Synthesis of Guanidine Derivatives and molecular recognition

Article abstract of DOI:10.1081/SCC-120017128

Five Guanidine Derivatives bearing acyl group were synthesized by the reaction of acyl chloride with 1,1,3,3-tetramethylguanidine. Their structures were confirmed by IR, ¹H-NMR, EI-MS, HRMS and elementary analysis. One of them (4a) was also cha

Full text of DOI:10.1081/SCC-120017128

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Synthesis of Guanidine Derivatives and Molecular
Recognition
Yanxing Qi a , Haixiang Gao a , Min Yang a , Chun-Gu Xia a & Jishuan Suo a
a State Key Laboratory for Oxo Synthesis and Selective Oxidation , Lanzhou Institute of
Chemical Physics , Chinese Academy of Sciences , Lanzhou, China
Published online: 21 Aug 2006.
To cite this article: Yanxing Qi , Haixiang Gao , Min Yang , Chun-Gu Xia & Jishuan Suo (2003) Synthesis of Guanidine
Derivatives and Molecular Recognition, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 33:7, 1073-1079, DOI: 10.1081/SCC-120017128
To link to this article: http://dx.doi.org/10.1081/SCC-120017128
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 7, pp. 1073–1079, 2003
Synthesis of Guanidine Derivatives and
Molecular Recognition
Yanxing Qi, Haixiang Gao, Min Yang,
*
Chun-Gu Xia, and Jishuan Suo
State Key Laboratory for Oxo Synthesis and Selective
Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou, China
ABSTRACT
Five Guanidine Derivatives bearing acyl group were synthesized by
the reaction of acyl chloride with 1,1,3,3-tetramethylguanidine. Their
structures were confirmed by IR, 1H-NMR, EI-MS, HRMS and
elementary analysis. One of them (4a) was also characterized by
X-ray. Preliminary results of interaction with phosphate-containing
biomolecules and adipate showed that all of them exhibited the
abilities of molecular recognition.
*Correspondence: Jishuan Suo, State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy
of Sciences, Lanzhou-730000, China; E-mail: jssuo@ns.lzb.ac.cn.
1073
DOI: 10.1081/SCC-120017128
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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1074
Qi et al.
Guanidine groups have been found in many important natural pro-
ducts such as guanine and arginine, and are known to play significant
roles in their biological activities.[1] For example, many of the novel
metabolites, which isolated from microorganisms, terrestrial inverte-
brates, and marine and freshwater organisms, contains single or multiple
guanidine units and possess unprecedented biological activity ranging
from antimicrobial, antiviral, and antifungal to neurotoxic.[2] In addition,
guanidine’s molecular recognition features are used for DNA base pair-
ing[3] and in the active sites of many enzymes,[4] and this functional group
also has high affinity for carboxylates, phosphates and metals.
Consequently, preparation of new guanidines and their hydrogen-bond-
mediated interaction of guanidinium ions with phosphate- and carbox-
ylate-containing biomolecules molecular recognition are of considerable
interest to chemists and biochemists.[5,6] Here we wish to report the new
synthesis and structural characterization of five guanidine derivatives
bearing acyl groups 3a–3b (Sch. 1) and 4(a–c) (Sch. 2).
The condensation of acyl chloride with 1,1,3,3-tetramethyl-guanidine
(TMG) gave the products 3a and 4a–c. The TMG acts not only
as nucleophilic reagent, but also as a base. Their IR spectra have corre-
sponding strong characteristic C¼N absorption (about 1600 cmÀ1), and
in their 1H-NMR spectra, the signal of N-methyl appeared as a singlet at
Scheme 1.
Scheme 2.

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Guanidine Derivatives
1075
about 3.0 ppm, and confirmed that all of them are guanidine derivatives
bearing chromophores. These compounds 3a–3b and 4a–c are all new
compounds to the literature. In addition, the complexes of transition
metals with guanidine and their derivates, including 1,1,3,3-tetra-
methyl-guanidine, were of considerable interest to chemists.[7–10] To our
knowledge, however, there were few previous examples of complexes
containing acyl guanidine ligands which have been structurally charac-
terized.[11] When we attempt to prepare new guanidine complexes with
transition metals, unexpectedly, we obtained crystal of 4a, which is suit-
1
able for X-ray analysis. As H NMR spectroscopy has been widely used
to investigate receptor-substrate interactions,[12] 1H NMR spectra of
nucleotide and adipate with or without host receptors (3–4) were
recorded and the selected data are listed in Table 1. Upon addition of
host receptors (3–4), the proton signals of substrates (Fig. 1) are shifted
significantly, which indicated that, as host receptors, all of the new gua-
Table 1. 1H NMR chemical shifts (ppm) for host receptors (3–4) in the absence
or presence of guest substrates (6–10).
Sample
ꢀa
ꢀb
ꢀc
ꢀd
ꢀe
ꢀf
ꢀg
6a
3.86
3.33
3.23
2.12
3.23
2.65
2.49
3.88
3.33
3.98
4.02
2.01
2.05
2.20
2.24
2.21
2.30
2.11
4.55
4.38
4.37
4.44
4.45
4.43
4.54
4.60
4.50
4.61
4.62
1.44
1.42
1.52
1.52
1.52
1.53
1.51
4.17
3.87
3.90
3.98
4.23
3.98
3.82
4.23
4.27
4.22
4.23
4.33
4.20
4.18
4.24
3.94
4.19
4.14
4.37
3.90
4.06
4.12
4.12
5.70
5.87
5.72
5.84
5.83
6.47
6.38
5.94
6.01
5.96
5.97
5.97
7.99
8.10
8.05
8.16
8.14
8.27
8.12
8.00
8.08
8.21
8.23
8.24
4a þ 6a
4b þ 6a
6b
b
4c þ 6
7a
8.50
8.45
8.37
8.48
8.55
8.42
8.44
4a þ 7a
8a
4a þ 8a
9c
3a þ 9c
10a
4b þ 10a
10c
3a þ 10c
3b þ 10c
10b
4c þ 10b
Solvent:
aD2O.
bD2O:(CD3)2CO¼4:1.
cDMSO-d6.

