Synthesis of dianhydrohexitole-based benzamidines as factor xa inhibitors using cross couplings, phenyl ether and amidine formations as key steps

Article abstract of DOI:10.1055/s-2003-41426

Starting with isosorbide or isomannide several dianhydrohexitole-based benzamidines were synthesized as potential factor Xa inhibitors. The key steps for the synthesis of the bisbenzamidines were nucleophilic aromatic substitutions and Mitsunobu reactions

Full text of DOI:10.1055/s-2003-41426

LETTER
1683
Synthesis of Dianhydrohexitole-based Benzamidines as Factor Xa Inhibitors
Using Cross Couplings, Phenyl Ether and Amidine Formations as Key Steps
Synthesis of
D
ianhydr
o
a
hexitole-b
r
k
zamidines o Vogler,a Ulrich Koert,*a Dieter Dorsch,b Johannes Gleitz,b Peter Raddatzb
a
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße, 35043 Marburg, Germany
b
Merck KgaA, Preclinical Research & Development, 64271 Darmstadt, Germany
Fax +49(6421)2825677; E-mail: koert@chemie.uni-marburg.de
Received 23 June 2003
Abstract: Starting with isosorbide or isomannide several dianhy-
drohexitole-based benzamidines were synthesized as potential fac-
tor Xa inhibitors. The key steps for the synthesis of the
bisbenzamidines were nucleophilic aromatic substitutions and
Mitsunobu reactions to build up phenylethers. Another type of
monobenzamidines had ortho-substituted biphenyl groups. Their
synthesis necessitated an optimization of cross coupling procedures
due to the great sterical hindrance of the ortho-substituent. The
benzamidines showed biological activity against factor Xa and
selectivity against other serine proteases.
O
O
HN
O
NH2
NH
O
3
4
NH2
HN
H2N
O
HN
O
NH2
O
O
Key words: isosorbide, dianhydrohexitoles, amidines, Negishi re-
action, factor Xa inhibitors
O
O
O
O
S
R
O
The serine protease factor Xa (fXa) plays a decisive role
in the blood coagulation cascade.1 Thus, it has emerged as
a very attractive target to develop orally active antithrom-
botic agents.2 Highly potent and specific inhibitors of fXa
can effectively block both venous and arterial thrombosis
formation.
NH
O
NH2
5 R=NH2
6 R=Me
Figure 2
We intended to use the dianhydrohexitoles isosorbide 1
(one exo-OH, one endo-OH, Figure 1) and isomannide 2
(two endo-OH) as molecular scaffolds linking two specif-
ic ligands for the S1 and S4 pockets of the fXa active site.
1 and 2 were already explored as successful templates for
RGD-mimetics3 in the development of integrin antago-
nists. They have the advantage of combining high rigidity
with stereochemical bias.
R1O
O
7 R1=TBS, R2=H 33%
8 R1=H, R2=TBS 16%
9 R1,R2=TBS 20%
a
O
1
OR2
HO
b
c
O
7
O
endo
HO
HO
O
CN
10
O
O
exo
O
O
O
d
OH
OH
11 R=CN
O
1
2
R
3 R=C(NH)NH2
O
Figure 1
O
R
Scheme 1 a) TBS-Cl, Im, DMF, 40 °C, 3 h, 7 33%, 8 16%, 9 20%.
b) NaH, 4-FC6H4CN, DMF; TBAF, THF, 23 %. c) NaH, 3-FC6H4CN,
DMF, 98%. d) LiHMDS, THF; HCl, EtOH/H2O; prep. HPLC, 23%.
Here we present a novel synthetic approach to the phe-
nylether benzamidines 3–6 with the isosorbide scaffold
(Figure 2) and evaluate their potential as fXa inhibitors.
The synthesis of 3 started with TBS-protection of isosor-
bide 1 (Scheme 1). Using the standard conditions (TBS-
Cl, imidazole, DMF) both monoprotected isomers 7
(33%) and 8 (16%) as well as diprotected 9 (20%) were
obtained besides 31% unreacted starting material. The
structures of 7 and 8 could be assigned by NMR analysis
Synlett 2003, No. 11, Print: 02 09 2003. Web: 25 08 2003.
