A Fast and Parallel Route to Cyclic Isothioureas and Guanidines with Use of Microwave-Assisted Chemistry

Article abstract of DOI:10.1021/jo030338m

A fast and simple approach to novel cyclic isothioureas and related guanidine derivatives is presented in this study. The construction of the central basic scaffolds is achieved solely by the application of microwave-assisted chemistry, without any need of activating agents or protecting group manipulations. The product formation of various substituted guanidines from the corresponding isothiouronium salts was controlled by the nucleophilicity of the counterion and influenced by the reaction temperature. Further, a new fast-track access to tetrahydropyrimidin-2-ylamines was developed.

Full text of DOI:10.1021/jo030338m

A F a st a n d P a r a llel Rou te to Cyclic Isoth iou r ea s a n d Gu a n id in es
w ith Use of Micr ow a ve-Assisted Ch em istr y
Helena Sandin, Marie-Louise Swanstein, and Eric Wellner*
Department of Drug Discovery, Active Biotech AB, Box 724, 22007 Lund, Sweden
eric.wellner@activebiotech.com
Received November 3, 2003
A fast and simple approach to novel cyclic isothioureas and related guanidine derivatives is
presented in this study. The construction of the central basic scaffolds is achieved solely by the
application of microwave-assisted chemistry, without any need of activating agents or protecting
group manipulations. The product formation of various substituted guanidines from the corre-
sponding isothiouronium salts was controlled by the nucleophilicity of the counterion and influenced
by the reaction temperature. Further, a new fast-track access to tetrahydropyrimidin-2-ylamines
was developed.
TABLE 1. Effects of Differ en t Rea ction Con d ition s on
th e F or m a tion of Ar yl Eth er s
In tr od u ction
Isothioureas as well as cyclic guanidines are frequently
used in bioactive compounds, mainly to modulate solubil-
ity or to pick up electrostatic interactions.1 However, their
use as central scaffolds in drug design is very limited due
to the lack of general applicable and mild synthetic
methods or straightforward protocols. Although the
construction of isothioureas and guanidines is known
from the dawn of organic chemistry,2 publications from
the last years demonstrate a continuous interest in the
development of synthetic methodologies for cyclic guani-
dines and their chemical precursors.3
entry substrate R1
R2
base
conditions
yield (3:4)
1
2
3
4
5
6
7
2a
2a
2b
2b
2c
2c
2d
Cl
Cl
Cl
Cl
Cl
Cl
CF3
o-Cl KHMDSa 180 °C, 500 s 30% (5:2)
o-Cl NaHb
170 °C, 250 s 54% (100:0)
KHMDSa 180 °C, 500 s 51% (5:1)
NaHb
170 °C, 250 s 63% (100:0)
In 2000 Marmillon et al.4 reported the reaction of
protected 1,3-diaminopropane-2-ol (1) with 1-chloro-4-
trifluoromethylbenzene. The resulting diamino ether 3
was cyclized to the corresponding thiourea with carbon
disulfide and a carbodiimide.5 The thiourea was finally
transformed in two thermal reactions to the guanidine.
Given the high temperatures employed in this protocol,
we were confident to shorten reaction times by applying
microwave-assisted procedures.6 Further, ab initio cal-
culations suggested chemoselectivity for the generation
H
H
m-Cl KHMDSa 180 °C, 500 s 52% (5:1)
m-Cl NaHb
H
NaHb
170 °C, 250 s 62%(100:0)
170 °C, 250 s 67% (100:0)
a
b
In DMF. In DMA.
of diaminoaryl ethers eradicating the need for protecting
group manipulations in the first step of the reaction. Here
we report a fast and efficient general strategy for the
parallel synthesis of compounds carrying isothioureas
and guanidines as a central motif.
(1) (a) Kienzle, F.; Kaiser, A.; Madhukar, S. C. Eur. Med. Chem.
1982, 17, 547. (b) Weinhardt, K.; Wallach, M. B.; Marx, M. J . Med.
Chem. 1985, 28, 694. (c) Laufer, S. A.; Striegel, H.-G.; Wagner, G. K.
J . Med. Chem. 2002, 45, 4695. (d) Rockway, T. W. Expert Opin. Ther.
Pat. 2003, 13, 773. (e) Chiron Corp. Expert Opin. Ther. Pat. 2003, 13,
551. (f) Donnelly, L. E.; Rogers, D. F. Expert Opin. Ther. Pat. 2003,
13, 1345. (g) Lehmann, J .; Rob, B. Liebigs Ann. Chem. 1994, 805.
(2) (a) Unger Liebigs Ann. Chem. 1846, 59, 69. (b) Heintz Ann. Phys.
1848, 74, 133. (c) Hofmann, A. W. Liebigs Ann. Chem. 1948, 67, 131.
(d) Beilstein; Geuther Liebigs Ann. Chem. 1858, 108, 94. (e) Maly Z.
Chem. 1869, 259. (f) Rathke, B. Ber. Dtsch. Chem. Ges. 1881, 14, 1774.
(3) (a) Katritzky, A. R.; Cai, X.; Rogovoy, B. V. J . Comb. Chem. 2003,
5, 392. (b) Woo, J . C. S.; MacKay, D. B. Tetrahedron Lett. 2003, 44,
2881. (c) Summary of guanylation and guanidinylation methods:
Powell, D. A.; Ramsden, P. D.; Batey, R. A. J . Org. Chem. 2003, 68,
2300. (d) Luthin, D. R.; Anderson, M. B. Bioorg. Med. Chem. Lett. 2002,
12, 3467. (e) Moroni, M.; Koksch, B.; Osipov, S. N.; Crucianelli, M.;
Frigerio, M.; Bravo, P.; Burger, K. J . Org. Chem. 2001, 66, 130.
(4) Marmillon, C.; Bompart, J .; Calas, M.; Escale, R.; Bonnet, P.-A.
Heterocycles 2000, 53, 1317.
Resu lts a n d Discu ssion
To find a more straightforward method to synthesize
diaminoaryl ether 3, we reacted 1,3-diaminopropane-2-
ol (1) directly with fluorobenzenes 2 (Table 1). The
reaction was first carried out in DMF with NaH or
KHMDS as base and the reaction mixture was heated
in the microwave at 170-180 °C for 250-500 s, respec-
tively. Many byproducts were formed in the reaction
probably due to the cleavage of DMF.7 Surprisingly, when
(6) Lindstro¨m, P.; Tierney, J .; Wathey, B.; Westman, J . Tedrahedron
2001, 57, 9225.
(7) Bretherick’s Handbook of Reactive Chemical Hazards, 5th ed.;
Butterworth-Heinemann: Boston, MA, 1995; Compound No. 4294.
(5) Mikolajczyk, M.; Kielbasinski, P. Tetrahedron 1981, 37, 233.
10.1021/jo030338m CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/06/2004
J . Org. Chem. 2004, 69, 1571-1580
1571

Sandin et al.
SCHEME 1
SCHEME 2 a
a
Reagents and conditions: (i) primary alkylamine, acetonitrile,
microwave or g70 °C; (ii) NH3/H2O, or water, microwave, 50-87%;
(iii) deprotonation of 7; (iv) NH3/EtOH, microwave, 88%.
KHMDS was used the major side reaction was the
formation of the aniline, despite the steric bulk of
KHMDS (Table 1, entries 1, 3, and 5).8 Keeping NaH as
a nonnucleophilic base, another approach was to replace
DMF with a solvent of similar properties. DMA seemed
to be a good alternative since it has the polar aprotic
properties needed to dissolve the alkoxides formed in the
reaction, and it is less prone toward decomposition in the
presence of NaH. When the reaction was carried out
under the conditions stated in Table 1, the pure products
3 could be isolated in moderate to good yields. Hence,
we found this reaction a facile and immediate method
for preparing diaminoaryl ethers without any need of
additional protecting and deprotecting steps.
We next examined the reactivity of the thioureas 6
toward different alkylating agents.14 When 6d was al-
lowed to react with MeI at 130 °C for 500 s in the
microwave, the product 7d was formed quantitatively
(Table 2, entry 1). To test the scope of this reaction, the
thioureas 6 were reacted with alkyl halides possessing
various functionalities. All isothioureas 7-14 were suc-
cessfully isolated in good to high yields. The obtained
results conspicuously demonstrate the feasibility of this
protocol. Reaction times and yields correlate with the
reactivity of the alkylhalides. In the case of the alkyl
chlorides, a catalytic amount of potassium iodide acceler-
ated the reaction.15
Turning to the synthesis of unsubstituted guanidines,
isothiouronium salts 7 were treated with aqueous am-
monia at 150 °C in the microwave. Mass spectrometry
showed molpeaks, which lay one mass unit above the
anticipated signal, indicating the formation of the cor-
responding ureas 1516 (Scheme 2). To prove this, 7a -d
were dissolved in pure water and heated in the micro-
wave. NMR spectroscopy and MS analysis confirmed that
in both cases only the ureas 15a -d were formed. In the
next attempt, we followed a procedure similar to that
used by Rathke,2f using NH3/EtOH and thereby increas-
ing the nucleophilicity of ammonia. Surprisingly, when
the mixtures were heated in the microwave the only
products obtained were the ethanol adducts 16a,b (Scheme
2).17 6-31G* Hartree-Fock calculations revealed a high
LUMO-HOMO gap between the isothiourea 7b and NH3
(14.88 eV) or EtOH (15.30 eV), respectively, giving no
After successfully obtaining the building blocks 3, we
set about preparing the thiourea substrates 6 (Scheme
1). According to the literature,9 a dithiocarbamate is
formed spontaneously when primary or secondary amines
are treated with CS2. Cyclization can then be achieved
by two different methods, either by addition of carbodi-
imide to facilitate the formation of isocyanate or by
thermolytic cleavage.5,9,10 We found the latter alternative
more straightforward. Since this method often requires
higher temperatures than the boiling point of the solvent,
we assumed that the reaction was suitable for microwave-
assisted chemistry. Addtion of CS2 to a solution of 3 in
EtOH resulted in immediate precipitation of the dithio-
carbamates 5. The thermal extrusion of H2S was then
carried out in the microwave, giving the cyclized products
6 within 200 s. The thioureas 6a -f crystallized sponta-
neously and the products could be filtered off without any
need for further purification. No intermolecular oligo- or
polymerization could be observed.11
(8) Sampson, D. F. J .; Simmonds, R. G.; Bradley, M. Tetrahedron
Lett. 2001, 42, 5517.
(9) (a) Ahlbrecht, H.; Kornetzki, D. Synthesis 1988, 775. (b) Ahl-
brecht, H.; Schmitt, C.; Kornetzki, D. Synthesis 1991, 637. (c) Mat-
sumura, N.; Konishi, T.; Hayashi, H.; Yasui, M.; Iwasaki, F.; Mizuno,
K. J . Heterocycl. Chem. 2002, 39, 189.
(12) Eichel, H. J .; Meyer, R. J .; Buzzi, P. F. J . Med. Chem. 1967,
10, 942.
(13) Li, G.; Ohtani, T. J . Heterocycl. Chem. 1997, 45, 2471.
(14) (a) Wilson, B. J . Chem. Soc. 1955, 1389. (b) Van Allan J . Org.
Chem. 1956, 21, 24. (c) Lantos, L.; Gombatz, K.; McGuire, M.; Pridgen,
L.; Remich, J .; Shilcrat, S. J . Org. Chem. 1988, 53, 4223 (d) Wei, J .;
Liu, H.; Dick, A. R.; Yamamoto, H.; He, Y.; Waldeck, D. J . Am. Chem.
Soc. 2002, 124, 9591.
(10) (a) Ferris, A. F.; Schutz, B. A. J . Org. Chem. 1963, 28, 71. (b)
Blonty, G. Liebigs Ann. Chem. 1982, 1927.
