Directed ortho Metalation and
Cross-Coupling of Naphthalene
1,8-bis(diethylamide): Research
Towards Nerve Growth Inhibitors
by
John M.D. Stephenson
jmdsdf@hotmail.com
410-1306
An undergraduate thesis
presented to the Queen’s University
Chemistry Department
in fulfillment of the Chem 417
requirement for the degree of
Engineering Chemistry
in Applied Science
Department of Chemistry
Queen’s University
Kingston, Ontario, Canada
March 29, 2004
Copyright © John M.D. Stephenson
John M.D. Stephenson
March 29, 2004
Acknowledgements
I would like to thank Professor Victor Snieckus for his guidance and supervision in my
work in organic chemistry. It has been an honor to be a part of an excellent team of
individuals as constituted by the members of the Snieckus group.
In particular, I would like to especially thank Chris Jones for his patience, perseverance
and direction in working on my undergraduate thesis. Todd Macklin has also been of
particular help in showing me time saving techniques for getting work done quickly and
efficiently without cutting any corners.
Extra thanks to the entire Snieckus group as the entire experience with the team, both in
the lab and the social dynamics outside of the lab, was thoroughly enjoyable.
i
John M.D. Stephenson
March 29, 2004
Abstract
Work in the synthesis of novel substituted naphthalene amides was motivated by interest in the
preparation of new Nerve Growth Factor inhibitor candidates related to the treatment of arthritis.
Work in our laboratories has recently demonstrated that the Directed ortho Metalation reaction
may be applied to the synthesis of 2- and 2,7- substituted naphthalene 1,8-bis(diethylamide), 1 
2 + 3. The aim of this study was to establish conditions for selective formation of 2 over 3 for E
= I and TMS will be presented. In addition, the Suzuki-Miyaura cross-coupling reaction of 2  4,
where R = phenyl and E=I, will presented.
CONEt2
CONEt2
CONEt2
CONEt2
CONEt2
R
E
1. s-BuLi
-78°C/THF
2. E+
1
RB(OH)2
base/Pd/DMF
2
4
CONEt2
CONEt2
E
E
3
ii
CONEt2
John M.D. Stephenson
March 29, 2004
Table of Contents
Acknowledgements .............................................................................................................. i
Abstract ............................................................................................................................... ii
1.0 Background ................................................................................................................... 1
2.0 Introduction ................................................................................................................... 2
2.1 Directed ortho Metalation (DoM) ............................................................................. 2
2.2 Suzuki-Miyaura Cross-Coupling .............................................................................. 3
3.0 Synthesis of Naphthalenes ............................................................................................ 5
4.0 Results ........................................................................................................................... 6
5.0 Discussion ..................................................................................................................... 8
6.0 Conclusions ................................................................................................................... 9
7.0 Future Direction ............................................................................................................ 9
8.0 Experimental ............................................................................................................... 10
General Procedure A: Standard workup ................................................................... 12
General Procedure B: Directed ortho Metalation ..................................................... 12
General Procedure C: Suzuki-Miyaura Palladium-Catalyzed Cross Coupling ........ 13
naphthalene 1,8-bis(diethylamide) (1) ...................................................................... 13
2-trimethylsilanylnaphthalene 1,8-bis(diethylamide) (2a) ....................................... 14
2-iodonaphthalene 1,8-bis(diethylamide) (2b) ......................................................... 15
2-phenylnaphthalene 1,8-bis(diethylamide) (4) ........................................................ 15
9.0 References ................................................................................................................... 17
iii
John M.D. Stephenson
March 29, 2004
1.0 Background
Work conducted in the Snieckus laboratories to form novel substituted naphthalene
amides was motivated by the study of Ross and coworkers1 who were interested in testing
new Nerve Growth Factor (NGF) inhibitor candidates for the management of pain caused
by pathologies such as arthritis.
