Regioselective Synthesis of Highly Substituted Aromatic Sulfides via Carbonyl-Alkyne Exchange Reaction

Article abstract of DOI:10.1021/jo990110s

Carbonyl-alkyne exchange reaction of 2,2-dimethyldihydropyran-4-thione-derived dienes with acetylenic ketones leads to highly substituted aromatic sulfides. The reaction proceeds with a high degree of regioselectivity and in good yields. Addition of Et₂AlCl considerably increases the scope of usable acetylenic ketones. The starting materials, dihydropyran-4-one and α-alkynyl ketone derivatives, are readily available reactive building blocks. Additional diversity can be introduced through straightforward derivatization reactions at the sulfur atom. The use of solid-supported reagents and trapping agents allows the reaction to be carried out in a parallel format which might render such a concept attractive for the synthesis of compound libraries.

Full text of DOI:10.1021/jo990110s

6182
J . Org. Chem. 1999, 64, 6182-6189
Regioselective Syn th esis of High ly Su bstitu ted Ar om a tic Su lfid es
via Ca r bon yl-Alk yn e Exch a n ge Rea ction †
Daniel Obrecht,*,‡ Cornelia Zumbrunn,§ and Klaus Mu¨ller
F. Hoffmann-La Roche AG, Pharma Research, CH-4070 Basel, Switzerland
Received J anuary 21, 1999
Carbonyl-alkyne exchange reaction of 2,2-dimethyldihydropyran-4-thione-derived dienes with
acetylenic ketones leads to highly substituted aromatic sulfides. The reaction proceeds with a high
degree of regioselectivity and in good yields. Addition of Et2AlCl considerably increases the scope
of usable acetylenic ketones. The starting materials, dihydropyran-4-one and R-alkynyl ketone
derivatives, are readily available reactive building blocks. Additional diversity can be introduced
through straightforward derivatization reactions at the sulfur atom. The use of solid-supported
reagents and trapping agents allows the reaction to be carried out in a parallel format which might
render such a concept attractive for the synthesis of compound libraries.
Sch em e 1
In tr od u ction
Highly substituted aromatic compounds are constitu-
ents of many complex natural products, pharmaceutical
drugs, agrochemicals, dyes, polymers, and additives.
Although many transformations using mainly electro-
philic and nucleophilic aromatic substitutions on the
aromatic nucleus have been described in the past, more
recent approaches resorted to the de novo construction
of the aromatic moiety using mainly [4+2] cycloaddition
strategies,1-9 ensuring a higher predictability and fidelity
of regiochemical control for the introduction of sterically
and electronically demanding functional groups. Further
approaches of successful de novo construction of highly
substituted aromatic compounds include trimerization of
acetylenes as described by Vollhardt10 and reactions of
cyclobutenones with acetylenes described by Danheiser,11
Liebeskind,12 and Moore.13
deficient acetylenes 2, yielding protected phenols 3
(Scheme 1), which has been studied previously in our
group,20 constitutes a novel approach for the regioselec-
tive de novo construction of highly functionalized aro-
matic compounds. Thus, in situ transformation of dihy-
dropyranones 1 into their corresponding silyl enol ethers
4 and [4+2] cycloaddition with acetylenes 2 yieldedsvia
bicyclic intermediates 5 and electrocyclic extrusion of
acetonesthe protected phenols 3 in good to excellent
yields (Scheme 1). The products were formed under very
mild conditions, tolerating a wide range of functional
groups. The high degree of regioselectivity observed in
this reaction is in accordance with simple FMO consid-
erations and earlier published work.21,22 Since both
dihydropyranone and R-alkynyl ketone derivatives are
synthetically readily available building blocks,20,23-27 this
The carbonyl-alkyne exchange (CAE) reaction14-19 of
2,2-dialkyl-2,3-dihydro-4H-pyran-4-ones 1 with electron-
† Dedicated to Prof. Dr. Robert E. Ireland on the occasion of his 70th
birthday.
‡ Present address: POLYPHOR Ltd., Winterthurerstr. 190, CH-8057
Zu¨rich, Switzerland.
§ Part of Ph.D. thesis of C.Z., University of Zu¨rich, 1998.
(1) Olsen, R. K.; Shao, R. J . Org. Chem. 1996, 61, 5852-5856.
(2) Furukawa, S.; Igarashi, J .; Shima, K.; Watanabe, M.; Kinoshita,
T. Chem. Pharm. Bull. 1990, 38, 5-7.
(3) Petrzilka, M.; Grayson, J . I. Synthesis 1981, 753-787.
(4) Avenoza, A.; Busto, J . H.; Cativiela, C.; Peregrina, J . M. Synthesis
1995, 671-674.
(5) Danishefsky, S. Acc. Chem. Res. 1981, 14, 400-406.
(6) Baker, R.; Rao, V. B.; Ravenscroft, P. D.; Swain, C. J . Synthesis
1983, 572-574.
(7) Carter, S. D.; Thetford, D.; Voyle, M. J . Chem. Soc., Perkin Trans.
1 1990, 1231-1233.
(8) Wong, H. N. C. Synthesis 1984, 787-790.
(9) Yamamoto, Y.; Nunokawa, K.; Ohno, M.; Eguchi, S. Synthesis
1996, 949-953.
(18) Tanyeli, C.; Tarhan, O. Synth. Commun. 1989, 19, 2453-2460.
(19) Ziegler, T.; Effenberger, F. Chem. Ber. 1987, 120, 1347-1355.
(20) Obrecht, D. Helv. Chim. Acta 1991, 74, 27-45.
(21) Salomon, R. G.; Burns, J . R.; Dominic, W. J . J . Org. Chem. 1976,
41, 2918-2920.
(10) Vollhardt, K. P. C. Acc. Chem. Res. 1977, 10, 1.
(11) Danheiser, R. L.; Nishida, A.; Savariar, S.; Trova, M. P.
Tetrahedron Lett. 1988, 29, 4917-4920.
(12) Huffmann, M. A.; Liebeskind, L. S. J . Am. Chem. Soc. 1991,
113, 2771-2772.
(22) Fleming, I. Book Frontier Orbitals and Organic Chemical
Reactions; J ohn Wiley & Sons, Ltd.: New York, 1976.
(23) Gelin, S.; Gelin, R. Bull. Soc. Chim. Fr. 1968, 288-230.
(24) Chantegrel, B.; Nadi, A.-I.; Gelin, S. Synthesis 1983, 948-949.
(25) Peterson, J . R.; Winter, T. J .; Miller, C. P. Synth. Commun.
1988, 18, 949-963.
(13) Xu, S. L.; Moore, H. W. J . Org. Chem. 1989, 54, 4024-4026.
(14) Effenberger, F.; Ziegler, T. Chem. Ber. 1987, 120, 1339-1346.
(15) Escudero, S.; Pe´rez, D.; Guitia´n, E.; Castedo, L. Tetrahedron
Lett. 1997, 38, 5375-5378.
(16) Kozikowski, A. P.; Schmiesing, R. Tetrahedron Lett. 1978, 44,
4241-4244.
(17) Tam, T. F.; Coles, P. Synthesis 1988, 383-386.
(26) Peterson, J . R.; Kirchhoff, E. W. Synlett 1990, 394-396.
(27) Dolmazon, R. Bull. Soc. Chim. Fr. 1987, 5, 873-876.
10.1021/jo990110s CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/05/1999

Synthesis of Highly Substituted Aromatic Sulfides
J . Org. Chem., Vol. 64, No. 17, 1999 6183
Ta ble 1. Syn th esis of Dih yd r op yr a n -4-th ion es 7a -g
reaction allows the synthesis of a wide range of aromatic
compounds. Nevertheless, this method showed some
limitations. Low yields were obtained in CAE reactions
when dihydropyranones bearing a slightly acidic hydro-
gen on the R1 substituent were used, which is probably
due to partial exocyclic enolization and thus formation
of dienes of type 6 (eq 1). Such s-trans-configurated
dienes are unable to undergo 1,4-cycloaddition reactions.
pyranone
R1
R2
conditions thione yield (%)
1a a
1ba
1ca
1d a
1ec
1fd
Ph
t-Bu
Me
H
Me
H
H
H
H
Me
H
rt/4 h
rt/6 h
rt/2 h
rt/6 h
rt/4 h
50 °C/4 h
7a
7b
7c
7d b
7e
7f
100
100
90
28
79
CO2n-Bu
Me
54
66
1ga
CO2t-Bu 70 °C/4 h
7g
a
b
Synthesized according to ref 20. Extremely volatile and
sensitive to hydrolysis. c Synthesized according to ref 23. Avail-
d
able from Aldrich.
this reaction prompted us to investigate its use in parallel
synthesis of aromatic compound libraries.
