Nucleophilic displacement reactions of 5′-derivatised nucleosides in a vibration ball mill

Article abstract of DOI:10.3762/bjoc.13.11

Vibration ball-milling in a zirconia-lined vessel afforded clean and quantitative nucleophilic displacement reactions between 4-methoxybenzylthiolate salts and nucleoside 5′-halides or 5′-tosylates in five to 60 minutes. Under these conditions, commonly-e

Full text of DOI:10.3762/bjoc.13.11

Nucleophilic displacement reactions of 5′-derivatised
nucleosides in a vibration ball mill
Olga Eguaogie1, Patrick F. Conlon1, Francesco Ravalico1, Jamie S. T. Sweet1,
Thomas B. Elder1, Louis P. Conway2, Marc E. Lennon1, David R. W. Hodgson2
and Joseph S. Vyle*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 87–92.
1School of Chemistry and Chemical Engineering, Queen’s University
Belfast, David Keir Building, Stranmillis Road, Belfast BT9 5AG, UK
and 2Durham University, Department of Chemistry, Lower Mountjoy,
Stockton Road, Durham DH1 3LE, UK
doi:10.3762/bjoc.13.11
Received: 22 August 2016
Accepted: 30 December 2016
Published: 13 January 2017
Email:
Joseph S. Vyle* - j.vyle@qub.ac.uk
Associate Editor: S. C. Zimmerman
* Corresponding author
© 2017 Eguaogie et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
ball mill; chalcogen; mechanochemistry; nucleophilic substitution;
nucleoside
Abstract
Vibration ball-milling in a zirconia-lined vessel afforded clean and quantitative nucleophilic displacement reactions between
4-methoxybenzylthiolate salts and nucleoside 5′-halides or 5′-tosylates in five to 60 minutes. Under these conditions, commonly-
encountered nucleoside cyclisation byproducts (especially of purine nucleosides) were not observed. Liquid-assisted grinding of the
same 5'-iodide and 5′-tosylate substrates with potassium selenocyanate in the presence of DMF produced the corresponding
5′-selenocyanates in variable yields over the course of between one and eleven hours thereby avoiding the preparation and use of
hygroscopic tetrabutylammonium salts.
Introduction
Nucleophilic displacement reactions of nucleoside derivatives pyrimidine nucleobases and (especially) the 5′-position of the
are well established owing to the accessibility of precursor sul- (deoxy)ribofuranoside are frequently observed during both acti-
fonate esters and halides [1]. Displacements with a diverse vation [7] and subsequent displacement reactions [8,9]. This
variety of both hard and soft nucleophiles have enabled the con- competition confounds the kind of systematic analysis de-
struction of natural products [2,3] and their analogues [4-6]. veloped recently by Hale and co-workers for sulfonate displace-
Typically, such reactions require the use of high-boiling, dipolar ment from furanosides [10] and convoluted optimisations of
aprotic solvents and anionic nucleophiles under anhydrous reaction conditions and nucleoside substrate (e.g., the leaving
conditions at elevated temperatures (up to 150 °C). Competing group [11] or nucleobase protection [12]) are therefore often re-
intramolecular cyclisation reactions between both purine and quired.
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Beilstein J. Org. Chem. 2017, 13, 87–92.
We anticipated that some of these issues could be ameliorated pletely avoided. We further demonstrate the application of
through mechanochemical mixing of reactants and substrates, liquid-assisted grinding to related displacements using potas-
with diverse solubility profiles, using minimal or no added sium selenocyanate.
