Selective N-Monoalkylation of 6-Aminouracils with Alcohols: An Environmentally Benign Protocol for the Synthesis of 6-Alkylaminouracils

Article abstract of DOI:10.1002/ejoc.201701445

A highly selective N-alkylation of 6-aminouracils with alcohols was achieved through the borrowing hydrogen approach using iridium catalysis. 6-Aminouracils and alcohols reacted in the presence of [Cp*IrI₂]₂ to give 6-monoalkyluracils selectively and in high yield (up to 99 %), usually in short reaction times (2 h). These results provide a new, green, and efficient protocol for the synthesis of 6-alkylaminouracils, which are very important intermediates for the synthesis of biologically active molecules.

Full text of DOI:10.1002/ejoc.201701445

A Journal of
Accepted Article
Title: Selective N-mono-alkylation of 6-aminouracils with alcohols:
An environmentally benign protocol for synthesis of 6-
alkylaminouracils
Authors: Anggi Eka Putra, Yohei Oe, and Tetsuo Ohta
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701445
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701445
Supported by

10.1002/ejoc.201701445
European Journal of Organic Chemistry
FULL PAPER
Selective N-mono-alkylation of 6-aminouracils with alcohols: An
environmentally benign protocol for synthesis of 6-
alkylaminouracils
Anggi Eka Putra,[a] Yohei Oe, * [a],[b] and Tetsuo Ohta[a],[b]
Abstract: A highly selective N-alkylation of 6-aminouracils with
alcohols achieved by using iridium catalysis on the basis of borrowing
hydrogen methodology is presented. Reactions of 6-aminouracils and
alcohols in the presence of [Cp*IrI2]2 were found to afford 6-
monoalkyluracils selectively in high yield (up to 99%), mostly in a short
reaction time (2 h). These results provide a new, green, and efficient
protocol to access 6-alkylaminouracils, which are very important
intermediates for synthesis of biologically active molecules.
other research groups have successfully achieved selective
alkylation of heterocyclic compounds including indoles, oxindoles,
coumarines, quinolones, and barbituric acids with alcohol via
borrowing hydrogen methodology.[10] Unlike the alkylation of
indoles in which the alkylation takes place at an unsaturated
carbon nucleophilic site rather than N-position,[10c,e,i] in the current
study, we found that highly selective N-mono-alkylation of 6-
aminouracils could be achieved with iridium catalysis under a
borrowing hydrogen condition without detecting any alkylation on
C=C bond position. This finding provides a new, green, and
efficient protocol to access 6-alkylaminouracil derivatives.
Introduction
O
N
As the main principle of green chemistry, minimizing the use
and generation of hazardous substances has become an
important consideration in modern chemical research.[1]
Particularly in organic chemistry, one general example is the
development of an alternative alkylating reagent to replace
haloalkanes. Alcohol is considered as an ideal replacement for
the haloalkanes because it has less toxicity and generates water
as a byproduct instead of inorganic salts.[2] Although alcohol is a
relatively inert electrophile, it has been proved to be a useful
alkylating reagent under a catalytic system called the “borrowing
hydrogen” or “hydrogen autotransfer” strategy.[2-5]
O
N
N
N
OMe
H
N
O
N
Urapidil
(antihypertensive drug)
O
N
HN
HN
O
N
OH
OH
O
N
OH
OH
OH
COO-
OH
HO
O
H
O
P
N
HO
O
O
N
COO-
COO-
H
O
O
Riboflavin
(Vitamin B)
Uracils that have an aminoalkyl group at 6-position (6-
aminoalkyluracilas) are known as key intermediates for synthesis
of various molecules that play important roles in biological
processes such as flavins, dezaflavins, purines, pteridines and
Cenzyme F420
Scheme 1. Representative examples of 6-alkylaminouracil moiety in bioactive
compounds
xanthines
derivatives
(Scheme
1).[6]
Generally,
6-
alkylaminouracils are prepared by treating 6-halouracils[7] or 6-
cyanouracil[8] with the corresponding amines. As general
alkylation of nucleophilic substances with haloalkanes,
quantitative amounts of toxic inorganic salts are formed (e.g., HCl,
HBr, HCN). One of the most direct routes to 6-alkylamino uracil is
direct N-alkylation of parent 6-aminouracils. However, this route
may face a chemoselectivity problem because 6-aminouracils
also react with electrophiles at C5 position.[9] We and several
O
O
Overall transformation
R1
O
R1
O
N
N
Cat.
+
HO
R2
N
NH2
N
N
R2
H
R1
H2O
R1
Cat.
Borrowing hydrogen
Cat.-H
O
O
R1
O
R1
N
N
+
R2
O
N
NH2
O
N
N
R2
[a]
[b]
A. E. Putra, Y. Oe, T. Ohta
Graduate School of Life and Medical Sciences
Doshisha University
1-3 Tatara Miyakodani, Kyotanabe-shi, Kyoto 610-0394, Japan
E-mail: yoe@mail.doshisha.ac.jp
Y. Oe, T. Ohta
Department of Biomedical Information, Faculty of Life and Medical
Sciences
Doshisha University
H2O
R1
R1
O
H2N
R2
O
R1
N
R1
N
R1
N
R2
or
O
N
NH2
O
O
N
N
O
NH2
R1
R1
Not Formed
R1
1-3 Tatara Miyakodani, Kyotanabe-shi, Kyoto 610-0394, Japan
Supporting information for this article is given via a link at the end of
the document.
