Potassium-alkyl magnesiates: Synthesis, structures and Mg-H exchange applications of aromatic and heterocyclic substrates

Article abstract of DOI:10.1039/c4cc05305b

Using structurally well-defined dipotassium-tetra(alkyl)magnesiates, a new straightforward methodology to promote regioselective Mg-H exchange reactions of a wide range of aromatic and heteroaromatic substrates is disclosed. Contacted ion pair intermediates are likely to be involved, with K being the key to facilitate the magnesiation processes. This journal is

Full text of DOI:10.1039/c4cc05305b

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Potassium-alkyl magnesiates: synthesis, structures
and Mg–H exchange applications of aromatic and
heterocyclic substrates†
Cite this: Chem. Commun., 2014,
0, 12859
5
Received 10th July 2014,
Accepted 2nd September 2014
a
a
b
a
a
Sharon E. Baillie, Tobias D. Bluemke, William Clegg, Alan R. Kennedy, Jan Klett,
b
a
a
Luca Russo, Marco de Tullio and Eva Hevia*
DOI: 10.1039/c4cc05305b
www.rsc.org/chemcomm
2,7
Using structurally well-defined dipotassium-tetra(alkyl)magnesiates, a power, and appear better suited for other reactions such as
8
new straightforward methodology to promote regioselective Mg–H Mg–halogen exchange or nucleophilic alkylation.
exchange reactions of a wide range of aromatic and heteroaromatic
Breaking new ground, here we report the synthesis and structural
substrates is disclosed. Contacted ion pair intermediates are likely to be authentication of a new mixed potassium–alkylmagnesium reagent
involved, with K being the key to facilitate the magnesiation processes. family. Assessing their reactivity with a range of arenes and hetero-
arenes, we present a new synthetically useful protocol to promote
Metallation, where an unreactive C–H bond is regioselectively
regioselective magnesiation under mild reaction conditions.
3
Potassium magnesiate [(C )KMgR ] (1) (R = CH SiMe ) was
transformed into a more reactive M–C bond, is a popular synthetic
6
H
6
3
2
1
9
tool for functionalizing aromatic molecules. Organolithium
prepared via co-complexation by mixing equimolar amounts of
the monometallic alkyls KR and MgR2 (Scheme 1 and ESI†).
Using the monosilyl group is pivotal here as it offers enhanced
reagents are extensively employed for this purpose; however their
usage usually offers limited functional group tolerance and generate
low-stability intermediates, often imposing sub-ambient temperature
1
0
solubility and stability compared to other C-based alkyl groups.
Furthermore its large steric bulk greatly limits its nucleophilic
1
protocols. A developing alternative strategy is to use alkali-metal
2
1
13
magnesiates. Operating by cooperative effects, these bimetallic
power. Crystalline 1 was characterised by H and C NMR and
1
1
reagents often display enhanced metallating power in direct
structurally defined by X-ray crystallography (Fig. 1a and b).
X-ray studies revealed a novel infinitely aggregated structure
(one-step) magnesiations of aromatic substrates containing a
1
1
rich variety of functional groups often incompatible with
organolithium reagents. Notable new reagents to this field are
Knochel’s ‘‘turbo-charged’’ reagent (TMP)MgXꢀLiCl (TMP =
for 1 (Fig. S1, ESI†), combining K–C and Mg–C bonds with
medium-long Kꢀ ꢀ ꢀMe electrostatic interactions [ranging from
1
2
3
.1352(18) to 3.4383(17) Å]. Its basic repeat unit comprises a
2,2,6,6-tetramethylpiperidide), and Na–Mg TMP–alkyl mixtures
trigonal planar Mg bonded to three monosilyl groups (Fig. 1a).
in alkali-metal-mediated magnesiation (AMMMg) processes
3
which can facilitate remote deprotonation of organic substrates.
