Suzuki-Miyaura cross-coupling of alkenyl tosylates with alkenyl MIDA boronates

Article abstract of DOI:10.1016/j.tetlet.2012.04.091

A practical procedure for the palladium-catalysed Suzuki-Miyaura coupling of various alkenyl tosylates with alkenyl MIDA boronates has been developed. Commercially available trans-bromo[N-succinimidyl-bis(triphenylphosphine)] palladium(II) [Pd(PPh₃

Full text of DOI:10.1016/j.tetlet.2012.04.091

Tetrahedron Letters 53 (2012) 3444–3447
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Tetrahedron Letters
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Suzuki–Miyaura cross-coupling of alkenyl tosylates with alkenyl MIDA
boronates
⇑
Monique Lüthy, Richard J.K. Taylor
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical procedure for the palladium-catalysed Suzuki–Miyaura coupling of various alkenyl tosylates
with alkenyl MIDA boronates has been developed. Commercially available trans-bromo[N-succinimidyl-
bis(triphenylphosphine)]palladium(II) [Pd(PPh3)2NBS] is an effective catalyst under the slow release
conditions of MIDA boronates; with less activated alkenyl tosylates addition of the cheap, air-stable
tricyclohexylphosphine tetrafluoroborate enhances reactivity.
Received 16 February 2012
Revised 29 March 2012
Accepted 19 April 2012
Available online 26 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Suzuki–Miyaura coupling
Alkenyl tosylates
Alkenyl MIDA boronates
Trans-bromo[N-succinimidyl-
bis(triphenylphosphine)]palladium(II)
Suzuki–Miyaura coupling reactions are an invaluable weapon
for the synthetic chemist in natural product and drug discovery
programmes.1 Although the majority of the early studies concen-
trated on the use of aryl and vinyl halides as the electrophilic cou-
pling partners, there has been increasing interest in the coupling
reactions of aryl and vinyl sulfonate esters.2 This approach is par-
ticularly valuable with sulfonate esters derived from enolisable
carbonyl compounds, and there are many elegant examples from
the pharmaceutical industry and in natural product synthesis.3–5
Most of these examples employ carbonyl-derived vinyl triflates
(and this method was the cornerstone of our recent synthesis of
dictyosphaeric acid A5). However, vinyl triflates are rather reactive
compounds and in recent years there have been considerable ad-
vances in the design of improved catalyst/ligand systems which
facilitate the Suzuki coupling reactions of the more tractable tosyl-
ate and mesylate analogues.6–13 Notable highlights of this method-
ology in drug research are the Suzuki coupling reactions of
thymidine mesitylenesulfonates14 and of carbapenem-derived vi-
nyl tosylates.15 However, vinyl tosylates are still relatively little
exploited, despite the fact that they are attractive coupling part-
ners—they are often crystalline and they are significantly more sta-
ble towards moisture and air than triflates and mesylates (and the
sulfonylating agents, TsCl and Ts2O, are relatively inexpensive).
As part of a natural product synthesis, we therefore chose as the
cornerstone the cross-coupling of alkenyl tosylates with alkenyl
boronates. Wishing both coupling partners to be bench-stable,
we opted to employ N-methyliminodiacetic acid (MIDA) boro-
nates, developed by Burke,16 as the nucleophilic partners
(Scheme 1). Not only are MIDA boronates stable on silica and upon
common bench storage, their use in a slow-release Suzuki proto-
col17 was anticipated to be advantageous in terms of suppressing
undesired side-reactions during reactions with less reactive alke-
nyl tosylates. Published examples involving the cross-coupling of
alkenyl tosylates and alkenyl boronates are rather scarce,18,19 and
to the best of our knowledge, there are no reported examples of
the Suzuki coupling of alkenyl sulfonates with MIDA boronates.20
Herein we demonstrate the successful cross-coupling of alkenyl
tosylates and alkenyl MIDA boronates under slow-release Suzuki–
Miyaura reaction conditions. We further show that alkenyl tosy-
lates can outperform the more labile alkenyl triflates in compara-
ble coupling processes.