(11) Interestingly, when 3f was cyclized with CS2, out of two possible
products only the thiourea 6f was formed. The alternative oxazolidi-
nethione12 could not be detected in the crude. When 3-aminopropane-
1,2-diol was treated with CS2 under the same conditions, only the
oxazolidinethione13 was isolated. This indicates that the six-membered-
ring system is less favored. The formation of 6f can be explained by
the higher nucleophilicity of nitrogen compared to oxygen.
(15) Norman, R. O. C.; Coxon, J . M. Principles of Organic Synthesis,
3rd ed.; Nelson Thornes: Cheltenham, UK, 2001; p 107.
(16) (a) Augustin, M.; Richter, M.; Salas, S. J . Prakt. Chem 1980,
322, 55. (b) Effenberger, F.; Beisswenger, T.; Dannenhauer, F. Chem.
Ber. 1988, 121, 2209.
(17) Birtwell, S.; Curd, F. H. S.; Hendry, J . A.; Rose, F. L. J . Chem.
Soc. 1948, 30, 1645.
1572 J . Org. Chem., Vol. 69, No. 5, 2004

Cyclic Isothioureas and Guanidines
TABLE 2. Syn th esis of Isoth iou r ea s w ith Use of a Micr ow a ve-Assisted P r otocol
yield of product (%) for R1
)
entry
R2X
2,4-Cl2
4-Cl
3,4-Cl2
4-CF3
time [s]/T [°C]
1
2
3
4
MeI
4-FPhCH2Br
NC(CH2)2Br
HO(CH2)2Br
2-H2NCO-4-ClPhO(CH2)2Cl
2-CH3CO-PhO(CH2)2Cl
4-ClPhO(CH2)2Cl
3-Me-4-NO2PhO(CH2)2Cl
7a (86)
8a (69)
9a (92)
10a (79)
7b (91)
8b (83)
9b (71)
10b (71)
11 (94)
7c (95)
8c (71)
9c (75)
10c (52)
7d (99)
8d (69)
9d (58)
10d (71)
500/130
600/150
600/150
600/150
1000/160
1000/160
1000/160
1000/160
5a
6a
7a
8a
12 (91)
13 (93)
14 (90)
a
Potassium iodide was added as a catalyst
SCHEME 3 a
TABLE 3. Syn th esis of Gu a n id in es fr om
Isoth iou r on iu m Iod id es F ollow in g a Sta n d a r d P r otocol
a
Reagents and conditions: (i) cyanogen bromide, 2-propanol,
120 °C, 600 s, microwave, 53-61%.
hint to a plainly preferred interaction. The total energy
of 2-ethoxytetrahydropyrimidine 16b and NH3 is, how-
ever, 4.40 kcal/mol below the total energy of the free
guanidine 17a and EtOH, making the ethanol adduct
16b the product development controlled product.18 When
using an inert solvent such as THF instead, no reaction
was observed. Other known synthetic equivalents to
ammonia are NaN3 and NaNH2 but these reactions were
also unsuccessful.
An alternative approach to the desired cyclic guanidine
is the reaction of a diamine with cyanogen bromide.19
However, the fusion of six-membered-ring systems often
requires long reaction times.20 Heating the reaction
mixture for only 600 s in the microwave afforded the
guanidines 17a -d in up to 60% yield and NMR spec-
troscopy verified complete ring closure (Scheme 3).
In an initial effort to prepare substituted guanidines,
we applied the procedure described in the literature.4,21
The isothiouronium iodides 7 were treated with the
primary amines 18 in acetonitrile (Table 3). In our hands,
this reaction proceeded very slowly; however, after 8 days
the products 19a -h could be isolated in good yields
(Table 3).
Since this type of reaction is known to require high
temperature and high pressure, we were confident to
shorten the reaction time significantly by microwave
heating. When the same reactions as above (Table 3,
entries 1 and 4) were carried out at 160 °C for 1000 s,
only one compound was obtained in each reaction.
Astonishingly, it was not the expected guanidine but the
thiourea 6 (Scheme 2). A possible explanation for this
unexpected outcome of the reaction is a re-attack of the
iodide ion on the methyl group of the isothiourea 7. The
formed methyl iodide then reacts immediately with the
primary amine shifting the equilibrium toward the
thiourea 6. A similar profile of reactivity was observed
when heating the reaction mixture in a sealed pressure
(18) The same calculations in water gave a somewhat less pro-
nounced difference of 2.40 kcal/mol.
(19) Ishikawa, F.; Kosayana, A.; Nakamura, S.; Kono, T. Chem.
Pharm. Bull. 1978, 26, 3657.
(20) Weinhardt, K.; Wallach M. B.; Marx, M. J . Med. Chem. 1985,
28, 694.
(21) (a) McKay, A. F.; Hatton, W. G. J . Am. Chem. Soc. 1956, 78,
1618. (b) Esser, F.; Pook, K. H.; Carpy, A.; Leger, J . M. Synthesis 1994,
1, 77.
J . Org. Chem, Vol. 69, No. 5, 2004 1573

Sandin et al.
TABLE 4. Syn th esis of Gu a n id in es fr om
Isoth iou r on iu m Tr iflu or oa ceta tes F ollow in g a
Micr ow a ve-Assisted P r otocol
F IGURE 1. Intramolecular proton transfer leading to the
formation of 20.
One particular exception in the synthesis of guanidines
19 was observed when the amino-alkoxy-benzamide 18h
(Figure 1) was submitted to our previously elaborated
pathway with use of microwave radiation. The reaction
completely failed to provide the expected guanidine 19h .
1
Instead, H NMR and 13C NMR spectroscopy confirmed
the loss of the phenoxy group and cyclization, resulting
in compound 20. The different results from this experi-
ment (Figure 1) and entry 8 (Table 3) suggest that high
temperatures and the presence of an intramolecular
proton source are crucial for the phenol to leave.
It is noteworthy that this peculiar reactivity profile of
the guanidine 19h is not shared by the isothiourea
analouge 11 (Table 2, entry 5).
In summary, we have developed a simple and efficient
approach to cyclic thioureas and guanidines. Most im-
portant, by using microwave-assisted chemistry it was
possible to assemble all intermediates and target mol-
ecules without any need of activation or protecting
groups. Applying our protocol, reaction- and workup
times could be cut to a minimum. Further, we discovered
a counterion-depending effect in the fusion of isothio-
uronium salts and primary amines. The best results were
achieved with trifluoroacetate giving all guanidines in
high yields. We expect that the methodology described
herein should offer a general access to the preparation
of the biologically important building blocks.
a
The compound was isolated as the hydrochloride.
tube above 70 °C. To eliminate the attack of the coun-
terion, the isothiouronium salt was neutralized to give
the unprotonated isothiourea. Unfortunately no reaction
occurred when the electrophilicity of 7 was decreased by
deprotonation. This is also in accordance with 6-31G*
Hartree-Fock calculations, which predict a more acces-
sible LUMO-lobe of C2 at the van der Waals surface in
the thiouronium salt. At the same time, the LUMO
energy of the cation (-0.59 eV for 7b) is lower than the
LUMO energy of the free base (3.43 eV). We therefore
surmised that the isothiourea must exist as a salt to
react. Hence, a less nucleophilic counterion than iodide
would be preferred. According to our hypothesis yields
gradually improved by exchanging the anion from iodide
to chloride and finally to trifluoroacetate. Treating the
TFA salts 21a ,b with the amines 18 in the microwave
at 160 °C for 2000 s afforded the guanidines 19i-t with
no thiourea formation (Table 4).
Exp er im en ta l Section
2-(3-Am in op r op oxy)-5-ch lor oben za m id e (18h ). To a
solution of 5-chloro-2-hydroxybenzamide (1.0 mmol, 171 mg)
and 1,3-diiodopropane (2.0 mmol, 592 mg) in MeCN (4 mL)
was added potassium carbonate (1.5 mmol, 207 mg). The
mixture was heated at 150 °C for 1000 s in the microwave.
The solvent was removed in vacuo and aqueous 1 M NaOH
added. The aqueous layer was extracted with CH2Cl2 and the
organic phase was dried (Na2SO4) and concentrated to give
the crude arylpropoxyiodide (300 mg). The iodide (0.9 mmol,
300 mg) was redissolved in DMA (4 mL) and potassium
phthalimide (0.9 mmol, 163 mg) was added. The mixture was
heated at 170 °C for 500 s in the microwave. DMA was
removed in vacuo and the residue was taken up in CH2Cl2,
washed with water, dried (Na2SO4), and concentrated. Methyl-
amine (4 mL, 8 M in EtOH) was added and the solution was
heated at 100 °C for 300 s in the microwave. The precipitate
was filtered off, the solution concentrated in vacuo, and EtOAc
added. The benzamide was precipitated from the solution as
hydrochloride with HCl/EtOAc (2.5 M) and washed with
EtOAc. The free base was extracted with CH2Cl2 from aqueous
5 M NaOH to give 18h in 70% overall yield. 1H NMR (400
MHz, CDCl3) δ 8.13 (d, J ) 2.8 Hz, 1H), 7.89 (br s, 1H), 7.36
(dd, J ) 8.8, 2.8 Hz, 1H), 6.91 (d, J ) 8.8 Hz, 1H), 6.48 (br s,
1H), 4.19 (t, J ) 6.1 Hz, 2H), 2.92 (t, J ) 6.6 Hz, 2H), 1.98
(mc, 2H), 1.30 (br s, 2H).
For a parallel synthesis methodology, an easy workup
procedure was required. Using our experience that
isothiourea reacts with ethanol, Wang resin was added
to the reaction mixture removing unreacted starting
material. The excess of the amine was then scavenged
by addition of methylisocyanate resin.22 Both resins were
simply filtered off to give the products in high yields.
(22) Booth, R. J .; Hodges, J . C. J . Am. Chem. Soc. 1997, 119, 4882.
1574 J . Org. Chem., Vol. 69, No. 5, 2004

Cyclic Isothioureas and Guanidines
Rep r esen ta tive Exp er im en ta l P r oced u r es for P r ep a -
r a tion of P h en oxyp r op a n e-1,3-d ia m in es: P r ep a r a tion of
2,4-Dich lor op h en oxyp r op a n e-1,3-d ia m in e (3a ). Meth od
A: 1,3-Diamino-2-hydroxypropane (1) (1.0 mmol, 91 mg) was
dissolved in dry DMF (1 mL). A solution of potassium hexam-
ethyldisilazane (1.0 mmol, 200 mg) in dry DMF (1.5 mL) was
added and the mixture was stirred for 20 min at room
temperature. 1,3-Dichloro-4-fluorobenzene (2a ) (4.3 mmol, 709
mg) was added and the reaction mixture was heated in the
microwave at 180 °C for 500 s. The solvent was removed in
vacuo to give a brown residue. HCl (1 N, 5 mL) was added
and the excess of fluorobenzene was extracted with diethyl
ether (3 × 3 mL). The aqueous layer was adjusted with
aqueous 5 M NaOH to pH >12 and extracted with CHCl3 (3
× 5 mL). The organic layer was dried over Na2SO4 and
concentrated in vacuo to give 3a as a brown oil. Crude yield:
113 mg.
4.89 (br s, 1H), 3.41-3.25 (m, 4H); 13C NMR (100 MHz, DMSO-
d6) δ 176.1, 151.6, 130.1, 128.6, 126.0, 124.5, 118.2, 66.6, 43.4.
ESI-MS: m/z (%) 235 [M - CS + H+], 277 (100) [M + H+].
Anal. Calcd for C10H10Cl2N2OS: C, 43.34; H, 3.64; N, 10.11;
S, 11.57. Found: C, 43.3; H, 3.87; N, 10.0; S, 11.4.
