Recyclization reactions of 1-alkylpyrimidinium salts

Article abstract of DOI:10.1515/HC.2011.025

The reaction of 4-amino-2-benzyl-1-methyl-5-ethoxycarbonylpyrimidinium iodide ( 3 ) with alcoholic methylamine resulted in the formation of the methylimine of 2-amino-4- hydroxy-6-methylamino-5-phenylpyridine-3-carbaldehyde ( 5 ). Heating of the same pyri

Full text of DOI:10.1515/HC.2011.025

Heterocycl. Commun., Vol. 17(3-4), pp. 129–133, 2011 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/HC.2011.025
Recyclization reactions of 1-alkylpyrimidinium salts
Ruben S. Vardanyan1, Gevork G. Danagulyan2,
exocyclic carbon atom (C–C recyclization), see Figure 1
(Vardanyan et al., 2005).
Armen D. Mkrtchyan2 and Victor J. Hruby1,*
1 Departments of Chemistry and Biochemistry, 1306
University Boulevard, University of Arizona, Tucson, AZ
85721, USA
2 Russian-Armenian (Slavonic) State University, 123 H.
To further investigate possibilities of pyrimidine ring recy-
Emin Street, Yerevan 375051, Republic of Armenia
Results and discussion
clizations, we have studied transformations of pyrimidinium
salts that can potentially be able to competitively undergo
various types of recyclizations: Dimroth rearrangement,
*Corresponding author
e-mail: hruby@email.arizona.edu
Kost-Sagitullin rearrangement and the new C–C recyclization
that we have found. The necessary structural requirements in
the model compounds are the presence of a 5-ethoxycarbonyl
Abstract
group, a quaternized nitrogen atom in the pyrimidine ring, and
The reaction of 4-amino-2-benzyl-1-methyl-5-ethoxycar-
bonylpyrimidinium iodide (3) with alcoholic methylamine
an exocyclic amine or methylene group in the α-position.
One of the appropriate model compounds, which satisfies
resulted in the formation of the methylimine of 2-amino-4-
the above-mentioned requirements, is 4-amino-2-benzyl-
hydroxy-6-methylamino-5-phenylpyridine-3-carbaldehyde
1-methyl-5-ethoxycarbonylpyrimidinium iodide (3). It was
(5). Heating of the same pyrimidinium salt in benzylam-
synthesized in quantitative yield by the reaction of phenyl-
ine gave a mixture of products of two C–C recyclizations:
acetamidine with ethyl(ethoxy-methylene)cyanoacetate (1)
2-benzyl-4-benzylamino-5-carbamoylpyrimidine (7) and the
followed by alkylation of the 4-amino-2-benzyl-5-ethoxycar-
benzylimine of 4-amino-2-benzyl-6-benzylaminopyrimidine-
bonylpyrimidine (2) obtained with methyl iodide, resulting in
5-carbaldehyde (8). The reaction of 2-amino-1,4-dimethyl-5-
the formation of 3 (Scheme 1).
ethoxycarbonylpyrimidinium iodide (10) with KOH ethanolic
For this pyrimidinium salt 3, we assumed the Kost-
solution gave a single product of C–C-recyclization: 2-amino-
Sagitullin type rearrangement and C–C recyclization. As a
5-acetyl-4-hydroxypyrimidine (11).
result of the reaction of pyrimidinium salt 3 with alcoholic
methylamine, i.e., under conditions of the Kost-Sagitullin
rearrangement (Danagulyan et al., 2000, 2001; Danagulyan
Keywords: pyrimidinium salt; recyclization.
and Sahakyan, 2004), we have isolated the methylimine of
2-amino-4-hydroxy-6-methylamino-5-phenylpyridine-3-car-
baldehyde (5), which is the product of a Kost-Sagitullin-type
Introduction
rearrangement (Scheme 2).
