Synthesis of 1-substituted 7-cyano-2,3-diphenylindolizines and evaluation of antioxidant properties

Article abstract of DOI:10.1002/1099-0690(200011)2000:22<3763::AID-EJOC3763>3.0.CO;2-S

Protocols for the synthesis of novel 1-substituted 7-cyano-2,3-diphenylindolizines from the corresponding indolizinol have been developed, and the compounds' abilities to act as antioxidants, i.e. to inhibit lipid peroxidation in vitro, have been examined

Full text of DOI:10.1002/1099-0690(200011)2000:22<3763::AID-EJOC3763>3.0.CO;2-S

FULL PAPER
Synthesis of 1-Substituted 7-Cyano-2,3-diphenylindolizines and Evaluation of
Antioxidant Properties
Ole Benny Østby,[a] Bjørn Dalhus,[a] Lise-Lotte Gundersen,*[a] Frode Rise,[a] Aalt Bast,[b] and
Guido R. M. M. Haenen[b]
Keywords: Antioxidants / Biaryls / Cross-coupling / Indolizine / Lithiation
Protocols for the synthesis of novel 1-substituted 7-cyano-2,3-
diphenylindolizines from the corresponding indolizinol have
been developed, and the compounds’ abilities to act as anti-
oxidants, i.e. to inhibit lipid peroxidation in vitro, have been
examined. 1-Bromo-7-cyano-2,3-diphenylindolizine 9 readily
termined by single-crystal X-ray diffraction methods at
150 K. An alternative strategy for the introduction of sub-
stituents at C-1 is by lithiation of the bromide 9 followed by
reaction with electrophiles. The ability of the indolizine de-
rivatives to inhibit lipid peroxidation in vitro was examined.
participates in Pd-catalysed coupling reactions with or- Lipid peroxidation of boiled rat liver microsomes was in-
ganotin, organozinc, and organoboron reagents. Similar
treatment of the corresponding indolizinyl triflate 6, on the
other hand, resulted only in partial cleavage of the triflate
duced by ascorbic acid/FeSO4 and peroxidation was deter-
mined by measuring the material reactive to thiobarbituric
acid. In particular, the indolizinyl acetate 4 and the triflate 6
back to the indolizinol, except in reaction with 1-ethoxy- appear to be highly active antioxidants, with IC50 values be-
ethenyl(tributyl)tin. Here, the unexpected acetal (1-ethoxy- low 1 µm in the bioassay.
ethoxy)indolizine 10 was formed. The structure of 10 was de-
Introduction
tuted indolizine derivatives, as well as their abilities to in-
hibit lipid peroxidation in vitro.
Compounds with antioxidant/radical-scavenging proper-
ties may have therapeutic potential, because free radicals
have been implicated in major diseases such as, for instance,
cancer, Parkinson’s disease, Alzheimer’s disease, stroke,
heart infarction and rheumatoid arthritis.[1] Inspired by the
fact that 1-indolizinols are easily oxidised to stable free rad-
icals,[2] we have previously prepared a number of indolizin-
ols O-protected as esters, ethers, carbonates, and carba-
mates (Figure 1). Several of these derivatives strongly inhib-
ited lipid peroxidation in vitro.[3,4] Regardless of the nature
of the O-substituent, otherwise identical indolizines exhib-
ited comparable activities in the test system. This finding
led us to infer that the indolizines themselves were acting
as antioxidants and not as pro-drugs; cleavage of O-sub-
stituents (especially methyl ethers) to give the unprotected
indolizinol in the test medium was highly unlikely. We pro-
posed that the indolizines may inhibit lipid peroxidation by
an electron donation mechanism. Cyclic voltammetry sup-
ported this hypothesis; reversible oxidation to the corres-
ponding radical cation with E° (vs. Fc/Fcϩ) in the range of
0.4Ϫ0.7 V was found for acetates, ethers and carbonates.[4]
Here we report the synthesis of a variety of novel 1-substi-
Figure 1. General structure for indolizine derivatives which inhibit
lipid peroxidation. The numbering of the indolizine nucleus used
throughout this paper is shown
Results and Discussion
We chose to prepare all of the indolizines reported here
via the indolizinol 3, which is readily generated in situ by
cyclisation of cyanopyridine 1 with commercially available
diphenylcyclopropenone 2[2a] (Scheme 1). Previous results
had led us to believe that an electron-withdrawing substitu-
ent in the indolizine 7-position was beneficial for lipid per-
oxidation inhibition.[4] The cyano group was chosen be-
cause: complete regioselectivity had been reported in the
reaction between pyridine 1 and cyclopropenone 2,[2a] the
indolizinol 3 is reasonably stable,[2a] and the cyano substitu-
ent was expected to be compatible with a variety of reac-
tion conditions.
Previously, we had reported high antioxidant activity for
acetates and methyl ethers of other 1-indolizinols,[4] and so
we first prepared the acetate 4[2a] and the methoxy com-
pound 5 (Scheme 1). We anticipated that conversion of the
hydroxy substituent in compound 3 into halides or sulfon-
ates would allow us to synthesise a number of 1-substituted
indolizines. Compound 3 was easily converted into the tri-
[a]
Department of Chemistry, University of Oslo,
P. O. Box 1033, Blindern, 0315 Oslo, Norway
Fax: (internat.) ϩ47-22/855-507
E-mail: l.l.gundersen@kjemi.uio.no
[b]
Department of Pharmacology and Toxicology, Faculty of
Medicine, University of Maastricht,
P. O. Box 616, 6200 MD Maastricht, The Netherlands
Eur. J. Org. Chem. 2000, 3763Ϫ3770
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/1122Ϫ3763 $ 17.50ϩ.50/0
3763

O. B. Østby, B. Dalhus, L.-L. Gundersen, F. Rise, A. Bast, G. R. M. M. Haenen
FULL PAPER
flate 6 resulted in extensive decomposition of the starting
material and no indolizine products could be detected, ex-
cept in the coupling with 1-ethoxyethenyl(tributyl)tin where
the unexpected acetal 10 was isolated in 20% yield
(Scheme 2). The formation of compound 10 is not com-
pletely understood, but most probably the triflate is cleaved
to give 3 during the reaction sequence. In the literature we
can find no other examples describing acetal formation
when 1-ethoxyethenyl(tributyl)tin is treated with phenols or
triflates. The structure of compound 10 was confirmed by
HMQC[9] and HMBC[10] NMR spectroscopy, as well as by
X-ray crystallography (Figure 2, Table 1). The asymmetric
unit of 10, with partial atom numbering, is shown in Fig-
ure 2. Two positions for the methyl group bound to C22
were located in the difference electron density map calcu-
lated from the atoms in the indolizine and phenyl moieties.
The side chain at C6 is disordered over two conformations.
Except for O1, all non-H atoms in the side chain were re-
fined over two positions. The two components, with occu-
pancy factors 0.517(5) and 0.483(5), were restrained to the
same 1Ϫ2 and 1Ϫ3 distances within an effective standard
˚
deviation of 0.03 A. Further pairs of disordered atoms in
each component share the same set of displacement para-
meters. Tables of geometric parameters, anisotropic dis-
placement parameters, coordinates of hydrogen atoms and
a listing of observed and calculated structure factors are
available from the correspondence author upon request.
Scheme 1. Reagents and conditions: i, DCE, ∆; ii, DMAP, Ac2O,
DCE; iii, NaH, MeI, THF; iv, DMAP, Tf2O, DCM, Ϫ78 °C; v,
TsCl, DMAP, Et3N, DCE, 0 °C; vi, POCl3, ∆; vii, Br2, PPh3,
MeCN, 70 °C
flate 6 and the tosylate 7 (Scheme 1). Conversion of a 5-
azaindolizinol into the corresponding chloride has been
achieved by refluxing the azaindolizinol with phosphorus
oxychloride (POCl3).[5,13] When the indolizinol 3 was sub-
jected to refluxing POCl3, the chloroindolizine 8 was indeed
formed, but only in low yield (attempts to make the chlor-
ide 8 by treatment of the indolizinol with triphenylphos-
phane dichloride were unsuccessful, however). Hence, we
transformed the indolizinol 3 into the more reactive brom-
ide 9 with triphenylphosphane dibromide[6] in dry acetonitr-
ile.
Scheme 2. Reagents and conditions: i, (Ph3P)4Pd, LiCl, THF, 50 °C
The indolizines 6؊9 were subjected to palladium-cata-
lysed cross coupling reaction conditions with organotin, or-
ganozinc or organoboron reagents. Tosylates are generally
poor substrates for such couplings, and the tosylate 7, not
unexpectedly, was inert under the reaction conditions em-
ployed. Comparable reactivities are often reported for
bromides and triflates in Pd-catalysed couplings,[7] but re-
markable differences were observed when the triflate 6 and
the bromide 9 were treated with organotin or organozinc
reagents in the presence of a palladium catalyst. Pd-cata-
lysed coupling with organozinc reagents can usually be con-
ducted under mild reaction conditions, but when the triflate
6 was treated with methylzinc bromide in the presence of
catalytic amounts of tetrakis(triphenylphosphane)palla-
dium(0), only cleavage of the triflate 6 to the indolizinol 3
was observed[8] and compound 3 was isolated in 65% yield.
