Solution phase combinatorial synthesis of biaryl libraries employing heterogeneous conditions for catalysis and isolation with size exclusion chromatography for purification

Article abstract of DOI:10.1021/jo982234v

A convenient and effective approach to the solution phase synthesis of biaryl libraries from iodoarenes is described enlisting 10% Pd-C as an inexpensive and readily available supported catalyst. Isolation and purification of small library mixtures, individual library members, and intermediates in the multistep sequence by a combination of liquid-liquid and liquid-solid extractions and size exclusion chromatography are detailed.

Full text of DOI:10.1021/jo982234v

2422
J . Org. Chem. 1999, 64, 2422-2427
Solu tion P h a se Com bin a tor ia l Syn th esis of Bia r yl Libr a r ies
Em p loyin g Heter ogen eou s Con d ition s for Ca ta lysis a n d Isola tion
w ith Size Exclu sion Ch r om a togr a p h y for P u r ifica tion
Dale L. Boger,*,† J oel Goldberg,† and Carl-Magnus Andersson‡,§
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La J olla, California 92037 and Lund University, Organic Chemistry 1,
P.O. Box 124, S-221 00 Lund, Sweden
Received November 9, 1998
A convenient and effective approach to the solution phase synthesis of biaryl libraries from
iodoarenes is described enlisting 10% Pd-C as an inexpensive and readily available supported
catalyst. Isolation and purification of small library mixtures, individual library members, and
intermediates in the multistep sequence by a combination of liquid-liquid and liquid-solid
extractions and size exclusion chromatography are detailed.
In tr od u ction
tionally in combination with olefin metathesis reactions,10
to produce multimilligram quantities of library mixtures
or individual compounds in multistep sequences. Typi-
cally, liquid-liquid or liquid-solid extractive purification
was used to reliably produce libraries of high purity for
screening purposes. As a complement to these structur-
ally flexible libraries, we have extended the convergent,
solution phase dimerization strategy to the preparation
of more rigid and densely functionalized systems. On the
basis of considerations related to target compound shape
and size as well as library deconvolution, biaryl formation
was selected as one of the primary strategies. However,
since the approach would constitute a rare example of
solution phase combinatorial synthesis based on carbon-
carbon bond formation under conditions where extractive
purification is precluded, a concern was the development
of reaction conditions and purification methods allowing
reliable production of highly pure biaryl mixtures.11
Herein, we disclose studies which address these concerns
Ligand-induced dimerization or oligomerization has
been established as a general mechanism for the activa-
tion of certain cell surface receptors.1 Important examples
of this, where hormone antagonists or agonists would be
of pharmacological significance, include tyrosine kinase
receptors2 and cytokine receptors.3 Accumulating evi-
dence that such receptor dimerization events may be
driven by hormone binding involving only a relatively
small cluster of residues,4 accompanied by stabilizing
inter-receptor interactions, has driven the search for
small molecule hormone antagonists and agonists. Pep-
tide5 as well as nonpeptide6 agonists promoting receptor
homodimerization have recently been identified through
the random screening of compound libraries. Comple-
mentary to such approaches, solution phase combinato-
rial chemistry7 provides a unique potential for generating
C2-symmetrical diversity through the synthetic conver-
gent dimerization of combinatorially assembled building
blocks. We have recently developed such solution phase
approaches which utilized amide bond formation,8,9 op-
(9) Boger, D. L.; Goldberg, J .; J iang, W.; Chai, W.; Ducray, P.; Lee,
J . K.; Ozer, R. S.; Andersson, C.-M. Bioorg. Med. Chem. 1998, 6, 1347.
Boger, D. L.; Ducray, P.; Chai, W.; J iang, W.; Goldberg, J . Bioorg. Med.
Chem. Lett. 1998, 8, 2339. Boger, D. L.; Ozer, R. S.; Andersson, C.-M.
Bioorg. Med. Chem. Lett. 1997, 7, 1903.
(10) Boger, D. L.; Chai, W.; J in, Q. J . Am. Chem. Soc. 1998, 120,
7220. Boger, D. L.; Chai, W. Tetrahedron 1998, 54, 3955. Boger, D. L.;
Chai, W.; Ozer, R. S.; Andersson, C.-M. Bioorg. Med. Chem. Lett. 1997,
7, 463.
† The Scripps Research Institute.