5-(4-Ch lor op h en oxy)t et r a h yd r op yr im id in e-2-t h ion e
(6b). Following the method described for 6a gave 6b as a
1
yellow solid. Yield 36%. H NMR (400 MHz, DMSO-d6) δ 7.88
(br s, 2H), 7.34 (d, J ) 8.9 Hz, 2H), 7.02 (d, J ) 8.9 Hz, 2H),
4.82 (br s, 1H), 3.39-3.22 (m, 4H); 13C NMR (100 MHz, DMSO-
d6) δ 176.0, 155.7, 129.9, 125.4, 118.2, 65.0, 43.5. ESI-MS: m/z
(%) 243 (100) [M + H+]. Anal. Calcd for C10H11ClN2OS: C,
49.48; H, 4.57; N, 11.54; S, 13.21. Found: C, 49.2; H, 4.64; N,
11.1; S, 12.6.
5-(3,4-D ic h lo r o p h e n o x y )t e t r a h y d r o p y r im id in e -2-
th ion e (6c). Following the method described for 6a gave 6c
1
as a yellow solid. Yield 53%. H NMR (400 MHz, DMSO-d6) δ
Meth od B: To a solution of 1,3-diamino-2-hydroxypropane
(1) (2.0 mmol, 180 mg) in dry DMA (3 mL) was added sodium
hydride (2.4 mmol, 58 mg). The mixture was stirred until the
sodium hydride was fully reacted. 1,3-Dichloro-4-fluorobenzene
(2a ) (2.2 mmol, 363 mg) was added and the reaction mixture
was heated in the microwave at 170 °C for 250 s. The solvent
was removed in vacuo to give a brown residue. HCl (1 N, 7
mL) was added and the solution was extracted with diethyl
ether (3 × 5 mL). The aqueous layer was adjusted with
aqueous 5 M NaOH to pH >12 and extracted with CHCl3 (3
× 5 mL). The organic layer was dried over Na2SO4 and
concentrated in vacuo to give 3a as a yellow oil. Yield 253 mg
7.89 (br s, 2H), 7.53 (d, J ) 8.9 Hz, 1H), 7.33 (d, J ) 2.9 Hz,
1H), 7.02 (dd, J ) 8.9, 2.9 Hz, 1H), 4.9 (br s, 1H), 3.40-3.22
(m, 4H); 13C NMR (100 MHz, DMSO-d6) δ 176.0, 156.4, 132.2,
131.6, 123.6, 118.3, 114.3, 65.5, 43.4. ESI-MS: m/z (%) 235
[M - CS + H+], 277 (100) [M + H+]. Anal. Calcd for C10H10
-
Cl2N2OS: C, 43.34; H, 3.64; N, 10.11; S, 11.57. Found: C, 43.3;
H, 3.94; N, 9.85; S, 11.7.
5-(4-Tr iflu or om eth ylp h en oxy)tetr a h yd r op yr im id in e-
2-th ion e (6d ). Following the method described for 6a gave
1
6d as a yellow solid. Yield 79%. H NMR (400 MHz, DMSO-
d6) δ 7.90 (br s, 2H), 7.66 (d, J ) 8.7 Hz, 2H), 7.18 (d, J ) 8.7
Hz, 2H), 4.97 (br s, 1H), 3.43-3.27 (m, 4H); 13C NMR (100
MHz, DMSO-d6) δ 176.0, 159.9, 127.5, 124.9, 122.1, 116.6, 64.9,
43.4. ESI-MS: m/z (%) 277 (100) [M + H+]. Anal. Calcd for
1
(54%). H NMR (500 MHz, CDCl3) δ 7.37 (d, J ) 2.6 Hz, 1H),
7.17 (dd, J ) 8.8, 2.6 Hz, 1H), 7.04 (d, J ) 8.8 Hz, 1H), 4.23
(mc, 1H), 3.05-3.00 (m, 4H); 13C NMR (125 MHz, CDCl3) δ
153.0, 130.1, 127.8, 126.5, 125.0, 117.3, 84.4, 43.2. ESI-MS:
m/z (%) 235 (100) [M + H+]. Anal. Calcd for C9H12Cl2N2O: C,
45.98; H, 5.14; N, 11.91. Found: C, 46.3; H, 5.48; N, 11.7.
C
11H11F3N2OS: C, 47.82; H, 4.01; N, 10.14; S, 11.60. Found:
C, 47.9; H, 4.12; N, 9.94; S, 11.1.
5-Ben zyltetr a h yd r op yr im id in e-2-th ion e (6e). Following
the method described for 6a gave 6e as a white solid. Yield
1
2-(4-Ch lor op h en oxy)p r op a n e-1,3-d ia m in e (3b). Follow-
ing method A described for 3a gave 3b as a brown oil. Crude
yield: 78 mg. Following method B described for 3a gave 3b
56%. H NMR (500 MHz, CDCl3) δ 7.89 (br s, 2H), 7.32-7.29
(m, 2H), 7.23-7.20 (m, 3H), 3.06-3.02 (m, 2H), 2.85-2.80 (m,
2H), 2.55 (d, J ) 7.5 Hz, 2H), 2.03 (mc, 1H); 13C NMR (125
MHz, CDCl3) δ 175.4, 139.0, 128.7, 128.3, 126.1, 44.4, 36.1,
30.9. ESI-MS: m/z (%) 207 (100) [M + H+].
1
as a yellow oil. Yield 63%. H NMR (500 MHz, CDCl3) δ 7.23
(m, J ) 9.0 Hz, 2H), 6.91 (m, J ) 9.0 Hz, 2H), 4.19 (mc, 1H),
2.98-2.97 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 157.0, 129.5,
126.0, 117.4, 81.8, 43.2. ESI-MS: m/z (%) 201 (100) [M + H+].
Anal. Calcd for C9H13ClN2O: C, 53.87; H, 6.53; N, 13.96.
Found: C, 53.3; H, 6.69; N, 13.32.
5-Hyd r oxytetr a h yd r op yr im id in e-2-th ion e (6f). Follow-
ing the method described for 6a gave 6f as a yellow solid. Yield
64%. 1H NMR (400 MHz, DMSO-d6) δ 7.72 (br s, 2H), 5.10 (br
s, 1H), 3.88 (br s, 1H), 3.17-3.14 (m, 2H), 2.94-2.90 (m, 2H);
13C NMR (100 MHz, DMSO-d6) δ 175.9, 58.6, 46.7. ESI-MS:
m/z (%) 133 (100) [M + H+]. Anal. Calcd for C4H8N2OS: C,
36.35; H, 6.10; N, 21.19. Found: C, 36.2; H, 6.04; N, 19.7.
Rep r esen ta tive Exp er im en ta l P r oced u r es for P r ep a -
r a tion of 5-P h en oxy-2-m eth ylsu lfa n yl-3,4,5,6-tetr a h yd r o-
p yr im id in -1-iu m Iod id e: P r ep a r a r tion of 5-(2,4-Dich lo-
r oph en oxy)-2-m eth ylsu lfan yl-3,4,5,6-tetr ah ydr opyr im idin -
1-iu m Iod id e (7a ). To a solution of 6a (0.5 mmol, 139 mg) in
MeCN (4 mL) was added methyl iodide (1.0 mmol, 142 mg)
and the reaction mixture was heated in the microwave at 130
°C for 500 s. The solvent was removed in vacuo and diethyl
ether (4 mL) was added to the residue. The precipitate was
filtered off, washed with ether, and dried in vacuo to give 7a
as a yellow solid. Yield 181 mg (86%). 1H NMR (400 MHz,
MeOH-d4) δ 7.50 (d, J ) 2.5 Hz, 1H), 7.35 (dd, J ) 8.8, 2.5
Hz, 1H), 7.28 (d, J ) 8.8 Hz, 1H), 5.19 (t, J ) 2.4 Hz, 1H),
3.71 (mc, J ) 2.4 Hz, 4H), 2.66 (s, 3H); 13C NMR (100 MHz,
MeOH-d4) δ 164.8, 150.3, 129.9, 128.0, 127.7, 125.5, 118.3,
65.6, 43.5, 12.3. ESI-MS: m/z (%) 291 (100) [M + H+].
Extraction from aqueous 1 M NaOH with CH2Cl2 gave the
free base as a white solid. Anal. Calcd for C11H12Cl2N2OS: C,
45.37; H, 4.15; N, 9.62; S, 11.01. Found: C, 45.1; H, 4.24; N,
9.58; S, 10.9.
2-(3,4-Dich lor op h en oxy)p r op a n e-1,3-d ia m in e (3c). Fol-
lowing method A described for 3a gave 3c as a brown oil. Crude
yield: 52%. Following method B described for 3a gave 3c as a
1
yellow oil. Yield 62%. H NMR (400 MHz, CDCl3) δ 7.33 (d, J
) 8.9 Hz, 1H), 7.10 (d, J ) 2.9 Hz, 1H), 6.84 (dd, J ) 8.9, 2.9
Hz, 1H), 4.19 (quint, J ) 5.3 Hz, 1H), 2.99 (mc, J ) 5.3 Hz,
4H); 13C NMR (100 MHz, CDCl3) δ 157.5, 133.0, 130.8, 124.4,
118.1, 115.8, 82.2, 43.0. ESI-MS: m/z (%) 235 (100) [M + H+].
2-(4-Tr iflu or om eth ylph en oxy)pr opan e-1,3-diam in e (3d).
Following method B described for 3a gave 3d as a yellow oil.
1
Yield 67%. H NMR (500 MHz, CDCl3) δ 7.54 (d, J ) 8.6 Hz,
2H), 7.04 (d, J ) 8.6 Hz, 2H), 4.33 (mc, 1H), 3.02 (d, 4H); 13C
NMR (100 MHz, CDCl3) δ 160.1, 127.1, 124.4, 123.2, 115.7,
81.4, 43.1. ESI-MS: m/z (%) 235 (100) [M + H+]. Anal. Calcd
for C10H13F3N2O: C, 51.28; H, 5.59; N, 11.96. Found: C, 50.2;
H, 5.86; N, 11.4.
Rep r esen ta tive Exp er im en ta l P r oced u r es for P r ep a -
r a t ion of 5-P h en oxyt et r a h yd r op yr im id in e-2-t h ion e:
P r ep a r a t ion of 5-(2,4-Dich lor op h en oxy)t et r a h yd r o-
p yr im id in e-2-th ion e (6a ). To a solution of 3a (1.0 mmol, 240
mg) in dry EtOH (2 mL) was added carbon disulfide (2.1 mmol,
160 mg) and the reaction mixture was heated in the microwave
at 140 °C for 200 s. The reaction mixture was allowed to attain
room temperature and diethyl ether (2 mL) was added. The
precipitate was filtered off, washed with ether, and dried in
vacuo to give 6a as a yellow solid. Yield 199 mg (70%). 1H NMR
(400 MHz, DMSO-d6) δ 7.89 (br s, 2H), 7.59 (d, J ) 2.5 Hz,
1H), 7.38 (dd, J ) 8.9, 2.5 Hz, 1H), 7.30 (d, J ) 8.9 Hz, 1H),
5-(4-Ch lor op h en oxy)-2-m eth ylsu lfa n yl-3,4,5,6-tetr a h y-
d r op yr im id in -1-iu m Iod id e (7b). Following the method
described for 7a gave 7b as a yellow solid. Yield 91%. 1H NMR
(400 MHz, MeOH-d4) δ 7.33 (d, J ) 8.7 Hz, 2H), 7.03 (d, J )
8.7 Hz, 2H), 5.09 (br s, 1H), 3.75-3.68 (m, 4H), 2.66 (s, 3H);
J . Org. Chem, Vol. 69, No. 5, 2004 1575

Sandin et al.
13C NMR (100 MHz, MeOH-d4) δ 164.7, 154.6, 129.4, 127.0,
117.7, 64.0, 43.5, 12.3. ESI-MS: m/z (%) 257 (100) [M + H+].
5-(3,4-Dich lor op h en oxy)-2-m et h ylsu lfa n yl-3,4,5,6-t et -
r a h yd r op yr im id in -1-iu m Iod id e (7c). Following the method
described for 7a gave 7c as a yellow solid. Yield 95%. 1H NMR
(400 MHz, MeOH-d4) δ 7.47 (d, J ) 8.9 Hz, 1H), 7.26 (d, J )
2.9 Hz, 1H), 7.00 (dd, J ) 8.9, 2.9 Hz, 1H), 5.12 (mc, 1H), 3.73-
3.66 (m, 4H), 2.65 (s, 3H); 13C NMR (100 MHz, MeOH-d4) δ
166.6, 157.0, 134.6, 132.8, 127.0, 120.0, 118.1, 66.1, 45.2, 14.0.