Interestingly most studies have focused on lithium or sodium
4
magnesiates, with little attention paid to their potassium congeners,
reflecting the greater challenge of manipulating and isolating their
5
potassium alkyl precursors. Common in existing magnesiate
reagents, the amide TMP appears to be the kinetic key driving their
Mg–H exchange processes. Notwithstanding in some cases, conco-
mitantly released TMP(H) can react with the some residual anionic
6
groups of the generated organometallic intermediate. Although this
complication could be avoided using homoalkyl species, it is known
that these magnesiates, such as [LiMgBu ], have limited metallating
3
a
WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde,
Glasgow, G1 1XL, UK. E-mail: eva.hevia@strath.ac.uk
b
School of Chemistry, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
†
Electronic supplementary information (ESI) available: Full experimental details, X-ray
crystallographic data and copies of the NMR spectra. CCDC 1010341–1010343. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc05305b
Scheme 1 Synthesis of potassium magnesiate 1 and donor-induced
redistribution processes to give higher-order species 2 and 3.
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Fig. 1 (a) Asymmetric unit of 1. (b) Fragment of the polymeric structure of 1 along the crystallographic b-axis. Dotted lines represent longer K–CH
3
interactions
(c) molecular structure of 2 (displacement ellipsoids are drawn at the 50% probability level. H atoms and minor disorder components are omitted for clarity).
Metals are connected by an alkyl group, which coordinates to K homoalkyl potassium magnesiates are extremely scarce, with
2
2 3 3 5 3 2
in an Z -fasion through its CH unit and to one SiMe Me the only precedents being allyl polymers [KMg(C H ) (THF) ]
1
5
group. K attains further coordination by p-engaging with a and [K
molecule of benzene and forming a long contact with a Me of
2
Mg (C
3
H
5
)
4
(THF)].
1
13
H and C NMR analysis of 2 and 3 suggests that the solid-state
another R group. One remaining alkyl binds in a similar monomeric contacted ion pair [(N-donor) K MgR ] constitutions
2
2
4
11
ambidentate mode to a neighbouring K atom along the crystallo- observed in the solid state are retained in C D solution.
6
6
graphic b-axis; whereas the other R group interacts through its
To probe the metallating ability of potassium magnesiates
methylene head with a Mg atom located in a perpendicular 1–3, we chose anisole (4a) as a substrate, a benchmark molecule
1
6
disposition and through one of its Me groups with another K in directed ortho metallation (DoM) (Table 1).
centre, giving rise to an intricate 2D network (Fig. S1 and ESI† for Control reactions of equimolar amounts of the homometallic
selected bond distances). Compound 1 shows excellent solubility components of 1–3, KR and MgR with 4a in hexane at 20 1C for 2h
. Its H and C spectra revealed a single set of alkyl showed sluggish reactivity. Whereas the addition of PMDETA does
11
2
1
13
6 6
in C D
11
signals, suggesting that its polymeric constitution is not retained not seem to affect the reactivity of MgR , it does increase the
in solution. DOSY H NMR studies, using internal standards, offer performance of KR (Table 1, entries 1 and 2). However, the resulting
2
1
6 6
further support for the deaggregation of 1 in C D solutions, aryl potassium intermediate is unstable and slowly decomposes.
ꢁ
1
estimating its size (in terms of FW) to be 433 g mol , consistent Probing the reactivity of the new potassium magnesiates, using
with monomeric {KMgR } units partially solvated by 1 or 2 lower-order 1 led to similar low conversions as those observed with
molecules of C (Fig. S5 and S6, ESI†).
Adding polydentate N-donors PMDETA (N,N,N ,N ,N - an excellent magnesiating reagent, affording conversions of 99%
3
1
1
D
6 6
KR (Table 1, entry 3). Remarkably, higher-order magnesiate 2 proved
0
00 00
0
0
pentamethyldiethylenetriamine) or TMEDA (N,N,N ,N -tetra- (Table 1, entry 4). Subsequent trapping of the metallated inter-
methylethylenediamine) to a suspension of 1 in hexane, not only mediate 5a with iodine furnished 2-iodoanisole (6a) in near quanti-
causes the deaggregation of its polymeric structure but also induces tative isolated yield (92%). Similarly, 5a undergoes carboxylation with
0
17
a redistribution process forming higher-order potassium-rich CO
magnesiates [(PMDETA) MgR ] (2) and [(TMEDA) MgR
3) with the concomitant elimination of MgR (Scheme 1).
X-ray studies revealed trinuclear structures for 2 and 3
2
, yielding 2-methoxybenzoic acid (6a ) in 84% yield.
