Development of a novel ionic support and its application in the ionic liquid phase assisted synthesis of a potent antithrombotic

Article abstract of DOI:10.1016/j.tetlet.2004.01.032

The synthesis of ionic support 1 and its application in the preparation of a set of amides and sulfonamides is described. The potential of 1 is further exemplified by its use in a one-pot multistep ionic liquid phase assisted synthesis of tirofiban analogue 2.

Full text of DOI:10.1016/j.tetlet.2004.01.032

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2171–2175
Development of a novel ionic support and its application in the ionic
liquid phase assisted synthesis of a potent antithromboticq
Martin de Kort,a,* Adriaan W. Tuin,b Suzanne Kuiper,a Hermen S. Overkleeft,b
Gijs A. van der Marelb and Rogier C. Buijsmana
aLead Discovery Unit, NV Organon, Molenstraat 110, PO Box 20, 5340 BHOss, The Netherlands
bLeiden Institute of Chemistry, Gorlaeus Laboratories, PO Box 9500, 2300 RA Leiden, The Netherlands
Received 28 November 2003; revised 22 December 2003; accepted 9 January 2004
Abstract—The synthesis of ionic support 1 and its application in the preparation of a set of amides and sulfonamides is described.
The potential of 1 is further exemplified by its use in a one-pot multistep ionic liquid phase assisted synthesis of tirofiban analogue 2.
ꢀ 2004 Elsevier Ltd. All rights reserved.
An important research objective within the pharma-
ceutical and the fine-chemical industries is the develop-
ment of strategies that enable the rapid generation of
new chemical entities. Ideally such synthesis strategies
should be highly flexible, allow (semi-)high throughput
chemistry, could be upscaled and should be environ-
mentally clean. In this respect, solid phase synthesis has
proven its merit in the combinatorial chemistry era.1 A
drawback of solid phase chemistry, however, is the fact
that many organic reactions routinely performed in
solution are often difficult to transfer to the solid sup-
port. Furthermore, the number of applications of solid
phase chemistry on an industrial scale so far is limited.
With the objective of ensuring the rapid generation of
compound libraries, homogeneous phase chemistry
strategies in combination with novel separation
methods2 are currently being pursued. Interesting tech-
niques emerging in this area include the application of
fluorous solvents and tags,3 polyethylene glycol sup-
ports,4 supercritical fluids,5 soluble polystyrene sup-
ports,6 microencapsulated catalysts7 and solid
supported (scavenger) reagents.8
Recently, ionic liquids have been recognised as novel,
environmentally benign solvents in synthetic chemistry.9
Ionic liquids have no detectable vapour pressure, are
thermally stable and have the ability to form a separate
phase10 in the presence of both aqueous and organic
solvents. Moreover, ionic liquids can be readily recy-
cled9 and are highly suitable for the recycling of a
variety of reagents, including organometallic cata-
lysts.9b;11 Finally, they have found recent applications as
additives in microwave accelerated synthesis.12;14b
The scope13 of ionic liquids has recently been expanded
by the introduction of additional functional groups in
the ionic liquid structure. These so-called task-specific
ionic liquids14 can be utilised as (supported) reagents or
catalysts with high affinity for the ionic liquid phase.
Task-specific ionic liquids are compatible with a variety
of organic transformations14a–g and have proven to be
useful for the extraction14h–j of specific chemicals.
In this paper, we report our results obtained with ionic
support 1, which is equipped with an aldehyde for
attaching amines by reductive amination. After transient
anchoring of reactants to 1, organic transformations can
be performed in a single batch of ionic liquid (e.g.,
[bmim][PF6], Fig. 1), while excess of reagent can be
removed by extraction with an organic or aqueous
phase. Finally, the products are obtained by acidic
removal of the ionic support and extraction into an
organic phase. We demonstrate the validity of our
strategy in the synthesis of a range of (sulfon)amides.