This study commenced with the Suzuki coupling of the known
dimedone-derived triflate, tosylate and mesylate 1a–c21–23 and
the known MIDA boronate 224 to give the previously reported
product 325 (Table 1). Initial studies were carried out using Burke’s
slow-release coupling protocol [3 mol % Pd(OAc)2, 6 mol % SPhos,
aq K3PO4] in 1,4-dioxane/water (5:1) at 60 °C in a sealed tube un-
der argon. Using these conditions, neither triflate 1a nor tosylate
1b underwent efficient coupling, with the less stable but more
reactive triflate being slightly superior to the tosylate (entries 1
and 2). Surprisingly, in both cases, complete decomposition of
the unreacted alkenyl sulfonate was observed.
We therefore went on to investigate the use of
Pd(PPh3)2NBS26,27 as catalyst as it has recently been used success-
fully for the Suzuki coupling of an alkenyl iodide with a MIDA bor-
⇑
Corresponding author. Tel.: +44 (0) 1904 322606; fax: +44 (0) 1904 324523.
E-mail address: richard.taylor@york.ac.uk (R.J.K. Taylor).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.091

M. Lüthy, R. J. K. Taylor / Tetrahedron Letters 53 (2012) 3444–3447
3445
X
X
N
Pd
B
+
O
O
R
Suzuki-Miyaura
coupling
O
O
OTs
X = O, H2
= BMIDA
R = alkyl, alkenyl, aryl
R
Scheme 1. Suzuki–Miyaura coupling of alkenyl tosylates and MIDA boronates.
onate in our laboratory.5 Pleasingly, using this catalyst, successful
coupling was achieved with all three sulfonates (entries 3–6).
The reaction with triflate 1a afforded the coupled product 3 in
71% yield (entry 3) whereas the crystalline tosylate 1b (which
was much easier to handle) furnished 3 in excellent (>90%) yield
in either aqueous K3PO4/1,4-dioxane or the more commonly em-
ployed aqueous Na2CO3/THF (entries 4 and 5). The reaction was
essentially complete after 6 h but overnight heating could be em-
ployed without loss of yield. Mesylate 1c also underwent coupling
but decomposition was observed and product 3 was obtained in
only moderate (48%) yield (entry 6).
The reaction temperature was investigated next using tosylate
1b, MIDA boronate 2 and catalytic Pd(PPh3)2NBS in THF/Na2CO3.
In accordance with Burke’s kinetic studies on the release of boronic
acid from MIDA boronates (1 h at 100 °C, 4–6 h at 60 °C and 24 h at
rt),17 the overnight reaction at 40 °C revealed that the release of the
free boronic acid from 2 indeed becomes the rate limiting factor.
Significant quantities of unreleased 2 (1.07 equiv/sulfonate) could
be recovered together with product 3 (68%) and 1b (32%) (entry
7). Carrying out the reaction at 80 °C shortened the time to 5 h
without a decrease in efficiency (entry 8). Most importantly, from
a practical viewpoint, using a conventional reaction set-up with a
reflux condenser gave 3 in almost quantitative isolated yield
(96%) after a reaction time of 6 h (entry 9).
(Table 2).28 The sealed tube method (overnight at 60 °C under ar-
gon) was examined in order to give a meaningful comparison.