Scheme 2. This work
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701445
European Journal of Organic Chemistry
FULL PAPER
Results and Discussion
Table 1. Optimization of reaction condition[a]
RuHCl(CO)(PPh3)3,[13] and {RuCl2(p-cyemene)]2/ 2 dppf}[14] were
used. On the basis of this screening, [Cp*IrI2]2 was selected for
this work. After further optimization, yield of 3aa was drastically
improved in the absence of any solvents but with an excess
amount of 2a (entry 6), where the aminouracil 1a was slightly
solved in 2a. With some optimization, the reaction yielded the
desired product 3aa in 91% only in 3 h and 0.5 mol% of [Cp*IrI2]2
(entry 12). We noticed that the corresponding N-mono-alkylated
3a was obtained selectively without other by-products such as C5-
alkylaminouracils or dialkylation products being detected.
O
N
O
Catalyst
KOH
N
OH
N
+
O
N
H
O
N
NH2
1a
2a
3aa
Entry
1
Catalyst (mol%)
[Cp*IrCl2]2 (1)
[Cp*IrI2]2 (1)
Solvent
t (h)
16
16
16
16
16
16
16
16
16
6
Yield (%)[b]
H2O
32
38
32
28
n.r.
95
93
86
93
94
92
91
75
With the optimized reaction condition in hand, we moved our
attention to check the scope and limitation of this reaction (Table
2). Initially, meta- and ortho-methylbenzyl alcohol (2b and 2c)
were tested. However, the reactions needed to be stopped earlier
because the reaction mixture was solidified after 1 h. A similar
result was also obtained when 4-chlorobenzyl (2f) alcohol was
2
H2O
3
[Cp*Ir(NH3)3][Cl]2 (2)
[Cp*Ir(NH3)3][I]2 (2)
IrCl3.nH2O (2)
[Cp*IrI2]2 (1)
H2O
4
H2O
1
subjected to the reaction. H NMR spectra of the solid mixture
5
H2O
revealed the formation of the corresponding products in 60-80%
yields. Most likely, the high melting point of the corresponding
product (>120°C) prevented vigorous stirring of reaction mixture
and adversely affected the conversion of reaction. Therefore, a
solvent-free system was clearly inefficient for this transformation.
To overcome this problem, t-amyl alcohol was introduced to the
reaction system, and we were glad to find that the reaction
smoothly yielded the corresponding products in excellent yields in
only 2 hours (Table 2). To the best of our knowledge, this is one
of the shortest reaction times for C-N bond formation through
borrowing hydrogen methodology, which generally requires 16 h
or more.[2b, d- f]
6[c]
7[c]
8[c]
9[c,d]
10[c,d]
11[d]
12[d]
13[d]
-
-
-
-
-
-
-
-
[Cp*IrI2]2 (0.5)
[Cp*IrI2]2 (0.2)
[Cp*IrI2]2 (0.5)
[Cp*IrI2]2 (0.5)
[Cp*IrI2]2 (0.5)
[Cp*IrI2]2 (0.5)
[Cp*IrI2]2 (0.5)
6
3
1
Table 2. Alkylation of 6-aminouracils with various aromatic alcoholsa
O
[a] Unless stated otherwise, reaction conditions: mixture of 1a (1 mmol), 2a (1.2
mmol), catalyst, KOH (30 mol%) in water (1mL) was heated at 120 °C for 16 h.
[b] Determined by 1H NMR. [c] 2 mmol of 2a was used. [d] KOH was 10 mol%.
O
R1
O
(0.5 mol%)
R1
O
N
[Cp*IrI2]2
N
+
KOH (10 mol%)
R2
OH
N
NH2
t-amyl alcohol, 120 o
N
N
R2
C, 2 h
R1
H
R1
Entry
1
6-aminouracil
Product
Yield (%)
Alcohol
Because most 6-aminouracils are highly soluble in hot water
but not in organic solvents,[11] we decided to begin our
investigation by conducting the reaction of 1,3-dimethyl-6-
aminouracils (1a) and 4-methylbenzylalcohol (2a) in water.
