Direct guanidinylation of aryl and heteroaryl halides via copper-catalyzed cross-coupling reaction

Article abstract of DOI:10.1021/jo202018w

A modified Ullmann reaction using p-methoxybenzyl (PMB) guanidine as guanidinylation agent yielded various aryl and heteroaryl guanidines in good yields.

Full text of DOI:10.1021/jo202018w

Article
pubs.acs.org/joc
Direct Guanidinylation of Aryl and Heteroaryl Halides via
Copper-Catalyzed Cross-Coupling Reaction
Hassan Hammoud, Martine Schmitt,* Frederic Bihel, Cyril Antheaume, and Jean-Jacques Bourguignon
́
́
́ ́ ́
Laboratoire d’Innovation Therapeutique, UMR 7200, Faculte de pharmacie, Universite de Strasbourg, 74 route du Rhin, BP 60024,
67401 Illkirch, France
S
* Supporting Information
ABSTRACT: A modified Ullmann reaction using p-methoxybenzyl (PMB) guanidine as guanidinylation agent yielded various
aryl and heteroaryl guanidines in good yields.
guanidine was reacted with highly electrophilic ortho-
bromobenzonitrile,4a providing easily 4-aminoquinazolines
with satisfactory yields. On the other hand, guanidinylation of
aryl and heteroaryl halides (X = Br or I) using free guanidine
presented limitations resulting from drastic experimental
conditions and the possibility to yield N,N′-diaryl or diheter-
oaryl guanidines, as the result of the multiple nucleophilic
characteristics of guanidine.4b
The development of palladium-catalyzed C−N bond forming
processes, as efficiently described by Buchwald6 and Hartwig,7
opened an avenue for novel synthetic approaches for chemists,
especially when compared with the classical Ullmann reaction
requiring high temperatures, highly polar solvents, and large
amounts of copper reagents as catalyst.8
Over the past decade, the copper-catalyzed modified
Ullmann reaction has emerged as a powerful approach by
means of additive copper chelating agents.9 Moreover, it could
be extended to other nitrogen-containing reagents such as
anilines, amides, and carbamates.10 Progress has been obtained
through the use of various copper-chelating agents (α-amino-
acids, β-aminoacids, phenolic derivatives, or ethylenediamine
derivatives), which dramatically increased the versatility of the
reaction (less drastic experimental conditions, higher yields).
The objective of this communication is to present a very
efficient method of guanidinylation of aromatics and hetero-
aromatics. A systematic survey of catalysts (Pd versus Cu) in
different experimental conditions and using different guani-
dinylation reagents has been carried out, highlighting the most
promising system allowing generalization of the reaction to a
large panel of aromatics and heteroaromatics.
INTRODUCTION
■
The transition-metal-catalyzed formation of carbon−nitrogen
bonds via cross-coupling reactions plays an important role in
the preparation of numerous products dealing with pharma-
ceutical sciences,1 allowing the introduction of various
nitrogen-based functions (amine, amide, urea, carbamate, etc.)
onto aromatic or heteroatomic cycles. N-Aryl and N-heteroaryl
guanidines represent an important class occurring in both
natural and synthetic compounds.2 The most straightforward
route for the synthesis of these compounds involves the
reaction of aromatic (or heteroaromatic) amines with electro-
philic thiourea derivatives as guanylation reagents, using toxic
reagents such as mercury salts.3
Although widely used, this methodology suffers from another
drawback resulting from poor nucleophilicities of the aromatic
amine reagent (anilines bearing electron-withdrawing groups,
heteroarylamines). On the basis of the umpolung concept, an
alternative approach was developed, as illustrated in Scheme 1.
Scheme 1. Guanylation (Method a) and Guanidinylation
(Method b) of Aromatics and Heteroaromatics (Umpolung
Concept)
Two examples of direct guanidinylation of aromatics and
heteroaromatics have been recently published.4,5 On one hand,
Received: October 6, 2011
Published: November 21, 2011
© 2011 American Chemical Society
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Article
RESULTS AND DISCUSSION
Table 1. Catalyst and Ligand Effects on Reactivity
■
Phenyl iodide was chosen for the model reaction and was
reacted with guanidine and guanidine derivatives first in
palladium cross-coupling reactions, as earlier described by
Buchwald with aniline, amides, ureas, or carbamates. Mono-
and diprotected guanidines were first selected for this purpose
in order to progressively decrease both the high basicity and
multiple nucleophilicity of guanidine (Chart 1).
Chart 1. Protected Guanidines
a
b
entry
catalyst
CuI
ligand
yield, %
c
c
c
1
2
L1
L8
L10
L8
L8
L8
L8
L8
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
61
58
59
41
29
38
54
71
63
60
12
9
CuI
3
CuI
4
CuBr
5
CuCl
6
CuCN
Cu(OAc)2
CuTc
7
c
c
8
9
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
10
11
12
13
14
15
16
17
18
75
5
In this work, the benzyl, p-methoxybenzyl (PMB), and o,p-
dimethoxybenzyl (DMB) guanidines 2a−2c were first used as
alternative ways to modulate both the basicity and the
nucleophilicity of guanidine11 (Chart 1). PMB and DMB
protective groups are known to be easily removed in TFA.
Palladium-catalyzed reactions, as described by Buchwald for
amidation of aromatics (Pd(OAc)2, Binap, or Xantphos,
Cs2CO3, dioxane, 105 °C), were first performed with phenyl
iodide. However N-carbamate guanidines 1a−1d yielded a
complex mixture of products, maybe as the result of the lability
of fairly stable carbamates.12 In addition, N-benzylguanidines
2a−2c did not show any significant reactivity in these
conditions. During the course of our preliminary studies, an
interesting work of Salva et al. dealing with copper-catalyzed
guanidinylation of aryl iodides with guanidine was published.4b
However, due to the double nucleophilicity of unsubstituted
guanidine, the authors obtained systematically N,N′-diarylation.