Resu lts a n d Discu ssion
Similarly, the synthesis was restricted to the use of
nonenolizable acetylenic ketones due to conversion of the
R-alkynyl ketone into a conjugated enyne system via
trans-silylation, thus inactivating the dienophile (eq 2).
Thiones 7a -g were readily available from the corre-
sponding dihydropyranones 1a -g by treatment with
Lawesson’s reagent28 (Table 1). Although dihydropy-
ranthiones 7 have a limited shelf life due to the inherent
instability of the thione group and should be stored at
low temperatures, they could be alkylated with NaH or
DBU as bases and a range of different alkyl halides to
give cyclic dienes 8a -m (Tables 2 and 3). These inter-
mediates could be isolated but were prone to electrocyclic
ring-opening (eq 3) to form linear products of type 9.
Therefore, intermediates 8 were directly reengaged in the
CAE reaction as purification on silica gel resulted in a
decrease of the overall yields.
The isolation of the intermediate dienes would therefore
be preferable in order to avoid the addition of silylating
agent and base during the cycloaddition step. Unfortu-
nately, isolation of 4 proved difficult due to the sensitivity
of the silyl enol ether toward hydrolysis.
In this paper, we describe the synthesis of dihydropy-
ranthiones 7 (Scheme 2) as the sulfur analogues of the
parent dihydropyranones 1 and their use in CAE reac-
tions. The increased stability toward hydrolysis of cyclic
dienes 8 as compared to the silyl enol ethers 4 allowed
the isolation of intermediates 8 and thus the stepwise
performance of CAE reactions. In addition, we could
demonstrate that Et2AlCl efficiently catalyzes the CAE
reaction between dienes of type 8 and dienophiles 2, thus
significantly broadening the scope of accessible substit-
uents and functional groups. The wide applicability of
Aromatic sulfides 10-25 resulting from CAE reaction
of dihydropyranthione-derived dienes and acetylenic
ketones 2a -f (Scheme 2) are listed in Table 2. Py-
ranthione 7c bearing a methyl group at position 6 was
converted into dienes 8h (R5 ) PMB) and 8i (R5 ) Bn)
and used in CAE reactions without concomitant exo-
enolization being observed (entries 12 and 13). In our
hands, the unsubstituted pyranthione 7d representing
a precursor for a cyclic analogue of Danishefsky’s diene
could not be used in CAE reactions.
Sch em e 2
After alkylation of the thione, electrocyclic ring-opening
was predominant and no cycloaddition product was
detectable. Danishefsky’s diene is thus highly comple-
mentary to the cyclic analogues of type 8. Best results
were obtained using dihydropyranthiones bearing bulky
and nonenolizable substituents in the 6-position (R1 )
Ph, t-Bu). Smaller substituents R1 (R1 ) Me, H) or
electron-withdrawing groups (R1 ) CO2n-Bu) seem to be
less effective in stabilizing the cyclic form of the diene.
(28) Cava, M. P.; Levinson, M. J . Tetrahedron 1985, 41, 5061.

6184 J . Org. Chem., Vol. 64, No. 17, 1999
Ta ble 2. Syn th esis of Ar om a tic Su lfid es via Th er m a l CAE Rea ction
Obrecht et al.
entry
thione
R1
R2
diene
R5
alkyne
R3
R4
temp (°C)
sulfide
yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
7a
7a
7a
7a
7a
7a
7a
7a
7b
7b
7b
7c
7c
7e
7f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
t-Bu
t-Bu
t-Bu
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
8a
8b
8b
8b
8b
8a
8c
8a
8f
PMBb
Bn
Bn
Bn
Bn
PMB
1-PhEe
PMB
PMB
PMB
Bn
PMB
Bn
PMB
Bn
2c
2c
2a
2e
2f
2a
2a
2b
2c
2f
2a
2c
2c
2c
2c
2c
CO2CH3
CO2CH3
CO2CH3
CH(OEt)2
CH2OTHP
CO2CH3
CO2CH3
H
CO2CH3
CH2OTHP
CO2CH3
CO2CH3
CO2CH3
CO2CH3
CO2CH3
CO2CH3
Ph
Ph
rt
rt
rt
rt
rt
rt
rt
110
50
rt
50
rt
rt
rt
110
100
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
77
89
OCH3
CF3
CF3
OCH3
OCH3
OCH3
Ph
CF3
OCH3
Ph
100c
97
79
85d
85d
47
85
86
60
42
8f
8g
8h
8i
8k
8l
CH3
CH3
CO2n-Bu
CH3
Ph
Ph
Ph
Ph
74
CH3
H
CO2t-Bu
27
71f
40
7g
8m
PMB
a
b
d
Isolated yield [%] over two steps. p-Methoxybenzyl. c Neat, yield based on purified and isolated diene. Neat. e 1-Phenylethyl. f Yield
based on isolated diene.
Ta ble 3. Syn th esis of Ar om a tic Su lfid es via Et2AlCl-Ca ta lyzed CAE Rea ction of Th ion e 7a
temp (°C)/amt of
Et2AlCl (equiv)
entry
diene
R1
R2
R5
alkyne
R3
R4
sulfide
yield (%)a
1
2
3
4
5
6
7
8
9
8a
8a
8d
8d
8a
8a
8d
8e
8d
8e
8d
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
PMBb
PMB
Hex
2b
2d
2g
2c
2h
2i
2k
2k
2l
H
OCH3
Ph
CH3
Ph
rt/3
17
26
27
28
29
30
31
32
33
34
35
90
79
93c
98
86
64
44
60
44
73
55
CH(OEt)2
CO2CH3
CO2CH3
SiMe3
Br
Br
Br
Br
SiMe3
SiMe3
rt/0.2
0/0.5
0/0.5
rt/0.2
rt/0.2
rt/1
rt/1.25
-10/1
0/1
Hex
PMB
PMB
Hex
CH3
Hex
Ph
Ph(OMe)3
OCH3
OCH3
CH3
Ph
10
11
CH3
Hex
2h
2h
Ph
0/1
a
b
Isolated yield over two steps. p-Methoxybenzyl. c 95:5 mixture of regioisomers.
Acetylenes bearing strong electron-withdrawing sub-
stituents were most efficient in the CAE reaction. Pro-
longed heating was necessary in reactions with less
reactive dienophiles such as methyl propiolate which was
incompatible with the limited thermal stability of some
of the dienes 8.
To overcome the problem of insufficient reactivity and
to broaden the range of acetylenic ketones amenable to
the CAE reaction, we explored the use of a Lewis acid
catalyst to increase the reactivity of the dienophiles. After
having screened several Lewis acids which are known
to catalyze cycloaddition reactions,29-36 we found that Et2-
AlCl indeed efficiently accelerated the CAE reaction.
Aromatic sulfides synthesized using Et2AlCl catalysis are
summarized in Table 3.
8) along with significant amounts of noncharacterized by-
products, complicating the purification of the final prod-
ucts.
Under Lewis acid-catalyzed conditions the reaction of
brominated or silylated actylenic ketones 2h -l (R3 ) Br,
SiMe3) became feasible (Table 3, entries 5-11). Thus,
products 19-35 (Table 3, entries 5-11) with R3 ) TMS
and Br constitute synthetically especially useful inter-
mediates for further derivatization reactions such as ipso-
substitutions and Pd-catalyzed cross-coupling reactions.
Without the use of Et2AlCl these dienophiles either were
too unreactive for the CAE reaction or underwent nu-
merous side reactions.
The amount of Lewis acid catalyst necessary for the
reaction depended largely on the nature of the alkyne.
R-Alkynyl ketones needed less than 1 equiv of catalyst
for completion of the reaction whereas propiolic esters
required stoichiometric amounts or more. In the latter
case, the aluminum appeared to coordinate tightly with
the products, which prevented the release of the catalyst.
