Catalyst and ring size effects on periselectivity of oxonium ylide rearrangements

Article abstract of DOI:10.1021/ol049493t

Diazoketones were subjected to carbene-transfer with Rh(II) or Cu(II) catalysts to probe the selectivity for rearrangement via five- or six-membered oxonium ylides. 4,5-Bis(benzyloxy) and 4-allyloxy-5-benzyloxy substrates 3a,b showed a large preference for rearrangement via the five-membered ylide under all conditions. However, a sharp divergence was seen with 5-allyloxy-4-benzyloxy substrate 3c, which underwent predominantly a [2,3]-shift to pyran 5c via the six-membered ylide with Cu(II) catalysis and a [1,2]-shift to furan 4c via the five-membered ylide with Rh(II) catalysis.

Full text of DOI:10.1021/ol049493t

ORGANIC
LETTERS
2004
Vol. 6, No. 10
1657-1660
Catalyst and Ring Size Effects on
Periselectivity of Oxonium Ylide
Rearrangements
,†
Fredrik P. Marmsa1ter,†,‡ John A. Vanecko,‡ and F. G. West*
Department of Chemistry, UniVersity of Alberta, W5-67 Gunning-Lemieux Chemistry
Centre, Edmonton, AB T6G 2G2, Canada, and Department of Chemistry,
UniVersity of Utah, 315 S. 1400 East, Rm 2020, Salt Lake City, Utah 84112
frederick.west@ualberta.ca
Received March 17, 2004
ABSTRACT
Diazoketones were subjected to carbene-transfer with Rh(II) or Cu(II) catalysts to probe the selectivity for rearrangement via five- or six-
membered oxonium ylides. 4,5-Bis(benzyloxy) and 4-allyloxy-5-benzyloxy substrates 3a,b showed a large preference for rearrangement via the
five-membered ylide under all conditions. However, a sharp divergence was seen with 5-allyloxy-4-benzyloxy substrate 3c, which underwent
predominantly a [2,3]-shift to pyran 5c via the six-membered ylide with Cu(II) catalysis and a [1,2]-shift to furan 4c via the five-membered ylide
with Rh(II) catalysis.
Cyclic oxonium ylides are readily generated from acyclic
diazoketone precursors with pendant ether moieties and
undergo rearrangement to functionalized tetrahydrofurans or
tetrahydropyrans when the ether contains a group capable
of migrating via [1,2]- or [2,3]-shift.1 This convenient entry
to cyclic ethers has been used in the construction of medium-
sized carbocycles2 and ethers,3 the natural product griseo-
fulvin,4 the cores of neoliacinic acid5 and the cladiellins,6
and polypyran domains such as those found in the marine
ladder toxins.7 The catalyst used in the carbene-transfer step
can play a dominant role in the product mixture. Alternative
metallocarbene processes can compete effectively with ylide
formation, and it has been noted on several occasions that
copper(II) catalysts are typically superior for the selective
formation of oxonium ylides at the expense of alternative
C-H insertion pathways.1f,3,7,8 Less well appreciated is the
potential for the catalyst to affect the ratio of ylide-deriVed
products. Although catalyst involvement in the ylide re-
arrangement step is not mechanistically necessary, there is
evidence that oxonium ylide rearrangements can proceed via
† University of Alberta.
‡ University of Utah.
(1) (a) Pirrung, M. P.; Werner, J. A. J. Am. Chem. Soc. 1986, 108, 6060-
6062. (b) Johnson, C. R.; Roskamp, E. J. J. Am. Chem. Soc. 1986, 108,
6062-6063. (c) Padwa, A.; Hornbuckle, S. F.; Fryxell, G. E.; Stull, P. D.
J. Org. Chem. 1989, 54, 817-824. (d) Eberlein, T. H.; West, F. G.; Tester,
R. W.; J. Org. Chem. 1992, 57, 3479-3472. (e) Clark, J. S. Tetrahedron
Lett. 1992, 33, 6193-6196. (f) Clark, J. S.; Krowiak, S. A.; Street, L. J.
