Development of a practical and sustainable strategy for the synthesis of ST1535 by an iron-catalyzed Kumada cross-coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2014.01.030

A simple, convenient, and environmentally friendly route to ST1535 employing an iron-catalyzed cross-coupling reaction and butylmagnesium chloride is described.

Full text of DOI:10.1016/j.tetlet.2014.01.030

Tetrahedron Letters 55 (2014) 1376–1378
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Development of a practical and sustainable strategy for the synthesis
of ST1535 by an iron-catalyzed Kumada cross-coupling reaction
b
b
b,
Francesca Bartoccini a, Giovanni Piersanti a, , Silvia Armaroli , Alberto Cerri , Walter Cabri
⇑
⇑
a Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino, Piazza Rinascimento 6, I-61029 Urbino, PU, Italy
b Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, convenient, and environmentally friendly route to ST1535 employing an iron-catalyzed
cross-coupling reaction and butylmagnesium chloride is described.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 26 October 2013
Revised 30 December 2013
Accepted 8 January 2014
Available online 15 January 2014
Keywords:
Iron-catalysis
Cross-coupling
Grignard reagent
Sustainability
A2A receptor antagonist
Transition metal-catalyzed cross-coupling reactions for the
selective formation of C–C bonds enable the preparation of a
myriad of structurally diverse and complex molecules that are
essential for the development of modern drugs, fine chemicals,
materials, and natural products.1 Palladium- and nickel-catalyzed
cross-coupling reactions represent almost all of the C–C bond-
forming reactions used in medicinal chemistry today.2 Thus, every
new clinical candidate will require a process-scale implementation
of a cross-coupling reaction. The constantly increasing world
market price of palladium,3 the toxicity of nickel compounds,4
the issue of residual contamination that may affect subsequent
transformations and purification, the necessity of extended
reaction times in many cases, and the addition of costly and
structurally complex ligands are prompting the search for power-
ful alternatives, especially for industrial processes. The past years
have witnessed the development of iron-catalyzed protocols,
which boast high operational practicality and synthetic efficiency:
the precatalysts are cheap and nontoxic iron salts; complex,
air-sensitive ligands are not required; the mild reaction conditions
tolerate various functional groups;5 and even more importantly,
the procedures can be applied to nitrogen-rich heterocycles such
as purines.6
As a part of our ongoing research project on developing new
adenosine A2A receptor antagonists as attractive nondopaminergic
anti-Parkinson’s agents7 as well as modern/smart procedures for
their synthesis,8 we required the preparation of several small
focused library arrays of 2-alkyl-6-amino-9-methyl-8-triazolpu-
rines. Among them, ST1535 is a highly selective adenosine A2A
receptor ligand antagonist with an interesting pharmacodynamic
profile and might be considered a good clinical candidate for the
treatment of Parkinson’s disease.9 Since the preparation of 2-alkyl-
substituted 6,8,9-functionalized purine derivatives is not straight-
forward and limited,10 we needed to identify a practical and
convenient way to access these compounds. Initially, the Stille
reaction was used to introduce different alkyl chains at the 2-posi-
tion of halopurine.7c Despite the fact that the Stille reaction was
very useful to introduce different alkyl chains at the less reactive
2-position of purine, it showed several drawbacks, including
reagents and byproduct toxicity, low turnover number and
turnover frequency, harsh reaction conditions (48 h; 120 °C), and
problematic final purification. More recently,8a we found that
2-halopurines could be efficiently and selectively alkylated by
applying a B-alkyl Suzuki–Miyaura cross-coupling reaction in the
presence of 3 equiv of Cs2CO3 and catalytic Pd(dppf)Cl2 in THF at
60 °C with 2.0 equiv of tri-n-alkylborane. A comparative study with
other C(sp3)-organometallics and a palladium catalyst revealed
that no other organometallics, including n-butylboronic acids,
could successfully produce the desired product. Furthermore, the
reported methodologies do not meet the basic requirements for
scale up, and a more sustainable procedure is needed.11
⇑
Corresponding authors. Tel.: +39 0722303320; fax: +39 0722303313 (G.P.); tel.:
+39 0257496211; fax: +39 025749629 (W.C.).
E-mail addresses: giovanni.piersanti@uniurb.it (G. Piersanti), walter.cabri@inde-
na.com (W. Cabri).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.030

