Universal solid-phase approach for the immobilization, derivatization, and resin-to-resin transfer reactions of boronic acids

Article abstract of DOI:10.1021/jo0106501

Boronic acid-containing molecules are employed in a broad range of biological, medicinal, and synthetic applications. These compounds, however, tend to be difficult to handle by solution-phase methods. Herein, this problem is addressed with the development of the first general solid-phase approach for the derivatization of functionalized boronic acids. This approach is based on the use of a diethanolamine resin anchor that facilitates boronic acid immobilization by avoiding the need for exhaustive removal of water in the esterification process. The immobilization of a wide variety of boronic acids onto N,N-diethanolaminomethyl polystyrene (DEAM-PS, 1) can be performed within minutes by simple stirring in anhydrous solvents at room temperature. Evidence for the formation of a bicyclic diethanolamine boronate with putative N-B coordination was shown by ¹H NMR analysis of DEAM-PS-supported p-tolylboronic acid. The hydrolytic cleavage of the same model boronic acid from the DEAM-PS resin was studied by UV spectroscopy. Hydrolysis and attachment were shown to occur under a rapidly attained equilibrium, and a large excess of water (> 32 equiv) is required to effect a practically quantitative release of boronic acids from DEAM-PS. Despite their relative sensitivity to water and alcohols, DEAM-PS-bound arylboronic acids functionalized with a formyl, a bromomethyl, a carboxyl, or an amino group can be transformed in good to excellent yields into a wide variety of amines, amides, anilides, and ureas, respectively. Ugi multicomponent reactions on DEAM-PS-supported aminobenzeneboronic acids, derivatization of multifunctional arylboronic acids, and sequential reactions can also be carried out efficiently. These new DEAM-PS-supported arylboronic acids can be employed directly into resin-to-resin transfer reactions (RRTR). This type of multiresin process helps eliminate time-consuming cleavage and transfer operations, thereby considerably simplifying the outlook of combinatorial library synthesis by manual or automated means. This concept was illustrated by a set of optimized procedures for the Suzuki cross-coupling and the borono-Mannich reactions.

Full text of DOI:10.1021/jo0106501

J . Org. Chem. 2002, 67, 3-15
3
Articles
Un iver sa l Solid -P h a se Ap p r oa ch for th e Im m obiliza tion ,
Der iva tiza tion , a n d Resin -to-Resin Tr a n sfer Rea ction s of Bor on ic
Acid s
Michel Gravel, Kim A. Thompson, Mark Zak, Christian Be´rube´, and Dennis G. Hall*
Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
dennis.hall@ualberta.ca
Received J une 26, 2001
Boronic acid-containing molecules are employed in a broad range of biological, medicinal, and
synthetic applications. These compounds, however, tend to be difficult to handle by solution-phase
methods. Herein, this problem is addressed with the development of the first general solid-phase
approach for the derivatization of functionalized boronic acids. This approach is based on the use
of a diethanolamine resin anchor that facilitates boronic acid immobilization by avoiding the need
for exhaustive removal of water in the esterification process. The immobilization of a wide variety
of boronic acids onto N,N-diethanolaminomethyl polystyrene (DEAM-PS, 1) can be performed within
minutes by simple stirring in anhydrous solvents at room temperature. Evidence for the formation
1
of a bicyclic diethanolamine boronate with putative N-B coordination was shown by H NMR
analysis of DEAM-PS-supported p-tolylboronic acid. The hydrolytic cleavage of the same model
boronic acid from the DEAM-PS resin was studied by UV spectroscopy. Hydrolysis and attachment
were shown to occur under a rapidly attained equilibrium, and a large excess of water (>32 equiv)
is required to effect a practically quantitative release of boronic acids from DEAM-PS. Despite
their relative sensitivity to water and alcohols, DEAM-PS-bound arylboronic acids functionalized
with a formyl, a bromomethyl, a carboxyl, or an amino group can be transformed in good to excellent
yields into a wide variety of amines, amides, anilides, and ureas, respectively. Ugi multicomponent
reactions on DEAM-PS-supported aminobenzeneboronic acids, derivatization of multifunctional
arylboronic acids, and sequential reactions can also be carried out efficiently. These new DEAM-
PS-supported arylboronic acids can be employed directly into resin-to-resin transfer reactions
(RRTR). This type of multiresin process helps eliminate time-consuming cleavage and transfer
operations, thereby considerably simplifying the outlook of combinatorial library synthesis by
manual or automated means. This concept was illustrated by a set of optimized procedures for the
Suzuki cross-coupling and the borono-Mannich reactions.
In tr od u ction
mendous popularity as substrates and building blocks in
organic synthesis and combinatorial chemistry. The well-
established Suzuki-Miyaura class of cross-coupling reac-
tions5,6 was recently complemented by a wide variety of
novel, synthetically useful methodologies that employ
boronic acids as substrates. Included among these new
reactions are Miyaura’s rhodium(I)-catalyzed addition to
aldehydes;7 variants of the latter for additions to acti-
vated8 and unactivated alkenes;9 copper diacetate-
promoted cross-coupling reactions with various active
hydrogen functionalities (nitrogen- or oxygen-contain-
Boronic acids have become an extremely important
class of organic compounds. They are employed in a
variety of biological and medicinal applications such as
carbohydrate recognition,1 protease enzyme inhibition,2
neutron capture therapy for cancer,3 and transmembrane
transport.4 In recent years, they have also gained tre-
* To whom correspondence should be addressed. Tel: (780)492-3141.
Fax: (780)492-8231.
(1) For reviews, see: (a) Wulff, G. Pure Appl. Chem. 1982, 2093-
2102. (b) J ames, T. D.; Sandanayake, S.; Shinkai, S. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1910-1922.
(2) For selected recent examples, see: (a) Kettner, C. A.; Shenvi, A.
B. J . Biol. Chem. 1984, 259, 15106. (b) Zhong, S.; Haghjoo K.; Kettner,
C.; J ordan, F. J . Am. Chem. Soc. 1995, 117, 7048. (c) Martichonok, V.;
J ones, J . B. J . Am. Chem. Soc. 1996, 118, 950-958. (d) Tian, Z.-Q.;
Brown, B. B.; Mack, D. P.; Hutton, C. A.; Bartlett, P. A. J . Org. Chem.
1997, 62, 514-522. (e) Priestley, E. S.; Decicco, C. P. Org. Lett. 2000,
2, 3095-3097.
(3) For reviews, see: (a) Barth, R. F.; Soloway, R. G. Sci. Am. 1990,
263, 68-73. (b) Hawthorne, F. Angew. Chem., Int. Ed. Engl. 1993, 32,
950-984. (c) Mehta, S. C.; Lu, D. R. Pharm. Res. 1996, 13, 344-351.
(d) Soloway, A. H.; Tjarks, W.; Barnum, B. A.; Rong, F. G.; Barth, R.
F.; Codogni, I. M.; Wilson, J . G. Chem. Rev. 1998, 98, 1515-1562.
(4) For a review, see: Smith, B. D.; Gardiner, S. J . Adv. Supramol.
Chem. 1999, 5, 157-202 and references therein.
(5) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457-2483. (b) Suzuki, A. Metal-Catalyzed Cross-Coupling Reac-
tions; Diederich, F., Stang, P. J ., Eds.; Wiley-VCH: Weinheim,
Germany, 1998; Chapter 2.
(6) For
a recent, noteworthy extension using acid chlorides as
coupling partners, see: (a) Bumagin, N. A. Tetrahedron Lett. 1999,
40, 3057-3060. (b) Haddach, M.; McCarthy, J . R. Tetrahedron Lett.
1999, 40, 3109-3112.
(7) (a) Sakai, M.; Ueda, M.; Miyaura, N. Angew. Chem., Int. Ed.
1998, 37, 3279-3281. (b) Ueda, M.; Miyaura, N. J . Org. Chem. 2000,
65, 4450-4452.
10.1021/jo0106501 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/29/2001

