Synthesis of symmetrical and unsymmetrical N, N ′-diaryl guanidines via copper/N-methylglycine-catalyzed arylation of guanidine nitrate

Article abstract of DOI:10.1021/jo300840x

CuI/N-methylglycine-catalyzed coupling reaction of guanidine nitrate with both aryl iodides and bromides takes place at 70-100 °C, affording symmetrical N,N′-diaryl guanidines with good to excellent yields. Unsymmetrical N,N′-diaryl guanidines can be assembled via monoarylation of guanidine nitrate with aryl iodides bearing a strong electron-withdrawing group and subsequent coupling with another aryl iodide.

Full text of DOI:10.1021/jo300840x

Note
pubs.acs.org/joc
Synthesis of Symmetrical and Unsymmetrical N,N′-Diaryl Guanidines
via Copper/N-Methylglycine-Catalyzed Arylation of Guanidine
Nitrate
Hui Xing,† Ye Zhang,† Yisheng Lai,*,† Yongwen Jiang,‡ and Dawei Ma*,‡
†State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
‡State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: CuI/N-methylglycine-catalyzed coupling reaction of guani-
dine nitrate with both aryl iodides and bromides takes place at 70−100 °C,
affording symmetrical N,N′-diaryl guanidines with good to excellent yields.
Unsymmetrical N,N′-diaryl guanidines can be assembled via monoarylation
of guanidine nitrate with aryl iodides bearing a strong electron-withdrawing
group and subsequent coupling with another aryl iodide.
n the past decade, great attention has been directed to
ligand-promoted Ullmann-type coupling reactions.1 These
N,N-dimethylglycine gave a decreased yield (Table 1, entry 2).
Similar results were observed in case of picolinic acid, 2-
methylquinolin-8-ol, and 2,2′-bipyridine as the ligands (Table 1,
entries 4−6). However, the best result was obtained when N-
methylglycine was employed (Table 1, entry 3). The
modification to the bases and solvents indicated that the best
combination was K3PO4 and acetonitrile (Table 1, entries 7−
11). Switching Cu(I) salts from CuI to CuBr, CuCl, and Cu2O
gave inferior results (Table 1, entries 12−14). Further
investigations revealed that there was no obvious loss in yield
when catalyst loading was reduced to 5 mol % (Table 1, entry
15). At 5 mol % catalyst loading, reaction could complete even
at 70 °C (Table 1, entry 16) but gave a decreased yield at 60 °C
(Table 1, entry 17). Taken together, we concluded that the
optimized conditions were using 5 mol % CuI and 10 mol % N-
methylglycine as the catalyst, K3PO4 as the base, acetonitrile as
the solvent, and carrying out the reaction at 70 °C.
The established optimized reaction conditions were then
examined by varying aryl halides. As summarized in Table 2,
besides electron-rich aryl iodides (Table 2, entries 2−4),
electron deficient aryl iodides were found to be applicable
(Table 2, entries 5−8). A good yield were observed when
relatively bulky 2-methyl iodobenzene was used, thereby giving
a facile method for preparing the σ-receptor ligand N,N′-di-o-
toylguanidine (DTG, 3e).8 Under the same reaction conditions,
poor conversions were seen when aryl bromides were used.
However, increasing the reaction temperatures to 90−100 °C
and the catalyst loading of CuI to 10 mol % could provide
satisfactory results (Table 2, entries 9−20). Although 2-
bromopyridine was compatible with these conditions (Table
2, entry 20), no desired coupling products were isolated when
other haloheteroarenes like 2-bromofuran, 2-bromothiophene,
I
efforts not only provide mild conditions for coupling of aryl
halides and nucleophiles, but also widen the reaction scope by
using unusual nucleophiles.1 In terms of N-nucleophiles,
sodium azide,2 ammonia,3 N-acyl hydrazines,3d,4 N-aryl
ureas,5 hydroxyamine derivatives6 and guanidines7 have been
recently found to be suitable coupling partners. The CuI/N,N-
diethylsalicylamide-catalyzed N-arylation of guanidine nitrate
reported by Antilla and co-workers offers a valuable method for
preparing N,N′-diaryl guanidines,7d which have been found to
display some interesting biological activities such as binding
with σ-receptors,8 blocking sodium channels,9 and antagonizing
NMDA receptors.10 However, in Antilla and co-workers’
studies only aryl iodides were examined, and reaction yields
in many cases were below 50%.7d Additionally, only symmetric
N,N′-diaryl guanidines could be prepared using this method.
