The synthesis and characterisation of deuteriated amides

Article abstract of DOI:10.1002/jlcr.737

Results are reported on the regioselective C-deuteriation of a series of enolates derived from the addition of sec-BuLi to a variety of substituted amides. The outcomes of the reactions are discussed in terms of the structural nature of the amides and the

Full text of DOI:10.1002/jlcr.737

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2003; 46: 1033–1053.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.737
Research Article
The synthesis and characterisation of deuteriated
amides
Gregory S. Coumbarides, Jason Eames* and Stephanos Ghilagaber
Department of Chemistry, Queen Mary, University of London,
London E1 4NS, UK
Summary
Results are reported on the regioselective C-deuteriation of a series of enolates
derived from the addition of sec-BuLi to a variety of substituted amides. The
outcomes of the reactions are discussed in terms of the structural nature of the
amides and the deuteriated sources employed. Copyright # 2003 John Wiley
& Sons, Ltd.
Key Words: deuterium donor; deprotonation-deuteriation; kinetic deuteria-
tion; d-amides and isotopic labels
Regioselective C-deuteriation adjacent to a carbonyl group to give
perdeuteriated aldehydes,1 ketones2 and esters3 is well documented. The
majority of these methods rely on sequential deprotonation and
deuteriation of an intermediate enolate under thermodynamic control.4
Generally, the more acidic the carbonyl-based acid, the more efficient
the deuteriation process.5 For weakly acidic carbonyl-based acids, such
as those derived from amides, it is unsurprising to find a limited number
of reports into proton-deuterium exchange under thermodynamic
*Correspondence to: Dr J. Eames, Department of Chemistry, Queen Mary, University of London,
London El 4NS, UK. E-mail: j.eames@qmw.ac.uk
Contract/grant sponsor: EPSRC
Contract/grant sponsor: The London University Central Research Fund
Contract/grant sponsor: The Nuffield Foundation
Contract/grant sponsor: The Royal Society and Goss Scientific
Copyright # 2003 John Wiley & Sons, Ltd.
Received 25 April 2003
Revised 14 May 2003
Accepted 26 May 2003

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G.S. COUMBARIDES ET AL.
control.6 In contrast, selective deuteriation has been shown to occur
under kinetic control by pre-forming the intermediate enolate. How-
ever, the method chosen to generate the intermediate enolate has been
shown to be important since the use of lithium amide bases, such as
lithium diisopropylamide (LDA)7 have been documented to lower the
overall deuterium incorporation due to internal proton return involving
the residual diisopropylamine base. However, in the absence of a
competitive base,9 the levels of D-incorporation were found to be
significantly higher.10 The structural nature of the deuterium donor is
also important; the use of a weakly D-acidic deuterium donor, such as
D2O is preferred since this promotes efficient regioselective C-deuteria-
tion to give the required deuteriated carbonyl derivative11 rather than
competitive O-deuteriation which has been shown to lead to loss of the
newly incorporated D-label.12
We now report our study into the synthesis of deuteriated amides
using a deprotonation–deuteriation strategy. We discuss the effects of
amide substitution and the nature of the deuterium donor on the level of
deuterium incorporation. For our study, we were required to synthesise
a series of structurally related amides 1,13 2,14 3,15 4,16 5,17 6,18 7,19 8,
9,16 10, 11,20 12,21 13, 14, 15 and 16. These were efficiently synthesised
by the addition of two equivalents of an amine (e.g. diisopropylamine)
to a stirred solution of the corresponding acid chloride in dichlor-
omethane to give the required amides 1, 2, 3, 4, 6, 7, 8, 9, 10, 12, 14 and
16. Further substitution at the C(2) position was easily achieved using
classical deprotonation and alkylation methodology by treatment of the
amides 4, 12 and 16 with either LDA or sec-BuLi in THF at ꢀ788C,
followed by the addition of methyl iodide, ethyl iodide, isopropyl iodide
and benzyl bromide to give the corresponding 2-alkyl substituted
amides 5, 11, 13 and 15.
We first probed the structural nature of the deuterium donor on the
efficiency of regioselective enolate C-deuteriation. We chose to use 2-
phenylpropionyl diisopropylamide 5 as our model compound due to its
UV activity, non-volatile nature and predictable enolate chemistry
(Table 1).17,22 To ensure efficient C-deuteriation, removal of the C(2)
proton in the starting amide 5 is paramount. In a related study,
Vedejs17,22 have shown that deprotonation of this amide can efficiently
occur when using sec-BuLi as the base. Under these conditions,17,22
addition of an excess of sec-BuLi (1.7 equivalents) to a stirred solution
of 2-phenylpropionyl diisopropylamide 5 in THF at ꢀ788C, followed by
addition of the deuterium donor (DA) gave the required 2-deuterio-2-
Copyright # 2003 John Wiley & Sons, Ltd.
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THE SYNTHESIS AND CHARACTERIZATION
1035
Table 1.
Entry
D-source
[(D):(H)]
Yield (%)
1
2
3
4
5
Acetic acid-d4
Nitromethane-d3
Acetonitrile-d3
D2O
98:2
98:2
h1:i99
98:2
77:23
66
61
81
65
64
Ethyl glycol-d2
phenylpropionyl amide 5-d1. The levels of deuterium incorporation were
1
measured by H NMR spectroscopy by integration of the singlet for
methyl group (CH3CD) in 5-d1 and the corresponding doublet
(CH3CH) for the unlabelled amide 5. For mildly D-acidic sources, such
as acetic acid-d4, nitromethane-d3 and D2O the level of D-incorporation
was near perfect (>98%) (Table 2), whereas, for simple diols, like
ethylene glycol-d2 the level of D-incorporation was significantly lower
than that for D2O.
For the remainder of this study, D2O was chosen as our deuterium
source primarily due to it being readily available, inexpensive and easy
to remove during the purification process. The required ‘base-free’
enolates were formed by direct addition of sec-BuLi (1.7 equivalents) to
a solution of the corresponding amides 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15 and 16 in THF at ꢀ788C. After stirring for 1 hour, two
equivalents of D2O were added, and the resulting solutions were stirred
for a further 2 h to give the corresponding deuteriated amides 1-d1, 2-d1,
3-d1, 4-d1, 6-d1, 7-d1, 8-d1, 9-d1, 10-d1, 11-d1, 12-d1, 13-d1, 14-d1, 15-d1
and 16-d1 in moderate to good yield. The substitution pattern at both
the C(2) and the N-position in the amides 1–16 appears to have little or
no effect on the level of deuterium incorporation; all gave similar levels
of D-incorporation (>98% D-incorporation). However, the substitu-
tion pattern at the C(2) position appears to have a significant effect on
the overall yield; the presence of an electron-withdrawing substituent
(such as a phenyl or aryl ring) adjacent to the carbonyl group improves
the chemical yield. This is presumably due to the increased acidity at the
C(2)-position favouring enolate formation rather than promoting direct
nucleophilic addition to the carbonyl group which is known to lead to
ketone formation.23
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G.S. COUMBARIDES ET AL.
Table 2.
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THE SYNTHESIS AND CHARACTERIZATION
1037
Table 2. Continued.
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G.S. COUMBARIDES ET AL.