4
J . Org. Chem., Vol. 67, No. 1, 2002
Gravel et al.
ing,10 thiols11); palladium- or nickel-catalyzed coupling
protocols involving sulfonium salts,12 thioesters,13 or
thioalkynes;14 nickel-catalyzed couplings with allylic
compounds;15 and mercury(II) acetate/lead tetraacetate-
promoted couplings with active methylene compounds.16
The three-component borono-Mannich reaction,17 first
reported by Petasis,17a allows the synthesis of various
R-amino acid and â-amino alcohol derivatives. There are
also a number of useful oxidative ipso-substitution
methodologies for arylboronic acids.18
Many of the reactions described above are amenable
to solid-phase and are thus particularly attractive for
(8) (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997,
16, 4229-4230. (b) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai,
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T.; Senda, T.; Takaya, Y.; Ogasawara, M. J . Am. Chem. Soc. 1999,
121, 11591-11592. (d) Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N.
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Ogasawara, M. J . Am. Chem. Soc. 2000, 122, 10716-10717.
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F igu r e 1. Immobilization and derivatization of functionalized
boronic acids using N,N-diethanolaminomethyl polystyrene
(DEAM-PS, 1).
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Saubern, S.; Adams, J .; Averill, K. M.; Chan, D. M. T.; Combs, A.
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combinatorial library synthesis. These new types of
synthetic transformations have created a demand for the
commercial availability of a larger number of function-
alized boronic acids. Yet, there are still relatively few
boronic acids on the market.19 The paucity of boronic
acids can be explained by the nonexistence of natural
ones and, in large part, by difficulties associated with the
synthesis and derivatization of even the simplest func-
tionalized ones by solution-phase methods. The isolation
of compounds containing a boronic acid functionality can
prove to be notoriously troublesome as a result of their
amphiphilic character. They exist as water-soluble tet-
rahedral boronate anions at high pH and are thought to
be hydrated at neutral pH20 so that even those bearing
a relatively hydrophobic group can be difficult to extract
quantitatively into organic solvents under standard
aqueous workup procedures. These problems are ampli-
fied when the desired boronic acid-containing compound
comprises other sites with basic or acidic functionalities.
Boronic acids are also typically slow-moving on silica gel
and, consequently, must often be purified by recrystal-
lization. In addition, although arylboronic acids are
relatively stable and can be handled without special
precautions, alkylboronic acids and, to some extent,
alkenylboronic acids are sensitive to oxidation even under
ambient air.21 Some of these problems can be alleviated
by protection of the boronic group as an ester.22 However,
these approaches require additional synthetic operations.
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93.
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Soc., Perkin Trans. 1 1995, 2083-2096.
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715-720.
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583-586. (b) Harwood, L. M.; Currie, G. S.; Drew, M. G. B.; Luke, R.
W. A. Chem. Commun. 1996, 1953-1954. (c) Petasis, N. A.; Zavialov,
I. A. J . Am. Chem. Soc. 1997, 119, 445-446. (d) Petasis, N. A.; Zavialov,
I. A. J . Am. Chem. Soc. 1998, 120, 11798-11799. (e) Hansen, T. K.;
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dron Lett. 1999, 40, 3651-3654. (f) Batey, R. A.; MacKay, B.;
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Li, M.; Peng, S. X.; Shao, X. Tetrahedron Lett. 2000, 41, 4835-4839.
(i) Golebiowski, A.; Klopfenstein, S. R.; Chen, J . J .; Shao, X. Tetrahe-
dron Lett. 2000, 41, 4841-4844. (j) Petasis, N. A.; Patel, Z. D.
Tetrahedron Lett. 2000, 41, 9607-9611. (k) Prakash, G. K. S.; Mandal,
M.; Schweizer, S.; Petasis, N. A.; Olah, G. A. Org. Lett. 2000, 2, 3173-
3176. (l) Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063-4066. (m)
Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron 2000, 56,
10023-10030. (n) Batey, R. A.; MacKay, D. B. Tetrahedron Lett. 2000,
41, 9935-9938. (o) Currie, G. S.; Drew, M. G. B.; Harwood, L. M.;
Hughes, D. J .; Luke, R. W. A.; Vickers, R. J . J . Chem. Soc., Perkin
Trans. 1 2000, 2982-2990. (p) Thompson, K. A.; Hall, D. G. Chem.
Commun. 2000, 2379-2380. (q) Petasis, N. A.; Boral, S. Tetrahedron
Lett. 2001, 42, 539-542. (r) Berre´e, F.; Debache, A.; Marsac, Y.;
Carboni, B. Tetrahedron Lett. 2001, 42, 3591-3594.
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A.; Olah, G. A. Synlett 1998, 141-142. Nitration: (b) Salzbrunn, S.;
Simon, J .; Prakash, G. K. S.; Petasis, N. A.; Olah, G. A. Synlett 2000,
1485. Oxidation to phenols: (c) Hawthorne, M. F. J . Org. Chem. 1957,
22, 1001. (d) Webb, K. S.; Levy, D. Tetrahedron Lett. 1995, 36, 5117.
Azidation: (e) Huber, M.-L.; Pinhey, J . T. J . Chem. Soc., Perkin Trans.
1 1990, 715-720.
(19) There are less than 150 different boronic acids (from a compila-
tion of the suppliers Aldrich, Lancaster, Frontier Scientific, and Combi-
Blocks), as compared to thousands of carboxylic acids and several
hundreds of different alcohols, just to name a few.
(20) Lorand, J . P.; Edwards, J . O. J . Org. Chem. 1959, 24, 769-
774.
(21) (a) Snyder, H. R.; Kuck, J . A.; J ohnson, J . R. J . Am. Chem. Soc.
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4228-4233.
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Springer: Berlin and Heidelberg, Germany, 1995; Section 1.4.2, p 17.

Reactions of Boronic Acids
J . Org. Chem., Vol. 67, No. 1, 2002
5
Sch em e 1
In view of all the above-mentioned impediments to
handling boronic acids in solution phase, it is clear that
a simple and general solid-phase approach for their
immobilization and derivatization would be of tremen-
dous usefulness. Indeed, solid-phase methods circumvent
the need for aqueous workup and other time-consuming
operations required to isolate the desired product from
excess reagents and byproducts.
Herein, we describe a detailed account of the prepara-
tion, characterization, properties, and synthetic applica-
tions of N,N-diethanolaminomethyl polystyrene (DEAM-
PS, 1)23,24 as support for the first general solid-phase
approach to the immobilization and derivatization of
boronic acids (Figure 1). Other types of supports based
on diol anchors have been described recently.25,26 How-
ever, unlike DEAM-PS, these supports do not allow the
straightforward attachment and cleavage of boronic acids
under mild conditions. The DEAM-PS resin can be used
for the immobilization of several types of functionalized
boronic acids that can undergo a wide variety of standard
synthetic transformations as stable, supported diethanol-
amine esters (X f Y in Figure 1). Several options are
available following the solid-phase derivatization of a
DEAM-PS-supported boronic acid. The resulting product
can be released either as a free boronic acid or through
a modifying cleavage procedure such as oxidation to form
a phenol derivative25a or as part of a reductive traceless
strategy for arene synthesis.25b Alternatively, in cases
where the new boronic acid is a substrate for a subse-
quent reaction, it is actually possible to streamline the
supported substrate directly into a resin-to-resin transfer
reaction (RRTR). By avoiding cleavage and transfer
operations, this type of multiresin system is particularly
attractive in combinatorial chemistry for use in auto-
mated library synthesis. In addition to these applications,
diethanolamine-based resins such as DEAM-PS could
also be useful as solid-supported scavengers23,27 or as
supports for affinity purification of boronic acids.
primary and secondary amines. The carbon/nitrogen/
oxygen ratio resulting from elemental analysis was
satisfactory and in accordance with the loading of AM-
PS stated by the supplier. In addition, coupling of
(fluorenylmethoxy)carbonyl (Fmoc) glycine to the hy-
droxyl groups, followed by piperidine treatment and
quantitative UV analysis of the fulvene adduct, confirmed
the expected ratio of two hydroxyethyl arms per nitrogen.
This preparative method, however, did not prove practi-
cal for making larger quantities of 1; thus, we sought to
develop a more convenient, pressure-free method. To this
end, we have found that resin 1 can be made with ease
from chloromethylated polystyrene (Merrifield) resin and
diethanolamine in the presence of sodium iodide in
N-methylpyrrolidinone (NMP) at room temperature.29
While the latter method is more conveniently carried out,
both methods afford DEAM-PS resin of similar charac-
teristics with identical efficiency at immobilizing boronic
acids.
For the immobilization, we found that p-tolylboronic
acid can be coupled in high yields by esterification with
1 through simple mixing for less than 15 min in anhy-
drous solvents at room temperature (vide infra). As
expected from the behavior of diethanolamine boronates
in solution phase,30 there was no need to drive the
reaction forward by exhaustive trapping of the water
released in this immobilization process. This constitutes
a significant advantage over other types of diols, whether
solid-supported or not, which usually require azeotropic
removal of the water.25,26 In fact, we have confirmed the
much lower efficiency of commercially available glycerol
resin.31 Using standard immobilization conditions devel-
oped for 1, PS-glycerol coupled to p-tolylboronic acid with
only 50% yield. These results highlight the importance
of the nitrogen atom from the aminodiol anchor of DEAM-
PS. Evidence for the existence of N-B coordination in
diethanolamine boronic esters has been reported with
soluble adducts.32 Because this seems to be a crucial
factor in the efficiency and ease with which DEAM-PS
resin immobilizes boronic acids, we were interested in
examining the role of the diethanolamine nitrogen in the
Resu lts
P r ep a r a tion a n d Ch a r a cter iza tion of N,N-Di-
eth a n ola m in om eth yl P olystyr en e (1). We have first
reported on the preparation of resin 1 from standard
cross-linked aminomethylpolystyrene (AM-PS) by means
of a double alkylation with ethylene oxide in a sealed tube
(Scheme 1).23 This transformation was carried out under
temperature conditions known in solution phase to
minimize quaternization of the desired tertiary amine.28
A ninhydrin test on the final resin obtained after 48 h of
reaction time hinted at the absence of any leftover
(23) Hall, D. G.; Tailor, J .; Gravel, M. Angew. Chem., Int. Ed. 1999,
38, 3064-3067.
(24) For another method of preparation of DEAM-PS, see: Arimori,
S.; Hartley, J . H.; Bell, M. L.; Oh, C. S.; J ames, T. D. Tetrahedron
Lett. 2000, 41, 10291-10294.
(25) (a) Carboni, B.; Pourbaix, C.; Carreaux, F.; Deleuze, H.;
Maillard, B. Tetrahedron Lett. 1999, 40, 7979-7983. (b) Pourbaix, C.;
Carreaux, F.; Carboni, B.; Deleuze, H. Chem. Commun. 2000, 1275-
1276. (c) Pourbaix, C.; Carreaux, F.; Carboni, B. Org. Lett. 2001, 3,
803-806.
(26) (a) Li, W.; Burgess, K. Tetrahedron Lett. 1999, 40, 6527-6530.
(b) Dunsdon, R. M.; Greening, J . R.; J ones, P. S.; J ordan, S.; Wilson,
F. X. Bioorg. Med. Chem. Lett. 2000, 10, 1577-1579.
(27) Bolton. G. L.; Booth, R. J .; Creswell, M. W.; Hodges, J . C.;
Warmus, J . S.; Wilson, M. W.; Kennedy, R. M. U.S. Patent WO97/
42230, 1997.
(29) For a related though less practical method requiring heating:
(a) Che, P.-Z.; Liu, J .; Wang, C.; Xing, B.; Kong, X.; Liu, H.; Song, Y.
J . Mol. Catal. (China) 1998, 12, 148-151. (b) Che, P.-Z.; Liu, J .; Liu,
H.; Wang, C.; Liu, D.; Xing, B.; Su, R.; Kong, X. Chin. J . Synth. Chem.
1998, 6, 69-74.
(30) (a) Letsinger, R. L.; Skoog, I. J . Am. Chem. Soc. 1955, 77, 2491-
2494. (b) Tripathy, P. B.; Matteson, D. S. Synthesis 1990, 200-206.
(31) Polystyrene-supported glycerol was purchased from Advanced
Chemtech Inc.
(28) Sundaram, P. K.; Sharma, M. M. Bull. Chem. Soc. J pn. 1969,
42, 3141-3147.
(32) Woods, W. G.; Bengelsdorf, I. S.; Hunter, D. L. J . Org. Chem.
1966, 31, 2766-2768.

