Hydrogen bond donor-acceptor-donor organocatalysis for conjugate addition of benzylidene barbiturates via complementary DAD-ADA hydrogen bonding

Article abstract of DOI:10.1039/c4ra04020a

A new class of hydrogen bond donor-acceptor-donor (HB-DAD) organocatalysts has been developed for conjugate addition of benzylidene barbiturates. HB-DAD organocatalyst 1a (featuring para-chloro-pyrimidine as the hydrogen bond acceptor (HBA), N-H as the hydrogen bond donor (HBD) and a trifluoroacetyl group as the electron withdrawing group (EWG)) is able to activate benzylidene barbiturates through complementary DAD-ADA hydrogen bonding. Using 1a in benzylidene barbiturate conjugate addition, good yields were achieved. The relative rate constant (k_rel = 2.9) of 1a in catalyzing the conjugate addition of benzylidene barbiturates and the binding constant (K_A = 8936 (±723) M^-1) of 1a with benzylidene barbiturates were determined by NMR and UV/Vis. spectroscopy studies. The excellent correlation (R² = 0.97) between the relative rate constant and binding affinity of 1a with benzylidene barbiturates provides support for the importance of DAD-ADA hydrogen bonding in organocatalysis. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra04020a

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PAPER
Hydrogen bond donor–acceptor–donor
organocatalysis for conjugate addition of
benzylidene barbiturates via complementary DAD–
ADA hydrogen bonding†
Cite this: RSC Adv., 2014, 4, 26748
Franco King-Chi Leung, Jian-Fang Cui, Tsz-Wai Hui, Zhong-Yuan Zhou
*
and Man-Kin Wong
A new class of hydrogen bond donor–acceptor–donor (HB-DAD) organocatalysts has been developed for
conjugate addition of benzylidene barbiturates. HB-DAD organocatalyst 1a (featuring para-chloro-
pyrimidine as the hydrogen bond acceptor (HBA), N–H as the hydrogen bond donor (HBD) and a
trifluoroacetyl group as the electron withdrawing group (EWG)) is able to activate benzylidene
barbiturates through complementary DAD–ADA hydrogen bonding. Using 1a in benzylidene barbiturate
conjugate addition, good yields were achieved. The relative rate constant (krel ¼ 2.9) of 1a in catalyzing
the conjugate addition of benzylidene barbiturates and the binding constant (KA ¼ 8936 (ꢀ723) Mꢁ1) of
1a with benzylidene barbiturates were determined by NMR and UV/Vis. spectroscopy studies. The
excellent correlation (R2 ¼ 0.97) between the relative rate constant and binding affinity of 1a with
benzylidene barbiturates provides support for the importance of DAD–ADA hydrogen bonding in
organocatalysis.
Received 2nd May 2014
Accepted 9th June 2014
DOI: 10.1039/c4ra04020a
www.rsc.org/advances
assembly.5 This class of hydrogen bonding system is of high
utility in various applications in materials science because of its
Introduction
highly directional nature. In addition, these three comple-
mentary DAD–ADA hydrogen bondings are strong binding
arrays.6 However, studies on the use of the complementary
DAD–ADA hydrogen bonding in organocatalysis have rarely
been explored.
Along with our ongoing interest in the development of
organocatalysis for organic synthesis7 and bioconjugation,8 we
envision that this highly directional and strong complementary
HB-DAD and HB-ADA systems could be developed as new
catalyst scaffolds and efficient activation modes for hydrogen
bond-based organocatalysis.
Hydrogen bond donor–donor (HB-DD) organocatalysis has
largely been developed as efficient methodologies to achieve
synthetic organic transformations.1 Over time, signicant
advancements have been made in HB-DD organocatalysis
employing thiourea-,2 guanidinium-3 and squaramide-based4
HB-DD organocatalysts. Given the success of the HB-DD orga-
nocatalysis, it remains a great interest to explore new catalyst
scaffolds for hydrogen bond-based organocatalysis.
In this work, we have designed HB-DAD organocatalysts
consisting of three components (1) hydrogen bond acceptor
(HBA), (2) hydrogen bond donor (HBD), and (3) electron with-
drawing group (EWG) (Scheme 1). The nitrogen atom in N-
heterocyclic aromatic rings including chloro-pyrimidine, pyri-
dine, and pyrazine were selected as HBA to give structurally
diverse catalyst scaffolds. Nitrogen–hydrogen (N–H bond), one
of the most electronegative hydrogen bonds, was chosen as
HBD in the design. The electron withdrawing group could be
used to tune the electrophilicity of the N–H bond.
