Synthesis and reactivity of 5-Br(I)-indolizines and their parallel cross-coupling reactions

Article abstract of DOI:10.1016/j.tet.2007.11.017

Poorly available 5-iodo- and 5-bromoindolizines were prepared via regioselective lithiation of indolizines followed by halogenation. 5-Halogenoindolizines were found to be passive toward nucleophiles, whereas they may be trifluoroacetylated at C-3 and inv

Full text of DOI:10.1016/j.tet.2007.11.017

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 749e756
www.elsevier.com/locate/tet
Synthesis and reactivity of 5-Br(I)-indolizines and their parallel
cross-coupling reactions
*
Alexey G. Kuznetsov, Alexander A. Bush, Eugene V. Babaev
Chemistry Department, Moscow State University, Moscow 119991, Russia
Received 3 April 2007; received in revised form 18 October 2007; accepted 1 November 2007
Available online 7 November 2007
Abstract
Poorly available 5-iodo- and 5-bromoindolizines were prepared via regioselective lithiation of indolizines followed by halogenation.
5-Halogenoindolizines were found to be passive toward nucleophiles, whereas they may be trifluoroacetylated at C-3 and involved in reaction
with DMAD giving cycl[3.2.2]azine. The first successful Suzuki-coupling of 5-bromo(iodo)indolizines with different arylboronic acids
(performed as a parallel synthesis) led to a series of 5-arylindolizines; the effect of substituents on the reaction yield was examined.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
N- and S-nucleophiles;7 the reactivity of simple 5-halogenoin-
dolizines remained unclear.8
Indolizines are an important class of heterocyclic com-
pounds with interesting photophysical and biological proper-
ties.1,2 There are nine non-equivalent positions around the
bicyclic indolizine structure, and many strategies have been
reviewed to prepare substituted indolizines with a different
arrangement of functional groups.1e3 However, one important
class of substituted indolizine, namely the 5-halogenoindoli-
zines I, remains poorly available.
One would expect that the position of the halogen in the in-
dolizines I should be equivalent to the a-position in 2-halogeno-
pyridines, and therefore a halogen could be easily substituted
by nucleophiles. According to most theoretical calculations
of indolizine reactivity (starting from earliest statements by
Coulson4 and Fukui5), position 5 should be most favorable
for nucleophilic attack. However, nucleophilic attack at C-5
was confirmed only for indolizines with an additional elec-
tron-withdrawing group at position 6 or 8. Two reported exam-
ples involve direct SNH amination at C-5 of 8-nitroindolizines6
and substitution of chlorine in 5-Cl-6-CN-indolizines by O-,
It is hard to introduce a halogen atom at position 5 of indo-
lizine by common methods, and our earlier attempts are shown
in Scheme 1. The Chichibabin reaction (route (a)), a standard
way to substituted indolizines, is useless for the target class I.
5-Chloro-2-methylindolizine has been once mentioned in
the old patent.9 However, careful reinvestigation of reaction
between 6-halogeno-2-picolines IIa and a-bromoketones
proved10 that the condensation products have the structures
IIb. The strategy that allows insertion of chlorine at position
5 (route (b)) is the reaction of 6-cyanoindolizine-5-ones IIIa
(that are preferable tautomeric forms of 5-hydroxyindolizines
IIIb) with POCl3 leading to 5-chloro-6-cyanoindolizines.7
Another strategy (route (c)) is the 1,3-dipolar cycloaddition
of the pyridinium ylides derived from 2-chloro-N-phenacyl-
pyridinium salts IVa leading to 3-aroyl-5-chloroindoli-
zines.11,12 A similar reaction of 2-bromopyridinium ylide
was also reported,13 however both 5-Cl- and 5-Br-derivatives
are unstable and quickly lose halogen atom due to an unusual
cyclization to tetracyclic structures IVb.11e13 In addition to
the strategies listed in Scheme 1, a novel gold-assisted
cycloisomerization of 2-propargylpyridines should be men-
tioned, since in a single example it led to a 1,2-substituted
5-bromoindolizine.14
* Corresponding author.
E-mail address: babaev@org.chem.msu.ru (E.V. Babaev).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.017

750
A.G. Kuznetsov et al. / Tetrahedron 64 (2008) 749e756
E
E
Hal+
+
n-BuLi
N+
E
R"
Hal=Cl,Br
(c)
Hal=Br,I
E
N
N
R'
R"
R"
Hal
Ar
(d)
Li
O
IVa
N
N
O
R'
E=CO2Et; X=Cl, NO2
IVb
R"
X
N
R'
R"
Hal
I
(a)
CH3
+Br-
(b)
CH3
R'
R'
IIIb
N
R"
R"
POCl3
Hal=Cl
O
+
N
N
OH
Hal=Cl,Br
O
IIb
O
Hal
IIIa
Br
R'
R'
IIa
Scheme 1.
In 1992 Renard and Gubin15 employed a promising method
4aec with 76e95% yields. Although the 5-Br(I)-indolizines
(oils or solids) obtained are unstable in air, they gave satisfac-
for the synthesis of a wide range of 5-substituted indolizines
by direct lithiation of 2-phenylindolizine, and further reactions
with different (mostly carbon) electrophiles. The only hetero-
atomic group inserted by this method was SiMe3. Earlier16 we
have reinvestigated this procedure, suggested the optimized
protocol of indolizine lithiation (due to observed low yields
of products), and succeeded in the preparation of a 5-iodoindo-
lizine capable of Suzuki cross-coupling. In this paper we
report applications of this strategy (route (d)) to the synthesis
of a series of 5-Br(I)-indolizines (with additional groups in the
pyrrole and pyridine rings). We found that such compounds
can be involved in Suzuki-coupling, and developed a con-
venient parallel protocol for this reaction leading to a library
of poorly investigated 5-arylindolizines. Reactivity of 5-Br(I)-
indolizines toward simple nucleo-, electro- and dienophiles
was also studied.
