Scalable synthesis of functionalised 2-pyridones via [4+2] cycloaddition reactions of 2-pyrazinones and alkynylboronates

Article abstract of DOI:10.1016/j.tet.2012.12.010

The multigram synthesis of N-protected 2-pyridone boronic acid derivatives via a [4+2] cycloaddition of alkynylboronates with 2-pyrazinones is presented. The reactions are highly chemoselective, and generally highly regioselective although trimethylsilyl-substituted alkynylboronates have proven to be an exception. Nonetheless, in this latter case, separation of regioisomers was successfully accomplished via high performance counter-current chromatography allowing isolation of analytically pure 2-pyridones. Further derivatisations of trimethylsilyl-substituted 2-pyridone boronates were performed providing access to a selection of functionalised scaffolds.

Full text of DOI:10.1016/j.tet.2012.12.010

Accepted Manuscript
Scalable synthesis of functionalised 2-pyridones via [4 + 2] cycloaddition reactions of
2-pyrazinones and alkynylboronates
Wesley R.R. Harker, Patrick M. Delaney, Michael Simms, Matthew J. Tozer, Joseph
P.A. Harrity
PII:
S0040-4020(12)01829-7
10.1016/j.tet.2012.12.010
TET 23822
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 September 2012
Revised Date: 9 November 2012
Accepted Date: 4 December 2012
Please cite this article as: Harker WRR, Delaney PM, Simms M, Tozer MJ, Harrity JPA, Scalable
synthesis of functionalised 2-pyridones via [4 + 2] cycloaddition reactions of 2-pyrazinones and
alkynylboronates, Tetrahedron (2013), doi: 10.1016/j.tet.2012.12.010.
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Scalable synthesis of functionalised 2-
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Wesley R. R. Harker, Patrick M. Delaney, Michael Simms, Matthew J. Tozer and Joseph P. A. Harrity

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Tetrahedron
journal homepage: www.elsevier.com
Scalable synthesis of functionalised 2-pyridones via [4 + 2] cycloaddition reactions of
2-pyrazinones and alkynylboronates
Wesley R. R. Harkera , Patrick M. Delaneyb, Michael Simmsb, Matthew J. Tozerb and Joseph P. A. Harritya,
aDepartment of Chemistry, University of Sheffield, BrooK Hill, Sheffield, S3 7HF, UK
bPeakdale Molecular, Peakdale Science Park, Sheffield Road, Chapel-en-le-Frith, High Peak, SK23 0PG, UK
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The multigram synthesis of N-protected 2-pyridone boronic acid derivatives via a [4 + 2]
cycloaddition of alkynylboronates with 2-pyrazinones is presented. The reactions are highly
chemoselective, and generally highly regioselective although trimethylsilyl-substituted
alkynylboronates have proven to be an exception. Nonetheless, in this latter case, separation of
regioisomers was successfully accomplished via high performance counter-current
chromatography allowing isolation of analytically pure 2-pyridones. Further derivatisations of
trimethylsilyl-substituted 2-pyridone boronates were performed providing access to a selection
of functionalised scaffolds.
Available online
Keywords:
2-Pyridone
Boronic Acid
Cycloaddition
2009 Elsevier Ltd. All rights reserved.
Regioselective
Counter-Current Chromatography
———
Corresponding author. Tel.: +44-114-222-9496; e-mail: j.harrity@sheffield.ac.uk

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2
Tetrahedron
1. Introduction
large scale synthesis of the requisite trimethylsilyl
alkynylboronate. As outlined in Scheme 2, a typical lab-scale
preparation furnished the silylalkyne in acceptable yield.
However, conducting the reaction at very low temperatures on
large scale poses significant challenges and so we decided to
optimise the process further in order to conduct the boronation
step at higher temperature. Pleasingly we found that the reaction
could be reliably performed at -30 °C, and that this procedure
could be successfully transferred into a 10 L reaction vessel,
allowing around 300 g of the alkyne to be generated in 65% yield
after recrystallisation.
2-Pyridones are found in a plethora of compounds exhibiting
interesting activities against a number of biological targets, and
are commonly employed as scaffolds in drug discovery.1 Recent
advances include reports by Pfizer that 2-pyridone containing
peptidomimetics form a class of orally bioavailable irreversible
human rhinovirus (HRV) 3C protease (3CP) inhibitors.2
Moreover, Vertex has demonstrated that 5-aryl-pyrid-2-ones
represent a family of potent Itk inhibitors.3
50 mmol scale
(i) nBuLi, Et2O, -78 °C;
TMS
TMS
BPin
(ii) PinBOiPr, -78 °C;
(iii) HCl, Et2O (1 M)
1a; 59%
Mass = 6.4 g
200 mmol scale
(i) nBuLi, Et2O, -30 °C;
TMS
TMS
BPin
(ii) PinBOiPr, -30 °C;
(iii) HCl, Et2O (1 M)
Figure 1. Representative bioactive 2-pyridones.
1a; 51%
Mass = 23 g
The importance of 2-pyridones to the drug discovery effort
therefore suggests that the development of efficient and scalable
routes to functionalised 2-pyridone cores bearing modular
functionality would promote the investigation of new chemical
space surrounding these valuable pharmacophores.
2 mol scale
(i) nBuLi, Et2O, -30 °C;
TMS
TMS
BPin
(ii) PinBOiPr, -30 °C;
(iii) HCl, Et2O (1 M)
1a; 65%
Mass = 299 g
Scheme 2. Optimisation studies towards a large scale synthesis of alkyne
Recent studies within our laboratories have focused on the
rapid assembly of aromatic and heteroaromatic boronic acid
derivatives via the development of cycloaddition techniques.4,5
Preliminary investigations associated with accessing pyridine and
2-pyridone derivatives have been successful, and are realised by
performing cycloadditions of alkynylboronates with 1,4-oxazin-
2-ones and 2-pyrazinones.6 This approach provides an effective
means of rapidly constructing pyridine-based heterocycles whilst
incorporating both boronate and halide functionality. Herein we
report a wider study of the 2-pyrazinone cycloaddition chemistry,
some representative orthogonal functionalisation reactions for the
generation of novel small molecule scaffolds and the
development of multigram synthesis platforms exploiting high
performance counter-current chromatography (HPCCC) for the
convenient separation of regioisomers.
1a.
With respect to the large scale synthesis of 2-pyrazinone
precursors, we were drawn to the recent procedure by Li and co-
workers that demonstrated an improved synthesis of these
heterocycles from the corresponding amino acetonitriles. This
modified procedure offered lower reaction temperatures and a
solvent exchange of non-volatile o-dichlorobenzene for the easily
removable toluene.8 Indeed, their protocol worked well in our
hands and we were able to generate multigram quantities of the
N-benzyl and N-glycinyl pyrazinones in good yield over two
steps (Scheme 3).
