Metal-catalyzed 1,2-shift of diverse migrating groups in allenyl systems as a new paradigm toward densely functionalized heterocycles

Article abstract of DOI:10.1021/ja0773507

A general, mild, and efficient 1,2-migration/cycloisomerization methodology toward multisubstituted 3-thio-, seleno-, halo-, aryl-, and alkyl-furans and pyrroles, as well as fused heterocycles, valuable building blocks for synthetic chemistry, has been developed. Moreover, regiodivergent conditions have been identified for C-4 bromo- and thio-substituted allenones and alkynones for the assembly of regioisomeric 2-hetero substituted furans selectively. It was demonstrated that, depending on reaction conditions, ambident substrates can be selectively transformed into furan products, as well as undergo selective 6-exo-dig or Nazarov cyclizations. Our mechanistic investigations have revealed that the transformation proceeds via allenylcarbonyl or allenylimine intermediates followed by 1,2-group migration to the allenyl sp carbon during cycloisomerization. It was found that 1,2-migration of chalcogens and halogens predominantly proceeds via formation of irenium intermediates. Analogous intermediate can also be proposed for 1,2-aryl shift. Furthermore, it was shown that the cycloisomerization cascade can be catalyzed by Bransted acids, albeit less efficiently, and commonly observed reactivity of Lewis acid catalysts cannot be attributed to the eventual formation of proton. Undoubtedly, thermally induced or Lewis acid-catalyzed transformations proceed via intramolecular Michael addition or activation of the enone moiety pathways, whereas certain carbophilic metals trigger carbenoid/oxonium type pathway. However, a facile cycloisomerization in the presence of cationic complexes, as well as observed migratory aptitude in the cycloisomerization of unsymmetrically disubstituted aryl- and alkylallenes, strongly supports electrophilic nature for this transformation. Full mechanistic details, as well as the scope of this transformation, are discussed.

Full text of DOI:10.1021/ja0773507

Published on Web 01/04/2008
Metal-Catalyzed 1,2-Shift of Diverse Migrating Groups in
Allenyl Systems as a New Paradigm toward Densely
Functionalized Heterocycles
Alexander S. Dudnik, Anna W. Sromek, Marina Rubina, Joseph T. Kim,
Alexander V. Kel’in, and Vladimir Gevorgyan*
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street, 4500 SES,
M/C 111, Chicago, Illinois 60607-7061
Received September 22, 2007; E-mail: vlad@uic.edu
Abstract: A general, mild, and efficient 1,2-migration/cycloisomerization methodology toward multisubstituted
3-thio-, seleno-, halo-, aryl-, and alkyl-furans and pyrroles, as well as fused heterocycles, valuable building
blocks for synthetic chemistry, has been developed. Moreover, regiodivergent conditions have been identified
for C-4 bromo- and thio-substituted allenones and alkynones for the assembly of regioisomeric 2-hetero
substituted furans selectively. It was demonstrated that, depending on reaction conditions, ambident
substrates can be selectively transformed into furan products, as well as undergo selective 6-exo-dig or
Nazarov cyclizations. Our mechanistic investigations have revealed that the transformation proceeds via
allenylcarbonyl or allenylimine intermediates followed by 1,2-group migration to the allenyl sp carbon during
cycloisomerization. It was found that 1,2-migration of chalcogens and halogens predominantly proceeds
via formation of irenium intermediates. Analogous intermediate can also be proposed for 1,2-aryl shift.
Furthermore, it was shown that the cycloisomerization cascade can be catalyzed by Brønsted acids, albeit
less efficiently, and commonly observed reactivity of Lewis acid catalysts cannot be attributed to the eventual
formation of proton. Undoubtedly, thermally induced or Lewis acid-catalyzed transformations proceed via
intramolecular Michael addition or activation of the enone moiety pathways, whereas certain carbophilic
metals trigger carbenoid/oxonium type pathway. However, a facile cycloisomerization in the presence of
cationic complexes, as well as observed migratory aptitude in the cycloisomerization of unsymmetrically
disubstituted aryl- and alkylallenes, strongly supports electrophilic nature for this transformation. Full
mechanistic details, as well as the scope of this transformation, are discussed.
heterocycles. Within this group,6 the variations of Paal-Knorr
synthesis5 has proven to be the most powerful method for the
synthesis of furans and pyrroles. However, this approach is
unsuitable for acid-sensitive substrates, as well as C-2 unsub-
stituted heterocycles, owing to the instability of the precursors.
Introduction
Furans and pyrroles are ubiquitous heterocycles, broadly
found in naturally occurring and biologically active com-
pounds,1,2 as well as in material science.3 Among these,
heterosubstituted furans and pyrroles represent an important
subclass, both as synthons4 and themselves as functionalized
heterocycles. Approaches toward functionalized five-membered
heterocycles can be divided into two groups: functionalization
of a preexisting heterocyclic core, and assembly of the ring from
acyclic precursors.5 Among the two, the latter route has greater
potential for rapidly obtaining diversity in functionalized
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J. AM. CHEM. SOC. 2008, 130, 1440-1452
10.1021/ja0773507 CCC: $40.75 © 2008 American Chemical Society

Diverse Migrating Groups in Allenyl Systems
A R T I C L E S
Scheme 1. General Cu-Catalyzed Cycloisomerization of Alkynyl
Ketones and Imines toward Furans and Pyrroles
As an alternative, focus has shifted lately to catalytic approaches
toward furans7 and pyrroles8 from acyclic substrates, which often
employ milder conditions and provide easy access to multisub-
stituted heterocyclic cores. Atom-economical cycloisomerization
methods are particularly attractive. Among them, transition
metal-catalyzed cycloisomerizations of allenyl ketones 1 intro-
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duced by Marshall7m-q (Cat ) Ag) and then elaborated by
Hashmi7i (Cat ) Au) have become one of the most powerful
methods for assembly of furan ring 2. Along this line, we have
recently developed a mild and efficient Cu-catalyzed cycloi-
somerization of alkynyl imines9 and ketones 310 into the
respective heterocycles 2 (Scheme 1). The reaction conditions,
which were developed, are compatible with both acid- and base-
sensitive substrates.9,10 Moreover, this method proved to be
especially efficient for the synthesis of C-2 unsubstituted
pyrroles 2, which are not readily available through traditional
condensation methods (Scheme 1).5 Mechanistic investigations
revealed that the reaction proceeds through an allenylimine or
-ketone intermediate 1, and that the propargylic protons
ultimately reside at the C-3 and C-4 positions of the ring
(Scheme 1).9,11
Despite a number of advantages of these protocols, their scope
is limited to the preparation of C-3 and C-4 unsubstituted
heterocycles only. We reasoned that this problem could be
alleviated if one of the hydrogens at C-4 in 4 is replaced with
a suitable migrating group Y. Thus, aiming at expanding the
scope of the migrating group, we have recently developed a set
of cascade methods for the synthesis of C-3 substituted pyrroles
and furans 7 proceeding via 1,2-shift of thio-,12 halogen-,13 and
aryl/alkyl-14 groups in allene 5 (Scheme 2).
Herein, we describe a more detailed study of these transfor-
mations, the synthesis of seleno-heterocycles including unprec-
edented 1,2-selenium migration, as well as a more thorough
mechanistic investigation of these unique cascade cycloisomer-
izations.
Results and Discussion
1,2-Sulfur Migration in the Synthesis of Heterocycles. 1,2-
Migration of chalcogenides15 is an important chemical trans-
formation, which is extensively used in carbohydrate chemistry
for substitution at the anomeric center,16,17 as well as in the
synthesis of stereodefined, nonaromatic heterocycles18,19 and
allylsulfides.18 Furthermore, 1,2-thio-shift is known to occur in
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J. AM. CHEM. SOC. VOL. 130, NO. 4, 2008 1441

