Carbanions with two N substituents: Nucleophilic acyl-group-transfer reagents

Article abstract of DOI:10.1002/anie.200700113

(Chemical Equation Presented) Without mercury or thallium: A new umpoled nucleophilic acylation reagent is formed in the direct deprotonation of 1,3,5-trimethyl-1,3,5-triazacyclohexane with butyllithium. The carbanionic center is flanked by two amino grou

Full text of DOI:10.1002/anie.200700113

Communications
DOI: 10.1002/anie.200700113
Alkyl Lithium Compounds
Carbanions with Two N Substituents: Nucleophilic Acyl-Group-
Transfer Reagents**
Daniel Bojer, Ina Kamps, Xin Tian, Alexander Hepp, Tania Pape, Roland Fröhlich, and
Norbert W. Mitzel*
Dedicated to Professor Helge Willner on the occasion of his 60th birthday
Among the many types of carbanionic systems, those in which
the carbanion is attached to a nitrogen atom are special, as
they belong to the group of formally nonstabilized or even
destabilized systems.[1] This can be rationalized by the
repulsive interaction of the carbanion with the adjacent
nitrogen lone pair. For this reason a-lithiated amines are in
general not easily accessible by direct deprotonation of
unexpectedly smoothly, and—in contrast to the twofold
terminal deprotonation of the related Me2NCH2NMe2—the
deprotonation in these systems occurs exclusively at a
position between two N atoms (Scheme 1).
amines; they are typically prepared by transmetalation,[2] by
[3]
À
À
cleavage of C S or C Te bonds, or by the use of a-
metalated amines such as the more easily deprotonated
amine–BF3 adducts.[4] There are only few exceptions, for
example aminals of the type RMeNCH2NMeR, which can be
deprotonated at both methyl groups simultaneously by direct
treatment with tBuLi;[5] 1,4,7-trimethyl-1,4,7-triazacyclono-
nane,[6] which reacts already with nBuLi to give a product
monolithiated at one methyl group; and N-methylpiperidine,
which is deprotonated at the CH3 group upon application of
Schlosserꢀs base.[7] The difficulties of a-lithiation can also be
considered in the context of the facilitated deprotonation of
systems with donor-functionalized side chains,[8] which led to
noticeable possibilities in synthesis.[9]
Scheme 1. Lithiation of TMTAC.
The lithiation always occurs selectively at a methylene
unit regardless of the solvent (various hydrocarbon or ether
solvents), temperatures (between À788C and ambient tem-
perature), and which base is used (n-, sec- , ortBuLi). The best
yields are achieved with tBuLi in hexane. In all cases the
product obtained consists of two equivalents of a deproton-
ated species and one equivalent of the free base TMTAC. The
reason is apparent from the crystal structure determination of
this compound (Figure 1).[14]
The chain aggregate consists of two crystallographically
independent units of dimeric 2-lithio-TMTAC (Figure 2),
which are alternatingly linked by two nitrogen atoms of a non-
lithiated TMTAC molecule. The dimers are centrosymmetric
aggregates, whereby the lithium atom is attached to the
carbanionic center of one ring and to the two nitrogen atoms
adjacent to the carbanionic C atom of the other ring. The
Our recent attempts to extend the metalation reaction of
iminium chlorides with low-valent Group 13 metal halides
(InCl, GaI etc.) resulting in a-metalated amines,[10] to the
metalation of formamidinium systems failed. Instead dispro-
portionation was observed, leading to hexahalogenodimeta-
lates and leaving the formamidinium ion unchanged.[11] Thus,
so far no carbanions with two directly attached amino
functions are known, and the closest related examples are a
few doubly[12] or triply[13] pyrazolyl-substituted carbanions.
We now report that the reaction of 1,3,5-trimethyl-1,3,5-
triazacyclohexane (TMTAC) with nBuLi in hexane proceeds
[*] D. Bojer, I. Kamps, Dr. X. Tian, Dr. A. Hepp, T. Pape,
Prof. Dr. N. W. Mitzel
Institut für Anorganische und Analytische Chemie
Westfälische Wilhelms-Universität Münster
Corrensstrasse 30, 48149 Münster (Germany)
Fax: (+49)251-83-36007
E-mail: mitzel@uni-muenster.de
Dr. R. Fröhlich
Organisch-chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstrasse 40, 48149 Münster (Germany)
Figure 1. Structure of a dimers of 2-lithio-TMTAC in aggregate 1.
Selected bond lengths [Š] and angles [8]: Li1’-C2 2.202(3), Li1-N2
2.174(3), Li1-N3 2.129(3), Li1-N2’’ 2.153(3), C2-N2 1.485(2), C2-N3
1.491(2); Li1’-C2-N2 67.4(1), Li1’-C2-N3 65.6(1), N2-Li1-N3 66.3(1),
N2-Li1-C2’ 121.2(1), N3-Li1-C2’ 119.3(1).
