Probing the nature and extent of stabilization within foiled carbenes: Homoallylic participation by a neighboring cyclopropane ring

Article abstract of DOI:10.1021/jo4004579

Oxadiazoline 6 was synthesized to generate endo-tricyclo[3.2.1.0 ^2,4]octan-8-ylidene (3) by either photolysis or thermolysis. Diastereomer 6a thermally decomposed twice as fast as 6b. Carbene 3 was trapped stereoselectively by acrylonitrile and diethylamine in high yields. It behaved as a nucleophilic carbene with electron-poor alkenes, like acrylonitrile, but as an electrophile with very electron-rich species, such as diethylamine. However, when the reactions were performed in cyclohexane and cyclohexene, isomerization of 3 was favored. Replacement of the double bond in 7-norbornenylidene (1) by the single bond in the endo-fused cyclopropane unit of carbene 3 led to similar outcomes. Carbene 3 rightfully belongs to the family of foiled carbenes.

Full text of DOI:10.1021/jo4004579

Article
pubs.acs.org/joc
Probing the Nature and Extent of Stabilization within Foiled
Carbenes: Homoallylic Participation by a Neighboring Cyclopropane
Ring
Ingrid Malene Apeland, Hanspeter Kahlig, Eberhard Lorbeer, and Udo H. Brinker*
̈
Institute of Organic Chemistry, University of Vienna, Wahringer Strasse 38, A-1090 Vienna, Austria
̈
S
* Supporting Information
ABSTRACT: Oxadiazoline 6 was synthesized to generate
endo-tricyclo[3.2.1.02,4]octan-8-ylidene (3) by either photolysis
or thermolysis. Diastereomer 6a thermally decomposed twice
as fast as 6b. Carbene 3 was trapped stereoselectively by
acrylonitrile and diethylamine in high yields. It behaved as a
nucleophilic carbene with electron-poor alkenes, like acryloni-
trile, but as an electrophile with very electron-rich species, such
as diethylamine. However, when the reactions were performed
in cyclohexane and cyclohexene, isomerization of 3 was
favored. Replacement of the double bond in 7-norbornenyli-
dene (1) by the single bond in the endo-fused cyclopropane
unit of carbene 3 led to similar outcomes. Carbene 3 rightfully
belongs to the family of foiled carbenes.
Scheme 1. Stabilization of Foiled Carbenes by Electron
Donation to the Divalent Carbon Atom
INTRODUCTION
■
In 1968, Gleiter and Hoffmann coined the term “foiled
carbenes” for a special class of singlet carbenes.1,2 These
reactive species are stabilized to some degree by electron
donation from an intramolecular π-bond into the empty p-
orbital of the divalent carbon atom (Figure 1). This results in
bond by ω = 37° when compared with norbornene.5 Early on,
it was suggested that such bending should be reflected in the
stereoselectivity of intermolecular reactions; a reactant should
approach the divalent carbon more easily from the face anti to
the double bond because more space is available.1 Indeed, a
substantial bias was observed for the addition of 1 with 3,3-
dimethylbutene.6 Pyrolysis of the corresponding tosylhydra-
zone carbene precursor (i.e., Bamford−Stevens reagent) in the
presence of the alkene gave two adducts wherein the tert-butyl
group was oriented syn or anti to the double bond in a ratio of
7:1. However, the combined yield of the two products
amounted to only 0.1%. The stereoselectivity was also
investigated using density functional theory (DFT).7 The
most stable transition state was obtained when 3,3-
dimethylbutene approached the divalent carbon of 1 anti to
the double bond with the bulky tert-butyl group directed head-
on to avoid a steric interaction with the exo hydrogens at C-5
and C-6 of 1. This course would lead to the syn product, which
was indeed the “major” product obtained experimentally.6
Figure 1. Interaction of the single bond Walsh orbital in carbene 3
mimics that of the double bond π-MO in carbene 1, thereby
establishing a two-electron, three-center bond with each carbene’s p-
AO.
the formation of a two-electron, three-center bond, a charge-
delocalized arrangement found in certain analogous (non-
classical) carbonium ions.3 Addition of the divalent carbon to
the double bond is foiled because it would lead to an impossibly
strained product featuring an inverted carbon atom with all four
bonds pointed in one hemisphere.
The classic example of a foiled carbene is norbornen-7-
ylidene (1) (Scheme 1a).4 Computations indicate that the
bridge containing the divalent carbon leans toward the double
Received: March 3, 2013
© XXXX American Chemical Society
A
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In order to achieve reasonable yields of intermolecular
products from foiled carbenes, one must recognize their
predominantly nucleophilic behavior.8,9 The introduction of
reactants that can behave as electron-pair acceptors is
warranted. For example, tricyclo[6.2.1.02,7]undec-9-en-11-yli-
dene (2) comprises 1 as a subunit (Scheme 1b). It was
generated by thermal decomposition of an oxadiazoline
precursor. Carbene 2 reacted stereoselectively, via anti
approach, with each of the following reactants: diethylamine
(77% yield),10 acrylonitrile (42% yield),7 and malononitrile
(29% yield).11
Cyclopropanes sometimes demonstrate a reactivity resem-
bling that of alkenes. DFT calculations indicate that the three-
membered ring of endo-tricyclo[3.2.1.02,4]octan-8-ylidene (3)
stabilizes the divalent carbon in a way similar to that of a double
bond (Figure 1 and Scheme 1c).12 Computations also suggest
the singlet electronic state of 3 to be lower in energy than the
triplet.12 Thus far, few experiments have been conducted to
support the existence of an interaction between the divalent
carbon atom and the cyclopropane ring.13 Although rearrange-
ments of 3 have been studied,13 its potential classification as a
foiled carbene could be more thoroughly assessed by examining
its intermolecular reactions. Herein, the results of such
experiments are presented. For these studies, oxadiazolines
were employed as carbene precursors. Their syntheses and
kinetics of decomposition are described as well.