CAE reactions of dienes derived from thiones bearing
electron-withdrawing groups such as 7f and 7g (Tables
1 and 2) could not be catalyzed, probably due to the fact
that the catalyst was deactivating the diene by coordina-
tion to the ester function. Those reactions were carried
out at 100-110 °C in a sealed tube without a Lewis acid
catalyst present.
The reaction with methyl propiolate under Lewis acid-
catalyzed reaction conditions gave sulfide 17 in 90% yield
(Table 3, entry 1). In contrast, the uncatalyzed reaction
gave the desired sulfide 17 in 47% yield (Table 2, entry
(29) Skowronska, A.; Dybrowski, P.; Koprowski, M.; Krawczyk, E.
Tetrahedron Lett. 1995, 36, 8133-8136.
(30) Vandenput, D. A. L.; Scheeren, H. W. Tetrahedron 1995, 51,
8383-8388.
(31) Roush, W. R.; Barda, D. A. J . Am. Chem. Soc. 1997, 119, 7402-
7403.
(32) Posner, G. H.; Dai, H.; Bull, D. S.; Lee, J .-K.; Eydoux, F.;
Ishihara, Y.; Welsh, W.; Pryor, N.; Petr, S., J r. J . Org. Chem. 1996,
61, 671-676.
(33) Marshman, R. W. Aldrichim. Acta 1995, 28, 77-92.
(34) Ishihara, K.; Kondo, S.; Kurihara, H.; Yamamoto, H. J . Org.
Chem. 1997, 62, 3026-3027.
Different reaction protocols allowing a simple workup
procedure were screened in order to use the CAE reaction
for combinatorial and parallel synthesis. Among the
several successful alkylation protocols amenable to the
alkylation of dihydropyranthiones 7, best results were
(35) Koreeda, M.; J ung, K.-J .; Ichita, J . J . Chem. Soc., Perkin Trans.
1 1989, 2129-2131.
(36) Corey, E. J .; Lee, T. W. Tetrahedron Lett. 1997, 38, 5755-
5758.

Synthesis of Highly Substituted Aromatic Sulfides
J . Org. Chem., Vol. 64, No. 17, 1999 6185
Sch em e 3
Sch em e 4
Ch a r t 1
obtained by treatment either with an alkyl halide and
NaH in DMF (general procedure A) or with 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) in dichloromethane (gen-
eral procedure B). The former procedure required aque-
ous workup for the isolation of the diene, whereas in the
latter a simple filtration over a small plug of silica gel
efficiently removed the byproducts. Obviously, method
B was more appropriate for parallel synthesis. In the
subsequent cycloaddition reaction the excess of R-alkynyl
ketone (1.05-2.0 equiv) was trapped with a polymer-
supported thiol.37 Thus, the polymer-bound 1,4-adducts
could be easily removed by simple filtration.
The aromatic sulfides generated by CAE reactions of
dihydropyranthiones with acetylenic ketones were fur-
ther derivatized. Additional molecular diversity on the
sulfur atom could be introduced by a trans-alkylation
protocol as depicted in Scheme 3. Treatment of the
p-methoxybenzyl thioether 21 with N-bromosuccinimide
(NBS) resulted in quantitative formation of disulfide 36.
Reductive cleavage of the disulfide using polymer-bound
triphenylphosphine and subsequent alkylation of the
intermediate thiophenols with different electrophiles in
a one-pot procedure37 gave sulfides 37-40. Again, the use
of solid-supported reagents facilitated workup and isola-
tion of the final products.
Another interesting derivatization consisted in a direct
transformation of the aromatic sulfides into sulfonam-
ides. Traditionally, sulfonamides are synthesized via the
corresponding sulfonic acids and sulfonyl chlorides, re-
quiring rather harsh reaction conditions. To synthesize
a wide range of aromatic sulfonamides, we developed a
simple two-step procedure to convert aromatic p-meth-
oxybenzyl sulfides into sulfonamides (Scheme 4, Chart
1). The reaction sequence involved thioether cleavage
with sulfuryl chloride as reported by Kharasch et al.39
to form the highly reactive and easily hydrolizable
sulfenyl chloride derivatives. In our case, isolation of the
sulfenyl chlorides was not necessary, and direct substitu-
tion with primary or secondary amines gave the inter-
mediate, rather unstable sulfenamide derivatives which
after filtration over a thin plug of aluminum oxide (N)
were oxidized with m-CPBA under buffered conditions
to give sulfonamides 41-45 in 30-60% overall yields.
Reaction conditions were not optimized, and disulfide
formation remained an important side reaction. Never-
theless, this protocol represents a mild alternative for the
synthesis of aromatic sulfonamides.
Su m m a r y
On the basis of the carbonyl-alkyne exchange reaction
of 2,2-dimethyl-2,3-dihydro-4H-pyran-4-thione-derived
cyclic dienes 8 and electron-deficient acetylenes, a novel
synthesis of aromatic sulfides has been developed. The
procedure allows the synthesis of highly substituted
benzenes with great potential for variation of functional
groups starting from readily available, highly reactive
building blocks under very mild conditions and in high
yields. The use of Et2AlCl as a Lewis acid catalyst
(37) Obrecht, D.; Villalgordo, J . M. Solid-Supported Combinatorial
and Parallel Synthesis of Small-Molecular-Weight Compound Librar-
ies; Baldwin, J . E., Williams, R. M., Eds.; Tetrahedron Organic Chem-
istry Series; Pergamon, Elsevier Science: New York, 1998; Vol. 17.
(38) Amos, R. A.; Fawcett, S. M. J . Org. Chem. 1984, 49, 2637-
2639.
(39) Kharasch, N.; Wehrmeister, H. L.; Tigerman, H. J . Am. Chem.
Soc. 1947, 69, 1612-1615; Kharasch, N.; Langford, R. B. J . Org. Chem.
1963, 28, 1901-1905.

6186 J . Org. Chem., Vol. 64, No. 17, 1999
Obrecht et al.
2.91 (s, 2 H); 2.03 (s, 3 H); 1.52 (s, 9 H, t-Bu); 1.40 (s, 6 H, 2
Me). MS (EI): m/z 256 (48, M+); 200 (100, [M - C4H8]+); 185
(36); 167 (42); 154 (30); 139 (18).
substantially increased the range of applicable acetylenic
dienophiles as also enolizable acetylenic ketones could
be employed. Reaction conditions were developed suitable
for automated parallel synthesis using a polymer-bound
thiol as trapping agent for the capture of excess dieno-
phile. The resulting aromatic sulfides could be efficiently
transformed by a reductive transalkylation procedure
using a polymer-bound phosphine either into products
37-40 (Scheme 3) or into sulfonamides 41-45 as de-
picted in Scheme 4. Hence, the described aromatic
sulfides 10-35 constitute platforms for further chemical
transformations into pharmacologically interesting mol-
ecules.
Alk yla tion of 2,2-Dim eth yl-2,3-d ih yd r op yr a n -4-th ion es
7. Gen er a l P r oced u r e A. To a stirred solution of thione 7
(0.5 mmol) in DMF (1.5 mL) at 0 °C under Ar were added alkyl
halide (1.2 equiv) and NaH dispersion (55%, 1.2 equiv). The
reaction mixture was stirred at 0 °C as indicated, poured onto
saturated NH4Cl solution, and extracted with ether. The
combined organic fractions were dried (MgSO4) and the
solvents evaporated. The crude dienes 8 were used without
further purification or analysis.
Alk yla tion of 2,2-Dim eth yl-2,3-d ih yd r op yr a n -4-th ion es
7. Gen er a l P r oced u r e B. To a stirred solution of thione 7
(0.5 mmol) in CH2Cl2 (2 mL) at room temperature under Ar
were added alkyl halide (1.2 equiv) and DBU (1.2 equiv). The
reaction mixture was stirred at room temperature as indicated
and filtered over silica gel (2 g), and the solvents were removed
under reduced pressure. The crude dienes 8 were used without
further purification or analysis.
