Pd/C-catalyzed alkylation of heterocyclic nucleophiles with alcohols through the "borrowing hydrogen" process

Article abstract of DOI:10.1002/ejoc.201501030

The alkylation of heterocyclic compounds is important for the synthesis of various biologically active compounds. In this paper, we present the development of a Pd/C-catalyzed alkylation of heterocyclic compounds using alcohols as the alkylating agents. T

Full text of DOI:10.1002/ejoc.201501030

FULL PAPER
DOI: 10.1002/ejoc.201501030
Pd/C-Catalyzed Alkylation of Heterocyclic Nucleophiles with Alcohols through
the “Borrowing Hydrogen” Process
Anggi Eka Putra,[a] Yohei Oe,[a,b] and Tetsuo Ohta*[a,b]
Keywords: Heterogeneous catalysis / Palladium / Hydrogen transfer / Nitrogen heterocycles / Alkylation / Alcohols
The alkylation of heterocyclic compounds is important for the
synthesis of various biologically active compounds. In this
paper, we present the development of a Pd/C-catalyzed
alkylation of heterocyclic compounds using alcohols as the
alkylating agents. This method gives the corresponding
alkylated heterocyclic compounds in high yields (up to 99%).
The commercially available catalyst can be recovered and
reused five times without significant loss of catalytic effi-
ciency, and the turnover number (TON) was as high as 900.
Moreover, the reaction could be scaled up.
Introduction
Heterocyclic compounds are an important class of or-
ganic substances due to their roles in biological processes.
Heterocyclic motifs are very common in natural products,
pharmaceuticals, and other biologically active synthetic
compounds.[1] Therefore, the development of a new, green,
and regioselective method for alkylating heterocyclic com-
pounds is an important subject. For example, the regio-
selective alkylation of coumarins, barbiturates, oxindoles,
and indoles is very important, because alkylated derivatives
of these heterocyclic compounds are intermediates for the
synthesis of various useful biologically active compounds,
some of which are shown in Figure 1.[2]
Recently, the use of alcohols as alkylating agents has re-
ceived much attention from organic chemists. There are sev-
eral advantages to this approach, such as the fact that water
is the only expected byproduct. Therefore, this method is
one of the most ideal alkylation methods from the perspec-
tive of green chemistry.[3] Although alcohols are rather un-
reactive as electrophiles, they can be activated through the
“borrowing hydrogen” method, in which they are temporar-
ily dehydrogenated to form aldehydes or ketones. After the
“activated” species is formed, it undergoes nucleophilic ad-
dition with a nucleophile to form an unsaturated intermedi-
ate. Finally, the “borrowed hydrogen” on the catalyst is re-
turned to give the corresponding alkylated product
(Scheme 1).[3] Based on this approach, various types of C–
Figure 1. Examples of pharmacologically active simple heterocy-
cles.
N and C–C bond-forming reactions with both homogen-
eous and heterogeneous catalysts have been developed to
date.[4] Although the use of heterogeneous catalysts is highly
promising for industrial purposes due to the possibility of
reusing the catalyst, to the best of our knowledge, the use
[a] Graduate School of Life and Medical Sciences, Doshisha
University,
1–3 Tatara Miyakodani, Kyotanabe, Kyoto 610-0394, Japan
E-mail: tota@mail.doshisha.ac.jp
http://biomedical.doshisha.ac.jp/en/overview/concept.html
[b] Department of Biomedical Information, Faculty of Life and
Medical Sciences, Doshisha University,
1–3 Tatara Miyakodani, Kyotanabe, Kyoto 610-0394, Japan
Supporting information and ORCID(s) from the author(s) for
this article are available on the WWW under http://dx.doi.org/
10.1002/ejoc.201501030.
Scheme 1. General concept of alcohol activation through the “bor-
rowing hydrogen” method.
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A. E. Putra, Y. Oe, T. Ohta
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of commercially available heterogeneous catalysts like Pd/C Table 1. Optimization of reaction conditions.[a]
in this method is rare.
Pd/C is one of the most well-known heterogeneous cata-
lysts for various synthetic organic purposes, including
hydrogenation,[5] dehydrogenation,[6] Suzuki–Miyaura cou-
pling,[7] and others.[8] Since Pd/C is relatively inexpensive,
commercially available, and in most cases reusable, it has
been used for large-scale reactions in industry.[9] We recently
reported that Pd/C effectively catalyzed the regioselective
alkylation of indoles with alcohols via the “borrowing
hydrogen” method to give the corresponding 3-alkylind-
oles.[10g] In this paper, we present the results of our work
on the development of a Pd/C-catalyzed alkylation with
alcohols through the “borrowing hydrogen” method for ge-
neral heterocyclic compounds such as coumarins, quinol-
inones, barbituric acids, and oxindoles.[10,11]
Entry
2a
[equiv.]
