One-pot synthesis of diverse: N, N ′-disubstituted guanidines from N -chlorophthalimide, isocyanides and amines via N -phthaloyl-guanidines

Article abstract of DOI:10.1039/c7ob03109b

A sequential one-pot approach towards N,N′-disubstituted guanidines from N-chlorophthalimide, isocyanides and amines is reported. This strategy provides straightforward and efficient access to diverse guanidines in yields up to 81% through previously unprecedented N-phthaloylguanidines. This protocol also features wide substrate scope and mild conditions.

Full text of DOI:10.1039/c7ob03109b

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One-pot synthesis of diverse N,N’-disubstituted
guanidines from N-chlorophthalimide, isocyanides
and amines via N-phthaloyl-guanidines†
Cite this: DOI: 10.1039/c7ob03109b
András Demjén,a,b Anikó Angyal,a,b János Wölfling, b László G. Puskása and
a
Iván Kanizsai
*
Received 15th December 2017,
Accepted 1st March 2018
A sequential one-pot approach towards N,N’-disubstituted guanidines from N-chlorophthalimide, isocya-
nides and amines is reported. This strategy provides straightforward and efficient access to diverse guani-
dines in yields up to 81% through previously unprecedented N-phthaloylguanidines. This protocol also
features wide substrate scope and mild conditions.
DOI: 10.1039/c7ob03109b
rsc.li/obc
available guanylating reagent di(imidazole-1-yl)methanimine
offers a more convenient access to N,N′-disubstituted guani-
Introduction
The guanidine functionality is a privileged structure in many dines through the stepwise displacement of its imidazole
natural products, biochemical processes and pharmaceuticals, groups by amines (Scheme 1c).16 Besides the necessary iso-
playing key roles in various biological functions.1 Moreover, lation of intermediates, the nucleophilicity of amines can
guanidines also serve as valuable scaffolds in organocatalysis2 strongly affect the sequence of substitution and the yield of
and precursors for the synthesis of heterocycles.3 The products, or even limit the achievable substitution pattern.
traditional synthesis of guanidines mainly relies on the Therefore, the development of a facile and general one-pot pro-
addition of amines to carbodiimides,4 or utilizes thioureas cedure for the synthesis of diverse N,N′-substituted guanidines
(usually bearing electron-withdrawing substituents) in con- is still highly desired.
junction with thiophilic metal salts,5 Mukaiyama’s reagent,6
coupling reagents,7 or other activating agents.8 S-Oxidized
thiourea derivatives9 and guanylating agents10 (such as
S-methylisothioureas, pyrazole-1-carboximidamide and its
derivatives, or triflyl guanidines) are also commonly employed.
Beyond the well-known11 and recently12 developed approaches,
a few isocyanide-based procedures have also been established,
albeit each method exclusively affords N,N′,N″-substituted
guanidines.13
Looking at the synthetic toolbox for the assembly of N,N′-di-
substituted guanidines, N-protected S-methylisothioureas are
often used as starting materials; however, the techniques avail-
able for the derivatization of isothioureas lack the achievable
diversity (Scheme 1a).14 N,N′-Disubstituted guanidines can
also be obtained from amines through cyanamides, but utiliz-
ation of toxic cyanogen bromide and harsh conditions are
required (Scheme 1b).15 The application of a commercially
aAVIDIN Ltd, Alsó kikötő sor 11/D, Szeged, H-6726, Hungary.
E-mail: i.kanizsai@avidinbiotech.com; Tel: (+36)-62-202-107
bDepartment of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, H-6720,
Hungary
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, mechanistic study, compound characterization data and copies of NMR
spectra. See DOI: 10.1039/c7ob03109b
Scheme 1 Classical and new routes to N,N’-disubstituted guanidines.
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Herein, we report a new approach for the synthesis of N,N′- N-chlorophthalimide to tert-butyl isocyanide took place rapidly
disubstituted guanidines employing N-chlorophthalimide, iso- in dichloromethane at 0 °C with full conversion. However,
cyanides and amines as substrates in a sequential one-pot pro- further reaction with p-anisidine led to the desired guanidine
tocol (Scheme 1d).
