Palladium-catalyzed coupling reactions of paramagnetic vinyl halides

Article abstract of DOI:10.1055/s-2002-35240

Suzuki, Heck and Sonogishira coupling reactions of paramagnetic vinyl bromides 1-6 gave monofunctional (7a,b), homobifunctional (8a,b, 24), and heterobifunctional pyrroline nitroxides (9-19, 31) under mild conditions in a one-step reaction. From these com

Full text of DOI:10.1055/s-2002-35240

PAPER
2365
Palladium-Catalyzed Coupling Reactions of Paramagnetic Vinyl Halides
Coupling
Reacta
m
m
agnetic Vinyl
H
a
á
a
Institute of Organic and Medicinal Chemistry, University of Pécs, 7643 Pécs, P. O. Box 99, Hungary
Fax +36(72)536219; E-mail: KHIDEG@main.pote.hu
b
c
ICN, Hungary, 4440 Tiszavasvári, P. O. Box 1, Hungary
Jules Stein Eye Institute and Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90095-7008, USA
Received 19 June 2002; revised 20 July 2002
find a simple method for introducing a second substituent
into the pyrroline ring.
Abstract: Suzuki, Heck and Sonogishira coupling reactions of
paramagnetic vinyl bromides 1–6 gave monofunctional (7a,b), ho-
mobifunctional (8a,b, 24), and heterobifunctional pyrroline nitrox-
ides (9–19, 31) under mild conditions in a one-step reaction. From
these compounds thiol-specific spin labels 26 and 28 and pyrroline
nitroxide annulated heterocycles 30 and 32 were synthesized. The
ethynyl derivative of pyrroline nitroxide 33 also can be used as an
acetylene reactant in Larock indole synthesis to give the paramag-
netic indole derivative 36.
Over the last decade the palladium-catalyzed cross cou-
pling reaction has become an extremely versatile tool for
synthetic organic chemists.11 These reactions are widely
used for synthesis of biaryls,12 heterobiaryls, natural
products13 and complex carbo- and heterocyclic14 systems
under mild reaction conditions. In this paper, we report
the first extension of palladium-catalyzed coupling reac-
tions to the chemistry of stable nitroxide free radicals. Al-
though Pd2+ salts are reported to form diamagnetic Pd
complexes with nitroxides,15 no problems were encoun-
tered in obtaining the expected products from cross-cou-
pling reactions.
Thus, the reaction of boronic acids,16 phenylacetylene, or
ethyl acrylate with 3-bromo- 1, 3-substituted-4-bromo- 3–
6 or 3,4-dibromopyrroline nitroxides 2, available by Fa-
vorskii reaction of 2,2,6,6-tetramethyl-4-oxopiperidine-1-
yloxyl,17,18 gives the corresponding polysubstituted pyrro-
line nitroxide free radicals. These radicals can be further
converted into spin labels suitable for chemical modifica-
tion of macromolecules or to pyrroline nitroxide annulat-
ed heterocycles. Monosubstituted and 3,4-disubstituted
pyrroline nitroxides have been successfully used in spin
labeling of proteins.6 Insertion of rigid phenyl spacers be-
tween the reactive function and the nitroxide ring of the
spin label, using the procedures outlined here will provide
a new series of spin labels to be explored (Figure 1).
Key words: alkynes, free radical, Suzuki reaction, heterocycles,
palladium
Stable nitroxide free radicals have found wide applica-
tions as co-oxidants,1 SOD mimics,2 spin traps for carbon
centered radicals3 and mediating radicals in polymeriza-
tion,4 thus making these molecules indispensable tools in
analytical, organic and polymer chemistry. Another im-
portant role for nitroxide free radicals is the site-directed
labeling technique for exploration of protein structure, dy-
namics and function.5 Recent studies have shown that the
internal motion of spin labeled side chains based on pyr-
roline nitroxides can be tuned by introduction of a second
substituent in the ring.6 This provides a powerful tool for
isolating the contribution of backbone dynamics to the
motion of the side chain. Moreover, second substituents in
the nitroxide ring can be used to control the hydrophobic-
ity, charge and H-bonding characteristics making it possi-
ble to create nitroxide mimics of natural side chains. Until
now these polysubstituted nitroxides were available only
by allylic rearrangements,7 Grignard reaction,8 Michael
additions9 or starting from appropriately functionalized
nitrones through many steps.10 A real challenge was to
Reaction of vinyl bromide 1 or 2 with one equivalent or
two equivalents of phenylboronic acid in a mixture of di-
oxane–water as solvent in the presence of Ba(OH)2 and
dichlorobis(triphenylphosphine)palladium(II) as catalyst
Figure 1 The structures of a new series of spin labels
Synthesis 2002, No. 16, Print: 14 11 2002.
Art Id.1437-210X,E;2002,0,16,2365,2372,ftx,en;P03102SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

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T. Kálai et al.
