Deliberately Losing Control of C?H Activation Processes in the Design of Small-Molecule-Fragment Arrays Targeting Peroxisomal Metabolism

Article abstract of DOI:10.1002/cmdc.202000543

Combined photochemical arylation, “nuisance effect” (S_NAr) reaction sequences have been employed in the design of small arrays for immediate deployment in medium-throughput X-ray protein–ligand structure determination. Reactions were deliberate

Full text of DOI:10.1002/cmdc.202000543

Accepted Article
Title: Deliberately Losing Control of C-H Activation Processes in
the Design of Small Molecule Fragment Arrays Targeting
Peroxisomal Metabolism
Authors: Raysa Kahn Tareque, Storm Hassell-Hart, Tobias Krojer,
Anthony Bradley, Srikannathasan Velupillai, Romain Talon,
Michael Fairhead, Iain J Day, kamlesh Bala, Robert felix, Paul
kemmitt, Paul Brennan, frank von Delft, Laura Díaz Sáez,
John Spencer, and Kilian Huber
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemMedChem 10.1002/cmdc.202000543
Link to VoR: https://doi.org/10.1002/cmdc.202000543
01/2020

10.1002/cmdc.202000543
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Deliberately Losing Control of C-H Activation Processes in the
Design of Small Molecule Fragment Arrays Targeting Peroxisomal
Metabolism
Raysa Khan Tareque,[a] Storm Hassell-Hart,[a] Tobias Krojer,[b] Anthony Bradley,[b] Srikannathasan Velupillai,[b] Romain Talon,[b] Michael Fairhead,[b] Iain J.
Day,[a] Kamlesh Bala,[a] Robert Felix,[c] Paul D. Kemmitt,[d] Paul Brennan,[b,f] Frank von Delft,[b,e,g] Laura Díaz Sáez,[b,f] Kilian Huber,[b,f] John Spencer,*, [a]
[a] Mr K. Bala, Drs R. Khan Tareque, S. Hassell-Hart, I. J. Day, Professor J. Spencer
Chemistry Deparment, School of Life Sciences, University of Sussex, BN19QJ, UK.
Email: j.spencer@sussex.ac.uk.
[b] Drs T. Krojer, A. Bradley, S. Velupillai, R. Talon, M. Fairhead, Laura Díaz Sáez, Prof. Dr. K. Huber. Profs. P. Brennan, F. Von Delft
Structural Genomics Consortium (SGC), Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.
[c] Dr R. Felix
Bio-Techne (Tocris Bioscience), The Watkins Building, Atlantic Road, Avonmouth, Bristol BS11 9QD, U.K.
[[d] Dr P. D. Kemmitt
Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, CB10 1XL, United Kingdom.
[e] Professor F. von Delft
Diamond Light Source (DLS), Harwell Science and Innovation Campus, Didcot OX11 0DE, U.K.
[f] Professor P Brennan, Dr Laura Díaz Sáez, Prof Dr. Kilian Huber
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
[g] Professor F. von Delft
Department of Biochemistry, University of Johannesburg, Auckland Park 2006, South Africa.
Supporting information for this article is given via a link at the end of the document.
reactions were observed (“nuisance effect”), when a nucleophilic
Abstract: combined photochemical arylation, “nuisance effect” (SNAr)
reaction sequences have been employed in the design of small arrays
for immediate deployment in medium throughput X-ray protein-ligand
structure determination. Reactions have been deliberately let “out of
control,” in terms of selectivity; for example the ortho-arylation of 2-
phenylpyridine gave five products resulting from mono-, bis- arylations
solvent such as methanol or ethanol was used.
combined with SNAr processes.
As a result, a number of
crystallographic hits against NUDT7, a key peroxisomal CoA ester
hydrolase, have been identified.
Introduction
Given their atom and step economy, C-H activation processes are
now commonplace in organic synthesis[1]. Highly decorated
bioactive or synthetically relevant molecules can be functionalized
via a late stage activation process, enabling the efficient
production of derivatives for e.g. structure activity studies or
pharmacokinetic evaluation, saving significant time and cost
Figure 1. Examples of diverse benzodiazepines formed from
ortho C-H activation processes.
Such a spectrum of reactivity opens up scope for performing ortho
C-H activations with complete control, driving towards the
formation of a single product in a highly efficient manner (see A,
Scheme 1). Conversely, from the previous example (Figure 1),
erosion of selectivity via the competing formation of bis-arylated
product, as in B or even total loss of control, as in C, where the
coupling partner has a group (Y in Scheme 1) capable of further
functionalisation, can also be envisioned. Outcome A is irrefutably
catalysis friendly whereas C might be more appropriate in a
medicinal chemistry setting, where making small arrays with
minimal work-up bottlenecks is desirable, given the high
compound attrition and cost of drug discovery.
compared to previous cumbersome multistep syntheses[2–14]
.
We have recently disclosed our findings on the microwave
mediated ortho-C-H activation of benzodiazepines using
iodonium salts under Pd catalysis (Figure 1)[15]. These processes
tend to give monoarylated products although, under more forcing
conditions, a second ortho-arylation was observed. Recent,
complementary, studies on the visible light mediated “Sanford”
arylation[16–18] of benzodiazepines using diazonium salts and dual
Ru/Pd catalysis led mainly to mono-functionalized product[19]
.
However, in the case of 2- or 4- substituted fluoro-benzene
diazonium salt coupling partners, further competing SNAr
1
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conversion and a good 75% combined isolated yield of 3f and 3a.
