Dehydromethylation of alkali metal salts of the utility amide 2,2,6,6-tetramethylpiperidide (TMP)

Article abstract of DOI:10.1039/c4cc04959d

A general thermolysis reaction for the transformation of Group 1 TMP compounds (LiTMP, NaTMP, KTMP) to 1-aza-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. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc04959d

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Dehydromethylation of alkali metal salts of the
utility amide 2,2,6,6-tetramethylpiperidide (TMP)†
Cite this: Chem. Commun., 2014,
0, 10588
5
a
a
a
Alan R. Kennedy, Sarah M. Leenhouts, John J. Liggat,
a
a
a
Received 29th June 2014,
Accepted 23rd July 2014
Antonio J. Martınez-Martınez, Kimberley Miller, Robert E. Mulvey,*
´ ´
a
b
b
Charles T. O’Hara,* Philip O’Keefe and Alan Steven
DOI: 10.1039/c4cc04959d
www.rsc.org/chemcomm
A general thermolysis reaction for the transformation of Group 1 Since even subtle modifications could have profound effects
TMP compounds (LiTMP, NaTMP, KTMP) to 1-aza-allylic TTHP deri- on reactivity we have pursued this goal in the present study.
vatives is reported. TMEDA accelerates the reaction and produces the Hints that direct TMP modification should be realisable are
crystalline complexes [(TMEDA)LiTTHP] and [(TMEDAꢀNaTTHP)
Methane elimination during the transformational process was con- (where X = Cl, Br, I) through observation of loss of Me(TMP)
2
2
]. found in mass spectrometric (20 eV) studies of (TMP) Al(X)
7
firmed via TVA coupled to MS.
fragments and in the characterisation of an osmium imine
8
complex, the imino ligand of which derives from LiTMP where
Lithium TMP (TMP = 2,2,6,6-tetramethylpiperidide) was intro- TMP has lost one Me arm completely and has another partially
duced inconspicuously in 1972 listed among tables of lithium severed through deprotonation. Here we report the remarkably
alkylamides comparing its performance as a non-nucleophilic straightforward conversion of the TMP skeleton to a 1-aza-allylic
base for ring opening cyclohexene oxide and for generating modification manifested in a novel isolable homologous series of
1
boron stabilised a-carbanions. Forty years on LiTMP is a leading alkali metal complexes. Conversion occurs via methane elimina-
2
utility amide, indispensable to the synthetic chemist for executing tion as established through Thermal Volatilisation Analysis (TVA),
selective deprotometallation on substrates in which nucleophilic with elimination becoming easier progressively for ‘‘M’’ in MTMP
3
addition is competitive using alkyllithium reagents. Much of in the sequence H o Li o Na o K.
the success of the TMP anion as a proton abstractor lies in its
Accessed through thermolysis in refluxing methylcyclo-
special architecture. Four electron donating methyl substitu- hexane solution, conversion of the alkali metal TMP compound
ents simultaneously sterically shield and electronically enhance to a TTHP (2,2,6-trimethyl-1,2,3,4-tetrahydropyridide) derivative
the adjacent anionic nitrogen, that heads a stable, cyclic frame- was demonstrated in five new compounds of empirical formula
x
work that cannot undergo b-hydride elimination. Exploiting [(TMEDA) M(TTHP)] where M = Li, x = 0, 1; M = Li, x = 1,
these attributes, a new generation of metallating agents 1ꢀTMEDA; M = Na, x = 0, 2; M = Na, x = 1, 2ꢀTMEDA and M = K,
0
0
has recently been developed using TMP as the Brønsted x = 0, 3 (TMEDA = N,N,N ,N -tetramethylethylenediamine) (Scheme 1).
base engine within bimetallic organometallic–amidometallic or Two important trends emerge from the synthetic data. TMEDA,
amidometallic–salt formulations. Lithium is often the mediator a bidentate chelating amine, exerts an activating effect. The
within these bimetallic bases enabling a nominally less reactive lithium case for example shows an increase in the TMP to TTHP
t
4
5
metal [e.g., Zn in ‘‘ Bu ZnꢀLiTMP’’; Mg in ‘‘(TMP)MgClꢀLiCl’’ ]
2
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
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 proce-
1
7
13
dures, full characterization, TVA, data and copies of H, Li and C NMR spectra.
XRD crystallographic data, CCDC 1002045 and 1002046. For ESI and crystal-
lographic data in CIF or other electronic format see DOI: 10.1039/c4cc04959d
a
b
Scheme 1 Thermolysis of MTMP to MTTHP. Conversion by NMR. Isolated
yield, quantitative conversion by NMR.
1
0588 | Chem. Commun., 2014, 50, 10588--10591
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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 h reflux reaction;
whereas potassium congener [K(TTHP)] 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 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
Fig. 2 Molecular structure of 2ꢀTMEDA. 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
0
equivalent atoms labelled with is ꢁx, ꢁy, ꢁz + 2.
ꢁ
+
[
TMP-Me-1e ] fragment with no peak observed for the unstable
ꢁ
+
molecular ion [TMP-1e ] .
respectively. Thus the former departs from the open dimer
1
All five new compounds have been characterised by H and structure of its TMP counterpart [(TMEDA)ꢀLi(TMP)Li(TMP)]
1
3
7
C (and also Li for 1 and 1ꢀTMEDA) NMR spectroscopy in [note the exact analogy (TMEDA)ꢀLiTMP is unknown in the solid
1
1
