Pyridino-directed lithiation of anisylpyridines: New access to functional pyridylphenols

Article abstract of DOI:10.1016/j.tet.2004.10.100

The lithiation of nine anisylpyridines has been studied. While usual reagents did not react or gave addition products on pyridine ring, the BuLi-LiDMAE (LiDMAE=Me₂N(CH₂)₂OLi) superbase induced exclusive pyridino directed metallation. The usefulness of this new reaction allowed the efficient preparation of a range of alpha functional pyridylphenols. A successful subsequent cyclisation of an appropriate isomer into corresponding benzofuropyridine was also performed.

Full text of DOI:10.1016/j.tet.2004.10.100

Tetrahedron 61 (2005) 3261–3269
Pyridino-directed lithiation of anisylpyridines:
new access to functional pyridylphenols
*
Michael Parmentier, Philippe Gros and Yves Fort
*
¨
` ´ ´
Synthese Organometallique et Reactivite, UMR CNRS 7565, Universite Henri Poincare, Bd des Aiguillettes,
´
`
54506, Vandoeuvre-les-Nancy, France
´
´
Received 28 July 2004; revised 29 September 2004; accepted 15 October 2004
Available online 10 December 2004
Abstract—The lithiation of nine anisylpyridines has been studied. While usual reagents did not react or gave addition products on pyridine
ring, the BuLi-LiDMAE (LiDMAEZMe2N(CH2)2OLi) superbase induced exclusive pyridino directed metallation. The usefulness of this
new reaction allowed the efficient preparation of a range of alpha functional pyridylphenols. A successful subsequent cyclisation of an
appropriate isomer into corresponding benzofuropyridine was also performed.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
allowing the selective functionalization of parent methoxy-
phenylpyridines are a valuable alternative to couplings for
the preparation of functional pyridylphenols. Our laboratory
has recently reported the selective C-2 pyridine ring
lithiation of phenylpyridines using the BuLi-containing
aggregates BuLi-LiDMAE (LiDMAEZMe2N(CH2)2OLi)5
which thus could be of great interest for introduction of
functionalities in the methoxy-phenylpyridine series.6 At
Pyridylphenols constitute key structures for biologically
active molecules (e.g., adrenergic receptor ligands),1 metal
ligands for asymmetric synthesis2 or building blocks for
supramolecular architectures.3 They are generally prepared
from halogenated heterocycles by Pd-catalyzed Suzuki3 or
Ni-catalyzed Corriu–Kumada–Tamao4 cross-couplings fol-
lowed by a demethylation step (Scheme 1).
´
the beginning of this work a paper by Queguiner and co-
workers4b appeared dealing with lithiation of some
methoxyphenylpyridines with LiTMP as basic reagent.
The aim was to metallate the pyridine ring using the remote
directing ability of the methoxy group. From this work it
appeared that lithiation of the pyridine ring was strongly
substrate dependent. Only 2-(2-methoxy-phenyl)pyridine 1
underwent lithiation with subsequent introduction of
electrophiles at the C-6 position but not at the expected
C-3 one! This latter selectivity could be attributed to an
internal cooperating lithium complexation by both the
pyridine nitrogen and methoxy group. This kind of
concomitant chelation effect was already observed in our
recent works on lithiation of phenylchloropyridine with
t-BuLi7 (Fig. 1).
This methodology however suffers from limitations when
functional pyridyl derivatives have to be coupled since
substituents can display steric hindrance, reactivity towards
the organometallic species (e.g., carbonyl moieties towards
Grignards) or act as poisons or competing ligands for the
catalyst (e.g., sulfides or phosphines). Thus, methodologies
Scheme 1. Usual synthetic route to pyridylphenols.
Keywords: Selective lithiation; Pyridino-direction; Anisylpyridines;
Cyclization.
* Corresponding authors. Tel.: C33 3 83 68 47 81; fax: C33 3 83 68 47 85;
e-mail addresses: philippe.gros@sor.uhp-nancy.fr;
yves.fort@sor.uhp-nancy.fr
Figure 1. Proposed models for cooperative internal chelations in
substituted phenylpyridines.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.100

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M. Parmentier et al. / Tetrahedron 61 (2005) 3261–3269
On the other hand lithiation did not occur with isomers
bearing a methoxy group more distant from nitrogen.
Indeed, 4 was found unreactive and 7 led to a dimer.
Consequently lithiation of these isomers could be achieved
using a reagent bringing an external lithium chelating agent
and the BuLi-LiDMAE superbase could be the ideal
candidate for such task due to its affinity for the pyridine
nitrogen5 (Fig. 2).
on the pyridine ring. Then we turned to lithiation with the
BuLi-LiDMAE reagent, which was expected to display
lower nucleophilicity.5
2.1. Lithiation of 2-anisylpyridines
2-Anisylpyridines 1–3 were first reacted with BuLi-
LiDMAE under usual conditions in hexane at various
temperatures (Scheme 3, Table 1). All substrates led to
efficient lithiation a to nitrogen. With 1, the selectivity was
´
in agreement with those observed by Queguiner and co-
workers.4b However the lithiation of this isomer was found
highly temperature-sensitive since lithiation conducted at
0 8C led, besides nucleophilic addition product 1a, to
the derivative 1c resulting from a bis-sulfuration of both the
pyridine and phenyl ring (ortho to methoxy) (run 1). The
temperature had to be decreased to K40 8C to ensure
selective monolithiation and good conversion (runs 3–5).
An increase of base amount and substitution of toluene to
hexane in the metallation step to improve the solubility of 1
in the reaction medium were also beneficial. This was not
necessary with 2–3 which were soluble in hexane. More-
over, no temperature effect was observed and 2a–3a were
obtained in good yields after metallation at 0 8C with
3 equiv of the reagent (runs 6–7).
Figure 2. Expected external chelation by lithium aggregates.
Herein we report a new process for the clean pyridino-
directed lithiation of methoxyphenylpyridines with high
selectivity regardless of the position of the methoxyphenyl
group on pyridine.
2. Results and discussion
A series of nine isomers was first prepared in acceptable to
good yields by Corriu–Kumada–Tamao couplings between
the appropriate anisylmagnesium bromides and bromo-
pyridines except for derivatives 7–9 for which 4-chloropyri-
dine was used (Scheme 2).
These different behaviours are in good agreement with the
relative heat of formation of potential carbanions in
substrates as depicted in Figure 3.8
As shown, the carbanion ortho to methoxy in 1 is
thermodynamically more stable than those a to nitrogen.
Deprotonation on pyridine ring is obtained as a single
reaction at low temperature (K40 8C) and is thus assumed
The first lithiation experiments were carried out with n-
BuLi, t-BuLi, n-BuLi-TMEDA and BuLi-t-BuOK under
various conditions. Sluggish reactions generally occurred
with all substrates leading to nucleophilic addition products
Scheme 2. Preparation of methoxyphenylpyridine 1–9.

