One-Pot Synthesis of C2 Symmetric and Asymmetric N,N′,N″-Substituted Guanidines from Aryl Isothiocyanates and Amines

Article abstract of DOI:10.1055/s-0035-1561201

Highly substituted guanidines were conveniently prepared through a one-pot reaction between aryl isothiocyanates and amines mediated by the Ph₃P-I₂/Et₃N system. The C ₂-symmetric N,N′,N″-substituted guanidines were readily accessed using a 1:2 molar ratio of an aryl isothiocyanate and an amine; while sequential addition of two different amines in equimolar ratios gave rise to asymmetric derivatives. Both primary and secondary amines were found to react preferentially with electron-deficient aryl isothiocyanates, rapidly providing guanidines in good yields under mild conditions.

Full text of DOI:10.1055/s-0035-1561201

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© Georg Thieme Verlag Stuttgart · New York
2015, 27, A–G
letter
A
S. Wangngae et al.
Letter
Synlett
One-Pot Synthesis of C2 Symmetric and Asymmetric N,N′,N′′-Sub-
stituted Guanidines from Aryl Isothiocyanates and Amines
Sirilak Wangngae
R1
N
R1
N
N
C
S
H
N
H
N
Mookda Pattarawarapan
Wong Phakhodee*
R1R2NH
R1R2NH
R2
Ar
R2
Ar
Ph3P, I2
Ph3P, I2
Et3N, CH2Cl2
Z
N
N
R1
R2
R3
R4
Et3N, CH2Cl2
then R3R4NH
Department of Chemistry and Center of Excellence for Inno-
vation in Chemistry, Faculty of Science, Chiang Mai University,
Chiang Mai 50200, Thailand
9 examples
(52–89%)
15 examples
(46–98%)
R1, R2, R3, R4 = H, alkyl or aryl
Z = NO2, CF3, F, Cl, H, Me
wongp2577@gmail.com
Received: 05.11.2015
Accepted after revision: 06.12.2015
Published online: 05.01.2016
diethyl azodicarboxylate,6 or bromine7 have previously
been reported for the preparation of carbodiimides from
N,N′-disubstituted ureas or thioureas; to the best of our
knowledge, only one study has performed a stepwise gua-
nylation of amines with resin-bound thioureas using Ph3P–
hexachloroethane as a dehydrosulfurizing agent.
In this study, we aimed to use an aryl isothiocyanate
as a precursor since it would allow easy access to both
C2-symmetric and asymmetric N,N′,N′′-substituted guan-
idines through controlling the nature and amount of the
amine counterparts. Additionally, numerous isothiocyanate
derivatives are commercially available or can be readily pre-
pared from amines or aldoxime precursors.8
DOI: 10.1055/s-0035-1561201; Art ID: st-2015-d0871-l
Abstract Highly substituted guanidines were conveniently prepared
through a one-pot reaction between aryl isothiocyanates and amines
mediated by the Ph3P–I2/Et3N system. The C2-symmetric N,N′,N′′-sub-
stituted guanidines were readily accessed using a 1:2 molar ratio of an
aryl isothiocyanate and an amine; while sequential addition of two dif-
ferent amines in equimolar ratios gave rise to asymmetric derivatives.
Both primary and secondary amines were found to react preferentially
with electron-deficient aryl isothiocyanates, rapidly providing guani-
dines in good yields under mild conditions.
Key words condensation, desulfurization, guanidine, isothiocyanate
It was envisaged that a thiourea generated in situ from
the reaction of an aryl isothiocyanate with an amine would
react with the preformed triphenylphosphine–diiodide in
the presence of base leading to the formation of pentacoor-
dinate phosphorous species I. Based on the reported litera-
ture,4b,9 the corresponding carbodiimide II should be readi-
Substituted guanidines are an important class of com-
pounds that exhibit widespread applications in the fields of
medicinal chemistry, supramolecular chemistry, sensors,
and catalysis.1 In particular, N,N′-dialkyl guanidine deriva-
tives have been widely used as ligands for the construction
of a variety of organometallic catalysts.2 As more complex
structures are necessary to achieve desired properties, a
new method that allows an easy access to highly substitut-
ed guanidines under mild conditions is of great interest.
