Synthesis of chiral α-aminoalkylpyrimidines using an enantioselective three-component reaction

Article abstract of DOI:10.1055/s-2004-829129

A range of chiral α-aminoalkylpyrimidines has been prepared in a modular fashion in 5 steps with up to 98% ee. The key step is a CuBr-catalyzed enantioselective asymmetric three-component synthesis of propargylic amines.

Full text of DOI:10.1055/s-2004-829129

PAPER
2015
Synthesis of Chiral a-Aminoalkylpyrimidines Using an Enantioselective
Three-Component Reaction
S
ynthesis of Chira
e
l
a
-Aminoa
n
lkylpyrimidi
r
ne
s
y Dube, Nina Gommermann, Paul Knochel*
Department Chemie, Ludwig-Maximilians-Universität, Butenandtstrasse 5-13, 81377, München, Germany
Fax +49(89)218077680; E-mail: Paul.Knochel@cup.uni-muenchen.de
Received 5 April 2004; revised 26 April 2004
Herein, we wish to report the conversion of propargyl-
amines of type 5 (obtained by the three-component reac-
tion) to chiral a-aminopyrimidines of type 6 by successive
reaction with an acid chloride 7 and an amidine 8. Pyrim-
idines are of great interest due to their potential biological
activity.5 Our approach provides a modular synthesis of a
new family of pyrimidines 6.
Abstract: A range of chiral a-aminoalkylpyrimidines has been pre-
pared in a modular fashion in 5 steps with up to 98% ee. The key
step is a CuBr-catalyzed enantioselective asymmetric three-compo-
nent synthesis of propargylic amines.
Key words: alkynes, asymmetric synthesis, C–H activation, copper
catalysis, heterocycles
The reaction of various aldehydes 4 (R4CHO) with diben-
zylamine 2a and trimethylsilylacetylene 3a in the pres-
ence of CuBr (5 mol%) and (R)-Quinap (5.5 mol%)
provided propargylamines 1a–d in 82–98% yield and 90–
98% ee. After treatment with Bu4NF (1.0 equiv, THF,
0 °C to 25 °C, 15 min), the corresponding terminal
alkynes 5a–d were obtained in 92–99% yield (Scheme 2).
Heterocyclic compounds have found numerous applica-
tions as pharmaceuticals and agrochemicals. Therefore,
the development of new and efficient syntheses of com-
plex heterocycles is an active field of research. The expe-
ditious and modular preparation of heterocyclic rings is of
special importance.1 Recently, we have developed a new
synthesis of chiral propargylamines of type 1 using three
components: an amine 2, an alkyne 3 and an aldehyde 4
(Scheme 1).2 This reaction is efficiently catalyzed with
CuBr3 (5 mol%) and (R)-Quinap4 (5.5 mol%) and produc-
es propargylic amines of type 5 with high enantioselectiv-
ity (up to 98% ee) and good yields (82–98%).
These terminal alkynes were subsequently acylated re-
sulting in the formation of the alkynones 9a–n in 84–97%
yield (Scheme 3 and Table 1). The acylation reaction was
best performed with acid chlorides 7 (R5COCl) in the
presence of Pd(PPh3)2Cl2 (2 mol%), CuI (4 mol%) and
Et3N (1 equiv) in THF (r.t., 2 h) according to the method
described by Müller.6 This synthetic procedure is espe-
cially well suited for aromatic and heterocyclic acid chlo-
rides 7 (Table 1, entries 1–7, 9–12, 15,16).
R3
CuBr (5 mol%)
toluene, r.t.
O
R4
R1
H
N
1–6 d
R3
R1
+
+
R2
R4
H
N
R2
For the reaction with aliphatic acid chlorides, it was found
advantageous to generate first the zinc acetylide by suc-
cessive deprotonation of the propargylic amines 5 with n-
BuLi and addition of ZnCl2. The reaction of this zinc spe-
cies with an acid chloride 7 (r.t., 12 h) in the absence of a
palladium catalyst led to the desired alkynones 9l–n in
90–92% yield (Scheme 3 and Table 1, entries 8, 13–14).7
The ring closure of compounds 9 to the chiral pyrimidines
of type 6 proceeded well with acetamidine 8a (Table 1,
N
2
3
4
1
PPh2
up to 99%;
up to 98% ee
(R)-Quinap (5.5 mol%)
R6
R6
N
N
R5COCl
R4
HN
NH2
R4
R5
7
8
NBn2
NBn2
5
6
Scheme 1 Formation of chiral a-aminopyrimidines of type 6.
Scheme 2 Preparation of propargylamines 5 by the three-component reaction and deprotection with TBAF.
SYNTHESIS 2004, No. 12, pp 2015–2025
x
x.
x
x
.
2
0
0
4
Advanced online publication: 01.07.2004
DOI: 10.1055/s-2004-829129; Art ID: T04104SS
© Georg Thieme Verlag Stuttgart · New York

2016
H. Dube et al.
PAPER
Table 1 Alkynones of Type 9 Prepared from the Chiral Propargylamines 5a–d and Further Transformation to 2,4,6-Substituted Pyrimidines of
Type 6
Entry Propargyl-
amine
Acid Chloride 7 (R5COCl) Product of Type 9
Yield
(%)a
Product of Type 6
Yield ee
(%)a
(%)
NBn2
NBn2
1
Me
N
N
R5
R5
O
NBn2
5a
5a
5a
7a: 2,4,5-(CF3)3C6H2COCl 9a: R5 = 2,4,5-(CF3)3C6H2
92
91
84
6a: R5 = 2,4,5-(CF3)3C6H2
6b: R5 = 4-ClC6H4
6c: R5 = Ph
75
77
82
96
96
96
2
3
7b: 4-ClC6H4COCl
7c: PhCOCl
9b: R5 = 4-ClC6H4
9c: R5 = Ph
NBn2
NBn2
Me
N
N
R5
R5
O
NBn2
4
5
6
7
8
5b
5b
5b
5b
5b
7d: 4-MeOC6H4COCl
7e: 2-furylCOCl
7f: t-BuCOCl
7c
9d: R5 = 4-MeOC6H4
9e: R5 = 2-furyl
9f: R5 = t-Bu
9g: R5 = Ph
97
95
96
96
90
6d: R5 = 4-MeOC6H4
6e: R5 = 2-furyl
6f: R5 = t-Bu
6g: R5 = Ph
6l: R5 = Me
Me
78
79
73
82
79
98
98
98
98
98
7g: MeCOCl
9l: R5 = Me
NBn2
NBn2
Cy
N
N
Cy
R5
Cy
R
O
NBn2
9
5c
7e
9h: R5 = 2-furyl
95
6h: R5 = 2-furyl
80
92
NBn2
NBn2
Me
nBu
nBu
N
N
R5
nBu
R5
O
9i: R5 = Ph
9j: R5 = t-Bu
9k: R5 = 2-furyl
NBn2
NBn2
6i: R5 = Ph
10
11
12
5d
5d
5d
7c
7f
7e
95
94
94
89
81
90
90
90
90
6j: R5 = t-Bu
6k: R5 = 2-furyl
NBn2
Ph
N
N
R5
R5
O
NBn2
13
14
5b
5b
7h: n-PrCOCl
9m: R5 = n-Pr
9n: R5 = c-C6H11
NBn2
92
90
6m: R5 = n-Pr
79
75
98
98
7i: c-C6H11COCl
6n: R5 = c-C6H11
NBn2
Ph
nBu
nBu
N
N
R5
nBu
R5
O
9i: R5 = Ph
NBn2
15
16
5d
5d
7c
7e
95
94
6o: R5 = Ph
6p: R5 = 2-furyl
90
98
90
90
9k: R5 = 2-furyl
a Yield of analytically pure product.
Synthesis 2004, No. 12, 2015–2025 © Thieme Stuttgart · New York

PAPER
Synthesis of Chiral a-Aminoalkylpyrimidines
2017
Unless otherwise indicated, all reactions were carried out with mag-
netic stirring and, with air or moisture sensitive compounds, in
flame-dried glassware under N2. Syringes were used to transfer re-
agents and solvents were purged with N2 prior to use. Reactions
were monitored by GC and GC-MS or TLC analysis.
entries 1–12) or benzamidine 8b (Table 1, entries 13–16)
(1.5–2.0 equiv) and sodium carbonate (3–4 equiv) in re-
fluxing acetonitrile (2 h–2 d) according to the method of
Adlington and Baldwin5 (Scheme 1 and Table 1).
Organolithium solutions were titrated using the method of
Paquette.9 ZnCl2 was dried at 650 °C under high vacuum for 30 min
and afterwards dissolved in anhyd THF.
General Procedures
Propargylamines ( )-1; GP 1a
In a dry and argon flushed 50 mL flask, equipped with a magnetic
stirrer and a septum, CuBr (36 mg, 0.25 mmol, 5 mol%) was sus-
pended in anhyd toluene (10 mL). Molecular sieves 4Å (2.5 g) and
n-decane (100 mg) were added, followed by trimethylsilylacetylene
(3a; 491 mg, 5 mmol), the aldehyde 4 (5 mmol) and dibenzylamine
(2a; 986 mg, 5 mmol). The reaction mixture was stirred at r.t. until
GC analysis showed full conversion. Molecular sieves 4Å was fil-
tered and washed with Et2O. The crude product was concentrated in
vacuo and purified by column chromatography on silica gel.
Scheme 3 Acylation of the terminal propargylamines 5.
Propargylamines (–)-1; GP 1b
In a dry and argon flushed 10 mL flask, equipped with a magnetic
stirrer and a rubber septum, CuBr (3.6 mg, 0.025 mmol, 5 mol%)
and (R)-Quinap (12.1 mg, 0.0275 mmol, 5.5 mol%) were suspended
in anhyd toluene (2 mL) and stirred for 30 min. Molecular sieves 4Å
(0.25 g) and n-decane (30 mg) were added, followed by trimethyl-
silylacetylene (3a; 49 mg, 0.5 mmol), the aldehyde 4 (0.5 mmol)
and dibenzylamine (2a, 99 mg, 0.5 mmol). The reaction mixture
was stirred at r.t. until GC analysis showed full conversion. The mo-
lecular sieves was filtered and washed with Et2O. The crude product
was concentrated in vacuo and purified by column chromatography
on silica gel.
We have verified that no racemization of the stereogenic
center at the a-position occurs by analyzing selected pyri-
midines 6 by HPLC using a chiral support (Chiracel OD-
H column). In each case both the chiral and racemic prod-
uct were analyzed.
The debenzylation of the amines of type 6 was readily ac-
complished by using Pd/C and H2 (1 bar)8 without affect-
ing the heterocyclic ring leading to the primary a-
aminopyrimidine 10 in 95% isolated yield (Scheme 4).
