An expedient synthesis of the fibril binding compound FSB via sequential Pd-catalyzed coupling reactions

Article abstract of DOI:10.1021/jo7026189

(Chemical Equation Presented) The styryl benzene derivative (E,E)-1-fluoro-2,5-bis(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (FSB), well-known for its binding to β-amyloid peptide fibrils, was synthesized in an efficient manner exploiting two sequential palladium(0)-catalyzed coupling reactions in a 34% overall yield. This is a substantial improvement to the previously reported synthesis of FSB in 1.1%.

Full text of DOI:10.1021/jo7026189

SCHEME 1. Previously Reported Synthesis of FSB
An Expedient Synthesis of the Fibril Binding
Compound FSB via Sequential Pd-Catalyzed
Coupling Reactions
Mette Louise H. Mantel, Lina S. Søbjerg, Tri H. V. Huynh,
Jean-Philippe Ebran, Anders T. Lindhardt (né Hansen),
Niels C. Nielsen, and Troels Skrydstrup*
The Center for Insoluble Protein Structures (inSPIN),
Department of Chemistry, and the Interdisciplinary
Nanoscience Center, UniVersity of Aarhus, Langelandsgade
140, 8000 Aarhus C, Denmark
ts@chem.au.dk
ReceiVed December 7, 2007
sizes and distribution in living AD patients upon treatment with
potential AD drugs, which target such ꢀ-amyloid plaques.6
The previous synthesis of FSB requires six steps in the longest
linear sequence starting from dimethylaniline with a total yield
of only 1.1% (Scheme 1).3 A low-yielding Wittig–Horner
reaction was exploited as the key assembling step. We have
recently been interested in studying the binding and sequence
selectivity of this fibril binding compound to a variety of
peptide-based fibrils. We therefore required a more effective
synthesis of FSB, as well as one that displays greater flexibility
to the introduction of variations into the FSB structure.
Considering the high unsaturated nature of this compound, as
well as the substitution pattern of the two identical alkenes, we
approached the synthesis of FSB exploring the use of two
palladium(0)-catalyzed coupling reactions. In this Note, we
report on a greatly improved synthesis of FSB exploiting this
methodology to afford the fibril binding compound in only three
linear steps.
The styryl benzene derivative (E,E)-1-fluoro-2,5-bis(3-hy-
droxycarbonyl-4-hydroxy)styrylbenzene (FSB), well-known
for its binding to ꢀ-amyloid peptide fibrils, was synthesized
in an efficient manner exploiting two sequential palladium(0)-
catalyzed coupling reactions in a 34% overall yield. This is
a substantial improvement to the previously reported syn-
thesis of FSB in 1.1%.
The retrosynthetic analysis of FSB suggested two possible
routes for accessing this styryl benzene by a Mizoroki-Heck
coupling as indicated in Scheme 2. Route a proposes a double
Pd(0)-catalyzed coupling between the vinyl benzoic acid deriva-
tive 1 and 1,4-dibromo-2-fluorobenzene (2).7 Installation of the
vinyl group in the former compound was envisaged to take place
via a Suzuki-Miyaura cross-coupling with the aryl halide 3 or
Mizoroki-Heck coupling from a corresponding triflate with
vinyl acetate.8 An alternative approach to FSB would proceed
through the Mizoroki-Heck coupling of the bromide 3 with
divinyl benzene 4 (route b). Similarly, the Mizoroki-Heck
acceptor 4 could potentially be accessed from 1,4-dibromo-2-
fluorobenzene (2) through the use of a Suzuki-Miyaura
vinylation step.
Alzheimer’s disease (AD) is a form of senile dementia, which
represents the third most prevalent disorder affecting senior
citizens. AD is a fatal disorder resulting in the destruction of
neuronal tissue in the brain and hence loss of memory,
consciousness, and intellectual activity. The fibrillation and
deposition of ꢀ-amyloid peptides (ꢀAP1-40 and ꢀAP1-42) into
amyloid plaques has generally been accepted as the principle
cause of AD.1 Recently, (E,E)-1-fluoro-2,5-bis(3-hydroxycar-
bonyl-4-hydroxy)styrylbenzene (FSB) has emerged as a potential
marker for detecting brain amyloids in mice by magnetic
resonance imaging.2–5 This work holds promise for developing
effective probes for detection and monitoring changes in plaque
(1) For some recent reviews, see: (a) Selkoe, D. J. Nat. Biotechnol. 2000,
18, 823. (b) Hardy, J. J. Alzheimer’s Dis. 2006, 9, 151. (c) Goedert, M.;
Spillantini, M. G. Science 2006, 314, 777.
