[1,2]- or [2,3]-rearrangement of onium ylides of allyl and benzyl ethers and sulfides via in situ-generated iodonium ylides

Article abstract of DOI:10.1021/ol061772o

(Chemical Equation Presented) Iodonium ylides, generated in situ with bisacetoxyiodobenzene, are converted to allyl- or benzyl-substituted oxonium or sulfonium ylides via rhodium- or copper-catalyzed carbene transfer. Except for the S-benzyl example, the

Full text of DOI:10.1021/ol061772o

ORGANIC
LETTERS
2006
Vol. 8, No. 19
4359-4361
[1,2]- or [2,3]-Rearrangement of Onium
Ylides of Allyl and Benzyl Ethers and
Sulfides via in Situ-Generated Iodonium
Ylides
Graham K. Murphy and F. G. West*
Department of Chemistry, UniVersity of Alberta, Edmonton, AB, Canada T6G 2G2
frederick.west@ualberta.ca
Received July 18, 2006
ABSTRACT
Iodonium ylides, generated in situ with bisacetoxyiodobenzene, are converted to allyl- or benzyl-substituted oxonium or sulfonium ylides via
rhodium- or copper-catalyzed carbene transfer. Except for the S-benzyl example, the resulting ylides undergo rearrangement to the corresponding
2-substituted heterocycles. This demonstrates the first use of iodonium ylides as diazoketone surrogates for the generation and rearrangement
of onium ylide intermediates. This abbreviated one-step method proceeds in comparable yields relative to the corresponding two-step route
employing diazoketone intermediates.
Diazoketones give rise to a wide variety of chemistry,
typically via their derived metallocarbenes, including C-H
insertion, cyclopropanation, and ylide formation.1 However,
widespread adoption of methods employing these intermedi-
ates has been limited, perhaps in part because of their
potentially hazardous properties. Recently, iodonium ylides
have received a great deal of attention as surrogates for
diazocarbonyl compounds in metallocarbene-mediated pro-
cesses.2 This approach has been very successful in the areas
of C-H insertion,3 cyclopropanation,4 and dipolar cycload-
ditions.5
Previous studies from our group have established the
synthetic value of rearrangement processes involving cyclic
oxonium ylides.6 In particular, Stevens [1,2]-shifts of acetal-
derived oxonium ylides offer a convenient entry to medium-
sized carbocycles and cyclic ethers.7 However, these methods
require the prior formation of diazoketone substrates, whose
preparation is not uniformly efficient. Here, we describe the
first application of in situ-generated iodonium ylides for the
formation and rearrangement of oxonium and sulfonium
ylides. This process entails an overall one-step conversion
of simple â-ketoesters with pendant allyl or benzyl ethers
or sulfides to cyclic ethers or sulfides.
(1) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; Wiley-Interscience: New
York, 1997.
(5) Mu¨ller, P.; Chappellet, S. HelV. Chim. Acta 2005, 88, 1010-1021.
(6) (a) Marmsa¨ter, F. P.; West, F. G. J. Am. Chem. Soc. 2001, 123, 5144-
5145. (b) Marmsa¨ter, F. P.; Vanecko, J. A.; West, F. G. Tetrahedron 2002,
58, 2027-2040. (c) Marmsa¨ter, F. P.; Vanecko, J. A.; West, F. G. Org.
Lett. 2004, 6, 1657-1660.
(7) (a) Tester, R. W.; West, F. G. Tetrahedron Lett. 1998, 39, 4631-
4634. (b) Marmsa¨ter, F. P.; Murphy, G. K.; West, F. G. J. Am. Chem. Soc.
2003, 125, 14724-14725. (c) Murphy, G. K.; West, F. G. Org. Lett. 2005,
7, 1801-1804. (d) Murphy, G. K.; Marmsa¨ter, F. P.; West, F. G. Can. J.
Chem. 2006, 84, in press.
(2) (a) Mu¨ller, P. Acc. Chem. Res. 2004, 37, 243-251. (b) Kirmse, W.
Eur. J. Org. Chem. 2005, 237-260.
(3) Camacho, M. B.; Clark, A. E.; Liebrecht, T. A.; DeLuca, J. P. J.
Am. Chem. Soc. 2000, 122, 5210-5211.
(4) (a) Dauban, P.; Saniere, L.; Tarrade, A.; Dodd, R. H. J. Am. Chem.
Soc. 2001, 123, 7707-7708. (b) Wurz, R. P.; Charette, A. B. Org. Lett.
2003, 5, 2327-2329. (c) Mu¨ller, P.; Ghanem, A. Org. Lett. 2004, 6, 4347-
4350.
10.1021/ol061772o CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/19/2006