Figure 2. Single-crystal X-ray diffraction was used to elucidate the
structures of the rel-(1′R,2r,2′R,4′S,5R,5′S)-5-methoxy-5-methylspiro-
[2,5-dihydro-1,3,4-oxadiazole-2,8′-tricyclo[3.2.1.02,4]octane] (6a) and
rel-(1′R,2s,2′R,4′S,5R,5′S)-5-methoxy-5-methylspiro[2,5-dihydro-
1,3,4-oxadiazole-2,8′-tricyclo[3.2.1.02,4]octane] (6b).
RESULTS AND DISCUSSION
■
Synthesis of Oxadiazolines as Carbene Precursors.
Oxadiazolines are quite versatile compounds and popular
carbene precursors.10,14 Depending on their substituents, they
decompose by different pathways to give a variety of products.
(1′R,2′R,4′S,5′S)-5-Methoxy-5-methylspiro[2,5-dihydro-1,3,4-
oxadiazole-2,8′-tricyclo[3.2.1.02,4]octane] (6) is expected to
generate the requisite carbene 3 by either photolysis or
thermolysis. Carbene 3, however, is not produced directly from
6, but through either a carbonyl ylide or a diazo intermediate
(vide infra). The necessary oxadiazoline 6 was synthesized from
ketone 4 (Scheme 2).15 Two diastereomers were produced (dr
Scheme 2. Synthesis of the Oxadiazoline (6) Used To
Generate Carbene 3
Figure 3. Decay of oxadiazolines 6a and 6b at 116 °C monitored using
their UV absorbance maxima and found to be first-order.
first expelling molecular nitrogen.14b,c Diastereomer 6a
decomposes about twice as fast as 6b, ostensibly because its
configuration allows the cyclopropane ring to anchimerically
assist with the expulsion of N2. Such an interpretation is
supported by results from solvolysis experiments with tricyclo-
[3.2.1.02,4]octan-8-ol derivatives, which have shown that the
relative orientation of the cyclopropyl subunit and the leaving
group at C-8 are decisive when considering the rates of
solvolysis.16 The order of observed reactivity is endo,anti ≫
exo,syn > endo,syn > exo,anti.17 Thus, it is not surprising that the
endo,anti relationship between the nitrogen and cyclopropyl
group of 6a accelerates its decomposition when compared with
that of 6b, which exhibits an endo,syn relationship. Among other
factors, the modest 2-fold rate increase may arise from
anchimeric assistance by the filled Walsh orbital of the
cyclopropane moiety of 6a into an antibonding MO, resulting
in the loss of N2.
= 1:1.7) in a combined yield of 83%. Isomers 6a and 6b were
separated by column chromatography, and the absolute
configuration of each pseudoasymmetric spirocyclic C atom
(i.e., r/syn vs s/anti) was determined by X-ray crystallography
(Figure 2).
Kinetics Measurements. The rate of thermolysis of 6a and
6b was measured at 116 °C (1 mg/mL in decane) by
monitoring the decay of the UV absorption maxima of their
oxadiazoline groups at λmax = 338 and 333 nm, respectively.
The decay of both 6a and 6b follows a first-order rate law with
rate constants k = 2.3 × 10−5 s−1 and k = 1.2 × 10−5 s−1,
respectively. These values are typical for the decomposition of
oxadiazolines (Figure 3),14e,k which normally thermolyze by
Reactions of endo-Tricyclo[3.2.1.02,4]octan-8-ylidene
(3). All thermolysis (165 °C) and photolysis (λ > 200 nm,
B
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Table 1. GC−MS Analysis of Product Distribution Obtained from Thermolysis and Photolysis of Oxadiazolines 6a and 6b in
Cyclohexane and Cyclohexene
concn
(mg/mL)
intermol. product yield
(%)
intramol. product 8 yield
intramol. product 9 yield
azine 11 yield
precursor
substrate
conditions
(%)
(%)
(%)
6a
6b
6a
6a
6b
6b
6a
6b
6a
6a
6b
6b
cyclohexane
10
10
10
6
Δ
Δ
3
4
55
17
27
23
44
20
71
71
15
20
12
25
3
1

31
47
31
31
38


40
35
25
17
hν
hν
hν
hν
Δ




5
2
2
11
5
3
1
cyclohexene
10
10
10
6
10
10
1
Δ
4
hν
hν
hν
hν
6
8
2
12
5
2
1
3
2
water bath, room temperature) experiments were conducted by
dissolving precursors 6a and 6b, respectively, in the solvent
under investigation. First, the chemistry of 3 in cyclohexane and
cyclohexene was studied under the conditions listed in Table 1.