NGF consists of two identical 119 subunit long amino acid sequences that form the
proteins quanternary structure. Binding of the NGF occurs at transmembrane
neurotrophin receptor and there exists interest to find novel compounds that bind to, but
do not activate, the receptor. This class of compounds is of great interest as they have
been shown to reduce suffering in patients afflicted with arthritis and NGF is implicated
in other diseases such as Alzheimer’s, epilepsy and stroke.2
Previously identified NGF inhibitors consist of substituted naphthalene imide structures
with an electron-withdrawing group such as a benzoic acid or ethanol moiety on the
imide functionality as shown in Figure 1. Availability of compounds that could be
screened was limited due to commercial availability of the precursors and ease of
preparation of the inhibitor candidates.3
1
John M.D. Stephenson
March 29, 2004
R
O
N
O
for NCP 205
R=
O
OH
for ALE 540
R=
OH
O2N
Figure 1: Previously identified NGF inhibitors
Target naphthalene imides for synthesis are shown in Figure 2. These molecules, a
challenge to prepare by classical methods, could potentially be prepared using Directed
ortho Metelation (DoM) and Suzuki-Miyaura cross-coupling synthetic strategy developed
in the Snieckus group.
EWG
R = H, SMe, I,
O
N
R
O
,
H
O
R
Figure 2: Examples of new target NGF inhibitor candidates
2.0 Introduction
2.1 Directed ortho Metalation (DoM)
Since the initial independent discoveries by Gilman4 and Wittig5 in the late 1930s that
anisole (X) would form an ortho lithiated species, the DoM reaction has become an
influential synthesis for regioselective electrophilic aromatic substitution. Gilman and
2
John M.D. Stephenson
March 29, 2004
Wittig both showed that the lithiated species (Y) could be functionalized to yield orthoanisic acid (Z) by treatment with carbon dioxide as shown in Scheme 1. In the first
published DoM reactions the lithium would coordinate to the methoxy group. The
methoxy group functioned as what is now called a Directed Metalation Group (DMG).
Since then many more DMGs including CONR2, OCONR2 and OCH2OCH3 have been
discovered.6 All of the groups are able to coordinate a lithium ion using a heteroatom
before deprotonation 7 , although recent research states that in some cases that
deprotonation can occur through a one-step metal-hydrogen exchange when TMEDA is
added.8,9 In addition a larger variety of electrophiles, such as TMSCl 10 , iodomethane,
dimethylformamide, B(OiPr)3
11
and trifluoroiodoethane
12
have been successfully
employed to introduce a variety of substituents ortho to the DMG.
OMe
OMe
OMe
n-BuLi
CO2
CO2H
Li
X
Y
Z
Scheme 1: First Directed ortho Metalation as performed by Gilman and Wittig
2.2 Suzuki-Miyaura Cross-Coupling
Carbon-carbon bonds can be formed through a variety of transition metal catalyzed crosscoupling
reactions
including
those
using
organomagnesiums,
organozincs,
organostannanes and organoborons. 13 Suzuki-Miyaura cross-coupling is a palladium
catalyzed process involving organoboron compounds. Suzuki and Miyaura discovered
this reaction in the late 1970s. 14 Original research took place with substituted aryl
3
John M.D. Stephenson
March 29, 2004
bromides and phenylboronic acid in benzene with an equivalent of sodium carbonate
using Pd(PPh3)4 as the catalyst.15 The reaction now includes the reaction of alkenyl16, aryl,
alkynyl, benzyl, allyl or alkyl halides or triflates with an aryl, alkenyl or alkyl boronic
acids or boronate esters in the presence of a base.17
Common
palladium
catalysts
include
the
previously mentioned
palladium(0)
tetrakis(triphenylphosphine) and palladium(II) catalysts such as Pd(dppf)Cl2 (dppf = 1,1bis(diphenylphosphino)ferrocene), Pd(dba)2 (dba = dibenzylideneacetone) and Pd(OAc)2.
