Ketoester methacrylate resin, secondary amine clean-up in the presence of primary amines

Article abstract of DOI:10.1039/b101395p

A ketoester resin was developed as the basis for a selective scavenger for primary amines in the presence of secondary amines. The utility of the scavenger was demonstrated with a range of reductive amination chemistries with both mono- and diamines. The resin's specificity is based on the removal of the primary amines via their enamines.

Full text of DOI:10.1039/b101395p

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Ketoester methacrylate resin, secondary amine clean-up in the
presence of primary amines
Zhanru Yu,a Sonia Alesso,a David Pears,*b Paul A. Worthington,c Richard W. A. Luked and
Mark Bradley*a
1
a Department of Chemistry, University of Southampton, Southampton, UK SO17 1BJ
b Avecia, PO Box 42, Hexagon House, Blackley, Manchester, UK M9 8ZS
c Syngenta, Jealott’s Hill Research Station, Bracknell, Berkshire, UK RG42 6EY
d AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, UK SK10 4TG
Received (in Cambridge, UK) 13th February 2001, Accepted 22nd June 2001
First published as an Advance Article on the web 27th July 2001
A ketoester resin was developed as the basis for a selective scavenger for primary amines in the presence of secondary
amines. The utility of the scavenger was demonstrated with a range of reductive amination chemistries with both
mono- and diamines. The resin’s specificity is based on the removal of the primary amines via their enamines.
Introduction
Combinatorial chemistry has emerged as a powerful tool for the
discovery of novel pharmaceutical agents and has revolution-
ized medicinal chemistry. It is generally divided into two
tactical domains: solid phase and solution phase synthesis. In
the solid phase synthesis approach, the solid support provides
an inherently simple means for the separation of the desired
product from excess reactants by simple filtration and rinsing
of the solid-supported product with solvent. When the final
product is cleaved from the solid support it is often found in a
substantially pure form.
However, short syntheses are often simply more practical in
solution than on a solid support when an efficient purification
Fig. 1 Some polymer based scavengers for amine removal.
strategy exists since no resin attachment and cleavage reactions
are required. Scavenging resins and reagents1–10 that have been
around for many years thus offer the potential of a new
approach to parallel and efficient purification methodologies.
The general concept involves the addition of one or more
solid-supported scavengers which selectively react with impur-
ities or excess starting materials present in the reaction mixture
on the basis of chemical compatibility. This process facilitates
the rapid recovery of the product without the need for
time-consuming chromatography. The resin bound impurity is
simply removed by a subsequent filtration step completing the
separation and leaving a solution of the desired product with
enhanced purity. This methodology combines the purification
and mass action advantages of solid phase synthesis with the
flexibility of solution phase synthesis.
Secondary amines, like primary amines, are amongst the
most popular class of building blocks for the library synthesis
of organic molecules. They are used in a broad range of syn-
thetic reactions and in the synthesis of nitrogen-containing
pharmaceutical and agricultural products. Although over-
alkylation occurs,11 reductive alkylation of primary amines with
aldehydes or ketones12–16 is one of the most useful method-
ologies in library syntheses of secondary amines. Excess
primary amines are usually used to reduce the over-alkylation
issue, thus, generating the problem of how to purify the second-
ary amine obtained or to remove selectively the primary amine
in the presence of the secondary. Traditional distillation and
chromatographic methods are unsuitable for chemical library
synthesis, and thus it was desirable to develop polymer
scavenging reagents for the selective removal of the primary
amines in the presence of the secondary.
Although several reports have described the removal of
amines using resins, which contain electrophilic functionalities,
such as isocyanates1,8 (Fig. 1, A), carboxylic acid chlorides1
(Fig. 1, B), diazonium species17 (Fig. 1, C) or isatoic†
anhydride18 (Fig. 1, D), to date only benzaldehyde resins1,2
(Fig. 1, E) can be used to selectively remove primary amines, via
imine formation from a mixture of primary and secondary
amines. A potential problem with the benzaldehyde resin
is that neither the resin itself, due to oxidation in air, nor the
imine formed after scavenging primary amines is particularly
stable.
