Supramolecular photochirogenesis with carbenes entrapped in cyclodextrins

Article abstract of DOI:10.1002/ejoc.200900899

Two achiral diazirines 1a and 1b have been encapsulated in the inherently chiral cavity of α-cyclodextrin (6-Cy), β-cyclodextrin (7-Cy) and permethylated β-cyclodextrin (TRIMEB) and photolyzed. Because of supramolecular photochirogenesis the generated carbenes afford intramolecular C-H insertion products not as a racemate but one enantiomer is slightly favored. With 1a at the (6-Cy)₂ the ee of product 7a is doubled. To the best of our knowledge for the first time for carbene -reactions, products are imprinted, though modestly, with handedness derived from Cys. The reaction of lb is highly dependent on the molecular reactor used for inclusion. Whereas 7-Cy is very efficient for favoring dimerization through azine formation, the use of TRIMEB permits exclusive formation of intramolecular insertion product 7b.

Full text of DOI:10.1002/ejoc.200900899

FULL PAPER
DOI: 10.1002/ejoc.200900899
Supramolecular Photochirogenesis with Carbenes Entrapped in Cyclodextrins[‡]
Jean-Luc Mieusset,[a] Gerald Wagner,[a] Kuan-Jen Su,[a] Marianne Steurer,[a]
Mirjana Pacar,[a] Michael Abraham,[a] and Udo H. Brinker*[a]
Keywords: Diazirines / Carbenes / Cyclodextrins / Supramolecular chemistry / Chiral induction
Two achiral diazirines 1a and 1b have been encapsulated in
reactions, products are imprinted, though modestly, with
the inherently chiral cavity of α-cyclodextrin (6-Cy), β-cyclo- handedness derived from Cys. The reaction of 1b is highly
dextrin (7-Cy) and permethylated β-cyclodextrin (TRIMEB)
and photolyzed. Because of supramolecular photochirogen-
esis the generated carbenes afford intramolecular C–H inser-
tion products not as a racemate but one enantiomer is slightly
favored. With 1a@(6-Cy)2 the ee of product 7a is doubled.
To the best of our knowledge for the first time for carbene
dependent on the molecular reactor used for inclusion.
Whereas 7-Cy is very efficient for favoring dimerization
through azine formation, the use of TRIMEB permits exclus-
ive formation of intramolecular insertion product 7b.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
considerably change the outcome of an intramolecular C–
H insertion reaction.
Introduction
It is often useful to perform a reaction in a constrained
system.[1] For example, zeolites are employed on a large
scale to force the isomerization of hydrocarbons in stereo-
type patterns, amongst others.[2] Indeed, the use of a host
molecule as a reaction vessel opens up the possibility to
synthesize products that would be difficult to obtain in
solution[3] or to modify the course of a reaction.[4] This
technique can also be applied to the generation of reactive
molecules which might get bottleable if they are incarcer-
ated in a host molecule.[5] It is particularly meaningful to
perform carbene reactions in a molecular reactor because
of the high reactivity of the divalent carbon atom. In fact,
methylene has been described as the most indiscriminating
reagent in chemistry.[6] Even if all other carbenes are partly
stabilized and therefore more selective,[7] they still tend to
generate product mixtures. This is especially true for C–H
insertion reactions by which only stabilized carbenes like
the nucleophilic foiled carbenes[8] or the electrophilic dihalo-
carbenes[9] give synthetically useful results. For more reac-
tive carbenes, encapsulation in a cavitand permits to reduce
the mobility of the intermediate, therefore lessening the
number of accessible bonds or lone-pairs that may act as
reaction partners and consequently, reducing the amount of
side-products. Moreover, the equilibrium conformation of a
guest molecule can also be modified.[10] This may permit to
In this paper we report about the inclusion of endo-spiro-
[bicyclo[3.2.1]octane-8,3Ј-[3H]diazirin]-3-ol (1a) and 3-
endo-methoxyspiro[bicyclo[3.2.1]octane-8,3Ј-[3H]diazirine]
(1b) in β-cyclodextrin (7-Cy), heptakis(2,3,6-tri-O-methyl)-
β-cyclodextrin (TRIMEB), and α-cyclodextrin (6-Cy)
(Scheme 1). We will show what kind of consequence the lo-
cal geometry at the reaction center has over the course of
the reaction and why different products are obtained.
Moreover, the rearrangement of carbene 4 induces a loss of
symmetry in the expected products 6 and 7. Thus, if this
reaction is performed in the chiral cavity of a cyclodextrin,
chirality might be imparted to the carbene products.[1e] Will
one of the enantiomers of 6 and 7 be formed in excess?
[‡] Carbene Rearrangements, 77. Part 76: J.-L. Mieusset, A.
Schrems, M. Abraham, V. B. Arion, U. H. Brinker, Tetrahedron
2009, 65, 765–770.
[a] Lehrstuhl für Physikalisch-Organische Chemie und Struktur-
chemie, Institut für Organische Chemie, Universität Wien,
Währinger Straße 38, 1090 Wien, Austria
Fax: +43-1-4277-52140
E-mail: udo.brinker@unive.ac.at
Scheme 1. Potential reactions of diazirines 1.
