Solvent-free synthesis of azole carboximidamides

Article abstract of DOI:10.1016/j.tetlet.2004.10.114

A one-pot procedure is described for the preparation of azole carboximidamides 2, 3 and guanidinylation of amines with 3. The X-ray crystal structure of 3b, has been determined. A one-pot procedure is described for the preparation of 1H-pyrazole-carboximidamides 2, 1H-benzotriazole-carboximidamides 3 and guanidinylation of amines with 3. The X-ray crystal structure of N,N-dimethyl-1H-benzotriazole-1-carboximidamide 3b, has been determined.

Full text of DOI:10.1016/j.tetlet.2004.10.114

Tetrahedron
Letters
Tetrahedron Letters 45(2004) 9423–9426
Solvent-free synthesis of azole carboximidamides
Sotir Zahariev,a,*,ꢀ Corrado Guarnaccia,a Doriano Lamba,b
a
Masa Cemazˇar and Sandor Pongor
a
ˇ
ˇ
´
aProtein Structure and Function Group, International Centre for Genetic Engineering and Biotechnology,
Padriciano 99, I-34012Trieste, Italy
`
Istituto di Cristallografia, CNR, Unita Staccata di Trieste, Area Science Park Basovizza, I-34012Trieste, Italy
b
Received 15July 2004; revised 15October 2004; accepted 20 October 2004
Abstract—A one-pot procedure is described for the preparation of 1H-pyrazole-carboximidamides 2, 1H-benzotriazole-carboximid-
amides 3 and guanidinylation of amines with 3. The X-ray crystal structure of N,N-dimethyl-1H-benzotriazole-1-carboximidamide
3b, has been determined.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Amidino (carboximidamide) group transfer reagents are
useful tools for the preparation of guanidines from
amines, both in solution and on a solid support.1–13
Derivatives of pyrazole 2 (Scheme 1) are selective inhibi-
tors of inducible nitric oxide synthase.14–16 The benzene
ring in benzotriazole causes 3 to be more reactive than
2.17,18 N,N0-diBoc-acylated 3, is significantly superior
in N-amidination of poorly nucleophilic or sterically
hindered secondary amines, than the corresponding pyr-
azol or triflyl compounds.19 The latter generate pro-
tected guanidines, which require an additional
deprotection step.
amide 317,18 is an ideal reagent for the synthesis of guani-
dines.24,25 It has higher reactivity and longer shelf
stability, while removal/regeneration and monitoring of
3 and benzotriazole at the end of the reaction sequence
is easier. In spite of these known advantages its use in solu-
tion- and solid-phase synthesis is relatively recent.26–31
For the preparation of 2 and 3 (Scheme 1 and Table 1)
we apply solvent-free classical heating (Method A)ꢁ or
ꢁ Method A: Typical procedure for preparation of 2 or 3 (on example
3b, Table 1, entry 16): 0.1mol (15.56g) dry powdered Bt–HÆHCl and
0.12mol (8.41g) Me2NCN were stirred at 80ꢁC (oil bath, under N2).
Bt–HÆHCl was dissolved in 1–2min. Some heat is evolved and
external cooling with ice water is necessary to keep the temperature
below 100ꢁC. After ꢀ5–7min the crystals of 3b were formed. The
reaction mixture was heated at 80ꢁC for 15min, the crystals were
cooled, washed with tBuOMe (30mL) and petroleum benzene
(30mL) and dried. Yield 18.5–18.7g (97.8–98.9%), purity 96–98.5%
(HPLC), mp 188–191 (dec.), increased to 191–192 (dec.) when
crystallized from EtOH/toluene. 1H NMR (DMSO-d6): d 11.56, (br s,
1H); 8.16 (d, J = 7.7Hz, 1H); 7.98, (d, J = 7.7Hz, 1H) 7.93, (t,
J = 8.2Hz, 1H) 7.83, (t, J = 8.2, 1H), 2.76, (s, 6H); ESI-MS (OR 30):
221.2 (2%, MNa+), 190.2 (76%, MH+), 162.2 (85%, MH+–N2), 146.1
(81%, MH+–NMe2); 120.1 (100%, Bt–HÆH+).