ESI-MS: m/z (%) 291 (100) [M + H+].
Extraction from aqueous 1 M NaOH with CH2Cl2 gave the
free base as a white solid. Anal. Calcd for C11H12Cl2N2OS: C,
45.37; H, 4.15; N, 9.62; S, 11.01. Found: C, 45.6; H, 4.40; N,
9.88; S, 10.2.
2-Meth ylsu lfa n yl-5-(4-tr iflu or om eth ylp h en oxy)-3,4,5,6-
tetr a h yd r op yr im id in -1-iu m Iod id e (7d ). Following the
method described for 7a gave 7d as a yellow solid. Yield 96%.
1H NMR (500 MHz, MeOH-d4) δ 7.68 (d, J ) 8.7 Hz, 2H), 7.22
(d, J ) 8.7 Hz, 2H), 5.26 (t, J ) 2.5 Hz, 1H), 3.80-3.73 (m,
4H), 2.68 (s, 3H); 13C NMR (125 MHz, MeOH-d4) δ 166.6, 160.5,
128.8, 117.8, 65.5, 45.3, 13.9. ESI-MS: m/z (%) 291 (100) [M
+ H+].
(m, 2H), 7.49-7.46 (m, 2H), 7.15-7.10 (m, 4H), 5.21 (t, J )
2.5 Hz, 1H), 4.45 (br s, 2H), 3.73 (mc, 4H); 13C NMR (125 MHz,
MeOH-d4) δ 164.5, 163.9, 160.4, 132.5, 128.7, 125.3, 117.8,
117.3, 65.5, 45.4, 36.5. ESI-MS: m/z (%) 385 (100) [M + H+].
Anal. Calcd for C18H17F4N2OSBr: C, 46.46; H, 3.68; N, 6.02;
S, 6.89. Found: C, 46.9; H, 3.88; N, 6.17; S, 6.67.
2-(2-Cya n oe t h ylsu lfa n yl)-5-(2,4-d ich lor op h e n oxy)-
3,4,5,6-tetr a h yd r op yr im id in -1-iu m Br om id e (9a ). Follow-
ing the method described for 8a gave 9a as a yellow solid. Yield
92%. 1H NMR (500 MHz, MeOH-d4) δ 7.49 (d, J ) 2.5 Hz, 1H),
7.34 (dd, J ) 8.8, 2.5 Hz, 1H), 7.28 (d, J ) 8.8 Hz, 1H), 5.20
(mc, 1H), 3.73-3.67 (m, 4H), 3.48 (t, J ) 6.7 Hz, 2H), 2.98 (t,
J ) 6.7 Hz, 2H); 13C NMR (125 MHz, MeOH-d4) δ 163.5, 152.1,
131.7, 129.8, 129.5, 127.0, 119.7, 119.1, 67.2, 45.5, 28.9, 19.8.
ESI-MS: m/z (%) 330 (100) [M + H+]. Anal. Calcd for C13H14
-
Cl2N3OSBr: C, 37.98; H, 3.43; N, 10.22. Found: C, 37.2; H,
3.52; N, 9.83.
5-(4-Ch lor op h en oxy)-2-(2-cya n oeth ylsu lfa n yl)-3,4,5,6-
tetr a h yd r op yr im id in -1-iu m Br om id e (9b). Following the
method described for 8a gave 9b as a yellow solid. Yield 71%.
1H NMR (500 MHz, MeOH-d4) δ 7.33-7.30 (m, J ) 9.0 Hz,
2H), 7.04-7.01 (m, J ) 9.0 Hz, 2H), 5.11 (t, J ) 2.5 Hz, 1H),
3.72-3.68 (m, 4H), 3.48 (t, J ) 6.6 Hz, 2H), 2.98 (t, J ) 6.6
Hz, 2H); 13C NMR (125 MHz, MeOH-d4) δ 163.5, 156.4, 131.2,
128.9, 119.5, 119.1, 65.7, 45.5, 28.9, 19.8. ESI-MS: m/z (%)
296 (100) [M + H+]. Anal. Calcd for C13H15ClN3OSBr: C, 41.45;
H, 4.01; N, 11.15; S, 8.51. Found: C, 41.2; H, 4.00; N, 11.1; S,
7.48.
2-(2-Cya n oe t h ylsu lfa n yl)-5-(3,4-d ich lor op h e n oxy)-
3,4,5,6-tetr a h yd r op yr im id in -1-iu m Br om id e (9c). Follow-
ing the method described for 8a gave 9c as a yellow solid. Yield
75%. 1H NMR (500 MHz, MeOH-d4) δ 7.44 (d, J ) 8.9 Hz, 1H),
7.25 (d, J ) 2.9 Hz, 1H), 6.99 (dd, J ) 8.9, 2.9 Hz, 1H), 5.12 (t,
J ) 2.5 Hz, 1H), 3.71-3.66 (m, 4H), 3.46 (t, J ) 6.6 Hz, 2H),
2.96 (t, J ) 6.6 Hz, 2H); 13C NMR (125 MHz, MeOH-d4) δ
163.6, 157.0, 134.6, 132.8, 127.0, 120.0, 119.1, 118.0, 66.0, 45.4,
28.9, 19.8. ESI-MS: m/z (%) 330 (100) [M + H+]. Anal. Calcd
for C13H14Cl2N3OSBr: C, 37.98; H, 3.43; N, 10.22; S, 7.80.
Found: C, 37.9; H, 3.61; N, 10.3; S, 7.36.
2-(2-Cya n oeth ylsu lfa n yl)-5-(4-tr iflu or om eth ylp h en oy)-
3,4,5,6-tetr a h yd r op yr im id in -1-iu m Br om id e (9d ). Follow-
ing the method described for 8a gave 9d as a yellow solid. Yield
58%. 1H NMR (500 MHz, MeOH-d4) δ 7.64 (d, J ) 8.8 Hz, 2H),
7.20 (d, J ) 8.8 Hz, 2H), 5.26 (t, J ) 2.5 Hz, 1H), 3.80-3.71
(m, 4H), 3.49 (t, 2H), 2.99 (t, 2H); 13C NMR (125 MHz, MeOH-
d4) δ 163.6, 160.4, 128.8, 126.1, 125.6, 119.1, 117.8, 65.4, 45.5,
28.9, 19.8. ESI-MS: m/z (%) 330 (100) [M + H+]. Anal. Calcd
for C14H15F3N3OSBr: C, 40.99; H, 3.68; N, 10.24; S, 7.82.
Found: C, 41.0; H, 3.87; N, 10.2; S, 7.31.
Extraction from aqueous 1 M NaOH with CH2Cl2 gave the
free base as a white solid. Anal. Calcd for C12H13F3N2OS: C,
49.65; H, 4.51; N, 9.65; S, 11.04. Found: C, 50.0; H, 4.61; N,
9.90; S, 10.9.
Rep r esen ta tive Exp er im en ta l P r oced u r es for P r ep a -
r a tion of 5-P h en oxy-2-a lk ylsu lfa n yl-3,4,5,6-tetr a h yd r o-
p yr im id in -1-iu m Br om id e: P r ep a r a t ion of 5-(2,4-Di-
c h lo r o p h e n o x y )-2-(4-flu o r o b e n zy ls u lfa n y l)-3,4,5,6-
tetr a h yd r op yr im id in -1-iu m Br om id e (8a ). To a solution
of 6a (0.1 mmol, 27 mg) in MeCN (1 mL) was added 4-fluo-
robenzyl bromide (0.4 mmol, 50 µL) and the reaction mixture
was heated in the microwave at 150 °C for 600 s. The solvent
was removed in vacuo, diethyl ether was added, and the
precipitate was triturated overnight. The solid was filtered off,
washed with ether, and dried in vacuo to give 8a as a yellow
solid. Yield: 29 mg (69%). 1H NMR (400 MHz, MeOH-d4) δ
7.50 (d, J ) 2.4 Hz, 1H), 7.44 (dd, J ) 8.5 Hz, J H,F ) 5.4 Hz,
2H), 7.34 (dd, J ) 8.8, 2.4 Hz, 1H), 7.21 (d, J ) 8.8 Hz, 1H),
7.11 (dd, J ) 8.5 Hz, J H,F ) 8.5 Hz, 2H), 5.13 (br s, 1H), 4.44
(s, 2H), 3.69 (br s, 4H); 13C NMR (100 MHz, MeOH-d4) δ 162.7,
162.5, 150.3, 130.7, 130.4, 129.9, 127.9, 127.8, 125.4, 118.2,
115.5, 65.7, 43.6, 34.7. ESI-MS: m/z (%) 385 (100) [M + H+].
Anal. Calcd for C17H16Cl2FN2OSBr: C, 43.80; H, 3.46; N, 6.01;
S, 6.88. Found: C, 44.0; H, 3.54; N, 5.99; S, 6.66.
5-(4-Ch lor oph en oxy)-2-(4-flu or oben zylsu lfa n yl)-3,4,5,6-
tetr a h yd r op yr im id in -1-iu m Br om id e (8b). Following the
method described for 8a gave 8b as a yellow solid. Yield 83%.
1H NMR (500 MHz, MeOH-d4) δ 7.31-7.28 (m, J ) 8.8 Hz,
J H,F ) 5.2 Hz, 2H), 7.16-7.14 (m, J ) 9.1 Hz, 2H), 6.97-6.94
(m, J ) 8.8 Hz, 2H), 6.76-6.74 (m, J ) 9.1 Hz, 2H), 4.88 (t, J
) 2,5 Hz, 1H), 4.28 (s, 2H), 3.51 (mc, 4H); 13C NMR (125 MHz,
MeOH-d4) δ 164.5, 164.0, 156.3, 132.5, 131.2, 128.8, 119.5,
117.3, 65.7, 45.4, 36.6. ESI-MS: m/z (%) 351 (100) [M + H+].
Anal. Calcd for C17H17ClFN2OSBr: C, 47.29; H, 3.97; N, 6.49;
S, 7.43. Found: C, 47.3; H, 3.96; N, 6.40; S, 7.08.
5-(2,4-Dich lor op h en oxy)-2-(2-h yd r oxyet h ylsu lfa n yl)-
3,4,5,6-tetr a h yd r op yr im id in -1-iu m Br om id e (10a ). Fol-
lowing the method described for 8a gave 10a as a yellow solid.
1
Yield 79%. H NMR (500 MHz, MeOH-d4) δ 7.49 (d, J ) 2.1
Hz, 1H), 7.34 (dd, J ) 8.8, 2.1 Hz, 1H), 7.27 (d, J ) 8.8 Hz,
1H), 5.16 (br s, 1H), 3.90 (t, J ) 5.2 Hz, 2H), 3.72 (mc, 4H),
3.33 (t, J ) 5.2 Hz, 2H); 13C NMR (125 MHz, MeOH-d4) δ
164.4, 150.3, 129.9, 127.9, 127.7, 125.5, 118.3, 65.7, 60.8, 43.5,
34.4. ESI-MS: m/z (%) 321 (100) [M + H+]. Anal. Calcd for
5-(3,4-Dich lor op h en oxy)-2-(4-flu or ob en zylsu lfa n yl)-
3,4,5,6-tetr a h yd r op yr im id in -1-iu m Br om id e (8c). Follow-
ing the method described for 8a gave 8c as a yellow solid. Yield
71%. 1H NMR (500 MHz, MeOH-d4) δ 7.49-7.46 (m, 2H), 7.48
(d, J ) 8.9 Hz, 1H), 7.16-7.13 (m, 2H), 7.14 (d, J ) 2.9 Hz,
1H), 6.92 (dd, J ) 8.9, 2.9 Hz, 1H), 5.10 (t, J ) 2.5 Hz, 1H),
4.45 (s, 2H), 3.69 (mc, 4H); 13C NMR (125 MHz, MeOH-d4) δ
165.0, 164.0, 156.9, 134.6, 132.7, 132.5, 127.0, 120.1, 117.9,
117.3, 66.0, 45.3, 36.5. ESI-MS: m/z (%) 385 (100) [M + H+].
