Preparation of functionalized 3,4-pyridynes via 2-magnesiated diaryl sulfonates

Article abstract of DOI:10.1016/j.tet.2007.01.027

The preparation of functionalized 3,4-pyridynes of type 1 as highly reactive intermediates has been achieved by the controlled elimination of readily generated 2-magnesiated diaryl sulfonates of type 2 obtained by a low temperature I/Mg- or Br/Mg-exchange starting from the corresponding halides of type 3. After trapping with furan, moderate to good yields of the desired functionalized cycloadducts of type 4 are obtained. The addition of a magnesium arylthiolate or magnesium phenylselenide to 3,4-pyridyne followed by quenching with an electrophile is also described.

Full text of DOI:10.1016/j.tet.2007.01.027

Tetrahedron 63 (2007) 2787–2797
Preparation of functionalized 3,4-pyridynes via 2-magnesiated
diaryl sulfonates
*
Wenwei Lin, Ling Chen and Paul Knochel
Department Chemie und Biochemie, Ludwig-Maximilians-Universita€t Mu€nchen, Butenandtstrasse 5-13, D-81377 Mu€nchen, Germany
Received 27 December 2006; accepted 16 January 2007
Available online 20 January 2007
Abstract—The preparation of functionalized 3,4-pyridynes of type 1 as highly reactive intermediates has been achieved by the controlled
elimination of readily generated 2-magnesiated diaryl sulfonates of type 2 obtained by a low temperature I/Mg- or Br/Mg-exchange starting
from the corresponding halides of type 3. After trapping with furan, moderate to good yields of the desired functionalized cycloadducts of type
4 are obtained. The addition of a magnesium arylthiolate or magnesium phenylselenide to 3,4-pyridyne followed by quenching with an
electrophile is also described.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
3-hydroxypyridine derivatives followed by reacting with
4-chlorobenzenesulfonyl chloride in the presence of Et3N in
CH2Cl2 at 25 ꢀC for 12 h. When treating the diiodo-pyridine
3c with i-PrMgCl in THF at ꢁ78 ꢀC, the I/Mg-exchange was
completed in 30 min. The corresponding Grignard reagent
was reacted with 1,2-dibromotetrafluoroethane (1.5 equiv)
followed by slowly warming to 25 ꢀC during 6 h, and finally
led to 4-bromo-2-iodo-6-methylpyridin-3-yl 4-chlorobenz-
enesulfonate (5) in 67% yield (Scheme 2).
3,4-Pyridyne (1a, see Table 1) is a highly reactive intermedi-
ate,1 which can react with a broad range of reagents (nucleo-
philes in addition reactions and alkenes in cycloadditions).
Whereas several methods for the generation of 3,4-pyridyne
have been developed,2 the preparation of functionalized 3,4-
pyridyne is often incompatible with the harsh basic condi-
tions, which are necessary for their syntheses.
Recently, we have developed a new method allowing the
generation of polyfunctional arylmagnesium compounds us-
ing an I/Mg- or Br/Mg-exchange.3 We have also found a new
preparation of polyfunctionalized arynes via the elimination
of 2-magnesiated diaryl sulfonates, and the resulting reactive
immediates arynes can be trapped efficiently with furan or
various nucleophiles in good yields.4 Herein, we wish to
apply the same strategy to the preparation of a broad range of
functionalized 3,4-pyridynes of type 1 using 4-chlorobenz-
enesulfonate as a leaving group (see Scheme 1). The reactive
intermediates functionalized 3,4-pyridynes 1 were trapped
by furan furnishing Diels–Alder cycloadducts of type 4
(Scheme 1 and Table 1).
4-Bromo-2-iodo-6-methylpyridin-3-yl
4-chlorobenzene-
sulfonate (5) did undergo a selective I/Mg-exchange
(i-PrMgCl, ꢁ78 ꢀC, 30 min) giving rise to the corresponding
Grignard reagent 6 as the major product. The intermediate
Grignard reagent 6 was reacted with S-phenyl arenethiosul-
fonates (1.2 equiv) leading to the products 3f and 3g in
45–63% yields. In addition, 6 was reacted with an allyl bro-
mide (2.0 equiv) in the presence of CuCN$2LiCl (1.0 equiv)
furnishing the product 3h in 55% yield. After transmetalla-
tion with ZnBr2 (1.1 equiv), the resulting zinc reagent was
reacted with ethyl 4-iodobenzoate (1.5 equiv) in the pres-
ence of Pd(dba)2 (5 mol %) and tri-(2-furyl)phosphine
(10 mol %) at 50 ꢀC for 3.5 days affording the product 3i
in 54% yield (Scheme 3).
2. Results and discussion
Compounds 3a–i were treated with i-PrMgCl or i-PrMgCl$
LiCl at ꢁ78 ꢀC within 0.5–6 h leading to the corresponding
Grignard reagents 2a–i. After warming to 25 ꢀC within 1–
16 h, functionalized 3,4-pyridynes 1a–i were formed and
trapped with furan leading to 4a–i in 32–88% yields (Table
1). Various functionalities like an iodine (or bromine or chlo-
rine) (Table 1, entries 2–5), a methoxy group (entry 5), an
aryl sulfide (entries 6 and 7), an allyl group (entry 8) and
an ester (entry 9) were readily tolerated on the pyridyne
The precursors 3a–e for the 3,4-pyridyne generation were
prepared via iodination5 or bromination6 of corresponding
Keywords: Magnesium; Functionalized organomagnesium reagents; Cyclo-
addition; Functionalized 3,4-pyridyne; Halogen–magnesium exchange.
* Corresponding author. Tel.: +49 89 2180 77679; fax: +49 89 2180 77680;
e-mail: paul.knochel@cup.uni-muenchen.de
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.027

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W. Lin et al. / Tetrahedron 63 (2007) 2787–2797
Table 1. Generation of functionalized 3,4-pyridynes of type 1 and their trapping with furan
Entry
1
Precursor of type 3
3,4-Pyridyne of type 1
Product of type 4
Yielda (%)
OSO2Ar
I
O
N
(0.5 hb; 2.5 hc)
54
N
N
4a
1a
3a
OSO2Ar
I
O
N
I
I
I
2
3
(0.5 hb; 1.5 hc)
45
75
N
N
I
1b
3b
4b
OSO2Ar
I
I
Me
O
N
N
(0.5 hb; 6 hc)
N
Me
1c
I
4c
Me
3c
OSO2Ar
Cl
Cl
I
I
O
N
4
5
6
7
8
(0.5 hb; 16 hc)
32
78
88
85
57
N
N
I
1d
Cl
I
3d
4d
OSO2Ar
OMe
Br
Br
OMe
O
N
(0.5 hd; 4 hc)
N
N
Br
1e
OMe
4e
Br
3e
OSO2Ar
S
S
Br
O
Cl
(0.5 hd; 1 hc)
N
N
Cl
Cl
Me
Me
N
S
4f
Me
1f
3f
OSO2Ar
S
S
Br
O
(0.5 hd; 1 hc)
N
N
Me
Me
N
N
S
4g
Me
1g
3g
Me
OSO2Ar
N
O
Br
N
(2 hd; 1 hc)
Me
Me
3h
1h
4h
Br
OSO2Ar
O
CO2Et
CO2Et
9
(6 hd; 1 hc)
76
N
Me
N
N
Me
Me
1i
CO2Et
3i
4i
a
Isolated yield of analytically pure product.
Reaction time for the I/Mg-exchange using i-PrMgCl at ꢁ78 ꢀC.
b
c
d
Reaction time for the formation of functionalized 3,4-pyridyne at room temperature using furan (5.0 equiv) as a trapping reagent.
Reaction time for the Br/Mg-exchange using i-PrMgCl$LiCl at ꢁ78 ꢀC.
intermediates. We also observed that more than one halogen
substituent on the pyridyne changed its reactivity and com-
plicated its subsequent quenching reaction. When there was
only one halogen substituent on pyridynes such as 1b,1c and
1e, their Diels–Alder reactions with furan went smoothly
giving rise to 4b,4c and 4e in 45–78% yields (entries 2, 3
and 5). However, with two halogen substituents on a pyri-
dyne like for 1d, its reaction with furan only led to the

W. Lin et al. / Tetrahedron 63 (2007) 2787–2797
2789
(or MgCl·LiCl)
Br
Br
i-PrMgCl
FG
N
i-PrMgCl or
FG
N
X
MgCl
OSO2Ar
I
OSO2Ar
MgCl
(1.05 equiv)
i-PrMgCl·LiCl
-78 °C
-78 °C, 30 min
OSO2Ar
OSO2Ar
Me
N
Me
N
2
Ar = 4-ClC6H4
Ar = 4-ClC6H4
5
3
-78 °C to 25 °C
6
Br
N
FG
FG
N
furan
OSO2Ar
S
O
N
ArSSO2Ph
N
(1.2 equiv)
Me
3f: 63%
4
1
-78 °C to 25 °C
1 h
MeO
Cl
N
N
Cl
Br
N
Me
N
S
PhSSO2Ph
(1.2 equiv)
Br
1e
I
OSO2Ar
1a
1b
1f
3g: 45%
3h: 55%
-78 °C to 25 °C
1 h
Me
Me
S
Ph
6
Me
N
Me
N
allyl bromide
(2.0 equiv)
CuCN·2LiCl
-78 °C to 25 °C
1 h
Br
N
1h
1i
CO2Et
OSO2Ar
OSO2Ar
Scheme 1. Preparation of functionalized 3,4-pyridynes of type 1.
I
Br
N
ZnBr2 (1.1 equiv)
Pd(dba)2 (5 mol %)
tfp (10 mol %)
1) i-PrMgCl (1.1 equiv)
-78 °C, 0.5 h
OSO2Ar
I
OSO2Ar
I
Br
N
2) BrF2CCF2Br (1.5 equiv)
-78 °C to 25 °C slowly
during 6 h
Me
N
Me
3i: 54%
ethyl 4-iodo-
benzoate
(1.5 equiv)
50 °C, 3.5 d
Me
Ar = 4-ClC6H4
3c
5: 67 %
CO2Et
Scheme 2. Preparation of 4-bromo-2-iodo-6-methylpyridin-3-yl 4-chloro-
benzenesulfonate (5).
Scheme 3. Preparation of 3f–i from 6 via an I/Mg-exchange with i-PrMgCl
followed by quenching with an electrophile.
cycloadduct 4d in 32% yield and the reaction did not go
further to completion even after 16 h at 25 ꢀC (entry 4).
