Controlled anion migrations with a mixed metal Li/K-TMP amide: General application to benzylic metalations

Article abstract of DOI:10.1021/ja110234v

A general method is described for benzylic metalation of o-, m-, and p-substituted toluenes using a mixed metal amide base generated from BuLi/KOtBu/TMP at -78 °C in THF. The excellent selectivity achieved can be rationalized by the ability of the mixed metal amide base to facilitate an anion migration from the kinetic (o-aryl) to the benzylic metalation site. Remarkably, this controlled anion migration is achievable with catalytic amounts of TMP at -78 °C.

Full text of DOI:10.1021/ja110234v

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pubs.acs.org/JACS
Controlled Anion Migrations with a Mixed Metal Li/K-TMP
Amide: General Application to Benzylic Metalations
Patricia Fleming and Donal F. O’Shea*
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Belfield,
Dublin 4, Ireland
S Supporting Information
b
Scheme 1. Ortho and Benzylic Metalation Sites of Substi-
tuted Toluenes (DG = directing group; M = metal)
ABSTRACT: A general method is described for benzylic
metalation of o-, m-, and p-substituted toluenes using a
mixed metal amide base generated from BuLi/KOtBu/
TMP at -78 °C in THF. The excellent selectivity achieved
can be rationalized by the ability of the mixed metal amide
base to facilitate an anion migration from the kinetic (o-aryl)
to the benzylic metalation site. Remarkably, this controlled
anion migration is achievable with catalytic amounts of
TMP at -78 °C.
Scheme 2. Selective Metalation of OMOM-Substituted cis-
Stilbene (M = K/Li)
irect aryl and alkyl metalation reactions are steeped in the
D
historical traditions of Wittig and Gilman yet have stood the
test of time and remain at the cutting edge of modern synthetic
methods. The concept of directed o-aryl deprotonation using
organolithium bases, first with the o-lithiation of anisole, ushered
in a new era of selective metalation chemistry.1 Since its incep-
tion, the synthetic utility of this transformation class has con-
tinually grown; in parallel, the mechanisms by which regioselec-
tivity is obtained have been comprehensively studied.2 The
ongoing development of enhanced reactivity and selectivity
profiles for direct aryl metalations using mixed Li/Zn- and Li/
Mg-tetramethylpiperidide (TMP) amides illustrates the contin-
ued importance of this class of transformation.3 Arguably of equal
synthetic utility is the associated metalation of the benzylic
position of substrates 1, 2, and 3 which is, by default, in com-
petition with o-metalation and can be, depending upon the
substrate, surprisingly challenging to achieve with good selec-
tivity (Scheme 1).4 As such, a general method for the benzylic
metalation of substituted toluenes with high and predictable
regiospecificity would be of particular interest due to the obvious
synthetic potential of such organometallics (Scheme 1).
In contrast to the development of mixed metal amide systems
for aryl metalations, their application to benzylic metalations
remains unexplored. In what may appear at first glance a distantly
related example, we have recently shown that, for o-OMOM-
substituted cis-stilbene 4, regioselective vinyl C-H metalation to
produce 5 required the mixed metal amide system LiTMP/
KOtBu (Scheme 2).5 In contrast, when alkyllithium base was
utilized, predominately o-aryl metalation was obtained. As other
reported uses of this Li/K-TMP amide are very rare, substantial
scope for development of this reagent exists.6
metalation selectivity obtained. As a starting point, the OMOM
substrates 1a, 2a, and 3a were chosen as, to the best of our
knowledge, the benzylic metalation of these substrates is un-
reported.7 This can be attributed to the fact that the OMOM
group is a strong ortho-directing substituent, therefore favoring
kinetic-controlled o-aryl metalated products. In order to achieve
benzylic metalation, reaction conditions that could overcome or
bypass the competing ortho-directing influence of the OMOM
group would be required. The three substrates were investigated
under identical reaction conditions by sequential treatment with
BuLi/KOtBu/TMP in THF, -78 °C, followed by quenching of
the reactions with CD3OD after 15 min. In order to illustrate and
gain an understanding of the influence of the mixed metal amide
on metalation regioselectivity, reactions were also carried out
with the mixed metal alkyl base BuLi/KOtBu under otherwise
identical conditions.8 In addition to routine analysis, products
were also analyzed by 2H NMR to give a conclusive view of the
site(s) of deuterium incorporation.
