An efficient microwave assisted synthesis of N′-aryl/(alkyl)-substituted N-(4-hydroxy-6-phenylpyrimidin-2-yl)guanidines: Scope and limitations

Article abstract of DOI:10.1016/j.tetlet.2017.03.063

Treatment of N-[(4-hydroxy-6-phenyl)pyrimidin-2-yl]cyanamide with 1° alkyl or arylamines in isopropyl alcohol for only 10?min at 110–120?°C under microwave conditions gave the corresponding N′-alkyl(aryl)guanidine derivatives in excellent yields (65–84%). Isolated yields were greatest when >1.0?equiv. of amines were employed, but excellent results were also obtained when aryl and alkylamines were reacted with a more atom-economical loading (1.0?equiv.; 70% and 72% ave. yields, respectively). Arylamines with either highly electron withdrawing substituents (e.g. CO₂H) or pi-deficient heterocycles (e.g. variously substituted aminopyridines) did not work well under these conditions, and reaction with ureas and/or amino acids did not give detectable products. Work-up was exceedingly simple, and involved simple collection and washing of product on a sintered glass funnel. Products were obtained in analytically pure form and required approximately 1?h to prepare, start to finish.

Full text of DOI:10.1016/j.tetlet.2017.03.063

Accepted Manuscript
An Efficient Microwave Assisted Synthesis of N ’-Aryl/(alkyl)-substituted N-
(4-hydroxy-6-phenylpyrimidin-2-yl)guanidines: Scope and Limitations
Paulo A. Machicao, Scott R. Burt, Ryan K. Christensen, Nathan B. Lohner, J.D.
Singleton, Matt A. Peterson
PII:
S0040-4039(17)30368-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.03.063
TETL 48764
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
9 February 2017
17 March 2017
19 March 2017
Please cite this article as: Machicao, P.A., Burt, S.R., Christensen, R.K., Lohner, N.B., Singleton, J.D., Peterson,
M.A., An Efficient Microwave Assisted Synthesis of N ’-Aryl/(alkyl)-substituted N-(4-hydroxy-6-
phenylpyrimidin-2-yl)guanidines: Scope and Limitations, Tetrahedron Letters (2017), doi: http://dx.doi.org/
1
0.1016/j.tetlet.2017.03.063
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An Efficient Microwave Assisted Synthesis of N’-Aryl/(alkyl)-substituted N-(4-
hydroxy-6-phenylpyrimidin-2-yl)guanidines: Scope and Limitations
a
a
a
a
a
Paulo A. Machicao, Scott R. Burt, Ryan K. Christensen, Nathan B. Lohner, J. D. Singleton, and Matt A.
Peterson *
a,
a
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602
∗
Corresponding author. Tel.: +0-801-422-6843; fax: +0-801-422-0153; email:matt_peterson@byu.edu
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Treatment of N-[(4-hydroxy-6-phenyl)pyrimidin-2-yl]cyanamide with 1° alkyl or arylamines in
isopropyl alcohol for only 10 minutes at 110–120 °C under microwave conditions gave the
’
corresponding N -alkyl(aryl)guanidine derivatives in excellent yields (65–84%). Isolated yields
were greatest when > 1.0 equiv. of amines were employed, but excellent results were also
obtained when aryl and alkylamines were reacted with a more atom-economical loading (1.0
equiv.; 70% and 72% ave. yields, respectively). Arylamines with either highly electron
Available online
2
withdrawing substituents (e.g. CO H) or pi-deficient heterocycles (e.g. variously substituted
aminopyridines) did not work well under these conditions, and reaction with ureas and/or amino
acids did not give detectable products. Work-up was exceedingly simple, and involved simple
collection and washing of product on a sintered glass funnel. Products were obtained in
analytically pure form and required approximately 1 h to prepare, start to finish.