‡ Lund University.
§ Present address: Acadia Pharmaceuticals, Fabriksparken 58, 2620
Glostrup, Denmark.
(1) (a) Hinterding, K.; Alonso-Diaz, D.; Waldmann, H. Angew.
Chem., Int. Ed. Engl. 1998, 37, 688. (b) Klemm, J . D.; Schreiber, S.
L.; Crabtree, G. R. Annu. Rev. Immunol. 1998, 16, 569.
(2) Weiss, A.; Schlessinger J . Cell 1998, 94, 277.
(3) Reineke, U.; Schneider-Mergener J . Angew. Chem., Int. Ed. 1998,
37, 769.
(4) Wells, J . A. Science 1996, 273, 449.
(5) Livnah, O.; Stura, E. A.; J ohnson, D. L.; Middleton, S. A.;
Mulcahy, L. S.; Wrighton, N. C.; Dower, W. J .; J olliffe, L. K.; Wilson,
I. A. Science 1996, 273, 464.
(6) Tian, S.; Lamb, P.; King, A. G.; Miller, S. G.; Kessler, L.; Luengo,
J . I.; Averill, L.; J ohnson, R. K.; Gleason, J . G.; Pelus, L. M.; Dillon, S.
B.; Rosen, J . Science 1998, 281, 257.
(7) For recent reviews on solution phase combinatorial chemistry,
see: Merrit, A. T. Comb. Chem. High Throughput Screening 1998, 1,
57. Coe, D.; Storer, R. Annu. Rep. Comb. Chem. Mol. Div. 1997, 1, 50.
For a review on polymer assisted solution-phase library synthesis,
see: Flynn, D. L.; Devraj, R. V.; Parlow, J . J . Curr. Op. Drug Discuss.
Dev. 1998, 1, 41.
(8) Cheng, S.; Comer, D. D.; Williams, J . P.; Myers, P. L.; Boger, D.
L. J . Am. Chem. Soc. 1996, 118, 2567. Boger, D. L.; Tarby, C. M.;
Myers, P. L.; Caporale, L. H. J . Am. Chem. Soc. 1996, 118, 2109.
Cheng, S.; Tarby, C. M.; Comer, D. D.; Williams, J . P.; Caporale, L.
H.; Myers, P. L.; Boger, D. L. Bioorg. Med. Chem. 1996, 4, 727.
(11) Biaryl libraries, see: Pryor, K. E.; Shipps, G. W., J r.; Skyler,
D. A.; Rebek, J ., J r. Tetrahedron 1998, 54, 4107 and Selway, C. N.;
Terrett, N. K. Bioorg. Med. Chem. 1996, 4, 645. (solution phase). For
solid-phase biaryl coupling libraries, see: Pavia, M. R.; Cohen, M. P.;
Dilley, G. J .; Dubuc, G. R.; Durgin, T. L.; Forman, F. W.; Hediger, M.
E.; Milot, G.; Powers, T. S.; Sucholeiki, I.; Zhou, S.; Hangaver, D. G.
Bioorg. Med. Chem. 1996, 4, 659. Blettner, C. G.; Ko¨nig, W. A.; Stenzel,
W.; Schotten, T. Synlett 1998, 295 (on soluble polymers). Neustadt, B.
R.; Smith, E. M.; Lindo, N.; Nechuta, T.; Bronnenkant, A.; Wu, A.;
Armstrong, L.; Kumar, C. Bioorg. Med. Chem. Lett. 1998, 8, 2395.
Chamoin, S.; Houldsworth, S.; Sniekus, V. Tetrahedron Lett. 1998,
39, 4175. Chamoin, S.; Houldsworth, S.; Kruse, C. G.; Bakker, I.;
Sniekus, V. Tetrahedron Lett. 1998, 39, 4179. Yoo, S.-E.; Seo, J -.S.;
Yi, K.-Y.; Gong, Y.-D. Tetrahedron Lett. 1997, 38, 1203. Guiles, J . W.;
J ohnson, S. G.; Murray, W. V. J . Org. Chem. 1996, 61, 5169. Larhed,
M.; Lindeberg, G.; Hallberg, A. Tetrahedron Lett. 1996, 37, 8219. Han,
Y.; Walker, S. D.; Young, R. N. Tetrahedron Lett. 1996, 37, 2703.