6
J . Org. Chem., Vol. 67, No. 1, 2002
Gravel et al.
F igu r e 3. Percentage of hydrolytic cleavage of DEAM-PS-
supported p-tolylboronic acid (2a ) followed by UV spectroscopy
(225 nm) as a function of water stoichiometry.
Im m obiliza tion a n d Clea va ge of Bor on ic Acid s.
To effect release of DEAM-PS-supported boronic acids,
we originally reported on the use of a wet THF solution
containing acetic acid (THF/H2O/AcOH 90:5:5).23 We have
since found that no acid is necessary and that a 5:95 H2O/
THF solution alone is sufficient to quickly liberate the
boronic acids from the support. To avoid product con-
tamination and boronic acid oxidation into the corre-
sponding phenol, it is preferable to employ a cleavage
solution prepared from air- and peroxide-free, freshly
distilled THF.33 To investigate the extent to which the
diethanolamine-boronate linkage is sensitive to water,
we have devised a UV spectroscopic assay whereby the
hydrolysis of DEAM-PS-supported p-tolylboronic acid
(2a ) was monitored quantitatively both in a time-related
fashion and with respect to the amount of water used.
In principle, a minimum of 2 mol equiv of water is
required to effect quantitative cleavage of DEAM-PS-
supported boronic acid 2. This type of boronate exchange
process involving water and a competing diol like DEAM-
PS (1), however, is usually under equilibrium:
F igu r e 2. Gel-phase 1H NMR spectra (500 MHz) of DEAM-
PS (A) and DEAM-PS-supported p-tolylboronic acid (B) using
a magic angle spinning nanoprobe. Solvent is CD2Cl2 (peak
identified by a dot). Conditions are as follows: A; acquisition
time (at) ) 3, pulse width (pw) ) 2.5, d1 ) 0, spinning at 2119
Hz. B; at ) 3, pw ) 2.0, d1 ) 0, spinning at 2300 Hz (Note
that the signal at 3.7 ppm is residual THF). PS: polystyrene
resonances.
2 + 2H2O a 1 + RB(OH)2
[1][RB(OH)2]
Keq
)
[2][H2O]2
A time profile of boronic acid release from 2a with
variable amounts of water (2, 10, and 30 equiv) showed
that the extent of boronic acid cleavage rapidly reached
a plateau within less than 1 min (data not shown). A
comparison of the percentage of boronic acid release with
different numbers of equivalents of water is shown in
Figure 3. Overall, the resulting data confirmed that
hydrolysis is under equilibrium and that a large excess
of water (>32 equiv) is required to provide a practically
quantitative hydrolysis. As a rule of thumb, such a
quantity of water corresponds roughly to the use of 10
mL of cleavage solution (5% H2O/THF) per gram of resin
at a 0.8 mmol/g of resin loading. This deduction, however,
polymer-supported case. To this end, we have compared
gel-phase proton NMR spectra of the free form of DEAM-
PS and the p-tolylboronic acid conjugated form (2a ) using
a magic angle spinning nanoprobe (Figure 2). Aside from
resonances exhibited by the polystyrene matrix, two
broad singlets show up at 2.6 and 3.5 ppm in the
spectrum of free DEAM-PS (Figure 2A). Presumably, the
largest, most unshielded peak contains resonances from
both benzylamino and hydroxymethyl methylenes. In
theory, upon formation of a cis fused bicyclic diethanol-
amine boronate adduct with two nonequivalent faces, the
ring hydrogens become diastereotopic. As expected, the
resulting spectrum of 2a (Figure 2B) showed extensive
degeneration of the methylenic protons in the hydroxy-
ethyl arms. As many as four peaks were now seen
between 2.2 and 3.6 ppm, thereby lending support to a
tetrahedral, nitrogen-coordinated boronic ester.
(33) The 2,6-di-tert-butyl-p-cresol used as stabilizer in nondistilled
THF often was found to accumulate in the polymer matrix of DEAM-
PS and contaminate the products upon cleavage. This can be prevented
by the use of distilled THF for resin washing and for the cleavage
solution. However, in the absence of the stabilizer, freshly distilled
THF must be used in order to avoid a presumed buildup of peroxides,
which cause oxidation of the boronic acids into the corresponding
phenols.

