An improved synthesis of some 5-substituted indolizines using regiospecific lithiation

Article abstract of DOI:10.3390/10091074

Various 2-substituted indolizines can be directly and selectively lithiated in the 5 position and subsequent reactions with different electrophiles lead to some novel classes of indolizines. In particular, previously unknown 5-formyl- and 5-iodoindolizine have been prepared by this way and the molecular structure of 5-formyl-2-phenylindolizine was confirmed by X-Ray analysis. The reactivity of the 5-CHO- and 5-COPh groups toward some nucleophiles has been examined, and some additional classes of derivatives (oximes and alcohols) have been obtained. The possibility of Suzuki cross-coupling of 5-iodoindolizines and boronic acids was proven.

Full text of DOI:10.3390/10091074

Molecules 2005, 10, 1074-1083
molecules
ISSN 1420-3049
http://www.mdpi.org
An Improved Synthesis of Some 5-Substituted Indolizines Using
Regiospecific Lithiation
Alexey G. Kuznetsov, Alexander A. Bush, Viktor B. Rybakov and Eugene V. Babaev*
Chemistry Department, Moscow State University, Moscow 119992, Russia.
* Author to whom correspondence should be addressed; E-mail: babaev@org.chem.msu.su
Received: 23 April 2005 / Published: 30 September 2005
Abstract: Various 2-substituted indolizines can be directly and selectively lithiated in the
5 position and subsequent reactions with different electrophiles lead to some novel
classes of indolizines. In particular, previously unknown 5-formyl- and 5-iodoindolizine
have been prepared by this way and the molecular structure of 5-formyl-2-
phenylindolizine was confirmed by X-Ray analysis. The reactivity of the 5-CHO- and 5-
COPh groups toward some nucleophiles has been examined, and some additional classes
of derivatives (oximes and alcohols) have been obtained. The possibility of Suzuki cross-
coupling of 5-iodoindolizines and boronic acids was proven.
Keywords: Direct lithiation, 5-lithiumindolizine, 5-formylindolizine, 5-iodoindolizine,
5-benzoylindolizine, Suzuki reaction, reduction, oxime.
Introduction
According to literature data, the first attempt at direct lithiation of indolizines corresponds to
Renard and Gubin [1], who achieved regioselective metallation of 2-phenylindolizine in the
5-position, followed by replacement of lithium by electrophiles. Our long involvement in the
chemistry of 5-substituted indolizines [2,3] and the failure to precisely reproduce the protocol
reported in [1] have stimulated our interest to the problem of indolizine lithiation. In addition some
common electrophiles (e.g. I+, CHO+) were not tested in reference [1], although the expected products
– 5-formyl and 5-iodoindolizines – are not readily available by common heterocyclic synthesis
methods. Thus, 5-iodoindolizines are still unknown, and there are only two references [4,5] devoted

Molecules 2005, 10
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to 5-formylindolizines prepared via [3+2]-cycloaddition (a stepwise preparation starting from
pyridinium ylides bearing an acetal group at position 2).
In this article we report our success in following areas:
– optimization of the protocol for direct lithiation of 2- and 1,2- substituted indolizines by varying
temperature and time of metallation;
– discovery of a novel and easy route to 5-formyl and 5-haloindolizines by means of direct lithiation
followed by electrophilic quench;
– the first Suzuki type cross-coupling reaction between 5-iodoindolizines and a boronic acid;
– follow-up of the chemistry of 5-formylindolizines and their derivatives;
– direct proof of the structure of 5-formyl-2-phenylindolizine by X-ray analysis.
Results and Discussion
Preparation of indolizines.
Starting indolizines were prepared by the standard Tchichibabin method [6]:
NaHCO3
CH3CN
R2
O
+
R1
or
PhH-
Me2CO
heating
N+
water
heating
R1
N
N
Br
Br
O
R1
R2
R2
1a-c
Substances 1
R1
R2
Ph
1a
1b
1c
H
H
tBu
tBu
Me
All the obtained indolizines 1a-c are known from the literature [6-8], and the intermediate
pyridinium salts were not isolated in some cases. The yields of indolizines 1 varied from 50% to 85%.
Direct lithiation of indolizines.
In the original literature procedure [1] reaction of n-BuLi at -40ºC with indolizine 1a (carrying out
the metallation for 2 hours at -40ºC) followed by reaction with PhCN gave 90% of 5-benzoyl-
indolizine 2d. In our hands, however, all attempts to precisely reproduce this protocol (even after
several runs) led to 2d in yields that never exceeded 10-15%. Better yields (that incidently were never
higher than 55%) have been obtained using a modified procedure. The changes were the following:
the substrate 1c was mixed with n-BuLi at -78 to -80ºC, and the stirring was continued at -20ºC for 5
hours to complete the metallation. Optimization was achieved by varying reaction time, temperature,
and amount of TMEDA. The optimal reaction time was found by TLC monitoring (an aliquot of