1
tory analytical and spectroscopic data (see Section 4). The H
NMR spectra of 3 and 4 were similar to the parent indolizines
1, and the initial signal 5-H (observed in 1) was absent in the
spectra of 3 and 4.
2.2. Reactions of indolizines 3, 4 with common nucleo-,
electro- and dienophiles
In contrast to the theoretical predictions mentioned above,
5-halogenoindolizines appeared to be completely passive in
their reactions with nucleophiles. Thus, heating of indolizines
i
i
3aec and 4aec with PrONa (in PrOH) or with morpholine
t
(in the presence of BuOK) at reflux for 24 h led only to un-
changed starting materials. Analogously, no changes were ob-
served in the reaction of 3a or 4a with diethyl sodiomalonate
(in EtOH, reflux for 24 h). The reason why 5-Br(I)-indolizines
behave differently from 2-Br(I)-pyridines may be explained by
the general p-excessive character of the indolizine nuclei pre-
served in structures 3 and 4.
2. Results and discussion
2.1. Synthesis of 5-bromo(iodo)indolizines
Electrophilic substitution in indolizines usually occurs
at position C-3; some exceptions have been found for
5-substituted indolizines. (Thus, 5-methylindolizines usually
give mixtures of 1- and 3-substituted products.) We found
that reaction of 5-bromoindolizine 3b with trifluoroacetic an-
hydride at 0 ꢁC led exclusively to the 3-COCF3 derivative 5
with 83% yield (Scheme 3). The regioselectivity of C-3 attack
clearly followed from H NMR spectroscopic data: the signal
of proton H3 disappeared, and all other peaks (excluding H8)
underwent insignificant downfield shift.19 It should be
The starting indolizines 1aed were prepared by known
procedures.17,18 The corresponding lithium derivatives 2aed
were formed in THF at ꢀ78 to ꢀ80 ꢁC with n-BuLi (and
TMEDA as co-reagent) using our optimized protocol for the
direct lithiation of 2-substituted indolizines (Scheme 2).16
Reaction of 2aed with 1,2-dibromotetrafluoroethane as
brominating agent led to 5-bromoindolizines 3aed in high
yields (80e98%). The reaction of lithium derivatives 2aec
with a THF solution of I2 gave 5-iodosubstituted indolizines
1
R3
R3
Li
R3
n-BuLi
THF, TMEDA
C2F4Br2 or I2
R1
N
R1
R2
R1
N
Hal
N
R2
2a-d
1a-d
3a-d Hal=Br
4a-c Hal=I
R2
1-4: a: R1=R3=H, R2=Ph; b: R1=R3=H, R2=tBu; c: R1=H, R2=tBu, R3=Me; d: R1=Me, R2=tBu, R3=H
Scheme 2.

A.G. Kuznetsov et al. / Tetrahedron 64 (2008) 749e756
751
mentioned that the 5-bromo substituent slightly increases the
basicity of the pyrrole fragment: protonation of indolizine
3b in CF3COOD occurred at C-3 (Scheme 3), and after 2
days the proton H-3 was completely exchanged, whereas the
parent 5-H indolizine 1b during the same time underwent
H/D exchange at C-3 only, in 25%.
Evidently, this [8þ2] cycloaddition (with HBr elimination)
is non-oxidative, and is similar to the behavior of
3-cyanoindolizine.20
2.3. Parallel cross-coupling reactions
Although the halogen atom in indolizines 3 and 4 is not
a leaving group in reactions with common nucleophiles, one
would expect the possibility of its replacement in Suzuki-
type cross-coupling reactions. We investigated the reactions
of 5-Br(I)-indolizines 3aec and 4aec with several arylboronic
acids (listed in Table 1) using PdCl2 as the catalyst, 1,4-dioxane/
H2O as the solvent, and K2CO3 as the base. All 36 reactions
were performed in parallel (heating, shaking, and filtration)
using a SynCore parallel reactor. The resulting 5-arylindoli-
zines 7aer were obtained in moderate to excellent yields
(Scheme 4, Table 1).
R
Nu: RO-
-
CF3COOD
or NR2H (NR2
)
N
N+
D
for 3b
R
H(D)
Nu
Br
DMAD
(CF3CO)2O
for 3b
N
Toluene,
80 °C, 2h
for 3d
Br
N
3b (R=H)
N
3d (R=Me)
O
Br
CF3
CO2Me
MeO2C
5
6
Scheme 3.
The yields in Table 1 allowed qualitative comparison of the
reactivity of indolizines in the cross-coupling reaction depend-
ing on the nature of the substituents at positions 2, 5, and 6.
Firstly, the reactivity of 5-Hal-2-tert-butylindolizines was
found to be generally higher than that of the corresponding
2-phenyl derivatives; this was evident for 5-bromo (3a,b)
and 5-iodo (4a,b) pairs of compounds. Secondly, the appear-
ance of the 6-methyl group in close vicinity to the halogen
atom at C-5 caused a decrease of reactivity (probably due to
steric effects). This trend was clear for 5-bromo derivative
Another well-known reactivity type of indolizine is [8þ2]
cycloaddition of dienophiles across the positions 3 and 5
(see review, Ref. 20). The reaction was usually studied for
5-unsubstituted indolizines, and initial cycloadducts (e.g.,
with alkynes) underwent spontaneous oxidation to aromatic
cycl[3.2.2]azines. We found that 5-bromoindolizine 3d does
not react with ethyl acrylate, whereas its reaction with
DMAD led to cycl[3.2.2]azine 6 in 87% yield (Scheme 3).