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Results
pyrolysis solves this problem giving only intramolecular re-
actions: 1b produces 6b and 7b in a ratio of 36:64 (34:66 for
1a). At this point it is worth noticing that the unsubstituted
bicyclo[3.2.1]octan-8-ylidene exclusively yields the C–H in-
sertion product.[12] The main reason for this difference in
reactivity resides in steric hindrance between the axial endo-
substituent with the C2H4 bridge which favors the re-
arrangement to the somewhat flat bicyclo[3.3.0]skeleton in
order to release this strain.
Photolyses in the Solid State
Photolysis of 1a@TRIMEB in the solid state leads exclu-
sively to the formation of tricyclooctanol 7a[11] and bi-
cyclooctenol 6a (Scheme 1) in a ratio of 79:21 (Table 1) as
determined by 1H NMR spectroscopy of the crude reaction
mixture. Since the CyЈs chiral recognition ability is low in
general, a small enantiomeric excess (ee = 4%) was deter-
mined by chiral HPLC for the formation of 7a. With 1a@7-
Cy, the outcome of the reaction is significantly different: 7a
and 6a are now formed in a ratio of 55:45. Moreover, al-
though the ee remains the same (4%), now the other enantio-
mer of 7a is formed preferentially. The highest selectivity is
observed with α-cyclodextrin, a smaller and less flexible
host: photolysis of 1a@(6-Cy)2 leads to the formation of 7a
and 6a in a ratio of 45:55, while the ee for 7a doubles to
8%.
Discussion
From a mechanistic point of view, it is known that by
thermal decomposition of most diazirines, carbenes are di-
rectly generated.[13] By photolysis, however, the situation is
more complex (Scheme 1). After excitation, diazirine 2 can
either directly form the final products, a process coined
RIES (Rearrangement In the Excited State),[14] generate
carbene 4 or ring-open to diazo compound 3,[15] an inter-
mediate that often can engender similar products than the
carbene. Cyclodextrins are particularly well suited as hosts
for carbene reactions, since it has been shown that the di-
valent carbon atom in alkylidenes does not interact with
ethereal oxygen[16] precluding the intermediacy of an ox-
onium ylide. In preliminary communications,[17] we have de-
scribed the complex of 1a with TRIMEB in solution and in
the solid state. Because of the lack of intramolecular hydro-
gen bonds, TRIMEB is more flexible and is better soluble
in water than 7-Cy. For the 1a@TRIMEB complex, it fol-
lows that the association constant with K = 460 –1 is about
one-twentieth lower than the one of 1a@7-Cy owing to the
higher flexibility of TRIMEB. Nonetheless, for a guest that
is slightly soluble in water, this is still a fairly high value.
The advantages of TRIMEB over 7-Cy are a better solubil-
ity of the complexes (7-Cy complexes tend to be poorly sol-
uble) and a larger size of the crystals obtained which facili-
tates structure analysis and identification of the products
resulting from photolysis. In contrast, if 7-Cy is used as
reaction vessel, the alkyl carbene to a significant amount
may also insert into the O–H bonds of the host,[18] a process
that also explains the low recovery of products after irradia-
tion of 1b@7-Cy. But since TRIMEB does not possess func-
tional groups or bonds which are susceptible to react easily
with a relatively nucleophilic alkyl carbene,[7] 1a only can
Table 1. Product distribution.
5/14
6/7
ee 7
1a@7-Cy
1a@TRIMEB
1a@(6-Cy)2
1a
45:55
21:79
55:45
34:66
4%
4%
8%
1b@7-Cy
1b@TRIMEB
1b
89:11
38:5
7b[11] exclusively
36:64
1b in benzene
15:42
More significant differences in the chemoselectivity were
observed from the photolyses of 1b. In 7-Cy the product
consists of a mixture of azine 5b (89%) and ketone 14b
(11%) (Scheme 2). In contrast, with 1b@TRIMEB, tricy-
clooctane 7b[11] is the sole product obtained from an intra-
molecular insertion of carbene 4b and no bicyclooctene 6b
is formed. As can be seen from these results, the composi-
tion of the products strongly depends on the host molecule
and thus can be explained by a corset effect caused by the
size of the reaction vessel.
rearrange
intramolecularly,
affording
endo-tricy-
clo[3.3.0.02,8]octan-3-ol (7a)[19] and bicyclo[3.3.0]oct-5-en-3-
ol (6a)[20] in a ratio depending on the host molecule used.
In the case of 1a@TRIMEB, the larger size of the cavity
also allows a total separation of one guest molecule from
another. The generated carbene then is surrounded by the
host only. Figure 1 shows the crystal structure obtained for
Scheme 2. Synthesis of carbene precursor 1a.
For comparison purposes, experiments have been per- 1a@TRIMEB. The driving force for the formation of this
formed using a classical approach: photolysis of 1b in a inclusion complex is the filling of the empty space inside
diluted solution (0.042 ) in benzene affords 6b and 7b in the cavity of TRIMEB by the suitably sized guest. In ad-
a ratio of 15:42. Under these conditions bimolecular reac- dition, the orientation of the diazirine is partly controlled
tions leading to formation of azine 5b are difficult to avoid by a hydrogen bond between the hydroxy group of the guest
and 38% of 5b are obtained as side-product. Gas phase and a glucosidic oxygen atom of the host.