In conclusion, we have shown that efficient regioselective C-
deuteriation of ‘base-free’ enolates (derived from carbonyl amides)
can occur under kinetic control using D2O as the deuterium donor. The
levels of D-incorporation were shown to be near perfect (>98%) for a
wide variety of substituted amides. It appears that single D-incorpora-
tion preferentially occurs. This is presumably due to the conjugate base
of the deuterium donor [lithium deuterium oxide (LiOD)] being not
sufficiently basic enough to enable thermodynamic equilibration. The
substitution pattern at the C(2) position appears to play a major role in
the reaction pathway. An acidifying substituent at the C(2) position
(such as a phenyl substituent) preferentially aids enolate formation –
without it competitive addition to the carbonyl group occurs.
We believe there are two main factors that are responsible for efficient
amide C-deuteriation under ‘base-free’ conditions; (a) the presence of an
electron-withdrawing substituent in the C(2) position to aid enolate
formation and (b) the use of a mildly D-acidic deuterium donor (like
D2O) to prevent competitive O-deuteriation which is known to lower
the overall level of D-incorportion.
Experimental
All solvents were distilled before use. Tetrahydrofuran (THF) and ether
were freshly distilled from LiAlH4. Triphenylmethane was used as the
indicator for THF. 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 JEOL EX 270 and Bruker AM 250, AMX 400 and AM 600 Fourier
transform spectrometer (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 machine
and mass spectra were recorded on a Kratos 50MSTC instrument using a
DS503 data system for high-resolution analysis.
N,N-Diisopropyl-ethanamide 113
A solution of acetyl chloride (2.91 g, 2.63 ml, 37.0 mmol) was added
slowly to a stirred solution of diisopropylamine (7.69 g, 10.71 ml,
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THE SYNTHESIS AND CHARACTERIZATION
1039
76 mmol) in dichloromethane (20 ml) at 08C. The mixture was stirred for
12 h. The resulting solution was extracted with ether (10 ml) and water
(10 ml). The organic layer was dried over magnesium sulphate and the
filtrate was evaporated to give the amide 1 (5.01 g, 95%) as a yellow
liquid; Rf [light petroleum : ether (7:3)] 0.15; nmax (film) 1631 cmꢀ1
(C ¼ O); dH(250 MHz, CDC13) 3.95–3.85 (1 H, m, NCH), 3.57–3.52
(1 H, m, NCH), 2.07 (3 H, s, COCH3), 1.37 (6 H, d, J 6.8, 2 ꢁ CH3) and
1.21 (6 H, d, J 6.7, 2 ꢁ CH3); dC (63 MHz, CDC13) 169.4 (CO), 49.2
(CNH), 45.4 (CNH), 23.8 (CH3CO), 20.9 (CH3) and 20.6 (CH3);
(Found MH+, 144.1382. C8H17NO requires 143.2260).
N,N-Diisopropyl-2-deuterio-ethanamide 1-d1
A solution of sec-butyllithium (0.87 ml, 1.4 M in cyclohexane,
1.22 mmol) was added dropwise to a stirred solution of the amide 1
(0.1 g, 0.70 mmol) in THF (1 ml) at ꢀ788C. The resulting solution was
stirred for a further 1 h. Deuterium oxide (31 mg, 28 ml, 1.55 mmol) was
added dropwise to this solution and stirred for a further 2 h. The
reaction was quenched by the addition of water (10 ml). The solution
was extracted with ether (3 ꢁ 10 ml), dried (MgSO4) and evaporated
under vacuum. The residue was purified by flash chromatography on
silica gel eluting with light petroleum ether–ether (7:3) to give the amide
1-d1 (25 mg, 25%) as an oil; Rf [light petroleum:ether (7:3)] 0.15; nmax
(film) 2116 cmꢀ1 (C–D) and 1636 cmꢀ1 (C ¼ O); dH (250 MHz, CDC13)
3.89–3.78 (1 H, septet, J 6.7, NCH), 3.51–3.46 (1 H, m, NCH), 2.00 (1 H,
d, J 3.6, CHAHB), 1.99 (1 H, d, J 4.3, CHAHB), 1.30 (6 H, d, J 6.8,
2 ꢁ CH3) and 1.15 (6 H, d, J 6.8, 2 ꢁ CH3); dC (62.5 MHz, CDC13) 169.5
1
(CO), 49.2 (CNH), 45.5 (CNH), 23.6 (1 C, triplet [1:1:1], JC,D=19.4,
CD), 20.9 (CH3) and 20.6 (CH3); (Found MH+, 145.1460. C8H17DNO
requires 145.1451).
N,N-Diisopropylpropanamide 214
In the same way as the amide 1, propionyl chloride (2.01 g, 1.92 ml,
22 mmol) and diisopropylamine (4.40 g, 6.12 ml, 44 mmol) in dichlor-
omethane (15 ml) gave the amide 2 (3.15 g, 91%) as a yellow liquid; Rf
[light petroleum:ether (7:3)] 0.33; nmax (film) 1626 cmꢀ1 (C ¼ O); dH
(250 MHz, CDC13) 3.99–3.94 (1 H, m, NCH), 3.62–3.42 (1 H, m, NCH),
2.35–2.26 (2 H, q, J 7.4, CH2CH3), 1.38 (6 H, d, J 6.5, 2 ꢁ CH3), 1.20
(6 H, d, J 6.4, 2 ꢁ CH3) and 1.12 (3 H, t, J 7.4, CH2CH3); dC (62.5 MHz,
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G.S. COUMBARIDES ET AL.
CDC13) 172.6 (CO), 48.0 (CNH), 45.4 (CNH), 28.3 (CH2CO), 20.9
(CH3), 20.7 (CH3) and 9.5 (CH2CH3) (Found MH+, 158.1550.
C9H19NO requires 157.2525).
N,N-Diisopropyl-2-deuterio-propanamide 2-d1
In the same way as the amide 1-d1, amide 2 (0.1 g, 0.63 mmol), sec-
butyllithium (0.79 ml, 1.4 M in cyclohexane, 1.12 mmol) and deuterium
oxide (28.8 mg, 26 ml, 1.44 mmol) gave the amide 2-d1 (25 mg, 25%) as
an oil; Rf [light petroleum:ether (7:3)] 0.33; nmax (film) 2173 cmꢀ1 (C-D)
and 1630 cmꢀ1 (C ¼ O); dH(250 MHz, CDC13) 3.88–3.77 (1 H, septet, J
6.6, NCH), 3.45–3.36 (1 H, m, NCH), 2.19–2.09 (1 H, m, CH), 1.23 (6 H,
d, J 6.7, 2 ꢁ CH3), 1.04 (6 H, d, J 6.7, 2 ꢁ CH3) and 0.97 (3 H, d, J 7.3,
CH3); dC (62.5 MHz, CDC13) 172.7 (CO), 48.1 (CNH), 45.5 (CNH),
1
28.0 (1 C, triplet [1:1:1], JC,D=19.4, CD), 20.9 (CH3), 20.7 (CH3) and
9.5 (CH2CH3) (Found MH+, 159.1614. C9H18DNO requires 158.1535).
