Magnesium-mediated benzothiazole activation: A room-temperature cascade of C-H deprotonation, C-C coupling, ring-opening, and nucleophilic addition reactions

Article abstract of DOI:10.1002/anie.201103275

Ligand domin(o)ated: In contrast to the straightforward deprotonation of benzothiazole using Grignard reagents, treatment of benzothiazole with 1 leads to a novel type of activation. The initial magnesiation initiates an unstoppable domino reaction of C-C coupling, ring opening, nucleophilic addition, and deprotonation to give 2. THF=tetrahydrofuran. Copyright

Full text of DOI:10.1002/anie.201103275

DOI: 10.1002/anie.201103275
Mixed-Metal Chemistry
Magnesium-Mediated Benzothiazole Activation: A Room-
À
À
Temperature Cascade of C H Deprotonation, C C Coupling,
Ring-Opening, and Nucleophilic Addition Reactions**
Victoria L. Blair, William Clegg, Alan R. Kennedy, Zoe Livingstone, Luca Russo, and
Eva Hevia*
Five-membered ring aromatic heterocycles, in particular 1,3-
azoles, are common building blocks for the synthesis of a
multitude of natural products, pharmaceuticals, and other
biologically active molecules.[1] An invaluable synthetic tool
which facilitates the incorporation of these heterocyclic rings
into more complex organic scaffoldings is deprotonative
metalation.[2] Thus, 1–3 azoles can be readily deprotonated at
the C2 position using conventional organometallics such as
organolithium or Grignard reagents,[3] as well as by more
sophisticated magnesiate[4] and zincate[5] systems. NMR and
solid-state structural studies have shown that while C2-
lithiated and magnesiated oxazoles undergo rapid isomer-
ization to the more stable ring-opened 2-(isocyano)enolate
forms,[4,6] metalated thiazoles are much more stable and do
not suffer such rearrangements.[6b] Thus C2-deprotonated
thiazoles can be efficiently prepared using magnesium-based
reagents such as Hauser bases[7] or Turbo Grignard reagents,[8]
and have been intercepted with electrophiles in high yields.
This methodology can also be used in large-scale reactions, as
shown by the 10 kg scale synthesis of argininylbenzo[d]thia-
zole (an intermediate to the trytapse inhibitor RWJ-56423)
for which deprotonation of benzothiazole by EtMgCl is a key
step.[9]
structure see Scheme 1 and Supporting Information) initiates
À
À
a domino reaction of C H deprotonation, C C coupling, ring
opening, nucleophilic addition, and intramolecular deproto-
nation.
Despite increasing interest in the synthesis of magnesium
compounds supported by highly bulky ligands, which have
been key to recent breakthroughs in magnesium chemistry,[10]
the effects that such ligands may have in the reactivity/
structure of alkali-metal magnesiates still remains largely
unknown. Our studies started by reacting sodium magnesiate
[NaMgBu3][11] with one equivalent of bis(silyl)amine {Ph2Si-
(NHAr*)2} (1),[12] which produced solvent-separated sodium
magnesiate [{Na(THF)6}+{(Ph2Si(NAr*)2)Mg(Bu)(THF)}À]
(2) in an 89% yield (see the Supporting Information for full
characterization). Building on our previous studies showing
that sodium magnesiates are regioselective bases enabling
direct magnesiation (alkali-metal-mediated) of a wide range
of aromatic molecules,[13] we decided to probe the ability of 2
as a base towards btz. The room temperature 1:1 reaction
formed a deep red solution which deposited a crop of red
crystals of 3 in 28% yield; this yield increased to 89% upon
using three equivalents of btz (Scheme 1).
In contrast with these reports which provide evidence of
the relatively straightforward C2 magnesiation of these
heterocycles, herein we report our findings on the remarkable
reactivity of new magnesium compounds supported by the
bulky chelating bis(silylamido) ligand {Ph2Si(NAr*)2}2À
(Ar* = 2,6-iPr2-C6H3) with benzothiazole (btz), which disclo-
ses an unprecedented type of activation promoted by a main-
group metal. Thus, isolation and structural identification of
key reaction intermediates suggest that the initial deproto-
nation (magnesiation) of benzothiazole by sodium magnesi-
ate [{Na(THF)6}+{(Ph2Si(NAr*)2)Mg(Bu)(THF)}À] (2; for
Scheme 1. Reaction of sodium magnesiate 2 with benzothiazole.
