Annulated and bridged tetrahydrofurans from alkenoxyl radical cyclization

Article abstract of DOI:10.1039/c4ob01266f

4-Pentenoxyl radicals sharing two or more carbon atoms with a cycloalkane cyclize in a predictable manner stereoselectively and regioselectively to afford in solutions of bromotrichloromethane cycloalkyl-fused or -bridged 2-bromomethyltetrahydrofurans in up to 95% yield. Stereoselectivity in alkenoxyl radical ring closures arises from cumulative steric effects. The substituent positioned the closest to the alkene carbon, which is being attacked by the oxygen radical, exerts the strongest stereodirecting effect. This principal inductor guides 5-exo-cyclization 2,3-trans- or 2,4-cis-selectively. The substituent located further from the attacked π-bond is the secondary inductor. A secondary inductor in the relative trans-configuration enhances stereodifferentiation by the primary inductor; a cis-configured secondary inductor decreases this effect. A secondary inductor is not able to overrule the guiding effect of a similar sized primary inductor. Intramolecular 4-pentenoxyl radical additions to a cyclohexene-bound exo-methylene group or to endocyclic double bonds proceed cis-specifically, as exemplified by synthesis of a diastereomerically pure bromobicyclo[2.2.1]heptyl-annulated tetrahydrofuran from the verbenylethyloxyl radical. According to theory, the experimental 2,3-cis-specificity in alkoxyl radical cyclization to an endocyclic π-bond arises from strain associated with the 2,3-trans-ring closure. This journal is

Full text of DOI:10.1039/c4ob01266f

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Annulated and bridged tetrahydrofurans from
alkenoxyl radical cyclization†‡
Cite this: Org. Biomol. Chem., 2014,
12, 8288
Christine Schur,a Harald Kelm,a Thomas Gottwald,b Arne Ludwig,b Rainer Kneuerb
and Jens Hartung*a
4-Pentenoxyl radicals sharing two or more carbon atoms with a cycloalkane cyclize in a predictable
manner stereoselectively and regioselectively to afford in solutions of bromotrichloromethane cycloalkyl-
fused or -bridged 2-bromomethyltetrahydrofurans in up to 95% yield. Stereoselectivity in alkenoxyl
radical ring closures arises from cumulative steric effects. The substituent positioned the closest to the
alkene carbon, which is being attacked by the oxygen radical, exerts the strongest stereodirecting effect.
This principal inductor guides 5-exo-cyclization 2,3-trans- or 2,4-cis-selectively. The substituent located
further from the attacked π-bond is the secondary inductor. A secondary inductor in the relative trans-
configuration enhances stereodifferentiation by the primary inductor; a cis-configured secondary induc-
tor decreases this effect. A secondary inductor is not able to overrule the guiding effect of a similar sized
primary inductor. Intramolecular 4-pentenoxyl radical additions to a cyclohexene-bound exo-methylene
group or to endocyclic double bonds proceed cis-specifically, as exemplified by synthesis of a diastereo-
merically pure bromobicyclo[2.2.1]heptyl-annulated tetrahydrofuran from the verbenylethyloxyl radical.
According to theory, the experimental 2,3-cis-specificity in alkoxyl radical cyclization to an endocyclic
π-bond arises from strain associated with the 2,3-trans-ring closure.
Received 17th June 2014,
Accepted 12th August 2014
DOI: 10.1039/c4ob01266f
www.rsc.org/obc
ratio at room temperature to <2/98 by shifting a tert-butyl
group from position 1 to position 3.8 In synthesis, 5-exo-
1. Introduction
4-Pentenoxyl radicals add intramolecularly to the inner alkene cyclized 4-pentenoxyl radicals are preferentially trapped by a
carbon with rate constants of 108 per second and above.1–6 heteroatom atom donor,10,11 for introducing halogen,12–14
Alkyl or ortho-substituted aryl groups in position 1 exert a alkylsulfanyl,15 or other synthetically useful functional
stereodirecting effect, leading to 2,5-trans-configured tetra- groups.16
hydrofurans as principal products. Carbon substituents at
The model to explain stereodifferentiation by a carbon
positions 2 and 3 direct 4-pentenoxyl radical cyclization 2,4-cis- substituent in 4-pentenoxyl radical cyclization predicts that
and 2,3-trans-selectively.7–9 Stereodifferentiation by alkyl or the intramolecular addition proceeds via a distorted twist-
aryl groups arises from steric effects, which gradually increases conformer of tetrahydrofuran as the favored transition struc-
as the distance between a controlling substituent and the ture (twist-model),8,17 differing from the cyclohexane-based
attacked π-bond shortens, for example from a 15/85-cis/trans- Beckwith–Houk-model for carbon radical cyclization.18,19
Application of the alkoxyl radical approach to synthesis of
more demanding targets, for example biologically active
aFachbereich Chemie, Organische Chemie, Technische Universität Kaiserslautern,
terpene-, acetogenin-, and fatty acid-derived cycloalkyl-fused
Erwin-Schrödinger-Straße, D-67663 Kaiserslautern, Germany.
tetrahydrofurans,20–22 requires to extend the model in order to
E-mail: hartung@chemie.uni-kl.de; Fax: +49-631-205-3921; Tel: +49-631-205-2431
bInstitut für Organische Chemie, Universität Würzburg, Am Hubland, 97074
predict the selectivity for constructing bicyclic compounds.7,23
Lessons from carbon radical chemistry have taught that stereo-
differentiation in synthesis of bicyclic compounds is difficult
to extrapolate by transferring results from monocycle to bicycle
formation, since transannular and other strain effects may
superimpose in an unpredictable manner.24,25 To find out
whether embedding two carbons of a 4-pentenoxyl radical into
a cycloaliphatic framework conserves or changes guidelines for
stereoselective tetrahydrofuran synthesis, we examined in this
study bromocyclization of cis/trans-cycloalkyl-bridged alkenoxyl
Würzburg, Germany
†Dedicated to the memory of Athelstan (Athel) L. J. Beckwith in recognition of
his pioneering and creative contributions to the chemistry of free radicals in
general and to free radical cyclizations in particular. We will miss his humor and
his intellectual approach to chemical science.
‡Electronic supplementary information (ESI) available: Standard instrumenta-
tion, the protocol for ESI containing instrumentation, synthesis of 4-pentenols,
O-pentenyl tosylates, carbon-13 spectra of selected compounds, calculated
atomic coordinates and energies of transition structures and radicals. CCDC
1008593. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c4ob01266f
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Scheme 1 Chain mechanism for synthesis of annulated bromomethyl-
Fig. 1 Classification of cycloalkyl-bridged 4-pentenoxyl radicals (type
A–C) and alkenoxyl radicals having an endocyclic carbon–carbon
double bond (type D–E; dotted red lines symbolize alkyl bridging).
tetrahydrofuran 3 from 3-alkenoxy-4-methylthiazole-2(3H)-thione 1
and BrCCl3 (the red dotted line symbolizes an alkyl-bridge; cf. Fig. 1 and
Scheme 2).
radicals, having the carbon–carbon double bond located in a
conformationally flexible side chain (types A and B), in the
exo-position of cyclohexane (type C), or incorporated into an
alicyclic core (types D and E, Fig. 1).
liberating oxygen radicals in an addition/fragmentation
sequence involving a mediator radical. The intermediate
formed by adding, for example, the trichloromethyl radical to
the thione sulfur of MTTOR 1 dissociates into 2-(trichloro-
The most important finding from the study shows that
cycloalkyl-bridged 4-pentenoxyl radicals cyclize in a predict-
able manner stereoselectively and regioselectively, to afford in
solutions of bromotrichloromethane cycloalkyl-annulated or
-bridged bromomethyltetrahydrofurans in up to 95% yield.
The principal stereoinductor is the substituent attached the
closest to the carbon–carbon double bond, which is being
attacked by the radical oxygen. A principal inductor guides
5-exo-cyclization 2,3-trans- or 2,4-cis-selectively. The substituent
bound further from the attacked π-bond is the secondary
methylsulfanyl)-4-methylthiazole
2 and oxygen radical I
(Scheme 1).14 4-Pentenoxyl radicals cyclize by intramolecularly
adding with rate constants of 108–109 s−1 at room temperature
to a terminal double bond, providing tetrahydrofuranylmethyl
radicals, for example II, in a fingerprint 5-exo/6-endo-regio-
selectivity of 98 : 2.17 Trapping of carbon radical II by bromo-
trichloromethane yields bromomethyltetrahydrofuran 3 as a
target product, and the trichloromethyl radical for propagating
the chain reaction.
2.1.2 Preparation and properties of 3-alkenoxy-4-
methylthiazole-2(3H)-thiones
inductor.
A trans-arranged secondary inductor enhances
(MTTORs). The
standard
stereocontrol of the primary inductor, and a cis-configured sec-
ondary inductor decreases this effect. A secondary inductor of
similar steric size, located further from the attacked π-bond is
not able to overrule the directing effect of the principal induc-
tor. Oxygen radicals attached via a methylene- or an ethylene-
spacer to cyclohexene cyclize cis-specifically, as exemplified by
synthesis of a diastereomerically pure bromobicyclo[2.2.1]-
heptyl-annulated tetrahydrofuran from a type-E radical. The
propensity of cyclohexenylethyloxyl radicals to cyclize 2,3-cis-
specifically arises from strain associated with the 2,3-trans-ring
closure, as derived by a Marcus analysis of density functional-
calculated reaction energies and barriers.
approach to synthesis of O-alkenyl thiohydroxamate 1 is substi-
tution of a leaving group from a carbon electrophile by the
4-methyl-2-thiooxothiazole-2(3H)-3-oxido
ion
(MTTO−;
Scheme 2).26 In the present study we used O-alkenyl tosylates
as carbon electrophiles, obtained in 69–96% yield from an
alkenol,28–31 p-toluenesulfonyl chloride, and 1,4-diazabicyclo-
[2.2.2]octane for buffering in situ-liberated hydrogen chloride
(ESI‡).32 Some alkenol syntheses required modification of the
original instruction, for example for preparing cis- and trans-
isomers of 2-(2-methylprop-1-enyl)-cyclohexylmethanol (for
1e)33,34 and β-verbenylethanol (for 1h; ESI‡).35 Treating O-pen-
tenyl tosylates at room temperature in solutions of dimethyl
formamide with the tetraethylammonium salt of MTTO− furn-
ished MTTORs 1a, 1b, and 1d–h in yields between 65% and
82% (Scheme 2). In position 2 substituted cyclohexyl tosylates
gave stereochemically pure target products cis-1c and trans-1c,
although in comparatively low yields. We explain this obser-
vation by steric shielding of the electrophilic carbon in 2-sub-
2. Results and interpretation
2.1 Alkenoxyl radicals from 3-alkenoxy-4-methylthiazole-
2(3H)-thiones
2.1.1 Alkenoxyl
radical
generation,
intramolecular stituted cyclohexyl tosylates toward the incoming nucleophile,
addition, and chain reaction. In extension to previous studies, the MTTO−-anion, in a SN2-reaction.36
we used derivatives of 3-alkenoxy-4-methylthiazole-2(3H)-
3-Alkenoxyl-4-methylthiazole-2(3H)-thiones obtained as
thione (MTTOR) 1 as progenitors for generating oxygen radi- described above are oils (1a–b, cis-1c, 1f) or crystalline solids
cals under non-oxidative and pH-neutral conditions.11,26,27 (trans-1c, 1d–e, 1g, 1h), stable for months when stored in vials
MTTORs (e.g. 1) are heterocyclic O-alkenyl thiohydroxamates, at room temperature. Recrystallizing 3-(methylcyclohexenyl)-
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Fig. 2 Ellipsoid graphic of 3-[(1-methylcyclohex-1-en-4-yl)-methyl-
oxy]-4-methylthiazole-2(3H)-thione (1g) in the solid state [major dia-
stereomer at 150 K; the (R,P)-isomer was arbitrarily chosen from the
racemate (R,P)/(S,M)-1g for presentation (50% probability level); hydro-
gen atoms are drawn as circles of an arbitrary radius; oxygen is depicted
in red, nitrogen in blue, and sulfur in orange; for depiction of the minor
diastereomer (S,P)/(R,M)-1g, see the ESI‡].
conformation of thiazolethione-derived O-alkyl thiohydroxa-
mates in solution and in the gas phase. The crystals available
for determining the structure of compound 1g were systemati-
cally disordered showing, according to the model used for
solving and refining the structure, a 78/22-ratio of diastereo-
mers at crystallographic independent sites.§ The diastereo-
mers differ with respect to the configuration at C8/C8a (ESI‡)
and the helicity at the nitrogen–oxygen bond, showing both
the characteristic offset of thiohydroxamate bound carbon 7
from the heterocyclic plane [major diastereomer (ds): C2–N3–
O1–C7 = 91.0(2)°; minor ds: C2–N3a–O1a–C7a = 59.8(6)°] and
bond lengths which are diagnostic for primary O-alkyl thio-
hydroxamates [major ds (Fig. 2): C2–S2 = 1.666(1) Å, C2–N3 =
1.358(2) Å, N3–O1 = 1.386(2) Å; minor ds (ESI‡): C2–N3a =
1.366(6) Å, N3a–O1a = 1.373(4) Å].42
2.1.3 Numbering of atom positions in O-alkenyl thio-
hydroxamates, alkenoxyl radicals, and cyclized products. Oxygen
and carbon differ in priority for systematically naming open
chain and heterocyclic organic compounds according to the
IUPAC convention. For the stereochemical discussion in this
article we numbered the 4-pentenyl chain in O-radical progeni-
tor 1 and alkenoxyl radical I as recommended by IUPAC for ali-
phatic compounds.43 A transition structure (TS)-I for 5-exo-
cyclization in the twist model is a derivative of tetrahydrofuran,
and thus numbered, similar to cyclized carbon radical II,
according to the Hantzsch–Widman notation for heterocyclic
compounds.44,45 For numbering positions in bicyclic bromo-
cyclization product 3, we used the von Baeyer convention
(Fig. 3).46,47
Scheme 2 Indexing, yields, and structure formulas of MTTORs 1a–h
prepared from O-alkenyl tosylates and 3-hydroxy-4-methylthiazole-2
(3H)-thione tetraethylammonium salt (segments drawn in red refer to
subunits represented by dotted lines in Fig. 1 and in Scheme 1).
methyloxy-thiazolethione 1g removed a regioisomer, which
had been formed with 5/95-selectivity as a by-product from the
[4 + 2]-cycloaddition between isoprene and methyl acrylate, in
the first step of the synthesis for constructing the 1,4-disubsti-
tuted cyclohexenyl nucleus.37,38
3-Alkenoxy-4-methylthiazole-2(3H)-thiones 1a–h show diag-
nostic carbon-13 chemical shifts for the thiocarbonyl carbon
(180–181 ppm) and the thiohydroxamate-bound carbon
(74.8–92.1 ppm). The compounds absorb in solutions of
methanol UV-light, leading to absorption-maxima at λ =
316–319 nm (lg ε ∼ 3.10–3.19 m2 mol−1). Photoexciting the tail
end of this absorption band with 350 nm light causes the
nitrogen–oxygen bond in 1 to break homolytically, liberating
oxygen radicals without an externally added initiator.39
In solution, 3-alkoxy-4-methylthiazole-2(3H)-thiones show
the phenomenon of hindered rotation about the nitrogen–
oxygen bond, becoming apparent in nuclear magnetic reson-
ance spectra of, for example, 3-isopropoxy-4-methyl-thiazole-
2(3H)-thione by signal coalescence at −60 °C, and a twofold set
of resonances below this temperature.40 The lowest in energy
conformer has the ester carbon C7 offset by almost 90 degrees
from the thiohydroxamate plane, to prevent close contacts
with the thione sulfur and methyl group in position 4 of the
heterocyclic core.41 The structure of 3-alkenyloxythiazolethione
2.2 Alkenoxyl radical addition to exocyclic double bonds
2.2.1 1,2-Annulation – 2-allylcycloalkyl-1-oxyl radical reac-
tions. For elucidating principles of stereocontrol exerted by a
cycloalkane fused in positions 1 and 2 to the 4-pentenoxyl
radical we investigated the size effect of the cycloaliphatic ring,
§Crystallographic data (excluding structure factors) for the structure in this
paper are deposited with the Cambridge Crystallographic Data Centre as sup-
1g in the solid state corresponds to the predicted minimum plementary publication [CCDC 1008593 (compound 1g)].