N,N-Diisopropyl-2-methylpropanamide 315
In the same way as the amide 1, iso-butyric chloride (3 g, 28 mmol) and
diisopropylamine (5.67 g, 7.9 ml, 56 mmol) in dichloromethane (30 ml)
gave the amide 3 (2.55 g, 53%) as an orange solid; Rf [light
petroleum:ether (7:3)] 0.24; nmax (KBr) 1634 cmꢀ1 (C ¼ O); dH
(250 MHz, CDC13) 4.07–3.96 (1 H, m, NCH), 3.59–3.49 (1 H, m,
NCH), 2.77–2.63 (1 H, septet, J 6.7, C(2)H), 1.35 (6 H, d, J 6.8,
2 ꢁ CH3), 1.23 (6 H, d, J 6.8, 2 ꢁ CH3) and 1.11 (6 H, d, J 6.7, 2 ꢁ CH3);
dC (62.5 MHz, CDC13) 176.1 (CO), 47.5 (CNH), 45.5 (CNH), 31.7
(CHCO), 21.4 (2 ꢁ CH3). 20.7 (2 ꢁ CH3) and 19.7 (2 ꢁ CH3) (Found
MH+, 172.1693. C10H21NO requires 171.2790).
N,N-Diisopropyl-2-deuterio-2-methylpropanamide 3-d1
In the same way as the amide 1-d1, amide 3 (0.1 g, 0.58 mmol), sec-
butyllithium (0.73 ml, 1.4 M in cyclohexane, 1.02 mmol) and deuterium
oxide (25.5 mg, 23 ml, 1.27 mmol) gave the amide 3-d1 (35 mg, 35%) as
an oil; Rf [light petroleum: ether (7:3)] 0.24; nmax (film) 2162 cmꢀ1 (C–D)
and 1634 cmꢀ1 (C ¼ O); dH (250 MHz, CDC13) 3.91–3.80 (1 H, m,
NCH), 3.57–3.44 (1 H, m, NCH), 1.20 (6 H, d, J 6.8, 2 ꢁ CH3), 1.08
(6 H, d, J 6.8, 2 ꢁ CH3) and 0.95 (6 H, s, CD(CH3)2); dC(62.5 MHz,
CDC13) 176.2 (CO), 47.4 (CNH), 45.5 (CNH), 31.4 (1 C, triplet [1:1:1],
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THE SYNTHESIS AND CHARACTERIZATION
1041
JCD=19.8, CD), 21.4 (2 ꢁ CH3), 20.7 (2 ꢁ CH3) and 19.6 (2 ꢁ CH3)
(Found MH+, 173.1770. C10H21DNO requires 173.1764).
N,N-Diisopropyl-2-phenylethanamide 416
In the same way as the amide 1, phenylacetyl chloride (24.53 g, 21.0 ml,
0.16 mol) and diisopropylamine (32.31 g, 45.0 ml, 0.34 mol) in dichlor-
omethane (240 ml) gave the amide 4 (33.83 g, 95%) as a yellow solid; Rf
[light petroleum: ether (7:3)] 0.18; m.p. 44–478C; nmax (KBr)
3001–2869 cmꢀ1 (aromatic, C–H) and 1625 cmꢀ1 (C ¼ O); dH(250 MHz,
CDCl3) 7.34–7.12 (5 H, m, 5 ꢁ CH; Ph), 4.04 (1 H, m, NCH), 3.69 (2 H,
s, PhCH2), 3.48–3.25 (1 H, m, NCH), 1 0.39 (6 H, d, J 6.8, 2 ꢁ CH3) and
1.11 (6 H, d, J 6.8, 2 ꢁ CH3); dC (62.5 MHz, CDCl3) 169.9 (CO), 135.9
(Ph), 128.6 (Ph), 128.5 (Ph), 126.5 (Ph), 49.4 (NCH), 45.8 (NCH), 43.5
(CHCO) and 20.6 (CH3) (Found MH+, 220.1702. C14H21NO requires
219.1622).
N,N-Diisopropyl-2-deuterio-2-phenylethanamide 4-d1
In the same way as amide 1, amide 4 (0.1 g, 0.46 mmol), sec-butyllithium
(0.57 ml, 1.4 M in cyclohexane. 0.81 mmol) and deuterium oxide
(19.9 mg, 18 ml, 0.91 mmol) gave the amide 4-d1 (79 mg, 78%); as an
oil; Rf [light petroleum: ether (7:3)] 0.18; nmax (film) 2172 cmꢀ1 (C–D)
and 1632 cmꢀ1 (C ¼ O); dH(250 MHz, CDC13) 7.47–7.11 (5 H, m,
5 ꢁ CH; Ph), 3.94–3.84 (1 H, septet, J 6.7, NCH), 3.62 (1 H, s, CH),
3.33–3.27 (1 H, septet, J 6.7, NCH), 1.35 (6 H, d, J 6.8, 2 ꢁ CH3) and
0.93 (6 H, d, J 6.7, 2 ꢁ CH3); dC(62.5 MHz, CDC13) 170.0 (CO), 135.8
(Ph), 128.6 (Ph), 128.4 (Ph), 126.5 (Ph), 49.4 (CNH), 45.8 (CNH), 43.2
1
(1 C, triplet [1:1:1], JC,D=19.4, CD) and 20.6 (CH3); (Found MH+,
221.1775. C14H20DNO requires 220.1696).
N,N-Diisopropyl-2-phenylpropanamide 517
LDA (19.78 ml, 1.5 M in THF, 30 mmol) was added dropwise to a
stirred solution of N,N-diisopropyl-2-phenylethanamide
4
(5 g,
23 mmol) in THF (60 ml) at ꢀ788C and stirred for 1 h. Methyl iodide
(3.41 g, 1.5 ml, 24 mmol) was added and the resulting solution was
stirred for 12 h. Water (100 ml) was then added and the mixture was
extracted with ether (3 ꢁ 200 ml). The combined organic layers were
dried (MgSO4) and evaporated under reduced pressure. The residue was
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G.S. COUMBARIDES ET AL.
purified by flash column chromatography on silica gel eluting with light
petroleum (b.p. 40–608C)–ether (9:1) to give the amide 5 (3.36 g, 61%)
as a yellow solid; Rf [light petroleum:ether (7:3)] 0.36; m.p. 39–408C;
nmax (KBr) 3057–2872 cmꢀ1 (aromatic, C–H) and 1638 cmꢀ1 (C ¼ O);
dH(250 MHz, CDC13) 7.34–7.18 (5 H, m, 5 ꢁ CH; Ph), 4.10–3.95 (1 H,
m, NCH), 3.83–3.75 (1 H, q, J 6.8, C(2)H), 3.32–3.25 (1 H, m, NCH),
1.45 (3 H, d, J 6.8, C(2)HCH3), 1.41 (3 H, d, J 76.8, CH3), 1.38 (3 H, d, J
6.7, CH3), 1.13 (3 H, d, J 6.7, CH3) and 0.58 (3 H, d, J 6.6, CH3); dC
(62.5 MHz, CDC13) 172.2 (CO), 143.1 (Ph), 128.2 (Ph), 127.2 (Ph),
126.6 (Ph), 48.4 (CHN), 45.8 (CHN), 44.9 (CHCO), 21.1 (CH3), 20.1
(CH3) and 19.2 (CH3) (Found MH+, 234.1861. C15H23NO requires
233.1782).
