The direct synthesis of unsymmetrical vicinal diamines from terminal alkynes: A tandem sequential approach for the synthesis of imidazolidinones

Article abstract of DOI:10.1055/s-0028-1083279

The combination of titanium-catalyzed anti-Markovni- kov hydroamination of terminal alkynes with the Strecker reaction is used in the synthesis of unsymmetrical vicinal diamines via the one-pot synthesis of α-cyanoamines. This methodology is further applied to the efficient synthesis of imidazolidinones. An easy-to-use bis(amidate)titanium precatalyst permits efficient approaches to heterocyclic chemistry from terminal alkynes. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083279

PAPER
97
The Direct Synthesis of Unsymmetrical Vicinal Diamines from Terminal
Alkynes: A Tandem Sequential Approach for the Synthesis of
Imidazolidinones
T
andem
S
equentia
l
l
Appro
i
ach
f
o
s
r
the
S
ynth
o
esis of Imid
n
a
zolidinones V. Lee,a Melanie Sajitz,b Laurel L. Schafer*a
a
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada
E-mail: Schafer@chem.ubc.ca
Organisch-Chemisches Institut, Wesfälische Wilhelms-Universität, Corrensstr. 40, 48149 Münster, Germany
b
Received 23 October 2008
O
N
Abstract: The combination of titanium-catalyzed anti-Markovni-
kov hydroamination of terminal alkynes with the Strecker reaction
is used in the synthesis of unsymmetrical vicinal diamines via the
one-pot synthesis of a-cyanoamines. This methodology is further
applied to the efficient synthesis of imidazolidinones. An easy-to-
use bis(amidate)titanium precatalyst permits efficient approaches to
heterocyclic chemistry from terminal alkynes.
Ti(NEt2)2
Ph
2
1
Key words: hydroamination, titanium, amines, heterocycles, tan-
dem reactions
Figure 1
Furthermore, complex 1 (Figure 1) is very tolerant of
many different functional groups, such as protected alco-
hols and amines, esters, and amides.15 This functional-
group tolerance and high regioselectivity, combined with
the fact that there are no byproducts formed during the hy-
droamination reaction results in the facile synthesis of a
wide variety of aldimines that do not require isolation or
purification before use in further synthetic steps.
The synthesis of functionalized nitrogen-containing mol-
ecules is of ongoing interest in organic chemistry, as these
molecules have found widespread applications in areas
such as pharmaceuticals,1–3 detergents, and dyes.4–7 Fur-
thermore, the development of new methodologies to syn-
thesize nitrogen-containing molecules from alternative
starting materials is of great importance, as this allows the The Strecker reaction uses imines as intermediates in the
chemist enhanced flexibility in synthetic design. Unsym- synthesis of a-cyanoamines and a-amino acid derivatives.
metrically substituted vicinal diamines belong to an im- Typically the imines are derived from aldehydes and are
portant class of nitrogen-containing molecules8–13 whose isolated and purified before use. Because the aldimine
synthesis is particularly challenging.12,14,15 Herein we functionality is easily hydrolyzed, this isolation step can
describe a tandem C–N- and C–C-bond-forming reaction lead to reduced substrate scope and low yields, especially
sequence resulting from the one-pot combination of cata- for alkylimines. However, catalytic hydroamination gen-
lytic hydroamination and the Strecker reaction and its ap- erates a broad range of aldimines quantitatively, with
plications in the efficient synthesis of unsymmetrical 100% atom economy, and do not require isolation. There-
vicinal diamines directly from terminal alkynes.
fore, the combination of catalytic hydroamination with the
Strecker reaction leads to the one-pot synthesis of a-cy-
anoamines from terminal alkynes (Scheme 1).68 The good
functional-group tolerance of hydroamination precatalyst
1 results in the potential incorporation of different func-
tionalities into the final a-cyanoamine products. Further-
more, these a-cyanoamines have the potential to be used
as intermediates in the synthesis of other important classes
of organic molecules, including a-amino acid derivatives
and b-amino alcohols.
Hydroamination is the addition of nitrogen and hydrogen
atoms across a carbon–carbon multiple bond that can be
efficiently mediated by a range of metal-based cata-
lysts.16–65 In the hydroamination of terminal alkynes
(Equation 1), we have reported bis(amidate)bis(amido)ti-
tanium precatalyst 1 (Figure 1) as an active and very
regioselective catalytic complex for the formation of the
anti-Markovnikov imine in the catalytic hydroamination
of terminal alkynes with primary amines.66,67
In particular, this contribution demonstrates that the a-cy-
anoamines formed through the tandem sequential reaction
using terminal alkyne substrates would be ideal precur-
sors in the synthesis of unsymmetrical vicinal diamines
(Scheme 1). Along with an unsymmetrical substitution
pattern, diamines formed through this route would contain
both a primary and a secondary amine in the same mole-
cule. Furthermore, these diamines can be used as precur-
sors for heterocycles such as piperazines,69 N,N¢-
substituted carbenes,70 imidazolidines,71 and imidazolidi-
nones.
R1
H
NR2
NR2
precatalyst 1
R1
+
+
H
R1
H2NR2
anti-Markovnikov
> 98% conversion
Markovnikov
not observed
Equation 1
SYNTHESIS 2009, No. 1, pp 0097–0104
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1083279; Art ID: C05108SS
© Georg Thieme Verlag Stuttgart · New York
0
2
.
