Palladium-catalyzed enantioselective conjugate addition of arylboronic acids

Article abstract of DOI:10.1021/ol052222d

(Chemical Equation Presented) The first asymmetric palladium-catalyzed conjugate addition of arylboronic acids to α,β-unsaturated aldehydes, ketones, and esters is described. For cyclic substrates, excellent chemo-, regio-, and enantioselectivities are achieved when a Pd(O₂CCF ₃)₂/DuPHOS catalyst is applied.

Full text of DOI:10.1021/ol052222d

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5309-5312
Palladium-Catalyzed Enantioselective
Conjugate Addition of Arylboronic Acids
Francesca Gini, Bart Hessen, and Adriaan J. Minnaard*
Department of Organic Chemistry and Molecular Inorganic Chemistry,
Stratingh Institute, UniVersity of Groningen, Nijenborgh 4,
9747 AG Groningen, The Netherlands
a.j.minnaard@rug.nl
Received September 14, 2005
ABSTRACT
The first asymmetric palladium-catalyzed conjugate addition of arylboronic acids to
r,â-unsaturated aldehydes, ketones, and esters is described.
For cyclic substrates, excellent chemo-, regio-, and enantioselectivities are achieved when a Pd(O2CCF3)2/DuPHOS catalyst is applied.
Carbon-carbon bond formation by catalytic asymmetric
conjugate addition of organometallic reagents is one of the
important reactions in organic synthesis.1 In the past decade,
considerable progress has been made in the transition-metal-
catalyzed transfer of alkyl and aryl groups.2 The asymmetric
conjugate addition of dialkylzinc reagents catalyzed by
copper complexes is now well established,3 and recently, also
the enantioselective addition of alkyl Grignard reagents to a
range of substrates was achieved.4
by Miyaura5 and Hayashi6 is the method of choice at present.
The stability and commercial availability of arylboronic acids
have contributed to the popularity of this method. High
enantioselectivities have been reported for the addition to a
large variety of R,â-unsaturated compounds.7 Next to BI-
NAP, also monodentate phosphonites8 amidophosphines,9
and phosphoramidites10 are used as chiral ligands. Very
recently, chiral dienes have been introduced that can be
applied as versatile ligands in this reaction type.11
For the enantioselective conjugate addition of aryl groups,
the rhodium-catalyzed arylboronic acid addition developed
Cationic palladium(II) complexes show relatively fast rates
for transmetalation of organoboron and -silicon compounds,
(1) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Tetrahedron Organic Chemistry Series 9; Pergamon: Oxford, 1992. (b)
Tomioka, K.; Nagaoka, Y. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: New
York, 1999; Vol. 3, Chapter 31.
(5) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16, 4229.
(6) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N. J.
Am. Chem. Soc. 1998, 120, 5579.
(7) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829.
(8) Reetz, M. T.; Moulin, D.; Gosberg, A. Org. Lett. 2001, 3, 4083.
(9) Kuriyama, M.; Nagai, K.; Yamada, K.; Miwa, Y.; Taga, T.; Tomioka,
K. J. Am. Chem. Soc. 2002, 124, 8932.
(10) (a) Jagt, R. B. C.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J.
Org. Lett. 2005, 7, 2433. (b) Boiteau, J.-G.; Imbos R.; Minnaard A. J.;
Feringa, B. L. Org. Lett. 2003, 5, 681, also see: Boiteau, J.-G.; Imbos, R.;
Minnaard A. J.; Feringa, B. L. Org. Lett. 2003, 5, 1385. (c) Boiteau, J.-G.;
Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2003, 68, 9481. (d) Duursma,
A.; Hoen, R.; Schuppan, J.; Hulst, R.; Minnaard, A. J.; Feringa, B. L. Org.
Lett. 2003, 5, 3111.
(11) (a) For a minireview, see: Glorius, F. Angew. Chem., Int. Ed. 2004,
43, 3364. (b) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am.
Chem. Soc. 2003, 125, 11508. (c) Defieber, C.; Paquin, J.-F.; Serna, S.;
Carreira, E. M. Org. Lett. 2004, 6, 3873.
(2) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171.
(3) (a) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. In Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim, 2002;
p 224. (b) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 19, 3221.
(4) (a) Lopez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J.
Am. Chem. Soc. 2004, 126, 12784. (b) Feringa, B. L.; Badorrey, R.; Pen˜a,
D.; Harutyunyan, S. R.; Minnaard, A. J. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5834. (c) Mazery, R. D.; Pullez, M.; Lo´pez, F.; Harutyunyan, S. R.;
Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 9966. The
enantioselective addition of diphenylzinc and phenylmagnesium bromide
to 2-cyclohexenone has also been achieved; see: (d) Pen˜a, D.; Lo´pez, F.;
Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2004,
1636.
10.1021/ol052222d CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/04/2005