2H NMR analysis of the products from the treatment of
substrates 1a, 2a, and 3a with BuLi/KOtBu (conditions A)
showed highly selective o-metalation with >93% incorporation
of D (Table 1, entries 1-3; Figure 1, spectra i, iii, v). In contrast,
reaction with BuLi/KOtBu/TMP (conditions B) gave almost
exclusively benzylic deuterated products with little or no detectable
Herein we illustrate the first general use of a mixed Li/K-TMP
amide for benzylic metalations and an understanding of the
Received: November 15, 2010
Published: January 25, 2011
r
2011 American Chemical Society
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Table 1. Selective Benzylic Metalations of OMOM-Substi-
tuted Toluenes 1a, 2a, and 3a (M = K/Li)
entry starting material conditions product
E
% Da % yield
1
1a
2a
3a
1a
2a
3a
1a
1a
2a
2a
3a
A
A
A
B
B
B
B
B
B
B
B
o-D-1a
o-D-2a
o-D-3a
Bn-D-1a
Bn-D-2a
Bn D-3a
6
D
D
D
D
D
D
98b
93b
96
80c
88c
20c
-
92
76
81
75
84
89
51d
69
59d
68
25d
2
3
Figure 1. 2H NMR spectra of deuterated products from metalation of
1a, 2a, 3a, and 1c with conditions A and B. *, CD2Cl2 peak.
4
5
6
the same molecule. For example, 2,5-dimethylanisole 1c offers
three possible sites for metalation: o-aryl, o-benzylic, and m-
benzylic. Reaction with BuLi/KOtBu gave no selectivity, with a
mixture of all possible deuterated isotopomers obtained follow-
ing CD3OD quench (Table 3, entry 1; Figure 1, spectrum vii).
Remarkably, metalation utilizing amide conditions B gave
excellent selectivity for the m-benzylic position as based upon
D incorporation (Table 3 entries 2, 3; Figure 1, spectrum viii).
These results are significant, as it is apparent that heteroatom
7
CO2Me
Sn(Bu)3
CO2Me
SnBu3
8
7
-
9
8
-
10
9
-
11
10
CO2Me
-
a Based on 1H NMR integration and confirmed with 2H NMR. b Trace
benzylic D observed in H NMR. c Trace o-D observed in H NMR.
d OMOM deprotected and crude material converted to ester prior to
purification (inset).
2
2
Table 2. Selective Benzylic Metalations of OMe-Substituted
Toluenes 1b and 2b (M = K/Li)
o-D (Table 1, entries 4-6; Figure 1, spectra ii, iv, vi). While
selectivity of D incorporation into the benzylic positions was
excellent, levels of D incorporation varied across the substrates
1a, 2a, and 3a at 80, 88, and 20%, respectively (Table 1, entries
4-6). This reflects the relative acidities of the benzylic protons
with, as would be expected, the 4-substituted derivative 3a being
the least acidic. Reaction of metalated 1a and 2a with other
electrophiles such as CO2 and Bu3SnCl gave the expected benzylic
substituted products 6-9 (Table 1, entries 7-10). The low pro-
duct yield achieved from para-substituted 3a limits the effective use
of this substrate for general electrophile reactions (Table 1, entry 11).
Examination of the related anisole series 1b and 2b with
conditions A gave mixtures of ortho and benzylic deuterium
incorporation of 60:40 and 50:50, respectively (Table 2, entries
1, 2). The contrasting lack of ortho selectivity for 1b and 2b in
comparison to the corresponding OMOM substrates 1a and 2a
can be rationalized in terms of the superior ortho-directing
power of the OMOM group. In contrast, when the mixed metal
amide conditions B were utilized and metalated intermediates
reacted with CD3OD, the benzylic deuterated products were
obtained with excellent selectivity, yield, and D incorporation
entry starting material conditions product(s)
E
o/Bn ratioa % yield
1
2
3
4
5
6
7
8
1b
2b
1b
2b
1b
1b
2b
2b
A
A
B
B
B
B
B
B
o/Bn-D-1b D
o/Bn-D-2b D
60:40
50:50
1:99
5:95
-
71
83
80b
96c
70
76
72
72
Bn-D-1b
Bn-D-2b
11
D
D
2
CO2H
(Table 2, entries 3, 4; SI for H NMR spectra). Alternative
12
Sn(Bu)3
CO2H
-
electrophiles provided the methoxyphenylacetic acids 11 and
13 and methoxybenzylstannanes 12 and 14 in good yields
(Table 2, entries 5-8).
