The Reactivity of Benzyl Lithium Species is Regulated by Intermediate Structures

Article abstract of DOI:10.1002/anie.201702377

The reaction of benzyl lithiums is an important aspect in organic and organometallic synthesis. Reported herein are detailed insights into the reactivity of benzyl lithiums as regulated by intermediate structures. By discussing the carbometalation of allylamines and the reaction of the formed benzyl-lithium compounds with electrophiles, the influence of the metal as well as the solvent on the electronic structure of the intermediate is described. This molecular structure strongly influences the reactivity of these intermediates. By choosing the appropriate reaction conditions, the regioselectivity of reactions with electrophiles can be regulated. With trimethylchlorosilane in n-pentane a selective reaction at the para-position takes place. In contrast, selective reaction at the benzylic position, with trimethylchlorostannane in tetrahydrofuran (THF) as a solvent, is accomplished.

Full text of DOI:10.1002/anie.201702377

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201702377
German Edition: DOI: 10.1002/ange.201702377
Lithiation
The Reactivity of Benzyl Lithium Species is Regulated by Intermediate
Structures
Ulrike Kroesen, Lena Knauer, and Carsten Strohmann*
Abstract: The reaction of benzyl lithiums is an important
aspect in organic and organometallic synthesis. Reported
herein are detailed insights into the reactivity of benzyl lithiums
as regulated by intermediate structures. By discussing the
carbometalation of allylamines and the reaction of the formed
benzyl-lithium compounds with electrophiles, the influence of
the metal as well as the solvent on the electronic structure of the
intermediate is described. This molecular structure strongly
influences the reactivity of these intermediates. By choosing the
appropriate reaction conditions, the regioselectivity of reac-
tions with electrophiles can be regulated. With trimethylchloro-
silane in n-pentane a selective reaction at the para-position
takes place. In contrast, selective reaction at the benzylic
position, with trimethylchlorostannane in tetrahydrofuran
(THF) as a solvent, is accomplished.
of the benzyl-lithium compound with electrophiles. A formal
negative charge at the benzylic position is formed. The
reaction of benzyl anions with electrophiles is well established
as the main reaction, whereas the reaction in the aromatic
para-position is only observed as a side reaction.[5] The
position of the lithium within the carbometalated product is
affected by the solvent and strongly influences the inter-
mediate electronic structure. Thus there is an impact on the
reactivity with added electrophiles (Figure 1).
A
llylamines are often used as important building blocks in
the synthesis of pharmaceuticals, for example Terbinafine.[1]
The deprotonation of allylamines with organometallic bases
and their use as homoenolate equivalents has already been
widely investigated.[2] By using the Lochmann–Schlosser base,
allylamines can be easily deprotonated and functionalized at
the g-position.[3] In contrast, allylamines offer a second
reactivity with organolithiums, as carbometalation of the
double bond is possible (Scheme 1).[4] This type of reaction is
relatively unknown and leads to the intermediates described
in the present paper.
Figure 1. Factors affecting the reaction of electrophiles at either the
benzylic or para position of benzyl-lithiums.
Herein we present a possible pathway to perform the
reaction with electrophiles at the para-position as the main
reaction. In a first experiment the carbometalation reaction of
the piperidinoallylamine 1 in n-pentane was carried out with
tert-butyllithium, followed by reaction with trimethylchloro-
silane. After a proton transfer, the para-substituted product 3
was obtained in an isolated yield of 82% (Scheme 2).
It was of special interest to identify the intermediate
structure of the organolithium compound to explain the
outcome of this reaction. The structure of the intermediate
Scheme 1. The two possible reaction pathways: deprotonation and
carbometalation of allylamines by organolithium compounds.
During our studies on the carbometalation of allylamines
we observed a selective carbometalation in n-pentane when
using tert-butyllithium and will now describe the conversion
[*] U. Kroesen, L. Knauer, Prof. Dr. C. Strohmann
Anorganische Chemie, Technische Universitꢀt Dortmund
Otto-Hahn-Straße 6, 44227 Dortmund (Germany)
E-mail: carsten.strohmann@tu-dortmund.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201702377.
Scheme 2. Carbolithiation of the piperidinoallylamine 1 with tert-butyl-
lithium and further reaction with trimethylchlorosilane at the para-
position in n-pentane.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
carbometalated species in n-pentane was successfully isolated
and characterized (Scheme 3).
The solvent-free carbolithiated piperidinoallylamine crys-
tals were monoclinic, space-group P21, and consisted of two
molecule, but in different chemical environments.[7] This
molecular structure is, to the best of our knowledge, the first
example for an alkyl lithium compound with one lithium–p-
system contact and one lithium–carbanion contact in a single
molecule.
