Lithium cadmate-mediated deprotonative metalation of anisole: Experimental and computational study

Article abstract of DOI:10.1021/jo100150s

Lithium cadmates bearing different ligands were compared with efficient (TMP)₃CdLi (TMP = 2,2,6,6-tetramethylpiperidino) for their ability to deprotometalate anisole. The generated arylcadmates were evidenced using I ₂. The results show that it is possible to replace only one of the TMP (with a piperidino, a diisopropylamino, a butyl, or a sec-butyl) without important yield drop. In the light of DFT calculations, reaction pathways were proposed for the deprotocadmations of anisole using a triamino, an alkyldiamino, and an aminodialkyl cadmate.

Full text of DOI:10.1021/jo100150s

pubs.acs.org/joc
is low. In addition, in the absence of polar solvents such as
0
Lithium Cadmate-Mediated Deprotonative
Metalation of Anisole: Experimental and
Computational Study
tetrahydrofuran (THF), activating agents such as N,N,N ,
0
N -tetramethylethylenediamine (TMEDA), or directing groups
able to disaggregate the base, the efficiency of reactions using
lithium compounds on their own as bases is limited.
The use of metal additives in order to modify the behavior
†
‡
Katia Sn ꢀe garoff, Shinsuke Komagawa,
Mitsuhiro Yonehara, Floris Chevallier, Philippe C. Gros,
‡
†
§
0
of bases is a challenging field. Various (R) (R )
n
0
MLi (M=
,
Masanobu Uchiyama,* and Florence Mongin*
‡
,†
n
0
metal, R, R =alkyl, amino, chloro...)-type compounds al-
ready prepared behave as superbases since such species
exhibit behaviors that cannot be reproduced by the mono-
metallic compounds on their own. Well-known examples of
†
Chimie et Photonique Mol eꢀ culaires, UMR 6510 CNRS,
Universit eꢀ de Rennes 1, B a^ timent 10A, Case 1003,
Campus Scientifique de Beaulieu, 35042 Rennes, France,
The Institute of Physical and Chemical Research, RIKEN,
-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan, and
SOR, SRSMC, CNRS, Universit eꢀ de Nancy, Boulevard des
Aiguillettes, 54506 Vanduvre-L eꢁ s-Nancy, France
‡
0
powerful RR MLi mixtures of organolithiums and M alkali
t
2
2
metal alkoxides BuLi- BuOK first described by Schlosser and
§
3
Lochmann, and BuLi-Me N(CH ) OLi developed in the pyri-
2
2 2
4
0
n
dine series by Gros and Fort. (R) (R ) MLi-type bases with
0
n
M different from an alkali metal have also been described
5
since then by different groups. Among them, examples are the
uchi_yama@riken.jp; florence.mongin@univ-rennes1.fr
Received January 28, 2010
t
mixed Li-Zn bases R Zn(TMP)Li( TMEDA) (R= Bu, Bu)
2
3
described by the groups of Kondo, Uchiyama, Mulvey and
6
7
Hevia and (TMP) Zn 2MgCl 2LiCl and TMPZnCl LiCl
8
2
3
2
3
3
developed by the group of Knochel.
We recently developed a mixed Li-Cd base, (TMP)39
CdLi, which allowed efficient and chemoselective reactions.
This base was easily prepared by mixing CdCl TMEDA
2
3
with 3 equiv of LiTMP, and its ate structure has been shown
on the basis of NMR spectroscopy and DFT calculation
studies. In order to identify the structural requirements to
meet in order to get an efficient metalation, the deprotona-
0
tion ability of different (R) (R )
n
CdLi compounds was
(3-n)
investigated.
The metalation of anisole by (TMP) CdLi (0.5 equiv of
3
Lithium cadmates bearing different ligands were com-
pared with efficient (TMP) CdLi (TMP=2,2,6,6-tetra-
CdCl TMEDA and 1.5 equiv of LiTMP) in THF at room
2
3
3
methylpiperidino) for their ability to deprotometalate
anisole. The generated arylcadmates were evidenced
using I . The results show that it is possible to replace
only one of the TMP (with a piperidino, a diisopropyla-
mino, a butyl, or a sec-butyl) without important yield
drop. In the light of DFT calculations, reaction pathways
were proposed for the deprotocadmations of anisole
using a triamino, an alkyldiamino, and an aminodialkyl
cadmate.
(2) Schlosser, M. Pure Appl. Chem. 1988, 60, 1627–1634.
(
(
3) Lochmann, L. Eur. J. Inorg. Chem. 2000, 7, 1115–1126.