The active species is Pd(0) and thus Pd(II) catalysts require reduction to Pd(0) before
they can participate in the catalytic cycle. This reduction will occur in situ by alkylation
with the substrate or by oxidation of the phophine ligands.
The mechanism by which the reaction proceeds is thought to occur via oxidative addition,
transmetalation and finally reductive elimination to give the products as shown in
Scheme 2.
Pd0
R1 R2
R1 X
Oxidative
Addition
Reductive
Elimination
R1 Pd2+X
R1 Pd2+R2
Transmetalation
BX(OH)2 R2 B(OH)2
Scheme 2: Suzuki-Miyaura Cross-Coupling Mechanism
4
John M.D. Stephenson
March 29, 2004
Oxidative elimination is the rate-determining step in the catalytic cycle. The reaction
proceeds fastest and in highest yield in decreasing rate and yield for I>OTf>Br>>Cl. 18
Suzuki-Miyaura cross-coupling is widely used in organic synthesis as the organoboron
compounds are generally not air or water sensitive and the metal byproduct generated is
non-toxic boric acid.
3.0 Synthesis of Naphthalenes
Substitution at the ortho positions in the naphthalene system is a challenge by
conventional electrophilic aromatic substitution. Directed ortho Metalation of some
naphthalene
compounds
has
taken
place.
19
Shimano
and
Meyers
20
used
napththyloxazolines to form 1-[4’-tert-butyloxazolin-2’-yl]naphthalene through DoM.
This intermediate was then used to produce novel β-amino acids.
Furthermore, concurrent substitution at the 2- and 7- positions of the naphthalene system
have been previously reported using DoM in the synthesis of 2,7-diformyl-1,8naphthalenediol 21 for use in forming trinucleating ligand systems. DoM has also
previously been combined with a Suzuki cross-coupling strategy on the naphthalene
system, for example the preparation of 1,8-dihydroxy-2,7-diphenylnaphthalene 22 , a
polydentate ligand for TiCl4. A similar methodology is explored here in.
The model compound selected to explore the DoM techniques of the naphthalene system
was naphthalene 1,8-bis(diethylamide) containing diethylamide, an extensively explored
5
John M.D. Stephenson
March 29, 2004
Directed Metalation Group (DMG). Previous work conducted in the Snieckus
laboratories23 has determined conditions for the formation of 2,7-di- substituted products
of this system.
The focus of this research is to explore producing mono substitution patterns using DoM
and Suzuki cross-coupling strategies. The target compounds are shown in Figure 3. This
research has been part of ongoing studies to establish conditions for selective formation
of 2-mono- substituted products over 2,7-di- substituted products.
CONEt2
CONEt2
O
R = H, Br, I, SMe, TMS,
,
H
R
Figure 3: 2-mono- substituted target molecules
4.0 Results
Metalation of naphthalene 1,8-bis(diethylamide) (1) at –78°C in THF with TMEDA
followed by quench with an electrophile led to the formation of 2,7-di (2) and 2-mono (3)
as well as the recovery of (1) as isolated by flash chromatography (Scheme 3).
6
John M.D. Stephenson
March 29, 2004
Table 1: Directed ortho Metalation Results
Electrophile
1 (%)
2 (%)
3 (%)
TMSCl
38
16 (2a)
25 (3a)
CF3CH2I
18
24 (2b)
35 (3b)
CONEt2
CONEt2
CONEt2
CONEt2
CONEt2
E
1. s-BuLi
E
CONEt2
E
+
-78°C/THF
2. E+
3
1
2
Where E+ = TMSCl or CF3H2I and E = TMS or I
Scheme 3: Directed ortho Metalation of 1
The Suzuki-Miyaura cross-coupling of the 2-iodo substituted naphthalene derivative (2b)
with phenylboronic acid was performed to afford 2-phenylnaphthalene 1,8bis(diethylamide) (4) in quantitative yield (Scheme 4).
