4,4,6-Trimethyl-2-vinyl-1,3,2-dioxaborinane: An efficient and selective 2-carbon building block for vinylboronate Suzuki-Miyaura coupling reactions

Article abstract of DOI:10.1055/s-2005-862354

An extremely simple and efficient palladium-catalyzed coupling procedure for the synthesis of functionalized styrenes and dienes is utilized to demonstrate how 4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane can be employed to selectively undergo Suzuki-Miyaura coupling with a range of halide substrates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-862354

LETTER
529
4,4,6-Trimethyl-2-vinyl-1,3,2-dioxaborinane: An Efficient and Selective
2-Carbon Building Block for Vinylboronate Suzuki–Miyaura Coupling
Reactions
2
-Carbon Building
n
Block for
V
d
inylboronate
r
S
uzuki–
e
Miyaur
a
C
w
a
GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK
Department of Chemistry, University of Durham, Science Laboratories, South Road, Durham, DH1 3LE, UK
Fax +44(191)3843747; E-mail: andy.whiting@durham.ac.uk
b
Received 28 October 2004
O
Abstract: An extremely simple and efficient palladium-catalyzed
coupling procedure for the synthesis of functionalized styrenes and
dienes is utilized to demonstrate how 4,4,6-trimethyl-2-vinyl-1,3,2-
dioxaborinane can be employed to selectively undergo Suzuki–
Miyaura coupling with a range of halide substrates.
HO
NH2
B
O
N
O
1
O
2
Key words: Suzuki–Miyaura coupling, palladium(0), vinylbor-
onate ester, chemoselectivity
HO
O
B
O
MeO
An ongoing program has focused on the stereocontrolled
synthesis of polyene natural products1 which featured the
total synthesis of the antibiotic and selective herbicide
phthoxazolin A (1, Figure 1).2 The strategy we have de-
veloped utilizes palladium(0)-catalyzed coupling of a two
carbon building block 2, the vinylboronate pinacol ester,
which is a vinyl dianion equivalent, since it is able to react
at either end following either a Heck or Suzuki–Miyaura
reaction pathway. The scope of the Heck coupling of the
vinylboronate 2 has been an ongoing investigation in our
group;3 formation of the Suzuki–Miyaura product has of-
ten been an undesirable result considering the synthetic
targets examined to date. Consequently, its potential was
never fully investigated and herein we report the efficient
use of a vinylboronate ester to selectively derive Suzuki–
Miyaura coupled products.
O
O
NH
HO
O
4
3
Figure 1 Synthetic targets and vinyl boronate esters
timize Heck couplings on vinylboronate esters, we there-
fore decided to examine the Suzuki–Miyaura coupling of
ester 4 to find out if, indeed, these systems were unsatis-
factory for these reactions as claimed.6 In this communi-
cation we report that, in fact, Suzuki–Miyaura couplings
of vinylboronate ester 4 is extremely efficient for the se-
lective preparation of styrenes and dienes, through reac-
tion with a range of aryl and alkenyl halide substrates
using a simple and convenient experimental procedure.
Classical Suzuki–Miyaura conditions were employed7 for
these coupling reactions, i.e. using tetrakistriphenylphos-
phinylpalladium(0) with either potassium tert-butoxide,
potassium hydroxide or silver(I) oxide8 as the bases, in re-
fluxing THF, which allows a simple and robust set up with
minimal required work up.7 A range of aromatic, hetero-
aromatic and vinyl halide substrates were investigated, the
results of which are summarized in Table 1.
More recently, during studies towards the synthesis of the
antibiotic and anticancer agent viridenomycin (3),4 prob-
lems with the long term stability (slow polymerization oc-
curs) of vinylboronate ester 2 led to the development of an
alternative vinylboronate ester, 4,4,6-trimethyl-2-vinyl-
1,3,2-dioxaborinane (4).5 This has been shown to be free
from the problems associated with polymerization upon
storage, as encountered with ester 2 and it is also a supe-
rior reagent for Heck coupling reactions on the vinyl-
boronate ester system.5
The most significant point to report from the results
shown in Table 1 is that the reaction shows complete
chemoselectivity for the Suzuki–Miyaura pathway under
conditions A to C (Table 1), i.e. there is no Heck-coupled
products observed in any of the reactions performed de-
spite the presence of a hindered boronate ester. This result
compares favorably with the Heck coupling selectivity of
boronate 4 which can give complete selectivity for the
Heck pathway simply by changing the reaction condi-
tions.3,5 Heck-selective reaction conditions are character-
ized by the application of typically a trialkylamine (e.g.
However, there have been recent reports which claim that
vinylboronate esters are not suitable for the efficient and
selective formation of terminal alkenes, particularly for
functionalized styrenes, via the Suzuki–Miyaura coupling
strategy.6 Having previously only examined trying to op-
SYNLETT 2005, No. 3, pp 0529–0531
1
6.
0
2.
2
0
0
5
Advanced online publication: 17.01.2005
DOI: 10.1055/s-2005-862354; Art ID: D32204ST
© Georg Thieme Verlag Stuttgart · New York

