'One-flask' transformation of isocyanates and isothiocyanates to guanidines hydrochloride by using sodium bis(trimethylsilyl)amide

Article abstract of DOI:10.1016/j.tet.2010.01.003

A 'one-flask' synthesis of guanidines was developed by reacting isocyanates and isothiocyanates with sodium bis(trimethylsilyl)amide followed by addition of primary or secondary amines with a catalytic amount of AlCl₃. The desired guanidines were obtained in good yields and the reaction was applicable to aliphatic and aromatic substrates. A plausible mechanism was proposed through the generation of cyanamide anion from isocyanates or isothiocyanates with sodium bis(trimethylsilyl)amide. Addition of amines and catalytic amount of AlCl₃ smoothly converted the cyanamides to the desired guanidines.

Full text of DOI:10.1016/j.tet.2010.01.003

Tetrahedron 66 (2010) 1892–1897
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
‘One-flask’ transformation of isocyanates and isothiocyanates to guanidines
hydrochloride by using sodium bis(trimethylsilyl)amide
,
Chun-Yen Chen b, Hui-Chang Lin a, Yu-Ying Huang a, Kun-Lung Chen d e, Jiann-Jyh Huang c,
,
a,
*
Mou-Yung Yeh b , Fung Fuh Wong
*
a Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91, Hsueh-Shih Rd. Taichung, Taiwan 40402, ROC
b Department of Chemistry, National Cheng Kung University, No. 1, Ta Hsueh Rd., Tainan, Taiwan 70101, ROC
c Development Center for Biotechnology, No. 101, Lane 169, Kangning St., Xizhi City, Taipei County, Taiwan 221, ROC
d Sustainable Environment Research Center, National Cheng Kung University, No 500, Sec. 3, An-ming Rd., Tainan City, Taiwan 709, ROC
e Department of Resources Engineering, National Cheng Kung University, No 1, Ta Hsueh Rd., Tainan, Taiwan 70101, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
A ‘one-flask’ synthesis of guanidines was developed by reacting isocyanates and isothiocyanates with
sodium bis(trimethylsilyl)amide followed by addition of primary or secondary amines with a catalytic
amount of AlCl3. The desired guanidines were obtained in good yields and the reaction was applicable to
aliphatic and aromatic substrates. A plausible mechanism was proposed through the generation of
cyanamide anion from isocyanates or isothiocyanates with sodium bis(trimethylsilyl)amide. Addition of
amines and catalytic amount of AlCl3 smoothly converted the cyanamides to the desired guanidines.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 28 September 2009
Received in revised form 24 December 2009
Accepted 5 January 2010
Available online 11 January 2010
Keywords:
Guanidines
Isocyanates
Isothiocyanates
Cyanamides
Sodium bis(trimethylsilyl)amide
1. Introduction
yl)methanimine,18 or isothiourea,19 dichloroisocyamides in solution-
phase14 or solid-phase20 synthesis. The newly established methods
Guanidine group is found in many natural occurring substances
isolated from algae, sponges, and micro-organisms1 and is re-
sponsible for the biological activity of many pharmaceutically ac-
tive compounds.2–4 Guanidine derivatives also exhibit a variety of
coordination modes and a range of donor properties. Therefore they
can be used as the efficient ligands for the construction of various
organometallic catalysts from a wide range of metal ions, especially
early transition metals and lanthanides.5–11
The conventional method for the preparation of guanidines utilize
carbamoyl isothiocyanates (Cbz–N]C]S)12,13 or S-alkylisothiouro-
nium salts14 as the starting material to react with amines or ammo-
nia. The disadvantage for these methods was the generation of
noxious sulfur species and methyl mercaptan by-products.14 Other
commonly alternative for the production of N,N0-disubstituted and
N,N0-diprotected guanidines are the reaction of amines or ammonia
derivatives with an electrophilic guanylating reagent15 including
cyanamides,16 carboiimides,17 chloroformamidines, di(imidazole-1-
are reported recently for the synthesis of guanidines by hydro-
amination of carbodiimides with metal complex catalysts21 or co-
ordinate rare earth metalamides.22 Some of those methods, however,
could not provide the satisfactory process since the starting materials
are corrosive, toxic, and moisture sensitive. The reactions also have
drawbacks such as low yields, long reaction times, harsh reaction
conditions, and the difficulties to be work up.
Sodium bis(trimethylsilyl)amide [NaN(SiMe3)2] is a commer-
cially available strong hindered base widely used in organic syn-
thetic chemistry.23–28 It is also a good nucleophile at elevated
temperature and can be used for functional group transformation,
including the selectively mono-O-demethylation of arenes,29 the
conversion of aromatic esters30 or aldehydes31 to nitriles. In our
previous work, we also find that NaN(SiMe3)2 acts as a de-
oxygenation and desulfurization agent to convert isocyanates and
isothiocyanates to cyanamides.32,33 In this paper, we expanded the
reaction to ‘one-flask’ synthesis of guanidines hydrochloride. Re-
action of NaN(SiMe3)2 with isocyanates or isothiocyanates followed
by addition of primary or secondary amines with catalytic amount
of AlCl3 in one flask provided the corresponding guanidines in good
yields. This new reaction can be applied in the transformation of
* Corresponding authors. Tel.: þ886 4 220 53366x5603; fax: þ886 4 220 78083.
E-mail addresses: ffwong@mail.cmu.edu.tw, wongfungfuh@yahoo.com.tw
(F.F. Wong).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.003

C.-Y. Chen et al. / Tetrahedron 66 (2010) 1892–1897
1893
aliphatic, cyclohexyl, and aromatic isocyanates or isothiocyanates
and the reaction mechanism involved 1,2-elimination.34
For the use of aliphatic isocyanate 1 and 2 as the substrates, the
reaction provided the desired guanidines 11 and 12 (Chart 1) in 77%
and 76% yields, respectively, by use of aniline hydrochloride
(PhNH2$HCl, entry 1 and 2 in Table 1) as the reaction amine. For ar-
omatic isocyanates 3–10 bearing various substituents including CH3,
Br, Cl, NO2, and OCH3 at ortho or meta or para position to the iso-
cyanato group, the reaction also gave the corresponding guanidines
13–20 in good yields (53–83%, see the entries 3–10 in Table 1).
