A New Synthesis of Butadienyl- and Styrylboronic Esters: Highly Reactive Intermediates for Suzuki Cross-Coupling

Article abstract of DOI:10.1021/ol0255817

(Matrix Presented) Alkoxy-functionalized butadienyl- and styrylboronic esters have been synthesized starting from α,β-unsaturated acetals. These derivatives readily cross-couple with aryl substrates, and the obtained products can be transformed under mild

Full text of DOI:10.1021/ol0255817

ORGANIC
LETTERS
2002
Vol. 4, No. 8
1275-1277
A New Synthesis of Butadienyl- and
Styrylboronic Esters: Highly Reactive
Intermediates for Suzuki Cross-Coupling
,‡
Paolo Balma Tivola,† Annamaria Deagostino,† Cristina Prandi,* and
,†
Paolo Venturello*
Dipartimento di Chimica Generale ed Organica Applicata dell’UniVersita`, Corso
Massimo D’Azeglio, 48, I 10125 Torino, Italy, and Dipartimento di Scienze e
Tecnologie AVanzate dell’UniVersita`, Corso Borsalino, 54, I 15100 Alessandria, Italy
Venturello@ch.unito.it
Received January 18, 2002 (Revised Manuscript Received March 8, 2002)
ABSTRACT
Alkoxy-functionalized butadienyl- and styrylboronic esters have been synthesized starting from r,â-unsaturated acetals. These derivatives
readily cross-couple with aryl substrates, and the obtained products can be transformed under mild conditions into aromatic ketones, achieving
the same result as an acylation reaction.
The Pd(0)-catalyzed cross-coupling reaction has become one
of the most popular methods of accessing biaryls, and in
particular the Suzuki-Miyaura reaction, using arylboronic
acid, has emerged as one of the most widely used.1 As
compared with the Stille cross-coupling,2 the Suzuki process
possesses the advantage that byproducts are nontoxic and
are easily separated from the target product.3 Catalyst systems
that allow coupling with aryl chlorides have been developed,
greatly expanding the scope of the reaction.4 Traditionally,
arylboronic acids have been prepared by reaction of an
aryllithium derivative, obtained by metal-halogen or metal-
hydrogen exchange, with trialkylborates.5 Moreover, it has
been recently reported that the in situ trapping with triiso-
propylborate of lithium intermediates is an excellent reagent
system for the synthesis of substituted arylboronic esters,
which were isolated as 2,2-dimethylpropan-1,3-diol (neo-
pentyl glycol) adducts.6 Although the Suzuki cross-coupling
is commonly used to prepare biaryls, reactions of vinyl
halides or triflates with arylboronic acids, to generate styrene
derivatives, are an important and interesting broadening of
the method. Much attention has been also focused on the
use of 1-alkenylboronic acids or their esters, because of the
variety 1-alkenylboron derivatives that are readily available
by stereodefined hydroboration reaction of alkynes.7 In
particular, 1,3-dienylboronates have been prepared by a three-
step sequence starting from the hydroboration of enynes with
† Dipartimento di Chimica Generale ed Organica Applicata.
‡ Dipartimento di Scienze e Tecnologie Avanzate.
(1) For reviews, see: Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457-2483. Stanforth, S. P. Tetrahedron 1998, 54, 263-303. Suzuki, A.
J. Organomet. Chem. 1999, 576, 147-168.
(2) Stille, J. K.; Milstein, D. J. Am. Chem. Soc. 1978, 100, 3636-3638.
For reviews, see: Stille, J. K. Angew. Chem., Int. Ed Engl. 1986, 25, 508-
524. Farina, V. Pure Appl. Chem. 1996, 68, 73-78. Farina, V.; Krishna-
murthy, V.; Scott, W. J. Org. React. 1997, 50, 1-652.
(3) Boyer, J. Toxicology 1989, 55, 253-298.
(4) Littke, F.; Fu, G. C. Angew. Chem., Int. Ed. Engl. 1998, 37, 3387-
3388. Wolfe, J. P.; Buchwald, L. Angew. Chem., Int. Ed. 1999, 38, 2413-
2414. Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem.
1999, 64, 3804-3805. Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc.
2000, 122, 4020-4028. LeBlond, C. R.; Andrews, A. T.; Sun, Y.; Sowa,
J. R., Jr. Org. Lett. 2001, 3, 1555-1557.
(5) Alo, B. I.; Kandil, A.; Patil, P. A.; Sharp, M. J.; Siddiqui, M. A.;
Snieckus, V. J. Org. Chem. 1991, 56, 3763-3768. Rocca, P.; Marsais, F.;
Godard, A.; Que´guiner, G. Tetrahedron 1993, 49, 49-64.
