Carbon-carbon bond formation and pyrrole synthesis via the [3,3] sigmatropic rearrangement of O-vinyl oxime ethers

Article abstract of DOI:10.1021/ol100659q

A new method for the synthesis of 2,4- and 2,3,4-substituted pyrroles in two or three steps from commercially available ketones and allyl hydroxylamine is described. An iridium-catalyzed isomerization reaction has been developed to convert O-allyl oximes

Full text of DOI:10.1021/ol100659q

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2290-2293
Carbon-Carbon Bond Formation and
Pyrrole Synthesis via the [3,3]
Sigmatropic Rearrangement of O-Vinyl
Oxime Ethers
Heng-Yen Wang, Daniel S. Mueller, Rachna M. Sachwani, Hannah N. Londino,
and Laura L. Anderson*
Department of Chemistry, UniVersity of Illinois, Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
lauralin@uic.edu
Received March 19, 2010
ABSTRACT
A new method for the synthesis of 2,4- and 2,3,4-substituted pyrroles in two or three steps from commercially available ketones and allyl
hydroxylamine is described. An iridium-catalyzed isomerization reaction has been developed to convert O-allyl oximes to O-vinyl oximes,
which undergo a facile [3,3] rearrangement to form 1,4-imino aldehyde Paal-Knorr intermediates that cyclize to afford the corresponding
pyrroles. Optimization and examples of the isomerization and pyrrole formation are discussed.
[3,3] Sigmatropic rearrangements, such as the Claisen and
Fisher-Indole reactions, are powerful methods for forming
new carbon-carbon bonds.1 A less familiar example is the
[3,3] rearrangement of O-vinyl oximes to give 1,4-imino
carbonyl compounds. Trofimov and co-workers have shown
that oximes can be added to acetylenes under strongly basic
conditions to form O-vinyl oximes that rearrange to 1,4-
imino carbonyl compounds and then participate in a
Paal-Knorr cyclization and condensation sequence.2 This
transformation is an intriguing alternative approach to the
synthesis of pyrroles because it uses the Paal-Knorr
sequence without requiring the synthesis of 1,4-dicarbonyl
compounds.3,4 Unfortunately, the Trofimov reaction is limited
in scope and efficiency. The strongly basic conditions limit
functional group compatibility. While 2,3-substituted pyrroles
can be accessed from acetylene and oximes which tolerate
(3) For classic syntheses of pyrroles and reviews of the preparation of
pyrroles, see: (a) Knorr, L. Chem. Ber. 1884, 17, 1635. (b) Paal, C. Chem.
Ber. 1885, 18, 367. (c) Kostyanovsky, R. G.; Kadorkina, G. K.; Mkhitaryan,
A. G.; Chervin, I. I.; Aliev, A. E. MendeleeV Commun. 1993, 21. (d)
Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1987, 43,
5171. (e) Black, D. S. Sci. Synth. 2001, 13, 441. (f) Ferreira, V. F.; De
Souza, M. C. B. V.; Cunha, A. C.; Pereira, L. O. R.; Ferreira, M. L. G.
(1) (a) Wipf, P. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, UK, 1991: Vol. 5, p 827. (b) Castro,
A. M. M. Chem. ReV. 2004, 104, 2939. (c) Moody, C. J. AdV. Heterocycl.
Chem. 1987, 42, 203. (d) Robinson, B. Chem. ReV. 1969, 69, 227. (e)
Hughes, D. L. Org. Prep. Proced. Int. 1993, 25, 607. (f) Downing, R. S.;
Kunkeler, P. J. In The Fischer Indole Synthesis; Sheldon, R. A., Bekkum,
H., Eds.; Wiley-VCH: New York, 2001; p 178.
Org. Prep. Proced. Int. 2001, 33, 411
.
(4) For recent examples of pyrrole syntheses, see: (a) Rivero, M. R.;
Buchwald, S. L. Org. Lett. 2007, 9, 973. (b) Martin, R.; Rivero, M. R.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 7079. (c) Lu, Y.;
Arndtsen, B. A. Angew. Chem., Int. Ed. 2008, 47, 5430. (d) Dong, H.; Shen,
M.; Redford, J. E.; Stokes, B. J.; Pumphrey, A. L.; Driver, T. G. Org. Lett.
