Mixed alkylamido aluminate as a kinetically controlled base

Article abstract of DOI:10.1021/ja804749y

The mechanisms by which directed ortho metalation (DoM) and postmetalation processes occur when aromatic compounds are treated with mixed alkylamido aluminate i-Bu₃Al(TMP)Li (TMP-aluminate 1; TMP = 2,2,6,6- tetramethylpiperidide) have been inve

Full text of DOI:10.1021/ja804749y

Published on Web 11/07/2008
Mixed Alkylamido Aluminate as a Kinetically Controlled Base
,
†
‡
‡
‡
Hiroshi Naka,* James V. Morey, Joanna Haywood, Dana J. Eisler,
‡
‡
†
†
Mary McPartlin, Felipe Garc ´ı a, Hironaga Kudo, Yoshinori Kondo,
,
⊥
,‡
Masanobu Uchiyama,* and Andrew E. H. Wheatley*
Graduate School of Pharmaceutical Sciences, Tohoku UniVersity, Aobayama, Aoba-ku,
Sendai 980-8578, Japan, Department of Chemistry, UniVersity of Cambridge, Lensfield Road,
Cambridge CB2 1EW, U.K., and AdVanced Elements Chemistry Laboratory, RIKEN,
2
-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
Received August 16, 2007; E-mail: naka@mail.pharm.tohoku.ac.jp; uchi_yama@riken.jp; aehw2@cam.ac.uk
Abstract: The mechanisms by which directed ortho metalation (DoM) and postmetalation processes occur
when aromatic compounds are treated with mixed alkylamido aluminate i-Bu
3
Al(TMP)Li (TMP-aluminate
1; TMP ) 2,2,6,6-tetramethylpiperidide) have been investigated by computation and X-ray diffraction.
Sequential reaction of ArC(dO)N(i-Pr)
2
(Ar ) phenyl, 1-naphthyl) with t-BuLi and i-Bu
3
Al in tetrahydrofuran
affords [2-(i-Bu Al)C H C(dO)N(i-Pr) ]Li·3THF (m ) 6, n ) 4, 7; m ) 10, n ) 6, 8). These data advance
3 m n 2
the structural evidence for ortho-aluminated functionalized aromatics and represent model intermediates
in DoM chemistry. Both 7 and 8 are found to resist reaction with HTMP, suggesting that ortho-aluminated
aromatics are incapable of exhibiting stepwise deprotonative reactivity of the type recently shown to pertain
to the related field of ortho zincation chemistry. Density functional theory calculations corroborate this view
and reveal the existence of substantial kinetic barriers both to one-step alkyl exchange and to amido-alkyl
exchange after an initial amido deprotonation reaction by aluminate bases. Rationalization of this dichotomy
comes from an evaluation of the inherent Lewis acidities of the Al and Zn centers. As a representative
synthetic application of this high kinetic reactivity of the TMP-aluminate, the highly regioselective
deprotonative functionalization of unsymmetrical ketones both under mild conditions and at elevated
temperatures is also presented.
Introduction
capable of smoothly affecting directed ortho metalation (DoM)
6-9
1
chemistry
promises to overcome limitations with the existing
Organoaluminum and aluminate compounds are among the
most important and frequently used organometallic species in
transmetalation methods that are employed to prepare aryl
aluminum compounds, namely, the restricted compatibility of
ancillary ligands (i.e., directing groups) toward aryllithium or
2
3
catalytic and synthetic organic scenarios. Recent work has
focusedontheirroleinpromotingtheformationofcarbon-carbon
and carbon-heteroatom bonds in aliphatic systems. However,
1
0
4
aryl Grignard reagents. The resulting search for new bases
capable of effecting DoM chemistry under the influence ofsbut
without chemically alteringssuch directing groups led us to
it is only recently that the potential of aromatic aluminum
compounds as synthetic building blocks has begun to be
5
design the heterometallic base TMP-aluminate 1 (i-Bu Al(TMP)-
3
developed. In particular, the generation of aluminate reagents
Li; TMP ) 2,2,6,6-tetramethylpiperidide; Chart 1) in 2004. This
†
has subsequently been used to regio- and chemoselectively
Tohoku University.
University of Cambridge.
RIKEN.
1
1
‡
elaborate a wide variety of functionalized aromatics.