Ph
Ph
Deprotection of the TMS Group Leading to Terminal Propar-
gylamines 5; GP 2
Pd/C, H2 (1 bar)
MeOH/CH2Cl2 (4/1)
N
N
N
N
The TMS-protected propargylamine 1 was dissolved in anhyd THF
(5 mL/mmol) and cooled to 0 °C. Bu4NF (1 M in THF) was added
dropwise. After 15 min, the conversion was complete according to
GC analysis. The reaction mixture was quenched with H2O (20 mL)
and extracted with Et2O (3 × 50 mL). The crude product was puri-
fied by column chromatography on silica gel.
Cy
Cy
r.t., 24 h
NBn2
NH2
6n
10: 95%; 98% ee
Scheme 4 Deprotection of the benzyl group leading to the chiral
primary amine 10.
Acylation of the Terminal Propargylamines 5 with Aromatic
Acid Chlorides 7 Leading to Alkynones 9; GP 3
In summary, we have developed a short and highly mod-
ular synthesis of new chiral aminopyrimidines of type 6
using a catalytic asymmetric three-component reaction
and involving finally five readily available compounds.
Further applications of this method towards the prepara-
tion of natural products are currently under way in our lab-
oratories.
In a dry and argon flushed 25 mL flask, equipped with a magnetic
stirrer and a septum, CuI (0.04 mmol, 4 mol%) and PdCl2(PPh3)2
(0.02 mmol, 2 mol%) were suspended in anhyd THF (3 mL). Et3N
(0.14 mL, 1 mmol) and acid chloride 7 (1 mmol) were added, fol-
lowed by the terminal propargylamine 5 (1 mmol). After stirring for
2 h at r.t., the reaction mixture was poured into H2O (20 mL) and the
aqueous phase was extracted with Et2O (3 × 50 mL). The organic
fractions were washed with brine (30 mL), dried (MgSO4) and con-
centrated in vacuo. The crude product was purified by flash chroma-
tography on silica gel.
Melting points were measured on a Büchi B 540 apparatus and are
uncorrected. NMR spectra were recorded in CDCl3 at 300 MHz for
1H NMR and 75 MHz for 13C NMR (Varian XL 300). Chemical
shifts are reported in ppm relative to TMS. IR spectra were recorded
on a Perkin-Elmer FT-IR Spectrum 1000. Low-resolution mass
spectra were recorded using a GC/MS combination of the type HP
6890/MSD 5973 fitted with a HP-5 column (30 m × 0.25 mm × 0.25
mm). High-resolution mass spectra were recorded on a Finnigan-
MAT 95Q spectrometer (EI, 70 eV). Microanalyses were per-
formed using a Heraeus CHN-Rapid-Elementaranalysator. Flash
column chromatography purifications were carried out using silica
gel 60 (silica, 0.063–0.200 mm, purchased from Merck, Darm-
stadt).
Acylation of the Terminal Propargylamines 5 with Aliphatic
Acid Chlorides 7 Leading to Alkynones 9; GP 4
A dry and argon flushed 25 mL flask, equipped with a magnetic stir-
rer and a rubber septum, was charged with a solution of the terminal
propargylamine 5 (1 mmol) in anhyd THF (2 mL) and n-hexane (2
mL). At –65 °C, n-BuLi (1.6 M in n-hexane, 0.75 mL, 1.2 mmol)
was slowly added and the reaction mixture was stirred at this tem-
perature for 20 min to complete the deprotonation. Then a solution
of ZnCl2 in THF (1 M solution in THF, 1.2 mL, 1.2 mmol) was add-
ed and the mixture was allowed to warm to r.t. The acid chloride 7
(1.5 mmol) was added and the mixture was stirred for 12 h at r.t. Af-
Synthesis 2004, No. 12, 2015–2025 © Thieme Stuttgart · New York

2018
H. Dube et al.
PAPER
terwards, the mixture was quenched with H2O (20 mL) and the
aqueous phase was extracted with Et2O (3 × 50 mL). The organic
fractions were washed with brine (30 mL), dried (MgSO4) and con-
centrated in vacuo. The crude product was purified by flash chroma-
tography on silica gel.
N,N-Dibenzyl-1-cyclohexylprop-2-yn-1-amine (1c)
Preparation according to GP 1a afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 99:1), ( )-1c as a color-
less solid (1.745 g, 90%).
IR (film): 2924s, 2852m, 2160m, 1494m, 1451m, 1248s, 1006m,
844vs, 737s, 698s cm–1.
1H NMR (300 MHz, CDCl3): d = 7.43–7.19 (m, 10 H), 3.80 (d, 2 H,
J = 13.7 Hz), 3.36 (d, 2 H, J = 13.7 Hz), 3.03 (d, 1 H, J = 10.6 Hz),
2.27 (d, 1 H, J = 13.1 Hz), 1.99 (d, 1 H, J = 13.1 Hz), 1.75–1.50 (m,
4 H), 1.32–0.98 (m, 3 H), 0.89–062 (m, 2 H), 0.26 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 139.8, 128.8, 128.2, 126.8, 103.5,
90.1, 58.6, 54.9, 39.5, 31.2, 30.3, 26.6, 26.2, 25.9, 0.5.
MS (70 eV, EI): m/z (%) = 307 (M+ – i-Pr, 27), 306 (100), 91 (34).
HRMS (EI): m/z calcd for C26H35NSi [M+]: 389.2539; found:
Pyrimidines 6; GP 5
A 10 mL flask, equipped with a magnetic stirrer and a reflux-con-
denser, was charged with the acylated propargylamine 7 (1 equiv),
the amidine hydrochloride 8 (1.2–2.0 equiv), Na2CO3 and H2O (cat.,
1 drop) in MeCN (5 mL/mmol). This reaction mixture was heated
to reflux until completion of the reaction was indicated by GC anal-
ysis. After cooling to r.t., the mixture was poured into H2O (20 mL)
and the aqueous phase was extracted with Et2O (3 × 50 mL). The
organic fractions were washed with brine (30 mL), dried (MgSO4)
and concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel.
389.2506.
Anal. Calcd for C26H35NSi: C, 80.14; H, 9.05; N, 3.59. Found: C,
79.90; H, 9.07; N, 3.54.
N,N-Dibenzyl-4-methyl-1-(trimethylsilyl)pent-1-yn-3-amine
(1a)
Preparation according to GP 1a afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 99:1), ( )-1a as a color-
less oil (1.608 g, 92%).
N,N-Dibenzyl-1-(trimethylsilyl)hept-1-yn-3-amine (1d)
Preparation according to GP 1a afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 99:1), ( )-1d as a color-
less oil (1.490 g, 87%).
Preparation according to GP 1b afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 99:1), (–)-1a as a color-
less oil (167 mg, 95%, 96% ee, the enantiomeric excess was
determined after desilylation); [a]D20 –268 (c = 0.65, CHCl3).
IR (film): 3064w, 3029w, 2958s, 2159m, 1495m, 1454m, 1250s,
842vs, 698s cm–1.
1H NMR (300 MHz, CDCl3): d = 7.22–7.00 (m, 10 H), 3.62 (d, 2 H,
J = 13.7 Hz), 3.19 (d, 2 H, J = 13.7 Hz), 3.21–3.15 (m, 1 H), 1.59–
1.35 (m, 2 H), 1.30–1.10 (m, 2 H), 1.10–0.94 (sext, 2 H, J = 7.3 Hz),
0.66 (t, 3 H, J = 7.3 Hz), 0.07 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 139.5, 128.4, 127.7, 126.4, 104.3,
88.6, 54.4, 51.9, 32.9, 28.0, 21.8, 13.5, 0.00.
MS (70 eV, EI): m/z (%) = 348 (5, M+ – CH3), 306 (100), 214 (4),
91 (85), 73 (12).
IR (film): 2959s, 2158m, 1494m, 1454s, 1249vs, 1019s, 842vs,
746s, 698vs cm–1.
1H NMR (300 MHz, CDCl3): d = 7.46–7.19 (m, 10 H), 3.83 (d, 2 H,
J = 13.7 Hz), 3.38 (d, 2 H, J = 13.7 Hz), 2.93 (d, 1 H, J = 10.2 Hz),
1.99–1.81 (m, 1 H), 1.00 (t, 6 H, J = 6.2 Hz), 0.28 (s, 9 H), 7.45–
7.42 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 139.8, 128.9, 128.2, 126.8, 103.8,
89.9, 59.9, 55.0, 30.6, 20.9, 19.9, 0.5.
MS (70 eV, EI): m/z (%) = 307 (M+ – i-Pr, 27), 306 (100), 91 (34).
HRMS (EI): m/z calcd for C23H30NSi [M+ – H]: 348.2148; found:
HRMS (EI): m/z calcd for C24H32NSi [M+ – H]: 362.2304; found:
362.2333.
Anal. Calcd for C24H33NSi: C, 79.28; H, 9.15; N, 3.85. Found: C,
79.19; H, 9.15; N, 3.83.
348.2166.
Anal. Calcd for C23H31NSi: C, 79.02; H, 8.94; N, 4.01. Found: C,
79.10; H, 9.17; N, 3.83.
N,N-Dibenzyl-4-methylpent-1-yn-3-amine (5a)
Preparation according to GP 2 on a 4.4 mmol scale afforded, after
column chromatographic purification (SiO2, pentane), (–)-5a as a
colorless oil (1.376 g, 99%, 96% ee); [a]D20 –201 (c = 0.39, CHCl3).
HPLC (OD-H, 100% n-heptane/0% i-PrOH, 0.8 mL/min):
tr (min) = 8 (–), 10 (+).
N,N-Dibenzyl-4-ethyl-1-(trimethylsilyl)hex-1-yn-3-amine (1b)
Preparation according to GP 1a afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 99:1), ( )-1b as a color-
less oil (1.614 g, 86%).
IR (film): 2959m, 1495m, 1454m, 746m, 698vs cm–1.
IR (film): 2962s, 2158m, 1494m, 1454m, 1250s, 842vs, 747m, 698s
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.42–7.16 (m, 10 H), 3.79 (d, 2 H,
J = 13.7 Hz), 3.34 (d, 2 H, J = 13.7 Hz), 3.16 (d, 1 H, J = 10.2 Hz),
1.75–1.18 (m, 5 H), 0.78 (t, 3 H, J = 7.3 Hz), 0.56 (t, 3 H, J = 7.5
Hz), 0.26 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 139.7, 129.1, 128.1, 126.8, 104.0,
90.0, 55.6, 55.0, 41.5, 22.1, 20.1, 10.6, 8.9, 0.5.
MS (70 eV, EI): m/z (%) = 362 (M+ – Me, 1), 307 (30); 306 (100),
91 (29).
1H NMR (300 MHz, CDCl3): d = 7.45–7.20 (m, 10 H), 3.84 (d, 2 H,
J = 13.7 Hz), 3.39 (d, 2 H, J = 13.7 Hz), 2.93 (dd, 1 H, J = 10.6, 2.2
Hz), 2.86 (d, 1 H, J = 2.2 Hz), 2.01–1.85 (m, 1 H), 1.01 (t, 6 H,
J = 6.6 Hz).
