Cleavage of C-N bonds in guanidine derivatives and its relevance to efficient C-N bonds formation

Article abstract of DOI:10.1016/j.tet.2015.01.050

Efficient nonenzymatic decomposition of guanidine derivatives with high structural and functional diversity into anilide products is achieved in the presence of Pd^II/Cu(II) carboxylates/CO, relying on a dual C-N bonds cleavage strategy. In this decomposition process, the cooperative action of Pd^II species, Cu(II) carboxylates, and CO provides not only the N-acylating agents but also an initiator to trigger this C-N bonds cleavage sequence. The current results indicate that Pd^II/Cu(II) carboxylates/CO system provides a convenient and practical method for highly selective cleavage of unreactive C-N single bonds.

Full text of DOI:10.1016/j.tet.2015.01.050

Tetrahedron xxx (2015) 1e10
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Tetrahedron
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Cleavage of CeN bonds in guanidine derivatives and its relevance
to efficient CeN bonds formation
*
Denghu Chang, Dan Zhu, Peng Zou, Lei Shi
Institute of Organic Chemistry, The Academy of Fundamental and Interdisciplinary Sciences, Harbin Institute of Technology, Harbin 150080, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient nonenzymatic decomposition of guanidine derivatives with high structural and functional di-
versity into anilide products is achieved in the presence of PdII/Cu(II) carboxylates/CO, relying on a dual
CeN bonds cleavage strategy. In this decomposition process, the cooperative action of PdII species, Cu(II)
carboxylates, and CO provides not only the N-acylating agents but also an initiator to trigger this CeN
bonds cleavage sequence. The current results indicate that PdII/Cu(II) carboxylates/CO system provides
a convenient and practical method for highly selective cleavage of unreactive CeN single bonds.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 25 November 2014
Received in revised form 10 January 2015
Accepted 23 January 2015
Available online xxx
Keywords:
Carbonenitrogen bonds cleavage
Carbon monoxide
Copper(II) carboxylates
Palladium
Anilides formation
1. Introduction
and as such cleavage of even one CeN bond in guanidine de-
rivatives performed by transition metals had never been observed
Over the past few decades, successful cleavage and/or formation
of the carbonenitrogen single bonds with the help of the transition
metal complexes has remained one of the most important and
challenging issues in organometallic chemistry,1 which has
attracted considerable attention of synthetic chemists because of
their potential applications in organic synthesis and pharmaceuti-
cal research. Despite the significant progress made in this field,
there are relatively few available protocols concerning the cleavage
of the unactivated carbonenitrogen single bonds, such as N-imino
bonds2 and N-cyano bonds,3 with concomitant formation of new
CeN bonds. It is worth noting that in 2013 Wang and Falck have
reported a first example of intramolecular cyanation of a styrene by
a rhodium-catalyzed NeCN cleavage reaction.3b
Among the numerous types of organic compounds possessing
the carbonenitrogen bonds, guanidines were chosen to test the
selective cleavage of unreactive CeN bonds because they are CeN
rich compounds including different types of CeN bonds. In addi-
tion, it is noteworthy that the decomposition of guanidine de-
rivatives with CeN cleaving enzymes in water existed extensively
in nature.4 However, very little information is available for the
transition metal promoted decomposition of guanidine derivatives,
until recently (Scheme 1).5 Herein, we describe a new class of
valuable cleavage of unreactive CeN single bonds using a PdII/Cu(II)
carboxylates/CO system, whereby nitrogen-rich guanidine de-
rivatives serve as double ‘N’ atom sources of amides through highly
selective cleavage of two carbonenitrogen single bonds in the
presence of carbonenitrogen multiple bonds. In contrast with en-
zymatic decomposition of guanidine derivatives,4 our strategy in-
volving the consecutive cleavage of two CeN single bonds is an
appealing alternative to the decomposition of guanidine derivatives
to substituted amines. To the best of our knowledge, the present
study constitutes the first example of the corresponding amide
bond construction from highly selective CeN bonds cleavage of
basic guanidine derivatives regardless of the electronic nature and
steric hindrance of the substituent on the aromatic ring.
2. Results and discussions
To explore the feasibility of the cleavage of two individual CeN
single bonds of guanidine derivatives in a one-pot procedure, we
commenced our investigations by examining the decomposition
reaction of diphenyl guanidine (1a) as a twofold aniline moiety
with various acetate salts. Although ammonium carboxylate salts
have been widely utilized for amidation by strong heating since
1885,6 little was known that the acetate salts alone can act as
a selective N-acetylating agent.7 After some experimentation, we
were intrigued to find that Cu(OAc)2 was more efficient than other
* Corresponding author. Tel.: þ86 451 86403860; e-mail address: lshi@hit.edu.cn
(L. Shi).
URL: http://homepage.hit.edu.cn/pages/shilei
http://dx.doi.org/10.1016/j.tet.2015.01.050
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
D. Chang et al. / Tetrahedron xxx (2015) 1e10
Scheme 1. Unreactive CeN bonds cleavage of guanidine derivatives.
metal salts (Table 1, entries 1e4), and the decomposition reaction of
diphenyl guanidine (1a) with 2.2 equiv of Cu(OAc)2 in acetonitrile
in the presence of CO afforded 16% yield of expected acetanilide
(2a). It showed that the needed reactivity is dramatically affected
by subtle changes of the metal used. It is worth noting that the
existence of CO atmosphere is indispensable for desired reactivity,
as verified by control experiments (Table 1, entries 5 and 6). Grat-
ifyingly, further investigation revealed that the addition of catalytic
PdII species, such as PdCl2 and Pd(OAc)2, gave dramatically im-
proved yield of the expected products (Table 1, entries 7 and 8).
Notably, the key modification to achieve higher yields was the use
of benzonitrile as a solvent at 120 ꢀC (Table 1, entry 9), which sig-
nificantly affects both the rate and outcome of the reaction, and
yield up to 70% after column chromatography purification. At
higher temperature (150 ꢀC) complex mixtures were observed and
anilide product 2a was obtained in a slightly lower yield of 58%
(Table 1, entry 10); lower temperatures below 60 ꢀC slowed down
the reaction without leading to better yields even after extended
reaction times. Furthermore, the amount of Cu(OAc)2 could be re-
duced to 1 equiv with only a slight decrease in the product yield,
while further decrease caused a significant yield drop to 40% (Table
1, entries 11 and 12). Finally, various additives (KI and NaI), ligands
(PPh3, XPhos, 1,2-bis(diphenylphosphino)ethane (dppe), etc.) and
solvents (DMSO and 1,4-dioxane) were also examined; however, no
improvement in yield was observed, alas to no avail. Based on the
facts mentioned above, the reaction conditions described in entries
7e9 and 11 were selected as the standard conditions for further
investigations depending on the specific substrates involved.
With the optimized reaction conditions established, a wide va-
riety of symmetrical N,N0-diaryl guanidines were submitted to the
decomposition process to investigate its substrate scope and gen-
erality (Table 2). As might be anticipated, the reaction proceeded
with moderate to good yields in the presence of both electron-
deficient and electron-rich aromatic systems. Thus, substrates
bearing substituents meta- and para-to the guanidines underwent
the decomposition to form anilide products in 38e89% yields. In
general, guanidines bearing electron-donating groups showed
better reactivity than those containing electron-withdrawing
groups. For instance, the reactions of substrate 1j with a methoxyl
group at the 4-position of the benzene ring, could be successfully
converted into the desired product 2j in 89% yield. On the other
hand, the substrates with p-COMe and p-CO2Me groups on the
benzene ring afforded the desired products 2g and 2h in 51% and
45% yields, respectively. Next to the expected products, 3% of
4-aminoacetophenone and 34% of methyl 4-aminobenzoate as the
byproduct were identified. In addition, various kinds of functional
groups such as alkyl, alkoxyl, fluoro, chloro, bromo, trifluoromethyl,
ester, ketone, and even oxidizable functional groups, such as eSMe,
were also tolerated under the established catalytic conditions.
Importantly, the successful preparation of 2e, 2f, 2k, and 2r with
an intact chlorine/bromine provide ample opportunities for
Table 1
Optimization of the reaction conditionsa
Entry
Solvent
M.C.f (equiv)
Catalyst
Yieldg (%)
1
2
3
4
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
PhCN
PhCN
MeCN
MeCN
KOAc (2.2)
AgOAc (2.2)
d
n.d.h
n.d.h
n.d.h
16
d
Pd(OAc)2 (2.2)
Cu(OAc)2 (2.2)
Cu(OAc)2 (2.2)
Cu(OAc)2 (2.2)
Cu(OAc)2 (2.2)
Cu(OAc)2 (2.2)
Cu(OAc)2 (2.2)
Cu(OAc)2 (2.2)
Cu(OAc)2 (1.0)
Cu(OAc)2 (0.5)
d
d
5b
6c
7
d
n.d.h
n.d.h
61
d
PdCl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
8
65
70
58
62
9d
10e
11
12
40
a
Reaction conditions: 1a (0.2 mmol), metal carboxylates, catalyst (0.01 mol),
solvent (2 mL), stirred at 60 ꢀC for 12 h under CO (1 atm).
b
N2 (1 atm) instead of CO.
c
Air (1 atm) instead of CO.
d
PhCN (2 mL), stirred at 120 ꢀC for 3 h.
e
PhCN (2 mL), stirred at 150 ꢀC for 3 h.
f
M.C.¼Metal carboxylates.
g
Yield of the isolated product¼{n(2a)/[2ꢁn (1a)]}ꢁ100%, n¼mole number of the
corresponding compounds.
h
Not detectable.