As a second step, the influence of the solvent on the
structure as well as on the reactivity was investigated. By
adding tetrahydrofuran (THF) as a polar solvent, the
structure in the crystal as well as in solution changed. Single
crystals of the carbolithiated product coordinated by THF
ꢀ
were obtained as triclinic crystals (space group P1). The
asymmetric unit contains one monomer with a lithium
coordinated by the benzylic anion, the piperidine nitrogen
center, and two THF molecules (Figure 3). The benzylic
group is less shielded than in the solvent-free dimer and the
negative charge is more concentrated on the carbanionic
center.
Scheme 3. Formation of two intermediate carbolithiated structures 2
and 4.
similar dimers in the asymmetric unit. It is homochiral, but
only the like diastereomer can be found in the crystal, and the
lithium is positioned trans to the tert-butyl group (Figure 2).
One of the lithium centers (Li1) is h6-coordinated by the
phenyl groups of two monomers while the other lithium (Li2)
is coordinated in a h1-coordination mode by the benzylic
carbon atoms of the monomers, as evidenced by the short
carbon–lithium distances [C3-Li2 2.301(9) ꢀ, C21-Li2 2.294-
(7) ꢀ]. Li2 is also coordinated by the two nitrogen centers of
the piperidine rings. This structure is unique, as only few
examples of lithium cations coordinated by p-systems, instead
of carbanions, are known in literature.[6] Also it should be
highlighted that there are two lithium atoms in the same
Figure 3. Molecular structure of 4 in the crystal.[8] Selected bond
lengths [ꢁ] and angles [8]: C2–C3 1.418(2), C3–C4 1.425(3), C4–C5
1.418(2), C5–C6 1.374(3), C4–C9 1.419(2), C8–C9 1.380(3), N–Li
2.134(3), C1–Li 2.424(3), C3–Li 2.297(3), Li–O1 1.935(3), Li–O2
1.975(3); C2-C3-C4 125.3(2).
To compare the molecular structure in the solid state with
the solution structure, NMR measurements were carried out.
7
In the Li NMR spectrum, with THF as a solvent, only one
signal at d = 0.8 ppm was observed. Furthermore the
1H NMR and 13C NMR spectra show signals corresponding
to a monomeric species. Crystals of the solvent-free carbo-
lithiated piperidinoallylamine had poor solubility in nonpolar
1
solvents. As the H and 13C NMR spectra in benzene show,
7
more than one stereoisomer exists in solution. The Li NMR
spectrum shows two different signals, one broad signal from
d = À1.3 to À4.2 ppm in the benzylic region as well as one
sharp signal at d = À7.3 ppm, which is indicative of a lithium
cation in between two p-systems.[10] This data suggests that in
solution a dimer is formed, where two different lithium
cations exist, one in between the two phenyl groups, and one
in a benzylic environment.
Figure 2. Molecular structure of 2 in the crystal.[8] One of two
molecules of the asymmetric cell is described. Selected bond lengths
[ꢁ]: C2–C3 1.500(6), C3–C4 1.398(7), C4–C5 1.435(6), C5–C6 1.370(6),
C4–C9 1.455(6), C8–C9 1.376(6), C3–Li2 2.301(9), C20–C21 1.517(6),
C21–C22 1.392(7), C22–C23 1.445(6), C23–C24 1.389(6), C22–C27
1.458(6), C26-C27 1.377(6), C21–Li2 2.294(7).
The structure in the solid state matched the solution-state
NMR data. To strengthen these results, quantum chemical
2
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
calculations of the NMR chemical shifts were performed
significantly shielded by the tert-butyl group. Furthermore,
using DFT-methods at the B3LYP/6-311 + G(2d,p)//B3LYP/
there is only one intramolecular handle (the piperidino
group) and, in a polar solvent such as THF, the lithium
cation can be detached from the carbanionic center. These
arguments show that the known reaction path with inversion
of the configuration might be energetically disfavored and
other competing reaction paths might become more relevant.
In experimental studies the influence of the intermediate
structure on the reactivity was examined. After the carbo-
metalation reaction in n-pentane, THF was added and the
reaction with the electrophile was carried out. As the reaction
with trimethylchlorosilane showed a 1:1 mixture of the
benzyl-substituted and the para-substituted product, the
experiment gives first hints that the changing structure,
depending on the solvent, has an essential influence on the
reactivity. In comparison to trimethylchlorosilane, an experi-
ment with trimethylchlorostannane was carried out. By
adding THF we have been able to show a selective reaction
at the benzylic position with a yield of 91% of 5 and
a diastereomeric ratio of 9:1 (Scheme 4).[12] The experiment
shows that it is possible to control the regioselectivity of the
reaction by knowing the behavior of the intermediate
structure. Also, the experiment shows a high diastereoselec-
tivity (9:1). In further experiments the influence of the metal,
the solvent, and the electrophile on the diastereoselectivity
will be examined.
