Ruthenium-catalyzed selective synthesis of monoalkylated barbituric acids through “borrowing hydrogen” methodology

Article abstract of DOI:10.1016/j.tetlet.2017.01.070

An environmentally benign alkylation of barbituric acids via “borrowing hydrogen” process with ruthenium catalysis has been established. The corresponding 5-(alkyl)barubituric acids were obtained in good to excellent yields with low catalyst loading. Vari

Full text of DOI:10.1016/j.tetlet.2017.01.070

Accepted Manuscript
Ruthenium-catalyzed selective synthesis of monoalkylated barbituric acids
through “Borrowing hydrogen” methodology
Anggi Eka Putra, Yohei Oe, Tetsuo Ohta
PII:
S0040-4039(17)30101-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.070
TETL 48573
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 November 2016
13 January 2017
23 January 2017
Please cite this article as: Eka Putra, A., Oe, Y., Ohta, T., Ruthenium-catalyzed selective synthesis of monoalkylated
barbituric acids through “Borrowing hydrogen” methodology, Tetrahedron Letters (2017), doi: http://dx.doi.org/
10.1016/j.tetlet.2017.01.070
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Tetrahedron Letters
Ruthenium-catalyzed selective synthesis of monoalkylated barbituric acids through
“Borrowing hydrogen” methodology
Anggi Eka Putra,a Yohei Oe*, a,b and Tetsuo Ohtaa,b
a Graduate School of Life and Medical Sciences, Doshisha University, 1-3 Tatara Miyakodani, Kyotanabe-shi, Kyoto 610-0394, Japan.
b Department of Biomedical Information, Faculty of Life and Medical Sciences. Doshisha University, 1-3 Tatara Miyakodani, Kyotanabe-shi, Kyoto 610-0394,
Japan.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An environmentally benign alkylation of barbituric acids via “borrowing hydrogen” process
with ruthenium catalysis has been established. The corresponding 5-(alkyl)barubituric acids
were obtained in good to excellent yields with low catalyst loading. Various substrates
including aliphatic alcohols were tolerated in the present catalytic system. A novel method for
construction of barbituric acid-fused benzopyrane derivatives was also dsemonstrated.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Barbituric acids
Alkylation
Alcohol
Borrowing hydrogen
Ruthenium catalysis
Nitrogen-containing heterocyclic compounds are skeletons of
The use of alkyl halides should be avoided from the viewpoint of
green chemistry, and traditional alkylation method using alkyl halides for
the alkylation of barbituric acids is ineffective because of unexpected
multiple alkylations.4 The Tsuji-Trost reaction of barbituric acids with
allyl alcohols or their derivatives has been reported for the alternative
barbituric acid alkylation, though multiple alkylations occurred.5
Reaction of barbituric acids with aldehydes or ketones followed by
reduction was found to be a more efficient way to install an alkyl group
on the barbituric acids; however, a two-step reaction and external
hydrogen sources were required.6-7 A simpler method was found to be
treatment of the barbituric acids with aldehydes (or ketones) followed by
hydrogenation in the presence of a Pt/C or Pd/C catalyst in a one-pot
scheme.8 Afterward, ethidines were found to be useful hydrogen donors
in the presence of organocatalyst.9 However, these two reactions also
required the use of additional hydrogen donors.
various biologically active substances.1 Barbituric acid is one of the most
important nitrogen-containing heterocyclic systems; it is found in various
natural and synthesized compounds of anesthetics, anti-inflammatory
drugs, analgesics, anxiolytics, anti-cancer drugs, HIV/AIDS protease
inhibitors, and others.2-3 Among them, its 5-alkylated motifs are an
important class of barbituric acid derivatives for medicines (Figure 1).
Therefore, the development of an efficient method for selective
alkylation of barbituric acids is very important for synthetic purposes.
O
Fg
HN
O
O
O
N
O
HN
HN
O
N
H
O
Alkylation of nucleophilic reagents with alcohols using transition
metal catalysts has been paid much attention.10-11 Although alcohol is a
relatively inert electrophile, it is a useful alkylating reagent under the
“borrowing hydrogen” conditions. This methodology also enabled us to
achieve environmentally benign alkylation of barbituric acids. Grigg
reported microwave-assisted alkylation of 1,3-dimethylbarbituric acids
with alcohol by using [Cp*IrCl2]2 as a catalyst, but the generality of the
O
N
H
O
Alphenal
O
Bucolome
HIV-1 and HIV-2
Protease Inhibitors
O
O
N
N
HN
HN
N
O
N
O
N
H
O
O
N
O
H
Caffeine
Barbital
Amobarbital
Figure 1. Examples of 5-alkylated barbituric acids motif on biologically
active molecules
Scheme 1 This Work
 Corresponding author.
e-mail: yoe@mail.doshisha.ac.jp (Y. Oe)