The classical approaches to guanidines involve nucleo-
philic addition of an amine with electrophilic guanylating
reagents.3 Among the available methods, the reaction of an
amine with carbodiimides commonly generated in a sepa-
rate step via dehydrosulfurization of thioureas or dehydra-
tion of ureas provides a relatively simple route to a range of
highly substituted guanidine derivatives.
S
Ph3P, I2
Ar
R1
Ar
N
C
S
R1R2NH
+
N
N
R2
H
Et3N
I
NR1R2
– Ph3P=S
R3R4NH
Ar
R1
Ph3P
Ar
when R2 = H
N
C
II
N
R1
N
S
R4
N
Ar
N
N
I
R2
R3
NR1R2
or
I–
R3R4NH
In a continuation of our study into reactions promoted
by the triphenylphosphine–iodine combination, we were
interested in replacing the traditional promoters used for
the guanylation of thioureas with this Ph3P–I2 system. Al-
though similar reagent combinations using Ph3P with addi-
tives such as carbon tetrachloride,4 carbon tetrabromide,5
– Ph3P=S
when R2 ≠ H
+
Ar
N C
NR1R2
I
N
Ar
III
IV
Scheme 1 Proposed mechanism for the Ph3P–I2-mediated guanylation
of amines
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 27, A–G

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S. Wangngae et al.
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Synlett
ArNCS 1;
NCS
NCS
NCS
NCS
NCS
NCS
O2N
F3C
Cl
F
1a
1b
1c
1d
1e
1f
Amine 2;
NH2
NH2
NH2
NH
NH2
NH2
N
O
H
MeO
2g
2a
2b
2c
2d
2e
2f
Figure 1 Structures of aryl isothiocyanates and amines used in the guanylation reaction
ly generated when R2 = H, while carbimidoyl iodide III or
the equivalent carbodiimide salt IV could be the key inter-
mediate formed when R2 ≠ H.10 In either case, thermody-
namically favorable triphenylphosphine sulfide is released
as a key driving force for the reaction. Subsequent reaction
of the formed intermediates with an amine then furnishes
the guanidine in one-pot (Scheme 1).
In our preliminary investigation, commercially available
4-nitrophenyl isothiocyanate (1a, 1 equiv) was reacted with
benzylamine (2a, 2 equiv) using Ph3P (1.2 equiv) and iodine
(1.2 equiv) in dichloromethane at room temperature. It was
found that, in the presence of triethylamine (5 equiv), the
corresponding guanidine 3a was obtained in 90% yield
within 10 minutes (Table 1, entry 1). It is noted that excess
base was used for deprotonation of the two protons of the
in situ generated thiourea as well as keeping the reaction
under basic conditions to enhance the reaction rate. Chang-
ing the base to diisopropylethylamine led to low product
yield (Table 1, entry 2); while other weak organic and inor-
ganic bases gave no conversion (Table 1, entries 3–5), possi-
bly due to their inability to abstract weakly acidic protons
attached to the nitrogen atoms of thiourea. A similar result
was also obtained in the absence of the base (Table 1, entry
6). Switching the reaction medium from dichloromethane
to other solvents also decreased the product yield, probably
resulting from solubility problems of the reactants as well
as instability of the formed carbodiimide intermediate.
To evaluate the scope and limitations of the Ph3P–I2 sys-
tem, a series of C2-symmetrical substituted guanidines was
synthesized using various aryl isothiocyanates and amines
(Figure 1) under the optimized reaction conditions.11 As
shown in Table 2, the yields and reaction times were varied
depending on the nucleophilicity of the amine nucleophiles
and electronic nature of aryl isothiocyanates. For electron-
deficient isothiocyanates, the substrate containing the NO2
group reacted readily with both primary and secondary al-
kylamines to provide the products in high yields (Table 2,
entries 1–5). The reaction with an aromatic amine contain-
ing the electron-donating OMe group (2f) also proceeded
without difficulty (Table 2, entry 6). However, the reaction
did not proceed with the weakly nucleophilic 4-nitroani-
line (data not shown). Addition of DMAP (10 mol%) also did
not lead to the product. Nevertheless, we noticed that the
formed thiourea was not soluble in the reaction media.