Scheme 3. Synthesis of pyrazin-2(1H)-ones 4 and 5.
With the appropriate precursors in hand, we turned our
attention to the [4 + 2] cycloaddition process. In our preliminary
work, we had conducted these reactions on small scale (<1
mmol), and so our first task was to establish the efficiency of this
process on gram-scale. Directly employing the conditions
o
Scheme 1. [4 + 2] Cycloaddition strategies to pyridine boronic ester
derivatives.
developed in our preliminary work (1,2-Cl2C6H4, 180 C, 18 h)
provided a mixture of compounds including the desired boronate,
starting pyrazinone and the product of protodeborylation. In
addition, removing o-dichlorobenzene on this scale proved to be
time consuming and unwieldy. With a view to improving the
overall process, and obviating the solvent removal in preparation
for larger scale runs, we decided to conduct the cycloadditions in
the absence of solvent, and to carefully monitor the reaction via
LC-MS and/or 1H NMR spectroscopy. In the event, we were
intrigued to note that the reaction reached high levels of
2. Results and discussion
As a means of establishing the potential of the 2-pyrazinone [4
+ 2] cycloaddition chemistry for the preparation of workable
quantities of 2-pyridone intermediates, we decided to undertake
the multigram synthesis of
a
trimethylsilyl-substituted
heterocycle product. We recognised that such compounds offered
the potential for further elaboration via electrophilic substitution
of the silyl group.7 Towards this end, we first carried out the

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conversion after only 2 hours on gram scale. Moreover, we found
it to be important to stop the reaction at the onset of
Table 1. Investigating the pyrazinone/alkynylboronate cycloaddition regiochemistry.9
Entry
R1
R2
Time (h)
Product
Composition (SM:ab:cd)
Regioselectivity (a:b) Yield (%)a
1
2
3
4
5
6
Bn; 4
H; 1b
nBu; 1c
Ph; 1d
H; 1b
nBu; 1c
Ph; 1d
2
8
3:97:0
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
8a; 61
Bn; 4
8
9
8:84:8
9a; 57
Bn; 4
20
2
10
11
12
13
9:85:6
10a; 68
11a; 60
12a; 51
13a; 56
CH2CO2Et; 5
CH2CO2Et; 5
CH2CO2Et; 5
0:90:10
36:54:10
9:74:17
8
20
aIsolated yield after column chromatography.
protodeborylation as continuation beyond this point results in
rapid and extensive product protodeborylation. Performing the
reaction under these conditions provided the expected product, to
our surprise however, this compound was generated as a 2:1
mixture of regioisomers.
chromatography techniques for the separation of compound
mixtures up to multigram scales.12 HPCCC is conducted in an
immiscible biphasic solvent medium and relies on the differing
partition coefficients of individual components within a mixture
as a mechanism for separation. The use of a liquid stationary
phase has numerous advantages over traditional chromatographic
methods such as increased sample loading capacity and improved
separation efficiency. Moreover, non-specific adsorption on solid
phase supports such as silica gel is completely avoided thereby
offering the potential for 100% sample recovery.13 With regard to
2-pyridones 6 and 7, effective separation by HPCCC first
required the determination of the component distribution
constants (D) in a suitable biphasic solvent mixture. Indeed, the
identification of an appropriate solvent combination for this
purpose is an acknowledged challenge in HPCCC, but we opted
to begin these investigations by employing the manufacturer
recommended HEMWat (heptane-ethyl acetate-methanol-water)
solvent mixtures which are based on the findings of Ito and co-
workers during their studies into establishing generally effective
mobile-stationary phase combinations.14
Scheme 4. Gram scale cycloaddition of alkyne 1a.
The discovery that the cycloaddition of 4 and 5 was poorly
regioselective contradicted our preliminary studies,6 and so we
decided to carry out
a thorough investigation of the
pyrazinone/alkynylboronate cycloaddition regiochemistry; our
results are summarised in Table 1.
We employed terminal alkyne 1b, as well as an example of an
alkyl- (1c) and aryl-substituted alkyne (1d) in this study.
Importantly, these results confirmed that both N-benzyl and N-
glycinyl pyrazinones underwent very highly selective reactions to
provide the corresponding 2-pyridones in acceptable yield.
Furthermore, we noted that the reaction profiles of these
cycloadditions are also considerably improved under neat
conditions and reaction times are significantly reduced. However,
in order to produce significant levels of boronic ester products
(ab > cd), the reactions must be stopped at the onset of product
protodeborylation.
In practice, dissolution of samples of crude reaction material
into
a range of HEMWat solvent mixtures allowed a
straightforward calculation of the distribution coefficient D by
quantifying the relative compound concentration in the stationary
phase (CS) divided by that in the mobile phase (CM).15 The
concentrations were estimated by HPLC analysis of hydrophilic
and hydrophobic layers.16 The HEMWat combinations are
generally chosen to provide D~1, as this provides the best
balance of sample resolution, whilst minimising sample band
broadening and lengthy retention times. However, the difference
in distribution coefficients is also critical to achieving good
separation and so we opted for solvent mixtures that displayed
∆D>0.3. From this analytical study, HEMWat 9 (20:5:20:5)
demonstrated optimal distribution constants for 6a and 6b of 1.42
and 0.57, respectively. In the case of 7a and 7b, HEMWat 7
(15:10:15:10) provided D of 0.57 and 0.23. We next set about
performing batch purification of theses samples on ~20 g scale of
crude material on the HPCCC platform. To our delight, this
technique delivered isomerically and analytically pure samples of
both 6a/6b and 7a/7b in good overall yield (Scheme 5).
Overall therefore, this study highlights that alkynylboronates
undergo highly regioselective [4 + 2] cycloaddition reactions
with 2-pyrazinones. Silyl-substituted alkynes appear to be an
exception and undergo cycloaddition with excellent
chemoselectivity (providing 2-pyridone rather than potentially
competing pyridine formation10) but with poor regiocontrol. The
discrepancy between the results observed in this study versus our
preliminary work is not clear but may result from selective
decomposition of the minor regioisomer during cycloaddition in
o-dichlorobenzene.11
Although the cycloaddition of the trimethylsilyl
alkynylboronate with both N-benzyl and N-glycinyl pyrazinones
exhibits modest regioselectivity, both regioisomers were of
significant interest as small molecule intermediates.