liquid [13-15]. Recently, Jicsinszky et al. described using a
planetary ball mill to perform substitution reactions of 6I-O-(p- Results and Discussion
toluenesulfonyl)-β-cyclodextrin (Ts-β-CD) with azide, halide or We initially examined VBM-facilitated reactions of 5′-chloro-
thiolate nucleophiles and thereby avoided intramolecular cycli- 5′-deoxyadenosine (CldA, 1a) with 4-methoxybenzylthiol
sation (commonly found under solution-phase conditions) [16]. (MobSH) to generate the corresponding 5′-thioether (MobSdA,
2a) as a model system (Scheme 1). Despite the known reac-
Following Sikchi and Hultin’s original description of nucleo- tions of 1a with aryl and alkyl chalcogenate salts [6], there is
side derivatisation in a low-energy, planetary ball mill [17], only a single (patent) report of CldA substitution using the
commercial, higher energy vibration mills have been used to Mob-thiolate anion (requiring 12 hours at up to 55 °C to
facilitate established [18-21] and unprecedented [22] nucleo- achieve 68% yield) [25].
side transformations. Remarkably, SN2 ball-milling chemistry
on nucleoside substrates has not, to the authors’ knowledge, Optimisation of VBM conditions was performed over several
been demonstrated, despite reports of similar chemistry on phases using 25 mL vessels and 15 mm diameter balls (both
glycoside derivatives [16,23] and α-amino acid analogues [24]. with either steel or zirconia components in contact with the
reaction mixtures) operating at 30 Hz (Table 1). Divakar and
We describe here the efficient displacement of 5'-chloride, Reese described the efficient synthesis of 2′-S-Mob-2′-thio-
iodide or tosylate leaving groups from nucleosides by uridine under solvothermal conditions using large excesses of
4-methoxybenzylthiolate using vibration ball milling (VBM) both MobSH (3 equiv) and 1,1,3,3-tetramethylguanidine (TMG,
where competing intramolecular cyclisation reactions are com- 5 equiv) [26] and applying this reagent stoichiometry to the ball
Scheme 1: Model reactions of 5′-chloro-5′-deoxyadenosine (1a) with 4-methoxybenzylthiolate salts used to optimise VBM conditions.
Table 1: Optimisation of VBM conditions for the reaction of 5′-chloro-5′-deoxyadenosine (1a) with MobSH. All reactions were carried out at 30 Hz for
60 minutes (unless otherwise stated).a
Entry
Base (equiv)
Scale
Jar/Ball
Equiv of MobSH
Isolation methodb
Yield (%)c
[mmol]
1
2
3
4
5
6
7
8
9
10
TMG (5.0)
TMG (5.0)
TMG (5.0)
–
1.05
0.35–1.0
0.35
0.35
0.35
0.35
0.35
1.05
1.0
steel
steel
steel
steel
steel
steel
steel
ZrO2
ZrO2
ZrO2
3.0
2.5
1.5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
A
A
–
68
19–52d
(70)e
–
–
Et3N (5.0)
Na2CO3 (7.0)
NaOH (7.0)
TMG (5.0)
TMG (5.0)
TMG (5.0)
–
–
–
–
–
(100)e
66
A
B
C
87
1.0
77
aMob: 4-methoxybenzyl; TMG: 1,1,3,3-tetramethylguanidine; bA: crystallisation; B: chromatography; C: trituration (see Supporting Information File 1
for details). cIsolated. dComplete reaction required up to 105 minutes (for 1.0 mmol scale) in service-aged vessels. eEstimated conversion by TLC.
88

Beilstein J. Org. Chem. 2017, 13, 87–92.
mill reaction gave complete and clean conversion of CldA (1a) entry 8) despite the lower density of ZrO2 (6.06 g cm−3) com-
into MobSdA (2a) monitored by TLC within 1 h in a previ- pared with steel (7.74 g cm−3).
ously unused steel vessel (Table 1, entry 1).