We reinvestigated this approach with PMB-guanidine 2a
expecting a lack of double substitution of guanidine. The role
of both the source of copper and the ligand was first evaluated
(Table 1).
A series of ligands comprising α-aminoacids (proline L8,
pipecolic acid L5), β-ketoenols or equivalents (L1, L2, L3, L4,
L6), ethylenediamines (L7, L9), or rigid 1,1-bispyridin (L10)
were chosen as reference ligands (Table 1).
Copper I and II acetates and different copper halides (Cl,
Br, I) or cyanide or thiophene-2-carboxylate were used as
catalysts. Interestingly, in the selected experimental conditions
described by Salva et al.4b (10 mol % of CuI, 20 mol % of L1,
6 equiv of K3PO4, MeCN, 100 °C, entry 1), N-phenyl-N′-PMB-
guanidine 3a was obtained with a satisfactory yield (61%) but
with still a significant amount of N,N′-diphenylguanidine, as
determined by HPLC.
65
96
70
43
a
The reaction used 1 mmol of PMB-guanidine and 1 mmol of
b
c
iodobenzene. Isolated yields. Small amount (16
diarylguanidine could be isolated from the mixture.
5%) of N,N′-
The replacement of CuI by CuOAc gave similar results
(entry 9), whereas replacement by other copper catalysts
provided less reactive systems (entries 4−7), with still a
significant amount of starting material after a 3 h reaction
period. The reaction using CuTc in place of CuI or CuOAc was
already performed by us. However, about 15% of disubstituted
adduct was obtained (entry 8). Keeping CuI, and replacing L1
by other ligands (L8 or L10), did not improve the reactivity
(entries 2 and 3).
Finally, we selected CuOAc for the next set of reactions
dealing with the choice of the most suitable ligand (Table 1,
entries 9−18).
The optimal conditions were obtained with proline L8 (entry
16), yielding the monosubstitued guanidine in a nearly
quantitative yield and with less than 2% of N,N′-diadduct.
The relative reactivity of N-benzyl guanidine derivatives 2a−
2c was also evaluated (Table 2, entries 1−3). A nearly
quantitative yield was obtained with PMB-guanidine. A 3 h
reaction time at 100 °C was found to be optimal (entries 1 and
4−6). The base had a dramatic effect in this reaction, as
replacing K3PO4 by carbonate salts or triethylamine gave no
reaction (entries 8−10). In addition, replacement of MeCN
by other solvents was also detrimental for reactivity (entries
11−17).
Table 3 summarizes our attempts to extend the scope of the
reaction to various aromatic and heteroaromatic systems.
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Table 2. Optimization of Reaction of N-Benzyl Guanidine
Derivatives with Iodobenzene
groups, the system was found to be relatively more reactive,
and the reaction yielded some amounts of N,N′-guanidine
disubstituted adduct (entries 9 and 10). On the other hand,
systems bearing electron-withdrawing groups were found to be
relatively less reactive, and the reaction time was prolonged to
24 h to obtain completion of the reaction (entries 11 and 12).
When considering a benzene ring bearing both chlorine and
iodine or bromine atoms (entries 4 and 11), no reaction took
place with chlorine. The phenol O-triflate was less reactive,
giving only 39% conversion after 3 h. Finally, various heteroaro-
matics bearing different leaving groups (Cl, Br, OTf) were also
checked (entries 14−20). 2-Bromo-heteroaromatics (pyridine,
pyrimidine, quinoline) showed satisfactory reactivity. A
regioselective reaction took place at position 2 of 2,5-dibromo-
pyridine (entry 17). In most cases, chloroaromatics and chloro-
heteroaromatics (2-chloropyrimidine, 2-chloropyridine, 2-
chloro-4-methylquinoline, 2,6-dichloropyridine, 3-chloro-6-
methylpyridazine) were not reactive, except for some specific
highly reactive systems (entry 19).
a
b
entry
R
base
solvent
temp, °C
yield, %
1
2
PMB
Bn
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
K2CO3
Et3N
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
dioxane
THF
100
100
100
25
96
90
88
0
3
DMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
4
5
60
63
78
80
0
6
80
7
120
100
100
100
115
100
110
100
90
8
9
0
10
11
12
13
14
15
16
17
0
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
13
0
This provided some chemoselectivity to polyhalogenated
heteroaromatics (entry 18). The pyridin-2-O-triflate showed
moderate activity, as already observed in the aromatic series
(entries 13 and 20).
The model reaction (entry 1) was applied with success to the
preparation of 4 g (19.6 mol) of iodobenzene with similar
yields (86%).
toluene
DMSO
ethanol
DMF
25
0
0
80
10
0
DCM
40
a
The reaction used 1 mmol of PMB-guanidine and 1 mmol of
b
iodobenzene. Isolated yields.
As initially expected, deprotection of aryl and heteroaryl
guanidine intermediates 3a−3n was efficiently performed in
trifluoroacetic acid in a microwave (100 °C for 12 min) and
yielded in all cases the expected aryl or heteroaryl guanidines 4
in good yields13 (89−97%).
Surprisingly, ortho-dibromobenzene was not reactive, where-
as ortho-diiodobenzene reacted smoothly giving directly N-
PMB-1H-2-aminobenzimidazole 5, which was further sub-
mitted to microwave irradiation in TFA aqueous solution to
The choice of the leaving group X was checked in our
standard experimental conditions (CuOAc, L8, K3PO4, MeCN,
100 °C, 3 h). All of the iodophenyl derivatives reacted
smoothly and gave the expected N-substituted compounds 3 in
good yields (entries 1−7).
The reaction was still efficient with bromophenyl derivatives
bearing either electron-withdrawing or electron-donating
groups (entries 8−12). However, with electron-donating
Table 3. Copper-Catalyzed Aryl and Heteroaryl Guanidinylation
a
b
c
The reaction used 1 mmol of PMB-guanidine and 1 mmol of iodobenzene. Isolated yields. Spectra details available in Supporting Information.
d
e
f
N,N′-Diarylguanidine was observed. Reaction time was increased to 24 h. Presence of starting material.