The reactivity of the triflate 6 was essentially the same
whether or not lithium chloride was added to the reaction
Figure 2. Molecular structure of 10 with partial atomic numbering.
Displacement ellipsoids drawn at the 50% probability level. H-
atoms arbitrarily scaled. Minor component of disordered side
mixture. All attempts to perform Stille coupling on the tri- chain drawn using open ellipsoids and broken lines
3764 Eur. J. Org. Chem. 2000, 3763Ϫ3770

Synthesis of 1-Substituted 7-Cyano-2,3-diphenylindolizines
FULL PAPER
Table 1. Crystal data, intensity collection and refinement data for
The yields of the coupling products 11 were generally
high and even the hindered o-methoxyphenylzinc reagent
participated in the coupling reaction to give compound 11g
in quite good yield. In several of the reactions, minor
quantities of the dimer 12 and also the reduced indolizine
13 (Scheme 3) was formed, and the isolated yields of some
coupling products (i.e. 11d and 11f) were somewhat reduced
thanks to the necessary, tedious separation from the by-
products. In the reaction with 1-ethoxyethenyl(tributyl)tin,
the initially formed enol ether was cleaved during workup,
and only the methyl ketone 11b could be isolated.
In order to evaluate the influence of the indolizine 1-sub-
stituent on antioxidant properties, we also needed the C-1
unsubstituted compound 13. We prepared this compound
in 92% yield by treatment of the bromoindolizine 9 with n-
butyllithium (nBuLi), with subsequent quenching with
aqueous ammonium chloride (Scheme 4). When only 1.0
equiv. of nBuLi was employed, the metal-halogen exchange
was completely selective and no attack on the cyano sub-
stituent was observed. Increasing the amount of nBuLi re-
sulted in mixtures of the cyanide 13 and the n-butyl ketone
14 after aqueous workup, and the ketone 14 was isolated in
high yield when a large excess (10 equiv.) of nBuLi was em-
ployed.
10
Empirical formula
Formula mass [g molϪ1
Crystal size [mm]
Colour, habit
C25H22N2O2
382.45
]
1.20ϫ0.35ϫ0.05
Yellow plates
Monoclinic
P21/c (No. 14)
a ϭ 15.2145(2)
b ϭ 5.9043(1)
c ϭ 23.2611(2)
β ϭ 103.644(1)
2030.6(1)
Crystal system
Space group
˚
Cell dimensions [A,°]
3
˚
Volume [ A ]
Z
4
Dcalcd. [g cmϪ3
]
1.251
Diffractometer
Radiation
T [K]
Siemens SMART[12]
˚
Mo-Kα (λ ϭ 0.71073 A)
150
2θ range [°]
2.51…26.38
16022
4144
No. of reflections measured
No. of reflections used in refinement
No. of reflections with I Ͼ 2σ(I) n
Refinement
3395
on F2
282
No. of refined parameters p
R ϭ Σ|∆F|/|Fo|[a] [I Ͼ 2σ(I)]
0.0658
Rw ϭ {Σ[w(∆F)2/w(Fo)2]}1/2[b] [I Ͼ 2σ(I)] 0.1519
S ϭ {Σ[w(∆F)2/(n-p)]}1/2 [I Ͼ 2σ(I)]
1.040
ϩ0.452, Ϫ0.427
Ϫ3
˚
Residual electron density [e A
]
[a] ∆F ϭ |Fo| Ϫ |Fc|. Ϫ [b] w ϭ (σ2(FO2) ϩ (0.0572P)2 ϩ 2.2873P)Ϫ1
,
2
where Pϭ(Fo ϩ 2Fc)/3.
When the lithiated indolizine described above was treated
with methyl iodide, we found that partial rearrangement to
the 8-lithioindolizine took place if the reaction mixture was
allowed to reach ambient temperature during the trapping
reaction; a minor amount of the 8-methyl isomer 15 was
formed together with the expected product 11j. We were not
able to isolate the compound 15 in pure form and the pro-
posed structure is based on the coupling pattern for the
On the other hand, the indolizinyl bromide 9 readily par-
ticipated in Pd-catalysed couplings with organotin, or-
ganozinc and organoboron reagents to give the desired
coupling products 11 (Scheme 3, Table 2). The choice of tin-
zinc, or boron as the metal in the organometallic coupling
partner was largely governed by the availability of the re-
agents. To the best of our knowledge, the examples reported
here constitute the first examples of Pd-catalysed cross-
couplings on 1-haloindolizines.
1
indolizine hydrogen resonances in the H NMR spectrum.
When the reaction temperature was kept at Ϫ78 °C during
the methylation, the formation of compound 11j was almost
specific. The 1-lithioindolizine reacted readily with benzal-
dehyde at Ϫ78 °C to give the adduct 16, and no regioiso-
mers could be detected.
The ability of the indolizine derivatives to inhibit lipid
peroxidation in vitro was examined and the results are
summarised in Table 3. The testing was performed as we
have described previously.[4] Lipid peroxidation of boiled rat
liver microsomes was induced by ascorbic acid/FeSO4 and
Scheme 3. Reagents and conditions: i, (Ph3P)4Pd, R-Met, see also
Table 2
Table 2. Palladium-catalysed cross coupling between the bromide 9 and organometallic reagents
R-Met
Solvent
Temp. [°C]
Time [h]
R in 11
Yield (%)
11
CH2ϭCHSnBu3
CH2ϭC(OEt)SnBu3
2-ThienylSnBu3
DMF
100
100
90
23
24
48
0.5
CH2ϭCH-
MeCO-
74, 11a
68, 11b
91, 11c
55, 11d
DMF
DMF
2-Thienyl-
3-Thienyl-
3-ThienylB(OH)2
Dioxane
NaOH (aq)
DMF
∆
2-FurylSnBu3
PhZnBr
o-MeOC6H4ZnBr
m-MeOC6H4ZnBr
p-MeOC6H4ZnBr
MeZnBr
90
60
60
60
60
∆
48
42
50
23
18
42
2-Furyl
Ph-
o-MeOC6H4-
m-MeOC6H4-
p-MeOC6H4-
Me-
97, 11e
71, 11f
55, 11g
70, 11h
78, 11i
75, 11j
THF
THF
THF
THF
Dioxane
Eur. J. Org. Chem. 2000, 3763Ϫ3770
3765

O. B. Østby, B. Dalhus, L.-L. Gundersen, F. Rise, A. Bast, G. R. M. M. Haenen
FULL PAPER
Conclusions
A variety of novel 1-substituted indolizines have been
prepared from the corresponding 1-indolizinol. Treatment
of the indolizinol with triphenylphosphane dibromide gives
the corresponding bromoindolizine, which readily particip-
ates in Pd-catalysed cross-coupling reactions. An alternative
strategy for the introduction of substituents at C-1 was also
developed; this consisted of lithiation of the bromide 9 fol-
lowed by completely regioselective reaction with elec-
trophiles at low temperatures. At higher temperatures, some
migration of lithium to the indolizine 8-position was ob-
served; after further fine-tuning it may be possible to direct
the lithiation reaction to give regioselective formation of
either the 1- or the 8-substituted indolizine, depending on
the reaction conditions. The antioxidant properties of the
indolizines described here were examined and the acetate 4
and the triflate 6 in particular were found to be strong in-
hibitors of lipid peroxidation in vitro, with IC50 values be-
low 1 µ.
Scheme 4. Reagents and conditions: i, nBuLi (1.1 equivs.), THF,
Ϫ78 °C; ii, NH4Cl (aq); iii, MeI, 9 h, Ϫ78 °C to room temp.; iv,
MeI, 47 h, Ϫ78 °C; v, nBuLi (10 equivs.), THF, Ϫ78 °C; vi,
PhCHO, 1.5 h, Ϫ78 °C
Experimental Section
General Remarks: The 1H NMR spectra were recorded at 500 MHz
with a Bruker Avance DRX 500 instrument, at 300 MHz with a
Bruker Avance DPX 300 instrument or at 200 MHz with a Bruker
Avance DPX 200 instrument. The 13C NMR spectra were recorded
at 125, 75 or 50 MHz using the above-mentioned spectrometers,
and the 19F NMR spectra were recorded at 188 MHz on the Bruker
Avance DPX 200 instrument. Ϫ Mass spectra were recorded at 70
eV ionising voltage with a VG Prospec instrument, and are pre-
sented as m/z (% rel. int.). Methane was used for chemical ionis-
ation (CI). Ϫ Elemental analyses were performed by Ilse Beetz Mi-
kroanalytisches Laboratorium, Kronach, Germany. Ϫ Melting
points are uncorrected. Ϫ Silica gel for flash chromatography was
purchased from Merck, Darmstadt, Germany (Merck No. 9385).