Recently, we found that combination of CuI and N-
methylglycine11 could catalyze the coupling reaction of
guanidine nitrate with both aryl iodides and bromides,
providing the corresponding symmetric N,N′-diaryl guanidines
with good to excellent yields. By tuning the reaction sequence,
we could assemble unsymmetric N,N-diaryl guanidines from
guanidine nitrate and two different aryl iodides. Herein, we
wish to disclose our results.
As shown in Table 1, we used reaction of 4-iodoanisole and
guanidine nitrate as a model to explore optimized reaction
conditions. Since Antilla and co-workers have described that L-
proline was not a good ligand for their transformation,7d we
initially attempted to modify Antilla’s conditions by changing
ligand from L-proline to trans-4-hydroxy-L-proline. Such
modification has been found to be effective for N-arylation of
ammonia and Boc-protected hydrazine.3d We were pleased that
CuI/trans-4-hydroxy-L-proline-catalyzed reaction worked well
in acetonitrile at 80 °C, affording diaryl guanidine 3a in 84%
yield (Table 1, entry 1). Changing the bidentate ligand1 to
Received: April 27, 2012
Published: June 1, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
Table 1. CuI-Catalyzed Coupling of Guanidine Nitrate with
4-Iodoanisole under Different Conditions
Table 2. Assembly of Symmetrical N,N-Diaryl Guanidines
via CuI/N-Methylglycine-Catalyzed Coupling of Aryl
Halides and Guanidine Nitrate
a
a
b
entry
X
Ar
product (yield (%) )
1
I
C6H5
3b (90)
3c (85)
3d (88)
2
I
4-CH3C6H4
3-CH3C6H4
2-CH3C6H4
3,4-(F)2C6H3
4-CF3C6H4
4-ClC6H4
3
I
c
4
I
3e (81)
5
I
3f (92)
3g (72)
6
I
b
entry
[Cu]
ligand
base
solvent
yield (%)
d
7
I
3h (72)
d
1
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
Cu2O
CuI
CuI
CuI
L1
L2
L3
L4
L5
L6
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
dioxane
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
84
41
90
15
70
72
31
40
41
58
37
70
57
54
8
I
4-MeO2CC6H4
4-MeOC6H4
C6H5
3i (65)
2
9
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
3a (80)
3b (81)
3c (78)
3d (77)
3
10
11
12
13
14
15
16
17
18
19
20
4
4-CH3C6H4
3-CH3C6H4
2-CH3C6H4
2-naphthyl
4-PhC6H4
5
c
6
3e (71)
7
3j (74)
e
8
3k (61)
e
9
4-MeSC6H4
3-ClC6H4
3l (67)
10
11
12
13
14
15
16
17
3m (82)
3n (85)
3o (75)
3p (72)
3-FC6H4
3-AcC6H4
2-pyridinyl
a
Reaction conditions: aryl halide (1 mmol), guanidine nitrate (1
c
90
mmol), CuI (0.05 mmol for entries 1−8, or 0.1 mmol for entries 9−
20), N-methylglycine (0.1 mmol for entries 1−8, or 0.2 mmol for
entries 9−20), K3PO4 (6 mmol), MeCN (5 mL), 70 °C, 8 h (for aryl
cd
,
90
ce
,
78
b
c
a
iodides) or 90 °C, 20 h. (for aryl bromides). Isolated yield. 2 mL of
Reaction conditions: 4-iodoanisole (1 mmol), guanidine nitrate (1
mmol), copper salt (0.1 mmol), ligand (0.2 mmol), base (6 mmol),
solvent (5 mL), 8 h. Isolated yield. 0.05 mmol of CuI and 0.1 mmol
d
MeCN was used. Reaction was performed with 1 mmol of aryl iodide
e
b
c
and 0.5 mmol of guanidine nitrate. Reaction was performed at 100 °C
d
for 32 h.
of N-methylglycine were used. Reaction was performed at 70 °C.
e
Reaction was performed at 60 °C.