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D. Chang et al. / Tetrahedron xxx (2015) 1e10
3
Table 2
Scope of symmetrical N,N0-diarylguanidinesa,d
subsequent functionalization via conventional transition metal-
catalyzed cross-coupling techniques. Besides the benzene ring,
naphthyl-substituted guanidine 1n was also compatible with this
novel decomposition, generating the corresponding anilide 2n in
51% yield. Surprisingly, substituting the arene ring with pyridine
completely impeded the formation of the corresponding anilide 2o,
and we therefore reasoned that the nitrogen center of pyridine with
a basic lone pair of electrons can coordinate readily with transition
metal ions, which is detrimental for the CeN single bond cleavage
process. In contrast to similar para substituted guanidine de-
rivatives, the presence of a substituent ortho to the guanidines af-
fords the anilides in slightly lower yield owing to the increased
effective size of metal coordination sphere. In the meantime, we
turned our attention to evaluating two substituents at the aryl
groups of guanidines, and we found that the desired 30,50-methyl-
acetanilide 2m could be furnished from 1m with a satisfactory yield
of 53%. However, it is hard to observe the generation of 20-bromo-
40-methylacetanilide 2s when we use 1s as the substrate, and we
assumed that the ortho-Br is fragile under our transition metal
system and incompatible in the reaction. Notably, the protected
NeH guanidine 1v failed to give the desired product 2v under
identical conditions, suggesting that the existence of NeH bonds is
essential. Furthermore, we have examined 1,3-dibenzylguanidine
(1w) and 1,3-dicyclohexylguanidine (1x) under our standard con-
ditions, and no expected products were detected.
electron-withdrawing substituents on the aniline moieties could be
successfully converted to two kinds of expected decomposition
products in reasonable yields, which mean that two CeN bonds
have been successively cleaved under the current catalytic condi-
tion. Actually, the irregular and slight ratio fluctuation of 4/40
around 1:1 strongly supported that two successive CeN bonds
cleavage of symmetrical and unsymmetrical guanidine derivatives
were realized in two relatively independent transition pathways,
respectively.
To evaluate the potential of our system, we further envisaged
the scope and limitations of decomposition process with various
Cu(II) carboxylates as illustrated in Table 4, which would enlarge
the molecular diversity. To our great delight, the decomposition
protocol took place efficiently and was successfully applied to
various Cu(II) carboxylates, such as cupric propionate 5a, cupric
formate 5b, cupric 2-ethylhexanoate 5c, cupric n-octadecanoate 5d,
and cupric benzoate 5e. Cu(II) trifluoroacetate 5f and Cu(II) meth-
anesulfonate 5g, failed to produce the desired anilide products.
Based on the known copper and palladium chemistry and the
above experimental results, the catalytic cycle of this process was
hypothesized as shown in Scheme 2. Similar to related reactions
with stoichiometric quantities of Pt complexes,5d it seems likely
that the mechanism proceeds via acetonitrile (or benzonitrile) co-
ordinated palladium(II) complexes. Their intermediacy can explain
the fact that the nature of the solvent has an important role for the
efficiency of the reaction; in acetonitrile or benzonitrile solution,
full conversion and high yields can be achieved presumably be-
cause acetonitrile or benzonitrile coordinated to the Pd(OAc)2. CO is
known to reduce PdII species to Pd0,8a and Pd0 was assumed to be
Subsequently, the scope of unsymmetrical N,N0-diaryl guani-
dines was assessed under the standard reaction conditions, and the
results are summarized in Table 3. As might be expected, the un-
symmetrical guanidine derivatives bearing electron-donating or
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4
D. Chang et al. / Tetrahedron xxx (2015) 1e10
Table 3
Scope of unsymmetrical N,N0-diarylguanidinesa,d
Entry
1
Substrate
Product
Yieldb (%)
R1¼3-Me
R2¼H
50%
50%
2
3
R1¼4-F
R2¼H
57%
57%
R1¼2-F
R2¼H
69%c
50%c
4
5
R1¼3-Cl
R2¼H
48%
57%
R1¼2-Cl
R2¼H
76%
40%
6
R1¼4-OMe
R2¼H
51%
65%
R1¼4-CF3
R2¼H
48%
50%
7
a
Reaction conditions: 3 (0.2 mmol), Cu(OAc)2 (0.44 mmol), Pd(OAc)2 (0.01 mmol), MeCN (2 mL), stirred at 60 ꢀC under CO (1 atm).
Yield based on NMR.
b
c
Isolated yield.
d
Yield of the product¼[n(4 or 40)/n(3aeg)]ꢁ100%, n¼mole number of the corresponding compounds.
Table 4
Scope of Cu(II) carboxylatesa,b
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D. Chang et al. / Tetrahedron xxx (2015) 1e10
5
Scheme 2. Proposed mechanism.
readily oxidized by Cu(OAc)2 to re-generate the active PdII catalyst
and liberate carboxylic anhydride.8b Subsequently, carboxylic an-
hydride reacts with N,N0-diaryl guanidine to give intermediate A as
proposed in Scheme 2. The acylation intermediate A was decom-
posed into the anilide products and N-arylcyanamide B, which is
the first CeN bond cleavage. Finally, the N-arylcyanamide B was
further decomposed to another anilide product, which would likely
have undergone secondary cleavage of the CeN bond.3a,3b Although
the mechanism details for the decomposition processes are not
completely clear yet, we believe that both the stability and the
reactivity of this intermediate A and B are crucial for the fate of this
transform. Meanwhile, the existence of Cu(II) carboxylates actually
play three roles in this reaction, which not only helped to cleave
two individual CeN bonds in the decomposition process but also
served as acylating agents and oxidants.
synthetic routes to guanidines could be irreversibly offered by the
reaction of amines with different guanylating reagents in the pre-
vious literature. However, our work may provide a first beneficial
complement and experimental evidence for the reverse trans-
formation from guanidines to protected amines (anilides).
To validate our supposition about the reaction mechanism,
several experimental results that support our tentative mechanism
were performed under our optimized conditions (Scheme 3). First,
the reaction of N,N0-diphenyl guanidine 1a with acetic anhydride
was carried out in acetonitrile at room temperature, and mono-
acetyl guanidine 7 was isolated, which is in line with the pre-
vious reports.9 Second, the reaction of independently synthesized 7
under the optimized conditions (Scheme 3, Eq. 1), which includes
5 mol % Pd(OAc)2, 1.0 equiv of Cu(OAc)2, under CO at 60 ꢀC, could
afford the desired product 2a in 65% yield with almost equal effi-
ciency to N,N0-diphenyl guanidine 1a as the substrate. This fact
clearly indicated that mono-acyl guanidines A might form at the
outset of the process. Third, the potential occurrence of N-aryl-
cyanamide B in our CeN bond cleavage approach was confirmed by
examining the reaction of 8 (Scheme 3, Eq. 2), which led to the
formation of acetanilide 2a in 34% yield. Particularly in Kukushkin’s
report,5d phenyl cyanamide 8 survived and failed to undergo fur-
ther CeN bond cleavage in the presence of stoichiometric quanti-
ties of Pt(II)bis-nitrile complexes, which indicated our catalytic
system is unique and unusual for two successive CeN single bonds
cleavage. Fourth, the use of nitrogen-rich N,N0-diphenyl urea and
N,N0-diphenyl thiourea as substrates failed to give access to de-
composition products, thus implying that the existence of eC(]
NH) is necessary for our CeN bond cleavage reaction. To our delight,
N-phenylguanidine 9 including the eC(]NH) group could be nor-
mally decomposed into acetanilide 2a with a synthetically useful
yield (Scheme 3, Eq. 3). Taken together, all of the above mentioned
verified our hypothesis to some extent. As far as we know, typical
Scheme 3. Mechanistic studies.
