CHAPTER 6

RESIN-TO-RESIN TRANSFER REACTIONS (RRTR) VIASONOGASHIRA COUPLING

Judit Tulla-Puche

Department of Chemistry, University of Minnesota, Minneapolis, MN; Institute forResearch in Biomedicine, Barcelona, Spain

Rita S. Majerle

Department of Chemistry, University of Minnesota, Minneapolis, MN; Departmentof Chemistry, Hamline University, St. Paul, MN

Fernando Albericio

Chemistry and Molecular Pharmacology Programme, Institute for Research inBiomedicine, Barcelona, Spain; Department of Organic Chemistry, University of

Barcelona, Spain

George Barany

Department of Chemistry, University of Minnesota, Minneapolis, MN

NH2

HOBr

O

Aminomethyl resi n

DIPCDI/HOBt

CH2Cl2-DMF (9:1)

BrO

NH

RCOOH or ArOH or RNH2

CsI, DIEA, DMF3Å molecular sieves

OO

NH

OArO

NH

NHRO

NH

or

or

R

O

(A)

CH2

Wang Resi n

PPh3, DIAD

(B)

2-Bromocrotyl resi n

O CH2 OH

HC C CH2 OH,

CH2 O CH2 O CH2 C CH

,

CH2Cl2

Synthesis of Starting Resins

Solid-Phase Organic Syntheses, Volume 2: Solid-Phase Palladium Chemistry, First Edition.Edited by Peter J. H. Scott.© 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.

59

60 RESIN-TO-RESIN TRANSFER REACTIONS (RRTR) VIA SONOGASHIRA COUPLING

OO

NH

OO

NH

O

I

O

HO

O

OH

O

OO

NH

O

I

OHO

O

OHPd

Pd

CH2CHC+

+

CH2Cl2-H2O (49:1)

CH2Cl2-H2O (49:1)

Resin-to-Resin Transfer

1 PROCEDURES

Materials were used as received unless indicated otherwise (note 1).

1.1 2-Bromocrotonyl-Resin

Aminomethyl resin (1.0 g, 1.6 mmol/g) was washed with CH2Cl2 (3 × 2min), swollen in CH2Cl2:N,N -dimethylformamide (DMF) (9:1, 6 mL),and placed into a 12-mL solid-phase synthesis reaction vessel. Next,a solution of 2-bromocrotonic acid (0.79 g, 4.8 mmol, note 2) and1-hydroxybenzotriazole (HOBt) (0.74 g, 4.8 mmol) in DMF (0.9 mL)was added, and the coupling reaction was initiated by the additionof N,N ′-diisopropylcarbodiimide (DIPCDI) (0.74 mL, 4.8 mmol). Thereaction mixture was agitated gently for 24 h at 25◦C, following which theresin was washed with DMF (3 × 2 mL) and CH2Cl2 (3 × 2 mL), andthe coupling was repeated. The yield was 98% (determined by DMTCltest, note 3).

1.2 Representative Procedure for Loading of Substrates onto2-Bromocrotonyl Resin

The functionalized resin (0.45 g, 1.6 mmol/g) was placed into a 6-mL solid-phase synthesis reaction vessel, suspended in DMF (2 mL), and reactedovernight at 40◦C with p-iodobenzoic acid (0.71 g, 2.9 mmol), cesiumiodide (0.75 g, 2.9 mmol), and diisopropylethylamine (DIEA) (0.50 mL,2.9 mmol) in the presence of several (∼10 spheres) 3 A molecular sieves.

PROCEDURES 61

On completion of the reaction, the sieves were removed manually, and theremaining brown resin was washed with DMF (3 × 1 min), MeOH (3 ×1 min), and CH2Cl2 (3 × 1 min), and dried in vacuo overnight. The yieldwas 89% (determined by elemental analysis of residual Br).

1.3 Representative Procedure for Loading of Phenols onto WangResin

Wang resin (0.75 g, 0.82 mmol/g) was placed into a 12-mL solid-phasesynthesis reaction vessel and washed with CH2Cl2 (3 × 1 min) and DMF(3 × 1 min). Meanwhile, working in a round bottom flask, p-iodophenol(2.75 g, 12.5 mmol) was dissolved in N-methylmorpholine (NMM) (50 mL).Next, PPh3 (3.28 g, 12.5 mmol) was added with stirring, until a clearsolution was obtained after about 10 min. Next, diisopropylazadicarboxylate(DIAD) (1.8 mL, 11.3 mmol) was added dropwise, followed by the solvatedWang resin (0.75 g, 0.82 mmol/g). The reaction was agitated gently for 40 hat 25◦C, then washed with DMF (5 × 2 min) and CH2Cl2 (5 × 2 min),and finally dried. The yield was 70% (determined by DMTCl test, note 3).

