Ionic liquid supports stable under conditions of peptide couplings, deprotections and traceless suzuki reactions

Article abstract of DOI:10.1135/cccc20070417

Ionic liquid supports (ILS) functionalized with carboxylic, alcoholic or amlno groups were synthesized, based on 1-methylimidazolium and pyridinium cations, and bromide, chloride, iodide and tetrafluoroborate anions. These reactive ionic liquids were fully characterized by NMR and HRMS. Ionic liquids based on l-(6-aminohexyl)-3-methylimidazolium iodide have been used in the conditions of peptide chemistry such as coupling and deprotection reactions. A method for attaching (bromophenyl)silanes to the ionic liquid supports was also developed to introduce traceless linkers. An ionic liquid with attached bromobenzene was reacted with ArB(OH)₂ under the Suzuki cross-coupling conditions and the resulting compound was cleaved by bromodesilylation with Br₂/pyridine to give the substituted products in good yields. The substrate loading of the ILS is high and can be tuned to between 2.5 and 50, mmol/g.

Full text of DOI:10.1135/cccc20070417

Ionic Liquid Supports
417
IONIC LIQUID SUPPORTS STABLE UNDER CONDITIONS OF PEPTIDE
COUPLINGS, DEPROTECTIONS AND TRACELESS SUZUKI REACTIONS
1
2,
Zoia MINCHEVA , Fabien BONNETTE and Olivier LAVASTRE *
Institut de chimie, UMR 6226 CNRS – Université de Rennes 1, Campus de Beaulieu,
35042 Rennes Cedex, France ; e-mail: 1 mincheva@univ-tours.fr, 2 olivier.lavastre@univ-rennes1.fr
Received Septem ber 7, 2006
Accepted Decem ber 14, 2006
Ion ic liquid supports (ILS) fun ction alized with carboxylic, alcoh olic or am in o groups were
syn th esized, based on 1-m eth ylim idazolium an d pyridin ium cation s, an d brom ide, ch loride,
iodide an d tetrafluoroborate an ion s. Th ese reactive ion ic liquids were fully ch aracterized by
NMR an d HRMS. Ion ic liquids based on 1-(6-am in oh exyl)-3-m eth ylim idazolium iodide h ave
been used in th e con dition s of peptide ch em istry such as couplin g an d deprotection reac-
tion s. A m eth od for attach in g (brom oph en yl)silan es to th e ion ic liquid supports was also de-
veloped to in troduce traceless lin kers. An ion ic liquid with attach ed brom oben zen e was
reacted with ArB(OH)2 un der th e Suzuki cross-couplin g con dition s an d th e resultin g com -
poun d was cleaved by brom odesilylation with Br2/pyridin e to give th e substituted products
in good yields. Th e substrate loadin g of th e ILS is h igh an d can be tun ed to between 2.5 an d
5.0 m m ol/g.
Keyw ord s: Ion ic liquid supports; Ion ic liquids; Meth ylim idazolium salts; Peptide couplin g;
Traceless lin kers; Suzuki cross-couplin g.
Com bin atorial ch em istry en com passes m an y strategies an d processes for
rapid syn th esis an d an alysis of large, organ ized collection s of com poun ds
kn own as libraries. Usin g com bin atorial syn th esis a large n um ber of prod-
ucts can be prepared sim ultan eously by com bin in g sets of ch em ical build-
in g blocks in just a few syn th etic steps. In recen t years, com bin atorial
ch em istry h as attracted en orm ous atten tion of ph arm aceutical in dustry
because it can greatly facilitate th e syn th esis of a large diversity of n ew drug
can didates for h igh -th rough put screen in g assays1.
For syn th esis of libraries, in soluble polym eric supports are used to facili-
tate product purification th rough sim ple filtration an d wash in g. A key as-
pect of an y solid-ph ase syn th esis (SPS) strategy is th e lin kage elem en t,
wh ich acts as a teth er to th e polym eric support m aterial2,3. Successful SPS
h as several sh ortcom in gs due to th e n ature of h eterogen eous reaction con -
dition s4,5. To overcom e th ese lim itation s, liquid-ph ase com bin atorial syn -
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 3, pp. 417–434
© 2007 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20070417

418
Mincheva, Bonnette, Lavastre:
th esis (LPCS) h as been developed as an altern ative m eth odology for th e
con struction of sm all m olecule libraries wh erein th e use of a soluble poly-
m eric support provides both th e advan tages of SPS an d th e ben efits of
classical solution -ph ase organ ic ch em istry. In an attem pt to do polym er-
supported ch em istry in solution , soluble polym ers an d fluorous system s
h ave been utilized6–10. Syn th etic approach es th at utilize soluble polym ers,
term ed liquid-ph ase ch em istry, com bin e th e advan tages of h om ogen eous
solution ch em istry (h igh reactivity, lack of diffusion ph en om en a, facile
com poun d ch aracterization ) with th ose of solid-ph ase m eth ods (use of ex-
cess reagen ts, easy isolation an d purification of products th rough precipita-
tion an d filtration ). Th e ch osen supports for liquid-ph ase syn th esis (LPS)
m ust also provide a reason able com prom ise between loadin g capacity an d
solubility. For large-scale application s, th e loadin g capacity of reactive
groups m ust be h igh an d th e presen ce of th e in ert m atrix n ot excessive,
such th at a big m olecule n o lon ger determ in es solubility properties.
Room -tem perature ion ic liquids are attractin g in creasin g in terest as an
en viron m en tally ben ign reaction m edia for organ ic an d organ om etallic
ch em istry11–13. Th ese solven ts presen t a n um ber of in terestin g properties:
n o vapor pressure, h igh th erm al an d ch em ical stability, wide liquid ran ge,
low m eltin g poin t, easy tun in g of solubility by m odification of an ion s an d
cation s14,15. It is possible, th rough a careful ch oice of startin g m aterials, to
prepare ion ic liquids th at are liquid at an d below room tem perature. Th e
scope of ion ic liquids h as recen tly been expan ded by th e in troduction of
addition al fun ction al groups in th e ion ic liquid structure. Th ese so-called
“task-specific” ion ic liquids can be utilized as supported reagen ts or cata-
lysts with h igh affin ity for th e ion ic liquid ph ase16–19
.
Reaction s could be perform ed in ion ic liquids as solven ts or as sup-
ports20–22. In th e latter case both th e substrate an d th e catalyst could be
lin ked by a covalen t bon d to ion ic liquid support offerin g th e sam e easy
work-up an d purification as stan dard polym eric solid supports. Ion ic liq-
uids based on m eth ylim idazolium com poun ds are favourable for in vestiga-
tion because of th eir air an d water stability, th eir wide liquid ran ge, th e
liquid state at room tem perature, an d th eir favourable viscosity an d den sity
ch aracteristics23–27
.
Wh ile th is is a m ajor step forward, th ere are still lim itation s to th e broad
application of ion ic liquid as support (ILS) in com bin atorial ch em istry. In a
previous n ote we reported a n ew strategy to obtain pure ion ic liquid sup-
ports with a h igh loadin g (3 m m ol/g) of prim ary am in o groups28. Our re-
sults sh ow an efficien t approach to obtain am in o-fun ction alized ion ic
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 3, pp. 417–434

Ionic Liquid Supports
419
liquids based on a ph th alim ide protectin g group. Th e first exam ple of a
traceless ion ic liquid support based on silicon lin ker was also reported.
In h igh -th rough put organ ic syn th esis, we h ave focused our studies on th e
developm en t of n ovel ion ic liquid supports for com bin atorial an d parallel
syn th esis; our m ost recen t work is described in th e presen t paper. We report
th e syn th esis of 15 n ew ion ic liquids based on 1-m eth ylim idazolium or
pyridin ium cation s, an d brom ide, ch loride, iodide or tetrafluoroborate an -
ion s. Ion ic liquids based on 1-(6-am in oh exyl)-3-m eth ylim idazolium iodide
h ave been tested in th e con dition s of peptide couplin g an d deprotection re-
action s. We also report th at th e well-ch aracterized Suzuki couplin g reaction
of ph en ylboron ic acid an d h aloben zen es to form biph en yl com poun ds is
readily accom plish ed usin g (brom oph en yl)silan es bon ded to ion ic liquids.
Electroph ilic cleavage of th e coupled products from th e ion ic liquid sup-
ports by brom odesilylation proceeds quickly an d with h igh yields.
RESULTS AND DISCUSSION
We h ave prepared a wide ran ge of ILS by varyin g th e cation , e.g. 1-m eth yl-
–
im idazolium an d pyridin ium , an d th e an ion such as Br–, Cl–, I–, BF4 .