Thus, this could be the reason for lack of conversion. Hence,
no further reaction with this amine was attempted.
Table 1 Optimization of Reaction Conditionsa
NCS
O2N
1a
H
Ph3P, I2
N
N
+
base, solvent
HN
NH2
O2N
3a
2a (2 equiv)
Entry
Base
Et3N
Solvent
Yield (%)
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
90
71
0
i-Pr2NEt
pyridine
imidazole
K2CO3
none
0
0
0
Other aryl isothiocyanates containing electron-with-
drawing groups such as F, Cl, CF3 were also found to react
smoothly with aliphatic amines to give high yields of the
products; although long reaction times were required, es-
pecially with the more hindered isopropylamine (Table 2,
entries 7–13).
Et3N
toluene
THF
55
78
Et3N
a Reaction conditions: 4-nitrophenyl isothiocyanate (1a, 0.28 mmol), ben-
zylamine (2a, 0.56 mmol), Ph3P (0.33 mmol), I2 (0.33 mmol), and base (1.4
mmol), solvent (2 mL), 0 °C to r.t. for 15 min.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 27, A–G

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Table 2 One-Pot Synthesis of C2-Symmetric N,N′,N′′-Trisubstituted Guanidinesa
R1
N
H
N
Ph3P, I2
R2
ArNCS
+
R1R2NH
Ar
Et3N, CH2Cl2
1
2 (2 equiv)
N
R1
R2
3
Entry
1
2
Time (min)
Yield (%)
H
N
N
HN
O2N
1
1a
2a
15
3a 90
H
N
N
2
1a
2b
15
HN
O2N
3b 98
H
N
N
N
3
4
1a
1a
2c
20
15
HN
HN
O2N
3c 96
H
N
2d
O2N
3d 89
O
N
N
5
1a
2e
15
N
O
O2N
3e 85
OMe
H
N
6
1a
2f
30
N
HN
O2N
OMe
3f 94
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S. Wangngae et al.
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Table 2 (continued)
Entry
1
2
Time (min)
Yield (%)
H
N
N
HN
F3C
7
1b
2a
45
3g 80
O
N
N
8
1b
2e
30
N
O
F3C
3h 77
H
N
N
9
10
11
1c
1c
1d
2b
2d
2b
60
75
60
HN
F
3i 65
H
N
N
HN
F
3j 75
H
N
N
HN
Cl
3k 87
H
N
N
N
12
1d
2d
45
HN
Cl
3l 76
O
N
13
1d
2e
75
N
O
Cl
3m 76
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 27, A–G

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S. Wangngae et al.
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Table 2 (continued)
Entry
1
2
Time (min)
Yield (%)
H
N
N
14
1e
2b
3 h
HN
3n 68
H
N
N
15
1f
2b
3 h
HN
3o 46
a Reaction conditions: aryl isothiocyanate (0.28 mmol), amine (0.56 mmol), Ph3P (0.33 mmol), I2 (0.33 mmol) and Et3N (1.4 mmol), CH2Cl2 (2 mL), 0 °C to r.t.
Using phenyl isothiocyanate 1e and the electron-rich
system 1f, reaction with cyclohexylamine was sluggish and
gave low conversions (Table 2, entries 14 and 15). Evidently,
the electron-donating substituent on the aromatic ring of
the aryl isothiocyanate causes the intermediates to be more
electron-rich and, as a result, nucleophilic attack by an
amine is less favorable.
It should be noted that N,N′-dialkylsubstituted guani-
dines are often synthesized from the reaction of amines
with 1,3-dialkylcarbodiimides through metal-catalyzed re-
actions.12 The methods generally require expensive cata-
lysts, harsh reaction conditions, and/or long reaction times.
Our protocol provides an alternative route to these types of
guanidines using inexpensive reagents under mild condi-
tions.
nyl isothiocyanate with various amines proceeded smooth-
ly to give the respective guanidines in high yields even with
the steric hindered diisopropylamine (2g, Table 3, entries
1–7). Again, the reaction was less effective with electron-
rich isothiocyanate substrates leading to the guanidine
products in moderate yields with some carbodiimide re-
maining. It is important to note that when N-cyclohexyl-N-
phenylcarbodiimide or N-cyclohexyl-N-(p-tolyl)carbodiim-
ide were prepared in a separate step before treatment with
morpholine, no guanylation reaction was observed after 16
hours. This observation suggested that, instead of the well-
known carbodiimide, other highly reactive intermediate(s)
such as carboimidoyl iodide could be involved in the Ph3P–
I2 mediated guanylation reaction with the in situ generated
N,N′-disubstituted thioureas.
