A Radical Version of the Bromo- and the Iodocyclization of Bis(homoallylic) Alcohols - The Synthesis of Halogenated Tetrahydrofurans by Stereoselective Alkoxyl Radical Ring Closures

Article abstract of DOI:10.1002/ejoc.200300107

A new synthesis of bromo- and iodomethyl-substituted tetrahydrofurans has been devised. The sequence starts with the conversion of aryl-functionalized bis(homoallylic) alcohols 1 into N-alkenoxythiazole-2(3H)-thiones 6 or pyridine-2(1H)-thiones 7. When photolyzed in the presence of appropriate trapping reagents, thiones 6 and 7 efficiently liberated substituted 4-penten-1-oxyl radicals 2, which underwent synthetically useful 5-exo-trig cyclizations. Cyclized radicals 3 were trapped with BrCCl₃ or an adequate iodine atom donor (either n-C₄F₉I or diethyl 2-iodo-2-methyl malonate) to provide halocyclization products 4 or 5. This strategy has been applied for the synthesis of 3-, 4-, or 5-phenyl-substituted 2-(1-bromo-1-methylethyl)tetrahydrofurans 4a-c (75-90%, 36-96% de), which were not attainable as major products from polar, for example NBS-mediated, bromocyclizations. Aryl-substituted 2-iodomethyl tetrahydrofurans 5 (46-80%) were prepared in a similar way starting from N-alkenoxypyridine-2(1H)-thiones 7 and a suitable iodine atom donor. Diastereomerically pure iodides cis-5 and trans-5 served as starting materials for a stereochemical analysis of disubstituted tetrahydrofurans by NMR spectroscopy and X-ray diffraction analysis. The results of this investigation clarified that all new alkoxyl radical cyclizations followed in terms of regio-and diastereoselectivity the general guidelines which had been established for this type of ring-closure reaction. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300107

FULL PAPER
A Radical Version of the Bromo- and the Iodocyclization of Bis(homoallylic)
Alcohols — The Synthesis of Halogenated Tetrahydrofurans by Stereoselective
Alkoxyl Radical Ring Closures
[a]
[a]
[a]
[a]
[a]
ˇ
Jens Hartung,* Rainer Kneuer, Stefanie Laug, Philipp Schmidt, Kristina Spehar,
Ingrid Svoboda,[b] and Hartmut Fuess[b]
Dedicated to Prof. Dr. Manfred Christl on the occasion of his 62nd birthday
Keywords: Radical reactions / Stereoselective synthesis / Cyclization / Halogens / Alcohols
A new synthesis of bromo- and iodomethyl-substituted tetra-
hydrofurans has been devised. The sequence starts with the
conversion of aryl-functionalized bis(homoallylic) alcohols 1
into N-alkenoxythiazole-2(3H)-thiones 6 or pyridine-2(1H)-
thiones 7. When photolyzed in the presence of appropriate
trapping reagents, thiones 6 and 7 efficiently liberated sub-
stituted 4-penten-1-oxyl radicals 2, which underwent syn-
thetically useful 5-exo-trig cyclizations. Cyclized radicals 3
were trapped with BrCCl3 or an adequate iodine atom donor
(either n-C4F9I or diethyl 2-iodo-2-methyl malonate) to pro-
vide halocyclization products 4 or 5. This strategy has been
applied for the synthesis of 3-, 4-, or 5-phenyl-substituted 2-
(1-bromo-1-methylethyl)tetrahydrofurans 4a−c (75−90%,
36−96% de), which were not attainable as major products
from polar, for example NBS-mediated, bromocyclizations.
Aryl-substituted 2-iodomethyl tetrahydrofurans 5 (46−80%)
were prepared in a similar way starting from N-alkenoxypyr-
idine-2(1H)-thiones 7 and a suitable iodine atom donor. Dias-
tereomerically pure iodides cis-5 and trans-5 served as start-
ing materials for a stereochemical analysis of disubstituted
tetrahydrofurans by NMR spectroscopy and X-ray diffraction
analysis. The results of this investigation clarified that all
new alkoxyl radical cyclizations followed in terms of regio-
and diastereoselectivity the general guidelines which had
been established for this type of ring-closure reaction.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
The most versatile and reliable procedure for the syn-
thesis of β-halogenated tetrahydrofurans generally starts
Halogenated tetrahydrofurans,[1] in particular those with from bis(homoallylic) alcohols 1, which, upon treatment
an exocyclic chloro, bromo or iodo functionality located in with compounds such as molecular bromine,[6Ϫ8]
the β-position to the ring oxygen atom, have become at- iodine,[6Ϫ8] organic trihalide salts,[9] N-bromosuccinimide
tractive targets in organic synthesis.[2,3] Their significance (NBS),[10] N-iodosuccinimide (NIS),[11] or more specialized
has been emphasized in the last decades due to the dis- reagents such as 2,4,4,6-tetrabromocyclohexadienone[12] or
covery that β-brominated tetrahydrofurans occur widely as 2,2-dibromomalodinitrile,[13] afford halocyclized products
secondary metabolites in the marine environment.[4] If puri- in generally useful yields. The role of the halogenating re-
fied and subjected to screening assays, several of these com- agent has been associated with an electrophilic activation
pounds exhibit marked cytotoxic properties and therefore of the olefinic π-bond. Intramolecular C-O bond formation
have the potential to contribute to future developments in follows.[6,14] The regioselectivity of this step is governed by
pharmacology.[5]
a combination of stereoelectronic and polar effects. The ob-
served diastereoselectivity, i.e. the facial selectivity for ad-
dition of the oxygen nucleophile to the π-bond, originates
in most instances from substrate control, unless the reaction
is governed by thermodynamic effects.[6]
[a]
Institut für Organische Chemie, Universität Würzburg
Am Hubland, 97074 Würzburg, Germany
[b]
Institut für Materialwissenschaft, Technische Universität
Darmstadt
Petersenstraße 23, 64287 Darmstadt, Germany
Fax: (internat.) ϩ49-(0)6151/166-023
E-mail: svoboda@.tu-darmstadt.de
Recent developments in this field of research have, how-
ever, clarified that the synthesis of bromomethyl-substituted
oxolanes starting from bis(homoallylic) alcohols such as 1
is also feasible if the heterocyclic core is constructed by an
alkenoxyl cyclization 2 Ǟ 3 (Figure 1).[15] Since intermedi-
ates 2 exhibit electrophilic properties, this strategy corre-
New Address: Fachbereich Chemie, Organische Chemie,
Universität Kaiserslautern
Erwin-Schrödinger-Straße 54, 67661 Kaiserslautern, Germany
Fax: (internat.) ϩ49-(0)631/205-3921
E-mail: hartung@chemie.uni-kl.de
Eur. J. Org. Chem. 2003, 4033Ϫ4052
DOI: 10.1002/ejoc.200300107
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J. Hartung, R. Kneuer, S. Laug, P. Schmidt, K. Spehar, I. Svoboda, H. Fuess
FULL PAPER
sponds to an Umpolung of the polar bromocyclization and phenyl-4-hexen-1-ol (1a)[21] and a combination of PPh3 and
is therefore expected to provide selectivities (ring size, rela- CCl4 (47%).[24] Treatment of this chloride with a 2.6-fold
tive configuration, functional group compatibility), which excess of 4-(p-chlorophenyl)-N-hydroxythiazole-2(3H)-
are, in principle, not attainable in ionic transform- thione tetraethylammonium salt provided, upon work up of
ations.[16,17] In view of these perspectives, we have per- the reaction mixture, 57% of 4-(p-chlorophenyl)-N-(5-
formed a mechanistic study on the radical version of the methyl-1-phenyl-4-hexen-1-oxy)thiazole-2(3H)-thione (6a,
halocyclization by addressing three major issues: (i) N- entry 1, Table 1) and 1,2-bis[4-(p-chlorophenyl)-2-thiazyl]di-
alkoxy-substituted thiazole-2(3H)-thiones 6 and pyridine- sulfane (23%, not shown in Table 1).[23] 2-, and 3-Phenyl-
2(1H)-thiones 7,[18Ϫ21] in combination with a larger set of substituted bis(homoallylic) alcohols 1b,[25] 1c, and 1f[26]
reactive halogen atom donors, were assessed in regard of were esterified with p-toluenesulfonyl chloride in the pres-
their utility to serve as reagents for the synthesis of halocy- ence of 1,4-diazabicyclo[2.2.2]octane (DABCO) to furnish
clization products 4 and 5; (ii) a stereochemical analysis of the corresponding tosylates (96% from 1b, 88% from 1c,
alkoxyl radical cyclization products was accomplished by and 83% from 1f, not shown in Table 1).[20,27] Treatment of
combining results from NMR and X-ray diffraction experi- these alkylating reagents with 4-(p-chlorophenyl)-N-
ments; (iii) selectivities from the radical version of the hydroxythiazole-2(3H)-thione tetraethylammonium salt in
bromocyclization were compared to those from NBS-me- anhydrous DMF afforded alkoxyl radical precursors 6b, 6c,
diated transformations, in order to characterize fields of ap- and 6f[23] in 45Ϫ53% yield (entries 2, 3, 7, Table 1). N-Al-
plication for both methods.
koxypyridine-2(1H)-thiones 7a,[21] 7d, and 7e were prepared
by adding PPh3 to a solution of 2,2Ј-dithiopyridine-1,1Ј-
dioxide[28] and a benzylic alkenol (i.e. 1a, 1d, or 1e) in
CH2Cl2 (entries 4Ϫ6, Table 1).[29] Phase-transfer-catalyzed
Table 1. Syntheses of N-alkoxythiazole-2(3H)-thiones 6 and N-al-
koxypyridine-2(1H)-thiones 7 from bis(homoallylic) alcohols 1[a]
Entry 6, 7 R1
R2
R3
R
Method[a] Yield [%]
Figure 1. Key steps for the design of a radical version of the halocy-
clization. Step 1: generation of alkoxyl radicals 2; step 2: stereo-
and regioselective ring-closure reaction; step 3: halogen atom trap-
ping; R1ϪR3 ϭ aryl or H; R ϭ H or CH3
1
2
3
4
5
6
7
8
9
6a C6H5
H
C6H5
H
H
H
H
H
CH3 a,c
CH3 b,c
57[b]
48
53
55
44
52
45
42
40
39
6b
6c
H
H
C6H5 CH3 b,c
H
H
H
H
H
H
C6H5
7a C6H5
7d p-C6H5C6H4
7e 2-C10H7
CH3
H
H
d
d
d
H
Results
6f
H
H
H
H
C6H5
C6H5
2-C10H7
H
H
H
H
H
b,c
b,e
b,e
b,e
7f
7g
7h
10
1. Preparation of Alkoxyl Radical Precursors
[a]
Reagents and conditions: (a) CCl4, PPh3; (b) TsCl, DABCO,
N-Alkoxy-4-(p-chlorophenyl)thiazole-2(3H)-thiones (6)
were prepared from N-hydroxy-4-(p-chlorophenyl)thiazole-
2(3H)-thione tetraethylammonium salt (not shown in
Table 1)[22,23] and suitable alkylating reagents. 6-Chloro-2-
CH2Cl2; (c) 4-(p-chlorophenyl)-N-hydroxythiazole-2(3H)-thione
tetraethylammonium salt, DMF; (d) 2,2Ј-dithiopyridine-1,1Ј-diox-
ide, PPh3, CH2Cl2; (e) N-hydroxypyridine-2(1H)-thione,
[b]
NBu4HSO4, K2CO3, CH3CN.
In addition: 23% of 1,2-bis[4-(p-
methyl-6-phenyl-2-hexene was synthesized from 5-methyl-1- chlorophenyl)-2-thiazyl]disulfane.[23]
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A Radical Version of the Bromo- and the Iodocyclization of Bis(homoallylic) Alcohols
FULL PAPER
selective O-alkylations of N-hydroxypyridine-2(1H)-thione ual decrease in the yield of bromocyclization product 4a to
(not shown in Table 1) with p-toluenesulfonic acid esters of 32% (1-bromo-1-chlorodimedone[34]), 26% (diethyl 2-
bis(homoallylic) alcohols 1f, 1g, and 1h in the presence of bromo-2-methylmalonate[35]), 25% (Br2C2Cl4), and 9% (n-
[20,30]
K2CO3 and NBu4HSO4
afforded 2-phenyl-, 2-(2- BrC6F13, Table 2, entries 2Ϫ5). In view of these findings
naphthyl)-, or 3-phenyl-substituted N-(4-penten-1-oxy)pyri- BrCCl3 was applied in photochemically initiated reactions
dinethiones 7f, 7g, and 7h in 39Ϫ42% yield (entries 8Ϫ10, starting from 2- or 3-phenyl-substituted N-(5-methyl-4-hex-
Table 1).
ene-1-oxy)thiazolethiones 6b or 6c, which provided 75% of
2,4-substituted oxolane 4b (cis:trans ϭ 68:32) and 90% of
diastereomerically
pure tetrahydrofuran trans-4c[15]
2. Formation of Bromo- and Iodocyclization Products from
N-Alkoxythiazolethiones 6 and Pyridinethiones 7
(Table 2, entries 6 and 7). Photolysis of N-(5-methyl-1-phe-
nyl-4-hexen-1-oxy)pyridinethione (7a) in the presence of
BrCCl3 afforded 88% (GC) of brominated tetrahydrofuran
4a (cis:trans ϭ 28:72, Table 2, entry 8). Application of di-
ethyl 2-bromo-2-methyl malonate (59% of 4a, GC), or n-
BrC6F13 (32% of 4a, GC) as trapping reagents was again
associated with a decrease in yield of target product 4a
(Table 2, entries 9 and 10).
Optimized conditions for the synthesis of bromocycliza-
tion products 4 were established in photochemically in-
itiated reactions between N-(5-methyl-1-phenyl-4-hexen-1-
oxy)thiazolethione (6a) or pyridinethione 7a and selected
bromine atom donors (Table 2). Other parameters, such as
the solvent (C6H6), the reaction temperature (T ϭ 15 °C),
and the method for initiating the alkoxyl radical reaction
Parameters for the synthesis of iodomethyl-substituted
starting either from 6 (250 W visible light discharge lamp) tetrahydrofurans 5 were elaborated starting from N-(2-phe-
or from 7 (150 W light bulb) were kept constant, since they nyl-4-penten-1-oxy)-substituted thiones 6f and 7f.[36] Opti-
had been optimized in previous studies.[23,31] Photolysis of mized conditions were found by photolyzing a solution of
a solution of thiazolethione 6a (co ϭ 0.18 ) and BrCCl3 thione 7f and diethyl 2-iodo-2-methylmalonate (c0 ϭ 0.1 )
(co ϭ 0.8 ) in C6H6 for 20 min provided, upon work up, in C6H6 for 3 min at 20 °C (visible light, Table 3, entry 1).
87% of 2-(1-bromo-1-methylethyl)-5-phenyltetrahydrofuran Purification of this reaction mixture by column chromato-
(4a; cis:trans ϭ 28:72, for stereochemical analysis see sec- graphy provided 72% of 2-iodomethyl-4-phenyltetrahydrofu-
tion 3) and 71% of 4-(p-chlorophenyl)-2-(trichloromethyl- ran (5f; cis:trans ϭ 87:13, for stereochemical analysis refer
sulfanyl)thiazole (8, X ϭ CCl3; Table 2, entry 1). In ad- to section 3) and 74% of diethyl 2-methyl-2-(pyridine-2-sul-
dition, 8% of 5-methyl-1-phenyl-4-hexen-1-one[33] and alk- fanyl)malonate [9, X ϭ C(CH3)(CO2C2H5)2]. Neither a
enol 1a were formed in a 3:1 ratio (GC). Replacement of change in solvent to CH2Cl2 (26% of 5f, GC), nor a modifi-
BrCCl3 by alternative bromine atom donors led to a grad- cation of the iodine atom donor to n-C4F9I (reaction in
Table 2. Stereoselective synthesis of bromocyclization products 4aϪc from alkoxyl radical precursors 6aϪc and 7a[a]
Entry
6, 7
BrϪX
4
R1
R2
R3
4 [%] (cis:trans)
8, 9 [%]
1
2
3
4
5
6
7
8
9
6a
6a
6a
6a
6a
6b
6c
7a
7a
7a
BrCCl3
4a
4a
4a
4a
4a
4b
4c
4a
4a
4a
C6H5
C6H5
C6H5
C6H5
C6H5
H
H
H
H
H
H
C6H5
H
H
H
H
H
H
H
H
H
C6H5
H
H
87[b] (28:72)
32 (28:72)
26[g] (30:70)
25 (28:72)
9 (30:70)
71 (8)[c]
Ϫ[e]
[d]
BrC8H10ClO2
Ϫ[e]
[f]
BrC8H13O4
Br2C2Cl4
BrC6F13
BrCCl3
BrCCl3
BrCCl3
Ϫ[e]
Ϫ[e]
75 (68:32)
67 (8)[c]
70 (8)[c]
Ϫ[e]
H
90 (Ͻ2:Ͼ98[h]
88 (28:72)
59 (29:71)
32 (28:72)
)
C6H5
C6H5
C6H5
Ϫ[e]
Ϫ[e]
[f]
BrC8H13O4
BrC6F13
10
H
H
[a]
[b]
Ar ϭ p-ClC6H4. Except for entries 1, 6, and 7, all yields were determined by GC using n-C14H30 as internal standard.
Additional
products: 6% of 5-methyl-1-phenyl-4-hexen-1-one,[33] 2% of 5-methyl-1-phenyl-4-hexen-1-ol (1a). 8: X ϭ CCl3. 2-Bromo-2-chlorodi-
[c]
[d]
medone.[34]
Not determined. Diethyl 2-bromo-2-methylmalonate.[35]
Additional products: 15% of 5-methyl-1-phenyl-4-hexen-1-
[e]
[f]
[g]
one,[33] 7% of 5-methyl-1-phenyl-4-hexen-1-ol (1a). cis-4c was not detected (1H NMR spectroscopy).
[h]
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J. Hartung, R. Kneuer, S. Laug, P. Schmidt, K. Spehar, I. Svoboda, H. Fuess
FULL PAPER
CH2Cl2, and 18% using C6H6 as solvent (Table 3, entries 7,
Table 3. Synthesis of 2-(iodomethyl)-4-phenyltetrahydrofuran (5f)
from thiones 6f and 7f[a]
8). In a final experiment, a solution of thiazolethione 6f
[37]
and n-C4F9I in C6H6 was treated at 20 °C with BEt3/O2
to afford target compound 5f in 72% yield (GC, 20 °C,
Table 3, entry 9).
According to the results from the optimization study
(Table 3), diethyl 2-iodo-2-methylmalonate and n-C4F9I
were applied as trapping reagent for the synthesis of iodo-
methyl-substituted tetrahydrofurans 5a, 5d, 5e, 5g, and 5h
on a preparative scale. The most effective of both trans-
formations are reported in Table 4. The stereochemical
analysis of iodocyclization products 5 is outlined in sec-
tion 3.
Photolysis of N-(5-methyl-1-phenyl-4-hexen-1-oxy)pyrid-
inethione 7a in the presence of n-C4F9I afforded 80% of
2-(1-iodo-1-methylethyl)-5-phenyl tetrahydrofuran (5a; cis:-
trans ϭ 29:71) as well as 84% of 2-perfluorobutylsulfanyl
Entry 6f,7f IϪX
Equiv.[b] Solvent Method[a] Yield of 5f [%]
1
2
3
4
5
6
7
8
9
7f IC8H13O4 [c] 3.7
7f IC8H13O4 [c] 1.5
C6H6
CH2Cl2 a
C6H6
CH2Cl2 a
a
72[d]
26
42
46
55
38
32
18
72
7f IC4F9
7f ICHI2
7f ICHI2
6f IC4F9
6f ICHI2
6f ICHI2
6f IC4F9
2.5
1.2
1.3
2.5
1.2
2.5
2.5
a
C6H6
C6H6
a
a
CH2Cl2 a
C6H6
C6H6
a
b
Table 5. Preparation of methyl-substituted tetrahydrofurans cis-10
and trans 10[a]
[a]
Ar ϭ p-ClC6H4. For all reactions: cis-5f:trans-5f ϭ 87:13; re-
agents and conditions: (a) hν, 15 °C; (b) BEt3/O2, 20 °C; except for
entry 1, all yields were determined by GC using n-C14H30 as in-
ternal standard. [b] Equiv. of I-X. [c] Diethyl 2-iodo-2-methylmalon-
ate.[35]
Preparative scale; in addition, 74% of diethyl 2-methyl-
[d]
2-(pyridine-2-sulfanyl)malonate (9) [X ϭ C(CH3)(CO2C2H5)2, for
structure refer to Table 2] was formed.
Entry 5, 10 R1
R2
R3 cis-10 [%] trans-10 [%]
C6H6: 42% of 5f) nor to CHI3 (5f: 55% in C6H6, 46% in
CH2Cl2, GC) led to comparable yields of target compound
5f (Table 3, entries 2Ϫ5). If N-(2-phenyl-4-penten-1-oxy)thi-
azolethione (6f) [λmax ϭ 320 nm (EtOH)] was used as rad-
ical precursor, the synthesis of iodocyclization product 5f
was preferentially conducted in a Rayonet chamber reac-
tor (350 nm).[36] For example, 38% of iodide 5f (cis:trans ϭ
87:13, GC) was obtained by photolyzing a solution thia-
zolethione 6f and n-C4F9I in C6H6 (Table 3, entry 6). Re-
placement of the iodine atom donor by CHI3 provided 32%
1
2
3
4
5
d
e
f
g
h
p-(C6H5)C6H4 H
2-C10H7
H
H
H
H
H
H
90
63
75
86
89
91
44
77
74
H
C6H5
2-C10H7 H
H
C6H5 56
[a]
Reagents and conditions: (a) column chromatography; dia-
stereomeric purity of iodomethyl tetrahydrofurans 5 (cis:trans.