The resulting solutions were subjected to GC−MS analysis, and
yields were determined using camphor as an internal standard.
As presented in Table 1, there were some cases in which
small peaks were detected in the chromatograms that might
derive from compounds formed by intermolecular reactions of
carbene 3 with cyclohexane (M+; m/z = 190) or cyclohexene
(M+; m/z = 188). However, the estimated yields were low (ca.
2−8%). This lack of reactivity indicates a stabilization of
carbene 3, but it could also mean that intramolecular reactions
are faster. Moreover, the slow addition to the electron-rich
double bond of cyclohexene suggests that 3 acts as a
nucleophilic carbene as gauged by the “philicity” scale of
carbenes in carbene−alkene addition reactions.18
Scheme 3. Products Formed by Thermolysis or Photolysis of
Oxadiazoline 6a or 6b in Cyclohexane or Cyclohexene
an isolated yield of 11%. The azine can derive either from the
reaction of carbene 3 with diazo compound 10, which is formed
by the loss of methyl acetate from oxadiazoline 6, or from a
bimolecular reaction of 10 with itself followed by the loss of N2
(Scheme 3b).23 These processes can occur simultaneously
wherein the dominating one depends on the solution’s
concentration. As an additional possibility, carbene 3 might
attack the remote N atom of precursor 6, which would
subsequently lose methyl acetate to afford 11. The GC−MS
results indicate that 11 is formed more frequently during
photolysis than thermolysis. Alternatively, oxadiazolines 6a and
6b can decompose by an initial loss of N2, yielding a carbonyl
ylide, which further collapses to carbene 3.14 The 13C NMR
spectrum of 11 revealed two sets of signals in a 1:1 ratio. After
evaporation of the solvent, the sample was redissolved and
allowed to stand for 3 h before another analysis. Subsequently,
the spectrum revealed one major and one minor set of signals.
However, the 1:1 ratio was reestablished over time as the two
species equilibrated (Figure S25 in the Supporting Informa-
tion).
In all experiments, significant formation of a product (M+;
m/z = 106) was observed. This presumably results from an
isomerization of 3. In order to identify this compound,
thermolysis of 6b was carried out in cyclohexane-d12, and the
reaction mixture was analyzed by NMR spectroscopy. Addi-
tionally, 6b was thermolyzed in pentane, and after concen-
tration, the resulting product mixture was subjected to
diffusion-edited NMR.19 Two spectra with attenuated signals
were obtained after conducting two pulsed-field gradient spin
echo experiments in which one had a very low gradient
amplitude and the other had a much higher one. A pure trace
for compound 8 was computed by subtracting these spectra
from each other after the vertical scale was adjusted to the peak
of the undesired background (Figure S13 in the Supporting
1
Information). The H NMR and 13C NMR signals were in
accordance with tetracyclo[3.3.0.02,8.04,6]octane (8) (Scheme
3a).20 In addition, a minor product with the same mass was
formed. It is thought to be tricyclo[3.3.0.04,6]oct-2-ene
(dihydrosemibullvalene) (9) (Scheme 3a), based on character-
istic 1H NMR patterns of the alkenyl hydrogens.14k,21
Compounds 8 and 9 have also been obtained from carbene 3
under different conditions (vide infra).13a,b A mechanism for
the formation of 8 and 9 was proposed involving a conversion
of 3 into 7,13b,22 as shown in Scheme 3a.
In previous experiments,13a,b the corresponding tosylhydra-
zone precursor of carbene 3 was thermolyzed in diglyme (i.e.,
2,5,8-trioxanonane) in the presence of 5.74 equiv of sodium
methoxide. In addition to products 8 and 9, three methyl ethers
were obtained, resulting from intermolecular reactions of
carbene 3 with methanol. These compounds are believed to
form through a carbenium ion pathway in which the carbene is
protonated. Either the carbenium ion or the carbene route can
be favored by varying the reaction conditions. Here, a different
Under nearly all reaction conditions (Table 1), endo-
tricyclo[3.2.1.02,4]octan-8-one azine (11) (Scheme 3b) was
formed. The compound was identified by scaling up the
reaction of the thermolysis of 6b in pentane, which gave 11 in
C
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Scheme 4. Thermolysis and Photolysis of Oxadiazolines 6a and 6b in the Presence of Methanol
carbene precursor was used (i.e., an oxadiazoline) that was
directly dissolved in methanol. This could lead to a different
outcome. In addition, the reactions were carried out under both
thermolytic and photolytic conditions.
prevented.16b,c The stereochemistry of product 16 is
determined by 15 originating from protonation of carbene 3.26
Next, conditions were needed where carbene 3 would react
directly with an added substrate. Because foiled carbenes in
general are nucleophilic, trapping them with an electron-
deficient alkene has proven to be successful.7 Thus, when 6a or
6b was thermolyzed in acrylonitrile, rel-(1s,1′R,2R,2′R,4′S,5′S)-
spiro[cyclopropane-1,8′-tricyclo[3.2.1.02,4]octane]-2-carboni-
trile (17) (Scheme 5) was formed exclusively in a yield of 76%
In all experiments, only methyl ethers were formed. In each
case, GC−MS of the crude sample showed one main product,
which was isolated by column chromatography and identified as
rac-(1R,2S,4S,5R,6R)-2-methoxytricyclo[3.3.0.04,6]octane (16)
(Scheme 4). Compound 16 is identical to the main methyl
ether obtained by the reported Bamford−Stevens reaction.13a,b
The isolated yields were considerably lower after chromatog-
raphy (Scheme 4). It is possible that 16 decomposes on silica
adsorbent because the crude products were quite pure
Scheme 5. Thermolysis of Oxadiazolines 6a and 6b in the
Presence of Acrylonitrile
1
according to H NMR analysis.