d -THF solution (see ESI†). Their common aza-allylic character though it exists in solution ]; but that the latter conforms to the
8
is implicated by the unsaturated NaC(CH ) = bC(H) unit within closed (NaN)
2
dimeric ring precedent of [(TMEDAꢀNaTMP)
2
].
3
their TTHP rings with CH
3
resonances located at 1.57, 1.55, Both 1ꢀTMEDA and 2ꢀTMEDA contain a cyclic 1-aza-allylic
1
2
1
.58, 1.56 and 1.55 ppm and those for b-C(H) at 3.37, 3.31, 3.27, (enamido not imidoalkyl) anion, derived from LiTMP and
.23 and 3.14 ppm for 1, 1ꢀTMEDA, 2, 2ꢀTMEDA and 3 respec- NaTMP respectively by loss of one Me and one adjacent b-H
3
tively. Four of the five new compounds capable of isolation in a atom (implying MeH elimination) to create a CQC double bond
pure solid form (the exception being 1) were further charac- locked within the NC ring. TTHP anions in both have compar-
5
terised by diffusion-ordered NMR spectroscopy (DOSY). able, and due to the imposed unsaturation, asymmetrical
9
Increasingly applied to alkali metal organic compounds, DOSY dimensions. Bond lengths in the contracted side [N1–C1–C2,
experiments can be employed to distinguish distinct components of 1.363(2)/1.357(3) Å in 1ꢀTMEDA; 1.356(2)/1.370(3) Å in 2ꢀTMEDA;
solution mixtures and to estimate their sizes, which are inversely cf., the opposite side N1–C5–C4, 1.469(2)/1.533(2) Å in 1ꢀTMEDA;
proportional to their diffusion coefficients (D). Measured against N1–C6–C5, 1.475(2)/1.536(3) Å in 2ꢀTMEDA, see ESI†] are consistent
internal references of known molecular weight, D values were with a delocalised NꢀꢀꢀCꢀꢀꢀC electronic distribution (Scheme 1). In
ꢁ
1
2
obtained from solution concentrations of 40 mg mL enabling keeping with sp hybridisation, carbon atoms C1 and C2 occupy
size estimation. Recently this method was used to distinguish distorted trigonal planar environments, meaning that the new anion
10
between tetrameric and trimeric polymorphs of LiTMP. Summar- has lost the chair conformation of TMP with pronounced ring
ising our DOSY results (see ESI†), the aggregation states of 1ꢀTMEDA puckering at bis-Me-substituted C5. All other structural parameters
3
and 2ꢀTMEDA seen in the crystal (see below) appear retained in appear unremarkable. Aza-allylic ligands often bind Z to alkali
1
2b
1
d
8
-THF solution though with TMEDA substituted by the stronger metals in contrast to the Z mode displayed in both 1ꢀTMEDA
monodentate donor in [(d
respectively. However, a monosolvated dimeric variant, [d
LiTTHP) ] cannot be ruled out in the former case. Mimicking its TMP bond in [(TMEDA)Li(TMP)Li(TMP)] [1.883(4) cf., 1.885(5) Å]
sodium congener, KTTHP 3 appears to exist as a bi-solvated dimer and the bridging M–TMP bond in [(TMEDAꢀNaTMP) ] [mean
(d -THFꢀKTTHP) ] in this polar medium. 2.459 cf., 2.470 Å]. TMEDA chelation completes the M bonding in
X-ray crystallographic characterisation of 1ꢀTMEDA and 2ꢀTMEDA 1ꢀTMEDA and 2ꢀTMEDA rendering Li three coordinate and Na
revealed monomeric (Fig. 1) and dimeric (Fig. 2) structures four coordinate. While TMEDA-chelated Na dimers are well
8
-THF)
2
ꢀLiTTHP] and [(d
8
-THFꢀNaTTHP)
2
]
and 2ꢀTMEDA. Consequently the M–N(TTHP) bond lengths are
8
-THFꢀ typical of comparable M–amido bonds such as the terminal M–
(
2
2
[
8
2
i
known [e.g., in (TMEDAꢀNaN Pr
2 2
) ], congeneric Li monomers
2a
are comparatively rare. 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 1ꢀTMEDA is
mononuclear. Hemisolvation versus full solvation is clearly a
key factor here since in solution [(TMEDA)Li(TMP)Li(TMP)] is
known to disassemble to a mixture of unsolvated, higher aggre-
gated LiTMP and mononuclear [(TMEDA)LiTMP], though in
excess TMEDA the latter forms exclusively.
Fig. 1 Molecular structure of 1ꢀTMEDA. Hydrogen atoms omitted for
clarity with exception of the olefinic hydrogen on C2. Thermal ellipsoids
are displayed at 30% probability.
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ꢁ
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
2
anions. Significantly no Me deprotonation (to CH ) was seen here
in contrast to that observed in a potassium aluminate bis-TMP
14
15
system nor was any metallation of TMEDA observed.
A simple thermally induced transformation of synthetically
Fig. 3 Overlay TVA thermogram of the methane evolution curves for important alkali metal TMP compounds to TTHP derivatives has
MTMP (M = Li, Na and K).
been established. Such decompositions could explain why LiTMP
can sometimes give poor yields in reactions performed at elevated
16
temperatures in hydrocarbon solvents. The fact that most TTHP
compounds can be made in high yield and high purity bodes well
for future studies screening their reactivity.
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
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,
T
peak 131 and 197 1C, 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 (163 1C, see
Fig. 3). For KTMP there is only a single gas evolution process,
dominated by non-condensable gases (100 1C). 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 4 Na 4 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-
(
Career Acceleration Fellowship, EP/J001872/1 and EP/L001497/1 to
C.T.O.H.; EP/K001183/1 to R.E.M). Prof. Hevia is also thanked for
insightful discussions.
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