2007, 9, 5191. (e) Milgram, B. C.; Eskildsen, K.; Richter, S. M.; Scheidt,
W. R.; Scheidt, K. A. J. Org. Chem. 2007, 72, 3941. (f) Khalili, B.; Jajarmi,
(2) For reviews of the Trofimov reaction see: (a) Mikhaleva, A. I.;
Zaitsev, A. B.; Trofimov, B. A. Russ. Chem. ReV. 2006, 75, 797. (b)
Trofimov, B. A. Curr. Org. Chem. 2002, 6, 1121. (c) Trofimov, B. A.;
Mikhaleva, A. I. Heterocycles 1994, 37, 1193. (d) Trofimov, B. A. AdV.
Heterocycl. Chem. 1990, 51, 177.
P.; Eftekhari-Sis, B.; Hashemi, M. M. J. Org. Chem. 2008, 73, 2090
.
10.1021/ol100659q  2010 American Chemical Society
Published on Web 04/22/2010

the harsh reaction conditions,5 the use of substituted alkynes
is rare and gives regioisomeric mixtures of products in low
yields (Scheme 1).6 These limitations are regrettable given
tion and the conversion of the O-vinyl oxime products to
pyrroles with mild heating (Scheme 1). The overall method
provides a simple, selective, and functional group tolerant
synthesis of 2,4- and 2,3,4-substituted pyrroles in two or three
steps from ketones and allyl hydroxylamine.
Alkene isomerization conditions for the conversion of
O-allyl oximes to O-vinyl oximes were screened for allyl
oxime 1a. This substrate was synthesized by a condensation
reaction between 4′-methoxyacetophenone and commericially
available, allyl hydroxylamine. Initially, known allylic ether
isomerization catalysts, such as [(Ph3P)3RhCl]/n-BuLi and
[(coe)2IrCl]2/PCy3/AgPF6, were tested and shown to be
ineffective for the desired transformation.9,10 Instead, a 1:2:2
mixture of [(cod)IrCl]2, NaBH4, and AgOTf successfully
catalyzed the conversion of 1a to 2a at 25 °C (Table 1, entries
Scheme 1. O-Vinyl Oximes as Precursors to Pyrroles
Table 1. Optimization of the O-Allyl Oxime Isomerization
Catalyst
entry
catalyst
yield (%)a
a Representative example.
1
2
3
4
5
6
7
(Ph3P)3RhCl/n-BuLi
NR
NRb
85
53
30
[(coe)2IrCl]2/2PCy3/2AgPF6
[(cod)IrCl]2/2NaBH4/2AgOTf
[(coe)2IrCl]2/2NaBH4/2AgOTf
(cod)2Rh(BF4)/NaBH4/AgOTf
[(coe)2RhCl]2/2NaBH4/2AgOTf
[(cod)IrCl]2/2LiAlH4/2AgOTf
the importance of substituted pyrrole architectures in me-
dicinal and material target molecules.7,8 To broaden the range
of pyrroles accessible from the [3,3] sigmatropic rearrange-
ment of O-vinyl oximes under more tolerant and efficient
conditions, we have developed an alkene isomerization
method to access O-vinyl oximes from easily prepared
O-allyl oximes. Here we report the scope of this isomeriza-
NR
89
a Determined by using 1H NMR spectroscopy with CH2Br2 as a
reference. b The reaction was done in THF and in 50:1 DCE:acetone.