Base
Solvent
Temp.
[°C]
3a[b]
[%]
4a[b]
[%]
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
6
7
1
1
1
K2CO3
K2CO3
KOH
NaOH
Na2CO3
Cs2CO3
–
–
–
–
–
–
–
–
–
–
–
–
–
–
140
150
150
150
150
150
150
150
150
150
120
120
57
77
83
83
60
50
76
80
91
58
52
56
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
24
Results and Discussion
Our study started with the benzylation of 4-hydroxycou-
marin (1). Coumarin 1 was treated with an excess of benzyl
alcohol (2a; 5 equiv.) to avoid dimerization, which would
lead to the formation of byproduct 4a. By heating the reac-
tion mixture at 140 °C in the presence of Pd/C (10 mol-%)
and KOH (1 equiv.), the desired benzylated 4-hydroxycou-
marin (i.e., 3a) was obtained in 57% yield (Table 1, entry 1).
No byproduct 4a was observed under these solvent-free
conditions. Referring to the reported mechanism, the reac-
tion may involve a base-catalyzed Knoevenagel reaction be-
tween the “activated alcohol” (i.e., benzaldehyde) and 4-
hydroxycoumarin to form an alkene intermediate.[10a,10b]
Screening of several bases revealed that the addition of
bases did not significantly affect the reaction (Table 1, en-
tries 2–6 vs. entry 7). Therefore, the optimization was con-
tinued without the addition of bases. Although a 91% yield
of the desired product (i.e., 3a) was obtained under solvent-
9
–
10
11
12
xylenes
toluene
tert-amyl
alcohol
1,4-dioxane
1,4-dioxane
32
20
13
14
1
2
–
–
120
120
65
99
26
n.d.
[a] Reaction conditions: a mixture of 4-hydroxycoumarin (1 mmol),
benzyl alcohol (prescribed amount), Pd/C (10%; 10 mol-%), base
(1 equiv.), and solvent (1 mL) was heated for 24 h under an argon
atmosphere. [b] Determined by 1H NMR spectroscopy with tri-
phenylmethane as an internal standard. n.d.: not detected.
free conditions, this required a large excess of the alcohol and meta positions gave the corresponding products in ex-
and a high temperature (Table 1, entry 9). We believe that cellent yields (Table 2, entries 2 and 3). In contrast, 4-chlo-
the alcohol acted not only as an alkylating agent, but also robenzyl alcohol (2d) had a negative effect on the reaction
as a solvent under the reaction conditions. In order to de- efficiency (Table 2, entry 4). The catalytic system also
crease the amount of alcohol required, we next examined worked well with the heteroaromatic alcohol 2-pyr-
reaction solvents. Initially, the reaction was tested in xylenes idinemethanol (2e). The use of 2e gave an 81% yield of
with equimolar amounts of benzyl alcohol and 1 at 150 °C, alkylated coumarin 3e. Interestingly, when the heterocyclic
and the corresponding alkylated 4-hydroxycoumarin (i.e., diol 2,6-bis(hydroxymethyl)pyridine (2f) was used as the al-
3a) was obtained in 58% yield, along with 24% of byprod- kylating agent, the reaction proceeded selectively to give
uct 4a (Table 1, entry 10). Similar reaction efficiencies were monoalkylated product 3f in 82% yield; no doubly alkyl-
observed when solvents with lower boiling points, such as ated product was detected by 1H NMR spectroscopic analy-
toluene, t-amyl alcohol, and 1,4-dioxane, were used at sis of the crude product. This method also gave the desired
120 °C in sealed tubes (Table 1, entries 11–13). As 1,4-diox- product (i.e., 3g) in good yield when 2-naphthylmethanol
ane gave a slightly better yield and chemoselectivity than (2g) was used (Table 2, entry 7). Unfortunately, the reaction
the other solvents (Table 1, entry 13), this solvent was cho- failed to give a satisfactory result when the aliphatic alcohol
sen for further optimization. When 2 equiv. of benzyl cyclohexylmethanol (2h) was used (Table 2, entry 8). With
alcohol (2a) was used to suppress the formation of 4a, the some changes in the reaction conditions, the method also
desired product (i.e., 3a) was obtained in an almost quanti- allowed the benzylation of 4-hydroxy-1-methylquinolinone
tative yield (Table 1, entry 14).
(5), as shown in Scheme 2.
