An efficient laboratory synthesis of α-deuteriated profens

Article abstract of DOI:10.1002/jlcr.1105

An efficient and practical laboratory synthesis of a series of 2-deuterio-2-arylpropionic acids (α-deuterioprofens) is described. The levels of deuterium incorporation are high and the products are synthetically useful. Copyright

Full text of DOI:10.1002/jlcr.1105

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd. Radiopharm 2006; 49: 903–914.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1105
Research Article
An efficient laboratory synthesis of a-deuteriated
profens
Gregory S. Coumbarides1, Marco Dingjan2, Jason Eames2,*, Anthony Flinn3
and Julian Northen3
1 Department of Chemistry, Queen Mary, University of London, Mile End Road,
London E1 4NS, UK
2 Department of Chemistry, University of Hull, Cottingham Road, Kingston upon Hull
HU6 7RX, UK
3 Onyx Scientific Limited, Units 97-98, Silverbriar, Sunderland Enterprise Park East,
Sunderland SR5 2TQ, UK
Summary
An efficient and practical laboratory synthesis of a series of 2-deuterio-2-arylpropionic
acids (a-deuterioprofens) is described. The levels of deuterium incorporation are high
and the products are synthetically useful. Copyright # 2006 John Wiley & Sons, Ltd.
Received 1 June 2006; Revised 12 June 2006; Accepted 12 June 2006
Key Words: carboxylic acids; deuterium; 2-phenyl-propionic acid and profens
Introduction
The synthesis of non-steroidal anti-inflammatory isotopically labelled profens
(2-aryl propionic acids) is well documented.1 These particular derivatives have
found widespread use as probes for their biological mode of action.2
Results and discussion
The continuing development of novel methodology for direct incorporation of
non-radioactive isotopic labels within organic molecules for chemical and
biological mechanistic studies is paramount.3 The majority of this attention
has focused on deuterium incorporation involving simple carbon–hydrogen
bond exchange reactions.4 Many of these processes rely on simple
*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
Copyright # 2006 John Wiley & Sons, Ltd.

904
G. S. COUMBARIDES ET AL.
O
O
O
O
O
O
1. n-BuLi
THF, -78 o
C
Ph
Me
Ph
HN
O
HN
O
N
O
N
O
Ph
CO2C6F5
2.
H
H
Me
(2 equiv.)
Ph
i-Pr
Ph
i-Pr
H
CH3
syn-: anti-4
95:5; 60%
syn-: anti-5
88:12; 60%
(R)-2
(rac)-1
(S)-3
Scheme 1.
deprotonation, followed by deuteriation at mildly acidic centres.5 For
experimental ease, most hydrogen–deuterium exchange reactions are per-
formed under thermodynamic control by using a suitable deuterium donor as
the reaction solvent to drive the reaction to completion.6
We have recently become interested in the parallel resolution7 of racemic
profen adducts, like (rac)-1, using a quasi-enantiomeric combination of
oxazolidinones, such as (R)-2 and (S)-3, as parallel resolving agents (Scheme
1).8 Addition of adduct (rac)-1 to a stirred solution of lithiated oxazolidinones
[derived from the deprotonation of (R)-2 and (S)-3 with n-BuLi] in THF at
ꢀ788C, gave the resolved adducts syn-4 and syn-5 in good yield with high
levels of diastereoselectivity (Scheme 1). In order to probe this reaction type
further, we were required to synthesize of a series of racemic deuterium
labelled profen acids, such as Ibuprofen [D1]-9, based on the parent skeleton of
2-phenyl-propionic acid 6 (Scheme 2). We chose to limit our attention to the
synthesis of four structurally related deuterium labelled adducts, namely, 2-
deuterio-2-phenyl-propionic acid [D1]-6, 2-deuterio-2-phenyl-butyric acid
[D1]-7, 2-deuterio-2-tolyl-propionic acid [D1]-8 and 2-deuterio-2-(4-isobutyl-
phenyl)-propionic acid [D1]-9 as these were structurally similar to the parent 2-
phenyl-propionic acid 6 (Scheme 2). We now report our laboratory synthesis
for these particular 2-deuterio-2-phenyl-propionic acids.
We first chose to use a synthetic procedure which was scaleable, relatively
inexpensive, and required little or no post-purification. With this aim in mind,
we first focused our attention on the synthesis of 2-deuterio-2-phenyl-
propionic acid [D1]-6 (Scheme 3). To ensure efficient proton–deuterium
exchange at the less acidic C(2) position of this carboxylic acid, we chose to
protect the carboxylic acid motif as its ethyl ester derivative. Treatment of the
2-phenyl-propionic acid 6 with toluene-p-sulphonic acid in ethanol, gave the
corresponding ethyl 2-phenyl-propionate 10 in 98% yield (Scheme 3). With
this substrate in hand, we next probed the synthesis of trideuteriomethyl 2-
deuterio-2-phenylpropionate [D4]-11 using traditional hydrogen–deuterium
exchange conditions (Scheme 3). For this hydrogen–deuterium exchange
process, we decided to use [D3]-NaOMe as our Brꢀnsted base (formed by the
simple addition of sodium hydride to [D4]-MeOH) as this process could easily
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 903–914
DOI: 10.1002/jlcr

EFFICIENT LABORATORY SYNTHESIS OF a-DEUTERIATED PROFENS
905
O
O
OH
OH
D
CH3
H
CH3
[D1]-6
6
O
O
OH
OH
D
CH3
H
CH3
[D1]-7
7
O
O
OH
OH
D
CH3
H
CH3
[D1]-8
8
O
O
OH
OH
D
CH3
H
CH3
[D1]-9
9
Scheme 2.