Anal. Calcd for C17H16Cl2FN2OSBr: C, 43.80; H, 3.46; N, 6.01;
S, 6.88. Found: C, 43.9; H, 3.51; N, 6.37; S, 6.40.
C
12H15Cl2N2O2SBr: C, 35.84; H, 3.76; N, 6.97; S, 7.97. Found:
C, 35.7; H, 3.78; N, 6.79; S, 7.20.
5-(4-Ch lor oph en oxy)-2-(2-h ydr oxyeth ylsu lfan yl)-3,4,5,6-
tetr a h yd r op yr im id in -1-iu m Br om id e (10b). Following the
method described for 8a gave 10b as a yellow solid. Yield 71%.
1H NMR (500 MHz, MeOH-d4) δ 7.33-7.31 (m, J ) 9.0 Hz,
2H), 7.03-7.01 (m, J ) 9.0 Hz, 2H), 5.07 (t, J ) 2.6 Hz, 1H),
3.88 (mc, 2H), 3.70-3.69 (m, 4H), 3.33-3.31 (m, 2H); 13C NMR
(125 MHz, MeOH-d4) δ 166.1, 156.4, 131.2, 128.8, 119.6, 65.9,
62.6, 45.3, 36.2. ESI-MS: m/z (%) 287 (100) [M + H+]. Anal.
Calcd for C12H16ClN2O2SBr: C, 39.20; H, 4.39; N, 7.62; S, 8.72.
Found: C, 39.6; H, 4.31; N, 7.77; S, 7.58.
2-(4-F lu or oben zylsu lfa n yl)-5-(4-tr iflu or om eth ylp h en -
oxy)-3,4,5,6-tetr a h yd r op yr im id in -1-iu m Br om id e (8d ).
Following the method described for 8a gave 8d as a yellow
5-(3,4-Dich lor op h en oxy)-2-(2-h yd r oxyet h ylsu lfa n yl)-
3,4,5,6-tetr a h yd r op yr im id in -1-iu m Br om id e (10c). Fol-
1
solid. Yield 69%. H NMR (500 MHz, MeOH-d4) δ 7.68-7.65
1576 J . Org. Chem., Vol. 69, No. 5, 2004

Cyclic Isothioureas and Guanidines
lowing the method described for 8a gave 10c as a yellow solid.
Yield 52%. H NMR (500 MHz, MeOH-d4) δ 7.46 (d, J ) 8.9
eth ylsu lfa n yl]-1,4,5,6-tetr a h yd r op yr im id in e (14). Follow-
ing the method described for 11 gave 14 as a yellow solid. Yield
90%. H NMR (500 MHz, CDCl3) δ 8.05 (d, J ) 10.0 Hz, 1H),
7.37 (d, J ) 2.5 Hz, 1H), 7.18 (dd, J ) 8.8, 2.5 Hz, 1H), 6.93
(d, J ) 8.8 Hz, 1H), 6.87-6.85 (m, 2H), 4.61 (mc, 1H), 4.25 (t,
J ) 6.8 Hz, 2H), 3.70-3.54 (m, 4H), 3.32 (mc, 2H), 2.61 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 162.1, 152.5, 151.3, 142.2,
137.1, 130.4, 127.7, 127.5, 126.0, 118.2, 118.0, 112.6, 69.6, 67.5,
28.8, 21.7. ESI-MS: m/z (%) 456 (100) [M + H+].
1
1
Hz, 1H), 7.26 (d, J ) 2.9 Hz, 1H), 7.00 (dd, J ) 8.9, 2.9 Hz,
1H), 5.11 (t, J ) 2.5 Hz, 1H), 3.88 (t, J ) 5.3 Hz, 2H), 3.70 (m,
4H), 3.32 (t, J ) 5.3 Hz, 2H); 13C NMR (125 MHz, MeOH-d4)
δ 166.1, 157.0, 134.6, 132.8, 127.0, 120.1, 118.1, 66.2, 62.6, 45.3,
36.2. ESI-MS: m/z (%) 321 (100) [M + H+]. Anal. Calcd for
C
12H15Cl2N2O2SBr: C, 35.84; H, 3.76; N, 6.97; S, 7.97. Found:
C, 35.6; H, 4.04; N, 7.22; S, 7.03.
Rep r esen ta tive Exp er im en ta l P r oced u r es for P r ep a -
r a tion of 5-P h en oxytetr a h yd r op yr im id in -2-on e: P r ep a -
r a tion of 5-(2,4-Dich lor op h en oxy)tetr a h yd r op yr im id in -
2-on e (15a ). Meth od A: Ammonium hydroxide (1 mL) was
added to 7a (0.10 mmol, 29 mg) and the mixture was heated
in the microwave at 150 °C for 500 s. All volatiles were
removed in vacuo giving 15a as a white solid. Yield: 23 mg
(87%).
2-(2-Hyd r oxyeth ylsu lfa n yl)-5-(4-tr iflu or om eth ylp h en -
oxy)-3,4,5,6-tetr a h yd r op yr im id in -1-iu m Br om id e (10d ).
Following the method described for 8a gave 10d as a yellow
solid. Yield 71%. 1H NMR (500 MHz, MeOH-d4) δ 7.64 (d, J )
8.8 Hz, 2H), 7.19 (d, J ) 8.8 Hz, 2H), 5.22 (t, J ) 2.5 Hz, 1H),
3.88 (t, J ) 5.3 Hz, 2H), 3.77-3.71 (m, 4H), 3.32 (t, J ) 5.3
Hz, 2H); 13C NMR (125 MHz, MeOH-d4) δ 166.1, 160.5, 128.8,
117.9, 65.5, 62.7, 45.3, 36.2. ESI-MS: m/z (%) 321 (100) [M +
H+]. Anal. Calcd for C13H16F3N2O2SBr: C, 38.92; H, 4.02; N,
6.98; S, 7.99. Found: C, 39.2; H, 4.20; N, 7.25; S, 7.44.
Gen er a l P r oced u r e for t h e Syn t h esis of (2-Ch lor o-
eth oxy)ben zen es. A mixture of the appropriate phenol (3
equiv), 1-bromo-2-chloroethane (1 equiv), potassium carbonate
(8 equiv), and acetonitrile were heated at 150 °C for 100 s in
the microwave. The solvent was removed and aqueous 1 M
NaOH was added to the residue. The aqueous layer was
extracted with CHCl3, and the organic layer was concentrated
under reduced pressure to afford the crude, which was used
without further purification.
Meth od B: Water (1 mL) was added to 7a (0.10 mmol, 29
mg) and the mixture was heated in the microwave at 150 °C
for 1000 s. Water was removed in vacuo to give 15a as a white
solid. Yield: 13 mg (50%). 1H NMR (500 MHz, DMSO-d6) δ
7.58 (d, J ) 2.4 Hz, 1H), 7.37 (dd, J ) 8.8, 2.4 Hz, 1H), 7.29
(d, J ) 8.8 Hz, 1H), 6.10 (br s, 2H), 4.79 (br s, 1H), 3.44-3-
24 (m, 4H); 13C NMR (125 MHz, DMSO-d6) δ 155.5, 151.8,
130.1, 128.5, 125.7, 124.4, 118.0, 68.3, 43.2. ESI-MS: m/z (%)
261 (100) [M + H+], 302 [M + ACN]. Anal. Calcd for C10H10
-
Cl2N2O2: C, 46.00; H, 3.86; N, 10.73. Found: C, 45.4; H, 4.19;
N, 10.6.
5-(4-Ch lor op h en oxy)tetr a h yd r op yr im id in -2-on e (15b).
Following method A described for 15a gave 15b as a white
solid. Yield 95%. Following method B described for 15a gave
Rep r esen ta tive Exp er im en ta l P r oced u r es for P r ep a -
r a tion of 5-P h en oxy-2-a lk ylsu lfa n yl-3,4,5,6-tetr a h yd r o-
p yr im id in iu m Ch lor id e: P r ep a r a tion of 2-[2-(2-Ca r ba m -
oyl-4-ch lor oph en oxy)eth ylsu lfan yl]-5-(4-ch lor oph en oxy)-
3,4,5,6-tetr ah ydr opyr im idin iu m Ch lor ide (11). To a solution
of 6b (0.10 mmol, 24 mg) and 5-chloro-2-(2-chloroethoxy)-
benzamide (0.15 mmol, 35 mg) in acetonitrile (0.6 mL) was
added a catalytic amount of potassium iodide and the mixture
was heated for 1000 s at 160 °C. The solvent was removed in
vacuo and the residue was extracted under vigorous agitation
with CH2Cl2 (2 mL) from aqueous 1 M NaOH (2 mL). The
organic layer was concentrated and submitted to flash column
chromatography EtOAc:MeOH:NEt3 (15:1:0 f 30:2:1) to give
1
15b as a white solid. Yield 35%. H NMR (400 MHz, DMSO-
d6) δ 7.33 (d, J ) 9.0 Hz, 2H), 7.01 (d, J ) 9.0 Hz, 2H), 6.08
(br s, 1H), 4.71 (br s, 1H), 3.38-3.22 (m, 4H). ESI-MS: m/z
(%) 227 (100) [M + H+].
5-(3,4-Dich lor op h en oxy)t et r a h yd r op yr im id in -2-on e
(15c). Following method A described for 15a gave 15c as a
white solid. Yield quantitative. Following method B described
for 15a gave 15c as a white solid. Yield 19%. 1H NMR (500
MHz, DMSO-d6) δ 7.54 (d, J ) 8.9 Hz, 1H), 7.33 (d, J ) 2.9
Hz, 1H), 7.03 (dd, J ) 8.9, 2.9 Hz, 1H), 6.12 (br s, 1H), 4.80
(mc, 1H), 3.38-3.23 (m, 4H); 13C NMR (125 MHz, DMSO-d6) δ
156.5, 155.4, 132.3, 131.5, 123.3, 118.2, 117.2, 67.0, 43.0. ESI-
MS: m/z (%) 261 [M + H+], 302 (100) [M + ACN]. Anal. Calcd
for C10H10Cl2N2O2: C, 46.00; H, 3.86; N, 10.73. Found: C, 45.2;
H, 4.08; N, 10.4.
5-(4-Tr iflu or om eth ylp h en oxy)tetr a h yd r op yr im id in -2-
on e (15d ). Following method A described for 15a gave 15d
as a white solid. Yield quantitative. Following method B
described for 15a gave 15d as a white solid. Yield: 17 mg
(65%). 1H NMR (500 MHz, DMSO-d6) δ 7.66 (d, J ) 8.6 Hz,
2H), 7.19 (d, J ) 8.6 Hz, 2H), 6.16 (br s, 1H), 4.88 (mc, 1H),
3.43-3.40 (m, 2H), 3.32-3.27 (m, 2H); 13C NMR (125 MHz,
DMSO-d6) δ 160.0, 155.4, 127.4, 124.9, 121.6, 116.4, 66.5, 43.0.
ESI-MS: m/z (%) 261 [M + H+], 302 (100) [M + ACN]. Anal.
Calcd for C11H11F3N2O2: C, 50.77; H, 4.26; N, 10.76. Found:
C, 50.6; H, 4.59; N, 10.6.