N,N-Diisopropyl-2-deuterio-phenylpropanamide 5-d1
A solution of sec-BuLi (0.54 ml, 1.4 M in cyclohexane, 0.75 mmol) was
added to the amide 5 (0.1 g, 0.43 mmol) in THF (3 ml) at ꢀ788C and
stirred for 1 h. Deuterium oxide (19 mg, 17 ml 0.94 mmol) was added and
the resulting solution was stirred for a further 1 h. The solution was
quenched with water (10 ml) and extracted with ether (10 ml), dried
(with MgSO4) ands the organic layer was evaporated to give the amide
5-d1 (66 mg, 65%) as an oil; Rf [light petroleum:ether (7:3)] 0.36; nmax
(film) 2158 cmꢀ1 (C–D) and 1636 cmꢀ1 (C ¼ O); dH (250 MHz, CDC13)
7.33–7.16 (5 H, m, 5 ꢁ CH; Ph), 4.06–3.92 (1 H, septet, J 6.7, NCH),
3.35–3.24 (1 H, septet, J 6.7, NCH), 1.45 (3 H, d, J 6.8, CH3), 1.39 (3 H,
s, CH3), 1.38 (3 H, d, J 6.9, CH3), 1.15 (3 H, d, J 6.7, CH3) and 0.58
(3 H, d, J 6.6, CH3); dC (62.5 MHz, CDCl3) 172.2 (CO), 143.0 (Ph),
128.8 (Ph), 127.2 (Ph), 126.5 (Ph), 48.3 (CNH), 45.8 (CNH), 44.4 (1 C,
triplet [1:1:1], 1JC.D=19.4, CD), 21.0 (CH3), 20.9 (CH3), 20.0 (CH3) and
19.6 (CH3); (Found MH+, 235.1912. C15H22DNO requires 234.1833).
N,N-Diethyl-2-phenyl-propanamide 618
In the same way as the amide 1, 2-phenylpropionyl chloride (3 g,
2.57 ml, 19 mmol) and diethylamine (2.78 g, 3.94 ml, 38 mmol) in
dichloromethane (30 ml) gave the amide 6 (2.78 g, 71%) as a yellow
liquid; Rf [light petroleum:ether (7:3)] 0.29; nmax (KBr) 3061–2872 cmꢀ1
(aromatic, CH) and 1639 cmꢀ1 (C=O); dH(250 MHz, CDC13) 7.37–7.17
(5 H, m, 5 ꢁ CH; Ph), 3.87–3.79 (1 H, q, J 7.0, CH), 3.57–3.43 (1 H, dq, J
13.5, J 7.1, CHAHBCH3), 3.39–3.04 (3 H, m, CHAHB and CH2), 1.44
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THE SYNTHESIS AND CHARACTERIZATION
1043
(3 H, d, J 6.9, C(2)HCH3), 1.08 (3 H, t, J 7.1, CH2CH3) and 1.00 (3 H, t,
J 7.1, CH2CH3); dC (62.5 MHz, CDC13) 172.7 (CO), 142.5 (Ph), 128.8
(Ph), 127.3 (Ph), 126.6 (Ph), 43.2 (CHCO), 41.6 (CH2N), 40.3 (CH2N),
21.0 (CH3), 14.2 (CH3CH2) and 12.8 (CH3CH2) (Found MH+,
206.1542. C13H19NO requires 205.1466).
N,N-Diethyl-2-deuterio-2-phenyl-propanamide 6-d1
In the same way as the amide 1-d1, amide 6 (0.1 g, 0.49 mmol), sec-
butyllithium (0.61 ml, 1.4 M in cyclohexane, 0.86 mmol) and deuterium
oxide (22.1 mg, 20 ml, 1.11 mmol) gave the amide 6-d1 (66 mg, 65%); Rf
[light petroleum:ether (7:3)] 0.29; nmax (film) 2156 cmꢀ1 (C–D) and
1637 cmꢀ1 (C ¼ O); dH(250 MHz, CDC13) 7.34–7.10 (5 H, m, 5 ꢁ CH;
Ph), 3.49–2.97 (4 H,m,2 ꢁ CH2), 1.36(3 H, s, CH3), 1.02 (3 H, t, J 7.1,
CH2CH3) and 0.91 (3 H, t, J 7.1, CH2CH3); dC (62.5 MHz, CDC13)
172.7 (CO), 142.4 (Ph), 128.8 (Ph), 127.2 (Ph), 126.6 (Ph), 42.8 (1 C,
triplet [1:1:1], 1JC,D=19.3, CD), 41.6 (CH2N), 40.3 (CH2N), 20.8 (CH3),
14.2 (CH3) and 12.8 (CH3) (Found MH+, 207.1598. C13H18DNO
requires 206.1519).
N-Cyclohexyl-2-phenyl-propanamide 719
In the same way as the amide 1, 2-phenylpropionyl chloride (3 g,
2.57 ml, 19.4 mmol) and piperidine (3.30 g, 3.84 ml, 38.8 mmol) in
dichloromethane (30 ml) gave the amide 7 (3.74 g, 89%) as a yellow
liquid; Rf [light petroleum:ether (7:3)] 0.28; nmax (KBr) 3061–2855 cmꢀ1
(aromatic, CH) and 1639 cmꢀ1 (C ¼ O); dH (250 MHz, CDCl3) 7.38–
7.17 (5 H, m, 5 ꢁ CH; Ph), 3.92–3.84 (1 H, q, J 6.6, CH), 3.76–3.71 (1 H,
m, NCHAHB), 3.43–3.27 (3 H, m, NCHAHB and NCH2), 1.54–1.36
(8 H, m, CH3, CHAHB and 2 ꢁ CH2) and 1.00–0.95 (1 H, m, CHAHB);
dC (62.5 MHz, CDCl3) 171.7 (CO), 142.5 (Ph), 128.8 (Ph), 127.3 (Ph),
126.6 (Ph), 46.6 (CH2N), 43.2 (CH2N), 43.1 (CHCO), 25.9 (CH2), 25.5
(CH2), 24.5 (CH2) and 20.8 (CH3) (Found MH+, 218.1553. C14H19NO
requires 217.1466).
N-Cyclohexyl-2-deuterio-2-phenyl-propanamide 7-d1
In the same way as the amide 1-d1, amide 7 (0.1 g, 0.46 mmol), sec-
butyllithium (0.57 ml, 1.4 M in cyclohexane, 0.80 mmol) and deuterium
oxide (19.9 mg, 18 ml, 1.0 mmol) gave the amide 7-d1; (75 mg, 75%); Rf
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[light petroleum:ether (7:3)] 0.28; nmax (film) 2158 cmꢀ1 (C–D) and
1638 cmꢀ1 (C ¼ O); dH(250 MHz, CDC13) 7.22–7.02 (5 H, m, 5 ꢁ CH;
Ph), 3.61–3.54 (1 H, m, CHAHB), 3.29–3.08 (3 H, m, CH2 and CHAHB)
and 138–1.11 (9 H, m, 3 ꢁ CH2 and CH3); dC(62.5 MHz, CDC13) 171.8
(CO), 142.4 (Ph), 128.8 (Ph), 127.2 (Ph), 126.6 (Ph), 46.6 (CH2N), 43.1
1
(CH2N), 42.8 (1 C, triplet [1:1:1], JC,D=19.4, CD), 25.9 (CH2), 25.5
(CH2), 24.5 (CH2) and 20.7 (CH3); (Found MH+, 219.1615.
C14H19DNO requires 218.1536).