Un ca ta lyzed CAE Rea ction s of Cyclic Dien es 8 w ith
Acetylen ic Keton es 2. Gen er a l P r oced u r e. To a solution
of the crude diene 8 (0.5 mmol) in toluene (500 µL) was added
acetylene 2 (1.2-2 equiv). The mixture was stirred as indicated
until all the diene was consumed. Polystyrene-bound thiol37,42
was added and the mixture stirred at room temperature until
the excess dienophile was trapped. Filtration and chromatog-
raphy on silica gel gave analytically pure products.
Ca ta lyzed CAE Rea ction s of Cyclic Dien es 8 w ith
Acetylen ic Keton es 2. Gen er a l P r oced u r e. To a solution
of the crude diene 8 (0.5 mmol) in toluene (500 µL) were added
acetylene 2 (1.2-2 equiv) and dropwise a solution of Et2AlCl
in toluene (1.8 M, 0.1-3 equiv). The mixture was stirred at
room temperature as indicated until disappearance of 8.
Polystyrene-bound thiol37,42 was added and the mixture stirred
at room temperature until the excess dienophile was trapped.
Filtration and chromatography on silica gel gave analytically
pure products.
Exp er im en ta l Section
Gen er a l P r oced u r es. Thin-layer chromatography (TLC)
was performed using E. Merck silica gel 60 F254 0.25 mm
plates. Visualization was accomplished using ultraviolet light
or one of the following stains: (a) 1% KMnO4, 2% NaHCO3 in
H2O or (b) o-toluidine (320 mg), acetic acid (60 mL), and KI (2
g) dissolved in H2O (1 L). Chromatography was performed
using E. Merck silica gel 60 (230-400 mesh). Solvent systems
are reported as volume percent mixtures. Chloroform was
filtered over alox prior to use. CH2Cl2 was distilled from CaH
and stored under Ar. Liquid reagents were distilled prior to
use. All other reagents were purchased from Fluka or Aldrich
and used without further purification. Highly loaded PS-PPh2
and PS-CH2SH resins were purchased from Polyphor Ltd.
Acetylenic ketones 2a -l were synthesized in analogy to
literature procedures.20,40-43
Syn th esis of 2,2-Dim eth yl-2,3-d ih yd r op yr a n -4-th ion es
7. Gen er a l P r oced u r e. To a stirred solution of dihydropy-
ranone 1 (10 mmol) in toluene (10 mL) was added Lawesson’s
reagent (0.6 equiv). The reaction mixture was stirred under
Ar as indicated. Purification by filtration over silica gel (120
g) with hexane/CH2Cl2 gave purple thiones 7 which are rather
unstable but can be stored at -20 °C for at least a month.
2,2-Dim eth yl-6-p h en yl-2,3-d ih yd r op yr a n -4-th ion e (7a ).
Meth yl 2-Ben zoyl-5-(4-m eth oxyben zylsu lfa n yl)bip h en -
yl-3-ca r boxyla te (10). Alkylation of 7a according to general
procedure A (2.5 h). CAE reaction with 2c (24 h at room
1
1
Quantitative. H NMR (400 MHz, CDCl3): δ 7.84 (d, 2 H, J )
temperature). Yellow oil. 77%. H NMR (250 MHz, CDCl3): δ
3.1); 7.51-7.49 (m, 1 H); 7.45-7.41 (m, H); 6.99 (s, 1 H); 2.97
(s, 2 H); 1.52 (s, 2 CH3). 13C NMR (100 MHz, CDCl3): δ 222.7;
160.4; 133.2; 131.8; 128.8; 127.1; 114.4; 80.4; 54.4; 25.8. IR
(NJ L): 1665; 1582; 765 cm-1. MS (EI): m/z 218 (86, [M]+); 203
(68, [M - CH3]+); 105 (100, [Ph - CO]+); 77 (53, [C6H5]+).
6-ter t-Bu t yl-2,2-d im et h yl-2,3-d ih yd r op yr a n -4-t h ion e
(7b). Quantitative. 1H NMR (250 MHz, CDCl3): δ 6.44 (s, 1
H); 2.88 (s, 2 H); 1.38 (s, 6 H, 2 CH3); 1.18 (s, 6 H, t-Bu). IR
(KBr): 1554m; 1257; 1156; 1088 cm-1. MS (EI): m/z 198 (100,
[M]+); 183 (32, [M - CH3]+); 141 (95, [M - t-Bu]+); 85 (55).
2,2,5,6-Tetr am eth yl-2,3-dih ydr opyr an -4-th ion e (7e). 79%.
1H NMR (250 MHz, CDCl3): δ 3.00 (s, 2 H); 2.09 (s, 3 H); 2.04
(s, 3 H); 1.36 (s, 6 H, 2 Me). MS (EI): m/z 170 (98, M+); 155
(100, [M - CH3]+).
7.98 (d, 1 H, J ) 1.8); 7.6-7.5 (m, 2 H); 7.45-7.3 (m, 1 H);
7.3-7.2 (m, 4 H); 7.2-7.05 (m, 5 H); 6.7-6.6 (m, 2 H); 4.20 (s,
2 H); 3.80 (s, 3 H, COOMe); 3.67 (s, 3 H, OMe). IR (film):
1727s; 1677s cm-1. MS (EI): m/z 468 (12, M+); 121 (100,
[CH2C6H4 - OMe]+).
Meth yl 2-Ben zoyl-5-(ben zylsu lfan yl)biph en yl-3-car box-
yla te (11). Alkylation of 7a according to general procedure B
(3 h). CAE reaction with 2c (3.5 h at room temperature).
1
Recrystallization from hexane/ether (3:1). 89%. H NMR (250
MHz, CDCl3): δ 7.98 (d, 1 H, J ) 1.9); 7.6-7.5 (m, 2 H); 7.42
(d, 1 H, J ) 1.9); 7.4-7.05 (m, 13 H); 4,24 (s, 2 H); 3.67 (s, 3
H, OMe). IR (KBr): 1727s; 1665s cm-1. MS (EI): m/z 438 (100,
M+); 406 (7); 361 (12); 91(15). Anal. Calcd for C28H22O3S
(438.54): C, 76.69; H, 5.06; S, 7.31. Found: C, 76.60; H, 5.04;
S, 7.18.
n -Bu tyl 6,6-Dim eth yl-4-th ioxo-5,6-d ih yd r o-4H-p yr a n -
1
Dim eth yl 5-(Ben zylsu lfa n yl)bip h en yl-2,3-d ica r boxyl-
a te (12). Alkylation of 7a according to general procedure A (3
h). CAE reaction with 2a (neat DMAD, 18 h). Yellow oil.
2-ca r boxyla te (7f). 54%. H NMR (250 MHz, CDCl3): δ 6.92
(s, 1 H); 4.28 (t, 2 H, J ) 6.6); 2.95 (s, 2 H); 1.8-1.6 (m, 2 H);
1.5-1.3 (m, 2 H); 1.47 (s, 6 H, 2 Me); 0.96 (t, 3 H, J ) 7.3). IR
(MIR): 1734s; 1567m; 1288s; 1260m; 1236s; 1218 s; 1087s
cm-1. MS (EI): m/z 242 (72, M+); 141(82); 125 (100); 115 (60);
57 (64).
1
Quantitative. H NMR (250 MHz, CDCl3): δ 7.69 (d, 1 H, J )
1.9); 7.4-7.25 (m, 11 H); 4,18 (s, 2 H); 3.89 (s, 3 H, OMe); 3.64
(s, 3 H, OMe). IR (film): 1732s cm-1. MS (EI): m/z 392 (100,
M+); 361 (20, [M - OCH3]+).
ter t-Bu tyl 2,6,6-Tr im eth yl-4-th ioxo-5,6-d ih yd r o-4H-p y-
r a n -3-ca r boxyla te (7g). 66%. 1H NMR (250 MHz, CDCl3): δ
1-[5-(Ben zylsu lfa n yl)-3-(d iet h oxym et h yl)b ip h en yl-2-
yl]-2,2,2-tr iflu or oeth a n on e (13). Alkylation of 7a according
to general procedure A (3 h). CAE reaction with 2e (2 equiv)
(40) Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, R. Angew.
Chem., Int. Ed. Engl. 1984, 23, 727.