5a in only 12% HPLC yield, along with an unexpected side-
product, which was identified as isoindolinone 6a (Table 1,
entry 1). In order to optimize the reaction conditions, various
solvents were tested (entries 1–15). Acetonitrile was found to
be the best medium affording 5a in 75% HPLC yield, while
non-polar solvents and ethers led to 6a predominantly. In
order to avoid the formation of the urea-type product, an-
hydrous solvents were used; however, “wet” acetonitrile pro-
vided 5a in almost identical yield (entry 15). Decreasing the
temperature gave 5a in lower yields, while elevated tempera-
tures had no significant effect on the outcome of the reaction
(entries 16–20). It is noteworthy, that the replacement of 1 with
N-bromo- or N-iodophthalimide resulted in complex reaction
mixtures and no trace of 5a or 6a.17
Results and discussion
At the outset of the study, the model reaction of
N-chlorophthalimide (1) with tert-butyl isocyanide (2a) and
p-anisidine (4a) was investigated (Table 1). On the basis of lit-
erature information on the addition of analogous
N-chloroamines to isocyanides,13a we presumed the need for
the prior formation of the imidoyl chloride intermediate 3a,
which
can
react
with
p-anisidine
to
furnish
N-phthaloylguanidine 5a. Pleasingly, the addition of
Interestingly, performing the reaction with aromatic isocya-
nide 2b under the optimized conditions failed to produce the
corresponding guanidine 5b (Table 2, entry 1). However, appli-
cation of an equimolar amount of base (KOtBu, DBU, Na2CO3
or tertiary aliphatic amine) in order to neutralize the liberated
hydrogen chloride promoted the formation of 5b (Table 2,
entries 7–12). Other bases were ineffective and gave access
only to isoindolinone 6a (Table 2, entries 2–6). The best result
Table 1 Optimization of the model reactiona
Table 2 The effect of base on the reaction performed with aromatic
isocyanide 2b a
Yield of
Entry
Solvent
Temp.b
5ac [%]
6ac [%]
1
2
3
4
5
6
7
8
CH2Cl2
DMSO
MeOH
1,4-Dioxane
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
−40 °C
−20 °C
0 °C
40 °C
60 °C
12
0
1
5
7
11
16
4
20
26
45
48
66
75
72
29
30
47
73
66
40
0
8
26
32
24
30
46
26
3
18
8
10
5
7
5
Et2O
Yield of
CHCl3
Toluene
EtOAc
DMF
Acetone
CH3NO2
IPA
MeCN
MeCNd
MeCN
MeCN
MeCN
MeCN
MeCN
Entry
Base
5bb [%]
6ab [%]
9
10
11
12
13
14
15
16
17
18
19
20
1
2
3
4
5
6
7
8
—
TMG
Proton Sponge
Pyridine
DMAP
N-Methylimidazole
KOtBu
0
0
0
0
0
0
1
2
10
39
47
48
32
13
23
45
46
48
16
13
32
28
41
31
13
11
2
DBU
9
Na2CO3
DABCO
DIPEA
10
11
12
6
NEt3
a Reaction conditions: N-Chlorophthalimide (0.25 mmol), anhydrous
solvent (0.50 ml), t-butyl isocyanide (1.1 equiv.), 15 min, 0 °C, then a Reaction conditions: N-Chlorophthalimide (0.25 mmol), anhydrous
p-anisidine (1.2 equiv.), 2 h. b Temperature after the addition of p-anisi- MeCN (0.50 ml), 4-methoxyphenyl isocyanide (1.1 equiv.), 15 min,
dine. c Yield was determined by HPLC (each product was calibrated). 0 °C, then base (1.0 equiv.) and p-anisidine (1.2 equiv.), r.t., 2 h. b Yield
d Non-dried solvent was used.
was determined by HPLC (each product was calibrated).
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Table 4 Scope of the one-pot three-step synthesis with respect to
isocyanidea
was achieved when triethylamine was utilized, providing 5b in
an acceptable 48% HPLC yield (Table 2, entry 12).