Reactions of Boronic Acids
J . Org. Chem., Vol. 67, No. 1, 2002
7
Ta ble 1. Im m obiliza tion of Va r iou s Bor on ic Acid s on to
1a
may not be generalized to all types of functionalized
boronic acids. In particular, some ortho-substituted aryl-
boronic acids may behave differently34 and prove to be
more difficult to liberate from DEAM-PS. In these cases,
a larger proportion of water or the use of acidic conditions
(THF/H2O/AcOH 90:5:5) may be advisable. The above
hydrolysis study also suggests that the reverse process,
boronic acid immobilization from DEAM-PS, by releasing
2 mol equiv of water cannot be quantitative in THF,
unless a large excess of boronic acid is employed to shift
the equilibrium. Otherwise, according to Figure 3, the
approximate maximum yield of immobilization for equimo-
lar amounts of DEAM-PS and boronic acid is 80%. Thus,
to optimize the yield of immobilization, the boronic acid
must be largely monodehydrated before use.35 Yet, one
molecule of water is released even from the corresponding
boroxines ((RBO)3), so the esterification process is limited
to about 90% efficiency in THF. The use of homogeneous
dehydrating agents such as tetramethylorthoformate
(TMOF) did not help to improve the immobilization
efficiency.
A series of boronic acids presenting different steric and
electronic characteristics was tested as a means to
evaluate the generality of immobilization onto DEAM-
PS (Table 1). These studies were carried out under
conditions planned to optimize the yield of immobiliza-
tion. Thus, a slight excess of the boronic acid (ca. 1.3
equiv), predried in vacuo as the monoanhydride form,
was shaken with DEAM-PS at room temperature for 1
h. Percentages of recovery are based on the amount of
boronic acid isolated after cleavage of 2 with H2O/THF
(5:95). A solvent profile study using p-tolylboronic acid
revealed that a wide range of anhydrous solvents can be
employed (entries 1-6, Table 1). Whereas THF was found
to be a general solvent to solubilize and immobilize
boronic acids efficiently, we have found that dichlo-
romethane provides higher yields of immobilization
(entry 5 vs entry 6, Table 1). Presumably, the limited
solubility of water in dichloromethane minimizes the
back-reaction (hydrolysis). When THF is used as solvent,
a wide variety of functionalized arylboronic acids pre-
senting different steric and electronic characteristics were
found to immobilize efficiently onto DEAM-PS (entries
6-18, Table 1). With the exceptions of o-carboxyphenyl-
boronic acid (entry 10, Table 1) and exceptionally hin-
dered or electron-poor arylboronic acids (entries 15 and
16, Table 1), the coupling yields were very high. Im-
mobilization of alkenylboronic acids is also possible (entry
18, Table 1). All of these boronic acids were recovered
intact, and the leftover DEAM-PS resin can be recycled
with no apparent loss of efficiency after neutralization
with base (dilute triethylamine) followed by the usual
rinses.
entry
R
solvent
yield (%)b
purityc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Br-C6H4
4-MeO-C6H4
4-HO2C-C6H4
2-HO2C-C6H4
3-H2N-C6H4
2-CHO-C6H4
4-PhO-C6H4
4-BrCH2-C6H4
2,6-di-Me-C6H3
2,4-di-F-C6H3
2-naphthyl
MeOH
NMP
Et2O
toluene
CH2Cl2
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
72
80
90
88
98
89
97
87
90
51
91
98d
93
85
46
46
89d
81
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
(E)-PhCHdCH
a
Coupling reactions were conducted by shaking resin 1 (1 equiv,
120 mg, 1.15 mmol/g) with the boronic acid (1.3 equiv) in the
indicated solvent (1.5 mL) at room temperature for 1 h in a
polypropylene fritted vessel. b Yields of boronic acid recovered after
cleavage from the resin with 5% H2O/THF for 1 min at room
temperature and washing with 5% H2O/THF (3×). The resin was
rinsed with the reaction solvent (3×) prior to cleavage. For entries
4 and 5, additional THF rinses were carried out (3×). The reported
yields are an average of mass balance and internal standardization
(see Supporting Information for details) based on the loading of
resin 1 measured by elemental analysis. c Estimated by compari-
son of 1H NMR spectra of starting and recovered boronic acids.
d
Calculated only from mass balance; the tendency of this boronic
acid to form anhydrides made NMR quantitation difficult.
Sch em e 2
acid to the 7:1 THF/ethanol solvent. Successive incuba-
tions of the resin under constant resin/solvent propor-
tions, followed by rinses with dry THF, revealed that
approximately 40% of the p-tolylboronic acid is released
from the resin under these conditions. The reverse
reaction (1 + p-tolylboronic acid) gave a similar outcome
under the same conditions, showing that the transes-
terification process is under equilibrium.
A diisobutanolaminomethyl-substituted resin (3) was
made from isobutylene oxide (Scheme 2) to investigate
whether increased steric bulk would improve tolerance
of the support to water and hydroxylic solvents. Im-
mobilization and cleavage of p-tolylboronic acid from
resin 3, however, did not show any improvement in this
respect when carried out under similar conditions as
those for resin 1. The relative sensitivity of the dietha-
Hydroxylic solvents such as methanol and ethanol
allow a dynamic transesterification process to take place,
leading to nonquantitative immobilization (Table 1, entry
1). We have measured the extent of transesterification
of DEAM-PS-supported p-tolylboronic acid (2a , R )
p-tolyl) in 7:1 THF/ethanol.17p Equilibrium was reached
within 15 min of exposure of the supported p-tolylboronic
(34) Cai, S. X.; Keana, J . F. W. Bioconjugate Chem. 1991, 2, 317-
322.
(35) Although commercial boronic acids tend to come as largely
dehydrated anhydride forms, it is advisable to further dry them in
vacuo prior to immobilization with DEAM-PS. For a pertinent review,
see: Lappert, M. F. Chem. Rev. 1956, 56, 959.

8
J . Org. Chem., Vol. 67, No. 1, 2002
Gravel et al.
Ta ble 2. Su bstitu tion Rea ction s on 5 a n d 6
nolamine boronic ester linkage to water and alcohols
should be taken into account when using DEAM-PS for
the derivatization of functionalized boronic acids. It
appears that anhydrous and alcohol-free reaction condi-
tions are preferable to avoid premature cleavage of
products. On the other hand, there can be significant
practical aspects to derivatizing functionalized boronic
acids on DEAM-PS, as they could be directly released in
an aqueous buffer required for biological screening.
Solid -P h a se Der iva tiza tion of F u n ction a lized Bo-
r on ic Acid s. We set out to develop a series of useful
solid-phase reaction protocols to derivatize functionalized,
DEAM-PS-supported boronic acids. To evaluate the scope
of reaction conditions compatible with DEAM-PS-sup-
ported boronic acids, simple functional group intercon-
version methods were examined (Tables 2-6). All sup-
ported substrates were easily prepared in high yield from
1 as described in the previous section. Most boronic acid
products obtained after cleavage with 5% H2O/THF were
not further purified and were characterized by mass
yieldb purityc
entry substrate conditionsa
product {R1, R2}
(%)
(%)
1
2
3
4
5
6
7
8
5
5
5
5
6
6
6
6
A
A
B
B
A
A
B
B
8a {H, CH2Ph}
69
50
85
75
69
53
98
94
95
>90
95
>95
>90
95
8b {H, CH2CH(CH3)2}
8c {(CH2)2O(CH2)2}
8d {Me, CH2Ph}
9a {H, CH2Ph}
9b {H, CH2CH(CH3)2}
9c {(CH2)2O(CH2)2}
9d {Me, CH2Ph}
>90
95
a
Reactions were carried out by shaking the supported benzyl
bromide with the amine in NMP at room temperature for ap-
proximately 5 h (typical scale, 0.12 mmol of 5 or 6). Conditions
were as follows: (A) 50 equiv of primary amine, use of low-loading
DEAM-PS resin (0.60 mmol/g); (B) 10 equiv of secondary amine,
use of either low-loading (0.60 mmol/g) or high-loading (1.14 mmol/
1
spectrometry, IR, and H and 13C NMR spectroscopy. The
reported yields of products are inclusive of the boronic
acid immobilization step, which as discussed in the
previous section, may not be quantitative.32 Percentage
yields were calculated as an average value of mass
balance and internal standardization with ethyl acetate
as compared with the theoretical loading of free DEAM-
PS resin. These two methods were almost always found
to be within a 5% range using optimized analytical
methods (see Supporting Information). The indicated
purity values for the products are a conservative estimate
based on inspection of NMR spectra and quantitation of
peaks from the expected product relative to signals from
possible byproducts and starting material. In general, all
compounds were obtained with a minimum of 90% purity,
and in a majority of cases, there were no detectable
byproducts by NMR analysis.
b
g) DEAM-PS resin. Nonoptimized yields of crude products after
cleavage from the resin with 5% H2O/THF and drying in vacuo
for greater than 12 h. The reported values are an average of mass
balance and internal standardization (see Supporting Information
for details). c Estimated from 1H and 13C NMR data.
Sch em e 3
with PhONa in the presence of iodide ion in NMP for 24
h provided ether derivative 10 only in moderate yield
after cleavage from the resin followed by rapid filtration
through silica gel. We suspect that the phenoxide ion
causes substantial premature cleavage from the resin.
The results for the reductive amination of supported
formyl-substituted benzeneboronic acids with various
primary and secondary amines are compiled in Table 3.
The single set of conditions found to avoid premature
cleavage of the boronic acid involves preformation of the
imine in THF and then addition of sodium borohydride
as the hydride source. Other hydride reagents tested (e.g.,
NaBH(OAc)3, NaBH3CN) led to premature cleavage of the
supported boronic acid. Interestingly, only the ortho
substrate 11 gave satisfactory yields of product 7 with
good purity. This chemistry thus complements the bro-
momethyl substitution method described above. The less
hindered meta and para substrates 12 and 13 gave the
respective amine products 8 and 9 in a significantly lower
purity. Although there was no evidence for double alky-
lation in the case of primary amines, the desired products
were accompanied by unidentified impurities. In a simi-
lar way, the inverse process, reductive alkylation of
supported aniline substrates (i.e., substrates 20-22), was
also unsuccessful both for aromatic and aliphatic alde-
hydes.
Table 2 summarizes the results for the substitution of
bromomethyl-derivatized benzeneboronic acids with rep-
resentative primary and secondary amines. In this case
involving amphoteric aminomethyl-substituted products,
the advantages of a solid-phase approach for product
isolation are optimal vis-a`-vis solution-phase methods.
The optimal conditions found from alkylations of meta
and para substrates 5 and 6 involve simple stirring of
DEAM-PS-supported bromomethylbenzeneboronic acid
with the amine in NMP for approximately 5 h at room
temperature. As much as 10 equiv of secondary amines
was employed to ensure reaction completion under these
conditions. To suppress cross-linking of the substrate by
double alkylation with primary amines, it was found to
be preferable to use a low-loading DEAM-PS resin (<0.60
mmol/g) with a larger excess of the amine (50 equiv).
Because of the large excess of primary amine reactant
used, the yields of the secondary amine products may
suffer from premature cleavage of the supported boronic
acid. Nonetheless, these protocols provided good to excel-
lent yields of isolated secondary and tertiary amine
products 8 and 9. Unfortunately, these and several other
conditions failed to provide any expected product in the
case of ortho-substituted substrate 4. For yet unexplained
reasons, facile premature cleavage was observed. These
ortho-aminomethyl-substituted products, however, can be
obtained from reductive amination chemistry (vide infra).
Sodium phenoxide has been used as an example of an
oxygen-based nucleophile (Scheme 3). Treatment of 6
The formation of amide derivatives from DEAM-PS-
supported carboxy-functionalized arylboronic acids proved
to be very general with respect to reaction conditions
(Table 4). A substrate limitation, however, was observed

