Development of resin-to-resin transfer reactions (RRTR) using Sonogashira chemistry

Article abstract of DOI:10.1016/j.tet.2004.12.029

Sonogashira chemistry can be used according to the 'resin-to-resin transfer reaction' (RRTR) concept. Two fragments, one containing the halide moiety and the second one incorporating the alkyne functionality, are anchored on different solid supports using

Full text of DOI:10.1016/j.tet.2004.12.029

Tetrahedron 61 (2005) 2195–2201
Development of resin-to-resin transfer reactions (RRTR) using
Sonogashira chemistry*
†
Judit Tulla-Puche and George Barany
*
Department of Chemistry, University of Minnesota, 207 Pleasant Street S.E., Minneapolis, MN 55455, USA
Received 19 October 2004; revised 9 December 2004; accepted 10 December 2004
Available online 18 January 2005
Abstract—Sonogashira chemistry can be used according to the ‘resin-to-resin transfer reaction’ (RRTR) concept. Two fragments, one
containing the halide moiety and the second one incorporating the alkyne functionality, are anchored on different solid supports using allyl
and/or Wang-type linkages. Treatment with Pd(0) cleaves the allyl-linked fragment(s) which subsequently undergo Sonogashira coupling
under the same conditions.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
to be a valuable tool in the drug discovery process due to
easy work-up procedures and to the possibility of auto-
mation. Once a suitable scaffold can be created repro-
ducibly, diversity may be introduced at every synthetic step,
resulting in a large number of analogues.
Solid-phase synthesis, as pioneered by Merrifield, is the
preferred route for synthesis of biologically important
peptides.1 This approach has been extended to other
biopolymers, as well as to small organic molecules.2 Over
the past decade, solid-phase organic synthesis (SPOS) has
attracted considerable attention because it offers several
advantages with respect to classical solution-phase
methods.3 The solid-phase approach allows reactions to be
driven to completion by using excess reagents which can be
easily removed from desired intermediate products, bound
to insoluble polymeric supports, by filtration and washing
steps that occur without manipulative losses. Many organic
reactions have been adapted to be effective with solid
supports; these include peptide bond formation, Grignard
reactions, Michael addition, multiple component conden-
sation, diazotization, olefination, oxidation, reductive amin-
ation, cycloadditions, and metal-catalyzed cross-coupling.4
Although several synthetic drugs possess structures with
little resemblance to those of natural products, compounds
originating from natural sources remain a major class of
therapeutic agents. The design of libraries based on natural
products as templates is an area of active interest.6
However, to date only a small number of non-peptidic
natural products have been accessed from simple precursors
by SPOS.7 To make libraries based on complex natural
product templates, the use of semisynthetic approaches
represents a good compromise between solution-phase and
solid-phase strategies. An advanced intermediate is syn-
thesized in solution, and is then attached to the support and
used as a scaffold for combinatorial diversification at several
positions.
Combinatorial chemistry is an emerging field that allows for
preparation of large libraries of chemical species using
specified reaction sequences.5 Synthesis is often followed
up by high-throughput screening to identify those molecules
that are biologically active. Combinatorial SPOS has proven
An obviously advantageous option would be to develop a
convergent approach for solid-phase synthesis of complex
molecules, where two (or more) fragments of a molecule are
synthesized separately on different supports, and then
coupled via a ‘resin-to-resin transfer reaction’ (RRTR)8
(Scheme 1).‡ Thus, each fragment can be diversified
independently, increasing the overall number of possible
analogues. This approach also circumvents problems that
could be encountered with a linear SPOS strategy involving
* Taken in part from the Ph.D. Thesis of Judit Tulla-Puche, University of
Minnesota, February 2004.
Keywords: Solid-phase organic synthesis; Resin-to-resin transfer reactions;
Sonogashira coupling.
* Corresponding author. Tel.: C1 612 625 1028; fax: C1 612 626 7541;
e-mail: barany@umn.edu
‡ This article uses the ‘RRTR’ expression, coined by DeGrado and
coworkers (Ref. 8b). As enunciated earlier by Patchornik (Ref. 8a), the
overall concept is described by the moniker ‘shadchan’ chemistry.