GC): 99:1 for cis-5d, Ͻ0.5:Ͼ99.5 for trans-5d, Ͼ99.5:Ͻ0.5 for cis-
5e, 2:98 for trans-5e, 97:3 for cis-5f, 3:97 for trans-5f, 99.5:0.5 for
cis-5g, 0.5:99.5 for trans-5g, 96:4 for cis-5h, 2:98 for trans-5h; (b)
of product 5f, if thione 6f was irradiated in a solution of LiH, LiAlH4, THF, ∆.
Table 4. Preparation of iodomethyl-substituted tetrahydrofurans 5 from N-alkoxypyridinethiones 7[a]
Entry
7
IϪX
R1
R2
R3
R
5 [%] (cis:trans)
5
9 [%]
1
2
3
4
5
7a
7d
7e
7g
7h
IC4F9
C6H5
p-C6H5C6H4
2-C10H7
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
80 (29:71)
40 (53:47)
72 (50:50)
46 (87:13)
72 (3:97)
5a
5d
5e
5g
5h
84
IC4F9
Ϫ[b]
73
[c]
[c]
[c]
IC8H13O4
IC8H13O4
IC8H13O4
2-C10H7
H
Ϫ[b]
Ϫ[b]
C6H5
[a]
[b]
[c]
Isolated yields. Not determined. Diethyl 2-iodo-2-methylmalonate.[35]
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A Radical Version of the Bromo- and the Iodocyclization of Bis(homoallylic) Alcohols
FULL PAPER
pyridine (9, X ϭ C4F9, Table 3, entry 1). 5-(p-Biphenylyl)- (2-naphthyl)tetrahydrofuran (5e, cis:trans ϭ 50:50) and 73%
2-(iodomethyl)tetrahydrofuran (5d) was prepared from of diethyl 2-methyl-2-(pyridine-2-sulfanyl)malonate [9, X ϭ
pyridinethione 7d and n-C4F9I in 40% yield (cis:trans ϭ C(CH3)(CO2C2H5)2, Table 4, entry 3]. In the same manner,
53:47, Table 4, entry 2). Photolysis of N-[1-(2-naphthyl)-4- 2-(iodomethyl)-4-(2-naphthyl) tetrahydrofuran (5g; 46%, ci-
pentenoxy]pyridinethione 7e in the presence of diethyl 2- s:trans ϭ 87:13, Table 4, entry 4), and 2-(iodomethyl)-3-
iodo-2-methylmalonate afforded 72% of 2-(iodomethyl)-5- phenyltetrahydrofuran (5h; 72%, cis:trans ϭ 3:97, Table 4,
entry 5) were obtained from pyridinethiones 7g and 7h
(Table 4).
3. Stereochemical Analysis of Disubstituted
Tetrahydrofurans
The relative configuration of the major bromocyclization
products (Table 2) was determined by NMR spectroscopy
Figure 2. Characteristic spectroscopic information for a stereoch-
emical analysis of disubstituted tetrahydrofurans 10 by NMR spec-
troscopy; R1 ϭ p-(C6H5)C6H4, 2-C10H7; R2 ϭ C6H5, 2-C10H7
Figure 3. Structures of disubstituted tetrahydrofurans trans-10d,
trans-11e, cis-11e, cis-11f, cis-11g, trans-11h in the solid state (aniso-
tropic displacement parameters are drawn at the 50% level) show-
ing labeling of selected non-H atoms; hydrogen atoms are depicted
as small circles of an arbitrary radius; Bp ϭ p-biphenylyl, Np ϭ 2-
naphthyl; see also ref. 1
Scheme 1. Synthesis of 2-(alkylsulfanyl)pyridine N-oxides 11; re-
agents and conditions: (a) N-hydroxypyridine-2(1H)-thione potass-
ium salt, DMF, 20 °C
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FULL PAPER
(chemical shift values, NOE experiments). This information the latter case, however, comparatively large chemical shift
was compared to results from a concise stereochemical differences between the two protons at C3 were indicative
analysis on diastereomerically pure iodocyclization prod- of a cis isomer (∆δ ϭ ഠ 0.8Ϫ1.5 ppm). Smaller differences
ucts cis-5a, cis-5dϪ5h and trans-5a, trans-5dϪh (dia- of between 0.5 and 0.0 ppm pointed to 2,4-trans-configured
stereomeric ratio: 99.5:0.5 to 96:4, GC, Table 5). The dia- heterocycles trans-10f, and trans-10g. Assignment of relative
stereomeric purity of tertiary iodides cis-5a and trans-5a configurations for 2,3-disubstituted tetrahydrofurans was
1
was determined by H NMR spectroscopy (Ͼ 96% de in possible by 13C NMR spectroscopy, since the γ-effect of
both cases) since both compounds decompose at elevated vicinal cis-arranged substituents in, for example, cis-10h led
temperatures. In view of this observation, only iodides cis- to a marked high-field shift of C2 (approx. 4 ppm) and C3
5dϪ5h and trans-5dϪ5h were converted into methyl-substi- (approx. 5 ppm).[39]
tuted tetrahydrofurans cis-10dϪh (56Ϫ90%) and trans-
10dϪh (44Ϫ91%) using a mixture of LiH and LiAlH4 in ments in solution (NMR) was supplemented by results from
hot THF. X-ray diffraction analysis. trans-2-(p-Biphenylyl)-5-methyl-
The stereochemical information obtained from experi-
Disubstituted tetrahydrofurans 10 were investigated by tetrahydrofuran (trans-10d) crystallized from EtOH as col-
one- and two-dimensional NMR spectroscopy (HMBC, orless needles which were suitable for this purpose. At-
HMQC, NOE, Figure 2). Significant NOEs were observed tempts to grow appropriate crystals from selected iodides 5
for protons which were located in relative 1,3-cis-arrange- were not successful. Therefore, the major diastereomers
ment at the tetrahydrofuran nucleus. This finding allowed a from each iodocyclization reaction, i.e. heterocycles cis-
clear cut differentiation between 2,5-cis-configured tetra- 5eϪg, trans-5e, and trans-5h (for 5a vide supra), were
hydrofurans cis-10d and cis-10e from diastereomers trans- treated with N-hydroxypyridine-2(1H)-thione potassium
10d and trans-10e. 2,5-trans-Disubstituted heterocycles salt in anhydrous DMF to provide 2-(alkylsulfanyl)pyridine
trans-10d and trans-10e were characterized by large vicinal N-oxides 11 in 75Ϫ91% yield (Scheme 1).
coupling constants between one of the protons at C3 and
Products 11 were recrystallized from appropriate solvent
mixtures and analyzed by X-ray diffraction. The results of
2
one of those at C4 (3JH,H ഠ 9Ϫ10 Hz, compare to JH,H
ഠ
12 Hz for 3-H and 4-H). The second pair of protons bound this study are shown in Figure 3 and Table 6. For the sake
to C3 and C4 in trans-10d exhibited a significantly smaller of clarity, the numbering of the ring carbon atoms in tetra-
3JH,H value of 3.3 Hz.[38] No comparable values were lo- hydrofurans 11 has been adapted to that of trans-10d.[1,40]
cated in the spectra of cis-10d and cis-11e. NOEs from the The assignment of conformers (Table 6) follows the twist
methyl substituents at C5 to the cis-arranged protons at C2 (T) and envelope (E) convention for saturated five-mem-
were typical for 2,5-trans-disubstituted tetrahydrofurans bered compounds.[41Ϫ44]
trans-10d and trans-10e. Similar NOEs were absent in 2,4-
trans-2-(p-Biphenylyl)-5-methyltetrahydrofuran
(trans-
trans-disubstituted heterocycles trans-10f and trans-10g. In 10d) crystallizes in the space group C2. The unit cell con-
˚
Table 6. Selected distances [A] and angles [°] of tetrahydrofurans trans-10d and 11 (X-ray crystallographic data)
Entry
Parameter[a]
trans-10d
trans-11e
cis-11e
cis-11f
cis-11g
trans-11h
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
conformer[a]
O1ϪC5
C5ϪC4
C4ϪC3
C3ϪC2
C2ϪO1
C2ϪO1ϪC5
O1ϪC5ϪC4
C5ϪC4ϪC3
C4ϪC3ϪC2
C3ϪC2ϪO1
O1ϪC5ϪC4ϪC3
C5ϪC4ϪC3ϪC2
C4ϪC3ϪC2ϪO1
C2ϪO1ϪC5ϪC4
C3ϪC2ϪO1ϪC5
C6ϪC5ϪO1ϪC2
C5ϪO1ϪC2ϪC7
O1ϪC2ϪC3ϪC7
O1ϪC5ϪC4ϪC7
3T4
E3
2T3
3T4
2T3
1T2
1.399(7)
1.50(1)
1.487(8)
1.518(8)
1.421(7)
1.420(8)
1.427(6)
1.43(1)
1.425(8)
1.533(8)
1.55(1)
1.528(9)
1.407(7)
1.424(4)
1.515(9)
1.52(1)
1.52(1)
1.438(8)
1.522(7)
1.504(8)
1.535(7)
1.436(6)
1.52(1)
1.53(1)
1.52(1)
1.40(1)
109.0(6)
105.4(7)
101.6(6)
98.1(7)
107.6(7)
35.1(9)
Ϫ41.0(9)
35.1(9)
Ϫ13(1)
Ϫ15(1)
Ϫ139.3(8)
Ϫ
1.522(5)
1.539(6)
1.448(7)
1.389(5)
110.9(5)
109.7(5)
109.4(4)
108.8(4)
107.0(3)
106.0(6)
102.9(5)
101.8(5)
104.8(4)
Ϫ29.0(7)
36.2(7)
Ϫ31.4(6)
9.2(7)
14.0(6)
136(1)
138.5(5)
Ϫ
104.9(6)
101.4(6)
102.6(6)
106.3(6)
Ϫ37.3(8)
36.1(8)
Ϫ23.0(8)
23.9(7)
Ϫ0.4(8)
146.0(6)
124.6(6)
Ϫ
105.1(4)
102.5(4)
103.4(5)
106.8(4)
35.8(5)
Ϫ31.9(5)
17.9(5)
Ϫ25.4(5)
4.7(5)
103.6(5)
100.9(5)
102.0(5)
108.5(5)
Ϫ40.2(7)
31.4(7)
Ϫ12.8(8)
33.9(7)
Ϫ13.1(8)
158.6(6)
Ϫ
104.9(3)
102.6(3)
105.1(6)
109.6(4)
25.6(7)
Ϫ9.4(5)
Ϫ10.9(7)
Ϫ33.9(5)
28.6(5)
Ϫ156.9(4)
Ϫ
96.1(4)
Ϫ119.4(4)
Ϫ
161.1(8)
Ϫ
Ϫ135.4(7)
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
149.3(3)
[a] The atom count within the tetrahydrofuran nucleus follows the HantzschϪWidman convention for conformational analysis (i.e. oxygen
has a higher priority than carbon).[40] For illustration purposes of results from X-ray crystallographic studies, the notation which is
outlined in Figure 3 has been applied consistently.[1] The graphics in Figure 3 and the parameters in Table 6 refer to the same enantiomer,
which was arbitrarily selected from the racemate that was present in the unit cell of trans-10d and 11.
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A Radical Version of the Bromo- and the Iodocyclization of Bis(homoallylic) Alcohols
FULL PAPER
tains both enantiomers, which adopt twist conformers of study in order to develop a halocyclization of alkenols,
3
opposite chirality [i.e. T4 for (2R*,5S*) and T4 (2S*,5R* which profits from mild reaction conditions and syntheti-
3
)]. In each enantiomer, the methyl and the p-biphenylyl cally useful radical selectivities.[16] The choice of aryl-substi-
group are located in pseudo-equatorial positions.[45] The tuted bis(homoallylic) alcohols 1 for this purpose has been
structure of trans-2-[5-(2-naphthyl)-2-tetrahydrofurylme- governed by their UV activity, which also facilitated spot-
thylsulfanyl]pyridine N-oxide (trans-11e) was solved and re- ting of bromo- or iodocyclization products 4 or 5 even in
fined in space group P21/n. The heterocyclic core for the minor concentrations on TLC plates in the course of the
(2S*,5S*)-enantiomer adopts an E3 conformation with the purification step (column chromatography). The major task
methylsulfanyl group positioned in an equatorial and the of the present contribution has been associated with finding
naphthyl entity in a bisectional arrangement. The enanti- matching combinations of: (i) a suitable method for initiat-
omer exhibits E3 geometry. The unit cell of cis-11e (space ing bromo- or iodocyclizations in a radical chain reaction,
group P21/n) contains 2T3- [(2S*,5R*)-enantiomer] and 2T3- (ii) an adequate trapping reagent for halogen atom delivery
configured tetrahydrofurans in a 1:1 ratio [(2R*,5S*)-en- onto a cyclized radical 3, and (iii) an appropriate chain-
antiomer]. The naphthyl substituent is positioned bisection- carrying radical X· that preferentially regenerates alkoxyl
ally and the methylsulfanyl group axially. Structure solution radical 2 in a succeeding step before competing side reac-
and refinement from data which were collected for cis-2- tions consume either the alkoxyl radical precursor, for ex-
(4-phenyl-2-tetrahydrofurylmethylsulfanyl)pyridine N-oxide ample 6a, or any essential intermediate of the cycle that is
(cis-11f) was successful in the triclinic space group P1. The outlined in Figure 4.[19]
¯
3
heterocyclic core adopts a T4 conformer for the (2R*,4S*)-
configured compound and a T4 arrangement for the en-
3
antiomer. The phenyl group in cis-11f is situated in an equa-
torial and the methylsulfanyl entity in a pseudo-equatorial
location. cis-2[4-(2-Naphthyl)-2-tetrahydrofurylmethylsul-
fanyl]pyridine N-oxide (cis-11g) crystallizes in the ortho-
rhombic space group Pbca. In (2S*,4R*)-11g, the β-naph-
thyl group is found in a pseudo-equatorial and the methyl-
sulfanyl side chain in an equatorial position. The tetra-
hydrofuran nucleus adopts a 2T3 geometry. The unit cell
contains four pairs of enantiomers of cis-11g. The structure
of trans-11h is characterized by a T2 conformation of the
1
heterocyclic core for the (2S*,3R*)-configured isomer; the
substituents are positioned in a pseudo-equatorial (C6H5)
and equatorial (CH2SC5H4NO) arrangement. This struc-
ture and its enantiomer are present in a 1:1 ratio in the unit
cell of trans-11h. The torsion angles O1ϪC5ϪC6ϪS1 are
Figure 4. Elementary reactions for the formation of bromocycliza-
50.6(6)° (cis-11g), Ϫ61.4(10)° (cis-11f), 62.1(6)° (cis-11e),
tion product 4a in a radical chain reaction starting from thia-
68.7(5)° (trans-11e), and 83.0(4)° (trans-11h). This obser-
vation is in agreement with the an approximate gauche ar-
rangement, which is energetically favored in 1,2-diacceptor-
substituted ethane entities.[46]
zolethione 6a. Step A: 5-exo-trig cyclization of alkoxyl radical 2a;
step B: bromine atom transfer onto cyclized radical 3a; step C:
addition of chain carrying ·CCl3 radical to starting thione 6a Ϫ
regeneration of alkoxyl radical 2a
1. Properties and Preparation of Alkoxyl Radical
Precursors
Discussion
The results from the present investigation show that the
N-Alkoxythiazole-2(3H)-thiones 6 and N-alkoxypyrid-
radical version of the bromo- and the iodocyclization is a ine-2(1H)-thiones 7 are similarly efficient sources of oxygen
feasible and synthetically very useful transformation. Its centered radicals.[23] Both types of compounds, however,
significant contribution for diastereoselective synthesis differ in regard of their thermal stability and absorption
arises from the fact that it is so far the only known method spectra.[23,48] Since light bulbs, which are commercially
for selectively converting 5,5-dimethyl-substituted bis(ho- available in any hardware store, are suited for initiating
moallylic) alcohols — a widespread structural motif among transformations starting from pyridinethiones 7, no special-
naturally occurring terpenols[47] — into 5-exo-halocyclized ized photochemical equipment was necessary in this case.
products without a notable interference from tetrahydropy- This set up also facilitated formation of photolabile alkyl
ran formation. With the advent of thiohydroxamate-derived iodides 5 in synthetically useful yields since reaction times
alkoxyl radical precursors,[18,19] the long-standing problem never exceeded 3 min.
of generating primary and secondary alkoxyl radicals under
The synthesis of pyridinethiones 7 is reasonably well-es-
neutral conditions, i.e. in the absence of oxidants, has been tablished. All compounds were purified by column chroma-
solved. This knowledge has been applied in the present tography. The inherent lability of pyridinethiones 7, how-
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J. Hartung, R. Kneuer, S. Laug, P. Schmidt, K. Spehar, I. Svoboda, H. Fuess
FULL PAPER
ever, precluded their extended storage. In particular the re- choice was straightforward as in earlier mechanistic studies
arrangement of secondary N-benzyloxy-substituted thiones the propensity of alkyl iodides to attack preferentially the
(e.g. 7a, 7d, and 7e, see Table 1) into corresponding 2-alkyl- sulfur instead of the oxygen nucleophile in N-hydroxypyri-
sulfanylpyridine N-oxides (i.e. the non-cyclized derivatives dine-2(1H)-thione-derived salts had been observed.[50Ϫ53]
of 11), was disturbing, since it often led to a complete waste This reaction provided extremely well crystallizing 2-alkyl-
of alkoxyl radical precursors within 12 h.[21] Therefore, sulfanyl pyridine N-oxides 11, which were in all instances
thiones 7 were immediately applied once they had been pre- suitable for X-ray diffraction experiments (Figure 3). The
pared and purified. If product stability tolerated extended results of this study were in agreement with the configura-
photochemical reaction times (approx. 20 min), or the use tions that had been derived from NMR spectroscopic in-
of near UV/A-light (e.g. from a Rayonet photoreactor vestigations (Figure 2).
equipped with 350 nm lamps), N-alkoxy-4-(p-chloro-
(ii) Bromocyclizations: Photochemically induced reactions
phenyl)thiazole-2(3H)-thiones 6 were used as O-radical between N-alkoxy-4-(p-chlorophenyl)thiazolethione 6a and
sources instead. Rearrangements of N-alkoxy compounds, BrCCl3 provided 2-(1-bromo-1-methylethyl)-5-phenyltetra-
such as 6a, into isomeric N-oxides have not been observed hydrofuran (4a) in synthetically useful yields. This reaction
in this study. Storage of heterocycles 6b and 6c in standard proceeds via a chain mechanism (Figure 4). It is known
glassware for months was feasible without decomposition from laser flash photolysis studies that UV/A- excitation of
of the material, although it was noted that thione 6a tended N-alkoxy-4-(p-chlorophenyl)thiazole-2(3H)-thiones [λmax
ഠ
to fragment into 5-methyl-1-phenyl-4-hexen-1-one,[33] and 320 nm (EtOH)] is followed by the generation of alkoxyl
4-(p-chlorophenyl)thiazole-2(3H)-thione if the sample was radicals.[54] Therefore, it was straightforward to assume in
kept in a refrigerator for more than a month.
this work that photoexcitation of thiazolethione 6a initiated
The synthesis of N-alkoxythiazolethiones 6 has been per- N-O homolysis and thus formation of the 5-methyl-1-phe-
formed in extension to established methods.[23,30] Isolation nyl-4-hexen-1-oxyl radical (2a). Intermediate 2a preferen-
of 1,2-bis[4-(p-chlorophenyl)-2-thiazyl]disulfane[23] as a side tially undergoes a 5-exo-trig-selective cyclization with a rate
product in significant amounts from one of these reactions constant k of more than 109 sϪ1 (30 °C) to afford carbon
was unexpected. This finding may contribute to uncover, in radical 3a in a kinetically controlled reaction (step A, Fig-
upcoming studies, the fate of the major fraction of 4-(p- ure 4).[21] Trapping of cyclized radical 3a with a bromine
chlorophenyl)-N-hydroxythiazole-2(3H)-thione
tetra- atom donor provided target compound 4a and radical X·
ethylammonium salt, which does not get converted into N- (step B, Figure 4). Favorable kinetics for the latter step are
alkoxy derivatives 6 in O-alkylation reactions.
in most instances, although not necessarily, associated with
low C-Br bond dissociation energies.[55] Since structurally
related bromine atom donors such as BrCCl3 (87% of 4a)
and Br2C2Cl4 (25% of 4a) provided strongly deviating re-
2. Formation of Bromo- and Iodo-Functionalized
Disubstituted Tetrahydrofurans
Alkoxyl radical precursors 6 and 7 have been applied for sults, step C was considered to significantly contribute to
the synthesis of halocyclization products and the effectiveness of the chain reaction. This interpretation
4
5
(Table 2Ϫ4). The discussion of heterocycle syntheses will originated from the fact that the chemical nature of chain
succeed that of a stereochemical analysis for disubstituted carrying radical X· differs considerably in all instances. Sup-
tetrahydrofurans 4 and 5, since the diastereoselectivity of port for this argument was taken from a control experiment
an alkoxyl radical cyclization is independent of the terminal that was performed by photolyzing alkoxyl radical precur-
halogen atom trapping step.