Ϫ Analytical thin layer chromatography was performed using E.
Merck silica gel 60F254 0.25 mm plates (Merck No. 1.05554). Ϫ
THF and 1,4-dioxane were distilled from sodium and benzo-
phenone, and acetonitrile, DMF, DCE, DCM, pyridine, and tri-
ethylamine were distilled from calcium hydride. Methanol was dis-
tilled from magnesium and iodine. Zinc bromide was dried at 125
°C under high vacuum for 2Ϫ4 h, weighed out, and dissolved in
dry THF to give a solution, which was stored under N2. Benzal-
dehyde was distilled under N2 prior to use. 7-Cyano-2,3-diphenylin-
dolizin-1-yl acetate 4[2a] was prepared as described before. All other
reagents were commercially available and used as received.
the peroxidation was determined by measuring the mat-
erials reactive to thiobarbituric acid. Compounds bearing
an oxygen atom in the indolizine 1-position (acetate 4,
methyl ether 5, triflate 6, and tosylate 7), and also the
benzyl alcohol 16, were all able to inhibit lipid peroxidation,
while the unsubstituted compound 13, the bromide 9 and
the coupling products 11 were essentially inactive. The acet-
ate 4 and the triflate 6 appear, especially, to be highly active
antioxidants, with IC50 values below 1 µ in the bioassay.
Further studies of the structure/activity relationships (SAR)
of indolizines as antioxidants are in progress.
Table 3. Antioxidant properties of 1-substituted 7-cyano-2,3-di-
phenylindolizine derivatives
Substituent in the indolizine 1-position IC50 values[a]
Compound
4
AcOϪ
0.15
5
MeOϪ
22.0
6
TfOϪ
0.60
3.64
7
TsOϪ
9
BrϪ
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
35.8
1-Methoxy-2,3-diphenylindolizine-7-carbonitrile (5): A mixture of
diphenylcyclopropenone (309 mg, 1.50 mmol) and 4-cyanopyridine
(156 mg, 1.50 mmol) in dry DCE (20 mL) was refluxed under N2
for 16 h, cooled and evaporated in vacuo. The residue was dissolved
in dry THF (40 mL), and sodium hydride (79 mg, 3.3 mmol) was
added. The resulting mixture was stirred under N2 at ambient tem-
perature for 1 h, after which iodomethane (468 mg, 3.30 mmol) was
added. After stirring at ambient temperature for 1 h, the reaction
mixture was evaporated in vacuo, the residue was dissolved in di-
ethyl ether (300 mL) and washed with water (100 mL). The dried
(MgSO4) organic solution was evaporated in vacuo and the product
was purified by flash chromatography, eluting with EtOAc/hexane
11a
11b
11c
11d
11e
11f
11g
11h
11i
13
16
CH2ϭCHϪ
MeCOϪ
2-ThienylϪ
3-ThienylϪ
2-FurylϪ
PhϪ
o-MeOC6H4Ϫ
m-MeOC6H4Ϫ
p-MeOC6H4Ϫ
HϪ
PhCH(OH)Ϫ
[a]
IC50 (µ) is the concentration which causes 50% inhibition of
lipid peroxidation after 30 min. The values are given as the mean of
3 separate experiments and the accuracy of the data is within 25%.
1
(1:19). Yield 457 mg (94%) of yellow crystals, m.p. 178 °C. Ϫ H
3766
Eur. J. Org. Chem. 2000, 3763Ϫ3770

Synthesis of 1-Substituted 7-Cyano-2,3-diphenylindolizines
FULL PAPER
NMR (500 MHz, [D6]acetone): δ ϭ 3.80 (s, 3 H, Me), 6.55 (dd, 1
eluting with EtOAc/hexane (1:9). Yield 25 mg (15%) of yellow crys-
H, J ϭ 7.4 and 1.8 Hz, 6-H), 7.2Ϫ7.4 (7 H, m, Ph), 7.4Ϫ7.5 (m, 3 tals, m.p. 183Ϫ184 °C. Ϫ Rf ϭ 0.34 (1:4, EtOAc/hexane). Ϫ 1H
H, Ph), 7.96 (dd, 1 H, J ϭ 7.4 and 1.0 Hz, 5-H), 8.08 (dd, 1 H,
J ϭ 1.8 and 1.0 Hz, 8-H). Ϫ 13C NMR (125 MHz, [D6]acetone):
δ ϭ 62.8, 98.0, 110.7, 119.7, 121.4, 121.8, 122.8, 124.2, 125.0, 127.7,
129.0, 129.5, 130.0, 130.8, 130.8, 131.4, 133.2, 140.5. Ϫ MS (EI);
NMR (500 MHz, CDCl3): δ ϭ 6.49 (dd, 1 H, J ϭ 7.4 and 1.8 Hz,
6-H), 7.2Ϫ7.3 (7 H, m, Ph), 7.3Ϫ7.4 (m, 3 H, Ph) 7.87 (dd, 1 H,
J ϭ 1.8 and 0.8 Hz, 8-H), 7.90 (dd, 1 H, J ϭ 7.4 and 0.8 Hz, 5-H).
Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ 99.9, 106.6, 110.8, 118.8,
m/z (%): 324 [Mϩ] (54), 309 (100), 149 (16), 131 (20), 122 (16), 103 122.5, 124.3, 125.5, 127.0, 127.5, 127.8, 128.2, 128.9, 129.2, 129.2,
(50), 81 (7), 68 (19). Ϫ C22H16N2O (324.38): calcd. C 81.46, H 4.97;
found C 81.73, H, 5.08.
130.4, 130.4, 131.0. Ϫ MS (EI); m/z (%): 328 [Mϩ] (100), 293 (24),
292 (20), 264 (4), 253 (2), 239 (3), 225 (3), 211 (3), 146 (12), 85 (24).
Ϫ HRMS C21H13N2Cl: calcd. 328.0767; found 328.0780.
7-Cyano-2,3-diphenylindolizin-1-yl Triflate (6): A mixture of di-
phenylcyclopropenone (206 mg, 1.00 mmol) and 4-cyanopyridine
(104 mg, 1.00 mmol) in dry DCE (40 mL) was refluxed under N2
for 16 h and evaporated in vacuo. The residue was dissolved in dry
1-Bromo-2,3-diphenylindolizine-7-carbonitrile (9): A mixture of di-
phenylcyclopropenone (103 mg, 0.50 mmol) and 4-cyanopyridine
(52 mg, 0.50 mmol) in dry DCE (10 mL) was refluxed under N2
DCM (120 mL) and DMAP (244 mg, 2.00 mmol) was added. The for 20 h, cooled and the solvent was removed under a stream of
resulting mixture was stirred under N2 at ambient temperature for
1.5 h and cooled to Ϫ78 °C, after which trifluoromethanesulfonic
anhydride (0.164 mL, 1.00 mmol) was added. After stirring at Ϫ78
°C for 1 h, the reaction mixture was allowed to reach ambient tem-
perature and evaporated in vacuo. The product was purified by
flash chromatography, eluting with EtOAc/hexane (1:29). Yield 389
mg (88%) of yellow crystals, m.p. 158Ϫ160 °C (decomp.). Ϫ 1H
N2. The residue was dissolved in dry acetonitrile (5 mL) and the
mixture was stirred at ambient temperature under N2. A mixture
of triphenylphosphane dibromide in acetonitrile [generated in a
separate flask from triphenylphosphane (393 mg, 1.50 mmol) and
bromine (240 mg, 1.50 mmol) in acetonitrile (3 mL) at 0 °C] was
added and the resulting mixture was stirred at 70 °C for 72 h, co-
oled and evaporated in vacuo. The product was purified by flash
NMR (200 MHz, [D6]acetone): δ ϭ 6.87 (dd, 1 H, J ϭ 7.4 and chromatography, eluting with EtOAc/hexane (1:29). Yield 151 mg
1.8 Hz, 6-H), 7.2Ϫ7.5 (m, 10 H, Ph), 8.15 (m, 1 H, 8-H), 8.21 (dd, (81%) of yellow crystals, m.p. 197Ϫ198 °C. Ϫ 1H NMR (300 MHz,
1 H, J ϭ 7.4 and 1.0 Hz, 5-H). Ϫ 13C NMR (50 MHz, [D6]ace-
CDCl3): δ ϭ 6.47 (dd, 1 H, J ϭ 7.4 and 1.7 Hz, 6-H), 7.1Ϫ7.4 (m,
tone): δ ϭ 103.1, 112.3, 118.6, 119.3 (q, JCF 320 Hz, CF3), 122.6, 10 H, Ph), 7.82 (dd, 1 H, J ϭ 1.7 and 0.9 Hz, 8-H), 7.89 (dd, 1 H,
123.2, 123.4, 124.2, 125.0, 126.1, 128.8, 129.3, 129.4, 130.1, 130.1,
J ϭ 7.4 and 0.9 Hz, 5-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ
93.4, 110.4, 110.9, 118.7, 122.8, 125.1, 126.2, 127.5, 128.0, 128.5,
130.8, 131.1, 131.6. Ϫ 19F NMR (188 MHz, [D6]acetone): δ ϭ
Ϫ73.6 (CF3). Ϫ MS (CI); m/z (%): 443 [M ϩ 1] (7), 339 (18), 325 128.8, 129.1, 129.1, 129.6, 130.3, 130.5. 132.2. Ϫ MS (EI); m/z (%):
(29), 310 (100), 295 (30), 279 (27), 178 (39), 165 (24), 105 (23), 65 374/372 [Mϩ] (100/100), 293 (54), 264 (8), 189 (7), 146 (31), 132
(63). Ϫ C22H13F3N2O3S (442.42): calcd. C 59.73, H 2.97; found C
(7). Ϫ C21H13BrN2 (373.24): calcd. C 67.58, H 3.51; found C 67.21,
59.87, H, 2.85.