0
1
.2
0
0
9

98
A. V. Lee et al.
PAPER
R1
H
H
H
2) TMSCN, r.t., 3 h
1 (5 mol%), C6H6
R1
N
R1
R2
+
3) sat. NH4Cl, r.t., 15 min
NR2
65 °C, 12 h
H2NR2
CN
2
O
NHR2
4) LiAlH4, Et2O, r.t., 12 h
5) oxalic acid, acetone
OH
R1
NH2
•
HO
O
3
Scheme 1
The combination of a terminal alkyne, a primary amine, various functional groups, have been synthesized by this
and precatalyst 1 (5 mol%) in benzene at 65 °C leads to tandem sequential reaction (Table 1).
the exclusive formation of the anti-Markovnikov imine in
quantitative conversion. Trimethylsilyl cyanide is then
All the a-cyanoamines are formed quantitatively from the
terminal alkyne starting material (Scheme 1, Table 1).
added to the reaction mixture via syringe at room temper-
While the purification of these molecules is not trivial,3
ature, and the resultant TMS-protected a-cyanoamines are
spectroscopic experiments show that only the amide pro-
ligand (resulting from the decomposition of 1 upon work-
up) is present in the crude reaction mixture. Because
quenched with saturated ammonium chloride to form the
a-cyanoamine products 2 in one pot (Scheme 1). A range
of alkyl-substituted a-cyanoamines 2a–m, incorporating
Table 1 Quantitative Formation of a-Cyanoamines 2a–i Synthesized Directly from Terminal Alkynes and Primary Aminesa
Entry
R1 (from alkyne)
R2 (from amine)
a-Cyanoamineb 2
HN
1
Bu
Allyl
2a
2b
CN
CN
HN
2
3
Bn
Ph
Allyl
H
N
2c
Allyl
Bn
CN
H
N
Ph
4
5
cyclohex-1-enyl
(CH2)3OTBDMS
2d
2e
CN
HN
Ph
Ph
Bn
TBDMSO
HN
CN
6
Bn
Bn
2f
CN
H
N
7
8
cyclohex-1-enyl
(CH2)3OTBDMS
i-Pr
i-Pr
2g
2h
CN
HN
TBDMSO
CN
9
Bu
i-Pr
2i
HN
CN
a See Scheme 1.
b All unpurified a-cyanoamines were characterized in the presence of the amide proligand.
Synthesis 2009, No. 1, 97–104 © Thieme Stuttgart · New York

PAPER
Tandem Sequential Approach for the Synthesis of Imidazolidinones
99
a-cyanoamines are used as intermediates in the formation undergo deprotection to give the amine. While these
of other functionalized small molecules, it is critical that straightforward compounds may be anticipated to have
the amide proligand does not interfere with further reac- been previously reported, it should be noted that six of the
tivity,68 and thus purification at this stage is unnecessary. eight diamines presented in Table 2 (exceptions being 3d
Allylamine can be used successfully as a substrate in this and 3e) are new compounds, and, as such, their full char-
reaction (Table 1, entries 1–3). Allylamine can be used as acterization data are included in the experimental section.
a protecting group for a primary amine and has an addi-
As mentioned earlier, diamines are useful starting materi-
tional functionality available for further reactions. It
als for the synthesis of various heterocycles including im-
should also be noted that, to the best of our knowledge, 1
idazolidinones. The imidazolidinone functionality has
been investigated in a number of compounds for pharma-
is the only reported group 4 hydroamination precatalyst
that can be used with the allylamine substrate. Benzyl-
ceutical applications.72–76 Furthermore, imidazolidinones
amine can also be used in this sequence with alkynes that
have been used as both ligands77 and chiral auxiliaries.78
contain alkyl or aryl groups, as well as protected alcohols
Here, the synthesis of three novel imidazolidinones 4a–c
from the corresponding diamines 3 is presented
(Equation 2, Table 3). This is accomplished with the reac-
tion of the appropriate diamine oxalates 3 with a base to
obtain the free diamines, followed by reaction with N,N-
carbonyldiimidazole (CDI) in refluxing tetrahydrofuran
(Equation 2). This leads to the formation of the corre-
(Table 1, entries 4–6). Benzylamine is an important sub-
strate, as the amine can be deprotected at a later step to
give the primary amine. Finally, more steric bulk can also
be incorporated into the amine substrate (see Table 1, en-
tries 7–9) along with alkynes possessing various function-
al groups.
The synthesis of unsymmetrical vicinal diamines 3a–h is sponding imidazolidinones 4 in high yields after column
accomplished through the reduction of the corresponding chromatography (Table 3).
a-cyanoamines 2 with lithium aluminum hydride
R2
(Scheme 1, Table 2). Following reduction, the free di-
amines obtained are susceptible to decomposition, and
consequently these highly functionalized compounds are
separated from the proligand by acid–base extraction and
subsequent precipitation of their corresponding oxalate
salts (Scheme 1). These materials may be stored indefi-
nitely. Representative examples of unsymmetrical di-
amines 3 that have been synthesized from terminal
alkynes by this methodology in good isolated yields over
five synthetic steps are shown in Table 2.