To investigate the scope of the reaction and the cleavability
of the phthaloyl moiety, six structurally different
N-phthaloylguanidines 5a–f were first synthesized by employ-
ing aliphatic (substrates 2a,c), benzylic (substrate 2d) or aro-
matic (substrates 2b,e) isocyanides and anilines bearing both
electron-donating (substrates 4a,c) and electron-withdrawing
groups (substrates 4b,d) (Table 3, entries 1–6). The reactions
proceeded smoothly in the presence of triethylamine under
the optimized conditions providing 5a–f in a non-protonated
form in 28–68% isolated yields.18 To our delight, further treat-
ment of 5a–f with methylhydrazine completely removed the
phthaloyl group in all cases, leading to the desired N,N′-di-
substituted guanidines 7a–f in excellent yields under mild con-
ditions (Table 3, entries 1–6).19,20 Obtaining the products as
hydrochloride salts facilitated the isolation procedure.
Although 5a–f were readily formed, their isolation proved to
be rather demanding and required individual chromato-
graphic conditions (see the ESI† for details). Therefore, we
decided to combine the steps of the N,N′-disubstituted guani-
dine synthesis into a sequential one-pot three-step protocol
and omit the isolation of N-phthaloylguanidine intermediates.
First, the scope of the combined method with respect to the
isocyanide reagent was evaluated, using 4a as an aniline input
(Table 4). Gratifyingly, both aliphatic and benzylic, as well as
Table 3 Synthesis and hydrazinolysis of N-phthaloyl-guanidinesa,b
a Reaction conditions: N-Chlorophthalimide (1.0 mmol), anhydrous
MeCN (2.0 ml), isocyanide (1.1 equiv.), 0 °C, 15 min, then Et3N (1.0
equiv.) and aniline (1.2 equiv.), r.t., 2 h, then MeNHNH2 (1.5 equiv.),
40 °C, 2 h. The products were isolated as hydrochloride salts. Isolated
yield (NMR yield in parenthesis). NMR yield was determined by
1H-NMR spectroscopy with 1,3,5-trimethoxybenzene as an internal
standard.
aromatic isocyanides could be subjected to the reaction;
however, their electronic nature had a notable impact on the
overall yield of the products. Benzylic and aliphatic isocyanides
(including the sterically hindered 1,1,3,3-tetramethylbutyl iso-
cyanide) provided the best results (7a and 7g–i, 51–69% iso-
lated yields), while aromatic isocyanides bearing electron-
donating MeO or electron-withdrawing F substituents deli-
vered the corresponding guanidine hydrochlorides 7b,j and 7k
in moderate yields (33–48%).
Unfortunately, the strongly electron-deficient 4-nitrophenyl
isocyanide was barely tolerated (7l, 22% isolated yield), while
methyl isocyanoacetate, TosMIC and 2-isocyano- or 3-isocyano-
pyridine did not afford the desired products.
Yieldc
[%]
Yieldc
[%]
Entry
2
R1
4
R2
5
7
1
2
3
4
5
6
2a t-Bu
4a 4-MeO 5a 68 (73) 7a 98 (99)
2b 4-MeOC6H4 4a 4-MeO 5b 31 (49) 7b 94 (98)
2b 4-MeOC6H4 4b 4-Br 5c 28 (44) 7c 96 (99)
4c 3,5-Me 5d 29 (64) 7d 96 (98)
4d 4-F 5e 48 (54) 7e 97 (99)
4e 5f 30 (47) 7f 96 (99)
2c c-Hex
2d Bn
2e 4-FC6H4
H
a Reaction conditions for the synthesis of 5a–f: N-Chlorophthalimide
(1.0 mmol), anhydrous MeCN (2.0 ml), isocyanide (1.1 equiv.), 0 °C,
15 min, then Et3N (1.0 equiv.) and aniline (1.2 equiv.), r.t., 2 h.
b Reaction conditions for the synthesis of 7a–f: Guanidine 5a–f
(0.25 mmol), MeCN (0.5 ml), MeNHNH2 (1.5 equiv.), 40 °C, 2 h, then
HCl/EtOH (3 equiv.), r.t., 15 min c Isolated yield (NMR yield in parenth-
esis). NMR yield was determined by 1H-NMR spectroscopy with 1,3,5-
trimethoxybenzene as an internal standard.
