Cyclization-carbonylation-cyclization coupling reaction of propargyl ureas with palladium(II)-bisoxazoline catalyst

Article abstract of DOI:10.3390/molecules17089220

The cyclization-carbonylation-cyclization coupling reaction (CCC-coupling reaction) of propargyl ureas catalyzed by Pd^II(box) complexes afforded symmetrical ketones bearing two 2-amino-2-oxazoline groups in good to moderate yields.

Full text of DOI:10.3390/molecules17089220

Molecules 2012, 17, 9220-9230; doi:10.3390/molecules17089220
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Cyclization-Carbonylation-Cyclization Coupling Reaction of
Propargyl Ureas with Palladium(II)-Bisoxazoline Catalyst
Taichi Kusakabe 1, Koujiro Kawaguchi 1, Miya Kawamura 1, Naohiko Niimura 1, Rong Shen 1,
Hiroyuki Takayama 2,* and Keisuke Kato 1,*
1
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510,
Japan; E-Mail: taichi.kusakabe@phar.toho-u.ac.jp (T.K.)
2
School of Pharmacy, Nihon Pharmaceutical University, 10281, Komuro, Inamachi, Kita-Adachigun,
Saitama 362-0806, Japan
* Authors to whom correspondence should be addressed; E-Mails: h.takayama@nichiyaku.ac.jp (H.T.);
kkk@phar.toho-u.ac.jp (K.K.); Tel./Fax: +81-474-721-805 (K.K.).
Received: 16 July 2012; in revised form: 30 July 2012 / Accepted: 31 July 2012 /
Published: 2 August 2012
Abstract: The cyclization-carbonylation-cyclization coupling reaction (CCC-coupling
reaction) of propargyl ureas catalyzed by PdII(box) complexes afforded symmetrical
ketones bearing two 2-amino-2-oxazoline groups in good to moderate yields.
Keywords: CCC-coupling; bisoxazoline; palladium; carbonylation; propargyl urea
1. Introduction
Oxazolines appear in numerous medicinally active compounds and natural products [1–3].
Among them, 2-amino-2-oxazolines show various interesting pharmacological properties such as
anti-hypertensive [4], antidepressant [5], appetite suppressant [6], nitric oxide synthase inhibitor [7]
and central nervous system activity [8]. Diarylketones are also frequently found in natural products and
pharmaceuticals [9,10]. In addition, they are good precursors for non-steroidal antiestrogen drugs
(e.g., tamoxifen) and diarylmethyl compounds [11]. Cascade reactions are important tools for
constructing a variety of heterocycles in one step starting from simple compounds [12,13]. Recently,
we reported the cyclization-carbonylation-cyclization (CCC)-coupling reaction of propargylic
acetates, amides, -propynyl-1,3-diketones, N-propargylanilines and o-alkynylphenols catalyzed by
palladium(II)-bisoxazoline (box) complexes (Scheme 1). Symmetrical ketones bearing two cyclic

Molecules 2012, 17
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orthoesters [14], oxazolines [14], oxabicyclic groups [15], quinolines [16] and benzofurans [16] were
obtained in a one-step reaction.
Scheme 1. Previous works and this work: CCC-coupling reaction of propargyl acetates,
amides and ureas.
In these transformations, the triple bond of the substrate coordinates to palladium(II) and undergoes
nucleophilic attack by the intramolecular nucleophile X, followed by CO insertion to produce the acyl
palladium intermediate A (Scheme 2). Coordination of the triple bond of a second molecule induces
the second cyclization. Reductive elimination then leads to formation of a ketone bearing two heterocyclic
groups. We believe that the box ligand enhances the -electrophilicity of palladium(II) [14–19], and
thus promotes coordination of the second triple bond to the acyl palladium intermediate A, leading to
dimerization. Previously, Bacchi et al. reported that the PdI2-KI catalyzed cyclization-alkoxycarbonylation
of propargyl urea 1a afforded 2-amino-2-oxazoline derivative 2a in 70% yield along with imidazoline
derivative 3a in 23% yield (Scheme 3) [20,21]. To extend our concept of the CCC-coupling reaction,
we investigated the PdII(box) catalyzed carbonylation reaction of propargyl ureas 1 (Scheme 1).