1
(45 min at room temperature). Yellow oil. 97%. H NMR (250
MHz, CDCl3): δ 7.5 (d, 1 H, J ) 1.9); 7.4-7.2 (m, 11 H); 5.61
(s, 1 H); 4.21 (s, 2 H); 3.52 (q, 4 H); 1.19 (t, 6 H). IR (film):
1735s; 1580 cm-1. MS (EI): m/z 474 (20, M+); 429 (20, [M -
OCH2CH3]+); 331 (18); 91 (100, Bn+).
1-[5-(Ben zylsu lfan yl)-3-(tetr ah ydr opyr an -2-yloxym eth -
yl)bip h en yl-2-yl]-2,2,2-tr iflu or oeth a n on e (14). Alkylation
of 7a according to general procedure A (3 h). CAE reaction
(41) Leroy, J . Synth. Commun. 1992, 22, 567-572.
(42) Chucholowski, A.; Masquelin, T.; Obrecht, D.; Stadlwieser, J .;
Villalgordo, J . M. Chimia 1996, 50, 525-530. Obrecht, D.; Abrecht,
Ch.; Grieder, A.; Villalgordo, J . M. Helv. Chim. Acta 1997, 80, 65-72.
(43) Obrecht, D. Helv. Chim. Acta 1989, 72, 447-458. Masquelin,
T.; Obrecht, D. Tetrahedron Lett. 1994, 35, 9387-9390. Masquelin,
T.; Obrecht, D. Tetrahedron 1997, 53, 641-646. Obrecht, D.; Gerber,
F.; Sprenger, D.; Masquelin, T. Helv. Chim. Acta 1997, 80, 531-537.

Synthesis of Highly Substituted Aromatic Sulfides
J . Org. Chem., Vol. 64, No. 17, 1999 6187
with 2f (2 equiv) (3 h at room temperature). Yellow oil. 79%.
1H NMR (250 MHz, CDCl3): δ 7.4-7.2 (m, 12 H); 4.73 (d, 1 H,
J ) 12.6); 4.65-4.55 (m, 1 H); 4.48 (d, 1 H, J ) 12.6); 4.22 (s,
2 H); 4.85-4.7 (m, 1 H); 3.6-3.45 (m, 1 H); 1.8-1.5 (m, 6 H).
IR (film): 1732s; 1579s cm-1. MS (EI): m/z 486 (5, M+); 386
(40, [M - THP]+); 263 (38); 91 (100, Bn+).
4.21 (s, 2 H); 3.64 (s, 3 H); 2.11 (s, 3 H). IR (MIR): 1721s;
1674s; 1583; 1267 cm-1. MS (EI): m/z 376 (58, M+); 91 (100).
Met h yl 2-Ben zoyl-5-(4-m et h oxyb en zylsu lfa n yl)-3,4-
d im eth ylben zoa te (23). Alkylation of 7e according to general
procedure B (1 h). CAE reaction with 2c (1.2 equiv) (24 h at
room temperature). Yellow oil. 27%. 1H NMR (250 MHz,
CDCl3): δ 7.91 (s, 1 H); 7.8-7.7 (m, 2 H); 7.6-7.45 (m, 1 H);
7.45-7.35 (m, 2 H); 7.3-7.2 (m, 2 H); 6.9-6.8 (m, 2 H); 4.14
(s, 2 H); 3.80 (s, 3 H); 3.65 (s, 3 H); 2.34 (s, 3 H); 2.07 (s, 3 H).
IR (MIR): 1715s; 1672s; 1511; 1165 cm-1. MS (EI): m/z 420
(14, M+); 389 (3, [M - OCH3]+); 121 (100).
1-Bu tyl-3-m eth yl 2-ben zoyl-5-(m eth ylsu lfa n yl)isop h -
th a la te (24). Alkylation of 7f according to general procedure
B (1 h). Isolation of the diene by chromatography. CAE reaction
with 2c (3 h at 110 °C). Yellow oil. 71%. IR (film): 1729s;
1681s; 1598; 1583 cm-1. MS (EI): m/z 386 (68, M+); 330 (26,
[M - C4H8]+); 313 (18); 253 (100); 221 (92); 105 (50).
4-ter t-Bu tyl 1-Meth yl 2-Ben zoyl-5-(4-m eth oxyben zyl-
su lfa n yl)-3-m eth ylter ep h th a la te (25). Alkylation of 7g
according to general procedure B (1 h). CAE reaction with 2c
(1.2 equiv) (5 h at 100 °C). Yellow oil. 40%. 1H NMR (250 MHz,
CDCl3): δ 7.84 (s, 1 H); 7.8-7.7 (m, 2 H); 7.65-7.5 (m, 1 H);
7.5-7.35 (m, 2 H); 7.3-7.2 (m, 2 H); 6.9-6.8 (m, 2 H); 4.14 (s,
2 H); 3.79 (s, 3 H); 3.64 (s, 3 H); 2.11 (s, 3 H); 1.61 (s, 9 H). IR
(film): 1726s; 1678s; 1610; 1512 cm-1. MS (EI): m/z 506 (12,
M+); 449 (52, [M - C4H8]+); 121 (100).
[3-(Diet h oxym et h yl)-5-(4-m et h oxyb en zylsu lfa n yl)b i-
p h en yl-2-yl]p h en ylm eth a n on e (26). Alkylation of 7a ac-
cording to general procedure A (2.5 h). CAE reaction with 2d
(1.2 equiv) and Et2AlCl (0.2 equiv) (24 h at room temperature).
Yellow oil. 79%. 1H NMR (250 MHz, CDCl3): δ 7.69 (d, 1 H, J
) 1.8); 7.55-7.45 (m, 2 H); 7.35-7.05 (m, 11 H); 6.9-6.8 (m,
2 H); 5.57 (s, 1 H); 4.19 (s, 2 H); 3.80 (s, 3 H); 3.6-3.3 (br, 4
H); 1.2-0.8 (br, 6 H). IR (film): 1665s; 1610; 1597 cm-1. MS
(EI): m/z 512 (10, M+); 483 (4, [M - C2H5]+); 467 (6, [M -
OC2H5]+); 437 (12); 121 (100).
Meth yl 2-Acetyl-5-(h exylsu lfa n yl)bip h en yl-3-ca r boxyl-
a te (27). Alkylation of 7a according to general procedure A
(2.5 h). CAE reaction with 2g (1.2 equiv) and Et2AlCl (0.5
equiv) (2 h at 0 °C). Yellow oil. 93% (ratio of regioisomers 95:
5). 1H NMR (250 MHz, CDCl3) (major isomer): δ 7.82 (d, 1 H,
J ) 1.9); 7.5-7.2 (m, 6 H); 3.88 (s, 3 H); 2.99 (t, 2 H, J ) 7.2);
2.07 (s, 3 H); 1.75-1.55 (m, 2 H); 1.5-1.2 (m, 6 H); 0.95-0.8
(m, 3 H). IR (film) (major isomer): 1727s; 1704s; 1582; 1574;
1092 cm-1. MS (EI) (major isomer): m/z 370 (28, M+); 355 (100,
[M - CH3]+); 271 (10).
Dim eth yl 5-(4-Meth oxyben zylsu lfa n yl)bip h en yl-2,3-d i-
ca r boxyla te (15). Alkylation of 7a according to general
procedure A (2 h). CAE reaction with DMAD (2a , 200 µL) (5 h
at room temperature). Yellow oil. 85%. 1H NMR (250 MHz,
CDCl3): δ 7.88 (d, 1 H, J ) 1.9); 7.4-7.2 (m, 8 H); 6.9-6.8 (m,
2 H); 4.15 (s, 2 H); 3.89 (s, 3 H); 3.79 (s, 3 H); 3.64 (s, 3 H). IR
(film): 1731s; 1609s; 1205 cm-1. MS (EI): m/z 422 (5, M+);
391 (4, [M - OCH3]+); 121 (100, [CH2C6H4 - OMe]+).
Dim eth yl 5-(1-P h en yleth ylsu lfa n yl)bip h en yl-2,3-d ica r -
boxyla te (16). Alkylation of 7a according to general procedure
A (2 h). CAE reaction with DMAD (2a , 200 µL) (4 h at room
1
temperature). Yellow oil. 85%. H NMR (250 MHz, CDCl3): δ
7.88 (d, 1 H, J ) 1.9); 7.4-7.2 (m, 11 H); 4.46 (q, 1 H, J ) 7.0);
3.88 (s, 3 H); 3.64 (s, 3 H); 1.67 (d, 3 H, J ) 7.0). IR (film):
1730s; 1577; 1203 cm-1. MS (EI): m/z 406 (8, M+); 375 (8, [M
- OCH3]+); 302 (24); 270 (48); 105 (100, [CH3CHC6H5]+).