Some of the frequently used pyrimidine ring modifications
are the recyclization reactions (Danagulyan, 2005; El Ashry
et al., 2010), the most frequently studied of which is the
Dimroth rearrangement (Brown, 1968; El Ashry et al., 1999)
involving the replacement of a nitrogen ring by an exocyclic
nitrogen atom (N–N recyclizations). This reaction is widely
used in the synthesis of various compounds that are unavail-
able by other methods and has become an important method
in organic synthesis industry applications for the creation of
various biologically active compounds and drugs (Suzuki
et al., 1992; Nicolai et al., 1994; Lai et al., 1996; Fujii and
Itaya, 1998, 1999; Nandeeshaiah and Ambekar, 1998; Loakes
et al., 1999; Anaflous et al., 2004). We have studied the trans-
formations of pyrimidines into pyridine derivatives (‘Kost-
Sagitullin rearrangement’, Sagitullin et al., 1978; Danagulyan
et al., 2000, 2001; Danagulyan and Sahakyan, 2004) in which
the nitrogen atom of a pyrimidine ring is substituted by the
exocyclic carbon atom in the second position. Recently we
reported a new type of nucleophilic recyclization of pyrim-
idines–substitution of the endocyclic carbon atom by the
The presence of the azomethine moiety in product 5 is
another important observation of this reaction. This means
that the C–N recyclization proceeds as a result of the nucleo-
phile being attacked at position 6 of the pyrimidine ring
rather than at position 4. In our previous studies (Vardanyan
et al., 2005) we have shown that for a similar transformation
of pyrimidine that is non-alkylated at the nitrogen atom, the
nucleophilic attack takes place at position 4 of the pyrimidine
ring. Actually, quaternization of the pyrimidine nitrogen atom
results in a shift of electron density in the heterocycle and, as
a consequence, a change in direction of the initial attack on
the nucleophile that leads to formation of the imine in position
5. The possible scheme for the rearrangement is presented in
Figure 2. It includes the opening of the pyrimidine ring at
the N(1)–C(6) bond followed by synchronous rotation around
both the C(2)–N(3) and C(4)–C(5) bonds, and then cycliza-
tion, which completes the rearrangement process–formally,
we can speak of two simultaneous rearrangements: a Kost-
Sagitullin rearrangement (N–C) and (C–C) recyclizations.
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130 R.S. Vardanyan et al.
X
N
O
OH
N
O
-
OH
Nu
Nu
N
N
N
N
OR
N
X
N
R
R
N
N
R
C
H
N
R
N
H
N
N
C-C recyclizations
N-N recyclizations
N-C recyclizations
Figure 1 Pyrimidine ring recyclizations.
O
O
NH2
NH
COOEt
Ph
N
O
N
NH2
Ph
N
1
2
MeI
-
NH
NH2
NH2
I
X
COOEt
COOEt
-
Me
COOEt
HN
+
N
+
N
+
Ph
Ph
Ph
N
Me
N
Me
N
4
-
I
I
3
Scheme 1 Synthesis of the starting model compound 4.
NH2
OH
Conclusions
H
C
COOEt
-
Ph
NHMe
MeN
MeNH2
N
+
4-Amino-2-benzyl-1-methyl-5-ethoxycarbonylpyrimidinium
iodide (3), when heated in benzylamine, is transformed into a
mixture of three products: the product of destructive aminoly-
sis 6 and two products of C–C recyclization, 7 and 8.
On the other hand, heating 2-amino-1,4-dimethyl-5-
ethoxycarbonylpyrimidinium iodide (10) with alcoholic
KOH yields 2-amino-5-acetyl-4-hydroxypyrimidine (11) as
the sole product. In this case, the product is derived from C–C
recyclization of the pyrimidinium salt.
Ph
N
Me
H2N
N
I
3
5
Scheme 2 Kost-Sagitullin rearrangement.
