Novel and Efficient Synthesis of DHPMs Catalyzed by di-DACH-Pyridylamide Ligands

Article abstract of DOI:10.1002/jhet.2259

Di-DACH-pyridylamide ligands, symmetrical bridged bis-Schiff base, and spiro pyrrolizines as catalysts in the synthesis of dihydropyrimidinethiones (DHPMs) using the Biginelli reaction is first reported. This new protocol has the advantages of environment

Full text of DOI:10.1002/jhet.2259

Month 2014
Novel and Efficient Synthesis of DHPMs Catalyzed by di-DACH-
Pyridylamide Ligands
Qingbao Song, Xiaoxia An, Fengfeng Che, and Tianhua Shen*
College of Chemical Engineering Science, Zhejiang University of Technology, Hangzhou 310014, People’s Republic of China
*
E-mail: shenth@zjut.edu.cn
Received February 13, 2014
DOI 10.1002/jhet.2259
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Di-DACH-pyridylamide ligands, symmetrical bridged bis-Schiff base, and spiro pyrrolizines as catalysts
in the synthesis of dihydropyrimidinethiones (DHPMs) using the Biginelli reaction is first reported. This new
protocol has the advantages of environmental friendliness, short reaction time, excellent yields, and simple
post-treatment procedure. A series of DHPMs were obtained in high yields (up to 98%) in only 6 h.
Moreover, based on the optimized condition, a novel Biginelli-like reaction was first developed.
J. Heterocyclic Chem., 00, 00 (2014).
Multifunctionalized 3,4-dihydropyrimidin-2(1H)-one de-
rivatives (DHPMs) are very important pharmacologically ac-
tive molecules and have found applications as calcium
channel modulators, α -adrenoceptor selective antagonists,
and inhibitors of the kinesin motor protein and HIV [1].
The Biginelli reaction [2], which is a three-component
reaction of an aromatic aldehyde, urea, and acetoacetate, is
the most efficient method for the assembly of these biologi-
cally significant heterocyclic compounds. In recent years,
in order to improve and modify this reaction, several cata-
lysts for the preparation of DHPMs have been explored.
allylation reaction [19–27]. It also has not been documented
that the diamide ligand was used to catalyze the Biginelli
reaction. Moreover, Schiff base is a compound containing
a C═N bond, and there are various kinds of Schiff base,
such as single Schiff base, double Schiff base, macrocyclic
Schiff base, and other types of Schiff base [28–31].
Symmetrical bis-Schiff base [32–38] plays an important role
in coordination chemistry because of its special structure.
Spiro pyrrolizines ring system represents an important class
of naturally occurring substances characterized by highly pro-
nounced biological properties. So far, no catalytic application
of these compounds in Biginelli reaction has been reported.
Da and co-workers [39] used L-proline amides as catalyst in
the Biginelli reaction; however, they obtained moderate yield
and long reaction time in this case. Chen [40] reported
bifunctional primary amine thiourea as catalyst, but it needs
a cumbersome post-treatment. Not long after, double axially
bis-phosphoryl imides were first applied in organocatalytic
Biginelli reaction by Zhang [41] and co-workers with the
complexity steps and high cost of crude material. In view of
these few successful examples, it is still desirable to develop
other new organocatalysts for the Biginelli reaction.
To the best of our knowledge of the open literatures,
there is no report on the use of di-DACH-pyridylamide
ligands, symmetrical bridged bis-Schiff base, and spiro
pyrrolizines as catalysts in the synthesis of DHPMs
during the progress of our current work. Herein, we wish
to disclose our study on the use of these new types of
ligands as catalysts in the synthesis of DHPMs using the
Biginelli reaction. Good to excellent yields and short reac-
tion time have been achieved without further purification.
1
a
These include assistance from FeCl -supported nanopore
3
silica [3], and ferric perchlorate [4], polyoxometalate [5],
transition metals containing halides [6–8], L-AAIL/ALCl3
[9], amino acids [10–13], and polymers [14–17] have been
used, but most types of reaction suffer from several main
drawbacks such as harsh conditions, strong acidic condition,
huge amounts of organic solvents, expensive catalysts, low
yields, low purity, long reaction time (from 2 days to a
week), and cumbersome product isolation procedures. Thus,
the primary task continues to attract the attention of
researchers seeking a milder and more efficient reaction
procedure as well as environment-friendly catalysts for the
synthesis of DHPMs to optimize the reaction conditions
and shorten the reaction time.