H, 3.66.
7-Cyano-2,3-diphenylindolizin-1-yl Tosylate (7): A mixture of di-
(1-Ethoxyethoxy)-2,3-diphenylindolizine-7-carbonitrile
(10):
phenylcyclopropenone (516 mg, 2.50 mmol) and 4-cyanopyridine
Tetrakis(triphenylphosphane)palladium(0) [generated from tris(di-
(260 mg, 2.50 mmol) in dry DCE (140 mL) was refluxed under N2 benzylideneacetone)dipalladium chloroform adduct (26 mg,
for 24 h and cooled to 0 °C, after which DMAP (610 mg,
5.00 mmol) and toluene-4-sulfonyl chloride (953 mg, 5.00 mmol)
0.025 mmol) and triphenylphosphane (52 mg, 0.20 mmol)] in dry
DMF (2.5 mL) was added to a solution of 7-cyano-2,3-diphenylin-
were added. The resulting mixture was stirred at 0 °C for 30 min dolizin-1-yl triflate 6 (442 mg, 1.00 mmol), lithium chloride (85 mg,
and at ambient temperature for 24 h. The reaction mixture was
washed with water (25 mL) and brine (25 mL), dried (MgSO4) and
evaporated in vacuo. The product was purified by flash chromato-
graphy, eluting with EtOAc/hexane (1:4). Yield 847 mg (73%) of
yellow crystals, m.p. 201Ϫ202 °C. Ϫ 1H NMR (200 MHz, [D6]ace-
2.0 mmol), and 1-ethoxyethenyl(tributyl)tin (0.439 mL, 1.30 mmol)
in DMF (1.5 mL). The resulting mixture was stirred for 1 h under
N2 at 50 °C, cooled and evaporated in vacuo. The residue was dis-
solved in a saturated solution of KF in MeOH and stirred for 1 h.
The mixture was evaporated in vacuo and the product was purified
tone): δ ϭ 2.33 (s, 3 H, Me), 6.75 (dd, 1 H, J ϭ 7.5 and 1.8 Hz, 6- by flash chromatography, eluting with EtOAc/hexane (1:29). Yield
1
H), 6.9Ϫ7.0 (m, 2 H, Ar), 7.1Ϫ7.5 (m, 2 H, Ar), 7.87 (dd, 1 H,
J ϭ 1.8 and 1.0 Hz, 8-H), 8.07 (dd, 1 H, J ϭ 7.5 and 1.0 Hz, 5-H).
Ϫ
76 mg (20%) of yellow crystals, m.p. 105Ϫ110 °C (decomp.). Ϫ H
NMR (500 MHz, [D6]acetone): δ ϭ 1.01 (t, 3 H, J ϭ 7.1 Hz, Me),
13C NMR (75 MHz, [D6]acetone): δ ϭ 21.6, 100.5, 110.8, 118.6, 1.25 (3 H, d, J ϭ 5.2 Hz, Me), 3.41 (m, 1 H, HA in CH2), 3.66 (m,
122.0, 122.8, 123.0, 123.4, 124.6, 126.5, 126.9, 127.8, 128.4, 128.9,
1 H, HB in CH2), 5.00 (1 H, q, J ϭ 5.2 Hz, CH), 6.59 (dd, 1 H,
129.2, 129.3, 129.9, 130.4, 130.5, 131.1, 145.3. Ϫ MS (EI); m/z (%): J ϭ 7.4 and 1.8 Hz, 6-H), 7.2Ϫ7.5 (m, 10 H, Ph), 8.01 (dd, 1 H,
464 [Mϩ] (3), 367 (7), 309 (100), 285 (46), 178 (7), 131 (11), 103 J ϭ 7.4 and 0.9 Hz, 5-H), 8.05 (dd, 1 H, J ϭ 1.8 and 0.9 Hz, 8-H).
(29), 91 (12), 65 (6). Ϫ C28H20N2O3S (464.55): calcd. C 72.40, H
Ϫ
13C NMR (50 MHz, [D6]acetone): δ ϭ 15.1, 20.5, 63.3, 98.0,
4.34; found C 72.51, H, 4.25.
104.5, 110.4, 119.2, 122.5, 122.7, 122.8, 123.9, 125.0, 127.4, 128.5,
129.0, 129.5, 130.3, 130.7, 131.0, 133.0, 135.7. Ϫ MS (CI); m/z (%):
383 [M ϩ 1] (1), 339 (4), 352 (6), 310 (100), 294 (18), 281 (2), 178
(7), 149 (5), 103 (4), 91 (4). Ϫ C25H22N2O2 (382.46): calcd. C 78.51,
H 5.80; found C 78.75, H, 5.94.
1-Chloro-2,3-diphenylindolizine-7-carbonitrile (8): A mixture of di-
phenylcyclopropenone (52 mg, 0.5 mmol) and 4-cyanopyridine
(103 mg, 0.50 mmol) in methanol (3 mL) was refluxed under N2
for 4 h and the resulting mixture was kept in the refrigerator for 24
h. The crystals formed were filtered off and refluxed in phosphorus
oxychloride (2 mL) under N2 for 24 h. After cooling to ambient
temperature, chloroform (25 mL) and ice (25 g) were added to the
reaction mixture and the phases were separated after the ice had
melted. The organic extract was washed with saturated aqueous
sodium carbonate solution (25 mL), dried (MgSO4), and evapor-
ated in vacuo. The product was purified by flash chromatography,
1-Ethenyl-2,3-diphenylindolizine-7-carbonitrile (11a): Tetrakis(tri-
phenylphosphane)palladium(0) [generated from tris(dibenzylidene-
acetone)dipalladium chloroform adduct (26 mg, 25 µmol) and tri-
phenylphosphane (52 mg, 200 µmol)] in dry DMF (7 mL) was ad-
ded to a solution of 1-bromo-7-cyano-2,3-diphenylindolizine 9 (373
mg, 1.00 mmol) and ethenyl(tributyl)tin (0.379 mL, 1.30 mmol) in
DMF (3 mL). The resulting mixture was stirred for 23 h under N2
Eur. J. Org. Chem. 2000, 3763Ϫ3770
3767

O. B. Østby, B. Dalhus, L.-L. Gundersen, F. Rise, A. Bast, G. R. M. M. Haenen
FULL PAPER
1
at 100 °C, cooled and evaporated in vacuo. The residue was dis-
solved in a saturated solution of KF in MeOH and stirred for 2 h.
