C-H Activation/Metalation Approaches for the Synthesis of Indolizine Derivatives

Article abstract of DOI:10.1002/ejoc.201900608

The C–H borylation of indolizines has not previously been reported. In this communication, we describe our preliminary efforts to apply this chemistry to this scaffold and contrast this approach to directed metalation. Through these methodologies, it was possible obtain a library of substituted indolizines functionalized on both the pyridinic and pyrrole rings.

Full text of DOI:10.1002/ejoc.201900608

A Journal of
Accepted Article
Title: C-H activation/metalation approaches for the synthesis of
indolizine derivatives
Authors: Giuliano Cesar Clososki, Patrick G. Steel, Camila Rodrigues
de Souza Bertallo, Thaís Rodrigues Arroio Rodrigues Arroio,
Ricardo Vessecchi, Monica F. Z. J. Toledo, and Scott Sadler
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900608
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900608
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10.1002/ejoc.201900608
European Journal of Organic Chemistry
COMMUNICATION
C-H Activation / metalation approaches for the synthesis of
indolizine derivatives
Camila R. de S. Bertallo, [a] Thais R. Arroio,[a] Mônica F. Z. J. Toledo,[a] Scott D. Saddler,[b] Ricardo
Vessecchi,[c] Patrick G. Steel,*[b] Giuliano C. Clososki*[a,c]
Abstract: The C-H borylation of indolizines has not previously been
reported and in this communication, we describe our preliminary
efforts to apply this chemistry to this scaffold and contrast this
approach to directed metalation. Through these methodologies were
possible obtain a library of substituted indolizines functionalized in
both pyridinic and pyrrole ring.
Introduction
Indolizines represent a privileged class of heterocycles that have
received considerable attention recently due to their significant
and broad range of activities (Figure 1). This include roles in many
biological active compounds such as anti-inflammatory,1
anticancer,2 antimicrobial,3 and antitubercular agents, among
others.4–12 In addition, owing to the luminescent properties of this
ring system, indolizine derivatives have found applications as
Figure 1. Some indolizines that present biological activity.
bioprobes in pH and turn-on/off fluorescent sensors,13–15 in the
detection of volatile organic compounds,16 lipid droplet
This diversity of function has encouraged the search for new and
accumulation,17 and in cell labeling.18 Moreover, substituted
efficient methods to generate novel analogues. Aromatic
indolizines have found roles in organic sensitizer components for
indolizines are commonly prepared from pyridines and pyrroles
photoresponsive materials19 and dye-sensitized solar cells.20
by several synthetic strategies including the classic
Tschitschibabin reaction, cycloaddition reactions, intramolecular
cyclizations, and cycloisomerisations.21-24 However, late stage
modification of a preformed indolizine ring can be desirable and
several strategies have been described. Given the electron rich
nature of the heterocyclic ring electrophilic substitution is
relatively facile leading to preferential substitution at C-1 and C-
3.25 Selective C-3 substitution can be achieved through palladium
catalyzed C-H activation, although this probably also proceeds via
a SEAr mechanism. Direct lithiation of the ring is also possible.
First reported by Renald and Gubin using 2-phenylindolizine as
substrate,26 this approach can be used to access a range of C-5
functionalized derivatives.27 One limitation of this approach is
functional group tolerance to the bases employed. In this regard
we have been exploring the direct metalation of indolizines as well
as other N-heterocycles28 using lithium and the mixed lithium-
magnesium bases TMPMgClLiCl and TMP2Mg2LiCl (TMP=
2,2,6,6-tetramethylpiperidinyl).29 Using indolizine-1-carboxylates
as a model substrates the selective synthesis of a variety of C-2
and C-5 difunctionalized indolizines could be achieved.28e An
alternative functional group tolerant approach to C-H activation
that is gaining significant popularity is C-H borylation mediated by
Iridium tris-boryl complexes.30 The C-H borylation of indolizines
has not previously been reported and in this communication, we
describe our preliminary efforts to apply this chemistry to this
scaffold and contrast this approach to directed metalation.
[a]
Camila R. de S. Bertallo, Thaís R. Arroio, Dr. Mônica F. Z. J. Toledo
and Prof. Dr. Giuliano C. Clososki
Núcleo de Pesquisas em Produtos Naturais e Sintéticos, Faculdade
de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São
Paulo, Av. do Café S/N, Ribeirão Preto - SP 14040-903, Brazil
Corresponding Author: Prof. Dr. Giuliano C. Clososki
E-mail:gclososki@fcfrp.usp.br.
http://fcfrp.usp.br/pg/pcf/corpo-docente/giuliano-cesar-clososki/
ORCID: 0000-0001-7605-4150
Prof. Dr. P. G. Steel and Dr. Scott D. Saddler
Department of Chemistry, Durham University
South Road, Durham DH1 3LE (UK).
E-mail: p.g.steel@durham.ac.uk
ORCID: 0000-0002-2493-5826
[b]
[c]
Prof. Dr. Ricardo Vessechi
Departamento de Química, Faculdade de Filosofia, Ciências e Letras
de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes
3900,
Ribeirão
Preto
-
SP
14040-901, Brazil
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900608
European Journal of Organic Chemistry
COMMUNICATION
Results and Discussion
As isolation of the boronate esters was challenging it proved
more practical to undertake a one pot conversion to the
corresponding biaryls (7a, 7b, 8a and 8b) which could be
achieved in moderate overall yields (Scheme 2, equations b and
c). Subsequently, we then turned to explore the diester 9.
Pleasingly, this combination of greater steric influence coupled
with a strong electron withdrawing effect proved to be successful.
After some experimentation, the best combination of selectivity
and conversion (87% by GC/MS) was achieved using MTBE as
solvent with 5 mol% of [Ir(OMe)cod]2, 10 mol% dtbpy and 1.0
equivalent of B2Pin2 at 80°C for 4h. This led to a mixture of
borylated products that proved difficult to resolve so a one pot
tandem C–H borylation Suzuki–Miyaura cross coupling process
was established. In this, following completion of the borylation
step, the reaction mixture was concentrated in vacuo and
Pd(dppf)Cl2, K3PO2 and dimethylacetamide (DMAc)/H2O (2:1)
added.35 As shown in equation d (Scheme 2), this led to the
formation of two arylated indolizine regioisomers (compounds 10
and 11) and a di-arylated product 12 with the major product being
the C-5 arylated product 10 (48% isolated yield). The formation
of the C-5,6 diarylated derivative 12 was particularly intriguing as
the possibility of formation of an intermediate with ortho Bpin
groups is normally sterically inhibited.