2
Table 1 Optimization of reaction condition.a
Table 2 Scope of alcohols.a
Entry
Catalyst
Base (mol%)
2a
Yield
(%)b
TOF
(h-1)c
(mol% metal)
(eq.)
1
2
3
4
5
[Cp*IrCl2]2 (1)
Pd(OAc)2 (1)
KOH (20)
KOH (20)
KOH (20)
KOH (20)
KOH (20)
2
2
2
2
2
78
68
77
26
88
25
32
22
-
Pd/C (1)
[RuCl2(p-cymene)2]2 (1)
[RuCl2(p-cymene)2]2/
37
2dppf (1)
6
7
RuHCl(CO)(PPh3)3 (1)
RuCl2(PPh3)3 (1)
RuCl2(PPh3)3 (1)
RuCl2(PPh3)3 (0.5)
RuCl2(PPh3)3 (1)
RuCl2(PPh3)3 (1)
RuCl2(PPh3)3(1)
RuCl2(PPh3)3 (1)
KOH (20)
KOH (20)
K2CO3 (20)
K2CO3 (20)
K2CO3 (5)
-
2
2
84
96
98
42
99
30
99
95
51
53
-
8
2
9
2
-
10
11
12
13d
2
-
2
-
K2CO3 (5)
K2CO3 (5)
1.2
1.2
-
-
a
Reaction condition: mixture of 1a (1 mmol), 2a, catalyst (1
mol% metal), and base were heated at 120oC in toluene for 24 h.
b
1
c
Determined by H NMR. Determined at initial conversion
points after 30 minutes. d for 8 h.
barbituric acids was not investigated.12 We also reported Pd/C-catalyzed
alkylation of 1,3-dimethylbarbituric acid and barbituric acid with
alcohols, but found that only benzylic alcohols could be used.11m
Therefore, an efficient catalytic system that tolerates a variety of
barbituric acids and alcohols is desired. Here, we report a general
alkylation of barbituric acids with alcohols via the hydrogen borrowing
method with a Ru catalyst, tolerating a variety alcohol substrates
including the aliphatic one (Scheme 1).
We tested a reaction of 1,3-dimethylbarbituric acid (1a) and benzyl
alcohol (2a) with several catalysts (Table 1). Although it has been
reported that [Cp*IrCl2]2 afforded a high yield of the corresponding
product 3aa under microwave irradiation,[12] this catalyst failed to give a
full conversion even for a long reaction time under conventional thermal
heating (entry 1). Pd(OAc)2 and Pd/C showed good catalytic activities,
respectively obtaining 3aa in 68% and 77% yield (entries 2 and 3).
Although [RuCl2(p-cymene)]2 itself afforded 3aa in moderate yield,
addition of DPPF improved the catalytic efficiency, obtaining 3aa in
88% yield (entries 4 and 5). With this result, we tested several ruthenium
complexes (entry 5-7) and found that RuCl2(PPh3)3 was superior than the
others, affording 3aa in 96% yield (entry 7). RuCl2(PPh3)3 also showed
the highest turnover frequency (TOF) among we tested. When K2CO3
was used instead of KOH, the catalytic efficiency slightly improved
(entry 8). Although reducing the catalyst loadings to 0.5 mol% Ru led to
a decrease in the product yield, high reaction efficiency was obtained
even with 5 mol% of K2CO3 (entries 9-11). A small excess of 2a (1.2
eq.) was enough to yield 3aa in sufficient yield (entry 12). Finally, it was
found that the reaction completed after 8 h (entry 13).13
a
Reaction condition: mixture of 1,3-dimethylbarbituric acid (1
mmol), alcohol (1.2 mmol), RuCl2(PPh3)3 (1 mol%), and K2CO3
With the optimized reaction condition in hand, we tested the scope
of alcohol substrates (Table 2). To our delight, all of the benzylic
alcohols having an electron donating group such as a methyl and
hydroxymethyl group at any position (ortho, para and meta) 2a-2f
b
(5 mol%) were heated at 120oC in toluene for 8 h. Yields were
determined by 1H NMR. c for 24 h. d at 150 oC.