Tetrahedron Lett. 1993, 34, 4385-4388. (g) Clark, J. S.; Fretwell, M.;
Whitlock, G. A.; Burns, C. J.; Fox, D. N. A. Tetrahedron Lett. 1998, 39,
97-100.
(4) Pirrung, M. C.; Brown, W. L.; Rege, S.; Laughton, P. J. Am. Chem.
Soc. 1991, 113, 8561-8562.
(5) Clark, J. S.; Dossetter, A. G.; Whittingham, W. G. Tetrahedron Lett.
1996, 37, 5605-5608.
(6) Clark, J. S.; Wong, Y. S. Chem. Commun. 2000, 1079-1080.
(7) (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.
(8) West, F. G.; Naidu, B. N.; Tester, R. W. J. Org. Chem. 1994, 59,
6892-6894.
(2) (a) West, F. G.; Eberlein, T. H.; Tester, R. W. J. Chem. Soc., Perkin
Trans. 1 1993, 2857-2859. (b) Clark, J. S.; Bate, A. L.; Grinter, T. Chem.
Commun. 2001, 459-460. (c) Marmsa¨ter, F. P.; Murphy, G. K.; West, F.
G. J. Am. Chem. Soc. 2003, 125, 14724-14725.
(3) Tester, R. W.; West, F. G. Tetrahedron Lett. 1998, 39, 4631-4634.
10.1021/ol049493t CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/07/2004

metal-associated ylides.4,9 Here we describe a remarkable,
catalyst-dependent selectivity for two isomeric ylide rear-
rangement products based on the nature of the migrating
groups.
While developing an oxonium ylide-based iterative pro-
cedure for the synthesis of polyethers, we observed that
reactions catalyzed by copper(II) trifluoroacetylacetonate
(Cu(tfacac)2) proceeded in excellent yield with an allyl
migrating group (1a). In contrast, with a benzyl migrating
group (1b), the main product resulted from C-H insertion
adjacent to the benzyl ether oxygen (Scheme 1).7 Since the
catalysis. The catalyst-dependent reversal in diastereoselec-
tivity observed for the rearrangement of 1a lent further
support to this notion.
The results seen with 1a,b were intriguing but involved
comparisons of product ratios from two structurally distinct
(albeit very similar) substrates. Therefore, a group of
diazoketone substrates was selected in which competitive
formation and rearrangement of two different oxonium ylides
via the same metallocarbene precursor was possible. We1d,7b
and others1e had previously noted that rearrangements
proceeding through five-membered cyclic oxonium ylides
generally occur with much higher efficiency than their
counterparts involving six-membered ylides. The substrates
to be examined would contrast the effect of ylide ring size
with the migrating group as a function of catalyst.
Scheme 1
The necessary diazoketones 3a-c could be prepared by
coupling ethyl diazoacetate with benzyloxyacetaldehyde or
allyloxyacetaldehyde in the presence of SnCl2 (Scheme 2).11
Scheme 2
cyclic oxonium ylide derived from 1b should have formed
under these conditions, this result was rationalized in terms
of a lower activation barrier for the concerted [2,3]-shift
pathway available in allyl migration as compared with the
stepwise [1,2]-shift mechanism required for benzyl migra-
tion.10 Slow rearrangement of the benzyl-substituted ylide
would allow reversion to the metallocarbene precursor with
consequent consumption via alternative pathways. However,
acceptable yields of benzyl migration by 1b were observed
with catalysis by rhodium(II) triphenylacetate (Rh2(tpa)4).
This result suggested a fundamental difference in the nature
of the ylides derived from 1b under copper and rhodium
The resulting ketoesters were then reduced, O-alkylated, and
converted to carboxylic acids 2a-c. These intermediates
underwent efficient carboxyl activation and diazomethane
acylation to furnish 3a-c.
