Synthesis of functionalized pyrroles via gold(l)-catalyzed aza-Claisen-type rearrangement

Article abstract of DOI:10.1021/ol0713032

Gold(l)-catalyzed cyclization of pentenynyl allyl tosylamides allows the rapid construction of functionalized pyrroles. The concerted aza-Claisen-type mechanism induces a complete selectivity of the process and allows the easy formation of quaternary cent

Full text of DOI:10.1021/ol0713032

ORGANIC
LETTERS
2007
Vol. 9, No. 16
3181-3184
Synthesis of Functionalized Pyrroles via
Gold(I)-Catalyzed aza-Claisen-Type
Rearrangement
Florin M. Istrate and Fabien Gagosz*
Laboratoire de Synthe`se Organique, UMR 7652 CNRS/Ecole Polytechnique,
Ecole Polytechnique, 91128 Palaiseau, France
gagosz@dcso.polytechnique.fr
Received June 1, 2007
ABSTRACT
Gold(I)-catalyzed cyclization of pentenynyl allyl tosylamides allows the rapid construction of functionalized pyrroles. The concerted aza-
Claisen-type mechanism induces a complete selectivity of the process and allows the easy formation of quaternary centers.
Pyrroles are structural motifs which are found in a wide
variety of natural products1 or pharmacologically active
substances2 and are frequently used in materials science.3
As a consequence, the development of practical synthetic
routes to access them remains of major interest. Recently,
the groups of Fu¨rstner, Yamamoto and Nakamura have
shown that gold and platinum catalysts were highly efficient
in converting o-alkynyl aryl derivatives of type 1 into a
variety of functionalized heterocycles 2 (eq 1).4 This
transformation operates Via a 5-endo cyclization followed
by a heteroatom to carbon shift of the electrophilic moiety
E.
(1) (a) Sundberg, R. J. In ComprehensiVe Heterocyclic Chemistry II;
Katritsky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Oxford, UK, 1996;
Vol. 2. For selected examples, see: (b) Aiello, A.; D’Esposito, M.;
Fattorusso, E.; Menna, M.; Mueller, W. E. G.; Perovic-Ottstadt, S.;
Schroeder, H. C. Bioorg. Med. Chem. 2006, 14, 17-24. (c) Lewer, P.;
Chapin, E. L.; Graupner, P. R.; Gilbert, J. R.; Peacock, C. J. Nat. Prod.
2003, 143-145. (d) Fu¨rstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582-
3603. (e) Balme, G. Angew. Chem., Int. Ed. 2004, 43, 6238-6241. (f)
Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213-7256.
(2) For selected examples, see: (a) Clark, B. R.; Capon, R. J.; Lacey,
E.; Tennant, S.; Gill, J. H. Org. Lett. 2006, 8, 701-704. (b) Bode, H. B.;
Irschik, H.; Wenzel, S. C.; Reichenbach, H.; Mueller, R.; Hoefle, G. J.
Nat. Prod. 2003, 1203-1206.
(3) (a) Curran, D.; Grimshaw, J.; Perera, S. D. Chem. Soc. ReV. 1991,
20, 391-404. For selected examples, see: (b) Ogawa, K.; Rasmussen, S.
C. Macromolecules 2006, 35, 1771-1778. (c) Facchetti, A.; Abbotto, A.;
Beverina, L.; van der Boom, M. E.; Dutta, P.; Evmenenko, G.; Pagani, G.
A.; Marks, T. J. Chem. Mater. 2003, 15, 1064-1072.
(4) Migration of allyl group: (a) Fu¨rstner, A.; Davies, P. W. J. Am. Chem.
Soc. 2005, 127, 15024-15025. (b) Shimada, T.; Nakamura, I.; Yamamoto,
Y. J. Am. Chem. Soc. 2004, 126, 10546-10547. (c) Nakamura, I.; Sato,
T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2006, 45, 4473-4475. (d) Cacchi,
S.; Fabrizi, G.; Pace, P. J. Org. Chem. 1998, 63, 1001-1011. (e) Arcadi,
A.; Cacchi, S.; Rosario, M. D.; Fabrizi, G.; Marinelli, F. J. Org. Chem.
1996, 61, 9280-9288. Acyl groups: (f) Reference 4b. Alkoxyalkyl
groups: (g) Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem.
Soc. 2005, 127, 15022-15023. (h) Reference 4c. (i) Reference 4a. Sulfonyl
groups: (j) Nakamura, I.; Yamagishi, U.; Song, D.; Konta, S.; Yamamoto,
Y. Angew. Chem., Int. Ed. 2007, 46, 2284-2287. (k) Fu¨rstner, A.; Heilmann,
E. K.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 4760-4763.
While this way might be envisaged for the synthesis of
pyrroles, the difficult and restricted access to the correspond-
ing substrates represents a severe synthetic limitation. By
analogy with the work of Fu¨rstner and co-workers on the
rearrangement of allyl pentynyl ether (Scheme 1, eq 2),5 we
rather envisaged that easily accessible substrates of type 3
(5) (a) Fu¨rstner, A.; Stelzer, F.; Szillat, H. J. Am. Chem. Soc. 2001, 123,
11863-11869. (b) Fu¨rstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc.
2000, 122, 6785-6786.
10.1021/ol0713032 CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/03/2007

