Counterion effects in a gold-catalyzed synthesis of pyrroles from alkynyl aziridines

Article abstract of DOI:10.1021/ol900609f

Aryl-substituted N-tosyl alkynyl aziridines undergo a gold-catalyzed ring expansion to afford 2,5-substituted pyrrole products. Under certain conditions, a ring-expansion and rearrangement leads to 2,4-substituted pyrroles. The reaction pathway is determi

Full text of DOI:10.1021/ol900609f

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2293-2296
Counterion Effects in a Gold-Catalyzed
Synthesis of Pyrroles from Alkynyl
Aziridines
Paul W. Davies* and Nicolas Martin
School of Chemistry, UniVersity of Birmingham, Edgbaston,
Birmingham, B15 2TT, U.K.
p.w.daVies@bham.ac.uk
Received March 23, 2009
ABSTRACT
Aryl-substituted N-tosyl alkynyl aziridines undergo a gold-catalyzed ring expansion to afford 2,5-substituted pyrrole products. Under certain
conditions, a ring-expansion and rearrangement leads to 2,4-substituted pyrroles. The reaction pathway is determined by the counterion to
the gold catalyst.
Over the past few years, the activation of an alkyne by a
π-acidic transition-metal catalyst, such as gold or platinum,
has been employed as the basis of a wide range of powerful
new transformations.1,2 Excellent chemoselectivity is dis-
played in processes which require experimentally simple and
mild conditions. The cationic gold systems prepared by a
metathesis reaction between a simple gold complex LAuCl
and a silver salt AgX (X ) “noncoordinating” counterion)
are widely applied and are particularly effective catalysts
which show superb reactivity profiles.3 The properties of this
catalyst system are tunable through modification of the
spectator ligand L or the counterion X, which provides a
vacant coordination site for the alkyne substrate to bind to
the gold fragment. Significant alterations have been made
to the spectator ligand (where L is a phosphine, phosphite,
or N-heterocyclic carbene ligand), while the effect of
modifying counterion X on the reactivity of cationic gold
catalysts is well accepted.4 However, the influence of the
counterion on determining the reaction pathway in cycloi-
somerizations is much less well established.5 Counterion
effects on the reaction pathway have recently been observed
in processes including diyne isomerization,6 cycloisomer-
ization of allenynes,7 the reaction of alkenyl allyl units,8 the
selective synthesis of fluorenes or styrenes,9 and in bromoal-
lenyl ketone cycloisomerization.10 The counterion has been
(1) For a discussion and review of π-acid alkyne activation by platinum
and gold see: Fu¨rstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46,
3410
.
(2) For selected recent reviews of gold catalysis: (a) Hashmi, A. S. K.
Chem. ReV. 2007, 107, 3180. (b) Li, J.; Brouwer, C.; He, C. Chem. ReV.
2008, 108, 3239. (c) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395C. (d)
Núnˇez, E. J.; Echavarren, A. M. Chem. ReV. 2008, 109, 3326. (e) Arcadi,
A. Chem. ReV. 2008, 109, 3266
.
(3) (a) Nieto-Oberhuber, C.; Paz Munˇoz, M.; Bunˇuel, E.; Nevado, C.;
Ca´rdenas, D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 2402.
(b) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc.
2004, 126, 4526. (c) Mamane, V.; Gress, T.; Krause, H.; Fu¨rstner, A. J. Am.
(4) For a comprehensive review concerning ligand effects in homoge-
neous gold catalysis, see: Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem.
ReV. 2008, 108, 3351.
Chem. Soc. 2004, 126, 8654
.
10.1021/ol900609f CCC: $40.75
Published on Web 05/08/2009
 2009 American Chemical Society

shown to be particularly important in the intramolecular
hydroalkoxylation of allenols,11 with a striking example
employing chiral counterions to effect enantiocontrol.12
In this Letter, we report a new gold-catalyzed synthesis
of N-tosyl-2,5-substituted pyrroles and demonstrate a coun-
terion effect which alters the course of the reaction to yield
N-tosyl-2,4-substituted pyrroles.