Marquais, S.; Arlt, M. Tetrahedron Lett. 1996, 37, 5491. Frenette, R.;
Friesen, R. W. Tetrahedron Lett. 1994, 35, 9177. Brown, S. D.;
Armstrong, R. W. J . Am. Chem. Soc. 1996, 118, 6331. Chenera, B.;
Finkelstein, J . A.; Veber, D. F. J . Am. Chem. Soc. 1995, 117, 11999.
Backes, B. J .; Ellman, J . A. J . Am. Chem. Soc. 1994, 116, 11171.
Forman, F. W.; Sucholeiki, I. J . Org. Chem. 1995, 60, 523.
10.1021/jo982234v CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/16/1999

Combinatorial Synthesis of Biaryl Libraries
J . Org. Chem., Vol. 64, No. 7, 1999 2423
using a representative set of 5-haloisophthalic acid
derivatives as coupling partners.
reaction in anhydrous DMF. A range of substrate con-
centrations were examined (0.1-1 M), and the more
dilute reaction mixtures provided greater amounts of
competitive reduction.
Resu lts a n d Discu ssion
Although the coupling results with the aryl bromide
1a were modest, the iodide 1b provided a very efficient
and selective route to the biaryl 2 under our modified
conditions. At concentrations ranging from 0.2-1.0 M in
DMF, 1a afforded the homocoupling product 2 very
cleanly using 0.1 equiv of Pd-C and 1.5 equiv of Et3N
with only a trace of 3 detected by NMR. Applying these
conditions to a diamide representative of the library
building blocks, N,N′-bis(4-fluorophenethyl)-5-iodoisoph-
thalamide14 (Ar 1-I, see below) established that the het-
erogeneous catalytic protocol was effective for homocou-
pling of such substrates. By using 0.1 equiv of Pd-C and
1.5 equiv of Et3N at 100 °C for 16 h (0.5 M in DMF), the
desired biaryl (Ar 1-Ar 1) was isolated in 93% yield (eq 3).
Rea ction Con d ition s. Anticipating coupling mixtures
of 5-haloisophthalamides in which the variations in the
N-substituents would not strongly affect the coupling
rate, the commercially available haloesters 1a and 1b
were chosen as prototypical model substrates. Our start-
ing point for reaction optimization was a recent com-
munication by Lemaire and co-workers,12 in which biaryls
and bipyridyls were obtained through homocoupling of
aromatic bromides or iodides in the presence of Pd(OAc)2
and Bu4NBr. In these studies, the highest coupling yields
resulted from reactions performed in a DMF, H2O,
2-propanol, K2CO3 mixture (eq 1). However, since basic
aqueous conditions typically are not compatible with
hydrolyzable functional groups, and therefore potentially
unreliable for combinatorial biaryl formation, modifica-
tions to the published procedure were examined (eq 2).
Similar reactions performed on several 5-iodoisophthal-
amides provided good to excellent yields of the biaryls
with only traces of reduction products observed by NMR
and/or HPLC. Subsequent experiments performed in
order to assess the rates of the homocoupling reactions
indicated that complete consumption of the starting
iodide required as little as 1-2 h. For mixture syntheses,
however, the overnight reaction time was retained to
ensure complete conversion since no appreciable degra-
dation of the products could be detected.
P r ep a r a tion of Com bin a tor ia l Libr a r ies: Syn th e-
sis. The building blocks for the mixture syntheses were
prepared in good yields from commercially available 1b
as shown in Scheme 1. A stock solution of the diacid
dichloride was portioned into solutions of the appropriate
amine and Hu¨nig’s base in either CH2Cl2 or THF.