[**] This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
Figure 2. Structure of the chains of aggregate 1.
Figure 3. Structure of the tetrameric units of 2-lithio-1,3-dimethyl-1,3-
diazacyclohexane in 2. Selected bond lengths [Š] and angles [8]: C1-Li1
2.123(4), C1-Li1’ 2.107(4), Li1’-N1 2.043(4), Li1’-N2 2.035(4), Li1···Li1’
3.163(5); N1-C1-N2 104.9(2), Li1-C1-N1 121.1(2), Li1-C1-N2 119.7(2),
C1-N1-Li1’ 71.4(2), C1-N2-Li1’ 71.5(2).
fourth coordination site of these lithium atoms is saturated by
a contact to a nitrogen atom of the bridging TMTAC unit.
Indicative of a repulsive interaction between the carbanions
À
and the adjacent nitrogen atoms are the C N bond lengths
(mean of four bonds: 1.489 Š), whereas the same N atoms
have shorter bonds to the adjacent CH2 groups in the ring
(mean: 1.456 Š).
Compound 1 was furthermore characterized by elemental
1
7
analysis and H, Li, and 13C NMR spectroscopy. The NMR
data clearly reflect the presence of lithiated and free TMTAC
units in a 2:1 ratio.
It must be mentioned that the lithiation of TMTAC was
used previously to prepare 2-deuterio-TMTAC; by 2-Li-
TMTAC was generated in situ and quenched with D2O.[13]
However, the reported yield of 91% is not consistent with our
findings for aggregate 1 consisting of a 2:1 mixture of lithiated
and non-lithiated TMTAC.
Another interesting point was the differing regioselectiv-
ity of the deprotonation of Me2NCH2NMe2 and of TMTAC
with alkyl lithium reagents. Although both compounds
contain a CH2(Me)NCH2N(Me)CH2 unit, the aminal is
deprotonated at the methyl groups, whereas TMTAC at the
seemingly unfavorable methylene position between the two
deactivating nitrogen atoms. This is surprising as the open-
chain aminal Me2NCH2NMe2 can adopt every conformation
that is adopted by the corresponding unit in TMTAC.
Therefore intramolecular electronic effects like the anomeric
effect seem not to be dominant here.[16]
It seemed more likely that the third N atom in TMTAC
might be responsible for the observed reactivity by precoor-
dinating BuLi in close proximity to the lithiation site. To test
this hypothesis we carried out a lithiation reaction with the
related heterocycle 1,3-dimethyl-1,3-diazacyclohexane, which
should have similar conformational behavior but does not
contain the third N atom. This compound can be deproton-
ated with tBuLi, and again surprisingly, the reaction occurs
selectively at the position between the two N atoms, proving
the irrelevance of the third N atom in TMTAC for the
observed regioselectivity of lithiation.
Figure 4. Structure of the cocrystallized 2 and tBuLi, including the
(tBuLi)4 units.
simultaneously interacting with the p systems of other
monomers.[17]
The carbanionic C atom of the 1,3-dimethyl-1,3-diazacy-
À
clohexan-2-yl ring is bound to a lithium atom (d(C1 Li1) =
2.123(4) Š). The two N atoms of this ring form bonds to
À
another Li atom (d(Li1’ N) = 2.043(4) and 2.035(4) Š). This
second Li atom is also close to the carbanionic C atom of this
À
ring, and with a Li C distance of 2.107(4) Š it is even closer
than the atom Li1. This distance is at the low end of the range
[15]
À
of Li C distances in a-lithiated amines (2.101–2.375 Š).
Each lithium atom is thus four-coordinate but has far from
tetrahedral coordination geometry. The structures in the
tBuLi tetramers are very similar to those found in pure
tBuLi.[16]
Compound 2 was further characterized by quenching it
with D2O, and the resulting 2-deuterio-1,3-dimethyl-1,3-
diazacyclohexane was identified by NMR and MS spectra.
This experiment indicates that the ring structure is behind the
regioselectivity of the lithiation of TMTAC to give 1, although
we cannot present a detailed mechanism.
