First total synthesis of a guanidine alkaloid Nitensidine D using immobilized ionic liquid, microwaves and formamidinesulfinic acid

Article abstract of DOI:10.1007/s12039-014-0723-8

An efficient first total synthesis of a naturally occurring guanidine alkaloid, Nitensidine D isolated from ethanol extract of Pterogyne nitens has been described. Geraniol has been used as the starting material. N-alkylation of phthalimide has been achieved using immobilized ionic liquid and formamidinesulfinic acid acts as the guanylating reagent. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-014-0723-8

c
J. Chem. Sci. Vol. 126, No. 6, November 2014, pp. 1869–1874. ꢀ Indian Academy of Sciences.
First total synthesis of a guanidine alkaloid Nitensidine D using
immobilized ionic liquid, microwaves and formamidinesulfinic acid
SHALLU, M L SHARMA and JASVINDER SINGH∗
Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University,
Chandigarh 160 014, India
e-mail: jsbrar_pu@yahoo.com
MS received 7 March 2014; accepted 16 October 2014
Abstract. An efficient first total synthesis of a naturally occurring guanidine alkaloid, Nitensidine D isolated
from ethanol extract of Pterogyne nitens has been described. Geraniol has been used as the starting material.
N-alkylation of phthalimide has been achieved using immobilized ionic liquid and formamidinesulfinic acid
acts as the guanylating reagent.
Keywords. Guanidine alkaloid; microwaves; immobilized ionic liquid; formamidinesulfinic acid.
1. Introduction
phytochemical studies with the leaves and fruits of P.
nitens have demonstrated the presence of two terpenoid
guanidine alkaloids (pterogynine,9 pterogynidine8 a),
three guanidine alkaloids (Nitensidine A, B, C) which
exhibited cytotoxic activity towards the DNA-repair-
deficient yeast mutant RS 321 and moderate cytotoxic
activity against CHO Aux B1 cells10 and phenolic com-
pounds with myeloperoxidase inhibitory and radical
scavenging activities.11 Further investigations of the
ethanolic extracts of P. nitens due to its cytotoxic activ-
ity in the MTT assay resulted in the isolation of two new
guanidine alkaloids Nitensidine D and E.12
The discovery of biologically active molecules is cru-
cial for both the development of new therapeutics1
and to provide tools for the elucidation of cellular
processes.2 Natural extracts, collections and combina-
torial libraries of synthetic compounds are screened for
searching these compounds. Natural products play an
important role, particularly in the anti-cancer and anti-
infective areas as greater than 60% of the drugs that are
now available were estimated to be derived from them.3
Many natural products containing guanidine have
been isolated and have attracted a lot of attention owing
to their wide range of biological activities,4 basically
arising from the two parallel interactions of the guani-
dinium ion with phosphate and carboxylate-containing
biomolecules.5 In addition, due to the strong binding
ability of guanidine with anionic compounds, guani-
dine containing molecules have applications as chem-
ical tools. Synthetic guanidine compounds have also
been utilized as host receptor molecules for phosphate
and carboxylate containing guest molecules.6
Ionic liquids (ILs) have become increasingly used
solvents and catalysts in ‘green’ chemistry due to their
unique properties.13 The most important technical prob-
lems in the industrial IL applications using soluble IL
catalysts, are their recovery and subsequent reuse or
disposal. Immobilization of the catalyst on a solid sup-
port provides the advantage of easy isolation at the end
of the reaction by simple filtration, avoiding tedious
processes of distillation, chromatographic separation,
etc.14 Past few years have witnessed a growing interest
in the use of microwaves in organic synthesis as they
make the reactions extremely fast, cleaner than conven-
tional reactions and lead to higher atom economy (less
chemical waste).15
A number of unusual guanidine alkaloids display-
ing a broad spectrum of biological activities have
been isolated from marine organisms7 whereas, in the
plant kingdom, these are restricted to the families of
Euphorbiaceae and Leguminosae.8 Pterogyne nitens
Tul. (Fabaceae, Caesalpinioideae) popularly known as
‘bálsamo,’ ‘yvira-ró,’ ‘cocal’ and ‘amendoinzeiro’ is
a native tree common in South America. Previous
In continuation of our interest16 in the development
of economic and rapid protocol, utilizing microwave
energy17 and ionic liquids, we report herein a simple
synthesis of Nitensidine D.
