Micellar catalysis of Suzuki-Miyaura cross-couplings with heteroaromatics in water

Article abstract of DOI:10.1021/ol801712e

(Chemical Equation Presented) Pd-catalyzed couplings involving several heteroaromatic halides (bromides and chlorides) as well as boronic acids can be done under exceedingly mild conditions (between rt and 40 °C) in pure water using commercially available Pd catalysts and PTS, a nanomicelle-forming amphiphile.

Full text of DOI:10.1021/ol801712e

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5329-5332
Micellar Catalysis of Suzuki-Miyaura
Cross-Couplings with Heteroaromatics
in Water
Bruce H. Lipshutz* and Alexander R. Abela
Department of Chemistry & Biochemistry, UniVersity of California,
Santa Barbara, California 93106
lipshutz@chem.ucsb.edu
Received July 25, 2008
ABSTRACT
Pd-catalyzed couplings involving several heteroaromatic halides (bromides and chlorides) as well as boronic acids can be done under exceedingly
mild conditions (between rt and 40 °C) in pure water using commercially available Pd catalysts and PTS, a nanomicelle-forming amphiphile.
The nanomicelle-forming, commercially available am-
phiphile PTS (polyoxyethanyl R-tocopheryl sebacate, 1,
Figure 1)1 was recently introduced as a contribution to green
chemistry;2 that is, as an enabling technology that facilitates
several transition-metal-catalyzed cross-coupling reactions
at room temperature in water as the only solvent.3a-c
Included among this group are Suzuki-Miyaura reactions
between aryl halides or pseudohalides and arylboronic acids.
The success of these Pd-catalyzed processes, which also
featured biaryl syntheses from aryl chlorides, suggested that
still more challenging heteroaromatic precursors as either or
both reaction partners might be amenable to this micellar
catalysis. Since heteroaromatic biaryls are especially valued
Figure 1. PEG-R-tocopheryl sebacate (PTS). PEG ) blue; R-to-
copheryl ) red; sebacate ) black.
in the pharmaceutical arena,4 and with significant attention
being paid of late to construction of such arrays,5 a broad-
based study has been conducted using aqueous PTS in the
absence of cosolvents. We now present results suggestive
of the scope and limitations of this technology based on
(1) Sigma Aldrich catalog no. 698717.
(2) Sheldon, R. A.; Ardens, I.; Hanefeld, U. Green Chemistry and
Catalysis; Wiley-VCH: Weinheim, Germany, 2007.
(4) (a) Capdeville, R.; Buchdunger, E.; Zimmermann, J.; Matter, A. Nat.
ReV. Drug DiscoVery 2002, 1, 493–502. (b) Boren, J.; Cascente, M.; Marin,
S.; Comin-Anduix, B.; Centelles, J. J.; Lim, S.; Bassilian, S.; Ahmed, S.;
Lee, W. N.; Boros, L. G. J. Biol. Chem. 2001, 276, 37747–37753.
(5) (a) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129,
3358–3366. (b) Guram, A. S.; Wang, X.; Bunel, E. E.; Faul, M. M.; Larsen,
R. D.; Martinelli, M. J. J. Org. Chem. 2007, 72, 5104–5112. (c) Kudo, N.;
Perseghini, M.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1282–1284.
(3) (a) Lipshutz, B. H.; Petersen, T. B.; Abela, A. R. Org. Lett. 2008,
10, 1333–1336. (b) Lipshutz, B. H.; Taft, B. R. Org. Lett. 2008, 10, 1329–
1332. (c) Lipshutz, B. H.; Chung, D. W.; Rich, B. L. Org. Lett. 2008, 10,
3793–3796. (d) Lipshutz, B. H.; Aguinaldo, G. T.; Ghorai, S.; Voigtritter,
K. Org. Lett. 2008, 10, 1325–1328. (e) Lipshutz, B. H.; Ghorai, S.;
Aguinaldo, G. T. AdV. Synth. Catal. 2008, 350, 953–956.
10.1021/ol801712e CCC: $40.75
Published on Web 11/11/2008
2008 American Chemical Society

Table 1. Cross-Couplings of Aryl/Heteroaryl Bromides with Aryl/Heteroaryl Boronic Acids Using Catalyst 3 in 2% PTS/Watera
a Standard conditions (unless otherwise noted): 0.5 M solution of aryl/heteroaryl bromide stirred in a 2% w/w PTS/water solution with 0.02 equiv of 3,
3.0 equiv of Et3N, and 2.0 equiv of boronic acid at the indicated temperature and time. b Isolated yield. c 1.5 equiv of boronic acid was used.
several representative heteroaromatic bromides and chlorides
as well as heteroaromatic boronic acids.
conversions were also lower. It has already been established
that the corresponding “on water”6 reactions do take place
but to highly variable degrees and, in these cases, are
seemingly not competitive.3 Several heteroaryl bromides
Catalysts 2 and 3 (Figure 2; 2%) were chosen on the basis
of their use in prior studies.3a,5b Typically, 1-2% PTS in
pure water was sufficient; attempts at higher loading (3%)
offered no advantage, and conversions were somewhat lower
under otherwise identical conditions. In the absence of PTS,
(6) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolib, H. C.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275–3279.
5330
Org. Lett., Vol. 10, No. 23, 2008