Scheme 1. Synthetic Approach to Functionalized Pyrroles
However, more surprisingly, allyl tosylamide 10a reacted
more slowly under the same reaction conditions to give
rearranged pyrrole 11a in a moderate 62% yield (Table 1,
Table 1. Optimization of the Catalytic System
could be valuable precusors for a gold(I) catalyzed synthesis
of pyrroles (Scheme 1, eq 3).6,7
Moreover, we were particularly intrigued by the mecha-
nistic aspect of this transformation which should determine
the selectivity of the rearrangement. Indeed, an N to C allyl
shift from intermediate 4 and 5 should lead to a mixture of
pyrroles 6 and 78 while a concerted aza-Claisen type
rearrangement of intermediate 4 should lead to a selective
formation of 6.
Following our recent success in using the air-stable
crystalline Ph3PAuNTf2 catalyst9 for the formation of C-C
or C-O bonds, we first chose this catalytic system to validate
our approach. Treatment of tosylamides 8a-c with 1 mol
% of Ph3PAuNTf2 in CH2Cl2 at room temperature rapidly
led to the expected pyrroles 9a-c (eq 4).10
a Determined by 1H NMR of the crude reaction mixture. b Isolated yield.
entry 1). Increasing the catalyst loading led to a complete
conversion of 10a and improved the yield (entry 2).
However, a rapid screening of various catalytic systems led
to the conclusion that the use of the more electrophilic (p-
CF3Ph)3PAuNTf2 12 was ideal, leading to the rapid formation
of 11a which was isolated in nearly quantitative yield (entry
3). Other catalysts such as biphenylphosphine-based catalyst
13, AuBr3, or AgNTf2 were less efficient or did not promote
the reaction (entries 4-6).
In the light of these preliminary results, experimental
conditions as mentioned in entry 3 were finally retained for
the study of the scope of this transformation Secondary
tosylamides 8a-c were functionalized with various substi-
tuted allylating agents and the corresponding products
isomerized (Table 2). As for substrate 10a, simple allylated
tosylamides 10b and 10c furnished the desired products 11b
and 11c in good yields while methallyl derivative 10d gave
pyrrole 11d in 89% yield (entries 1-3). Examples compiled
in entries 4-11 are in agreement with the concerted aza-
Claisen type mechanism since the exclusiVe formation of
branched products was obserVed. Indeed, no linear product
resulting from a formal N to C shift of the allylic moiety
(6) For recent reviews on gold catalysis, see: (a) Gorin, D. J.; Toste, F.
D. Nature 2007, 46, 395-403. (b) Fu¨rstner, A.; Davies, P. W. Angew.
Chem., Int. Ed. 2007, 46, 2-42. (c) Hashmi, S. A.; Huchings, G. J. Angew.
Chem., Int. Ed. 2006, 45, 7896-7936. For selected recent examples of gold-
(I)-catalyzed reactions, see: (d) Lee, J. H.; Toste, F. D. Angew. Chem., Int.
Ed. 2007, 46, 912-914. (e) Witham, C. A.; Mauleon, P.; Shapiro, N. D.;
Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 5838-5839. (f)
Hashmi, S. A.; Salathe´, R.; Frey, W. Eur. J. Org. Chem. 2007, 1648-
1652. (g) Zhang, Z.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2007, 45,
283-285. (h) Binder, J. T.; Crone, B.; Kirsch, S. F.; Lie´bert, C.; Menz, H.
Eur. J. Org. Chem. 2007, 1636-1647. (i) Huang, X.; Zhang, L. J. Am.
Chem. Soc. 2007, 129, 6398-6399. (j) Lo´pez, S.; Herrero-Go´mez, E.; Pe´rez-
Gala´n, P.; Nieto-Oberhuber, C.; Echavarren, A. M. Angew. Chem., Int. Ed.
2006, 44, 6029-6032. (k) Sun, J.; Conley, M. P.; Zhang, L.; Kozmin, S.
A. J. Am. Chem. Soc. 2006, 128, 9705-9710.
(7) For a similar rearrangement leading to indoles, see: (a) Cariou, K.;
Ronan, B.; Mignani, S.; Fensterbank, L.; Malacria, M. Angew. Chem., Int.
Ed. 2007, 46, 1881-1884. For an other gold(I)-catalyzed synthesis of
pyrroles, see: (b) Binder, J. T.; Kirsch S. F. Org. Lett. 2006, 8, 2151-
2153. For an analogous gold(I)-catalyzed formation of furans from (Z)-2-
en-4-yn-1-ols, see: (c) Liu, Y.; Song, F.; Song, Z.; Liu, M.; Yan, B. Org.
Lett. 2005, 7, 5409-5412.
(8) As previously reported by Fu¨rstner and co-workers (see ref 5).
(9) (a) Buzas, A.; Istrate, F.; Gagosz, F. Org. Lett. 2006, 8, 1957-1959.
(b) Buzas, A.; Gagosz, F. Org. Lett. 2006, 8, 515-518. (c) Mezailles, N.;
Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133-4136. (d) Buzas, A.;
Gagosz, F. Synlett. 2006, 2727-2730.
(10) For Pd- and Cu-catalyzed formation of pyrroles from 1-alkylamino
(Z)-2-en-4-ynes, see: (a) Gabriele, B.; Salerno, G.; Fazio, A.; Bossio, M.
R. Tetrahedron Lett. 2001, 42, 1339-1342. (b) Gabriele, B.; Salerno, G.;
Fazio, A. J. Org. Chem. 2003, 68, 7853-7861. See also ref 7b.
3182
Org. Lett., Vol. 9, No. 16, 2007