13C NMR (75 MHz, CDCl3): d = 139.6, 128.8, 128.2, 126.9, 81.2,
73.2, 59.0, 54.9, 30.6, 20.7, 19.3.
MS (70 eV, EI): m/z (%) = 235 (18), 234 (M+ – i-Pr, 100), 91 (16).
HRMS (EI): m/z calcd for C20H22N [M+ – H]: 276.1752; found:
276.1720.
HRMS (EI): m/z calcd for C25H36NSi [M+ + H]: 378.2617; found:
378.2617.
Anal. Calcd for C20H23N: C, 86.59; H, 8.36; N, 5.05: Found: C,
86.25; H, 8.20; N, 4.98.
Anal. Calcd for C25H36NSi: C, 79.51; H, 9.34; N, 3.71. Found: C,
79.49; H, 9.37; N, 3.69.
N,N-Dibenzyl-4-ethylhex-1-yn-3-amine (5b)
Preparation according to GP 2 on a 4 mmol scale afforded, after col-
umn chromatographic purification (SiO2, pentane), ( )-5b as a col-
orless oil (1.198 g, 98%).
Synthesis 2004, No. 12, 2015–2025 © Thieme Stuttgart · New York

PAPER
Synthesis of Chiral a-Aminoalkylpyrimidines
2019
IR (film): 3302m, 2963s, 2937m, 1495m, 1454m, 748m, 698s cm–1.
1H NMR (300 MHz, CDCl3): d = 7.97–7.86 (m, 1 H), 7.44–7.21 (m,
10 H), 7.12–7.01 (m, 1 H), 3.92 (d, 2 H, J = 13.7 Hz), 3.46 (d, 2 H,
J = 13.7 Hz), 3.20 (d, 1 H, J = 10.2 Hz), 2.16–1.99 (m, 1 H), 1.08–
1.00 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 171.3, 138.8, 128.9, 128.4, 127.2,
122.3, 119.5, 119.2, 107.2, 95.3, 85.7, 59.5, 55.1, 30.4, 20.7, 19.9.
1H NMR (300 MHz, CDCl3): d = 7.43–7.18 (m, 10 H), 3.81 (d, 2 H,
J = 13.7 Hz), 3.36 (d, 2 H, J = 13.7 Hz), 3.17 (dd, 1 H, J = 10.0, 1.6
Hz), 2.85 (d, 1 H, J = 2.2 Hz), 1.77–1.22 (m, 5 H), 0.77 (t, 3 H,
J = 7.3 Hz), 0.57 (t, 3 H, J = 7.3 Hz).
13C NMR (75 MHz, CDCl3): d = 139.6, 129.0, 128.2, 126.9, 81.3,
73.4, 55.0, 54.6, 41.4, 21.9, 19.9, 10.4, 8.9.
MS (70 eV, EI): m/z (%) = 433 (M+ – 2 H, 4), 418 (5), 392 (48), 276
(1), 225 (2), 194 (3), 159 (22), 91 (100), 65 (5).
HRMS (EI): m/z calcd for C27H22F3NO [M+ – 2 H]: 433.1652;
MS (70 eV, EI): m/z (%) = 235 (20), 234 (M+ – 1-ethylpropyl, 100),
91 (74).
found: 433.1630.
HRMS (EI): m/z calcd for C22H26N [M+ – H]: 304.2065, found:
304.2075.
Anal. Calcd for C27H24F3NO: C, 74.47; H, 5.55; N, 3.22. Found: C,
74.30; H, 5.59; N, 3.17.
Anal. Calcd for C22H27N: C, 86.51; H, 8.91; N, 4.59: Found: C,
86.45; H, 9.07; N, 4.57.
1-(4-Chlorophenyl)-4-(dibenzylamino)-5-methylhex-2-yn-1-
one (9b)
Preparation according to GP 3 afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 97:3), ( )-9b as a yellow
oil (379 mg, 91%).
N,N-Dibenzyl-1-cyclohexylprop-2-yn-1-amine (5c)
Preparation according to GP 2 on a 4.4 mmol scale afforded, after
column chromatographic purification (SiO2, pentane), ( )-5c as a
colorless solid (1.376 g, 99%); mp 75–76 °C.
IR (film): 2962m, 2931w, 2209m, 1650vs, 1586s, 1494w, 1454m,
1400w, 1257vs, 1170m, 1093vs, 1014m, 846w, 746s, 699s cm–1.
IR (film): 3302s, 2926vs, 2851s, 1495m, 1448m, 746s, 698s cm–1.
1H NMR (300 MHz, CDCl3): d = 7.44–7.17 (m, 10 H), 3.83 (d, 2 H,
J = 14.0 Hz), 3.38 (d, 2 H, J = 14.0 Hz), 3.04 (dd, 1 H, J = 10.4, 2.2
Hz), 2.35 (d, 1 H, J = 2.2 Hz), 2.28 (d, 1 H, J = 13.0 Hz), 2.01, (d,
1 H, J = 13.0 Hz), 1.75–1.51 (m, 4 H), 1.31–0.98 (m, 3 H), 0.92–
0.64 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 139.7, 128.8, 128.2, 126.8, 81.0,
73.5, 57.6, 54.8, 39.5, 31.2, 30.2, 26.5, 26.1, 25.9.
MS (70 eV, EI): m/z (%) = 235 (21), 234 (M+ – c-C6H11, 100), 91
(88).
HRMS (EI): m/z calcd for C23H27N [M+]: 317.2143; found:
317.2139.
1H NMR (400 MHz, CDCl3): d = 8.08–8.03 (m, 2 H), 7.45–7.39 (m,
2 H), 7.33 (d, 4 H, J = 7.3 Hz), 7.25 (t, 4 H, J = 7.3 Hz), 7.17 (t, 2
H, J = 7.3 Hz), 3.87 (d, 2 H, J = 13.8 Hz), 3.39 (d, 2 H, J = 13.8 Hz),
3.15 (d, 1 H, J = 10.4 Hz), 2.09–0.96 (m, 1 H), 0.99 (t, 6 H, J = 6.3
Hz).
13C NMR (100 MHz, CDCl3): d = 176.5, 140.7, 138.8, 135.5, 130.8,
129.0, 128.9, 128.4, 127.2, 94.3, 84.3, 59.6, 55.3, 30.5, 20.8, 19.9.
MS (70 eV, EI): m/z (%) = 413 (M+ – 2 H, 8), 398 (9), 372 (37), 281
(3), 207 (7), 139 (22), 91 (100), 65 (4).
HRMS (EI): m/z calcd for C27H24ClNO [M+ – 2 H]: 413.1545,
found: 413.1562.
Anal. Calcd for C23H27N: C, 87.02; H, 8.57; N, 4.41. Found: C,
86.74; H, 8.37; N, 4.32.
Anal. Calcd for C27H26ClNO: C, 77.96; H, 6.30; N, 3.37: Found: C,
77.49; H, 6.45; N, 3.41.
N,N-Dibenzylhept-1-yn-3-amine (5d)
4-(Dibenzylamino)-5-methyl-1-phenylhex-2-yn-1-one (9c)
Preparation according to GP 3 afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 98:2), (–)-9c as a light
yellow solid (321 mg, 84%, 96% ee); mp 105–107 °C; [a]D20 –227
(c = 1.06, CHCl3). HPLC (OD-H, 99% n-heptane/1% i-PrOH, 0.2
mL/min): tr(min) = 28 (–), 39 (+).
Preparation according to GP 2 on a 2 mmol scale afforded, after col-
umn chromatographic purification (SiO2, pentane), ( )-5d as a col-
orless oil (535 mg, 92%).
IR (film): 3302m, 2956s, 2934s, 2860m, 1494m, 1454s, 746s,
698vs cm–1.
1H NMR (600 MHz, CDCl3): d = 7.41 (d, 4 H), J = 7.7 Hz, 7.33 (t,
4 H, J = 7.3 Hz), 7.25 (t, 2 H, J = 7.3 Hz), 3.85 (d, 2 H, J = 13.8 Hz),
3.46–3.40 (m, 3 H), 2.33 (d, 1 H, J = 1.3 Hz), 1.83–1.73 (m, 1 H),
1.71–1.63 (m, 1 H), 1.50–1.33 (m, 2 H), 1.25–1.17 (m, 2 H), 0.87 (t,
3 H, J = 7.3 Hz).
13C NMR (150 MHz, CDCl3): d = 139.7, 128.8, 128.2, 126.9, 82.2,
72.4, 54.7, 51.5, 33.4, 28.4, 22.2, 13.9.
MS (70 eV, EI): m/z (%) = 290 (1, M+-H), 235 (22), 234 (98), 181
(11), 92 (100), 65 (10).
HRMS (EI): m/z calcd for C21H25N [M+ – H]: 290.1909; found:
290.1885.
IR (film): 2963m, 2807w, 2209m, 1639vs, 1598m, 1579m, 1494w,
1451m, 1313m, 1262vs, 1173w, 1086m, 1068m, 746m, 697vs cm–1.
1H NMR (300 MHz, CDCl3): d = 8.25–8.19 (m, 2 H), 7.68–7.21 (m,
13 H), 3.95 (d, 2 H, J = 13.7 Hz), 3.49 (d, 2 H, J = 13.7 Hz), 3.23
(d, 1 H, J = 10.6 Hz), 2.18–2.03 (m, 1 H), 1.08 (d, 6 H, J = 6.2 Hz).
13C NMR (75 MHz, CDCl3): d = 177.9, 138.9, 137.0, 134.0, 129.5,
128.9, 128.6, 128.4, 127.1, 93.6, 84.6, 59.5, 55.2, 30.5, 20.9, 19.9.
MS (70 eV, EI): m/z (%) = 381 (M+, <1), 338 (100), 246 (1), 181
(1), 115 (1), 105 (7) 91 (52), 77 (2), 65 (2).
HRMS (EI): m/z calcd for C27H27NO [M+]: 381.2093; found:
390.2082.
Anal. Calcd for C21H25N: C, 86.55; H, 8.65; N, 4.81. Found: C,
86.84; H, 8.80; N, 4.97.
4-(Dibenzylamino)-5-ethyl-1-(4-methoxyphenyl)hept-2-yn-1-
one (9d)
Preparation according to GP 3 afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 95:5), ( )-9d as a yellow
oil (428 mg, 97%).
4-(Dibenzylamino)-5-methyl-1-(2,4,5-trifluorophenyl)hex-2-
yn-1-one (9a)
Preparation according to GP 3 afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 95:5), ( )-9a as a color-
less oil (401 mg, 92%).
IR (film): 2963m, 2934m, 2209m, 1640s, 1597s, 1509m, 1454m,
1316m, 1257vs, 1165s, 1029m, 845w, 749m, 699m cm–1.