sor 6a in the absence of an additional trapping reagent for
(i) Stereochemical Analysis: Emphasis has been placed on about 30 min (typical reaction time for the synthesis of 4).
an investigation of diastereomerically pure iodides cis-5 and 4-(p-chlorophenyl)-2-[5-phenyltetrahydrofuryl-2-(1-methyl-
trans-5. Replacement of the iodine functionality in 5 by hy- ethyl-1-sulfanyl)]thiazole, the expected addition product of
drogen furnishes aryl-substituted 2-methyltetrahydrofurans cyclized radical 3a and the thiocarbonyl group in starting
10. Heterocycles 10 exhibit considerably simplified 1H thione 6a, was not identified in such an experiment.[56] This
NMR spectra in terms of multiplicity and overlap of signals observation implies that a suitable bromine atom donor in
and therefore provided significant information in order to this sequence has to a combine a favorable C-Br bond dis-
assign the relative configuration of each product (Figure 2). sociation energy (231 Ϯ 4 kJ·molϪ1 for BrCCl3) with an
The feasibility of this approach for conformationally flex- adequate affinity of the newly formed radical X· (e.g. ·CCl3)
ible saturated five-membered cyclic compounds has been for addition to the thiocarbonyl group in thiones 6. The
questioned in the literature.[49] The results from the present same principles should apply for bromocyclizations starting
study, however, show that guidelines exist which are suited from the corresponding N-alkenoxypyridine-2(1H)-thione,
to assign relative configurations in disubstituted oxolanes for example 7a. In view of their favorable characteristics,
from NMR spectroscopic information alone. The potential however, we restricted ourselves to the use of thiazolthiones
of this approach has been emphasized by results of X-ray 6b and 6c for conducting syntheses of tetrahydrofurans 4b
diffraction analyses. The task of converting the major dia- and 4c. It was noteworthy that 5-exo-trig cyclizations of
stereomer of each iodocyclization product into an appropri- 5,5-dimethyl-1- or -3-phenyl-4-penten-1-oxyl radicals 2a or
ate crystalline derivative was accomplished by preparing the 2c proceeded with an increased stereochemical preference
corresponding 2-alkylsulfanyl pyridine N-oxides 11. This for the formation of products trans-4a or trans-4c in com-
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A Radical Version of the Bromo- and the Iodocyclization of Bis(homoallylic) Alcohols
FULL PAPER
parison to those intermediates lacking the two methyl sub- sulfanyl)pyridine, the assumed ·CHI2-radical trapping prod-
stituents at the terminal position of the olefinic π- uct of pyridinethione 7f, was not identified. Optimized con-
bond.[15,20] The opposite, however, was the case in cycliza- ditions were applied for the synthesis of 2-(1-iodo-1-methyl-
tions of the 5,5-dimethyl-2-phenyl-4-penten-1-oxyl radical ethyl)-5-phenyltetrahydrofuran (5a). This compound is not
2b.
This
transformation
proceeded
with
a
accessible from alkenol 1a and molecular iodine because
decreased 2,4-cis-selectivity (4b: cis:trans 68:32) in compari- the polar iodocyclization affords trans-3-iodo-2,2-dimethyl-
son to its derivative 2f (e.g. see below for 5f: cis:trans ϭ 6-phenyltetrahydropyran as the sole product (Exp. Sect.).
87:13).
In terms of efficiency of the reagents n-C4F9I and diethyl
The synthetic utility of the new bromocyclization became 2-iodo-2-methylmalonate, it was not possible to predict in
obvious once the radical selectivities were compared to advance which iodine atom donor would serve for what
those from polar reactions (see Exp. Sect.). In contrast to a synthetic purpose. On an experimental level, a complete de-
persistent selectivity for tetrahydrofuran formation as seen colorization of a previously yellow reaction mixture (color
in the ring-closure reaction of radicals 2aϪh, regioselectivit- of thione 7) pointed to an efficient tetrahydrofuran syn-
ies in polar bromocyclizations of bis(homoallylic) alcohols thesis, whereas faint yellow to brown solutions were fre-
1 were strongly dependent on the substitution pattern at the quently indicative of low yields of iodides 5.
terminal position of the olefinic π-bond.[2,57] For example,
The observed diastereoselectivities for the synthesis of
treatment of 1-, 2-, or 3-substituted 4-penten-1-ols 1f, 1h, aryl-substituted 2-iodomethyl tetrahydrofurans 5 are in
and 1i with NBS furnished tetrahydrofurans 4f, 4h, 4i, agreement with the alkoxyl radical mechanism that is out-
whereas bromocyclizations of 5,5-dimethyl-substituted bis- lined in Figures 1 and 4. For example, a lack of stereochem-
(homoallylic) alcohols 1aϪc under these conditions pro- ical preference for the formation of either diastereomer of
ceeded 6-endo-selectively (Scheme 2).
5d and 5e is indicative of alkoxyl radicals 2d and 2e as reac-
tive intermediates.[20] Polar iodocyclizations of alkenols 1d
and 1e would have been in favor of the corresponding trans-
diastereomer (5d from 1d: cis:trans ϭ 23:77, 5e from 1e:
cis:trans ϭ 27:73). Cyclizations of 2-substituted 4-penten-1-
oxyl radicals 2f and 2g proceeded cis-selectively and fur-
nished, after iodine atom trapping, heterocycles 5f and 5g
(both: cis:trans ϭ 87:13). The latter two transformations
were qualitatively and quantitatively similar to results from
polar iodocyclizations (5f from 1f: cis:trans ϭ 84:16; 5g
from 1g: cis:trans ϭ 82:18). The observed diastereoselec-
tivity in the synthesis of 2,3-disubstituted tetrahydrofuran
trans-5h from the alkoxyl radical pathway (cis:trans ϭ 3:97)
exceeded that from the polar iodocyclization (cis:trans ϭ
20:80) significantly.[51]
Finally, the formation of 2-(iodomethyl)-4-phenyltetra-
hydrofuran (5f) from thiazolethione 6f and n-C4F9I in a
BEt3/O2-initiated reaction deserves a comment. We re-
frained from pursuing this chemistry further in the present
work because its efficiency on an analytical level was not
superior to the yield of iodide 5f on a preparative scale
using a photochemically initiated transformation. Still, the
approach to initiate halocyclizations with the BEt3/O2 sys-
tem has the potential to further contribute to the develop-
Scheme 2. Regioselectivities in polar bromocyclizations of selected
bis(homoallylic) alcohols 1; for details see Exp. Sect. [a] 4f: R1, R3 ϭ
H, R2 ϭ C6H5, 60% (cis:trans ϭ 78:22); 4h: R1, R2 ϭ H, R3
ϭ
C6H5, 54% (cis:trans ϭ 33:67); 4i: R1 ϭ C6H5, R2, R3 ϭ H, 81%
[b]
(cis:trans ϭ 33:67). from 1a (R1 ϭ C6H5, R2, R3 ϭ H): 79% of
12a (cis:trans ϭ 6:94), 7% of 4a (cis:trans ϭ 33:67); from 1b (R1,
R3 ϭ H, R2 ϭ C6H5): 67% of 12b (cis:trans ϭ Ͼ98:Ͻ2), 17% of
4b (cis:trans ϭ 67:33); from 1c (R1, R2 ϭ H, R3 ϭ C6H5): 76% of
12c (cis:trans ϭ Ͻ2:Ͼ98), 3% of 4c (cis:trans ϭ Ͻ2:Ͼ98)
(iii) Iodocyclizations: Iodomethyl-substituted tetrahydro- ment of this chemistry and is therefore under current inves-
furans 5 were preferentially obtained in photochemically in- tigation.
duced radical reactions starting from N-alkoxypyridine-
2(1H)-thiones 7. Compounds with low C-I bond dis-
sociation energies [(BDE): 205 Ϯ 4 kJ·molϪ1 in n-C4F9I;
Conclusion
193.1 kJ·molϪ1 in CHI3)[55b]] and high rate constants for
iodine atom transfer onto alkyl radicals (k ϭ 2.2Ϫ5.6 ϫ
The radical version of the halocyclization is a feasible
108 Ϫ1
s
Ϫ1, T ϭ 50 °C, C6H6 for diethyl 2-iodo-2-methyl- and synthetically very useful transformation. Its potential
malonate)[35] have been applied for this purpose. The fact for stereoselective synthesis arises from the fact that it is the
that 2-perfluorobutylsulfanyl pyridine (9, X ϭ C4F9) and only known method so far for preparing 5-exo-halocyclized
diethyl 2-methyl-2-(2-pyridylsulfanyl)malonate [9, X ϭ products from 5,5-dimethyl-substituted bis(homoallylic) al-
C(CH3)(CO2C2H5)2] have been isolated in yields that corres- cohols 1 without a notable interference from tetrahydropy-
ponded to those of heterocycles 5 is in agreement with the ran formation. The general sequence starts with the conver-
mechanism that is outlined in Figure 4. 2-(Diiodomethyl- sion of alkenols 1 into N-(alkenoxy)-4-(p-chlorophenyl)thia-
Eur. J. Org. Chem. 2003, 4033Ϫ4052
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J. Hartung, R. Kneuer, S. Laug, P. Schmidt, K. Spehar, I. Svoboda, H. Fuess
FULL PAPER
matography [SiO2, petroleum ether/acetone ϭ 9:1 (v/v)] to afford
2.56 g (43%) of 5-methyl-3-phenyl-4-hexenal as a colorless oil. H
NMR (250 MHz): δ ϭ 1.72 (s, 6 H, 6-H, 7-H), 2.76 (mc, 2 H, 2-
zole-2(3H)-thiones 6, or the corresponding pyridine-2(1H)-
thiones 7. Photolysis of thiazolethiones 6 in the presence of
BrCCl3 furnished bromocyclization products 4 in syntheti-
cally useful yields (75Ϫ90%) and diastereoselectivities
(36Ϫ96% de). Other bromine atom donors such as n-
BrC6F13, Br2C2Cl4, 2-bromo-2-chlorodimedone, or diethyl
2-bromo-2-methylmalonate were less efficient for this pur-
pose. Iodocyclized tetrahydrofurans 5 were preferentially
obtained in photochemically initiated reactions between N-
1
H), 4.13 (dt, Jd ϭ 6.7, Jt ϭ 9.3 Hz 1 H, 3-H), 5.29 (dquint, Jd
ϭ
9.3, Jquint ϭ 1.5 Hz, 1 H, 4-H), 7.15Ϫ7.36 (m, 5 H, Ar-H), 9.70 (t,
Jt ϭ 2.2 Hz 1 H, 1-H) ppm. 13C NMR (63 MHz): δ ϭ 18.7 (C-6),
26.5 (C-7), 39.4 (C-3), 42.0 (C-2), 126.7 (C-Ar), 127.2 (C-Ar), 128.4
(C-4, C-Ar), 133.6 (C-5), 139.8(C-Ar), 200.2 (C-1) ppm. MS (70 eV,
EI): m/z (%) ϭ 188 (21) [Mϩ], 173 (45) [Mϩ Ϫ CH3], 145 (100)
[C11H13ϩ], 117 (62) [C9H9ϩ]. C13H16O (188.3): calcd. C 82.94, H
alkenoxypyridine-2(1H)-thiones 7 and either n-C4F9I or di- 8.57; found C 83.16, H 8.51. 5-Methyl-3-phenyl-4-hexenal (2.48 g,
13.17 mmol) was added to a slurry of LiAlH4 (0.25 g, 6.6 mmol)
and anhydrous Et2O (35 mL) according to a general method for
reducing carbonyl compounds into alcohols.[61] Standard work up
of the reaction mixture provided a residue, which was purified by
distillation (150 °C/0.05 mbar) to afford 2.00 g (80%) of bis(ho-
moallylic) alcohol 1c as a colorless oil. H NMR (250 MHz): δ ϭ
1.69 (d, J ϭ 1.4 Hz, 3 H, 6-H), 1.71 (d, J ϭ 1.4 Hz, 3 H, 7-H),
1.81Ϫ2.03 (m, 2 H, 2-H), 3.62 (t, J ϭ 6.4 Hz, 2 H, 1-H), 3.67 (dt,
ethyl 2-iodo-2-methyl malonate.
Experimental Section
1
General Remarks: NMR: Unless otherwise noted in CDCl3 with
Bruker AC 200, AC 250, WM 400, or DMX 600 instruments at 20
°C. Residual protons of deuterated solvent [δH (CDCl3)
ϭ
Jd ϭ 6.4, Jt ϭ 9.3 Hz, 1 H, 3-H), 5.30 (dquint, Jd ϭ 9.3, Jquint
ϭ
7.26 ppm; δH (CD3OD) ϭ 3.38 ppm] or their respective resonances
in 13C NMR spectra [δC (CDCl3) ϭ 77.0 ppm; δC (CD3OD) ϭ
49.3 ppm] were used as internal standards. 19F NMR spectra were
referenced against CFCl3 as internal standard. NOE experiments:
Samples were dissolved in CDCl3, deaerated by three consecutive
freeze-pump-thaw cycles and sealed, irradiation time D2 ϭ 3.0 s
(derived from inversion recovery experiments). Spectra were re-
corded with a Bruker WM 400 spectrometer. IR: in CCl4 in NaCl
cuvettes (0.5 mm) with PerkinϪElmer 1600 FTIR. UV: in EtOH in
1-cm quartz cuvettes with PerkinϪElmer spectrophotometer 330.
MS: Varian MATCH 7 spectrometer (electroimpact, El, 70 eV).
1.4 Hz, 1 H, 4-H), 7.16Ϫ7.33 (m, 5 H, Ar-H) ppm. 13C NMR
(63 MHz): δ ϭ 18.6 (C-6), 26.4 (C-7), 35.8 (C-3), 43.6 (C-2), 65.8
(C-1), 126.4 (C-Ar), 127.8 (C-Ar), 128.6 (C-4, C-Ar), 134.1 (C-5),
143.5 (C-Ar) ppm. MS (70 eV, EI): m/z (%) ϭ 190 (10) [Mϩ], 145
(100) [C11H13ϩ], 117 (32) [C9H9ϩ]. C13H18O (190.3): calcd. C 82.06,
H 9.53; found C 81.73, H 9.21.
1-(p-Biphenylyl)-4-penten-1-ol (1d) and 1-(2-Naphthyl)-4-penten-1-ol
(1e): Bis(homoallylic) alcohols 1d or 1e were prepared from a solu-
tion of 3-butenylmagnesium bromide (0.06 mol) in anhydrous THF
(25 mL), which was treated in a dropwise manner with either 4-(p-
biphenylyl)carbaldehyde (preparation of 1d: 9.91 g, 0.06 mol dis-
solved in 20 mL of dry THF) or naphthalene-2-carbaldehyde (prep-
aration of 1e: 8.76 g, 0.06 mol dissolved in 20 mL of anhydrous
THF).[62] Crude products were purified by column chromatography
[SiO2, gradient: petroleum ether/ EtOAc ϭ 9:1 (v/v) Ǟ petroleum
ether/EtOAc ϭ 8:2 (v/v)] or by recrystallization from petroleum
ether (ca. 50 mL).
DTA: DuPont thermal analyzer 9000; scanning rate 10 °C minϪ1
;
samples were enclosed in metal containers under nitrogen atmos-
phere. C,H,N,S analyses: Microanalytisches Labor, Universität
Würzburg, Carlo Erba 1106 or LECO CHNS-932. GC: Carlo Erba
GC 6000 (Vega Series), FID, connected to Spectra Physics inte-
grator 4290. Helium was used as carrier gas, injector and detector
temperature 240 °C, DB-5 (for bromides 4 and iodides 5) and DB-
225 (for aryl-substituted methyltetrahydrofurans 10) from J & W
Scientific. Photochemical equipment: Osram Power Star HQI/D,
250 W or Southern New England Rayonet chamber reactor
equipped with 350 nm light bulbs (for thiazolethiones 6); Philips
150 W Spotline R 80 (for pyridinethiones 7). 5-Methyl-1-phenyl-
4-hexen-1-ol (1a),[21] 5-methyl-2-phenyl-4-hexen-1-ol (1b),[25] 2-phe-
nyl-4-hexen-1-ol (1f),[20] 3-phenyl-4-penten-1-ol (1h),[20] 2-bromo-2-
chlorodimedone,[34] diethyl 2-bromo-2-methylmalonate,[35] diethyl
2-iodo-2-methylmalonate,[35] 2,2Ј-dithiopyridine-1,1Ј-dioxide,[28] N-
1-(p-Biphenylyl)-4-penten-1-ol (1d): Yield: 9.50 g (72%), colorless
1
needles, m.p. 69Ϫ70 °C. H NMR (250 MHz): δ ϭ 1.78 (m, 2 H,
2-H), 2.03 (br. s, 1 H, OH), 2.19 (mc, 2 H, 3-H), 4.85 (dd, J ϭ 5.5,
7.3 Hz, 1 H, 1-H), 5.00Ϫ5.13 (m, 2 H, 5-H), 5.88 (ddt, Jd ϭ 10.1,
17.1, Jt ϭ 6.7 Hz, 1 H, 4-H), 7.34Ϫ7.49 (m, 5 H, Ar-H), 7.57Ϫ7.64
(m, 4 H, Ar-H) ppm. 13C NMR (63 MHz): δ ϭ 30.5, 38.5, 74.2,
115.5, 126.8, 127.5, 127.6, 127.7, 129.2, 138.6, 140.9, 141.3,
144.1 ppm. MS (70 eV, EI): m/z (%) ϭ 238 (12) [Mϩ], 183 (100)
[Mϩ Ϫ C4H7], 77 (34) [C6H5ϩ]. C17H18O (238.3): calcd. C 85.67,
H 7.61; found C 85.33, H 7.53.
hydroxypyridine-2(1H)-thione,[28]
(E)-4-phenyl-3-buten-1-ol,[58]
and 1-chloro-5-methyl-1-phenyl-4-hexene[21] were prepared accord-
ing to published procedures. Trapping reagents BrCCl3, n-BrC6F13,
Br2C2Cl4, CHI3, n-C4F9I were obtained from commercial suppliers
and were used as received. All solvents were distilled prior to use
and purified according to standard procedures.[59] Petroleum ether
refers to the fraction boiling between 55Ϫ60 °C. Silica gel for col-
umn chromatography (0.063Ϫ0.200 mm) was obtained from
Woelm.
1-(2-Naphthyl)-4-penten-1-ol (1e): Yield: 7.11 g (61%), colorless
1
needles, m.p. 38Ϫ39 °C. H NMR (250 MHz): δ ϭ 1.83Ϫ2.07 (m,
2 H, 2-H), 2.09Ϫ2.24 (m, 2 H, 3-H), 2.37 (br. s, 1 H, OH), 4.84 (t,
J ϭ 6.1 Hz, 1 H, 1-H), 5.01Ϫ5.13 (m, 2 H, 5-H), 5.88 (ddt, Jd
ϭ
10.1, 17.1, Jt ϭ 6.7 Hz, 1 H, 4-H), 7.46Ϫ7.55 (m, 3 H, Ar-H),
7.77Ϫ7.89 (m, 4 H, Ar-H) ppm. 13C NMR (63 MHz): δ ϭ 30.5,
38.8, 74.5, 115.5, 124.5, 125.1, 126.3, 126.6, 128.2, 128.4, 128.8,
133.4, 133.7, 138.6, 142.4 ppm. MS (70 eV, EI): m/z (%) ϭ 212 (32)
[Mϩ], 194 (9) [Mϩ Ϫ H2O], 157 (100) [Mϩ Ϫ C7H4], 129 (88)
[C10H9ϩ]. C15H16O (212.3): calcd. C 84.87, H 7.60; found C 84.52,
H 7.47.
1. Preparation of Substituted Bis(homoallylic) Alcohols 1
5-Methyl-3-phenyl-4-hexen-1-ol
(1c):
Hg(OAc)2
(0.505 g,
1.58 mmol) was added to a solution of (E)-4-phenyl-3-buten-1-ol[58]
(4.00 g, 31.7 mmol) in ethyl vinyl ether (20 mL). The reaction mix-
2-(2-Naphthyl)-4-penten-1-ol (1g): A solution of allyl bromide
ture was stirred for 24 h at 50 °C.[60] Afterwards, K2CO3 (0.5 g) (12.10 g, 0.10 mol) in anhydrous Et2O (20 mL) was added to a
was added and the volatiles were removed under reduced pressure
slurry of magnesium turnings (2.21 g, 0.09 mol)] and dry Et2O at
(600 mbar/ 40 °C). The remaining oil was purified by column chro-
0 °C (80 mL). The reaction mixture was stirred at room tempera-
4042
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Eur. J. Org. Chem. 2003, 4033Ϫ4052

A Radical Version of the Bromo- and the Iodocyclization of Bis(homoallylic) Alcohols
FULL PAPER
ture to allow completion of formation of the Grignard reagent and
and 6c) in anhydrous DMF (11 mL) under argon. The reaction
mixture was stirred for 4Ϫ7 days in the dark and was afterwards
was then treated at 0 °C with a solution of 2-naphthyloxirane[63]
(5.45 g, 0.03 mol) in anhydrous THF (50 mL) as described for the poured into H2O (40 mL). The mixture was extracted with Et2O (2
synthesis of 2-phenyl-4-penten-1-ol (1f) from styrene oxide.[26] The
ϫ 40 mL). The combined organic phases were washed with 2 
crude product was purified by column chromatography [SiO2,
aqueous sodium hydroxide (30 mL) and dried (MgSO4). The sol-
petroleum ether/ EtOAc ϭ 8:2 (v/v)] to provide 2.99 g (44%) of vent was removed (40 °C/900 mbar) to afford a brown oil, which
alkenol 1g as a colorless oil (Rf ϭ 0.15). 1H NMR (250 MHz): δ ϭ was purified by column chromatography [SiO2, petroleum ether/
2.53 (mc, 2 H, 3-H), 3.05 (quint, J ϭ 7.0 Hz, 2-H), 3.82 (dd, J ϭ Et2O ϭ 1:1 (v/v) or petroleum ether/Et2O/CH2Cl2 ϭ 5:1:1 (v/v/v)].