O
O
NHR2
1) sat. NaHCO3
N
OH
•
R1
NH2
NH
HO
2) CDI, THF,
reflux, 12 h
R1
O
3
4
Equation 2
The synthesis of these molecules is very efficient and no-
tably requires only one purification step by column chro-
matography. The intermediate compounds, namely the a-
cyanoamines 2 and the vicinal diamines 3, can both be
used without purification towards the synthesis of the im-
idazolidinones 4. Furthermore, while both the vicinal di-
amines 3 and the imidazolidinones 4 are synthesized in a
The synthesized diamines 3a–h (Table 2) contain various
functionalities in the backbone including long alkyl
chains, aryl substituents, and cyclic alkyl substituents.
The nitrogen substituents include the bulky isopropyl
group, a benzyl functionality that can be removed, and an
allyl group that could lead to further functionalization or
Table 2 Diamines 3 Synthesized by a Tandem Reaction Sequence
Entry
Diamine product
R2
3
Yielda (%)
1
2
Bn
i-Pr
3a
3b
65
69
O
NHR2
OH
•
NH2
HO
O
O
3
3c
59
Allyl
Bn
4
5
3d
3e
55
54
NHR2
NH2
i-Pr
OH
•
HO
6
7
3f
60
56
O
Allyl
Bn
3g
O
NHR2
NH2
OH
•
HO
8
3h
50
Allyl
O
a Overall isolated yield calculated from terminal alkyne.
Synthesis 2009, No. 1, 97–104 © Thieme Stuttgart · New York

100
A. V. Lee et al.
PAPER
NMR facility on a Bruker Avance 300 spectrometer [300 MHz (1H)
and 75 MHz (13C)], a Bruker Avance 400 spectrometer [400 MHz
(1H) and 100 MHz (13C)] or a Bruker Avance 600 spectrometer [600
MHz (1H) and 150 MHz (13C)], and chemical shifts are given rela-
tive to residual solvent. IR spectra were recorded on a Nicolet 4700
FT-IR spectrophotometer in transmission mode as KBr discs be-
tween 400 and 4000 cm–1 at a resolution of 4 cm–1. LR-MS were
obtained using ESI-MS and APCI-MS (atmospheric pressure chem-
ical ionization mass spectrometry) in the UBC Chemistry Mass
Spectrometry facility on the open-access MS. EI-MS, HRMS, and
elemental analysis were performed by the UBC Chemistry Mass
Spectrometry facility. Plates used for TLC (0.2-mm silica gel 60
F254 on alumina) and silica gel used for column chromatography
(70–230 and 230–400 mesh) were purchased from Silicycle
(Montreal, QC, Canada). TLC spots were visualized under a UVG-
54 Mineralight® short-wave UV lamp (l = 254 nm). The following
compounds were synthesized according to literature procedures: N-
(2,6-diisopropylphenyl)benzamide,66 bis[N-(2,6-diisopropylphe-
nyl)benzamidato]bis(diethylamido)titanium (1),66 3-phenylprop-1-
yne,83 and 1-(tert-butyldimethylsiloxy)pent-4-yne.84
Table 3 Imidazolidinones 4 Synthesized from Diamines 3
Entry
1
Imidazolidinone
4
Yielda (%)
82 (53)b
Ph
N
4a
O
N
H
Ph
N
2
4
4b
4c
75 (41)b
85 (48)b
O
O
N
H
Ph
N
N
H
a-Cyanoamines 2; General Procedure
a Isolated yield of 4 from diamine 3, after column chromatography.
b Overall yield of 4 calculated from the corresponding terminal
alkyne.
An oven-dried 110-mL Schlenk tube was brought into the glovebox
and charged with alkyne (1.7 mmol), primary amine (3.4 mmol), 1
(0.06 g, 0.09 mmol), and benzene (2 mL). The Schlenk flask was
sealed with a greased glass stopper and sidearm stopcock, and re-
moved from the glovebox. The soln was stirred at 65 °C for 12 h be-
fore it was cooled to r.t. The soln was then frozen using liquid N2,
and the headspace of the flask was evacuated under vacuum. The
flask was warmed to r.t., and then taped with electrical tape before
racemic fashion here, there are established methodologies
for their resolution through diastereomer formation.79–82
In conclusion, we have described a tandem C–N- and C–
C-bond-forming reaction sequence that uses a titanium- it was brought back into the glovebox where TMSCN (0.23 mL, 1.7
mmol) was added by syringe. The flask was again sealed and re-
catalyzed anti-Markovnikov hydroamination as a key step
moved from the glovebox, and then stirred for 3 h within a fume
for generating imines in situ for application in the Strecker
hood. The soln was then opened to the atmosphere, diluted with
reaction. This methodology has been used to synthesize a
CH2Cl2 (20 mL), and quenched with sat. NH4Cl (20 mL). The or-
number of important classes of organic molecules such as
ganic layer was separated and the aqueous layer was extracted with
a-cyanoamines, unsymmetrical vicinal diamines, and im-
idazolidinones from terminal alkynes. In particular, the
atom-economical, catalytic formation of the aldimines,
along with the one-pot formation of a-cyanoamines repre-
sent an efficient methodology that is environmentally
friendly by reducing solvent volumes typically required
for multiple isolation and purification steps. Ongoing ef-
forts focus on asymmetric versions of this reaction to pre-
pare enantiomerically enriched unsymmetrical vicinal
diamines as important compounds in heterocycle synthe-
sis.
CH2Cl2 (2 × 20 mL). The combined organic layers were washed
with brine (1 × 20 mL), dried (MgSO4), filtered, and concentrated
under reduced pressure to give the a-cyanoamine 2 as a pale yellow
oily compound. All characterizations of the crude products were
performed in the presence of the amide proligand from the hy-
droamination precatalyst, which was present in the samples as 9–
13% of the reaction mixture. The signals in the NMR spectra from
the proligand66 are not listed. All crude products were isolated in
quantitative yield.