Met h yl 5-(4-Met h oxyb en zylsu lfa n yl)b ip h en yl-2-ca r -
boxyla te (17). Alkylation of 7a according to general procedure
A (2.5 h). CAE reaction with methyl propiolate (2b, 6 equiv)
and Et2AlCl (1.8 M in toluene, 3 equiv) (2 h at room temper-
ature). Recrystallization from hexane. 90%. 1H NMR (250
MHz, CDCl3): δ 7.75 (d, 1 H, J ) 8.7); 7.4-7.2 (m, 10 H); 6.83
(d, 2 H, J ) 8.7); 4.16 (s, 2 H); 3.79 (s, 3 H); 3.61 (s, 3 H). IR
(KBr): 1727s; 1609; 1585; 1107 cm-1. MS (EI): m/z 364 (12,
M+); 121 (100, [CH2C6H4 - OMe]+). Anal. Calcd for C22H20O3S
(364.46): C, 72.50; H, 5.53; S, 8.80. Found: C, 72.45; H, 5.77;
S, 8.84.
Meth yl 2-Ben zoyl-3-ter t-bu tyl-5-(4-m eth oxyben zylsu l-
fa n yl)ben zoa te (18). Alkylation of 7b according to general
procedure A (2.5 h). CAE reaction with 2c (1.1 equiv) (3 h at
50 °C). Yellow oil. 85%. 1H NMR (250 MHz, CDCl3): δ 8.3-
7.55 (br, 2 H); 7.82 (d, 1 H, J ) 1.9); 7.58 (d, 1 H, J ) 1.9);
7.55-7.3 (m, 3 H); 7.3-7.2 (m, 2 H); 6.9-6.8 (m, 2 H); 4.16 (s,
2 H); 3.79 (s, 3 H); 3.51 (s, 3 H); 1.21 (s, 9 H). IR (film): 1727s;
1679s cm-1. MS (EI): m/z 448 (5, M+); 121 (100, [CH2C6H4-
OMe]+).
1-[2-ter t-Bu t yl-4-(4-m et h oxyb en zylsu lfa n yl)-6-(t et r a -
h yd r op yr a n -2-yloxym eth yl)p h en yl]-2,2,2-tr iflu or oeth a -
n on e (19). Alkylation of 7b according to general procedure A
(3 h). CAE reaction with 2f (2 equiv) (6 h at room temperature).
Yellow oil. 86%. 1H NMR (250 MHz, CDCl3): δ 7.3-7.25 (m, 4
H); 6.9-6.8 (m, 2 H); 4.65-4.55 (m, 2 H); 4.3-4.2 (m, 1 H);
4.13 (s, 2 H); 3.85-3.7 (m, 1 H); 3.79 (s, 3 H); 3.6-3.45 (m, 1
H); 1.75-1.45 (m, 6 H); 1.27 (s, 9 H). IR (film): 1738s; 1610;
1580 cm-1. MS (EI): m/z 496 (3, M+); 121 (100, [CH2C6H4-
OMe]+).
Dim et h yl 3-ter t-Bu t yl-5-(4-m et h oxyb en zylsu lfa n yl)-
p h th a la te (20). Alkylation of 7b according to general proce-
dure A (2 h). CAE reaction with DMAD (2a , 2 equiv) (6 h at
50 °C). Yellow oil. 60%. 1H NMR (250 MHz, CDCl3): δ 7.77
(d, 1 H, J ) 1.9); 7.48 (d, 1 H, J ) 1.9); 7.3-7.2 (m, 2 H); 6.9-
6.8 (m, 2 H); 4.11 (s, 2 H); 3.87 (s, 3 H); 3.86 (s, 3 H); 3.78 (s,
3 H); 1.32 (s, 9 H). IR (film): 1734s; 1664s; 1075 cm-1. MS
(EI): m/z 402 (7, M+); 371 (5, [M - OMe]+); 121 (100,
[CH2C6H4OMe]+).
Meth yl 2-Ben zoyl-5-(h exylsu lfa n yl)bip h en yl-3-ca r box-
yla te (28). Alkylation of 7a according to general procedure A
(2.5 h). CAE reaction with 2c (1.05 equiv) and Et2AlCl (0.5
1
equiv) (2 h at 0 °C). Crystallization from methanol. 98%. H
NMR (250 MHz, CDCl3): δ 7.94 (d, 1 H, J ) 1.9); 7.65-7.55
(m, 2 H); 7.5-7.2 (m, 3 H); 7.44 (d, 1 H, J ) 1.9); 7.17 (s, 5 H);
3.67 (s, 3 H); 3.03 (t, 2 H, J ) 7.2); 1.8-1.6 (m, 2 H); 1.55-
1.25 (m, 6 H); 0.95-0.8 (m, 3 H). IR (KBr): 1727s; 1678s; 1582
cm-1. MS (EI): m/z 432 (100, M+); 355 (82, [M - C6H5]+); 271
(24); 105 (20). Anal. Calcd for C27H28O3S (432.59): C, 74.97;
H, 6.52; S, 7.41. Found: C, 74.91; H, 6.59; S, 7.51.
[5-(4-Meth oxy-ben zylsu lfa n yl)-3-(tr im eth ylsila n yl)bi-
p h en yl-2-yl]p h en ylm eth a n on e (29). Alkylation of 7a ac-
cording to general procedure A (2.5 h). CAE reaction with 2h
(1.2 equiv) and Et2AlCl (0.2 equiv) (5 h at room temperature).
Crystallization from methanol. 86%. 1H NMR (250 MHz,
CDCl3): δ 7.52 (d, 1 H, J ) 1.8); 7.45-7.4 (m, 2 H); 7.3-7.25
(m, 4 H); 7.2-7.05 (m, 7 H); 6.9-6.8 (m, 2 H); 4.16 (s, 2 H);
Meth yl 2-Ben zoyl-5-(4-m eth oxyben zylsu lfan yl)-3-m eth -
ylben zoa te (21). Alkylation of 7c according to general pro-
cedure B (2 h). CAE reaction with 2c (1.2 equiv) (3 h at room
1
temperature). Yellow oil. 42%. H NMR (250 MHz, CDCl3): δ
3.80 (s, 3 H); 0.14 (s, 9 H). IR (KBr): 1663s; 1558; 1267 cm-1
.
7.85 (s, 1 H); 7.75-7.7 (m, 2 H); 7.6-7.5 (m, 1 H); 7.5-7.4 (m,
2 H); 7.33 (s, 1 H); 7.3-7.25 (m, 2 H); 6.85-6.8 (m, 2 H); 4.17
(s, 2 H); 3.80 (s, 3 H); 3.64 (s, 3 H); 2.11 (s, 3 H). IR (film):
1724s; 1676s; 1610; 1597; 1584 cm-1. MS (EI): m/z 406 (40,
M+); 375 (10, [M - OCH3]+); 257 (12); 121 (100).
MS (EI): m/z 482 (4, M+); 467 (40, [M - CH3]+); 346 (10); 121
(100). Anal. Calcd for C30H30O2SSi (482.71): C, 74.65; H, 6.26;
S, 6.64. Found: C, 74.48; H, 6.02; S, 6.59.
[3-Br om o-5-(4-m eth oxyben zylsu lfa n yl)bip h en yl-2-yl]-
(3,4,5-tr im eth oxyp h en yl)m eth a n on e (30). Alkylation of 7a
according to general procedure A (2.5 h). CAE reaction with
2i (1.2 equiv) and Et2AlCl (0.2 equiv) (5 h at room tempera-
Meth yl 2-Ben zoyl-5-(ben zylsu lfan yl)-3-m eth ylben zoate
(22). Alkylation of 7c according to general procedure B (2.5
h). CAE reaction with 2c (1.2 equiv) (3 h at room temperature).