CONEt2
CONEt2
CONEt2
CONEt2
I
RB(OH)2
base/Pd/DMF
2b
4
Scheme 4: Suzuki-Miyaura cross-coupling reaction
7
John M.D. Stephenson
March 29, 2004
5.0 Discussion
2-mono substituted naphthalene 1,8-bis(diethylamide) to form 2a and 2b was obtained in
low yield using TMSCl and CF3H2I (38% and 18% respectively).
Deuteration studies have been performed in the Snieckus laboratories on naphthalene 1,8bis(diethylamide) as shown in Figure 4. These results show that a mixture of starting
material (4%), 2-mono- (33%) and 2,7-di- (63%) substituted products are formed when
1.1eq of base, TMEDA and electrophile are used.
Figure 4: MS results of deuterating 1 with 1.1eq of s-BuLi, TMEDA and CD3OD.
The results presented for the introduction of iodo and trimethylsilyl groups also show a
mixture of 2-mono- products and starting material: a mixture consistent with the results
obtained from the deuteration studies.
Attempts at using dimethylformamide to introduce a single aldehyde group and dimethyl
disulfide to introduce a single methylsulfide group proved difficult. The resulting
products could not be separated via flash chromatography. Perhaps the differences in
8
John M.D. Stephenson
March 29, 2004
polarities of the 2,7-di- and 2-mono- substituted compounds are too close to be separated
by the standard 12” column chromatography used.
The quantitative yield obtained for 2-phenylnaphthalene 1,8-bis(diethylamide) (4) is an
excellent result compared to the previous preparation of the 2,7-diphenyl- substituted
product, which took place in a moderate yield of 51%.23
6.0 Conclusions
Mono ortho substituted naphthalene 1,8-bis(diethylamide) have been prepared with with
TMS, iodo and phenyl functional groups using DoM techniques or a DoM/SuzukiMiyaura strategy.
Similar to deuterium studies showing 33% 2-deuterated and 63% 2,7-dideuterated
naphthalene derivatives with 1.1eq of s-BuLi and 1.1eq of TMEDA, the preceding results
also show a mixture of mono- and di- substituted products in similar ratios.
7.0 Future Direction
More work should be done in optimizing the reaction conditions that could be used to
provide a higher yield of 2-mono- substituted products.
9
John M.D. Stephenson
March 29, 2004
Directed Remote Metalation (DReM) has become an important synthetic utility for its
ability to create five-membered ring systems, such as fluorenones24 and pharmaceuticals
such as Raloxifene.25 Previously in the Snieckus laboratories a fluorenone derivative (X)
has been obtained from the 2,7-diphenyl naphthalene (Y) in 39% yield23 (Scheme 5).
O
CONEt2
CONEt2
CONEt2
LDA
X
-10°C to rt
36h
Y
Scheme 5: Synthesis of a fluorenone
In the future it would be interesting, as a proof of concept, to perform a similar DreM
reaction on 4 (Scheme 6).
O
CONEt2
CONEt2
CONEt2
LDA
4
-10°C to rt
36h
Scheme 6: Potential formation of a fluorenone using DReM
Now that the methodology to create 2-mono- substituted products has been confirmed by
the results presented in this work, it would be extremely exciting to go forward and attach
imides to the naphthalene derivatives—to form potential, but untested, NGF inhibitors.
10
John M.D. Stephenson
March 29, 2004
8.0 Experimental
Uncorrected melting points were established using a Fischer Scientific hot stage
apparatus. 1H NMR (300 MHz) spectra were obtained on a Bruker AV-300 machine in
deuterated chloroform (CDCl3). 1H NMR (400 MHz) were obtained on a Bruker AV-400
machine using CDCl3. In reporting NMR spectra, the following acronyms were used to
designate the multiplicity peaks: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet.