Here we wish to report the full details of a ketoester resin
(Fig. 1, F), designed as a selective scavenger for primary amines
in the presence of secondary amines.
Results and discussion
1
Model compounds
Initially, a primary amine, benzylamine (BnNH2) and two
secondary amines, N-benzylmethylamine (BnNHMe) and
dibenzylamine (Bn2NH) were selected as model compounds to
test the new ketoester resin. HPLC was used as the analytical
tool. Mixtures of benzylamine with N-benzylmethylamine or
dibenzylamine were treated with the ketoester resin in different
solvents at different temperatures. The results are shown in
Figs. 2 and 3. The purities of the secondary amines increased,
† The IUPAC name for isatoic acid is 2-(carboxyamino)benzoic acid.
DOI: 10.1039/b101395p
J. Chem. Soc., Perkin Trans. 1, 2001, 1947–1952
This journal is © The Royal Society of Chemistry 2001
1947

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Fig. 2 Removal of BnNH2 in the presence of BnNHMe.
Fig. 4 Carbonyl compounds and primary amines used in reductive
alkylation library synthesis.
Scheme 1 a) MeOH, 2 h; b) MeOH, 24 h, Amberlite IRA 400
borohydride resin (2 eq.); c) MeOH–CH2Cl2 (1 : 1, v/v), 36 h, ketoester
resin (2 or 3 eq.).
With 3,4-dimethoxyphenyl methyl ketone, no secondary
amines were produced presumedly because of its low reac-
tivity in the imine-forming step, only 1-(3,4-dimethoxyphenyl)-
ethanol was isolated.
Fig. 3 Removal of BnNH2 in the presence of Bn2NH.
i.e. the primary amine, benzylamine, was removed. As expected,
the rates of removal of benzylamine were faster at higher tem-
perature (40 ЊC) and when a greater excess of resin was used. In
less than 9 hours, the purities of the secondary amines reached
>90% (40 ЊC and 4 eq. resin used). At lower molar ratios of
resin (2 eq.), the purities went to >91% after 30 hours. These
results indicated that the ketoester resin had high selectivity for
primary amines over secondary amines.
3
Structure of the resin scavenged primary amines
Why is the new ketoester resin able to selectively remove
primary amines in the presence of the secondary? One of
the reasons is the higher stability of the enamino ester derived
from the primary amine compared to the one derived from the
secondary due to formation of an intramolecular H-bond
(Scheme 2).
2
Application of the ketoester resin in the library synthesis of
secondary amines
After studying model compounds, the ketoester resin was used
in a library synthesis of secondary amines by reductive alkyl-
ation as shown in Scheme 1. Benzaldehyde, pentan-2-one
and 3,4-dimethoxyphenyl methyl ketone were selected as
the carbonyl compounds, while the primary amines used were
2-furylmethylamine, benzylamine, 2-(aminomethyl)pyridine,
diphenylmethylamine, 2,2-diphenylethylamine, 2-phenylethyl-
amine, 1-naphthylmethylamine, along with two primary
diamines, 1,4-diaminocyclohexane and p-xylylenediamine [1,4-
bis(aminomethyl)benzene] (Fig. 4). The results obtained are
presented in Table 1, and show that the secondary amines were
obtained in high purities and good yields.
Scheme 2 Possible structures of the resin scavenged primary and
secondary amines.
A simple model compound, formed by reaction of methyl
acetoacetate with one equivalent of benzylamine in methanol
to give methyl 3-benzylaminobut-2-enoate in 95% yield
The alkylated diamines were also obtained in high purities as
shown in Table 2, although the yields were less impressive.