A survey of the literature reveals that compounds 2 and 3
have been prepared by (i) prolonged heating of benzo-
triazole/pyrazole with acids and cyanamides in organic
solvents,1,17,20 (ii) from azoles and carbodiimide,19 (iii)
from aminoguanidine and b-diketones11 or pyrimidines21
and (iv) by reaction of amines with di(benzotriazol-
1-yl)methanimine22 or benzotriazole-1-carboximidoyl
chlorides.23 In contrast to 2, benzotriazole–carboximid-
The hydrochlorides of 3,5-dimethyl-1H-pyrazole, 1H-Indazole, 1H-
[1,2,3]triazole, 1H-[1,2,4]triazole and the trifluoromethanesulfonates
of 5-nitro-1H-benzotriazole, 5-chloro-1H-benzotriazole, 1H-benzo-
triazole-5-carboxylic acid 5,6-dichloro-1H-benzotriazole reacts in a
similar way, but the hydrochlorides, 4-methylbenzene-sulfonates or
trifluoromethanesulfonates of 1H-imidazole and 1H-tetrazole do not
react.
Keywords: Solvent-free; N-Carboximidamides; Pyrazole; Benzotriaz-
ole; Cyanamides; Guanidinylation; MW irradiation.
*
Corresponding author. Tel.: +39 040 3757341; fax: +39 040
226555; e-mail: sotir@icgeb.org
ꢀ Contract/grant sponsor: EU. Contract/grant number: ENGEM
QLK3-CT-2001-00448 and Contract/grant sponsor: CNR, Italy.
Contract/grant number: 01.00122.PF33.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.114

9424
S. Zahariev et al. / Tetrahedron Letters 45 (2004) 9423–9426
LG
NR3R4
b
a
N
N
LG-H HZ +
N
C NR1R2
1a-g
C
NR1R2
C
NR1R2
N
solvent-free
N
NR HZ
NR HZ
N
1a. R1=R2=H
1e. R1=R2=Bzl
2a-d
3a-g
4
1f. R1=R2=Allyl
LG = Py-
LG = Bt-
series 3a-g
1b. R1=R2=Me
1c. R1=R2=Et
1g. R1=H; R2=tBu
series 2a-d
1d. R1=R2=CH(CH3)2
HZ: organic or inorganic acid
Scheme 1. Reagents and conditions: (a) Method A: D (À20 to +80ꢁC), 5–360min; Method B: MW irradiation, 0.5–12min; (b) 1 or 2 (5M in MeCN)/
NEt3/HNR3R4 = 2/2/1, 60ꢁC, 2–6h.
Table 1. Solvent-free reaction of cyanamides with salts of pyrazole/benzotriazole to 1a–d or 2a–h under heating or MW irradiation
Entry
Cyanamide
Azole salt
Molar ratio column 2/3
Reaction conditions
Purityb (%)
Yield (%)
min
ꢁC
Method
Pyrazole carboximidamides hydrochlorides (1)
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1b
1b
1c
1d
Py–HÆHCl
Py–HÆHCl
Py–HÆHCl
Py–HÆHCl
Py–HÆHCl
Py–HÆHCl
Py–HÆHCl
Py–HÆHCl
1.0/1.0
1.3/1.0
1.3/1.0
1.2/1.0
1.2/1.0
1.2/1.0
1.2/1.0
1.2/1.0
720
6
24
80
D
92
98
90
98
Dc
0.4
30
80d
MWa
D
9592
96
80
d
94
92
90
95
0.580
0.580
30
MWa
MWa
D
94
94
d
80
80
97
4530
720
D
Salts of benzotriazole carboximidamides (2)
9
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1d
1d
1e
1f
Bt–HÆTos–OH
Bt–HÆTos–OH
Bt–HÆTos–OH
Bt–HÆHCl
Bt–HÆHCl
Bt–HÆHCl
Bt–HÆTFMSA
Bt–HÆHCl
Bt–HÆHCl
Bt–HÆHCl
Bt–HÆHCl
1.0/1.0
1.2/1.0
1.2/1.0
1.1/1.0
1.1/1.0
1.1/1.0
1.2/1.0
1.2/1.0
1.2/1.0
1.2/1.0
1.3/1.0
1.3/1.0
1.2/1.0
1.2/1.0
1.2/1.0
1440
10
100
80
D
7717
99
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Dc
MWa
D
99
97
0.8
360 (720)
30
80d
23
96
92 (97)
98
97
85(90)
96
95
80
d
Dc
MWa
D
2 · 0.580
30
30
1
À20 to +24
87
98
—
94
80
D
80d
80
MWa
94
96
91
92
30
1440
4
D
D
D
D
D
D
80
25—
68
Bt–HÆTFMSA
Bt–HÆHCl
Bt–HÆHCl
À20 to +40
—
92
60
60
60
80
80
80
97
9590
96
1g
Bt–HÆHCl
90
D—heating in oil bath; MW—heating by domestic microwave oven type LG, MS-255NB (1300W).