In the synthesis of asymmetrically N,N′,N′′-substituted
guanidines, the above guanylation procedure was repeated,
with the modification that two different amines were add-
ed sequentially in the one-pot procedure.11 Addition of the
first amine to an aryl isothiocyanate at 1:1 molar ratio pro-
vided a substituted thiourea. After treatment with the
Ph3P–I2 combination in the presence of triethylamine, the
second amine (1 equiv) was added to the mixture, that was
allowed to stir until the reaction was complete (15–60
min).
In summary, we have reported a convenient one-pot
procedure for the synthesis of both symmetrically and
asymmetrically substituted guanidines directly from aryl
isothiocyanates and amines. With the Ph3P–I2/Et3N system,
electron-withdrawing substituents on the isothiocyanates
accelerate the reaction; whereas less reactive electron-rich
derivatives require longer times for reaction completion.
Both primary and secondary amines could be guanylated in
satisfactory yields under mild conditions. An investigation
into the mechanism underlying the guanylation process is
ongoing and will be reported shortly.
As shown in Table 3, isolation of the formed thiourea
prior to guanylation with the second amine was unneces-
sary since the reaction of the electron-deficient 4-nitrophe-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 27, A–G

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Table 3 (continued)
Entry
R1R2NH R3R4NH Yield (%)
Table 3 One-Pot Synthesis of Asymmetric N,N′,N′′-Trisubstituted
Guanidinesa
1
R1
O
H
i) Ph3P, I2,
N
N
N
N
Et3N, CH2Cl2
Ar
R2
ArNCS
+
R1R2NH
N
7
1a
2e
2b
ii) R3R4NH
R3
R4
HN
1
O2N
3
R1R2NH R3R4NH Yield (%)
3v 85
Entry
1
H
N
N
H
N
N
N
O
8
9
1e
2b
2b
2e
2e
1
1a
2a
2b
HN
O2N
3w 52
3p 84
H
N
N
H
N
N
O
N
N
1f
2
3
1a
1a
2a
2a
2c
HN
O2N
3q 89
3x 55
a Reaction conditions: aryl isothiocyanate (0.28 mmol), R1R2NH (0.28
mmol), Ph3P (0.33 mmol), I2 (0.33 mmol), and Et3N (1.4 mmol), CH2Cl2 (2
mL), 0 °C to r.t., then R3R4NH (0.28 mmol).
H
N
2d
HN
O2N
3r 83
Acknowledgment
Financial support from the Thailand Research Fund through the Royal
Golden Jubilee Ph.D. Program to S.W. (Grant No. PHD/0206/2556) as
well as the Center of Excellence for Innovation in Chemistry (PERCH-
CIC), Chiang Mai University, Thailand are gratefully acknowledged.
H
N
N
4
1a
2a
2e
N
O
O2N
Supporting Information
3s 85
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561201.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
N
NH
5
1a
2a
2g
N
O2N
References and Notes
3t 87
(1) (a) Berlinck, R. G. S.; Burtoloso, A. C. B.; Trindade-Silva, A. E.;
Romminger, S.; Morais, R. P.; Bandeira, K.; Mizuno, C. M. Nat.
Prod. Rep. 2010, 27, 1871. (b) Ishikawa, T. Chem. Pharm. Bull.
2010, 58, 1555. (c) Leow, D.; Tan, C.-H. Chem. Asian J. 2009, 4,
488. (d) Selig, P. Synthesis 2013, 45, 703.
H
N
N
(2) (a) Boerner, J.; dos Santos Vieira, I.; Jones, M. D.; Doering, A.;
Kuckling, D.; Floerke, U.; Herres-Pawlis, S. Eur. J. Inorg. Chem.
2011, 4441. (b) Viehmann, P.; Hecht, S. Beilstein J. Org. Chem.