Also, a functionalized 3,4-pyridyne with one substituent on
6-position led to an increase yield, and the additional steric
hindrance near the nitrogen atom gave rise to cleaner reac-
tions with furan. For instance, 1c was reacted with furan lead-
ing to 4c in 75% yield, while 1b was trapped with furan
giving rise to 4b in 45% yield probably due to further nucleo-
philic addition of the pyridine nitrogen atom of 1b (entries 2
and 3). The stabilization of 3,4-pyridynes by an alkoxy group
or a sulfide function in 2-position was essential to afford the
Diels–Alder cycloaddition products 4e–g in good yields
(78–88%) after trapping the reactive intermediates in situ
1e–g with furan (entries 5–7). Alkyl groups have little
electron-donating ability for stabilizing the functionalized
3,4-pyridyne 1h. Therefore, the reaction of 1h with furan
furnished the product 4h in 57% yield (entry 8). Finally,
a 3,4-pyridyne with an aryl group bearing an ester function,
such as 1i, was trapped with furan in situ giving rise to 4i
in 76% yield (entry 9).
3,4-pyridyne (1a) followed by quenching with DMF
(3.0 equiv) giving rise to 12a and 12b in 54% and 32%
yields, respectively (The crude H NMR ratio was 12a/
12b¼62:38) (Scheme 5).
1
The magnesium arylthiolate 7 (2.0 equiv) also added to the
functionalized 3,4-pyridyne 3f followed by quenching with
Br
Br
SMgCl
Br
7
S
(2.0 equiv)
MgCl
N
-78 °C to 25 °C
2.5 h
MgCl
+
S
MgCl
N
OSO2Ar
9a
9b
N
2a: Ar = 4-ClC6H4
Br
S
Br
Interestingly, the magnesium arylthiolate 7 (2.0 equiv)
added successfully to 3,4-pyridyne (1a) followed by quench-
ing with saturated aqueous NH4Cl solution lead to 8a and 8b
in 53% and 32% yields, respectively. The resulting Grignard
reagents 9a and 9b could be formylated with DMF
(3.0 equiv) furnishing 10a and 10b in 50% and 31% yields,
respectively (The crude 1H NMR ratio was 10a/10b¼64:36)
(Scheme 4). In addition, magnesium phenylselenide (11)
was also a good nucleophile for the addition reaction of
S
N
E
N
H3O+ or DMF
+
E
9a + 9b
-40 °C to 25 °C
1 h
8a: E = H, 53%
10a: E = CHO, 50%
8b: E = H, 32%
10b: E = CHO, 31%
(The crude 1H-NMR ratio was 10a : 10b = 64 : 36)
Scheme 4. The addition of magnesium arylthiolate 7 to 3,4-pyridyne (1a).

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W. Lin et al. / Tetrahedron 63 (2007) 2787–2797
PhSeMgCl
with a fluorescent indicator. Column chromatography was
11
SePh
N
CHO
N
carried out on silica gel 60 F254 (70–230 mesh). NMR data
were recorded on a 600, 400 or 300 MHz NMR spectro-
meter. The ionization method used was electron impact
ionization (EI, 70 eV). Melting points are uncorrected.
1) -78 °C to 25 °C
2.5 h
2) DMF
-40 °C to 25 °C
1 h
(2.0 equiv)
CHO
PhSe
+
MgCl
12a: 54%
12b: 32%
OSO2Ar
4.2. Preparation of the reagent i-PrMgCl
(The crude 1H-NMR ratio was 12a : 12b = 62 : 38)
N
A dry three-necked flask equipped with an argon inlet,
a dropping funnel and a thermometer was charged with mag-
nesium turnings (110 mmol). A small amount of THF was
added to cover the magnesium, and a solution of isopropyl
chloride (100 mmol) in THF (50 mL) was added dropwise,
keeping the temperature of the mixture below 30 ꢀC (water
bath). After the addition was completed, the reaction mix-
ture was stirred for 12 h at room temperature. The grey solu-
tion of i-PrMgCl was cannulated to another flask under
argon and removed in this way from excess of magnesium.
An yield of ca. 95–98% of i-PrMgCl was obtained and the
i-PrMgCl-solution was titrated prior to use according to
the reported literature.8
2a: Ar = 4-ClC6H4
Scheme 5. The addition of magnesium phenylselenide (11) to 3,4-pyridyne
(1a).
iodine lead to 13a as the major product in 66% isolated yield.
(The crude GC ratio was 13a/13b¼84:16.) The correspond-
ing Grignard reagents underwent allylation with allyl bro-
mide (4.0 equiv) in the presence of CuCN$2LiCl (0.5 equiv)
affording 14a as the major product in 64% isolated yield
(Scheme 6).
Br
Br
SMgCl
Br
4.3. Preparation of the reagent i-PrMgCl$LiCl
7
S
N
E
N
(2.0 equiv)
1) -78 °C to 25 °C
1 h
Magnesium turnings (110 mmol) and anhydrous LiCl
(100 mmol) were placed in an argon-flushed flask, and
THF (50 mL) was added. A solution of i-PrCl (100 mmol)
in THF (50 mL) was slowly added at room temperature.
The reaction starts within a few minutes. After addition,
the reaction mixture was stirred for 12 h at room tempera-
ture. The grey solution of i-PrMgCl$LiCl was cannulated
to another flask under argon and removed in this way from
excess of magnesium. An yield of ca. 95–98% of
i-PrMgCl$LiClwas obtained and thei-PrMgCl$LiClsolution
is titrated prior to use according to the reported literature.8
E
S
S
S
+
Me
2) I2 or allyl bromide
(CuCN·2LiCl)
Me
MgCl
-40 °C to 25 °C
1 h
OSO2Ar
Cl
Cl
Me
N
S
13a: E = I, 66%
13b: E = I
14a: E = allyl, 64% 14b: E = allyl
(The crude GC ratio = 13a : 13b = 84 : 16)
Cl
2f: Ar = 4-ClC6H4
4.4. Starting materials
Scheme 6. The addition of magnesium arylthiolate 7 to the functionalized
3,4-pyridyne 3f.
The following starting materials were prepared according to
the procedures of literature: 3a,5a,b 3b,5 3c,d,5c 3e,6 benzene-
thiosulfonic acid S-(4-chloro-phenyl) ester,7 2-methoxy-
pyridin-3-ol6a and 3-hydroxy-4-iodopyridine.5b
3. Conclusion
In conclusion, we have developed a new and general prepa-
ration of functionalized 3,4-pyridynes using the easily
tunable elimination of 2-magnesium arylsulfonates. In addi-
tion, we have showed a procedure allowing the thio- and
seleno-magnesiation of 3,4-pyridynes. The resulting aryl-
magnesium species can be trapped with electrophiles in con-
trast to most previously reported addition reactions. Further
applications of this convenient preparation of fuctionalized
arynes are underway in our laboratories.
4.5. Typical procedure for the formation of arylsulfo-
nates 3a–e from the corresponding phenols (TP 1)
A dry 250-mL round-bottomed flask, equipped with a mag-
netic stirrer and a septum, was charged with a solution of
corresponding 3-hydroxypyridine derivative (50 mmol) in
dry CH2Cl2 (100 mL). After cooling to 0 ꢀC, Et3N (20.9 mL,
150 mmol) was added, and then 4-chlorobenzenesulfonyl
chloride (12.7 g, 60 mmol) was added portionwise. After
the addition was completed, the reaction mixture was stirred
at 25 ꢀC overnight. Then this mixture was diluted with
100 mLCH2Cl2.SaturatedaqueousNH4Clsolution(100 mL)
was then added, and then the resulting mixture was extracted
with CH2Cl2 (2ꢂ100 mL). The organic extracts were
dried over anhydrous Na2SO4 and concentrated. Purification
by flash chromatography furnished the desired products
(3a–e).
4. Experimental
4.1. General methods
Unless otherwise indicated, all reactions were carried out
under an argon atmosphere. THF and Et2O were distilled
from sodium/benzophenone. CH2Cl2 and DMF were dis-
tilled from CaH2. Reactions were monitored by gas chro-
matography (GC) analysis of worked up reaction aliquots.
Analytical thin-layer chromatography (TLC) was performed
using Merck silica gel 60 F254 plates (0.25 mm) precoated
4.5.1. 4-Iodopyridin-3-yl 4-chlorobenzenesulfonate (3a).
Prepared according to TP 1 from 3-hydroxy-4-iodopyridine

W. Lin et al. / Tetrahedron 63 (2007) 2787–2797
2791
(11.1 g, 50.0 mmol), triethylamine (20.9 mL, 150 mmol)
and 4-chlorobenzenesulfonyl chloride (12.7 g, 60.0 mmol).
Recrystallization from ethanol yielded 3a as a yellow solid
Water was evaporated and 2,4-diiodo-3-hydroxy-6-methyl-
pyridine was obtained as a crude product (a brown solid).
1
(16.1 g, 81%). Mp: 135.3–136.1 ꢀC. H NMR (300 MHz,
2,4-Diiodo-3-hydroxy-6-methylpyridine:
mp:
109.2–
3
1
CDCl3, 25 ꢀC) d/ppm: 8.40 (s, 1H), 8.10 (d, J¼5.1 Hz,
110.6 ꢀC. H NMR (300 MHz, CD3SOCD3, 25 ꢀC) d/ppm:
7.61 (s, 1H), 2.29 (s, 3H). 13C NMR (75 MHz, CD3SOCD3,
25 ꢀC) d/ppm: 152.0, 151.2, 132.7, 111.0, 98.5, 21.5. MS
(70 eV, EI) m/z (%): 361 (100) [M+], 235 (59), 234 (60),
108 (17), 107 (59), 79 (11), 78 (14), 52 (21), 51 (19). IR
(KBr) ~n (cmꢁ1): 3416 (br s), 1606 (w), 1562 (w), 1510
(w), 1430 (w), 1240 (w), 1211 (w), 714 (w). HRMS (EI)
for C6H5ONI2 (360.8461): found 360.8447.
1H), 7.89–7.83 (m, 2H), 7.74 (d, 3J¼5.1 Hz, 1H), 7.58–7.51
(m, 2H). 13C NMR (75 MHz, CDCl3, 25 ꢀC) d/ppm: 148.7,
148.1, 144.3, 142.3, 135.3, 134.2, 131.0, 130.6, 102.2. MS
(70 eV, EI) m/z (%): 395 (56) [M+], 192 (4), 175 (100),
165 (12), 111 (65), 93 (14). IR (KBr) ~n (cmꢁ1): 3103 (m),
3044 (w), 1586 (m), 1562 (s), 1478 (m), 1393 (vs), 1200
(s), 1174 (vs), 1087 (s), 864 (s), 767 (vs), 718 (s), 618 (s),
565 (s), 484 (m). HRMS (EI) for C11H735ClINO3S
(394.8880): found 394.8846.