To further explore the generality of our protocol, various
anilines were subjected to the one-pot reaction applying the
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Table 5 Scope of the one-pot three-step synthesis with respect to
anilinea
Yieldb
[%]
Entry
2
R1
4
R2
H
R3
2,4-F
H
4-CF3
3-I
3,5-Me
4-Me-3-NO2 7q
4-F
4-(NMe2)
H
4-Br
H
H
4-CN
H
7
1
2
3
4
5
6
7
8
2a t-Bu
2a t-Bu
2f
2f
2c c-Hex
2c c-Hex
2d Bn
2d Bn
2b 4-MeOC6H4
2b 4-MeOC6H4
4f
7m 73 (78)
4g Me
4h
4i
4c
4j
4d
4k
4e
4b
7n
7o
7p
7d
66 (71)
55 (61)
64 (68)
56 (58)
35 (38)
52 (54)
47 (51)
42 (43)
34 (42)
43 (45)
t-Octyl
t-Octyl
H
H
H
H
H
H
H
H
H
H
H
H
Scheme 2 Unexpected ring-opening with aliphatic amine 8a.
7e
7r
7s
7c
7t
7f
7u
7v
9
10
11
12
13
14
2g 3,4,5-MeOC6H2 4e
2e 4-FC6H4
2e 4-FC6H4
2h 4-NO2C6H4
4e
4l
4e
37 (39) the temperature (−40 °C) was not successful. Nevertheless, we
27 (33)
35 (37)
reasoned that product 9a might also be transformed to the
desired N,N′-disubstituted guanidine 10a by a straightforward
a Reaction conditions: N-Chlorophthalimide (1.0 mmol), anhydrous
MeCN (2.0 ml), isocyanide (1.1 equiv.), 0 °C, 15 min, then Et3N (1.0
equiv.) and aniline (1.2 equiv.), r.t., 2 h, then MeNHNH2 (1.5 equiv.),
40 °C, 2 h. The products were isolated as hydrochloride salts. b Isolated
yield (NMR yield in parenthesis). NMR yield was determined by
1H-NMR spectroscopy with 1,3,5-trimethoxybenzene as an internal
standard.
intramolecular cleavage. Our hypothesis was supported by the
reaction mechanism of phthalimide deprotection with ali-
phatic amines.21 Indeed, simply heating 9a alone in refluxing
acetonitrile for 10 h readily generated guanidine 10a in an
almost quantitative yield (Scheme 2).
Afterwards, a series of primary aliphatic and aralkyl amines
were tested in a combined one-pot three-step manner (Table 6,
entries 1–9). Intermediates 9a–i were formed smoothly by
previously utilized isocyanides (Table 5, entries 1–14). reacting 1 with isocyanides and amines under slightly modi-
Interestingly, both electron-rich and electron-poor anilines fied conditions (2.2 equivalents of primary amine were used).
were equally tolerated. The electronic effect of substituents Subsequent heating of the reaction mixtures at reflux tempera-
was not significant, with the exception of the nitro group (sub- ture gave complete conversion of 9a–i within 10 h furnishing,
strate 4j, Table 5, entry 6). Even N-substituted anilines could in all cases, guanidine hydrochlorides in moderate to good
be used, as exemplified by N-methylaniline (Table 5, entry 2). yields (44–81%). We were pleased to find that bifunctional ali-
Guanidines derived from aliphatic and benzyl isocyanides phatic amines, such as aminoalcohol 8b and Boc-protected
were obtained in the highest yields (7d,e and 7m–r, up to 73% diaminobutane 8d, were compatible with the protocol and pro-
isolated yield), while aromatic isocyanides, especially with elec- vided the corresponding guanidines 10b and 10d in 80% and
tron-withdrawing substituents, furnished the corresponding 55% isolated yields, respectively (Table 6, entries 2 and 4).
7c,f and 7s–v products in lower yields ranging from 27 to 43%. Moreover, propargylamine (8e) and the sterically demanding
These results suggest that the overall performance of our tert-butylamine (8f) were also well tolerated (Table 6, entries 5
method principally depends on the reactivity of the isocyanide and 6). Alternatively, N-alkyl-N′-aryl guanidines are readily
component.
