Iridium-Catalysed C-H Borylation of 2-Pyridones; Bisfunctionalisation of CC4

Article abstract of DOI:10.1055/s-0036-1591594

The high regioselectivity associated with the iridium-catalysed borylation of pyridones has been exploited to provide a very direct and efficient entry to C(10) doubly substituted CC4 variants of cytisine. Two approaches have been evaluated based on (i) C-H activation of cytisine (or an N-substituted derivative) followed by N-alkylation (to enable dimer formation) and (ii) direct C-H activation and borylation of CC4 itself. Both approaches provide access to C(10)-functionalized CC4 derivatives, but direct borylation of CC4 allows for a wider range of functional group interconversions to be tolerated.

Full text of DOI:10.1055/s-0036-1591594

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–J
paper
A
en
A. Honraedt et al.
Paper
Synthesis
Iridium-Catalysed C–H Borylation of 2-Pyridones;
Bisfunctionalisation of CC4
Aurélien Honraedta
Worawat Niwetmarina
Cecilia Gottib
Hugo Rego Campello*a
Timothy Gallagher*a
X
10
[Ir(cod)(OMe)]2
dtbpy
R
N
10
B2pin2
THF, 24 h, reflux
N
N
R
N
O
Y
R = H
X = Br
X = Bpin
O
R = H, Me, Bn, Boc
(–)-cytisine (R = H)
a School of Chemistry, University of Bristol, BS8 1TS, Bristol, UK
hugo.regocampello@bristol.ac.uk
[Ir(cod)(OMe)]2
dtbpy
10
N
2
10
t.gallagher@bristol.ac.uk
b CNR, Institute of Neuroscience, Biometra Department, University
of Milan, 20129 Milan, Italy
B2pin2
THF, 24 h, reflux
100%
O
Y
N
N
N
N
N
O
O
CC4
Y = Bpin
Y = Br
Y = Bpin/Br
Y = various
10
Received: 06.04.2018
Accepted after revision: 18.05.2018
Published online: 29.06.2018
We had carried out broadly the same study of both sim-
ple and more complex 2-pyridones to determine basic reac-
tivity patterns, as described by Hirano and Miura.4 Our re-
sults paralleled those reported earlier, although we as-
sessed product distribution (and reaction efficiency)
following in situ bromination7 of the initial Bpin ester to
give bromopyridones 2–5 (Scheme 1, Table 1). There were,
however, differences in terms of the approach we have
used, which we note here. In our hands, for example, the
parent 2-pyridone 1a was unreactive8 towards C–H activa-
tion; we observed no conversion under our standard condi-
tions in which we used 4,4′-di-tert-butyl-2,2′-bipyridyl
(dtbpy) as the bipyridyl ligand. More generally, and based
on our experience with related substrates, the presence of
an acidic NH (as in 1a) inhibits Ir-catalysed borylation.
DOI: 10.1055/s-0036-1591594; Art ID: ss-2018-t0235-op
Abstract The high regioselectivity associated with the iridium-cata-
lysed borylation of pyridones has been exploited to provide a very di-
rect and efficient entry to C(10) doubly substituted CC4 variants of cy-
tisine. Two approaches have been evaluated based on (i) C–H activation
of cytisine (or an N-substituted derivative) followed by N-alkylation (to
enable dimer formation) and (ii) direct C–H activation and borylation of
CC4 itself. Both approaches provide access to C(10)-functionalized CC4
derivatives, but direct borylation of CC4 allows for a wider range of
functional group interconversions to be tolerated.
Key words 2-pyridone, iridium-catalyzed borylation, C–H functional-
ization, CC4, cytisine
The Ir-catalysed borylation of arenes and heteroarenes
offers a very direct entry to boronic esters that underpins a
wide range of effective synthetic transformations.1 With
arenes, the C–H activation process is generally sterically
controlled, but within heteroarenes electronic effects (e.g.,
relative acidity) of competing C–H sites influence the re-
giochemical outcome.2 Pyridines and related heterocycles
have received attention,3 and the recent publication by
Hirano and Miura4 describing Ir-catalysed borylation of
2-pyridones prompted us to report our related results in
this area.
Br
Br
1. [Ir(cod)(OMe)]2 (1 mol%)
dtbpy (2 mol%)
B2pin2 (0.7 equiv)
THF [0.7 M], 24–48 h, reflux
4
N
R
2
O
N
R
3
O
5
6
3
2. CuBr2 (3.0 equiv)
MeOH/H2O
80 °C, 24 h
Br
N
R
1a–e
O
Br
Br
O
Br
N
R
4
O
N
R
5
Scheme 1 Ir-catalysed borylation/in situ bromination7 of simple 2-pyr-
Pyridones, which offer a predictable but constrained se-
lectivity for electrophilic substitution at C(3) and C(5), have
added complexity: two potential metal binding sites associ-
ated with the substrate. In earlier work, Hirano and Miura5
exploited an N-pyridyl moiety as a directing function (to
functionalize at C(6)) but otherwise access to pyridone-
based boronic esters relies on electrophilic halogenation as
a key step.6 As a consequence, direct C–H functionalisation
offers an opportunity to extend significantly the range of
pyridone substitution patterns available.
idones
Within the simple pyridone series shown in Scheme 1,
some level of double C–H activation was also observed (via
dibrominated products 4 and 5) but consistently C(5) sub-
stitution (3 + 5) was preferred over C(4) (2 + 4). The ob-
served double insertion was a result of C–H activation/
borylation rather than an additional bromination occurring
in step 2 (Scheme 1)9 and the proportion of dibrominated
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

B
A. Honraedt et al.
Paper
Synthesis
Table 1 Regiochemistry of C–H Activation in Simple 2-Pyridones
Substrate
R
Conversion (%)
2/3/4/5a
–
Isolated yield (%)b
1a
1b
1c
1d
1e
H
0[c]
no conversion observed
Me
Bu
Bn
Boc
100
≥90
≥90
0[c]
5:35:39:21
26:53:6:15
35:65:0:0
–
2b + 3b (38); 4b (22); 5b (11)
2c + 3c (69); 5c (10)
2d + 3d (83)
no conversion observed
a Product ratios, following in situ bromination7 were based on 1H NMR spectroscopic analysis; see text and the Supporting Information.
b Monobromo isomers 2 and 3 were inseparable by chromatography and the combined yield is shown.
c See text.8,9
adducts observed appears to be linked to the size of the N-
substituent (compare products from 1b vs. 1c vs. 1d). Inter-
estingly, the N-benzyl variant 1d gave only pyridone substi-
tution, with no indication that borylation of the N-benzyl
residue was competitive (however, see below). The N-Boc
variant 1e failed to react but the issue here was that rapid
N-Boc cleavage occurred under the reaction conditions
(based on 1H NMR analysis) releasing the unreactive parent
2-pyridone 1a.
Our primary interest in this area has, however, been on
the application of this C–H activation process to the devel-
opment of novel heterocyclic ligands that are specific for
the α4β2 nicotinic acetylcholine receptor (nAChR).10 This
subtype is the high affinity nicotine receptor and, with
smoking, responsible for some 7 million deaths annually
(with an associated huge social burden in terms of health-
care expenditure and lost productivity11), is a target of in-
terest for treating tobacco addiction. The pyridone-based
cytisine (Tabex®, 6a; Figure 1),12 as well as the structurally
related varenicline (Chantix®),13 target the α4β2 nAChR,
providing the basis of a smoking cessation therapy.
We have evaluated (–)-cytisine (6a) as well as a series of
derivatives, including N-tert-butoxycarbonylcytisine (6e)
and CC4 (7), as substrates for Ir-catalysed borylation, with
the objective of gaining access to C(10). CC4 (7) is a cytis-
ine-based dimer ligand where the ability to access C(10)
was of particular interest given this ligand’s nicotinic pro-
file. In 2013, Gotti and Sparatore reported CC4 (7) as a par-
tial agonist for both the α4β2 and α6β2 nAChR subtypes
and suggested an improved profile for smoking cessation
due to the high selectivity displayed by CC4 for β2-contain-
ing nAChR subtypes.14
Our hypothesis, based on crystallographic data based on
cytisine and varenicline bound to acetylcholine binding
protein (AChBP),15 was that substitution at C(10) provides
an opportunity to interact with the variable (complementa-
ry) region of the nAChR, which is associated with subtype
differentiation.16 Previous work by Kozikowski and Kellar,
as well ourselves, had generated C(10)-substituted variants
of cytisine.17 However, these involved lengthy synthetic se-
quences that limited the range of variation that was accessi-
ble. Furthermore, this earlier work gave racemic products,
which is problematic especially when contemplating con-
struction of dimeric ligands based on CC4.