The mixture was evaporated in vacuo and the product was purified
by flash chromatography, eluting with EtOAc/hexane (1:49, 1:39,
Yield 103 mg (55%) of yellow crystals, m.p. 257 °C. Ϫ H NMR
(500 MHz, CDCl3): δ ϭ 6.46 (dd, 1 H, J ϭ 7.4 and 1.8 Hz, 6-H),
6.78 (dd, 1 H, J ϭ 5.0 and 1.3 Hz, 4-H in thienyl), 7.0 (m, 2 H,
Ph), 7.03 (dd, 1 H, J ϭ 3.0 and 1.3 Hz, 2-H in thienyl), 7.1Ϫ7.2
(m, 3 H, Ph), 7.2Ϫ7.3 (m, 3 H, Ph and 5-H in thienyl), 7.3Ϫ7.4
1:29, 1:19 and finally 1:9). Yield 236 mg (74%) of yellow crystals,
1
m.p. 156Ϫ157 °C. Ϫ H NMR (500 MHz, CDCl3): δ ϭ 5.10 (dd, (m, 3 H, Ph), 7.91 (dd, 1 H, J ϭ 7.4 and 0.9 Hz, 5-H), 7.92 (dd, 1
1 H, J ϭ 11.5 and 1.5 Hz, ϭCH2), 5.30 (dd, 1 H, J ϭ 17.8 and
1.5 Hz, ϭCH2), 6.37 (dd, 1 H, J ϭ 7.5 and 1.7 Hz, 6-H), 6.60 (dd, 99.5, 110.5, 114.1, 119.3, 122.5, 122.7, 125.5, 125.8, 126.4, 126.9,
H, J ϭ 1.8 and 0.9 Hz, 8-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ
1 H, J ϭ 17.8 and 11.5 Hz, CHϭ), 7.0Ϫ7.1 (m, 2 H, Ph), 7.1Ϫ7.2
128.0, 128.4, 128.6, 128.9, 129.1, 129.1, 129.7, 130.4, 130.7, 133.3,
(m, 5 H, Ph), 7.2 (m, 3 H, Ph), 7.80 (dd, 1 H, J ϭ 7.5 and 1.0 Hz, 133.5. Ϫ MS (EI); m/z (%): 376 [Mϩ] (100), 342 (2), 339 (3), 298
5-H), 7.96 (dd, 1 H, J ϭ 1.7 and 1.0 Hz, 8-H). Ϫ 13C NMR (6), 271 (7), 239 (3), 188 (3), 166 (2). Ϫ C25H16N2S (376.49): calcd.
(125 MHz, CDCl3): δ ϭ 100.3, 110.9, 115.0, 115.8, 119.5, 123.3,
125.8, 126.8, 127.4, 128.4, 128.4, 128.8, 129.3, 129.9, 130.0, 130.8,
131.1, 134.1, one signal was hidden. Ϫ MS (EI); m/z (%): 320 [Mϩ]
(100), 319 (96), 242 (11), 215 (12), 159 (7), 152 (9). Ϫ C23H16N2
(320.39): calcd. C 86.22, H 5.03; found C 85.96, H, 4.84.
C 79.76, H 4.28; found C 79.48, H, 4.24.
1-(2-Furyl)-2,3-diphenylindolizine-7-carbonitrile (11e): The title
compound was prepared from 1-bromo-7-cyano-2,3-diphenylindol-
izine 9 (224 mg, 0.600 mmol) and 2-furyl(tributyl)tin (278 mg,
0.780 mmol) in DMF (5 mL) as described for compound 11a above
and in Table 2. The product was purified by flash chromatography,
eluting with EtOAc/hexane (1:99, 1:29, and finally 1:19). Yield 209
1-Acetyl-2,3-diphenylindolizine-7-carbonitrile (11b): The title com-
pound was prepared from 1-bromo-7-cyano-2,3-diphenylindolizine
9 (113 mg, 0.30 mmol) and 1-ethoxyethenyl(tributyl)tin (142 mg, mg (97%) of yellow crystals, m.p. 233Ϫ234 °C. Ϫ 1H NMR
0.390 mmol) in DMF (4 mL) as described for compound 11a above
and in Table 2. The product was purified by flash chromatography,
eluting with EtOAc/hexane (1:99, 1:39, 1:29, and finally 1:19). Yield
(200 MHz, CDCl3): δ ϭ 5.64 (dd, 1 H, J ϭ 3.4 and 0.7 Hz, 3-H in
furyl), 6.16 (dd, 1 H, J ϭ 3.4 and 1.9 Hz, 4-H in furyl), 6.40 (dd,
1 H, J ϭ 7.4 and 1.8 Hz, 6-H), 7.0Ϫ7.3 (m, 10 H, Ph), 7.30 (dd, 1
69 mg (68%) of yellow crystals, m.p. 187Ϫ189 °C. Ϫ 1H NMR H, J ϭ 1.9 and 0.7 Hz, 5-H in furyl), 7.80 (dd, 1 H, J ϭ 7.4 and
(300 MHz, [D6]acetone): δ ϭ 1.93 (s, 3 H, Me), 7.05 (dd, 1 H, J ϭ
7.3 and 1.9 Hz, 6-H), 7.3Ϫ7.5 (m, 10 H, Ph), 8.21 (dd, 1 H, J ϭ (50 MHz, CDCl3): δ ϭ 100.7, 106.8, 109.0, 110.7, 111.1, 119.2,
1.0 Hz, 5-H), 8.36 (dd, 1 H, J ϭ 1.8 and 1.0 Hz, 8-H). Ϫ 13C NMR
7.3 and 1.0 Hz, 5-H), 8.84 (dd, 1 H, J ϭ 1.9 and 1.0 Hz, 8-H). Ϫ
13C NMR (75 MHz, [D6]acetone): δ ϭ 30.8, 106.2, 116.0, 117.1,
118.9, 124.9, 127.6, 128.6, 128.7, 128.9, 129.8, 129.8, 129.8, 131.6,
122.6, 127.2, 127.4, 127.5, 127.9, 128.2, 128.5, 128.9, 129.3, 130.2,
130.6, 133.8, 141.0, 149.3, 1 signal was hidden. Ϫ MS (EI); m/z
(%): 360 [Mϩ] (100), 331 (28), 329 (19), 316 (3), 305 (4), 255 (8),
131.7, 132.7, 132.9, 135.5, 194.4. Ϫ MS (EI); m/z (%): 336 [Mϩ] 237 (3), 228 (3), 195 (4), 165 (6), 158 (7). Ϫ C25H16N2O (360.42):
(88), 321 (100), 299 (10), 293 (28), 264 (6), 203 (27), 168 (11), 146 calcd. C 83.31, H 4.47; found C 83.18, H, 4.76.
(9), 129 (6). Ϫ C23H16N2O (336.39): calcd. C 82.12, H 4.79; found
1,2,3-Triphenylindolizine-7-carbonitrile (11f): A solution of phenyl-
magnesium bromide (1.11 , 1.80 mL, 2.00 mmol) in THF was
C 82.26, H, 4.93.
2,3-Diphenyl-1-(2-thienyl)indolizine-7-carbonitrile (11c): The title
compound was prepared from 1-bromo-7-cyano-2,3-diphenylindol-
added dropwise to a stirred solution of zinc bromide (1.08 , 2.04
mL, 2.20 mmol) in dry THF (6 mL) at Ϫ78 °C under N2. When
izine 9 (205 mg, 0.550 mmol) and 2-thienyl(tributyl)tin (0.227 mL, the addition was complete, the resulting mixture was stirred for 1
0.720 mmol) in DMF (5 mL) as described for compound 11a above
and in Table 2. The product was purified by flash chromatography,
eluting with EtOAc/hexane (1:99, 1:39, and finally 1:29). Yield 188
mg (91%) of yellow crystals, m.p. 217Ϫ218 °C. Ϫ 1H NMR
h at Ϫ78 °C and at ambient temperature for 30 min. Tetrakis(tri-
phenylphosphane)palladium(0) [generated from tris(dibenzylidene-
acetone)dipalladium chloroform adduct (26 mg, 25 µmol) and tri-
phenylphosphane (52 mg, 0.20 mmol)] and 9 (373 mg, 1.00 mmol)
(300 MHz, CDCl3): δ ϭ 6.43 (dd, 1 H, J ϭ 7.4 and 1.7 Hz, 6-H), in dry THF (14 mL) were added and the reaction mixture was
6.79 (dd, 1 H, J ϭ 3.5 and 1.1 Hz, 3-H in thienyl), 6.88 (dd, 1 H, stirred for 42 h at 60 °C, cooled and evaporated in vacuo. The
J ϭ 5.1 and 3.5 Hz, 4-H in thienyl), 6.9Ϫ7.0 (m, 2 H, Ph), 7.0Ϫ7.1 product was purified by flash chromatography, eluting with EtOAc/
(m, 3 H, Ph), 7.1Ϫ7.2 (m, 3 H, Ph and 5-H in thienyl), 7.2Ϫ7.3
(m, 3 H, Ph), 7.85 (dd, 1 H, J ϭ 7.4 and 0.9 Hz, 5-H), 7.99 (1 H,
hexane (1:99, 1:39, 1:29, 1:19, 1:9, 1:4, and finally 1:1), and recrys-
tallised from 2-propanol. Yield 263 mg (71%) of yellow crystals,
1
br s, 8-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 100.1, 110.7, 112.0, m.p. 239Ϫ240 °C. Ϫ Rf ϭ 0.30 (1:4, EtOAc/hexane). Ϫ H NMR
119.1, 122.6, 125.4, 125.8, 126.7, 126.7, 127.0, 127.2, 127.9, 128.6, (300 MHz, CDCl3): δ ϭ 6.45 (dd, 1 H, J ϭ 7.4 and 1.8 Hz, 6-H),
128.7, 129.0, 129.5, 129.6, 130.4, 130.9, 133.1, 134.4. Ϫ MS (EI);
6.9Ϫ7.0 (m, 2 H, Ph), 7.0Ϫ7.1 (m, 3 H, Ph), 7.1Ϫ7.4 (m, 10 H,
m/z (%): 376 [Mϩ] (100), 342 (2), 331 (2), 329 (2), 298 (5), 273 (4), Ph), 7.86 (dd, 1 H, J ϭ 7.4 and 1.0 Hz, 5-H), 7.90 (dd, 1 H, J ϭ
271 (5), 239 (3), 149 (8). Ϫ C25H16N2S (376.49): calcd. C 79.76, H 1.8 and 1.0 Hz, 8-H). Ϫ 13C NMR (50 MHz, CDCl3): δ ϭ 99.6,
4.28; found C 79.58, H, 4.46.