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(10 mol%) at 100 °C gave radical 7a or radical 8a, respec- bis(diphenylphosphino)ferrocene]dichloropalladium(II)
tively. The latter reaction allowed a modification from the [PdCl2(dppf)], to give a pinacolylboronic acid derivative
dibromo compound 2 with a 0.5 equivalent of phenylbo- that could be coupled to alkyl or aryl halogenides
ronic acid to give 3-bromo-2,2,5,5-tetramethyl-4-phenyl- (Scheme 2). Reaction of bromobenzene with the non-iso-
2,5-dihydro-1H-pyrrol-1-yloxyl radical (6). The Suzuki lated pinacolylboronic acid derivative with additional
coupling reaction can be extended for substituted phenyl- amounts of PdCl2(dppf) and aqueous Na2CO3 solution
boronic acids, thus 4-hydroxymethylphenylboronic acid gave compound 12, although in lower yield than in the di-
gave 7b radical or 8b radical. Reaction of phenylboronic rect reaction with phenylboronic acid. Reaction of phenyl-
acid with activated -bromo- , -unsaturated paramagnet- 1,4-diboronic acid with aldehyde 4 gave 20 biradical as a
ic aldehyde 4 gave radical 12. Similarly coupling phenyl- possible polyradical building block.
boronic acid with the non-activated paramagnetic
bromoallylic alcohol 3 gave compound 9.
-
The Wadsworth–Emmons reaction19 of aldehyde 4 with
triethylphosphono acetate and NaH in THF gave the radi-
Suzuki coupling reactions allow the introduction not only cal 21. Reaction of compound 21 with 2.5 equivalents of
of aromatic substituents but also alkyl or alkenyl substitu- ethyl acrylate perbromide, a twofold excess triethylamine,
ents. Thus coupling of 4 with methyl or hexenylboronic 4 mol% Pd(OAc)2 and triphenylphosphine in DMF gave
acids gave radical 10 and radical 11, respectively. Intro- directly compound 24, published recently from our labor-
duction of these substituents in the presence of free nitrox- atory by a Diels–Alder reaction and aromatization.20 Dur-
yl radical was previously possible only by a multistep and ing the reaction we did not observe the formation of
sometimes low yield synthetic route. Introduction of an radical 22 available independently by twofold Wads-
aryl- or heteroaryl substituent was also feasible from cou- worth–Emmons reaction from dialdehyde 23.20
pling the aldehyde 4 and 1-naphthylboronic acid, 2-furyl-
The 6 -electrocyclization21 of compound 22, either spon-
boronic acid, 4-dibenzofuranboronic acid or 2-
taneously or by heating with activated manganese dioxide
thienylboronic acid to give aldehydes 13 or 14 or 15 or 16,
in toluene, also gave compound 24.
respectively. Reaction of -bromo- , -unsaturated para-
The hydroxymethyl side chains of compound 7b and 8b
magnetic ester 5 with phenylboronic acid using K2CO3 in-
can be converted further through the mesylate into benzyl-
stead of Ba(OH)2 to avoid ester hydrolysis led to radical
ic bromide compounds 25 and 27 with LiBr in acetone
17. Reaction of compound 6 with 4-hydroxymethylphe-
(Scheme 3). These benzylic bromides can be converted
with NaSSO2CH3 in aqueous EtOH into the thiol-specific
nylboronic acid gave the unsymmetrically substituted
pyrroline nitroxide radical 18. Reaction of compound 4
with 4-(dimethylamino)phenylboronic acid provided ba-
methanethiosulfonates 26 and 28 capable of cysteine side
chain labeling22,23 and, in case of compound 28, capable of
sic substituent containing compound 19 (Scheme 1).
crosslinking pairs of cysteine residues in a protein.
Compound 4 was reacted with bis(pinacolato)diboron in
DMF in the presence of KOAc and [1,1 -
Scheme 1 Reagents and conditions: (a) R3B(OH)2 (1.1 equiv or 2.1 equiv for 8a, 8b), K2CO3 or Ba(OH)2 (1.0 equiv), PdCl2(PPh3)2 (0.05
equiv), dioxane–H2O, 100 °C, 2–4 h, 40–75%
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Coupling Reactions of Paramagnetic Vinyl Halides
2367
Scheme 2 Reagents and conditions: (a) (i): pinacolborane (1.1 equiv), PdCl2(dppf) (0.03 equiv), KOAc (3.0 equiv), DMF, 80 °C, 2 h, then
(ii): PhBr (2.0 equiv), PdCl2(pddf) (0.03 equiv), 2 M aq Na2CO3 (2.5 equiv), 80 °C, 12 h (18%); (b) phenyl-1,4-diboronic acid (0.55 equiv),
PdCl2(PPh3)2 (0.05 equiv), Ba(OH)2 (1.0 equiv), dioxane–H2O (4:1), 100 °C, 3 h, 44%; (c) (EtO)2P(O)CH2CO2Et (1.2 equiv), THF, NaH (1.2
equiv), 0 °C to r.t., 30 min, then 65 °C, 2 h, 80%; (d) Pd(OAc)2 (0.04 equiv) Ph3P (0.2 equiv), ethyl acrylate (2.5 equiv), Et3N, DMF, 100 °C,
30 h, then MnO2 (0.5 equiv), O2, 30 min, 31%; (e) (EtO)2P(O)CH2CO2Et (2.2 equiv), THF, NaH (2.2 eqiv), 0 °C to r.t., 30 min, then 65 °C, 2
h, 66%; (f) activated MnO2 (6.0 equiv), toluene, 110 °C, 2 h (43%)
compound 17, can be converted into the corresponding
acid azide with NaN3 in acetone–water at 0 °C
(Scheme 4). The potentially explosive azide was not iso-
lated, but was subjected to Curtius rearrangement24,25 and
cyclization in diphenyl ether to give radical 30.
