A simple one-pot synthesis of triflyl guanidines: Access to highly substituted electron-poor guanidines

Article abstract of DOI:10.1016/j.tetlet.2009.09.040

Unsymmetrical di- and trisubstituted triflyl guanidines are accessed through a simple, one-pot protocol from the corresponding isothiocyanate and amine. Furthermore, in the presence of base, trisubstituted triflyl guanidines are alkylated to obtain tetras

Full text of DOI:10.1016/j.tetlet.2009.09.040

Tetrahedron Letters 50 (2009) 6540–6542
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A simple one-pot synthesis of triflyl guanidines: access to highly
substituted electron-poor guanidines
*
Karen Thai, Craig W. Clement, Michel Gravel
Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, Canada SK S7N 5C9
a r t i c l e i n f o
a b s t r a c t
Article history:
Unsymmetrical di- and trisubstituted triflyl guanidines are accessed through a simple, one-pot protocol
from the corresponding isothiocyanate and amine. Furthermore, in the presence of base, trisubstituted
triflyl guanidines are alkylated to obtain tetrasubstituted triflyl guanidines in high yields and complete
regioselectivity.
Received 21 August 2009
Revised 4 September 2009
Accepted 8 September 2009
Available online 12 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Guanidines
Isothiocyanates
Trifluoromethanesulfonamide
Regioselective alkylation
Guanidine functionalities play a key role in many biologically
active natural products and pharmaceutically relevant compounds.
Moreover, compounds containing a trifluoromethanesulfonyl (tri-
flyl) guanidine moiety have been found to be useful in treating dis-
eases prevented by or ameliorated with potassium channel
openers1 and for the treatment of chemokine mediated diseases
and disorders.2 Furthermore, Kinoshita and co-workers have re-
ported the use of dialkylated triflyl guanidines as useful insecti-
cides or acaricides.3 In addition to their biological properties,
Goodman and co-workers have reported the use of diacylated tri-
flyl guanidines as a class of efficient guanylating reagents.4
To date, a limited number of methods to synthesize triflyl guan-
idines have been disclosed.5 Among those methods, the triflyl
group is introduced with triflic anhydride or in multiple steps,6,7
some involving tedious protecting group introduction and re-
moval.8 We were interested in the application of electron-poor
guanidines, including triflyl guanidines, as chiral catalysts. How-
ever, none of the published methods for the synthesis of triflyl
guanidines could be applied to the unsymmetrical triflyl guani-
dines we envisioned.9
synthesis of trisubstituted triflyl guanidines without the use of
protecting groups and, in addition, the substitution pattern would
be dependent solely on the starting materials used.
Unfortunately, the reaction conditions were not directly appli-
cable to the synthesis of triflyl guanidines. A thiourea side product
was observed, which was typically inseparable from the desired
guanidine. To circumvent the formation of the thiourea side prod-
uct, the isothiocyanate needed to be completely consumed before
the addition of the amine in the second step. A larger excess of tri-
fluoromethanesulfonamide (1.5 equiv) was therefore required. In
addition, the reaction was performed at elevated temperatures to
ensure the complete consumption of the isothiocyanate. With the
modified reaction conditions, the thiourea byproduct was not
observed in the final product. Excess amine (2 equiv) was also re-
quired to cleanly furnish the guanidines in high yield, which were
then precipitated out of solution through the addition of water,
without the need for further purification. In the cases where the
guanidine did not precipitate, the crude reaction mixture was eas-
ily purified by column chromatography.
To determine the scope and limitations of the one-pot synthesis
of di- and trisubstituted triflyl guanidines, various isothiocyanates
and primary and secondary amines were investigated (Table 1).
A one-pot method to synthesize acyl,10 sulfamoyl, methanesul-
fonyl, and benzenesulfonyl guanidines11 was developed by Shi and
co-workers, following a one-pot method for the synthesis of cyano-
guanidines (Scheme 1).12 We envisioned that, with slight modifica-
tions, a similar process would allow access to unsymmetrical triflyl
guanidines in a one-pot protocol. This protocol would enable the
EWG-NH2 (1.1 equiv.), NaH (1.1 equiv.),
60 oC or rt, DMF (0.4 M); then
EWG
N
Ar-NCS
Ar
R
N
N
R-NH2 (1.1 equiv), EDCI (1.1 equiv.)
H
H
* Corresponding author. Tel.: +1 306 966 7785; fax: +1 306 966 4730.
E-mail address: michel.gravel@usask.ca (M. Gravel).
Scheme 1. Shi and co-workers’ one-pot protocol for the synthesis of sulfamoyl and
sulfonyl guanidines.11 Ar = Ph, PhCH2CH2; EWG = SO2NH2, SO2NMe2, SO2Me, SO2Ph.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.040

