References and Notes
1
De Luca L.
Curr.
Med. Chem.
2006,
13:
1
2a
Al-Shaar AH.
Gilmour DW.
Lythgoe DJ.
McClenaghan I.
Ramsden CA.
J.
Chem. Soc., Perkin Trans. 1
1992,
2779
2b
Al-Shaar AH.
Chambers RK.
Gilmour DW.
Lythgoe DJ.
McClenaghan I.
Ramsden CA.
J.
Chem. Soc., Perkin Trans. 1
1992,
2789
2c
McLaughlin M.
Mohareb RM.
Rapoport H.
J.
Org. Chem.
2003,
68:
50
2d
Zuliani V.
Cocconcelli G.
Fantini M.
Ghiron C.
Rivara M.
J.
Org. Chem.
2007,
72:
4551
2e
Soh CH.
Chui WK.
Lam Y.
J.
Comb. Chem.
2006,
8:
464
3a
De Corte B.
Denis J.-M.
De Kimpe N.
J. Org. Chem.
1987,
52:
1147
3b
Alonso ER.
Tehrani KA.
Boelens M.
Knight DW.
Yu V.
De Kimpe N.
Tetrahedron
Lett.
2001,
42:
3921
3c
Jursic BS.
Douelle F.
Bowdy K.
Stevens ED.
Tetrahedron
Lett.
2002,
43:
5361
3d
Roychowdhury A.
Kumar VV.
Bhaduri AP.
Synth. Commun.
2006,
36:
715
3e
Fontaine P.
Chiaroni A.
Masson G.
Zhu J.
Org. Lett.
2008,
10:
1509
4
Wang J.
Xu F.
Cai T.
Shen Q.
Org.
Lett.
2008,
10:
445
5
Gabrielsen B.
Phelan MJ.
Barthel-Rosa L.
See C.
Huggins JW.
Kefauver DF.
Monath TP.
Ussery MA.
Chmurny GN.
Schubert EM.
Upadhya K.
Kwong C.
Carter DA.
Secrist JA.
Kirsi JJ.
Shannon WM.
Sidwell R.
Kini GD.
Robinst RK.
J.
Med. Chem.
1992,
35:
3231
6a
Cusack NJ.
Shaw G.
Litchfield GJ.
J. Chem. Soc.
C
1971,
150
6b
Barder TE.
Peng P.
Okamoto A.
Ealick SE.
Stubbe J.
Biochemistry
2007,
46:
2842
7
Baxter RL.
Scott AI.
Comprehensive
Heterocyclic Chemistry
Vol. 1:
Katritzky AR.
Rees CW.
Pergamon
Press;
Oxford:
1984.
p.87
8
Kadir K.
Shaw G.
Wright D.
J.
Chem. Soc., Perkin Trans. 1
1980,
2728
9a
Alves MJ.
Booth BL.
Freitas AP.
Proença MF.
J. Chem. Soc., Perkin Trans. 1
1992,
913
9b
Booth BL.
Dias AM.
Proença MF.
J. Chem. Soc., Perkin Trans. 1
1992,
2119
9c
Booth BL.
Cabral IM.
Dias AM.
Freitas AP.
Matos-Beja AM.
Proença MF.
Ramos-Silva M.
J.
Chem Soc., Perkin Trans. 1
2001,
1241
9d
Alves MJ.
Carvalho MA.
Carvalho S.
Dias AM.
Fernandes FH.
Proença MF.
Eur
J. Org. Chem.
2007,
4881
10a
Dias AM.
Cabral IM.
Vila-Chã AS.
Proença MF.
Synlett
2007,
1231
10b
Dias AM.
Cabral IM.
Vila-Chã AS.
Cunha D.
Senhorães N.
Nobre S.
Sousa C.
Proença MF.
Synlett
2010,
2792
10c
Senhorães N.
Dias AM.
Conde LM.
Proença MF.
Synlett
2011,
181
11
Zhao L.
Liang F.
Bi X.
Sun S.
Liu Q.
J. Org. Chem.
2006,
71:
1094
12
General Procedure
for the Synthesis of 1˙TFA Salts
TFA (1.0
equiv) was added to a suspension of imidazole 1 (1.0-2.0
mmol) in CH2Cl2 or MeCN (3.0-5.0
mL) at r.t. leading to a homogeneous solution. After 1 min, a yellow solid
precipitated from solution and was filtered and washed with Et2O
to give compound 1˙TFA (76-88%).