A R T I C L E S
Dudnik et al.
Scheme 2. Introduction of Different Migrating Groups toward Trisubstituted Heterocycles
Scheme 3. 1,2-H Vs 1,2-S Migration during Cycloisomerization
Table 1. Optimization of Cycloisomerization of Thioalkynones
aromatic rings20 and to carbenoid centers.21 Known 1,2-
migrations of chalcogens can be classified as two types: 1,2-
migration from sp3 center to adjacent sp3 center via a thiiranium
or seleniranium intermediate16 and 1,2-migration from either
sp3 or sp2 center to another sp2-carbon.7an,20,22 However, prior
to our work,12 there were no reports on 1,2-migration of the
thio-group from an olefinic sp2 carbon to an sp center.
During investigation of the scope of the recently found Cu-
catalyzed transformation of alkynyl ketones and imines 3 into
2,5-disubstituted furans10 and pyrroles 2,9 it was discovered that
heating of thioalkynyl ketone 8 in DMA in the presence of CuI
(10 mol %) not only produced the targeted 2,5-disubstituted
furan 10 but also a small amount of the 2,4-disubstituted furan
11 (Scheme 3).
entry
catalyst
GC ratio 10:11
NMR yield (%)a
1
2
3
4
5
CuI
AuCl3
PtCl2
Pd(MeCN)2Cl2
(Et3P)AuCl
5:1
1:1.4
1:2.5
1:3.5
20:1
66b
5
traces
2
63
a NMR yields calculated using dibromomethane as an internal standard.
b DMA used as solvent.
from an even more preferential 1,2-hydrogen vs 1,2-thio shift
in 9 (Table 1).
Brief optimization of this reaction revealed that AuCl3, PtCl2,
and PdCl2(MeCN)2 led largely to decomposition. However,
employment of (Et3P)AuCl afforded a 20:1 mixture of regioi-
someric furans favoring “normal” product 10, likely resulting
Intrigued by the unexpected observation of the 3-thiofuran
11, we endeavored to investigate the formation of this product
more thoroughly. Initially, we hypothesized that the two
products arise from a common allenyl ketone intermediate 9.9,23
The “normal” product 10 forms from the copper-assisted ring
closure, followed by the base-assisted intramolecular proton
transfer.9,10 The regioisomeric furan 11 was thought to result
from the intramolecular Michael addition of sulfur at the allenic
carbon, forming an intermediate aromatic thiirenium zwitterion
6 (Scheme 2),24,25 which underwent further cycloisomerization
to give 11. It occurred to us that if the above concept is correct,
then replacement of one of the propargylic hydrogens in 8 with
any other nonmigrating group should enforce selective 1,2-
migration of the thio group to produce the 3-thio substituted
furan. To examine this proposal, thioalkynone 12a was subjected
to the cycloisomerization conditions described above. Remark-
ably, cycloisomerization of 12a proceeded smoothly to give
3-thio substituted furan 14a as a single regioisomer in excellent
yield (Scheme 4).
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P. J. Org. Chem. 2002, 67, 2854. (g) Hamel, P. Tetrahedron Lett. 1997,
38, 8473.
(19) (a) Xu, F.; Shi, W.; Wang, J. J. Org. Chem. 2005, 70, 4191. (b) Jiao, L.;
Zhang, Q.; Liang, Y.; Zhang, S.; Xu, J. J. Org. Chem. 2006, 71, 815.
(20) For sulfur migration in carbohydrates, see: (a) Smoliakova, I. P. Curr.
Org. Chem. 2000, 4, 589. (b) Johnston, B. D.; Pinto, B. M. J. Org. Chem.
2000, 65, 4607. (c) Yu, B.; Yang, Z. Org. Lett. 2001, 3, 377. (d) Yang, Z.;
Yu, B. Carbohydrate Res. 2001, 333, 105. (e) Yu, B.; Yang, Z. Tetrahedron
Lett. 2000, 41, 2961. (f) Yang, Z.; Cao, H.; Hu, J,; Shan, R.; Yu, B.
Tetrahedron 2003, 59, 249. (g) Yu, B.; Wang, P. Org. Lett. 2002, 4, 1919.
(h) Viso, A.; Poopeiko, N.; Castillon, S. Tetrahedron Lett. 2000, 41, 407.
(i) Nicolaou, K. C.; Ladduwahetty, T.; Randall, J. L.; Chucholowski, A. J.
Am. Chem. Soc. 1986, 108, 2466. (j) Nicolaou, K. C.; Fylaktakidou, K. C.;
Monenschein, H.; Li, Y.; Wetershausen. B.; Mitchell, H. J.; Wei, H-x.;
Guntupalli, P.; Hepworth, D.; Sugita, K. J. Am. Chem. Soc. 2003, 125,
15433. (k) Nicolaou, K. C.; Rodriguez, R. M.; Mitchell, H. J.; Suzuki, H.;
Fylaktakidou, K. C.; Baudoin, O.; van Delft, F. L. Chem.-Eur. J. 2000, 6,
3095. (l) Pratt, M. R.; Bertozzi, C. R. J. Am. Chem. Soc. 2003, 125, 6149.
(m) Liptak, A.; Sajtos, F.; Janossy, L.; Gehle, D.; Szilagyi, L. Org. Lett.
2003, 5, 3671. (n) Maiareanu, C.; Kanai, A.; Wiebel, J-M.; Pale, P. J. Carb.
Chem. 2005, 24, 831.
Naturally, next we investigated the scope of a selective
migrative cycloisomerization of substituted propargylsulfides
(23) For the base- or transition metal-base-assisted propargyl-allenyl isomer-
ization, see, for example: (a) Garratt, P. J.; Neoh, S. B. J. Am. Chem. Soc.
1975, 97, 3255. (b) Oku, M.; Arai, S.; Katayama, K.; Shioiri, T. Synlett
2000, 493. (c) Yeo, S.-K.; Shiro, M.; Kanematsu, K. J. Org. Chem. 1994,
59, 1621. (d) Watanabe, S.-i.; Miura, Y.; Iwamura, T.; Nagasawa, H.;
Kataoka, T. Tetrahedron Lett. 2007, 48, 813. (e) Ma, S.; Hao, X.; Meng,
X.; Huang, X. J. Org. Chem. 2004, 69, 5720. (f) Wang, Y.; Burton, D. J.
Org. Lett. 2006, 8, 5295. (g) Lepore, S. D.; Khoram, A.; Bromfield, D. C.;
Cohn, P.; Jairaj, V.; Silvestri, M. A. J. Org. Chem. 2005, 70, 7443.
(24) For stable thiirenium ions, see for example: (a) Lucchini, V.; Modena,
G.; Valle, G.; Capozzi, G. J. Org. Chem. 1981, 46, 4720. (b) Lucchini, V.;
Modena, G.; Pasquato, L. Gazz. Chim. Ital. 1997, 127, 177.
(21) For selenium migration in carbohydrates, see: (a) Nicolaou, K. C.; Mitchell,
H. J.; Fylaktakidou, K. C.; Suzuki, H.; Rodriguez, R. M. Angew. Chem.,
Int. Ed. 2000, 39, 1089. (b) Nicolaou, K. C.; Fylaktakidou, K. C.; Mitchell,
H. J.; van Delft, F. L.; Rodriguez, R. M.; Conley, S. R.; Jin, Z. Chem. Eur.
J. 2000, 6, 3166. (c) Poopeiko, N.; Fernandez, R.; Barrena, M. I.; Castillon,
S. J. Org. Chem. 1999, 64, 1375. See also ref. 16h.
(22) (a) Plate, R.; Nivard. R. J. F.; Ottenheijm, H. C. J. Tetrahedron 1986, 42,
4503. (b) Hamel, P. J. Org. Chem. 2002, 67, 2854. (c) Volontereo, A.;
Zanda, M.; Bravo, P.; Fronza, G.; Cavicchio, G.; Crucianelli, M. J. Org.
Chem. 1997, 62, 8031. (d) Peng, L.; Zhang, X.; Zhang, S.; Wang, J. J.
Org. Chem. 2007, 72, 1192.
(25) (a) Lucchini, V.; Modena, G.; Pasquato, L. J. Am. Chem. Soc. 1993, 115,
4527. (b) Destro, R.; Lucchini, V.; Modena, G.; Pasquato, L. J. Org. Chem.
2000, 65, 3367.
9
1442 J. AM. CHEM. SOC. VOL. 130, NO. 4, 2008