Compounds 11–20 were fully characterized by spectroscopic
methods and consistent with the literature data.18,35–39 Served as an
2. Result and discussion
Scheme 1 illustrated the typical reaction condition for the one-
flask synthesis of guanidines. The isocyanates 1–10, whose struc-
tures were shown in Table 1, reacted with 1.2 equiv of NaN(SiMe3)2
in THF at room temperature for 30–60 min. The reaction was
expected to generate the cyanamide anions (Ar–Nꢀ–C^N).32 After
the isocyanates were fully consumed, primary or secondary amines
hydrochloride were subsequently added to the reaction mixture
with a catalytic amount AlCl3 (10 mol %). The reaction was heated at
reflux for 6–12 h to give the desired guanidines hydrochloride
11–23 in solid form (see Table 1 and Chart 1).
example, compound 13 possessed
a characteristic peak at
154.12 ppm, which represented the 13C in PhNH–C(]NH)–
NHPh$HCl salt. The IR absorptions of 13 showed peaks at 1660 cmꢀ1
for the stretching of the –C]NH group and at 3263 cmꢀ1 for the
stretching of the –NH group. Results in Table 1 demonstrated that
various aliphatic and aromatic isocyanates were suitable for the one-
flask transformation.
1. NaN(SiMe3)2, THF, r.t.
NH HCl
R1 NCO
We then investigated the effect of substituents on the phenyl
ring of the amines on the reactivity of the reaction. Use of p-tolu-
idine hydrochloride, 4-(trifluoromethyl)aniline hydrochloride, and
4-benzyloxyaniline hydrochloride to react with the cyanamide
anion generated from isocyanate 3 and 2 provided the corre-
sponding guanidines 19, 21, and 22 in good yields (64–86%, see
entry 11–13 in Table 1). The yields were similar with that from the
use of simple aniline. Applying 4-methoxyphenyl isocyanate 10
under the same condition with the secondary amine dimethyl-
amine hydrochloride (see entry 14 of Table 1) also afforded gua-
nidine 23 in 57% yield.
For the investigation of Lewis acid catalyst, we chose phenyl
isocyanate 3 as the model to seek for the best reaction condition and
amount of the catalyst for the ‘one-flask’ transformation. When
compound 3 completely consumed in the reaction, the reaction
mixture was allowed to react with aniline hydrochloride with var-
ious Lewis acid catalysts,40 including aluminum chloride (AlCl3),41
boron trifluoride diethyl etherate (BF3$OEt2), ceric ammonium ni-
trate (CAN),42 palladium chloride (PdCl2), palladium acetylaceto-
nate (Pd(acac)2), hexafluoroisopropanol ((CF3)2CHOH),43 titanium
chloride (TiCl4), and tributylbrorane.44 Guanidine 13 was isolated
and the results were shown in Table 2. We found that the use of
10 mol % of aluminum chloride and ceric ammonium nitrate (CAN)
gave compound 13 in better isolated yields (70% and 62%, see the
Table 2). However, increasing the amount AlCl3 catalyst added to the
reaction from 10 to 40 mol % dramatically reduced the yield of
the product to 27% (entry 3). Using more AlCl3 would decrease the
yields of 3 (see entries 3–6 in Table 2).
In our previous research, we found isothiocyanates possess the
similar reactivity with isocyanates and can also react with NaN-
(SiMe3)2 to produce cyanamides.41 Therefore we applied the re-
action to convert isothiocyanate to guanidine (see Scheme 2). First,
the reaction was applied to t-butyl isothiocyanate 24, phenyl iso-
thiocyanate 25, and aromatic isothiocyanates 26–28 with methyl
group at the ortho, meta, para position (see entry 1–5 in Table 3).
They were treated with 1.2 equiv of NaN(SiMe3)2 followed by ani-
line hydrochloride (PhNH2$HCl) and catalytic amount AlCl3
(10 mol %). The corresponding guanidine products 13, 14, 17, 19, and
31 were also obtained in 62–86% yields.
When p-toluidine hydrochloride (p-Me–PhNH2$HCl) and cata-
lytic amount of AlCl3 reacted with phenyl isothiocyanate 25 and 1-
naphthyl isothiocyanate 29 with NaN(SiMe3)2, the reaction also
provided the corresponding guanidine 19 and 32 in 82% and 68%
yields, respectively (see the entries 6 and 7 of Table 3). Application
of the same procedure by using n-propylamine hydrochloride (n-
PrNH2$HCl) and 1,4-phenylene diamine hydrochloride for phenyl
isothiocyanate 25, 3-methylphenyl isothiocyanate 27, and
4-methoxyphenyl isothiocyanate 30 also gave the similar results
(44–84%, see the entries 8–10 of Table 3). All the desired
2. HNR2R3 HCl, AlCl3, at reflux
R1N
NR2R3
11-23
1-10
Scheme 1.
Table 1
Transformations of isocyanates to the corresponding guanidines
Entry Isocyanates R1NCO
Amine HCl Salts
Guanidinesa Yield (%)b
NCO
1
1
2
NH2Ph$HCl
11
12
77
76
2
NH2Ph$HCl
NH2Ph$HCl
NCO
3
3
4
13
14
70
71
NCO
Me
4
NH2Ph$HCl
NH2Ph$HCl
NH2Ph$HCl
NH2Ph$HCl
NCO
Cl
5
5
6
7
15
16
53
62
NCO
O2N
6
NCO
Me
7
17
18
83
66
NCO
8
8
9
NH2Ph$HCl
NH2Ph$HCl
Br
NCO
9
19
20
19
21
76
66
64
86
84
Me
NCO
NCO
10
11
12
13
10 NH2Ph$HCl
MeO
3
2
2
p-Me–PhNH2$HCl
p-CF3–PhNH2$HCl
NCO
NCO
NCO
p-PhOCH2–PhNH2$HCl 22
14
10 NHMe2$HCl
NCO
23
57
MeO
a
Compounds 11–16, 18–20, and 23 were reported previously,34–39 our spectro-
scopic data (11–14,34–37 18,38 19,37 and 2339) are consistent with those of an au-
thentic sample or published data in the literature.
b
AlCl3 (10% w/w) was used as the Lewis acid catalyst.