Table 2 continued.a
Scheme 3One-pot synthesis of fused-benzopyrans.a
a
Reaction condition: mixture of 1,3-dimethylba
1
mmol), salicyl alcohol (1.2 mmol), RuCl2(PPh3)3 (1 mol%), and
K2CO3 (5 mol%) were heated at 120oC in toluene for 6 h. 30
mol% of p-TSA was added then the mixture was reheated at
120oC until completion of reaction. Yields were determined by
1H NMR. b Reaction time for alkylation was 9 h.
a
Next, we moved our attention to the influence of substituents on
nitrogen atoms of barbituric acids (Scheme 2). Both reactions of 2a with
N- cyclohexyl 1b and N-phenyl 1c took place to afford the corre-
sponding alkylated products 3ba and 3ca in 84% and 99% yield. Of note
is that the reaction of barbituric acid (1d) with 2a provided 5-
benzylated product 3da in 83% yield without accompanying formation
of the corresponding N- and O-alkylated by-products.
Reaction condition: mixture of 1,3-dimethylbarbituric acid (1
mmol), alcohol (1.2 mmol), RuCl2(PPh3)3 (1 mol%), and K2CO3
(5 mol%) were heated at 120oC in toluene for 8 h. Yields were
b
determined by 1H NMR. c for 24 h. d at 150 oC.
Scheme 2Scope of barbituric acids.a,b
It was considered that the present “Borrowing hydrogen” alkylation
of barbituric acid with salicyl alcohols 2p-r followed by the
intramolecular cyclization with the acid catalyst would afford the
corresponding benzopyrane derivatives (Scheme 3), which is the key
structure of bioactive compounds such as antagonists for neuropeptide S
receptor (NPSR),14 and we found that this type of heterocyclic
compounds were efficiently synthesized via the present catalytic reaction.
Thus, after the present catalytic alkylation of barbituric acids 1a with
salicyl alcohols 2p-r under the optimized reaction conditions, p-
toluenesulfonic acid (30 mol%) was added to the reaction mixture and
then the reaction mixture was stirred for several hours to afford the
corresponding barubituric acid -fused benzopyrane derivatives 4a-c in 90-
93% yields in one-pot.
In conclusion, we demonstrated here a general ruthenium-catalyzed
alkylation of barbituric acids by using alcohol as an alkylating reagent. 15
Our system tolerates aliphatic alcohols and several types of substituent
on the nitrogen atoms of barbituric acids. In addition, the efficient
synthesis of barbituric acid-fused benzopyrane derivatives through the
present catalytic alkylation of barbituric acids with salicyl alcohols