It is well known that di-DACH-pyridylamide ligands are
multidentate nitrogen-donor ligands with amine and/or
pyridine-type nitrogen atoms [18]. Conformational flexibil-
ity in these multidentate nitrogen-donor ligands often plays
a crucial role in their catalytic capabilities in many reactions,
such as the Ullmann reaction, the Henry reaction, and
©
2014 HeteroCorporation

Q. Song, X. An, F. Che, and T. Shen
Vol 000
RESULTS AND DISCUSSION
(Table 1, entries 8–11). Symmetrical bridged bis-Schiff base
e and 5f were superior to a series of spiro pyrrolizines,
5
Initially, the catalytic Biginelli reaction was carried out
in absence of any catalyst. It was found that no product
was formed. This shows that the catalyst was necessary
for this reaction (Table 1, entry 1).
which promoted the Biginelli reaction with higher yields
in 45% and 47% (Table 1, entries 6–7). Encouragingly,
we found that di-DACH-pyridylamide ligands 5d could
effectively catalyze this reaction to provide the desired
product DHPM 4a in moderate yield of 73% in 24 h
Di-DACH-pyridylamide ligands, symmetrical bridged
bis-Schiff base, and spiro pyrrolizines, to the best of our
knowledge, had not been reported to be used in the Biginelli
reaction, so we needed to investigate the eligibility of the
catalysts for our purpose. The reaction mixture of benzalde-
hyde 1, urea 2, ethyl acetoacetate 3, HCl, and each catalyst
in THF was stirred at room temperature for 24h to afford
the mixture of DHPM 4a. Screening results of catalysts
are listed in Table 1. It was found that, when the reaction
was carried out with spiro pyrrolizines such as 5g, 5h, 5i,
and 5j, low yields (<30%) of products were observed
(
Table 1, entry 5). Loading of 5d of 5, 10, and 20 mol% was
tested, and the results are summarized in Table 1 (entries 5,
2, and 13). It could be seen that 10 mol% loading of 5d
1
was optimal, while higher amounts of 5d led to a slight
decrease in yield. The yields indicated that overuse of the
catalyst was needless and unfavorable for this reaction.
To optimize the reaction conditions further, the solvent
effect was reinvestigated with the optimum catalyst 5d at
room temperature for 12 h, and the best result was obtained
Table 1
Screening catalysts for the Biginelli reaction.
a
b
b
Entry
Cat.
Temp. (°C)
Time (h)
Yield (%)
Entry
Cat.
Temp. (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
Nil
5a
5b
5c
5d
5e
5f
25
25
25
25
25
25
25
24
24
24
24
24
24
24
<5
52
46
68
73
45
47
8
9
10
11
12
13
5g
5h
5i
25
25
25
25
25
25
24
24
24
24
24
24
29
17
21
13
51
75
5j
5d
c
d
5d
a
The reaction was carried out on a 0.5 mmol scale, and the ratio of 1/2/3 is 1/1.5/3.
Yield of isolated product.
b
c
Catalyst 5d (5 mol%) was used.
d
Catalyst 5d (20 mol%) was used.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Novel and Efficient Synthesis of DHPMs Catalyzed by di-DACH-Pyridylamide
Ligands
in THF (Table 2, entry 5). When toluene was used as the
solvent, it is hard to separate the products without any
improvement in terms of yield (Table 2, entry 6). When
the reaction was performed in polar solvents, such as
C H OH, DMSO, H O, and i-PrOH, the product DHPM
the rate of reaction enhancing it with temperature (Table 2,
entry 5 and entries 13–16). It can be noticed that there was
not much appreciable change in yield even when the
reaction was changed from 6 to 8 h. To further decrease
the reaction time, we concluded that the DHPM formation
was most desirable at 67°C for 6 h (Table 2, entries 16–21).
Several Brønsted acids and Lewis acids were reported to
2
5
2
was formed in lower yields (<15%) (Table 2, entries 1–4).
When the reaction was performed in DCM, CHCl , or
3
catalyze the Biginelli reaction such as HCl, H SO , TsOH,
4
-dioxane, low yields were obtained (Table 2, entries 7–9).
2
4
LiBr, InBr , FeCl , and so on [42]. Next, in order to
Next, the effects of time and temperature on this reaction
were evaluated. We attempted to relate yields to what will
happen if we keep the temperature constant at room temper-
ature. It was observed that the formation of the product
increases with time duration (Table 2, entry 5 and entries
3
3
improve the efficiency, different acid cocatalysts combined
with 5d were employed to catalyze this reaction. In our
investigation, Lewis acids such as FeCl , ZnCl , and
3
2
MgCl were not effective in promoting the reactivity of this
2
reaction at all (Table 3, entries 9–11). Moderate yields of the
product were obtained with HCOOH and p-TSA
1
0–12). It was found that there was not much appreciable
change in yield even when the reaction was carried out from
2 to 24h (Table 2, entry 5, and Table 1, entry 7). Subse-
(
Table 3, entries 3 and 7). We also screened organic
1
acids. When benzoic acid, 2,4,5-trifluorophenylacetic
acid, p-fluoroboric acid, and HOAc were used in the
reaction, low yields were obtained (Table 3, entries 1,
quently, the effect of temperature on the rate of reaction
was studied. The temperature of the reaction was gradually
increased from room temperature to 67°C (the boiling point
of THF). The effect of temperature was clearly distinct on
2
, and 6). Inorganic acids, such as H PO and HCl, could
3 4
Table 2
a
Optimization of solvent, temperature, and time for the Biginelli reaction.