7.3, 11.0 Hz, 1 H, 1-H), 3.88 (dd, J ϭ 6.1, 11.0 Hz, 1 H, 1-H),
4-(p-Chlorophenyl)-N-[5-Methyl-1-phenyl-4-hexen-1-oxy]thiazole-
4.94Ϫ5.10 (m, 2 H, 5-H), 5.75 (ddt, Jd ϭ 10.7, 17.7, Jt ϭ 6.4 Hz, 2(3H)-thione (6a): Yield: 476 mg (1.14 mmol, 57%), colorless crys-
1 H, 4-H), 7.36 (dd, J ϭ 1.8, 8.5 Hz, 1 H, Ar-H), 7.48 (mc, 2 H,
Ar-H), 7.68 (d, J ϭ 1.5 Hz, 1 H, Ar-H), 7.78Ϫ7.48 (m, 3 H, Ar-
H) ppm. 13C NMR (63 MHz): δ ϭ 36.5, 48.3, 66.7, 116.4, 125.5,
tals, Rf ϭ 0.35 [petroleum ether/Et2O ϭ 1:1 (v/v)], m.p. 102 Ϯ 2 °C
(DTA). H NMR (CDCl3, 250 MHz): δ ϭ 1.44 (s, 3 H, 6-H), 1.64
(s, 3 H, 7-H), 1.75Ϫ2.10 (m, 4 H, 2-H, 3-H), 5.07 (t, J ϭ 6.8 Hz,
1
126.0, 126.1, 126.9, 127.5, 127.6, 128.3, 132.5, 133.4, 136.2, 1 H, 1-H), 5.99 (dd, J ϭ 8.2, 6.4 Hz, 1 H, 4-H), 6.18 (s, 1 H, 5Ј-
139.3 ppm. MS (70 eV, EI): m/z (%) ϭ 212 (40) [Mϩ], 181 (51) [Mϩ H), 6.81 (d, J ϭ 7.5 Hz, 2 H, Ar-H), 6.98 (d, J ϭ 8.4 Hz, 2 H, Ar-
Ϫ CH2OH], 153 (100) [C10H7C2H2ϩ], 129 (41) [C10H8ϩ]. C15H16O H), 7.17Ϫ7.35 (m, 5 H, Ph-H) ppm. 13C NMR (CDCl3, 63 MHz):
(212.8): calcd. C 84.87, H 7.60; found C 84.98, H 7.73.
2. Preparation of Alkoxyl Radical Precursors
2.1 N-Alkoxythiazolethiones 6:
δ ϭ 17.7, 24.1, 25.6, 32.3, 86.3, 104.3, 123.0, 127.3, 128.0, 128.4,
128.9, 129.1, 129.6, 132.6, 135.7, 141.7, 172.3 (CϭS) ppm. MS
(70 eV, EI): m/z (%)
ϭ Ϫ H], 227 (100)
416 (0.1) [Mϩ
[Cl(C6H4)C3H2NS2ϩ], 192 (17) [(C6H4)C3H2NS2ϩ], 168 (46)
[Cl(C6H4)C2H3NOϩ], 134 (22) [C9H10Oϩ]. C22H22ClNOS2 (416.0)
calcd. C 63.52, H 5.33, N 3.37, S 15.42; found C 63.29, H 5.61, N
3.18, S 14.29.
Substituted 4-Penten-1-yl p-Toluenesulfonates: A solution of bis(ho-
moallylic) alcohol 1b or 1c (500 mg, 2.63 mmol) and DABCO
(590 mg, 5.26 mmol) in CH2Cl2 (2.5 mL) was treated with p-tolu-
enesulfonyl chloride (751 mg, 3.94 mmol) at 0 °C. The slurry was
stirred for 1 h at 0 °C, diluted with Et2O (10 mL), and then treated
with aqueous 2  HCl (10 mL) in order to dissolve the colorless
precipitate. The organic layer was separated and the aqueous phase
was washed with Et2O (2 ϫ 10 mL). The combined organic phases
were extracted with 2  aqueous HCl, satd. aqueous NaHCO3, and
brine (10 mL each), and dried (MgSO4). The solvent was removed
under reduced pressure (40 °C/ 900 mbar) to afford analytically
pure alkyl p-toluenesulfonate.
1,2-Bis[4-(p-chlorophenyl)-2-thiazyl]disulfane:[23] Yield: 208 mg
(23%), colorless crystals, Rf ϭ 0.45 [petroleum ether/Et2O ϭ 1:1 (v/
v)], m.p. 156 °C (ref.[30] 156Ϫ158 °C). 1H NMR spectroscopic data
are in agreement with reported values.[30]
4-(p-Chlorophenyl)-N-[5-Methyl-2-phenyl-4-hexen-1-oxy]-thiazole-
2(3H)-thione (6b): Yield: 398 mg (0.96 mmol, 48%), colorless crys-
tals, Rf ϭ 0.40 [petroleum ether/Et2O/CH2Cl2 ϭ 5:1:1 (v/v/v)], m.p.
1
98 Ϯ 2 °C (DTA). H NMR (CDCl3, 250 MHz): δ ϭ 1.64 (s, 3 H,
6-H), 1.76 (s, 3 H, 7-H), 2.29Ϫ2.40 (m, 1 H, 3-H), 2.49Ϫ2.61 (m,
1 H, 3-H), 3.17 (quint, J ϭ 6.4 Hz, 1 H, 2-H), 4.26 (t, J ϭ 7.6 Hz,
1 H, 1-H), 4.56 (dd, J ϭ 5.7, 7.6 Hz, 1 H, 1-H), 5.10 (mc, 1 H, 4-
H), 6.61 (s, 1 H, 5Ј-H), 7.15Ϫ7.21 (m, 2 H, Ph-H), 7.35Ϫ7.55 (m,
7 H, Ar-H) ppm. 13C NMR (CDCl3, 63 MHz): δ ϭ 17.8, 25.6,
31.1, 44.6, 79.2, 105.2, 120.9, 126.0, 126.7, 127.7, 128.3, 128.9,
129.3, 133.6, 135.9, 139.8, 140.9, 176.6 (CϭS) ppm. MS (70 eV,
EI): m/z (%) ϭ 188 (12) [C13H16Oϩ], 120 (100) [C8H8Oϩ], 104 (39)
[C8H8ϩ], 91 (46) [C7H7ϩ]. C22H22ClNOS2 (416.0) calcd. C 63.52,
H 5.33, N 3.37, S 15.42; found C 63.23, H 5.24, N 3.39, S 15.43.
4-(p-Chlorophenyl)-N-[5-methyl-3-phenyl-4-hexen-1-oxy]-thiazole-
2(3H)-thione (6c): Yield: 443 mg (1.07 mmol, 53%), colorless crys-
tals, Rf ϭ 0.40 [petroleum ether/Et2O/CH2Cl2 ϭ 5:1:1 (v/v/v)], m.p.
100 Ϯ 2 °C (DTA). 1H NMR (CDCl3, 250 MHz): δ ϭ 1.69 (s, 3
H, 6-H), 1.74 (s, 3 H, 7-H), 2.02 (mc, 2 H, 2-H), 3.56 (dt, Jd ϭ 6.3,
Jt ϭ 7.5 Hz, 1 H, 3-H), 4.12 (t, J ϭ 6.7 Hz, 2 H, 1-H), 5.20 (dquint,
Jd ϭ 9.3, J ϭ 1.2 Hz, 1 H, 4-H), 6.57 (s, 1 H, 5Ј-H), 7.09 (mc, 2
H, Ar-H), 7.23Ϫ7.36 (m, 3 H, Ph-H), 7.52Ϫ7.59 (m, 4 H, Ph-H,
Ar-H) ppm. 13C NMR (CDCl3, 63 MHz): δ ϭ 18.6, 26.2, 35.0,
40.8, 75.4, 105.8, 126.5, 127.1, 127.8, 128.4, 129.6, 130.0, 133.1,
136.7, 140.3, 144.8, 181.1 (CϭS) ppm. MS (70 eV, EI): m/z (%) ϭ
226 (5) [C9H5NClS2ϩ], 188 (31) [C13H16Oϩ], 117 (47) [C9H9ϩ], 91
(42) [C7H7ϩ]. C22H22ClNOS2 (416.0) calcd. C 63.52, H 5.33, N
3.37, S 15.42; found C 63.16, H 5.28, N 3.37, S 15.19.
5-Methyl-2-phenyl-4-hexen-1-yl p-Toluenesulfonate: Yield 2.52 g
1
(96%), colorless oil. H NMR (250 MHz): δ ϭ 1.50 (s, 3 H, 6-H),
1.60 (s, 3 H, 7-H), 2.21Ϫ2.30 (m, 1 H, 3 H), 2.35Ϫ2.50 (m, 1 H, 3
H), 2.43 (s, 3 H, CH3), 2.91 (quint, Jquint ϭ 6.4 Hz, 1 H, 2-H), 4.13
(ddd, J ϭ 6.4, 6.7, 9.6 Hz, 2 H, 1-H), 4.92 (mc, 1 H, 4-H), 7.06 (m,
2 H, Ar-H), 7.21Ϫ7.38 (m, 5 H, Ph-H), 7.62 (d, Jd ϭ 8.2 Hz, 2 H,
Ar-H) ppm. 13C NMR (63 MHz): δ ϭ 17.8 (C-6), 21.6 (CH3), 25.7
(C-7), 30.5 (C-3), 45.2 (C-2), 73.2 (C-1), 120.6 (C-4), 126.9, 127.8,
127.8 (C-Ar), 128.4 (C-5), 128.5, 129.7, 134.0, 140.5, 144.5 (C-Ar)
ppm. MS (70 eV, EI): m/z (%) ϭ 190 (6) [Mϩ Ϫ C7H7SO3], 155
(20) [C7H7SO3ϩ], 104 (41) [C8H8ϩ], 91 (100) [C7H7ϩ]. C20H24O3S
(344.5): calcd. C 69.74, H 7.02, S 9.31; found C 70.02, H 6.92,
S 8.96.
5-Methyl-3-phenyl-4-hexen-1-yl p-Toluenesulfonate: Yield 2.32 g
(88%), colorless oil. 1H NMR (250 MHz): δ ϭ 1.60 (d, J ϭ 1.4 Hz,
3 H, 6-H), 1.66 (d, J ϭ 1.4 Hz, 3 H, 7-H), 1.83Ϫ2.08 (m, 1 H, 2-
H), 2.45 (s, 3 H, CH3), 3.59 (dt, Jd ϭ 6.9, Jt ϭ 9.3 Hz, 1 H, 3-H),
3.91Ϫ 4.06 (m, 2 H, 1-H), 5.16 (dquint, Jd ϭ 9.3, Jquint ϭ 1.4 Hz,
1 H, 4-H), 7.08Ϫ7.35 (m, 7 H, Ar-H), 7.76 (d, J ϭ 8.2 Hz, 2 H,
Ar-H) ppm. 13C NMR (63 MHz): δ ϭ 18.1 (C-6), 25.9 (C-7), 29.9
(CH3), 34.6 (C-3), 40.9 (C-2), 71.1 (C-1), 126.0 (C-4). 126.4, 127.2,
127.4, 127.9 (C-Ar), 128.3 (C-5), 128.5, 136.9, 137.5, 144.5 (C-Ar)
ppm. MS (70 eV, EI): m/z (%) ϭ 190 (10) [Mϩ Ϫ C7H7SO3], 155
(30) [C7H7SO3ϩ], 91 (100) [C7H7ϩ]. C20H24O3S (344.5): calcd. C
69.74, H 7.02, S 9.31; found C 68.96, H 6.78, S 9.58.
2.2 Preparation of N-(Alkoxyl)pyridine-2(1H)-thiones 7d and 7e
from 2,2Ј-Dithiopyridine-1,1Ј-dioxide
A solution of bis(homoallylic) alcohols 1d or 1e (3.60 mmol) in
anhydrous CH2Cl2 was treated with 2,2Ј-dithiopyridine-1,1Ј-diox-
ide[28] (1.00 g, 4.00 mmol) and triphenylphosphane (1.05 g,
4.00 mmol), in an extension of the method outlined in ref.[29]
N-Alkoxythiazolethiones 6: A flame-dried, round-bottomed flask
was charged with 4-(p-chlorophenyl)-N-hydroxythiazole-2(3H)-
thione tetraethylammonium salt (1.28 g, 5.27 mmol) and a solution
of 6-chloro-2-methyl-6-phenyl-2-hexene (417 mg, 2.00 mmol, for N-[1-(p-Biphenylyl)-4-penten-1-oxy]pyridine-2(1H)-thione
6a) or an appropriate alkenyl tosylate (689 mg, 2.00 mmol, for 6b
(7d):
Yield: 1.28 g (37%), yellow oil. 1H NMR (250 MHz): δ ϭ
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4043

ˇ
J. Hartung, R. Kneuer, S. Laug, P. Schmidt, K. Spehar, I. Svoboda, H. Fuess
FULL PAPER
2.06Ϫ2.20 (m, 3 H, 2-H, 3-H), 2.51Ϫ2.59 (m, 1 H, 2-H), 4.16Ϫ5.05
(m, 2 H, CH2), 5.86 (ddt, Jd ϭ 10.3, 16.2, Jt ϭ 5.9 Hz, 1 H, 4-H), 1 H, 2-H), 4.54 (t, J ϭ 8.1 Hz, 1 H, 1-H), 4.88 (dd, J ϭ 5.9, 8.5 Hz,
5.95 (dd, J ϭ 6.3, 8.5 Hz, 1 H, 1-H), 6.18 (dt, Jd ϭ 1.8, Jt ϭ 7.0 Hz, 1 H, 1-H), 4.99 (d, J ϭ 9.9 Hz, 1 H, 5-H), 5.07 (d, J ϭ 16.9 Hz, 1
1 H, 5Ј-H), 7.00 (ddd, J ϭ 1.8, 7.0, 8.8 Hz, 1 H, 4Ј-H), 7.02 (mc, 1 H, 5-H), 5.74 (ddt, Jd ϭ 9.9, 16.9, Jt ϭ 7.0 Hz, 1 H, 4-H), 6.43 (dt,
H, Ar-H), 7.31Ϫ7.40 (m, 3 H, Ar-H), 7.44 (mc, 2 H, Ar-H), 7.59 Jd ϭ 1.8, Jt ϭ 7.0 Hz, 1 H, CH), 7.07 (mc, 1 H, CH), 7.33 (mc, 1
(mc, 4 H, Ar-H), 7.64 (dd, J ϭ 1.5, 7.9 Hz, 1 H, 6Ј-H) ppm. 13C H, Ar-H), 7.42 (dd, J ϭ 1.8, 8.5 Hz, 1 H, CH), 7.48 (mc, 2 H, Ar-
(400 MHz): δ ϭ 2.60 (mc, 1 H, 3-H), 2.74 (mc, 1-H, 3-H), 3.44 (mc,
NMR (63 MHz): δ ϭ 29.4, 32.3, 85.8, 111.6, 115.2, 127.0, 127.4,
127.7, 128.8, 129.2, 132.5, 135.7, 137.4, 137.7, 139.4, 140.1, 142.3,
H), 7.62 (dd, J ϭ 1.8, 8.8 Hz, 1 H, CH), 7.74 (br. s, 1 H, Ar-H),
7.80Ϫ7.85 (m, 3 H, Ar-H) ppm. 13C NMR (100 MHz): δ ϭ 36.9,
175.9 (CϭS) ppm. IR (CCl4): ν˜ ϭ 1087, 1131, 1176, 1276, 1408, 44.4, 79.6, 112.9, 117.2, 125.8, 125.9, 126.2, 126.9, 127.7, 127.8,
1447, 1525, 1609, 1639, 2975, 3087 cmϪ1. MS (70 eV, EI): m/z
128.4, 132.6, 132.7, 135.3, 137.7, 138.1, 138.1, 176.0 (CϭS) ppm.
(%) ϭ 238 (3) [C17H18Oϩ], 181 (100) [C12H9COϩ], 152 (41) MS (70 eV, EI): m/z (%) ϭ 321 (13) [Mϩ], 211 (35) [C15H15Oϩ],
[C12H8ϩ], 127 (4) [C5H5NOSϩ]. C22H21NOS (347.5): calcd. C 194 (61) [C15H14ϩ], 179 (64) [C14H11ϩ], 141 (90) [C11H9ϩ], 111 (100)
76.05, H 6.09, N 4.03, S 9.27; found C 75.99, H 6.49, N 3.97,
S 8.79.
[C5H5NSϩ]. C20H19NOS (321.4): calcd. C 74.73, H 5.96, N 4.36, S
9.98; found C 74.09, H 5.72, N 4.19, S 9.68.
N-[1-(2-Naphthyl)-4-penten-1-oxy]pyridine-2(1H)-thione (7e): Yield:
1.08 g (46%), tan solid, m.p. 104Ϫ105 °C. 1H NMR (250 MHz):
δ ϭ 2.07Ϫ2.21 (m, 3 H, 2-H, 3-H, 3-H), 2.58Ϫ2.69 (m, 1 H, 2-H),
4.96Ϫ5.03 (m, 2 H, 5-H), 5.86 (ddt, Jd ϭ 16.9, 10.3, Jt ϭ 6.2 Hz 1
H, 4-H), 6.02Ϫ6.08 (m, 2 H, 1-H, 5Ј-H), 6.92Ϫ6.96 (m, 2 H, Ar-
H), 7.49Ϫ7.55 (m, 2 H, Ar-H, 4Ј-H), 7.59 (dd, J ϭ 1.8, 8.4 Hz, 1
H, 3Ј-H), 7.62Ϫ7.66 (m, 2 H, Ar-H), 7.76 (mc, 1 H, Ar-H), 7.86
(mc, 1 H, 6Ј-H), 7.91 (d, J ϭ 8.4 Hz, 1 H, Ar-H) ppm. 13C NMR
(63 MHz): δ ϭ 29.4, 32.4, 86.4, 111.6, 115.2, 124.8, 126.6, 127.7,
128.2, 129.1, 129.3, 132.5, 133.1, 133.8, 134.1, 137.4, 137.8, 139.3,
176.0 (CϭS) ppm. IR (CCl4): ν˜ ϭ 1132, 1176, 1224, 1276, 1408,
1448, 1525, 1609, 1639, 2905, 3048 cmϪ1. MS (70 eV, EI): m/z
(%) ϭ 321 (2) [Mϩ], 194 (28) [C15H14ϩ], 141 (41) [C11H9ϩ], 127
(25) [C5H5NOSϩ]. C20H19NOS (321.4): calcd. C 74.73, H 5.96, N
4.63, S 9.97; found C 74.53, H 6.08, N 4.57, S 9.97.
3. Bromocyclizations
3.1 Preparation of Bromocyclized Products 4 from N-Alkoxythiazo-
lethiones 6: A solution of an N-alkenoxy-4-(p-chlorophenyl)thia-
zole-2(3H)-thione 6 (34.5 mg, 0.100 mmol) and BrCCl3 (159 mg,
0.800 mmol) in deaerated (Ar) C6H6 (1 mL) was photolyzed for
15 min in a Rayonet chamber reactor. Afterwards, solvent and
residual BrCCl3 were removed under reduced pressure (40 °C/
200 mbar) to provide an oily residue which was distilled (150 °C/
0.05 mbar) and purified by column chromatography (SiO2).
2-(1-Bromo-1-methylethyl)-5-phenyltetrahydrofuran (4a): Yield:
23.5 mg (87%), colorless oil, b.p. 130 °C/ 10Ϫ2 mbar (Kugelrohr),
cis:trans ϭ 28:72, Rf ϭ 0.60 [petroleum ether/EtOAc ϭ 9:1(v/v)]
ppm. MS (70 eV, EI): m/z (%) ϭ 270/268 (2) [Mϩ], 147 (100)
[C10H11Oϩ], 129 (29) [C10H11OϩϪH2O], 104 (100) [C8H8ϩ], 91 (39)
[C7H7ϩ], 77 (12) [C6H5ϩ], 43 (18) [C2H3Oϩ], 41 (19) [C3H5ϩ].