1948
J. Chem. Soc., Perkin Trans. 1, 2001, 1947–1952

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Table 1 Results of reductive alkylation
Compound
R1
R2
R3
Purity (%)
Yield (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Pr
Pr
Pr
Pr
Pr
Pr
Pr
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Furan-2-ylmethyl
Benzyl
Pyridin-2-ylmethyl
Benzhydryl
2,2-Diphenylethyl
Phenylethyl
Naphthalen-1-ylmethyl
Furan-2-ylmethyl
Benzyl
Pyridin-2-ylmethyl
Benzhydryl
2,2-Diphenylethyl
Phenylethyl
>95b
100a
>95b
87b
88
81
86
80
69
87
72
69
83
87
68
69
85
71
93b
100a
>95b
>95b
>95b
100a
74b
81b
95b
Naphthalen-1-ylmethyl
86b
a Purity obtained by HPLC. b Purity obtained by 1H NMR.
Table 2 Reductive alkylation of primary diamines
Compounds (5 = Bn–NH–Z–NH–Bn)
Z
Puritya (%)
86
Yield (%)
38
5a
5b
>95
41
a Purity obtained by 1H NMR.
amine is more stable than the one derived from the secondary
amine due to H-bonding considerations.
Fig. 5 Two possible structures of the resin trapped primary amines.
Experimental
All chemicals were of reagent grade and were used without
further purification unless otherwise stated. Infra-red (IR) spec-
tra were recorded on a Bio-Rad Golden Gate FTS 135 spectro-
photometer. NMR spectra were recorded on a Bruker AC 300
(1H NMR at 300 MHz, 13C NMR at 75 MHz) spectrometer, a
Bruker DPX 400 (1H NMR at 400 MHz, 13C NMR at 100
MHz) spectrometer. Mass spectra were recorded on a VG
Platform Quadruple Electrospray Ionization spectrometer.
HPLC analyses were performed on an HPLC System:
Hewlett Packard Chemstation: HP series 1100. Column:
Prodigy 5 ODS3, 150 × 3 mm, Phenomenex; UV detector: 254
nm. Mobile phase: gradient from water (0.1% TFA) to MeCN
Scheme
3
Preparation of methyl 3-benzylaminobut-2-enoate in
solution.
(Scheme 3), was examined by 13C NMR and compared with the
equivalent resin bound products.
There were two possible forms for the resin once it had
reacted with primary amines: one the enamino ester and the
other the imino ester (Fig. 5).
Gel-phase 13C NMR of the resins before and after scavenging
benzylamine (Fig. 6a and b) was carried out. These two spectra
showed that the keto group (200.2 ppm) and the methylene
group (50.2 ppm) of the ketoester resin had disappeared and
that an enamino group (84.0 and 162.7 ppm) appeared, i.e. the
stable form is the enamino ester. In addition, Fig. 6a shows that
the ketoester resin exists with only a small proportion of the
resin in the enol form prior to the scavenging of primary
amines.
(0.042% TFA) in 20 minutes. Flow rate: 0.5 ml minϪ1
.
Test of ketoester resin with model compounds
To a solution of benzylamine (1.6 mmol) and secondary amine
(N-benzylmethylamine or dibenzylamine) (2.5 mmol) in the
corresponding solvent (8.0 ml) (see notes in Figs. 2, 3) was
added ketoester resin (3.0 mmol gϪ1 resin) (1.0 g) at different
temperatures. The solution (10 ml) was taken from the suspen-
sion and diluted with acetonitrile (total volume 1.0 ml). The
samples were analyzed by RP-HPLC. Benzylamine (6.9 min),
N-benzylmethylamine (7.2 min) and dibenzylamine (9.7 min).
Time = 0 is immediately before the addition of the resin.
The 13C NMR spectra of the resins following reaction with
benzylamine and the synthetic sample of methyl 3-benzyl-
aminobut-2-enoate (Fig. 6b and 6c) were found to be almost
identical. These results show that the product of the primary
amine ketoester resin exists exclusively in the enamine
form.
Reductive alkylation of primary amines
In conclusion, it has been shown that the ketoester can be
used as a scavenging reagent for primary amines in the presence
of secondary amines. Its application in library synthesis has
been demonstrated. The structure of the resin scavenged
primary amine has been studied. One of the reasons for
the selective removal of primary amine in the presence of the
secondary is that the enamino ester derived from the primary
To a solution of the corresponding carbonyl compound
(0.5 mmol) in methanol (1.5 ml) was added the primary amine
(0.8 mmol). The resulting solution was shaken for two hours
at room temperature to allow imine formation, and then
Amberlite IRA 400 borohydride resin (2.5 mmol NaBH4 gϪ1
resin) (0.4 g, 1.0 mmol) was added to the solution. The resulting
suspension was shaken for 24 hours at room temperature.