Table 1
The yields (%) for 5-arylindolizines
Boronic acid
Indolizine
N
N
N
I
N
Br
I
N
N
Br
Br
I
B(OH)2
76
80
97
84
7a
7b
7c
7d
70
73
86
72
87
78
90
79
7g
7h
7i
49
44
47
44
87
78
96
90
7m
7n
7o
64
41
32
68
MeO
B(OH)2
B(OH)2
F3C
B(OH)2
B(OH)2
7j
7p
O
93
96
7e
7f
82
84
87
91
7k
7l
36
52
87
95
7q
7r
70
72
Cl
Cl
B(OH)2
CHO

752
A.G. Kuznetsov et al. / Tetrahedron 64 (2008) 749e756
R'
R'
Ar
Ar in 7 (R',R" see Table):
a,g,m: p-MeOC6H4;
PdCl2
1,4-dioxane-H2O
K2CO3
ArB(OH)2
+
b,h,n: Ph;
N
Hal
N
c,i,o: p-CF3C6H4;
3a-c
4a-c
7a-r
d,j,p: 2-benzofuranyl;
e,k,q: 3,4-diClC6H3;
f,l,r: m-CHOC6H4
R"
R"
3,4: a R'=H, R"=Ph; b R'=H, R"=tBu; c R'=Me, R"=tBu
Scheme 4.
3b and its 6-methyl homologue 3c, and for the homologous
pair of 6-H/6-Me-5-iodo-derivatives 4b,c. Interestingly, the
difference in reactivity of 5-iodo and 5-bromo groups is
negligible for 6-unsubstituted indolizines (cf. the yields for
3a and 4a or 3b and 4b), whereas for the 6-methyl series
the yields of 5-iodoindolizine 4c were 2e3 times higher
against 5-bromoindolizine 3c.
solution of I2 (22 mmol) was slowly added. The mixture was
allowed to warm to room temperature and treated with a satu-
rated solution of ammonium chloride. The organic layer was
separated and the aqueous layer was extracted with dichloro-
methane. After drying over anhydrous Na2SO4 and evapora-
tion of the organic solvents, the crude product was purified
by column chromatography on silica gel (eluent hexane).
3. Conclusion
4.2.1. 5-Bromo-2-phenylindolizine (3a)
From 2-phenylindolizine (1a). Yield of 3a: 80%; light yel-
low solid, mp: 85e87 ꢁC; 1H NMR: d¼7.87 (1H, s, H3),
7.70e7.68 (2H, m, Ph-H), 7.42e7.38 (2H, m, Ph-H), 7.36
(1H, d, H6, J67¼8.6 Hz), 7.29e7.24 (1H, m, Ph-H), 6.88
(1H, s, H1), 6.77 (1H, d, H8, J78¼7.0 Hz), 6.58e6.54 (1H, m,
H7); elemental analysis calcd (%) for C14H10BrN (272.14):
C 61.79, H 3.70, N 5.15; found: C 61.99, H 3.62, N 5.28.
Regioselective lithiation followed by halogenation opens
a new route to previously poorly available 5-bromo- and 5-
iodoindolizines. Although these compounds are not stable in
air, they can be involved in Suzuki-coupling reaction and serve
as suitable precursors of a poorly investigated family of
5-arylindolizines. 5-Br(I)-indolizines kept p-excessive proper-
ties: they can not be involved in nucleophilic substitution reac-
tions, but can react with some electrophiles and dienophiles.
4.2.2. 5-Iodo-2-phenylindolizine (4a)
From 2-phenylindolizine (1a). Yield of 4a: 76%; light yel-
1
4. Experimental
low solid, mp: 105e107 ꢁC; H NMR: d¼7.85 (1H, s, H3),
7.68e7.66 (2H, m, Ph-H), 7.42e7.35 (3H, m, Ph-H), 7.24e
7.22 (1H, m, H6), 7.06 (1H, d, H8, J78¼7.7 Hz), 6.94 (1H, s,
H1), 6.45e6.43 (1H, m, H7); elemental analysis calcd (%)
for C14H10IN (319.14): C 52.69, H 3.16, N 4.39; found: C
53.01, H 3.43, N 4.58.
4.1. General
All melting points are uncorrected. IR spectra were obtained
1
using a UR-20 spectrometer. H and 13C NMR spectra were
1
recorded on AM 400 Bruker spectrometer for H at 360 MHz
(in DMSO-d6) and for 13C at 100 MHz (in DMSO-d6 or ace-
tone-d6). THF was distilled over benzophenone/sodium and
used immediately. TMEDA was distilled over sodium. The
freshly prepared solution of n-BuLi in hexane (1.19 M) was
titrated according to a known procedure.21 All boronic acids
were supplied by Aldrich. All reactions involving air-sensitive
reagents were performed using syringeeseptum cap techniques
in oven-dried glassware under a dry argon/nitrogen atmo-
sphere. Parallel cross-coupling and parallel evaporation were
4.2.3. 5-Bromo-2-tert-butylindolizine (3b)
From 2-tert-butylindolizine (1b). Yield of 3b: 97%; a yel-
low oil that formed crystals upon standing at 9 ꢁC; IR
(neat): 1620, 1500, 1480 cmꢀ1
;
1H NMR: d¼7.35 (1H, s,
H3), 7.28 (1H, d, H6, J67¼8.9 Hz), 6.73 (1H, d, H8, J78¼
6.6 Hz), 6.55e6.50 (1H, m, H7), 6.48 (1H, s, H1), 1.35 (9H,
t
s, Bu); 13C NMR (acetone-d6): 140.9, 133.8, 117.4, 117.1,
113.6, 109.1, 99.5, 99.4, 31.5 (C(CH3)3), 30.8 (C(CH3)3); ele-
mental analysis calcd (%) for C12H14BrN (252.15): C 57.16, H
5.60, N 5.55; found: C 56.95, H 5.63, N 5.77; 1H NMR
(CF3COOD): d¼9.30 (1H, m), 8.95 (2H, m, H6þH8), 8.03
¨
performed and accelerated using the BUCHI SynCore Reactor
(with its filtration unit, vacuum pump V-501 and vacuum
controller V-805).22
t
(1H, s, H1), 6.43 (1H, s, 3-CHD), 2.46 (9H, s, Bu).