10
N
In this paper, we have evaluated two approaches to the
synthesis of C(10) modified variants of CC4 (7): (i) C–H acti-
vation of cytisine to enable access to a C(10)-modified
‘monomer’ unit (e.g., bromide 9), dimer formation (via N-
alkylation), followed by further elaboration; and (ii) direct
and double C–H activation at C(10) of CC4 (7), followed by
further functional group manipulation.
The first approach required C–H activation of (–)-cytis-
ine (6a), itself an effective substrate for Ir-catalysed boryla-
tion (Scheme 2). Complete conversion (as judged by
1H NMR analysis) did require an excess (1.5 equivalents) of
B2pin2; however, isolation and purification of the product
C(10) boronate ester 8a proved problematic. N-Methylcytis-
ine (6b) is also an efficient substrate, however, N-benzylcy-
tisine (6c) and N-carboxybenzylcytisine (6d) showed com-
peting borylation within the aryl moiety of the N-protect-
ing group; it is interesting to compare this to the reactivity
NH
NH
N
N
O
varenicline (Chantix®
)
(−)-cytisine (6a)
10
O
N
N
O
N
N
CC4 (7)
10
Figure 1 (–)-Cytisine (6a), varenicline, and CC4 (7); C(10) within the
pyridone moiety is indicated
In their 2017 paper,4 Hirano and Miura described the
borylation of N-tert-butoxycarbonylcytisine (6e; see be-
low), and, here, we wish to report our independent work in
this area and an extension to more complex cytisine-based
ligands.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

C
A. Honraedt et al.
Paper
Synthesis
of pyridone 1d. Further details of this study, including opti-
mization of key reaction parameters, are available in the
Supporting Information.
Ir-catalysed borylation of CC4 (7), so double C–H activa-
tion of each C(10) site, proceeds smoothly, which offers the
advantage of more direct access to bisbromide 10 (Scheme
4).
pinB
The transformation of CC4 7 (likely due to the presence
of two basic amine centres) required an excess of B2pin2
(2.80 equivalents) to achieve full conversion. However,
workup was particularly straightforward and simply in-
volved washing the crude (solid) product with diethyl
ether. This served to remove the excess of B2pin2 as well as
other byproducts, providing 11 with a high level of purity
and in essentially quantitative yield. Bisboronate 11 was
then readily and efficiently converted into key bisbromide
10. Both bisbromide 10 and bisboronate ester 11 are of val-
ue and have been applied to generate a representative se-
ries of CC4 derivatives 12a–i (Scheme 4, Table 2). Pd(0) cat-
alysed C–C bond formation provides the bis(cyano),
bis(methyl)18 and the Suzuki cross-coupled products 12a–c,
respectively. Transformations of bromide 10 also encom-
passed amidation (to give 12d) and amination (to give 12e
and 12f), as well as carbonylation (to give 12g) and Heck
coupling (to give 12h) reactions. We have evaluated the use
of Cu(I)-based amidation (to prepare 12d), but reaction of
bisbromide 10 with acetamide and CuI (with TMEDA) led to
the formation of an insoluble solid, which is suggestive of a
complex being formed between 10 and Cu(I).
[Ir(cod)(OMe)]2 (1 mol%)
dtbpy (2 mol%)
10
NR
NR
N
N
B2pin2 (see text)
THF [0.7 M], 18 h, reflux
O
O
(yields based on 1H NMR)
6a R = H
8a R = H 100%
8b R = Me 98%
8c R = Bn (see text)
8d R = Cbz (see text)
6b R = Me
6c R = Bn
6d R = Cbz
pinB
10
[Ir(cod)(OMe)]2 (1 mol%)
dtbpy (2 mol%)
N
NBoc
NBoc
N
B2pin2 (0.70 equiv)
O
O
THF [0.7 M], 18 h, reflux
6e
8e
100%
Scheme 2 Site-selective Ir-catalysed borylation of (–)-cytisine 6a,
N-substituted cytisine derivatives 6b–d, and N-Boc cytisine 6e
In common with Hirano and Miura, we observed very
efficient Ir-catalysed borylation of N-tert-butoxycarbonyl-
cytisine 6e (Scheme 2). In our hands, and using dtbpy as the
preferred ligand in combination with 0.7 equivalents of
B2pin2, we achieved essentially quantitative borylation of
6e to give 8e. This was completely selective for C(10) and
was readily scaled (to 5 g, 17 mmol of 6e). This result com-
pares to 77% yield (on a 0.2 mmol scale, but using a differ-
ent pyridyl ligand) reported earlier.4 Isolation of (crude) 8e
was straightforward with no requirement for any further
purification in terms of the use of this Bpin intermediate in
subsequent manipulations.
Boronate 8e was converted efficiently into 10-bromocy-
tisine (9) (with concomitant N-Boc cleavage occurring un-
der the Cu-mediated conditions used) and dimer formation
using 1,2-dibromoethane provided the CC4-based bisbro-
mide 10 in good (70%) overall yield (Scheme 3). Bisbromide
10 was a key intermediate for accessing a range of C(10)-
substituted CC4 variants (see below).
Y
[Ir(cod)(OMe)]2 (4 mol%)
dtbpy (8 mol%)
N
N
O
Y
O
N
N
CC4 7
B2pin2 (2.80 equiv)
THF [0.7 M], 20 h, reflux
11 Y = Bpin
10 Y = Br
CuBr2
100% (based on 1H NMR)
MeOH, H2O
48 h, r.t.
79% from 7
Y
10
10 or 11
N
O
N
N
N
O
See Table 2
for conditions
and yields
12a-i
10
Y
Scheme 4 Double C–H activation of CC4 7; use of bisbromide 10 and
bisboronate 11 to generate a series of C(10) substituted CC4 ligands
12a–i
pinB
Br
10
CuBr2
MeOH, H2O
NH
N
N
NBoc
24 h, 80 °C
85%
O
O
The use of bisboronate 11 to access C(10)-functionalised
CC4 derivatives was exemplified by direct oxidation of 11,
leading to the bishydroxy ligand 12i in 54% yield. Further
studies in this area are underway, but bisboroate ester 11
has been successfully used in Suzuki cross-coupling reac-
tions involving aryl halides.
8e
9
Br
Br
Br
K2CO3
O
N
N
N
N
PhMe, reflux
24 h, 82%
O
10
In summary, and with full acknowledgment to the re-
cent work of Hirano and Miura,4 we have also successfully
applied iridium-catalysed borylation to 2-pyridones, with
our focus around biologically important substrates exem-
plified by cytisine 6a and CC4 7. Pyridones are generally ex-
cellent substrates for this mode of C–H activation, although
Br
Scheme 3 Synthesis of 10-bromo CC4 (10) via C(10) functionalisation
of N-tert-butoxycarbonylcytisine (8e) followed by dimer formation
based on 10-bromocytisine (9)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

D
A. Honraedt et al.
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Synthesis
Table 2 CC4 Derivatives 12a–i via Modification of 10 or 11
Compound
10-Substituent Y
Reaction conditions
Yield (%)
12aa
12ba
12ca
12da
12ea
CN
Pd(PPh3)4, Zn(CN)2, DMF, 80 °C
88
83
91
71
71
Me
PdCl2(PPh3)2, Me4Sn, toluene, 100 °C
4-MeC6H5
NHAcc
PdCl2(PPh3)3, 4-TolB(OH)2, K2CO3, THF/H2O, 80 °C
Pd(OAc)2, Xantphos, MeCONH2, Cs2CO3, dioxane
Pd(OAc)2, BINAP, HNMe2, NaOtBu, toluene, 65 °C
c
NMe2
12fa
Pd(OAc)2, BINAP, morpholine, NaOtBu, toluene, 100 °C
82
N
O
12ga
12ha
12ib
CO2Mec
Pd(OAc)2 (40 mol%), dppp, Et3N, CO, DMF/MeOH (0.1 M in 10), 80 °C
Pd2(dba)3, P(tBu)3, Cy2NMe, ethyl acrylate, dioxane
NaOH, 30% H2O2
85
72
54
CH=CHCO2Etc
OHc
a Prepared from bisbromide 10.
b Prepared from bisboronate 11.
c Products were isolated as the HCl salts.
our experience is that NH pyridones (as in 1a) are less effec-
tive. In addition, the presence of a basic (amine) centre (as
in 6a and 7) does tend to require an excess of B2pin2 for
complete conversion. Nevertheless, and given the excep-
tionally clean conversions, product isolation is straightfor-
ward and the crude boronate esters (e.g., 11) are very effec-
tive as substrates for downstream functionalisation. Details
of receptor binding studies (including nicotinic subtype se-
lectivities) and full agonist functional characteristics of the
novel CC4 ligands described here will be reported in due
course.
determined by the University of Bristol mass spectroscopy service by
electrospray ionisation (ESI+) using a Bruker Daltonics micrOTOF II
spectrometer.
