Pd-catalyzed regioselective and stereospecific Suzuki-Miyaura coupling of allylic carbonates with arylboronic acids

Article abstract of DOI:10.1021/ol203154j

The Pd-catalyzed Suzuki-Miyaura coupling reaction of unsymmetric 1,3-disubstituted secondary allylic carbonates with arylboronic acids has been developed in a wet solvent under a base-free system to afford allyl-aryl coupling products in a high level of isolated yields with complete regio- and E/Z-selectivities with good to excellent chemoselectivities. The coupling reaction of optically active allyl carbonates gave allyl-aryl coupling products with excellent enantioselectivities with inversion of the stereochemistry. This coupling method was successfully applied to the synthesis of (S)-naproxen.

Full text of DOI:10.1021/ol203154j

ORGANIC
LETTERS
2012
Vol. 14, No. 1
390–393
Pd-Catalyzed Regioselective and
Stereospecific SuzukiÀMiyaura
Coupling of Allylic Carbonates with
Arylboronic Acids
Chenguang Li,† Juxiang Xing,† Jingming Zhao,† Patrick Huynh,†,§ Wanbin Zhang,†
Pingkai Jiang,†,‡ and Yong Jian Zhang*,†,‡
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University,
800 Dongchuan Road, Shanghai 200240, P. R. China, Shanghai Key Laboratory of
Electrical Insulation and Thermal Aging, Shanghai Jiao Tong University,
800 Dongchuan Road, Sthanghai 200240, P. R. China , and CPE Lyon, 43 Boulevard du
11 Novembre 1918, 69622 Villeurbanne, France
yjian@sjtu.edu.cn
Received November 24, 2011
ABSTRACT
The Pd-catalyzed SuzukiÀMiyaura coupling reaction of unsymmetric 1,3-disubstituted secondary allylic carbonates with arylboronic acids has
been developed in a wet solvent under a base-free system to afford allylÀaryl coupling products in a high level of isolated yields with complete
regio- and E/Z-selectivities with good to excellent chemoselectivities. The coupling reaction of optically active allyl carbonates gave allylÀaryl
coupling products with excellent enantioselectivities with inversion of the stereochemistry. This coupling method was successfully applied to the
synthesis of (S)-naproxen.
The Pd-catalyzed SuzukiÀMiyaura coupling reaction is
one of the most powerful methods for CÀC bond forma-
tion because of the broad functional group tolerance, the
availability of organoboronic acids, and the lack of toxic
byproducts.1 A broad range of electrophiles undergo
cross-couplings with organoboronic acids, including
alkyl, aryl, akenyl, and alkynyl groups. However, the
coupling reaction with allylic derivatives has been rarely
reported,2 and in most of the reports, the allylic partners
have been confined to primary allylic halides or alcohol
derivatives. The allylÀaryl coupling reaction of unsym-
metric 1,3-disubstituted secondary allylic alcohol deriva-
tives with arylboronic acids remains a significant
challenge.3 Generally, the reaction starts with oxidative
addition of palladium(0) to an allylic partner 1a to
produce a π-allylpalladium intermediate, which subse-
quently undergoes transmetalation with arylboronic acid
† School of Chemistry and Chemical Engineering, Shanghai Jiao Tong
University.
‡ Shanghai Key Laboratory of Electrical Insulation and Thermal Aging,
Shanghai Jiao Tong University.
§ CPE Lyon.
(1) (a) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555. (b) Martin, R.;
Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461. (c) Miyaura, N. Top.
Curr. Chem. 2002, 219, 11. (d) Kotha, S.; Lahiri, K.; Kashinath, D.
Tetrahedron 2002, 58, 9633. (e) Miyaura, N.; Suzuki, A. Chem. Rev.
1995, 95, 2457.
(2) For a review, see: (a) Pigge, F. C. Synthesis 2010, 1745. For
selected recent examples, see:(b) Nishikata, T.; Lipshutz, B. H. J. Am.
Chem. Soc. 2009, 131, 12103. (c) Yamada, Y. M. A.; Watanabe, T.;
Torii, K.; Uozumi, Y. Chem. Commun. 2009, 5594. (d) Mino, T.;
Kajiwara, K.; Shirae, Y.; Sakamoto, M.; Fujita, T. Synlett 2008, 2711.
(e) Tsukamoto, H.; Uchiyama, T.; Suzuki, T.; Kondo, Y. Org. Biomol.
(3) There is only one effective example for allylÀaryl coupling
reaction of secondary allylic acetates with arylboronic acids using
heterogeneous palladium catalyst in the presence of excess base; see:
Uozumi, Y.; Danjo, H.; Hayashi, T. J. Org. Chem. 1999, 64, 3384.
ꢀ
ꢀ
€
Chem. 2008, 6, 3005. (f) Najera, C.; Gil-Molto, J.; Karlstrom, S. Adv.
Synth. Catal 2004, 346, 1798. (g) Tsukamoto, H.; Sato, M.; Kondo, Y.
Chem. Commun. 2004, 1200.
r
10.1021/ol203154j
Published on Web 12/20/2011
2011 American Chemical Society