Isolation of the pure diamides (Ar -I) was accomplished
either by liquid-liquid extractive workup or precipitation
from dilute hydrochloric acid, and they were stored as
stock solutions in DMF. The amine entries included in
the prototypical libraries discussed herein (Scheme 1)
were chosen to sample functional groups that would
highlight the generality of the procedure, and to span a
range of polarities15 allowing reasonable separation on
HPLC. Thus, primary and secondary amines containing
oxidizable (alcohol) and hydrolytically labile (carbamate,
acetal) functionality were included. For identification
purposes, the corresponding reduction byproducts (Ar -
H) were prepared analogously from commercially avail-
able isophthaloyl dichloride. Enlisting the protocol for
preparing homodimers discussed above, the mixed cou-
Using the bromide 1a , reaction in DMF in the presence
of Bu4NBr (0.5 equiv), Et3N (1 equiv), and Pd(OAc)2 (0.1
equiv) provided a 2:1 mixture of coupled product 2 and
reduced product 3 with complete consumption of starting
material after 16 h at 115 °C. In efforts to simplify
product isolation, heterogeneous catalysts were exam-
ined, and replacing Pd(OAc)2 with palladium on carbon
(10% Pd-C) was productive,13 although the total con-
sumption of 1a required treatment with 0.2 equiv of
Pd-C for 24 h at 100 °C and provided a slightly less
favorable 1-2:1 mixture of the products 2 and 3. Further
examination of the reaction conditions showed that the
Bu4NBr could be excluded with no effect on the reaction
outcome, that the amount of Et3N was an important
variable since increasing its concentration provided a
faster reaction rate, and that K2CO3 did not support the
(12) Penalva, V.; Hassan, J .; Lavenot, L.; Gozzi, C.; Lemaire, M.
Tetrahedron Lett. 1998, 39, 2559. For the use of Pd(OAc)2 in neat Et3N
(100 °C), see: Clark, F. R. S.; Norman, R. O. C.; Thomas, C. B. J . Chem.
Soc., Perkin Trans. 1 1975, 121.
(13) For an early example of the use of PdBC in Heck arylations,
see: Hallberg, A.; Westfelt, L.; Andersson, C.-M. Synth. Commun.
1985, 15, 1131.
(14) Although the corresponding bromide also provided the desired
homodimer under identical conditions, the iodide was preferred due
to a faster conversion and much lower propensity for competitive
reduction.
(15) Aryl iodides Ar 1-I through Ar 5-I showed Rf values between 0.1
and 0.8 in EtOAc.

2424 J . Org. Chem., Vol. 64, No. 7, 1999
Boger et al.
Sch em e 1
pling reactions were examined. Employing the iodides
Ar 1-I through Ar 5-I in a pairwise fashion as described
generically in eq 4, the reaction afforded the expected
2:1:1 ratio of hetero- and homodimers. A typical HPLC
trace of a crude product mixture obtained after extractive
workup (see below) is shown in Figure 1. The yields
varied from 75-95% depending on the scale and workup
procedure used (see below), but the ratio between het-
erodimers, homodimers, and reduction products was
invariant, illustrating that the iodide reactivities were
not influenced by the nature of the amide substituents.
F igu r e 2. (a) HPLC trace (254 nm) of the crude reaction
mixture obtained from homocoupling of Ar 1-I, Ar 2-I, and Ar 5-I
(2:2:2:1:1:1 mixture of unsymmetrical and symmetrical biar-
yls). Reduction products and starting iodides appear at 7, 12,
and 26 min and 15, 22, and 35 min, respectively. (b) HPLC
trace (254 nm) of the purified product mixture obtained from
homocoupling of Ar 1-I, Ar 2-I, and Ar 2-I.
The statistical dimerization of n building blocks (Ar -
I) should deliver a mixture of [n(n + 1)]/2 products.
According to the present protocol, the product mixture
should further consist of n homodimers Ar m -Ar m and
[[n(n + 1)]/2] - n heterodimers Ar n -Ar m in relative,
individual molar ratios of 1:2. Thus, increasing the
number of building blocks favors the relative concentra-
tion of the heterodimers. Increasing the mixture com-
plexity to six compounds by reacting three iodides still
allowed good separation by HPLC, and the mixture
resulting from homocoupling of Ar 1-I, Ar 2-I, and Ar 5-I
serves well to illustrate this. The composition of the
mixture was qualitatively consistent with the expected
statistical distribution (Figure 2a) and deviations from
the theoretical 2:2:2:1:1:1 ratio observed upon integration
of the peaks (actual values were 2.0:2.2:2.4:1.0:1.3:1.0)
were presumably derived from slight differences in
extinction coefficients of the products at 254 nm. The
mixture represented in Figure 2 was obtained in quan-
titative yield on a 75 µmol scale (32 mg). Similar results
F igu r e 1. HPLC trace (254 nm) of the crude reaction mixture
obtained from homocoupling of Ar 1-I and Ar 2-I. Reduction
products (Ar-H) and starting iodides (Ar-I) appear at 12 and
26 min, and 22 and 35 min, respectively (arrows). See
Experimental Section for HPLC conditions.

