Optimised conditions for styrene syntheses using Suzuki-Miyaura couplings and catalyst-ligand-base pre-mixes

Article abstract of DOI:10.1016/j.tetlet.2012.06.089

Optimised conditions are reported for Suzuki-Miyaura couplings between N-tosyl-2-bromo-benzylamines and -phenethylamines with vinylboronic acids, using pre-mixes of catalyst, ligand and base, leading to the corresponding 2-tosylaminomethyl- and 2-tosylami

Full text of DOI:10.1016/j.tetlet.2012.06.089

Tetrahedron Letters 53 (2012) 4654–4656
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Tetrahedron Letters
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Optimised conditions for styrene syntheses using Suzuki–Miyaura
couplings and catalyst-ligand-base pre-mixes
Laura Henderson a, David W. Knight a, , Piotr Rutkowski a, Andrew C. Williams b
⇑
a School of Chemistry, Cardiff University, Main College, Park Place, Cardiff CF10 3AT, UK
b Eli Lilly & Co., Ltd, Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 26 June 2012
Optimised conditions are reported for Suzuki–Miyaura couplings between N-tosyl-2-bromo-benzylam-
ines and -phenethylamines with vinylboronic acids, using pre-mixes of catalyst, ligand and base, leading
to the corresponding 2-tosylaminomethyl- and 2-tosylaminoethyl-styrenes in generally excellent yields,
using microwave excitation at 100 °C.
Keywords:
Suzuki–Miyaura
Styrenes
Ó 2012 Elsevier Ltd. All rights reserved.
Vinylboronic acids
Optimised
Microwave
In connection with another project (see following Letter), we re-
cently required a representative series of the 2-tosylaminoalkyl
styrenes 1 and 2 (Scheme 1). Amongst the many possibilities, such
as aldehyde olefinations (Wittig, Julia, etc.) and dehydration reac-
tions, use of one of the ubiquitous palladium-catalysed coupling
reactions, which have all now reached a high level of sophistication
in terms of both the range of experimental conditions and the
choice of ligands which are available, seemed to offer the greatest
flexibility and practicality. Amongst these options, the Suzuki–
Miyaura method1 featuring couplings between an aryl bromide 3
and a vinylboronic acid 4 appeared especially attractive, particu-
larly in view of the wide variety of experimental parameters now
regularly employed for such couplings.2 Further, we wished to ex-
plore the practicality of employing pre-formed mixtures of suitable
phosphine ligands, bases and catalysts, as these are especially con-
venient reagent combinations for general combinatorial synthesis.
This is especially so when their deployment obviates the rather
tiresome and time-consuming necessity of weighing small
amounts of both ligand and metal source, which are usually only
required in such quantities for the synthesis of such libraries of re-
lated compounds. A range of these types of pre-mixes were readily
available as these are in regular use in the Lilly Research Laborato-
ries,3 which presented us with an ideal opportunity to attempt to
define optimum conditions for their application in the desired sty-
rene synthesis at least, as well as, hopefully, for many other
applications.