Although the presence of water might be problematic due to
reversible reaction on the formation of imine intermediate, several
iridium complexes have been reported to successfully catalyze
the amination of alcohol in water.[12] Thus, we screened iridium
catalysts, and the results are outlined in Table 1 (entries 1-5). We
observed the formation of the corresponding product 3aa in 32%
yield without detecting other byproducts by using [Cp*IrCl2]2 (2
mol% of Ir) in the presence of KOH (30 mol%) at 120 °C in water
(entry 1). This result contradicts a previous report that aminouracil
1a reacted with aldehydes selectively at C5 position followed by
a second nucleophilic attack to produce bis(6-aminouracil-5-
yl)methanes in water.[9a] Selective N-alkylation was also observed
when water soluble [Cp*Ir(NH3)3][X]2 (X= Cl or I) was used as a
catalyst (entries 3-4). Slightly better yield was obtained by using
[Cp*IrI2]2 to give the corresponding N-alkylated product 3aa in
38% yield (entry 2). On the other hand, no reactions were
detected when simple iridium salts IrCl3.nH2O as well as several
ruthenium complexes known as active catalysts for borrowing
O
O
N
N
N
OH
OH
96 (89)
95 (89)
95 (94)
O
O
N
O
N
H
O
N
NH2
2a
2b
3aa
1a
1a
1a
2
3
N
N
H
3ab
O
N
OH
O
N
N
H
2c
3ac
O
N
OH
4
5
1a
1a
96 (86)
92(90)
O
N
N
H
MeO
2d
2e
OMe
3ad
O
N
N
OH
O
N
H
3ae
hydrogen
reactions
such
as
RuCl2(PPh3)3,[3,10d-e]
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701445
European Journal of Organic Chemistry
FULL PAPER
Table 2. (Continued)
Table 3. Alkylation of 6-aminouracils 1a with various aliphatic alcoholsa
O
O
Entry 6-aminouracil
Product
Yield (%)
96 (91)
Alcohol
(0.5 mol%)
N
[Cp*IrI2]2
KOH (10 mol%)
N
O
N
+
R
OH
O
N
NH2
N
N
t-amyl alcohol, 120 o
O
R
N
OH
C, 24 h
H
1a
6
1a
2
3
O
N
H
Cl
Entry
Alcohol
Product
Yield (%)
64 (52)
Cl
3af
2f
O
O
N
N
OH
N
1[b]
2[c]
3
7
8[b]
1a
1a
62
OH
N
N
H
O
F3C
75 (73)
N
H
3am
O
2g
CF3
2m
3ag
O
N
O
MeO
MeO
N
OH
N
1a
9
96 (93)
38 (37)
86 (75)
OH
2n
OMe
OMe
O
N
H
N
N
O
H
2h
3ah
3an
O
O
O
O
N
N
OH
N
OH
1a
1a
10
11
98 (89)
89 (79)
O
O
O
N
O
N
H
3ai
N
N
O
H
2i
2j
2o
3ao
O
OH
N
N
4
5
74 (66)
80 (78)
N
N
H
O
OH
N
O
N
H
O
O
3aj
2p
2q
O
3ap
N
1a
12
13
99 (91)
60 (50)
OH
OH
OH
O
N
N
H
3ak
N
O
N
H
3aq
2k
O
O
N
1a
OH
O
N
O
N
H
3al
O
N
6
88 (73)
2l
N
N
H
O
O
2r
Et
O
3ar
Et
N
N
N
14
15
16
94 (84)
2e
N
N
H
a Reaction conditions: A mixtuire of aminouracils (1 mmol), alcohols (1.2 mmol),
[Cp*IrI2]2 (0.5 mol%), KOH (10 mol%), and t-amyl alcohol (1 mL) was heated at
120°C for 2 h. Yield was determined by 1H NMR, and values in parentheses
indicated isolated yield. b Reaction time was 30 h. cEthanol (2 mL) was used as
solvent at 110 °C.
O
N
NH2
Et
Et
2b
3be
O
O
Bn
O
Bn
O
N
2e
2e
93 (79)
N
N
H
By using the re-optimized conditions above, we tested various
types of aromatic alcohols as well 6-aminouracils (Table 2). All
primary benzylic alcohols having electron donating groups such
as methyl- and methoxy- at any position yielded the
corresponding 6-alkylaminouracils in excellent yield (entries 1-4,
9). Similar results were also obtained when an electron
withdrawing group such as 4-chlorobenzyl alcohol was used.
Although it gave a lower yield, a strong electron withdrawing
group (-CF3) was also tolerated. Excellent yields were observed
when napththalenementhanols were subjected to the reaction
system (entries 11-12). Lower yield was obtained when furfuryl
alcohol were used (60% yield, entry 13). On the other hand,
excellent results were obtained when 1,3-diethyl- and 1,3-
dibenzyluracil were used as substrates (entries 14-15).
Unfortunately, no reaction was detected when unalkylated 6-
aminouracil 1d was subjected to the reaction, apparently due to
its poor solubility (entry 16). The desired N-alkylated product was
N
NH2
Bn
Bn
2c
3ce
O
O
HN
HN
O
N
H
1d
n. r.
NH2
O
N
N
H
H
3de
a Reaction conditions: A mixtuire of aminouracils (1 mmol), alcohols (1.2 mmol),
[Cp*IrI2]2 (0.5 mol%), KOH (10 mol%), and t-amyl alcohol (1 mL) was heated at
120°C for 2 h. Yield was determined by 1H NMR, and values in parentheses
indicated isolated yield. b Reaction time was 6 h.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701445
European Journal of Organic Chemistry
FULL PAPER
3.40 (s, 3H), 4.19 (d, J = 5.2 Hz), 4.86 (br, 1H), 4. 88 (s, 1H), 7.26 (s, 4H).
13C NMR (100 Hz, CDCl3) δ: 21.04, 27.71, 28.57, 47.11, 76.23, 127.59,
129.68, 132.78, 138.13, 151.81, 152.64, 162.89. HRMS: Calcd. For
C14H17N3O2 259.1321; Found 260.1396 [M + H]+
not also obtained by the reaction of 1a with 1-phenylethanol under
the similar reaction conditions for 18 h.
