Evidence for heterolytic cleavage of a cyclic oxonium ylide: Implications for the mechanism of the Stevens [1,2]-shift

Article abstract of DOI:10.1039/c7cc07716e

Formation and rearrangement of several oxonium ylides containing cyclopropylcarbinyl migrating groups were studied. Efficient ring-contraction by [1,2]-shift to form cyclopropane-substituted cyclobutanones was observed, with no competing cyclopropane fragmentation. Substitution with the hypersensitive mechanistic probe (trans,trans-2-methoxy-3-phenylcyclopropyl)methyl led to cyclopropane fragmentation via an apparent heterolytic pathway, providing the first evidence for ion pair intermediates from ylide cleavage, and suggesting a possible alternative heterolytic mechanism for the Stevens [1,2]-shift.

Full text of DOI:10.1039/c7cc07716e

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Evidence for Heterolytic Cleavage of a Cyclic Oxonium Ylide:
Implications for the Mechanism of the Stevens [1,2]-Shift†
Seyedeh Nargess Hosseini,a Jeffrey R. Johnstona and F. G. Westa
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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Formation and rearrangement of several oxonium ylides
containing cyclopropylcarbinyl migrating groups were studied.
Efficient ring-contraction by [1,2]-shift to form cyclopropane-
substituted cyclobutanones was observed, with no competing
cyclopropane fragmentation. Substitution with the hypersensitive
mechanistic
probe
(trans,trans-2-methoxy-3-
phenylcyclopropyl)methyl led to cyclopropane fragmentation via
an apparent heterolytic pathway, providing the first evidence for
ion pair intermediates from ylide cleavage, and suggesting a
possible alternative heterolytic mechanism for the Stevens [1,2]-
shift.
Scheme 1 Evidence of radical pairs in oxonium ylide [1,2]-shifts
group in such a process. The cyclopropylcarbinyl radical is a
well-known radical clock, with its rearrangement to the 3-
butenyl radical occurring at a rate of 1 x 108 s-1 at 25 °C.9 To
the best of our knowledge, Stevens rearrangement of
cyclopropylcarbinyl-substituted oxonium ylides has not been
examined,10 and its competence as a migrating group and the
fate of the cyclopropane ring were of interest to us.11
Oxonium ylides are versatile intermediates suitable for the
construction of a variety of complex targets.1 Typically they are
generated via nucleophilic trapping of metallocarbenes by
ethers, usually in an intramolecular process to limit alternative
metallocarbene reactivity. The resulting cyclic ylides can
undergo a variety of subsequent transformations, including
[2,3]-sigmatropic rearrangement,2 Stevens [1,2]-shift,3
Diazoketone 1a was selected for initial study, with the
expectation that metallocarbene 2a would generate cyclic
oxonium ylide 3a, whose rearrangement would afford [1,2]-
shift products 6a and/or 7a (Scheme 2) Observation of 7a
would offer strong evidence for the intermediacy of a radical
pair consisting of tetrahydrofuranone radical 4a and
cyclopropylcarbinyl radical 5a. In the event, treatment of 1a
sequential
electrophilic/nucleophilic
trapping,4
or
fragmentation.5
Among these pathways, the Stevens [1,2]-shift entails an
unusually complex mechanistic odyssey. Concerted migration
of one of the ylide substituents from heteroatom to carbon is
symmetry-forbidden,6 leading to various alternative stepwise
mechanistic proposals. In the context of the corresponding
ammonium ylides, Ollis and co-workers provided strong
evidence for migration via homolysis and radical pair
recombination.7 The observation of homodimeric side-
products in some oxonium ylide examples suggested that a
similar mechanism was in effect for these intermediates
(Scheme 1).8
‡
with Cu(hfacac)2 in dichloroethane (DCE) at reflux furnished
carbene dimer 8a (mixture of E/Z isomers) as the sole isolable
product. Exclusive formation of products derived from 2a
suggests slow rearrangement of oxonium ylide 3a, with
preferential reaction via the metallocarbene side of the
equilibrium.12
We imagined that the rate of oxonium ylide rearrangement
could be affected by the degree of radical stabilization on the
Based upon the assumption that [1,2]-shifts of oxonium
ylides proceed through a homolytic mechanism, we were
interested in the fate of a cyclopropyl-substituted migrating
migrating
group,
and
therefore
prepared
1-
phenylcyclopropylcarbinyl substrate 1b
.