accessible from aromatic isocyanides as well, as demonstrated
As an extension of the one-pot protocol towards N,N′-dia- by the synthesis of 7h (Table 6, entry 9). Although their syn-
lkylguanidines, we next surveyed the reaction of isobutylamine thetic routes are somewhat different, it is noteworthy that ali-
(8a) with 1 and 2a under standard conditions (Scheme 2). phatic and aralkyl amines provided the corresponding guani-
Surprisingly, no appreciable amount of guanidine 10a was pro- dines generally in better yields compared to anilines (see the
duced and no trace of the expected intermediate 5g could be two complementary synthesis of 7h). This, most probably, is
detected. Instead, compound 9a was isolated as the main due to their higher nucleophilicity.
product, presumably as a result of the subsequent reaction of
Based on the above results and observations, a plausible
5g with an additional molecule of amine. Unfortunately, pre- mechanism is proposed (Scheme 3). In the first step,
venting the instantaneous ring-opening reaction by decreasing N-chlorophthalimide 1 undergoes α-addition to isocyanide to
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Table 6 One-pot three-step synthesis of N,N’-disubstituted guanidines from aliphatic and aralkyl aminesa
Entry
1
2
8
Product
Yieldb [%]
81 (84)
2a
R1 = t-Bu
8a
R2 = i-Bu
10a
2
3
2a
2f
R1 = t-Bu
8b
8c
R2 = HO(CH2)5
10b
10c
80 (85)
72 (78)
R1 = t-Octyl
R2 = C6H5(CH2)2
4
5
2f
R1 = t-Octyl
R1 = c-Hex
8d
8e
R2 = BocNH(CH2)4
R2 = HCCCH2
10d
10e
55 (62)
44 (47)
2c
6
7
2c
R1 = c-Hex
8f
R2 = t-Bu
10f
64 (68)
71 (75)
2d
R1 = Bn
8g
R2 = c-Hex
10g
8
9
2d
2b
R1 = Bn
8h
8g
10h
7h
53 (64)
66 (70)
R1 = 4-MeOC6H4
R2 = c-Hex
a Reaction conditions: N-Chlorophthalimide (1.0 mmol), anhydrous MeCN (2.0 ml), isocyanide (1.1 equiv.), 0 °C, 15 min, then Et3N (1.0 equiv.)
and amine (2.2 equiv.), r.t., 2 h, then reflux, 10 h. The products were isolated as hydrochloride salts. b Isolated yield (NMR yield in parenthesis).
NMR yield was determined by 1H-NMR spectroscopy with 1,3,5-trimethoxybenzene as an internal standard.
Scheme 3 Proposed reaction mechanism.
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form imidoyl chloride B through nitrilium species A. Then, (1.1 mmol) was added and stirred at 0 °C for 15 min. Then tri-
nucleophilic attack of the amine takes place, which can occur ethylamine (1.0 mmol, 140 µL) and subsequently primary
either on the imidoyl carbon to provide guanidine products amine (2.2 mmol) were added and the mixture was warmed to
(route A), or on the carbonyl carbon to give intermediate C room temperature. After stirring for 2 h, the reaction mixture
(route B). The subsequent rearrangement of C results in iso- was warmed to reflux temperature and the stirring was contin-
indolone D along with an isocyanate by-product. Finally, D ued for 10 h. Then the reaction mixture was poured into
undergoes tautomerization to afford the more stable22 isoindo- aqueous NaOH solution (30 mL, 1 M) and extracted with
linone 6. To support the mechanism, the formation of isocya- chloroform (4 × 50 mL). The organic layers were combined,
nate was confirmed by control experiments and a representa- dried over anhydrous Na2SO4 and concentrated in vacuo until
tive example of B was also isolated (see the ESI† for details).
the complete removal of the solvent and triethylamine. The
residue was purified by flash column chromatography on
neutral alumina (RediSep Rf; EtOAc : hexanes 0 : 100–100 :
0 gradient, then eluent switch to methanol : chloroform 0 :
100–1 : 10 gradient) to afford the pure guanidine base, which
was then treated with HCl in ethanol (1 M, 2–3 equiv.) and
stirred at room temperature for 15 min. Finally, evaporation to
dryness followed by trituration with n-hexane or diisopropyl
ether or diethyl ether (if necessary) gave pure guanidine hydro-
chlorides 10a–h.