Having determined the optimized reaction conditions, we
In 2001, Jursic and Neumann reported a one-pot, two-
then tested the set of alcohols shown in Table 2. Benzylic step C-5 alkylation of barbituric acids by treatment of bar-
alcohols with electron-donating methyl groups at the para bituric acids 7 with aldehydes or ketones, followed by Pd/
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Pd/C-Catalyzed Alkylation of Heterocyclic Nucleophiles
Table 2. Alkylation of 4-hydroxycoumarin with alcohols.[a]
C-catalyzed hydrogenation of the resulting products with
hydrogen gas as the hydrogen donor.[12] We were curious
as to whether our method could be used for the one-step
alkylation of barbituric acids without an additional
hydrogen donor. To examine this possibility, 1,3-dimethyl-
barbituric acid (7a) was treated with benzyl alcohol (2a)
under the optimized reaction conditions described above.
We were pleased to find that a nearly quantitative yield of
the corresponding benzylated barbituric acid (i.e., 8aa) was
obtained. Even with only 5 mol-% of Pd/C, the correspond-
ing benzylated product (i.e., 8aa) was obtained in 99% yield
(Table 3, entry 1). On the basis of this result, we went on to
test several alcohols in the reaction, and the results are out-
lined in Table 3. Generally, the the electronic properties of
the alcohols determined their behavior in the reaction, and
the effects seen here were similar to those observed in the
alkylation of 4-hydroxycoumarin described above. The
alcohols with electron-donating groups gave the corre-
sponding products in high yields, while those with electron-
withdrawing groups gave poor yields. Good results were ob-
tained when the substituent was in either the para or the
ortho position, while lower yields were obtained with benz-
ylic alcohols with a substituent in the meta position. An
excellent result was also observed when 7a was alkylated
using 2-naphthalenemethanol (2g; Table 3, entry 8). More-
over, this method was also found to be effective for the alk-
ylation of unalkylated barbituric acid 7b (Scheme 3). In this
case, no N- or O-alkylated products were obtained.
We were also interested in the alkylation of oxindole, be-
cause of its biological activity and abundance in nature.[13]
Therefore, we tested our catalytic system on the benzylation
of oxindole (9). However, we found that only 15% of the
oxindole was benzylated under the reaction conditions de-
scribed above, presumably due to the fact that the methyl-
ene group of 9 is less reactive than those in 1,3-dicarbonyls
1 and 7. The addition of K2CO3 (20 mol-%) to the reaction
mixture greatly improved the efficiency of the reaction, and
3-benzyloxindole (10a) was formed in 94% yield. The use
of a stronger base, KOH instead of K2CO3, further in-
creased the product yield to 99% (Table 4, entry 1).
The scope of alcohol substrates in the alkylation of 9 was
similar to the other alkylation reactions discussed above.
Benzyl alcohols with electron-donating groups successfully
gave the desired alkylated oxindoles in high yields. In con-
trast, benzyl alcohols with electron-withdrawing groups did
not give satisfactory results. A nearly quantitative yield of
the desired alkylated product (i.e., 10e) was obtained when
2-pyridinylmethanol was used (Table 4, entry 6). The use of
2,6-bis(hydroxymethyl)pyridine resulted in the formation of
monoalkylated product 10f in 81% yield (Table 4, entry 7).
When the secondary alcohol 1-phenylethanol (2l) was used,
the desired product was obtained in the form of two dia-
stereomers in reasonable yield (Table 4, entry 9).
[a] Reaction conditions: a mixture of 4-hydroxycoumarin (1 mmol),
alcohol (2 mmol), and Pd/C (10%; 10 mol-%) in 1,4-dioxane
(1 mL) was heated at 120 °C for 24 h under an argon atmosphere.
[b] Determined by H NMR spectropscopy with triphenylmethane
as the internal standard. [c] The amount of alcohol used was
3 mmol.
1
Finally, we investigated the scalability of the method and
the reusability of the Pd/C catalyst. To test the scalability
and turnover, we first carried out the reaction with 1,3-di-
methylbarbituric acid (7a; 10 mmol) with benzyl alcohol
(2a; 2 equiv.) in the presence of Pd/C (0.1 mol-%) in 1,4-
Scheme 2. Pd/C-catalyzed benzylation of 4-hydroxy-1-methylquin-
olinone.
Eur. J. Org. Chem. 2015, 7799–7805
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A. E. Putra, Y. Oe, T. Ohta
Table 4. Alkylation of oxindole with alcohols.[a]
FULL PAPER
Table 3. Alkylation of 1,3-barbituric acids with alcohols.[a]
[a] Reaction conditions: a mixture of 1,3-dimethylbarbituric acid
(1 mmol), alcohol (2 mmol), and Pd/C (10%; 5 mol-%) in 1,4-diox-
ane (1 mL) was heated for 120 °C for 24 h under an argon atmo-
sphere. [b] Determined by 1H NMR spectroscopy, using tri-
phenylmethane as the internal standard. [c] 150 °C using xylenes as
the solvent.