a process that is generally slow for transition metals.12 This
has stimulated research toward their use in conjugate addition
reactions where the transmetalation is a critical step. Denmark
and Amishiro and also Miyaura et al. have studied the
addition of arylsiloxanes to R,â-unsaturated compounds,13,14
whereas Miyaura et al. reported catalyst systems that are able
to transfer arylboronic acids.15 Recently, the palladium
catalyzed asymmetric conjugate addition of triarylbismuth
reagents16 and aryltrifluoroborates17 was reported by the same
group. The asymmetric conjugate addition of the parent
arylboronic acids, however, has been elusive until now.18
Herein, we report the first enantioselective palladium
catalyzed conjugate addition of arylboronic acids to a variety
of R,â-unsaturated compounds.
The reaction afforded exclusively the desired conjugate
addition product without traces either of the 1,2-addition
product or the Heck coupling product.
Nevertheless, despite the consistently high ee, the rate of
the reaction varied considerably from run to run. This
inconsistency could be avoided by using Pd(O2CCF3)2 instead
of Pd(OAc)2/TfOH, suggesting it had its origin in the acetate/
triflate exchange reaction. This led to reproducible and
shorter reaction times without effecting the ee (Table 1, entry
Table 1. Asymmetric 1,4-Addition of Boronic Acid 2 to
2-Cyclohexenonea
Initial experiments were carried out using the addition of
phenylboronic acid 2a to 2-cyclohexenone 1a as the bench-
mark reaction. It has been shown previously that cationic
palladium enolates are much more susceptible to hydrolytic
Pd-C bond cleavage than neutral palladium species.19 Fast
Pd-C cleavage is essential to avoid competing â-hydride
elimination leading to Heck-type products.20 To create an
electrophilic Pd(II) complex with weakly coordinating
anions, Pd(OAc)2 was used in combination with triflic acid
(TfOH).
entry ligand ArBX2 2 time (h) yieldb (%) of 3 eec (%)
1
2d
3
4
5
6
7
8
9
L3
L3
L4
L5
L3
L3
L3
L3
L3
L3
L3
2a
2a
2a
2a
2b
2c
2d
2e
2f
6
30
24
6
18
18
18
18
18
24
24
80 (3a)
85 (3a)
nd
80 (3a)
80 (3b)
>99 (3c)
>99 (3d)
98 (3e)
90 (3f)
0 (3g)
98 (R)
98 (R)
98 (R)
98 (R)
99 (R)
99 (R)
97 (+)
98 (+)
97
Of the bidentate ligands tested (Figure 1), Josiphos L*1
and its analogue L*2 did not show any activity over 48 h at
10
11
2g
2h
40 (3h)e
98
a Reactions were carried out in THF/H2O (10/1) in the presence of 5
mol % of Pd(O2CCF3)2 and 5.5 mol % of ligand at 50 °C unless stated
otherwise. All reactions gave full conversion (TLC and NMR) unless stated
otherwise. b Isolated yields after column chromatography. c Absolute con-
figuration shown in parentheses. d Reaction performed with 1 mol % of
catalyst. e 60% conversion.
1). The catalyst loading could be decreased, and on 1 mmol
scale, 85% yield, 98% ee was obtained with 1 mol % of
catalyst in 30 h (entry 2).
With these reaction conditions established, the performance
of the related ligands L*4 and L*5 was studied (Figure 1).
The application of Me-BPE L*4 resulted in a much slower
reaction: after 24 h only 25% conversion was observed (98%
ee). Et-DuPHOS L*5, on the other hand, showed the same
activity and excellent selectivity as Me-DuPHOS L*3 (Table
1, entry 4).21
In the next stage, the scope of this new method for various
boronic acids was examined, applying L*3 as the ligand and
1a as the substrate (Table 1). High yields and excellent ee’s
were obtained in the addition of o-, m-, and p-tolylboronic
Figure 1. Chiral bidentate phosphines used in this study.
50 °C. In contrast, Me-DuPHOS L*3 gave full conversion
to the desired product in 12 h with an excellent 98% ee.
(12) (a) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Organometallics 2004,
23, 4317. For a comprehensive overview of palladium chemistry, see: (b)
Handbook of Organopalladium Chemistry for Organic synthesis; Negishi,
E., Ed.; John Wiley & Sons: New York, 2002.
(13) Denmark, S. E.; Amishiro, N. J. Org. Chem. 2003, 68, 6997.
(14) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Chem. Lett. 2003, 32,
752.
(15) (a) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Angew. Chem., Int.
Ed. 2003, 42, 2768. (b) For the coupling of arylboronic acids to alkynes,
see: Zhou, C.; Larock, R. C. Org. Lett. 2005, 7, 259 and references therein.
(16) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Chem. Commun. 2004,
1822.
(17) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Chem. Lett. 2005, 34,
720.
(18) It should be noted that the palladium(II)-catalyzed addition of
arylboronic acids to bicyclic alkenes has been reported; see: Lautens, M.;
Dockendorff, C. Org. Lett. 2003, 5, 3695. The asymmetric version using
Tol-BINAP afforded ee’s up to 71%.
(19) Albe´niz, A. C.; Catalina, N. M.; Espinet, P.; Redo´n, R. Organo-
metallics 1999, 18, 5571.
(20) The oxidative Heck-arylation using arylboronic acids and Pd/
phenanthroline complexes has recently been reported, see: (a) Andappan,
M. M. S.; Nilsson, P.; Larhed, M. Chem. Commun. 2004, 218. (b) Andappan,
M. M. S.; Nilsson, P.; Von Schenck, H.; Larhed, M. J. Org. Chem. 2004,
69, 5212.
(21) Although all reactions were performed in THF/water 10:1 as solvent,
reactions can be performed as well in pure THF. Reaction rates are
somewhat decreased but ee’s are unaffected.
5310
Org. Lett., Vol. 7, No. 23, 2005