1H NMR (600 MHz, CDCl3): d = 8.21 (d, 2 H, J = 8.6 Hz), 7.41 (d,
4 H, J = 7.5 Hz), 7.34 (t, 4 H, J = 7.5 Hz), 7.26 (t, 2 H, J = 7.5 Hz),
IR (film): 2199m, 1662m, 1641s, 1620s, 1514vs, 1430s, 1337s,
1295m, 1232s, 1194m, 1176m, 1146s, 797m, 748m, 699s cm–1.
Synthesis 2004, No. 12, 2015–2025 © Thieme Stuttgart · New York

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H. Dube et al.
PAPER
7.01 (d, 2 H, J = 8.6 Hz), 3.93 (d, 2 H, J = 15.1 Hz), 3.92 (s, 3 H),
3.43–3.37 (m, 3 H), 1.77–1.71 (m, 1 H), 1.71–1.59 (m, 2 H), 1.45–
1.36 (m, 1 H), 1.35–1.26 (m, 1 H), 0.83 (t, 3 H, J = 7.3 Hz), 0.61 (t,
3 H, J = 7.3 Hz).
1H NMR (300 MHz, CDCl3): d = 8.27–8.20 (m, 2 H), 7.68–7.60 (m,
1 H), 7.58–7.49 (m, 2 H), 7.44–7.21 (m, 10 H), 3.94 (d, 2 H,
J = 13.7 Hz), 3.54–3.43 (m, 3 H), 1.90–1.63 (m, 3 H), 1.60–1.30 (m,
2 H), 0.82 (t, 3 H, J = 7.3 Hz), 0.61 (t, 3 H, J = 7.3 Hz).
13C NMR (150 MHz, CDCl3): d = 176.6, 164.4, 139.0, 131.9, 130.5,
129.1, 128.3, 127.1, 113.9, 93.0, 84.8, 55.6, 55.3, 55.3, 41.4, 22.2,
20.0, 10.4, 8.8.
13C NMR (75 MHz, CDCl3): d = 177.9, 138.9, 137.1, 134.0, 129.5,
129.1, 128.6, 128.4, 127.2, 94.0, 84.5, 55.4, 55.3, 41.4, 22.2, 20.0,
10.4, 8.8.
MS (70 eV, EI): m/z (%) = 439 (M+, <1), 368 (100), 348 (1), 318
MS (70 eV, EI): m/z (%) = 409 (M+, <1), 338 (100), 312 (1), 246
(1), 278 (3), 234 (1), 181 (2), 135 (29), 91 (79).
(2), 194 (1), 181 (2), 115 (3), 105 (16), 91 (87), 77 (6), 65 (5).
HRMS (EI): m/z calcd for C30H33NO2 [M+]: 439.2511; found:
HRMS (EI): m/z calcd for C29H31NO [M+]: 409.2406; found:
439.2520.
409.2443.
Anal. Calcd for C30H33NO2: C, 81.97; H, 7.57; N, 3.19. Found: C,
81.95; H, 7.48; N, 3.17.
Anal. Calcd for C29H31NO: C, 85.04; H, 7.63; N, 3.42: Found: C,
85.44; H, 7.53; N, 3.40.
4-(Dibenzylamino)-5-ethyl-1-(2-furyl)hept-2-yn-1-one (9e)
Preparation according to GP 3 afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 9:1), ( )-9e as a brown
oil (380 mg, 95%).
4-Cyclohexyl-4-(dibenzylamino)-1-(2-furyl)but-2-yn-1-one (9h)
Preparation according to GP 3 afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 95:5), ( )-9h as a bright
yellow solid (389 mg, 95%); mp 119–120 °C.
IR (film): 2963m, 2936m, 2219m, 2198m, 1638vs, 1567m, 1494m,
1463s, 1394m, 1299m, 1281m, 1168m, 1102m, 1017m, 746m,
699m cm–1.
IR (film): 2929s, 2851m, 2200w, 1637vs, 1566m, 1494m, 1462s,
1396m, 1305m, 1173w, 1108m, 1015m, 884w, 739m, 699s, 594w
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.69 (dd, 1 H, J = 1.8 Hz, 0.9 Hz),
7.44–7.20 (m, 11 H), 6.62 (dd, 1 H, J = 3.5 Hz, 1.8 Hz), 3.91 (d, 2
H, J = 13.7 Hz), 3.52–3.39 (m, 3 H), 1.87–1.61 (m, 3 H), 1.54–1.27
(m, 2 H), 0.81 (t, 3 H, J = 7.3 Hz), 0.59 (t, 3 H, J = 7.3 Hz).
13C NMR (75 MHz, CDCl3): d = 164.7, 153.5, 147.9, 138.8, 129.0,
128.3, 127.2, 120.3, 112.6, 92.9, 84.1, 55.3, 41.3, 22.1, 20.0, 10.4,
8.8.
1H NMR (300 MHz, CDCl3): d = 7.69 (dd, 1 H, J = 1.8, 0.9 Hz),
7.45–7.20 (m, 11 H), 6.61 (dd, 1 H, J = 3.5, 1.8 Hz), 3.93 (d, 2 H,
J = 13.7 Hz), 3.48 (d, 2 H, J = 13.7 Hz), 3.32 (d, 1 H, J = 10.2 Hz),
2.30 (d, 1 H, J = 12.8 Hz), 2.02 (d, 1 H, J = 12.8 Hz), 1.85–1.55 (m,
4 H), 1.34–0.70 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 164.7, 153.4, 147.8, 138.9, 128.7,
128.3, 127.1, 120.4, 112.6, 92.4, 84.1, 58.2, 55.1, 39.3, 31.2, 30.2,
26.4, 25.9, 25.7.
MS (70 eV, EI): m/z (%) = 397 (M+ – 2 H, 1), 368 (6), 328 (16), 304
(3), 281 (1), 207 (4), 194 (3), 175 (2), 95 (18), 91 (100), 65 (7).
MS (70 eV, EI): m/z (%) = 411 (M+, 2), 328 (100), 302 (1), 236 (1),
181 (1), 91 (19), 65 (1).
HRMS (EI): m/z calcd for C28H29NO2 [M+]: 411.2198; found:
HRMS (EI): m/z calcd for C27H27NO2 [M+ – 2 H]: 397.2040; found:
397.2021.
411.2214.
Anal. Calcd for C27H29NO2: C, 81.17; H, 7.32; N, 3.51: Found: C,
80.96; H, 7.38; N, 3.48.
Anal. Calcd for C28H29NO2: C, 81.72; H, 7.10; N, 3.40: Found: C,
81.61; H, 7.10; N, 3.34.
6-(Dibenzylamino)-7-ethyl-2,2-dimethylnon-4-yn-3-one (9f)
Preparation according to GP 3 afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 96:4), ( )-9f as a color-
less oil (374 mg, 96%).
4-(Dibenzylamino)-1-phenyloct-2-yn-1-one (9i)
Preparation according to GP 3 afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 98.5:1.5), ( )-9i as a yel-
low oil (376 mg, 95%).
IR (film): 2966s, 2933m, 2876m, 2194m, 1671vs, 1454m, 1128m,
748m, 699m cm–1.
1H NMR (300 MHz, CDCl3): d = 7.41–7.20 (m, 10 H), 3.87 (d, 2 H,
J = 13.5 Hz), 3.44–3.32 (m, 3 H), 1.81–1.54 (m, 3 H), 1.52–1.23 (m,
2 H), 1.29 (s, 9 H), 0.78 (t, 3 H, J = 7.5 Hz), 0.58 (t, 3 H, J = 7.5 Hz).
13C NMR (75 MHz, CDCl3): d = 194.0, 138.9, 129.0, 128.3, 127.2,
92.6, 83.9, 55.3, 55.1, 44.7, 41.3, 26.3, 22.1, 20.0, 10.3, 8.8.
MS (70 eV, EI): m/z (%) = 390 (M+ + 1 H, <1), 318 (100), 280 (3),
234 (2), 181 (2), 91 (29).
HRMS (EI): m/z calcd for C27H36NO [M+ + 1 H]: 390.2798; found:
390.2787.
IR (film): 3063m, 3029m, 2956m, 2932m, 2860m, 2210m, 1645vs,
1598m, 1581m, 1494m, 1451s, 1312m, 1260vs, 1174m, 1069m,
1025m, 747m, 699vs cm–1.
1H NMR (300 MHz, CDCl3): d = 8.24–8.17 (m, 2 H), 7.68–7.60 (m,
1 H), 7.56–7.48 (m, 2 H), 7.44–7.20 (m, 10 H), 3.95 (d, 2 H,
J = 13.7 Hz), 3.70 (t, 1 H, J = 7.5 Hz), 3.51 (d, 2 H, J = 13.7 Hz),
1.95–1.71 (m, 2 H), 1.60–1.13 (m, 4 H), 0.87 (t, 3 H, J = 7.1 Hz).
13C NMR (75 MHz, CDCl3): d = 177.9, 139.1, 137.0, 134.0, 129.5,
128.8, 128.3, 127.1, 94.3, 83.6, 55.1, 52.0, 32.9, 28.4, 22.2, 13.9.
MS (70 eV, EI): m/z (%) = 395 (M+, <1), 338 (100), 246 (1), 196
(3), 181 (1), 115 (1), 105 (9) 91 (62), 77 (2), 65 (2).
Anal. Calcd for C27H35NO: C, 83.24; H, 9.06; N, 3.60: Found: C,
83.23; H, 9.15; N, 3.58.
HRMS (EI): m/z calcd for C28H29NO [M+]: 395.2249; found:
395.2233.
4-(Dibenzylamino)-5-ethyl-1-phenylhept-2-yn-1-one (9g)
Preparation according to GP 3 afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 95:5), ( )-9g as a color-
less solid (395 mg, 0.96 mmol, 96%). mp.: 76-77 °C.
Anal. Calcd for C28H29NO: C, 85.02; H, 7.39; N, 3.54. Found: C,
84.79; H, 7.42; N, 3.50.
6-(Dibenzylamino)-2,2-dimethyldec-4-yn-3-one (9j)
Preparation according to GP 3 afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 98:2), ( )-9j as a color-
less oil (352 mg, 94%).
IR (film): 2968m, 2941m, 2209m, 1640vs, 1598m, 1579m, 1494m,
1450m, 1312m, 1261vs, 1172m, 1086m, 1069m, 748m, 734m,
697vs cm–1.
Synthesis 2004, No. 12, 2015–2025 © Thieme Stuttgart · New York

PAPER
Synthesis of Chiral a-Aminoalkylpyrimidines
2021
IR (film): 2961s, 2870m, 2195m, 1671vs, 1494m, 1454m, 1365m,
1132s, 746m, 698s cm–1.
IR (film): 3029w, 2964vs, 2936s, 2877m, 2197m, 1675vs, 1495m,
1454s, 1162m, 1071m, 748s, 699s cm–1.