4a was isolated in 69% yield after heating for 8 h (Table 3,
entry 1). Using 3-methyliodobenzene for second coupling
reaction gave a similar result (Table 3, entry 2). When sterically
hindered 2-iodoanisole was employed, the desired product 4c
was isolated in only 49% yield (Table 3, entry 3), presumably
because in second coupling step both coupling partners are less
reactive. Importantly, two electron-deficient aryl iodides could
be utilized for second coupling (Table 3, entries 4 and 5),
which would allow assembly of unsymmetrical N,N′-diaryl
guanidines in a more diverse manner. Next, we attempted to
use 3-nitroiodobenzene as a coupling starter and found that our
sequential-controlled reaction procedure was still reliable,
although slightly low yields were obtained (Table 3, entries
6−8). The similar results were observed when 1-(4-
iodophenyl)ethanone (Table 3, entry 9) and methyl 4-
iodobenzoate (Table 3, entry 10) were employed as the
coupling starters. Noteworthy is that in these reactions, the
corresponding symmetrical N,N′-diaryl guanidines were still
isolated as the minor products. Although more condition
studies are required to minimize the side reactions, our method
is still comparable with those reported9,10,12 previously because
of its convenient operation and use of commercially available
starting materials and inexpensive reagents.
5-bromoindole, and 6-bromoindole were used. More studies
are needed to solve this problem.
When 4-chlorophenyl iodide and methyl 4-iodobenzoate
were used, some monoarylation products were isolated. This
problem could be solved by decreasing the amount of
guanidine nitrate to 0.5 equiv (Table 2, entries 7 and 8). It is
easy to understand because after the first arylation, the electron-
withdrawing groups in aromatic ring should make the resultant
N-aryl guanidines less reactive. In this case excess guanidine
nitrate could compete with N-aryl guanidines to make the
coupling stop at the monoarylation stage. When more electron-
deficient 4-nitroiodobenzene was employed under our standard
conditions, N-(4-nitrophenyl)guanidine was found to be a
major product, while diarylation product was isolated in a very
low yield.
The poor ability of electron-deficient aryl halides for forming
diarylation products inplied that we could develop a method to
obtain unsymmetrical N,N′-diaryl guanidines via a sequential-
controlled one-pot coupling reaction. The idea was to carry out
the coupling of guanidine nitrate with aryl iodides bearing a
strong withdrawing group first, and then add another aryl
iodide for second coupling reaction. Accordingly, we conducted
a coupling reaction of 4-nitroiodobenzene with guanidine
nitrate at 70 °C. After 10 h, 4-iodoanisole was added for further
coupling. As we desired, unsymmetrical N,N′-diaryl guanidine
The detailed mechanism for this transformation is still
unclear. However, we proposed a possible catalytic cycle as
outlined in Scheme 1. It is known that N-methylglycine and
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The Journal of Organic Chemistry
Note
Table 3. One-Pot Synthesis of Unsymmetrical N,N′-
Diarylguanidines
EXPERIMENTAL SECTION
■
a
General Procedure for Synthesis of Symmetrical N,N′-
Diarylguanidines. A Schlenk tube was charged with aryl halides
(1.0 mmol), guanidine nitrate (1.0 mmol), N-methylgycine (8.9 mg,
0.1 mmol (for aryl iodides) or 17.8 mg, 0.2 mmol (for aryl bromides)),
recrystallized CuI (9.5 mg, 0.05 mmol (for aryl iodides) or 19.0 mg,
0.1 mmol (for aryl bromides)), and K3PO4 (1.27 g, 6 mmol). The tube
was evacuated and backfilled with argon before MeCN (5 mL) was
added. The reaction mixture was stirred at the indicated temperatures
until the corresponding aryl halide was completely consumed as
monitored by TLC. The reaction mixture was extracted with ethyl
acetate. The organic layer was washed with water and brine and dried
over Na2SO4. Removal of solvent in vacuo followed by purification
with column chromatography on silica gel (50:1−20:1 methylene
chloride/methanol as eluent) provided the desired product.
b
entry
Y
Z
product (yield (%) )
1
2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
3-NO2
3-NO2
3-NO2
4-Ac
4-OMe
3-Me
4a (69)
4b (70)
c
1,3-Bis(4-methoxyphenyl)guanidine (3a). 122 mg (90% yield),
white solid: mp 154−156 °C; 1H NMR (300 MHz, CDCl3) δ 7.02 (d,
J = 8.7 Hz, 4H), 6.83 (d, J = 8.4 Hz, 4H), 5.16 (br s, 2H), 3.77 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 155.9 (2C), 151.1, 136.7 (2C), 124.7
3
2-OMe
4-Cl
4c (49)
4
4d (62)
4e (64)
4f (55)
4g (59)
4h (50)
4i (61)
4j (57)
5
4-CO2Me
4-OMe
3-Me
6
(4C), 114.6 (4C), 55.4 (2C); ESI-MS m/z 272.4 (M + H)+; FT-
HRMS (ESI) calcd for C15H18N3O2 (M + H)+ 272.1393, found
272.1391.