K
2 2
4
K
2 2
4
]
1
3
(
2
1
4
Table 1 Metallation of anisole (4a) using different alkyl Li, Na, K and
11
(Fig. 1c and Fig. S3, ESI† respectively). Both compounds display a Mg reagents
central C4-coordinated Mg atom flanked by two donor-solvated K
cations. Interestingly, the different hapticities of the N-ligands
impose remarkable differences in their structural motifs. Thus,
containing PMDETA ligated 2, displays a linear KꢀꢀꢀMgꢀꢀꢀK arrange-
ment [174.18(3)1] with each R group bridging Mg with a K centre
a
b
14
Entry
MR
Conversion to 5a (%)
(Fig. 1c). Contrastingly, in TMEDA-solvate 3, in order to attain
c
coordinative saturation, each K needs to bind to three monosilyl
groups. Thus two of the four R groups in 3 bridge between the three
1
2
3
4
5
6
7
MgR
KR
KMgR
(PMDETA)
(TMEDA)
(TMEDA)
2
0(0)
c
20(57)
3
(1)
15
99
5
10
0
metals (through C8 and C5 in Fig. S2, ESI†) through their CH
2
2
K
2
2
MgR
MgR
4
4
(2)
heads, while the remaining ones connect Mg with only one K atom.
These distinct bonding modes must contribute significantly to the
marked non-linearity of the KꢀꢀꢀMgꢀꢀꢀK vector [100.14(19)1]. Unlike 2,
in 3 there are several KꢀꢀꢀMe medium-long contacts, one of which
involves a K atom from a neighboring unit, giving rise to an extended
2
Li
Na
2
2
MgR
MgR
4
(PMDETA)
2
K
2
4
(3) + 18-crown-6
a
b
1
.0 mmol of 4a and 1.0 mmol of MR were used. Conversion was
determined by GC analysis of iodolysed reaction aliquots, using an
internal standard (heptadecane). In brackets conversion shown when
c
1
1
linear chain structure (Fig. S4, ESI†). Structurally defined adding 0.5 mmol of PMDETA.
1
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Disclosing a dramatic alkali-metal effect, attempts to achieve an Table 2 Potassium-mediated-magnesiations of various aromatic and
heteroaromatic substrates using 2
efficient metallation of 4a using related higher-order lithium- and
sodium magnesiates [(TMEDA) Li MgR ] (which displays the same
c
d
2
2
4
Entry Substrate
Conditions
Product
18
structure as 2) and [(TMEDA) Na MgR ] were unsuccessful
2
2
4
(Table 1, entries 5 and 6). Further evidence of the crucial role of
K for the success of these magnesiation reactions was found when
the reaction of 2 with 4a was carried out in the presence of
1
0 1C, 1.5 h, 1.0 equiv.
2
equivalents of 18-crown-6, which is known to have a high affinity
towards potassium cations, which completely shuts down metalla-
tion (Table 1, entry 7). These findings suggest that these reactions
must operate via contacted-ion pair mixed-metal intermediates
2
3
0 1C, 1.5 h, 1.0 equiv.
0 1C, 1.5 h, 0.33 equiv.
(CIP), being genuine examples of potassium-mediated magnesia-
tions. The enhanced reactivity of 2 can be rationalised by the
synergic partnership between the metals. By forming a higher-order
magnesiate, the low kinetic basicity of the Mg–C bonds in MgR
2
can be overcome, but the K cations also play a major role in the
process, coordinating to anisole, bringing its ortho-H in close
proximity to the activated magnesiate anion. Interestingly, studies
using sub-stoichiometric amounts of 2, demonstrate its ability
to display polybasic behaviour (Table S1, ESI†). Using 0.33 and
4
5
6
20 1C, 2 h, 0.33 equiv.
0 1C, 2 h, 0.33 equiv.
0 1C, 2 h, 0.33 equiv.
0.25 equivalents of 2 leads to 88 and 74% conversions of 4a
respectively, which suggest that up to three of its four potential
11
basic arms are active in the deprotonation reaction.
In order to explore the scope of 2, we next studied its
reactivity towards several unsaturated substrates (Table 2).