1894
C.-Y. Chen et al. / Tetrahedron 66 (2010) 1892–1897
NH HCl
NHPh
NH HCl
NHPh
NH HCl
NHPh
NH HCl
NHPh
N
H
N
H
N
H
N
H
Me
Me
11
12
13
14
NH HCl
NH HCl
NHPh
NH HCl
NHPh
N
H
NHPh
O2N
N
H
N
H
Cl
15
16
17
MeO
Br
Me
NH HCl
NH HCl
NHPh
NH HCl
NHPh
N
H
N
H
N
H
N
H
19
20
18
MeO
NH HCl
NH HCl
NH HCl
NMe2
N
H
N
H
CF3
N
H
N
H
CH2OPh
N
H
21
22
23
Chart 1.
Table 2
reactivity difference between isocyanates and isothiocyanates lay on
the rate for the formation of cyanamide anion 37 (R1–Nꢀ–C^N).
Based on our previous studies, the isothiocyanates are more active
than isocyanates to react with NaN(SiMe3)2 to generate cyanamides.
In this one-flask transformation, we observed the quicker
The study of Lewis Acid catalyzed transformations of phenyl isocyanate to
N,N0-diphenyl guanidine
Entry
Lewis Acid
Catalyst
N,N’-Diphenyl
Guanidine 13
Yield (%)
Amounta
(w/w %)
1
2
3
4
5
6
7
Without catalyst
d
16
70
27
21
12
<5
3
Table 3
Aluminum Chloride AlCl3
Aluminum Chloride AlCl3
Aluminum Chloride AlCl3
Aluminum Chloride AlCl3
Aluminum Chloride AlCl3
Boron Trifluoride
diethyl etherate BF3$OEt2
Ceric Ammonium
Nitrate (CAN)
Palladium Chloride PdCl2
Palladium Acetylacetonate Pd(acac)2
Hexafluoroisopropanol (CF3)2CHOH
Titanium Chloride TiCl4
Tributylborane
10%
40%
80%
120%
200%
10%
Transformations of isothiocyanates to the corresponding guanidines
Entry Isothiocyanates R1NCS
Amine HCl Salts
24 NH2Ph$HCl
Guanidinesa Yield (%)
1
31
13
74
85
NCS
8
10%
62
2
25 NH2Ph$HCl
26 NH2Ph$HCl
NCS
9
10%
10%
10%
10%
10%
14
d
Me
10
11
12
13
3
14
17
62
86
25
22
23
NCS
Me
a
4
27 NH2Ph$HCl
Based on the weight of phenyl isocyanate.
NCS
5
28 NH2Ph$HCl
19
19
77
82
Me
NCS
NCS
1. NaN(SiMe3)2, THF, r.t.
R1 NCS
NH HCl
NR2R3
2. HNR2R3 HCl, AlCl3, at reflux
R1N
6
7
25 p-Me–PhNH2$HCl
24-30
13, 14, 17, 19, 31-35
NCS
Scheme 2.
29 p-Me–PhNH2$HCl
32
68
N,N0-disubstituted guanidines 13, 14, 17, 19, and 31–35 were fully
characterized by spectroscopic methods (see Chart 2).
8
9
25 n-PrNH2$HCl
30 n-PrNH2$HCl
NCS
33
34
84
63
NCS
A plausible mechanism for the conversion of isocyanate or iso-
thiocyanate to N,N0-disubstituted guanidine hydrochloride was
depicted in Scheme 3. NaN(SiMe3)2 underwent nucleophilic addition
to 36, and the deoxygenation and desulfurization via intramolecular
1,2-elimination took place to give cyanamide anion 37 (R1–Nꢀ–
C^N) and (Me3Si)2O or (Me3Si)2S as by-products.31,32,45 When pri-
mary or secondary amine hydrochloride with catalytic amount AlCl3
were added, sequential protonation and hydroamination occurred to
provide the final N,N0-disubstituted guanidine hydrochloride 39. The
MeO
Me
H2N
NH2
HCl
10
27
35
44
NCS
a
Compounds 13–14, 19, 31, and 33 were reported previously,36–39 our spectro-
scopic data (13,36 14, 19,37 23,39 31,34 and 3334) are consistent with those of an
authentic sample or published data in the literature.
37

C.-Y. Chen et al. / Tetrahedron 66 (2010) 1892–1897
1895
NH HCl
NH(p-Me)Ph
eluent) to give the corresponding guanidine hydrochloride prod-
ucts in 53–86%.
NH HCl
NH HCl
NHPh
HN
n
NH -Pr
4.1.1. N-Isopropyl-N0-phenyl guanidine hydrochloride (11)35. White
N
H
N
H
solid; mp 126–127 ꢂC; 1H NMR (CDCl3, 300 MHz)
d 1.13 (d, 6H,
J¼6.32 Hz, 2ꢁCH3), 4.08 (m, 1H, CH), 7.06 (d, 2H, J¼7.42 Hz, ArH),
33
31
32
7.18–7.20 (m, 1H, ArH), 7.24–7.29 (m, 2H, ArH); 13C NMR (CDCl3,
75 MHz)
d 22.37, 44.45, 125.48, 127.54, 129.83, 133.94, 154.09; IR
Me
MeO
(diffuse reflectance) 3265 (m), 3092 (m), 2971 (m), 1659 (s), 1625
(s), 1588 (s), 1495 (m), 1457 (w), 1387 (w), 1324 (w), 1257 (w), 1167
(m), 1129 (m), 1050 (w), 759 (m), 694 (m) cmꢀ1; MS (ESI) m/z: 178
(MþþH).
NH HCl
NH HCl
n
NH -Pr
N
H
N
H
N
H
NH2
34
35
4.1.2. N-Cyclohexyl-N0-phenyl guanidine hydrochloride (12)18. Yellow
Chart 2.
solid; mp 190–191 ꢂC; 1H NMR (CDCl3, 300 MHz)
d 1.14–1.52 (m, 6H,
3ꢁCH2), 1.64–1.69 (m, 2H, CH2), 1.93–1.96 (m, 2H, CH2), 3.84 (m, 1H,
disappearance of the isothiocyanates than isocyanates before the
addition of amines and AlCl3 in the transformation. The reaction
proceeded faster by use of isothiocyanates as the reactants, though
no significant differences in the yields were observed between the
two substrates.
