Pd-mediated C-C and C-S bond formation on solid support: A scope and limitations study

Article abstract of DOI:10.1055/s-1998-22661

The scope and limitations of Pd(0)-mediated coupling reactions between aromatic halides linked to a polystyrene resin and boronic acid derivatives (Suzuki coupling), aromatic and vinylic tin compounds (Stille coupling), as well as thiols are reported. For all reactions, conditions were optimized and evaluated with various reagents. In many cases, upon cleavage from the solid support, products were obtained in excellent yields. In most cases, the optimized reaction conditions are superior to those previously reported in the literature.

Full text of DOI:10.1055/s-1998-22661

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Pd-Mediated C-C and C-S Bond Formation on Solid Support: A Scope and Limitations Study
*
Sebastian Wendeborn, Sabine Berteina, Wolfgang K.-D. Brill, Alain De Mesmaeker
Novartis AG, Basel, Switzerland
Email: alain.de_mesmaeker@cp.novartis.com; Fax: +41-61-697-8529
Received 20 January 1998
Abstract. The scope and limitations of Pd(0)-mediated coupling
reactions between aromatic halides linked to a polystyrene resin and
boronic acid derivatives (Suzuki coupling), aromatic and vinylic tin
compounds (Stille coupling), as well as thiols are reported. For all
reactions, conditions were optimized and evaluated with various
reagents. In many cases, upon cleavage from the solid support, products
were obtained in excellent yields. In most cases, the optimized reaction
conditions are superior to those previously reported in the literature.
The emergence of combinatorial chemistry stimulated intensive efforts
in the application of reactions broadly used in solution to the solid phase
1
synthesis. Among the versatile reactions already investigated on solid
support, the Pd-mediated C-C bond formation received much attention
due to its enormous potential for the derivatization of functionalized
2
structures. A major feature of the Pd-catalyzed coupling reactions
between aromatic (or vinylic) iodides and various nucleophilic reagents
is their compatibility with most functional groups, which, consequently,
do not require to be protected. Although several recent reports
encouraged the use of Pd-mediated C-C bond-forming reactions on
solid support, generally applicable procedures leading to single products
of defined structures in high purity and high overall yield were not yet
3
available. We describe here improved procedures resulting from our
scope and limitation studies which allow, in many cases, high
conversion of the starting material into the desired products. The
improved procedures described here were identified using polystyrene
bound aryl iodides. Later on, these procedures were successfully
translated with only marginal changes to various highly functionalized
4
core structures.
For the work described, we used three linkers for the connection of
5
aromatic iodides to polystyrene. Aromatic aryl halides attached
through a base labile linker were readily obtained as outlined in Scheme
1. The p-alkoxybenzoate esters 5, 6 and 7 were resistant to basic
conditions required for the Suzuki coupling, but were found to be
sufficiently labile for transesterification with NaOMe at RT, allowing
efficient recovery of reaction products from the solid phase. The acid
6
labile Rink linker 9 was also used in this study (Scheme 2). In many
instances, we observed that products obtained from the base labile linker
5 had higher purity compared with those obtained from the Rink-resin 9.
It must be stressed, that all reactions reported here were performed on a
scale (typically 150-200 mg beads; 0.7 mmol/g) allowing the isolation
activated by electron withdrawing substituents) are much less suitable
for solid phase Suzuki coupling reactions. Whereas the use of both
catalysts, Pd(Ph P) and Pd(OAc) results in complete consumption of
3
4
2
of at least 20 mg crude product. Yields, therefore, refer to the weight of
starting material, the reaction under ‘ligand free’ conditions is much
1
the crude products corrected by the purity evaluated by H NMR (400
1
8
cleaner based on H-NMR of the crude product (entries 3 and 4).
MHz). In some cases, weight of products purified by flash
chromatography are reported in parentheses. The structure of all
Conditions recently recommended in the literature for solution phase
9
chemistry (entries 9, 10) gave unsatisfactory results, even at 140°C.
1
compounds were established by H-NMR and mass spectroscopy. The
Entries 5-8 elude to the time required for the reaction to reach
completion: the starting material is not completely consumed if reaction
times are less than 12h. This is in contrast to rather short reaction times
in control experiments performed in solution, where completion was
reached in less than 1h under similar conditions. Therefore, reactions
were run for 24h to assure complete conversion. In most cases, these
reaction conditions gave satisfactory to excellent results, with a few
exceptions (entries 13, 15, 32). In case of the aldehyde containing
boronic acid (entry 15) we were uncertain whether the coupling- or the
use of HPLC for yield- and purity determination was avoided, thus
allowing a fair comparison of results obtained by traditional solution
chemistry and solid phase chemistry.
7
Suzuki couplings. Table 1 summarizes the results obtained using 21
boronic acid derivatives in the Pd-mediated couplings with 5 and 7
under various reaction conditions. Entries 1 and 2 compare the coupling
efficiency of an aryl bromide vs. an aryl iodide under our standard
reaction conditions (B). These results suggest that aryl bromides (not

