Probing the regioselective C-deuteriation of lithium enolates derived from 2-methyl-tetralone in the presence of substituted tertiary amines

Article abstract of DOI:10.1002/jlcr.1089

Results are reported on the regioselective C-deuteriation of 2-methyl-tetralone using a series of D-sources and tertiary amines as potential mediators. The results presented further aid the understanding of kinetic deuteriation of both 'base-containing' and 'base-free' enolates. Copyright

Full text of DOI:10.1002/jlcr.1089

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JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2006; 49: 707–732.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1089
Research Article
Probing the regioselective C-deuteriation of lithium
enolates derived from 2-methyl-tetralone in the
presence of substituted tertiary amines
Mothia Begum1, Sameer Chavda1, Gregory S. Coumbarides1, Marco Dingan2,
Jason Eames2,*, Michael J. Suggate1 and Neluka Weerasooriya1
1 Department of Chemistry, Queen Mary, University of London, London E1 4NS, UK
2 Department of Chemistry, University of Hull, Cottingham Road, Kingston upon Hull,
HU6 7RX, UK
Summary
Results are reported on the regioselective C-deuteriation of 2-methyl-tetralone using a
series of D-sources and tertiary amines as potential mediators. The results presented
further aid the understanding of kinetic deuteriation of both ‘base-containing’ and
‘base-free’ enolates. Copyright # 2006 John Wiley & Sons, Ltd.
Received 30 March 2006; Revised 8 May 2006; Accepted 8 May 2006
Key Words: amines; ammonium salts; D-enols; deuterium; enolates; internal
deuterium transfer and 2-methyl-tetralone
Introduction
The understanding of proton transfer in chemical and biological systems is
becoming an increasingly important area.1 The absolute rates of many proton
transfer processes are well known,2 but the chemical significance of these
processes are less documented.3 Over the last 20 years,4 an enormous amount
of attention has focused on the synthetic applicability of enolates within
organic chemistry, and these studies have unequivocally shown them to be
highly valued synthetic intermediates. Within this domain, numerous groups5,y
have focused their attention on controlling enantio-,7 diastereo-6 and
regioselective8 protonation of enol(ate)s with some notable successes. From
*Correspondence to: Jason Eames, Department of Chemistry, University of Hull, Cottingham Road,
Kingston Upon Hull, HU6 7RX, UK. E-mail: j.eames@hull.ac.uk
y For additional information see Zimmerman.6
Copyright # 2006 John Wiley & Sons, Ltd.

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708
M. BEGUM ET AL.
Li NH(i-Pr)2
O
O
O
CD3CO2D
D2O
LDA
THF, -78oC
Me
D
Me
Me
Ot-Bu
Ot-Bu
Ot-Bu
H
Me
[D1]-1
Me
Me
1
2a
up to 30 % D-incorporation
n-BuLi, THF, -78oC
Li LiN(i-Pr)2
Ot-Bu
O
O
Me
Ot-Bu
D
CD3CO2D
D2O
Me
Me
Me
2b
[D1]-1
98 % D-incorporation
Scheme 1.
these studies, it is somewhat surprising to find only a limited amount of
attention has been paid to elemental protonation processes using traditional
synthetic methodology.9 Most importantly within this area, Seebach and co-
workers have reported within their seminal paper10 the concept of internal
proton return. They have shown that simple deprotonation of an ester (e.g. 1)
with lithium diisopropylamide (LDA), followed by addition (of a solution) of
acetic acid-d4 in D2O (to this intermediate lithium enolate diisopropylamine
complex 2a) gave moderate D-incorporation (of up to 30%) (Scheme 1).10 By
comparison, the levels of deuterium incorporation could be increased
dramatically to greater than 98% by sequential deprotonation of the
intermediate complex, 2a, using n-butyl lithium to give the lithium enolate-
lithium amide complex 2b (Scheme 1). The removal of the unwanted and
problematic NH proton (from the residue diisopropylamine in 2a to give 2b)
has lead to the concept of internal proton return10 in which the NH proton of
the intermediate amine (in 2a) can be re-delivered back to the enolate (during
the deuterium quench) to give the unlabelled ester 1 (Scheme 1). Additional
evidence for this proton return has come from a complementary internal
deuterium return; de-deuteriation of the related ester [D1]-1 with lithium
diisopropylamide, followed by attempted protonation with acetic acid (in
H2O) simply re-formed the original ester [D1]-1 with moderate levels of D-
incorporation (70%) (Scheme 2).10 This reaction must proceed via the related
lithium enolate-diisopropylamine complex [D1]-2a, which evidently must allow
efficient internal deuterium return (back to the lithium enolate to give [D1]-1)
in the presence of acetic acid (Scheme 2).10
Over the last few years, whilst attempting to get a better understanding of
related enantioselective processes,11 we have probed the mechanism of
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 707–732
DOI: 10.1002/jlcr