M. Parmentier et al. / Tetrahedron 61 (2005) 3261–3269
3263
Scheme 3. Lithiation of 1–3 with BuLi-LiDMAE.
Table 1. Study of pyridino lithiation in 1–3a
Entry
Substrate
Base (equiv)
T (8C)
Products (yield,%)b
Isolated yield (%)
1
2
3
4
5
6
7
1
1
1
1
1
2
3
3
3
3
4
4
3
3
0
1a (18) C1b (36) C1c (20)
—
—
—
70
85c
85
76
K78
K40
K40
K40
0
1b (15)
1b (73)
1b (80)
1b (91)
2a (92)
3a (85)
0
a All reactions performed on 2 mmol of substrate.
b GC yield.
c Metallation performed in toluene.
to be under kinetic control. On the other hand dilithiation at
both a to nitrogen and ortho to methoxy was observed only
at higher temperature (0 8C) rather under thermodynamic
conditions. With the two other isomers 2–3, the carbanion a
to nitrogen is always the most stable explaining exclusive
lithiation at this position even at 0 8C. The inertness of these
latter substrates towards LTMP could be explained by the
insufficient basicity of such reagent to abstract both the
phenyl and pyridine protons. With BuLi-LiDMAE, chela-
tion by the pyridine nitrogen and higher basicity allowed the
deprotonation of the pyridinic site.
Several functional derivatives were prepared efficiently,
especially alcohol 3d and ketone 2d not easy to obtain via
classical couplings and the new P,N,O ligand 1f. Note that 1
again behaved differently from 2 and 3 since it was not fully
deuterated indicating that incomplete lithiation may be due
to competitive chelation of lithium aggregates by the
methoxy group thus partially impeding lithiation a to
nitrogen.
2.2. Lithiation of 3- and 4-anisylpyridines
Then, we turned to the lithiation of isomers 4–9 displaying
two available protons a to the pyridine nitrogen thus
offering possibility for new selectivities (Fig. 4).
These selective lithiations were subsequently exploited for
introduction of functionalities on the pyridine ring.
Substrates 1–3 were then lithiated under the best conditions
reported in Table 1 and reacted with various electrophiles
(Table 2).
We first studied substrates 4 and 7 with a methoxy group at
the ortho position on the phenyl ring which was expected to
induce directing effects on pyridine (Scheme 4). As already
observed with derivative 1, 4 was poorly soluble in hexane
and best results were obtained when metallation was
performed in toluene at K20 8C. The lithiation occurred
exclusively at C-6 and not at C-2 as could be expected from
the directing power of the methoxy and a potential
cooperative effect. This selectivity could be attributed to
steric hindrance generated by the methoxyphenyl group at
the C-2 position preventing the formation of aggregates.
Note that such a compound was found inert towards LTMP
supporting the need for external chelation to ensure pyridine
lithiation and the role of steric hindrance. The reaction
Figure 3. Calculated relative heats of formation (kcal/mol) of potential
carbanions in 1–3.

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M. Parmentier et al. / Tetrahedron 61 (2005) 3261–3269
Table 2. Preparation of functional methoxyphenylpyridines from 1–3
Substrate
Electrophile
Product
Yield (%)a
1
1
1
D2O
C2Cl6
ClPPh2
EZD, 1d
EZCl, 1e
EZPPh2, 1f
80 (d%Z75)b
82
50
2
2
2
D2O
CBr4
PhCONMe2
EZD, 2b
EZBr, 2c
EZCOPh, 2d
75 (d%O95)b
74
78
3
3
3
D2O
C2Cl6
PhCHO
EZD, 3b
EZCl, 3c
EZCH(OH)Ph, 3d
80 (d%O98)b
90
75
a Isolated yield after column chromatography.
b Determined by 1H NMR.
Figure 4. Potential deprotonation sites in 4 and 7.
conditions were then applied to isomer 7. As shown,
lithiation also occurred selectively a to nitrogen. Interest-
ingly, 7 did not lead to the radical induced dimerisation
product9 as was observed with LTMP indicating actual
formation of the lithio intermediate (supported by a
deuteration experiment) and subsequent stabilisation by
lithium aggregates. A number of functionalities were further
introduced efficiently leading to a range of new derivatives.
Scheme 5. Lithiation of 5, 6, 8, 9. For conditions see Scheme 4.
substrates 5, 6 and 9 were soluble in hexane and the reaction
proceeded as well in this solvent.
We then studied the remaining isomers 5, 6, 8 and 9
(Scheme 5). These compounds were lithiated under the
above determined conditions. The reaction was also
selectively pyridino directed at the a position. Note that
We next focused on the use of this new reaction for
preparation of bifunctional derivatives via iterative lithia-
tions. Then, compounds 4b and 4c bearing synthetically
useful and base compatible substituents were first subjected
Scheme 4. Lithiation of 4 and 7. Conditions: (i) BuLi-LiDMAE (3 equiv), toluene, K20 8C, 1 h. (ii) MeOD or MeSSMe or C2Cl6 or ClPPh2 (3.2 equiv), THF,
K78 8C to rt, 1 h.

M. Parmentier et al. / Tetrahedron 61 (2005) 3261–3269
3265
to reaction with BuLi-LiDMAE in order to check the ability
of the available a proton to be abstracted (Scheme 6).
3. Conclusion
We have developed an efficient methodology for the
functionalisation of nine methoxyphenylpyridines. The
BuLi-LiDMAE superbase effected a selective pyridino
directed lithiation a to nitrogen. The obtained functional
derivatives were smoothly deprotected under mild con-
ditions and converted into the corresponding phenols. Work
is now in progress to extend such reactions to the
preparation of various functional benzofuropyridines such
as 15 and fused polyheterocyclic compounds.
4. Experimental
4.1. General
Et2O, THF, and hexane were distilled and stored over
sodium wire before use. 2-Dimethylaminoethanol was
distilled under nitrogen and stored on molecular sieves.
n-BuLi was used as a 1.6 M solution in hexanes. All other
reagents were commercially available and used as such. 1H
and 13C and 31P NMR were obtained in CDCl3 (unless
otherwise stated) on a Bruker AC400 instrument at 400, 100
and 162 MHz respectively. GC experiments were per-
formed on a Shimadzu chromatograph fitted with a 15 m
capillary column. GC/MS (EI) were obtained on HP5971
spectrometer.
Scheme 6. Sequential lithiations. Conditions: (i) (1) BuLi-LiDMAE
(3 equiv), toluene, K20 8C, 1 h. (2) MeSSMe or C2Cl6 or ClSiMe3
(3.2 equiv), THF, K78 8C to K20 8C, 1 h. (ii) (1) LTMP (3.2 equiv), THF,
K20 8C, 1 h. (2) C2Cl6 (3.5 equiv), THF, K20 8C 1 h.