J. Chem. Soc., Perkin Trans. 1, 2001, 1947–1952
1949

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Fig. 6 Comparison of the 13C NMR spectra of the ketoester resin (a) before and (b) after amine addition, and of (c) methyl 3-benzylaminobut-2-
enoate.
Dichloromethane (1.5 ml) was then added. Ketoester resin (3.0
mmol gϪ1 resin) (0.2 g, 0.6 mmol) was added to the suspension.
The resulting suspension was shaken for 36 hours at room tem-
perature. The resin was filtered off and the solution was evapor-
ated to give the corresponding products (see Tables 1 and 2).
15H, ArH). 13C NMR (CDCl3, 75 MHz, δ, ppm): 52.1 (CH2),
66.6 (CH), 127.0, 127.1 (2), 127.4 (4), 128.3 (2), 128.5 (2) and
128.6 (4) (15 × ArCH), 140.6 and 144.1 (2) (3 × ArC). MS (EI),
m/z (%): 274.2 (M ϩ H)ϩ (100), and 348.2 (M ϩ 75)ϩ (31).
N-Benzyl-2,2-diphenylethylamine (4e) [132286-13-6]. Yield:
69%. tR/min: 12.8. H NMR (CDCl3, 300 MHz, δ, ppm): 1.56
1
N-Benzylfuran-2-ylmethylamine(4a)[4439-53-6]‡.Yield:88%.
tR/min: 8.9. 1H NMR (CDCl3, 300 MHz, δ, ppm): 1.86 (br, 1H,
NH), 3.82 (s, 4H, 2 × CH2), 6.22 (d, J = 3.0 Hz, 1H, ArH), 6.35
(dd, J = 3.0 and 1.5 Hz, 1H, ArH), 7.35–7.37 (m, 5H, ArH), and
7.40 (d, J = 1.5 Hz, 1H, ArH). 13C NMR (CDCl3, 75 MHz,
δ, ppm): 45.5 (CH2), 53.0 (CH2), 107.2, 110.3, 127.2, 128.4 (2),
128.6 (2) and 142.0 (8 × ArCH), 140.0 and 154.0 (2 × ArC). MS
(EI), m/z (%): 188.0 (M ϩ H)ϩ (100), and 229.2 (M ϩ 42)ϩ (25).
(br, 1H, NH), 3.30 (d, J = 7.5 Hz, 2H, CH2), 3.87 (s, 2H, CH2),
4.30 (t, J = 7.5 Hz, 1H, CH), and 7.22–7.39 (m, 15H, ArH). 13
C
NMR (CDCl3, 75 MHz, δ, ppm): 47.0 (CH2), 53.9 (CH), 54.0
(CH2), 126.8 (2), 127.2, 128.25 (4), 128.32 (2), 128.6 (2) and
128.8 (4) (15 × ArCH), 140.2 and 143.0 (2) (3 × ArC). MS (EI),
m/z (%): 288.2 (M ϩ H)ϩ (100), and 289.3 (M ϩ 2)ϩ (20).
N-Benzylphenethylamine (4f ) [3647-71-0]. Yield: 87%.
tR/min: 10.8. 1H NMR (CDCl3, 300 MHz, δ, ppm): 1.65 (br, 1H,
NH), 2.89–3.00 (m, 4H, 2 × CH2), 3.87 (s, 2H, CH2), and 7.25–
7.41 (m, 10H, ArH). 13C NMR (CDCl3, 75 MHz, δ, ppm): 36.6
(CH2), 50.8 (CH2), 54.1 (CH2), 126.4, 127.1, 128.3 (2), 128.6 (2),
128.7 (2) and 129.0 (2) (10 × ArCH), 140.2 and 140.4
(2 × ArC). MS (EI), m/z (%): 212.1 (M ϩ H)ϩ (100), and 253.2
(M ϩ 42)ϩ (15).