Yellow oil. 74%. 1H NMR (250 MHz, CDCl3): δ 7.88 (d, 1 H, J
) 1.9); 7.8-7.7 (m, 2 H); 7.6-7.5 (m, 1 H); 7.5-7.2 (m, 8 H);
1
ture). Crystallization from hexane. 64%. H NMR (250 MHz,
CDCl3): δ 7.54 (d, 1 H, J ) 1.8); 7.3-7.1 (m, 8 H); 6.9-6.8 (m,
4 H); 4.18 (s, 2 H); 3.87 (s, 3 H); 3.80 (s, 3 H); 3.76 (s, 6 H). IR

6188 J . Org. Chem., Vol. 64, No. 17, 1999
Obrecht et al.
(KBr): 1667s; 1615; 1582 cm-1. MS (EI): m/z 578 (18, M+, 1
Br); 429 (10, 1 Br); 121 (100).
1 H); 7.5-7.35 (m, 3 H); 3.65 (s, 3 H); 2.93 (d, 2 H, J ) 7.0);
2.15 (s, 3 H); 1.2-1.0 (m, 1 H); 0.7-0.55 (m, 2 H); 0.35-0.25
(m, 2 H). IR (film): 1724s; 1676s; 1583 cm-1. MS (EI): m/z
340 (100, M+); 307 (18); 267 (25); 254 (64); 105 (24); 77 (10);
55 (16).
Meth yl 3-Br om o-5-(h exylsu lfa n yl)bip h en yl-2-ca r box-
yla te (31). Alkylation of 7a according to general procedure A
(2.5 h). CAE reaction with 2k (2 equiv) and Et2AlCl (1 equiv)
(2 h at room temperature). White solid. 44%. 1H NMR (250
MHz, CDCl3): δ 7.45 (d, 1 H, J ) 1.9); 7.45-7.3 (m, 5 H); 7.19
(d, 1 H, J ) 1.9); 3.64 (s, 3 H); 2.95 (t, 2 H, J ) 7.2); 1.75-1.55
(m, 2 H); 1.5-1.2 (m, 6 H); 0.95-0.8 (m, 3 H). IR (film): 1737s;
1582s; 1574 cm-1. MS (EI): m/z 406 (100, M+, 1 Br); 375 (12,
[M - OMe]+, 1 Br); 322 (40, 1 Br); 291 (50, 1 Br).
Meth yl 2-Ben zoyl-3-m eth yl-5-(3-oxobu tylsu lfa n yl)ben -
zoa te (40). From 36 and methyl vinyl ketone according to
literature procedures.38 80%. 1H NMR (250 MHz, CDCl3): δ
7.85 (s, 1 H); 7.8-7.7 (m, 2 H); 7.6-7.5 (m, 1 H); 7.5-7.35 (m,
3 H); 3.66 (s, 3 H); 3.22 (t, 2 H, J ) 7.1); 2.83 (t, 2 H, J ) 7.1);
2.20 (s, 3 H); 2.15 (s, 3 H). IR (KBr): 1723s; 1667s; 1582 cm-1
.
Meth yl 3-Br om o-5-(m eth ylsu lfa n yl)bip h en yl-2-ca r box-
yla te (32). Alkylation of 7a according to general procedure A
(2.5 h). CAE reaction with 2k (1.2 equiv) and Et2AlCl (1.25
equiv) (2 h at room temperature). 60%. Crystallization from
MS (EI): m/z 356 (76, M+); 323 (24); 281 (100); 279 (60, [M -
C6H5]+); 253 (29); 209 (35); 105 (28); 77 (25); 43 (32).
Syn th esis of Su lfon a m id es. Gen er a l P r oced u r e. F or
P r im a r y Am in es. To a solution of p-methoxybenzyl thioether
(0.2 mmol, 1 equiv) in CH2Cl2 (1.5 mL) was added SO2Cl2 (1.1
equiv) to form the sulfenyl chloride (15 min). This yellow
solution was added dropwise to a solution of primary amine
(2.2 equiv) in CH2Cl2. The reaction mixture was stirred at room
temperature for 2-3 h before being filtered over a short Alox
(N) column (ca. 2 g). The sulfenamide was washed down the
column with CHCl3, the solvents were evaporated, and the
residue was dissolved in CH2Cl2. NaOAc (10 equiv) and
m-CPBA (3 equiv) were added, and the reaction mixture was
stirred at room temperature for 2-3 h, poured onto NaHCO3-
(satd), and extracted with ether. The products were purified
by chromatography on silica gel.
1
methanol. H NMR (250 MHz, CDCl3): δ 7.45-7.3 (m, 6 H);
7.15 (d, 1 H, J ) 1.9); 3.64 (s, 3 H); 2.51 (s, 3 H). IR (KBr):
1732s; 1583s; 1574 cm-1. MS (EI): m/z 336 (100, M+, 1 Br);
305 (76, [M - OMe]+, 1 Br); 226 (18); 183 (16); 139 (18).
1-(3-Br om o-5-(h exylsu lfa n yl)b ip h en yl-2-yl)et h a n on e
(33). Alkylation of 7a according to general procedure B (2.5
h). CAE reaction with 2l (1.2 equiv) and Et2AlCl (1 equiv) (1.5
h at -10 °C). Amorphous solid. 44%. 1H NMR (250 MHz,
CDCl3): δ 7.46 (d, 1 H, J ) 1.7); 7.45-7.3 (m, 3 H); 7.3-7.25
(m, 2 H); 7.19 (d, 1 H, J ) 1.7); 2.96 (t, 2 H, J ) 7.2); 2.05 (s,
3 H); 1.75-1.55 (m, 2 H); 1.5-1.2 (m, 6 H); 0.95-0.8 (m, 3 H).
IR (KBr): 1709s; 1581s; 1573 cm-1. MS (EI): m/z 390 (62, M+,
1 Br); 375 (100, [M - CH3]+, 1 Br); 291 (20, 1 Br); 212 (10);
184 (12).
F or Secon d a r y Am in es. To a solution of p-methoxybenzyl
thioether (0.2 mmol, 1 equiv) in CH2Cl2 (1.5 mL) was added
SO2Cl2 (1.1 equiv) to form the sulfenyl chloride. After 15 min,
the amine (2.2 equiv) was added dropwise. The reaction
mixture was stirred at room temperature for 2-3 h before
being filtered over a short Alox (N) column (ca. 2 g). The
sulfenamide was washed down the column with CHCl3, the
solvents were evaporated, and the residue was dissolved in
CH2Cl2. NaOAc (10 equiv) and m-CPBA (3 equiv) were added,
and the reaction mixture was stirred at room temperature for
2-3 h, poured onto NaHCO3(satd), and extracted with ether.
The products were purified by chromatography on silica gel.
Meth yl 2-Ben zoyl-3-ter t-bu tyl-5-(4-m eth oxyben zylsu lf-
a m oyl)ben zoa te (41). From 18 and 4-methoxybenzylamine.
31%. 1H NMR (250 MHz, CDCl3): δ 8.30 (d, 1 H, J ) 2.1);
8.21 (d, 1 H, J ) 2.1); 8.25-7.7 (br, 2 H); 7.6-7.3 (m, 3 H);
7.15-7.05 (m, 2 H); 6.85-6.75 (m, 2 H); 4.79 (t, 1 NH, J ) 6);
4.20 (d, 2 H, J ) 6); 3.77 (s, 3 H); 3.59 (s, 3 H); 1.29 (s, 9 H).
IR (film): 1730s; 1681s; 1612; 1597; 1584; 1165 cm-1. MS
(ISP): m/z 518 ([M + Na]+); 513 ([M + NH4]+); 496 ([M + H]+);
464 ([M - OCH3]+).
(5-(Meth ylsu lfa n yl)-3-(tr im eth ylsila n yl)bip h en yl-2-yl)-
p h en ylm eth a n on e (34). Alkylation of 7a according to general
procedure A (2.5 h). CAE reaction with 2h (1.2 equiv) and Et2-
AlCl (1 equiv) (1 h at 0 °C). Yellow oil. 73%. 1H NMR (250
MHz, CDCl3): δ 7.55 (d, 1 H, J ) 1.9); 7.5-7.4 (m, 2 H); 7.55-
7.0 (m, 9 H); 2.56 (s, 3 H); 0.19 (s, 9 H). IR (film): 1664s; 1597;
1581 cm-1. MS (EI): m/z 376 (5, M+); 361 (100, [M - CH3]+).