Using zirconia components, reaction mixtures were viscous pale
The efficiency of chloride displacement from CldA (1a) was yellow-brown liquids which could be readily removed from the
compromised in the presence of fewer equivalents of thiol vessel by rinsing with methanol and water and subsequently
(Table 1, entries 2 and 3). Furthermore, in the absence of base purified by chromatography (Table 1, entry 9) or trituration
(Table 1, entry 4) or using different bases (Table 1, entries 5 (Table 1, entry 10).
and 6), no such reaction was observed and CldA remained
untransformed. In the presence of sodium hydroxide, an effi- Using these optimised conditions, we explored displacement
cient reaction was observed by TLC (Table 1, entry 7), how- reactions of a variety of 5′-tosyl- and 5′-iodo-nucleoside deriva-
ever, the intractability of the resultant reaction mixtures and tives and in all cases, we observed rapid, complete and clean
higher corrosion levels led to further studies being exclusively conversions, with very good to excellent isolated yields
restricted to TMG.
(Scheme 2).
During multiple iterations of the reaction using steel compo- 5′-Tosyladenosine (TsA, 1b) was transformed more efficiently
nents, highly variable rates and yields were found (Table 1, than the corresponding halonucleoside and no additional
entry 2). We correlated these yields, the degree of discoloura- handling was required during work-up of the thioether product
tion of the reaction mixtures and their levels of contamination (2a). Likewise, 5′-tosylthymidine (TsT, 1c) was rapidly con-
by metallic, particulate matter with the service-age of the steel sumed. Only in the case of IdT (1d) were any (minor) impuri-
vessel. These observations appear consistent with previously ties observed when all reagents were added to the vessel prior to
described chemical (leaching) and physical (pitting and exfolia- commencing VBM. These impurities were avoided by pre-
tion) corrosion of steel vessels in the presence of sulfur-contain- milling the substrate with MobSH prior to addition of the base
ing materials [27] although Lamaty and co-workers described (during the initial milling, no chemical reaction was observed).
contrary results [28]. Specifically, in this latter case, a compre- In addition, the work-up developed for MobSdA (2a) had to be
hensive survey of metal concentrations within reaction mix- modified in response to the aqueous solubility of nucleosides
tures from both planetary and vibration ball mills was per- containing lactam groups which are deprotonated under basic
formed and showed lower contamination in the service-aged conditions, i.e., MobSdT (2b) and MobSdG (2c) [29,30]. In
steel vessel although it should be noted that the steel vessels these cases, reaction mixtures were removed from the vessels
were from different sources. However, in agreement with this using water and ethyl acetate. Careful acidification of the
work, we, too were able to remove metallic impurities by ex- aqueous phase enabled MobSdT (2b) to be extracted into ethyl
tracting the reaction mixture into an organic solvent, filtering acetate prior to trituration. Following the same procedure, crys-
the suspension (if solid particulates were present) and crys- tallisation of MobSdG (2c) was induced during acidification.
tallising the residue (isolation procedure A). We thus moved to The minimum time required for complete consumption of TsT
using zirconia components, where no solid impurities were ob- (1c) was found to be five minutes and the isolation procedure
served, and the yield of MobSdA (2a) was comparable (Table 1, could be further expedited (at some cost to the recovery of 2b)
Scheme 2: Thiolate displacement reactions of 5′-derivatised nucleosides using VBM.
89

Beilstein J. Org. Chem. 2017, 13, 87–92.
by removing the reaction mixture from the jar in acetonitrile, with excess KSeCN (3 equiv). As found previously, the addi-
precipitation from water under acid conditions and triturating tion of catalytic TBAI (vide supra) did not alter this outcome
the solids (see Supporting Information File 1 for details). We nor did the use of a larger excess (5 equiv) of selenocyanate.
note that only 2b has been described previously in peer- The addition of DMF to the reaction of TsA (1b) with KSeCN
reviewed literature although without details of its preparation suppressed the formation of a polar side-product (putative
[31].
N3,5′-cyclonucleoside – also observed as the sole product using
LAG in the absence of selenocyanate) sufficiently for the corre-
Following reports of halogen exchange reactions using both sponding 5′-selenocyanate (3a) to be isolated in poor yield after
stoichiometric [16,32,33] and catalytic [24] halide ions using LAG for 11 hours. Suspending the reaction mixture in metha-
ball milling, we investigated the capacity of iodide to accelerate nol and quenching excess selenocyanate with benzyl bromide
the rate of mechanochemically-activated displacement from enabled pure 3a to be isolated following extensive purification.