† Current address: Almirall-Prodesfarma-Barcelona Science Park Unit,
Barcelona Science Park, Josep Samitier 1-5, 08028-Barcelona.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.12.029

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J. Tulla-Puche, G. Barany / Tetrahedron 61 (2005) 2195–2201
generally mild conditions used that do not require strict
exclusion of water or oxygen from solvent and atmo-
sphere.10 Specifically, Sonogashira coupling,11 which
involves coupling of aryl halides with alkynes, has been
investigated. Solid-phase Sonogashira coupling was
included as part of recently reported strategies to form
furopyridines and furoquinolines.12
Scheme 1. Schematic representation of resin-to-resin transfer reactions.
potentially incompatible reaction conditions. Although
some triphasic reactions between two solid supports were
explored in the 1970s as a way to probe mechanisms,9 only a
few examples have been reported that use RRTR for the
construction of carbon–carbon bonds.8
2. Results and discussion
2.1. Overall strategy
Three different strategies for resin-to-resin Sonogashira
transfer can be envisaged (Scheme 2). These are: (A)
attachment of an alkyne-substrate to an allyl resin, together
with attachment of an iodo-containing molecule to a
p-alkoxybenzyl ester (Wang) resin; (B) the opposite
The present work focuses on palladium-catalyzed cross-
couplings as key reactions for condensation of two
fragments. Such couplings have been applied successfully
in the solid-phase mode, and are popular because of the
Scheme 2. Strategies for resin-to-resin Sonogashira transfer.
Scheme 3. Synthesis of starting resins.

J. Tulla-Puche, G. Barany / Tetrahedron 61 (2005) 2195–2201
2197
Table 1. Efficiencies of loading various substrates onto solid supportsa
TFA treatment releases the Sonogashira coupling product
into solution. In the third strategy, both components are
released upon exposure to Pd(0), and Sonogashira coupling
occurs in solution.
Entry
Substrate
Yield (%)
Allyl resinb Wang resinc
1
89
97
86
98
2.2. Synthesis of starting resins
RRTR strategies require appropriate ‘donor’ and ‘acceptor’
resins. For construction of the allyl resin, a 2-bromocrotonic
acid linker13 was added to an aminomethyl resin
(1.6 mmol/g) by N,N0-diisopropylcarbodiimide (DIPCDI)-
mediated coupling (Scheme 3). Carboxylic acids, phenols,
and anilines were then loaded in the presence of CsI and
N,N-diisopropylethylamine (DIEA) in N,N-dimethylforma-
mide (DMF). For the ‘acceptor’ Wang-type resins (0.82–
1.2 mmol/g), Mitsunobu coupling allowed for attachment of
phenol and alcohol moieties, whereas carboxylic acids were
loaded by treatment with DIPCDI, 1-hydroxybenzotriazole
(HOBt), and 4-(N,N-dimethylamino)pyridine (DMAP). In
most cases, substrates were incorporated in moderate to
excellent yields, after a single coupling or (occasionally)
repeat coupling (Table 1). For allyl resins, yields ranged
from 89 to 97%, whereas for Wang resin, yields were
between 70 and 96%.
2
3
4
95d
91
70d
N.R.
e
5
6
92d
N.R.
96
a Anchoring chemistries are summarized in Scheme 3. Procedures are in
Sections 4.1.3, 4.1.4, and 4.1.5. N.R. means no reaction.
b Yield determined by elemental analysis for residual Br, and compared to
the theoretical loading.
2.3. Cleavage efficiencies
c Yield determined by DMTCl test (Ref. 3) to measure the remaining free
OH, which was compared to the theoretical loading.
d The reported yields involve two rounds of alkylation, following the
procedure of Section 4.1.3.