(6) Kristensen, J.; Lyse´n, M.; Vedsø, P.; Begtrup, M. Org. Lett. 2001,
3, 1435-1437.
10.1021/ol0255817 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/20/2002

ditional synthetic modifications; namely, the sequence “cross-
coupling and hydrolysis” corresponds to a two-step carbon-
ylative coupling (Schemes 3 and 4).14
Scheme 1
Scheme 4
various hydroborating agents.8 Moreover, as stated by
Molander and Ito,9 much of the recent development of the
Suzuki coupling reaction has focused on metal catalysts
rather than on expanding the range of organoboron coupling
partners, which should be an equally important endeavor.
The synthesis of polyenic structures has been of great
interest to organic chemistry owing not only to their presence
in natural products10 but also to their importance as useful
chemicals in the perfume industry and other fields.11 Our
interest in the synthesis of stereodefined substituted dienes
required the development of diverse organometallic reagents
and protocols for the preparation of key building blocks.12
In the course of these studies we have set up a new synthesis
of alkoxy-functionalized butadienyl- and styrylboronic es-
ters,13 and resorting to the particular reactivity of these
derivatives, we have successfully carried out their cross-
coupling with various aryl halides and triflates under very
mild experimental conditions (Schemes 1 and 2). Further-
Treatment of crotonaldehyde diethyl acetal (1) at -95 °C
with Schlosser’s LIC-KOR base (LIC, butyllithium; KOR,
potassium tert-butoxide)15 readily gives R-metalated 1-ethoxy-
buta-1,3-diene (2). Subsequent reaction with triisopropyl-
borate leads to immediate disappearance of the deep red color
due to metalated diene. Aqueous workup of the reaction
mixture affords intermediate 3, which owing to its instability
was trapped with 2,2-dimethylpropane-1,3-diol or 2,3-
dimethylbutane-2,3-diol, giving the corresponding boronic
ester 4a or 4b, respectively (Scheme 1).
Resorting to an analogous synthetic design styrylboronic
ester 6 has been prepared starting from phenyl acetaldehyde
dimethyl acetal 5 (Scheme 2).
As outlined in Table 1, the cross-coupling reaction of
butadienyl and styrylboronic esters proceeds with satisfactory
Scheme 2
(7) Brown, H. C. Organic Syntheses Via Boranes; Wiley: New York,
1975. Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1972, 94, 4370-437.
Lane, C. F. Tetrahedron 1976, 32, 981-990. Colberg, J. C.; Rane, A.;
Soderquist, J. A. J. Am. Chem. Soc. 1993, 115, 6065-6071.
(8) Vaultier, M.; Truchet, F.; Carboni, B.; Hoffmann, R. W.; Denne, I.
Tetrahedron Lett. 1987, 28, 4169-4172. Renard, P.-Y.; Lallemand, J.-Y.
Tetrahedron: Asymmetry 1996, 9, 2523-2424. Six, Y.; Lallemand, J.-Y.
Tetrahedron Lett. 1999, 40, 1295-1296 and references therein.
(9) Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393-396.
(10) Baker, R.; Bradshaw J. W. S. In Aliphatic and Related Natural
Product Chemistry; Gunstone, F. D., Ed.; Specialist Periodical Report, Royal
Society of Chemistry: London, 1983; Vol. 3. Nicolau, K. C.; Ramphal, J.
Y.; Petasis, N. A.; Serhan, C. N. Angew. Chem., Int. Ed. Engl. 1991, 30,
1100-1116. Launay, V.; Beaudet, I.; Quintard, J.-P. Bull. Soc. Chim. Fr.
1997, 134, 937-946. Dominguez, B.; Iglesia, B.; de Lera, A. R. J. Org.
Chem. 1998, 63, 4135-4139. Lipshutz, B. H.; Ullman, B.; Lindsley, C.;
Pecchi, S.; Buzard, D. J.; Dickson, D. J. Org. Chem. 1998, 63, 6092-
6093.
more, the method we have set up allows us to achieve
coupling products suitably functionalized to undergo ad-
(11) Goldbach, M.; Ja¨kel, E.; Schneider, M. P. J. Chem. Soc., Chem.
Commun. 1987, 1434-1435.
Scheme 3
(12) Venturello, P. J. Chem. Soc., Chem. Commun. 1992, 1032-1033.
Balma Tivola, P.; Deagostino, A.; Prandi, C.; Venturello, P. J. Chem. Soc.,
Perkin Trans. 1 2001, 437-441 and references therein.
(13) Owing to the different mechanism, boronic esters have been obtained
with the double bond configuration opposite to that from the hydroboration
reaction of alkynes.
(14) Wakita, Y.; Yasunaga, T.; Akita, M.; Kojima, M. J. Organomet.