b
Entry
Solvent
Temp. (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
C
2
H
5
OH
25
25
25
25
25
25
25
25
25
25
25
25
40
50
60
12
12
12
12
12
12
12
12
12
8
15
6
10
9
DMSO
H
i-PrOH
THF
Toluene
DCM
CH
1, 4-Dioxane
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
2
O
69
56
42
39
30
62
55
53
73
80
89
90
92
91
86
80
77
3
Cl
1
1
1
1
1
1
1
1
1
1
2
2
0
1
2
3
4
5
6
7
8
9
0
1
6
4
12
12
12
12
8
6
5
4
2
Reflux 67
67
67
67
67
67
THF
a
Reagents and conditions: after stirring a solution of HCl (10 mol%), benzaldehyde (0.5 mmol), and urea (0.75 mmol),
in 2 mL of solvent at specified temperature for 1 h, catalyst 5d (10 mol%) and ethyl acetoacetate (1.5 mmol) were
added sequentially.
b
Yield of isolated product.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Q. Song, X. An, F. Che, and T. Shen
Vol 000
Table 3
a
Optimization of acid for the Biginelli reaction.
b
Entry
Acid
Yield (%)
c
1
2
3
4
5
6
7
8
9
TFPA
Trace
45
63
89
59
27
56
31
HOAc
HCOOH
HCl
H
3
PO
4
Benzoic acid
p-TSA
p-Fluoroboric acid
FeCl
ZnCl
MgCl
3
Trace
Trace
22
1
1
0
1
2
2
a
After stirring a solution of specified acid (10 mol%), benzaldehyde (0.5 mmol), and urea (0.75 mmol), in 2 mL of
THF at 67°C for 1 h, catalyst 5d (10 mol%) and ethyl acetoacetate (1.5 mmol) were added sequentially.
b
Yield of isolated product.
c
TFPA: 2,4,5-trifluorophenylacetic acid.
promote the reaction effectively in the yield from 59 to
THF at 67°C. Good to excellent yields (>90%) have been
achieved without further purification. This new protocol has
the advantages of environmental friendliness, short reaction
time, excellent yields, and simple post-treatment procedure,
which make it a useful and attractive protocol for scale-up
synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives.
Moreover, based on the optimized condition, a novel
Biginelli-like reaction was first successfully reported.
8
9% (Table 2, entries 4 and 5).
With the optimal conditions in hand, the Biginelli reac-
tions of a variety of aldehydes with urea and ethyl
acetoacetate were then investigated. As shown in Table 4,
a variety of substituted benzaldehydes 4a–4j could undergo
the reactions to afford DHPMs in high yields ranging from
7
3 to 98%. Obviously, the electronic effect of the substitu-
ent of aromatic aldehydes had much influence on this
reaction. Aldehydes with electron withdrawing substituents
such as –NO , –F, –Cl, and –Br (Table 4, entries 2–7) gave
2
EXPERIMENTAL
similar high yields. However, aldehydes with electron
donating substituents such as –Me and –OMe led to a signif-
icant decrease in yields (Table 4, entries 8 and 9). Benzalde-
hyde as the simplest aromatic aldehyde can obtain 92%
yield (Table 4, entry 1). And high yield (95%) was obtained
when sterically hindered 1-naphthyl aldehyde 4j was
employed (Table 4, entry 10).
Under the optimized condition, it also encouraged us to
explore Biginelli-like reaction. In my experience, a straight
substitution of bridged dialdehyde [43] b for aldehyde was
reacted with urea and ethyl acetoacetate under reflux to
successfully afford bis-DHPM c as white powder solid in
All the chemicals were analytical grade reagents and were used
without further purification. H NMR spectra and C NMR spec-
1
13
tra were recorded on a Bruker Avance III 500 MHz spectrometer
1
(
Bruker, Switzerland) and using DMSO-d
6
(500MHz for H or
13
125 MHz for C, respectively) as solvent. IR spectra were
recorded on a Bruker TENSOR 27 spectrometer (Bruker Optics,
Germany). Melting points were taken on a SGW X-4 digital
display microscopic melting point apparatus (Shanghai Wuguang
Company, China). Mass spectra were carried out on Varian 1200
(
Thermo Fisher Scientific, America). Microanalyses were taken
on a Costech ECS 4010 CHNSO elemental analyzer (Costech,
Italy). The reaction mixture was monitored by silica gel plates
(60F-254; Qingdao Jiyida Silica Reagent Factory, China).
General procedure for synthesis of diamide ligands
7
8% yield (Scheme 1).
5
a–5d.
Following closely a literature procedure [44], we
In conclusion, we have reported a novel, efficient, and
can obtain that the title compounds 5a–5d was isolated as
practical synthesis protocol of DHPMs via the Biginelli reac-
tion of an aromatic aldehyde, urea, and ethyl acetoacetate
catalyzed by DACH-pyridyl diamide ligands 5d and HCl in
a white powder solid. And 5a is a known compound.
N,N′-(Cyclohexane-1,2-diyl)dipicolinamide (5a). White
powder, mp 170–173°C [44].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Novel and Efficient Synthesis of DHPMs Catalyzed by di-DACH-Pyridylamide
Ligands
Table 4
a
Scope of the Biginelli reaction catalyzed by 5d.
b
Entry
Product
Ar
Yield (%)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
C
6
H
5
92
96
95
98
97
98
97
78
73
95
2-NO
3-NO
4-NO
4-FC H
6 4
6 4
4-ClC H
4-BrC
4-MeC
4-MeOC
1-Naphthyl
2
2
2
C
C
C
6
6
6
H
H
H
4
4
4
6 4
H
H
6 4
6 4
H
1
0
4j
a
After stirring a solution of HCl (10 mol%), 1a (0.5 mmol), and urea (0.75 mmol), in 2 mL of THF at 67°C for 1 h, catalyst 5d
(
10 mol%) and ethyl acetoacetate (1.5 mmol) were added sequentially.