Table 2. Scope of Au(I)-Catalyzed Synthesis of Pyrrolesa
a Reaction conditions: 0.1 M of substrate in CH2Cl2 with 2 mol % of 12 at rt. b Isolated yields. c Z/E ) 1:3.5. d Z/E ) 1:2.6.
could be observed whatever the substrate used.11 Crotyl
derivatives 10e,f and cinnamyl derivatives 10g,h were thus
efficiently isomerized into the corresponding pyrroles 11e,f
and 11g,h in yields ranging from 89% to 98%. More
interestingly, tosylamides 10i-l bearing allylic moieties
disubstituted at the terminal vinylic position reacted with no
observable difference in rate even if the steric hindrance in
the postulated aza-Claisen intermediate was increased. This
behavior strongly contrasts with the generally less efficient
classical Claisen or aza-Claisen reaction of substrates pos-
sessing the same substitution pattern. To the best of our
knowledge, metal-catalyzed isomerization of such substituted
allyl substrates has never been reported before.12 It is also
noteworthy that the isomerizations of tosylamides 10i-l
bearing a prenyl, a geranyl, or a pentenynyl moiety operate
under mild conditions at room temperature and produce
pyrroles possessing a new quaternary center on the side chain
in high yields (84-93%). Interestingly, in the case of
substrate 10l, the second alkyne moiety remains unchanged
with no detectable products derived from a possible cycliza-
tion onto the pyrrole ring. From a reactivity point of view,
allylic substrates bearing substituents at the terminal position
tend to react more rapidly as the consequence of a probable
higher stabilization of the incipient positive charge in the
postulated aza-Claisen intermediate.
To account for these observations, a mechanistic manifold
for the formation of the pyrroles is proposed in Scheme 2.
Scheme 2. Proposed Mechanism
1
(11) Within the limits of detection by H NMR.
In contrast with what was previously observed by Fu¨rstner
and co-workers for the rearrangement of allyl pentynyl ether,5
the results obtained in this study strongly suggest that no
(12) Examples reported by Fu¨rstner and coworkers dealt with the
rearrangement of substrates bearing allylic moieties monosubstituted at the
terminal vinylic position.
Org. Lett., Vol. 9, No. 16, 2007
3183