In addition to 16, endo,syn-tricyclo[3.2.1.02,4]octan-8-ol (14)
was formed in 26% yield during the thermolysis of 6a in
methanol (Scheme 4). The production of alcohol 14 is best
explained by protonation of the proximal ylide intermediate 12
with methanol to afford 13, which locks in the stereo-
configuration at C-8. Subsequent methanolysis of 13 gives
14. A similar reaction sequence was observed for the
oxadiazoline precursor of 2.24 In contrast, the distal ylide
intermediate formed from 6b (not shown) might be
destabilized by electron donation from the three-membered
ring because of the aforementioned endo,anti relationship. This
may lead to its collapse before being trapped by a proton.
However, proton transfer rates to a negatively charged C atom
are extremely fast. The experiments with methanol therefore
stand as the single example where 6a and 6b reacted differently.
Because 14 is not formed during photolysis, it can be assumed
that the oxadiazoline decomposes through diazo intermediate
10 rather than ylide 12.
The formal insertion reaction of foiled carbenes into
methanol has been shown to occur through initial protonation
of the carbene to give a carbenium ion.25 The positive charge in
15 is delocalized among C-2, C-4, and C-8. Product 16 is
formed by an attack of methanol at C-2 or C-4. This indicates
that the charge is concentrated largely at these identical carbon
atoms. In addition, the delocalized charge in 15 shields it from
an attack by methanol at the exo positions of C-4 and C-2.
Thus, formation of the corresponding exo-methyl ether of 16 is
or 81%, respectively. These values are considerably higher than
those obtained for carbene 2. The stereochemistry of 17 was
assigned with the help of two-dimensional NMR experiments.
Because the reaction occurs stereoselectively (i.e., the cyano
group is always found to be anti to the cyclopropane), it can be
assumed that the product is formed through a concerted
mechanism, which is expected for a singlet carbene.2c The
assumed transition state is shown in Scheme 5. Previous DFT
calculations suggest that the anti product is formed with
electron-poor alkenes, whereas the syn product is preferred with
electron-rich alkenes.7 In both cases, the alkene approaches the
divalent carbon anti to the stabilizing moiety (i.e., double bond
or cyclopropane ring), but subsequent stereoelectronic effects
determine how the alkene’s substituents are orientated in the
product. Both the nucleophilic behavior and the diastereose-
lectivity in this reaction provide strong evidence for a foiled
carbene 3.
Foiled carbenes can also exhibit ambiphilicity. For example,
carbene 2 was successfully trapped by highly nucleophilic
diethylamine.10 Therefore, thermolyses were carried out for
D
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two-dimensional COSY, NOESY, HMBC, and HMQC spectra were
used to derive proton and carbon assignments. The diffusion edited
NMR experiments were done on the DRX 600, where a longitudinal
eddy current delay sequence with 1 ms smoothened square bipolar
gradient pulse pairs29 was used, with a diffusion delay set to 100 ms.
Two spectra were recorded, one with 3% and the second with 73%
gradient amplitude. The resulting 1H NMR spectra were subtracted by
scaling the signal intensity of the background signals to equal heights,
giving a trace with only compound 8 (Figure S13 in the Supporting
Information). Infrared spectra were measured with an ATR attach-
ment, and the absorptions are given in wavenumbers (cm−1). HRMS
was performed on a mass spectrometer outfitted with a TOF analyzer
using ESI techniques, or a double-focusing sector field analyzer using
EI (70 eV) techniques. Single-crystal X-ray analyses were performed
on a diffractometer. Photolysis experiments were carried out using a
medium pressure mercury lamp doped with FeI2 (λmax = 370 nm),
which was placed in a water-cooled jacket made of quartz. GC−MS
data were obtained using an instrument equipped with a mass selective
detector (70 eV) on a 30 m × 0.25 mm HP-5MS poly-
(methylphenylsiloxane) (95% dimethyl and 5% diphenyl, 0.25 μm
film thickness) capillary column using helium as the carrier gas.
General Settings for GC−MS Analysis. Pressure: 0.416 bar.
Flow: 0.7 mL/min. Average velocity: 32 cm/s. Injection volume: 1.0
μL. Split ratio: 1:25. Injection temperature: 270 °C. Starting
temperature: 80 °C for 2 min. Ramp: 5 °C/min up to 145 °C.
Ramp: 15 °C/min up to 220 °C. Isotherm: 220 °C for 3 min. Ramp:
15 °C/min up to 270 °C. Isotherm: 270 °C for 3 min.