Unfortunately however, purification of these regioisomers and
even separation from any residual pyrazinone or
protodeborylated product was difficult via conventional
chromatographic techniques due to co-elution. High performance
counter-current chromatography (HPCCC) has emerged in recent
years as an effective alternative to solid support-based
Scheme 5. Multi-gram cycloadditions and HPCCC purification with alkyne
1a.

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4
Tetrahedron
With multigram quantities of both the 5- and 4-boronic-2-
proceeded in lower yields, as we observed competing reduction
of the pyridone ring. With regard to the 4-boronic-2-pyridone
isomer 6b, this was found to efficiently undergo
bromodesilylation (17), desilylation (18), boronate oxidation
(19)17 and protodeborylation (20) all in good yields. The addition
of electrophiles to selectively form isomers 16, 17, and 18 all
highlight the propensity for substitution of the 2-pyrone at C-5.
pyridones 6a/7a and 6b/7b in pure form, we wanted to establish
the orthogonality of the silyl and boronate groups in some
representative functional group interconversion reactions; our
results are depicted in Scheme 6. We found that the 5-boronic-2-
pyridone fragment 6a can be efficiently desilylated (8), converted
to the trifluoroborate (14) and bromodeboronated (16) all in good
yield. However, hydrogenolysis (15) of the N-benzyl group
Scheme 6. Expanding the synthetic potential of 5- & 4-boronic-2-pyridone isomers.
General Procedure 1 –
3. Conclusions
Synthesis of Amino-Acetonitrile Hydrochlorides 2 and 3
To a solution of chloroacetonitrile (1.1 eq.) in acetonitrile was
added the primary amine (1 eq.), potassium carbonate (3 eq.) and
sodium iodide (1 mol%). The reaction mixture was stirred at 80
°C for 18 hours after which the precipitate was filtered and
mother liquor concentrated in vacuo to yield a dark oil. The
amino acetonitrile was dissolved in diethylether and treated with
ethereal 1N HCl (excess) to yield the hydrochloride salt which
was filtered and dried under vacuum to yield the desired product.
The synthesis of 2-pyridone boronic acid derivatives on
multigram scales has been achieved. Optimisation of the
cycloaddition demonstrated that close monitoring of the reaction
was imperative to limit product protodeborylation. The reactions
were most effectively performed in the absence of solvent,
thereby avoiding issues relating to removal of non-volatile o-
dichlorobenzene during purification. We also demonstrated the
potential of high performance counter-current chromatography
for the efficient and multigram purification of regioisomers.
Further derivatisations of the purified regioisomer scaffolds were
performed, showing excellent scope as synthetic building blocks
and portraying the ability to explore new chemical space within a
variety of industrially relevant 2-pyridone bioactive compounds.
General Procedure 2 –
Synthesis of N-Alkylated 2-Pyrazinones 4 and 5
To a suspension of amino acetonitrile hydrochloride in toluene at
0 °C was added oxalyl chloride (5 eq.) and the reaction mixture
was heated to 55 °C for 18 hours. The resulting solution was
concentrated in vacuo, the residue was dissolved in
dichloromethane, treated with saturated KH2PO4 and stirred for
30 minutes. The organics were then extracted with
dichloromethane dried over MgSO4, filtered and concentrated in
vacuo to yield the desired 2-pyrazinones which were further
purified by flash column chromatography on silica gel using
ethyl acetate/petroleum ether 40-60° (20:80).
4. Experimental section
4.1. General Experimental Information
General information and procedures have been reported
elsewhere.18 All solvents and reagents were purified according to
published methods.19 Experimental data for pyridines 9 and 10
has been reported previously.6 Alkynylboronates were prepared
according to the procedure of Brown and co-workers.20
4.2. General Experimental Procedures
General Procedure 3 –

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5
Synthesis of 2-Pyridones 6 and 7
To the appropriate pyrazinone (1 eq.) was added
trimethyl((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
MHz, CDCl3) δ: 53.6, 124.1, 126.0, 128.8, 129.2, 129.4, 133.5,
147.4, 151.9; HRMS (ESI, +ve) m/z calcd. for C11H9N2O135Cl2
255.0092, found 255.0098 (M+H)+.
yl)ethynyl)silane (2 eq.) and the mixture was heated at 180 °C.
The reaction was monitored by 1H NMR spectroscopy, and
halted upon detection of product deborylation. The reaction
mixtures were purified by counter-current chromatography.
Ethyl 2-(3,5-dichloro-2-oxopyrazin-1(2H)-yl)acetate 5
Ethyl 2-((cyanomethyl)amino)acetate hydrochloride (19.0 g, 106
mmol) 3 in toluene (200 mL), oxalyl chloride (68 g, 45 mL, 533
mmol) were combined according to general procedure 2, yielding
Trimethyl((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)ethynyl)silane 1a
ethyl 2-(3,5-dichloro-2-oxopyrazin-1(2H)-yl)acetate
5
as
a
:
brown solid (16.0 g, 62%). M.p. 61–64 °C; FTIR (film/cm-1) υmax
3069 (m), 3036 (m), 2932 (m), 2843 (m), 1745 (s), 1663 (s),
1597 (s); 1H NMR (250 MHz, CDCl3) δ: 1.33 (t, 3H, J = 6.9 Hz),
4.29 (q, 2H, J = 6.9 Hz), 4.66 (s, 2H), 7.22 (s, 1H); 13C NMR (62
MHz, CDCl3) δ: 14.0, 51.0, 62.7, 124.0, 127.1, 147.3, 151.7,
165.7; HRMS (ESI, +ve) m/z calcd. for C8H9N2O335Cl2 250.9990,
found 251.0000 (M+H)+.
To a solution of trimethylsilyl acetylene (200 g, 2.04 mol, 1 eq.)
