Iron catalysed cross-couplings of azetidines-application to the formal synthesis of a pharmacologically active molecule

Article abstract of DOI:10.1039/c4cc09337b

A protocol for the coupling of 3-iodoazetidines with Grignard reagents in the presence of an iron catalyst has been developed. A variety of aryl, heteroaryl, vinyl and alkyl Grignards were shown to participate in the coupling process to give the products in good to excellent yields. Furthermore, a short formal synthesis towards a pharmacologically active molecule was shown. This journal is

Full text of DOI:10.1039/c4cc09337b

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Iron catalysed cross-couplings of azetidines –
application to the formal synthesis of a
pharmacologically active molecule†
Cite this:DOI: 10.1039/c4cc09337b
Received 22nd November 2014,
Accepted 17th December 2014
Dixit Parmar, Lena Henkel, Josef Dib and Magnus Rueping*
DOI: 10.1039/c4cc09337b
www.rsc.org/chemcomm
A protocol for the coupling of 3-iodoazetidines with Grignard
reagents in the presence of an iron catalyst has been developed.
A variety of aryl, heteroaryl, vinyl and alkyl Grignards were shown to
participate in the coupling process to give the products in good to
excellent yields. Furthermore, a short formal synthesis towards a
pharmacologically active molecule was shown.
Small nitrogen-containing heterocycles are highly desirable
structural motifs, which when installed within molecules can
provide beneficial attributes sought after in both the agrochemical
and pharmaceutical industries.1 Within this family, azetidines are
particularly interesting units since they possess a reasonable
stability whilst providing strong molecular rigidity.2 Azetidines
can be found both in nature and in numerous practical applica-
tions with perhaps the highest-profile azetidine being azelnidipine
which is sold as a calcium channel blocker.3 Closely related to this,
azetidines possessing aryl substitution at the 3-position are highly
sought after compounds and have been found to display an array
of pharmacological activities.4
Traditionally, 5- and 6-membered nitrogen-heterocycles have
managed to find fame in commercial applications; however
4-membered azetidines have lagged behind their larger family
members. We postulated that this may be due to the lack of
synthetic methodology devoted to the incorporation and function-
alisation of these structural units. The most typical procedure for
the coupling of azetidines is through the use of palladium
catalysis (Fig. 1).5 Operationally, the azetidine first has to be
transformed to the corresponding organo-zinc complex followed
by subsequent reaction with a suitable aryl iodide in the presence
of a palladium catalyst and a phosphine ligand. Alternatively,
Fig. 1 Previous works and this work in context.
nickel catalyzed procedures in the presence of a ligand have has demonstrated the metal-free coupling between hydrazones
featured in reports which utilised either aryl boronic acids or and boronic acids.7 In light of this, and building on our recent
aryl bromides with limited success.6 Recently, a report by Ley report on transition metal catalysis8 we sought to unlock this
constraint, and thus develop a more appealing method. We
proposed to harness a cheap iron catalyst in the absence of any
additional ligands and to use more readily available and easily
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074,
Aachen, Germany. E-mail: Magnus.Rueping@rwth-aachen.de;
prepared Grignard reagents. The last decade has seen rising
Fax: +49-241-8092665; Tel: +49-241-8094686
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4cc09337b interest in iron catalysis, which has led to the development of
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highly useful methodologies.9 Unlike typical transition-metals,
iron lies claim to existing in abundance, being relatively low-cost and
possessing low toxicity. In particular, iron-catalyzed cross-coupling,
usually with Grignard reagents has attracted an exceptional amount
of attention.10 Although the use of secondary alkyl halides as
coupling partners is known,11 cross-couplings of azetidine
units under iron catalysis remains rare.12
We began our study, inspired by Nakamura’s original work11a
by looking at the cross-coupling of phenyl magnesium bromide