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Supramolecular Photochirogenesis with Entrapped Carbenes
Scheme 3. Synthesis of carbene precursor 1b.
Conclusions
The utilization of TRIMEB as a molecular reactor for a
carbene reaction instead of native cyclodextrin offers sig-
nificant advantages: it permits to avoid reaction of the car-
bene with the O–H bonds of the cyclodextrin rims. In the
case of 1b, it also prevents the formation of dimeric azine
because the larger size of the cavity allows to fully enclose
the carbene precursor and to separate it from other precur-
sor molecules. Moreover, to the best of our knowledge for
the first time for carbene reactions within α- and β-cyclo-
dextrins, a modest enantioselectivity for the product forma-
tion has been observed. The imprinted chirality was highest
when the reaction was performed in the smaller cavity of α-
cyclodextrin.
Figure 1. Crystal structure of 1a@TRIMEB showing the packing
of the complex.[17b] The hydrogen atoms are omitted for clarity.
In contrast, however, in 1b@7-Cy, in the solid state, the
diazirine groups are probably positioned in a head-to-head
arrangement. This is the most plausible explanation for the
fact that high yields of azine 5 are obtained. The in situ
generated carbene is directly and efficiently trapped by a
second diazirine in a barrier-free process forming a diazirin-
ium ylide that concomitantly rearranges to the correspond-
ing azine.[21]
Experimental Section
General Methods: Melting points are uncorrected. 1H and 13C
NMR spectra were recorded on a 400 MHz spectrometer. CDCl3
or [D6]DMSO were used as solvents. The chemical shifts at δ =
7.26 ppm and 77.0 ppm of CHCl3 were used as internal standards
for 1H and 13C spectra, respectively (2.50 and 39.43 for DMSO).
Conventional 2D COSY, NOESY, HMBC, and HMQC spectra
were used to derive proton and carbon assignments. When neces-
sary, 1D TOCSY spectra were also recorded.
Synthesis of the Diazirines
Both carbene precursors used in this study were synthe-
sized from ketal 13a as depicted in Scheme 2 following pro-
cedures developed previously.[22–24] Alternatively, com-
pound 14a is also accessible from a reaction between 1-
cyclopentenylpyrrolidine and 3-chloro-2-(chloromethyl)-1-
phenylpropan-1-one.[25,26]
Diazirine 1a was obtained in good yield (61%, 2 steps)
by treatment of ketone 14a with ammonia and hydroxyl-
amine sulfonic acid (HOSA) in methanol followed by oxi-
dation with iodine and triethylamine in methanol.
General Procedure for the Preparation of the Complex: The cyclo-
dextrin was dissolved in a minimal amount of water. Neat diazirine
1 (1 equiv.) was added to the solution, ultrasonicated for 1 min,
and stirred for 1 h. The suspension was suction-filtered through a
sintered glass funnel (porosity 4 frit). The residue was washed with
water and dried.
Diazirine 1b was prepared by an analog procedure after
methylation of ketal 13a with dimethyl sulfate (Scheme 3).
We have optimized the removal of the ketal group which
proceeds more cleanly in aqueous acetone with 0.1  HCl.
If the reaction is performed in an acidic methanol/water
mixture as described in the literature, the crude product
tends to be contaminated by significant amounts of di-
methyl ketal 16a. Dimethyl ketals 16a and 16b, respectively,
are also formed in traces as side-products in the diazirine
synthesis. The identity of byproducts 16 was determined by
independent syntheses, i.e., treatment of ketones 14 with tri-
methyl orthoformate.
General Procedure for the Photolysis in the Solid State: The com-
plexes were photolyzed with a Heraeus TQ718-Z4, 700 W lamp
(doped with FeI2) in Pyrex glassware after the flask has been alter-
nately evacuated and filled with argon for three times. The crude
products were analyzed by NMR spectroscopy and GC-MS after
separation from the host molecule.
1a@7-Cy (643 mg, 0.5 mmol) was photolyzed overnight at 12 °C.
The powder was then submitted to continuous extraction with
dichloromethane yielding 65 mg (ca. 94% recovery) of products de-
rived from the guest. NMR analysis revealed the presence of tricy-
clooctanol 7a and bicyclooctenol 6a in a ratio of 55:45. Chiral
HPLC [Chiracel OD-H column (Column Nr.: ODH0CE-GJ020),
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U. H. Brinker et al.
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hexanes/2-propanol 98:2, 0.7 mL/min, T = 20 °C, RID] allowed the
quantification of the enantiomeric excess for 7a: enantiomer 1, tR
= 14.1 min, 48%; enantiomer 2, tR = 15.1 min, 52%.
reduced with Na2S2O5 and methanol was partially rotary evapo-
rated. The methanol solution was then diluted with water and brine
and extracted three times with pentane, yielding 1.409 g of product.