Diverse Migrating Groups in Allenyl Systems
A R T I C L E S
Scheme 4. Selective 1,2-Sufur Migration during
Cycloisomerization of 12a
high yields (entries 5-7). The alkylsulfanyl group migrated with
efficiency comparable to its phenylsulfanyl-analog to give the
corresponding furan 14h in 72% yield (entry 8). Moreover, it
was found that thiopropargyl imines 12i-n underwent a similar
transformation in the presence of CuI to give the corresponding
3-thio-substituted pyrroles 14i-n in good yields (entries 9-14).
Again, the dodecylsulfanyl-group (entry 10) migrated compa-
rably to the phenylsulfanyl-analog (entry 9) and the THP-
protected alcohol functionality was tolerated (entry 14). It is
worth mentioning that all synthesized pyrroles have deprotect-
able groups at the nitrogen atom, such as tert-butyl- (14i,j entries
9,10),26 trityl- (14k, entry 11),27 and 3-(ethylbutyryl)- (EB)9,28
(14l-n, entries 12-14), and thus can be easily further func-
tionalized at the nitrogen site. In addition, fused pyrrolohetero-
cycle 14o was smoothly synthesized in a preparative scale from
12o.
Table 2. Cycloisomerization of Thioalkynones and
Thioalkynimines 12 into 3-Thiofurans 14
Generally, transformation of thiopropargyl-ketones or imines
12 into furans and pyrroles 14 required presence of 0.2-5 equiv
of triethylamine as a base.11 However, when phenylthioprop-
argylketone 12g possessing tetrahydro-2H-pyran-2-yloxy moiety
was subjected to the cycloisomerization conditions in the
absence of the base, dihydro-2H-pyran-6-yl derivative 15 was
formed in 93% yield along with the trace amounts of the
expected furan 14g (Scheme 5). Normally, in the presence of
base, 12g undergoes a facile prototropic rearrangement to
allenylsulfide 13g, which via a putative thiirenium intermediate
i, transforms into furan 14g. We hypothesized that in the absence
of base this route is unlikely. Instead, 12g undergoes a
competitive 6-exo-dig cyclization to form 2-yledene-tetrahydro-
2H-pyranium intermediate ii which, upon fragmentation with
the loss of 3,4-dihydro-2H-pyran, gives enone iii. Subsequent
Cu-assisted isomerization of the latter produces the thermody-
namically more stable enone 15. This was confirmed by DFT
calculations (B3LYP; 6-31G*: +3.6 kcal/mol and +6.6 kcal/
mol ground state energy differences for (E)-iii and (Z)-iii over
15, accordingly).
1,2-Selenium Migration in the Synthesis of Heterocycles.
Motivated by the successful 1,2-thio migration during the
cycloisomerization reaction of alkynyl ketones and imines, we
next attempted to incorporate 1,2-selenium migration into the
cycloisomerization cascade. Selenoheterocycles are important
units which have found broad applications in biological studies
as cytotoxic antitumor agents,29 as NMR active tracers, and in
protein-enzyme interaction studies.30 Synthesis of nonaromatic
selenoheterocycles, including selenolactones, is well known. The
majority of syntheses involve electrophilic activation of an
unsaturated bond followed by intramolecular ring closure.31 In
contrast, only a few scattered methods have been reported for
the synthesis of 3-seleno-furans and pyrroles, including a Paal-
Knorr approach,32 unselective electrophilic selenation,33 and
a Isolated yields, reactions were performed on 1 mmol scale. b Reaction
was performed on 3.89 mmol scale under the following conditions: 0.5
equiv CuBr, 1:7 Et3N:DMA, 0.08M, 150 °C, 12 h.
en route to 3-thiosubstituted heterocycles. Accordingly, a series
of alkyl-substituted propargyl sulfides 12 were synthesized and
subjected to the cycloisomerization reaction (Table 2). Cycloi-
somerization of thiopropargylketones 12a,b,c proceeded un-
eventfully, affording the trisubstituted furans 14a,b,c in good
to excellent yields (entries 1-3). Gratifyingly, thiopropargyla-
ldehyde 12d underwent smooth and selective cycloisomeriza-
tion, producing 2-butyl-3-(phenylthio)furan (14d) in 71% yield
as a single reaction product (Table 2, entry 4). Cycloisomer-
ization of (phenylthio)propargylketones possessing alkenyl-
(12e), ester- (12f), and tetrahydro-2H-pyran-2-yloxy- (12g)
functionalities in the side chain proceeded readily, affording
the corresponding trisubstituted furans 14e-g in good to very
(26) For deprotection of N-Bu-t-group in pyrroles, see: (a) Leroy, J.; Wakselman,
C. Tetrahedron Lett. 1994, 35, 8605. (b) La Porta, P.; Capuzzi, L.; Bettarini,
F. Synthesis 1994, 3, 287.
(27) For deprotection of N-Tr-group in pyrroles, see: Chadwick, D. J.; Hodgson,
S.T. J. Chem. Soc. Perkin Trans 1 1983, 93.
(28) For deprotection of analogous group in pyrroles, see: Roder, E.; Wiedenfeld,
H.; Bourauel, T. Liebigs Ann. Chem. 1985, 1708.
(29) Abele, E.; Popelis, J.; Shestakova, I.; Domracheva, I.; Arsenyan, P.;
Lukevics, E. Chem. Heterocycl. Comp. 2004, 40, 742.
(30) (a) Budisa, N.; Pal, P. P.; Alefelder, S.; Birle, P.; Krywcun, T.; Rubini,
M.; Wenger, W.; Bae, J. H.; Steiner, T. Biol. Chem. 2004, 385, 191. (b)
Bae, J. H.; Alefelder, S.; Kaiser, J. T.; Friedrich, R.; Moroder, L.; Huber,
R.; Budisa, N. J. Mol. Biol. 2001, 309, 925. (c) Boles, J. O.; Henderson,
J.; Hatch, D.; Silks, L. A. Biochem. Biophys. Res. Commun. 2002, 298,
257. (d) Welch, M.; Phillips, R. S. Bioorg. Med. Chem. Lett. 1999, 9, 637.
9
J. AM. CHEM. SOC. VOL. 130, NO. 4, 2008 1443

A R T I C L E S
Dudnik et al.
Scheme 5. Competitive 6-exo-dig Cyclization of 12g in the Absence of the Base
Table 3. Cycloisomerization of Selenoalkynone 16a into Furans
17a and 18
halogen-selenium exchange.34 These methods suffer from
significant drawbacks, including limited scope of products,
imperfect regioselectivity, and low yields. We reasoned that our
1,2-migration/cycloisomerization methodology might be a per-
fect and convenient solution for the synthesis of 3-seleno-furans
and pyrroles.
entry
catalyst
17a (%)a
18 (%)a
1
2
3
4
5
6
AuCl3
PtCl2
Pd(MeCN)2Cl2
none
CuCl
24
70
13
34
30
33
-
To this end, cycloisomerization of propargylselenoalkynone
16a toward furan 17a was examined in the presence of different
transition metal catalysts (Table 3). Surprisingly, cycloisomer-
ization of 16a in the presence of gold, platinum, and palladium
catalysts (entries 1-3) provided formation of furan 17a along
with notable amounts of regioisomeric furan 18, product of the
competitiVe 1,2-alkyl migration/cyclization cascade. It was found
that heating of 16a in toluene without catalyst afforded the target
furan 17a almost exclusively, albeit in 38% yield (entry 4). The
selectivity and yield were improved by employing CuCl as the
catalyst, affording 17a as the sole regioisomer in 57% yield
(entry 5). Employment of CuCl catalyst in DMA:Et3N solvent
mixture at room temperature produced furan 17a in 96% yield
(entry 6).
38
57b
96c
-
CuCl
-
a NMR yields calculated using dibromomethane as an internal standard
for reactions performed on 0.1 mmol scale. b Reaction was performed on
0.5 mmol scale under the following conditions: 5 mol % CuCl, 10:1
DMA:Et3N, rt.
addition to the t-butyl ketone 16a, alkynal 16b and methyl- and
phenyl ketones 16c and 16d underwent cycloisomerization
cleanly to afford the corresponding furans 17b-d in good yields
(Table 4, entries 1-3). A benzylic group was also tolerated,
affording trisubstituted furan 17e in 71% yield and even
disubstituted furan 17f in 53% yield (entries 4, 5).35 Next, we
tested the feasibility of applying this methodology for the
synthesis of selenopyrroles. Indeed, it was found that propar-
gylseleno alkynylimines 16g,h smoothly underwent cycloi-
somerization at room temperature to afford the corresponding
N-protected9,26-28 pyrroles 17g,h in 74 and 57% yields,
respectively (Table 4, entries 6, 7). However, cycloisomerization
of sterically hindered N-trityl alkynyl imine 16i required heating
at 110 °C to give pyrrole 17i in 54% yield (Table 4, entry 8).
1,2-Halogen Migration in the Synthesis of Halofurans.
Transformations involving selective 1,2-halogen migration
have not been reported until recently,36 when Iwasawa and
then Fu¨rstner disclosed 1,2-iodine,37 and 1,2-iodine and -bromine
Next, the scope of this transformation was examined employ-
ing the optimized reaction conditions. It was found that, in
(31) (a) Nicolau, K. C. Tetrahedron 1981, 37, 4097. (b) Nicolaou, K. C.; Seitz,
S. P.; Sipio, W. J.; Blount, J. F. J. Am. Chem. Soc. 1979, 101, 3884. (c)
Clive, D. L. J.; Chittattu, G. J. Chem. Soc. Chem. Commun. 1977, 484. (d)
Aprile, C.; Gruttadauria, M.; Amato, M. E.; D’Anna, F.; Lo Meo, P.; Riela,
S.; Noto, R. Tetrahedron 2003, 59, 2241. (e) Tiecco, M.; Testaferri, L.;
Temperini, A.; Bagnoli, L.; Marini, F.; Santi, C. Synlett 2003, 655. (f)
Tiecco, M.; Testaferri, L.; Bagnoli, L. Tetrahedron 1996, 52, 6811. (g)
Van de Weghe, P.; Bourg, S.; Eustache, J. Tetrahedron 2003, 59, 7365.
(h) Denmark, S. E.; Edwards, M. G. J. Org. Chem. 2006, 71, 7293. (i)
Back, T. G.; Moussa, Z.; Parvez, M. J. Org. Chem. 2002, 67, 499. (j) Wang,
X.; Houk, K. N.; Spichty, M.; Wirth, T. J. Am. Chem. Soc. 1999, 121,
8567. (k) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67,
3437. Larock, R. C. J. Org. CHem. 2002, 67, 1905. (l) Pannecoucke, X.;
Outurquin, F.; Paulmier, C. Eur. J. Org. Chem. 2002, 995. (m) Berthe, B.;
Outurquin, F.; Paulmier, C. Tetrahedron Lett. 1997, 38, 1393. (n) Jones,
A. D.; Knight, D. W.; Redfern, A. L.; Gilmore, J. Tetrahedron Lett. 1999,
40, 3267. (o) Jones, A. D.; Redfern, A. L.; Knight, D. W.; Morgan, I. R.;
Williams, A. C. Tetrahedron 2006, 62, 9247.
(32) (a) D’Onofrio, F.; Margarita, R.; Parlanti, L.; Pernazza, D.; Piancatelli, G.
Tetrahedron 1997, 53, 15843.
(33) (a) Hartke, K.; Wendebourg, H. H. Liebigs Ann. Chem. 1989, 5, 415. (b)
Hartke, K.; Wendebourg, H. H. Heterocycles 1988, 27, 639.
(35) It should be mentioned, however, that attempts to cycloisomerize primary
propargyl selenides led to formation of detectable amounts of diphenyl
diselenide only, probably due to the lower stability of the less substituted
allene intermediate 19.
(34) (a) Agenas, L. B.; Lindgren, B. ArkiV foer Kemi 1968, 29, 479. (b) Agenas,
L. B.; Lindgren, B. ArkiV foer Kemi 1967, 28, 145. (c) Chierici, L. Farm.
Ed. Sci. 1953, 8, 156. (d) Vvedensky, V. Yu.; Brandsma, L.; Shtefan, E.
D.; Trofimov, B. A. Tetrahedron 1997, 53, 13079. (e) Vvedensky, V. Yu.;
Brandsma, L.; Shtefan, E. D.; Trofimov, B. A. Tetrahedron 1997, 53, 16783.
See also ref 28.
(36) For scattered reports on non-selective halogen migration in unsaturated
systems, see for example: (a) Bunnett, J. F. Acc. Chem. Res. 1972, 54,
140. (b) Morton, H. E.; Leanna, M. R. Tetrahedron Lett. 1993, 34, 4481.
(c) Samuel, S. P.; Nin, T.-q.; Erickson, K. L. J. Am. Chem. Soc. 1989,
111, 1429.
(37) Miura, T.; Iwasawa, N. J. Am. Chem. Soc. 2002, 124, 518.
9
1444 J. AM. CHEM. SOC. VOL. 130, NO. 4, 2008