Scheme 3 Reagents and conditions: (a) (i): MsCl (1.1 for 25 or 2.2
equiv for 27), Et3N (1.1 equiv for 25 or 2.2 equiv for 27), CH2Cl2,
0 °C to r.t., 1 h; (ii): LiBr (2.0 equiv for 25 or 4.0 equiv for 27), ace-
Scheme 4 Reagents and conditions: (a) NaN3 (3.0 equiv), acetone–
tone, 55 °C, 1 h, 35–47%; (b) NaSSO2CH3 (2.0 equiv for 26 or 4.0
H2O, 0 °C, 1 h, then Et2O extr., Ph2O, r.t. to 258 °C, 5–10 min, 31%
equiv for 28), acetone–H2O, 30 min, 55 °C, 22–31%
Aldehyde 4 in a Sonogishira reaction with phenylacety-
lene in DMF and in the presence of triethylamine, 10
mol% CuI, and 5 mol% dichlorobis(triphenylphos-
phine)palladium(II) as catalyst afforded radical 31. Com-
The 3,4-bifunctionalized pyrroline nitroxides can be used
for construction of carbo- and heterocycle annulated pyr-
roline nitroxide radicals. The previously published mixed
anhydride ester 29,10 now more readily available from
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T. Kálai et al.
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ser. The IR (Specord 75) spectra were in each case consistent with
the assigned structure. Mass spectra were recorded on a VG TRIO-
2 instrument in the EI mode (70 eV, direct inlet) or with a thermo-
spray technique. Samples were analysed in the bypass mode. The
sample solution in MeOH (10 L) was introduced via the thermo-
spray interface. The mobile phase was a MeOH–H2O (1:1) solution
containing 0.1 M NH4OAc. The capillary tip temperature was 230
°C, the electrode voltage was 180 V and the source temperature was
210 °C. ESR spectra were obtained from 10–5 molar solutions
(CHCl3), using a Bruker ECS-106 spectrometer. All monoradicals
exhibited three equally spaced lines with aN = 15.1–15.5 G. Biradi-
cal 20 exhibited quintet lines. Preparative flash column chromatog-
raphy was performed on Merck Kieselgel 60 (0.040–0.063 mm).
Qualitative TLC was carried out on commercially prepared plates
(20 20 0.02 cm) coated with Merck Kieselgel GF254. All the bo-
ronic acids, CuI and palladium catalysts were purchased from Sig-
ma-Aldrich, Hungary. Compounds 1,17 2,17 3,18 4,17 5,31 23,20 3320
were prepared according to published procedures and compounds
9,10 12,31 17,10 24,20 2910 have been previously described from our
laboratory using other methods. The physical and spectral data of all
new compounds are listed in Table 1.
pound 31 with hydroxylamine hydrochloride and K2CO3
at reflux in aqueous EtOH via the oxime yielded radical
32 (Scheme 5).26,27
Scheme 5 Reagents and conditions: (a) PhC CH (1.0 equiv),
PdCl2(PPh3)2 (0.05 equiv), CuI (0.1 equiv), Et3N–DMF, 80 °C, 3 h,
72%; (b) HONH2 HCl (1.0 equiv), K2CO3 (1.0 equiv), EtOH–H2O, 78
°C, 1 h, then K2CO3 (1.0 equiv), EtOH, 78 °C, 3 h, 82%
In an inversion of the Sonogishira reaction, paramagnetic
acetylene compound 33 was reacted with 2-iodoaniline in
a mixture of DMF and Et3N in the presence of catalytic
CuI and Pd(PPh3)2Cl2 at 80 °C (Scheme 6). The crude
product was treated with methanesulfonyl chloride in
CH2Cl2 to give compound 34. Compound 34 was cyclised
with K2CO3 in acetonitrile to give radical 35.28 This com-
pound was demesylated with KOH by heating at reflux in
MeOH to give paramagnetic indole29 derivative 36. The
paramagnetic indole 36 proved to be available in a one-
pot reaction from compound 33 and 2-iodoaniline30 with
formation of only 2-substituted regioisomer 36, which
was identical with the product of the above multistep re-
action.
Suzuki Coupling of Paramagnetic Vinyl Bromides 1–6; General
Procedure
A mixture of vinyl bromide 1, 2, 3, 4, 5, or 6 (1.0 mmol), the appro-
piate boronic acid (1.1 mmol), Ba(OH)2 8H2O (315 mg, 1.0 mmol)
or K2CO3 (138 mg, 1.0 mmol for 5) and PdCl2(Ph3P)2 (35 mg, 0.05
mmol) in dioxane (8 mL) and H2O (2 mL) was stirred and refluxed
until the starting compounds were consumed (2–4 h). After cooling,
the dioxane was evaporated under reduced pressure, the residue was
dissolved in brine (10 mL), extracted with EtOAc (2 10 mL),
dried (MgSO4), filtered, evaporated and purified by flash column
chromatography (hexane–Et2O or hexane–EtOAc) to give the prod-
uct or a mixture of products (6 and 8a).