We obtained single crystals of this lithiated product 2
cocrystallized with tBuLi. The molecular structure of a
tetramer of 2 in these crystals is shown in Figure 3; the
crystal structure containing also tetramers of tBuLi is
displayed in Figure 4.[12] The tetrameric aggregation motif
resembles distantly the aggregation of tetrameric lithium
aryls, in which the Li atoms are s-bound to the aryl rings and
Compound 1 is related to the dialkoxymethyllithum
compounds[20] and the Corey–Seebach reagents, the 2-lithio-
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Communications
1,3-dithianes,[17] which are the examples par excellence of the
aminal system would be easily lithiated in the correct position
and also efficiently cleaved under acidic conditions to liberate
the corresponding acylated compound. We are currently
working on these aspects as well as studying the reaction
mechanism, for which a complex-induced proximity effect[24]
seems likely.
umpolung principle.[18] Like these dithianes, 1 can be used as a
nucleophilic transfer reagent for acyl groups, which makes it a
highly useful compound in organic synthesis. We have
demonstrated this protocol by reacting 1 with several electro-
philes (Scheme 2).
Received: January 9, 2007
Published online: April 20, 2007
Keywords: acylation · aggregation · lithiation · regioselectivity ·
.
umpolung
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Scheme 2. Nucleophilic acylation of carbonyl compounds with 1.
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Engl. 1996, 35, 2378.
Hydrolytic workup under acidic conditions leads to the
expected degradation of the polyaminal-type system, the
TMTAC ring, and liberation of the acylated product. This is
remarkable as this method does thus not require mercury-or
thallium-containing reagents for liberation of the aldehyde—
a notable advantage over the classical Corey–Seebach
method in terms of preparative ease and ecological issues.
The further development of Corey–Seebach reagents is a
topic currently studied by DeglꢀInnocenti, Policino, and
Capperucci, who employed silyl heterocycles as formyl
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To show that the intermediate products, the hydroxy-
methyl derivatives of TMTAC, can be isolated as stable
compounds, we crystallized the product of the reaction of 1
with benzophenone after careful hydrolysis: 2-(hydroxydi-
phenylmethyl)-1,3,5-trimethyl-1,3,5-triazacyclohexane (3a).
Its molecular structure in the crystal is shown in Figure 5. In
a further test reaction of 1 with bromodiphenylmethane, no
addition of a TMTAC function could be observed, but the
reductive coupling of Ph2CHBr gave 1,1,2,2-tetraphenyl-
ethane in 72% yield.
Clearly the precursors and conditions of these reactions
can be further optimized. The most suitable cyclic (poly)-
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¯
[14] Crystal structure determinations. 1: C18H243Li2N9, triclinic, P1,
a = 9.092(1), b = 11.037(1), c = 12.942(1) Š, a = 77.92(1), b =
82.23(1), g = 80.92(1)8, V= 1247.0(2) Š3, Z = 2, 1calcd
=
1.064 gcmÀ3
, l = 0.71073 Š, 2qmax. = 55.88, T= 192(2) K, m =
0.067 mmÀ1. 16280 measured and 5934 independent reflections
(Rint = 0.067). 269 parameters, R1 = 0.053 for 3387 reflections
with Fo > 4s(Fo) and wR2 = 0.145 for all 5934 data. Max./min.
residual election density À0.18/0.20 eŠÀ3. 2: C9H20Li2N3, tetrag-
3
¯
onal, I4, a = 17.460(2), c = 8.2195(14) Š, V= 2505.8(6) Š , Z = 4,
1calcd = 0.976 gcmÀ3, l = 0.71073 Š, 2qmax. = 50.08, T= 153(2) K,
m = 0.055 mmÀ1. 10172 measured and 2219 independent reflec-
tions (Rint = 0.039). 130 parameters, R1 = 0.052 for 1881 reflec-
tions with Fo > 4s(Fo) and wR2 = 0.145 for all 2219 data. Max./
minÀ1. residual electron density À0.15/0.23 eŠÀ3. 3: C19H25N3O,
Figure 5. Molecular structure of 3a. Selected bond lengths [Š] and
angles [8]: C1-C2 1.531(2), C1-C14 1.583(2), C1-O1 1.422(2); O1-C1-
C14 106.1(1), C2-C1-C14 110.9(1).
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Angewandte
Chemie
monoclinic, P21/n, a = 9.009(4), b = 9.489(4), c = 19.599(9) Š,
b = 92.5(9), V= 1673.9(13) Š3, Z = 4, 1calcd = 1.236 gcmÀ3, l =
0.71073 Š, 2qmax. = 50.08, T= 153(2) K, m = 0.078 mmÀ1. 13043
measured and 2951 independent reflections (Rint = 0.043). 215
parameters, R1 = 0.042 for 2393 reflections with Fo > 4s(Fo) and
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wR2 = 0.094 for all 2951 data. Max./min. residual electron
À3
density À0.22/0.18 eŠ
.
Programs: a) SHELXTL 6.10,
Bruker-AXS X-Ray Instrumentation Inc., Madison, WI, 2000;
b) G. M. Sheldrick, SHELXL-93, Program for Crystal Structure
Refinement, Universität Göttingen, 1993. CCDC-632841 (1),
CCDC-632842 (2), and CCDC-632843 (3a) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
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