(6) Qu, W.; Kung, M.-P.; Hou, C.; Oya, S.; Kung, H. F. J. Med. Chem.
2007, 50, 3380 and references cited therein.
(2) Skovronsky, D. M.; Zhang, B.; Kung, M.-P.; Kung, H. F.; Trojanowski,
J. Q.; Lee, V. M.-Y. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 7609.
(3) Sato, K.; Higuchi, M.; Iwata, N.; Saito, T. C.; Sasamoto, K. Eur. J. Med.
Chem. 2004, 39, 573.
(7) For some recent reviews on the Heck reaction, see: (a) Heck, R. F. Synlett
2006, 2855. (b) Phan, N. T. S.; Van Der Sluys, M.; Jones, C. W. AdV. Synth.
Catal. 2006, 348, 609. (c) Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron
2005, 61, 11771.
(4) Higuchi, M.; Iwata, N.; Matsuba, Y.; Sato, K.; Sasamoto, K.; Saido, T. C.
Nat. Neurosci. 2005, 8, 527.
(8) For some recent reviews on the Suzuki-Miyaura reaction, see: (a) Kotha,
S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633. (b) Bellina, F.; Carpita,
A.; Rossi, R. Synthesis 2004, 2419. (c) Nam, T. S. P.; Matthew, V.; Christopher,
W. J. AdV. Synth. Catal. 2006, 348, 609.
(5) Masuda, M.; Suzuki, N.; Taniguchi, S.; Oikawa, T.; Nonaka, T.; Iwatsubo,
T.; Hisanaga, S.-i.; Goedert, M.; Hasewaga, M. Biochemistry 2006, 45, 6085.
3570 J. Org. Chem. 2008, 73, 3570–3573
10.1021/jo7026189 CCC: $40.75 2008 American Chemical Society
Published on Web 03/26/2008

SCHEME 2. Retrosynthetic Analysis of FSB
SCHEME 4. Coupling Attempts with Styrene 7
SCHEME 3. Preparation of Styrene 7
Mizoroki-Heck coupling approach from an aryl triflate.11
Transformation of 5-hydroxysalicylic acid to the triflate 8 could
be achieved in four steps in a 50% overall yield. Subsequent
Mizoroki-Heck coupling with vinyl acetate in the presence of
palladium acetate and the ligand dppp provided the required
styrene 7, though in a modest yield.11
Not quite satisfied with the efficiency of the synthesis of 7,
we finally resorted to a more practical route to this alkene,
involving the direct Pd(0)-promoted Suzuki-Miyaura coupling
of bromide 5 with the 2,4,6-trivinylcyclotriboroxane ·pyridine
complex in refluxing DME/H2O (Scheme 4).12 In this way, 7
could be secured in a 62% yield. The successful preparation of
this styrene derivative was nevertheless overshadowed by its
reluctance to couple with 1,4-dibromo-2-fluorobenzene (2) under
a variety of conditions including those reported by Fu and
Littke13 using Pd(OAc)2 and P(t-Bu)3 and Jeffery with Pd(OAc)2/
K2CO3/Bu4NBr.14 In these cases, the reactions failed to proceed
with no indication of the formation of the tetramethylated
derivative 9 of FSB.