[a] Reaction conditions: a mixture of oxindole (1 mmol), alcohol
(2 mmol), Pd/C (10%; 10 mol-%), and KOH (20 mol-%) in 1,4-di-
oxane (1 mL) was heated at 120 °C for 24 h under an argon atmo-
sphere. [b] Determined by 1H NMR spectroscopy, using tri-
phenylmethane as the internal standard.
Scheme 3. Pd/C-catalyzed benzylation of barbituric acid.
standard reaction conditions (5 mol-% of Pd/C, 1,4-diox-
ane, 120 °C, 24 h), an almost quantitative yield of product
dioxane (2 mL). After 98 h, the product yield reached 90% 8aa was obtained, and the catalyst was recovered by simple
(turnover number, TON = 900). The Pd/C catalyst could filtration and reused. The catalyst could be reused for five
also be reused, as illustrated in Figure 2. Thus, under the cycles without significant loss of activity.
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Eur. J. Org. Chem. 2015, 7799–7805

Pd/C-Catalyzed Alkylation of Heterocyclic Nucleophiles
gel column chromatography or recrystallized to give the 3-alkylated
4-hydroxycoumarins. A similar procedure was used for the alkyl-
ation of 1,3-barbituric acid and oxindole with the following excep-
tions: the amount of Pd/C was 5 mol-% (0.05 mmol) for 1,3-barbi-
turic acid, and KOH (11.3 mg, 0.02 mmol) was added to the reac-
tion mixture for the alkylation of oxindole.
3-Benzyl-4-hydroxycoumarin (3a): Isolated as a white solid. 1H
NMR (400 MHz, [D6]DMSO): δ = 3.90 (s, 2 H), 7.16–7.17 (m, 1
H), 7.26 (d, J = 4.4 Hz, 4 H), 7.35–7.39 (m, 2 H), 7.59–7.63 (m, 1
H), 7.99 (dd, J = 1.6, 8.4 Hz, 1 H), 11.67 (br., 1 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 29.58, 104.69, 116.66, 116.69, 123.80,
124.36, 126.33, 128.57, 128.65, 132.32, 140.25, 152.47, 160.94,
163.29 ppm. MS (GC): m/z = 252 [M]+. CAS registry number:
15074-18-7.
4-Hydroxy-3-(4-methylbenzyl)coumarin (3b): Isolated as a white so-
1
lid. H NMR (400 MHz, CDCl3): δ = 2.29 (s, 3 H), 3.97 (s, 2 H),
7.10 (d, J = 8 Hz, 2 H), 7.21–7.06 (m, 4 H), 7.49–7.54 (m, 1 H),
7.77 (dd, J = 1.2, 8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 21.02, 29.70, 104.46, 115.78, 116.53, 122.85, 123.95, 128.35,
129.94, 131.88, 134.36, 136.97, 152.47, 160.58, 164.09 ppm. MS
(GC): m/z = 266 [M]+. CAS registry number: 6619-24-5.
Figure 2. Recycling of the Pd/C catalyst. Reaction conditions: a
mixture of 1,3-dimethylbarbituric acid (10 mmol), alcohol
(20 mmol), and Pd/C (10%; 5 mol-%) in 1,4-dioxane (10 mL) was
heated at 120 °C for 24 h under an argon atmosphere. The Pd/C
was collected by filtration under argon, and washed with dry sol-
vent before reuse, yields were determined by 1H NMR spec-
troscopy, using triphenylmethane as the internal standard.
4-Hydroxy-3-(3-methylbenzyl)coumarin (3c): Isolated as a white so-
1
lid. H NMR (400 MHz, [D6]DMSO): δ = 2.25 (s, 3 H), 3.86 (s, 2
H), 6.97 (d, J = 7.2 Hz, 1 H), 7.02–7.06 (m, 2 H), 7.13 (t, J =
7.2 Hz, 1 H), 7.37 (d, J = 7.6 Hz, 2 H), 7.59–7.63 (m, 1 H), 7.99
(dd, J = 1.2, 8.2 Hz, 1 H), 11.63 (br., 1 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 21.50, 29.51, 104.76, 116.66, 116.71,
123.80, 124.35, 125.67, 126.99, 128.55, 129.17, 132.29, 137.62,
140.16, 152.46, 160.89, 163.30 ppm. MS (GC): m/z = 266 [M]+.
CAS registry number: 6432-71-9.