Gas chromatography with mass spectroscopy (GC/MS) data was obtained on a Varian
Chrompack Saturn GC/MS 2000 as well as a Agilent Technologies Network GC System
coupled with a S973 inert MS detector using a 7683 series autosampler and injector. Thin
Layer Chromatography (TLC) analysis was performed on SiliCycle aluminum backed
ultra pure silica gel TLC plates. Whatman qualitative 150mm filter paper was employed
for gravity filtration. A Büchi Rotavapor R-114 with a Büchi Waterbath B-480 was used
prior to high-vacuum to fully remove solvents from the products.
Tetrahydrofuran (THF) [CAS #109-99-9] was purified through distillation under an argon
atmosphere from sodium benzophenone ketyl. All other dry solvents were purchased
from Aldrich Chemical Company and were at least 99.9% pure and anhydrous. Secbutyllithium (s-BuLi) [CAS #598-30-1] as a solution of in cyclohexane was also
purchased from Aldrich. The s-BuLi was stored in a sealed glass bottle using a rubber
septum to prevent contact with the atmosphere. The concentration of the solution was
periodically checked titrated using sec-butanol [CAS #78-92-2] using 1,10phenanthroline [CAS #12678-01-2] as an indicator. All reactions were carried out under
an argon atmosphere in oven or flame dried borosilicate glassware using syringe-septum
11
John M.D. Stephenson
March 29, 2004
techniques to transfer reagents where applicable. Using a dry-ice acetone bath to form a
slurry, cryogenic temperatures of approximately -78°C were obtained to carry out the
directed ortho metalation and the addition of electrophiles. Internal temperatures of the
reaction flasks were determined using a Barnant Dual J stainless steel-sheathed
thermocouple.
N,N,N',N'-tetramethylethylenediamine
(TMEDA)
and
dried
over
potassium hydroxide prior to use. All other commodity chemicals were also purchased
from Aldrich unless otherwise mentioned.
General Procedure A: Standard workup
The phrase “standard workup” as referred to in the following experimental refers to
extracting three times with an equal volume of ethyl acetate. The organic layer is then
dried with anhydrous sodium sulfate, gravity filtered and concentrated on the rotary
evaporator.
General Procedure B: Directed ortho Metalation
1 was dissolved in anhydrous THF at a concentration of 0.1M in a flame-dried round
bottom flask containing a magnetic stirbar. TMEDA [CAS #110-18-9] was then
introduced, also at a concentration of 0.1M. The solution was cooled to -78°C and a
thermocouple was used to monitor the internal temperature of the reaction. Magnetic
stirring was started. Without allowing the solution to rise above a temperature of -70°C a
solution of s-BuLi in cyclohexane was added dropwise. It continued to stir for 45mins
before the addition of the appropriate electrophile, again ensuring that the temperature
12
John M.D. Stephenson
March 29, 2004
did not rise above -70°C. The solution was then stirred for a further 45 minutes and the
resulting post-reaction solution was allowed to warm to room temperature, followed by
the addition of a saturated aqueous solution of ammonium chloride. Finally the product
was concentrated via the “standard workup” as outlined in General Procedure A.
General Procedure C: Suzuki-Miyaura Palladium-Catalyzed Cross Coupling
To a Schlenk tube containing the halogenated compound, dimethylformamide, K3PO4
and the boronic acid was added Pd(PPh3)4 using glove bag techniques. The Schlenk tube
was degassed at least 4x to remove any oxygen from the solvent. The reaction was heated
to 150°C until the reaction was completed as monitored by GC/MS. The reaction was
allowed to cool to room temperature and three equal parts of distilled water was added to
the reaction mixture. The product was concentrated via the “standard workup” as outlined
in General Procedure A.
naphthalene 1,8-bis(diethylamide) (1)
1 was prepared by Jones23 through reacting diethylamine [CAS
CONEt2
CONEt2
#109-89-7] with naphthalene-1,8-dicarbonyl chloride dissolved in
dichloromethane
and
triethylamine.