Chem. 1986, 301, C17-C20. Grigg, R.; Redpath, J.; Sridharan, V.; Wilson,
D. Tetrahedron Lett. 1994, 35, 7661-7664.
(15) Schlosser, M. J. Organomet. Chem. 1967, 8, 9-16. Schlosser, M.
Mod. Synth. Methods 1992, 6, 227-271. Mordini, A. In AdVances in
Carbanion Chemistry; Snieckus, V., Ed.; JAI Press Inc.: Greenwich, CT,
1992; Vol. 1, pp 1-45. Schlosser, M.; Faigl, F.; Franzini, L.; Geneste, H.;
Katsoulos, G.; Zhong, G. Pure Appl. Chem. 1994, 66, 1439-1446.
Lochmann, L. Eur. J. Inorg. Chem. 2000, 1115-1126.
1276
Org. Lett., Vol. 4, No. 8, 2002

Table 1. Cross-Coupling Reaction of Butadienyl (4a and 4b)
and Styrylboronic (6) Esters with Various Aryl Halides and
Triflatesa
Table 2. Hydrolysis of Functionalized Cross-Coupling
Derivativesa
entry
cross-coupling product
ketone
yield (%)b
boronic
ester
reaction
yield
1
2
3
10
11
18
14
15
19
90
87
95
entry
substrate
PhI
PhI
PhI
product conditionsb (°C) (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
4a
4b
6
4a
4a
4b
6
4a
4a
4b
6
7
7
16
9
A (25)
A (25)
A (25)
A (25)
A (25)
A (25)
A (25)
A (25)
B (25)
A (25)
A (25)
B (25)
A (25)
A (25)
A (25)
A (60)
B (25)
C (60)
C (25)
A (25)
82
71
88
75
70
89
92
90
78
83
85
65
75
90
30
83
10
20
45
85
a The spectral data for all new compounds are consistent the structures
proposed. b Isolated and purified products.
o-MeOPhI
p-MeOPhI
p-MeOPhI
p-MeOPhI
p-MeCOPhI
p-MeCOPhI
p-MeCOPhI
p-MeCOPhI
p-MeCOPhI
p-HOPhI
p-H2NPhI
PhBr
10
10
17
11
11
11
18
18
12
13
7
In summary, we have developed a new method for the
synthesis of organoborates that cross-couple effectively with
a broad spectrum of aryl substrates. This method should be
useful in synthetic organic chemistry because of the acces-
sibility of starting material. Additionally, we have reported
that butadienyl- and styrylboronic esters can be coupled under
mild conditions. Moreover, the present method thus provides
a new and effective approach to functionalized aromatic
ketones.
6
4a
4a
4a
4a
4a
4a
4a
4a
PhBr
7
Acknowledgment. Support has been provided by Italian
CNR and MIUR.
p-MeOPhCl
p-MeOPhCl
p-MeCOPhCl
p-MePhOTf
10
10
11
8
OL0255817
mmol, 2.4 mL). The solution was allowed to warm to 25 °C and then
quenched with saturated aqueous NH4Cl (10 mL). The organic phase was
diluted with Et2O and then washed with brine. After anhydrification (Na2-
SO4) and evaporation of the solvent, the crude product was diluted with
toluene (30 mL) and treated with 2,2-dimethyl-1,3-propandiol (5 mmol,
0.52 g). The mixture was stirred at 25 °C overnight under an inert
atmosphere. The organic phase was diluted with diethyl ether and washed
with water. Drying (Na2SO4) and removal of the solvent gave 0.98 g (93%)
of analytically pure (E)-2-[(1-ethoxy)buta-1,3-dienyl]-5,5-dimethyl-[1,3,2]-
dioxaborinane (4a) as a pale yellow oil: 1H NMR (400 MHz; CDCl3) δ
0.94 (s, 6 H), 1.28 (t, J ) 6.5 Hz, 3 H), 3.67 (s, 4 H), 3.72 (q, J ) 6.5 Hz,
2 H), 4.86 (dd, J ) 10.0, 1.0, 1 H), 5.03 (dd, J ) 16.0, 1.0, 1 H), 5.97 (d,
J ) 10.0 Hz, 1 H), 7.04 (dt, J ) 16.0, 10.0 Hz, 1 H); 13C NMR (100.4
MHz; CDCl3) δ 15.28, 21.86, 31.66, 62.50, 72.27, 113.92, 116.76, 118.22,
134.06; MS (EI, 70 eV) m/z (%) 210 (30), 181 (48), 113 (19), 95 (28), 69
(100). Under an inert atmosphere the boronic ester 4a (0.5 mmol, 0.10 g)
was dissolved in toluene (5 mL), and then aqueous 2 M K2CO3 (0.5 mL),