1.4 Representative Coupling of Propargyl Alcohols to Wang Resin

Wang resin (0.75 g, 0.82 mmol/g) was placed into a 12-mL solid-phasesynthesis reaction vessel, washed with CH2Cl2 (3 × 1 mL), swollen inCH2Cl2 (5 mL, 15 min), and drained. Next, a solution of propargyl alco-hol (0.475 mL, 10 equiv.) in CH2Cl2 (2 mL) was added to the swollenresin. Meanwhile, diisopropylazadicarboxylate (DIAD, 1.45 g, 10 equiv.)in CH2Cl2 (2.0 mL) was added dropwise to a solution of PPh3 (0.21 mL,10 equiv.) in CH2Cl2 (2.0 mL) over 3 min. This DIAD/PPh3 solution wasadded to the resin and agitated for 4 h at 25◦C, drained, washed with CH2Cl2(5 × 5 mL), and dried. The yield was 87% (determined by DMTCl test,note 3).

1.5 Representative Procedure for Cleavage of p-Iodobenzoic Acidfrom Allyl Resin

Allyl-resin-bound iodobenzoic acid (0.8 g, 0.82 mmol) was placed in a12-mL solid-phase synthesis reaction vessel and combined with a solution

62 RESIN-TO-RESIN TRANSFER REACTIONS (RRTR) VIA SONOGASHIRA COUPLING

of Pd(PPh3)2Cl2 (286 mg, 2.0 equiv.) and DIEA (85 μL, 0.6 equiv.) intetrahydrofuran (THF) (6.0 mL). The reaction was agitated for 24 h at25◦C, following which the resin was removed by filtration. The filtratewas combined with H2O (1 mL), and the organic phase was separated,washed with H2O (3 × 1 mL) and brine (1 × 1 mL), dried (MgSO4), andconcentrated in vacuo. The yield was 48%; purity, 91% (note 3).

1.6 General Procedure for Sonogashira Resin-to-Resin TransferReactions Using Allyl-Resin-Bound Aryl Iodide and

Wang-Resin-Bound Alkyne

Allyl-resin-bound p-iodobenzoic acid (62.5 mg, 1.6 mmol/g) and Wang-resin-bound propargyl alcohol (100 mg, 1.2 mmol/g) were placed in avial, CH2Cl2:H2O (49:1, 5 mL) was added, and the combined resins wereallowed to swell for 15 min. Next, CuI (3 mg, 0.1 equiv.), DIEA (7 mL, 25equiv.), and Pd(PPh3)2Cl2 (170 mg, 2.0 equiv.) were added, the vial wascapped with a septum, and argon was flushed through for 15 min (note 4).The reaction mixture was agitated on a mechanical shaker for 90 min andtransferred to a polypropylene syringe equipped with a fritted bottom. Thereagents and solvents were drained, and the resins were washed with THF(10 × 0.5 min), DMF (5 × 1 min), and CH2Cl2 (5 × 1 min). The filtratewas concentrated in vacuo, dissolved in EtOAc (2 mL), washed with H2O(3 × 2 mL) and brine (2 × 1 mL), dried (MgSO4), and concentrated invacuo. The yield was 41%; purity, 81%.

1.7 General Procedure for Sonogashira Resin-to-Resin TransferReactions Using Allyl-Resin-Bound Substrates

Allyl-resin-bound 7-heptynoic acid (100 mg, 1.6 mmol/g) and allyl-resin-bound p-iodobenzoic acid (100 mg, 1.2 mmol/g) were placed into a 12-mLsolid-phase synthesis reaction vessel, CH2Cl2:H2O (49:1, 5 mL) wasadded, and the combined resins were allowed to swell for 15 min. Next,CuI (3 mg, 0.1 equiv.), morpholine (0.7 mL, 50 equiv.), and Pd(PPh3)4(185 mg, 1.0 equiv.) were added; the vial was capped with a septum; andargon was flushed through for 15 min. The reaction mixture was agitatedon a mechanical shaker for 90 min and then transferred to a polypropylenesyringe equipped with a fritted bottom. The reagents were drained, andthe resins were washed with THF (10 × 0.5 min), DMF (5 × 1 min),CH2Cl2 (5 × 1 min), and 0.02 M sodium diethyl dithiocarbamate in DMF

DISCUSSION 63

(3 × 15 min). The resin was then washed with DMF (3 × 5 mL)and CH2Cl2. Cleavage from the resin was effected by treatment withTFA:CH2Cl2 (1:1) for 1 h. The filtrate was concentrated in vacuo,dissolved in EtOAc (2 mL) and washed with H2O (3 × 2 mL) and brine(2 × 1 mL), dried (MgSO4), and concentrated in vacuo. The yield was55%; purity, 79%.