CH), 7.17 (d, 2H, J¼7.07 Hz, ArH), 7.24–7.28 (m,1H, ArH), 7.33–7.38 (m,
2H, ArH), 9.82 (br, 1H, NH); 13C NMR (CDCl3, 75 MHz)
d 24.05, 25.05,
32.59, 50.88, 125.71, 127.73, 130.07, 134.26, 154.27; IR (diffuse re-
flectance) 3263 (m), 3097 (m), 2930 (m), 2852 (w),1660 (s),1632 (s),
1589 (m),1505 (w),1494 (w),1455 (w),1361 (w),1259 (w),1128 (m),
1025 (w), 895 (w), 761 (m), 693 (s) cmꢀ1; MS (ESI) m/z: 218 (MþþH).
NH HCl
1. NaN(SiMe3)2
R1 NCX
R1N
NR2R3
39
2. HNR2R3 HCl
X = O, S
4.1.3. N,N0-Diphenyl guanidine hydrochloride (13)36. White solid;
36
mp 134–135 ꢂC; 1H NMR (DMSO-d6, 300 MHz)
d
7.22–7.31 (m, 6H,
ArH), 7.39–7.44 (m, 4H, ArH); 13C NMR (DMSO-d6, 75 MHz)
124.22, 126.51, 130.00, 136.47, 154.12; IR (diffuse reflectance) 3263
NaN(SiMe3)2
d
(w), 3099 (m), 2931 (m), 1660 (s), 1633 (s), 1494 (m), 1452 (m), 1362
(m), 1257 (m), 1130 (m), 1026 (w), 895 (w), 762 (m), 694 (s) cmꢀ1
;
Me3SiOSiMe3 or
Me3SiSSiMe3
MS (ESI) m/z: 212 (MþþH).
H or AlCl3
4.1.4. N-Phenyl-N0-o-tolyl guanidine hydrochloride (14)37. Yellow
solid; mp 131–132 ꢂC; 1H NMR (CDCl3, 300 MHz)
2.25 (s, 3H, CH3),
7.11–7.22 (m, 7H, ArH), 7.27–7.32 (m, 2H, ArH); 13C NMR (CDCl3,
75 MHz) 17.92,125.68,127.19,127.52,128.25,129.10,130.17,131.75,
131.79,133.47,135.76,155.01; IR (diffuse reflectance) 3154 (m),1631
(m), 1585 (m), 1492 (m), 1383 (s), 1231 (w), 1192 (w), 1117 (w), 824
(m), 754 (m), 695 (w), 496 (w) cmꢀ1; MS (ESI) m/z: 226 (MþþH).
H
R1
N
CN
R1
N C N
d
2
3
l
R2 3NH
R
R R NH HC
37
38
d
Scheme 3.
3. Conclusion
In conclusion, we have successfully developed a new ‘one-flask’
method for the synthesis of N,N0-disubstituted guanidine hydro-
chloride by reacting isocyanates and isothiocyanates with NaN-
(SiMe3)2 followed by addition of primary or secondary amines with
AlCl3 as the catalyst. This methodology can be applied to aliphatic
or aromatic isocyanates and isothiocyanates, and the resultant
guanidines could be obtained in good yields. A plausible mecha-
nism was proposed for the transformation through cyanamide as
the key intermediate.
4.1.5. N-Phenyl-N0-(2-chloro-phenyl) guanidine hydrochloride
(15). Yellow solid; mp 128–129 ꢂC; 1H NMR (CDCl3, 300 MHz)
d
7.04–7.09 (m, 6H, ArH), 7.18–7.21 (m, 2H, ArH), 7.25 (d, 1H,
J¼6.76 Hz, ArH), 7.44 (br s, 3H, NH); 13C NMR (CDCl3, 75 MHz)
d
124.38, 126.84, 127.56, 127.77, 128.37, 129.45, 130.19, 130.37,
132.72, 134.50, 153.96; IR (diffuse reflectance) 3147 (m), 1631 (m),
1485 (m), 1444 (m), 1372 (m), 1294 (w), 1233 (w), 1130 (w), 1063
(m), 1033 (w), 755 (m), 734 (m), 696 (m), 499 cmꢀ1; MS (ESI) m/z:
248 (Mþþ3), 246 (MþþH); Anal. Calcd for C13H13Cl2N3: C, 55.34; H,
4.64; N, 14.89. Found: C, 55.38; H, 4.67; N, 14.92.
4. Experimental section
4.1.6. N-(3-Nitro-phenyl)-N0-phenyl
(16). Yellow solid; mp 138–139 ꢂC; 1H NMR (CDCl3, 300 MHz)
5.59 (br s, 3H, NH), 6.96–7.04 (m, 3H, ArH), 7.14–7.31 (m, 4H, ArH),
7.67–7.69 (m, 1H, ArH), 7.74 (s, 1H, ArH); 13C NMR (CDCl3, 75 MHz)
117.34, 117.70, 123.05, 124.74, 129.07, 129.40, 129.88, 139.28,
145.39, 148.61, 150.80; IR (diffuse reflectance) 3456 (w), 3311 (w),
3090 (w), 2923 (w), 2852 (w), 1635 (m), 1583 (m), 1515 (s), 1444
(m), 1343 (s), 1301 (m), 1236 (m), 1077 (w), 995 (w), 889 (w), 798
(w), 737 (m), 692 (m) cmꢀ1; MS (ESI) m/z: 257 (MþþH); Anal. Calcd
for C13H13Cl N4O2: C, 53.34; H, 4.48; N, 19.14. Found: C, 53.38; H,
4.51; N, 19.10.