Art Id.1437-2096,E;2003,0,11,1683,1687,ftx,en;G14703ST.pdf.
DOI: 10.1055/s-2003-41426
© Georg Thieme Verlag Stuttgart · New York

1684
M. Vogler et al.
LETTER
and IR spectroscopy. Due to the intramolecular hydrogen
bond of the endo-OH group with the ether oxygens, 8
shows a lower hydroxy IR absorption than 7 (diluted so-
lution in CCl4):4 3625 cm–1 for the exo-OH in 7, but 3553
cm–1 for endo-OH in 8. A comparing look at the NMR
spectra of 1, 2, 7 and 8 in DMSO-d6 reveals that the pro-
tons of exo hydroxy functions in dianhydrohexitoles are
shifted down-field compared to the endo ones. Together
with a precise analysis of the coupling constants5 this
NMR assignment is consistent with the IR data.
R1O
12 R1=TBS, R2=H 43%
13 R1,R2=TBS 33%
a
O
2
O
OR2
HO
b
O
c
12
CN
O
O
14
The exo-alcohol 7 was then converted to the phenylether
10 by nucleophilic substitution with 4-fluorobenzonitrile
and subsequent TBAF-mediated deprotection. Unexpect-
edly, only 23% 10 were obtained, but 55% of 2,5-O,O-
bis-(4-cyanophenyl)-isosorbide. Due to the lability of the
endo-OTBS group in 7 under the reaction conditions of
the aromatic substitution (NaH, DMF, 60 °C), silyl cleav-
age occurred already at this stage resulting in the forma-
tion of 10. A nucleophilic aromatic substitution of alcohol
10 with 3-fluorobenzonitrile gave the bisnitrile (98%). Fi-
nally, the reaction of 11 in an one-pot procedure with
LiHMDS6,7 and a subsequent hydrolysis using ethanolic
HCl led to the target bisamidine 3. After purification by
preparative HPLC (CH3CN/H2O + 0.1% TFA) and lyo-
philization 3 could be isolated as bisamidinium-trifluoro-
acetic salt.7
R
O
d
15 R=CN
O
R
4 R=C(NH)NH2
O
O
Scheme 2 a) TBS-Cl, Im, DMF, 12 43%, 13 33%. b) 3-HOC6H4CN,
DEAD, PPh3, THF; TBAF, THF, 79%. c) NaH, 4-FC6H4CN, DMF,
15 93%. d) LiHMDS, THF; HCl, EtOH/H2O, 48%.
compound 21. A Suzuki protocol using standard condi-
tions [Pd(PPh3)4, PhMe, aq. Na2CO3, reflux] with 2-(tert-
butylaminosulfonyl)-phenylboronic acid (19) to build up
the biphenyl moiety is described in the literature,9a but due
to the great steric hindrance of the ortho-SO2NHtBu-sub-
stituent the yield was only 58%. We tried several Suzuki
procedures14 to optimize this coupling step. But none of
these methods gave satisfying yields (maximum 44%). As
a consequence we examined Negishi conditions15
[Pd2(dba)3, PPh3, LiCl, THF reflux] using the correspond-
ing aryl zinc intermediate 20 (from PhSO2NHt-Bu by
ortho-lithiation and transmetallation). This worked well
and produced the coupling product 21 in 83% yield. Hy-
drogenolysis of the benzylether provided the alcohol 22.
The synthesis of bisamidine 4 was accomplished as de-
picted in Scheme 2. First, one hydroxy function of iso-
mannide 2 was TBS-protected to the monosilylether 12
(43% yield).8 Since the endo-hydroxy group in isoman-
nide 2 is intramolecularly hydrogen bound to the ether
oxygens, the alcohol-alcoholate reactivity difference is
low in this case. The free endo-OH in 12 was then inverted
to the exo-phenylether by a Mitsunobu reaction with 3-hy-
droxybenzonitrile. After TBAF-mediated silyl ether
cleavage isosorbide-based 14 was isolated in 79% yield.