2-(Allylamino)heptanenitrile (2a)
3
1H NMR (400 MHz, CDCl3): d = 0.91 (t, J = 6.8 Hz, 3 H, CH3),
1.32–1.42 [m, 4 H, (CH2)2], 1.50–1.52 (m, 2 H, CH2), 1.70–1.77 (m,
2 H, CH2), 3.30–3.32 (m, 1 H, NCH2), 3.50–3.56 (m, 3 H, NCH2,
3
2
Except where otherwise noted, all reactions and manipulations were
carried out at r.t. without precautions to exclude atmospheric mois-
ture. All solvents for workup procedures were used as received from
Aldrich or Sigma. Anhydrous benzene and Et2O were purified on an
alumina column and stored under a N2 atmosphere. Ti(NMe2)4 was
purchased and used as received. Hex-1-yne, phenylacetylene, and
1-ethynylcyclohexene were purchased from Aldrich. All alkynes
were dried over 4 Å MS for 12 h before they were distilled, and de-
gassed. The alkynes were then transferred into a N2-filled glovebox
and further dried over 4 Å MS for an additional 12 h before use. All
primary amines were purchased from Aldrich and dried over CaH2
for 12 h before they were distilled and degassed. The amines were
then stored in the N2-filled glovebox and further dried over 4 Å MS
for an additional 12 h before use. All other chemicals were reagent
grade and used as received from commercial suppliers. All NMR
spectra were acquired from samples in deuterated solvents (pur-
chased from Cambridge Isotope Labs) at r.t. in the UBC Chemistry
NCH), 5.17 (d, J = 10 Hz, J = 0.6 Hz, 1 H, HCCH2), 5.28 (d,
3J = 17 Hz, 2J = 1.4 Hz, 1 H, NCCH2), 5.82–5.89 (m, 1 H, HCCH2).
13C NMR (100 MHz, CDCl3): d = 15.4, 22.5, 25.4, 31.3, 33.6, 49.9,
50.3, 117.6, 120.4, 135.2.
MS (CI): m/z (%) = 167.3 (100) [M + H].
HRMS (CI): m/z [M + H]+ calcd for C10H19N2: 167.1548; found:
167.1542.
2-(Allylamino)-4-phenylbutanenitrile (2b)
1H NMR (400 MHz, CDCl3): d = 1.46 (br s, 1 H, NH), 2.07–2.17
(m, 2 H, CH2), 2.79–2.93 (m, 2 H, CH2), 3.25–3.31 (m, 1 H, NCH2),
3.48–3.55 (m, 2 H, NCH2, NCH), 5.16 (d, 3J = 10 Hz, 1 H, HCCH2),
3
5.27 (d, J = 16 Hz, 1 H, HCCH2), 5.81–5.91 (m, 1 H, HCCH2),
7.08–7.37 (m, 5 H, Ar H).
13C NMR (100 MHz, CDCl3): d = 31.8, 35.1, 49.1, 50.2, 117.5,
120.2, 126.5, 128.5, 128.7, 135.0, 140.0.
Synthesis 2009, No. 1, 97–104 © Thieme Stuttgart · New York

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Tandem Sequential Approach for the Synthesis of Imidazolidinones
101
MS (CI): m/z (%) = 201.3 (100) [M + H], 174.3 (100) [M – CN].
HRMS (EI): m/z [M]+ calcd for C12H20N2: 192.16265; found:
192.16277.
HRMS (CI): m/z [M + H]+ calcd for C13H17N2: 201.1392; found:
201.1388.
6-(tert-Butyldimethylsiloxy)-2-(isopropylamino)hexanenitrile
(2h)
2-(Allylamino)-3-phenylpropanenitrile (2c)
1H NMR (400 MHz, CDCl3): d = 0.05 [s, 6 H, Si(CH3)2], 0.90 [s, 9
H, SiC(CH3)3], 1.03 [d, 3J = 6.0 Hz, 3 H, CH(CH3)2], 1.12 [d,
3J = 6.4 Hz, 3 H, CH(CH3)2], 1.52–1.56 [m, 4 H, (CH2)2], 1.76–1.80
1H NMR (400 MHz, CDCl3): d = 1.63 (br s, 1 H, NH), 3.00–3.20
(m, 2 H, PhCH2), 3.29 (dd, 2J = 12 Hz, 3J = 6.4 Hz, 1 H, NHCH2),
3.52 (dd, 2J = 13 Hz, 3J = 5 Hz, 1 H, NHCH2), 3.80 (t, 3J = 6.6 Hz,
3
(m, 2 H, CH2), 3.10 [sept, J = 6.0 Hz, 1 H, CH(CH3)2], 3.56 (t,
3
2
1 H, PhCH2CH), 5.17 (d, J = 10 Hz, J = 0.8 Hz, 1 H, HCCH2),
5.26 (d, 3J = 16 Hz, 2J = 1.2 Hz, 1 H, HCCH2), 5.78–5.88 (m, 1 H,
HCCH2), 7.20–7.42 (m, 5 H, Ar H).
13C NMR (100 MHz, CDCl3): d = 39.6, 50.3, 51.0, 117.8, 119.7,
127.7, 128.9, 129.7, 135.0, 146.6.