p-MeOC6H4I (0.6 mmol, 0.14 g), EtOH (0.5 mL), and Pd[(C6H5)3P]4 (3%,
17 mg) were added. The reaction mixture was stirred at 25 °C to
completeness (TLC or GC control). Addition of saturated aqueous NH4Cl
(5 mL) followed by extraction with Et2O, drying (Na2SO4), and evaporation
under vacuum provided crude 1-(1-ethoxybuta-1,3-dienyl)-4-methoxyben-
zene (10), which was purified by column chromatography (petroleum ether/
Et2O 8:2) (70 mg, 70%): 1H NMR (400 MHz; CDCl3) δ 1.28 (t, J ) 6.5
Hz, 3 H),), 3.82 (s, 3 H), 3.92 (q, J ) 6.5 Hz, 2 H), 4.79 (dd, J ) 10.0, 1.0
Hz, 1 H), 5.09 (dd, J ) 16.0, 1.0 Hz, 1 H), 5.56 (d, J ) 10.0 Hz, 1 H),
6.45 (dt, J ) 16.0, 10.0 Hz, 1 H), 6.69 (d, J ) 7 Hz, 2H), 7.38 (d, J ) 7
Hz, 2 H); 13C NMR (100.4 MHz; CDCl3) δ 14.80, 55.37, 63.49, 102.84,
111.77, 113.45, 116.42, 130.48, 134.17, 138.25, 157.83, 159.82; MS (EI,
70 eV) m/z (%) 204 (52), 173 (31), 159 (99), 135 (84), 115 (65). Amberlyst
15 (4.6 mequiv/g, 37 mg) was suspended in CH3Cl (10 mL), and the
substrate 10 (5.0 mmol, 010 g) was added with stirring at 25 °C. After 30
min the resin was filtered off, and the reaction mixture was treated with
K2CO3, filtered, and concentrated under vacuum to give crude 1-(4-
methoxyphenyl)-but-2-en-1-one (14), which was purified by column chro-
matography (petroleum ether/Et2O 8:2) (0.08 g, 90%):1H NMR (400 MHz,
CDCl3) δ 1.97 (dd, J ) 6.5, 1.5 Hz, 3 H), 3.90 (s, 3 H), 6.80 (dq, J ) 15,
1.5 Hz, 1 H), 6.89 (d, J ) 7.2 Hz, 2 H), 6.94 (dq, J ) 15, 6.5, 1 H), 7.94
(d, J ) 7.2 Hz, 2 H); 13C NMR (100.4 MHz; CDCl3) δ 18.4, 55.53, 113.79,
127.19, 129.10, 130.87, 144.03, 163.33, 189.07; MS (EI, 70 eV) m/z (%)
176 (M+, 42), 135 (100), 77 (31), 69 (14), 63 (15), 41 (19).
a The spectral data for all new compounds are consistent the structures
proposed. b A ) [(C6H5)3P]4Pd, aqueous (2 M) K2CO3, toluene; B )
[(C6H5CHdCH)2CO]3Pd2, (o-CH3C6H4)3P, KF, THF; C ) [(C6H5CHdCH)2-
CO]3Pd2, (o-CH3C6H4)3P, aqueous (2 M) K2CO3, THF. c Isolated and
purified products.
yields in most cases, regardless of the electronic character
of the aryl iodides (compare, for instance, entries 1, 4, and
8 or 3, 7, and 11).
Although we have not attempted to improve the yields by
modifying the reaction conditions (i.e., catalyst and/or
phosphine) and have worked in the presence of triarylphos-
phines,16 cross-coupling products have been obtained even
with electron-neutral aryl bromide (entries 15 and 16), in
moderate yield with electron-poor aryl chlorides (entry 19),
and in very low yields with electron-rich aryl chlorides
(entries 17 and 18).
We have successively carried out the hydrolysis of the
cross-coupling derivatives 10, 11, and 18 and prepared the
corresponding carbonyl derivatives 14, 15, and 19 with
excellent yields, under very mild conditions (Schemes 3 and
4 and Table 2), achieving the very same result as an acylation
of activated and deactivated aromatic substrates.17
(16) G. C. Fu and A. F. Littke have proved that triarylphosphines result
in ineffective ligands in Suzuki cross-coupling of aryl chlorides (see ref 4).
(17) Typical Procedure. To a cooled solution (-95 °C) of t-BuOK (1.4
g, 12.5 mmol) in anhydrous THF (10 mL) were consecutively added acetal
1 (0.72 g, 5.0 mmol) and BuLi (7.8 mL, 12.5 mmol) dropwise under stirring.
After 2 h the purple-red solution was treated with triisopropylborate (10.0
Org. Lett., Vol. 4, No. 8, 2002
1277