Scheme 2. Our concept of a cyclization-carbonylation-cyclization coupling reaction
(CCC coupling reaction) of propargylic compounds.

Molecules 2012, 17
Scheme 3. Bacchi et al.: PdI2-KI catalyzed cyclization-alkoxycarbonylation of 1 [20,21].
9222
Me
Me
Me
Me
Me
Me
HN
PdI2/KI, Air
N
O
nPrHN
+
CO, MeOH
23bar, 65 C
CO2Me
HN
O
N
O
nPr
CO2Me
NHnPr
3a : 23%
2a : 70%
1a
2. Results and Discussion
2.1. Optimization Studies
Initially, we selected 1a as a standard substrate to search for potential catalysts (Table 1). The
reaction of 1a with (CH3CN)2PdCl2 (5 mol %) in the presence of p-benzoquinone (1.5 equiv.) in
methanol under a carbon monoxide atmosphere (balloon) generated the dimeric ketone 4a in 46%
yield, along with monomeric ester 2a (36% yield) (Table 1, entry 1). These products were easily
separated by chromatography on silica gel.
Table 1. Optimization of reaction condition.
Catalyst
(5 mol %)
(CH3CN)2PdCl2
Pd(tfa)2
[Pd(bipy)Cl2]
(Ph3P)2PdCl2
Pd(PPh3)4
[Pd(L)(tfa)2]
[Pd(L)(tfa)2]
[Pd(L)(tfa)2]
[Pd(L)(tfa)2]
[Pd(L)(tfa)2]
Yield of
4a (%)
4a: 46
4a: 24
4a: 29
4a: 16
-
4a: 83
4a: 61
4a: 30
Yield of
2a (%)
2a: 36
2a: 20
2a: 13
2a: 61
2a: 44
2a: 17
2a: 21
2a: 29
Entry
Conditions
1
2
3
4
5
6
7
8
rt, 24 h
−20 °C, 24 h
rt, 24 h
rt, 19 h
rt, 24 h
rt, 24 h
50 °C, 3 h
−20 °C, 24 h
rt, 24 h
9 a
10 b
N.R.
N.R.
rt, 24 h
a CH2Cl2 was used as solvent; b DMF was used as solvent.
Pd(tfa)2 and 2,2′-bipyridine complex also gave a mixture of products 4a and 2a in low yields (Table 1,
entries 2–3). The use of phosphine complexes, (Ph3P)2PdCl2 and Pd(PPh3)4, afforded monomeric ester
2a as a major product (Table 1, entries 4–5). Next, an attempt was made to use the box complex
[Pd(L)(tfa)2] according to our previous results [14–19]. As expected, the reaction occurred smoothly,
and the yield of 4a improved to 83% (Table 1, entry 6). Higher temperatures reduced both the reaction
time and the dimer 4a:monomer 2a ratio (Table 1, entry 7). Lower temperatures reduced the yields of
both products (Table 1, entry 8). Furthermore, CH2Cl2 and DMF were not suitable as solvents (Table 1,

Molecules 2012, 17
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entries 9–10). The structure of the dimeric ketone 4a was confirmed by comparing the corresponding
1H- and 13C-NMR data with those of similar oxazolines [22].
2.2. Substrate Scope and Limitations
Having optimized the reaction conditions, we examined the reaction of various propargyl ureas 1b–j
with the box complex [Pd(L)(tfa)2] (Table 2).
Table 2. CCC-coupling reaction of propargyl ureas 1.