4.2. Preparation of 5-Br(I)-indolizines (general
procedure)
4.2.4. 5-Iodo-2-tert-butylindolizine (4b)
From 2-tert-butylindolizine (1b). Yield of 4b: 95%; light
green solid, mp: 57e59 ꢁC; IR (neat): 1615, 1490,
1
To a solution of indolizine 1aed (20 mmol) and TMEDA
(22 mmol) in anhydrous THF (70 mL) at ꢀ80 ꢁC, a solution
of n-BuLi (18.5 mL, 1.19 M, 1.1 equiv) was added with stir-
ring. The mixture was allowed to warm to ꢀ20 ꢁC, and kept
at this temperature for a further 2 h. A yellow color appeared.
Then the mixture was cooled to ꢀ80 ꢁC, and 1,2-dibromo-
tetrafluoroethane (BrCF2)2 (22 mmol) or a dry THF (30 mL)
1475 cmꢀ1; H NMR: d¼7.32 (1H, s, H3), 7.28 (1H, d, H6,
J67¼8.9 Hz), 6.96 (1H, d, H8, J78¼6.8 Hz), 6.53 (1H, s, H1),
6.37e6.33 (1H, m, H7), 1.35 (9H, s, tBu); 13C NMR
(acetone-d6): 140.2, 132.7, 121.6, 118.0, 117.3, 113.1, 99.5,
88.4, 31.6 (C(CH3)3), 30.7 (C(CH3)3); elemental analysis
calcd (%) for C12H14IN (299.15): C 48.18, H 4.72, N 4.68;
found: C 48.03, H 4.93, N 4.57.

A.G. Kuznetsov et al. / Tetrahedron 64 (2008) 749e756
753
4.2.5. 5-Bromo-6-methyl-2-tert-butylindolizine (3c)
to cool to room temperature, the organic solvent was
evaporated, and the crude product was purified by column
chromatography on silica gel (eluent hexane/CHCl3; 9:1).
The cycl[3.2.2]azine 6 was isolated as a deep yellow solid
(0.260 g, 87%). Mp: 121e123 ꢁC; IR (Nujol): 1745, 1700,
From 6-methyl-2-tert-butylindolizine (1c). Yield of 3c:
1
92%; light yellow solid, mp: 28e30 ꢁC; H NMR: d¼7.35
(1H, s, H3), 7.19 (1H, d, H8, J78¼6.3 Hz), 6.52 (1H, d, H7,
J78¼6.3 Hz), 6.41 (1H, s, H1), 2.35 (3H, s, Me), 1.35 (9H, s,
tBu); elemental analysis calcd (%) for C13H16BrN (266.18):
C 58.66, H 6.06, N 5.26; found: C 58.52, H 6.20, N 5.51.
1
1545 cmꢀ1; H NMR: d¼8.27 (1H, d, H6, J67¼8.0 Hz), 7.96
(1H, d, H8, J78¼6.8 Hz), 7.91e7.86 (1H, m, H7), 3.94 (6H,
t
s, 2COOMe), 2.76 (3H, s, Me), 1.57 (9H, s, Bu); 13C NMR
4.2.6. 5-Iodo-6-methyl-2-tert-butylindolizine (4c)
(DMSO-d6): 167.5 (COOCH3), 163.8 (COOCH3), 142.7,
133.1, 127.1, 125.2, 124.5, 122.0, 121.9, 115.1, 112.0,
108.6, 52.9 (COOCH3), 51.7 (COOCH3), 33.9 (C(CH3)3),
31.1 (C(CH3)3), 12.2 (C(4)-CH3); MS m/z (%) 327 (66), 312
(6), 296 (20), 282 (5), 281 (18), 280 (100), 248 (6), 191 (6),
178 (8), 110 (9), 96 (5), 43 (11); elemental analysis calcd
(%) for C19H21NO4 (327.38): C 69.71, H 6.47, N 4.28; found:
C 69.62, H 6.43, N 4.18.
From 6-methyl-2-tert-butylindolizine (1c). Yield of 4c:
1
87%; light yellow-green solid, mp: 39e41 ꢁC; H NMR: d¼
7.38 (1H, s, H3), 7.18 (1H, d, H8, J78¼6.2 Hz), 6.51e6.49
(2H, m, H1þH7), 2.37 (3H, s, Me), 1.35 (9H, s, tBu); elemental
analysis calcd (%) for C13H16IN (313.18): C 49.86, H 5.15, N
4.47; found: C 49.60, H 5.48, N 4.71.
4.2.7. 5-Bromo-1-methyl-2-tert-butylindolizine (3d)
From 1-methyl-2-tert-butylindolizine (1d). Yield of 3d:
4.5. Parallel cross-coupling of 5-Br(I)-indolizines with
arylboronic acids
1
98%; yellow oil; H NMR: d¼7.30 (1H, d, H6, J67¼9.8 Hz),
7.28 (1H, s, H3), 6.68 (1H, d, H8, J78¼6.6 Hz), 6.54e6.51
t
(1H, m, H7), 2.43 (3H, s, Me), 1.37 (9H, s, Bu); elemental
The experiments were performed in a SynCoreÔ module.
The solutions of 5-Br(I)-indolizine derivative (1 mmol), aryl-
boronic acid (1.1 mmol), and K2CO3 (2 mmol) in pure 1,4-di-
oxane (7 mL) and water (1 mL) at room temperature were
placed in 24 Syncore flasks under a nitrogen atmosphere,
and a solution of 0.1 M PdCl2 in water (0.05 mL, 0.5 mol %)
was added to each flask. The flasks were shaken and heated
at 80 ꢁC for 24 h. The flasks were cooled to room temperature
and palladium black was removed by parallel filtration using
a Buchi filtration unit under a nitrogen atmosphere. The fil-
trates were concentrated by parallel evaporation and water
(5 mL) was added to each flask. Then the mixtures were
manually extracted with CHCl3, the organic layers were dried
over anhydrous Na2SO4, and evaporated. The residues were
purified by column chromatography on silica gel. The parallel
procedure was repeated for other 12 combinations of indoli-
zines and boronic acids.
analysis calcd (%) for C13H16BrN (266.18): C 58.66, H
6.06, N 5.26; found: C 58.71, H 6.22, N 5.51.