3-Bromo-2,2,5,5-tetramethyl-4-phenyl-2,5-dihydro-1H-pyrrol-
1-yloxyl Radical (6)
In conclusion, palladium-catalyzed cross-coupling reac-
tions were used with paramagnetic vinyl halides to give
polysubstituted pyrroline nitroxide derivatives in a one-
pot reaction. This method is greatly favored over the pre-
viously employed multistep reactions, and opens up sim-
pler pathways for preparation of pyrroline nitroxides with
carbocyclic and heterocyclic substituents.
Yield: 124 mg (42%); mp 89–91 °C; Rf 0.48 (hexane–Et2O, 2:1).
2,2,5,5-Tetramethyl-3-phenyl-2,5-dihydro-1H-pyrrol-1-yloxyl
Radical (7a)
Yield: 155 mg (72%); mp 48–50 °C; Rf 0.39 (hexane–Et2O, 2:1).
3-[4-(Hydroxymethyl)phenyl]-2,2,5,5-tetramethyl-2,5-dihydro-
1H-pyrrol-1-yloxyl Radical (7b)
Yield: 135 mg (55%); mp 128–129 °C; Rf 0.18 (CHCl3–Et2O, 2:1).
Melting points were determined with a Boetius micro melting point
apparatus and are uncorrected. Elemental analyses (C, H, N, S)
were performed on a Carlo Erba EA 1110 CHNS elemental analy-
3-Hydroxymethyl-2,2,5,5-tetramethyl-4-phenyl-2,5-dihydro-
1H-pyrrol-1-yloxyl Radical (9)
Yield: 157 mg (64%); mp 111–113 °C; Rf 0.25 (hexane–EtOAc).
Scheme 6 Reagents and conditions: (a) 2-iodoaniline (1.0 equiv), PdCl2(Ph3P)2 (0.05 equiv), CuI (0.1 equiv), Et3N, r.t., 4 h, then MsCl (1.1
equiv), Et3N (1.1 equiv), CH2Cl2, 0 °C to r.t., 12 h, 36%; (b) K2CO3 (1.0 equiv), MeCN, 82 °C, 8 h, 78%; (c) KOH (2.0 equiv), MeOH, 65 °C,
4 h, 44%; (d) 33 (2.0 equiv), 2-iodoaniline (1.0 equiv), Pd(OAc)2 (0.05 equiv), K2CO3 (5.0 equiv), Ph3P (0.05 equiv), Bu4NCl (1.0 equiv), DMF,
100 °C, 3 h, 50%
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Coupling Reactions of Paramagnetic Vinyl Halides
2369
Table 1 Compounds 6–36 Prepared
Compounda Yield
Mp (°C)
89–91
IR (neat or Nujol) (cm–1)
1635 (C=C), 1595 (C=C)
MS m/z
6
42
294/296 (M+, 55/55), 280/282 (16/16), 264/266 (18/18),
185 (100)
7a
7b
8a
8b
72
55
63
45
40
48
51
58
60
65
41
69
44
80
66
47
31
35
48–50
128–129
164
1560, 1590 (C=C)
216 (M+, 30), 201 (79), 186 (77), 143 (100)
246 (M+, 16), 232 (79), 216 (83), 143 (100)
292 (M+, 100), 278 (60), 262 (47), 91 (86)
TSP: [M + H]+: 353
3340 (OH), 1590 (C=C)
1590 (C=C)
173–174
104–106
oil
3400 (OH), 1580 (C=C)
1650 (C=O), 1615 (C=C)
1655 (C=O), 1625 (C=C)
1660 (C=O), 1610, 1560 (C=C)
1660 (C=O), 1590 (C=C)
1660 (C=O), 1610, 1590 (C=C)
1660 (C=O), 1580 (C=C)
3400 (OH), 1590 (C=C)
1665 (C=O), 1600, 1510 (C=C)
1660 (C=O), 1600 (C=C)
1710 (C=O), 1620, 1570 (C=C)
1700 (C=O), 1600 (C=C)
1590 (C=C)
10
182 (M+, 47), 167 (46), 152 (47), 41 (100)
250 (M+, 6), 236 (17), 220 (28), 41 (100)
294 (M+, 100), 249 (88), 193 (51), 165 (52)
234 (M+, 40), 219 (39), 204 (52), 39 (100)
334 (M+, 100), 320 (60), 304 (45), 184 (68)
250 (M+, 21), 235 (18), 220 (31), 39 (100)
322 (M+, 28), 308 (20), 292 (13), 212 (100)
287 (M+, 44), 257 (86), 186 (77), 136 (100)
TSP: [M + H]+: 411
11
13
14
15
16
18
19
20
21
22
25
26
27
129–130
60–62
137–138
87–89
101–103
48–50
213–215
85–87
316/318 (M+, 42/42), 223 (48), 162 (71), 41 (100)
TSP: [M + H]+: 337
100–102
43–45
308/310 (M+, 11/11), 214 (80), 199 (88), 42 (100)
340 (M+, 4), 326 (6), 310 (9), 43 (100)
95–97
1590 (C=C)
147–150
1580 (C=C)
476/478/480 (M+, 8/16/8), 462/464/466 (17/35/17),
382/384 (26/26), 43 (100)
28
30
31
22
31
72
161–163
>265
1590 (C=C)
TSP: [M + H]+: 541
1640 (C=O), 1590 (C=C)
257 (M+, 28), 243 (62), 227 (100), 212 (33)
268 (M+, 11), 254 (100), 238 (47), 223 (19)
117–118
2180 (C C), 1660 (C=O)
1590, 1570 (C=C)
32
34
35
36
82
261–263
173–175
128–130
180–182
1590 (C=C)
1580 (C=C)
1580 (C=C)
3300 (NH)
283 (M+, 48), 269 (30), 252 (100), 210 (48)
333 (M+, 3), 224 (65), 208 (60), 79 (100)
333 (M+,10), 319 (23), 303 (31), 224 (100)
255 (M+, 30), 241 (32), 225 (100), 210 (89)
36
78
44b, 50c
a Satisfactory microanalyses obtained: C 0.23, H 0.20, N 0.21.