2 DISCUSSION

To expand a chemist’s repertoire, it is useful to include convergentapproaches for solid-phase synthesis of complex molecules, where two (ormore) fragments of a molecule are synthesized separately on different sup-ports, and then coupled via a “resin-to-resin transfer reaction” (RRTR) [3].

Songogashira couplings [4] are palladium-catalyzed cross-couplingsbetween aryl halides and alkynes. These couplings have been appliedsuccessfully in the solid-phase mode, and mild conditions that do notrequire strict exclusion of water or oxygen from solvent and atmosphereshould be used [5].

The synthesis of starting resins in RRTR strategies require appropriate“donor” and “acceptor” resins. Three approaches to this are (i) attachmentof an alkyne substrate to an allyl resin, together with attachment of an iodo-containing molecule to a p-alkoxybenzyl ester (Wang) resin; (ii) the inversestrategy, with the iodo-substrate anchored to an allyl resin and the alkynemoiety linked to the Wang resin; and (iii) attachment of both componentsto the solid support via an allyl linker. In the first two of these, Pd(0) treat-ment effects cleavage of a molecule from the allyl resin and also catalyzesthe subsequent coupling to the second resin; later, TFA treatment releasesthe Sonogashira coupling product into solution. In the third strategy, bothcomponents are released on exposure to Pd(0), and Sonogashira couplingoccurs in solution. The strategy chosen depends on the starting alkynes andaryl halides chosen. Although coupling between two substrates, both linkedto allyl resin, worked best in our hands, it was not possible to immobilizepropargyl alcohol onto the allyl resin, and we were thus limited [6].

For construction of the allyl resin, a 2-bromocrotonic acid linker[1] was added to an aminomethyl resin by DIPCDI-mediated coupling.Carboxylic acids, phenols, and anilines were loaded in the presence ofCsI and DIEA in DMF. For the “acceptor” Wang-type resins, Mitsunobucoupling allowed for attachment of phenol and alcohol moieties, whereascarboxylic acids were loaded by treatment with DIPCDI, HOBt, and4-(N,N -dimethylamino)pyridine (DMAP). In most cases, substrates wereincorporated in moderate to excellent yields, after a single coupling or

64 RESIN-TO-RESIN TRANSFER REACTIONS (RRTR) VIA SONOGASHIRA COUPLING

(occasionally) repeat coupling. For allyl resins, yields ranged from 89% to97%, whereas for Wang resin, yields were between 70% and 96%.

Previous studies to optimize conditions for cleavage of amino acids andpeptides from allyl resins have shown that nucleophiles such as morpholineand nBu3SnH act as good allyl scavengers, and Pd(PPh3)4 is the cata-lyst that usually gives the best results [7]. Since a goal of this work was toeffect concomitant cleavage/Sonogashira coupling [4], we found that piperi-dine, DIEA, Et2NH, or Et3N as base; THF as solvent; and Pd(PPh3)4 orPd(PPh3)2Cl2 as catalyst were also suitable. In the cases under consider-ation, cleavages from allyl resins were optimal at 25◦C with Pd(PPh3)4and morpholine in CH2Cl2:H2O (49:1) or THF:DMSO:0.5 N aqueous HCl(2:2:1). The catalyst Pd(PPh3)2Cl2, used in conjunction with DIEA in THF,also gave moderate yields.

Conditions for cleavage of the substrates from the resin often wereorthogonal to conditions optimal for Sonogashira coupling. Where thealkyne moiety is linked to the allyl resin and the iodophenol moiety isanchored to Wang resin (eventually released, after RRTR, by treatmentwith TFA:CH2Cl2 (1:1)), the system Pd(PPh3)4/CuI/morpholine inTHF:DMSO:0.5 N aqueous HCl (2:2:1), which was best for cleavage,gave very low yields for coupling. For two other systems tested,Pd(PPh3)2Cl2/CuI/DIEA in THF and Pd(PPh3)4/CuI/morpholine inCH2Cl2:H2O (49:1), overall yields ranged from 26% to 47%. Where theiodophenol is linked to the allyl resin and the alkyne moiety is anchoredto the Wang resin, results were similar. Overall yields ranged between28% and 44% in better systems, and were poor in the system optimizedfor cleavage. Overall best results were obtained when both substrates areanchored to allyl resins, and Pd(0) treatments effecting cleavage of thesubstrates and subsequent coupling in solution gave yields ranging from42% to 61%, indicating that Sonogashira coupling chemistry is moreefficient when both components are free in solution.

For more successful RRTR sequences, palladium is required in levelsequimolar or higher to the resin-bound substrate. It is difficult to establishwhether or not the metal serves as a true catalyst. A mechanistic explanationfor these empirical observations is not yet forthcoming.

