Palladium-catalyzed cross-coupling reactions of paramagnetic vinyl bromides and paramagnetic boronic acids

Article abstract of DOI:10.1055/s-2006-926279

Suzuki reactions are utilized for the synthesis of heterobifunctional cross-linking reagents (thiol- or aminospecific and photoactivatable), polyaromatics (such as phenanthrene) and heterocycles (such as coumarin and quinoline), anellated nitroxides and p

Full text of DOI:10.1055/s-2006-926279

PAPER
439
Palladium-Catalyzed Cross-Coupling Reactions of Paramagnetic Vinyl
Bromides and Paramagnetic Boronic Acids
P
alladium-Catal
a
yze
d
Cross
m
-
Coupling Reaction
á
s
s Kálai,a József Jekő,b Zoltán Berente,c Kálmán Hideg*a
a
Institute of Organic and Medicinal Chemistry, University of Pécs, P. O. Box 99, 7602 Pécs, Hungary
Fax +36(72)536219; E-mail: kalman.hideg@aok.pte.hu
b
c
ICN, Hungary, P.O. Box 1, 4440 Tiszavasvári, Hungary
Institute of Biochemistry and Medical Chemistry, University of Pécs, P. O. Box 99, 7602 Pécs, Hungary
Received 25 July 2005; revised 18 August 2005
Dedicated to Prof. Ernõ Brücher on the occasion of his 70th birthday
of cross-coupling reactions to paramagnetic vinyl halo-
genides to obtain new spin labels, double (spin and fluo-
Abstract: Suzuki reactions are utilized for the synthesis of hetero-
bifunctional cross-linking reagents (thiol- or aminospecific and
photoactivatable), polyaromatics (such as phenanthrene) and het-
erocycles (such as coumarin and quinoline), anellated nitroxides
rescence) sensor molecules with
a
polyaromatic
fluorophore, paramagnetically modified bioactive mole-
and paramagnetic, biologically active molecules (such as cis-stil- cules, and new paramagnetic boronic acid esters.
bene and nicotinamide). Furthermore, the synthesis of new vinyl
In the cross-coupling spin-label reagent synthesis b-bro-
and allyl boronic acid esters is also reported.
mo-a,b-unsaturated ester 113 reacted with 4-benzoyl-
Key words: boron, cross-coupling, free radicals, heterocycles, pal-
phenylboronic acid under N2 in aqueous dioxane in the
ladium
presence of Na2CO3 base and Pd(PPh3)4 as catalyst to give
compound 2a. The introduction of the benzophenone
group makes this reagent photoactivatable at 350 nm. Es-
ter 2a was hydrolyzed to acid 2b, which was converted
into succinate 2c with DCC and N-hydroxysuccinimide.
This means that 2c is a cross-linking reagent with an ami-
no-specific and with a photoactivatable arm. Reaction of
compound 1 with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenol under the above conditions directly gave
A variety of applications of stable nitroxide free radicals
has been described to date. The most important ones are
spin-labelling,1 utilization as a co-oxidant,2 as double (flu-
orescent and spin) sensor reagent,3 as building blocks of
organic magnets4 and oxymmetry reagents,5 just to men-
tion a few.
Today, most of these applications require properly de- paramagnetic coumarin 3 as a result of the Suzuki cross-
signed stable nitroxide free radicals; however, the forma- coupling reaction followed by a base-catalyzed transester-
tion of the carbon–carbon bond is often a troublesome ification reaction. The Suzuki reaction of alcohol 4 with 4-
reaction in the presence of a nitroxide free radical moiety. benzoylphenylboronic acid gave compound 5a in which
Several methods have been reported from our and other the alcohol substituent was converted into bromide 5b via
laboratories, such as Grignard reaction,6 Wittig reaction,7 its mesylate. This bromide was replaced with SSO2CH3,
aldol condensation,8 Michael addition9 and Diels–Alder which is a thiol-specific arm, forming a cleavable S–S
reaction.10 Recently, we have found that the palladium- bond with a cysteine side-chain,16 meaning that com-
catalyzed cross-coupling reactions11 can be accomplished pound 5c can be regarded as a thiolspecific and photoac-
under mild conditions and tolerate a wide variety of func- tivatable cross-linking spin-label reagent. It can be
tional groups including the nitroxide moiety. This obser- utilized in a similar way as the earlier published cross-
vation was important because the application of linking reagent with an aromatic azide (photoactivatable
palladium-catalyzed cross-coupling reactions increases arm) and with a methanethiosulfonate (thiolspecific
exponentially. We were able to underline this tendency12 arm)17 (Scheme 1).
also in nitroxide chemistry by showing the possibility of
synthesizing a variety polysubstituted nitroxides. The
only prerequisite of this cross-coupling reaction is the
Continuing our earlier work on heterocycle-anellated ni-
troxides, aldehyde 6 was treated with 2-(4,4,5,5-tetrame-
thyl-1,3,2-dioxaborolan-2-yl)aniline in the presence of an
synthesis of paramagnetic vinyl halogenides available
aqueous Na2CO3/dioxane solution and Pd(PPh3)4 as cata-
from the Favorskii reaction13 or from the oxidation of hy-
lyst, giving quinoline derivative 7 in a one-pot procedure
drazones.14 The other challenge in this field was the syn-
with an imine formation and Suzuki cross-coupling reac-
thesis of a paramagnetic boronic acid15 in order to couple
tion.18 It is interesting to note that heating aniline with
the paramagnetic boronic acid with any aryl, vinyl, or
hetaryl halogenides. In this paper we extend the utilization
compound 6 in DMF gave isoquinoline 8 which is an iso-
mer of compound 7.19 Reaction of b-bromo-a,b-unsatur-
ated nitrile
9
with 2-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)aniline in the presence of Cs2CO3, ami-
noadamantane bases and Pd(OAc)2 as catalyst gave the
SYNTHESIS 2006, No. 3, pp 0439–0446
Advanced online publication: 11.01.2006
DOI: 10.1055/s-2006-926279; Art ID: P10305SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
6
paramagnetic
(Scheme 2).