Previous studies to optimize conditions for cleavage of
amino acids and peptides from allyl resins have shown that
nucleophiles such as morpholine and nBu3SnH act as good
allyl scavengers, and Pd(PPh3)4 is the catalyst that usually
gives the best results.14 Since a goal of this work was to
effect concomitant cleavage/Sonogashira coupling,
additional conditions reported for Sonogashira chemistry
were explored.11 These included the use of piperidine,
DIEA, Et2NH or Et3N as bases, THF as solvent, and
Pd(PPh3)4 or Pd(PPh3)2Cl2 as catalysts. In the cases under
consideration, cleavages from allyl resins were optimal, at
e Not relevant because the substrate does not have a functional group that
can react with Wang resin.
strategy, with the iodo-substrate anchored to an allyl resin
and the alkyne moiety linked to Wang resin; and (C)
attachment of both components to the solid support via an
allyl linker. In the first two of these, Pd(0) treatment effects
cleavage of a molecule from the allyl resin and also
catalyzes the subsequent coupling to the second resin; later,
Table 2. Efficiencies of Pd(0)-mediated cleavages of resin-bound p-iodobenzoic acida
Entry
Catalyst (equiv)
Base (mL)
Solvent (mL)
Time (h)
Temp (8C)
Purity (%)
Yield (%)
1
2
3
4
5
6
7
8
9
10
Pd(PPh3)4 (0.3)
Pd(PPh3)4 (1.0)
Pd(PPh3)2Cl2 (2.0)
Pd(PPh3)4 (1.0)
Pd(PPh3)2Cl2 (2.0)
Pd(PPh3)2Cl2 (2.0)
Pd(PPh3)2Cl2 (2.0)
Pd(PPh3)2Cl2 (2.0)
Pd(PPh3)2Cl2 (1.0)
Pd(PPh3)4 (0.15)
Piperidine (1.0)
Piperidine (1.0)
Piperidine (1.0)
Morpholine (0.44)
DIEA (0.6)
DIEA (2.8)
Et3N (2.2)
Et2NH (0.43)
Bu3SnH (0.1)
Morpholine (0.7)
THF (1.0)
THF (1.0)
THF (1.0)
CH2Cl2–H2O (49:1) (5.0)
THF (6.0)
THF (6.0)
THF (6.0)
THF (7.0)
CH2Cl2 (3.0)
THF–DMSO–0.5 N aqueous
HCl (2:2:1) (1.25)
13
19
18
24
24
24
24
24
24
23
65
65
50
25
25
25
25
25
25
25
76
81
75
89
91
88
—
75
82
71
12
21
15
57
48
41
0
14
8
58
11
12
Pd(PPh3)4 (0.15)
Morpholine (2.7)
THF–0.5 N aqueous HCl) (1:1) 19
(3.0)
25
25
67
76
43
14
Pd(PPh3)2Cl2 (0.15) Morpholine (2.7)
THF–DMSO–0.5 N aqueous
HCl (2:2:1) (3.0)
24
a The substrate resin for cleavage (100 mg), prepared according to Section 4.1.2, was treated and analyzed further as described in Section 4.1.6. All equivalents
are with respect to the theoretical maximum loading (1.6 mmol/g). Yield was calculated based on the weight of product obtained, normalized for the purity
determined by analytical HPLC, and compared to the theoretical maximum based on the loading (1.6 mmol/g) of the starting resin.

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J. Tulla-Puche, G. Barany / Tetrahedron 61 (2005) 2195–2201
Table 3. Sonogashira RRTR using Strategy Aa
Entry
1
Product
Conditions
Purity (%)
81
Yield (%)
34
Pd(PPh3)2Cl2 (2.0 equiv), CuI (0.1 equiv), DIEA
(25 equiv), THF
2
3
Pd(PPh3)4 (1.0 equiv), CuI (0.1 equiv), morpholine
(50 equiv), CH2Cl2–H2O (49:1)
77
86
47
7
Pd(PPh3)4 (0.15 equiv), CuI (0.1 equiv), morpholine
(50 equiv), THF–DMSO–0.5 N aqueous HCl (2:2:1)
4
5
6
Pd(PPh3)2Cl2 (2.0 equiv), CuI (0.1 equiv), DIEA
(25 equiv), THF
84
71
—
41
26
0
Pd(PPh3)4 (1.0 equiv), CuI (0.1 equiv), morpholine
(50 equiv), CH2Cl2–H2O (49:1)
Pd(PPh3)4 (0.15 equiv), CuI (0.1 equiv), morpholine
(50 equiv), THF–DMSO–0.5 N aqueous HCl (2:2:1)
a The substrate resins (100 mg), prepared according to Sections 4.1.3 and 4.1.4, were treated and analyzed further as described in Section 4.1.7. All equivalents
are with respect to the theoretical maximum loading (1.2 mmol/g). Cleavages were performed by treatment with TFA–CH2Cl2 (1:1) for 90 min. Purity refers
to the relative area upon analytical HPLC of the main peak. Yield was calculated based on the weight of product obtained, normalized for the purity
determined by analytical HPLC, and compared to the theoretical maximum based on the loading (1.2 mmol/g) of the starting resin.