7
8
3-CF3
9
4-OMe
4-OMe
1,3-Diphenylguanidine (3b). 95 mg (90% yield), white solid: mp
1
10
4-CO2Me
147−149 °C; H NMR (300 MHz, CDCl3) δ 7.33−7.26 (m, 4H),
a
Reaction conditions: aryl iodide (1 mmol), guanidine nitrate (1
mmol), CuI (0.1 mmol), N-methylglycine (0.2 mmol), K3PO4 (6
mmol), MeCN (5 mL), 70 °C, 10 h, and then another aryl iodide (1
7.13- 7.04 (m, 6H), 4.74 (br s, 3H); 13C NMR (100 MHz, CDCl3) δ
150.1, 143.6 (2C), 129.3 (4C), 123.2 (2C), 122.9 (4C); ESI-MS m/z
212.0 (M + H)+; FT-HRMS (ESI) calcd for C13H14N3 (M + H)+
212.1182, found 212.1186.
b
c
mmol), 8 h. Isolated yield. Second coupling was performed at 90 °C
for 12 h.
1,3-Di-p-tolylguanidine (3c). 102 mg (85% yield), white solid:
mp 128−130 °C; 1H NMR (300 MHz, CDCl3) δ 7.11 (d, J = 8.1 Hz,
4H), 7.00 (d, J = 8.4 Hz, 4H), 4.80 (br, s, 3H), 2.31 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 150.5, 140.4 (2C), 133.1 (2C), 130.0 (4C),
123.3 (4C), 20.8 (2C); ESI-MS m/z 240.1 (M + H)+; FT-HRMS
(ESI) calcd for C15H17N3 (M + H)+ 240.1495, found 240.1492.
1,3-Di-m-tolylguanidine (3d). 105 mg (88% yield), white solid:
Scheme 1
1
mp 99−101 °C; H NMR (300 MHz, CDCl3) δ 7.19 (t, J = 7.2 Hz,
2H), 6.93−6.86 (m, 6H), 4.82 (br s, 3H), 2.29 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 150.1, 143.6 (2C), 139.2 (2C), 129.2 (2C),
124.1 (2C), 123.8 (2C), 119.9 (2C), 21.4 (2C); ESI-MS m/z 240.1
(M + H)+; FT-HRMS (ESI) calcd for C15H17N3 (M + H)+ 240.1495,
found 240.1492.
1,3-Di-o-tolylguanidine (3e). 97 mg (81% yield), white solid: mp
1
177−178 °C; H NMR (300 MHz, CDCl3) δ 7.16−6.99 (m, 8H),
5.78 (br s, 3H), 2.20 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 150.3,
140.3 (2C), 132.9 (2C), 130.9 (2C), 126.9 (2C), 124.93 (2C), 124.85
(2C), 17.9 (2C); ESI-MS m/z 240.1 (M + H)+; FT-HRMS (ESI)
calcd for C15H17N3 (M + H)+ 240.1495, found 240.1500.
1,3-Bis(3,4-difluorophenyl)guanidine (3f). 130 mg (92% yield),
white solid: mp 1554−156 °C; 1H NMR (300 MHz, CD3OD) δ
7.21−7.08 (m, 4H), 6.89−6.85 (m, 2H); 13C NMR (100 MHz,
CD3OD) δ 151.3 (dd, 2C, J = 243.5, 13.8 Hz), 152.4, 147.0 (dd, 2C, J
= 239.1, 13.1 Hz), 142.8 (d, 2C, J = 6.6 Hz), 118.5 (dd, 2C, J = 5.1, 2.9
Hz), 117.9 (d, 2C, J = 16.8 Hz), 111.6 (d, 2C, J = 18.9 Hz); ESI-MS
m/z 284.2 (M + H)+; FT-HRMS (ESI) calcd for C13H10F4N3 (M +
H)+ 284.0805, found 284.0802.
CuI could form the chelate A, which might coordinate with
guanidine (or N-arylguanidine 2) to give the complex B.
Oxidative addition of B to aryl halide could deliver the Cu(III)
complex C, which was reacted with base to afford the complex
D. Reductive elimination of D would produce 2 (or 4) and
regenerate the Cu(I) complex A.
1,3-Bis(4-(trifluoromethyl)phenyl)guanidine (3g). 125 mg
(72% yield), white solid: mp 107−109 °C; 1H NMR (300 MHz,
CDCl3) δ 7.48 (d, J = 8.4 Hz, 4 H), 7.22 (d, J = 8.4 Hz, 4 H), 6.54 (br
s, 3 H); 13C NMR (100 MHz, CDCl3) δ 152.5, 140.4 (2C), 128.1 (q,
2C, J = 32.1 Hz), 126.9 (q, 4C, J = 3.6 Hz), 123.7 (q, 2C, J = 270.5
Hz), 123.3 (4C); ESI-MS m/z 348.0 (M + H)+; FT-HRMS (ESI)
calcd for C15H12F6N3 (M + H)+ 348.0929, found 348.0920.