2-aminoquinoline20
derivative
10

440
T. Kálai et al.
PAPER
O
ratio). Vinyl bromide 12 was converted into O-acetyl-pro-
tected (to avoid O-butylation) derivative 14.21 Treatment
of compound 14 with n-BuLi22 at –78 °C afforded the 3-
lithiopyrroline whose reaction with trimethylborate gave
the corresponding boronic acid. After the oxidation of the
nitroxide, the formed boronic acid was not purified, but
after isolation it was converted into its pinacolate ester 15
with pinacol alcohol in the presence of MgSO4 in
MeOH.23 Suzuki reaction of dibromide 11 and 1-naphth-
ylboronic acid in a sealed tube in the presence of DBU as
base and Pd2(dba)3 as catalyst furnished paramagnetic cy-
clopent[a]acenaphthylene 16.24 Our next polyaromatic
target was phenanthrene. The Suzuki cross-coupling of
bromide 12 and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)aniline in the presence of Pd(PPh3)4 as catalyst
provided amine 17. Diazotation of the aromatic amide and
heating of an aqueous solution of the diazonium salt in the
presence of Cu powder gave phenanthrene-anellated ni-
troxide 18 in a Pschorr reaction (Scheme 3).18
O
Br
CO2Et
Q
a
N
N
O
O
2
a
Q
1
OC2H5
c
O
O
b
b
c
OH
O
N
d
O
N
O
5
a
X
O
OH
e
O
3
b
c
Br
f
SSO2CH3
X
Br
OH
a
N
N
O
O
O
B
O
4
Br
5
c
Scheme 1 Reagents and conditions: (a) 4-Benzoylphenylboronic
acid (1 equiv), Pd(PPh3)4 (0.05 equiv), dioxane/aq Na2CO3, under N2,
N
O
N
4
h, 53–68%; (b) 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-
OAc
yl)phenol (1.1 equiv), Pd(PPh3)4 (0.05 equiv), dioxane/aq Na2CO3,
under N2, 2 h, 76%; (c) NaOH/MeOH, reflux, 1 h, then r.t., 12 h, H+,
78%; (d) N-Hydroxysuccinimide (1 equiv), DCC (1 equiv), EtOAc,
r.t., 3 h, 55%; (e) MsCl (1.1 equiv), Et3N (1.1 equiv), CH2Cl2, 0 °C →
r.t., 1 h, then LiBr, acetone, reflux, 30 min, 49%; (f) NaSSO2CH3 (2.0
equiv), acetone–H2O, reflux, 45 min, 62%
14
15
b
Br
Br
Br
a
+
N
N
N
O
N
O
13
O
11
O
12
Br
O
d
e
a
N
7
H2N
b
N
O
N
O
f
6
N
8
N
N
O
N
O
O
O
N
Br
CN
16
18
17
c
Scheme 3 Reagents and conditions: (a) Phenylboronic acid (1
equiv), PdCl2(PPh3)2, (0.05 equiv), Ba(OH)2·9H2O (1 equiv), diox-
ane–H2O, reflux, 2 h, under N2, 24% for 12 and 20% for 13; (b)
Ascorbic acid (10 equiv), dioxane–H2O, then extraction, AcCl (1.1
equiv), Et3N (1.1 equiv), 0 °C → r.t., 1 h, 55%; (c) n-BuLi (2 equiv),
THF, –78 °C, then B(OMe)3 (1.1 equiv), –78 °C → r.t., 2 h, then
MeOH, H2O, r.t., 12 h, extraction, MnO2 (0.1 equiv), 15 min, then
azeotropic dry pinacol, (1.2 equiv), MgSO4, MeOH, 12 h, 33%; (d) 1-
Naphthylboronic acid (1.1 equiv), DBU (1.0 equiv), Pd2(dba)3 (0.25
equiv), P(Cy)3 (0.6 equiv), DMF, sealed tube, 48 h, 150 °C, 29%; (e)
2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.1 equiv),
Pd(PPh3)4 (0.05 equiv), dioxane/aq Na2CO3, under N2, 2 h, 61%; (f)
NaNO2 (1.1 equiv), aq 1 M HCl, 0 °C, 30 min, then Cu powder/H2O,
60 °C, 40 min, 27%
N
N
NH2
O
10
9
Scheme 2 Reagents and conditions: (a) 2-(4,4,5,5-Tetramethyl-
1,3,2-dioxaborolan-2yl)aniline (1.1 equiv), Pd(PPh3)4 (0.05 equiv),
dioxane/aq Na2CO3, under N2, 2 h, 38%; (b) Aniline (1.1 equiv),
DMF, 80 °C, 3 h, 56%; (c) 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaboro-
lan-2-yl)aniline (1.1 equiv), Pd(OAc)2 (0.05 equiv), 1-adamantane-
amine (0.4 equiv), Cs2CO3 (2.2 equiv), dioxane, 16 h, 45%
Reaction of dibromide 11 with one equivalent of phenyl-
boronic acid gave a mixture of compounds 12 and 13 (2:3
Synthesis 2006, No. 3, 439–446 © Thieme Stuttgart · New York

PAPER
Palladium-Catalyzed Cross-Coupling Reactions
441
Starting from 4-oxo-TEMPO (19) we synthesized its 4- NaOH29 yielded alcohol 26,10 which we prepared more
iodo-1,2,3,6-tetrahydropyridine derivative.25 Treatment economically earlier. The addition of bis(pinacolato)dibo-
of the starting ketone with hydrazine hydrate followed by ron to asymmetric diene 2730 afforded pinacolate ester 28.
1
oxidation with iodine in diethyl ether in the presence of This 1,2-addition was proven by H NMR spectroscopy
tetramethyl guanidine (TMG) yielded compound 20. Un- studies on the O-acetyl derivative of 28. The assumed ar-
fortunately, our attempt to obtain the six-membered para- rangement of protons was confirmed by mononuclear de-
magnetic boronic acid failed when the O-acetyl-protected coupling experiments: selective irradiation of the CH
derivative of 20 was treated with n-BuLi followed by triplet (d = 1.79 ppm) only resulted in the change of the
B(OMe)3. Therefore, compound 21 could be produced CH2 multiplet (d = 1.03 ppm). This proton arrangement is
only in a reaction of compound 20 with bis(pinacolato)di- true only for the 1,2-addition product. The addition of
boron and PdCl2(dppf) as catalyst and KOAc as base in bis(pinacolato)diboron to paramagnetic terminal acety-
DMSO,26 but only in low (28%) because of the formation lene 29 in DMF catalyzed by Pt(PPh3)4 afforded com-
of biradical 22. Compound 21 was used for paramagnetic pound 30.31 A Suzuki reaction of this bis(vinylboronic
modification of 5-bromo-nicotinamide in a Suzuki reac- acid) and 4-bromophenol provided paramagnetic Z-hy-
tion under the conditions used above, i.e. refluxing boron- droxystilbene compound 31 (Scheme 5). The importance
ic acid 21 with 5-bromo nicotinamide in an aqueous of this type of compound is well supported by the fact that
Na2CO3/dioxane solution in the presence of Pd(PPh3)4 as several hydroxylated stilbenes exhibit important biologi-
catalyst (Scheme 4).
cal properties.32
In conclusion, Suzuki reactions can be accomplished with
paramagnetic vinyl halogenides in synthetic target-orient-
ed syntheses to create heterocycles, carbocycles, anellated
nitroxides as well as cross-linking spin-label reagents.