In entry 2, higher conversions of 3g were found but with a lower
overall yield of 3f. Entries 4 and 5 are in line with the earlier work
of Sanford et al., who obtained a 62% conversion to 3 in the
absence of a Ru catalyst, at ambient temperature, whereas
entries 3 and 6 show that low conversions are observed in the
absence of light. It was anticipated that the ratio of the products
could be influenced by the sequence in which the reactions were
performed; for instance, the ratio of the ether to fluoro products,
3a vs 3f, was significantly increased when 2a was heated to reflux
in methanol first, to initiate the SNAr process (entry 7) prior to the
addition of the other reagents.
Scheme 1. Extremes of reactivity scenarios in ortho C-H
activation chemistry with varying degrees of control. R1-Y is a
coupling partner with a group, Y, capable of further reactivity; X is
a halogen or diazonium group.
Table 1. Varying C-H activation conditions.
It was our intention to undertake a proof of principle feasibility
study of the development of C-H activation chemistry capable of
losing control, in the selectivity (not health and safety) context,
creating small arrays and diverse mixtures of compounds for
immediate deployment in a medicinal chemistry setting with
minimal work up or purification[20–23]. To assist in the process,
protein crystallographic screening of the small arrays vs a key
peroxisomal protein of current interest was used as a means of
validating this approach (vide infra).
Entry
Light
Ru(bpy)3Cl2.6H2O Temp.
mol%
Conversion
LC-MS (%)
(3f:3a)
source
a
b
1
2
2.5
2.5
reflux
reflux
85 (4:1)
60 (2:1)
c
3
2.5
reflux
25 (2:1)
1. Results and Discussion
a
a
4
5
-
-
reflux
r.t.
65 (6:1)
We chose 1-phenylpyrrolidin-2-ones as a starting point given their
low molecular weight, potential as drug-like fragments as well as
their known ability to undergo C-H activation. Controlled Sanford
arylations of diazonium salts on 1-phenylpyrrolidin-2-one using
dual Pd/Ru catalysis and slightly modified standard literature
conditions (reflux vs. ambient temperature)[17], in our hands, led
to one major product 3, in good to excellent yields (Scheme 2).
58 (20:1)
c
6
7
-
reflux
reflux
20 (99:
trace)
a
31
(1:4)d
a 26W compact fluorescent light bulb, b daylight. c in absence of
light. d 2a and MeOH were refluxed first (1h) then the other
components were added and reacted for 4h.
Using the optimized conditions, a small array of arylated products
was formed (Scheme 3). Interestingly, under identical conditions,
a higher ratio of the ether product from ethanol was achieved in
comparison with methanol, i.e. 3g vs. 3a. The reaction of i-PrOH
gave a low yield of 3h, which was obtained as an inseparable
mixture with 3f. Unsurprisingly, ortho-substituted analogues 3i
and 3j can also be synthesised.
Scheme 2. Controlled Arylations.
Next, we tested the possibility of losing control by performing
nuisance effect reactions on the fluorodiazonium salt 2a (Table 1)
where there is a possibility of an SNAr reaction on 2a prior to the
CH activation. The best conditions (entry 1) gave excellent
2
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Reaction of 4 with excess 4-fluorodiazonium salt was carried out
under reflux in methanol and gratifyingly led to five products 5a –
5e, resulting from a combination of mono, di-arylation and
combined “nuisance effects” i.e “no control” (Scheme 6). The
components were separable or were subjected, as a crude
mixture/small array, for protein X-ray studies.
Scheme 3. 1-Phenylpyrrolidin-2-one derivatives (isolated yields)
from C-H activation/nuisance effect reactions.
Next, a one-pot reaction, employing a mixture of alcohols, led to
Scheme 6. Out of control small array of 2-phenylpyridine
a
small array of ether products alongside the expected
derivatives from combined C-H arylation and nuisance effects.
fluorobiphenyl 3f (Scheme 4). We did not observe any significant
bis-arylations in these reactions and the array was subjected,
without purification, to an X-ray protein crystallographic analysis.
This process is somewhat limited i.e. just the three alcohols tried,
other nucleophiles e.g. thiols gave mixed results and similar C-H
activation attempts with simple benzamides in methanol, such as
N-phenylacetamide, N-methyl-N-phenylacetamide2,2‐dimethyl‐
N‐phenylpropanamide and N,2,2‐trimethyl‐N‐phenylpropanamide,
led predominantly to bis(4‐methoxyphenol)diazene. Solvent
screens gave little improvement or any extra SNAr scope, e.g.
DCE, 1,4-dioxane, DME, xylenes, i-PrOH, t-BuOH, DMSO, MeCN,
phenol, and acetone led to little change in yields in these
processes.
Scheme 4. Losing control: small array of 1-phenyl-2-pyrrolidinone
derivatives formed from a mixture of alcohols.
Similarly, a small array of monoarylated compounds can be
produced by using a mixture of diazonium salts. The mixture of
products was deployed immediately in an X-ray protein
crystallographic screen without any further purification (vide infra)
(Scheme 5).
The above arrays were subjected to X-ray crystallographic
evaluation against NUDT7, a member of the superfamily of
enzymes, Nudix hydrolases, which, hydrolyse a wide range of
pyrophosphates and are thought to act as cellular
“housecleaners.”[24,25] Two isoforms of NUDT7 have been
identified: NUDT7 and NUDT7. The former is a peroxisomal
CoA ester diphosphatase, whereas NUDT7 is an inactive splice
variant[26]. NUDT7 regulates CoA metabolism by hydrolysing
CoA esters to various fatty acids of varying chain lengths of acyl-
phosphopantetheines and 3’,5’-ADP[27–29]
.
Recently, the
Scheme 5. Synthesis of a small array from mixture of diazonium
salt precursors. a LC-MS conversion rates.
upregulation of NUDT7 has been implicated in high risk of
inflammatory bowel disease, colorectal cancer and pantothenate
kinase-associated neurodegeneration (PKAN)[30][31]
.