O
O
TsOH
EtOH
Ph
Ph
OH
OEt
H
CH3
H
CH3
6
10; 98%
O
O
NaH
(0.2 equiv.)
Ph
Ph
NaH
THF/D2O
OH
OCD3
CD3OD
(15 equiv.)
D
CH3
[D1]-6; 95%
[(D):(H) = 97:3]
D
CH3
[D4]-11; 72%
[(D):(H) = 97:3]
Scheme 3.
be monitored by 1H NMR spectroscopy. Addition of sodium hydride
(ꢁ40 mol%) to a stirred solution of ethyl 2-phenyl-propionate 10 and [D4]-
MeOH (ꢁ30 equivalents) in THF at room temperature, gave after 24 h, the
required trideuteriomethyl 2-deuterio-2-phenylpropionate [D4]-11 in 72%
yield with good levels of deuterium incorporation (½Dꢂ : ½Hꢂ ¼ 82 : 18). The
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 903–914
DOI: 10.1002/jlcr

906
G. S. COUMBARIDES ET AL.
O
O
TsOH
Ar
Ar
OH
OEt
EtOH
H
R
H
R
10-14
6-9
Starting material
Ar
Entry
Ethyl ester
R
10; 98%
12; 95%
13; 95%
14; 98%
1
2
3
4
6
7
8
9
Ph
Ph
Me
Et
Tol
Me
Me
4-i-Bu-C6H4
Scheme 4.
levels of deuterium incorporation could be increased further to > 95 : 55 ð½Dꢂ :
½HꢂÞ by doubly repeating this procedure.y It is interesting to note that trans-
etherification of the ethyl ester 10 to the trideuteriomethyl ester [D3]-11 occurs
faster than simple hydrogen–deuterium exchange. Hydrolysis of ester [D4]-11
using sodium hydride in THF/D2O (ratio ¼ 3 : 1 by volume), followed by an
acidic work-up [using dilute HCl (3 M)] gave, the required 2-deuterio-2-
propionic acid [D1]-6 in good yield (95%) and with high levels of deuterium
incorporation (½Dꢂ : ½Hꢂ ¼ 97 : 3).
With this information in hand, we next chose to investigate the deuteriation
of a variety of 2-aryl-substituted carboxylic acids 6, 7, 8 and 9 under our
standard conditions (as outlined in Schemes 2 and 3). The ethyl esters 12, 13
and 14 were efficiently synthesized in good yields (95–98%) by refluxing the
corresponding 2-aryl-substituted carboxylic acids 7, 8 and 9 and toluene-p-
sulphonic acid in ethanol for 12 h (Scheme 4). Deuteriation of these ethyl esters
10, 12, 13 and 14 at their C(2)-position was achieved by three sequential
hydrogen–deuterium exchange reactions using NaOMe in [D1]-MeOH to give
the corresponding methyl esters [D1]-11, [D1]-15, [D1]-16 and [D1]-17,
respectively, in good yields (Scheme 5). The levels of deuterium incorporation
1
were determined by H NMR spectroscopy and were shown to be excellent
(½Dꢂ : ½Hꢂ ¼> 94 : 56). Formation of the mono-deuteriated 2-aryl-substituted
carboxylic acids [D1]-6, [D1]-7, [D1]-8 and [D1]-9 were achieved in excellent
yield (ꢁ50%) by addition of sodium hydride to a stirred solution of the
methyl esters [D1]-11, [D1]-15, [D1]-16 and [D1]-17 in THF/D2O (ratio ¼ 3 : 1
by volume). The levels of deuterium incorporation were found to be
y The levels of deuterium incorporation ð½Dꢂ : ½HꢂÞ from the first, second and third sequential reactions were
82 : 18, 92 : 8 and 97 : 3, respectively.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 903–914
DOI: 10.1002/jlcr

EFFICIENT LABORATORY SYNTHESIS OF a-DEUTERIATED PROFENS
907
O
O
O
NaH (0.2 equiv.)
NaH
Ar
Ar
Ar
OH
OCH3
OEt
THF/D2O
CH3OD (15 equiv.)
D
R
D
R
H
R
[D1]-6 and [D1]-7-9
10 and 12-14
[D1]-11 and [D1]-15-17
Ethyl ester
Entry
[D1]-methyl ester ([D]:[H]) [D1]-carboxylic acid ([D]:[H])
Ar
R
96:4
95:5
97:3
94:6
[D1]-6; 87%
[D1]-7; 63%
[D1]-8; 83%
97:3
95:5
97:3
94:6
1
[D1]-11; 83%
[D1]-15; 57%
[D1]-16; 48%
10
Ph
Ph
Tol
Me
Et
2
3
12
13
Me
[D1]-9; 80%
4-i-Bu-C6H4
[D1]-17; 44%
4
14
Me
Scheme 5.