Retrosynthetic analysis of Nitensidine D (scheme 1)
revealed that geranyl amine could well act as the start-
ing precursor.
∗For correspondence
1869

1870
Shallu et al.
5.06 (t, 1H, J = 4.2 Hz, -CH =C(Me)2), 5.30 (t,
NH2
1H, J = 8.4 Hz, =CH-CH2-Br). 13C NMR (CDCl3,
75 MHz): δ 15.90, 17.71, 25.67, 26.17, 29.66, 39.50,
120.54, 123.53, 131.96, 143.56. IR (neat)/νmax (cm−1):
838, 985, 1082, 1108, 1376, 1594, 1654, 2855, 2925,
2966.
H2N
N
Guanylation
2.2 N-geranyl phthalimide (3)
A mixture of phthalimide (4.8 mmol, 0.70 g), ger-
anyl bromide (2, 6.0 mmol, 1.30 g), immobilized IL
(0.20 g, 0.20 mmol, 3 mol%) and potassium carbon-
ate (18.8 mmol, 2.6 g) was heated in a commercial
microwave oven in an open Erlenmeyer flask at 60–
65◦C for 9 min. having 50:10s heating:cooling cycle
each at 80% power level. After cooling down, the reac-
tion mixture was extracted with methylene chloride (2
× 25 mL). The combined extract was dried over anhy-
drous Na2SO4, filtered and evaporated to get a dark
brown residue. It was purified over a silica gel column
using hexane:EtOAc (96:4) as the eluent to give N-
geranyl phthalimide (3) in 83% yield (1.127 g) as white
crystalline powder. M.p. = 57–58◦C.18
H2N
Gabriel Reaction/Hydrolysis
O
+
NH
Br
O
Scheme 1. Retrosynthetic Analysis.
1H NMR (CDCl3, 300 MHz): δ 1.48 (s, 3H, -CH3),
1.54 (s, 3H, -CH3), 1.74 (s, 3H, -CH3), 1.91–1.99
(m, 4H, -CH2-CH2-), 4.19 (d, 2H, J = 6.9 Hz, -
CH2-N-), 4.94 (t, 1H, J = 6.9 Hz, -CH =C(Me)2),
5.18 (t, 1H, J = 6.9 Hz, =CH-CH2-N-), 7.59–7.62
(m, 2H, ArH), 7.73–7.75 (m, 2H, ArH). 13C NMR
(CDCl3, 75 MHz): δ 16.34, 17.63, 25.69, 26.28, 35.73,
39.46, 118.00, 123.07, 123.82, 131.56, 132.36, 133.67,
140.53, 167.93. IR (neat)/νmax (cm−1): 946, 1085, 1171,
1395, 1653, 1711, 1770, 2929.
2. Experimental
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra
were recorded (δ/ppm) on a Jeol A1 300F spectropho-
tometer for solutions in CDCl3 with tetramethylsilane
(TMS) as internal standard. FT-IR was recorded using
Perkin Elmer model 1430 spectrometer. Microwave
oven used was focused mono-mode Plazmatronika RM
2001 PC (800W). Melting points were recorded on a
Buchi R-535 apparatus.
2.1 Geranyl bromide (2)
2.3 Geranyl amine (4)
A solution of geraniol (1, 26 mmol, 4.0 g) and CBr4 Hydrazine hydrate (0.66 mL, 21 mmol) was added to a
(30 mmol, 10.0 g) in DCM (11 mL) was prepared in stirred solution of N-geranyl phthalimide (3, 2.6 mmol,
a 100 mL flask and cooled to 0◦C. PPh3 (28 mmol, 0.736 g) in absolute EtOH (10 mL) and the solution was
7.3 g) was added in portions for over 30 min with vig- heated to reflux for 8 h. Further, it was cooled to r.t. and
orous stirring. Upon addition of triphenyl phosphine, the solvent was removed under reduced pressure. Then
the colourless solution turns pale brown and stirred 20% NaOH solution (10 mL) was added to the residue
for an additional 4 h at room temperature. The mixture and extracted with CH2Cl2 (3 × 15 mL). The combined
was concentrated to brown oil, quickly added to stir- organic extract was dried over anhydrous Na2SO4, fil-
ring hexane (22 mL), white ppt. so formed were filtered tered and evaporated to get pure geranyl amine (4) in
and remaining solution was concentrated and was puri- 93% yield (0.37 g) as light yellow oil.
fied over a silica gel column (98:2 hexane:EtOAc) to
give geranyl bromide (2) in 80% yield (4.5 g) as pale 1.56 (s, 3H, -CH3), 1.61 (s, 3H, -CH3), 1.92–2.00 (m,
1H NMR (CDCl3, 300 MHz): δ 1.53 (s, 3H, -CH3),
yellow oil.