25 8C with Pd(PPh3)4 and morpholine in CH2Cl2–H2O
(49:1) or THF–DMSO–0.5 N aqueous HCl (2:2:1) (Table 2,
entries 4 and 10). The catalyst Pd(PPh3)2Cl2, used in
conjunction with DIEA in THF, also gave moderate yields
(Table 2, entry 5). Elevated temperatures did not improve
yields (Table 2, entries 1–3).
A (Table 3), where the alkyne moiety is linked to the allyl
resin and the iodophenol moiety is anchored to Wang resin
[eventually released, after RRTR, by treatment with TFA–
CH2Cl2 (1:1)], the system Pd(PPh3)4/CuI/morpholine in
THF–DMSO–0.5 N aqueous HCl (2:2:1), which was best
for cleavage, gave very low yields for coupling (Table 3,
entries 3 and 6). For two other systems tested, Pd(PPh3)2Cl2/
CuI/DIEA in THF and Pd(PPh3)4/CuI/morpholine in
CH2Cl2–H2O (49:1), overall yields ranged from 26 to
47% (Table 3, entries 1, 2, 4, and 5). For strategy B
(Table 4), where the iodophenol is linked to the allyl resin,
2.4. Resin-to-resin Sonogashira transfer reactions
Conditions described in the previous section were studied
for Sonogashira RRTR (Scheme 2; Tables 3–5). For strategy
Table 4. Sonogashira RRTR using strategy Ba
Entry
1
Product
Conditions
Purity (%)
81
Yield (%)
41
Pd(PPh3)2Cl2 (2.0 equiv), CuI (0.1 equiv), DIEA
(25 equiv), THF
2
3
Pd(PPh3)4 (1.0 equiv), CuI (0.1 equiv), morpholine
(50 equiv), CH2Cl2–H2O (49:1)
74
—
44
0
Pd(PPh3)4 (0.15 equiv), CuI (0.1 equiv), morpholine
(50 equiv), THF–DMSO–0.5 N aqueous HCl (2:2:1)
4
5
6
Pd(PPh3)2Cl2 (2.0 equiv), CuI (0.1 equiv), DIEA
(25 equiv), THF
83
79
—
28
35
0
Pd(PPh3)4 (1.0 equiv), CuI (0.1 equiv), morpholine
(50 equiv), CH2Cl2–H2O (49:1)
Pd(PPh3)4 (0.15 equiv), CuI (0.1 equiv), morpholine
(50 equiv), THF–DMSO–0.5 N aqueous HCl (2:2:1)
a The substrate resins (100 mg), prepared according to Sections 4.1.3 and 4.1.4, were treated and analyzed further as described in Section 4.1.7. All equivalents
are with respect to the theoretical maximum loading (1.2 mmol/g). Cleavages were performed by treatment with TFA–CH2Cl2 (1:1) for 90 min. Purity refers
to the relative area upon analytical HPLC of the main peak. Yield was calculated based on the weight of product obtained, normalized for the purity
determined by analytical HPLC, and compared to the theoretical maximum based on the loading (1.2 mmol/g) of the starting resin.

