Synthesis of highly basic hexasubstituted biguanides by environmentally friendly methods

Article abstract of DOI:10.1055/s-0033-1339876

A series of hexasubstituted biguanides was synthetized employing nonconventional and environmentally friendly methods. Their properties were studied computationally (basicity) and experimentally (basicity and catalytic properties in transesterification reaction). Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1339876

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Synthesis of Highly Basic Hexasubstituted Biguanides by Environmentally
Friendly Methods
Synthesis of Highly Basic Hexasubstituted Biguanides
Zoran Glasovac, Pavle Trošelj, Iva Jušinski, Davor Margetić,* Mirjana Eckert-Maksić*
Laboratory for Physical Organic Chemistry, Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička c. 54,
10000 Zagreb, Croatia
Fax +385(1)4561008; E-mail: margetid@irb.hr; E-mail: mmaksic@emma.irb.hr
Received: 29.07.2013; Accepted: 05.09.2013
explore possibility of applying different eco-friendly pro-
Abstract: A series of hexasubstituted biguanides was synthetized
cedures for their preparation. Next, brief discussion on
employing nonconventional and environmentally friendly methods.
their gas-phase and solution basicities predicted by quan-
Their properties were studied computationally (basicity) and exper-
tum chemical calculations are included. Finally, we com-
pare catalytic ability of the newly prepared compounds in
transesterification of vegetable oil with those of previous-
ly studied guanidine derivatives.
imentally (basicity and catalytic properties in transesterification re-
action).
Key words: guanidines, superbases, green chemistry, solid-phase
synthesis, nucleophilic addition, catalysis
A series of seven biguanides 3a–g9 was prepared by reac-
tion of tetramethylguanidine (1) to carbodiimides 2a–g
(Scheme 1). Reaction conditions were optimized for each
carbodiimide and are listed in Table 1 and in the Support-
ing Information (Table S1).10,11
Guanidine derivatives occupy an important role in the de-
sign of strong nonionic organic bases, primarily due to
their high catalytic potential in a number of synthetically
important reactions,1,2 to mention only the transesterifica-
tion of vegetable oils, which is a key step in the production
of biodiesel.3,4 In the course of these studies, considerable
attention, both experimentally and computationally, has
been paid to molecular modifications of the parent mole-
cule leading to an enhancement of its basicity. This was
achieved through electronic effects by changing the na-
ture and the site of attachment(s) of substituents at the
guanidine moiety, substitution by flexible heteroalkyl
chains which are capable of forming intramolecular hy-
drogen bonds (IMHB), implementing structural rigidity as
in proton sponges,5 enlargement of the guanidine frame-
work leading to polyguanides, etc.6 In contrast to guani-
dines, basicity of biguanides and their higher analogues
has been less thoroughly explored. In the recent theoreti-
cal work it was shown that increasing the number of gua-
nidine subunits in the molecule and the presence of
bifurcation centers in the higher analogues significantly
increases basicity relative to that of the parent guanidine,
due to a pronounced increase in the resonance interaction
in the corresponding conjugate acid.7 In previous studies
we have reported on the gas-phase basicity and pKa values
in acetonitrile of several guanidines with a special empha-
sis put on compounds capable of forming intramolecular
hydrogen bonds upon protonation.8 In the course of these
studies, we became confronted with a lack of suitable ref-
erence bases which would allow precise determination of
the proton affinity and/or pKa values. We felt it, therefore
worthwhile to extend a number of available bases starting
with a series of biguanide derivatives described in this
work. Our primary goal in undertaking this study was to
R1
R1
N
H
N
NMe2
N NMe2
N
+
R2HN
N
Me2N
NMe2
R2
2a–g
1
3a–g
a R1 = R2 = i-Pr, b R1 = R2 = c-Hex, c R1 = Et, R2 = Me2N(CH2)3, d R1
Me2N(CH2)3, e R1 = R2 = MeO(CH2)3, f R1 = Me2N(CH2)3, R2 = Ph,
g R1 = Me2N(CH2)3, R2 = 4-MeOC6H4
=
Scheme 1 Reaction of tetramethylguanidine (1) with carbodiimides
Table 1 Synthesis of Biguanides 3a–g
Base Methoda
Conditions
Conv.