Yield of
4 (%)
4a: 83
4b: 73
4c: 61
4d: 58
4e: 66
4f: 89
4g: 74
4h: 24
Yield of
2 (%)
2a: 17
2b: 10
2c: 25
2d: 20
2e: 30
2f: 11
2g: 20
2h: 23
Entry
R1
R2
Conditions
1
2
3
4
5
6
7
Me
Me
Me
Me
nPr
Bn
nBu
Phenethyl
Cyclohexyl
Phenethyl
Cyclohexyl
Ph
rt, 24 h
rt, 18 h
rt, 20 h
7 °C, 48 h
rt, 24 h
rt, 24 h
Me
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
H
rt, 24 h
rt, 40 h
rt, 48 h
rt, 24 h
8
9 a
10
H
N.R.
N.R.
Phenethyl
a 1i was recovered (41%).
The reactions proceeded well for substrates 1a–g bearing two methyl groups in the propargylic
position (R1 = Me) (Table 2, entries 1–5). The bulky cyclohexyl group in the propargylic position
(R1 = –(CH2)5–) did not affect the yields of 4f and 4g (Table 2, entries 6 and 7). The alkyl substituent
of the terminal nitrogen (R2) was found to be important for promoting the cyclization, lower yields
were obtained for 1h (R2 = Ph) (Table 2, entry 8). The reaction of unsubstituted 1i (R2 = H) did not
proceed (Table 2, entry 9). In addition, the gem-dialkyl effect [23] plays a fundamental role for the
success of the reaction; the reaction of substrate 1j having no substituent on the propargylic position
did not proceed (Table 2, entry 10).
2.3. Preparation of [Pd(L)(tfa)2]
Ligand L was prepared according to the previously reported procedure (Scheme 4) [24,25].
Condensation of 2,2-dimethyl-malononitrile with (±)-phenylglycinol using Zn(OTf)2 in toluene
afforded a mixture of L (racemic) and L′ (meso) [18,26]. Chromatographic separation of the mixture
gave the compounds in 34% and 38% yields, respectively. The key [Pd(L)(tfa)2] [28] catalyst was
easily obtained as a stable solid by simple filtration from a methanolic mixture of L and Pd(tfa)2.

Molecules 2012, 17
9224
Scheme 4. Preparation of [Pd(L)(tfa)2].
3. Experimental
3.1. General
All melting points were measured on a Yanaco MP-3S micro melting point apparatus and are
1
13
uncorrected. H-, C-NMR and HMBC spectra were recorded on JEOL AL 400 and JEOL Lambda
500 spectrometer spectrometers in CDCl3 with Me4Si as an internal reference. 13C-NMR spectra were
recorded at 100 MHz. In the case of CD2Cl2, solvent peaks were used as a reference (5.32 ppm for 1H,
and 53.8 ppm for 13C). High-resolution mass spectra (HR-MS) were obtained with JEOL GC Mate II,
JMS-SX102 and JEOL JMS 600H spectrometer. IR spectra were recorded with JASCO FT/IR-300
spectrometer. All reagents were purchased from commercial sources and used without purification. All
evaporations were performed under reduced pressure. For column chromatography, silica gel
(Kieselgel 60) was employed.
3.2. Preparation of Substrates 1a–j
The substrates 1a–j were prepared according to the literature [27]. The substrates 1, except
for 1a [20] and 1b [20] are new compounds [22].
3.3. General Procedure for the CCC-Coupling Reaction of 1
A 50-mL two-neck round-bottom flask containing a magnetic stirring bar, substrate 1 (0.5 mmol),
p-benzoquinone (1.5 mmol) and MeOH (7 mL) was fitted with a rubber septum and a three-way
stopcock connected to a balloon filled with carbon monoxide. The apparatus was purged with carbon
monoxide by pump-filling via the three-way stopcock. A MeOH (1 mL) suspension of [Pd(L)(tfa)2]
(0.025 mmol) was added to the stirred solution at an appropriate temperature using a syringe. The
remaining [Pd(L)(tfa)2] was washed in MeOH (1 mL) twice. After stirring at the appropriate
temperature for a period of time, the mixture was diluted with CH2Cl2 (50 mL) and washed with 3%
NaOH (40 mL). The aqueous layer was extracted with CH2Cl2 (50 mL) twice and the combined
organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was purified by

Molecules 2012, 17
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chromatography on silica gel. The fraction eluted with hexane-AcOEt (30/1–1/1) afforded the
monomeric ester 2 and the dimeric ketone 4. 4 was then precipitated from the reaction mixture and the
resulting precipitate was collected by filtration and washed with cold MeOH (1 mL × 2). The filtrate
was reprocessed via the above procedure to provide additional products after chromatography.