Treatment of this
compound with Cu(hfacac)2 in DCE at reflux provided the [1,2]-
shift product 6b in good yield, with none of the carbene dimer
8b. Also notable were the isolation of minor amounts of
bis(tetrahydrofuranone) 9, and the absence of any homoallyl
migration product 7b. As noted earlier, observation of homo-
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oxonium ylide to undergo cleavage and [1,2]-shift; in this case
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DOI: 10.1039/C7CC07716E
the adjacent ring methylene was sufficient for clean
rearrangement. Several other cases were also studied, varying
the degree of substitution on the migrating carbon (1d) or the
oxygen substituent (1e,f). In all cases the cyclobutanones
were formed efficiently, though in varying ratios of
diastereomers. No products of cyclopropane fragmentation
were seen in any of these cases.
The absence of any products of cyclopropylcarbinyl–
homoallyl rearrangement for substrates 1c
uncertainty on our part as to whether [1,2]-shift by the
corresponding ylides occurred via radical intermediates.
Isolation of from the reaction of 1b suggests that at least
-f provoked
3
9
some of that reaction proceeds through a homolysis manifold,
but other pathways such as heterolysis or metal-assisted
migration might also be available.12b,15 We therefore turned to
the hypersensitive mechanistic probe described by Newcomb
and co-workers, wherein alternative cyclopropane cleavage
pathways are expected depending upon the intervention of a
radical or cationic center at the cyclopropylcarbinyl position
(Scheme 3).16 Aldehyde 10 was subjected to aldol addition,
Scheme 2 Attempted oxonium ylide formation/rearrangement of cyclopropylcarbinyl
ethers
and the resulting hydroxyester diastereomers 11a
separated and subjected to 3 successive steps to afford
substrates 12a
b,# which were then subjected to the standard
,b were
dimers such as
9 is a compelling indicator for radical
intermediates. Formation of 6b to the exclusion of 7b is
consistent with reports that the 1-phenylcyclopropylcarbinyl
radical undergoes reversible ring-opening, with the equilibrium
favoring the ring-closed form.13
,
conditions for ylide formation and rearrangement. In the
event, 12a afforded a complex mixture of products from which
the only isolable components were diastereomeric
tetrahydrooxepines 15a and 16a §
These products are
.
The notable difference in the behavior of 1a and 1b points
to the sensitivity of the migrating center to stabilizing
substituents, prompting us to examine substrate 1c, in which
the cyclopropyl-substituted migrating group was now
endocyclic in the intermediate ylide 3c (Table 1). [1,2]-Shift of
this group would entail a net ring-contraction to afford
presumed to result from ring closure through the carbonyl
oxygen of zwitterion 14a, which results from heterolytic
cyclopropane fragmentation of ylide 13a. None of the
corresponding homolytic fragmentation products (resulting
from cleavage adjacent to the phenyl group) were isolated, nor
were any cycloheptanones (the product of attack through the
enolate carbon of 14a). Preferential cyclization to afford 15a
and 16a rather than cycloheptanones may be due to a
preference by the oxocarbenium ion intermediate to react
cyclobutanone 6c 14
A range of reaction conditions were
.
surveyed (see ESI), with the optimal ones (Cu(hfacac)2 in DCM
at reflux) furnishing cyclobutanones 6c in 80% yield and as a
6:1 ratio of cis:trans diastereomers.* Treatment of substrate 1c
with rhodium catalyst also generated the cyclobutanones 6c
with 73% yield and with a dr of 2.2:1 (entry 2). Successful ring-
contraction of 1c shows that the presence of a strongly
stabilizing aryl group is not required for the intermediate
Table 1 Cyclobutanones by cyclopropyl-directed ring-contraction of oxonium ylides
Entry
Substrate
R1
R2
Catalyst
Yield 6
(cis:trans)a
80 (6:1)
1
2
3
4
5
1c
1c
1d
1e
1f
Me
Me
Me
Et
H
H
Me
H
H
Cu(hfacac)2
Rh2(OAc)4
Cu(hfacac)2
Cu(hfacac)2
Cu(hfacac)2
73 (2.2:1)
50 (1.4:1)
70 (6:1)
i-Pr
78 (4.8:1)
aYields given are for isolated product after purification. Ratios were determined
1H NMR analysis via integration of ether O–C–H resonances.