530
A. P. Lightfoot et al.
LETTER
Table 1 Pd-Catalyzed Coupling of Vinylboronate 4 with a Range of Aryl and Alkenyl Halides
O
Conditions A, B or C
B
R
X
R
O
8
5: X = I
6: X = Br
7: X = Cl
4
a–h
a: R = Ph
Conditions:
Ph
b: R = p-MeC6H4
A: 1.2 equiv 4, 5 mol% Pd(PPh3)4, 1.2 equiv
t-BuOK, THF, 67 °C, 24 h.
B: 1.2 equiv 4, 5 mol% Pd(PPh3)4, 1.2 equiv
KOH, THF, 67 °C, 24 h.
C: 1.2 equiv 4, 5 mol% Pd(PPh3)4, 2 equiv
Ag2O, THF, 67 °C, 24 h.
c: R = p-MeOC6H4
d: R = p-CF3C6H4
e: R = 1-Naphthyl
f: R = E-Styryl
Ph
9
Ph
g: R = Z-Styryl
10
h: R = 2-Pyridyl
Entry
Substrate
Expected producta
Conditions and yields (%)
B – KOHb
A – t-BuOKb
C – Ag2Oc
1
5a
5b
5c
5d
5e
5f
8a
8b
8c
8d
8e
8f
62
73
68
66
75
74
63c
51
83
90
76
96
51
56
0
2
75
3
95
4
87
5
65
6
26c (9 35%e)
7
5g
6a
6b
6c
6d
6e
6h
7a
8g
8a
8b
8c
8d
8e
8h
8a
0e (10 51%a,d
)
46c (10 24%a,d
)
8
56
52
65
71
60
41
0
36
35
28
50
58
31
0
9
0
10
0
11
11d
0
12
13
39b
0
14
a See ref.9
b GC yield determined through the use of undecane as the calibrated internal standard.
c Isolated yield is that after silica gel column chromatography.
d Determined by calculation from the 1H NMR of the crude product.
e See ref.10
Bu3N or Et3N) or other non-nucleophilic bases (e.g. boronate ‘ate’-complex in equilibrium. While the inter-
phenanthroline),3 whereas the Suzuki–Miyaura reaction mediacy of ‘ate’-complexes of type 12 may be essential in
conditions are optimized by using nucleophilic oxygen determining which coupling process proceeds more effi-
bases. We believe that the major factor which decides the ciently, there may also be additional factors operating,
chemoselectivity of the coupling process is whether the such as changes in the palladium ligand coordination
vinylboronate is quarterernized as an ‘ate’-complex (i.e. which also affect the selectivity.11
12, Scheme 1) causing the vinylboronate to undergo
The yields in Table 1 obtained for each of the different
halides used demonstrates the established reactivity trend
of iodides (entries 1–7) being more reactive than bromides
(entries 8–13), which in turn are much more reactive than
the chlorides; these fail to react at all (entry 14) under the
reactions conditions reported here. These results are indic-
transmetallation with the intermediate palladium(II) com-
plex 11 deriving Suzuki–Miyaura coupled products 8,11 or
whether it is neutral (i.e. 15) due to being hindered around
boron. This forces the palladium(II) complex 11 to add
across the double bond of 15 and derive Heck products 17
(see Scheme 1) due to the fact that trialkylamines or non-
ative of a rate determining step which involves an oxida-
nucleophilic amines do not efficiently produce the vinyl-
tive addition of the halide to the active palladium(0)
Synlett 2005, No. 3, 529–531 © Thieme Stuttgart · New York