in diethyl ether (4 L) at -30 °C under argon in a 10 L jacketed
vessel was added nBuLi (1.8 mol in hexanes, 1.14 L, 2.04 mol, 1
eq.) by cautious dropwise addition (internal reaction temperature
rose to ≤ - 21 °C) and the reaction mixture was allowed to stir at
this temperature for 1 hour prior to warming to 0 °C. After 30
minutes the reaction mixture was cooled to -50 °C and 2-
isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (380 g, 2.04
mol, 1 eq.) was added dropwise and the reaction mixture was
stirred overnight. To the white precipitate was added ethereal 2N
HCl (1.33 L, 2.65 mol, 1.3 eq.) and the reaction was warmed to -
10 °C and stirred for 1.5 hours, filtered through celite,
concentrated in vacuo and allowed to recrystallise in the
1-Benzyl-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-4-(trimethylsilyl)pyridin-2(1H)-one 6a &
1-Benzyl-3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-5-(trimethylsilyl)pyridin-2(1H)-one 6b
1-Benzyl-3,5-dichloropyrazin-2(1H)-one (35 g, 137 mmol) 4 and
trimethyl((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)ethynyl)silane (62.0 g, 275 mmol) 1a were combined
according to general procedure 3, yielding a 2:1 regioisomeric
refrigerator,
yielding
trimethyl((4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)ethynyl)silane 1a as a white crystalline solid
(299 g, 65 %, obtained by 4 successive recrystallisations from the
mixture of
1-benzyl-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-
°
1
mother liquor). M.p. 91–93 C; H NMR (250 MHz, CDCl3) δ:
0.00 (9H, s), 1.09 (12H, s); 13C NMR (62 MHz, CDCl3) δ: -0.5,
24.6, 84.4, 111.3. All data in accordance with literature.21
dioxaborolan-2-yl)-4-(trimethylsilyl)pyridin-2(1H)-one 6a (as the
major component) and 1-benzyl-3-chloro-4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)-5-(trimethylsilyl)pyridin-2(1H)-one 6b
(as the minor). Separation of regioisomers was initially facilitated
by heptane recrystallisation of the major regioisomer and the
residual mixture was purified by HPCCC.
2-(Benzylamino)acetonitrile hydrochloride 2
Benzylamine (194 g, 1.81 mol) in acetonitrile (2 L),
chloroacetonitrile (150 g, 1.99 mol), potassium carbonate (749 g,
1.80 mol), sodium iodide (2.70 g, 18 mmol) and ethereal 1N HCl
were combined according to general procedure 1, yielding 2-
(benzylamino)acetonitrile hydrochloride 2 as a brown solid (333
1-Benzyl-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-4-(trimethylsilyl)pyridin-2(1H)-one 6a obtained as a pale
°
brown solid (26.2 g, 46%). M.p. 151–153 C; FTIR (film/cm-1)
°
g, 92%). M.p. 91–93 C; FTIR (film/cm-1) υmax: 3258 (m), 3069
υmax: 3062 (w), 3032 (w), 2978 (m), 2958 (m), 2895 (m), 1756
1
1
(w), 3010 (w), 2248 (m), 2126 (m); H NMR (250 MHz, d6-
(m), 1646 (s), 1586 (s); H NMR (250 MHz, CDCl3) δ: 0.43 (s,
DMSO) δ: 4.19 (s, 2H), 4.27 (s, 2H), 7.34–7.49 (m, 3H), 7.50–
7.62 (m, 2H), 10.58 (br s, 2H); 13C NMR (62 MHz, d6-DMSO) δ:
33.8, 50.5, 114.5, 129.2, 129.6, 130.6, 131.9; HRMS (ESI, +ve)
m/z calcd. for C9H11N11 147.0922, found 147.0921 (M+H)+.
9H), 1.30 (s, 12H), 5.15 (s, 2H), 7.29–7.42 (m, 5H), 7.63 (s,
1H); 13C NMR (62 MHz, CDCl3) δ: 1.5, 24.8, 53.5, 84.1, 128.1,
128.3, 128.8, 134.4, 135.8, 141.6, 153.6, 157.9; HRMS (ESI,
+ve) m/z calcd. for C21H30B1N1O3Si135Cl1 418.1777, found
418.1768 (M+H)+.
Ethyl 2-((cyanomethyl)amino)acetate hydrochloride 3
Glycine ethyl ester hydrochloride (75.3 g, 540 mmol) in
acetonitrile (1 L), chloroacetonitrile (50 g, 660 mmol), potassium
carbonate (249 g, 1.80 mol), sodium iodide (900 mg, 6 mmol)
and ethereal 1N HCl were combined according to general
procedure 1, yielding ethyl 2-((cyanomethyl)amino)acetate
1-Benzyl-3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-5-(trimethylsilyl)pyridin-2(1H)-one 6b obtained as a pale
°
brown solid (12.1 g, 21%). M.p. 149–152 C; FTIR (film/cm-1)
υmax: 3084 (w), 2981 (m), 2906 (w), 1748 (s), 1645 (s); 1H NMR
(250 MHz, CDCl3) δ: 0.25 (s, 9H), 1.43 (s, 12H), 5.16 (s, 2H),
7.23–7.41 (m, 6H); 13C NMR (62 MHz, CDCl3) δ: -0.4, 25.5,
53.2, 85.2, 116.3, 128.1, 128.2, 128.8, 131.0, 135.8, 139.5, 157.6;
HRMS (ESI, +ve) m/z calcd. for C21H30B1N1O3Si135Cl1 418.1777,
found 418.1782 (M+H)+.
°
hydrochloride 3 as a brown solid (96 g, 100%). M.p. 91–93 C;
FTIR (film/cm-1) υmax: 3328 (m), 3073 (w), 3028 (m), 2921 (m),
1
2840 (m), 1659 (m); H NMR (250 MHz, d6-DMSO) δ: 1.23 (t,
3H, J = 7.0 Hz), 3.91 (s, 2H), 4.19 (q, 2H, J = 7.0 Hz), 4.20 (s,
2H), 8.99 (br s, 1H); 13C NMR (62 MHz, d6-DMSO) δ: 14.4,
34.5, 47.4, 62.0, 115.1, 167.4; HRMS (ESI, +ve) m/z calcd. for
C6H11N2O2 143.0821, found 143.0819 (M+H)+.
1-Benzyl-3-chloro-4-(trimethylsilyl)pyridin-2(1H)-one 6c
A small amount of 6c was isolated from HPCCC purification of
°
6a & 6b. M.p. 70 C (dec.); FTIR (film/cm-1) υmax: 3069 (m),
1
1-Benzyl-3,5-dichloropyrazin-2(1H)-one 4
3036 (m), 2958 (m), 2903 (m), 1641 (s), 1589 (s); H NMR (400
2-(Benzylamino)acetonitrile hydrochloride (73.0 g, 386 mmol) 2
in toluene (500 mL), oxalyl chloride (245 g, 164 mL, 1.93 mol)
were combined according to general procedure 2, yielding 1-
benzyl-3,5-dichloropyrazin-2(1H)-one 4 as a brown solid (85.0
MHz, CDCl3) δ: 0.34 (s, 9H), 5.19 (s, 2H), 6.16 (d, 1H, J = 7.0
Hz), 7.20 (d, 1H, J = 7.0 Hz), 7.30–7.39 (m, 5H); 13C NMR (100
MHz, CDCl3) δ: 0.0, 54.7, 110.9, 129.7, 130.0, 130.4, 134.7,
135.1, 137.3, 151.3, 159.6; HRMS (ESI, +ve) m/z calcd. for
C15H19N1O3Si135Cl1 292.0924, found 292.0927 (M+H)+.