Heating the pyrimidinium salt 3 in benzylamine (Scheme 3)
gave a mixture of acyclic product 6 and two products of
C–C recyclizations: 2-benzyl-4-benzylamino-5-carbamo-
ylpyrimidine (7) and the benzylimine of 4-amino-2-benzyl-
6-benzylaminopyrimidine-5-carbaldehyde (8). The reaction
of 2-amino-1,4-dimethyl-5-ethoxycarbonylpyrimidinium
iodide (10) with KOH ethanolic solution (Scheme 4) gave
a single product of C–C recyclization: 2-amino-5-acetyl-4-
hydroxypyrimidine (11).
Experimental
General
Nuclear magnetic resonance (NMR) spectra were acquired on Varian
Mercury 300 with a resonance frequency of 300.08 MHz for the 1H
NH2
NH2
NH2
COOEt
COOEt
COOEt
N
N
+
N
Ph
H
Ph
Ph
H
N
Me
NHMe
N
Me
NH
Me
NHMe
H2NMe
-
I
3
NH2
NH2
Ph
H
H
NH2
H
H
NHMe
NHMe
N
NMe
N
N
O
MeHN
OH
MeHN
OEt
MeN
O
Ph
Ph
5
Figure 2 Proposed mechanism for the synthesis of 5 from 3.
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Reactions of 1-alkylpyrimidinium salts 131
O
Ph
CH2Ph
N
H
NH2
NHCH2Ph
COOEt
-
CONH2
6
PhCH2NH2
N
+
N
Ph
Ph
N
Me
N
I
7
NH2
3
CH NCH2Ph
NHCH2Ph
N
Ph
N
8
Scheme 3 Simultaneous rearrangements in the presence of benzylamine.
Me
Me
OH
COOEt
COOEt
MeI
KOH
COMe
N
+
N
N
H2N
N
Me
H2N
N
-
I
H2N
N
10
9
11
Scheme 4 Pure C–C recyclization of the pyrimidinium salt in KOH solution.
nucleus and 75.46 MHz for the 13C nucleus. The sample temperature
was 303 K. The coupling constants, J, are given in Hz. Thin layer
chromatography (TLC) was performed on Silufol UV-254 platelets,
developed by iodine vapors and Erlich reagent.
for C15H18N3IO2: C, 45.13; H, 4.54; N, 10.53. Found: C, 45.34; H,
4.49; N, 10.66.
Reaction of 4-amino-2-benzyl-1-methyl-
5-ethoxycarbonylpyrimidinium iodide (3)
with methylamine
4-Amino-2-benzyl-5-ethoxycarbonylpyrimidine (2)
Here, 5.97 g (0.035 mol) of phenylacetamidine hydrochloride
was added to a solution of sodium ethoxide prepared from 0.81 g
(0.035 mol) of metallic sodium and 20 ml of dry ethanol. The mix-
ture was stirred for 30 min and then the resulting sodium chloride
precipitate was rapidly filtered off under reduced pressure. The
residue was treated with a solution of 5.92 g (0.035 mol) of ethyl
(ethoxymethylene)cyanoacetate (1) (Deno, 1947; Jones, 1952) in
10 ml of dry ethanol. The mixture was heated at reflux for 4 h, the
alcohol was then removed and the residue thoroughly washed with
acetone to afford 4.2 g (47%) of 4-amino-2-benzyl-5-ethoxycarbon-
ylpyrimidine (2); mp 159–160°C, Rf 0.66 (acetone/toluene, 1:1);
1H NMR (DMSO-d6): δ 1.38 (3H, t, J=7.1, CH2CH3), 3.96 (2H,
s, CH2C 6H5), 4.33 (2H, q, J=7.1, OCH2), 7.1–7.3 (5H, m, C6H5),
7.5–7.6 (2H, br s, NH2), 8.68 (1H, s, 6-H). Analysis calculated for
C14H15N3O2: C, 65.35; H, 5.88; N, 16.33. Found: C, 65.64; H, 5.79;
N, 16.16.