Conclusions
In conclusion, we have developed a new and efficient synthesis
of N,N′-disubstituted guanidines from readily available
N-chlorophthalimide, isocyanides and amines in a sequential
one-pot manner. The reactions proceed through the formation
of N-phthaloylguanidines, which represent a novel class of
guanidines. This operationally simple method tolerates both
aromatic and aliphatic substrates in all possible combinations,
providing general and diverse access to N-alkyl-N′-aryl, N-aryl-
N′-aryl and N-alkyl-N′-alkyl guanidines with broad substrate
scope.
Conflicts of interest
There are no conflicts to declare.
Experimental section
General procedure for the one-pot synthesis of guanidines
Notes and references
1 For general reviews, see: (a) F. Saczewski and L. Balewski,
Expert Opin. Ther. Pat., 2009, 19, 1417; (b) F. Saczewski and
L. Balewski, Expert Opin. Ther. Pat., 2013, 23, 965;
(c) L. Peterlin-Mašič and D. Kikelj, Tetrahedron, 2001, 57,
7073; (d) D. Castagnolo, S. Schenone and M. Botta, Chem.
Rev., 2011, 111, 5247; (e) R. G. S. Berlinck and
S. Romminger, Nat. Prod. Rep., 2016, 33, 456.
2 For general reviews, see: (a) T. Ishikawa and T. Kumamoto,
Synthesis, 2006, 737; (b) J. E. Taylor, S. D. Bull and
J. M. J. Williams, Chem. Soc. Rev., 2012, 41, 2109;
(c) P. Selig, Synthesis, 2013, 703. For recent example, see:
(d) X.-T. Gao, C.-C. Gan, S.-Y. Liu, F. Zhou, H.-H. Wu and
J. Zhou, ACS Catal., 2017, 7, 8588.
7a–v
To a cooled suspension of N-chlorophthalimide (1.0 mmol,
182 mg) in anhydrous acetonitrile (2 mL) isocyanide
(1.1 mmol) was added and stirred at 0 °C for 15 min. Then tri-
ethylamine (1.0 mmol, 140 µL) and subsequently the corres-
ponding aniline (1.2 mmol) were added and the reaction
mixture was allowed to warm to room temperature. After stir-
ring for 2 h, methylhydrazine (1.5 mmol, 79 µL) was added,
and the stirring was continued at 40 °C for 2 h. Then the reac-
tion mixture was poured into aqueous NaOH solution (30 mL,
1 M) and extracted with chloroform (4 × 50 mL). The organic
layers were combined, dried over anhydrous Na2SO4 and con-
centrated in vacuo until complete removal of the solvent and
triethylamine. The residue was purified by flash column
chromatography on neutral alumina (RediSep Rf;
EtOAc : hexanes 0 : 100–100 : 0 gradient, then eluent switch to
methanol : chloroform 0 : 100–1 : 10 gradient) to afford the
pure guanidine base, which was then treated with HCl in
ethanol (1 M, 2–3 equiv.) and stirred at room temperature for
15 min. Finally, evaporation to dryness followed by trituration
with n-hexane or diisopropyl ether or diethyl ether (if necess-
ary) gave pure guanidine hydrochlorides 7a–v.