Yield of isolated product.
b
J=5.7, 3.9Hz, 1H), 2.06 (d, J= 13.2 Hz, 1H), 1.69 (d, J=8.2Hz,
Scheme 1. Biginelli-like reaction.
13
1H), 1.39 (d, J= 9.2 Hz, 1H), 1.30–1.16 (m, 1H); C NMR
(
1
126 MHz, DMSO) δ 166.05, 148.40, 145.64, 139.33, 133.91,
28.55, 52.29, 30.27, 23.42; MS m/z 462 (M ). Anal. Calcd. for
+
C H Cl N O : C, 46.78; H, 3.49; N, 12.12. Found: C, 46.76; H,
18
16
4 4 2
3
.47; N, 12.13%.
N,N′-(Cyclohexane-1,2-diyl)bis(3,6-dichloropicolinamide)
À1
(
5d). White powder; yield 71%; mp 209–211°C; IR (KBr, cm ):
3
1
6
441, 2940, 2655, 2352, 2081, 1624, 1570, 1429, 1397, 1332, 1245,
181, 1095, 882; H NMR (500 MHz, DMSO) δ 8.25 (dd, J= 106.0,
4.7 Hz, 1H), 7.90 (d, J=8.4Hz, 1H), 7.41–7.37 (m, 1H), 2.05
1
(
1
d, J= 13.3 Hz, 1H), 1.70 (d, J=8.4Hz, 1H), 1.39 (d, J=9.2Hz,
H), 1.28–1.18 (m, 1H); C NMR (126 MHz, DMSO) δ 167.64,
13
1
57.96, 147.35, 140.34, 124.60, 123.36, 52.13, 29.90, 23.28; MS
+
m/z 462 (M ). Anal. Calcd. for C18
H16Cl
4
N
4
O
2
: C, 46.78; H, 3.49;
N, 12.12. Found: C, 46.76; H, 3.47; N, 12.13%.
General procedure for synthesis of symmetrical bridged
bis-Schiff base 5e and 5f. Following closely a literature
procedure [45], first, we can obtain the yellow crystalline solid b.
Then, to a solution of 4-(2-amino-3-hydroxy-3,3-diphenyl-propyl)-
phenol (2 mmol) in 10 mL 95% EtOH was added substituted 2,2′-
N,N′-(Cyclohexane-1,2-diyl)bis(6-chloropicolinamide)
5b). White powder; yield 72%; mp 201–205°C; IR (KBr, cm ):
À1
(
3
1
(
7
(
1
1
439, 2931, 2557, 2198, 1637, 1572, 1443, 1382, 1364, 1246, 1364,
(butane-1,4-diylbis(oxy)) dibenzaldehyde (4 mmol) b. The resulting
1
246, 1161, 1067, 960, 844; H NMR (500 MHz, DMSO) δ 8.48
solution was vigorously stirred for 24 h at room temperature, and
then the reaction was vacuum filtered to remove the solvent. The
crude product was purified by silica gel flash column
chromatography or recrystallized to give the resulting symmetrical
bridged bis-Schiff base as a white solid, in high yield (>81%).
2,2′-((1E,1′E)-(((Butane-1,4-diylbis(oxy))bis(2,1-phenylene))
bis(methanylylidene))bis(azanylylidene))bis(1,1,3-triphenylpropan-
s, 1H), 8.30 (dd, J = 4.7, 1.9 Hz, 1H), 7.88 (dd, J = 7.5, 1.8 Hz, 1H),
.36 (dd, J = 7.5, 4.8 Hz, 1H), 3.03 (dd, J = 11.7, 7.6 Hz, 1H), 2.03
d, J = 12.9Hz, 1H), 1.69 (d, J = 8.2 Hz, 1H), 1.36 (d, J = 9.3 Hz,
1
3
H), 1.28–1.14 (m, 1H); C NMR (126 MHz, DMSO) δ 168.42,
48.42, 146.64, 137.89, 135.73, 122.73, 52.57, 30.50, 23.52; MS
+
m/z 392 (M ). Anal. Calcd. for C18
2 4 2
H18Cl N O : C, 54.97; H,
4
.61; N, 14.25. Found: C, 54.96; H, 4.58; N, 14.23%.
N,N′-(Cyclohexane-1,2-diyl)bis(3,4-dichloropicolinamide)
1-ol) (5e).