We next examined the ability of the mixed metal amide
conditions to differentiate between two benzylic positions on
13
-
14
Sn(Bu)3
-
a Based on 1H NMR integration and confirmed with 2H NMR. b 90% D
incorporation. c 97% D incorporation.
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Table 3. Selective Benzylic Metalation of 2,5-Dimethyl-
anisole 1c (M = K/Li)
Scheme 3. Caryl to Cbenzyl Anion Migration with Catalytic
TMP for 1a and 2a
entry
conditions
product
E
Bn-D 1c:2c
% yield (D)
1
2
3
4
5
A
B
B
B
B
mixture
Bn-D-2c
Bn-D-2c
15
D
D
D
-
-
5:95
5:95
-
88 (75)
86 (98)a
60a
CO2H
60a
Table 4. Selective Benzylic Metalations (M = K/Li)
16
SnBu3
-
a Increased equivalents used: 2 equiv of BuLi, 2 equiv of KOtBu, 1 equiv
of TMP.
coordination is not a factor to be considered in the overall
outcome under these metalation conditions and that the m-
benzylic position, being the most acidic in this particular sub-
strate, is the favored site of deprotonation. Again the use of
alternative electrophiles confirmed the metalation selectivity
(entries 4, 5).
As illustrated above, the amide portion of the mixed metal
amide plays a key role in the selectivity obtained. The need for an
amide rather than a coordinating amine was investigated by using
N,N,N0,N00,N00-pentamethyldiethylenetriamine in the reaction
instead of TMP with substrates 1a and 2a. In both cases,
following CD3OD quench, only o-D products were observed.
To exemplify this role, the use of catalytic TMP with BuLi/
KOtBu was investigated with 1a and 2a as substrates. The
experiments were designed to show the reaction progress over
time with samples removed and deuterated at different time
points following treatment of the substrates with BuLi/KOtBu
and 10% TMP. After 5 min, both reactions showed a mixture of o-
and benzylic-D products. Yet analysis after 15 min for 1a and 60
min for 2a gave exclusively benzylic-D products (Scheme 3, 2H
NMR spectra). This remarkable process can be viewed as an in
situ Caryl to Cbenzyl anion migration.9 In effect, this triad of
reagents can correct for any o-metalation that occurs under the
reaction conditions, leading to highly regioselective benzylic
metalated products. The migration process required the addition
of TMP, as holding the reaction for prolonged periods without
TMP did not facilitate the migration.
Several other ortho-, meta-, and para-substituted toluenes,
substituted with various groups including amino, fluoro, amido,
and sulfonamido, have been metalated and reacted with electro-
philes (Table 4). A consistent high degree of benzylic selec-
tivity was maintained for all the different substituents when deutero
products were analyzed (Table 4, entries 2, 6, 9, 12, 15; SI). The
p-amide- and p-sulfonamide-substituted toluenes gave excellent
results, as their electron-withdrawing nature promoted p-benzylic
deprotonation, in contrast to the OMOM group (Table 4, entries
12-16). In addition, dimethoxy- and methoxy(dimethyl)-
a Substrate added to base mixture at -78 °C. b Increased equivalents of
reagents used: 3.2 equiv of BuLi, 3.2 equiv of KOtBu, 3 equiv of TMP.
substituted toluenes 2d and 2e also gave good results under
our reaction conditions (Table 4, entries 6-11).
In conclusion, the use of BuLi/KOtBu/TMP to in situ
generate a mixed Li/K metal amide has proven to be an efficient
and general method to achieve hitherto difficult benzylic metala-
tions with excellent selectivity. When added sequentially, the
triad of reagents can link together to facilitate an anion migration
from the ortho to the benzylic positions at -78 °C. Further
investigations of the synthetic applications of this reagent
mixture and its mechanistic basis are ongoing, the findings of
which will be reported in due course.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, ana-
b
lytical data, and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
donal.f.oshea@ucd.ie
’ ACKNOWLEDGMENT
We thank Science Foundation Ireland, The Irish Research
Council for Science, Engineering and Technology, and ERA-
Chemistry for financial support. Thanks to Dr. J. Muldoon for
NMR analysis.
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