3 For selected examples, see: (a) W. Zeghida, J. Debray,
S. Chierici, P. Dumy and M. Demeunynck, J. Org. Chem.,
2008, 73, 2473; (b) X. Deng, H. McAllister and N. S. Mani,
J. Org. Chem., 2009, 74, 5742.
4 For general reviews, see: (a) C. Alonso-Moreno, A. Antiñolo,
F. Carrillo-Hermosilla and A. Oterob, Chem. Soc. Rev., 2014,
43, 3406; (b) W.-X. Zhang, L. Xu and Z. Xi, Chem. Commun.,
2015, 51, 254. For selected examples, see: (c) T.-G. Ong,
G. P. A. Yap and D. S. Richeson, J. Am. Chem. Soc., 2003,
125, 8100; (d) F. Montilla, A. Pastor and A. Galindo,
J. Organomet. Chem., 2004, 689, 993; (e) W.-X. Zhang,
M. Nishiura and Z. Hou, Synlett, 2006, 1213; (f) H. Shen,
H.-S. Chan and Z. Xie, Organometallics, 2006, 25, 5515;
(g) T.-G. Ong, J. S. O’Brien, I. Korobkov and D. S. Richeson,
Organometallics, 2006, 25, 4728; (h) Q. Li, S. Wang, S. Zhou,
General procedure for the one-pot synthesis of guanidines
10a–h
To a cooled suspension of N-chlorophthalimide (1.0 mmol,
182 mg) in anhydrous acetonitrile (2 mL) isocyanide
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G. Yang, X. Zhu and Y. Liu, J. Org. Chem., 2007, 72, 6763; 13 (a) R. Abu-El-Halawa and J. C. Jochims, Chem. Ber., 1983,
(i) W.-X. Zhang, M. Nishiura and Z. Hou, Chem. – Eur. J.,
2007, 13, 4037; ( j) W.-X. Zhang, D. Li, Z. Wang and Z. Xi,
Organometallics, 2009, 28, 882; (k) C. Alonso-Moreno,
F. Carrillo-Hermosilla, A. Garcés, A. Otero, I. López-Solera,
A. M. Rodríguez and A. Antiñolo, Organometallics, 2010, 29,
2789; (l) D. Li, J. Guang, W.-X. Zhang, Y. Wang and Z. Xi,
Org. Biomol. Chem., 2010, 8, 1816; (m) S. Pottabathula and
B. Royo, Tetrahedron Lett., 2012, 53, 5156.
116, 1834; (b) R. Bossio, S. Marcaccini and R. Pepino,
Tetrahedron Lett., 1995, 36, 2325; (c) R. Bossio,
S. Marcaccini and R. Pepino, J. Org. Chem., 1996, 61, 2202;
(d) A. R. Katritzky, B. Rogovoy, C. Klein, H. Insuasty,
V. Vvedensky and B. Insuasty, J. Org. Chem., 2001, 66, 2854;
(e) A. Czarna, B. Beck, S. Srivastava, G. M. Popowicz,
S. Wolf, Y. Huang, M. Bista, T. A. Holak and A. Dömling,
Angew. Chem., Int. Ed., 2010, 49, 5352; (f) T.-H. Zhu,
S.-Y. Wang, T.-Q. Wei and S.-J. Ji, Adv. Synth. Catal., 2015,
357, 823; (g) Z.-Y. Gu, Y. Liu, F. Wang, X. Bao, S.-Y. Wang
and S.-J. Ji, ACS Catal., 2017, 7, 3893.
5 For selected examples, see: (a) C. Levallet, J. Lerpiniere and
S. Y. Ko, Tetrahedron, 1997, 53, 5291; (b) S. Cunha, B. R. de
Lima and A. R. de Souza, Tetrahedron Lett., 2002, 43, 49;
(c) D. H. O’Donovan and I. Rozas, Tetrahedron Lett., 2011, 14 For selected examples, see: (a) H.-O. Kim, F. Mathew and
52, 4117; (d) B. Kelly and I. Rozas, Tetrahedron Lett., 2013,
54, 3982.
6 Y. F. Yong, J. A. Kowalski and M. A. Lipton, J. Org. Chem.,
1997, 62, 1540.
C. Ogbu, Synlett, 1999, 193; (b) T. Suhs and B. König, Chem.
– Eur. J., 2006, 12, 8150; (c) E. Tassoni, F. Giannessi,
T. Brunetti, P. Pessotto, M. Renzulli, M. Travagli,
S. Rajamäki, S. Prati, S. Dottori, F. Corelli, W. Cabri,
P. Carminati and M. Botta, J. Med. Chem., 2008, 51, 3073.
7 For selected examples, see: (a) B. R. Linton, A. J. Carr,
B. P. Orner and A. D. Hamilton, J. Org. Chem., 2000, 65, 15 For selected examples, see: (a) X. Bi, C. Lopez, C. J. Bacchi,
1566; (b) M. Li, L. J. Wilson and D. E. Portlock, Tetrahedron
Lett., 2001, 42, 2273; (c) D. S. Ermolat’ev, J. B. Bariwal,
H. P. L. Steenackers, S. C. J. De Keersmaecker and E. V. Van
der Eycken, Angew. Chem., Int. Ed., 2010, 49, 9465.