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13
unreacted aryl iodide were recovered. The use of methoxy ethanol
instead of the dioxane-H O mixture disfavors the coupling reaction
2
14
(compare entry 30, Table 1 with entry 6 Table 3).
15,16
Stille couplings.
Upon screening several reaction conditions, two
protocols were found to work best for Stille coupling on solid phase
(Table 4). The procedure involving Pd (dba) and triphenyl arsine gave
2
3
16a
superior results in most cases.
Electron poor aryl tin reagents gave
less satisfactory results (entry 3). It is worthwhile pointing out, that
coupling results with electron rich aryltin derivatives (entries 8, 9, Table
4) were much inferior to the results obtained with the corresponding
17
boronic acids (entry 33, Table 1). The Stille coupling reactions were
also performed on aryl iodides bound to the Rink resin with comparable
18
results (data not shown).
Coupling with terminal thiols. The coupling of thiols with aromatic
19
halides has received relatively little attention.
We decided to
investigate this reaction for the elaboration of combinatorial libraries,
realizing the large number of commercially available thiols and the rich
chemistry of sulfur containing compounds. Table 5 summarizes our
results. All thiols coupled in excellent yields under optimized reaction
cleavage reactions were responsible for the reduced yields. Additional
experiments (Table 3) revealed, that coupling yields with 4-
formylphenylboronic acid are low irrespective of the reaction and
cleavage conditions used. In some cases, reactions did not reach
completion (for example entries 23 - 28): doubling the amount of all
reagents lead to increased yields and crude product quality (B→C).
However, yields were even higher when double couplings were
10
performed (B→D). Noteworthy is the distinct difference in reactivity
between the 2-thiopheneboronic acid and the 3-thiopheneboronic acid
(entries 23 - 28). Both substrates gave incomplete conversion under the
standard conditions B. However, the 3-thiopheneboronic acid required
more stringent reaction conditions than the 2-thiopheneboronic acid
(entries 25 and 28). The 4-hydroxymethylphenylboronic acid (entry 29)
gave poor results, presumably due to low solubility of the reagent under
the reaction conditions, even though this substrate gave excellent results
in control experiments in solution. Ortho electron withdrawing
substituents on the phenylboronic acids disfavor the coupling,
presumably due to a combination of steric hindrance and increased rate
11b
of base catalyzed deboronation (entries 16 - 19).
Incomplete
conversion is observed even when larger excess of reagent (conditions
C) or double coupling (conditions D) are employed. The cyclic boronate
ester (entry 20) can be used efficiently in the Pd-mediated coupling
reaction under nonaqueous reaction conditions, where deboronation
11
does not take place. This modification is also useful when non
aqueous reaction conditions are required for other reasons. In contrast to
the electron withdrawing ortho substituents, electron releasing ortho
substituents on the boronic acid gave satisfactory results, even though
conditions C or D are required to reach complete reactions. Alkyl-9BBN
12
derivatives can be coupled efficiently to aryl halides (entry 40).
Coupling with the corresponding 2-iodobenzylalcohols 6 proceeded
also well, as shown in Table 2 (compare entry 2, Table 2 with entry 22,
Table 1).
In order to determine whether low coupling yields with 4-
formylphenylboronic acid were due to the strongly basic coupling and/
or cleavage conditions (entry 15, Table 1), we performed the coupling
with an aryl iodide bound to the solid support by the acid labile Rink
linker (9, Table 3). Even under less basic reaction conditions (entries 1-
5, Table 3) substituting K CO by KF, and acidic cleavage conditions,
2
3
the yields of the desired product remained low and large amounts of

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conditions. Only one example (entries 2, 3) required the use of double
amount of reagents in order to achieve complete conversion. For a
successful reaction, it was important to premix all reagents at 60°C,
prior to adding the thiol. Otherwise, reactions did not reach completion,
20
presumably due to unproductive binding of the thiol to the catalyst.
Although Pd-mediated reactions on solid support of aryl iodides with
tin, boronic acid and thiol derivatives furnished generally the desired
products in high yield and purity, it is necessary to use a large excess of
reagents, substantial amounts of “catalyst”, and long reaction times at
elevated temperature. In several cases, even under optimized conditions,
unsatisfactory results were obtained.