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Fig. 3 Convention used in this article for numbering atoms in product classes associated with alkoxyl radical reactions, exemplified for alkenoxy-
thiazolethione cis-1c, derived 4-alkenoxyl radical cis-Ic, the transition structure for the 5-exo-cyclization TS-cis-Ic, 5-exo-cyclized carbon radical
cis-IIc, and bicyclic bromocyclization product cis-3c.
Table 1 Products formed from 3-(cis-2-allylcyclopentyloxy)-thiazolethiones cis-1a–b and BrCCl3
Entry
cis-1
R
Conditions
2/%
cis-3a–b/% (1,3-cis : trans)
4/%
1
2
3
4
1a
1a
1b
1b
H
H
CH3
CH3
hν/25 °C
AIBN/80 °C
hν/25 °C
85
87
73
75
3a: 10 (70 : 30)
3a: 8 (71 : 29)
3b: 49 (64 : 36)
3b: 34 (56 : 44)
4a: 60
4a: 54
4b: 31
4b: 35
AIBN/80 °C
Table 3 Products formed from 3-(cis-2-allylcyclohexyloxy)-thiazo-
lethione cis-1c and BrCCl3
Table 2 Products formed from 3-(trans-2-allylcyclopentyloxy)-thiazo-
lethione trans-1a and BrCCl3
cis-3c/%
(6,8-cis : trans)
trans-3/%
(1,3-cis : trans)
Entry
Conditions
2/%
4c/%
Entry
Conditions
2/%
4a/%
a
1
2
hν/25 °C
AIBN/80 °C
73
74
45 (89 : 11)
61 (68 : 32)
—
a
1
2
hν/25 °C
AIBN/80 °C
56
85
—
44 (14)b
73 (14)b
12
a
—
a Not detected (NMR).
a Not detected (NMR). b Figures in brackets refer to the yield of 5,7-
dibromo-9,9,9-trichlorononanal.
Table 4 Products formed from 3-(trans-2-allylcyclohexyloxy)-thiazo-
lethione trans-1c and BrCCl3
the relative configuration of substituents, and substitution at
the terminal alkene carbon on reactivity and selectivity of type-
A alkenoxyl radicals (Tables 1–4).
(i) Methods of alkenoxyl radical generation and product analy-
sis. Photolyzing solutions of O-alkenyl thiohydroxamates 1a–c
in benzene containing 10 equivalents (1.67 M) of bromotri-
chloromethane, using Rayonet® chamber apparatus equipped
with 350 nm illuminants, quantitatively consume the starting
material within 30 minutes, as determined by thin layer
chromatography. Reaction mixtures from photochemical
experiments tended to turn turbid and yellow. A gas chromato-
gram (GC) recorded by the end of the reaction time provided
information on the original product pattern and distribution.
trans-3c/%
(6,8-cis : trans)
Entry
Conditions
2/%
4/%
a
1
2
hν/25 °C
AIBN/80 °C
92
80
49 (8 : 92)
70 (13 : 87)
—
8
a Not detected (NMR).
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Column chromatography furnished samples of purified 2-(tri-
chloromethylsulfanyl)-4-methyl-1,3-thiazole (2), 5-exo-bromocy-
clized products 3a–c, and β-fragmented unsaturated
5-bromoaldehydes 4a–b, for collecting analytical data (Tables
1–4, and Experimental). Solutions from thermally initiated
reactions were in addition charged with 15 mole percent of
azo-α,α-bis-(isobutyronitrile) (AIBN) as the initiator. Such mix-
tures remained clear but tended to turn yellow by the end of
the reaction.
Scheme 3 Competing reaction pathways for mechanistically interpret-
ing the origin and yields of 5-exo-cyclization- versus β-fragmentation-
(ii) Product pattern and kinetic interpretation. Reactions
between O-(2-allylcycloalkyl) thiohydroxamates cis-1a–c and products from 2-allylcycloalkyloxyl radicals Ia–c (R = H, CH3; for details
associated with rate constants kβ, kBr, and kadd, see the text).
bromotrichloromethane furnish bromomethyltetrahydrofurans
cis-3a–c, with the yields gradually decreasing for thermally
initiated reactions from 61% for cis-3c through 34% for cis-3b
to 8% for cis-3a (Table 1, entries 2 and 4; Table 3, entry 2). The calibrating the competition system with the aid of absolute
rate constants leads to a similar order of magnitude for the
k
reactions gave bromoaldehydes 4a–c as co-products in yields
increasing from 12% for 4c, through 35% for 4b to 54% to 4a.
Photolyzing or heating O-(2-allylcyclopentyl) thiohydroxamate
trans-1a in the presence of bromotrichloromethane provided
add/kβ ratio.2,49
The propensity of cyclopentane-fused 4-pentenoxyl radicals
to provide β-fragmented products, such as bromoaldehydes
bromooctanal 4a, but no bromomethyltetrahydrofuran trans- 4a–b, arises from strain, being ∼20 kJ mol−1 higher for cyclo-
3a as secured by independent analysis of an authentic sample pentane than for cyclohexane.50 Substituting methyl for hydro-
gen at the terminal alkene carbon increases the fraction of the
of the compound (ESI‡). The ratio of the bromocyclized
product trans-3c and bromoaldehyde 4c obtained from O-cyclo- 5-exo-cyclized product from cis-3a to cis-3b, which we address
hexylallyl ester trans-1c is similar to the ratio of cis-3c and 4c to a rate enhancing polar effect of the methyl group in oxygen
radical additions.51
obtained from the stereoisomer cis-1c (entry 2 in Tables 3 and
4). The pattern of products obtained from radical reactions
conducted at 80 °C in summary is similar, except for bromoal- oxyl radicals Ia–c cyclize 2,4-cis-selectively showing that the
substituent in position 2 is the principal stereoinductor for
ments. None of the reactions furnished 2-allylcycloalkanols or 5-exo-cyclization of type-A radicals. A trans-arranged secondary
(iii) Stereochemical guidelines. 1,2-Cycloalkyl-bridged 4-penten-
dehyde 4c, which did not form in the room temperature experi-
2-allylcycloalkanones in verifiable amounts (GC-MS).
inductor in position 1 enhances the directing effect of the
principal inductor; cis-configured secondary inductor
a
In kinetically controlled reactions, the quotient between
bromomethyltetrahydrofuran 3 and bromoaldehyde 4 is equi- decreases this effect.
valent to the relative rate constant for the addition (kadd) versus
β-fragmentation (kβ) (Scheme 3). Kinetic control for oxygen
(iv) On the origin of 2,4-cis-selectivity in 5-exo-cyclization of
type-A 4-pentenoxyl radicals. To understand the origin of 2,4-
radical addition to terminal double bonds is documented.8 cis-selectivity, we modelled transition structures (TS) of 2-allyl-
For the following reason we suggest that the sequence cyclohexyl-1-oxyl radical 5-exo-cyclization Ic
leading to bromoaldehyde 4 under conditions chosen in this
→ IIc, using
assessed electronic structure methods.14,52
study also is kinetically controlled. In 1.67 molar solution
For stereochemical analysis, we considered transition struc-
of bromotrichloromethane, the effective rate constant for tures for 2,4-cis-(TS1) and 2,4-trans-cyclization (TS2) of allyl-
cyclohexyloxyl radicals cis/trans-Ic (Fig. 4 and ESI;‡ see also
bromine atom trapping by secondary alkyl radicals, such as III,
is approximately 4.3 × 108 s−1, based on kBr for the 6-hepten-2-yl section 2.4). Transition structure searches according to an estab-
radical (2.6 × 108 M−1 s−1; 26 °C)48 as a reference. The rate lished methodology17 (ESI‡) led to twist (T)-conformers of
constant kadd for the 4-formylbutyl radical 5-exo-cyclization
tetrahydrofuran (Fig. 4), similar to intermediates modelled for
(8.7 × 105 s−1; 80 °C),49 serving as a reference for the reaction 5-exo-cyclization of monosubstituted 4-pentenoxyl radicals.8
III → I, is by almost three orders of magnitude slower than the The radical oxygen in transition structures TS1,2-cis/trans-Ic lies
for stereoelectronic reasons in a plane defined by inner alkene
effective rate of bromine atom transfer from bromotrichloro-
methane to the secondary carbon radical III.
carbon (C5) and the allylic carbon (C4). Carbons 2 and 3 are
2
For comparing rates of 5-exo-cyclization to rates of β-frag- offset into opposite directions from this plane, leading to T3-
(TS2-cis-Ic, TS1-trans-Ic, and TS2-trans-Ic) and 2T3-conformers of
mentation for intermediates Ia–c, we standardized reactant
concentrations and used a tenfold molar excess of bromotri- tetrahydrofuran (TS1-cis-Ic). cis/trans-Diastereodifferentiation,
chloromethane. Under such conditions, the ratio of bromide 3 in this model, occurs by rotating the vinyl substituent by 180
to 4 corresponds to the quotient kadd/kβ, gradually increasing
degrees about the bond between carbons 4 and 5. Positioning
along the series of radicals trans-Ia (krel = 0), cis-Ia (0.2), cis-Ib the vinyl group and carbon 3 on opposite sides of the twist
(1.0) to cis/trans-Ic (krel = 5–9). Dividing kadd for the 4-penten- plane prevents eclipsing of hydrogens at carbons 4 and 5, thus
favoring transition structures TS1-cis-Ic and TS1-trans-Ic.
oxyl radical cyclisation (5.2 × 108 s−1; 26 °C) by kβ for the
cyclopentoxyl radical β-fragmentation (4.7 × 108 s−1; 80 °C) for Favored transition structures furthermore have the cyclohexyl-
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Table 6 Products formed from 3-{[(2-methylpropenyl)-cyclohexyl]-
methyloxy}-thiazolethione 1e and BrCCl3
Entry
1e
Conditions
2/%
3e/% (6,7-cis : trans)
1
2
3
4
cis
cis
trans
trans
hν/25 °C
AIBN/80 °C
hν/25 °C
82
90
79
98
1,6-cis: 80a (>99 : 1)
1,6-cis: 95a (>99 : 1)
1,6-trans: 81a (>99 : 1)
1,6-trans: 94a (>99 : 1)
AIBN/80 °C
a Single diastereomer, according to proton-NMR- and GC-MS-data.
Fig. 4 Modelled transition structures for 2,4-cis (TS1) and 2,4-trans
(TS2)-cyclization of alkenoxyl radicals cis-Ic (top) and trans-Ic (bottom).
methane furnish 81% of 7-bromomethyltetrahydrofuran cis-3d
and 95% of bromoisopropyl derivative cis-3e (entry 2 in Tables
5 and 6). The former reaction provided in addition 5% of the
diastereomerically pure 6-endo-cyclized product cis-5d, which
was not obtained from dimethylvinyl-congener cis-1e (GC-MS).
Heating O-(2-vinylcycloalkyl-1-methyloxy) thiohydroxamate
trans-1d in the presence of bromotrichloromethane furnishes
an 80/20-mixture of 5-exo/6-endo-bromocyclized products trans-
3d and trans-5d, whereas O-[2-(dimethylvinyl)-cyclohexyl-
methyl] ester trans-1e affords bromopropyltetrahydrofuran
trans-3e as a single diastereomer (Tables 5 and 6, entry 4).
Photochemical reactions gave 13–20% lower yields of bromo-
cyclization products 3 and 5 taken together, and 8–19% less
thiazole 2, than thermally initiated reactions (entries 1 and 3
in Tables 5 and 6).
Black circles represent hydrogens experiencing close contacts (dH,H
=
2.423 Å; B3LYP/6-31+G**), open circles symbolize eclipsed hydrogens
(H–C4–C3–H = 2.1°). aStereodescriptor referring to the configuration at
carbons 2 and 4 in cyclized radical IIc (cf. Fig. 3). bStereodescriptor
referring to the configuration at carbons 2 and 3 in TS-Ic.
substituent in position 3 bound equatorially to the distorted
tetrahydrofuran nucleus (Fig. 4). Positioning the cyclohexyl-
substituent at carbon 3 axially leads to transannular repulsion
between the hydrogen attached to carbon 5 and one of the
axial cyclohexane hydrogens (TS2-cis-Ic). The lowest in energy
transition structure modelled for the 2,4-trans-ring closure of
trans-Ic (TS2-trans-Ic; Fig. 4, bottom right) shows an eclipsing
of hydrogens at carbons 4 and 5.
2.2.2 2,3-Annulation
–
2-(vinylcyclohexyl)-methyloxyl
(ii) Effect of methyl substitution at the terminal alkene carbon.
Substituting two hydrogens at the terminal alkene carbon by
methyl improves the stereoselectivity and regioselectivity in
cyclization of type-B 4-pentenoxyl radicals (Tables 5 and 6).
Terminal methyl groups furthermore improve the regioselecti-
vity of the intramolecular addition, occurring with 80/20-selecti-
vity for trans-Id, 94/6 for cis-Id, and 5-exo-specifically for cis/
trans-Ie (GC-MS; Table 5, entries 2 and 4, and Table 6).
radical reactions. For elucidating principles controlling
the stereoselectivity in cyclization of 2,3-cyclohexyl-bridged
4-pentenoxyl radicals (type B), we investigated bromocycliza-
tion of 2-vinyl- and 3-(2-dimethylvinylcyclohexylmethyloxy)-
thiazolethiones cis/trans-1d–e (Tables 5 and 6).
(i) Methods of alkenoxyl radical generation and product analy-
sis. Thermally induced reactions between O-(2-vinylcycloalkyl-
1-methyloxy) thiohydroxamates cis-1d/e and bromotrichloro-
Table 5 Bromocyclization products formed from 3-[(2-vinylcyclohexyl)methyloxy]-thiazolethione 1d and BrCCl3
Entry
1d
Conditions
2/%
3d/% (6,7-cis : trans)
5d/% (1,2-cis : trans)
1
2
3
4
cis
cis
trans
trans
hν/25 °C
AIBN/80 °C
hν/25 °C
71
88
78
97
1,6-cisa: 70 (20 : 80)
1,6-cisa: 81 (21 : 79)
1,6-transa: 57 (7 : 93)
1,6-transa: 70 (10 : 90)
1,6-cisa: 3 (99 : 1)
1,6-cisa: 5 (99 : 1)
1,6-transa: 10 (50 : 50)
1,6-transa: 17 (41 : 59)
AIBN/80 °C
a Stereodescriptor referring to the configuration of bridgehead carbons in products 3d and 5d.
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Table 7 Products formed from 3-[2-(2-methylenecyclohexyl)-ethyl-1-
oxy]-thiazolethione 1f and BrCCl3
Entry
Conditions
2/%
cis-3f/%
5f/% (cis : trans)
1
2
hν/25 °C
AIBN/80 °C
54
80
24
35
21 (19 : 81)
22 (32 : 68)
stereomer, bridgehead brominated oxadecalin 5f, and 2-
(trichloromethylsulfanyl)-thiazole 2, when heated in the pres-
ence of bromotrichloromethane at 80 °C (Table 7, entry 2). The
photochemical reaction provides a similar product pattern,
although lower yields of compounds 2 and cis-3f. The fraction
of bromotetrahydropyran 5f remained almost unchanged
(Table 7, entry 1).
Fig. 5 Transition structure models for explaining the origin of 2,3-
trans-stereoselectivity in 5-exo-cyclization type-B pentenoxyl radicals,
exemplified by favored intermediates TS1-cis/trans-Id and disfavored
intermediates TS2-cis/trans-Id. Hydrogen atoms drawn as black circles
give rise to 1,3-diaxial repulsion, ecliptically arranged hydrogens are
drawn as open circles. aStereodescriptor referring to the configuration
at carbons 2 and 3 in cyclized radical IId (cf. Fig. 3). bStereodescriptor
referring to the configuration at carbons 3 and 4 in TS-Id.
