1,2-Halogen migration in haloallenyl ketones: Regiodivergent synthesis of halofurans

Article abstract of DOI:10.1021/ja053290y

Selective 1,2-iodine, bromine, and chlorine migration in haloallenyl ketones in the presence of Au catalyst has been demonstrated. It was found that, depending on the nature of the Au catalyst used, either selective bromine migration or hydrogen shift occ

Full text of DOI:10.1021/ja053290y

Published on Web 07/12/2005
1,2-Halogen Migration in Haloallenyl Ketones: Regiodivergent Synthesis of
Halofurans
Anna W. Sromek, Marina Rubina, and Vladimir Gevorgyan*
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061
Received May 19, 2005; E-mail: vlad@uic.edu
Transformations involving selective 1,2-halogen migration have
not been reported until recently,1 when Iwasawa and then Fu¨rstner
disclosed 1,2-iodine,2 and 1,2-iodine and -bromine migration,3
respectively, in alkynyl halides to produce fused haloarenes (eq
1). Furthermore, Liu showed a 1,2-iodine shift in a Ru alkylidene
complex (eq 2).4 Both transformations involved metal carbenoid
intermediates and were used in the synthesis of carbocycles. To
the best of our knowledge, no syntheses of halogenated heterocycles
involving halogen migration have been reported to date. Herein,
we wish to report Au-catalyzed selective 1,2-migration of iodine,
bromine, and chlorine, proceeding via a halirenium intermediate,
leading to 3-halofurans in good to excellent yields (eq 3).
furan 3a as a major product (entry 6). The latter was also exclusively
obtained in the presence of Au(PEt3)Cl (entry 8).
We propose two complementary pathways for selective formation
of 2 and 3 (Scheme 1). According to path A, oxophilic Au(III)
species coordinates to oxygen (a) provoking intramolecular Michael
addition of Br to the enone moiety, leading to bromoirenium
zwitterion b,13 which, via subsequent addition-elimination, fur-
nishes 3-bromofuran 2 (path A). Alternatively, the rather more
π-philic Au(I) species coordinates to the distal double bond of allene
(c), activating it toward intramolecular attack of oxygen followed
by tautomerization to form gold carbenoid species d. The latter,
after 1,2-hydride shift,14 furnishes 2-bromofuran 3 (path B).
Table 1. Optimization of Au-Catalyzed Synthesis of Halofurans
catalyst
2 mol %)
solvent
(1 M)
T
entry
(1
−
(
°
C)
2:3a
1
2
3
4
5
6
7
8
AuCl3
toluene
toluene
toluene
toluene
toluene
THF
rt
95:5
88:12
97:3
AuCl3
0
AuCl3
40
50
70
rt
rt
rt
AuCl3
98:2
AuCl3
98:2
5:95
16:84
<1:99
Halofurans, important building blocks, are traditionally obtained
by electrophilic halogenation of furans,5 via halogen-induced
cyclizations6 or cyclocondensations of halogenated precursors.7
Most of these approaches require employment of strongly electro-
philic reagents, thus limiting their application to substrates lacking
acid-sensitive functionalities. We have recently reported the Cu-
catalyzed synthesis of 3-thiofurans, which involved selective 1,2-
migration of a thio group in thioallenyl ketones, proceeding via a
thiirenium intermediate (eq 4).8
AuCl3
Au(PPh3)Cl
Au(PEt3)Cl
toluene
toluene
a GC ratios.
Scheme 1. Proposed Pathways for the Synthesis of Halofurans 2
and 3
We hypothesized that replacement of sulfur with halogen might
provide convenient access to 3-halofurans. Inspired by this idea,
we subjected bromoallenyl ketone 1a9 to a Cu-catalyzed cycloi-
somerization (eq 5),10 which indeed led to formation of 3-bromo-
furan 2a, albeit in poor yield (20-30%). In contrast, AgBF4, which
proved to be efficient in the cycloisomerization of different allenyl
ketones,11 did not catalyze this reaction at all. Employment of PtCl2,
however, produced 3-bromofuran 2a in 50% yield along with small
amounts of 2-bromofuran 3a. To our delight, employment of AuCl3
afforded 3-bromofuran 2a in 86% yield with high selectivity (Table
1, entry 1),12 which was further improved by elevation of reaction
temperature (entries 4 and 5). Surprisingly, switching solvent to
THF caused a dramatic change in selectivity, affording 2-bromo-
To gain additional support for path A, we tested Brønsted and
Lewis acids as potential catalysts for this transformation. It was
found that this reaction proceeds selectively in the presence of AlCl3
and even silica gel, affording 3-bromofuran 2a, albeit in low yield.10
The reversal of regioselectivity observed in the AuCl3-catalyzed
reaction in THF (Table 1, entry 6) can be attributed to a decrease
of oxophilicity of the Au(III) complex in ethereal solvent. To verify
whether selective formation of 2-bromofuran 3 proceeds via 1,2-
hydride shift (path B), we subjected deuterated allenyl ketone d-1k
to the cycloisomerization conditions (eq 6). This reaction produced
a mixture of 2- and 3-bromofurans in a ratio of 2.4:1 without
9
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J. AM. CHEM. SOC. 2005, 127, 10500-10501
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C O M M U N I C A T I O N S
detectable loss of deuterium,15 thus strongly supporting path B.16,17
efficient approach to different types of 3-halofurans, some of which
are not available via existing methodologies.
Acknowledgment. The support of the National Institutes of
Health (GM-64444) and the National Science Foundation (CHE
0354613) is gratefully acknowledged.
Supporting Information Available: Preparative procedures, ana-
lytical and spectral data. This material is available free of charge via
the Internet at http://pubs.acs.org.
Next, we investigated the scope of this cascade transformation.
Thus, differently substituted haloallenyl ketones were subjected to
Au(III)-catalyzed cycloisomerization (eq 7, Table 2). It was found
that a variety of alkyl- and aryl-substituted bromoallenyl ketones
and aldehydes underwent smooth cycloisomerization, affording
3-bromofurans in good to excellent yields (entries 1-5). Remark-
ably, this method allowed for efficient synthesis of halofurans
possessing hydroxymethyl (2e) and alkene (2f) functionalities,
which are incompatible with known methods employing electro-
philic reagents. It was found that fully substituted iodoallenyl
ketones reacted more slowly than their bromo analogues, producing
corresponding furans in good yield (entry 6). Gratifyingly, ambident
disubstituted allenyl iodides underwent exclusive iodine migration
to afford 2-alkyl- and -aryl-substituted iodofurans in 97 and 71%
yields, respectively (entries 7 and 8). Chloroallene 1j also underwent
this transformation to produce 3-chlorofuran 2j.18
References
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B.; Jones, S.; Knight, D. W. Tetrahedron Lett. 2001, 42, 5945. (b) Sniady,
A.; Wheeler, K. A.; Dembinski, R. Org. Lett. 2005, 7, 1769. (c) Schultz-
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(9) Bromoallene 1a contained trace to notable amounts of bromopropargyl
ketone 4a, from which it was obtained. Under reaction conditions, 4 under-
went rapid isomerization to 1. The same applies to iodoallene 1i (see Table
2). Facile propargyl-allenyl isomerization of propargyl ketones in the pres-
ence of gold catalyst was previously observed by Hashmi; see ref 12c.
Table 2. Au-Catalyzed Synthesis of Halofurans
(10) See Supporting Information for details.
(11) (a) Marshall, J. A.; Robinson, E. D. J. Org. Chem. 1990, 55, 3450. (b)
Sromek, A. W.; Kel’in, A. V.; Gevorgyan, V. Angew. Chem., Int. Ed.
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(12) 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. For Au-catalyzed synthesis of heterocycles, see:
(c) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew. Chem.,
Int. Ed. 2000, 39, 2285. (d) Yao, T.; Zhang, X.; Larock, R. C. J. Am.
Chem. Soc. 2004, 126, 11164. (e) Zhang, L.; Kozmin, S. A. J. Am. Chem.
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3, 2537. For Au-catalyzed carbocyclizations, see, for example: (g)
Fu¨rstner, A.; Hannen, P. Chem. Commun. 2004, 2546. (h) Shi, X.; Gorin,
D. J.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 5802. (i) Luzung, M. R.;
Markham, J. P.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 10858. (j)
Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 11806. (k) Nieto-
Oberhuber, C.; Lopez, S.; Echavarren, A. M. J. Am. Chem. Soc. 2005,
127, 6178. See also ref 3.
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(15) This is in striking contrast to cycloisomerization of alkynyl imines, where
significant loss of deuterium was observed. See: Kel’in, A. V.; Sromek,
A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074.
(16) Decrease in regioselectivity of deuterium versus bromine migration is
explained by the isotope effect analogous to that observed by Hashmi in
the Pd-catalyzed cycloisomerization of allenyl ketones. See: Hashmi, A.
S. K.; Ruppert, T. L.; Kno¨fel, T.; Bats, J. W. J. Org. Chem. 1997, 62,
7295.
a Isolated yield. b A 7:1 mixture of 1i and 4i was employed.9
(17) Apparently, rapid AuCl3-catalyzed propargyl-allenyl isomerization (see
ref 9) is responsible for partial incorporation of deuterium in position 3
of d-2k (4 for d-3k).
(18) Much more sluggish reaction of 1j is in accordance with decreased ability
of the Cl atom to form halirenium species b (Scheme 1).
In summary, we have demonstrated Au(III)-catalyzed 1,2-iodine,
-bromine, and -chlorine migration in haloallenyl ketones, proceeding
via a halirenium intermediate. This chemistry is interesting not only
as a novel cascade transformation but also as a mild, selective, and
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