1
Dibenzylamine (4b) [103-49-1]. Yield: 81%. tR/min: 9.7. H
NMR (CDCl3, 300 MHz, δ, ppm): 1.76 (br, 1H, NH), 3.87 (s,
4H, 2 × CH2), and 7.40–7.42 (m, 10H, ArH). 13C NMR
(CDCl3, 75 MHz, δ, ppm): 53.4 (2 × CH2), 127.2 (2), 128.4 (4),
and 128.6 (4) (10 × ArCH), 140.5 (2 × ArC). MS (EI), m/z (%):
198.1 (M ϩ H)ϩ (100), and 239.2 (M ϩ 42)ϩ (20).
N-Benzylpyridin-2-ylmethylamine (4c) [18081-89-5]. Yield:
86%. tR/min: 8.5. 1H NMR (CDCl3, 300 MHz, δ, ppm): 2.26 (br,
1H, NH), 3.82 (s, 2H, CH2), 3.90 (s, 2H, CH2), 7.09–7.14 (m,
1H, ArH), 7.22–7.36 (m, 6H, ArH), 7.59 (td, J = 7.5 and 1.5 Hz,
1H, ArH), and 8.53 (d, J = 5.1 Hz, 1H, ArH). 13C NMR
(CDCl3, 75 MHz, δ, ppm): 53.6 (CH2), 54.6 (CH2), 122.1, 122.5,
127.1, 128.4 (2), 128.5 (2), 136.6 and 149.4 (9 × ArCH), 140.3
and 159.9 (2 × ArC). MS (EI), m/z (%): 199.1 (M ϩ H)ϩ (100).
N-Benzylnaphthalen-1-ylmethylamine (4g) [14393-12-5].
Yield: 72%. tR/min: 11.8. 1H NMR (CDCl3, 300 MHz, δ, ppm):
1.82 (br, 1H, NH), 3.98 (s, 2H, CH2), 4.31 (s, 2H, CH2), 7.35–
7.57 (m, 9H, ArH), 7.85 (d, J = 8.1 Hz, 1H, ArH), 7.93 (d,
J = 8.1 Hz, 1H, ArH), and 8.16 (d, J = 8.1 Hz, 1H, ArH). 13C
NMR (CDCl3, 75 MHz, δ, ppm): 51.0 (CH2), 53.9 (CH2), 124.0,
125.6, 125.8, 126.3, 126.4, 127.3, 128.0, 128.5 (2), 128.7 (2) and
128.9 (12 × ArCH), 132.1, 134.1, 135.9 and 140.4 (4 × ArC).
MS (EI), m/z (%): 248.2 (M ϩ H)ϩ (100), 249.3 (M ϩ 2)ϩ (18),
and 298.2 (M ϩ 52)ϩ (31).
N-Benzhydrylbenzylamine (4d) [5669-43-2]. Yield: 80%.
tR/min: 12.7. 1H NMR (CDCl3, 300 MHz, δ, ppm): 1.98 (br, 1H,
NH), 3.84 (s, 2H, CH2), 4.96 (s, 1H, CH), and 7.30–7.55 (m,
N-(Furan-2-ylmethyl)-1-methylbutylamine (4h). Yield: 69%.
tR/min: 8.7. 1H NMR (CDCl3, 300 MHz, δ, ppm): 0.91 (t,
‡ CAS registry numbers are given for known compounds.