After obtaining good results for the alkylation of 6-
aminouracils with aromatic alcohols, we then tested the aliphatic
alcohols in the reaction (Table 3). To our delight, all tested
aliphatic alcohols including linear (2m, n), branched (2o-q) and
alicyclic (2r) alcohols are generally tolerated to give the N-mono-
alkylated products in moderate to excellent yields, though longer
reaction time was required.
6-(3-Methylbenzylamino)-1,3-dimethyluracil (3ab): Isolated as white
solid. 1H NMR (400 Hz, CDCl3) δ: 2.33 (s, 3H), 3.28 (s, 3H), 3.39 (s, 3H),
4.19 (d, J = 4.8Hz), 4.78 (br, 1H), 4.86 (s, 1H), 7.19-7.25 (m, 4H). 13C NMR
(100 Hz, CDCl3) δ: 18.92, 27.78, 28.71, 45.57, 76.18, 126.53, 128.36,
128.54, 130.92, 133.59, 136.41, 151.86, 152.74, 162.97. HRMS: Calcd.
For C14H17N3O2 259.1321; Found 260.1396 [M + H]+
Finally, we investigated the catalytic activity of [Cp*IrCl2]2
under the re-optimized reaction conditions again, since the
chloride complex is commercially avairable unlike the iodide one.
However, the reaction of 1a with 2a by using [Cp*IrCl2]2 instead of
[Cp*IrCl2]2 afforded 3aa in slightly lower 88% NMR yield (vs 96%
in entry 1, Table 2). Similarly, only 13% NMR yield of 3am was
obtained by the reaction of 1a with 1-butanol (2m) in the presence
of [Cp*IrCl2]2 catalyst (vs 64% in entry 1, Table 3). These results
indicatated that [Cp*IrI2]2 is better catalyst for the presnt N-
alkylation of 6-aminouracils with primary alcohols than the
comercially available chloride complex.
6-(2-Methylbenzylamino)-1,3-dimethyluracil (3ac): Isolated as white
solid. 1H NMR (400 Hz, CDCl3) δ: 2.34 (s, 3H), 3.28 (s, 3H), 3.41 (s, 3H),
4.19 (d, J = 4.8Hz), 4.85 (s, 1H), 5.10 (br, 1H), 7.07-7.13 (m, 3H), 7.25 (t,
J = 7.6Hz, 3H). 13C NMR (100 Hz, CDCl3) δ: 21.34, 27.72, 28.68, 47.27,
76.16, 124.53, 128.23, 128.90, 128.95, 135.86, 138.81, 151.83, 152.80,
162.96. HRMS: Calcd. For C14H17N3O2 259.1321; Found 260.1396 [M +
H]+
6-(4-Methoxybenzylamino)-1,3-dimethyluracil (3ad): Isolated as
colorless needles. 1H NMR (400 Hz, CDCl3) δ: 3.29 (s, 3H), 3.39 (s, 3H),
4.16 (d, J = 4.8 Hz, 2H), 4.88 (s, 1H), 6.89 (d, J = 8.0 Hz, 2H), 7.22 (d, J =
8.8 Hz, 2H). 13C NMR (100 Hz, CDCl3) δ: 27.74, 28.62, 46.88, 55.31, 76.19,
114.41, 127.81, 129.05, 151.84, 152.65, 159.57, 162.93. HRMS: Calcd.
For C14H17N3O3 275.1270; Found 276.1356 [M + H]+
Conclusions
6-Benzylamino-1,3-dimethyluracil (3ae): Isolated as white solid. 1H
NMR (400 Hz, CDCl3) δ: 3.23 (s, 3H), 3.40 (s, 3H), 4.19 (d, J = 5.2 Hz, 2H),
4.74 (s, 1H), 5.9 (br, 1H), 7.22-7.33 (m, 5H). 13C NMR (100 Hz, CDCl3) δ:
27.62, 28.84, 46.91, 75.80, 127.13, 127.89, 128.80, 136.12, 151.73,
153.12, 163.03. HRMS: Calcd. For C13H15N3O2 245.1164; Found
246.1246 [M + H]+
We successfully developed a highly selective N-mono-alkylation
of 6-aminouracils with alcohols by using iridium catalysis on the
basis of borrowing hydrogen methodology. This result provides an
efficient and green approach to synthesize 6-alkylaminouracils,
which are useful intermediates for various biological active
compounds. A wide range of substrates was tolerated to afford the
corresponding 6-alkylaminouracils in high yields and selectively in
a short reaction time.
6-(4-Chlorobenzylamino)-1,3-dimethyluracil (3af): Isolated as white
1
solid. H NMR (400 Hz, CDCl3) δ: 3.62 (s, 3H), 3.42 (s, 3H), 4.20 (d, J =
5.2 Hz, 2H), 4.74 (s, 1H), 5.46 (br, 1H), 7.20 (d, J = 8.4 Hz), 7.31 (d, J =
6.8 Hz). 13C NMR (100 Hz, CDCl3) δ: 27.74, 28.82, 76.18, 128.67, 129.11,
133.96, 134.50, 151.72, 152.85, 162.92. HRMS: Calcd. For C13H14ClN3O2
279.0775; Found 280.0852 [M + H]+
6-(4-Trifluoromethylbenzylamino)-1,3-dimethyluracil (3ag): Isolated
as white solid. 1H NMR (400 Hz, CDCl3) δ: 3.27 (s, 3H), 3.45 (s, 3H), 3.32
(d, J = 5.2 Hz, 2H), 4.75 (s, 1H), 5.32 (br, 1H), 7.40 (d, J = 8.0Hz, 2H), 7.62
(d, J = 8.0 Hz, 2H). 13C NMR (100 Hz, CDCl3) δ: 27.82, 28.82, 46.69, 76.54,
125.99, 126.02, 127.57, 130.36, 140.07, 151.79, 152.81, 162.89. HRMS:
Calcd. For C14H14F3N3O2 313.1038; Found 314.1109 [M + H]+
Acknowledgement
The authors thank Mr. Naoto Hamaguchi for his helping several
experiments in Table 2 and 3.
