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Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Dehydromethylation of utility amide 2,2,6,6tetramethylpiperidide (TMP) to aza-allyl 2,2,6trimethyl-1,2,3,4-tetrahydropyridide (TTHP): synthesis
of a homologous series of alkali metal (Li, Na, K) TTHP
compounds†
DOI: 10.1039/x0xx00000x
www.rsc.org/
Alan R. Kennedy,a Sarah M. Leenhouts,a John J. Liggat,a Antonio J. MartínezMartínez,a Kimberley Miller,a Robert E. Mulvey,*a Charles T. O’Hara,*a Philip
O’Keefe,b and Alan Stevenb
A general thermolysis reaction for the transformation of
Group 1 TMP compounds (LiTMP, NaTMP, KTMP) to 1aza-allylic TTHP derivatives is reported. TMEDA accelerates
the reaction and produces the crystalline complexes
[(TMEDA)LiTTHP] and [(TMEDANaTTHP)2]. Methane
elimination during the transformational process was
confirmed via TVA coupled to MS.
Lithium TMP (TMP=2,2,6,6-tetramethylpiperidide) was introduced
inconspicuously in 1972 listed among tables of lithium alkylamides
comparing its performance as a non-nucleophilic base for ring
opening cyclohexene oxide and for generating boron stabilised carbanions.1 Forty years on LiTMP is a leading utility amide,2
indispensable to the synthetic chemist for executing selective
deprotometallation on substrates in which nucleophilic addition is
competitive using alkyllithium reagents.3 Much of the success of the
TMP anion as a proton abstractor lies in its special architecture. Four
electron donating methyl substituents simultaneously sterically
shield and electronically enhance the adjacent anionic nitrogen, that
heads a stable, cyclic framework that cannot undergo -hydride
elimination. Exploiting these attributes, a new generation of
metallating agents has recently been developed using TMP as the
Brønsted base engine within bimetallic organometallicamidometallic or amidometallic-salt formulations. Lithium is often
the mediator within these bimetallic bases enabling a nominally less
reactive metal [e.g., Zn in “tBu2ZnLiTMP”;4 Mg in
“(TMP)MgClLiCl”5] to perform the TMP-executed deprotonation.
To our knowledge no previous study has deliberately attempted to
modify the special architecture of TMP starting from TMP itself.6
Since even subtle modifications could have profound effects on
reactivity we have pursued this goal in the present study. Hints that
direct TMP modification should be realisable are found in mass
spectrometric (70 eV) studies of (TMP)2Al(X) (where X = Me, nBu,
Ph, tBuS) through observation of loss of Me(TMP) fragments7 and in
the characterisation of an osmium imine complex,8 the imino ligand
of which derives from LiTMP where TMP has lost one Me arm
completely and has another partially severed through deprotonation.
Here we report the remarkably straightforward conversion of the
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TMP skeleton to a 1-aza-allylic modification manifested in a novel
isolable homologous series of alkali metal complexes. Conversion
occurs via methane elimination as established through Thermal
Volatilisation Analysis (TVA), with elimination becoming easier
progressively for “M” in MTMP in the sequence H<Li<Na<K.
methylcyclohexane
N
N
101 ºC, t
- CH4
M·(TMEDA)x
M·(TMEDA)x
M x t (h) Yield (%)
N
TMP
N
TTHP
Li
Li
Na
Na
K
0
1
0
1
0
18
18
12
6
3
25a
17b
82b
87b
83b
1
1·TMEDA
2
2·TMEDA
3
Scheme 1. Thermolysis of MTMP to MTTHP. a Conversion by
NMR. b Isolated yield, quantitative conversion by NMR.
Accessed through thermolysis in refluxing methylcyclohexane
solution, conversion of the alkali metal TMP compound to a TTHP
(2,2,6-trimethyl-1,2,3,4-tetrahydropyridide)
derivative
was
demonstrated in five new compounds of empirical formula
[(TMEDA)xM(TTHP)] where M=Li, x=0, 1; M=Li, x=1,
1TMEDA; M=Na, x=0, 2; M=Na, x=1, 2TMEDA and M=K, x=0,
3 (TMEDA=N,N,N,N-tetramethylethylenediamine) (Scheme 1).
Two important trends emerge from the synthetic data. TMEDA, a
bidentate chelating amine, exerts an activating effect. The lithium
case for example shows an increase in the TMP to TTHP conversion
from 25% to 100% on adding TMEDA. Reflux times for comparable
yields of TTHP products are also significantly reduced by TMEDA
intervention. A group trend is also evident with increasing
conversion rates on increasing the size of the alkali metal. In the
extreme case [Li(TTHP)], 1, is only accessible in a 25% (in situ
NMR studies) yield following an 18 hour reflux reaction; whereas
potassium congener [K(TTHP)] 3 can be obtained in an isolated
crystalline yield of 83% (quantitative by NMR data) after heating the
reaction solution to reflux for only 3 h. Continuing this trend, when
M is H in TMP(H) a 24 h reflux reaction failed to produce any
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conversion at all indicating that an alkali metal is essential for the
thermally induced TMP dehydromethylation. Interestingly, however,
TMP(H) can undergo loss of one Me arm under the greater power of
electron impact ionisation (EI) during a GCMS study as evidenced
by a peak at 126.22 corresponding to a [TMP-Me-1e−]+ fragment
with no peak observed for the unstable molecular ion [TMP-1e−]+.