CldA (1a). However, we observed no change in the reaction
rate following addition of NaI (500, 50 or 5 mol %) or TBAI In contrast, LAG of TsT (1c) with DMF for 9 h achieved 90%
(50 or 5 mol %).
conversion (by TLC) to a single product. Likewise, efficient
(ca. 95%) conversions were observed with IdT (1d) and IdG
Following the successful application of VBM using a thiolate (1e) although maximal conversion of IdG was achieved within
nucleophile, we were prompted to explore related reactions of one hour in the absence of added liquid (the reaction was inhib-
alkylselenols. However, the sensitivity of such compounds ited in the presence of DMF). During these studies, LAG of
towards aerial oxidation meant that, in our hands, an efficient both purine and pyrimidine substrates in the presence of ethyl
and reproducible reaction of the nucleoside substrates with acetate or hexane was attempted but in all cases the levels of
MobSeH was not achieved in a ball mill. We therefore moved transformation were reduced compared with DMF. Extraction
to investigate displacements using potassium selenocyanate of NCSedT (3b) from the reaction vessels in methanol and
which is commercially available, less sensitive to oxidation, and quenching excess inorganic selenocyanate with benzyl bromide
is known to react selectively at selenium in reactions with alkyl enabled the product to be purified by silica gel column chroma-
halides [34]. We confirmed the efficiency of such VBM- tography. In the absence of the quench step, contamination of
promoted chemistry using benzyl bromide and MobCl as model the product by varying levels of inorganic selenocyanate was
substrates in the presence of KSeCN (1.1 equiv). Both reac- found.
tions proceeded cleanly to completion within 60 minutes at
30 Hz and BnSeCN and MobSeCN were isolated in yields of Although the reaction mixture derived from IdG (1e) could be
97% and 99%, respectively (see Supporting Information File 1). extracted directly as a solid or into DMSO-d6 from which mass
We observed more variable outcomes when using KSeCN on spectrometry, 77Se and 1H NMR data consistent with the forma-
nucleoside substrates (Scheme 3).
tion of NCSedG (3c) in high yield was inferred, in our hands,
this product could not be readily purified. In particular, during
In contrast with the rapid and clean displacement reactions of trituration with solvents in which excess KSeCN was soluble
5′-adenosine derivatives in the presence of a thiolate nucleo- (e.g., acetone), a loss in the 77Se NMR signal associated with 3c
phile, we found CldA (1a) remained untransformed during (dry) (δSe 186.8) was observed concomitant with an enhancement in
VBM or liquid-assisted grinding (LAG) in the presence of DMF that of the putative corresponding diselenide (δSe 283.1).
Scheme 3: Selenocyanate displacement reactions of 5′-derivatised nucleosides using liquid-assisted grinding (LAG) or VBM.
90

Beilstein J. Org. Chem. 2017, 13, 87–92.
12.Jahn, W. Chem. Ber. 1965, 98, 1705–1708.
Belostotskii et al. have previously reported the synthesis of
5'-selenocyanate-nucleoside derivatives [35]; however, our ap-
proach offers the convenience of an 'off-the-shelf' reagent rather
than requiring the synthesis of a tetrabutylammonium (TBA)
salt. Furthermore, KSeCN does not suffer from the formation of
hydrates that frequently modulate the efficiency of TBA salts
[36,37] and the inconsistent reaction outcomes associated with
the hygroscopic nature of such salts is particularly poignant in
the light of the reported solvent-dependency also observed with
KSeCN under Finkelstein conditions [38]. Finally, our ap-
proach also offers the convenience of employing tosylate and
halide precursors rather than relying on the esoteric tresylate
leaving group system.