Hydrogen bond donor–acceptor–donor (HB-DAD) and
hydrogen bond acceptor–donor–acceptor (HB-ADA) systems are
common in supramolecular chemistry, mainly acting as
supramolecular linking units in non-covalent polymer
Benzylidene barbiturates are biologically active compounds9
and synthetic building blocks.10 We considered benzylidene
barbiturates as HB-ADA substrates because of (1) the imide
group functioning as HB-ADA moiety and (2) the electron
State Key Laboratory of Chirosciences and Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon,
Hong Kong, China. E-mail: mankin.wong@polyu.edu.hk; Fax: +852 3400-8701
† Electronic supplementary information (ESI) available. CCDC 991734. See DOI:
10.1039/c4ra04020a
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HB-DAD organocatalysts in catalyzing conjugate addition of
benzylidene barbiturates and binding constant studies of HB-
DAD organocatalysts with HB-ADA benzylidene barbiturates
were conducted. The excellent correlation between the binding
constants and relative rate constants of HB-DAD organo-
catalysts provides support for HB-DAD as the catalyst scaffold in
organocatalysis.
Results and discussion
Preparation of HB-DAD organocatalysts 1–4 and HB-ADA
Scheme 1 Design of HB-DAD organocatalysts containing (1) HBA, (2)
HBD, and (3) electron withdrawing group. Complementary DAD–ADA
hydrogen bonding between HB-DAD organocatalysts and HB-ADA
benzylidene barbiturates.
benzylidene barbiturates 5 and 7
HB-DAD organocatalysts 1a–c and 3a–c were prepared by amide
coupling of 2,6-diamino-4-chloropyrimidine/2,6-diaminopyr-
azine with acid chlorides/anhydrides and obtained in 18–68%
isolated yield. In addition, 1a was characterized by X-ray crys-
tallography (see ESI†). HB-DAD organocatalysts 2a,12 2b,13 2c,14
4a,15 4b, and 4c16 were synthesized according to literature
reports. HB-ADA benzylidene barbiturates 5 and 7 were
prepared by condensation of barbiturate acid derivatives with
various benzaldehydes and obtained in 24–95% isolated yield.
The E/Z ratio of the alkene moieties of 5 and 7 were found to be
1 : 1 by NMR studies.
decient alkene unit amenable for nucleophilic attack. The
complementary hydrogen bonding mode of HB-DAD organo-
catalysts and HB-ADA benzylidene barbiturates is depicted in
Scheme 1.
In 2011, Spange and co-workers found that a gradual
adjustment of electrophilicity of a barbiturate merocyanine is
achieved through cooperative DAD–ADA hydrogen bond.11a
Substituent effects of HB-DAD receptors are transmitted to the
reactive center of electrophilic HB-ADA substrates so that a ne
adjustment of their reactivity would be possible.11b,c
Catalytic activities of HB-DAD organocatalysts 1–3 in
conjugate addition of benzylidene barbiturates
In the present work, we developed a organocatalytic conju-
gate addition of benzylidene barbiturates with 2-methylfuran
catalyzed by HB-DAD organocatalysts through the comple-
mentary DAD–ADA hydrogen bonding. Kinetic studies of
As shown in Scheme 2, the catalytic activity of 20 mol% of 1a in
conjugate addition of benzylidene barbiturate 5a (0.05 mmol)
and 2-methylfuran (0.05 mmol) at 25 ꢂC in 24 h were
Scheme 2 Catalytic activities of HB-DAD organocatalysts 1–3 in conjugate addition of 5a.
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HB-DAD organocatalysts is in the order of 1a-triuoroacetyl
group > 1b-hexanoyl group > 1c-pivaloyl group. Interestingly,
this trend of activating effect of the EWG on the catalytic
activities of 1 also applies for HB-DAD organocatalysts 2 and 3.
Using 1a with chloro-pyrimidine as the HBA, adduct 6a was
obtained in 61% yield while 2a with pyridine as the HBA gave
49% yield of 6a. The reaction using 3a with pyrazine as the HBA
gave only 44% yield of 6a. These results indicated that the
activating effect of HBA on catalytic activities of HB-DAD orga-
nocatalysts is in the order of 1a-chloro-pyrimidine > 2a-pyridine
> 3a-pyrazine.
The importance of hydrogen bond donors and acceptors in
HB-DAD organocatalyst scaffolds
Scheme 3 2a and 4a in catalyzing conjugate addition of 5a.
To investigate the importance of hydrogen bond donors and
acceptors of HB-DAD organocatalysts in catalyzing the conju-
gate addition, hydrogen bond organocatalysts including D–D
class 4a, DA- class 4b and D- -class 4c were employed for
conjugate addition of benzylidene barbiturate 5a by 2-
methylfuran.
Using 4a, adduct 6a was obtained in 28% yield. In contrast,
the reaction using 2a gave adduct 6a in 49% yield (Scheme 3).
Note that 2a has a nitrogen atom yet 4a bears a C–H bond. Thus,
the nitrogen atom (HBA) of 2a in the DAD–ADA hydrogen
bonding is essential to give catalytic activities on conjugate
addition of 5a.
Scheme 4 2a, 4b and 4c in catalyzing conjugate addition of 5a.
Conjugate addition of 5a using DA- class 4b (bearing one
triuoroacetamide group) and nitrogen atom (HBA) and D-
-class 4c (bearing one triuoroacetamide group) gave adduct 6a
in 28% yield (Scheme 4). As a comparison, 2a (bearing HB-DAD
catalyst scaffold) gave 49% yield. The higher yield of 2a than 4b
and 4c indicated that the triuoroacetamide group and
nitrogen atom are important for the catalysis.
