The synthesis and characterization of 2-trideuteriomethyl and 2,2-di(trideuteriomethyl) aryl ketones

Article abstract of DOI:10.1002/jlcr.603

Results are reported on the synthesis and characterization of a variety of trideuteriomethyl aryl ketones. Copyright

Full text of DOI:10.1002/jlcr.603

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2002; 45: 935–942.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.603
Research Article
The synthesis and characterization of
2-Trideuteriomethyl and 2,2-
Di(trideuteriomethyl) Aryl Ketones
Gregory S. Coumbarides, Jason Eames*, and Neluka Weerasooriya
Department of Chemistry, Queen Mary, University of London, Mile End Road,
London E1 4NS, UK
Summary
Results are reported on the synthesis and characterization of a variety of
trideuteriomethyl aryl ketones. Copyright # 2002 John Wiley & Sons, Ltd.
1
Key Words: deuterium; enolates; C NMR spectroscopy; 2-methyl aryl ketones;
3
trideuteriomethyl substitution
Introduction
The selective incorporation of non-radioactive isotopic labels into
organic molecules for biological and chemical studies is an increasingly
1
important area. For example, the use of a trideuteriomethyl (CD )
3
group within synthesis is widespread; it has found application in the
2
elucidation of reaction mechanisms and the determination of
3,4
ambiguous stereochemistry. The majority of these studies have relied
on this CD substituent being spectroscopically inactive (through the
3
1
use of H NMR spectroscopy). By comparison, studies involving
5
*Correspondence to: J. Eames, Department of Chemistry, Queen Mary, University of London,
Mile End Road, London, E1 4NS, UK. E-mail: j.eames@qmw.ac.uk.
Contract/grant sponsors: University of London, London University Central Research Fund, The
Nuffield Foundation, GOSS Scientific Instruments Ltd., The Royal Society; contract/grant
number: NUF-NAF 99
Copyright # 2002 John Wiley & Sons, Ltd.
Received 30 January 2002
Revised 22 March 2002
Accepted 4 April 2002

9
36
G. S. COUMBARIDES ET AL.
1
3
6
C NMR spectroscopy are rare. This is not that surprising due to the
7
long (T ) relaxation time for a CD substituent which causes the signal
1
3
intensity of the required septet (1:3:6:7:6:3:1) to be particularly weak.
13
The intensity of this signal in the C NMR spectra can be improved by
running the sample neat or as a concentrated solution in the presence of
a suitable solvent. However, this strategy does rely on the sample being
readily available and in reasonable quantity (>1 g). Usually, this
procedure is only practical for samples which do not contain hydrogen
such as common NMR solvents (e.g. acetone-d , DMSO-d and
6
6
methanol-d4).
We have recently been interested in the regioselective deuteriation of
‘
base-free’ enolates such as 2 (formed by the addition of MeLi to the
silyl enol ether 1) to give 2-deuterio-2-methyl aromatic ketones 3 under
kinetic control. We have extended this methodology further towards the
8
synthesis of perdeuteriated ketones like 4, 5 and 6. During the course of
this study we became interested in the synthesis and characteristic
1
behaviour of related trideuteriomethyl (CD ) groups using C NMR
3
3
spectroscopy Scheme 1.
1
3
We now report the synthesis of a variety of CD3 and CD3
containing aryl ketones, and comment on the relative shape and
1
3
intensity of the associated signal by C NMR spectroscopy. We
originally chose an aryl ketone framework for our study since many of
the required non-labelled methyl derivatives, such as 2-methyltetralone
1
have been previously synthesized in our laboratory by the simple
9
addition of methyl iodide to the lithium enolate 8 – formed by the
addition of lithium diisopropylamide (LDA) to the parent ketone,
tetralone 7. We argued that replacing methyl iodide for an isotopic
Scheme 1. Synthesis of 2-deuterio aryl ketones 3–6
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 935–942