4.3. 5-Bromo-2-tert-butyl-3-trifluoroacetylindolizine (5)
by acylation reaction
Trifluoroacetic anhydride (1 mL) was added with stirring to
a solution of indolizine 3b (0.252 g, 1.0 mmol) in anhydrous
THF (10 mL) at 0 ꢁC. The mixture turned yellow. The solution
was kept at 0 ꢁC (1 h) and then treated with a saturated solu-
tion of ammonium chloride. The organic layer was separated
and the aqueous layer was extracted with dichloromethane.
After drying over anhydrous Na2SO4 and evaporation of the
organic solvents, the crude product was purified by column
chromatography on silica gel (eluent hexane/CHCl3; 9:1).
The isolated product was 5-bromo-3-trifluoroacetyl-2-tert-
butylindolizine 5a (0.291 g, 83%) as a deep yellow solid.
Mp: 48e50 ꢁC; IR (Nujol): 1695, 1525, 1490 cmꢀ1
;
1H
4.5.1. 5-(4-Methoxyphenyl)-2-tert-butylindolizine (7a)
NMR: d¼7.36 (1H, d, H6, J67¼7.6 Hz), 6.87 (1H, d, H8, J78¼
Column chromatography of residue using an eluent (hex-
ane/CHCl3; 9:1) yielded 7a from 4-methoxyphenylboronic
acid and 5-bromoindolizine 3b (70%) or 5-iodoindolizine 4b
(76%) as a white solid. Mp: 113e115 ꢁC; 1H NMR: d¼
7.54e7.52 (2H, m, 5-Ar), 7.19 (1H, d, H6, J67¼8.9 Hz), 7.08
(1H, s, H3), 7.05e7.03 (2H, m, 5-Ar), 6.67e6.64 (1H, m,
H7), 6.32 (1H, s, H1), 6.26 (1H, d, H8, J78¼5.0 Hz), 3.87
7.0 Hz), 6.80e6.76 (1H, m, H7), 6.53 (1H, s, H1), 1.38 (9H,
t
s, Bu); 13C NMR (DMSO-d6): 177.8 (q, JCeF¼34.4 Hz,
CCOCF3), 148.3, 138.2, 123.8, 118.6, 118.5, 116.7 (q, JCeF
¼
293.8 Hz, COCF3), 116.2, 115.8, 103.2, 32.3 (C(CH3)3), 30.8
(C(CH3)3); elemental analysis calcd (%) for C14H13BrF3NO
(348.17): C 48.30, H 3.76, N 4.02; found: C 48.47, H 3.68,
N 4.21.
t
(3H, s, OMe), 1.28 (9H, s, Bu); elemental analysis calcd
(%) for C19H21NO (279.38): C 81.68, H 7.58, N 5.01; found:
C 81.33, H 7.84, N 5.23.
4.4. Dimethyl 3-tert-butyl-4-methylpyrrolo[2,1,5-cd]-
indolizine-1,2-dicarboxylate (6) by [8þ2] cycloaddition
reaction
4.5.2. 5-Phenyl-2-tert-butylindolizine (7b)
Column chromatography of residue using hexane as an
eluent yielded 7b from phenylboronic acid and 5-bromoindo-
lizine 3b (73%) or 5-iodoindolizine 4b (80%) as a white solid.
Mp: 68e70 ꢁC; 1H NMR: d¼7.62e7.60 (2H, m, 5-Ph), 7.52e
7.44 (3H, m, 5-Ph), 7.23 (1H, d, H6, J67¼8.7 Hz), 7.10 (1H, s,
H3), 6.69e6.65 (1H, m, H7), 6.35 (1H, s, H1), 6.30 (1H, d, H8,
Dimethyl acetylendicarboxylate (0.170 g, 0.146 mL,
1 mmol) was added to a solution of bromoindolizine 3d
(0.266 g, 1.0 mmol) in anhydrous toluene (10 mL) at room
temperature. The mixture was heated to 80 ꢁC and kept at
this temperature for 2 h with stirring. The mixture was allowed

754
A.G. Kuznetsov et al. / Tetrahedron 64 (2008) 749e756
t
J78¼7.9 Hz), 1.28 (9H, s, Bu); elemental analysis calcd (%)
for C18H19N (249.35): C 86.70, H 7.68, N 5.62; found: C
86.47, H 8.01, N 5.88.
4.5.7. 5-(4-Methoxyphenyl)-6-methyl-2-tert-butylindolizine
(7g)
Column chromatography of residue using an eluent (hex-
ane/CHCl3; 9:1) yielded 7g from 4-methoxyphenylboronic
acid and 5-bromoindolizine 3c (49%) or 5-iodoindolizine 4c
(87%) as a white solid. Mp: 139e141 ꢁC; 1H NMR: d¼
7.28e7.25 (2H, m, 5-Ar), 7.15 (1H, d, H7, J78¼8.5 Hz),
7.10e7.06 (2H, m, 5-Ar), 6.56 (1H, d, H8, J78¼8.5 Hz), 6.51
(1H, s, H3), 6.24 (1H, s, H1), 3.86 (3H, s, OMe), 1.98 (3H,
4.5.3. 5-(4-Trifluoromethylphenyl)-2-tert-butylindolizine
(7c)
Column chromatography of residue using hexane as an el-
uent yielded 7c from 4-trifluoromethylphenylboronic acid and
5-bromoindolizine 3b (86%) or 5-iodoindolizine 4b (97%) as
t
1
a yellow-green solid. Mp: 123e125 ꢁC; H NMR: d¼7.87e
s, Me), 1.27 (9H, s, Bu); elemental analysis calcd (%) for
C20H23NO (293.41): C 81.87, H 7.90, N 4.77; found: C
82.02, H 7.83, N 4.92.