6-(3,4-Dimethoxybenzylamino)-1,3-dimethyluracil (3ah): Isolated as
white solid. 1H NMR (400 Hz, CDCl3) δ: 3.31 (s, 3H), 3.40 (s, 3H), 3.88 (d,
J = 2.4 Hz, 6H), 4.17 (d, J = 4.8Hz, 2H), 4.63 (br, 1H), 4.93 (s, 1H), 6.82
(s, 1H), 8.86-6.87 (m, 2H). 13C NMR (100 Hz, CDCl3) δ: 27.78, 28.59, 47.41,
55.97, 76.31, 111.09, 111.50, 120.28, 128.17, 149.16, 149.47, 151.85,
152.54, 162.89. HRMS: Calcd. For C15H19N3O4 305.1376; Found
306.1454 [M + H]+
Experimental Section
General Information: Nuclear magnetic resonance (NMR) spectra were
recorded with a Bruker Ascend 400 spectrometer (400 MHz) with
tetramethylsilane at 0 ppm as the internal standard for the H NMR (400
MHz) and CDCl3 at 77 ppm and DMSO-d6 at 44 ppm for the 13C NMR (100
MHz). High resolution mass spectrometry (HRMS) spectra were recorded
with a JEOL JMS-700. Reagents obtained from commercial sources were
used without further purification.
1
6-Piperonylamino-1,3-dimethyluracil (3ai): Isolated as white solid. 1H
NMR (400 Hz, DMSO-d6) δ: 3.06 (s, 3H), 3.35 (s, 3H), 4.22 (s, 2H), 4.54
(s, 1H), 5.99 (s, 2H), 6.82-6.88 (m, 2H), 6.94 (s, 1H), 7.42 (s, 1H). 13C NMR
(100 Hz, CDCl3) δ: 27.52, 29.77, 45.58, 74.87, 101.36, 107.89, 108.57,
120.52, 132.24, 146.70, 147.91, 151.92, 153.54, 161.91. HRMS: Calcd.
For C14H15N3O4 289.1063; Found 290.1145 [M + H]+
Procedure for N-monoalkylation of 6-aminouracils: 6-aminouracils (2
mmol), alcohol (2.4 mmol), [Cp*IrI2]2 (0.005 mmol), KOH (0.01 mmol) and
t-amyl alcohol (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, purged with Ar gas and stirred at
120 °C for 2 hours. After the reaction finished, the solvent was evaporated
under reduced pressure, and pure corresponding products were isolated
by column chromatography or re-crystallization.
6-(2-Naphthalenylmethylamino)-1,3-dimethyluracil (3aj): Isolated as
white solid. 1H NMR (400 Hz, CDCl3) δ: 3.28 (s, 3H), 3.39 (s, 3H), 4.32 (d,
J = 5.2 Hz, 1H), 4.88 (s, 1H), 5.1 (br, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.48-
7.51 (m, 2H), 7.70 (s, 1H), 7.78-7.84 (m, 3H). 13C NMR (100 Hz, CDCl3) δ:
27.76, 28.69, 47.47, 76.30, 125.13, 126.40, 126.58, 126.64, 127.69,
127.73, 128.98, 132.97, 133.19, 133.24, 151.79, 152.76, 162.93. HRMS:
Calcd. For C17H17N3O2 295.1321; Found 296.1403 [M + H]+
6-(4-Methylbenzylamino)-1,3-dimethyluracil
colorless needles. 1H NMR (400 Hz, CDCl3) δ: 2.35 (s, 3H), 3.29 (s, 3H),
(3aa):
Isolated
as
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701445
European Journal of Organic Chemistry
FULL PAPER
6-(1-Naphthalenylmethylamino)-1,3-dimethyluracil (3ak): Isolated as
white solid. 1H NMR (400 Hz, CDCl3) δ: 3.29 (d, J = 4.0 Hz, 6H), 4.60 (d,
J = 4.4 Hz, 2H), 4.79 (br, 1H), 5.00 (s, 1H), 7.44-7.46 (m, 2H), 7.52-7.58
(m, 2H), 7.84-7.91 (m, 3H). 13C NMR (100 Hz, CDCl3) δ: 27.77, 28.62,
45.67, 76.18, 122.71, 125.38, 126.28, 126.97, 127.02, 129.07, 129.40,
130.85, 131.16, 133.94, 151.79, 152.55, 162.94. HRMS: Calcd. For
C17H17N3O2 295.1321; Found 296.1403 [M + H]+
[1]
[2]
P. Anastas, N. Eghbali, Chem. Soc. Rev. 2010, 39, 301-312
For selected reviews on borrowing hydrogen, see: F. Huang, Z. Liu, Z.