The 5-exo/6-endo-selectivity of radical If (53 : 47) at room
temperature falls below the value reported for the 4-methyl-4-
pentenoxyl radical (69 : 31) and is higher than the regioselectiv-
ity determined for the 4-tert-butyl-4-pentenoxyl radical
(46 : 54).17 Regioselectivity in 4-pentenoxyl radical cyclization
originates from a balance between FMO attractions, torsional
strain, and steric shielding. A carbon substituent in position
4 lowers the barrier for 6-endo-addition based on favorable fron-
tier molecular orbital (FMO) interactions for the C,O-addition
to the terminal carbon. Steric blocking of the incoming oxygen
radical gradually lowers the rate of 5-exo-addition as the size of
the carbon substituent in position 4 increases. The fraction
tetrahydropyranyl radical IVf obtained from 6-endo-cyclization
of If is in line with the general mechanistic interpretation.17
Homolytic bromination of tetrahydropyranyl radical IVf occurs
for steric reasons preferentially from the axial side (Scheme 4),
similar to bromination of structurally related cyclohexyl
radicals.53
(iii) Stereochemical guidelines. 2,3-Cycloalkyl-bridged 4-pen-
tenoxyl radicals Id–e cyclize 2,3-trans-selectively, indicating
that the principal stereoinductor in cyclization of type-B radi-
cals is the substituent in position 3 of the radical. Fusing
4-pentenoxyl radicals in relative trans-positions of cyclohexane
enhances stereodifferentiation by the principal inductor.
(iv) On the origin of 2,3-trans-selectivity in 5-exo-cyclization of
type-B 4-pentenoxyl radicals. Models built as instructed in
section 2.1 show that type-B cyclohexyl-bridged 4-pentenoxyl
radicals cis/trans-Id–e cyclize 2,3-trans-selectively, because
steric constraints disfavor the 2,3-cis-mode of ring closure. In
transition structures for 2,3-cis-cyclization, van der Waals
repulsion between the (E)-positioned alkene substituent and
the axially arranged hydrogens raises conformational free
energy. The second aspect raising conformational free energy
thus disfavoring a transition structure is eclipsing of hydro-
gens bound to carbons 4 and 5 (for TS2-trans-Id and TS2-cis-Id;
Fig. 5). Extending the size of the (E)-substituent from hydrogen
to methyl raises transannular repulsion, explaining the stereo-
directing effect of a terminal substituent in cyclization of cis/
trans-Ie.
(ii) Stereochemical guideline. Methylenecyclohexylethoxyl
radical If cyclizes 2,3-cis-specifically (Scheme 4).
2.2.3 3,4-Annulation
– 2-(2-methylenecyclohexyl)-1-ethyl-
oxyl radical reactions. To explore the selectivity in intramole-
cular addition of a 3,4-cyclohexyl-bridged 4-pentenoxyl radical
(type C), we investigated photochemical and thermal reactions
between 3-[2-(2-methylenecyclohexyl)-ethyloxy]-thiazolethione
1f and bromotrichloromethane (Table 7).
(i) Methods of alkoxyl radical generation and product analysis.
3-[2-(2-methylenecyclohexyl)-ethyloxy]-thiazolethione 1f fur-
Scheme 4 Stereoselectivity in cyclization of the 1-methylenecyclo-
nishes the 5-exo-bromocyclized product cis-3f as a single dia- hexyl-2-ethyloxyl radical If (type C).
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Table 8 Products formed from 3-[(1-methylcyclohex-1-en-4-yl)-methyloxy]-thiazolethione 1g and BrCCl3 and diagnostic proton-NMR shift values
of bromocyclization product 3ga
Entry
Conditions
2/%
3g/% (1,2-cis : trans)
1
2
hν/25 °C
AIBN/80 °C
69
76
64 (28 : 72)
72 (19 : 81)
a Protons experiencing deshielding by changing the position of the carbon–bromine bond from anti to syn, and vice versa, are printed in blue.
2.3 Cyclization onto endocyclic double bonds
(iii) Verbenylethyloxyl radical chemistry. In extension to the
chemistry summarized in this article, we propose that tricyclic
products 6 and 7 arise from a sequence composed of intra-
molecular addition Ih → cis-IIh, ring-opening of cyclobutylmethyl
radical cis-IIh, and bromine atom trapping by rearranged radi-
cals V and VI (Scheme 7). 1,2-Shifting of the methylene bridge
releases cyclobutyl strain in radical cis-IIh, leading to the sec-
ondary carbon radical V. For steric reasons, we expect trapping
of the bicyclic radical V by bromotrichloromethane to occur
from the concave face due to shielding of the convex side with
the vicinal exo-oriented methyl group. The minor product 7,
according to the proposed model, results from 1,2-shifting of
the dimethylmethylene bridge cis-IIh → VI and subsequent
homolytic bromination.
For investigating the stereoselectivity in intramolecular
addition to endocyclic double bonds we examined bromocycli-
zation of 3-[2-(2-methylenecyclohexyl)-ethyloxy]-thiazolethione
1g (type D; section 3.1) and verbenylethanol-derived thio-
hydroxamate 1h (type E; section 3.2).
2.3.1 The (cyclohexen-4-yl-)-methyloxyl radical cycliza-
tion. (i) Methods of alkoxyl radical generation and product ana-
lysis. Photochemical and thermal reactions between 3-[(1-
methylcyclohex-1-en-4-yl)-methyloxy]-thiazolethione 1g and
bromotrichloromethane furnish the 5-exo-bromocyclized
product 3g and substituted thiazole 2 (Table 8, entries 1
and 2).
Bicyclic tetrahydrofuran 3g forms at 80 °C as a 19/81-
mixture of 1,2-cis/trans-stereoisomers. Resonances of protons
in β- and γ-positions to the carbon–bromine bond experience a
shift dispersion by ∼0.5 ppm upon changing orientation of the
bromosubstituent from anticlinal or antiperiplanar to syncl-
inal (Table 8). We address this phenomenon to magnetic
anisotropy induced by the carbon–bromine bond, possibly
in combination with three nonbonding electron pairs at
bromine.54
2.4 Strain effects in alkoxyl radical additions
For estimating differences in energy barriers associated with
2,3-cis- and 2,3-trans-cyclization of type-E alkenoxyl radicals,
we modelled energetics associated with 5-exo-cyclization using
electronic structure methods.55,56 The 2-(cyclohexen-3-yl)-ethyl-
oxyl radical Ii, in this approach, served as a truncated model
for the verbenyl-4-ethyloxyl radical Ih, while the 4-pentenoxyl
radical 5-exo-cyclization Ij → IIj and the methoxyl radical
addition to the inner carbon of propene served as references
(Schemes 8 and 9).
(i) Density functional theory. For computing ground state
energies of radicals and energies of transition structures, we
used Becke’s three parameter Lee–Young–Parr-hybrid func-
tional (B3LYP)57,58 and Becke’s half and half Lee–Young–Parr
hybrid functional (BHandHLYP)59 in combination with
6-31+G**- and 6-311G**-basis sets.56 All selected density func-
tional/basis set-combinations reproduce experimental stereo-
and regioselectivity for oxygen radical addition to carbon–
carbon double bonds with a precision coming close to the
accuracy for determining experimental selectivity.8,14,17,52,60
(ii) Theoretical approach. For calculating equilibrium struc-
tures of conformational flexible molecules and transition
structures associated with radical addition to carbon–carbon
double bonds we used an established strategy.8,14 According to
theory, the 2-(cyclohexen-3-yl)-ethyloxyl radical Ii favors
(ii) Stereochemical guideline. Cyclohexenylmethyloxyl radical
1g cyclizes 2,4-cis-specifically (Scheme 5).
2.3.2 The verbenylethyloxyl radical cyclization. (i) Products
from photochemical activation. Verbenylethanol-derived thio-
hydroxamate 1h furnishes tricyclic bromides 6 and 7 in a total
yield of 61%, besides 79% of 2-(trichloromethylsulfanyl)-4-
methylthiazole 2, when photolyzed in the presence of bromo-
trichloromethane (Scheme 6).
(ii) Stereochemical guideline. Cyclohexenylethyloxyl radical
Ih cyclizes cis-specifically (Scheme 7).
Scheme 5 2,4-cis-cyclization of alkenoxyl radical Ig (type D; from 1g).
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Scheme 6 Formation of bicyclic products from 3-(verbenylethyloxy)-thiazole-2(3H)-thione 1h.
Attempts to localize a transition structure for the trans-5-exo-
cyclization of conformer pa-Ii led to TS1-trans-Ii, already avail-
able from conformer pe-Ii.
(iii) Quality of the models. Computed wavefunctions charac-
terizing equilibrium structures show expectation values for the
spin operator 〈S2〉 close to 0.75 for oxygen and carbon radicals
(ESI‡), as expected for doublet states. Wavefunctions describ-
ing transition structures show 〈S2〉-values of ∼0.77 for B3LYP-
calculated intermediates and 0.82–0.84 for BHandHLYP-calcu-
lated transition structures (ESI‡). The effect of spin contami-
nation in BHandHLYP-calculated transition structures was
discussed previously, but is not considered relevant for attain-
ing reasonable precision in determining computed relative
energies.52
Scheme 7 Proposed pathways for product formation from verbenyl-
ethyloxyl radical Ih (type E; from 1h).
(iv) Methoxyl radical addition to propene. Theory predicts a
lower barrier for methoxyl radical addition to the terminal
carbon than for addition to the inner carbon of propene
(ΔG298 = −5.0 to −8.5 kJ mol−1; ESI‡). The decision to compare
structure and energetics from the disfavored mode of addition
to data obtained for monocycle and bicycle formation was
guided by structural similarity between TS-Ii–j and TS-VII on
one side, and derived addition products IIi–j, VIII on the other
(Table 9, Schemes 8 and 9).
pseudo-equatorial (pe) positioning of the ethyloxyl radical side
to pseudo-axial (pa), as expressed by a modelled 90/10-mixture
of pe/pa-conformers of Ii at 298 K (B3LYP/6-31+G**; ESI‡).
Both conformers served as starting points for modeling 5-exo-
cyclizations.
Equilibrium structures of propene, alkoxyl radicals Ii–k,
cyclized radicals IIi–j, and the addition product VIII lack in
negative eigenvalues of second derivatives of energy-mini-
mized wavefunctions. Transition structures TS-I and TS-VII
show one imaginary frequency i, describing the trajectory of
oxygen radical addition to the inner alkene carbon (Table 9).61
(v) Thermochemistry. Cyclization of the 2-(cyclohexen-3-yl)-
ethyloxyl radical Ii → IIi, according to zero-point energy cor-
rected reaction energies (B3LYP/6-31+G**), is for all considered
Scheme 8 Structure formulas of radicals and intermediates associated with the 1-(cyclohexen-3-yl)-ethyl-2-oxyl radical 5-exo-cyclization (pe =
pseudo-equatorial; pa = pseudo-axial; ax = axial; eq = equatorial).
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104 degrees, being more acute than the angle calculated for
the highest in the energy transition structure TS-trans-Ii (3T4)
(121–122 degrees; Table 9). Absolute values of improper
torsion angles ω for transition structures TS-Ii, TS-Ij, and TS-
VIII, according to B3LYP- and BHandHLYP-theory, are close to
160 degrees, indicating the hybridization change at the
attacked carbon from sp2 (ω = 180° for propene) toward sp3
(122° for propane).
Superimposing atomic coordinates of 4-pentenoxyl radical
cores illustrates that density functional-calculated favored tran-
sition structures for the cyclohexenylethyloxyl radical cycliza-
tion and the 4-pentenoxyl radical ring closure are nearly
identical (Fig. 6). A 3T4-conformation, as predicted by theory
Scheme 9 Structure formulas of radicals and intermediates associated
with the 4-pentenoxyl radical 5-exo-cyclization (top) and methoxyl
radical addition to the inner carbon of propene (bottom; for discussion
of TS1-VII, refer to the text and the ESI‡).
2
for TS-cis-Ii (3T4), is separated by only 36 degrees from a T3-
conformer in TS-Ij (2T3) on the pseudorotatory cycle of
tetrahydrofuran.62
Table 9 Selected geometrical parameters of transition structures TS1,2
cis/trans-Ii, TS-j and TS-VIIa
-
(vii) Energy barriers. The barrier for 2,3-cis-cyclization of
cyclohexenylethyloxyl radical Ii (ΔE‡ = 17 kJ mol−1) is similar
to the barrier predicted by B3LYP-theory for the 4-pentenoxyl
radical 5-exo-cyclization (20 kJ mol−1) and the methoxyl radical
addition to propene (21 kJ mol−1). BHandHLYP-computed bar-
riers for 2,3-cis-cyclization of Ii and 5-exo-cyclization of Ij are
higher, but generally show the same trends (Table 10).
The computed relative Gibbs free energy of activation for
the 2,3-trans-mode of cyclization is 55 kJ mol−1 above the value
for the lowest in the energy pathway of 2,3-cis-ring closure
(B3LYP; 58 kJ mol−1 for BHandHLYP calculations using either
the 6-31+G** or the 6-311G** basis set; ESI‡). A Gibbs free acti-
vation energy difference of 55 kJ mol−1 translates for a kineti-
cally controlled reaction and a temperature of 298.15 K into a
relative rate constant of 4 × 109 in favor of the 2,3-cis-cycliza-
tion. Detecting a 2,3-trans-bromocyclized product with such a
precision was beyond the capability of analytic instruments
used in the study.
d = O1–
α = O1–
ω = H5–C4–
I
ib/cm−1
C5c/Å
C5–C6d/°
C5–C6e/°
TS1-cis-Ii (3T4)
−342
2.077
103.5
161.6
(−496)
[−529]
−397
(2.024)
[2.018]
2.042
(2.003)
[1.986]
2.058
(2.010)
[1.990]
2.046
(1.996)
[1.997]
2.061
(103.9)
[103.0]
122.7
(121.6)
[121.3]
100.8
(101.5)
[101.6]
99.1
(100.4)
[100.5]
98.3
(159.4)
[158.5]
152.9
(152.2)
[151.5]
−160.5
(−158.6)
[−157.6]
162.1
(159.9)
[159.0]
161.2
(158.6)
[157.8]
TS1-trans-Ii (3T4)
TS2-cis-Ii (2T3)
TS-Ij
(−547)
[−575]
−353
(−500)
[−531]
−382
(−531)
[−558]
−334
(−489)
[−517]
TS2-VIIf
(1.999)
[1.979]
(100.6)
[100.8]
a B3LYP/6-31+G**-calculated values; numbers in parentheses arise
from BHandHLYP/6-31+G**-calculations and values in brackets from
BHandHLYP/6-311G**-calculations. b i = imaginary mode of vibration.
c O–C2 for TS2-VII. d O–C2–C1 for TS2-VII. e C–C2–H2–C1 for TS2-VII.
f For the transition structure TS1-VII, refer to the ESI.