3.3.1. Dimeric Ketone 4a
Hexane/AcOEt = 1/1. Colorless needles; mp 186–191 °C; 1H-NMR (CDCl3) δ 0.95 (6 H, t, J = 7.2 Hz),
1.55–1.65 (4 H, m), 1.63 (12 H, s), 3.20 (4 H, t, J = 7.2 Hz), 4.11 (2 H, br-s), 5.91 (2 H, s); 13C-NMR
(CDCl3) δ 11.2 (2C), 22.9 (2C), 25.4 (4C), 44.6 (2C), 71.0 (2C), 103.2 (2C), 154.4 (2C), 177.2 (2C),
186.4; IR (KBr): 3203, 3114, 2963, 2877, 1724, 1629, 1370, 1183, 969, 930 cm−1; HRMS-EI:m/z [M+]
calcd for C19H30N4O3: 362.2318; found: 362.2315.
3.3.2. (2E)-Methyl 2-[4,4-dimethyl-2-(propylamino)-5(4H)-oxazolylidene]acetate (2a)
Hexane/AcOEt = 4/1. Spectral data were identical to those described in the literature [20].
3.3.3. Dimeric Ketone 4b
Hexane/AcOEt = 1/1. Colorless needles; mp 155–158 °C; 1H-NMR (CDCl3) δ 1.65 (12 H, s), 4.40
13
(2 H, s), 5.92 (2 H, s), 7.26–7.36 (10 H, m); C-NMR (CDCl3) δ 25.4 (4C), 46.8 (2C), 70.9 (2C),
103.5 (2C), 127.6 (4C), 127.7 (2C), 128.7 (4C), 137.8 (2C), 154.6 (2C), 176.9 (2C), 186.2; IR (KBr): 2930,
1730, 1630, 1182, 966, 933 cm−1; HRMS-EI:m/z [M+] calcd for C27H30N4O3: 458.2318; found: 458.2320.
3.3.4. (2E)-Methyl 2-[4,4-dimethyl-2-(phenylmethylamino)-5(4H)-oxazolylidene]acetate (2b)
Hexane/AcOEt = 4/1. Spectral data were identical to those described in the literature [20].
3.3.5. Dimeric Ketone 4c
Hexane/AcOEt = 1/1. Colorless needles; mp 189–191 °C;1H-NMR (CDCl3) δ 0.94 (6 H, t, J = 7.2 Hz),
1.33–1.59 (8 H, m), 1.63 (12 H, s), 3.23 (4 H, t, J = 7.2 Hz), 4.07 (2 H, br-s), 5.91 (2 H, s); 13C-NMR
(CDCl3) δ 13.8 (2C), 19.9 (2C), 25.4 (4C), 31.7(2C), 42.6 (2C), 71.0 (2C), 103.2 (2C), 154.4 (2C),
177.1 (2C), 186.4; IR (KBr): 3206, 2965, 1725, 1627, 1184, 929 cm−1; HRMS-EI:m/z [M+] calcd for
C21H34N4O3: 390.2631; found: 390.2632.
3.3.6. (2E)-Methyl 2-[4,4-dimethyl-2-(butylamino)-5(4H)-oxazolylidene]acetate (2c)
Hexane/AcOEt = 4/1. Colorless needles; mp 96–99 °C; 1H-NMR (CDCl3) δ 0.94 (3 H, t, J = 7.2 Hz),
1.35–1.43 (2 H, m), 1.52–1.62 (8 H, m), 3.23 (2 H, t, J = 7.2 Hz), 3.69 (3 H, s), 4.13 (1 H, br-s), 5.54
13
(1 H, s); C-NMR (CDCl3) δ 13.7, 19.9, 25.9 (2C), 31.7, 42.6, 51.1, 70.7, 92.6, 154.3, 166.6, 178.5;
IR (KBr): 3179, 2967, 1723, 1708, 1689, 1656, 1172, 1095 cm−1; HRMS-EI:m/z [M+] calcd for
C12H20N2O3: 240.1474; found: 240.1473.