⊥
(
(
1) (a) Mole, T.; Jeffrey, E. A. Organoaluminum Compounds; Elsevier:
Amsterdam, 1972. (b) Negishi, E. J. Organomet. Chem. Libr. 1976,
(4) (a) Novak, T.; Tan, Z.; Liang, B.; Negishi, E.-i. J. Am. Chem. Soc.
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E.-i. J. Am. Chem. Soc. 2006, 128, 2770–2771.
1
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933. (b) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356–363.
(c) Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979, 26, 1–360.
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D. R.; Boss, S. R.; Clayden, J.; Haigh, R.; Kirmani, B. A.; Linton,
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43, 2135–2138.
1
04–106. (e) Arai, T.; Bougauchi, M.; Sasai, H.; Shibasaki, M. J. Org.
Chem. 1996, 61, 2926–2927. (f) Iida, T.; Yamamoto, N.; Sasai, H.;
Shibasaki, M. J. Am. Chem. Soc. 1997, 119, 4783–4784.
(
3) (a) Saito, S. Aluminum in Organic Synthesis. In Main Group Metals
in Organic Synthesis;Yamamoto, H., Oshima, K., Eds.; Wiley-VCH:
Weinheim, 2004; Vol. 1, Chapter 6 and references cited therein. (b)
Taylor, M. S.; Zalatan, D. N.; Lerchner, A. M.; Jacobsen, E. N. J. Am.
Chem. Soc. 2005, 127, 1313–1317. (c) Wieland, L. C.; Deng, H.;
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5390–5395.
1
5456.
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10.1021/ja804749y CCC: $40.75

2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 16193–16200 9 16193

A R T I C L E S
Naka et al.
Chart 1
demand from a synthetic viewpoint. These would be free from
undesired spectator ligand scrambling, assuring the structure and
reactivity of the intermediate, and this would greatly expand their
potential applications as substrates in controlled synthetic proce-
dures. Recent structural work on aluminate chemistry has dem-
onstrated that, in contrast to their passivity with respect to zincates,
ancillary Lewis bases are susceptible to reaction with aluminate
21
substrates. More recently, the successful isolation of ortho
aluminate [2-(i-Bu3Al)C6H4C(dO)N(i-Pr)2]Li·3THF 7 was re-
22
ported. However, rationalization of the observation of kinetic
control (that is, amide elimination) was not attempted, and it
remained unclear whether conversion of the kinetic aluminate to a
thermodynamic metalate by stepwise quenching of the librated
amine was possible, Viz., the multifarious structure types noted for
zincate chemistry.
Chart 2
Although zinc and aluminum are oblique neighbors in the
periodic table and have been classified as typical metals with
similar reactivities, their similarity is essentially superficial
because they belong to different groups (Groups 12 and 13),
along with the significant difference between Al(III) and Zn(II)
in terms of structural and electronic properties and Lewis acidity
of the central metal. Thus, it is of interest to rationalize theo-
retically, and corroborate experimentally, the fundamental
differences between TMP-zincate and TMP-aluminate that will
be of help for designing new reactions and functional ate bases
containing these molecular frameworks. In this paper we report
the experimental and theoretical elucidation of these metalation
and postmetalation processes for TMP-aluminate 1, focusing
on its reactivity toward N,N-dialkylbenzamides (Scheme 2).
We have probed two metalation routes and one postmetalation
process (as shown in Scheme 2) using density functional theory
In the related field of organozinc chemistry, we developed TMP-
12
zincate (t-Bu2Zn(TMP)Li, 2a) as a chemoselective base in 1999,
its sodium analogue (t-Bu2Zn(TMP)Na ·TMEDA, 3) having been
13
introduced more recently by Mulvey et al. Extensive investiga-
1
4-16
tions of both the synthetic utility
properties
and structural and mechanistic
1
7-20
of these zincates have been undertaken and have
revealed that (i) deprotonation of arenes by TMP-zincates involves
TMP ligand mediation rather than alkyl (e.g., t-Bu) ligand
17,19
mediation and gives a dialkylarylzincate 4 (Scheme 1)
and (ii)
in many cases, metalated arylzincate subsequently reacts with the
generated HTMP to eliminate an alkyl ligand and to give
20
thermodynamically favorable alkylamidoarylzincate 5. Moreover,
for DG ) C(dO)N(i-Pr)2, an alkyldiarylzincate has been found to
form from precursor 2a (R ) t-Bu), while triarylzincate complex
(DFT) calculations. These investigations have revealed that ortho
alumination proceeds by a mechanism different from that
exhibited by ostensibly analogous zincate bases. We next report
the successful synthesis and structural characterization of ortho-
deprotonated aromatic aluminum compounds that represent
putative intermediates in directed ortho alumination chemistry
and which have been used to examine the (in)ability of ortho
aluminates to undergo ligand scrambling. Finally, we propose
a rationalization of the demonstrable differences between TMP-
aluminate and -zincate activity.