Furthermore, the application of 1 in the multistep ionic
Keywords: Ionic liquid; Supported chemistry; Sulfonamide; Multistep
synthesis; Tirofiban.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.01.032
* Corresponding author. Tel.: +31-412-663691; fax: +31-412-663508;
e-mail: m.dekort@organon.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.032

2172
M. de Kort et al. / Tetrahedron Letters 45 (2004) 2171–2175
Cl
N+
H
X
N
+/-
+
+/-
a
O
N
N
OMe
N
H
6a-d
R
1
O
1
H
[bmim][BF4] X = BF4
[bmim][PF6] X = PF6
1
O
b
O
H
N
R
H
N
OH
+/-
SO2
c,d
R
R2
1
N
R
1
NH
2 R= phenyl
3 R= n-butyl
R
2
O
9a-d R2 = Ts
10a-d R2 = Tol
7a-d R2 = Ts
8a-d R2 = Tol
Figure 1.
Scheme 2. Ionic phase synthesis of (sulfon)amides. All reactions were
performed in [bmim][PF6]. (a) R1NH2, NaHB(OAc)3, 16 h; (b) TsCl or
TolCl, Et3N, 2 h. (c) 2% HPF6, 10 min; (d) satd NaHCO3, then
extraction with Et2O.
phase assisted synthesis of 2, a potent analogue of the
antiplatelet drug tirofiban 3, is presented.
The synthesis of N-methylimidazolium based ionic
support 1, the ionic analogue of the known AMEBA
solid support,15 was readily accomplished by alkyl-
ation16 of the phenol 4 with 1,4-dichlorobutane and
subsequent substitution of chloride 5 with N-methyl-
imidazole under microwave irradiation. Imidazolium
chloride 1 (obtained in 75% yield over the two steps;
90% pure based on HPLC) could be readily dissolved in
[bmim][PF6] and showed neither leakage to the aqueous
nor to the organic phase, thus avoiding any need to
convert 1 into the corresponding PFÀ6 salt. The solution
of 1 in [bmim][PF6] can be stored at room temperature
for 6 months without any sign of decomposition
(Scheme 1).
In the final step, the (sulfon)amides were liberated from
the ionic support using acidic conditions. Upon treat-
ment with trifluoroacetic acid (TFA) all target com-
pounds were completely removed. Unfortunately, the
high concentration of TFA required (upto 50%) led to
the in situ formation of [bmim][TFA], which was present
as a contaminant in all products.19 To our satisfaction,
however, short (10 min) exposure of the ionic supported
(sulfon)amides to 2% HPF6 followed by extraction
(diethyl ether) from the ionic phase and concentration of
the organic phase provided target compounds 9a–d and
10a–d in promising yields with reasonable to excellent
purities (see Table 1).20 Although extraction of the
products from the ionic phase is still unoptimised, the
yields and purities are comparable to those reported for
the conventional AMEBA solid support.
In order to determine the scope of ionic support 1 in
ionic phase assisted synthesis, we set out to prepare
(Scheme 2) a set of diverse sulfonamides and amides (see
Table 1). Treatment of a solution of compound 1 in
[bmim][PF6] with four commercially available amines in
the presence of NaHB(OAc)3 gave, after reductive
amination,17 the ionic supported amines 6a–d.The
reaction mixtures were divided and the amines either
sulfonylated with tosyl chloride (TsCl) or acylated with
4-methylphenylcarbonyl chloride (TolCl) to give ionic
tagged sulfonamides 7a–d and amides 8a–d, respectively.
After each step, excess of reagents were removed by
consecutive extractions with diethyl ether and water.18
An important advantage of the sequence of reactions
outlined here is the possibility of monitoring all reac-
tions by HPLC/MS,21 as is demonstrated for the con-
version of 1 into 9b (see Fig. 2). Of further interest is our
observation that in all examples presented here no
leakage of the ionic supported substrates into the
aqueous or organic phase occurred.
Having established the effectiveness of ionic support 1 in
the synthesis of (sulfon)amides, we set out to explore its
potential in the multistep synthesis of sulfonylated
tyrosine derivative 2, a highly potent analogue of the
antithrombotic drug tirofiban (3, Fig. 1).