2
The amido group (–CONR ) is regarded a strong ortho-directing
group, and metallation using 2 proceeded smoothly and efficiently
at 0 1C, leading to 2-iodo-N,N-diisopropylbenzamide (6b) in 94%
yield, following I2 quenching (Table 2, entry 1). Metallation of
trifluoromethylbenzene (4c) formed two ortho and meta metallated
regioisomers in 85 and 5% yields (Table 2, entry 2). Reaction
of 2 with 1,3-difluorobenzene (4d) occurred at the most acidic
7
8
9
0 1C, 2 h, 0.33 equiv.
2-position with carboxylation furnishing the tri-substituted
arene 6d in 52% yield (Table 2, entry 3). Similarly 1,2-dimethoxy-
benzene 4e reacts with 0.33 equiv. of 2 at room temperature to
exclusively afford 6e in a 70% yield (Table 2, entry 4). Due to their
vast synthetic relevance, selective functionalization of pyridines
using metallation under mild conditions is highly desirable.
Generally, organolithium metalation reactions need to be carried
out at ꢁ78 1C and regioselective control can be challenging. We
tested the reaction of 2 with the three different regioisomers of
20 1C, 1.5 h, 0.33 equiv.
20 1C, 1.5 h, 0.33 equiv. No reaction
20 1C, 1.5 h, 0.33 equiv.
2-, 3- and 4-methoxypyridine (4f–h, Table 2, entries 5–7).
10
11
12
Although ether-functionalities are not regarded as strong directing
16a
groups, deprotonation occurred in all three cases regioselectively
ortho to the OMe group under mild conditions (0 1C, 2 h),
19
producing iodopyridines 6f–h in 58–75% isolated yield.
20 1C, 1.5 h, 0.33 equiv.
Moving on to diazoles, the metallation of 1-methyl-1H-
pyrazole (4i) proceeded efficiently in the 5-position and iodination
furnished 6i in near quantitative yield using 0.33 equivalents of 2
(92%, Table 2, entry 8). However, on blocking the 5-position by a
20 1C, 1.5 h, 0.33 equiv.
Me substituent (4j), no metallation was observed (Table 2, entry 9).
The similar heterocycles 1-methyl-1H-benzo[d]imidazole (4k) and
triazole derivative 4l were efficiently metallated and iodinated at
room temperature, affording 6k and 6l in excellent yields (82–93%;
Table 2, entries 10 and 11). Finally, oxygen and sulphur containing
heterocycles (4m–o) did not pose any problems and reaction with
13
20 1C, 1.5 h, 0.33 equiv.
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Table 2 (continued)
Fundamentals to Applications, ed. R. Luisi and V. Capriati, Wiley-VCH
Verlag & Co, Weinheim, Germany, 2014.
2 F. Mongin and A. Harrison-Marchand, Chem. Soc. Rev., 2013,
c
d
Entry Substrate
Conditions
Product
113, 7563.
3
(a) R. E. Mulvey, F. Mongin, M. Uchiyama and Y. Kondo, Angew.
Chem., Int. Ed., 2007, 46, 3802; (b) B. Haag, M. Mosrin, H. Ila,
V. Malakhov and P. Knochel, Angew. Chem., Int. Ed., 2011, 50, 9794.
A. J. Martinez, D. R. Armstrong, B. Conway, B. J. Fleming, J. Klett,
A. R. Kennedy, R. E. Mulvey, S. D. Robertson and C. T. O’Hara, Chem.
Sci., 2014, 5, 771.
1
4
20 1C, 1.5 h, 0.33 equiv.
4
a
c
b
0
.5 mmol of substrate was used. 1.5 mmol of substrate were used.
Time, temperature and amount of base 2 for the metalation reactions.
Yields refer to isolated yields of analytically pure products (495%
d
5 C. Unkelbach, D. F. O’Shea and C. Strohmann, Angew. Chem., Int.
Ed., 2014, 53, 553.
6 W. Clegg, B. Conway, P. Garcia-Alvarez, A. R. Kennedy, R. E. Mulvey,
L. Russo, J. Sasmannshausen and T. Tuttle, Chem. – Eur. J., 2009,
purity determined by NMR or GC-analysis), unless otherwise stated.
e
1
Yield was determined by H-NMR analysis using an internal standard
ferrocene).
(
1
5, 10702.
