1686
M. Vogler et al.
LETTER
(8) McDougal, P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. J.
Org. Chem. 1986, 51, 3388.
Acknowledgment
This work was supported by Merck KgaA, Darmstadt, Germany.
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(7) (a) General procedure for the preparation of bisamidines 3
and 4 from bisnitriles by the LiHMDS6 method: A oven-
dried Schlenck-flask equipped with a rubber septum is
charged with HMDS (2.6 mmol) in THF (3 mL) under argon
atmosphere and cooled by an ice bath. After addition of n-
BuLi (3.0 mmol, 2.5 M in hexane) and stirring for 1 h a
solution of the bisnitrile (0.52 mmol) in THF (3 mL) was
added. The reaction mixture turned dark red or brown. It was
stirred for 24 h at room temperature and then quenched with
6 M HCl in ethanol (2 mL). After 1 h the solvents were
removed in vacuo. The residue was solved in few MeOH and
purified by preparative HPLC (Rainin RP18, H2O/CH3CN
mixtures with 0.1% TFA). The bisamidine was isolated as a
TFA salt by lyophilization resulting in a colorless powder.
(b) Analytical data of 3 and 4: 2-O-(4¢-Amidinophenyl)-5-
O-(3¢¢-amidinophenyl)-1,4:3,6-dianhydro-D-sorbitol
trifluoroacetic acid salt (3):
(11) Dains, F. B.; Eberly, F. Org. Synth., Coll. Vol. II; Wiley:
New York, 1943, 355.
(12) Doyle, M. P.; Siegfried, B.; Dellaria, J. F. J. Org. Chem.
1977, 42, 2426.
(13) Baik, W.; Kim, J. M.; Kim, Y. S.; Lee, S. W. European
Symposium on Organic Chemistry 12; Poster presentation:
Groningen Netherlands, 2001.
(14) Coupling of boronic acid 19 using several Suzuki methods:
(a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457;
standard conditions: PdCl2(PPh3)2, Bu4NBr (cat.), aq.
Na2CO3, PhMe reflux, 44%. (b) Wallow, T. I.; Novak, B. M.
J. Org. Chem. 1994, 59, 5034; Pd(OAc)2, aq. Na2CO3, THF
reflux, 0%. (c) Wolfe, J. P.; Singer, R. A.; Yang, B. H.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550;
Pd(OAc)2, 2-(di-tert-butylphosphino)-biphenyl, KF, THF
reflux, 0%. (d) Alo, B. I.; Kandil, A.; Patil, P. A.; Sharp, M.
J.; Siddiqui, M. A.; Snieckus, V. J. Org. Chem. 1991, 56,
3763; Pd2(dba)3, PPh3, aq. Na2CO3, DME reflux, 35%.
(e) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207;
Pd2(dba)3, PPh3, Ba(OH)2, DME/H2O reflux, 39%.
(15) (a) Savage, S. A.; Smith, A. P.; Fraser, C. L. J. Org. Chem.
1998, 63, 10048. (b) Negishi coupling of aryl iodide 18: An
oven-dried Schlenk-flask equipped with a rubber septum
was charged with 1.29 g (6.0 mmol) PhSO2NHt-Bu in 15 mL
THF under an argon atmosphere and cooled in an ice bath.
After addition of 8.2 mL n-BuLi (1.6 M in hexanes) the
solution was stirred for 2 h. A thick, pale yellow precipitate
formed. 1.82 g (13.4 mmol) ZnCl2 beads were added (the
precipitate dissolves) and 1 h later a solution of 2.19 g (5.0
mmol) 18, 185 mg (0.2 mmol) Pd2(dba)3 and 262 mg (1.0
mmol) PPh3 in 10 mL THF was transferred into the reaction
mixture. After addition of 424 mg (10.0 mmol) dried LiCl
the reaction mixture was refluxed for 70 h. 100 mL sat. aq.
NH4Cl and 100 mL MTBE were added and the aqueous
layer was extracted three times with MTBE. The combined
organic fractions were washed with brine and dried over
MgSO4. Purification by flash chromatography (pentane/
MTBE 2:1→1:1) yielded 2.18 g (4.2 mmol, 83%) pure 21.