1,3-Bis(4-chlorophenyl)guanidine (3h). 101 mg (72% yield),
white solid: mp 138−140 °C; 1H NMR (300 MHz, CDCl3) δ 7.33 (d,
J = 8.7 Hz, 4H), 7.17 (d, J = 8.4 Hz, 4H), 6.64 (br s, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 153.9, 135.4 (2C), 130.2 (2C), 129.5 (4C),
125.8 (4C); ESI-MS m/z 279.9 (M + H)+; FT-HRMS (ESI) calcd for
C13H11Cl2N3 (M + H)+ 280.0393, found 280.0387.
In a conclusion, we have revealed that N-methylglycine is an
effective ligand for promoting CuI-catalyzed direct arylation of
guanidine. A number of functionalized aryl iodides and aryl
bromides could be employed as the coupling partners, affording
the corresponding symmetrical N,N′-diaryl guanidines with
great diversity. When aryl iodides bearing a strong electron-
withdrawing group were used, the reaction could be stopped at
the monoarylation stage, and the resultant coupling products
could couple with another aryl iodide in situ to afford
unsymmetrical N,N′-diaryl guanidines. Thus, our method
provides a valuable and alternative approach for preparing
N,N′-diaryl guanidines.
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The Journal of Organic Chemistry
Note
Dimethyl 4,4′-((Iminomethylene)bis(azanediyl))dibenzoate
1-(4-Methoxyphenyl)-3-(4-nitrophenyl)guanidine (4a). 197
mg (69% yield), yellow solid: mp 181−183 °C; 1H NMR (300
MHz, CD3OD) δ 8.13 (d, J = 9.3 Hz, 2H), 7.26 (d, J = 9.3 Hz, 2H),
7.14 (d, J = 9. 0 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 3.76 (s, 3H); 13C
NMR (100 MHz, CD3OD) δ 157.6, 155.6, 153.3, 142.5, 135.8, 125.8
(2C), 125.0 (2C), 122.4 (2C), 115.3 (2C), 55.7; ESI-MS m/z 287.1
(M + H)+; FT-HRMS (ESI) calcd for C14H15N4O3 (M + H)+
287.1139, found 287.1140.
1
(3i). 106 mg (65% yield), white solid: mp 166−168 °C; H NMR
(400 MHz, CD3OD) δ 8.06 (d, J = 8.4 Hz, 4H), 7.42 (d, J = 8.8 Hz,
4H), 3.90 (s, 6H); 13C NMR (100 MHz, CD3OD) δ 167.6 (2C),
154.5, 143.4 (2C), 131.9 (4C), 128.1 (2C), 123.7 (4C), 52.5 (2C);
ESI-MS m/z 328.1 (M + H)+; FT-HRMS (ESI) calcd for C17H18N3O4
(M + H)+ 328.1292, found 328.1296.
1,3-Di(naphthalen-2-yl)guanidine (3j). 115 mg (74% yield),
1
white solid: mp 125−127 °C; H NMR (300 MHz, CD3OD) δ 7.99
1-(4-Nitrophenyl)-3-(m-tolyl)guanidine (4b). 189 mg (70%
(d, J = 8.7 Hz, 2H), 7.92−7.89 (m, 6H), 7.55−7.48 (m, 6H); 13C
NMR (100 MHz, CD3OD) δ 156.4, 135.0 (2C), 133.7 (2C), 133.5
(2C), 130.9 (2C), 128.7 (2C), 128.6 (2C), 127.9 (2C), 127.4 (2C),
124.2 (2C), 124.1 (2C); ESI-MS m/z 312.1 (M + H)+; FT-HRMS
(ESI) calcd for C21H18N3 (M + H)+ 312.1495, found 312.1506.
1,3-Di([1,1′-biphenyl]-4-yl)guanidine (3k). 111 mg (61%
1
yield), yellow solid: mp 182−184 °C; H NMR (300 MHz, CD3OD)
δ 8.13 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 9.0 Hz, 2H), 7.16 (t, J = 7.8 Hz,
1H), 7.04−6.99 (m, 2H), 6.85 (d, J = 7.5 Hz, 1H), 2.30 (s, 3H); 13C
NMR (100 MHz, CD3OD) δ 155.1, 152.3, 143.6, 142.5, 139.8, 129.7
(2C), 125.8 (2C), 124.7, 123.3, 122.2, 119.8, 21.3; ESI-MS m/z 271.1
(M + H)+; FT-HRMS (ESI) calcd for C14H15N4O2 (M + H)+
271.1189, found 271.1190.