6
has formed from 2b (R ) Et) by the repetition of a stepwise
sequence of the type that gave 5, demonstrating the potential for
20
polybasicity in TMP-zincate systems.
While the polybasicity of TMP-zincates implies the possibility
of systems that require only a catalytic quantity of TMP functional-
ity, kinetically controlled bases with monobasicity are also in high
(
(
10) Eisch, J. J. In ComprehensiVe Organometallic Chemistry; Wilkinson,
G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon Press: Oxford, 1982;
Vol. 6, Chap. 6 and references cited therein.
11) (a) Uchiyama, M.; Naka, H.; Matsumoto, Y.; Ohwada, T. J. Am. Chem.
Soc. 2004, 126, 10526–10527. (b) Naka, H.; Uchiyama, M.; Matsu-
moto, Y.; Wheatley, A. E. H.; McPartlin, M.; Morey, J. V.; Kondo,
Y. J. Am. Chem. Soc. 2007, 129, 1921–1930.
Results and Discussion
1
. DFT Calculations. To shed light on the mechanism of
directed ortho alumination, the possible pathways for the
deprotonative metalation of N,N-dimethylbenzamide using
Me3Al(NMe2)Li·OMe2 have been modeled using DFT calcula-
(
12) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am. Chem.
Soc. 1999, 121, 3539–3540.
(
13) Andrikopoulos, P. C.; Armstrong, D. R.; Barley, H. R. L.; Clegg, W.;
Dale, S. H.; Hevia, E.; Honeyman, G. W.; Kennedy, A. R.; Mulvey,
R. E. J. Am. Chem. Soc. 2005, 127, 6184–6185.
23
tions (Figure 1). Although the choice of this simplified model
(
(
14) For a review of DoM using zincate complexes, see: Mulvey, R. E.;
Mongin, F.; Uchiyama, M.; Kondo, Y. Angew. Chem., Int. Ed. 2007,
system may lead to an underestimation of the steric effects of
bulky groups (e.g., i-Bu), the essence of the actual reaction
4
6, 3802–3824.
24
should still be observable in this model system. Hence, for
15) (a) Uchiyama, M.; Miyoshi, T.; Kajihara, Y.; Sakamoto, T.; Otani,
example, reaction of substrates RT gives the relatively stable
electrostatic complexes IM1 and IM3. In each of these, the
lithium ion is associated with the carbonyl group of the aromatic
Y.; Ohwada, T.; Kondo, Y. J. Am. Chem. Soc. 2002, 124, 8514–8515.
(
b) 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.
(
(
(
(
(
16) Hevia, E.; Honeyman, G. W.; Kennedy, A. R.; Mulvey, R. E. J. Am.
Chem. Soc. 2005, 127, 13106–13107.
´
(21) (a) Garc ´ı a-Alvarez, J.; Graham, D. V.; Kennedy, A. R.; Mulvey, R. E.;
17) Uchiyama, M.; Matsumoto, Y.; Nobuto, D.; Furuyama, T.; Yamaguchi,
K.; Morokuma, K. J. Am. Chem. Soc. 2006, 128, 8748–8750.
18) Clegg, W.; Dale, S. H.; Harrington, R. W.; Hevia, E.; Honeyman,
G. W.; Mulvey, R. E. Angew. Chem., Int. Ed. 2006, 45, 2374–2377.
19) Uchiyama, M.; Matsumoto, Y.; Usui, S.; Hashimoto, Y.; Morokuma,
K. Angew. Chem., Int. Ed. 2007, 46, 926–929.
Weatherstone, S. Chem. Commun. 2006, 3208–3210. (b) Garc ´ı a-
´
Alvarez, J.; Hevia, E.; Kennedy, A. R.; Klett, J.; Mulvey, R. E. Chem.