(isolated yield, %)b
3a
MWf
120 °C, 40 min
ball (12 mm), 2 h
50 balls (3 mm), 2 h
6 kbar, r.t., 96 h
50 °C, 2 h
>99 (56)
15
HVSM-1g
HVSM-2g
HP
40
66 (65)c
53
US
thermal
MW
(94)4
95 (63)
63
3b
120 °C, 90 min
80 °C, 2.5 h, Y(OTf)3
80 °C, 2 h, Yb(OTf)3·H2O 62
HVSM-2
HP
50 balls (3 mm), 2 h
6 kbar, r.t., 24 h
50 °C, 2 h
5
n.r.i
43
SYNLETT 2013, 24, 2540–2544
US
Advanced online publication: 14.10.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
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2
0
9
6
DOI: 10.1055/s-0033-1339876; Art ID: ST-2013-D0714-C
© Georg Thieme Verlag Stuttgart · New York
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Synthesis of Highly Basic Hexasubstituted Biguanides
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Table 1 Synthesis of Biguanides 3a–g (continued)
tioning between CH2Cl2 and H2O and (except for the
biguanides 3f and 3g) distillation of the product under
high vacuum. Details of the synthetic procedures are giv-
en in the Supporting Information.
Base Methoda
Conditions
Conv.
(isolated yield, %)b
3c
3d
3e
3fh
MW
120 °C, 5 min
>98 (89)
tracesd
tracese
n/df (44)
90 (77)
>98 (43)
<5 polym.
10
The following nonclassical, environmentally friendly
methods were employed: microwave heating,12 high-
speed vibrational milling,13 high pressure,14 and ultra-
sound.15 Obtained results were compared with those ob-
tained by classical thermal reactions carried out in the
present work or taken from ref. 4. To the best of our
knowledge, our work is the first account on the use of high
pressure, mechanochemistry, and ultrasound for the syn-
thesis of this type of compounds, while the reaction under
microwave heating was used previously for the synthesis
of biguanides from amine and guanidine.16
HVSM-1
HP
ball (12 mm), 30 Hz, 2 h
6 kbar, r.t., 24 h
50 °C, 2 h
US
thermal
MW
90 °C, dry THF, 1 h
90 °C, 5 min
HSVM-1
HP
ball (12 mm), 1 h
6 kbar, r.t., 24 h
50 °C, 1 h
The inspection of results reveals that microwave reactions
are the best in respect to reaction time and conversion into
products. Isolated yields are moderate to high (56–92%),
and in the most cases the reaction is completed within five
minutes.17 In all cases formation of some polymeric mate-
rials and unidentified side products was observed at the el-
evated temperatures (>90 °C). On the other hand, at the
temperatures below 80 °C, reactions slowed down, but
products were cleaner. Reaction conditions given in Table
1 represent a balance between minimizing amount of side
products and shortening of the reaction time.
US
50 (33)
98 (34)
>95 (80)
44
thermal
MW
90 °C, dry THF, 1 h
90 °C, 10 min
HVSM-1
HP
ball (12 mm), 1 h
6 kbar, r.t., 24 h
50 °C, 2 h
traces
US
68 (18)
96 (54)
98 (95)
95 (82)
80 (64)
91(74)
99 (93)
99 (92)
94 (86)
75 (57)
86 (75)
99 (93)
thermal
MW
90 °C, dry THF, 1 h
90 °C, 5 min
To avoid undesirable temperature effects we next per-
formed reactions under high pressure, mechanochemical,
and ultrasonic conditions at room temperature. However,
condensations conducted at extremely high pressure (6
kbar) led only in few cases to satisfactory conversion into
biguanides. The rest of carbodiimides afforded traces of
products (2b, 2c, and 2e), while in the case of 2d prefer-
ential formation of the polymeric unidentified material
was observed. The best results were achieved for 3f and
3g (64 and 57% of the isolated yield, respectively). It is in-
teresting to note that for both of these compounds the iso-
lated yields were significantly lower than the extent of
conversion, indicating that partial conversion of the car-
bodiimides to the undesired side products took place dur-
ing the reaction and isolation of the products. In some
cases, like, for example, in the reaction of carbodiimide
2a, conversion into products could be improved by pro-
longed pressurization. Similar results were obtained in the
solid-state reactions carried out in the ball mill. The best
conversion was achieved in the synthesis of 3f and 3g (95
and 94%), while the other reactions were not successful.