Further, the required coupling partners were also readily avail-
able in appropriate quantities. Sulfonamide 3a was obtained in one
step from commercially available 2-bromobenzylamine by direct
tosylation [TsCl (1.0 equiv), DMAP (cat.), Et3N (1.1 equiv), CH2Cl2,
0–20 °C, 16 h; 87%; mp 78–80 °C4], while the homologous sulfon-
amide 3b was obtained from a Mitsunobu coupling between 2-
bromophenethanol and TsNHBoc5 [Ph3P then DIAD, 0 °C, THF,
15 min. then alcohol (1.0 equiv), 20 min then TsNHBoc (1.01 equiv)
then 20 °C, 16 h (94%), followed by deprotection using 20% TFA–
CH2Cl2, 20 °C, 2 h; 99%; mp 62–63 °C6]. All the vinylboronic acids
4 employed in this study were obtained by hydroboration of the
corresponding aryl alkynes using catecholborane.7
The necessity for this type of study was revealed immediately
when an attempted Suzuki–Miyaura coupling between sulfon-
amide 3a and (E)-2-phenylboronic acid 5 using relatively routine
microwave-assisted conditions1,2c led to essentially none of the de-
sired product 6 (Scheme 2) on the first attempt. In a subsequent
reaction, a small amount of product 6 was detected by 1H NMR
analysis of the crude product when wet DMF was used as the sol-
vent. As such polar solvent systems, especially water,2d generally
favour these types of couplings, we chose to standardise upon
1:1 aqueous DMF in subsequent studies, then systematically to
evaluate the various combinations of palladium source, phosphine
ligand and base, with a view to securing a successful version of the
coupling shown in Scheme 2. In particular, the use of a rather more
sterically hindered phosphine ligand seemed especially likely to be
productive.2f
Although perhaps rather counter-intuitive, such sterically hin-
dered species, whose likely positive contribution was suggested
many years ago by Heck, have subsequently made many significant
⇑
Corresponding author.
E-mail address: knightdw@cf.ac.uk (D.W. Knight).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.089

L. Henderson et al. / Tetrahedron Letters 53 (2012) 4654–4656
4655
Table 2
NHTs
a
Solvent optimisation of couplings between 3a and 5 using Pd(OAc)2–dtbpf–K3PO4
Entry
Solvent
% Yield
NHTs
( )n
R
1
2
3
4
1,4-Dioxane–H2O
1:1 Toluene–H2O
1:1 Ethanol–H2O
H2O
92
89
90
72
1
2
Br
+
(HO)2B
NHTs
R
a
All reactions run at 100 °C, 100 W for 0.5 h.
4
3
a) n = 0
b) n = 1
R
Table 3
Optimised yields from couplings of sulfonamides 3 and vinylboronic acids 5 using
Scheme 1. The key Suzuki–Miyaura disconnection.
Pd(OAc)2–dtbpf–K3PO4
NHTs
( )n
NHTs
( )n
NHTs
( )n
NHTs
NHTs
Ph
i)
(HO)2B
+
Br
Ph
Cl
F
3a
5
6
7
8
9
a) n = 0 (90%) (= 6)
a) n = 0 (81%)
b) n = 1 (85%)
a) n = 0 (91%)
b) n = 1 (60%)
b) n = 1 (99%)
Scheme 2. Reagents and conditions: (i) 1 equiv each of 3a and 5 in DMF, 5 mol %
Pd(PPh3)4, NaHCO3, 100 W, 100 °C, 0.5 h.
NHTs
NHTs
NHTs
( )n
( )n
( )n
advances to the viability of a diversity of palladium-catalysed cou-
pling chemistry.8 Such sterically hindered species often work well
in combination with milder bases such as potassium carbonate or
potassium phosphate.9 The results of some of these optimisation
experiments are presented in Table 1.
CF3
10
11
12
a) n = 0 (99%)
b) n = 1 (99%)
a) n = 0 (96%)
b) n = 1 (99%)
a) n = 0 (83%)
b) n = 1 (69%)
Evidently, the highly hindered phosphine ligand dtbpf [1,10-
bis(di-tert-butylphosphino)ferrocene] (entries 3 and 4) was effec-
tive, as was the use of potassium phosphate9 and the change to
aqueous DMF. In the quest for an even higher yielding and more
efficient process, we chose to use the catalyst combination em-
ployed in entry 3 as the basis of a solvent study, the outcomes of
which are shown in Table 2.
NHTs
( )n
NHTs
( )n
13
14
a) n = 0 (97%)
b) n = 1 (94%)
a) n = 0 (95%)
b) n = 1 (86%)
Although all three of the mixed solvent systems (entries 1–3)
gave very similar yields, for reasons of convenience, volatility
and lack of toxicity, we chose to use 1:1 aqueous ethanol in subse-
quent reactions. Although, all three aqueous solvent mixtures
delivered essentially the same isolated yields, this particular com-
bination gave the cleanest ‘crude’ product 6, which contained no
starting material 3a according to 1H NMR analysis immediately
after isolation.
as these would be rapidly converted into the corresponding boro-
nic acids under the aqueous conditions used in the optimised
procedure.