N,N-Dicyclohexyl-2-phenyl-propanamide 8
In the same way as the amide 1, 2-phenylpropionyl chloride (2 g,
12 mmol) and dicyclohexyl amine (4.35 g, 4.77 ml, 24 mmol) in
dichloromethane (20 ml) gave amide 8 (3.65 g, 98%) as a yellow solid;
Rf [light petroleum:ether (7:3)] 0.44; m.p. 70–738C; nmax (KBr)
3061–2855 cmꢀ1 (aromatic, CH) and 1639 cmꢀ1 (C ¼ O); dH
(250 MHz, CDC13) 7.37–7.11 (5 H, m, 5 ꢁ CH; Ph), 3.83–3.75 (1 H, q,
J 6.7, CH), 3.59–3.50 (1 H, m, NCH), 2.82–2.59 (2 H, m, NCH and
CHAHB) and 1.96–0.99 (22 H, m, CH3, CHAHB and 9 ꢁ CH2); dC
(67.5 MHz, CDC13) 172.5 (CO), 143.4 (Ph), 128.8 (Ph), 127.3 (Ph),
126.5 (Ph), 57.4 (NCH), 56.2 (NCH), 45.2 (CHCO), 30.9 (CH2), 30.3
(2 ꢁ CH2), 30.2 (CH2), 26.8 (CH2), 26.6 (CH2), 26.2 (CH2), 25.8 (CH2),
25.6 (CH2), 25.3 (CH2) and 21.0 (CH3) (Found MH+, 314.2492.
C21H31NO requires 313.2405).
N,N-Dicyclohexyl-2-deuterio-2-phenyl-propanamide 8-d1
In the same way as the amide 1-d1, amide 8 (0.1 g, 0.32 mmol), sec-
butyllithium (0.40 ml, 1.4 M in cyclohexane, 0.56 mmol) and deuterium
oxide (14.4 mg, 13 ml, 0.72 mmol) gave the amide 8-d1; (77 mg, 75%); Rf
[light petroleum:ether (7:3)] 0.44; nmax (film) 2191 cmꢀ1 (C–D) and
1638 cmꢀ1 (C ¼ O); dH(250 MHz, CDC13) 7.33–7.16 (5 H, m, 5 ꢁ CH;
Ph), 3.62–3.50 (1 H, m, NCH), 2.90–2.68 (1 H, m, NCH), 2.66–2.44
(2 H, m, CH2) and 1.90–0.52 (21 H, m, 9 ꢁ CH2 and CH3); dC
(62.5 MHz, CDC13) 172.6 (CO), 143.1 (Ph), 128.7 (Ph), 127.1 (Ph),
126.4 (Ph), 57.4 (CHN), 56.2 (CHN), 44.6 (1 C, triplet [1:1:1],
1JC,D=19.4, CD), 31.3 (CH2), 30.2 (2 ꢁ CH2), 29.2 (CH2), 26.7 (CH2),
26.6 (CH2), 26.1 (CH2), 25.7 (CH2), 25.5 (CH2), 25.2 (CH2) and 20.7
(CH3) (Found MH+, 315.2555. C21H30DNO requires 314.2476).
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1045
N,N-Diisopropyl-2-phenylbutanamide 916
In the same way as the amide 1, 2-phenylbutyryl chloride (1 g,
5.4 mmol), diisopropylamine (1.09 g, 1.52 ml, 10.8 mmol) in dichlor-
omethane (5 ml) gave the amide 9 (1.04 g, 77%) as a yellow solid; Rf
[light petroleum:ether (7:3)] 0.44; m.p. 55–608C; nmax (KBr) 3064–
2869 cmꢀ1 (aromatic, C–H) and 1634 cmꢀ1 (C ¼ O); dH(250 MHz,
CDC13) 7.33–7.17 (5 H, m, Ph), 4.13–4.00 (1 H, m, NCH), 3.52–3.46
(1 H, t, J 7.2, C(2)H), 3.36–3.24 (1 H, m, NCH), 2.20–2.01 (1 H, septet, J
7.3. CHAHBCH3), 1.75–1.58 (1 H, septet, J 7.1, CHAHBCH3), 1.44 (3 H,
d, J 6.8, NCHCH3), 1.35 (3 H, d, J 6.8, NCHCH3), 1.14 (3 H, d, J 6.7,
NCHCH3), 0.90–0.84 (3 H, t, J 7.4, CH2CH3) and 0.63 (3 H, d, J 6.6,
NCHCH3); dC(62.5 MHz, CDC13); 171.5 (CO), 141.2 (Ph), 128.5 (Ph),
127.7 (Ph), 126.4 (Ph), 52.5 (CHCO), 48.2 (CHN), 45.8 (CHN), 28.2
(CH2), 20.9 (CH3), 20.8 (CH3), 20.1 (CH3), 19.8 (CH3) and 12.4 (CH3);
(Found MH+, 248. Ci6H25NO requires 247).
N,N-Diisopropyl-2-deuterio-2-phenylbutanamide 9-d1
In the same way as the amide 1-d1, the amide 9 (0.1 g, 0.40 mmol), sec-
butyllithium (51 ml, 1.4 M in cyclohexane, 0.71 mmol) and deuterium
oxide (17.7 mg, 16 ml, 0.88 mmol) gave the amide 9-d1 (50 mg, 50%); Rf
[light petroleum:ether (7:3)] 0.44; nmax (film) 2147 cmꢀ1 (C–D) and
1637 cmꢀ1 (C ¼ O); dH (250 MHz, CDC13) 7.33–7.16 (5 H, m, 5 ꢁ CH;
Ph), 4.14–3.98 (1 H, septet, J 6.1 NCH), 3.33–3.27 (1 H, m, NCH),
2.17–2.03 (1 H, dq, J 13.6 and 7.3, CHAHB), 1.73–1.59 (1 H, dq, J 13.7
and 7.3, CHAHB), 1.44 (3 H, d, J 6.8, CH3), 1.35 (3 H, d, J 6.8; CH3),
1.15 (3 H, d, J 6.7, CH3), 0.87 (3 H, t, J 7.3, CH2CH3) and 0.63 (3 H, d, J
6.6, CH3); dC (62.5 MHz, CDC13) 171.7 (CO), 141.2 (Ph), 128.6 (Ph),
l
127.8 (Ph), 126.5 (Ph), 52.1 (1 C, triplet [1:1:1], JC,D=19.4, CD), 48.1
(CHN), 45.9 (CHN), 28.2 (CH2), 21.0 (CH3), 20.9 (CH3), 20.2 (CH3),
19.9 (CH3) and 12.4 (CH3CH2); (Found MH+, 249.2062. C16H24DNO
requires 248.1983).
N,N-Diisopropyl-3-methyl-2-phenylbutanamide 10
In the same way as the amide 1, a-isopropylphenylacetyl chloride
(2.27 g, 12 mmol) and diisopropylamine (2.43 g, 3.38 ml, 24 mmol) in
dichloromethane (20 ml) gave the amide 10 (2.58 g, 85%) as a yellow
solid; Rf [light petroleum:ether (7:3)] 0.54; m.p. 29–318C; nmax (KBr)
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3061–2870 (aromatic, CH) and 1634 cmꢀ1 (C ¼ O); dH (250 MHz,
CDC13) 7.31–7.16 (5 H, m, 5 ꢁ CH; Ph), 4.25–4.14 (1 H, m, NCH),
3.35–3.27 (1 H, m, NCH), 3.20 (1 H, d, J 9.7, C(2)H), 2.50–2.36 (1 H, m,
C(2)HCH), 1.43 (3 H, d, J 6.8, CH3), 1.30 (3 H, d, J 6.7, CH3), 1.18 (3 H,
d, J 6.7, CH3), 1.02 (3 H, d, J 6.4, CH3), 0.74 (3 H, d, J 6.6, CH3) and
0.65 (3 H, d, J 6.8, CH3); dC (62.5 MHz, CDC13) 171.6 (CO), 140.0 (Ph),
128.4 (Ph), 126.5 (Ph), 58.0 (CHCO), 48.2 (CHN), 45.9 (CHN), 32.2
(CHCHCO), 22.3 (CH3), 21.1 (CH3), 20.8 (CH3), 20.5 (CH3). 20.3
(CH3) and 20.2 (CH3); (Found MH+, 262.2163. C17H27NO requires
262.4013).