O
A solution of ionic support 1 (0.125 M) in [bmim][PF6]
was charged by reductive amination with O-allyl-L-
OMe
H
H
tyrosine(O-allyl) 1122 to give intermediate 12. Sulfonyl-
ation of the secondary amine function in 12 with
phenylsulfonyl chloride was complete after 1 h as judged
by HPLC/MS analysis. After extractive work-up (water
followed by diethyl ether), the resulting intermediate 13
was deprotected by a Pd-catalysed deallylation,23 which
a
HO
Cl
OMe
O
O
4
1
5
b
H
O
=
+/-
Scheme 1. (a) 1,4-Dichlorobutane, Bu4NHSO4, 3 M NaOH, reflux,
16 h, 75%; (b) 2.0 equiv N-methylimidazole, CH3CN, microwave,
170 ꢁC, 30 min, quant.
Products 9a,c and 10a have been previously prepared on the
AMEBA solid support.15

M. de Kort et al. / Tetrahedron Letters 45 (2004) 2171–2175
Table 1. IL phase synthesis of (sulfon)amides
2173
Entry
Amine (R1NH2)
Product
Yield (%)
50
Puritya (%)
99 (95)
OMe
OMe
1
H2N
TsNH
9a
9b
9c
OMe
OMe
OMe
OMe
2
3
4
5
6
7
8
50
54
32
52
26
52
41
89 (90)
TsNH
TsNH
H2N
100 (>95)
65 (55)b
100 (95)
95 (95)
H2N
O
O
OMe
OMe
TsNH
H2N
9d
OMe
OMe
TolNH
H2N
H2N
10a
OMe
OMe
OMe
OMe
TolNH
TolNH
10b
10c
100 (95)
H2N
O
O
OMe
OMe
80 (85)b
TolNH
H2N
10d
a Numbers in parentheses denote purity based on 1H NMRanalysis.
b Only impurity observed was disulfonylated or acylated product resulting from poor extraction of the excess aniline.
proceeded smoothly at elevated temperature to yield 14.
In the penultimate step, the phenolic hydroxyl group in
14 was alkylated in a regioselective manner with N-Boc-
4-(4-iodobutyl)-piperidine24 under the influence of NaH
to give product 15.
were in full accordance with those reported25 (Scheme
3).
In conclusion, we have disclosed a novel readily acces-
sible ionic support 1 and have demonstrated its use in
ionic liquid phase assisted organic synthesis. To our
knowledge this is the first time a multistep synthesis
comprising five consecutive steps has been carried out in
a single batch of ionic liquid. Our method represents an
attractive alternative to classical solid and fluorous
phase synthesis strategies and combines the advantage
of performing homogeneous chemistry on a relatively
large scale while avoiding of large excesses of reagents.
Finally, cleavage from the ionic support and concomi-
tant deprotection of the product was effected by treat-
ment with 2% HPF6. Quenching of the reaction mixture
with Et3N and extraction with water gave, after purifi-
cation by preparative HPLC/MS chromatography, tar-
get compound 2 in 11% yield over the five steps (based
on 1). All the spectroscopic data of tirofiban analogue 2

2174
M. de Kort et al. / Tetrahedron Letters 45 (2004) 2171–2175
References and notes
9b
1. (a) Adang, A. E. P.; Hermkens, P. H. H. Curr. Med.
Chem. 2001, 8, 985–998; (b) Combinatorial Chemistry;
Jung, G., Ed.; Wiley-VCH: Weinheim, 1999.
2. Tzschucke, C. C.; Markert, C.; Bannwarth, W.; Roller, S.;
Hebel, A.; Haag, R. Angew. Chem., Int. Ed. 2002, 41,
3964–4000.