Materials. Dry pentane was obtained by distillation from calcium
hydride. Cyclohexane, cyclohexene, acrylonitrile, diethylamine, and
methanol were distilled and dried over molecular sieves (3 Å or 4 Å)
before use. Commercially available compounds were used without
further purification. Ketone 4 was synthesized according to the
literature.16b,30 Analytical TLC was performed on aluminum plates
with silica gel 60 F254, and detection was obtained with an iodine
chamber or a UV lamp at λ = 254 nm. Flash chromatography was
conducted using silica gel 60 (230−400 mesh) as the stationary phase
with hexane, ethyl acetate, and dichloromethane in different ratios as
the mobile phase.
both 6a and 6b in the neat amine. One main product was
obtained from both reactions: endo,anti-N,N-diethyltricyclo-
[3.2.1.02,4]octan-8-amine (19) (Scheme 6), in yields of 67%
Scheme 6. Thermolysis of Oxadiazolines 6a and 6b in the
Presence of Diethylamine
and 59% from 6a and 6b, respectively. The GC−MS
chromatograms showed a small amount of an additional
compound with the same molar mass as 19 in ratios of 30:1 and
58:1, respectively. This minor product could be the syn analog
of 19, or it could result from a reaction of diethylamine with
carbene 7. The reaction 6 → 19 is assumed to proceed through
ylide intermediate 18 (Scheme 6),10,27 thereby preserving the
diastereoselectivity of step 3 → 18.28 The stereochemistry of
product 19 suggests an anti approach of diethylamine. In any
case, however, an anti approach is necessary to obtain 19 even if
the mechanism involves a concerted insertion of carbene 3 into
the N−H bond. Thus, this reaction also suggests a foiled
carbene 3 as an intermediate.
CONCLUSION
■
The experiments described above support that endo-tricyclo-
[3.2.1.02,4]octan-8-ylidene (3) is a stabilized carbene. The
occupied Walsh orbitals of the three-membered ring donate
electron density into the empty p-orbital of the divalent carbon
(Figure 1), causing the main bridge to bend toward the
cyclopropane ring as is the case with alkenylidene 1. This is
reflected in intermolecular reactions with acrylonitrile and
diethylamine, which both approach the divalent carbon anti to
the cyclopropane unit. Oxadiazolines 6a and 6b are useful
precursors of 3. The two diastereomers show almost identical
reactivities, although 6a thermally decomposes about twice as
fast as 6b. Azine 11 was isolated in nearly all reactions (Table
1). It is formed more frequently during photolysis than
thermolysis. In the thermolysis of 6a, ylide intermediate 12 was
trapped with methanol to give the tricyclic alcohol 14. Carbene
3 is added as a nucleophile to acrylonitrile and as an
electrophile to diethylamine in high yields. The reactions are
stereoselective. Replacing the CHCH unit in 7-norborneny-
lidene (1) with an endo-fused cyclopropane ring, as in carbene
3, leads to comparable reactive behavior. Thus, on the basis of
the experiments outlined in this study, carbene 3 rightfully
belongs to the family of foiled carbenes.
rac-(1′R,2′R,4′S,5′S)-5-Methoxy-5-methylspiro[2,5-dihydro-1,3,4-
oxadiazole-2,8′-tricyclo[3.2.1.02,4]octane] (6). Ketone 4 (1.830 g,
14.98 mmol) and acetyl hydrazide (1.225 g, 16.54 mmol) were
dissolved in methanol (100 mL) and refluxed for 3 h. The reaction
mixture was cooled to 0 °C, and PhI(OAc)2 (5.308 g, 16.48 mmol)
was added over a period of 5 min. The mixture was stirred overnight as
the ice bath melted. The solvent was removed on a rotary evaporator,
and the product was isolated as a diastereomeric mixture (6a:6b =
1:1.7) by column chromatography using hexane/ethyl acetate (4:1) as
eluant to give 6 (2.594 g, 83%). The two diastereomers were separated
by column chromatography using hexane/dichloromethane (2:3) as
eluant, affording 6a and 6b as white solids.
rel-(1′R,2r,2′R,4′S,5R,5′S)-5-Methoxy-5-methylspiro[2,5-dihydro-
1,3,4-oxadiazole-2,8′-tricyclo[3.2.1.02,4]octane] (6a). mp: 35−39 °C.