1950
J. Chem. Soc., Perkin Trans. 1, 2001, 1947–1952

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J = 7.5 Hz, 3H, Me), 1.06 (d, J = 6.0 Hz, 3H, Me), 1.29–1.49 (m,
4H, 2 × CH2), 1.72 (br, 1H, NH), 2.63–2.71 (m, 1H, N-CH),
3.75 (d, J = 14.7 Hz, 1H, CH), 3.83 (d, J = 14.1 Hz, 1H, CH),
6.17 (d, J = 3.0 Hz, 1H, ArH), 6.31 (dd, J = 3.0 and 2.1 Hz, 1H,
ArH), and 7.36 (s, 1H, ArH). 13C NMR (CDCl3, 75 MHz,
δ, ppm): 14.4 (Me), 19.3 (CH2), 20.2 (Me), 39.3 (CH2), 43.8
(CH2), 51.9 (CH), 106.8, 110.2 and 141.8 (3 × ArCH), and
154.3 (ArC).
(CH2), 53.4 (CH), 123.9, 125.6, 125.8, 126.3 (2), 127.9 and 128.9
(7 × ArCH), 132.0, 134.1, and 136.6 (3 × ArC). MS (EI), m/z
(%): 228.1 (M ϩ H)ϩ (100).
N,NЈ-Dibenzylcyclohexane-1,4-diamine (5a). Yield: 38%.
tR/min: 8.4. 1H NMR (CDCl3, 300 MHz, δ, ppm): 1.14–1.20 (m,
8H, 4 × CH2), 1.94–2.00 (m, 2H, 2 × NH), 2.44–2.56 (m, 2H,
N-CH), 3.80 (s, 4H, 2 × CH2), 7.31 (s, 6H, ArH), and 7.32 (s,
4H, ArH). 13C NMR (CDCl3, 75 MHz, δ, ppm): 32.2 (CH2),
51.5 (N-CH), 56.4 (N-CH2), 127.0 (2), 128.2 (4), and 128.6 (4)
(10 × ArCH), and 140.9 (2 × ArC). MS (EI), m/z (%): 295.3
(M ϩ H)ϩ (50), and 188.0 (100).
N-Benzyl-1-methylbutylamine (4i) [61806-76-6]. Yield: 83%.
tR/min: 9.8.1H NMR (CDCl3, 300 MHz, δ, ppm): 0.93 (t, J = 7.5
Hz, 3H, Me), 1.10 (d, J = 6.6 Hz, 3H, Me), 1.30–1.55 (m, 4H,
2 × CH2), 2.66–2.76 (m, 1H, N-CH), 3.75 (d, J = 12.5 Hz, 1H,
CH), 3.85 (d, J = 12.5 Hz, 1H, CH), 7.33 (s, 3H, ArH), and 7.35
(s, 2H, ArH). 13C NMR (CDCl3, 75 MHz, δ, ppm): 14.5 (Me),
19.4 (CH2), 20.5 (Me), 39.5 (CH2), 51.5 (CH2), 52.4 (CH),
127.0, 128.3 (2) and 128.5 (2) (5 × ArCH), and 141.0 (ArC). MS
(EI), m/z (%): 178.0 (M ϩ H)ϩ (100).
Benzyl[4-(benzylaminomethyl)benzyl]amine (5b) [25790-41-
4]. Yield: 41%. tR/min: 9.1. 1H NMR (CDCl3, 300 MHz,
δ, ppm): 1.79 (br, 2H, 2 × NH), 3.845 (s, 4H, 2 × CH2), 3.853
(s, 4H, 2 × CH2), and 7.36–7.40 (m, 14H, ArH). 13C NMR
(CDCl3, 75 MHz, δ, ppm): 53.1 (CH2), 53.3 (CH2), 127.2 (2),
128.37 (4), 128.44 (4) and 128.6 (4) (14 × ArCH), 139.2, and
140.5 (2) (3 × ArC). MS (EI), m/z (%): 317.3 (M ϩ H)ϩ (100),
and 200.2 (77).