acid (Figure 2, Table 1). Also, the electron-rich o- and
m-anisylboronic acids afforded the expected products in high
yield of the volatile product 3i. A comparable ee was
obtained in the addition to 2-cycloheptenone (86% ee)
leading to 3j. The use of L*5 led to virtually the same results.
To study whether the substrate scope could be extended
beyond enones, lactone 1d was subjected to the same reaction
conditions. Full conversion and a high 94% ee was obtained.
Again, no 1,2-addition or Heck-type products could be
detected.
Dihydropyridone 1e is an important substrate in the
synthesis of alkaloids. It has proven to be a challenging
substrate in the rhodium-catalyzed boronic acid addition due
to its low reactivity.10a,23 By applying the Pd(O2CCF3)2/Me-
DuPHOS catalyst at 70 °C, however, the reaction went to
full completion and afforded the product with essentially
complete enantioselectivity (>99% ee).
Linear substrates turned out to be considerably less
reactive. Enone 1f showed 60% conversion (45% yield) in
18 h using a combination of phenylboroxine 2i and slow
addition of water. No Heck-type products were observed,
and a reasonable 82% ee was obtained, comparable with the
results obtained by Miyaura et al. in the palladium/Chira-
PHOS/Cu(BF4)2 catalyzed asymmetric addition of arylbis-
muth compounds.16
Figure 2. Substrates and boronic acids used in this study.
The asymmetric rhodium-catalyzed arylboronic acid ad-
dition to unsaturated aldehydes has been troublesome, partly
because of competing 1,2-addition. Very recently the group
of Carreira reported excellent results in the conjugate addition
to aryl-substituted enals.24 The sole paper on the use of
aliphatic enals as substrates reported moderate yields but high
enantioselectivities.25 In the corresponding palladium-
catalyzed conjugate addition of boronic acids using an achiral
ligand (dppe),15a good yields were obtained. Interestingly,
using Pd(O2CCF3)2/Me-DuPHOS as the catalyst, 2-E-hexenal
underwent selective conjugate addition, without formation
of the 1,2-addition product. The conversion was only 42%,
however, and a moderate 49% ee was obtained, which comes
close to the results reported with triphenylbismuth.26
In sharp contrast with the reaction of 1f and 1g, the
addition to methyl-E-crotonate took a different course
(Scheme 1). In this reaction, the Heck coupling product
yield and excellent ee. In contrast, m-nitrophenylboronic acid
refused to react, whereas m-chlorophenylboronic acid gave
incomplete conversion (Table 1, entry 11). This parallels the
observations by Larhed et al. in the corresponding oxidative
Heck arylation where they observed a lack of reactivity in
the use of electron poor arylboronic acids that can be due to
their slow insertion into Pd(II) complexes.22
Using 2-cyclopentenone as substrate (Table 2), a somewhat
lower (but still useful) 82% ee was obtained. As full
Table 2. Asymmetric 1,4-Addition of Boronic Acid 2 to
R,â-Unsaturated Compoundsa
entry substrate 1 ArBX2 2 time (h) yieldb (%) of 3 eec (%)
1d
2e
3
1b
1c
1d
1e
1f
1g
1h
1i
2a
2a
2if
2a
2if
2if
2a
2a
6
18
5
22
18
24
22
22
75 (3i)
55 (3j)
75 (3k)
60 (3l)
45 (3m)h
30 (3n)i
nd (3o)j
0 (3p)
82 (R)
86 (R)
94 (S)
>99 (R)
82
4g
5
Scheme 1
6
7
8
49
8k
a Reactions were carried out in THF/H2O (10/1) in the presence of 5
mol % of Pd(O2CCF3)2 and 5.5 mol % of (R,R)-Me-DuPHOS at 50 °C
unless stated otherwise. All reactions gave full conversion (TLC and NMR)
unless stated otherwise. b Isolated yields after column chromatography.
c Absolute configuration is shown in parentheses. d Reaction performed at
room temperature. e 1c was purchased with 80% purity. f A solution of 20
vol % of water in THF was added at 0.1 mL/h by means of a syringe pump
over the reaction time (see the Supporting Information). g Reaction per-
formed at 70 °C. h 60% conversion. i 42% conversion. j The crude reaction
mixture consisted of 27% of 3o and 73% of Heck coupling product 4. k ee
of the 1,4-product.
dominates, together with 27% of racemic conjugate addition
product.27 This parallels the results in the Pd(dppe)(PhCN)2-
(22) See ref 20a: in that study, boronic acids with electronwithdrawing
groups at the meta position gave only moderate yield and para substituents
refused to react.
(23) Shintani, R.; Tokunaga, N.; Doi, H.; Hayashi, T. J. Am. Chem. Soc.
2004, 126, 6240.
(24) (a) Paquin, J.-F.; Defieber, C.; Stephenson, C. R. J.; Carreira, E.
M. J. Am. Chem. Soc. 2005, 127, 10850. For examples using achiral
catalysts, see: (b) Ueda, M.; Miyaura, N. J. Org. Chem. 2000, 65, 4450.
(25) Itooka, R.; Igushi, Y.; Miyaura, N. J. Org. Chem. 2003, 68, 6000.
conversion was reached at 50 °C in less than 4 h, the reaction
was carried out at room temperature in order to increase the
Org. Lett., Vol. 7, No. 23, 2005
5311