Figure 1. (a) Methyl doublet for 9 at 1.50 ppm (3JC,H=7.2 Hz) and (b) methyl
singlet for [D1]-9 at 1.50 ppm
1
unchanged throughout the synthetic sequence and were determined by H
NMR spectroscopy (as illustrated in Figure 1).
In conclusion, we have reported an efficient and cost effective laboratory
synthesis of deuteriated 2-aryl-substituted carboxylic acids [D1]-6, [D1]-7, [D1]-
8 and [D1]-9 which requires minimal purification. These products were formed
in high yield (for example, [D1]-6 formed from 6 in 67% – over three steps)
with high levels of isotopic incorporation (½Dꢂ : ½Hꢂ ¼> 97 : 53). The nearest
Copyright # 2006 John Wiley & Sons, Ltd.
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G. S. COUMBARIDES ET AL.
analogy for this procedure is that reported by Lloyd and co-workers.9 They
have shown that efficient deuteriation of ethyl 2-phenylpropionate 10 can
occur using sodium in deuteriated ethanol (CAUTION – FLAMMABLE),
followed by subsequent hydrolysis of ethyl 2-deuterio-2-phenylpropionate
[D1]-11 using NaOD (formed by addition of sodium deuteride in D2O) gave,
after an acidic work-up (with aqueous HCl) and post-purification (distilla-
tion), 2-deuterio-2-phenylpropionic acid [D1]-6 in 74% yield of unspecified
isotopic incorporation. By comparison, our protocol is less expensive, more
practical and requires no post-purification leading to deuteriated profens in
good to high yield with defined isotopic incorporation (½Dꢂ : ½Hꢂ ¼> 94 : 56).
Experimental
General. All solvents were distilled before use. All reactions were carried out
under nitrogen using oven-dried glassware. Flash column chromatography
was carried out using Merck Kieselgel 60 (230–400 mesh). Thin layer
chromatography (TLC) was carried out on commercially available pre-coated
plates (Merck Kieselgel 60F254 silica). Proton and carbon NMR spectra were
recorded on a Bruker 250 and 400 MHz Fourier transform spectrometers
using an internal deuterium lock. Chemical shifts are quoted in parts per
million downfield from tetramethylsilane. Carbon NMR spectra were
recorded with broad proton decoupling. Infrared spectra were recorded on a
Shimadzu 8300 FTIR spectrometer and mass spectra were recorded on a
Kratos 50MSTC spectrometer using a DS503 data system for high-resolution
analysis. The levels of D-incorporation were determined by a combination of
mass, proton and carbon NMR spectra.
Ethyl 2-phenylpropionate 10. Toluene-p-sulphonic acid (0.68 g, 3.62 mmol)
was added to a stirred solution of 2-phenyl-propionic acid 6 (5.07 g,
33.80 mmol in ethanol (anhydrous, 30 ml) at room temperature. The solution
was then heated to 858C and left to reflux for 12 h. The resulting solution was
cooled down to room temperature and the solvent was removed under reduced
pressure. The residue was dissolved in dichloromethane and washed with
aqueous potassium hydroxide (20 ml). The organic phases were dried (over
MgSO4) and evaporated under reduced pressure to give the ethyl ester 10
(5.90 g, 98%) as a colourless oil; RF [light petroleum (40–608C):diethyl ether
ð9 : 1Þ] 0.43; nmax (film)/cmꢀ1 1733 (C¼¼O); dH (270 MHz; CDCl3) 7.35–7.20
(5 H, m, 5 ꢃ CH; Ph), 4.14–4.10 (1 H, m, CH2), 3.70 (1 H, q, J 7.2, CH), 1.49
(3 H, d, J 7.2, CHCH3) and 1.20 (3 H, t, J 7.2, CH2CH3); dC (100 MHz;
CDCl3) 175.0 (C¼¼O), 141.1 (i-C; Ph), 129.0, 128.0 and 127.5 (3 ꢃ CH; Ph),
61.1 (CH2CH3), 45.9 (CHCH3), 19.0 (CHCH3) and 14.5 (CH2CH3) (found
MNH+4 , 196.1331; C11H18NO2 requires 196.1331). The aqueous phase was
then acidified to pH ¼ 1 using HCl (3 M) and extracted with dichloromethane
Copyright # 2006 John Wiley & Sons, Ltd.
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EFFICIENT LABORATORY SYNTHESIS OF a-DEUTERIATED PROFENS
909
(3 ꢃ 20 ml). The combined organic phases were dried (over MgSO4) and
evaporated under reduced pressure to give recovered 2-phenyl-propionic acid
6 (48 mg, 0.32 mmol) which was spectroscopically identical to that previously
obtained.