Another crop of 0.505 g was obtained through extraction of the
water phase with CH2Cl2 and column chromatography with hex-
anes/ethyl acetate (70:30). Total yield 1.914 g (61%) m.p. 144–
145 °C. 1H NMR (400 MHz, CDCl3): δ = 1.00 (d, J = 3.1 Hz, 2
H, H1 + H5), 1.38 (s, 1 H, OH), 1.88 (d-hept, J = 14.9, 1.2 Hz, 2
1a@TRIMEB (1582 mg, 1 mmol) was photolyzed overnight at
12 °C. NMR of the crude product showed the absence of diazirine
1a and the presence of tricyclooctanol 7a and bicyclooctenol 6a in
a ratio of 79:21. Column chromatography with CH2Cl2 followed
by hexanes/Et2O (50:50) lead to the isolation of 52 mg (0.42 mmol,
42%) of 7a. Chiral HPLC [Chiracel OD-H column (Column Nr.:
ODH0CE-GJ020), hexanes/2-propanol 98:2, 0.7 mL/min, RID] al-
lowed the quantification of the enantiomeric excess: enantiomer 1,
tR = 14.1 min, 52%; enantiomer 2, tR = 15.1 min, 48%.
H, H2
+ H4endo), 2.06–2.16 (m, 4 H, H6 + H7), 2.24 (ddd, J =
endo
14.9, 4.8, 3.2 Hz, 2 H, H2
+ H4exo), 4.28 (t, J = 4.8 Hz, 1 H,
exo
H3) ppm. 13C NMR (100 MHz, CDCl3): δ = 26.3, 36.3, 38.3, 41.8,
66.6 ppm. IR (CDCl ): ν = 3612, 2942, 2921, 2888, 2848, 1574,
˜
3
1288, 1253, 1228, 1190, 1076, 1050, 1029 cm–1. MS (EI): m/z (%)
= 152 (M+) [0.01], 151 (0.01), 124 (0.1), 123 (0.7), 109 (4), 105 (4),
95 (11), 91 (22), 80 (40), 79 (100). MS (CI): m/z = 153, 135, 123,
107 (100), 79. HRMS: calcd. for C8H12O (M+ – N2): 124.0888,
found 124.0892.
1a@(6-Cy)2 (1.11 g, 0.53 mmol) was photolyzed at 12 °C for 16 h.
NMR of the crude product showed the presence of tricyclooctanol
7a and bicyclooctenol 6a in a ratio of 45:55. Extraction with
CH2Cl2 followed by chromatography (hexanes/Et2O, 50:50) lead to
the isolation of 7.5 mg (0.06 mmol, 11%) of 7a. Chiral HPLC [Chi-
racel OD-H column (Column Nr.: ODH0CE-GJ020), hexanes/2-
propanol 98:2, flow: 0.7 mL/min, RID] allowed the quantification
of the enantiomeric excess: enantiomer 1, tR = 14.2 min, 54%; en-
antiomer 2, tR = 15.3 min, 46%.
3-endo-Methoxyspiro[bicyclo[3.2.1]octane-8,3Ј-[3H]diazirine] (1b):
3-endo-Methoxybicyclo[3.2.1]octan-8-one (14b) (2.821 g, 18 mmol)
was stirred in a 8  solution of NH3 in MeOH at –30 °C for 3 h.
The temperature then was lowered to –60 °C and 1 equiv. of HOSA
was added in portions during 1 h. The reaction mixture was stirred
overnight, making sure that the temperature only slowly increased.
Methanol and ammonia were then rotary evaporated. The residue
was dissolved again in 70 mL of MeOH. After addition of NEt3
(3.8 mL, 27 mmol) I2 was added in portions until no decolorization
took place. Excess of I2 was reduced with Na2S2O5 and methanol
was partially rotary evaporated. The methanol solution was then
diluted with water and brine and extracted three times with pen-
tane. Extraction of the water phase with CH2Cl2 gave no further
product. The product was purified further by column chromatog-
raphy with hexanes/toluene (5:1); yield 2.29 g (77%). 1H NMR
(400 MHz, CDCl3): δ = 0.96 (br. s, 2 H), 1.99–2.02 (m, 4 H), 2.03–
2.06 (m, 4 H), 3.30 (s, 3 H), 3.60 (tt, J = 3.7, 2.2 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 26.1, 34.2, 36.3, 42.3, 56.5,
1b@7-Cy (382 mg, 0.294 mmol) was photolyzed overnight at 12 °C.
The powder was then extracted with dichloromethane, yielding
13 mg of product (44% recovery) consisting of a mixture of 89%
azine 5b and 11% of ketone 14b.
1b@TRIMEB (929 mg, 0.582 mmol) was photolyzed overnight at
12 °C. NMR of the crude product shows the absence of diazirine
1b and bicyclooctene 6b. Column chromatography with pentane/
Et2O (90:10) lead to the isolation of 29 mg (0.21 mmol, 36%) of
7b.
Photolysis of Diazirine 1b in Benzene: Diazirine 1b (105 mg,
0.63 mmol) was dissolved in 15 mL of benzene. The solution was
degassed and irradiated for 3 h at 12 °C. The solvent was rotary-
evaporated, yielding 83 mg of a mixture containing 38% of azine
5b, 42% of 3-endo-methoxytricyclo[3.3.0.02,8]octane (7b), 15% of
rac-(1R,3S)-3-methoxybicyclo[3.3.0]oct-5-ene (6b), and 5% of
ketone 14b.