Paramagnetic boronic acids can be applied in C–C bond
forming reactions in the presence of a great variety of
functional groups which are retained to obtain bioactive
paramagnetic molecules.
I
O
a
N
O
N
O
20
19
b
O
N
Melting points were determined with a Boetius micro melting point
apparatus and are uncorrected. Elemental analyses (C, H, N, S)
were performed on Fisons EA 1110 CHNS elemental analyzer. The
IR (Specord 85) spectra were in each case consistent with the as-
signed structure. Mass spectra were recorded on Thermoquest Au-
O
O
B
+
1
tomass Multi and VG TRIO-2 instruments in EI mode. H NMR
N
O
spectra were recorded on a Varian UNITYINOVA 400 WB spectrom-
eter. Chemical shifts are referenced to Me4Si. Measurements were
run at 298K-probe temperature in CDCl3 solution. To obtain high-
resolution NMR spectra of the radicals those compounds were re-
duced by co-dissolved PhNHNHPh additive. ESR spectra were tak-
en on a Miniscope MS 200 in 10–4 M CHCl3 solution. All
monoradicals gave triplet lines between aN = 14.7–15.1 G whereas
biradical 22 gave a quintet line at aN1 = 15.2 G, aN2 = 7.4 G. Flash
column chromatography was performed on Merck Kieselgel 60
(0.040–0.063 mm). Qualitative TLC was carried out on commer-
cially prepared plates (20 × 20 × 0.02 cm) coated with Merck Kie-
selgel GF254. 4-Benzoylphenylboronic acid, 2-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)aniline, 2-(4,4,5,5-tetramethyl-1,3,2-di-
oxaborolan-2-yl)phenol, 1-naphthyl boronic acid, compound 19 as
well as palladium and platinum catalysts were purchased from Ald-
rich. Compounds 1, 4, 6, 9,33 11, 13,11 24, 26, 2910 and 2730 were
prepared according to published procedures.
N
O
22
21
O
c
N
CONH2
N
23
Scheme 4 Reagents and conditions: (a) N2H4·H2O (6 equiv), EtOH,
r.t., 3 h, then reflux, 1 h, H2O–CHCl3 extraction, PbO2 (0.1 equiv), O2,
30 min, then TMG (3.5 equiv), I2 (2.2 equiv), Et2O, 1 h, r.t., 59%; (b)
Bis(pinacolato)diboron (1.1 equiv), PdCl2(dppf) (0.05 equiv), KOAc
(3 equiv), DMSO, 80 °C, 3 h, under N2, 28% for 21 and 65% for 22;
(c) 5-Bromonicotinamide, Pd(PPh3)4 (0.05 equiv), dioxane/aq
Na2CO3, under N2, 2 h, 39%
Suzuki Coupling Reaction (2a, 3, 5a, 7, 17, 23, 31); General Pro-
cedure
A solution of vinylic bromide (1, 4, 6, 12, 5-bromonicotinamide, or
4-bromophenol) (2.0 mmol) and Pd(PPh3)4 (100 mg, 0.1 mmol) in
dioxane (10 mL) was purged with N2 for 5 min. Then boronic acid
or boronic acid ester (2.0 mmol, for 31 only 1.0 mmol diester) was
added followed by aq Na2CO3 (10%, 10 mL). The mixture was
An interesting approach for allyl boronic acid is the addi-
tion reaction of bis(pinacolato)diboron to alkenes in tolu-
ene in the presence of Pt(PPh3)4 as catalyst.27 In a 1,4-
addition reaction symmetrical paramagnetic diene 24 stirred and heated to reflux under N2 until the consumption of the
starting halogen compound (2–8 h, followed by TLC). After cool-
gave bis(boronic acid ester) 25. Our attempts to use the al-
lyl boronic ester compound for a C–C bond formation28
ing, the dark-yellow or brown solution was evaporated in vacuo,
brine (10 mL) was added and the aqueous phase was washed with
failed; however, oxidation with H2O2 in the presence of
CHCl3 (2 × 20 mL). The organic phase was dried (MgSO4), filtered
Synthesis 2006, No. 3, 439–446 © Thieme Stuttgart · New York

442
T. Kálai et al.
PAPER
O
O
O
O
B
B
HO
OH
a
b
N
O
N
O
N
O
25
24
26
O
O
B
O
O
B
a
N
N
O
O
28
27
OH
HO
O
O
B
O
O
B
d
c
N
O
N
N
O
O
29
30
31
Scheme 5 Reagents and conditions: (a) Bis(pinacolato)diboron (1 equiv), Pt(PPh3)4 (0.05 equiv), toluene, reflux, 5 h, under N2, 38–63%; (b)
30% H2O2, aq NaOH, MeOH, reflux 2 h, 67%; (c) Bis(pinacolato)diboron (1 equiv), Pt(PPh3)4 (0.05 equiv), DMF, 80 °C, 24 h, under N2, 42%;
(d) 4-Bromophenol (2.0 equiv), Pd(PPh3)4 (0.1 equiv), dioxane/aq Na2CO3, under N2, 8 h, 40%
and evaporated. The residue was purified by flash column chroma-
tography (hexane–EtOAc or CHCl3–Et2O) to give the compounds
in 38–76% yield.
4-(4-Benzoylphenyl)-3-hydroxymethyl-2,2,5,5-tetramethyl-2,5-
dihydro-1H-pyrrol-1-yloxyl Radical (5a)
From compound 4 and 4-benzoylphenylboronic acid with 4 h heat-
ing.
4-(4-Benzoylphenyl)-3-carbethoxy-2,2,5,5-tetramethyl-2,5-di-
hydro-1H-pyrrol-1-yloxyl Radical (2a)
From compound 1 and 4-benzoylphenylboronic acid with 4 h heat-
ing.