Scheme 5 1a and thiourea A in catalyzing conjugate addition of 5a.
Using HB-DD organocatalyst thiourea
A
(3,5-bis(tri-
uoromethyl)phenyl thiourea),18 adduct 6a was obtained in
64% yield (Scheme 5) while using HB-DAD organocatalyst 1a
gave 61%. The results indicated that 1a afforded comparable
catalytic activity to thiourea A in conjugate addition of 5a.
investigated. Adduct 6a was obtained in 61% yield, using
toluene as internal standard determined by 1H NMR studies. In
the absence of 1a, 6a was obtained in 28% yield.
To optimize the reaction conditions of the conjugate addi-
tion of benzylidene barbiturate 5a with 2-methylfuran, reaction
temperature, choice of solvents, and amount of HB-DAD orga-
nocatalyst 1a used were studied (see ESI†). The conjugate
addition in the presence of 20 mol% of 1a in CH2Cl2 at 25 ꢂC in
24 h was found to be the optimized reaction conditions. The
catalytic activities of a variety of HB-DAD organocatalysts 1–3
towards conjugate addition of benzylidene barbiturate 5a were
examined accordingly (Scheme 2).
Using 1a with triuoroacetyl group as the EWG, adduct 6a
was obtained in 61% yield. Yet, 40% yield of 6a was obtained
using 1b (bearing hexanoyl group as the EWG). The results
indicated that the electron withdrawing triuoroacetyl group is
important to achieve high catalytic activity.17 1c with pivaloyl
group as the EWG gave no enhancement to yield of 6a. These
ndings indicated that the steric effect of the pivaloyl group
would lead to poor catalytic activity in the reaction. Hence,
the activating effect of the EWG on the catalytic activities of
Substrate scope of conjugate addition of benzylidene
barbiturates 5 and 7
The substrate scope of conjugate addition was examined by
using a variety of benzylidene barbiturates. Treatment of a
series of benzylidene barbiturates 5a–o with 2-methylfuran
furnished the corresponding adducts 6a–o (Table 1). As shown,
the conjugate additions were conducted in the presence of 20
mol% of 1a at 25 ꢂC in 24 h. The 1a-catalyzed conjugate addition
worked well for electron rich benzylidene barbiturates 5a–h
with good yield (Table 1; entries 1–8) because of the low back-
ground NMR yield of the reactions. Particularly, 1a-catalyzed
conjugate addition of 5b and 5e–5h bearing para-alkoxy phenyl
groups afforded good yield (entries 2 and 5–8) while the
conjugate addition of 5d bearing an ortho-methoxy phenyl
group could give even higher yield (entry 4). In contrast, 5c
bearing a meta-methoxy phenyl group gave a higher value of
background NMR yield (65%), probably due to the methoxy
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Table 1 Substrate scope of 1a-catalytzed conjugate addition of benzylidene barbiturates 5a–5o
Entrya
1
Substrate
Ar
Product
Isolated yield (%)
55
NMR yieldb (%)
61
Background NMR yieldb,c (%)
28
5a
6a
2
3
5b
5c
6b
6c
52
78
57
80
25
65
4
5d
6d
25
22
7
5
6
5e
5f
6e
6f
30
16
30
20
17
7
7
8
5g
5h
6g
6h
65
47
70
50
31
21
9
5i
5j
6i
6j
66
73
69
71
30
36
10
11
12
5k
5l
6k
6l
79
35
84
38
60
16
13
14
5m
5n
6m
6n
95
95
96
97
87
76
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Table 1 (Contd.)
Entrya
Substrate
Ar
Product
Isolated yield (%)
98
NMR yieldb (%)
Background NMR yieldb,c (%)
15
5o
6o
99
99
a
Reaction conditions: 5a–5o (0.05 mmol), 2-methylfuran (0.05 mmol), 1a (0.01 mmol), CH2Cl2 (1 mL), 25 ꢂC, 24 h. b Yields were determined by 1H
NMR of the crude product using toluene as the internal standard. c Without addition of 1a.
group in the meta-position contributes less positive mesomeric inductive and mesomeric effect on the phenyl rings. In this
effect. The results indicated that benzylidene barbiturates connection, benzylidene barbiturates bearing electron donating
bearing electron donating groups could lead to better yield groups led to better yield with low background yield.
because of the lower background yield.
Conjugate additions of 5m–o bearing electron decient
Interestingly, 5i bearing an isopropyl phenyl group, 5j substituents –Cl, –Br and –CN gave high background NMR yield
bearing a t-butyl phenyl group and 5l bearing a napthalene (76–99%) (entries 13–15). These ndings indicated that the
group led to the corresponding adducts in good yield (entries electrophilicity of benzylidene barbiturates was a crucial factor
9,10 and 12) and low background NMR yield (16–36%). in governing the yield in the reaction.