1
yield), white solid: mp 218−220 °C; H NMR (300 MHz, CD3OD)
δ 7.75 (d, J = 8.7 Hz, 4H), 7.65 (d, J = 7.5 Hz, 4H), 7.48−7.43 (m,
8H), 7.39−7.34 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 156.2,
141.4 (2C), 141.0 (2C), 135.6 (2C), 129.8 (4C), 129.3 (4C), 128.6
1-(2-Methoxyphenyl)-3-(4-nitrophenyl)guanidine (4c). 140
mg (49% yield), yellow solid: mp 153−155 °C; 1H NMR (300
MHz, CD3OD) δ 8.22 (d, J = 8.7 Hz, 2H), 7.45−7.38 (m, 3H), 7.22
(t, J = 7.8 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H),
3.91 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 155.4, 154.6, 146.6,
145.4, 129.3, 127.3, 126.0 (2C), 125.8, 123.9 (2C), 122.0, 113.1, 56.2;
ESI-MS m/z 287.0 (M + H)+; FT-HRMS (ESI) calcd for C14H15N4O3
(M + H)+ 287.1139, found 287.1147.
1-(4-Chlorophenyl)-3-(4-nitrophenyl)guanidine (4d). 180 mg
(62% yield), yellow solid: mp 95−97 °C; 1H NMR (300 MHz,
CDCl3) δ 8.17 (d, J = 9.0 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 7.21 (d, J
= 9.0 Hz, 2H), 7.13 (d, J = 8.7 Hz, 2H), 3.89 (br s, 3H); 13C NMR
(100 MHz, CD3OD) δ 151.6, 142.7, 130.4, 129.8, 129.8 (2C), 128.4,
125.8 (2C), 123.9 (2C), 121.7 (2C); ESI-MS m/z 291.0 (M + H)+;
FT-HRMS (ESI) calcd for C13H12ClN4O2 (M + H)+ 291.0643, found
291.0645.
+
(2C), 127.7 (4C), 126.3 (4C); ESI-MS m/z 364.1 (M + H) ; FT-
+
HRMS (ESI) calcd for C25H22N3 (M + H)
364.1806.
364.1808, found
1,3-Bis(4-(methylthio)phenyl)guanidine (3l). 102 mg (67%
1
yield), colorless oil: H NMR (300 MHz, CDCl3) δ 7.22 (d, J = 8.7
Hz, 4H), 7.15 (d, J = 8.7 Hz, 4H), 2.45 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 152.3, 136.1 (2C), 135.4 (2C), 128.2 (4C), 124.5 (4C),
16.4 (2C); ESI-MS m/z 304.1 (M + H)+; FT-HRMS (ESI) calcd for
C15H18N3S2 (M + H)+ 304.0937, found 304.0940.
1,3-Bis(3-chlorophenyl)guanidine (3m). 115 mg (82% yield),
white solid: mp 145−147 °C; 1H NMR (300 MHz, CDCl3) δ 7.22 (t, J
= 7.8 Hz, 2H), 7.13 (t, J = 1.8 Hz, 4H), 7.05−6.96 (m, 4H), 4.55 (br s,
3H); 13C NMR (100 MHz, CD3OD) δ 152.1, 146.9 (2C), 135.3 (2C),
131.0 (2C), 123.1 (2C), 122.6 (2C), 120.9 (2C); ESI-MS m/z 280.0
(M + H)+; FT-HRMS (ESI) calcd for C13H12Cl2N3 (M + H)+
280.0403, found 280.0402.
1,3-Bis(3-fuorophenyl)guanidine (3n). 105 mg (85% yield),
white solid: mp 119−121 °C; 1H NMR (300 MHz, CD3OD) δ 7.35−
7.28 (m, 2H), 7.09−6.99 (m, 4H), 6.80 (td, J = 8.4, 2.1 Hz, 2H); 13C
NMR (100 MHz, CD3OD) δ 165.8 (d, 2C, J = 242.1 Hz), 153.1, 145.1
(d, 2C, J = 10.2 Hz), 131.4 (d, 2C, J = 9.5 Hz), 119.07 (d, 2C, J = 2.2
Hz), 111.07 (d, 2C, J = 21.9 Hz), 110.5 (d, 2C, J = 24.1 Hz); ESI-MS
m/z 248.0 (M + H)+; FT-HRMS (ESI) calcd for C13H12F2N3 (M +
H)+ 248.0994, found 248.0983.