THE SYNTHESIS AND CHARACTERIZATION OF
937
Scheme 2. Synthesis of 2-trideuteriomethyl aromatic ketones 10–15
variant, like trideuteriomethyl iodide (CD I), should allow access to the
3
required trideuteriomethyl derivatives. By treatment of tetralone 7,
indanone 16 and benzosuberone 19 with an appropriate amount of
LDA and trideuteriomethyl iodide gave the corresponding 2-trideuter-
iomethyl 10–12 and 2,2-di-trideuteriomethyl derivatives 20, 23 and 27 in
good chemical yield Scheme 2.
1
These derivatives were easily characterized using H NMR spectro-
scopy; the most noticeable feature was the disappearance of one or both
of the two C(2)H protons adjacent to the carbonyl group. Equally, the
2
required septet (1:3:6:7:6:3:1) for the CD substituent was generally
3
13
missing from the C NMR spectra. However, for the 2-trideuter-
iomethyl aryl ketone 10, the CD group gave a triplet-like signal (ratio
3
:7:6 – 1JC;H ¼ 19:8 Hz) at 15.5 ppm (in the C NMR spectrum),
indicating only three (6:7:6) of a possible seven lines of the septet
13
6
(1:3:6:7:6:3:1), whereas for those derivatives 20, 23 and 27 which contain
two magnetically equivalent trideuteriomethyl groups, the signal
intensity was improved slightly to reveal a quintet (ratio 3:6:7:6:3) at
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 935–942

9
38
G. S. COUMBARIDES ET AL.
13
approximately 24 ppm in the C NMR spectra with characteristic
C,D coupling of 20 Hz. This lack of signal intensity was due to a
longer (T ) relaxation time associated with this CD substituent because
1
3
of the small magnetic moment associated with the neighbouring
1
deuterium atom. For example, the relaxation time for a CD3
3
1
substituent in 2,2-di-trideuteriomethyl-[ C]-indanone 28 was found
3
to be; T ¼ 28:21 seconds and T ¼ 0:76 seconds (determined by
1
2
1
3
C NMR spectroscopy at 150 MHz in CDCl3).
The full seven lines of the septet could only be observed by
incorporation of a C-13 isotopic label on the carbon bearing
1
the CD3 group. The required 2-trideuteriomethyl-[ C] and 2,2-
3
13
trideuteriomethyl-[ C]-labelled ketones 13–15, and 28, 31 and 34,
respectively, were easily synthesized in good yield using our standard
1
deprotonation-methylation protocol by replacing CD I with CD3I.
3
3
The presence of this C-13 label allowed the carbon–deuterium
coupling to be accurately determined (Table 1: 1JC;D ¼ 19:4 ꢀ 0:2 Hz).
We have also assumed that similar C–D couplings (in the
1
3
13
natural abundance C NMR spectra) are also present in the non- C
labelled ketones (e.g. 2-trideuteriomethyl tetralone 11) even though
1
the original septet for the CD group in the C NMR spectrum
3
3
was absent.
We additionally synthesized a series of unsymmetrically labelled 2,2-
dimethyl aryl ketones 21, 22, 24–26, 29, 30, 32 and 33 to probe the effect
of having different isotopically labelled methyl substitutents present in
the same molecule. These were efficiently synthesized by deprotonation
of the corresponding mono-substituted aryl ketone 9, 11, 14, 17 and 18
with LDA and methylation using an appropriately isotopically labelled
methyl iodide. For those ketones 21, 22, 24, 25 and 26 which contained
a single CD group, no carbon signal for the CD substituent was
3
3
1
3
observed by C NMR spectroscopy, whereas for those derivatives 26
13
and 28–34 which contained two C groups, the required septet
1
3
1:3:6:7:6:3:1) was easily detected in the C NMR spectra (between
(
2
3.6 and 24.5 ppm), slightly downfield with respect to the 2-methyl
aryl ketones. There was also found to be only slight variation in
carbon–deuterium coupling (19.2–20.2 Hz: Table 1). This difference was
presumably due to the combination of different isotopic substitution
patterns being present. Furthermore, there was also found to be a
1
3
negative isotope shift for a CD substituent with respect to both a CH
3
3
13
group (0.19 ppm – from 32) and a CH group (0.57 ppm – from 33).
3
This chemical shift difference was due to a combination of the more
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 935–942

THE SYNTHESIS AND CHARACTERIZATION OF
939
1
Table 1 Synthesis of CD and CD labelled aryl ketones 20–34
3
3
3
electropositive deuterium atom and C-13 labelled carbon atom causing
the isotopically labelled methyl substituent to resonate at a slightly
higher field.
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 935–942

