Cleavage of 2-(Arylamino)-4,6-dimethoxypyrimidines to yield arylguanidines

Article abstract of DOI:10.1002/ejoc.201402179

A novel method for the synthesis of aryl-substituted guanidines in good overall yields is presented; it consists of the acidic cleavage of 2-(arylamino)-4,6-dimethoxypyrimidines, which were prepared by coupling aryl bromides with 2-amino-4,6-dimethoxypyrimidine. This methodology introduces a new means of protection for the guanidine functionality. Copyright

Full text of DOI:10.1002/ejoc.201402179

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402179
Cleavage of 2-(Arylamino)-4,6-dimethoxypyrimidines To Yield Arylguanidines
Julian W. Shaw,[a] David H. Grayson,[a] and Isabel Rozas*[a]
Keywords: Synthetic methods / Cleavage reactions / Nitrogen heterocycles / Protecting groups / Guanidine
A novel method for the synthesis of aryl-substituted guanid-
ines in good overall yields is presented; it consists of the
acidic cleavage of 2-(arylamino)-4,6-dimethoxypyrimidines,
which were prepared by coupling aryl bromides with
2-amino-4,6-dimethoxypyrimidine. This methodology intro-
duces a new means of protection for the guanidine function-
ality.
Introduction
Aryl-substituted guanidines have found a myriad of uses
in medicinal chemistry, such as anesthetics,[1] antacid
agents,[2] minor groove binders,[3–7] α2-adrenoceptor antag-
onists,[8–10] and F1F0-ATPase inhibitors.[11] Their presence
is ubiquitous in both marine and terrestrial natural prod-
ucts.[12] For those reasons, the synthesis of aryl-substituted
guanidines has been extensively studied in recent years.[13,14]
Existing methods for their assembly are often problematic
because toxic reagents are used,[15] the guanidine precursor
is expensive,[16] and there is a need for high molecular
weight protecting groups.[8] All are potentially disadvan-
tageous features of many syntheses. There is, therefore, a
need for the development of more efficient protocols for
their preparation. The aim of the present work was to de-
vise an environmentally friendly, cost-effective, and atom-
economical [compared to the use of typical carbamate pro-
tecting groups, e.g., tert-butoxycarbonyl (Boc) or benzyl-
oxycarbonyl (CBz)] method to meet this need.
Figure 1. Potential for pyrimidine systems to yield guanidines.
We initially synthesized a family of 2-(arylamino)pyrim-
idines,[18] and with the realization that both Chichibabin[19]
and Dimroth types of reaction[20] may be able to break the
aromaticity of the pyrimidine moiety, we designed experi-
ments to cleave the heteroaromatic ring. The simple 2-
(phenylamino)pyrimidine (1) system was exposed separately
to a number of sulfur, oxygen, and nitrogen nucleophiles
and to a range of acidic and basic conditions at a wide
variety of temperatures, but very low reactivity towards ring
cleavage was generally observed (for selected examples, see
entries 1, 2, and 4 in Table 1).
Table 1. Investigation into pyrimidine ring cleavage. All reactions
were performed at 100 °C.
Results and Discussion
We first investigated the use of 2-(arylamino)pyrimidine
derivatives as potential synthons for aryl-substituted guan-
idines. Inspired by the work of Al-Mourabit,[17] we planned
to synthesize a number of 2-(arylamino)pyrimidines and ex-
amine the susceptibility of the pyrimidine ring system
towards cleavage to unmask the corresponding N-aryl-sub-
stituted guanidines (Figure 1).
Entry
R
Reactant
Solvent
Yield [%][a]
1
2
3
4
5
6
7
H
H
OMe
H
OMe
OMe
OMe
NH2OH·HCl
1 m NaOH
1 m NaOH
4 m HCl
4 m HCl
6 m HCl
EtOH
H2O
H2O
H2O
H2O
H2O
H2O/AcOH
Ͻ5
Ͻ5
0[b]
Ͻ5
76
84
100
6 m HCl
[a] Based on recovered starting material. [b] No reaction occurred.
[a] School of Chemistry, Trinity Biomedical Sciences Institute,
Trinity College Dublin,
After extensive experimentation, we found that increas-
ing the electron density of the pyrimidine system by intro-
ducing methoxy groups at both the 4- and 6-positions made
it more susceptible to ring cleavage through hydrolytic pro-
152-160 Pearse St., Dublin 2, Ireland
E-mail: rozasi@tcd.ie
http://www.tcd.ie/Chemistry/staff/people/Rozas/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402179.