A dry 250-mL round-bottomed flask, equipped with a
magnetic stirrer and a septum, was charged with a solution
of 2,4-diiodo-3-hydroxy-6-methylpyridine (crude product)
in dry CH2Cl2 (100 mL). After cooling to 0 ꢀC, Et3N
(18.8 mL, 135 mmol) was added, and then 4-chlorobenzene-
sulfonyl chloride (23.5 g, 108 mmol) was added portion-
wise. After addition was completed, the reaction mixture
was stirred at room temperature overnight. Then this mixture
was diluted with 100 mL CH2Cl2. Saturated aqueous NH4Cl
solution (100 mL) was then added, and then the resulting
mixture was extracted with CH2Cl2 (2ꢂ100 mL). The or-
ganic extracts were dried over anhydrous Na2SO4, and con-
centrated. Purification by flash chromatography (n-pentane/
ether¼40:1) yielded 3c (30.05 g, 55%; the total yield over
three steps) as a brown solid. Mp: 119.4–121.4 ꢀC. 1H NMR
(300 MHz, CDCl3, 25 ꢀC) d/ppm: 8.00–7.95 (m, 2H), 7.61–
7.56 (m, 3H), 2.48 (s, 3H). 13C NMR (75 MHz, CDCl3,
25 ꢀC) d/ppm: 158.8, 147.9, 141.8, 136.1, 134.4, 130.5,
129.8, 112.9, 101.7, 22.9. MS (70 eV, EI) m/z (%): 537 (37),
535 (100) [M+], 360 (85), 332 (19), 233 (90), 177 (28), 175
(77), 159 (20), 111 (38), 78 (26), 51 (19). IR (KBr) ~n (cmꢁ1):
3086 (w), 1546 (m), 1504 (m), 1476 (w), 1402 (m), 1380 (s),
1320 (m), 1242 (m), 1200 (m), 1185 (s), 1176 (vs), 1088 (m),
1061 (m), 1015 (w), 870 (w), 846 (w), 814 (s), 759 (s), 742
(m), 703 (m), 683 (s), 624 (m), 617 (m). HRMS (EI) for
C12H8O3NI2S35Cl (534.8003): found 534.7997.
4.5.2. 2,4-Diiodo-pyridin-3-ol. To a solution of 3-hydroxy-
4-iodo-pyridine (2.21 g, 10 mmol) and Na2CO3 (2.22 g,
21 mmol) in water was added iodine (2.54 g, 10 mmol)
with stirring at 20 ꢀC for 2 h. Then HCl(aq) is added carefully
until approximate pH 4. The solid is filtered off and dried
to give 3-hydroxy-2,4-diiodo-pyridine as a brown solid
1
(2.78 g, 80%). Mp: 179.0–180.3 ꢀC. H NMR (300 MHz,
CD3SOCD3, 25 ꢀC) d/ppm: 10.22 (s, 1H), 7.75 (d, 3J¼
3
4.5 Hz, 1H), 7.54 (d, J¼4.5 Hz, 1H). 13C NMR (75 MHz,
CD3SOCD3, 25 ꢀC) d/ppm: 153.5, 143.3, 133.7, 112.1, 97.1.
MS (70 eV, EI) m/z (%): 347 (100) [M+], 221 (19), 220 (64),
165 (11), 127 (14), 93 (30), 66 (12), 65 (11), 64 (20). IR
(KBr) ~n (cmꢁ1): 3437 (br s), 1628 (w), 1524 (m), 1446
(m), 1409 (w), 1265 (w), 1149 (m), 1079 (w), 1061 (w),
812 (w), 706 (m). HRMS (EI) for C5H3ONI2 (346.8304):
found 346.8304.
4.5.3. 2,4-Diiodo-pyridin-3-yl 4-chlorobenzenesulfonate
(3b). Prepared according to TP 1 from 2,4-diiodo-pyridin-
3-ol (2.08 g, 6.0 mmol), 4-chlorobenzenesulfonyl chloride
(1.52 g, 7.2 mmol) and triethylamine (1.26 mL, 9.0 mmol).
Purification by flash chromatography (n-pentane/ether¼
10:1) yielded 3b as a white solid (2.354 g, 75%). Mp:
1
145.4–146.2 ꢀC. H NMR (300 MHz, CDCl3, 25 ꢀC) d/
3
ppm: 8.01–7.96 (m, 2H), 7.85 (d, J¼4.9 Hz, 1H), 7.73 (d,
3J¼4.9 Hz, 1H), 7.63–7.58 (m, 2H). 13C NMR (75 MHz,
CDCl3, 25 ꢀC) d/ppm: 150.1, 148.4, 141.9, 136.1, 134.9,
130.5, 129.8, 114.3, 101.8. MS (70 eV, EI) m/z (%): 523
(18), 521 (50) [M+], 219 (25), 177 (34), 175 (100), 113 (12),
111 (40), 75 (11), 64 (14). IR (KBr) ~n (cmꢁ1): 3096 (w),
1537 (m), 1520 (w), 1478 (w), 1425 (w), 1401 (m), 1382
(vs), 1353 (s), 1223 (m), 1200 (m), 1189 (s), 1178 (s),
1088 (m), 1078 (w), 1061 (w), 1015 (w), 850 (m), 830 (m),
762 (s), 718 (s), 690 (s), 617 (s), 566 (s), 481 (w). HRMS (EI)
for C11H6O3NIS35Cl2 (520.7846): found 520.7827.
4.5.5. 4-Chloro-benzenesulfonic acid 2-chloro-4,6-
diiodo-pyridin-3-yl ester (3d). To a solution of 2-chloro-
3-hydroxypyridine (2.60 g, 20 mmol) and Na2CO3 (4.45 g,
42 mmol) in water was added iodine (5.33 g, 21 mmol)
with stirring at 20 ꢀC overnight. Then HCl(aq) is added care-
fully until approximate pH 3. The solid is filtered off and
dried to give 2-chloro-3-hydroxy-6-iodopyridine as a crude
product (a yellow solid). To a solution of 2-chloro-3-
hydroxy-6-iodopyridine (without further purification) and
Na2CO3 (4.45 g, 42 mmol) in water was added iodine
(5.33 g, 21 mmol) with stirring at 20 ꢀC overnight. Then
HCl(aq) is added carefully until approximate pH 6. Water
was evaporated and 4,6-diiodo-3-hydroxy-6-methylpyridine
was obtained as a crude product (a brown solid). A dry 250-
mL round-bottomed flask, equipped with a magnetic stirrer
and a septum, was charged with a solution of 4,6-diiodo-3-
hydroxy-6-methylpyridine (crude product) in dry CH2Cl2
(100 mL). After cooling to 0 ꢀC, Et3N (4.18 mL, 30 mmol)
was added, and then 4-chlorobenzenesulfonyl chloride
(4.35 g, 20 mmol) was added portionwise. After addition
was completed, the reaction mixture was stirred at room
temperature overnight. Then this mixture was diluted with
100 mL CH2Cl2. Saturated aqueous NH4Cl solution
4.5.4. 2,4-Diiodo-6-methylpyridin-3-yl 4-chlorobenzene-
sulfonate (3c). To a solution of 3-hydroxy-6-methylpyridine
(11.0 g, 100 mmol) and Na2CO3 (22.3 g, 210 mmol) in
water was added iodine (25.4 g, 100 mmol) with stirring at
20 ꢀC. After 1 h, the iodine colour has disappeared. Then
HCl(aq) is added carefully until approximate pH 3. The solid
is filtered off and dried to give 2-iodo-3-hydroxy-6-methyl-
pyridine as a crude product (a yellow solid). To a solution of
2-iodo-3-hydroxy-6-methylpyridine (without further purifi-
cation) and Na2CO3 (22.3 g, 210 mmol) in water was added
iodine (25.4 g, 100 mmol) with stirring at 20 ꢀC overnight.
Then HCl(aq) is added carefully until approximate pH 6.

2792
W. Lin et al. / Tetrahedron 63 (2007) 2787–2797
(100 mL) was then added, and then the resulting mixture was
extracted with CH2Cl2 (2ꢂ100 mL). The organic extracts
were dried over anhydrous Na2SO4, and concentrated. Puri-
fication by flash chromatography (n-pentane/ether¼80:1)
yielded 3d (6.45 g, 57%; the total yield over three steps)
(3ꢂ100 mL). The organic fractions were dried over
Na2SO4, and concentrated in vacuo. Purification by flash
chromatography (n-pentane/ether¼50:1) yielded 5 (9.82 g,
67%) as a yellow solid. Mp: 112.6–113.8 ꢀC. 1H NMR
(300 MHz, CDCl3, 25 ꢀC) d/ppm: 7.99–7.94 (m, 2H),
7.60–7.55 (m, 2H), 7.34 (s, 1H), 2.50 (s, 3H). 13C NMR
(75 MHz, CDCl3, 25 ꢀC) d/ppm: 159.1, 144.8, 141.7,
135.9, 130.3, 129.7, 128.1, 127.1, 114.4, 23.3. MS (70 eV,
EI) m/z (%): 491 (13), 489 (40), 487 (33) [M+], 314 (29),
312 (28), 286 (17), 284 (17), 177 (41), 175 (100), 159
(14), 113 (12), 111 (41), 78 (19), 75 (14), 51 (16). IR
(neat) ~n (cmꢁ1): 1558 (m), 1513 (w), 1473 (w), 1390 (vs),
1325 (m), 1283 (w), 1244 (m), 1202 (w), 1183 (s), 1092
(m), 1064 (m), 1012 (w), 878 (w), 826 (m), 820 (s), 760
(m), 741 (w), 728 (m), 701 (m), 680 (m), 620 (m). HRMS
(EI) for C12H8O3NIS79Br35Cl (486.8141): found 486.8141.
as
a
yellow solid. Mp: 141.7–142.7 ꢀC. 1H NMR
(300 MHz, CDCl3, 25 ꢀC) d/ppm: 8.13 (s, 1H), 7.98–7.93
(m, 2H), 7.61–7.56 (m, 2H). 13C NMR (75 MHz, CDCl3,
25 ꢀC) d/ppm: 145.7, 144.4, 144.3, 141.9, 135.4, 130.0,
129.8, 112.0, 105.8. MS (70 eV, EI) m/z (%): 557 (13)
[M+], 555 (21), 380 (10), 253 (16), 177 (37), 175 (100),
113 (13), 111 (42), 75 (12). IR (KBr) ~n (cmꢁ1): 3085 (w),
1587 (w), 1527 (s), 1512 (s), 1395 (vs), 1381 (vs), 1309 (s),
1282 (w), 1231 (w), 1210 (m), 1187 (s), 1170 (m), 1086
(m), 1072 (m), 1014 (w), 867 (s), 823 (w), 779 (s), 758 (s),
728 (s), 656 (w), 625 (s), 580 (m), 481 (m). HRMS (EI) for
C11H5O3NI2S35Cl2 (554.7457): found 554.7453.