1H NMR (300 MHz, CDCl3): d = 7.40–7.20 (m, 10 H), 3.89 (d, 2 H,
J = 13.7 Hz), 3.58 (t, 1 H, J = 7.7 Hz), 3.41 (d, 2 H, J = 13.7 Hz),
1.87–1.62 (m, 2 H), 1.52–1.12 (m, 4 H), 1.28 (s, 9 H), 0.84 (t, 3 H,
J = 7.1 Hz).
13C NMR (75 MHz, CDCl3): d = 193.9, 139.1, 128.7, 128.3, 127.1,
93.1, 82.7, 55.1, 44.7, 32.9, 28.3, 26.2, 22.1, 13.9.
1H NMR (300 MHz, CDCl3): d = 7.38 (d, 4 H, J = 7.2 Hz), 7.32 (t,
4 H, J = 7.2 Hz), 7.25 (t, 2 H, J = 7.2 Hz), 3.86 (d, 2 H, J = 13.4 Hz),
3.33–3.25 (m, 3 H), 2.63 (t, 2 H, J = 7.3 Hz), 1.78–1.15 (m, 7 H),
1.03 (t, 3 H, J = 7.5 Hz), 0.79 (t, 3 H, J = 7.5 Hz), 0.57 (t, 3 H),
J = 7.3 Hz.
13C NMR (75 MHz, CDCl3): d = 188.0, 138.9, 129.0, 128.3, 127.1,
91.4, 85.9, 55.2, 55.0, 47.8, 41.3, 22.1, 20.0, 17.9, 13.6, 10.4, 8.8.
MS (70 eV, EI): m/z (%) = 375 (M+, <1), 318 (100), 266 (5), 234
(1), 196 (2), 181 (2), 115 (1), 91 (60), 79 (2), 57 (7).
MS (70 eV, EI): m/z (%) = 374 (M+ – 1 H, <1), 304 (100), 234 (4),
181 (2), 91 (40).
HRMS (EI): m/z calcd for C26H33NO [M+]: 375.2562; found:
375.2549.
HRMS (EI): m/z calcd for C26H32NO [M+ – 1 H]: 374.2483; found:
374.2457.
Anal. Calcd for C26H33NO: C, 83.15; H, 8.86; N, 3.73. Found: C,
83.14; H, 8.82; N, 3.70.
Anal. Calcd for C26H33NO: C, 83.15; H, 8.86; N, 3.73. Found: C,
83.35; H, 8.87; N, 3.66.
4-(Dibenzylamino)-1-(2-furyl)oct-2-yn-1-one (9k)
Preparation according to GP 3 afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 95:5), ( )-9k as a brown
oil (362 mg, 94%).
1-Cyclohexyl-4-(dibenzylamino)-5-ethylhept-2-yn-1-one (9n)
Preparation according to GP 4 afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 97:3), ( )-9n as a color-
less oil (375 mg, 90%).
IR (film): 3029m, 2956m, 2933m, 2861m, 2202m, 1640vs, 1567m,
1494m, 1463vs, 1394s, 1299m, 1168m, 1096m, 1014m, 884m,
745s, 699s cm–1.
IR (film): 2933vs, 2856m, 2200m, 1664vs, 1494w, 1453m, 1237w,
1162m, 1119m, 748s, 700s cm–1.
1H NMR (300 MHz, CDCl3): d = 7.69 (s, 1 H), 7.42–7.36 (m, 5 H),
7.32 (t, 4 H, J = 7.5 Hz), 7.27–7.22 (m, 2 H), 6.63–6.59 (m, 1 H),
3.92 (d, 2 H, J = 13.5 Hz), 3.64 (t, 1 H, J = 7.7 Hz), 3.48 (d, 2 H,
J = 13.5 Hz), 1.88–1.71 (m, 2 H), 1.51–1.34 (m, 2 H), 1.26–1.16 (m,
2 H), 0.86 (t, 3 H, J = 7.3 Hz).
13C NMR (75 MHz, CDCl3): d = 164.7, 153.4, 147.9, 139.0, 128.8,
128.3, 127.1, 120.5, 112.6, 93.2, 82.9, 55.0, 52.0, 32.8, 28.3, 22.1,
13.9.
1H NMR (300 MHz, CDCl3): d = 7.40–7.20 (m, 10 H), 3.85 (d, 2 H,
J = 13.7 Hz), 3.42–3.31 (m, 3 H), 2.47 (tt, 1 H, J = 10.9, 3.5 Hz),
2.11–2.00 (m, 2 H), 1.89–1.17 (m, 13 H), 0.78 (t, 3 H, J = 7.5 Hz),
0.57 (t, 3 H, J = 7.5 Hz).
13C NMR (75 MHz, CDCl3): d = 191.4, 138.9, 129.0, 128.3, 127.1,
92.1, 85.1, 55.2, 55.1, 52.6, 41.3, 28.5, 25.9, 25.4, 22.1, 20.0, 10.4,
8.8.
MS (70 eV, EI): m/z (%) = 386 (M+ – CHO, 1), 344 (100), 281 (11),
234 (13), 207 (35), 194 (8), 91 (91), 83 (16).
MS (70 eV, EI): m/z (%) = 385 (M+, <1), 328 (100), 302 (2), 236
(1), 196 (2), 91 (24).
HRMS (EI): m/z calcd for C26H27NO2 [M+]: 385.2042; found:
Anal. Calcd for C29H37NO: C, 83.81; H, 8.97; N, 3.37. Found: C,
83.60; H, 8.98; N, 3.31.
385.2037.
N,N-Dibenzyl-2-methyl-1-[2-methyl-6-(2,4,5-trifluorophenyl)-
4-pyrimidinyl]-1-propanamine (6a)
Preparation according to GP 5 on a 0.81 mmol scale afforded, after
column chromatographic purification (SiO2, pentane–Et2O, 98:2),
( )-6a as a colorless solid (291 mg, 75%); mp 114–115 °C.
Anal. Calcd for C26H27NO2: C, 81.01; H, 7.06; N, 3.63: Found: C,
80.56; H, 7.07; N, 3.61.
5-(Dibenzylamino)-6-ethyloct-3-yn-2-one (9l)
Preparation according to GP 4 afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 96:4), ( )-9l as a bright
yellow oil (312 mg, 90%).
IR (film): 2960m, 1627m, 1575vs, 1541vs, 1516vs, 1495m, 1454m,
1398m, 1360m, 1208m, 1142m, 886m, 782m, 748m, 700s cm–1.
IR (film): 2966m, 2936m, 2190m, 1679vs, 1494m, 1453m, 1356m,
1216s, 747s, 696s cm–1.
1H NMR (400 MHz, CDCl3): d = 8.13–8.04 (m, 1 H), 7.85 (d, 4 H,
J = 7.5 Hz), 7.25 (t, 4 H, J = 7.5 Hz), 7.21–7.12 (m, 3 H), 7.03–6.94
(m, 1 H), 3.99 (d, 2 H, J = 14.2 Hz), 3.19 (d, 1 H, J = 10.7 Hz), 2.99
(d, 2 H, J = 14.2 Hz), 2.76 (s, 3 H), 2.61–2.49 (m, 1 H), 1.15 (d, 3
H, J = 6.5 Hz), 0.53 (d, 3 H, J = 6.5 Hz).
13C NMR (100 MHz, CDCl3): d = 168.1, 167.5, 157.9, 157.2, 139.9,
128.8, 128.3, 126.9, 118.8, 118.3, 118.1, 106.7, 106.5, 106.4, 106.2,
69.4, 54.1, 27.4, 26.6, 20.6, 20.2.
1H NMR (300 MHz, CDCl3): d = 7.37 (d, 4 H, J = 7.3 Hz), 7.32 (t,
4 H, J = 7.3 Hz), 7.25 (t, 2 H, J = 7.3 Hz), 3.85 (d, 2 H, J = 13.3 Hz),
3.38–3.32 (m, 3 H), 2.44 (s, 3 H), 1.75–1.66 (m, 2 H), 1.65–1.57 (m,
1 H), 1.49–1.40 (m, 1 H), 1.33–1.25 (m, 1 H), 0.79 (t, 3 H, J = 7.3
Hz), 0.57 (t, 3 H, J = 7.3 Hz).
13C NMR (75 MHz, CDCl3): d = 185.4, 138.9, 129.0, 128.3, 127.1,
91.4, 86.4, 55.2, 55.0, 41.2, 33.3, 22.1, 19.9, 10.4, 8.7.
MS (70 eV, EI): m/z (%) = 474 (M+ – H, <1), 432 (21), 384 (12),
341 (9), 325 (11), 280 (28), 265 (100), 196 (55), 91 (37).
HRMS (EI): m/z calcd for C29H27F3N3 [M+ – H]: 474.2156; found:
MS (70 eV, EI): m/z (%) = 346 (M+ – 1 H, <1), 318 (1), 304 (1), 276
(100), 234 (2), 181 (3), 142 (1), 115 (2), 91 (75), 65 (4), 43 (2).
474.2153.
HRMS (EI): m/z calcd for C24H28NO [M+ – 1 H]: 346.2170, found:
346.2152.
Anal. Calcd for C29H28F3N3: C, 73.24; H, 8.84; N, 5.93. Found: C,
73.10; H, 8.56; N, 6.06.
Anal. Calcd for C24H29NO: C, 82.95; H, 8.41; N, 4.03. Found: C,
83.21; H, 8.46; N, 4.03.
N,N-Dibenzyl-1-[6-(4-chlorophenyl)-2-methyl-4-pyrimidinyl]-
2-methyl-1-propanamine (6b)
Preparation according to GP 5 on a 0.80 mmol scale afforded, after
column chromatographic purification (SiO2, pentane–Et2O, 98:2),
( )-6b as a colorless solid (279 mg, 76%); mp 58–63 °C.
7-(Dibenzylamino)-8-ethyldec-5-yn-4-one (9m)
Preparation according to GP 4 afforded, after column chromato-
graphic purification (SiO2, pentane–Et2O, 98:2), ( )-9m as a color-
less oil (345 mg, 92%).
Synthesis 2004, No. 12, 2015–2025 © Thieme Stuttgart · New York

2022
H. Dube et al.
PAPER
IR (film): 2958m, 1582vs, 1571vs, 1534vs, 1493s, 1453m, 1403m,
1092s, 1014m, 834m, 739s, 698s cm–1.
HRMS (EI): m/z calcd for C32H36N3O [M+ – H]: 478.2858; found:
478.2868.
1H NMR (400 MHz, CDCl3): d = 8.08–8.02 (m, 2 H), 7.54–7.47 (m,
2 H), 7.44 (d, 4 H, J = 7.2 Hz), 7.39–7.22 (m, 6 H), 7.08 (s, 1 H),
4.10 (d, 2 H, J = 14.2 Hz), 3.31 (d, 1 H, J = 11.1 Hz), 3.11 (d, 2 H,
J = 14.2 Hz), 2.86 (s, 3 H), 2.76–2.57 (m, 1 H), 1.27 (d, 3 H, J = 6.4
Hz), 0.65 (d, 3 H, J = 6.4 Hz).
