
Percent conversion to product based on 1H NMR analysis. Au(I) =
(acetonitrile)[(2-biphenyl)-di-tert-butylphosphine] gold(I).
The second phase of the work was directed towards the cata-
lytic rearrangement of O-vinyl oxime 5a to pyrrole 6a.
Noble metals are known to catalyse related [3,3]-sigmatropic
rearrangements,12 including the Overman13 and Claisen
reactions.14 Toluene was found to be the best solvent for the
clean formation of pyrrole 6a from O-vinyl oxime 5a. A
variety of noble metal catalysts were screened under micro-
wave irradiation conditions, and the catalytic system derived
from Ph3PAuCl and AgBF4 was optimal (for selected examples,
see Table 1). Thus, rearrangement of 5a in the microwave at
100 1C afforded the desired pyrrole 6a in 68% yield. Experi-
ments involving prolonged heating, inclusion of PPh3 or
AgBF4 and the use of other gold(I) catalysts indicated that
the specific gold-complex is necessary for the reaction to
proceed at 100 1C. To the best of our knowledge this is the
first example of noble metal catalysis of both the rearrangement
of O-vinyl oximes to pyrroles and of N–O bond cleavage.
We next developed a more practical method for the gold-
catalysed rearrangement of O-vinyl oximes under thermal
conditions that eliminated the need for microwave irradiation.
For example, stirring O-vinyl oxime 4a in the presence of
PPh3AuCl and AgBF4 in toluene at 100 1C for 12 h gave the
desired pyrrole 7a in good yield (Scheme 2). Several features
of the gold-catalysed method are noteworthy. Microwave
irradiation was not required to rearrange and dehydrate the
O-vinyl oxime to form the pyrrole. The reaction proceeded at
100 1C in contrast to the 170 1C required for a thermal
rearrangement. This method proved particularly amenable
to a-methyl-a-aromatic ketoxime substrates. Interestingly,
substituents at the R1-position and non-aromatic groups at
the R-position, substrates that are incompatible with our
thermal nucleophilic catalysis conditions,7 also gave good
yields of the corresponding pyrroles 7e, 7g–h. Additionally,
the pyrroles were isolated as the unsubstituted free NH com-
pounds with little to no polymerisation observed. The O-vinyl
oximes that did not rearrange to give the desired pyrroles
afforded significant amounts of the oximes precursor indicating
the predominance of the known retro-Michael reaction
(vide infra).
Scheme 2 Gold-catalysed rearrangement of O-vinyl oximes to form
pyrroles.
Finally, a gold-catalysed one-pot synthesis of pyrroles from
activated alkynes and oximes was investigated. The gold
should act as a multifaceted catalyst (MFC)15 and promote
the two mechanistically distinct steps of the reaction; the
addition of the oxime to the alkyne and the subsequent
rearrangement to the pyrrole. The acetylene moiety is a strong
s-donor and weak p-acceptor16 towards the highly Lewis-
acidic gold catalysts17 making attack of the oxime oxygen onto
the intrinsically electrophilic gold–alkyne complex highly
favorable. Thus, reaction of acetophenone oxime 1a with 2
in the presence of PPh3AuCl and AgOTF afforded the desired
pyrrole 7a in good yield (Scheme 3). Experiments involving
prolonged heating of 1a and 2 and the addition of AgOTf only
gave starting material. Similar to the rearrangement of O-vinyl
oximes 5 to pyrroles 6, the reaction of 1a with mono-ester 3
gave a lower yield of pyrrole 6a. This is possibly due to the
Scheme 3 Gold multifaceted catalysis reaction for the synthesis of
pyrroles.
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competing retro-Michael reaction followed by insertion of the
catalyst into the alkynyl CH bond to form a gold–alkyne
compound.18 The overall process may follow a pathway that
is similar to the Trofimov reaction. Initial gold-catalysed
addition of oxime 1a to the alkyne gives O-vinyl oxime 8,
which could then undergo a 1,3-hydrogen shift to afford diene
9. A gold-catalysed cyclisation induced rearrangement15 to
give 1,4-iminoaldehyde 10, followed by cyclodehydration
would give the pyrrole, in a manner analogous to the Paal–
Knorr pyrrole synthesis. The gold-complex catalyses both the
formation of the O-vinyl oxime and its rearrangement to the
pyrrole, but the precise role of the catalyst in each of these
proposed steps is unclear and future efforts will be directed
towards characterising intermediates to elucidate the reaction
mechanism.19
3 B. A. Trofimov and A. I. Mikhaleva, Heterocycles, 1994, 37,
1193–1232.
4 For examples of the use of the Trofimov reaction in synthesis,
see: (a) F. Gonzales, J. F. Sanz-Cervera and R. M. Williams,
Tetrahedron Lett., 1999, 40, 4519–4522; (b) G. A. Pinna,
M. A. Pirisi, G. Chelucci, J. M. Mussinu, G. Murineddu,
G. Lorga, P. S. D’Aquila and G. Serra, Bioorg. Med. Chem.,
2002, 10, 2485–2496; (c) A. M. Vasil’tsov, A. V. Ivanov,
A. I. Mikhaleva and B. A. Trofimov, Tetrahedron Lett., 2010,
51, 1690–1692.