Scheme 3. Proposed Mechanism of Pyrrole Formation
As key structural constituents in biologically active
compounds and functional materials, and useful synthetic
intermediates for complex molecule preparation, pyrroles are
attractive targets for methodology development. Gold-
catalyzed cycloisomerization approaches to pyrroles are
potentially attractive due to the intrinsic atom-economy and
the mild and practical reaction conditions employed alongside
excellent functional group tolerance.13,14
With this in mind, we became interested in a gold-
catalyzed ring expansion of alkynyl aziridines 1 as a means
to access pyrroles. As a prospective cyclization precursor, 1
can be prepared by a modular coupling of a readily accessible
imine and a propargylic sulfonium ylide according to the
method of Dai which leads to the cis-aziridine in high
diastereoselectivity (Scheme 1).15
of PPh3AuCl and AgOTf in toluene at room temperature
(entry 1, Table 1).17 Pleasingly, the desired pyrrole 5a was
Table 1. Survey of Reaction Conditions for the
Cycloisomerization of Alkynyl Aziridinesa
Scheme 1. Alkynyl Aziridine Preparation
entry
X )
solvent
toluene
time/h
% yieldb
5:6
1
2
3
4
5
6
7
8
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
NTf2
NTf2
PF6
PF6
OTs
OTs
OTs
4
0.75
1
20
20
2
20
20
20
20
36
48
24
24
3
75
60
50
29
72
56
79
79
42
45
60
63
<10
<10
98
24:1
1:7.6
1:24
0:1
1.1:1
>50:1
>50:1
15:1
1:5
2.8:1
2:1
20:1
1:0
CH2Cl2
ClCH2CH2Cl
CH3NO2
CHCl3
EtOH
Et2O
o-xylene
CH2Cl2
toluene
CH2Cl2
toluene
The AuCl3-catalyzed ring expansion of 2,2-disubstituted
alkynyl epoxides to 2,4-substituted furans (Scheme 2)
9
10
11
12
13
14
15
Scheme 2. Furan Synthesis by Ring Expansion
ClCH2CH2Cl
toluene
1:0
1:0
ClCH2CH2Clc
a AgX (5 mol %), PPh3AuCl (5 mol %), 1 (0.1 mmol), solvent (0.5
mL) with all reactions run at rt unless otherwise specified. b Yields calculated
by NMR against a known quantity of internal standard. c Reaction performed
at 70 °C.
provided good precedent for triggering a ring expansion
through activation of the alkyne in 1 by a π-acidic template
(Scheme 3).16 While our 2,3-disubstituted aziridines have a
reduced electronic bias toward ring opening with the desired
regioselectivity, we thought that the π-bond selective and
strongly electrophilic cationic gold systems LAuX would be
sufficient to activate the system toward our desired reactivity.
After coordination of gold, ring-opening and attack of the
nitrogen to the distal position of the alkyne would afford
the metal-substituted cation 3. Aromatization by proton
elimination followed by protodemetalation should be facile
to afford the desired pyrrole and release the catalyst.
Our studies commenced with phenyl-substituted alkynyl
aziridine 1a, which was subjected to a standard combination
formed in good yield. However, a small amount of isomeric
byproduct was observed. When the reaction was performed
in dichloromethane, this unexpected isomer was isolated as
the major product and identified as the 2,4-substituted
regioisomer 6a (entry 2).18 6a was a major component of
the product when the reaction was performed in 1,2-
dichloroethane, nitromethane, and chloroform. Alternatively,
when ethanol, ether, or xylene were employed as solvent,
isomer 5a was favored. A similar trend was observed when
the triflimidate and hexafluorophosphate counterions were
employed with either toluene or dichloromethane (entries
9-12).