7b
6b
OMe
OMe
H2N
1
ꢀ
3. (a) Horvath, I. T. Acc. Chem. Res. 1998, 31, 641–650; (b)
Curran, D. P. Angew. Chem., Int. Ed. 1998, 37, 1175–1196;
(c) Filippov, D. V.; van Zoelen, D. J.; Oldfield, S. P.; van
der Marel, G. A.; Overkleeft, H. S.; Drijfhout, J. W.; van
Boom, J. H. Tetrahedron Lett. 2002, 43, 7809–7812; (d) de
Visser, P. C.; van Helden, M.; Filippov, D. V.; van der
Marel, G. A.; Drijfhout, J. W.; van Boom, J. H.; Noort,
D.; Overkleeft, H. S. Tetrahedron Lett. 2003, 44, 9013–
9016.
[bmim][PF6]
4. (a) Porcheddu, A.; Ruda, G. F.; Sega, A.; Taddei, M. Eur.
J. Org. Chem. 2003, 907–912; (b) Spanka, C.; Wentworth,
P., Jr.; Janda, K. D. Comb. Chem. High Throughput
Screening 2002, 5, 233–240.
5. Jessop, P. G.; Ikariya, T.; Noyori, R. Chem. Rev. 1999, 99,
475–493.
1
2
3
4
5
6
Figure 2. HPLC traces of crude ionic phase reaction mixtures
(1 fi 6b fi 7b fi 9b; entry 2, Table 1). Column: Luna C18; gradient:
7 min, 1/9 fi 9/1, v/v, MeCN/H2O containing 0.05% TFA.
6. (a) Bergbreiter, D. E.; Li, C. Org. Lett. 2003, 5, 2445–2447;
(b) Toy, P. H.; Janda, K. D. Acc. Chem. Res. 2000, 33,
546–554.
7. Kobayashi, S.; Akiyama, R. Chem. Commun. 2003, 449–
460.
O
O
+/-
H2N
N
O
a
O
R
8. Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.;
Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.;
Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1
2000, 3815–4195.
O
O
12 R = H
13 R = PhSO2
b
11
9. Reviews on ionic liquids: (a) Wasserscheid, P.; Keim, W.
Angew. Chem., Int. Ed. 2000, 39, 3772–3789; (b) Dupont,
J.; de Souza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002, 102,
3667; (c) Welton, T. Chem. Rev. 1999, 99, 3667; (d)
Gordon, C. M. Appl. Catal. A 2001, 222, 101; (e) Olivier-
Bourbigou, H.; Magna, L. J. Mol. Catal. A: Chem. 2002,
182–183, 419; (f) Ionic Liquids in Synthesis; Wasserscheid,
P., Welton, T., Eds.; Wiley-VCH: Weinheim, 2003.
10. (a) Swatloski, R. P.; Visser, A. E.; Reichert, W. M.;
Broker, G. A.; Farina, L. M.; Holbrey, J. D.; Rogers,
R . D.Chem. Commun. 2001, 2070–2071, and references
cited therein; (b) Gutowski, K. E.; Broker, G. A.;
Willauer, H. D.; Huddleston, J. G.; Swatloski, R. P.;
Holbrey, J. D.; Rogers, R. D. J. Am. Chem. Soc. 2003,
125, 6632–6633.
+/-
O
N
+/-
O
N
PhSO2
OH
PhSO2
OH
d
c
Boc
N
O
OH
14
15
O
H
N
OH
SO2
e,f
NH
11. Buijsman, R.; van Vuuren, E.; Sterrenburg, J. G. Org.
Lett. 2001, 3, 3785–3787.
2
O
12. (a) Leadbeater, N. E.; Torenius, H. M.; Tye, H. Tetrahe-
dron 2003, 59, 2253–2258; (b) Namboodiri, V. V.; Varma,
R . S.Tetrahedron Lett. 2002, 43, 5381–5383.
13. (a) Dzyuba, S. V.; Bartsch, R. A. Tetrahedron Lett. 2002,
43, 4657–4659; (b) Aki, S. N. V. K.; Brennecke, J. F.;
Samanta, A. Chem. Commun. 2001, 413–414.