To overcome these problems, we proceeded to examine route
b, as illustrated in Scheme 5. In this case, 5-bromosalicylic acid
was first converted to the acetal ester 10,15 thereby simplifying
the deprotection of the hydroxyl and carboxylic acid groups at
the end of the synthesis. Vinylation of 1,4-dibromo-2-fluo-
robenzene with trivinylcyclotriboroxane, using slightly modified
conditions of a previously reported method,12 provided the
required 2,5-divinyl-1-fluorobenzene 4 in a 56% yield. Mizoroki-
Heck coupling of 4 with 2.2 equiv of the bromide 10 did not
take place under previously reported conditions with use of a
bulky phosphine ligand (Pd2dba3, P(t-Bu)3, Cy2NMe in dioxane
at 40 °C).13 However, after some experimentation it was found
that by adding lithium chloride to the reaction mixture in DMF
and raising the reaction temperature to 100 °C, an acceptable
60% yield of the protected FSB 11 was obtained. Changing the
phosphine ligand to X-Phos and P(o-Tol)3, for example, or
application of the conditions developed by Jeffery11 did not
improve the yield of this Mizoroki-Heck step. Furthermore,
coupling with the iodide derivative of 10 did provide full
Initial efforts to access FSB via a more efficient synthesis
were focused on route a (Scheme 2). This required the
introduction of a vinyl group onto a salicylic acid derivative,
which was pursued by means of three approaches. In the first
case, 5-bromosalicylic acid was transformed to its methyl ester
under Fischer conditions followed by methylation of the
hydroxyl group furnishing the protected aryl bromide 5 (Scheme
3). Palladium-catalyzed boronation with bis(pinacolato)diboron
afforded the boron ester 6 in 49% yield.9 However, several
attempts to cross-couple 6 with the vinyl tosylate to the
disubstituted styrene 7 with an electron-rich Pd(0)-complex were
unsuccessful.10 Alternatively, 7 was prepared by using a
(11) Cabri, W.; Candiani, I.; Bedeschi, A. J. Org. Chem. 1992, 57, 3558.
(12) Kerins, F.; O’Shea, D. F. J. Org. Chem. 2002, 67, 4968.
(13) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989.
(14) Diez-Barra, E.; García-Martínez, J. C.; Merino, S.; del Ray, R.;
Rodríguez-Lopez, J.; Sánchez-Verdú, P.; Tejeda, T. J. Org. Chem. 2001, 66,
5664.
(9) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508.
(10) (a) Hansen, A. L.; Ebran, J.-P.; Gøgsig, T.; Skrydstrup, T. J. Org. Chem.
2007, 72, 6464. (b) Hansen, A. L.; Ebran, J.-P.; Ahlquist, M.; Norrby, P.-O.;
Skrydstrup, T. Angew. Chem., Int. Ed. 2006, 45, 3349.
(15) Bajwa, N.; Jennings, M. P. J. Org. Chem. 2006, 71, 3646.
J. Org. Chem. Vol. 73, No. 9, 2008 3571

SCHEME 5. Synthesis of FSB
reported in six steps. Additionally an FSB analogue was
prepared applying the developed method in an overall yield of
57% proving the adaptability of the reported protocol. Further
work is now underway to make use of this synthetic route for
the preparation of alternative analogues of FSB and to study
their fibril binding properties. In addition, studies are currently
in progress to examine the amino acid sequence selectivity of
FSB with a variety of fibril structures. These results will be
reported in due course.
Experimental Section
2-Fluoro-1,4-divinylbenzene (4). 1,4-Dibromo-2-fluorobenzene
(102 mg, 0.394 mmol), Pd(OAc)2 (8.92 mg, 0.039 mmol), PPh3
(27 mg, 0.197 mmol), K2CO3 (110 mg, 0.788 mmol), and 2,4,6-
trivinylcyclotriboroxane·pyridine complex (95 mg, 0.39 mmol)
were added to a sample vial in a glovebox. DME (3.5 mL) and
H2O (1 mL) were then added and the sample vial was fitted with
a Teflon sealed screwcap and removed from the glovebox. The
reaction mixture was heated to 85 °C for 24 h and then cooled to
20 °C; H2O (5 mL) was added and the crude reaction was extracted
with ether (3 × 20 mL). The combined organic phases were washed
with H2O (2 × 15 mL) and brine (2 × 10 mL). The organic phase
was dried over MgSO4. After concentration in vacuo at 20 °C, the
crude product was purified by flash chromatography on silica gel
with pentane as eluent. This afforded 33 mg of the title compound
(56% yield) as a clear colorless liquid. 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.44 (t, 1H, J ) 8 Hz), 7.14 (dd, 1H, J ) 2, 8 Hz), 7.09
(dd, 1H, J ) 2, 11.6 Hz), 6.85 (dd, 1H, J ) 11.2, 17.6 Hz), 6.66
(dd, 1H, J ) 10.8, 17.6 Hz), 5.82 (dd, 1H, J ) 1.2, 17.6 Hz), 5.75
(d, 1H, J ) 17.6 Hz), 5.36 (dd, 1H, J ) 1.2, 11.2 Hz), 5.29 (d, 1H,
J ) 10.8 Hz). 13C NMR (100 MHz, CDCl3) δ (ppm) 161.9, 159.4,
139.2, 139.1, 135.8, 129.3, 127.3, 124.9, 122.3, 116.5, 115.3, 113.3,
113.0. 19F NMR (377 MHz, CDCl3) δ (ppm) –119.5. GCMS C10H9F
[M+] calcd 148, found 148.