a 260 W.
b Determined by RP HPLC (area): Column Zorbax 300SB 5RP18, gradient 0–100% MeCN containing 0.1% TFA in 15min, and/or TLC (SiO2):
CHCl3/MeOH/AcOH = 10/3/1; DCM/EtOAc/EtOH/AcOH (7:1:1:1).
c 0.1M scale, 20M Bt–HÆHCl in MeCN.
d Final temperature, according to the glass thermometer immediately after stopping MW-heating.
microwave irradiation32 (Method B)§ of pyrazole or
benzotriazole salts with organic or inorganic acids
(pKa from À2 to À13) and 5–30% excess of various
cyanamides. These methods were extended to a number
of azoles.ꢁ All cyanamides, with an exception of those
sterically hindered (Table 1, entries 8 and 20), afford
the expected products 2 and 3 almost quantitatively
and the reaction time is exceedingly short. The synthesis
of 2 and 3 by Method B is advantageous since the reac-
tion rate is speed-up by several orders of magnitude. The
optimal temperature for azole salts with Tos–OH,
H2SO4 and HCl was ꢀ60–80ꢁC; for TFMSA salts it
was <40ꢁC, but the conversion rate is high even at room
temperature (Table 1, entries 1 and 12). In terms of
yields, reaction times as well as the ease of work-up
and scale-up, both methods are superior to those previ-
ously reported1,14,17 (Table 1, entry 9). The use/cost of
the solvents have been minimized. Crude 3 was found
sufficiently pure to be used in a simple, one-pot guanidin-
ylation of amines. In addition, both 3 and benzotriazole,
§ Method B: MW assisted one-pot parallel synthesis of reagents 3a (3b)
and guanidinylation11 of amines (see Table 2): 0.156g (1mmol) Bt–
HÆHCl, 1.2mmol H2NCN or Me2NCN were heated for 0.5min in
domestic MW oven (260W) in a 2mL stopped tube. Two minutes
later were added 0.5mmol of the corresponding amine (see Table 2) in
0.5mL MeCN and 1mmol TEA. The tubes were stopped again,
sonificated for 30s (Branson 2200) and heated for 6h at 60ꢁC in
Multi-Block heater. The solvents were evaporated to dryness
(SpeedVac Concentrator), the dried compound was dissolved in
water (3 · 2mL), pH was adjusted (if necessary) with 0.1N HCl to
pH ꢀ 7.5and extracted with EtOAc (5 · 3mL). The water phases
were desalted/purified separately on anion-exchange resin columns
(Fractogel EMD TMAE 650, Merck in HOÀ form, 10mL each one)
by eluting with water. The collected fractions of 4 were freeze-dried.
The NMR/HPLC purity of prepared guanidines were 93–99%.