b Method A.
c Method B.
3-Formyl-2,2,4,5,5-pentamethyl-2,5-dihydro-1H-pyrrol-1-ylox-
yl Radical (10)
3-Formyl-2,2,5,5-tetramethyl-4-phenyl-2,5-dihydro-1H-pyrrol-
1-yloxyl Radical (12)
Yield: 73 mg (40%); mp 104–106 °C; Rf 0.28 (hexane–EtOAc, 2:1).
Yield: 183 mg (75%); mp 112–113 °C; Rf 0.32 (hexane–Et2O).
3-Formyl-4-[(1E)-hex-1-enyl]-2,2,5,5-tetramethyl-2,5-dihydro-
1H-pyrrol-1-yloxyl Radical (11)
3-Formyl-2,2,5,5-tetramethyl-4-(1-naphthyl)-2,5-dihydro-1H-
pyrrol-1-yloxyl Radical (13)
Yield: 120 mg (48%); oil; Rf 0.32 (hexane–Et2O, 2:1).
Yield: 150 mg (51%); mp 129–130 °C, Rf 0.48 (hexane–EtOAc,
2:1).
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3-Formyl-4-(2-furyl)-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyr-
rol-1-yloxyl Radical (14)
Yield: 135 mg (58%); mp 60–62 °C; Rf 0.39 (hexane–EtOAc, 2:1).
was stirred and refluxed for 3 h. After cooling, the dioxane was
evaporated under reduced pressure, the residue was dissolved in 2.0
M aq HCl (10 mL), extracted with EtOAc (2 10 mL), dried
(MgSO4), filtered, evaporated and purified by flash column chro-
matography (hexane–EtOAc) to give 180 mg (44%) of 20; mp 213–
215 °C; Rf 0.32 (CHCl3–Et2O, 2:1).
4-(Dibenzo[b,d]furan-3-yl)-3-formyl-2,2,5,5-tetramethyl-2,5-di-
hydro-1H-pyrrol-1-yloxyl Radical (15)
Yield: 200 mg (60%); mp 137–138 °C; Rf 0.45 (hexane–EtOAc,
2:1).
Wadsworth–Emmons Reactions of Paramagnetic Aldehydes 4
and 23; General Procedure
3-Formyl-2,2,5,5-tetramethyl-4-(2-thienyl)-2,5-dihydro-1H-
pyrrol-1-yloxyl Radical (16)
Yield: 163 mg (65%); mp 87–89 °C, Rf 0.46 (hexane–EtOAc, 2:1).
To a stirred solution of NaH (144 mg, 6.0 mmol or 264 mg, 11.0
mmol in the case of 21) in anhyd THF (20 mL) was added triethyl
phosphonoacetate (1.34 g, 6.0 mmol or 2.46 g, 11.0 mmol in the
case of 21) in THF (5 mL) dropwise at 0 °C, and stirred for 30 min
at r.t. under N2. A solution of 4 (1.23 g, 5.0 mmol) or 23 (980 mg,
5.0 mmol) in THF (10 mL) was then added dropwise, the mixture
was refluxed for 2 h, and allowed to stand overnight. The solvent
was evaporated, brine (20 mL) was added, extracted with EtOAc (2
20 mL), dried (MgSO4), filtered, and the solvent was evaporated.
Chromatographic purification (hexane–Et2O) provided 21 or 22.
3-Ethoxycarbonyl-2,2,5,5-tetramethyl-4-phenyl-2,5-dihydro-
1H-pyrrol-1-yloxyl Radical (17)
Yield: 110 mg (40%); mp 75–77 °C; Rf 0.46 (hexane–Et2O, 2:1).
3-[4-(Hydroxymethyl)phenyl]- 2,2,5,5-tetramethyl-4-phenyl-
2,5-dihydro-1H-pyrrol-1-yloxyl Radical (18)
Yield: 141 mg (43%); mp 101–103 °C; Rf 0.25 (CHCl3–Et2O, 2:1).