Reactions of Boronic Acids
J . Org. Chem., Vol. 67, No. 1, 2002
9
Ta ble 3. Red u ctive Am in a tion on Ald eh yd e 11a
Ta ble 5. An ilid e Syn th esis fr om An ilin es 20-22a
yieldb purityc
entry substr condnsa
product {R}
23a {CH2CH3}
23b {Ph}
24a {CH2CH3}
24b {Ph}
24a {CH2CH3}
24b {Ph}
24c {CH2CH2CHdCH2}
24d {CCPh}
(%)
(%)
entry substrate
product {R1, R2}
yieldb (%) purityc (%)
1
2
20
20
21
21
21
21
21
21
21
22
22
B
B
A
A
B
B
B
B
B
B
B
61
60
42
52
72
82
70
75
>95
>90
>90
>95
95
1
2
3
4
11
11
11
11
7a {H, CH2Ph}
66
55
62
73
>90
>90
95
7b {H, CH2CH(CH3)2}
7c {H, (CH2)3Ph}
7d {H, (CH2)3CH3}
3
4
5
6
>95
a
95
Typical scale was 0.1 mmol. Reactions were carried out by
7
8
9
10
11
>95
>95
95
preforming the imine from supported aldehyde and the amine (2
equiv) in THF at room temperature for approximately 2.5 h.
Sodium borohydride was added, and the suspension was shaken
24e {(S)CH(Me)NHFmoc} 51
b
25a {CH2CH3}
25b {Ph}
61
46
>95
95
for approximately 4 h. Nonoptimized yields of crude products
after cleavage from the resin with 5% H2O/THF and drying in
vacuo for greater than 12 h. The reported values are an average
of mass balance and internal standardization (see Supporting
Information for details). c Estimated from 1H and 13C NMR data.
a
Typical scale was 0.1 mmol. Conditions were as follows: (A)
reactions were carried out by shaking the supported aniline with
the carboxylic acid (2 equiv), DIC (2 equiv), and HOBT/H2O (2
equiv) in DMF at room temperature for 20 h; (B) reactions were
carried out by shaking the supported aniline with the carboxylic
acid (2 equiv), PyBOP (2 equiv), and DIPEA (4 equiv) in NMP at
Ta ble 4. Am id e Syn th esis fr om 15 a n d 16
b
room temperature for 20 h. Nonoptimized yields of crude prod-
ucts after cleavage from the resin with 5% H2O/THF and drying
in vacuo for greater than 12 h. The reported values are usually
an average of mass balance and internal standardization (see
Supporting Information for details). c Estimated from 1H and 13C
NMR data.
yieldb purityc
carbodiimide/1-hydroxybenzotriazole (HOBT) protocols
was satisfactory for the coupling of both primary and
secondary amines and even aromatic amines (entries 4
and 11, Table 4). In the most unfavorable cases, however,
it was found to be preferable to employ coupling reagents
such as benzotriazole-1-yl-oxy-tris-pyrrolidino-phospho-
nium hexafluorophosphate (PyBOP) or 2-(1H-benzotria-
zole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophos-
phate (HBTU). This is exemplified for the case of
isopropylamine (entry 9, Table 4). Moreover, we have
found that conditions using these coupling reagents
generally induce less premature cleavage as compared
to those using carbodiimide reagents.
A noticeable example of amide formation with sup-
ported boronic acids is that of entry 15 (Table 4) involving
16 and N,N-diethylethylenediamine. The resulting am-
photeric p-boronobenzamide product 19h , a known mela-
noma-seeking agent with potential use in boron neutron
capture therapy,36 was obtained pure in a 70% yield after
cleavage from the resin. Previously reported syntheses
of 19h involve protection of the boronic acid and extensive
manipulations such as successive recrystallizations.36
entry substr condnsa
product {R1, R2}
(%)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
15
15
15
15
15
15
15
16
16
16
16
16
16
16
16
A
A
A
B
A
A
A
B
B
A
A
A
A
B
A
18a {H, (CH2)3Ph }
18b {H, CH(CH3)2}
18c {H, (CH2)3CH3}
18d {H, Ph}
18e {Et, Et}
18f {Bu, Bu}
18g {CH2Ph, CH2Ph}
19a {H, (CH2)3Ph }
19b {H, CH(CH3)2}
19c {H, (CH2)3CH3}
19d {H, Ph}
57
60
56
82
77
79
60
65
81
64
67
59
53
70
70
95
>90
>90
>95
90
90
>90
>95
>95
95
>95
>90
90
19e {Et, Et}
19f {Bu, Bu}
19g {CH2Ph, CH2Ph}
19h {H, CH2CH2NEt2}
95
>95
a
Typical scale was 0.1 mmol. Conditions were as follows: (A)
reactions were carried out by shaking the supported carboxylic
acid with the amine (4 equiv), diisopropylcarbodiimide (DIC) (4
equiv), and HOBT/H2O (4 equiv) in NMP or DMF at room
temperature for 18 h; (B) reactions were carried out by shaking
the supported carboxylic acid with the amine (2 equiv), diisopro-
pylethylamine (DIPEA) (4 equiv), and PyBOP (2 equiv) in DMF
b
at room temperature for 20 h. Nonoptimized yields of crude
products after cleavage from the resin with 5% H2O/THF and
drying in vacuo for greater than 12 h. The reported values are an
average of mass balance and internal standardization (see Sup-
porting Information for details). c Estimated from 1H and 13C NMR
data.
We have previously shown that borono-anilide deriva-
tives can be obtained from the reaction of DEAM-PS-
supported aminobenzeneboronic acids with acid chlo-
rides.37 Herein, we report that compounds of this sort can
also be isolated in a variable range of yields (ca. 50%-
80%) by reaction of carboxylic acids with supported
anilines 20-22 (Table 5). All three substitution patterns
are possible for this type of chemistry. The optimal
as the ortho-substituted substrate 14 failed to provide
the expected coupling products. As shown in Table 1, the
yield of immobilization of o-carboxyphenylboronic acid to
DEAM-PS is low (entry 10, Table 1), and it was cleaved
prematurely during reactions. The meta- and para-
carboxy-substituted substrates 15 and 16 provided good
yields of amide products. In most cases, the use of
(36) Parry, D.; Papon, J .; Moins, N.; Moreau, M.-F.; Morin, C. Bioorg.
Med. Chem. Lett. 1997, 7, 361-364.
(37) Gravel, M.; Be´rube´, C.; Hall, D. G. J . Comb. Chem. 2000, 2,
228-231.

10 J . Org. Chem., Vol. 67, No. 1, 2002
Gravel et al.
Ta ble 6. Syn th esis of Ur ea s fr om An ilin es 21 a n d 22
F igu r e 4. Possible forms of o-acylaminobenzeneboronic acids
(23) in hydroxylic solvents (e.g., water or methanol). Structure
B is the naphthalene-like form originating from dehydrative
cyclization of A. Structure C is the putative ate form arising
from 1,4-addition of water or methanol.
yieldb purityc
entry substrate conditionsa
product {R}
(%)
(%)
1
2
3
4
5
6
7
8
9
21
21
21
21
21
22
22
22
22
B
A
A
A
A
B
A
A
A
27a {CH(CH3)2}
27b {Ph}
66
79
95
>95
>95
>95
95
>95
>95
>95
95
27c {4-MeO-C6H4} 82
27d {4-NO2-C6H4}
27e {Ph}
28a {CH(CH3)2}
28b {Ph}
80
85
65
85
reagents and conditions found are the use of PyBOP as
a coupling agent in NMP or DMF for 20 h at room
temperature. As shown from entries 3-6 (Table 5), a
comparison of carbodiimide methods with the use of
PyBOP revealed the superiority of the latter method. A
wide variety of carboxylic acids was tested, including
Fmoc-protected alanine (entry 9, Table 5), which provided
a 51% yield of the expected amide product 24e. All meta-
and para-substituted substrates provided the expected
anilide products. According to ES-MS analysis, it appears
that the ortho-substituted anilides 23 rather exist in a
cyclic monodehydrated form (Form B in Figure 4).38 This
is probably true even in aqueous or alcoholic solutions
as a consequence of the partial aromatic character of
these boron-containing heterocycles. In fact, it has even
been proposed that these and similar compounds such
as ureas can add one molecule of water or alcohol by 1,4-
addition and thus exist in equilibrium with form C
(Figure 4).39 These ortho-acylamino-substituted ben-
zeneboronic acids (23) were found to have limited solubil-
ity in all solvents; thus, they were also characterized as
their pinacol ester (form A, Figure 4) in order to unam-
biguously demonstrate their identity by 1H and 13C NMR.
Ureas of type 27 and 28 were isolated from the reaction
of the respective meta- and para-substituted anilines 21
and 22 with various isocyanates of different electronic
characteristics in dichloromethane for 5-6 h at room
temperature (Table 6). An example of thiourea was also
obtained with ease (27e, entry 5, Table 6). Yields of
products are excellent for all reported examples regard-
less of the electronic characteristics of the isocyanate
reagent. Unfortunately, the ortho-substituted substrate
20 provided products 26 accompanied with varying
amounts of double addition products. This was found to
be unavoidable even when using a minimal quantity of
isocyanate.
28c {4-MeO-C6H4} 88
28d {4-NO2-C6H4} 92
a
Typical scale was 0.1 mmol. Conditions were as follows: (A)
reactions were carried out by shaking the supported aniline with
the isocyanate (2 equiv) in CH2Cl2 at room temperature for 5-6
h; (B) reactions were performed as described in A but with a longer
b
reaction time (20-45 h). Nonoptimized yields of crude products
after cleavage from the resin with 5% H2O/THF and drying in
vacuo for greater than 12 h. The reported values are usually an
average of mass balance and internal standardization (see Sup-
porting Information for details). c Estimated from 1H and 13C NMR
data.
Sch em e 4
shown in eq 1 of Scheme 5, the para-bromomethyl-
substituted substrate 6 was first treated with benzyl-
amine as described above (Table 2). Following resin
washes, the resulting substitution product was reacted
with p-methoxyphenylisocyanate to give 31. The expected
boronic acid product 32 was obtained in 64% yield and
high purity after cleavage from the support. In a similar
fashion, supported 3-amino-5-carboxyphenylboronic acid
(33) was treated with p-methoxyphenyl isocyanate (eq
2, Scheme 5). The carboxyl functionality was then coupled
with isopropylamine to give, after treatment of resin 34
with wet THF, the final product 35 in 73% yield. Amide
formation can also be effected as the first step on the
same substrate, which can then undergo a Ugi reaction
involving the aniline functionality, ultimately providing
boronic acid 37 (eq 3, Scheme 5). In principle, the use of
In addition to the functional group transformations
described above, we examined whether more elaborate
types of transformations could be tolerated by the di-
ethanolamine-boronate resin linkage. For instance, a
prototypical Ugi multicomponent reaction40 was carried
out with success on DEAM-PS-supported aniline 21 and
provided dipeptide derivative 30 in high purity after
cleavage of its resin-bound form 29 (Scheme 4). Deriva-
tization of multifunctional arylboronic acids and sequen-
tial transformations were also examined (Scheme 5). As
(38) Soloway, A. H. J . Am. Chem. Soc. 1960, 82, 2442-2444.
(39) Groziak, M. P.; Ganguly, A. D.; Robinson, P. D. J . Am. Chem.
Soc. 1994, 116, 7597-7605.
(40) (a) Ugi, I.; Do¨mling, A.; Ho¨rl, W. Endeavour 1994, 18, 115-
122. (b) Do¨mling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168-
3210.