Diverse Migrating Groups in Allenyl Systems
A R T I C L E S
Table 4. Synthesis of 3-Seleno-Furans and Pyrroles 17
Table 5. Catalyst Optimization for Cycloisomerization of
Bromoallenyl Ketone 20a
entry
cat. (mol %)
solvent
time
GC yield, % (21a:22a)
1
2
3
4
5
6
7
8
9
CuCl (10)
CuI (10)
AgBF4 (5)
PtCl2 (5)
AuCl3 (1)
AuCl3 (1)
Au(PPh3)Cl (1)
Au(PEt3)Cl (1)
AlCl3 (50)
SiO2
toluene
toluene
DCM
toluene
toluene
THF
toluene
toluene
toluene
toluene
1 day
1 day
1 day
3 h
5 min
5 min
9 h
9 h
16 h
16 h
29 (21a only)
21 (21a only)
traces
50 (96:4)
86 (95:5)
78 (5:95)
N/D (16:84)
N/D (<1:99)
27 (21a only)
21 (21a only)
10
precursors.42 Most of these approaches require employment of
strongly electrophilic reagents, thus limiting their application
to substrates lacking acid-sensitive functionalities. With the
successful development of 1,2-thio- and seleno migration/
cycloisomerization approach for the synthesis of trisubstituted
furans and pyrroles, we sought to further expand the scope of
this methodology. Thus, we turned our attention to the synthesis
of 3-halofurans.
We hypothesized that replacement of chalcogens (X ) RS
and RSe) with halogen (X ) Cl, Br, I) in the proposed
intermediate iW12 might provide convenient access to 3-halo-
furans (eq 1). To test this idea, the Cu-catalyzed cycloisomer-
ization of bromoallenyl ketone 20a43 was examined, which,
indeed, led to the
a Isolated yields for reactions performed on 0.5 mmol scale. b 15 mol %
CuCl, 20% Et3N, 0.5 M in DMA, rt. c 5 mol % CuCl, 10:1 DMA:Et3N, rt.
d 30 mol % CuCl, 5 equiv Et3N, 0.5 M in DMA, rt. e 30 mol % CuCl, 5
equiv Et3N, 0.5 M in DMA, 110 °C.
migration,38 respectively, in alkynyl halides to produce fused
haloarenes. Furthermore, Liu showed 1,2-iodine shift in a Ru
alkylidene complex.39 Some of these transformations involved
metal carbenoid intermediates and were used in the synthesis
of carbocycles.38,39 To the best of our knowledge, the synthesis
of halogenated heterocycles proceeding through a halirenium
intermediate has not been previously reported.
Halofurans, important building blocks, are traditionally
obtained by electrophilic halogenation of furans,40 via halogen-
induced cyclizations,41 or cyclocondensations of halogenated
formation of 3-bromofuran 21a, albeit in poor yield (Table 5,
entries 1-2). In contrast, AgBF4, which proved efficient in
cycloisomerization of different allenyl ketones,44 did not catalyze
this reaction at all (entry 3). Employment of PtCl2, however,
produced 3-bromofuran 21a in 50% yield along with small
amounts of 2-bromofuran 22a (entry 4). To our delight,
employment of AuCl3 afforded 3-bromofuran 21a in 86% yield
with high selectivity (Table 5, entry 5).43,45 Surprisingly,
switching solvent to THF caused a dramatic change in selectiv-
ity, affording 2-bromofuran 22a as a major product (entry 6).
The latter was also exclusively obtained in the presence of Au-
(PEt3)Cl (entry 8). It was found that selective cycloisomerization
of 20a can be also achieved in the presence of AlCl3 and even
silica gel, affording 3-bromofuran 21a, though in low yield
(entries 9-10).
(38) Mamane, V.; Hannen, P.; Fu¨rstner, A. Chem.-Eur. J. 2004, 10, 4556.
(39) Shen, H.-C.; Pal, S.; Lian, J.-J.; Liu, R.-S. J. Am. Chem. Soc. 2003, 125,
15762.
(40) For examples on electrophilic halogenations of furans, see: (a) Keegstra,
M. A.; Klomp, A. J. A.; Brandsma, L. Synth. Commun. 1990, 20, 3371.
(b) Verkruijsse, H. D.; Keegstra, M. A.; Brandsma, L. Synth. Commun.
1989, 19, 1047. (c) Song, Z. Z; Wong, H. N. C. Liebigs Ann. Chem. 1994,
1, 29. (d) Yang, Y.; Wong, H. N. C. Tetrahedron 1994, 50, 9583. (e) Kondo,
Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am. Chem. Soc. 1999, 11,
3539. (f) Gilman, H.; Mallory, H. E.; Wright, G. F. J. Am. Chem. Soc.
1932, 54, 733. (g) Dickman, D. A; Ku, Y.-Y.; Morton, H. E.; Chemburkar,
S. R.; Patel, H. H.; Thomas, A.; Plata, D. J.; Sawick, D. P. Tetrahedron:
Asymm. 1997, 8, 1791. (h) Aiello, E.; Dattolo, G.; Cirrincione, G.; Almerico,
A. M.; D’Asdia, I. J. Heterocycl. Chem. 1982, 19, 977. (i) Belen’kii, L. I.;
Gromova, G. P.; Gol’dfarb, Ya. L. Chem. Heterocycl. Comp. 1978, 246.
(j) Oleinik, A. F.; Solov’ena, N. P.; Turchin, K. F.; Sheinker, Yu. N.;
Novitskii, K. Yu.; Smirnova, E. N.; Dozorova, E. N. Chem. Heterocycl.
Comp. 1980, 334. (k) Belen’kii, L. I.; Gromova, G. T.; Gol’dfarb, Ya. L.
Chem. Heterocycl. Comp. 1975, 1249. (l) Nolan, S. M.; Cohen, T. J. Org.
Chem. 1981, 46, 2473. (m) Nazarova, Z. N.; Babaev, Yu. A.; Umanskaya,
L. G. Chem. Heterocycl. Comp. 1969, 5, 17. (n) Bures, E. J.; Keay, B. A.
Tetrahedron Lett. 1988, 29, 1247. (o) Bures, E.; Nieman, J. A.; Yu, S.;
Spinazze, P. G.; Bontront, J.-L. J.; Hunt, I. R.; Rauk, A.; Keay, B. A. J.
Org. Chem. 1997, 62, 8750. (p) Carpenter, A. J.; Chadwick, D. J. J. Org.
Chem. 1985, 50, 4362. (q) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto,
T J. Am. Chem. Soc. 1999, 121, 3539.
(42) For examples of cyclocondensation of halogen-containing precursors, see:
(a) Tanabe, Y.; Wakimura, K.; Nishii, Y.; Muroya, Y. Synthesis 1996, 388.
(b) Mee, S. P. H.; Lee, V.; Baldwin, J. E.; Cowley, A. Tetrahedron 2004,
60, 3695. (c) Kraus, G. A.; Wang, X. Synth. Commun. 1998, 28, 1093. (d)
Reich, H. D.; Olson, R. E. J. Org. Chem. 1987, 52, 2315.
(41) For halogen induced cyclizations, see: (a) Bew, S. P.; Knight, D. W. Chem.
Commun.1996, 1007. (b) El-Taeb, G. M. M.; Evans, A. B.; Jones, S.;
Knight, D. W. Tetrahedron Lett. 2001, 42, 5945. (c) Rao, M. S.; Esho, N.;
Sergeant, C.; Dembinski, R. J. Org. Chem. 2003, 68, 6788. (d) Sniady, A.;
Wheeler, K. A.; Dembinski, R. Org. Lett. 2005, 7, 1769. (e) Schultz-
Fademrecht, C.; Zimmerman, M.; Frohlich, R.; Hoppe, D. Synlett 2003,
1969. (f) Obrecht, D. HelV. Chim. Acta 1989, 72, 447. (g) Reich, H. J.;
Olson, R. E. J. Org. Chem. 1987, 52, 2315. (h) Gorzynski, M.; Rewicki,
D. Liebigs Ann. Chem. 1986, 625.
(43) Bromoallene 20a contained trace to notable amounts of bromopropargyl
ketone, from which it was obtained. Under reaction conditions bromopro-
pargyl ketone underwent rapid isomerization to 20a. The same applies to
iodoallenes 20i and 20k (see Table 6). Facile propargyl-allenyl isomer-
ization of propargyl ketones in the presence of gold catalyst was previously
observed; see ref 7i.
(44) (a) See ref 7n. (b) Sromek, A. W.; Kel’in, A. V.; Gevorgyan, V. Angew.
Chem., Int. Ed. 2004, 43, 2280.
9
J. AM. CHEM. SOC. VOL. 130, NO. 4, 2008 1445