Conclusions
4-Hydroxy-3-(2-pyridinylmethyl)coumarin (3e): Isolated as a yellow-
ish solid. 1H NMR (400 MHz, CDCl3): δ = 4.22 (s, 2 H), 7.25–7.32
(m, 3 H), 7.47–7.51 (m, 2 H), 7.80 (td, J = 1.6, 8 Hz, 1 H), 7.96
(dd, J = 1.2, 8.2 Hz, 1 H), 8.47 (d, J = 4 Hz, 1 H), 11.55 (br., 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 32.72, 101.07, 116.17,
117.70, 122.43, 123.58, 123.60, 123.85, 131.60, 139.28, 146.33,
152.63, 159.92, 164.11, 165.34 ppm. MS (GC): m/z = 253 [M]+.
CAS registry number: 1261157-51-0.
We have described an alkylation method for heterocycles
that uses benzylic alcohols as the alkylating agents, and
commercially available Pd/C as the catalyst. The method
was demonstrated using 4-hydroxycoumarin, 4-hydroxy-1-
methylquinolinone, barbituric acids, and oxindole. We suc-
cessfully carried out a gram-scale reaction, and showed that
the catalyst was reusable with negligible loss of efficiency,
even after five cycles.
4-Hydroxy-3-(6-hydroxymethyl-2-pyridinylmethyl)coumarin
(3f):
This compound is unknown. Isolated as a white solid. 1H NMR
(400 MHz, [D6]DMSO): δ = 4.09 (s, 2 H), 4.62 (s, 2 H), 7.30–7.37
(m, 3 H), 7.44 (d, J = 8 Hz, 1 H), 7.58–7.62 (m, 1 H), 7.87–7.95
(m, 2 H), 9.57 (br., 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 32.36, 63.61, 101.21, 116.50, 117.66, 119.59, 121.62, 123.94,
124.27, 132.38, 139.99, 152.64, 158.61, 160.61, 163.32, 164.33 ppm.
HRMS: calcd. for C16H13NO4 [M + H]+ 283.0845; found 284.0923.
Experimental Section
General Information: Nuclear magnetic resonance (NMR) spectra
were measured with a Bruker Ascend 400 spectrometer (400 MHz),
using tetramethylsilane at δ = 0 ppm as the internal standard for
1H NMR spectra (400 MHz), and CDCl3 at δ = 77 ppm or [D6]-
DMSO at δ = 40 ppm for 13C NMR spectra (100 MHz). Mass spec-
tral (GC–MS) data were recorded with a Shimadzu QP5000 instru-
ment. High-resolution mass spectra (HRMS) were recorded with a
JEOL JMS-700 instrument, using meta-nitrobenzyl alcohol as the
matrix, and PEG-200 as the calibration standard. Reagents and
dry solvents obtained from commercial sources were used without
further purification.
4-Hydroxy-3-(2-naphthalenylmethyl)coumarin (3g): Isolated as a
white solid. 1H NMR (400 MHz, [D6]DMSO): δ = 4.08 (s, 2 H),
7.36–7.47 (m, 5 H), 7.62 (td, J = 1.6, 8 Hz, 1 H), 7.71 (s, 1 H),
7.81–7.85 (m, 3 H), 8.02 (dd, J = 1.2, 7.6 Hz, 1 H), 11.76 (br., 1 H)
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 29.86, 104.46, 116.73,
116.75, 123.89, 124.40, 125.72, 126.23, 126.44, 127.71, 127.81,
127.87, 128.14, 132.11, 132.39, 133.53, 137.89, 152.56, 161.19,
163.37 ppm. MS (GC): m/z = 266 [M]+. CAS registry number:
166281-56-7.
Procedure for the Alkylation of 4-Hydroxycoumarin with Alcohols:
4-Hydroxycoumarin (162 mg, 1 mmol), a representative alcohol
(2 mmol), Pd/C (10%; 106 mg, 0.1 mmol), and dry 1,4-dioxane
(1 mL) were added to an argon-purged 20 mL reaction tube
equipped with a J-Young stop valve. The mixture was degassed
using three or more freeze–pump–thaw cycles, and was then purged
with argon gas. The reaction mixture was stirred at 120 °C for 24 h,
then it was filtered through Celite, and the filtrate was evaporated
under reduced pressure. The crude product was purified by silica
3-Benzyl-4-hydroxy-1-methylquinolinone (6a): Isolated as a white
1
solid. H NMR (400 MHz, [D6]DMSO): δ = 3.58 (s, 3 H), 3.99 (s,
2 H), 7.10–7.14 (m, 1 H), 7.19–7.28 (m, 5 H), 7.48 (d, J = 8 Hz, 1
H), 7.60 (t, J = 8 Hz, 1 H), 8.03 (d, J = 8 Hz, 1 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 29.69, 29.84, 110.88, 114.85, 116.62,
121.76, 123.64, 126.01, 128.47, 128.74, 130.99, 138.99, 141.22,
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A. E. Putra, Y. Oe, T. Ohta
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156.98, 163.14 ppm. MS (GC): m/z = 265 [M]+. CAS registry
number: 72587-96-3.