1
11 as a white solid. Yield 94%. H NMR (400 MHz, DMSO) δ
10.12 (s, 2H), 7.75 (s, 1H), 7.69 (d, J ) 2.8 Hz, 1H), 7.65 (s,
1H), 7.53 (dd, J ) 8.9, 2.8 Hz, 1H), 7.36 (d, J ) 9.0 Hz, 2H),
7.20 (d, J ) 8.9 Hz, 1H), 7.04 (d, J ) 9.0 Hz, 2H), 5.10 (t, J )
2.3 Hz, 1H), 4.35 (t, J ) 5.7 Hz, 2H), 3.74 (t, J ) 5.7 Hz, 2H),
3.66 (dd, J ) 14.8, 2.3 Hz, 2H), 3.55 (d, J ) 14.8 Hz, 2H); 13
C
NMR (100 MHz, DMSO) δ 165.1, 161.0, 154.5, 154.2, 131.5,
129.7, 129.4, 125.5, 124.8, 117.9, 115.1, 67.1, 63.5, 43.3, 30.1.
ESI-MS: m/z (%) 440 (100) [M + H+].
1-(2-{2-[5-(2,4-Dich lor op h en oxy)-1,4,5,6-t et r a h yd r o-
pyr im idin -2-ylsu lfan yl]eth oxy}ph en yl)eth an on e (12). Fol-
lowing the method described for 11 gave 12 as a white solid.
Yield 91%. 1H NMR (500 MHz, CDCl3) δ 7.74 (dd, J ) 7.9, 1.8
Hz, 1H), 7.42 (ddd, J ) 9.1, 7.9, 1.5 Hz, 1H), 7.36 (d, J ) 2.6
Hz, 1H), 7.17 (dd, J ) 8.8, 2.6 Hz, 1H), 7.00 (m, 2H), 6.93 (d,
J ) 8.8 Hz, 1H), 4.60 (mc, 1H), 4.29 (t, J ) 6.2 Hz, 2H), 3.60
(br s, 4H), 3.41 (t, J ) 6.2 Hz, 2H), 2.65 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 199.9, 157.9, 152.6, 151.4, 133.7, 130.5, 130.4,
127.7, 127.4, 126.0, 120.8, 118.3, 112.5, 69.7, 67.6, 32.2, 29.4.
ESI-MS: m/z (%) 439 (100) [M + H+].
5-(2,4-Dich lor op h en oxy)-2-et h oxy-1,4,5,6-t et r a h yd r o-
p yr im id in e (16a ). 7a (0.10 mmol, 29 mg) was washed with 1
M aqueous NaOH and extracted with CHCl3. The solvent was
removed in vacuo, the residue was added to ammonia in
ethanol (1 mL), and the solution was heated in the microwave
at 150 °C for 1000 s. Ammonia and ethanol were removed in
vacuo giving 16a as a white solid. Yield: 28 mg (99%). 1H NMR
(500 MHz, MeOH-d4) δ 7.45 (d, J ) 2.6 Hz, 1H), 7.30 (dd, J )
8.8, 2.6 Hz, 1H), 7.19 (d, J ) 8.8 Hz, 1H), 4.74 (mc, 1H), 3.64
2-[2-(4-Ch lor op h e n oxy)e t h ylsu lfa n yl]-5-(2,4-d ich lo-
r op h en oxy)-1,4,5,6-tetr a h yd r op yr im id in e (13). Following
the method described for 11 gave 13 as a white solid. Yield
1
93%. H NMR (500 MHz, CDCl3) δ 7.37 (d, J ) 2.5 Hz, 1H),
7.20 (d, J ) 9.1 Hz, 2H), 7.17 (dd, J ) 8.8, 2.5 Hz, 1H), 6.92
(d, J ) 8.8 Hz, 1H), 6.86 (d, J ) 9.1 Hz, 2H), 4.59 (mc, 1H),
4.15 (t, J ) 6.6 Hz, 2H), 3.60-3.56 (m, 4H), 3.32 (t, J ) 6.6
Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 157.1, 152.8, 151.4,
130.4, 129.3, 127.6, 127.5, 126.1, 125.8, 118.4, 116.0, 69.7, 67.5,
46.2, 29.3. ESI-MS: m/z (%) 431 (100) [M + H+].
(q, J ) 7.0 Hz, 2H), 3.52 (mc, 4H), 1.21 (t, J ) 7.0 Hz, 3H); 13
C
NMR (125 MHz, MeOH-d4) δ 157.9, 153.5, 131.4, 129.3, 128.2,
127.1, 119.5, 70.4, 58.7, 45.9, 18.8. ESI-MS: m/z (%) 289 (100)
[M + H+]. Anal. Calcd for C12H14Cl2N2O2: C, 49.84; H, 4.88;
N, 9.69. Found: C, 49.2; H, 5.14; N, 9.75.
5-(2,4-Dich lor oph en oxy)-2-[2-(3-m eth yl-4-n itr oph en oxy)-
5-(4-Ch lor op h en oxy)-2-eth oxy-1,4,5,6-tetr a h yd r op yr i-
J . Org. Chem, Vol. 69, No. 5, 2004 1577

Sandin et al.
m id in e (16b). Following the method described for 16a gave
16b as a white solid. Yield 99%. H NMR (400 MHz, MeOH-
129.9, 129.1, 129.0, 127.8, 127.0, 117.9, 65.3, 43.8, 47.0, 35.4.
ESI-MS: m/z (%) 330 (100) [M + H+].
1
d4) δ 7.27 (d, J ) 4.0 Hz, 2H), 7.26 (d, J ) 4.0 Hz, 2H), 4.63
(mc, 1H), 4.03 (q, J ) 7.1 Hz, 2H), 3.47 (mc, 4H), 1.25 (t, J )
7.1 Hz, 3H); 13C NMR (100 MHz, MeOH-d4) δ 155.9, 155.3,
129.0, 125.7, 117.3, 67.0, 61.1, 44.2, 13.4.
[5-(4-Ch lor op h en oxy)-1,4,5,6-t et r a h yd r op yr im id in -2-
yl][2-(4-m eth oxyp h en yl)eth yl]a m m on iu m Iod id e (19b).
Following the method described for 19a gave 19b as a yellow
1
oil. Yield 67%. H NMR (500 MHz, CDCl3) δ 7.61 (t, J ) 5.8
Rep r esen ta tive Exp er im en ta l P r oced u r es for P r ep a -
r a tion of 2-Am in o-5-p h en oxy-3,4,5,6-tetr a h yd r op yr im i-
din -1-iu m Br om ide: 2-Am in o-5-(4-ch lor oph en oxy)-3,4,5,6-
tetr a h yd r op yr im id in -1-iu m Br om id e (17a ). To a solution
of cyanogen bromide (1.2 mmol, 127 mg) in 2-propanol (2.5
mL) was added 3b (1.0 mmol, 200 mg) and the reaction
mixture was heated in the microwave at 120 °C for 600 s.
Isopropyl ether (2.5 mL) was added and the precipitate was
filtered off, washed with isopropyl ether, and dried in vacuo
over P4O10 to give 17a as a white solid. Yield 61%. 1H NMR
(400 MHz, DMSO-d6) δ 7.68 (br s, NH, 2H), 7.36 (d, J ) 9.0
Hz, 1H), 7.05 (d, J ) 9.0 Hz, 1H), 6.95 (br s, NH, 1H), 4.93
(mc, 1H), 3.44 (mc, 4H); 13C NMR (100 MHz, DMSO-d6) δ 155.4,
153.7, 129.9, 125.7, 118.3, 65.9, 41.6. ESI-MS: m/z (%) 226
(100) [M + H+]. Anal. Calcd for C10H13BrClN3O: C, 39.18; H,
4.27; N, 13.71. Found: C, 39.6; H, 4.25; N, 13.5.
Hz, 1H), 7.26 (d, J ) 9.0 Hz, 2H), 7.23 (d, J ) 8.7 Hz, 2H),
6.84 (d, J ) 8.7 Hz, 2H), 6.81 (d, J ) 9.0 Hz, 2H), 4.58 (mc,
1H), 3.72 (s, 3H), 3.47 (dt, J ) 6.8, 5.8 Hz, 2H), 3.46-3.40 (m,
4H), 2.89 (t, J ) 6.8 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ
158.6, 154.3, 153.3, 130.2, 129.9, 129.7, 127.8, 117.8, 114.4,
65.3, 55.3, 44.1, 42.0, 34.6. ESI-MS: m/z (%) 360 (100) [M +
H+]. Anal. Calcd for C19H23ClIN3O2: C, 46.79; H, 4.75; N, 8.61.
Found: C, 46.2; H, 5.33; N, 8.13.
(3,3-Dip h en ylp r op yl)[5-(4-ch lor op h en oxy)-1,4,5,6-tet-
r a h yd r op yr im id in -2-yl]a m m on iu m Iod id e (19c). Follow-
ing the method described for 19a gave 19c as a yellow solid.
1
Yield 61%. H NMR (400 MHz, CDCl3) δ 7.64 (t, J ) 5.6 Hz,
1H), 7.30-7.15 (m, 10H), 7.24 (d, J ) 8.9 Hz, 2H), 6.80 (d, J
) 8.9 Hz, 2H), 4.59 (mc, 1H), 4.23 (t, J ) 8.1 Hz, 1H), 3.50-
3.40 (m, 4H), 3.20 (dt, J ) 6.9, 5.6 Hz, 2H), 2.38 (dt, J ) 8.1,
6.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 154.2, 153.0, 143.2,
129.9, 128.7, 127.9, 127.8, 117.9, 65.3, 47.6, 41.9, 40.1, 34.3.
2-Am in o-5-(3,4-d ich lor op h en oxy)-3,4,5,6-t et r a h yd r o-
p yr im id in -1-iu m Br om id e (17b). Following the method
described for 17a gave 17b as a white solid. Yield 53%. 1H
NMR (400 MHz, MeOH-d4) δ 7.46 (d, J ) 8.9 Hz, 1H), 7.24 (d,
J ) 2.9 Hz, 1H), 6.99 (dd, J ) 8.9, 2.9 Hz, 1H), 4.97 (mc, 1H),
3.56-3.52 (m, 4H); 13C NMR (100 MHz, MeOH-d4) δ 155.5,
154.0, 132.7, 130.9, 124.9, 118.1, 116.2, 65.3, 41.3. ESI-MS:
m/z (%) 260 (100) [M + H+], 301 [M + ACN]. Anal. Calcd for
ESI-MS: m/z (%) 420 (100) [M + H+]. Anal. Calcd for C25H27
-
ClIN3O: C, 54.81; H, 4,97; N, 7.67. Found: C, 54.4; H, 5.40;
N, 7.45.
(3,3-Dip h en ylp r op yl)[5-(4-t r iflu or om et h ylp h en oxy)-
1,4,5,6-tetr ah ydr opyr im idin -2-yl]am m on iu m Iodide (19d).
Following the method described for 19a gave 19d as a yellow
solid. Yield 73%. 1H NMR (500 MHz, CDCl3) δ 7.70 (t, J ) 5.4
Hz, 1H), 7.55 (d, J ) 8.6 Hz, 2H), 7.30-7.15 (m, 10H), 6.94 (d,
J ) 8.6 Hz, 2H), 4.74 (mc, 1H), 4.23 (t, J ) 8.0 Hz, 1H), 3.50
(br s, 4H), 3.20 (dt, J ) 6.9, 5.4 Hz, 2H), 2.39 (dt, J ) 8.0, 6.9
Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 158.1, 152.9, 143.2,
128.7, 127.9, 127.4, 126.7, 116.0, 64.7, 47.7, 41.9, 40.1, 34.3.
ESI-MS: m/z (%) 454 (100) [M + H+].
C
10H12Cl2N3OBr: C, 35.22; H, 3.55; N, 12.32. Found: C, 35.3;
H, 3.81; N, 11.6.
2-Am in o-5-(4-t r iflu or om et h ylp h en oxy)-3,4,5,6-t et r a -
h ydr opyr im idin -1-iu m Br om ide (17c). Following the method
described for 17a gave 17c as a white solid. Yield 57%. 1H
NMR (400 MHz, DMSO-d6) δ 7.68 (d, J ) 8.8 Hz, 2H), 7.22 (d,
J ) 8.8 Hz, 2H), 6.98 (br s, 2H), 5.08 (br s, 1H), 3.48 (mc, 4H);
13C NMR (100 MHz, DMSO-d6) δ 159.5, 153.7, 127.6, 124.9,
122.4, 116.7, 64.9, 41.6.