Molecules 2005, 10
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reaction mixture was taken every 30 min and quenched with an excess of an electrophile. The final
optimized protocol is given in the Experimental. Lithiation of indolizines 1b,c required shorter times
(2 hours) compared with 5 hours for 1a (under the same conditions).
R1
R1
R1
E
n-BuLi
R2
R2
R2
N
N
THF, TMEDA
adding -78oC,
then -20oC, 5h
N
Li
E
1a-c
2a-e
Preparation of 5-substituted indolizines
Direct lithiation of indolozines 1a-c followed by treatment with DMF gave 5-formylindolizines
2a-c in good yields (75-95%, Table 1). The obtained crystalline substances presented deep colors
ranging from orange-brown to dark-brown (in contrast to the well-known isomeric 3-formyl
derivatives of indolizines that are colorless).
R1
R1
PhCN
R2
R2
or
DMF
or
N
N
Li
E
I2
2
E = C(O)Ph, CHO, I
1
In the H-NMR spectra of formylindolizines 2a-c (Table 2) the signal of proton H3 is shifted to
low field (8.7 - 9.2 ppm), whereas in the parent indolizines 1 this signal appears at 6.8-7.2 ppm. This
downfield shift can be clearly explained by a "peri-effect" caused by magnetic anisotropy of the
5-formyl group located at the peri-position with respect to proton H3. Earlier an analogous effect was
observed for 1-COR-, 3-COR-, and 8-COR-substituted indolizines, where the corresponding signals
of protons located at the peri-positions (H8, H5 and H1 respectively) underwent a downfield shift, see
review [9].
Table 1. Characteristics of 5-Substituted indolizines
Indolizine
E
Product
2a
Yield,%
Mp, ºC
1a
1b
1c
1a
1b
CHO
CHO
CHO
C(O)Ph
I
74
94
95
55
96
128-130
81-83
2b
2c
37-39
2d
284-286 (lit. 286) [1]
57-59
2e

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Table 2. 1H-NMR spectra of 5-formyl indolizines 2a-c.
Chemical shifts, ppm (J, Hz)
No.
2a
H1, s
7.04
6.61
-
H3, s H6, d (J67)
H7, m
6.95
6.86
6.78
H8, d (J78) CHO, s HR1,R2
9.18
8.71
8.65
7.83 (8.7)
7.71 (8.6)
7.71 (8.7)
7.52 (6.9)
7.42 (7.2)
7.35 (7.4)
9.88
9.81
9.75
m: 7.71; 7.39; 7.24 (2-Ph)
s, 1.37 (2-tBu)
s, 2.47 (1-CH3); s, 1.42 (2- tBu)
2b
2c
Finally, the structure of 5-formylindolizine 2a was proven by X-ray analysis, Figure 1. The main
feature of this structure is the very short (2.44 Å) distance between the oxygen atom of the formyl
group and the H3 hydrogen atom (this peculiarity may be linked to the above discussed peri-effect in
the 1H-NMR spectra of 2a.)
Figure 1.
Successful introduction of the formyl group at position 5 has stimulated our interest in
investigating the possibility of inserting a halogen atom at this position. 5-Halogen derivatives of
indolizines cannot be obtained by the direct Tchichibabin method [10], and the reported synthesis of
5-chloro- [11] and 5-bromoindolizines [12] involved dipolar cycloaddition strategies. 5-iodo-
indolizines remain unknown. It is possible to introduce I or Br substituents at positions 1 or 3 by
direct halogenation of 3- or 1-acylindolizines respectively [13, 14]. It was shown that 1-bromo-2,3,7-
trisubstituted indolizines may be converted to 1-iodoindolizine via 1-lithium derivative [15].
Although no attempts have been performed yet to halogenate 5-lithioindolizines, the structurally
related 5-lithium-2,3-diazaindolizine reacted with bromine abnormally leading to cleavage of the
azole fragment [16]. We now report our success in preparing of 5-iodoindolizine via lithium-iodine
exchange at position 5. Iodine added to the 5-lithio derivative of indolizine 1b to give 5-iodo-
indolizine 2e in high yield.