With the aim of comparing the two C-H activation procedures we
selected a small focused set of indolizines containing functional
groups that have previously been shown to enable directed
metalation chemistry. The nitriles (5, 6) and diester 9 could easily
be prepared through cycloaddition of pyridine derived ylid and the
acrylonitrile and dimethyl fumarate respectively.31
With substrates in hand we then considered their borylation using
as a standard reagent, the catalyst derived from [Ir(OMe)cod]2/
dtbpy (4,4’-di-t-butylbipyridine) and B2Pin2 as the source of
boron.32,33 As the Ir catalyzed borylation of the parent indolizine
has not been previously reported we initially explored this
substrate to ascertain if there was any intrinisic selectivity within
this heterocyclic scaffold. Surpringly, given the latent azole within
the indolizine structure this proved to be a rather reluctant
substrate requiring elevated temperatures (80˚C) to observe any
significant reactivity. Moreover, in line with many unsubstitued
polycyclic arenes, at this temperature, the unhindered nature of
the substrate led to a complex mixture of both mono- and bis-
borylated products. Introduction of an additional heteratom into
the five membered ring (compounds 1 and 3) enhanced the
reactivity with borylation occurring remote from the azinyl
nitrogen as would be expected .34 In both cases the initially formed
boronate ester proved difficult to purify and confirmation of
regiochemistry was obtained by in situ Suzuki-Miyaura cross
coupling reactions that afforded products 2 and 4 in 31 and 41%
yields, respectively (Scheme 1).
Scheme 1. C-H borylations of 1 and 3 followed by Suzuki-Miyaura cross
coupling reactions.
The addition of an electron withdrawing substituent is also well
known to be strongly activating towards borylation. In particular,
benzonitriles are viable substrates in which the substituent has
only a limited steric influence. In line with this precedent, 2-
cyanoindolizine 5 reacted to afford a complex mixture of mono-
borylated and di-borylated products (Scheme 2, equation a).
Within this, substitution at C-1 and C-3 in the five membered ring
was favored consistent both with the known propensity for a
nitrile to activate ortho C-H bonds to borylation and the high
reactivity of azole rings. Whilst at higher temperatures and
longer reactions time 1-cyanoindolizine 6 gave a similar output,
lowering both the reaction temperature and time led to the
formation of only two regioisomers at C-3 (compound 7a) or C-6
(compound 8a), albeit with only low conversion (45% by GC/MS).
Scheme 2. C-H borylation of 5, 6 and 9 followed by Suzuki-Miyaura cross
coupling reactions.
Having demonstrated that the borylation of indolizines was
possible we then turned to examine the substituted indolizines (5,
6 and 9) in the direct metalation process. In all cases we used the
trapping reaction with iodine as a standard marker of selectivity.
We had previously employed the directed regioselective
metalation of 1-ester-substituted indolizines using LDA and
TMPMgClLiCl under mild conditions. Application of this strategy
allowed the synthesis of a variety of C-2 and C-5 difunctionalized
indolizines after reaction of the corresponding organometallic
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10.1002/ejoc.201900608
European Journal of Organic Chemistry
COMMUNICATION
intermediates with different electrophiles.28e In a similar fashion,
we evaluated the reactivity of diester 9 using lithium and
magnesium amides. Interesting, albeit no reaction was observed
using LDA or TMPLi, the metalation occurred smoothly at room
temperature within 5h using 2 equivalents of TMPMgCl∙LiCl, as
verified by CG-MS analysis of the crude reaction mixtures
quenched with iodine. On a preparative scale, solvent extraction
and purification with flash chromatography allowed iodide 13a to
be isolated in 87% yield (Table 1, entry 1). Moreover, quenching
intermediate with dimethylformamide gave the trisubstituted
indolizine bearing an aldehyde group at C-5 position 13b with
60% yield (Table 1, entry 2). Remarkably, as already observed in
other indolizine substrates,29 a regioselectivity dependent upon
the electrophile was observed when the reaction was quenched
with diphenyldisulfide to give 14a (Table 1, entry 3). The same
regioselectivity was observed in palladium-catalyzed coupling
reactions, important tools to functionalize aromatics and
heterocyclic substrates.36 After, transmetalation of the
organomagnesium intermediate with ZnCl2, Negishi cross-
This divergence in selectivity potentially arises through a
dynamic equilibrium between the anionic species since pKa
calculations (computed at B3LYP/6-31+G(d,p) level in
Gaussian 03 software)37 indicate similar acidity of the
hydrogens at C-3 and C-5 positions (Scheme 3). We speculate
that the generation of the C-3 anion is favored by chelation of
the magnesium counter-ion by the proximal ester. Consistent
with this hypothesis, in situ trapping38 experiments with
chlorotrimethylsilane afforded the corresponding 3-silylated
derivative as the major product (see SI). Disruption of the
chelate by a coordinating electrophile (iodide) allows anion
equilibration and leads to formation of the sterically less
hindered anion and formation of the 5-substituted product. In
contrast reaction with non-coordinating reagents (ZnCl2) traps
the coordinated anion faster than exchange can occur. Whilst
a base mediated halogen dance39 provides an alternative
mechanism that leads to the formation of iodide 13a, that
cannot be excluded, the order of events with addition of the
electrophile (I2) only occurring after complete metalation leads
us to favor the former scenario.
coupling reactions
with iodobenzene or
1-bromo-4-
(trifluoromethyl)benzene in the presence of [Pd(PPh3)4] (10mol%)
produced the C-3 arylated derivatives 14b or 14c in 64 and 76%
yields, respectively (Table 1, entries 4 and 5).
Table 1. Selective metalation of 5 followed by reaction with electrophiles.
Entry
1
Electrophile
I2
Product
Yield
(%)[a]
87
Scheme 3. Dynamic equilibrium of anionic species derived from the reaction of
9 with TMPMgClLiCl
2
3
DMF
60
75
With 1-cyanoindolizine 6, complete metalation was achieved within
30 min using 1.4 equivalents of LDA at 0°C leading, on reaction
with iodine, and isobutyraldehyde to the C-5 indolizine derivatives
15a-b, respectively (Scheme 4, equations a and b). This result is
consistent with simple pKa calculations (See SI) which reveal that
the C-5 hydrogen is the more acidic (pKa 26.0). On switching to
the magnesium bases, an ortho metalation effect enabled by the
cyano group was expected leading to the formation of the C-2
substituted products. However, a dependence on the electrophile
was again observed with the isobutyraldehyde reacting at C-2 to
give 16a (Scheme 4, equation c) possibly via a chelate
mechanism, whilst the iodide, as previously noted, disrupted the
weak chelation to the nitrile group leading to rapid anion
isomerization and formation of the C-5 product 15a (Scheme 4,
equation d). The metalation of 2-cyanoindolizine 5 was best
achieved using the mixed lithium magnesium bases TMPMgClLiCl
and TMP2Mg2LiCl. As before, the ultimate product isolated
depended on the nature of the electrophile. Thus, reaction of 5 with
3 equivalents of TMPMgClLiCl for 1 hour followed by addition of
trimethylsilyl chloride gave the C-3 silylated derivative 17b in 67%
yield (Scheme 4, equation e). Functionalization at C-3 position was
also observed when the same reaction was quenched with
hexachloroethane, allowing the isolation of chloride 17b in 62%
yield (Scheme 4, equation f). A very similar result was obtained
when the diamide TMP2Mg2LiCl was used as a base (2 equiv),
(C6H5S)2
4
5
PhI
64[b]
Br(C6H4)CF3
76[b]
[a]Isolated yields, [b]Obtained via Negishi cross-coupling using 10 mol%
Pd(PPh3)4 after transmetalation with 2 equiv. of ZnCl2 at rt for 30 min.