However, 5k bearing a phenyl group afforded 60% background
We further examined the scope of this reaction by changing
NMR yield (entry 11). Note that the alkyl- and aryl-substituents the substituents on the barbiturate acid moiety of benzylidene
on the phenyl ring of benzylidene barbiturates have positive barbiturates 7a–d to give the corresponding adducts 8a–d
Table 2 Substrate scope of 1a-catalytzed conjugate addition of benzylidene barbiturates 7a-7d
Entrya
Substrate
R
Ar
Product
8a
Isolated yield (%)
NMR yieldb (%)
Background NMR yieldb,c (%)
1
2
7a
7b
CH3
CH3
20
20
25
18
5
6
8b
3
7c
8c
46
75
48
73
27
61
4
7d
8d
a
Reaction conditions: 7a–7d (0.05 mmol), 2-methylfuran (0.05 mmol), 1a (0.01 mmol), CH2Cl2 (1 mL), 25 ꢂC, 24 h. b Yields were determined by 1H
c
NMR of the crude product using toluene or ethyl acetate as the internal standard. Without addition of 1a.
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Time course experiments using 20 mol% of HB-DAD orga-
nocatalysts 1a, 1b, 1c, 2a, 2b, and 3a in conjugate additions of
5a (0.025 mmol; 0.05 M) with 2-methylfuran (0.25 mmol; 0.5 M)
to give adduct 6a in CDCl3 at 25 ꢂC in 120 min were monitored
1
by H NMR.19,20 As shown in Fig. 1, the reaction orders were
nearly constant over time indicating the absence of product
inhibition. Using 1a gave adduct 6a in 66% yield while using 2a
gave adduct 6a in 56% yield. Both 1b and 2b were found to be
catalytically active, giving 6a in 52% and 49% yields, respec-
tively. In addition, the conjugate addition using 3a could lead to
adduct 6a in 44% yield. However, 1c was found to be inactive to
catalyze conjugate addition of 5a with 2-methylfuran (yield ¼
22%). With reference to the increasing acidity of the HBD (N–H)
moieties of HB-DAD organocatalysts, the reaction rate is in the
order of 1a > 2a > 1b > 2b > 3a.
Scheme 6 1a and thiourea A in catalyzing conjugate addition of 5a
with nucleophiles.
(Table 2). Benzylidene barbiturates 7a and 7b (R ¼ methyl)
afforded good yield (Table 2, entries 1 and 2). In contrast,
conjugate additions of 7c and 7d (R ¼ m-tolyl) gave high back-
ground NMR yield (27–61%; entries 3 and 4). The difference in
the background NMR yield was possibly due to the increased
electrophilicity of benzylidene barbiturates (7c and 7d) (i.e., m-
tolyl group giving negative mesomeric effect on the benzylidene
barbiturates).
Furthermore, we examined the scope of nucleophiles (1-
methylindole, indole, 5-methoxylindole, thiophene, dibenzoyl-
methane and ethylbenzyolacetate) in 1a- and thiourea A-cata-
lyzed conjugate additions of 5a. However, no yield increase of
the reaction was observed using 1a or thiourea A (Scheme 6 and
Table S4 and S5†). In this regard, 1a and thiourea A have shown
similar behavior in catalyzing conjugate addition of 5a.
Kinetic studies of HB-DAD organocatalysts
With a 10-fold excess of 2-methylfuran, all the conjugate addi-
tions of 5a were regarded as pseudo-rst-order, and the corre-
sponding rate constant kobs were determined and depicted in
Table 3. For the determination of kobs, the kinetics data was
plotted as ln[5a] against the reaction time.19 The rate constant
kobs was determined by the negative slope of the plot (see ESI†).
On the basis of the rate constant (kobs), the relative rate
constant (krel) of HB-DAD organocatalysts were calculated.20,21
The relative rate constant (krel) of 1a-catalyzed conjugate addition
of 5a was 2.9 (Table 3; entry 1). The relative rate constant suggests
that 20 mol% of HB-DAD organocatalyst 1a increases the conju-
gate addition rate by a factor of ¼ 2.9. The krel of 2a was 2.2 (entry
4) while the krel of 3a was calculated as 1.2 (entry 6). In addition,
Fig. 1 Time course experiments of HB-DAD organocatalyst-catalyzed conjugate addition of 5a with 2-methylfuran.
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Table 3 Rate constants determined by 1H NMR studies
studies were employed. In these studies, binding constants were
monitored with UV/Vis. spectroscopy titration experiments.11,22
The linearized Scatchard plot was used in determining the
binding constants of 1a, 1b, 2a, and 2b with barbiturate 9 (see
ESI†). The binding constant (KA ¼ 8936 (ꢀ723) Mꢁ1; Table 4,
entry 1) was obtained for 1a. These results indicated that using
the triuoroacetyl group as the EWG led to a signicant increase
in the binding affinity. Notably, chloro-pyrimidine is a better
HBA than pyridine in achieving high binding affinity. With the
increasing acidity of HBD (N–H) moieties in HB-DAD organo-
catalysts, the stability of hydrogen bonding complexes is in the
order of 1a > 2a > 1b > 2b.