Molecules 2012, 17
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3.3.7. Dimeric Ketone 4d
Hexane/AcOEt = 1/1. Colorless needles; mp 180–182 °C; 1H-NMR (CDCl3) δ 1.63 (12 H, s), 2.89
(4 H, t, J = 6.8 Hz), 3.51 (4 H, t, J = 6.8 Hz), 4.01 (2 H, br-s), 5.87 (2 H, s), 7.19–7.33 (10 H, m);
13C-NMR (CDCl3) δ 25.4 (4C), 35.4 (2C), 43.7 (2C), 71.0 (2C), 103.3 (2C), 126.7 (2C), 128.7 (4C),
128.8 (4C), 138.4 (2C), 154.2 (2C), 177.0 (2C), 186.4; IR (KBr): 3211, 3108, 2942, 1736, 1626, 1180,
966, 931 cm−1; HRMS-EI:m/z [M+] calcd for C29H34N4O3: 486.2631; found: 486.2631.
3.3.8. (2E)-Methyl 2-[4,4-dimethyl-2-(phenylethylamino)-5(4H)-oxazolylidene]acetate (2d)
Hexane/AcOEt = 3/1. Brown oil; 1H-NMR (CDCl3) δ 1.62 (6 H, s), 2.89 (2 H, t, J = 6.8 Hz), 3.51
13
(2 H, t, J = 6.8 Hz), 3.68 (3 H, s), 4.35 (1 H, br-s), 5.52 (1 H, s), 7.19–7.31 (5 H, m); C-NMR
(CDCl3) δ 25.9 (2C), 35.5, 43.6, 51.1, 70.7, 92.9, 126.7, 128.7 (2C), 128.8 (2C), 138.3, 154.3, 166.5,
178.2; IR (KBr): 3360, 3193, 2972, 1724, 1657, 1106, 1048 cm−1; HRMS-EI:m/z [M+] calcd for
C16H20N2O3: 288.1474; found: 288.1471.
3.3.9. Dimeric Ketone 4e
Hexane/AcOEt = 4/1. Colorless needles; mp 243–246 °C; 1H-NMR (CDCl3) δ 1.19–1.95 (22 H, m),
1.85 (12 H, s), 3.55 (2 H, m), 6.25 (2 H, s); 13C-NMR (CDCl3) δ 24.5 (4C), 24.7 (4C), 24.7 (2C), 32.7
(4C), 53.2 (2C), 64.9 (2C), 107.0 (2C), 156.4 (2C), 170.5 (2C), 184.1; IR (KBr): 3205, 2933, 2857, 1729,
1625, 1367, 1182, 990, 928 cm−1; HRMS-EI:m/z [M+] calcd for C25H38N4O3: 442.2944; found: 442.2943.
3.3.10. (2E)-Methyl 2-[4,4-dimethyl-2-(cyclohexylethylamino)-5(4H)-oxazolylidene]acetate (2e)
Hexane/AcOEt = 5/1. Colorless needles; mp 125–127 °C; 1H-NMR (CDCl3) δ 1.15–2.06 (10 H, m),
13
1.62 (6 H, s), 3.46 (1 H, m), 3.69 (3 H, s), 4.04 (1 H, br-s), 5.53 (1 H, s); C-NMR (CDCl3) δ 24.6,
25.5 (2C), 25.9 (2C), 33.3 (2C), 51.0, 51.3, 70.8, 92.4, 153.3, 166.6, 178.5; IR (KBr): 3206, 2934, 2856,
1717, 1658, 1538, 1102 cm−1; HRMS-EI:m/z [M+] calcd for C14H22N2O3: 266.1631; found: 266.1633.