Combinatorial Synthesis of Biaryl Libraries
J . Org. Chem., Vol. 64, No. 7, 1999 2425
Ta ble 1. Molecu la r Weigh ts of Bia r yls P r ep a r ed
Therefore, we routinely utilize ion-exchange resins (liquid-
solid extraction) for the isolation of mixtures in order not
to compromise their original composition. Thus, the
mixtures disclosed herein and related larger libraries
were isolated by diluting the crude reaction mixtures
with CHCl3/CH3OH, brief stirring with a mixture of acidic
and basic ion-exchange resins, filtration, and evaporation.
The biaryl mixtures were generally isolated as yellow oils
which solidified on standing using this technique.
P u r ifica tion . Transition metal-catalyzed homo- or
cross-coupling reactions are frequently accompanied by
reduction of the substrates.16 Although the levels of re-
duction products we observed with the 5-iodoisophthal-
amides were not a significant concern, more extensive
reduction has been observed with other substrates and
could become a limiting factor in extending the method-
ology. Recognition that the dimerization inherently doubles
the molecular size of the library components irrespective
of the linkage strategy suggested purification via size
exclusion chromatography. The product biaryls Ar -Ar
possess molecular weights of 726.9-1047.1 (Table 1),
whereas the starting materials Ar -I and reduction byprod-
ucts Ar -H spanned molecular weights of 490.4-650.5 and
354.5-524.6, respectively. A proper grouping of diversity
entries should readily produce similar or better size
characteristics for virtually any library constructed ac-
cording to similar principles. We have found that simple
gravity size exclusion chromatography is an effective
method for purifying such biaryl libraries. This technique
allows the use of a variety of polar protic and aprotic
solvents in combination with a very robust and reusable
polymeric stationary phase. A comparison of the HPLC
traces reproduced in Figures 2 and 3 illustrates the
effectiveness of the technique (examples used THF as the
mobile phase). Removal of lower molecular weight im-
purities occurred without complications due to the dif-
ferences in polarity of the mixture components, and the
separation was sufficiently good to allow simple filtration
collection of only a few large (10 mL) fractions. Similar
separations have been successfully conducted with mix-
tures containing higher levels of reduction byproducts
and with larger mixtures of compounds. Importantly, the
stoichiometric integrity of the desired combinatorial
biaryl mixture was unaltered by size exclusion chroma-
tography, making it especially useful for purifying diverse
mixtures, for which standard adsorption or partition-
based chromatography would be more difficult.
F igu r e 3. (a) HPLC trace (254 nm) of the crude mixture of
15 biaryls Ar 1-Ar 1-Ar 5-Ar 5(2:2:2:2:2:2:2:2:2:2:1:1:1:1:1) ob-
tained from homocoupling of Ar 1-5-I. Identification of compo-
nents was accomplished using HPLC-MS. (b) HPLC trace (254
nm) of the purified mixture of biaryls Ar 1-Ar 1-Ar 5-Ar 5.
were observed upon expanding the library size, although
chromatographic analysis becomes increasingly difficult.
The mixture of 15 biaryls produced by reacting all five
iodides (Ar 1-I-Ar 5-I) was characterized by HPLC-MS,
which confirmed the presence of all the expected coupling
products (Figure 3a), and integration of well-resolved
peaks was consistent with a statistical product distribu-
tion.
Isola tion . Three different methods have been em-
ployed for the isolation of the individual coupling prod-
ucts or biaryl mixtures. The heterogeneous reaction
conditions provided for convenient filtration removal of
the catalyst, leaving only removal of polar reaction
byproducts (triethylammonium iodide and excess Et3N)
and solvent. Although the latter was readily accom-
plished through liquid-liquid extraction using EtOAc
and 10% aqueous hydrochloric acid, liquid-solid extrac-
tion procedures8 have proven especially useful. In addi-
tion, dilution of the reaction mixture followed by filtration
through a short pad of silica gel has been used with good
results, but might present complications with mixtures
containing components of highly dissimilar polarity.15
Con clu sion s
Biaryl libraries may be prepared in high yields and
under mild conditions through the solution phase, and
palladium-catalyzed homocoupling of iodoarene mixtures
and palladium on carbon may be used as a convenient
(16) See: Hassan, J .; Penalva, V.; Lavenot, L.; Gozzi, C.; Lemaire,
M. Tetrahedron 1998, 54, 13793.

2426 J . Org. Chem., Vol. 64, No. 7, 1999
Boger et al.