All five new compounds have been characterised by 1H and 13C (and
also 7Li for 1 and 1TMEDA) NMR spectroscopy in d8-THF
solution (see ESI). Their common aza-allylic character is implicated
by the unsaturated NC(CH3)=C(H) unit within their TTHP rings
with CH3 resonances located at 1.57, 1.55, 1.58, 1.56 and 1.55 ppm
and those for -C(H) at 3.37, 3.31, 3.27, 3.23 and 3.14 ppm for 1,
1TMEDA, 2, 2TMEDA and 3 respectively. Four of the five new
compounds capable of isolation in a pure solid form (the exception
being 1) were further characterised by diffusion-ordered NMR
spectroscopy (DOSY). Increasingly applied to alkali metal organic
compounds,9 DOSY experiments can be employed to distinguish
distinct components of solution mixtures and to estimate their sizes,
which are inversely proportional to their diffusion coefficients (D).
Measured against internal references of known molecular weight, D
values were obtained from solution concentrations of 40 mgmL-1
enabling size estimation. Recently this method was used to
distinguish between tetrameric and trimeric polymorphs of LiTMP.10
Summarising our DOSY results (see ESI), the aggregation states of
1TMEDA and 2TMEDA seen in the crystal (see below) appear
retained in d8-THF solution though with TMEDA substituted by the
stronger monodentate donor in [(d8-THF)2LiTTHP] and [(d8THFNaTTHP)2] respectively. However, a monosolvated dimeric
variant, [d8-THF(LiTTHP)2] cannot be ruled out in the former case.
Mimicking its sodium congener, KTTHP 3 appears to exist as a bisolvated dimer [(d8-THFKTTHP)2] in this polar medium.
X-ray crystallographic characterisation of 1TMEDA and
2TMEDA revealed monomeric (Fig. 1) and dimeric (Fig. 2)
structures respectively. Thus the former departs from the open dimer
structure of its TMP counterpart [(TMEDA)Li(TMP)Li(TMP)]
[note the exact analogy (TMEDA)LiTMP is unknown in the solid
though it exists in solution11]; but that the latter conforms to the
closed (NaN)2 dimeric ring precedent of [(TMEDANaTMP)2]. Both
1TMEDA and 2TMEDA contain a cyclic 1-aza-allylic (enamido
not imidoalkyl)12 anion, derived from LiTMP and NaTMP
respectively by loss of one Me and one adjacent -H atom (implying
MeH elimination) to create a C=C double bond locked within the
NC5 ring. TTHP anions in both have comparable, and due to the
imposed unsaturation, asymmetrical dimensions. Bond lengths in the
contracted side [N1-C1-C2, 1.363(2)/1.357(3) Å in 1TMEDA;
1.356(2)/1.370(3)Å in 2TMEDA; cf., the opposite side N1-C5-C4,
1.469(2)/1.533(2)Å in 1TMEDA; N1-C6-C5, 1.475(2)/1.536(3)Å in
2TMEDA, see ESI] are consistent with a delocalised NCN
electronic distribution. In keeping with sp2 hybridisation, carbon
atoms C1 and C2 occupy distorted trigonal planar environments,
meaning that the new anion has lost the chair conformation of TMP
Figure 1. Molecular structure of 1TMEDA. Hydrogen atoms
omitted for clarity with exception of the olefinic hydrogen on C2.
Thermal ellipsoids are displayed at 30% probability.
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Figure 2. Molecular structure of 2TMEDA. Hydrogen atoms
omitted for simplicity with exception of the olefinic hydrogen on
C2. Thermal ellipsoids are displayed at 35% probability. The
symmetry operation to generate the equivalent atoms labelled with ’
is -x,-y,-z+2.
with pronounced ring puckering at bis-Me-substituted C5. All other
structural parameters appear unremarkable. Aza-allylic ligands often
bind 3 to alkali metals12b in contrast to the 1 mode displayed in
both 1TMEDA and 2TMEDA. Consequently the M-N(TTHP)
bond lengths are typical of comparable M-amido bonds such as the
terminal M-TMP bond in [(TMEDA)Li(TMP)Li(TMP)] [1.883(4)
cf., 1.885(5)Å] and the bridging M-TMP bond in
[(TMEDANaTMP)2] [mean 2.459 cf., 2.470Å]. TMEDA chelation
completes the M bonding in 1TMEDA and 2TMEDA rendering Li
three coordinate and Na four coordinate .While TMEDA-chelated
Na dimers are well known [e.g., in (TMEDANaNiPr2)2], congeneric
Li monomers are comparatively rare.2a To force monomerisation a
TMEDA-complexed Li must be partnered by an anion of sufficient
steric stature. TMP with its greater steric bulk would therefore seem
the better prospect for effecting monomerisation, yet
[(TMEDA)Li(TMP)Li(TMP)] is dinuclear whereas 1TMEDA is
mononuclear. Hemisolvation versus full solvation is clearly a key
factor here since in solution [(TMEDALi(TMP)Li(TMP)] is known
to disassemble to a mixture of unsolvated, higher aggregated LiTMP
and mononuclear [(TMEDA)LiTMP], though in excess TMEDA the
latter forms exclusively.