One-Pot Iridium-Catalysed Borylation of 2-Pyridones and Subse-
quent Bromination; General Procedure 1
A Schlenk tube was charged with the 2-pyridone substrate (1.0
mmol) [in the case of a liquid substrate, this was added neat after the
solvent], [Ir(cod)(OMe)]2 (6.6 mg, 0.01 equiv), 4,4′-di-tert-butyl-2,2′-
dipyridyl (5.4 mg, 0.02 equiv) and bis(pinacolato)diboron (178 mg,
0.70 equiv). After purging with nitrogen, deoxygenated and anhy-
drous THF (1.4 mL) was added and the reaction mixture was heated at
reflux for 48 h (in cases where full conversion occurred after 24 h, the
reaction was halted at that time). The volatile materials were then re-
moved under reduced pressure and the crude product was dissolved
in MeOH (2.5 mL) and a solution of CuBr2 (670 mg, 3.0 mmol) in H2O
(2.5 mL) was added. The reaction mixture was heated at 80 °C for 18 h
under air, cooled to r.t., diluted with NH4OH (5 mL, 15% aq) and ex-
tracted with CH2Cl2 (5 × 5 mL). The combined extracts were dried
(MgSO4), filtered and concentrated in vacuo. Purification of the crude
reaction mixture by flash column chromatography on silica gel af-
forded the desired product.
All reagents were purchased from commercial suppliers and used
without further purification unless otherwise stated. Anhydrous sol-
vents were obtained by distillation using standard procedures or by
using the Anhydrous Engineering Ltd. double alumina and alumina-
copper catalysed drying columns. Reactions requiring anhydrous con-
ditions were run under an atmosphere of dry nitrogen; glassware and
needles were flamed-dried prior to use or placed in the oven (150 °C)
for at least 2 h and allowed to cool either in a dessicator, under vacu-
um, or an atmosphere of nitrogen. Thin-layer chromatography was
performed using aluminium backed 60 F254 silica plates. Visualisa-
tion was achieved by UV fluorescence or a basic KMnO4 or ninhydrin
solution and heat. Flash column chromatography was performed on
silica gel (Aldrich 40–63 μm, 230–400 mesh) and reverse-phase chro-
matography was performed on an automated Biotage Isolera™ Spek-
tra Four using gradient elution on pre-packed Biotage® C18 columns.
Infrared spectra were recorded with a Perkin Elmer Spectrum One FT-
IR spectrophotometer as solids or neat films in the range of 600–4000
cm–1. NMR spectra were recorded with either a Varian 400 MHz or
500 MHz, or JEOL ECP 400 MHz spectrometer. Chemical shifts are
quoted in parts per million, coupling constants are given in Hz to the
nearest 0.5 Hz. 1H and 13C NMR spectra are referenced to the appro-
priate residual peak. DEPT 135, COSY, HSQC and HMBC were used
where necessary to assign NMR spectra. Melting points were deter-
mined with a Reichert melting point apparatus. Mass spectra were
Table 1 shows the product distributions of 2–5 but no attempt was
made to optimise monosubstitution (vs. disubstitution) in the case of
1b or 1c.
Tandem Borylation/Bromination of 1-Methylpyridin-2(1H)-one
(1b)
According to General Procedure 1, analysis of the 1H NMR spectrum of
the crude reaction mixture showed a conversion of 100%. Products 5-
bromo-1-methylpyridin-2(1H)-one (3b), 4-bromo-1-methylpyridin-
2(1H)-one (2b), 4,6-dibromo-1- methylpyridin-2(1H)-one (4b) and
3,5-dibromo-1-methylpyridin-2(1H)-one (5b) were generated in a
35:5:39:21 ratio.
Purification by flash column chromatography on silica gel (n-hexane–
EtOAc, 70:30 to EtOAc, 100%) gave an inseparable 95:5 mixture of 5-
bromo-1-methylpyridin-2(1H)-one (3b) and 4-bromo-1-methylpyri-
din-2(1H)-one (2b) (71 mg, 38%) as an orange oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

E
A. Honraedt et al.
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Synthesis
2b (minor component)
Yield: 158 mg (69%); yellow oil.
HRMS-ESI: m/z [M + H]+ calcd for C9H1379BrNO: 230.0175; found:
Rf = 0.24 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.11 (d, J = 7.5 Hz, 1 H), 6.79 (d,
J = 2.0 Hz, 1 H), 6.28 (dd, J = 2.0, 7.5 Hz, 1 H), 3.50 (s, 3 H). The spec-
troscopic properties of this compound were consistent with data
available in literature.19a
230.0175.
2c (minor component)
Rf = 0.22 (n-hexane–EtOAc, 70:30).
1H NMR (400 MHz, CDCl3): δ = 7.08 (d, J = 7.5 Hz, 1 H), 6.76 (d,
J = 2.0 Hz, 1 H), 6.28 (dd, J = 2.0, 7.5 Hz, 1 H), 3.93 (t, J = 7.5 Hz, 2 H),
1.75–1.67 (m, 2 H), 1.39–1.30 (m, 2 H), 0.93 (t, J = 7.5 Hz, 3 H).
3b (major component)
Rf = 0.24 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 2.5 Hz, 1 H), 7.33 (dd,
J = 2.5, 9.5 Hz, 1 H), 6.46 (d, J = 9.5 Hz, 1 H), 3.50 (s, 3 H). The spectro-
scopic properties of this compound were consistent with data avail-
able in literature.19a
13C NMR (100 MHz, CDCl3): δ = 161.2, 137.3, 135.0, 123.0, 110.0, 49.4,
31.1, 19.8, 13.6.
3c (major component)
Rf = 0.17 (n-hexane–EtOAc, 70:30).
4,6-Dibromo-1-methylpyridin-2(1H)-one (4b)
1H NMR (400 MHz, CDCl3): δ = 7.35 (d, J = 2.5 Hz, 1 H), 7.28 (dd,
J = 2.5, 9.5 Hz, 1 H), 6.43 (d, J = 9.5 Hz, 1 H), 3.87 (m, 2 H), 1.71–1.62
(m, 2 H), 1.38–1.27 (m, 2 H), 0.93–0.88 (m, 3 H).
Yield: 58 mg (22%); off-white solid; Rf = 0.59 (EtOAc).
IR (neat): 3111, 2922, 2851, 1650, 1566, 1495 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.75 (s, 1 H), 6.66 (s, 1 H), 3.68 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 161.5, 134.8, 128.3, 120.7, 114.4, 36.4.
13C NMR (100 MHz, CDCl3): δ = 160.9, 142.1, 137.3, 122.2, 97.6, 49.8,
31.3, 19.8, 13.6.
HRMS-ESI: m/z [M + H]+ calcd for C6H679Br2NO: 265.8811; found:
265.8799.