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References and Notes
1.
a) Balkenhohl, F.; von dem Bussche-Hünnefeld, C.; Lansky, A.;
Zechel, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2288. b)
Hermkens, P.H.H.; Ottenheijm, H.C.J.; Rees, D. Tetrahedron
1996, 52, 4527. c) Gallop, M.A.; Barrett, R.W.; Dower, W.J.;
Foder, S.P.A.; Gordon, E.M. J. Med. Chem. 1994, 37, 1233. d)
Gordon, E.M.; Barrett, R.W.; Dower, W.J.; Foder, S.P.A.; Gallop,
M.A. J. Med. Chem. 1994, 37, 1385.
2.
For Stille couplings see: a) Forman, F.W.; Sucholeiki, I. J. Org.
Chem. 1995, 60, 523. b) Plunkett, M.J.; Ellman, J.A. J. Am. Chem.
Soc. 1995, 117, 3306. c) Deshpande, M.S. Tetrahedron Lett. 1994,
35, 5613. For Suzuki couplings see: d) Frenette, R.; Friesen, R.W.
Tetrahedron Lett. 1994, 35, 9177. e) Backes, B.J.; Ellman, J.A. J.
Am. Chem. Soc. 1994, 116, 11171. f) Piettre, S.R.; Baltzer, S.
Tetrahedron Lett. 1997, 38, 1197. g) Yoo, S.; Seo, J.; Yi, K., Gong,
Y. Tetrahedron Lett. 1997, 38, 1203. For Heck reactions see: h)
Yu, K.-L.; Deshpande, M.S.; Dolatrai, M.V. Tetrahedron Lett.
1994, 35, 8919. i) Hiroshige, M.; Hauske, J.R.; Zhou, P.
Tetrahedron Lett. 1995, 36, 4567. j) For others see: Young, K.Y.;
Nelson, J.C.; Moore, J.S. J. Am. Chem. Soc. 1994, 116, 10841. For
use of polymer bound Pd-catalyst see: k) Jang, S.-B. Tetrahedron
Lett. 1997, 38, 1793.
3.
In most examples (reference 2) much more reactive electron poor
aromatic halides are used in the Pd-coupling reactions.
4.
5.
Manuscripts in preparation.
Polystyrene beads, cross-linked with 1% divinyl benzene were
used for all experiments; functionalization was approximately 0.7
mmol/g.
6.
7.
Rink, H. Tetrahedron Lett. 1987, 28, 3787.
Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513.
8.
9.
Wallow, T.I.; Novak, B.M. J. Org. Chem. 1994, 59, 5034.
Beller, M.; Fischer, H.; Herrmann, W.A.; Öfele, K.; Brossmer, C.
Angew. Chem., Int. Ed. Eng. 1995, 34, 1848.
10. Double couplings imply complete removal of all reagents and side
products through washing of the resin before submitting it under
identical coupling conditions for a second time. If the washing
step is avoided, no significantly increased yields were observed,
presumably due to accumulation of catalyst poisoning side
products.
11. a) Sato, M; Miyaura, N.; Suzuki, A. Chem. Lett. 1989, 1405. b)
Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 3, 207.
12. Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314.
13. Wright, S.W.; Hageman, D.L.; McClure, L.D. J. Org. Chem. 1994,
59, 6095.
14. Representative protocol for the Suzuki-coupling on the solid
phase: To resin 5 (0.4 g, 0.205 mmol) were added freshly distilled
dioxane (3.5 ml,), p-trifluoromethylbenzene boronic acid (156
mg, 0.820 mmol) and K CO (138 mg, 1.85 mmol) dissolved in
2
3
H O (0.56 ml) and the resulting suspension was degassed with
2
argon for 20 min. Pd(OAc) (5 mg, 0.02 mmol) was added at once
2
and the reaction was shaken at 100°C for 24h. The solid phase was
filtered and washed with 5 ml each of dioxane (6 x), H O (6 x),
2
EtOH:H O (1:1, 3 x), EtOH (3 x) and Et O (3 x). The resin was
2
2
dried under high vacuum and suspended in dioxane (6.6 ml).
Sodium (28 mg, 1.23 mmol) was dissolved in MeOH (1.6 ml) and
the resulting solution of NaOMe was added. The reaction mixture
was shaken for 24h at RT. The resin was filtered off and further