3.3.11. Dimeric Ketone 4f
1
Hexane/AcOEt = 10/1. Colorless needles; mp 186–190 °C; H-NMR (CDCl3) δ 1.32–1.80 (16 H,
m), 2.65–2.72 (4 H, m), 2.89 (4 H, t, J = 6.8 Hz), 3.51 (4 H, t, J = 6.8 Hz), 4.06 (2 H, br-s), 5.88 (2 H,
13
s), 7.19–7.31 (10 H, m); C-NMR (CDCl3) δ 22.3 (4C), 25.2 (2C), 32.9 (4C), 35.7 (2C), 43.9 (2C),
74.4 (2C), 103.6 (2C), 126.6 (2C), 128.7 (4C), 128.9 (4C), 138.6 (2C), 153.6 (2C), 177.3 (2C), 186.3;
IR (KBr): 3418, 2930, 2860, 1720, 1625, 1014, 976, 931 cm−1; HRMS-EI:m/z [M+] calcd for
C35H42N4O3: 566.3257; found: 566.3260.
3.3.12. Monomeric Ester 2f
Hexane/AcOEt = 15/1. Colorless needles; mp 104–106 °C; 1H-NMR (CDCl3) δ 1.37–1.82 (8 H, m),
2.55–2.62 (2 H, m), 2.89 (2 H, t, J = 6.8 Hz), 3.51 (2 H, t, J = 6.8 Hz), 3.68 (3 H, s), 4.09 (1 H, br-s),
13
5.52 (1 H, s); C-NMR (CDCl3) δ 22.2 (2C), 25.1, 33.6 (2C), 35.6, 43.9, 51.1, 74.2, 92.6, 126.6,

Molecules 2012, 17
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128.7, 128.8, 138.6, 153.5, 166.7, 179.2; IR (KBr): 3111, 2969, 1732, 1655, 1127, 1065 cm−1; HRMS-
EI:m/z [M+] calcd for C19H24N2O3: 328.1787; found: 328.1786.
3.3.13. Dimeric Ketone 4g
1
Hexane/AcOEt = 15/1. Colorless needles; mp 189–191 °C; H-NMR (CDCl3) δ 1.11–1.79 (32 H,
m), 2.00–2.03 (4 H, m), 2.65–2.72 (4 H, m), 3.40–3.47 (2 H, m), 3.94 (2 H, br-s), 5.91 (2 H, s);
13C-NMR (CDCl3) δ 22.3 (4C), 24.6 (4C), 25.1 (2C), 25.5 (2C), 32.8 (4C), 33.2 (4C), 51.3 (2C), 74.2
(2C), 103.4 (2C), 153.0 (2C), 177.3 (2C), 186.3; IR (KBr): 3430, 2928, 2855, 1710, 1624, 1498, 996,
927 cm−1; HRMS-EI:m/z [M+] calcd for C31H46N4O3: 522.3570; found: 522.3568.
3.3.14. Monomeric Estere 2g
1
Hexane/AcOEt = 20/1. Colorless needles; mp 133–135 °C; H-NMR (CDCl3) δ 1.12–2.05 (18 H,
13
m), 2.55–2.62 (2 H, m), 3.42–3.50 (1 H, m), 3.69 (3 H, s), 3.96 (1 H, br-s), 5.54 (1 H, s); C-NMR
(CDCl3) δ 22.2 (2C), 24.6 (2C), 25.2, 25.6, 33.2 (2C), 33.4 (2C),51.1, 51.4, 74.2, 92.4, 152.8, 166.8,
179.3; IR (KBr): 3358, 2932, 2857, 1707, 1644, 1518, 1125, 1066 cm−1; HRMS-EI:m/z [M+] calcd for
C17H26N2O3: 306.1944; found: 306.1945.