As shown, the C-2 position was lithiated in slightly lower
yield than was the C-6 one in 4, presumably due to the
previously proposed steric effects. However bifunctional
derivatives 10a–c were obtained in good overall yields
(typically 60% from 4). Reaction of 4c with LTMP yielded
exclusively the 2,3-dichloro derivative in 60% yield
indicating the poor remote directing power of the methoxy
group compared to those of chlorine on pyridine.
4.2. Preparation of starting anisylpyridines
To a mixture of appropriate bromo or chloropyridine
(9 mmol), Ni(acac)2 (120 mg, 0.45 mmol) and dppe
(180 mg, 0.45 mmol) in THF (30 mL) was added dropwise
the appropriate anisylmagnesium bromide (10 mmol) (pre-
pared by dropwise addition of the anisyl bromide (10 mmol)
to a refluxing suspension of Mg turnings (240 mg, 10 mmol)
in THF). The mixture was then stirred for 18 h at room
temperature before hydrolysis with water (20 mL). The
aqueous layer was then extracted twice with diethyl ether,
dried over MgSO4, and evaporated under vacuum. The
crude products were then purified by column chromato-
graphy on silica gel.
In order to demonstrate the usefulness of our methodology
for the synthesis of functional pyridylphenols we examined
the demethylation of some of the prepared derivatives
(Scheme 7). We chose chlorinated compounds, which are
useful precursors for further introduction of diversity. A
clean demethylation was obtained by reaction of 4c, 10b and
11 with BBr3 solutions in CH2Cl2 at room temperature
furnishing the expected phenols in high yields. Finally,
crude phenol 14 was not purified and involved as such in
cyclisation under basic conditions leading to chlorinated
benzofuropyridine 15 in good yield (70%).
4.2.1. 2-(2-Methoxyphenyl)pyridine 1. Column chromato-
graphy (80% hexanes/AcOEt) afforded 1 (1.33 g, 80%) as a
pale yellow oil. Spectrocopic data consistent with that
reported in the literature.10
4.2.2. 2-(3-Methoxyphenyl)pyridine 2.11 Column chroma-
tography (80% hexanes/AcOEt) afforded 2 (1.35 g, 81%) as
a pale yellow oil. dH 3.89 (s, 3H), 6.96 (d, JZ9.0 Hz, 1H),
7.22–7.24 (m, 1H), 7.38 (t, JZ8.0 Hz, 1H), 7.52 (t, JZ
1.4 Hz, 1H), 7.52–7.60 (m, 1H), 7.71–7.75 (m, 2H), 8.68 (d,
JZ4.8 Hz, 1H). dC 55.6, 112.3, 115.4, 119.6, 120.9, 122.5,
130.0, 137, 141.2, 149.9, 157.5, 160.4. m/z (EI) 185 (M,
100), 154 (MK31, 100), 140 (MK45, 22), 126 (MK59, 8),
114 (MK71, 9), 89 (MK96, 4), 63 (MK122, 4%).
4.2.3. 2-(4-Methoxyphenyl)pyridine3.12 Column chromato-
graphy (80% hexanes/AcOEt) afforded 3 (1.41 g, 85%) as a
white solid. Mp 54–55 8C [Lit10a 53–55 8C]. dH 3.89 (s, 3H),
7.02 (d, JZ8.9 Hz, 2H), 7.18 (dd, JZ3.4, 1.4 Hz, 1H),
Scheme 7. (i) BBr3 (5 equiv),CH2Cl2, K78 8C then rt overnight. (ii) K2CO3
(3 equiv), CH3CN, reflux, 5 h.

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M. Parmentier et al. / Tetrahedron 61 (2005) 3261–3269
7.68–7.75 (m, 2H), 7.97 (d, JZ9.0 Hz, 2H), 8.67 (d, JZ
5.3 Hz, 1H). dC 55.7, 114.5, 120.2, 121.8, 128.5, 137, 149.9.
m/z (EI) 185 (M, 100), 170 (MK15, 42), 142 (MK43, 74),
141 (MK44, 56), 115 (MK70, 21), 89 (MK96, 17),78
(MK107, 9), 63 (MK122, 21), 51 (MK134, 14%).
crude products were then purified by column chromato-
graphy with hexane/AcOEt mixture as eluent.
4.3.1. Compound 1b. (522 mg, 85%) was obtained as a
yellow viscous oil after column chromatography (90%
hexanes/AcOEt) as eluents. dH 2.59 (s, 3H), 3.80 (s, 3H), 6.9
(d, JZ8.2 Hz, 1H), 7.0 (d, JZ3.0 Hz, 1H), 7.1 (d, JZ
3.0 Hz, 1H), 7.33 (d, JZ7.2 Hz, 1H), 7.44 (d, JZ7.9 Hz,
1H), 7.6 (d, JZ7.9 Hz, 1H), 7.94 (m, 1H). dC 13.4, 55.8,
111.7, 119.7, 120.7, 121.2, 128.9, 130.2, 131.4, 135.9,
155.4, 157.4, 158.9. m/z (EI) 231 (M, 100), 230 (MK1, 42),
200 (MK31, 48), 198 (MK33, 92), 180 (MK51, 28), 170
(MK61, 40), 154 (MK77, 42), 140 (MK91, 28), 115 (MK
116, 31%). Anal. Calcd for C13H13NOS: C%, 67.50; H%,
5.66; N%, 6.06. Found C%, 67.35; H%, 5.53; N%, 5.84.
4.2.4. 3-(2-Methoxyphenyl)pyridine 4. Column chromato-
graphy (80% hexanes/AcOEt) afforded 4 (1.33 g, 80%) as a
colourless oil. Spectrocopic data consistent with that
reported in the literature.10a,13
4.2.5. 3-(3-Methoxyphenyl)pyridine 5. Column chromato-
graphy (80% hexanes/AcOEt) afforded 5 (1.08 g, 65%) as a
pale yellow oil. Spectrocopic data consistent with that
reported in the literature.14
4.2.6. 3-(4-Methoxyphenyl)pyridine 6. Column chromato-
graphy (70% hexanes/AcOEt) afforded 6 (1.16 g, 70%) as a
white solid. Mp 59–60 8C [Lit10a 60–61 8C]. dH 3.85 (s, 3H),
6.99 (d, JZ8.4 Hz, 2H), 7.32 (dd, JZ7.8, 4.8 Hz, 1H), 7.51
(d, JZ8.5 Hz, 2H), 7.82 (d, JZ7.9 Hz, 1H), 8.55 (s, 1H),
8.82 (s, 1H). dC 55.5, 114.7, 123.7, 128.4, 130.4, 134.0,
148.0, 148.4, 159.9. m/z (EI) 185 (M, 100), 170 (MK15,
40), 142 (MK43, 32), 115 (MK70, 16), 89 (MK96, 10), 63
(MK122, 10%).