Yellow solid; yield: 413 mg (53%); mp 134–136 °C; Rf = 0.23
(CHCl3–Et2O, 2:1).
IR (nujol): 3400 (OH), 1660 (C=O), 1560 (C=C) cm–1.
MS (EI): m/z (%) = 350 (M+, 4), 335 (3), 128 (15), 105 (100), 77
Yellow solid; yield: 533 mg (68%); mp 100–101 °C; Rf = 0.44 (hex-
ane–EtOAc, 2:1).
(79).
IR (nujol): 1710, 1660 (C=O), 1590 (C=C) cm–1.
MS (EI): m/z (%) = 392 (M+, 13), 377 (2), 105 (100), 77 (53).
Anal. Calcd for C22H24NO3: C, 75.40; H, 6.90; N, 4.00. Found: C,
75.36; H, 6.88; N, 3.89.
Anal. Calcd for C24H26NO4: C, 73.45; H, 6.68; N, 3.57. Found: C,
73.39; H, 6.62; N, 3.41.
1,1,3,3-Tetramethyl-1,3-dihydro-2H-pyrrolo[3,4-c]quinolin-2-
yloxyl Radical (7)
From compound 6 and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)aniline with 2 h heating.
1,1,3,3-Tetramethyl-2,3-dihydrochromeno[3,4-c]pyrrol-4(1H)-
4-one-2-yloxyl Radical (3)
From compound 1 and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)phenol with 2 h heating.
Yellow solid; yield: 183 mg (38%); mp 157–159 °C; Rf = 0.25 (hex-
ane–EtOAc, 2:1).
IR (nujol): 1650 (C=N), 1570 (C=C) cm–1.
MS (EI): m/z (%) = 241 (M+, 91), 226 (95), 211 (100), 196 (62).
Yellow solid; yield: 392 mg (76%); mp 205–206 °C; Rf = 0.4 (hex-
ane–EtOAc, 2:1).
IR (nujol): 1720 (C=O), 1600, 1570 (C=C) cm–1.
MS (EI): m/z (%) = 258 (M+, 59), 243 (100), 228 (59), 213 (67), 115
Anal. Calcd for C15H17N2O: C, 74.66; H, 7.10; N, 11.61. Found: C,
74.52; H, 7.06; N, 11.57.
(33).
3-(2-Aminophenyl)- 2,2,5,5-tetramethyl-4-phenyl-2,5-dihydro-
1H-pyrrol-1-yloxyl Radical (17)
From compound 12 and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)aniline with 2 h heating.
Anal. Calcd for C15H16NO3: C, 69.75; H, 6.24; N, 5.42. Found: C,
69.80; H, 6.22; N, 5.24.
Yellow solid; yield: 374 mg (61%); mp 160–163 °C; Rf = 0.29 (hex-
ane–EtOAc, 2:1).
Synthesis 2006, No. 3, 439–446 © Thieme Stuttgart · New York

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Palladium-Catalyzed Cross-Coupling Reactions
443
IR (nujol): 3440, 3300 (NH2), 1610, 1565 (C=C) cm–1.
MS (EI): m/z (%) = 307 (M+, 39), 292 (7), 277 (44), 262 (27), 234
4-(4-Benzoylphenyl)-3-bromomethyl-2,2,5,5-tetramethyl-2,5-
dihydro-1H-pyrrol-1-yloxyl Radical (5b)
To a solution of alcohol 5a (700 mg, 2.0 mmol) and Et3N (2.2
mmol) in CH2Cl2 (20 mL), methanesulfonylchloride (252 mg, 2.2
mmol) dissolved in CH2Cl2 (5 mL) was added dropwise at 0 °C. The
mixture was stirred at r.t. for 1 h, then the reaction mixture was
washed with H2O (10 mL), the organic phase was separated, dried
(MgSO4), filtered off and evaporated. The residue was dissolved in
anhyd acetone (20 mL), then LiBr (348 mg, 4.0 mmol) was added
and the reaction mixture was stirred and boiled at gentle reflux for
30 min. After cooling, the acetone was evaporated, the residue was
partitioned between H2O (10 mL) and EtOAc (20 mL). The phases
were then separated and the aqueous phase was washed again with
EtOAc (10 mL). The combined organic phase was dried (MgSO4),
filtered and evaporated. The residue was purified by flash column
chromatography (hexane–EtOAc, 2:1) to give compound 5b.
(100).
Anal. Calcd for C20H23N2O: C, 78.14; H, 7.54; N, 9.11. Found: C,
78.02; H, 7.48; N, 9.00.
1′-Oxyl-2′,2′,6′,6′-tetramethyl-1′,2′,3′,6′-tetrahydro-[3,4′]-bipy-
ridyl-5-carboxylic Acid (23)
From 5-bromonicotinamide and compound 21 with 2 h heating.
Yellow solid; yield: 213 mg (39%); mp 145–147 °C; Rf = 0.18
(CHCl3–MeOH, 9:1).
IR (nujol): 3360, 3160 (NH2), 1640 (C=O), 1605 (N–C=O) cm–1.
MS (EI): m/z (%) = 274 (M+, 50), 244 (15), 229 (100).
Anal. Calcd for C15H20N3O2: C, 65.67; H, 7.35; N, 15.32. Found: C,
65.61; H, 7.29; N, 15.30.
Yellow solid; yield: 404 mg (49%); mp 112–113 °C; Rf = 0.42 (hex-
ane–EtOAc, 2:1).
IR (nujol): 1660 (C=O), 1560 (C=C) cm–1.
MS (EI): m/z (%) = 414/412 (M+, 10/10), 399/397 (1/1), 318 (8),
105 (100), 77 (48).
3-[(E)-1,2-Bis(4-hydroxyphenyl)vinyl]-2,2,5,5-tetramethyl-2,5-
dihydro-1H-pyrrol-1-yloxyl Radical (31)
From 4-bromophenol (2 equiv) and diboronic acid ester 30 with 8 h
heating.
Anal. Calcd for C22H23BrNO2: C, 63.93; H, 5.61; N, 3.39. Found: C,
64.03; H, 5.53; N, 3.32.
Yellow solid; yield: 140 mg (40%); mp 228–230 °C; Rf = 0.25
(CHCl3–MeOH, 9:1).