In many examples, after a simple aqueous work-up, the prod-
ucts obtained were pure enough for use in a subsequent synthetic
step, in particular if a concentrated ethereal solution was passed
through a short pad of silica gel. Although we used the optimised
procedure10 routinely,11 we have also found that the amount of
pre-mix used can be reduced to as little as one tenth of the amount
specified herein (i.e., 0.04 g of pre-mix per 0.30 mmol of sulfon-
amide 3) given that all reactants and solvents were scrupulously
clean. This resulted in no noticeable diminution in the yields.
In summary, we believe this optimised procedure represents a
general and practicable approach which should find ready applica-
tion to the construction of these types of arylalkene.
This optimised procedure10 was then applied to the synthesis of
a selection of substituted styrenes from the 2-bromosulfonamide
3a and also one-carbon homologues from the phenethyl sulfon-
amide 3b. The structures of all products are collected below, to-
gether with the associated isolated yields in Table 3.
In general, yields were excellent and were not noticeably af-
fected by the nature of the boronic acid, whether this was carrying
an aromatic or an alkenyl substituent. Unsurprisingly, there was
also very little change in the yields of styrenes when boronates
were used, specifically 4,4,5,5,-tetramethyl-1,3,2-dioxaborolanes,
Table 1
Acknowledgment
Optimisation of couplings between 3a and 5 (Scheme 2)a
Entry
Cat./ligand/base
Solvent
% Yield
We are grateful to Eli Lilly and Co., Ltd and the EPSRC for finan-
cial support.
1
2
3
4
5
6
7
Pd(PPh3)4–NaHCO3
Pd(OAc)2–PCy3–K3PO4
Pd(OAc)2–dtbpf–K3PO4
Pd(dba)2–dtbpf–K3PO4
Pd(Qb)2–K2CO3
DMF
0
61
63
43
58
47
37
1:1 DMF–H2O
1:1 DMF–H2O
1:1 DMF–H2O
1:1 DMF–H2O
1:1 DMF–H2O
H2O
References and notes
1. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483; (b) Suzuki, A. J.
Organomet. Chem. 1999, 576, 147–168; (c) Kotha, S.; Lahiri, K.; Kashinath, D.
Tetrahedron 2002, 58, 9633–9695; (d) Bellina, F.; Carpita, A.; Rossi, R. Synthesis
2004, 2419–2440.
2. (a) See for example: (a) Marion, N.; Nolan, S. P., Acc. Chem. Res. 2008, 41, 1440–
1449, N-heterocyclic carbenes as phosphine ligands.; (b) Felpin, F.-X.; Ayad, T.;
Pd(PPh3)4–NaOH
Pd(OAc)2–K2CO3
a
All reactions run at 100 °C, 100 W for 0.5 h.
Q = quinoline-8-carboxylate.
b

4656
L. Henderson et al. / Tetrahedron Letters 53 (2012) 4654–4656
Mitra, S. Eur. J. Org. Chem. 2006, 2679–2690. Pd-C as catalysts; (c) Singh, B. K.;
(1.3 equiv) were suspended in 1:1 aqueous EtOH (3 ml per 0.30 mmol of
sulfonamide 3). To this suspension was added the Suzuki–Miyaura pre-mix
[0.55 wt% Pd(OAc)2, 1.05 wt% dtbpf and 98.4 wt% K3PO4] (0.425 g per
0.30 mmol of sulfonamide 3) and the resulting mixture placed in a micro-
wave oven and heated using a power of 100 W to 100 °C for 0.5 h. The cooled
mixture was then extracted with Et2O (3 ꢀ 15 ml) and the combined organic
extracts washed with saturated NaCl (30 ml) then dried (MgSO4), filtered and
evaporated. Usually, the crude product was of sufficient purity, especially after
filtration of an ethereal solution through a pad of silica gel, for direct use in a
Kaval, N.; Tomar, S.; Van der Eycken, E.; Parmar, V. S. Org. Process Res. Dev. 2008,
12, 468–474. microwave assisted; (d) Polshettiwar, V.; Decottignies, A.; Len, C.;
Fihri, A. ChemSusChem 2010, 3, 502–522. water as solvent; (e) Narayanan, R.