Molecules 2005, 10
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Reactivity of the 5-COR group
The 5-benzoyl derivative 2d was found to be inert towards common reactions of carbonyl
compounds (hydroxylamine, 2,4-dinitrophenylhydrazine in different conditions) though the benzoyl
group can be removed by the action of alkali.
NH2OH or
2,4-DNPH
NaOH
Ph
Ph
N
O
N
EtOH
reflux
2d
1a
Ph
The formyl derivatives 2a-c were more reactive toward hydroxylamine and 2,4-dinitro-
phenylhydrazine, however the products formed were extremely unstable. A change from
hydroxylamine to NH2OMe resulted in the formation under mild conditions (ethanol, pyridine, RT, 5
hours) of almost quantitative yields of stable canary-yellow oximes 3a-c. The oximes 3 darken during
storage. One would suppose that the unexpected instability of oximes and hydrazones may be caused
by a sort of tautomerism promoted by an acidic hydrogen from the OH and even NH groups; in the
case of O-Me oximes such acidity is impossible. The removal of the formyl group from indolizines
2a-c under the action of alkali was also observed.
R1
R1
NH2OH
MeONH2*HCl
Py, EtOH
Unstable
products
R2
R2
N
N
N
or
2,4-DNPH
OMe
CHO
2a-c
3a-c
Table 3. Characteristics of O-Me oximes 3 of 5-formylindolizines
5-Formylindolizine
Oxime
3a
Yield,%
89
Mp, ºC
82-84
49-51
69-71
2a
2b
2c
3b
96
3c
quant.
Table 4. 1H-NMR spectra of O-Me oximes of 5-formylindolizines.
No.
3a
Chemical shifts, ppm (J, Hz)
H1, s
H3, s
H6, d (J67)
H7, m
H8, d (J78)
6.93
CH=N, s
OMe, s
HR1,R2
6.92
8.84
7.56 (9.1)
6.81
8.40
4.13
m: 7.68; 7.38; 7.23 (2-Ph)
(6.9)
3b
3c
6.50
-
8.34
8.30
7.43 (8.9)
7.43 (8.7)
6.72
6.65
6.82
8.31
8.26
4.07
4.05
s, 1.37 (2-tBu)
(6.7)
6.76
s, 2.46 (1-CH3);
s, 1.41 (2- tBu)
(6.7)

Molecules 2005, 10
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Reduction of the 5-formyl group.
The 5-formyl group readily underwent reduction upon reaction with NaBH4 under mild conditions
yielding 5-hydroxymethylindolizines 4. Alcohols 4 were nearly colorless crystals which became light-
green upon storage. The yields were nearly quantitative.
R1
R1
NaBH4
EtOH
R2
R2
N
N
CHO
CH2OH
3
2
Table 5. Characteristics of 5-CH2OH indolizines 4
5-Formylindolizine
Product
Yield,%
quant.
Mp, ºC
110-112
82
2a
2b
2c
4a
4b
4c
quant.
quant.
76-78
Table 6. 1H-NMR spectra of 5-CH2OH indolizines 4
No.
4a
Chemical shifts, ppm (J, Hz)
OCH2, d
-OH, t
H1, s
H3, s
H6, d (J67)
H7, m
H8, d (J78)
HR1,R2
(JCH2OH
)
(JCH2OH)
6.73
7.77
7.34*
6.70
6.58 (6.6)
4.72**
5.33**
m: 7.68; 7.39*;
7.19 (2-Ph)
s, 1.35 (2-tBu)
s, 2.40
4b
4c
6.31
-
7.19
7.10
7.21 (9.3)
7.19 (9.4)
6.22
6.56
6.49 (6.3)
6.42 (6.9)
4.64 (4.5)
4.60 (5.4)
5.24 (4.5)
5.19 (5.4)
(1-CH3);
s, 1.40
(2- tBu)
*) Peak H6 overlapped with multiplet of Ph group.
**) Broad signal.