Commun. 2007, 2402–2404.
´
(22) Conway, B.; Hevia, E.; Garc ´ı a-Alvarez, J.; Graham, D. V.; Kennedy,
A. R.; Mulvey, R. E. Chem. Commun. 2007, 5241–5243.
(23) (a) Becke, A. D. Phys. ReV. A 1998, 38, 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.
1998, B37, 785–788.
20) Kondo, Y.; Morey, J. V.; Morgan, J. C.; Naka, H.; Nobuto, D.; Raithby,
P. R.; Uchiyama, M.; Wheatley, A. E. H. J. Am. Chem. Soc. 2007,
1
29, 12734–12738.
1
6194 J. AM. CHEM. SOC. 9 VOL. 130, NO. 48, 2008

Aluminate as a Kinetically Controlled Base
A R T I C L E S
20
Scheme 1. Stepwise DoM Pathway of TMP-Zincates (DG ) Directing Group)
Scheme 2. Possible Intermediates and Reaction Pathways in the DoM of N,N-Dialkylbenzamides by 1
substrate, behavior that closely resembles that observed experi-
aluminum, we identified two (TS1 and TS2) that were accessible
via reasonable activation energies (Figures 2 and 3).
The Me2N-mediated deprotonation process (IM1-TS1-IM2)
revealed an activation barrier of +30.7 kcal/mol en route to
forming aluminated aromatic compound IM2. In contrast, an
mentally in adducts between N,N-diisopropylbenzamide and
1
1b,22
R3Al(TMP)Li (R ) Me, i-Bu)
Of several possible transition
states for the deprotonation of the aromatic substrate N,N-
dimethylbenzamide, mediated by Me2N and Me ligands on the
Figure 1. Modeled pathways for the deprotonative alumination of N,N-dimethylbenzamide by Me3Al(NMe2)Li·OMe2: deprotonation by the NMe2 ligand
IM1-TS1-IM2), deprotonation by a Me ligand (IM3-TS2-IM4), and quench of Me2NH by a Me ligand (IM2-TS3-IM4).
(
J. AM. CHEM. SOC. 9 VOL. 130, NO. 48, 2008 16195

A R T I C L E S
Naka et al.
Figure 2. Summary of possible deprotonative aluminations of N,N-dimethylbenzamide by Me3Al(NMe2)Li·OMe2 at the B3LYP/6-31+G* level of theory.
Energy changes for deprotonation by the NMe2 ligand (TS1) with subsequent quench (TS3) or for deprotonation by the Me ligand (TS2) are shown in
2
5
kcal/mol and are relative to IM1.
Figure 3. Transition-state structures for possible deprotonative aluminations of N,N-dimethylbenzamide by Me3Al(NMe2)Li ·OMe2 (B3LYP/6-31+G* level):
a) deprotonation by the NMe2 ligand (TS1); (b) deprotonation by a Me ligand (TS2); and (c) the successive quench path (TS3). Relative energies and free
energies (in parentheses) are given in kcal/mol and are relative to IM1. TS1-3 are “open form” transition states, and no “closed form” transition states were
(
2
6
located for these pathways.
activation barrier of +52.6 kcal/mol strongly suggested that
deprotonation by a methyl ligand in Me3Al(NMe2)Li·OMe2
the energy of the transition state relative to IM1 was +51.2
kcal/mol (+20.5 kcal/mol higher than that of TS1 and only 3.6
kcal/mol lower than that of TS2). These data strongly suggest
that the deprotonation of Me2NH by an Al-bonded alkyl ligand
is very unlikelysa conclusion significantly at odds with a recent
(
IM3-TS2-IM4) was kinetically unfavorable (TS2 being +24.1
11b
kcal/mol less stable than TS1).
A transition state for the
Me2NH-mediated quench of a methyl ligand on the aluminum
center (IM2-TS3-IM4) was also identified. However, this
pathway required an activation barrier of +37.7 kcal/mol, and
20
tandem DFT/structural study of zincate reactivity but consis-
tent with crystallographic observation of trialkylarylaluminate
2
2
7
.