followed by the treatment with p-TSA in one-pot were presented.
a
Reaction condition: mixture of barbituric acids (1 mmol),
benzyl alcohol (1.2 mmol), RuCl2(PPh3)3 (1 mol%), and K2CO3
(5 mol%) were heated at 120oC in toluene for 8 h. Yields were
b
determined by 1H NMR. c Catalyst loading was 2 mol%. d in 1,4-
dioxane at 135 oC
References and notes
afforded good to excellent yields of the corresponding alkylated products
3aa-3af (entries 2-6). As well as benzylic alcohol having an electron
withdrawing group 2g and 2h, the reaction using benzylic alcohol
containing an electron withdrawing group also gave a very satisfying
result (entries 7-8); even a very strong electron withdrawing group such
as a trifluoromethyl group was tolerated (entry 8). Although the reaction
time had to be prolonged to 24 h, 2-naphthylmethanol (2i) was found to
give an excellent yield of the corresponding product 3ai (99% yield,
entry 9). Unfortunately, the yield was lower (72%) when 1-
napthpthylmethanol (2j) was used (entry 10). Alcohols such as piperonyl
alcohol (2k) and furanyl alcohol (2l) bearing a heterocyclic substituent to
give the corresponding products 3ak and 3al in 97% and 94% yield
(entries 11 and 12). We were pleased to find that the aliphatic alcohols
were also usable in the present catalytic transformation (entries 13-15).
The reaction of 1,3-dimethylbarbituric acid (1a) with 1-hexanol (2m) and
1-octanol (2n) nicely proceeded to afford high yields of the
corresponding 5-alkylbarbituric acids 2am and 2an (entries 13 and 14).
1.
a) J. Dinges, C. Lamberth (eds), Bioactive Heterocyclic
Compound Classes: Pharmaceuticals, Wiley-VCH Verlag GmbH
& Co. KGaA, Weinheim, Germany, 2012. b) M. Bandini, A.
Melloni, S. Tommasi, A. Umani-Ronchi, Synlett, 2005, 1199; c)
A. R. Katritzky, Handbook of Heterocyclic Chemistry, Pergamon
Press, New York, 1985.
2.
3.
J. T. Bojarski, J. L. Mokrosz, H. J. Barton, M. H. Paluchowska,
Adv. Heterocycl. Chem. 1985, 38, 229.
For examples, see a) D. Kosk-Kosicka, I. Fomitcheva, M. M.
Lopez, Biochemistry, 1990, 35, 900; b) S.-H. Kim, A.T.
Pudzianowski, K. J. Leavitt, J. Barbosa, P. A. McDonnell, W. J.
Metzler, B. M. Rankin, R. Liu, W. Vaccaro, W. Pitts, Bioorg.
Med. Chem. Lett. 2005, 15, 1101; c) D. M. Neumann, A.
Cammarata, G. Backes, G. E. Palmer, B. S. Jursic, Bioorg. Med.
Chem. 2014, 22, 813.
4.
For examples, see: a) J. V. Tate, W. N. Tinnerman, V. Jurevics, H.
Jeskey, E. R. Biehl, J. Heterocyclic. Chem. 1986, 23, 9; b) S.