°
g, 87%). M.p. 76–78 C; FTIR (film/cm-1) υmax: 3062 (m), 2988
(m), 2962 (m), 1748 (s), 1645 (s); 1H NMR (250 MHz, CDCl3) δ:
5.13 (s, 2H), 7.21 (s, 1H), 7.31–7.46 (m, 5H); 13C NMR (62

ACCEPTED MANUSCRIPT
6
Tetrahedron
Ethyl 2-(3-chloro-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-
°
dioxaborolan-2-yl)-4-(trimethylsilyl)pyridin-1(2H)-yl)acetate 7a
&
yl)acetate (41 mg, 60 %) 11. M.p. 131–134 C; FTIR (film/cm-1)
υmax: 3073 (w), 3043 (m), 2952 (m), 2895 (w), 1622 (s), 1574 (s);
1H NMR (250 MHz, CDCl3) δ: 1.31 (t, 3H, J = 6.9 Hz), 1.32 (s,
12H), 4.27 (q, 2H, J = 6.9 Hz), 4.69 (s, 2H), 7.64 (d, 1H, J = 1.8
Hz), 7.85 (d, 1H, J = 1.8 Hz); 13C NMR (100 MHz, CDCl3) δ:
14.0, 24.7, 51.4, 62.1, 84.4, 125.5, 142.0, 144.3, 159.1, 167.0;
HRMS (ESI, +ve) m/z calcd. for C19H30B1N1O535Cl1 398.1906,
found 398.1907 (M+H)+.
Ethyl 2-(3-chloro-2-oxo-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-5-(trimethylsilyl)pyridin-1(2H)-yl)acetate 7b
Ethyl 2-(3,5-dichloro-2-oxopyrazin-1(2H)-yl)acetate (22 g, 88
mmol) 5 and trimethyl((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)ethynyl)silane (39.6 g, 176 mmol) 1a were combined
according to general procedure 3, yielding a 2:1 regioisomeric
mixture of 7a (as the major component) and 7b (as the minor).
Separation of regioisomers was accomplished by HPCCC.
Ethyl 2-(4-butyl-3-chloro-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)pyridin-1(2H)-yl)acetate 12
To ethyl 2-(3,5-dichloro-2-oxopyrazin-1(2H)-yl)acetate (50 mg,
0.20 mmol, 1 eq.) 5 was added 2-(hex-1-yn-1-yl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (125 mg, 0.60 mmol, 3 eq.) 1c
and the mixture was heated at 180 °C. The reaction was closely
Ethyl
2-(3-chloro-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-4-(trimethylsilyl)-pyridin-1(2H)-yl)acetate 7a
was obtained as a yellow/brown solid (16 g, 44%). M.p. 108–110
°C; FTIR (film/cm-1) υma1x: 3054 (w), 2981 (m), 2910 (w), 2240
(m), 1749 (s), 1650 (s); H NMR (250 MHz, CDCl3) δ: 0.40 (s,
9H), 1.30 (t, 3H, J = 7.0 Hz), 1.31 (s, 12H), 4.26 (q, 2H, J = 7.0
Hz), 4.63 (s, 2H), 7.53 (s, 1H); 13C NMR (62 MHz, CDCl3) δ:
1.7, 14.1, 24.9, 51.5, 61.9, 84.2, 133.9, 142.3, 154.5, 157.8,
167.1; HRMS (ESI, +ve) m/z calcd. for C18H30B1N1O5Si135Cl1
414.1675, found 414.1660 (M+H)+.
1
monitored by H NMR spectroscopy and was complete after 8
hours. The crude product was purified by flash column
chromatography using gradient elution ethyl acetate:petroleum
ether 40-60° (5:95-20:80) to yield ethyl 2-(4-butyl-3-chloro-2-
oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-
1(2H)-yl)acetate (41 mg, 51 %) 12. M.p. 137–139 °C; FTIR
(film/cm-1) υmax: 3062 (w), 2988 (m), 2969 (m), 2932 (m), 2252
1
(m), 1711 (s), 1650 (s); H NMR (400 MHz, CDCl3) δ: 0.97 (t,
Ethyl
2-(3-chloro-2-oxo-4-(4,4,5,5-tetramethyl-1,3,2-
3H, J = 6.7 Hz), 1.31 (t, 3H, J = 7.2 Hz), 1.32 (s, 12H), 1.39–1.58
(m, 4H), 2.96 (app. t, 2H, J = 7.5 Hz), 4.26 (q, 2H, J = 7.2 Hz),
4.67 (s, 2H), 7.69 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 13.8,
14.1, 22.9, 24.7, 31.3, 32.6, 51.3, 61.9, 83.8, 124.1, 144.1, 156.6,
158.8, 167.2; HRMS (ESI, +ve) m/z calcd. for C15H22B1N1O535Cl1
342.1286, found 342.1280 (M+H)+.
dioxaborolan-2-yl)-5-(trimethylsilyl)-pyridin-1(2H)-yl)acetate 7b
was obtained as a yellow/brown solid (4.5 g, 12%). M.p. 128–
°
130 C; FTIR (film/cm-1) υmax: 3166 (w), 3081 (w), 2978 (m),
2903 (m), 2829 (m), 2703 (m), 1645 (s), 1595 (s); 1H NMR (250
MHz, CDCl3) δ: 0.30 (s, 9H), 1.30 (t, 3H, J = 5.9 Hz), 1.45 (s,
12H), 4.26 (q, 2H, J = 5.9 Hz), 4.65 (s, 2H), 7.06 (s, 1H); 13C
NMR (62 MHz, CDCl3) δ: -0.4, 14.1, 25.5, 51.5, 61.9, 85.3,
116.5, 130.8, 140.1, 157.4, 167.1; HRMS (ESI, +ve) m/z calcd.
for C18H30B1N1O5Si135Cl1 414.1675, found 414.1660 (M+H)+.