5-Be n zyl-3,4,5,6-t e t r a h yd r op yr im id in -2-yla m m on i-
u m Br om id e (17d ). Following the method described for 17a ,
using 3e23,24 as starting material, gave 17d as a white solid.
Yield 56%. 1H NMR (400 MHz, CDCl3) δ 7.67 (br s, 2H), 7.33-
7.23 (m, 3H), 7.13 (d, J ) 7.0 Hz, 2H), 6.88 (br s, 2H), 3.35 (d,
J ) 12.0 Hz, 2H), 3.01 (dd, J ) 11.0, 9.5 Hz, 2H), 2.64 (d, J )
7.5 Hz, 2H), 2.25 (mc, 1H); 13C NMR (100 MHz, CDCl3) δ 154.7,
137.4, 128.8, 128.7, 127.0, 43.0, 36.9, 32.1. ESI-MS: m/z (%)
190 (100) [M + H+]. Anal. Calcd for C11H16BrN3: C, 48.90; H,
5.97; N, 15.55. Found: C, 49.2; H, 6.54; N, 15.6.
Rep r esen ta tive Exp er im en ta l P r oced u r es for P r ep a -
r a tion of [5-P h en oxy-1,4,5,6-tetr a h yd r op yr im id in -2-yl]-
a lk yla m m on iu m Iod id e: P r ep a r a t ion of [5-(4-Ch lor o-
p h en oxy)-1,4,5,6-t et r a h yd r op yr im id in -2-yl]p h en et h yl-
a m m on iu m Iod id e (19a ). To a solution of the isothiouronium
iodide 7b (39 mg, 0.10 mmol) in acetonitrile (2 mL) was added
phenethylamine 18a (13 mg, 0.11 mmol) and the mixture was
heated at 90 °C for 6 d. The mixture was diluted with THF (4
mL) and the excess of the amine was scavenged with use of
methyl isocyanate on polystyrene (0.20 mmol). After 3 h of
agitation at room temperature, the resin was filtered off and
washed with CH2Cl2 (2 mL) and MeOH (2 mL), and the organic
layer was concentrated in vacuo. Flash column chromatogra-
phy (EtOAc:MeOH; 15:1 f 10:1) of the residue afforded 19a
as a yellow solid. Yield: 20 mg (69%). 1H NMR (400 MHz,
CDCl3) δ 7.54 (t, J ) 6.8 Hz, 1H), 7.31-7.21 (m, 5H), 7.26 (d,
J ) 8.9 Hz, 2H), 6.82 (d, J ) 8.9 Hz, 2H), 4.58 (mc, 1H), 3.54
(dt, J ) 6.8, 6.6 Hz, 2H), 3.45-3.39 (m, 4H), 2.95 (t, J ) 6.6
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 154.3, 153.2, 137.8,
[3-(2-oxop yr r olid in -1-yl)p r op yl][5-(4-t r iflu or om et h -
ylp h en oxy)-1,4,5,6-t et r a h yd r op yr im id in -2-yl]a m m on i-
u m Iod id e (19e). Following the method described for 19a gave
1
19e as a yellow oil. Yield 84%. H NMR (500 MHz, CDCl3) δ
8.36 (br s, 1H), 7.88-7.81 (m, 1H), 7.58 (d, J ) 8.2 Hz, 2H),
7.00 (d, J ) 8.2 Hz, 2H), 4.84 (mc, 1H), 3.57 (mc, 4H), 3.50 (t,
J ) 7.2 Hz, 2H), 3.33-3.29 (m, 4H), 2.46-2.42 (m, 2H), 2.14-
2.07 (m, 2H), 1.86 (mc, 2H); 13C NMR (100 MHz, CDCl3) δ
177.2, 158.4, 154.9, 127.4, 116.1, 65.2, 48.6, 41.9, 40.7, 39.7,
31.3, 29.5, 17.8. ESI-MS: m/z (%) 385 (100) [M + H+].
[3-(Met h ylp h en yla m in o)p r op yl][5-(4-t r iflu or om et h -
ylp h en oxy)-1,4,5,6-t et r a h yd r op yr im id in -2-yl]a m m on i-
u m Iod id e (19f). Following the method described for 19a gave
1
19f as a yellow oil. Yield 86%. H NMR (500 MHz, CDCl3) δ
7.80-7.71 (m, 3H), 7.56 (d, J ) 8.8 Hz, 2H), 7.21 (dd, J ) 8.7,
7.4 Hz, 1H), 6.92-6.88 (m, 4H), 6.83 (t, J ) 7.4 Hz, 1H), 4.68
(mc, 1H), 3.42 (br s, 4H), 3.31 (dd, J ) 6.1, 6.0 Hz, 2H), 3.25
(t, J ) 6.3 Hz, 2H), 2.84 (s, 3H), 1.93 (tt, J ) 6.3, 6.1 Hz, 2H);
13C NMR (125 MHz, CDCl3) δ 158.2, 154.0, 149.9, 129.5, 127.4,
125.0, 120.6, 116.6, 115.7, 64.7, 48.5, 42.0, 40.7, 38.5, 26.8. ESI-
MS: m/z (%) 224 (100), 245 (80), 407 (55) [M + H+].
(2-P h en ylpr opyl)[5-(4-tr iflu or om eth ylph en oxy)-1,4,5,6-
tetr a h yd r op yr im id in -2-yl]a m m on iu m Iod id e (19g). Fol-
lowing the method described for 19a gave 19g as a yellow oil.
1
Yield 46%. H NMR (500 MHz, CDCl3) δ 7.65 (t, J ) 6.1 Hz,
1H), 7.57 (d, 2H, J ) 8.8 Hz, 2H), 7.35-7.31 (m, 4H), 7.20
(mc, 1H), 6.93 (d, J ) 8.8 Hz, 2H), 4.69 (mc, 1H), 3.50-3.33
(m, 6H), 3.12-3.09 (m, 1H), 1.39 (d, J ) 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 153.2, 143.1, 129.1, 127.5, 127.4, 115.9,
64.7, 49.6, 41.9, 39.9, 18.7. ESI-MS: m/z (%) 378 (100) [M +
H+].
[3-(2-Ca r b a m oyl-4-ch lor op h en oxy)p r op yl]-[5-(4-ch lo-
r op h en oxy)-1,4,5,6-t et r a h yd r op yr im id in -2-yl]a m m on i-
u m Iod id e (19h ). Following the method described for 19a
(23) Ramalingam, K.; Raju, N.; Nanjappan, P.; Nowotnik, D. P.
Tetrahedron 1995, 51, 2875.
(24) Brown, H. C.; Narashimhan, S.; Choi, Y. M. Synthesis 1981,
37, 233.
1
gave 19h as a pale yellow oil. Yield 33%. H NMR (500 MHz,
CDCl3) δ 7.70 (t, J ) 5.8 Hz, 1H), 7.61 (s, 1H), 7.54 (d, J ) 2.7
1578 J . Org. Chem., Vol. 69, No. 5, 2004

Cyclic Isothioureas and Guanidines
Hz, 1H), 7.34 (dd, J ) 8.9, 2.7 Hz, 1H), 7.23 (d, J ) 9.0 Hz,
2H), 6.90 (d, J ) 8.9 Hz, 1H), 6.77 (d, J ) 9.0 Hz, 2H), 6.55 (s,
1H), 6.12 (s, 1H), 4.60 (mc, 1H), 4.18 (t, J ) 5.3 Hz, 2H), 3.61
(dt, J ) 5.8, 5.7 Hz, 2H), 3.51 (mc, 4H), 2.15 (mc, 2H); 13C NMR
(125 MHz, CDCl3) δ 168.4, 154.8, 154.5, 153.0, 132.9, 129.9,
128.9, 127.6, 126.1, 123.4, 117.8, 114.0, 66.4, 65.6, 42.1, 39.6,
28.2. ESI-MS: m/z (%) 438 (100) [M + H+].
) 5.3 Hz, 1H), 7.36 (d, J ) 8.9 Hz, 1H), 7.30-7.18 (m, 10H),
6.98 (d, J ) 2.9 Hz, 1H), 6.74 (dd, J ) 8.9, 2.9 Hz, 1H), 4.61
(mc, 1H), 4.05 (t, J ) 8.0 Hz, 1H), 3.50-3.40 (m, 4H), 3.07 (dt,
J ) 6.5, 5.3 Hz, 2H), 2.39 (dt, J ) 8.0, 6.5 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 154.7, 153.0, 143.3, 133.5, 131.3, 128.8,
127.8, 126.8, 126.2, 118.1, 115.9, 65.6, 48.0, 41.9, 39.4, 34.5.
ESI-MS: m/z (%) 454 (100) [M + H+].
Gen er a l P r oced u r e for th e Tr a n sfor m a tion of 2-Me-
t h ylsu lfa n yl-5-p h en oxy-3,4,5,6-t et r a h yd r op yr im id in -1-
iu m Iod id e in to Its Tr iflu or oa ceta te F or m 21. The ap-
propriate iodide salt 7 was deprotonated in aqueous 1 M NaOH
and extracted with CHCl3. The organic layer was concentrated
in vacuo and CH2Cl2 was added. Trifluoroacetic acid (5 equiv)
was carefully added and all volatiles were removed in vacuo.
The residue was recrystallized from MeOH/Et2O to give 21 as
a pale yellow solid.
[5-(4-Ch lor op h en oxy)-1,4,5,6-t et r a h yd r op yr im id in -2-
yl](2-p h en oxyeth yl)a m m on iu m Ch lor id e (19n ). Following
the method described for 19i gave the trifluoroacetate salt.
After extraction from 1 M NaOH with EtOAc, the guanidine
was precipitated from 2.5 M HCl/EtOAc, washed (EtOAc,
Et2O), and dried in vacuo to give 19n as a yellow oil. Yield
84%. 1H NMR (500 MHz, CDCl3) δ 8.92 (t, J ) 5.6 Hz, 1H),
7.29-7.26 (m, 2H), 7.21 (d, J ) 8.9 Hz, 2H), 7.03 (t, J ) 7.4
Hz, 1H), 6.80 (d, J ) 7.8 Hz, 2H), 6.76 (d, J ) 8.9 Hz, 2H),
4.68 (br s, 1H), 4.16 (t, J ) 4.4 Hz, 2H), 3.67 (mc, 2H), 3.67-
3.51 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 157.2, 155.0, 154.2,
129.9, 129.9, 127.6, 122.4, 117.7, 114.7, 69.0, 65.3, 42.1, 41.8.
ESI-MS: m/z (%) 346 (100) [M + H+].
Rep r esen ta tive Exp er im en ta l P r oced u r es for P r ep a -
r a tion of 5-P h en oxy-1,4,5,6-tetr a h yd r op yr im id in -2-yl]-
a lk yla m m on iu m : P r ep a r a tion of [5-(4-Ch lor op h en oxy)-
1,4,5,6-tetr ah ydr opyr im idin -2-yl]isobu tylam m on iu m Tr i-
flu or oa ceta te (19i). To a solution of the isothiouronium
trifluoroacetate 21a (37 mg, 0.10 mmol) in acetonitrile (0.6 mL)
was added isobutylamine 18i (8 mg, 0.11 mmol) and the
mixture was heated for 800 s at 160 °C in the microwave. The
mixture was diluted with acetonitrile (0.3 mL) and THF (0.9
mL) and the excess of 21a was scavenged with Wang resin
(0.25 mmol). After the mixture was heated for an additional
1000 s at 150 °C in the microwave, methyl isocyanate on resin
(0.30 mmol) was added to remove the unreacted amine. The
resins were filtered off and washed with CH2Cl2 (2 mL) and
MeOH (2 × 2 mL), and the organic layer was concentrated in
[5-(3,4-Dich lor op h en oxy)-1,4,5,6-tetr a h yd r op yr im id in -
2-yl](3-p h en ylp r op yl)a m m on iu m Tr iflu or oa ceta te (19o).