(viii) Marcus analysis. For analyzing strain and electronic
effects on barriers of 5-exo-alkenoxyl radical cyclization, we
split zero-point vibrational energy-corrected electronic barriers
(ΔE‡) into an intrinsic (ΔE‡ ) and a thermodynamic term
i
pathways strongly exothermic (ΔRE = −35 to −47 kJ mol−1), (ΔE‡TD), using Marcus theory (Fig. 7, Table 10, eqn (1)–
pointing to a notable barrier for the reverse reaction, the (3)).63–65 The intrinsic part describes contributions of strain
β-fragmentation. Computed energetics for the addition Ii → IIi and steric repulsion in a thermoneutral degenerated reaction
are similar to the values calculated for the 4-pentenoxyl radical to the barrier ΔE‡i in a transition structure located half way on
ring closure Ij → IIj (ΔRE = −41 kJ mol−1), and are less exother- the reaction coordinate (x‡ = 0.5) between reactant(s) (x = 0)
mic than the methoxyl radical addition to the inner carbon and product(s) (x = 1; Fig. 7). The thermodynamic part of the
of propene (ΔRE = −53 mol−1). BHandHLYP-calculations barrier ΔE‡ describes energy changes arising from incipient
TD
provide similar trends for reaction energies, except for a stron- bond forming and bond breaking in a transition structure.
ger driving force for the intermolecular addition (Table 10).
qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
ΔRE
2
2
‡
‡
‡
(vi) Transition structures. The distance d between the radical
oxygen and the attacked carbon, as predicted by B3LYP theory
for transition structures of cyclohexenylethyloxyl radical cycli-
zation (2.04–2.08 Å), 4-pentenoxyl radical cyclization (2.05 Å)
and methoxyl radical addition to propene (2.06 Å), is margin-
ally wider than those obtained from BHandHLYP-calculations
(1.98–2.02 Å; Table 9). Values for the angle α describing oxygen
radical attack to the inner alkene carbon are grouped for all
ΔE
ꢀ
þ
ðΔE Þ ꢀ ðΔREÞðΔE Þ
2
‡
ΔE
¼
ð1Þ
i
ꢀ
ꢁ
1
2
ΔRE
‡
x
¼
1 þ
ð2Þ
ð3Þ
‡
4ΔE
ΔE‡ ¼ ΔE‡i þ ΔE‡
TD
(ix) Localizing transition structures – the x‡-value. According
calculated transition structures in the range between 98 and to Marcus theory, reaction energies and barriers obtained from
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Table 10 Zero-point vibrational energy-corrected activation energies (ΔE‡), reaction energies (ΔRE), intrinsic energy barriers (ΔE‡ ), thermodynamic
TD
i
contribution ΔE‡ to ΔE‡, free energy differences [ΔG298 = G298(I) − G298(II) or ΔG298 = [G298(Ik) + G298(propene)] − G298(VIII)] and approximated
transition location x‡ for alkoxyl radical additions (Schemes 8 and 9, eqn (1)–(3))
Reaction
Method
ΔE‡/kJ mol−1
ΔRE/kJ mol−1
ΔE‡ /kJ mol−1
ΔE‡TD/kJ mol−1
x‡
i
pe-Ii → cis-IIi (ax)
B3LYP/6-31+G**
16.7
39.3
40.6
73.1
99.1
100.7
17.4
39.5
40.9
19.8
41.0
41.7
20.5
37.3
36.3
−44.1
−46.4
−44.7
−34.5
−35.7
−33.7
−46.8
−50.4
−49.0
−40.5
−43.5
−41.8
−53.8
−61.2
−61.0
35.4
60.3
60.9
89.5
116.3
116.9
37.1
62.2
63.1
37.3
60.8
60.8
43.2
64.2
63.1
−18.6
−21.0
−20.3
−16.4
−17.2
−16.2
−19.7
−22.7
−22.1
−17.5
−19.8
−19.1
−22.7
−27.0
−26.8
0.2
0.4
0.4
0.4
0.5
0.5
0.2
0.3
0.4
0.2
0.4
0.4
0.2
0.3
0.3
BHandHLYP/6-31+G**
BHandHLYP/6-311G**
B3LYP/6-31+G**
BHandHLYP/6-31+G**
BHandHLYP/6-311G**
B3LYP/6-31+G**
BHandHLYP/6-31+G**
BHandHLYP/6-311G**
B3LYP/6-31+G**
BHandHLYP/6-31+G**
BHandHLYP/6-311G**
B3LYP/6-31+G**
pe-Ii → trans-IIi
pa-Ii → cis-IIi (eq)
Ij → IIj
Ik + propene → VIII
BHandHLYP/6-31+G**
BHandHLYP/6-311G**
Fig. 7 Potential energy curves E(x) for reaction associated with an
energy change ΔRE across a barrier ΔE‡, having an intrinsic barrier ΔE‡ ,
according to Marcus-theory, and harmonic potentials of the identical
i
Fig. 6 Match plot of B3LYP/6-31+G**-computed transition structures
TS-cis-Ii (3T4) (blue) and TS-Ij (2T3) (yellow).
curvature for the initial (x = 0) and final state (x = 1).
B3LYP-calculations translate into a x‡-value of 0.2 for position-
ing transition structures on the respective reaction coordinates
for C,O-addition (eqn (2)). Transition structures predicted
from BHandHLYP-calculated energies are positioned later on
the same reaction coordinate (x‡ = 0.3–0.5), due to higher bar-
riers ΔE‡. Considering the magnitude of the experimental rate
constant kadd = 5 × 108 s−1 for the 4-pentenoxyl 5-exo-cycliza-
tion Ij → IIj2 and computed significant reaction energies, we
expect transition structures of alkoxyl radical additions in
extension to the Hammond-postulate66 to be localized early on
a reaction coordinate, rather than midway between reactant I
and product II.
4-pentenoxyl radical 5-exo-cyclization Ij → IIj (−18 kJ mol−1
;
B3LYP/6-31+G**), and the barrier for methoxyl radical addition
to the inner carbon of propene (−23 kJ mol−1). BHandHLYP-
computed energies lead to more negative thermodynamic bar-
riers, but show otherwise similar trends. From the data we
concluded that the thermodynamic barrier is not the key
parameter for explaining the experimental 2,3-cis-specificity of
verbenylethyloxyl radical cyclization.
(xi) The role of the intrinsic barrier. Intrinsic barriers mod-
elled for 2,3-cis-cyclization of cyclohexenylethyloxyl radical Ii
(ΔE‡ = 35–37 kJ mol−1, B3LYP; for BHandHLYP-calculated
i
values, refer to Table 10) and 5-exo-cyclization of 4-pentenoxyl
radical Ij (37 kJ mol−1) are marginally smaller than the intrin-
sic barrier for methoxyl radical addition to the inner carbon of
propene (43 kJ mol−1). An intrinsic barrier of 90 kJ mol−1 pre-
dicted for 2,3-trans-cyclization of the cyclohexenylethyloxyl
radical Ii exceeds the value for the barriers of all other investi-
gated oxygen radical additions in the study by far. From this
information we concluded that the experimentally observed
2,3-cis-stereospecificity of the verbenylethyloxyl radical cycliza-
(x) The role of the thermodynamic barrier. In transition struc-
tures associated with alkoxyl radical addition to alkenes, inci-
pient carbon–oxygen bond formation and carbon–carbon
π-bond breaking in summary is exothermic, lowering the
intrinsic barrier by a thermodynamic contribution of −19 to
−20 kJ mol−1. This thermodynamic barrier ΔE‡ is surpris-
TD
ingly similar for 2,3-cis- and 2,3-trans-ring cyclization of cyclo-
hexenylethyloxyl radical Ii (−16 to −20 kJ mol−1), the
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tion originates from a large intrinsic barrier associated with
the 2,3-trans-ring closure.
4. Experimental
4.1. General
For general laboratory practice and instrumentation see ref. 42
and the ESI.‡
3. Concluding remarks
4.2. General methods
Cycloalkyl-fused and -bridged 4-pentenoxyl radicals provide
4.2.1 3-Hydroxy-4-methylthiazole-2(3H)-thione tetraethyl-
bicyclic and tricyclic tetrahydrofurans by 5-exo-cyclizations. ammonium salt (MTTO−NEt4 ). A solution of 3-hydroxy-4-
The selectivity determining step is the intramolecular oxygen methylthiazole-2(3H)-thione (MTTOH; 1.3 mmol) in methanol
radical addition to the carbon–carbon double bond, occurring (2 mL) was treated at 20 °C with a 1.5 M solution of tetraethyl-
in most instances with notable stereochemical preference. ammonium hydroxide in methanol (0.87 mL, 1.3 mmol) and
From the observed stereoselectivities we concluded that a stirred for 1 hour. The solvent was removed under reduced
system exists, which can be summed up by two new directives pressure and the residue was freeze-dried for 12–14 hours.
+
for predicting the stereochemical outcome of similar cycliza-
4.2.2 Synthesis of O-alkenylthiohydroxamates. A suspen-
tions not exemplified in this article. The new guidelines sup- sion of 3-hydroxy-4-methylthiazole-2(3H)-thione tetraethyl-
plement the set of existing directives, developed for predicting ammonium salt (1.3 mmol) in anhydrous dimethyl
the major products in synthesis of monocyclic disubstituted formamide (1 mL) was treated at 20 °C with a solution of an
tetrahydrofurans by the oxygen radical method.7,14,67
alkenyl p-toluenesulfonate (1 mmol) in anhydrous dimethyl
The first of the new guidelines ranks the hierarchy of two formamide (1 mL) for the time span specified in section
similarly sized stereoinductors by the distance between the 3. The resulting solution was stirred at 20 °C or 40–50 °C (for
alkyl group and the alkene carbon which is being approached specific information, see synthetic procedures in section 4.3)
by the oxygen radical. This guideline states that the substituent diluted with dichloromethane (10 mL) and washed with an
positioned the closest to the attacked alkene carbon is the aqueous 2 M solution of sodium hydroxide (10 mL) and water
principal (primary) inductor, guiding 5-exo-cyclization 2,3- (3 × 10 mL). The organic layer was separated, dried (MgSO4),
trans- and 2,4-cis-selectively. The substituent bound further and concentrated under reduced pressure to leave a residue,
from the attacked π-bond is the secondary inductor, enhancing which was purified by chromatography (SiO2) or crystallized
stereodifferentiation exerted by the principal inductor in the (solvent specification in section 4.3).
case of the trans-configuration, and decreasing this effect in
the case of the cis-configuration. A secondary inductor is not
4.3 3-Alkenyloxy-4-methylthiazole-2(3H)-thiones
able to overrule the guiding effect of a similarly sized primary
inductor. The first guideline applies to 5-exo-cyclization of thiazole-2(3H)-thione cis-(1a). From trans-2-(prop-2-en-1-yl)-
type-A and type-B 4-pentenoxyl radicals (Fig. 1). cyclopent-1-yl 4-toluenesulfonate (4.22 g, 15.1 mmol); reaction
4.3.1 3-[cis-2-(Prop-2-en-1-yl)-cyclopent-1-yloxy]-4-methyl-
The second new directive states that 4-pentenoxyl radical time: 72 hours at 20 °C, the eluent used for chromatography:
5-exo-cyclization to a cyclohexene-bound exo-methylene group dichloromethane–pentane = 2 : 1 (v/v), Rf = 0.51. Yield: 2.67 g
or an endocyclic double bond occurs cis-specifically. The (10.5 mmol, 70%), colorless oil.36 1H-NMR (CDCl3, 600 MHz)
second guideline refers to intramolecular addition of type-C–E δ 1.60–1.75 (m, 3 H), 1.80–1.84 (m, 1 H), 1.87–1.93 (m, 2 H),
radicals (Fig. 1).
2.03–2.06 (m, 1 H), 2.22 (d, J = 1.2 Hz, 3 H), 2.22–2.27 (m, 1 H),
From the hierarchy of similar-sized inductors we expect a 2.67–2.71 (m, 1 H), 4.99–5.01 (m, 1 H), 5.08 (dq, Jd = 17.0, Jq =
substituent located in position 3 to also control the stereo- 1.7 Hz, 1 H), 5.74–5.77 (m, 1 H), 5.98–6.05 (m, 1 H), 6.16 (q, J =
selectivity in 5-exo-cyclization of 4-pentenoxyl radicals having 0.9 Hz, 1 H). 13C-NMR (CDCl3, 150 MHz) δ 13.8, 21.8, 29.2,
similar sized substituents attached to carbons 1, 2, and 29.3, 30.1, 45.2, 88.2, 102.9, 115.4, 137.9, 139.2, 181.0. UV
3. According to the first new guideline, a group in position 2 (methanol): λmax (lg ε/m2 mol−1) 319 nm (3.14), 210 nm (3.05).
will be secondary and a group in position 1 the least effective, Anal. Calcd for C12H17NOS2 (255.40): C, 56.43; H, 6.71; N, 5.48;
the tertiary inductor. From today’s point of view we expect the S, 25.11; Found: C, 56.48; H, 6.56; N, 5.68; S, 25.27.
stereoisomer of a 1,2,3-substituted 4-pentenoxyl radical corres-
4.3.2 3-[trans-2-(Prop-2-en-1-yl)-cyclopent-1-yloxy]-4-methyl-
ponding to an all-trans-configured type-A and type-B radical to thiazole-2(3H)-thione trans-(1a). From cis-2-(prop-2-en-1-yl)-
cyclize with notable 2,3-trans-, 2,4-cis-, and 2,5-trans-selectivity, cyclopent-1-yl 4-toluenesulfonate (1.85 g, 6.60 mmol); reaction
possibly providing a single diastereomer. In the same model, a time: 1 hour at 45 °C; the eluent used for chromatography:
sterically more demanding substituent in position 2, for diethyl ether–pentane = 1 : 1 (v/v), Rf = 0.38. Yield: 1.13 g
example tert-butyl, should be able to overrule the effect of a (4.42 mmol, 67%), yellow oil.36 1H-NMR (CDCl3, 400 MHz)
smaller group in position 3, such as methyl. Stereochemical δ 1.28–1.37 (m, 1 H), 1.67–1.84 (m, 3 H), 1.86–1.93 (m, 1 H),
questions of this kind attracted our attention and are being 1.98–2.09 (m, 1 H), 2.21–2.30 (m, 2 H), 2.24 (d, J = 1.2 Hz, 3 H),
pursued at the moment in our laboratory, with the aim to 2.22–2.27 (m, 1 H), 4.97–5.05 (m, 2 H), 5.43–5.46 (m, 1 H), 5.78
provide new solutions to synthesis of functionalized ethers (ddt, Jd = 17.0, 10.2, Jt = 6.8 Hz, 1 H), 6.16 (q, J = 1.4 Hz, 1 H).
from oxygen radical addition to alkenes.
13C-NMR (CDCl3, 100 MHz) δ 14.1, 23.2, 30.4, 30.6, 37.6, 43.7,
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92.1, 102.9, 116.3, 136.4, 138.8, 181.0. UV (methanol): λmax standing at −18 °C. M.p. = 61–62 °C. 1H-NMR (CDCl3,
(lg ε/m2 mol−1) 319 nm (3.17), 208 nm (3.09). Anal. Calcd for 400 MHz) δ 1.34–1.65 (m, 6 H), 1.67–1.79 (m, 2 H), 2.16–2.22
C12H17NOS2 (255.40): C, 56.43; H, 6.71; N, 5.48; S, 25.11; (m, 1 H), 2.23 (d, J = 1.2 Hz, 3 H), 2.50 (dq, Jd = 8.3, Jq = 4.1 Hz,
Found: C, 56.49; H, 6.85; N, 5.46; S, 24.96.
1 H), 4.18 (dt, Jd = 23.0, Jt = 7.1 Hz, 2 H), 4.98–5.12 (m, 2 H),
4.3.3 3-[cis-2-(3-Methylbut-2-en-1-yl)-cyclopent-1-yloxy]-4- 6.02 (ddd, J = 17.1, 10.4, 8.4 Hz, 1 H), 6.14 (d, J = 1.2 Hz, 1 H).
methylthiazole-2(3H)-thione cis-(1b). From [trans-2-(3-methyl- 13C-NMR (CDCl3, 100 MHz) δ 13.5, 22.2, 24.3, 25.5, 30.5, 38.5,
but-2-en-1-yl)-cyclopent-1-yl] 4-toluenesulfonate (2.48 g, 40.9, 78.2, 102.6, 115.8, 137.7, 138.4, 180.2. UV (methanol):
8.04 mmol); reaction time: 21 hours at 20 °C; the eluent used λmax (lg ε/m2 mol−1) 316 nm (3.19), 206 nm (3.11). Anal. Calcd
for chromatography: diethyl ether–pentane = 1 : 2 (v/v), Rf = for C13H19NOS2 (269.42): C, 57.96; H, 7.11; N, 5.20; S, 23.80;
0.30. Yield: 1.49 g (5.26 mmol, 65%), colorless oil. 1H-NMR Found: C, 57.89; H, 6.94; N, 5.20; S, 23.44.
(CDCl3, 400 MHz) δ 1.59–1.76 (m, 3 H), 1.64 (s, 3 H), 1.71 (s,
4.3.7 3-[trans-2-(Eth-1-en-1-yl)-cyclohex-1-ylmethyloxy]-4-
3 H), 1.77–2.03 (m, 4 H), 2.18–2.30 (m, 1 H), 2.23 (d, J = 1.4 Hz, methylthiazole-2(3H)-thione trans-(1d). From [trans-2-(eth-1-
3 H), 2.47–2.59 (m, 1 H), 5.33 (ddt, Jd = 7.9, 6.5, Jt = 1.5 Hz, en-1-yl)-cyclohex-1-ylmethyl] 4-toluenesulfonate (650 mg,
1 H), 5.72 (td, Jt = 4.5, Jd = 1.7 Hz, 1 H), 6.15 (d, J = 1.4 Hz, 2.20 mmol); reaction time: 3 h at 40 °C; the eluent used for
1 H). 13C-NMR (CDCl3, 100 MHz) δ 13.8, 17.9, 21.9, 25.8, 27.1, chromatography: diethyl ether–pentane = 1 : 2 (v/v), Rf = 0.33.