1H NMR (400.13 MHz, CDCl3): δ 3.09 (s, 3H), 2.38−2.16 (m, 3H),
2.03−1.97 (m, 1H), 1.68−1.59 (m, 2H), 1.63 (s, 3H), 1.44−1.34 (m,
3H), 1.06−1.01 (dt, J = 7.4 Hz (t), 6.5 Hz (d), 1H). 13C NMR
(100.62 MHz, CDCl3): δ 142.3 (C), 130.2 (C), 50.2 (CH3), 45.0
(CH), 43.7 (CH), 24.3 (CH2), 24.1 (CH2), 23.1 (CH3), 20.7 (CH),
20.6 (CH), 16.7 (CH2). IR: ν 3069 (w), 2964 (m), 2880 (w), 1568
(w), 1477 (w), 1446 (w), 1377 (m), 1309 (w), 1240 (m), 1203 (s),
1131 (s), 1081 (m), 1045 (s), 987 (w), 927 (s), 907 (s), 872 (s), 787
(w), 760 (m) cm−1. MS (EI, 70 eV): m/z 208 [M]+ (<1), 177 (7), 153
(4), 115 (6), 105 (38), 91 (100), 78 (48), 65 (10), 51 (7). HRMS
(ESI): m/z [M + H]+ calcd for C11H17N2O2 209.1290; found
209.1289. Anal. Calcd for C11H16N2O2: C, 63.44; H, 7.74; N, 13.45; O,
15.37. Found: C, 63.76; H, 7.61; N, 13.34; O, 15.21.
EXPERIMENTAL SECTION
■
Equipment. Melting points were measured on a melting point
microscope and are uncorrected. The NMR spectra were obtained on
either a DRX 400 WB instrument, operating at a frequency of 400.13
MHz for 1H and 100.62 MHz for 13C, or a DRX 600 at a frequency of
1
600.13 MHz for H and 150.95 MHz for 13C. The chemical shifts are
1
rel-(1′R,2s,2′R,4′S,5R,5′S)-5-Methoxy-5-methylspiro[2,5-dihydro-
1,3,4-oxadiazole-2,8′-tricyclo[3.2.1.02,4]octane] (6b). mp: 54−58 °C.
1H NMR (400.13 MHz, CDCl3): δ 3.05 (s, 3H), 2.26−2.21 (m, 1H),
given in parts per million with respect to TMS. For the H NMR
spectra, the residual peak of CDCl3 (δH = 7.26 ppm) or cyclohexane-
d12 (δH = 1.38 ppm) was used as an internal standard. For the 13C
NMR spectra, the central peak of the CDCl3 triplet (δC = 77.16 ppm)
was used as an internal standard. Conventional gradient-enhanced
2.05−1.99 (m, 1H), 1.83−1.73 (m, 3H), 1.72−1.64 (m, 1H), 1.58 (s,
3H), 1.39−1.24 (m, 2H), 1.17−1.11 (m, 1H), 0.95−0.88 (m, 1H). 13
C
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NMR (100.62 MHz, CDCl3): δ 141.1 (C), 131.8 (C), 50.1 (CH3),
44.7 (CH), 43.4 (CH), 25.8 (CH2), 25.7 (CH2), 23.0 (CH3), 16.9
(CH), 16.6 (CH), 12.2 (CH2). IR: ν 3042 (w), 2966 (m), 2877 (w),
1560 (w), 1472 (w), 1448 (w), 1376 (m), 1313 (w), 1238 (m), 1201
(s), 1138 (s), 1083 (m), 1051 (s), 977 (w), 913 (s), 869 (m), 791
(m), 761 (m) cm−1. MS (EI, 70 eV): m/z 208 [M]+ (<1), 177 (9),
153 (5), 115 (6), 105 (38), 91 (100), 78 (45), 65 (8), 51 (6). HRMS
(EI, 70 eV): m/z [M]+ calcd for C11H16N2O2 208.1212; found
208.1215. Anal. Calcd for C11H16N2O2: C, 63.44; H, 7.74; N, 13.45; O,
15.37. Found: C, 63.65; H, 7.63; N, 13.31; O, 14.93.
vacuo. The crude product was subjected to column chromatography
using hexane/ethyl acetate (9:1) as eluant, giving 16 (0.042 g, 44%) as
a yellow liquid.
From photolysis of 6a: A solution of oxadiazoline 6a (0.100 g, 0.480
mmol) in methanol (5 mL) was degassed with argon and photolyzed
for 7 h, using a water bath for cooling. The reaction mixture was
filtered and concentrated in vacuo. The crude product was subjected
to column chromatography using hexane/ethyl acetate (9:1) as eluant,
giving 16 (0.022 g, 33%) as a yellow liquid.
From photolysis of 6b: A solution of oxadiazoline 6b (0.100 g,
0.480 mmol) in methanol (5 mL) was degassed with argon and
photolyzed for 7 h, using a water bath for cooling. The reaction
mixture was filtered and concentrated in vacuo. The crude product was
subjected to column chromatography using hexane/ethyl acetate
(9:1), giving 16 (0.031 g, 47%) as a yellow liquid. Spectroscopic data
were in agreement with the literature.13b
General Procedure for GC−MS Analysis of Thermolysis and
Photolysis of Oxadiazolines 6a and 6b in Cyclohexane and
Cyclohexene. For thermolysis, the oxadiazoline was dissolved in
either cyclohexane or cyclohexene and stirred in a pressure tube at 165
°C for 3−6 h. For photolysis, the oxadiazoline was dissolved in either
cyclohexane or cyclohexene in a round-bottomed flask equipped with a
rubber septum. The solution was degassed with argon and subjected to
photolysis for 6−15 h. The temperature was controlled with a water
bath. Camphor was added as an internal standard to the resultant
reaction mixtures before GC−MS analysis.