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give 2-aminobenzimidazoles 6a and 6b.13 In good agreement with
earlier results in Table 3, ortho-dibromobenzene bearing a methoxy
group showed a relatively better reactivity (Table 4, entries 1 and 4).
DMSO) δ 3.74 (s, 3H), 3.79 (s, 3H), 4.13 (s, 2H), 6.50 (dd, J = 2.3
Hz, J = 8.3 Hz, 1H), 6.55 (d, J = 2.3 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H),
7.76 (br s, 4H), 8.40 (s, 1H); 13C NMR (100 MHz, DMSO) δ 160.1,
157.6, 157.2, 128.7, 117.4, 104.4, 98.3, 55.4, 55.2; HRMS (ESI) for
[C10H16N3O2] calcd 210.1237, found 210.1229.
a
Table 4. Benzimidazole Synthesis with PMB-Guanidine
1-Benzylguanidine Hemisulfate (Bn-Guanidine), Compound
2c. Following the general procedure, the product was obtained by
recrystallization to give Bn-guanidine as a white solid: 5.5 g, 62% yield;
1
mp 208.2−209.6 °C; H NMR (400 MHz, DMSO) δ 4.26 (s, 2H),
7.22−7.25 (m, 1H), 7.31 (d, J = 4.4 Hz, 4H), 7.81 (br s, 4H), 8.97
(s, 1H); 13C NMR (100 MHz, DMSO) δ 157.2, 137.9, 128.3, 127.1,
127.0, 43.5; HRMS (ESI) for [C8H12N3] calcd 150.1025, found
150.1026.
b
c
entry
X
X′
R
yield 5, %
1
2
3
4
Br
Br
I
Br
I
H
H
H
0
62
90
51
General Procedure for the Cross-Coupling of Aryl or
Heteroaryl Halide with PMB-Guanidines 3 and 5. Aryl (or
heteroaryl) halide 1 (1 mmol), PMB-guanidine hemisulfate 2a
(228.2 mg, 1 mmol), CuOAc (12.2 mg, 0.10 mmol), L-proline
(23 mg, 0.20 mmol), and K3PO4 (1.23 g, 6 equiv) were mixed in a
flame-dried process vial (10−20 mL) equipped with a magnetic stir
bar. The reaction mixture was then capped with a Teflon septum
under argon, and anhydrous acetonitrile (6 mL) was added using a
syringe. The reaction was microwave heated at 100 °C for 4 h. After
complete consumption of the starting material shown by HPLC,
AcOEt (30 mL) and H2O (30 mL) were added. The separated
aqueous layer was extracted with AcOEt (2 × 30 mL). The combined
organic layers were washed with brine (40 mL), dried over Na2SO4,
and concentrated in vacuum. The remaining residue was purified by
column chromatography on silica gel to afford the desired product 3
(or 5).
I
Br
Br
4-OMe
a
Reaction conditions: (i) 10 mol % of CuOAc, 20 mol % of L8, 6 equiv
of K3PO4, MeCN, 100 °C, 20 h; (ii) TFA with 0.1 M concentration,
MW, 100 °C, 12 min. The reaction used 1 mmol of PMB-guanidine
and 1 mmol of iodobenzene. Isolated yields
b
c
In conclusion, the use of N-PMB-guanidine as a
guanidinylation agent is particularly efficient, as it dramatically
suppresses double substitution, which generally occurred in a
previous method using copper-catalyzed guanidinylation
reaction with free guanidine. In addition, the method could
be applied to the production of several grams of aryl halides
with about the same yield. Easy removal of the PMB protective
group in TFA led to versatile substitutions of both aromatics
and heteroaromatics. As a first application of the method, a
novel preparation of 2-aminobenzimidazoles was proposed.
1-(4-Methoxybenzyl)-3-phenylguanidine, Compound 3a. Fol-
lowing the general procedure, the product was obtained by silica gel
chromatography (AcOEt/MeOH/NEt3 = 9:1:0.1, Rf = 0.38) to give 1-
(4-methoxybenzyl)-3-phenylguanidine as a white solid: 244 mg, 96%
yield. In the same condition using 4 g of iodobenzene, the reaction
1
gives 4.28 g of 3a: 86% yield; mp 136.1−138.9 °C; H NMR (400
EXPERIMENTAL SECTION
General Experimental Methods. All reactions were carried out
in flame-dried screw cap test tubes with magnetic stirring. Reactions
were run under an inert atmosphere of argon gas. Yields refer to
isolated compounds, estimated to be >97% pure as determined H
NMR and HPLC.
■
MHz, CDCl3) δ 3.65 (s, 3H), 4.21 (s, 2H), 6.51 (br s, 2H), 6.72 (d,
J = 8.7 Hz, 2H), 6.85 (d, J = 7.5 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H), 7.11
(d, J = 8.7 Hz, 2H), 7.17 (t, J = 7.7 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 159.1, 154.0, 140.9, 129.7, 129.2, 128.7, 125.1, 124.5, 114.2,
55.3, 45.2; HRMS (ESI) for [C15H18N3O] calcd 256.1444, found
256.1444.
1
1H NMR and 13C NMR were recorded at 400 and 100 MHz,
respectively, for CDCl3 solutions. 19F NMR was measured at 373 MHz
for CDCl3 solutions with trichlorofluoromethane as an external
standard. Chemical shifts (δ) are reported in parts per million (ppm)
for 1H and for 13C NMR spectra. The coupling constants, J, are
reported in hertz (Hz). TMS was used as the internal reference. High-
resolution mass spectra (HRMS) were measured with electrospray
ionization (ESI). All microwave reactions were carried out in sealed
tubes in an Initiator microwave reactor (Biotage Inc.).