4.3.2. Compound 1d.4b (396 mg, 80%, d%O75) was
obtained as a yellow oil after column chromatography
(90% hexanes/AcOEt). dH 3.83 (s, 3H), 6.99 (d, JZ8.3 Hz,
1H), 7.07 (dt, JZ7.3, 0.7 Hz, 1H), 7.17 (d, JZ7.5 Hz, 2H),
7.36 (dt, JZ7.8, 2.1 Hz, 1H), 7.68 (d, JZ7.8 Hz, 1H), 7.81
(dd, JZ7.8, 1.0 Hz, 1H). dC 55.9, 111.7, 125.5, 125.7,
128.6, 128.9, [129.2, 129.4, 129.6], 131.05, 135.9, 149.8,
156.3, 157.3. m/z (EI) 186 (M, 73), 185 (MK1, 100), 156
(MK30, 66), 155 (MK31, 100), 142 (MK44, 12), 128
(MK58, 17), 116 (MK70, 13), 81 (MK105, 58),63 (MK
123, 21%).
4.2.7. 4-(2-Methoxyphenyl)pyridine 7. 4-Chloropyridine
was used as halopyridine. Column chromatography (70%
hexanes/AcOEt) afforded 7 (1.08 g, 65%) as a white solid.
Mp 63–64 8C [Lit10a 63–65 8C]. Spectrocopic data consist-
ent with that reported in the literature.15
4.3.3. Compound 1e. (478 mg, 82%) was obtained as a pale
yellow oil after column chromatography (90% hexanes/
AcOEt). dH 3.88 (s, 3H), 7.01 (d, JZ8.4 Hz, 1H), 7.10 (dt,
JZ7.3, 1.0 Hz, 1H), 7.24 (d, JZ7.8 Hz, 1H), 7.40 (dt, JZ
8.0, 2.1 Hz, 1H), 7.66 (d, JZ7.8 Hz, 1H), 7.84 (dd, JZ7.6,
0.8 Hz, 1H), 7.88 (dd, JZ7.8, 1.8 Hz, 1H). dC 55.9, 111.7,
121.5, 122.4, 123.9, 127.7, 130.9, 131.7, 138.7, 151.1,
156.8, 157.4. MS (EI) m/z: 219 (M, 72), 218 (MK1, 100),
189 (MK30, 28), 154 (MK65, 36), 140 (MK79, 13), 127
(MK92, 15), 114 (MK105, 32%).
4.2.8. 4-(3-Methoxyphenyl)pyridine 8.15 4-Chloropyridine
was used as halopyridine. Column chromatography (50%
hexanes/AcOEt) afforded 8 (0.92 g, 55%) as a pale yellow
oil. Spectrocopic data consistent with that reported in the
literature.15
4.2.9. 4-(4-Methoxyphenyl)pyridine 9. 4-Chloropyridine
was used as halopyridine. Column chromatography (50%
hexanes/AcOEt) afforded 9 (0.75 g, 45%) as a white solid.
Mp 94–96 8C [Lit10a 95–96 8C]. dH 3.88 (s, 3H), 7.03 (d, JZ
8.7 Hz, 2H), 7.48 (d, JZ5.9 Hz, 2H), 7.62 (d, JZ8.6 Hz,
2H), 8.64 (d, JZ5.5 Hz, 2H). dC 55.8, 114.9, 121.5, 128.5,
150.6. MS (EI) m/z: 185 (M, 100), 170 (MK15, 26), 142
(MK43, 34), 115 (MK70, 24), 89 (MK96, 10), 63 (MK
122, 10%).
4.3.4. Compound 1f. (491 mg, 50%) was obtained as a
white solid after recrystallisation in MeOH. Mp 166–
168 8C. dH 3.83 (s, 3H), 6.99 (m, 3H), 7.3–7.5 (m, 11H),
7.55 (dd, JZ7.8, 2.0 Hz, 1H), 7.77 (dd, JZ5.2, 1.8 Hz, 2H).
dC 55.7, 111.5, 121.2, 123.8, 125.9, 128.8, 128.6, 129.0,
130.1, 131.8, 134.2, 136.6. dP K3.30. Anal. Calcd for
C24H20NOP: C%, 78.04; H%, 5.46; N%, 3.79. Found C%,
78.15; H%, 5.43; N%, 3.80.
4.3.5. Compound 2a. (522 mg, 85%) was obtained as a
yellow oil after column chromatography using (90%
hexanes/AcOEt). dH 2.66 (s, 3H), 3.88 (s, 3H), 6.9 (dd,
JZ6.5, 2.4 Hz, 1H), 7.1 (d, JZ7.5 Hz, 1H), 7.37 (d, JZ
7.9 Hz, 1H), 7.42 (d, JZ4.0 Hz, 1H), 7.54 (d, JZ7.9 Hz,
1H), 7.62–7.67 (m, 2H). dC 13.5, 55.6, 112.7, 114.9, 115.9,
119.5, 130.0, 136.7, 140.9, 159.6, 160.7. m/z (EI) 231 (M,
100), 230 (MK1, 62), 185 (MK46, 13), 170 (MK61, 8),
154 (MK77, 9), 142 (MK89, 20), 140 (MK91, 9), 115
(MK116, 10%).
4.3. Procedure for lithiation of anisylpyridines
A solution of 2-dimethylaminoethanol (0.8 mL, 8 mmol) in
hexane or toluene (10 mL) was cooled at 0 8C and treated
dropwise with n-BuLi (10 mL, 16 mmol). After 30 min at
0 8C, a solution of the anisylpyridine (2 mmol for 4 equiv of
n-BuLi LiDMAE or 2.66 mmol for 3 equiv) in hexane or
toluene (5 mL) was added dropwise. After 1 h at appropriate
temperature, the red brown reaction mixture was cooled to
K78 8C and treated with a solution of appropriate
electrophile in THF (20 mL). After 30 min at K78 8C, the
temperature was allowed to raise the room temperature.