3. Conclusion
To conclude, we have unveiled an unprecedented one-step de-
composition process of guanidine derivatives with high structural
and functional diversity into anilide products in the presence of
PdII/Cu(II) carboxylates/CO, relying on a dual CeN bonds cleavage
strategy. Particularly, this study shows clearly, for the first time that
the weakly acidic anilides could be obtained from the de-
composition of strong basic N,N0-diaryl guanidines as double ani-
line backbones through a rather challenging cleavage of inert
N-imino and N-cyano single bonds, thus standing out from known
amide syntheses. In this decomposition process, the cooperative
action of PdII species, Cu(II) carboxylates, and CO, which acted not
only as the N-acylating agents but also an initiator to trigger this
CeN bond cleavage sequence, is crucial to promoting this reaction
with good yields. In parallel with the enzymatic decomposition
pathway, we offered a novel and interesting possibility for guani-
dine decomposition under transition metal-catalyzed reaction
conditions. More importantly, it would provide a revealing insight
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6
D. Chang et al. / Tetrahedron xxx (2015) 1e10
for exploring the ability of our competent PdII/Cu(II) carboxylates/
CO system for the highly selective cleavage and transformation of
other compounds including inert CeN bonds. Further mechanistic
investigations, extensive explorations and synthetic applications of
PdII/Cu(II) carboxylates/CO system in various CeN bonds cleavage
are currently underway in our laboratory.
for [MþH]þ (C13H12Cl2N3) requires m/z 280.0408, found m/z
280.0417.
4.2.4. 1,3-Bis(4-acetylphenyl)guanidine (1g). Pale-yellow solid. Mp:
211e212 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.95 (d, J¼8.6 Hz, 4H;
H
Ar), 7.23 (d, J¼8.6 Hz, 4H; HAr), 2.58 (s, 6H; CH3). HRMS (ESþ) exact
mass calculated for [MþH]þ (C17H18N3O2) requires m/z 296.1399,
found m/z 296.1408.
4. Experimental section
4.1. General comments
4.2.5. Dimethyl
(1h). White solid. Mp: 201e202 ꢀC; 1H NMR (400 MHz, CDCl3):
4,40-(iminomethylene)bis(azanediyl)dibenzoate
d
7.99 (d, J¼8.5 Hz, 4H; HAr), 7.19 (d, J¼8.5 Hz, 4H; HAr), 3.90 (s, 6H;
Unless otherwise noted, all reagents were purchased from
commercial sources and used without further purification. The
reaction solvent, MeCN was dried by refluxing over CaH2, and
freshly distilled prior to use. All reactions were monitored by TLC
and visualized by UV lamp (254 nm)/or by staining with a solution
of 10 g phosphomolybdic acid and 100 mL EtOH followed by
heating. Flash column chromatography was performed using
230e400 mesh silica gel. Melting point ranges were determined on
OCH3). HRMS (ESþ) exact mass calculated for [MþH]þ (C17H18N3O4)
requires m/z 328.1297, found m/z 328.1299.
4.2.6. 1,3-Bis(4-(trifluoromethyl)phenyl)guanidine (1i). White solid.
Mp: 165e166 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.56 (d, J¼8.4 Hz, 4H;
H
Ar), 7.23 (d, J¼8.4 Hz, 4H; HAr). HRMS (ESþ) exact mass calculated
for [MþH]þ (C15H12F6N3) requires m/z 348.0935, found m/z
348.0937.
a BUCHI Melting Point B-540 apparatus and are uncorrected. 1H
€
NMR (400 MHz) and 13C NMR (100 MHz) spectra were obtained on
4.2.7. 1,3-Bis(4-methoxyphenyl)guanidine (1j). White solid. Mp:
Bruker AV-400 instrument. Chemical shifts for 1H NMR spectra
154e156 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.04 (d, J¼8.5 Hz, 4H;
were reported in
d
parts per million (ppm) referenced to an internal
HAr), 6.85 (d, J¼8.5 Hz, 4H; HAr), 3.78 (s, 6H; OCH3). HRMS (ESþ)
SiMe4 standard. The abbreviations s, br s, d, t, q, and m stand for the
resonance multiplicity singlet, broad singlet, doublet, triplet,
quartet, and multiplet, respectively. HR-ESI-MS spectra were
recorded on a Bruker Esquire LC mass spectrometer using electro-
spray ionization.
exact mass calculated for [MþH]þ (C15H18N3O2) requires m/z
272.1399, found m/z 272.1398.
4.2.8. 1,3-Di(pyridin-2-yl)guanidine
(1o). White
solid.
Mp:
175e176 ꢀC; 1H NMR (400 MHz, CDCl3):
d
8.19e8.20 (m, 2H; HAr),
Caution: CO is particularly dangerous. These procedures should
be carried out by knowledgeable laboratory scientists.
1a and 1p were obtained from commercial suppliers.
7.38e7.51 (m, 2H; HAr), 6.65e6.84 (m, 4H; HAr). HRMS (ESþ) exact
mass calculated for [MþH]þ (C11H12N5) requires m/z 214.1093,
found m/z 214.1093.
4.2. General procedure for synthesis of symmetrical N,N0-di-
substituted guanidines 1b, 1c, 1e, 1g, 1h, 1i, 1j, and 1o ac-
cording to Ma’s method10 (method A)
4.3. General procedure for synthesis of symmetrical N,N0-di-
substituted guanidines 1d, 1f, 1k, 1l, 1m, 1n, 1q, 1r, 1s, 1t, 1u,
and 1v according to Keana’s method11 (method B)
A Schlenk tube was charged with aryl halides (1.0 mmol), gua-
nidine nitrate (1.0 mmol), N-methylglycine (8.9 mg, 0.1 mmol (for
aryl iodides) or 17.8 mg, 0.2 mmol (for aryl bromides)), recrystal-
lized 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 back-filled with N2 before MeCN (5 mL) was added.
The reaction mixture was stirred at 70 ꢀC 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 by evaporation in vacuo followed by purifica-
tion with column chromatography on silica gel (50:1e20:1 meth-
ylene chloride/methanol as eluent) provided the desired products.
To a stirred solution of the appropriate amine (10 mmol) in EtOH
(3e5 mL) at 0 ꢀC was carefully added a solution of BrCN (11 mmol,
1.1 equiv) in EtOH (1e2 mL). After the exotherm subsided, the re-
action mixture was allowed to warm to 25 ꢀC and was then heated
at 150 ꢀC for 15e30 min, while N2 was swept through the flask to
completely remove the boiling solvent. The fused reaction mixture
was allowed to cool to 25 ꢀC, and the resulting glassy solid was
taken up in hot EtOH (10e15 mL), treated with decolorizing char-
coal (50e60 mg), and filtered through Celite. The filtrate was di-
luted with aqueous 1 N NaOH (10e20 mL), and the precipitated
guanidine free base was filtered off. The analytical sample was
obtained by repeated crystallizations from aqueous EtOH.
4.2.1. 1,3-Di-m-tolylguanidine (1b). White solid. Mp: 110e111 ꢀC;
4.3.1. 1,3-Bis(4-fluorophenyl)guanidine (1d). White solid. Mp:
1H NMR (400 MHz, CDCl3):
d
7.16 (t, J¼7.6 Hz, 2H; HAr), 6.84e6.92
136e138 ꢀC; 1H NMR (400 MHz, CDCl3):
d 7.17e6.90 (m, 8H; HAr),
(m, 6H; HAr), 2.28 (s, 6H; CH3). HRMS (ESþ) exact mass calculated
4.96 (br s, 3H; NH). HRMS (ESþ) exact mass calculated for [MþH]þ
(C13H12F2N3) requires m/z 248.0994, found m/z 248.1001.
for [MþH]þ (C15H18N3) requires m/z 240.1501, found m/z 240.1510.
4.2.2. 1,3-Di-p-tolylguanidine (1c). White solid. Mp: 168e170 ꢀC;
4.3.2. 1,3-Bis(4-bromophenyl)guanidine (1f). Yellow solid. Mp:
1H NMR (400 MHz, CDCl3):
d
7.11 (d, J¼8.2 Hz, 4H; HAr), 7.00 (d,
155e157 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.41 (d, J¼7.0 Hz, 4H; HAr),
J¼8.2 Hz, 4H; HAr), 2.31 (s, 6H; CH3). HRMS (ESþ) exact mass cal-
culated for [MþH]þ (C15H18N3) requires m/z 240.1501, found m/z
240.1501.
7.00 (d, J¼7.0 Hz, 4H; HAr), 4.62 (br s, 3H; NH). HRMS (ESþ) exact
mass calculated for [MþH]þ (C13H12Br2N3) requires m/z 369.9372,
found m/z 369.9373.
4.2.3. 1,3-Bis(4-chlorophenyl)guanidine (1e). White solid. Mp:
4.3.3. 1,3-Bis(3-chlorophenyl)guanidine (1k). White solid. Mp:
145e147 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.23 (d, J¼8.7 Hz, 4H;
147e148 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.21e7.25 (m, 2H; HAr),
H
Ar), 7.00 (d, J¼8.7 Hz, 4H; HAr). HRMS (ESþ) exact mass calculated
7.18e7.12 (m, 2H; HAr), 7.06e6.96 (m, 4H; HAr), 4.82 (br s, 3H; NH).