4H, -CH2-CH2-), 2.14 (bs, 2H, -NH2), 3.22 (d, 2H,
1H NMR (CDCl3, 300 MHz): δ 1.68 (s, 3H, -CH3), J = 6.9 Hz, -CH2-NH2), 5.01 (t, 1H, J = 5.4 Hz, -
1.74 (s, 3H, -CH3), 1.75 (s, 3H, -CH3), 2.04–2.14 (m, CH =C(Me)2), 5.18 (t, 1H, J = 6.9 Hz, =CH-CH2-
4H, -CH2-CH2-), 4.02 (d, 2H, J = 8.4 Hz, -CH2-Br), NH2). 13C NMR (CDCl3, 75 MHz): δ 16.05, 17.60,

First total synthesis of Nitensidine D
1871
25.60, 26.45, 39.31, 124.06, 124.82, 131.47, 137.08. IR 2.6 Nitensidine D (9)
(neat)/νmax (cm−1): 830, 984, 1045, 1107, 1376, 1446,
To an aqueous solution of NaOH (1.0 mL, 4.6 mmol,
0.184 g) and geranyl amine (4, 2.0 mmol, 0.306 g),
formamidinesulfinic acid (6, 2.30 mmol, 0.248 g) was
added in small portions over 30 min. After approx. 1/3
of formamidinesulfinic acid was added, the reaction
mixture became a viscous suspension. The suspension
was stirred at r.t. overnight, then heated to 60◦C and
stirred for additional 30 min. It resulted into the for-
mation of light brown oil which was extracted from
the aqueous solution by CHCl3, washed with brine
and dried over anhydrous Na2SO4. Solvent was evapo-
rated under reduced pressure and the viscous liquid thus
obtained was purified over a column of neutral Al2O3
using CHCl3: MeOH (96:4) as the eluent to give Niten-
sidine D (9) as colourless oil in 81% (0.32 g) yield in the
form of a mixture of tautomers in 25.8:74.2 ratio (figure 1).
1H NMR (CDCl3, 300 MHz): δ 1.18 (bs, 2H, -NH2),
1.52 (s, 3H, -CH3), 1.59 (s, 6H, 2 × -CH3), 1.93–
1.99 (m, 4H, -CH2-CH2-), 3.65 (t, 2H, J = 6.0, -CH2-
N=C(NH2)2, 74.2%), 3.99 (d, 2H, J = 6.6, -CH2-NH-
C=NH(NH2), 25.8%), 4.16 (bs, 1H, -NHH), 4.46 (bs,
1H, -NHH), 4.96 (t, 1H, J = 7.0, -CH =C(Me)2),
5.11 (t, 1H, J = 6.0, =CH-CH2-N=C(NH2)2). 13C
NMR (CDCl3, 75 MHz): δ 16.36, 17.85, 25.84, 26.58,
38.85, 39.65, 121.61, 124.12, 131.44, 138.73, 158.18.
IR (neat)/νmax (cm−1): 815, 1073, 1567, 1631, 1722. MS
m/z: [M+1]+ 196.2, [M+2]+ 197.2, 179.2 (calculated
for C11H21N3 195.3079).
1587, 1667, 2856, 2916, 2966, 3289, 3363.
2.4 Formamidinesulfinic acid (6)
Peracetic acid was prepared by slowly adding acetic
anhydride (50 mL) to 30% hydrogen peroxide (45 g)
cooled in an ice bath. The addition of two drops of con-
centrated sulphuric acid caused a violent reaction. After
the reaction has subsided, acetic anhydride (110 mL)
was slowly added to the cooled mixture. The mixture
was allowed to warm gradually to r.t. and left to stand
for at least one day. Methanol (160 mL) was added and
the solution was cooled to 10◦C in an ice bath. A solu-
tion of thiourea (5, 10 g) in methanol (500 mL) was also
cooled. The latter was added to the oxidizing mixture
in portions at such a rate as to maintain the temperature
below 10◦C (hotter reaction mixtures led to more for-
mamidinesulfonic acid as the product). The solid started
forming along with the addition of thiourea and after
the complete addition it was filtered and washed with
several portions of cold methanol. The product (6) was
obtained in 86% yield (12.2 g) as white powder. M.p. =
125◦C.