5-Bromo-1-benzylpyridin-2(1H)-one (3d) and 4-Bromo-1-ben-
zylpyridin-2(1H)-one (2d)
Prepared from 1-benzylpyridin-2(1H)-one (1d) using General Proce-
dure 1. Analysis of the 1H NMR spectrum of the crude product
showed a conversion of ≥90% and a 65:35 ratio of 5-bromo-1-ben-
zylpyridin-2(1H)-one (3d) and 4-bromo-1-benzylpyridin-2(1H)-one
(2d), respectively. Purification by flash column chromatography on
silica gel (n-hexane–EtOAc, 75:25) gave an inseparable 65:35 mix-
ture.
3,5-Dibromo-1-methylpyridin-2(1H)-one (5b)
Yield: 28 mg (11%); white solid; Rf = 0.51 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 2.0 Hz, 1 H), 7.43 (d,
J = 2.0 Hz, 1 H), 3.58 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.0, 143.8, 137.5, 117.4, 96.5, 39.0.
The spectroscopic properties of this compound were consistent with
the data available in literature.19b
Yield: 219 mg (83%); pale-yellow oil.
HRMS-ESI: m/z [M + H]+ calcd for C12H1179BrNO: 264.0019; found:
264.0014.
Tandem Borylation/Bromination Reaction of 1-Butylpyridin-
2(1H)-one (1c)
According to General Procedure 1, analysis of the 1H NMR spectrum of
the crude reaction mixture showed a conversion of ≥90%. Products 5-
bromo-1-butylpyridin-2(1H)-one (3c), 4-bromo-1-butylpyridin-
2(1H)-one (2c), 4,6-dibromo-1-butylpyridin-2(1H)-one (4c) and 3,5-
2d (minor component)
1H NMR (400 MHz, CDCl3): δ = 7.46–7.21 (m, 5 H), 7.10 (d, J = 7.0 Hz,
1 H), 6.83 (s, 1 H), 6.50 (d, J = 10.0 Hz, 1 H), 5.06–4.98 (m, 2 H).
dibromo-1-butylpyridin-2(1H)-one (5c) were generated in
53:26:6:15 ratio.
a
3d (major component)
1H NMR (400 MHz, CDCl3): δ = 7.46–7.21 (m, 7 H), 6.51 (d, J = 10.0 Hz,
1 H), 5.07 (s, 2 H). The spectroscopic properties of this compound
were consistent with the data available in literature.19c
Purification by flash chromatography on silica gel (n-hexane–EtOAc,
75:25) gave:
3,5-Dibromo-1-butylpyridin-2(1H)-one (5c)
Iridium-Catalysed C–H Borylation of (–)-Cytisine (6a)
Synthesis of 10-(Bpin)cytisine (8a)
Yield: 31 mg (10%); yellow oil; Rf = 0.38 (n-hexane–EtOAc, 70:30).
IR (neat): 2957, 2929, 1646, 1587, 1514, 1436, 1373, 1215, 1124, 847,
756, 711 cm–1
.
A Schlenk tube was charged with (–)-cytisine (6a) (190 mg, 1.0
mmol), [Ir(cod)(OMe)]2 (6.6 mg, 0.01 equiv), 4,4′-2,2′-di-tert-butyl-
bispyridyl (5.4 mg, 0.02 equiv) and bis(pinacolato)diboron (380 mg,
1.50 equiv) and was placed under vacuum and backfilled with nitro-
gen for three times. THF (1.4 mL) was added and the reaction mixture
was heated at reflux for 24 h. After this time, the volatile materials
were removed under reduced pressure and 8a, which was unstable to
silica chromatography, was partially characterised without further
purification and obtained as a brown foam.
1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 2.5 Hz, 1 H), 7.37 (d,
J = 2.5 Hz, 1 H), 3.93 (t, J = 7.5 Hz, 2 H), 1.75–1.67 (m, 2 H), 1.39–1.30
(m, 2 H), 0.93 (t, J = 7.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 157.5, 143.5, 136.8, 117.8, 96.4, 51.4,
31.1, 19.8, 13.6.
HRMS-ESI: m/z [M + H]+ calcd for C9H1279Br2NO: 307.9280; found:
307.9279.
1H NMR (500 MHz, CDCl3): δ = 6.88 (d, J = 1.0 Hz, 1 H), 6.27 (s, 1 H),
4.11 (d, J = 15.5 Hz, 1 H), 3.86 (dd, J = 6.5, 15.5 Hz, 1 H), 3.15–2.78 (m,
5 H), 3.21 (s, 1 H), 1.94–1.91 (m, 2 H), 1.23 (s, 12 H).
5-Bromo-1-butylpyridin-2(1H)-one (3c) and 4-Bromo-1-butylpyr-
idin-2(1H)-one (2c)
Obtained as an inseparable 68:32 mixture.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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A. Honraedt et al.
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Synthesis
13C NMR (125 MHz, CDCl3): δ = 163.1, 149.2, 124.1, 108.8, 84.4, 82.7,
53.3, 52.3, 49.6, 35.1, 27.5, 25.5, 14.5.
1H NMR (400 MHz, CDCl3): δ = 1.46 (s, 1 H), 1.94 (s, 2 H), 2.33 (m,
1 H), 2.87 (m, 1 H), 2.97–3.10 (m, 4 H), 3.83 (dd, J = 15.5, 6.5 Hz, 1 H),
4.04 (d, J = 15.5 Hz, 1 H), 6.17 (d, J = 2.0 Hz, 1 H), 6.67 (d, J = 2.0 Hz,
1 H).
Iridium-Catalysed C–H Borylation of N-tert-Butoxycarbonylcytis-
ine (6e)
13C NMR (100 MHz, CDCl3): δ = 26.2, 27.6, 35.5, 49.8, 52.9, 53.7, 108.8,
118.7, 135.0, 151.6, 162.5.
HRMS-ESI: m/z [M + H]+ calcd for C11H1479BrN2O: 269.0284; found:
N-Boc 10-(Bpin)cytisine (8e)
A Schlenk tube was charged with N-tert-butoxycarbonylcytisine (6e)
(290 mg, 1.0 mmol), [Ir(cod)(OMe)]2 (6.6 mg, 0.01 equiv), 4,4′-di-tert-
butyl-2,2′-dipyridyl (5.4 mg, 0.02 equiv) and bis(pinacolato)diboron
(178 mg, 0.70 equiv) and was placed under vacuum and backfilled
with nitrogen for three times. THF (1.4 mL) was added and the reac-
tion mixture was heated at reflux for 18 h. After this time, 1H NMR
showed essentially 100% conversion, the volatile materials were re-
moved under reduced pressure without external heating. The crude
product 8e was shown to be essentially pure by 1H NMR analysis.
Simple trituration of crude 8e in Et2O removed the excess of B2pin2 as
well as other related byproducts, providing 8e in quantitative yield in
a high level of purity as a pale-yellow foam; Rf = 0.23 (CH2Cl2–MeOH,
95:5).
269.0289.
Bromide 9 was previously reported by Durkin using a very different
approach and only as the racemate.17c
1,2-Bis(10-bromo-N-cytisinyl)ethane 10
via dimer formation using bromide 9: A solution of bromide 9 (2.28 g,
8.40 mmol) and K2CO3 (934 mg, 6.72 mmol) in toluene (4.2 mL) con-
taining 1,2-dibromoethane (0.40 mL, 4.20 mmol) was heated in a re-
sealable tube at 110 °C for 24 h. After cooling, the solution was fil-
tered through Celite® and washed with MeOH. Purification of the res-
idue by flash column chromatography [CH2Cl2–MeOH–NH4OH,
95:5:0.5] gave bisbromide 10 (1.95 g, 82%) as a pale-yellow solid.
via double C–H activation of CC4 (7): A Schlenk tube was charged with
CC4 (7) (168 mg, 0.41 mmol), [Ir(cod)(OMe)]2 (11 mg, 0.04 equiv),
4,4′-di-tert-butyl-2,2′-dipyridyl (8.8 mg, 0.08 equiv) and bis(pinacola-
to)diboron (293 mg, 2.8 equiv) and was placed under vacuum and
backfilled with nitrogen for three times. THF (2.0 mL, 0.7 M) was add-
ed and the reaction mixture was heated at reflux for 20 h. After this
time 1H NMR analysis showed essentially 100% conversion. The vola-
tile materials were removed under reduced pressure without external
heating and simple trituration (washing) of crude product using Et2O
provided 11 (270 mg, 100%) as a pale-yellow solid; mp 159–162 °C.