The cross-coupling with activated tosylate 4, a lactone analogue
of 1b, showed similarly efficient coupling under standard condi-
tions (entry 1). By contrast, the efficiency dropped drastically with
less activated, sterically hindered alkenyl tosylate 5. The expected
product 15 was only formed in 33% yield and all remaining tosylate
5 (67%) was recovered (entry 2). We tentatively attributed the
incomplete reaction to insufficient catalyst reactivity and a screen-
ing of simple phosphine ligands as additives with Pd(PPh3)2NBS
confirmed this assumption. With triphenylphosphine, the conver-
sion was doubled and on changing to more electron-donating li-
gands such as SPhos and tricyclohexylphosphine the reaction
was further accelerated. Pleasingly, a quantitative yield was
achieved with the inexpensive and air-stable PCy3ÁHBF4 salt. Simi-
larly, with the pyrone-derived tosylate 6, the use of Pd(PPh3)2NBS/
PCy3ÁHBF4 was required for optimum yield (98%, entry 3). Pyrones
such as product 16 possess antimicrobial and cytotoxic activities
and their synthesis has been studied previously, but with signifi-
cantly lower yields.29 Interestingly, the reaction with coumarin-de-
rived tosylate 7 was slightly more efficient without the additional
PCy3ÁHBF4 ligand but incomplete conversion was observed never-
theless (57%, entry 4). This lower reactivity may be explained by
the high aromatic character of 7. In accord with this suggestion,
phenyl tosylate (8, entry 5) was inert under both sets of reaction
conditions. However, simple unactivated alkenyl tosylates 9–11
With optimised conditions in hand, we went on to examine the
scope of the coupling process with a variety of known tosylates
Table 1
Investigation and optimisation of reaction conditionsa
O
O
BMIDA
C6H13
2 (1.1 equiv.)
OSO2R
Pd-catalyst (3 mol%)
A: Pd(OAc)2/SPhos
B: Pd(PPh3)2NBS
base (7.5 equiv)
solvent/water (5:1)
Δ, 5-17 h
C6H13
1a (SO2R = Tf)
1b (SO2R = Ts)
1c (SO2R = Ms)
3
Entry
1 (SO2R)
Catalyst
Base
Solvent
Tempb (°C)
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
8
9
a (Tf)
b (Ts)
a (Tf)
b (Ts)
b (Ts)
c (Ms)
b (Ts)
b (Ts)
b (Ts)
A
A
B
B
B
B
B
B
B
K3PO4
K3PO4
K3PO4
K3PO4
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
1,4-Dioxane
60
60
60
60
60
60
40
80
67g
15
6
15
6
22
8
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
THF
THF
THF
71
94d
93e
48
68f
96
96
6
17
17
5
THF
THF
6
a
b
c
d
e
f
SPhos = 2-Dicyclohexylphosphino-2,6-dimethoxybiphenyl; Pd(PPh3)2NBS = trans-bromo[N-succinimidyl-bis(triphenylphosphine)]palladium(II); BMIDA—see Scheme 1.
Oil bath temperature except for entry 9.
Isolated yield.
Overnight heating gave 91% isolated yield.
Overnight heating gave 95% isolated yield.
Yield based on recovered sulfone was 100%.
Reflux under N2.
g

3446
M. Lüthy, R. J. K. Taylor / Tetrahedron Letters 53 (2012) 3444–3447
Table 2
Suzuki–Miyaura coupling of various tosylates with MIDA boronate 2a
Entry
Tosylate
Product
Additional phosphine (6 mol %)
Recovered tosylateb (%)
Yieldb (%)
O
O
O
O
1
None
—
90
OTs
C6H13
CO2Et
14
4
None
PPh3
67
35
33
65
CO2Et
SPhos
PCy3
PCy3ÁHBF4
28
—
—
72
2
3
OTs
95
99c
C6H13
15
O
5
O
O
None
PCy3ÁHBF4
24
—
73
98
O
O
O
OTs
C6H13
16
O
6
None
PCy3ÁHBF4
36
39
57
41
O
4
OTs
C6H13
17
7
None
PCy3ÁHBF4
100d
100d
—
—
OTs
5
6
7
C6H13
18
8
9
None
PCy3ÁHBF4
91d
—
9
88d
OTs
C6H13
19
BocN
BocN
OTs
PCy3ÁHBF4
—
—
91
97
C6H13
20
10
8
PCy3ÁHBF4
OTs
C6H13
21
22
11
OTs
9
PCy3ÁHBF4
PCy3ÁHBF4
47
52
52
48
C6H13
12
Ph
Ph
Ph
Ph
10
OTs
13
23
C6H13
a
Reaction conditions: alkenyl tosylate (0.40 mmol), MIDA boronate 2 (0.44 mmol), Pd(PPh3)2NBS (3 mol %) and additional phosphine (6 mol %) in degassed THF (5 mL), aq
Na2CO3 (3 M in degassed H2O, 1 mL), heated in sealed tube under argon, at 60 °C overnight (16–21 h).
b
Isolated yield.