Entry
Catalyst
kobs ꢃ 10ꢁ4 (sꢁ1
)
kcat ꢃ 10ꢁ4 (sꢁ1
)
krel
2.9
1.8
ꢁ0.03
2.2
1.4
1.2
—
1
2
3
4
5
6
7
1a
1b
1c
2a
2b
3a
—
1.48
1.05
0.37
1.22
0.90
0.82
0.38
1.11
0.67
ꢁ0.01
0.84
0.52
0.44
kuncata ¼ 0.38
Table 4 Binding constants of HB-DAD organocatalysts
Correlation of rate constants and binding constants of HB-
DAD organocatalysts
A gradually escalating trend of relative rate constants of
conjugate addition of 5a was obtained in kinetic studies while
increasing trend in binding affinity was also determined in
binding studies. Particularly,
a correlation was observed
between kinetic and binding studies. The natural logarithm of
the binding constants and relative rate constants were listed in
Table S8 (see ESI†).20b By plotting of ln KA against ln krel of HB-
DAD organocatalysts, a linear correlation (R2 ¼ 0.97) was
obtained (Fig. 2). The results indicated that a higher binding
constant gave a higher relative rate of the conjugate addition.
Entry
Catalyst
KA (Mꢁ1
)
1
2
3
4
1a
1b
2a
2b
8936 (ꢀ723)
6447 (ꢀ380)
7747 (ꢀ367)
4895 (ꢀ1019)
Conclusion
In summary, we have developed new hydrogen bond-based
organocatalysis using HB-DAD catalyst scaffold in catalyzing the
conjugate addition of benzylidene barbiturates. The catalytic
activities of HB-DAD organocatalyst 1a were comparable to
thiourea A. The catalytic activities of the HB-DAD catalyst scaf-
folds were supported by the correlation of rate constants and
binding constants. This work would lay down a foundation for
the development of chiral HB-DAD organocatalysts for asym-
metric catalysis.
Experimental section
General procedure for synthesis of HB-DAD organocatalysts 1a
and 3a
A mixture of 2,6-diamino-N-heterocyclic compounds (1.0 mmol)
and triuoroacetic anhydride (3.0 mmol) in CH2Cl2 (10 mL) was
stirred under nitrogen atmosphere at room temperature for 24
h. The reaction mixture was added with water (5 mL) and
extracted with ethyl acetate (3 ꢃ 10 mL). The combined organic
layers were dried over anhydrous Na2SO4, ltered, and
concentrated. The residue was puried by ash column chro-
matography on silica gel using ethyl acetate–hexane as eluent to
give 1a (58% yield) and 3a (68% yield).
Fig. 2 Correlation of natural logarithm rate constants and binding
constants of HB-DAD organocatalysts.
the krel of 1b and 2b were 1.8 and 1.4, respectively (entries 2 and
5). The krel of 1c was ꢁ0.03 (entry 3), meaning that 20 mol% of 1c
gave no catalytic activity to conjugate addition of 5a with 2-
methylfuran. These results indicated that the more electron
decient EWG (triuoroacetyl group) afforded the higher cata-
lytic activities than using the hexanoyl group as the EWG.
General procedure for synthesis of HB-DAD organocatalysts
1b, 1c, 3b and 3c
Binding studies of HB-DAD organocatalysts
To quantify the binding affinity of HB-DAD organocatalysts and
A mixture of 2,6-diamino-N-heterocyclic compounds (1.0
HB-ADA benzylidene barbiturate derivatives, binding constant mmol), acid chloride (2.5 mmol), 4-dimethylaminopyridine
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(0.2 mmol) and triethylamine (2.5 mmol) in CH2Cl2 (10 mL) was
stirred under nitrogen atmosphere at room temperature for 24
h. The reaction mixture was treated with water (5 mL) and
extracted with ethyl acetate (3 ꢃ 10 mL). The combined organic
layers were dried over anhydrous Na2SO4, ltered, and
concentrated. The residue was puried by ash column chro-
matography on silica gel using ethyl acetate–hexane as eluent to
give 1b (15% yield), 1c (62% yield), 3b (58% yield) and 3c (58%
yield).
Acknowledgements
We thank the nancial support of Hong Kong Research Grants
Council (PolyU 5031/11P). The Hong Kong Polytechnic Univer-
sity (G-YM50). We also thank Dr Michael Fuk-Yee Kwong and
Ms Pui-Ying Choy of PolyU for providing some benzaldehyde
substrates.
Notes and references
1 (a) A. Berkessel and H. Groeger, Asymmetric Organocatalysis:
from Biomimetic Concepts to Applications in Asymmetric
Synthesis, University Science Books, Mill Valley, 2005; (b)
A. G. Doyle and E. N. Jacobsen, Chem. Rev., 2007, 107,
5713; (c) X. Yu and W. Wang, Chem.–Asian J., 2008, 3, 516;
(d) Z. Zhang and P. R. Schreiner, Chem. Soc. Rev., 2009, 38,
1187; (e) D. Leow and C. H. Tan, Chem.–Asian. J., 2009, 4,
488; (f) E. N. Jacobsen and D. W. C. MacMillan, Proc. Natl.