The hydrolysis was then performed at 0 8C with H2O. The
aqueous layer was then extracted twice with diethyl ether,
dried over MgSO4, and evaporated under vacuum. The
4.3.6. Compound 2b. (371 mg, 75%, d%O98) was
obtained as a yellow viscous oil after column chromato-
graphy (90% hexanes/AcOEt). dH 3.89 (s, 3H), 6.96 (d, JZ
9.0 Hz, 1H), 7.27 (d, JZ8.8 Hz, 1H), 7.38 (d, JZ8.0 Hz,

M. Parmentier et al. / Tetrahedron 61 (2005) 3261–3269
3267
1H), 7.52 (d, JZ1.4 Hz, 1H), 7.50–7.68 (m, 3H). dC 55.6,
117.3, 120.9, [122.5, 122.8, 123.1], 126.7, 130.7, 133.3,
134.9, 150.1, 158.4, 162.8. m/z (EI) 186 (M, 100), 171 (MK
15, 35), 143 (MK43, 57), 116 (MK70, 15), 90 (MK96,
11), 63 (MK123, 17%).
hexanes/AcOEt). dH 3.89 (s, 3H), 4.69 (d, JZ5.0 Hz, 1H),
5.82 (d, JZ3.5 Hz, 1H), 6.96 (d, JZ7.5 Hz, 1H), 7.02 (d,
JZ8.9 Hz, 2H), 7.28–7.37 (m, 3H), 7.41 (d, JZ7 Hz, 2H),
7.57 (d, JZ7.6 Hz, 1H), 7.63 (d, JZ7.8 Hz, 1H), 8.02 (d,
JZ7.0 Hz, 2H). dC 55.5, 74.9, 114.3, 118.4, 119.2, 127.1,
127.4, 128.0, 128.4, 128.7, 137.8, 143.5, 155.2, 160.4,
160.9. m/z (EI) 291 (M, 100), 214 (MK77, 72), 185 (MK
106, 37), 170 (MK121, 24%).
4.3.7. Compound 2c. (519 mg, 74%) was obtained as a light
brown oil after column chromatography using (90%
hexanes/AcOEt). dH 3.89 (s, 3H), 6.96 (d, JZ9.0 Hz, 1H),
7.39 (dd, JZ7.6, 3.1 Hz, 2H), 7.52 (s, 1H), 7.52–7.57 (m,
2H), 7.65 (d, JZ7.2 Hz, 1H). dC 55.7, 112.6, 115.8, 119.4,
119.6, 126.7, 130.0, 139.1, 142.3, 160.4. m/z (EI) 264 (M,
100), 233 (MK31, 32), 184 (MK80, 7), 169 (MK95, 24),
154 (MK110, 73), 140 (MK124, 67), 127 (MK137, 34),
114 (MK150, 40), 92 (MK172, 32), 77 (MK187, 32), 63
(MK201, 57%), 51 (MK213, 30%). Anal. Calcd for
C12H10BrNO: C%, 54.57; H%, 3.82; N%, 5.30. Found
C%, 54.85; H%, 3.76; N%, 5.06.
4.3.13. Compound 4a. (346 mg, 70%, d%O98) was
obtained as a yellow oil after column chromatography
(90% hexanes/AcOEt). dH 3.84 (s, 3H), 7.03 (d, JZ8.3 Hz,
1H), 7.08 (dt, JZ7.6, 0.8 Hz, 1H), 7.34 (dd, JZ7.8, 1.5 Hz,
2H), 7.39 (dt, JZ7.8, 1.8 Hz, 1H), 7.88 (dd, JZ8.0, 2.3 Hz,
1H), 8.79 (d, JZ1.7 Hz, 1H). dC 55.9, 111.6, 121.4, 123.1,
[127.4, 127.7, 128.0], 129.9, 131.0, 134.6, 137.2, 150.6,
157.0. m/z (EI) 186 (M, 100), 171 (MK15, 51), 116 (MK
70, 30%).
4.3.8. Compound 2d. (600 mg, 78%) was obtained as a
yellow oil after column chromatography (90% hexanes/
AcOEt). dH 3.84 (s, 3H), 6.97 (dd, JZ5.6, 2.7 Hz, 1H), 7.38
(d, JZ7.9 Hz, 1H), 7.51 (d, JZ7.6 Hz, 2H), 7.57–7.66 (m,
3H), 7.96 (d, JZ5.5 Hz, 2H), 8.02 (d, JZ4.1 Hz, 1H), 8.22
(dd, JZ7.0, 1.7 Hz, 2H). dC 55.5, 112.4, 115.7, 122.8,
123.2, 128.2, 130.1, 131.6, 133.0, 136.7, 138.1, 154.8,
160.4. m/z (EI) 288 (MK1, 100), 260 (MK29, 80), 230
(MK59, 14), 105 (MK184, 25), 77 (MK112, 28%). Anal.
Calcd for C19H15NO2: C%, 78.87; H%, 5.23; N%, 4.84.
Found C%, 78.75; H%, 5.35; N%, 4.96.
4.3.14. Compound 4b. (516 mg, 84%) was obtained as a
yellow oil after column chromatography (90% hexanes/
AcOEt). dH 2.60 (s, 3H), 3.81 (s, 3H), 6.98 (dd, JZ8.0,
0.7 Hz, 1H), 7.0 (td, JZ8.0, 1.1 Hz, 1H), 7.21 (dd, JZ8.0,
1.1 Hz, 1H), 7.30 (dd, JZ7.0, 1.9 Hz, 1H), 7.34 (dt, JZ7.0,
1.9 Hz, 1H), 7.69 (dd, JZ6.1, 2.3 Hz, 1H), 8.61 (d, JZ
2.3 Hz, 1H). dC 13.8, 55.9, 111.7, 121.0, 121.5, 127.2,
129.6, 130.7, 137.3, 150.1, 158.5. m/z (EI) 230 (MK1, 100),
198 (MK33, 16), 185 (MK46, 13), 169 (MK62, 8), 115
(MK116, 9%).
4.3.15. Compound 4c. (478 mg, 82%) was obtained as a
yellow oil after column chromatography (90% hexanes/
AcOEt). dH 3.80 (s, 3H), 7.01–7.07 (m, 2H), 7.25–7.41 (m,
3H), 7.82 (dd, JZ8.3, 2.4 Hz, 1H), 8.51 (d, JZ2.4 Hz, 1H).
dC 55.6, 111.5, 121.3, 123.6, 125.7, 130.1, 130.5, 133.3,
139.8, 149.7, 150.1, 156.6. m/z (EI) 221 (MC2, 33), 219
(M, 100), 204 (MK15, 25), 169 (MK50, 20), 168 (MK51,
29), 140 (MK79, 27%).
4.3.9. Compound 3a. (467 mg, 76%) was obtained as a
yellow oil after column chromatography (90% hexanes/
AcOEt). dH 2.66 (s, 3H), 3.87 (s, 3H), 6.99 (d, JZ8.6 Hz,
2H), 7.07 (d, JZ7.9 Hz, 1H), 7.36 (d, JZ8.6 Hz, 1H), 7.51
(d, JZ7.5 Hz, 1H), 8.01 (d, JZ9 Hz, 2H). dC 13.3, 55.5,
114.2, 114.9, 119.4, 128.2, 131.8, 136.6, 156.4, 159.2,
160.7. m/z (EI) 231 (M, 100), 230 (MK1, 62), 185 (MK46,
17), 170 (MK61, 34), 140 (MK91, 11), 115 (MK116,
12%).