Trideuteriomethyl 2-deuterio-2-phenylpropionate [D4]-11. Sodium hydride
(71 mg, 60% dispersion in oil, 2.96 mmol) was slowly added to a stirred
solution of methanol-d4 (4.44 g, 5 ml, 126.6 mmol) in THF (20 ml) at 08C. The
resulting solution was stirred for 15 min at 08C. Ethyl 2-phenylpropionate 10
(1.50 g, 8.41 mmol) was slowly added dropwise and the solution was allowed to
warm up to room temperature over 12 h. The reaction was quenched with D2O
(5 ml) and extracted with dichloromethane (3 ꢃ 10 ml). The combined organic
layers were dried (over MgSO4) and evaporated under reduced pressure to
give trideuteriomethyl 2-deuterio-2-phenylpropionate [D4]-11 ð1:02 g; 72%Þ
(½Dꢂ : ½Hꢂ ¼ 84 : 16). The procedure was repeated twice more to give the
trideuteriomethyl 2-deuterio-2-phenylpropionate [D4]-11 ð1:02 g; 72%Þ
(½Dꢂ : ½Hꢂ ¼ 97 : 3) as an oil; RF [light petroleum (40–608C):diethyl ether
ð9 : 1Þ] 0.45; nmax (CH2Cl2)/cmꢀ1 2200 (C-D) and 1718 (C¼¼O); dH (270 MHz;
CDCl3) 7.35–7.21 (5 H, m, 5 ꢃ CH; Ph) and 1.49 (3 H, s, CH3); dC (100 MHz;
CDCl3) 175.5 (C¼¼O), 140.9 (i-C; Ph), 129.0, 127.9 and 127.5 (3 ꢃ CH; Ph),
51.3 (1 C, septet ½1 : 3 : 6 : 7 : 6 : 3 : 1ꢂ, 1JC;D ¼ 22:3, CD3), 45.1 (1 C, t [1:1:1],
1JC,D 19.9, CDCH3) and 18.9 (CDCH3); (found MNH+4 , 186.1427;
C10H12D4NO2 requires 186.1427). Isotope shift at C(2) was 0.36 ppm
(36.4 Hz at 100.613 MHz). For 6-d1; found MNH+4 , 197.1394; C11H17DNO2
requires 197.1395. Negative isotopic shift for CD3 group at 51.3 ppm was
74.9 Hz (0.745 ppm at 100.6 MHz) and CD group at 45.4 ppm was 38.0 Hz
(0.378 ppm at 100.6 MHz).
2-Deuterio-2-phenylpropionic acid [D1]-6: hydrolysis of trideuteriomethyl 2-
deuterio-2-phenylpropionate [D4]-11. Sodium hydride (0.20 g, 8.25 mmol) was
slowly added to a stirred solution of trideuteriomethyl 2-deuterio-2-
phenylpropionate [D4]-11 (0.69 g, 4.08 mmol) in THF/D2O (20 ml, 3 : 1) at
room temperature. The resulting solution was stirred for 12 h. The reaction
was quenched with water (20 ml), acidified with HCl ð4 M; 5 mlÞ, and extracted
with dichloromethane (3 ꢃ 20 ml). The combined organic layers were dried
(over MgSO4) and evaporated under reduced pressure to give 2-deuterio-2-
phenylpropionic acid [D1]-6 (0.59 g, 95%) (½Dꢂ : ½Hꢂ ¼ 97 : 3); nmax (film)/cmꢀ1
2305 (CD) and 1705 (C¼¼O); dH (270 MHz; CDCl3) 7.36–7.21 (5 H, m,
5 ꢃ CH; Ph) and 1.50 (3 H, s, CH3); dC (100 MHz; CDCl3) 180.7 (C¼¼O),
140.1 (i-C; Ph), 129.1, 128.0 and 127.8 (3 ꢃ CH; Ph), 45.8 (1 C, s, unlabelled
CDCH3), 45.4 (1 C, t ½1 : 1 : 1ꢂ, 1JC,D 20.1, CDCH3) and 18.4 (CDCH3) (found
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910
G. S. COUMBARIDES ET AL.
MNH+4 , 169.1081; C9H13DNO2 requires 169.1082). Isotope shift at C(2) was
0.27 ppm (27.1 Hz at 100.613 MHz).
Methyl 2-deuterio-2-phenylpropionate [D1]-11. Sodium hydride (0.18 g, 60%
dispersion in oil, 4.50 mmol) was slowly added to a stirred solution of
methanol–d1 (4.06 g, 123 mmol) in THF (20 ml) at 08C. The resulting solution
was stirred for 15 min at 08C. Ethyl 2-phenylpropionate 10 ð4:01 g; 22:50 mmolÞ
was slowly added dropwise and the solution was allowed to warm up to room
temperature over 12 h. The reaction was quenched with H2O (20 ml) and
extracted with dichloromethane (3 ꢃ 10 ml). The combined organic layers were
dried (over MgSO4) and evaporated under reduced pressure to give methyl
2-deuterio-2-phenylpropionate [D1]-11 (3.05 g, 83%) (½Dꢂ : ½Hꢂ ¼> 97 : 53);
nmax (film); cmꢀ1 2185 (C-D) and 1732 (C¼¼O); dH (400 MHz; CDCl3) 7.27–
7.15 (5 H, m, 5 ꢃ CH; Ph) and 1.41 (3 H, s, CH3); dC (100 MHz; CDCl3) 174.9
(C¼¼O), 140.4 (i-C; Ph), 128.6, 127.4 and 127.1 (3 ꢃ CH; Ph), 51.9 (CH3), 44.7
(1 C, t [1:1:1], JC,D 20.0, CDCH3) and 18.4 (CDCH3); (found MNH+4 ,
1
197.1394; C11H17DNO2 requires 197.1395). The negative isotope shift at C(2)
was 0.37 ppm (37.6 Hz at 100.6 MHz).