N,N-Diisopropyl-2-deuterio-3-methyl-2-phenylbutanamide 10-d1
In the same way as the amide 1-d1, the amide 10 (0.1 g, 0.38 mmol), sec-
butyllithium (0.48 ml, 1.4 M in cyclohexane, 0.67 mmol) and deuterium
oxide (16.6 mg, 15 ml, 0.83 mmol) gave the amide 10-d1 (65 mg, 65%); Rf
[light petroleum:ether (7:3)] 0.54; nmax (film) 2158 cmꢀ1 (C–D) and
1638 cmꢀ1 (C ¼ O); dH(250 MHz, CDCl3) 7.37–7.16 (5 H, m, 5 ꢁ CH;
Ph), 4.25–4.14 (1 H, septet, J 6.7, NCH), 3.32–3.27 (1 H, m, NCH),
2.48–2.37 (1 H, septet, J 6.5, CDCH), 1.43 (3 H, d, J 6.8, CH3), 1.30
(3 H, d, J 6.8, CH3), 1.18 (3 H, d, J 6.7, CH3), 1.02 (3 H, d, J 6.4, CH3),
0.74 (3 H, d, J 6.6, CH3) and 0.65 (3 H, d, J 6.8, CH3); dC (62.5 MHz,
CDCl3) 171.7, 139.9, 128.4, 126.5, 57.5 (1 C, triplet [1:1:1], 1JC,D=19.8,
CD), 48.2 (CHN), 45.9 (CHN), 32.1 (CDCH), 22.3 (CH3), 21.1 (CH3),
20.8 (CH3), 20.5 (CH3), 20.3 (CH3) and 20.2 (CH3); (Found MH+,
263.2243. C17H26DNO requires 262.2164).
N,N-Diisopropyl-2,3-diphenylpropanamide 1120
In the same way as the amide 5, amide 4 (3.0 g, 14 mmol), sec-
butyllithium (11 ml, 1.4 M in cyclohexane, 15 mmol) and benzyl
bromide (2.59 g, 1.8 ml, 14 mmol) in THF (30 ml) gave the amide 11
(2.42 g, 56%) as a yellow solid; Rf [light petroleum:ether (7:3)] 0.18; m.p.
62–668C; nmax (film) 3084–2872 (aromatic, CH) and 1638 cmꢀ1 (C ¼ O);
dH (250 MHz, CDCl3) 7.30–7.05 (10 H, m, 10 ꢁ CH; 2 ꢁ Ph), 4.04–3.96
(1 H, m, NCH), 3.71 (1 H, t, J 7.3, C(2)H), 3.54–3.44 (1 H, dd, J 13.3
and 7.2, CHAHB), 3.39–3.16 (1 H, m, NCH), 2.92–2.84 (1 H, dd, J 13.4
and 6.9, CHAHB), 1.36 (3 H, d, J 6.8, CH3), 1.35 (3 H, d, J 6.7, CH3),
0.98 (3 H, d, J 6.7, CH3) and 0.63 (3 H, d, J 6.6, CH3); dC (62.5 MHz,
CDCl3) 171.1 (CO), 140.5 (Ph), 129.3 (Ph), 128.6 (Ph), 128.0 (Ph), 127.9
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1047
(Ph), 126.7 (Ph), 125.9 (Ph), 52.4 (CHCO), 48.4 (CHN), 45.9 (CHN),
41.4 (CH2Ph), 20.8 (2 ꢁ CH3), 20.2 (CH3) and 20.0 (CH3) (Found
MH+, 310.2160. C21H27NO requires 309.4441).
N,N-Diisopropyl-2-deuterio-2,3-diphenylpropanamide 11-d1
In the same way as the amide 1-d1, the amide 11 (0.1 g, 0.32 mmol), sec-
butyllithium (0.41 ml, 1.4 M in cyclohexane, 0.57 mmol) and deuterium
oxide (14.4 mg, 13 ml, 0.72 mmol) gave the amide 11-d1 (66 mg, 67%); Rf
[light petroleum:ether (7:3)] 0.18; nmax (film) 2148 cmꢀ1 (C–D) and
1632 cmꢀ1 (C ¼ O); dH (250 MHz, CDC13) 7.30–7.05 (10 H, m, 10 ꢁ CH;
2 ꢁ Ph), 4.03–3.92 (1 H, septet, J 6.7, NCH), 3.50 (1 H, d, J 13.4,
CHAHB), 3.29–3.24 (1 H, m, NCH), 2.88 (1 H, d, J 13.4, CHAHB), 1.35
(3 H, d, J 6.8, CH3), 1.34 (3 H, d, J 6.7, CH3), 0.97 (3 H, d, J 67, CH3)
and 0.63(3 H, d, J 6.6, CH3); dC (62.5 MHz, CDCl3) 171.1 (CO), 140.4
(Ph), 129.3 (Ph), 128.6 (Ph), 128.0 (Ph), 127.9 (Ph), 126.7 (Ph), 125.9
(Ph), 52.3 (1 C, triplet [1:1:1], JC,D=19.2, CD), 48.4 (CNH), 45.9
(CNH), 41.2 (CH2Ph), 20.8 (2 ꢁ CH3), 20.2 (CH3) and 20.0 (CH3)
(Found MH+, 311.2226. C21H26DNO requires 310.2147).
N,N-Diisopropyl-2-(4-methoxyphenyl)-ethanamide 1221
In the same way as the amide 1, 4-methoxyphenylacetyl chloride (2.5 g,
13 mmol) and diisopropylamine (2.69 g, 3.75 ml, 27 mmol) in dichlor-
omethane (25 ml) gave the amide 12 (3 g, 92%) as a white solid; Rf [light
petroleunrether (7:3)] 0.11; m.p. 53–618C; nmax (KBr) 3001–2837
(aromatic, CH) and 1634 cmꢀ1 (C ¼ O); dH (250 MHz, CDC13) 7.15
(2 H, d, J 8.7, 2 ꢁ CH; Ar; 2,6-CH), 6.85 (2 H, d, J 8.7, 2 ꢁ CH; Ar; 3,5-
CH), 4.06–3.87 (1 H, m, NCH), 3.79 (3 H, s, OCH3), 3.61 (2 H, s, CH2),
3.50–3.37 (1 H, m, NCH), 1.41 (6 H, d, J 6.8, 2 ꢁ CH3) and 1.02 (6 H, d,
J 6.7, 2 ꢁ CH3); dC(62.5 MHz, CDCl3) 170.2 (CO), 158.3 (Ph), 129.5
(Ph), 127.9 (Ph), 114.1 (Ph), 55.3 (CH3O), 49.3 (CNH), 45.8 (CNH),
42.5 (CH2CO), 20.7 (CH3) and, 20.6 (CH3) (Found MH+, 250.1799.
C15H23NO2 requires 249.1728).