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10.1002/ejoc.201900608
European Journal of Organic Chemistry
COMMUNICATION
leading to the same product 17b in 63% yield (Scheme 4, equation regioselectivity of the reactions being dependent upon the base and
g). In contrast, quenching the reaction with iodine afforded the C-5 electrophile used. DFT calculations illustrated how the substituents
substituted product 18a in 47% yield (Scheme 4, equation h).
affect the acidity of the aromatic hydrogens. In summary, these two
strategies enable the selective access to a set of substituted indolizines
functionalized in either pyridinic or pyrrole ring. The scope of these
methodologies and their applicability towards the synthesis of
biologically active molecules are currently being investigated in our
laboratories.
Experimental Section
The solvents were purified according to standard procedures. The
starting materials were purchased from Sigma-Aldrich Corp. All air-
sensitive and/or water-sensitive reactions were carried out with dry
solvents under anhydrous conditions and under nitrogen atmosphere.
Standard syringe techniques were applied for the transfer of dry
solvents and air-sensitive reagents. The reactions were monitored by
TLC on Merck silica gel (60 F 254) by using UV light as a visualizing
agent and 5% vanillin in 10% H2SO4 with heating as a developing agent.
Sigma– Aldrich silica gel (particle size 0.040–0.063 nm), pre-packed
silica Redisep® Rf cartridges and pre-packed C18 silica Redisep® Rf
cartridges (Teledyne Isco CombiFlash Rf machine) were used for flash
chromatography. NMR spectra were recorded with a Bruker DPX 300,
1
400, 500 and 600 (at 300, 400, 500 and 600 MHz for H and 75, 100,
125 and 151 MHz for 13C, respectively.) instrument while using CDCl3
or DMSO-d6 as solvent. The chemical shifts are reported as δ units in
parts per million (ppm) relative to the solvent residual peak as the
internal reference. Infrared (IR) spectra of all synthesized compounds
were recorded on Perkin-Elmer- mod.1420 in KBr pellets or in a
Diamond ATR (attenuated total reflection) accessory (Golden Gate).
Assigned peaks are reported in wavenumbers (cm-1). Mass spectra
(MS) were measured with Shimadzu GCMS-QP2010 mass
spectrometer. HRMS spectra were measured with a Bruker Daltonics
micrOTOF QII/ESI-TOF, LTQFT mass spectrometer or QToF mass
spectrometer. Dimethyl indolizine-1,2-dicarboxylate, indolizine-1-
carbonitrile, indolizine-2-carbonitrile and [Ir(OMe)cod]2 were prepared
as previously reported.30
General Procedure 1A: In
a glovebox, a premixed solution of
[Ir(COD)OMe]2 (1.5 mol%), dtbpy (3 mol%) and B2pin2 (0.5 equiv) (or
HBpin (1.0 equiv) where stated) in MTBE (2.5 mL) was added to a thick-
walled microwave synthesis vial containing the stated heterocycle (1.0
equiv). The mixture was shaken vigorously to ensure complete mixing,
and then the mixture was stirred at room temperature or heated at 80 ̊C
for the stated time. In-situ NMR reaction monitoring was carried out. The
reaction was stirred for 16h at room temperature before being
concentrated in vacuo. A tandem Suzuki-Miyaura cross-coupling reaction
was then carried out. To the crude borylation mixture under N2, was
added Pd(Amphos)Cl2 (40 mg, 0.056 mmol), Na2CO3(aq) (2M, 197 mg,
1.86 mmol), 3-iodo-fluorobenzene (248 mg, 1.12 mmol) in DME (3 mL)
at 80°C for 3h. The reaction mixture was diluted with water and extracted
into EtOAc. The organic phase was dried over MgSO4, filtered and
concentrated in vacuo to give the crude product.
Scheme 4. Selective metalation of cyanoindolizines 5 and 6
3-(3-fluorophenyl)pyrazolo[1,5-a]pyridine
2:
From
3-(3-
fluorophenyl)pyrazolo[1,5-a]pyridine (110 mg, 0,93 mmol) and 3-
iodofluorobenzene (248 mg, 1.12 mmol). Purification by reverse phase
chromatography using pre-packed C18 silica Redisep® Rf cartridges and
a 0-100% MeOH in H2O (containing 0.1% HCOOH) gradient elution,
constant of flow 35 mL/min. Yield: 61 mg, (31%), pale yellow oil. 1H NMR
(600 MHz, CDCl3, 25ºC) δ 8.38 (d, J = 7.7, 1H), 8.03 (s, 1H), 7.69 (d, J =
7.7, 1H), 7.35 (m, 2H), 7.24 (m, 1H), 7.16 (t, J = 7.7, 1H), 6.95 (m, 1 H),
6.77 (t, J = 7.7, 1H). 13C NMR (151 MHz, CDCl3) δ 163.4 (d, JF,C = 246.0
Hz), 140.6, 137.1, 135.5, 130.6, 129.3, 124.5, 122.7, 117.4, 113.7 (d, J =
22.0), 113.0 (d, JF,C = 21.1 Hz), 112.3, 111.9 (d, JF,C = 2.3 Hz). IR νmax
(ATR) 1634, 1613, 1584, 1546, 1531, 1453, 1366, 1260, 1217, 1178,
Conclusions
In this report, we have described for the first time the C-H borylation of
indolizines, which allowed the synthesis of arylated derivatives after in
situ Suzuki-Miyaura cross coupling reactions. Directed metalation of the
same substrates followed by reaction with electrophiles afforded the
functionalized derivatives in reasonable to good yields, with the
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10.1002/ejoc.201900608
European Journal of Organic Chemistry
COMMUNICATION
1017, 904 cm−1. HRMS (ESI) m/z ([M+H]+ calcd for C13H10N2F 213.0828,
found 213.0814.