Reactions of Boronic Acids
J . Org. Chem., Vol. 67, No. 1, 2002 11
Sch em e 5
DEAM-PS is not limited to the procedures described
herein, and many other types of transformations could
be envisaged. These examples clearly demonstrate that
multistep transformations can be carried out with high
efficiency provided that anhydrous reaction conditions
are employed to minimize premature release of the
DEAM-PS-supported boronic acid. Synthetic schemes
such as these ones could be employed to rapidly assemble
two-dimensional combinatorial libraries of new boronic
acids for biological screening or as building blocks for
subsequent reactions. All of these reactions could be
performed easily on a gram scale, especially with the use
of high-loading DEAM-PS. The use of DEAM-PS resin
for solid-phase derivatization of functionalized boronic
acids is also potentially advantageous for handling and
storage purposes. Indeed, boronic acids can be protected
against slow air oxidation through immobilization as
diethanolamine adducts.
Ap p lica t ion s of DE AM-P S-Su p p or t ed Bor on ic
Acids in Resin -to-Resin Tr an sfer Reaction s (RRTR).
In comparison with the traditional approach to solid-
phase synthesis in which a single resin-bound substrate
is employed, the simultaneous use of two or more
heterogeneous substrates, reagents, or catalysts has
seldom found real synthetic utility.41 RRTR constitute one
type of multiresin system that further simplifies the
practice of solid-phase organic synthesis (SPOS).42 In
RRTR systems, one resin-bound substrate is transferred
to solution phase by the action of a phase-transfer agent,
or chaperone, and then coupled in situ to another resin-
bound substrate. This concept allows for the convergent
solid-phase synthesis and eventual coupling of fragments
for which a linear SPOS strategy would involve incom-
patible reaction conditions.
In combinatorial chemistry, the concept of RRTR could
find applications for the construction of new product
libraries in which each resin-bound substrate is a mem-
ber of a respective library assembled by solid-phase
synthesis. As shown in the previous section, the DEAM-
PS resin facilitates the synthesis of functionalized aryl-
boronic acids that can otherwise be difficult to isolate and
handle in solution. Their direct use with another resin-
bound substrate in RRTR processes could eliminate time-
consuming cleavage and transfer operations, thereby
considerably simplifying the outlook of library synthesis
by manual or automated means. The use of DEAM-PS-
supported boronic acids facilitates the transfer of small
quantities of boronic acid and also circumvents their
tendency to dehydrate by forming anhydrides that are
difficult to weigh out accurately.
Phase transfer in RRTR processes involving DEAM-
PS-boronate adducts could be promoted from exposure
to water or alcohols under conditions that must be
compatible with the desired reaction. Both the added
phase-transfer agent and the released DEAM-PS resin
must be inert to all reagents used in these processes.
With this in mind, we have developed a strategy for resin-
to-resin Suzuki coupling reactions via phase transfer of
DEAM-PS-supported arylboronic acids under both aque-
ous and anhydrous conditions.37 The potential of these
methods was demonstrated with the convergent solid-
phase synthesis of compounds with unsymmetrically
functionalized biphenyl units such as those represented
in several biologically active molecules.43
(41) For selected examples, see: (a) Rebek, J . Tetrahedron 1979,
35, 723-731. (b) Cohen, B. J .; Kraus, M. A.; Patchornik, A. J . Am.
Chem. Soc. 1981, 103, 7620-7629. (c) Parlow, J . Tetrahedron Lett.
1995, 36, 1395-1396.
(42) For a recent example involving amide bond formation, see:
Hamuro, Y.; Scialdone, M. A.; DeGrado, W. F. J . Am. Chem. Soc. 1999,
121, 1636-1644.