We also observed that in reactions of 2f and 2g the dis-
crepancy between conversion and the isolated yields was
smaller than in the corresponding high-pressure reactions.
In preparation of 3a, an attempt was also made to increase
efficacy of mechanochemical reactions by increasing the
number of stainless steel balls (see Supporting Informa-
tion for details) in a planetary ball mill. It was found that
the conversion of carbodiimide 2a increased up to 40%
when the 50 balls were used. Sonochemical syntheses of
biguanides were also conducted at a temperature slightly
above room temperature. Again, excellent conversions
HVSM-1
HP
ball (12 mm), 1 h
6 kbar, r.t., 24 h
40 °C, 1 h
US
thermal
90 °C, dry THF, 2 h
90 °C, 5 min
3gh MW
HVSM-1
ball (12 mm), 1 h
6 kbar, r.t., 24 h
40 °C, 1 h
HP
US
thermal
90 °C, dry THF, 2 h
a MW: microwave heating; HSVM: high-speed vibrational milling;
HP: high pressure; US: ultrasound.
b Isolated yields are given in parentheses.
c n(TMG)/n(DIC) = 1:1.3; yields were determined from the crude
product mixture and corrected for the presence of the reactants ac-
cording to the GC analysis.
d Complete loss of EDCI was observed indicating polymerization or
formation of some insoluble product.
e Solidification of material.
f Not determined.
g HSVM-1: MM 400 vibrational mill, 30 Hz, NaCl; HSVM-2: plane-
tary mill (PM 200), 500 rpm, NaCl.
h Conditions for 3f,g: Na2SO4: HSVM (1 equiv), other methods:
0.1 equiv.
i n.r. = no reaction.
Extent of conversion of the reactants into the products was
determined by GC analysis. Isolation of the products in-
cluded removal of the reactants under high vacuum, parti-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2540–2544

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Z. Glasovac et al.
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(>90%) were achieved in the case of 2f and 2g, while the
other carbodiimides were less reactive.
Table 2 Calculated Acid/Base Thermodynamic Properties of Bi-
guanides 3a–g in the Gas and the Solution Phase (MeCN)
To summarize, under all experimental conditions applied,
2a and 2b showed the lowest reactivity and acceptable
yields were obtained only under microwave-heating con-
ditions at 120 °C. The GC analysis showed the formation
of a large amount of the side products as evidenced by the
largest difference between extent of conversion and the
isolated yield. Attempts were also made to increase reac-
tivity of 2b at lower temperature under microwave condi-
tions by addition of Y(OTf)3 or Yb(OTf)3·H2O. Obtained
results showed small if any improvement in comparison to
the reaction under microwave heating carried out without
catalysts.
Base Proton affinity Gas-phase basicities pKa
pKa
pKa
(kcal·mol–1)
(kcal·mol–1)
(M1)a (M2)b (UV)
3a
264.9
257.3
27.8
28.4 26.2
(31.8)4
3b
3c
3d
3e
3f
267.9
268.6
274.7
269.7
264.0
266.9
261.3
260.4
265.8
260.6
256.0
259.4
29.1
27.9
29.1
26.3
25.1
26.2
29.7 (31.5)4
27.8 27.0
28.2
–
25.5 26.6
25.1 25.8
26.3 26.4
Based on the above results we can classify reactions into
three groups: first, in which carbodiimides of low reactiv-
ity (2a and 2b) give significant amount of the target bigu-
anides under prolonged heating; second: in which reactive
carbodiimides 2f and 2g react smoothly and fast irrespec-
tively of the method employed giving stable biguanides 3f
and 3g; and the third group in which reactive carbodi-
imides (2c–e) give very good yields at the elevated tem-
perature, but the concurrent side reactions take place. This
particularly holds for the compound 2d which gives the
lowest yield under microwave heating and practically no
product if the reactions are conducted at the room temper-
ature (high pressure).