110.5, 119.0, 119.2, 122.4, 125.7, 126.3, 126.6, 126.7, 127.9, 128.4,
128.5, 128.5, 129.0, 129.0, 129.8, 130.1, 130.5, 130.9, 133.2, 133.4.
Ϫ MS (EI); m/z (%): 370 [Mϩ] (100), 292 (14), 291 (7), 267 (6), 265
(14), 177 (7), 176 (6), 165 (5), 146 (5). Ϫ HRMS C27H18N2: calcd.
370.1470; found 370.1481.
2,3-Diphenyl-1-(3-thienyl)indolizine-7-carbonitrile (11d): Tetrakis-
(triphenylphosphane)palladium(0) [generated from tris(dibenzylid-
eneacetone)dipalladium chloroform adduct (13 mg, 13 µmol) and
triphenylphosphane (26 mg, 0.10 mmol)] in dry dioxane (3 mL) was
added to a solution of 1-bromo-7-cyano-2,3-diphenylindolizine 9
(187 mg, 0.500 mmol) and 3-thiopheneboronic acid (83 mg,
1-(2-Methoxyphenyl)-2,3-diphenylindolizine-7-carbonitrile (11g): A
solution of 2-methoxyphenylmagnesium bromide (0.95 , 1.05 mL,
0.65 mmol) in dioxane (2 mL). The resulting mixture was stirred at 1.00 mmol) was added dropwise to a stirred solution of zinc brom-
reflux for 20 min and cooled, after which diethyl ether (50 mL) and
EtOAc (50 mL) were added. The mixture was washed with water
(2ϫ 50 mL), dried (MgSO4), and evaporated in vacuo. The product
was purified by flash chromatography, eluting with EtOAc/hexane
(1:49, 1:29, and finally 1:9), and recrystallised from 2-propanol.
ide (1.23 , 1.06 mL, 1.30 mmol) in dry THF (2 mL) at Ϫ78 °C
under N2. When the addition was complete, the resulting mixture
was stirred for 1 h at Ϫ78 °C and at ambient temperature for 30
min. Tetrakis(triphenylphosphane)palladium(0) [generated from
tris(dibenzylideneacetone)dipalladium chloroform adduct (13 mg,
3768
Eur. J. Org. Chem. 2000, 3763Ϫ3770

Synthesis of 1-Substituted 7-Cyano-2,3-diphenylindolizines
FULL PAPER
13 µmol) and triphenylphosphane (26 mg, 0.10 mmol)] in dry THF
(1 mL) and 1-bromo-7-cyano-2,3-diphenylindolizine 9 (187 mg,
0.500 mmol) in dry THF (3 mL) were added and the reaction mix-
ture was stirred for 50 h at 60 °C. After cooling to ambient temper-
6-H), 7.1Ϫ7.3 (m, 10 H, Ph), 7.86 (dd, 1 H, J ϭ 1.7 and 0.9 Hz, 8-
H), 7.88 (dd, 1 H, J ϭ 7.4 and 0.9 Hz, 5-H). Ϫ 13C NMR
(300 MHz, CDCl3): δ ϭ 9.4, 97.4, 109.7, 113.1, 119.6, 122.0, 124.9,
125.6, 126.7, 128.1, 128.2, 128.7, 128.9, 130.1, 130.2, 130.3, 130.4,
ature, EtOAc (75 mL) and diethyl ether (75 mL) were added and 134.0. Ϫ MS (EI); m/z (%): 308 [Mϩ] (100), 307 (27), 292 (5), 231
the mixture was washed with saturated ammonium chloride solu-
tion (50 mL) and water (50 mL) and evaporated in vacuo. Traces
of water were removed by azeotropic evaporation with a small
quantity of acetone in vacuo. The product was purified by flash
chromatography, eluting with EtOAc/hexane (1:49, 1:29, and finally
1:9). Yield 111 mg (55%) of yellow crystals, m.p. 200Ϫ202 °C. Ϫ
1H NMR (300 MHz, CDCl3): δ ϭ 3.48 (s, 3 H, Me), 6.58 (dd, 1
H, J ϭ 7.4 and 1.7 Hz, 6-H), 6.9Ϫ7.0 (m, 1 H, Ph), 7.0Ϫ7.1 (m, 3
H, Ph), 7.1Ϫ7.2 (m, 3 H, Ph), 7.3 (m, 1 H, Ph), 7.4Ϫ7.5 (m, 6 H,
Ph), 7.85 (dd, 1 H, J ϭ 1.7 and 0.9 Hz, 8-H), 8.05 (dd, 1 H, J ϭ
7.4 and 0.9 Hz, 5-H). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ 54.9,
99.0, 110.1, 111.3, 115.2, 119.3, 120.6, 122.0, 122.3, 125.8, 126.0,
126.2, 127.6, 128.3, 128.6, 128.8, 128.9, 129.8, 129.9, 129.9, 130.5,
132.3, 134.4, 156.9. Ϫ MS (EI); m/z (%): 400 [Mϩ] (100), 385 (6),
357 (8), 292 (9), 280 (6), 252 (5), 177 (8). Ϫ C28H20N2O (400.48):
calcd. C 83.98, H 5.03; found C 83.95, H, 4.94.
(3), 229 (4), 223 (64), 154 (5), 146 (12). Ϫ HRMS (C22H16N2):
calcd. 308.1313; found 308.1301.
Procedure B: n-Butyllithium (0.340 mL of a 1.62  solution in hex-
ane, 0.550 mmol) was added dropwise to a stirred solution of 1-
bromo-7-cyano-2,3-diphenylindolizine 9 (187 mg, 0.500 mmol) in
dry THF (20 mL) at Ϫ78 °C under N2, and the mixture was stirred
at Ϫ78 °C for 1 h, after which iodomethane (0.093 mL, 1.50 mmol)
was added. The resulting mixture was stirred at Ϫ78 °C for an
additional 48 h. EtOAc (50 mL), diethyl ether (50 mL) and satur-
ated aqueous ammonium chloride (30 mL) were added to the cold
reaction mixture. The phases were separated and the organic layer
was washed with water (30 mL), dried (MgSO4) and evaporated in
vacuo. The product was purified by flash chromatography, eluting
with Et3N/hexane (1:49), followed by crystallisation from 2-pro-
panol to give the compound 11j (116 mg, 75%). When the temper-
ature of this reaction was allowed to reach ambient levels during
methylation, flash chromatography of the crude product also gave
fractions containing an 82:18 mixture of the 1-methylindolizine 11j
and 7-cyano-8-methyl-2,3-diphenylindolizine 15. The 1H NMR res-
onances belonging to compound 15 are given. 1H NMR (300 MHz,
CDCl3): δ ϭ 2.74 (s, 3 H, Me), 6.54 (d, 1 H, J ϭ 7.5 Hz, 6-H), 7.01
(1 H, br s, 1-H), 7.2Ϫ7.5 (m, 10 H, Ph), 7.82 (d, 1 H, J ϭ 7.5 Hz,
5-H).