2012, 8, 1825. (c) Raab, V.; Harms, K.; Sundermeyer, J.;
Kovacevic, B.; Maksic, Z. B. J. Org. Chem. 2003, 68, 8790.
(d) Herres-Pawlis, S.; Floerke, U.; Henkel, G. Eur. J. Inorg. Chem.
2005, 3815. (e) Herres-Pawlis, S.; Neuba, A.; Seewald, O.;
Seshadri, T.; Egold, H.; Floerke, U.; Henkel, G. Eur. J. Org. Chem.
2005, 4879. (f) Herres-Pawlis, S.; Seshadri, T.; Florke, U.; Henkel,
G. Z. Anorg. Allg. Chem. 2009, 635, 1209. (g) Hoffmann, A.;
Boerner, J.; Floerke, U.; Herres-Pawlis, S. Inorg. Chim. Acta 2009,
362, 1185. (h) Maronna, A.; Bindewald, E.; Kaifer, E.; Wadepohl,
6
1a
2b
2f
HN
O2N
OMe
3u 79
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 27, A–G

G
S. Wangngae et al.
Letter
Synlett
H.; Himmel, H.-J. Eur. J. Inorg. Chem. 2011, 1302. (i) Reinmuth,
M.; Neuhaeuser, C.; Walter, P.; Enders, M.; Kaifer, E.; Himmel,
H.-J. Eur. J. Inorg. Chem. 2011, 83.
N-(Dimorpholinomethylene)-4-nitroaniline (3e, Table
Entry 5)
2
Yellow solid (0.0761 g, 85%); mp 158–159 °C; Rf = 0.38 (EtOAc).
FTIR (neat): νmax = 2965, 2854, 1547, 1321, 1265, 1111 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 8.0 Hz, 2 H), 6.76 (d, J =
8.0 Hz, 2 H), 3.66 (s, 8 H), 3.16 (s, 8 H). 13C NMR (100 MHz,
CDCl3): δ = 157.0, 150.9, 141.4, 125.3, 121.4, 66.3, 49.2.
(3) (a) Katritzky, A. R.; Rogovoy, B. V. ARKIVOC 2005, 49. (b) Kumar,
S.; Singh, U.; Singh, L. Orient. J. Chem. 2007, 23, 541. (c) Alonso-
Moreno, C.; Antinolo, A.; Carrillo-Hermosilla, F.; Otero, A. Chem.
Soc. Rev. 2014, 43, 3406.
(4) (a) Appel, R.; Kleinstueck, R.; Ziehn, K. D. Chem. Ber. 1971, 104,
1335. (b) Lukyanenko, N. G.; Kirichenko, T. I.; Limich, V. V. Syn-
thesis 1986, 928. (c) Taschner M. J.; Triphenylphosphine–Carbon
Tetrachloride, In e-EROS Encyclopedia of Reagents for Organic
Synthesis [Online]; Wiley & Sons, Posted April 15, 2001.
(5) (a) Han, M.; Hahn, H.-G. Bull. Korean Chem. Soc. 2012, 33, 1371.
(b) Aburano, D.; Yoshida, T.; Miyakoshi, N.; Mukai, C. J. Org.
Chem. 2007, 72, 6878. (c) Bayram, M.; Blaeser, D.; Woelper, C.;
Schulz, S. Organometallics 2014, 33, 2080. (d) Yu, R. T.; Rovis, T.
J. Am. Chem. Soc. 2008, 130, 3262.
(6) Mitsunobu, O.; Kato, K.; Tomari, M. Tetrahedron 1970, 26, 5731.
(7) (a) Palomo, C.; Mestres, R. Synthesis 1981, 373. (b) Palomo, C.;
Mestres, R. Bull. Soc. Chim. Fr. 1981, 361. (c) Lee, J. Y.; Park, S. J.;
Park, S. J.; Lee, M. J.; Rhim, H.; Seo, S. H.; Kim, K.-S. Bioorg. Med.
Chem. Lett. 2006, 16, 5014. (d) Lee, Y. S.; Lee, B. H.; Park, S. J.;
Kang, S. B.; Rhim, H.; Park, J.-Y.; Lee, J.-H.; Jeong, S.-W.; Lee, J. Y.