Ar 4-I: 1H NMR 8.53 (d, 2H, J ) 7.5 Hz), 8.28 (m, 3H), 4.04
(q, 4H, J ) 7.1 Hz), 3.97 (br m, 6H, partially overlapping with
q), 2.91 (br m, 4H), 1.80 (br m, 4H), 1.42 (br m, 4H), 1.18 (t,
6H, J ) 7.1 Hz); HRMS calcd for C24H33IN4O6 733.0499 (M +
Cs+), found 733.0525.
and inexpensive supported catalyst for these reactions.
The direct convergent solution phase dimerization of
combinatorially assembled iodoarene building blocks
provides an effective and rapid route to symmetrical and
unsymmetrical structures that would be precluded by
typical solid-phase techniques where the combining com-
ponents would typically be on mutually exclusive solid-
phases. Purification of such library mixtures based on
molecular size allows for mixture purification with com-
plete conservation of the product mixture composition.
1
Ar 5-I: H NMR 8.65 (t, 2H, J ) 5.5 Hz), 8.28 (s, 3H), 4.35
(t, 2H, J ) 5.2 Hz), 3.38 (m, 4H), 3.24 (m, 4H), 1.56-1.20 (m,
16H); HRMS calcd for C20H31IN2O4 491.1407 (M + H+), found
491.1393.
Syn th esis of Hom od im er s. The preparation of Ar 1-Ar 1
is typical: a vial containing Et3N (20 µL, 0.15 mmol) and 10%
Pd-C (10.6 mg, 0.01 mmol) was treated with a solution of
Ar 1-I (53.4 mg, 0.1 mmol) in DMF (0.2 mL). The vial was
capped and stirred at 100 °C (oil bath) for 16 h.
Exp er im en ta l Section
Gen er a l. 1H NMR spectra were recorded at 250 MHz in
DMSO-d6, and chemical shifts were determined using residual
solvent protons set to 2.50 ppm as reference. HRMS was
performed using the FAB technique. Mixtures were character-
ized using electrospray ionization. HPLC analyses were per-
formed on a Bondapak C18, 125 Å column (3.9 × 300 mm) using
a flow rate of 1 mL/min. A gradient going from 50% to 80%
CH3OH in 0.07% aqueous trifluoroacetic acid over 40 min was
employed. DMF and CH3OH were HPLC grade. Palladium on
carbon (10% Pd-C) was purchased from Aldrich, Bio-Beads
S-X8 resin was purchased from Bio-Rad Laboratories, and
dimethyl 5-iodoisophthalate was purchased from Trans World
Chemicals.
Extr a ctive Wor k u p . The reaction mixture was diluted
with 50 mL of EtOAc and filtered into a separatory funnel.
The organic layer was washed with 10% aqueous HCl (50 mL),
H2O (50 mL), and saturated aqueous NaCl (25 mL), dried (Na2-
SO4), and concentrated to afford 38 mg (93%) of Ar 1-Ar 1 as a
yellow oil, which gave off-white crystals upon trituration with
CH3OH.
Wor k u p Usin g Silica Gel F iltr a tion . The crude reaction
mixture was diluted with 4 mL of an EtOAc/CH3OH mixture
(95/5). The solution was filtered through 0.7 g of silica gel in
a pasteur pipet, which was rinsed with an additional 15 mL
of the solvent mixture. Evaporation of the solvents afforded a
75% yield of the biaryl as a pale oil.
Bu ild in g Block s. Dimethyl 5-iodoisophthalate (5.6 g) was
dissolved in a mixture of CH3OH (50 mL) and H2O (20 mL).
LiOH‚H2O (3.0 g) was added, and the mixture was stirred
overnight. Addition of H2O (200 mL) and extraction with
EtOAc followed by acidification (HCl) and filtration gave
5-iodoisophthalic acid as a moist white solid (6.4 g). Without
drying, the acid (2.5 g) was dissolved in SOCl2 (20 mL)
containing one drop of DMF. After the initial foaming had
ceased, the mixture was warmed at reflux for 4 h. The SOCl2
was removed by rotary evaporation followed by concentration
from anhydrous toluene twice. Removal of residual solvent
under vacuum provided 2.47 g of an oil (lit. mp 43-44 °C)17
which was dissolved in 10 mL of anhydrous toluene and
refrigerated. The following procedures are representative for
the preparation of 5-iodoisophthalamides (Ar -I) or isophthal-
amides (Ar -H).