4.5.8. 4-Chloro-benzenesulfonic acid 4-bromo-2-(4-
chloro-phenylsulfanyl)-6-methylpyridin-3-yl ester (3f).
A dry and argon-flushed 25-mL Schlenk-flask, equipped with
a magnetic stirrer and a septum, was charged with a solution
of 4-bromo-2-iodo-6-methylpyridin-3-yl 4-chlorobenzene-
sulfonate (5) (2.41 g, 4.0 mmol) in dry THF (8.0 mL).
i-PrMgCl (0.87 M/THF, 4.71 mL, 4.1 mmol) was then
added dropwise at ꢁ78 ꢀC. After 30 min, benzenethiosul-
fonic acid S-(4-chloro-phenyl) ester (1.25 g, 4.4 mmol) in
dry THF (3 mL) was added slowly at ꢁ78 ꢀC, and the result-
ing mixture was warmed to room temperature and stirred for
1 h. Thereafter, the reaction was quenched with saturated
aqueous NH4Cl solution (50 mL). The aqueous phase was
extracted with CH2Cl2 (3ꢂ60 mL). The organic fractions
were dried over Na2SO4, and concentrated in vacuo. Purifi-
cation by flash chromatography (n-pentane/ether¼50:1)
yielded 3f (1.28 g, 63%) as a white solid. Mp: 109.3–
4.5.6. 4-Chloro-benzenesulfonic acid 4,6-dibromo-2-
methoxy-pyridin-3-ylester(3e). A 100-mL round-bottomed
flask, equipped with a magnetic stirring bar was charged
with 2-methoxy-pyridin-3-ol (2.50 g, 20 mmol) and dis-
solved in CCl4 (100 mL). N-Bromosuccinimide (7.48 g,
42 mmol) was added portionwise and the reaction mixture
was stirred at room temperature for 72 h in darkness. The
progress of the reaction was followed by GC and GC–MS
spectroscopies. After the reaction was complete, the solvent
was evaporated, diluted with CH2Cl2 (50 mL), washed with
water (30 mL), extracted with CH2Cl2 (50 mLꢂ3) and ether
(50 mLꢂ3) and dried over anhydrous Na2SO4. After fil-
tration, the solvent was evaporated in vacuo to obtain the
crude product (4,6-dibromo-2-methoxy-pyridin-3-ol) for
the next step. The compound 3e was prepared according to
TP 1 from the crude 4,6-dibromo-2-methoxy-pyridin-3-ol,
4-chlorobenzenesulfonyl chloride (16.2 g, 74 mmol) and
triethylamine (12.9 mL, 93 mmol). Filtration and then puri-
fication by flash chromatography (n-pentane/ether¼250:1)
yielded 3e as a white solid (1.83 g, 20% for two steps).
1
111.2 ꢀC. H NMR (300 MHz, CDCl3, 25 ꢀC) d/ppm:
8.03–7.97 (m, 2H), 7.60–7.54 (m, 2H), 7.36–7.28 (m, 4H),
7.15 (s, 1H), 2.31 (s, 3H). 13C NMR (75 MHz, CDCl3,
25 ꢀC) d/ppm: 157.5, 153.8, 141.5, 139.6, 135.9, 135.5,
135.0, 130.1, 129.5, 129.0, 128.2, 127.6, 125.3, 23.5. MS
(70 eV, EI) m/z (%): 505 (10), 503 (6) [M+], 443 (20), 442
(11), 441 (41), 440 (9), 439 (24), 332 (16), 331 (16), 330
(53), 329 (12), 328 (39), 296 (16), 295 (100), 294 (15),
293 (100), 267 (12), 265 (12), 251 (11), 249 (24), 248 (9),
186 (10), 111 (13), 108 (9), 51 (15). IR (KBr) ~n (cmꢁ1):
3104 (w), 1572 (w), 1557 (w), 1537 (m), 1476 (m), 1414
(m), 1380 (vs), 1334 (m), 1262 (m), 1200 (w), 1177 (s),
1090 (s), 1071 (m), 1015 (w), 828 (s), 818 (m), 758 (s),
746 (m), 702 (m), 680 (m), 636 (m). HRMS (EI) for
C18H12O379Br35Cl2S2 (502.8819): found 502.8816.
1
Mp: 115.0–117.5 ꢀC. H NMR (600 MHz, CDCl3, 25 ꢀC)
d/ppm: 7.95–7.90 (m, 2H), 7.59–7.54 (m, 2H), 7.30 (s, 1H),
13
3.77 (s, 3H). C NMR (150 MHz, CDCl3, 25 ꢀC) d/ppm:
157.0, 141.2, 135.6, 135.5, 132.2, 129.9, 129.8, 129.3,
124.5, 54.9. MS (70 eV, EI) m/z (%): 459 (9), 457 (12), 455
(5) [M+], 284 (46), 283 (7), 282 (100), 280 (48), 213 (9),
211 (6), 177 (5), 175 (14), 160 (5), 159 (9), 158 (5), 113
(6), 111 (19), 75 (9). IR (KBr) ~n (cmꢁ1): 3088 (w), 1570
(m), 1473 (m), 1390 (m), 1321 (vs), 1283 (m), 1141 (s),
1090 (s), 1071 (s), 1009 (m), 830 (m), 820 (m), 752 (m),
745 (m), 702 (w). HRMS (EI) for C12H8O4N79Br235ClS
(454.8229): found 454.8204.
4.5.9. 4-Chloro-benzenesulfonic acid 4-bromo-6-methyl-
2-phenylsulfanyl-pyridin-3-yl ester (3g). A dry and argon-
flushed 25-mL Schlenk-flask, equipped with a magnetic
stirrer and a septum, was charged with a solution of 4-bromo-
2-iodo-6-methylpyridin-3-yl 4-chlorobenzenesulfonate (5)
(1.466 g, 3.0 mmol) in dry THF (9.0 mL). i-PrMgCl
(0.87 M/THF, 3.57 mL, 3.1 mmol) was then added dropwise
at ꢁ78 ꢀC. After 30 min, S-phenyl benzenethiosulfonate
(875 mg, 3.5 mmol) in dry THF (3 mL) was added slowly
at ꢁ78 ꢀC, and the resulting mixture was warmed to room
temperature and stirred for 1 h. Thereafter, the reaction
was quenched with saturated aqueous NH4Cl solution
(50 mL). The aqueous phase was extracted with CH2Cl2
4.5.7. Synthesis of 4-bromo-2-iodo-6-methylpyridin-3-yl
4-chlorobenzenesulfonate (5). A dry and argon-flushed
250-mL Schlenk-flask, equipped with a magnetic stirrer
and a septum, was charged with a solution of 2,4-diiodo-6-
methylpyridin-3-yl 4-chlorobenzenesulfonate 3c (16.1 g,
30 mmol) in dry THF (60 mL). i-PrMgCl (0.87 M/THF,
37.9 mL, 1.1 equiv) was then added dropwise at
ꢁ78 ꢀC. After 30 min, 1,2-dibromotetrafluoroethane(13.3 g,
50 mmol) was added slowly at ꢁ78 ꢀC, and the resulting
mixture was warmed up slowly to room temperature during
6 h. Thereafter, the reaction was quenched with saturated
aqueous NH4Cl solution and extracted with CH2Cl2

W. Lin et al. / Tetrahedron 63 (2007) 2787–2797
2793
(3ꢂ50 mL). The organic fractions were dried over Na2SO4,
and concentrated in vacuo. Purification by flash chromato-
graphy (n-pentane/ether¼50:1) and recrystallization (etha-
nol/acetone¼1:1) yielded 3g (636 mg, 45%) as a white
solid. Mp: 86.7–89.1 ꢀC. 1H NMR (300 MHz, CDCl3,
25 ꢀC) d/ppm: 8.04–7.98 (m, 2H), 7.59–7.53 (m, 2H),
7.41–7.30 (m, 5H), 7.15 (s, 1H), 2.30 (s, 3H). 13C NMR
(75 MHz, CDCl3, 25 ꢀC) d/ppm: 157.4, 154.1, 141.3, 139.7,
135.6, 134.4, 130.1, 129.8, 129.5, 128.8, 128.6, 127.6, 125.1,
23.5. MS (70 eV, EI) m/z (%): 471 (3), 469 (2) [M+],
407 (20), 405 (15), 297 (35), 296 (100), 295 (35), 294
(94), 280 (14), 278 (15), 216 (11), 215 (21), 214 (13), 187
(18), 186 (21), 111 (10), 109 (11), 77 (12), 51 (21). IR
(KBr) ~n (cmꢁ1): 3098 (w), 1553 (m), 1538 (m), 1474
(m), 1442 (w), 1410 (m), 1383 (vs), 1330 (m), 1284 (w),
1262 (m), 1198 (w), 1180 (s), 1168 (s), 1093 (m), 1070
(m), 832 (s), 759 (s), 747 (m), 704 (m), 682 (s), 629 (m).
HRMS (EI) for C18H13O379Br35ClS2 (468.9209): found
468.9223.
Schlenk-flask, equipped with a magnetic stirrer and a sep-
tum, was charged with Pd(dba)2 (290 mg, 5 mol %) and
tris-o-furylphosphine (250 mg, 10 mol %) in dry THF
(8 mL). The initial red colour disappeared after 2 min lead-
ing to yellow solution and ethyl 4-iodobenzoate (4.27 g,
15.0 mmol) was added. This solution was added, via cannula
after 10 min stirring, to the reaction mixture at ꢁ78 ꢀC. The
reaction mixture was stirred at 50 ꢀC for 4 days. Thereafter,
the reaction was quenched with saturated aqueous NH4Cl
solution (50 mL). The aqueous phase was extracted with
CH2Cl2 (3ꢂ100 mL). The organic fractions were dried
over Na2SO4, and concentrated in vacuo. Purification by
flash chromatography (n-pentane/ether¼50:1) yielded 3i
1
(2.759 g, 54%) as a white solid. Mp: 130.0–131.0 ꢀC. H
NMR (300 MHz, CDCl3, 25 ꢀC) d/ppm: 7.87–7.82 (m,
2H), 7.56–7.51 (m, 2H), 7.47 (s, 1H), 7.43–7.38 (m, 2H),
3
7.19–7.14 (m, 2H), 4.41 (q, J¼7.1 Hz, 2H), 2.58 (s, 3H),
1.44 (t, 3J¼7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3,
25 ꢀC) d/ppm: 165.9, 157.9, 152.0, 141.0, 141.0, 140.5,
134.9, 130.8, 130.0, 129.2, 129.2, 129.2, 127.8, 61.2, 23.9,
14.3. MS (70 eV, EI) m/z (%): 511 (20), 509 (14) [M+],
336 (24), 334 (24), 308 (25), 306 (25), 292 (45), 291 (27),
290 (53), 289 (21), 264 (93), 263 (21), 262 (98), 211 (50),
184 (14), 183 (100), 182 (42), 154 (23), 133 (20), 131
(20), 113 (14), 111 (32), 75 (19), 52 (18), 51 (41). IR
(KBr) ~n (cmꢁ1): 2984 (w), 1711 (vs), 1576 (w), 1556 (m),
1474 (w), 1431 (w), 1390 (s), 1271 (s), 1209 (m), 1184 (s),
1157 (m), 1107 (m), 1090 (m), 1062 (m), 1016 (w), 826
(s), 783 (m), 757 (m), 701 (m), 676 (m), 632 (m). HRMS
(EI) for C21H18O5N79Br35ClS, [M++H] (509.9778): found
509.9771.