Eur. J. Org. Chem. 2014, 3565–3569
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3565

J. W. Shaw, D. H. Grayson, I. Rozas
SHORT COMMUNICATION
cesses. Thus, 4,6-dimethoxy-2-(phenylamino)pyrimidine (2) Table 3. Synthesis of substituted 2-(arylamino)-4,6-dimethoxypyr-
imidines 4–15.[a]
was chosen as a substrate with significant potential for
more facile pyrimidine ring cleavage. A single literature ex-
ample shows the instability of dimethoxypyrimidines to
acidic conditions. Thus, Moulard and co-workers reported
the preparation of 1-(3-ethylsulfonylpyridin-2-yl)guanidine
as a side product by treating 2-[(3-ethylsulfonylpyridin-2-yl)-
amino]-4,6-dimethoxypyrimidine with concentrated HCl.[21]
Initial investigations were very promising (Table 1, en-
try 5), and a screening of acidic reaction conditions showed
Entry
R
Compound
Yield [%]
that treatment of 2 with 6 m HCl at 100 °C in a 1:1 mixture
of H2O/AcOH led to complete cleavage of the pyrimidine
ring to yield corresponding aryl-substituted guanidine
hydrochloride 3 (Table 1, entry 7). Owing to the low solubi-
lity of the pyrimidine substrates, the use of AcOH as a co-
solvent was necessary. On the basis of this encouraging re-
sult, we then optimized the synthesis of N-phenyl-2-amino-
4,6-dimethoxypyrimidine (2) by utilizing Buchwald–Hart-
wig amination chemistry (Table 2).[22]
1
2
3
4
5
6
7
8
4-OMe
3-OMe
2-OMe
4-F
3-Br
2-F
4-CN
3-CN
2-CN
4-NO2
3-NO2
2-Ph
4
5
86
91
97
88
94
6
7
8
9
84
10
11
12
13
14
15
73[b]
66[b]
68[b]
50[b]
51[b]
68
9
10
11
12
Table 2. Optimization of the Pd-mediated coupling of bromobenz-
ene and 2-amino-4,6-dimethoxypyrimidine.[a]
[a] Reaction conditions: Pd2(dba)3 (2-mol-%), Xantphos (3-mol-
%), NaOtBu (1.5 mmol), toluene (1.5 mL per mmol of aryl halide),
95 °C, 8–12 h. [b] K3PO4 was used as the base.
1
high purity (as determined by H NMR spectroscopy), and
chromatography was not required.
Table 4. Examples of ring cleavage reactions.
Entry Ligand[b]
Base
Solvent
Yield [%]
1
2
3
4
5
Xphos
Xphos
Xphos
BINAP
Xantphos
NaOtBu
NaOtBu
K3PO4
NaOtBu
NaOtBu
toluene
1,4-dioxane
toluene
toluene
toluene
58
57
50
67
96
Entry
R
Compound
Yield [%]
[a] Reaction conditions: Pd2(dba)3 (2-mol-%), ligand (3-mol-%),
NaOtBu (1.5 mmol), toluene (1.5 mL per mmol of aryl halide),
95 °C, 8–12 h; dba = dibenzylideneacetone. [b] Xphos = 2-dicyclo-
1
2
3
4
5
6
7
8
4-H
3
98
94
84
90
74
87
84
62
75
84
46
74
65
4-OMe
3-OMe
2-OMe
4-F
3-Br
2-F
16
17
18
19
20
21
22
23
24
25
26
27
hexylphosphino-2Ј,4Ј,6Ј-triisopropylbiphenyl, BINAP
=
2,2Ј-
bis(diphenylphosphino)-1,1Ј-binaphthyl, Xantphos = 4,5-bis(di-
phenylphosphino)-9,9-dimethylxanthene.
The use of the most effective combination, that is,
Pd2(dba)3, Xantphos, and NaOtBu in toluene at 95 °C, gen-
erated the set of pyrimidines 4–15 in good to excellent yields
(Table 3), and the reaction was reproducible on a multigram
scale.[23] These conditions were tolerant of electron-with-
drawing, electron-donating, and/or sterically bulky substitu-
ents located in different positions on the aryl ring (Table 3).
In the particular cases of 10–14, K3PO4 was used as a base
owing to the presence of electron-withdrawing substituents
4-CN/4-CO2H[a]
3-CN/3-CO2H[a]
2-CN
9
10
11
12
13
4-NO2
3-NO2
2-Ph
[a] Starting material R = CN; product R = CO2H.
Not unexpectedly, a cyano group in the meta or para
on the aryl bromide ring. K3PO4 proved to be a superior position of the aryl ring was partially converted into the
base to NaOtBu in these cases, as previously documented corresponding carboxylic acid (see 22 and 23) under these
for Buchwald–Hartwig coupling reactions.[22b]
reaction conditions. Interestingly however, a cyano group
The members of the synthesized 2-(arylamino)-4,6-di- in the ortho position remained intact throughout these
methoxypyrimidine family (i.e., 2, 4–15) were then exposed hydrolysis reactions to yield 24; we observed similar effects
to the conditions that we had developed for pyrimidine ring previously.[18]
cleavage, and each yielded (Table 4) the corresponding aryl-
It might be thought that the ortho-cyano group of aryl
substituted guanidine (i.e., 3, 16–27) in good to excellent pyrimidine 12 is not hydrolyzed because of steric effects;
yields. Gratifyingly, the compounds could be obtained in however, the nitrile function is not bulky, and the pyrimid-
3566
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3565–3569

Cleavage of 2-(Arylamino)-4,6-dimethoxypyrimidines
(qC), 155.3 (qC), 159.1 (qC), 171.9 (2 qC) ppm. HRMS: calcd. for
C13H16N3O3 [M+ + H] 262.1192; found 262.1194.
ine ring can rotate to avoid steric clash. Comparing the pKa
values (calculated with Marvin[24]) of the starting pyrimid-
ines, we found that ortho derivative 12 had a pKa = 10.7,
whereas for para and meta isomers 10 and 11, the pKa was
12.4. We performed a computational study at the B3LYP/
6-31+G** level[25] and optimized both starting 2-(cyano-
phenyl)pyrimidine (12) and corresponding final guanid-
inium salt 24. In the case of 12, there seems to be an attrac-
tion between the linking NH and the nitrile π system,
whereas in final salt 24 this effect is even larger, which is
indicative of an attractive interaction between the positive
charge of the guanidinium moiety and the CN group. These
calculations indicated that there were attractive interactions
over the cyano group that protected it from hydrolysis.