S. Zahariev et al. / Tetrahedron Letters 45 (2004) 9423–9426
9425
Table 2. Guanidinylation of selected amines§ with reagents 3a and 3b: series 3a, R = H; series 3b, R = Me
Amine
Reagent
Guanidine (4)
Yield (%)
MH+ (found) (ESI-MS)e
Z–Orn–OHa
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3b
Z–Arg–OH
Z–aDma–OH
97
309.2
95337.2
97
98
Boc–NHNH2
Boc–NHNHC(@NH)NR2
175.2
203.1
150.2
178.2
166.1
194.2
164.3
192.1
136.1
C6H5CH2NH2
C6H5CH2ONH2
C6H5CH2NHCH3
C6H5NH2
C6H5CH2NHC(@NH)NR2
C6H5CH2ONHC(@NH)NR2
C6H5CH2ON(CH3)C(@NH)NR2
C6H5NHC(@NH)NR2
99
99
99
99
94
87
98
95164.1
95196.1
95224.1
98b
98b
0
2,4-(MeO)2C6H5NH2
4-NH2C6H4NH2
[(CH3)2CH]NH
(NH2CH2CH2)2NH
H–Lys–OH
2,4-(MeO)2C6H5NHC(@NH)NR2
4-NH2C6H4NHC(@NH)NR2
151.2
179.1
—
0
—
[R2N(HN@)CNHCH2CH2]2NH
99c
216.4
244.4
287.3f
99d
96
Me2NC(NH)–Lys[C(NH)NMe2]–OH
a 0.2M in MeCN/H2O = 5/1, 2.5h at 60ꢁC. The half time for guanidinylation of Z–Orn–OH with 3a/3b was <1min.
b Only NH2C6H4NHC(NH)NH2, respectively NH2C6H4NHC(@NH)N(CH3)2 were detected by LCMS.
c Triamine/monoguandylated-/diguanidinylated-/triguanidinylated-triamine = 0.0/0.1/99.1/0.8 (ESI-MS).
d Triamine/monoguandylated-/diguanidinylated-/triguanidinylated-triamine = 0.00/0.15/99.60/0.25 (ESI-MS).
e In water/MeCN (1/1, v/v), containing 0.2% HCOOH.
f 0.2M in MeCN/H2O = 4/1 reaction with 4equiv 3b, 4h at 60ꢁC, and this procedure was repeated one more time.
present in crude 3 or as result of N-amidination, are well
soluble in organic solvents, so the isolation11 of the
corresponding guanidines (up to tetra-substituted) can
be carried out without activating agents or protecting
group manipulations (Table 2).§ The crystal structure– of
3b, a reagent for the preparation of Nx,Nx-dimethyl-
arginine (aDma) in solution and on solid support,k has
been determined.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2004.10.114.
References and notes
In conclusion, we have presented two simple
eco-friendly methods for the preparation of azole
carboximidamides that are valuable synthons for
guanidinylation of amines both in solution and on the
solid supports.
1. Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. J. Org.
Chem. 1992, 57, 2497–2502, and references cited therein.
2. Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. Tetrahedron
Lett. 1993, 34, 3389–3392.
3. Drake, B.; Patek, M.; Lebl, M. Synthesis 1994, 579–
582.
4. Yong, Y. F.; Kowalski, J. A.; Thoen, J. C.; Lipton, M. A.
Tetrahedron Lett. 1999, 40, 53–56.
5. Ho, K. C.; Sun, C. M. Bioorg. Med. Chem. Lett. 1999, 9,
1517–1520.
6. Golding, B. T.; Mitchinson, A.; Clegg, W.; Elsegood, M.
R. J.; Griffin, R. J. J. Chem. Soc., Perkin Trans. 1 1999, 3,
349–356.
7. Patek, M.; Smrcina, M.; Nakanishi, E.; Izawa, H. J.
Comb. Chem. 2000, 2, 370–377.
8. Goodman, M.; Zapf, C.; Rew, Y. Biopolymers 2001, 60,
229–245.
9. Zhang, Y.; Kennan, A. J. Org. Lett. 2001, 3, 2341–2344.
10. Zapf, C. W.; Creighton, C. J.; Tomioka, M.; Goodman,
M. Org. Lett. 2001, 3, 1133–1136.
11. Draeger, G.; Solodenko, W.; Messinger, J.; Schoen, U.;
Kirschning, A. Tetrahedron Lett. 2002, 43, 1401–1404, and
references cited therein.
12. Zapf, C. W.; Goodman, M. J. Org. Chem. 2003, 68,
10092–10097.