J = 4.4, 13.6 Hz, 1 H), 3.74 (dd, J = 4.8, 9.2 Hz, 1 H), 6.72 (d, J
= 7.2 Hz, 1 H), 6.84–6.90 (m, 2 H), 7.15–7.26 (m, 6 H), 9.2 (br., 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 36.61, 47.59, 109.82,
121.98, 124.79, 126.65, 127.95, 128.32, 128.98, 129.41, 137.81,
141.55, 180.01 ppm. MS (GC): m/z = 223 [M]+. CAS registry
number: 7511-08-2.
5-Benzyl-1,3-dimethylbarbituric Acid (8aa): Isolated as a white so-
lid. 1H NMR (400 MHz, CDCl3): δ = 3.12 (s, 6 H), 3.47 (d, J =
4.8 Hz, 2 H), 3.78 (t, J = 4.8 Hz, 1 H), 7.02–7.04 (m, 2 H), 2.23–
7.25 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 28.18, 37.89,
50.69, 127.83, 128.60, 128.84, 135.09, 150.98, 168.28 ppm. MS
(GC): m/z = 246 [M]+. CAS registry number: 15018-52-7.
1
3-(4-Methylbenzyl)oxindole (10b): H NMR (400 MHz, CDCl3): δ
= 2.30 (s, 3 H), 2.89 (dd, J = 9.2, 13.8 Hz, 1 H), 3.45 (dd, J = 4.4,
13.6 Hz, 1 H), 3.72 (dd, J = 4.4, 8.6 Hz, 1 H), 6.76 (d, J = 7.2 Hz,
1 H), 6.84 (d, J = 8.0 Hz, 1 H), 6.87–6.91 (m, 1 H), 7.03–7.07 (m,
4 H), 7.13–7.17 (m, 1 H), 8.79 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.05, 36.21, 47.61, 109.69, 121.97, 124.85, 127.89,
129.02, 129.13, 129.27, 134.68, 136.14, 141.45, 179.76 ppm. MS
(GC): m/z = 237 [M]+. CAS registry number: 170956-94-2. Isolated
as yellow solid.
1,3-Dimethyl-5-(4-methylbenzyl)barbituric Acid (8ab): Isolated as a
1
white solid. H NMR (400 MHz, CDCl3): δ = 2.28 (s, 3 H), 3.13
(s, 6 H), 3.42 (d, J = 4.8 Hz, 2 H), 3.75 (t, J = 4.8 Hz, 1 H), 6.90
(d, J = 8 Hz, 2 H), 7.03 (d, J = 7.6 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.08, 28.18, 37.60, 50.78, 128.73, 129.28,
131.94, 137.47, 151.07, 168.39 ppm. MS (GC): m/z = 260 [M]+.
CAS registry number: 361446-71-1.
3-(3-Methylbenzyl)oxindole (10c): Isolated as a yellow solid. 1H
NMR (400 MHz, CDCl3): δ = 2.28 (s, 3 H), 2.85 (dd, J = 9.6,
15.6 Hz, 1 H), 3.47 (dd, J = 4.0, 13.6 Hz, 1 H), 3.73 (dd, J = 4.4,
9.4 Hz, 1 H), 6.71 (d, J = 7.6 Hz, 1 H), 6.85–6.90 (m, 2 H), 6.97–
7.03 (m, 3 H), 7.12–7.17 (m, 2 H), 9.04 (br., 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.36, 36.62, 47.55, 109.75, 121.96, 124.89,
126.41, 127.39, 127.91, 128.21, 129.13, 130.18, 137.83, 137.93,
141.49, 179.93 ppm. MS (GC): m/z = 237 [M]+. CAS registry
number: 931696-20-7.
1,3-Dimethyl-5-(3-methylbenzyl)barbituric Acid (8ac): This com-
pound is unknown. Isolated as white needles. 1H NMR (400 MHz,
CDCl3): δ = 2.27 (s, 3 H), 3.12 (s, 6 H), 3.41 (d, J = 4.4 Hz, 2 H),
3.76 (t, J = 4.8 Hz, 1 H), 6.81 (d, J = 7.6 Hz, 1 H), 6.84 (s, 1 H),
7.04 (d, J = 7.6 Hz, 1 H), 7.12 (t, J = 7.6 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.19, 28.07, 38.08, 50.72, 125.76, 128.41,
128.51, 129.47, 134.89, 138.29, 150.98, 168.37 ppm. HRMS: calcd.
for C14H16N2O3 [M + H]+ 260.1161; found 261.1238.