4,6-Dimethoxy-2-[(3-methoxyphenyl)amino]pyrimidine (5): Yield
91% (237 mg). Yellow oil. Rf = 0.49 (hexane/EtOAc, 80:20). IR
(film): ν = 3397, 2947, 2834, 2216, 1604, 1571, 1446, 1413, 1355,
˜
1
1285, 1191, 1156, 1059, 965, 911, 851, 799, 768, 729, 685 cm–1. H
NMR (400 MHz, CDCl3): δ = 3.80 (s, 3 H), 3.92 (s, 6 H), 5.59 (s,
1 H), 6.59 (dd, J = 2.8, 8 Hz, 1 H), 7.05 (dd, J = 2.8, 8 Hz, 1 H),
7.11 (br. s, NH), 7.20 (app t, 1 H), 7.49 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 53.9 (2 CH3), 55.1 (CH3), 81.3 (CH), 104.7
(CH), 107.8 (CH), 111.2 (CH), 129.4 (CH), 141.1 (qC), 158.7 (qC),
160.1 (qC), 171.8 (2 qC) ppm. HRMS: calcd. for C13H16N3O3 [M+
+ H] 262.1192; found 262.1195.
4,6-Dimethoxy-2-[(2-methoxyphenyl)amino]pyrimidine (6): Yield
97% (252 mg). Off white solid. Rf = 0.57 (hexane/EtOAc, 80:20).
M.p. 104–106 °C. IR (film): ν = 3430, 2938, 1576, 1481, 1437, 1416,
˜
1382, 1294, 1247, 1192, 1160, 1028, 916, 768, 734, 690 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 3.92 (s, 3 H), 3.94 (s, 6 H), 5.57 (s,
1 H), 6.88–6.99 (m, 3 H), 7.59 (br. s, NH), 8.51–8.53 (m, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 54.0 (2 CH3), 55.5 (CH3), 81.3
(CH), 109.8 (CH), 118.4 (CH), 120.8 (CH), 121.4 (CH), 129.4 (qC),
147.6 (qC), 158.8 (qC), 171.9 (2 qC) ppm. HRMS: calcd. for
C13H16N3O3 [M+ + H] 262.1192; found 262.1194.
Conclusions
We developed a novel method for the synthesis of aryl-
substituted guanidines, which offers an inexpensive and en-
vironmentally friendly alternative to classical literature pro-
cedures.[1–17]
2-[(4-Fluorophenyl)amino]-4,6-dimethoxypyrimidine (7): Yield 88%
(220 mg). White solid. Rf = 0.42 (hexane/EtOAc, 80:20). M.p. 92–
Experimental Section
94 °C. IR (film): ν = 3428, 2969, 1614, 1578, 1544, 1507, 1463,
˜
1373, 1357, 1274, 1192, 1104, 1011, 858, 824, 781, 747, 713 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.89 (s, 6 H), 5.57 (s, 1 H), 6.96
(br. s, NH), 6.98–7.03 (m, 2 H), 7.53–7.57 (m, 2 H) ppm. 13C NMR
General Procedure for the Coupling of Aryl Halides with 2-Amino-
4,6-dimethoxypyrimidine: An oven-dried Schlenk tube was charged
with a stir bar, Pd2(dba)3 (2 mol-%, 18 mg), and Xantphos
(3 mol-%, 17 mg). 2-Amino-4,6-dimethoxypyrimidine (1.5 mmol,
1.5 equiv., 232 mg) was added, followed by base (1.5 mmol,
1.5 equiv.) and the aryl halide (1 mmol, 1 equiv.), if the aryl halide
was a solid. The Schlenk tube was put under vacuum and back
filled with argon three times. Freshly distilled toluene
(1.5 mLmmol–1 aryl halide) was added. If the aryl halide was a
liquid, it was now added to the solution. The Schlenk tube was
then placed in an oil bath with vigorous stirring at 95 °C. The reac-
tion was monitored by TLC, and once complete (typically 6–12 h),
it was cooled to room temperature and diluted with EtOAc
(10 mL). The reaction mixture was filtered through Celite, and any
remaining residues in the Schlenk tube were washed out with
EtOAc (10 mL). The organic phase was then washed with water
(50 mL). The aqueous phase was extracted with EtOAc (3ϫ
50 mL), and the combined organic layer was washed with brine
(50 mL), dried with MgSO4, and concentrated under reduced pres-
sure. The crude product was then purified by flash column
chromatography (silica gel, 100% hexanes Ǟ 60% hexanes/40%
ethyl acetate) to yield the target compound.