Acad. Sci. U. S. A., 2010, 107, 20618.
General procedure for synthesis of benzylidene barbiturates
A mixture of barbiturate acid (2.0 mmol) and benzaldehyde (2.0
mmol) in EtOH (10 mL) was reuxed for 2–12 h. The reaction
mixture was allowed to cool to room temperature and ltered to
obtain solid/crystalline crude products. The residue was puri-
ed by ash column chromatography on silica gel using ethyl
acetate–hexane as eluent to give benzylidene barbiturates in 24–
95% yield.
2 (a) M. S. Sigman and E. N. Jacobsen, J. Am. Chem. Soc., 1998,
120, 4901; (b) T. P. Yoon and E. N. Jacobsen, Angew. Chem.,
Int. Ed., 2005, 44, 466; (c) Y. Hoashi, T. Okino and
Y. Takemoto, Angew. Chem., Int. Ed., 2005, 44, 4032; (d)
T. Inokuma, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc.,
2006, 128, 9413; (e) D. A. Yalalov, S. B. Tsogoeva,
T. E. Shubina, I. M. Martynova and T. Clark, Angew. Chem.,
Int. Ed., 2008, 47, 6624; (f) K. L. Kimmel, M. T. Robak and
J. A. Ellman, J. Am. Chem. Soc., 2009, 131, 8754; (g) W. Yang
and D. M. Du, Org. Lett., 2010, 12, 5450; (h) K. Asano and
S. Matsubara, J. Am. Chem. Soc., 2011, 133, 16711; (i) J. Xu,
Y. Hu, D. Huang, K. Wang, C. Xu and T. Niu, Adv. Synth.
Catal., 2012, 354, 515–526; (j) K. Bera and
I. N. N. Namboothiri, Adv. Synth. Catal., 2013, 355, 1265;
(k) J. C. Anderson and P. J. Koovits, Chem. Sci., 2013, 4,
2897; (l) A. R. Brown, C. Uyeda, C. A. Brotherton and
E. N. Jacobsen, J. Am. Chem. Soc., 2013, 135, 6747; (m)
M. P. Lalonde, M. A. McGowan, N. S. Rajapaksa and
E. N. Jacobsen, J. Am. Chem. Soc., 2013, 135, 1891; (n)
H. N. Yuan, S. Wang, J. Nie, W. Meng, Q. Yao and J. A. Ma,
Angew. Chem., Int. Ed., 2013, 52, 3869; (o) H. Y. Bae,
J. H. Sim, J. W. Lee, B. List and C. E. Song, Angew. Chem.,
Int. Ed., 2013, 52, 12143; (p) S. Diosdado, J. Etxabe,
Procedure for catalytic conjugate additions of benzylidene
barbiturates
A mixture of benzylidene barbiturates 5 (0.05 mmol), 2-methyl-
furan (0.05 mmol) and HB-DAD organocatalyst 1a (0.01 mmol)
in CH2Cl2 (1 mL) was stirred at 25 ꢂC for 24 h. The product yield
was determined by crude 1H NMR with toluene (0.02 mmol) as
internal standard. The reaction mixture was concentrated. The
residue was puried by ash column chromatography on silica
gel using ethyl acetate–hexane as eluent to obtain isolated yield.
Kinetics study
All reactions were conducted with 0.025 mmol of benzylidene
barbiturate 5a, 0.25 mmol of 2-methylfuran, 0.03 mmol of
dichloromethane (internal standard) and 20 mol% of HB-DAD
organocatalysts. Stock solutions of 5a (0.083 M; 0.05 mmol of 5a
in 0.6 mL of CDCl3) and the HB-DAD organocatalysts (0.05 M;
0.01 mmol of HB-DAD organocatalysts in 0.2 mL of CDCl3) were
prepared in 2 mL vials. A NMR tube was charged with 0.3 mL of
5a stock solution followed by 0.1 mL of HB-DAD organocatalysts
stock solution and 1.98 mL of dichloromethane. The mixture
was made up to 0.5 mL with CDCl3. Aer adding 22.3 mL of 2-
methylfuran, the rst NMR spectrum was taken 5 min aer the
addition. Additional NMR spectra were recorded every 5 min for
a total of 120 min.
´
J. Izquierdo, A. Landa, A. Mielgo, I. Olaizola, R. Lopez and
C. Palomo, Angew. Chem., Int. Ed., 2013, 52, 11846.
3 (a) Y. Sohtome, Y. Hashimoto and K. Nagasawa, Adv. Synth.
Catal., 2005, 347, 1643; (b) C. Uyeda and E. N. Jacobsen, J.
Am. Chem. Soc., 2008, 130, 9228; (c) M. P. Coles, Chem.