The
naphthalene-1,8-
dicarbonyl chloride, itself, was also prepared using a literature
procedure26 via reacting commercially available 1,8-naphthalic anhydride [CAS #81-845] from Aldrich and phosphorus pentachloride [CAS #10026-13-8] using phosphorous
oxychloride [CAS #10025-87-3] as a solvent. The product was purified using flash (1:1
13
John M.D. Stephenson
March 29, 2004
EtOAc:hexanes) and its identity verified using IR, NMR and MS. The reaction scheme is
shown below in Scheme 7.23
O
O
COCl
O
CONEt2
COCl
PCl5
Et2NH
POCl3
reflux
3 days
NEt3
Stir overnight
CONEt2
Scheme 7: Synthesis of bis(diethylamide) starting material
2-trimethylsilanylnaphthalene 1,8-bis(diethylamide) (2a)
CONE t2
General Procedure B was conducted using the following
CONE t2
TMS
materials: 0.326g 1 (1mmol, 1eq), 0.86ml (1.1mmol, 1.1eq)
1.04M s-BuLi in cyclohexane, 0.14mL (1.1mmol, 1.1eq)
chlorotrimethylsilane (TMSCl) [CAS #75-77-4] and 5ml THF.
Flash chromatography (2:1 EtOAc:hexanes), gave 2a (0.0652g, 16%) as a white
compound. NMR (300MHz, CDCl3) 7.86-7.84 (d, J=8.3 Hz, 2H), 7.71-7.69 (d, J=8.3
Hz, 1H), 7.52-7.47 (t, J=7.1 Hz, 1H), 7.38-7.35 (dd, J=1.3, 7.0 Hz, 1H), 3.95-3.73 (m,
2H), 3.47-3.18 (m, 2H), .99-2.91 (m, 4H),.33-1.28 (t, J=7.3 Hz, 6H),0.89-0.83
(m, 6H),0.37 (s, 9H). MS m/z (rel. intensity) 398 (M+, 6), 326 (62), 298 (36), 282 (42),
252 (100), 72 (41).
14
John M.D. Stephenson
March 29, 2004
2-iodonaphthalene 1,8-bis(diethylamide) (2b)
CONEt2
CONEt2
I
General Procedure B was conducted using the following materials: 0.326g 1 (1mmol,
1eq), 0.83mL (1.1mmol, 1.1eq) 1.32M s-BuLi in cyclohexane, 0.11ml (1.1mmol, 1.1eq)
2-iodo-1,1,1-trifluoroethane [CAS #353-83-3] and 5ml THF. Flash chromatography (6:4
EtOAc:hexanes) gave 2b (0.1066g, 24%) as a white compound. NMR (400MHz, CDCl3)
7.90-7.88 (d, J=8.6 Hz, 1H), 7.82-7.80 (dd, J=1.3, 8.1 Hz, 1H), 7.52-7.48 (m, 2H),
7.34-7.32 (dd, J=1.3, 7.1 Hz, 1H), -3.98 (m, 1H), 3.86-3.78 (m, 1H), .33-3.24
(m, 1H), 3.19-3.07 (m, 5H), .38-1.34 (t, J=7.2 Hz, 3H),.33-1.29 (t, J=7.2 Hz,
3H),.18-1.15 (t, J=7.2 Hz, 3H),1.00-0.96 (t, J=7.2 Hz, 3H). MS m/z (rel. intensity)
452 (M+,18), 379 (36), 352 (48), 306 (37), 252 (100), 72 (55).