7
H. Haward, O. Bayh, C. Hoarau, F. Tr ´e court, G. Qu ´e guiner and
2
led to regioselective deprotonation at the 2-position. The corre-
F. Marsais, Tetrahedron, 2008, 64, 3236.
8 M. Hatano, T. Matsumura and T. Ishihara, Org. Lett., 2005, 7, 573.
S. E. Baillie, W. Clegg, P. Garcia-Alvarez, E. Hevia, A. R. Kennedy,
J. Klett and L. Russo, Chem. Commun., 2011, 47, 388.
0
0
sponding iodinated (6m–o) and carboxylated (6m , 6n ) hetero-
cycles were produced in equally high yields (81–95%, Table 2,
9
entries 12–14). With unsubstituted thiophene (4o) 8% of twofold 10 W. Clegg, B. Conway, A. R. Kennedy, J. Klett, R. E. Mulvey and
0
L. Russo, Eur. J. Inorg. Chem., 2011, 721.
1 See ESI† for details.
metallation leading to 2,5-diiodothiophene (6o ) was observed.
1
1
In summary, we have uncovered the structures of a new
family of homoalkyl potassium magnesiates. Revealing an
important donor effect, addition of polydentate N-Lewis bases to
the highly aggregated magnesiate 1, not only induces formation of
smaller aggregates but also changes the mixed-metal formulation,
to higher-order magnesiates 2 and 3. A new straightforward
methodology, using 2 as a metallating reagent, to promote
2 These values are similar to those previously reported for the
structure of [MeK] where K also forms long distance interactions
with the Me groups of other units (mean Kꢀ ꢀ ꢀMe, 3.441 Å) which are
significantly elongated when compared to the K–Me distances
towards the carboanion (2.447 Å), see E. Weiss, T. Lambertsen,
B. Schubert and J. K. Cockcroft, J. Organomet. Chem., 1988, 358, 1.
3 Compounds 2 and 3 can also be rationally synthesized by reaction of
1
the relevant N-donor, KR and MgR
2
in a 2 : 2 : 1 ratio (isolated
crystalline yields 78 and 45% for 2 and 3 respectively).
regioselective Mg–H exchange of a wide range of aromatic and 14 Similar linear arrangements have been described as classical ‘‘Weiss
motifs’’ in related Li and Na magnesiate structures, see: E. Weiss,
Angew. Chem., Int. Ed. Engl., 1993, 32, 1501.
5 C. Lichtenberg, T. P. Spaniol, I. Peckermann, T. P. Hanusa and
J. Okuda, J. Am. Chem. Soc., 2013, 135, 811.
6 For DoM reactions see: (a) V. Snieckus, Chem. Rev., 1990, 90, 879;
heteroaromatic substrates under mild reaction conditions has
been disclosed. Our studies suggest the involvement of CIP
1
intermediates, with the presence of K being the key to facilitate
these novel magnesiation reactions.
We thank the EPSRC, the Carnegie Trust for the Universities
of Scotland the Royal Society and the ERC for their generous
sponsorship of this research and Professor R. E. Mulvey for
insightful discussions.
1
(
b) A. Wagner, J. R. Desmurs, V. Pe and C. Mioskowski, Angew.
Chem., Int. Ed., 2002, 41, 340; (c) S. Wunderlich, T. Bresser, C. Dunst,
G. Monzon and P. Knochel, Synthesis, 2010, 2670.
7 For an insightful discussion on the ortho-lithiation of anisole see
ref. 16a.
8 S. E. Baillie, W. Clegg, P. Garcia-Alvarez, E. Hevia, A. R. Kennedy,
J. Klett and L. Russo, Organometallics, 2012, 31, 5131.
1
1
Notes and references
19 For regioselective metalation of 4f in 2-position and 4h in 6-position
overriding the directing effect see: (a) S. M. Manolikakes, N. M. Barl,
C. S ¨a mann and P. Knochel, Z. Naturforsch., 2013, 68b, 411; (b) M. Jaric,
B. A. Haag, A. Unsinn, K. Karaghiosoff and P. Knochel, Angew. Chem.,
Int. Ed., 2010, 49, 5451.
1
(a) M. Schlosser, in Organometallics in Synthesis. A Manual, ed.
M. Schlosser, Wiley, Chichester, 2nd edn, 2002, p. 1; (b) E. Carl
and D. Stalke, in Lithium Compounds in Organic Synthesis: From
1
2862 | Chem. Commun., 2014, 50, 12859--12862
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