Yu, Angew. Chem. Int. Ed. 2016, 55, 862–875; b) Q. Yang, Q. Wang, Z.
Yu, Chem. Soc. Rev. 2015, 44, 2305–2329; c) Y. Obora, ACS Catal.
2014, 4, 3972–3981; d) S. Bahn, S. Imm, L. Neubert, M. Zhang, H.
Neumann, M. Beller. ChemCatChem. 2011, 3, 1853-1864; e) G. Guillena,
D. J Ramon, M. Yus, Chem .Rev. 2010, 110, 1611-1641; f) M. H. S. A.
Hamid, P. A. Slatford, J. M. J. Williams, Adv. Synth. Catal. 2007, 349,
1555–1575
6-(2-Furanylmethylamino)-1,3-dimethyluracil (3al): Isolated white solid.
1H NMR (400 Hz, CDCl3) δ: 3.34 (s, 3H), 3.44 (s, 3H), 3.79 (s, 2H), 4.73
(s, 2H), 6.15 (d, J = 3.6 Hz, 1H), 6.28 (d, J = 3.0 Hz, 1H), 7.284 (d, J = 2.0
Hz, 1H). 13C NMR (100 Hz, CDCl3) δ: 22.56, 28.31, 29.13, 86.09, 105.88,
110.59, 141.21, 150.80, 151.23, 153.36, 162.34. HRMS: Calcd. For
C11H13N3O3 235.0957; Found 236.1036 [M + H]+
[3]
[4]
For pioneering works on borrowing hydrogen, see: a) Y. Tsuji, K. T. Huh,
Y. Ohsugi, Y. Watanabe, J. Org. Chem. 1985, 50, 1365–1370; b) Y.
Watanabe, Y. Tsuji, H. Ige, Y. Ohsugi, T. Ohta, J. Org. Chem. 1984, 49,
3359–3363; c) Y. Watanabe, T. Ohta, Y. Tsuji, Bull. Chem. Soc. Jpn.
1983, 56, 2647–2651; d) R. Grigg, T. R. B. Mitchell, S. Sutthivaiyakit and
N. Tongpenyai. J. Chem. Soc., Chem. Comm. 1981, 611-612; e) Y.
Watanabe, Y. Tsuji, Y. Ohsugi. Tetrahedron. Lett. 1981, 22, 2667-2670
For recent examples, see: a) W. M. Akhtar, C. B. Cheong, J. R. Frost, K.
E. Christensen, N. G. Stevenson, T. J. Donohoe, J. Am. Chem. Soc.
2017, 139, 2577–2580; b) S. Elangovan, J. Neumann, J.-B. Sortais, K.
Junge, C. Darcel, M. Beller, Nat. Commun. 2016, 7, 12641; c) Z. Yin, H.
Zeng, J. Wu, S. Zheng, G. Zhang, ACS Catal. 2016, 6, 6546–6550; d) N.
Deibl, R. Kempe, J. Am. Chem. Soc. 2016, 138, 10786–10789; e) C.
Schlepphorst, B. Maji, F. Glorius, ACS Catal. 2016, 6, 4184–4188; f) Y.
Yang, A. Qin, K. Zhao, D. Wang, X. Shi, Adv. Synth. Catal. 2016, 358,
1433–1439; g) K. O. Marichev, J. M. Takacs, ACS Catal. 2016, 6, 2205–
2210; h) S. Rösler, M. Ertl, T. Irrgang, R. Kempe, Angew. Chem. Int. Ed.
2015, 15046–15050; i) S. Elangovan, J.-B. Sortais, M. Beller, C. Darcel,
Angew. Chem. Int. Ed. 2015, 54, 14483-14486
6-Butylamino-1,3-dimethyluracil (3am): Isolated as white solid. 1H NMR
(400 Hz, CDCl3) δ: 0.96 (t, J = 7.2 Hz, 3H), 1.37-1.46 (m, 2H), 1.61-1.68
(m, 2H), 3.08-3.13 (m, 2H), 3.31 (s, 3H), 3.40 (s, 3H), 4.45 (br, 1H), 4.86
(s, 1H). 13C NMR (100 Hz, CDCl3) δ: 13.63, 20.06, 27.72, 28.40, 30.49,
42.96, 75.53, 151.91, 152.84, 162.95. HRMS: Calcd. For C10H17N3O2
211.1321; Found 212.1400 [M + H]+
6-Isobutylamino-1,3-dimethyluracil (3ao): Isolated as white solid. 1H
NMR (400 Hz, CDCl3) δ: 0.99 (d, J = 6.8 Hz, 6H), 1.93-2.00 (m, 1H), 2.92
(t, J = 6.2 Hz), 3.30 (s, 3H), 3.42 (s, 3H), 4.76 (br, 1H), 4.83 (s, 1H). 13
C
NMR (100 Hz, CDCl3) δ: 20.16, 27,23, 27.68, 28.45, 50.68, 75.41, 151.89,
152.99, 162.93. HRMS: Calcd. For C10H17N3O2 211.1321; Found
212.1400 [M + H]+
6-(3-Methylbutylamino)-1,3-dimethyluracil (3ap): Isolated as white solid.