9
40
G. S. COUMBARIDES ET AL.
In conclusion, we have reported an efficient synthesis of a variety of
2
-deuteriomethyl aryl ketones 10–15 and 20–34. We have shown
that the signal intensity and observed splitting pattern associated with
13
a CD substituent (by C NMR spectroscopy) is varied. The required
3
septet (1:3:6:7:6:3:1) could only be detected by using a C-13 label to
increase the signal intensity of the trideuteriomethyl (CD ) signal. The
3
effect of deuterium in a CD group lowers the intensity at least 20 times
3
(
with respect to a CH group) giving rise to a septet (1:3:6:7:6:3:1) with a
3
13
characteristic (1JC;D
)
C–D coupling of approximately 20 Hz. Further-
1
3
more, we have also noticed the relative signal intensity in the C NMR
spectra for each isotopic methyl substituent is in the order;
1
3
13
CH > CD >CH >CD . The additional presence of a C label is
13
3
3
3
3
13
13
particularly interesting for both CH and CD containing deriva-
3
3
1
tives, since this gives rise to either a doublet ( J
13
¼ 35 Hz) or triplet
C;C
(1
JC;C ¼ 35 Hz) in the C NMR spectra for the C(2) position when
either one or two C-13 labelled methyl substituents ( CH and/or
1
3
3
1
3
CD ) are present.
3
Typical procedure: 2-trideuteriomethyltetralone 11-d -tetralone 7
3
(
(
0.70 g, 0.63 ml, 6.8 mmol) was slowly added to a solution of LDA
4.5 ml, 1.5 M in THF, 6.8 mmol) in THF (20 ml) at ꢁ788C and stirred
for 30 min. Trideuteriomethyl iodide-d (0.98 g, 0.4 ml. 6.8 mmol) was
3
added dropwise and the resulting solution was allowed to warm to room
temperature, and stirred for 12 h. The reaction was quenched by the
addition of water (10 ml). A solution of NH Cl (saturated, 10 ml) was
4
added and the mixture was extracted with ether (3 ꢂ 50 ml). The
combined organic layers were dried (MgSO ) and evaporated under
4
reduced pressure. The residue was purified by flash column chromato-
graphy on silica gel eluting with light petroleum (b.p. 40–608C)-ether
(19:1) to give 2-trideuteriomethyltetralone 11-d (0.64 g, 58%) as an oil;
3
R [light petroleum (40–608C):ether (9:1)] 0.5; n
(film)/cm 2061 (CD),
f
max
1
681 (CO); d (250 MHz, CDCl ) 8.05 (1 H, d, J 7.7, CH; Ar), 7.45 (1 H,
H
3
t, J 7.7, CH; Ar), 7.31 (1 H, d, J 7.7, CH; Ar), 7.22 (1 H, d, J 7.7, CH;
Ar), 3.10–2.93 (2 H, m, CH ), 2.62–2.54 (1 H, dd, J 11.9 and 4.4,
2
MeCH), 2.25–2.15 (1 H, m, CH CH ) and 1.96–1.80 (1 H, m,
A
B
CH CH ); d (100.6 MHz, CDCl ) 200.7, 144.2, 133.0, 132.4, 128.7,
A
B
c
3
+
1
27.4, 126.5, 42.4, 31.3 and 28.8 (Found M , 163.1083. C H D O
11 9 3
requires M, 163.1076); m/z 164 (100%, M+H) and 163 (60, M). The
absence of the septet [1:3:6:7:6:3:1] around 15 ppm for the CD
3
13
substituent in the C NMR spectra is common due to a long relaxation
time.
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 935–942