7.86 (4H, m, 5-Ar), 7.28 (1H, d, H6, J67¼9.0 Hz), 7.11 (1H,
s, H3), 6.69e6.65 (1H, m, H7), 6.39 (1H, s, H1), 6.37 (1H,
d, H8, J78¼6.1 Hz), 1.28 (9H, s, tBu); elemental analysis calcd
(%) for C19H18F3N (317.35): C 71.91, H 5.72, N 4.41; found:
C 71.63, H 5.98, N 4.67.
4.5.8. 6-Methyl-5-phenyl-2-tert-butylindolizine (7h)
Column chromatography of residue using hexane as an
eluent yielded 7h from phenylboronic acid and 5-bromoindo-
lizine 3c (44%) or 5-iodoindolizine 4c (78%) as a white solid.
4.5.4. 5-(2-Benzofuranyl)-2-tert-butylindolizine (7d)
1
Mp: 79e81ꢁC; H NMR: d¼7.59e7.55 (2H, m, 5-Ph), 7.51e
Column chromatography of residue using hexane as an
eluent yielded 7d from 2-benzofuranylboronic acid and 5-bro-
moindolizine 3b (72%) or 5-iodoindolizine 4b (84%) as a light
7.47 (1H, m, 5-Ph), 7.39e7.36 (2H, m, 5-Ph), 7.18 (1H, d, H7,
J78¼8.7 Hz), 6.58 (1H, d, H8, J78¼8.7 Hz), 6.47 (1H, s, H3),
6.27 (1H, s, H1), 1.98 (3H, s, Me), 1.22 (9H, s, tBu); elemental
analysis calcd (%) for C19H21N (263.38): C 86.65, H 8.04, N
5.32; found: C 86.31, H 8.27, N 5.64.
1
yellow solid. Mp: 76e78 ꢁC; H NMR: d¼7.78 (1H, s, H3),
7.70 (1H, d, 5-Ar, J¼7.2 Hz), 7.58 (1H, d, 5-Ar, J¼
7.7 Hz), 7.50 (1H, s, 5-H3), 7.41e7.34 (2H, m, 5-Ar), 7.31e
7.27 (1H, m, 5-Ar), 7.12 (1H, d, H8, J78¼7.0 Hz), 6.77e6.74
4.5.9. 5-(4-Trifluoromethylphenyl)-6-methyl-2-tert-
butylindolizine (7i)
t
(1H, m, H7), 6.49 (1H, s, H1), 1.39 (9H, s, Bu); elemental
analysis calcd (%) for C20H19NO (289.37): C 83.01, H 6.62,
N, 4.84; found: C 82.74, H 6.91, N 5.09.
Column chromatography of residue using hexane as an el-
uent yielded 7i from 4-trifluoromethylphenylboronic acid and
5-bromoindolizine 3c (47%) or 5-iodoindolizine 4c (90%) as
1
a yellow-green solid. Mp: 151e153 ꢁC; H NMR: d¼7.90e
4.5.5. 5-(3,4-Dichlorophenyl)-2-tert-butylindolizine (7e)
Column chromatography of residue using hexane as an
eluent yielded 7e from 3,4-dichlorophenylboronic acid and
5-bromoindolizine 3b (82%) or 5-iodoindolizine 4b (93%)
7.86 (2H, m, 5-Ar), 7.62e6.59 (2H, m, 5-Ar), 7.22 (1H, d,
H7, J78¼8.5 Hz), 6.60 (1H, d, H8, J78¼8.5 Hz), 6.45 (1H, s,
t
H3), 6.30 (1H, s, H1), 1.98 (3H, s, Me), 1.22 (9H, s, Bu);
1
as a yellow solid. Mp: 81e83 ꢁC; H NMR: d¼7.78 (1H, s,
elemental analysis calcd (%) for C20H20F3N (331.37): C
72.49, H 6.08, N 4.23; found: C 72.24, H 6.33, N 4.57.
0
5-H2), 7.70 (1H, d, 5-H2 , J¼7.4 Hz), 7.62e6.59 (1H, m,
0
5-H3 ), 7.28 (1H, d, H6, J67¼8.8 Hz), 7.09 (1H, s, H3),
6.69e6.66 (1H, m, H7), 6.39 (1H, s, H1), 6.36 (1H, d, H8,
4.5.10. 5-(2-Benzofuranyl)-6-methyl-2-tert-butylindolizine
(7j)
t
J78¼7.6 Hz), 1.28 (9H, s, Bu); elemental analysis calcd (%)
for C18H17Cl2N (318.24): C 67.93, H 5.38, N 4.40; found: C
67.65, H 5.74, N 4.72.
Column chromatography of residue using hexane as an
eluent yielded 7j from 2-benzofuranylboronic acid and 5-bro-
moindolizine 3c (44%) or 5-iodoindolizine 4c (79%) as a deep
1
4.5.6. 5-(3-Formylphenyl)-2-tert-butylindolizine (7f)
yellow solid. Mp: 77e79 ꢁC; H NMR: d¼7.71 (1H, d, 5-Ar,
Column chromatography of residue using an eluent (hex-
ane/CHCl3; 9:1) yielded 7f from 3-formylphenylboronic acid
and 5-bromoindolizine 3b (84%) or 5-iodoindolizine 4b
(96%) as a yellow solid. Mp: 62e65 ꢁC; IR (neat): 1705,
J¼6.7 Hz), 7.58 (1H, d, H7, J78¼8.6 Hz), 7.40e7.35 (1H, m,
5-Ar), 7.32e7.26 (2H, m, 5-Ar), 7.17 (1H, s, 5-H3), 7.03
(1H, s, H3), 6.56 (1H, d, H8, J78¼8.6 Hz), 6.35 (1H, s, H1),
t
2.25 (3H, s, Me), 1.27 (9H, s, Bu); elemental analysis calcd
1
1625, 1600, 1585 cmꢀ1; H NMR: d¼10.05 (1H, s, CHO),
(%) for C21H21NO (303.41): C 83.13, H 6.98, N, 4.62; found:
C 83.08, H 6.81, N 4.81.