2.3 N-[2-(2-Naphthyl)-4-penten-1-oxy]pyridine-2(1H)-thione (7g): 2-
(2-Naphthyl)-4-penten-1-ol (1g) (580 mg, 2.73 mmol) and p-tolu-
C13H17BrO (269.2) calcd. C 58.00, H 6.37; found C 57.90, H 6.30.
1
enesulfonyl chloride (781 mg, 4.10 mmol) were dissolved in CH2Cl2 cis-4a: H NMR (CDCl3, 250 MHz): δ ϭ 1.82 (s, 3 H, 2Ј-H), 1.84
(3 mL) and treated with DABCO (613 mg, 5.46 mmol) according (s, 3 H, 3Ј-H), 2.04Ϫ2.19 (m, 2 H, 3-H), 2.20Ϫ2.34 (m, 2 H, 4-H),
to the method reported in ref.[27] Work up of the reaction mixture
provided 981 mg (98%) of 2-(2-naphthyl)-4-penten-1-yl p-toluene-
sulfonate as a colorless liquid. Rf ϭ 0.76 [SiO2, petroleum ether/
3.96 (dd, J ϭ 6.1, 7.6 Hz, 1 H, 2-H), 4.90 (dd, J ϭ 5.8, 9.5 Hz, 1
H, 5-H), 7.24Ϫ7.38 (m, 5 H, Ph-H) ppm. 13C NMR (CDCl3,
63 MHz): δ ϭ 29.2 (C-2Ј), 29.7 (C-3Ј), 31.4 (C-4), 34.7 (C-3), 69.3
CH2Cl2/ CH3OH ϭ 10:4:1 (v/v/v)]. 1H NMR (250 MHz): δ ϭ 2.34 (C-1Ј), 82.0 (C-2), 86.4 (C-5), 126.0, 127.3, 128.5, 142.0 (C-Ph).
(s, 3 H, CH3), 2.52 (mc, 2 H, 3-H), 3.17 (mc, 1 H, 2-H), 4.18 (dd, trans-4a: 1H NMR (CDCl3, 250 MHz): δ ϭ 1.78 (s, 3 H, 2Ј-H),
J ϭ 6.4, 9.5 Hz, 1 H, 1-H), 4.26 (dd, J ϭ 7.0, 9.8 Hz, 1 H, 1-H), 1.84 (s, 3 H, 3Ј-H), 1.81Ϫ1.98 (m, 1 H, 3-H), 2.03Ϫ2.19 (m, 1 H,
4.95 (d, J ϭ 10.1 Hz, 1 H, 5-H), 5.00 (d, J ϭ 17.1 Hz, 1 H, 5-H),
4-H), 2.14Ϫ2.36 (m, 1 H, 3-H), 2.38Ϫ2.47 (m, 1 H, 4-H), 4.11 (dd,
5.63 (ddt, Jd ϭ 10.1, 17.1, Jt ϭ 7.0 Hz, 1 H, 4-H), 7.08 (d, J ϭ J ϭ 6.7, 8.2 Hz, 1 H, 2-H), 5.12 (dd, J ϭ 5.7, 9.0 Hz, 1 H, 5-H),
8.9 Hz, 2 H, Ar-H), 7.19 (dd, J ϭ 1.8, 8.6 Hz, 1 H, Ar-H), 7.24Ϫ7.38 (m, 5 H, Ph-H) ppm. 13C NMR (CDCl3, 63 MHz): δ ϭ
7.44Ϫ7.48 (m, 3 H, Ar-H), 7.54 (d, J ϭ 8.2 Hz, 2 H, Ar-H), 29.8 (C-2Ј), 29.9 (C-3Ј), 31.1 (C-4), 35.7 (C-3), 68.4 (C-1Ј), 82.0 (C-
7.69Ϫ7.73 (m, 2 H, Ar-H), 7.79 (mc, 1 H, Ar-H) ppm. 13C NMR
2), 87.1 (C-5), 125.7, 127.4, 128.3, 142.9 (C-Ph) ppm.
(63 MHz): δ ϭ 21.5, 36.0, 44.8, 73.1, 117.4, 125.7, 125.8, 126.1, 4-[(p-Chlorophenyl)-2-trichloromethylsulfanyl]thiazole (8) (X
126.6, 127.5, 127.6, 127.7, 128.2, 129.5, 132.6, 132.6, 134.9, 137.3, CCl3): Distillation of the reaction mixture from the photoreaction
144.5 ppm. MS (70 eV, EI): m/z (%) ϭ 366 (5) [Mϩ], 325 (3) of thione 6a and BrCCl3 provided tetrahydrofuran 4a and a residue.
؍
[C19H17O3Sϩ], 194 (59) [C15H14ϩ], 179 (32) [C14H11ϩ], 155 (79)
This residue was recrystallized from petroleum ether/CH2Cl2 to
[C7H7O2Sϩ], 91 (100) [C7H7ϩ]. C22H22O3S (366.5): calcd. C 72.10, provide 24.5 mg (71%) of thiazole 8 as colorless crystals: m.p. 102
1
H 6.05, S 8.75; found C 71.86, H 6.10, S 8.47. A flame-dried, °C, Rf ϭ 0.85 [petroleum ether/Et2O/CH2Cl2 ϭ 10:1:1 (v/v/v)]. H
round-bottomed flask was charged with N-hydroxypyridine-2(1H)-
thione tetraethylammonium salt (169 mg, 0.657 mmol), 2-(2-naph-
NMR (250 MHz): δ ϭ 7.42 (mc, 2 H, 2Ј-H), 7.84 (s, 1 H, 5-H),
7.89 (mc, 2 H, 3Ј-H) ppm. 13C NMR (CDCl3, 63 MHz): δ ϭ 96.7,
thyl)-4-penten-1-yl p-toluenesulfonate (219 mg, 0.598 mmol) and 120.8, 127.8, 129.1, 131.8, 134.8, 154.8, 156.7 ppm. MS (70 eV, EI):
anhydrous DMF (1 mL). The reaction mixture was stirred for 48 h
m/z (%) ϭ 345 (28) [Mϩ], 310 (8) [Mϩ Ϫ Cl], 226 (63) [Mϩ
in the dark at 20 °C and was then poured into H2O (10 mL). The CCl3], 191 (26) [C9H5NS2ϩ], 168 (100) [C8H5ClSϩ]. C10H5Cl4NS2
Ϫ
organic layer was separated and the aqueous phase extracted with
Et2O (3 ϫ 10 mL). The combined organic phases were washed with
2  aqueous NaOH (10 mL) and dried (MgSO4). Removal of the
solvent under reduced pressure afforded a dark yellow oil which
was purified by column chromatography [SiO2, MTB/petroleum
ether ϭ 2:1 (v/v)] to afford analytically pure N-[2-(2-naphthyl)-4-
(345.1): calcd. C 34.81, H 1.46, N 4.06, S 18.58; found C 35.78, H
2.06, N 3.94, S 17.88.
2-(1-Bromo-1-methylethyl)-4-phenyltetrahydrofuran (4b): Yield:
20.2 mg (75%), colorless oil, b.p. 130 °C/ 10Ϫ2 mbar (Kugelrohr),
cis:trans ϭ 68:32. MS (70 eV, EI): m/z (%) ϭ 270/268 (7) [Mϩ], 147
(59) [C10H11Oϩ], 131 (90) [C10H11ϩ], 117 (35) [C9H9ϩ], 104 (100)
penten-1-oxy]pyridine-2(1H)-thione (7g) (76.6 mg, 40%). Yellow [C8H8ϩ], 91 (92) [C7H7ϩ], 77 (16) [C6H5ϩ], 71 (21) [C4H7Oϩ], 51
oil, Rf ϭ 0.50 [MTB/petroleum ether ϭ 2:1 (v/v)]. 1H NMR
(15) [C4H3ϩ], 43 (30) [C2H3Oϩ], 41 (23) [C3H5ϩ], 39 (14) [C3H3ϩ].
4044
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4033Ϫ4052

A Radical Version of the Bromo- and the Iodocyclization of Bis(homoallylic) Alcohols
FULL PAPER
C13H17BrO (269.2) calcd. C 58.00, H 6.37; found C 57.71, H 6.10.
1.61Ϫ1.71 (m, 1 H, 5-H), 1.73Ϫ1.88 (m, 1 H, 5-H), 2.19Ϫ2.29 (m,
2 H, 4-H), 3.99 (dd, J ϭ 8.2, 8.5 Hz, 1 H, 3-H), 4.62 (dd, J ϭ 2.7,
cis-4b: Rf ϭ 0.70 [petroleum ether/Et2O/CH2Cl2 ϭ 10:1:1 (v/v/v)].
1H NMR (CDCl3, 250 MHz): δ ϭ 1.75 (s, 3 H, 2Ј-H), 1.84 (s, 3 H, 11.6 Hz, 1 H, 5-H), 7.19Ϫ7.28 (m, 5 H, Ph-H) ppm. 13C NMR
3Ј-H), 2.06Ϫ2.20 (m, 1 H, 3-H), 2.43Ϫ2.53 (m, 1 H, 3-H),
(CDCl3, 63 MHz): δ ϭ 18.0 (C-2Ј), 29.6 (C-3Ј), 32.1 (C-4), 36.5 (C-
3.45Ϫ3.60 (m, 1 H, 4-H), 3.90 (dd, J ϭ 8.1, 10.1 Hz, 1 H, 5-H), 5), 57.3 (C-3), 72.2 (C-6), 76.1 (C-2), 125.9, 127.5, 128.4, 142.4 (C-
3.98 (dd, J ϭ 6.1, 9.3 Hz, 1 H, 2-H), 4.26 (t, J ϭ 8.1 Hz, 1 H, 5-
H), 7.21Ϫ7.36 (m, 5 H, Ph-H) ppm. 13C NMR (CDCl3, 63 MHz):
δ ϭ 30.3 (C-2Ј), 30.7 (C-3Ј), 37.7 (C-3), 45.6 (C-4), 68.9 (C-1Ј), 75.2
(C-5), 87.3 (C-2), 126.3, 127.2, 128.7, 140.0 (C-Ph) ppm.
Ph) ppm.
Bromocyclization of 5-Methyl-2-phenyl-4-hexen-1-ol (1b)
2-(1-Bromo-1-methylethyl)-4-phenyltetrahydrofuran (4b): Yield:
46.4 mg (17%), colorless oil, b.p. 130 °C/10Ϫ2 mbar (Kugelrohr),
cis:trans ϭ 67:33.
trans-4b: Rf ϭ 0.80 [petroleum ether/Et2O/CH2Cl2 ϭ 10:1:1 (v/v/
1
v)]. H NMR (CDCl3, 250 MHz): δ ϭ 1.74 (s, 3 H, 2Ј-H), 1.81 (s,
3 H, 3Ј-H), 2.09Ϫ2.19 (m, 1 H, 3-H), 2.37Ϫ2.49 (m, 1 H, 3-H),
3.51 (dq, Jd ϭ 8.8, Jq ϭ 6.9 Hz, 1 H, 4-H), 3.88 (dd, J ϭ 6.9,
8.6 Hz, 1 H, 5-H), 4.03 (dd, J ϭ 6.7, 7.9 Hz, 1 H, 2-H), 4.33 (dd,
J ϭ 6.9, 8.6 Hz, 1 H, 5-H), 7.20Ϫ7.37 (m, 5 H, Ph-H) ppm. 13C
NMR (CDCl3, 63 MHz): δ ϭ 29.8 (C-2Ј), 30.9 (C-3Ј), 37.3 (C-3),
44.9 (C-4), 68.7 (C-1Ј), 75.3 (C-5), 88.2 (C-2), 126.6, 127.1, 128.6,
140.0 (C-Ph) ppm.
cis-3-Bromo-2,2-dimethyl-5-phenyltetrahydropyran cis-(12b): Yield:
181 mg (67%); colorless crystals, m.p. 64 °C, b.p. 145 °C/10Ϫ2 mbar
(Kugelrohr), cis:trans ϭ Ͻ2:Ͼ98, Rf ϭ 0.40 [petroleum ether/ace-
tone/CH2Cl2 ϭ 8:1:1 (v/v/v)]. 1H NMR (CDCl3, 250 MHz): δ ϭ
1.43 (s, 3 H, 1Ј-H), 1.48 (s, 3 H, 2Ј-H), 2.31Ϫ2.44 (m, 2 H, 4-H),
3.03 (sept, J ϭ 5.5 Hz, 1 H, 5-H), 3.64Ϫ3.82 (m, 2 H, 6-H), 4.10
(ddd, J ϭ 7.3, 9.5, 11.3 Hz, 1 H, 3-H), 7.20Ϫ7.33 (m, 5 H, Ph-H)
ppm. 13C NMR (CDCl3, 63 MHz): δ ϭ 17.4 (C-2Ј), 29.2 (C-1Ј),
38.0 (C-4), 45.5 (C-5), 56.4 (C-3), 66.5 (C-6), 75.0 (C-2), 127.1,
127.2, 128.7, 140.0 (C-Ph) ppm. MS (70 eV, EI): m/z (%) ϭ 270/
268 (6) [Mϩ], 212/210 (21) [Mϩ Ϫ2CH3Ϫ2CH2], 131 (100)
[C10H11ϩ], 117 (24) [C9H9ϩ], 104 (87) [C8H8ϩ], 91 (70) [C7H7ϩ], 77
(12) [C6H5ϩ]. C13H17BrO (269.2) calcd. C 58.00, H 6.37; found C
58.17, H 6.16.
2-(1-Bromo-1-methylethyl)-3-phenyl tetrahydrofuran (4c): Yield:
24.1 mg (90%), colorless oil, b.p. 130 °C/ 10Ϫ2 mbar (Kugelrohr),
cis:trans ϭ Ͻ2:Ͼ98. trans-4c: Rf ϭ 0.75 [petroleum ether/Et2O/
1
CH2Cl2 ϭ 10:1:1 (v/v/v)]. H NMR (CDCl3, 250 MHz): δ ϭ 1.57
(s, 3 H, 2Ј-H), 1.76 (s, 3 H, 3Ј-H), 2.00Ϫ2.15 (m, 1 H, 4-H),
2.41Ϫ2.54 (m, 1 H, 4-H), 3.45 (dt, Jd ϭ 6.9, Jt ϭ 8.4 Hz, 1 H, 3-
H), 3.89 (d, J ϭ 6.9 Hz, 1 H, 2-H), 4.13 (dd, J ϭ 5.7, 7.9 Hz, 2 H,
5-H), 7.18Ϫ7.34 (m, 5 H, Ph-H) ppm. 13C NMR (CDCl3,
63 MHz): δ ϭ 31.5 (C-2Ј), 31.9 (C-3Ј), 38.2 (C-4), 49.0 (C-3), 69.3
(C-1Ј), 75.4 (C-5), 93.1 (C-2), 127.7, 128.6, 128.8, 137.3 (C-Ph)
Bromocyclization of 5-Methyl-3-phenyl-4-hexen-1-ol (1c)
ppm. MS (70 eV, EI): m/z (%) ϭ 270/268 (2) [Mϩ], 188 (5) [Mϩ
Ϫ
2-(1-Bromo-1-methylethyl)-3-phenyltetrahydrofuran (4c): Yield:
HBr], 147 (99) [C10H11Oϩ], 117 (100) [C9H9ϩ], 91 (76) [C7H7ϩ]. 9.1 mg (3%), colorless oil, b.p. 130 °C/10Ϫ2 mbar (Kugelrohr), cis:-
C13H17BrO (269.2) calcd. C 58.00, H 6.37; found C 57.67, H 6.21.
trans ϭ Ͻ2:Ͼ98.
3.2 NBS-Mediated Bromocylizations of Bis(homoallylic) Alcohols 1
trans-3-Bromo-2,2-dimethyl-4-phenyltetrahydropyran
trans-(12c):
Yield: 204 mg (76%), colorless crystals, m.p. 81 °C, b.p. 145 °C/
Alkenol 1 (190 mg, 1.00 mmol) and NBS (267 mg, 1.50 mmol) were
dissolved in CH2Cl2 (2 mL). The reaction mixture was stirred for
72 h at 25 °C. Afterwards, petroleum ether was added (2 mL) and
the precipitate was filtered off. The solids were washed with petro-
leum ether (2 ϫ 2 mL) and the combined organic phases were
treated with NaOAc (15 mg). Subsequently, the solvent was re-
moved under reduced pressure (40 °C/450 mbar) to afford a crude
product, which was distilled (Kugelrohr, 150 °C/0.05 mbar). The
distillate was purified by column chromatography (SiO2).
10Ϫ2 mbar (Kugelrohr), cis:trans ϭ Ͻ2:Ͼ98, Rf ϭ 0.40 [petroleum
ether/acetone/CH2Cl2
ϭ
8:1:1 (v/v/v)]. 1H NMR (CDCl3,
250 MHz): δ ϭ 1.48 (s, 3 H, 1Ј-H), 1.53 (s, 3 H, 2Ј-H), 1.85 (dddd,
J ϭ 1.8, 2.8, 4.6, 13.7 Hz, 1 H, 5-H), 1.97 (dddd, J ϭ 1.8, 5.8, 12.0,
13.7 Hz, 1 H, 5-H), 3.17 (ddd, J ϭ 4.6, 11.8, 12.0 Hz, 1 H, 4-H),
3.76 (ddd, J ϭ 1.8, 5.8, 12.0 Hz, 1 H, 6-H), 3.84 (dt, Jd ϭ 2.8, Jt ϭ
12.0 Hz, 1 H, 6-H), 4.09 (d, J ϭ 11.8 Hz, 1 H, 3-H), 7.19Ϫ7.39 (m,
5 H, Ph-H) ppm. 13C NMR (CDCl3, 63 MHz): δ ϭ 18.2 (C-2Ј),
30.0 (C-1Ј), 37.0 (C-5), 47.0 (C-4), 60.9 (C-3), 63.3 (C-6), 76.0 (C-
2), 127.0, 127.3, 128.5, 143.5 (C-Ph) ppm. MS (70 eV, EI): m/z
(%) ϭ 270/268 (7) [Mϩ], 189 (51) [Mϩ Ϫ Br], 147 (36) [C10H11Oϩ],
131 (100) [C10H11ϩ], 91 (65) [C7H7ϩ]. C13H17BrO (269.2) calcd. C
58.00, H 6.37; found C 58.36, H 6.25.
Bromocyclization of 5-Methyl-1-phenyl-4-hexen-1-ol (1a)
2-(1-Bromo-2-methylethyl)-5-phenyl tetrahydrofuran (4a): Yield:
19.4 mg (7%), cis:trans ϭ 33:67, colorless oil, Rf ϭ 0.60 [petroleum
ether/EtOAc ϭ 9:1 (v/v)].
Bromocyclization of 2-Phenyl-4-penten-1-ol (1f)
3-Bromo-2,2-dimethyl-6-phenyltetrahydropyran (12a): Yield: 212 mg
(0.79 mmol, 79%), colorless crystals, m.p. 39 °C, b.p. 130 °C/ 10Ϫ2
mbar (Kugelrohr), cis:trans ϭ 6:94. MS (70 eV, EI): m/z (%) ϭ 270/
2-Bromomethyl-4-phenyltetrahydrofuran (4f): Yield: 144 mg (60%)
from 1f (162 mg, 1.00 mmol) and NBS (267 mg, 1.50 mmol) in
268 (1) [Mϩ], 212/210 (3) [Mϩ Ϫ 2CH3Ϫ2CH2], 172 (24) [Mϩ Ϫ Br CH2Cl2 (10 mL), colorless oil, b.p. 125 °C/10Ϫ2 mbar (Kugelrohr);
Ϫ HO], 147 (30) [C10H11Oϩ], 129 (21) [C10H11Oϩ Ϫ H2O], 121 (47) cis:trans ϭ 78:22. MS (70 eV, EI): m/z (%) ϭ 242/240 (6) [Mϩ],
[C8H9Oϩ], 104 (100) [C8H8ϩ], 91 (33) [C7H7ϩ], 77 (21) [C6H5ϩ]. 160 (15) [Mϩ Ϫ HBr], 147 (100) [Mϩ Ϫ CH2Br], 91 (66) [C7H7ϩ].
C13H17BrO (269.2) calcd. C 58.00, H 6.37; found C 57.58, H 6.06.
C11H13BrO (241.1) calcd. C 54.80, H 5.85; found C 54.51, H 5.31.
cis-4f: Rf ϭ 0.55 [petroleum ether/acetone/CH2Cl2 ϭ 5:1:1 (v/v/v)].
1
cis-12a: Rf ϭ 0.30 [petroleum ether/EtOAc ϭ 9:1 (v/v)]. H NMR
(CDCl3, 250 MHz): δ ϭ 1.44 (s, 3 H, 1Ј-H), 1.51 (s, 3 H, 2Ј-H), 1H NMR (250 MHz): δ ϭ 1.87Ϫ2.00 (m, 1 H, 3-H), 2.51Ϫ2.61 (m,
1.61Ϫ1.71 (m, 2 H, 4-H), 2.12Ϫ2.22 (m, 2 H, 5-H), 4.28 (dd, J ϭ
2.5, 3.7 Hz, 1 H, 3-H), 4.70 (dd, J ϭ 3.0, 11.6 Hz, 1 H, 5-H), H, 4-H), 3.89 (dd, J ϭ 8.2, 9.2 Hz, 1 H, 5-H), 4.25 (t, J ϭ 8.2 Hz,
7.29Ϫ7.44 (m, 5 H, Ph-H) ppm. 13C NMR (CDCl3, 63 MHz): δ ϭ
1 H, 5-H), 4.30Ϫ4.42 (mc, 1 H, 2-H), 7.21Ϫ7.37 (m, 5 H, Ph-H)
22.5 (C-2Ј), 28.3 (C-3Ј), 30.0 (C-4), 32.1 (C-5), 59.3 (C-3), 72.8 (C- ppm. 13C NMR (63 MHz): δ ϭ 35.8 (C-3), 39.4 (C-1Ј), 45.6 (C-4),
1 H, 3-H), 3.48 (dd, J ϭ 5.4, 1.4 Hz, 2 H, 1Ј-H), 3.45Ϫ3.61 (m, 1
6), 74.1 (C-2), 126.2, 127.5, 128.4, 142.1 (C-Ph) ppm.