Molecules 2010, 15, 2124–2138. nanocatalysts; (f) Fleckenstein, C. A.; Plenio, H.
Chem. Soc. Rev. 2010, 39, 694–711. sterically demanding phosphines.
3. Rosen, B. R.; Ruble, J. C.; Beauchamp, T. J.; Navarro, A. Org. Lett. 2011, 13, 2564–
2567.
4. Zhu, M.; Fujita, K.; Yamaguchi, R. Org. Lett. 2010, 12, 1336–1339.
5. Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.; Harris, G. D., Jr.;
Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709–5712.
11
subsequent reaction.
11. (E)-4-Methyl-N-(2-(4-methylstyryl)benzyl)benzenesulfonamide (11a): Using the
6. Sherman, E. S.; Fuller, P. H.; Kasi, D.; Chemler, S. R. J. Org. Chem. 2007, 72, 3896–
3905.
general
methylbenzenesulfonamide
procedure,
reaction
(3a)
between
(0.100 g,
N-(2-bromobenzyl)-4-
0.294 mmol), (E)-2-(4-
7. Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1971, 93, 1816–1818.
8. For an early review, see: (a) Colacot, T. J. Chem. Rev. 2003, 103, 3101–3118; For
use in couplings with aryl chlorides, see: (b) Colacot, T. J.; Shea, H. A. Org. Lett.
2004, 6, 3731–3734; For examples of the effectiveness of increasing ligand
substituent steric bulk, see: (c) Grasa, G. A.; Colacot, T. J. Org. Lett. 2007, 9,
5489–5492.
9. See, for example: Griffiths, C.; Leadbeater, N. E. Tetrahedron Lett. 2000, 41,
2487–2490.
10. Generaliszed procedure for Suzuki–Miyaura couplings leading to styrenes 7
methylphenyl)-vinylboronic acid (0.062 g, 0.384 mmol) and the Pd(OAc)2–
dtbpf–K3PO4 pre-mix (0.425 g) in 1:1 aqueous EtOH (3 ml) gave the
sulfonamide 11a (0.106 g, 96%) as a yellow oil which showed dH (400 MHz,
CDCl3) 7.64 (d, 2H, J 8.3 Hz, 2 ꢀ ArH), 7.39 (d, 2H, J 8.3 Hz, 2 ꢀ ArH), 7.30–7.11
(m, 6H), 7.10–7.02 (m, 3H), 6.95 (d, 1H, J 15.8 Hz), 4.16 (d, 2H, J 6.6 Hz, CH2N),
2.34 (6H, s, 2 ꢀ ArMe); dC (100 MHz, CDCl3) 146.5 (s), 136.9 (2 ꢀ s), 135.5
(3 ꢀ s), 132.8 (2 ꢀ d), 130.5 (2 ꢀ d), 129.8 (2 ꢀ d), 129.7 (2 ꢀ d), 129.6 (2 ꢀ d),
127.8 (d), 127.2 (2 ꢀ d), 123.5 (d), 41.5 (t), 21.6 (2 ꢀ q);
mmax (film) 3289, 3021,
2921, 1598, 1512, 1448, 1274 815, 750 cmꢁ1; HRMS (EI) m/z 377.1438 (M+,
and 8: Sulfonamide
3
(0.30 mmol, 1 equiv) and
a
vinylboronic acid
4
100%); C23H23NO2S requires M, 377.1450.