doi:10.1002/cber.19650980604
13.James, S. L.; Adams, C. J.; Bolm, C.; Braga, D.; Collier, P.; Friščić, T.;
Grepioni, F.; Harris, K. D. M.; Hyett, G.; Jones, W.; Krebs, A.; Mack, J.;
Maini, L.; Orpen, A. G.; Parkin, I. P.; Shearouse, W. C.; Steed, J. W.;
Waddell, D. C. Chem. Soc. Rev. 2012, 41, 413–447.
doi:10.1039/C1CS15171A
14.Wang, G.-W. Chem. Soc. Rev. 2013, 42, 7668–7700.
doi:10.1039/c3cs35526h
15.Tan, D.; Loots, L.; Friščić, T. Chem. Commun. 2016, 52, 7760–7781.
doi:10.1039/C6CC02015A
16.Jicsinszky, L.; Caporaso, M.; Tuza, K.; Martina, K.; Gaudino, E. C.;
Cravotto, G. ACS Sustainable Chem. Eng. 2016, 4, 919–929.
doi:10.1021/acssuschemeng.5b01006
17.Sikchi, S. A.; Hultin, P. G. J. Org. Chem. 2006, 71, 5888–5891.
doi:10.1021/jo060430t
18.Giri, N.; Bowen, C.; Vyle, J. S.; James, S. L. Green Chem. 2008, 10,
627–628. doi:10.1039/b801455h
Supporting Information
19.Patil, P. R.; Kartha, K. P. R. J. Carbohydr. Chem. 2008, 27, 279–293.
doi:10.1080/07328300802218713
Supporting Information File 1
Experimental part.
20.Ravalico, F.; James, S. L.; Vyle, J. S. Green Chem. 2011, 13,
1778–1783. doi:10.1039/c1gc15131b
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-11-S1.pdf]
21.Ravalico, F.; Messina, I.; Berberian, M. V.; James, S. L.; Migaud, M. E.;
Vyle, J. S. Org. Biomol. Chem. 2011, 9, 6496–6497.
doi:10.1039/c1ob06041d
22.Eguaogie, O.; Cooke, L. A.; Martin, P. M. L.; Ravalico, F.;
Conway, L. P.; Hodgson, D. R. W.; Law, C. J.; Vyle, J. S.
Org. Biomol. Chem. 2016, 14, 1201–1205. doi:10.1039/C5OB02061A
23.Patil, P. R.; Kartha, K. P. R. Green Chem. 2009, 11, 953–956.
doi:10.1039/b904454j
Acknowledgements
Funding was provided by: the School of Chemistry and Chemi-
cal Engineering, QUB (FR, PFC); EPSRC (EP/P505488/1 –
LPC) and by the authors (JSV, OE). We acknowledge Ryan
McNamee and Chantale Belkiri for preparing some starting
materials. Conor McGrann, Richard Murphy and Darren
Baskerville aided with NMR and/or mass spectra.
24.Métro, T.-X.; Salom-Roig, X. J.; Reverte, M.; Martinez, J.; Lamaty, F.
Green Chem. 2015, 17, 204–208. doi:10.1039/C4GC01416B
25.Bloom, L. A.; Boritzki, T. J.; Kung, P.-P.; Ogden, R. C.; Skalitzky, D. J.;
Zehnder, L. R.; Kuhn, L. A.; Meng, J. J. Combination therapies for
treating methylthioadenosine phosphorylase deficient cells. U.S. Pat.
Appl. US20040043959 A1, March 4, 2004.