4.3.16. Compound 4d. (535 mg, 50%) was obtained as a
white solid after column chromatography using 80:20
hexanes–AcOEt as eluents. Mp 150–151 8C. dH 3.81 (s,
3H), 6.97–7.07 (m, 2H), 7.12 (d, JZ8.3 Hz, 1H), 7.30–7.50
(m, 12H), 7.74 (dd, JZ6.3, 1.7 Hz, 1H), 8.9 (d, JZ2.1 Hz,
1H). dC 55.5, 111.5, 121.3, 126.9, 127.5, 128.7, 128.9,
129.3, 129.9, 130.9, 134.7, 136.59, 136,65, 151.12, 161.7,
161.9. dP K3.69. Anal. Calcd for C24H20NOP: C%, 78.04;
H%, 5.46; N%, 3.79. Found C%, 78.16; H%, 5.44; N%,
3.83.
4.3.10. Compound 3b. (396 mg, 80%, d%O98) was
obtained as a yellow oil after column chromatography
(80% hexanes/AcOEt). dH 3.85 (s, 3H), 7.01 (d, JZ9.0 Hz,
2H), 7.16 (d, JZ6.8 Hz, 1H), 7.65–7.70 (m, 2H), 7.97 (d,
JZ9.0 Hz, 2H). dC 55.7, 114.5, 120.2, [121.8, 122.2, 122.6],
128.5, 137, 149.9. m/z (EI) 187 (MC1, 36), 186 (M, 100),
171 (MK15, 35), 143 (MK43, 57), 116 (MK70, 15), 90
(MK96, 11), 63 (MK123, 17%).
4.3.11. Compound 3c. (553 mg, 90%) was obtained as a
white solid after column chromatography (90% hexanes/
AcOEt). Mp 77–79 8C. dH 3.83 (s, 3H), 6.95 (d, JZ8.9 Hz,
2H), 7.14 (dd, JZ7.1, 1.0 Hz, 1H), 7.53 (dd, JZ8.9, 1.0 Hz,
1H), 7.59 (d, JZ7.5 Hz), 7.93 (d, JZ9.0 Hz, 2H). dC 55.5,
114.4, 117.9, 121.8, 128.6, 139.3, 142.9, 151.4, 157.9,
161.1. m/z (EI) 221 (MC2, 33), 219 (M, 100), 204 (MK15,
17), 176 (MK43, 25), 141 (MK78, 18%). Anal. Calcd for
C12H10ClNO: C%, 65.61; H%, 4.59; N%, 6.38. Found C%,
65.50; H%, 4.60; N%, 6.26.
4.3.17. Compound 5a. (430 mg, 70%) was obtained as a
yellow oil after column chromatography (90% hexanes/
AcOEt). dH 2.60 (s, 3H), 3.85 (s, 3H), 6.91 (dd, JZ8.2,
2.4 Hz, 1H), 7.06 (s, 1H), 7.12 (d, JZ7.6 Hz, 1H), 7.23 (d,
JZ8.2 Hz, 1H), 7.37 (d, JZ7.8 Hz, 1H), 7.68 (dd, JZ8.3,
2.4 Hz, 1H), 8.58 (d, JZ4.8 Hz, 1H), 8.67 (s, 1H). dC 13.5,
55.4, 112.7, 113.2, 119.3, 121.4, 130.3, 132.2, 134.5, 139.2,
147.8, 159.1, 160.2. m/z (EI) 231 (M, 100), 198 (MK33,
27), 185 (MK46, 19), 115 (MK116, 21), 63 (MK168,
12%). Anal. Calcd for C13H13NOS: C%, 67.50; H%, 5.66;
N%, 6.06. Found C%, 67.34; H%, 5.68; N%, 6.09.
4.3.12. Compound 3d. (580 mg, 75%) was obtained as a
yellow viscous oil after column chromatography (90%
4.3.18. Compound 6a. (460 mg, 75%) was obtained as a

3268
M. Parmentier et al. / Tetrahedron 61 (2005) 3261–3269
yellow oil after column chromatography (90% hexanes/
AcOEt). Spectrocopic data consistent with that reported in
the literature.8a,16
4.3.25. Compound 10a. (516 mg, 70%) was obtained as a
yellow oil after column chromatography (90% hexanes/
AcOEt). dH 2.51 (s, 3H), 2.62 (s, 3H), 3.75 (s, 3H), 6.93 (d,
JZ7.9 Hz, 1H), 6.97 (d, JZ8.6 Hz, 1H), 7.01 (d, JZ
7.4 Hz, 1H), 7.19 (d, JZ7.8 Hz, 2H), 7.37 (dt, JZ8.2,
1.6 Hz, 1H). dC 13.7, 13.9, 56.0, 89.3, 111.7, 116.5, 120.9,
126.9, 128.3, 130.2, 131.7, 137.5, 154.4, 157.7, 158.4. m/z
(EI) 277 (M, 80), 246 (MK31, 100), 230 (MK47, 75), 212
(MK65, 32).
4.3.19. Compound 7a. (346 mg, 93%, d%O95) was
obtained as a yellow oil after column chromatography
(80% hexanes/AcOEt). dH 3.83 (s, 3H), 7.04 (dd, JZ8.3,
5.5 Hz, 2H), 7.26–7.43 (m, 3H), 7.47 (s, 1H), 8.62 (d, JZ
3 Hz, 1H). dC 55.7, 111.6, 121.2, 124.4, 127.8, [129.7,
130.2, 130.7], 146.5, 149.7, 156.7. m/z (EI) 186 (M, 100),
171 (MK15, 30), 157 (MK29, 15), 116 (MK70, 38), 63
(MK123, 17%).
4.3.26. Compound 10b. (484 mg, 72%) was obtained as a
yellow viscous oil after column chromatography using
90:10 hexanes–AcOEt as eluents. dH 3.79 (s, 3H), 6.99 (d,
JZ8.4 Hz, 1H), 7.03 (t, JZ7.5 Hz, 1H), 7.18 (dd, JZ7.5,
1.7 Hz, 1H), 7.31 (d, JZ7.8 Hz, 1H), 7.42 (dd, JZ8.4,
1.8 Hz, 3H), 7.59 (d, JZ7.9 Hz, 1H). dC 55.9, 111.5, 120.9,
123.0, 125.7, 130.8, 131.0, 133.3, 142.8, 149.2, 150.1,
156.9. m/z (EI) 255 (MC2, 40), 253 (M, 63), 218 (MK35,
100), 203 (MK50, 72), 140 (MK113, 19%).