J. Tulla-Puche, G. Barany / Tetrahedron 61 (2005) 2195–2201
2199
Table 5. Sonogashira RRTR using strategy Ca
Entry
1
Product
Conditions
Purity (%)
78
Yield (%)
47
Pd(PPh3)2Cl2 (2.0 equiv), CuI (0.1 equiv), DIEA
(25 equiv), THF
2
3
Pd(PPh3)4 (1.0 equiv), CuI (0.1 equiv), morpholine
(50 equiv), CH2Cl2–H2O (49:1)
69
82
61
21
Pd(PPh3)4 (0.15 equiv), CuI (0.1 equiv), morpholine
(50 equiv), THF–DMSO–0.5 N aqueous HCl (2:2:1)
4
5
6
Pd(PPh3)2Cl2 (2.0 equiv), CuI (0.1 equiv), DIEA
(25 equiv), THF
80
79
86
42
55
13
Pd(PPh3)4 (1.0 equiv), CuI (0.1 equiv), morpholine
(50 equiv), CH2Cl2–H2O (49:1)
Pd(PPh3)4 (0.15 equiv), CuI (0.1 equiv), morpholine
(50 equiv), THF–DMSO–0.5 N aqueous HCl (2:2:1)
a The substrate resins (100 mg), prepared according to Section 4.1.3, were treated and analyzed further as described in Section 4.1.7. All equivalents are with
respect to the theoretical maximum loading (1.6 mmol/g). Purity refers to the relative area upon analytical HPLC of the main peak. Yield was calculated
based on the weight of product obtained, normalized for the purity determined by analytical HPLC, and compared to the theoretical maximum based on the
loading (1.6 mmol/g) of the starting resin.
and the alkyne moiety is anchored to Wang resin, results
were similar. Overall yields ranged between 28 and 44% in
the two better systems, and were poor in the system
optimized for cleavage.
4. Experimental
4.1. General
Wang resin and aminomethyl resin, both based on 1%
crosslinked polystyrene, were purchased from Novabio-
Strategy C (Table 5) gave the overall best results. In this
case, both substrates are anchored to allyl resins, and Pd(0)
treatments effecting cleavage of the substrates and sub-
sequent coupling in solution gave yields ranging from 42 to
61%. (Table 5, entries 1, 2, 4, and 5). Thus, Sonogashira
coupling chemistry is more efficient when both components
are free in solution.
¨
chem (Laufelfingen, Switzerland). CH2Cl2 was distilled
from CaH2, and tetrahydrofuran (THF) was distilled from
sodium/benzophenone. Sonogashira couplings were carried
out in capped vials under argon atmosphere. Analytical
HPLC was performed on a Beckman instrument configured
with two 112 pumps and a 165 wavelength variable
detector, using a Vydac C18 analytical reversed-phase
˚
Note that for the more successful RRTR sequences
(Strategies A, B, C; Tables 3–5), palladium is required in
levels equimolar or higher to the resin-bound substrate.
Thus, it is difficult to establish whether or not the metal
serves as a true catalyst. A mechanistic explanation for these
empirical observations is not yet forthcoming.
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% aqueous TFA–0.1% TFA in CH3CN were run, at
1.2 mL/min flow rate, from 9:1 to 1:1 over 40 min.
Preparative HPLC was carried out on a Waters instrument
using a Vydac C18 semi-preparative reversed-phase column
˚
(218TP1010; 10 mm particle size; 300 A; 1!25 cm) with
UV detection at 220 and 280 nm, using H2O and CH3CN as
eluents. Linear gradients of 0.1% aqueous TFA–0.1% TFA
in CH3CN were run, at 5.0 mL/min flow rate, from 9:1 to 1:1
3. Conclusions
1
over 60 min. H NMR spectra were acquired on a Varian
VI-500 spectrometer. Fast atom bombardment mass spec-
troscopy (FABMS) was performed on a VG7070E-HF mass
spectrometer.
The Sonogashira reaction has been evaluated as a transfer
reaction between two resins for solid-phase synthesis. In
transfer reactions, two converging fragments of a molecule
are synthesized, each on a different support, and then
coupled. The best results in the present studies were
obtained when both substrates were anchored to allyl resins.
Release of the two moieties by Pd(0), and subsequent
coupling in solution gave up to 61% yield. This strategy, or
variations thereof, should be applicable to SPOS of complex
molecules, with the opportunity to avoid tedious purification
of intermediates.