8 For selected examples, see: (a) A. Porcheddu, L. D. Luca
and G. Giacomelli, Synlett, 2009, 3368; (b) P. S. Dangate
and K. G. Akamanchi, Tetrahedron Lett., 2012, 53, 6765;
D. Rattendi and P. M. Woster, Bioorg. Med. Chem. Lett.,
2006, 16, 3229; (b) L. Zhang, R. Sathunuru, T. Luong,
V. Melendez, M. P. Kozar and A. J. Lin, Bioorg. Med. Chem.,
2011, 19, 1541; (c) P. J. Klein, J. A. M. Christiaans,
A. Metaxas, R. C. Schuit, A. A. Lammertsma, B. N. M. van
Berckel and A. D. Windhorst, Bioorg. Med. Chem., 2015, 23,
1189.
(c) S. Wangngae, M. Pattarawarapan and W. Phakhodee, 16 (a) J. P. Ferris, C.-H. Huang and W. J. Hagan Jr., Nucleosides
Synlett, 2015, 1121.
Nucleotides, 1989, 8, 407; (b) Y.-Q. Wu, S. K. Hamilton,
D. E. Wilkinson and G. S. Hamilton, J. Org. Chem., 2002,
67, 7553; (c) V. D. Jadhav and F. P. Schmidtchen, J. Org.
Chem., 2008, 73, 1077; (d) A. Turočkin, R. Honeker,
W. Raven and P. Selig, J. Org. Chem., 2016, 81, 4516.
17 Application of NCS led to the corresponding succinimidyl
analogue of 5a, however, in lower isolated yield (51%). On
the other hand, no desired product was observed by means
of NBS or NIS.
9 For selected examples, see: (a) A. Miller and J. J. Bischoff,
Synthesis, 1986, 777; (b) C. A. Maryanoff, R. C. Stanzione,
J. N. Plampin and J. E. Mills, J. Org. Chem., 1986, 51, 1882;
(c) N. Srinivasan and K. Ramadas, Tetrahedron Lett., 2001,
42, 343.
10 For
a general review, see: (a) A. R. Katritzky and
B. V. Rogovoy, ARKIVOC, 2005, 49. For selected examples, see:
(b) C. R. Rasmussen, F. J. Villani Jr., B. E. Reynolds,
J. N. Plampin, A. R. Hood, L. R. Hecker, S. O. Nortey, 18 In order to evaluate the effectiveness of the isolation pro-
A. Hanslin, M. J. Costanzo, R. M. Howse Jr. and
A. J. Molinari, Synthesis, 1988, 460; (c) K. Feichtinger, C. Zapf,
cedures, NMR yields obtained from crude reaction mix-
tures are also shown.
H. L. Sings and M. Goodman, J. Org. Chem., 1998, 63, 3804; 19 It should be noted that similar efficiencies were observed
(d) H.-J. Musiol and L. Moroder, Org. Lett., 2001, 3, 3859.
11 For a general review, see: S. Tahir, A. Badshah and
R. A. Hussain, Bioorg. Chem., 2015, 59, 39.
when hydrazine monohydrate was utilized, but the separ-
ation of the byproduct phthalhydrazide from N,N′-di-
substituted guanidines was tedious.
12 (a) C.-Y. Chen, H.-C. Lin, Y.-Y. Huang, K.-L. Chen, 20 The succinimidyl analogue of 5a (see ref. 17) could not be
J.-J. Huang, M.-Y. Yeh and F. F. Wong, Tetrahedron, 2010,
66, 1892; (b) R. E. Looper, T. J. Haussener and
J. B. C. Mack, J. Org. Chem., 2011, 76, 6967; (c) J. Li and
transformed to the desired N,N′-disubstituted guanidine 7a
by hydrazinolysis (MeNHNH2, MeCN) even at reflux
temperature.
L. Neuville, Org. Lett., 2013, 15, 6124; (d) J. Li, H. Wang, 21 P. G. M. Wuts, Greene’s Protective Groups in Organic
Y. Hou, W. Yu, S. Xu and Y. Zhang, Eur. J. Org. Chem., 2016, Synthesis, Wiley, Hoboken, 5th edn, 2014.
2388; (e) M. Baeten and B. U. W. Maes, Adv. Synth. Catal., 22 S. Scherbakow, J. C. Namyslo, M. Gjikaj and A. Schmidt,
2016, 358, 826.
Synlett, 2009, 1964.
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