1-(4-Methoxybenzyl)-3-(o-tolyl)guanidine, Compound 3b. Fol-
lowing the general procedure, the product was obtained by silica gel
chromatography (AcOEt/MeOH/NEt3 = 9:1:0.08, Rf = 0.30) to give
1-(4-methoxybenzyl)-3-(o-tolyl)guanidine as a white solid: 247 mg,
92% yield; mp 98.1−101.3 °C; 1H NMR (400 MHz, CDCl3) δ 2.06 (s,
3H), 3.72 (s, 3H), 4.09 (br s, 1H), 4.27 (s, 2H), 6.76−6.80 (m, 3H),
6.87 (t, J = 6.5 Hz, 1H), 7.04 (t, J = 6.8 Hz, 1H), 7.08 (d, J = 7.6 Hz,
1H), 7.17 (br s, 2H); 13C NMR (100 MHz, CDCl3) δ 158.9, 151.1,
146.0, 132.0, 130.7, 128.7, 126.8, 123.6, 123.1, 114.1, 55.4, 45.3, 17.9;
HRMS (ESI) for [C16H20N3O] calcd 270.1601, found 270.1602.
1-(4-Methoxybenzyl)-3-(4-methoxyphenyl)guanidine, Com-
pound 3c. Following the general procedure, the product was obtained
by silica gel chromatography (AcOEt/MeOH/NEt3 = 9:1:0.1, Rf =
0.21) to give 1-(4-methoxybenzyl)-3-(4-methoxyphenyl) guanidine as
a white solid: 210 mg, 74% yield; mp 158.2−161.6 °C; 1H NMR (400
MHz, CDCl3) δ 3.66 (d, J = 6.3 Hz, 6H), 4.17 (s, 2H), 5.97 (br s, 1H),
6.68−6.76 (m, 6H), 7.09 (d, J = 8.7 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 158.9, 156.2, 153.8, 137.1, 130.2, 128.6, 125.3, 114.8, 114.1,
55.5, 55.3, 44.8; HRMS (ESI) for [C16H20N3O2] calcd 286.1550,
found 286.1552.
General Procedure for Preparation of Protected Guani-
dine13 2. A solution of 2-methylthiopseudourea sulfate (5.0 g,
1.0 equiv, 35.92 mmol) and substituted benzylamine (2.0 equiv, 71.84
mmol) was dissolved in water (50 mL) and ethanol (50 mL). The
mixture was stirred at reflux for 20 h and connected to a series of
bleach traps. The mixture was cooled, and solvent was removed under
vacuum to give crude product, which was purified by recrystallization
from hot water (20 mL). Purified product was collected by filtration
and dried in the oven to give the title compound 2 (62−80%).
1-(4-Methoxybenzyl)guanidine Hemisulfate (PMB-Guanidine),
Compound 2a. Following the general procedure, the product was
obtained by recrystallization to give PMB-guanidine as a white solid:
1
1-(4-(Dimethylamino)phenyl)-3-(4-methoxybenzyl)guanidine,
Compound 3d. Following the general procedure, the product was
obtained by flash chromatography (H2O/MeOH = 6:4, Rf = 0.27) to
give 1-(4-(dimethylamino)phenyl)-3-(4-methoxybenzyl)guanidine as a
6.5 g, 80% yield; mp 205.6−207.9 °C; H NMR (400 MHz, DMSO)
δ 3.72 (s, 3H), 4.18 (s, 2H), 6.88 (d, J = 8.7 Hz, 2H), 7.25 (d, J =
8.7 Hz, 2H), 7.77 (br s, 4H) 8.89 (s, 1H); 13C NMR (100 MHz,
DMSO) δ 158.4, 157.1, 129.8, 128.5, 113.7, 55.0, 43.1; HRMS (ESI)
for [C9H14N3O] calcd 180.1131, found 180.1123.
1
white solid: 235 mg, 79% yield; mp 223.1−225.9 °C; H NMR (400
MHz, CDCl3) δ 2.83 (s, 6H), 3.64 (s, 3H), 4.40 (s, 2H), 6.51 (d, J =
6.4 Hz, 2H), 6.70 (d, J = 7.2 Hz, 2H), 6.85 (d, J = 6.0 Hz, 2H), 7.18
(d, J = 5.8 Hz, 2H), 9.39 (br s, 2H); 13C NMR (100 MHz, CDCl3)
δ 159.2, 156.1, 150.2, 129.1, 127.8, 127.6, 121.4, 114.2, 112.9, 55.3,
1-(2,4-Dimethoxybenzyl)guanidine Hemisulfate (DMB-Guani-
dine), Compound 2b. Following the general procedure, the product
was obtained by recrystallization to give DMB-guanidine as a white
solid: 6.4 g, 69% yield; mp 236.3−238.1 °C; H NMR (400 MHz,
1
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1
45.4, 40.4; HRMS (ESI) for [C17H23N4O] calcd 299,1866, found
299,1863.
solid: 288 mg, 94% yield; mp 116.1−118.9 °C; H NMR (400 MHz,
CDCl3) δ 3.71 (s, 3H), 4.38 (s, 2H), 6.83 (d, J = 8.7 Hz, 2H), 6.96 (d,
J = 8.8 Hz, 1H), 7.20−7.22 (m, 1H), 7.26 (d, J = 8.7 Hz, 2H), 7.45 (td,
J = 1.0 Hz, J = 6.7 Hz, 1H), 7.49−7.55 (m, 2H), 7.81 (d, J = 8.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 160.8, 159.3, 157.4, 146.1,
137.0, 129.1, 128.4, 127.3, 126.2, 124.4, 123.4, 120.5, 114.4, 113.9,
55.3, 45.1; HRMS (ESI) for [C18H19N4O] calcd 307.1553, found
307.1551.