2-Deuterio-2-phenylpropionic acid [D1]-6: hydrolysis of methyl 2-deuterio-2-
phenylpropionate [D1]-11. Sodium hydride (0.554 g, 13.85 mmol) was slowly
added to a stirred solution of methyl 2-deuterio-2-phenylpropionate [D1]-11
(1.90 g, 11.50 mmol) in THF/D2O (20 ml, 3 : 1) at room temperature. The
resulting solution was stirred for 12 h. The reaction was quenched with water
(20 ml), acidified with HCl (2 M, 10 ml), and extracted with dichloromethane
(3 ꢃ 20 ml). The combined organic layers were dried (over MgSO4) and
evaporated under reduced pressure to give 2-deuterio-2-phenylpropionic acid
[D1]-6 (1.52 g, 87%) (½Dꢂ : ½Hꢂ ¼ 96 : 4) as an oil, which was spectroscopically
identical to that previously obtained.
Ethyl 2-phenyl butyrate 12. In the same way as ethyl ester 10, 2-phenyl-butyric
acid 7 (5.11 g, 31.5 mmol) and toluene-p-sulphonic acid (0.62 g, 3.27 mmol) in
EtOH (30 ml) gave, the ethyl ester 12 (5.69 g, 95%) as an oil; nmax (film); cmꢀ1
1733 (C¼¼O); dH (400 MHz; CDCl3) 7.33–7.23 (5 H, m, Ph), 4.19–4.05 (2 H,
m, OCH2), 3.49 (1 H, t, J 7.5, PhCH), 2.12–2.08 (1 H, m, CHAHBCH3),
1.82–1.78 (1 H, m, CHAHBCH3), 1.20 (3 H, t, J 7.1, CH3CH2O) and 0.89 (3 H,
t, J 7.3, CH3CH2); dC (100 MHz; CDCl3) 174.0 (C¼¼O), 139.2 (i-C; Ph),
128.4, 127.9 and 127.0 (3 ꢃ CH; Ph), 60.5 (CH2O), 53.5 (PhCH), 26.7
(CH2CH), 14.1 (CH3CH2O) and 12.1 (CH3CH2) (found MH+, 193.1221;
C12H17O2 requires 193.1223).
Ethyl 2-tolyl-propionate 13. In the same way as ethyl ester 10, 2-tolyl-
propionic acid 8 (5.20 g, 31.7 mmol) and toluene-p-sulphonic acid (0.61 g,
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EFFICIENT LABORATORY SYNTHESIS OF a-DEUTERIATED PROFENS
911
3.22 mmol) in EtOH (30 ml) gave, the ethyl ester 13 (5.76 g, 95%) as an oil;
nmax (film); cmꢀ1 1733 (C¼¼O); dH (400 MHz; CDCl3) 7.19 (2 H, d, J 8.2,
2 ꢃ CH; Ar), 7.11 (2 H, d, J 8.2, 2 ꢃ CH; Ar), 4.18–4.04 (2 H, m, OCH2), 3.65
(1 H, q, J 7.1, PhCH), 2.32 (3 H, s, CH3; Ar), 1.46 (3 H, d, J 7.1, CH3CH) and
1.19 (3 H, t, J 6.9, CH3CH2O); dC (100 MHz; CDCl3) 174.7 (C¼¼O), 137.7 and
136.6 (2 ꢃ i-C; Ar), 129.2 and 127.2 (2 ꢃ CH; Ar), 60.6 (CH2O), 45.1 (PhCH),
21.0 (CH3; Ar), 18.6 (CH3CH2) and 14.1 (CH3CH2O); m/z 91.1 (50%,
CH3C6H4), 118.9 (100, M – CO2Et) and 192 (40, M+).
Ethyl 2-(2-isobutylphenyl)-propionate 14. In the same way as ethyl ester 10, 2-
(2-isobutylphenyl)-propionic acid 9 (5.08 g, 24.6 mmol) and toluene-p-sulpho-
nic acid (0.49 g, 2.6 mmol) in EtOH (30 ml) gave, the ethyl ester 14 (5.63 g,
98%) as an oil; nmax (film); cmꢀ1 1734 (C¼¼O); dH (400 MHz; CDCl3) 7.20
(2 H, d, J 8.1, 2 ꢃ CH; Ar), 7.09 (2 H, d, J 8.1, 2 ꢃ CH; Ar), 4.19–4.06 (2 H, m,
OCH2), 3.67 (1 H, q, J 7.1, PhCH), 2.44 (2 H, d, J 7.1, CHCH2), 1.84 (1 H,
septet, J 6.6, CH(CH3)2), 1.47 (3 H, d, J 7.1, CH3CH), 1.20 (1 H, t, J 6.9,
CH3CH2O) and 0.88 (6 H, d, J 6.6, CH(CH3)2); dC (100 MHz; CDCl3) 174.4
(C¼¼O), 140.4 and 137.8 (2 ꢃ i-C; Ar), 129.2 and 127.1 (2 ꢃ CH; Ar), 60.6
(CH2O), 45.1 (PhCH), 45.1 (CH(CH3)2), 30.1 (ArCH2) 22.3 (CH(CH3)2), 18.5
(CH3CH2) and 14.1 (CH3CH2O) (found MNa+, 257.1513; C15H22O2Na
requires 257.1512).