5 O. V. Petrova, L. N. Sobenina, I. A. Ushakov, A. I. Mikhaleva,
S. Hyun and B. A. Trofimov, ARKIVOC, 2009, iv, 14–20.
6 H. Y. Wang, D. S. Mueller, R. M. Sachwani, H. N. Londino and
L. L. Anderson, Org. Lett., 2010, 12, 2290–2293.
7 S. Ngwerume and J. E. Camp, J. Org. Chem., 2010, 75, 6271–6274.
8 For the thermal rearrangements of O-vinyl oximes to form
pyrroles, see: (a) T. Sheradsky, Tetrahedron Lett., 1970, 11,
25–26; (b) G. A. Pinna, M. A. Pirisi and G. Paglietti, J. Chem.
Res., Synop., 1990, 360–361; (c) T. E. Glotova, E. Y. Schmidt,
M. Y. Dvorko, I. A. Ushakov, A. I. Mikhaleva and
B. A. Trofimov, Tetrahedron Lett., 2010, 51, 6189–6191.
9 For reviews, see: (a) N. T. Patil and Y. Yamamoto, Chem. Rev.,
2008, 108, 3395–3442; (b) A. S. K. Hashmi, Chem. Rev., 2007, 107,
3180–3211.
In summary, we have developed a simple and effective
gold-catalysed synthesis of pyrroles from O-vinyl oximes. In
particular, we note the amenability of this novel method to the
regioselective generation of di-, tri- and tetra-substituted
pyrroles. A functional group handle at C3/C4 of the pyrrole
is also incorporated, whilst the need for strongly basic con-
ditions or high temperatures was eliminated. A mild gold-
catalysed one-pot synthesis of pyrrole from activated alkynes
and oximes was also developed. Importantly, the formation of
pyrroles and other heterocycles should be accessible from the
intermolecular addition of oximes to unactivated alkynes.20
On going work is concerned with the further development of
the one-pot gold-catalysed pyrrole formation reaction of both
activated and unactivated alkynes as well as application of this
method towards the synthesis of biologically active natural
products. The results of these studies will be reported in due
course.
10 For examples of the use of gold catalysis with oximes, see:
(a) R. S. Ramon, J. Bosson, S. Dıez-Gonzalez, N. Marion and
´ ´ ´
S. P. Nolan, J. Org. Chem., 2010, 75, 1197–1202; (b) M. Ueda,
A. Sato, Y. Ikeda, T. Miyoshi, T. Naito and O. Miyata, Org. Lett.,
2010, 12, 2594–2597; (c) A. Corma and S. Pedro, Science, 2006,
313, 332–334.
11 For the related use of PPh3 as a nucleophilic catalyst for the
synthesis of O-vinyl oximes, see: (a) I. Yavari and A. Ramazani,
Synth. Commun., 1997, 27, 1449–1454; (b) B. A. Trofimov,
T. E. Glotova, M. Y. Dvorko, I. A. Ushakov, E. Y. Schmidt
and A. I. Mikhaleva, Tetrahedron, 2010, 66, 7527–7532.
12 Y. Liu, J. Qian, S. Lou and Z. Xu, J. Org. Chem., 2010, 75,
6300–6303.
13 (a) L. E. Overman, C. B. Campbell and F. M. Knoll, J. Am. Chem.
Soc., 1978, 100, 4822–4834; (b) I. Jaunzeme and A. Jirgensons,
Synlett, 2005, 2984–2986.
14 K. C. Majumdar, S. Alam and B. Chattopadhyay, Tetrahedron,
2008, 64, 597–643.
15 For a review, see: N. Shindoh, Y. Takemoto and K. Takasu,
Chem.–Eur. J., 2009, 15, 12168–12179.
We gratefully acknowledge the School of Chemistry at the
University of Nottingham for financial support.
16 D. J. Gorin and F. D. Toste, Nature, 2007, 446, 395–403.
17 Y. Yamamoto, J. Org. Chem., 2007, 72, 7817–7831.
18 T. de Haro and C. Nevado, J. Am. Chem. Soc., 2010, 132,
1512–1513.
19 A. S. K. Hashmi, Angew. Chem., Int. Ed., 2010, 49,
5232–5241.
20 For an example of the related gold-catalysed addition of phenols to
unactivated alkynes, see: M. R. Kuram, M. Bhanuchandra and
A. K. Sahoo, J. Org. Chem., 2010, 75, 2247–225.
Notes and references
1 For a review, see: T. L. Gilchrist, J. Chem. Soc., Perkin Trans. 1,
2001, 2491–2515.
2 For recent examples of the use of oximes in heterocycle formation,
see: (a) K. Narasaka, Pure Appl. Chem., 2003, 73, 19–28;
(b) K. Parthasarathy and C. H. Cheng, J. Org. Chem., 2009, 74,
9359–9364.
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Chem. Commun., 2011, 47, 1857–1859 1859