A detailed analysis of the NMR coupling constants5 of 14
proved the inversion of the stereocenter. After nucleo-
philic aromatic substitution of 14 with 4-fluorobenzoni-
trile to the bisnitrile 15 (93%), a subsequent bisamidine
formation led to the target compound 4.
The synthesis of 5 continued with a Mitsunobu inversion
using 3-hydroxybenzonitrile to yield the phenylether 23
(Scheme 3). For the conversion of the cyano function into
an amidine group, a two-step procedure via amide oximes
was most successful.16 First, the benzonitrile was trans-
formed via the amide oxime followed by acetylation and
a heterogenous hydrogenation with palladium on charcoal
or Raney-nickel17 into the desired benzamidine. Finally,
the tert-butyl protecting group was cleaved from the sul-
fone amide by treatment with a 10:1 mixture of TFA/ani-
sole to produce 5.16b
Since the in vitro data of the bisamidines 3 and 4 showed
high potency against fXa, we intended to optimize the
new dianhydrohexitole lead structure with regard to better
pharmacokinetic properties. Thus, one benzamidine moi-
ety was replaced by a less basic, more lipophilic ortho-
SO2NH2-substituted biphenyl group (5 and 6, Figure 2).9
The synthesis of 5 started with the monobenzylation of 2
to mono-benzyl-isomannide 16, which was allowed to re-
act with 4-fluoronitrobenzene to 17 in 95% yield. After re-
duction of the nitro group to an amine, the transformation
into an aryl bromide or iodide was envisaged. Sandmeyer
conditions with catalytic10,11 or stochiometric12 amounts
of copper salts were unsatisfying (maximum 39% for the
bromide and 64% for the iodide). Alternatively, we tried
a new procedure13 with KI, KNO2 and HBr in DMSO.
This gave reliably high yields of the iodide 18 of 80%. In
the next step, 18 had to be cross-coupled to the biphenyl
The synthesis of the sulfone 6 is summarized in Scheme 4.
Suzuki coupling of commercially available 2-(methyl-
thio)benzeneboronic acid with iodide 18 gave thioether 24
with 70% yield.14e Magnesium monoperoxo phthalate
oxidation18 to the sulfone and hydrogenolytic benzyl ether
cleavage gave the alcohol 25 (86% for both steps). The
Mitsunobu reaction using the oxadiazolylphenol 2619 led
to an isosorbide-based precursor 27, which could be con-
verted to the amidine 6 by hydrogenolysis (96%).
The biological screening of the dianhydrosugar-based
amidines 3–6 began with the potency determination
against factor Xa. Subsequently, the activity against
Synlett 2003, No. 11, 1683–1687 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Synthesis of Dianhydrohexitole-based Benzamidines
1685
20
Li
SO2NtBu
HO
R1
O
O
a
b
ZnCl
O
O
O
O
O
2
S
NH
d
O
O
O
OR2
OBn
OBn
17 R1=NO2
18 R1=I
21 R2=Bn
22 R2=H
16
c
e
O
O
f
g
O
O
O
O
O
O
O
S
NH
S
H2N
O
O
NH
O
CN
23
5
NH2
Scheme 3 a) NaH, DMF, TBAI (cat.), BnBr, 48%. b) NaH, DMF, 4-FC6H4NO2, 95%. c) H2, MeOH/THF, Pd/C 100%; KI, KNO2, DMSO,
HBr, 81%. d) PhSO2NHtBu, n-BuLi, THF; ZnCl2; LiCl, Pd2(dba)3, PPh3, 83%. e) H2, Pd(OH)2/C, THF/MeOH, 100%. f) DIAD, PPh3,
4-HOC6H4CN, THF, 46%. g) NH2OH·HCl, Na2CO3, THF/EtOH/H2O; MeOH/HOAc, Ac2O; H2, Pd/C; TFA, PhOMe, 53%.