1H NMR (400 Hz, CDCl3) δ: 0.95 (d, J = 6.4 Hz), 1.53-1.58 (m, 2H), 1.65-
1.71 (m, 1H), 3.09-3.14 (m, 2H), 3.31 (s, 3H), 3.40 (s, 3H), 4.67 (br, 1H),
4.84 (s, 1H). 13C NMR (100 Hz, CDCl3) δ: 22.32, 25.93, 27.68, 28.47, 37.25,
41.50,75.32, 151.88, 152.92, 162.96. HRMS: Calcd. For C11H19N3O2
225.1427;Found 226.1551 [M + H]+
[5]
For enantioselective version, see: a) C. S. Lim, T. T. Quach, Y. Zhao,
Angew. Chem. Int. Ed. 2017, 7176–7180; b) M. Roudier, T. Constantieux,
A. Quintard, J. Rodriguez, ACS Catal. 2016, 6, 5236–5244; c) M. Peña-
López, H. Neumann, M. Beller, Angew. Chem. Int. Ed. 2016, 55, 7826–
7830; d) F. G. Mutti, T. Knaus, N. S. Scrutton, M. Breuer, N. J. Turner,
Science 2015, 439, 1525-1529; e) N. J. Oldenhuis, V. M. Dong, Z. Guan,
2014, 136, 12548-12551; f) Y. Zhang, C. S. Lim, D. S. B. Sim, H. J. Pan,
Y. Zhao, Angew. Chem. Int. Ed. 2014, 53, 1399–1403; g) A. E. Putra, Y.
Oe, T. Ohta, Eur. J. Org. Chem. 2013, 6146–6151; h) D. J. Shermer, P.
A. Slatford, D. D. Edney, J. M. J. Williams, Tetrahedron Asymm. 2007,
18, 2845–2848
6-(2-Methylbutylamino)-1,3-dimethyluracil (3aq): Isolated as slightly
yellowish solid. 1H NMR (400 Hz, CDCl3) δ: 0.92-0.98 (m, 6H), 1.17-1.28
(m, 1H), 1.41-1.49 (m, 1H), 1.71-1.77 (m, 1H), 2.86-2.92 (m, 1H), 3.00-
3.06 (m, 1H), 3.31 (s, 3H), 3.41 (s, 3H), 4.46 (br, 1H), 4.85 (s, 1H). 13C
NMR (100 Hz, CDCl3) δ: 11.11, 17.27, 27.11, 27.73, 28.37, 33.65, 49.05,
75.61, 151.91, 152.90, 162.92. HRMS: Calcd. For C11H19N3O2 225.1427;
Found 226.1551 [M + H]+
[6]
a) A. J. Corbett, S. B. G. Eckle, R. W. Birkinshaw, L. Liu, O. Patel, J.
Mahony, Z. Chen, R. Reantragoon, B. Meehan, H. Cao, et al., Nature
2014, 509, 361–365; b) A. Raoof, P. Depledge, N. M. Hamilton, N. S.
Hamilton, J. R. Hitchin, G. V. Hopkins, A. M. Jordan, et al., J. Med. Chem.
2013, 56, 6352-6370; c) F. E. Zilly, A. Taglieber, F. Schulz, F. Hollmann,
M. T. Reetz, Chem. Commun. 2009, 7152–7154.
6-(Cyclohexylmethylamino)-1,3-dimethyluracil (3ar): Isolated as light
yellow solid. 1H NMR (400 Hz, CDCl3) δ: 0.92-1.01 (m, 2H), 1.15-1.30 (m,
3H), 1.61-1.77 (m, 6H), 2.94 (t, J = 6.2 Hz, 2H), 3.30 (s, 3H), 3.41 (s, 3H),
4.78 (br, 1H), 4.83 (s, 1H). 13C NMR (100 Hz, CDCl3) δ: 25.59, 26.17, 27.68,
28.47, 30.97, 36.48, 49.54, 75.36, 151.89, 153.01, 162.96. HRMS: Calcd.
For C13H21N3O2 251.1634; Found 252.1712 [M + H]+
[7]
[8]
M. P. Dickens, P. Roxburgh, A. Hock, M. Mezna, B. Kellam, K. H.
Vousden, P. M. Fischer, Bioorg. Med. Chem. 2013, 21, 6868–6877
a) J. B. Lin, J. L. He, Y. C. Shih, T. C. Chien, Tetrahedron Lett. 2011, 52,
3969–3972; b) Y. J. Wu, C. C. Liau, C. H. Jen, Y. C. Shih, T. C. Chien,
Chem. Commun. 2010, 46, 4821-4823
6-Benzylamino-1,3-ethyluracil (3be) Isolated as white solid. 1H NMR
(400 Hz, CDCl3) δ: 1.16 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 3.90-
3.99 (m, 4H), 4.22 (d, J = 5.2 Hz, 2H), 4.77 (s, 1H), 5.36 (br, 1H), 7.25-
7.38 (m, 5H). 13C NMR (100 Hz, CDCl3) δ: 13.15, 13.43, 36.04, 37.10,
47.08, 76.45, 127.24, 128.07, 128.99, 136.23, 151.13, 152.23, 162.69.
HRMS: Calcd. For C15H19N3O2 273.1477; Found 274.1555 [M + H]+
[9]
a) S. Das, A. J. Thakur, Eur. J. Org. Chem. 2011, 2301–2308. b) M.