1-(4-Chlorophenyl)-3-(4-methoxybenzyl)guanidine, Compound
3e. Following the general procedure, the product was obtained by
silica gel chromatography (AcOEt/MeOH/NEt3 = 9:1:0.2, Rf = 0.34)
to give 1-(4-chlorophenyl)-3-(4-methoxybenzyl)guanidine as a white
1
solid: 240 mg, 83% yield; mp 169.5−171.8 °C; H NMR (400 MHz,
CDCl3) δ 3.53 (br s, 3H), 3.73 (s, 3H), 4.27 (s, 2H), 6.83 (dd, J = 8.7
Hz, J = 3.8 Hz, 4H), 7.16 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 159.1, 151.4, 147.8, 130.6, 129.4,
1-(6-Chloropyridin-3-yl)-3-(4-methoxybenzyl)guanidine, Com-
pound 3l. Following the general procedure, the product was obtained
by silica gel chromatography (AcOEt/MeOH/NEt3 = 9:1:0.4, Rf =
0.29) to give 1-(6-chloropyridin-3-yl)-3-(4-methoxybenzyl) guanidine
128.8, 127.3, 124.7, 114.2, 55.3, 45.6; HRMS (ESI) for [C15H17-
ClN3O] calcd 290.1055, found 290.1054.
1
as a white solid: 246 mg, 85% yield; mp 123.9−124.5 °C; H NMR
1-(4-Methoxybenzyl)-3-(4-nitrophenyl)guanidine, Compound
3f. Following the general procedure, the product was obtained by
silica gel chromatography (AcOEt/MeOH/NEt3 = 9:1:0.2, Rf = 0.33)
to give 1-(4-methoxybenzyl)-3-(4-nitrophenyl)guanidine as a yellow
(400 MHz, CDCl3) δ 3.72 (s, 3H), 4.02 (br s, 2H), 4.26 (s, 2H), 6.81
(d, J = 8.7 Hz, 2H), 7.07−7.13 (m, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.88
(d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 159.1, 152.2,
145.2, 144.7, 143.7, 133.8, 130.3, 128.8, 124.4, 114.2, 55.3, 45.5;
HRMS (ESI) for [C14H16ClN4O] calcd 291.1007, found 291.1008.
1-(5-Bromopyridin-2-yl)-3-(4-methoxybenzyl)guanidine, Com-
pound 3m. Following the general procedure, the product was
1
solid: 239 mg, 80% yield; mp 127.8−129.3 °C; H NMR (400 MHz,
CDCl3) δ 3.73 (s, 3H), 4.30 (s, 2H), 4.36 (br s, 3H), 6.82 (d, J = 8.7
Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 8.05 (d,
J = 9.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 159.2, 157.1, 151.4,
141.9, 130.2, 128.8, 125.5, 123.2, 114.3, 55.3, 45.5; HRMS (ESI) for
[C15H17N4O3] calcd 301.1295, found 301.1293.
obtained by silica gel chromatography (AcOEt/MeOH/NEt3
=
9:1:0.4, Rf = 0.31) to give 1-(5-bromopyridin-2-yl)-3-(4-methoxybenzyl)
guanidine as a white solid: 170 mg, 51% yield; mp 201.3−204.7 °C;
1H NMR (400 MHz, CDCl3) δ 3.71 (s, 3H), 4.27 (s, 2H), 5.25 (br s,
2H), 6.63 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 8.7 Hz, 3H), 7.18 (d,
J = 8.4 Hz, 2H), 7.43 (dd, J = 2.6 Hz, J = 8.8 Hz, 1H), 8.03 (d, J = 2.6 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 160.3, 159.2, 156.7, 146.2,
139.8, 129.4, 128.4, 120.2, 114.3, 110.0, 55.3, 45.0; HRMS (ESI) for
[C14H16BrN4O] calcd 335.0502, found 335.0499.
1-(2,4-Difluorophenyl)-3-(4-methoxybenzyl)guanidine, Com-
pound 3g. Following the general procedure, the product was
obtained by silica gel chromatography (AcOEt/MeOH/NEt3
=
9:1:0.3, Rf = 0.32) to give 1-(2,4-difluorophenyl)-3-(4-methoxybenzyl)
guanidine as a white solid: 252 mg, 87% yield; mp 144.4−146.1 °C;
1H NMR (400 MHz, CDCl3) δ 3.41 (br s, 3H), 3.73 (s, 3H), 4.29 (s,
2H), 6.71−6.86 (m, 5H), 7.21 (d, J = 8.8 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 159.5, 159.4, 159.1, 157.1, 156.9, 156.6, 156.4, 152.6,
132.5, 130.4, 128.7, 126.2, 126.2, 126.1, 126.1, 114.2, 111.4, 111.3,
111.2, 111.1, 104.7, 104.5, 104.2, 55.3, 45.5; HRMS (ESI) for
[C15H16F2N3O] calcd 292.1256, found 292.1260.
1-(6-Chloropyridazin-3-yl)-3-(4-methoxybenzyl)guanidine, Com-
pound 3n. Following the general procedure, the product was
obtained by silica gel chromatography (AcOEt/MeOH/NEt3
=
9:1:0.3, Rf = 0.21) to give 1-(6-chloropyridazin-3-yl)-3-(4-methox-
ybenzyl) guanidine as a white solid: 124 mg, 43% yield; mp 156.3−
158.8 °C; H NMR (400 MHz, CDCl3) δ 3.72 (s, 3H), 4.34 (s, 2H),
5.81 (br s, 2H), 6.81 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 9.1 Hz, 1H), 7.14
(d, J = 9.1 Hz, 1H), 7.19 (d, J = 8.5 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 163.0, 159.3, 156.9, 148.3, 129.3, 128.7, 128.4, 127.3, 114.4,
55.3, 45.3; HRMS (ESI) for [C13H15ClN5O] calcd 292.0960, found
292.0964.