4.5.10. 2-Allyl-4-bromo-6-methylpyridin-3-yl 4-chloro-
benzenesulfonate (3h). A dry and argon-flushed 50-mL
Schlenk-flask, equipped with a magnetic stirrer and a sep-
tum, was charged with a solution of 4-bromo-2-iodo-6-
methylpyridin-3-yl 4-chlorobenzenesulfonate (5) (1.466 g,
3.0 mmol) in dry THF (6.0 mL). i-PrMgCl (0.87 M in
THF, 3.79 mL, 1.1 equiv) was then added dropwise at
ꢁ78 ꢀC. After 30 min, CuCN$2LiCl (1.0 M in THF,
1.50 mL, 0.5 equiv) was added slowly at ꢁ78 ꢀC, and the re-
sulting mixture was stirred at this temperature for 10 min.
Then allyl bromide (0.43 mL, 5.0 mmol, 1.7 equiv) was
added at ꢁ78 ꢀC, and the resulting mixture was warmed to
room temperature and stirred for 1 h. Thereafter, the reaction
was quenched with saturated aqueous NH4Cl solution
(50 mL). The aqueous phase was extracted with CH2Cl2 (3ꢂ
40 mL). The organic fractions were dried over Na2SO4, and
concentrated in vacuo. Purification by flash chromatography
(n-pentane/ether¼30:1) yielded 3h (0.665 g, 55%) as a col-
4.6. Typical procedure for the generation and trapping
of functionalized 3,4-pyridynes 4 with furan (TP 2):
4-(5-methyl-11-oxa-4-aza-tricyclo[6.2.1.02,7]undeca-
2(7),3,5,9-tetraen-3-yl)-benzoic acid ethyl ester (4i)
A dry and argon-flushed 10-mL Schlenk-tube, equipped
with a magnetic stirrer and a septum, was charged with a so-
lution of the corresponding arylsulfonate of type 3i (255 mg,
0.5 mmol) in dry THF (2 mL). i-PrMgCl$LiCl (0.51 mL,
0.51 mmol, 1.00 M in THF) was then added dropwise at
ꢁ78 ꢀC. After 6 h, furan (170 mg, 2.5 mmol) was added
slowly at ꢁ78 ꢀC, and the resulting mixture was warmed
to 25 ꢀC and stirred for 1 h. Saturated aqueous NH4Cl solu-
tion (50 mL) was then added, and then the resulting mixture
was extracted with CH2Cl2 (3ꢂ40 mL). The organic extracts
were dried over anhydrous Na2SO4 and concentrated. Puri-
fication by flash chromatography (pentane/diethyl ether¼
10:1) furnished the product 4i as a pale yellow solid
1
ourless oil. H NMR (600 MHz, CDCl3, 25 ꢀC) d/ppm:
7.96–7.93 (m, 2H), 7.57–7.54 (m, 2H), 7.22 (s, 1H), 6.03–
5.95 (m, 1H), 5.13–5.07 (m, 2H), 3.65–3.62 (m, 2H), 2.48
13
(s, 3H). C NMR (150 MHz, CDCl3, 25 ꢀC) d/ppm:
157.4, 155.4, 141.4, 140.7, 135.1, 133.9, 129.9, 129.6, 127.4,
126.3, 117.1, 38.1, 23.7. MS (70 eV, EI) m/z (%): 403 (10)
[M+], 402 (18), 400 (14), 229 (19), 228 (99), 227 (27), 226
(100), 175 (12), 148 (11), 147 (22), 146 (15), 144 (12),
119 (23), 118 (22), 111 (24), 75 (12), 51 (20). IR (KBr)
~n (cmꢁ1): 1586 (w), 1562 (s), 1476 (w), 1431 (m), 1373
(s), 1277 (w), 1205 (m), 1186 (vs), 1089 (s), 1014 (w), 910
(m), 844 (s), 806 (s), 758 (s), 730 (s), 706 (m), 676 (m),
645 (m). HRMS (EI) for C15H13ClBrNO3S (402.9488):
found 402.9402.
1
(117 mg, 76%). Mp: 148.6–150.1 ꢀC. H NMR (300 MHz,
CDCl3, 25 ꢀC) d/ppm: 8.18–8.13 (m, 2H), 7.74–7.69 (m,
3
3
2H), 7.20 (dd, J¼5.6 Hz, J¼1.8 Hz, 1H), 7.13 (s, 1H),
3
3
4.5.11. 4-[4-Bromo-3-(4-chloro-benzenesulfonyloxy)-6-
methylpyridin-2-yl]-benzoic acid ethyl ester (3i). A dry
and argon-flushed 250-mL Schlenk-flask, equipped with
a magnetic stirrer and a septum, was charged with a solution
of 4-bromo-2-iodo-6-methylpyridin-3-yl 4-chlorobenzene-
sulfonate (5) (4.89 g, 10.0 mmol) in dry THF (20 mL).
i-PrMgCl (0.87 M/THF, 12.65 mL, 1.1 equiv) was then
added dropwise at ꢁ78 ꢀC and stirred for 30 min. ZnBr2
(1.0 M/THF, 11.0 mL, 1.1 equiv) was added to the magnesi-
ated arene at ꢁ78 ꢀC. Another dry and argon-flushed 25-mL
7.06 (dd, J¼5.6 Hz, J¼1.9 Hz, 1H), 5.93–5.91 (m, 1H),
3
5.74–5.72 (m, 1H), 4.41 (q, J¼7.1 Hz, 2H), 2.59 (s, 3H),
1.42 (t, 3J¼7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3,
25 ꢀC) d/ppm: 166.3, 160.0, 156.4, 147.3, 143.1, 142.8,
142.1, 139.2, 130.3, 129.9, 127.8, 115.6, 81.7, 81.3, 61.0,
24.7, 14.3. MS (70 eV, EI) m/z (%): 307 (14) [M+], 291
(13), 281 (35), 280 (23), 279 (100), 278 (17), 262 (27),
253 (14), 252 (12), 251 (96), 250 (24), 234 (17), 225 (13),
218 (20), 206 (22), 205 (17), 204 (24), 178 (11), 165 (14),
164 (11). IR (neat) ~n (cmꢁ1): 2983 (w), 1708 (vs), 1610

2794
W. Lin et al. / Tetrahedron 63 (2007) 2787–2797
(m), 1584 (w), 1404 (w), 1369 (w), 1278 (s), 1222 (w), 1108
(m), 1078 (w), 1016 (m), 862 (m), 843 (m), 816 (w), 761 (m),
718 (w), 704 (m), 650 (w). HRMS (EI) for C19H17O3N
(307.1208): found 307.1222.
4.6.4. 3-Chloro-5-iodo-11-oxa-4-aza-tricyclo[6.2.1.02,7]-
undeca-2(7),3,5,9-tetraene (4d). Prepared according to
TP 2 from 4-chloro-benzenesulfonic acid 2-chloro-4,6-
diiodo-pyridin-3-yl ester (3d) (556 mg, 1.0 mmol), i-
PrMgCl (1.21 mL, 1.05 mmol, 0.87 M in THF) and furan
(340 mg, 5.0 mmol). Reaction condition: ꢁ78 ꢀC, 0.5 h;
25 ꢀC, 16 h. Purification by flash chromatography (n-
pentane/diethyl ether¼30:1) yielded 4d as a white solid
4.6.1. 11-Oxa-4-aza-tricyclo[6.2.1.02,7]undeca-2(7),3,5,9-
tetraene (4a). Prepared according to TP 2 from 4-iodo-
pyridin-3-yl 4-chlorobenzenesulfonate (3a) (396 mg,
1.0 mmol), i-PrMgCl (1.21 mL, 1.05 mmol, 0.87 M in
THF) and furan (340 mg, 5.0 mmol). Reaction condition:
ꢁ78 ꢀC, 0.5 h; 25 ꢀC, 2.5 h. Purification by flash chromato-
graphy (n-pentane/diethyl ether¼2:1) yielded 4a as a yellow
1
(98 mg, 32%). Mp: 123.1–124.2 ꢀC. H NMR (300 MHz,
3
CDCl3, 25 ꢀC) d/ppm: 7.59 (s, 1H), 7.12 (dd, J¼5.5 Hz,
3J¼1.9 Hz, 1H), 6.99 (dd, 3J¼5.5 Hz, 3J¼1.9 Hz, 1H),
5.80–5.77 (m, 1H), 5.73–5.70 (m, 1H). 13C NMR (75 MHz,
CDCl3, 25 ꢀC) d/ppm: 164.2, 143.9, 142.9, 141.9, 140.7,
126.6, 113.0, 81.9, 80.5. MS (70 eV, EI) m/z (%): 307 (6),
305 (20) [M+], 281 (7), 279 (23), 277 (12), 241 (9), 152
(44), 151 (13), 150 (100), 149 (12), 123 (12), 115 (7), 114
(25). IR (KBr) ~n (cmꢁ1): 1598, 1553, 1402, 1300, 1284,
1204, 1134, 1054, 853, 814, 805, 728, 642. HRMS (EI) for
C9H5ON35ClI (304.9104): found 304.9087.
1
oil (79 mg, 54%). H NMR (300 MHz, CDCl3, 25 ꢀC)
d/ppm: 8.40 (s, 1H), 8.23 (d, 3J¼4.6 Hz, 1H), 7.18 (d,
3J¼4.6 Hz, 1H), 6.99 (dd, 3J¼5.6 Hz, 3J¼1.8 Hz, 1H),
3
3
6.93 (dd, J¼5.6 Hz, J¼1.8 Hz, 1H), 5.77–5.75 (m, 1H),
13
5.68–5.66 (m, 1H). C NMR (75 MHz, CDCl3, 25 ꢀC)
d/ppm: 158.8, 147.2, 144.1, 143.3, 141.8, 139.6, 116.0,
81.5, 80.4. MS (70 eV, EI) m/z (%): 145 (8) [M+], 119
(21), 118 (9), 117 (100), 116 (20), 91 (8), 90 (39), 89 (40),
64 (7), 63 (18). IR (film) ~n (cmꢁ1): 1584 (w), 1414 (w),
1282 (w), 1126 (w), 1019 (w), 995 (w), 876 (w), 850 (s),
836 (m), 705 (m), 645 (w), 592 (w). HRMS (EI) for
C9H7ON (145.0528): found 145.0525.