74.8 (C-5), 78.9 (C-2), 126.8, 127.2, 128.6, 140.7 ppm.
trans-12a: Rf ϭ 0.60 [petroleum ether/EtOAc ϭ 9:1 (v/v)]. 1H NMR trans-4f: Rf ϭ 0.57 [petroleum ether/acetone/CH2Cl2 ϭ 5:1:1 (v/v/
1
(CDCl3, 250 MHz): δ ϭ 1.39 (s, 3 H, 1Ј-H), 1.44 (s, 3 H, 2Ј-H),
v)]. H NMR (250 MHz): δ ϭ 2.15Ϫ2.36 (m, 2 H, 3-H), 3.48 (dd,
Eur. J. Org. Chem. 2003, 4033Ϫ4052
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4045

ˇ
J. Hartung, R. Kneuer, S. Laug, P. Schmidt, K. Spehar, I. Svoboda, H. Fuess
FULL PAPER
J ϭ 2.0, 5.7 Hz, 2 H, 1Ј-H), 3.45Ϫ3.61 (m, 1 H, 4-H), 3.83 (dd,
J ϭ 7.6, 8.5 Hz, 1 H, 5-H), 4.31 (dd, J ϭ 7.0, 8.5 Hz, 1 H, 5-H),
4.41Ϫ4.50 (m, 1 H, 2-H), 7.21Ϫ7.37 (m, 5 H, Ph-H) ppm. 13C
NMR (63 MHz): δ ϭ 29.5 (C-3), 38.3 (C-1Ј), 44.4 (C-4), 75.1 (C-
5), 78.3 (C-2), 126.7, 127.2, 128.6, 141.4 ppm.
purified by column chromatography (SiO2, petroleum ether/Et2O).
General Procedure 2: A Schlenk flask equipped with an argon inlet
was charged with thiazolethione 6f (34.3 mg, 88.4 µmol), n-C14H30
as internal standard (GC), anhydrous C6H6 (1.2 mL) and n-C4F9I
(76.5 mg, 0221 mmol) in the dark. Air was removed by freeze-
pump-thaw cycles using argon as inert gas. After addition of a solu-
tion of BEt3 (22 µL, 1.0  in C6H14), air was introduced into the
solution via a syringe pump (25 µL/min) over a period of 20 min.
Product formation and yields of 2-iodomethyl-4-phenyl-tetrahydro-
furan (5f) were determined by GC analysis.
Bromocyclization of 3-Phenyl-4-penten-1-ol (1h)
2-Bromomethyl-3-phenyltetrahydrofuran (4h): Yield: 131 mg (54%)
from 1h (162 mg, 1.00 mmol) and NBS (267 mg, 1.50 mmol) in
CH2Cl2 (10 mL), colorless oil, b.p. 120 °C/ 10Ϫ2 mbar (Kugelrohr),
cis:trans ϭ 33:67. MS (70 eV, EI): m/z (%) ϭ 242/240 (6) [Mϩ], 147
(29) [Mϩ Ϫ CH2Br], 118 (100) [C9H10ϩ], 91 (44) [C7H7ϩ].
C11H13BrO (241.1) calcd. C 54.80, H 5.85; found C 53.28, H 5.19.
cis-4h: Rf ϭ 0.42 [petroleum ether/acetone/CH2Cl2 ϭ 5:1:1 (v/v/v)].
1H NMR (250 MHz): δ ϭ 2.12Ϫ2.27 (m, 1 H, 4-H), 2.37Ϫ2.51 (m,
1 H, 4-H), 2.89 (dd, J ϭ 5.2 10.4 Hz, 1 H, 1Ј-H), 3.04 (dd, J ϭ 7.9,
10.4 Hz, 1 H, 1Ј-H), 3.50 (dt, Jd ϭ 8.2, Jt ϭ 5.8 Hz, 1 H, 3-H),
3.95 (td, Jt ϭ 8.9, Jd ϭ 7.3 Hz, 1 H, 5-H), 4.20Ϫ4.28 (m, 2 H, 5-
H, 2-H), 7.15Ϫ7.35 (m, 5 H, Ph-H) ppm. 13C NMR (63 MHz): δ ϭ
34.8 (C-1Ј), 35.3 (C-4), 49.3 (C-3), 68.5 (C-5), 84.7 (C-2), 127.1,
127.5, 128.9, 140.5 ppm.
trans-4h: Rf ϭ 0.46 [petroleum ether/acetone/CH2Cl2 ϭ 5:1:1 (v/v/
v)]. 1H NMR (250 MHz): δ ϭ 2.14Ϫ2.25 (m, 1 H, 4-H), 2.35Ϫ2.48
(m, 1 H, 4-H), 3.21 (td, Jt ϭ 9.5, Jd ϭ 7.9 Hz, 1 H, 3-H), 3.39 (dd,
J ϭ 5.3, 10.7 Hz, 1 H, 1Ј-H), 3.54 (dd, J ϭ 3.7, 10.7 Hz, 1 H, 1Ј-
H), 4.01Ϫ4.08 (m, 1 H, 2-H), 4.04Ϫ4.16 (m, 2 H, 5-H), 7.16Ϫ7.35
(m, 5 H, Ph-H) ppm. 13C NMR (63 MHz): δ ϭ 32.8 (C-1Ј), 33.1
(C-4), 47.6 (C-3), 67.6 (C-5), 82.1 (C-2), 126.9, 127.7, 128.5,
140.0 ppm.
2-(1-Iodo-1-methylethyl)-5-phenyltetrahydrofuran (5a): Application
of general procedure 1 [7a: 164 mg (0.548 mmol), n-C4F9I: (474 mg,
1.37 mmol), C6H6: 8 mL] afforded 139.1 mg of 5a (80%): colorless
oil, cis:trans ϭ 29:71. MS (70 eV, EI): m/z (%) ϭ 316 (1) [Mϩ], 189
(88) [Mϩ Ϫ I], 147 (18) [C10H11Oϩ], 105 (100) [C7H5Oϩ]. C13H17IO
(316.2): calcd. C 49.38, H 5.42; found C 49.29, H 5.17.
cis-5a: Yield 40.1 mg (23%), colorless oil, Rf ϭ 0.61 [SiO2, petro-
leum ether/ Et2O ϭ 9:1 (v/v)]. 1H NMR (250 MHz): δ ϭ 1.82Ϫ2.10
(m, 2 H, CH2), 1.97 (s, 3 H, CH3), 2.01 (s, 3 H, CH3), 2.13Ϫ2.32
(m, 2 H, CH2), 3.33 (dd, J ϭ 5.8, 7.9 Hz, 1 H, 2-H), 4.90 (dd, J ϭ
5.8, 9.5 Hz, 1 H, 5-H), 7.24Ϫ7.37 (m, 3 H, Ar-H), 7.45Ϫ7.49 (m,
2 H, Ar-H) ppm. 13C NMR (100 MHz): δ ϭ 31.2, 33.6, 34.5, 82.0
(C-2), 88.1 (C-5), 125.6, 126.1, 127.4, 128.3 ppm.
trans-5a: Yield: 99 mg (57%), colorless oil, Rf ϭ 0.69 [SiO2, petro-
leum ether/ Et2O ϭ 9:1 (v/v)]. 1H NMR (250 MHz): δ ϭ 1.86Ϫ2.08
(m, 1 H, CH2), 1.93 (s, 3 H, CH3), 2.02 (s, 3 H, CH3), 2.19Ϫ2.58
(m, 3 H, CH2), 3.53 (dd, J ϭ 6.4, 8.2 Hz, 1 H, 2-H), 5.17 (dd, J ϭ
5.8, 8.9 Hz, 1 H, 5-H), 7.23Ϫ7.37 (m, 5 H, Ar-H) ppm. 13C NMR
(100 MHz): δ ϭ 18.2, 32.2, 33.6, 34.3, 35.7, 81.9 (C-2), 88.8 (C-5),
125.6, 127.2, 128.3, 128.8 ppm.
Bromocyclization of 1-Phenyl-4-penten-1-ol (1i)
2-Bromomethyl-5-phenyltetrahydrofuran (4i):[20] Yield: 196 mg
(81%) from 1i (162 mg, 1.00 mmol) and NBS (267 mg, 1.50 mmol)
in CH2Cl2 (10 mL), colorless oil, b.p. 120 °C/ 10Ϫ2 mbar (Kugel-
rohr), cis:trans ϭ 33:67.
2-(Nonafluorobutylsulfanyl)pyridine (9, X ؍ C4F9): Yield: 152 mg
(84%), colorless liquid. H NMR (250 MHz): δ ϭ 7.36 (ddd, J ϭ
1
1.1, 4.8, 7.5 Hz, 1 H, Ar-H), 7.68 (d, J ϭ 7.8 Hz, 1 H, Ar-H), 7.74
(td, Jt ϭ 7.7, Jd ϭ 2.0 Hz, 1 H, Ar-H), 8.66 (dd, J ϭ 1.9, 4.8 Hz,
1 H, Ar-H) ppm. 13C NMR (63 MHz): δ ϭ 124.6, 131.1, 137.6,
147.5, 150.9. 13C NMR (75 MHz, 19F-decoupled): δ ϭ 108.6, 110.2,
117.3, 123.4, 124.6, 131.1, 137.7, 147.3, 150.9 ppm. 19F NMR
(565 MHz): δ ϭ Ϫ82.4, Ϫ87.2, Ϫ121.5, Ϫ126.9 ppm. MS (70 eV,
EI): m/z (%) ϭ 329 (28) [Mϩ], 160 (27) [C6H4F2NSϩ], 78 (100)
[C5H4Nϩ]. C9H4F9NS (329.2): calcd. C 32.84, H 1.22, N 4.25, S
9.74; found C 33.10, H 1.40, N 4.54, S 9.77.
cis-4i: Rf ϭ 0.42 [petroleum ether/acetone/CH2Cl2 ϭ 5:1:1 (v/v/v)].
1H NMR (250 MHz): δ ϭ 1.86Ϫ2.01 (m, 2 H, 3-H, 4-H),
2.17Ϫ2.35 (m, 2 H, 3-H, 4-H), 3.50 (dd, J ϭ 6.3, 10.1 Hz, 1 H, 1Ј-
H), 3.58 (dd, J ϭ 5.4, 10.1 Hz, 1 H, 1Ј-H), 4.31Ϫ4.39 (m, 1 H, 2-
H), 4.96 (dd, J ϭ 5.9, 8.1 Hz, 1 H, 5-H), 7.24Ϫ7.41 (m, 5 H, Ph-
H) ppm.
1
trans-4i: Rf ϭ 0.60 [petroleum ether/EtOAc ϭ 5:1 (v/v)]. H NMR
(250 MHz): δ ϭ 1.86Ϫ2.01 (m, 2 H, 3-H, 4-H), 2.17Ϫ2.35 (m, 1
H, 4-H), 2.38Ϫ2.56 (m, 1 H, 3-H), 3.46 (dd, J ϭ 7.2, 10.1 Hz, 1
H, 1Ј-H), 3.55 (dd, J ϭ 3.8, 10.1 Hz, 1 H, 1Ј-H), 4.43Ϫ4.52 (m, 1
H, 2-H), 5.10 (dd, J ϭ 6.1, 8.3 Hz, 1 H, 5-H), 7.24Ϫ7.41 (m, 5 H,
Ph-H) ppm.
2-(Iodomethyl)-5-(p-biphenylyl)tetrahydrofuran (5d): Application of
general procedure 1 [7d: 13.8 mg (0.039 mmol), n-C4F9I: 43.2 mg
(0.125 mmol), C6H6: 1 mL] provided 5.68 mg of 5d (40%), cis:-
trans ϭ 53:47.
2-(Iodomethyl)-5-(2-naphthyl)tetrahydrofuran (5e): Application of
general procedure 1 [7e: 15.9 mg (0.049 mmol), IC8H13O4: 37.0 mg
(0.124 mmol), C6H6: 1 mL] furnished 11.9 mg of 5e (72%), cis:-
trans ϭ 50:50.
4. Iodocyclizations
4.1 Photolysis of Thiazolethiones 6 and Pyridinethiones 7 in the Pres-
ence of Iodine Atom Donors
2-(Iodomethyl)-4-phenyltetrahydrofuran (5f): Application of general
procedure 1 [7f: 228.0 mg (0.840 mmol), IC8H13O4: 630.0 mg
(2.1 mmol), C6H6: 12 mL] yielded 174 mg of 5f (72%), cis:trans ϭ
13:87.
General procedure 1: A Schlenk flask equipped with an argon inlet
was charged with radical precursor 6 or 7 (0.3 mmol) and anhy-
drous solvent (C6H6 or CH2Cl2, 5 mL) in the dark. After addition
of an iodine atom donor (CHI3, diethyl 2-iodo-2-methylmalonate,
or n-C4F9I; for exact combinations refer to Table 3 and 4). The air
was removed from this mixture by three consecutive freeze-pump-
Diethyl
2-Methyl-2-(2-pyridylsulfany)malonate
[9,
X
؍
C(CH3)(CO2C2H5)2]:[35] Yield: 175 mg (73%): colorless liquid. 1H
thaw cycles using Ar as inert gas. The reaction mixture was photo- NMR (250 MHz): δ ϭ 1.21 (t, J ϭ 7.0 Hz, 6 H, CH3), 1.96 (s, 3
lyzed at 20 °C (20 min in a Rayonet for thiazolethiones 6 or 3 min
with an 150 W light bulb for pyridinethiones 7). Upon complete
consumption of the alkoxyl radical precursor, the solvent was re-
moved under reduced pressure to provide an oily residue that was
H, CH3), 4.22 (q, J ϭ 7.0 Hz, 4 H, CH2), 7.02 (mc, 1 H, CH), 7.26
(mc, 1 H, CH), 7.50 (mc, 1 H, CH), 8.35 (mc, 1 H, CH) ppm. 13C
NMR (63 MHz): δ ϭ 13.9, 23.2, 59.9 (CϪS), 62.3, 120.6, 124.0,
136.1, 149.1, 156.1, 169.0 (CϭO) ppm.
4046
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4033Ϫ4052

A Radical Version of the Bromo- and the Iodocyclization of Bis(homoallylic) Alcohols
FULL PAPER
2-(Iodomethyl)-4-(2-naphthyl)tetrahydrofuran (5g): Application of
general procedure 1 [7g: 21.8 mg (0.068 mmol), IC8H13O4: 71.2 mg tan oil. H NMR (250 MHz): δ ϭ 1.87Ϫ2.08 (m, 2 H, 3-H, 4-H),
cis-5e: Rf ϭ 0.45 [petroleum ether/EtOAc ϭ 9:1 (v/v)], 0.30 g (18%),
1
(0.24 mmol), C6H6: 1 mL] provided 9.20 mg of 5g (40%), cis:-
trans ϭ 13:87.
2.18Ϫ2.32 (m, 1 H, 3-H), 2.34Ϫ2.45 (m, 1 H, 4-H), 3.39 (dd, J ϭ
6.7, 10.1 Hz, 1 H, CH2I), 3.47 (dd, J ϭ 4.6, 10.1 Hz, 1 H, CH2I),
4.24 (tt, J ϭ 4.9, 7.3 Hz, 1 H, 2-H), 5.14 (dd, J ϭ 6.4, 7.6 Hz, 1 H,
5-H), 7.44Ϫ7.54 (m, 3 H, Ar-H), 7.80Ϫ7.87 (m, 4 H, Ar-H) ppm.
13C NMR (63 MHz): δ ϭ 11.1, 32.4 (C-3), 34.8 (C-4), 79.3 (C-2),
82.8 (C-5), 124.5, 124.9, 126.2, 126.5, 128.1, 128.4, 128.6, 133.4,
133.7, 140.2 ppm. MS (70 eV, EI): m/z (%) ϭ 338 (13) [Mϩ], 156
(100) [C10H7CHOϩ]. C15H15IO (338.2): calcd. C 53.27, H 4.47;
found C 53.23, H 4.31.
2-(Iodomethyl)-3-phenyl tetrahydrofuran (5h): Application of gen-
eral procedure 1 [7 h: (193 mg, 0.71 mmol), IC8H13O4: (521 mg,
1.74 mmol), C6H6: 10 mL] furnished 148 mg of 5h (72%), cis:-
trans ϭ 3:97.
4.2 Reaction between Bis(homoallylic) Alcohols 1 and Iodine
trans-5e: Rf ϭ 0.50 [petroleum ether/EtOAc ϭ 9:1 (v/v)], 0.79 g
(46%), tan oil. 1H NMR (250 MHz): δ ϭ 1.69Ϫ1.82 (m, 1 H, 3-
H), 1.82Ϫ1.95 (m, 1 H, 4-H), 2.12Ϫ2.27 (m, 1 H, 3-H), 2.28Ϫ2.42
(m, 1 H, 4-H), 3.20 (dd, J ϭ 7.3, 10.1 Hz, 1 H, CH2I), 3.29 (dd,
J ϭ 4.6, 10.1 Hz, 1 H, CH2I), 4.28 (tdd, Jt ϭ 7.3, Jd ϭ 4.6, 6.1 Hz,
1 H, 2-H), 5.16 (dd, J ϭ 6.4, 8.2 Hz, 1 H, 5-H), 7.27Ϫ7.39 (m, 3
H, Ar-H), 7.66Ϫ7.71 (m, 4 H, Ar-H) ppm. 13C NMR (63 MHz):
δ ϭ 11.4, 33.3 (C-3), 35.8 (C-4), 79.6 (C-2), 82.1 (C-5), 124.2, 124.5,
126.1, 126.5, 128.1, 128.3, 128.7, 133.3, 133.7, 140.6 ppm. MS
(70 eV, EI): m/z (%) ϭ 338 (51) [Mϩ], 211 (12) [Mϩ Ϫ I], 155 (45)
[C10H7COϩ], 83 (100). C15H15IO (338.2): calcd. C 53.27, H 4.47;
found C 53.02, H 4.20.
General Procedure: Iodine (2.25 g, 8.90 mmol) was dissolved in re-
agent grade CH3CN. The flask was immersed in an ice bath and a
saturated aqueous solution of NaHCO3 (5 mL) was added. Bis(ho-
moallylic) alcohol 1 (5.00 mmol) was added in a dropwise manner.
Solid substrates 1 were added in small portions over a period of
10 min. A likewise prepared reaction mixture was stirred for 1 h at
0 °C and for 4 h at 20 °C. Afterwards, the brown reaction mixture
was concentrated under reduced pressure to provide a brown oil
that was taken up in MTB (40 mL). The organic phase was washed
with an aqueous solution of Na2S2O3 [10% (w/w), 2 ϫ 10 mL)],
H2O, brine (20 mL each). It was dried (MgSO4) and concentrated
under reduced pressure to afford the product, in all instances, as
an orange viscous oil, which was purified by column chromatogra-
phy [SiO2 petroleum ether/ MTB ϭ 9:1 (v/v)].
2-(Iodomethyl)-4-(2-naphthyl)tetrahydrofuran (5g): Yield: 1.62 g
(96%), cis:trans ϭ 82:18, tan oil.
cis-5g: Rf ϭ 0.40 [petroleum ether/EtOAc ϭ 9:1 (v/v)], 1.25 g (74%),
tan oil. 1H NMR (250 MHz): δ ϭ 1.94 (ddd, J ϭ 9.2, 10.7, 12.5 Hz,
1 H, 3-H), 2.65 (ddd, J ϭ 5.8, 7.3, 12.8 Hz, 1 H, 3-H), 3.40 (dd,
J ϭ 6.0, 10.1 Hz, 1 H, CH2I), 3.43 (dd, J ϭ 5.2, 10.1 Hz, 1 H,
trans-3-Iodo-2,2-dimethyl-6-phenyltetrahydropyran: (not shown in
the graphics, refer to discussion, section 2). Yield: 0.96 g (62%),
colorless crystals, m.p. 52Ϫ53 °C, Rf ϭ 0.82 [petroleum ether/
1
Et2O ϭ 5:1 (v/v)]. H NMR (250 MHz): δ ϭ 1.49 (s, 3 H, CH3),
CH2I), 4.04 (t, J ϭ 8.6 Hz, 1 H, 5-H), 4.22 (dq, Jd ϭ 9.5, Jq
ϭ
1.61 (s, 3 H, CH3), 1.66Ϫ1.76 (m, 2 H, CH2), 2.36Ϫ2.60 (m, 2 H,
CH2), 4.25 (dd, J ϭ 4.9, 12.2 Hz, 1 H, 3-H), 4.73 (mc, 1 H, 6-H),
7.25Ϫ7.34 (m, 5 H, Ar-H) ppm. 13C NMR (63 MHz): δ ϭ 19.5,
31.1, 34.7, 37.7, 37.8, 72.4 (C-6), 75.8 (C-2), 125.8, 127.2, 128.4,
142.6 ppm. MS (70 eV, EI): m/z (%) ϭ 316 (1) [Mϩ], 258 (6) [Mϩ
Ϫ C3H6O], 189 (12) [Mϩ Ϫ I], 131 (31) [C10H11ϩ], 104 (100) [C8H8].