3J = 6.8 Hz, 1 H, CH), 3.61–3.65 (m, 2 H, OCH2).
13C NMR (100 MHz, CDCl3): d = –5.1, 18.5, 21.5, 22.3, 23.8, 25.8,
32.3, 34.0, 47.1, 48.3, 62.8, 120.7.
MS (CI): m/z (%) = 285.3 (70) [M + H], 258.4 (100) [M – CN].
MS (CI): m/z (%) = 187.3 (100) [M + H].
HRMS (EI): m/z [M]+ calcd for C15H32N2OSi: 284.22839; found:
284.22825.
HRMS (EI): m/z [M]+ calcd for C12H14N2: 186.11570; found:
186.11579.
2-(Isopropylamino)heptanenitrile (2i)
1H NMR (300 MHz, benzene-d6): d = 0.62 (br s, 1 H, NH), 0.77–
0.83 [m, 9 H, CH(CH3)2, CH3], 1.02–1.30 [m, 8 H, (CH2)4], 2.91
[sept, 3J = 6.2 Hz, 1 H, CH(CH3)2], 3.09 (t, 3J = 6.0 Hz, 1 H, CH).
2-(Benzylamino)-3-cyclohex-1-enylpropanenitrile (2d)
1H NMR (400 MHz, CDCl3): d = 1.53–1.63 [m, 4 H, (CH2)2], 1.83–
2.03 [m, 4 H, (CH2)2], 2.51–2.54 (m, 2 H, CH2), 3.60 (t, 3J = 7.2 Hz,
1 H, CH), 3.82 (d, 2J = 13 Hz, 1 H, NCH2Ph), 4.09 (d, 2J = 13 Hz, 1
H, NCH2Ph), 5.60–5.62 (m, 1 H, CH), 7.22–7.59 (m, 5 H, Ar H).
13C NMR (75 MHz, benzene-d6): d = 14.1, 21.4, 22.7, 23.7, 25.6,
31.5, 34.2, 46.9, 48.1, 120.5.
13C NMR (100 MHz, CDCl3): d = 22.2, 22.9, 25.4, 28.4, 42.0, 43.4,
51.7, 120.4, 126.8, 127.7, 128.2, 129.0, 131.9, 138.6.
ESI-MS: m/z (%) = 169.2 (100) [M + H], 142.3 (90) [M – CN].
ESI-HRMS: m/z [M + H]+ calcd for C10H21N2: 169.1705; found:
MS (CI): m/z (%) = 241.4 (70) [M + H], 214.4 (40) [M – CN].
169.1701.
HRMS (EI): m/z [M]+ calcd for C16H20N2: 240.16265; found:
240.16152.
Diamines 3; General Procedure
An oven-dried 110-mL Schlenk flask was charged with alkyne (4.9
mmol), primary amine (5.4 mmol), precatalyst 1 (0.18 g, 0.24
mmol), and benzene (6 mL). The Schlenk flask was sealed with a
greased glass stopper and sidearm stopcock, and removed from the
glovebox. The soln was stirred at 65 °C for 12 h before it was cooled
to r.t. The soln was then frozen using liquid N2, and the headspace
of the flask was evacuated under vacuum. The flask was warmed to
r.t., and taped with electrical tape before being brought back into the
glovebox where TMSCN (0.65 mL, 4.9 mmol) was added by sy-
ringe. After the mixture had stirred for an additional 3 h, it was di-
luted with CH2Cl2 (30 mL), quenched with sat. NH4Cl (30 mL),
extracted with CH2Cl2 (3 × 30 mL), washed with brine (1 × 30 mL),
dried (MgSO4), filtered, and concentrated under reduced pressure to
give the a-cyanoamine 2.
2-(Benzylamino)-6-(tert-butyldimethylsiloxy)hexanenitrile (2e)
1H NMR (400 MHz, CDCl3): d = 0.06 [s, 6 H, Si(CH3)2], 0.91 [s, 9
H, SiC(CH3)3], 1.49–1.60 [m, 4 H, (CH2)2], 1.78–1.83 (m, 2 H,
3
3
CH2), 3.51 (t, J = 6.8 Hz, 1 H, CH), 3.62 (t, J = 5.6 Hz, 2 H,
2
2
OCH2), 3.84 (d, J = 13 Hz, 1 H, NCH2Ph), 4.08 (d, J = 13 Hz, 1
H, NCH2Ph), 7.24–7.36 (m, 5 H, Ar H).
13C NMR (100 MHz, CDCl3): d = –5.2, 18.5, 22.4, 26.1, 32.3, 33.5,
50.0, 51.8, 62.8, 120.4, 127.7, 128.5, 128.7, 138.6.
MS (CI): m/z (%) = 333.3 (100) [M + H].
HRMS (EI): m/z [M]+ calcd for C19H32N2OSi: 332.22839; found:
332.22828.
Anhyd Et2O (10 mL) was added to the a-cyanoamine and the soln
was transferred to an oven-dried round-bottom flask that was
charged with a Teflon-coated stirrer bar, and covered with a N2 at-
mosphere. LAH (0.37 g, 9.8 mmol) was added to the soln in small
portions over 20 min. The slurry was stirred at r.t. for 12 h. Subse-
quently, H2O (0.37 mL) was added slowly to the soln, followed by
1 M NaOH (0.37 mL), and a further portion of H2O (1.11 mL). The
soln was stirred until a white precipitate had formed and there was
no gray solid left in the reaction flask. It was then filtered into a sep-
aratory funnel and the white solid was washed with Et2O (20 mL).