Scheme 3 Preparation and rearrangement of hypersensitive mechanistic probe 12a
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with the harder oxygen nucleophile.17 It should be noted that
15a and 16a can form only from the (Z)-isomer of 14a, and to
whatever extent fragmentation affords the (E)-alkene,
numerous uncharacterizable pathways are expected to
predominate.16b,18 This stereospecific reactivity, together with
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2
3
the lability of oxepines 15a and 16a §§
is likely responsible for
,
the low mass balance for this transformation.
The connectivity of 15a and 16a was determined via HMBC
analysis, in which clear evidence was seen for cyclopropane
fragmentation adjacent to the methoxy group rather than the
phenyl (see ESI). The relative stereochemical configurations of
these isomers was assigned based upon the vicinal coupling
constants of the adjacent methine protons on C2 and C3 of the
oxepine ring, as well as NOE correlations that clearly showed
an (E)-geometry in each case for the exocyclic enol ether
moieties.
In the case of this sensitive mechanistic probe, the only
identifiable pathway for cyclopropane fragmentations
proceeds through apparent ionic intermediates, offering the
first evidence for ion pair intermediates from cleavage of
oxonium ylides. The heterolytic fragmentation pathway may
intervene in the mechanism of the corresponding Stevens
[1,2]-shift. This result, in conjunction with prior examples
involving apparent homolytic mechanisms, suggests that the
reaction manifold is quite sensitive to the structure of the
migrating group.19 In particular, oxonium or sulfonium ylide
substrates possessing anomeric acetal migrating carbons3,20
seem well suited to heterolysis, suggesting a careful re-
examination of those examples for solvent and substituent
effects. Continuing efforts in this regard are ongoing and will
be reported in due course.
4
5
6
7
8
9
10 The anionic counterpart, a [1,2]-Wittig rearrangement of
benzyl cyclopropylcarbinyl ether, has been reported, with
observation of only minor amounts of ring-opened homoallyl
product: P. T. Lansbury and V. A. Pattison, J. Am. Chem. Soc.
1962, 84, 4295.
11 Cyclopropyl groups are reported to have a small but
significant stabilizing effect on neighboring radical centers:
(a) A. L. Cooksy, H. F. King and W. H. Richardson, Org. Chem.
This work was supported by NSERC (RGPIN 249822). We
thank Dr. Robert McDonald of the University of Alberta X-ray
Crystallography Laboratory for the structure determination of
2003, 68, 9441; (b) D. C. Nonhebel, Chem. Soc. Rev., 1993, 22,
347.
12 Evidence for metallocarbene-oxonium ylide equilibration has
been reported: (a) F. P. Marmsäter, J. A. Vanecko and F. G.
West, Tetrahedron 2002, 58, 2027; (b) F. P. Marmsäter, J. A.
the carboxylic acid precursor to 12b
.
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H. Horner, F. N. Martinez, C. Tronche and M. Newcomb, J.
Am. Chem. Soc. 2000, 122, 2988.
Conflicts of interest
There are no conflicts to declare.
14 For previous examples of cyclobutanone formation via ring-
contraction of 5-membered oxonium ylides, see: (a) E. J.
Notes and references
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15 J. S. Clark and K. E. Hansen, Chem. Eur. J. 2014, 20, 5454.
,
‡ Subsequent to the original report,8 we have found that soluble
Cu(II) catalysts are superior to Rh(II) catalysts for oxonium ylide
formation from diazo precursors.
7
* Cyclobutanone stereoisomers were assigned via TROESY 16 (a) M. Newcomb and D. L. Chestney, J Am Chem Soc, 1994,
analysis. See ESI for details.
The relative configuration of the carboxylic acid precursor to
diastereomeric diazoketone 12b was determined via X-ray
crystallographic analysis (see ESI).
§ Methoxy diastereomer 12b furnished an intractable mixture of
116, 9753. (b) M.-H. Le Tadic-Biadatti and M. Newcomb, J
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#
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functionalities in 15a and 16a render them sensitive to 18 For an example of predominant fragmentation to form an
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Angelis and M. Orfanopoulos, Org. Lett, 2006. , 39.
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19 A similar observation has been made in the context of
ammonium ylide [1,2]-shifts: Y. Maeda and Y. Sato, J. Chem.
Soc., Perkin Trans. 1 1997, 1491.
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Evidence for heterolytic cleavage of a cyclic oxonium ylide: implications for the
mechanism of the Stevens [1,2]-shift
Seyedeh Nargess Hosseini, Jeffrey R. Johnston and F. G. West
In contrast to prior evidence for a homolytic mechanism, a cyclopropylcarbinyl-substituted oxonium ylide
furnished cleavage products consistent with a zwitterionic intermediate.