IR (nujol): 3300 (OH), 1610, 1560 (C=C) cm–1.
MS (EI): m/z (%) = 350 (M+, 21), 336 (23), 320 (100), 305 (48).
4-(4-Benzoylphenyl)-3-methanethiosulfonylmethyl-2,2,5,5-tet-
ramethyl-2,5-dihydro-1H-pyrrol-1-yloxyl Radical (5c)
A solution of bromide 5b (413 mg, 1.0 mmol) and NaSSO2CH3
(268 mg, 2.0 mmol) in acetone (15 mL) and H2O (5 mL) was boiled
at gentle reflux for 45 min. After cooling, the acetone was evaporat-
ed in vacuo, H2O (10 mL) and CHCl3 (15 mL) were added and the
methanethiosulfonate was extracted into the organic phase. After
separation, the organic phase was dried (MgSO4), filtered and evap-
orated. The residue was purified by flash column chromatography
(hexane–EtOAc, 1:1, then CHCl3–Et2O, 2:1) to give compound 5c.
Anal. Calcd for C22H24NO3: C, 75.40; H, 6.90; N, 4.00. Found: C,
75.25; H, 6.86; N, 3.83.
4-(4-Benzoylphenyl)-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyr-
rol-1-yloxyl-3-carboxylic Acid Radical (2b)
To a solution of compound 2a (392 mg, 1.00 mmol) in MeOH (10
mL), 10% aq NaOH (5 mL) was added and the mixture was boiled
under gentle reflux for 1 h and then allowed to stay at r.t. overnight.
After evaporating the alcohol, the mixture was acidified with 5% aq
H2SO4. The precipitated solid was dried on air and it was pure
enough for the next reaction step. 50 mg of the compound were pu-
rified by chromatography (CHCl3–MeOH, 9:1) for analysis.
Yellow solid; yield: 275 mg (62%); mp 136–138 °C; Rf = 0.54
(CHCl3–Et2O, 2:1).
IR (nujol): 1660 (C=O), 1560 (C=C) cm–1.
MS (EI): m/z (%) = 444 (M+, 12), 414 (12), 105 (100), 77 (60).
Yield: 284 mg (78%); mp 224–226 °C; Rf = 0.44 (CHCl3–MeOH,
9:1).
IR (nujol): 3400 (OH), 1690, 1660 (C=O), 1590 (C=C) cm–1.
Anal. Calcd for C23H26NO4S2: C, 62.14; H, 5.89; N, 3.15; S, 14.42.
Found: C, 62.07; H, 5.85; N, 3.29; S, 14.25.
MS (EI): m/z (%) = 364 (M+, 2), 349 (1), 319 (4), 105 (100), 77 (53).
1,1,3,3-Tetramethyl-1,3-dihydro-2H-pyrrolo[3,4-b]quinolin-2-
yloxyl Radical (8)
Anal. Calcd for C22H22NO4: C, 72.51; H, 6.08; N, 3.84. Found: C,
72.55; H, 6.00; N, 3.79.
A solution of aniline (511 mg, 5.5 mmol) and aldehyde 6 (1.23 g,
5.0 mmol) in DMF (15 mL) was stirred at 80 °C for the consumption
of aldehyde 6 (3 h). DMF was removed under reduced pressure, the
residue was dissolved in CH2Cl2 (20 mL) and washed with H2O (10
mL). The organic phase was separated, dried (MgSO4), filtered and
evaporated. Compound 8 was obtained after flash chromatography
(hexane–EtOAc, 2:1).
4-(4-Benzoylphenyl)-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyr-
rol-1-yloxyl-3-carboxylic Acid N-Succinimide Ester Radical
(2c)
To a mixture of compound 2b (182 mg, 0.5 mmol) and N-hydroxy-
succinimide (58 mg, 0.5 mmol) in anhyd EtOAc (10 mL), DCC
(103 mg, 0.5 mmol) dissolved in anhyd EtOAc (5 mL) was added
dropwise at r.t. After stirring at r.t. for 3 h the precipitated dicyclo-
hexyl urea was filtered off, the filtrate was evaporated and the resi-
due was purified by flash column chromatography (CHCl3–Et2O,
2:1) to yield compound 2c.
Yellow solid; yield: 675 mg (56%); mp 156–158 °C; Rf = 0.54 (hex-
ane–EtOAc, 2:1).
IR (nujol): 1640 (C=N), 1570 (C=C) cm–1.
MS (EI): m/z (%) = 241 (M+, 49), 226 (26), 211 (100), 196 (80).
Anal. Calcd for C15H17N2O: C, 74.66; H, 7.10; N, 11.61. Found: C,
74.58; H, 7.03; N, 11.55.
Yellow solid; yield: 127 mg (55%); mp 71–73 °C, Rf = 0.6 (CHCl3–
Et2O, 2:1).
IR (nujol): 1780, 1730, 1660 (C=O), 1590 (C=C) cm–1.
MS (EI): m/z (%) = 461 (M+, 9), 446 (1), 347 (3), 105 (100), 77 (64).
4-Amino-1,1,3,3-tetramethyl-1,3-dihydro-2H-pyrrolo[3,4-
c]quinolin-2-yloxyl Radical (10)
A mixture of compound 9 (244 mg, 1.0 mmol) and Pd(OAc)2 (12
mg, 0.05 mmol) in dioxane (15 mL) was purged with N2 for 10 min.
Adamantylamine hydrochloride (76 mg, 0.4 mmol), 2-(4,4,5,5-tet-
ramethyl-1,3,2-dioxaborolan-2-yl)aniline (241 mg, 1.1 mmol) and
Anal. Calcd for C26H25N2O6: C, 67.67; H, 5.46; N, 6.07. Found: C,
67.58; H, 5.44; N, 6.03.
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444
T. Kálai et al.
PAPER
Cs2CO3 (715 mg, 2.2 mmol) were added and the mixture was stirred
under reflux for 16 h under N2. After cooling to r.t. the mixture was
concentrated in vacuo to a quarter of its initial volume and parti-
tioned between H2O (10 mL) and CHCl3 (20 mL). The organic
phase was separated, the aqueous phase was washed with CHCl3
(10 mL) and the combined organic phases were dried (MgSO4), fil-
tered and evaporated. The residue was purified by flash column
chromatography (CHCl3–MeOH) to give compound 10.
Anal. Calcd for C16H20BrNO2: C, 56.82; H, 5.96; N, 4.14. Found: C,
56.69; H, 5.91; N, 4.05.