12 J . Org. Chem., Vol. 67, No. 1, 2002
Gravel et al.
Ta ble 7. An h yd r ou s Su zu k i RRTR of 2a a n d 38: Effect
of Tr a n sfer Agen t on Con ver sion a
transfer temp time convn
entry solvent
base
agent
(°C) (h) (%)d
b
1
2
3
4
5
6
7
DMF
N(CH2CH2OH)3b
105 20
105 20
85 20
40
45
PhMe N(CH2CH2OH)3
dioxane NH(CH2CH2OH)2
b
45
b
DMF
DMF
DMF
DMF
Et3Nb
Et3Nc
Et3Nb
Et3Nc
(HOCH2)2c 105 20
100
100
100
85
(HOCH2)2b 105 20
(HOCH2)2c
(HOCH2)2
85 20
85 20
a
Typical trials were carried out with 38 (40 mg, 0.55 mmol/g)
and 2 (4 equiv, 107 mg, 0.82 mmol/g) in 2 mL of degassed solvent
b
with ca. 10-20 mol % of Pd(PPh3)4 as catalyst. A large excess
F igu r e 5. Resin-to-resin transfer between DEAM-PS-sup-
ported boronic acids (2) and haloarene resins by a Suzuki cross-
coupling reaction.
d
was used, ca. 10% v/v. c 20 equiv was used. Measured by 1H NMR
integration of representative signals on crude reaction products.
Ta ble 8. An h yd r ou s Su zu k i RRTR of 2a a n d 38: Effect
of Ba se a n d Tem p er a tu r e u n d er P d 2(d ba )3 Ca ta lysis (50
m ol %)a
Sch em e 6
entry
base
temp (°C)
conversion (%)b
yield (%)c
1
2
NaOH
Ba(OH)2
K2CO3
Cs2CO3
K3PO4
KF
60
60
60
60
60
60
25
60
60
25
d
d
0d
0d
3
d
0d
4
d
d
>98
78
>98
>98
72
0d
5
0d
6
>98
74
>98
>98
71
7
KF
8
CsF
9
Et3N
10
Et3N
a
Typical trials were carried out with 38 (20 mg, 0.55 mmol/g)
and 2a (3.2 equiv, 45 mg, 0.79 mmol/g) with the indicated base
(10 equiv) and 50 mol % Pd2(dba)3 as catalyst in DMF/ethylene
Herein, we describe the full optimization of the anhy-
drous Suzuki RRTR system. As shown conceptually in
Figure 5, transesterification on the DEAM-PS-boronate
linkage is expected to liberate the boronic acid in solution
(as an ester) so that it can be transferred in situ to a
haloarene resin under palladium(0) catalysis and added
base.44
b
glycol 10:1 (2.5 mL) for 18 h. Measured by 1H NMR integration
of representative signals on crude reaction products. c Nonopti-
mized yields of crude products after cleavage from the resin and
drying in vacuo for greater than 12 h. The reported values are
usually an average of mass balance and internal standardization
d
(see Supporting Information for details). Premature cleavage.
As a working model, the transfer of DEAM-PS resin-
bound p-tolylboronic acid (2a ) to Wang resin-bound
p-iodobenzoic acid (38)45 was attempted with different
stoichiometries under various solvent, base, and temper-
ature conditions (Scheme 6). The resulting resin mixture
was then treated with 1:1 trifluoroacetic acid/dichlo-
romethane to liberate the biphenyl product 39 and, if any,
unreacted p-iodobenzoic acid. Any boronic acid still
attached to the DEAM-PS support can be rinsed off prior
to cleavage by carrying out aqueous washes. The leftover
DEAM-PS resin does not liberate any byproducts upon
treatment with TFA. The conversion results for optimiza-
tion of the transfer agent are summarized in Table 7.
These assays were carried out with 4 equiv of DEAM-
PS-supported p-tolylboronic acid and 10-20% Pd(0)
catalyst loading in various solvents and at various
temperatures.
Knowing the propensity of diethanolamine and tri-
ethanolamine to transesterify boronic esters,30 we exam-
ined their use as phase-transfer agents that could also
function as the required base. However, as shown from
entries 1-3 (Table 7), they were surprisingly ineffective.46
The use of triethylamine as base in DMF, in conjunction
with added diol, was then explored. Whereas pinacol led
to low conversions (data not shown), the use of ethylene
glycol as transfer agent was found to be satisfactory
(entries 4-7, Table 7). When triethylamine and ethylene
glycol (1:1) were used in large excess, full conversion was
achieved at 85 °C for 20 h (entry 6, Table 7). Eventually,
it was also found that substitution of Pd(PPh3)4 for a
phosphine-free catalyst, Pd2(dba)3, led to crude reaction
products of higher purity.47
Next, we explored the effect of the nature of the base
on conversion using 50 mol % Pd2(dba)3 at 60 °C (Table
8). To this end, we found that only fluoride and triethyl-
amine were satisfactory and even provided some biphenyl
product at room temperature (entries 7 and 10, Table 8).
We then sought general optimal conditions that are mild
enough to minimize alcoholysis of the Wang ester linker
while still providing complete coupling within 20 h at 105
°C with only 1.5 equiv of DEAM-PS-supported boronic
acid and with a lower catalyst loading (Table 9). Triethyl-
amine, essentially as a cosolvent (entries 7-8, Table 9),
(46) Control experiments have shown that these are competent
transesterification agents; they release p-tolylboronic acid from DEAM-
PS almost entirely after 0.5 h in a 9:1 mixture of DMF/triethylamine
at 105 °C. Thus, to explain their lower efficiency, we suspect that
transmetalation of the corresponding diethanolamine and pinacol
boronic esters with the PS-Ar-Pd-I intermediate is significantly
slower as compared to that of the ethylene glycol esters.
(43) Duncia, J . V.; Carini, J . D.; Chiu, A. T.; J ohnson, A. L.; Price,
W. A.; Wong, P. C.; Wexler, R. R.; Timmermans, P. B. M. W. M. Med.
Res. Rev. 1992, 12, 149.
(44) For a recent review discussing Suzuki cross-coupling reactions
using a single supported substrate, see: Sammelson, R. E.; Kurth, M.
J . Chem. Rev. 2001, 101, 137-202.
(45) Guiles, J . W.; J ohnson, S. G.; Murray, W. V. J . Org. Chem. 1996,
61, 5169-5171.
(47) Most final compounds were obtained as brown powders, sug-
gesting the presence of residual palladium species (palladium black)
that remained strongly absorbed to the polymer matrix prior to
cleavage from the resin. Crude products can be further purified by
chromatography to eliminate these impurities.

Reactions of Boronic Acids
J . Org. Chem., Vol. 67, No. 1, 2002 13
Sch em e 7
Ta ble 9. An h yd r ou s Su zu k i RRTR of 2a a n d 38: Effect
2a and 38 in the absence of ethylene glycol gave largely
incomplete transfer as shown by a lower than 50%
conversion to product 39. Treatment of DEAM-PS-sup-
ported p-tolylboronic acid alone in hot anhydrous DMF/
Et3N (9:1, 105 °C, 24 h) led to less than 25% leaching of
the boronic acid. These experiments confirmed the ex-
pected advantage of using the phase-transfer agent. In
fact, ethylene glycol transesterifies the resin-bound bo-
ronic acid within a time scale that minimizes any rate
lowering of the cross-coupling. When resin 2a was treated
for 0.5 h in an 8:1:1 mixture of DMF/triethylamine/
ethylene glycol at 105 °C, less than 10% of the boronic
acid remained bound to the DEAM-PS support after 0.5
h.
The usefulness of DEAM-PS to synthesize new aryl-
boronic acids and the potential of the resin-to-resin
Suzuki coupling strategy were clearly demonstrated by
the convergent syntheses of unsymmetrically function-
alized biphenyl compounds (Scheme 7, eqs 1-3). The
DEAM-PS-supported amide derivative 1‚19a was made
as described in Table 4. Following washing and drying
operations, it was reacted with 38 using the optimal
conditions of Table 9, affording 4,4′-biphenyl dicarboxylic
acid monoamide 41 after cleavage from the resin mixture
(40 + 1) (eq 1, Scheme 7). This example makes a very
significant case for using a convergent RRTR strategy
in solid-phase synthesis. Indeed, as p-carboxybenzene-
boronic acid is inept as a substrate in Suzuki reactions,50
a linear solid-phase strategy involving its coupling to 38
followed by amide formation would not be possible.
of Ba se a n d Ca ta lyst a t High Tem p er a tu r e (105 °C)a
entry
base
catalyst
conversion (%)b
yield (%)c
1
2
3
4
5
6
7
8
NaF
TBAF
CsF
Pd2(dba)3
29
>98
>98
93
33
<2
3
65
48
58
63
64
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
KF
KF
PdCl2(dppf)
Pd2(dba)3
>98
Et3Nd
Et3Nd
Et3Nd
42
PdCl2(dppf)
81
PdCl2(dppf)e
>98
a
Typical trials were carried out with 38 (40 mg, 0.98 mmol/g)
and 2 (1.5 equiv, 58 mg, 1.07 mmol/g) with the indicated base (10
equiv) and catalyst (10 mol % Pd2(dba)3 or 20 mol % PdCl2(dppf))
in DMF/ethylene glycol 10:1 (2.5 mL) at 105 °C for 20 h.
Measured by 1H NMR integration of representative signals on
b
crude reaction products. c Nonoptimized yields of crude products
after cleavage from the resin and drying in vacuo for greater than
12 h. The reported values are based on internal standardization
d
(see Supporting Information for details). A large excess was used
(0.25 mL). e The catalyst was added in two portions, one at the
start and one after 8 h.
was found to be the most effective base in combination
with 20% PdCl2(dppf) as catalyst. The latter was prefer-
ably added in two to three portions at a few hours
interval in order to minimize the effects of catalyst
inactivation.47 Interestingly, although the use of cesium
fluoride and TBAF as bases led to full conversion (entries
2-3, Table 9), unlike potassium fluoride, they induced
complete premature cleavage of the product at 105 °C.
This most likely occurs by alcoholysis of the Wang ester
linker with ethylene glycol. Efforts to lower the effective
temperature of reaction by using Buchwald’s48 or Fu’s49
newly discovered ligand systems failed.
(48) Old, D. W.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc.
Control experiments were devised to confirm the role
and the efficiency of ethylene glycol as the phase-transfer
agent. Resin-to-resin cross-coupling of model substrates
1998, 120, 9722-9723.
(49) Littke, A.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387-
3388.