Average yield over two runs.
Percentage (by NMR) in the substrate/product-ratio of the crude mixture.
c
d
were high yielding substrates for the coupling reaction under the
PCy3ÁHBF4 conditions (88–97%, entries 6–8). Some limitations of
this methodology were observed with the cyclooctenyl tosylate
12 and with the hindered vinyl tosylate 13, where only moderate
conversions were obtained after overnight reactions (entries 9
and 10).

M. Lüthy, R. J. K. Taylor / Tetrahedron Letters 53 (2012) 3444–3447
3447
O
O
BMIDA
(1.1 equiv.)
R
BMIDA
Pd(PPh3)2NBS (3 mol%)
aq Na2CO3
THF, reflux, 6 h
OTs
24
1b
R
93-98%
O
O
O
O
R
Ph
Ph
28: 98% (E/Z = 6/94)
3 (R = C6H13): 96%
29 (R = C8H17): 96%
30: 93%
31: 96%
Scheme 2. Scope of MIDA boronates in the Suzuki coupling with tosylate 1b.
4. Jacks, T. E.; Belmont, D. T.; Briggs, C. A.; Horne, N. M.; Kanter, G. D.; Karrick, G.
L.; Krikke, J. J.; McCabe, R. J.; Mustakis, J. G.; Nanninga, T. N.; Risedorph, G. S.;
Seamans, R. E.; Skeean, R.; Winkle, D. D.; Zennie, T. M. Org. Process Res. Dev.
2004, 8, 201.
5. Burns, A. R.; McAllister, G. D.; Shanahan, S. E.; Taylor, R. J. K. Angew. Chem., Int.
Ed. 2010, 49, 5574.
6. Bhayana, B.; Fors, B. P.; Buchwald, S. L. Org. Lett. 2009, 11, 3954.
7. Nguyen, H. N.; Huang, X. H.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818.
8. Chung, K. H.; So, C. M.; Wong, S. M.; Luk, C. H.; Zhou, Z.; Lau, C. P.; Kwong, F. Y.
Chem. Commun. 2012, 48, 1967.
9. Wong, P. Y.; Chow, W. K.; Chung, K. H.; So, C. M.; Lau, C. P.; Kwong, F. Y. Chem.
Commun. 2011, 47, 8328.
The scope of the nucleophilic coupling partner was tested next
with the previously employed cis-propenyl MIDA boronate 24,5 as
well as with MIDA boronates 25–27,30 using tosylate 1b with a
conventional reflux procedure (Scheme 2). This procedure is of
high practical convenience and excellent yields (>90%) were ob-
tained in all cases. The stereochemistry of the alkenyl group in
the boronate is retained affording, for example, product 28 as the
Z-isomer with only minor traces of the E-isomer, although acid-
catalysed isomerisation was observed to be fairly rapid.
In summary, we have shown that activated and unactivated
alkenyl tosylates can undergo efficient coupling with a variety of
alkenyl groups derived from MIDA boronates in a practical Suzu-
ki–Miyaura cross-coupling reaction. The process involves air stable
and commercially available Pd(PPh3)2NBS as precatalyst and does
not require expensive phosphine ligands. The use of the cheap
and easy to handle PCy3ÁHBF4 salt is sufficient to achieve nearly
quantitative yields with less activated substrates. We are confident
that this robust and practical procedure will be of general use, for
example in the synthesis of synthetic building blocks, as well as for
library synthesis. Furthermore, both the use of alkenyl tosylates
that are easily derived from carbonyl precursors and MIDA boro-
nates, which are known to be stable to a variety of reaction condi-
tions make this method an attractive tool for total synthesis. We
are currently applying this procedure to more complex systems
as part of a natural product synthesis programme.
10. So, C. M.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int. Ed. 2008, 47, 8059.
11. So, C. M.; Lau, C. P.; Chan, A. S. C.; Kwong, F. Y. J. Org. Chem. 2008, 73, 7731.
12. Gogsig, T. M.; Sobjerg, L. S.; Lindhardt, A. T.; Jensen, K. L.; Skrydstrup, T. J. Org.
Chem. 2008, 73, 3404.