75.9 ppm. IR (CDCl ): ν = 2941, 2873, 2845, 2822, 1574, 1263,
˜
3
1192, 1123, 1078, 1068, 1046, 1034 cm–1. MS (EI): m/z (%) = 138
(2) [M+ – N2], 123 (4), 106 (21), 91 (60), 79 (100), 123 (4), 106 (21),
91 (60), 79 (100). C9H14N2O (166.22): calcd. C 65.03, H 8.49, N
16.85; found C 65.27, H 8.56, N 16.83. HRMS: Calcd. for C9H14O
(M+ – N2): 138.1045, found 138.1048.
Pyrolysis of endo-Spiro[bicyclo[3.2.1]octane-8,3Ј-[3H]diazirine]-3-ol
(1a): A three-necked round-bottomed flask was equipped with a
small distillation bridge with a cooling trap (–78 °C). The flask was
heated to 330 °C and 100 mg of diazirine 1a were slowly dropped
under vacuo, affording 54 mg (66%) of a mixture of 66% of endo-
tricyclo[3.3.0.02,8]octan-3-ol (7a) and 34% of rac-(1R,3S)-bicy-
clo[3.3.0]oct-5-en-3-ol (6a).
1,2-Bis(3-endo-hydroxybicyclo[3.2.1]octan-8-ylidene)hydrazine (5a):
3-endo-Hydroxybicyclo[3.2.1]octan-8-one (14a) (400 mg, 2.86
mmol) and 69 mg of N2H4·H2O were refluxed overnight in 15 mL
of methanol. The mixture was poured into water, extracted with
CH2Cl2, dried with MgSO4 and rotary evaporated, yielding 257 mg
(65%) of azine 5a that could be recrystallized from chloroform;
Pyrolysis of 3-endo-Methoxyspiro[bicyclo[3.2.1]octane-8,3Ј-[3H]di-
azirine] (1b): A three-necked round-bottomed flask was equipped
with a small distillation bridge with a cooling trap (–78 °C). The
flask was heated to 260 °C and 41 mg of diazirine 1b were slowly
dropped under an argon stream, yielding 20 mg (48%) of a mixture
of 64% of 7b and 36% of 6b.
1
m.p. 218–222 °C. H NMR (400 MHz, CDCl3): δ = 1.35 (s, 2 H),
1.75–2.30 (m, 16 H), 2.59 (br. s, 2 H), 3.15–3.35 (m, 2 H), 4.11 (br.
1
s, 2 H) ppm. H NMR (400 MHz, [D6]DMSO): δ = 1.54–1.72 (m,
4 H), 1.76–2.22 (m, 12 H), 2.38–2.44 (m, 2 H), 3.00–3.16 (m, 2 H),
3.87 (br. s, 2 H), 4.50 (d, J = 2.5 Hz, 2 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 24.4, 24.6, 25.0, 25.1, 33.3, 33.4, 39.3,
41.9, 42.2, 44.1, 44.3, 63.67, 63.70, 177.4, 178.4 ppm. MS: m/z (%)
= 76 (32) [M+], 258 (3), 232 (26), 214 (4), 188 (8), 138 (93), 121
(14), 120 (13), 92 (60), 91 (100), 79 (20), 55 (21). HRMS: Calcd.
for C16H24N2O2: 276.1838, Found: 276.1835.
endo-Spiro[bicyclo[3.2.1]octane-8,3Ј-[3H]diazirine]-3-ol (1a):[16] 3-
endo-Hydroxybicyclo[3.2.1]octane-8-one (14a) (2.91 g, 20.8 mmol)
was stirred in a 8  solution of NH3 in MeOH at –30 °C for 2 h.
The temperature then was lowered to –60 °C and 1 equiv. of hy-
droxylamine-O-sulfonic acid (HOSA) was added in portions during
1 h. The reaction mixture was stirred overnight, making sure that
the temperature only slowly increased. Methanol and ammonia
were then rotary evaporated. The residue was dissolved again in
1,2-Bis(3-endo-methoxybicyclo[3.2.1]octan-8-ylidene)hydrazine (5b):
3-endo-Methoxybicyclo[3.2.1]octan-8-one (14b) (500 mg, 3.24
mmol) and 89 mg of N2H4·H2O were refluxed overnight in 10 mL
70 mL of MeOH. NEt3 (5 mL) was first added and I2 was added of methanol. The mixture was rotary evaporated, yielding 493 mg
1
in portions until no decolorization took place. The excess of I2 was
(100%) of azine 5b; m.p. 88–90 °C. H NMR (400 MHz, CDCl3):
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Supramolecular Photochirogenesis with Entrapped Carbenes
δ = 1.66–2.10 (m, 12 H), 2.12–2.21 (m, 2 H), 2.26–2.33 (m, 2 H), 13.6 Hz, 2 H), 1.81–1.87 (m, 4 H), 1.91–1.96 (m, 2 H), 2.22 (dd, J
2.52–2.57 (m, 2 H), 3.10–3.28 (m, 2 H), 3.28 (s, 6 H), 3.40–3.46 (m,
2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.8, 24.9, 25.3, 25.4,
33.7, 33.8, 38.6, 38.9, 40.0, 40.5, 40.6, 56.5, 75.40, 75.43, 178.2,
= 15, 5 Hz, 2 H), 3.92–3.97 (m, 4 H), 4.03 (tdt, J = 5, 2.8, 1.2 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.1, 38.27, 38.34,
63.7, 64.7, 65.3, 116.5 ppm. IR (CDCl ): ν = 3604, 2945, 2880,
˜
3
179.1 ppm. IR (CDCl ): ν = 2939, 2873, 2821, 1677, 1442, 1436, 2849, 1367, 1346, 1013, 947, 893 cm–1. MS: m/z (%) = 184 (25)
˜
3
1425, 1278, 1199, 1116, 1077, 1068, 1040 cm–1. MS: m/z (%) = 304 [M+], 167 (7), 113 (100), 99 (78), 96 (57), 89 (52), 55 (38). HRMS:
(43) [M+], 289 (6), 273 (4), 272 (3), 246 (54), 231 (6), 214 (6), 188 Calcd. for C10H16O3: 184.1099, found 184.1103.