LETTER
2-Carbon Building Block for Vinylboronate Suzuki–Miyaura Coupling Reactions
531
species in the catalytic cycle. This is further demonstrated bromide in situ and coupling with different boronic acids.6
when examining the syntheses of para-substituted sty- Further studies on the optimization of these reactions is
renes (entries 1–4 and 8–11). In general, and best demon- underway, particularly with respect to the bromides, and
strated under conditions B, the yields obtained increase the factors which affect the chemoselectivity of the
with the electron-withdrawing nature of the substituent Suzuki–Miyaura vs. Heck coupling. These details and ap-
group.
plication of these reactions for use in natural product and
polyene synthesis will be reported in due course.
L
Pd
X
L
OR
Pd(0)L2
-
X
R
X
+
L
R
L
R
Pd
B
O
Acknowledgment
OR
O
-
O
11
B
14
13
We are grateful to the EPSRC for a DTA award to S.J.R.T. and to
GlaxoSmithKline Pharmaceuticals for a CASE studentship.
O
12
(-PdL2)
B
O
R
O
8
15
References
Suzuki-Miyaura
product
R
(1) Thirsk, C.; Whiting, A. J. Chem. Soc., Perkin Trans. 1 2002,
8, 999.
R
L
R'3N
Heck
product
(2) (a) Omura, S.; Tanaka, Y.; Kanaya, I.; Shinose, M.;
Takahashi, Y. J. Antibiot. 1990, 43, 1034. (b) Henaff, N.;
Whiting, A. Org. Lett. 1999, 1, 1137. (c) Henaff, N.;
Whiting, A. Tetrahedron 2000, 56, 5193.
Pd
X
L
(-HX)
B
O
B
O
O
O
(-PdL2)
17
16
(3) (a) Hunt, A. R.; Stewart, S. K.; Whiting, A. Tetrahedron
Lett. 1993, 34, 3599. (b) Stewart, S. K.; Whiting, A. J.
Organomet. Chem. 1994, 482, 293. (c) Stewart, S. K.;
Whiting, A. Tetrahedron Lett. 1995, 36, 3925.
Scheme 1 Mechanistic explanation for formation of the Heck vs.
Suzuki–Miyaura coupled products
(4) (a) Nakagawa, M.; Furihata, K.; Hayakawa, Y.; Seto, H.
Tetrahedron Lett. 1991, 32, 659. (b)Hasegawa, T.;Kamiya,
T.; Henmi, T.; Iwasaki, H.; Yamatodani, S. J. Antibiot. 1975,
28, 167. (c) Nakagawa, M.; Toda, Y.; Furihata, K.;
Hayakawa, Y.; Seto, H. J. Antibiot. 1992, 45, 1133.
(5) Lightfoot, A. P.; Maw, G.; Thirsk, C.; Twiddle, S. J. R.;
Whiting, A. Tetrahedron Lett. 2003, 44, 7645.
(6) (a) Lando, V. R.; Monteiro, A. L. Org. Lett. 2003, 5, 2891.
(b) Molander, G. A.; Rivero, M. R. Org. Lett. 2002, 4, 107.
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8424.
Of particular interest with respect to the synthesis of con-
jugated systems and polyenes are the reactions of the (E)-
and (Z)-styryl iodides (entries 6, 7). The (E)-styryl iodide
(5f) showed good coupling under conditions B and C,
however, use of potassium tert-butoxide led to the forma-
tion of phenylacetylene 10, which reacted further with
(E)-styryl iodide (5f) to form the corresponding ene-yne
9. For the (Z)-styryl iodide (5g), good coupling was again
observed when using conditions B (some phenylacetylene
produced) and C. When using potassium tert-butoxide,
the major product was phenylacetylene, with only trace
coupling to derive either the diene or ene-yne, which un-
derlines the considerably increased susceptibility towards
elimination of HI of the (Z)- vs. (E)-alkenyl iodides 5g vs.
5f, respectively. Hence, for sensitive substrates, the
choice of base in such coupling reactions is vitally impor-
tant.
(7) Typical Procedure, Conditions A.
To an oven dried Schlenk-like tube under argon was added
Pd(PPh3)4 (39 mg, 33.8 mmol) and t-BuOK (91 mg, 0.81
mmol), followed by THF (6 mL), substrate (0.675 mmol)
and boronate 4 (0.125 g, 0.81 mmol). The tube was heated at
67 °C for 24 h before cooling, dilution with Et2O (30 mL)
and filtration through Celite. This solution was treated with
undecane (50 mL, 37.5 mg) and a portion was analyzed by
GC. 1H NMR analysis to determine the Heck: Suzuki ratio,
which was carried out after evaporation to give the crude
product. Purification was carried out by silica gel column
chromatography (hexane as eluant).
When comparing the use of the different bases used for
the coupling reactions (Table 1), for example with the io-
dides (with the exception of styryl systems), the order of
reactivity generally followed the trend of t-BuOK > KOH,
with the use of Ag2O giving variable results depending on
the nature of the halide substrate.
(8) Uenishi, J.; Beau, J.; Armstrong, R. W.; Kishi, Y. J. Am.
Chem. Soc. 1987, 109, 4756.
(9) Characterization data for products 8a–e, 8h and 10 was
consistent with commercial samples. See: (a) 8f: Lebel, H.
V.; Paquet, V. Organometallics 2004, 23, 1187. (b) 8g:
Chinkov, N.; Majumdar, S.; Marek, I. J. Am. Chem. Soc.
2002, 124, 10282.
(10) Tinnemans, A. H. A.; Laarhoven, W. H. J. Chem. Soc.,
Perkin Trans. 2 1976, 10, 1104.
(11) Miyaura, N. J. Organomet. Chem. 2002, 653, 54.
The results obtained (Table 1) demonstrate the potential
use of the vinylboronate 4 in Suzuki–Miyaura coupling
reactions for a range of substrates, which are generally
much more convenient than using a strong alkylating
agent such as 1,2-dibromoethane generating vinyl
Synlett 2005, No. 3, 529–531 © Thieme Stuttgart · New York