2294
Org. Lett., Vol. 11, No. 11, 2009

Switching counterion to tosylate led to isomer 5a as the
sole product, regardless of solvent (entries 13 and 14). The
reaction was considerably slower than previously observed;
however, mild heating allowed a quantitative yield of pure
pyrrole 5a to be obtained in 3 h (entry 15). The lower activity
of the Ph3PAuOTs system is assigned to the tighter ion pair
present in comparison to Ph3PAuOTf.
A range of aryl-substituted aziridines were then prepared
to further study these effects. The substrates were subjected
to three sets of conditions based on the use of PPh3AuCl as
precatalyst (Table 2): System A employs AgOTf in dichlo-
systems A and B. Increased amounts of 2,5-isomer 5 were
seen when the bromine was in the ortho-position (entries 7
and 8 vs entries 4 and 5). The presence of a more electron-
rich aromatic substituent (1d and 1f) led to the 2,4-isomer 6
as the major product (entries 10 and 16).19 The substitution
pattern of the benzene unit remains unchanged over the
process. Interestingly, the presence of an additional aryl unit
at the alkyne terminus appears to aid the formation of 6 under
certain conditions (entries 17 vs 11).
The results can be explained by considering the basicity
of the counterion. In the presence of a sufficiently basic
counterion such as tosylate (System C), proton elimination
and transfer from 3 is facilitated (Scheme 4, Path I),
regardless of reaction solvent. In the absence of such a
counterion, an aromatic or otherwise weakly Lewis basic
solvent can also mediate the proton transfer pathway, at a
sufficient rate to see formation of 5 (System B). The
intermediacy of the vinyl gold unit is established by the
predominant incorporation of a deuterium label in that
position when the reaction was run in D2O-washed 1,2-
Table 2. Gold-Catalyzed Synthesis of Pyrrolesa
(5) For a recent report exploring the position and effect of counterion
on alkene-cationic gold fragments, see: Zuccaccia, D.; Belpassi, L.;
Tarantelli, F.; Macchione, A. J. Am. Chem. Soc. 2009, 31, 3170.
(6) Lian, J. J.; Chen, P. C.; Lin, Y. P.; Ting, H. C.; Liu, R.-S. J. Am.
Chem. Soc. 2006, 128, 11372.
(7) (a) Lemie`re, G.; Gandon, V.; Agenet, N.; Goddard, J.-P.; de Kozak,
A.; Aubert, C.; Fensterbank, L; Malacria, M. Angew. Chem., Int. Ed. 2006,
45, 7596. (b) Lin, G.-Y; Yang, C.-Y; Liu, R.-S. J. Org. Chem. 2007, 72,
6753.
(8) Bhunia, S.; Liu, R.-S. J. Am. Chem. Soc. 2008, 130, 16488.
(9) Gorin, D. G.; Watson, I. D. G.; Toste, F. D. J. Am. Chem. Soc. 2008,
130, 3736.
(10) (a) Xia, Y.; Dudnik, A. S.; Gevorgyan, V.; Li, Y. J. Am. Chem.
Soc. 2008, 130, 6940. (b) Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am.
Chem. Soc. 2005, 127, 10500. (c) Dudnik, A. S.; Sromek, A. W.; Rubina,
M.; Kim, J. T.; Kel’in, A. V.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130,
1440.
(11) Zhang, Z.; Liu, C.; Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer,
R. A. J. Am. Chem. Soc. 2006, 128, 9066.
(12) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007,
317, 496.
(13) For selected reviews of heterocycle synthesis by gold, see: (a) Patil,
N.; Yamamoto, Y. Chem. ReV. 2008, 108, 3395. (b) Kirsch, S. F. Synthesis
2008, 3183. (c) Patil, N. T.; Yamamoto, Y. ArkiVoc 2007, 121. (d) Shen,
H. C. Tetrahedron 2008, 64, 7847. (e) Shen, H. C. Tetrahedron 2008, 64,
3885.