( )
Y
NH2
N
N
+
n
N
+
-
-
X
X
Y = OH, COOH, Si(CH3)2(PhBr)
X = Br, Cl, I, BF4, n = 0, 1, 4 or 5
X = Br, BF4
Th ese two cation s were selected because th eir precursors 1-m eth yl-
im idazole an d pyridin e are com m ercially available an d provide a sim ple ac-
cess to a wide variety of fun ction alized ion ic liquids con tain in g stan dard
reactive h ydroxy, carboxylic or am in o groups Y. Th us, a direct an alogy with
ch em istry on beads is applicable to th e ILS.
1-Alkyl-3-m eth ylim idazolium brom ides 2b, 2c, 2d , 2g an d ch lorides 2a,
2f were prepared by a sim ple on e-step solven t-free m eth od, by h eatin g
1-m eth ylim idazole (Im ) or pyridin e (Py) with 2-brom oeth ylam in e h ydro-
brom ide, 6-brom ohexanoic acid, 3-brom opropanoic acid, 6-chlorohexan-1-ol
an d 1-brom o-4-[(ch lorom eth yl)dim eth ylsilyl]ben zen e (Sch em e 1, Table I).
( )
Y
X
n
NaBF4
1-methylimidazole
or pyridine
-
-
+
Y
+
Y
CH3CN
X = Br, Cl, I
Y = OH, COOH, NH2,
Si(CH3)2(PhBr)
2a-2g
(X- = Br, Cl, I)
3a-3d, 3f, 3g
(X- = BF4)
n = 0, 1, 4 or 5
SCHEME 1
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420
Mincheva, Bonnette, Lavastre:
Brom ides 2b an d 2c were con ven ien tly used as im m ediate precursors for
th e syn th esis of several h eterocyclic betain es29–31. Th ere were n o data for
th e m ass an d spectral ch aracterisation of th e products obtain ed.
Wh ile th e ch em istry of ion ic liquids fun ction alized with h ydroxy, form yl
or keto group was reported16,17,32,33, n o m ultistep process in volvin g an
am in o-fun ction alized ion ic liquid h as been described. Th is could be ex-
plain ed by th e lack of a direct an d fully gen eral access to am in o ion ic liq-
TABLE I
Preparation s of ion ic liquids 2a–2g from h aloalkan es un der solven t-free reaction con dition s
Tem p., °C
Tim e, h
( )
En try
Product
Yield, %
Y
n
X
( )
OH
-
( )
OH
N
+
N
1
2
3
4
5
6
7
80
24
2a
2b
2c
2d
2ea
2f
95
65
85
56
75
84
30
5
5
Cl
Cl
( )
COOH
-
N
N
4
( )
+
COOH
COOH
70
4
Br
4
Br
COOH
-
70
4
N
N
+
Br
Br
Br
NH2
HBr
NH2
-
N
N
N
70
4
+
Br
O
( )
NH2
( )
N
N
THF
5
+
5
-
Cl
I
reflux, 16
NaI
O
CH3
Si
CH3
Si
70
48
Br
Br
N
N
+
-
Cl
CH3
CH3
CI
+
NH2
HBr
NH2
80
24
2g
Br
N
-
Br
a
After deprotection with h ydrazin e.
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 3, pp. 417–434

Ionic Liquid Supports
421
uids supports. Two m eth ods of syn th esizin g am in o ion ic liquid supports
were in vestigated. Th e first strategy was th e stan dard approach to produce
im idazolium ion ic liquids by th e direct reaction between 1-m eth ylim id-
azole an d h alogen ated substrate (Sch em e 1). A task-specific am in o ion ic liq-
uid was effectively obtain ed by th e reaction of 1-butylim idazole with
2-brom opropylam in e h ydrobrom ide34
.
However in th e case in th e case of 2-brom oeth ylam in e h ydrobrom ide, as
alkylation reagen t a side product HMeIm +Br– was form ed in an am oun t of
36–50%, (Sch em e 2). Th e com poun d with th e NH2-en d group 2d was ob-
1
tain ed in a yield of 56%, due to th e side reaction (Sch em e 2). H NMR an al-
ysis of th e crude product in dicated th e form ation of a m ajor product,
wh ich is th e desired ion ic liquid 2d , togeth er with by-products due to th e
polyam in es.
(i) Br(CH2)2NH2.HCl
(
)
NH
N
N
N
N
n
NH2
+
-
(ii) Et3N in MeOH r.t.
X
1 (Im)
O
2d (n = 0), 4a-4c (n = 1-3), X = Br-
3d (n = 0), 5a-5c (n = 1-3), X = BF4
-
( )
N
THF, reflux
5
Cl
NaI
O
6
O
NH2-NH2
( )
N
( )
NH2
5
N
N
N
N
5
+
+
EtOH, reflux
-
-
I
I
O
2e
7
SCHEME 2
Mass spectrom etry in dicated th at th e com poun d 1-(2-am in oeth yl)-
3-m eth ylim idazolium brom ide (2d ) was th e prin cipal product with th ree
m in or by-products due to th e form ation of polyam in es 4a–4c. As in dicated
in Sch em e 2, th e m ajor by-product from th e direct alkylation reaction of
1-m eth ylim idazole is 4a (n = 1). It is th erefore reason able to expect th at th e
m ajor by-product of 3d would be com poun d 5a (n = 1) (Sch em e 2). Th e
m ultiplicity of th e reaction products (at least 4 com pon en ts) m ade im prac-
tical th e isolation of in dividual com poun ds for com plete an d un equivocal
ch aracterization . HRMS an alysis of th e m ajor com pon en ts was perform ed;
th e results of th e MS an d 1H NMR data are con sisten t with th e suggested
structures. By-products 4a–4c an d 5a–5c were iden tified as [M+] C8H17N4
(m/z = 169, n = 1), [M+] C10H22N5 (m/z = 212, n = 2) an d [M+] C12H27N6
(m/z = 255, n = 3). Th ese results in dicated th at th e direct alkylation reaction
with 2-brom oeth ylam in e h ydrobrom ide is n ot gen eral an d is really depen d-
en t on startin g com poun ds.
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422
Mincheva, Bonnette, Lavastre:
In a previous paper, th e syn th esis of 1-m eth yl-3-(6-ph th alim idoh exyl)-
im idazolium iodide (7) was reported28. Our results sh ow an efficien t ap-
proach to am in o-fun ction alized ion ic liquids based on th e ph th alim ide
protectin g group, capable of preven tin g by-product form ation . Th e in ter-
m ediate 7 (Sch em e 2) was obtain ed by alkylation of 1-m eth ylim idazole
with 1-ch loro-6-ph th alim idoh exan e (6) in th e presen ce of NaI in a h igh
yield (90%) an d purity as in dicated by 1H an d 13C NMR spectrom etry28
.
Reaction of 7 with h ydrazin e gives com poun d (2e) in a h igh yield an d
with out con tam in ation with polyam in es.
Th e syn th esis of 1-(2-am in oeth yl)pyridin ium brom ide (2g) (Table I) h as
been previously perform ed usin g th e Gabriel m eth od35. We reported an -
oth er successful preparation of th is com poun d from 2-brom oeth ylam in e
h ydrobrom ide an d pyridin e (h eatin g at 80 °C). Th e reaction of 1-(2-am in o-
eth yl)pyridin ium h ydrobrom ide with K2CO3 in CH3CN at room tem pera-
ture th en resulted in th e form ation of free am in o group. Th e cation of th ese
n ew ion ic liquids 2e an d 2g is an im idazolium /pyridin ium ion to wh ich a
prim ary am in e m oiety is covalen tly teth ered.
For all fun ction alized ion ic liquids 2, reaction s were assessed to h ave
gon e to com pletion if th e 1H an d 13C NMR spectra sh owed n o sign als of
1-m eth ylim idazole or pyridin e. Th is approach gen erally allowed products
of excellen t purity to be isolated, th e un reacted startin g m aterial bein g th e
on ly con tam in an t in som e cases. Th e obtain ed ion ic liquids 2a–2g were
sim ply purified by wash in g. Com paratively good yields (65–95% relative to
1-m eth ylim idazole) of th e desired com poun ds were obtain ed (Table I). Sub-
sequen t an ion m etath esis with am m on ium tetrafluoroborate (2.5 equiv.) in
CH3CN at 60 °C produced th e desired ion ic liquids 3a–3d , 3f an d 3g in
alm ost quan titative yields (86–95%) (Sch em e 1 an d Table II).
Product ch aracterization was carried out usin g IR, 1H an d 13C NMR
spectroscopy. Valen ce vibration of th e NH2 (3420–3580 cm –1), CO
(1714–1734 cm –1) an d OH an d COOH (3400–3562 cm –1) groups are clearly
seen in IR spectra of th e com poun ds studied. Th e IR spectra of
tetrafluoroborates 3 sh ow th e ch aracteristic B–F ban ds at 1040–1060 cm –1
,
as h as already been observed for related com poun ds36. Th e free am in o
group in com poun ds 2d , 2e an d 2g is proved un am biguously by 1H NMR
spectra in DMSO-d6 by th e appearan ce of a broad m ultiplet cen tred at
2.5–3.0 ppm . A triplet of th e N–CH2 group due to th e reaction of
1-m eth ylim idazole an d correspon din g alkylation reagen t is observed at
4.15–4.61 ppm . Th e structure of th e n ew ion ic liquids was also determ in ed
by m ass spectrom etry an d 13C NMR.