Commun., 2009, 3659; (d) D. Leow and C. H. Tan, Synlett,
2010, 11, 1589; (e) Y. Sohtome, N. Horitsugi, R. Takagi and
K. Nagasawa, Adv. Synth. Catal., 2011, 353, 2631; (f) X. Fu
and C. H. Tan, Chem.Commun., 2011, 47, 8210; (g)
M. Odagi, K. Furukori, T. Watanabe and K. Nagasawa,
Chem.–Eur. J., 2013, 19, 16740.
Binding study
Ten graduated asks (5 mL) were added with 0.5 mL of stock
solution of barbiturate 9 (2 ꢃ 10ꢁ4 M; 2 ꢃ 10ꢁ2 mmol of
barbiturate 9 in 100.0 mL of CH2Cl2) (nal concentration: 2 ꢃ
10ꢁ5 M) and 0, 20, 40, 80, 160, 320, 640, 1260, 2560, 3000 mL
(corresponding to a 2–290 fold excess) of a stock solution of HB-
DAD organocatalysts (9.67 ꢃ 10ꢁ3 M; 9.67 ꢃ 10ꢁ2 mmol of HB-
DAD organocatalysts in 10.0 mL of CH2Cl2), and lled up to 5
mL with CH2Cl2. The change in absorbance was monitored and
evaluated by linearized Scatchard plot. The given values of KA
were the average of two runs.
4 (a) J. P. Malerich, K. Hagohara and V. H. Rawal, J. Am. Chem.
Soc., 2008, 130, 14416; (b) Y. Zhu, J. P. Malerich and
V. H. Rawal, Angew. Chem., Int. Ed., 2010, 49, 153; (c)
Y. Qian, G. Ma, A. Lv, H. L. Zhu, J. Zhao and V. H. Rawal,
This journal is © The Royal Society of Chemistry 2014
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Paper
Chem. Commun., 2010, 46, 3004; (d) D. Q. Xu, Y. F. Wang, 10 (a) K. Tanaka, X. Cheng, T. Kimura and F. Yoneda, Chem.
W. Zhang, S. P. Luo, A. G. Zhong, A. B. Xia and Z. Y. Xu,
Chem.–Eur. J., 2010, 16, 4177; (e) L. Dai, S. Wang and
F. Chen, Adv. Synth. Catal., 2010, 352, 2137; (f) H. Y. Bae,
S. Some, J. H. Lee, J. Kim, M. J. Song, S. Lee, Y. J. Zhang
and C. E. Song, Adv. Synth. Catal., 2011, 353, 3196; (g)
Pharm. Bull., 1986, 34, 3945; (b) K. Tanaka, X. Cheng and
F. Yoneda, Tetrahedron, 1988, 44, 3241; (c) A. Ikeda,
Y. Kawabe, T. Sakai and K. Kaeasaki, Chem. Lett., 1989,
1803; (d) J. D. Figueroa-Villar, C. E. Rangel and L. N. Dos
Santos, Synth. Commun., 1992, 22, 1159.
W. Yang and D. Du, Adv. Synth. Catal., 2011, 353, 1241; (h) 11 (a) M. Bauer and S. Spange, Angew. Chem., Int. Ed., 2011, 50,
´
J. Aleman, A. Parra, H. Jiang and K. A. Jøgensen, Chem.–
9727; (b) A. Niemz and V. M. Rotello, Acc. Chem. Res., 1999,
32, 44; (c) S. S. Agasti, S. T. Caldwell, G. Cooke,
B. J. Jordan, A. Kennedy, N. Kryvokhyzha, G. Rabani,
S. Rana, A. Sanyalc and V. M. Rotello, Chem. Commun.,
2008, 4123.
Eur. J., 2011, 17, 6890; (i) R. I. Storer, C. Aciro and
L. H. Jones, Chem. Soc. Rev., 2011, 40, 2330; (j) D. Mailhol,
M. D. M. S. Duque, W. Raimondi, D. Bonne,
T. Constantieux, Y. Coquerel and J. Rodriguez, Adv. Synth.
Catal., 2012, 354, 3523; (k) P. Kasaplar, P. Riente, 12 I. Bolz, D. Schaarschmidt, T. Ruffer, H. Lang and S. Spange,
`
C. Hartmann and M. A. Pericas, Adv. Synth. Catal., 2012,
Angew. Chem., Int. Ed., 2009, 48, 7440.
354, 2905; (l) H. Yu, Q. Wang, Y. Wang, H. Song, Z. Zhou 13 D. Benito-Garagorri, E. Becker, J. Wiedermann, W. Lackner,
and C. Tang, Chem.–Asian J., 2013, 8, 2859; (m) H. Wang,
Y. Wang, H. Song, Z. Zhou and C. Tang, Eur. J. Org. Chem.,
M. Pollak, K. Mereiter, J. Kisala and K. Kirchner,
Organometallics, 2006, 25, 1900.