6-phenylindolizine-1-carbonitrile 8a: From indolizine-1-carbonitrile
(71 mg, 0.5 mmol) and iodobenzene (0.07 mL, 0.65 mmol), pre-packed
silica Redisep® Rf cartridges (ethyl acetate/hexane 1/9), yield: 11 mg
(10%), brown oil. 1H NMR (600 MHz, CDCl3, 25°C) δ 8.20 (t, J = 1.3 Hz,
1H), 7.71 (d, J = 9.2 Hz, 1H), 7.58 – 7.54 (m, 2H), 7.48 (dd, J = 8.4, 7.0
Hz, 2H), 7.44 – 7.39 (m, 1H), 7.34 (dd, J = 9.3, 1.6 Hz, 1H), 7.31 (d, J
= 3.0 Hz, 1H), 7.06 (d, J = 2.9 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ
129.3, 128.3, 127.6, 127.0, 123.4, 120.4, 118.0, 117.6, 117.0, 114,5.
Accurate mass (EI): calcd for C15H10N2 218.0844, found 218.0952.
General Procedure 1B : In a glovebox, a premixed solution of
[Ir(COD)OMe]2 (1.5 mol%), dtbpy (3 mol%) and B2pin2 (1.0 equiv) (or
HBpin (1.0 equiv) where stated) in MTBE (2.5 mL) was added to a thick-
walled microwave synthesis vial containing pyrazolo[1,2-a]pyridine 3
(118 mg, 1 mmol). The mixture was shaken vigorously to ensure
complete mixing, and then the mixture was stirred at 80 ̊C for 24h. In-
situ NMR reaction monitoring was carried out. The 3-(Bpin) desire
product was obtained in 85% conversion (1H NMR). The Suzuki-
Miyaura step was carried out for 2h with Pd(Amphos)Cl2 (39 mg, 0.05
mmol), K3PO4 (425 mg, 2 mmol), 3-iodoanisole (257 mg, 1.1 mmol) in
DMAc:H2O (10:1) (2.5 mL) at 50°C. The reaction mixture was diluted
with water and extracted into EtOAc. The organic phase was dried over
MgSO4, filtered and concentrated in vacuo to give the crude product.
3-(4-(trifluoromethyl)phenyl)indolizine-1-carbonitrile 7b: From
indolizine-1-carbonitrile (71 mg, 0.5 mmol) and 1-bromo-4-
(trifluoromethyl)benzene (0.09 mL, 0.65 mmol), pre-packed silica
Redisep® Rf cartridges (ethyl acetate/hexane 2/8), yield: 42 mg (33%),
1
pale yellow solid, mp: 157-158°C. H NMR (700 MHz, CDCl3, 25°C) δ
8.29 (dt, J = 7.1, 1.1 Hz, 1H, H-5), 7.80 – 7.76 (m, 2H), 7.72 (dt, J = 9.0,
1.2 Hz, 1H, H-2’), 7.68 – 7.64 (m, 2H), 7.14 (ddd, J = 9.0, 6.6, 1.0 Hz,
1H, H-7), 7.12 (s, 1H, H-3), 6.81 (td, J = 6.9, 1.3 Hz, 1H, H-6). 13C NMR
(176 MHz, CDCl3) δ 139.0, 133.9, 130.5 (q, JF,C = 32,7 Hz, C-4’) 128.80,
126.4 (q, JF,C = 3.7 Hz, 2C, C-3’, C-5’), 125.5, 124.8 (q, JF,C 272 Hz,
CF3), 123.6, 123.2, 123.1, 118.6, 117.3, 116.5, 113.8, 83.1. Accurate
mass (EI): calcd for C16H9F3N2 286.0718, found 286.0820.
3-(3-methoxyphenyl)imidazo[1,2-a]pyridine 4: From pyrazolo[1,2-
a]pyridine 3 (118 mg, 1 mmol) and 3-iodoanisole (257 mg, 1.1 mmol).
Purification was achieved using automated Teledyne Isco CombiFlash
Rf machine with a pre-packed silica Redisep® Rf cartridges (ethyl
acetate/hexane 0-50%) at a constant flow rate of 35 mL/min. Yield: 92
mg (41%), grey amorphous solid. 1H NMR (700 MHz, CDCl3, 25 ºC) δ
8.37 (d, J = 7.6, 1H), 7.70 (s, 1H), 7.67 (d, J = 7.6, 1H), 7.43 (t, J = 7.9,
1H), 7.20 (m, 1H), 7.15 (d, J = 7.9, 1H), 7.09 (m, 1H), 6.96 (dd, J = 7.9,
1.9, 41H), 6.81 (t, J = 7.6, 1H), 3.87 (s, 3H); 13C NMR (176 MHz, CDCl3)
δ 160.2, 146.2, 132.6, 130.6, 130.2, 125.6, 124.2, 123.5, 120.2, 118.3,
113.7, 113.5, 112.5, 55.4. IR νmax (ATR) 1602, 1580, 1501, 1299,
1283, 1237, 1165, 1047 cm−1; HRMS (ESI) m/z ([M+H]+ calcd for
C14H13N2O 225.1030, found 225.1019.
6-(4-(trifluoromethyl)phenyl)indolizine-1-carbonitrile 8b: From
indolizine-1-carbonitrile (71 mg, 0.5 mmol) and 1-bromo-4-
(trifluoromethyl)benzene (0.09 mL, 0.65 mmol), pre-packed silica
Redisep® Rf cartridges (ethyl acetate/hexane 2/8), yield: 17 mg (12%),
brown oil. 1H NMR (600 MHz, CDCl3, 25°C) δ 8.11 (dd, J = 7.1, 0.9 Hz,
1H, H-5), 7.87 (dd, J = 1.8, 0.9 Hz, 1H. H-8), 7.77 – 7.72 (m, 4H), 7.30
(d, J = 3.1 Hz, 1H, H-3), 7.08 (d, J = 2.9 Hz, 1H, H-2), 7.04 (dd, J = 7.2,
1.9 Hz, 1H, H-7). 13C NMR (151 MHz, CDCl3) δ 141.7, 137.9, 133.8,
130.5 (q, JF,C = 32.6 Hz, C-4’), 127.08, 126.86, 126.1 (q, JF,C = 3.7 Hz,
C-3’, C-5’), 124.17 (q, JF,C = 272 Hz, CF3), 117.98, 116.81, 115.56,
114.19, 112.58, 83.31. Accurate mass (EI): calcd for C16H9F3N2
286.0718, found 286.0805.