White powder; yield 81%; mp 177–181°C; IR (KBr,
À1
cm ): 3251, 2949, 1651, 1602, 1492, 1450, 1384, 1253, 1167, 752,
À1
1
(
5c). White powder; yield 77%; mp 197–199°C; IR (KBr, cm ):
701; H NMR (500 MHz, DMSO) δ 8.75 (s, 1H), 7.72 (d, J=7.5Hz,
3
9
1
426, 2943, 2492, 2134, 1608, 1530, 1371, 1225, 1192, 1152, 1046,
34, 895, 843; H NMR (500 MHz, DMSO) δ 8.72 (d, J=1.9Hz,
H), 8.50 (d, J= 38.7 Hz, 1H), 8.29 (d, J= 1.9Hz, 1H), 3.11 (dd,
4H), 7.65 (d, J= 7.5 Hz, 2H), 7.38 (d, J= 5.5 Hz, 2H), 7.35 (d,
J= 2.4 Hz, 1H), 7.33 (d, J= 7.9 Hz, 2H), 7.31 (d, J= 4.3 Hz, 4H), 7.27
(d, J= 7.3 Hz, 2H), 7.06 (t, J= 7.2 Hz, 2H), 4.68 (d, J= 5.2 Hz, 1H),
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Q. Song, X. An, F. Che, and T. Shen
Vol 000
+
4
.09 (d, J= 32.2 Hz, 2H), 2.96 (d, J= 13.7 Hz, 1H), 2.83 (d, J=6.3Hz,
64.42, 52.85, 48.29, 30.60, 27.17, 21.23; MS m/z 422 (M ). Anal.
+
2H), 1.79 (s, 2H); MS m/z 869 (M ). Anal. Calcd. for C H N O : C,
Calcd. For C H N O : C, 79.59; H, 6.20; N, 6.63. Found: C, 79.55;
6
0
56
2
4
28 26 2 2
82.92; H, 6.49; N, 3.22. Found: C, 82.90; H, 6.45; N, 3.24%.
H, 6.29; N, 6.67%.
2
,2′-((1E,1′E)-(((Butane-1,4-diylbis(oxy))bis(2,1-phenylene))
(1′R,2′S)-2′-Benzoyl-5-chloro-1′-phenyl-1′,2′,5′,6′,7′,7a′-
hexahydrospiro[indoline-3,3′-pyrrolizin]-2-one (5j). White
bis(methanylylidene))bis(azanylylidene))bis(1,1,2-triphenylethanol)
5f). White powder; yield 75%; mp 217–221°C; IR (KBr, cm ):
278, 3059, 2968, 2869, 1591, 1547, 1491, 1447, 1177, 1029, 971,
À1
À1
(
3
7
(
2
(
(
(
powder; yield 82%; IR (KBr, cm ): 3414, 3027, 2955, 2936,
1
2873, 1730, 1676, 1365, 1305, 1164, 982, 861; H NMR
1
71, 740, 698, 538; H NMR (500 MHz, DMSO) δ 8.27 (s, 1H), 7.86
d, J= 7.5 Hz, 1H), 7.46–7.42 (m, 2H), 7.33 (dd, J= 10.5, 3.1 Hz,
H), 7.21 (d, J= 2.3 Hz, 1H), 7.10 (dd, J= 14.6, 7.2 Hz, 2H), 7.02
t, J= 7.3 Hz, 1H), 6.76 (s, 1H), 5.58 (d, J= 5.2 Hz, 1H), 4.26–4.18
m, 1H), 4.13 (s, 1H), 4.07–3.99 (m, 1H), 1.99 (s, 1H), 0.91–0.76
m, 1H); MS m/z 841 (M ). Anal. Calcd. for C58
H, 6.23; N, 3.33. Found: C, 82.81; H, 6.25; N, 3.35%.
General procedure for synthesis of spiro pyrrolizines
g–5j. A mixture of isatin (1.0 mmol), L-proline (1.2mmol),
and chalcone (1.1 mmol) in methanol was refluxed for 6 h and
then cooled to room temperature. The solvent was removed under
reduced pressure, and the crude product obtained was purified by
column chromatography using petroleum ether/ethyl acetate (4:1)
as eluent.
3
(500 MHz, CDCl ) δ 8.39 (s, 1H), 7.52 (d, J = 7.3 Hz, 2H), 7.44
(dd, J = 8.2, 1.1 Hz, 2H), 7.38–7.30 (m, 3H), 7.25–7.17 (m, 4H),
7.12 (dd, J = 8.3, 2.1Hz, 1H), 4.95 (d, J = 11.4 Hz, 1H), 4.26 (dt,
J = 9.8, 6.3 Hz, 1H), 3.89 (dd, J = 11.0, 10.3Hz, 1H), 3.49 (s, 1H),
2.73–2.62 (m, 2H), 2.10–2.01 (m, 1H), 2.01–1.89 (m, 2H),
+
13
H
52
N
2
O
4
: C, 82.83;
3
1.80–1.72 (m, 1H); C NMR (126 MHz, CDCl ) δ 196.65,
180.32, 139.37, 139.11, 136.99, 133.04, 129.50, 128.73, 128.24,
128.08, 127.92, 127.84, 127.77, 127.09, 126.89, 110.90, 77.27,
77.01, 76.76, 73.47, 72.00, 64.45, 52.87, 48.18, 30.54, 27.31; MS
5
+
m/z 442 (M ). Anal. Calcd. For C H ClN O : C, 73.21; H,
2
7
23
2 2
5.23; N, 6.32. Found: C, 73.25; H, 5.29; N, 6.27%.