1-(3-Methoxyphenyl)-2,3-diphenylindolizine-7-carbonitrile
(11h):
The title compound was prepared from 1-bromo-7-cyano-2,3-di-
phenylindolizine 9 (93 mg, 0.25 mmol) and 3-methoxyphenylmag-
nesium bromide as described for compound 11g above and in
Table 2. The product was purified by flash chromatography, eluting
with EtOAc/hexane (1:49, 1:29, 1:19, and finally 1:9). Yield 70 mg
(70%) of yellow crystals, m.p. 244Ϫ245 °C. Ϫ 1H NMR (500 MHz,
CDCl3): δ ϭ 3.58 (s, 3 H, Me), 6.49 (dd, 1 H, J ϭ 7.3 and 1.0 Hz,
6-H), 6.65 (dd, 1 H, J ϭ 2.4 and 1.6 Hz, Ph), 6.8 (m, 2 H, Ph),
6.9Ϫ7.0 (m, 2 H, Ph), 7.1 (m, 3 H, Ph), 7.2 (m, 1 H, Ph), 7.2Ϫ7.3
(m, 2 H, Ph), 7.3Ϫ7.4 (m, 3 H, Ph), 7.9Ϫ8.0 (m, 2 H, 5-H and 8-
H). Ϫ 13C NMR (300 MHz, CDCl3): δ ϭ 55.0, 99.7, 110.5, 112.6,
115.5, 118.9, 119.3, 122.5, 125.8, 126.4, 126.7, 128.0, 128.4, 128.5,
129.1, 129.1, 129.5, 129.8, 130.5, 130.9, 133.5, 134.6, 159.5. Ϫ MS
(EI); m/z (%): 400 [Mϩ] (100), 355 (4), 279 (8), 252 (4), 103 (5), 77
(13). Ϫ C28H20N2O (400.48): calcd. C 83.98, H 5.03; found C 83.53,
H, 4.85.
2,2Ј,3,3Ј-Tetraphenyl-1,1Ј-biindolizine-7,7Ј-dicarbonitrile (12): The
title compound was formed in minor amounts in several of the
coupling reactions described above and isolated as a yellow wax.
Rf ϭ 0.22 (1:4, EtOAc/hexane). Ϫ 1H NMR (300 MHz, CDCl3):
δ ϭ 6.59 (dd, 2 H, J ϭ 7.4 and J ϭ 1.7 Hz, 6-H and 6Ј-H), 6.7Ϫ6.8
(m, 4 H, Ph), 6.9Ϫ7.1 (m, 6 H, Ph), 7.3Ϫ7.5 (m, 10 H, Ph), 7.57
(dd, 2 H, J ϭ 1.7 and J ϭ 0.7 Hz, 8-H and 8Ј-H), 8.08 (dd, 2 H,
J ϭ 7.4 and J ϭ 0.7 Hz, 5-H and 5Ј-H). Ϫ 13C NMR (75 MHz,
CDCl3): δ ϭ 99.4, 109.8, 110.5, 119.0, 122.6, 125.5, 126.2, 126.5,
127.7, 128.5, 129.1, 129.2, 129.8, 129.9, 130.5, 130.7, 133.5. Ϫ MS
(EI); m/z (%): 586 [Mϩ] (100), 509 (3), 481 (3), 431 (2), 405 (5), 293
(20), 254 (5).
1-(4-Methoxyphenyl)-2,3-diphenylindolizine-7-carbonitrile (11i): The
title compound was prepared from 1-bromo-7-cyano-2,3-di-
phenylindolizine 9 (93 mg, 0.25 mmol) and 4-methoxyphenylmag-
nesium bromide as described for compound 11g above and in
Table 2. The product was purified by flash chromatography, eluting
with EtOAc/hexane (1:49, 1:29, and finally 1:9). Yield 78 mg (78%)
of yellow crystals, m.p. 195Ϫ196 °C. Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 3.58 (s, 3 H, Me), 6.56 (dd, 1 H, J ϭ 7.4 and 1.8 Hz,
6-H), 6.9Ϫ7.0 (m, 2 H, Ph), 7.1Ϫ7.2 (m, 2 H, Ph), 7.2Ϫ7.3 (m, 5
H, Ph), 7.4 (m, 2 H, Ph), 7.4Ϫ7.5 (m, 3 H, Ph), 7.99 (dd, 1 H, J ϭ
1.8 and 0.9 Hz, 8-H), 8.04 (dd, 1 H, J ϭ 7.4 and 0.9 Hz, 5-H). Ϫ
13C NMR (125 MHz, CDCl3): δ ϭ 55.1, 99.1, 110.3, 113.9, 118.7,
119.2, 122.3, 125.4, 126.1, 126.5, 127.8, 128.3, 128.4, 128.8, 128.9,
129.8, 130.4, 130.8, 131.1, 133.4, 158.4. Ϫ MS (EI); m/z (%): 400
[Mϩ] (100), 385 (26), 355 (3), 279 (8), 252 (4), 77 (9). Ϫ C28H20N2O
(400.48): calcd. C 83.98, H 5.03; found C 84.19, H, 5.43.
2,3-Diphenylindolizine-7-carbonitrile (13): n-Butyllithium (0.288 mL
of a 1.7  solution in hexane, 0.490 mmol) was added dropwise to
a stirred solution of 1-bromo-7-cyano-2,3-diphenylindolizine 9 (183
mg, 0.490 mmol) in dry THF (20 mL) at Ϫ78 °C under N2 and the
resulting mixture was stirred at Ϫ78 °C for an additional 2 h before
saturated aqueous ammonium chloride solution (1 mL) was added.
The reaction mixture was allowed to reach ambient temperature,
the phases were separated and the organic layer was evaporated in
vacuo. The crude product was recrystallised from dichloromethane/
hexane. Yield 133 mg (92%) of yellow crystals, m.p. 234Ϫ235 °C.
1
Ϫ H NMR (200 MHz, CDCl3): δ ϭ 6.38 (dd, 1 H, J ϭ 7.4 and
1.8 Hz, 6-H), 6.83 (1 H, br s, 1-H), 7.1Ϫ7.4 (m, 10 H, Ph), 7.70 (1
H, br s, 8-H), 7.77 (1 H, br d, J ϭ 7.4 Hz, 5-H). Ϫ 13C NMR
(50 MHz, CDCl3): δ ϭ 99.3, 104.6, 110.1, 119.2, 122.5, 125.4,
126.2, 126.9, 128.4, 128.8, 128.8, 129.4, 130.3, 130.5, 130.6, 134.5
one signal was hidden. Ϫ MS (EI); m/z (%): 294 [Mϩ] (100), 278
(2), 266 (3), 264 (3), 254 (3), 234 (3), 216 (3), 189 (7), 165 (5), 146
(12), 139 (6). Ϫ C21H14N2 (294.35): calcd. C 85.69, H 4.79; found
C 85.65, H, 4.83.
1-Methyl-2,3-diphenylindolizine-7-carbonitrile (11j). ؊ Procedure A:
The title compound was prepared from 1-bromo-7-cyano-2,3-di-
phenylindolizine 9 (93 mg, 0.25 mmol) and methylmagnesium
chloride as described for compound 11g above and in Table 2. The
product was purified by flash chromatography, eluting with Et3N/
hexane (1:19). Yield 58 mg (75%) of yellow crystals, m.p. 185Ϫ186
°C. Ϫ Rf ϭ 0.41 (1:4, EtOAc/hexane). Ϫ 1H NMR (300 MHz,
7-Pentanoyl-2,3-diphenylindolizine (14): n-Butyllithium (2.94 mL of
CDCl3): δ ϭ 2.29 (s, 3 H, Me), 6.37 (dd, 1 H, J ϭ 7.4 and 1.7 Hz, a 1.70  solution in hexane, 5.00 mmol) was added dropwise to a
Eur. J. Org. Chem. 2000, 3763Ϫ3770 3769

O. B. Østby, B. Dalhus, L.-L. Gundersen, F. Rise, A. Bast, G. R. M. M. Haenen
˚
FULL PAPER
stirred solution of 1-bromo-7-cyano-2,3-diphenylindolizine 9 (187
0.03 A, using the SAME command of SHELXTL.[11] Further pairs
mg, 0.500 mmol) in dry THF (20 mL) at Ϫ78 °C under N2 and the of disordered atoms in each component share the same set of dis-
resulting mixture was stirred at Ϫ78 °C for an additional 2 h, after
which saturated aqueous ammonium chloride solution (1 mL) was
added. The reaction mixture was allowed to reach ambient temper-
ature, the phases were separated and the organic layer was evapor-
ated in vacuo. The product was purified by flash chromatography,
eluting with EtOAc/hexane (1:29). Yield 156 mg (88%) of yellow
crystals, m.p. 134Ϫ135 °C. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ
1.01 (t, 3 H, J ϭ 7.3 Hz, Me), 1.4Ϫ1.5 (m, 2 H, CH2), 1.7Ϫ1.8 (m,
2 H, CH2), 2.98 (t, 2 H, J ϭ 7.5 Hz, CH2CO), 7.04 (1 H, s, 1-H),
7.09 (dd, 1 H, J ϭ 7.5 and 1.8 Hz, 6-H), 7.2Ϫ7.4 (m, 5 H, Ph),
7.4Ϫ7.6 (m, 5 H, Ph), 7.94 (1 H, br d, J ϭ 7.5 Hz, 5-H), 8.15 (1
H, br s, 8-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 14.0, 22.6, 27.0,
37.4, 105.4, 108.4, 121.7, 121.9, 124.8, 126.2, 126.6, 128.3, 128.4,
128.7, 129.2, 130.0, 130.6, 130.8, 131.0, 135.1, 198.2. Ϫ MS (EI);
m/z (%): 353 [Mϩ] (100), 311 (43), 296 (44), 268 (34), 267 (41), 239
(10), 191 (7), 165 (5), 155 (8), 133 (6). Ϫ C25H23NO (353.47): calcd.