Bioorg. Med. Chem. Lett. 2004, 14, 3379. (e) Kennemur, J. G.;
Clark, J. B.; Tian, G.; Novak, B. M. Macromolecules 2010, 43, 1867.
(f) Heo, J. H.; Seo, H. N.; Choe, Y. J.; Kim, S.; Oh, C. R.; Kim, Y. D.;
Rhim, H.; Choo, D. J.; Kim, J.; Lee, J. Y. Bioorg. Med. Chem. Lett.
2008, 18, 3899.
(8) (a) Sakai, S.; Fujinami, T.; Aizawa, T. Bull. Chem. Soc. Jpn. 1975,
48, 2981. (b) Kim, J. N.; Jung, K. S.; Lee, H. J.; Son, J. S. Tetrahe-
dron Lett. 1997, 38, 1597. (c) Li, Z.; Qian, X.; Liu, Z.; Li, Z.; Song,
G. Org. Prep. Proced. Int. 2000, 32, 571. (d) Wong, R.; Dolman, S.
J. J. Org. Chem. 2007, 72, 3969. (e) Kaboudin, B.; Jafari, E. Synthe-
sis 2008, 2683. (f) Munch, H.; Hansen, J. S.; Pittelkow, M.;
Christensen, J. B.; Boas, U. Tetrahedron Lett. 2008, 49, 3117.
(g) Sun, N.; Li, B.; Shao, J.; Mo, W.; Hu, B.; Shen, Z.; Hu, X. Beil-
stein J. Org. Chem. 2012, 8, 61. (h) Zhang, Z.; Wu, H.-H.; Tan, Y.-J.
RSC Adv. 2013, 3, 16940.
1,3-Dibenzyl-2-[4-(trifluoromethyl)phenyl]guanidine
Table 2, Entry 7)
(3g,
Colorless oil (0.0859 g, 80%). Rf = 0.36 (30% EtOAc–hexane). FTIR
(neat): νmax = 3426, 3289, 3031, 2922, 2871, 1632, 1596, 1323,
1
1164 cm–1. H NMR (400 MHz, CDCl3): δ = 7.52 (d, J = 8.4 Hz, 2
H), 7.35–7.26 (m, 6 H), 7.24–7.22 (m, 4 H), 7.01 (d, J = 8.4 Hz, 2
H), 4.36 (s, 4 H). 13C NMR (100 MHz, CDCl3): δ = 153.3, 151.1,
138.4, 128.8, 128.6, 127.6, 127.2, 126.6 (q, J = 14.8 Hz), 123.5,
46.0.
1-Benzyl-3-cyclohexyl-2-(4-nitrophenyl)guanidine
Table 3, Entry 1)
Yellow solid (0.0828 g, 84%); mp 109–110 °C. Rf = 0.33 (30%
EtOAc–hexane). FTIR (neat): νmax = 3393, 3275, 2931, 2854,
1617, 1572, 1451, 1307, 1108 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 8.08 (d, J = 8.8 Hz, 2 H), 7.38–7.28 (m, 5 H), 6.95 (d, J = 8.8 Hz,
2 H), 4.39 (s, 2 H), 3.41–3.36 (m, 1 H), 1.92–1.88 (m, 2 H), 1.65–
1.61 (m, 2 H), 1.57–1.53 (m, 1 H), 1.32–1.22 (m, 2 H), 1.17–1.06
(m, 3 H). 13C NMR (100 MHz, CDCl3): δ = 156.4, 151.6, 141.4,
138.0, 128.9, 127.8, 127.4, 125.5, 122.6, 50.7, 46.3, 33.4, 25.4,
24.6.
(3p,
1-Benzyl-3-butyl-2-(4-nitrophenyl)guanidine (3q, Table 3,
Entry 2)
Yellow oil (0.0813 g, 89%). Rf = 0.30 (30% EtOAc–hexanes). FTIR
(neat): νmax = 3417, 3298, 2957, 2930, 2871, 1571, 1493, 1306,
1
1107 cm–1. H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 8.8 Hz, 2
H), 7.38–7.29 (m, 5 H), 6.97 (d, J = 8.8 Hz, 2 H), 4.42 (s, 2 H), 3.14
(t, J = 7.2 Hz, 2 H), 1.50–1.43 (m, 2 H), 1.30–1.22 (m, 2 H), 0.87
(t, J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 156.4, 152.1,
141.6, 138.0, 129.0, 127.9, 127.4, 125.5, 122.8, 46.2, 42.0, 31.6,
19.9, 13.7.