To test the limits of this chemistry, i.e. scenario C in Scheme 1,
we attempted out of control reactions on a different scaffold,
namely 2-phenylpyridine 4. This was partly driven by the fact that
scaffold 1 did not lead to any observed bis-arylations. Interestingly,
many literature C-H activations on 4 are carried out on methylated
phenylpyridines, presumably to limit reactivity to a single
All arrays above were submitted for X-ray analysis; of note, only
3f was detected from the small array shown with 3a and 3c
(Scheme 5).[32] Individually purified, compounds 3a, 3c, 3d and
3f were found to crystallise in NUDT7 (Figure 2) involving
predominantly van der Waals interactions.
arylation[17,18]
.
3
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Figure 2. Crystal structures of NUDT7 in complex with compounds 3a, 3c, 3d and 3f. (a) Cartoon representation of ligand-free
NUDT7 with the NUDIX box coloured in cyan. The compound binding region is highlighted by with a red square. (b-e) Magnified views
of the bound compounds: (b) compound 3a (PDB iD 5QGM); (c) compound 3c (PDB ID 5QHC); (d) compound 3d (PDB ID 5QHB); (e)
compound 3f (PDB ID 5QHE).
An overlay of independent X-ray co-crystals of 3a and an
independent carbamate fragment NU181 showed their proximity
Thereafter, we attempted to merge the two fragments with the aim
of improving activity as well as to combine covalent binding due
to the presence of a proximal Cys residue (C73) in the protein.[33]
Demethylation of 3a was achieved using boron tribromide to
afford 3k, which, upon attempted reaction with an isocyanate, led
to an insoluble mixture.
in the binding pocket and
opportunity (Figure 3).
a potential fragment merging
Scheme 7. Demethylation of 3a.
Figure 3. Overlay of NUDT7 in complex with compound 3a
(PDB ID 5QGM) and in complex with NU181 (PDB ID 5QH1).
The protein structure of 5QH1 is omitted for clarity.
Next, the 4-nitrobiaryl pyrrolidinone compound 3e was reduced to
aniline 3l using tin(II) chloride dihydrate and was further
functionalized (Scheme 8) to afford the maleimide 3m and the
amides 3n and 3o respectively. As with the desired carbamate
4
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synthesis (Scheme 7), the attempted synthesis of a urea product
was hampered by the formation of an inseparable mixture of
insoluble products.
General Information
All commercially purchased materials and solvents were used
without further purification unless specified otherwise. NMR
spectra were recorded on a Varian VNMRS 500 (1H 500 MHz, 13
C
126 MHz) spectrometer and prepared in deuterated solvents such
as CDCl3 and DMSO-d6. 1H and 13C chemical shifts were
recorded in parts per million (ppm). Multiplicity of 1H-NMR peaks
are indicated by s – singlet, d – doublet, dd – doublets of doublets,
t – triplet, pt – pseudo triplet, q – quartet, m – multiplet and
coupling
constants
are
given
in
Hertz
(Hz). Electronspray ionisation – high resolution mass spectra
(ESI-HRMS) were obtained using a Bruker Daltonics Apex III
where Apollo ESI was used as the ESI source. All analyses were
conducted by Dr A. K. Abdul-Sada. The molecular ion peaks [M]+
were recorded in mass to charge (m/z) ratio. LC-MS spectra were
acquired using Shimadzu LC-MS 2020, on a Gemini 5 m C18
110 Å. column. All X-ray analyses were performed at the UK
National Crystallography Services, Southampton. Purifications
were performed by flash chromatography on silica gel columns or
C18 columns using a Combi flash RF 75 PSI, ISCO unit.
Scheme 8. Functionalization of 1-(4’-aminobiphenyl-2-
yl)pyrrolidin-2-one, 3l. a) SnCl2.2H2O, EtOAc, 70oC, o/n; b)
chloroacetyl chloride, Et3N, CH2Cl2, o/n; c) chlorobenzoyl
chloride, Et3N, CH2Cl2, o/n; d) 3-chlorophenyl isocyanate, Et3N,
CH2Cl2, o/n; e) i. maleic anhydride, CHCl3, 2h ii. Acetic anhydride,
sodium acetate, 2h, reflux.
1-(4’-Fluorobiphenyl-2-yl)pyrrolidin-2-one (3f); 1-(4’-
Methoxybiphenyl-2-yl)pyrrolidin-2-one (3a) “Standard method.”
1-Phenyl-2-pyrrolidinone
(0.065
g,
0.40
mmol),
4-
fluorobenzenediazonium tetrafluoroborate (0.35 g, 1.67 mmol),
palladium (II) acetate (0.009 g, 0.04 mmol) and Ru(bpy)3Cl2.6H2O
(0.007 g, 0.01 mmol) were suspended in degassed, anhydrous
methanol (4 mL). Two fluorescent light bulbs (26 W) were placed
on either side of the reaction vessel and the reaction mixture was
heated at reflux for 4 hours under inert atmosphere. The reaction
mixture was allowed to cool to ambient temperature, diluted with
ethyl acetate (50 mL) and washed with water (20 mL) and
aqueous sodium sulphite (10%, 35 mL x 2). The combined
aqueous layers were extracted with ethyl acetate (50 mL) and
thereafter the combined organic layer was washed with brine (50
mL), dried (MgSO4) and concentrated under reduced pressure.
The resulting crude material was purified by reversed phase
chromatography (water/acetonitrile with 0.1% formic acid, 5 min
at 0%, 30%-90%). The reaction generated two products, 3f was
obtained as a viscous oil (0.062 g, 61%) and 3a was obtained also
as a viscous oil (0.015 g, 14%). The spectral data were concurrent
with those reported.16
Unfortunately, none of these compounds described, including 3n
- 3o, above displayed any appreciable binding in a SPR assay
towards NUDT7 or any binding in Xray protein crystallographic
analyses.