guanidine
hydrochloride
4.1. General procedure for the ‘one-flask’ formation of
guanidines hydrochloride from isocyanates or isothiocyanates
d
Isocyanates or isothiocyanates (1.0 mmol, 1.0 equiv) and sodium
bis(trimethylsilyl)amide (2.0 M in THF, 1.5 or 1.2 mmol, 1.2 equiv)
were added into a two-necked flask at room temperature under
nitrogen gas for 1 h. After isocyanates or isothiocyanates were
completely consumed and converted to the cyanamide anion in-
termediates, various aniline hydrochloride (2.2 mmol, 2.2 equiv)
with aluminum chloride catalyst (AlCl3, (0.1 mmol, 0.1 equiv, 10%
w/w)) was added toward the reaction mixture and heated at reflux
for 6–12 h under N2. After the reaction was completed, the reaction
mixture was filtrated, washed with CH2Cl2 (20 mLꢁ2), and con-
centrated under reduced pressure. The residue was purified by
column chromatography on silica gel (10% MeOH in CH2Cl2 as
d
4.1.7. N-Phenyl-N0-m-tolyl guanidine hydrochloride (17). Yellow
solid; mp 182–184 ꢂC; 1H NMR (CDCl3, 300 MHz)
d
2.24 (s, 3H, CH3),
6.30 (br s, 3H, NH), 6.93–7.00 (m, 3H, ArH), 7.13–7.20 (m, 4H, ArH),
7.26–7.31 (m, 2H, ArH); 13C NMR (CDCl3, 75 MHz)
21.11, 121.96,
d

1896
C.-Y. Chen et al. / Tetrahedron 66 (2010) 1892–1897
125.07, 125.68, 127.52, 128.35, 129.60, 129.81, 133.74, 133.99, 140.06,
154.31; IR (diffuse reflectance) 3270 (m), 2916 (m), 1635 (s), 1597
(s), 1577 (s), 1497 (m), 1459 (m), 1379 (s), 1307 (s), 1225 (s), 823 (m),
753 (s), 735 (m), 690 (m) cmꢀ1; MS (ESI) m/z: 226 (MþþH); HRMS
(ESI) calcd for C14H16N3 (MþHþ) 226.1344, found 226.1345.
(w), 1299 (w), 1246 (m), 1179 (w), 1108 (w), 1022 (w), 833 (w), 814
(w), 768 (w), 589 (w), 522 (w) cmꢀ1; MS (ESI) m/z: 194 (MþþH).
4.1.14. N-tert-Butyl-N0-phenyl guanidine hydrochloride (31)35. Yellow
solid; mp 101–102 ꢂC; 1H NMR (CDCl3, 300 MHz)
d
1.35 (s, 9H,
3ꢁCH3), 7.10 (d, 2H, J¼7.42 Hz, ArH), 7.21–7.24 (m, 1H, ArH), 7.28–
7.33 (m, 2H, ArH); 13C NMR (CDCl3, 75 MHz)
28.86, 52.38, 125.12,
4.1.8. N-(4-Bromo-phenyl)-N0-phenyl
(18)38. White solid; mp 175–176 ꢂC; 1H NMR (CDCl3, 300 MHz)
6.80 (br s, 1H, NH), 7.11 (d, 2H, J¼6.69 Hz, ArH), 7.22–7.35 (m, 5H,
ArH), 7.44 (d, 2H, J¼6.51. Hz, ArH), 9.84 (br s,1H, NH),10.08 (br s,1H,
NH); 13C NMR (CDCl3, 75 MHz)
120.64, 124.80, 126.21, 127.56,
guanidine
hydrochloride
d
127.42, 129.91, 134.06, 153.62; IR (diffuse reflectance) 3458 (w),
3275 (w), 3183 (m), 2975 (m), 1623 (s), 1590 (s), 1394 (s), 1304 (m),
1203 (m), 1165 (w), 1040 (w), 934 (w), 821 (w), 755 (m), 695 (s)
cmꢀ1; MS (ESI) m/z: 192 (MþþH). HRMS (ESI) calcd for C11H18N3
(MþþH) 192.1501, found 192.1502.
d
d
129.78, 132.68, 132.98, 133.54, 154.05; IR (diffuse reflectance) 3439
(m), 3164 (m), 2934 (m), 1631 (m), 1486 (m), 1382 (s), 1231 (m),
1071 (w), 1011 (w), 824 (m), 754 (w), 695 (w), 500 (w) cmꢀ1; MS
(ESI) m/z: 292 (Mþþ3), 290 (MþþH).
4.1.15. N-(
solid; mp 210–211 ꢂC; 1H NMR (DMSO-d6, 300 MHz)
CH3), 7.23–7.29 (m, 3H, ArH), 7.57–7.69 (m, 5H, ArH), 7.96–8.05 (m,
3H, ArH); 13C NMR (DMSO-d6, 75 MHz)
20.98, 122.78, 125.21,
a
-Naphthyl)-N0-p-tolyl guanidine hydrochloride (32). Yellow
2.32 (s, 3H,
d
4.1.9. N-Phenyl-N0-p-tolyl guanidine hydrochloride (19)37. Yellow
d
solid; mp 129–130 ꢂC; 1H NMR (DMSO-d6, 300 MHz)
d
2.31 (s, 3H,
CH3), 7.18–7.31 (m, 7H, ArH), 7.41–7.46 (m, 2H, ArH); 13C NMR
(DMSO-d6, 75 MHz) 20.95, 124.33, 124.65, 126.51, 129.99, 130.45,
125.50, 126.49, 127.02, 127.33, 128.43, 128.82, 129.91, 130.47, 131.87,
133.46, 134.59, 136.30, 155.41; IR (diffuse reflectance) 3130 (m),
2931 (m), 1623 (s), 1595 (s), 1573 (s), 1511 (m), 1394 (m), 1272 (w),
1252 (w), 1234 (w), 1174 (w), 1105 (w), 1018 (w), 803 (m), 785 (s),
774 (s), 749(m) cmꢀ1; MS (ESI) m/z: 276 (MþþH); HRMS (ESI) calcd
for C18H18N3 (MþþH) 276.1501, found 276.1502.
d
133.56, 136.12, 136.43, 154.32; IR (diffuse reflectance) 3273 (m),
3102 (m), 2934 (m), 1634 (s), 1576 (s), 1512 (m), 1498 (m), 1451 (m),
1381 (s), 1313 (m), 1227 (m), 1091 (w), 1041 (w), 824 (m), 748 (m),
693 (m) cmꢀ1; MS (ESI) m/z: 226 (MþþH).