THF=tetrahydrofuran.
[*] Dr. V. L. Blair, Dr. A. R. Kennedy, Z. Livingstone, Dr. E. Hevia
Department of Pure and Applied Chemistry, WestCHEM, University
of Strathclyde, 295 Cathedral Street, G1 1XL, Glasgow (UK)
E-mail: eva.hevia@strath.ac.uk
X-ray crystallographic studies unveiled the complex
molecular assembly of 3 (Figure 1) that features two similar
magnesium centers (each solvated by THF) connected by the
two newly generated trianionic fragments A (Figure 2), with
Prof. W. Clegg, Dr. L. Russo
School of Natural Sciences (Chemistry)
University of Newcastle, Newcastle upon Tyne, NE1 7RU (UK)
two negative charges localized on an S and N atom, and a
[**] We thank the EPSRC, the Royal Society (University Research
Fellowship to E.H.), and the University of Strathclyde (studentship
to Z.L.) for their generous sponsorship of this research.
2
=
third one delocalized over the central sp C and the C N
bonds of the two neighboring benzothiazolyl rings. The
contacted-ion pair magnesiate 3 is completed by two THF-
solvated Na atoms.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103275.
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Communications
between the chemistry of lanthanides and alkaline earth
metal complexes,[16] a tentative mechanism to rationalize the
formation of 3 can be proposed (Scheme 2). Thus, initially
sodium magnesiate 2 mediates the deprotonation of two btz
molecules, while the third btz acts as a neutral N-donor ligand
to Mg (step a, Scheme 2).[17] This coordination would favor
the intramolecular nucleophilic attack of one benzothiazolyl
unit onto the C2 position of the btz molecule, thus bringing
À
about dearomatization of the latter and forming a new C C
bond (step b, Scheme 2).[17] This putative intermediate can
then undergo ring opening of the nonaromatic ring, through
À
=
C S cleavage, to form an electrophilic C N bond (step c,
Scheme 2) which in turn can react with the remaining
benzothiazolyl to generate a dianionic organic fragment
resulting from coupling three initial btz molecules (step d,
Scheme 2). Finally, this intermediate can be internally depro-
tonated at the remaining aliphatic sp3 CH by the remaining
basic arm of 2, thereby generating the sodium magnesiate
containing the trianionic fragment A (which can then
dimerize to yield 3) along with the concomitant formation
of bis(amide) 1 (detected by 1H NMR spectroscopy).
Figure 1. Molecular structure of 3 with hydrogen and THF ligands
coordinated to Mg atoms omitted for clarity.
Unlike the f-block imidazole activation studies, where
reactions had to be thermally induced (T= 85–1008C, 2–
3 days),[15a,b] the reaction of 2 with btz to yield 3 appears much
faster, occurring almost instantaneously at room temperature
as evidenced by 1H NMR monitoring. To detect some possible
Figure 2. Representation of fragments A and B resulting from the
benzothiazole activation reactions.
From the constitution of
A, it appears that three mol-
ecules of btz have been acti-
vated, with one undergoing
ring opening (resulting from
À
a C S bond cleavage) and
coupling with two other ben-
zothiazolyl units. Further-
more, the lack of H atoms
at the original C2 positions
of the three btz molecules,
suggests that all three (two
amido and one alkyl) poten-
tial basic arms of magnesiate
2 are used in forming 3.[14]
This was supported by
Scheme 2. Proposed mechanism for the formation of 3 (solvating THF molecules on Mg are omitted for
1H NMR analysis of the clarity).
reaction filtrate, which con-
firmed the presence of bis-
(silyl)amine {Ph2Si(NHAr*)2} (1) as a major co-product.
Contrasting with previous reports that btz can be quantita-
tively magnesiated at the C2 position by the Knochel base
(TMP)MgCl.LiCl, these results seem more related to the
reactivity exhibited by d0fn metal alkyl complexes (M = Sc, Y,
Lu, U) supported by 1,1’-ferrocenylene bis(amide).[15] Elegant
mechanistic studies by Diaconescu reveal that these com-
pounds can promote ring-opening reactions of methyl imida-
reaction intermediates, the reaction was performed at 08C,
producing novel sodium magnesiate 4 as an orange crystalline
solid along with traces of 3 (Figure 3).
X-ray crystallographic studies established the molecular
structure of 4, with its 4:3 Na/Mg ratio which implies that it is
formed through a disproportionation process. Remarkably 4
also contains two units of the same trianionic fragment A that
is present in 3, but its coordination mode differs significantly
to that in 3 (Figure 3). Surprisingly, the structure also contains
two of the novel dianionic fragment B.