1H NMR (400.13 MHz, CDCl3): δ 3.80−3.72 (m, 1H), 3.22 (s,
3H), 2.60−2.51 (m, 1H), 2.25−2.12 (m, 1H), 1.99−1.88 (m, 1H),
1.83−1.69 (m, 2H), 1.69−1.57 (m, 1H), 1.49−1.39 (m, 2H), 1.16−
1.05 (m, 2H). 13C NMR (100.62 MHz, CDCl3): δ 88.1 (CH), 56.8
(CH3), 43.6 (CH), 30.3 (CH2), 27.3 (CH2), 27.2 (CH), 26.0 (CH),
24.1 (CH2), 19.2 (CH). IR: ν 3029 (m), 2943 (m), 2867 (m), 1736
(m), 1471 (m), 1450 (m), 1367 (m), 1349 (m), 1212 (m), 1177 (m),
1117 (s), 1098 (s), 975 (m) cm−1. MS (EI, 70 eV): m/z 138 [M]+ (4),
123 (3), 106 (28), 91 (21), 84 (10), 79 (45), 71 (100), 67 (17), 53
(5). HRMS (EI, 70 eV): m/z [M]+ calcd for C9H14O 138.1045; found
138.1044.
rel-(1s,1′R,2R,2′R,4′S,5′S)-Spiro[cyclopropane-1,8′-tricyclo-
[3.2.1.02,4]octane]-2-carbonitrile (17). From thermolysis of 6a: A
solution of oxadiazoline 6a (0.122 g, 0.586 mmol) in acrylonitrile (6
mL) was stirred in a pressure tube for 4 h at 165 °C. The reaction
mixture was filtered and concentrated in vacuo. The product was
isolated by column chromatography using hexane/ethyl acetate (4:1)
as eluant, giving 17 (0.071 g, 76%) as a white solid.
Tetracyclo[3.3.0.02,8.04,6]octane (8). A solution of oxadiazoline 6b
(0.319 g, 1.53 mmol) in pentane (20 mL) was stirred in a pressure
tube for 4 h at 165 °C. Pentane was carefully removed by Kugelrohr
distillation, and the residue was subjected to gradient NMR analysis.
Spectroscopic data were in agreement with the literature.20
1H NMR (600.13 MHz, CDCl3): δ 1.74−1.69 (m, 2H), 1.65−1.55
(m, 4H), 1.29−1.25 (m, 4H). 13C NMR (150.95 MHz, CDCl3): δ 25.7
(CH), 24.0 (CH2), 21.8 (CH).
Thermolysis of 6b in Cyclohexane-d12. A solution of oxadiazoline
6b (0.030 g, 0.14 mmol) in cyclohexane-d12 (1 mL) was stirred in a
pressure tube for 3 h at 165 °C. The reaction mixture was subjected to
1
NMR analysis (see Figure S18 in the Supporting Information for H
NMR spectrum of the mixture).
endo-Tricyclo[3.2.1.02,4]octan-8-one Azine (11). A solution of
oxadiazoline 6b (0.254 g, 1.22 mmol) in pentane (3 mL) was stirred in
a pressure tube for 4 h at 165 °C. The reaction mixture was filtered
and concentrated. The product was isolated by column chromatog-
raphy using hexane/ethyl acetate (1:1) as eluant, giving 11 (0.016 g,
11%) as a sticky white solid.
From thermolysis of 6b: A solution of oxadiazoline 6b (0.125 g,
0.600 mmol) in acrylonitrile (6 mL) was stirred in a pressure tube for
4 h at 165 °C. The reaction mixture was filtered and concentrated in
vacuo. The product was isolated by column chromatography using
hexane/ethyl acetate (4:1) as eluant, giving 17 (0.077 g, 81%) as a
white solid.
1
mp: 130−143 °C. H NMR (600.13 MHz, CDCl3): δ 3.21−3.14
1
(m, 2H), 2.54−2.46 (m, 2H), 1.69−1.51 (m, 4H), 1.47−1.36 (m, 4H),
1.28−1.16 (m, 4H), 1.03−0.97 (m, 2H), 0.97−0.90 (m, 2H). 13C
NMR (150.95 MHz, CDCl3): δ 180.88 and 180.79 (C), 37.62 and
37.61 (CH), 32.44 and 32.42 (CH), 24.04 and 24.00 (CH2), 23.44 and
23.42 (CH2), 15.29 and 15.28 (CH), 14.79 and 14.76 (CH), 11.48 and
11.44 (CH2). IR: ν 3029 (m), 2950 (m), 2873 (m), 1682 (s), 1523
(m), 1473 (m), 1311 (m), 1301 (m), 1180 (w), 1147 (m), 1108 (m),
1047 (m), 1030 (m), 928 (m), 789 (m), 757 (s), 719 (m) cm−1. MS
(EI, 70 eV): m/z 240 [M]+ (12), 174 (3), 120 (36), 93 (100), 77 (27),
65 (13), 54 (7). HRMS (ESI): m/z [M + H]+ calcd for C16H21N2
241.1705; found 241.1696.
mp: 34−36 °C. H NMR (400.13 MHz, CDCl3): δ 2.02−1.94 (m,
1H), 1.84−1.70 (m, 1H), 1.68−1.48 (m, 4H), 1.42−1.19 (m, 5H),
1.14−1.08 (m, 1H), 0.88−0.83 (dt, J = 7.4 Hz (t), 6.3 Hz (d), 1H).