7
6-31 + G(d) level.[10] For the monomeric species a Li chem-
ical shift of d = 1.2 ppm was calculated, and fits well to the
measured data. For the dimeric species the calculations result
in chemical shifts of d = 0.7 and À5.7 ppm. The calculations
are in accordance with the observed 7Li NMR measurements,
most notably the chemical shift of d = À7.3 ppm is an explicit
sign of a lithium–aryl sandwich complex in solution.[9]
To underline the crystallographic results and provide
insight into the influence of the intermediate structure on
possible reactions with electrophiles, quantum chemical
calculations were conducted. The Connolly surface was
calculated to show the accessibility of reactive centers in the
examined intermediates (Figure 4). The electrostatic poten-
tial of the solvent-free structure shows good accessibility at
Figure 4. Visualization of the electrostatic potential of 2 from the
sideview (left) and frontview (right) [MEP (Connolly surface, probe-
radius 1.6 ꢁ); B3LYP/6-31+G(d).[10]
Scheme 4. Carbolithiation of the piperidinoallylamine and further reac-
tion with trimethylchlorostannane in THF.
the para-position and also underlines that the benzylic
position is relatively shielded. A bulky electrophile such as
trimethylchlorosilane can only react in the less shielded para-
position. The intermediate structure in the solid state as well
as the corresponding quantum chemical calculations indicate
clearly that the electronic structure can lead to the para-
substituted product as the main product of the reaction of the
benzyl-lithium compound with electrophiles.
Additional calculations of the NBO charges on the
B3LYP/6-31 + G(d) level complete these results. In the
dimeric molecule NBO charges are À0.589 and À0.601 at
the benzylic positions and À0.420 and À0.417 at the para-
positions. As the benzylic position is shielded and the charges
do not differ significantly, a reaction in the benzylic position is
hindered in comparison to the reaction in the para position. In
the case of the monomeric molecule, the benzylic position is
less shielded in comparison to the dimeric structure. The
NBO charge in the benzylic position amounts to À0.669 in
comparison to À0.353 in the para-position, thus making
a reaction of electrophiles at the benzylic position more
probable.
In conclusion, our studies on the carbometalation of
allylamines have revealed the importance of the choice of
solvent and its influence on the intermediate structure of
benzyl-lithium compounds. We also showed the effect that
structure has on the reactivity of the metalated species.
Depending on the solvent and electrophile we carried out
a selective reaction at either the benzylic position or the para-
position of the phenyl group. Calculations together with
experimental results lead to well-grounded explanations for
the reactivity of these benzyl-lithium compounds. The inter-
mediate structure strongly influences the reaction mechanism
pathway of electrophilic addition and therefore results in the
regioselectivity of this reaction. Additionally, the solvent-free
intermediate structure represents one of only a handful of
lithium structures with two nonequivalent lithium cations, one
of which is part of a lithium–aryl sandwich complex. It is the
first known example of an alkyl lithium compound having one
lithium–aryl sandwich complex and one lithium coordinated
by a carbanionic center.
In general benzyl lithiums react, in less polar solvents, by
undergoing inversion from a backside attack, as we have
demonstrated in our studies on a-lithiated benzylsilanes.[11] In
the presented example the backside of the molecule is
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
R. E. Mulvey, S. D. Robertson, Inorg. Chem. 2013, 52, 12023 –
12032; e) C. Mꢂck-Lichtenfeld, H. Ahlbrecht, Tetrahedron 1999,
55, 2609 – 2624.
Acknowledgments
We thank the Deutsche Forschungsgemeinschaft (DFG) for
financial support. U.K. thanks the FCI for a Chemiefonds
Fellowship.
[6] Examples for lithium cations coordinated by a p-system: a) S.
Kohrt, S. Dachwitz, C. G. Daniliuc, G. Kehr, G. Erker, Dalton
Trans. 2015, 44, 21032 – 21040; b) C. ꢃffing, R. Koppe, H.
Schnçckel, Organometallics 1998, 17, 3512 – 3515; c) M. I. Arz,
D. Gei, G. Schnakenburg, A. C. Filippou, J. Am. Chem. Soc.
2016, 138, 4589 – 4600; d) S. Horchler, E. Parisini, H. W. Roesky,
H.-G. Schmidt, M. Noltemeyer, J. Chem. Soc. Dalton Trans.