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PROBING THE REGIOSELECTIVE C-DEUTERIATION OF LITHIUM ENOLATES 709
Li ND(i-Pr)2
O
O
O
CH3CO2H
H2O
Me
D
Me
D
LDA
THF, -78oC
Me
Ot-Bu
Ot-Bu
Ot-Bu
Me
[D1]-1
Me
[D1]-1
Me
[D1]-2a
70 % D-incorporation
Scheme 2.
Li NH(i-Pr)2
O
H
O
O
Me
Me
Me
CD3CO2D
LDA, THF
-78oC
3; 90%
([D]:[H] = 2:98)
4a
3
1. LDA, THF, -78oC
2. Me3SiCl
Li
O
OSi(CH3)3
Me
O
D
Me
Me
MeLi, THF
CD3CO2D
-78oC
[D1]-3; 68%
([D]:[H] = >95:5)
4b
5
Scheme 3.
C-deuteriation of 2-methyl-tetralone 3z with some success.12 We have shown,
as predicted from Seebach’s studies,10 simple deprotonation of 2-methyl-
tetralone 3 with LDA, followed by addition of CD3CO2D to the correspond-
ing lithium enolate complex 4a, gave the recovered 2-methyl-tetralone 3 with
no deuterium incorporation ([D]:[H]=2:98) (Scheme 3). However, by simple
removal of the unwanted residual diisopropylamne from the enolate complex
4a (via formation of the corresponding silyl enol ether 5 and addition of MeLi)
to re-form the ‘residual base-free’ enolate 4b does increase the levels of
deuterium incorporation to greater than 95% (Scheme 3).12
We have probed the deuteriation of related lithium enolate-amine
complexes, like [D11]-4c (formed by addition of a secondary amine, deuteriated
z Many of these reports have focused their attention on the use of the commercially available ketone,
2-methyl tetralone 3, as their substrate of choice due to its predictable enol(ate) configuration, UV activity
and non-volatile nature.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 707–732
DOI: 10.1002/jlcr

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M. BEGUM ET AL.
710
piperidine (C5D10ND), to a solution of the pre-formed ‘residual base-free’
enolate 4b in THF), and have shown that internal deuterium transfer {from
the D-labelled amine to the 2-methyl-tetralone [D1]-3 ([D]:[H]=9:91)} can
occur in the presence of unlabelled acetic acid and Me3SiCl (Scheme 4). Near
perfect levels of D-incorporation can be achieved by quenching the lithium
enolate-amine complex [D11]-4c with CD3CO2D to give the corresponding
2-deuterio-2-methyl-tetralone [D1]-3 ([D]:[H]=>95:5) (Scheme 4). By com-
parison, similar levels of deuterium incorporation were found to occur by
addition of CD3CO2D to the corresponding ‘base-free’ enolate 4b (Scheme 3).
In an attempt to get a better understanding of the role the ‘residual amine’
itself, we chose to investigate the deuteriation of lithium enolate-amine
complexes containing non-protic amines, like tertiary amines (NR3), using a
variety of D-sources (e.g. [D4]-acetic acid, [D4]-MeOH and D2O) (Scheme 5).
For our study, we chose to focus our attention on the use of simple amines
such as triethylamine 6 and dimethylbenzylamine 7, and 1,2-diamines, like
1,4-diazabicyclo[2.2.2]octane (DABCO) 8 and N,N,N0,N0-tetramethylethyle-
nediamine (TMEDA) 9 (Scheme 6).
OSiMe3
Me
DNC5D10
Me
OLi
OLi
Me
C5D10ND
MeLi
- Me4Si
4b
[D11]-4c
5
O
D
OLi DNC5D10
Me
O
D
Me
Me
1. CD3CO2D
2. Me3SiCl
1. CH3CO2H
2. Me3SiCl
[D1]-3; 72%
[D11]-4c
[D1]-3; 71%
([D]:[H] = >95:5)
([D]:[H] = 9:91)
Scheme 4.
O
OLi NR3
Me
OLi
D
Me
Me
NR3
D-source
[D1]-3
4d
4b
Scheme 5.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 707–732
DOI: 10.1002/jlcr