General procedure for synthesis of DHPMs (4a–4j). After
stirring a solution of HCl (10 mol%), 1a (0.5 mmol), and urea
(0.75 mmol), in 2 mL of THF at 67°C for 1 h, catalyst 5d (10 mol
%) and ethyl acetoacetate (1.5 mmol) were added sequentially.
Then, the crude product was purified by recrystallization with
ethanol to afford 4a–4j.
(
3′S,4′R)-3′-Benzoyl-1′-isopropyl-4′-phenylspiro[indoline-
3
,2′-pyrrolidin]-2-one (5g). White crystal; yield 89%; IR (KBr,
À1
cm ): 3188, 3060, 2963, 2870, 1734, 1677, 1616, 1470, 1448,
1
1
385, 1329; H NMR (500 MHz, CDCl
J= 7.3 Hz, 2H), 7.40–7.35 (m, 2H), 7.32 (dd, J= 12.4, 4.6 Hz, 3H),
.20 (dd, J=7.2, 5.9Hz, 2H), 7.16 (t, J=7.8Hz, 2H), 7.02
td, J= 7.6, 1.2Hz, 1H), 6.98 (dd, J= 11.0, 4.0 Hz, 1H), 6.47
d, J= 7.5 Hz, 1H), 4.64 (d, J= 10.6 Hz, 1H), 4.04 (t, J= 10.7 Hz,
H), 3.94 (dd, J= 10.7, 4.4 Hz, 1H), 2.16 (s, 1H), 1.83
qd, J= 11.3, 6.8 Hz, 1H), 0.99 (d, J = 6.8 Hz, 3H), 0.92
d, J=6.9Hz, 3H); C NMR (126 MHz, CDCl ) δ 197.36, 181.96,
40.63, 139.87, 137.23, 132.71, 129.93, 129.11, 128.66, 128.49,
28.09, 127.62, 126.81, 125.73, 123.07, 109.38, 77.29, 77.03,
3
) δ 7.79 (s, 1H), 7.55 (d,
Ethyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-
1
carboxylate (4a). White solid; yield 92%; mp 199–203°C; H
7
(
(
1
(
(
1
1
7
NMR (500 MHz, DMSO): δ (ppm) 1.09 (t, J= 7.2Hz, 3H), 2.25
(s, 3H), 3.98 (dd, J = 7.2 Hz, 14.4 Hz, 2H), 5.15 (d, J = 2.8 Hz, 1H),
7.23–7.34 (m, 5H), 7.74 (s, 1H), 9.19 (s, 1H).
Ethyl-6-methyl-4-(2-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-
1
5-carboxylate (4b). White solid; yield 96%; mp 218–221°C; H NMR
13
(500 MHz, DMSO): δ (ppm) 1.21 (t, J= 7.4 Hz, 3H), 2.26 (s, 3H), 4.20
(dd, J= 7.0 Hz, 14.2 Hz, 2H), 5.13 (d, J= 2.8 Hz, 1H), 7.47 (s, 1H), 7.52
(s, 1H), 7.70 (s, 1H), 7.96 (s, 1H), 8.31 (d, J= 8.8 Hz, 2H).
3
6.78, 69.62, 68.64, 64.14, 51.18, 30.26, 20.52, 17.42; MS m/z 410
Ethyl-6-methyl-4-(3-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-
+
1
(
M ). Anal. Calcd. for C27
24 2 2
H N O : C, 79.00; H, 6.38; N, 6.82.
5-carboxylate (4c). White solid; yield 95%; mp 227–231°C; H NMR
Found: C, 78.97; H, 6.34; N, 6.78%.
1′R,2′S)-2′-Benzoyl-1′-phenyl-1′,2′,5′,6′,7′,7a′-hexahydrospiro
indoline-3,3′-pyrrolizin]-2-one (5h). White crystal; yield 84%;
IR (KBr, cm ):3363, 3184, 3030, 2959, 2114, 1896, 1618, 1352,
(500 MHz, DMSO): δ (ppm) 1.29 (t, J= 7.2 Hz, 3H), 2.23 (s, 3H), 4.18
(dd, J= 7.2 Hz, 14.2 Hz, 2H), 5.12 (d, J= 2.8 Hz, 1H), 7.59 (s, 1H), 7.62
(s, 1H), 8.07 (s, 1H), 8.12 (s, 1H), 8.48 (d, J= 8.8 Hz, 2H).
(
[
À1
Ethyl-6-methyl-4-(4-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-
1
1
1
(
(
067; H NMR (500 MHz, CDCl
d, J=7.3Hz, 2H), 7.42–7.38 (m, 2H), 7.37–7.30 (m, 3H), 7.27
d, J=7.6Hz, 4H), 7.23 (d, J= 7.3 Hz, 1H), 7.19 (dd, J= 13.4,
3
) δ 7.84 (s, 1H), 7.53
5-carboxylate (4d). White solid; yield 98%; mp 205–208°C; H NMR
(500 MHz, DMSO): δ (ppm) 1.11 (t, J= 7.2 Hz, 3H), 2.29 (s, 3H), 4.00
(dd, J= 7.2 Hz, 14.4 Hz, 2H), 5.29 (d, J=2.8Hz, 1H), 7.52 (d,
J= 8.8 Hz, 2H), 7.90 (s, 1H), 8.23 (d, J=8.8Hz, 2H), 9.37 (s, 1H).