4.3.20. Compound 7b. (323 mg, 70%) was obtained as a
yellow oil after column chromatography (90% hexanes/
AcOEt). dH 2.57 (s, 3H), 3.79 (s, 3H), 6.94–7.05 (m, 2H),
7.14 (dd, JZ5.5, 1.7 Hz, 1H), 7.26–7.39 (m, 3H), 8.43 (dd,
JZ5.5, 0.7 Hz, 1H). dC 12.8, 55.7, 111.6, 113.1, 121.5,
124.5, 127.8, 130.3, 130.6, 146.4, 149.7, 156.7, 170.2. m/z
(EI) 231 (M, 100), 198 (MK33, 25), 185 (MK46, 31), 115
(MK116, 33).
4.3.27. Compound 10c. (503 mg, 65%) was obtained as a
yellow oil after column chromatography (90% hexanes/
AcOEt). dH 0.30 (s, 9H), 3.73 (s, 3H), 6.91–6.99 (m, 2H),
7.06 (dt, JZ7.5, 2.0 Hz, 1H), 7.21 (d, JZ8.2 Hz, 1H), 7.35–
7.42 (m, 2H). dCK0.69, 55.3, 110.6, 120.2, 129.8, 131.5,
139.2, 150.2, 157.1. m/z (EI) 291 (M, 20), 276 (MK15, 61),
261 (MK30, 55), 256 (MK35, 90), 246 (MK45,100), 73
(MK218, 71%).
4.3.21. Compound 7c. (404 mg, 65%) was obtained as an
orange oil after column chromatography (80% hexanes/
AcOEt). dH 3.84 (s, 3H), 6.98–7.09 (m, 2H), 7.01 (dd, JZ
7.5, 1.7 Hz, 2H), 7.44 (dd, JZ3.8, 1.4 Hz, 1H), 7.89 (s, 1H),
8.34 (d, JZ5.2 Hz, 1H). dC 55.8, 111.7, 114.3, 121.3, 123.7,
130.5, 130.9, 135.3, 150.3. m/z (EI) 311 (M, 75), 184 (MK
127, 74), 169 (MK142, 100), 140 (MK171, 16). Anal.
Calcd for C12H10INO: C%, 46.33; H%, 3.24; N%, 4.50.
Found C%, 46.52; H%, 3.29; N%, 4.40.
4.3.28. Preparation of 11 by lithiation of 4c with LTMP.
To a solution of TMP (0.58 mL, 3.4 mmol) in THF (5 mL)
cooled at K30 8C was added dropwise n-BuLi (2 mL,
3.2 mmol). The medium was then allowed to warm at 0 8C
for 30 min and cooled at K20 8C. A solution of 4c (219 mg,
1 mmol) in THF (2 mL) was then added drowpise. The red
solution was stirred for 1 h at the same temperature and
cooled at K78 8C. A solution of C2Cl6 (830 mg, 3.5 mmol)
in THF (10 mL) was then added dropwise. The reaction
medium was then allowed to warm to 0 8C and hydrolysed
with H2O (5 mL). The aqueous layer was then extracted
twice with diethyl ether, dried over MgSO4, and evaporated
under vacuum. Column chromatography (90% hexanes/
AcOEt) yielded 11 (538 mg, 80%) as a white solid. Mp
81 8C. dH 3.84 (s, 3H), 7.00 (d, JZ8.3 Hz, 1H), 7.06 (t, JZ
7.4 Hz, 1H), 7.29 (dd, JZ7.6, 1.6 Hz, 1H), 7.40 (dt, JZ8.1,
1.6 Hz, 1H), 7.97 (d, JZ2.1 Hz, 1H), 8.43 (d, JZ2.1 Hz,
1H). dC 55.9, 111.7, 121.6, 124.5, 130.7, 130.8, 134.9,
139.8, 140.2, 147.9, 156.8, 160.1. m/z (EI) 255 (MC2, 66),
253 (M, 100), 238 (MK15, 13), 203 (MK50, 53), 174 (MK
79, 20), 140 (MK113, 16), 63 (MK190, 15%). Anal. Calcd
for C12H9Cl2NO: C%, 56.72; H%, 3.57; N%, 5.51. Found
C%, 56.83; H%, 3.47; N%, 5.43.
4.3.22. Compound 7d. (349 mg, 68%) was obtained as an
orange oil after column chromatography (80% hexanes/
AcOEt). dH 0.82 (t, 3H, JZ7.3 Hz, 1H), 1.56 (s, 3H), 1.81–
1.92 (m, 2H), 5.03 (s, 1H), 3.85 (s, 3H), 7.03 (d, JZ8.3 Hz,
1H), 7.09 (d, JZ7.6 Hz, 1H), 7.36–7.44 (m, 3H), 7.49 (s,
1H), 8.54 (d, JZ5 Hz, 1H). dC 8.53, 29.30, 36.49, 55.95,
74.36, 111.85, 120.27, 121.47, 122.97, 130.59, 130.92,
147.17, 147.70, 156.9, 160.87, 164.89. m/z (EI) 257 (M, 2),
242 (MK15, 15), 228 (MK29, 100), 212 (MK45, 15), 185
(MK72, 10), 170 (MK87, 10), 115 (MK142, 9).
4.3.23. Compound 8a. (370 mg, 80%) was obtained as a
yellow oil after column chromatography (90% hexanes/
AcOEt). dH 2.60 (s, 3H), 3.84 (s, 3H), 6.95 (dd, JZ8.2,
2.5 Hz, 1H), 7.10 (d, JZ1.7 Hz, 1H), 7.16 (dd, JZ5.3,
1.8 Hz, 2H), 7.32–7.35 (m, 2H), 8.46 (d, JZ5.3 Hz, 1H). dC
13.7, 55.7, 113.2, 114.8, 118.0, 119.6, 119.8, 130.5, 139.9,
148.6, 150.1, 160.5, 160.9. m/z (EI) 231 (M, 100), 185 (MK
46, 37), 115 (MK116, 18%). Anal. Calcd for C13H13NOS:
C%, 67.50; H%, 5.66; N%, 6.06. Found C%, 67.39; H%,
5.59; N%, 6.07.
4.4. Procedure for demethylation anisylpyridines
4.3.24. Compound 9a.15 (324 mg, 70%) was obtained as a
yellow oil after column chromatography (90% hexanes/
AcOEt). dH 2.60 (s, 3H), 3.84 (s, 3H), 6.97 (d, JZ8.0 Hz,
2H), 7.15 (d, JZ5.3 Hz, 1H), 7.35 (s, 1H), 7.55 (d, JZ
7.7 Hz, 2H), 8.43 (d, JZ5.3 Hz, 1H). dC 13.8, 55.8, 114.9,
117.5, 118.9, 128.6, 130.6, 148.2, 150.0, 160.7, 161.0. m/z
(EI) 231 (M, 100), 230 (MK1, 63), 185 (MK46, 42), 170
(MK61, 14), 115 (MK116, 22%).