The organic layer was extracted with 1 M HCl (3 × 30 mL). The
combined aqueous layers were washed with CH2Cl2 (2 × 90 mL)
and hexanes (1 × 90 mL). Then 5 M aq NaOH was added to the
acidic aqueous layer until it was basic, as indicated by pH paper.
The aqueous layer was extracted with CH2Cl2 (3 × 100 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure. The re-
sultant oil was dissolved in a minimum amount of acetone and
transferred to a small round-bottom flask. A soln of oxalic acid
(0.44 g, 4.9 mmol) was prepared in a minimal amount of acetone
and added dropwise to the soln containing the diamine in acetone.
A white precipitate was immediately obvious. After complete addi-
tion of the oxalic acid, the precipitate was filtered, washed with
Et2O (30 mL), and dried under high vacuum. Generally, the recov-
ered precipitate did not require any further purification, although re-
2-(Benzylamino)-4-phenylbutanenitrile (2f)
1H NMR (300 MHz, benzene-d6): d = 0.64 (br s, 1 H, NH), 1.49–
1.57 (m, 2 H, PhCH2CH2), 2.42 (t, 3J = 7.5 Hz, 2 H, PhCH2), 2.91
(t, 3J = 7.7 Hz, 1 H, CH), 3.42 (d, 2J = 13 Hz, 1 H, NCH2Ph), 3.66
(d, 2J = 13 Hz, 1 H, NCH2Ph), 6.88–6.90 (m, 2 H, Ar H), 7.01–7.13
(m, 8 H, Ar H).
13C NMR (75 MHz, benzene-d6): d = 31.8, 35.2, 48.8, 51.6, 119.8,
126.5, 127.7, 128.6, 128.6, 128.8, 131.5, 139.1, 140.5.
ESI-MS: m/z (%) = 251.3 (80) [M + H], 224.3 (30) [M – CN].
HRMS (CI): m/z [M + H]+ calcd for C17H19N2: 251.1548; found:
251.1544.
3-Cyclohex-1-enyl-2-(isopropylamino)propanenitrile (2g)
1H NMR (400 MHz, CDCl3): d = 1.04 [d, 3J = 6.4 Hz, 3 H,
CH(CH3)2], 1.12 [d, 3J = 6.4 Hz, 3 H, CH(CH3)2], 1.53–1.73 [m, 4
H, (CH2)2], 1.97–2.04 [m, 4 H, (CH2)2], 2.23–2.43 (m, 2 H, CH2),
3.11 [sept, 3J = 6.0 Hz, 1 H, CH(CH3)2], 3.68 (t, J = 6.4 Hz, 1 H,
3
CH), 5.61–5.63 (m, 1 H, CH).
13C NMR (100 MHz, CDCl3): d = 21.5, 22,2, 22.9, 23.9, 25.4, 28.5,
42.4, 47.1, 47.3, 120.7, 126.7, 131.9.
MS (CI): m/z (%) =193.4 (100) [M + H].
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102
A. V. Lee et al.
PAPER
crystallization could be performed from mixtures of EtOH or
MeOH and H2O if necessary. The hygroscopic nature of these com-
pounds along with the diprotic nature of the oxalic acid rendered
elemental analysis unsuccessful as a characterization technique.
ESI-MS: m/z (%) = 193.3 (100) [M + H].
ESI-HRMS: m/z [M + H]+ calcd for C12H21N2: 193.1705; found:
193.1710.
N2-Allyl-3-phenylpropane-1,2-diamine·Oxalate (3f)
Yield: 60%.
1H NMR (300 MHz, D2O): d = 3.09–3.14 (m, 1 H, PhCH2), 3.24–
3.29 (m, 1 H, PhCH2), 3.34–3.39 (m, 1 H, CH2NH2), 3.44–3.50 (m,
1 H, CH2NH2), 3.73–3.83 (m, 2 H, NCH2), 3.92–3.95 (m, 1 H,
CH2CH), 5.49–5.53 (m, 2 H, HCCH2), 5.82–5.89 (m, 1 H, HCCH2),
7.37–7.48 (m, 5 H, Ar H).
N2-Benzylheptane-1,2-diamine·Oxalate (3a)
Yield: 65%.
1H NMR (400 MHz, D2O): d = 0.86–0.88 (m, 3 H, CH3), 1.31–1.40
[m, 6 H, (CH2)3], 1.84–1.90 (m, 2 H, CH2), 3.42 (d, 3J = 5.7 Hz, 2
H, CHCH2NH2), 3.61–3.65 (m, 1 H, CH), 4.32 (d, 2J = 13 Hz, 1 H,
2
NCH2Ph), 4.38 (d, J = 13 Hz, 1 H, NCH2Ph), 7.49–7.51 (m, 5 H,
Ar H).
13C NMR (100 MHz, D2O): d = 35.3, 40.1, 48.6, 57.2, 125.4, 127.8,
129.1, 130.3, 130.4, 134.9, 168.8.
13C NMR (100 MHz, D2O): d = 14.1, 22.6, 24.5, 28.6, 31.5, 40.0,
50.0, 56.6, 130.4, 130.7, 130.9, 131.1, 166.8.
ESI-MS: m/z (%) = 191.3 (100) [M + H], 174.3 [M – NH2].
ESI-HRMS: m/z [M + H]+ calcd for C12H19N2: 191.1548; found:
191.1544.