Methyl 2-deuterio-2-phenyl butyrate [D1]-15. In the same way as methyl ester
[D1]-11, ethyl 2-phenyl-butyrate 12 (4.05 g, 21.09 mmol) and sodium hydride
(0.34 g, 60% dispersion in oil, 8.45 mmol) and [D1]-MeOH (5 ml) in THF
(20 ml) gave, after three repetitions the methyl ester [D1]-15 (2.14 g, 57%) as an
oil; nmax (CH2Cl2); cmꢀ1 2158 (CD) and 1732 (C¼¼O); dH (400 MHz; CDCl3)
7.33–7.23 (5 H, m, Ph), 3.65 (3 H, s, OCH3), 2.12–2.08 (1 H, m, CHAHBCH3),
1.84–1.80 (1 H, m, CHAHBCH3) and 0.89 (3 H, t, J 7.3, CH3CH2); dC
(100 MHz; CDCl3) 174.4 (C¼¼O), 139.0 (i-C; Ph), 128.5, 127.8 and 127.1
(3 ꢃ CH; Ph), 52.8 (1 C, t ½1 : 1 : 1ꢂ, J 19.9, PhCD), 51.7 (CH3O), 26.5
(CH2CD) and 12.1 (CH3CH2) (found MNH+4 , 197.1396; C11H17DNO2
requires 197.1395). The negative Isotopic shift at 0.89 ppm (for CH3) is
0.006 ppm (2.52 Hz at 400 MHz) and at 52.8 (PhCD) is 0.413 ppm (41.5 Hz at
100.6 MHz).
Methyl 2-deuterio-2-tolyl-propionate [D1]-16. In the same way as methyl ester
[D1]-11, ethyl 2-tolyl-propionate 13 (4.00 g, 20.85 mmol) and sodium hydride
(0.36 g, 60% dispersion in oil, 8.40 mmol) and [D1]-MeOH (5 ml) in THF
(20 ml) gave, the methyl ester [D1]-16 (1.80 g, 48%) as an oil; nmax (CH2Cl2);
cmꢀ1 2146 (CD) and 1737 (C¼¼O); dH (400 MHz; CDCl3) 7.21 (2 H, d, J 8.2,
2 ꢃ CH; Ar), 7.15 (2 H, d, J 8.2, 2 ꢃ CH; Ar), 3.66 (3 H, s, OCH3), 2.33 (3 H, s,
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CH3; Ar) and 1.49 (3 H, s, CH3CD); dC (100 MHz; CDCl3) 175.0 (C¼¼O),
137.4 and 136.6 (2 ꢃ i-C; Ar), 129.2 and 127.2 (2 ꢃ CH; Ar), 51.8 (CH3O), 44.5
(1 C, t ½1 : 1 : 1ꢂ, J 19.9, PhCD), 20.9 (CH3; Ar) and 18.4 (CH3CH) (found
MNH+4 , 197.1398; C11H17DNO2 requires 197.1395). The negative isotopic
shift at 44.5 ppm was 0.367 ppm (39.9 Hz at 100.6 MHz).
Methyl 2-deuterio-2-(2-isobutylphenyl)-propionate [D1]-17. In the same way
as methyl ester [D1]-11, ethyl 2-(2-isobutylphenyl)-propionate 14 (4.01 g,
17.13 mmol) and sodium hydride (0.27 g, 60% dispersion in oil, 6.98 mmol)
and [D1]-MeOH (5 ml) in THF (20 ml) gave, the methyl ester [D1]-17 (1.65 g,
44%) as an oil; nmax (CH2Cl2); cmꢀ1 2196 (CD) and 1739 (C¼¼O); dH
(400 MHz; CDCl3) 7.21 (2 H, d, J 8.1, 2 ꢃ CH; Ar), 7.10 (2 H, d, J 8.1, 2 ꢃ CH;
Ar), 3.65 (3 H, s, OCH3), 2.45 (2 H, d, J 7.2, CHCH2), 1.84 (1 H, septet, J 6.7,
CH(CH3)2), 1.48 (3 H, s, CH3CH) and 0.90 (6 H, d, J 6.7, CH(CH3)2); dC
(100 MHz; CDCl3) 175.1 (C¼¼O), 140.4 and 137.7 (2 ꢃ i-C; Ar), 129.2 and
127.0 (2 ꢃ CH; Ar), 51.8 (CH3O), 45.0 (CH(CH3)2), 44.7 (1 C, t ½1 : 1 : 1ꢂ, J
19.5, PhCD), 30.1 (ArCH2) 22.3 (CH(CH3)2) and 18.4 (CH3CH) (found
MNH+4 , 239.1863; C14H19DNO2 requires 239.1864). The negative isotopic
shift at 44.7 ppm was 0.393 ppm (39.5 Hz at 100.6 MHz).