A R T I C L E S
Dudnik et al.
Table 6. 1,2-Halogen Migration/Cycloisomerization toward
Halofurans 21
went this transformation to produce 3-chlorofuran 21j. However,
the observed much more sluggish reaction of 20j was attributed
to the decreased ability of chlorine to form halirenium species
iW (eq 1). Cycloisomerization of ambident trisubstituted allenyl
iodide 20k possessing more bulky n-propyl group at C-2 than
that in iodoallenes 20h,i produced of 2:1 mixture of 3- and
2-iodofurans 21k and 21l, respectively.
1,2-Alkyl/Aryl Migration in the Synthesis of Furans. As
discussed above, cycloisomerization of C-4 monosubstituted
allenyl ketones 23 in the presence of transition metal catalysts
can be used as an efficient approach for the assembly of the
furan ring via formal 1,2-hydrogen shift (eq 2).7i,m-q
Inspired by the observation of competitive 1,2-alkyl migration
during cycloisomerization of selenoalkynone 16a into 3-alkyl-
furan 18 (Table 3, entries 1-3), we envisioned that development
of a cascade transformation involving a 1,2-migration of an
alkyl/aryl group8k,46,47,48,49 in allenylketones is also feasible. If
successful, this approach may allow for the rapid assembly of
fully carbon-substituted furans. To this end, the possible
cycloisomerization of allene 25 into furan 26 in the presence
of different catalysts was tested (Table 7). It was found that
employment of Au(I) and Au(III) halides gave low yields of
furan 26. Gratifyingly, switching to cationic Au(I) complexes
lead to formation of expected furan in nearly quantitative yield
(entries 3-4). Analogously to gold halides, Pt(II), Pt(IV), and
Pd(II) salts were inefficient in this reaction (entries 5-7). Use
of Cu(I) halides resulted in no reaction, whereas employment
of cationic Ag(I), Cu(I), and Cu(II) salts produced 26 in
moderate to high yields. Encouraged by these results, we have
also examined main group metals in this reaction. Surprisingly,
Al-, Si-, Sn-, and In triflates provided moderate to excellent
yields of desired furan 26. Although Au(PPh3)OTf, AgOTf, In-
(OTf)3, Sn(OTf)2, and TIPSOTf were nearly equally efficient
in the cascade cycloisomerization of 25 to 26, In(OTf)3 appeared
to be a more general catalyst with respect to the substrate
scope.11
a Isolated yields, reactions were performed on 0.29-1 mmol scale with
1 M concentration of 20. b Mixture of allene and corresponding propargyl
isomer was employed (see Supporting Information). c Mixture (2:1) of 21k
1
and 21l by H NMR.
Next, we investigated the scope of this cascade transforma-
tion. Thus, differently substituted haloallenyl ketones were
subjected to Au(III)-catalyzed cycloisomerization (Table 6). It
was found that a variety of alkyl and aryl-substituted bromoal-
lenyl ketones and aldehydes 20 underwent smooth cycloisomer-
ization, affording 3-bromofurans 21 in good to excellent yields
(entries 1-5). Remarkably, this method allowed for efficient
synthesis of halofurans possessing hydroxymethyl (21e) and
alkene (21f) functionalities, which are incompatible with known
methods employing electrophilic reagents. It was found that fully
substituted iodoallenyl ketone 20g reacted more slowly than its
bromo-analogs, producing corresponding furans 21g in good
yield (entry 6). Gratifyingly, ambident disubstituted allenyl
iodides 20h,i underwent exclusive 1,2-iodine migration to afford
2-alkyl and -aryl substituted iodofurans 21h,i in 97 and 71%
yields, respectively (entries 7,8). Chloroallene 20j also under-
(46) For examples of 1,2-shift in carbenoids, see: (a) Xiao, F.; Wang, J. J.
Org. Chem. 2006, 71, 5789, and references therein. (b) Markham, J. P.;
Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 9708. (c) Jime´nez-
Nu´n˜ez, E.; Claverie, C. K.; Nieto-Oberhuber, C.; Echavarren, A. M. Angew.
Chem., Int. Ed. 2006, 45, 5452. (d) Kirsch, S. F.; Binder, J. T.; Crone, B.;
Duschek, A.; Haug, T. T.; Lie´bert, C.; Menz, H. Angew. Chem., Int. Ed.
2007, 46, 2310.
(47) For general reviews, see: (a) Ducrot, P. H. In One or more CH and/or CC
bond(s) formed by rearrangement; Katritzky, A. R., Taylor, R. J. K., Eds.;
Comprehensive Organic Functional Group Transformations II; Elsevier:
Oxford, UK, 2005; Vol. 1, p 375. (b) Constantieux, T.; Rodriguez, J. In
Synthesis by fragmentation and rearrangement; Cossy, J., Ed.; Science of
Synthesis; Thieme: New York, 2005; Vol. 26, p 413. (c) Pattenden, G.,
Ed.; In Carbon-Carbon σ-Bond Formation: Rearrangement Reactions;
Trost, B. M., Fleming, I., Eds.; Comprehensive organic synthesis: selectiv-
ity, strategy, and efficiency in modern organic chemistry; Pergamon
Press: New York, 1991; Vol. 3, p 705.
(48) For a synthesis of carbocycles involving 1,2-alkyl shift to carbenoid center
in allenes, see: (a) Funami, H.; Kusama, H.; Iwasawa, N. Angew. Chem.,
Int. Ed. 2006, 46, 909. (b) Lee, J. H.; Toste, F. D. Angew. Chem., Int. Ed.
2007, 46, 912.
(45) For recent reviews on Au-catalyzed reactions, see: (a) Hoffmann-Ro¨der,
A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387. (b) Hashmi, A. S. K.
Gold Bull. 2004, 37, 51. (c) Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180.
(d) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45,
7896. (e) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2005, 44, 6990. For
selected examples of Au-catalyzed synthesis of heterocycles, see: (f) Yao,
T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 11164. (g)
Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2005, 127, 6962. (h)
Hoffmann-Ro¨der, A.; Krause, N. Org. Lett. 2001, 3, 2537. For Au-catalyzed
carbocyclizations, see for example: (i) Fu¨rstner, A.; Hannen, P. Chem.
Comm. 2004, 2546. (j) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem.
Soc. 2005, 127, 5802. (k) Luzung, M. R.; Markham, J. P.; Toste, F. D. J.
Am. Chem. Soc. 2004, 126, 10858. (l) Zhang, L.; Kozmin, S. A. J. Am.
Chem. Soc. 2004, 126, 11806. (m) Nieto-Oberhuber, C.; Lopez, S.;
Echavarren, A. M. J. Am. Chem. Soc. 2005, 127, 6178. See also ref. 38.
(n) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395. (o) Fu¨rstner, A.;
Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410.
(49) (a) For a synthesis of dehydrofuranones via 1,2-alkyl shift, analogous to a
formal ketol rearrangement, see: Kirsch, S. F.; Binder, J. T.; Lie´bert, C.;
Menz, H. Angew. Chem., Int. Ed. 2006, 45, 5878, and references therein.
(b) See, also: Crone, B.; Kirsch, S. F. J. Org. Chem. 2007, 72, 5435.
9
1446 J. AM. CHEM. SOC. VOL. 130, NO. 4, 2008