4) Gros, P. C.; Fort, Y. Eur. J. Org. Chem. 2009, 4199–4209.
2
(5) For reviews, see: (a) Mulvey, R. E. Organometallics 2006, 25, 1060–
075. (b) Mulvey, R. E.; Mongin, F.; Uchiyama, M.; Kondo, Y. Angew.
Chem., Int. Ed. 2007, 46, 3802–3824. (c) Mulvey, R. E. Acc. Chem. Res. 2009,
2, 743–755.
(6) (a) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am. Chem.
Soc. 1999, 121, 3539–3540. (b) Uchiyama, M.; Miyoshi, T.; Kajihara, Y.;
Sakamoto, T.; Otani, Y.; Ohwada, T.; Kondo, Y. J. Am. Chem. Soc. 2002,
124, 8514–8515. (c) Barley, H. R. L.; Clegg, W.; Dale, S. H.; Hevia, E.;
Honeyman, G. W.; Kennedy, A. R.; Mulvey, R. E. Angew. Chem., Int. Ed.
1
4
2
005, 44, 6018–6021. (d) Clegg, W.; Dale, S. H.; Hevia, E.; Honeyman,
G. W.; Mulvey, R. E. Angew. Chem., Int. Ed. 2006, 45, 2370–2374. (e) Clegg,
W.; Dale, S. H.; Harrington, R. W.; Hevia, E.; Honeyman, G. W.; Mulvey,
R. E. Angew. Chem., Int. Ed. 2006, 45, 2374–2377. (f) Clegg, W.; Dale, S. H.;
Drummond, A. M.; Hevia, E.; Honeyman, G. W.; Mulvey, R. E. J. Am.
Chem. Soc. 2006, 128, 7434–7435. (g) Uchiyama, M.; Matsumoto, Y.;
Nobuto, D.; Furuyama, T.; Yamaguchi, K.; Morokuma, K. J. Am. Chem.
Soc. 2006, 128, 8748–8750. (h) Uchiyama, M.; Kobayashi, Y.; Furuyama, T.;
Nakamura, S.; Kajihara, Y.; Miyoshi, T.; Sakamoto, T.; Kondo, Y.;
Morokuma, K. J. Am. Chem. Soc. 2008, 130, 472–480. (i) Clegg, W.;
Conway, B.; Hevia, E.; McCall, M. D.; Russo, L.; Mulvey, R. E. J. Am.
Chem. Soc. 2009, 131, 2375–2384.
The deprotonative metalation has been widely used as a
powerful method for the regioselective functionalization of
1
aromatic compounds. Organolithiums and hindered
lithium amides have been largely employed for this purpose
because they are either commercially available or can be
readily prepared in ethers and alkanes. However, their
compatibility with sensitive substrates and functional groups
(
7) (a) Wunderlich, S. H.; Knochel, P. Angew. Chem., Int. Ed. 2007, 46,
7685–7688. (b) Wunderlich, S.; Knochel, P. Chem. Commun. 2008, 6387–
389. (c) Wunderlich, S. H.; Knochel, P. Org. Lett. 2008, 10, 4705–4707.
6
(
d) Mosrin, M.; Knochel, P. Chem.;Eur. J. 2009, 15, 1468–1477.
(8) Mosrin, M.; Knochel, P. Org. Lett. 2009, 11, 1837–1840.
(9) (a) L’Helgoual’ch, J.-M.; Bentabed-Ababsa, G.; Chevallier, F.;
(
1) For excellent reviews, see: (a) Gschwend, H. W.; Rodriguez, H. R.
Org. React. 1979, 26, 1–360. (b) Beak, P.; Snieckus, V. Acc. Chem. Res. 1982,
5, 306–312. (c) Snieckus, V. Chem. Rev. 1990, 90, 879–933. (d) Gant, T. G.;
Meyers, A. I. Tetrahedron 1994, 50, 2297–2360. (e) Schlosser, M. In Organo-
metallics in Synthesis, 2nd ed.; Schlosser, M., Ed.; Wiley: New York, 2002;
Chapter I.
1
Yonehara, M.; Uchiyama, M.; Derdour, A.; Mongin, F. Chem. Commun.
2008, 5375–5377. (b) Sn ꢀe garoff, K.; L’Helgoual’ch, J.-M.; Bentabed-Ababsa,
G.; Nguyen, T. T.; Chevallier, F.; Yonehara, M.; Uchiyama, M.; Derdour,
A.; Mongin, F. Chem.;Eur. J. 2009, 15, 10280–10290.