General Procedure 1C: One-pot C-H borylation/Suzuki-Miyaura Cross-
coupling of substituted indolizines
A thick-walled microwave synthesis vial was charged with the
corresponding indolizine (0.5 mmol, 1.0 equiv) and degassed MTBE
(1mL) (vial A). A separate vial was charged with [Ir(COD)OMe]2 (5
mol%), dtbpy (10 mol%), B2pin2 (1.0 equiv) and it was evacuated and
placed under N2 with three evacuation/refill cycles, before degassed
MTBE was added. The vial was sealed with a crimp top septum cap
and shaken to develop a deep red colour. Once it was homogeneous,
the solution of vial A was added to vial B. The vial was heated (vide
Scheme 2) for 1h or 4h. Upon completion (determinated by GC-MS)
the volatiles were removed in vacuo to afford the crude boronate
product. Pd(dppf)Cl2 (10 mol%), K2PO3 (1 equiv.) and aryl halide
(Scheme 2; 1.3 equiv) were added, and the vial was sealed and
purged with three evacuation/refill (Ar) cycles. DMAc/H2O (2mL/1 mL)
was added, and the mixture was heated to 80°C for 12h in an oil bath.
The reaction mixture was diluted with water (10 mL) and extracted
with AcOEt (3 × 10 mL). The combined organic extracts were washed
with brine (10 mL), dried over anhydrous MgSO4, filtered through
Celite, and concentrated in vacuo to afford the crude product. The
residue was purified by pre-packed silica Redisep® Rf cartridges with
the stated solvent gradient and at a constant flow rate of 35 mL/min
using an automated Teledyne Isco CombiFlash Rf machine.
Dimethyl-5-(4-(trifluoromethyl)phenyl)indolizine-1,2-dicarboxylate
10: From dimethyl indolizine-1,2-dicarboxylate (116.5 mg, 0.5 mmol)
and 1-bromo-4-(trifluoromethyl)benzene (0.09 mL, 0.65 mmol), pre-
packed silica Redisep® Rf cartridges (ethyl acetate/hexane 1/9), yield:
90 mg (48%), pale yellow solid, mp: 147°C. 1H NMR (600 MHz, CDCl3,
25°C) δ 8.21 (ddd, J = 9.2, 1.2, 0.6 Hz, 1H, H-8), 7.83 (dt, J = 8.1, 0.8
Hz, 2H, H-3’, H-5’), 7.73 – 7.70 (m, 2H,H-2’, H-6’ ), 7.57 (d, J = 0.7 Hz,
1H, H-3), 7.17 (dd, J = 9.3, 6.8 Hz, 1H, H-7 ), 6.72 (dd, J = 6.8, 1.2 Hz,
1H, H-6), 3.93 (s, 3H), 3.87 (s, 3H). 13C NMR (151 MHz, CDCl3) 13C
NMR (151 MHz, CDCl3) δ 165.2, 164.4, 137.3, 137.1, 136.6, 132.5,
132.3, 132.0 (q, JF,C = 32.8 Hz, C-4’) 130.4, 129.4, 126.4 (q, JF,C = 3.7
Hz, C-3’, C-5’),126.6 (q, JF,C = 272 Hz, CF3), 123.33, 122.91, 121.90,
120.32, 115.17, 114.86, 114.12, 103.75, 52.34, 51.57. Accurate mass
(EI): calcd for C19H14F3NO4 377.0875, found 377. 0965.
Dimethyl-6-(4-(trifluoromethyl)phenyl)indolizine-1,2-
dicarboxylate 11: From dimethyl indolizine-1,2-dicarboxylate (116.5
mg, 0.5 mmol) and 1-bromo-4-(trifluoromethyl)benzene (0.09 mL,
0.65 mmol), pre-packed silica Redisep® Rf cartridges (ethyl
acetate/hexane 1/9), yield: 33 mg (12%), pale yellow solid, mp: 172-
173°C. 1H NMR (600 MHz, CDCl3, 25°C) δ 8.23 (dt, J = 9.5, 0.8 Hz,
1H, H-8), 8.16 (dd, J = 1.6, 1.0 Hz, 1H, H-5), 7.77 – 7.72 (m, 2H, H-
3’, H-5’), 7.72 (s, 1H, H-3), 7.67 (dt, J = 8.0, 0.8 Hz, 2H, H-2’, H-6’),
7.33 (dd, J = 9.5, 1.6 Hz, 1H, H-7), 3.93 (d, J = 1.0 Hz, 6H). 13C NMR
(151 MHz, CDCl3) δ 164.8, 164.1, 140.4, 135.2, 130.3 (q, JF,C = 32.6
Hz, C-4’), 127.1, 126.6, 126.1 (q, JF,C = 3.9 Hz, C-3’, C-5’), 126.11,
126.1, 124.0 (q, JF,C = 272 Hz, CF3), 123.5, 123.3, 123.1, 122.3, 121.0,
117.5, 103.3, 52.2, 51.4. Accurate mass (EI): calcd for C19H14F3NO4
377.0875, found 377. 0965.
3-phenylindolizine-1-carbonitrile 7a: From indolizine-1-carbonitrile
(71 mg, 0.5 mmol) and iodobenzene (0.07 mL, 0.65 mmol), pre-packed
silica Redisep® Rf cartridges (ethyl acetate/hexane 2/8), yield: 33 mg
(30%), brown oil. 1H NMR (600 MHz, CDCl3, 25°C) δ 8.28 (d, J = 7.2
Hz, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.55 – 7.50 (m, 4H), 7.46 – 7.42 (m,
1H), 7.09 (ddd, J = 9.0, 6.6, 1.0 Hz, 1H), 7.05 (s, 1H), 6.74 (td, J = 6.8,
1.3 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ 138.6, 130.4, 129.4, 128.9,
128.8, 127.1, 126.7, 123.9, 122.5, 118.4, 117.1, 116.4, 113.2, 82.4.
Accurate mass (EI): calcd for C15H10N2 218.0844, found 218.0927.
Dimethyl-5,6-bis(4-(trifluoromethyl)phenyl)indolizine-1,2-
dicarboxylate 12: From dimethyl indolizine-1,2-dicarboxylate (116.5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900608
European Journal of Organic Chemistry
COMMUNICATION
mg, 0.5 mmol) and 1-bromo-4-(trifluoromethyl)benzene (0.09 mL,
0.65 mmol), pre-packed silica Redisep® Rf cartridges (ethyl
acetate/hexane 1/9), yield: 31 mg (12%), yellow solid, mp: 203-204°C.