4.1.1. 2-Bromocrotonic acid. Following the literature,13
crotonic acid (20 g, 0.23 mol) and N-bromosuccimide
(NBS) (46 g, 0.25 mol) were dis0solved in dry toluene
(200 mL) and brought to reflux. 2,2 -Azobisisobutyronitrile
(AIBN) (0.5 g, 3.7 mmol) was added, and reflux was
continued for 2 h. Next, the reaction was cooled to 10 8C,
filtered, and the filtrate was evaporated. Recrystallization

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J. Tulla-Puche, G. Barany / Tetrahedron 61 (2005) 2195–2201
from cold CCl4 gave the title product as a white crystalline
solid (17.7 g, 47%). H NMR (CDCl3) d 7.12 (dd, JZ7.5,
procedure was unsuccessful for 6-iodo-2-picolin-5-ol, and
gave a 96% yield for propargyl alcohol (Table 1).
1
1.5 Hz, 1H), 6.05 (dd, JZ15.5, 1.5 Hz, 1H), 4.04 (dd, JZ
7.5, 1.5 Hz, 2H). FAB-MS m/z calcd 163.9, found 165.0
[MCH]C.
4.1.6. Representative procedure for cleavage of p-iodo-
benzoic acid from allyl resin. Resin-bound iodobenzoic
acid (100 mg), prepared according to Section 4.1.2, was
combined with the reagents and solvents indicated in
Table 2, as well as CuI (3 mg, 0.1 equiv). After reaction
for the indicated time under ambient conditions or with
heating, the resin was filtered. The filtrate was combined
with H2O (1 mL), and the organic phase was separated,
washed with H2O (3!1 mL) and brine (1!1 mL), dried
(MgSO4), and evaporated. The residue was dissolved in
MeOH (1 mL) and injected in the HPLC. Purities reported
on Table 2 refer to the relative area upon analytical HPLC of
the main peak, which corresponded to an authentic standard
of p-iodobenzoic acid.
4.1.2. Attachment of 2-bromocrotonic acid to amino-
methyl resin. Title resin (1.0 g, 1.6 mmol/g) was washed
with CH2Cl2 (3!2 min) and swollen in CH2Cl2–DMF (9:1)
(6 mL). 2-Bromocrotonic acid (0.79 g, 4.8 mmol) and
1-hydroxybenzotriazole (HOBt) (0.74 g, 4.8 mmol) were
dissolved in DMF (0.9 mL), and added to the resin. Next,
reaction was initiated by addition of N,N0-diisopropyl-
carbodiimide (DIPCDI) (0.74 mL, 4.8 mmol), and the
reaction proceeded for 24 h at 25 8C. The resin was washed
with DMF (3!2 min) and CH2Cl2 (3!2 min) and the
coupling was repeated once more. Yield: 98% (determined
from DMTCl test3).
4.1.3. Representative procedure for loading of substrates
onto 2-bromocrotonyl-resin.15 The title resin (0.45 g,
1.6 mmol/g) was suspended in DMF (2 mL) and reacted
with p-iodobenzoic acid (0.71 g, 2.88 mmol), cesium iodide
(0.75 g, 2.88 mmol), and DIEA (0.50 mL, 2.88 mmol) at
40 8C overnight, in the presence of several (w10 spheres)
4.1.7. General procedure for Sonogashira resin-to-resin
transfer reactions. The procedures for the three strategies
studied were essentially the same (see Tables 3–5). Resin-
bound p-iodobenzoic acid (62.5 mg, 1.6 mmol/g) and
resin-bound propargyl alcohol (100 mg, 1.2 mmol/g) were
weighed in a vial, and the appropriate solvent (~5 mL) was
added. After swelling the resins for 15 min, CuI (3 mg,
0.1 equiv) and the Pd catalyst (see Tables) were added, the
vial was capped with a septum, and argon was flushed
through for 15 min. The reaction mixture was agitated on a
mechanical shaker for the appropriate time, and was then
transferred to a polypropylene syringe. For strategies A and
B, the reagents were drained and the resins were washed
with THF (10!0.5 min), DMF (5!1 min), 0.02 M sodium
diethyl dithiocarbamate in DMF (3!15 min), DMF (3!
1 min) and CH2Cl2 (5!1 min). Cleavage was effected by
treatment with TFA–CH2Cl2 (1:1) for 1 h. For strategy C,
the reagents were drained and the resins washed with THF
(10!0.5 min), DMF (5!1 min), and CH2Cl2 (5!1 min).