SCHEME 6. Synthesis of FSB Analogue
6-Bromo-2,2-dimethylbenzo[1,3]dioxin-4-one (10). 5-Bromo-
salicylic acid (0.5 g, 2.3 mmol) in trifluoroacetic acid (3.45 mL,
20 mmol) was cooled to 0 °C. Trifluoroacetic anhydride (3.2 mL,
10 mmol) and acetone (0.5 mL, 6.9 mmol) were added and the
mixturewas reacted for 48 h at 20 °C. The crude reaction mixture
was concentrated in vacuo, quenched with saturated NaHCO3, and
extracted with EtOAc (3 × 25 mL). The combined organic phases
were washed with water (2 × 25 mL) and brine (2 × 25 mL). The
organic phase was dried over MgSO4. After concentration in vacuo
the crude product was purified by flash chromatography on silica
gel with EtOAc/pentane 1:19 as eluent. This afforded 258 mg of
conversion, but afforded a complex mixture of products as
observed by NMR analysis of the crude reaction mixture.
Finally, a deprotection step with KOH/H2O in refluxing THF
provided a quantitative yield of FSB in an overall yield of 34%.
Next we decided to test this three-step protocol in the
synthesis of the FSB analogue (E,E)-1-fluoro-2,4-bis(3-hy-
droxycarbonyl-4-hydroxy)styrylbenzene, the results of which are
shown in Scheme 6. Applying the previously reported method
for the vinylation of 1,3-dibromo-4-fluorobenzene (12), using
the 2,4,6-trivinylcyclotriboroxane·pyridine complex, afforded
the desired 1-fluoro-2,4-divinylbenzene. Mizoroki-Heck cou-
pling with 2 equiv of 10 to 1-fluoro-2,4-divinylbenzene in
dioxane as the solvent provided the analogue-precursor 13 in a
57% isolated yield over two steps. Once again deprotection with
KOH in refluxing THF/H2O allowed for the quantitative
isolation of the desired FSB-analogue 14 providing an excellent
overall yield of 57%.
1
the title compound (44% yield) as a white solid. Mp 65.2 °C. H
NMR (400 MHz, CDCl3) δ (ppm) 8.08 (d, 1H, J ) 2.4 Hz), 7.64
(dd, 1H, J ) 2.4, 8.8 Hz), 6.87 (d, 1H, J ) 8.8 Hz), 1.73 (s, 6H).
13C NMR (100 MHz, CDCl3) δ (ppm) 160.0, 155.1, 139.3, 132.2,
119.3, 115.2, 115.0, 107.0, 26.0, 25.9. HRMS C10H9BrO3 [M +
Na+] calcd 278.9633, found 278.9633.
(E,E)-1-Fluoro-2,5-bis(2,2-dimethylbenzo[1,3]dioxin-4-one)styry-
lbenzene (11). 10 (80.2 mg, 0.31 mmol), HBF4P(t-Bu)3 (4.0 mg,
0.014 mmol), lithium chloride (6.0 mg, 0.14 mmol), and Cy2NMe
(61 µL, 0.28 mmol) were added to a sample vial in a glovebox. 4
(21.0 mg, 0.14 mmol) in DMF (1 mL) and PdCl2(COD) (2.0 mg,
0.007 mmol) in DMF (2 mL) were then added and the sample vial
was fitted with a Teflon sealed screwcap and removed from the
glovebox. The reaction mixture was reacted for 22 h at 100 °C
and then allowed to cool to 20 °C. Et2O (70 mL) was added and
the crude reaction mixture was washed with water (4 × 50 mL)
and brine (1 × 50 mL). The organic phase was dried over Na2SO4.