3-Bromo-4-[(1E)-3-ethoxyprop-1-enyl]-2,2,5,5-tetramethyl-2,5-
dihydro-1H-pyrrol-1-yloxyl Radical (21)
Yield: 1.26 g (80%); mp 85–87 °C; Rf 0.36 (hexane–Et2O, 2:1).
3-Formyl-4-[4-(dimethylamino)phenyl]-2,2,5,5-tetramethyl-
2,5-dihydro-1H-pyrrol-1-yloxyl Radical (19)
Yield: 200 mg (69%); mp 48–50 °C; Rf 0.61 (hexane–EtOAc, 2:1).
3,4-Bis[(1E)-3-ethoxyprop-1-enyl]-2,2,5,5-tetramethyl-2,5-di-
hydro-1H-pyrrol-1-yloxyl Radical (22)
Yield: 1.10 g (66%); mp 100–102 °C; Rf 0.32 (hexane–EtOAc, 2:1).
Twofold Suzuki Coupling of Paramagnetic Vinyl Bromide 2;
General Procedure (8a,b)
A mixture of vinyl bromide 2 (298 mg, 1.0 mmol), phenylboronic
acid (256 mg, 2.1 mmol) or 4-(hydroxymethyl)phenylboronic acid
(319 mg, 2.1 mmol), Ba(OH)2 8H2O (631 mg, 2.0 mmol) and
PdCl2(Ph3P)2 (70 mg, 0.1 mmol) in dioxane (8 mL) and H2O (2 mL)
was stirred and refluxed for 6 h. After cooling, the dioxane was
evaporated under reduced pressure, the residue was dissolved in
brine (10 mL), extracted with EtOAc (2 10 mL) or CHCl3 (2 15
mL) in the case of 8b, dried (MgSO4), filtered, evaporated and pu-
rified by flash column chromatography (hexane–EtOAc or CHCl3–
Et2O) to give the product 8a or 8b.
Diethyl 1,1,3,3-Tetramethylisoindoline-5,6-dicarboxylate-2-
yloxyl Radical (24)
Method A: A mixture of 21 (634 mg, 2.0 mmol), Pd(OAc)2 (18 mg,
0.08 mmol) and Ph3P (105 mg, 0.4 mmol) in DMF (20 mL) was
stirred for 10 min under N2. Et3N (505 mg, 5.0 mmol) and ethyl
acrylate (500 mg, 5.0 mmol) were then added and the mixture was
stirred at 100 °C for 30 h under an inert atmosphere. After cooling,
the solvent was evaporated under reduced pressure, the residue was
dissolved in brine (15 mL), extracted with EtOAc (3 10 mL), dried
(MgSO4), filtered and evaporated. The residue was dissolved in
CHCl3 (20 mL), activated MnO2 (86 mg, 1.0 mmol) was added, and
O2 was bubbled through for 30 min. The MnO2 was filtered off, the
solvent was evaporated and the residue was purified by flash col-
umn chromatography to give the compound 24, yield: 212 mg
(34%), mp 120 °C; Rf 0.19 (hexane–Et2O, 2:1).
2,2,5,5-Tetramethyl-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-
yloxyl Radical (8a)
Yield: 183 mg (63%); mp 164 °C; Rf 0.37 (hexane–Et2O, 2:1).
3,4-Bis[(4-hydroxymethyl)phenyl]-2,2,5,5-tetramethyl-2,5-di-
hydro-1H-pyrrol-1-yloxyl Radical (8b)
Yield: 158 mg (45%); mp 173–174 °C; Rf 0.21 (CHCl3–MeOH,
9:1).
Method B: To a stirred solution of compound 22 (168 mg, 0.5
mmol) in toluene (10 mL) was added activated MnO2 (258 mg, 3.0
mmol) and the mixture was stirred and refluxed for 2 h. The mixture
was filtered, the toluene was evaporated and the residue was puri-
fied by flash column chromatography (hexane–Et2O) to give the ti-
tle compound 24; yield: 72 mg (46%).
3-Formyl-2,2,5,5-tetramethyl-4-phenyl-2,5-dihydro-1H-pyrrol-
1-yloxyl Radical (12) via in situ Boronate
A mixture of compound 4 (248 mg, 1.0 mmol), KOAc (249 mg, 3.0
mmol), pinacolborane (279 mg, 1.1 mmol), PdCl2(dppf) (24 mg,
0.03 mmol) in anhyd DMF (6 mL) was stirred under N2 for 2 h at 80
°C. After cooling, bromobenzene (314 mg, 2.0 mmol), PdCl2(dppf)
(24 mg, 0.03 mmol) and 2.0 M aq Na2CO3 (2.5 mL) was added and
the mixture was stirred under N2 for 12 h at 80 °C. After cooling,
the solvents were evaporated under reduced pressure, the residue
was dissolved in brine (10 mL), extracted with EtOAc (2 10 mL),
dried (MgSO4), filtered, and evaporated. The residue was purified
by flash column chromatography to give compound 12; yield: 45
mg (18%); mp 112–113 °C; Rf 0.32 (hexane–Et2O).