Diverse Migrating Groups in Allenyl Systems
A R T I C L E S
Table 7. Optimization of Reaction Conditions for
Cycloisomerization of 25
presence of TTBP for TMSOTf vs TfOH, observed reactivity
for the Lewis acid catalysts cannot be attributed to the formation
of eventual Brønsted acid catalyst. It should be emphasized,
however, that TfOH, indeed, is able to catalyze cycloisomer-
ization of 25 into 26 even with slightly better efficiency for
some 4,4-diaryl substituted allenyl ketones (entry 14 vs 15).
However, cycloisomerization of 4-methyl-1,4-diphenyl alle-
nylketone in the presence of TfOH catalyst appeared to be
notably less efficient (entry 16) compared to that in the presence
of In(OTf)3 (entry 17).
Having in hand a set of optimized conditions, cycloisomer-
ization of differently substituted allenyl ketones 25a-n was
examined (Table 9). Cycloisomerization of 4,4-diphenyl sub-
stituted allenyl ketones 25a-d proceeded smoothly to provide
good to high yields of furans 26a-d. Selective 1,2-migration
of phenyl over methyl group occurred in allenyl ketone 25e to
give 26e in 72% yield (entry 5). In contrast to the methyl-, 1,2-
migration of the ethyl group competed with the phenyl group
in 25f, which resulted in formation of a 2.3:1 mixture of
regioisomeric furans 26f and 26g, respectively (entry 6).52
Cyclopentylideneallenyl ketone 25h underwent smooth cycliza-
tion with ring expansion to give fused furan 26h in 75% yield
(entry 7). Not surprisingly, cycloisomerization of allenyl ketone
25i, possessing more thermodynamically stable 6-membered ring
or 25j, having two methyl groups, provided corresponding furans
26i and 26j in low yields only (entries 8 and 9). It was also
demonstrated that a variety of functional groups such as
methoxy- (entry 10), bromo- (entry 11), nitro- (entry 12), and
cyano- (entry 13) were perfectly tolerated under these reaction
conditions.
entry
cat
mol %
solvent
T,
°
C
yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
AuBr3
AuI
Au(PPh3)OTf
Au(PPh3)OTf
PtCl2
5
5
1
5
5
5
5
5
5
5
5
5
20
5
5
20
5
5
5
tolueneb
tolueneb
tolueneb
DCMc
100
100
100
rt
100
100
100
100
100
100
100
100
rt
100
100
rt
100
100
100
100
23
traces
100 (89)
99
21
21
35
0
42
95
toluened
toluened
toluened
toluened
toluened
toluenee
toluenee
toluenee
DCMc
PtCl4
Pd(PhCN)2Cl2
CuX (XdCl, Br, I)
[CuOTf]2•PhH
Cu(OTf)2
AgPF6
AgOTf
AgOTf
Al(OTf)3
Zn(OTf)2
TMSOTf
In(OTf)3
Sn(OTf)2
TIPSOTf
TMSNTf2
47
(80)
70 (62)
64
toluenee
toluenee
DCMd
39
82 (62)
91 (81)
97 (81)
100 (81)
72
toluenee
toluenee
toluenee
toluenee
5
a NMR yield, isolated yield in parentheses (entries 1-4: Ar ) p-Br-
C6H4; entries 5-20: Ar ) Ph). b Solution (0.05 M) of 25. c Solution (0.02
M) of 25. d Solution (1 M) of 25. e Solution (0.1 M) of 25.
In light of the recent observations that eventual Brønsted acids
are the true catalysts in some transition metal-catalyzed trans-
formations,50 we investigated what role, if any, Brønsted acids
may play in the herein described cycloisomerization reaction.
To this end, the cycloisomerization of 25 by several catalysts
in the presence of proton scavenger, TTBP, was examined
(Table 8).51 It was found that cycloisomerization of allenyl
ketone 25 at 100 °C in toluene in the presence of TfOH or Sn-
(OTf)2 provided furan 26 in almost quantitative NMR yield with
comparable rates (entries 1 and 10). The same result was
observed for reactions performed in 1,2-dichloroethane for
AgOTf, TMSOTf, and TfOH catalysts (entries 4, 6, and 8).
Addition of the TTBP negligibly affected cycloisomerization
reaction for both catalysts in toluene solvent series (entries 2
and 3), owing to the most probable dissociation of Lewis acid-
Lewis base complex at the elevated temperature. In contrast,
addition of TTBP for the 1,2-dichloroethane experiments
completely suppressed the cycloisomerization reaction at room
temperature for TfOH and TMSOTf, and even at 80 °C for
AgOTf (entries 5, 8, and 11). However, elevation of the reaction
temperature allowed for the formation of furan 26 albeit in lower
yields and increased reaction times (entries 6, 9 and 12).
Accordingly, TMSOTf-TTBP pair provided 61% of furan
product, whereas only 36% yield was achieved for the TfOH-
TTBP pair after more prolonged reaction time. Thus, taking
into consideration the more efficient cycloisomerization in the
It was also shown that trisubstituted furan 26b can be directly
obtained from alkynyl ketone 27b (eq 3), albeit the yield for
this one-pot transformation was somewhat lower compared to
that for cycloisomerization of allene 25b (Table 9, entry 2).
The intermediacy of 25b has been confirmed by GC/MS
monitoring of the reaction course. However, this approach is
moderately efficient only for the propargylic systems which can
undergo facile alkynyl-allenyl isomerization, such as in the 27b,
as attempts on direct cycloisomerization of cyclopentyl-
substituted alkynone 27h failed (eq 4).
It should be noted that the cycloisomerization course of C-1
phenyl substituted allenyl ketones in the presence of Lewis acid
catalysts is greatly affected by the bulkiness of C-2 substituent.
Thus, cycloisomerization of C-2 methyl substituted allenylketone
25d in the presence of main group triflates produced furan 26d
along with notable amounts of methylene-indan-1-one 28d.11
Employment of TMSOTf allowed for the formation of 28d in
95% yield as a sole product (Scheme 6). We hypothesized that
(50) There has been a recent discussion on the role of Brønsted acids in
homogenous transition metal-catalyzed reactions. For the most relevant
references, see: (a) Hashmi, A. S. K. Catal. Today 2007, 122, 211. (b) Li,
Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N. W.; He, C. Org. Lett.
2006, 8, 4175. (c) Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.; Utsunomiya,
M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179. (d) Rhee, J. U.; Krische, M. J.
Org. Lett. 2005, 7, 2493.
(51) For, use of TTBP as a TfOH scavenger, see for example: Crich, D.;
Vinogradova, O. J. Org. Chem. 2006, 71, 8473.
(52) See mechanistic discussion below and refs 70 and 71.
9
J. AM. CHEM. SOC. VOL. 130, NO. 4, 2008 1447

A R T I C L E S
Dudnik et al.
Table 8. Comparison of Lewis and Brønsted Acid Catalysts for Cycloisomerization of Allenyl Ketones
entry
R
Ar
cat (mol %)
additive (mol %)
solvent
T,
°
C
time, h
NMR yield (%)a,b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
p-C6H4-CN
p-C6H4-CN
p-C6H4-CN
p-C6H4-CN
p-C6H4-CN
p-C6H4-CN
p-C6H4-CN
p-C6H4-CN
p-C6H4-CN
p-C6H4-CN
p-C6H4-CN
p-C6H4-CN
p-C6H4-CN
p-C6H4-OMe
p-C6H4-OMe
Ph
TfOH (10)
TfOH (10)
Sn(OTf)2 (5)
TfOH (20)
TfOH (20)
-
toluene
toluene
toluene
DCE
DCE
DCE
DCE
DCE
DCE
DCE
100
100
100
rt
rt
95
rt
rt
95
80
1.5
2.0
2.0
1.0
24
96
>99
91
96
0
TTBP (40)
TTBP (20)
-
TTBPc (40)
TfOH (20)
TTBP (40)
48
36
TMSOTf (20)
TMSOTf (20)
TMSOTf (20)
AgOTf (20)
AgOTf (20)
AgOTf (20)
Sn(OTf)2 (5)
TfOH (10)
-
1.0
4.0
24
2.0
2.0
48
1.5
1.0
2.0
1.0
12
>99
TTBP (40)
0
TTBP (40)
61
-
>99
TTBP (40)
DCE
DCE
80
95
0
TTBP (40)
19
>99
88
79
52
77
-
-
-
-
-
toluene
toluene
toluene
toluene
toluene
100
100
100
100
100
In(OTf)3 (5)
TfOH (10)
In(OTf)3 (5)
Ph
a Reactions were performed on 0.1 mmol scale. b Dibromomethane was used as the standard. c TTBP ) 2,4,6-tris-tert-butylpyrimidine.
Table 9. Metal-Catalyzed Synthesis of Furans 26
phenyl groups. A facile aromatic Nazarov cyclization of Wi
produces indanone 28d53 in nearly quantitative yield (Scheme
6).
Mechanistic Discussion. Naturally, we were interested in the
investigation of the mechanisms of herein described 1,2-
migration/cycloisomerization cascade transformations of alky-
nyl- or allenylketones and -imines into corresponding furans
and pyrroles. Our thorough studies revealed many similarities
observed during cascade cycloisomerizations of C-4 diversely
substituted alkynyl and allenyl systems involving 1,2-migration
of various groups as the key step in the assembly of heterocyclic
cores.
Initially, we hypothesized that migrative cycloisomerization
of thioalkynones 12 involves a Cu-assisted prototropic rear-
rangement, thus proceeding via involvement of a reactive allenyl
intermediate 9/13.9,10,12,54 Analogous allenyl intermediate 19 was
proposed for 1,2-selenium migrative cycloisomerization of
selenoalkynones 16, whereas 1,2-halogen or 1,2-alkyl/aryl
migrations were achieved utilizing the corresponding allenyl
compounds 20 and 25 as starting materials. Indeed, failure to
perform efficient cycloisomerization directly from propargylic
ketones (eq 3 vs eq 4), where essential propargyl-allenyl
isomerization is largely suppressed, confirmed the allenyl system
to be a viable and necessary intermediate in the 1,2-alkyl/aryl
migrative cycloisomerization.
Moreover, to gain the support for the involvement of allenyl
intermediate 13, thioallenones 13a,p were prepared by inde-
pendent methods and subjected to the cycloisomerization
conditions described above (see Table 2). Remarkably, it was
found that thioallenyl arylketone 13a, even in the absence of
CuI catalyst, underwent quantitatiVe thermal transformation to
a Isolated yield. b Reactions were performed on 0.25-0.8 mmol scale.
c p-Xylene was used as a solvent. d NMR yield. e Mixture (2.3:1) of 26f:
(53) (a) For the most recent reviews on Nazarov cyclization and related
transformations, see: (a) Frontier, A. J.; Collison, C. Tetrahedron 2005,
61, 7577, and references therein. (b) Pellissier, H. Tetrahedron 2005, 61,
6479, and references therein. (c) Tius, M. A.; Acc. Chem. Res. 2003, 36,
284. (d) Tius, M. A.; Eur. J. Org. Chem. 2005, 2193. (e) See also: Hashmi,
A. S. K.; Bats, J. W.; Choi, J.-H.; Schwarz, L. Tetrahedron Lett. 1998, 39,
7491.
1
1
26g by H NMR. f Mixture (2.2:1) of 26f:26g by H NMR.
activation of the carbonyl function in 25d by a Lewis acid
produces rotamers W and Wi. The latter, in the case of 25d, is
favored over W, which suffers the repulsion between methyl and
(54) For the cuprate-assisted transformation of propargylic thioacetals into allenyl
copper species, see: ref 8c and d.
9
1448 J. AM. CHEM. SOC. VOL. 130, NO. 4, 2008