DOI: 10.1021/jo100150s
r 2010 American Chemical Society
Published on Web 04/13/2010
J. Org. Chem. 2010, 75, 3117–3120 3117

Sn ꢀe garoff et al.
JOCNote
TABLE 1. Metalation of Anisole Using Different Homo- and Heteroleptic Li-Cd Bases Followed by Trapping with I
2
entry
putative base (n)
(TMP) CdLi (0.5)
(P) CdLi (1)
(HMDS) CdLi (1)
(DA) CdLi (1)
(P)Cd(TMP) Li (1)
yield (%)
entry
putative base (n)
yield (%)
1
2
3
4
5
6
7
8
9
3
75
0
0
12
13
14
15
16
17
18
19
20
21
Bu
Bu
2
2
3
Cd(TMP)Li (0.5)
Cd(TMP)Li (1)
CdLi (0.5)
7
28
9
75
8
39
3
51
13
0
3
3
Bu
s
3
42
75
21
3
84
39
34
78
BuCd(TMP)
2
Li (1)
Cd(TMP)Li (1)
Li (1)
Cd(TMP)Li (1)
TMSCH Cd(TMP)
s
t
2
Bu
2
(HMDS)Cd(TMP)
(TMP)Cd(HMDS)
2
Li (1)
Li (1)
BuCd(TMP)
2
t
2
Bu
2
(DA)Cd(TMP)
(TMP)Cd(DA)
2
Li (1)
Li (1)
2
2
Li (1)
Cd(TMP)Li (1)
CdLi (1)
2
(TMSCH
(TMSCH
2
)
)
2
1
1
0
1
BuCd(TMP)
BuCd(TMP)
2
2
Li (0.5)
Li (1)
2
3
FIGURE 1. Reactants, intermediates, complexes, and TSs in the deprotonation reaction of anisole with (Me
˚
energy changes at the B3LYP/631SVPs level are shown in A and kcal/mol, respectively.
2
N)
3
CdLi. Bond lengths and
temperature for 2 h, followed by subsequent trapping with I ,
2
the number of TMP groups, were obtained employing
Bu Cd(TMP)Li and Bu CdLi (entries 12-14). Similar
results were observed by replacing TMP groups of
1
0
proceeds in 75% yield (Table 1, entry 1). Amines such as
piperidine, diisopropylamine, and even 1,1,1,3,3,3-hexam-
ethyldisilazane are less expensive than HTMP, and the use of
the corresponding amino groups in homo- and heteroleptic
2
3
s
(TMP) CdLi with Bu groups (entries 15,16). With Bu
t
3
(entries 17,18) and Me SiCH (entries 19-21) groups,
3
2
bases was considered. Putative (P) CdLi (P=piperidino) and
3
yields still decrease with increasing numbers of alkyl
groups but, in these cases, the reaction efficiency is poorer
(HMDS) CdLi (HMDS = N(SiMe ) ) failed in metalating
anisole (entries 2,3). In contrast, the expected 2-iodoanisole
3 3 2
s
than observed with Bu and Bu groups.
i
was isolated in 42% yield with (DA) CdLi (DA = N Pr ),
provided that 1 equiv was used (entry 4).
The deprotonative metalation using cadmate bases
was theoretically investigated using DFT calculations. To
this purpose, (Me N) CdLi, MeCd(NMe ) Li, and Me Cd-
3
2
1
1
The use of heteroleptic Li-Cd amides bearing one or two
TMP ligand(s) was then attempted. It was found possible to
2
3
2 2
2
(NMe )Li were, respectively, employed as models for
2
replace one of the three TMP groups of (TMP) CdLi with a P
3
(TMP) CdLi, RCd(TMP) Li, and R Cd(TMP)Li. A mole-
3
2
2
group without altering the efficiency of the reaction (entry 5).
In contrast, the use of one or two HMDS groups resulted in
low yields (entries 6,7). As observed by replacing one TMP
with a P, the use of one DA group for two remaining TMP
proved efficient, affording the iodide in 84% yield (entry 8).
The replacement of a second TMP led to a low conversion of
cule of Me O (instead of THF) was incorporated to complete
2
lithium atom coordination. Although the choice of this
simplified model system may lead to an underestimation of
the steric effects of bulky groups, the essential character of the
reaction should still be observable using this model system.
Reaction Pathway of Deprotonation of Anisole with
Lithium Tris(dimethylamino)cadmate (Figure 1). Among sev-
eral possibilities for the deprotonation reaction using
(Me N) CdLi, we identified two plausible reaction pathways
anisole; the 39% yield obtained with (TMP)Cd(DA) Li
2
(entry 9) is similar to that of 42% observed using (DA) CdLi.