Molecules 2005, 10
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Suzuki-type cross-coupling reaction between 5-iodoindolizine and arylboronic acid.
With the goal of investigating the reactivity of the 5-iodo derivative we examined the possibility
of Suzuki-type coupling reaction between 5-iodo-2-tert-butylindolizine 2e and 4-methoxyphenyl-
boronic acid:
B(OH)2
Na2CO3
(n-Bu)4NHSO4
N
+
N
Pd(PPh3)2Cl2
MeOH-H2O
I
OMe
400C
2e
5
OMe
The reaction proceeded in high yield (94%) in alcoholic-aqueous medium and required mild
conditions and one of simplest PdII-catalysts. The structure of the product 5 was clearly confirmed by
NMR data. This result confirmed the high capacity of the iodine atom in 5-iodoindolizines for
substitution and C-C-bond formation. Meanwhile, our test experiments to form a C-N bond with some
amines using PdII and Pd0 catalysts up to now failed.
Conclusions
We have optimized and expanded the protocol for direct lithiation of indolizines and discovered
two new classes of indolizine derivatives, namely 5-formylindolizines and 5-iodoindolizines.
Carbonyl groups at position 5 of indolizine ring behave somewhat unexpectedly, forming no stable
oximes and hydrazones and being easily removed under the action of alkali. Nevertheless, some
further modifications of the 5-formyl group (reduction and formation of OMe-oxime) remain
possible. The first example of Suzuki-type coupling reaction between 5-iodoindolizine and
arylboronic acid is demonstrated.
Acknowledgments
This work was supported by RFBR (Grant No. 04-03-32823-a).
Experimental
General
1H-NMR spectra were recorded using a Bruker AC 400 NMR spectrometer at 360 MHz. All
reagents and chemicals were obtained from Acros or Merck and were used as received unless
otherwise noted. THF was refluxed over sodium with benzophenone for 3-4 hours and then distilled
in an argon atmosphere. TMEDA (N,N,N’,N’-tetramethylethylenediamine) was distilled over sodium
in an argon atmosphere. DMF was stirred with calcium hydride powder for 2-3 hours at 70-80ºC, and

Molecules 2005, 10
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then DMF decanted and distilled under reduced pressure. The obtained DMF was again distilled with
addition of phthalic anhydride under reduced pressure under an argon atmosphere and stored in
refrigerator (at -12ºC).
Procedure for direct lithiation of indolizine 1 and preparing 5-formylindolizines 2.
A flame-dried 3-necked round bottom flask (500 mL) equipped with a Teflon coated magnetic stir
bar, dropping funnel with by-pass (with rubber septum on top neck), thermometer and gas inlet
adapter was filled with argon and charged with 2-phenylindolizine 1a (3.0 g, 15.5 mmol). Then
anhydrous THF (200mL) and freshly distilled TMEDA (11.8 mL, 72.5 mmol) were added. The
resulting mixture was degassed in vacuo and the apparatus backfilled with argon. The dropping funnel
was charged with a solution of n-butyllithium (via syringe). The mixture was stirred for an additional
10 min at RT for the purpose of dissolving the 2-phenylindolizine. Then the mixture was cooled to
-78 to -80 ºC, and n-butyllithium (27.2 mL, 31 mmol, 1.24 M solution in n-hexane) was added
dropwise. The temperature was allowed to increase up to -20ºC, and the reaction mixture was stirred
at -20ºC for an additional period of time (5h in the case of 1a, 2h for 1b,c). Then DMF (3.1 mL, 31
mmol) was added, the cooling bath was removed, and the reaction mixture was allowed to warm up to
RT. The obtained light-green solution was poured into saturated aqueous NH4Cl and extracted with
ethyl acetate. The organic phase was washed with brine, dried (Na2SO4) and evaporated in vacuo.
5-formyl-2-phenylindolizine (2a, brown crystals, 2.5g, 74%) was obtained by recrystallization of the
residue from iPrOH. 5-Formyl-2-tert-butylindolizine (2b, red crystals) and 5-formyl-1-methyl-2-tert-
butylindolizine (2c, red-brown solid) were obtained using column chromatography (silica gel Merck,
1
eluent: hexane). For the yields and characteristics of indolizines 2a-c see Table 1; for H-NMR data
see Table 2.
Typical procedure for preparation of O-Me oximes 3.
To a stirred solution of 2a (0.5g, 2.3 mmol) in EtOH (5 mL) pyridine (0.18 mL, 2.3 mmol) and
methoxylamine hydrochloride (0.19g 2.3 mmol) were added, and the mixture was stirred at RT for 5
h. Then the reaction mixture was filtered and the precipitate (a canary-yellow solid) was identified as
pure oxime 3a. The mother liquors were evaporated and purified by recrystallization from i-PrOH.
Overall yield of 3a was 0.5g (89%). For the yields and characteristics of OMe-oximes 3a-c see Table
1
3; for H-NMR data see Table 4. In the reaction between 5-formylindolizine 2a and hydroxylamine
hydrochloride (in the presence or absence of organic bases) an intensely green new solid appeared.
This precipitate was insoluble in most solvents and according to 1H-NMR, was a complex mixture. In
the reaction of 2a with 2,4-DNPH the formation of a new substance can be detected (orange-yellow
spot on TLC), however it decomposed during isolation. In reactions of 2a or 2d with sodium
hydroxide the deacylation to 1a was observed.
Typical procedure for reduction of 5-formylindolizines 2.
5-Formyl-2-phenylindolizine (2a, 1g, 4.53 mmol) was dissolved in EtOH (10 mL) and NaBH4
(0.088g, 2.26 mmol) was added to the solution. The mixture was stirred at 0°C for 30 min. Then the