IR (neat)/νmax (cm−1): 597, 1054, 1186, 1462.
2.5 N-Hexyl guanidine (8)
To an aqueous solution of NaOH (1.0 mL, 4.6 mmol,
0.184 g) and hexyl amine (7, 2.0 mmol, 0.202 g), for-
3. Results and Discussion
mamidinesulfinic acid (6, 2.30 mmol, 0.248 g) was To start with the synthesis geranyl bromide was pre-
added in small portions over 30 min. After approx. pared from geraniol using CBr4/PPh3 in 80% yield
1/3 of formamidinesulfinic acid was added, the reac- (scheme 2).19
tion mixture became a viscous suspension. The sus-
Further geranyl bromide was required to be con-
pension was stirred at r.t. overnight, then heated to verted to geranyl amine via Gabriel reaction. First step
60◦C and stirred for additional 30 min. The solid prod- in the Gabriel reaction is the N–alkylation of phthal-
uct was obtained by cold filtration. White solid was imide to prepare N-alkyl phthalimide, which is further
crystallized from H2O and the resulting white crys- hydrolysed to give an amine as the final product. Var-
tals were washed with small portions of cold MeOH ious routes are available for their synthesis, however,
giving N-hexyl guanidine (8) in 85% yield (0.24g). some of these methods are limited by harsh reaction
M.p. = 140◦C.
conditions, long reaction times, low yields, use of toxic
1H NMR (CDCl3/DMSO-d6, 300 MHz): δ 0.82 (t, solvents or catalysts, etc.20
3H, J = 6.6, -CH3), 1.22 (m, 6H, -(CH2)3-CH3), 1.45
To overcome these shortcomings, the N-alkylation
(m, 2H, -CH2-CH2-N=C(NH2)2), 3.02 (t, 1H, J = 7.2, of phthalimide has been carried out by using a novel
-CHH-N=C(NH2)2), 3.24 (t, 1H, J = 7.2, -CHH- method involving immobilized IL i.e., SiO2-propyl-
N=C(NH2)2), 7.2 (bs, 1H, -CH2-NH-C(=NH)-NH2), tri-butyl chloride ([SiO2-PTB]Cl-) as a heterogeneous
7.9 (bs, 3H, -NH2-C=NH). 13C NMR (CDCl3/DMSO- phase transfer catalyst under microwave irradiation and
d6, 75 MHz): δ 14.37, 22.65, 26.48, 29.04, 31.55, 40.21, solvent free conditions. The reaction conditions were
157.21. IR (neat)/νmax (cm−1): 997, 1063, 1269, 1376, first optimized taking N-benzylation of phthalimide
1463, 1633, 1718, 2852, 2922, 3167, 3333.
with benzyl chloride as the model reaction to get the best

1872
Shallu et al.
(a)
Br
HO
1
2
3
(b)
O
(c)
N
H2N
4
O
Scheme 2. (a) CBr4, PPh3, DCM, 4h, rt, stirr; (b) Phthalimide, K2CO3,
SiO2-IL, MWI, 9min, 60-65◦C; (c) NH2NH2·H2O, EtOH, 8h, reflux.
minimum reaction time. Not only time, but the power better than the rest ones, but the reactions usually
of microwave oven, temperature of operation, as well as require a strong basic media and/or heat for some
quantity of the catalyst were also optimised to give the substrates. There are several reports that use S-oxides
best conditions as reported.