14. (a) Task-specific ionic liquids: Ionic Liquids in Synthesis;
Wasserscheid, P., Welton, T., Eds.; Wiley-VCH: Wein-
heim, 2003; pp 33–40; (b) Fraga-Dubreuil, J.; Bazureau, J.
P. Tetrahedron 2003, 59, 6121–6130; (c) Fraga-Dubreuil,
J.; Bazureau, J. P. Tetrahedron Lett. 2001, 42, 6097–6100;
(d) Bates, E. D.; Mayton, R. D.; Ntai, I.; Davis, J. H., Jr.
J. Am. Chem. Soc. 2002, 124, 926–927; (e) Mehnert, C. P.;
Cook, R. A.; Dispenziere, N. C.; Afeworki, M. J. Am.
Chem. Soc. 2002, 124, 12932–12933; (f) Miao, W.; Chan,
T. H. Org. Lett. 2003, 5, 5003–5005; (g) Anjaiah, S.;
11% yield over 5 steps
Scheme 3. Ionic phase assisted synthesis of tirofiban analogue 2. All
reactions are performed in [bmim][PF6]. (a) NaBH(OAc)3, HOAc,
16 h; (b) PhSO2Cl, Et3N, 1 h; (c) 2 mol % Pd(PPh3)4, pyrrolidine, 90 ꢁC,
45 min; (d) NaH, then N-Boc-4-(4-iodobutyl)-piperidine, 16 h; (e) 2%
HPF6, 10 min; (f) Et3N, then extraction with H2O.
An attractive feature of this ionic phase approach is the
fact that reactions can be monitored at all times by
common techniques such as HPLC/MS. The rapidly
increasing number of publications on organic reactions
in ionic liquids is an impetus to expand the utilisation of
ionic phase assisted synthesis strategies. Expansion of
the method presented here towards differently func-
tionalised ionic supports, and the synthesis of more
complex target molecules are currently being pursued.
ꢀ
Chandrasekhar, S.; Gree, R. Tetrahedron Lett. 2004, 45,
569–571; (h) Visser, A. E.; Swatloski, R. P.; Reichert, W.
M.; Davis, J. H., Jr.; Rogers, R. D.; Mayton, R.; Sheff, S.;
Wierzbicki, A. Chem. Commun. 2001, 135–136; (i) Yao,

M. de Kort et al. / Tetrahedron Letters 45 (2004) 2171–2175
2175
Q.; Zhang, Y. Angew. Chem., Int. Ed. 2003, 42, 3395–3398;
(j) Audic, N.; Clavier, H.; Mauduit, M.; Guillemin, J.-C.
J. Am. Chem. Soc. 2003, 125, 9248–9249.
1H NMR(CDCl , 400 MHz), 9a: d 2.43 (s, 3H), 2.70 (t,
3
2H), 3.18 (q, 2H), 3.79 (s, 3H), 4.27 (t, 1H), 6.81 (d, 2H),
6.99 (d, 2H), 7.29 (d, 2H), 7.70 (d, 2H); 9b: d 2.43 (s, 3H),
2.71 (t, 2H), 3.19 (q, 2H), 3.82 (s, 3H), 3.84 (s, 3H), 4.27 (t,
1H), 6.56 (d, 1H), 6.63 (dd, 1H), 6.77 (d, 1H), 7.28 (d, 2H),
7.67 (d, 2H); 9c: d 1.06–1.27 (m, 5H), 1.47–1.78 (m, 6H),
2.43 (s, 3H), 3.12 (q, 2H), 4.32 (d, 1H), 7.30 (d, 2H), 7.76
(d, 2H); 9d: d 2.38 (s, 3H), 3.87 (s, 3H), 4.20 (t, 1H), 7.11
(d, 2H), 7.34 (d, 2H), 7.72 (d, 2H), 7.92 (d, 2H); 10a: d 2.38
(s, 3H), 2.87 (t, 2H), 3.67 (q, 2H), 3.81 (s, 3H), 6.06 (b,
1H), 6.87 (d, 2H), 7.15 (d, 2H), 7.21 (d, 2H), 7.59 (d, 2H);
10b: d 2.39 (s, 3H), 2.88 (t, 2H), 3.69 (q, 2H), 3.84 (s, 3H),
3.88 (s, 3H), 6.74–6.84 (m, 3H), 7.21 (d, 2H), 7.59 (d, 2H);
10c: d 1.16–1.29 (m, 3H), 1.38–1.49 (m, 2H), 1.62–1.70 (m,
1H), 1.72–1.79 (m, 2H), 1.99–2.08 (m, 2H), 2.39 (s, 3H),
3.92–4.02 (m, 1H), 6.11 (bs, 1H), 7.22 (d, 2H), 7.64 (d,
2H); 10d: d 2.44 (s, 3H), 3.92 (s, 3H), 7.31 (d, 2H), 7.74 (d,
2H), 7.78 (d, 2H), 8.06 (d, 2H).