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 3, pp. 417–434

Ionic Liquid Supports
423
TABLE II
Structure an d yields of tetrafluoroborates 3
En try
Substrate
Product
Yield, %
( )
OH
-
N
N
N
N
5
1
2a
3a
3b
3c
3d
3f
92
93
86
93
95
75
+
+
BF4
( )
COOH
4
2
3
4
5
6
2b
2c
2d
2f
-
BF4
COOH
N
N
N
N
+
+
-
BF4
NH2
-
BF4
CH3
Si
Br
N
N
+
CH3
-
BF4
NH2
+
2g
3g
N
-
BF4
It is kn own th at, in th e presen ce of 1,3-diisopropylcarbodiim ide (DIC)
an d 4-dim eth ylam in opyridin e (DMAP) as catalyst37,38, esters an d am ides are
obtain ed un der m ild con dition s an d with good yields. We used th e ILS 2e
as a reagen t for th e acylation reaction to obtain th e am ide-fun ction alized
ion ic liquids accordin g to Sch em e 3. Th e acylation of th e am in o group of
2e was carried out usin g Boc-L-Ala (Boc-L-alan in e) an d Fm oc-Ah x
(Fm oc-6-am in oh exan oic acid). Th e form ation of am ide bon d was proved by
1H NMR spectra. Th ere is n o broad m ultiplet at 2.5–3.0 ppm , assign ed to
th e free NH2 group of th e startin g ILS 2e. Th e N-tert-butyloxycarbon yl (Boc)
was com pletely rem oved upon treatm en t with sm all excess of CF3COOH at
room tem perature to give th e desired ion ic liquid 9 39. Th e (fluoren -9-yl-
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 3, pp. 417–434

424
Mincheva, Bonnette, Lavastre:
m eth yloxy)carbon yl (Fm oc) group un dergoes n on -h ydrolytic cleavage by
treatm en t of th e protected ion ic liquid 10 with piperidin e in CH3CN, to
40
give th e desired ion ic liquid in th e free base form 11
.
CH3
CH3
(i)
( )
(ii)
NH
NHBoc
( )
NH
NH2
N
N
N
N
5
+
5
+
-
O
-
O
8
9
I
I
( )
NH2
N
N
5
+
-
I
2e
( )
NH
( )
( )
NH
(iv)
( )
N
N
N
N
5
NHFmoc
5
NH2
+
5
+
5
(iii)
-
O
-
O
I
I
10
11
(i) Boc-L-Ala, DIC, CH3CN, r.t.; (ii) CF3COOH, CH2Cl2, r.t.;
(iii) Fmoc-Ahx, DIC, CH3CN/DMF,r.t.; (iv) piperidine, CH3CN, r.t.
SCHEME 3
Th ese results in dicated th at 2e is com patible with stan dard am ide cou-
plin g reaction s an d with th e acid an d basic con dition s gen erally used to
rem ove th e protectin g group or to cleave an ch ored m olecules from th e
support.
Sin ce th e biph en yl un it is an im portan t ph arm acoph ore presen t in a vari-
ety of biologically active com poun ds41, we wish ed to determ in e wh eth er
th e syn th esis of th is m oiety would be am en able to an ion ic LPS strategy. In
addition , we also report sim ple an d efficien t m eth od of attach in g ph en yl-
silan es to ILS.
Plun kett an d Ellm an 42 reported th e first application of silicon as a
cleavable lin ker for SPS. Various reports in th e past several years described
oth er successful preparation s of silicon lin kers43–45. Attach m en t of th e lin k-
ers to a solid support was straigh tforward. A variety of resin s were produced
in th is m an n er with substrate loadin g ca. 1 m equiv./g in each case46,47
.
Silicon -directed substitution of arylsilan es is a well-studied process in
solution 46,48–50. Yet few exam ples of th is reaction on a solid support h ave
appeared in th e literature. Th e startin g com poun d 1-brom o-4-[(ch loro-
m eth yl)dim eth ylsilyl]ben zen e (12) was prepared from 1,4-dibrom oben zen e
in 81% yield46,51. It sh ould be m en tion ed th at th e syn th esis h as been de-
scribed of silan e-lin ked biph en yl 13 by lith iation of 4-brom obiph en yl with
BuLi, followed by treatm en t with ch loro(ch lorom eth yl)dim eth ylsilan e52
.
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 3, pp. 417–434

Ionic Liquid Supports
425
We reported an oth er successful m eth od for th e preparation of 13 by th e
Suzuki couplin g from 12. Th e attach m en t of th e silicon -based lin kers 12
an d 13 to 1-m eth ylim idazole was perform ed at 70 °C by a sim ple on e-step
solven t-free m eth od (Sch em e 4).
Br
Br
Br
16
17
(iv)
(iv)
CH3
Si
CH3
Si
(i), (ii)
(A)
(iii)
Br
N
N
N
N
+
+
CH3
CH3
-
-
15
X
BF4
CH3
Si
2f: X- = Cl
3f: X- = BF4
(i)
Br
-
Cl
CH3
CH3
Si
CH3
Si
12
(iii)
(B)
(i)
Cl
N
N
+
CH3
CH3
-
13
14
Cl
(i) 1-methylimidazole, 70 oC, 48 h, (2f), 24 h (14); (ii) NH4BF4 2.5 equiv, dry CH3CN, 60 oC, 18 h;
(iii) PhB(OH)2, 3% [Pd(PPh3)4], Et3N/DMF(1:1), 24 h, 90 oC; (iv) 6.0 equiv Br2, 3.0 equiv pyridine,
CH2Cl2, 0 oC, 24 h
SCHEME 4
Good yields of th e desired com poun ds (84% for 2f an d 80% for 14 rela-
tive to 1-m eth ylim idazole) were obtain ed. Subsequen t an ion m etath esis
with am m on ium tetrafluoroborate (2.5 equiv.) in CH3CN at 60 °C produced
th e desired ion ic liquids 3f an d 15 in alm ost quan titative yields (95 an d
90%) (Sch em e 4). Th e structure of th ese n ew ion ic liquids was determ in ed
from 1H, 13C NMR data an d m ass spectra.
Th e Suzuki couplin g reaction on solid support, studied by Fren ette an d
Friesen 47, was em ployed as th e key C–C bon d-form in g reaction 53 due to its
m ildn ess an d toleran ce to a wide scope of fun ction alities. Two syn th etic
strategies were developed for th e preparation of com poun d 15 as outlin ed
in Sch em e 4. In th e direct route A, th e n ovel 1-[(biph en yl-4-yldim eth yl-
silyl)m eth yl]-3-m eth ylim idazolium tetrafluoroborate (15) was easily pre-
pared via Suzuki couplin g reaction with ILS 3f.
By route B, 15 was prepared in th ree separate steps by reaction of
1-m eth ylim idazole with 1-brom o-4-[(ch lorom eth yl)dim eth ylsilyl]ben zen e
(12) an d subsequen t ion exch an ge with NH4BF4.
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Mincheva, Bonnette, Lavastre:
Th e two silan e-lin ked brom oph en yls 3f an d 12 were first reacted with
Ph B(OH)2 un der stan dard an h ydrous con dition s54,55 (3–5% [Pd(PPh 3)4],
Et3N/DMF (1:1), 90 °C for 24 h ). Both brom oph en yls were useful substrates
in th is reaction un dergoin g facile palladium -catalyzed couplin g with
ph en ylboron ic acid to give ion ic-liquid-bon ded biph en yl 15 an d silan e-
lin ked biph en yl 13. Th e biph en yl products are obtain ed in h igh yields
with out sign ifican t con tam in ation with by-products or startin g brom o
com poun ds. Th e coupled ion ic liquid 3f an d 15 were th en subjected to
electroph ilic cleavage by brom odesilylation to give th e desired substituted
com poun ds 16 an d 17 in good yield (Sch em e 4). An alysis of com poun d 17
1
by H NMR an d HRMS in dicated th at th e product was con tam in ated with
<3% dibrom obiph en yl on ly.
In sum m ary, several fun ction alized ion ic liquids sh owin g th e stan dard re-
active groups gen erally used on polym eric beads such as carboxylic, h y-
droxy or am in o groups were reported. We h ave sh own th at th e n ew
am in o-fun ction alized ion ic liquid supports derived from 1-m eth ylim id-
azole can be used in th e classical con dition s of peptide couplin gs an d
deprotection reaction s. Th e com patibility of th e im idazolium un it was
dem on strated for DIC or DMAP couplin g reaction s of protected am in o ac-
ids an d for classical cleavage of Boc or Fm oc protectin g groups. Exten sion
to parallel syn th esis of libraries usin g fun ction alized ion ic liquids an d pep-
tide ch em istry is possible usin g cleavable lin kers.