13C NMR (100.62 MHz, CDCl3): δ 121.0 (C), 54.4 (C), 41.7 (CH),
40.7 (CH), 26.8 (CH2), 26.4 (CH2), 21.7 (CH), 21.2 (CH), 16.1
(CH2), 14.6 (CH2), 3.9 (CH). IR: ν 3028 (m), 2959 (s), 2877 (m),
2228 (s), 1474 (m), 1442 (m), 1386 (w), 1317 (m), 1302 (m), 1205
(w), 1173 (m), 1113 (m), 1097 (m), 1037 (m), 1010 (s), 963 (m),
928 (s), 837 (m), 786 (s), 732 (s) cm−1. MS (EI, 70 eV): m/z 159
[M]+ (<1), 144 (4), 130 (15), 117 (15), 104 (21), 91 (50), 78 (100),
65 (10), 51 (9). HRMS (ESI): m/z [M + Na]+ calcd for C11H13NNa
182.0946; found 182.0947.
endo,syn-Tricyclo[3.2.1.02,4]octan-8-ol (14). See the procedure
below for thermolysis of 6a in methanol. 14 was isolated (0.022 g,
26%) as a white solid. Spectroscopic data were in agreement with the
literature.16b,31
endo,anti-N,N-Diethyltricyclo[3.2.1.02,4]octan-8-amine (19).
From thermolysis of 6a: A solution of oxadiazoline 6a (0.122 g,
0.586 mmol) in diethylamine (6 mL) was stirred in a pressure tube for
4 h at 165 °C. The reaction mixture was filtered and concentrated in
vacuo. The product was isolated by column chromatography using
ethyl acetate as eluant, giving 19 (0.070 g, 67%) as a yellow liquid.
From thermolysis of 6b: A solution of oxadiazoline 6b (0.120 g,
0.576 mmol) in diethylamine (6 mL) was stirred in a pressure tube for
4 h at 165 °C. The reaction mixture was filtered and concentrated in
vacuo. The product was isolated by column chromatography using
ethyl acetate as eluant, giving 19 (0.061 g, 59%) as a yellow liquid.
1H NMR (400.13 MHz, CDCl3): δ 2.94−2.91 (m, 1H), 2.59−2.50
(q, J = 7.1 Hz, 4H), 2.20−2.14 (m, 2H), 1.68−1.58 (m, 2H), 1.28−
1.19 (m, 2H), 0.97−0.92 (t, J = 7.1 Hz, 6H), 0.92−0.85 (m, 3H),
0.56−0.49 (dt, J = 7.4 Hz (t), 6.0 Hz (d), 1H). 13C NMR (100.62
MHz, CDCl3): δ 83.2 (CH), 43.6 (CH2), 38.4 (CH), 25.1 (CH2), 19.1
(CH), 12.2 (CH2), 10.8 (CH3). IR: ν 3022 (m), 2964 (s), 2816 (m),
1469 (m), 1369 (m), 1209 (m), 1180 (m), 1121 (m), 1070 (m), 1038
1H NMR (400.13 MHz, CDCl3): δ 4.27−4.16 (m, 1H), 2.32−2.24
(m, 1H), 2.07−1.99 (m, 2H), 1.61−1.51 (m, 2H), 1.50−1.40 (m, 2H),
1.31−1.23 (m, 1H), 1.10−0.97 (m, 3H). 13C NMR (100.62 MHz,
CDCl3): δ 93.8 (CH), 41.0 (CH), 24.2 (CH2), 19.8 (CH), 18.7
(CH2).
rac-(1R,2S,4S,5R,6R)-2-Methoxytricyclo[3.3.0.04,6]octane (16).
From thermolysis of 6a: A solution of oxadiazoline 6a (0.141 g,
0.677 mmol) in methanol (7.5 mL) was stirred in a pressure tube for 4
h at 165 °C. The reaction mixture was filtered and concentrated in
vacuo. The crude product was subjected to column chromatography
using hexane/ethyl acetate (9:1) as eluant, giving 16 (0.026 g, 28%) as
a yellow liquid.
From thermolysis of 6b: A solution of oxadiazoline 6b (0.143 g,
0.687 mmol) in methanol (7.5 mL) was stirred in a pressure tube for 4
h at 165 °C. The reaction mixture was filtered and concentrated in
F
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Article
(m), 988 (w), 791 (m), 740 (m) cm−1. MS (EI, 70 eV): m/z 179 [M]+
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(ESI): m/z [M + H]+ calcd for C12H22N 180.1752; found 180.1746.
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ASSOCIATED CONTENT
* Supporting Information
■
S
NMR spectra for all new compounds and CIFs for crystallo-
graphic data of 6a and 6b. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Udo.Brinker@univie.ac.at
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. V. B. Arion, A. Roller (Institute of Inorganic
Chemistry, University of Vienna), and Dr. J. Graf (Incoatec,
Geesthacht, Germany) for single-crystal X-ray analyses; Prof. L.
Brecker (Institute of Organic Chemistry, University of Vienna)
for NMR interpretation; and Prof. D. Krois (Institute of
Organic Chemistry, University of Vienna) and Dr. M. G.
Rosenberg (The State University of New York at Binghamton)
for helpful discussions. We thank the reviewers for their
valuable suggestions.
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