To explore the feasibility of this approach, we prepared
several substrates via the monoalkylation of the dianion of
methyl acetoacetate8 with bromomethyl ethers and sulfides
1a-d9 to give 2a-d in moderate yield (Scheme 1). Diazo-
3a-c underwent conversion to the corresponding tetrahy-
drofuranones 4a,b or tetrahydrothiophenone 4c with either
catalyst. Product 4b, resulting from a benzyl [1,2]-shift, was
formed in only moderate yields (entries 3 and 4). This result
is consistent with previous observations regarding the relative
efficiency of [1,2]- and [2,3]-shifts of oxonium ylides.6
Sulfide 3c required longer reaction times (entries 5 and 6),
possibly because of a combination of catalyst deactivation
by sulfur12 and the decreased reactivity of sulfonium ylides
as compared to their oxonium counterparts. Finally, the
S-benzyl substrate 3d furnished only the intermediate sul-
fonium ylide 5 under the reaction conditions. Isolation of
the ylide intermediate may occur because of the relatively
high barrier for a Stevens [1,2]-shift (presumed to involve
initial homolytic cleavage) together with the aforementioned
lower reactivity of sulfonium ylides.13 Moody has observed
a similar result with the homologous ylide 6.14
Scheme 1
transfer10 using p-toluenesulfonyl azide then afforded diazo-
ketoesters 3a-d.
Initial experiments were carried out using the diazo
substrates 3a-d and either copper(II) bis(hexafluoroacetyl-
acetonate) (Cu(hfacac)2) or Rh2(OAc)4 (Table 1). These
Using the results above as a baseline, we next set out to
examine possible conditions for direct generation of the ylide
intermediates from ketoesters 2a-d via in situ formation of
iodonium ylides (Table 2). Initial experiments using substrate
2a employed conditions previously shown to be effective in
other types of carbene-transfer processes mediated by in situ-
generated iodonium ylides.4c,15 We were gratified to find that
treatment of 2a in MeOH with a slight excess of PhI(OAc)2,
2 equiv of KOH, and catalytic Rh2(OAc)4 (entry 1) did
indeed furnish oxonium ylide rearrangement product 4a in
reasonable yield (55%), albeit clearly inferior to the overall
yield of the two-step sequence employing the initial diazo-
transfer reaction (see Scheme 1 and Table 1, entry 1).
Incremental improvements were seen when the solvent was
changed to CH2Cl2 and K2CO3 was substituted for KOH
(entries 2 and 3). Optimal results were obtained with the
base Cs2CO3, furnishing the product 4a in 80% yield (entry
4).16 These conditions were then applied to the other three
substrates. Both 2b (entry 6) and 2c (entry 8) were converted
to the desired cyclic products in yields well above those
obtained by the two-step procedure. On the other hand, Cu-
(hfacac)2 was found to be substantially inferior under the in
Table 1. Carbene-Transfer and Ylide Rearrangement Reactions
of Diazocarbonyl Substrates 3a-da
product
entry substrate
R
X
catalyst
time (h) (% yield)b
1
2
3
4
5
6
7
8
3a
3a
3b
3b
3c
3c
3d
3d
CH2dCH
CH2dCH
Ph
O
O
O
O
S
S
S
S
Rh2(OAc)4
Cu(hfacac)2
Rh2(OAc)4
Cu(hfacac)2
Rh2(OAc)4
Cu(hfacac)2
Rh2(OAc)4
Cu(hfacac)2
0.2
1
1
4a (88)
4a (99)
4b (39)
4b (34)
4c (63)
4c (89)
5c
Ph
16
CH2dCH
CH2dCH
Ph
24
24
24
24
Ph
5c
a Substrates in CH2Cl2 were added dropwise by cannula to a mixture of
catalyst (3 mol % of Rh2(OAc)4 or 10 mol % of Cu(hfacac)2) in CH2Cl2
and stirred until complete consumption was observed. Reactions employing
Rh2(OAc)4 were carried out at room temperature, whereas those using
Cu(hfacac)2 were carried out at reflux. b Yields are for isolated material
after chromatography. c Sulfur ylide 5 was the only product observed in
the crude reaction mixture. Yields are not reported because only small
amounts of pure material were isolated for analytical purposes (see
Supporting Information).
(10) Regitz, M. Angew. Chem., Int. Ed. Engl. 1967, 6, 733-749.
(11) West, F. G.; Naidu, B. N.; Tester, R. W. J. Org. Chem. 1994, 59,
6892-6894.
(12) (a) Davies, H. M. L. In Nitrogen, Oxygen and Sulfur Ylides in
Synthesis: A Practical Approach; Clark, J. S., Ed.; Oxford University
Press: Oxford, 2002; pp 156-163. (b) See also: Felthouse, T. R. Prog.
Inorg. Chem. 1982, 29, 73-154.
(13) Extended heating of sulfonium ylide 5 in toluene failed to effect
the desired [1,2]-shift process.
(14) Moody, C. J.; Taylor, R. J. Tetrahedron 1990, 46, 6501-6524.
(15) Prakash, O.; Sharma, V.; Tanwar, M. P. Can. J. Chem. 1999, 77,
1191-1195.
catalysts were chosen for their broad applicability in various
onium ylide-mediated processes.11 In the event, substrates
(8) Huckin, S. N.; Weiler, L. J. Am. Chem. Soc. 1974, 96, 1082-1087.
(9) (a) Kawasaki, T.; Kimachi, T. Tetrahedron 1999, 55, 6847-6862.
(b) Reich, H. J.; Jasperse, C. P.; Renga, J. M. J. Org. Chem. 1986, 51,
2981-2988.
(16) Treatment of 2a with PhI(OAc)2 and base in the absence of any
catalyst and in new glassware furnished low yields of 4a in the same time
frame as the Rh2(OAc)4-catalyzed reaction, indicating the existence of a
minor background uncatalyzed process.
4360
Org. Lett., Vol. 8, No. 19, 2006