We h ave also dem on strated versatility an d utility of n ovel ion ic-
liquid-supported ph en ylsilan es for liquid-ph ase syn th esis un der Suzuki re-
action . With th ese results, furth er studies will be directed toward parallel
syn th esis an d buildin g a com bin atorial library based on Suzuki reaction s.
EXPERIMENTAL
All reaction s were carried out in an in ert atm osph ere. Solven ts were dried an d distilled un -
13
der dry n itrogen usin g stan dard procedures. 1H an d
C NMR spectra were recorded on a
Bruker DPX 200 at 200.131 an d 50.32 MHz, respectively. Ch em ical sh ifts are given in δ-scale
(ppm ), couplin g con stan ts, J, in Hz. In frared spectra (cm –1) were recorded on a Bruker IFS 28
FT spectrom eter as KBr pellets or film . High -resolution m ass spectrom etry (HRMS) m easure-
m en t was taken on a ZABSpec TOF Microm ass an d on a Varian MAT 311 at an ion izin g po-
ten tial of 70 eV in th e Cen tre Région al de Mesures Ph ysiques de l’Ouest (CRMPO, Ren n es,
Fran ce). Elem en tal an alyses were perform ed usin g Flash EA 1112 equipm en t. All reagen ts
were purch ased from Acros, Aldrich Ch im ie, Advan ced Ch em Tech , Propeptide, an d Fluka,
Fran ce an d used with out furth er purification .
1-Meth yl-3-(6-ph th alim idoh exyl)im idazolium iodide (7) was obtain ed by alkylation of
1-m eth ylim idazole with 1-ch loro-6-ph th alim idoh exan e (6) in th e presen ce of NaI accordin g
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Ionic Liquid Supports
427
to ref.28. Th e startin g product 1-brom o-4-[(ch lorom eth yl)dim eth ylsilyl]ben zen e (12) was pre-
pared accordin g to refs46,51
.
Syn th esis of Com poun ds 2a–2c an d 2f. Gen eral Procedure
A stirred m ixture of 1-m eth ylim idazole (1 equiv.) an d h alide RX (n equiv.) was h eated un der
n itrogen un der th e con dition s given in Table I. Th e resultin g viscous liquid was allowed to
cool to room tem perature, th en treated with a solven t (10 m l) an d stirred vigorously for 30
m in . Th e solven t was decan ted an d th e process repeated several tim es. Th e product was
dried un der vacuum at 70 °C.
1-(6-Hydroxyhexyl)-3-methylimidazolium chloride (2a). From 2 equiv. of RX. Viscous liquid
(wash ed with dieth yl eth er). Yield 95%. 1H NMR (CD3OD): 1.32–1.53 (m , 6 H, (CH2)3); 1.86
(quin t., 2 H, J = 7.04, CH2); 3.50 (t, 2 H, J = 6.22, CH2OH); 3.89 (s, 3 H, N-CH3); 4.14 (t,
2 H, J = 6.27, CH2-Nrin g); 7.52 (s, 1 H, rin g H5); 7.59 (s, 1 H, rin g H4); 8.90 (s, 1 H, rin g H2).
13C NMR (CD3OD): 24.94 (CH2); 25.64 (CH2); 29.74 (CH2); 31.93 (CH2); 35.16 (N-CH3);
49.37 (CH2-Nrin g); 61.42 (CH2OH); 122.26 (rin g C5); 123.57 (rin g C4); 136.53 (rin g C2).
HRMS (EI): calculated for C10H19N2O [M+] 183.1497; foun d: 183.1494.
1-(5-Carboxypentyl)-3-methylimidazolium bromide (2b). From 1 equiv. of RX. Crystals, m .p.
29
103–105 °C
(wash ed with aceton e). Yield 65%. IR (KBr disk): 1165, 1235, 1400, 1467,
1564, 1714, 2861, 2941, 3055, 3112, 3140, 3419. 1H NMR (DMSO-d6): 1.17 (m , 2 H, CH2);
1.45 (quin t., 2 H, J = 7.8, CH2); 1.72 (quin t., 2 H, J = 7.35, CH2); 2.14 (t, 2 H, J = 7.15, CH2);
3.79 (s, 3 H, N-CH3); 4.09 (t, 2 H, J = 7.10, CH2-Nrin g); 7.67 (t, 1 H, J = 1.58, rin g H5); 7.73
(t, 1 H, J = 1.62, rin g H4); 9.14 (s, 1 H, rin g H2). 13C NMR (DMSO-d6): 24.21 (CH2); 25.48
(CH2); 29.58 (CH2); 33.82 (CH2); 36.25 (N-CH3); 49.02 (CH2-Nrin g); 122.72 (rin g C5); 124.05
(rin g C4); 137.00 (rin g C2); 178.84 (C=O). HRMS (LSIMS, Cs+): calculated for C10H17N2O2
[M+] 197.1290; foun d: 197.1291.
1-(2-Carboxyethyl)-3-methylimidazolium bromide (2c). From 1 equiv. of RX. Viscous liquid
(wash ed with aceton e). Yield 85%. IR (film ): 1168, 1405, 1576, 1725, 3087, 3399. 1H NMR
(DMSO-d6): 2.77 (t, 2 H, J = 6.45, CH2COOH); 3.79 (s, 3 H, N-CH3); 4.28 (t, 2 H, J = 6.26,
CH2-Nrin g); 7.65 (s, 1 H, rin g H5); 7.73 (s, 1 H, rin g H4); 9.15 (s, 1 H, rin g H2). 13C NMR
(DMSO-d6): 34.85 (CH2COOH); 36.21 (N-CH3); 45.50 (CH2-Nrin g); 122.88 (rin g C5); 123.86
(rin g Im C4); 137.39 (rin g C2); 172.37 (C=O). HRMS (LSIMS, Cs+): calculated for C7H11N2O2
[M+] 155.0821; foun d: 155.0823.
1-{[(4-Bromophenyl)dimethylsilyl]methyl}-3-methylimidazolium chloride (2f). From 1 equiv. of
RX. Sticky solid (wash ed with dieth yl eth er). Yield 84%. 1H NMR (DMSO-d6): 0.38 (s, 6 H,
Si(CH3)2); 3.86 (s, 3 H, N-CH3); 4.22 (s, 2 H, SiCH2); 7.50–7.64 (m , 5 H, Harom + rin g H5);
7.74 (s, 1 H, rin g H4); 9.21 (s, 1 H, rin g H2). 13C NMR (DMSO-d6): –3.80 (Si(CH3)2); 36.59
(N-CH3); 40.47 (SiCH2); 123.83 (rin g C5); 124.43 (rin g C4); 125.06, 131.84, 134.69, 136.70
(Carom ); 136.90 (rin g C2). HRMS (LSIMS, Cs+): calculated for C13H1879BrN2Si [M+] 309.0423;
foun d: 309.0421.
1-(2-Am in oeth yl)-3-m eth ylim idazolium Brom ide (2d )
1-(2-Am in oeth yl)-3-m eth ylim idazolium h ydrobrom ide was prepared accordin g to th e gen eral
procedure from 1 equiv. of RX. Th e viscous liquid was wash ed with aceton itrile. To a stirred
solution of crude h ydrobrom ide in an h ydrous MeOH (10 m l), Et3N (2.47 g, 24.4 m m ol) was
added dropwise un der n itrogen atm osph ere an d th e m ixture was stirred at room tem pera-
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428
Mincheva, Bonnette, Lavastre:
ture for 2 h . Th e precipitate of Et3N·HBr was filtered off an d wash ed with MeOH (2 × 2 m l).
Th e resultin g solution was con cen trated to dryn ess, CH2Cl2 (5 m l) was th en added an d
stirred vigorously for 30 m in . Th e solven t was decan ted an d th e process repeated 5 tim es.
Th e product was dried un der vacuum at 70 °C to yield 1.12 g of pure sticky solid (yield 56%,
based on 1-m eth ylim idazole). IR (film ): 1173, 1459, 1519, 1577, 2017, 2479, 3416. 1H NMR
(DMSO-d6): 2.85 (m , 2 H, NH2); 3.30 (t, 2 H, J = 5.71, CH2NH2); 3.80 (s, 3 H, N-CH3); 4.42
(t, 2 H, J = 5.65, CH2-Nrin g); 7.71 (s, 1 H, rin g H5); 7.77 (s, 1 H, rin g H4); 9.17 (s, 1 H, rin g
H2). 13C NMR (DMSO-d6): 36.32 (CH2NH2); 39.01 (N-CH3); 46.75 (CH2-Nrin g); 122.92 (rin g
C5); 124.28 (rin g C4); 137.81 (rin g C2). HRMS (LSIMS, Cs+): calculated for C12H2479BrN6
[2 M+, Br–]+ 331.1246; foun d: 331.1248.