(c) Analytical data of 2-O-benzyl-5-O-[4¢-(2¢¢-tert-
[a]D20 = +49, [a]57820 = +51, [a]54620 = +58, [a]43620 = +100,
[a]36520 = +160 (c 0.099, H2O); 1H NMR (300 MHz, DMSO-
d6) d = 3.87–4.05 (m, 4 H, 1-H2, 6-H2), 4.61 (d, J = 4.1 Hz,
1 H, 3-H), 5.02–5.13 (m, 3 H, 2-H, 4-H, 5-H), 7.19–7.44 (m,
5 H, 2¢-H, 6¢-H, 2¢¢-H, 4¢¢-H, 6¢¢-H), 7.55 (t, J = 7.9 Hz, 1 H,
5¢¢-H), 7.79 (pd, J = 9.0 Hz, 2 H, 3¢-H, 5¢-H), 8.88–9.29 [m,
8 H, 2 × C(NH2)2]. 13C NMR (75 MHz, DMSO-d6) d = 71.2,
72.7 (C-1, C-6), 77.4, 81.1, 81.5, 86.0 (C-2, C-3, C-4, C-5),
115.1 (C-2¢¢), 115.4 (C-2¢, C-6¢), 120.1 (C-4¢), 120.8, 121.1
(C-4¢¢, C-6¢¢), 129.9 (C-3¢¢), 130.3 (C-3¢, C-5¢), 130.8 (C-5¢¢),
156.9 (C-1¢¢), 162.5 (C-1¢), 164.9, 165.4 [2 × C(NH2)2];
HRMS (FAB): m/z calcd 383.1719, found 383.1717
(C20H23N4O4, M + H+). 2-O-(3¢-Amidinophenyl)-5-O-(4¢¢-
amidinophenyl)-1,4:3,6-dianhydro-D-sorbitol
trifluoroacetic acid salt (4):
[a]D21 = +46, [a]57821 = +49, [a]54621 = +55, [a]43621 = +94,
[a]36521 = +157 (c 0.267, H2O); 1H NMR (300 MHz, DMSO-
d6) d = 3.86–4.10 (m, 4 H, 1-H2, 6-H2), 4.60 (d, J = 4.7 Hz,
1 H, 3-H), 5.00–5.15 (m, 3 H, 2-H, 4-H, 5-H), 7.18 (pd, J =
9.0 Hz, 2H, 2¢¢-H, 6¢¢-H), 7.34–7.45 (m, 3 H, 2¢-H, 4¢-H, 6¢-
H), 7.53 (t, J = 7.9 Hz, 1 H, 5¢-H), 7.83 (pd, J = 8.9 Hz, 2 H,
3¢¢-H, 5¢¢-H), 9.00–9.35 [m, 8 H, 2 × C(NH2)2]; 13C NMR (75
MHz, DMSO-d6) d = 70.9, 72.8 (C-1, C-6), 77.3, 80.8, 81.6,
86.0 (C-2, C-3, C-4, C-5), 114.6 (C-2¢), 115.7 (C-2¢¢, C-6¢¢),
120.5, 120.7 (C-4¢, C-6¢), 120.6 (C-4¢¢), 129.6 (C-3¢), 130.6
(C-3¢¢, C-5¢¢), 158.0 (C-1¢), 161.1 (C-1¢¢), 164.9, 165.5 [2 ×
C(NH2)2]; HRMS (FAB): m/z calcd. 383.1719, found
383.1715 (C20H23N4O4, M + H+).
butylamino-sulfonylphenyl)-phenyl]-1,4:3,6-dianhydro-D-
mannitol (21): colorless solid; Mp 62 °C; [a]D20 = +128,
[a]57820 = +133, [a]54620 = +152 (c 1.008, CHCl3); 1H NMR
(500 MHz, CDCl3) d = 0.98 [s, 9 H, C(CH3)3], 3.58 (s, 1 H,
NH), 3.78 (t, J = 8.7 Hz, 1H, 1-H), 3.94 (dd, J = 8.6 Hz, 7.0
Hz, 1H, 1-H), 4.06–4.12 (m, 2 H, 2-H, 6-H), 4.20 (dd, J = 9.4
Synlett 2003, No. 11, 1683–1687 ISSN 1234-567-89 © Thieme Stuttgart · New York