Conclusion
This proof of principle study has shown that it is indeed possible
to get “more bang for your buck” by allowing C-H activations to
lose a certain degree of control. By creating small arrays for
immediate deployment in biological studies, purification
bottlenecks are reduced and direct X-ray analysis vs new protein
targets of interest are indeed possible. This study is, nevertheless
limited to a narrow range of chemically-similar directing group-
containing substrates, a few alcohols as nucleophiles and and
also relies on an x-ray screening of impure mixtures since not all
techniques are that tolerant. However, it may highlight the need
to check for competing “nuisance effect” reactions when using
fluorobenzene diazonium salts in alcoholic solutions. It
nevertheless gives us the confidence to try larger, more diverse
arrays in biological studies. Results of these endeavours are
ongoing and will be published in due course.
1-(4’-Methoxybiphenyl-2-yl)pyrrolidin-2-one (3a)
3a was synthesised on a bigger scale by combining 1-phenyl-2-
pyrrolidinone (0.50 g, 3.1 mmol), 4-methoxybenzenediazonium
tetrafluoroborate (2.75 g, 12.4 mmol), palladium (II) acetate
Experimental Section
5
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3
(0.069 g, 0.31 mmol) and Ru(bpy)3Cl2.6H2O (0.58 g, 0.078 mmol)
were suspended in degassed, anhydrous methanol (30 mL). Two
fluorescent light bulbs (26 W) were placed on either side of the
reaction vessel and the reaction mixture was heated at reflux for
4 hours under inert atmosphere. The reaction mixture was
allowed to cool to ambient temperature, diluted with ethyl acetate
(50 mL) and washed with water (20 mL) and aqueous sodium
sulphite (10%, 35 mL x 2). The combined aqueous layers were
extracted with ethyl acetate (50 mL) and thereafter the combined
organic layer was washed with brine (50 mL), dried (MgSO4) and
concentrated under reduced pressure. The resulting crude
material was purified by reversed phase chromatography
(water/acetonitrile with 0.1% formic acid, 5 min at 0%, 30%-90%).
Product 3a was obtained as a viscous oil (0.64 g, 77%).
COCH2CH2CH2N, 2H), 2.64 (t, JHH = 8.0 Hz, COCH2CH2CH2N
1H), 2.44 (t, 3JHH = 8.0 Hz, COCH2CH2CH2N x 4, 8H), 2.23 – 2.16
(m, COCH2CH2CH2N, 1H), 1.90 (q, 3JHH
=
7.5 Hz,
COCH2CH2CH2N, 2H), 1.37 (d, 3JHH = 6.0 Hz, O-CHCH3CH3, 6H).
HRMS-ESI (m/z) calculated for C19H21NO2 [+H] +: 296.1650,
found: 296.1647. LCMS ratio (UV) = 3h 18%, tR 12.37 min, 3f,
75%, tR 12.29 min.
1-(2’-Fluorobiphenyl-2-yl)pyrrolidin-2-one (3i); 1-(2’-
Methoxybiphenyl-2-yl)pyrrolidin-2-one (3j)
This reaction was performed on a 0.30 mmol scale by the general
procedure but with 2-fluorobenzenediazonium tetrafluoroborate
(0.25 g, 1.20 mmol). Starting material, 1-phenyl-2-pyrrolidinone
was recovered (0.006 g, 0.037 mmol) and two products were
generated; product 3i was obtained as a viscous oil (0.022 g,
32%) and 3j was obtained as a viscous oil (0.027 g, 39%).3i: 1H-
NMR (500 MHz) CDCl3: δ = 7.46 – 7.42 (m, ArH, 1H), 7.41 – 7.37
(m, ArH, 2H), 7.36 – 7.31 (m, ArH, 3H), 7.20 – 7.16 (m, ArH, 1H),
7.15 – 7.10 (m, ArH, 1H), 3.39 (t, 3JHH = 7.0 Hz, COCH2CH2CH2N,
1-(4’-Ethoxybiphenyl-2-yl)pyrrolidin-2-one (3g)
The standard method was used except that ethanol (5 mL) was
used as the solvent instead of methanol. Starting material, 1-
phenyl-2-pyrrolidinone (0.007 g, 0.043 mmol) was recovered and
two products were generated, product 3f was obtained as an oil
(0.038 g, 42%) and product 3g was obtained also as an oil (0.028
g, 28%). 1H-NMR (500 MHz) CDCl3: δ = 7.40 – 7.34 (m, ArH, 3H),
2H), 2.35 (t, 3JHH = 8.0 Hz, COCH2CH2CH2N, 2H), 1.91 (p, 3JHH
=
7.5 Hz, COCH2CH2CH2N, 2H). 13C-NMR (126 MHz) CDCl3: δ =
174.8 (C=O), 165.4 (d, 1JFC = 246.5 Hz, ArC), 137.8 (ArC), 133.5
(ArC), 131.6 (ArC), 131.5 (ArC), 131.4 (ArC), 129.6 (d, 3JFC = 8.0
Hz, ArC), 129.1 (ArC), 127.6 (d, 3JFC = 8.5 Hz, ArC), 126.7 (d, 2JFC
3
7.33 – 7.28 (m, ArH, 3H), 6.93 (d, JHH = 8.5 Hz, ArH, 2H), 4.08
3
3
(q, JHH = 7.0 Hz, O-CH2CH3, 2H), 3.23 (t, JHH = 7.0 Hz,
3
4
2
COCH2CH2CH2N, 2H), 2.44 (t, JHH = 8.0 Hz, COCH2CH2CH2N,
= 16.0 Hz, ArC), 124.1 (d, JFC = 3.5 Hz, ArC), 115.4 (d, JFC =
2H), 1.89 (p, 3JHH = 7.5 Hz, COCH2CH2CH2N, 2H), 1.45 (t, 3JHH
=
22.5 Hz, ArC), 50.2 (COCH2CH2CH2N), 31.3 (COCH2CH2CH2N),
19.1 (COCH2CH2CH2N). HRMS-ESI (m/z) calculated for
C16H14FNO [+Na]+: 278.0952, found: 278.0952. LCMS purity (UV)
= 96 %, tR 12.30 min. 3j: 1H-NMR (500 MHz) CDCl3: δ = 7.42 –
7.0 Hz, O-CH2CH3, 3H). 13C-NMR (126 MHz) CDCl3: δ = 175.6
(C=O), 158.6 (ArC), 139.4 (ArC), 136.4 (ArC), 131.4 (ArC), 130.9
(ArC), 129.5 (2 x ArC), 128.4 (ArC), 128.1 (ArC), 127.9 (ArC),
114.4 (2x ArC), 63.5 (O-CH2CH3), 50.1 (COCH2CH2CH2N), 31.2
(COCH2CH2CH2N), 19.0 (COCH2CH2CH2N), 14.8 (O-CH2CH3).