Treatment of 3a-c with Rh2(OAc)4, Rh2(tpa)4, Cu(tfacac)2,
and copper(II) hexafluoroacetylacetonate (Cu(hfacac)2) fur-
nished rearrangement products 4 and 5 in generally good to
excellent overall yields (mixtures of cis and trans diastere-
omers) and varying ratios (Table 1). Bis(benzyl) ether
substrate 3a, with comparable migrating groups on both
oxygens, was examined first (entries 1-4). In all cases,
regardless of catalyst, the major product was 4a, resulting
from benzyl [1,2]-shift via the five-membered cyclic oxo-
nium ylide. Small amounts of the corresponding pyranone
5a were seen in all cases, and enol ether 6a, the product of
benzyl [1,4]-shift, was also observed under copper catalysis.
Enol ether 6a is presumed to form from the same five-
membered ylide that furnishes 4a; thus, products derived
from the five-membered ylide were favored in all four cases
by ratios ranging from 3.2 to 9.1:1. Both 4a and 5a were
(9) Observation of significant levels of asymmetric induction in rhodium-
or copper-catalyzed oxonium ylide rearrangements suggests that the metal
remains associated during the rearrangement step: (a) Pierson, N.; Ferna´dez-
Garcia´, C.; McKervey, M. A. Tetrahedron Lett. 1997, 38, 4705-4708. (b)
Doyle, M. P.; Forbes, D. C.; Vasbinder, M. M.; Peterson, C. S. J. Am.
Chem. Soc. 1998, 120, 7653-7654. (c) Clark, J. S.; Fretwell, M.; Whitlock,
G. A.; Burns, C. J.; Fox, D. N. A. Tetrahedron Lett. 1998, 39, 97-100. (d)
Hodgson, D. M.; Petroliagi, M. Tetrahedron: Asymmetry 2001, 12, 877-
881. (e) Kitagaki, S.; Yanamoto, Y.; Tsutsui, H.; Anada, M.; Nakajima,
M.; Hashimoto, S. Tetrahedron Lett. 2001, 42, 6361-6364. See also ref
1g. (f) Review: Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A. Chem.
Soc. ReV. 2001, 30, 50-61.
(10) Radical-pair mechanism for ammonium ylide rearrangements is well
established: Ollis, W. D.; Rey, M.; Sutherland, I. O. J. Chem. Soc., Perkin
Trans. 1 1983, 1009-1027. We have also observed dimeric products
consistent with radical intermediates (ref 1d).
(11) (a) Marotta, E.; Righi, P.; Rosini, G. Org. Lett. 2000, 2, 4145-
4148. (b) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258-
3260.
1658
Org. Lett., Vol. 6, No. 10, 2004

dependence was observed for this substrate (entries 10-14).
With Cu(tfacac)2, pyranone 5c was formed in good yield
(1.4:1 dr), with minor amounts of furanone 4c and enol ether
6c. In contrast, both rhodium(II) catalysts furnished mainly
the furanone 4c (4c/5c ) 1.8 to 3.1:1). Only Cu(hfacac)2
was relatively unselective, giving similar amounts of 4c and
5c along with 19% of 6c.
Table 1. Copper and Rhodium-Catalyzed Carbene-Transfer
Reactions of 3a-c
In previous examples containing only a γ-alkoxy group,
large amounts of cyclopentanone products resulting from
C-H insertion were formed at the expense of [1,2]-shift
products resulting from six-membered ylides.1,8 In these
cases, the relative contributions of diminished six-membered
ylide cyclization rate and the known activating effect of an
adjacent alkoxy group on C-H insertion rate13 were difficult
to determine. The metallocarbenes derived from 3a-c have
a greater range of options. Aside from addition to the
γ-alkoxy group and cyclopentanone formation by C-H
insertion, the metallocarbenes can add to the closer â-alkoxy
group to give a five-membered ylide. Five-membered ylide
formation is possible for 1a,b; however, these ylides lack a
competent migrating group, and this process remains un-
detectable. In contrast, either ylide derived from 3a-c is
subject to rearrangement. Cyclopropanation of the remote
alkene is also possible for the allyl ethers 3b and 3c. Bis-
(benzyl) ether 3a furnished furanone 4a as the major product
with all catalysts (with Rh(II) catalysts providing higher
yields), and no cyclopentanone C-H insertion products were
isolated. These results suggest that cyclization to the five-
membered ylide is strongly favored over C-H insertion.