(5-(Hexylsu lfa n yl)-3-(tr im eth ylsila n yl)bip h en yl-2-yl)-
p h en ylm eth a n on e (35). Alkylation of 7a according to general
procedure A (2.5 h). CAE reaction with 2h (1.2 equiv) and Et2-
AlCl (1 equiv) (2 h at 0 °C). Yellow oil. 55%. 1H NMR (250
MHz, CDCl3): δ 7.57 (d, 1 H, J ) 1.9); 7.5-7.4 (m, 2 H); 7.55-
7.0 (m, 9 H); 3.0 (t, 2 H, J ) 7.3); 1.8-1.6 (m, 2 H); 1.55-1.25
(m, 6 H) 0.9-0.8 (m, 3 H); 0.19 (s, 9 H). IR (KBr): 1665s; 1597;
1560 cm-1. MS (EI): m/z 446 (5, M+); 431 (100, [M - CH3]+).
4,4′-Dib en zoyl-3,3′-d im et h yl-5,5′-d isu lfa n ed iyld ib en -
zoic Acid Dim eth yl Ester (36). To a solution of 21 (240 mg,
0.59 mmol) in acetonitrile (10 mL) at room temperature was
added NBS (116 mg, 1.1 equiv). After 1 h, the solvent was
evaporated and the product purified by chromatography on
SiO2 (20 g, hexane/ether, 2:1) to give 170 mg (quantitative) of
Met h yl 2-Ben zoyl-3-ter t-b u t yl-5-[2-(4-ch lor op h en yl)-
eth ylsu lfa m oyl]ben zoa te (42). From 18 and 2-(4-chlorophe-
1
1
36 as a slightly brown oil which solidifies upon standing. H
nyl)ethylamine. 53%. H NMR (250 MHz, CDCl3): δ 8.30 (d,
NMR (250 MHz, CDCl3): δ 8.09 (s, 2 H); 7.8-7.7 (m, 4 H);
7.60 (s, 2 H); 7.6-7.5 (m, 2 H); 7.5-7.4 (m, 4 H); 3.67 (s, 6 H);
2.18 (s, 6 H). IR (film): 1716s; 1678s; 1610; 1582 cm-1. MS
(EI): m/z 570 (27, M+); 539 (8, [M - OCH3]+); 506 (36, [M -
S2]+); 300 (24), 253 (100); 209 (34); 165 (33); 105 (80); 77 (62).
Meth yl 2-Ben zoyl-5-[2-(4-br om op h en yl)-2-oxoeth ylsu l-
fa n yl]-3-m eth ylben zoa te (37). From 36 and 4-bromophena-
cyl bromide according to literature procedures.38 84%. 1H NMR
(250 MHz, CDCl3): δ 7.91 (s, 1 H); 7.9-7.8 (m, 2 H); 7.8-7.7
(m, 2 H); 7.7-7.6 (m, 2 H); 7.6-7.5 (m, 1 H); 7.5-7.4 (m, 2 H);
4.34 (s, 2 H); 3.64 (s, 3 H); 2.14 (s, 3 H). IR (MIR): 1717s;
1683s; 1672; 1581 cm-1. MS (EI): m/z 482 (66, M+, 1 Br); 451
(10, [M - OCH3]+, 1 Br); 267 (12); 183 (100, 1 Br).
Meth yl 2-Ben zoyl-3-m eth yl-5-(m eth ylsu lfan yl)ben zoate
(38). From 36 and methyl iodide according to literature
procedures.38 White amorphous solid. 40%. 1H NMR (250 MHz,
CDCl3): δ 7.8-7.7 (m, 3 H); 7.65-7.5 (m, 1 H); 7.5-7.35 (m,
2 H); 7.31 (s, 1 H); 3.65 (s, 3 H); 2.55 (s, 3 H); 2.16 (s, 3 H). IR
(KBr): 1722s; 1674s; 1588 cm-1. MS (EI): m/z 300 (76, M+);
267 (77); 223 (100); 165 (10); 105 (14); 77 (10).
1 H, J ) 2.1); 8.23 (d, 1 H, J ) 2.1); 8.2-7.3 (br, 5 H); 7.3-7.2
(m, 2 H); 7.1-7.0 (m, 2 H); 4.45 (t, 1 NH, J ) 6.5); 3.59 (s, 3
H); 3.30 (q, 2 H, J ) 6.5); 2.82 (t, 2 H, J ) 6.5); 1.30 (s, 9 H).
IR (film): 1730s; 1681s; 1495 cm-1. MS (ISP): m/z 531 ([M +
NH4]+, 1 Cl); 514 ([M + H]+, 1 Cl); 482 ([M - OCH3]+, 1 Cl).
Eth yl 4-[4-Ben zoyl-3-ter t-bu tyl-5-(m eth oxyca r bon yl)-
ben zen esu lfon yl]p ip er a zin e-1-ca r boxyla te (43). From 18
and 1-(ethoxycarbonyl)piperazine. 61%. 1H NMR (250 MHz,
CDCl3): δ 8.23 (d, 1 H, J ) 2.1); 8.13 (d, 1 H, J ) 2.1); 8.2-
7.3 (br, 5 H); 4.13 (q, 2 H, J ) 7.1); 3.7-3.5 (m, 4 H); 3.60 (s,
3 H); 3.1-2.95 (m, 4 H): 1.32 (s, 9 H); 1.25 (t, 3 H, J ) 7.1).
IR (film): 1731s; 1702s; 1596 cm-1. MS (EI): m/z 516 (2, M+);
485 (5, [M - OCH3]+); 452 (12, [M - SO2]+); 296 (18); 264 (33);
157 (100).
Meth yl 2-Ben zoyl-3-ter t-bu tyl-5-(3-m eth oxyp h en ylsu lf-
a m oyl)ben zoa te (44). From 18 and 3-methoxyaniline. 29%.
1H NMR (250 MHz, CDCl3): δ 8.35 (d, 1 H, J ) 2.1); 7.99 (d,
1 H, J ) 2.1); 8.2-7.0 (br m, 7 H); 6.75-6.55 (m, 3 H); 6.49
(br, NH); 3.77 (s, 3 H); 3.58 (s, 3 H); 1.16 (s, 9 H). IR (film):
1730s; 1681s; 1606; 1596; 1291; 1154 cm-1. MS (EI): m/z 481
(100, M+); 385 (48); 372 (72); 370 (88); 340 (15); 105 (28).
P h en yl[5-(p yr r olid in e-1-su lfon yl)-3-(tr im eth ylsila n yl)-
bip h en yl-2-yl]m eth a n on e (45). From 29 and pyrrolidine.
61%. 1H NMR (250 MHz, CDCl3): δ 8.10 (d, 1 H, J ) 1.8);
Met h yl 2-Ben zoyl-5-(cyclop r op ylm et h ylsu lfa n yl)-3-
m eth ylben zoa te (39). From 36 and (bromomethyl)cyclopro-
1
pane according to literature procedures.38 70%. H NMR (250
MHz, CDCl3): δ 7.87 (s, 1 H); 7.8-7.7 (m, 2 H); 7.65-7.5 (m,

Synthesis of Highly Substituted Aromatic Sulfides
J . Org. Chem., Vol. 64, No. 17, 1999 6189
7.86 (d, 1 H, J ) 1.8); 7.5-7.4 (m, 2 H); 7.4-7.3 (m, 1 H); 7.2-
7.05 (m, 7 H); 3.35-3.25 (m, 4 H); 1.9-1.8 (m, 4 H); 0.2 (s, 9
H). MS (ISP): m/z 481 (100, [M + NH4]+); 464 (10, [M + H]+).
and H. Heimgartner (Zu¨rich) for their valuable advice
and fruitful discussions.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
Ack n ow led gm en t. We thank our colleagues from
Pharma Research, F. Hoffmann-La Roche Ltd., for IR
(Mr. A. Bubendorf), NMR (Dr. W. Arnold), MS (Mr. W.
Meister), and elemental analyses (Dr. S. Mu¨ller). We
also thank Professors J . Baldwin (Oxford), H.-J . Hansen,
spectra of a selection of CAE reaction products (compounds
11, 13, 15, 18, 21-23, 25, 29, 30, and 32-35). This material
is available free of charge via the Internet at http://pubs.acs.org.
J O990110S