N,N-Diisopropyl-2-deuterio-2-(4-methoxyphenyl)-ethanamide 12-d1
In the same way as the amide 1-d1, amide 12 (50 mg, 0.20 mmol), sec-
butyllithium (0.25 ml, 1.4 M in cyclohexane, 0.35 mmol) and deuterium
oxide (11.1 mg, 10 ml, 0.55 mmol) gave the amide 12-d1, (36 mg, 73%); Rf
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[light petroleum:ether (7:3)] 0.11; nmax (film) 2144 cmꢀ1 (C–D) and
1636 cmꢀ1 (C ¼ O); dH(250 MHz, CDCl3) 7.15 (2 H, d, J 6.7, 2 ꢁ CH;
Ar; 3,5-CH), 6.84 (2 H, d, J 6.6, 2 ꢁ CH; Ar; 2,6-CH), 4.02–3.88 (1 H, m,
NCH), 3.78 (3 H, s, OCH3), 3.59 (1 H, s, CH), 3.39–3.34 (1 H, m, NCH),
1.41 (6 H, d, J 6.8, 2 ꢁ CH3) and 1.01 (6 H, d, J 6.7, 2 ꢁ CH3):
dC(62.5 MHz, CDCl3) 170.3 (CO), 158.3 (Ph), 129.5 (Ph), 127.7 (Ph),
114.1 (Ph), 55.2 (CH3O), 49.3 (CNH), 45.8 (CNH), 42.2 (1 C, triplet
1
[1:1:1], JC,D=19.4, CD), 20.6 (CH3) and 20.5 (CH3) (Found MH+,
251.1676. C15H22DNO2 requires 250.1799).
N,N-Diisopropyl-2-(4-methoxyphenyl)-propanamide 13
In the same way as the amide 5, amide 12 (2.9 g, 12 mmol), LDA (12 ml,
1.5 M in THF, 18 mmol) and methyl iodide (2.05 g, 0.90 ml, 14 mmol) in
THF (35 ml) gave the amide 13 (2.01 g, 67%) as a white solid; Rf [light
petroleum:ether (7:3)] 0.27; m.p. 47–538C; nmax (KBr) 3001-2835
(aromatic, CH) and 1638 cmꢀ1 (C ¼ O); dH(250 MHz, CDCl3) 7.13
(2 H, d, J 8.7, 2 ꢁ CH; Ar; 3,5-CH), 6.82 (2 H, d, J 8.7, 2 ꢁ CH; Ar; 2,6-
CH), 4.04–3.93 (1 H, m, NCH), 3.77–3.69 (4 H, m, OCH3 and CH),
3.29–3.22 (1 H, m, NCH), 1.40 (3 H, d, J 6.8, CH3), 1.37 (6 H, d, J 6.7,
2 ꢁ CH3), 1.12 (3 H, d, J 6.7, CH3) and 0.58 (3 H, d, J 6.6, CH3); dC
(62.5 MHz, CDCl3) 172.5 (CO), 158.2 (Ph), 135.2 (Ph), 130.1 (Ph), 128.2
(Ph), 114.2 (Ph), 55.2 (CH3O), 43.2 (CHN), 45.8 (CHN), 43.8 (CHCO),
21.1 (CH3), 21.0 (CH3), 20.1 (CH3) and 19.8 (CH3) (Found MH+,
260.1968. C15H25NO2 requires 263.3742.)
N,N-Diisopropyl-2-deuterio-2-(4-methoxyphenyl)-propanamide 13-d1
In the same way as the amide 1-d1, amide 13 (50 mg, 0.19 mmol), sec-
butyllithium (0.24 ml, 1.4 M in cyclohexane, 33 mmol) and deuterium
oxide (11.1 mg, 10 ml, 0.55 mmol) gave the amide 13-d1 (29 mg, 58%); Rf
[light petroleum:ether (7:3)] 0.27; nmax (film) 2158 cmꢀ1 (C–D) and
1638 cmꢀ1 (C ¼ O); dH (250 MHz, CDC13) 7.01 (2 H, d, J 6.6, 2 ꢁ CH;
Ar; 3,5-CH), 6.78 (2 H. d J 6.7, 2 ꢁ CH; Ar; 2,6-CH), 4.00-3.89 (1 H,
septet, J 6.7, NCH), 3.72 (3 H, s, OCH3), 3.27-3.21 (1 H, m, NCH), 1.37
(3 H, d, J 6.8, CH3), 1.31 (3 H, d, J 5.5, CH3), 1.30 (3 H, s, CH3), 1.07
(3 H, d, J 6.7, CH3) and 0.57 (3 H, d, J 6.6, CH3); dC (62.5 MHz,
CDC13) 172.5 (CO), 158.2 (Ph), 135.1 (Ph), 128.2 (Ph), 128.1 (Ph), 114.2
(Ph), 55.2 (CH3O), 48.2 (CHN), 45.8 (CHN), 43.1 (1 C, triplet [1:1:1],
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THE SYNTHESIS AND CHARACTERIZATION
1049
1JC,D=19.7, CD), 21.0 (CH3), 20.1 (CH3) and 19.8 (CH3) (Found
MH+, 265.2020. C16H24DNO2 requires 264.1941).
N,N-Diisopropyl-2-(2-methylphenyl)-ethanamide 14
In the same way as the amide 1, o-tolylacetyl chloride (1.5 g, 8.90 mmol)
and diisopropylamine (1.82 g, 2.54 ml, 18 mmol) in dichloromethane
(12 ml) gave the amide 14 (1.97 g, 47%); Rf [light petroleum:ether (7:3)]
0.17; m.p. 26–308C; nmax (KBr) 2999–2874 cmꢀ1 (aromatic, CH) and
1639 cmꢀ1 (C ¼ O); dH(250 MHz, CDCl3) 7.23–7.06 (4 H, m, 4 ꢁ CH;
Ar), 3.95–3.84 (1 H, m, NCH), 3.70 (2 H, s, CH2), 3.45–3.39 (1 H, m,
NCH), 2.26 (3 H, s, CH3), 1.44 (6 H, d, J 6.8, 2 ꢁ CH3) and 1.10 (6 H, d,
J 6.8, 2 ꢁ CH3); dC (63 MHz, CDC13) 169.9 (CO) 136.2 (Ar), 134.6 (Ar),
130.2 (Ar), 128.8 (Ar), 126.7 (Ar), 126.1 (Ar), 49.2 (CNH)5 4.5.9 (CNH),
40.8 (CHCO), 20.7 (CH3) and 19.6 (CH3) (Found MH+, 234.1861
C15H23NO requires 234.1782).
N,N-Diisopropyl-2-deuterio-2-(2-methylphenyl)-ethanamide 14-d1
In the same way as the amide 1-d1, amide 14 (0.1 g, 0.43 mmol), sec-
butyllithium (0.54 ml, 1.4 M in cyclohexane, 0.75 mmol) and deuterium
oxide (18.8 mg, 17 ml, 0.94 mmol) gave the amide 14-d1, (90 mg, 89%); Rf
[light petroleum: ether (7:3)] 0.17; nmax (film) 2163 cmꢀ1 (C–D) and
1636 cmꢀ1 (C ¼ O); dH(250 MHz, CDCl3) 7.19–7.13 (4 H, m, 4 ꢁ CH;
Ar), 3.95–3.84 (1 H, m, NCH), 3.60 (1 H, s, CH), 3.48–3.37 (1 H, septet,
J 6.7, NCH), 2.25 (3 H, s, CH3). 1 44 (6 H. d, J 6.8, 2 ꢁ CH3) and 1.09
(6 H, d, J 6.7, 2 ꢁ CH3); dC (62.5 MHz, CDCl3) 170.0 (CO), 136.2 (Ar),
134.4 (Ar), 130.2 (Ar), 128.7 (Ar), 126.8 (Ar), 126.1 (Ar), 49.3 (CNH),
1
45.9 (CNH), 40.4 (1 C, triplet [1:1:1], JC,D=19.4, CD), 20.6 (CH3)
and 19.6 (CH3); (Found MH+, 235.1910. C15H22DNO requires
234.1831).