1-3). Other common Ir(I) and Rh(I) catalyst precursors were
screened under the isomerization conditions but were less
efficient than [(cod)IrCl]2 (Table 1, entries 3-6). The
addition of phosphine ligands to the catalyst mixture and
the removal of AgOTf also inhibited the reaction. Several
reducing agents were screened and LiAlH4 and NaBH4 were
found to give the highest yields of 2a (Table 1, entries 3
and 7). A 2:1 ratio of the reducing reagent to the iridium
dimer was required because larger concentrations of the
reducing reagent provided small amounts of a side product
produced by reduction of the allyl group to an n-propyl
group.11 THF and MeCN were determined to be optimal
solvents for the isomerization. A significant decrease in yield
(5) For examples of the Trofimov reaction with acetylene, see: (a)
Mikhaleva, A. I.; Trofimov, B. A.; Vasil’ev, A. N. Zh. Org. Khim. 1979,
15, 602. (b) Korostova, S. E.; Mikhaleva, A. I.; Vasil’tsov, A. M.; Trofimov,
B. A. Russ. J. Org. Chem. 1998, 34, 911. (c) Trofimov, B. A.; Zaitsev,
A. B.; Schmidt, E. Y.; Vasil’tsov, A. M.; Mikhaleva, A. I.; Ushakov, I. A.;
Vashchenko, A. V.; Zorina, N. V. Tetrahedron Lett. 2004, 45, 3789. (d)
Trofimov, B. A.; Schmidt, E. Y.; Zorina, N. V.; Senotrusova, E. Y.; Protsuk,
N. I.; Ushakov, I. A.; Mikhaleva, A. I.; Meallet-Renault, R.; Clavier, G.
Tetrahedron Lett. 2008, 49, 4362. (e) Schmidt, E. Y.; Mikhaleva, A. I.;
Vasil’tsov, A. M.; Zaitsev, A. B.; Zorina, N. V. ARKIVOC 2005, 7, 11.
(6) For examples of regioisomeric mixtures of products obtained from
the use of terminal alkynes in the Trofimov reaction see: (a) Petrova, O. V.;
Sobenina, L. N.; Ushakov, I. A.; Mikhaleva, A. I.; Hyun, S. H.; Trofimov,
B. A. ARKIVOC 2009, 4, 14. (b) Trofimov, B. A.; Tarasova, O. A.;
Mikhaleva, A. I.; Kalinina, N. A.; Sinegovskya, L. M.; Henkelmann, J.
Synthesis 2000, 1585.
(7) For examples of the biological activity and medicinal application of
pyrroles, see: (a) Dewick, P. M. Medicinal Natural Products: A Biosynthetic
Approach; John Wiley& Sons Inc.: Chichester, UK, 2009. (b) Barton,
D. H. R.; Nakanishi, K.; MethCohn, O.; Kelly, J. W. ComprehensiVe Natural
Products Chemistry; Pergamon Press: Oxford, UK, 1999. (c) Cacchi, S.;
Fabrizi, G. Chem. ReV. 2005, 105, 2873. (d) Maryanoff, B. E.; Zhang, H.;
Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. ReV. 2004, 104, 1431.
(e) Saracoglu, N. Top. Heterocycl. Chem. 2007, 11, 1. (f) Zomax: McLeod,
D. C. Drug Intell. Clin. Pharm. 1981, 15, 522. (g) Atorvastin (Lipitor):
Roth, B. D. US4681893, 1987. (h) Muchowski, J. M. AdV. Med. Chem.
(9) For related syntheses of allyl vinyl ethers which undergo subsequent
Claisen rearrangements, see: (a) Wang, K.; Bungard, C. J.; Nelson, S. G.
Org. Lett. 2007, 9, 2325. (b) Nelson, S. G.; Bungard, C. J.; Wang, K. J. Am.
Chem. Soc. 2003, 125, 13000. (c) Schmidt, B. Synlett 2004, 9, 1541. (d)
Tanaka, K.; Okazaki, E.; Shibata, Y. J. Am. Chem. Soc. 2009, 131, 10822,
and references cited within
.
(10) For examples of allylic ether isomerizations see: (a) Tanaka, K.
Compr. Organomet. Chem. III 2007, 10, 71. (b) Corey, E. J.; Suggs, J. W.
J. Org. Chem. 1973, 38, 3224. (c) Boons, G.-J.; Isles, S. J. Org. Chem.
1992, 4, 181
.
(8) For examples of pyrrole structures in material applications see: (a)
Tshibaka, T.; Ulliel Roche, I.; Dufresne, S.; Lubell, W. D.; Skene, W. G.
J. Org. Chem. 2009, 74, 9497. (b) Walczak, R. M.; Reynolds, J. R. AdV.
1996, 61, 4262
.
(11) See the Supporting Information for full characterization of the O-n-
Mater. 2006, 18, 1121
.
propyl oxime reduction product.