4.6.5. 5-Bromo-3-methoxy-11-oxa-4-aza-tricyclo-
[6.2.1.02,7]undeca-2(7),3,5,9-tetraene
(4e).
Prepared
according to TP 2 from 4-chloro-benzenesulfonic acid 4,6-
dibromo-2-methoxy-pyridin-3-yl ester (3e) (229 mg,
0.5 mmol), i-PrMgCl$LiCl (0.51 mL, 0.51 mmol, 1.00 M
in THF) and furan (170 mg, 2.5 mmol). Reaction condition:
ꢁ78 ꢀC, 0.5 h; 25 ꢀC, 4 h. Purification by flash chromato-
graphy (n-pentane/diethyl ether¼100:1) yielded 4e as a col-
4.6.2. 3-Iodo-11-oxa-4-aza-tricyclo[6.2.1.02,7]undeca-
2(7),3,5,9-tetraene (4b). Prepared according to TP 2 from
2,4-diiodo-pyridin-3-yl 4-chlorobenzenesulfonate (3b)
(522 mg, 1.0 mmol), i-PrMgCl (1.21 mL, 1.05 mmol,
0.87 M in THF) and furan (340 mg, 5.0 mmol). Reaction
condition: ꢁ78 ꢀC, 0.5 h; 25 ꢀC, 1.5 h. Purification by flash
chromatography (n-pentane/diethyl ether¼10:1) yielded 4b
as a white solid (123 mg, 45%). Mp: 91.8–93.8 ꢀC. 1H NMR
(300 MHz, CDCl3, 25 ꢀC) d/ppm: 8.03 (d, 3J¼4.7 Hz, 1H),
1
ourless oil (100 mg, 78%). H NMR (300 MHz, CDCl3,
25 ꢀC) d/ppm: 7.12–7.08 (m, 2H), 6.97 (dd, 3J¼5.5 Hz,
3J¼1.9 Hz, 1H), 5.84–5.81 (m, 1H), 5.67–5.64 (m, 1H),
13
3.93 (s, 3H). C NMR (75 MHz, CDCl3, 25 ꢀC) d/ppm:
166.2, 155.9, 143.6, 141.7, 135.7, 129.3, 115.0, 81.9, 79.3,
54.1. MS (70 eV, EI) m/z (%): 255 (15), 253 (17) [M+],
229 (29), 227 (52), 226 (99), 225 (34), 224 (100), 212
(15), 210 (17), 198 (29), 197 (18), 196 (23), 195 (13), 185
(29), 183 (27), 148 (26), 146 (20), 145 (19), 131 (21), 130
(41), 116 (19), 115 (17), 103 (15), 102 (13), 76 (19). IR
(neat) ~n (cmꢁ1): 2950 (w), 1600 (m), 1572 (s), 1458 (m),
1411 (w), 1354 (vs), 1279 (m), 1079 (m), 1060 (m), 994
(m), 864 (m), 842 (m), 728 (w), 649 (w). HRMS (EI) for
C10H8O2N79Br (252.9738): found 252.9716.
3
3
3
7.16 (d, J¼4.7 Hz, 1H), 7.14 (dd, J¼5.6 Hz, J¼1.8 Hz,
3
3
1H), 7.03 (dd, J¼5.6 Hz, J¼1.8 Hz, 1H), 5.85–5.82 (m,
1H), 5.61–5.58 (m, 1H). 13C NMR (75 MHz, CDCl3,
25 ꢀC) d/ppm: 160.4, 152.0, 148.8, 143.0, 142.5, 115.7,
107.1, 84.0, 83.0. MS (70 eV, EI) m/z (%): 271 (22) [M+],
245 (11), 243 (29), 144 (14), 118 (20), 117 (10), 116
(100), 115 (35), 89 (28), 63 (11). IR (KBr) ~n (cmꢁ1): 1560,
1410, 1396, 1270, 1116, 856, 832, 731, 654. HRMS (EI)
for C9H6ONI (270.9494): found 270.9507.
4.6.6. 3-(4-Chloro-phenylsulfanyl)-5-methyl-11-oxa-4-
aza-tricyclo[6.2.1.02,7]undeca-2(7),3,5,9-tetraene (4f).
Prepared according to TP 2 from 4-chloro-benzenesulfonic
acid 4-bromo-2-(4-chloro-phenylsulfanyl)-6-methylpyri-
din-3-yl ester (3f) (253 mg, 0.5 mmol), i-PrMgCl$LiCl
(0.51 mL, 0.51 mmol, 1.00 M in THF) and furan (170 mg,
2.5 mmol). Reaction condition: ꢁ78 ꢀC, 0.5 h; 25 ꢀC, 1 h.
Purification by flash chromatography (n-pentane/diethyl
ether¼3:1) yielded 4f as a yellow solid (134 mg, 88%).
4.6.3. 3-Iodo-5-methyl-11-oxa-4-aza-tricyclo[6.2.1.02,7]-
undeca-2(7),3,5,9-tetraene (4c). Prepared according to TP
2 from 2,4-diiodo-6-methylpyridin-3-yl 4-chlorobenzene-
sulfonate (3c) (536 mg, 1.0 mmol), i-PrMgCl (1.21 mL,
1.05 mmol, 0.87 M in THF) and furan (340 mg,
5.0 mmol). Reaction condition: ꢁ78 ꢀC, 0.5 h; 25 ꢀC, 6 h.
Purification by flash chromatography (n-pentane/diethyl
1
ether¼2:1) yielded 4c as a yellow oil (214 mg, 75%). H
NMR (300 MHz, CDCl3, 25 ꢀC) d/ppm: 7.09 (dd, 3J¼
Mp: 98.1–101.2 ꢀC. H NMR (300 MHz, CDCl3, 25 ꢀC)
1
3
3
5.6 Hz, J¼1.9 Hz, 1H), 7.00 (s, 1H), 6.96 (dd, J¼5.6 Hz,
3J¼1.9 Hz, 1H), 5.77–5.75 (m, 1H), 5.54–5.52 (m, 1H),
d/ppm: 7.29–7.20 (m, 4H), 6.92 (s, 1H), 6.82 (dd, 3J¼
3
3
3
5.5 Hz, J¼1.9 Hz, 1H), 6.57 (dd, J¼5.5 Hz, J¼1.9 Hz,
1H), 5.57–5.54 (m, 1H), 5.34–5.31 (m, 1H), 2.41 (s, 3H).
13C NMR (75 MHz, CDCl3, 25 ꢀC) d/ppm: 160.7, 157.2,
146.4, 143.0, 142.7, 141.7, 133.8, 133.1, 132.4, 129.4,
114.9, 81.7, 80.5, 24.5. MS (70 eV, EI) m/z (%): 303 (35),
302 (23), 301 (88) [M+], 300 (20), 275 (43), 274 (63), 273
(70), 272 (100), 257 (24), 247 (29), 240 (34), 237 (31),
236 (23), 108 (29), 103 (31), 77 (42), 63 (20). IR (neat)
~n (cmꢁ1): 3077 (w), 2612 (w), 1558 (m), 1476 (s), 1443
13
2.44 (s, 3H). C NMR (75 MHz, CDCl3, 25 ꢀC) d/ppm:
160.6, 158.6, 148.7, 143.0, 142.0, 115.8, 105.8, 83.8, 82.9,
24.2. MS (70 eV, EI) m/z (%): 285 (12) [M+], 257 (20),
132 (14), 130 (100), 129 (28), 103 (35), 77 (13). IR (neat)
~n (cmꢁ1): 1613 (w), 1549 (s), 1428 (m), 1322 (m), 1280
(m), 1180 (s), 1080 (s), 1004 (w), 910 (w), 865 (w), 851
(vs), 838 (s), 795 (m), 727 (m), 702 (s), 646 (m). HRMS
(EI) for C10H8ONI (284.9651): found 284.9633.

W. Lin et al. / Tetrahedron 63 (2007) 2787–2797
2795
(w), 1428 (m), 1390 (m), 1326 (w), 1282 (m), 1201 (m),
1086 (vs), 1007 (m), 860 (m), 848 (s), 826 (s), 810 (m),
750 (m), 709 (s), 649 (m). HRMS (EI) for C16H12ON35ClS
(301.0328): found 301.0339.
solution, extracted with CH2Cl2 (3ꢂ40 mL) and dried over
anhydrous Na2SO4. After filtration, the solvent was evapo-
rated in vacuo. Purification by flash chromatography (n-
pentane/diethyl ether¼10:1) yielded 8a as a yellow solid
(141 mg, 53%) and 8b as a yellow oil (85 mg, 32%). Mp:
1
4.6.7. 5-Methyl-3-phenylsulfanyl-11-oxa-4-aza-tri-
cyclo[6.2.1.02,7]undeca-2(7),3,5,9-tetraene (4g). Prepared
according to TP 2 from 4-chloro-benzenesulfonic acid
4-bromo-6-methyl-2-phenylsulfanyl-pyridin-3-yl ester (3f)
(235 mg, 0.5 mmol), i-PrMgCl$LiCl (0.51 mL, 0.51 mmol,
1.00 M in THF) and furan (170 mg, 2.5 mmol). Reaction
condition: ꢁ78 ꢀC, 0.5 h; 25 ꢀC, 1 h. Purification by flash
chromatography (n-pentane/diethyl ether¼8:1) yielded 4g
as a yellow oil (114 mg, 85%). 1H NMR (300 MHz,
CDCl3, 25 ꢀC) d/ppm: 7.46–7.40 (m, 2H), 7.37–7.29 (m,
70.5–71.8 ꢀC. H NMR (300 MHz, CDCl3, 25 ꢀC) d/ppm:
8.34 (d, 3J¼5.3 Hz, 2H), 7.60–7.52 (m, 2H), 7.44–7.34 (m,
2H), 6.99–6.98 (m, 2H). 13C NMR (75 MHz, CDCl3,
25 ꢀC) d/ppm: 149.5, 149.4, 136.4, 133.1, 128.7, 124.2,
120.9. MS (70 eV, EI) m/z (%): 265 (100) [M+], 186 (60),
154 (5), 115 (14), 93 (10), 78 (7), 51 (4). IR (KBr)
~n (cmꢁ1): 3044 (w), 1567 (m), 1472 (m), 1405 (m), 1386
(m), 1189 (w), 1086 (m), 1008 (m), 814 (m), 705 (m), 618
(m). HRMS (EI) for C11H879BrNS (264.9561): found
264.9586.