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1076
Qi et al.
Figure 1. Structures of substrates 6, 7, 8, 9 and 10.
nidine derivatives (3–4) have the abilities of molecular recognition for
phosphate (6–9) and adipate (10). The other molecular recognition details
of these compounds will be published elsewhere.
EXPERIMENTAL
The TMG (1,1,3,3-tetramethylguanidine) were obtained from Berqi
Chemical Co. All melting points were uncorrected. The yields refer to
isolated products. FT-IR spectra were recorded on a Nicolet 10 DX
1
spectrometer (KBr). H-NMR spectra were obtained on a Bruker AC-
P 200 M NMR instrument in CDCl3 or DMSO-d6 solution with TMS as
internal reference. EI-MS spectra were obtained with a VG AB-HS
instrument. HRMS (ESI) spectra were obtained with a Bruker
Daltonics APEX II 47e FTICR-HRMS instrument. A Rigaku AFC 7R
X-ray diffraction instrument was used for crystal analysis.

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Guanidine Derivatives
General Procedure for the Preparation of Compound 3a and 4
1077
In a flame-dried round-bottomed flask were placed 20 mmol TMG
ꢀ
and 20 mLTHF. The mixture was cooled to 9 C by an ice water bath.
10 mmol acyl chloride in 10 mLTHF was added dropwise to this stirred
solution. A white precipitate ([TMGH]þꢁClÀ) was formed immediately.
During the addition, the reaction temperature was maintained at 9–18ꢀC
about 1 h. After naphthoyl chloride or derivatives of benzoyl chloride
solution had been added, the ice water bath was removed. The resulting
white slurry was allowed to stir for additional 2 h at room temperature,
filtered, and the precipitate was washed with chloroform. The solvents
were removed by rotary evaporator to yield yellow syrup. The crude
product was dissolved in benzene, and the white precipitate
([TMGH]þꢁClÀ) was removed by filtering. Removal of the solvent in
vacuo left a residue, which was recrystallized from H2O to give products
3a, or column chromatographed on silica gel (eluted with CHCl3:
CH3OH ¼ 15:1) (products 4a–4c).
Preparation of Compound 3b
In a round-bottomed flask was placed 27 mmol Guanidine hydro-
chloride and 4.5 g 50% aqueous NaOH. The mixture was warmed to
40ꢀC and stirred for 10 min. To this stirred solution were added 15 mL
acetone and the mixture was cooled to 0ꢀC. Then 27 mmol p-toluene-
sulfonyl chloride in 20 mLacetone was added dropwise to the above
mixture. After acyl chloride had been added, the solution was allowed
to stir for additional 0.5 h at 0ꢀC, The pH value was adjusted to 4–5 with
80% acetic acid. The solvent was removed by rotary evaporator to
yield white syrup. Crystallization of the residue from pyridine yielded
compound 3b.
.
Preparation of Crystal of 4a HClO4
To a stirred solution of 4a in CH3OH was added 1 equiv. of HClO4
in water. The mixture was stirred for 10 min, filtered, and left at
room temperature for two weeks to give colorless crystals, which are
.
suitable for X-ray analysis. The X-ray structure of 4a HClO4 is
shown in Fig. 2.
4-methylbenzenesulfonyl-(1,1,3,3-tetramethylguanidine) (3a). Yield,
79%; M.p.:142–144ꢀC; H NMR (DMSO-d6): ꢀ ppm 7.63 (d, 2H), 7.28
1