4.1.16. N-Phenyl-N0-propyl guanidine hydrochloride (33)35. Yellow
4.1.10. N-(4-Methoxy-phenyl)-N0-phenyl guanidine hydrochloride
solid; mp 94–95 ꢂC; 1H NMR (CDCl3, 300 MHz)
d 0.85 (t, 3H,
(20). Yellow solid; mp 139–140 ꢂC; 1H NMR (CDCl3, 300 MHz)
d
3.65
J¼7.31 Hz, CH3), 1.46–1.58 (m, 2H, CH2), 3.15–3.21(m, 2H, CH2), 6.82
(br s, 2H, NH), 7.11 (d, 2H, J¼7.38 Hz, ArH), 7.18–7.23 (m, 1H, ArH),
7.29–7.34 (m, 2H, ArH), 9.42 (br s, 1H, NH); 13C NMR (CDCl3,
(s, 3H, OCH3), 6.76 (d, 2H, J¼8.70 Hz, ArH), 7.03 (d, 2H, J¼8.70 Hz,
ArH), 7.10 (d, 2H, J¼8.7 Hz, ArH), 7.14–7.17 (m,1H, ArH), 7.22–7.27 (m,
2H, ArH); 13C NMR (CDCl3, 75 MHz)
d
55.50, 115.20, 124.98, 126.02,
75 MHz) d 10.86, 21.72, 43.46, 125.03, 127.41, 129.88, 134.19, 154.88;
127.18, 127.73, 130.02, 133.97, 154.70, 159.19; IR (diffuse reflectance)
3153 (m), 2930 (m),1631 (m),1505 (m),1453 (w),1379 (w),1300 (w),
1247 (m),1179 (w),1109 (w),1027 (m), 828 (m), 757 (m), 696 (w), 524
(w) cmꢀ1; MS (ESI) m/z: 242 (MþþH); Anal. Calcd for C14H15N3O: C,
69.69; H, 6.27; N, 17.41. Found: C, 69.65; H, 6.30; N, 17.43.
IR (diffuse reflectance) 3422 (m), 3188 (m), 2968 (m), 2056 (m),
1632 (m), 1384 (m), 1142 (m), 1075 (w), 1042 (w), 825 (m), 757 (m),
698 (w) cmꢀ1; MS (ESI) m/z: 178 (MþþH). HRMS (ESI) calcd for
C10H16N3 (MþþH) 178.1344, found 178.1346.
4.1.17. N-(4-Methoxy-phenyl)-N0-propyl guanidine hydrochloride
4.1.11. N-Cyclohexyl-N0-4-trifluoromethylphenyl guanidine hydro-
(34). Yellow solid; mp 74–75 ꢂC; 1H NMR (CDCl3, 300 MHz)
d 0.88
chloride (21). Yellow solid; mp 131–132 ꢂC; 1H NMR (CDCl3,
(t, 3H, J¼7.32 Hz, CH3), 1.51–1.60 (m, 2H, CH2), 3.18–3.24 (m, 2H,
300 MHz) d 1.14–1.53 (m, 6H, CH2),1.62–1.68 (m, 2H, CH2),1.92–1.96
CH2), 3.75 (s, 3H, OCH3), 6.85 (d, 2H, J¼8.45 Hz, ArH), 7.07 (d, 2H,
(m, 2H, CH2), 3.87 (m, 1H, CH), 7.33 (d, 2H, J¼7.95 Hz, ArH), 7.60 (d,
J¼8.45, ArH); 13C NMR (CDCl3, 75 MHz)
d 11.03, 21.92, 43.56, 55.46,
2H, J¼7.95 Hz, ArH); 13C NMR (CDCl3, 75 MHz)
d
24.18, 24.95, 32.53,
115.18, 126.46, 127.58, 155.60, 159.09; IR (diffuse reflectance) 3285
(m), 3174 (m), 2966 (m), 2054 (m), 1632 (s), 1511 (m), 1383 (s), 1246
(s), 1180 (m), 1108 (w), 1029 (m), 825 (m), 783 (w), 715 (w), 523 (w)
cmꢀ1; MS (ESI) m/z: 208 (MþþH). HRMS (ESI) calcd for C11H18N3O
(MþþH) 208.1450, found 208.1452.
51.18, 124.66, 127.18, 129.06, 138.09, 153.84; IR (diffuse reflectance)
3273 (m), 3108 (m), 2932 (m), 1644 (s), 1633 (s), 1614 (m), 1509 (w),
1452 (w), 1386 (w), 1318 (s), 1263 (w), 1161 (m), 1114 (s), 1067 (m),
1017 (m), 837 (m), 828 (m) cmꢀ1; MS (ESI) m/z: 286 (MþþH); HRMS
(ESI) calcd for C14H19F3N3 (MþþH) 286.1531, found 286.1532.
4.1.18. N-(4-Amino-phenyl)-N0- m-tolyl guanidine hydrochloride
4.1.12. N-Cyclohexyl-N0-4-benzyloxyphenyl guanidine hydrochloride
(35). Yellow solid; mp 161–162 ꢂC; 1H NMR (DMSO-d6, 300 MHz)
(22). White solid; mp 144–145 ꢂC; 1H NMR (DMSO-d6, 300 MHz)
d
2.31 (s, 3H, CH3), 6.60 (d, 2H, J¼8.38 Hz, ArH), 6.94 (d, 2H, J¼8.38 Hz,
ArH), 7.03–7.09 (m, 3H, ArH), 7.27–7.30 (m, 1H, ArH); 13C NMR
(DMSO-d6, 75 MHz) 21.21, 114.54, 121.56, 122.90, 124.99, 127.07,
d
1.15–1.53 (m, 6H, CH2), 1.67–1.69 (m, 2H, CH2), 1.83–1.86 (m, 2H,
CH2), 3.59–3.63 (m, 1H, CH), 5.11 (s, 2H, OCH2), 7.06 (d, 2H,
d
J¼8.46 Hz, ArH), 7.15 (d, 2H, J¼8.46 Hz, ArH), 7.32–7.46 (m, 5H,
129.63,136.00,139.26,146.25,148.43,154.75; IR (diffuse reflectance)
3415 (m), 3159 (m), 2920 (m),1630 (m),1513 (m),1372 (w),1173 (w),
1092 (w), 825 (w), 695 (w), 518 (w) cmꢀ1; MS (ESI) m/z: 241 (MþþH).
HRMS (ESI) calcd for C14H17N4 (MþþH) 241.1453, found 241.1451.