(SbF6)2-catalyzed addition of phenylboronic acid to ethyl
acrylate.28 The attempt to use methyl 2-acetamido acrylate
1i as substrate29 only resulted in recovery of starting material.
In conclusion, we have shown that the palladium-catalyzed
asymmetric conjugate addition of boronic acids is feasible.
Catalysts based on palladium trifluoroacetate and Me-
DuPHOS or Et-DuPHOS afford excellent results for several
substrates, comparable to the best rhodium-based systems.
For linear substrates results are unsatisfactory as yet. In
particular, the complete absence of Heck-type products,
except in case of 1h, is remarkable and encouraging. The
method is readily applicable: the catalyst is formed in situ
at room temperature and both the ligand L*3 and Pd(O2-
CCF3)2 are commercially available. A significant advantage
over existing palladium-catalyzed conjugate additions is the
application of arylboronic acids instead of the less readily
available aryltrifluoroborates and triarylbismuths. Reaction
conditions are mild, and the scope seems to be broad,
although further study is required to improve the performance
with noncyclic substrates.
(26) The palladium/ChiraPHOS/Cu(BF4)2-catalyzed addition of triphen-
ylbismuth to 2-hexenal afforded the conjugate addition product in 55% yield,
68% ee; see ref 16.
(27) The composition of the reaction mixture was determined by GC-
MS and 1H NMR analysis. The enantioselectivity of 3o in the mixture was
determined by chiral GC. Compound 4 was synthesized for comparison
according to a literature procedure (See Supporting Information).
(28) (a) Reference 15a. The rhodium-catalyzed enantioselective addition
of arylboronic acids to substituted cinnamic esters has recently been reported;
see: (b) Paquin, J.-F.; Stephenson, C. R. J.; Defieber, C.; Carreira, E. M.
Org. Lett. 2005, 7, 3821. The rhodium-catalyzed enantioselective addition
to aliphatic esters has been reported in: (c) Takaya, Y.; Senda, T.;
Kurushima, H.; Ogasawara, M.; Hayashi, T. Tetrahedron: Asymmetry 1999,
10, 4047. (d) Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. J. Org. Chem.
2000, 65, 5951. (e) Navarre, L.; Pucheault, M.; Darses, S.; Genet, J.-P.
Tetrahedron Lett. 2005, 46, 4247.
Acknowledgment. We thank T. Tiemersma for GC and
HPLC support and A. Kiewiet for mass spectrometry. Prof.
B. L. Feringa is acknowledged for valuable discussions.
Supporting Information Available: Experimental pro-
cedures, NMR spectra, and chromatographic data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(29) Substrate 1i has been used successfully in the corresponding
rhodium-catalyzed reaction; see: Navarre, L.; Darses, S.; Genet, J.-P. Angew.
Chem., Int. Ed. 2004, 43, 719 and references therein.
OL052222D
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Org. Lett., Vol. 7, No. 23, 2005