À
zole, involving C H activation of the heterocycle and
À
subsequent C C coupling reactions, with the bis(amide)
ancillary ligand playing an important role in stabilizing/
trapping reaction intermediates involved.[15a] Based on these
earlier studies, and considering the similarities recently noted
Featuring two negative charges localized at S and N
atoms, B has been formed by the activation of two btz
molecules which have coupled with a Bu group from the
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Dimeric 6 contains the trianionic fragment A bridging two
Mg centers, thus demonstrating that even in the absence of
the alkali metal, Mg ligated by {Ph2Si(NAr*)2}2À can promote
the same type of btz activation (albeit in a less clean and lower
yielding reaction), but more surprising is the presence of a
bridging SHÀ ligand, which presumably results from the
À
cleavage of two C S bonds of a btz ring. Although sulfur
extrusion processes have been previously reported for
substituted thiazoles and related thiazolium salts,[23] to our
knowledge this Mg-mediated bond-cleavage reaction has no
precedent though it shares some features with the recent
bimetallic-induced fragmentation of THF reported by
Mulvey et al. In this report a Na magnesiate simultaneously
Figure 3. Representation of 4.
À
sodium magnesiate 2. Unlike A, only one btz molecule has
been deprotonated whereas the other one that has undergone
ring opening retains its hydrogen atom;[18] this structure
therefore supports steps b and c in Scheme 2, thus implying
that it is a non-deprotonated heterocyclic molecule that
experiences dearomatization with a subsequent ring-opening
reaction. Furthermore, the presence of a Bu group in B
suggests that deprotonation appears to be the rate-determin-
ing step of this process. The formation of B can be
rationalized similarly as proposed for A (Scheme 2), where
now as a result of the lower temperature, a single btz molecule
is deprotonated (with 2 acting as a mono-amido base, leaving
the Bu group bonded to Mg)[19] with a subsequent similar fast
cleaves two C O bonds from THF, thus generating an oxo-
dianion which is trapped in the core of an inverse crown.[24]
We should cautiously mention that 6 is obtained as a minor
product, and no other organometallic species from the
reaction could be identified. However formation of 6
indicates that the bis(amido) ligand coordinated to Mg can
initiate (to a certain extent) a related cascade of reactions to
that observed for sodium magnesiate 2.
In summary, where previous organomagnesium reagents
simply deprotonate btz, this new ate modification, its key
constituent being a bulky bis(amido) ligand, initiates a
remarkable cascade process with btz comprising at least five
distinct reaction types.
À
C C coupling and intramolecular ring-opening reaction that
=
is then terminated by the Bu nucleophilic addition to the C N
bond (see Scheme S1 in the Supporting Information). In this Experimental Section
Full experimental details and characterization of compounds 2–6 are
case, the intramolecular deprotonation (step e, Scheme 2)
does not occur, probably because it would generate a highly
unstable carbanion with a negative charge a to an amido
nitrogen atom.[20,21] The fact that even at low temperature
compounds 3 and 4 can be obtained, highlights that these
activation processes generating A and B are genuine exam-
ples of cascade chemistry, which once initiated (by magne-
siation of one of two btz molecules), are followed by an
unstoppable, unique sequence of fast intramolecular reac-
tions.
Intrigued by the unusual activity of the bulky bis(amido)
ligand in these reactions, contrasting with previous reports
where related ligands acts as steric stabilizers for low
oxidation state zinc and lanthanide complexes,[22] we studied
the reaction of the Mg bis(amide) complex [(Ph2Si-
(NAr*)2)Mg(THF)2] (5) with two equivalents of btz. Being
homometallic, 5 is expected to be much less basic than its
magnesiate analogue 2. However a reaction did occur
producing complex 6 (yield upon isolation: 9%) which was
analyzed by NMR spectroscopy and X-ray crystallography
(Scheme 3 and see the Supporting Information).
included in the Supporting Information. CCDC 822041 (2), 822042
(3), 822043 (4), and 822044 (6) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
Received: May 12, 2011
Published online: July 22, 2011
Keywords: cascade reactions · heterocylces · magnesium ·
.
metalation · mixed-metal chemistry
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Scheme 3. Reaction of homometallic magnesium bis(amide) 5 with
benzothiazole
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Communications
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= À À =
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