Keywords:
N-[(4-hydroxy-6-phenyl)pyrimidin-2-yl]guanidine
Compound libraries
Microwave assisted synthesis
2
009 Elsevier Ltd. All rights reserved.
4
-hydroxypyrimidines and their 4-(1H) or 4-(3H)
Our interest in the title compounds stemmed from their
possession of both the 4-hydroxypyrimidine and guanidine
moieties, each of which had previously been shown to impart
favorable biological properties (vide supra). As has been
demonstrated in numerous cases, microwave irradiation
frequently leads to shorter reaction times, decreased formation of
1
, 2
pyrimidinone tautomers are an interesting class of compounds
that have been extensively studied. The stimulus for these
studies derives from their activities in a wide variety of biological
contexts including potential use as antiviral, anticancer,
antimicrobial, antimalarial, anti-inflammatory, or anti-ulcer
therapeutics. Select derivatives have also exhibited potential for
treating diabetes, arthritis, and neurodegenerative disorders,
while others have been studied for their activities as enzyme
inhibitors, interferon inducing agents, angiotensin receptor
blockers, and calcium receptor antagonists.
molecular structures which incorporate the 4-hydroxypyrimidine
moiety as part of their core also exhibit interesting biological
properties, including fungicidal,
obesity activities. Interest in 4-hydroxypyrimidines has also
been stimulated by their potential use in a variety of
supramolecular systems.
guanidine moiety are also widely recognized, and include such
diverse activities as anti-bacterial, anti-microbial, anti-parasitic,
and anti-viral, as has been noted in several recent comprehensive
3
4
5
6
7
8
2
2
byproducts, and enhanced isolated yields.
As a base-line
9
10
11
experiment, we attempted to reproduce the method of Werbel and
co-workers for compound 2a (Scheme 1). In our hands,
compound 2a was obtained in very modest yield (23%, crude),
and even lower yields were obtained after recrystallization. Not
surprisingly, cyclohexylamine failed to give any detectable
product (3e) under these conditions, most likely due to the
required use of acid catalyst, which would be expected to
protonate the alkylamine and greatly reduce or suppress its
nucleophilicity.
1
2
13
1
4
15
More complex
1
6
17
insecticidal,
and anti-
1
8
1
9
The biological properties of the
Here, we report that simple treatment of N-[(4-hydroxy-6-
phenyl)pyrimidin-2-yl]cyanamide (1) with aniline (1.0 equiv.) in
isopropyl alcohol at 110–120 °C for only 10 minutes in a
microwave reactor (Scheme 2) gave desired product 2a in
excellent yields (67–75%). Product was obtained in pure form
after rinsing with minimal volumes of ice-cold isopropyl alcohol
2
0
reviews.
As part of our research into developing methods for rapid
creation of compound libraries that could be screened for novel
biological activities, we became interested in modifying the
method of Werbel and co-workers for preparing N’-aryl-
substituted N-(4-hydroxypyrimidin-2-yl)guanidines to give the
desired products more efficiently using microwave irradiation.
2
3
(Table 1). Investigation of the impact of varying equivalents of
amine revealed that for aniline, yields were not dramatically
improved by using > 1.0 equiv. (Table 1, entries 1–3). Indeed, in
some cases (e.g. p-octylphenylamine), yields were dramatically
2
1

2
Scheme 1. Reagents and conditions: RNH (1.0 equiv.), HCl (0.5 equiv.),
2
-ethoxyethanol:H O (3:1; 0.7 M), reflux 24 h.
2
2
Scheme 2. Reagents and conditions: RNH , 2-propanol, microwave
irradiation, 10 min, 110–120°C.