(100 MHz, CDCl3): δ = 53.9 (2 CH3), 81.0 (CH), 115.2 (d, JC,F
=
23 Hz, 2 CH), 120.7 (d, JC,F = 15 Hz, 2 CH), 136.6 (qC), 158.8 (q,
C1), 159.4 (d, JC,F = 240 Hz, CF), 172.0 (2 qC) ppm. HRMS:
calcd. for C12H12FN3O2 [M+ + H] 250.0992; found 250.0994.
2-[(3-Bromophenyl)amino]-4,6-dimethoxypyrimidine (8): Yield 94%
(292 mg). Off white solid. Rf = 0.39 (hexane/EtOAc, 80:20). M.p.
84–86 °C. IR (film): ν = 3423, 2945, 1604, 1578, 1481, 1420, 1360,
˜
1301, 1230, 1214, 1195, 1160, 1060, 1008, 933, 872, 766, 734,
1
676 cm–1. H NMR (400 MHz, CDCl3): δ = 3.93 (s, 6 H), 5.61 (s,
1 H), 6.93 (br. s, NH), 7.15 (m, 2 H), 7.36 (d, J = 7.2 Hz, 1 H),
8.12 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 54.0 (2 CH3),
81.9 (CH), 117.2 (CH), 121.9 (CH), 122.5 (qC), 124.8 (CH), 129.9
(CH), 141.0 (qC), 158.4 (qC), 171.4 (2 qC) ppm. HRMS: calcd. for
C12H12BrN3O2 [M+ + H] 310.0191; found 310.0190.
2-[(2-Fluorophenyl)amino]-4,6-dimethoxypyrimidine (9): Yield 84%
(210 mg). Yellow oil. Rf = 0.54 (hexane/EtOAc, 80:20). IR (film):
ν = 3431, 3312, 2945, 1622, 1572, 1536, 1433, 1415, 1357, 1212,
˜
1192, 1159, 1103, 1059, 981, 878, 849, 740, 690 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 3.93 (s, 6 H), 5.61 (s, 1 H), 6.94 (m, 1 H),
7.06–7.14 (m, 2 H), 7.16 (br. s, NH), 8.50 (app t, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 54.0 (2 CH3), 81.7 (CH), 114.6 (d,
JC,F = 20 Hz, CH), 120.4 (CH), 121.9 (d, JC,F = 8 Hz, CH), 124.1
4,6-Dimethoxy-2-(phenylamino)pyrimidine (2):[26] Yield 96%. White
solid. Rf = 0.5 (hexane/EtOAc, 80:20). M.p. 76–78 °C (ref.[26] 73–
1
75 °C). H NMR (400 MHz, CDCl3): δ = 3.91 (s, 6 H), 5.58 (s, 1
(d, JC,F = 3 Hz, CH), 128.1 (d, JC,F = 9 Hz, qC), 153.5 (d, JC,F
=
H), 7.01 (t, J = 7.2 Hz, 1 H), 7.09 (br. s, NH), 7.31 (app t, 2 H),
7.62 (d, J = 8 Hz, 2 H) ppm. In agreement with literature values.[26]
260 Hz, CF), 158.4 (qC), 171.9 (2 qC) ppm. HRMS: calcd. for
C12H12FN3O3 [M+ + H] 250.0992; found 250.0994.
4,6-Dimethoxy-2-[(4-methoxyphenyl)amino]pyrimidine (4): Yield
86% (224 mg). Off white crystal. Rf = 0.46 (hexane/EtOAc, 80:20). 2-[(4-Cyanophenyl)amino]-4,6-dimethoxypyrimidine (10): Yield 73%
M.p. 86–87 °C. IR (film): ν = 3234, 3067, 2960, 1865, 1606, 1583, (167 mg). White powder. Rf = 0.31 (hexane/EtOAc, 80:20). M.p.
˜
1510, 1446, 1300, 1257, 1232, 1034, 1008, 885, 822, 787, 676,
144–145 °C. IR (film): ν = 3423, 3397, 2947, 2220, 1601, 1576,
˜
1
660 cm–1. H NMR (400 MHz, CDCl3): δ = 3.79 (s, 3 H), 3.89 (s, 1510, 1480, 1455, 1359, 1305, 1281, 1193, 1161, 1060, 1008, 933,
1
6 H), 5.54 (s, 1 H), 6.85 (br. s, NH), 6.87 (d, J = 9.2 Hz, 2 H), 7.51
872, 766, 707, 687 cm–1. H NMR (400 MHz, CDCl3): δ = 3.93 (s,
(d, J = 9.2 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 53.8 6 H), 5.66 (s, 1 H), 7.16 (br. s, NH), 7.59 (d, J = 8 Hz, 2 H), 7.75
(2 CH3), 55.5 (CH3), 80.6 (CH), 114.0 (2 CH), 121.0 (2 CH), 132.9
(d, J = 8 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 54.3 (2
Eur. J. Org. Chem. 2014, 3565–3569
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3567

J. W. Shaw, D. H. Grayson, I. Rozas
CH3), 82.5 (CH), 104.6 (qC), 118.3 (2 CH), 119.4 (qC), 133.2 (2 heated to reflux. For the reaction to proceed successfully, the
SHORT COMMUNICATION
CH), 143.7 (qC), 157.8 (qC), 171.9 (2 qC) ppm. HRMS: calcd. for
round-bottomed flask needed to be covered with aluminum foil
and fully submerged in an oil bath at 100 °C. The reaction was
monitored by TLC; all TLC samples were basified by using Et3N.