(19), 152 (100), 120 (31), 93 (37), 79 (19), 58 (20). C18H28N2O2
3-endo-Methoxybicyclo[3.2.1]octan-8-one Ethylene Ketal (13b): 3-
endo-Hydroxybicyclo[3.2.1]octan-8-one ethylene ketal (13a) (17 g,
92.4 mmol) was dissolved in dry diethyl ether and added dropwise
(304.43): calcd. C 71.02, H 9.27, N 9.20; found C 71.14, H 9.41, N
9.22. HRMS: Calcd. for C18H28N2O2: 304.2151, Found: 304.2146.
rac-(1R,3S)-Bicyclo[3.3.0]oct-5-en-3-ol
(6a):[19]
1H
NMR
to a suspension of 37 g (924 mmol) of 60% NaH (freshly washed
with hexanes) in dry ether. Then, dimethyl sulfate (26.4 mL, 35.0 g,
277 mmol) was added dropwise. After completion, the mixture was
stirred for 1 h at room temperature and then refluxed overnight.
The excess of NaH was destroyed by adding 50 mL of MeOH drop-
wise to the mixture which then was poured into a saturated
NaHCO3 solution, extracted with CH2Cl2, dried with MgSO4, ro-
tary evaporated, and distilled (b.p. 75–76 °C, 1 Torr), yielding
(400 MHz, CDCl3): δ = 1.13 (ddd, J = 12.4, 9.7, 7.0 Hz, 1 H), 1.22–
1.28 (m, 1 H), 1.39–1.51 (m, 1 H), 2.08–2.18 (m, 2 H), 2.31 (qui, J
= 6.6 Hz, 1 H), 2.42–2.62 (m, 3 H), 2.76–2.87 (m, 1 H), 4.52 (qui,
J = 6.4 Hz, 1 H), 5.38 (br. s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 33.0, 35.2, 36.6, 42.2, 49.2, 76.5, 119.9, 150.3 ppm. IR
(CDCl ): ν = 3611, 3053, 2955, 2935, 2891, 2850, 1429, 1322, 1249,
˜
3
1236, 1203, 1148, 1121, 1048 cm–1. MS: m/z (%) = 124 (20) [M+],
109 (3), 106 (8), 95 (12), 91 (14), 80 (100), 67 (11). HRMS: Calcd.
for C8H12O: 124.0888, found 124.0890.
1
15.34 g (77.5 mmol, 84%) of methyl ether 13b as an oil. H NMR
(400 MHz, CDCl3): δ = 1.72–1.85 (m, 6 H), 1.92 (br. d, J = 14.8 Hz,
2 H), 2.03 (br. d, J = 14.8 Hz, 2 H), 3.25 (s, 3 H), 3.35 (br. t, J =
5.2 Hz, 1 H), 3.91–3.94 (m, 4 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 24.9, 33.9, 38.3, 56.1, 63.7, 64.7, 74.7, 116.9 ppm. IR
rac-(1R,3S)-3-Methoxybicyclo[3.3.0]oct-5-ene (6b): 1H NMR
(400 MHz, CDCl3): δ = 1.10 (ddd, J = 11.6, 10.9, 7.8 Hz, 1 H),
1.39–1.49 (m, 1 H), 2.12–2.22 (m, 2 H), 2.27–2.33 (m, 1 H), 2.42–
2.56 (m, 3 H), 2.73–2.82 (m, 1 H), 3.31 (s, 3 H), 4.08 (br. qui, J =
6.8 Hz, 1 H), 5.30–5.33 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 31.4, 32.4, 36.8, 39.0, 49.1, 56.8, 85.3, 119.1,
149.9 ppm.