0
8.11 (1H, s, 5-H2), 7.99 (1H, d, 5-H2 , J¼8.0 Hz), 7.91 (1H,
0
0
d, 5-H4 , J¼8.0 Hz), 7.74e7.70 (1H, m, 5-H3 ), 7.27 (1H, d,
H6, J67¼8.9 Hz), 7.05 (1H, s, H3), 6.70e6.66 (1H, m, H7),
6.37 (1H, d, H8, J78¼6.2 Hz), 6.36 (1H, s, H1), 1.24 (9H, s,
tBu); 13C NMR (acetone-d6): 192.6 (CHO), 141.7, 138.5,
137.5, 136.1, 135.2, 134.9, 130.9, 130.5, 128.0, 119.1,
117.8, 111.8, 107.3, 98.8, 32.1 (C(CH3)3), 31.6 (C(CH3)3);
elemental analysis calcd (%) for C19H19NO (277.36): C
82.28, H 6.90, N 5.05; found: C 78.27, H 6.96, N 4.60.
LSMS: 278; 279.23
4.5.11. 5-(3,4-Dichlorophenyl)-6-methyl-2-tert-
butylindolizine (7k)
Column chromatography of residue using hexane as an
eluent yielded 7k from 3,4-dichlorophenylboronic acid and
5-bromoindolizine 3c (36%) or 5-iodoindolizine 4c (87%) as
a yellow solid. Mp: 153e155 ꢁC; 1H NMR: d¼7.83 (1H,
0
s, 5-H2), 7.75 (1H, d, 5-H2 , J¼9.0 Hz), 7.60e7.56 (1H,
0
m, 5-H3 ), 7.21 (1H, d, H7, J78¼8.6 Hz), 6.58 (1H, d, H8,

A.G. Kuznetsov et al. / Tetrahedron 64 (2008) 749e756
755
J78¼8.6 Hz), 6.51 (1H, s, H3), 6.30 (1H, s, H1), 1.99 (3H, s,
yellow solid. Mp: 169e171 ꢁC; 1H NMR: d¼8.32 (1H, s,
5-H3), 7.77e7.69 (4H, m), 7.63e7.61 (1H, m), 7.51e7.49
(1H, m), 7.40e7.35 (3H, m), 7.33e7.28 (1H, m), 7.25e7.20
(2H, m), 6.91 (1H, s, H1), 6.84 (1H, m, H7); elemental analysis
calcd (%) for C22H15NO (309.36): C 85.41, H 4.89, N 4.53;
found: C 85.28, H 5.06, N 4.71.
t
Me), 1.23 (9H, s, Bu); elemental analysis calcd (%) for
C19H19Cl2N (332.28): C 68.68, H 5.76, N 4.22; found: C
68.85, H 5.75, N 4.27.
4.5.12. 5-(3-Formylphenyl)-6-methyl-2-tert-butylindolizine
(7l)
Column chromatography of residue using an eluent (hex-
ane/CHCl3; 9:1) yielded 7l from 3-formylphenylboronic acid
and 5-bromoindolizine 3c (52%) or 5-iodoindolizine 4c
(91%) as a yellow solid. Mp: 116e118 ꢁC; IR (Nujol):
4.5.17. 5-(3,4-Dichlorophenyl)-2-phenylindolizine (7q)
Column chromatography of residue using hexane as an
eluent yielded 7q from 3,4-dichlorophenylboronic acid and
5-bromoindolizine 3a (70%) or 5-iodoindolizine 4a (87%) as
1690, 1600 cmꢀ1
;
1H NMR: d¼10.11 (1H, s, CHO), 8.06
1
a yellow solid. Mp: 142e144 ꢁC; H NMR: d¼7.83 (1H, d,
0
(1H, d, 5-H2 , J¼6.9 Hz), 7.93 (1H, s, 5-H2), 7.83e7.89 (1H,
0
5-H2, J¼2.5 Hz), 7.75 (1H, d, 5-H2 , J¼8.4 Hz), 7.69e7.66
0
0
m, 5-H3 ), 7.71 (1H, d, 5-H4 , J¼7.5 Hz), 7.23 (1H, d, H7,
J78¼9.0 Hz), 6.61 (1H, d, H8, J78¼8.6 Hz), 6.45 (1H, s, H3),
6.30 (1H, s, H1), 1.99 (3H, s, Me), 1.22 (9H, s, tBu); elemental
analysis calcd (%) for C20H21NO (291.40): C 82.44, H 7.26, N
4.81; found: C 82.38, H 7.38, N 4.85.
0
(1H, m, 5-H3 ), 7.61e7.58 (3H, m), 7.40 (1H, d, H6, J67¼
10.8 Hz), 7.33e7.30 (2H, m), 7.20e7.16 (1H, m), 6.82 (1H,
s, H1), 6.78 (1H, m, H7), 6.45 (1H, d, H8, J78¼9.8 Hz);
elemental analysis calcd (%) for C20H13Cl2N (338.23): C
71.02, H 3.87, N 4.14; found: C 70.74, H 4.13, N 4.45.
4.5.13. 5-(4-Methoxyphenyl)-2-phenylindolizine (7m)
Column chromatography of residue using an eluent (hex-
ane/CHCl3; 9:1) yielded 7m from 4-methoxyphenylboronic
acid and 5-bromoindolizine 3a (64%) or 5-iodoindolizine 4a
(87%) as a white solid. Mp: 146e148 ꢁC; 1H NMR: d¼
7.66e7.54 (5H, m), 7.37e7.26 (3H, m), 7.18e7.06 (3H, m),
6.75e6.72 (2H, m), 6.37 (1H, d, H8, J78¼10.2 Hz), 3.88
(3H, s, OMe); elemental analysis calcd (%) for C21H17NO
(299.37): C 84.25, H 5.72, N 4.68; found: C 84.06, H 5.98,
N 4.91.