Once the reaction was deemed complete, it was allowed to cool to
room temperature. The solution was washed with EtOAc (3ϫ
10 mL) and CH2Cl2/MeOH (20% MeOH, 1ϫ 10 mL) to remove
any unreacted starting materials, and then the aqueous phase was
concentrated under reduced pressure to yield the target aryl-substi-
tuted guanidine as the hydrochloride salt.
C13H13N4O2 [M+ + H] 257.1039; found 257.1038.
2-[(3-Cyanophenyl)amino]-4,6-dimethoxypyrimidine (11): Yield 66%
(168 mg). Yellow/white solid. Rf = 0.30 (hexane/EtOAc, 80:20).
M.p. 141–143 °C. IR (film): ν = 3327, 2950, 2230, 1607, 1572, 1543,
˜
1463, 1432, 1363, 1286, 1244, 1194, 1163, 1113, 1060, 1005, 984,
1
847, 804, 787, 769, 699, 684 cm–1. H NMR (400 MHz, CDCl3): δ
= 3.92 (s, 6 H), 5.64 (s, 1 H), 7.20 (br. s, NH), 7.26 (d, J = 7.6 Hz,
1 H), 7.37 (app t, 1 H), 7.65 (d, J = 8 Hz, 1 H), 8.22 (s, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 54.1 (2 CH3), 81.9 (CH), 112.7 Phenylguanidine Hydrochloride (3): Yield 10–98%. 1H NMR
(qC), 119.2 (qC), 121.9 (CH), 122.9 (CH), 125.4 (CH), 129.6 (CH),
140.4 (qC), 158.2 (qC), 171.9 (2 qC) ppm. HRMS: calcd. for
C13H13N4O2 [M+ + H] 257.1039; found 257.1039.
(400 MHz, D2O): δ = 7.06 (d, J = 7.6 Hz, 2 H), 7.23 (d, J = 7 Hz,
1 H), 7.31 (t, J = 7.2 Hz, 2 H) ppm. HRMS: calcd. for C7H10N3
[M+ + H] 136.0875; found 136.0870. In agreement with literature
values.[10]
2-[(2-Cyanophenyl)amino]-4,6-dimethoxypyrimidine (12): Yield 70%
(179 mg). White powder. Rf = 0.39 (hexane/EtOAc, 80:20). M.p.
1-(4-Methoxyphenyl)guanidine Hydrochloride (16): Yield 94%. IR
132–134 °C. IR (film): ν = 3399, 3123, 3012, 2948, 2861, 2215,
˜
(film): ν = 3398, 3131, 2978, 2497, 1671, 1630, 1293, 1176, 1015,
˜
1
828, 682 cm–1. H NMR (400 MHz, D2O): δ = 3.71 (s, 3 H), 6.92
1638, 1604, 1570, 1540, 1496, 1471, 1415, 1358, 1282, 1108, 1006,
948, 871, 803, 769, 689 cm–1. 1H NMR (400 MHz, CDCl3): δ =
3.93 (s, 6 H), 5.67 (s, 1 H), 7.04 (t, J = 8 Hz, 1 H), 7.43 (br. s, NH),
7.53–7.58 (m, 2 H), 8.61 (d, J = 9.2 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 54.2 (2 CH3), 82.8 (CH), 100.9 (qC), 117.0
(qC), 119.6 (CH), 121.8 (CH), 132.5 (CH), 133.7 (CH), 142.5 (qC),
157.7 (qC), 171.8 (2 qC) ppm. HRMS: calcd. for C13H13N4O2
257.1039 [M+ + H]; found 257.1033.
(d, J = 7.2 Hz, 2 H), 7.14 (d, J = 7.2 Hz, 2 H) ppm. 13C NMR
(100 MHz, D2O): δ = 58.0 (CH3), 117.8 (2 CH), 129.4 (qC), 130.6
(2 CH), 159.2 (qC), 161.2 (qC) ppm. HRMS: calcd. for C8H12N3O
[M+ + H] 166.0980; found 166.0973.
1-(3-Methoxyphenyl)guanidine Hydrochloride (17): Yield 84%. IR
(film): ν = 3147, 2430, 1660, 1579, 1457, 1205, 1040, 857, 690 cm–1.
˜
1H NMR (400 MHz, D2O): δ = 3.70 (s, 3 H), 6.79 (m, 2 H), 6.87
(d, J = 8 Hz, 1 H), 7.29 (app t, 1 H) ppm. 13C NMR (100 MHz,
D2O): δ = 55.6 (CH3), 113.4 (CH), 113.5 (CH), 118.2 (CH), 136.3
(qC), 159.4 (qC), 160.1 (qC) ppm. HRMS: calcd. for C8H12N3O
[M+ + H] 166.0980; found 166.0983.
4,6-Dimethoxy-2-[(4-nitrophenyl)amino]pyrimidine (13): Yield 50%.
Yellow powder. Rf = 0.55 (hexane/EtOAc, 1:1). M.p. 198–201 °C.