[5-Amino-1-(2-hydroxyethyl)-1
H
-imidazol-4-yl] (Cyano)methaniminium
2,2,2-Trifluoroacetate (1a˙TFA)
Mp >110 ˚C
(dec.). ¹H NMR (300 MHz, DMSO-d
6): δ = 10.21
(br s, 1 H), 8.79 (br s, 2 H), 7.91 (s, 1 H), 7.32 (t, J = 50 Hz,
0.2 H), 5.20 (s, 1 H), 4.11 (t, J = 4.7
Hz, 2 H), 3.83 (t, J = 4.7
Hz, 2 H). ¹³C NMR (75 MHz, DMSO-d
6): δ = 158.08
(q, J = 32
Hz), 152.62, 141.68, 131.83, 118.58, 116.44 (q, J = 300
Hz), 112.51, 57.74, 45.59. Anal. Calcd for C9H8F3N5O3˙H2O:
C, 36.9; H, 3.0; F, 23.9; N, 19.90. Found: C, 36.9; H, 3.4; F, 23.6;
N, 20.2. IR (mull): 3422, 3092, 3059, 1690 (CO), 1663, 1576 cm-¹.
13
General Procedure
for the Synthesis of 3b×TFA
Method
B
TFA (1 equiv) was added
to a suspension of imidazole 1b (1.7 mmol)
in EtOH (3 mL), and the mixture was stirred for 1 d at r.t. The
solid was filtered and washed with EtOH and Et2O (3b×TFA, 69%).
[5-Amino-1-(4-methoxyphenyl)-1
H
-imidazol-4-yl] (Ethoxy)methaniminium
2,2,2-Trifluoroacetate (3b˙TFA)
Mp 241-242 ˚C. ¹H
NMR (300 MHz, DMSO-d
6): δ = 9.94 (br
s, 1 H), 9.57 (br s, 1 H), 7.58 (s, 1 H), 7.40 (d, J = 9.0
Hz, 2 H), 7.13 (d, J = 8.7
Hz, 2 H), 6.61 (s, 2 H), 4.52 (q, J = 6.9 Hz,
2 H), 3.82 (s, 3 H), 1.30 (t, J = 6.9
Hz, 3 H). ¹³C NMR (75 MHz, DMSO-d
6): δ = 165.64,
159.88, 157.94 (q, J = 31 Hz),
148.05, 135.50, 127.73, 125.69, 117.94 (q, J = 299
Hz), 115.22, 105.10, 67.36, 55.66, 13.96. Anal. Calcd for C15H17N4O4:
C, 48.13; H, 4.58; N, 14.97. Found: C, 48.55; H, 4.44; N, 15.23.
IR (mull): 3471, 3108, 2700, 1673, 1634, 1513 cm-¹.
14
Typical Procedure
for the Synthesis of 4a
Method
A
A suspension of 1a˙TFA (2.4 mmol) in cold H2O
(4-5 mL) was stirred at 4 ˚C. After 13 d the solid
was filtered and washed with cold H2O to give 4a (60%).
5-Amino-1-(2-hydroxyethyl)-1
H
-imidazole-4-carbonyl Cyanide
4a
Mp >196 ˚C (dec.). ¹H
NMR (300 MHz, DMSO-d
6): δ = 7.71
(br s, 2 H), 7.42 (s, 1 H), 5.15 (br s, 1 H), 4.02 (t, J = 4.8 Hz,
2 H), 3.73 (t, J = 4.8
Hz, 2 H). ¹³C NMR (75 MHz, DMSO-d
6): δ = 155.49,
151.48, 137.58, 121.29, 115.68, 59.37, 46.09. Anal. Calcd for C7H8N4O2:
C, 46.67; H, 4.48; N, 31.10. Found: C, 46.70; H, 4.31; N, 30.82.
IR (mull): 3409, 3316, 3235, 3160, 3125, 2221, 1642, 1613, 1563,
1527 cm-¹.
15
Typical Procedure
for the Synthesis of Amidines 5
Method
B
TFA (1.0 equiv) was added to a suspension of 1b (1.36 mmol) in MeCN (4.0 mL). The mixture
was stirred at r.t. leading to a yellow precipitate. Addition of
benzylamine resulted in a white solid. The mixture was stirred at
r.t. for 1 d. The solid was filtered and washed with MeCN and Et2O to
give 5b˙TFA (84%). A
solution of aq Na2CO3 (1.4 mL, 2 equiv) was
added to a suspension of 5b˙TFA (0.34
mmol) in EtOH (0.5 mL) at r.t., under magnetic stirring. After 5
min, the solution was kept in an ice bath for 1 h. The precipitate was
filtered and washed with ice water (93%).
Method D
AcOH
(1 equiv) was added to a suspension of imidazole 1f (2.70
mmol) in MeCN (2 mL) followed by addition of benzylamine. The mixture
was stirred at ca. 40 ˚C for 20 min. After 10 min at 0 ˚C,
the solid was filtered and washed with cold MeCN and cold Et2O
to give 5f˙AcOH (76%).