Diverse Migrating Groups in Allenyl Systems
A R T I C L E S
Scheme 6. Nazarov Cyclization of Tetrasubstituted Phenyl-allenylketone 25d
Scheme 8. Proposed Irenium Intermediates in the 1,2-Chalcogen
Migration/Cycloisomerization Cascade
14a. In contrast, attempts to perform analogous thermal cyclo-
isomerization of thioallenylalkylketone 13p resulted in a total
decomposition of the starting material, whereas 82% of 14p
was isolated when reaction was performed at room temperature
in the presence of 5 mol % of CuI (Figure 1).
Figure 1. Direct Cycloisomerization of Thioallenones 13 into Furans
14.
Scheme 9. Proposed Halirenium Intermediates in the 1,2-Halogen
Migration/Cycloisomerization Cascade
Furthermore, we hypothesized that, considering the enhanced
acidity of the propargylic proton of selenoalkynones 16,55
cycloisomerization of the latter should involve very facile
propargyl-allenyl isomerization, leading to allenone inter-
mediate 19. Indeed, when a subcatalytic loading of copper
chloride was used (Scheme 7 vs Table 4, entry 1), allenal 19b
Scheme 7. Direct Observation of Selenoallenic Intermediate 19b
Thus, based on the experimental data disclosed above, it is
believed that all of the herein reported 1,2-migration/cycloi-
somerization cascade transformations most likely proceed via
allenyl intermediates.
As discussed above, both thioallenone 13a (Figure 1) and
seleno alkynone 16a (Table 3, entry 4) in the absence of the
copper catalyst underwent thermal 1,2-migration/cycloisomer-
ization transformation to give corresponding 3-chalcogeno-
furans. Such reactivity can only be rationalized by involvement
of intramolecular Michael addition of chalcogen at the enone
moiety of the allenone to give intermediate thiirenium24,25 or
selenirenium57 zwitterions Wii and Wiii respectively (Scheme 8).
Subsequent nucleophilic attack by oxygen or nitrogen at the
irenium moiety, followed by either AdN-E or SN2-Vin25 pro-
cesses, furnishes the formation of furan 14. Employment of
transition metal catalysts, such as Cu, Au, Pd, and Pt, in similar
accumulated in the reaction mixture (Scheme 7). Subsequent
treatment of the isolated allenal 19b with copper chloride in
DMA at room temperature afforded furan 17b in good yield
(Scheme 7).56
(55) (a) Reich, H. J.; Shah, S. K.; Gold, P. M.; Olson, R. E. J. Am. Chem.
Soc. 1981, 103, 3112. (b) Reich, H. J.; Shah, S. K. J. Am. Chem. Soc.
1977, 99, 263. (c) Reich, H. J.; Gold, P. M.; Chow, F. Tetrahedron Lett.
1979, 4433.
(56) The more facile propargyl-allenyl isomerization for selenoalkynones is well
supported by notable cycloisomerization of 16a under thermal conditions
in the absence of base and Cu-catalyst (Table 3, entry 4).
(57) (a) Schmid, G. H.; Garratt, D. G. Tetrahedron Lett. 1975, 3991. (b)
Poleschner, H.; Seppelt, K. J. Chem. Soc. Perkin Trans. 1 2002, 23,
2668.
9
J. AM. CHEM. SOC. VOL. 130, NO. 4, 2008 1449

A R T I C L E S
Dudnik et al.
Scheme 10. Deuterium Labeling Study of Bromoallenone 4-d-20m
Scheme 11. Proposed Cationic Intermediates in the 1,2-Alkyl/Aryl
Migration/Cycloisomerization Cascade Triggered by Lewis Acid
Catalysts
Scheme 12. Proposed Intermediates in the Transition
Metal-catalyzed 1,2-Alkyl/Aryl Migration/ Cycloisomerization
Cascade
through any type of carbenoid intermediates, we subjected
deuterated allenyl ketone 4-d-20m to the cycloisomerization
conditions (Scheme 10). This reaction produced a mixture of
2- and 3- bromo-furans d-22m and d-21m in a ratio of 2.4:1
respectively without a detectable loss of deuterium.61,62 It
appears that rapid AuCl3-catalyzed propargyl-allenyl isomer-
ization is responsible for partial incorporation of deuterium in
position 3 of d-21m (4 for d-22m). Nonetheless, observation
of the clean 1,2-hydride shift63 was rationalized by involvement
of resonance intermediates xiW and xW (Scheme 10). Accord-
ingly, more π-philic Au species (AuCl3 in ethereal solvents, as
well as R3PAu(I)Cl catalysts) coordinate to the distal double
bond of allene (xiii), activating it toward intramolecular nu-
cleophilic attack of oxygen followed by tautomerization to form
gold carbenoid species xW. The latter furnishes 2-bromofuran
d-22m after subsequent 1,2-hydride shift.63
As it was proposed for 1,2-halogen migration in haloallenones
20 in the presence of oxophilic catalysts (Scheme 9), 1,2-
migration of alkyl/aryl group in allenylketones 25, which
required employment of highly cationic metal triflates or strong
Brønsted acids, could be, in turn, rationalized only via involve-
ment of the similar intermediates xWi-xWiii (Scheme 11).
Thus,1,2-alkyl or -aryl migration in the intermediate Lewis acid-
activated enone moiety of allenone 25, xWi,64 produces either
vinyl cation xWii65 or phenonium intermediate xWiii. Direct
cyclization of xWii or, alternatively, sequence of either AdN-E
or SN2-Vin processes from xWiii furnishes furan 26 (Scheme 11).
cycloisomerizations facilitated the propargyl-allenyl isomeriza-
tion, and potentially also stabilized the formed enolate or
enaminate in irenium species ix and x, which undergent
analogous to Wii and Wiii cyclization into 3-chalcogeno-furans
17 (Scheme 8).58
An analogous scenario involving 1,2-migration of nucleo-
philic entities to the electrophilic sp center of allenone is
responsible for the migrative cycloisomerization catalyzed by
Lewis or Brønsted acids. In these cases, activation of enone
moiety by these catalysts dramatically increases electrophilicity
at C-3 of allenyl intermediate and, thus, provokes a more facile
1,2-migration of an adjacent group. Indeed, observed selective
cycloisomerization of bromoallenylketone 20a into 3-bromo-
furan 21a in the presence of AlCl3 or silica gel (Table 5, entries
9-10) could only be explained by involvement of a similar to
Wii-x halirenium intermediate xi.59 This, taken together with the
reasonably high oxophilicity of AuCl3 in noncoordinating
media,60 suggests that 1,2-halogen migration/cycloisomerization
cascade proceeds via analogous to 1,2-chalcogen migration
pathway involving intermediate xii to give 3-halofuran 21
(Scheme 9). The reversal of regioselectivity observed in the
AuCl3-catalyzed reaction in THF (Table 5, entry 6), can be
attributed to a decreased oxophilicity of Au(III) complex in
ethereal solvent. The same reactivity was observed for more
π-philic Au(I) species (Table 5, entries 7 and 8). To verify
whether selective formation of 2-bromofuran 22 proceeds
(61) This is in striking contrast to cycloisomerization of alkynyl imines and
ketones, where significant loss of deuterium was observed; see refs 9 and
12.
(62) Decrease in regioselectivity of deuterium vs bromine migration is explained
by the isotope effect analogous to that observed by Hashmi in the Pd-
catalyzed cycloisomerization of allenyl ketones; see ref 7s.
(63) For 1,2-hydride shift in Au- and Pt-carbenoid intermediates, see for
example: (a) Fu¨rstner, A.; Stelzer, F.; Szillat, H. J. Am. Chem. Soc. 2001,
123, 11863. (b) Mamane, V.; Gress, T.; Krause, H.; Fu¨rstner, A. J. Am.
Chem. Soc. 2004, 126, 8654. See also refs 8k, 45h, and 48a,b.
(64) For activation of enone moiety by Lewis acids see, for example: (a) Childs,
R. F.; Mulholland, D. L.; Nixon, A. Can. J. Chem. 1982, 60, 801. (b)
Schwier, T.; Gevorgyan, V. Org. Lett. 2005, 7, 5191.
(65) For examples of 1,2-shift in vinyl cations, see: (a) Capozzi, G.; Lucchini,
V.; Marcuzzi, F.; Melloni, G. Tetrahedron Lett. 1976, 17, 717. (b) Jaeckel,
K. P.; Hanack, M. Tetrahedron Lett. 1974, 15, 1637.
(58) It should be noted that involvement of any possible ionization
pathways during cycloisomerization of thioalkynones 12 was ruled out by
the absence of scrambling for alkyl- and arylthio- groups in crossover
experiment.
(59) For halirenium species, see for example: (a) Noguchi, M.; Okada, H.;
Watanabe, M.; Okuda, K.; Nakamura, O. Tetrahedron 1996, 52, 6581. (b)
Lucchini, V.; Modena, G.; Pasquato, L. J. Am. Chem. Soc. 1995, 117, 2297.
(60) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817.
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1450 J. AM. CHEM. SOC. VOL. 130, NO. 4, 2008