IR (neat): 3433, 2977, 1688, 1657, 1563, 1423 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.85 (s, 1 H), 6.31 (s, 1 H), 4.34–4.10
(m, 3 H), 3.80 (dd, J = 6.5, 15.5 Hz, 1 H), 3.07–2.91 (m, 3 H), 2.41 (s,
1 H), 1.95–1.88 (m, 2 H), 1.41–1.09 (m, 21 H).
13C NMR (100 MHz, CDCl3): δ = 162.9, 154.6/154.3 (rotamers),
147.9/147.5 (rotamers), 124.4, 109.3/108.8 (rotamers), 84.4,
82.6/80.3, 79.7/75.0 (2 C, rotamers), 51.7/50.6/50.3/49.2 (2 C, rotam-
ers), 48.9, 34.7, 28.0 (4 C), 27.5, 26.1, 24.8/24.6 (3 C, rotamers); C-Bpin
was not observed.
11B NMR (96.4 MHz, CDCl3): δ = 28.94 (br s).
IR (neat): 2936, 1652, 1562, 1333, 1142, 847, 703 cm–1
.
HRMS-ESI: m/z [M + H]+ calcd for C22H33BN2NaO5: 439.2379; found:
439.2373.
1H NMR (500 MHz, CDCl3): δ = 6.86 (s, 2 H), 6.23 (s, 2 H), 3.98 (d,
J = 15.5 Hz, 2 H), 3.84 (dd, J = 7.0, 15.5 Hz, 2 H), 2.82 (s, 4 H), 2.73 (m,
2 H), 2.35 (s, 2 H), 2.27–2.11 (m, 8 H), 1.80 (d, J = 12.5 Hz, 2 H), 1.69
(m, 2 H), 1.35 (s, 24 H).
The spectroscopic properties of this compound were consistent with
the data reported by Hirano and Miura.4
13C NMR (126 MHz, CDCl3): δ = 163.0, 150.5, 123.7, 107.9, 84.3, 60.4,
60.1, 55.2, 50.1, 35.5, 28.0, 25.4, 24.8, 24.6.
10-Bromocytisine 9
A Schlenk tube was charged with N-tert-butoxycarbonylcytisine (6e)
(2.90 g, 10 mmol), [Ir(cod)(OMe)]2 (66 mg, 1 mol%), 4,4′-di-tert-butyl-
2,2′-bispyridine (54 mg, 2 mol%), and bis(pinacolato)diboron (1.78 g,
7.0 mmol). After purging with N2, THF (14 mL) was added and the re-
action mixture was heated at reflux for 24 h. The solution was cooled
to r.t. and concentrated in vacuo without external heating to give
crude 8e, which was used directly in the next step without further
purification.
The bisboronate 11 (prepared above) was dissolved in MeOH (2.5 mL)
and the solution was cooled to 0 °C. A solution of CuBr2 (550 mg, 2.47
mmol) in water (2.5 mL) was added and the mixture was stirred at r.t.
for 48 h under air before the reaction was quenched by the addition of
NH4OH (15 mL, 15% aq. sol). The aqueous phase was extracted with
CH2Cl2 (3 × 25 mL) and the combined organic layers were dried
(MgSO4), filtered and concentrated in vacuo. Purification of the crude
product by flash column chromatography afforded bisbromide 10
(185 mg, 79%) as a pale-yellow solid; mp 173 °C (CH2Cl2–n-hexane),
Rf = 0.31 (CH2Cl2–MeOH, 95:5); [α]D24 –108 (c 1.0, MeOH).
To a solution of crude 8e in MeOH (25 mL), was added a solution of
copper(II) bromide (6.70 g, 30 mmol) in water (25 mL). The reaction
mixture was stirred at 80 °C for 24 h under air. NH4OH (50 mL, 15% aq
soln) was added, and the aqueous phase was extracted with CH2Cl2
(3 × 50 mL). The combined organic phases were concentrated in vac-
uo and the residue was partitioned between HCl (50 mL, 3 M aq soln)
and CH2Cl2 (50 mL). The aqueous phase was washed with CH2Cl2
(2 × 50 mL), basified with NH4OH (concd) until pH 10 and extracted
with CH2Cl2 (5 × 50 mL). The combined organic phases were dried
(Na2SO4), filtered, and concentrated in vacuo to give 9.
IR (neat): 2935, 2785, 1634, 1534, 811 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.68 (d, J = 13.0 Hz, 2 H), 1.80 (d, J =
13.0 Hz, 2 H), 2.09–2.26 (m, 6 H), 2.26–2.38 (s, 4 H), 2.67 (d, J =
11.5 Hz, 2 H), 2.76 (s, 2 H), 2.83 (d, J = 11.5 Hz, 2 H), 3.75 (dd, J = 15.0,
6.5 Hz, 2 H), 3.92 (d, J = 15.0, 2 H), 6.12 (d, J = 2.0, 2 H), 6.65 (d, J = 2.0,
2 H).
13C NMR (101 MHz, CDCl3): δ = 25.8, 27.9, 35.7, 50.2, 55.2, 60.2, 60.6,
108.5, 118.6, 134.7, 152.3, 162.5.
Yield: 2.28 g (85%); colourless solid; mp 153 °C (CH2Cl2–MeOH); Rf =
0.20 (CH2Cl2–MeOH, 90:10).
HRMS-ESI: m/z [M + H]+ calcd for C24H2979Br2N4O2: 563.0652; found:
563.0647.
IR (neat): 3335, 3061, 2934, 2791, 2741, 1622, 1531 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

G
A. Honraedt et al.
Paper
Synthesis
1,2-Bis(10-cyano-N-(–)-cytisinyl)ethane (12a)
13C NMR (101 MHz, CDCl3): δ = 21.3, 26.0, 28.1, 36.0, 50.0, 55.0, 60.2,
60.5, 103.7, 112.6, 126.6, 129.7, 135.1, 139.2, 150.4, 151.6, 163.8.
HRMS-ESI: m/z [M + H]+ calcd for C38H44N4O2: 587.3381; found:
587.3366.
A Schlenk tube was charged with bromide 10 (169 mg, 0.30 mmol),
Pd(PPh3)4 (27 mg, 0.08 equiv) and zinc cyanide (42 mg, 1.2 equiv),
placed under vacuum and backfilled with nitrogen for three times.
DMF (1 mL, 0.8 M) was added, and the reaction mixture was stirred at
80 °C for 24 h. The solvent was removed in vacuo. Purification of the
crude product by flash column chromatography [CH2Cl2–MeOH, 2%
MeOH] afforded 12a (119 mg, 88%) as a pale-yellow solid; mp 168–
171 °C; Rf = 0.11 [CH2Cl2–MeOH, 2% MeOH].
1,2-Bis(10-(N-acetylamino)-N-cytisinyl)ethane Hydrochloride Salt
(12d)
A Schlenk tube was charged with dibromide 10 (141 mg, 0.25 mmol),
acetamide (35 mg, 0.60 mmol), Pd(OAc)2 (1 mg, 5 μmol, 2 mol%), 4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene (6 mg, 10 μmol, 4
mol%), and Cs2CO3 (244 mg, 0.75 mmol). After purging with nitrogen,
1,4-dioxane (0.50 mL) was added and the reaction mixture was
stirred at 100 °C for 20 h. The solution was cooled to r.t. and diluted
with CH2Cl2 (10 mL), filtered through Celite®, and concentrated in
vacuo. Purification of the residue by flash column chromatography
[CH2Cl2–MeOH–NH4OH, 95:5:0.5 to 92:8:0.8] gave 12d (110 mg, 84%)
as a colourless solid. The resulting solid was dissolved in a solution of
HCl in MeOH (0.37 mL, 0.5 M), acetone was added (40 mL), and the
solution was stirred for 3 h. The precipitate was filtered off and dried
in vacuo to give the HCl salt of 12d.