The filtrate was evaporated, dissolved in EtOAc (2 mL) and
washed with H2O (3!2 mL), and brine (2!1 mL), dried
(MgSO4) and evaporated.
˚
3 A molecular sieves. Upon completion of the reaction, the
sieves were separated manually with a tweezer, and the
remaining brown resin was washed with DMF (3!1 min),
MeOH (3!1 min), and CH2Cl2 (3!1 min), and dried in
vacuo overnight. Yield: 89% (determined by elemental
analysis on residual Br). The same overall procedure,
applied to five other substrates, was carried out as
summarized further in Table 1, with yields listed under
the column ‘Allyl resin’.
4.1.4. Representative procedure for loading of car-
boxylic acids onto Wang resin. Title resin (1.0 g,
1.0 mmol/g) was washed with CH2Cl2 (3!1 min) and
DMF (3!1 min), and swollen in CH2Cl2–DMF (9:1). In a
vial, p-iodobenzoic acid (0.99 g, 4.0 mmol) and HOBt
(0.61 g, 4.0 mmol) were dissolved in DMF (2 mL), and
added to the resin. Coupling was initiated by addition of
DIPCDI (0.6 mL, 4.0 mmol) and 4-(N,N-dimethylamino)-
pyridine (DMAP) (12 mg, 0.1 mmol), and the reaction
proceeded overnight at 25 8C. The resin was washed with
DMF (3!2 min) and CH2Cl2 (3!2 min), and dried. Yield:
86% (determined from DMTCl test3). The same overall
procedure, applied to 3-iodo-4-methylbenzoic acid, gave a
98% yield.
4.1.8. 4-(3-Hydroxy-1-propynyl)benzoic acid. After the
experiment described in Table 5, entry 2, was carried out,
the product mixture was concentrated and applied to
preparative HPLC and eluted with H2O–CH3CN using
experimental conditions described in Section 4.1, to provide
the pure material which was characterized further: 1H NMR
(DMSO-d6) d 10.4 (broad s, 1H), 7.94 (d, JZ8.4 Hz, 2H),
7.69 (d, JZ8.4 Hz, 2H), 4.24 (s, 2H). FAB-MS m/z calcd
176.0, found 176.9 [MCH]C. This compound was obtained
previously by Bumagin and co-workers16 using an all-
solution Sonogashira coupling.
4.1.5. Representative procedure for loading of phenols
onto Wang resin. Title resin (0.75 g, 0.82 mmol/g) was
washed with CH2Cl2 (3!1 min) and DMF (3!1 min). In a
round-bottom flask, p-iodophenol (2.75 g, 12.5 mmol) was
dissolved in N-methylmorpholine (NMM) (50 mL), PPh3
(3.28 g, 12.5 mmol) was added, and the suspension was
stirred for 10 min until a clear solution was obtained. Next,
diisopropylazadicarboxylate (DIAD) (1.80 mL, 11.3 mmol)
was added dropwise, followed by addition of the Wang resin
(0.75 g, 0.82 mmol/g). The reaction was mechanically
stirred for 40 h at 25 8C, then washed with DMF (5!
2 min) and CH2Cl2, (5!2 min), and finally dried. Yield:
70% (determined by DMTCl test3). The same overall
4.1.9. 7-(4-Hydroxyphenyl)-6-heptynoic acid. After the
experiment described in Table 5, entry 5 was carried out, a
similar HPLC purification gave the characterizable
material: 1H NMR (CDCl3) d 6.83 (d, JZ8.4 Hz, 2H),
7.15 (d, JZ8.4 Hz, 2H), 2.34 (t, JZ7.2 Hz, 2H), 1.98 (t, JZ
7.0 Hz, 2H), 1.52 (m, 4H). FAB-MS m/z calcd 218.1, found
219.3 [MCH]C.

J. Tulla-Puche, G. Barany / Tetrahedron 61 (2005) 2195–2201
2201
Joseph, R.; Shair, M. D. J. Am. Chem. Soc. 2000, 122,
422–423.
Acknowledgements
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We thank Professor Fernando Albericio for encouragement
and critical reading of the manuscript. This work was
supported by the NIH (GM 42722).
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