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extracted with 5 ml each of dioxane (4 x), H O (6 x), phosphate
concentration 43.8 mg (98%) of crude product (entry 2, Table 4)
was obtained which was shown to be 98% pure by H-NMR (400
2
1
buffer, pH=7 (3 x), dioxane (3 x), EtOH:H O (1:1, 3 x), EtOH (3
2
x), ether (3 x). The combined liquid phases were concentrated and
MHz).
the resulting solid was extracted with CH Cl . After filtration
2
2
19. a) Kosugi, M.; Shimizu, T.; Migita, T. Chem. Lett. 1978, 13. b)
Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.; Kato, Y.; Kosugi,
M. Bull. Chem. Soc. Jpn. 1980, 53, 1385. c) Ciattini, P.G.; Morera,
E.; Ortar, G. Tetrahedron Lett. 1995, 36, 4133. d) Rajagopalan, S.;
Radke, G.; Evans, M.; Tomich, J.M. Synth. Commun. 1996, 26,
1431.
through celite and concentration 46.7 mg (90.3%) of crude
product (entry 11, Table 1) was obtained which was shown to be
1
pure by H-NMR (400 MHz).
15. Kwon, H.B.; McKee, B.H.; Stille, J.K. J. Org. Chem. 1990, 55,
3114.
16. a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585. b)
Aliprantis, A.O.; Canary, J.W. J. Am. Chem. Soc. 1994, 116, 6985.
20. Representative protocol for the coupling with terminal thiols on
the solid phase: To resin 5 (0.3 g, 0.154 mmol) was added DMA
(6.1 ml), 1,1’-bis(diphenylphosphino)ferrocene (68.1 mg, 0.123
17. Segelstein, B.E.; Butler, T.W.; Chenard, B.L. J. Org. Chem. 1995,
60, 12.
mmol), tris(dibenzylideneacetone)dipalladium(0) (28.2 mg, 0.031
i
mmol) and Et N Pr (158 mg, 1.23 mmol) and the resulting
18. Representative protocol for the Stille-coupling on the solid phase:
To resin 5 (0.5 g, 0.256 mmol) were added freshly distilled
dioxane (5.1 ml), 2-(tributylstannyl)furan (297 mg, 0.769 mmol)
2
suspension was degassed for 20 min. 3-Phenylpropyl mercaptan
(93 mg, 0.614 mmol) was added and the reaction mixture was
shaken at 60°C for 24h. The solid phase was filtered and washed
with 5 ml each of dioxane (6 x), CH Cl (6 x), MeOH (3 x),
and Ph As (32 mg, 0.103 mmol) and the resulting suspension was
3
degassed with argon for 20 min. Pd (dba) (23.5 mg, 0.026 mmol)
2
2
2
3
dioxane (3 x) and Et O (3 x). The resin was dried under vacuum
was added at once and the reaction was shaken at 50°C for 24h.
The solid phase was filtered and washed with 5 ml each of
2
and suspended in dioxane (4.9 ml). Sodium (21 mg, 0.922 mmol)
was dissolved in MeOH (1.2 ml) and the resulting solution of
NaOMe was added. The reaction mixture was shaken for 24h at
RT. The resin was filtered off and further extracted with 5 ml each
dioxane (6 x), CH Cl (6 x), MeOH (3 x), dioxane (3 x) and Et O
2
2
2
(3 x). The resin was dried under vacuum and suspended in
dioxane (8.3 ml). Sodium (35 mg, 1.53 mmol) was dissolved in
MeOH (2.1 ml) and the resulting solution of NaOMe was added.
The reaction mixture was shaken for 24h at RT. The resin was
filtered off and further extracted with 5 ml each of dioxane (4 x),
of dioxane (4 x), H O (6 x), phosphate buffer, pH=7 (3 x), dioxane
2
(3 x), EtOH:H O (1:1, 3 x), EtOH (3 x), ether (3 x). The combined
2
liquid phases were concentrated and the resulting solid was
H O (6 x), phosphate buffer, pH=7 (3 x), dioxane (3 x),
extracted with CH Cl . After filtration through celite and
2 2
2
EtOH:H O (1:1, 3 x), EtOH (3 x), ether (3 x). The combined
liquid phases were concentrated and the resulting solid was
concentration 38 mg (96%) of crude product (entry 1, Table 5)
was obtained which was shown to be pure by H-NMR (400
2
1
extracted with CH Cl . After filtration through celite and
MHz).
2
2