3-[4-(Bromomethyl)phenyl]-2,2,5,5-tetramethyl-2,5-dihydro-
1H-pyrrol-1-yloxyl Radical (25) and 3,4-Bis[4-(bromometh-
yl)phenyl]-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-1-yloxyl
Radical (27)
To a solution of benzylic alcohol 7b (492 mg, 2.0 mmol), or 8b (704
mg, 2.0 mmol) and Et3N (222 mg, 2.2 mmol or 444 mg, 4.4 mmol
in the case of 27) in CH2Cl2 (20 mL) was added methanesulfonyl
chloride (252 mg, 2.2 mmol or 504 mg, 4.4 mmol in case of 27) at
0 °C and the mixture was stirred at r.t. for 1 h. The mixture was then
washed with H2O (10 mL), dried (MgSO4), filtered, and the solvent
evaporated. The residue was dissolved in anhyd acetone (20 mL),
and to this solution was added LiBr (348 mg, 4.0 mmol or 696 mg,
8.0 mmol in the case of 27) and the mixture was heated at reflux and
stirred for 1 h. After cooling, the acetone was evaporated, the resi-
due was dissolved in Et2O (20 mL), washed with H2O (10 mL), the
organic phase was separated, dried (MgSO4), filtered, evaporated
and the residue was purified by flash column chromatography to
3-Formyl-4-[4-(3-formyl-2,2,5,5-tetramethyl-1-oxyl-2,5-dihy-
dro-1H-pyrrol-4-yl)phenyl]-2,2,5,5-tetramethyl-2,5-dihydro-
1H-pyrrol-1-yloxyl Biradical (20)
A mixture of compound 4 (494 mg, 2.0 mmol), phenyl-1,4-diboron-
ic acid (165 mg, 1.0 mmol), Ba(OH)2 8H2O (630 mg, 2.0 mmol) and
PdCl2(PPh3)2 (70 mg, 0.1 mmol) in dioxane (8 mL) and H2O (2 mL)
Synthesis 2002, No. 16, 2365–2372 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Coupling Reactions of Paramagnetic Vinyl Halides
2371
give 25; yield: 290 mg (47%); mp 43–45 °C; Rf 0.25 (hexane–Et2O,
2:1) or 27; yield: 334 mg (35%); mp 147–150 °C; Rf 0.41 (hexane–
EtOAc, 2:1).
(10 mL) was added, extracted with CHCl3 (2 10 mL), the organic
phase was dried (MgSO4), filtered and evaporated. The residue was
dissolved in a mixture of anhyd CH2Cl2 (10 mL) and Et3N (220 mg,
2.2 mmol) and methanesulfonyl chloride (252 mg, 2.2 mmol) was
added at 0 °C and the mixture was allowed to stay at r.t. for over-
night. The mixture was washed with brine (10 mL), the organic
phase was separated, dried (MgSO4), filtered, evaporated and the
residue was purified by flash column chromatography to give the ti-
tle compound 34; yield: 240 mg (36%); mp 173–175 °C as a brown
solid; Rf 0.19 (hexane–EtOAc, 2:1).
3-[4-(Methanethiosulfonylmethyl)phenyl]-2,2,5,5-tetramethyl-
2,5-dihydro-1H-pyrrol-1-yloxyl Radical (26) and 3,4-Bis[4-
(methanethiosulfonylmethyl)phenyl]-2,2,5,5-tetramethyl-2,5-
dihydro-1H-pyrrol-1-yloxyl Radical (28)
To a solution of 25 (309 mg, 1.0 mmol) or the dibromo compound
27 (478 mg, 1.0 mmol) in acetone (10 mL) and H2O (5 mL) was
added NaSSO2Me (268 mg, 2.0 mmol or 536 mg, 4.0 mmol in the
case of 28) and the mixture was refluxed for 30 min. After cooling,
the acetone was evaporated, the aqueous phase was extracted with
1-Methanesulfonyl-2-(1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-
1H-pyrrol-3-yl)-1H-indole Radical (35)
CHCl3 (2
10 mL), the organic phase was separated, dried
A solution of compound 34 (333 mg, 1.0 mmol) and K2CO3 (138
mg, 1.0 mmol) in MeCN (10 mL) was stirred and refluxed for 8 h.
After cooling, the mixture was filtered, the filtrate was evaporated
in a vacuum, the residue was dissolved in CHCl3 (15 mL), washed
with brine (10 mL), the organic phase was separated, dried
(MgSO4), filtered, evaporated and the residue was purified by flash
column chromatography (hexane–EtOAc) to give the title com-
pound 35; yield: 259 mg (78%); mp 128–130 °C as a brown solid;
Rf 0.34 (hexane–EtOAc, 2:1).
(MgSO4), filtered, evaporated, and the residue was purified by flash
column chromatography to give compound 26; yield: 105 mg
(31%); mp 95–97 °C; Rf 0.20 (hexane–EtOAc, 2:1) or 28; yield: 119
mg (22%); mp 161–163 °C; Rf 0.26 (CHCl3–Et2O, 2:1).