2-Deuterio-2-phenyl butyric acid [D1]-7. In the same way as carboxylic acid
[D1]-6, methyl 2-deuterio-2-phenyl-butyrate [D1]-15 (1.0 g, 5.63 mmol) and
sodium hydride (0.28 g, 60% dispersion in oil, 7.05 mmol) in THF/D2O (20 ml,
3 : 1) gave, 2-deuterio-2-phenyl butyric acid [D1]-7 (0.59 g, 63%) as an oil; nmax
(CH2Cl2); cmꢀ1 3500–3000 (br OH), 2313 (CD) and 1704 (C¼¼O); dH
(400 MHz; CDCl3) 7.34–7.25 (5 H, m, Ph), 2.10 (1 H, dq, J 14.6 and 7.3,
CHAHB), 1.80 (1 H, dq, J 14.6 and 7.3, CHAHB) and 0.9 (3 H, t, J 7.3, CH3);
dC (100 MHz; CDCl3) 180.2 (C¼¼O), 138.3 (i-C; Ph), 128.6, 128.0 and 127.4
(3 ꢃ CH; Ph), 52.8 (1 C, t ½1 : 1 : 1ꢂ, J 20.0, PhCD), 26.1 (CH2CD) and 12.0
(CH3CH2) (found MNH4+, 183.1237; C10H11DNO2 requires 183.1238). The
negative isotopic shift at 52.8 ppm was 0.413 ppm (41.5 Hz at 100.6 MHz).
2-Deuterio-2-tolyl-propionic acid [D1]-8. In the same way as carboxylic acid
[D1]-6, methyl 2-deuterio-2-tolyl-propionate [D1]-16 (1.06 g, 5.90 mmol) and
sodium hydride (0.29 g, 60% dispersion in oil, 7.20 mmol) in THF/D2O (20 ml,
3 : 1) gave, 2-deuterio-2-tolyl-propionic acid [D1]-8 (0.81 g, 83%) as an oil;
m.p. 38–398C; nmax (CH2Cl2); cmꢀ1 2305 (CD) and 1707 (C¼¼O); dH
(400 MHz; CDCl3) 7.15 (2 H, dt, J 8.2 and 2.0, 2 ꢃ CH; Ar), 7.14 (2 H br d,
8.2, 2 ꢃ CH; Ar), 2.39 (3 H, s, CH3; Ar) and 1.48 (3 H, s, CH3CD); dC
(100 MHz; CDCl3) 180.7 (C¼¼O), 137.0 and 136.6 (2 ꢃ i-C; Ar), 129.3 and
127.4 (2 ꢃ CH; Ar), 44.5 (1 C, t ½1 : 1 : 1ꢂ, J 20.3, ArCD), 21.0 (CH3) and 17.0
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EFFICIENT LABORATORY SYNTHESIS OF a-DEUTERIATED PROFENS
913
(CH3) (found MNH+4 , 183.1234; C10H11DNO2 requires 183.1238). The
negative isotopic shift at 44.5 ppm was 0.336 ppm (36.9 Hz at 100.6 MHz).
2-Deuterio-2-(2-isobutylphenyl)-propionic acid [D1]-9. In the same way as
carboxylic acid [D1]-6, methyl 2-deuterio-2-(2-isobutylphenyl)-propionate
[D1]-17 (1.02 g, 4.61 mmol) and sodium hydride (0.24 g, 60% dispersion in
oil, 5.90 mmol) in THF/D2O (20 ml, 3 : 1) gave, 2-deuterio-2-(2-isobutylphe-
nyl)-propionic acid [D1]-9 (0.76 g, 80%) as an oil; m.p. 71–738C; nmax
(CH2Cl2); cmꢀ1 2345 (CD) and 1704 (C¼¼O); dH (400 MHz; CDCl3) 7.22 (2 H,
dt, J 8.2 and 2.2, 2 ꢃ CH; Ar), 7.10 (2 H, dt, J 8.2 and 2.2, 2 ꢃ CH; Ar), 2.42
(2 H, d, J 6.9, CH2Ar), 1.88 (1 H, m, CH(CH3)2), 1.49 (3 H, s, CH3CD) and
0.88 (6 H, d, J 6.6, CH(CH3)2); dC (100 MHz; CDCl3) 180.6 (C¼¼O), 140.8 and
136.8 (2 ꢃ i-C; Ar), 129.3 and 127.2 (2 ꢃ CH; Ar), 45.0 (CH(CH3)2), 44.6 (1 C,
t ½1 : 1 : 1ꢂ, J 19.9, ArCD), 30.1 (CH2) 22.3 (CH(CH3)2) and 17.0 (CH3) (found
MNH+4 , 225.1709; C13H17DNO2 requires 225.1708). The negative isotopic
shift at 44.6 ppm was 0.369 ppm (36.5 Hz at 100.6 MHz).
Characterization data for unlabelled acids
2-Phenylpropionic acid 6. nmax(CHCl3)/cmꢀ1 1706 (C¼¼O); dH (250 MHz;
CDCl3) 7.45–6.98 (5 H, m, 5 ꢃ CH; Ph), 3.75 (1 H, q, J 7.2, CHCO) and 1.5
(3 H, d, J 7.2, CH3CH); dC (67.9 MHz; CDCl3) 181.4 (C¼¼O), 139.9 (i-C; Ph),
128.9, 127.8 and 127.6 (3 ꢃ CH; Ph), 45.6 (PhCH) and 18.3 (CH3) (found
MH+ 151.0750. C9H11NO2 requires 151.0759).