1,3-Dimethyl-5-(2-naphthylmethyl)barbituric Acid (8ag): Isolated as
1
3-(2-Pyridinylmethyl)oxindole (10e): Isolated as a yellow solid. H
1
a white solid. H NMR (400 MHz, [D6]DMSO): δ = 3.01 (s, 6 H),
NMR (400 MHz, CDCl3): δ = 3.14 (dd, J = 9.2, 14.4 Hz, 1 H),
3.62 (dd, J = 4.8, 14.2 Hz, 1 H), 4.15 (dd, J = 5.2, 9.2 Hz, 1 H),
6.69 (d, J = 7.6 Hz, 1 H), 6.82–6.87 (m, 2 H), 7.10–7.17 (m, 3 H),
7.56–7.60 (m, 1 H), 8.56–8.58 (m, 1 H), 9.5 (br., 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 38.70, 45.67, 109.79, 121.74, 121.95,
123.88, 124.49, 127.84, 129.41, 136.29, 141.68, 149.35, 158.21,
180.39 ppm. MS (GC): m/z = 224 [M]+. CAS registry number:
3367-84-8.
3.44 (d, J = 4.8 Hz, 2 H), 4.14 (t, J = 5.2 Hz, 1 H), 7.21 (d, J =
8.4 Hz, 1 H), 7.47 (t, J = 3.6 Hz, 2 H), 7.58 (s, 1 H), 7.79–7.86 (m,
3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 28.40, 35.89,
50.80, 126.19, 126.64, 127.59, 127.92, 128.21, 132.33, 133.36,
135.30 ppm. MS (GC): m/z = 296 [M]+. CAS registry number:
590372-34-2.
5-(3,4-Dimethoxybenzyl)-1,3-dimethylbarbituric Acid (8ai): Isolated
as a white solid. 1H NMR (400 MHz, CDCl3): δ = 3.15 (s, 6 H),
3.42 (d, J = 4.8 Hz, 2 H), 3.75 (t, J = 4.4 Hz, 1 H), 3.80 (s, 3 H),
3.83 (s, 2 H), 6.55–6.59 (m, 2 H), 6.71 (d, J = 8 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 28.18, 37.26, 50.69, 55.71, 55.75,
110.93, 111.83, 121.07, 127.46, 148.42, 148.78, 150.90, 168.31 ppm.
MS (GC): m/z = 206 [M]+. CAS registry number: 321657-26-5.
3-(6-Hydroxymethyl-2-pyridinylmethyl)oxindole (10f): This com-
pound is unknown. Isolated as a yellow solid. 1H NMR (400 MHz,
CDCl3): δ = 3.19 (dd, J = 8.0, 14.8 Hz, 1 H), 3.51 (dd, J = 4.8,
14.8 Hz, 1 H), 3.96 (dd, J = 4.8, 7.8 Hz, 1 H), 4.08 (br., 1 H), 4.57
(s, 2 H), 6.67 (d, J = 7.6 Hz, 1 H), 6.74–6.77 (m, 2 H), 6.95 (d, J
= 7.6 Hz, 2 H), 7.02 (t, J = 8.0 Hz, 1 H), 7.45 (t, J = 7.6 Hz, 1 H),
9.40 (br., 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 37.62,
45.41, 63.81, 109.88, 118.36, 121.97, 122.29, 124.15, 127.87, 129.40,
137.01, 141.78, 156.89, 158.41, 180.42 ppm. HRMS: calcd. for
C15H14N2O2 [M + H]+ 254.1055; found 255.1134.
3-(2-Naphthylmethyl)oxindole (10g): Isolated as a white solid. 1H
NMR (400 MHz, CDCl3): δ = 3.06 (dd, J = 9.6, 7 Hz, 1 H), 3.63
(dd, J = 4.4, 6.8 Hz, 1 H), 3.83 (dd, J = 4.4, 4.6 Hz, 1 H), 6.70 (d,
J = 7.6 Hz, 1 H), 6.82–6.85 (m, 2 H), 7.13 (t, J = 7.6 Hz, 1 H),
7.33 (dd, J = 1.6, 4.2 Hz, 1 H), 7.41–7.43 (m, 2 H), 7.60 (s, 1 H),
7.69–7.79 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 36.76,
47.42, 109.82, 121.98, 124.77, 125.50, 125.94, 127.49, 127.56,
127.59, 127.94, 127.96, 128.01, 128.94, 132.25, 133.28, 135.34,
141.48, 179.90 ppm. MS (GC): m/z = 273 [M]+. CAS registry
number: 1202521-48-9.