2,2,5,5-Tetramethyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-di-
oxaborolan-2-yl)-2,5-dihydro-1H-pyrrol-1-yloxyl Radical (15)
To a stirred solution of compound 14 (1.35 g, 4.0 mmol) in anhyd
THF (15 mL), BuLi (3.2 mL, 8.0 mmol in 2.5 M hexane solution)
was added dropwise under N2 at –78 °C. The reaction mixture was
stirred at this temperature for 60 min, then trimethyl borate (520 mg,
5.0 mmol) in THF (5 mL) was added dropwise over 30 min and the
mixture was stirred for another 2 h at –78 °C. After warming the so-
lution to 0 °C MeOH (1 mL) was added followed by H2O (10 mL)
and the mixture was stirred overnight on air at r.t. Then the mixture
was diluted with Et2O (15 mL), the organic phase was separated and
the aqueous phase was acidified with AcOH and extracted again
with Et2O (10 mL). The combined organic phase was dried
(MgSO4), activated MnO2 (5.0 mmol, 430 mg) was added and O2
was bubbled through for 15 min. The mixture was filtered, evapo-
rated and the residue was suspended in toluene (50 mL) and heated
under reflux for 1 h in a Dean–Stark apparatus to remove water. The
toluene was evaporated and the residue was dissolved in anhyd
MeOH (20 mL). MgSO4 (4.8 g, 40 mmol) and anhyd pinacol (472
mg, 4.0 mmol) were added and the mixture was stirred overnight at
r.t. Then the MgSO4 was filtered off, the filtrate was evaporated and
the residue was partitioned between H2O (10 mL) and EtOAc (20
mL). The organic phase was dried (MgSO4), filtered and evaporated
and the residue was purified by flash column chromatography (hex-
ane–EtOAc, 2:1) to yield compound 15.
Beige solid; yield: 115 mg (45%); mp 188–190 °C; Rf = 0.30
(CHCl3–MeOH, 9:1).
IR (nujol): 3430, 3300 (NH2), 1640 (C=N), 1625 (C=C) cm–1.
MS (EI): m/z (%) = 256 (M+, 93), 241 (100), 226 (82), 211 (47).
Anal. Calcd for C15H18N3O: C, 70.29; H, 7.08; N, 16.39. Found: C,
70.21; H, 7.00; N, 16.28.
3-Bromo-2,2,5,5-tetramethyl-4-phenyl-2,5-dihydro-1H-pyrrol-
1-yloxyl Radical (12)
A solution of compound 11 (2.98 g, 10.0 mmol), phenylboronic
acid (1.21 g, 10.0 mmol), PdCl2(PPh3)2 (350 mg, 0.5 mmol) and
Ba(OH)2·8H2O (3.15 g, 10.0 mmol) in dioxane (32 mL) and H2O (8
mL) was stirred and heated to reflux for 2 h under N2. After cooling,
the brownish-black mixture was filtered through celite and the celite
pad was washed with MeOH (20 mL). The filtrate was evaporated
in vacuo and the residue was partitioned between EtOAc (30 mL)
and H2O (15 mL). The organic phase was separated, dried (MgSO4),
filtered and evaporated. The residue was purified by flash column
chromatography (hexane–Et2O, 2:1) to give a first colorless band
(diffuse spot on TLC) as biphenyl, followed by the starting com-
pound 11 as the second band. The third band contained compound
12 and the fourth contained compound 13 [yield: 584 mg (20%);
Rf = 0.37 (hexane–Et2O, 2:1)].
Yellow solid; yield: 452 mg (33%); mp 148–150 °C; Rf = 0.71 (hex-
ane–EtOAc, 2:1).
IR (nujol): 1600, 1560 (C=C) cm–1.
MS (EI): m/z (%) = 342 (M+, 28), 327 (52), 312 (100).
Compound 12
Anal. Calcd for C20H29BNO3: C, 70.19; H, 8.54; N, 4.09. Found: C,
70.12; H, 8.39; N, 4.18.
Yield: 708 mg (24%); mp 88–90 °C; Rf = 0.60 (hexane–Et2O, 2:1).
IR (nujol): 1600, 1550 (C=C) cm–1.
MS (EI): m/z (%) = 296/294 (M+, 26/26), 266/264 (11), 200 (15),
7,7,9,9-Tetramethyl-7,9-dihydro-8H-acenaphtho[1,2-c]pyrrol-
8-yloxyl Radical (16)
185 (100).
A 50 mL pressure tube equipped with stirring bar was filled with
Pd2(dba)3 (258 mg, 0,25 mmol), compound 11 (298 mg, 1.0 mmol),
1-naphthaleneboronic acid (189 mg, 1.1 mmol), tricyclohexyl phos-
phine (168 mg, 0.6 mmol), DBU (1 mL) and DMF (10 mL) and the
mixture was purged with N2 for 10 min. Then the tube was closed,
immersed in an oil bath and the solution was stirred at 150 °C for
48 h. After cooling, the mixture was diluted with CH2Cl2 (30 mL)
and filtered through celite. Then solvents were evaporated under re-
duced pressure and the residue was partitioned between Et2O (20
mL) and H2O (10 mL). The organic phase was separated, dried
(MgSO4), filtered and evaporated. The residue was purified by flash
column chromatography (hexane–EtOAc, 2:1) to give compound
16.
Anal. Calcd for C14H17BrNO: C, 56.96; H, 5.80; N, 4.74. Found: C,
56.88; H, 5.76; N, 4.78.
1-(Acetyloxy)-3-bromo-2,2,5,5-tetramethyl-4-phenyl-2,5-dihy-
dro-1H-pyrrole (14)
To a solution of radical 12 (1.47 g, 5.0 mmol) in dioxane (30 mL),
a solution of ascorbic acid (8.8 g, 50 mmol) in H2O (10 mL) was
added and the mixture was stirred at 40 °C for 15 min under N2. The
pale yellow or colorless solution was extracted with CHCl3 (2 × 20
mL) and dried (MgSO4) under N2. First acetyl chloride (430 mg, 5.5
mmol) was added followed by Et3N (slowly, 555 mg, 5.5 mmol)
while the temperature was kept below 10 °C. Stirring was continued
for 1 h at r.t., the mixture was filtered and the filtrate was evaporated
in vacuo. The residue was partitioned between brine (10 mL) and
EtOAc (15 mL). The aqueous phase was washed with EtOAc
(2 × 10 mL), the combined organic phase was dried (MgSO4), fil-
tered, evaporated and after flash chromatography (hexane–Et2O,
2:1) the O-acetyl derivative was obtained.