3
(TMP) CdLi was next compared with RCd(TMP) Li
and R Cd(TMP)Li (R = alkyl). By replacing one TMP
3
2
2
3
through Li-assisted and Cd-assisted deprotonation TSs (TS1
and TS2). In both cases, the reaction coordinates started with
formation of a relatively stable initial complex (IM1 or IM2)
between anisole oxygen and the countercation Li or the
central Cd metal. This indicated that the regioselectivity of
the ortho cadmation reaction can be explained by a coordi-
native approximation effect between functional group and the
Li or Cd metal, enabling initial complex formation and
orienting the ate base ligand exclusively toward aromatic
2
group with one Bu, the metalation of anisole still took
place efficiently, provided that 1 equiv of base was used
1
entries 10,11). Decidedly lower yields, decreasing with
1
(
(
10) The synergy of the reaction was demonstrated using either LiTMP or
TMP) Cd; see ref 9.
3
11) The 75% yield obtained using 0.5 equiv of (TMP) CdLi was not
(
2
(
equaled using 0.5 equiv of any of the other Li-Cd combinations. Similar
results were obtained in some cases provided that 1 equiv of base was used.
3
118 J. Org. Chem. Vol. 75, No. 9, 2010

Sn ꢀe garoff et al.
JOCNote
FIGURE 2. Reactants, intermediates, complexes, and TSs in the deprotonation reaction of anisole with MeCd(NMe
details.
2
)
2
Li. See Figure 1 for
ortho hydrogen. The Li-assisted deprotonation (path 1) is a
pathway similar to that seen in TMP-Zn-ate mediated DoM
Reaction Pathway of Deprotonation of Anisole with
Lithium Dialkyl(dimethylamino)cadmate (Figure 3). Two
structures are also a priori possible for Me Cd(NMe )Li,
6
g
reactions and takes place via “open form TS” (TS1) with a
reasonable activation energy (þ22.0 kcal/mol). The Cd-
assisted deprotonation (path 2), an unique pathway of this
Cd-ate base, proceeds smoothly with a smaller activation
energy (19.5 kcal/mol). This deprotonation is facilitated by
the direct push-pull synergy of the Lewis acidic Cd metal and
2
2
i.e., the unsymmetrical one (in RT4) and the symmetrical one
(in RT5): the former structure is computed to be much more
stable, mainly due to the stable Me N Li, than the latter
2
3 3 3
one by 17.0 kcal/mol. Initial electrostatic coordination of Li
to anisole oxygen occurs, resulting in the formation of a
complex (IM6) with a stabilization energy of 7.4 kcal/mol.
the negatively charged NMe moiety to generate a stable
2
product (PD2). The stabilization energy is very large (-26.8
kcal/mol) because this deprotonation occurs with mainte-
nance of the stable Me N Li NMe coordination.
From IM6, the DoM reaction using the Me N ligand can
2
take two pathways through TS6 (“closed form” TS, path 6)
and TS7 (“open form” TS, path 7). Although the activation
energies are only 0.7 kcal/mol higher than that of the DoM
reaction with MeCd(μ-NMe ) Li (path 3), the deprotona-
2
3 3 3 3 3 3
2
Reaction Pathway of Deprotonation of Anisole with
Lithium Bis(dimethylamino)alkylcadmate (Figure 2). The
computational results of deprotonation with MeCd(NMe ) -
2
2
2
2
tion occurs with more than 10 kcal/mol endothermicity. This
large energy loss is a result of the cleavage of the stable
Me N Li bond and of the rather small energy gain to
Li indicated that the Li-assisted pathway via the “open form”
TS (path 3) is the most probable. In this pathway, the DoM
reaction proceeds through TS3 by using one of the Me N
2
3 3 3
2
form a C Li bond at the expense of the Me N Li bond
3 3 3 3 3
3
2
ligands of MeCd(μ-NMe ) Li (in RT2). The activation energy
2
2
cleavage. These results indicate that path 6 and 7 are
kinetically favored but thermodynamically unfavored.