IR (neat): 3350, 2236, 1647, 1562, 1534, 1473 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 6.68 (d, J = 2.0 Hz, 2 H), 6.02 (d, J =
2.0 Hz, 2 H), 3.92 (d, J = 15.0 Hz, 2 H), 2.09 (dd, J = 6.5, 15.0 Hz, 2 H),
2.88 (s, 2 H), 2.81 (d, J = 11.5 Hz, 2 H), 2.69 (d, J = 11.5, 2 H), 2.36 (s,
2 H), 2.20 (m, 8 H), 1.83 (d, J = 15.0 Hz, 2 H), 1.72 (d, J = 15.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 161.4, 154.4, 122.6, 121.1, 116.3,
103.6, 60.3, 60.0, 55.1, 50.6, 35.6, 27.6, 25.3.
HRMS-ESI: m/z [M + Na]+ calcd for C26H28N6NaO2: 479.2166; found:
479.2164.
1,2-Bis(10-Methyl-N-cytisinyl)ethane (12b)
Yield: 105 mg (71%); pale-yellow solid; mp >200 °C (MeOH–acetone);
Rf = 0.12 [CH2Cl2–MeOH, 90:10]; [α]D24 –122 (c 1.0, MeOH).
A Schlenk tube was charged with bromide 10 (175 mg, 0.31 mmol),
PdCl2(PPh3)2 (22 mg, 0.10 equiv) and it was placed under vacuum and
backfilled with nitrogen for three times. The solids were dissolved in
toluene (2 mL), tetramethyltin (0.22 mL, 5.0 equiv) was added and the
solution was heated at 100 °C for 24 h. The mixture was cooled, EtOAc
(15 mL) was added and the solution was filtered through Celite® and
concentrated. Purification of the crude product by flash column chro-
matography [CH2Cl2–MeOH, 5% MeOH] afforded 12b (111 mg, 83%) as
a colourless foam; Rf = 0.47 [CH2Cl2–MeOH, 5% MeOH].
IR (neat): 2933, 2793, 1699, 1640, 1548, 1257, 845, 728 cm–1
.
1H NMR (400 MHz, D2O): δ = 1.66 (s, 4 H), 2.00–2.20 (m, 12 H), 2.25–
2.35 (m, 4 H), 2.60 (d, J = 11.0 Hz, 2 H), 2.75–2.89 (m, 4 H), 3.75 (m,
4 H), 6.46 (m, 2 H), 6.50 (m, 2 H), 7.17 (m, 2 H).
13C NMR (101 MHz, D2O): δ = 23.6, 24.5, 27.3, 35.3, 50.3, 54.2, 59.1,
59.7, 100.0, 101.8, 148.6, 153.4, 165.3, 173.6.
HRMS-ESI: m/z [M + H]+ calcd for C28H37N6O4: 521.2871; found:
521.2859.
IR (neat): 3406, 2931, 1645, 1539, 1471, 1367, 1136, 617 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 6.23 (s, 2 H), 5.74 (s, 2 H), 3.95 (dd,
J = 15.0 Hz, 2 H), 3.78 (dd, J = 7.0, 17.0 Hz, 2 H), 2.83 (d, J = 10.0 Hz,
2 H), 2.74 (s, 2 H), 2.66 (d, J = 10.0 Hz, 2 H), 2.34 (s, 2 H), 2.25 (m, 2 H),
2.21–2.11 (m, 12 H), 1.78 (d, J = 12.0 Hz, 2 H), 1.67 (d, J = 12.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 163.5, 150.6, 149.7, 115.2, 106.8, 60.6,
60.1, 55.0, 49.7, 35.5, 28.0, 25.6, 21.2.
1,2-Bis(10-(N,N′-dimethylamino)-N-cytisinyl)ethane Hydrochlo-
ride Salt (12e)
A sealed tube with screwed cap was charged with dibromide 10 (141
mg, 0.25 mmol), Pd(OAc)2 (6 mg, 25 μmol, 10 mol%), BINAP (21 mg,
35 μmol, 14 mol%) and NaOtBu (120 mg, 1.25 mmol). After purging
with N2, toluene (1.7 mL) and dimethylamine (0.50 mL, 1 M in THF,
0.50 mmol) were added. The tube was sealed and the reaction mix-
ture was stirred at 65 °C for 20 h. The solution was cooled to r.t. and
partitioned between water (10 mL) and CH2Cl2 (10 mL), and the aque-
ous phase was extracted with CH2Cl2 (4 × 10 mL). The combined or-
ganic phases were dried (Na2SO4), filtered, and concentrated in vacuo.
Purification of the residue by flash column chromatography [CH2Cl2–
MeOH–NH4OH, 95:5:0.5 to 92:8:0.8] gave 12e (96 mg, 78%) as a pale-
yellow solid.
HRMS-ESI: m/z [M + Na]+ calcd for C26H34N4NaO2: 457.2574; found:
457.2574.
1,2-Bis(10-p-tolyl-N-cytisinyl)ethane (12c)
A Schlenk tube was charged with 10 (282 mg, 0.50 mmol), Pd-
Cl2(PPh3)2 (35 mg, 50 μmol, 10 mol%), p-tolyl boronic acid (163 mg,
1.20 mmol) and K2CO3 (347 mg, 2.50 mmol). After purging with nitro-
gen, THF (5.0 mL) and water (1.2 mL) were added and the reaction
mixture was heated at reflux for 23 h. The solution was cooled to r.t.
and partitioned between CH2Cl2 (5 mL) and water (5.0 mL), and the
aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The combined
organic phases were dried (Na2SO4), filtered, and concentrated in vac-
uo. Purification of the residue by flash column chromatography
[CH2Cl2–MeOH–NH4OH, 95:5:0.5] gave 12c.
The resulting solid was dissolved in a solution of HCl in MeOH (0.37
mL, 0.5 M), acetone was added (40 mL) and the mixture was stirred
for 3 h. The precipitate was filtered off and dried in vacuo to give the
HCl salt of 12e.
Yield: 100 mg (71%); pale-yellow solid; mp >200 °C (MeOH–acetone);
Rf = 0.18 (CH2Cl2–MeOH, 90:10); [α]D25 +5 (c 1.0, water).
Yield: 266 mg (91%); yellow solid; mp >200 °C (CH2Cl2–n-hexane);
Rf = 0.20 [CH2Cl2–MeOH, 95:5]; [α]D24 –120 (c 1.0, MeOH).
IR (neat): 2926, 2800, 1635, 1531, 1331, 1138, 801 cm–1
.
1H NMR (400 MHz, D2O): δ = 1.95 (s, 4 H), 2.71 (s, 2 H), 2.95 (s, 12 H),
3.17 (dd, J = 1.5, 12.5 Hz, 2 H), 3.24 (dd, J = 1.5, 12.1 Hz, 2 H), 3.37 (m,
6 H), 3.49 (d, J = 12.5 Hz, 2 H), 3.57 (d, J = 12.5 Hz, 2 H), 3.92 (dd, J =
15.0, 6.0 Hz, 2 H), 4.00 (d, J = 15.0 Hz, 2 H), 6.31 (s, 2 H); H5 and H5′
were not detected.
13C NMR (101 MHz, D2O): δ = 22.6, 26.2, 33.0, 39.1, 48.3, 51.7, 57.7,
58.4, 101.5, 146.7, 157.6, 161.4.
IR (neat): 2933, 2768, 1648, 1564, 809 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.70 (d, J = 13.0 Hz, 2 H), 1.83 (d, J =
13.0 Hz, 2 H), 2.13 (s, 2 H), 2.24 (m, 4 H), 2.37 (m, 10 H), 2.67 (m, 2 H),
2.83 (m, 4 H), 3.83 (dd, J = 6.5, 15.0 Hz, 2 H), 4.00 (d, J = 15.0 Hz, 2 H),
6.02 (d, J = 2.0 Hz, 2 H), 6.60 (d, J = 2.0 Hz, 2 H), 7.17 (d, J = 8.0 Hz,
4 H), 7.34 (d, J = 8.0 Hz, 4 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

H
A. Honraedt et al.
Paper
Synthesis
HRMS-ESI: m/z [M + H]+ calcd for C28H41N6O2: 493.3286; found:
Diethyl 1,2-Bis(N-(–)-cytisinyl)ethane-10-ethyl Acrylate Hydro-
493.3279.
chloride Salt (12h)
A Schlenk tube was charged with dibromide 10 (141 mg, 0.25 mmol)
and Pd2(dba)3 (11 mg, 5 mol%), placed under vacuum and backfilled
with nitrogen for three times. 1,4-Dioxane (2.2 mL) was added, fol-
lowed by tributylphosphine (0.25 mL, 0.1 M in 1,4-dioxane, 10 mol%),
dicyclohexylmethylamine (0.12 mL, 0.55 mmol), and ethyl acrylate
(0.11 mL, 1.00 mmol). The reaction mixture was stirred at r.t. for 24 h.