29.1, 29.4, 46.0, 88.5, 102.8, 123.5, 132.0, 139.2, 181.0. UV Yield: 466 mg (1.73 mmol, 79%), yellow oil, which crystallizes
(methanol): λmax (lg ε/m2 mol−1) 318 nm (3.14), 205 nm (3.16). from diethyl ether to afford colorless crystals. M.p. = 51–52 °C.
Anal. Calcd for C14H21NOS2 (283.45): C, 59.32; H, 7.47; N, 4.94; 1H-NMR (CDCl3, 400 MHz) δ 1.14–1.41 (m, 4 H), 1.65–1.82 (m,
S, 22.62; Found: C, 59.33; H, 7.38; N, 5.03; S, 22.47.
4 H), 1.84–1.96 (m, 1 H), 2.14–2.29 (m, 1 H), 2.24 (d, J = 1.0 Hz,
4.3.4 3-[cis-2-(Prop-2-en-1-yl)-cyclohex-1-yloxy]-4-methyl- 3 H), 4.10 (t, J = 7.6 Hz, 1 H), 4.41 (dd, J = 7.3, 3.4 Hz, 1 H),
thiazole-2(3H)-thione cis-(1c). From [trans-2-(prop-2-en-1-yl- 4.97–5.04 (m, 2 H), 5.71 (ddd, J = 17.2, 10.0, 9.1 Hz, 1 H), 6.13
cyclohex-1-yl] 4-toluenesulfonate (6.30 g, 21.4 mmol); reaction (d, J = 0.7 Hz, 1 H). 13C-NMR (CDCl3, 100 MHz) δ 13.5, 25.4,
time: 13 days at 40 °C; the eluent used for chromatography: 25.6, 29.5, 33.5, 41.0, 44.6, 79.3, 102.6, 114.9, 137.7, 142.2,
diethyl ether–pentane = 1 : 2 (v/v), Rf = 0.28. Conversion 84%. 180.3. UV (methanol): λmax (lg ε/m2 mol−1) 317 nm (3.13),
Yield: 637 mg (2.36 mmol, 11%), colorless oil. 1H-NMR 208 nm (3.05). Anal. Calcd for C13H19NOS2 (269.42): C, 57.96;
(CDCl3, 600 MHz) δ 1.23–1.49 (m, 4 H), 1.54–1.83 (m, 4 H), H, 7.11; N, 5.20; S, 23.80; Found: C, 57.92; H, 7.05; N, 5.20; S,
2.09–2.38 (m, 2 H), 2.25 (s, 3 H), 2.55–2.62 (m, 1 H), 4.99–5.08 23.70.
(m, 2 H), 5.25–5.32 (m, 1 H), 5.73–5.84 (m, 1 H), 6.16 (d, J =
4.3.8 3-[cis-2-(2-Methylprop-1-en-1-yl)-cyclohex-1-ylmethyl-
1.2 Hz, 1 H). 13C-NMR (CDCl3, 150 MHz) δ 14.2, 20.4, 23.8, oxy]-4-methylthiazole-2(3H)-thione cis-(1e). From [cis-2-(2-
26.1, 26.7, 30.5, 37.5, 85.2, 102.8, 116.1, 137.2, 139.1, 180.7. UV methylprop-1-en-1-yl)-cyclohex-1-ylmethyl] 4-toluenesulfonate
(methanol): λmax (lg ε/m2 mol−1) 318 nm (3.18), 210 nm (3.12). (1.06 g, 3.28 mmol); reaction time: 4 hours at 50 °C; the eluent
Anal. Calcd for C13H19NOS2 (269.42): C, 57.96; H, 7.11; N, 5.20; used for chromatography: diethyl ether–pentane = 1 : 2 (v/v),
S, 23.80; Found: C, 57.94; H, 7.34; N, 5.47; S, 23.73.
Rf = 0.31. Yield: 761 mg (2.56 mmol, 78%), colorless oil, color-
4.3.5 3-[trans-2-(Prop-2-en-1-yl)-cyclohex-1-yloxy]-4-methyl- less crystals on standing at 20 °C. M.p. = 78 °C. 1H-NMR
thiazole-2(3H)-thione trans-(1c). From [cis-2-(prop-2-en-1-yl)- (CDCl3, 400 MHz) δ 1.29–1.56 (m, 6 H), 1.62 (d, J = 1.5 Hz, 3 H)
cyclohex-1-yl] 4-toluenesulfonate (1.63 g, 5.54 mmol); reaction 1.67–1.81 (m, 2 H), 1.71 (d, J = 1.5 Hz, 3 H), 2.11–2.25 (m, 1 H),
time: 3 hours at 45 °C; the eluent used for chromatography: 2.21 (d, J = 1.4 Hz, 3 H), 2.71–2.80 (m, 1 H), 4.15 (d, J = 6.8 Hz,
diethyl ether–pentane = 1 : 2 (v/v), Rf = 0.32. Yield: 412 mg 2 H), 5.35 (ddt, Jd = 9.8, 3.0, Jt = 1.5 Hz, 1 H), 6.13 (q, J =
(1.53 mmol, 28%), colorless oil, which crystallizes on standing 1.4 Hz, 1 H). 13C-NMR (CDCl3, 100 MHz) δ 13.1, 18.0, 21.9,
at 20 °C. M.p. = 62–63 °C. 1H-NMR (CDCl3, 400 MHz) 24.8, 25.0, 26.2, 31.8, 34.3, 38.9, 78.9, 102.5, 123.5, 132.9,
δ 1.03–1.13 (m, 1 H), 1.14–1.30 (m, 2 H), 1.32–1.44 (m, 1 H), 137.8, 180.3. UV (methanol): λmax (lg ε/m2 mol−1) 316 nm
1.61–1.73 (m, 2 H), 1.73–1.84 (m, 2 H), 1.87–1.96 (m, 1 H), 2.13 (3.10), 204 nm (3.18). Anal. Calcd for C15H23NOS2 (297.48):
(dt, Jd = 14.3, Jt = 8.3 Hz, 1 H), 2.24 (d, J = 1.2 Hz, 3 H), 2.83 C, 60.56; H, 7.79; N, 4.71; S, 21.55; Found: C, 60.43; H, 7.68; N,
(dddd, J = 14.1, 4.8, 3.4, 1.9 Hz, 1 H), 4.94–5.15 (m, 3 H), 4.76; S, 21.43.
5.79–5.97 (m, 1 H), 6.15 (d, J = 1.2 Hz, 1 H). 13C-NMR (CDCl3,
4.3.9 3-[trans-2-(2-Methylprop-1-en-1-yl)-cyclohex-1-ylmethyl-
100 MHz) δ 14.1, 24.2, 25.0, 30.19, 30.23, 36.4, 41.8, 86.0, oxy]-4-methyl-thiazole-2(3H)-thione trans-(1e). From [trans-2-
102.8, 116.3, 136.8, 139.2, 180.7. UV (methanol): λmax (lg ε/m2 (2-methylprop-1-en-1-yl)-cyclohex-1-ylmethyl] 4-toluenesulfo-
mol−1
)
318 nm (3.14), 211 nm (3.04). Anal. Calcd for nate (2.72 g, 8.44 mmol); reaction time: 2 hours at 45 °C; the
C13H19NOS2 (269.42): C, 57.96; H, 7.11; N, 5.20; S, 23.80; eluent used for chromatography: diethyl ether–pentane = 1 : 2
Found: C, 58.16; H, 7.16; N, 5.19; S, 23.67. (v/v), Rf = 0.31. Yield: 1.86 g (6.25 mmol, 74%), yellow oil,
4.3.6 3-[cis-2-(Eth-1-en-1-yl)-cyclohex-1-ylmethyloxy]-4-methyl- which was crystallized from ethyl acetate to afford a colorless
1
thiazole-2(3H)-thione cis-(1d). From [cis-2-(eth-1-en-1-yl)-cyclo- solid. M.p. = 47–48 °C. H-NMR (CDCl3, 400 MHz) δ 1.01–1.15
hex-1-ylmethyl] 4-toluenesulfonate (1.50 g, 5.10 mmol); (m, 1 H), 1.20–1.40 (m, 3 H), 1.54–1.86 (m, 4 H), 1.57 (d, J =
reaction time: 3 hours at 50 °C; the eluent used for chromato- 1.0 Hz, 3 H), 1.67 (d, J = 0.7 Hz, 3 H), 1.98–2.11 (m, 1 H),
graphy: diethyl ether–pentane = 1 : 2 (v/v), Rf = 0.33. Yield: 2.14–2.29 (m, 1 H), 2.22 (d, J = 1.2 Hz, 3 H), 4.07 (t, J = 7.6 Hz,
1.03 g (3.81 mmol, 75%), colorless oil, which crystallizes on 1 H), 4.35 (dd, J = 7.3, 3.2 Hz, 1 H), 4.97 (dt, Jd = 9.3, Jt =
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1.5 Hz, 1 H), 6.12 (d, J = 1.5 Hz, 1 H). 13C-NMR (CDCl3, 180.4. Anal. Calcd for C16H23NOS2 (309.49): C, 62.09; H, 7.49;
100 MHz) δ 13.2, 18.1, 25.6, 25.7, 25.8, 29.9, 33.4, 38.7, 42.1, N, 4.53; S, 20.72; Found: C, 61.81; H, 7.51; N, 4.56; S, 21.09.
79.5, 102.5, 128.8, 131.7, 137.8, 180.2. UV (methanol): λmax
4.4 Alkoxyl radical reactions
(lg ε/m2 mol−1) 317 nm (3.13), 209 nm (3.02). Anal. Calcd for
C15H23NOS2 (297.48): C, 60.56; H, 7.79; N, 4.71; S, 21.55;
Found: C, 60.41; H, 7.73; N, 4.74; S, 21.47.
4.4.1 Photochemical reactions. A solution of 3-alkoxythi-
azolethione 1 (1.00 mmol, c01 = 0.17 M) and BrCCl3 (10 mmol,
4.3.10 3-[2-(1-Methylenecyclohex-2-yl)-eth-1-yl-2-oxy]-4-methyl- c0BrCCl3 = 1.67 M) in dry C6H6 (6 mL) was photolyzed at ∼25 °C
thiazole-2(3H)-thione (1f). From [2-(1-methylenecyclohex-2-yl)- in a Rayonet® chamber reactor equipped with twelve 350 nm
ethyl] 4-toluenesulfonate (3.60 mg, 12.2 mmol); reaction time: illuminants, until the starting material was completely con-
1 hour at 50 °C; the eluent used for chromatography: diethyl sumed (∼30 min, tlc). The solution was concentrated under
ether–pentane = 1 : 1 (v/v), Rf = 0.39. Yield: 2.57 g (9.54 mmol, reduced pressure (10 mbar, 40 °C) to leave an oil, which was
78%), yellow oil. 1H-NMR (CDCl3, 400 MHz) δ 1.25–1.38 (m, purified by chromatography (SiO2).
1 H), 1.42–1.55 (m, 2 H), 1.56–1.74 (m, 2 H), 1.76–1.89 (m,
4.4.2 Thermal reactions. A solution of 3-alkoxythiazol-
2 H), 2.03 (ddd, J = 13.0, 8.5, 4.5 Hz, 1 H), 2.14 (td, Jt = 14.1, ethione 1 (1.00 mmol, c01 = 0.17 M), BrCCl3 (10 mmol, cB0rCCl3
=
Jd = 7.2 Hz, 1 H), 2.20–2.39 (m, 2 H), 2.27 (d, J = 1.2 Hz, 3 H), 1.67 M), and AIBN (25 mol%) in dry C6H6 (6 mL) was heated to
4.38 (q, J = 7.3 Hz, 1 H), 4.45 (q, J = 7.3 Hz, 1 H), 4.60 (s, 1 H), 80 °C for 30 min. After complete consumption of 1 (tlc), the
4.70 (s, 1 H), 6.15 (d, J = 1.2 Hz, 1 H). 13C-NMR (CDCl3, solvent was removed under reduced pressure (10 mbar, 40 °C)
100 MHz) δ 13.4, 24.1, 28.6, 30.0, 34.0, 34.7, 39.4, 74.8, 102.6, to leave a residue, which was purified by chromatography
106.1, 137.7, 151.6, 180.3. UV (methanol): λmax (lg ε/m2 mol−1
316 nm (3.18), 206 nm (3.10). Anal. Calcd for C13H19NOS2
(269.42): C, 57.96; H, 7.11; N, 5.20; S, 23.80. Found: C, 57.74; 1-yloxy]-4-methylthiazole-2(3H)-thione cis-(1a). Photochemical
H, 7.12; N, 5.14; S, 23.93. reaction. cis-1a 528 mg (2.07 mmol); the eluent used for
)
(SiO2).
4.4.3 Conversion of 3-[cis-2-(prop-2-en-1-yl)-cyclopent-
4.3.11 3-[(1-Methylcyclohex-1-en-4-yl)-methyloxy]-4-methyl- column chromatography: diethyl ether–pentane = 1 : 5 (v/v).
thiazole-2(3H)thione (1g). From [(1-methylcyclohex-1-en-4-yl)- 3-Bromomethyl-2-oxabicyclo[3.3.0]octane cis-(3a). Yield: 42.3 mg
methyl] 4-toluenesulfonate (4.20 g, 15.0 mmol); reaction time: (206 µmol, 10%), yellow liquid, 70/30-mixture of 1,3-cis/trans-
75 hours at 20 °C or 2 hours at 40 °C. Yield: 3.13 g (12.3 mmol, isomers, i.e. rel-(1S,3S,5S)-3a/rel-(1S,3R,5S)-3a. Rf = 0.48 for
82%), yellow oil, which was crystallized from methanol–ethyl diethyl ether–pentane = 1 : 5 (v/v). Anal. Calcd for C8H13BrO
acetate [2/1 (v/v)] to afford colorless crystals. M.p. 99–100 °C. (205.09): C, 46.85; H, 6.39; Found: C, 46.73; H, 6.40. rel-
1
1H-NMR (CDCl3, 400 MHz) δ 1.40–1.49 (m, 1 H), 1.63 (s, 3 H), (1S,3S,5S)-3a: H-NMR (CDCl3, 400 MHz) δ 1.37–1.47 (m, 1 H),
1.86–2.02 (m, 4 H), 2.09–2.25 (m, 2 H), 2.26 (d, J = 1.2 Hz, 3 H), 1.50–1.68 (m, 3 H), 1.69–1.92 (m, 3 H), 1.98 (ddd, J = 12.8, 8.7,
4.22–4.32 (m, 2 H), 5.34–5.44 (m, 1 H), 6.16 (d, J = 1.2 Hz, 1 H). 7.2 Hz, 1 H), 2.68–2.75 (m, 1 H), 3.29–3.36 (m, 1 H), 3.36–3.42
13C-NMR (CDCl3, 100 MHz) δ 13.4, 23.5, 25.5, 28.1, 29.0, 32.5, (m, 1 H), 4.23 (quin, J = 6.2 Hz, 1 H), 4.60 (t, J = 4.8 Hz, 1 H).
74.8, 102.7, 119.1, 134.0, 137.7, 180.3. UV (methanol): λmax 13C-NMR (CDCl3, 100 MHz): δ 24.6, 32.8, 34.7, 35.5, 38.4, 42.8,
(lg ε/m2 mol−1) 317 nm (3.11), 206 nm (3.06). Anal. Calc. for 78.8, 85.7. rel-(1S,3R,5S)-3a: 1H-NMR (CDCl3, 400 MHz)
C12H17NOS2 (255.39): C, 56.43; H, 6.71; N, 5.49; S, 25.11; δ 1.16–1.30 (m, 1 H), 1.37–1.47 (m, 1 H), 1.50–1.68 (m, 3 H),
Found: C, 56.34; H, 6.69; N, 5.46; S, 25.26. X-ray crystallogra- 1.69–1.92 (m, 2 H), 2.22–2.35 (m, 1 H), 2.65–2.78 (m, 1 H), 3.44
phy. T = 150(2) K, λ = 0.71073 Å, monoclinic, P21/n, a = 9.1980(3) (d, J = 5.5 Hz, 2 H), 3.89 (dq, Jd = 10.3, Jq = 5.3 Hz, 1 H), 4.45 (t,
Å, b = 13.3225(3) Å, c = 10.6301(3) Å, β = 100.318(3)°, Z = 4, J = 6.3 Hz, 1 H). 13C-NMR (CDCl3, 100 MHz). δ 23.3, 33.2, 33.8,
µ = 0.395 mm−1, completeness 99.6% (2θ = 57.0), goodness-of- 34.6, 39.3, 42.9, 78.8, 85.8. 4-Methyl-2-(trichloromethylsulfanyl)-
fit on F2 = 1.009; final R indices [I > 2σ(I)]: R1 = 0.0373, wR2 = thiazole (2). Yield: 438 mg (1.76 mmol, 85%), yellow liquid.