F. Bartoccini et al. / Tetrahedron Letters 55 (2014) 1376–1378
1377
In light of these considerations, we thought it appropriate to re-
Reported method7c
M: SnBu3 (MW = 290)
Pd(PPh3)4 (20 mol%)
NMP, 120 °C, 48 h
79% yield
port our findings12 regarding an iron-catalyzed cross-coupling
reaction between a 2-chloropurine derivative and butylmagnesium
chloride, a key step in the synthesis of ST1535 (Scheme 1).
NBn2
NBn2
N
N
The reaction of 2-chloropurine 1 (1 mmol) with the n-butyl
Grignard reagent (1.2 equiv, 2 M in THF) proceeded under mild
and practical reaction conditions in the presence of 10 mol % of ir-
on(III) tris(acetylacetonate) [Fe(acac)3] as the precatalyst in THF/
NMP (6:1 v/v, 15 mL) at room temperature in 1 h to give 2 in
91% yield of isolated product.13 Competitive reactions with the
alkyl organometallics (e.g., spontaneous decomposition via b-elim-
ination or by proto-demetalation, isomerization or homocoupling)
did not occur. The transformation also worked well with a number
of alternative iron precatalysts (data not shown), albeit in lower
yield than with Fe(acac)3. As Fe(acac)3 is cheap and nonhygro-
scopic, it is the most appropriate precatalyst in terms of its practi-
cality. While lower catalyst loadings led to slightly reduced yields,
the exceptionally low cost of iron and the ease of catalyst removal
made the use of 10 mol % loading inconsequential. The absence of
NMP and/or THF as well as the use of ligands such as N,N,N0,N0-tet-
ramethylethylenediamine (TMEDA) resulted in longer reaction
times and major consumption of Grignard reagent due to decom-
position. A 10-fold and 100-fold increase in the reaction scale
afforded 2 in 88% and 87% yields of isolated product, respectively.
Thus, with coupling product 2 in our hands, an easy, simple syn-
thesis of ST1535 was accomplished using the reported three-step
procedure:7c (i) regioselective bromination of C8, (ii) bromide dis-
placement with triazole, and (iii) removal of the N-benzyl group by
TFSA to afford ST1535 in good overall yield. The scope of this iron-
catalyzed cross-coupling also includes alkylmagnesium reagents
ranging from the small EtMgCl to those bearing longer alkyl chains
such as n-hexyl and phenethyl.14 In all cases, levels of conversion
were high (>90%) and gave clean products. Lower levels of conver-
sion were seen with the generally less reactive benzyl system.
Comparing the direct butylation using the Grignard reagent
with the organoboron- and stannous-based variants shown in
Scheme 2, the most prominent features are the short reaction
times and very mild reaction temperatures, while still maintaining
high yields. Although organomagnesium reagents are highly reac-
tive, the fact that they are easily accessible, among the cheapest of
organometallic reagents commercially available on large-scale and
have a well-established methodology for safe handling that has
contributed to their widespread use in synthetic chemistry is an
added benefit of this procedure. Despite the tremendous success
of palladium-catalyzed cross-coupling reactions with different
nucleophiles, complementary methods that are cheap and mild,
avoid toxic waste, and feature improved step- and atom-economy
are still highly warranted. The examples shown in Scheme 2 illus-
trate how, through the use of butylmagnesium reagents, the need
to prepare Bu4Sn or Bu3B reagents might be avoided, the
sometimes notorious problems with purification (complete
N
N
Reported method8a
M: BBu2 (MW = 124)
PdCl2(dppf) (6 mol%),
Cs2CO3 (3 equiv)
THF, 60 °C, 16 h
85% yield
N
Cl
N
N
N
2
Me
Me
1
M
This work
M: MgCl (MW = 59)
Fe(acac)3 (10 mol%)
NMP/THF, r.t., 1 h
91% yield
Scheme 2. Comparison of established methods and the present cross-coupling
protocol with organomagnesium chloride reagents and an iron catalyst.
removal of toxic and nonpolar Sn side products) are eliminated,
the amount of waste products is drastically reduced, and excess
base (e.g., 3 equiv of Cs2CO3) is not required.
In summary, we have developed a cheaper and more environ-
mentally friendly synthesis of ST1535, a promising molecule for
the treatment of Parkinson’s disease, using a direct iron-catalyzed
cross-coupling of the butylmagnesium chloride reagent and a
2-chloropurine derivative, which are well-known challenging
substrates in palladium-mediated cross-coupling chemistry. The
cross-coupling reaction takes place under mild conditions with dif-
ferent alkyl Grignard reagents, a short reaction time, and with a
reduction of waste. The results from the present study have dem-
onstrated, for the first time, that iron-catalyzed cross-coupling of
cheap and readily available alkylmagnesium reagents represents
a valuable alternative for the mild, cheap, and atom-economic for-
mation of C–C bonds for the construction of 2-alkylpurines, thus
increasing the likelihood that this chemistry could be adopted as
an alternative to precious metal catalysis in an industrial setting.
Acknowledgments
The authors from the University of Urbino gratefully acknowl-
edge financial support from Sigma Tau.
References and notes
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NBn2
NBn2
MgCl
N
N
N
N
N
N
N
Cl
N
Fe Catalysis
Me
Me
2
1
Inexpensive and
enviromentally benign catalyst
Nucleophilic coupling partner
easily available on laboratory,
pilot and plant scales
NH2
N
N
N
N
N
N
N
Me
ST1535
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medicinal chemistry, too often leads to low reactivity in palladium-catalyzed
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Scheme 1. Iron-catalyzed butylation of 2-chloropurine 1,
synthesis of ST1535.
a key step in the