(14) For examples of gold-catalyzed pyrrole synthesis, see: (a) Witham,
C. A.; Mauleon, P.; Shapiro, N. D.; Sherry, B. D.; Toste, F. D. J. Am.
Chem. Soc. 2007, 129, 5838. (b) Istrate, F. M.; Gagosz, F. Org. Lett. 2007,
9, 3181. (c) Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 128,
12050. (d) Harrison, T. J.; Kozak, J. A.; Corbella-Pane´, M.; Dake, G. R. J.
Org. Chem. 2006, 71, 4525. (e) Gorin, D. J.; Davis, N. R; Toste, F. D.
J. Am. Chem. Soc. 2005, 127, 11260. (f) Arcadi, A.; Di Guiseppe, S.;
Marinelli, F.; Rossi, E. Tetrahedron: Asymmetry 2001, 12, 2715. (g) Arcadi,
A.; Di Guiseppe, S.; Marinelli, F.; Rossi, E. AdV. Synth. Catal. 2001, 343,
443.
a All reactions are run using 0.2 mmol of substrate with 5 mol % of
gold and silver species at 0.2 M concentration. b System A employs AgOTf
in CH2Cl2 at rt. System B employs AgOTf in toluene at rt. System C
employs AgOTs in ClCH2CH2Cl at 70 °C. c Isolated percentage yields of
1
pyrrole products with ratio of isomers determined from H NMR.
(15) Li, A. H.; Zhou, Y. G.; Dai, L. X.; Hou, X. L.; Xia, L. J.; Lin, L.
J. Org. Chem. 1998, 63, 4338.
romethane; System B employs AgOTf in toluene; System C
employs AgOTs in 1,2-dichloroethane at 70 °C.
(16) (a) Hashmi, A. S. K.; Sinha, P. AdV. Synth. Catal. 2004, 346, 432.
(b) Yoshida, M.; Al-Amin, M.; Matsuda, K.; Shishido, K. Tetrahedron Lett.
2008, 49, 5021.
Across all substrates, the use of System C led exclusively
to the single isomers 5a-5f in quantitative yield (Table 2).
Reaction workup and purification consisted solely of filtering
the reaction mixture through a plug of silica gel. System B
generally gave a mixture of isomers 5 and 6 with the ratio
dependent on the nature of the substituents. System A
generally led to the formation of isomer 6 as the major (or
sole) product.
(17) Throughout this study, the aziridines were used as mixtures of the
cis- and trans-diastereomers, with the cis-diastereomer predominant. See
Supporting Information for ratios.
(18) Isomers 5a and 6a were distinguished spectroscopically by a
comparison of the chemical shifts for the protons attached to the pyrrole
rings [(1H NMR; CDCl3) 5a: 6.07 ppm and 6.04 ppm (J ) 3.3 Hz); 6a:
7.58 ppm and 6.33 ppm (J ) 1.9 Hz)]. 6a shows the relative deshielding
which is characteristic for a proton in the 5-position of a pyrrole. 1D GOESY
(NOE) experiments confirm the regiochemistry within 6a (see Supporting
Information).
Aziridines substituted with electron-deficient aryl units (1b
and 1c) give lower proportions of the 2,4-isomer 6 with
(19) The use of the 4-methoxyphenyl substituent led to degradation of
the starting material.
Org. Lett., Vol. 11, No. 11, 2009
2295

our process. However, when substrates bearing electron-
deficient aryl units were employed, a significant amount of
product resulting from direct deprotonation of 3 was
observed. Substrate 1c was therefore subjected to catalyst
systems derived from AgBF4 and AgSbF6 to see if a similar
trend was observed. While use of AgSbF6 was ineffective,
using AgBF4 did give a slight improvement in the ratio of
6b to 5b. However, the reaction rate and overall recovery
of pyrrole were severely reduced (see Supporting Informa-
tion).