1H NMR (600 MHz, CDCl3, 25°C) δ 8.50 (d, J = 1.6 Hz, 1H, H-8), 7.90
– 7.85 (m, 2H), 7.83 – 7.77 (m, 4H), 7.73 (d, J = 8.3 Hz, 2H), 7.59 (d,
J = 0.6 Hz, 1H, H-3), 7.02 (d, J = 1.9 Hz, 1H, H-7), 3.95 (s, 3H), 3.89
(s, 3H). 13C NMR (151 MHz, CDCl3) 165.4, 164.8, 142.2, 137.5, 137.4,
135.2, 132.4, 132.2, 130.5, 130.3, 130.2, 129.3, 127.6, 127.0, 126.5
(q, JF,C = 3.6 Hz, 2C), 126.0 (q, JF,C = 3.7 Hz, 2C), 125.4, 124.0 (q,
JF,C = 272 Hz, CF3), 123.5 (q, JF,C = 298 Hz, CF3), 118.1, 115.7, 114.7,
105.2, 52.8, 52.1. Accurate mass (EI): calcd for C26H17F6NO4
521.1062, found 521.1141.
51.7. HRMS (ESI) m/z ([M+H]+ calcd for C18H15NO4S 342.0722, found
342.0796.
5-iodoindolizine-1-carbonitrile and 2-iodoindolizine-1-carbonitrile
15a and regioisomer: From indolizine-1-carbonitrile (71 mg, 0.5
mmol) and I2 (228.4 mg, 0,9 mmol), silica gel (ethyl acetate/hexane:
8/2.).1H NMR (400 MHz, CDCl3, 25°C) δ 8.10 (dd, J = 7.0 Hz, 1Hz,
1H), 7.66 (d, J = 8.9 Hz, 1.07 H), 7.62 (dd, J = 9.0 Hz, 1.0 Hz, 0.92 H),
7.55 (d, J = 3.0 Hz, 0.92 H), 7.29 (d, J = 7.0 Hz, 1.20 H), 7.21 (s, 0.93
H), 7.10-7.14 (m, 1.96 H), 6.91 (t, J = 6.8 Hz, 1.17 H), 6.80 (dd, J = 9.0
Hz, 7.0 Hz, 1.02 H). 13C NMR (100 MHz, CDCl3) δ 140.4, 138.3, 127.2,
125.3, 125.2, 122.7, 122.4, 119.1, 117.7, 117.6, 116.5, 115.7, 113.8,
88.1, 84.7. Note: proportional integration of H. 96:4 (product 15a).
General Procedure 2 - Preparation of TMPMgCl·LiCl in THF: In a
dry and nitrogen-flushed Schlenk flask equipped with a magnetic
stirring bar and was charged with i-PrMgCl·LiCl (1.0 M in THF, 20 mL,
20 mmol). Then, 2,2,6,6-tetramethylpiperidine (3.52 mL, 21 mmol)
was added dropwise through a syringe within 3 min. The mixture was
stirred until the gas evolution ceased (24−48h). Titration against
benzoic acid in THF (0°C) in the presence of 4-
(phenylazo)diphenylamine as the indicator showed the base
concentration ranged from 0.90 to 0.98 M.
5-iodoindolizine-1-carbonitrile 15a: From indolizine-1-carbonitrile (71
mg, 0.5 mmol) and I2 (228.4 mg, 0.9 mmol), silica gel (ethyl
acetate/hexane: 8/2.), yield: 104 mg (78%), green solid, mp: 131°C, IR
(KBr): 2976, 2917, 2211, 1490, 1293, 1179, 765, 725, 684. 1H NMR
(400 MHz, CDCl3, 25°C ) δ 7.66 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 3.0
Hz, 1H), 7.29 (d, J = 7.0 Hz, 1H), 7.11 (d, J = 3.0 Hz, 1H), 6.80 (dd, J =
8.8 Hz, 7.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 138.3, 125.3, 122.4,
119.1, 117.6, 116.5, 113.8, 88.1, 84.6. HRMS (ESI) m/z 268.9570
([M+H]+ calcd for C9H5IN2: 268.9573.
General Procedure 3: Selective Magnesiation of indolizines: In a
dry round-bottom flask sob N2 under magnetic stirring containing 2 mL
of THF and start material (0.50 mmol), amounts of TMPMgCl·LiCl
(vide Table 1 and Scheme 3) was added dropwise to the reaction
mixture. After stirring for 1h to 5h (see Table 1 and Scheme 3) a
solution of an appropriate electrophile (1.8 equiv) in THF (1.0 mL) was
added, and the reaction mixture was kept under stirring for 6h (for
iodine) to 12h (other electrophiles). The reaction was quenched with
saturated aqueous NH4Cl, the products were extracted with ethyl
acetate (3 × 15 mL), and the organic layer was dried over MgSO4. The
solvent was removed under reduction pressure. The residue was
purified by flash column chromatography (silica gel, ethyl
acetate/hexanes).
2-(1-hydroxy-2-methylpropyl)indolizine-1-carbonitrile 16a: From
indolizine-1-carbonitrile (71 mg, 0.5 mmol) and isobutyraldehyde (0.09
mL, 0.9 mmol), silica gel (ethyl acetate/hexane: 3/7), yield: 88 mg
(82%), brown oil. IR (KBr): 3429, 2962, 2873, 2211, 1513, 1461, 1368,
1311, 1162, 1011, 829, 745. 1H NMR (400 MHz, DMSO-d6, 25°C) δ
8.34 (d, J = 7.0 Hz, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.05 (ddd, J = 9.0 Hz,
7.0 Hz, 0.8 Hz, 1H), 6.87 (s, 1H), 6.76 (td, J = 7.0 Hz, 1.1 Hz, 1H), 4.59
(d, J = 8.0 Hz, 1H), 2.29 (sext, J = 6.7 Hz, 1H), 1.15 (d, J = 6.6 Hz, 3H),
6.86 (d, J = 6,6 Hz, 3H).13C NMR (101 MHz, DMSO-d6) δ 138.6, 126.8,
125.4, 122.2, 117.6, 117.1, 115.0, 112.5, 80.1, 72.5, 31.9, 19.7, 18.6.
HRMS (ESI) m/z ([M+H]+ calcd for C13H14N2O + Na+ 237.0998, found
237.100.
Dimethyl-5-iodoindolizine-1,2-dicarboxylate 13a: From dimethyl
indolizine-1,2-dicarboxylate (116.5 mg, 0.5 mmol) and I2 (342.6.4 mg,
0.9 mmol), silica gel (ethyl acetate/hexane: 2/8), yield: 156 mg (87%),
brown solid, mp: 91-93ºC. 1H NMR (400 MHz, DMSO-d6, 25°C) δ 8.04
(d, J = 9.1 Hz, 1H, H-8), 7.97 (s, 1H, H-3), 7.53 (dd, J = 7.1, 1.1 Hz,
1H, H-6), 6.98 (dd, J = 9.1, 7.0 Hz, 1H, H-7), 3.83 (s, 3H), 3.80 (s,
3H).13C NMR (101 MHz, DMSO -d6) δ 164.3, 163.4, 135.6, 125.9,
124.4, 121.0, 120.7, 118.8, 103.6, 91.5, 52.1, 51.3. HRMS (ESI) m/z
([M+H]+ calcd for C12H10INO4 359.9655, found 359.9729.