N-(1-Methylbutyl)pyridin-2-ylmethylamine (4j). Yield: 87%.
tR/min: 8.2. 1H NMR (CDCl3, 300 MHz, δ, ppm): 0.86 (t,
J = 7.5 Hz, 3H, Me), 1.05 (d, J = 6.6 Hz, 3H, Me), 1.24–1.50 (m,
4H, 2 × CH2), 2.27 (br, 1H, NH), 2.61–2.67 (m, 1H, N-CH),
3.81 (d, J = 13.2 Hz, 1H, CH), 3.90 (d, J = 14.0 Hz, 1H, CH),
7.10 (dd, J = 7.4 and 5.2 Hz, 1H, ArH), 7.25 (d, J = 7.5 Hz, 1H,
ArH), 7.57 (td, J = 7.5 and 1.5 Hz, 1H, ArH), and 8.49 (d,
J = 5.2 Hz, 1H, ArH). 13C NMR (CDCl3, 75 MHz, δ, ppm):
14.4 (Me), 19.3 (CH2), 20.3 (Me), 39.5 (CH2), 52.7 (CH2), 52.8
(CH), 122.0, 122.5, 136.5 and 149.3 (4 × ArCH), and 160.1
(ArC). MS (EI), m/z (%): 179.1 (M ϩ H)ϩ (100).
Reaction of ketoester resin with benzylamine
A suspension of benzylamine (1.0 mmol) and ketoester resin
(3.0 mmol gϪ1 resin) (0.2 g, 0.6 mmol) in propan-2-ol (4.0 ml)
was shaken for 48 hours at room temperature. The resin was
collected and washed with propan-2-ol and THF several
times. After drying in vacuo, the resin was analyzed by IR and
gel-phase NMR in C6D6.
IR (νmax/cmϪ1): 697, 732, 781, 1028, 1071, 1108, 1160, 1231,
1269, 1451, 1494, 1599, 1650, 1723, 2938, and 3292. 13C NMR
(C6D6, 100 MHz, δ, ppm): 19.5 (Me), 46.9 (CH2), 50.0 (OMe),
N-Benzhydryl-1-methylbutylamine (4k). Yield: 68%. tR/min:
12.3. 1H NMR (CDCl3, 300 MHz, δ, ppm): 0.98 (t, J = 7.4 Hz,
3H, Me), 1.16 (d, J = 6.0 Hz, 3H, Me), 1.38–1.61 (m, 4H,
2 × CH2), 1.81 (br, 1H, NH), 2.66–2.72 (m, 1H, N-CH), 5.28 (s,
1H, N-CH-Ph2), and 7.28–7.52 (m, 10H, ArH). 13C NMR
(CDCl3, 75 MHz, δ, ppm): 14.6 (Me), 19.4 (CH2), 20.8 (Me),
40.1 (CH2), 50.2 (CH), 64.3 (N-CH), 127.2 (4), 127.7 (2), and
128.7 (4) (10 × ArCH), and 145.8 (2 × ArC). MS (EI), m/z (%):
254.2 (M ϩ H)ϩ (100).
84.0 (᎐CH), 162.7 (᎐C–N), and 170.7 (OC᎐O).
᎐
᎐
᎐
Ketoester resin: IR (νmax/cmϪ1): 701, 761, 1019, 1143, 1314,
1360, 1451, 1493, 1715, and 2935. 13C NMR (C6D6, 100 MHz,
δ, ppm): 30.3 (Me), 50.2 (CH ), 90.2 (᎐CH), 167.5 (OC᎐O), and
᎐
᎐
2
200.2 (C᎐O).
᎐
Preparation of methyl 3-benzylaminobut-2-enoate
A mixture of benzylamine (1.0 mmol) and an equimolar
amount of methyl acetoacetate in methanol (20 ml) was shaken
for 30 minutes at room temperature. After removal of the
solvent, the residue was washed with a little hexane (2 ml) to
give methyl 3-benzylaminobut-2-enoate, which was used with-
out further purification.