endo-Tricyclo[3.3.0.02,8]octan-3-ol (7a):[18] 1H NMR (400 MHz,
CDCl3): δ = 1.21 (dd, J = 14.2, 0.9 Hz, 1 H), 1.47–1.62 (m, 3 H),
1.90–2.04 (m, 2 H), 2.08 (q, J = 6.1 Hz, 1 H), 2.17–2.25 (m, 1 H),
2.29–2.36 (dtd, J = 14.2, 9.2, 1.0 Hz, 1 H), 2.62 (q, J = 6.5 Hz, 1
H), 4.84 (qui, J = 4.2 Hz, 1 H, H3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 24.5, 28.0, 34.1, 34.8, 40.9, 43.0, 47.0, 76.7 ppm. IR
(CDCl ): ν = 2941, 2882, 2822, 1440, 1425, 1342, 1226, 1211, 1189,
˜
3
1166, 1153, 1120, 1075, 1059, 1022, 1007 cm–1. MS: m/z (%) = 198
(79) [M+], 183 (20), 167 (32), 139 (21), 113 (66), 103 (100), 99 (100),
55 (69). C11H18O3 (198.26): calcd. C 66.64, H 9.15; found C 66.58,
H 9.21. HRMS: Calcd. for C11H18O3: 198.1256, found 198.1250.
3-endo-Hydroxybicyclo[3.2.1]octan-8-one (14a):[23] Ketal 13a
(34.33 g, 186.6 mmol) was dissolved in 160 mL of acetone and
160 mL of H2O. Then 20 mL of 1  HCl were added. After re-
fluxing for 3 h, the reaction mixture was neutralized with NaHCO3.
The weakly basic solution was extracted twice with CH2Cl2, the
organic layer was dried with magnesium sulfate, suction-filtered
through a sintered funnel and rotary evaporated. The crude prod-
uct was then recrystallized from Et2O/hexanes. The remaining
mother liquor was chromatographed with hexanes/ethyl acetate
(65:35); yield 18.23 g (130 mmol, 70%). 1H NMR (400 MHz,
CDCl3): δ = 1.60 (br. s, 1 H), 1.92–1.97 (m, 2 H), 2.20–2.28 (m, 4
H), 2.32–2.39 (m, 4 H), 4.12 (t, J = 4.9 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 22.7, 43.7, 45.1, 65.4, 222.5 ppm. IR
(CDCl ): ν = 3617, 3453, 3029, 2938, 2879, 2863, 1438, 1406, 1339,
˜
3
1316, 1207, 1064, 1025 cm–1. MS: m/z (%) = 124 (3) [M+], 109 (3),
106 (86), 95 (14), 91 (70), 79 (56), 67 (100). HRMS: Calcd. for
C8H12O: 124.0888, found 124.0891.
3-endo-Methoxytricyclo[3.3.0.02,8]octane (7b): 1H NMR (400 MHz,
CDCl3): δ = 1.31 (d, J = 13.9 Hz, 1 H, H4endo), 1.48–1.57 (m, 3 H,
H2 + H6
+ H8), 1.80–1.89 (m, 1 H, H7exo), 1.91–2.02 (m, 1 H,
endo
H6exo), 2.09 (q, J = 6.1 Hz, 1 H, H1), 2.20–2.25 (m, 1 H, H7endo),
2.29–2.36 (m, 1 H, H4exo), 2.62 (q, J = 6.7 Hz, 1 H, H5), 3.32 (s, 3
H, HMe), 4.34 (dd, J = 9.3, 4.3 Hz, 1 H, H3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 24.2 (C7), 28.5 (C2), 30.3 (C8), 34.2 (C1),
40.6 (C6), 42.4 (C5), 44.7 (C4), 56.5 (CMe), 85.3 (C3) ppm. MS: m/z
(%) = 138 (5) [M+], 106 (95), 91 (91), 85 (93), 84 (100), 78 (84), 72
(76), 67 (82). HRMS: Calcd. for C9H14O: 138.1045, found
138.1043.
(CDCl ): ν = 3612, 2944, 2922, 2883, 1741, 1196, 1077, 1050, 1026
˜
3
cm–1. MS: m/z (%) = 140 (16) [M+], 122 (5), 111 (11), 95 (40), 79
(63), 71 (75), 68 (77), 57 (71), 55 (100). HRMS: Calcd. for C8H12O2:
140.0837, found 140.0835.
3-endo-Methoxybicyclo[3.2.1]octan-8-one (14b): Ketal 13b (14.9 g,
75.2 mmol) was dissolved in 72 mL of acetone, and 72 mL of H2O
and 8.5 mL of 1  HCl were added. After 2 h of refluxing, the
acetone was partially evaporated and the reaction mixture was neu-
tralized with NaHCO3. The weakly basic solution was extracted
endo-Spiro[bicyclo[3.2.1]octane-8,2Ј-[1,3]dioxolane]-3-ol (13a):[23,24]
Hg(OAc)2 (25.0 g, 78.5 mmol) was dissolved in 80 mL of H2O. To
this solution, 80 mL of THF were added and afterwards bi- twice with CH2Cl2, the organic layer was dried with magnesium
cyclo[3.2.1]oct-2-en-8-one ethylene ketal (12) (13.03 g, 78.5 mmol).