A mixture of 3 (1 g, 0.0025 mol) and alcoholic methylamine (20 ml,
10%) was heated for 10 h in a sealed tube immersed in a boiling
water bath. The solvent and the excess methylamine were removed
under reduced pressure. The residue was thoroughly extracted with
hot benzene and after removal of the solvent the product was separat-
ed on a silica gel column eluting with benzene/acetone (1:1) to give
0.35 g (55%) of methylimine of 2-amino-4-hydroxy-6-methylamino-
5-phenylpyridine-3-carbaldehyde (5); mp 140–141°C; Rf 0.52 (ben-
1
zene/acetone, 1:1); H NMR (CDCl3), δ, ppm, J (Hz): 3.20 (3H, s,
N–CH3), 3.23 (3H, d, J=5.1, NHCH3), 5.01 (1H, br s, NH), 5.58 (1H,
br s, NH), 7.3–7.44 (5H, m, C6H5), 9.98 (1H, br s, NHCH3), 10.17
(1H, s, CH=N). Analysis calculated for C14H16N4O: C, 65.61; H,
6.29; N, 21.86. Found: C, 65.68; H, 6.47; N, 21.76.
Reaction of 4-amino-2-benzyl-1-methyl-
5-ethoxycarbonylpyrimidinium iodide (3)
with benzylamine
Preparation of 4-amino-2-benzyl-1-methyl-5-
ethoxycarbonylpyrimidinium iodide (3)
A mixture of 3 (0.8 g, 0.002 mol) and benzylamine (5 ml) was heated
for 8 h in a sealed tube in a boiling water bath. After removal of the
excess benzylamine under reduced pressure, the residue was extract-
ed with hot benzene. The solvent was removed and products 6 to 8
obtained were separated on a silica gel column eluting with benzene/
acetone (10:1).
A solution of 4-amino-2-benzyl-5-ethoxycarbonylpyrimidine (2,
2.57 g, 0.01 mol) in methyl iodide (5 ml) was heated in a sealed tube
in a boiling water bath for 10 h. The resulting precipitate of 3 was
washed with hot hexanes to afford 3.69 g (92%); mp 219–220°C; Rf
1
0.52 (isopropanol/ammonia/water, 7: 0.5:1); H NMR (DMSO-d6):
δ 1.42 (3H, t, J=7.1, CH2CH3), 4.02 (3H, s, N–CH3), 4.43 (2H, s,
CH2C 6H5), 4.43 (2H, q, J=7.1, OCH2), 7.34 (5H, m, C6H5), 8.79 (1H,
br s, NH), 9.18 (1H, s, 6-H), 9.82 (1H, br s, NH). Analysis calculated
N-(Benzyl)phenylacetamide (6) Yield 0.15 g (33%); mp 117–
118°C; Rf 0.76 (benzene/acetone, 1:1); H NMR (CDCl3): δ 3.62
1
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132 R.S. Vardanyan et al.
(2H, s, CH2), 4.42 (2H, d, J=5.9, CH2NH), 5.68 (1H, br s, NH), 7.3
(10H, m, 2C6H5). Analysis calculated for C15H15NO: C, 79.97; H,
6.71; N, 6.22. Found: C, 79.58; H, 6.49; N, 6.66.
(11): mp 296–298°C; Rf 0.5 (ethanol); 1H NMR (DMSO-d6): δ 2.57
(3H, s, CH3), 6.69 (2H, br s, NH2), 8.64 (1H, s, 6-H), 10.8–12.1 (1H,
br s, OH). Analysis calculated for C6H7N3O2: C, 47.06; H, 4.61; N,
27.44. Found: C, 46.77; H, 4.35; N, 27.59.
2-Benzyl-4-benzylamino-5-carbamoylpyrimidine (7) Yield
1
0.18 g (28%); mp 210–211°C; Rf 0.48 (benzene/acetone, 1:1); H
References
NMR (CDCl3), δ, ppm, J (Hz): 4.17 (2H, s, CH2C6H5), 4.58 (2H, d,
J=5.7, CH2NH), 7.3 (10H, m, 2C6H5), 7.43 (1H, br s, NH), 8.11 (1H,
br s, NH), 9.02 (1H, s, 6-H). Analysis calculated for C19H18N4O: C,
71.68; H, 5.70; N, 17.60. Found: C, 71.58; H, 5.47; N, 17.66.