HRMS-ESI (m/z) calculated for C18H19NO2 [+H] +: 282.1489,
found: 282.1487. LCMS purity (UV) = 97 %, tR 11.85 min.
3
7.37 (m, ArH, 1H), 7.37 – 7.31 (m, ArH, 4H), 7.22 (d, JHH = 7.5
3
Hz, ArH, 1H), 7.00 (d, JHH = 7.5 Hz, ArH, 1H), 6.98 – 6.94 (m,
3
ArH, 1H), 3.76 (s, O-CH3, 3H), 3.26 (t, JHH = 7.0 Hz,
COCH2CH2CH2CN, 2H), 2.34 (t,3JHH = 8.0 Hz, COCH2CH2CH2N,
3
2H), 1.82 (p, JHH = 7.5 Hz, COCH2CH2CH2CN, 2H). 13C-NMR
(126 MHz) CDCl3: δ = 174.7 (C=O), 156.4 (ArC), 137.3 (ArC),
136.0 (ArC), 131.8 (ArC), 130.9 (ArC), 129.1 (ArC), 128.3 (ArC),
128.0 (ArC), 127.8 (ArC), 127.2 (ArC), 120.6 (ArC), 110.7 (ArC),
55.5 (O-CH3), 49.9 (COCH2CH2CH2N), 31.3 (COCH2CH2CH2N),
19.2 (COCH2CH2CH2N). HRMS-ESI (m/z) calculated for
C17H17NO2 [+Na] +: 290.1151, found: 290.1151. LCMS purity (UV)
= 94 %, tR 11.65 min.
1-(4’-Isopropoxybiphenyl-2-yl)pyrrolidin-2-one (3h)
The usual method was used but 2-propanol (5 mL) was used as
the solvent instead of methanol. Starting material, 1-phenyl-2-
pyrrolidinone (0.027 g, 0.17 mmol) was recovered and two
products were generated, product 3f was obtained as a white
solid (0.019 g, 32%) and a mixture of 3f and 3h was obtained an
oil (0.0059 g, 9%) in 1:4 ratio as determined by 1H-NMR and LC-
MS.
1-(4’-Trifluoromethylbiphenyl-2-yl)pyrrolidin-2-one (3b)
The general method was used on a 0.3 mmol scale with 4-
trifluoromethylbenzene diazonium tetrafluoroborate (1.2 mmol,
0.31 g). The spectral data of 3b – 3e were concurrent with those
reported.[16]
3f/3hmixture: 1H-NMR (500 MHz) CDCl3: δ = 7.62 – 7.52 (m, ArH,
1H), 7.42 – 7.35 (m, ArH, 4H), 7.32 – 7.26 (m, ArH, 3H), 6.91 (d,
3JHH = 8.5 Hz, ArH, 2H), 4.62 – 4.55 (m, O-CHCH3CH3, 1H), 3.92
3
3
(t, JHH = 7.0 Hz, COCH2CH2CH2N, 1H), 3.22 (t, JHH = 7.0 Hz,
6
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10.1002/cmdc.202000543
ChemMedChem
FULL PAPER
The combined organic layers were dried (MgSO4) and
concentrated under reduced pressure to afford the product as a
white solid (0.62 g, 88%). 1H-NMR (500 MHz) DMSO-D6: δ = 7.34
– 7.24 (m, ArH, 3H), 7.20 (d, 3JHH = 7.5 Hz, ArH, 1H), 6.96 (d, 3JHH
= 7.5 Hz, ArH, 2H), 6.61 – 6.52 (m, ArH, 2H), 3.18 (t, 3JHH = 7.0
1-(3’-Trifluoromethylbiphenyl-2-yl)pyrrolidin-2-one (3c)
The general method was used on a 0.3 mmol scale with 3-
trifluoromethylbenzene diazonium tetrafluoroborate (1.2 mmol,
0.31 g). The title product was obtained as an oil (0.082 g, 90%).
Hz, COCH2CH2CH2N, 2H), 2.25 (t, 3JHH
=
8.0 Hz,
COCH2CH2CH2N, 2H), 1.82 (p, 3JHH = 7.5 Hz, COCH2CH2CH2N,
2H). 13C-NMR (126 MHz) CDCl3: δ = 175.7 (C=O), 145.9 (ArC),
139.6 (ArC), 136.2 (ArC), 130.8 (ArC), 130.8 (ArC), 129.3 (ArC x
2), 129.2(ArC), 128.4 (ArC), 128.0 (ArC), 127.8 (ArC), 115.0 (ArC
x 2), 49.9 (COCH2CH2CH2N), 31.1 (COCH2CH2CH2N), 19.0
(COCH2CH2CH2N). HRMS-ESI (m/z) calculated for C16H16N2O
[+H] +: 253.1335, found: 253.1328. LCMS purity (UV) = 95%, tR
13.38 min.