Anal. Calcd for C32H37N3O: C, 80.13; H, 7.78; N, 8.76. Found: C,
79.99; H, 7.95; N, 8.43.
N,N-Dibenzyl-2-ethyl-1-[6-(2-furyl)-2-methyl-4-pyrimidinyl]-
1-butanamine (6e)
Preparation according to GP 5 on a 0.84 mmol scale afforded, after
column chromatographic purification (SiO2, pentane–Et2O, 95:5),
( )-6e as a bright yellow solid (291 mg, 79%); mp 116–117 °C.
13C NMR (100 MHz, CDCl3): d = 168.2, 167.3, 162.0, 140.0, 136.8,
135.9, 129.2, 128.7, 128.4, 128.3, 126.9, 114.1, 69.5, 54.1, 27.4,
26.6, 20.7, 20.2.
IR (film): 2965 (m), 2935 (m), 1604 (vs), 1564 (vs), 1538 (s), 1487
(m), 1453 (m), 1396 (m), 1012 (w), 744 (s), 698 (s).
MS (70 eV, EI): m/z (%) = 456 (M+ + H, <1), 412 (17), 364 (10),
321 (6), 260 (50), 245 (100), 218 (12), 196 (65), 91 (78).
1H NMR (300 MHz, CDCl3): d = 7.63 (dd, 1 H, J = 1.8 Hz, 0.9 Hz),
7.42 (d, 4 H, J = 7.3 Hz), 7.37–7.20 (m, 7H), 7.11 (s, 1 H), 6.60 (dd,
1 H, J = 3.5 Hz, 1.8 Hz), 4.04 (d, 2 H, J = 14.2 Hz), 3.51 (d, 1 H,
J = 11.5 Hz), 3.08 (d, 2 H, J = 14.2 Hz), 2.81 (s, 3 H), 2.41–2.28 (m,
1 H), 2.05–1.89 (m, 1 H), 1.73–1.57 (m, 1 H), 1.15–0.88 (m, 2 H),
0.79 (t, 3 H, J = 7.5 Hz), 0.64 (t, 3 H, J = 7.5 Hz).
13C NMR (75 MHz, CDCl3): d = 167.9, 167.1, 154.6, 152.3, 144.8,
140.0, 129.0, 128.2, 126.8, 112.4, 112.1, 111.7, 65.0, 54.1, 38.3,
26.6, 21.6, 19.9, 10.2, 9.4.
HRMS (EI): m/z calcd for C29H31ClN3 [M+ + H]: 456.2207; found:
456.2178.
Anal. Calcd for C29H30ClN3: C, 76.38; H, 6.63; N, 9.21; Cl, 7.77.
Found: C, 76.54; H, 6.61; N, 9.16; Cl, 7.74.
N,N-Dibenzyl-2-methyl-1-(2-methyl-6-phenyl-4-pyrimidinyl)-
1-propanamine (6c)
Preparation according to GP 5 on a 0.78 mmol scale afforded, after
column chromatographic purification (SiO2, pentane–Et2O, 98:2),
( )-6c as a bright pink solid (271 mg, 82%, 96% ee); mp 95–97 °C;.
[a]D20 –192 (c = 1.36, CHCl3). HPLC (OD-H, 98% n-heptane/2% i-
PrOH, 0.5 mL/min): tr (min) = 8 (–), 10 (+).
MS (70 eV, EI): m/z (%) = 440 (M+ + H, 1), 368 (18), 328 (3), 277
(7), 244 (34), 215 (100), 196 (10), 174 (4), 91 (40).
HRMS (EI): m/z calcd for C29H34N3O [M+ + H]: 440.2703; found:
IR (film): 3062m, 2958m, 2925m, 1576vs, 1538vs, 1494m, 1453m,
1394m, 1366m, 1070m, 1028m, 769m, 744m, 726m, 698s, 640m
cm–1.
1H NMR (300 MHz, CDCl3): d = 8.13–8.05 (m, 2 H), 7.56–7.49 (m,
3 H), 7.44 (d, 4 H, J = 7.5 Hz), 7.34 (t, 4 H, J = 7.5 Hz), 7.25 (t, 2
H, J = 7.5 Hz), 7.12 (s, 1 H), 4.09 (d, 2 H, J = 14.2 Hz), 3.31 (d, 1
H, J = 10.6 Hz), 3.12 (d, 2 H, J = 14.2 Hz), 2.86 (s, 3 H), 2.74–2.57
(m, 1 H), 1.26 (d, 3 H, J = 6.4 Hz), 0.65 (d, 3 H, J = 6.4 Hz).
440.2681.
Anal. Calcd for C29H33N3O: C, 79.20; H, 7.57; N, 9.56. Found: C,
79.51; H, 7.64; N, 9.16.
N,N-Dibenzyl-1-(6-tert-butyl-2-methyl-4-pyrimidinyl)-2-ethyl-
1-butanamine (6f)
Preparation according to GP 5 on a 0.84 mmol scale afforded, after
column chromatographic purification (SiO2, pentane–Et2O, 98:2),
( )-6f as a colorless oil (260 mg, 73%).
13C NMR (75 MHz, CDCl3): d = 168.0, 167.0, 163.3, 140.0, 137.5,
130.6, 128.9, 128.8, 127.1, 126.8, 114.4, 114.3, 69.6, 54.1, 27.5,
26.6, 20.7, 20.2.
IR (film): 2963vs, 2933s, 1576vs, 1539vs, 1494m, 1454m, 1398m,
1362m, 1071w, 1028w, 743s, 698s cm–1.
MS (70 eV, EI): m/z (%) = 420 (M+ – H, 1), 378 (28), 330 (17), 287
(13), 271 (6), 226 (90), 211 (100), 196 (43), 184 (7), 91 (56), 65 (5).
HRMS (EI): m/z calcd for C29H30N3 [M+ – H]: 420.2439; found:
420.2482.
1H NMR (300 MHz, CDCl3): d = 7.43–7.19 (m, 10 H), 6.71 (s, 1 H),
4.03 (d, 2 H, J = 13.9 Hz), 3.41 (d, 1 H, J = 11.1 Hz), 2.99 (d, 2 H,
J = 13.9 Hz), 2.76 (s, 3 H), 2.40–2.26 (m, 1 H), 2.02–1.88 (m, 1 H),
1.72–1.57 (m, 1 H), 1.37 (s, 9 H), 1.06–0.85 (m, 2 H), 0.80 (t, 3 H,
J = 7.5 Hz), 0.61 (t, 3 H, J = 7.5 Hz).
13C NMR (75 MHz, CDCl3): d = 176.7, 166.9, 165.9, 140.1, 128.9,
128.2, 126.8, 114.2, 65.1, 54.1, 38.4, 37.1, 29.5, 26.6, 21.7, 20.0,
10.3, 9.5.
Anal. Calcd for C29H31N3: C, 82.62; H, 7.41; N, 9.97. Found: C,
82.17; H, 7.34; N, 9.69.
N,N-Dibenzyl-2-ethyl-1-[6-(4-methoxyphenyl)-2-methyl-4-py-
rimidinyl]-1-butanamine (6d)
MS (70 eV, EI): m/z (%) = 430 (M+ + H, 3), 358 (65), 338 (29), 267
Preparation according to GP 5 on a 0.95 mmol scale afforded, after
column chromatographic purification (SiO2, pentane–Et2O, 95:5),
( )-6d as a bright yellow solid (313 mg, 78%); mp 60–62 °C.
(13), 251 (10), 234 (70), 205 (100), 196 (56), 91 (68).
HRMS (EI): m/z calcd for C29H39N3 [M+ + H]: 430.3223; found:
430.3232.
IR (film): 2962m, 2933m, 1609m, 1575vs, 1535s, 1513s, 1454m,
1254s, 1175m, 1029m, 835m, 746m, 698s, 574m cm–1.
Anal. Calcd for C29H39N3: C, 81.07; H, 9.15; N, 9.78: Found: C,
80.53; H, 9.08; N, 9.50.
1H NMR (400 MHz, CDCl3): d = 8.07 (d, 2 H, J = 8.6 Hz), 7.41 (d,
4 H, J = 7.3 Hz), 7.33 (t, 4 H, J = 7.3 Hz), 7.24 (t, 2 H, J = 7.3 Hz),
7.07 (s, 1 H), 7.04 (d, 2 H, J = 8.6 Hz), 4.04 (d, 2 H, J = 13.9 Hz),
3.89 (s, 3 H), 3.52 (d, 1 H, J = 10.7 Hz), 3.10 (d, 2 H, J = 13.9 Hz),
2.83 (s, 3 H), 2.40–2.33 (m, 1 H), 2.02–1.93 (m, 1 H), 1.71–1.62 (m,
1 H), 1.12–1.02 (m, 1 H), 1.00–0.89 (m, 1 H), 0.81 (t, 3 H, J = 7.1
Hz), 0.64 (t, 3 H, J = 7.1 Hz).
13C NMR (100 MHz, CDCl3): d = 167.8, 166.8, 162.7, 161.8, 140.1,
128.9, 128.6, 128.3, 128.2, 126.8, 114.3, 113.9, 113.6, 65.1, 55.4,
54.2, 38.4, 26.6, 21.7, 19.9, 10.3, 9.4.
N,N-Dibenzyl-2-ethyl-1-(2-methyl-6-phenyl-4-pyrimidinyl)-1-
butanamine (6g)
Preparation according to GP 5 on a 0.84 mmol scale afforded, after
column chromatographic purification (SiO2, pentane–Et2O, 98:2),
( )-6g as a colorless oil (260 mg, 73%).
IR (film): 2963vs, 2933s, 1576vs, 1539vs, 1494m, 1454m, 1398m,
1362m, 1071w, 1028w, 743s, 698s cm–1.
1H NMR (300 MHz, CDCl3): d = 7.43–7.19 (m, 10 H), 6.71 (s, 1 H),
4.03 (d, 2 H, J = 13.9 Hz), 3.41 (d, 1 H, J = 11.1 Hz), 2.99 (d, 2 H,
J = 13.9 Hz), 2.76 (s, 3 H), 2.40–2.26 (m, 1 H), 2.02–1.88 (m, 1 H),
1.72–1.57 (m, 1 H), 1.37 (s, 9 H), 1.06–0.85 (m, 2 H), 0.80 (t, 3 H,
J = 7.5 Hz), 0.61 (t, 3 H, J = 7.5 Hz).
MS (70 eV, EI): m/z (%) = 478 (M+ – H, <1), 408 (16), 388 (6), 368
(5), 317 (7), 301 (5), 284 (33), 255 (100), 214 (9), 196 (5), 91 (54),
65 (4).