Suspected methane elimination leading to TTHP formation was
confirmed for all MTMP (M=Li, Na, K) complexes via TVA
performed under high vacuum, coupled to MS. Full product scans
(see ESI) show LiTMP evolves gas in two distinct steps, Tpeak 131
and 197ºC, with considerable production of non-condensable
products associated with the second step. NaTMP behaves similarly
but with the higher temperature process more dominant and moving
to lower temperature (163ºC, see Fig. 3). For KTMP there is only a
single gas evolution process, dominated by non-condensable gases
(100ºC). In all cases, simultaneous MS shows the non-condensable
gases to be predominantly methane with only traces of hydrogen and
ethene. The release temperatures (Tpeak, Li>Na>K) follow the
decreasing degree of difficulty trend in forming the metal-attached
TTHP complexes found in the synthetic work. A possible
mechanism for these MTMP to MTTHP transformations could
involve initial elimination of “MMe” or “(TMEDA)MMe”, a
transient highly reactive form of the known metal alkyls that in turn
can deprotonate the remaining imine (2,2,6-trimethyl-2,3,4,5tetrahydropyridine, 4) at the acidic allylic 5 site, to generate the
TTHP derivatives (Scheme 2). Analogies can be drawn with the
mechanisms of amido to aza-allyl conversions found in alkali metal
dibenzylamido and methylbenzyl(benzyl)amido systems involving
“MH” or “MMe” eliminations followed by imine deprotonations
releasing H2 or MeH respectively,12d, 12e, 13 with, as here, gas
elimination most favoured by larger alkali metals and by adding
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donor ligands, though these systems are stabilised by the presence of
Figure 3. Overlay TVA thermogram of the methane evolution
curves for MTMP (M=Li, Na and K).
aryl groups in contrast to our fully aliphatic systems. Elimination of
“LiMe” from LiTMP and a subsequent Me− executed deprotonation
has also been implicated in forming the aforementioned osmium
complex, though the deprotonation occurs at a lateral Me site to
generate an imidoalkyl isomer of the enamido TTHP anion.
Significantly our TVA studies of MTMP compounds did not detect
any ethane (only traces of ethene from a secondary decomposition
process, see ESI), thus decreasing the likelihood of an alternative
mechanism involving Me radicals not anions. Significantly no Me
deprotonation (to CH2) was seen here in contrast to that observed in
a potassium aluminate bis-TMP system14 nor was any metallation of
TMEDA observed.15
H
D
N
M·(TMEDA)x
N
- CH4
M·(TMEDA)x
H H
"(TMEDA)x·MMe"
- "(TMEDA)x·MMe"
N
- MeH
4
Scheme 2. Possible mechanism for the MTMPMTTHP
transformation [M=Li (1, 1TMEDA), Na (2, 2TMEDA), K (3)].
Conclusions
A simple thermally induced transformation of synthetically
important alkali metal TMP compounds to TTHP derivatives has
been established. Such decompositions could explain why LiTMP
can sometimes give poor yields in reactions performed at elevated
temperatures in hydrocarbon solvents.16 The fact that most TTHP
compounds can be made in high yield and high purity bodes well for
future studies screening their reactivity.
Notes and references
a
WestCHEM, Department of Pure and Applied Chemistry, University of
Strathclyde, Glasgow, G1 1XL, UK. E-mail: r.e.mulvey@strath.ac.uk;
charlie.ohara@strath.ac.uk.
b
Chemical Development, AstraZeneca, Silk Road Business Park, Charter
Way, Macclesfield, SK10 2NA, UK.
† Electronic Supplementary Information (ESI) available: Experimental
procedures, full characterization, TVA, data and copies of 1H, 7Li and 13C
NMR spectra. XRD crystallographic data, CCDC [1002045-1002046].
See DOI: 10.1039/c000000x/
This journal is © The Royal Society of Chemistry 2012
We gratefully acknowledge financial support from AstraZeneca and the
University of Strathclyde (studentship to S.M.L.), the Royal Society
(Wolfson research merit award to R.E.M.) and the EPSRC (Career
Acceleration Fellowship, EP/J001872/1 to C.T.O.H.; EP/K001183/1 to
R.E.M). Prof. Hevia is also thanked for insightful discussions.
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