1-(4’-Methylbiphenyl-2-yl)pyrrolidin-2-one (3d)
The general method was used on a 0.3 mmol scale with 4-
methylbenzene diazonium tetrafluoroborate (1.21 mmol, 0.25 g).
The title product was obtained as an oil (0.051 g, 67%).
1-(4’-Nitrobiphenyl-2-yl)pyrrolidin-2-one (3e)
The general method was used on a 3.5 mmol scale with 4-
nitrobenzene diazonium tetrafluoroborate (11 mmol, 2.61 g). The
title product was obtained as an oil (0.86 g, 87%).
1-[2'-(2-Oxopyrrolidin-1-yl)biphenyl-4-yl]1H-pyrrole-2,5-dione
(3m)
1-(4’-Hydroxybiphenyl-2-yl)pyrrolidin-2-one (3k)
1-(4’-aminobiphenyl-2-yl)pyrrolidin-2-one (0.20 mmol, 0.050 g),
maleic anhydride (0.24 mmol, 0.024 g) were dissolved in CHCl3
(3 mL) and stirred for 2 h. The reaction mixture was concentrated
under reduced pressure. To a stirred solution of the crude maleic
acid in acetic anhydride (19.5 mmol, 2.0 g) was added sodium
acetate (0.40 mmol, 0.033 g) and heated at reflux for 2 h. After
cooling to ambient temperature, the reaction was quenched with
water (20 mL) and extracted with ethyl acetate (20 mL x 2). The
combined organic layers were dried (Na2SO4) and concentrated
under reduced pressure. The crude mixture was purified by
column chromatography (hexane/ethyl acetate over 0% - 10%
gradient) to afford the title compound as a yellow solid (0.036g,
54%). 1H-NMR (500 MHz) CDCl3: δ = 7.48 (d, 3JHH = 8.5 Hz, ArH,
2H), 7.44 – 7.41 (m, ArH, 2H), 7.40 – 7.38 (m, ArH, 3H), 7.35 –
7.31 (m, ArH, 1H), 6.88 (s, COCHCHCO, 2H), 3.25 (t, 3JHH = 7.0
To a stirred solution of 1-(4’-methoxybiphenyl-2-yl)pyrrolidin-2-
one (1.6 mmol, 0.42 g) in DCM (10mL) was added 1M BBr3 (10
mL) in DCM dropwise at 0oC under inert atmosphere. The
reaction mixture was allowed to warm to ambient temperature and
stirred for additional 16 h. The resulting mixture was carefully
quenched with saturated sodium bicarbonate (50 mL) and the
mixture was extracted with DCM (40mL x 2). The combined
organic layer was dried (MgSO4) and concentrated under reduced
pressure. The resulting crude product was triturated with diethyl
ether overnight. The precipitate was collected by filtration to afford
1
a grey solid (0.24 g, 58%). H-NMR (500 MHz) DMSO-D6: δ =
7.36 – 7.29 (m, ArH, 3H), 7.26 – 7.22 (m, ArH, 1H), 7.10 (d, 3JHH
3
= 8.7 Hz, 2H), 6.81 – 6.76 (m, ArH, 2H), 3.19 (t, JHH = 7.0 Hz,
3
COCH2CH2CH2N, 2H), 2.23 (t, JHH = 8.0 Hz, COCH2CH2CH2N,
2H), 1.81 (p, 3JHH = 7.5 Hz, COCH2CH2CH2N, 2H).13C-NMR (126
MHz) DMSO-D6: δ = 174.7 (C=O), 157.3 (ArC), 137.3 (ArC), 139.5
(ArC), 136.9 (ArC), 130.9 (ArC), 129.8 (ArC), 129.5 (ArC x 2),
129.0 (ArC), 128.1 (ArC), 128.0 (ArC), 115.7 (ArC x 2), 49.9
Hz, COCH2CH2CH2N, 2H), 2.45 (t, 3JHH
=
8.0 Hz,
COCH2CH2CH2N, 2H), 1.91 (p, 3JHH = 7.5 Hz, COCH2CH2CH2N,
2H). 13C-NMR (126 MHz) CDCl3: δ = 175.8 (CH2NC=O), 169.4
(CHCONCOCH), 138.7 (ArC), 136.4 (ArC), 134.3 (ArC x 2), 130.8
(ArC), 130.7 (ArC), 129.1 (ArC x 2), 129.0 (ArC), 128.5 (ArC),
128.2 (ArC), 125.8 (ArC x 2), 50.3 (COCH2CH2CH2N), 31.2
(COCH2CH2CH2N), 19.0 (COCH2CH2CH2N). HRMS-ESI (m/z)
(COCH2CH2CH2N),
31.1
(COCH2CH2CH2N),
19.0
(COCH2CH2CH2N). HRMS-ESI (m/z) calculated for C16H15NO2
[+H] +: 267.1259, found: 267.1262 LCMS purity (UV) = 99%, tR
18.51 min.
+
calculated for C20H16N2O3 [+H] : 333.1234, found: 333.1225.
LCMS purity (UV) = 97 %, tR 18.77 min.
1-(4’-Aminobiphenyl-2-yl)pyrrolidin-2-one (3l)
To a stirred solution of 1-(4’-nitrobiphenyl-2-yl)pyrrolidin-2-one
(2.8 mmol, 0.8 g) in ethyl acetate (20mL) was added tin(ll) chloride
2-Chloro-N-[2'-(2-oxopyrrolidin-1-yl)biphenyl-4-yl]acetamide
(3n)
0
dihydrate (14 mmol, 3.2 g) and the reaction was stirred at 70 C
To a stirred solution of 1-(4’-aminobiphenyl-2-yl)pyrrolidin-2-one
(0.38 mmol, 0.095 g) and triethylamine (0.38 mmol, 0.05 mL) in
anhydrous DCM (8 mL) was added chloroacetyl chloride (0.46
overnight. The resulting mixture was neutralised with saturated
sodium bicarbonate and extracted with ethyl acetate (40 mL x 2).