1-(6-Am in oh exyl)-3-m eth ylim idazolium Iodide (2e)
To a solution of 1-m eth yl-3-(6-ph th alim idoh exyl)im idazolium iodide (7; 650 m g, 1.48 m m ol)
in eth an ol (5 m l), h ydrazin e (107 µl, 2.22 m m ol) was added dropwise. Th e m ixture was
stirred an d refluxed for 15 h . Th en , th e cooled m ixture was filtered an d th e filtrate con cen -
trated un der reduced pressure. Th e residue was wash ed twice with dieth yl eth er (10 m l) an d
dried un der vacuum to give 343 m g of yellow oil. Th e product was sufficien tly pure for fur-
th er syn th esis (yield 75%). 1H NMR (DMSO-d6): 1.22–1.33 (m , 6 H, (CH2)3CH2NH2); 1.77 (q,
2 H, J = 7.40, CH2CH2-Nrin g); 2.53 (t, 2 H, J = 6.39, CH2NH2); 3.85 (s, 3 H, N-CH3); 4.15 (t,
2 H, J = 7.15, CH2-Nrin g); 7.70 (s, 1 H, rin g H5); 7.77 (s, 1 H, rin g H4); 9.11 (s, 1 H, rin g H2).
13C NMR (DMSO-d6): 26.17 (CH2); 26.45 (CH2); 30.25 (CH2); 31.99 (CH2); 39.16 (N-CH3);
41.49 (CH2NH2); 49.59 (CH2-Nrin g); 123.14 (rin g C5); 124.49 (rin g C4); 137.35 (rin g C2).
HRMS (EI): calculated for C10H20N3 [M+] 182.1653; foun d: 182.1657.
1-(2-Am in oeth yl)pyridin ium Brom ide (2g)
1-(2-Am in oeth yl)pyridin ium h ydrobrom ide was prepared accordin g to th e gen eral procedure
from 3 equiv. of RX. Wh ite solid (wash ed with aceton itrile). Yield 90%. To a stirred suspen -
sion of th e h ydrobrom ide (2.02 g, 7.1 m m ol) in an h ydrous CH3CN (15 m l), solid K2CO3
(2.94 g, 21.28 m m ol) was added un der n itrogen an d th e m ixture stirred at room tem perature
for 24 h . Th e in soluble m aterials were rem oved by filtration an d wash ed 2 × with CH3CN
(10 m l). Th e filtrates were con cen trated to dryn ess to afford 0.43 g of 2g as a viscous oil
(yield 30%, based on th e 2-brom oeth ylam in e h ydrobrom ide). Th e ion ic liquid could be used
with n o furth er treatm en t. 1H NMR (DMSO-d6): 3.06 (t, 2 H, J = 5.59, CH2NH2); 3.64 (m ,
2 H, CH2NH2); 4.61 (t, 2 H, J = 5.58, CH2-Nrin g); 8.18 (t, 2 H, J = 7.04, 2 Harom ); 8.63 (t, H,
J = 7.78, Harom ); 9.09 (d, 2 H, J = 5.44, 2 Harom ). 13C NMR (DMSO-d6): 43.12 (CH2NH2);
63.97 (CH2-Nrin g); 128.37, 145.96, 146.11 (Carom ). HRMS (LSIMS, Cs+): calculated for
C7H11N2 [M+] 123.0922; foun d: 123.0925.
Syn th esis of Tetrafluoroborates 3a–3d an d 3f, 3g. Gen eral Procedure
To a solution of ion ic liquid 2a–2d , 2f, 2g (1.80 m m ol) in an h ydrous aceton itrile (10 m l)
am m on ium tetrafluoroborate (0.47 g, 4.51 m m ol) was added. Th e reaction m ixture was
h eated un der n itrogen atm osph ere at 60 °C for 18 h . After filtration to rem ove th e precipi-
tated salts (NH4X an d th e excess of NH4BF4), th e solution was con cen trated to dryn ess. Th e
residue is dried in vacuum at 70 °C to give a viscous liquid, wh ich could be used with out
furth er treatm en t.
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Ionic Liquid Supports
429
1-(6-Hydroxyhexyl)-3-methylimidazolium tetrafluoroborate (3a ). Yield 92%. 1H NMR
(DMSO-d6): 1.21–1.34 (m , 6 H, (CH2)3); 1.71 (m , 2 H, CH2); 3.30 (t, 2 H, J = 6.04, CH2); 3.77
(s, 3 H, N-CH3); 4.07 (t, 2 H, J = 7.16, CH2-Nrin g); 7.52 (s, 1 H, rin g H5); 7.70 (s,1 H, rin g H4);
9.00 (s, 1 H, rin g H2). 13C NMR (CD3OD): 25.73 (CH2); 26.23 (CH2); 30.28 (CH2); 33.05
(CH2); 36.55 (N-CH3); 49.64 (CH2-Nrin g); 61.39 (CH2OH); 123.08 (rin g C5); 124.43 (rin g C4);
– +
137.29 (rin g C2). HRMS (EI): calculated for C20H3811BF4N4O2 [2 M+, BF4
453.3026.
] 453.3028; foun d:
1-(5-Carboxypentyl)-3-methylimidazolium tetrafluoroborate (3b). Yield 93%. IR (film ): 1058,
1458, 1576, 1734, 2869, 2945, 3162, 3337, 3560. 1H NMR (DMSO-d6): 1.19 (m , 2 H, CH2);
1.45 (quin t., 2 H, J = 7.64, CH2); 1.72 (quin t., 2 H, J = 7.28, CH2); 2.15 (t, 2 H, J = 7.15,
CH2); 3.77 (s, 3 H, N-CH3); 4.08 (t, 2 H, J = 7.16, CH2-Nrin g); 7.60 (t, 1 H, J = 1.69, rin g H5);
7.67 (t, 1 H, J = 1.76, rin g H4); 8.99 (s, 1 H, rin g H2). 13C NMR (DMSO-d6): 24.19 (CH2);
25.40 (CH2); 29.53 (CH2); 33.77 (CH2); 36.16 (N-CH3); 49.03 (CH2-Nrin g); 122.68 (rin g C5);
124.03 (rin g C4); 136.95 (rin g C2); 174.88 (C=O). HRMS (LSIMS, Cs+): calculated for
– +
C
20H3411BF4N4O4 [2 M+, BF4
] 481.2609; foun d: 481.2607.
1-(2-Carboxyethyl)-3-methylimidazolium tetrafluoroborate (3c). Yield 86%. IR (film ): 1040,
1428, 1732, 3377, 3562. 1H NMR (DMSO-d6): 2.43 (s, 2 H, CH2COOH); 3.77 (s, 3 H, N-CH3);
4.27 (s, 2 H, CH2-Nrin g); 7.58 (s, 1 H, rin g H5); 7.67 (s, 1 H, rin g H4); 9.01 (s, 1 H, rin g H2).
13C NMR (DMSO-d6): 34.66 (CH2COOH); 36.11 (N-CH3); 45.45 (CH2-Nrin g); 122.85 (rin g C5);
123.83 (rin g C4); 137.34 (rin g C2); 172.42 (C=O). HRMS (LSIMS, Cs+): calculated for
– +
C
14H2211BF4N4O4 [2 M+, BF4
] 397.1670; foun d: 397.1673.
1-(2-Aminoethyl)-3-methylimidazolium tetrafluoroborate (3d ). Yield 93%. IR (film ): 1053,
1454, 1579, 2950, 3125, 3165, 3250, 3350, 3588. 1H NMR (DMSO-d6): 2.88 (m , 2 H,
CH2NH2); 3.26 (t, 2 H, J = 5.79, CH2NH2); 3.79 (s, 3 H, N-CH3); 4.33 (t, 2 H, J = 5.78,
CH2-Nrin g); 7.65 (s, 1 H, rin g H5); 7.66 (s, 1 H, rin g H4); 8.97 (s, 1 H, rin g H2). 13C NMR
(DMSO-d6): 36.18 (CH2NH2); 38.97 (N-CH3); 46.88 (CH2-Nrin g); 122.93 (rin g C5); 124.28
– +
(rin g C4); 137.74 (rin g C2). HRMS (EI): calculated for C12H2411BF4N6 [2 M+, BF4
foun d: 339.2096.