3g
a Using the equation pKa = 0.545 ΔGa′MeCN – 133.5, ref. 18.
b Using the equation pKa = 0.608 ΔGa′MeCN – 152.9, ref. 19.
basicities of the compounds are similar to the most basic
representatives of recently measured series of heteroalkyl-
substituted guanidines.8d These new biguanides fill the ba-
sicity scale between 256 and 266 kcal·mol–1 what until
now was reserved for phosphazenes. Thus, the biguanides
prepared in this work provide a suitable set of the refer-
ence bases for experimental measurements of pKa values
in the range of 25.5–27.0.
In the case of less reactive carbodiimides, microwave-
heating reaction conditions were superior to thermally
conducted reactions (conversion and yields), which are
environmentally less friendly, since reactions are carried
out in organic solvent and reaction times are much longer.
Another ‘green’ aspect is the reduced use of organic sol-
vent in reactions under microwave heating, which was
needed only for product isolation.
Gas-phase basicities and proton affinities of
biguanides 3a–g were calculated at B3LYP/6-
311+G-(2df,p)//B3LYP/6-31G(d) level of theory. Calcula-
tion of their pKa in acetonitrile solution was conducted us-
ing either IPCM/B3LYP/6-311+G(2df,p)//B3LYP/6-
Figure 1 Optimized structures of the protonated forms of biguanides
3b and 3d
Biguanides 3b and 3d (Figure 1) are calculated to be the
most basic and their estimated pKa values go up to 29 pKa
units, what is comparable to the P2-phosphazenes20 and
1,8-bis(hexamethyltriaminophosphazenyl)naphthalene.21
In acetonitrile, the basicity increase due to intramolecular
hydrogen bonds is less pronounced than in the gas phase,
and 3f has the lowest pKa. The measured pKa values are in
fair agreement with the computationally predicted values
(differences are smaller than 0.7 pKa units for 3f and 3g).
It should be, however, stressed that our pKa value for 3a is
significantly lower than the value reported previously in
ref. 4. We assume that the reason for that could be as-
cribed to uncertainty of the method used earlier. The latter
is corroborated with the fact that pKa values of 3a and 3b
are higher by ca. 2–3 pKa units than our values predicted
by M1 and M2 equations, and in the reverse relative order,
while our experimentally determined pKa value of 3a is
much closer to the calculated values. Furthermore, the
31G(d)
(M118)
or
IEF-PCM/B3LYP/6-
311+G(2df,p)//B3LYP/6-31G(d) (M219) models which
were proved to give very good agreement with the exper-
imental data on structurally similar compounds in our pre-
vious papers.18 The pKa values of biguanides 3a–g with
exception for the most basic ones (3b and 3d) were also
measured by UV spectroscopy (in MeCN, Table 2).
All bases prepared in this study have much higher (20–30
kcal·mol–1) proton affinities than a standard proton sponge
(245 kcal·mol–1) and thus belong to the superbase class.1
Biguanide 3d possesses the highest proton affinity and
gas-phase basicity, as a consequence of stabilization of
the protonated form by two intramolecular hydrogen
bonds (Figure 1). The biguanides with substituents capa-
ble of forming only one intramolecular hydrogen bond
are, as expected, less basic (3e–g). Absolute gas-phase
Synlett 2013, 24, 2540–2544
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Synthesis of Highly Basic Hexasubstituted Biguanides
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Table 3 Transesterification of Vegetable Oila,b
measured pKa value of 3a is close to that of 3c as predicted
by calculations.
Base
Conv. (%)
Catalytic activity of the prepared biguanides 3a–g was ex-
plored in transesterification reaction of vegetable oil
(Scheme 2), and the results are given in Table 3. Reactions
were conducted using the reactant ratio and conditions as
described in literature.22 Detailed description of the proce-
dure is given in the Supporting Information. For the sake
of comparison catalytic activities of the known guanidine
organic base triazabicyclodecene (TBD) and guanidines
Gu1–3,23 were also determined. Overall, all examined
bases proved to be highly active at the 2% molar loading
and within one hour reaction is nearly completed (>90%).
At the low catalyst loading (0.5 mol%) differences in re-
activities between bases are more pronounced – biguanide
3b is the most active, while biguanides 3d and 3f are the
least active. These differences are correlated with basicity
in the case of 3b and 3f: biguanide 3b is the most basic,
while 3f is the least basic in acetonitrile [pKa (M1)]. On
the other hand, 3d is predicted to be equally basic as 3b
[pKa (M1) = 29.1], but shows lower activity. The activity
of most potent biguanide 3b is comparable to that of TBD
and significantly better than those of Gu1–3.