4.5.18. 5-(3-Formylphenyl)-2-phenylindolizine (7r)
Column chromatography of residue using an eluent (hex-
ane/CHCl3; 9:1) yielded 7r from 3-formylphenylboronic
acid and 5-bromoindolizine 3a (72%) or 5-iodoindolizine 4a
(95%) as a yellow solid. Mp: >132 ꢁC (dec); IR (Nujol):
1
1695, 1605, 1580 cmꢀ1; H NMR: d¼10.11 (1H, s, CHO),
0
8.23 (1H, s, 5-H2), 8.07 (1H, d, 5-H2 , J¼7.4 Hz), 7.99 (1H,
0
0
d, 5-H4 , J¼6.3 Hz), 7.81e7.77 (1H, m, 5-H3 ), 7.62e7.57
(2H, m), 7.44e7.16 (5H, m), 6.82 (1H, s, H1), 6.77 (1H, m,
H7), 6.49 (1H, d, H8, J78¼9.4 Hz); elemental analysis calcd
(%) for C21H15NO (297.35): C 84.82, H 5.08, N 4.71; found:
C 84.51, H 5.34, N 4.96.
4.5.14. 2,5-Diphenylindolizine (7n)
Column chromatography of residue using hexane as an
eluent yielded 7n from phenylboronic acid and 5-bromoindo-
lizine 3a (41%) or 5-iodoindolizine 4a (78%) as a white solid.
Acknowledgements
1
Mp: 92e94 ꢁC; H NMR: d¼7.95e7.88 (2H, m), 7.73e7.67
This work was supported by Russian Foundation of Basic
Research (RFBR Grant no. 07-03-00921).
(3H, m), 7.44e7.35 (5H, m), 7.24e7.22 (1H, m), 7.11e7.10
(1H, m), 7.01 (1H, s, H1), 6.99e6.97 (1H, m), 6.66e6.64
(1H, m, H7); elemental analysis calcd (%) for C20H15N
(269.34): C 89.19, H 5.61, N 5.20; found: C 88.86, H 5.90,
N 5.54.
Supplementary data
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2007.11.017.
4.5.15. 5-(4-Trifluoromethylphenyl)-2-phenylindolizine (7o)
Column chromatography of residue using hexane as an
eluent yielded 7o from 4-trifluoromethylphenylboronic acid
and 5-bromoindolizine 3a (32%) or 5-iodoindolizine 4a
References and notes
1
(96%) as a white-green solid. Mp: 129e131 ꢁC; H NMR:
1. Flitsch, W. Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Ress,
C. W., Eds.; Pergamon: Oxford, 1984; Vol. 4, p 443.
d¼7.94e7.86 (4H, m), 7.63e7.58 (3H, m), 7.42 (1H, d, H6,
J67¼7.2 Hz), 7.33e7.29 (2H, m), 7.20e7.16 (1H, m), 6.82
(1H, s, H1), 6.80e6.78 (1H, m, H7), 6.49 (1H, d, H8, J78¼
10.8 Hz); elemental analysis calcd (%) for C21H14F3N
(337.34): C 74.77, H 4.18, N 4.15; found: C 74.37, H 4.38,
N 4.43.
2. Tielmann, P.; Hoenke, C. Tetrahedron Lett. 2006, 47, 261 and references
therein.
3. (a) Swinborne, P.-J.; Hunt, J. H.; Klinkert, G. Adv. Heterocycl. Chem.
1978, 23, 103; (b) Prostakov, N. S.; Baktybaev, O. B. Russ. Chem. Rev.
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4. Longuet-Higgins, H. C.; Coulson, C. A. Trans. Faraday Soc. 1947, 43, 87.
5. Fukui, K.; Yonezawa, T.; Nagata, C.; Shirgu, H. J. Chem. Phys. 1954, 22,
1433.
4.5.16. 5-(2-Benzofuranyl)-2-phenylindolizine (7p)
Column chromatography of residue using hexane as an
eluent yielded 7p from 2-benzofuranylboronic acid and 5-bro-
moindolizine 3a (68%) or 5-iodoindolizine 4a (90%) as a deep
6. Kost, A. N.; Sagitullin, R. S.; Gromov, S. P. Heterocycles, Special Issue
1977, 7, 997.

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7. Babaev, E. V.; Vasilevich, N. I.; Ivushkina, A. S. Beilstein J. Org. Chem.
2005, 1, 9.
16. Kuznetsov, A. G.; Bush, A. A.; Rybakov, V. B.; Babaev, E. V. Molecules
2005, 10, 1074.
8. We thank the referee for paying attention to the recent report on the
preparation of 3-anilino-1-cyano derivatives of 5-Cl(F)-indolizines (by
Ugi-reaction) and their nucleophilic substitution at C-5: Bedjeguelal, K.;
17. Tschischibabin, A. E. Ber. Dtsch. Chem. Ges. 1927, 60, 1607.
18. (a) Armarego, W. L. F. J. Chem. Soc. 1964, 11, 4226; (b) Reid, D. H.;
Webster, R. G.; McKenzie, S. J. Chem. Soc., Perkin Trans. 1 1979, 2334.
19. In the case of C-1 substitution onewould expect strong downfield shift of the
signal of peri-proton H8, see review: Babaev, E. V.; Torocheshnikov, V. N.;
Bobrovsky, S. I. Chem. Heterocycl. Compd. (Engl. Transl.) 1995, 31, 1079.
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´
Bienayme, H.; Dumoulin, A.; Poigny, S.; Schmitt, P.; Tam, E. Bioorg.
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1
and quickly decomposed to a green liquid. Although its H NMR spectra
were in full agreement with the structure, LCMS data confirmed that 7f
contains an impurity (12%) with an intractable peak M¼404.