To a solution of appropriate anisylpyridine (1 mmol) in dry
dichloromethane at K78 8C was added dropwise a solution
of boron tribromide (5 mmol, 5 mL of a 1 M solution in
dichloromethane). After addition the mixture was stirred
overnight at room temperature, then treated with water and
extracted with ethyl acetate. The organic layer was then
dried over anhydrous MgSO4, and evaporated under
vacuum.

M. Parmentier et al. / Tetrahedron 61 (2005) 3261–3269
3269
Garrison, D. T.; Gobel, M. J.; Hodson, S. J.; Irving, P. E.
Bioorg. Med. Chem. Lett. 2002, 12, 471–475.
2. Blume, F.; Zemolka, S.; Fey, T.; Kranich, R.; Schmalza, H.-G.
Adv. Synth. Catal. 2002, 344, 868–883.
4.4.1. Compound 12. (165 mg, 80%) was obtained as a
white solid after recrystallisation in dichloromethane. Mp
171–173 8C. dH 7.01– 7.09 (m, 2H), 7.34 (t, JZ7.4 Hz, 1H),
7.43 (d, JZ7.4 Hz, 1H), 7.64 (d, JZ8.3 Hz, 1H), 8.12 (d,
JZ8.3 Hz, 1H), 8.67 (s, 1H), 9.99 (s, 1H). dC 114.6, 118.2,
121.3, 122.3, 128.2, 128.6, 131.9, 138.4, 146.6, 148.0,
152.9. m/z (EI) 207 (MC2, 32), 205 (M, 100), 170 (MK35,
34), 115 (MK90, 22%). Anal. Calcd for C11H8ClNO: C%,
64.25; H%, 3.92; N%, 6.81. Found C%, 64.43; H%, 3.83;
N%, 6.77.
3. Benaglia, M.; Ponzini, F.; Woods, C. R.; Siegel, J. S. Org. Lett.
2001, 3, 967–969.
¨ ¨
4. (a) Bohm, V. P. W.; Weskamp, T.; Gstottmayr, C. W. K.;
Herrmann, W. A. Angew. Chem. Int. Ed. 2000, 39, 1602–1603.
´ ´
(b) Rebstock, A.-S.; Mongin, F.; Trecourt, F.; Queguiner, G.
Org. Biomol. Chem. 2003, 1, 3064–3068.
5. For a review on reactivity of BuLi-LiDMAE see Gros, Ph.;
Fort, Y. Eur. J. Org. Chem. 2002, 20, 3375–3383.
6. Gros, P.; Fort, Y. J. Org. Chem. 2003, 68, 2028–2029.
7. Fort, Y.; Rodriguez, A. L. J. Org. Chem. 2003, 68, 4918–4922.
8. The heat of formations of potential carbanions were performed
with MOPAC using the semi-emprical PM3 method.
9. This kind of dimerisation has been observed previously by
Newkome. A pyridine radical anion was detected by EPR. See
Newkome, G.; Hager, D. J. Org. Chem. 1982, 47, 600–603.
10. (a) Riggio, G.; Hopff, W.; Herbert, H.; Alfred, A.; Waser, P. G.
Helv. Chim. Acta 1983, 66, 1039–1045. (b) Maeyama, K.;
Kobayashi, M.; Yonezawa, N. Synth. Commun. 2001, 31,
869–875.
4.4.2. Compound 13. (200 mg, 84%) was obtained as a
white solid after recrystallisation in dichloromethane. Mp
162–164 8C. dH 7.02– 7.11 (m, 2H), 7.37 (t, JZ7.6 Hz, 1H),
7.50 (d, JZ7.5 Hz, 1H), 8.39 (s, 1H), 8.68 (s, 1H), 10.14 (s,
1H). dC 114.7, 118.3, 119.9, 126.9, 128.8, 133.5, 137.8,
143.7, 146.2, 149.5, 153.1. m/z (EI) 241 (MC2, 58), 239
(M, 100), 204 (MK35, 19), 140 (MK99, 14). Anal. Calcd
for C11H8Cl2NO: C%, 55.03; H%, 2.94; N%, 5.83. Found
C%, 55.21; H%, 2.83; N%, 5.87.
4.4.3. Compound 15. The title compound was prepared as
above described in 90% yield (GC) and dissolved as such in
acetonitrile (10 mL), potassium carbonate was then added
(410 mg, 3 mmol) and the mixture was refluxed for 5 h.
After removal of solvent, the residue was treated with water
and extracted with chloroform. The organic layer was dried
over anhydrous MgSO4, and evaporated under vacuum.
Column chromatography (90% hexanes–AcOEt) yielded 15
(142 mg, 70%) as a white solid. Mp 155–156 8C [Lit.17 150–
157 8C]. dH 7.40–7.45 (m, 2H), 7.54 (dt, JZ7.2, 1.4 Hz,
1H), 7.64 (d, JZ7.2 Hz, 1H), 7.92 (dd, JZ8.6, 2.5 Hz, 1H),
8.20 (d, JZ7.9 Hz, 1H). dC 111.48, 112.7, 119.8, 120.7,
122.2, 124.2, 128.2, 128.9, 131.9. m/z (EI) 205 (MC2, 34),
203 (M, 100), 168 (MK35, 21%), 140 (MK63, 24%). Anal.
Calcd for C11H6ClNO: C%, 64.88; H%, 2.97; N%, 6.88.
Found C%, 64.69; H%, 3.01; N%, 6.77.
11. Gutierrez, M. A.; Newkome, G. R.; Selbin, J. J. Organomet.
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12. Adjabeng, G.; Brenstrum, T.; Wilson, J.; Frampton, C.;
Robertson, A.; Hillhouse, J.; McNulty, J.; Capretta, A. Org.
Lett. 2003, 5, 953–956.
13. Mongin, F.; Mojovic, L.; Guillamet, B.; Trecourt, F.;
Queguiner, G. J. Org. Chem. 2002, 67, 8991–8994.
14. Grayson, N. A.; Bowen, W. D.; Rice, K. C. Heterocycles 1992,
34, 2281–2292.
15. le Gall, E.; Gosmini, C.; Nedelec, J.-Y.; Perichon, J.
Tetrahedron 2001, 57, 1923–1928.
16. Thomas, A. D.; Asokan, C. V. Tetrahedron Lett. 2002, 43,
2273–2276.
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References and notes
1. Bishop, M. J.; Barvian, K. A.; Berman, J.; Bigham, E. C.;