13. Zhang, L. A.; Meng, T. H.; Wu, J. J. Org. Chem. 2007, 72, 9346.
14. Kang, S. B.; De Clercq, E.; Lakshman, M. K. J. Org. Chem. 2007, 72, 5724.
15. Huffman, M. A.; Yasuda, N. Synlett 1999, 471.
16. Burke, M. D.; Gillis, E. P.; Lee, S. J.; Knapp, D. M.; Gray, K. C. U.S. Patent
20090030238 A1, 2009.
17. Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961.
18. Steinhuebel, D.; Baxter, J. M.; Palucki, M.; Davies, I. W. J. Org. Chem. 2005, 70,
10124.
19. Wu, J.; Zhu, Q.; Wang, L. S.; Fathi, R.; Yang, Z. J. Org. Chem. 2003, 68, 670.
20. During the preparation of this manuscript an example of the Suzuki–Miyaura
coupling of aryl triflates with MIDA boronates was reported: Dick, G. R.;
Woerly, E. M.; Burke, M. D. Angew. Chem., Int. Ed. 2012, 51, 2667.
21. Triflate 1a: Stang, P. J.; Treptow, W. L. J. Med. Chem. 1981, 24, 468.
22. Tosylate 1b: Feigenbaum, A.; Pete, J. P.; Scholler, D. J. Org. Chem. 1984, 49, 2355.
23. Mesylate 1c: Kowalski, C. J.; Fields, K. W. J. Org. Chem. 1981, 46, 197.
24. Uno, B. E.; Gillis, E. P.; Burke, M. D. Tetrahedron 2009, 65, 3130.
25. Knochel, P.; Rao, C. J. Tetrahedron 1993, 49, 29.
26. Burns, M. J.; Fairlamb, I. J. S.; Kapdi, A. R.; Sehnal, P.; Taylor, R. J. K. Org. Lett.
2007, 9, 5397; Fairlamb, I. J. S.; Sehnal, P.; Taylor, R. J. K. Synthesis 2009, 508.
27. Crawforth, C. M.; Burling, S.; Fairlamb, I. J. S.; Taylor, R. J. K.; Whitwood, A. C.
Chem. Commun. 2003, 2194; Crawforth, C. M.; Burling, S.; Fairlamb, I. J. S.;
Kapdi, A. R.; Taylor, R. J. K.; Whitwood, A. C. Tetrahedron 2005, 61, 9736.
28. All tosylates 4–13 were synthesised according to reported procedures from the
corresponding ketone or b-dicarbonyl compound and were generally isolated
as stable solids (see Supplementary data).
Acknowledgement
This work was supported by the Swiss National Science Founda-
tion (SNSF).
29. Fairlamb, I. J. S.; Marrison, L. R.; Dickinson, J. M.; Lu, F. J.; Schmidt, J. P. Bioorg.
Med. Chem. 2004, 12, 4285.
Supplementary data
30. A straightforward approach to generate MIDA boronates 2 and 25–27 was
developed using a hydroboration/transesterification sequence starting from
commercially available or known alkynes with catecholborane and MIDA as
the only reagents (see Supplementary data).
Supplementary data (general procedures and spectral data)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.04.091.
catecholborane (1 equiv)
neat, 70 °C, 3 h
References and notes
2 53% (R = C6H13
25 59% (R = C8H17
26 74% (R = Ph)
)
)
BMIDA
R
R
1. Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6722.
then MIDA (1 equiv)
DMSO, 60 °C, 3-16 h
2. For an excellent review of transition metal catalysed cross-coupling of enol-
and phenol-based electrophiles, including sulfonates, see: Li, B. J.; Yu, D. G.;
Sun, C. L.; Shi, Z. J. Chem. Eur. J. 2011, 17, 1728.
27 66% (R = CHCHPh)
3. Elitzin, V. I.; Harvey, K. A.; Kim, H.; Salmons, M.; Sharp, M. J.; Tabet, E. A.;
Toczko, M. A. Org. Process Res. Dev. 2010, 14, 912.