Base 0.5 mol%
Base 1 mol%
Base 2 mol%
3a
55
77
96
93
90
93
61
80
99
91
91
94
93
95
95
94
97
91
93
94
95
96
92
3b
89
3c
72
3d
69
3e
75
3f
35
3g
61
TBD
Gu1c
Gu2c
Gu3c
95 (81)
54
74
74
a Conditions: 1 h, 70 °C, oil (8.0 g), MeOH (2.0 g), catalyst (0.5 mol).
b Obtained by 1H NMR analysis.
c Gu = guanidine, Gu1: R1 = R2 = n-Pr; R3 = 3-dimethylaminopropyl,
Gu2: R1 = R2 = 3-dimethylaminopropyl; R3 = n-Pr, Gu3:
R1 = R2 = R3 = 3-dimethylaminopropyl.23
O
R
OH
O
O
O
O
base
O
R
R
OH
+
3
R
MeOH
MeO
Supporting Information for this article is available online at
70 °C, 1 h
OH
O
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
6
4
5
Scheme 2 Transesterification of vegetable oil with methanol
References and Notes
(1) Margetić, D. In Superbases for Organic Synthesis:
Guanidines, Amidines, Phosphazenes and Related
Organocatalysts Ishikawa T; Wiley: Chichester, 2009,
Chap. 9, 4.
(2) Ishikawa, T.; Isobe, T. Chem. Eur. J. 2003, 8, 552.
(3) (a) Demirbas, A. Biodiesel. A Realistic Fuel Alternative for
Diesel Engines; Springer: London, 2008. (b) Van Gerpen, J.
Fuel Process. Technol. 2005, 86, 1097. (c) Eckert-Maksić,
M.; Glasovac, Z. EP 1786763, 2009.
A small library of the biguanide was prepared using dif-
ferent eco-friendly methods and their performance criti-
cally examined. Their proton affinity, gas-phase basicity,
and pKa values were calculated and compared with the
measured pKa values of the selected representatives. All
bases prepared in this study have significantly higher (20–
30 kcal·mol–1) basicities than N,N,N′,N′-tetramethyl-1,8-
naphthalenediamine (DMAN) proton sponge and could
be classified as superbases. The calculated gas-phase ba-
sicity values fall in the range of 256–266 kcal·mol–1 mak-
ing biguanides 3a–g suitable reference bases for basicity
measurements in this region. The importance of intramo-
lecular hydrogen bonds in amplifying basicity is demon-
strated computationally and experimentally. The prepared
biguanides proved to be efficient catalysts in the trans-
esterification reaction of the vegetable oil.
(4) Gelbard, G.; Vielfaure-Joly, F. Tetrahedron Lett. 1998, 39,
2743.
(5) (a) Margetić, D.; Ishikawa, T.; Kumamoto, T. Eur. J. Org.
Chem. 2010, 6563. (b) Margetić, D.; Trošelj, P.; Ishikawa,
T.; Kumamoto, T. Bull. Chem. Soc. Jpn. 2010, 83, 1055.
(6) Maksić, Z. B.; Kovačević, B.; Vianello, R. Chem. Rev. 2012,
112, 5240.
(7) Maksić, Z. B.; Kovačević, B. J. Org. Chem. 2000, 65, 3303.
(8) (a) Kovačević, B.; Glasovac, Z.; Maksić, Z. B. J. Phys. Org.
Chem. 2002, 15, 765. (b) Eckert-Maksić, M.; Glasovac, Z.;
Trošelj, P.; Kütt, A.; Rodima, T.; Koppel, I.; Koppel, I. A.
Eur. J. Org. Chem. 2008, 5176. (c) Glasovac, Z.; Štrukil, V.;
Eckert-Maksić, M.; Schroeder, D.; Kaczorowska, M.;
Schwarz, H. Int. J. Mass Spectrom. 2008, 270, 39.
(d) Glasovac, Z.; Pavošević, F.; Štrukil, V.; Eckert-Maksić,
M.; Schlangen, M.; Kretschmer, R. Int. J. Mass Spectrom.