ArH); 13C NMR (DMSO-d6, 75 MHz)
d 24.40, 25.25, 32.58, 50.05,
69.89, 116.07, 127.38, 128.13, 128.32, 128.49, 128.88, 137.30, 154.88,
157.35; IR (diffuse reflectance) 3272 (m), 3133 (m), 2928 (m), 2856
(m), 1659 (s), 1625 (s), 1588 (m), 1504 (s), 1452 (m), 1384 (w), 1362
(w), 1298 (w), 1244 (s), 1174 (m), 1120 (m), 1026 (m), 829 (m), 740
(m), 693 (s) cmꢀ1; MS (ESI) m/z: 324 (MþþH); HRMS (ESI) calcd for
C20H26N3O (MþþH) 324.2076, found 324.2074.
Acknowledgements
We are grateful to the China Medical University (CMU98-S-40)
and the National Science Council of Republic of China for financial
support (NSC-98-2221-E-039-003-).
4.1.13. N0-(4-Methoxy-phenyl)-N,N-dimethyl guanidine hydrochlo-
ride (23)39. Yellow solid; mp 186–187 ꢂC; 1H NMR (CDCl3,
300 MHz)
d
3.05 (s, 6H, N(CH3)2), 3.71 (s, 3H, CH3), 6.76 (d, 2H,
Supplementary data
J¼8.76 Hz, ArH), 7.02 (d, 2H, J¼8.76 Hz, ArH); 13C NMR (CDCl3,
75 MHz)
d
39.51, 55.38, 114.81, 126.92, 127.79, 155.82, 158.42; IR
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.01.003.
(diffuse reflectance) 3416 (m), 3193 (m), 1626 (m), 1513 (m), 1454

C.-Y. Chen et al. / Tetrahedron 66 (2010) 1892–1897
1897
19. (a) Patrick, C. K.; Monica, F.; John, A. F. Tetrahedron Lett. 1998, 39, 2663–2666;
(b) John, A. J.; Catherine, A. T.; Courtney, E. P. Tetrahedron Lett. 1998, 39, 5899–
5902.
20. For a recent review, see (a) Katritzky, A. R.; Rogovoy, B. V. ARKIVOC 2005, iv,
49–87 and references cited therein; (b) Ghosh, A. K.; Hol, W. G. J.; Fan, E. J. Org.
Chem. 2001, 66, 2161–2164; (c) Yu, Y.; Ostresh, J. M.; Houghten, R. A. J. Org.
Chem. 2002, 67, 3138–3141 and references cited therein.
References and notes
1. Berlinck, R. G. S. Nat. Prod. Rep. 2002, 19, 617–619.
2. Guanidines: Historical, Biological, Biochemical and Clinical Aspects of Naturally
Occurring Guanidino Compounds; Mori, A., Cohen, B. D., Lowenthal, A., Eds.;
Plenum: New York, NY, 1985.
3. Guanidines 2: Further Explorations of the Biological and Clinical Significance of
Guanidino Compounds; Mori, A., Cohen, B. D., Koide, H., Eds.; Plenum: New York,
NY, 1987.
21. For a recent review, see (a) Ong, T.-G.; Yap, G. P. A.; Richeson, D. S. J. Am. Chem.
´
D.; Pastor, A.; Galindo, A.
Soc. 2003, 125, 8100–8101; (b) Montilla, F.; del Rıo,
Organometallics 2006, 25, 4996–5002; (c) Zhang, W.-X.; Nishiura, M.; Hou, Z.
Chem.dEur. J. 2007, 13, 4037–4051; (d) Montilla, F.; Pastor, A.; Galindo, A. J.
Organomet. Chem. 2004, 689, 993–996 and references cited therein.
22. (a) Zhou, S.; Wang, S.; Yang, G. S.; Liu, X.; Sheng, E.; Zhang, K.; Cheng, L.; Huang,
Z. Polyhedron 2003, 22, 1019–1024; (b) Schuetz, S. A.; Day, V. W.; Sommer, R. D.;
Rheingold, A. L.; Belot, J. A. Inorg. Chem. 2001, 40, 5292–5295; (c) Zhou, S.;
Wang, S.; Yang, G.; Li, Q.; Zhang, L.; Yao, Z.; Zhou, Z.; Song, H.-B. Organometallics
2007, 26, 3755–3761; (d) Li, Q.; Wang, S.; Zhou, S.; Yang, G.; Zhu, X.; Liu, Y. J.
Org. Chem. 2007, 72, 6763–6767.
23. Paquette, L. A. Encyclopedia of Reagents for Organic Synthesis; Wiley: Chichester,
UK, 1995;; p 4564.
24. Chow, S.; Wen, K.; Sanghvi, Y. S.; Theodorakis, E. A. Bioorg. Med. Chem. Lett.
2003, 13, 1631–1634.
4. (a) Berlinck, R. G. S. Fortschr. Chem. Org. Naturst. 1995, 66, 119–295; (b) Lam, P. Y.
S.; Clarck, C. G.; Li, R.; Pinto, D. J. P.; Orwat, M. J.; Galemmo, R. A.; Fevig, J. M.;
Teleha, C. A.; Smallwood, A. M.; Rossi, R. A.; Wright, M. R.; Bai, S. A.; He, K.;
Luettgen, J. M.; Wong, P. C.; Knabb, R. M.; Wexler, R. R. J. Med. Chem. 2003, 46,
4405–4408; (c) Fresneda, P. M.; Delgado, S.; Francesch, A.; Manzanares, I.;
Cuevas, C.; Molina, P. J. Med. Chem. 2006, 49, 1217–1221; (d) Cole, D. C.; Manas,
E. S.; Stock, J. R.; Condon, J. S.; Jennings, L. D.; Aulabaugh, A.; Chopra, R.;
Cowling, R.; Ellingboe, J. W.; Fan, K. Y.; Harrison, B. L.; Hu, Y.; Jacobsen, S.; Jin,
G.; Lin, L.; Lovering, F. E.; Malams, M. S.; Stahl, M. L.; Strand, J.; Sukhedeo, M. N.;
Svenson, K.; Turner, M. J.; Wagner, E.; Wu, J.; Zhou, P.; Bard, J. J. Med. Chem.
2006, 49, 6158–6161.
5. (a) Cui, P.; Chen, Y. F.; Li, G. Y. Angew. Chem., Int. Ed. 2008, 47, 9944–9947.