reduced with excess amine. In the case of p-octylphenylamine,
the low yield observed when 5.0 equiv. amine was used (Table 1,
entry 6) resulted from the insolubility of unreacted amine in the
In summary, we have developed an efficient one-pot method
for converting N-[(4-hydroxy-6-phenyl)pyrimidin-2-yl]cyan-
’
amide (1) to the corresponding N -alkyl or N’-arylguanidine
2
4
ice-cold isopropyl alcohol used to fully precipitate the product.
Since treatment of compound 1 with varying amounts of aniline
2.0 – 3.0 equiv.) did not improve yields significantly (Table 1,
derivatives (2–3). The method is simple and efficient and avoids
the limitations associated with the previously reported method for
preparing the title compounds (Scheme 1). The present method
involved microwave assisted conversion of compound 1 to
compounds 2–3 with optimized yields ranging from 57–84% for
the arylamines (ave. = 70%; Table 1) and from 65–80% for the
unhindered 1° alkylamines examined (ave = 72%, Table 2). The
method did possess some limitations given that electron deficient
arylamines, ureas, or amino acids did not give detectable
products, and highly hindered 1° alkylamines were also
ineffective substrates for this reaction. However, the efficiency
of the method with an array of electron rich arylamines and
unhindered 1°alklamines, demonstrates its potential as a versatile
tool for preparing libraries of compounds that may prove useful
in a number of biologically and medicinally relevant contexts.
There is currently a great deal of interest in such libraries, given
the broad range of activities reported for 4-hydroxypyrimidine
and/or guanidine derivatives in general, including antibacterial,
antimicrobial, antiviral, antimalarial, antifungal, antitumor, anti-
(
entries 2–3), for all subsequent reactions, the more atom-
economical loading of arylamine was used (1.0 equiv.), giving
most products in excellent yields (70–80%). One exception to
this was the yields obtained for the halo-substituted aniline
derivatives (2h-n) where maximal yields were achieved when 3.0
equiv. of arylamine were employed (Table 1, entries 12–24).
The microwave conditions also proved useful for preparing
derivatives from alkylamines (Table 2). Yields for unhindered 1°
alkylamine were generally high (65–82%), but sterically hindered
1
° alkylamines (e.g. 1-adamantylamine, tert-butylamine) gave
products in low yields, which were also contaminated with large
amounts of starting material under all conditions examined
(
Table 2). A majority of the 2° amines we examined failed to
give solid product (e.g. diethylamine, diisopropylamine, N-
methylaniline), and the yield for the only example we examined
that gave isolable solid product was quite modest (entry 14).
inflammatory, anti-diabetic, and antiulcer activities.
These
In order to further test the scope of this reaction, compound 1
was treated with a range of different nucleophiles (Table 3).
Desired products were formed in only trace amounts for any of
the amines evaluated (as determined by MS and TLC analysis).
This was true even when multiple equiv. of the amine were
employed (5.0 equiv.). This general lack of reactivity is most
likely due to the electron deficient nature of the nucleophiles
involved, as one would expect for the pi-deficient
heteroarylamines (entries 1–4), p-aminobenzoic acid (entry 5),
and ureas (entries 6–7). Interestingly, none of the amino acids
tested gave detectable products, even when Hünigs base (1.0
equiv.) was added to deprotonate the zwitterion (entry 9). In
every instance examined (Table 3), the major product detected
was the isopropoxy derivative (5) which resulted from competing
activities, in addition to the broad array of biomolecular targets
modulated or inhibited by appropriately functionalized 4-
hydroxypyrimidine and/or guanidine derivatives, suggest that the
method described herein may prove useful for identifying novel
analogues with unprecedented activities that could prove useful
in these or other applications.
Acknowledgments
Generous support from the College of Physical and
Mathematical Sciences at Brigham Young University is
gratefully acknowledged.
2
4,
addition of isopropyl alcohol to the nitrile moiety (Scheme 3).
2
5
Supplementary Material
Supplementary data (detailed experimental procedures and
NMR data for all new for compounds associated with this article)
can be found in the online version at doi:xxxxxxxxx.
1
1
Scheme 3. Reagents and conditions: R NH
amine, urea, or amino acid), 2-propanol, microwave irradiation, 10 min, 110–
20°C.
2 2
(R NH = electron deficient
1
The overall method employed for these syntheses was very
simple and involved heating a solution of the amine in HPLC-
grade isopropyl alcohol for only 10 minutes at 110–120 °C in a
2
6
microwave reactor. Work-up involved chilling the product on
ice to ensure complete precipitation, then collection and washing
of solid product with ice-cold isopropyl alcohol (3 X 1.0 mL) on
a fine porosity sintered glass funnel. Products were obtained in
analytically pure form (after drying in vacuo), as determined by
1
13
H and C NMR, and elemental analysis (see Supplementary
Material). Total preparation times were approximately 1 h,
including work-up/isolation.