Figure 3. Coupling partners that may lead to low conversions.
various ligands, temperatures, and times), and 2-furylboronic
acid (with either aromatic or heteroaromatic bromides; e10%
conversion).
Heteroaromatic chlorides were particularly difficult to
couple, even when using nonheteroaromatic boronic acids.
As illustrated in Table 2, most required heating to 40 °C, a
switch to ligand 2, and reaction times approaching 1 day.
Highest levels of conversion were realized, again, using 2%
PTS. For example (entry A), lower conversions and conse-
quently lower isolated yields of product biaryl 14 were
observed with 1% PTS, while full conversion occurred at
40 °C in the presence of 2% PTS/H2O. Quinacrine derivative
15 (entry B) was smoothly prepared using p-anisylboronic
acid, but the corresponding coupling with 3-thienylboronic
acid (5; see Table 1) or acid 6 failed under otherwise identical
conditions. 2,3-Dichloropyridine selectively coupled with 2,3-
dimethylboronic acid at the 2-position, but the 3-arylated was
also formed (18%) in a combined yield of 80% (entry C; no
bis-adduct was seen). Two biaryl products 16 and 17
resulting from cross couplings at rt with 2-chloro-5-trifluo-
romethylpyridine were each formed in high yield (entries D
Figure 2. Catalyst complexes and ligands used in this study.
were screened, as shown in Table 1, including 3-pyridyl
(entry 1), 5-pyrimidyl (entry 2), 3-quinolyl (entry 3),
4-isoquinolyl (entry 4), and 3-benzothiophenyl (entry 5)
derivatives. Combinations with both aryl and heteroaryl
boronic acids led to high isolated yields within a 4-20 h
time frame, used mainly at room temperature. Aryl bromides
7, 9, and 12 (entries 6-8), likewise, led to biaryls 8, 11,
and 13, respectively, under related conditions, although mild
heating to 40 °C was needed due to the lower reactivity of
these boronic acids. Overall, isolated yields can be expected
to be quite good. Some combinations, however, were
problematic (Figure 3), such as the case of 3-pyridylboronic
acid (10) with heteroaryl bromides (low conversions; com-
pare with Table 1, entries 7 and 8); 2-bromothiazole, with
aromatic boronic acids (no greater than 70% conversion with
c
Table 2. Couplings with Heteroaryl Chlorides (in blue) Using Catalyst 2 in PTS/Watera
-
a Standard reaction conditions (unless otherwise noted): 0.5 M solution of aryl/heteroaryl chloride in 2% w/w PTS/water with 0.02 equiv of 2, 3.0 equiv
of Et3N, and 2.0 equiv of boronic acid at the indicated temperature and time. b All yields isolated. c All surfactants used as 2% w/w solutions in water unless
otherwise noted. d Precursor chloride used as the commercially available 2H2O, 2HCl salt under the following conditions: 0.2 M solution of heteroaryl
chloride in 2% PTS/water, using 5.0 equiv of Et3N. e 1% w/w PTS/water solution used. f 1 equiv of boronic acid.
Org. Lett., Vol. 10, No. 23, 2008
5331

Scheme 1
Figure 4. Other surfactants used as comparisons.
and E). Thiophene derivative 17 could be made at 25 °C
from either the boronic acid or trifluoroborate salt7 as
coupling partner.
a Isolated yield reported by Buchwald et al.5a using Pd2(dba)3 as
precatalyst and 1.5 equiv of 5. b Isolated yield using Pd(OAc)2 as precatalyst
and 2.0 equiv of 5 in 2% PTS/water.
Comparisons as to the effectiveness of PTS as surfactant
with two other common, nonionic amphiphiles, can be made
en route to products 14 and 18: (1) the (structurally) closely
related TPGS8 and (2) the traditional 2-component species
Triton X-1009 (Figure 4). The results show a similar trend
noted previously for Pd-catalyzed (Heck3b and Suzuki-
Miyaura3a) and Ru-mediated olefin metathesis (CM3d and
RCM3e) reactions. That is, while other surfactants “work”
to varying degrees, in general, PTS appears to provide a
hydrophilic lipophilic balance (HLB)10 and particle size that
best accommodates both educts and catalysts.
The potential for these reactions to take place under green
conditions is further demonstrated by direct comparison of
the coupling between sterically demanding and electronically
deactivated aryl chloride 19 and 3-thiophenylboronic acid 5
(Scheme 1). Thus, in lieu of an organic solvent, several
equivalents of inorganic salt as base, and 100 °C heating,5a
micellar PTS leads to the desired heterobiaryl 20 in water,
using volatile triethylamine as base, and very gentle heating
to only 38 °C. The isolated yield of biaryl 20 (90%) also
compares favorably with the reported level of efficiency.5a
In summary, a variety of water-insoluble heteroaromatic
coupling partners are amenable to Suzuki-Miyaura cross-
couplings under very mild conditions (rt up to 40 °C) using
PTS technology. This approach offers an important envi-
ronmentally sound alternative in our efforts toward removing
organic solvents from organic reactions.
Acknowledgment. Financial support provided by Zymes,
LLC is warmly acknowledged. Catalysts 2 and 3 were
generously provided by Johnson Matthey.
(7) (a) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275–286,
and references therein. (b) Darses, S.; Genet, J.-P. Chem. ReV. 2008, 108,
288–325.
Supporting Information Available: Detailed experimen-
tal procedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(8) PCI-102B Eastman Vitamin E TPGS NF. For applications and
properties, see http://www.eastman.com/NR/rdonlyres/A2FE037B-0778-
4A90-A0FC-5D07BE51064A/0/PCI102.pdf (accessed June 2008).
(9) Triton X-100: CAS registry no. 9002-93-1.
(10) Pasquali, R. C.; Taurozzi, M. P.; Bregni, C. Int. J. Pharm. 2008,
356., 44–51.
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