] 339.2092;
1-{[(4-Bromophenyl)dimethylsilyl]methyl}-3-methylimidazolium tetrafluoroborate (3f). Yield
95%. 1H NMR (DMSO-d6): 0.39 (s, 6 H, Si(CH3)2); 3.83 (s, 3 H, N-CH3); 4.13 (s, 2 H, SiCH2);
7.43–7.66 (m , 6 H, 4 Harom + rin g H5, H4); 8.83 (s, 1 H, rin g H2). 13C NMR (DMSO-d6): –3.94
(Si(CH3)2); 36.59 (N-CH3); 40.58 (SiCH2); 123.86 (rin g C5); 124.51 (rin g C4); 125.13, 131.89,
134.53 (Carom ); 136.51 (rin g C2); 136.80 (Carom ). HRMS (LSIMS, Cs+): calculated for
– +
C
26H3611B81Br2F4N4Si2 [2 M+, BF4
] 707.0861; foun d: 707.0851.
1-(2-Aminoethyl)pyridinium tetrafluoroborate (3g). Yield 75%. 1H NMR (DMSO-d6): 3.15 (t,
2 H, J = 5.62, CH2NH2); 3.45 (m , 2 H, CH2NH2); 4.60 (t, 2 H, J = 5.64, CH2-Nrin g); 8.17 (t,
2 H, J = 6.96, 2 Harom ); 8.62 (t, H, J = 7.81, Harom ); 8.99 (d, 2 H, J = 5.48, 2 Harom ). 13C NMR
(DMSO-d6): 40.44 (CH2NH2); 61.27 (CH2-Nrin g); 126.60, 143.99, 144.38 (Carom ). HRMS
– +
(LSIMS, Cs+): calculated for C14H22BF4N4 [2 M+, BF4
] 333.1876; foun d: 333.1878.
1-[(Biph en yl-4-yldim eth ylsilyl)m eth yl]-3-m eth ylim idazolium Tetrafluoroborate (15)
Th e title com poun d was prepared accordin g to th e gen eral procedure for th e syn th esis of
tetrafluoroborates from 14. Viscous liquid. Yield 90%. 1H NMR (DMSO-d6): 0.42 (s, 6 H,
Si(CH3)2); 3.83 (s, 3 H, N-CH3); 4.17 (s, 2 H, SiCH2); 7.42–7.73 (m , 11 H, 9 Harom + rin g H5,
H4); 8.90 (s, 1 H, rin g H2). 13C NMR (DMSO-d6): –4.28 (Si(CH3)2); 36.11 (N-CH3); 40.99
(SiCH2); 123.41, 123.99, 126.74, 127.17, 127.72, 129.48, 133.56, 134.90, 136.25, 139.58,
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430
Mincheva, Bonnette, Lavastre:
– +
142.08 (Carom ). HRMS (LSIMS, Cs+): calculated for C38H4611BF4N4Si2 [2 M+, BF4
foun d: 701.3301.
] 701.3290;
1-{6-[N-(tert-Butyloxycarbon yl)-L-alan ylam ido]h exyl}-3-m eth ylim idazolium Iodide (8)
To a solution of 1-(6-am in oh exyl)-3-m eth ylim idazolium iodide (2e; 200 m g, 0.65 m m ol) in
CH3CN (2.5 m l) a solution of Boc-L-Ala (1.53 g, 8.08 m m ol) an d a solution of DIC (263 m g,
2.08 m m ol) in CH3CN (5 m l) were successively added. Th e m ixture was stirred at room tem -
perature for 16 h . A wh ite precipitate of N,N′-diisopropylurea was form ed. Th e m ixture was
filtered off an d th e filtrate con cen trated un der reduced pressure. Th e residue was wash ed
twice with dieth yl eth er (20 m l) an d dissolved in THF (20 m l). Th en th e precipitate form ed
was filtered off. Th is operation was repeated th ree tim es to en sure com plete rem oval of
N,N′-diisopropylurea. Th e filtrate was con cen trated un der reduced pressure to give 101 m g of
yellow oil (yield 26%). 1H NMR (CDCl3): 1.33–1.53 (m , 18 H, (CH2)3CH2NH, C(CH3)3,
CHCH3); 1.94 (m , 2 H, CH2CH2-Nrin g); 3.70 (m , 2 H, CH2NH); 4.08 (s, 3 H, N-CH3); 4.20 (m ,
1 H, CHCH3); 4.34 (t, 2 H, J = 7.04, CH2-Nrin g); 5.45 (d, 1 H, J = 7.48, NHBoc); 7.00 (m , 1 H,
CH2NHCO); 7.53 (s, 1 H, rin g H5); 7.59 (s, 1 H, rin g H4); 9.81 (s, 1 H, rin g H2). 13C NMR
(CDCl3): 14.73 (CH3CH); 20.95 (CH2); 21.14 (CH2); 24.16 (C(CH3)3); 24.55 (CH2); 25.58
(CH2); 32.98 (N-CH3); 34.76 (CH2NH); 45.93 (CH2-Nrin g); 46.57 (CHCH3); 76.53 (C(CH3)3);
120.36 (rin g C5); 121.52 (rin g C4); 134.66 (rin g C2); 153.90 (NHCOO); 172.14 (NHCOCH).
HRMS (EI): calculated for C18H33N4O3 [M+] 353.2553; foun d: 353.2548. For C18H33IN4O3
(480.4) calculated: 45.00% C, 6.92% H, 11.66% N; foun d: 44.87% C, 7.19% H, 11.31% N.
1-[6-(L-Alan in am ido)h exyl]-3-m eth ylim idazolium Iodide (9)
Two-steps method. To a solution of 1-{6-[N-(tert-butyloxycarbon yl)-L-alan ylam ido]h exyl}-
3-m eth ylim idazolium iodide (8; 35 m g, 0.08 m m ol) in dich lorom eth an e (4 m l), a solution of
trifluoroacetic acid (12 µl, 0.145 m m ol) in th e sam e solven t (1 m l) was added un der stirrin g.
Th e m ixture was stirred at room tem perature for 15 h . Th e solven t was rem oved un der re-
duced pressure an d th e residue was dissolved in toluen e (5 m l). Th en th e trifluoroacetic acid
was co-evaporated with th e solven t (5×). Th e yellow oil was wash ed 3 × with dieth yl eth er
(10 m l), dissolved in THF (10 m l), an d th e precipitate form ed was filtered off. Th e filtrate
was con cen trated un der reduced pressure to give 20 m g of 9 as colorless oil (yield 70%).
1H NMR (D2O): 1.18–1.34 (m , 4 H, (CH2)2); 1.45 (m , 5 H, CH3CH + CH2); 1.80 (q, 2 H, J =
7.15, CH2 CH2-Nrin g); 3.15 (q, 2 H, J = 6.73, CH2NHCO); 3.82 (s, 3 H, N-CH3); 3.91 (q, 1 H,
J1 = 7.05, J2 = 14.30, CHCH3); 4.12 (t, 2 H, J = 7.16, CH2-Nrin g); 7.35 (s, 1 H, rin g H5); 7.40
(s, 1 H, rin g H4); 8.63 (1, s, rin g H2). 13C NMR (D2O): 16.68 (CHCH3); 24.99 (CH2); 25.38
(CH2); 27.98 (CH2); 29.12 (CH2); 35.72 (N-CH3); 39.35 (CH2NH); 49.16 (CH2-Nrin g); 49.50
(CHCH3); 122.22 (rin g C5); 123.55 (rin g C4); 135.81 (rin g C2); 170.47 (CONH). HRMS (EI):
calculated for C13H25N4NaO [M+] 253.20284; foun d: 253.2023.
One-step method. Direct syn th esis of 9. To a solution of 1-(6-am in oh exyl)-3-m eth yl-
im idazolium iodide (2e; 100 m g, 0.32 m m ol) in CH3CN (3 m l), a solution of Boc-L-Ala
(67 m g, 0.35 m m ol) an d a solution of DIC (53 m g, 0.42 m m ol) in CH3CN (1 m l) were suc-
cessively added. Th e m ixture was stirred at room tem perature for 16 h . A wh ite precipitate
of N,N′-diisopropylurea was form ed (an aliquot of th e m ixture was an alyzed by 1H NMR; th e
con version was 96%). Th e m ixture was filtered off an d th e filtrate was added dropwise to di-
eth yl eth er (40 m l). Th e product an d th e residual N,N′-diisopropylurea were precipitated as
oran ge oil. Th is m ixture was directly in troduced in to th e n ext reaction . To a solution of th e
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residue (109 m g) in dich lorom eth an e (2 m l), trifluoroacetic acid (64 µl, 0.56 m m ol) was ad-
ded dropwise un der stirrin g. Th e m ixture was stirred at room tem perature for 15 h . Th e sol-
ven t was rem oved un der reduced pressure an d th e residue was dissolved in toluen e (5 m l).
Th en trifluoroacetic acid was co-evaporated with th e solven t (5×). Th e yellow oil was wash ed
3 × with dieth yl eth er (5 m l) to give 70 m g of 9 as a colorless oil. Total yield of 9 was 67%.