N,N′-Bis[2-(4-flu or op h en yl)eth yl]-5-iod oisop h th a la m -
id e (Ar 1-I). A mixture of 4-fluorophenethylamine (1.5 mmol,
209 mg) and i-Pr2NEt (1.5 mmol, 194 mg, 0.26 mL) in
anhydrous CH2Cl2 (10 mL) was treated with 0.7 mL (0.5 mmol)
of a stock solution of 5-iodoisophthaloyl chloride (exothermic).
A precipitate was observed after reaction overnight. EtOAc
(50 mL) was added, and the solution was washed sequentially
with 10% aqueous HCl (2H), 5% aqueous K2CO3, and saturated
aqueous NaCl. Drying (Na2SO4) and evaporation afforded the
title diamide as a white solid (0.24 g, 88%).
Wor k u p Usin g Ion Exch a n ge Resin s. The reaction
mixture was diluted to 10 mL using a CHCl3/CH3OH mixture
(1/1). Strongly acidic (Dowex 50WX8-200, 1 g) and strongly
basic (Amberlite IRA-400, 0.5 g) ion-exchange resins were
added, and the mixture was stirred for
a few minutes.
Filtration and additional washing of the resins and catalyst
followed by concentration gave an 82% yield of the biaryl as a
yellow oil.
Ar 1-Ar 1: 1H NMR 8.89 (t, 4H, J ) 5.5 Hz), 8.32 (s, 6H), 7.32
(m, 8H), 7.13 (m, 8H), 3.53 (m, 8H), 2.88 (t, 8H, J ) 7.2 Hz);
HRMS calcd for C48H42F4N4O4 947.2197 (M + Cs+), found
947.2228. The presence of minor amounts (<5%) of the
reduction product (Ar 1-H) was evident from diagnostic peaks
at 8.25 (d), 7.91 (dd) and 7.54 (t). HPLC analysis confirmed a
high purity of the biaryl product (47 min retention time) with
only trace peaks accounting for reduction product (26 min) and
starting material (35 min).
Gen er a l P r oced u r e for th e Gen er a tion of Com bin a -
tor ia l Mixtu r es. The synthesis of the mixture of six biaryls
(Figure 2) is representative: a 4 mL vial equipped with a stir
bar was charged with 10% Pd-C (7.5 mg, 0.1 equiv) and Et3N
(15 µL, 0.11 mmol, 1.5 equiv). The iodides (Ar 1-I, Ar 2-I, and
Ar 5-I) were added via syringe (125 µL of 0.2 M stock solutions
in DMF, 25 µmol each), the vial was capped and warmed with
stirring at 100 °C for 16 h. After cooling, the reaction mixture
was diluted with 10 mL of a CHCl3/CH3OH mixture (1/1) and
transferred to a 20 mL vial containing ion-exchange resins
(0.75 g of Dowex 50WX8-200 and 0.38 g of Amberlite IRA-
400). After stirring for 5 min, filtration and evaporation
afforded 32 mg (quantitative yield based on the weighted
average molecular weight of 845 g/mol) of a yellow oil. HPLC
analysis (see Figure 2) indicated the presence of six biaryl
products in a distribution reflecting a statistical dimerization.
Similarly, the mixture coupling of all five iodides provided
a statistical mixture of 15 biaryls. HPLC-MS analysis of the
product mixture confirmed its integrity; a Bondapak C18, 125
Å column (3.9 × 300 mm) was used with a flow rate of 1 mL/
min and a gradient of 50% to 80% CH3OH in 0.07% aqueous
trifluoroacetic acid over 40 min (Figure 3); ESMS pos: t ) 14.8
min, M + H+ 831 (Ar 3-Ar 3); t ) 17.2 min, M + H+ 779 (Ar 3-
Ar 5); t ) 19.1 min, M + H+ 727 (Ar 5-Ar 5); t ) 22.3 min, M +
H+ 939 (Ar 2-Ar 3); t ) 23.5 min, M + H+ 887 (Ar 2-Ar 5); t )
25.9 min, M + H+ 889 (Ar 3-Ar 4); t ) 26.8 min, M + H+ 837
(Ar 4-Ar 5); t ) 28.0 min, M + H+ 1047 (Ar 2-Ar 2); t ) 30.4 min,
M + H+ 997 (Ar 2-Ar 4); t ) 33.1 min, M + H+ 771 (Ar 1-Ar 5)
and 823 (Ar 1-Ar 3); t ) 34.1 min, M + H+ 947 (Ar 4-Ar 4); t )
36.6 min, M + H+ 931 (Ar 1-Ar 2); t ) 39.9 min, M + H+ 881
(Ar 1-Ar 4); t ) 44.2 min, M + H+ 815 (Ar 1-Ar 1).