References
1. Levene, P. A.; Tipson, R. S. J. Biol. Chem. 1934, 106, 113–124.
2. Baddiley, J.; Trauth, O.; Weygand, F. Nature 1951, 167, 359–360.
doi:10.1038/167359b0
26.Divakar, K. J.; Reese, C. B. J. Chem. Soc., Perkin Trans. 1 1982,
1625–1628. doi:10.1039/P19820001625
27.Štefanić, G.; Krehula, S.; Štefanić, I. Chem. Commun. 2013, 49,
9245–9247. doi:10.1039/c3cc44803g
3. Davisson, V. J.; Davis, D. R.; Dixit, V. M.; Poulter, C. D. J. Org. Chem.
1987, 52, 1794–1801. doi:10.1021/jo00385a026
28.Métro, T.-X.; Bonnamour, J.; Reidon, T.; Duprez, A.; Sarpoulet, J.;
Martinez, J.; Lamaty, F. Chem. – Eur. J. 2015, 21, 12787–12796.
doi:10.1002/chem.201501325
4. Anglin, J. L.; Deng, L.; Yao, Y.; Cai, G.; Liu, Z.; Jiang, H.; Cheng, G.;
Chen, P.; Dong, S.; Song, Y. J. Med. Chem. 2012, 55, 8066–8074.
doi:10.1021/jm300917h
29.Brear, P.; Freeman, G. R.; Shankey, M. C.; Trmčić, M.;
Hodgson, D. R. W. Chem. Commun. 2009, 4980–4981.
doi:10.1039/b908727c
5. Bothwell, I. R.; Luo, M. Org. Lett. 2014, 16, 3056–3059.
doi:10.1021/ol501169y
30.Conway, L. P.; Mikkola, S.; O'Donoghue, A. C.; Hodgson, D. R. W.
Org. Biomol. Chem. 2016, 14, 7361–7367. doi:10.1039/C6OB01270A
31.Hatano, A.; Nishimura, M.; Souta, I. Biocontrol Sci. 2009, 14, 55–60.
doi:10.4265/bio.14.55
6. Wnuk, S. F. Tetrahedron 1993, 49, 9877–9936.
doi:10.1016/S0040-4020(01)80190-3
7. Amiable, C.; Pochet, S. Tetrahedron 2015, 71, 2525–2529.
doi:10.1016/j.tet.2015.03.020
32.Machover, S. B. Understanding the Solvent-free Nucleophilic
Substitution Reaction Performed in the High Speed Ball Mill (HSBM):
Reactions of Secondary Alkyl Halides and Alkali Metal-Halogen Salts.
MS Thesis, University of Cincinnati, 2011.
8. Townsend, A. P.; Roth, S.; Williams, H. E. L.; Stylianou, E.;
Thomas, N. R. Org. Lett. 2009, 11, 2976–2979. doi:10.1021/ol9009859
9. Mieczkowski, A.; Roy, V.; Agrofoglio, L. A. Chem. Rev. 2010, 110,
1828–1856. doi:10.1021/cr900329y
33.Vogel, P.; Figueira, S.; Muthukrishnan, S.; Mack, J. Tetrahedron Lett.
2009, 50, 55–56. doi:10.1016/j.tetlet.2008.10.079
10.Hale, K. J.; Hough, L.; Manaviazar, S.; Calabrese, A. Org. Lett. 2015,
17, 1738–1741. doi:10.1021/acs.orglett.5b00511
11.Jahn-Hofmann, K.; Engels, J. W. Helv. Chim. Acta 2004, 87,
2812–2828. doi:10.1002/hlca.200490252
34.Heredia, A. A. Synlett 2014, 25, 748–749. doi:10.1055/s-0033-1340638
35.Belostotskii, A. M.; Lexner, J.; Hassner, A. Tetrahedron Lett. 1999, 40,
1181–1184. doi:10.1016/S0040-4039(98)02559-3
91

Beilstein J. Org. Chem. 2017, 13, 87–92.
36.McMullan, R.; Jeffrey, G. A. J. Phys. Chem. 1959, 31, 1231–1234.
doi:10.1063/1.1730574
37.Nelson, K. V.; Benjamin, I. J. Phys. Chem. C 2011, 115, 2290–2296.
doi:10.1021/jp110796n
38.Jacob, L. A.; Matos, B.; Mostafa, C.; Rodriguez, J.; Tillotson, J. K.
Molecules 2004, 9, 622–626. doi:10.3390/90800622
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