2-Phenyl butyric acid 7. nmax (CH2Cl2); cmꢀ1 3500–3000 (br OH) and 1704
(C¼¼O); dH (400 MHz; CDCl3) 7.34–7.24 (5 H, m, Ph), 3.46 (1 H, t, J 7.7,
PhCH), 2.12–2.08 (1 H, m, CHAHB), 1.82–1.78 (1 H, m, CHAHB) and 0.9 (3 H,
t, J 7.3, CH3); dC (100 MHz; CDCl3) 180.7 (C¼¼O), 138.3 (i-C; Ph), 128.6,
128.0 and 127.4 (3 ꢃ CH; Ph), 53.3 (PhCH), 26.2 (CH2CH) and 12.0
(CH3CH2) (found MNH4+, 182.1177; C10H16NO2 requires 182.1176).
2-Tolyl-propionic acid 8. nmax (CH2Cl2); cmꢀ1 1707 (C¼¼O); dH (400 MHz;
CDCl3) 7.23 (2 H, dt, J 8.2 and 2.0, 2 ꢃ CH; Ar), 7.14 (2 H br d, 8.2, 2 ꢃ CH;
Ar), 2.39 (3 H, s, CH3; Ar), 3.72 (1 H, q, J 7.2, PhCH), 2.34 (3 H, s, CH3; Ar)
and 1.50 (3 H, d, J 7.3, CH3CH); dC (100 MHz; CDCl3) 181.1 (C¼¼O), 137.0
and 136.7 (2 ꢃ i-C; Ar), 129.3 and 127.4 (2 ꢃ CH; Ar), 44.9 (ArCH), 21.0
(CH3) and 18.0 (CH3) (found MNH+4 , 182.1177; C10H16NO2 requires
182.1176).
2-(2-Isobutylphenyl)-propionic acid 9. nmax (CH2Cl2); cmꢀ1 1704 (C¼¼O); dH
(400 MHz; CDCl3) 7.22 (2 H, dt, J 8.2 and 2.2, 2 ꢃ CH; Ar), 7.11 (2 H, dt, J 8.2
and 2.2, 2 ꢃ CH; Ar), 3.71 (1 H, q, J 7.2, PhCH), 2.42 (2 H, d, J 7.1, CH2Ar),
1.88 (1 H, br nonet, J 6.6, CH(CH3)2), 1.50 (3 H, d, J 7.2, CH3CH) and 0.90
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(6 H, d, J 6.6, CH(CH3)2); dC (100 MHz; CDCl3) 181.0 (C¼¼O), 140.8 and
136.9 (2 ꢃ i-C; Ar), 129.3 and 127.2 (2 ꢃ CH; Ar), 45.0 (CH(CH3)2), 44.9
(ArCH), 30.1 (CH2) 22.3 (CH(CH3)2) and 18.0 (CH3) (found MNH+4 ,
224.1648; C13H22NO2 requires 224.1651).
References
1. (a) Cram DJ, Uyeda RT. J Am Chem Soc 1964; 86: 5466–5477; (b) Chiao W-B,
Saunders WH. J Am Chem Soc 1978; 100: 2802–2805; (c) Kato D, Mitsuda S, Ohta
H. J Org Chem 2003; 68: 7234–7242.
2. Shyadehi AZ, Hardinh JJ. J Label Compd Radiopharm 1999; 42: 207–213; and
references cited therein.
3. IwataReuyl D, Basak A, Townsend CA. J Am Chem Soc 1999; 121: 11 356–11 368.
4. Kingsbury CA. J Org Chem 1998; 63: 3838–3846.
5. Gerlach U, Hungis S. Angew Chem Int Ed Engl 1987; 26: 1283–1285.
¨
6. (a) Creary X. J Org Chem 1976; 41: 3740–3743; (b) Wolf RA, Migliori MJ, Fuery
PH, Gagnier PR, Sabeta IC, Trocino RJ. J Am Chem Soc 1978; 100: 7967–7976; (c)
Padwa A, Alexander E. J Am Chem Soc 1970; 92: 5674–5681; (d) Mohrig JR,
Rosenberg RE, Apostol JW, Bastienaansen M, Evans JW, Franklin SJ, Frisbie
CD; Fu SS, Hamm ML, Hirose CB, Hunstad DA, James TL, King RW, Larson
CJ, Latham HA, Owen DA, Stein KA, Warnet R. J Am Chem Soc 1997; 119:
479–486; (d) Nemr AE, Tsuchiya T. Tetrahedron Lett 1998; 39: 3543–3546, and
references cited therein.
7. (a) Coumbarides GS, Dingjan M, Eames J, Flinn A, Motevalli M, Northen J,
Yohannes Y. Synlett 2006; 101–105; (b) Coumbarides GS, Eames J, Flinn A,
Northen J, Yohannes Y. Tetrahedron Lett 2005; 46: 849–853.
8. Coumbarides GS, Dingjan M, Eames J, Flinn A, Northen J, Yohannes Y.
Tetrahedron Lett 2005; 46: 2897–2902.
9. Thomason MJ, Rhys-Williams W, Hung Y-F, Hanlon GW, Lloyd AW. Chirality
1997; 9: 254–260.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 903–914
DOI: 10.1002/jlcr