Ethyl-4-(4-fluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-
5
1
.7 Hz, 2H), 7.13 (td, J=7.7, 0.9Hz, 1H), 7.03 (dd, J=7.7, 7.1Hz,
H), 6.56 (d, J= 7.7 Hz, 1H), 4.96 (d, J= 11.4 Hz, 1H), 4.28 (dt,
1
J=9.8, 6.3Hz, 1H), 3.96–3.89 (m, 1H), 2.76–2.60 (m, 2H), 2.05
td, J= 12.2, 7.0 Hz, 1H), 1.99–1.87 (m, 2H), 1.77 (dt, J= 13.2,
5-carboxylate (4e). White solid; yield 97%; mp 182–186°C; H NMR
(
7
(500 MHz, DMSO): δ (ppm) 1.09 (t, J= 6.8 Hz, 3H), 2.25 (s, 3H), 3.98
(dd, J= 6.8 Hz, 13.6 Hz, 2H), 5.15 (d, J=2.8Hz, 1H), 7.13–7.17 (m, 2H),
7.25–7.29 (m, 2H), 7.76 (s, 1H), 9.24 (s, 1H).
+
.6 Hz, 3H); MS m/z 408 (M ). Anal. Calcd. for C H N O : C,
27 24 2 2
7
9.39; H, 5.92; N, 6.86. Found: C, 79.36; H, 5.93; N, 6.87%.
1′R,2′S)-2′-Benzoyl-5-methyl-1′-phenyl-1′,2′,5′,6′,7′,7a′-
(
Ethyl-4-(4-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-
1
hexahydrospiro[indoline-3,3′-pyrrolizin]-2-one (5i).
powder; yield 80%; IR (KBr, cm ): 3665, 3359, 3071, 3025, 2969,
White
5-carboxylate (4f). White solid; yield 98%; mp 211–215°C; H NMR
À1
(500 MHz, DMSO): δ (ppm) 1.09 (t, J= 7.2 Hz, 3H), 2.25 (s, 3H), 2.26
(s, 3H), 3.98 (dd, J= 6.6 Hz, 13.8 Hz, 2H), 5.15 (d, J= 2.4 Hz, 1H), 7.25
(d, J=8.1Hz, 2H), 7.39 (d, J= 8.1 Hz, 2H), 7.78 (s, 1H), 9.26 (s, 1H).
Ethyl-4-(4-bromophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-
1
2
874, 1715, 1682, 1616, 1475, 1446, 1283, 998; H NMR (500 MHz,
CDCl ) δ 7.92 (s, 1H), 7.54 (d, J= 7.3 Hz, 2H), 7.43–7.38 (m, 2H),
.34 (dt, J= 13.1, 6.5 Hz, 3H), 7.20 (dt, J= 22.3, 7.6 Hz, 3H), 7.05
s, 1H), 6.92 (d, J= 7.8 Hz, 1H), 6.46 (d, J= 7.9 Hz, 1H), 4.94
d, J= 11.4 Hz, 1H), 4.28 (dt, J=9.8, 6.3Hz, 1H), 3.97–3.89 (m, 1H),
.74 (dt, J= 14.5, 7.2 Hz, 1H), 2.69–2.62 (m, 1H), 2.36 (s, 3H), 2.06
td, J= 12.2, 7.0 Hz, 1H), 1.99–1.88 (m, 2H), 1.78 (dt, J= 13.2,
3
7
(
(
2
(
7
1
1
1
5-carboxylate (4g). White solid; yield 97%; mp 206–209°C; H NMR
(500 MHz, DMSO): δ (ppm) 1.09 (t, J= 6.6 Hz, 3H), 2.26 (s, 3H), 3.99
(dd, J= 6.3 Hz, 13.2 Hz, 2H), 5.14 (d, J= 2.8 Hz, 1H), 7.20 (d, J=8.1Hz,
2H), 7.53 (d, J= 7.8 Hz, 2H), 7.77 (s, 1H), 9.25 (s, 1H).
13
.6 Hz, 1H); C NMR (126 MHz, CDCl
38.23, 137.19, 132.78, 131.70, 129.81, 128.67, 128.15, 128.08,
27.89, 126.96, 124.97, 109.72, 77.29, 77.03, 76.78, 73.59, 72.04,
3
) δ 197.11, 180.65, 139.83,
Ethyl-6-methyl-2-oxo-4-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-
1
5-carboxylate (4h). White solid; yield 78%; mp 233–236°C; H
NMR (500 MHz, DMSO): δ (ppm) 1.10 (t, J = 7.0 Hz, 3H), 2.25 (s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Novel and Efficient Synthesis of DHPMs Catalyzed by di-DACH-Pyridylamide
Ligands
3
H), 2.26 (s, 3H), 3.99 (dd, J = 7.2 Hz, 14.4Hz, 2H), 5.11 (d,
[9] Karthikeyan, P.; Kumar, S.-S.; Arunrao, A.-S.; Narayan, M.-P.;
Bhagat, P.-R. Res Chem Intermed 2013, 39, 1335.