Dabiri, S. C. Azimi, H. R. Khavasi, A. Bazgir, Tetrahedron 2008, 64,
7307–7311
[10] Examples of selective alkylation of heterocycles via borrowing hydrogen
including our works: a) A. E. Putra, Y. Oe, T. Ohta, Tetrahedron Lett.
2017, 1098-1101; b) A. E. Putra, Y. Oe, T. Ohta, Eur. J. Org. Chem. 2015,
7799–7805; c) S. Bartolucci, M. Mari, A. Bedini, G. Piersanti, G. Spadoni,
J. Org. Chem. 2015, 80, 3217-3222; d) A. Montagut-Romans, M. Boulven,
M. Lemaire, F. Popowycz, New J. Chem. 2014, 38, 1794-1801; e) A. E.
Putra, K. Takigawa, H. Tanaka, Y. Ito, Y. Oe, T. Ohta, Eur. J. Org. Chem.
2013, 6344–6354; f) S. Bähn, S. Imm, K. Mevius, L. Neubert, A. Tillack,
J. M. J. Williams, M. Beller, Chem. Eur. J. 2010, 16, 3590–3593; g) R.
Grigg, S. Whitney, V. Sridharan, A. Keep, A. Derrick, Tetrahedron 2009,
65, 4375–4383; h) R. Grigg, S. Whitney, V. Sridharan, A. Keep, A.
Derrick, Tetrahedron 2009, 65, 7468–7473; i) S. Whitneys, R. Grigg, A.
Derrick, A. Keep, Org. Lett. 2007, 9, 3299–3302
6-Benzylamino-1,3-dibenzyluracil (3ce): Isolated as white solid. 1H
NMR (400 Hz, CDCl3) δ: 4.02 (d, J = 5.2 Hz), 4.79 (s, 1H), 4.96 (br, 1H),
5.12 (d, J = 10.0 Hz, 4H), 6.89-6.91 (m, 2H), 7.12-7.15 (m, 2H), 7.21-7.31
(m, 9H), 7.44 (d, J = 6.8 Hz, 2H). 13C NMR (100 Hz, CDCl3) δ: 44.33, 45.84,
47.12, 126.29, 127.10, 127.32, 128.04, 128.31, 128.35, 128.65, 128.92,
129.39, 135.15, 135.83, 137.61, 152.18, 152.78, 162.64. HRMS: Calcd.
For C25H23N3O2 397.1790; Found 398.1863 [M + H]+
Keywords: Aminouracils •Alcohols •Selective alkylation •
Borrowing hydrogen • Iridium catalysis
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701445
European Journal of Organic Chemistry
FULL PAPER
[11] S. H. Yalkowsky, Y. He, P. Jain, Handbook of Aqueous Solubility Data
(2nd ed.), CRC Press, Boca Raton, 2010
[12] a) R. Kawahara, K. Fujita, R. Yamaguchi, J. Am. Chem. Soc. 2010, 3,
15108–15111; b) R. Kawahara, K. I. Fujita, R. Yamaguchi, Adv. Synth.
Catal. 2011, 353, 1161–1168; c) A. Saidi, A. J. Blacker, G. W. Lamb, S.
P. Marsden, J. E. Taylor, J. M. J. Williams, Org. Process Res. Dev. 2010,
14, 1046–1049; d) O. Saidi, A. J. Blacker, M. M. Farah, S. P. Marsden,
J. M. J. Williams, Chem. Commun., 2010, 46, 1541–1543; e) K. Fujita, Y.
Enoki, R. Yamaguchi, Tetrahedron, 2008, 64, 1943-1954; D. Balcells, A.
Nova, E. Clot, D. Gnanamgari, R. H. Crabtree, O. Eisenstein,
Organometallics, 2008, 27, 2529-2535.
[13] a) A. Denichoux, T. Fukuyama, T. Doi, J. Horiguchi, I. Ryu, Org. Lett.
2010, 12, 1–3; b) T. Kuwahara, T. Fukuyama, I. Ryu, Org. Lett. 2012, 14,
4703–4705
[14] a) M. H. S. A. Hamid, C. L. Allen, G. W. Lamb, A. C. Maxwell, H. C.
Maytum, A. J. A. Watson, J. M. J. Williams, J. Am. Chem. Soc. 2009, 131.
1766–1774
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701445
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Full Paper
O
O
O
Borrowing hydrogen*
[Ir]
R1
O
R1
O
R1
O
[Ir]
N
R3
NH2
N
N
+
HO
R3
Anggi Eka Putra, Yohei Oe*, Tetsuo
Ohta
N
N
NH2
N
N
R3
H2O
H
R2
R2
R2
Not formed
21 examples,
Mostly > 90% yield
Page No. – Page No.
Selective N-mono-alkylation of 6-
aminouracils with alcohols: An
environmentally benign protocol for
synthesis of 6-alkylaminouracils
Highly selective N-mono-alkylation of 6-aminouracils with alcohols achieved by
using iridium catalysis on the basis of borrowing hydrogen methodology is
demonstrated. This reaction provides an efficient and green approach to synthesize
6-alkylaminouracils, which are useful intermediates in organic synthesis.
*one or two words that highlight the emphasis of the paper or the field of the study
This article is protected by copyright. All rights reserved.