Ethyl 2-(3-chloro-2-oxo-4-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)pyridin-1(2H)-yl)acetate 13
To ethyl 2-(3,5-dichloro-2-oxopyrazin-1(2H)-yl)acetate (50 mg,
0.20 mmol, 1 eq.) 5 was added 2-(phenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (137 mg, 0.60 mmol, 3 eq.) 1d and the
mixture was heated at 180 °C. The reaction was closely
1-Benzyl-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)pyridin-2(1H)-one 8
To a suspension of caesium fluoride (73 mg, 0.48 mmol, 2 eq.) in
ethanol/acetonitrile (5 mL) was added 1-benzyl-3-chloro-5-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-
(trimethylsilyl)pyridin-2(1H)-one 6a (100 mg, 0.24 mmol, 1 eq.)
and heated to 50 °C. The reaction was complete after 2 hours and
the reaction mixture was filtered through silica, concentrated in
vacuo and the residue was subjected to flash column
chromatography using gradient elution ethyl acetate:petroleum
1
monitored by H NMR spectroscopy and was complete after 8
hours. The crude product was purified by flash column
chromatography using gradient elution ethyl acetate:petroleum
ether 40-60° (5:95-20:80) to yield ethyl 2-(4-phenyl-3-chloro-2-
oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-
1(2H)-yl)acetate (46 mg, 56 %) 13. FTIR (film/cm-1) υmax: 3001
(w), 2958 (m), 2927 (m), 1663 (m), 1617 (s); 1H NMR (500
MHz, CDCl3) δ: 1.06 (s, 12H), 1.31 (t, 3H, J = 7.5 Hz), 4.27 (q,
2H, J = 7.5 Hz), 4.71 (s, 2H), 7.18–7.24 (m, 3H), 7.34–7.41 (m,
2H), 7.60 (s, 1H); 13C NMR (125 MHz, CDCl3) δ: 14.1, 24.4,
51.5, 62.0, 83.7, 124.3, 127.6, 127.9, 128.2, 137.9, 142.7, 154.1,
159.0, 167.1; HRMS (ESI, +ve) m/z calcd. for C21H26B1N1O535Cl1
418.1593, found 418.1592 (M+H)+.
ether (5:95-10:90) to yield
1-benzyl-3-chloro-5-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 14 as an
amorphous solid (75 mg, 91%). FTIR (film/cm-1) υmax: 3068 (w),
1
3030 (m), 2979 (m), 2953 (m), 2907 (w), 1651 (s), 1597 (s); H
NMR (250 MHz, CDCl3) δ: 1.31 (s, 12H), 5.20 (s, 2H), 7.30–
7.39 (m, 5H), 7.75 (app. d, 1H, J = 2.0 Hz), 7.81 (app. d, 1H, J =
2.0 Hz); 13C NMR (100 MHz, CDCl3) δ: 24.7, 53.5, 84.3, 125.8,
128.2, 128.8 (×2), 135.7, 141.5, 143.7, 159.4; HRMS (ESI, +ve)
m/z calcd. for C18H22B1N1O335Cl1 346.1381, found 346.1376
(M+H)+.
1-Benzyl-3-chloro-5-(potassium triflouroboryl)-4-
(trimethylsilyl)pyridin-2(1H)-one 14
To a solution of 1-benzyl-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-4-(trimethylsilyl)pyridin-2(1H)-one 6a in
THF at 0 °C was added an aqueous solution of KHF2 (7.90 g, 100
mmol, 6 eq.). The reaction mixture was stirred overnight,
concentrated in vacuo, washed with acetone and recrystallized
Ethyl 2-(3-chloro-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)pyridin-1(2H)-yl)acetate 11
To ethyl 2-(3,5-dichloro-2-oxopyrazin-1(2H)-yl)acetate (50 mg,
0.20 mmol, 1 eq.) 5 was added 2-ethynyl-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (91 mg, 0.60 mmol, 3 eq.) 1b and the
mixture was heated at 180 °C. The reaction was closely
from
CHCl3
to
yield
1-benzyl-3-chloro-5-(potassium
trifluorboryl)-4-(trimethylsilyl)pyridine-2-(1H)-one 14 as a white
°
solid (5.50 g, 87%). M.p. 135–140 C; FTIR (film/cm-1) υmax
:
1
1
3069 (m), 3036 (m), 2988 (m), 1673 (s), 1595 (s); H NMR (250
MHz, CDCl3) δ: 0.34 (s, 9H), 5.10 (s, 2H), 7.22–7.40 (m, 6H);
13C NMR (125 MHz, d6-DMSO) δ: 2.01 (q, J = 5.4 Hz), 51.7,
127.4, 127.7, 128.4, 131.7, 136.5 (q, J = 2.9 Hz), 137.5, 154.8,
monitored by H NMR spectroscopy and was complete after 2
hours. The crude product was purified by flash column
chromatography using gradient elution ethyl acetate:petroleum
ether 40-60° (5:95-20:80) to yield ethyl 2-(3-chloro-2-oxo-5-

ACCEPTED MANUSCRIPT
7
156.4; HRMS (ESI, +ve) m/z calcd. for C15H17B1N1O1Si1F135Cl1
(film/cm-1) υmax: 3053 (w), 2981 (m), 2933 (w), 1653 (s), 1603
1
358.0813, found 358.0815 (M+H)+.
(s); H NMR (250 MHz, CDCl3) δ: 1.37 (s, 12H), 5.18 (s, 2H),
6.29 (d, 1H, J = 6.8 Hz), 7.20 (d, 1H, J = 6.8 Hz), 7.29–7.38 (m,
5H); 13C NMR (125 MHz, CDCl3) δ: 24.7, 53.1, 84.9, 108.8,
128.1, 128.2, 128.8, 132.2, 134.0, 135.7, 158.5; HRMS (ESI,
3-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
4-(trimethylsilyl)pyridin-2(1H)-one 15
+ve) m/z calcd. for C18H22B1N1O335Cl1 346.1381,
found
To an autoclave was added 1-benzyl-3-chloro-5-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trimethylsilyl)pyridin-
2(1H)-one 6a (7.00 g, 17 mmol, 1 eq.), industrial methylated
spirits (50 mL) and Pd/C 10% (1.80 g, 2 mmol, 10 mol%). The
autoclave was sealed and pressurised with H2 (60 atm.) and
heated at 50 °C. After 6 days the reaction mixture was filtered
through celite, concentrated in vacuo and subjected to flash
column chromatography using gradient elution ethyl
acetate:petroleum ether 40-60° (20:80-30-70) to yield 3-chloro-5-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-
346.1374 (M+H)+.