The free energy profiles for TS1-3 are depicted in Figure
This result showed good agreement with the total electronic
(
(
24) Both Me3Al(TMP)Li and Me3Al(TMP)Li · THF adopt structures
analogous to that of i-Bu3Al(TMP)Li · THF. See ref 11b for details.
25) We have also identified an energetically plausible intermediate,
IM2′, which can be formed by the dissociation of HNMe2 from
IM2 (for IM2′, ∆Erel ) +6.9 kcal/mol and ∆Grel )-4.9 kcal/mol,
both energies being relative to IM2).
27
3.
energies.
In summary, the calculated energies in the present system
suggest that the model aluminate reagent serves exclusively as
1
6196 J. AM. CHEM. SOC. 9 VOL. 130, NO. 48, 2008

Aluminate as a Kinetically Controlled Base
A R T I C L E S
Scheme 3. Summary of the Theoretically Predicted Reactivity of 1
an amido base rather than as an alkyl base in DoM reactions.
2.060(4), C44-Al2 2.062(5) Å for the two independent
2
2
Interestingly, the successive quench of alkyl ligands by in situ
molecules in 8 (cf. 2.050(4) Å in 7) ] and with the Al center
residing essentially in the aromatic plane. The alkali metal is
supported by the amide carbonyl [O1-Li1 1.884(9), O5-Li2
2
0
formed secondary amine-demonstrated for zincate DoM sis
not replicated here (Scheme 3).
2
2
2
. Solid-State and Solution Structure and Reactivity. With
1.874(8) Å in 8, (cf. 1.860(7) Å in 7) ] and thereafter by three
the theoretical study suggesting that TMP-aluminates operate
only as single-step, kinetically controlled bases in DoM, we
decided to explore the predilection of a pre-isolated aluminated
aromatic (cf. IM2) for undergoing postmetalation processes of
the type described above. We took an indirect approach, first
generating and characterizing a putative intermediate by the
transmetalation of an ortho lithioarene using i-Bu3Al and then
investigating whether this species reacted with HTMP.
solvent molecules (Chart 2, Figure 4). Consistent with previously
reported data on laterally lithiated aromatic tertiary amides,
7b,30
tris(THF)-solvation means that that there is no interaction
between Li+ and the site of deprotonation. This allows the
directing tertiary amide group to reside nearly perpendicular to
31
the aromatic plane in order to minimize steric interactions
[
(
C3-C2-C1-O1 98.9(6), C44-C43-C42-O5 97.7(6)° in 8,
22
cf. 99.7(4)° in 7) ].
We selected N,N-diisopropylbenzamide and -naphthamide as
suitable aromatic substrates since we had already established
the stability of their sterically hindered amide functions toward
We next sought to investigate the dissolution of TMP-
aluminate 1, of ortho aluminates 7 and 8, and also the behavior
of solution ortho aluminate species in the presence of HTMP
(see Supporting Information). The primary aims here were to
reveal whether complexes such as 7 and 8 resist amine
coordination and amine-alkyl ligand exchange (as theoretically
suggested, Scheme 3), to evaluate whether tris(THF)-solvation
of the alkali metal inhibits reaction or whether desolvation can
occur, and last, to determine whether 7/8 act as intermediates
7
t-BuLi. Accordingly, ortho lithiation in tetrahydrofuran (THF)
2
8
was followed by the introduction of i-Bu3Al. The resulting
systems could be made to deposit crystalline material that NMR
spectroscopy suggested to be ortho deprotonated and to contain
both Al and Li. Crystallographic analysis confirmed this,
revealing the tris(THF)-solvated monomers [2-(i-Bu3Al)-
CmHnC(dO)N(i-Pr)2]Li·3THF (m ) 6, n ) 4, 7; m ) 10, n )
20
2
8
in stepwise deprotonation (cf. ortho zincate reactivity, Scheme
). Cryoscopic measurements on both 7 and 8 in benzene point
6
, 8), illustrated in Figure 4. In the course of this work, an
22,29
1
independent determination of the structure of 7 was reported
to partial desolvation occurring in solution, with mean observed
molecular masses of 291-357 (for 7) and 206-307 (for 8),
suggesting the loss of 0-1 THF molecules from 7 and 1-3
THF molecules from 8. This behavior has precedent in both
experimental and theoretical aspects of directed metalation.