ESI-MS: m/z (%) = 221.3 (100) [M + H].
ESI-HRMS: m/z [M + H]+ calcd for C14H25N2: 221.2018; found:
221.2017.
N2-Benzyl-3-cyclohex-1-enylpropane-1,2-diamine·Oxalate (3g)
Yield: 56%.
1H NMR (400 MHz, D2O): d = 1.51–1.69 [m, 4 H, (CH2)2], 1.83–
2.03 [m, 4 H, (CH2)2], 2.46–2.58 (m, 2 H, CH2CH), 3.33–3.51 (m,
2 H, CH2NH2), 3.68–3.71 (m, 1 H, CH2CH), 4.37 (s, 2 H, NCH2Ph),
5.75 (s, 1 H, CH), 7.47–7.50 (m, 5 H, Ar H).
N2-Isopropylheptane-1,2-diamine·Oxalate (3b)
Yield: 69%.
1H NMR (300 MHz, D2O): d = 0.87–0.90 (m, 3 H, CH3), 1.29–1.37
[m, 12 H, CH(CH3)2, (CH2)3], 1.76–1.81 (m, 2 H, CH2), 3.37 (d,
3J = 5.7 Hz, 2 H, CHCH2NH2), 3.58–3.65 [m, 2 H, CH(CH3)2, CH].
13C NMR (75 MHz, D2O): d = 13.2, 18.0, 18.4, 21.8, 23.4, 27.8,
30.7, 39.0, 49.1, 52.8, 165.2.
13C NMR (150 MHz, D2O): d = 20.8, 21.5, 24.3, 26.5, 36.9, 38.8,
48.4, 52.1, 128.3, 128.9, 129.3, 129.5, 130.1, 165.2.
ESI-MS: m/z (%) = 173.3 (70) [M + H].
ESI-HRMS: m/z [M + H]+ calcd for C10H25N2: 173.2018; found:
173.2012.
ESI-MS: m/z (%) = 245.3 (100) [M + H].
ESI-HRMS: m/z [M + H]+ calcd for C16H25N2: 245.2018; found:
245.2020.
N2-Allylheptane-1,2-diamine·Oxalate (3c)
Yield: 59%.
1H NMR (300 MHz, D2O): d = 0.87–0.91 (m, 3 H, CH3), 1.32–1.45
[m, 6 H, (CH2)3], 1.80–1.86 (m, 2 H, CH2), 3.40–3.43 (m, 2 H,
CH2NH2), 3.59–3.65 (m, 1 H, CH2CH), 3.77–3.82 (m, 2 H, NCH2),
5.53–5.61 (m, 2 H, HCCH2), 5.87–6.00 (m, 1 H, HCCH2).
N2-Allyl-3-cyclohex-1-enylpropane-1,2-diamine·Oxalate (3h)
Yield: 50%.
1H NMR (300 MHz, D2O): d = 1.46–1.56 [m, 4 H, (CH2)2], 1.86–
1.94 [m, 4 H, (CH2)2], 2.35–2.42 (m, 2 H, CH2CH), 3.27–3.33 (m,
2 H, CH2NH2), 3.62–3.73 (m, 3 H, CH2CH), 5.43–5.46 (m, 2 H,
HCCH2), 5.49 (br s, 1 H, HCC), 5.71–5.90 (m, 1 H, HCCH2).
13C NMR (100 MHz, D2O): d = 14.1, 22.6, 24.4, 28.6, 31.5, 39.7,
48.5, 56.1, 125.3, 127.8, 167.2.
13C NMR (100 MHz, D2O): d = 22.4, 23.1, 25.8, 28.2, 38.2, 40.4,
48.4, 53.7, 125.5, 127.8, 129.6, 131.7, 169.0.
ESI-MS: m/z (%) = 171.3 (100) [M + H].
ESI-HRMS: m/z [M + H]+ calcd for C10H23N2: 171.1861; found:
171.1863.
ESI-MS: m/z (%) = 195.3 (50) [M + H], 178.2 [M – NH2].
ESI-HRMS: m/z [M + H]+ calcd for C12H23N2: 195.1861; found:
195.1857.
N2-Benzyl-3-phenylpropane-1,2-diamine·Oxalate (3d)
Yield: 55%.
Imidazolidinones; General Procedure
The diamine as the oxalate salt 3 (synthesized by the route described
above; ca. 0.40 g) was dissolved in sat. NaHCO3 (30 mL). The pH
of the soln was determined to ensure that it was basic; if not, sat.
NaHCO3 was added 1 mL at a time until the soln was basic. The
aqueous layer was extracted with CH2Cl2 (3 × 30 mL) and the com-
bined organic layers were dried (MgSO4), filtered, and concentrated
under reduced pressure. The diamine was then further dried on a
high-vacuum line. To a flask containing free diamine (1.1 mmol, for
example) was added anhyd THF (2 mL) and CDI (0.20 g, 1.2
mmol). The soln was then heated at reflux for 12 h and subsequently
cooled to r.t. The solvent was removed under reduced pressure to
yield the crude imidazolidinone 4, which was purified by column
chromatography (silica gel, MeOH–CH2Cl2 5:95). The yields given
below are calculated from the diamine starting material 3.