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D. Chang et al. / Tetrahedron xxx (2015) 1e10
7
HRMS (ESþ) exact mass calculated for [MþH]þ (C13H12Cl2N3)
NH), 3.46 (s, 2H, 2CH), 1.92e1.42 (m, 10H), 1.40e0.79 (m, 10H). 13
C
requires m/z 280.0403, found m/z 280.0410.
NMR (150 MHz, DMSO) d 153.8 (C]NH), 49.4 (2C), 32.2 (4CH2), 24.8
(4CH2), 24.1 (2CH2). HRMS (ESþ) exact mass calculated for [MþH]þ
(C13H26N3) requires m/z 224.2121, found m/z 224.2124.
4.3.4. 1,3-Bis(3-methoxyphenyl)guanidine (1l). White solid. Mp:
133e134 ꢀC; 1H NMR (400 MHz, CDCl3):
d 7.19e7.23 (m, 2H; HAr),
6.74e6.66 (m, 4H; HAr), 6.60e6.63 (m, 2H; HAr), 3.76 (s, 6H; OCH3).
HRMS (ESþ) exact mass calculated for [MþH]þ (C15H18N3O2)
requires m/z 272.1394, found m/z 272.1397.
4.4. General procedure for the synthesis of unsymmetrical
N,N0-disubstituted guanidines 3a, 3b, 3c, 3d, 3e, 3f, and 3g
according to Keana’s method11 (method C)
4.3.5. 1,3-Bis(3,5-dimethylphenyl)guanidine (1m). White solid. Mp:
A stirred mixture of the appropriate cyanamide (10 mmol) and
amine hydrohalide salt (10 mmol) in chlorobenzene (30 mL) was
heated at90e130 ꢀC underN2 for 2e10 h. The reactionwasmonitored
by TLC (CHCl3/EtOH/Et3N, 75:20:5). On cooling to 25 ꢀC, the title
compoundsprecipitatedfromsolutionastheirhydrohalidesaltswere
filtered off, and washed with dichloromethane (CH2Cl2) (3ꢁ5 mL) to
removeresidualchlorobenzene. Whentheguanidinehydrohalidedid
not precipitate from the cooled reaction mixture, the solvent was
evaporated, and the residue was taken up in aqueous 1 N HCl (15 mL).
The solution was basified with 1 N NaOH, and the precipitated gua-
nidine free base was filtered off. The guanidine free base was crys-
tallized by dissolution in EtOH (20e30 mg/mL), followed by slow
addition of H2O. The analytical sample was obtained after two further
recrystallizations. Typically, the guanidine hydrohalide salts were
crystallized inside a closed Et2O-containing chamber, by the slow
diffusion of Et2O into a loosely covered flask containing a solution of
the guanidine salt in absolute EtOH (20e40 mg/mL). Two such
recrystallizations provided the analytical material.
159e160 ꢀC; 1H NMR (400 MHz, CDCl3):
d 6.72 (s, 4H; HAr), 6.70
(s, 2H; HAr), 2.27 (s, 12H; CH3). HRMS (ESþ) exact mass calculated
for [MþH]þ (C17H22N3) requires m/z 268.1808, found m/z 268.1820.
4.3.6. 1,3-Di(naphthalen-1-yl)guanidine (1n). Gray solid. Mp:
201e202 ꢀC; 1H NMR (400 MHz, CDCl3):
d 8.30e7.31 (m, 14H; HAr).
HRMS (ESþ) exact mass calculated for [MþH]þ (C21H18N3) requires
m/z 312.1495, found m/z 312.1508.
4.3.7. 1,3-Bis(2-fluorophenyl)guanidine (1q). White solid. Mp:
116e117 ꢀC; 1H NMR (400 MHz, CDCl3):
d 7.45e7.49 (m, 2H; HAr),
7.07e7.11 (m, 4H; HAr), 6.98e7.03 (m, 2H; HAr), 4.73 (br s, 3H; NH).
HRMS (ESþ) exact mass calculated for [MþH]þ (C13H12F2N3) re-
quires m/z 248.0994, found m/z 248.1009.
4.3.8. 1,3-Bis(2-chlorophenyl)guanidine (1r). White solid. Mp:
166e167 ꢀC; 1H NMR (400 MHz, CDCl3):
d 7.53e7.64 (m, 2H; HAr),
7.36e7.42 (m, 2H; HAr), 7.20e7.25 (m, 2H; HAr), 6.95e7.02 (m, 2H;
H
Ar). HRMS (ESþ) exact mass calculated for [MþH]þ (C13H12Cl2N3)
4.4.1. 1-Phenyl-3-m-tolylguanidine
116e118 ꢀC; 1H NMR (400 MHz, CDCl3):
7.24e6.79 (m, 7H; HAr), 4.95 (br s, 3H; NH), 2.32 (s, 3H; CH3). 13
NMR (100 MHz, CDCl3): 149.0 (C]NH), 139.4, 129.4, 129.3, 123.6,
(3a). Pink
solid.
Mp:
requires m/z 280.0403, found m/z 280.0409.
d
7.28e7.35 (m, 2H; HAr),
C
4.3.9. 1,3-Bis(2-bromo-4-methylphenyl)guanidine (1s). White solid.
d
Mp: 193e194 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.31e7.43 (m, 4H;
122.9, 119.9, 21.4 (CH3). HRMS (ESþ) exact mass calculated for
H
Ar), 7.05e7.13 (m, 2H; HAr), 2.29 (s, 6H; CH3). HRMS (ESþ) exact
[MþH]þ (C14H16N3) requires m/z 226.1339, found m/z 226.1343.
mass calculated for [MþH]þ (C15H16Br2N3) requires m/z 397.9685,
found m/z 397.9692.
4.4.2. 1-(4-Fluorophenyl)-3-phenylguanidine (3b). Pink solid. Mp:
114e116 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.28e7.35 (m, 2H; HAr),
4.3.10. 1,3-Bis(2-methoxyphenyl)guanidine (1t). Brown solid. Mp:
7.15e6.96 (m, 7H; HAr), 4.91 (br s, 3H; NH). 13C NMR (100 MHz,
99e101 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.40 (d, J¼6.9 Hz, 2H; HAr),
CDCl3): d 149.4 (C]NH), 129.5, 124.6, 122.9, 116.2, 116.0. HRMS
7.02e6.88 (m, 6H; HAr), 3.84 (s, 6H; OCH3). HRMS (ESþ) exact mass
calculated for [MþH]þ (C15H18N3O2) requires m/z 272.1394, found
m/z 272.1390.
(ESþ) exact mass calculated for [MþH]þ (C13H13FN3) requires m/z
230.1088, found m/z 230.1098.
4.4.3. 1-(2-Fluorophenyl)-3-phenylguanidine (3c). White solid. Mp:
4.3.11. 1,3-Bis(2-(methylthio)phenyl)guanidine (1u). White solid.
121e122 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.31e7.35 (m, 3H; HAr),
7.17e7.22 (m, 2H; HAr), 7.06e7.12 (m, 3H; HAr), 6.97e6.99 (m, 1H;
Ar), 4.81 (br s, 3H; NH). 13C NMR (100 MHz, CDCl3):
129.5, 124.7
Mp: 140e141 ꢀC; 1H NMR (400 MHz, CDCl3):
d 7.26e7.29 (m, 4H;
H
Ar), 7.16e7.19 (m, 2H; HAr), 7.03e7.07 (m, 2H; HAr), 2.41 (s, 6H;
H
d
CH3). HRMS (ESþ) exact mass calculated for [MþH]þ (C15H18N3S2)
requires m/z 304.0942, found m/z 304.0947.
(d, J¼3.7 Hz), 123.0, 116.1, 115.9. HRMS (ESþ) exact mass calculated
for [MþH]þ (C13H13FN3) requires m/z 230.1088, found m/z 230.1098.
4.3.12. 1,3-Diethyl-1,3-diphenylguanidine (1v). Yellow oil. 1H NMR
4.4.4. 1-(3-Chlorophenyl)-3-phenylguanidine (3d). Brownsolid. Mp:
(400 MHz, CDCl3):
d
7.14 (t, J¼7.9 Hz, 4H; HAr), 6.96 (t, J¼7.4 Hz, 2H;
104e105 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.29e7.36 (m, 2H; HAr),
7.25e7.14 (m, 3H; HAr), 7.13e7.07 (m, 2H; HAr), 7.03e6.92 (m, 2H;
Ar), 4.91 (br s, 3H; NH).13C NMR (100 MHz, CDCl3):
149.0 (C]NH),
HAr), 6.88 (d, J¼8.6 Hz, 4H; HAr), 3.63 (q, J¼7.1 Hz, 4H; CH2), 1.08 (t,
J¼7.1 Hz, 6H; CH3). 13C NMR (100 MHz, CDCl3):
d
161.6 (C]NH),
H
d
144.8 (2CAr), 128.6 (4CHAr), 124.3 (2CHAr), 123.6 (4CHAr), 45.8
(2CH2), 13.1 (2CH3). HRMS (ESþ) exact mass calculated for [MþH]þ
(C17H22N3) requires m/z 268.1808, found m/z 268.1810.