1,3-Bis(3-acetylphenyl)guanidine (3o). 110 mg (75% yield),
white solid: mp 147−149 °C; 1H NMR (300 MHz, CDCl3) δ 7.68 (s,
2H), 7.61 (d, J = 7.5 Hz, 2H), 7.47−7.36 (m, 4H), 4.51 (br s, 3H),
2.55 (s, 6H); 13C NMR (100 MHz, CD3OD) δ 200.4 (2C), 152.4,
145.9 (2C), 139.0 (2C), 130.2 (2C), 127.8 (2C), 123.4 (2C), 122.5
(2C), 26.6 (2C); ESI-MS m/z 296.1 (M + H)+; FT-HRMS (ESI)
calcd for C17H18N3O2 (M + H)+ 296.1393, found 296.1393.
1,3-Di(pyridin-2-yl)guanidine (3p). 77 mg (72% yield), white
solid: mp 144−146 °C; 1H NMR (400 MHz, CD3OD) δ 8.42 (dd, J =
5.2, 1.2 Hz, 2H), 7.92 (td, J = 8.0, 2.0 Hz, 2H), 7.27−7.24 (m, 2H),
7.22 (d, J = 6.3 Hz, 2H); 13C NMR (100 MHz, CD3OD) δ 154.3,
153.1 (2C), 147.6 (2C), 140.8 (2C), 121.2 (2C), 115.1 (2C); ESI-MS
m/z 214.0 (M + H)+; FT-HRMS (ESI) calcd for C11H12N5 (M + H)+
214.1087, found 214.1089.
General Procedure for Synthesis of Unsymmetrical N,N′-
Diarylguanidines. A Schlenk tube was charged with aryl iodide (1.0
mmol), guanidine nitrate (1.0 mmol), N-methylgycine (17.8 mg, 0.2
mmol), recrystallized CuI (19.0 mg, 0.1 mmol), and K3PO4 (1.27 g, 6
mmol). The tube was evacuated and backfilled with argon before
MeCN (5 mL) was added. The reaction mixture was stirred at 70 °C
for 10 h before another aryl iodide (1 mmol) was added. After the
resultant mixture was heated at 70 °C for 8−12 h, it was extracted with
ethyl acetate. The organic layer was washed with water and brine and
dried over Na2SO4. Removal of solvent in vacuo followed by
purification with column chromatography on silica gel (50:1−20:1
methylene chloride/methanol as eluent) provided the corresponding
product.
Methyl 4-(3-(4-Nitrophenyl)guanidino)benzoate (4e). 201 mg
1
(64% yield), yellow solid: mp 220−222 °C; H NMR (300 MHz,
CD3OD) δ 8.20 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 8.1 Hz, 2H), 7.38 (t, J
= 7.2 Hz, 4H), 3.88 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ
167.0, 148.7, 142.3, 131.2 (2C), 126.0, 125.6 (2C), 123.9, 121.5 (2C),
120.7 (2C), 115.8, 51.8.; ESI-MS m/z 315.0 (M + H)+; FT-HRMS
(ESI) calcd for C15H15N4O4 (M + H)+ 315.1089, found 315.1093.
1-(4-Methoxyphenyl)-3-(3-nitrophenyl)guanidine (4f). 151
mg (55% yield), yellow solid: mp 105−107 °C; 1H NMR (300
MHz, CD3OD) δ 8.19 (s, 1H), 8.14 (d, J = 5.7 Hz, 1H), 7.73−7.65
(m, 2H), 7.29 (d, J = 9.0 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 3.82 (s,
3H); 13C NMR (100 MHz, CD3OD) δ 159.7, 155.6, 150.2, 141.9,
131.5, 131.1, 130.6, 127.3 (2C), 120.7, 119.7, 115.8 (2C), 55.8; ESI-
MS m/z 287.0 (M + H)+; FT-HRMS (ESI) calcd for C14H15N4O3 (M
+ H)+ 287.1139, found 287.1140.