N,N′-Bis(6-h yd r oxyh exyl)-5-iod oisop h th a la m id e (Ar 5-
I). A mixture of 6-aminohexan-1-ol (1.8 mmol, 210 mg) and
i-Pr2NEt (1.73 mmol, 0.3 mL) in 10 mL of anhydrous CH2Cl2
was treated with 0.7 mL (0.5 mmol) of 5-iodoisophthaloyl
chloride in toluene. After stirring overnight, the product was
isolated through addition of 20 mL of 10% aqueous HCl and
filtration. The solid was washed with H2O and dried in vacuo
to give 0.13 g (51%).
1
Ar 1-I: H NMR 8.75 (t, 2H, J ) 5.5 Hz), 8.24 (s, 3H), 7.25
(m, 4H), 7.10 (m, 4H), 3.43 (m, 4H), 2.81 (t, 4H, J ) 7.2 Hz);
HRMS calcd for C24H21F2IN2O2 666.9670 (M + Cs+), found
666.9652.
Ar 2-I: 1H NMR 9.16 (t, 2H, J ) 5.7 Hz), 8.38 (d, 1H, J )
1.4 Hz), 8.36 (d, 2H, J ) 1.4 Hz), 6.65 (s, 4H), 4.41 (d, 4H, J
) 5.7 Hz), 3.75 (s, 12H), 3.62 (s, 6H); HRMS calcd for C28H31
-
IN2O8 783.0180 (M + Cs+), found 783.0206.
Ar 3-I: 1H NMR 7.83 (d, 2H, J ) 1.4 Hz), 7.46 (t, 1H, 1.4
Hz), 3.90 (s, 8H), 3.64 (br s, 4H), 1.62 (br s, 8H). Remaining
protons were obscured by the H2O signal at 3.3 ppm; HRMS
calcd for C22H27IN2O6 674.9968 (M + Cs+), found 674.9987.
(17) Kraft, A. Liebigs Ann. 1997, 1463.

Combinatorial Synthesis of Biaryl Libraries
J . Org. Chem., Vol. 64, No. 7, 1999 2427
Size Exclu sion Ch r om a togr a p h y. A standard flash col-
umn charged with 100 g of Bio-Beads SX-8 resin was used for
mixture purification. The column was typically washed with
10-50 mL of HPLC grade THF before the sample (5-25 mg
dissolved in 1 mL of THF) was loaded via syringe. Additional
THF was introduced on top of the resin and the column
connected to a THF reservoir using standard Teflon tubing.
Elution under gravity conditions gave a flow rate of about 2
mL/min. The first 100 mL of eluent were recirculated, and then
five 10 mL fractions were collected. The most concentrated
fraction (invariably the second 10 mL fraction in our case) was
selected (by spotting on a TLC plate and visually estimating
UV absorption) and concentrated under a stream of N2. HPLC
analysis of the main fraction as well as subsequent fractions
showed efficient removal of reduction byproducts and traces
of starting materials. Typical HPLC traces are reproduced in
Figures 2 and 3.
Ack n ow led gm en t. This work was supported finan-
cially by the National Institutes of Health (CA78045),
J ohnson and J ohnson, and the award of a predoctoral
fellowship (J .G., NDSEG-1995). C.-M. Andersson grate-
fully acknowledges Knut and Alice Wallenbergs Stiftelse
and The Swedish Natural Science Research Council for
financial support. We also thank Professor M. Lemaire
for making a preprint of reference 16 available and Dr.
K. Wa¨rnmark for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
Ar n -I and Ar 1-Ar 1. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O982234V