15. Fivush, A. M.; Willson, T. M. Tetrahedron Lett. 1997, 38,
7151–7154.
16. Hardcastle, I. R.; Rowlands, M. G.; Houghton, J.; Parr, I.
B.; Potter, G. A.; Jarman, M. J. Med. Chem. 1995, 38,
241–248.
17. Howarth, J.; James, P.; Ryan, R. Synth. Commun. 2001,
2935–2938.
18. Procedure for 7 and 8: Four 2 mL portions of a 0.125 M
solution of ionic support 1 in [bmim][PF6] were vigorously
stirred with the amine (0.38 mmol, see Table 1) in the
presence of NaHB(OAc)3 (0.16 g, 0.75 mmol) and AcOH
(6 lL, 0.1 mmol). After 16 h, the ionic phases were
extracted with Et2O (3 · 3 mL) and H2O (3 · 3 mL) and
dried in vacuo (5 mbar) at 60 ꢁC for 2 h. The ionic phases
containing 6a–d were then treated with Et3N (88 lL,
0.63 mmol), followed by TsCl (47 mg, 0.25 mmol) or TolCl
(33 lL, 0.25 mmol). After 2 h the excesses of reagents were
removed by extractive work-up (3 · 2 mL H2O and Et2O,
respectively).
21. (a) Stepnowski, P.; Muller, A.; Behrend, P.; Ranke, J.;
Hoffmann, J.; Jastorff, B. J. Chromatogr. A 2003, 993,
173–178; (b) Dyson, P. J.; McIndoe, J. S.; Zhao, D. Chem.
Commun. 2003, 508–509.
19. Traces of this contaminant could be easily removed by
filtration through SiO2.
22. Beugelmans, R.; Bourdet, S.; Bigot, A.; Zhu, J. Tetrahe-
dron Lett. 1994, 35, 4349–4350.
20. Procedure for 9 and 10: The [bmim][PF6] solutions
containing ionic supported 7 or 8 were each treated with
30 lL of 60% aq HPF6 (CAUTION! – corrosive) while
stirring for 10 min. The dark red coloured ionic phase
(containing 2% HPF6) was washed with satd aq NaHCO3
(2 · 1 mL) and extracted with Et2O (3 · 2 mL). The com-
bined organic phases were rinsed with H2O (2 · 1 mL),
dried (MgSO4) and the target compounds 9a–d and 10a–d
were obtained by removal of Et2O under reduced pressure.
23. Deziel, R. Tetrahedron Lett. 1987, 28, 4371–4372.
24. Jiang, J.; Wang, W.; Sane, D. C.; Wang, B. Bioorg. Chem.
2001, 29, 357–379.
25. Egbertson, M. S.; Chang, C. T.-C.; Duggan, M. E.;
Gould, R. J.; Halczenko, W.; Hartman, G. D.; Laswell,
W. L.; Lynch, J. J., Jr.; Lynch, R. J.; Manno, P. D.;
Naylor, A. M.; Prugh, J. D.; Ramjit, D. R.; Sitko, G. R.;
Smith, R. S.; Turchi, L. M.; Zhang, G. J. Med. Chem.
1994, 37, 2537–2551.