THE SYNTHESIS AND CHARACTERIZATION OF
941
1
3
2
-Trideuteriomethyl-[ C]-tetralone 14-d : In the same way as 2-
3
trideuteriomethyl tetralone 11-d , tetralone 7 (1.4 g, 1.27 ml, 9.8 mmol),
3
1
LDA (6.5 ml, 1.5 M in THF, 9.8 mmol) and methyl-[ C]-iodide-d
3
3
(1.4 g, 0.6 ml. 9.8 mmol) gave, after column chromatography on
silica get eluting with light petroleum ether–ether (19:1) 2-trideuter-
1
iomethyl-[ C]-tetralone 14-d (0.91g, 57%) as an oil; Rf [light
3
3
petroleum (40–608C):ether (9:1)] 0.5; nmax (film)/cm 2065 (CD)
and 1685 (CO); d (250 MHz, CDCl ) 8.05 (1 H, d, J 7.7, CH; Ar),
H
3
7
7
2
.45 (1 H, t, J 7.7, CH; Ar), 7.32 (1 H, d, J 7.5, CH; Ar), 7.24 (1 H, d, J
.5, CH; Ar), 3.12–2.93 (2 H, m, CH ), 2.62–2.53 (1 H, m, MeCH),
2
.26–2.14 (1 H, m, CH CH ) and 1.97–1.79 (1 H, m, CH CH ); d
A
B
A
B
c
(
67.5 MHz, CDCl ) 200.7, 144.1, 133.1, 132.7, 128.7, 127.4, 126.6, 42.4
3
13
1 C, d, 1JC;C 36.1, C C), 31.3, 28.8 and 14.6 (1 C, septet [1:3:6:7:6:3:1],
(
1JC2D 19.4, CD ) (Found M , 164.1133. C
13
+
13
CH D O requires M,
9 3
3
10
1
64.1102).
,2-Di(trideuteriomethyl)tetralone 23-d : In the same way as
2
6
2
5
-trideuteriomethyl tetralone 11-d , tetralone 7 (0.81 g, 0.73 ml,
3
.5 mmol), LDA (4.5 ml, 1.5 M in THF, 11 mmol) and methyl iodide-
d3 (1.61 g, 0.7 ml. 11 mmol) gave, after column chromatography on silica
get eluting with light petroleum ether–ether (19:1) the 2,2-di(trideuter-
iomethyl)tetralone 23-d (0.77 g, 78%) as an oil; R [light petroleum (40-
6
f
6
08C):ether (9:1)] 0.6; nmax (film)/cm 2062 (CD) and 1679 (CO); d (250
H
MHz, CDCl ) 8.05 (1 H, d, J 7.5 CH; Ar), 7.42 (1 H, t, J 7.5, CH; Ar),
3
7
6
1
.25 (1 H, t, J 7.5, CH; Ar), 7.20 (1 H, d, J 7.5, CH; Ar), 2.95 (2 H, t, J
.3, CH ) and 1.95 (2 H, t, J 6.3, CH ); d (62.5 MHz, CDCl ) 202.9,
2
2
c
3
43.4, 132.9, 131.5, 128.7, 127.9, 126.6, 41.2, 36.5 25.7 and 23.4 (2 C,
+
quintet [3:6:7:6:3], 1JC-D 20.5, CD ) (Found MH , 181.1508. C H D O
3
12
9
6
requires MH, 181.1500).
,2-Di(trideuteriomethyl)-[ C]-tetralone 31-d : In the same way as 2-
13
2
6
trideuteriomethyl tetralone 11-d , tetralone 7 (0.2 g, 0.18 ml, 1.37 mmol),
3
1
LDA (1.8 ml, 1.5 M in THF, 2.74 mmol) and trideuteriomethyl-[ C]
3
iodide-d (0.4 g, 0.18 ml. 2.74 mmol) gave, after column chromatography
3
on silica get eluting with light petroleum ether–ether (19:1) the 2,2-
1
3
di(trideuteriomethyl-[ C]-tetralone 31-d (0.18 g, 71%) as an oil; R
6
f
[
light petroleum (40–608C):ether (9:1)] 0.6; nmax (film)/cm 2052 (CD) and
1
682 (CO); d (250 MHz, CDCl ) 8.05 (1 H, d, J 7.8, CH; Ar), 7.45 (1
H
3
H, t, J 7.6, CH; Ar), 7.25 (1 H, d, J 7.5, CH; Ar), 7.21 (1 H, d, J 7.5, CH;
3
Ar), 2.99 (2 H, t, J 6.2, CH ) and 1.97 (2 H, tt, J
2
¼ 6:4 and
H;H
3JC;H ¼ 3:8, CH ); d (100.62 MHz, CDCl ) 202.9, 143.3, 132.9, 131.4,
2
c
3
1
13
1
28.6, 127.9, 126.5, 41.1 (1 C, t, J
¼ 33:7, C C), 36.4, 25.6 and 23.4
C;C
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 935–942

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G. S. COUMBARIDES ET AL.
13
1 C, septet [1:3:6:7:6:3:1], 1JC;D ¼ 19:6,
+
CD ) (Found MH ,
3
(
1
3
1
83.1560. C C H D O requires MH, 183.1567).
10 2 9 6
Acknowledgements
We thank Queen Mary, University of London for a college student-
ship (to N.W.), the London University Central Research Fund, The
Nuffield Foundation (NUF-NAF 99), GOSS Scientific Instruments Ltd.
and The Royal Society for their generous financial assistance.
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Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 935–942