Yellow solid; yield: 76 mg (29%); mp 111–113 °C; Rf = 0.36 (hex-
ane–EtOAc, 2:1).
IR (nujol): 1560, 1540, 1510 (C=C) cm–1.
MS (EI): m/z (%) = 264 (M+, 9), 249 (12), 234 (100), 219 (74).
Anal. Calcd for C18H18NO: C, 81.79; H, 6.86; N, 5.30. Found: C,
81.72; H, 6.81; N, 5.14.
White solid; yield: 930 mg (55%); mp 75–76 °C; Rf = 0.50 (hexane–
Et2O, 2:1).
1,1,3,3-Tetramethyl-1,3-dihydro-2H-dibenzo[e,g]isoindol-2-
yloxyl Radical (18)
To a stirred solution of compound 17 (307 mg, 1.0 mmol) in aq 1 M
HCl (10 mL), NaNO2 (76 mg, 1.1 mmol) dissolved in H2O (5 mL)
was added dropwise at 0 °C and the mixture was stirred at this tem-
perature for 30 min. The solution of the diazonium salt was poured
onto a vigorously stirred suspension of Cu powder (5 g, 78.0 mmol)
IR (nujol): 1750 (C=O), 1590 (C=C) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.20 (s, 3 H, CH3), 1.33 (s, 3 H,
CH3), 1.38 (s, 6 H, CH3), 2.16 (s, 3 H, CH3CO), 7.17–7.37 (m, 5 H,
Ar).
MS (EI): m/z (%) = 339/337 (M+, 1/1), 324/322 (22/22), 297/295
(16/16), 282/280 (100/100).
Synthesis 2006, No. 3, 439–446 © Thieme Stuttgart · New York

PAPER
Palladium-Catalyzed Cross-Coupling Reactions
Compound 22
445
in H2O (10 mL) and the mixture was heated to 60 °C and stirred at
this temperature for 40 min. After cooling, the aqueous phase was
extracted with EtOAc (2 × 10 mL), the combined organic phase was
dried (MgSO4), filtered and evaporated. Chromatographic purifica-
tion (hexane–EtOAc, 2:1) of the residue afforded the paramagnetic
phenanthrene derivative 18.
Yield: 99 mg (32%); mp 222–224 °C; Rf = 0.54 (hexane–EtOAc,
2:1).
IR (nujol): 1630 (C=C) cm–1.
MS (EI): m/z (%) = 306 (M+, 13), 233 (58), 41 (100).
Yield: 78 mg (27%); mp 174–176 °C; Rf = 0.42 (hexane–EtOAc,
2:1).
IR (nujol): 1600, 1560 (C=C) cm–1.
MS (EI): m/z (%) = 290 (M+, 33), 275 (100), 260 (41).
Anal. Calcd for C18H30N2O2: C, 70.55; H, 9.87; N, 9.14. Found: C,
70.39; H, 9.79; N, 9.00.
Addition of Bis(pinacolato)diboron to Dienes and Acetylene (25,
28, 30); General Procedure
Anal. Calcd for C20H20NO: C, 82.72; H, 6.94; N, 4.82. Found: C,
82.68; H, 6.94; N, 4.69.
A solution of bis(pinacolato)diboron (508 mg, 2.0 mmol) and
Pt(PPh3)4 (124 mg, 0.1 mmol) in toluene (10 mL, for 25 and 28) or
in DMF (10 mL, for 30) was purged with N2. Then diene 24 or 27,
or acetylene 29 was added and the mixture was heated to reflux in
toluene for 5 h (25 and 28) or heated at 80 °C for 24 h (30) under
N2. After cooling, the solvents were evaporated under reduced pres-
sure, the residue was taken up in EtOAc (20 mL), and washed with
H2O (10 mL). The organic phase was separated, dried (MgSO4), fil-
tered and evaporated and the residue was purified by flash column
chromatography (hexane–EtOAc, 2:1) to give the diboronic esters
in 38–63%.
4-Iodo-2,2,6,6-tetramethyl-3,6-dihydropyridin-1(2H)-yloxyl
Radical (20)
Compound 19 (8.5 g, 50 mmol) dissolved in EtOH (30 mL) was
added dropwise to hydrazine hydrate (0.3 mol, 15 mL) during 3 h.
Then the mixture was boiled at gentle reflux for 1 h. After cooling,
the colorless solution was evaporated to dryness, the residue was
taken up in a mixture of CHCl3–MeOH (9:1, 50 mL). The organic
phase was washed with brine (10 mL), separated, dried (MgSO4).
Then PbO2 (1.19 g, 5.0 mmol) was added and O2 was bubbled
through for 30 min. The orange solution was filtered, evaporated
and the remaining orange thick oil (hydrazone) was stored in a re-
frigerator or used immediately. This hydrazone was dissolved in an-
hyd Et2O (30 mL) and added dropwise to a stirred solution of I2
(27.9 g, 0.11 mol) and tetramethyl guanidine (20.12 g, 0.175 mol)
in Et2O (50 mL). After addition of hydrazone, the mixture was
stirred at r.t. for 60 min, diluted with Et2O (40 mL), and washed
with H2O (30 mL) and then with 5% aq H2SO4 (60 mL). The organic
phase was separated, dried (MgSO4), filtered and evaporated. The
dark brown residue was purified by flash column chromatography
(hexane–Et2O, 2:1). The first green band was discarded and the sec-
ond orange-pink band contained compound 20.
2,2,5,5-Tetramethyl-3,4-bis[(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)methyl]-2,5-dihydro-1H-pyrrol-1-yloxyl Radical
(25)
Yield: 529 mg (63%); mp 78–80 °C; Rf = 0.51 (hexane–EtOAc,
2:1).
IR (nujol): 1650 (C=C) cm–1.
1H NMR [400 MHz, CDCl3 + (PhNH)2]: d = 1.25 (s, 24 H, CH3),
1.41 (s, 12 H, CH3), 1.66 (s, 4 H, CH2).
MS (EI): m/z (%) = 420 (M+, 11), 405 (10), 390 (100).
Anal. Calcd for C22H40B2NO5: C, 62.89; H, 9.60; N, 3.33. Found: C,
62.81; H, 9.57; N, 3.21.