7
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10.1002/cmdc.202000543
ChemMedChem
FULL PAPER
mmol, 0.052 g) dropwise at 0oC. The reaction mixture was
allowed to warm to ambient temperature and stirred overnight.
The reaction mixture was concentrated under reduced pressure.
The residue was washed with washed with water (10 mL x 3) and
the resulting precipitate was collected by filtration to afford the
tetrafluoroborate (104 mg, 0.40 mmol). The products 3a, 3c and
3f were obtained as a mixture with the ratio of 15%, 22% and 40%
respectively (determined by LC-MS).
Reaction with 2-Phenylpyridine
1
final product as a while solid (0.093g, 75%). H-NMR (500 MHz)
2-Phenylpyridine (0.078 g, 0.50 mmol), 4-fluorodiazonium
tetrafluoroborate (0.42 g, 2.0 mmol), palladium (II) acetate (0.011
g, 0.05 mmol) and Ru(bpy)3Cl2.6H2O (0.009 g, 0.013 mmol) were
suspended in degassed, anhydrous methanol (4 mL). Two
fluorescent light bulbs (26 W) were placed on either side of the
reaction vessel and the mixture was heated at reflux for 4 hours.
The reaction mixture was allowed to cool to ambient temperature,
diluted with ethyl acetate (40 mL) and washed with water (20 mL)
and aqueous sodium sulphite (10%, 35 mL x 2). The combined
aqueous layers were extracted with ethyl acetate (50 mL) and
thereafter the combined organic layers were washed with brine
(50 mL), dried (MgSO4) and concentrated under reduced
pressure. The resulting crude material was purified by reversed
phase chromatography (water/acetonitrile with 0.1% formic acid,
CDCl3: δ = 8.55 (s, NH, 1H), 7.59 (d, 3JHH = 8.1 Hz, ArH, 2H), 7.41
3
– 7.33 (m, ArH, 5H), 7.30 (d, JHH = 7.2 Hz, ArH, 1H), 4.17 (s,
COCH2Cl, 2H), 3.27 (t, 3JHH = 7.0 Hz, COCH2CH2CH2N, 2H), 2.42
3
3
(t, JHH = 8.0 Hz, COCH2CH2CH2N, 2H), 1.90 (p, JHH = 7.5 Hz,
COCH2CH2CH2N, 2H). 13C-NMR (126 MHz) CDCl3: δ = 175.7
(CH2NC=O), 164.0 (NHC=O), 138.9 (ArC), 136.5 (ArC), 136.2
(ArC), 135.8 (ArC), 130.8 (ArC), 128.7 (ArC x 2), 128.3 (ArC),
128.2 (ArC), 119.9 (ArC x 2), 50.3 (COCH2CH2CH2N), 43.0
(COCH2Cl), 31.2 (COCH2CH2CH2N), 19.0 (COCH2CH2CH2N).
HRMS-ESI (m/z) calculated for C18H17ClN2O2 [+H] +: 329.1051,
found: 329.1053. LCMS purity (UV) = 97%, tR 19.77 min.
2-Chloro-N-[2'-(2-oxopyrrolidin-1-yl)biphenyl-4-yl]acetamide (3o)
To a stirred solution of 1-(4’-aminobiphenyl-2-yl)pyrrolidin-2-one
(0.39 mmol, 0.10 g) and triethylamine ( 1.98 mmol, 0.20 g) in
anhydrous DCM (10 mL) was added 3-chlorobenzoyl chloride
(1.2 mmol, 0.21 g) and the reaction mixture was stirred overnight.
The reaction mixture was concentrated under reduced pressure
and the crude product was purified by column chromatography
(DCM/methanol over 0% - 10% gradient) to afford the title product
5
min at 0%, 30%-90%). Starting material, 1-phenyl-2-
pyrrolidinone was recovered (0.008 g, 0.052 mmol) and five
products were generated from this reaction:
2-(4’-Fluorobiphenyl-2-yl)pyridine (5a)
The title compound was obtained as a viscous oil (0.018 g, 16%).