1-(4-Methoxybenzyl)-3-(naphthalen-2-yl)guanidine, Compound
3h. Following the general procedure, the product was obtained by
silica gel chromatography (AcOEt/MeOH/NEt3 = 9:1:0.2, Rf = 0.3) to
give 1-(4-methoxybenzyl)-3-(naphthalen-2-yl)guanidine as a white
1
1
solid: 268 mg, 88% yield; mp 145.1−146.8 °C; H NMR (400 MHz,
CDCl3) δ 3.70 (s, 3H), 4.14 (br s, 2H), 4.28 (s, 2H), 6.79 (d, J = 8.7
Hz, 2H), 7.05 (dd, J = 2.0 Hz, J = 8.7 Hz, 1H), 7.17 (br s, 2H), 7.22
(d, J = 1.9 Hz, 1H), 7.27 (t, J = 8.2 Hz, 1H), 7.34 (t, J = 6.9 Hz, 1H),
7.60 (d, J = 8.2 Hz, 1H), 7.68 (dd, J = 3.2 Hz, J = 5.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 159.1, 152.2, 145.7, 134.6, 130.5, 130.1,
129.3, 128.7, 127.6, 126.9, 126.1, 124.6, 124.2, 119.4, 114.2, 55.3, 45.5;
HRMS (ESI) for [C19H20N3O] calcd 306.1601, found 306.1603.
1-(4-Methoxybenzyl)-3-(pyridin-2-yl)guanidine, Compound
3i. Following the general procedure, the product was obtained by
silica gel chromatography (AcOEt/MeOH/NEt3 = 9:1:0.4, Rf = 0.3) to
give 1-(4-methoxybenzyl)-3-(pyridin-2-yl)guanidine as a white solid:
234 mg, 91% yield; mp 153.9−154.7.8 °C; 1H NMR (400 MHz, CDCl3)
δ 3.72 (s, 3H), 4.32 (s, 2H), 6.65 (td, J = 0.8 Hz, J = 6.0 Hz,1H),
6.77−6.82 (m, 3H), 7.22 (d, J = 8.7 Hz, 2H), 7.43 (td, J = 2.0 Hz, J =
8.4 Hz, 1H), 8.03 (dd, J = 1.4 Hz, J = 4.9 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 162.2, 159.2, 156.5, 145.6, 137.3, 129.8, 128.3,
119.1, 115.2, 114.3, 55.3, 45.1; HRMS (ESI) for [C14H17N4O] calcd
257.1397, found 257.1396.
N-(4-Methoxybenzyl)-1H-benzo[d]imidazol-2-amine, Compound
5a. Following the general procedure, the product was obtained by
silica gel chromatography (AcOEt/heptane = 2:1, Rf = 0.31) to give
N-(4-methoxybenzyl)-1H-benzo[d]imidazol-2-amine as a white solid:
227 mg, 90% yield; mp 206.4−208.6 °C; 1H NMR (400 MHz,
DMSO) δ 3.72 (s, 3H), 4.44 (d, J = 5.9 Hz, 2H), 6.84−6.87 (m, 3H),
6.89 (s, 1H), 7.02 (t, J = 7.4 Hz, 12.8 Hz, 1H), 7.11−7.13 (m, 2H),
7.32 (d, J = 8.2 Hz, 2H), 10.75 (s, 1H); 13C NMR (100 MHz, DMSO)
δ 180.1, 158.2, 155.4, 132.2, 128.5, 119.0, 118.8, 113.6, 55.0, 45.1;
HRMS (ESI) for [C15H16N3O] calcd 254.1288, found 254.1291.
5-Methoxy-N-(4-methoxybenzyl)-1H-benzo[d]imidazol-2-amine,
Compound 5b. Following the general procedure, the product was
obtained by silica gel chromatography (AcOEt/heptane =2:1, Rf =
0.25) to give 5-methoxy-N-(4-methoxybenzyl)-1H-benzo[d]imidazol-
2-amine as a white solid: 145 mg, 51% yield; mp 173.5−175.3 °C; 1H
NMR (400 MHz, CDCl3) δ 3.67 (s, 3H), 3.68 (s, 3H), 5.31 (br s,
2H), 6.56 (d, J = 7.4 Hz, 1H), 6.70−6.74 (m, 3H), 7.01 (d, J = 8.5 Hz,
1H), 7.12 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 159.1,
155.4, 141.6, 139.6, 130.0, 128.5, 114.2, 113.9, 111.9, 108.1, 98.3, 55.9,
55.3, 46.7; HRMS (ESI) for [C16H18N3O2] calcd 284.1393, found
284.1391.
1-(4-Methoxybenzyl)-3-(pyrimidin-2-yl)guanidine, Compound
3j. Following the general procedure, the product was obtained by
silica gel chromatography (AcOEt/MeOH/NEt3 = 9:1:0.4, Rf = 0.23)
to give 1-(4-methoxybenzyl)-3-(pyrimidin-2-yl)guanidine as a white
1
solid: 189 mg, 73% yield; mp 155.1−157.3 °C; H NMR (400 MHz,
CDCl3) δ 3.70 (s, 3H), 4.42 (s, 2H), 6.56 (t, J = 4.8 Hz, 1H), 6.80 (d,
J = 8.7 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H), 8.30 (d, J = 4.9 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 165.5, 159.1, 158.2, 157.2, 129.7, 128.5,
114.3, 113.9, 112.1, 55.3, 45.1; HRMS (ESI) for [C13H16N5O] calcd
258.1349, found 258.1347.
1-(4-Methoxybenzyl)-3-(quinolin-2-yl)guanidine, Compound
3k. Following the general procedure, the product was obtained by
silica gel chromatography (AcOEt/MeOH/NEt3 = 9:1:0.3, Rf = 0.33)
to give 1-(4-methoxybenzyl)-3-(quinolin-2-yl)guanidine as a white
General Procedure for the Deprotection of the PMB Group
of Guanidines 4 and 6. Compound 3 (0.5 mmol) and trifluoro-
acetic acid (2 mL) were mixed in a flame-dried process vial (2−5 mL)
equipped with a magnetic stir bar. The reaction mixture was then
capped with a Teflon septum. The mixture was irradiated at 100 °C in
a microwave (3 bar) for 10 min and after cooled to 40 °C. The
trifluoroacetic acid was concentrated in vacuum, and the crude sample
was triturated with a mixture solvent (heptane/Et2O 1/1) to provide
the desired solid product 4 (or 6) as the triflate salt.