6. Pi, C. F.; Zhang, Z. X.; Pang, Z.; Zhang, J.; Luo, J.; Chen, Z. X.; Weng, L. H.; Zhou,
X. G. Organometallics 2007, 26, 1934–1946.
7. Pi, C. F.; Liu, R. T.; Zheng, P. Z.; Chen, Z. X.; Zhou, X. G. Inorg. Chem. 2007, 46,
5252–5259.
25. Bargiggia, F.; Piva, O. Tetrahedron: Asymmetry 2003, 14, 1819–1827.
´
´
26. Perard-Viret, J.; Prange, T.; Tomas, A.; Royer, J. Tetrahedron 2002, 58, 5103–5108.
27. Fieser, F.; Fieser, L. F. Reagents for Organic Synthesis; John Wiley: New York, NY,
1974; Vol. 4; p 298.
8. Shen, Q. S.; Huang, W.; Wang, J. L.; Zhou, X. G. Organometallics 2008, 27,
301–303.
9. Jones, C.; Junk, P. C.; Platts, J. A.; Stasch, A. J. Am. Chem. Soc. 2006, 128, 2206–
2207.
28. de Parrodi, C. A.; Clara-Sosa, A.; Pe´rez, L.; Quintero, L.; Maran˜o´n, V.; Toscano, R. A.;
Avin˜a, J. A.; Rojas-Lima, S.; Juaristi, E. Tetrahedron: Asymmetry 2001, 12, 69–79.
29. Hwu, J. R.; Wong, F. F.; Huang, J.-J.; Tsay, S.-C. J. Org. Chem. 1997, 62, 4097–4104.
30. Hwu, J. R.; Hsu, C. H.; Wong, F. F.; Chung, C.-S.; Hakimelahi, G. H. Synthesis 1998,
329–332.
31. Hwu, J. R.; Wong, F. F. Eur. J. Org. Chem. 2006, 10, 2513–2516.
32. Wong, F. F.; Chen, C.-Y.; Huang, J.-J.; Yeh, M.-Y. Synlett 2006, 559–562.
33. Chen, C.-Y.; Wong, F. F.; Huang, J.-J.; Lin, S.-K.; Yeh, M.-Y. Tetrahedron Lett. 2008,
49, 6505–6507.
34. Hwu,J.R.;Das,A. R.;Yang,C.W.;Huang, J.-J.;Hsu,M. H. Org. Lett.2005, 7, 3211–3214.
35. Kiselev, L. A.; Shvetsova-Shilovskaya, K. D.; Khanina, L. N.; Mel’nikov, N. N.
J. Org. Chem. USSR 1968, 4, 459–463.
36. Tanatani, A.; Kagechika, H.; Azumaya, I.; Yamaguchi, K.; Shudo, K. Chem. Pharm.
Bull. 1996, 44, 1135–1137.
37. Joshua, C. P.; Rajasekharan, K. N. Indian J. Chem., Sect. B 1976, 14B, 967–970.
38. Partridge, M. W.; Turner, H. A. J. Pharm. Pharmacol. 1953, 5, 103–105.
39. King, H.; Tonkin, I. M. J. Chem. Soc. 1946, 1063–1069.
40. Cunha, S.; Rodrigues, M. T., Jr. Tetrahedron Lett. 2006, 47, 6955–6956.
41. (a) Koketsu, M.; Fukuta, Y.; Ishihara, H. Tetrahedron Lett. 2001, 42, 6333–6335;
(b) Garigipati, R. S. Tetrahedron Lett. 1990, 33, 1969–1972.
42. Varala, R.; Sreelatha, N.; Adapa, S. R. Synlett 2006, 1549–1553.
43. Snider, B. B.; O’Hare, S. M. Tetrahedron Lett. 2001, 42, 2455–2458.
44. Hshen, H.; Xie, Z. J. Organomet. Chem. 2009, 694, 1652–1657.
45. Wang, C.; Song, Q.; Xi, Z. Tetrahedron 2004, 60, 5207–5214.
10. Rowley, C. N.; DiLabio, G. A.; Barry, S. T. Inorg. Chem. 2005, 44, 1983–1991.
´
11. Carmalt, C. J.; Newport, A. C.; Oneill, S. A.; Parkin, I. P.; White, D. J. P.; Williams,
D. J. Inorg. Chem. 2005, 44, 615–619.
12. Linton, B. R.; Carr, A. J.; Orner, B. P.; Hamilton, A. D. J. Org. Chem. 2000, 65, 1566–
1568.
13. Nathaniel, I. M.; Joshua, J. W.; Michael, A. M. Org. Lett. 2006, 8, 4035–4038.
14. (a) Braun, C. E. J. Am. Chem. Soc. 1933, 55, 1280–1284; (b) McKay, A. F.; Hatton,
W. G.; Braun, R. O. J. Am. Chem. Soc. 1956, 78, 6144–6147; (c) Brand, E.; Brand, F.
C. Collect. In Organic Syntheses; Wiley: New York, NY, 1955; Vol. 111, p 440; (d)
Jen, T.; Van Hoeven, H.; Groves, W.; McLean, R. A.; Loev, B. J. Med. Chem. 1975,
18, 90–99; (e) The Organic Chemistry of Drug Synthesis; Lednicer, D., Mitacher, L.
A., Eds.; John Wiley and Sons: New York, NY, 1980; Vol. I; 1977, and Vol. II.
15. Maryanoff, C. A.; Stanzione, R. C.; Plampin, J. N.; Mills, J. E. J. Org. Chem. 1986, 51,
1882–1884.
16. (a) Hu, L. Y.; Guo, J.; Magar, S. S.; Fischer, J. B.; Burke-Howie, K. J.; Durant, G. J.
J. Med. Chem. 1997, 40, 4281–4289; (b) Reddy, N. L.; Hu, L.-Y.; Cotter, R. E.;
Fischer, J. B.; Wong, W. J.; McBurney, R. N.; Weber, E.; Holmes, D. L.; Wong, S.
T.; Prasad, R.; Keana, J. F. W. J. Med. Chem. 1994, 37, 260–267.
17. David, H. D.; Samuel, W. G.; James, A. L. Tetrahedron Lett. 1997, 38, 3377–3380.
18. Wu, Y.-Q.; Hamilton, S. K.; Wilkinson, D. E.; Hamilton, G. S. J. Org. Chem. 2002,
67, 7553–7556.