Further, Pd2(dba)3 (11 mg, 5 mol%), tri-tert-butylphosphine (0.25 mL,
0.1 M in 1,4-dioxane, 10 mol%) and ethyl acrylate (0.11 mL, 1.00
mmol) were added and the reaction mixture was stirred further for
24 h. The mixture was filtered through Celite® and washed with
EtOAc (20 mL), and the solvent was removed in vacuo. Purification of
the crude product by flash column chromatography [CH2Cl2–MeOH–
NH4OH, 95:5:0.5] gave a brown solid (111 mg, 85%). The resulting sol-
id was dissolved in HCl (0.37 mL, 0.5 M in MeOH). Acetone was added
(40 mL) and the mixture was stirred for 3 h. The precipitate was fil-
tered off and dried in vacuo to give 12h.
1,2-Bis(10-morpholino-N-cytisinyl)ethane (12f)
A Schlenk tube was charged with dibromide 10 (141 mg, 0.25 mmol),
morpholine (87 μL, 1.00 mmol), Pd(OAc)2 (6 mg, 25 μmol, 10 mol%),
BINAP (21 mg, 35 μmol, 14 mol%) and NaOtBu (120 mg, 1.25 mmol).
After purging with N2, toluene (1.7 mL) was added and the reaction
mixture was stirred at 100 °C for 21 h. The solution was partitioned
between water (10 mL) and CH2Cl2 (10 mL), and the aqueous phase
was extracted with CH2Cl2 (4 × 10 mL). The combined organic phases
were dried (Na2SO4), filtered, and concentrated in vacuo. Purification
of the residue by flash column chromatography [CH2Cl2–MeOH–
NH4OH, 95:5:0.5 to 92:8:0.8] gave 12f.
Yield: 119 mg (82%); pale-yellow solid; mp >200 °C (CH2Cl2–n-Hex-
ane); Rf = 0.18 (CH2Cl2–MeOH, 90:10); [α]D24 –38 (c 1.0, MeOH).
IR (neat): 2926, 2851, 1636, 1530, 1236, 1119, 803 cm–1
1H NMR (400 MHz, CDCl3): δ = 1.65 (d, J = 13.0 Hz, 2 H), 1.77 (d, J =
13.0 Hz, 2 H), 2.16–2.26 (m, 8 H), 2.30 (s, 2 H), 2.70 (m, 4 H), 2.82 (m,
2 H), 3.19 (m, 8 H), 3.67 (dd, J = 7.0, 14.5 Hz, 2 H), 3.77 (t, J = 5.0 Hz,
8 H), 3.88 (d, J = 14.5 Hz, 2 H), 5.63 (d, J = 2.5 Hz, 2 H), 5.66 (d, J =
2.5 Hz, 2 H).
13C NMR (101 MHz, CDCl3): δ = 26.2, 28.0, 36.2, 46.7, 49.2, 55.2, 60.1,
61.0, 66.5, 94.7, 95.3, 100.0, 151.1, 157.2, 164.5.
HRMS-ESI: m/z [M + H]+ calcd for C32H45N6O4: 577.34297; found:
577.3509.
.
Yield: 121 mg (72%); yellow solid; mp >200 °C; Rf = 0.22 [CH2Cl2–
MeOH, 95:5]; [α]D25 –75 (c 1.0, water).
IR (neat): 2945, 1720, 1656, 1574, 1544, 1443, 1253, 1178, 1092 cm–1
.
1H NMR (400 MHz, D2O): δ = 1.22 (t, J = 7.0 Hz, 6 H), 1.91 (s, 4 H), 2.66
(s, 2 H), 2.95 (m, 4 H), 3.07 (s, 4 H), 3.18 (d, J = 12.0 Hz, 2 H), 3.26 (s,
2 H), 3.37 (d, J = 12.0 Hz, 2 H), 3.84 (dd, J = 6.5, 16.0 Hz, 2 H), 3.98 (d,
J = 16.0 Hz, 2 H), 4.18 (q, J = 7.0 Hz, 4 H), 6.51 (s, 2 H), 6.52 (d, J =
16.0 Hz, 2 H), 6.54 (s, 2 H), 7.39 (d, J = 16.0 Hz, 2 H).
13C NMR (101 MHz, D2O): δ = 13.4, 23.0, 26.5, 33.6, 49.2, 52.4, 57.8,
58.9, 62.3, 106.5, 116.5, 124.3, 141.3, 146.3, 148.6, 164.8, 168.0.
HRMS-ESI: m/z [M + H]+ calcd for C34H43N4O6: 603.3177; found:
603.3169.
Methyl 1,2-Bis(N-(–)-cytisinyl)ethane-10-carboxylate Hydrochlo-
ride Salt (12g)
A Schlenk flask was charged with dibromide 10 (141 mg, 0.25 mmol),
trimethylamine (87 μL, 0.62 mmol), 1,3-bis(diphenylphosphino)pro-
pane (20 mg, 20 mol%) and Pd(OAc)2 (22 mg, 40 mol%). After purging
with nitrogen, DMF (0.6 mL) and MeOH (0.6 mL) were added, and the
flask was placed under a CO atmosphere (ca. 1 atm, balloon) and the
reaction mixture was heated at 80 °C for 20 h. The solution was
cooled to r.t., filtered through Celite®, and concentrated in vacuo. Pu-
rification of the residue by flash column chromatography [CH2Cl2–
MeOH–NH4OH, 95:5:0.5] gave 12g (111 mg, 85%) as a dark-yellow
solid.
1,2-Bis(10-hydroxy-N-cytisinyl)ethane Hydrochloride Salt (12i)
A Schlenk tube was charged with CC4 7 (203 mg, 0.50 mmol),
[Ir(cod)(OMe)]2 (6.6 mg, 0.02 equiv), 4,4′-di-tert-butyl-2,2′-dipyridyl
(5.4 mg, 0.04 equiv) and bis(pinacolato)diboron (177 mg, 1.4 equiv)
and was placed under vacuum and backfilled with nitrogen for three
times. THF (1.0 mL, 0.5 M) was added and the reaction mixture was
heated at reflux for 20 h. After this time 1H NMR analysis showed es-
sentially 100% conversion. The solution was allowed to reach r.t. and
then cooled to 0 °C. A solution 2 M NaOH (1.5 mL, 6 equiv) was added
followed by the addition of H2O2 (1.0 mL, 30% w/w in water), the
Schlenk tube was removed from the ice bath and the reaction mixture
was stirred for 24 h. The solvent was removed in vacuo. The crude
material was dissolved in a solution of HCl in MeOH (1 mL, 0.5 M) and
Et2O (15 mL) was added. The precipitate was filtered off and dried un-
der vacuum. Purification by reverse-phase chromatography using a
Biotage SNAP Ultra C18 12g column and gradient elution (water to
MeCN) afforded 12i.
The resulting solid was dissolved in a solution of HCl in MeOH (0.37
mL, 0.5 M in MeOH), acetone was added (40 mL) and the mixture was
stirred for 3 h. The precipitate was filtered off and dried in vacuo to
give 12g.
Yield: 111 mg (85%); yellow solid; mp >200 °C (MeOH–acetone); Rf =
0.28 (CH2Cl2–MeOH, 95:5); [α]D25 –180 (c 1.0, water).
IR (neat): 2953, 1720, 1658, 1576, 1545, 1442, 1251, 775 cm–1
.
1H NMR (400 MHz, D2O): δ = 1.98 (s, 4 H), 2.79 (s, 2 H), 3.17 (d, J =
12.5 Hz, 2 H), 3.25 (d, J = 10.5 Hz, 2 H), 3.33 (s, 4 H), 3.45 (m, 4 H),
3.55 (d, J = 12.5 Hz, 2 H), 3.83 (s, 6 H), 3.91 (dd, J = 16.0, 6.5 Hz, 2 H),
4.00 (d, J = 16.0 Hz, 2 H), 6.80 (s, 2 H), 6.97 (s, 2 H).