IR (film): ν = 3374, 2961, 2918, 2849, 2491, 1596, 1573, 1546, 1488,
˜
1389, 1318, 1303, 1260, 1191, 1110, 1055, 929, 846, 795, 686 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.97 (s, 6 H), 5.71 (s, 1 H), 7.74
(br. s, NH), 7.79 (d, J = 8.8 Hz, 2 H), 8.22 (d, J = 8.8 Hz, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 52.3 (2 CH3), 80.2 (CH),
115.4 (2 CH), 122.7 (2 CH), 139.5 (qC), 142.6 (qC), 154.4 (qC),
169.0 (2 qC) ppm. HRMS: calcd. for C12H13N4O4 [M+ + H]
277.0937; found 277.0942.
1-(2-Methoxyphenyl)guanidine Hydrochloride (18): Yield 90%. IR
(film): ν = 3312, 3155, 2972, 2462, 1667, 1455, 1287, 1161, 1045,
˜
1
789 cm–1. H NMR (400 MHz, D2O): δ = 3.75 (s, 3 H), 6.95 (app
t, 1 H), 7.05 (d, J = 8 Hz, 1 H), 7.17 (d, J = 8 Hz, 1 H), 7.31 (app
t, 1 H) ppm. 13C NMR (100 MHz, D2O): δ = 55.8 (CH3), 113.0
(CH), 121.4 (CH), 122.0 (qC), 128.2 (CH), 130.1 (CH), 154.4 (qC),
156.6 (qC) ppm. HRMS: calcd. for C8H12N3O [M+ + H] 166.0980;
found 166.0977.
4,6-Dimethoxy-2-[(3-nitrophenyl)amino]pyrimidine (14): Yield 51%.
Yellow powder. Rf = 0.56 (hexane/EtOAc, 1:1). M.p. 171–172 °C.
IR (film): ν = 3374, 2961, 2918, 2849, 2491, 1596, 1576, 1546, 1488,
˜
1-(4-Fluorophenyl)guanidine Hydrochloride (19): Yield 74%. IR
1389, 1318, 1303, 1260, 1191, 1110, 1055, 929, 846, 795, 686 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.99 (s, 6 H), 5.67 (s, 1 H), 7.44
(app t, 1 H), 7.60 (dd, J = 1.2, 8 Hz, 1 H), 7.72 (br. s, NH), 7.86
(dd, J = 1.2, 8 Hz, 1 H), 9.12 (app t, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 54.5 (2 CH3), 81.6 (CH), 113.5 (CH), 117.0
(CH), 124.2 (CH), 129.4 (CH), 140.6 (qC), 148.9 (qC), 157.8 (qC),
171.8 (2 qC) ppm. HRMS: calcd. for C12H13N4O4 [M+ + H]
277.0937; found 277.0940.
1
(film): ν = 3311, 3139, 1665, 1590, 1507, 1215, 831, 793 cm–1. H
˜
NMR (400 MHz, D2O): δ = 7.20–7.24 (m, 2 H), 7.28–7.41 (m, 2
H) ppm. 13C NMR (100 MHz, D2O): δ = 119.2 (d, JC,F = 9 Hz, 2
C), 131.1 (d, JC,F = 9 Hz, 2 C), 132.5 (d, qC, JC,F = 2.3 Hz), 159.1
(qC), 163.1 (d, qC, JC,F = 244 Hz) ppm. HRMS: calcd. for
C7H8FN3 [M+ + H] 154.0781; found 154.0771.
1-(3-Bromophenyl)guanidine Hydrochloride (20): Yield 87%. IR
(film): ν = 3319, 3133, 1668, 1568, 1476, 1301, 1069, 859, 671 cm–1.
˜
2-[(1,1Ј-Biphenyl-2-yl)amino]-4,6-dimethoxypyrimidine (15): Yield
68% (208 mg). Fluffy white solid. Rf = 0.58 (hexane/EtOAc, 80:20).
1H NMR (600 MHz, D2O): δ = 7.17 (d, J = 8 Hz, 1 H), 7.27 (app
t, 1 H), 7.42 (s, 1 H), 7.45 (d, J = 8 Hz, 1 H) ppm. 13C NMR
(125 MHz, D2O): δ = 122.2 (qC), 124.5 (CH), 128.6 (CH), 130.8
(CH), 131.2 (CH), 135.4 (qC), 156.1 (qC) ppm. HRMS: calcd. for
C7H9BrN3 [M+ + H] 213.9980; found 213.9984.
M.p. 81–82 °C. IR (film): ν = 3423, 2942, 1602, 1578, 1537, 1481,
˜
1359, 1283, 1195, 1060, 943, 857, 774, 759, 737, 688 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 3.87 (s, 6 H), 5.56 (s, 1 H), 6.92 (br. s, NH),
7.09 (app t, 1 H), 7.23 (m, 1 H), 7.34–7.50 (m, 6 H), 8.49 (d, J =
8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 54.0 (2 CH3),
1-(2-Fluorophenyl)guanidine Hydrochloride (21): Yield 84%. IR
80.9 (CH), 120.4 (CH), 122.3 (CH), 127.7 (CH), 128.0 (CH), 129.0 (film): ν˜ = 3323, 3146, 1672, 1621, 1501, 1423, 1264, 1106,
(2 CH), 129.5 (2 CH), 130.2 (CH), 131.7 (qC), 136.5 (qC), 138.6 759 cm–1. 1H NMR (600 MHz, D2O): δ = 7.17–7.27 (m, 4 H) ppm.