Accordingly, trisolvated [2-(MeCH)C10H6C(dO)N(i-Pr)2]-
with bond lengths equal within experimental error to ours, so
in this paper we will report only those observed for 8 and quote
2
2
the literature values for 7. Despite conformational disorder
of some ligands in the structures of 7 and 8, the gross structures
are well established and demonstrate controlled ortho alumi-
2
8
7
nation by the insertion of i-Bu3Al into a C-Li bond [C3-Al1
Figure 4. Molecular structures of monomeric ortho aluminates (a) 7 and (b) (one of the crystallographically independent molecules of) 8 plotted at 30%
probability and with minor i-Bu and THF disorder and all H-atoms omitted for clarity. For 7 see also ref 22.
J. AM. CHEM. SOC. 9 VOL. 130, NO. 48, 2008 16197

A R T I C L E S
Naka et al.
Figure 5. Optimized transition-state structures for the methyl ligand quench of secondary amine in (a) model aluminate Me3Al(Ar)Li·(OMe2)(NHMe2)
20
(
TS3, Ar ) C6H4C(dO)NMe2, OMe2 ) S, B3LYP/6-31+G* level) and (b) model zincate Me2Zn(Ar)Li ·(OMe2)(NHMe2) (B3LYP/631SVP level). Solvents
are omitted for clarity. Distances given in angstroms.
of a lithiated aromatic amide electronically satisfies the metal,
the removal of even one solvent molecule causes the metal to
7
b
seek further coordination. Accordingly, HTMP (1 or 2 equiv)
was added to ortho aluminate 7 (either pre-isolated and
redissolved or else generated in situ) in hydrocarbon solvent at
room temperature. After being heated to reflux, mixtures were
stored at -30 °C and the crystalline deposits isolated and found
to be unreacted 7 (in isolated yields of up to 69%). Evidence
for the complete passivity of ortho aluminates toward HTMP
came from H and C NMR spectroscopic analyses of samples
of 7 and 8 dissolved in (nonpolar) benzene or (Lewis basic)
THF before and after the introduction of excess HTMP by
injection. In either solvent, chemical shifts attributable to 7 or
Figure 6. (a) Disfavored operation of the transition state in the deproto-
nation of Me2NH by a methyl ligand bonded to Al. (b) Favored operation
of the transition state in the deprotonation of Me2NH by a methyl ligand
bonded to Zn (S ) OMe2).
1
13
Li·3THF, in which the metal ion fails to interact with the
deprotonated R-carbon in the lateral group in the solid state,
has been shown to undergo partial desolvation with the
8
were unambiguously found to be unchanged upon the
application of amine, nor was any formation of new aromatic
2
8
3
0
species observed, even after heating to reflux. The generality
of this passivity has also been demonstrated by employing the
aliphatic amines diethylamine and diisopropylamine in conjunc-
tion with both 7 and 8. Finally, extensive experiments carried
out on TMP-aluminate 1, 7, and 8 in THF (see ref 11b for 1
and Supporting Information for 7 and 8) have established their
identities in THF solution and have not shown the detectable
concomitant formation of a metal-carbon bond. Moreover,
previous theoretical work has shown that, whereas trisolvation
(
(
26) (a) Zhao, P.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 4008–
4
009. (b) Zhao, P.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 14411–
4424. (c) Zhao, P.; Condo, A.; Keresztes, I.; Collum, D. B. J. Am.
1
Chem. Soc. 2004, 126, 3113–3118. (d) Qu, B.; Collum, D. B. J. Am.
Chem. Soc. 2005, 127, 10820–10821.
+
formation of any other species, including [Li · 4THF] [i-
27) The prediction of accurate Gibbs free energy profiles for reactions in
solution remains a challenge for quantum chemical methods, especially
in cases in which solvent exchange (association and/or dissociation)
takes place at the metal atom. However, favorable error cancelation
is expected in the comparison of the similar transition states TS1-3.
28) See Supporting Information.
-
Bu4Al] . While this last species was observed as a crystalline
2
2
deposit by ourselves, and reported by others, following
attempts to synthesize 1 in bulk THF, our NMR data do not
(
(
29) The structure of 7, reported independently, resulted from the reaction
of TMP-aluminate 1 with N,N-diisopropylbenzamide (ref 22). Although
not significantly different from ours, the reported structural parameters
for 7 have slightly lower esd’s.