4
Kotha, A. C. Deb, R. V. Kumar, Bioorg. Med. Chem. Lett. 2005,
15, 1039.
5.
6.
B. M. Trost, G. M. Schroeder, J. Org. Chem. 65, 1569 (2000).
H. Cui, G. F. Ruda, J. Carrero-Lérida, L. M. Ruiz-Pérez, I. H.
Gilbert, D. González-Pacanowska, Eur. J. Med. Chem. 2010, 45,
5140.
7.
8.
9.
B. S. Jursic, E. D. Stevens, Tetrahedron Lett., 2003, 44, 2203.
B. S. Jursic, D. M. Neumann, Tetrahedron Lett., 2001, 42, 4103.
D. B. Ramachary, M. Kishor, Y. V. Reddy, Eur. J. Org. Chem.
2008, 975.
10. For reviews, see: a) Q. Yang, Q. Wang, Z. Yu, Chem. Soc. Rev.
2015, 44, 2305; b) K. Shimizu, Catal. Sci. Technol. 2015, 5, 1412;
c) S. Bahn, S. Imm, L. Neubert, M. Zhang, H. Neumann, M.
Beller. ChemCatChem. 2011, 3, 1853; d) G. Guillena, D. J
Ramon, M. Yus, Chem .Rev. 2010, 110, 1611; e) M. S. A. Hamid,
P. A. Slatford, J. M. J. Williams. Adv. Synth. Catal. 2007, 349,
1555.
11. For recent examples including our recent works, see: a) S. M. A.
H. Siddiki, K. Kon, K. Shimizu, Green Chem. 2015, 17, 173–177;
c) S. Bartolucci, M. Mari, A. Bedini, G. Piersanti, G. Spadoni, J.
Org. Chem. 2015, 80, 3217-3222; d) Z.-Q. Rong, Y. Zhang, R. H.
B. Chua, H.-J. Pan, Y. Zhao, J. Am. Chem. Soc. 2015, 137, 4944-
4947; e) C. Chaudhari, S. M. A. H. Siddiki, K. Kon, A. Tomita, Y.
Tai, K. Shimizu, Catal. Sci. Technol. 2014, 4, 1064-1069; f) A.
Montagut-Romans, M. Boulven, M. Lemaire, F. Popowycz, New
J. Chem. 2014, 38, 1794-1801; g) Y. Zhang, C. S. Lim, D. S. B.
Sim, H. J. Pan, Y. Zhao, Angew. Chem. Int. Ed. 2014, 53, 1399–
1403; h) W. M. J. Ma, T. D. James, J. M. J. Williams, Org. Lett.
2013, 15, 4850–4853; i) C. Chaudhari, S. M. A H. Siddiki, K.
Shimizu, Tetrahedron Lett. 2013, 54, 6490–6493; j) L. Guo, Y.
Liu, W. Yao, X. Leng, Z. Huang, Org. Lett. 2013, 15, 1144–1147;
k) M. L. Buil, M. A. Esteruelas, J. Herrero, S. Izquierdo, I. M.
Pastor, M. Yus, ACS Catal. 2013, 3, 2072–2075; k) A. E. Putra, K.
Takigawa, H. Tanaka, Y. Ito, Y. Oe, T. Ohta, Eur. J. Org. Chem.
2013, 6344–6354; l) A. E. Putra, Y. Oe, T. Ohta, Eur. J. Org.
Chem. 2013, 6146–6151; m) A. E. Putra, Y. Oe, T. Ohta. Eur. J.
Org. Chem. 2015, 7799.
12. C. Löfberg, R. Grigg, A. Keep, A. Derrick, V. Sridharan, C.
Kilner, Chem. Comm. 2006, 5000.
13. The time course of the reaction was shown in supplementary data.
14. K. P. Kumar, S. Satyanarayana, P. L. Reddy, G. Narasimhulu, N.
Ravirala, B. V. S. Reddy, Tetrahedron Lett. 2012, 53, 1738, and
references there in.
15. Procedure for alkylation of barbituric acid: Barbituric acids 1
(1 mmol), alcohol 2 (1.2 mmol), RuCl2(PPh3)3 (9.6 mg, 1 mol%),
K2CO3 (6.9 mg, 5 mol%) and dry toluene (1 mL) were added to
an Ar-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 then purged with Ar gas. After the reaction
mixture was stirred at 120 °C for prescribed reaction time, solvent
was evaporated under reduced pressure. The crude product was
purified by silica gel column chromatography by using EtOAc and
hexane with appropriate ratio to give pure corresponding alkylated
barbituric acids 3.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Ruthenium-Catalyzed Selective Synthesis of
Monoalkylated Barbituric Acid Derivatives through
“Borrowing hydrogen” methodology
Leave this area blank for abstract info.
Anggi Eka Putra, Yohei Oe*, and Tetsuo Ohta
Highlights

A general ruthenium-catalyzed alkylation of barbituric acids by using alcohol as an alkylating reagent was
demonstrated.


The alkylation was proceeded at C5 position selectively.
The catalysis tolerated several substrate combinations including aliphatic alcohols.