1-[6-(6-{[(Fluoren -9-ylm eth oxy)carbon yl]am in o}h exan oylam in o)h exyl]-
3-m eth ylim idazolium Iodide (10)
To a solution of 1-(6-am in oh exyl)-3-m eth ylim idazolium iodide (2e; 400 m g, 1.29 m m ol) in
CH3CN (2 m l) a solution of Fm oc-6-am in oh exan oic acid (Fm oc-Ah x; 500 m g, 1.42 m m ol) in
CH3CN (2.5 m l) an d DMF (0.5 m l), an d a solution of DIC (210 m g, 1.67 m m ol) in CH3CN
(5 m l) were successively added. Th e m ixture was stirred at room tem perature for 16 h an d
th en a wh ite precipitate of N,N′-diisopropylurea was form ed. Th e m ixture was filtered off
an d th e filtrate con cen trated un der reduced pressure. Th e residue was wash ed 6 × with di-
eth yl eth er (10 m l), dissolved in dich lorom eth an e (1 m l) an d th en th e solution was cooled
in an ice-bath to –5 °C. Th e solid form ed was filtered off, wash ed with pen tan e an d vac-
uum -dried to give 480 m g of wh ite powder (yield 58%). 1H NMR (CD2Cl2): 1.25–1.68 (m , 12
H, 2 (CH2)3); 1.95 (q, 2 H, J = 6.97, CH2CH2-Nrin g); 2.24 (t, 2 H, J = 7.33, NHCOCH2);
3.13–3.23 (m , 4 H, CH2NHCOCH2 + CH2NHCOO); 4.01 (s, 3 H, N-CH3); 4.23–4.34 (m , 5 H,
CH2O + CHCH2O + CH2-Nrin g); 5.45 (t, 1 H, NHCOO); 6.66 (t, 1 H, NHCOCH2); 7.30–7.46
(m , 6 H, 4 CH(Fm oc)) + rin g H5, H4); 7.66 (d, 2 H, J = 3.58, 2 CH(Fm oc)); 7.80 (d, 2 H, J =
3.76, 2 CH(Fm oc)); 9.87 (s, 1 H, rin g H2). 13C NMR (CD2Cl2): 25.25 (CH2); 25.34 (CH2); 25.82
(CH2); 26.17 (CH2); 28.93 (CH2); 29.50 (CH2); 29.65 (CH2); 36.30 (CH2); 36.71 (N-CH3);
38.65 (CH2NHCOO); 40.71 (CH2NHCOCH2); 47.27 (OCH2CH(Fm oc)); 49.76 (CH2-Nrin g);
66.35 (OCH2CH(Fm oc)); 119.89 (CH(Fm oc)); 122.29 (rin g C5); 123.33 (rin g C4); 125.21,
127.05, 127.63 (CH(Fm oc)); 136.80 (rin g C2); 141.20, 144.15 (CH(Fm oc)); 156.37 (NHCOO);
173.08 (NHCOCH2). For C31H41IN4O3 (643.6) calculated: 57.76% C, 6.41% H, 8.69% N;
foun d: 57.96% C, 6.96% H, 8.90% N.
1-[6-(6-Am in oh exan oylam in o)h exyl]-3-m eth ylim idazolium Iodide (11)
To a solution of 1-[6-(6-{[(Fluoren -9-ylm eth oxy)carbon yl]am in o}h exan oylam in o)h exyl]-
3-m eth ylim idazolium iodide (10; 100 m g, 0.155 m m ol) in CH3CN (5 m l), piperidin e (38 µl,
0.39 m m ol) was added dropwise. Th e m ixture was stirred at room tem perature for 24 h an d
th en th e wh ite precipitate form ed was filtered off. Th e filtrate was con cen trated un der re-
duced pressure to give 50 m g of a wh ite solid. Th e product obtain ed was wash ed 3 × with
dieth yl eth er (yield 76%). 1H NMR (D2O): 1.12–1.56 (m , 12 H, 2 (CH2)3); 1.77 (t, 3 H, J =
7.09, CH2CH2-Nrin g); 2.14 (t, 2 H, J =7.35, NHCOCH2); 2.57 (t, 2 H, J = 7.16, CH2NH2); 3.06
(t, 2 H, J = 6.78, CH2NHCO); 3.79 (s, 3 H, N-CH3); 4.09 (t, 2 H, J = 7.15, CH2-Nrin g); 7.33 (s,
1 H, rin g H5); 7.37 (s, 1 H, rin g H4); 9.11 (s, 1 H, rin g H2). 13C NMR (D2O): 25.00 (CH2);
25.26 (CH2); 25.42 (CH2); 25.51 (CH2); 28.10 (CH2); 29.16 (CH2); 35.70 (CH2); 35.79 (N-CH3
+ NHCOCH2); 39.05 (CH2NH2); 40.28 (CH2NH); 49.50 (CH2-Nrin g); 122.20 (rin g C5); 123.52
(rin g C4); 140.83 (rin g C2); 176.80 (NHCO). HRMS (EI): calculated for C16H31N4O [M+]
295.2498; foun d: 295.2495. For C16H31IN4O (422.4) calculated: 45.50% C, 7.40% H, 13.27% N;
foun d: 46.17% C, 7.35% H, 10.55% N.
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432
Mincheva, Bonnette, Lavastre:
Syn th esis of 4-[(Ch lorom eth yl)dim eth ylsilyl]biph en yl (13) by
Suzuki Couplin g of 1-Brom o-4-[(ch lorom eth yl)dim eth ylsilyl]ben zen e (12)
A stirred m ixture of 12 (0.97 g, 3.68 m m ol), ph en ylboron ic acid (1.35 g, 11.04 m m ol), an d
0.23 g (5 m ole %) of [Pd(PPh 3)4] an d 15 m l DMF/Et3N (1:1) was h eated at 90 °C overn igh t
un der n itrogen atm osph ere. Th e m ixture was cooled to room tem perature an d th e solven ts
were distilled off un der reduced pressure. Th e residue was partition ed between dieth yl eth er
an d brin e. Th e organ ic extracts were dried with an h ydrous MgSO4 an d con cen trated un der
reduced pressure. Purification of th e crude product by colum n ch rom atograph y on silica gel
with h eptan e as eluen t afforded 0.58 g of pure crystallin e 13 (yield 60%). 1H NMR
(DMSO-d6): 0.43 (s, 6 H, Si(CH3)2); 3.18 (s, 2 H, SiCH2); 7.50–7.71 (m , 9 H, Harom ). 13C NMR
(DMSO-d6): –4.10 (Si(CH3)2); 30.62 (SiCH2); 126.55, 127.14, 128.07, 129.36, 134.84, 135.08,
140.34, 141.75 (Carom ). HRMS (EI): calculated for C15H1735ClSi [M+] 260.0788; foun d:
260.0774.
1-[(Biph en yl-4-yldim eth ylsilyl)m eth yl]-3-m eth ylim idazolium Ch loride (14)
Th e title com poun d was prepared accordin g to th e gen eral procedure from 1-m eth ylim id-
azole (0.11 g, 1.34 m m ol) an d 13 (0.35 g, 1.34 m m ol). Viscous liquid. Yield 80%. 1H NMR
(DMSO-d6): 0.40 (s, 6 H, Si(CH3)2); 3.83 (s, 3 H, N-CH3); 4.18 (s, 2 H, SiCH2); 7.42–7.69 (m ,
11 H, 9 Harom + rin g H5, H4); 9.02 (s, 1 H, rin g H2). 13C NMR (DMSO-d6): –4.15 (Si(CH3)2);
36.15 (N-CH3); 41.15 (SiCH2); 123.42, 124.00, 126.73, 127.18, 128.26, 129.45, 133.66,
134.95, 136.22, 140,15, 142.06 (Carom ). HRMS (EI): calculated for C19H23N2Si [M+] 307.1631;
foun d: 307.1637.
Cleavage with Brom in e: Syn th esis of 1,4-Dibrom oben zen e (16)
To a solution of 3f (270 m g, 0.68 m m ol) in CH2Cl2 (15 m l) at 0 °C 3.0 equiv. of pyridin e
(0.16 m l, 2.04 m m ol) an d 6.0 equiv. of Br2 were added. Th e m ixture was stirred at 0 °C for
2 h an d th en th e cleavage solution was rem oved by rotary evaporation . Th e brown crude re-
action m ixture was diluted with dieth yl eth er an d th e organ ic layer was wash ed with brin e,
dried, con cen trated an d th en taken up in h exan e. Th e brigh t-red color of brom in e oil was
rem oved by filtration an d th e organ ic layer was con cen trated to give 30 m g (30%) of th e de-
sired product as wh ite crystals. Th e fin al product 16 h as been detected an d ch aracterized by
com parison with an auth en tic sam ple of 1,4-dibrom oben zen e (Acros). 1H NMR (DMSO-d6):
7.55 (s, 4 H, Harom ). 13C NMR (DMSO-d6): 121.57, 134.29 (Carom ).