allyl cation is formed during the reaction. The results shown
in entries 4-11 (Table 2) serve as a mechanistic probe
indicating a more concerted mechanism in the present case
and tend to exclude the possibility of a simple N to C allyl
shift. The key step of this transformation may therefore be
seen as a gold-catalyzed aza-Claisen type reaction. The
following reaction pathway is therefore envisaged: gold(I)
activation of the triple bond in substrate 14 promotes the
nucleophilic addition of the tosylamide and leads to the
formation of the cationic vinyl gold intermediate 15. A
subsequent aza-Claisen-type rearrangement furnishes inter-
mediate 16, which is presumably in equilibrium with the
gold(I) tosylenamide complex 17. A proton loss from one
of these two intermediates allows the aromatization of the
system and the formation of a new gold intermediate 18.
This latter is subsequently protodemetalated to finally give
pyrrole 19.
This mechanism is partly supported by a crossover
experiment in which an equimolar mixture of tosylamides
10f and 10g was reacted under standard conditions. As a
probe of the internal delivery of the allylic fragment, pyrroles
11f and 11g were the only products formed in this reaction
with no detectable products derived from a crossover of these
fragments.11
To further highlight the synthetic potential of this trans-
formation, reactions of tosylamides bearing an internal alkyne
were attempted. Unfortunately, cinnamyl derivative 20
possessing either a phenyl or a methyl group at the terminal
position of the alkyne did not lead to the corresponding
pyrrole even in the presence of 5 mol % of the catalyst (eq
5). This lack of reactivity might be attributed to an increased
steric hindrance during the nucleophilic addition step of the
tosylamide moiety onto the gold(I)-activated alkyne (from
14 to 15, Scheme 2).
of Fu¨rstner and Yamamoto,4a,c migration of an ethoxymethyl
group was attempted. Even if this reaction proved to be very
sensitive, vinyl pyrrole 27, presumably derived from the
intermediate ethoxy pyrrole 26, could, however, be obtained
in a poor 15% yield along with 31% of pyrrole 9a (eq 8).14
In summary, we have developed a new gold(I)-catalyzed
formation of functionalized pyrroles, which is characterized
by its efficiency, the mild conditions employed and the easy
formation of quaternary centers. The complete selectivity
observed in the structure of the final product is in agreement
with the postulated aza-Claisen type rearrangement. Further
studies of this new gold(I)-catalyzed process and its applica-
tion to the synthesis of other heterocycles are underway.
Acknowledgment. We thank Prof. S. Z. Zard (CNRS/
Ecole Polytechnique) for helpful discussions and Rhodia
Chimie Fine for a gift of HNTf2.
Tosylamides 21 and 22 lacking the allyl fragment were,
however, transformed into pyrroles 23 and 24 under the same
conditions (eqs 6 and 7).13 Finally, by analogy with the work
Supporting Information Available: Experimental pro-
cedures and spectral data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0713032
(13) Formation of pyrrole 24 might be the result of a gold(I) or proton
catalyzed isomerization of the intermediate allyl pyrrole which seems to
be unstable under the reaction conditions. Such a behavior was already
observed for the gold catalyzed formation of furans (see ref 7b).
(14) Elimination of ethanol from intermediate 26 might be a gold(I)- or
a proton-catalyzed reaction.
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Org. Lett., Vol. 9, No. 16, 2007