3
3
3H), 6.95 (s, 1H), 6.83 (dd, J¼5.5 Hz, J¼1.9 Hz, 1H),
6.47 (dd, 3J¼5.5 Hz, 3J¼1.9 Hz, 1H), 5.58 (dd, 3J¼
4.6.10. 3-(4-Bromo-phenylsulfanyl)-pyridine (8b). 1H
NMR (300 MHz, CDCl3, 25 ꢀC) d/ppm: 8.58 (d, 4J¼
4
3
4
1.9 Hz, J¼0.9 Hz, 1H), 5.19 (dd, J¼1.9 Hz, J¼0.9 Hz,
13
3
4
1H), 2.48 (s, 3H). C NMR (75 MHz, CDCl3, 25 ꢀC)
1.9 Hz, 1H), 8.51 (dd, J¼4.9 Hz, J¼1.3 Hz, 1H), 7.66–
7.59 (m, 1H), 7.51–7.42 (m, 2H), 7.29–7.20 (m, 3H). 13C
NMR (75 MHz, CDCl3, 25 ꢀC) d/ppm: 151.2, 148.1, 138.4,
133.4, 132.8, 132.5, 124.0, 121.9. MS (70 eV, EI) m/z (%):
265 (100) [M+], 240 (4), 186 (50), 154 (4), 115 (7), 93 (6).
IR (KBr) ~n (cmꢁ1): 3045 (w), 1630 (w), 1552 (vs), 1467
(s), 1404 (s), 1382 (m), 1087 (m), 1067 (m), 1008 (s), 818
(s), 805 (s), 699 (m), 528 (m), 491 (s). HRMS (EI) for
C11H879BrNS (264.9561): found 264.9568.
d/ppm: 160.6, 156.7, 147.8, 142.8, 142.6, 141.4, 133.6,
132.4, 129.3, 127.9, 114.5, 81.5, 80.4, 24.4. MS (70 eV,
EI) m/z (%): 267 (81) [M+], 266 (23), 250 (37), 246 (30),
245 (25), 241 (20), 240 (35), 239 (57), 238 (100), 231 (27),
223 (36), 213 (25), 77 (25), 57 (24). IR (neat) ~n (cmꢁ1): 1612
(w), 1555 (s), 1477 (m), 1440 (m), 1424 (s), 1324 (m), 1280
(m), 1204 (m), 1186 (w), 1086 (m), 1024 (w), 1007 (w), 890
(w), 845 (vs), 812 (m), 730 (s), 703 (s), 689 (s), 650 (s).
HRMS (EI) for C16H13ONS (267.0718): found 267.0694.
4.6.11. 4-(4-Bromo-phenylsulfanyl)-pyridine-3-carb-
aldehyde (10a). A dry and argon-flushed 25-mL Schlenk-
flask, equipped with a magnetic stirrer and a septum, was
charged with a solution of 4-bromothiophenol (380 mg,
2.0 mmol) in dry THF (5 mL). After cooling to ꢁ78 ꢀC,
i-PrMgCl (2.81 mL, 3.0 equiv, 1.07 M in THF) was then
added dropwise and stirred for 10 min. 4-Chloro-benzene-
sulfonic acid 4-iodopyridin-3-yl ester (3a) (395 mg,
1.00 mmol) dissolved in dry THF (2 mL) was added and
stirred vigorously for 30 min at the same temperature.
Thereafter the resulting mixture was warmed to 25 ꢀC and
stirred for 2.5 h. The reaction mixture was cooled to
ꢁ78 ꢀC, added with DMF (219 mg, 3.00 mmol), warmed
to 25 ꢀC and stirred for 1 h. The reaction was quenched
with saturated aqueous NH4Cl solution, extracted with
CH2Cl2 (3ꢂ40 mL) and dried over anhydrous Na2SO4. After
filtration, the solvent was evaporated in vacuo. Purification
by flash chromatography (n-pentane/diethyl ether¼5:1)
yielded 10a as a pale yellow solid (147 mg, 50%) and 10b
as a yellow solid (91 mg, 31%). Mp: 89.8–91.0 ꢀC. 1H
NMR (300 MHz, CDCl3, 25 ꢀC) d/ppm: 10.22 (s, 1H),
4.6.8. 3-Allyl-5-methyl-11-oxa-4-aza-tricyclo[6.2.1.02,7]-
undeca-2(7),3,5,9-tetraene (4h). Prepared according to
TP 2 from 2-allyl-4-bromo-6-methylpyridin-3-yl 4-chloro-
benzenesulfonate (3h) (403 mg, 1.0 mmol), i-PrMgCl$LiCl
(1.02 mL, 1.02 mmol, 1.00 M in THF) and furan (340 mg,
5.0 mmol). Reaction condition: ꢁ78 ꢀC, 2 h; 25 ꢀC, 1 h.
Purification by flash chromatography (n-pentane/diethyl
1
ether¼5:1) yielded 4h as a yellow oil (114 mg, 57%). H
NMR (400 MHz, CDCl3, 25 ꢀC) d/ppm: 6.98 (dd,
3J¼5.6 Hz, 3J¼1.9 Hz, 1H), 6.97 (s, 1H), 6.91 (dd,
3
3J¼5.6 Hz, J¼1.9 Hz, 1H), 6.03–5.92 (m, 1H), 5.82–5.81
(m, 1H), 5.64–5.63 (m, 1H), 5.11–5.01 (m, 2H), 3.62–3.46
(m, 2H), 2.47 (s, 3H). 13C NMR (100 MHz, CDCl3, 25 ꢀC)
d/ppm: 159.6, 155.8, 148.7, 143.0, 141.6, 139.4, 135.7,
116.4, 114.4, 81.6, 80.3, 40.4, 24.5. MS (70 eV, EI) m/z
(%): 199 (55) [M+], 198 (100), 173 (37), 172 (53), 171
(70), 170 (70), 169 (19), 168 (22), 155 (16), 154 (14), 145
(14), 144 (20), 130 (12), 128 (14), 115 (13), 103 (11), 77
(21), 63 (10), 51 (12). IR (neat) ~n (cmꢁ1): 1616 (w), 1587
(m), 1433 (m), 1367 (w), 1280 (w), 845 (s), 700 (m), 647
(m). HRMS (EI) for C13H13ON (199.0997): found 199.0967.
3
8.90 (s, 1H), 8.37 (d, J¼5.8 Hz, 1H), 7.68–7.61 (m, 2H),
7.47–7.39 (m, 2H), 6.67 (d, 3J(H,H)¼5.8 Hz, 1H). 13C
NMR (75 MHz, CDCl3, 25 ꢀC) d/ppm: 190.3, 154.9,
154.4, 152.1, 137.3, 133.6, 127.6, 125.4, 120.4, 112.6. MS
(70 eV, EI) m/z (%): 295 (76) [M+], 266 (6), 185 (24), 137
(100), 105 (18), 77 (6), 50 (4). IR (KBr) ~n (cmꢁ1): 3081
(w), 2849 (w), 2760 (w), 1684 (vs), 1576 (s), 1523 (s),
1466 (s), 1358 (s), 1256 (m), 1183 (s), 1066 (s), 1008 (vs),
816 (vs), 730 (m), 685 (m), 479 (m). HRMS (EI) for
C12H879BrNOS (294.9510): found 294.9511.
4.6.9. 4-(4-Bromo-phenylsulfanyl)-pyridine (8a). A dry
and argon-flushed 25-mL Schlenk-flask, equipped with
a magnetic stirrer and a septum, was charged with a solution
of 4-bromothiophenol (380 mg, 2.0 mmol) in dry THF
(5 mL). After cooling to ꢁ78 ꢀC, i-PrMgCl (2.81 mL,
3.0 equiv, 1.07 M in THF) was then added dropwise and
stirred for 10 min. 4-Chloro-benzenesulfonic acid 4-iodo-
pyridin-3-yl ester (3a) (395 mg, 1.0 mmol) dissolved in
dry THF (2 mL) was added and stirred vigorously for
30 min at the same temperature. Thereafter the resulting
mixture was warmed to 25 ꢀC and stirred for 2.5 h. The
reaction was quenched with saturated aqueous NH4Cl
4.6.12. 3-(4-Bromo-phenylsulfanyl)-pyridine-4-carb-
1
aldehyde (10b). Mp: 85.7–87.3 ꢀC. H NMR (300 MHz,
3
CDCl3, 25 ꢀC) d/ppm: 10.39 (s, 1H), 8.65 (d, J¼4.9 Hz,

2796
W. Lin et al. / Tetrahedron 63 (2007) 2787–2797
3
1H), 8.43 (s, 1H), 7.66 (d, J¼4.9 Hz, 1H), 7.55–7.48 (m,
2H), 7.33–7.25 (m, 2H). 13C NMR (75 MHz, CDCl3, 25 ꢀC)
d/ppm: 190.6, 152.1, 148.3, 138.9, 134.2, 133.1, 131.2,
123.3, 123.1, 112.6. MS (70 eV, EI) m/z (%): 265 (100)
[M+], 266 (25), 214 (30), 185 (54), 137 (18), 109 (9). IR
(KBr) ~n (cmꢁ1): 3080 (w), 2843 (w), 2752 (w), 1925 (w),
1691 (vs), 1467 (s), 1387 (s), 1387 (m), 1204 (m), 1138
(m), 1067 (m), 1009 (s), 826 (s), 729 (m), 658 (m), 525
(m), 480 (m). HRMS (EI) for C12H879BrNOS (294.9510):
found 294.9471.
3.0 equiv, 1.07 M in THF) was then added dropwise and
stirred for 10 min. 4-Chloro-benzenesulfonic acid 4-bromo-
2-(4-chloro-phenylsulfanyl)-6-methylpyridin-3-yl ester (3f)
(253 mg, 0.5 mmol) dissolved in dry THF (2 mL) was added
and stirred vigorously for 30 min at the same temperature.