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Benzylimine of 4-amino-2-benzyl-6-benzylaminopyrimidine-
5-carbaldehyde (8) Yield 0.2 g (25%); mp 92–93°C; Rf 0.44
(benzene/acetone, 1:1); 1H NMR (CDCl3): δ 3.94 (2H, s, CH2C 6H5),
4.75 (2H, d, J=6.2, CH2NH), 5.18 (2H, s, CH2N), 7.1–7.4 (15H,
m, 3 C6H5), 10.2 (1H, s, CH=N), 10.24 (1H, t, J=6.2, NH); 13C
NMR (CDCl3): δ 42.4 (2-CH2), 44.7 (CH2NH), 45.5 (CH2N=), 96.7
(5-C), 134.1 (O-Ph), 136.1 (m-Ph), 138.07 (ipso-Ph), 160.7 (6-C),
163.9 (4-C), 165.2 (2-C), 190.7 (CH=N). Analysis calculated for
C26H25N5: C, 76.63; H, 6.18; N, 17.19. Found: C, 73.58; H, 5.47;
N, 16.33.
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2-Amino-4-methyl-5-ethoxycarbonylpyrimidine (9) Here 3.2 g
(0.0335 mol) of guanidine hydrochloride was added to a solution of
sodium ethoxide prepared from 2.3 g (0.1 mol) of metallic sodium
and 40 ml of absolute ethanol. After 30 min the NaCl precipitate that
had formed was rapidly filtered off and 5.95 g (0.032 mol) of ethyl
(ethoxymethylene)acetoacetate was added to the filtrate. The mix-
ture was heated over a steam bath for 1 h and then the solvent was
removed under reduced pressure. The residue was treated with 25 ml
of 10% HCl and the mixture stirred for 30 min. The resulting crystals
were filtered off and washed with acetone to yield 4.9 g (85%) of
product 9; mp 210–211°C; Rf 0.68 (toluene/acetone, 3:1); 1H NMR
(DMSO-d6): δ 1.28 (3H, t, J=7.1, CH2CH3), 2.68 (3H, s, 4-CH3), 4.30
(2H, q, J=7.1, OCH2), 7.2 (2H, s, NH2), 8.62 (1H, s, 6-H). Analysis
calculated for C8H11N3O2: C, 53.03; H, 6.12; N, 23.19. Found: C,
53.32; H, 5.93; N, 23.08.
2-Amino-1,4-dimethyl-5-ethoxycarbonylpyrimidinium iodide
(10) Here, 4 ml of methyl iodide was added to 1.81 g (0.01 mol)
of 2-amino-4-methyl-5-ethoxycarbonylpyrimidine (9) and the mix-
ture heated for 10 h in a sealed ampoule over a water-bath. After
the excess methyl iodide was removed, the crystals that had formed
were filtered off and thoroughly washed with hot hexane to give 3.1 g
(96%) of product 10; mp 179–181°C; Rf 0.48 (isopropanol/ammonia/
water, 7:0.5:1); 1H NMR (DMSO-d6): δ 1.41 (3H, t, J=7.1, CH2CH3),
2.78 (3H, s, 4-CH3), 3.90 (3H, s, N-CH3), 4.38 (2H, q, J=7.1, OCH2),
9.18 (1H, s, 6-H), 9.18 (1H, br s, NH), 9.78 (1H, br s, NH). Analysis
calculated for C9H14N3IO2: C, 33.45; H, 4.37; N, 13.00. Found: C,
33.34; H, 4.52; N, 13.24.
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A solution of potassium hydroxide prepared from 0.56 g (0.01 mol)
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tone to give 0.34 g (74%) of 2-amino-5-acetyl-4-hydroxypyrimidine
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Recevied May 4, 2011; accepted June 15, 2011
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