Method E
A
catalytic amount of AcOH was added to a suspension of imidazole 1f (1.52 mmol) in MeCN (2 mL) followed
by addition of benzylamine (1.2 equiv). The mixture was stirred at
ca. 40 ˚C for 9 h followed by 10 min at 0 ˚C.
After addition of EtOH (1 mL) the solid was filtered and washed
with cold MeCN and ice-cold Et2O to give 5f˙AcOH (63%).
5-Amino-
N
-benzyl-1-(4-methoxyphenyl)-1
H
-imidazole-4-carboximidamide
2,2,2-Trifluoroacetate (5b˙TFA)
Mp
163-164 ˚C. ¹H NMR (300 MHz,
DMSO-d
6): δ = 9.00 (br
s, 1 H), 8.27 (br s, 1 H), 7.59 (s, 1 H), 7.42-7.36 (m,
6 H), 7.30 (m, 1 H), 7.13 (d, J = 8.7
Hz, 2 H), 6.31 (br s, 2 H), 4.67 (s, 2 H), 3.83 (s, 3 H). ¹³C
NMR (75 MHz, DMSO-d
6): δ = 159.78,
157.91 (q, J = 30.5
Hz), 155.94, 143.11, 136.95, 133.77, 128.53, 127.90, 127.40, 127.12,
125.92, 117.35 (q, J = 299.0
Hz), 115.12, 106.92, 55.60, 44.10. Anal. Calcd for C20H20F3N5O3:
C, 55.17; H, 4.63; N, 16.08. Found: C, 55.27; H, 4.75; N, 16.04.
IR (mull): 3394, 3311, 3203, 1676, 1645 (CO), 1616 cm-¹.
5-Amino-
N
-benzyl-1-(4-methoxyphenyl)-1
H
-imidazole-4-carboximidamide
(5b)
Mp 157-158 ˚C. ¹H
NMR (300 MHz, DMSO-d
6): δ = 7.40 (d, J = 9.0 Hz,
2 H), 7.37 (d, J = 6.9
Hz, 2 H), 7.30 (t, J = 7.8 Hz,
2 H), 7.26 (s, 1 H), 7.19 (t, J = 7.2
Hz, 1 H), 7.08 (d, J = 9.0
Hz, 2 H), 6.02 (br s, 2 H), 5.90 (br s, 2 H), 4.32 (s, 2 H), 3.80
(s, 3 H). ¹³C NMR (75 MHz, DMSO-d
6): δ = 158.76,
154.60 (br), 142.31 (br), 139.55, 128.64, 128.12, 127.85, 127.30,
126.07, 125.99, 114.85, 114.20, 55.51, 49.11 (br). Anal. Calcd for
C18H19N5O: C, 67.27;
H, 5.96; N, 21.79. Found: C, 67.35; H, 5.83; N, 21.57. IR (mull):
3495, 3390, 3321, 3262, 3117, 1623, 1588, 1517 cm-¹.
16
Typical Procedure
for the Synthesis of 6b
TFA (1 equiv) was added to
a suspension of 1b (1.4 mmol) at 30 ˚C.
Benzylamine was added, and the solution was stirred at r.t. for
18 h. The product was filtered and washed with EtOH, MeCN, and Et2O
(6b, 58%).
5-Amino-
N
-benzyl-1-(4-methoxyphenyl)-1
H
-imidazole-4-carbimidoyl
Cyanide (6b)
Mp 163-165 ˚C. ¹H
NMR (300 MHz, DMSO-d
6): δ = 7.39 (s,
1 H), 7.41 (dt, J = 9.6,
2.1 Hz, 2 H), 7.36-7.34 (m, 4 H), 7.26-7.25 (m,
1 H), 7.10 (dt, J = 9.3,
2.1 Hz, 2 H), 6.45 (br s, 2 H), 4.95 (s, 2 H), 3.81 (s, 3 H). ¹³C
NMR (75 MHz, DMSO-d
6): δ = 159.34,
143.43, 139.34, 138.11, 132.17, 128.59, 127.63, 127.08, 126.64,
126.49, 115.78, 115.04, 110.02, 59.84, 55.57. Anal. Calcd for C19H17N5O:
C, 68.87; H, 5.17; N, 21.13. Found: C, 68.87; H, 5.03; N, 21.14.
IR (mull): 3307, 3184, 3127, 3065, 3029, 1614, 1580, 1539, 1518
cm-¹.
17 CCDC 825265 and 825266 contain the
supplementary crystallographic data for this paper (compounds 5i˙AcOH and 5m,
respectively). These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif,
or by emailing data_request@ccdc.cam.ac.uk, or
by contacting The Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 (1223)336033.