13C NMR (101 MHz, D2O): δ = 22.4, 26.3, 33.1, 49.0, 51.5, 53.4, 57.6,
58.4, 107.5, 118.4, 141.32, 148.1, 164.8, 166.5.
Yield: 118 mg (54%); colourless solid; mp >200 °C; [α]D20 –115 (c 6.5,
MeOH).
IR (neat): 2974, 1638, 1543, 1085, 1044, 878, 624 cm–1
.
1H NMR (500 MHz, MeOD): δ = 5.85 (d, J = 2.5 Hz, 2 H), 5.71 (d, J =
2.5 Hz, 2 H), 3.88 (d, J = 15.5 Hz, 2 H), 3.73 (dd, J = 15.5, 7.5 Hz, 2 H),
2.89 (d, J = 11.0 Hz, 2 H), 2.82 (s, 2 H), 2.72 (d, J = 11.0 Hz, 2 H), 2.38–
2.28 (m, 4 H), 2.26–2.16 (m, 6 H), 1.82 (d, J = 13.5 Hz, 2 H), 1.69 (d, J =
13.5 Hz, 2 H).
HRMS-ESI: m/z [M + H]+ calcd for C28H35N4O6: 523.2551; found:
523.2550.
13C NMR (125 MHz, D2O): δ = 167.3, 165.7, 152.9, 99.7, 95.9, 60.2,
59.8, 54.8, 49.6, 35.6, 28.0, 25.2.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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A. Honraedt et al.
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Synthesis
HRMS-ESI: m/z [M + H]+ calcd for C24H30N4NaO4: 461.2159; found:
461.2137.
K.; Sperry, J. J. Org. Chem. 2015, 80, 1006. (d) Baggett, A. W.;
Vasiliu, M.; Li, B.; Dixon, D. A.; Liu, S. Y. J. Am. Chem. Soc. 2015,
137, 5536. (e) Sadler, S. A.; Hones, A. C.; Roberts, B.; Blakemore,
D.; Marder, T. B.; Steel, P. G. J. Org. Chem. 2015, 80, 5308. (f) For
mechanistic studies using 1,10-phenanthroline as ligand in het-
ereocylic systems, see: Johannson Seechurn, C. C. C.; Sivakumar,
V.; Satoskar, D.; Colacot, T. J. Organometallics 2014, 33, 3514.
(4) Miura, W.; Hirano, K.; Miura, M. Synthesis 2017, 49, 4745; note
these authors used gel permeation chromatography to isolate
the boronate ester product derived from N-Boc cytisine.
Funding Information
Financial support from the Royal Thai Government, University of Bris-
tol and EPSRC (EP/N024117/1) is acknowledged.
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Acknowledgment
(5) Miura, W.; Hirano, K.; Miura, M. Org. Lett. 2016, 18, 3742.
(6) Borylation of 2-pyridones is commonly done by a palladium-
catalysed reaction with the corresponding halogenated 2-pyri-
done and bis(pinacolatodiboron) (B2pin2). For selected exam-
ples, see: (a) Hong, J. B.; Davidson, J. P.; Jin, Q. W.; Lee, G. R.;
Matchett, M.; O’Brien, E.; Welch, M.; Bingenheimer, B.; Sarma,
K. Org. Process Res. Dev. 2014, 18, 228. (b) Kaila, N.; Follows, B.;
Leung, L.; Thomason, J.; Huang, A.; Moretto, A.; Janz, K.; Lowe,
M.; Mansour, T. S.; Hubeau, C.; Page, K.; Morgan, P.; Fish, S.; Xu,
X.; Williams, C.; Saiah, E. J. Med. Chem. 2014, 57, 1299. (c) Lou,
Y.; Han, X. C.; Kuglstatter, A.; Kondru, R. K.; Sweeney, Z. K.; Soth,
M.; McIntosh, J.; Litman, R.; Suh, J.; Kocer, B.; Davis, D.; Park, J.;
Frauchiger, S.; Dewdney, N.; Zecic, H.; Taygerly, J. P.; Sarma, K.;
Hong, J.; Hill, R. J.; Gabriel, T.; Goldstein, D. M.; Owens, T. D.
J. Med. Chem. 2015, 58, 512. (d) Zhao, X. G.; Xin, M. H.; Huang,
W.; Ren, Y. L.; Jin, Q.; Tang, F.; Jiang, H. L.; Wang, Y. Z.; Yang, J.;
Mo, S. F.; Xiang, H. Bioorg. Med. Chem. 2015, 23, 348.
(7) For the tandem one/pot iridium-borylation/bromination condi-
tions used, see: (a) Murphy, J. M.; Liao, X.; Hartwig, J. F. J. Am.
Chem. Soc. 2007, 129, 15434. (b) For a one-pot protocol to
prepare arylboronic acids and aryl trifluoroborates, see:
Murphy, J. M.; Tzschucke, C. C.; Hartwig, J. F. Org. Lett. 2007, 9,
757. In situ bromination proved to be more reliable than isola-
tion of the intially formed boronate esters, which may link to
stability issues. 2-Boronate derivatives of pyridines are known
to be unstable towards protodeborylation; see ref. 2g and
(c) Cox, P. A.; Leach, A. G.; Campbell, A. D.; Lloyd-Jones, G. C.
J. Am. Chem. Soc. 2016, 138, 9145.
(8) Catalyst inhibition by coordination of 1a would explain the
issues we have observed for unsubstituted (i.e., NH) pyridones.
No C–H activation of substrate 1b (which is otherwise a viable
substrate) was observed when a mixture of 1a and 1b was used,
suggesting that 1a deactivates the Ir catalyst. Catalyst inhibition
via coordination of an azinyl N to a vacant coordination site on
Ir also retards reactions involving pyridines, see refs 2g and 2j.
(9) In the case of simple pyridone substrates (Table 1), no mono C–
H insertion at C(3) and/or C(6) was detected, demonstrating
that initial reaction occurs at C(4) and/or C(5) (to give 2 and 3).
This then leads to subsequent activation of (and reaction at)
C(6) or C(3), respectively, leading to the double C–H insertion
products 4 and 5. Reaction of 1b with 0.5 equiv of B2pin2 led to a
lower conversion and reaction of 1b with 1.0 equiv of B2pin2 led
to faster conversion (24 h instead of 48 h). In both cases, the
same proportions of products 2–5 were observed. Monobro-
mides 2 and 3 did not undergo further (i.e., additional) substitu-
tion when exposed to the bromination conditions shown in
Scheme 1.
We thank Achieve Life Sciences and Allychem Co. Ltd. for generous
gifts of (–)-cytisine and bis(pinacolato)diboron, respectively.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591594.
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2013, 168, 835; CC4 7 was reported to bind to the α4β2 and α7
nicotinic acetylcholine receptors with Ki values of 26 nM and
13000 nM, respectively. This compares to Ki values for cytisine
6a of 2.1 nM (at α4β2) and 228 nM (at α7). Correspondingly,
whereas CC4 is less potent at α4β2, this dimeric ligand is more
selective for this receptor than for α7 when compared to cytis-
ine (and indeed varenicline, see Figure 1).
(20) We have carried out preliminary pharmacological evaluation
(using binding methods obtained as described earlier[14]) of two
ligands 12d and 12g shown in this paper. Ligand 12d had Ki
values of 4142 nM at human α4β2; 45610 nM at human α7.
Ligand 12g had Ki values of 7360 nM at human α4β2; 45890 nM
at human α7. This indicates that these two substitution changes
(NHAc and CO2Me respectively) lead to both a significant reduc-
tion of binding affinity at each of α4β2 and α7, as well as a loss
of subtype selectivity by one to two orders of magnitude across
these two nicotinic receptors, as compared to CC4. Details of a
more extensive study to understand the structure-activity rela-
tionships involved here will be published in due course.
(15) Rucktooa, P.; Haseler, C. A.; van Elk, R.; Smit, A. B.; Gallagher, T.;
Sixma, T. K. J. Biol. Chem. 2012, 287, 23283; See also ref. 17b for
earlier docking studies. Details of our computational studies
will be reported elsewhere.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J