1-(3-Nitrophenyl)-3-(m-tolyl)guanidine (4g). 159 mg (59%
1
yield), yellow solid: mp 163−165 °C; H NMR (400 MHz, CD3OD)
δ 8.14 (t, J = 1.8 Hz, 1H), 8.05 (dt, J = 7.6, 2.0 Hz, 1H), 7.67−7.60 (m,
2H), 7.29 (t, J = 7.8 Hz, 1H), 7.16 (s, 1H), 7.13−7.07 (m, 2H), 2.36
(s, 3H); 13C NMR (100 MHz, CD3OD) δ 152.7, 150.2, 149.6, 143.4,
139.8, 130.6, 129.7, 129.4, 124.6, 123.4, 119.8, 117.6, 117.0, 21.3; ESI-
MS m/z 271.0 (M + H)+; FT-HRMS (ESI) calcd for C14H15N4O2 (M
+ H)+ 271.1190, found 271.1193.
1-(3-Nitrophenyl)-3-(3-(trifluoromethyl)phenyl)guanidine
(4h). 162 mg (50% yield), yellow solid: mp 90−92 °C; 1H NMR (400
MHz, CD3OD) δ 8.10 (t, J = 2.0 Hz, 1H), 8.09−7.83 (m, 1H), 7.59 (s,
1H), 7.56−7.46 (m, 4H), 7.29 (d, J = 6.8 Hz, 1H); 13C NMR (100
MHz, CD3OD) δ 154.6, 150.2, 142.0, 140.8, 132.7 (q, 1C, J = 32.1
Hz), 131.4, 131.3, 130.5, 127.9, 125.1 (q, 1C, J = 269.8 Hz), 122.7 (q,
1C, J = 3.6 Hz), 121.1 (q, 1C, J = 3.7 Hz), 120.5, 119.1; ESI-MS m/z
325.0 (M + H)+; FT-HRMS (ESI) calcd for C14H12F3N4O2 (M + H)+
325.0907, found 325.0904.
1-(4-Acetylphenyl)-3-(4-methoxyphenyl)guanidine (4i). 172
1
mg (61% yield), white solid: mp 153−155 °C; H NMR (300 MHz,
CDCl3) δ 7.89 (d, J = 9.0 Hz, 2H), 7.12 (dd, J = 8.7, 1.5 Hz, 4H), 6.87
(d, J = 9.0 Hz, 2H), 4.45 (br s, 3H), 3.79 (s, 3H), 2.55 (s, 3H); 13C
NMR (100 MHz, CD3OD) δ 199.5, 157.3, 152.8, 152.7, 136.9, 131.4,
130.9 (2C), 124.9 (2C), 121.9 (2C), 115.3 (2C), 55.7, 26.1; ESI-MS
5452
dx.doi.org/10.1021/jo300840x | J. Org. Chem. 2012, 77, 5449−5453

The Journal of Organic Chemistry
Note
m/z 284.1 (M + H)+; FT-HRMS (ESI) calcd for C16H18N3O2 (M +
H)+ 284.1394, found 284.1400.
(9) Reddy, N. L.; Fan, W.; Magar, S. S.; Perlman, M. E.; Yost, E.;
Zhang, L.; Berlove, D.; Fischer, J. B.; Burke-Howie, K.; Wolcott, T.;
Durant, G. J. J. Med. Chem. 1998, 41, 3298.
(10) (a) 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. (b) Hu, L.-Y.;
Guo, J.; Magar, S. S.; Fischer, J. B.; Burke-Howie, K. J.; Durant, G. J. J.
Med. Chem. 1997, 40, 4281.
Methyl 4-(3-(4-Methoxyphenyl)guanidino)benzoate (4j). 170
1
mg (57% yield), white solid: mp 192−194 °C; H NMR (300 MHz,
CD3OD) δ 8.09 (d, J = 8.7 Hz, 2H), 7.44 (d, J = 8.7 Hz, 2H), 7.29 (d,
J = 9.0 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 3.91 (s, 3H), 3.83 (s, 3H);
13C NMR (100 MHz, CD3OD) δ 167.5, 160.6, 156.3, 141.3, 132.1
(2C), 129.2, 128.2, 128.1 (2C), 124.6 (2C), 116.1 (2C), 55.8, 52.6;
ESI-MS m/z 300.1 (M + H)+; FT-HRMS (ESI) calcd for C16H18N3O3
(M + H)+ 300.1343, found 300.1352.
(11) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453. (b) Zhang,
H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164.
(12) For a review, see: Katritzky, A. R.; Rogovoy, B. V. ARKIVOC
2005, vi, 49.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H NMR and 13C NMR spectra for all new products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Madw@mail.sioc.ac.cn; lcpu333@yahoo.com.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the Chinese Academy of Sciences,
National Natural Science Foundation of China (Grant
20621062 & 20572119) and Ministry of Science & Technology
(Grant 2009CB940900) for their financial support.
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