3-(trimethylsilyl)indolizine-2-carbonitrile 17a: From indolizine-1-
carbonitrile (71 mg, 0.5 mmol) and TMSCl (0.12 mL, 0.9 mmol), silica
gel (ethyl acetate/hexane: 8/2.), yield: 72 mg (67%), grey oil. IR (KBr):
3128, 3055, 2960, 2226, 1519, 1422, 1349, 1310, 1249, 1120, 772,
627. 1H NMR (400 MHz, CDCl3, 25°C) δ 8.03 (dd, J = 7.1 Hz, 1.0 Hz,
1H), 7.41 (dt, J = 9.0 Hz, 1.1 Hz, 1H), 6.83 (ddd, J = 9.0 Hz, 6.5 Hz, 1.0
Hz, 1H), 6.77 (s, 1H), 6.63 (m, 1H), 0.52 (s, 9H), 13C NMR (100 MHz,
CDCl3) δ 136.1, 128.9, 126.2, 120.0, 119.6, 118.0, 112.8, 105.8, 105.4,
-0.77 (3C). HRMS (ESI) m/z ([M+H]+ calcd for C12H14N2Si 215.0999,
found 215.1005.
Dimethyl-5-formylindolizine-1,2-dicarboxylate 13b: From dimethyl
indolizine-1,2-dicarboxylate (116.5 mg, 0.5 mmol) and DMF (0.12 mL,
1.5 mmol), silica gel (ethyl acetate/hexane: 3/7), yield: 78 mg (60%),
brown oil. 1H NMR (500 MHz, DMSO-d6, 25°C) δ 9.95 (d, J = 10.5
Hz, 1H), 8.99 (s, 1H, H-3), 8.31 (d, J = 9.0 Hz, 1H, H-8), 7.95 – 7.85
(m, 1H, H-6), 7.43 (dd, J = 9.0, 7.0 Hz, 1H, H-7), 3.84 (d, J = 4.2 Hz,
6H). 13C NMR (126 MHz, DMSO-d6) δ 187.0, 163.9, 163.1, 135.0,
131.0, 128.6, 125.7, 122.4, 122.1, 117.8, 104.5, 52.0, 51.5. HRMS
(ESI) m/z ([M+H]+ calcd for C13H11NO5 262.0637, found 262.0713.
3-chloroindolizine-2-carbonitrile 17b: From indolizine-1-carbonitrile
(71 mg, 0.5 mmol) and hexachloroethane (214 mg, 0.9 mmol), silica gel
(ethyl acetate/hexane: 8/2.), yield: 45 mg (51%), grey oil. 1H NMR (400
MHz, CDCl3, 25°C) δ 7.91 (d, J = 7.0 Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H),
6.77-6.86 (m, 2H), 6.73 (s, 1H), 13C NMR (CDCl3, 100 MHz) δ 131.7,
121.6, 119.8, 119.3, 114.4, 113.7, 112.5, 102.0, 96.6. HRMS (ESI) m/z
([M+H]+ calcd for C9H5ClN2 177.0141, found 177.0160.
General Procedure 4: Selective magnesiation of indolizines
followed by Negishi Cross Coupling Reaction: After magnesiation
step (according to GP3), the temperature was warmed at 0ºC, and
ZnCl2 (1.0 M in THF, 2.0 equiv) was added dropwise to the reaction
mixture. The temperature was kept for 30 min. Then, a THF solution of
[Pd(PPh3)4] (10 mol%) and 1 mL of a THF solution of appropriate
electrophile (1.8 equiv) were added, and the reaction mixture was kept
under stirring for 12h at 60°C. The reaction was quenched with
saturated aqueous NH4Cl; the products were extracted with ethyl
acetate (3 × 15 mL), and the organic layer was dried over MgSO4. The
solvent was removed under reduction pressure. The residue was
Dimethyl-3-(phenylthio)indolizine-1,2-dicarboxylate 14a: From
dimethyl indolizine-1,2-dicarboxylate (116.5 mg, 0.5 mmol) and
diphenylsulfane (131.0 mg, 0.6 mmol), silica gel (ethyl acetate/hexane:
3/7), yield: 128 mg (75%), orange oil. 1H NMR (400 MHz, DMSO-d6,
25°C) δ 8.44 (dd, J = 7.0, 1.2 Hz, 1H, H-8), 8.16 (dt, J = 9.0, 1.3 Hz,
1H, H-5), 7.43 (ddd, J = 9.1, 6.9, 1.1 Hz, 1H, H-6), 7.31 – 7.24 (m, 2H),
7.24 – 7.17 (m, 1H, H-7), 7.14 – 7.06 (m, 3H), 3.86 (s, 3H), 3.82 (s, 3H).
13C NMR (101 MHz, DMSO-d6) δ 165.6, 163.0, 136.8, 133.7, 131.6,
129.9, 127.3, 127.3, 126.7, 125.1, 119.6, 115.4, 110.1, 101.6, 53.0,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900608
European Journal of Organic Chemistry
COMMUNICATION
purified by flash column chromatography (silica gel, ethyl
acetate/hexanes). Results are presented in Table 1.
THF (1.0 mL) was added, and the reaction mixture was kept under
stirring for 2h (for iodine) and 12h (other electrophiles). The reaction
was quenched with saturated aqueous NH4Cl, the products were
extracted with ethyl acetate (3 × 15mL), and the organic layers were
dried over MgSO4. The solvent was removed under reduced
pressure. The residue was purified by flash column chromatography
(silica gel, ethyl acetate/hexanes). Results are presented in Scheme
3.
Dimethyl 3-phenylindolizine-1,2-dicarboxylate 14b: From dimethyl
indolizine-1,2-dicarboxylate (116.5 mg, 0.5 mmol) and iodobenzene
(0.10 mL, 0.9 mmol) silica gel (ethyl acetate/hexane 2/8), yield 99 mg
(64%), green oil.1H NMR (400 MHz, CDCl3, 25°C) δ 8.23 (dt, J = 9.1, 1.3
Hz, 1H), 8.05 (dt, J = 7.1, 1.1 Hz, 1H), 7.51 (dd, J = 4.2, 0.8 Hz, 4H), 7.49
– 7.45 (m, 1H), 7.13 (ddd, J = 9.2, 6.6, 1.1 Hz, 1H), 6.72 (td, J = 6.9, 1.4
Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 167.0,
164.4, 135.4, 130.1, 129.2, 129.0, 125.2, 123.7, 122.2, 120.5, 113.6,
102.1, 52.6, 51.4. HRMS (ESI) m/z ([M+H]+ calcd for C18H15NO4
310.1001, found 310. 1069.