Synthesis 2004, No. 12, 2015–2025 © Thieme Stuttgart · New York

PAPER
Synthesis of Chiral a-Aminoalkylpyrimidines
2023
13C NMR (75 MHz, CDCl3): d = 176.7, 166.9, 165.9, 140.1, 128.9,
128.2, 126.8, 114.2, 65.1, 54.1, 38.4, 37.1, 29.5, 26.6, 21.7, 20.0,
10.3, 9.5.
MS (70 eV, EI): m/z (%) = 430 (M+ + H, 3), 358 (65), 338 (29), 267
(13), 251 (10), 234 (70), 205 (100), 196 (56), 91 (68).
HRMS (EI): m/z calcd for C29H39N3 [M+ + H]: 430.3223; found:
430.3232.
1H NMR (300 MHz, CDCl3): d = 7.40–7.18 (m, 10 H), 6.86 (s, 1 H),
3.90 (d, 2 H, J = 13.9 Hz), 3.64 (t, 1 H, J = 7.3 Hz), 3.29 (d, 2 H,
J = 13.9 Hz), 2.72 (s, 3 H), 2.10–1.85 (m, 2 H), 1.45–1.12 (m, 13
H), 0.87 (t, 3 H, J = 7.1 Hz).
13C NMR (75 MHz, CDCl3): d = 176.9, 168.0, 166.7, 140.3, 128.8,
128.2, 126.8, 113.2, 65.8, 62.5, 54.1, 37.2, 29.5, 28.9, 26.5, 22.7,
14.0.
MS (70 eV, EI): m/z (%) = 416 (M+ + H, <1), 358 (3), 324 (10), 266
(7), 220 (50), 196 (39), 177 (100), 164 (5), 91 (26).
HRMS (EI): m/z calcd for C28H38N3 [M+ + H]: 416.3066; found:
Anal. Calcd for C29H39N3: C, 81.07; H, 9.15; N, 9.78. Found: C,
80.53; H, 9.08; N, 9.50.
N,N-Dibenzyl(cyclohexyl)[6-(2-furyl)-2-methyl-4-pyrimidi-
nyl]methanamine (6h)
Preparation according to GP 5 on a 1.0 mmol scale afforded, after
column chromatographic purification (SiO2, pentane–Et2O, 95:5),
( )-6h as a colorless solid (360 mg, 80%); mp 145–147 °C.
416.3096.
Anal. Calcd for C28H37N3: C, 80.92; H, 8.97; N, 10.11. Found: C,
81.06; H, 8.96; N, 10.08.
N,N-Dibenzyl-1-[6-(2-furyl)-2-methyl-4-pyrimidinyl]-1-pen-
tanamine (6k)
Preparation according to GP 5 on a 0.48 mmol scale afforded, after
column chromatographic purification (SiO2, pentane–Et2O, 9:1),
( )-6k as a yellow oil (183 mg, 90%).
IR (film): 2925s, 2850m, 1604vs, 1564vs, 1538m, 1486m, 1452m,
1398w, 744m, 698m cm–1.
1H NMR (300 MHz, CDCl3): d = 7.62 (dd, 1 H, J = 1.8, 0.9 Hz),
7.42 (d, 4 H, J = 7.5 Hz), 7.33 (t, 4 H, J = 7.5 Hz), 7.28–7.20 (m, 3
H), 7.04 (s, 1 H), 6.59 (dd, 1 H, J = 3.5, 1.8 Hz), 4.04 (d, 2 H,
J = 14.2 Hz), 3.38 (d, 1 H, J = 10.6 Hz), 3.11 (d, 2 H, J = 14.2 Hz),
2.80 (s, 3 H), 2.52 (d, 1 H, J = 11.9 Hz), 2.37–2.21 (m, 1 H), 1.85–
1.73 (m, 1 H), 1.69–1.47 (m, 2 H), 1.38–0.91 (m, 5 H), 0.74–0.58
(m, 1 H).
13C NMR (75 MHz, CDCl3): d = 168.0, 166.9, 154.6, 152.2, 144.8,
140.1, 128.8, 128.2, 126.8, 112.4, 112.3, 111.8, 68.3, 54.0, 36.7,
31.0, 30.3, 26.7, 26.6, 26.1, 26.0.
IR (film): 2956m, 2930m, 2858m, 1605vs, 1565vs, 1539s, 1487s,
1454m, 1398m, 1011m, 885w, 745s, 698s cm–1.
1H NMR (300 MHz, CDCl3): d = 7.62 (d, 1 H, J = 1.3 Hz), 7.39 (d,
4 H, J = 7.1 Hz), 7.32 (t, 4 H, J = 7.3 Hz), 7.27–7.19 (m, 4 H), 6.59
(dd, 1 H, J = 1.8, 0.9 Hz), 3.92 (d, 2 H, J = 14.2 Hz), 3.72 (t, 1 H,
J = 7.3 Hz), 3.37 (d, 2 H, J = 14.2 Hz), 2.78 (s, 3 H), 2.10–1.87 (m,
2 H), 1.49–1.14 (m, 4 H), 0.86 (t, 3 H, J = 7.1 Hz).
13C NMR (75 MHz, CDCl3): d = 169.1, 167.7, 154.9, 152.3, 144.7,
140.2, 128.8, 128.2, 126.8, 112.3, 111.6, 111.3, 62.5, 54.2, 29.3,
28.8, 26.4, 22.6, 14.0.
MS (70 eV, EI): m/z (%) = 452 (M+ + H, <1), 368 (11), 328 (3), 277
(3), 256 (100), 213 (24), 196 (10), 174 (10), 91 (35).
HRMS (EI): m/z calcd for C28H32N3O [M+ + H]: 452.2703; found:
MS (70 eV, EI): m/z (%) = 425 (M+, <1), 368 (2), 334 (4), 266 (3),
452.2689.
230 (52), 196 (5), 187 (100), 174 (9), 91 (57), 65 (5).
Anal. Calcd for C28H31N3O: C, 79.79; H, 7.37; N, 9.30. Found: C,
79.62; H, 7.53; N, 8.94.
HRMS (EI): m/z calcd for C28H31N3O [M+]: 425.2467; found:
425.2459.
Anal. Calcd for C28H31N3O: C, 79.02; H, 7.34; N, 9.87. Found: C,
79.01; H, 7.47; N, 9.88.
N,N-Dibenzyl-1-(2-methyl-6-phenyl-4-pyrimidinyl)-1-pentan-
amine (6i)
Preparation according to GP 5 on a 0.26 mmol scale afforded, after
column chromatographic purification (SiO2, pentane–Et2O, 95:5),
( )-6i as a colorless oil (101 mg, 89%).
N,N-Dibenzyl-1-(2,6-dimethyl-4-pyrimidinyl)-2-ethyl-1-butan-
amine (6l)
Preparation according to GP 5 on a 0.70 mmol scale afforded, after
column chromatographic purification (SiO2, pentane–Et2O, 4:1),
( )-6l as a bright yellow solid (214 mg, 79%); mp 96–97 °C.
IR (film): 3028m, 2956m, 2929m, 1574vs, 1539vs, 1495m, 1454m,
1395m, 1073m, 1028m, 768m, 746m, 698s cm–1.
1H NMR (300 MHz, CDCl3): d = 8.10–8.02 (m, 2 H), 7.56–7.46 (m,
3 H), 7.42–7.19 (m, 11 H), 3.93 (d, 2 H, J = 14.2 Hz), 3.75 (t, 1 H),
J = 7.3 Hz, 3.40 (d, 2 H, J = 14.2 Hz), 2.82 (s, 3 H), 2.12–1.91 (m,
2 H), 1.46–1.17 (m, 4 H), 0.87 (t, 3 H, J = 7.1 Hz).
13C NMR (75 MHz, CDCl3): d = 169.2, 167.8, 163.6, 140.2, 137.6,
130.5, 128.9, 128.8, 128.2, 127.2, 126.8, 113.6, 62.6, 54.2, 29.2,
28.9, 26.5, 22.7, 14.0.
MS (70 eV, EI): m/z (%) = 436 (M+ + H, 1), 378 (4), 344 (10), 287
(2), 266 (4), 240 (53), 197 (100), 184 (6), 91 (21).
HRMS (EI): m/z calcd for C30H34N3 [M+ + H]: 436.2753; found:
436.2716.
IR (film): 2962s, 2936m, 1581vs, 1546s, 1494m, 1454s, 1398m,
1360m, 1074w, 1029w, 750s, 736m, 699s cm–1.
1H NMR (600 MHz, CDCl3): d = 7.40 (d, 4 H, J = 6.0 Hz), 7.33 (t,
4 H, J = 6.0 Hz), 7.25 (d, 2 H, J = 6.0 Hz), 6.66 (s, 1 H), 4.00 (d, 2
H, J = 13.3 Hz), 3.44 (d, 1 H, J = 10.3 Hz), 3.03 (d, 2 H, J = 13.3
Hz), 2.77 (s, 3 H), 2.54 (s, 3 H), 2.35–2.26 (m, 1 H), 2.00–1.91 (m,
1 H), 1.70–1.59 (m, 1 H), 1.07–0.97 (m, 1 H), 0.95–0.85 (m, 1 H),
0.78 (t, 3 H, J = 4.7 Hz), 0.63 (t, 3 H, J = 4.7 Hz).
13C NMR (150 MHz, CDCl3): d = 167.3, 166.2, 165.7, 140.0, 128.9,
128.2, 126.8, 118.1, 64.7, 54.1, 38.3, 26.3, 24.2, 21.5, 19.8, 10.2,
9.3.
MS (70 eV, EI): m/z (%) = 388 (M+ + H, 1), 316 (35), 296 (15), 280
N,N-Dibenzyl-1-(6-tert-butyl-2-methyl-4-pyrimidinyl)-1-pen-
tanamine (6j)
Preparation according to GP 5 on a 0.30 mmol scale afforded, after
column chromatographic purification (SiO2, pentane–Et2O, 95:5),
( )-6j as a colorless oil (101 mg, 81%).
(2), 225 (9), 196 (34), 192 (28), 163 (100), 91 (49).
HRMS (EI): m/z calcd for C26H34N3 [M+ + H]: 388.2753; found:
388.2759.
N,N-Dibenzyl-2-ethyl-1-(2-phenyl-6-propyl-4-pyrimidinyl)-1-
butanamine (6m)
Preparation according to GP 5 on a 0.65 mmol scale afforded, after
column chromatographic purification (SiO2, pentane–Et2O, 98:2),
( )-6m as a colorless solid (241 mg, 79%); mp 66–68 °C.
IR (film): 3063m, 3028m, 2957vs, 2930s, 2860m, 1575vs, 1540vs,
1494m, 1454s, 1392s, 1362m, 1340m, 1232w, 1127w, 1073m,
1028m, 745s, 698vs cm–1.
Synthesis 2004, No. 12, 2015–2025 © Thieme Stuttgart · New York

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H. Dube et al.