1,1,3,3-Tetramethyl-1,3,4,5-tetrahydro-2,4H-pyrrolo[3,4-c]iso-
quinolin-5-on-2-yloxyl Radical (30)
To a solution of mixed anhydride 29 (332 mg, 1.0 mmol) in acetone
(15 mL) was added at 0 °C a solution of NaN3 (195 mg, 3.0 mmol)
in H2O (8 mL). The mixture was stirred for 1 h at 0 °C and the ace-
tone was evaporated under vacuum (no heating !) upon which the
acid azide separated out as oily drops. This solution was extracted
with Et2O (2 10 mL), Ph2O (6 mL) was added, then Et2O was
evaporated very cautiously and the diphenyl ether solution of the
acid azide was heated just to reflux. After cooling the solution was
poured into hexane (50 mL), the precipitated product was filtered
and purified further by flash column chromatography (CHCl3–
Et2O, CHCl3–MeOH) to give 30; yield: 80 mg (31%); mp >265 °C;
Rf 0.31 (CHCl3–MeOH, 9:1).
3-(1H-Indol-2-yl)-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-
1-yloxyl Radical (36)
Method A: A solution of compound 35 (333 mg, 1.0 mmol) and
KOH (112 mg, 2.0 mmol) in MeOH (10 mL) was refluxed for 4 h.
After cooling, the solvent was evaporated, the residue was dissolved
in H2O (10 mL), extracted with Et2O (2 10 mL), the organic phas-
es were combined, dried (MgSO4), filtered, evaporated and the res-
idue was purified by flash column chromatography (hexane–Et2O)
to give compound 36; yield: 112 mg (44%); mp 180–182 °C; Rf
0.43 (hexane–EtOAc, 2:1).
Method B: A solution of alkyne 33 (328 mg, 2.0 mmol), 2-iodoa-
niline (219 mg, 1.0 mmol), Pd(OAc)2 (12.0 mg, 0.05 mmol), K2CO3
(690 mg, 5.0 mmol), Ph3P (13 mg, 0.05 mmol) and Bu4NCl (277
mg, 1.0 mmol) in DMF (10 mL) was stirred and refluxed for 3 h at
100 °C under N2. After cooling the mixture was filtered, the filtrate
was evaporated to dryness under reduced pressure, the residue was
dissolved in brine (10 mL), extracted with EtOAc (2 15 mL), the
combined organic phases were dried (MgSO4), filtered and evapo-
rated and the residue was purified by flash column chromatography
(hexane–Et2O) to give compound 36 as a yellow solid and identical
with the product obtained by Method A; yield: 128 mg (50%).
2,2,5,5-Tetramethyl-4-phenylethynyl-2,5-dihydro-1H-pyrrole-
3-carbaldehyde-1-yloxyl Radical (31)
A mixture of compound 4 (247 mg, 1.0 mmol), PdCl2(PPh3)2 (35
mg, 0.05 mmol), and CuI (19 mg, 0.1 mmol) in DMF (10 mL) and
Et3N (2.02 g, 20.0 mmol) was stirred at 80 °C under N2 for 30 min,
then phenylacetylene (102 mg, 1.0 mmol) was added and the mix-
ture was stirred and refluxed for 3 h. After cooling the solvents were
evaporated, the residue was dissolved in brine (10 mL), extracted
with EtOAc (2 10 mL), the organic phase was separated, dried
(MgSO4), filtered, evaporated and the residue was purified by flash
column chromatography (hexane–Et2O) to give 31; yield: 193 mg
(72%); mp 117–118 °C; Rf 0.44 (hexane–EtOAc, 2:1).
Acknowledgments
1,1,3,3-Tetramethyl-6-phenyl-1,3-dihydro-2H-pyrrolo[3,4-c]-
pyridin-5-oxide-2-yloxyl Radical (32)
This work was supported by a grant from Hungarian National Rese-
arch Foundations (OTKA T34307, T030013 and M 028226). Bo-
lyai fellowship for T. K. from Hungarian Academy of Sciences is
gratefully acknowledged. The authors thank Viola H. Csokona for
technical assistance and elemental analysis and Mária Szabó for
mass spectral measurements (ICN, Hungary).
A solution of compound 31 (268 mg, 1.0 mmol), K2CO3 (138 mg,
1.0 mmol) and hydroxylamine hydrochloride (69.5 mg, 1.0 mmol)
in EtOH (10 mL) and H2O (2 mL) was refluxed for 1 h. The mixture
was evaporated to dryness, the residue was dissolved in EtOH (10
mL), K2CO3 (138 mg, 1.0 mmol) was added, and the mixture was
stirred and refluxed for 3 h. After cooling the solvent was evaporat-
ed, the residue was dissolved in CHCl3 (10 mL), washed with H2O
(10 mL), the organic phase was separated, dried (MgSO4), filtered,
evaporated and the residue was purified by flash column chroma-
tography (CHCl3–Et2O) to give the title compound 32; yield: 232
mg (82%) as a yellow solid; mp 261–263 °C; Rf 0.28 (CHCl3–
MeOH, 9:1).
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Synthesis 2002, No. 16, 2365–2372 ISSN 0039-7881 © Thieme Stuttgart · New York