2-phenylnaphthalene 1,8-bis(diethylamide) (4)
General Procedure C was conducted using the
CONEt2
CONEt2
following materials: 0.117g 3 (0.259mmol, 1eq),
0.030g
Pd(PPh3)4
(0.0259mmol,
0.1eq),
0.038g
phenylboronic acid (0.311mmol, 1.2eq) [CAS #98-806], 0.158g K3PO4 (0.746mmol, 2.4eq), 5ml DMF. Flash chromatography (6:4
EtOAc:hexanes) gave 0.107g 4 (0.259mmol, 100%) as a colorless oil. NMR (400MHz,
15
John M.D. Stephenson
March 29, 2004
CDCl3) 7.91-7.86 (t, J=9.7 Hz, 2H), 7.56-7.54 (d, J=6.7 Hz, 2H), 7.49-7.47 (d, J=8.9
Hz, 2H), 7.39-7.33 (d, J=7.4 Hz, 4H), 3.85-3.79 (q, J=6.7 Hz, 2H), 3.46-3.37 (q,
J=7.5 Hz, 1H), 3.31-3.23 (m, 2H), 3.12-3.01 (m, 1H), 2.85-2.74 (q, J=6.9 Hz,
2H),1.33-1.30 (t, J=7.2 Hz, 3H), 1.14-1.11 (t, J=7.2 Hz, 3H),0.76-0.72 (t, J=7.2 Hz,
3H),0.69-0.65 (t, J=7.2 Hz, 3H). MS m/z (rel. intensity) 402 (M+,28), 330 (100), 302
(89), 258 (63), 202 (59), 72 (79).
16
John M.D. Stephenson
March 29, 2004
9.0 References
1
Marone, S.; Ross, G. 2000, World Patent No. WO0069829.
2
Shamovsky, I.L.; Ross, G.M.; Riopelle, R.J.; Weaver, D.F.; J. Am. Chem. Soc. 1999,
121(42), 9797-9806.
3
Jones, C.; Ross, G. Personal communication.
4
Gilman, H.; Bebb, R. J. Am. Chem. Soc. 1939, 61, 109-112.
5
Wittig, G.; Fuhrmann, G. Chem. Ber. 1940, 73, 1197.
6
Snieckus, V. Chem. Rev. 1990, 90, 879-933.
7
Stratakis, M. J. Org. Chem. 1997, 62, 3024-3025.
8
Whisler, M.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem. Int. Ed. 2004, 43, 2-21.
9
Anderson, D.; Faibish, N.; Beak, P. J. Am. Chem. Soc. 1999, 121, 7553-7558.
10
MacNeil, S.; Familoni, O; Snieckus, V. J. Org. Chem. 2001, 66, 3662-3670.
11
Hartung, C.; Fecher, A.; Chapell, B.; Snieckus, V. Org. Lett. 2003, 5, 1899-1902.
12
Blackmore, I.; Boa, A.; Murray, E.; Michael, D.; Woodward, S. Tet. Lett. 1999, 40,
6671-6672.
13
Diederich, F. and Stang, P.J. Metal Catalyzed Cross-coupling Reactions. J. Wiley &
Sons, Weinheim.
14
Miyaura, N.; Yamada, K., Suzuki, A. Tet. Lett. 1979, 20, 3437-3440.
15
Miyaura, N.; Suzuki, A. Chem. Commun. 1979, 866.
16
Chang, H.; Young, M. Bull. Korean Chem. Soc. 2002, 23, 663-664.
17
Suzuki, A. Pure Appl. Chem. 1991, 63, 419-422.
17
John M.D. Stephenson
18
March 29, 2004
Smith, G.B.; Dezeny, G.C.; Hughes, D.L.; King, A.O., Verhoeven, T.R.; J. Org. Chem.
1994, 59, 8151-8156.
19
Gant, T.G.; Meyers, A.I. Tetrahedron. 1994, 50, 2297-2360.
20
Shimano, M; Meyers, A.I. J. Am. Chem. Soc. 1994, 116, 6437-6438.
21
Glasser, T.; Liratzis, I. Synlett. 2004, 4, 735-737.
22
Poirier, M.; Simard, M.; Wuest, J. D. Organometallics. 1996, 15, 1296-1300.
23
Jones, C.; Snieckus, V. Unpublished results.
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