C13H17IO (316.2): calcd. C 49.38, H 5.42; found C 49.09, H 5.27.
6.1 Hz, 1 H, 2-H), 4.34 (t, J ϭ 8.5 Hz, 1 H, 5-H), 7.42 (dd, J ϭ
1.8, 8.6 Hz, 1 H, Ar-H), 7.47Ϫ7.54 (m, 2 H, Ar-H), 7.70 (mc, 1 H,
Ar-H), 7.79Ϫ7.87 (m, 3 H, Ar-H) ppm. 13C NMR (63 MHz): δ ϭ
10.2, 41.1, 45.9, 74.7, 79.2, 125.4, 125.6, 126.1, 127.5, 127.6, 128.3,
132.3, 133.4, 138.3 ppm. MS (70 eV, EI): m/z (%) ϭ 338 (28) [Mϩ],
211 (19) [Mϩ Ϫ I], 155 (100) [C10H7COϩ]. C15H15IO (338.2): calcd.
C 53.27, H 4.47; found C 53.24, H 4.40.
trans-5g: Rf ϭ 0.43 [petroleum ether/EtOAc ϭ 9:1 (v/v)], 0.29 g
(17%), colorless needles, m.p. 85Ϫ86 °C. 1H NMR (250 MHz): δ ϭ
2.31 (mc, 2 H, 3-H), 3.33Ϫ3.36 (m, 2 H, CH2I), 3.70 (mc, 1 H, 4-
H), 3.97 (dd, J ϭ 7.3, 8.5 Hz, 1 H, 5-H), 4.35 (quint, J ϭ 6.4 Hz,
1 H, 6-H), 4.41 (dd, J ϭ 7.0, 8.6 Hz, 1 H, 5-H), 7.38 (dd, J ϭ 1.8,
8.5 Hz, 1 H, Ar-H), 7.44Ϫ7.53 (m, 2 H, Ar-H), 7.69 (br. s, 1 H,
Ar-H), 7.79Ϫ7.86 (m, 3 H, Ar-H) ppm. 13C NMR (63 MHz): δ ϭ
10.6, 39.8, 44.7, 75.0, 78.5, 125.4, 125.5, 125.6, 126.2, 127.5 (2 C),
128.3, 132.2, 133.4, 139.0 ppm. MS (70 eV, EI): m/z (%) ϭ 338 (64)
[Mϩ], 211 (26) [Mϩ Ϫ I], 155 (100) [C10H7COϩ]. C15H15IO (338.2):
calcd. C 53.27, H 4.47; found C 53.15, H 4.43.
5-(p-Biphenylyl)-2-iodomethyltetrahydrofuran (5d): Yield 1.69 g
(93%), tan oil, cis:trans ϭ 23:77.
cis-5d: Rf ϭ 0.45 (petroleum ether/EtOAc ϭ 9:1 (v/v)], 0.24 g
1
(13%), tan oil. H NMR (250 MHz): δ ϭ 1.86Ϫ2.01 (m, 2 H, 4-H,
3-H), 2.18Ϫ2.29 (m, 1 H, 3-H), 2.29Ϫ2.44 (m, 1 H, 4-H), 3.37 (dd,
J ϭ 6.4, 9.8 Hz, 1 H, CH2I), 3.43 (dd, J ϭ 4.6, 9.8 Hz, 1 H, CH2I),
4.20 (mc, 1 H, 2-H), 5.02 (t, J ϭ 6.3 Hz, 1 H, 2-H), 7.21Ϫ7.38 (m,
5 H, Ar-H), 7.46Ϫ7.52 (m, 4 H, Ar-H) ppm. 13C NMR (63 MHz):
δ ϭ 11.1, 32.4 (C-3), 34.8 (C-4), 79.1 (C-2), 82.4 (C-5),126.8, 127.5,
127.6, 127.7, 129.1, 140.9, 141.4, 141.8 ppm. MS (70 eV, EI): m/z
(%) ϭ 364 (14) [Mϩ], 237 (4) [Mϩ Ϫ I], 181 (100) [C6H5C6H4COϩ].
C17H17IO (364.2): calcd. C 56.06, H 4.70; found C 55.84, H 4.58.
trans-5d: Rf ϭ 0.50 [petroleum ether/EtOAc ϭ 9:1 (v/v)]; 0.73 g
(46%); tan oil. 1H NMR (250 MHz): δ ϭ 1.69Ϫ1.83 (m, 1 H, 3-
H), 1.83Ϫ1.96 (m, 1 H, 4 H), 2.23 (mc, 1 H, 3 H), 2.36 (mc, 1 H,
4 H), 3.21 (dd, J ϭ 7.3, 9.8 Hz, 1 H, CH2I), 3.30 (dd, J ϭ 4.6,
9.8 Hz, 1 H, CH2I), 4.26 (ddt, Jd ϭ 4.6, 13.4, Jt ϭ 7.3 Hz, 1 H, 2-
H), 5.07 (dd, J ϭ 5.8, 8.2 Hz, 1 H, 5-H), 7.21Ϫ7.38 (m, 5 H, Ar-
H), 7.46Ϫ7.52 (m, 4 H, Ar-H) ppm. 13C NMR (63 MHz): δ ϭ 11.4,
33.4 (C-3), 35.8 (C-4), 79.4 (C-2), 81.8 (C-5), 126.5. 127.5, 127.6,
127.7, 129.2, 140.8, 141.3, 142.2 ppm. MS (70 eV, EI): m/z (%) ϭ
364 (57) [Mϩ], 55 (100) [C4H7ϩ]. C17H17IO (364.2): calcd. C 56.06,
H 4.70; found C 55.95, H 4.78.
2-(Iodomethyl)-4-phenyltetrahydrofuran (5f) [trans-5f: Rf ϭ 0.65,
cis-5f: Rf ϭ 0.60, petroleum ether/EtOAc ϭ 9:1 (v/v)], and 2-iodo-
methyl-3-phenyl tetrahydrofuran (5h) [cis-5h: Rf ϭ 0.55, trans-5h:
Rf ϭ 0.50, petroleum ether/ EtOAc ϭ 9:1 (v/v)] have been pre-
pared previously.[20,26]
5. Synthesis of Aryl-Substituted Methyltetrahydrofurans 10
General Procedure: LiH (0.10 g, 12.6 mmol) and LiAlH4 (0.25 g,
6.60 mmol) were placed into a three-necked round-bottomed flask
containing nitrogen. Anhydrous THF (30 mL) was added followed
by a solution of (iodomethyl)tetrahydrofuran 5 (3.00 mmol) in an-
hydrous THF (5 mL). The reaction mixture was refluxed for 2 h
2-(Iodomethyl)-5-(2-naphthyl)tetrahydrofuran (5e): Yield: 1.45 g and stirred for 14 h at 20 °C. H2O was added at 0 °C until no
(86%), cis:trans ϭ 27:73, tan oil.
further hydrogen evolved. Precipitated salts were dissolved by ad-
Eur. J. Org. Chem. 2003, 4033Ϫ4052
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4047

ˇ
J. Hartung, R. Kneuer, S. Laug, P. Schmidt, K. Spehar, I. Svoboda, H. Fuess
FULL PAPER
dition of dilute sulfuric acid [10% (v/v)]. The organic phase was
(600 MHz): δ ϭ 1.36 (d, J ϭ 6.1 Hz, 3 H, CH3), 1.63 (dt, Jt ϭ 9.9,
separated and the aqueous phase was extracted with MTB (3 ϫ Jd ϭ 12.3 Hz, 1 H, 3-H), 2.46 (ddd, J ϭ 5.4, 7.7, 12.6 Hz, 1 H, 3-
20 mL). Combined organic phases were washed with an aqueous
solution of Na2S2O3 [2 ϫ 30 mL, 10% (w/w)], and brine (30 mL).
After drying (MgSO4), the organic solvent was removed under re-
duced pressure to afford in all instances colorless oils which were
purified by column chromatography [petroleum ether/MTB 9:1
(v/v)].
H), 3.47 (dq, Jd ϭ 10.1, Jq ϭ 7.9 Hz, 1 H, 4-H), 3.84 (t, J ϭ 8.0 Hz,
1 H, 5-H), 4.13 (t, J ϭ 8.0 Hz, 1 H, 5-H), 4.14 (dquint, Jd ϭ 9.7,
Jquint ϭ 6.0 Hz, 1 H, 2-H), 7.19Ϫ7.37 (m, 5 H, Ph-H) ppm. 13C
NMR (63 MHz): δ ϭ 21.3, 43.3 (C-3), 46.4 (C-4), 74.8 (C-5), 77.0
(C-2), 126.9, 127.6, 129.0, 143.3.
trans-2-Methyl-4-phenyltetrahydrofuran
(trans-10f):[20]
Yield:
cis-2-(p-Biphenyl-4-yl)-5-methyltetrahydrofuran (cis-10d): Yield:
0.21 g (91%) from 0.36 g of cis-5d (1.00 mmol), colorless oil. 1H
NMR (600 MHz): δ ϭ 1.43 (d, J ϭ 6.1 Hz, 3 H, CH3), 1.63 (dddd,
J ϭ 6.8, 7.3, 9.0, 12.2 Hz, 1 H, 3-H), 1.89 (dddd, J ϭ 6.4, 7.3, 9.2,
12.7 Hz, 1 H, 4-H), 2.11 (ddt, Jd ϭ 8.3, 12.6, Jt ϭ 6.4 Hz, 1 H, 3-
H), 2.33 (ddt, Jd ϭ 8.1, 12.6, Jt ϭ 7.1 Hz, 1 H, 4-H), 4.18 (sext,
J ϭ 6.2 Hz, 1 H, 2-H), 4.93 (t, J ϭ 7.3 Hz, 1 H, 5-H), 7.32 (mc, 1
H, Ar-H), 7.41Ϫ7.44 (m, 4 H, Ar-H), 7.76 (mc, 2 H, Ar-H), 7.78
(mc, 2 H, Ar-H) ppm. 13C NMR (63 MHz): δ ϭ 21.8, 33.6 (C-3),
35.0 (C-4), 76.4 (C-2), 81.2 (C-5), 126.5, 126.8, 127.5, 127.6, 129.2,
140.5, 141.5, 143.1 ppm. MS (70 eV, EI): m/z (%) ϭ 283 (100) [Mϩ],
181 (96) (C6H5C6H4COϩ]. C17H18O (238.3): calcd. 85.67, H 7.61;
found C 85.44, H 7.56.
71.9 mg (44%) from 288 mg of trans-5f (1.00 mmol), colorless
liquid. H NMR (600 MHz): δ ϭ 1.30 (d, J ϭ 6.2 Hz, 3 H, CH3),
1
1.97 (ddd, J ϭ 6.3, 9.0, 12.5 Hz, 1 H, 3-H), 2.14 (dt, Jd ϭ 12.5,
Jt ϭ 7.1 Hz, 1 H, 3-H), 3.47 (quint, J ϭ 7.5 Hz, 1 H, 4-H), 3.70 (t,
J ϭ 7.3 Hz, 1 H, 5-H), 4.26 (dd, J ϭ 7.6, 8.0 Hz, 1 H, 5-H), 4.30
(sext, J ϭ 6.3 Hz, 1 H, 2-H), 7.21 (mc, 1 H, Ph-H), 7.24Ϫ7.26 (m,
2 H, Ph-H), 7.31 (mc, 1 H, Ph-H) ppm. 13C NMR (63 MHz): δ ϭ
22.1, 41.8 (C-3), 45.2 (C-4), 74.8 (C-5), 75.5 (C-2), 126.8, 127.7,
129.0, 143.1 ppm.
cis-2-Methyl-4-(2-naphthyl)tetrahydrofuran (cis-10g): Yield: 0.55 g
(86%) from 1.01 g of cis-5g (3.00 mmol), colorless liquid. 1H NMR
(600 MHz): δ ϭ 1.44 (d, J ϭ 6.1 Hz, 3 H, CH3), 1.75 (dt, Jd
ϭ
12.2, Jt ϭ 9.8 Hz, 1 H, 3-H), 2.54 (ddd, J ϭ 5.5, 7.6, 12.5 Hz 1 H,
3-H), 3.66 (dq, Jd ϭ 9.5, Jq ϭ 7.9 Hz, 1 H, 4-H), 4.00 (t, J ϭ
8.6 Hz, 1 H, 5-H), 4.21 (dquint, Jd ϭ 9.5, Jquint ϭ 5.8 Hz, 1 H, 2-
H), 4.24 (t, J ϭ 7.9 Hz, 1 H, 5-H), 7.42Ϫ7.54 (m, 3 H, Ar-H), 7.71
(br. s, 1 H, Ar-H), 7.81Ϫ7.87 (m, 3 H, Ar-H) ppm. 13C NMR
(63 MHz): δ ϭ 20.8, 42.8 (C-3), 45.9 (C-4), 74.2 (C-5), 75.4 (C-2),
125.4, 125.5, 126.0, 127.5, 127.6, 128.3, 132.2, 133.4, 140.4 ppm.
MS (70 eV, EI): m/z (%) ϭ 212 (52) [Mϩ], 167 (100) [C10H7C3H4ϩ],
128 (17) [C10H8ϩ]. C15H16O (212.3): calcd. C 84.87, H, 7.60; found
C 85.08, H 7.86.
trans-2-(p-Biphenyl-4-yl)-5-methyltetrahydrofuran
(trans-10d):
Yield: 0.64 g (89%) from 1.10 g of trans-5d (3.02 mmol), colorless
needles (EtOH), m.p. 34Ϫ35 °C. 1H NMR (600 MHz): δ ϭ 1.35
(d, J ϭ 6.2 Hz, 3 H, CH3), 1.55 (dddd, J ϭ 7.6, 8.0, 9.9, 12.4 Hz,
1 H, 3-H), 1.93 (dddd, J ϭ 7.6, 8.2, 9.9, 12.4 Hz, 1 H, 4-H), 2.19
(dddd, J ϭ 3.3, 7.5, 6.0, 12.4 Hz, 1 H, 3-H), 2.43 (dddd, J ϭ 3.3,
6.9, 7.2, 12.4 Hz, 1 H, 4-H), 4.93 (dquint, Jd ϭ 8.1, Jquint ϭ 6.0 Hz,
1 H, 2-H), 5.11 (dd, J ϭ 6.8, 7.9 Hz, 1 H, 5-H), 7.32 (mc, 1 H, Ar-
H), 7.43Ϫ7.49 (m, 4 H, Ar-H), 7.57Ϫ7.69 (m, 4 H, Ar-H) ppm.
13C NMR (63 MHz): δ ϭ 22.0, 34.7 (C-3), 36.0 (C-4), 76.4 (C-2),
80.5 (C-5), 126.5, 127.5, 127.6, 129.2, 140.4, 141.5, 143.5. MS
(70 eV, EI): m/z (%) ϭ 238 (95) [Mϩ], 181 (100) [C6H5C6H4COϩ].
HRMS C17H18O (238.3): calcd. 238.1358; found 238.1359.
trans-2-Methyl-4-(2-naphthyl)tetrahydrofuran (trans-10g): Yield:
0.15 g (77%) from 0.31 g of trans-5g (0.92 mmol), colorless liquid.
1H NMR (600 MHz): δ ϭ 1.38 (d, J ϭ 6.1 Hz, 3 H, CH3), 2.06
(ddd, J ϭ 6.4, 8.1, 12.5 Hz, 1 H, 4-H), 2.27 (dt, Jd ϭ 12.5, Jt ϭ
7.0 Hz, 1 H, 4-H), 3.67 (quint, J ϭ 7.3 Hz, 1 H, 3-H), 3.87 (t, J ϭ
8.5 Hz, 1 H, 2-H), 4.37 (dd, J ϭ 7.3, 8.6 Hz, 1 H, 2-H), 4.44 (sext,
J ϭ 6.4 Hz, 1 H, 5-H), 7.42 (dd, J ϭ 1.8, 8.6 Hz, 1 H, Ar-H),
7.45Ϫ7.54 (m, 2 H, Ar-H), 7.71 (d, J ϭ 0.9 Hz, 1 H, Ar-H),
7.80Ϫ7.88 (m, 3 H, Ar-H) ppm. 13C NMR (63 MHz): δ ϭ 21.6,
41.3 (C-3), 44.8 (C-4), 74.5 (C-5), 75.4 (C-2), 125.4, 125.5, 125.7,
126.0, 127.4, 127.5, 128.2, 132.2, 133.4, 140.1 ppm. MS (70 eV, EI):
m/z (%) ϭ 212 (26) [Mϩ], 167 (66) [C10H7C3H4ϩ], 154 (100)
[C10H7C2H3ϩ],128 (24) [C10H8ϩ]. C15H16O (212.3): calcd. C 84.87,
H, 7.60; found C 84.33, H 7.28.
cis-2-Methyl-5-(2-naphthyl)tetrahydrofuran (cis-10e): Yield: 0.19 g
(90%) from 0.34 g of cis-5e (1.00 mmol), colorless oil. 1H NMR
(600 MHz): δ ϭ 1.44 (d, J ϭ 6.1 Hz, 3 H, CH3), 1.59Ϫ1.75 (m, 1
H, 4-H), 1.87Ϫ2.03 (m, 1 H, 3-H), 2.05Ϫ2.26 (m, 1 H, 4-H),
2.32Ϫ2.52 (m, 1 H, 3-H), 4.24 (dquint, Jd ϭ 7.3, Jquint ϭ 6.1 Hz,
1 H, 5-H), 5.07 (t, J ϭ 7.3 Hz, 1 H, 2-H), 7.42Ϫ7.52 (m, 3 H, Ar-
H), 7.80Ϫ7.88 (m, 4 H, Ar-H) ppm. 13C NMR (63 MHz, CDCl3):
δ ϭ 21.8, 33.6 (C-3), 35.0 (C-4), 76.6 (C-2), 81.5 (C-5), 124.4, 124.7,
126.0, 126.4, 128.1, 128.3, 128.5, 133.2, 133.7, 141.4 ppm. MS
(70 eV, EI): m/z (%) ϭ 212 (77) [Mϩ], 155 (100) [C10H8COϩ], 128
(78) [C10H8ϩ]. C15H16O (212.3): calcd. C 84.87, H, 7.60; found C
84.58, H 7.35.
cis-2-Methyl-3-phenyltetrahydrofuran (cis-10h):[39b] Yield: 90.8 mg
(56%) from 288 mg of cis-5h (1.00 mmol), colorless liquid. 1H
NMR (600 MHz): δ ϭ 0.84 (d, J ϭ 6.4 Hz, 3 H, CH3), 2.18 (dddd,
J ϭ 5.7, 7.8, 8.8, 13.1 Hz, 1 H, 4-H), 2.38 (ddt, Jd ϭ 4.4, 12.8, Jt ϭ
8.4 Hz, 1 H, 4-H), 3.33 (dt, Jd ϭ 8.3, Jt ϭ 6.2 Hz, 1 H, 3-H), 3.86
(dt, Jd ϭ 8.5, Jt ϭ 7.9 Hz, 1 H, 5-H), 4.15 (quint, J ϭ 6.4 Hz, 1
H, 2-H), 4.16 (td, Jt ϭ 8.7, Jd ϭ 4.4 Hz, 1 H, 5-H), 7.21Ϫ7.25 (m,
5 H, Ph-H) ppm. 13C NMR (63 MHz): δ ϭ 17.3, 33.2 (C-4), 48.8
(C-3), 67.4 (C-5), 78.6 (C-2), 126.7, 128.6, 128.8. 142.2 ppm.
trans-2-Methyl-5-(2-naphthyl)tetrahydrofuran (trans-10e): Yield:
0.56 g (84%) from 1.06 g of trans-5e (3.14 mmol), colorless oil. H
1
NMR (600 MHz): δ ϭ 1.38 (d, J ϭ 6.1 Hz, 3 H, CH3), 1.68 (ddt,
Jd ϭ 10.2, 12.1, Jt ϭ 7.6 Hz, 1 H, 3-H), 1.96 (dddd, J ϭ 7.6, 8.2,
10.0, 12.4 Hz, 1 H, 4-H), 2.20 (dddd, J ϭ 3.4, 6.0, 7.5, 12.1 Hz, 1
H, 3-H), 2.46 (dddd, J ϭ 3.2, 6.8, 7.3, 12.5 Hz, 1 H, 4-H), 4.45
(dquint, Jd ϭ 8.0, Jquint ϭ 6.0 Hz, 1 H, 2-H), 5.22 (t, J ϭ 7.5 Hz,
1 H, 5-H), 7.43Ϫ7.48 (m, 3 H, Ar-H), 7.81Ϫ7.83 (m, 4 H, Ar-H)
ppm. 13C NMR (63 MHz): δ ϭ 22.1, 34.7 (C-3), 36.0 (C-4), 76.5
(C-2), 80.8 (C-5), 124.3, 124.5, 126.0, 126.4, 128.1, 128.3, 128.6,
133.2, 133.8, 141.9 ppm. MS (70 eV, EI): m/z (%) ϭ 212 (100) [Mϩ],
155 (72) [C10H8COϩ]. C15H16O (212.3): calcd. C 84.87, H 7.60;
found C 84.77, H 7.62.
trans-2-Methyl-3-phenyltetrahydrofuran (trans-10h):[39b] Yield:
0.44 g (91%) from 0.86 (3.00 mmol) trans-5h; colorless liquid. 1H
NMR (600 MHz): δ ϭ 1.22 (d, J ϭ 6.0 Hz, 3 H, CH3), 2.13 (dddd,
J ϭ 7.9, 8.1, 9.5, 12.5 Hz, 1 H, 4-H), 2.39 (dddd, J ϭ 5.6, 6.7, 8.5,
12.5 Hz, 1 H, 4-H), 2.80 (q, J ϭ 8.7 Hz, 1 H, 3-H), 3.87 (dq, Jd ϭ
8.7, Jq ϭ 6.1 Hz, 1 H, 2-H), 4.02 (dd, J ϭ 5.4, 8.0 Hz, 1 H, 5-H),
4.03 (dd, J ϭ 6.7, 7.1 Hz, 1 H, 5-H), 7.21Ϫ7.25 (m, 5 H, Ph-H)
cis-2-Methyl-4-phenyltetrahydrofuran (cis-10f):[20] Yield: 0.37 g
(75%) from 0.86 g of cis-5f (2.00 mmol), colorless liquid. 1H NMR
4048
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4033Ϫ4052

A Radical Version of the Bromo- and the Iodocyclization of Bis(homoallylic) Alcohols
ppm. 13C NMR (63 MHz): δ ϭ 19.4, 35.9 (C-4), 53.4 (C-3), 67.8 1 H, 5Ј-H), 7.19 (dt, Jt ϭ 8.2, Jd ϭ 1.0 Hz, 1 H, 4Ј-H), 7.32 (dd,
FULL PAPER
(C-5), 82.6 (C-2), 127.1, 128.0, 129.0, 142.0 ppm.