Diverse Migrating Groups in Allenyl Systems
A R T I C L E S
Scheme 13. Generalized Mechanism for the Metal-Catalyzed Synthesis of Furans via Allene Intermediate Involving 1,2-Migration of
Different Migrating Groups
Taking into account the successful transformation of 25 into
26 employing cationic Au(I), Ag(I), and Cu(I) catalysts, we
hypothesized that in the case of π-acids, migrative cascade
cycloisomerization of allenone 25 follows the pathway analo-
gous to that proposed for 1,2-halogen migration66 (Scheme 10)
and involves similar to xiW and xW resonance metal-oxonium
xix and carbenoid xx intermediates. Thus, sequence of
1,5-alkyl/aryl shift67 and metal elimination or direct 1,2-alkyl/
aryl shift63 in xix or xx, respectively, produces furan 26 (Scheme
12).
Considering all the experimental data disclosed above, a
generalized mechanism for the synthesis of furans involving
1,2-migration of different migrating groups is outlined in
Scheme 13. It is proposed that a thermally induced and Cu-
catalyzed 1,2-migration of chalcogenides (Y ) SR and SeR)
proceeds via paths A and B, respectively.68 Alternatively, Lewis
or Brønsted acid-catalyzed cycloisomerization of allenones (X
) O) involving 1,2-shifts of halogen (Y ) Hal), alkyl, and aryl
(Y ) C) groups is postulated to follow path B, whereas
carbophilic catalysts trigger reaction which proceeds through
path C. Nevertheless, employment of transition metal catalysts
in the 1,2-chalcogen migration/cycloisomerization cascade, such
as Au(I), Au(III), Pd(II), and Pt(II),69 may involve a competitive
π-system activation pathway C proceeding via 1,2-21 or 1,5-
chalcogen migration in the carbenoid/oxonium intermediates
36/37.
The observed competitive 1,2-hydrogen migration for thio-
alkynone 4 (R1, R2 ) H, 8, Table 1, entries 2-5), and competing
1,2-migration of butyl group in selenoalkynone 4 (R1 ) Bu, R2
) H, 16a,Table 3, entries 1-3), in case of π-philic catalysts,
can be attributed to the 1,2-hydride or -alkyl shifts to the
electrophilic center in 36/37 (Path E). Alternatively, 1,2-shifts65
of these groups can also occur through the activated enone
intermediate 32 via equally feasible path D. In contrast to that
discussed above, selective/competitive 1,2-hydrogen vs -halogen
migration in haloallenones 5 (R1 ) H, 20, Table 5), catalyzed
by carbophilic gold catalysts, can only be rationalized via the
path E. The observed migratory aptitude trends during 1,2-alkyl/
aryl migration/cycloisomerization cascade strongly support
(69) For Pd-carbenoid species in the synthesis of furans, see ref 7s. For Pd-
catalyzed rearrangement see: (a) Rautenstrauch, V.; Burger, U.; Wirthner,
P. Chimia 1985, 39, 225. (b) Rautenstrauch, V. J. Org. Chem. 1984, 49,
950. (c) Kataoka, H.; Watanabe, K.; Goto, K. Tetrahedron Lett.
1990, 31, 4181. (d) Mahrwald, R.; Schick, H. Angew. Chem., Int. Ed. Engl.
1991, 30, 593. (e) Kato, K.; Yamamoto, Y.; Akita, Y. H. Tetrahedron Lett.
2002, 43, 6587. For Pt-catalyzed rearrangment see: (f) Harrak, Y.;
Blaszykowski, C.; Bernard, M.; Cariou, K.; Mainetti, E.; Mouries, V.;
Dhimane, A.-L.; Fensterbank, L.; Malacria, M. J. Am. Chem. Soc. 2004,
126, 8656. For Au-catalyzed rearrangement, see: (g) Mamane, V.; Gress,
T.; Krause, H.; Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126, 8654. See also
refs 8k and 45.
(66) See also ref 7q.
(67) (a) Miller, B. J. Am. Chem. Soc. 1970, 92, 432. (b) Dolbier, W. R.; Anapolle,
K. E.; McCullagh, L.; Matsui, K.; Riemann, J. M.; Rolison, D. J. Org.
Chem. 1979, 44, 2845. (c) Oda, M.; Breslow, R. Tetrahedron Lett. 1973,
14, 2537.
(68) A control experiment, where thioalkynone 8 was subjected to the prolonged
cycloisomerization conditions and monitored by GC for changes in
distribution of products 10 and 11, ruled out any routes involving
intraannular 1,2-sulfur migration20 from 2-thio- to 3-thiofuran after assembly
of the furan core.
9
J. AM. CHEM. SOC. VOL. 130, NO. 4, 2008 1451

A R T I C L E S
Dudnik et al.
Conclusion
predominant involvement of cationic intermediate represented
by the resonance structure 37 over metal-carbenoid resonance
structure 36 for Au and Ag triflate catalysts. Thus, the migratory
aptitude of phenyl- vs methyl group (>100:1) is in a good
agreement with that reported in literature for the cationic
rearrangements.70,71 In addition, no cyclopropanation product
34j was observed in the cycloisomerization of dimethylallenyl
ketone 25j in the presence of Au(I) and Ag(I) catalysts, although
this transformation proceeding via carbenoid intermediate xxii
was reported48a to give fused cyclopropane 40 as a major product
in the cycloisomerization of a carbocyclic analog of 25j, 39
(eq 5 and 6). Thus, although carbenoid intermediate, such as
xxi or 37, and/or its attributed reactivity cannot be completely
ruled out at this point for 1,2-alkyl/aryl migrative cyclization,
it is considered to be substantially less likely.
In conclusion, a mild, efficient, and functional group-tolerant
migration/cycloisomerization approach toward multisubstituted
heterocycles has been developed. This cascade reaction has
proven to be a powerful methodology toward diversely substi-
tuted heterocycles. The cycloisomerization approach is gen-
eral: a variety of propargyl sulfides and selenides, as well as
haloallenes or aryl- and alkylallenones, have been successfully
employed to produce hetero-substituted furans, pyrroles, and
even an indolizine in good to excellent yields. Moreover,
regiodivergent conditions have been identified for cycloisomer-
ization of bromo- and thioallenones to obtain regioisomeric
2-hetero substituted furans selectively. Mechanistic studies
strongly support the involvement of an irenium type intermediate
in all cases where migration occurs. Additionally, mechanistic
studies indicate that propargyl chalcogenides undergo necessary
isomerization into the corresponding allene during the cascade
cycloisomerization. Even though the involvement of π-system
activation pathway for certain transition metal-catalyzed cy-
cloisomerizations of chalcogenoalkynones or -allenones could
not be completely ruled out, it is considered as less likely. Facile
cycloisomerization in the presence of cationic complexes, as
well as observed migratory aptitude in the cycloisomerization
of unsymmetrically substituted aryl- and alkylallenes, strongly
supports electrophilic mechanism for this transformation.
Acknowledgment. The support of the National Institute of
Health (GM-64444) and the National Science Foundation (CHE
0710749) is gratefully acknowledged.
Supporting Information Available: Experimental procedures
and analytical and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
(70) Saunders, W. H.; Paine, R. H. J. Am. Chem. Soc. 1961, 83, 882.
(71) The observed migratory aptitude trends (Ph vs. Et, and Ph vs. Me) do not
correspond to those reported in literature for 1,2-alkyl migration to carbenoid
center. See, for example: (a) Philip, H.; Keating, J. Tetrahedron Lett. 1961,
2, 523. (b) Graf von der Schulenburg, W.; Hopf, H.; Walsh, R. Angew.
Chem., Int. Ed. 1999, 38, 1128.
JA0773507
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1452 J. AM. CHEM. SOC. VOL. 130, NO. 4, 2008