Thereafter the resulting mixture was warmed to 25 ꢀC and
stirred for 1 h. The reaction mixture was cooled to
ꢁ78 ꢀC, added with iodine (508 mg, 2.0 mmol), warmed
to 25 ꢀC and stirred for 1 h. The reaction was quenched
with 5% aqueous Na2S2O3 and saturated aqueous NH4Cl
solution, extracted with CH2Cl2 (3ꢂ40 mL) and dried over
anhydrous Na2SO4. After filtration, the solvent was evapo-
rated in vacuo. Purification by flash chromatography (n-
pentane/diethyl ether¼50:1) yielded 13a as a white solid
CDCl3, 25 ꢀC) d/ppm: 7.63–7.58 (m, 2H), 7.47–7.38 (m,
4H), 7.37–7.32 (m, 2H), 6.02 (s, 1H), 2.08 (s, 3H). 13C NMR
(75 MHz, CDCl3, 25 ꢀC) d/ppm: 161.3, 157.7, 155.4, 137.4,
136.5, 135.2, 133.8, 131.6, 130.1, 129.4, 125.2, 117.0, 89.7,
24.3. MS (70 eV, EI) m/z (%): 551 (27), 550 (27), 549 (83)
[M+], 548 (44), 547 (56), 546 (23), 424 (25), 423 (30), 422
(83), 421 (52), 420 (100), 419 (29), 418 (39), 386 (17),
342 (19), 341 (16), 340 (38), 257 (22), 256 (22), 229 (20),
196 (22), 171 (21), 153 (29), 152 (17), 108 (31). IR (neat)
~n (cmꢁ1): 1538 (m), 1502 (m), 1468 (m), 1434 (w), 1384
(m), 1309 (m), 1091 (m), 1084 (w), 1066 (w), 1010 (m),
992 (m), 817 (s), 786 (m), 745 (m), 730 (m), 718 (w).
HRMS (EI) for C18H1279Br35ClINS2 (546.8328): found
546.8322.
4.6.13. 4-Phenylselanyl-pyridine-3-carbaldehyde (12a).
A dry and argon-flushed 25-mL Schlenk-flask, equipped
with a magnetic stirrer and a septum, was charged with a so-
lution of phenylselenol (305 mg, 2.0 mmol) in dry THF
(5 mL). After cooling to ꢁ78 ꢀC, i-PrMgCl (2.81 mL,
3.0 equiv, 1.07 M in THF) was then added dropwise and
stirred for 10 min. 4-Chloro-benzenesulfonic acid 4-iodo-
pyridin-3-yl ester (3a) (395 mg, 1.0 mmol) dissolved in
dry THF (2 mL) was added and stirred vigorously for
30 min at the same temperature. Thereafter the resulting
mixture was warmed to 25 ꢀC and stirred for 2.5 h. The re-
action mixture was cooled to ꢁ78 ꢀC, added with DMF
(219 mg, 3.00 mmol), warmed to 25 ꢀC and stirred for 1 h.
The reaction was quenched with saturated aqueous NH4Cl
solution, extracted with CH2Cl2 (3ꢂ40 mL) and dried over
anhydrous Na2SO4. After filtration, the solvent was evapo-
rated in vacuo. Purification by flash chromatography (n-pen-
tane/diethyl ether¼5:1) yielded 12a as a pale yellow solid
(142 mg, 54%) and 12b as a yellow solid (84 mg, 32%).
1
(182 mg, 66%). Mp: 216.1–217.7 ꢀC. H NMR (300 MHz,
1
Mp: 94.7–98.2 ꢀC. H NMR (300 MHz, CDCl3, 25 ꢀC)
4.6.16. 3-Allyl-4-(4-bromo-phenylsulfanyl)-2-(4-chloro-
phenylsulfanyl)-6-methylpyridine (14a). A dry and argon-
flushed 25-mL Schlenk-flask, equipped with a magnetic
stirrer and a septum, was charged with a solution of 4-bro-
mothiophenol (190 mg, 1.0 mmol) in dry THF (1 mL). After
cooling to ꢁ78 ꢀC, i-PrMgCl$LiCl (1.41 mL, 3.0 equiv,
1.07 M in THF) was then added dropwise and stirred for
10 min. 4-Chloro-benzenesulfonicacid4-bromo-2-(4-chloro-
phenylsulfanyl)-6-methylpyridin-3-yl ester (3f) (253 mg,
0.5 mmol) dissolved in dry THF (2 mL) was added and
stirred vigorously for 30 min at the same temperature. There-
after the resulting mixture was warmed to 25 ꢀC and stirred
for 1 h. The reaction mixture was cooled to ꢁ78 ꢀC,
and then CuCN$2LiCl (1.0 M in THF, 0.5 mL, 0.5 equiv)
was added and stirred for 20 min. Allyl bromide (0.17 mL,
2.0 mmol, 4.0 equiv) was added at ꢁ78 ꢀC, and the solution
was allowed to warm to 25 ꢀC and kept stirring for 1 h. The
reaction was quenched with saturated aqueous NH4Cl solu-
tion, extracted with CH2Cl2 (3ꢂ40 mL) and dried over anhy-
drous Na2SO4. After filtration, the solvent was evaporated in
vacuo. Purification by flash chromatography (n-pentane/
diethyl ether¼200:1) yielded 14a as a white solid (149 mg,
3
d/ppm: 10.18 (s, 1H), 8.84 (s, 1H), 8.23 (d, J¼5.5 Hz,
1H), 7.67–7.60 (m, 2H), 7.53–7.40 (m, 3H), 6.81 (d,
3J¼5.5 Hz, 1H). C NMR (75 MHz, CDCl3, 25 ꢀC) d/
13
ppm: 191.1, 155.7, 152.5, 151.9, 137.2, 130.1, 130.0,
129.3, 126.0, 123.3. MS (70 eV, EI) m/z (%): 263 (100)
[M+], 234 (17), 185 (58), 157 (16), 127 (6), 115 (9), 105
(15), 77 (19), 51 (16). IR (KBr) ~n (cmꢁ1): 3068 (w), 2838
(w), 2745 (w), 1709 (m), 1683 (vs), 1571 (vs), 1524 (m),
1461 (m), 1389 (m), 1255 (m), 1188 (m), 1067 (m), 914
(w), 851 (s), 748 (m), 690 (m), 660 (m), 523 (w), 480 (w).
HRMS (EI) for C12H9NOSe (262.9849): found 262.9846.
4.6.14. 3-Phenylselanyl-pyridine-4-carbaldehyde (12b).
Mp: 38.8–41.0 ꢀC. H NMR (300 MHz, CDCl3, 25 ꢀC)
1
3
d/ppm: 10.24 (s, 1H), 8.59 (d, J¼4.9 Hz, 1H), 8.31 (s,
1H), 7.68–7.59 (m, 3H), 7.46–7.33 (m, 3H). 13C NMR
(75 MHz, CDCl3, 25 ꢀC) d/ppm: 191.9, 151.6, 147.2,
138.5, 136.1, 133.1, 130.0, 129.4, 126.7, 125.6. MS
(70 eV, EI) m/z (%): 263 (100) [M+], 234 (32), 185 (24),
155 (32), 127 (6), 115 (7), 105 (6), 77 (16), 51 (9). IR
(KBr) ~n (cmꢁ1): 3068 (w), 2820 (w), 1686 (s), 1568 (w),
1466 (m), 1438 (m), 1404 (m), 1276 (m), 1229 (m), 1206
(m), 1156 (m), 1093 (m), 1020 (m), 916 (w), 856 (m), 818
(m), 744 (m), 693 (m), 657 (m), 513 (w), 480 (m). HRMS
(EI) for C12H9NOSe (262.9849): found 262.9859.
1
64%). Mp: 163.2–164.4 ꢀC. H NMR (300 MHz, CDCl3,
25 ꢀC) d/ppm: 7.58–7.53 (m, 2H), 7.42–7.27 (m, 6H), 6.36
(s, 1H), 6.01–5.87 (m, 1H), 5.16–5.07 (m, 2H), 3.74–3.69
13
(m, 2H), 2.19 (s, 3H). C NMR (75 MHz, CDCl3, 25 ꢀC)
d/ppm: 156.4, 156.1, 149.0, 136.1, 134.6, 133.7, 133.2,
133.0, 131.1, 130.1, 128.8, 127.8, 123.8, 118.8, 116.8,
34.0, 24.0. MS (70 eV, EI) m/z (%): 463 (9) [M+], 462 (7),
461 (6), 450 (33), 449 (23), 448 (100), 447 (17), 446 (69),
368 (14), 97 (18), 95 (12), 85 (13), 83 (16), 71 (19), 69
(18), 57 (28), 55 (19), 43 (20). IR (neat) ~n (cmꢁ1): 1557
(m), 1518 (m), 1471 (m), 1416 (m), 1385 (w), 1335 (m),
4.6.15. 4-(4-Bromo-phenylsulfanyl)-2-(4-chloro-phenyl-
sulfanyl)-3-iodo-6-methylpyridine (13a).
argon-flushed 25-mL Schlenk-flask, equipped with a mag-
netic stirrer and a septum, was charged with a solution of
4-bromothiophenol (190 mg, 1.0 mmol) in dry THF (1 mL).
After cooling to ꢁ78 ꢀC, i-PrMgCl$LiCl (1.41 mL,
A dry and

W. Lin et al. / Tetrahedron 63 (2007) 2787–2797
2797
M.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 4415; (c)
Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
1174 (w), 1090 (s), 1167 (m), 1008 (s), 914 (m), 820 (vs),
802 (s), 777 (s), 746 (m), 730 (m). HRMS (EI) for
C21H1779Br35ClNS2 (460.9674): found 460.9680.
€
897; (d) Boymond, L.; Rottlander, M.; Cahiez, G.; Knochel, P.
Angew. Chem., Int. Ed. 1998, 37, 1701; (e) Sapountzis, I.;
Knochel, P. Angew. Chem., Int. Ed. 2002, 41, 1610; (f)
Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
3333; (g) Boudet, N.; Knochel, P. Org. Lett. 2006, 8, 3737; (h)
Baron, O.; Knochel, P. Angew. Chem., Int. Ed. 2005, 44, 3133;
(i) Liu, C.-Y.; Knochel, P. Org. Lett. 2005, 7, 2543; (j) Ren,
H.; Krasovskiy, A.; Knochel, P. Chem. Commun. 2005, 543;
(k) Ren, H.; Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6, 4215.
4. (a) Lin, W.; Ilgen, F.; Knochel, P. Tetrahedron Lett. 2006, 47,
1941; (b) Lin, W.; Sapountzis, I.; Knochel, P. Angew. Chem.,
Int. Ed. 2005, 44, 4258; Angew. Chem. 2005, 117, 4330; (c)
Sapountzis, I.; Lin, W.; Fischer, M.; Knochel, P. Angew.
Chem., Int. Ed. 2004, 43, 4364; Angew. Chem. 2004, 116, 4464.
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Acknowledgements
We thank the Fonds der Chemischen Industrie, the Deutsche
Forschungsgemeinschaft (DFG) and Merck Research Labo-
ratories (MSD) for financial support. We also thank Cheme-
tall GmbH (Frankfurt) and BASFAG (Ludwigshafen) for the
generous gift of chemicals.
References and notes
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