K. Thai et al. / Tetrahedron Letters 50 (2009) 6540–6542
6541
Table 1
Table 2
Synthesis of triflyl guanidines
Regioselective synthesis of tetra-substituted triflyl guanidines
Tf
Tf
Tf
N
Tf-NH2 (1.5 equiv.), NaH (1.5 equiv.),
N
N
N
NaH, CH2Cl2
R4-X
DMF(0.4 M), 80 oC; then
R1
R2
R1
R2
R1
R2
R1-NCS
N
N
R3
N
N
N
R3
R2R3-NH (2 equiv.),
EDCI (1.1 equiv.), rt
H
H
R4 R3
1a-j
1b-c, g
2b-c, g
Entry
Product
R1
R2
R3
Yielda (%)
Entry
Product
R1
R2
R3
R4
Yielda (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Bn
Bn
iPr
tBu
Ph
Ph
Bn
Bn
Bn
H
80
93
99
52
53
66
53
90
75
74
1b
2b
3c
2g
2b
2c
Ph
Ph
Ph
Ph
Bn
Bn
Me
Me
Bn
Bn
Bn
Me
87
76
100
Me
Bn
iPr
H
H
Me
H
a
b
c
Yield of isolated pure product.
Reaction was performed using 1.2 equiv of BnBr.
Reaction was performed using DMF as solvent and 2.2 equiv of MeI.
8
4-MeO–C6H4
3,5-(CF3)2–C6H3
2,4,6-(CH3)3–C6H2
9b
10
H
H
1j
HMBC (see Supplementary Material).14 Benzylation of 1g selec-
tively furnishes 2g in 87% yield (entry 1). Simply modifying the
starting materials can control the substitution pattern of tetrasub-
stituted triflyl guanidines. Regioisomers 2b and 2c can be accessed
selectively in high yields by simply varying the alkylating reagent
and the amine used to synthesize the trisubstituted triflyl guani-
dine precursor (entries 2–3). To the best of our knowledge, this
method constitutes the first example of highly regioselective alkyl-
ation of unsymmetrical guanidines.
In summary, the synthesis of di- and trisubstituted guanidines
can be achieved in high yield using a simple, one-pot protocol. Fur-
thermore, tetrasubstituted triflyl guanidines can be synthesized
with complete regioselectivity from the corresponding trisubsti-
tuted guanidine. This modular approach allows control over the
substitution pattern, which poses a significant challenge to access
highly substituted guanidines.
a
Yield of isolated pure product.
The first step was performed at room temperature. EDCI = N-(3-dimethylami-
nopropyl)-N-ethylcarbodiimide hydrochloride. Tf = CF3SO2.
b
Phenyl isothiocyanate and benzylamine furnished the desired
triflyl guanidine in 80% yield (entry 1). To our delight, unhindered
secondary amines afforded the desired guanidine in high yield (en-
tries 2–3). Interestingly, even severely hindered amines such as
diisopropylamine and t-butylamine furnished the desired guani-
dines 1d–e in good yields. Primary and secondary aromatic amines
can also be used (entries 6 and 7). The lower yield obtained for 1f
and 1g is presumably a consequence of the steric hindrance of
secondary anilines. We then examined the effect of the isothiocy-
anate’s electronic and steric properties on the reaction outcome.
Gratifyingly, both electron-deficient and electron-rich aryl isothio-
cyanates cleanly furnished triflyl guanidines 1h and 1i (entries
8
and 9). Due to the reactive nature of 3,5-bis(trifluoro-
Experimental
methyl)phenyl isothiocyanate, heating was not required for the
first step. Finally, triflyl guanidine 1j can be synthesized from mesi-
tyl isothiocyanate in 74% yield, indicating that steric bulk in the
isothiocyanate used is of no consequence to the reaction outcome
(entry 10).
General procedure for the synthesis of trisubstituted triflyl
guanidines: N-((benzylamino)(phenylamino) methylene)
trifluoromethanesulfonamide (1a)
As a result of the multiple substitution patterns possible, highly
substituted guanidines pose a significant challenge as synthetic
targets. Although several methods have been developed for the
alkylation of symmetrical guanidines,5,13 alkylation of unsymmetri-
cal guanidines typically suffers from poor or moderate regioselec-
tivity (Scheme 2).13a,c
With the goal of synthesizing fully substituted triflyl guanidines
in mind, we were delighted that trisubstituted triflyl guanidines of
type 1 furnished a single regioisomer in high yield in the presence
of NaH and an alkyl halide (Table 2). The alkylation occurred exclu-
sively at the nitrogen atom bearing the R1 group, as determined by
Sodium hydride (22 mg, 0.56 mmol, 60% in mineral oil) was
added to
(95 mg, 0.56 mmol) in dry DMF (1.0 mL) at room temperature.
After 5 min, phenyl isothiocyanate (44 L, 0.37 mmol) was added
a stirring solution of trifluoromethanesulfonamide
l
and the reaction mixture was heated to 80 °C until the complete
consumption of the isothiocyanate was observed by thin layer
chromatography, then the reaction was cooled to room tempera-
ture. Benzylamine (39 lL, 0.74 mmol) was added, followed by EDCI
(78 mg, 0.37 mmol), and the reaction was stirred for 20 h. The reac-
tion was quenched with distilled water (2 mL) and stirred for 5 min
at room temperature. The white precipitate formed was filtered
and washed with water (3 Â 10 mL) and hexanes (3 Â 10 mL).
White solid (105 mg, 81% yield). Mp: 119–124 °C. IR mmax 3330,
Tf
1604, 1335, 1209, 1180, 1049 cmÀ1 1H NMR (500 MHz, CDCl3) d
.
Tf
N
N
R1
R2
Base
R1
R2
8.91 (br s, 1H), 7.48–7.45 (m, 2H), 7.41–7.38 (m, 1H), 7.36–7.28
(m, 3H), 7.23–7.20 (m, 4H), 5.34 (br s, 1H), 4.57 (d, J = 5.7 Hz,
2H); 13C NMR (125 MHz, CDCl3) d 156.0, 136.6, 133.9, 130.9,
129.2, 128.3, 127.7, 126.9, 124.2, 117.8 (q, J = 320 Hz), 45.9; HRMS
(EI+) m/z calcd for C15H14F3N3O2S [M]+: 357.0759, found: 357.0756.
N
N
R3
N
N
R3
H
1
E+
E
N
Tf
Tf
General procedure for the synthesis of tetrasubstituted
triflyl guanidines: N-((benzyl(phenyl) amino) methyl(phenyl)-
amino) methylene)trifluoromethanesulfonamide) (2g)
N
N
R1
R2
R1
R2
N
R3
N
E
N
R3
Sodium hydride (5 mg, 0.12 mmol, 60% in mineral oil) was
Scheme 2. Regioselectivity problem: alkylation of guanidines under basic
conditions.
added to a solution of guanidine 1g (36 mg, 0.10 mmol) and benzyl