0.0891.
Rf = 0.40 for diethyl ether–pentane = 1 : 5 (v/v). 1H-NMR
4.3.12 3-[{(1S,4S,5R)-2,6,6-Trimethyl-bicyclo[3.1.1]-hept-2- (CDCl3, 400 MHz) δ 2.57 (s, 3 H), 7.30 (s, 1 H). 13C-NMR
en-4-yl}eth-1-yl-2-oxy]-4-methylthiazole-2(3H)-thione (1h). From (CDCl3, 100 MHz) δ 17.3, 96.9, 122.6, 153.2, 155.8. Anal. Calcd
[2-{(1S,4S,5R)-2,6,6-trimethylbicyclo-[3.1.1]hept-2-en-4-yl]}-ethyl] for C5H4NCl3S2 (248.57): C, 24.16; H, 1.62; N, 5.64; S, 25.80.
4-toluenesulfonate (686 mg, 2.05 mmol); reaction time: Found: C, 24.17; H, 1.82; N, 5.70; S, 25.50. 5-Bromoct-7-enal
20 hours at 20 °C; the eluent used for chromatography: diethyl (4a). Yield: 253.6 mg (1.24 mmol, 60%), yellow liquid. Rf = 0.28
ether–pentane = 1 : 2 (v/v), Rf = 0.28. Yield: 463 mg (1.50 mmol, for diethyl ether–pentane
=
1 : 5 (v/v). 1H-NMR (CDCl3,
73%) colorless oil, which crystallizes on standing at 20 °C. 600 MHz) δ 1.71–1.97 (m, 4 H), 2.43–2.54 (m, 2 H), 2.62 (t, J =
[α]2D5 = −52.9 (c = 1.02/ethanol). 1H-NMR (CDCl3, 600 MHz) 6.6 Hz, 2 H), 3.91–4.11 (m, 1 H), 5.10–5.18 (m, 2 H), 5.84
δ 0.86 (s, 3 H), 1.15 (d, J = 9.0 Hz, 1 H), 1.29 (s, 3 H), 1.67 (t, J = (ddt, Jd = 17.0, 10.3, Jt = 6.9 Hz, 1 H), 9.78 (t, J = 1.6 Hz, 1 H).
1.7 Hz, 3 H), 1.79 (dq, Jd = 14.0, Jq = 7.0 Hz, 1 H), 1.89 (dq, Jd = 13C-NMR (CDCl3, 100 MHz) δ 20.1, 37.5, 43.0, 43.2, 55.3,
13.8 Hz, Jq = 6.9 Hz, 1 H), 1.95–2.05 (m, 2 H), 2.21 (dt, Jd = 8.8, 118.1, 134.5, 201.8. HRMS (EI+) m/z 204.0149/206.0124 (M+);
Jt = 5.6 Hz, 1 H), 2.28 (d, J = 1.0 Hz, 3 H), 2.48–2.57 (m, 1 H), calculated mass for C8H13OBr+: 204.0150/206.0129. Thermal
4.41–4.52 (m, 2 H), 5.19 (d, J = 0.8 Hz, 1 H), 6.15 (d, J = 1.0 Hz, reaction. cis-1a 526 mg (2.06 mmol). Eluent used for
1 H). 13C-NMR (CDCl3, 150 MHz) δ 13.5, 20.4, 22.9, 26.5, 27.8, column chromatography: diethyl ether–pentane = 1 : 5 (v/v).
31.6, 36.4, 40.8, 45.1, 47.6, 75.0, 102.7, 119.3, 137.7, 145.5, 3-Bromomethyl-2-oxabicyclo[3.3.0]octane cis-(3a). Yield: 33.4 mg
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(163 µmol, 8%), yellow liquid, 71/29-mixture of 1,3-cis/trans- 2.63–2.75 (m, 1 H), 3.91 (dd, J = 8.0, 6.6 Hz, 1 H), 4.61–4.67 (m,
isomers, i.e. rel-(1S,3S,5S)-3a/rel-(1S,3R,5S)-3a. 4-Methyl-2-(tri- 1 H). 13C-NMR (CDCl3, 100 MHz) δ 24.9, 30.1, 30.8, 33.0, 34.9,
chloromethylsulfanyl)-thiazole (2). Yield: 446 mg (1.80 mmol, 36.8, 43.5, 69.3, 86.7, 87.2. 4-Methyl-2-(trichloromethylsulfanyl)-
87%), yellow liquid. 5-Bromoct-7-enal (4a). Yield: 230 mg thiazole (2). Yield: 190 mg (764 μmol, 73%), pale yellow liquid.
(1.12 mmol, 54%), yellow liquid.
5-Brom-8-methylnon-7-enal (4b). Yield: 75.6 mg (324 μmol,
4.4.4 Conversion of 3-[trans-2-(prop-2-en-1-yl)-cyclopent-1- 31%), pale yellow liquid. Rf = 0.25 for diethyl ether–pentane =
yloxy]-4-methylthiazole-2(3H)-thione trans-(1a). Photochemical 1 : 5 (v/v). 1H-NMR (CDCl3, 400 MHz) δ 1.62 (s, 3 H), 1.72 (s,
reaction: trans-1a 203 mg (795 µmol); eluent used for column 3 H), 1.76–2.02 (m, 4 H), 2.37–2.68 (m, 4 H), 3.93–4.03 (m,
chromatography: diethyl ether–pentane = 1 : 5 (v/v). 4-Methyl-2- 1 H), 5.17 (t, J = 7.0 Hz, 1 H), 9.78 (s, 1 H). 13C-NMR (CDCl3,
(trichloromethylsulfanyl)-thiazole (2). Yield: 110 mg (443 μmol, 150 MHz) δ 18.1, 20.3, 25.8, 37.5, 37.8, 43.1, 56.9, 120.5, 134.8,
56%), yellow liquid. 5-Bromoct-7-enal (4a). Yield: 72.5 mg 201.9. HRMS (EI+) m/z 232.0463/234.0452 (M+); calculated
(354 μmol, 44%), yellow liquid. Unlike-5,7-dibromo-9,9,9-tri- mass for C10H17OBr+: 232.0463/234.0442. Thermal reaction. cis-
chlorononanal. Yield: 9.3 mg (23.1 μmol, 3%), yellow liquid. 1b 292 mg (1.03 mmol); eluent used for column chromato-
Rf = 0.22 for diethyl ether–pentane = 1 : 5 (v/v). 1H-NMR graphy: diethyl ether–pentane = 1 : 5 (v/v). 3-(2-Bromoprop-2-yl)-
(CDCl3, 400 MHz) δ 1.72–2.05 (m, 4 H), 2.40–2.67 (m, 4 H), 2-oxoabicyclo[3.3.0]octane cis-3b. Yield: 81.8 mg (351 μmol,
3.23 (dd, J = 15.9, 4.8 Hz, 1 H), 3.47 (dd, J = 16.0, 5.3 Hz, 1 H), 34%), 56/44-mixture of 1,3-cis/trans-isomers, i.e. rel-(1S,3S,5S)-
4.18–4.29 (m, 1 H), 4.37 (ddt, Jd = 8.0, 6.6, Jt = 5.1 Hz, 1 H), 3b/rel-(1S,3R,5S)-3b, yellow oil. 4-Methyl-2-(trichloromethylsulfa-
9.80 (t, J = 1.5 Hz, 1 H). 13C-NMR (CDCl3, 100 MHz) δ 19.6, nyl)-thiazole (2). Yield: 193 mg (776 μmol, 75%), yellow liquid.
35.8, 42.9, 44.8, 48.3, 51.9, 62.3, 96.6, 201.5. HRMS (EI+) 5-Brom-8-methylnon-7-enal (4b). Yield: 84.2 mg (361 μmol,
m/z 400.8288/402.8250 (M
−
H); calculated mass for 35%), yellow liquid.
C9H12OCl3Br2 : 400.8291/402.8261. Like-5,7-dibromo-9,9,9-tri- 4.4.6 Conversion of 3-[cis-(2-prop-2-en-1-yl)-cyclohex-1-
chlorononanal. Yield: 36.8 mg (91.2 μmol, 11%), yellow liquid. yloxy]-4-methylthiazole-2(3H)-thione cis-(1c). Photochemical
+
Rf = 0.20 for diethyl ether–pentane = 1 : 5 (v/v). 1H-NMR reaction: cis-1c 137 mg (508 μmol); eluent used for chromato-
(CDCl3, 600 MHz) δ 1.75–2.01 (m, 4 H), 2.23 (ddd, J = 15.3, graphy: diethyl ether–pentane = 1 : 10 (v/v). 8-(Bromomethyl)-7-
11.6, 2.1 Hz, 1 H), 2.46–2.61 (m, 3 H), 3.24 (dd, J = 15.7, 6.2 Hz, oxabicyclo[4.3.0]nonane cis-(3c). Yield: 50.2 mg (229 μmol,
1 H), 3.57 (dd, J = 15.7, 4.6 Hz, 1 H), 4.21–4.35 (m, 1 H), 4.70 45%), 89/11-mixture of 6,8-cis/trans-isomers i.e. rel-(1S,6S,8S)-
(dddd, J = 11.2, 6.5, 4.4, 2.4 Hz, 1 H), 9.80 (t, J = 1.2 Hz, 1 H). 3c/rel-(1S,6S,8R)-3c, colorless liquid. Rf = 0.44 for diethyl ether–
13C-NMR (CDCl3, 100 MHz) δ 20.0, 38.2, 42.9, 47.5, 48.0, 54.4, pentane = 1 : 10 (v/v). Anal. Calcd for C9H15BrO (219.12): C,
62.6, 96.6, 201.5. HRMS (EI+) m/z 400.8314/402.8297/404.8233 49.33; H, 6.90. Found: C, 49.46; H, 6.80. rel-(1S,6S,8S)-3c.
H); calculated mass for C9H12OCl3Br2 : 400.8300/ 1H-NMR (CDCl3, 400 MHz) δ 1.21–1.29 (m, 1 H), 1.31–1.37 (m,
+
(M
−
402.8312/404.8232. Thermal reaction. trans-1a 250 mg (979 1 H), 1.38–1.45 (m, 1 H), 1.47–1.56 (m, 3 H), 1.57–1.70 (m,
µmol); eluent used for column chromatography: diethyl ether– 2 H), 1.76–1.85 (m, 1 H), 2.12–2.20 (m, 2 H), 3.40 (dd, J = 10.0,
pentane = 1 : 5 (v/v). 4-Methyl-2-(trichloromethylsulfanyl)-thiazole 6.7 Hz, 1 H), 3.53 (dd, J = 10.0, 5.9 Hz, 1 H), 3.91 (q, J = 5.0 Hz,
(2). Yield: 208 mg (836 μmol, 85%), yellow liquid. 5-Bromoct-7- 1 H), 4.15 (quin, J = 6.7 Hz, 1 H). 13C-NMR (CDCl3, 100 MHz)
enal (4a). Yield: 145.5 mg (709 μmol, 73%), yellow liquid. δ 21.4, 23.5, 28.5, 29.0, 36.4, 36.5, 37.6, 77.8, 78.3. rel-
1
Unlike-5,7-dibromo-9,9,9-trichlorononanal. Yield: 19.2 mg (1S,6S,8R)-3c. H-NMR (CDCl3, 400 MHz) δ 1.17–1.70 (m, 7 H),
(47.6 μmol, 5%), yellow liquid. Like-5,7-dibromo-9,9,9-trichloro- 1.76–1.85 (m, 1 H), 1.87–1.94 (m, 2 H), 2.06–2.12 (m, 1 H), 3.39
nonanal. Yield: 34.1 mg (84.5 μmol, 9%), yellow liquid.
4.4.5 Conversion of 3-[cis-2-(3-methylbut-2-en-1-yl)-cyclo- (q, J = 3.8 Hz, 1 H), 4.37–4.43 (m, 1 H). 13C-NMR (CDCl3,
pent-1-yloxy]-4-methylthiazole-2(3H)-thione cis-(1b). Photo- 100 MHz) δ 20.5, 24.0, 27.6, 28.1, 37.2, 37.8, 38.4, 76.4, 77.7.
(dd, J = 6.6, 10.0 Hz, 1 H), 3.47 (dd, J = 10.0, 5.0 Hz, 1 H), 4.05
chemical reaction. cis-1b 296 mg (1.04 mmol); eluent used 4-Methyl-2-(trichloromethylsulfanyl)-thiazole (2). Yield: 92.8 mg
for column chromatography: diethyl ether–pentane = 1 : 5 (v/v). (373 μmol, 73%), colorless liquid. Rf = 0.36 for diethyl ether–
3-(2-Bromoprop-2-yl)-2-oxabicyclo[3.3.0]octane cis-3b. Yield: pentane
= 1 : 10 (v/v). Thermal reaction. cis-1c 81.6 mg
119 mg (510 μmol, 49%), 64/36-mixture of 1,3-cis/trans- (303 μmol); eluent used for chromatography: diethyl ether–
isomers, i.e. rel-(1S,3S,5S)-3b/rel-(1S,3R,5S)-3b, pale yellow oil. pentane
= 1 : 10 (v/v). 8-(Bromomethyl)-7-oxabicyclo[4.3.0]-
Rf = 0.56 for diethyl ether–pentane = 1 : 5 (v/v). HRMS (EI+) m/z nonane cis-(3c). Yield: 40.6 mg (185 μmol, 61%), 68/32-mixture
231.0399/233.0372 (M − H); calculated mass for C10H16OBr+: of 6,8-cis/6,8-trans-isomers, i.e. rel-(1S,6S,8S)-3c/rel-(1S,6S,8R)-
231.0385/233.0364.