2013, in press.
Acknowledgement
The Ministry of Science, Education and Sport of Croatia is grateful-
ly acknowledged for financial support (grants 098-0982933-3218
and 098-0982929-2920).
(9) Biguanides 3a and 3b are known compounds, see ref. 4.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2540–2544

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Z. Glasovac et al.
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(10) General Procedures
DMSO-d6): δ = 1.58 (q, J = 6.9 Hz, 2 H), 2.11 (s, 12 H), 2.23
(t, J = 7.0 Hz, 2 H), 2.75 (s, 12 H), 2.98 (t, J = 6.7 Hz, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 27.8, 39.6, 45.6, 49.0,
57.3, 157.7, 161.6.
Microwave Reaction
The reactants were mixed in the nitrogen-flushed cuvette in
the ratio 1/2 = 1:1.3 on the 2 mmol scale. The cuvette was
heated under microwave irradiation for the desired reaction
time (see Tables 1 and S1). Formed biguanides were isolated
according to the procedure given below.
Compound 3e: colorless viscous oil. 1H NMR (600 MHz,
CD3CN): δ = 1.71 (q, J = 6.5 Hz, 4 H), 2.74 (s, 12 H), 2.99
(t, J = 6.5 Hz, 4 H), 3.32 (s, 6 H), 3.42 (t, J = 6.5 Hz, 4 H).
13C NMR (150 MHz, DMSO-d6): δ = 31.1, 39.1, 49.0, 58.2,
71.1, 156.0, 159.0.
High-Speed Vibrational Milling Reaction
Reactants were mixed in a stainless steel jar and milled
under conditions given in Tables 1 or S1. After milling for
the desired period of time, CH2Cl2 was added, and the
product mixture was filtered over Celite and charcoal and
washed with CH2Cl2. Filtrate was evaporated to dryness, and
the product was isolated as described below.
Compound 3f: brownish-yellow viscous oil. 1H NMR (600
MHz, CDCl3): δ = 1.74 (q, J = 7.0 Hz, 2 H), 2.20 (s, 6 H),
2.33 (t, J = 7.0 Hz, 2 H), 2.50 (s, 12 H), 3.31 (t, J = 7.0 Hz, 2
H), 3.71 (s, 3 H), 6.68 (d, J = 8.85 Hz, 2 H), 6.75 (d, J = 8.85
Hz, 2 H). 13C NMR (150 MHz, CDCl3): δ = 27.8, 38.6, 40.6,
45.6, 57.9, 120.3, 122.7, 128.1, 150.2, 155.7, 160.7.
Compound 3g: brownish-yellow viscous oil. 1H NMR (600
MHz, CDCl3): δ = 1.74 (q, J = 7.0 Hz, 2 H), 2.20 (s, 6 H),
2.33 (t, J = 7.0 Hz, 2 H), 2.50 (s, 12 H), 3.31 (t, J = 7.0 Hz, 2
H), 3.71 (s, 3 H), 6.68 (d, J = 8.85 Hz, 2 H), 6.75 (d, J = 8.85
Hz, 2 H). 13C NMR (150 MHz, CDCl3): δ = 27.8, 38.7, 40.6,
45.5, 55.6, 57.9, 113.6, 123.4, 128.2, 154.0, 155.8, 160.4.
For further details see Supporting Information.
(12) Margetić, D. Microwave Assisted Cycloaddition Reactions;
Nova Science Publishers: New York, 2011.
(13) (a) Margetić, D. Kem. Ind. 2005, 54, 351. (b) Štrukil, V.;
Margetić, D.; Igrc, M. D.; Eckert-Maksić, M.; Friščić, T.
Chem. Commun. 2012, 48, 9705. (c) Štrukil, V.; Igrc, M. D.;
Fábián, L.; Eckert-Maksić, M.; Childs, S. L.; Reid, D. G.;
Duer, M. J.; Halasz, I.; Mottillo, C.; Friščić, T. Green Chem.
2012, 14, 2462.
(14) Organic Synthesis at High Pressures; Matsumoto, K.;
Acheson, R. M., Eds.; Wiley: New York, 1991.