130.4, 129.5, 122.9, 122.8, 121.0. HRMS (ESþ) exact mass calculated
for[MþH]þ (C13H13ClN3)requiresm/z 246.0793, foundm/z 246.0801.
4.4.5. 1-(2-Chlorophenyl)-3-phenylguanidine (3e). White solid. Mp:
4.3.13. 1,3-Dibenzylguanidine (1w). White solid. Mp: 187e188 ꢀC.
124e125 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.28e7.43 (m, 4H; HAr),
7.20e7.22 (m, 3H; HAr), 7.09e7.11 (m, 1H; HAr), 6.94e6.99 (m, 1H;
Ar), 4.78 (br s, 3H; NH). 13C NMR (100 MHz, CDCl3):
148.8 (C]
1H NMR (400 MHz, DMSO)
d
8.16 (br s, 3H, NH), 7.52e7.14 (m, 10H),
4.47 (s, 4H, CH2). 13C NMR (150 MHz, DMSO)
d
156.2 (C]NH), 137.4
H
d
(2CAr), 128.5 (4CHAr), 127.4 (2CHAr), 127.2 (4CHAr), 43.9 (2CH2).
HRMS (ESþ) exact mass calculated for [MþH]þ (C15H18N3) requires
m/z 240.1495, found m/z 240.1494.
NH), 123.0, 129.5, 127.7, 124.3, 123.5, 122.8. HRMS (ESþ) exact mass
calculated for [MþH]þ (C13H13ClN3) requires m/z 246.0793, found
m/z 246.0793.
4.3.14. 1,3-Dicyclohexylguanidine
(1x). White
solid.
Mp:
4.4.6. 1-(4-Methoxyphenyl)-3-phenylguanidine (3f). Brown solid.
157e158 ꢀC. 1H NMR (400 MHz, DMSO)
d
7.32 (br d, J¼59.2 Hz, 3H,
Mp: 129e130 ꢀC; 1H NMR (400 MHz, CDCl3):
d 7.27e7.38 (m, 2H;
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8
D. Chang et al. / Tetrahedron xxx (2015) 1e10
HAr), 6.96e7.16 (m, 5H; HAr), 6.81e6.93 (m, 2H; HAr), 3.79 (s, 3H;
OCH3). 13C NMR (100 MHz, CDCl3):
149.8 (C]NH), 129.5, 125.4,
(br s, 1H; NH), 7.52 (d, J¼8.9 Hz, 2H; HAr), 7.15 (d, J¼8.9 Hz, 2H; HAr),
1.94 (s, 3H; CH3). 13C NMR (100 MHz, acetone):
168.4 (C]O),138.5
d
d
123.0, 114.8, 55.5 (OCH3). HRMS (ESþ) exact mass calculated for
(CAr), 128.5 (2CHAr), 127.4 (CAr), 120.6 (2CHAr), 23.3 (CH3). HRMS
(ESþ) exact mass calculated for [MþH]þ (C8H9ClNO) requires m/z
170.0367, found m/z 170.0375.
[MþH]þ (C14H16N3O) requires m/z 242.1288, found m/z 242.1299.
4.4.7. 1-Phenyl-3-(4-(trifluoromethyl)phenyl)guanidine (3g). Brown
solid. Mp: 163e164 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.51e7.62 (m,
2H; HAr), 7.30e7.42 (m, 2H; HAr), 7.04e7.24 (m, 5H; HAr), 5.03 (br s,
3H; NH).13C NMR (100 MHz, CDCl3):
148.9 (C]NH),129.6,126.6 (q,
4.5.6. N-(4-Bromophenyl)acetamide (2f). White solid, 46.5 mg, 54%
isolated yield. Mp: 165e166 ꢀC; 1H NMR (400 MHz, MeOD):
d
7.48
(d, J¼8.9 Hz, 2H; HAr), 7.42 (d, J¼8.9 Hz, 2H; HAr), 2.11 (s, 3H; CH3).
13C NMR (100 MHz, MeOD):
171.7 (C]O), 139.3 (CAr), 132.8
d
J¼3.8 Hz), 124.4, 123.0, 122.5. HRMS (ESþ) exact mass calculated for
[MþH]þ (C14H13F3N3) requires m/z 280.1056, found m/z 280.1069.
Note: Because of the presence of tautomers, we found that, as
previously reported by other,12 some 13C NMR signals are hardly
detectable for most of guanidines; only obvious signals are reported.
d
(2CHAr), 122.8 (2CHAr), 117.4 (CAr), 23.8 (CH3). HRMS (ESþ) exact
mass calculated for [MþH]þ (C8H9BrNO) requires m/z 213.9862,
found m/z 213.9865.
4.5.7. N-(4-Acetylphenyl)acetamide (2g). White solid, 36.3 mg, 51%
isolated yield. Mp: 166e167 ꢀC; 1H NMR (400 MHz, MeOD):
4.5. General procedure for the synthesis of acetanilides from
guanidines
d
7.99e7.92 (m, 2H; HAr), 7.69 (d, J¼8.8 Hz, 2H; HAr), 2.56 (s, 3H;
CH3), 2.15 (s, 3H; CH3). 13C NMR (100 MHz, MeOD):
d
199.4 (C]O),
To a screw-cap reaction tube was added symmetrical N,N0-di-
substituted guanidines 1a (0.2 mmol), Pd(OAc)2 (5 mol %, 2.2 mg),
Cu(OAc)2 (0.2 mmol, 36.3 mg). The reaction tube was evacuated and
back-filled with CO (three times, balloon). MeCN (2 mL) was added
using a syringe and the mixture was heated to the desired tem-
perature with use of an oil bath. When the reaction was completed
(detected by TLC), the mixture was cooled to room temperature and
vented to discharge the excess CO. The solvent was concentrated by
evaporation in vacuo. The residue was purified by flash column
chromatography on silica gel to afford the desired product amides
2a with petroleum ether/ethyl acetate as the eluent.
172.0 (C]O), 144.8 (CAr), 133.6 (CAr), 130.7 (2CHAr), 120.0 (2CHAr),
26.5 (CH3), 24.1 (CH3). HRMS (ESþ) exact mass calculated for
[MþH]þ (C10H12NO2) requires m/z 178.0863, found m/z 178.0868.
4.5.8. Methyl 4-acetamidobenzoate (2h). Yellow solid, 34.8 mg, 45%
isolated yield. Mp: 127e128 ꢀC; 1H NMR (400 MHz, CDCl3):
d
8.15 (br
s,1H; NH), 7.98 (d, J¼8.6 Hz, 2H; HAr), 7.62 (d, J¼8.6 Hz, 2H; HAr), 3.90
(s, 3H; OCH3), 2.20 (s, 3H; CH3). 13C NMR (100 MHz, CDCl3):
169.0
d
(C]O), 166.8 (C]O), 142.4 (CAr), 130.8 (2CHAr), 125.5 (CAr), 118.9
(2CHAr), 52.1 (OCH3), 24.7 (CH3). HRMS (ESþ) exact mass calculated
for [MþH]þ (C10H12NO3) requires m/z 194.0812, found m/z 194.0812.
4.5.1. N-Phenylacetamide (2a). White solid, 37.9 mg, 70% isolated
4.5.9. Methyl 4-aminobenzoate. Yellow solid, 20.7 mg, 34% isolated
yield. Mp: 113e114 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.72 (br s, 1H;
yield. Mp: 129e130 ꢀC; 1H NMR (400 MHz, acetone):
d 7.88 (d,
NH), 7.43 (d, J¼7.9 Hz, 2H; HAr), 7.19e7.24 (m, 2H; HAr), 7.02 (t,
J¼8.8 Hz, 2H; HAr), 7.02 (d, J¼8.8 Hz, 2H; HAr), 3.73 (s, 3H; OCH3). 13
C
J¼7.4 Hz, 1H; HAr), 2.07 (s, 3H; CH3). 13C NMR (100 MHz, CDCl3):
NMR (100 MHz, acetone): d 166.6 (C]O), 144.1 (CAr), 132.2 (2CHAr),
d
168.8 (C]O), 138.0 (CAr), 129.0 (2CHAr), 124.3 (CHAr), 120.1
125.7 (CAr), 115.7 (2CHAr), 52.2 (OCH3). HRMS (ESþ) exact mass
calculated for [MþH]þ (C8H10NO2) requires m/z 152.0706, found m/
z 152.0713.
(2CHAr), 24.5 (CH3). HRMS (ESþ) exact mass calculated for [MþH]þ
(C8H10NO) requires m/z 136.0757, found m/z 136.0762.