O
O
a
b
c
O
O
O
O
S
S
18
N
N
O
O
O
HO
OBn
OH
24
25
26
O
O
d
O
O
O
O
O
O
S
S
O
O
NH
N
N
O
O
O
27
6
NH2
Scheme 4 a) 2-CH3SC6H4B(OH)2, Pd2(dba)3, PPh3, Ba(OH)2, DME/H2O, 70%. b) MMPP, CH2Cl2/EtOH/H2O; H2, Pd(OH)2/C, MeOH/
EtOAc, 86%. c) DIAD, PPh3, THF, 92%. d) H2, Pd/C, MeOH/HOAc, 96%.
thrombin, trypsin and plasmin were measured in order to tions of the biphenyl unit with the protein, the inhibitors 5
get informations about the general specifity for serine pro- and 6 show not only high potency, but a better selectivity
teases. The in vitro data were measured as IC50 values against trypsin. The reason might be, that the structural
(Table 1).
differences between the fXa and trypsin active sites play
a greater role in the specific interactions with the biphenyl
unit compared to a benzamidine.
Table 1 Biological Activity of the Dianhydrosugar-based
Benzamidines 3–6 Against fXa, Thrombin, Trypsin and Plasmin
In summary, a novel highly active and selective lead
structure for fXa inhibitors was developed with rigid but
stereodefined dianhydrohexitole scaffolds. A synthetic
access to the class of isosorbide-based bisbenzamidines
was developed with nucleophilic aromatic substitutions of
fluorobenzonitriles, Mitsunobu reactions and amidine for-
mation with LiHMDS as key steps. The biphenyl com-
pounds 5 and 6 were synthesized from isomannide 2. An
optimized synthetic route to the aryl halide uses Suzuki
and Negishi couplings to build up the biphenyl moiety.
Despite a sterically demanding ortho-substituent an effi-
cient novel Negishi protocol gave the target compound in
very good yield. Current work is aimed to further optimize
this lead structure in terms of higher biological activity
and bioavailability.
IC50/mM
Compd.
fXa
0.18
0.15
1.0
Thrombin
>10
Trypsin
6.3
Plasmin
>10
3
4
5
6
>10
8.0
>10
>10
>10
>10
1.3
>10
>10
>10
The biological activities of the isosorbide-based bisa-
midines 3 and 4 with a substitution pattern ‘inverse’ to
each other (meta-/para-benzamidine) are active against
fXa and selective against thrombin and plasmin. But the
trypsin-selectivity is low. Due to the favorable interac-
Synlett 2003, No. 11, 1683–1687 ISSN 1234-567-89 © Thieme Stuttgart · New York

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.
(9) (a) Quan, M. L.; Liauw, A. Y.; Ellis, C. D.; Pruitt, J. R.;
Carini, D. J.; Bostrom, L. L.; Huang, P. P.; Harrison, K.;
Knabb, R. M.; Thoolen, M. J.; Wong, P. C.; Wexler, R. R. J.
Med. Chem. 1999, 42, 2752. (b) Quan, M. L.; Ellis, C. D.;
Liauw, A. Y.; Alexander, R. S.; Knabb, R. M.; Lam, G.;
Wright, M. R.; Wong, P. C.; Wexler, R. R. J. Med. Chem.
1999, 42, 2760. (c) Fevig, J. M.; Pinto, D. J.; Han, Q.; Quan,
M. L.; Pruitt, J. R.; Jacobson, I. C.; Galemmo, R. A.; Wang,
S. A.; Orwat, M. J.; Bostrom, L. L.; Wong, P. C.; Lam, P. Y.
S.; Wexler, R. R. Bioorg. Med. Chem. Lett. 2001, 11, 641.
(d) Jia, Z. J.; Wu, Y.; Huang, W.; Goldman, E.; Zhang, P.;
Woolfrey, J.; Wong, P.; Huang, B.; Sinha, U.; Park, G.;
Reed, A.; Scarborough, R. M.; Zhu, B.-Y. Bioorg. Med.
Chem. Lett. 2002, 12, 1651. (e) Su, T.; Wu, Y.; Doughan,
B.; Jia, Z. J.; Woolfrey, J.; Huang, B.; Park, G.; Sinha, U.;
Scarborough, R. M.; Zhu, B.-Y. Bioorg. Med. Chem. Lett.