Orange solid; yield: 8.26 g (59%); mp 63–65 °C; Rf = 0.70 (hexane–
Et2O, 2:1).
IR (nujol): 1650 (C=C) cm–1.
MS (EI): m/z (%) = 280 (M+, 10), 250 (3), 153 (20), 81 (100).
3-[1,2-Bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]-
2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-1-yloxyl Radical
(28)
Yield: 319 mg (38%); mp 71–73 °C; Rf = 0.51 (hexane–EtOAc,
Anal. Calcd for C9H15INO: C, 38.59; H, 5.40; N, 5.00. Found: C,
38.51; H, 5.39; N, 4.90.
2:1).
IR (nujol): 1650 (C=C) cm–1.
1H NMR of OAc derivative (400 MHz, CDCl3): d = 1.05 (m, J = 3.2
Hz, 2 H, CH2) 1.21 (s, 36 H, CH3), 1.79 (t, J = 1.6 Hz, 1 H, CH),
2.13 (s, 3 H, CH3CO), 5.25 (d, J = 1.6 Hz, 1 H, =CH).
2,2,6,6-Tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-3,6-dihydropyridin-1(2H)-yloxyl Radical (21) and
2,2,6,6,2′,2′,6′,6′-Octamethyl-1,2,3,6,1′,2′,3′,6,′-octahydro-
[4,4′]-bipyridin-1,1′-diyloxyl Diradical (22)
MS (EI): m/z (%) = 420 (M+, 7), 406 (16), 390 (100).
A solution of bis(pinacolato)diboron (279 mg, 1.1 mmol),
PdCl2(dppf) (40 mg, 0.05 mmol), KOAc 294 mg (3.0 mmol) in
DMSO (6 mL) was flushed with N2 for 10 min. Then compound 20
(280 mg, 1.0 mmol) was added and the mixture was stirred at 80 °C
for 3 h. After cooling, the mixture was poured onto H2O (20 mL)
and extracted with Et2O (2 × 15 mL). The organic phase was dried
(MgSO4), filtered and evaporated and the residue was purified by
flash column chromatography (hexane–Et2O, 2:1, then hexane–
EtOAc, 2:1). The first band contained a small amount of starting
compound 20, the second band gave compounds 21 and the third
was 22.
Anal. Calcd for C22H40B2NO5: C, 62.89; H, 9.60; N, 3.33. Found: C,
62.78; H, 9.53; N, 3.19.
3-[(E)-1,2-Bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vi-
nyl]-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-1-yloxyl Radi-
cal (30)
Yield: 351 mg (42%); mp 69–71 °C; Rf = 0.51 (hexane–EtOAc,
2:1).
IR (nujol): 1650 (C=C) cm–1.
MS (EI): m/z (%) = 418 (M+, 8), 403 (25), 388 (100).
Compound 21
Anal. Calcd for C22H38B2NO5: C, 63.19; H, 9.16; N, 3.35. Found: C,
63.02; H, 9.11; N, 3.26.
Yield: 78 mg (28%); mp 180 °C; Rf = 0.71 (hexane–EtOAc, 2:1).
IR (nujol): 1640 (C=C) cm–1.
MS (EI): m/z (%) = 280 (M+, 14), 266 (100), 250 (52), 235 (21).
3,4-Bis(hydroxymethyl)-2,2,5,5-tetramethyl-2,5-dihydro-1H-
pyrrol-1-yloxyl Radical (26)
To a stirred solution of compound 25 (420 mg, 1.0 mmol) in MeOH
(10 mL), 10% aq NaOH solution (1 mL) and 30% H2O2 (1 mL) were
added and the mixture was heated to reflux for 2 h. After cooling,
Anal. Calcd for C15H27BNO3: C, 64.30; H, 9.71; N, 5.00. Found: C,
64.27; H, 9.62; N, 4.87.
Synthesis 2006, No. 3, 439–446 © Thieme Stuttgart · New York

446
T. Kálai et al.
PAPER
the mixture was extracted with CHCl3 (2 × 10 mL), the organic
phase was dried (MgSO4), filtered and evaporated. Compound 26
was obtained after flash column chromatography purification
(CHCl3–MeOH, 9:1).
(13) Zhdanov, R. I. In Bioactive Spin Labels; Zhdanov, R. I., Ed.;
Springer-Verlag: Berlin, 1992, 23–82.
(14) Barton, H. R.; Bashiardes, G.; Fourrey, J.-L. Tetrahedron
1988, 44, 147.
(15) Kálai, T.; Jekő, J.; Hideg, K. Tetrahedron Lett. 2004, 45,
8395.
(16) Berliner, L. J.; Grünwald, J.; Hankovszky, H. O.; Hideg, K.
Anal. Biochem. 1982, 119, 450.
Yellow solid; yield: 134 mg (67%); mp 155–156 °C; Rf = 0.55
(CHCl3–MeOH, 9:1).
(17) Lösel, R. M.; Philipp, R.; Kálai, T.; Hideg, K.; Trommer, W.
Acknowledgment
E. Bioconjugate Chem. 1999, 10, 578.
This work was supported by a grant from Hungarian National Rese-
arch Foundations (OTKA T042951, T48334 and M045190). The
authors thank Noémi Lazsányi for elemental analyses and Mária
Szabó for mass spectral measurements (ICN, Hungary).
(18) Mátyus, P.; Maes, B. U. W.; Riedl, Z.; Hajós, G.; Lemiére,
G. L. F.; Tapolcsányi, P.; Monsieurs, K.; Éliás, O.;
Dommisse, R. A.; Krajsovszky, G. Synlett 2004, 1123.
(19) Sampathkumar, N. M.; Kumar, N. V.; Rajendran, S. P.
Synth. Commun. 2004, 34, 2019.
(20) Gug, F.; Blondel, M.; Deaban, N.; Bouaziz, S.; Vierfond, J.-
M.; Galons, H. Tetrahedron Lett. 2005, 46, 3725.
(21) Keana, J. F. W.; Hideg, K.; Birrell, G. B.; Hankovszky, H.
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(22) Clayden, J. Organolithiums: Selectivity for Synthesis;
Elsevier: Oxford, 2002.
(23) Chaumel, H.; Le Drian, C.; Defoin, A. Synthesis 2002, 757.
(24) Wegner, H. A.; Scott, T. A.; de Meijere, A. J. Org. Chem.
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