with 3-iodoazetidine 1a to give the corresponding product 2a.
Initial optimisations of a variety of iron catalysts revealed FeCl3
and Fe(acac)3 to be suitable for the desired transformation with
the latter performing slightly better (entries 1 and 2). A tempera-
ture screen revealed that the reaction produced marginally better
yields at À20 1C and at À78 1C the reaction was completely
switched off (entries 3–5). Our base line conditions always made
use of TMEDA as an additive and its role in iron catalysis has been
the subject of mechanistic studies.13 In our hands, the use of
alternative additives was briefly explored but no reactivity was
observed in these cases (entries 6–8) (Table 1).
Fig. 2 depicts the scope we explored with regards to azetidines
coupling with Grignard reagents under the optimised conditions. In
general, the coupling functions efficiently with a variety of Grignard
reagents to yield the corresponding 3-substituted azetidines 2 in
good yields. For unsubstituted phenyl and naphthyl Grignard
reagents, the reaction proceeded efficiently and performed almost
identically with a variety of protecting groups on the nitrogen
(2a–c and 2g–h). This was also shown to be the case for 4-methyl
substituted Grignard (2d–f). The reaction could also be scaled
up in the case of 2a to a 1 mmol procedure with no detrimental
effects to the yield. On a practical note, we found that visualisa-
Fig. 2 Azetidine cross-couplings with Grignard reagents.
tion of the products containing the benzhydryl protecting group aromatic Grignards. Pleasingly, we found that commercially avail-
on thin layer chromatography (tlc) plates was much easier. For able methyl magnesium bromide functioned as expected to give
that sole reason, it was chosen to proceed with further examples the corresponding product 2n in 62% yield. Focusing on sp2-
using this group. Substitution at the 4-position of the aromatic hybridised partners, we were delighted to find both vinyl and
was tolerated in good to modest yields (2i–j) whilst substitution at di-methyl vinyl groups to undergo coupling (2o–p).
the 3-position was also equally accepted (2k–l). A bulky iPr group
Following this, we decided to explore the score of heterocyclic-
at the 2-position (2l) was surprisingly well tolerated, delivering the Grignard reagents and found both 1,3-benzodioxole and Boc-
product in excellent yield. The scope of the coupling reaction was protected indole to be suitable coupling components to yield
next expanded to include alkyl, vinyl and various alternative the corresponding products (2q and 2s) in good yields. To our
delight, an anisole-derived Grignard also delivered the desired
Table 1 Selected optimisation of catalyst, temperature and additivea
product (2r) albeit in a lower yield. We propose that the most likely
mechanism of this reaction follows the classically established
pathway of an Fe(I)/Fe(III) couple, whereby an Fe(I) species is
initially generated by reduction by the Grignard reagent followed
by straight-forward oxidative addition, transmetallation and finally
reductive elimination steps to complete the cycle.14 It should
however be appreciated that the mechanism described may well
be simplified, and the exact nature of the iron species is unknown
and could be dependent on the nature of Grignard reagent used.15
To demonstrate the potential and benefit of this method-
ology, we sought to utilise our conditions for the preparation of a
pharmacologically active molecule. We choose compound 6 as a
suitable challenge, which was recently filed under a patent by
Vernalis Research Limited for possessing activity against central
nervous system (CNS) disorders.4b Their synthesis of this compound
Entry
Catalyst (mol%)
Temp. (1C)
Additive
Yield (%)
1
2
3
4
5
6
7
8
FeCl3 (5)
0
0
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
DABCO
NMP
53
64
67
71
—
—
—
—
Fe(acac)3 (5)
Fe(acac)3 (10)
Fe(acac)3 (10)
Fe(acac)3 (10)
Fe(acac)3 (10)
Fe(acac)3 (10)
Fe(acac)3 (10)
rt
À20
À78
À20
À20
À20
Et3N
a
Yield of isolated product.
Chem. Commun.
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Notes and references
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D. P. would like to thank the Alexander von Humboldt
Foundation for the Humboldt Research Fellowship Award for
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