2013, 48441; (n) T. Lu and S. E. Wheeler, Chem.–Eur. J., 14 Z. Xu, P. Daka, I. Budik, H. Wang, F. Q. Bai and H. X. Zhang,
2013, 19, 15141; (o) Y. Liu, Y. Wang, H. Song, Z. Zhou and
C. Tang, Adv. Synth. Catal., 2013, 355, 2544.
5 (a) K. P. Nair, V. Breedveld and M. Weck, Macromolecules,
Eur. J. Org. Chem., 2009, 4581.
15 M. Habel, C. Niederalt, S. Grimme, M. Nieger and F. Vogtle,
Eur. J. Org. Chem., 1998, 1471.
´
´
2008, 41, 3429; (b) F. Herbst, K. Schroeter, I. Gunkel, 16 J. Barluenga, J. M. Alvarez-Gutierrez, A. Ballesteros and
´
S. Groeger, T. Thurn-Albrecht, J. Balbach and W. H. Binder, J. M. Gonzalez, Angew. Chem., Int. Ed., 2007, 46, 1281.
Macromolecules, 2010, 43, 10006; (c) K. P. Nair, V. Breedveld 17 (a) Z. Tian, A. Fattahi, L. Lis and S. R. Kass, J. Am. Chem. Soc.,
and M. Weck, So Matter, 2011, 7, 533; (d) S. Seiffert and
J. Sprakel, Chem. Soc. Rev., 2012, 41, 909.
2009, 131, 16984; (b) A. Shokri, X. B. Wang and S. R. Kass, J.
Am. Chem. Soc., 2013, 135, 9525.
6 (a) Y. Ducharme and J. D. Wuest, J. Org. Chem., 1988, 53, 18 K. M. Lippert, K. Hof, D. Gerbig, D. Ley, H. Hausmann,
5787; (b) W. L. Jørgensen and J. Pranata, J. Am. Chem. Soc.,
1990, 112, 2008; (c) J. Pranta, S. G. Wierschke and
S. Guenther and P. R. Schreiner, Eur. J. Org. Chem., 2012,
5919.
W. L. Jørgensen, J. Am. Chem. Soc., 1991, 113, 2810; (d) 19 All reactions were conducted with 0.025 mmol of
J. Sartorius and H. J. Schneider, Chem.–Eur. J., 1996, 2,
1446; (e) F. H. Beijer, H. Kooijman, A. L. Spek,
R. P. Sijbesma and E. W. Meijer, Angew. Chem., Int. Ed.,
1998, 37, 75.
7 (a) W. K. Chan, W. Y. Yu, C. M. Che and M. K. Wong, J. Org.
Chem., 2003, 68, 6576; (b) Y. S. Fung, S. C. Yan and
M. K. Wong, Org. Biomol. Chem., 2012, 10, 3122.
benzylidene barbiturate 5a, 0.25 mmol of 2-methylfuran,
0.03 mmol of internal standard dichloromethane and 20
mol% of HB-DAD organocatalysts. The solutions were
mixed thoroughly. The rst NMR spectrum was taken 5
min aer the addition of 2-methylfuran. Additional NMR
spectra were recorded every 5 min for a total of 120 min.
20 (a) A. Wittkopp and P. R. Schreiner, Chem.–Eur. J., 2003, 9,
407; (b) P. N. H. Huynh, R. R. Walvoord and
M. C. Kozlowski, J. Am. Chem. Soc., 2012, 134, 15621.
8 G. L. Li, K. K. Y. Kung, L. Zou, H. C. Chong, Y. C. Leung,
K. H. Wong and M. K. Wong, Chem. Commun., 2012, 48, 3527.
9 (a) D. G. Barceloux, Barbiturates: Amobarbital, Butalbital, 21 The calculation of relative rate constant of 1a, kobs(1a) ¼
Pentobarbital, Secobarbital, in Medical Toxicology of Drug
Abuse: Synthesized Chemicals and Psychoactive Plants, John
Wiley and Sons, 2012, pp. 467–485; (b) R. Michelucci,
E. Pansini, C. Tassinari, Phenobarbital, Primidone and
0.000148 sꢁ1, kobs(background) ¼ kuncata ¼ 0.0000377 sꢁ1, kcat
¼ kobs(1a) ꢁ kuncata ¼ 0.000148 ꢁ 0.0000377 ¼ 0.000111
sꢁ1, krel ¼ kcat/kuncata ¼ 0.000111/0.000038 ¼ 2.9 at 20
mol% of 1a.
Other Barbiturates, in The Treatment of Epilepsy, Wiley- 22 (a) K. A. Connors, Binding Constants: The Measurement of
Blackwell, 3rd edn, 2009, pp. 585–603; (c) N. L. Harrison
and M. A. Simmonds, Br. J. Pharmacol., 1983, 80, 387; (d)
Molecular Complex Stability, Wiley-VCH, Weinheim, 1987;
(b) C. W. Davies, Ion association, Butterworths,
Washington, 1962, ch. 4.
¨
W. Loscher and M. A. Rogawski, Epilepsia, 2012, 53, 12; (e)
M. Bialer, Epilepsia, 2012, 53, 3.
26756 | RSC Adv., 2014, 4, 26748–26756
This journal is © The Royal Society of Chemistry 2014