Cleavage with Brom in e: Syn th esis of 4-Brom obiph en yl (17)
A stirred m ixture of 3f (0.5 g, 1.25 m m ol), ph en ylboron ic acid (0.23 g, 1.87 m m ol) an d
0.047 g (3 m ole %) of [Pd(PPh 3)4] an d 2 m l DMF/Et3N (1:1) was h eated at 90 °C overn igh t
un der n itrogen . Th e m ixture was cooled to room tem perature, th e solven ts were distilled
off un der reduced pressure, an d th e residue was th en subjected to electroph ilic cleavage.
To a solution of th e crude 15 in CH2Cl2 (15 m l) at 0 °C 3.0 equiv. of pyridin e (0.30 m l,
3.75 m m ol) an d 6.0 equiv. of Br2 (0.38 m l, 7.49 m m ol) were added. Th e m ixture was stirred
at 0 °C for 2 h an d th en th e cleavage solution was rem oved by rotary evaporation . Th e
brown crude residue was partition ed between dieth yl eth er an d brin e. Th e organ ic extracts
were dried with an h ydrous MgSO4 an d con cen trated un der reduced pressure. Purification by
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colum n ch rom atograph y on silica gel with eth tyl acetate/h eptan e (1:9) as eluen t afforded
160 m g of pure 4-brom obiph en yl (17; yield 55%). 1H NMR (DMSO-d6): 7.40–7.70 (m , 9 H,
H
arom ). 13C NMR (DMSO-d6): 127.47, 127.56, 128.74, 129.68, 129.94, 132.69, 134.31, 140.21
(Carom ). HRMS (EI): calculated for C12H979Br [M+] 231.9888; foun d: 231.9893.
The authors are grateful to the CNRS for the one-year Research Associate position for Z. Mincheva.
REFERENCES
1. a) Jacoby E., Schuffenhauer A., Popov M., Azzaoui K., Havill B., Schopfer U., Engeloch C.,
Stanek J., Acklin P., Rigollier P., Stoll F., Koch G., Meier P., Orain D., Giger R., Hinrichs J.,
Malagu K., Zimmermann J., Roth H. J.: Curr. Top. Med. Chem. 2005, 5, 397; b) Eichler J.:
Combinat. Chem. High Throughput Screen. 2005, 8, 135; c) Gennari C., Piarulli U.: Chem.
Rev. 2003, 103, 3071; d) Adang A. E. P., Hermkens P. H. H.: Curr. Med. Chem. 2001, 8,
985; e) Oliver S. F., Abell C.: Curr. Opin. Chem. Biol. 1999, 3, 299; f) Kenseth J. R.,
Coldiron S. J.: Curr. Opin. Chem. Biol. 2004, 8, 418.
2. Guillier F., Orain D., Bradley M.: Chem. Rev. 2000, 100, 2091.
3. James I. W.: Tetrahedron 1999, 55, 4855.
4. Booth R. J., Hodges J. C.: Acc. Chem. Res. 1999, 32, 18.
5. Brown A. R., Hermkens P. H. H., Ottenheijm H. C. J., Rees D. C.: Synlett 1998, 817.
6. Gravert D. J., Janda K. D.: Chem. Rev. 1997, 97, 489.
7. Toy P. H., Janda K. D.: Acc. Chem. Res. 2000, 33, 546.
8. Harwig C. W., Gravert D. J., Janda K. D.: Chemtracts 1999, 12, 1.
9. Wentworth P., Jr., Janda K. D.: Chem. Commun. 1999, 1917.
10. Parlow J. J., Devraj R. V., South M. S.: Curr. Opin. Chem. Biol. 1999, 3, 320.
11. Mehnert C. P.: Chem.-Eur. J. 2005, 11, 50.
12. Dupont J., Souza R. F., Suarez P. A. Z.: Chem. Rev. 2002, 102, 3667.
13. Olivier-Bourbigou H., Magna L.: J. Mol. Catal. A: Chem. 2002, 182–183, 419.
14. Wasserscheid P., Keim W.: Angew. Chem., Int. Ed. 2000, 39, 3772.
15. Welton T.: Chem. Rev. 1999, 99, 2071.
16. Fraga-Dubreuil J., Bazureau J. P.: Tetrahedron 2003, 59, 6121.
17. Hakkou H., Eynde J. J. V., Hamelin J., Bazureau J. P.: Tetrahedron 2004, 60, 3745.
18. Singh R. P., Manandhar S., Shreeve J. M.: Synthesis 2003, 10, 1579.
19. Singh R. P., Meshri D. T.: Collect. Czech. Chem. Commun. 2006, 71, 1265.
20. Handy S. T., Okello M.: J. Org. Chem. 2005, 70, 2874.
21. Kort M., Tuin A. W., Kuiper S., Overkleeft H. S., Marel G. A., Buijsman R. C.: Tetrahedron
Lett. 2004, 45, 2171.
22. Anjaiah S., Chandrasekhar S., Grée R.: Tetrahedron Lett. 2004, 45, 569.
23. Garcia M. T., Gathergood N., Scammells P. J.: Green Chem. 2005, 7, 9.
24. Branco L. C., Rosa J. N., Moura Ramos J. J., Afonso C. A. M.: Chem. Eur. J. 2002, 8, 3671.
25. Bonhôte P., Dias A. P., Papageorgiou N., Kalyanasundaram K., Grätzel M.: Inorg. Chem.
1996, 35, 1168.
26. Gordon C. M., McCluskey A.: J. Chem. Soc., Chem. Commun. 1999, 1431.
27. Hasan M., Kozhevnikov I. V., Siddiqui M. R. H., Steiner A., Winterton N.: Inorg. Chem.
1999, 38, 5637.
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 3, pp. 417–434

434
Mincheva, Bonnette, Lavastre:
28. Bonnette F., Mincheva Z., Lavastre O.: Combinat. Chem. High Throughput Screen. 2006, 9,
229.
29. Alcalde E., Dinarés I., Pons J. M., Roca T.: Chem. Lett. 1994, 2195.
30. Alcalde E., Gisbert M., Perez G. L.: Chem. Lett. 1992, 2357.
31. Alcalde E., Gisbert M., Perez G. L.: Heterocycles 1996, 567.
32. Dubreuil J. F., Bazureau J. P.: Tetrahedron Lett. 2000, 41, 7351.
33. Wasserscheid P., Drieben-Holscher B., Van Hal R., Steffens H., Zimmermann J.: Chem.
Commun. 2003, 2038.
34. Bates E. D., Mayton R. D., Ntai I., Davis J. H.: J. Am. Chem. Soc. 2002, 124, 926.
35. Gabriel S.: Chem. Ber. 1920, 1990.
36. Fuller J., Carlin R. T., De Long H. C., Haworth D.: J. Chem. Soc., Chem. Commun. 1994,
299.
37. Hassner A., Alexanian V.: Tetrahedron Lett. 1978, 19, 4475.
38. Hassner A., Krepski L. R., Alexanian V.: Tetrahedron 1978, 34, 2069.
39. Lott R. S., Chauhan V. S., Stammer C. H.: J. Chem. Soc., Chem. Commun. 1979, 11, 495.
40. Carpino L. A., Han G. Y.: J. Org. Chem. 1973, 38, 4218.
41. McCarthy P. A.: Med. Res. Rev. 1993, 13, 139.
42. Plunkett M. J., Ellman J. A.: J. Org. Chem. 1995, 60, 6006.
43. Chenera B., Finkelstein J. A., Veber D. F.: J. Am. Chem. Soc. 1995, 117, 11999.
44. Woolard F. X., Paetsch J., Ellman J. A.: J. Org. Chem. 1997, 62, 6102.
45. Hu Y., Porco J. A., Labadie J. W., Gooding O. W.: J. Org. Chem. 1998, 63, 4518.
46. Han Y., Walker D. S., Young R. N.: Tetrahedron Lett. 1996, 37, 2703.
47. Frenette R., Frisen W.: Tetrahedron Lett. 1994, 35, 9177.
48. Chan T. H., Fleming I.: Synthesis 1979, 761.
49. Plunkett M. J., Ellman J. A.: J. Org. Chem. 1997, 62, 2885.
50. Brown S. D., Armstrong R. W.: J. Org. Chem. 1997, 62, 7076.
51. Boons G. J. P. H., Elie C. J. J., van der Marel G. A., van Boom J. H.: Tetrahedron Lett.
1990, 31, 2197.
52. Moberg W. K.: Eur. Pat. Appl. EP 68813 A2, 1983; Chem. Abstr. 1983, 98, 198430.
53. Miyaura N., Suzuki A.: Chem. Rev. 1995, 95, 2457.
54. Thompson W. J., Gaudino J.: J. Org. Chem. 1984, 49, 5237.
55. Miao W., Chan T.: Org. Lett. 2003, 5, 5003.
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 3, pp. 417–434