rel-(1S,3S,5S)-3b:
1H-NMR
(CDCl3, 3c, colorless liquid. 4-Methyl-2-(trichloromethylsulfanyl)-thiazole
400 MHz) δ 1.35–1.51 (m, 2 H), 1.51–1.67 (m, 3 H), 1.71 (s, (2). Yield: 55.9 mg (225 μmol, 74%), colorless liquid. 6-Bromo-
3 H), 1.75 (s, 3 H), 1.78–1.86 (m, 1 H), 1.91 (dd, J = 13.1, 8-nonenal (4c). Yield: 7.8 mg (36.0 μmol, 12%), yellow oil.
6.0 Hz, 1 H), 2.21 (ddd, J = 12.3, 9.5, 5.5 Hz, 1 H), 2.63–2.75
4.4.7 Conversion of 3-[trans-(2-prop-2-en-1-yl)-cyclohex-1-
(m, 1 H), 3.62 (dd, J = 10.5, 5.4 Hz, 1 H), 4.45 (t, J = 6.3, Hz, yloxy)]-4-methylthiazole-2(3H)-thione trans-(1c). Photochemical
1 H). 13C-NMR (CDCl3, 100 MHz) δ 23.5, 30.3, 30.6, 33.4, 33.9, reaction. trans-1c 139 mg (516 μmol); eluent used for chromato-
37.1, 42.4, 67.0, 85.3, 86.7. rel-(1S,3R,5S)-3b: 1H-NMR (CDCl3, graphy: light petroleum–diethyl ether = 5 : 1 (v/v). 8-(Bromo-
400 MHz) δ 1.35–1.51 (m, 1 H), 1.51–1.76 (m, 6 H), 1.69 (s, methyl)-7-oxabicyclo[4.3.0]nonane28 trans-(3c). Yield: 55.0 mg
3 H), 1.73 (s, 3 H), 2.12 (dt, Jd = 12.9, Jt = 8.5 Hz, 1 H), (251 μmol, 49%), 8/92-mixture of 6,8-cis/6,8-trans-isomers,
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i.e. rel-(1R,6S,8S)-3c/rel-(1R,6S,8R)-3c, colorless liquid. Rf = 0.50 1 H) 3.98–4.06 (m, 1 H). 13C-NMR (CDCl3, 100 MHz) δ 22.4,
for diethyl ether–pentane 1 : 5 (v/v). rel-(1R,6S,8S)-3c: 23.5, 25.4, 25.9, 35.9, 38.4, 41.8, 72.8, 80.6. 4-Methyl-2-(trichloro-
=
1H-NMR (CDCl3, 400 MHz) δ 1.04–1.58 (m, 6 H), 1.67–2.13 (m, methylsulfanyl)-thiazole (2). Yield: 85.3 mg (343 μmol, 71%),
5 H), 3.11 (dt, Jd = 3.7 Hz, Jt = 10.4 Hz, 1 H), 3.34 (dd, J = 6.7, colorless liquid. Thermal reaction. cis-1d 136 mg (505 μmol);
10.1 Hz, 1 H), 3.42 (dd, J = 4.9, 10.1 Hz, 1 H), 4.20–4.24 (m, eluent used for chromatography: diethyl ether–pentane = 1 : 10
1 H). 13C-NMR (CDCl3, 100 MHz) δ 24.2, 25.7, 28.9, 31.2, 35.3, (v/v). 2-Bromo-4-oxabicyclo[4.4.0]decane cis-(5d). Yield: 5.6 mg
36.3, 43.9, 76.7, 84.5. rel-(1R,6S,8R)-3c: 1H-NMR (CDCl3, (25.6 μmol, 5%), i.e. rel-(1S,2S,6R)-5d, yellow liquid. 6,7-cis-7-
400 MHz) δ 1.08–1.53 (m, 6 H), 2.18–2.24 (m, 1 H), 1.69–2.12 Bromomethyl-8-oxabicyclo[4.3.0]nonane cis-(3d). Yield: 19.0 mg
(m, 4 H), 3.23 (dt, Jd = 4.0 Hz, Jt = 10.4 Hz, 1 H), 3.41 (dd, J = (86.7 μmol, 17%), rel-(1R,6S,7R)-3d colorless liquid. 6,7-trans-7-
6.5, 10.1 Hz, 1 H), 3.50 (dd, J = 5.3, 10.1 Hz, 1 H), 4.24–4.30 Bromomethyl-8-oxabicyclo[4.3.0]nonane cis-(3d). Yield: 70.5 mg
(m, 1 H). 13C-NMR (CDCl3, 100 MHz) δ 24.2, 25.5, 28.8, 31.3, (322 μmol, 64%), i.e. rel-(1R,6S,7S)-3d colorless liquid.
36.7, 37.1, 46.3, 77.3, 83.3. Thermal reaction. cis-1c 111 mg 4-Methyl-2-(trichloromethylsulfanyl)-thiazole (2). Yield: 111 mg
(412 μmol); eluent used for chromatography: diethyl ether– (446 μmol, 88%), colorless liquid.
pentane = 1 : 5 (v/v). 8-(Bromomethyl)-7-oxabicyclo[4.3.0]nonane
4.4.9 Conversion of 3-[trans-2-(eth-1-en-1-yl)-cyclohex-1-
trans-(3c). Yield: 63.1 mg (288 μmol, 70%), 13/87-mixture of ylmethyloxy]-4-methylthiazole-2(3H)-thione trans-(1d). Photo-
6,8-cis/trans-isomers, i.e. rel-(1R,6S,8S)-3c/rel-(1R,6S,8R)-3c, pale chemical reaction. trans-1d 276 mg (1.02 mmol); eluent used
yellow liquid. 4-Methyl-2-(trichloromethylsulfanyl)-thiazole (2). for chromatography: diethyl ether–pentane
= 1 : 10 (v/v).
Yield: 81.8 mg (329 μmol, 80%), yellow liquid. 6-Bromo-8- 2-Bromo-4-oxabicyclo[4.4.0]decane trans-(5d). Yield: 11.8 mg
nonenal (4c). Yield: 7.4 mg (33.8 μmol, 8%), yellow oil. 1H-NMR (53.9 μmol, 5%), rel-(1S,2S,6S)-5d colorless liquid. Rf = 0.46 for
1
(CDCl3, 400 MHz) δ 1.36–1.52 (m, 1 H), 1.54–1.74 (m, 3 H), diethyl ether–pentane = 1 : 10 (v/v). H-NMR (CDCl3, 400 MHz)
1.76–1.90 (m, 2 H), 2.47 (dt, Jd = 7.1, Jt = 1.8 Hz, 2 H), 2.61 (tt, δ 0.84–1.04 (m, 2 H), 1.24–1.42 (m, 3 H), 1.44–1.55 (m, 2 H),
J = 6.7, 1.3 Hz, 2 H), 4.02 (dtd, Jd = 8.2, 4.9, Jt = 6.5, Hz, 1 H), 1.73–1.84 (m, 2 H), 2.13–2.23 (m, 1 H), 3.13 (t, J = 10.9 Hz,
5.09–5.19 (m, 2 H), 5.75–5.93 (m, 1 H), 9.78 (t, J = 1.6 Hz, 1 H). 1 H), 3.43–3.57 (m, 1 H), 3.70–3.88 (m, 2 H), 4.12 (dd, J = 11.1,
13C-NMR (CDCl3, 100 MHz) δ 21.4, 27.1, 38.0, 43.3, 43.7, 55.8, 4.7 Hz, 1 H). 13C-NMR (CDCl3, 100 MHz) δ 25.75, 25.83, 27.6,
118.0, 134.7, 202.3. HRMS (EI+) m/z 218.0296/220.0282 (M+); 30.7, 44.1, 49.7, 54.4, 73.2, 73.7. Anal. Calcd for C9H15BrO
calculated mass for C9H15OBr+: 218.0306/220.0286.
4.4.8 Conversion of
3-[cis-2-(eth-1-en-1-yl)-cyclohex-1- (EI+) m/z 218.0298/220.0277 (M+); calculated mass for
ylmethyloxy]-4-methylthiazole-2(3H)-thione
cis-(1d). Photo- C9H15OBr+: 218.0306/220.0286. 4-Methyl-2-(trichloromethylsulfa-
(219.12): C, 49.33; H, 6.90. Found: C, 48.88; H, 6.86. HRMS
chemical reaction. Yield of cis-1d: 131 mg (487 μmol); eluent nyl)-thiazole (2). Yield: 199 mg (801 μmol, 78%), colorless
used for chromatography: diethyl ether–pentane = 1 : 10 (v/v). liquid. 93/7-mixture of exo/endo-isomers 7-Bromomethyl-8-oxa-
2-Bromo-4-oxabicyclo[4.4.0]decane cis-(5d). Yield: 3.5 mg bicyclo[4.3.0]nonane trans-(3d) and 2-Bromo-4-oxabicyclo-[4.4.0]-
(16.0 μmol, 3%), i.e. rel-(1S,2S,6R)-5d, yellow liquid. Rf = 0.46 decane trans-(5d). Yield: 137 mg (624 μmol, 61%), 7/93-mixture
for diethyl ether–pentane = 1 : 10 (v/v). 1H-NMR (CDCl3, of 6,7-cis/trans-isomers, i.e. rel-(1S,6S,7R)-3d/rel-(1S,6S,7S)-3d
600 MHz) δ 1.18–1.53 (m, 6 H), 1.63–1.89 (m, 2 H), 1.97–2.07 and rel-(1S,2R,6S)-5d, colorless liquid. Rf = 0.25 for diethyl
(m, 1 H), 2.09–2.23 (m, 1 H), 3.47 (t, J = 10.8 Hz, 1 H), ether–pentane = 1 : 10 (v/v). Anal. Calcd for C9H15BrO (219.12):
3.57–3.65 (m, 1 H), 3.67–3.76 (m, 1 H), 4.14 (dd, J = 11.1, C, 49.33; H, 6.90. Found: C, 49.04; H, 6.93. rel-(1S,6S,7S)-3d.
4.7 Hz, 1 H), 4.34 (td, Jt = 10.6, Jd = 4.5 Hz, 1 H). 13C-NMR 1H-NMR (CDCl3, 400 MHz) δ 1.03–1.19 (m, 2 H), 1.20–1.38 (m,
(CDCl3, 150 MHz, −37.3 °C) δ 19.7, 25.1, 25.9, 28.5, 39.4, 42.2, 3 H), 1.66–1.97 (m, 5 H), 3.36–3.45 (m, 2 H), 3.52–3.58 (m,
49.5, 73.3, 73.6. HRMS (EI+) m/z 218.0307/220.0286 (M+); calcu- 1 H), 3.71 (ddd, J = 9.7, 5.5, 4.2 Hz, 1 H), 3.96 (t, J = 7.3 Hz, 1 H).
lated mass for C9H15OBr+: 218.0306/220.0286. 7-Bromomethyl- 13C-NMR (CDCl3, 100 MHz) δ 25.3, 25.5, 27.4, 27.7, 35.3, 46.3,
8-oxabicyclo[4.3.0]nonane cis-(3d). Yield: 75.1 mg (343 μmol, 49.7, 72.3, 81.6. rel-(1S,6S,7R)-3d. 1H-NMR (CDCl3, 400 MHz)
70%), colorless liquid, 20/80-mixture of 6,7-cis/6,7-trans- δ 0.98–1.11 (m, 1 H), 1.14–1.28 (m, 3 H), 1.62–1.72 (m, 2 H),
isomers, i.e. rel-(1R,6S,7R)-3d/rel-(1R,6S,7S)-3d. Rf = 0.31 for 1.75–1.97 (m, 4 H), 3.15–3.24 (m, 1 H), 3.25–3.34 (m, 2 H),
diethyl ether–pentane = 1 : 10 (v/v). Anal. Calcd for C9H15BrO 3.97–4.04 (m, 1 H), 4.21–4.29 (m, 1 H). 13C-NMR (CDCl3,
(219.12): C, 49.33; H, 6.90. Found: C, 49.24; H, 6.88. rel- 100 MHz) δ 25.4, 26.0, 26.2, 27.8, 33.9, 42.7, 48.0, 72.7, 79.6.
(1R,6S,7R)-3d. 1H-NMR (CDCl3, 400 MHz) δ 1.13–1.22 (m, 2 H), HRMS (EI+) m/z 125.0940 (M − CH2Br); calculated mass for
1.23–1.39 (m, 1 H), 1.46–1.56 (m, 1 H), 1.57–1.67 (m, 3 H), C8H13O+: 125.0966. rel-(1S,2R,6S)-5d. 1H-NMR (CDCl3,
1.72–1.80 (m, 1 H), 2.12 (dq, Jd = 10.7, Jq = 5.4 Hz, 1 H), 400 MHz) δ 1.03–1.38 (m, 3 H), 1.49–1.56 (m, 2 H), 1.66–1.97
2.48–2.60 (m, 1 H), 3.30–3.37 (m, 1 H) 3.37–3.46 (m, 1 H), 3.80 (m, 5 H), 3.05 (t, J = 11.1 Hz, 1 H), 3.80–3.86 (m, 2 H),
(dd, J = 11.1, 7.8 Hz, 1 H), 3.87–3.93 (m, 1 H), 4.15 (td, Jt = 7.2, 4.11–4.16 (m, 2 H). 13C-NMR (CDCl3, 100 MHz) δ 25.2, 25.7,
Jd = 4.2 Hz, 1 H). 13C-NMR (CDCl3, 100 MHz) δ 20.7, 20.8, 23.6, 27.5, 31.4, 36.4, 45.4, 57.0, 73.5, 73.8. HRMS (EI+) m/z
24.4, 30.8, 38.1, 40.4, 69.4, 82.7. rel-(1R,6S,7S)-3d. 1H-NMR 218.0304/220.0287 (M+); calculated mass for C9H15OBr+:
(CDCl3, 400 MHz) δ 1.23–1.36 (m, 1 H), 1.39–1.49 (m, 3 H), 218.0306/220.0286. Thermal reaction. cis-1d 270 mg
1.52–1.60 (m, 2 H), 1.61–1.70 (m, 2 H), 2.14 (quin, J = 6.0 Hz, (1.00 μmol); eluent used for chromatography: diethyl ether–
1 H), 2.20–2.30 (m, 1 H), 3.33–3.40 (m, 1 H), 3.42–3.49 (m, pentane = 1 : 10 (v/v). 2-Bromo-4-oxabicyclo[4.4.0]decane trans-
1 H), 3.66 (dd, J = 8.1, 4.4 Hz, 1 H) 3.89 (dd, J = 8.0, 5.9 Hz, (5d). Yield: 21.7 mg (99.0 μmol, 10%), rel-(1S,2S,6S)-5d yellow
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liquid. 4-Methyl-2-(trichloromethylsulfanyl)-thiazole (2). Yield: 12.1, 4.2 Hz, 1 H), 3.51 (br. t, J = 10.0 Hz, 1 H), 3.78 (d, J = 11.4
243 mg (977 μmol, 98%), colorless liquid. 91/9-mixture of exo/ Hz, 1 H), 3.92 (d, J = 11.6 Hz, 1 H), 4.01 (br. d, J = 10.0 Hz,
endo-isomers 7-Bromomethyl-8-oxabicyclo[4.3.0]nonane trans- 1 H). 1H-NMR (CDCl3, 600 MHz, −39.7 °C) δ 1.35–1.45 (m,
(3d) and 2-Bromo-4-oxabicyclo[4.4.0]decane trans-(5d). Yield: 3 H), 1.46–1.53 (m, 1 H), 1.65–1.72 (m, 2 H), 1.73–1.82 (m,
168 mg (767 μmol, 77%), 10/90-mixture of 6,7-cis/6,7-trans- 1 H), 2.03–2.13 (m, 2 H), 2.15–2.21 (m, 1 H), 2.26–2.33 (m,
isomers, i.e. rel-(1S,6S,7R)-3d/rel-(1S,6S,7S)-3d and rel- 1 H), 3.46–3.52 (m, 1 H), 3.78 (d, J = 11.2 Hz, 1 H), 3.91 (d, J =
(1S,2R,6S)-5d, pale yellow liquid.
4.4.10 Conversion of 3-[cis-2-(2-methylprop-2-en-1-yl)-cyclo- 150 MHz, −39.7 °C) δ 19.3, 22.7, 27.3, 29.4, 32.1, 42.0, 68.7,
hex-1-ylmethyloxy]-4-methylthiazole-2(3H)-thione cis-(1e). 72.9, 78.4. Anal. Calcd for C9H15BrO (219.12): C, 49.33; H, 6.90;
11.2 Hz, 1 H), 4.03 (dd, J = 11.3, 4.8 Hz, 1 H). 13C-NMR (CDCl3,
Photochemical reaction. cis-1e 161 mg (541 μmol); eluent used Found: C, 49.58; H, 6.83. cis-(1-bromomethyl)-9-oxabicyclo[4.3.0]-
for chromatography: diethyl ether–pentane = 1 : 10 (v/v). 7-(2- nonane cis-(3f). Yield: 53.6 mg (245 μmol, 24%), pale yellow
Bromoprop-2-yl)-8-oxabicyclo[4.3.0]nonane
cis-(3e).
Yield: liquid. Rf = 0.36 for diethyl ether–pentane = 1 : 10 (v/v).