(15) Luche, J. L. Synthetic Organic Sonochemistry; Plenum
Press: New York, 1998.
High-Pressure Reaction
The mixture of reactants in a molar ratio of 1/2 = 1:1.3 on the
1 mmol scale in the closed Teflon reaction vessel was
subjected to the pressure of 6–8 kbar. After 24 h reaction the
mixture was transferred into the flask, and the conversion
was analyzed by GC.
Ultrasound Reaction
The reaction mixture was prepared in the same way as for the
microwave-assisted reaction. The cuvette was immersed in
the water bath preheated to 50 °C and agitated using
ultrasound. Conversion of the carbodiimides into the
products was determined by GC.
Thermal Reaction
The solution of reactants in dry THF (1 mL) was prepared in
a microwave cuvette, closed, and immersed in an oil bath
preheated to 90 °C. The progress of the reaction was
followed by GC analysis after 1 or 2 h. The reaction mixture
was then cooled, and the product was isolated as described
below.
Isolation of the Products
The crude reaction mixture was transferred into the reaction
flask, and the excess of 1 was removed via bulb-to-bulb
distillation under reduced pressure. The obtained viscous
material was dissolved in CH2Cl2 (7 mL) and washed with
H2O. The crude product was obtained either by evaporation
of the water (3b–e) or dichloromethane layer (3a, 3f, and
3g). Biguanide 3b was washed 7 times with 10 mL of H2O
until complete transfer into the water layer was achieved. In
other cases, 3 × 7 mL H2O portions were sufficient for the
extractions. The hydrochloride salt of 3c was deprotonated
by dissolving the crude salt in dry MeOH (10 mL)
containing NaOH (1 mol equiv). The solution was stirred for
30 min at r.t. and evaporated to dryness. The remaining
material was mulled in CH2Cl2, and the solid was collected
by filtration. The filtrate was evaporated to dryness and
subjected to vacuum distillation. Biguanides 3a–e were
further purified by vacuum distillation at 2–5·10–5 mbar
(10–3 Pa) at the oil bath temperature of 150–180 °C.
(11) New compounds gave satisfactory physical and spectral data
(1H NMR, 13C NMR, and HRMS spectra).
(16) Mayer, S.; Daigle, D. M.; Brown, E. D.; Khatri, J.; Organ,
M. G. J. Comb. Chem. 2004, 6, 776.
(17) Control of the temperature is critical and overheating must
be avoided – the temperature was not allowed to rise above
90 °C.
(18) Glasovac, Z.; Eckert-Maksić, M.; Maksić, Z. B. New J.
Chem. 2009, 33, 588.
(19) Štrukil, V.; Glasovac, Z.; Đilović, I.; Matković-Čalogović,
D.; Šuman, L.; Kralj, M.; Eckert-Maksić, M. Eur. J. Org.
Chem. 2012, 6758.
(20) Kaljurand, I.; Kütt, A.; Sooväli, L.; Rodima, T.; Mäemets,
V.; Leito, I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019.
(21) See: Raab, V.; Gautchenova, K.; Merkoulov, A.; Harms, K.;
Sundermayer, J.; Kovačević, B.; Maksić, Z. B. J. Am. Chem.
Soc. 2005, 127, 17656.
(22) Schuchardt, U.; Vargas, R. M.; Gelbard, G. J. Mol. Catal. A:
Chem. 1995, 99, 65; the experimental setup was modified
with respect to the original paper (see Supporting
Information).
(23) Substitution numbering (Figure 2).
Selected Physical and Spectral Data
Compound 3c: colorless viscous oil. 1H NMR (600 MHz,
CD3CN): δ = 1.06 (t, J = 7.2 Hz, 3 H), 1.59 (q, J = 7.1 Hz, 2
H), 2.16 (s, 6 H), 2.27 (t, J = 7.2 Hz, 2 H), 2.73 (s, 12 H),
2.90–3.00 (m, 4 H). 13C NMR (150 MHz, CD3CN): δ = 16.4,
29.5, 38.9, 39.3, 43.2, 45.4, 58.6, 156.2, 159.9.
Compound 3d: colorless viscous oil. 1H NMR (300 MHz,
R1
N
R2
N
NH
R3
H
Figure 2
Synlett 2013, 24, 2540–2544
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