In conclusion, the Sonogashira reaction has been used as a transfer reac-tion between two resins for solid-phase synthesis. In transfer reactions,two converging fragments of a molecule are synthesized, each on a dif-ferent support, and then coupled. The best results in the present studieswere obtained when both substrates were anchored to allyl resins. Releaseof the two moieties by Pd(0), and subsequent coupling in solution gaveup to 61% yield. This strategy, or variations thereof, should be applicable

NOTES 65

to solid-phase organic synthesis (SPOS) of complex molecules, with theopportunity to avoid tedious purification of intermediates.

WASTE DISPOSAL INFORMATION

All toxic materials were disposed of in accordance with Prudent Practicesin the Laboratory (Washington, D.C.: National Academy Press, 1995).

APPENDIX: EXPERIMENTAL SUPPLEMENT

4-(3-Hydroxy-1-propynyl)benzoic acid. 1H NMR (DMSO-d6) δ10.4(broad s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 7.69 Hz, 2H) 4.24(s, 2H). FAB-MS m/z calcd 176.0, found 176.9 [M + H]+.

7-(4-Hydroxyphenyl)-6-heptynoic acid. 1H NMR (CDCl3) δ 6.83 (d, J= 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 2.34 (t, J = 7.2 Hz, 2H), 1.98(t, J = 7.0 Hz, 2H), 1.52 (m, 4H). FAB-MS m/z calcd 218.1, found 219.3[M + H]+.

NOTES

1. CH2Cl2 was distilled from CaH2, and THF was distilled from sodium/benzophenone.Sonogashira couplings were carried out in capped vials under a dry argon atmosphere.Analytical high performance liquid chromatography (HPLC) was performed using aVydac C18 analytical reversed-phase column (210TP54; 5 mm particle size; 300 A;0.46 × 25 cm) with UV detection at 220 and 280 nm. Linear gradients of 0.1% aqueousTFA:0.1% TFA in CH3CN were run, at 1.2 mL/min flow rate, from 9:1 to 1:1 over40 min. Preparative HPLC was carried out using a Vydac C18 semipreparative reversed-phase column (218TP1010; 10 mm particle size; 300 A; 1 × 25 cm) with UV detectionat 220 and 280 nm, using H2O and CH3CN as eluents. Linear gradients of 0.1% aqueousTFA:0.1% TFA in CH3CN were run, at 5.0 mL/min flow rate, from 9:1 to 1:1 over60 min.

2. 2-Bromocrotonic acid was synthesized as follows: a solution of crotonic acid (20 g,0.23 mol) and N -bromosuccimide (NBS) (46 g, 0.25 mol) in dry toluene (200 mL) wasbrought to reflux. Next, 2,2′-azobisisobutyronitrile (AIBN) (0.5 g, 3.7 mmol) was addedand reflux continued for 2 h. The reaction mixture was then cooled to 10◦C and filtered,and the filtrate was concentrated in vacuo. Recrystallization from cold CCl4 gave theproduct as a white crystalline solid (17.7 g, 47%) [1].

3. 4,4′-Dimethoxytrityl chloride (DMTCl) can be used to quantify free amines or alcoholson-resin [2]. The resin is prewashed with CH2Cl2 and treated with a stock solutionof 0.25 M 4,4′- dimethyoxytrityl chloride, 0.25 M (nBu)4NClO4, and 3% collidine inCH2Cl2 for 5 min. The resin is extensively washed with CH2Cl2 (7×) and treated with2% dichloroacetic acid in CH2Cl2 (7×) for 10 min. The acid washings are collected, andthe absorbance of the trityl cation is measured at 498 nm (ε = 76, 000 M−1 cm−1).

66 RESIN-TO-RESIN TRANSFER REACTIONS (RRTR) VIA SONOGASHIRA COUPLING

4. Pd(PPh3)4 or Pd(PPh3)2Cl2 can be used as a catalyst. Proven nucleophilic scavengersinclude DIEA, morpholine, and nBu3SnH.

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2. Bunn BA, editor. The combinatorial index. New York: Academic Press; 1998. p. 219.

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4. (a) Sonogashira K, Tohda Y, Hagihara N. Tetrahedron Lett 1975;50:4467; (b) Sono-gashira K. In: Diederich F, Stang PJ, editors. Volume 1, Metal-catalyzed cross-couplingreactions. Weinheim, Germany: Wiley-VCH; 1998. p 203; (c) Sonogashira K. In: NeigishiE-I, editor. Volume 1, Handbook of organopalladium chemistry for organic synthesis.Hoboken (NJ): John Wiley and Sons; 2002. p. 493.

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