Molecules 2005, 10
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solvent was evaporated and water (10 mL) was added. The mixture was extracted with CH2Cl2 (3x15
mL), and the organic phase was dried (Na2SO4). Evaporation of the organic solution gave 1 g of
5-hydroxymethyl-2-phenylindolizine 4a (99%) as a colorless solid. Upon exposure to air the
substance became light-green. For the yields and characteristics of alcohols 4a-c see Table 5; for 1H-
NMR data see Table 6.
Preparation of 5-iodo-2-tert-butylindolizine 2e via direct lithiation.
The lithiation protocol was exactly the same as described above for preparation of indolizines
2a-c. The starting materials were 2-tert-butylindolizine 1b (1.0 g, 5.78 mmol), anhydrous THF (60
mL), freshly distilled TMEDA (1.75 mL, 11.6 mmol) and n-butyllithium (5.12 mL, 6.35 mmol, 1.24
M solution in n-hexane). The stirring time at -20ºC (to complete the lithiation) was reduced to 2
hours. To the obtained solution of 5-lithium-2-tert-butylindolizine a solution of iodine (1.62 g, 6.35
mmol) in anhydrous THF was added, the cooling bath was removed, and the reaction mixture was
allowed to warm up to RT. The obtained dark solution was poured into saturated aqueous NH4Cl and
extracted with ethyl acetate. The organic phase was washed with aqueous Na2SO3 (until the organic
layer became almost colorless) and with brine, dried (Na2SO4), and evaporated in vacuo giving 1.67 g
1
(96%) of green crystals of 5-iodo-2-tert-butylindolizine (2e). Mp 57-59°C; H-NMR in DMSO-D6, δ
(ppm): 7.32 (1H, s, H3), 7.28 (1H, d, H6, J67 = 8.9 Hz), 6.96 (1H, d, H8, J78 = 6.8 Hz), 6.53 (1H, s, H1),
6.36 (1H, m, H7), 1.35 (9H, s, tBu)
Cross-coupling reaction between 5-iodo-2-tert-butylindolizine 2e and p-methoxybenzeneboronic acid.
5-Iodo-2-tert-butylindolizine (2e, 0.299 g, 1 mmol), p-methoxybenzeneboronic acid (0.160 g, 1.05
mmol), sodium carbonate (0.265 g, 2.5 mmol) and tetra-n-butylammonium hydrosulfate (0.034 g, 0.1
mmol) were dissolved in the mixture of methanol (5 mL) and water (3 mL). The resulting mixture
was purged with argon for 10 min. Then the reaction mixture was heated to 40ºC and
bis(triphenylphosphine)palladium dichoride Pd(PPh3)2Cl2 (0.035g, 0.05 mmol, 5 mol %) was added.
The reaction mixture was stirred at 40ºC for an additional 5 hours (until the TLC confirmed that the
reaction was complete). Methanol was removed under reduced pressure, and water (10 mL) was
added to the residue. The mixture was extracted with CHCl3, the organic layer was separated and
dried (Na2SO4). Silica gel (3 g) was added to the organic solution, and the mixture was evaporated in
vacuo. The obtained dry silica gel containing the crude product was placed onto the column for
HPLC, and the product was purified using hexane as eluent. 5-(p-Methoxyphenyl)-2-tert-
1
butylindolizine (5, 0.262g, 94%) was obtained as colorless crystals, Mp 113-115°C; H-NMR in
DMSO-D6, δ (ppm): 7.53 (2H, m, Ar), 7.20 (1H, d, H6, J67=9.1 Hz), 7.09 (1H, s, H3), 7.04 (2H, m,
Ar), 6.65 (1H, m, H7), 6.32 (1H, s, H1) 6.27 (1H, d, H8, J78=6.2 Hz), 3.87 (3H, s, OCH3), 1.28 (9H, s,
tBu).

Molecules 2005, 10
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