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Article
1-Phenylguanidine Triflate, Compound 4a. Following the general
procedure, the product was obtained by filtration to give 1-phenylguani-
dine triflate as a white solid, 118 mg, 95% yield; mp 175.1−177.3 °C;
1H NMR (400 MHz, DMSO) δ 7.23−7.31 (m, 3H), 7.46 (t, J = 7.2 Hz,
2H), 7.61 (br s, 4H), 10.08 (s, 1H); 13C NMR (100 MHz, DMSO)
δ 155.9, 135.4, 129.6, 126.3, 124.4; HRMS (ESI) for [C7H10N3] calcd
136.0869, found 136.0870.
1-(Pyrimidin-2-yl)guanidine Triflate, Compound 4j. Following
the general procedure, the product was obtained by filtration to give
1-(pyrimidin-2-yl)guanidine triflate as a white solid: 113 mg, 90%
yield; mp 165.1−167.2 °C; 1H NMR (400 MHz, DMSO) δ 7.32 (t, J =
5.0 Hz, 1H), 8.41 (br s, 4H), 8.74 (d, J = 4.5 Hz, 2H), 11.08 (s, 1H);
13C NMR (100 MHz, DMSO) δ 158.6, 156.9, 155.1, 117.2; HRMS
(ESI) for [C5H8N5] calcd 138.0774, found 138.0770.
1-(o-Tolyl)guanidine Triflate, Compound 4b. Following the
general procedure, the product was obtained by filtration to give 1-
(o-tolyl)guanidine triflate as a white solid: 118 mg, 90% yield; mp
145.3−146.8 °C; 1H NMR (400 MHz, DMSO) δ 2.22 (s, 3H), 7.20−
7.30 (m, 4H), 7.37 (br s, 4H), 9.58 (s, 1H); 13C NMR (100 MHz,
DMSO) δ 155.8, 135.2, 132.6, 131.2, 128.4, 127.5, 127.3, 17.1; HRMS
(ESI) for [C8H12N3] calcd 150.1025, found 150.1020.
1-(4-Methoxyphenyl)guanidine Triflate, Compound 4c. Follow-
ing the general procedure, the product was obtained by filtration to
give 1-(4-methoxyphenyl)guanidine triflate as a white solid: 135 mg,
97% yield; mp 157.6−159.1 °C; 1H NMR (400 MHz, DMSO) δ 3.77
(s, 3H), 7.01 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.36 (br s,
4H), 9.64 (s, 1H); 13C NMR (100 MHz, DMSO) δ 158.1, 156.3,
127.5, 127.2, 114.8, 55.4; HRMS (ESI) for [C8H12N3O] calcd 166.0974,
found 166.0969.
1-(Quinolin-2-yl)guanidine triflate, Compound 4k. Following the
general procedure, the product was obtained by filtration to give 1-
(quinolin-2-yl)guanidine triflate as a white solid: 143 mg, 95% yield;
mp 208.7−210.3 °C; 1H NMR (400 MHz, DMSO) δ 7.22 (d, J = 8.9
Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.59 (d, J =
8.0 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.71
(br s, 4H), 11.53, (s, 1H); 13C NMR (100 MHz, DMSO) δ 155.5,
151.3, 144.6, 139.7, 130.6, 127.9, 126.9, 125.7, 124.9, 113.6; HRMS
(ESI) for [C10H11N4] calcd 187.0978, found 187.0974.
1-(6-Chloropyridin-3-yl)guanidine Triflate, Compound 4l. Fol-
lowing the general procedure, the product was obtained by filtration to
give 1-(6-chloropyridin-3-yl)guanidine triflate as a white solid: 128 mg,
90% yield; mp 146.2−148.6 °C; 1H NMR (400 MHz, DMSO) δ 7.61
(d, J = 8.5 Hz, 1H), 7.76−7.79 (m, 5H), 8.34 (s, 1H), 10.14 (s, 1H);
13C NMR (100 MHz, DMSO) δ 156.3, 147.4, 146.4, 136.4, 132.1,
1-(4-(Dimethylamino)phenyl)guanidine Triflate, Compound
4d. Following the general procedure, the product was obtained by
filtration to give 1-(4-(dimethylamino)phenyl)guanidine triflate as a
white solid: 130 mg, 89% yield; mp 139.7−142.1 °C; H NMR (400
MHz, DMSO) δ 6.85 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H),
7.43 (s, 4H), 9.77 (s, 1H); 13C NMR (100 MHz, DMSO) δ 156.6,
148.8, 126.6, 124.1, 113.5, 40.4; HRMS (ESI) for [C9H15N4] calcd
179.1291, found 179.1284.
124.9; HRMS (ESI) for [C6H8ClN4] calcd 171.0432, found 171.0424.
1-(5-Bromopyridin-2-yl)guanidine Triflate, Compound 4m. Fol-
lowing the general procedure, the product was obtained by filtration to
give 1-(5-bromopyridin-2-yl)guanidine triflate as a white solid, 150 mg,
91% yield; mp 154.3−157.8 °C; 1H NMR (400 MHz, DMSO) δ 7.07
(d, J = 8.8 Hz, 1H), 8.11 (dd, J = 2.5 Hz, J = 8.8 Hz, 1H), 8.43−8.50
(m, 5H), 11.59 (s, 1H); 13C NMR (100 MHz, DMSO) δ 155.1, 150.9,
147.1, 141.9, 115.2, 113.7; HRMS (ESI) for [C6H8BrN4] calcd
214.9926, found 214.9919.
1
1-(4-Chlorophenyl)guanidine Triflate, Compound 4e. Following
the general procedure, the product was obtained by filtration to give
1-(4-chlorophenyl)guanidine triflate as a white solid: 129 mg, 91%
1-(6-Chloropyridazin-3-yl)guanidine Triflate, Compound
4n. Following the general procedure, the product was obtained by
filtration to give 1-(6-chloropyridazin-3-yl)guanidine triflate as a white
1
yield; mp 139.6−141.0 °C; H NMR (400 MHz, DMSO) δ 7.28 (d,
1
J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.59 (br s, 4H), 9.95 (s, 1H);
13C NMR (100 MHz, DMSO) δ 155.9, 134.4, 130.6, 129.6, 126.5;
HRMS (ESI) for [C7H9ClN3] calcd 170.0479, found 170.0485.