1378
F. Bartoccini et al. / Tetrahedron Letters 55 (2014) 1376–1378
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13. Synthesis of dibenzyl(2-n-butyl-9-methyl-9H-purin-6-yl)amine:
A flame-dried
two-necked flask is charged under argon with N,N-dibenzyl-2-chloro-9-
methyl-9H-purin-6-amine 1 (40 g, 0.11 mol), Fe(acac)3 (3.9 g, 0.011 mol), THF
(1.4 L), and N-methylpyrrolidone (NMP, 220 mL).
A
solution of n-
butylmagnesium chloride (2 M in THF, 65 mL, 0.13 mol) is added via syringe
to the resulting orange solution, causing an immediate color change to dark
brown. The resulting mixture is stirred for 1 h, and the reaction is diluted with
AcOEt and is carefully quenched upon the addition of aq HCl (1 M, 300 mL). The
phases were separated, and the aqueous phase was further extracted with
AcOEt. The combined organic phases were washed with aq HCl (0.1 M,
300 mL). The organic phase was dried over anhydrous sodium sulfate and
evaporated under reduced pressure to give a residue that was purified by flash
chromatography (cyclohexanes–ethyl acetate 7:3), providing the title
compound as a colorless oil (38.5 g, 91%). Its analytical and spectroscopic
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14. For NMR spectra of ethyl, butyl, phenetyl derivatives see reference 7a and 8a: For
hexyl: 1H NMR (200 MHz, CDCl3) d 0.89 (t, J = 8.0 Hz, 3H), 1.34–1.44 (m, 6H),
1.78–1.92 (m, 2H), 2.87 (t, J = 8 Hz, 2H), 3.79 (s, 3H), 4.95 (br, 2H), 5.53 (br s,
2H), 7.32 (s, 10H), 7.66 (s, 1H); MS (ESI) 414 (M+1)+.