of thiourea i.e., thiourea dioxide/formamidinesulfinic
Then, we proceeded towards geranyl bromide as the acid27 [HN=C(NH2)SO2H] and thiourea triox-
reactant which gave the best yield when it was irradi- ide/formamidinesulfonic acid28 [HN=C(NH2)SO3H]
ated for 9 min. The reaction resulted into the formation for the preparation of N-formamidinylamines. Instead
of N-geranyl phthalimide as a white solid in 89% yield. of the easy accessibility of formamidinesulfinic acid,
Hydrolysis of the so formed N-geranyl phthalimide was only formamidinesulfonic acid and its derivatives were
done using Ing-Manske procedure involving hydrazine studied in detail. Reason for this neglect could be
hydrate in absolute EtOH under refluxing conditions the earlier reports which claimed that formamidine-
i.e., hydrazinolysis21 to give geranyl amine as a light sulfinic acid gave much poorer yields for guanylation
yellow oil in 93% yield.
reactions.29 Recently, considering this fact that the
The next task was the conversion of an amine to valuable conversion was at least possible with this
a guanidine, where amine nitrogen is incorporated cheaper reagent, its N-formamidinylation capability
into the newly formed guanidine functional group with amino acids was explored.30 The best yields were
i.e., guanylation. The common methods for producing obtained (up to 92%) when the reactions were carried
guanidino compounds are the reactions of ammonia or out in the presence of aqueous sodium hydroxide. The
amine derivatives with cyanamides,22 carbodiimides,23 awesome results so found in this latest discovery for
chloroformamidines,24 etc. Generally, these mate- amino acids, prompted us to screen amines as well for
rials are toxic, corrosive and/or moisture sensitive. the N-formamidinylation reaction using formamidine-
Other popular methods are reactions of amines with sulfinic acid. Formamidinesulfinic acid was prepared
substituted S-methylisothiourea,25 or 2,5-dimethyl-1- by oxidizing thiourea with peracetic acid in methanol
guanylpyrazole.26 The last two methods are generally (scheme 3).28a
S
SO2H
(d)
H2N
NH2
H2N
NH
5
6
NH2
SO2H
(e)
(e)
+
H2N
H2N
N
H2N
NH
6
8
7
NH2
SO2H
+
H2N
H2N
N
H2N
NH
9
6
4
Nitensidine D
Scheme 3. (d) CH3COOOH, MeOH, below 10◦C; (e) aq. NaOH, stirr, 24h at rt, 30min at 60◦ C.

First total synthesis of Nitensidine D
1873
NH2
NH
H2N
N
H2N
N
H
9
9a
Figure 1. Imine tautomeric forms of guanidine alkaloid Nitensidine D.
In a preliminary experiment, we chose an aliphatic Acknowledgements
amine i.e., hexyl amine as the substrate and car-
The authors are thankful to CSIR and UGC-New Delhi
(India) for providing financial assistance.
ried out its N-formamidinylation using aqueous
sodium hydroxide at room temperature. It gave N-
hexylguanidine as an off white solid in 85% yield. Then
some aromatic amines like aniline, 4-chloroaniline and
4-amino benzoic acid were taken. In this case, either
no or very little conversions (5%, 0% and 10% respec-
tively) were obtained. Therefore, we believe that this
approach would not be practical for aromatic amines,
but it is indeed a reliable, inexpensive and efficient
method for conversion of aliphatic amines into the cor-
responding N-formamidinyl derivatives. Thus, we pro-
ceeded towards the reaction of geranyl amine with for-
mamidinesulfinic acid under the same set of condi-
tions to obtain the title compound i.e., Nitensidine D in
81% yield (scheme 3). Spectral data of the synthesized
title compound were compatible with that reported in
literature.12 Also, its structure was in agreement with
a tautomeric form having imine feature which most of
the natural guanidines occurring in plants and animals
include (figure 1). It is also clear from the proton NMR
data that both the tautomers are present in 25.8:74.2
ratio.
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4. Conclusions
In conclusion, we have achieved an efficient first total
synthesis of a naturally occurring guanidine alkaloid,
Nitensidine D isolated from ethanol extract of Pterog-
yne nitens. Geraniol (1) has been used as the start-
ing material. The key steps in the synthesis involved
the microwave induced N-alkylation of phthalimide
using immobilized ionic liquid [SiO2-PTB]Cl- and N-
formamidinylation of geranyl amine using formamidi-
nesulfinic acid [HN=C(NH2)SO2H] to afford the title
compound (9).
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Supporting Information
Supporting information is available at www.ias.ac.in/
1
chemsci. H NMR, 13C NMR, IR and Mass spectra of
the title compound Nitensidine D are available in the
electronic supplementary information.

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