PAPER
IR (film): 2963s, 2929m, 1588m, 1570vs, 1539vs, 1453m, 1377vs,
1028w, 745m, 695s cm–1.
MS (70 eV, EI): m/z (%) = 498 (M+ + H, 1), 406 (5), 302 (48), 259
(100), 246 (9), 196 (12), 91 (23).
1H NMR (600 MHz, CDCl3): d = 8.61–8.56 (m, 2 H), 7.55–7.48 (m,
3 H), 7.42 (d, 4 H, J = 7.3 Hz), 7.34 (t, 4 H, J = 7.3 Hz), 7.25 (t, 2
H, J = 7.3 Hz), 6.70 (s, 1 H), 4.12 (d, 2 H, J = 14.1 Hz), 3.53 (d, 1
H, J = 11.1 Hz), 3.12 (d, 2 H, J = 14.1 Hz), 2.84 (t, 2 H, J = 7.7 Hz),
2.48–2.38 (m, 1 H), 2.06–1.97 (m, 1 H), 1.96–1.85 (m, 2 H), 1.74–
1.62 (m, 1 H), 1.07 (t, 3 H, J = 7.4 Hz), 1.11–0.8 (m, 2 H), 0.82 (t,
3 H, J = 7.4 Hz), 0.62 (t, 3 H, J = 7.4 Hz).
13C NMR (150 MHz, CDCl3): d = 170.0, 166.2, 163.7, 140.1, 138.5,
130.3, 129.0, 128.4, 128.3, 128.2, 126.8, 118.8, 64.9, 54.4, 40.0,
38.7, 22.2, 21.6, 20.0, 13.9, 10.2, 9.6.
HRMS (EI): m/z calcd for C35H36N3 [M+ + H]: 498.2910; found:
498.2884.
Anal. Calcd for C35H35N3: C, 84.47; H, 7.09; N, 8.44. Found: C,
84.17; H, 7.02; N, 8.28.
N,N-Dibenzyl-1-[6-(2-furyl)-2-phenyl-4-pyrimidinyl]-1-pentan-
amine (6p)
Preparation according to GP 5 on a 0.87 mmol scale afforded, after
column chromatographic purification (SiO2, pentane–Et2O, 98:2),
( )-6p as a colorless oil (413 mg, 98%).
MS (70 eV, EI): m/z (%) = 476 (M+ – H, <1), 406 (20), 386 (12),
315 (5), 299 (5), 282 (30), 253 (100), 224 (4), 196 (13), 104 (5), 91
(53).
IR (film): 3063w, 3028w, 2955m, 2930m, 1604vs, 1558vs, 1534vs,
1486s, 1454m, 1386s, 1368s, 1073w, 1028m, 1008m, 747vs, 699vs
cm–1.
HRMS (EI): m/z calcd for C33H38N3 [M+ – H]: 476.3065; found:
476.3060.
1H NMR (300 MHz, CDCl3): d = 8.49–8.57 (m, 2 H), 7.58–7.12 (m,
16 H), 6.54 (dd, 1 H, J = 3.4, 1.7 Hz), 3.92 (d, 2 H, J = 14.0 Hz),
3.74 (t, 1 H, J = 7.3 Hz), 3.34 (d, 2 H, J = 14.0 Hz), 2.06–1.95 (m,
2 H), 1.42–1.14 (m, 4 H), 0.79 (t, 3 H, J = 7.1 Hz).
13C NMR (75 MHz, CDCl3): d = 169.3, 163.8, 155.3, 152.7, 144.7,
140.3, 138.1, 130.5, 128.9, 128.4, 128.3, 128.2, 126.8, 112.4, 112.1,
111.9, 62.4, 54.3, 29.4, 28.9, 22.7, 14.0.
Anal. Calcd for C33H39N3: C, 82.97; H, 8.23; N, 8.80. Found: C,
83.19; H, 8.37; N, 8.68.
N,N-Dibenzyl-1-(6-cyclohexyl-2-phenyl-4-pyrimidinyl)-2-ethyl-
1-butanamine (6n)
Preparation according to GP 5 on a 0.83 mmol scale afforded, after
column chromatographic purification (SiO2, pentane–Et2O, 98:2),
( )-6n as a colorless solid (322 mg, 75%); mp 118–119 °C.
MS (70 eV, EI): m/z (%) = 488 (M+ + H, <1), 430 (2), 396 (5), 339
(2), 292 (50), 249 (100), 236 (13), 196 (11), 91 (42).
HRMS (EI): m/z calcd for C33H34N3O [M+ + H]: 488.2703; found:
488.2747.
IR (film): 2962m, 2928s, 2852m, 1588m, 1569s, 1538vs, 1451m,
1380s, 1028w, 745w, 698vs cm–1.
Anal. Calcd for C33H33N3O: C, 81.28; H, 6.82; N, 8.62. Found: C,
80.87; H, 6.89; N, 8.42.
1H NMR (600 MHz, CDCl3): d = 8.61 (d, 2 H, J = 6.5 Hz), 7.55–
7.46 (m, 3 H), 7.43 (d, 4 H, J = 7.3 Hz), 7.35 (t, 4 H, J = 7.3 Hz),
7.26 (t, 2 H, J = 7.3 Hz), 6.69 (s, 1 H), 4.12 (d, 2 H, J = 14.0 Hz),
3.52 (d, 1 H, J = 10.7 Hz), 3.11 (d, 2 H, J = 14.0 Hz), 2.77 (tt, 1 H,
J = 11.8, 3.4 Hz), 2.47–2.40 (m, 1 H), 2.13–1.89 (m, 5 H), 1.82 (d,
1 H, J = 12.9 Hz), 1.74–1.58 (m, 3 H), 1.56–1.45 (m, 2 H), 1.40–
1.31 (m, 1 H), 1.10–1.01 (m, 1 H), 0.99–0.91 (m, 1 H), 0.83 (t, 3 H,
J = 7.3 Hz), 0.63 (t, 3 H, J = 7.3 Hz).
1-(6-Cyclohexyl-2-phenyl-4-pyrimidinyl)-2-ethyl-1-butan-
amine (10)
In a 10 mL flask, the dibenzyl protected amine 6p (246 mg, 0.48
mmol) was dissolved in MeOH (3 mL) and CH2Cl2 (2 mL), and
10% Pd/C (120 mg) was added. After stirring for 2 d under H2 at-
mosphere (1 bar), the reaction was complete according to TLC anal-
ysis. Pd/C was filtered through Celite and washed with Et2O. The
solvents were evaporated and the crude product was purified by col-
umn chromatography (SiO2, CH2Cl2–MeOH, 9: 1) affording 10a as
a yellow oil (155 mg, 95%).
13C NMR (150 MHz, CDCl3): d = 166.2, 163.4, 140.2, 138.6, 130.3,
129.0, 128.4, 128.3, 128.2, 126.8, 117.1, 109.3, 64.9, 54.3, 46.0,
38.6, 32.4, 32.1, 26.4, 26.3, 26.1, 21.6, 20.0, 10.2, 9.5.
MS (70 eV, EI): m/z (%) = 518 (M+ + H, <1), 446 (29), 426 (16),
355 (6), 322 (20), 293 (100), 265 (2), 196 (6), 91 (19).
HRMS (EI): m/z calcd for C36H44N3 [M+ + H]: 518.3536; found:
518.3528.
IR (film): 2961m, 2929vs, 2854m, 1590s, 1571s, 1540vs, 1450m,
1379s, 1028w, 864w, 767w, 697s cm–1.
1H NMR (600 MHz, CDCl3): d = 8.53–8.48 (m, 2 H), 7.49–7.43 (m,
3 H), 6.98 (s, 1 H), 3.96 (d, 1 H, J = 5.5 Hz), 2.70 (tt, 1 H, J = 11.9,
3.5 Hz), 2.04–1.24 (m, 17 H), 0.93 (t, 3 H, J = 7.5 Hz), 0.85 (t, 3 H
J = 7.5 Hz).
Anal. Calcd for C36H43N3: C, 83.51; H, 8.37; N, 8.12. Found: C,
83.10; H, 8.33; N, 7.92.
N,N-Dibenzyl-1-(2,6-diphenyl-4-pyrimidinyl)-1-pentanamine
(6o)
Preparation according to GP 5 on a 0.78 mmol scale afforded, after
column chromatographic purification (SiO2, pentane–Et2O, 98:2),
( )-6o as a bright yellow oil (348 mg, 90%).
13C NMR (150 MHz, CDCl3): d = 174.5, 172.6, 163.4, 138.4, 130.2,
128.3, 128.3, 114.0, 57.9, 47.3, 46.1, 32.2, 32.1, 26.3, 26.0, 22.7,
21.0, 11.7, 11.5.
MS (70 eV, EI): m/z (%) = 335 (M+ – 2 H, 1), 266 (100), 252 (1),
211 (4), 157 (1), 104 (3), 80 (1), 41 (1).
IR (film): 3062m, 3028m, 2927m, 1590m, 1568s, 1533s, 1494m,
1453m, 1376m, 1027w, 746w, 691s cm–1.
1H NMR (300 MHz, CDCl3): d = 8.73–8.65 (m, 2 H), 8.29–8.21 (m,
2 H), 7.62–7.49 (m, 6 H), 7.47–7.21 (m, 11 H), 4.04 (d, J = 13.9 Hz,
2 H), 3.86 (t, J = 7.1 Hz, 1 H), 3.47 (d, 2 H, J = 13.9 Hz), 2.20–2.09
(m, 2 H), 1.57–1.25 (m, 4 H), 0.90 (t, 3 H, J = 7.1 Hz).
13C NMR (75 MHz, CDCl3): d = 169.4, 163.9, 163.5, 140.3, 138.3,
137.5, 130.7, 130.7, 128.9, 128.8, 128.5, 128.4, 128.3, 127.2, 126.9,
114.3, 62.5, 54.3, 29.3, 29.0, 22.8, 14.1.
HRMS (EI): m/z calcd for C22H29N3 [M+ – 2 H]: 335.2360; found:
335.2361.
Acknowledgment
We thank the Fonds der Chemischen Industrie, the DFG (SPP 1118
‘Sekundäre Wechselwirkungen als Steuerungsprinzip zur gerichte-
ten Funktionalisierung reaktionsträger Substrate’) for a fellowship
for N. G. We thank the Chemetall GmbH (Frankfurt), Degussa AG
(Frankfurt), BASF AG (Ludwigshafen) and Wacker AG (Munich)
for the generous gift of chemicals.
Synthesis 2004, No. 12, 2015–2025 © Thieme Stuttgart · New York

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Synthesis of Chiral a-Aminoalkylpyrimidines
2025
(4) (a) Valk, J. M.; Whitlock, G. A.; Layzell, T. P.; Brown, J. M.
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Synthesis 2004, No. 12, 2015–2025 © Thieme Stuttgart · New York