1-Benzyl-3-chloro-4-hydroxy-5-
(trimethylsilyl)pyridin-2(1H)-one 19
To a solution of 1-benzyl-3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-5-(trimethylsilyl)pyridin-2(1H)-one 6b (50
mg, 0.12 mmol, 1 eq.) in ethanol (5 mL) was added sodium
carbonate (13 mg, 0.12 mmol, 1 eq.) and aqueous hydrogen
peroxide (30% w/v, 120 µl, 1 mL/mol). The reaction was allowed
to stir for 1 hour, after which was filtered through a plug of
magnesium sulfate and concentrated in vacuo to yield 1-benzyl-
3-chloro-4-hydroxy-5-(trimethylsilyl)pyridin-2(1H)-one 19 as a
waxy solid (35 mg, 95%). FTIR (film/cm-1) υmax: 3354 (br), 2980
(m), 2895 (w), 1749 (s), 1650 (s); 1H NMR (250 MHz, CDCl3) δ:
0.24 (s, 9H), 5.16 (s, 2H), 6.48 (br. s, 1H), 7.10 (s, 1H), 7.31–
7.44 (m, 5H); 13C NMR (62 MHz, CDCl3) δ: 0.0, 53.9, 107.5,
108.8, 129.4, 129.5, 130.2, 137.3, 141.3, 160.8, 164.4; HRMS
(ESI, +ve) m/z calcd. for C15H19B1N1O2Si135Cl1 308.0874, found
308.0861 (M+H)+.
(trimethylsilyl)pyridin-2(1H)-one 15 (2.00 g, 38%) as a faint
°
brown solid. M.p. 188–189 C; FTIR (film/cm-1) υmax: 3165 (w),
1
3132 (w), 2988 (m), 2903 (w), 1644 (s); H NMR (250 MHz,
CDCl3) δ: 0.46 (s, 9H), 1.32 (s, 12H), 7.78 (s, 1H), 13.20 (br. s,
1H); 13C NMR (62 MHz, CDCl3) δ: 1.5, 24.9, 84.1, 132.9, 139.0,
156.9, 160.3; HRMS (ESI, +ve) m/z calcd. for
C14H24B1N1O3Si135Cl1 328.1307, found 328.1315 (M+H)+.
1-Benzyl-5-bromo-3-chloro-4-
(trimethylsilyl)pyridin-2(1H)-one 16
To
a
solution
of
1-benzyl-5-bromo-3-chloro-4-
(trimethylsilyl)pyridin-2(1H)-one 6a (100 mg, 0.24 mmol, 1 eq.)
in acetonitrile was added N-bromosuccinimide (212 mg, 1.19
mmol, 5 eq.) and heated at 50 °C. After 2 hours the reaction was
filtered through a plug of silica and concentrated in vacuo to
1-Benzyl-3-chloro-5-(trimethylsilyl)pyridin-2(1H)-one 20
To a suspension of caesium fluoride (73 mg, 0.48 mmol, 2 eq.) in
ethanol/acetonitrile (5 mL) was added 1-benzyl-3-chloro-5-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trimethyl-
silyl)pyridin-2(1H)-one 6b (100 mg, 0.24 mmol, 1 eq.) and
heated to 50 °C. The reaction was stirred for 2 hours and filtered
through silica, concentrated in vacuo and the residue was
subjected to flash column chromatography using ethyl
acetate:petroleum ether (10:90) to yield 1-benzyl-3-chloro-5-
(trimethylsilyl)pyridin-2(1H)-one 20 as an amorphous solid (66
mg, 95%). FTIR (film/cm-1) υmax: 3064 (w), 3030 (w), 2954 (m),
yield
1-benzyl-5-bromo-3-chloro-4-(trimethylsilyl)pyridin-
2(1H)-one 16 as an amorphous solid (100 mg, 100%). FTIR
(film/cm-1) υmax: 3068 (m), 3026 (m), 2979 (m), 2903 (m), 1650
(s), 1587 (s); 1H NMR (500 MHz, CDCl3) δ: 0.49 (s, 9H), 5.09 (s,
2H), 7.29–7.42 (m, 6H); 13C NMR (100 MHz, CDCl3) δ: 2.5,
53.3, 102.5, 128.5, 128.7, 129.1 (x2), 134.8, 135.1, 149.6, 157.0;
HRMS (ESI, +ve) m/z calcd. for C15H18N1O1Si1Br135Cl1
370.0030, found 370.0047 (M+H)+.
1
2896 (w), 1649 (s), 1594 (s), 1519 (m); H NMR (250 MHz,
CDCl3) δ: 0.21 (s, 9H), 5.20 (s, 2H), 7.22 (d, 1H, J = 1.7 Hz),
7.31–7.40 (m, 5 H), 7.53 (d, 1H, J = 1.7 Hz); 13C NMR (100
MHz, CDCl3) δ: 0.0, 54.7, 116.2, 127.9, 129.6, 129.7, 130.3,
137.2, 141.2, 142.4, 160.2; HRMS (ESI, +ve) m/z calcd. for
C15H19N1O1Si135Cl1 292.0924, found 292.0919 (M+H)+.
1-Benzyl-5-bromo-3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)pyridin-2(1H)-one 17
To a solution of 1-benzyl-3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-5-(trimethylsilyl)pyridin-2(1H)-one 6b (100
mg, 0.24 mmol,
1 eq.) in acetonitrile was added N-
bromosuccinimide (212 mg, 1.19 mmol, 5 eq.) and heated at 50
°C. After 2 hours the reaction was filtered through a plug of silica
and concentrated in vacuo to yield 1-benzyl-5-bromo-3-chloro-4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one
17 as an amorphous solid (102 mg, 100%). FTIR (film/cm-1)
υmax: 3091 (w), 3061 (w), 3033 (w), 2980 (m), 2942 (w), 1652
Acknowledgments
We thank the EPSRC and Peakdale Molecular for funding.
References and notes
1
(s), 1594 (s), 1521 (w); H NMR (400 MHz, CDCl3) δ: 1.42 (s,
12H), 5.15 (s, 2H), 7.26–7.33 (m, 2H), 7.32–7.40 (m, 4H); 13
C
1. 1. (a) Pemberton, N.; Chorell, E.; Almqvist, F. Microwave-
assisted synthesis and functionalization of 2-pyridones, 2-
quinolones and other ring-fused 2-pyridones. In Topics in
Heterocyclic Chem.; Van der Eycken, E.; Kappe, C. O., Eds.;
Springer, 2006; Vol. 1, pp 1-30. (b) Carles, L.; Narkunan, K.;
Penlou, S.; Rousset, L.; Bouchu, D.; Ciufolini, M. A. J. Org.
Chem., 2002, 67, 4304.
2. Dragovich, P. S.; Prins, T. J.; Zhou, R.; Johnson, T. O.; Hua, Y.;
Luu, H. T.; Sakata, S. K.; Brown, E. L.; Maldonado, F. C.;
Tuntland, T.; Lee, C. A.; Fuhrman, S. A.; Zalman, L. S.; Patick,
A. K.; Matthews, D. A.; Wu, E. Y.; Guo, M.; Borer, B. C.;
Nayyar, N. K.; Moran, T.; Chen, L.; Rejto, P. A.; Rose, P. W.;
Guzman, M. C.; Dovalsantos, E. Z.; Lee, S.; McGee, K.;
Mohajeri, M.; Liese, A.; Tao, J.; Kosa, M. B.; Liu, B.; Batugo, M.