N-Cyclohexyl-N′-phenylmorpholine-4-carboximidamide
(3w, Table 3 Entry 8)
(9) Kilburn, J. P.; Lau, J.; Jones, R. C. F. Tetrahedron 2002, 58, 1739.
(10) Yavari, I.; Khalili, G.; Mirzaei, A. Helv. Chim. Acta 2010, 93, 72.
(11) General Procedure
Colorless oil (0.0418 g, 52% yield). Rf = 0.25 (40% EtOAc–hex-
anes). FTIR (neat): νmax = 3374, 2928, 2853, 1620, 1588, 1116
cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.26 (t, J = 7.6 Hz, 2 H), 6.99
(t, J = 7.6 Hz, 1 H), 6.83 (d, J = 7.6 Hz, 2 H), 3.71 (t, J = 4.8 Hz, 4 H),
3.22 (t, J = 4.8 Hz, 4 H), 3.11–3.04 (m, 1 H), 1.88–1.84 (m, 2 H),
1.68–1.62 (m, 2 H), 1.57–1.53 (m, 1 H), 1.27–1.16 (m, 2 H),
1.10–1.01 (m, 3 H). 13C NMR (100 MHz, CDCl3): δ = 156.2, 147.2,
129.3, 122.5, 66.6, 53.8, 48.6, 33.8, 25.3, 25.2.
Amine (0.56 mmol) and Et3N (1.4 mmol) were added to a solu-
tion of aryl isothiocyanate (0.28 mmol) in CH2Cl2 (2 mL). After
stirring at r.t. for 10 min, the mixture was cooled to 0 °C, then
Ph3P (0.33 mmol) and iodine (0.33 mmol) were added in one
portion. The reaction mixture was stirred at r.t. until reaction
completion as indicated by TLC. The reaction mixture was
washed with H2O, and the combined organic layers were dried
over anhydrous Na2SO4 before filtering and concentrating in
vacuo. The residue was purified by flash column chromatogra-
phy to give the product. All products were identified by NMR
spectroscopic and mass spectrometric analysis. In the synthesis
of asymmetrically substituted guanidines, the amount of the
first amine added to aryl isothiocyanate was reduced to 0.28
mmol, while the second amine (0.28 mmol) was added after
treatment with Ph3P–I2 when the formed thiourea has com-
pletely disappeared (ca. 5–10 min).
(12) (a) Shen, H.; Chan, H.-S.; Xie, Z. Organometallics 2006, 25, 5515.
(b) Li, Q.; Wang, S.; Zhou, S.; Yang, G.; Zhu, X.; Liu, Y. J. Org.
Chem. 2007, 72, 6763. (c) Du, Z.; Li, W.; Zhu, X.; Xu, F.; Shen, Q. J.
Org. Chem. 2008, 73, 8966. (d) Li, D.; Guang, J.; Zhang, W.-X.;
Wang, Y.; Xi, Z. Org. Biomol. Chem. 2010, 8, 1816. (e) Zhang, X.;
Wang, C.; Qian, C.; Han, F.; Xu, F.; Shen, Q. Tetrahedron 2011, 67,
8790. (f) Li, Z.; Xue, M.; Yao, H.; Sun, H.; Zhang, Y.; Shen, Q. J.
Organomet. Chem. 2012, 713, 27. (g) Pottabathula, S.; Royo, B.
Tetrahedron Lett. 2012, 53, 5156. (h) Mannepalli, L. K.; Dupati,
V.; Vallabha, S. J.; Sunkara, V. M. J. Chem. Sci. 2013, 125, 1339.
(i) Wei, Y.; Wang, S.; Zhou, S.; Feng, Z.; Guo, L.; Zhu, X.; Mu, X.;
Yao, F. Organometallics 2015, 34, 1882.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 27, A–G