N,N-Diisopropyl-2-(2-methylphenyl)-propanamide 15
In the same way as the amide 5, amide 14 (1.5 g, 6.44 mmol), LDA
(4.7 ml, 1.5 M in THF, 7.08 mmol) and methyl iodide (0.91 g, 0.40 ml,
6.42 mmol) in THF (20 ml) gave the amide 15 (1.05 g, 66%) as a white
solid; Rf [light petroleum: ether (7:3)] 0.37; m.p. 72–768C; nmax (film)
2999–2866 cmꢀ1 (aromatic, CH) and 1634 cmꢀ1 (C ¼ O); dH(250 MHz,
CDCl3) 7.21–7.01 (4 H, m, 4 ꢁ CH, Ar), 3.86–3.80 (1 H, q, J 6.8,
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G.S. COUMBARIDES ET AL.
C(2)H), 3.71–3.53 (1 H, m, NCH), 3.32–3.14 (1 H, m, NCH), 2.34 (3 H,
s, CH3; Ar), 1.43 (3 H, d, J 6.8, CH3), 1.41 (3 H, d, J 6.8, CH3), 1.26
(3 H, d, J 6.8, CH3), 1.08 (3 H, d; J 6.7, CH3) and 0.46 (3 H, d, J 6.6,
CH3); dC (62.5 MHz, CDCl3) 172.8 (CO), 141.3 (Ar), 134.0 (Ar), 130.5
(Ar), 126.7 (Ar), 126.5 (Ar), 48.2 (CHN), 45.7 (CHN), 41.0 (CHCO),
21.0 (CH3), 20.9 (CH3), 19.9 (CH3), 19.2 (CH3) and 18.9 (CH3) (Found
MH+, 248.2021. C16H25NO requires 247.1935).
N,N-Diisopropyl-2-deuterio-2-(2-methylphenyl)-propanamide 15-d1
In the same way as the amide 1, amide 15 (0.1 g, 0.40 mmol), sec-
butyllithium (0.51 ml, 1.4 M in cyclohexane, 0.70 mmol) and deuterium
oxide (17.7 mg, 16 ml, 0.88 mmol) gave the amide 15-d1, (91 mg, 91%); Rf
[light petroleum: ether (7:3)] 0.37; nmax (film) 2162 cmꢀ1 (C–D) and
1636 cmꢀ1 (C ¼ O); dH(250 MHz, CDC13) 7.20–7.07 (4 H, m, 4 ꢁ CH;
Ph), 3.76–3.60 (1 H, septet, J 6.7, NCH), 3.31–3.20 (1 H, septet, J 6.8,
NCH), 2.35 (3 H, s, CH3) 1.46 (3 H, d, J 6.8, CH3), 1.41 (3 H, d, J 6.8,
CH3), 1.32 (3 H, s, CH3), 1.12 (3 H, d, J 6.7, CH3) and 0.50 (3 H, d, J
6.6, CH3); dC(62.5 MHz, CDCl3) 172.8 (CO), 141.3 (Ar), 133.9 (Ar),
130.5 (Ar), 126.7 (Ar), 126.6 (Ar), 126.5 (Ar), 48.2 (CHN), 45.7 (CHN),
40.7 (1 C, triplet [1:1:1], 1JC,D=19.4, CD), 21.0 (CH3), 20.9 (CH3), 19.9
(CH3), 19.2 (CH3) and 18.8 (CH3); (Found MH+, 249.2070.
C15H24DNO requires 248.1991.)
N,N-Diisopropyl-2-(2,4,6-trimethylphenyl)-ethanamide 16
In the same way as the amide 1, mesitylacetyl chloride (1.50 g,
8.13 mmol) and diisopropylamine (1.65 g, 2.29 ml, 16 mmol) in dichlor-
omethane (15 ml) gave the amide 16 (1.69 g. 85%) as a white solid; Rf
[light petroleum: ether (7:3)] 0.16; m.p. 85–928C; nmax (film)
2999–2866 cmꢀ1 (aromatic, CH) and 1638 cmꢀ1 (C ¼ O); dH
(250 MHz, CDCl3) 6.83 (2 H, s, 2 ꢁ CH; Ar; 3,5-CH), 4.21-4.10 (1 H,
m, NCH), 3.58 (2 H, s, CH2), 3.49–3.41 (1 H, m, NCH), 2.33 (3 H, s,
CH3; Ar, 4-CH3), 2.20 (6 H, s, 2 ꢁ CH3; Ar; 2,6-CH3), 1.38 (6 H, d, J
6.7, 2 ꢁ CH3) and 1.24 (6 H, d, J 6.7, 2 ꢁ CH3); dC (62.5 MHz, CDCl3)
168.9 (CO), 136.6 (Ar), 135.7 (Ar), 130.7 (Ar), 128.8 (Ar), 48.5 (CNH),
46.0 (CNH), 35.7 (CHCO), 21.0 (CH3), 20.9 (CH3), 20.8 (CH3) and 20.2
(CH3) (Found MH+, 262.2162. C17H27NO requires 261.2092).
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THE SYNTHESIS AND CHARACTERIZATION
1051
N,N-Diisopropyl-2-deuterio-2-(2,4,6-trimethylphenyl)-ethanamide 16-d1
In the same way as the amide 1-d1, amide 16 (50 mg, 0.19 mmol), sec-
butyllithium (0.24 ml, 1.4 M in cyclohexane, 33 mmol) and deuterium
oxide (11.1 mg, 10 ml, 0.55 mmol) gave the amide 16-d1 (36 mg, 72%); Rf
[light petroleum: ether (7:3)] 0.16; nmax (film) 2155 cmꢀ1 (C–D) and
1636 cmꢀ1 (C ¼ O); dH(250 MHz, CDCl3) 6.76 (2 H, s, 2 ꢁ CH; Ar; 3,5–
CH), 4.14-4.03 (1 H, septet, J 6.8, NCH), 3.49 (1 H, s, CH), 3.42–3.32
(1 H, m, NCH), 2.17 (3 H, s, CH3), 2.14 (6 H, s, 2 ꢁ CH3), 1.32 (6 H, d, J
6.8, 2 ꢁ CH3) and 1.17 (6 H, d, J 6.7, 2 ꢁ CH3); dC (62.5 MHz, CDCl3)
168.9 (CO), 136.6 (Ph), 135.7 (Ph), 130.7 (Ph), 128.7 (Ph), 48.4 (CHN),
46.0 (CHN), 35.4 (1 C, triplet [1:1:1], 1JC,D=19.4, CD), 20.9 (CH3), 20.8
(CH3), 20.7 (CH3) and 20.2 (CH3); (Found MH+, 263.2240.
C17H26DNO requires 262.2161).
Acknowledgements
We thank the EPSRC, The London University Central Research
Fund, The Nuffield Foundation, The Royal Society and Goss
Scientific for their generous support. We are grateful to the EPSRC
National Mass Spectrometry Service (Swansea) for accurate mass
determination.
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