R.; Gleeson, J.-P. R.; Wu, Z. P.; Liu, J.; Meador, III, J. P.; Ferre,
R. A. J. Med. Chem. 2003, 46, 4572.
NMR (100 MHz, CDCl3) δ: 24.7, 53.3, 85.7, 98.9, 128.2, 128.5,
129.0, 130.6, 134.9, 135.1, 156.8; HRMS (ESI, +ve) m/z calcd.
for C18H21B1N1O335Cl1Br1 424.0486, found 424.0482 (M+H)+.
1-Benzyl-3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)pyridin-2(1H)-one 18
To a solution of 1-benzyl-3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-5-(trimethylsilyl)pyridin-2(1H)-one 6b (100
mg, 0.24 mmol, 1 eq.) in trifluoroacetic acid/dichloromethane (2
mL) was heated to 50 °C over 18 hours. The reaction mixture
was concentrated in vacuo and triturated with chloroform to yield
1-benzyl-3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)pyridin-2(1H)-one 18 as a yellow oil (59 mg, 71%). FTIR

ACCEPTED MANUSCRIPT
8
Tetrahedron
3. Charrier, J.-D.; Miller, A.; Kay, D. P.; Brenchley, G.; Twin, H.
C.; Collier, P. N.; Ramaya, S.; Keily, S. B.; Durrant, S. J.;
Knegtel, R. M. A.; Tanner, A. J.; Brown, K.; Curnock, A. P.;
Jimenez, J.-M. J. Med. Chem. 2011, 54, 2341.
4. For examples of pericyclic cycloadditions see: (a) Moore, J. E.;
Goodenough, K. M.; Spinks, D.; Harrity, J. P. A. Synlett 2002,
2071; (b) Moore, J. E.; Davies, M. W.; Goodenough, K. M.;
Wybrow, R. A. J.; York, M.; Johnson, C. N.; Harrity, J. P. A.
Tetrahedron 2005, 61, 6707; (c) Helm, M. D.; Moore, J. E.; Plant,
A.; Harrity, J. P. A. Angew. Chem. Int. Ed. 2005, 44, 3889; (d)
Moore, J. E.; York, M.; Harrity, J. P. A. Synlett 2005, 860; (e)
Delaney, P. M.; Moore, J. E.; Harrity, J. P. A. Chem. Commun.
2006, 3323; (f) Browne, D. L.; Helm, M. D.; Plant, A.; Harrity, J.
P. A. Angew. Chem. Int. Ed. 2007, 46, 8656; (g) Gomez-Bengoa,
E. ; Helm, M. D.; Plant, A.; Harrity, J. P. A. J. Am. Chem. Soc.
2007, 129, 2691; (h) Delaney, P. M.; Browne, D. L.; Adams, H.;
Plant, A.; Harrity, J. P .A. Tetrahedron 2008, 64, 866; (i) Browne,
D. L.; Vivat, J. F.; Plant, A.; Gomez-Bengoa, E.; Harrity, J. P. A.
J. Am. Chem. Soc. 2009, 131, 7762.
5. Metal catalysed cycloadditions have also been widely studied: (a)
Gandon, V.; Leboeuf, D.; Amslinger, S.; Vollhardt, K. P. C.;
Malacria, M.; Aubert, C. Angew. Chem. Int. Ed. 2005, 44, 7114;
(b) Hilt, G.; Smolko, K. I. Angew. Chem. Int. Ed. 2003, 42, 2795;
(c) Yamamoto, Y.; Ishii, J.-i.; Nishiyama, H.; Itoh, K. J. Am.
Chem. Soc. 2004, 126, 3712; (d) Auvinet, A.-L.; Harrity, J. P. A.;
Hilt, G. J. Org. Chem. 2010, 75, 3893; (e) Auvinet, A.-L.; Harrity,
J. P. A. Angew. Chem. Int. Ed. 2011, 50, 2769.
6. Delaney, P. M.; Huang, J.; Macdonald, S. J. F.; Harrity, J. P. A.
Org. Lett. 2008, 10, 781.
7. Huang, J.; Macdonald, S. J. F.; Harrity, J. P. A. Chem. Commun.
2009, 436.
8. Li, J.; Smith, D.; Krishnananthan, S.; Hartz, R. A.; Dasgupta, B.;
Ahuja, V.; Schmitz, W. D.; Bronson, J. J.; Mathur, A.; Barrish, J.
C.; Chen, B.-C. Org. Process Res. Dev. 2012, 16, 156.
9. Starting material:product ratios and regioselectivities were
estimated by 400 MHz 1H NMR spectroscopy on crude reaction
mixtures. Regiochemical assignments by nOe spectroscopy have
been reported previously.6
10. (a) Tutonda, M.; Vanderzande, D.; Hendrickx, M.; Hoornaert, G.
Tetrahedron 1990, 46, 5715; (b) Pawar, V.G.; De Borggraeve,
W.M. Synthesis 2006, 2799.
11. It has been noted that 6b displayed instability during storage for a
few weeks at 0 oC, with significant levels of product
protodeborylation observed. In contrast, 6a is stable towards
sample storage for several weeks.
12. DeAmicis, C.; Edwards, N. A.; Giles, M. B.; Harris, G. H.;
Hewitson, P.; Janaway, L.; Ignatova, S. J. Chromatogr. A 2011,
1218, 6122.
13. Sutherland, I. A. J. Chromatogr. A 2007, 1151, 6.
14. (a) Oka, F.; Oka, H.; Ito, Y. J. Chromatogr. A 1991, 538, 99; (b)
Ito, Y. J. Chromatogr. A 2005, 1065, 145.
15. When the stationary phase is aqueous and the mobile phase is
organic, the system is said to be run in ‘normal phase’.
Conversely, when the mobile phase is defined as aqueous the
system is in ‘reverse phase’.
16. The distribution coefficient calculations are documented in the
Supplementary Material.
17. Boronate oxidation of 7b was also shown to successfully produce
phenol pyridine 21.
18. Pattended, L. C.; Adams, H.; Smith, S. A.; Harrity, J. P. A.
tetrahedron 2008, 64, 2951.
19. Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification of
Laboratory Chemicals. Pergamon: Oxford, 1996.
20. Brown, H. C.; Bhat, N. G.; Srebnik, M. Tetrahedron Lett. 1988,
29, 2631.
21. Molander, G. A.; Ellis, N. M. J. Org. Chem. 2008, 73, 6841.
Supplementary Data
NMR spectra of new compounds and details of purification
procedures using counter-current chromatography.