J = 2.8 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H),
[
[
10] Bose, D.-S.; Fatima, L.; Mereyala, H.-B. J Org Chem 2003, 68, 587.
11] Zhang, H.; Zhou, Z.; Xiao, Z.; Xu, F.; Shen, Q. Tetrahedron
7
.70 (s, 1H), 9.17 (s, 1H).
Ethyl-4-(4-methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyri
Lett 2009, 50, 1622.
midine-5-carboxylate (4i). White solid; yield 73%; mp 201–205°C;
[
[
[
12] Rafiee, E.; Shahbazi, F. J Mol Catal A 2006, 57, 250.
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14] Salehi, P.; Dabiri, M.; Zolfigol, M.-A.; Fard, M.-A.-B.
1
H NMR (500 MHz, DMSO): δ (ppm) 1.10 (t, J= 7.0 Hz, 3H), 2.24 (s,
3
H), 3.71 (s, 3H), 3.98 (dd, J= 6.4 Hz, 13.2 Hz, 2H), 5.10 (d,
J=2.8Hz, 1H), 6.87 (d, J= 8.0 Hz, 2H), 7.15 (d, J= 8.0 Hz, 2H),
.68 (s, 1H), 9.17 (s, 1H).
Tetrahedron Lett 2003, 44, 2889.
[15] Zhu, Y.-L.; Huang, S.-L.; Wan, J.-P.; Yan, L.; Pan, Y.-J.;
Wu, A. Org Lett 2006, 8, 2599.
7
Ethyl-6-methyl-4-(4-(naphthalen-1-yl)phenyl)-2-oxo-1,2,3,4-
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tetrahydropyrimidine-5-carboxylate (4j). White solid; yield 95%;
mp 232–236°C; H NMR (500 MHz, DMSO): δ (ppm) 0.81 (t,
J= 6.9 Hz, 3H), 2.36 (s, 3H), 3.79 (dd, J= 7.5 Hz, 15 Hz, 2H), 6.05
1
20, 1059.
[17] Ahmed, B.; Khan, R.-A.; Habibullah, K.-M. Tetrahedron Lett
2009, 50, 2889.
(d, J= 2.4 Hz, 1H), 7.39–7.59 (m, 4H), 7.46 (s, 1H), 7.84 (d,
[
18] Dezhahang, Z.; Poopari, M.-R.; Xu, Y.-J. Chem Asian J 2013,
8, 1205.
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tallics 2007, 26, 65.
J= 7.8 Hz, 1H), 7.94 (d, J= 7.5 Hz, 1H), 8.30 (d, J= 7.8 Hz, 1H),
9.25 (s, 1H).
General procedure for synthesis of bis-DHPM (c). After
[
stirring a solution of HCl (10 mol%), b (0.25 mmol), and urea
(
0.75 mmol), in 2 mL of THF at 67°C for 1 h, catalyst 5d
[21] Zhang, H.; Chen, L.; Song, H.; Li, G. Inorg Chim Acta 2011,
(
10 mol%) and ethyl acetoacetate (1.5 mmol) were added
366, 320.
sequentially. After completion of the reaction (monitored by
TLC), the reaction mixture was cooled to room temperature,
and the precipitated product was filtered and washed with
cooled ethanol (1 mL × 2) to afford the pure product as a solid
powder in good to excellent yield without further purification.
Diethyl4,4′-((butane-1,4-diylbis(oxy)) bis(2,1-phenylene))bis(6-methyl-
[
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2
-oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylate) (c).
White
À1
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powder; yield 78%; IR (KBr, cm ): 3409, 3222, 31,112, 2956,
[
[
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1
1
(
(
(
689, 1647, 1598, 1489, 1234, 1082, 1045, 756; H NMR
500 MHz, DMSO) δ 9.22–9.09 (m, 1H), 7.24–7.17 (m, 2H), 7.08
ddd, J=7.4, 4.3, 1.6Hz, 1H), 7.00 (t, J=9.1Hz, 1H), 6.87
t, J= 7.4 Hz, 1H), 5.54–5.49 (m, 1H), 4.08 (ddd, J= 13.1, 9.2,
7
9, 139.
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4
1
1
1
5
.3 Hz, 2H), 3.93–3.86 (m, 2H), 2.29–2.26 (m, 3H), 1.97 (s, 2H),
13
.03–0.98 (m, 3H); C NMR (126 MHz, DMSO) δ 189.15,
65.32, 156.22, 156.09, 152.03, 148.52, 131.67, 128.60, 128.00,
27.80, 119.92, 111.97, 97.40, 91.03, 67.72, 67.53, 60.72, 58.87,
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8
[
4.28, 50.29, 49.98, 45.20, 25.61, 25.48, 17.71, 13.92; MS m/z 606
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+
(M ). Anal. Calcd. for C H N O : C, 63.35; H, 6.31; N, 9.24.
32
38
4
8
Found: C, 63.32; H, 6.29; N, 9.25%.
[
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[
Acknowledgment. We gratefully acknowledge financial support
from the Foundation of Natural Science of Zhejiang Province (no.
LY12B02016).
[
2
2
2
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet