Metal-catalyzed [1,2]-alkyl shift in allenyl ketones: Synthesis of multisubstituted furans

Article abstract of DOI:10.1002/anie.200701128

(Chemical Equation Presented) Even fused furans can be prepared by cycloisomerization of substituted allenyl ketones. The cascade reaction involves a [1,2]-migration of alkyl or aryl groups in allenyl ketones as the key step. Facile reaction in the presence of cationic complexes, as well as migratory aptitude in the cycloisomerization of unsymmetrically substituted allenes, strongly supports an electrophilic mechanism for this transformation.

Full text of DOI:10.1002/anie.200701128

Angewandte
Chemie
DOI: 10.1002/anie.200701128
Furan Synthesis
Metal-Catalyzed [1,2]-Alkyl Shift in Allenyl Ketones: Synthesis of
Multisubstituted Furans**
Alexander S. Dudnik and Vladimir Gevorgyan*
[
a]
Cycloisomerization of allenyl ketones is an efficient approach
for the assembly of the furan ring, an important heterocyclic
Table 1: Optimization of reaction conditions.
[
1]
unit. This transformation in the presence of transition-metal
[2]
catalysts was first reported by Marshall et al. and later by
[
3]
Hashmi et al. for the synthesis of furans [G = H, Eq. (1)].
Recently, we have developed a set of transition-metal-
catalyzed cascade transformations of allenyl ketones involv-
[b]
[c]
Entry Catalyst
mol% Solvent
T [8C] Yield [%]
[
d]
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
AuBr3
AuI
[Au(PPh )]OTf
[Au(PPh )]OTf
PtCl2
5
5
1
5
5
5
5
5
5
5
5
5
20
5
5
20
5
5
5
toluene
toluene
toluene
100
100
100
RT
23
traces
100 (89)
99
[
4]
[5]
[d]
ing 1,2-migration of various groups (G = SR,
Hal,
[d]
[
6]
OP(O)(OR) , OC(O)R, OSO R ) to produce up to tetra-
3
2
2
[
e]
CH Cl
2 2
3
substituted furans [Eq. (1)]. Herein, we wish to report a novel
metal-catalyzed [1,2]-alkyl shift in allenyl ketones as a key
step in the formation of up to fully carbon-substituted furans
[
f]
[f]
[f]
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH Cl
2 2
toluene
toluene
CH Cl
toluene
toluene
toluene
toluene
100
100
100
100
100
100
100
100
RT
100
100
RT
100
100
100
100
21
21
35
0
42
95
47
(80)
70 (62)
64
PtCl4
[PdCl (PhCN) ]
2
2
[f]
[
Eq. (1)].
CuX (X=Cl, Br, I)
CuOTf·PhH
Cu(OTf)2
AgPF6
AgOTf
AgOTf
Al(OTf)3
Zn(OTf)2
TMSOTf
In(OTf)3
Sn(OTf)2
TIPSOTf
TMSNTf2
[f]
[
g]
g]
g]
1
1
1
1
1
1
1
1
1
1
2
[
[
[
e]
[
g]
g]
[
39
[
2
e]
82 (62)
91 (81)
97 (81)
100 (81)
72
2
[
g]
g]
g]
g]
[
[
[
5
[
a] Entries 1–4: Ar=p-Br-C H ; entries 5–20: Ar=Ph. [b] Tf=trifluoro-
6 4
methanesulfonyl, TIPS=triisopropylsilyl, TMS=trimethylsilyl. [c] Yield
determined from NMR spectrum; yield of isolated product in paren-
theses. [d] 0.05m solution of 3. [e] 0.02m solution of 3. [f] 1m solution of
Recently, we reported the Au-catalyzed regiodivergent
synthesis of halofurans. It was found that in the presence of
Au catalysts clean hydrogen migration from 1 occurs to form
[
5]
I
3. [g] 0.1m solution of 3.
2
[Eq. (2)]. The absence of H/D-scrambling, in contrast to
[
7]
that observed in the Cu/base-assisted synthesis of pyrroles,
supported the clean [1,2]-hydrogen shift to the carbenoid
[
5]
center in intermediate i.
It occurred to us that 1,2-migration of an alkyl/aryl
[
8–11]
group by this mechanism is also feasible,
which
may allow for the assembly of fully carbon-substituted
furans. To this end, we have tested the possible
cycloisomerization of allene 3 to give furan 4 in the
presence of different catalysts (Table 1). We have
I
III
found that employment of Au and Au halides gave
low yields of furan 4 (Table 1, entries 1 and 2).
I
[
*] A. S. Dudnik, Prof. V. Gevorgyan
Department of Chemistry
University of Illinois at Chicago
Gratifyingly, switching to cationic Au complexes led to
formation of 4k in nearly quantitative yield (Table 1, entries 3
II
IV
II
and 4). In analogy to gold halides, Pt , Pt , and Pd salts were
845 West Taylor Street, Room 4500, Chicago, IL 60607 (USA)
I
inefficient in this reaction (Table 1, entries 5–7). Use of Cu
halides resulted in no reaction (Table 1, entry 8), while
Fax: (+1)312-355-0836
E-mail: vlad@uic.edu
Homepage: http://www.chem.uic.edu/vggroup
I
I
II
employment of cationic Ag , Cu , and Cu salts produced 4
in moderate to high yields (Table 1, entries 9–13). Encour-
aged by these results, we also tested main-group metals in this
reaction. Surprisingly, Al, Si, Sn, and In triflates provided
moderate to excellent yields of desired furan 4 (Table 1,
[
**] The support of the National Institutes of Health (GM-64444) is
gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 5195 –5197
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5195

Communications
entries 14, 16–19). Although [Au(PPh )]OTf, AgOTf, In-
3
(
OTf) , Sn(OTf) , and TIPSOTf were nearly equally
3
2
efficient in the cascade cycloisomerization of 3 to give 4,
In(OTf) appeared to be a more general catalyst with
3
[
12]
respect to the substrate scope.
Next, cycloisomerization of differently substituted
allenyl ketones 3a–m was examined under the optimized
conditions (Table 2). Thus, cycloisomerization of 4,4-
diphenyl-substituted allenyl ketones 3b–d proceeded
smoothly to provide good to high yields of furans 4b–d
I
and Au salts, activate the carbon–carbon double bond of
allene (see 9) and trigger nucleophilic attack of a carbonyl
oxygen lone pair at the terminal carbon of the allene moiety
[
2c,5]
(
Table 2, entries 2–4). Selective migration of the phenyl over
the methyl group occurred in allenyl ketone 3e to give 4e in
2% yield (Table 2, entry 5). Not surprisingly, cycloisomeri-
to form cyclic oxonium intermediate 10.
[1,5]-Alkyl
(Scheme 1, path B) to form 11 with subsequent
elimination of metal gives 4. The involvement of an electro-
[
16]
shift
7
zation of allenyl ketone 3i, possess-
ing two methyl groups, provided the
corresponding furan 4i in low yield Table 2: Lewis acid catalyzed synthesis of furans.
only (Table 2, entry 8). In contrast
to the disfavored methyl-group
migration in Table 2, entry 5, migra-
tion of the ethyl group competed
[a]
Entry
1
Allenyl ketone
Furan
Yield [%]
with the phenyl group in 3 f, which
resulted in formation of a 2.3:1
mixture of regioisomeric furans 4 f
and 4g, respectively (Table 2,
entry 6). Cyclopentylidene allenyl
ketone 3h underwent smooth cycli-
[b]
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
81
[
c]
2
3
4
5
64
[
13]
zation with ring expansion to give
90
79
fused furan 4h in 75% yield
(
Table 2, entry 7). It was also dem-
onstrated that a variety of func-
tional groups such as methoxy
[d]
(
Table 2, entry 9), bromo (Table 2,
[
e,f]
entry 10), nitro (Table 2, entry 11),
and cyano (Table 2, entry 12) were
perfectly tolerated under these
reaction conditions.
In addition, we have shown that
trisubstituted furan 4b can be
obtained directly from alkynyl
ketone 5b [Eq. (3)]. However, the
yield for this one-pot transforma-
tion was somewhat lower than that
for cycloisomerization of allene 3b
72 (52)
[
g]
4
4
f
88
6
3 f
[
h,f,i]
g
(76)
7
8
9
3h
3i
4h
4i
75
[
f]
10
62
(
Table 2, entry 2).
We propose the following mech-
anism for the cascade transforma-
3j
4j
tion of allenyl ketone 3 into furan 4
[
h]
(
Scheme 1). Cycloisomerization in
1
1
1
0
1
2
3k
3l
4k
4l
93 (89)
the presence of oxophilic Lewis
acids, such as In, Sn, and Si triflates,
follows path A, according to which,
the Lewis acid activates the enone
moiety (see 6) to form vinyl cation
[
b]
85
94
[b]
3m
4m
[
14]
7.
[1,2]-Alkyl shift in 7 produces
[
15]
the regioisomeric vinyl cation 8,
[
[
1
a] Yield of isolated product; 0.25–0.8-mmol scale, In(OTf) was used unless otherwise mentioned.
b] 5 mol% Sn(OTf) was used. [c] 10 mol% In(OTf) was used. [d] 20 mol% AgOTf/p-xylene, 1408C,
h. [e] 2 mol% [Au(PPh )]OTf was used. [f] Yield determined from NMR spectrum. [g] 2.3:1 mixture of
3
which, upon cyclization, transforms
into furan 4 and regenerates the
2
3
3
1
Lewis acid catalyst. Alternatively, 4 f:4g by H NMR spectroscopy. [h] 1 mol% [Au(PPh )]OTf was used. [i] 2.2:1 mixture of 4 f:4g by
3
I
I
1
p-philic catalysts, such as Ag , Cu ,
H NMR spectroscopy.
5
196
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Angew. Chem. Int. Ed. 2007, 46, 5195 –5197

Angewandte
Chemie
Schwarz, J.-H. Choi, T. M. Frost, Angew. Chem. 2000, 112,
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2
[
[
[
[
[
1
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[
9] For general reviews, see: a) “One or more CH and/or CC
bond(s) formed by rearrangement”: P. H. Ducrot in
Comprehensive Organic Functional Group Transforma-
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Elsevier, Oxford, UK, 2005, pp. 375 – 426; b) “Carbon–
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try, Vol. 3 (Eds: B. M. Trost, I. Fleming), Pergamon, New
York, 1991, pp. 705 – 1043.
Scheme 1. Proposed mechanisms for the synthesis of furans 4.
[
10] While this manuscript was in preparation, two independ-
philic mechanism (Scheme 1, paths A and B) is supported by
the data presented in Table 2. Thus, the migratory aptitude of
a phenyl vs. that of a methyl group (> 100:1) is in good
agreement with that reported in the literature for rearrange-
ent works on synthesis of carbocycles involving [1,2]-alkyl shifts
to carbenoid center in allenes were reported. See: a) H. Funami,
H. Kusama, N. Iwasawa, Angew. Chem. Int. Ed. 2007, 46, 909;
b) J. H. Lee, F. D. Toste, Angew. Chem. Int. Ed. 2007, 46, 912.
[11] For a synthesis of dehydrofuranones by [1,2]-alkyl shift, analo-
gous to a formal ketol rearrangement, see: S. F. Kirsch, J. T.
Binder, C. LiØbert, H. Menz, Angew. Chem. 2006, 118, 6010;
Angew. Chem. Int. Ed. 2006, 45, 5878, and references therein.
[
17]
ments of cations. Although a mechanism involving [1,2]-
[
5,8]
alkyl shift in the carbenoid intermediate 12
(Scheme 1,
path C) cannot be completely ruled out at this point, it is
[
18,19]
considered to be less likely.
[
[
12] See the Supporting Information for details.
13] For examples of ring expansions in the synthesis of carbocycles
proceeding by a carbenoid mechanism, see Ref. [9].
In summary, we have developed a novel metal-catalyzed
method for the synthesis of furans, which proceeds by an
unprecedented [1,2]-alkyl shift in allenyl ketones. This
method allows for efficient synthesis of up to fully carbon-
substituted and fused furans.
[14] For activation of enone moiety by Lewis acids see, for example:
a) R. F. Childs, D. L. Mulholland, A. Nixon, Can. J. Chem. 1982,
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15] For examples of [1,2]-shifts in vinyl cations, see: a) G. Capozzi, V.
6
[
Lucchini, F. Marcuzzi, G. Melloni, Tetrahedron Lett. 1976, 17,
Received: March 15, 2007
Published online: May 25, 2007
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[
16] a) B. Miller, J. Am. Chem. Soc. 1970, 92, 432; b) W. R. Dolbier,
K. E. Anapolle, L. McCullagh, K. Matsui, J. M. Riemann, D.
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17] W. H. Saunders, R. H. Paine, J. Am. Chem. Soc. 1961, 83, 882.
18] 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 a carbenoid center. See, for example: a) H.
Philip, J. Keating, Tetrahedron Lett. 1961, 2, 523; b) W. Graf
von der Schulenburg, H. Hopf, R. Walsh, Angew. Chem. 1999,
111, 1200; Angew. Chem. Int. Ed. 1999, 38, 1128.
Keywords: allenyl ketones · furans · gold · Lewis acids ·
.
rearrangment
[
[
[
1] For a recent review, see: S. F. Kirsch, Org. Biomol. Chem. 2006,
4, 2076.
[
2] a) J. A. Marshall, E. D. Robinson, J. Org. Chem. 1990, 55, 3450;
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[19] No cyclopropanation product was observed in the cycloisome-
rization of dimethylallenyl ketone 3i; however, this transforma-
tion was reported as a major process in the cycloisomerization of
a carbocyclic analogue of 12. See Ref. [9a].
[
Angew. Chem. Int. Ed. 2007, 46, 5195 –5197
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5197