2001, 11, 2947. (f) Pruitt, J. R.; Pinto, D. J.; Estrella, M. J.;
Bostrom, L. L.; Knabb, R. M.; Wong, P. C.; Wright, M. R.;
Wexler, R. R. Bioorg. Med. Chem. Lett. 2000, 10, 685.
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(1) Davie, E. W.; Fujikawa, K.; Kisiel, W. Biochemistry 1991,
30, 10363.
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Curr. Med. Chem. 2001, 8, 101. (b) Samama, M. M.
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Life Sci. 2002, 59, 189. (d) Leadley, R. J. Jr. Curr. Top.
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(3) Osterkamp, F.; Wehlan, H.; Koert, U.; Wiesner, M.;
Raddatz, P.; Goodman, S. L. Tetrahedron 1999, 55, 10713.
(4) Brimacombe, J. S.; Foster, A. B.; Stacey, M.; Whiffen, D. H.
Tetrahedron 1958, 4, 351.
(5) Hopton, F. J.; Thomas, G. H. S. Can. J. Chem. 1969, 47,
2395.
(6) Boeré, R. T.; Oakley, R. T.; Reed, R. W. J. Orgmet. Chem.
1987, 331, 161.
(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

LETTER
Hz, 6.0 Hz, 1 H, 6-H), 4.60 (d, J = 11.9 Hz, 1 H, CHHPh),
Synthesis of Dianhydrohexitole-based Benzamidines
1687
atmosphere in dry TFA/anisole (10:1) for 24 h. Purification
by flash chromatography (CH2Cl2/MeOH/TFA, 100:2:1 →
100:5:1), concentration of all product fractions and
4.62 (t, J = 4.7 Hz, 1 H, 3-H), 4.78 (d, J = 11.9 Hz, 1 H,
CHHPh), 4.79–4.85 (m, 2 H, 4-H, 5-H), 7.04 (pd, J = 8.7 Hz,
2H, 2¢-H, 6¢-H), 7.29 (dd, J = 7.7 Hz, 1.0 Hz, 1 H, 6¢¢¢-H),
7.29–7.40 (m, 5 H, Ph-H), 7.43–7.47 (m, 3 H, 3¢-H, 5¢-H,
4¢¢¢-H), 7.53 (td, J = 7.6 Hz, 1.2 Hz, 1H, 5¢¢¢-H), 8.15 (dd, J
= 7.9 Hz, 1.0 Hz, 1H, 3¢¢¢-H); 13C NMR (75 MHz, CDCl3) d
= 29.7 [C(CH3)3], 54.3 [C(CH3)3], 71.0, 71.6, 72.6 (C-1, C-
6, CH2Ph), 77.9, 78.9, 80.6, 80.8 (C-2, C-3, C-4, C-5), 114.9
(C-2¢, C-6¢), 127.6, 128.1 (C-3¢¢, C-6¢¢), 127.9, 128.4 (Ph-C),
131.1 (C-3¢, C-5¢), 131.7, 132.4 (C-4¢¢, C-5¢¢), 132.2 (C-4¢),
137.6 (Ph-Cq), 139.4 (C-1¢¢), 142.2 (C-2¢¢), 158.1 (C-1¢);
IR(film): 3371, 2973, 2876, 1607, 1514, 1467, 1324, 1245,
1152, 1128, 1076, 988, 834, 765 cm–1; Anal. calcd. for
C29H33NO6S (523.65) C 66.52, H 6.35, N 2.68, found
C 66.41, H 6.01, N 2.48.