Also, the results with 3b are in accord with prior observations
seen with 1a,b: allyl-substituted oxonium ylides appear to
undergo fast rearrangement, leading to good yields of
furanone 4b regardless of the catalyst.
catalyst/
conditionsa
yield 4 yield 5
other
entry substrate
(%)b
(%)b products
1
2
3a
3a
3a
3a
3b
3b
3b
3b
3b
3c
3c
3c
3c
3c
Cu(tfacac)2/40 °C
Cu(hfacac)2/40 °C
Rh2(OAc)4/rt
33
48
56
58
96
71
96
51
54
16
38
50
54
56
8
13
13
18
6a (40%)
6a (16%)
3
4
5
6
Rh2(tpa)4/rt
Cu(tfacac)2/40°C
Cu(hfacac)2/40°C
Rh2(OAc)4/rt
7
8
9
Rh2(tpa)4/rt
7b (12%)
7b (20%)
6c (12%)
6c (19%)
Rh2(tpa)4/40 °C
Cu(tfacac)2/40 °C
Cu(hfacac)2/40 °C
Rh2(OAc)4/rt
Rh2(tpa)4/rt
Rh2(tpa)4/rt/hexane
10
11
12
13
14
67
29
27
22
18
a Dichloromethane (0.01 M) was used as the solvent in all cases except
entry 14. Catalyst loading was 10 mol % for copper catalysts and 3 mol %
for rhodium catalysts. b Isolated yields after chromatography. Both diastere-
omers of 4a-c and 5a,c were isolated in all cases (ratios generally e 2:1).
Substantial catalyst dependence for furanone vs pyranone
products was seen for mixed bis(ether) substrate 3c. Selective
formation of 4c with Rh(II) catalysts is consistent with
preferential cyclization to the five-membered ylide. However,
reversal to a >4:1 ratio of 5c/4c in the case of Cu(tfacac)2
indicates that the nature of the migrating group can override
the inherent selectivity for five- vs six-membered ylides. This
result strongly suggests that equilibration may occur between
the two possible ylide intermediates 8 and 9 (Scheme 3).
The presence of a better migrating group in the minor ylide
isomer would allow predominant reactivity via that inter-
mediate. The contrasting results with rhodium catalysts may
be due to either diminished ylide equilibration or no special
preference by Rh-derived ylides for allyl vs benzyl migration.
Moreover, even a relatively minor change in the ligand of
the copper catalyst (Cu(tfacac)2 vs Cu(hfacac)2) eliminated
the selectivity for pyranone 5c. As with 3a and 3b, no C-H
insertion products were isolated in any of these examples.
The origin of the large preference for allyl over benzyl
migrating groups by oxonium ylides derived from Cu(tfacac)2
formed as mixtures of diastereomers in all cases (1.5:1 to
4:1). Given the relatively low ratios and the primary
mechanistic focus on migrating group selectivity,12 individual
stereoisomers were not rigorously assigned in this case.
Substrate 3b has the option of allyl migration via a five-
membered ylide or benzyl migration via a six-membered
ylide (entries 5-9). The apparent preference for reaction via
five-membered ylides seen with 3a was expected to be
reinforced by the more facile allyl [2,3]-shift vs a benzyl
[1,2]-shift. This was the case, with good to excellent yields
of 4b and none of the pyranone 5b isolated in all runs.
However, Rh2(tpa)4 did furnish minor amounts of cyclopro-
pane 7b. Raising the temperature led to small increases in
the yields of both 4b and 7b. As with 3a, furanone 4b was
formed as a mixture of diastereomers (ca. 1:1).