4.5.2. N-m-Tolylacetamide (2b). Brown solid, 34.6 mg, 58% isolated
4.5.10. N-(4-(Trifluoromethyl)phenyl)acetamide (2i). White solid,
49.9 mg, 61% isolated yield. Mp: 149e150 ꢀC; 1H NMR (400 MHz,
yield. Mp: 64e65 ꢀC; 1H NMR (400 MHz, CDCl3):
d 8.02 (br s, 1H;
NH), 7.35 (s, 1H; HAr), 7.29 (d, J¼8.0 Hz, 1H; HAr), 7.16 (t, J¼7.8 Hz,
CDCl3):
d
7.63 (d, J¼8.3 Hz, 2H; HAr), 7.56 (d, J¼8.3 Hz, 2H; HAr), 2.20
1H; HAr), 6.89 (d, J¼7.5 Hz, 1H; HAr), 2.28 (s, 3H; CH3), 2.12 (s, 3H;
(s, 3H; CH3). 13C NMR (100 MHz, CDCl3):
d
168.7 (C]O), 140.9 (CAr),
CH3). 13C NMR (100 MHz, CDCl3):
d
169.0 (C]O), 138.8 (CAr), 138.0
126.3 (q, J¼4.0 Hz; 2CHAr), 126.0 (q, J¼33.0 Hz; CAr), 124.1
(q, J¼271.5 Hz; CF3), 119.4 (2CHAr), 24.7 (CH3). HRMS (ESþ) exact
mass calculated for [MþH]þ (C9H9F3NO) requires m/z 204.0631,
found m/z 204.0631.
(CAr), 128.7 (CHAr), 125.1 (CHAr), 120.8 (CHAr), 117.2 (CHAr), 24.4
(CH3), 21.5 (CH3). HRMS (ESþ) exact mass calculated for [MþH]þ
(C9H12NO) requires m/z 150.0913, found m/z 150.0917.
4.5.3. N-p-Tolylacetamide (2c). White solid, 35.3 mg, 59% isolated
4.5.11. N-(4-Methoxyphenyl)acetamide (2j). White solid, 58.8 mg,
89% isolated yield. Mp: 124e125 ꢀC; 1H NMR (400 MHz, CDCl3):
yield. Mp: 148e149 ꢀC; 1H NMR (400 MHz, acetone):
d
9.09 (br s,
1H; NH), 7.51 (d, J¼8.3 Hz, 2H; HAr), 7.08 (d, J¼8.3 Hz, 2H; HAr), 2.26
(s, 3H; CH3), 2.05 (s, 3H; CH3). 13C NMR (100 MHz, acetone):
168.7
d
7.81 (br s, 1H; NH), 7.37 (d, J¼9.0 Hz, 2H; HAr), 6.81 (d, J¼9.0 Hz,
2H; HAr), 3.76 (s, 3H; OCH3), 2.10 (s, 3H; CH3). 13C NMR (100 MHz,
CDCl3): 168.7 (C]O), 156.4 (CAr), 131.1 (CAr), 122.1 (2CHAr), 114.1
d
(C]O), 138.0 (CAr), 133.2 (CAr), 129.9 (2CHAr), 120.0 (2CHAr), 24.2
(CH3), 20.8 (CH3). HRMS (ESþ) exact mass calculated for [MþH]þ
(C9H12NO) requires m/z 150.0913, found m/z 150.0916.
d
(2CHAr), 55.5 (OCH3), 24.2 (CH3). HRMS (ESþ) exact mass calculated
for [MþH]þ (C9H12NO2) requires m/z 166.0863, found m/z 166.0867.
4.5.4. N-(4-Fluorophenyl)acetamide (2d). White solid, 39.4 mg, 64%
4.5.12. N-(3-Chlorophenyl)acetamide (2k). Brown solid, 31.5 mg,
isolated yield. Mp: 152e153 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.53
(br s, 1H; NH), 7.46e7.30 (m, 2H; HAr), 6.74e7.02 (m, 2H; HAr), 2.08
(s, 3H; CH3). 13C NMR (100 MHz, CDCl3):
167.5 (C]O), 158.4 (d,
46% isolated yield. Mp: 79e81 ꢀC; 1H NMR (400 MHz, CDCl3):
d 8.02
(br s, 1H; NH), 7.56 (s, 1H; HAr), 7.26 (d, J¼8.0 Hz, 1H; HAr), 7.12 (t,
d
J¼8.1 Hz, 1H; HAr), 6.98 (d, J¼7.9 Hz, 1H; HAr), 2.09 (s, 3H; CH3). 13
C
J¼243.5 Hz; CAr-F), 132.9 (d, J¼2.6 Hz; CAr), 120.9 (d, J¼7.8 Hz;
2CHAr), 114.6 (d, J¼22.4 Hz; 2CHAr), 23.3 (CH3). HRMS (ESþ) exact
mass calculated for [MþH]þ (C8H9FNO) requires m/z 154.0663,
found m/z 154.0662.
NMR (100 MHz, CDCl3): d 169.1 (C]O), 139.1 (CAr), 134.5 (CAr), 129.9
(CHAr), 124.3 (CHAr), 120.1 (CHAr), 118.0 (CHAr), 24.5 (CH3). HRMS
(ESþ) exact mass calculated for [MþH]þ (C8H9ClNO) requires m/z
170.0367, found m/z 170.0371.
4.5.5. N-(4-Chlorophenyl)acetamide (2e). White solid, 45.6 mg, 67%
4.5.13. N-(3-Methoxyphenyl)acetamide (2l). White solid, 25.2 mg,
isolated yield. Mp: 174e175 ꢀC; 1H NMR (400 MHz, acetone):
d
9.29
38% isolated yield. Mp: 87e88 ꢀC; 1H NMR (400 MHz, CDCl3):
d 7.27
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D. Chang et al. / Tetrahedron xxx (2015) 1e10
9
(s, 1H; HAr), 7.20 (t, J¼8.1 Hz, 1H; HAr), 6.96 (d, J¼7.9 Hz, 1H; HAr),
132.8 (CHAr), 128.8 (CHAr), 125.2 (CAr), 124.4 (CHAr), 120.7 (CHAr),
24.9 (CH3), 18.9 (CH3). HRMS (ESþ) exact mass calculated for
[MþH]þ (C9H12NOS) requires m/z 182.0634, found m/z 182.0633.
6.66 (d, J¼8.2 Hz, 1H; HAr), 3.80 (s, 3H; OCH3), 2.17 (s, 3H; CH3). 13
C
NMR (100 MHz, CDCl3): d 168.3 (C]O),160.2 (CAr), 139.1 (CAr),129.7
(CHAr), 111.9 (CHAr), 110.1 (CHAr), 105.7 (CHAr), 55.3 (OCH3), 24.7
(CH3). HRMS (ESþ) exact mass calculated for [MþH]þ (C9H12NO2)
requires m/z 166.0863, found m/z 166.0864.
4.6. General procedure for the synthesis of anilides by other
copper(II) carboxylates
4.5.14. N-(3,5-Dimethylphenyl)acetamide
34.8 mg, 53% isolated yield. Mp: 135e137 ꢀC; 1H NMR (400 MHz,
CDCl3): 7.74 (br s, 1H; NH), 7.05 (s, 2H; HAr), 6.64 (s, 1H; HAr), 2.17
(s, 6H; CH3), 2.05 (s, 3H; CH3). 13C NMR (100 MHz, CDCl3):
168.8
(2m). Brown
solid,
To a screw-cap reaction tube was added symmetrical N,N0-di-
substituted guanidines 1a (0.2 mmol), PdCl2 (5 mol %, 1.8 mg), CuX2
(0.44 mmol). The reaction tube was evacuated and back-filled with
CO (three times, balloon). PhCN (2 mL) was added using a syringe
and the mixture was heated to the desired temperature with use of
an oil bath. When the reaction was completed (detected by TLC),
the mixture was cooled to room temperature and vented to dis-
charge the excess CO. After the reaction was completed, the solvent
was concentrated by evaporation in vacuo. The residue was purified
by flash column chromatography on silica gel to afford the desired
product Amides 6a with petroleum ether/ethyl acetate as the
eluent.
d
d
(C]O), 138.6 (2CAr), 137.9 (CAr), 126.0 (CHAr), 117.9 (2CHAr), 24.5
(CH3), 21.3 (2CH3). HRMS (ESþ) exact mass calculated for [MþH]þ
(C10H14NO) requires m/z 164.1070, found m/z 164.1072.
4.5.15. N-(Naphthalen-1-yl)acetamide (2n). Gray solid, 38.0 mg,
51% isolated yield. Mp: 160e161 ꢀC; 1H NMR (400 MHz, MeOD):
d
8.07e7.37 (m, 7H; HAr), 2.27 (s, 3H; CH3). 13C NMR (100 MHz,
MeOD):
d 172.9 (C]O), 135.8 (CAr), 134.2 (CAr), 130.2 (CAr), 129.4
(CHAr), 127.6 (CHAr), 127.3 (CHAr), 127.2 (CHAr), 126.5 (CHAr), 124.1
(CHAr), 123.4 (CHAr), 23.2 (CH3). HRMS (ESþ) exact mass calculated
for [MþH]þ (C12H12NO) requires m/z 186.0913, found m/z 186.0913.