Org. Lett., Vol. 12, No. 10, 2010
2291

was observed when the reaction was run in toluene and only
starting material was observed when the reaction was run in
CH2Cl2. On the basis of these results, the optimal catalytic
conditions for substrate screening were determined to be 5
mol % [(cod)IrCl]2, 10 mol % NaBH4 or LiAlH4, and 10
mol % AgOTf in THF.
isomerization is a mild, general, and efficient method for
the synthesis of O-vinyl oximes that uses simple starting
materials and provides a facile entry into the study of O-vinyl
oximes as precursors to pyrroles.
Several O-vinyl oximes prepared in Scheme 2 were tested
as precursors to 1,4-imino aldehyde Paal-Knorr intermedi-
ates and pyrroles.15 As shown in Scheme 3, conversion of
A variety of O-vinyl oxime ethers12 were synthesized in
good yield from the corresponding O-allyl oxime ethers,
using the isomerization conditions determined in Table 1
(Scheme 2). The predominantly E-O-allyl oxime substrates
Scheme 3. Conversion of O-Vinyl Oximes to Pyrroles
Scheme 2. Isomerization of O-Allyl Oximes to O-Vinyl Oximes
a Regioselectivity ratio.
O-vinyl oximes to 2,4- and 2,3,4-substituted pyrroles was
achieved by mild heating in the presence of molecular
sieves.16 The pyrroles were isolated in good yield after the
three-step sequence involving [3,3] rearrangement, cycliza-
tion, and dehydration.17 Pyrrole formation was sensitive to
solvent choice and substrate concentration: a 0.4 M dioxane
solution afforded optimal yields. Electron-donating substi-
tutents on the aryl ring of the acetophenone-derived oximes
favored pyrrole formation (3a vs 3e) but substitution at the
R-carbon had little effect on the efficiency of the transforma-
tion (3h, 3i, and 3j). For substrates derived from dialkyl
ketones, the pyrrole synthesis favored enamine formation at
the more enolizable R-carbon atom for 2n and the most
sterically accessible position for 2o. The transformation of
a NaBH4 was used instead of LiAlH4. b DIBAL-H was used instead of
LiAlH4.
used for these reactions were selected to illustrate the
functional group tolerance of the isomerization and were
prepared by simple allyl hydroxylamine condensations with
the corresponding ketones.13 Both electron-poor and electron-
rich aryl oximes, as well as pyridyl-substituted substrates,
were tolerated under the isomerization conditions. Alkyl, aryl,
and ester functional groups were also allowed at the
enolizable position of the allyl oximes. The preference for
NaBH4 or LiAlH4 as a reducing agent was related to
functional group compatibility. The O-vinyl oxime products
of the isomerizations were isolated with vinyl E:Z ratios of
approximately 1:2 and favored a cis-relationship between the
O-substituent and the enolizable carbon atom.14 Overall, the
results in Scheme 2 show that the iridium-catalyzed alkene
1
O-vinyl oximes to pyrroles was monitored by H and 13C
1
(14) Oxime and vinyl isomers were identified by H-1H nOe experi-
ments. The minor Z-O-allyl oxime isomer of the starting material was not
observed as unreacted starting material; therefore, it is likely that isomer-
ization to the E-oxime isomer occurs with isomerization of the allyl group
to the vinyl group.
(15) For examples of cascade processes involving the Stetter reaction
or oxidative enolate coupling with the Paal-Knorr reaction, see: (a) Szakal-
Quin, G.; Graham, D. G.; Millington, D. S.; Maltby, D. A.; McPhail, A. T.
J. Org. Chem. 1986, 51, 621. (b) Lee, C. K.; Lee, I.-S. H.; Noland, W. E.
Heterocycles 2007, 71, 419. (c) Bharadwaj, A. R.; Scheidt, K. A. Org. Lett.
2004, 6, 2465. (d) Braun, R. U.; Mu¨ller, T. J. J. Synthesis 2004, 14, 2391.
(e) Periasamy, M.; Srinivas, G.; Seenivasaperumal, M. J. Chem. Res. 2004,
270.