1,3-Dimethyl-5-(4-methoxybenzyl)barbituric Acid (8aj): Isolated as
1
a white solid. H NMR (400 MHz, CDCl3): δ = 3.13 (s, 6 H), 3.41
(d, J = 4.8 Hz, 2 H), 3.73 (t, J = 4.8 Hz, 1 H), 3.76 (s, 3 H), 6.75
(d, J = 8.8 Hz, 2 H), 6.94 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 28.15, 39.10, 50.80, 55.12, 113.89, 126.93,
129.93, 150.98, 159.05, 168.36 ppm. MS (GC): m/z = 276 [M]+.
CAS registry number: 114656-99-4.
1,3-Dimethyl-5-(2-methylbenzyl)barbituric Acid (8ak): This com-
pound is unknown. Isolated as white needles. 1H NMR (400 MHz,
CDCl3): δ = 2.27 (s, 3 H), 3.16 (s, 6 H), 3.46 (d, J = 5.2 Hz, 2 H),
3.75 (t, J = 5.6 Hz, 1 H), 6.93 (d, J = 7.2 Hz, 1 H), 7.05–7.09 (m,
1 H), 7.11–7.13 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
19.20, 28.29, 34.44, 50.34, 125.83, 127.60, 129.17, 130.70, 133.71,
136.44, 151.17, 168.45 ppm. MS (GC): m/z = 260 [M]+ HRMS:
calcd. for C14H16N2O3 [M + H]+ 260.1161; found 261.1238.
3-(4-Methoxybenzyl)oxindole (10j): Isolated as a yellow solid. 1H
NMR (400 MHz, CDCl3): δ = 2.92 (dd, J = 9.2, 13.8 Hz, 1 H),
3.41 (dd, J = 4.8, 13.8 Hz, 1 H), 3.70 (dd, J = 4.4, 8.8 Hz, 1 H),
3.76 (s, 3 H), 6.76–6.83 (m, 4 H), 6.90 (t, J = 7.6 Hz, 1 H), 7.06 (d,
1
5-Benzylbarbituric Acid (8ba): Isolated as a white solid. H NMR
(400 MHz, [D6]DMSO): δ = 3.25 (d, J = 4.8 Hz, 2 H), 3.90 (t, J =
5.2 Hz, 1 H), 7.05 (d, J = 6.8 Hz, 2 H), 7.20–7.27 (m, 3 H), 11.17
(s, 2 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 33.80, 49.91,
127.08, 128.81, 129.29, 137.90, 151.09, 170.52 ppm. MS (GC): m/z
= 218 [M]+. CAS registry number: 5909-45-5.
3-Benzyloxindole (10a): Isolated as a yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 2.92 (dd, J = 9.2, 13.6 Hz, 1 H), 3.48 (dd,
J = 9.2 Hz, 2 H), 7.16 (t, J = 7.6 Hz, 3 H), 8.45 (br., 1 H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 35.75, 47.69, 55.17, 109.59, 113.69,
122.01, 124.86, 127.90, 129.06, 129.70, 130.41, 141.37, 158.34,
179.40 ppm. MS (GC): m/z = 253 [M]+. CAS registry number:
170956-93-1.
7804
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7799–7805

Pd/C-Catalyzed Alkylation of Heterocyclic Nucleophiles
1
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J = 7.2 Hz, 3 H, minor), 3.47–3.54 (m, 1 H, minor), 3.65 (d, J =
5.6 Hz, 1 H, minor), 3.78 (d, J = 4 Hz, 1 H, major), 3.80–3.83 (m,
1 H, major), 6.50 (d, J = 7.6 Hz, 2 H, major), 6.75 (d, J = 7.6 Hz,
2 H, major), 6.82–7.26 (m, 8 H), 8.46 (s, 1 H, minor), 8.83 (s, 1 H,
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141.93, 142.05, 142.72, 179.04, 179.45 ppm. CAS registry number:
140701-16-2.
[6]
[7]
Procedure for Recycling Pd/C: 1,3-Dimethylbarbituric acid (1.56 g,
10 mmol), benzyl alcohol (20 mmol), Pd/C (10%; 1.06 g, 1 mmol),
and dry 1,4-dioxane (10 mL) were added to an argon-purged
100 mL reaction tube equipped with a J-Young stopcock. The mix-
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stirred at 120 °C for 24 h, then the Pd/C was collected by filtration
under an Ar atmosphere, washed with dry 1,4-dioxane, and dried
under vacuum before use in the next cycle. The yield of benzylated
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Received: August 6, 2015
Published Online: November 3, 2015
Eur. J. Org. Chem. 2015, 7799–7805
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7805