6542
K. Thai et al. / Tetrahedron Letters 50 (2009) 6540–6542
bromide (12 lL, 0.101) in dry CH2Cl2 (500 lL) at 0 °C. The reaction
References and notes
was warmed up to room temperature and stirred for 20 h. The
reaction was quenched with distilled water (2 mL) and extracted
with CH2Cl2 (3 Â 5 mL). The combined organic extracts were dried
over Na2SO4, then concentrated under reduced pressure. The crude
product was purified by column chromatography (4:1 hexanes/
EtOAc, Rf = 0.38) to yield a white solid (39 mg, 87% yield). Mp:
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62–64 °C. IR mmax 1511, 1409, 1333, 1213, 1136, 693 cmÀ1 1H
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6.70 (dd, J = 12.5, 7.3 Hz, 2H), 6.50 (d, J = 6.7 Hz, 2H), 4.97 (s, 2H),
3.50 (s, 3H); 13C NMR (125 MHz, CDCl3) d 161.6, 143.9, 142.1,
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(q, J = 319 Hz), 57.4, 43.2; HRMS (EI+) m/z calcd for C22H20F3N3O2S
[M]+: 447.1228, found: 447.1233.
Acknowledgments
9. Thai, K.; Gravel, M., submitted for publication.
We thank the Natural Sciences and Engineering Research Coun-
cil of Canada (NSERC), the Canada Foundation for innovation (CFI),
and the University of Saskatchewan for financial support.
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Supplementary data
14. 1H NMR of crude reaction mixtures only indicates the presence of the product
and unreacted starting materials.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.040.