The yellow color disappeared after complete addition. After stir-
ring for 1 h in a water bath at room temperature, 80 mL of 3 
NaOH was added followed by 80 mL of a solution of sodium
borohydride (1.484 g, 39.25 mmol) in 3  NaOH. The mixture was
allowed to react for 1 h and the settled mercury was decanted. The
water phase was saturated with NaCl, extracted with CH2Cl2, dried
with MgSO4 and rotary evaporated affording a crude product that
was contaminated with unreacted alkene. Crystallization from Et2O
furnished 11.01 g (59.8 mmol, 76%) of alcohol 13a. 1H NMR
(400 MHz, CDCl3): δ = 1.26 (d, J = 2.8 Hz, 1 H), 1.75 (d, J =
sulfate, suction-filtered through a sintered glass funnel and rotary
evaporated. The crude product was then distilled (b.p. 45–46 °C,
1
0.8 Torr), yielding 8.374 g (54.4 mmol, 72%) ketone as an oil. H
NMR (400 MHz, CDCl3): δ = 1.86 (m, 2 H), 2.12–2.21 (m, 6 H),
2.38 (br. d, J = 12.9 Hz, 2 H), 3.31 (s, 3 H), 3.42 (tt, J = 5.0, 1.3 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.4, 41.0, 43.7, 56.5,
74.6, 222.7 ppm. IR (CDCl ): ν = 2940, 2876, 2822, 1731, 1712,
˜
3
1438, 1427, 1278, 1247, 1201, 1154, 1115, 1071, 1042, 1030 cm–1.
MS: m/z (%) = 154 (100) [M+], 139 (4), 126 (18), 122 (40), 111
(13), 94 (45), 79 (46), 71 (41), 55 (62). HRMS: Calcd. for C9H14O2:
154.0994, found 154.0992.
Eur. J. Org. Chem. 2009, 5907–5912
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5911

U. H. Brinker et al.
FULL PAPER
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3-endo-Hydroxybicyclo[3.2.1]octan-8-one Dimethyl Ketal (16a):
Ketone 14a (500 mg, 3.57 mmol) was stirred at 60 °C in 20 mL of
dry MeOH with trimethyl formate (0.468 mL, 4.2 mmol, 454 mg)
and 14 mg of pTsOH for 1 h. Then 10 mL of the solution were
distilled from a Vigreux column. Na2CO3 and brine were added
and the reaction mixture was extracted with CH2Cl2, dried with
MgSO4, rotary evaporated, and recrystallized from hexanes; yield
1
574 mg (3.09 mmol, 86%); m.p. 61–61.5 °C. H NMR (400 MHz,
CDCl3): δ = 1.25 (s, 1 H), 1.65–1.80 (m, 4 H), 1.86–1.92 (m, 2 H),
2.05–2.15 (m, 4 H), 3.19 (s, 3 H), 3.22 (s, 3 H), 4.03 (s, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 25.5, 36.2, 37.3, 47.5, 49.7, 65.7,
[6]
[7]
J.-L. Mieusset, U. H. Brinker, J. Org. Chem. 2008, 73, 1553–
1558.
109.0 ppm. IR (CDCl ): ν = 3613, 2944, 2889, 2833, 1443, 1427,
˜
3
[8]
[9]
J.-L. Mieusset, A. Schrems, M. Abraham, V. B. Arion, U. H.
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1008 cm–1. MS: m/z (%) = 186 (100) [M+], 169 (3), 155 (9), 143 (3),
137 (3), 127 (7), 115 (38), 101 (100), 91 (72), 55 (93). C10H18O3
(186.25): calcd. C 64.49, H 9.74; found C 64.57, H 9.96. HRMS:
Calcd. for C10H18O3: 186.1256, found 186.1251.
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Ketone 14b (500 mg, 3.24 mmol) was stirred at 60 °C in 20 mL of
dry MeOH with trimethyl formate (0.426 mL, 3.89 mmol, 413 mg)
and 12 mg of pTsOH for 1 h. Then 10 mL of the solution was dis-
tilled from a Vigreux column. Na2CO3 and brine were added and
the reaction mixture was extracted with CH2Cl2, dried with MgSO4
and rotary evaporated. The turnover was quantitative according to
GC; yield 418 mg (2.09 mmol, 65%). 1H NMR (400 MHz, CDCl3):
δ = 1.6–1.9 (m, 8 H), 2.05 (qui, J = 3.5 Hz, 2 H), 3.14 (s, 3 H),
3.19 (s, 3 H), 3.22 (s, 3 H), 3.33 (tt, J = 4.8, 1.3 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 25.3, 32.8, 36.2, 47.4, 49.6, 56.1,
[12]
[13]
[14]
75.0, 109.4 ppm. IR (CDCl ): ν = 3000, 2938, 2872, 2831, 1434,
˜
3
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MS: m/z (%) = 200 (93) [M+], 185 (18), 169 (80), 153 (8), 137 (18),
115 (27), 105 (59), 101 (100), 93 (30), 55 (29). HRMS: Calcd. for
C11H20O3: 200.1412, found 200.1417.
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Acknowledgments
The authors thank the Fonds zur Förderung der wissenschaftlichen
Forschung in Österreich (project P12533-CHE) for financial sup-
port and Cerestar USA, Inc. and Wacker Chemie, Germany, for
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Published Online: October 8, 2009
5912
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5907–5912