1H NMR (300 MHz, D2O): d = 3.13–3.20 (m, 1 H, PhCH2), 3.28–
3.36 (m, 1 H, PhCH2), 3.40–3.52 (m, 2 H, CH2NH2), 3.92–3.98 (m,
1 H, CH2CH), 4.38 (s, 2 H, NCH2Ph), 7.34–7.48 (m, 10 H, Ar H).
13C NMR (100 MHz, D2O): d = 35.4, 40.3, 50.1, 57.5, 129.1, 130.2,
130.3, 130.4, 130.6, 130.8, 131.1, 134.9, 169.4.
ESI-MS: m/z (%) = 241.3 (100) [M + H].
ESI-HRMS: m/z [M + H]+ calcd for C16H21N2: 241.1705; found:
241.1700.
N2-Isopropyl-3-phenylpropane-1,2-diamine·Oxalate (3e)
Yield: 54%.
1H NMR (400 MHz, D2O): d = 1.34 [d, 3J = 4.4 Hz, 6 H, CH(CH3)2],
3.11–3.16 (m, 1 H, PhCH2), 3.24–3.29 (m, 1 H, PhCH2), 3.35–3.46
(m, 2 H, CH2NH2), 3.59–3.65 [m, 1 H, CH(CH3)2], 3.95–3.98 (m, 1
H, CH2CH), 7.39–7.50 (m, 5 H, Ar H).
1-Benzyl-5-pentylimidazolidin-2-one (4a)
Yield: 82%.
3
1H NMR (400 MHz, CDCl3): d = 0.86 (t, J = 6.8 Hz, 3 H, CH3),
13C NMR (100 MHz, D2O): d = 18.7, 19.4, 35.4, 40.4, 50.3, 54.9,
129.1, 130.3, 130.4, 134.8, 167.7.
1.19–1.26 [m, 6 H, (CH2)3], 1.36–1.44 (m, 1 H, CHCH2), 1.61–1.63
(m, 1 H, CHCH2), 3.06–3.11 (m, 1 H, CH), 3.41–3.52 (m, 2 H,
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Tandem Sequential Approach for the Synthesis of Imidazolidinones
103
2
NHCH2), 4.03 (d, 2J = 15 Hz, 1 H, PhCH2), 4.75 (d, J = 15 Hz, 1
(10) Szmuszkovicz, J.; Von Voigtlander, P. F. J. Med. Chem.
H, PhCH2), 5.31 (s, 1 H, NH), 7.21–7.35 (m, 5 H, Ar H).
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13C NMR (100 MHz, CDCl3): d = 14.1, 22.7, 24.3, 31.8, 31.8, 45.6,
47.1, 51.8, 127.8, 128.2, 128.9, 136.7, 154.5.
ESI-MS: m/z (%) = 269.2 (100) [M + Na], 247.3 (10) [M + H].
ESI-HRMS: m/z [M + Na]+ calcd for C15H22N2ONa: 269.1630;
found: 269.1624.
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1,5-Dibenzylimidazolidin-2-one (4b)
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44, 5662.
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Yield: 75%.
1H NMR (300 MHz, CDCl3): d = 2.59–2.65 (m, 1 H, PhCH2), 3.05–
3.11 (m, 2 H, PhCH2, NHCH2), 3.22–3.26 (m, 1 H, NHCH2), 3.69–
3.75 (m, 1 H, CH2CH), 4.07 (d, 2J = 15 Hz, 1 H, NCH2Ph), 4.69 (br
s, 1 H, NH), 4.86 (d, 2J = 15 Hz, 1 H, NCH2Ph), 7.10–7.37 (m, 5 H,
Ar H).
13C NMR (100 MHz, CDCl3): d = 38.8, 43.8, 45.5, 56.3, 127.0,
127.7, 128.4, 128.8, 128.9, 129.3, 136.9, 137.2, 162.4.
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found: 289.1308.
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1-Benzyl-5-(cyclohex-1-enylmethyl)imidazolidin-2-one (4c)
Yield: 85%.
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1H NMR (400 MHz, CDCl3): d = 1.50–1.52 (m, 4 H, CH2), 1.71–
1.73 (m, 2 H, CH2), 1.94–1.99 (m, 3 H, CH2, CCH2), 2.38 (d, 3J = 12
Hz, 1 H, CCH2), 3.07 (t, 3J = 7.8 Hz, 1 H, NHCH2), 3.35 (t, 3J = 8.6
Hz, 1 H, NHCH2), 3.54–3.57 (m, 1 H, CH), 4.06 (d, 2J = 15 Hz, 1
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2
H, PhCH2), 4.77 (d, J = 15 Hz, 1 H, PhCH2), 4.95 (s, 1 H, NH),
5.39 (s, 1 H, HCC), 7.25–7.42 (m, 5 H, Ar H).
13C NMR (100 MHz, CDCl3): d = 22.4, 22.9, 25.4, 28.7, 41.3, 44.1,
45.2, 53.5, 124.9, 127.5, 128.2, 128.7, 133.1, 137.6, 162.8.
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ESI-MS: m/z (%) = 293.2 (100) [M + Na], 271.2 (60) [M + H].
ESI-HRMS: m/z [M + Na]+ calcd for C17H22N2ONa: 293.1630;
found: 293.1625.
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Acknowledgment
We are grateful to the NSERC for financial support of this work.
A.V.L. wishes to thank NSERC for a graduate scholarship. M.S.
thanks the Sonderforschungsbereich 424 (Deutsche Forschungsge-
meinschaft) and Prof. E.-U. Würthwein for the opportunity to parti-
cipate in an academic exchange to UBC. L.L.S. is an Alfred P.
Sloan Fellow.
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