(30) Armstrong, D. R.; Clayden, J.; Haigh, R.; Linton, D. J.; Schooler, P.;
Wheatley, A. E. H. Chem. Commun. 2003, 1694–1695.
(31) Bond, A.; Clayden, J.; Wheatley, A. E. H. Acta Crystallogr. E 2001,
E57, o292-o294.
1
6198 J. AM. CHEM. SOC. 9 VOL. 130, NO. 48, 2008

Aluminate as a Kinetically Controlled Base
A R T I C L E S
Scheme 4. Regioselective Deprotonation of an Unsymmetrical Ketone Using i-Bu3Al(TMP)Li (1)
3
2
Table 1. Kinetically Controlled Regioselective Functionalization of
electron configuration (Figure 6b). This allows Zn to stabilize
a
Unsymmetrical Ketones Using 1
the loosely associated [Me2N]- anion, lowering the total
activation energy for this quench step. In short, the decreased
inherent Lewis acidity of Al prevents replication of the
2
0
quenching process noted recently for Zn.
. Synthetic Application of the Kinetic Basicity of TMP-
4
Aluminate. The present DFT/solid-state/solution combined
study has shown that TMP-aluminate 1 is a highly kinetically
controlled base. With this kinetic reactivity, we expected that
1
should show extremely high kinetic selectivity in reactions
that offer mixtures of kinetically preferred and thermody-
namically preferred products. Thus, we tested the regiose-
lective functionalization of unsymmetrical ketones using 1
(
Scheme 4, Table 1).
Methyl isopropyl ketone 9a was treated with 1.1 equiv of 1
at 0 °C in THF, and it was found that the kinetically preferred
a
Unless otherwise noted, reactions were conducted using ketone (1.0
1
3
enolate was selectively formed (estimated using C NMR
spectroscopy at -50 °C). Electrophilic trapping of this enolate
intermediate with benzaldehyde proceeded smoothly to give only
the expected regioisomer 10a in 81% yield, with none of the
thermodynamically preferred isomer 11a being detected. Other
unsymmetrical acyclic and cyclic ketones (9b,c) were similarly
functionalized regioselectively (Table 1).
equiv) and 1 (1.1 equiv) in THF under the conditions noted, and
quenched with benzaldehyde (1.0 equiv, room temperature,
1
h).
b
c
Isolated yield. Only a single regioisomer was detected. Mixture of
d
diastereomers. Quenched with TMSCl (4.0 equiv.).
support its formation as a significant solution species in systems
that contain, or have been treated with, 1.
Overall, experimental evidence strongly supports the view
that 7 and 8 (both putative intermediates in directed ortho
alumination using TMP-aluminate 1) dissolve to give a partially
desolvated solution species that is, nevertheless, inert to amines.
This suggests that the deprotonation of HTMP by an i-Bu ligand
in aluminated aromatic complexes is an unlikely step in the
deprotonative alumination of arenes by 1. Consistent with the
DFT analysis (Vide supra), this conclusion contrasts markedly
with that reached in our previous study of apparently analogous
To our surprise, the regioselectivity highlighted in Table 1
was maintained even under harsh conditions, such as the reflux
temperature of THF (65 °C) for 18 h (entries 2, 4). The
intermediate was also trapped with TMSCl to give only the
kinetic silyl enol ether 12c. Regioselective deprotonation of these
unsymmetrical ketones has hitherto required the use of lithium
amides under low temperature conditions to achieve high
regioselectivity and to avoid undesirable side reactions at the
33
2
0
electrophilic functional groups. In contrast, the present results
clearly show that the TMP-aluminate 1 is a highly chemose-
lective, kinetically controlled base that can be used even at
elevated temperatures.
TMP-zincates.
. Origin of the Differing Reactivities of TMP-Aluminates
3
and TMP-Zincates. The present theoretical and experimental
investigation has shown that TMP-aluminate 1 (i) acts as an
amido base but, unlike its zincate analogues, (ii) exhibits only
single-step DoM behavior. To elucidate the origin of the
different reactivities observed for aluminate and zincate
systems, the structures of the transition states for the quench-
ing of amine by a metal-bonded alkyl group were analyzed
in detail (Figure 5).