N-(2,2-Diphenylethyl)-1-methylbutylamine (4l). Yield: 69%.
tR/min: 12.7. H NMR (CDCl3, 300 MHz, δ, ppm): 0.88 (t,
1
J = 7.4 Hz, 3H, Me), 1.06 (d, J = 6.6 Hz, 3H, Me), 1.18–1.47 (m,
4H, 2 × CH2), 2.63–2.73 (m, 1H, N–CH), 3.22 (dd, J = 11.0 and
8.1 Hz, 1H, CH), 3.32 (dd, J = 11.0 and 8.1 Hz, 1H, CH), 4.23
(t, J = 8.1 Hz, 1H, CH), and 7.21–7.37 (m, 10H, ArH). 13C
NMR (CDCl3, 75 MHz, δ, ppm): 14.4 (Me), 19.3 (CH2), 20.5
(Me), 39.4 (CH2), 51.5 (CH), 52.2 (CH2), 53.1 (CH), 126.7 (2),
128.2 (4), and 128.8 (4) (10 × ArCH), and 143.2 (2 × ArC). MS
(EI), m/z (%): 268.3 (M ϩ H)ϩ (100).
Yield: 95%. IR (νmax/cmϪ1): 692, 728, 782, 846, 928, 972, 1013,
1057, 1070, 1115, 1167, 1184, 1233, 1281, 1313, 1375, 1441,
1470, 1504, 1568, 1596, 1640, 2981, and 3320. 1H NMR (C6D6,
300 MHz, δ, ppm): 1.38 (s, 3H, Me), 3.54 (s, 3H, OMe), 3.72 (d,
J = 6.0 Hz, 2H, -CH ), 4.76 (s, 1H, ᎐CH), 7.01 (m, 5H, ArH),
᎐
2
and 9.31 (br, 1H, NH). 13C NMR (C6D6, 75 MHz, δ, ppm): 19.0
N-(1-Methylbutyl)phenethylamine (4m) [71797-48-3]. Yield:
85%. tR/min: 10.4. 1H NMR (CDCl3, 300 MHz, δ, ppm): 0.91 (t,
J = 7.5 Hz, 3H, Me), 1.05 (d, J = 6.6 Hz, 3H, Me), 1.22–1.47 (m,
4H, 2 × CH2), 2.59–2.69 (m, 1H, N-CH), 2.73–3.00 (m, 4H,
2 × CH2), 7.23 (d, J = 6.6 Hz, 3H, ArH), and 7.29 (d, J = 6.9
Hz, 2H, ArH). 13C NMR (CDCl3, 75 MHz, δ, ppm): 14.4 (Me),
19.3 (CH2), 20.4 (Me), 36.7 (CH2), 39.5 (CH2), 48.8 (CH2), 53.0
(CH), 126.3, 128.6 (2) and 128.8 (2) (5 × ArCH), and 140.3
(ArC). MS (EI), m/z (%): 192.1 (M ϩ H)ϩ (100).
(Me), 46.5 (CH ), 50.0 (OMe), 83.9 (᎐CH), 126.8 (2), 127.4, and
᎐
2
129.0 (2) (5 × ArCH), 139.7 (ArC), 161.8 (᎐C–N), and 171.3
᎐
(MeOC᎐O). MS (EI), m/z (%): 206.1 (M ϩ H)ϩ (100), and
᎐
207.1 (M ϩ 2)ϩ (15).
Acknowledgements
We would like to thank AstraZeneca/Avecia for a strategic
research fellowship (ZY) and a studentship (SA), and Avecia
Ltd for the supply of resins and technical support.
N-(1-Methylbutyl)naphthalen-1-ylmethylamine (4n). Yield:
71%. tR/min: 11.6. 1H NMR (CDCl3, 300 MHz, δ, ppm): 0.96 (t,
J = 7.4 Hz, 3H, Me), 1.21 (d, J = 6.6 Hz, 3H, Me), 1.34–1.65 (m,
4H, 2 × CH2), 2.80–2.90 (m, 1H, N-CH), 4.21 (d, J = 13.2 Hz,
1H, CH), 4.31 (d, J = 13.2 Hz, 1H, CH), 7.43–7.60 (m, 4H,
ArH), 7.80 (d, J = 8.1 Hz, 1H, Ar), 7.90 (d, J = 8.1 Hz, 1H, Ar),
and 8.16 (d, J = 8.1 Hz, 1H, ArH). 13C NMR (CDCl3, 75 MHz,
δ, ppm): 14.5 (Me), 19.5 (CH2), 20.7 (Me), 39.6 (CH2), 49.5
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