4.6.1. N-Phenylpropionamide (6a). White solid, 28.8 mg, 48% iso-
lated yield. Mp: 106e108 ꢀC; 1H NMR (400 MHz, CDCl3):
4.5.16. N-o-Tolylacetamide (2p). Brown solid, 22.1 mg, 37% isolated
d
7.47e7.58 (m, 2H; HAr), 7.26e7.36 (m, 2H; HAr), 7.05e7.16 (m, 1H;
yield. Mp: 125e126 ꢀC; 1H NMR (400 MHz, CDCl3):
d 7.60 (d,
H
Ar), 2.51e2.27 (m, 2H; CH2), 1.21e1.27 (m, 3H; CH3). 13C NMR
J¼8.0 Hz, 1H; HAr), 7.41 (br s, 1H; NH), 7.10e7.20 (m, 2H; HAr), 7.05
(100 MHz, CDCl3):
d 172.3 (C]O), 138.0 (CAr), 129.0 (2CHAr), 124.2
(t, J¼7.3 Hz, 1H; HAr), 2.20 (s, 3H; CH3), 2.12 (s, 3H; CH3). 13C NMR
(CHAr), 119.9 (2CHAr), 30.7 (CH2), 9.7 (CH3). HRMS (ESþ) exact mass
calculated for [MþH]þ (C9H12NO) requires m/z 150.0913, found m/z
150.0918.
(100 MHz, CDCl3):
d 168.8 (C]O), 135.7 (CAr), 130.5 (CHAr), 130.2
(CAr), 126.6 (CHAr), 125.5 (CHAr), 124.1 (CHAr), 24.0 (CH3), 17.8 (CH3).
HRMS (ESþ) exact mass calculated for [MþH]þ (C9H12NO) requires
m/z 150.0913, found m/z 150.0914.
4.6.2. N-Phenylformamide (6b). Brown solid, 16.6 mg, 34% isolated
yield. Mp: 46e48 ꢀC; 1H NMR (400 MHz, CDCl3):
d
8.71 (d, J¼9.5 Hz,
1H), 8.38 (s, 1H), 8.22 (s, 1H), 7.54 (d, J¼7.7 Hz, 2H), 7.32e7.38 (m,
4H), 7.23e7.00 (m, 4H). 13C NMR (100 MHz, CDCl3):
162.6, 159.0,
4.5.17. N-(2-Fluorophenyl)acetamide (2q). White solid, 32.7 mg,
53% isolated yield. Mp: 74e76 ꢀC; 1H NMR (400 MHz, CDCl3):
d
d
8.25 (t, J¼7.9 Hz, 1H; HAr), 7.61 (br s, 1H; NH), 7.00e7.12 (m, 3H;
136.9, 136.7, 129.8, 129.1, 125.3, 124.9, 120.0, 118.9. HRMS (ESþ)
exact mass calculated for [MþH]þ (C7H8NO) requires m/z 122.0600,
found m/z 122.0606.
H
Ar), 2.21 (s, 3H; CH3). 13C NMR (100 MHz, CDCl3):
d
168.6 (C]O),
152.5 (d, J¼243.4 Hz; CAr-F), 126.3 (d, J¼10.0 Hz; CAr), 124.5
(d, J¼3.6 Hz, CHAr), 124.4 (d, J¼7.6 Hz; CHAr), 122.1 (CHAr), 114.8
(d, J¼19.3 Hz; CHAr), 24.5 (CH3). HRMS (ESþ) exact mass calcu-
lated for [MþH]þ (C8H9FNO) requires m/z 154.0663, found m/z
154.0666.
4.6.3. 2-Ethyl-N-phenylhexanamide (6c). White solid, 17.0 mg, 19%
isolated yield. Mp: 86e88 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.55 (d,
J¼7.9 Hz, 2H; HAr), 7.31 (t, J¼7.8 Hz, 2H; HAr), 7.10 (t, J¼7.4 Hz, 1H;
Ar), 2.05e2.15 (m, 1H; CH), 1.64e1.78 (m, 2H; CH2), 1.45e1.60 (m,
H
4.5.18. N-(2-Chlorophenyl)acetamide (2r). Gray solid, 46.8 mg, 69%
2H; CH2), 1.23e1.38 (m, 4H; 2CH2), 0.95 (t, J¼7.4 Hz, 3H; CH3), 0.88
isolated yield. Mp: 86e88 ꢀC; 1H NMR (400 MHz, CDCl3):
d 8.32 (d,
(t, J¼6.7 Hz, 3H; CH3). 13C NMR (100 MHz, CDCl3):
d 174.5 (C]O),
J¼8.0 Hz, 1H; HAr), 7.69 (br s, 1H; NH), 7.34 (d, J¼8.0 Hz, 1H; HAr),
138.0 (CAr), 129.0 (2CHAr), 124.2 (CHAr), 120.0 (2CHAr), 50.8 (CH),
32.6 (CH2), 29.9 (CH2), 26.2 (CH2), 22.8 (CH2), 14.0 (CH3), 12.1 (CH3).
HRMS (ESþ) exact mass calculated for [MþH]þ (C14H22NO) requires
m/z 220.1696, found m/z 220.1698.
7.28e7.19 (m, 1H; HAr), 7.02 (t, J¼7.5 Hz, 1H; HAr), 2.22 (s, 3H; CH3).
13C NMR (100 MHz, CDCl3):
d 168.3 (C]O), 134.6 (CAr), 129.0 (CHAr),
127.7 (CHAr), 124.7 (CHAr), 122.7 (CAr), 121.8 (CHAr), 24.8 (CH3).
HRMS (ESþ) exact mass calculated for [MþH]þ (C8H9ClNO) requires
m/z 170.0367, found m/z 170.0373.
4.6.4. N-Phenylstearamide (6d). White solid, 46.3 mg, 32% isolated
yield. Mp: 82e83 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.51 (d, J¼8.0 Hz,
4.5.19. N-(2-Methoxyphenyl)acetamide (2t). White solid, 48.2 mg,
2H; HAr), 7.31 (t, J¼7.9 Hz, 2H; HAr), 7.19 (br s, 1H), 7.09 (t, J¼7.3 Hz,
1H; HAr), 2.34 (t, J¼7.6 Hz, 2H; CH2), 1.82e1.62 (m, 2H; CH2),
1.20e1.40 (m, 28H; CH2), 0.88 (t, J¼6.8 Hz, 3H; CH3). 13C NMR
70% isolated yield. Mp: 79e81 ꢀC; 1H NMR (400 MHz, CDCl3):
d 8.35
(d, J¼7.1 Hz, 1H; HAr), 7.77 (br s, 1H; NH), 6.85e7.05 (m, 3H; HAr),
3.87 (s, 3H; OCH3), 2.19 (s, 3H; CH3). 13C NMR (100 MHz, CDCl3):
(100 MHz, CDCl3):
d 171.4 (C]O), 138.0 (CAr), 129.0 (2CHAr), 124.2
d
168.2 (C]O), 147.7 (CAr), 127.7 (CAr), 123.6 (CHAr), 121.1 (CHAr),
(CHAr), 119.8 (2CHAr), 37.9, 31.9, 29.7e29.3, 25.6, 22.7, 14.1. HRMS
(ESþ) exact mass calculated for [MþH]þ (C24H42NO) requires m/z
360.3261, found m/z 360.3268.
119.8 (CHAr), 109.9 (CHAr), 55.6 (OCH3), 24.8 (CH3). HRMS (ESþ)
exact mass calculated for [MþH]þ (C9H12NO2) requires m/z
166.0863, found m/z 166.0866.
4.6.5. N-Phenylbenzamide (6e). White solid, 36.4 mg, 46% isolated
yield. Mp: 161e163 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.86 (d, J¼7.3 Hz,
4.5.20. N-(2-(Methylthio)phenyl)acetamide
24.9 mg, 34% isolated yield. Mp: 103e104 ꢀC; 1H NMR (400 MHz,
CDCl3):
8.27e8.29 (m, 2H; NH, HAr), 7.46 (d, J¼7.5 Hz, 1H; HAr),
7.27 (t, J¼7.6 Hz, 1H; HAr), 7.06 (t, J¼7.4 Hz, 1H; HAr), 2.38 (s, 3H),
2.23 (s, 3H). 13C NMR (100 MHz, CDCl3):
168.4 (C]O), 138.3 (CAr),
(2u). White
solid,
2H; HAr), 7.64 (d, J¼7.7 Hz, 2H; HAr), 7.58e7.34 (m, 5H; HAr), 7.15 (t,
J¼7.4 Hz, 1H; HAr). 13C NMR (100 MHz, CDCl3):
d
165.8 (C]O), 134.0
d
(CAr), 135.0 (CAr), 131.8 (CHAr), 129.1 (2CHAr), 128.8 (2CHAr), 127.0
d
(2CHAr), 124.6 (CHAr), 120.2 (2CHAr). HRMS (ESþ) exact mass
Please cite this article in press as: Chang, D.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.01.050

10
D. Chang et al. / Tetrahedron xxx (2015) 1e10
calculated for [MþH]þ (C13H12NO) requires m/z 198.0913, found m/z
the NCET (NCET-12-0145), and the ‘Technology Foundation for Se-
lected Overseas Chinese Scholar’ of Ministry of Human Resources
and Social Securityof China (MOHRSS). We thankProf. H. Mayr (LMU
198.0918.