C 84.95, H 6.56; found C 84.50, H 6.36.
placement parameters. The crystal data and refinement results of
the structure 10 are listed in Table 1. Reference number CCDC
142363.
Acknowledgments
The purchase of the 200, 300, and 500 MHz Bruker Spectrospin
Avance instruments and the Siemens SMART diffractometer used
in this study was made possible through financial support from the
Research Council of Norway (NFR). The assistance of Mr. Marc
A. J. G. Fischer in the lipid peroxidation experiments is gratefully
acknowledged.
[1] [1a]
[1b]
B. Halliwell, Drugs 1991, 42, 569Ϫ605. Ϫ
C. A. Rice-
Evans, A. T. Diplock, Free Radical Biol. Med. 1993, 15, 77Ϫ96.
Ϫ
[1c]
[1d]
A. Bast, Pharmacochem. Libr. 1993, 20, 159Ϫ166. Ϫ
B. Halliwell, Chem. Edu. 1995, 123Ϫ124.
[2] [2a]
D. H. Wadsworth, S. L. Bender, D. L. Smith, H. R. Luss,
[2b]
1-(α-Hydroxybenzyl)-2,3-diphenylindolizine-7-carbonitrile (16): n-
Butyllithium (0.170 mL of a 1.62  solution in hexane, 0.280 mmol)
was added dropwise to a stirred solution of 1-bromo-7-cyano-2,3-
diphenylindolizine 9 (93 mg, 0.25 mmol) in dry THF (10 mL) at
Ϫ78 °C under N2 and the mixture was stirred at Ϫ78 °C for 30
min, after which benzaldehyde (0.076 mL, 0.75 mmol) was added.
The resulting mixture was stirred at Ϫ78 °C for an additional 1.5
h. EtOAc (25 mL), diethyl ether (25 mL), and saturated aqueous
ammonium chloride (30 mL) were added to the cold reaction mix-
ture. The phases were separated and the organic layer was washed
with water (2 ϫ 30 mL), dried (MgSO4), and evaporated in vacuo.
The product was purified by flash chromatography, eluting with
EtOAc/hexane (1:99, 1:29, and finally 1:9). Yield 87 mg (87%) of a
yellow wax. Rf ϭ 0.15 (1:4, EtOAc/hexane). Ϫ 1H NMR (500 MHz,
CDCl3): δ ϭ 2.18 (d, 1 H, J ϭ 3.3 Hz, OH), 6.11 (d, 1 H, J ϭ
3.3 Hz, CH), 6.47 (dd, 1 H, J ϭ 7.4 and 1.8 Hz, 6-H), 7.1 (m, 2 H,
Ph), 7.2Ϫ7.3 (m, 6 H, Ph), 7.3Ϫ7.4 (m, 7 H, Ph), 7.87 (dd, 1 H,
J ϭ 1.8 and 0.8 Hz, 8-H), 7.95 (dd, 1 H, J ϭ 7.4 and 0.8 Hz, 5-H).
C. H. Weidner, J. Org. Chem. 1986, 51, 4639Ϫ4644. Ϫ
D.
H. Wadsworth, C. H. Weidner, S. L. Bender, R. H. Nuttall, H.
[2c]
R. Luss, J. Org. Chem. 1989, 54, 3652Ϫ3660. Ϫ
Weidner, D. H. Wadsworth, S. L. Bender, D. J. Beltman, J. Org.
C. H.
[2d]
Chem. 1989, 54, 3660Ϫ3664. Ϫ
C. H. Weidner, F. M.
Michaels, D. J. Beltman, C. J. Montgomery, D. H. Wadsworth,
B. T. Briggs, M. L. Picone, J. Org. Chem. 1991, 56, 5594Ϫ5598.
F. Rise, H. Wikström, S. Ugland, D. Dijkstra, L.-L. Gund-
ersen, P. De Boer, A. Bast, G. Haenen, Ø. Antonsen, Y. Liao,
A. I. Nasir, PCT Int. Appl. WO 9621,662/1996; Chem. Abstr.
1996, 125, 195681.
A. I. Nasir, L.-L. Gundersen, F. Rise, Ø. Antonsen, T. Kris-
tensen, B. Langhelle, A. Bast, I. Custers, G. R. M. M. Haenen,
H. Wikström, Bioorg. Med. Chem. Lett. 1998, 8, 1829Ϫ1832.
J. W. Lown, K. Matsumoto, Can. J. Chem. 1971, 49,
1165Ϫ1175.
[3]
[4]
[5]
[6] [6a]
G. A. Wiley, R. L. Hershkowitz, B. M. Rein, B. C. Chung,
[6b]
J. Am. Chem Soc. 1964, 86, 964Ϫ965. Ϫ
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K. Ritter, Synthesis 1993, 735Ϫ762.
J. P. Schaefer, J.
[7]
[8]
For other recent examples of cleavage of aryl triflates to
phenols under Pd-catalysed coupling conditions, see for in-
Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ 69.5, 99.2, 110.5, 119.2, 119.3,
[8a]
stance:
1264Ϫ1267. Ϫ
J. P. Wolfe, S. L. Buchwald, J. Org. Chem. 1997, 62,
[8b]
122.5, 125.8, 125.9, 126.8, 127.3, 127.5, 127.9, 128.2, 128.4, 128.5,
129.0, 129.7, 130.2, 130.7, 133.4, 143.5. Ϫ MS (EI); m/z (%): 400
[Mϩ] (100), 384 (9), 383 (28), 323 (52), 293 (7), 105 (9), 78 (57), 77
(94). Ϫ HRMS C28H20N2O: calcd. 400.1576; found 400.1584.
J. Louie, M. S. Driver, B. C. Haman, J. F.
Hartwig, J. Org. Chem. 1997, 62, 1268Ϫ1273. Ϫ [8c] H. Kubota,
K. C. Rice, Tetrahedron Lett. 1998, 39, 2907Ϫ2910.
[9a] R. E. Hurd, B. K. John, J. Magn. Reson. 1991, 91, 648Ϫ653.
[9]
[9b]
Ϫ
G. W. Vuister, R. Boelens, R. Kaptein, R. E. Hurd, B.
K. John, P. C. M. Van Zijl, J. Am. Chem. Soc. 1991, 113,
X-ray Crystallographic Study: Single crystals for X-ray crystallo-
graphy were obtained by slow evaporation of hexane into a
dichloromethane solution of 10. X-ray diffraction data were col-
lected on a Siemens SMART diffractometer. Positional parameters
for all heavy atoms were refined. Hydrogen atoms were kept in
idealised positions, refining a single CϪH bond length for all H
atoms connected to the same C atom. Heavy atoms were refined
anisotropically, whereas Uiso for the hydrogen atoms were fixed at
1.2ϫUeq (for ϪCHϪ and CH2) and 1.5ϫUeq (for ϪCH3) of the
bonded C atom. The side chain at C6 is disordered over two con-
formations. Except for O1, all non-H atoms in the side chain were
refined over two positions. The two components, with occupancy
factors 0.517(5) and 0.483(5), where restrained to have the same
1Ϫ2 and 1Ϫ3 distances within an effective standard deviation of
[9c]
9688Ϫ9690. Ϫ
J.-M. Tyburn, I. M. Brereton, D. M. Dod-
drell, J. Magn. Reson. 1992, 97, 305Ϫ312.
[10]
[11]
P. L. Rinaldi, P. Keifer, J. Magn. Reson., Ser A 1994, 108,
259Ϫ262.
G. M. Sheldrick, (1994). SHELXTL. Structure Determination
Programs. Version 5.03. Siemens Analytical X-Ray Instruments
Inc., Madison, Wisconsin, USA.
Siemens (1995). SMART and SAINT. Area Detector Control
and Integration Software. Siemens Analytical X-Ray Instru-
ments Inc., Madison, Wisconsin, USA.
[12]
[13]
Lown and Matsumoto actually reported the synthesis of 3-
chloro-5-azaindolizine from 5-azaindolizin-3-ol (ref. [5]), but
Weidner et al. later showed that the hydroxy group must have
been situated in the indolizine 1-position, see ref. [2d].
Received April 4, 2000
[O00174]
3770
Eur. J. Org. Chem. 2000, 3763Ϫ3770