5-iodoindolizine-2-carbonitrile 18a: From dimethyl indolizine-2-
carbonitrile (71 mg, 0,5 mmol) and I2 (228.4 mg, 0,9 mmol), silica gel
(ethyl acetate/hexane: 8/2.), yield: 104 mg (78%), pale yellow solid,
mp: 140-142°C. IR (KBr): 3133, 3119, 2962, 2229, 1493, 1288, 1207,
1125, 788, 721. 1H NMR (400 MHz, CDCl3, 25°C) δ 7.95 (m, 1H),
7.42 (d, J = 9.0 Hz, 1H), 7.19 (dd, J = 6.9 Hz, 1.0 Hz, 1H), 6.93 (d, J
= 1.6 Hz, 1H), 6.56 (dd, J = 9.0 Hz, 6.9 Hz, 1H). 13C NMR (400 MHz,
CDCl3) δ 133.2, 125.5, 122.9, 119.9, 119.6, 115.9, 105.0, 97.2, 85.8.
HRMS (ESI) m/z ([M+H]+ calcd for C9H5IN2 268.9570, found
268.9574.
Dimethyl 3-(4-(trifluoromethyl)phenyl)indolizine-1,2-dicarboxylate
14c: From dimethyl indolizine-1,2-dicarboxylate (116.5 mg, 0.5 mmol)
and 1-bromo-4-(trifluoromethyl)benzene (0.12 mL, 0.9 mmol), silica gel
(ethyl acetate/hexane 2/8), yields 143 mg (76%).1H NMR (400 MHz,
CDCl3, 25°C) δ 8.26 (dt, J = 9.1, 1.2 Hz, 1H, H-8), 8.03 (dt, J = 7.2, 1.1
Hz, 1H, H-5), 7.81 – 7.74 (m, 2H), 7.70 – 7.63 (m, 2H), 7.21 – 7.13 (m,
1H, H-7), 6.78 (td, J = 6.9, 1.3 Hz, 1H, H-6), 3.91 (s, 3H), 3.82 (s, 3H).13
C
NMR (101 MHz, CDCl3) δ 166.64, 164.19, 135.72, 130.42, 126.3 (q, JF,C
= 3.1, 2.7 Hz, 2C, C-3‘, C5‘), 124.1 (q, JF,C = 272 Hz, CF3), 120.8, 114.1,
102.7, 52.8, 51.6. HRMS (ESI) m/z ([M+H]+ calcd for C19H14F3NO4
378.0875, found 378.0941.
Acknowledgments
Authors are grateful to FAPESP (Process 2015/03007-1,
2014/2360-1, 2011/20742-6 and 2018/14150-8), FAPESP-
Durham University (Sprint project 2017/50381•1), CNPq
(442384/2014-9) and Capes for financial support. SDS thank
Astra Zeneca and the EPSRC for support a studentship. PGS
General Procedure 5: Selective Lithiation of indolizines using
LDA: In a dry round-bottom flask under magnetic stirring, LDA was
prepared by addition of n-butyllithium (2.35 M in hexanes, 0.70 mmol,
0.30 mL, 1.4 equiv) to a solution of diisopropylamine (0.77 mmol,
0.10mL, 1.54 equiv) in THF (1 mL) at −70°C. After 15 min, the reaction
mixture was warmed to 0°C and stirred for 20 min at the same
temperature. After, indolizine-carbonitrile (71 mg, 0.5 mmol) in THF (2
mL) was added dropwise to the reaction mixture. After stirring for 30
min at 0°C, a solution of an appropriate electrophile (1.8 equiv) in THF
(1.0 mL) was added, and the reaction mixture was kept under stirring
for 2h (for iodine) and 12h (other electrophiles). The reaction was
quenched with saturated aqueous NH4Cl, the products were extracted
with ethyl acetate (3 × 15mL), and the organic layers were dried over
MgSO4. The solvent was removed under reduced pressure. The
residue was purified by flash column chromatography (silica gel,
hexanes/ethyl acetate). Results are presented in Scheme 3.
acknowledges receipt of
Collaboration Award IC160044.
a Royal Society International
Keywords: C-H borylation • C-H metalation • Indolizines •
Suzuki-Miyaura cross coupling • Negishi cross coupling
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5-(1-hydroxy-2-methylpropyl)indolizine-1-carbonitrile 15b : From
indolizine-1-carbonitrile (71 mg, 0,5 mmol) and isobutyraldehyde (0.09
mL, 0.9 mmol), silica gel (ethyl acetate/hexane: 3/7), yield: 79 mg
(74%), brown oil. IR (KBr): 3426, 3104, 2962, 2928, 2867, 2203, 1520,
1464, 1389, 1259, 1159, 1010, 787, 695.1H NMR (400 MHz, CDCl3,
25°C) δ 7.44-7.46 (m, 2H), 7.05 (dd, J = 8.9 Hz, J = 6.8 Hz, 1H), 6.96
(d, J = 3.0 Hz, 1H), 6.81 (d, J = 6.7 Hz, 1H), 4.70 (d, J = 6.4 Hz, 1H),
2.29 (sext, J = 6.6 Hz, 1H), 1.03 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz,
3H).13C NMR (100 MHz, CDCl3) δ 139.5, 138.9, 122.1, 117.2, 116.4,
116.3, 112.4, 111.1, 81.1, 77.3, 77.0, 76.6, 75.9, 30.1, 19.7, 17.3.
HRMS (ESI) m/z ([M+H]+ calcd for C13H14N2O + Na+ 237.0998 found
237.1003.
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General Procedure 6: Selective Magnesiation of indolizines
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Functionalized indolizines
Camila R. de S. Bertallo, Thais R. Arroio,
Mônica F. Z. J. Toledo, Scott D. Saddler,
Ricardo Vessechi, Patrick G. Steel,*
Giuliano C. Clososki*[a]
Page No. – Page No.
Indolizines represent a privileged class of heterocycles with several applications in
Organic Synthesis and Medicinal Chemistry. In this work, the C-H borylation of aryl
indolizines is described for the first time and contrasted to directed metalation.
These complementary approaches allowed us to obtain a variety of substituted
indolizines functionalized in both pyridinic and pyrrole ring.
C-H Activation / metalation
approaches for the synthesis of
indolizine derivatives
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