Following the method described for 19i gave 19o as a pale
1
yellow solid. Yield 78%. H NMR (500 MHz, CDCl3) δ 8.55 (t,
J ) 5.2 Hz, 1H), 7.33 (d, J ) 8.9 Hz, 1H), 7.27-7.23 (m, 2H),
7.18-7.15 (m, 3H), 6.96 (d, J ) 2.9 Hz, 1H), 6.72 (dd, 1H, J )
8.9, 2.9 Hz, 1H), 4.56 (mc, 1H), 3.52-3.42 (m, 4H), 3.18 (dt, J
) 7.1, 5.2 Hz, 2H), 2.68 (t, J ) 7.6 Hz, 2H), 2.83 (tt, J ) 7.6,
7.1 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 154.9, 153.0, 140.7,
133.4, 131.2, 128.6, 128.5, 126.2, 126.0, 118.2, 116.0, 65.8, 41.9,
40.6, 32.6, 30.3. ESI-MS: m/z (%) 378 (100) [M + H+]. Anal.
Calcd for C21H22Cl2F3N3O3: C, 51.23; H, 4.50; N, 8.53. Found:
C, 51.7; H, 5.10; N, 8.70.
1
vacuo to give 19i as a yellow oil. Yield 20 mg (71%). H NMR
(500 MHz, CDCl3) δ 8.90 (t, J ) 5.4 Hz, 1H), 7.26 (d, J ) 8.6
Hz, 2H), 6.83 (d, J ) 8.6 Hz, 2H), 4.65 (mc, 1H), 4.60-4.49
(m, 4H), 2.93 (dd, J ) 6.8, 5.4 Hz, 2H), 1.89 (mc, 1H), 0.94 (d,
J ) 6.7 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 154.4, 153.2,
129.9, 127.7, 117.8, 65.8, 48.7, 42.1, 28.2, 20.0. ESI-MS: m/z
(%) 282 (100) [M + H+]. Anal. Calcd for C16H21ClF3N3O3: C,
48.55; H, 5.35; N, 10.62. Found: C, 48.4; H, 5.62; N, 10.4.
5-(3,4-Dich lor op h e n oxy)-2-(2-m e t h oxye t h yla m in o)-
3,4,5,6-tetr a h yd r op yr im id in -1-iu m Ch lor id e (19p ). Fol-
lowing the method described for 19i gave 19p as a yellow solid.
1
Yield 70%. H NMR (400 MHz, MeOH-d4) δ 7.46 (d, J ) 8.8
Hz, 1H), 7.24 (d, J ) 2.7 Hz, 1H), 7.00 (dd, J ) 8.8, 2.7 Hz,
1H), 4.98 (br s, 1H), 3.58 (mc, 4H), 3.54 (t, 2H), 3.41-3.31 (m,
5H); 13C NMR (100 MHz, MeOH-d4) δ 155.5, 153.4, 132.7,
130.9, 124.9, 118.2, 116.2, 70.5, 65.6, 57.8, 41.5, 40.9.
[5-(4-Ch lor op h en oxy)-1,4,5,6-t et r a h yd r op yr im id in -2-
yl](3-(d im eth yla m in o)p r op yl)a m m on iu m Tr iflu or oa ce-
ta te (19j). Following the method described for 19i gave 19j
[5-(4-Ch lor op h en oxy)-1,4,5,6-t et r a h yd r op yr im id in -2-
yl][2-(4-m et h oxyp h en oxy)et h yl]a m m on iu m Tr iflu or o-
a ceta te (19q). Following the method described for 19i gave
1
as a yellow oil. Yield 77%. H NMR (500 MHz, CDCl3) δ 7.27
(d, J ) 8.8 Hz, 2H), 6.83 (d, J ) 8.8 Hz, 2H), 4.67 (mc, 1H),
3.58-3.43 (m, 4H), 3.29-3.19 (m, 2H), 2.50-2.18 (m, 2H), 2.19
(s, 6H), 1.74 (br s, 2H); 13C NMR (125 MHz, CDCl3) δ 154.5,
129.9, 127.4, 117.2, 65.5, 53.3, 44.1, 42.9, 37.4, 27.2. ESI-MS:
m/z (%) 311 (100) [M + H+].
1
19q as a yellow oil. Yield 76%. H NMR (500 MHz, CDCl3) δ
10.22 (mc, 1H), 7.22 (d, J ) 9.0 Hz, 2H), 6.83-6.77 (m, 4H),
6.74 (d, J ) 9.1 Hz, 2H), 4.71 (mc, 1H), 4.08 (mc, 2H), 3.78 (s,
3H), 3.67-3.53 (m, 4H), 3.61-3.57 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 155.4, 155.1, 154.2, 151.1, 129.9, 127.6, 117.7,
116.0, 114.9, 71.1, 65.5, 55.7, 42.1, 41.7. ESI-MS: m/z (%) 376
(100) [M + H+].
(2-Acetyla m in oeth yl)-[5-(4-ch lor op h en oxy)-3,4,5,6-tet-
r ah ydr opyr im idin -2-yl]am m on iu m Tr iflu or oacetate (19k).
Following the method described for 19i gave 19k as a yellow
solid. Yield 81%. 1H NMR (500 MHz, CDCl3) δ 9.41 (br s, 1H),
7.24 (d, J ) 8.8 Hz, 2H), 6.85 (d, J ) 8.8 Hz, 2H), 4.67 (mc,
1H), 3.64-3.53 (m, 4H), 3.33 (mc, 2H), 3.28 (mc, 2H), 2.01 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 172.9, 154.5, 153.6, 129.9,
127.7, 117.8, 65.7, 42.0, 39.7, 39.4, 22.8. ESI-MS: m/z (%) 311
(100) [M + H+].
[5-(3,4-Dich lor op h en oxy)-1,4,5,6-tetr a h yd r op yr im id in -
2-yl][2-(2,4-d ich lor op h en yl)eth yl]a m m on iu m Tr iflu or o-
a ceta te (19r ). Following the method described for 19i gave
1
19r as a colorless oil. Yield 35%. H NMR (500 MHz, CDCl3)
δ 9.36 (br s, 1H), 7.36-7.34 (m, 2H), 7.28 (d, J ) 8.4 Hz, 1H),
7.20 (d, J ) 2.0 Hz, 1H), 7.18 (d, J ) 2.0 Hz, 1H), 6.97 (d, J )
2.9 Hz, 1H), 6.73 (dd, J ) 8.9, 2.9 Hz, 1H), 4.63 (mc, 1H), 3.57-
3.45 (m, 4H), 3.39 (mc, 2H), 3.00 (t, J ) 7.2 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 154.7, 153.2, 134.3, 133.8, 133.5, 132.5,
131.3, 129.3, 127.7, 126.3, 118.3, 116.0, 65.7, 42.0, 40.6, 32.8.
ESI-MS: m/z (%) 434 (100) [M + H+].
[5-(4-Ch lor op h en oxy)-1,4,5,6-t et r a h yd r op yr im id in -2-
yl]p yr id in -2-ylm eth yla m m on iu m Tr iflu or oa ceta te (19l).
Following the method described for 19i gave 19l as a yellow
1
oil. Yield 53%. H NMR (500 MHz, CDCl3) δ 10.21 (t, J ) 5.8
Hz, 1H), 8.44 (ddd, J ) 5.0, 1.6, 0.8 Hz, 1H), 7.78 (ddd, J )
7.7, 7.7, 1.6 Hz, 1H), 7.34 (d, J ) 7.7 Hz, 1H), 7.32 (ddd, J )
7.7, 5.0, 1.1 Hz, 1H), 7.26 (d, J ) 9.0 Hz, 2H), 6.82 (d, J ) 9.0
Hz, 2H), 4.70 (mc, 1H), 4.38 (d, J ) 5.8 Hz, 2H), 3.64-3.53
(m, 4H); 13C NMR (125 MHz, CDCl3) δ 156.9, 155.9, 154.4,
148.3, 138.5, 129.8, 127.7, 123.9, 123.5, 118.0, 65.4, 47.5, 42.0.
ESI-MS: m/z (%) 317 (100) [M + H+].
[5-(4-Ch lor op h en oxy)-1,4,5,6-t et r a h yd r op yr im id in -2-
yl](m or p h olin -4-ylp r op yl)a m m on iu m Tr iflu or oa cet a t e
(19s). Following the method described for 19i gave 19s as a
1
yellow oil. Yield 93%. H NMR (500 MHz, CDCl3) δ 7.27 (d, J
) 9.0 Hz, 2H), 6.81 (d, J ) 9.0 Hz, 2H), 4.67 (mc, 1H), 3.72 (br
s, 1H), 3.59 (br s, 4H), 3.57-3.46 (m, 4H), 3.22 (t, J ) 6.8 Hz,
2H), 2.43 (t, J ) 6.0 Hz, 2H), 2.38 (br s, 4H), 1.74 (mc, 2H);
13C NMR (125 MHz, CDCl3) δ 154.8, 154.5, 129.9, 127.2, 117.1,
66.7, 65.8, 53.0, 52.6, 42.1, 37.6, 25.7. ESI-MS: m/z (%) 353
(100) [M + H+].
[5-(3,4-Dich lor op h en oxy)-1,4,5,6-tetr a h yd r op yr im id in -
2-yl](3,3-d ip h en ylp r op yl)a m m on iu m Tr iflu or oa cet a t e
(19m ). Following the method described for 19i gave 19m as a
1
yellow oil. Yield 32%. H NMR (500 MHz, CDCl3) δ 9.74 (t, J
J . Org. Chem, Vol. 69, No. 5, 2004 1579

Sandin et al.
[5-(4-Ch lor op h en oxy)-3,4,5,6-t et r a h yd r op yr im id in -2-
yl](3-p h en ot h ia zin -10-ylp r op yl)a m m on iu m Tr iflu or o-
a ceta te (19t). Following the method described for 19i gave
71%. 1H NMR (500 MHz, CDCl3) δ 9.93 (br s, 2H), 7.28 (d,
J ) 9.0 Hz, 2H), 6.85 (d, J ) 9.0 Hz, 2H), 4.69 (mc, 1H), 3.63-
3.25 (m, 10H), 2.10-2.00 (m, 2H); 13C NMR (125 MHz, CDCl3)
δ 154.4, 151.2, 129.9, 127.8, 117.8, 66.4, 50.3, 47.2, 41.2, 37.9,
20.7. ESI-MS: m/z (%) 266 (100) [M + H+].
1
19t as a yellow oil. Yield 80%. H NMR (500 MHz, CDCl3) δ
9.53 (t, J ) 6.3 Hz), 7.28-7.21 (m, 6H), 7.02-6.87 (m, 4H),
6.69 (d, J ) 9.0 Hz, 2H), 4.29 (mc, 1H), 3.99 (t, J ) 5.7 Hz,
2H), 3.19 (dt, J ) 6.3, 5.5 Hz, 2H), 2.14 (br s, 2H); 13C NMR
(125 MHz, CDCl3) δ 154.5, 153.1, 145.2, 129.8, 128.2, 128.0,
127.5, 125.9, 123.7, 117.6, 116.6, 65.5, 42.2, 41.8, 36.7, 26.0.
ESI-MS: m/z (%) 465 (100) [M + H+].
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 19a -t and 20 and a listing of the
binding energies of 7b, 16b, and unprotonated 17a . This
material is available free of charge via the Internet at
http://pubs.acs.org.
7-(4-Ch lor op h en oxy)-1,3,4,6,7,8-h exa h yd r o-2H-p yr im -
id o[1,2-a ]p yr im id in iu m Tr iflu or oa ceta te (20). Following
the method described for 19i gave 20 as a yellow oil. Yield
J O030338M
1580 J . Org. Chem., Vol. 69, No. 5, 2004