The spectral data were concurrent with those reported.[34]
2-(4’-Methoxybiphenyl-2-yl)pyridine (5b)
1
as a white amorphous solid (0.11 g, 72%). H-NMR (500 MHz)
The title compound was obtained as a green/yellow oil (0.022 g,
19%). The spectral data were concurrent with those reported.[34]
CDCl3: δ = 8.72 (s, NH, 1H), 7.95 – 7.90 (m, ArH, 1H), 7.79 (d,
3JHH = 7.5 Hz, ArH, 1H), 7.72 (d, 3JHH = 8.5 Hz, ArH, 2H), 7.50 (dd,
2-(4,4’-Fluorobiphenyl-2,6-yl)pyridine (5c)
3,4
J
= 8.0, 2.0 Hz, ArH, 1H), 7.40 – 7.34 (m, ArH, 6H), 7.32 –
7.26 (m, 1H), 3.31 (t, 3JHH = 7.0 Hz, ArH, COCH2CH2CH2N, 2H),
HH
The title product was obtained as a viscous oil (0.012 g, 8%). The
spectral data were concurrent with those reported. [34]
3
3
2.38 (t, JHH = 8.0 Hz, COCH2CH2CH2N, 2H), 1.91 (p, JHH = 7.5
Hz, COCH2CH2CH2N, 2H). 13C-NMR (126 MHz) CDCl3: δ = 175.8
(CH2NC=O), 164.6 (NHC=O), 139.1 (ArC), 137.8 (ArC), 136.6
(ArC), 136.1 (ArC), 135.1 (ArC), 134.7 (ArC), 131.8 (ArC), 130.9
(ArC), 129.9 (ArC), 128.9 (ArC x 2), 128.5 (ArC), 127.6 (ArC),
125.5 (ArC x 2), 50.5 (COCH2CH2CH2N), 31.2 (COCH2CH2CH2N),
18.9 (COCH2CH2CH2N). HRMS-ESI (m/z) calculated for
2-(4,4’-Fluoromethoxybiphenyl-2,6-yl)pyridine (5d)
The title compound was obtained as a viscous oil (0.024 g,
15%).1H-NMR (500 MHz) CDCl3: δ = 8.37 – 8.32 (m, ArH, 1H),
7.49 (pt, 3JHH = 7.5 Hz, ArH, 1H), 7.45 – 7.42 (m, ArH, 1H), 7.38
(d, 3JHH = 7.5 Hz, ArH, 1H), 7.35 – 7.30 (m, ArH, 1H), 7.07 – 7.03
3
(m, ArH, 2H), 7.01 (d, JHH = 8.5 Hz, ArH, 2H), 6.95 – 6.92 (m,
3
ArH, 1H), 6.87 – 6.81 (m, ArH, 3H), 6.69 (d, ArH, JHH = 8.5 Hz,
+
C23H19ClN2O2 [+H] : 391.1208, found: 391.1199. LCMS purity
2H), 3.75 (s, O-CH3, 3H). 13C-NMR (126 MHz) CDCl3: δ = 161.5
(d, 1JFC = 246.0 Hz, ArC), 158.9 (ArC), 158.2 (ArC), 148.4 (ArC),
141.5 (ArC), 140.8 (ArC), 137.5 (ArC), 135.2 (ArC), 133.7 (ArC),
(UV) = 91 %, tR 18.38 min.
One-pot Reaction Towards 3a, 3c, and 3f
3
131.1 (d, JFC = 7.8 Hz; 2 x ArC), 130.7 (2 x ArC), 128.6 (ArC),
This reaction was performed following the standard procedure by
using 1-phenyl-2-pyrrolidinone (0.048 g, 0.3 mmol) and a mixture
of 4-fluorobenzene diazonium tetrafluoroborate (84 mg, 0.40
mmol), 4-methoxybenzene diazonium tetrafluoroborate (89 mg,
129.1 (ArC), 128.2 (ArC), 126.9 (ArC), 126.6 (ArC), 121.0 (ArC),
114.5 (d, 2JFC = 21.1 Hz; 2 x ArC), 113.2 (2 x ArC), 55.1 (O-CH3).
+
HRMS-ESI (m/z) calculated for C24H18FNO [+H] : 356.1445,
found: 356.1444. LCMS purity (UV) = 93 %, tR 16.35 min.
0.40
mmol)
and
3-trifluoromethylbenzene
diazonium
8
This article is protected by copyright. All rights reserved.

10.1002/cmdc.202000543
ChemMedChem
FULL PAPER
2-(4,4’-Methoxybiphenyl-2,6-yl)pyridine (5e)
[1]
[2]
J. J. Li, Ed. , C-H Bond Activation in Organic Synthesis,
CRC Press, 2017.
The title compound was obtained as a green/yellow oil (0.016 g,
10%). The spectral data were concurrent with those reported.[34]
D. A. DiRocco, K. Dykstra, S. Krska, P. Vachal, D. V.
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Crystallographic Methods
NUDT7 was expressed and purified as described previously[32,33]
NUDT7 was crystallised in sitting drops at 20 °C by mixing 100 nL
of 30 mg/mL protein in 10 mM Na-HEPES pH 7.5, 500 mM NaCl,
5% glycerol with 50 nL of reservoir solution containing 0.1 M
BisTris pH 5.5, 0.1 M ammonium acetate, and 6% (w/v) PEG
10000. NUDT7 crystals were soaked with a mixture containing
600 nL of 100 mM of the respective compound in DMSO with
1200 nL of reservoir solution. Crystals were incubated overnight
at room temperature and then harvested (without further
cryoprotection) and flash-cooled in liquid nitrogen.
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All X-ray diffraction data were collected on beamline I04-1 at the
Diamond Light Source. Diffraction data were automatically
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Acknowledgment. R.K.T. was funded by an EPSRC/AZ funded
PhD studentship (EP/M507568/1) with additional support from
AstraZeneca [14550001 (SME)] and Tocris Biosciences. EPSRC
(EP/P026990/1) (S.H.-H., J.S., F.v.D., P.B.) are acknowledged for
funding this research. The authors would like to thank Diamond
Light Source for beamtime (proposal lb18145), and the staff of
beamlines I04-1 and the XChem facility for assistance with crystal
testing and data collection. The SGC is a registered charity
(number 1097737) that receives funds from AbbVie, Bayer
Pharma AG, Boehringer Ingelheim, Canada Foundation for
Innovation, Eshelman Institute for Innovation, Genome Canada,
Innovative Medicines Initiative (EU/EFPIA)[ULTRA-DD grant no.
115766], Janssen, Merck KGaA Darmstadt Germany, MSD,
Novartis Pharma AG, Ontario Ministry of Economic Development
and Innovation, Pfizer, FAPDF, CAPES, CNPq, Sꢀo Paulo
Research Foundation-FAPESP, Takeda, and Wellcome
[106169/ZZ14/Z].
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10.1002/cmdc.202000543
ChemMedChem
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C-H activation reactions coupled with “nuisance effect” SNAr
processes have been designed to “lose control” in order to make
discrete libraries for immediate testing, by x-ray, versus targets
of current interest. Although somewhat limited, these reactions
may encourage others to try to reduce synthetic/work-up
bottlenecks and use crystallography as a more routine analytical
format for drug discovery.
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