Conclusions
In summary, the present theoretical and experimental study
has revealed that TMP-aluminate 1 (i) acts as an amido base
but, unlike its zincate analogues, (ii) exhibits only single-step
DoM reactivity. Moreover, rationalization of this dichotomy
comes from an evaluation of the inherent Lewis acidities of
the Al and Zn centers.
The structures of the transition states in Figure 5 are similar
in principle: in each case the Me2NH is deprotonated by a Me
ligand in concerted (SN2) fashion with a slightly bent N-H-Me
angle (Al, 156.0°; Zn, 169.0°), the Me2N ligand is anchored by
The single-step mechanism proposed for aluminate bases
points to their stoichiometric reaction. This mode of reactivity
does not offer the potential, recently noted in zincate DoM
+
Li (Al, N-Li 1.92 Å; Zn, N-Li 1.97 Å), and the methyl ligand
2
0
chemistry, for polybasicity and the use of a catalytic quantity
is dissociating from Al or Zn to form methane (Al, Al-Me
34
of amine. However, such stoichiometric reactivity does clarify
2
.34 Å; Zn, Zn-Me 2.32 Å). Importantly, however, the
Me2N· · ·Al distance (3.56 Å) is significantly longer than
Me2N· · ·Zn (2.77 Å), a difference that can be explained by the
lower Lewis acidity of aluminum (Figure 6). Because Al is
coordinatively saturated by the three alkyl moieties and the aryl
(
32) (a) Uchiyama, M.; Koike, M.; Kameda, M.; Kondo, Y.; Sakamoto, T.
J. Am. Chem. Soc. 1996, 118, 8733–8734. (b) Uchiyama, M.; Kameda,
M.; Mishima, O.; Yokoyama, N.; Koike, M.; Kondo, Y.; Sakamoto,
T. J. Am. Chem. Soc. 1998, 120, 4934–4946.
-
ligand, it is unable to stabilize the [Me2N] anion that is
(33) Clayden, J. Organolithiums: SelectiVity for Synthesis; Pergamon/
Elsevier Science: Oxford, 2002.
emerging in the transition state (Figure 6a). In contrast, zinc is
unsaturated (16e in its valence shell) and is therefore capable
of accepting two more electrons to achieve a saturated 18-
(
34) Hodgson, D. M.; Chung, Y. K.; Nuzzo, I.; Freixas, G.; Kulikiewicz,
K. K.; Cleator, E.; Paris, J.-M. J. Am. Chem. Soc. 2007, 129, 4456–
4462.
J. AM. CHEM. SOC. 9 VOL. 130, NO. 48, 2008 16199

A R T I C L E S
Naka et al.
the status of the dummy ligand (i.e., the i-Bu group) and ensures
freedom from undesired and uncontrolled ligand scrambling.
Because the choice of spectator ligand can strongly influence
the reactivity of the aromatic moiety (as a nucleophile, a base,
a transmetalation reagent, a benzyne generator, etc.), such a
mechanistic deduction has clear implications for future work
in this field and for the design of new organometallic reagents
for synthesis. Moreover, it implies that logical and controlled
switching of DoM reactivity can be achieved through the
selection of aluminate or zincate bases.
Tohoku-Kaihatsu Memorial Foundation, the Exploratory Research
Program for Young Scientists (ERYS), and a Grant-in-Aid for
Young Scientists (B) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan (H.N.). We thank Prof. Paul
Raithby (University of Bath, UK) for assistance with crystallography
and Miss Sylvia Gonzalez-Calera for help with NMR spectroscopy.
The calculations were performed using the RIKEN Super Combined
Cluster (RSCC) facility. We also thank Dr. Daisuke Nobuto (The
University of Tokyo) for technical assistance.
Supporting Information Available: Synthetic procedures,
spectroscopic data, computational coordinates, and details of
modeling programs used; X-ray crystallographic data, in CIF
format. This material is available free of charge via the Internet
at http://pubs.acs.org.
Acknowledgment. This research was partly supported by the
Astellas Foundation, The Sumitomo Foundation, Hoansha, and a
Grant-in-Aid for Young Scientists (A) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan (to
M.U.). We also gratefully acknowledge the UK EPSRC (J.V.M.,
J.H., D.J.E.) and Newnham and Trinity Colleges, Cambridge (F.G.)
for financial support. This research was also supported by the
JA804749Y
1
6200 J. AM. CHEM. SOC. 9 VOL. 130, NO. 48, 2008