1997, 2761 – 2763; e) F. Lips, J. C. Fettinger, P. P. Power, Poly-
hedron 2014, 79, 207 – 212.
Conflict of interest
The authors declare no conflict of interest.
[7] Molecular structures with two different lithium cations, one of
Keywords: allylic compounds · lithiation · regioselectivity ·
them coordinated by
a p-system: a) Q. F. Mokuolu, P. A.
structure-activity relationships · X-ray diffraction
Duckmantion, P. B. Hitchcock, C. Wilson, A. J. Blake, L.
Shukla, J. B. Love, Dalton Trans. 2004, 1960 – 1970; b) B. Eich-
horn, H. Noth, T. Seifert, Eur. J. Inorg. Chem. 1999, 2355 – 2368;
c) R. Bomparola, R. P. Davies, S. Hornaeur, A. J. P. White,
Dalton Trans. 2014, 43, 14359 – 14367.
[8] CCDC 1530477 (2) and 1530478 (4) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre.
[9] R. H. Cox, H. W. Terry, J. Magn. Reson. 1974, 14, 317 – 322.
[10] Detailed information on the used theoretical methods see:
a) V. H. Gessner, S. G. Koller, C. Strohmann, A.-M. L. Hogan,
D. F. OꢄShea, Chem. Eur. J. 2011, 17, 2996 – 3004; b) K. Gçtz,
V. H. Gessner, C. Unkelbach, M. Kaupp, C. Strohmann, Z.
Anorg. Allg. Chem. 2013, 639, 2077 – 2085.
[1] B. Sigurgeirsson, S. Billstein, T. Rantanen, T. Ruzicka, E.
di Fonzo, B. J. Vermeer, M. J. Goodfield, E. G. Evans, Br. J.
Dermatol. 1999, 141, 5 – 14.
[2] a) H. Ahlbrecht, U. Beyer, Synthesis 1999, 365 – 390; b) F.
Haeffner, M. A. Jacobson, I. Keresztes, P. G. Williard, J. Am.
Chem. Soc. 2004, 126, 17032 – 17039.
[3] a) H. Ahlbrecht, A. Kramer, Chem. Ber. 1996, 129, 1161 – 1168;
b) L. Lochmann, J. Pospꢁsil, D. Lꢁm, Tetrahedron Lett. 1966, 7,
257 – 262; c) M. Schlosser, Angew. Chem. Int. Ed. Engl. 1974, 13,
701 – 706; Angew. Chem. 1974, 86, 751 – 756.
[11] H. Ott, C. Dꢅschlein, D. Leusser, D. Schildbach, T. Seibel, D.
Stalke, C. Strohmann, J. Am. Chem. Soc. 2008, 130, 11901 –
11911.
[12] NOE-experiments were ambiguous because of the equal size of
substituents. Crystallization of the product structure to deter-
mine the main diastereomer has not succeeded.
[4] a) S. Klein, I. Marek, J. F. Poisson, J. F. Normant, J. Am. Chem.
Soc. 1995, 117, 8853 – 8854; b) S. Norsikian, I. Marek, S. Klein,
J. F. Poisson, J. F. Normant, Chem. Eur. J. 1999, 5, 2055 – 2068;
c) C. Unkelbach, C. Strohmann, J. Am. Chem. Soc. 2009, 131,
17044 – 17045.
[5] a) S. G. Koller, U. Kroesen, C. Strohmann, Chem. Eur. J. 2015,
21, 641 – 647; b) C. Strohmann, K. Lehmen, K. Wild, D.
Schildbach, Organometallics 2002, 21, 3079 – 3081; c) M. G.
Davidson, D. Garcia-Vivo, A. R. Kennedy, R. E. Mulvey, S. D.
Robertson, Chem. Eur. J. 2011, 17, 3364 – 3369; d) D. R.
Armstrong, M. G. Davidson, D. Garcia-Vivo, A. R. Kennedy,
Manuscript received: March 6, 2017
Revised: March 23, 2017
Final Article published: && &&, &&&&
4
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Lithiation
U. Kroesen, L. Knauer,
C. Strohmann*
&&&& — &&&&
The Reactivity of Benzyl Lithium Species
is Regulated by Intermediate Structures
A benzyl-lithium complex, with non-
equivalent environments for its two lith-
ium centers, leads to unexpected regio-
selective reactions with electrophiles (E+)
at the para-position. By changing the
solvent to tetrahydrofuran, a monomer is
formed and electrophiles react at the
benzylic position.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!