3.3.15. Dimeric Ketone 4h
1
Hexane/AcOEt = 10/1. Colorless needles; mp 300 °C; H-NMR (CDCl3) δ 1.46–1.91 (16 H, m),
2.67–2.73 (4 H, m), 6.30 (2 H, s), 7.16–7.56 (10 H, m); 13C-NMR (CDCl3) δ 21.4 (4C), 23.9 (2C), 31.9
(4C), 69.4 (2C), 108.4 (2C), 122.5 (4C), 127.8 (2C), 129.8 (4C), 133.2 (2C), 155.9 (2C), 169.3 (2C),
183.7; IR (KBr): 3411, 2928, 2859, 1715, 1628, 1603, 1535, 996 cm−1; HRMS-EI:m/z [M+] calcd for
C31H34N4O3: 510.2631; found: 510.2629.
3.3.16. Dimeric Ketone 2h
1
Hexane/AcOEt = 30/1. Colorless needles; mp 121–124 °C; H-NMR (CD2Cl2) δ 1.40–1.89 (8 H,
m), 2.61–2.68 (2 H, m), 3.68 (3 H, s), 5.62 (1 H, s), 7.03 (1 H, t, J = 7.6 Hz), 7.32 (2 H, dd, J = 7.6, 8.0
Hz), 7.55 (2 H, d, J = 8.0 Hz); 13C-NMR (CD2Cl2) δ 22.7 (2C), 25.6, 33.6 (2C), 51.4, 75.4, 93.4, 118.2
(2C), 122.9, 129.3 (2C), 139.1, 149.5, 166.7, 177.4; IR (KBr): 3298, 2929, 1688, 1605, 1552, 1315,
1151, 1064 cm−1; HRMS-EI:m/z [M+] calcd for C17H20N2O3: 300.1474; found: 300.1472.
3.4. Preparation of Ligands and Racemic-[Pd(L)(tfa)2]
3.4.1. Preparation of L and L′
To a mixture of dimethylmalononitrile (681 mg, 7.23 mmol) and (±)-phenylglycinol (2.00 g,
14.5 mmol) in anhydrous toluene (160 mL) under Ar was added zinc triflate (2.63 g, 7.23 mmol), and
the mixture was refluxed for 3 days. The mixture was allowed to cool, and was then diluted with a
saturated NaHCO3 aqueous solution (200 mL) and CHCl3 (300 mL). After vigorously stirring for 1 h,
the layers were separated. The aqueous layer was extracted with CHCl3 (50 mL) twice. The combined
organic layers were dried with MgSO4 and concentrated in vacuo. The crude products were purified by

Molecules 2012, 17
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column chromatography on silica-gel (70 g). The fraction eluted with hexane/ethyl acetate (7/1)
(containing 0.5% Et3N) afforded L′ (914 mg, 38%) [10] and L (818 mg, 34%) as pale yellow oils.
3.4.2. Preparation of [Pd(L)(tfa)2]
To a stirring solution of L (307 mg, 0.92 mmol) in MeOH (4 mL) was added Pd(tfa)2 (305 mg,
0.92 mmol) in MeOH (3 mL). The [Pd(L)(tfa)2] was then precipitated from the reaction mixture, and
the resulting precipitate was collected by filtration and washed with cold MeOH (1 mL) to give
racemic-[Pd(L)(tfa)2] [28] as a white powder (483 mg, 79%).
4. Conclusions
In conclusion, we have presented a cyclization-carbonylation-cyclization coupling reaction
(CCC-coupling reaction) of propargyl ureas 1 catalyzed by PdII(box) complexes. Symmetrical ketones
possessing two 2-amino-2-oxazoline groups were obtained in moderate to good yields. We believe that
the box ligand enhances the -electrophilicity of palladium(II), and thus promotes coordination of the
triple bond (second molecule) to the acyl palladium intermediate A, leading to the dimerization
reaction. We are currently investigating additional cascade reactions based on the cyclization-
carbonylation-cyclization strategy for the synthesis of other types of ketones containing two hetero-
cyclic groups.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/17/8/9220/s1.
Acknowledgments
This research was supported by Grant-in-Aid for Scientific Research (C) (24590026).
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