Scheme 4. Possible Regiodivergence Pathway
In summary, the effect of the counterion on reaction path
is demonstrated in a new gold-catalyzed pyrrole synthesis
from alkynyl aziridines. The atom-economic formation of
2,5-substituted pyrroles proceeds with quantitative yields and
avoids extractive workup or lengthy purification with
PPh3AuOTs as catalyst. A novel reaction pathway is accessed
on changing the catalyst system to PPh3AuOTf, affording
2,4-substituted pyrroles. This study highlights the importance
of selecting the correct counterion for gold-catalyzed pro-
cesses as it can play an important role in determining reaction
pathway.
dichloroethane (see Supporting Information). When both
counterion and solvent are insufficiently basic (System A),
path I is disfavored, and an alternative pathway takes
precedence.20 Although the mechanism is not yet established,
a 1,2-aryl shift would place the aryl unit in the 4-position
and afford intermediate 7.21 Electron-deficient aromatic units
will be less prone to undergo the shift, matching the results
seen. The proton to be eliminated is now adjacent to the
gold fragment. Subjecting 5f to reaction System A led to no
interconversion to 6f.
Further studies to explore the impact of counterions on
pathway determination in gold catalysis are ongoing, as are
explorations of the scope and mechanism of this process.
A recent thorough theoretical and experimental investiga-
tion into the gold-catalyzed reactions of bromoallenyl ketones
shows a gold-associated chloride participating in H-migra-
tion. In the same work, the tetrafluoroborate and hexafluo-
roantimonate counterions are shown to be highly effective
at bypassing H-migration in favor of alternate pathways,
while the triflate counterion is sufficiently basic to mediate
H-migration.9,22
Acknowledgment. We thank the University of Birming-
ham and EPSRC for financial support and Johnson Matthey
plc for a generous loan of metal salts. This research was in
part supported through Birmingham Science City: Innovative
Uses for Advanced Materials in the Modern World (West
Midlands Centre for Advanced Materials Project 2), with
support from Advantage West Midlands (AWM), and in part
funded by the European Regional Development Fund
(ERDF).
In contrast, the triflate counterion is shown to be relatively
ineffective at mediating the H-migration path from 3 to 5 in
(20) An alternative analysis is that close association of a Lewis basic
counterion or solvent to the cation may disfavor or block the orbital
alignment required for the 1,2-aryl shift to take place.
Supporting Information Available: Experimental details
1
and H and 13C NMR spectra for compounds 1, 5, and 6.
(21) For examples of 1,2-alkyl and aryl shifts in gold-catalyzed reactions
see, ref 13d and (a) Kirsch, S. F.; Binder, J. T.; Lie´bert, C.; Menz, H. Angew.
Chem., Int. Ed. 2006, 45, 5878. (b) Lee, J. H.; Toste, F. D. Angew. Chem.,
Int. Ed. 2007, 46, 912. (c) Dudnik, A. S.; Gevorgyan, V. Angew. Chem.,
Int. Ed. 2007, 46, 5195. (d) Dudnik, A. S.; Schwier, T.; Gevorgyan, V.
Org. Lett. 2007, 9, 3181. For a review, see: (e) Crone, B.; Kirsch, S. F.
Chem.sEur. J. 2008, 14, 3514.
1D GOESY spectra for 6a. Reaction scheme, experimental
1
details, and H NMR spectra for the reaction of 1d in the
presence of D2O. Reaction schemes for the cyclization of
1c employing AgBF4 and AgSbF6. This material is available
free of charge via the Internet at http://pubs.acs.org.
(22) For a theoretical investigation into the role of a triflate counterion
in the proton-transfer step of gold-catalyzed hydroamination of alkenes,
see: Kova´cs, G.; Ujaque, G.; Lledo´s, A. J. Am. Chem. Soc. 2008, 130, 853
.
OL900609F
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