The two ylide reactivity options available for substrate 3c
were expected to be more evenly balanced. Ring-closure
kinetics should favor the five-membered ylide, while migrat-
ing group preferences should lead to products derived from
the six-membered ylide. In the event, a strong catalyst
(13) (a) Adams, J.; Poupart, M. A.; Grenier, L.; Schaller, C.; Ouimet,
N.; Frenette, R. Tetrahedron Lett. 1989, 30, 1749-1752. (b) Wang, P.;
Adams, J. J. Am. Chem. Soc. 1994, 116, 3296-3305. (c) Davies, H. M. L.;
Antoulinakis, E. G.; Hansen, T. Org. Lett. 1999, 1, 383-385. (d) Davies,
H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063-
3070.
(12) Rigorous distinction of furanones 4 from pyranones 5 was ac-
complished using HMBC correlations through the ring oxygen, IR CdO
stretches (1755-1760 cm-1 for 4 and 1715-1730 cm-1 for 5) and
characteristic CdO 13C chemical shifts (215-216 ppm for 4 and 207-209
ppm for 5).
Org. Lett., Vol. 6, No. 10, 2004
1659

in the [1,2]-shift mechanism, in accord with previous
examples of catalyst-dependent asymmetric induction.9 Metal
participation could take the form of a concerted benzyl-
transfer in analogy to that proposed by Roskamp and
Johnson,1b or may proceed through stepwise benzyl-transfer
to the metal followed by reductive elimination, a process
suggested by Dhavale and co-workers.14
Scheme 3
The critical role played by the choice of transition metal
catalyst used in carbene-transfer processes is well-known.
Given the indirect evidence for continuing association of the
metal catalyst following metallocarbene addition to ethers
to form oxonium ylides, it should not be surprising that
catalyst choice can also impact ylide reactivity. The simple
4,5-dialkoxy-1-diazo-2-pentanones examined in this study
present options for competing ylides of different ring sizes
and migrating groups. There is a strong preference for
rearrangement via the five-membered oxonium ylide over
the six-membered alternative. However, in the case of Cu-
(tfacac)2, selective allyl migration can override the five-ring
preference to give mainly pyranone products from the six-
membered ylide. This can be rationalized by slow rearrange-
ment of the initially formed five-membered O-benzyl
oxonium ylide, permitting equilibration with the six-
membered O-allyl isomer and relatively fast rearrangement
of this intermediate. The absence of cyclopentanone products
in any of the examples is especially notable, indicating the
favorability of ylide formation over C-H insertion processes.
These results highlight the importance of catalyst choice not
only in control of metallocarbene generation and chemo-
selectivity but also in the optimization of any process
proceeding via oxonium ylide intermediates.
is uncertain. As noted above, this could be due simply to
the availability of a lower energy concerted [2,3]-shift
mechanism, whereas benzyl groups must migrate by a
stepwise [1,2]-shift. The isolation of [1,4]-shift products 6a
and 6c from the copper-catalyzed rearrangement of 3a and
3c is consistent with the notion that the intermediate O-benzyl
ylides 8a,c rearrange via radical-pair intermediates (Scheme
4). However, the corresponding rhodium-catalyzed reactions
Scheme 4
Acknowledgment. Acknowledgment is made to the
donors of the Petroleum Research Fund, administered by the
American Chemical Society, for support of this work. We
also thank the Natural Sciences and Engineering Research
Council of Canada and the University of Alberta.
Supporting Information Available: Full experimental
procedures for the preparation and rearrangement of 3a-c
and characterization data and copies of NMR spectra for
3-7. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL049493T
furnished none of the [1,4]-shift products and showed no
preference for allyl over benzyl migrating groups. One
possible explanation is direct involvement by the Rh catalyst
(14) Karche, N. P.; Jachak, S. M.; Dhavale, D. D. J. Org. Chem. 2001,
66, 6323-6332.
1660
Org. Lett., Vol. 6, No. 10, 2004