1
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6
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3
Details of the preliminary results used in our selection of
solvent, reaction time, and reaction temperature are provided
in the Supplementary Material. Summarized briefly, the
conditions we selected gave the maximum yields while still
affording the ease and simplicity of collecting analytically
pure compound via simple filtration.
2
4
Low yields for compounds 2c (Method D) and 3i (Method
E) can be rationalized as follows: (2c): The excess 4-
octylaniline co-precipitated in the ice-cold isopropyl alcohol
thus necessitating the use of room temperature solvent to
wash it from the product. In addition, larger quantities of the
room temperature isopropyl alcohol were required to wash
away the precipitated 4-octylaniline than were used for
isolating products from other substrates. (3i): The major
products for this reaction were compound 5 and 2-amino-4-
hydroxy-6-phenylpyrimidine. We attribute the failure of
Method E with this substrate to the steric hindrance associated
with tert-butylamine and the increased basicity of the reaction
medium (when using 10 equiv. of amine) which would
enhance the rate of base-promoted hydrolysis of the
cyanamide and as well as favor addition of the isopropyl
alcohol rather than give the desired product.
2
5
Varying amounts of the product resulting from hydrolysis
of compound 1 (i.e., 2-amino-4-hydroxy-6-phenylpyrimidine,
m/z [M+H] = 188) were observed in all reactions, and
compound 5 was also observed as a byproduct in reactions
used to prepare compounds 2a–n and 3a–j.
2
6
The general experimental procedure for preparing
compound 2a is as follows: To a solution of aniline (11 mg,
.12 mmol) in HPLC-grade 2-propanol (1.0 mL) was added
0
N-(4-hydroxypyrimidin-2-yl)cyanamide (25 mg, 0.12 mmol).
The resulting suspension was heated for 10 minutes in a CEM
Corp. Discover-S microwave reactor oven using 10 mL
Pressure Vials pressure-rated up to 35 Bar (Cat. No. 908035).
Temperatures ranged between 110-120 °C during the reaction
period. (Maximum temperature setting was 125 °C with 10
minutes ramping time. Cooling times were typically 30
minutes). After chilling on ice, the resulting precipitate was
collected on a sintered glass funnel (fine porosity) and washed
with ice-cold 2-propanol (3 X 1.0 mL). Product (2a) was
obtained in 67–75% as a white solid with no further
1
purification necessary. H NMR (DMSO-d
6
, 500MHz) δ 11.4
(
bs, 1H), 9.12 (bs, 1H), 7.90–7.88 (m, 2H), 7.70 (d, J = 8.0
Hz, 2H), 7.48–7.47 (m, 3H), 7.28 (t, J = 8.0 Hz, 2H), 7.01 (t,
1
3
J = 7.5 Hz, 1H), 6.27 (s, 1H); C NMR (DMSO-d
δ 164.6, 160.9, 159.1, 156.5, 139.5, 137.8, 130.4, 129.15,
29.14, 127.0, 123.0, 120.9, 101.9; HRMS Calcd. for
O [M+H]: 306.1360; Found: 306.1355; Anal. Calc.
O: C, 66.87; H, 4.95; Found: C, 66.47; H, 4.89.
6
, 125MHz)
1
17 16 5
C H N
for C17H N
15 5






An efficient method for preparing the title compounds is presented
The reaction requires only 10 minutes at 110–120 °C under microwave conditions
Products were obtained in excellent yields (65-84%)
Products were obtained in analytically pure form
Total preparation time was approx. 1 h (including isolation)