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1078
Qi et al.
.
Figure 2. Molecular structure of 4a HClO4 (ORTEP view).
(d, 2H), 2.83 (s, 12H), 2.34 (s, 3H); HRMS for C12H20O2N3S (M þ1),
Calcd. 270.1271, Found, 270.1267; IR (KBr): 2948, 2893, 1561, 1527,
1471, 1394, 1331, 1264, 1161, 1132, 887, 811, 676 cmÀ1; Anal. calcd. for
C12H19O2N3S: C, 53.51; H, 7.12; N, 15.61; S, 11.88. Found: C, 53.23;
H, 7.27; N, 15.74; S, 11.81.
4-methylbenzenesulfonylguanidine (3b). Yield, 65%; M.p.: 213–215ꢀC;
1H NMR (DMSO-d6): ꢀ ppm 7.63(d, 2H), 7.29 (d, 2H), 3.33 (s, 4H), 2.35
(s, 3H); HRMS for C8H12O2N3S (M þ1), Calcd. 214.0645, Found,
214.0639; IR (KBr): 3491, 3436, 3353, 1621, 1531, 1241, 1181, 1134,
834, 818, 677 cmÀ1; Anal. calcd. for C8H11O2N3S: C, 45.06; H, 5.20; N,
19.72; S, 15.01. Found: C, 44.91; H, 5.10; N, 19.59; S, 14.89.
2-bromobenzyl-(1,1,3,3-tetramethylguanidine) (4a). Yield, 90%; M.p.:
93.3–95ꢀC; 1H NMR (DMSO-d6): ꢀ ppm 7.58 (d, 1H), 7.55 (d, 1H),
7.19–7.38 (m, 2H), 2.91 (s, 12H); EI/MS (m/z): 297 (Mþ), 282, 253,
218, 183 (100), 155, 130, 76; IR (KBr): 3057, 2956, 1588, 1522 (C¼N),
1398, 1229, 1170, 865 cmÀ1; Anal. calcd. for C12H16BrN3O: C, 48.48; H,
5.43; N, 14.14. Found: C, 48.53; H, 5.51; N, 14.21.
1-naphthoyl-(1,1,3,3-tetramethylguanidine) (4b). Yield, 91%; M.p.:
108–110ꢀC; H NMR (CDCl3): ꢀ ppm 9.01 (d, 1H), 8.09 (d, 1H), 7.86
1
(m, 2H), 7.55–7.43 (m, 3H), 3.01 (s, 12H); EI-MS (m/z): 269 (Mþ), 252,
226, 225 (100), 182, 155, 142, 127; IR (KBr): 3010, 2866, 1583, 1522,
1405, 1359, 1227, 1160, 1037, 810 cmÀ1; Anal. calcd. for C16H19N3O:
C, 71.33; H, 7.12; N, 15.61. Found: C, 71.18; H, 7.23; N, 15.69.
2-naphthoyl-(1,1,3,3-tetramethylguanidine) (4c). Yield, 87%; M.p.:
126–127ꢀC; H NMR (CDCl3): ꢀ ppm 8.69 (s, 1H), 8.25 (m, 1H), 7.93
1
(m, 1H), 7.83 (m, 2H), 7.46 (m, 2H), 2.93 (s, 12H); EI/MS (m/z): 269
(Mþ), 226, 225, 155 (98), 127 (100), 126, 71; IR (KBr): 2925, 2866, 1604,
1519, 1401, 1357, 1154, 1018, 981 cmÀ1; Anal. calcd. for C16H19N3O: C,
71.33; H, 7.12; N, 15.61. Found: C, 71.18; H, 7.26; N, 15.70.

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Guanidine Derivatives
1079
ACKNOWLEDGMENT
This work was funded by National Natural Science Foundation of
China (No. 29933050).
REFERENCES
1. Toshio Nishikawa; Norio Ohyabu; Noboru Yamamoto; Minoru
Isobe. Tetrahedron 1999, 55, 4325–4340.
2. Berlinck, R.G.S. Fortschr. Chem. Org. Naturst. 1995, 66, 119.
3. Heinz E. Moser; Peter B. Dervan Science 1987, 238, 645–650.
4. Fukutomi, R.; Tanatani, A.; Kakuta, H.; Tomioka, N.; Hashimoto,
Y. Tetrahydron Lett. 1998, 39, 6475.
5. Hannon, C.L.; Anslyn, E.V. Bioorganic Chemistry Frontieres 1993,
3, 193–255.
6. Schmidtchen, F.P.; Berger, M. Chem. Rev. 1997, 97, 1609.
7. Longhi, R.; Drago, R.S. Inorg. Chem. 1965, 4, 11.
8. Bailey, P.J.; Grant, K.J.; Pace, S.; Parsons, S.; Stewart, L.J.
J. Chem. Soc. Dalton Trans. 1997, 4263.
9. Holman, K.T.; Robinson, S.D.; Sahajpal, A.; Steed, J.W. J. Chem.
Soc. Dalton Trans. 1999, 15.
10. Tin, M.K.T.; Yap, G.P.A.; Richeson, D.S. Inog. Chem. 1999,
38, 998.
11. Alfred, G.O.; Werner, R.M.; Ulrich, W.S. Helv. Chim. Acta 1992,
75 (1), 184–189.
12. Whitlock, B.J.; Whitlock, H.W. J. Am. Chem. Soc. 1994, 116,
2301–2311.
Received in Japan November 19, 2001

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