– The structure of 3b (crystals from MeCN, see Supplementary data)
was unambiguously confirmed by X-ray crystallographic analysis
using synchrotron radiation data collected at ELETTRA (XRD-1
beamline), Trieste, Italy. Crystallographic data have been deposited
with the Cambridge Crystallographic Data Centre (CCDC) as
supplementary publication number CCDC 235826. An interesting
feature of the crystal structure 3b is the twisting of the N,N-dimethyl-
carboxamidinium moiety out of the plane of the benzotriazole ring
system. The angle between the mean planes is of 37.9ꢁ. The
corresponding angle in the crystal structure of the structurally related
benzotriazole-1-carboxamidinium17 is of 20.5ꢁ [Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1 EZ, UK (fax: +44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk)].
k Guanidinylation of resin bound ornithine-containing peptides: Boc-
Orn-Ser(But)-Ile-Asn(Trt)-Ile-Asp(OBut)-Leu-Thr(But)-Lys(Boc)-2-
ClTrt Resin (0.05mmol, loading 0.32mmol/g) react with 4equivs 3a–
c/4equiv DIEA in THF (0.3M) overnight at room temperature, after
clevage/deprotection form quantitatively (LCMS) H-
Orn[C(NH)N(R)2]-SINIDLTK-OH, where R1 = R2 = H, Me or Et.
13. Tian, Z. P.; Roeske, R. W. Int. J. Pept. Protein Res. 1991,
37, 425–429.

9426
S. Zahariev et al. / Tetrahedron Letters 45 (2004) 9423–9426
14. Southan, G. J.; Gauld, D.; Lubeskie, A.; Zingarelli, B.;
Cuzzocrea, S.; Salzman, A. L.; Szabo, C.; Wolff, D. J.
Biochem. Pharmacol. 1997, 54, 409–417.
15. Lee, Y.; Martasek, P.; Roman, L. J.; Silverman, R. B.
Bioorg. Med. Chem. Lett. 2000, 10, 2771–2774.
16. Salerno, L.; Sorrenti, V.; Di Giacomo, C.; Romeo, G.;
Siracusa, M. A. Curr. Pharm. Des. 2002, 8, 177–200.
17. Katritzky, A. R.; Parris, R.; Allin, S.; Steel, P. J. Synth.
Commun. 1995, 25, 1173–1186.
24. Katritzky, A. R.; Rogovoy, B. V. Chemistry 2003, 9, 4586–
4593.
25. Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V.
Chem. Rev. 1998, 98, 409–548.
26. Katritzky, A. R.; Rogovoy, B. V.; Kovalenko, K. V. J.
Org. Chem. 2003, 68, 4941–4943.
27. Katritzky, A. R.; Rogovoy, B. V.; Vvedensky, V.;
Kovalenko, K.; Forood, B. J. Comb. Chem. 2002, 4,
290–294, and references cited therein.
18. Staab, H. A.; Bauer, H.; Schneider, K. M. Azolides in
Organic Synthesis and Biochemistry; Wiley-VCH: Wein-
heim, 1998; pp 282 and 283.
28. Katritzky, A. R.; Rogovoy, B. V.; Vvedensky, V. Y.;
Kovalenko, K.; Steel, P. J.; Markov, V. I.; Forood, B.
Synthesis 2001, 897–903.
19. Musiol, H. J.; Moroder, L. Org. Lett. 2001, 3, 3859–3861,
and references cited therein.
29. Makara, G. M.; Yao Ma, Y.; Laura Margarida, M. Org.
Lett. 2002, 4, 1751–1754.
20. Kampf, A. Chem. Ber. 1904, 37, 1681–1684.
21. Menichi, G.; Naciri, J.; Kokel, B.; Hubert-Habart, M.
Heterocycles 1984, 22, 2013–2017.
22. Katritzky, A. R.; Rogovoy, B. V.; Chassaing, C.; Vve-
densky, V. J. Org. Chem. 2000, 65, 8080–8082.
30. Makara, G. M.; Schell, P.; Hanson, K.; Moccia, D.
Tetrahedron Lett. 2002, 43, 5043–5045.
31. Katritzky, A. R.; Rogovoy, B. V.; Cai, X.; Kirichenko,
N.; Kovalenko, K. V. J. Org. Chem. 2004, 69, 309–
313.
23. Katritzky, A. R.; Rogovoy, B.; Klein, C.; Insuasty, H.;
Vvedensky, V.; Insuasty, B. J. Org. Chem. 2001, 66, 2854–2857.
32. Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199–
9223.