(qC), 158.8 (qC), 171.9 (qC) ppm. HRMS: calcd. for C18H18N3O3
[M+ + H] 308.1399; found 308.1393.
13C NMR (125 MHz, D2O): δ = 116.6 (d, JC,F = 16 Hz), 121.4 (d,
JC,F = 16 Hz, qC), 125.2 (CH), 128.7 (CH), 130.4 (d, J = 6 Hz,
qC), 153.3 (qC), 156.5 (d, JC,F = 206 Hz, CF) ppm. HRMS: calcd.
for C7H8FN3 [M+ + H] 154.0781; found 154.0775.
General Procedure for the Cleavage of 2-(Arylamino)-4,6-dimeth-
oxypyrimidine: Water (0.21 mL) and 12 m HCl (0.42 mL, 20 equiv.)
were added to a mixture of 2-(arylamino)-4,6-dimethoxypyrimidine
(0.25 mmol, 1 equiv.) in AcOH (0.21 mL), and the mixture was
1-(4-Carboxyphenyl)guanidine Hydrochloride (22): 62%. IR (film):
ν = 3314, 2456, 2345, 2329, 2311, 1693, 1622, 1567, 1345, 1117,
˜
3568
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3565–3569

Cleavage of 2-(Arylamino)-4,6-dimethoxypyrimidines
1
1040, 827, 764 cm–1. H NMR (400 MHz, D2O): δ = 7.39 (d, J =
8 Hz, 2 H), 8.03 (d, J = 8 Hz, 2 H) ppm. 13C NMR (100 MHz,
D2O): δ = 124.2 (2 CH), 129.0 (qC), 131.2 (2 CH), 139.0 (qC),
[1] S. S. Patel, C. J. Dunn, H. M. Bryson, CNS Drugs 1996, 6, 474–
497.
155.9 (qC), 170.1 (qC) ppm. HRMS: calcd. for C8H10N3O2 [M+
H] 180.0773; found 180.0764.
+
[2] T. J. Humphries, G. J. Merritt, Aliment. Pharmacol. Ther. 1999,
13, 18–26 (Suppl. 3).
[3] C. McKeever, M. Kaiser, I. Rozas, J. Med. Chem. 2013, 56,
700–711.
1-(3-Carboxyphenyl)guanidine Hydrochloride (23): Yield 75%. IR
(film): ν = 3369, 3171, 3069, 2871, 2345, 1699, 1654, 1577, 1346,
[4] P. S. Nagle, F. Rodriguez, S. J. Quinn, D. H. O’Donovan, J. M.
Kelly, B. Nguyen, W. D. Wilson, I. Rozas, Org. Biomol. Chem.
2010, 8, 5558–5567.
[5] P. S. Nagle, F. Rodriguez, A. Kahvedzic, S. Quinn, I. Rozas, J.
Med. Chem. 2009, 52, 7113–7121.
[6] F. Rodriguez, I. Rozas, M. Kaiser, R. Brun, B. Nguyen, W. D.
Wilson, R. N. Garcia, C. J. Dardonville, J. Med. Chem. 2008,
51, 909–923.
˜
1
1215, 1082, 767 cm–1. H NMR (400 MHz, D2O): δ = 7.57 (d, J =
8 Hz, 1 H), 7.61 (app t, 1 H), 7.90 (s, 1 H), 7.99 (d, J = 8 Hz, 1 H)
ppm. 13C NMR (100 MHz, D2O): δ = 126.6 (CH), 128.7 (CH),
130.2 (CH), 130.4 (CH), 132.1 (qC), 134.5 (qC), 156.3 (qC), 169.9
(qC) ppm. HRMS: calcd. for C8H10N3O2 [M+ + H] 180.0773;
found 180.0766.
[7] C. Bailly, R. K. Arafa, F. A. Tanious, W. Laine, C. Tardy, A.
Lansiaux, P. Colson, D. W. Boykin, W. D. Wilson, Biochemistry
2005, 44, 1941–1952.
[8] F. Rodriguez, I. Rozas, A. M. Erdozain, J. J. Meana, L. F. Cal-
lado, J. Med. Chem. 2009, 52, 601–609.
[9] A. Goonan, A. Kahvedzic, F. Rodriguez, P. Nagle, T. McCabe,
I. Rozas, A. M. Erdozain, J. J. Meana, L. F. Callado, Bioorg.
Med. Chem. 2008, 16, 8210–8217.
[10] F. Rodriguez, I. Rozas, J. E. Ortega, J. J. Meana, L. F. Callado,
J. Med. Chem. 2008, 51, 3304–3312.
[11] G. Rosse, ACS Med. Chem. Lett. 2012, 3, 952–952.
[12] R. G. Berlinck, A. E. Trindade-Silva, M. F. Santos, Nat. Prod.
Rep. 2012, 29, 1382–1406.
[13] T. Suhs, B. Konig, Mini-Rev. Org. Chem. 2006, 3, 315–331.
[14] T. R. M. Rauws, B. U. W. Maes, Chem. Soc. Rev. 2012, 41,
2463–2497.
[15] K. S. Kim, L. Qian, Tetrahedron Lett. 1993, 34, 7677–7680.