Scheme 2
Table 2. Carbene-Transfer and Ylide Rearrangement Reactions
of â-Ketoester Substrates 2a-da
time product two-step
entry substrate base
catalyst
KOHd Rh2(OAc)4
KOH Rh2(OAc)4
K2CO3 Rh2(OAc)4
(h) (% yield)b yieldb,c
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2b
2b
2c
2c
2d
2d
1.5 4a (55)
68
68
68
68
77
35
31
55
77
8
3
4a (63)
4a (67)
4a (80)
4a (9)
Cs2CO3 Rh2(OAc)4 12
Cs2CO3 Cu(hfacac)2 10
Cs2CO3 Rh2(OAc)4
Cs2CO3 Cu(hfacac)2 12
Cs2CO3 Rh2(OAc)4 19
Cs2CO3 Cu(hfacac)2 64
Cs2CO3 Rh2(OAc)4 24
Cs2CO3 Cu(hfacac)2 14
0.5 4b (41)
e
4c (78)
4c (32)
5f
10
11
5f
a All reactions (except entry 1) were carried out in 0.05 M CH2Cl2 at
room temperature using 1.1 equiv of PhI(OAc)2, 2.1 equiv of base, and 3
mol % of Rh2(OAc)4 or 10 mol % of Cu(hfacac)2. Reactions were worked
up when judged complete by TLC or GC analysis. b Yields are for isolated
material after chromatography. c Overall yield for the alternative two-step
diazotransfer/carbene-transfer process per Scheme 1 and Table 1. d The
experiment described in entry 1 was carried out in MeOH. e Product 4b
was not detected in the reaction mixture despite extended reaction times.
f Sulfur ylide 5 was the only product observed in the crude reaction mixture.
Yields were not determined in these cases.
dihydrobenzofuranone 4e using a variety of rhodium(II) or
copper(II) catalysts. The simple ketoester 2e could also be
converted to 4e, but yields were moderate and required
extended reaction times. Thus, in contrast to the simple
aliphatic cases from Table 2, the two-step protocol via the
diazo compound appears to be superior in this case.
This work describes the first examples of the direct
conversion of active methylene-containing compounds to
oxonium or sulfonium ylides via in situ-generated iodonium
ylide and metallocarbene intermediates. Rearrangement
products (via a [1,2]- or [2,3]-shift) are formed efficiently
and, for the simple acyclic substrates 2a-c, in yields
comparable to the corresponding two-step protocol employ-
ing diazocarbonyl intermediates. Substrate 2d, containing an
S-benzyl substituent, underwent conversion to the sulfonium
ylide without subsequent rearrangement, and this product was
fully characterized. Further applications of this methodology
are presently under study and will be reported in due course.
situ activation conditions (entries 5, 7, and 9). Reductive
activation of copper(II) catalysts by a sacrificial quantity of
diazocarbonyl compounds has been suggested to occur prior
to various copper-catalyzed carbene-transfer processes;17,18
the absence of any diazoketone in these experiments may
be responsible for the low conversion seen in these cases.
Finally, as in the diazo substrates, the S-benzyl case gave
only the unreactive sulfur ylide 5.
Next, aromatic ketoester 2e was prepared and subjected
to diazotransfer to give the known substrate 3e19 (Scheme
2). Diazo compound 3e underwent efficient conversion to
(17) (a) Salomon, R. G.; Kochi, J. K. J. Am. Chem. Soc. 1973, 95, 3300-
3310. (b) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911-936. (c)
Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV. 2003,
103, 977-1050.
Acknowledgment. We thank NSERC for support of this
work and NSERC and the Alberta Heritage Foundation for
Medical Research for Graduate Studentships (G.K.M.).
(18) For other discussions regarding reductive activation of copper(II)
catalysts, see: (a) Wulfman, D. S. Tetrahedron 1976, 32, 1231-1240. (b)
Dauben, W. G.; Hendricks, R. T.; Luzzio, M. J.; Ng, H. P. Tetrahedron
Lett. 1990, 31, 6969-6972. (c) Ichiyanagi, T.; Shimizu, M.; Fujisawa, T.
Tetrahedron 1997, 53, 9599-9610. (d) Kirmse, W. Angew. Chem., Int. Ed.
2003, 42, 1088-1093.
Supporting Information Available: Experimental pro-
cedures and spectral data for all intermediates. This material
is available free of charge via the Internet at http://pubs.acs.org.
(19) Pirrung, M. C.; Werner, J. A. J. Am. Chem. Soc. 1986, 108, 6060-
6062.
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