1-(4-Nitrophenyl)guanidine Triflate, Compound 4f. Following
the general procedure, the product was obtained by filtration to give
1-(4-nitrophenyl)guanidine triflate as a white solid: 133 mg, 90% yield;
mp 207.3−209.1 °C; 1H NMR (400 MHz, DMSO) δ 7.47 (d, J = 9.0
Hz, 2H), 8.01 (br s, 4H), 8.29 (d, J = 8.9 Hz, 2H), 10.50 (s, 1H); 13C
NMR (100 MHz, DMSO) δ 155.4, 143.9, 142.9, 125.2, 122.8; HRMS
(ESI) for [C7H9N4O2] calcd 181.0720, found 181.0713.
solid: 127 mg, 89% yield; mp 176.5−178.3 °C; H NMR (400 MHz,
DMSO) δ 7.04 (d, J = 9.9 Hz, 1H), 7.27 (d, J = 9.9 Hz, 1H), 8.13 (s,
4H), 11.13 (s, 1H); 13C NMR (100 MHz, DMSO) δ 158.9, 154.7,
140.7, 133.1, 128.8; HRMS (ESI) for [C5H7ClN5] calcd 172.0384,
found 172.0379.
1H-Benzo[d]imidazol-2-amine Triflate, Compound 6a. Following
the general procedure, the product was obtained by filtration to give
1H-benzo[d]imidazol-2-amine triflate as a white solid: 117 mg, 95%
yield; mp 263.5−264.1 °C; 1H NMR (400 MHz, DMSO) δ 7.20−7.22
(m, 2H), 7.35−7.37 (m, 2H), 8.55 (br s, 2H), 12.80 (s, 2H); 13C
NMR (100 MHz, DMSO) δ 150.1, 129.1, 123.3, 111.2; HRMS (ESI)
for [C7H8N3] calcd 134.0712, found 134.0710.
1-(2,4-Difluorophenyl)guanidine Triflate, Compound 4g. Follow-
ing the general procedure, the product was obtained by filtration to
give 1-(2,4-difluorophenyl)guanidine triflate as a white solid: 136 mg,
95% yield; mp 125.6−127.8 °C; 1H NMR (400 MHz, DMSO) δ 7.18
(td, J = 2.0 Hz, J = 8.5 Hz, 1H), 7.43−7.49 (m, 2H), 7.64 (br s, 4H),
9.78 (s, 1H); 13C NMR (400 MHz, DMSO) δ 162.7, 162.6, 160.3,
160.2, 158.8, 158.7, 156.2, 130.6, 130.5, 118.6, 118.6, 118.5, 118.5,
112.5, 112.3, 105.5, 105.2, 104.9; HRMS (ESI) for [C7H8F2N3] calcd
172.0680, found 172.0674.
5-Methoxy-1H-benzo[d]imidazol-2-amine Triflate, Compound
6b. Following the general procedure, the product was obtained by
filtration to give 5-methoxy-1H-benzo[d]imidazol-2-amine triflate as a
1
white solid: 128 mg, 92% yield; mp 193.7−195.3 °C; H NMR (400
MHz, DMSO) δ 3.77 (s, 3H), 6.79−7.25 (m, 3H), 8.37 (s, 1H), 12.37
(br s, 2H); 13C NMR (100 MHz, DMSO) δ 155.9, 130.8, 129.7, 123.7,
111.8, 109.9, 96.8, 55.7; HRMS (ESI) for [C8H10N3O] calcd 164.0818,
found 164.0812.
1-(Naphthalen-2-yl)guanidine Triflate, Compound 4h. Following
the general procedure, the product was obtained by filtration to give
1-(naphthalen-2-yl)guanidine triflate as a white solid: 140 mg, 94%
ASSOCIATED CONTENT
■
1
yield; mp 135.3−136.7 °C; H NMR (400 MHz, DMSO) δ 7.39 (d,
S
* Supporting Information
J = 8.7 Hz, 1H), 7.52−7.58 (m, 2H), 7.66 (br s, 4H), 7.79 (s, 1H),
7.95 (t, J = 7.0 Hz, 2H), 8.01 (d, J = 8.8 Hz, 1H), 10.18, (s, 1H); 13C
NMR (100 MHz, DMSO) δ 155.6, 133.2, 132.2, 131.4, 129.7, 127.6,
127.6, 126.9, 126.4, 123.2, 122.5; HRMS (ESI) for [C11H12N3] calcd
186.1025, found 186.1017.
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mschmitt@unistra.fr.
■
1-(Pyridin-2-yl)guanidine Triflate, Compound 4i. Following the
general procedure, the product was obtained by filtration to give 1-
(pyridin-2-yl)guanidine triflate as a white solid: 116 mg, 93% yield; mp
159.1−161.2 °C; 1H NMR (MHz, DMSO) δ 7.08 (d, J = 8.3 Hz, 1H),
7.19 (t, J = 6.3 Hz, 1H), 7.89 (t, J = 6.8 Hz, 1H), 8.33 (d, J = 4.3 Hz,
1H), 8.46 (br s, 4H), 11.24 (s, 1H); 13C NMR (MHz, DMSO) δ
155.2, 152.0, 146.6, 139.6, 119.3, 113.3; HRMS (ESI) for [C6H9N4]
calcd 137.0821, found 137.0819.
ACKNOWLEDGMENTS
This project was supported by the Alsace region (Reg
Alsace), the University of Strasbourg (UdS), and the National
Center of Scientific Research (CNRS). We thank Mr. Patrick
■
́
ion
422
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The Journal of Organic Chemistry
Wehrung for analytical studies, the minister
Article
̀
́
e de l’economie, des
finances et de l’industrie, and OSEO innovation.
REFERENCES
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