After concentration in vacuo the crude product was purified by flash
chromatography on silica gel with CH2Cl2 as eluent. Recrystalli-
zation in CH2Cl2 afforded 43 mg of the title compound (60% yield)
as colorless crystals. Mp 280 °C dec. 1H NMR (400 MHz, CDCl3)
δ (ppm) 8.12 (d, 1H, J ) 2.0 Hz), 8.11 (d, 1H, J ) 2.0 Hz), 7.74
In summary, we have reported on a greatly improved
synthesis of FSB in three linear steps with an overall yield of
34% from 1,4-dibromo-2-fluorobenzene (26% from 5-bromo-
salicylic acid) exploiting two palladium-catalyzed coupling
reactions in comparison to the 1.1% overall yield previously
3572 J. Org. Chem. Vol. 73, No. 9, 2008

(dd, 1H, J ) 2.0, 8.8 Hz), 7.67 (dd, 1H, J ) 2.0, 8.8 Hz), 7.56 (t,
1H, J ) 8.0 Hz), 7.28–7.04 (m, 6H), 6.99 (d, 2H, J ) 8.8 Hz),
1.76 (s, 12H). 13C NMR (100 MHz, CDCl3) δ (ppm) 162.1, 161.2,
159.6, 155.7, 138.44, 138.35, 134.6, 134.5, 132.5, 132.0, 128.91,
128.86, 127.9, 127.80, 127.77, 127.6, 127.5, 127.4, 124.4, 124.3,
122.9, 122.8, 121.4, 121.3, 117.81, 117.79, 113.92, 113.89, 113.5,
113.3, 106.79, 106.76, 26.0 (4C). 19F NMR (377 MHz, CDCl3) δ
(ppm) –118.0. HRMS C30H25FO6 [M + Na+] calcd 523.1533, found
523.1537.
7.76 (t, 1H, J ) 8.4 Hz), 7.47 (dd, 1H, J ) 1.6, 8.4 Hz), 7.43 (dd,
1H, J ) 1.6, 14 Hz), 7.34 (d, 1H, J ) 16.4 Hz), 7.33 (d, 1H, J )
16.4 Hz), 7.14 (d, 1H, J ) 16.4 Hz), 7.13 (d, 1H, J ) 16.4 Hz),
6.984 (d, 1H, J ) 8.4 Hz), 6. 977 (d, 1H, J ) 8.8 Hz). 13C NMR
(100 MHz, CDCl3) δ (ppm) 171.7, 171.6, 161.1, 161.0, 158.6,
138.6, 133.0, 132.9, 129.7, 128.8, 128.7, 128.2, 128.1, 127.3, 125.3,
123.5, 123.4, 122.8, 118.2, 117.73, 117.67, 113.6, 112.9, 112.7.
19F NMR (377 MHz, DMSO-d6) δ (ppm) –119.2.
(E,E)-1-Fluoro-2,5-bis(3-hydroxycarbonyl-4-hydroxy)styrylben-
zene (FSB)3. Potassium hydroxide (7.6 mg, 0.14 mmol) in H2O
(1.5 mL) was added to a solution of 11 (13.5 mg, 0.03 mmol) in
THF (3 mL) and the reaction mixture was refluxed for 10 h at
85 °C and then allowed to cool to 20 °C. The crude suspension
was acidified (pH ∼1) with HCl (2 M) and the precipitated solid
was collected and washed several times with water. Hot
acetonitrile was used to transfer the solid to a flask and coevapo-
ration with toluene and chloroform afforded 11.2 mg of FSB
(quantitative yield) as a yellow powder. 1H NMR (400 MHz,
DMSO-d6) δ (ppm) 8.00 (d, 1H, J ) 2 Hz), 7.98 (d, 1H, J ) 2
Hz), 7.83 (dd, 1H, J ) 2, 8.8 Hz), 7.79 (dd, 1H, J ) 2, 8.4 Hz),
Acknowledgment. We are grateful for generous financial
support from the Danish National Research Foundation, the
Carlsberg Foundation, the Lundbeck Foundation, and the
University of Aarhus.
Supporting Information Available: Experimental details and
copies of 1H NMR, 13C NMR, and 19F NMR spectra for
compounds 4, 10, 11, FSB, 13, and 14. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO7026189
J. Org. Chem. Vol. 73, No. 9, 2008 3573