€
4.7. Synthesis of N-phenyl-N-(N-phenylcarbamimidoyl)acet-
Munchen) for helpful discussions.
amide (7)
Diphenylguanidine (10 mmol, 2.11 g) was dissolved in 30 mL
acetonitrile. Acetic anhydride (5 mmol) dissolved in acetonitrile
(20 mL) was slowly added to the mixture and stirred overnight at
room temperature. The reaction mixture was extracted with ethyl
acetate. The organic layer was washed with water and brine and
dried over Na2SO4. Removal of solvent by evaporation in vacuo
followed by purification with column chromatography on silica gel
provided the desired products.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.01.050.
References and notes
1. (a) Larock, R. C. Comprehensive Organic Transformations: A Guide to Functional
ꢀ
Group Preparations, 2nd ed.; Wiley-VCH: New York, NY, 1999; (b) Kocienski, P. J.
4.7.1. N-Phenyl-N-(N-phenylcarbamimidoyl)acetamide (7). White
Protecting Groups, 3rd ed.; Thieme: Stuttgart, Germany, 2005; (c) Wuts, P. G. M.;
Greene, T. W. Greene’s Protective Groups in Organic Synthesis, 4th ed.; John Wiley
& Sons: Hoboken, NJ, 2007.
2. A possible ring-opening reaction mechanism through the cleavage of a N-imino
bond was reported, see: Kuninobu, Y.; Uesugi, T.; Kawata, A.; Takai, K. Angew.
Chem., Int. Ed. 2011, 50, 10406e10408.
3. (a) Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2011, 50,
519e522; (b) Wang, R.; Falck, J. R. Chem. Commun. 2013, 6516e6518; (c) Wang,
R.; Falck, J. R. RSC Adv. 2014, 4, 1062e1066; (d) Wang, R.; Falck, J. R. Catal. Rev.
2014, 56, 288e331; (e) Miyazaki, Y.; Ohta, N.; Semba, K.; Nakao, Y. J. Am. Chem.
Soc. 2014, 136, 3732e3735; (f) Pan, Z.; Pound, S. M.; Rondla, N. R.; Douglas, C. J.
Angew. Chem., Int. Ed. 2014, 53, 5170e5174; (g) Rao, B.; Zeng, X. Org. Lett. 2014,
16, 314e317.
4. (a) Kalyankar, G. D.; Ikawa, M.; Snell, E. E. J. Biol. Chem. 1958, 233, 1175e1178; (b)
Lewis, C. A., Jr.; Wolfenden, R. J. Am. Chem. Soc. 2014, 136, 130e136 and refer-
ences therein.
5. (a) Ong, T.-G.; Yap, G. P. A.; Richeson, D. S. J. Am. Chem. Soc. 2003, 125,
8100e8101; (b) Shen, H.; Chan, H.-S.; Xie, Z. J. Am. Chem. Soc. 2007, 129,
12934e12935; (c) Shen, H.; Xie, Z. Organometallics 2008, 27, 2685e2687; (d)
Shen, H.; Wang, Y.; Xie, Z. Org. Lett. 2011, 13, 4562e4565; (e) Ajellal, N.; Lyu-
bov, D. M.; Sinenkov, M. A.; Fukin, G. K.; Cherkasov, A. V.; Thomas, C. M.;
Carpentier, J.-F.; Trifonov, A. A. Chem.dEur. J. 2008, 14, 5440e5448; (f)
Gushchin, P. V.; Tyan, M. R.; Bokach, N. A.; Revenco, M. D.; Haukka, M.; Wang,
M.-Y.; Lai, C.-H.; Chou, P.-T.; Kukushkin, V. Y. Inorg. Chem. 2008, 47,
11487e11500; (g) Gushchin, P. V.; Kuznetsov, M. L.; Haukka, M.; Wang, M.-J.;
Gribanov, A. V.; Kukushkin, V. Y. Inorg. Chem. 2009, 48, 2583e2592; (h) Coyle,
solid. Mp: 92e94 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.53e7.18 (m, 7H;
Ar), 6.96 (t, J¼7.3 Hz,1H; HAr), 6.77 (d, J¼7.1 Hz, 2H; HAr), 6.21 (br s,
2H), 1.96 (s, 3H; CH3). 13C NMR (100 MHz, CDCl3):
174.1 (C]O),
H
d
150.6 (C]NH), 148.0 (CAr), 140.6 (CAr), 129.5 (2CHAr), 129.4 (2CHAr),
129.0 (2CHAr), 128.4 (CHAr), 122.8 (CHAr), 121.9 (2CHAr), 26.4 (CH3).
HRMS (ESþ) exact mass calculated for [MþH]þ (C15H16N3O) re-
quires m/z 254.1288, found m/z 254.1298.
4.8. Synthesis of N-phenylcyanamide (8) according to Neu-
ville’s method13
Cyanogen bromide (20.0 mmol, 2.08 g, 2.0 equiv) was dissolved
in 20 mL toluene under argon, aniline (10.0 mmol, 1.0 equiv) and
NaHCO3 (35.0 mmol, 2.94 g, 3.5 equiv) were added to the mixture
and stirred for 3 h at room temperature. The mixture was quenched
with water and extracted with EtOAc (3ꢁ40 mL). The organic layers
were combined, washed with H2O and brine, dried by MgSO4, and
concentrated under reduced pressure to give a residue, which was
purified by flash chromatography (SiO2, eluent: DCM/heptane¼1:1).
€
J. P.; Johnson, P. A.; Dilabio, G. A.; Barry, S. T.; Muller, J. Inorg. Chem. 2010, 49,
2844e2850; (i) Zhang, J.; Yi, W.; Chen, Z.; Zhou, X. J. Chem. Soc., Dalton Trans.
4.8.1. N-Phenylcyanamide (8). Yellow oil.1H NMR (400 MHz, CDCl3):
2013, 42, 5826e5831.
d
7.34 (t, J¼7.9 Hz, 2H; HAr), 7.09 (t, J¼7.5 Hz, 1H; HAr), 7.06e6.97 (m,
6. (a) Coleman, G. H.; Alvarado, A. M. Org. Synth. 1923, 3, 3e5; (b) Mitchell, J. A.;
Reid, E. E. J. Am. Chem. Soc. 1931, 53, 1879e1883.
7. For zinc acetate as a selective N-acetylating agent, see: Brahmachari, G.; Laskar,
2H;HAr).13C NMR(100MHz, CDCl3):
d
137.2 (CAr),129.8(2CHAr),123.7
(CHAr), 115.4 (2CHAr), 111.3 (CN). HRMS (ESþ) exact mass calculated
for [MþH]þ (C7H7N2) requires m/z 119.0604, found m/z 119.0605.
S.; Sarkar, S. J. Chem. Res. 2010, 288e295.
8. (a) Moiseev, I. I. Pure Appl. Chem. 1989, 61, 1755e1762; (b) Guan, Z.-H.; Chen, M.;
Ren, Z.-H. J. Am. Chem. Soc. 2012, 134, 17490e17493.
4.9. Synthesis of 1-phenylguanidine (9)
According to Al-Mourabit’s method.14
Acknowledgements
9. (a) M’Creath, D. Ber. Dtsch. Chem. Ges. 1875, 8, 1181e1182; (b) Busch, M.; Blume,
G.; Pungs, E. J. Prakt. Chem. 1909, 79, 513e546.
10. Xing, H.; Zhang, Y.; Lai, Y.; Jiang, Y.; Ma, D. J. Org. Chem. 2012, 77, 5449e5453.
11. Scherz, M. W.; Fialeix, M.; Fischer, J. B.; Reddy, N. L.; Server, A. C.; Sonders, M. S.;
Tester, B. C.; Weber, E.; Wong, S. T.; Keana, F. W. J. Med. Chem. 1990, 33,
2421e2429.
12. Lv, X.; Bao, W. J. Org. Chem. 2009, 74, 5618e5621.
13. Li, J.; Neuville, L. Org. Lett. 2013, 15, 6124e6127.
14. Tran, M. Q.; Ermolenko, L.; Retailleau, P.; Nguyen, T. B.; Al-Mourabit, A. Org. Lett.
Financial support was provided by the ‘Hundred Talents Pro-
gram’ of Harbin Institute of Technology (HIT), the NSFC (21202027),
2014, 16, 920e923.
Please cite this article in press as: Chang, D.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.01.050