[16] T. J. Baker, Y. Rew, M. Goodman, Pure Appl. Chem. 2000, 72,
347–354. Goodman’s reagent [1,3-di-Boc-2-(trifluoromethyl-
sulfonyl)guanidine] is commercially available from Sigma–Ald-
rich priced at j79.60g–1.
[17] C. Schroif-Gregoire, N. Travert, A. Zaparucha, A. Al-Moura-
bit, Org. Lett. 2006, 8, 2961–2964.
1-(2-Cyanophenyl)guanidine Hydrochloride (24): Yield 84%. IR
(film): ν = 3302, 3103, 3044, 2879, 2260, 1685, 1479, 1415, 1157,
˜
1
751 cm–1. H NMR (400 MHz, D2O): δ = 7.31 (d, J = 8 Hz, 1 H),
7.45 (app t, 1 H), 7.81 (app t, 1 H), 7.98 (d, J = 8 Hz, 1 H) ppm.
13C NMR (100 MHz, D2O): δ = 114.4 (qC), 116.7 (CH), 125.9
(CH), 126.9 (CH), 137.0 (CH), 137.6 (qC), 150.2 (qC), 161.4 (qC)
ppm. HRMS: calcd. for C8H9N4 [M+ + H] 161.0827; found
161.0828.
1-(4-Nitrophenyl)guanidine Hydrochloride (25): Yield 46%. IR
(film): ν = 3186, 1707, 1672, 1582, 1420, 1341, 1247, 1170, 853,
˜
697 cm–1. 1H NMR (400 MHz, D2O): δ = 7.38 (d, J = 8.8 Hz, 2
H), 8.20 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR (100 MHz, D2O): δ
= 124.2 (2 CH), 125.4 (2 CH), 141.5 (qC), 145.3 (qC), 155.7 (qC)
ppm. HRMS: calcd. for C7H9N4O2 [M+ + H] 181.1640; found
181.1645.
1-(3-Nitrophenyl)guanidine Hydrochloride (26): Yield 74%. IR
(film): ν = 3313, 3115, 2582, 1671, 1631, 1525, 1416, 1349, 1249,
˜
1093, 832, 805, 660 cm–1. 1H NMR (400 MHz, D2O): δ = 7.55–7.61
(m, 2 H), 8.08–8.10 (m, 2 H) ppm. 13C NMR (100 MHz, D2O): δ
= 119.9 (CH), 122.7 (CH), 131.1 (CH), 132.0 (CH), 136.0 (qC),
[18] J. W. Shaw, D. H. Grayson, I. Rozas, ARKIVOC 2014, 2, 161–
174.
148.7 (qC), 169.1 (qC) ppm. HRMS: calcd. for C7H9N4O2 [M+
H] 181.1640; found 181.1642.
+
[19] For a review of Chichibabin reaction see: C. K. McGill, A.
Rappa, Adv. Heterocycl. Chem. 1988, 44, 1–79.
[20] For a review of the Dimroth reaction, see: T. Fujii, T. Itaya,
Heterocycles 1998, 48, 359–390.
1-(1,1Ј-Biphenyl-2-yl)guanidine Hydrochloride (27): Yield 65%. IR
(film): ν = 3146, 2407, 1709, 1611, 1480, 1228, 763 cm–1. 1H NMR
˜
(400 MHz, D2O): δ = 7.43–7.58 (m, 9 H) ppm. 13C NMR
(100 MHz, D2O): δ = 127.8 (CH), 128.5 (CH), 128.6 (2 CH), 128.6
(2 CH), 129.1 (CH), 129.3 (CH), 131.1 (CH), 138.0 (qC), 139.8
(qC), 156.2 (qC), 171.3 (qC) ppm. HRMS: calcd. for C13H14N3
[M+ + H] 212.1188; found 212.1178.
[21] J. Rouchaud, O. Neus, C. Moulard, Bull. Soc. Chim. Belg. 1997,
106, 151–157.
[22] For reviews on C–N bond-forming cross-coupling reactions,
see: a) J. Bariwalab, E. van der Eycken, Chem. Soc. Rev. 2013,
42, 9283–9303; b) D. S. Surry, S. L. Buchwald, Chem. Sci. 2011,
2, 27–50.
[23] On a 2 g scale, a yield of 95% was obtained for the reaction of
bromobenzene with 2-amino-4,6-dimethoxypyrimidine under
the optimized conditions.
Supporting Information (see footnote on the first page of this arti-
1
cle): H NMR and 13C NMR spectra and computational results.
[24] Marvin, v. 6.0, ChemAxon, http://www.chemaxon.com/.
[25] These computations were performed by using the Gaussian09
package; see full reference in the Supporting Information.
[26] X. Chen, J. Wu, Z.-C. Shang, M.-F. Chen, Y.-P. Sun, J. Ly, M.-
K. Lei, P.-Z. Zhang, Tetrahedron Lett. 2008, 49, 495–499.
Received: March 3, 2014
Acknowledgments
This work was funded by the School of Chemistry, University of
Dublin, Trinity College (grant to J. W. S.). The authors would like
to thank Drs. John O’Brien, Manuel Ruether, Martin Feeney, and
Gary Hessman for spectroscopic data.
Published Online: April 23,2014
Eur. J. Org. Chem. 2014, 3565–3569
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3569