6. Preparation of 2-Alkylsulfanylpyridine N-oxides 11
6.1 N-Hydroxypyridine-2(1H)-thione Potassium Salt[64]
J ϭ 1.8, 8.5 Hz, 1 H, 3Ј-H), 7.36Ϫ7.49 (m, 3 H, Ar-H), 7.74Ϫ7.81
(m, 4 H, Ar-H), 8.23 (dd, J ϭ 0.9, 6.5 Hz, 1 H, 6Ј-H) ppm. 13C
NMR (63 MHz): δ ϭ 32.3 (C-3), 35.5 (C-4), 36.3, 78.1 (C-2), 81.8
(C-5), 120.9, 122.2, 124.2, 124.5, 126.1, 126.2, 126.5, 128.1, 128.3,
128.6, 133.2, 133.6, 139.1, 140.6, 152.5 (C-5) ppm. MS (70 eV, EI):
m/z (%) ϭ 320 (100) [Mϩ Ϫ OH], 210 (17) [Mϩ Ϫ C5H5NOS].
C20H19NO2S (337.4): calcd. C 71.19, H 5.68, N 4.15, S 9.41; found
C 70.93, H 5.75, N 4.12, S. 9.41.
A round-bottomed flask was charged with N-hydroxypyridine-
2(1H)-thione[28b] (10.74 g, 0.084 mol) and 95% aqueous EtOH
(50 mL). A solution of KOH (4.74 g, 0.084 mol) in EtOH (50 mL)
was added at 20 °C and stirring was continued for 15 min. All
volatiles were removed under reduced pressure to afford a colorless
oil which was freeze dried. The colorless powder was dissolved in
a minimum volume of anhydrous EtOH (20 °C). Anhydrous diethyl
ether was added at 20 °C until the faint cloudiness no longer disap-
peared. The flask was stoppered and kept at 5 °C for 14 h where-
upon N-hydroxypyridine-2(1H)-thione potassium salt precipitated.
Yield: 12.19 g (88%), colorless needles, 1H NMR (200 MHz,
CD3OD): δ ϭ 6.76 (ddd, J ϭ 2.0, 7.1, 8.7 Hz, 1 H, 5-H), 7.02 (td,
Jt ϭ 8.3, Jd ϭ 1.4 Hz, 1 H, 4-H), 7.56 (dd, J ϭ 1.8, 8.3 Hz, 1 H,
3-H), 8.05 (d, J ϭ 6.6 Hz, 1 H, 6-H) ppm. 13C NMR (50 MHz,
CD3OD): δ ϭ 116.9, 128.4, 134.0, 139.6, 168.0 ppm. C5H4KNOS
(165.6): calcd. C 36.34, H 2.44, N 8.48, S 19.40; found C 36.18, H
2.24, N 8.43, S 19.24.
cis-2-{[(4-Phenyltetrahydrofuran-2-yl)methyl]sulfanyl}pyridine
N-
Oxide (cis-11f): 0.92 g (91%), colorless needles, m.p. 88Ϫ89 °C. 1H
NMR (250 MHz): δ ϭ 1.95 (ddd, J ϭ 9.5, 10.4, 12.5 Hz, 1 H, 3-
H), 2.56 (ddd, J ϭ 5.5, 7.3, 12.8 Hz, 1 H, 3-H), 3.15 (dd, J ϭ 6.4,
12.8 Hz, 1 H, 6-H), 3.25 (dd, J ϭ 4.9, 12.8 Hz, 1 H, 6-H), 3.49 (tt,
J ϭ 7.6, 10.7 Hz, 1 H, 4-H), 3.83 (t, J ϭ 8.5 Hz, 1 H, 5-H), 4.17
(t, J ϭ 7.9 Hz, 1 H, 5-H), 4.37 (dq, Jd ϭ 9.5, Jq ϭ 5.5 Hz, 1 H, 2-
H), 7.03 (dt, Jd ϭ 2.1, Jt ϭ 7.3 Hz, 1 H, 5Ј-H), 7.17Ϫ7.33 (m, 7
H, Ar-H), 8.22 (d, J ϭ 6.1 Hz, 1 H, 6Ј-H) ppm. 13C NMR
(63 MHz): δ ϭ 36.0, 40.5 (C-3), 45.9 (C-4), 75.1 (C-5), 78.4 (C-2),
120.9, 122.7, 126.0, 127.2, 127.6, 129.1, 139.1, 141.1, 152.4 (C-5)
ppm. MS (70 eV, EI): m/z (%) ϭ 287 (4) [Mϩ], 270 (20) [Mϩ
Ϫ
OH], 161 (79) [Mϩ C5H5NOS], 127 (100) [C5H5NOSϩ].
Ϫ
C16H17NO2S (287.4): calcd. C 66.87, H 5.96, N 4.87, S 11.16; found
C 66.77, H 5.92, N 4.82, S 10.96.
6.2 2-Alkylsulfanylpyridine N-oxides 11
N-Hydroxypyridine-2(1H)-thione
potassium
salt
(0.58 g,
cis-2-({[5-(2-Naphthyl)tetrahydrofuran-2-yl]methyl}sulfanyl)pyridine
N-Oxide (cis-11g): 1.02 g (86%), colorless needles, m.p. 105Ϫ106
°C. H NMR (250 MHz): δ ϭ 1.99 (ddd, J ϭ 9.5, 10.4, 12.5 Hz, 1
H, 3-H), 2.58 (ddd, J ϭ 5.8, 7.6, 12.8 Hz, 1 H, 3-H), 3.11 (dd, J ϭ
6.4, 12.8 Hz, 1 H, 6-H), 3.21 (dd, J ϭ 5.2, 12.8 Hz, 1 H, 6Ј-H),
3.60 (dq, Jq ϭ 7.9, Jd ϭ 10.1 Hz, 1 H, 4-H), 3.89 (t, J ϭ 8.6 Hz, 1
3.50 mmol) and alkyl iodide 5 (3.50 mmol) were dissolved in anhy-
drous DMF (20 mL) at 20 °C. The reaction mixture was stirred for
24 h at room temperature (20 °C) and was then poured into 2 
aqueous NaOH (20 mL). This mixture was extracted with CH2Cl2
(3 ϫ 20 mL) and the combined organic phases were washed with
H2O (2 ϫ 20 mL), saturated aqueous NaHCO3 (20 mL) and brine
(20 mL). A clear yellowish solution was obtained, which was dried
(MgSO4) and concentrated under reduced pressure. The remaining
oil was purified by adsorptive filtration through a short pad of
silica gel. MTB was used as eluent to wash off a minor yellowish
impurity. Subsequently, pyridine N-oxides 11 were eluted from this
column using acetone (Rf ϭ 0.35Ϫ0.40). Heterocycles 11 were
recrystallized from CH2Cl2/MTB.
1
H, 5-H), 4.18 (t, J ϭ 8.2 Hz, 1 H, 5-H), 4.35 (dq, Jd ϭ 9.5, Jq
ϭ
5.8 Hz, 1 H, 2-H), 6.96 (ddd, J ϭ 1.8, 6.4, 8.2 Hz, 1 H, 5Ј-H), 7.14
(dt, Jt ϭ 8.6, Jd ϭ 1.2 Hz, 1 H, 4Ј-H), 7.31 (dd, J ϭ 1.8, 8.2 Hz, 1
H, 3Ј-H), 7.32Ϫ7.42 (m, 3 H, Ar-H), 7.60 (br. s, 1 H, Ar-H),
7.65Ϫ7.70 (m, 3 H, Ar-H), 8.24 (d, J ϭ 6.1 Hz, 1 H, 6Ј-H) ppm.
13C NMR (63 MHz): δ ϭ 35.9, 40.1 (C-3), 45.5 (C-4), 74.5 (C-5),
77.9 (C-2), 120.5, 121.8, 125.3, 125.5 (2 C), 125.6, 126.2, 127.4,
127.5, 128.4, 132.3, 133.3, 138.4, 138.7 (C-6Ј), 151.9 (C-2Ј) ppm.
MS (70 eV, EI): m/z (%) ϭ 337 (8) [Mϩ], 320 (25) [Mϩ Ϫ OH],
211 (100) [Mϩ Ϫ C5H5NOS], 127 (88) [C5H5NOSϩ]. C20H19NO2S
(337.44): calcd. C 71.19, H 5.68, N 4.15, S 9.50; found C 70.98, H
5.86, N 4.10, S 9.32.
cis-2-({[5-(2-Naphthyl)tetrahydrofuran-2-yl]methyl}sulfanyl]pyridine
N-Oxide (cis-11e): Yield: 0.97 g (82%), colorless block-shaped crys-
1
tals, m.p. 106Ϫ107 °C. H NMR (250 MHz): δ ϭ 1.88Ϫ2.07 (m, 2
H, 3-H, 4-H), 2.13Ϫ2.30 (m, 1 H, 3-H), 2.30Ϫ2.45 (m, 1 H, 4-H),
3.15 (dd, J ϭ 7.0, 13.1 Hz, 1 H, 6-H), 3.29 (dd, J ϭ 4.6, 13.1 Hz,
6-H), 4.40 (mc, 1 H, 2-H), 5.04 (t, J ϭ 7.0 Hz, 1 H, 5-H), 6.99 (ddd,
J ϭ 1.8, 6.4, 8.2 Hz, 1 H, 5Ј-H), 7.16 (dt, Jd ϭ 1.2, Jt ϭ 8.2 Hz, 1
H, 4Ј-H), 7.31 (dd, J ϭ 1.5, 8.2 Hz, 1 H, 3Ј-H), 7.38Ϫ7.47 (m, 3
H, Ar-H), 7.75Ϫ7.81 (m, 4 H, Ar-H), 8.24 (dt, Jd ϭ 6.4, Jt ϭ
0.6 Hz, 1 H, 6Ј-H) ppm. 13C NMR (63 MHz): δ ϭ 31.5 (C-3), 34.4
(C-4), 36.0, 77.9 (C-2), 82.3 (C-5), 120.9, 122.3, 124.4, 124.8, 126.0,
126.2, 126.5, 128.1, 128.3, 128.6, 133.3, 133.6, 139.1, 139.9, 152.5
(C-5) ppm. MS (70 eV, EI): m/z (%) ϭ 337 (1) [Mϩ], 320 (8) [Mϩ
Ϫ OH], 211 (89) [Mϩ Ϫ C5H4NOS], 210 (100) [Mϩ Ϫ C5H5NOS].
C20H19NO2S (337.4): calcd. C 71.19, H 5.68, N 4.15, S 9.50; found
C 70.86, H 5.79, N 4.05, S 9.40.
trans-2-{[(3-Phenyltetrahydrofuran-2-yl)methyl]sulfanyl}pyridine N-
Oxide (trans-11h): Yield: 0.82 g (82%), colorless needles, m.p.
115Ϫ116 °C. H NMR (250 MHz): δ ϭ 2.15 (dq, Jd ϭ 12.5, Jq ϭ
1
8.2 Hz, 1 H, 4-H), 2.39 (dddd, J ϭ 4.9, 7.0, 8.2, 12.8 Hz, 1 H, 4-H),
2.96 (dd, J ϭ 5.8, 13.4 Hz, 1 H, 6-H), 3.16 (dd, J ϭ 3.7, 13.4 Hz, 1
H, 6-H), 3.27 (q, J ϭ 9.2 Hz, 1 H, 3-H), 3.94Ϫ4.08 (m, 2 H, 5-H),
4.13 (ddd, J ϭ 3.7, 5.5, 8.9 Hz, 1 H, 2-H), 6.93Ϫ7.02 (m, 1 H, Ar-
H), 7.07Ϫ7.14 (m, 2 H, Ar-H), 7.18Ϫ7.35 (m, 5 H, Ar-H), 8.17 (d,
J ϭ 6.1 Hz, 1 H, 6Ј-H) ppm. 13C NMR (63 MHz): δ ϭ 34.1, 35.5
(C-4), 50.3 (C-3), 68.7 (C-5), 84.6 (C-2), 120.7, 122.3, 125.9, 127.5,
128.1, 129.3, 139.0, 140.8, 152.7 (C-5Ј) ppm. MS (70 eV, EI): m/z
(%) ϭ 287 (4) [Mϩ], 270 (7) [Mϩ Ϫ OH], 161 (100) [Mϩ
Ϫ
C5H5NOS]. C16H17NO2S (287.4): calcd. C 66.87, H 5.96, N 4.87,
S 11.16; found C 66.57, H 5.97, N 4.79, S 10.95.
trans-2-({[5-(2-Naphthyl)tetrahydrofuran-2-yl]methyl}sulfanyl]-
pyridine N-Oxide (trans-11e): Yield: 0.89 g (75%), colorless block-
shaped crystals, m.p. 155Ϫ156 °C. 1H NMR (250 MHz): δ ϭ
1.89Ϫ2.13 (m, 2 H, 3-H, 4-H), 2.22Ϫ2.36 (m, 1 H, 3-H), 2.41Ϫ2.54
7. X-ray Crystallographic Study
(m, 1 H, 4-H), 3.14 (dd, J ϭ 6.7, 12.8 Hz, 1 H, 6-H), 3.25 (dd, J ϭ Suitable crystals were obtained by slowly cooling a concentrated
4.9, 12.8 Hz, 1 H, 6-H), 4.61 (qd, Jq ϭ 6.7, Jd ϭ 4.9 Hz, 1 H, 2-
H), 5.21 (t, J ϭ 7.3 Hz, 1 H, 5-H), 7.00 (ddd, J ϭ 1.8, 6.7, 8.2 Hz,
solution of trans-10d in EtOH, cis-11g in methanol or by slowly
condensing MTB into acetone/CH2Cl2 solutions of trans-11e or cis-
Eur. J. Org. Chem. 2003, 4033Ϫ4052
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4049

ˇ
J. Hartung, R. Kneuer, S. Laug, P. Schmidt, K. Spehar, I. Svoboda, H. Fuess
FULL PAPER
Table 7. Crystallographic data for tetrahydrofurans trans-10d, cis-11e, trans-11e, cis-11f, cis-11g, trans-11h[a]
trans-10d
trans-11e
cis-11e
cis-11f
cis-11g
trans-11h
Empirical formula
Molecular mass
Temperature [K]
C17H18O
238.35
293(2)
0.71093
monoclinic
C2
16.731(4)
5.800(2)
14.801(4)
90
108.49(2)
90
1362.1(7)
4
C20H19NO2S
337.46
299(2)
0.71093
monoclinic
P21/n
6.510(3)
8.507(2)
30.452(8)
90
92.10(2)
90
1685(1)
4
C20H19NO2S C16H17NO2S
C20H19NO2S
337.46
304(2)
0.71093
orthorhombic
Pbca
8.772(4)
17.828(8)
22.041(6)
90
90
90
3447(2)
8
0.157
C16H17NO2S
287.40
300(2)
0.71093
monoclinic
P21/c
5.816(2)
8.930(2)
27.524(5)
90
91.81(2)
90
1428.8(6)
4
337.46
299(2)
0.71093
monoclinic
P21/n
9.401(3)
6.515(3)
27.791(3)
90
99.25(2)
90
1680.0(6)
4
287.40
303(2)
0.71093
triclinic
PϪ1
5.869(3)
9.032(2)
14.128(2)
100.88(1)
97.02(2)
98.57(3)
718.5(4)
2
˚
Wavelength [A]
Crystal system
Space group
˚
a (A)
˚
b (A)
˚
c (A)
α (°)
β (°)
γ (°)
3
˚
Volume (A )
Z
Absorption coeff. (mmϪ1)0.066
0.196
1.330
712
0.196
1.334
0.215
1.328
0.215
1.336
608
ρ calcd. (g cmϪ1
)
1.162
512
1.301
1424
F (000)
712
304
Crystal size (mm)
Θ range (°)
0.75 ϫ 0.10 ϫ 0.050.55 ϫ 0.20 ϫ 0.100.5 ϫ 0.2 ϫ 0.10.80 ϫ 0.13 ϫ 0.050.70 ϫ 0.33 ϫ 0.140.80 ϫ 0.22 ϫ 0.22
1.45Ϫ22.99
Ϫ18 Յ h Յ 18
0 Յ k Յ 6
Ϫ16 Յ l Յ 16
2133
1.34Ϫ22.99
Ϫ7 Յ h Յ 3
Ϫ9 Յ k Յ 0
Ϫ33 Յ l Յ 33
3582
1.49Ϫ22.98
Ϫ10 Յ h Յ 3 Ϫ7 Յ h Յ 3
Ϫ7 Յ k Յ 0 Ϫ11 Յ k Յ 11
Ϫ30 Յ l Յ 30 Ϫ17 Յ l Յ 17
1.49Ϫ25.97
1.85Ϫ25.97
Ϫ10 Յ h Յ 1
Ϫ21 Յ k Յ 0
Ϫ27 Յ l Յ 10
3528
1.48Ϫ22.98
Ϫ6 Յ h Յ 6
Ϫ9 Յ k Յ 0
Ϫ30 Յ l Յ 30
3984
Index ranges
Reflections collected
3312
4420
Independent reflections 1069
2330
2318/0/218
1.217
2335
2333/0/275
1.036
2821
2821/0/182
1.072
3373
2132/0/217
1.045
1995
1995/0/182
1.082
Data/restraints/param.
1069/1/176
1.094
Goodness-of-fit on F2
[a]
All data were collected on an Enraf Nonius CAD4 four circle diffractometer using Mo-Kα radiation. No absorption corrections were
applied. The structures were solved with either SHELXS-86[65] (all but cis-11f) or SHELXS-97 (cis-11f)[66] and refined with SHELXL-
93[67] (all but cis-11f) or SHELXL-97[68] (cis-11f). All hydrogen atoms were positioned geometrically. Thermal ellipsoids graphics were
obtained from ORTEP-III.[69]
that of trans-10d. The following abbreviations have been used:
Bp ϭ p-biphenylyl; DABCO ϭ 1,4-diazabicyclo[2.2.2]octane;
DTA ϭ differential thermal analysis; NBS ϭ N-bromosuc-
cinimide; MTB ϭ tert-butyl methyl ether; Np ϭ 2-naphthyl.
11g, or by condensing cyclohexane in an EtOAc solution of trans-
11h at 20 °C. Further details can be found in Table 7.
CCDC-203365 (trans-10d), -203367 (cis-11e), -203366 (trans-11e),
-203368 (cis-11f), -203370 (cis-11g) and -203369 (trans-11h) contain
the supplementary crystallographic data for this paper. These data
can be obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html [or from the Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, UK; Fax: (in-
ternat.) ϩ44-1223/336-033; E-mail: deposit@ccdc.cam.ac.uk].
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Acknowledgments
This work was generously supported by the Fonds der Chemischen
Industrie and the Deutsche Forschungsgemeinschaft (grants Ha
1705/3Ϫ3 and /5Ϫ2, and Graduiertenkolleg 690 ‘‘Elektronendichte
Ϫ Theorie und Experiment’’). Also, we express our gratitude to Dr.
Michael Grüne for recording 19F NMR spectra and Dipl.-Chem.
Thomas Gottwald for helpful discussions and technical assistance.
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4033Ϫ4052

A Radical Version of the Bromo- and the Iodocyclization of Bis(homoallylic) Alcohols
FULL PAPER
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