The computed predilection accounts for the experimental
observation that dialkylamidocadmate complexes are al-
most inert in the deprotonative cadmation reaction of ani-
sole (Table 1, entries 12,13). Deprotonation by the μ-Me
ligand on Cd (path 8) was also found to be kinetically
unfavorable, requiring a much higher activation energy of
of path 3 is 4.4 kcal/mol higher than that of the Cd-assisted
pathway (path 2) in the reaction with (Me N) CdLi. This
calculation indicates that the reaction of RCd(TMP) Li
2
(Table 1, entry 11) proceeds as well as the reaction of (TMP)3-
CdLi. The reaction pathway via the “closed form” TS4 (path 4)
is rather unfavorable. A Cd-assisted deprotonation pathway
2
3
(
path 5) was also identified, and the activation energy (þ20.2
kcal/mol) is energetically more favorable than that of the Li-
assisted “open form” pathway (path 3) by 3.7 kcal/mol because
of direct activation of the Cd-N bond by anisole oxygen. This
pathway, however, first requires the reformation of the most
stable symmetric cadmate in RT2 to an unstable unsymmetric
one in RT3, including the dissociation of the stable Li 3 3 3 N
bond, a process leading the 16.2 kcal/mol loss of energy.
Therefore, this pathway is much less likely to take place than
those of Li-assisted deprotonation shown in Figure 2.
3
2.7 kcal/mol.
In summary, among all the homo- and heteroleptic
Li-Cd amides tested, (TMP) CdLi was the more efficient
3
reagent; by replacing one TMP with a P or a DA group,
similar yields were obtained but with a double amount of
base, as if P and DA were unable to act as bases. A ligand of
(TMP)
CdLi could be replaced in the same way with a Bu or
3
s
a Bu group.
J. Org. Chem. Vol. 75, No. 9, 2010 3119

Sn ꢀe garoff et al.
JOCNote
FIGURE 3. Reactants, intermediates, complexes, and TSs in the deprotonation reaction of anisole with Me
details.
Cd(NMe )Li. See Figure 1 for
2 2
From a mechanistic point of view, the DFT calculations
revealed that the metalation with (TMP) CdLi proceeds
Computational Details
3
All calculations were carried out with the Gaussian 03
program package. The molecular structures and harmonic
through a Cd-assisted transition state while pathways with
higher activation energies and Li-assisted transition states
were found with RCd(TMP) Li and R Cd(TMP)Li (R =
16
vibrational frequencies were obtained using the hybrid density
functional method based on Becke’s three-parameter exchange
function and the Lee-Yang-Parr nonlocal correlation func-
2
2
alkyl). The mechanism of the anisole deprotonation using
6
g,i
17
18
TMP-dialkyl zincates has been the subject of studies.
A
tional (B3LYP). We used Ahlrichs’ SVP all-electron basis set
for the cadmium atom and 6-31G* for the other atoms (denoted
as 631SVPs in the text). Geometry optimization and vibrat-
ional analysis were performed at the same level. All stationary
points were optimized without any symmetry assumptions and
characterized by normal coordinate analysis at the same level of
theory (number of imaginary frequencies, NIMAG, 0 for mini-
ma and 1 for TSs).
two-step mechanism has been proposed where the lithium
zincate first acts as an amino base, and thus generated
HTMP then returns back to zinc through 2-anisyl- or R-
mediated deprotonation. Studies will be soon started in
order to identify the species present in reaction mixtures
coming from metalation steps using Li-Cd combinations
and to possibly propose more complete mechanisms.
(TMP) CdLi proved to allow amazing reactions such as
the dideprotonation of sensitive pyrazine and ferrocene
3
Acknowledgment. We gratefully acknowledge the financial
support of R ꢀe gion Bretagne (to K.S.) and Agence Nationale de
la Recherche (ACTIVATE program) (to K.S. and M.U.).
The calculations were performed by using the RIKEN
Integrated Cluster of Clusters (RICC) facility.
1
2
1
3
esters,
which cannot be achieved using other
0
0
R) (R ) MLi-type bases. To overcome concerns about in-
n n
herent toxicity of cadmium compounds, new mixed Li-
metal bases of ate type are under development.
(
1
4
Supporting Information Available: Experimental proce-
dures, computational methods, Cartesian coordinates, and total
electron energies. This material is available free of charge via the
Internet at http://pubs.acs.org.
Experimental Section
1
5
All bases were synthesized from CdCl
2
3 TMEDA.
(
12) L’Helgoual’ch, J.-M.; Bentabed-Ababsa, G.; Chevallier, F.; Derdour,
A.; Mongin, F. Synthesis 2008, 4033–4035.
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Wallingford, CT, 2004.
(17) (a) Becke, A. D. Phys. Rev. 1988, A38, 3098–3100. (b) Becke, A. D.
J. Chem. Phys. 1993, 98, 1372–1377. (c) Becke, A. D. J. Chem. Phys. 1993,
98, 5648–5652. (d) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. 1988, B37,
785–788.
(
(
Poisoning and Drug Overdose, 3rd ed.; Haddad, L. M., Shannon, M.,
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3
120 J. Org. Chem. Vol. 75, No. 9, 2010