107 mg (433 μmol, 80%), i.e. rel-(1R,6S,7S)-3e, pale yellow 1H-NMR (CDCl3, 600 MHz) δ 1.27–1.33 (m, 1 H), 1.34–1.44 (m,
liquid. Rf = 0.48 for diethyl ether–pentane = 1 : 10 (v/v). 2 H), 1.47–1.56 (m, 2 H), 1.61 (m, 1 H), 1.73 (m, 1 H), 1.78–1.85
1H-NMR (CDCl3, 600 MHz) δ 1.32–1.43 (m, 2 H) 1.45–1.55 (m, (m, 2 H), 2.09 (m, 1 H), 2.26 (quin, J = 6.6 Hz, 1 H), 3.35 (d, J =
3 H) 1.59–1.67 (m, 2 H) 1.68–1.76 (m, 7 H) 2.25–2.33 (m, 2 H) 10.6 Hz, 1 H), 3.46 (d, J = 10.6 Hz, 1 H), 3.90 (td, Jt = 8.7, Jd =
3.63–3.69 (m, 2 H) 3.91 (dd, J = 8.2, 5.9 Hz, 1 H). 13C-NMR 5.6 Hz, 1 H), 3.97 (td, Jt = 8.5, Jd = 6.5 Hz, 1 H). 13C-NMR
(CDCl3, 100 MHz) δ 23.1 (2C, HMQC), 25.2, 28.1, 30.1, 30.9, (CDCl3, 100 MHz) δ 22.0, 22.5, 27.3, 30.8, 30.9, 39.2, 39.8, 65.4,
38.6, 40.3, 69.9, 72.6, 90.1. Anal. Calcd for C11H19BrO (247.17): 81.6. Anal. Calcd for C9H15BrO (219.12): C, 49.33; H, 6.90;
C, 53.45; H, 7.75; Found: C, 53.32; H, 7.59. 4-Methyl-2-(trichloro- Found: C, 49.17; H, 6.79. 4-Methyl-2-(trichloromethylsulfanyl)-
methylsulfanyl)-thiazole (2). Yield: 110 mg (443 μmol, 82%), thiazole (2). Yield: 137 mg (551 μmol, 54%), pale yellow liquid.
pale yellow liquid. Thermal reaction: cis-1e 151 mg (508 μmol); trans-(1-Bromo)-3-oxabicyclo[4.4.0]decane
trans-(5f).
Yield:
eluent used for chromatography: diethyl ether–pentane = 1 : 10 37.1 mg (169 μmol, 17%), yellow liquid. Rf = 0.28 for diethyl
1
(v/v). 7-(2-Bromoprop-2-yl)-8-oxabicyclo[4.3.0]nonane cis-(3e). ether–pentane = 1 : 10 (v/v). H-NMR (CDCl3, 400 MHz) δ 1.12
Yield: 119 mg (481 μmol, 95%), i.e. rel-(1R,6S,7S)-3e, pale (tt, J = 11.4, 3.6 Hz, 1 H), 1.22–1.36 (m, 2 H), 1.37–1.51 (m,
yellow liquid. 4-Methyl-2-(trichloromethylsulfanyl)-thiazole (2). 3 H), 1.63–1.71 (m, 1 H), 1.73–1.87 (m, 2 H), 1.90–2.06 (m, 2 H),
Yield: 114 mg (460 μmol, 90%), colorless liquid.
3.35 (d, J = 12.1 Hz, 1 H), 3.50 (td, Jt = 12.0, Jd = 2.5 Hz, 1 H),
4.4.11 Conversion of 3-[trans-2-(2-methylprop-2-en-1-yl)- 3.98 (d, J = 12.3 Hz, 1 H), 4.07 (dd, J = 11.5, 4.7 Hz, 1 H).
cyclohex-1-ylmethyloxy]-4-methylthiazole-2(3H)-thione trans- 13C-NMR (CDCl3, 150 MHz) δ 21.8, 25.6, 29.0, 29.8, 36.3, 45.2,
(1e). Photochemical reaction. trans-1e 140 mg (471 μmol); 68.8, 76.9, 78.4. Anal. Calcd for C9H15BrO (219.12): C, 49.33; H,
eluent used for chromatography: diethyl ether–pentane = 1 : 10 6.90; Found: C, 49.33; H, 7.02. Thermal reaction. 1f 270 mg
(v/v). 7-(2-Bromoprop-2-yl)-8-oxabicyclo[4.3.0]nonane trans-(3e). (1.00 mmol); eluent used for column chromatography: diethyl
Yield: 94.4 mg (382 μmol, 81%), i.e. rel-(1S,6S,7S)-3e, colorless ether–pentane
= 1 : 10 (v/v). cis-1-Bromo-3-oxabicyclo[4.4.0]-
liquid. Rf = 0.39 for diethyl ether–pentane = 1 : 10 (v/v). decane cis-(5f). Yield: 14.8 mg (67.5 μmol, 7%), yellow liquid.
1H-NMR (CDCl3, 400 MHz) δ ppm 1.04–1.35 (m, 4 H) 1.46–1.58 cis-(1-Bromomethyl)-9-oxabicyclo[4.3.0]nonane cis-(3f). Yield:
(m, 1 H) 1.68–1.91 (m, 4 H), 1.74 (s, 3 H), 1.77 (s, 3 H), 76.7 mg (350 μmol, 35%), pale yellow liquid. trans-1-Bromo-3-
2.06–2.14 (m, 1 H), 3.37 (dd, J = 11.3, 7.4 Hz, 1 H), 3.44 (d, J = oxabicyclo[4.4.0]decane trans-(5f). Yield: 33.5 mg (153 μmol,
9.2 Hz, 1 H), 3.92 (t, J = 7.1 Hz, 1 H). 13C-NMR (CDCl3, 15%), yellow liquid. 4-Methyl-2-(trichloromethylsulfanyl)-thiazole
150 MHz) δ 25.3, 25.9, 27.3, 30.5, 30.7, 31.0, 47.2, 47.8, 69.3, (2). Yield: 199 mg (801 μmol, 80%), pale yellow liquid.
72.1, 89.4. Anal. Calcd for C11H19BrO (247.17): C, 53.45; H,
4.4.13 Conversion of 3-[(1-methylcyclohex-1-en-4-yl)-methyl-
7.75; Found: C, 53.62; H, 7.82. 4-Methyl-2-(trichloromethylsulfa- oxy]-4-methylthiazole-2(3H)-thione (1g). Photochemical reac-
nyl)-thiazole (2). Yield: 92.4 mg (372 μmol, 79%), colorless tion: 1g 536 mg (2.10 mmol); eluent used for column
liquid. Thermal reaction. trans-1e 147 mg (495 μmol); eluent chromatography: diethylether–acetone–pentane
=
1 : 1 : 15
used for chromatography: diethyl ether–pentane = 1 : 10 (v/v). (v/v/v). rel-(1R,4R,5R)-4-Bromo-4-methyl-6-oxabicyclo[3.2.1]octane
7-(2-Bromoprop-2-yl)-8-oxabicyclo[4.3.0]nonane trans-(3e). Yield: trans-(3g). Yield: 213 mg (1.04 mmol, 50%), pale yellow liquid.
115 mg (465 μmol, 94%), i.e. rel-(1S,6S,7S)-3e, colorless liquid. Rf = 0.46 for diethyl ether–acetone–pentane = 1 : 1 : 15 (v/v/v).
4-Methyl-2-(trichloromethylsulfanyl)-thiazole (2). Yield: 120 mg 1H-NMR (CDCl3, 400 MHz) δ 1.48–1.57 (m, 1 H), 1.77 (s, 3 H),
(483 μmol, 98%), colorless liquid.
1.79–1.89 (m, 2 H), 1.90–1.96 (m, 1 H), 1.97–2.06 (m, 1 H),
4.4.12 Conversion of 3-[2-(1-methylenecyclohex-2-yl)-ethyl- 2.33–2.39 (m, 1 H), 2.58 (d, J = 11.9 Hz, 1 H), 3.73–3.88 (m,
oxy]-4-methylthiazole-2(3H)-thione (1f). Photochemical reac- 2 H), 4.10 (d, J = 5.8 Hz, 1 H). 13C-NMR (CDCl3, 100 MHz) δ 26.8,
tion. 1f 275 mg (1.02 mmol); eluent used for chromatography: 32.3, 33.9, 35.4, 36.4, 67.9, 72.3, 83.0. Anal. Calcd for
diethyl ether–pentane = 1 : 10 (v/v). cis-(1-Bromo)-3-oxabicyclo- C8H13BrO (205.09): C, 46.85; H, 6.39; Found: C, 46.74; H, 6.36.
[4.4.0]decane cis-(5f). Yield: 8.2 mg (37.4 μmol, 4%), yellow 4-Methyl-2-(trichloromethylsulfanyl)-thiazole (2). Yield: 358 mg
liquid. Rf = 0.46 for diethyl ether–pentane = 1 : 10 (v/v). (1.44 mmol, 69%), pale yellow liquid. Rf = 0.35 for diethyl
1H-NMR (CDCl3, 400 MHz, 22.2 °C) δ 1.31–1.59 (m, 4 H), ether–acetone–pentane
1.62–1.90 (m, 3 H), 1.96–2.25 (m, 3 H), 2.34 (ddd, J = 14.7, Bromo-4-methyl-6-oxabicyclo[3.2.1]octane cis-(3g). Yield: 62.0 mg
= 1 : 1 : 15 (v/v/v). rel-(1R,4S,5R)-4-
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(302 μmol, 14%), pale yellow liquid. Rf = 0.22 for diethyl ether–
acetone–pentane = 1 : 1 : 15 (v/v/v) 1H-NMR (CDCl3, 600 MHz)
δ 1.51–1.62 (m, 2 H), 1.72–1.82 (m, 1 H), 1.78 (s, 3 H), 1.94 (d,
J = 12.0 Hz, 1 H), 2.05 (dd, J = 13.6, 5.9 Hz, 1 H), 2.42–2.46 (m,
1 H), 2.51 (td, Jt = 13.2, Jd = 7.0 Hz, 1 H), 3.85 (ddd, J = 8.1, 4.4,
1.4 Hz, 1 H), 3.93 (d, J = 7.9 Hz, 1 H), 4.31 (d, J = 6.1 Hz, 1 H).
13C-NMR (CDCl3, 100 MHz): δ 28.7 (2C, HMQC), 34.1, 34.4,
37.5, 71.4, 71.5, 84.9. Anal. Calcd for C8H13BrO (205.09): C,
46.85; H, 6.39. Found: C, 46.87; H, 6.37. Thermal reaction. 1g
513 mg (2.00 mmol); eluent used for column chromatography:
diethyl ether–acetone–pentane = 1 : 1 : 15 (v/v/v). rel-(1R,4R,5R)-
4-Bromo-4-methyl-6-oxabicyclo[3.2.1]octane trans-(3g). Yield:
238 mg (1.16 mmol, 58%), pale yellow liquid. 4-Methyl-2-(tri-
chloromethylsulfanyl)-thiazole (2). Yield: 377 mg (1.52 mmol,
76%), pale yellow liquid. rel-(1R,4S,5R)-4-Bromo-4-methyl-6-oxa-
bicyclo[3.2.1]octane cis-(3g). Yield: 57.2 mg (279 μmol, 14%),
pale yellow liquid.
2 J. Hartung and F. Gallou, J. Org. Chem., 1995, 60, 6706–
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3 M. Rueda-Becerril, J. C. T. Leung, C. R. Dunbar and
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4 J. M. Surzur, M. P. Bertrand and R. Nougier, Tetrahedron
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5 J. M. Surzur and M. P. Bertrand, Bull. Soc. Chim. Fr., 1973,
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6 R. D. Rieke and N. A. Moore, J. Org. Chem., 1972, 37, 413–
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7 J. Hartung, T. Gottwald and K. Špehar, Synthesis, 2002,
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8 J. Hartung, K. Daniel, C. Rummey and G. Bringmann, Org.
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9 For stereodirecting effects of amino- or silyloxy groups see:
M. Zlotorzynska, H. Zhai and G. M. Sammis, J. Org. Chem.,
2010, 75, 864–872.
4.4.14 Conversion of 3-[{(1S,4S,5R)-2,6,6-trimethylbicyclo- 10 J. Hartung, R. Kneuer, S. Laug, P. Schmidt, K. Špehar,
[3.1.1]-hept-2-en-4-yl}-ethyloxy]-4-methylthiazole-2(3H)-thione
I. Svoboda and H. Fuess, Eur. J. Org. Chem., 2003, 4033–
(1h). Photochemical reaction. 1h 305 mg (985 μmol); eluent
4052.
used for chromatography: diethyl ether–pentane = 1 : 4 (v/v). 11 J. Hartung, T. Gottwald and M. Greb, Synlett, 2004, 65–68.
rel-(1R,2S,6S,7S,9S)-9-bromo-1,8,8-trimethyl-3-oxatricyclo[5.2.1.02,6]- 12 J. Hartung and R. Kneuer, Tetrahedron: Asymmetry, 2003,
decane (6). Yield: 148.2 mg (58%), yellow liquid. [α]2D5 = 36.6
(c = 0.85/ethanol). H-NMR (CDCl3, 600 MHz): δ 1.08 (s, 3 H), 13 N. Schneiders, T. Gottwald and J. Hartung, Eur. J. Org.
14, 3019–3031.
1
1.10 (s, 3 H), 1.15 (s, 3 H), 1.33 (dd, J = 11.1, 1.7 Hz, 1 H),
1.35–1.41 (m, 1 H), 1.55 (dd, J = 11.3, 1.3 Hz, 1 H), 1.60 (s, 14 C. Schur, N. Becker, U. Bergsträßer, T. Gottwald and
1 H), 2.04 (dddd, J = 12.1, 9.5, 5.8, 1.3 Hz, 1 H), 2.60–2.66 (m, J. Hartung, Tetrahedron, 2011, 67, 2338–2347.
1 H), 3.40 (ddd, J = 11.1, 8.6, 5.9 Hz, 1 H), 3.79 (s, 1 H), 3.88–3.97 15 P. Fries, M. K. Müller and J. Hartung, Org. Biomol. Chem.,
(m, 2 H). 13C-NMR (CDCl3, 100 MHz): δ 15.4, 25.9, 30.3, 31.8,
2013, 11, 2630–2637.
34.9, 40.5, 41.8, 50.9, 53.4, 67.9, 72.1, 83.4. HRMS (EI+) m/z 16 P. Fries and J. Hartung, J. Am. Chem. Soc., 2011, 133, 3906–
258.0612 (M+); calculated mass for C12H19OBr+: 258.0442 260.
3912.
4-Methyl-2-(trichloromethylsulfanyl)-thiazol (2). Yield: 193 mg 17 J. Hartung, R. Kneuer, C. Rummey and G. Bringmann,
(774 μmol, 79%), colorless liquid. rel-(1S,2S,6S,7S,9S)-9-bromo- J. Am. Chem. Soc., 2004, 126, 12121–12129.
1,10,10-trimethyl-3-oxatricyclo[5.2.1.02,6]-decane
(7). Yield: 18 A. L. J. Beckwith and C. H. Schiesser, Tetrahedron, 1985, 41,
7.7 mg (3%). 1H-NMR (CDCl3, 400 MHz) δ 0.93 (s, 3 H), 1.05 (s,
3925–3941.
6 H), 1.81–2.04 (m, 4 H), 2.32–2.42 (m, 1 H), 3.01 (ttd, Jt = 9.7, 19 K. N. Houk, M. N. Paddon-Row, D. C. Spellmeyer,
Chem., 2009, 799–801.
4.7, Jd = 1.4 Hz, 1 H), 3.85–3.93 (m, 1 H), 4.30 (ddd, J = 11.2,
5.8, 1.7 Hz, 1 H), 4.35–4.44 (m, 2 H). 13C-NMR (CDCl3,
100 MHz) δ 13.8, 20.4, 20.5, 26.0, 31.2, 43.0, 47.2, 51.8, 53.2,
N. G. Rondan and S. Nagase, J. Org. Chem., 1986, 51, 2874–
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53.8, 71.7, 91.2. HRMS (EI+) m/z 258.0612/260.0612 (M+); calcu- 20 M. Stoll and M. Hinder, Helv. Chim. Acta, 1950, 33, 1251–
lated mass for C12H19OBr+: 258.0619/260.0599.
1261; J. M. Castro, S. Salido, J. Altarejos, M. Nogueras and
A. Sanchez, Tetrahedron, 2002, 58, 5941–5949.
21 R. R. Gadikota, A. I. Keller, C. S. Callam and T. L. Lowary,
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Acknowledgements
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This work is part of Ph.D. theses of C. S., T. G., and R. K., and
an undergraduate research project of A. L. We express our
gratitude to the State Rheinland-Pfalz (scholarship for
C. S. and equipment for computational chemistry), and the
Deutsche Forschungsgemeinschaft (grant Ha1705/5-2) for
financial support.
Notes and references
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27 T. Gottwald, M. Greb and J. Hartung, Synlett, 2004, 65–68.
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