subsequent precipitation with MTBE/hexane gave 5 as TFA
salt. (c) Analytical data of 2-O-(4¢-amidinophenyl)-5-O-[4¢¢-
(2¢¢¢-aminosulfonylphenyl)-phenyl]-1,4:3,6-dianhydro-D-
20
sorbitol trifluoroacetic acid salt (5): colorless solid; [a]D
+51, [a]57820 = +54, [a]54620 = +61, [a]43620 = +108, [a]365
=
=
20
+174 (c 0.407, CH2Cl2/MeOH, 1:1); 1H NMR (500 MHz,
DMSO-d6) d = 3.56 (d, J = 10.4 Hz, 1 H, 1-H), 3.89 (dd, J =
9.4 Hz, 5.4 Hz, 1 H, 6-H), 4.07 (dd, J = 9.4 Hz, 5.7 Hz, 1 H,
6-H), 4.11 (dd, J = 10.4 Hz, 3.8 Hz, 1 H, 1-H), 4.62 (d, J =
5.1 Hz, 1 H, 3-H), 4.97 (q, J = 5.5 Hz, 1 H, 5-H), 5.04 (t, J =
5.0 Hz, 1 H, 4-H), 5.11 (d, J = 3.3 Hz, 1 H, 2-H), 7.02 (pd, J
= 8.7 Hz, 2 H, 2¢¢-H, 6¢¢-H), 7.13 (s, 2 H, SO2NH2), 7.20 (pd,
J = 8.9 Hz, 2 H, 2¢-H, 6¢-H), 7.29 (d, J = 7.5 Hz, 1 H, 6¢¢¢-H),
7.32 (pd, J = 8.7 Hz, 2 H, 3¢¢-H, 5¢¢-H), 7.53 (t, J = 7.5 Hz, 1
H), 7.59 (t, J = 7.4 Hz, 1 H, 4¢¢¢-H, 5¢¢¢-H), 7.83 (pd, J = 8.8
Hz, 2 H, 3¢-H, 5¢-H), 8.01 (d, J = 7.8 Hz, 1 H, 3¢¢¢-H), 9.01/
9.15 [s/s, 4 H, C(NH2)2]; 13C NMR (75 MHz, DMSO-d6) d =
70.9, 71.7 (C-1, C-6), 77.1, 80.7, 81.8, 86.0 (C-2, C-3, C-4,
C-5), 114.3 (C-2¢¢, C-6¢¢), 115.7 (C-2¢, C-6¢), 120.6 (C-4¢),
127.4 (C-3¢¢¢, C-6¢¢¢), 130.5, 130.6 (C-3¢, C-5¢, C-3¢¢, C-5¢¢),
131.6, 132.7 (C-4¢¢, C-4¢¢¢, C-5¢¢¢), 139.8 (C-1¢¢¢), 142.4 (C-
2¢¢¢), 157.3 (C-1¢¢), 161.2 (C-1¢), 164.9 [C(NH2)2]; HRMS
(ESI) m/z calcd. 496.1542, found 496.1544 (C25H26N3O6S,
M + H+).
(16) (a) Judkins, B. D.; Allen, D. G.; Cook, T. A.; Evans, B.;
Sardharwala, T. E. Synth. Commun. 1996, 26, 4351.
(b) Preparation of benzamidine 5 via amide oxime:
Benzonitrile 23 (1 mmol) was dissolved in 10 mL THF/
EtOH (1:1). After addition of NH2OH·HCl (3 mmol),
Na2CO3 (2 mmol) and 10 mL water the mixture was heated
to 80 °C and stirred for 20 h (TLC monitoring). After cooling
20 mL water was added and the aqueous layer was extracted
three times each with 20 mL CH2Cl2. The combined organic
fractions were dried over MgSO4 and the solvents were
removed in vacuo. The crude amide oxime was then
dissolved in 30 mL MeOH/HOAc (1:1) and Ac2O (2 mmol)
was added. After 30 min Pd/C was added and the reaction
mixture was vigorously stirred under hydrogen atmosphere
(HPLC monitoring, Rainin RP18, H2O/CH3CN mixtures +
0.1% TFA). Finally, the solution was filtrated over a pad of
celite and the solvents were completely removed in vacuo.
The crude bezamidine was then stirred under an argon
(17) Pd/C is preferred, since the use of Raney-nickel in MeOH/
AcOH leads to the formation of minor amounts of Ni(OAc)2,
which is difficult to remove by chromatography.
(18) Brougham, P.; Cooper, M. S.; Cummerson, D. A.; Heaney,
H.; Thompson, N. Synthesis 1987, 1015.
(19) Krone, W. Chem. Ber. 1891, 24, 834.
Synlett 2003, No. 11, 1683–1687 ISSN 1234-567-89 © Thieme Stuttgart · New York