14 J . Org. Chem., Vol. 67, No. 1, 2002
Gravel et al.
F igu r e 6. Resin-to-resin transfer by a borono-Mannich reaction between DEAM-PS-supported boronic acids (2) and resin-bound
iminium intermediates formed from dialkylamino resins (e.g., 48) and glyoxylic acid.
Ta ble 10. Op tim iza tion of th e Solven t System , a t 65 °C
The Suzuki RRTR strategy is also useful to afford
for 24 H, for th e Bor on o-Ma n n ich RRTR of 48 a n d 2a To
monoalkylated biphenyl dibenzylamines (Scheme 7, eq
2). For example, DEAM-PS-bound p-(N-morpholino-
methyl)benzeneboronic acid (9c) (Table 2) was treated
with trityl-PS-bound m-iodobenzylamine (42) under a
slightly modified RRTR method (KF as base) and, after
cleavage of the resin mixture, afforded crude diamine 44
Give 50a a
entry
solvent
conversion (%)b
1
2
3
4
5
7:1 DMF/EtOH
65
54
23
37
79
7:1 DMF/n-BuOH
7:1 dioxane/n-BuOH
7:1 THF/(HOCH2)2
7:1 THF/EtOH
1
in 82% yield and high purity (>90% by H NMR).51 As
shown through the isolation of 47, monoacylated biphenyl
dianilines can also be synthesized efficiently (Scheme 7,
eq 3). In the above examples, cleavage and handling of
the boronic acid prior to the Suzuki coupling was obvi-
ously eliminated, and there was no need for transferring
the resin to a new reaction vessel after washing and
drying operations. These advantages have been demon-
strated in the synthesis of a small model library of
biphenyl compounds using a commercial, semiautomated,
parallel synthesizer.37,52
a
Preparation of resin substrates, RRTR trials, and subsequent
cleavage of the resin mixture were carried out as indicated in the
b
Supporting Information. Based on the relative amounts of prod-
uct and bis(trifluoroacetate) salt 51 calculated by integration of
relevant signals by 1H NMR after 24 h of reaction time.
Ta ble 11. P r ep a r a tion of Ar ylglycin e Der iva tives by a
Bor on o-Ma n n ich RRTRa
amino
entry resin
DEAM-PS-
boronate 2
conversion yield
product
(%)b
(%)c
1
2
3
4
5
6
7
8
48
48
48
48
48
48
52
56
R ) 4-Me-C6H4
R ) 2-Me-C6H4
R ) 4-MeO-C6H4
R ) 4-Br-C6H4
R ) 1-Naph
R ) E-HCdCH(Bu)
R ) 4-MeO-C6H4
R ) 4-MeO-C6H4
50a
50b
50c
50d
50e
50f
54c
57c
79
81
90
21
85
89
95
76
85
73
The boronic acid Mannich reaction is compatible with
a wide range of solvents, including hydroxylic ones.17
Thus, an alcohol cosolvent could act as the neutral phase-
transfer agent required to cleave the DEAM-PS-sup-
ported boronic acids under mild conditions appropriate
to a RRTR system. The boronic acid liberated in situ as
an ester could then add to the iminium intermediate
formed between a dialkylamino-functionalized resin and
an activated aldehyde such as glyoxylic acid (Figure
6).17c,17p The resulting arylglycine products obtained after
cleavage of the resin mixture are compounds of particular
interest for their biological activity.53 We have first
optimized conditions using DEAM-PS-supported p-tolyl-
boronic acid (2a , R ) 4-Me-C6H4-), piperazinetrityl resin
(48), and glyoxylic acid in a semiautomated synthesizer.52
The reaction was found to be rather slow and strongly
dependent on the nature of the solvent system, THF/
EtOH (7:1) being identified as the best mixture (Table
10). Optimal experimental conditions first involve incu-
>95
10
90
>95
91
82
a
Preparation of resin substrates, RRTR trials, and subsequent
cleavage of the resin mixture were carried out as indicated in the
b
Supporting Information. Based on the relative amounts of prod-
uct and respective bis(trifluoroacetate) salt 51, 55, or 58 calculated
by integration of relevant signals by 1H NMR after 24-48 h of
reaction time. c Yields of crude product based on 1H NMR analysis
with an internal standard.
bating the dialkylamino resin with glyoxylic acid mono-
hydrate (1.1 equiv) for 2 h in dry THF at room temper-
ature. Then, 4 equiv of DEAM-PS-bound boronic acid (2)
is added along with the appropriate volume of 8:3 THF/
EtOH. The suspension is shaken at 65 °C for up to 48 h.
In this way, conversion levels superior to 75% were
observed in the case of p-tolylboronic acid, as seen after
cleavage of the final resin mixture 1 and 49a with 5%
trifluroacetic acid/dichloromethane to give the corre-
sponding amino acid product 50a as a bis(trifluroroace-
tate) salt (Table 11, entry 1). The rest of the unreacted
starting resin 48 is cleaved into the bis(trifluoroacetate)
salt of piperazine (51), which can be eventually removed
by precipitation (Scheme 8). There are no other byprod-
ucts observed, as the leftover DEAM-PS resin (1) does
not give any artifacts upon treatment with trifluoroacetic
acid in the product release step. As indicated above, the
transesterification of resin 2 with ethanol, a process
(50) As reported in: Wendeborn, S.; Berteina, S.; Brill, W. K.-D.;
De Mesmaeker, A. D. Synlett 1998, 671-575. Our own attempts at
coupling p-carboxybenzene boronic acid also failed.
(51) A linear synthesis based on the cross-coupling of 42 with
p-(bromomethyl)benzeneboronic acid would be hampered by incompat-
ible reaction conditions. The basic conditions required in the Suzuki
coupling could promote nucleophilic displacement on the benzylic
bromide which, in addition, can react slowly with palladium(0) by
oxidative addition.
(52) A Quest 210 instrument with solvent wash unit was employed
(Argonaut Technologies). Cleavage was effected in line, and crude
products were obtained after evaporation of solvents.
(53) For example, see: Bedingfield, J . S.; Kemp, M. C.; J ane, D. E.;
Tse, H. W.; Roberts, P. J .; Watkins, J . J . Pharmacol. 1995, 116, 3323-
3330.

Reactions of Boronic Acids
Sch em e 8
J . Org. Chem., Vol. 67, No. 1, 2002 15
a RRTR format provide yields comparable to reactions
using nonsupported boronic acids.
The concept of RTRR involving DEAM-PS-supported
boronic acids, successfully demonstrated in this article
for the Suzuki cross-coupling and the borono-Mannich
reactions, could potentially be expanded to other types
of processes employing boronic acids as substrates.
Con clu sion s
This article describes the first general solid-phase
approach to the immobilization and derivatization of
functionalized boronic acids. This approach is based on
the use of N,N-diethanolaminomethyl polystyrene (DEAM-
PS), a support containing a diethanolamine resin anchor
that facilitates the immobilization of a wide variety of
boronic acids in anhydrous solvents at room temperature.
Evidence for the formation of a bicyclic diethanolamine
boronate with putative N-B coordination was shown by
1H NMR analysis of DEAM-PS-supported p-tolylboronic
acid. From UV spectroscopic studies using the same
boronic acid as a model, hydrolysis and attachment were
shown to occur under a rapidly attained equilibrium.
DEAM-PS-supported arylboronic acids functionalized
with a formyl, a bromomethyl, a carboxyl, or an amino
group can be transformed in good to excellent yields into
a wide variety of amines, amides, anilides, and ureas,
respectively. Moreover, Ugi multicomponent reactions,
derivatization of multifunctional arylboronic acids, and
sequential reactions can also be carried out efficiently.
These novel boronic acid derivatives can be released
mildly from the DEAM-PS support by simple stirring in
a wet THF solution (5% H2O/THF). Alternatively, the
DEAM-PS-supported arylboronic acids can be employed
directly into resin-to-resin transfer reactions. This type
of multiresin process helps eliminate time-consuming
cleavage and transfer operations, thereby considerably
simplifying the outlook of combinatorial library synthesis
by manual or automated means. Herein, this concept was
illustrated with a set of optimized procedures for the
Suzuki cross-coupling and the borono-Mannich reactions.
Overall, the use of DEAM-PS resin greatly facilitates
access to functionalized arylboronic acid derivatives that
can be otherwise difficult to synthesize and isolate by
solution-phase methods. Thus, this general solid-phase
approach has significant practical value for all organic
and combinatorial chemists performing research involv-
ing the use of boronic acids.
Sch em e 9
required for phase transfer of the boronic acid, appears
to be a dynamic equilibrium. The latter process is driven
forward by the large excess of ethanol and through
consumption of the boronic acid which adds to the
putative iminium intermediate to form the supported
product 49 (Figure 6). In fact, because of the trans-
esterification equilibrium, there is some leftover DEAM-
PS-supported boronic acid (2) at the end. Consequently,
it is necessary to include water/THF washes in order to
rinse off all excess boronic acid from the resin mixture
prior to the acidolytic cleavage of products 50.
Next, we have studied substrate generality for this new
RRTR system (Scheme 8). As shown in Table 11, conver-
sion values and product yields were generally good,
except for the RRTR of electron-poor arylboronic acids.
Thus, conversion values were highest for DEAM-PS-
supported p-methoxybenzeneboronic acid (entries 3, 7,
8, Table 11) and lowest for p-bromobenzeneboronic acid
(entry 4, Table 11). According to entry 6 in Table 11,
DEAM-PS-supported alkenylboronic acids are also ap-
propriate substrates. An example using an acyclic amine
(56) was equally successful (entry 8, Table 11), showing
that in principle a variety of secondary amines such as
terminal N-alkylamino acids could be employed (Scheme
9).17m Although only electron-rich arylboronic acids cur-
rently provide satisfactory conversions to crude material
of high purity, analytically pure samples of most reported
compounds can be obtained following precipitation with
a methanol/ether system and filtration of the unreacted
dialkylamine as a bis(trifluoroacetate) diammonium salt.
We have also confirmed that the examples performed in
Exp er im en ta l Section
Full experimental details and characterization of new
compounds are provided in the Supporting Information.
Ack n ow led gm en t. This research was supported by
the Natural Sciences and Engineering Research Council
(NSERC) of Canada (operating and CRD grants) and
by a Canadian Society for Chemistry (CSC) combina-
torial chemistry grant sponsored by AstraZeneca, Bio-
chem Pharma, Boehringer Ingelheim, and Merck Frosst.
NSERC is gratefully acknowledged for graduate schol-
arships (to M.G. and K.A.T.) and for summer under-
graduate scholarships (to M.Z. and C.B.). The authors
thank Annie Tykwinski for the cover graphics design.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details, characterization of new compounds, and reproductions
of proton and carbon NMR spectra for all reported compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O0106501