(12) (a) For the base-mediated synthesis of benzophenone-derived
O-vinyl oximes from alkynes see: Zaitsev, A. B.; Vasil’tsov, A. M.; Schmidt,
E. Y.; Mikhaleva, A. I.; Morozova, L. V.; Afonin, A. V.; Ushakov, I. A.;
Trofimov, B. A. Tetrahedron 2002, 58, 10043. (b) For the base-mediated
synthesis of O-vinyl oximes with enolizable oximes, see: Trofimov, B. A.;
Mikhaleva, A. I.; Vasil’tsov, A. M.; Schmidt, E. Y.; Tarasova, O. A.;
Morozova, L. V.; Sobenina, L. N.; Preiss, T.; Henkelmann, J. Synthesis
2000, 1125.
(16) E:Z mixtures of the O-vinyl oximes were used for the synthesis of
pyrroles.
(17) Less than 5% of 2 and the corresponding ketone were isolated with
the pyrrole products. The remainder of the starting material is most likely
converted into a highly colored polymeric material that remains physisorbed
to silica gel.
(13) O-allyl oxime 1m was synthesized by a substitution reaction
between the corresponding oxime and allyl bromide.
2292
Org. Lett., Vol. 12, No. 10, 2010

Although a clear electronic trend for pyrrole formation
was not established in Scheme 3, cyano-substitution at the
enolizable R-carbon of O-vinyl oximes was shown to
dramatically favor the [3,3] rearrangement and subsequent
Paal-Knorr reaction. When subjected to the iridium-
catalyzed isomerization conditions at 25 °C, cyano-substi-
tuted O-allyl oxime substrate 1q gave the corresponding
pyrrole in a one-flask procedure in 74% yield (Scheme 5).
Further investigation showed that this reactivity was con-
sistent for several cyano-substituted acetophenones and that
electron-donating groups on the aryl ring facilitated the
reaction. These results suggest that pyrrole formation is
particularly facile for these substrates.
1
Scheme 4
.
Observation of Paal-Knorr Intermediate by H and
13C NMR Spectroscopy
NMR spectroscopy to observe the 1,4-imino carbonyl
intermediate: the [3,3] rearrangement of 2e occurs between
2 and 4 h at 75 °C (Scheme 4) to give imino aldehyde 4e.
The subsequent cyclization and condensation that are neces-
sary to form 3e requires an additional 10-12 h of heating
in the presence of molecular sieves.
A one-flask procedure for the conversion of O-allyl oximes
to pyrroles was tested for comparison to the two-step
procedure. O-Allyl oximes 1a, 1h, and 1j were subjected to
isomerization reaction conditions for 12 h and then heated
to 75 °C for 24 h (Scheme 5). The isolated yields from these
In summary, we have shown that O-vinyl oximes can be
synthesized from O-allyl oximes by an iridium-catalyzed
isomerization reaction and that O-vinyl oximes can be
thermally converted to pyrroles. Cyano-substituted O-allyl
oximes have also been identified as substrates that are
particularly amenable to this reaction sequence and can be
directly converted to the corresponding pyrroles at 25 °C.
This new isomerization reaction provides reliable and
reproducible access to a variety of O-vinyl oximes as well
as facile entry into subsequent [3,3] rearrangements and use
in the preparation of 2,4- and 2,3,4-substituted pyrroles in a
two- or three-step procedure from commericially available
starting materials. Future work will concentrate on expanding
the scope and controlling selectivity of the isomerization
reaction and pyrrole synthesis. Isolation and study of the
reaction intermediates will also be targeted to explore the
breadth of the transformation.
Scheme 5. Conversion of O-Allyl Oximes to Pyrroles
Acknowledgment. We would like to thank Profs. T. G.
Driver (UIC) and D. J. Wardrop (UIC) for insightful
discussions and chemicals. We would also like to thank Mr.
Furong Sun (UIUC) for mass spectrometry data and the
University of Illinois at Chicago for funding.
transformations corresponded to the sum of the yields from
the two-step procedure. No deleterious effect was observed
due to the presence of the iridium catalyst during pyrrole
formation. The one-flask procedure also allowed for an
extension of the method to include substrates such as 1p,
which were slow to isomerize at 25 °C.
Supporting Information Available: Experimental pro-
cedures, expanded optimization tables, and compound char-
acterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL100659Q
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