γ-selective allylÀaryl coupling reaction using nitrogen-based
ligands(eq1).11 The reaction was catalyzed by cationic acetoxo-
palladium(II) to afford allylÀaryl coupling products with
R to γ chirality transfer with retention of the stereochemistry.
Scheme 1. AllylÀAryl Coupling vs β-H Elimination
to give a π-allyl(aryl)palladium intermediate, followed by
reductive elimination to afford allylÀaryl products
(Scheme 1).2a,4 However, the reaction generally gave
conjugated diene 5a instead of the desired coupling
products because the π-allylpalladium intermediate un-
derwent the β-H elimination more quickly than the
transmetalation with arylboronic acid.2a,5 This phenom-
enon might be one explanation for the limited develop-
ment of SuzukiÀMiyaura coupling with secondary allylic
fragments.
Although transition-metal-catalyzed allylic arylation
with arylmetallic reagents is another powerful approach
for allylÀaryl coupling, the reactions have not been well
exploited, and the arylmetallic reagents have mostly been
limited to highly reactive ones, such as aryl Grignard,6
zinc,7 and aluminum8 reagents. The allylic arylation with
arylboronic acid derivatives has been much less explored
because of their poor nucleophilicity.9,10 Most recently,
Sawamura and co-workers reported a Pd(II)-catalyzed
Herein, we disclose an effective method for the Pd-
catalyzed SuzukiÀMiyaura coupling reaction of unsym-
metric 1,3-disubstituted secondary allylic carbonates12
with arylboronic acids (eq 2). The reaction afforded the
allylÀaryl coupling products in a high level of isolated
yields with excellent chemo- and regioselectivity. The
reaction of optically active allylic carbonates furnished
allylÀaryl coupling products with excellent enantioselec-
tivities with inversion of the absolute configuration. The
methodology provides a simple and practical protocol
that allows rapid access to allylÀaryl coupling products
using in-situ-generated palladiumÀphosphine complex
as a catalyst and a wet solvent under a base-free system.
Preliminary studies demonstrated that the in-situ-gen-
erated palladium complex from Pd(OAc)213,14 (2 mol %)
and triphenylphosphine (4 mol %) was found to catalyze
the coupling of allylic carbonate 1a with phenylboronic
acid (2a) in THF in the presence of water (500 mol %) at
50 °C, affording allylÀaryl coupling product 3a in 87%
isolated yield with complete regio- and E/Z-selectivities
with a trace amount of β-H elimination product 5a
(Table 1, entry 1). Notably, water played a significant role
in the coupling reaction.15 The coupling reaction can
tolerate different allylic carbonate to give allylÀaryl cou-
pling product with the same efficiency (Table 1, entry 2).
Under identical reaction conditions, however, the reac-
tions of allylic acetate and benzoylate gave comparatively
poor results (Table 1, entries 3 and 4). The reaction
efficiency was also sensitive to the nature of the phosphine
(4) For Pd-catalyzed regioselective allylic alkylation, see: (a) Norsikian,
S.; Chang, C.-W. Curr. Org. Synth. 2009, 6, 264. (b) Trost, B. M.; Van
Vranken, D. L. Chem. Rev. 1996, 96, 395.
(5) (a) ref 2e. (b) Bouyssi, D.; Gerusz, V.; Balme, G. Eur. J. Org.
Chem. 2002, 2445. (c) Chen, H.; Deng, M.-Z. J. Organomet. Chem. 2000,
603, 189. (d) Kobayashi, Y.; Mizojiri, R.; Ikeda, E. J. Org. Chem. 1996,
61, 5391. (e) Tsuji, J.; Yamakawa, T.; Kaito, M.; Mandai, T. Tetra-
hedron Lett. 1978, 24, 2075.
(6) (a) Lauer, A. M.; Mahmud, F.; Wu, J. J. Am. Chem. Soc. 2011,
133, 9119. (b) Selim, K. B.; Nakanishi, H.; Matsumoto, Y.; Yamamoto,
ꢀ
Y.; Yamada, K.; Tomioka, K. J. Org. Chem. 2011, 76, 1398. (c) Thalen,
ꢀ
€
L. K.; Sumic, A.; Bogar, K.; Norinder, J.; Persson, A. K. A.; Backvall
€
J.-E. J. Org. Chem. 2010, 75, 6842. (d) Lolsberg, W.; Ye, S.; Schmalz
H.-G. Adv. Synth. Catal. 2010, 352, 2023. (e) Selim, K. B.; Matsumoto,
Y.; Yamada, K.; Tomioka, K. Angew. Chem., Int. Ed. 2009, 48, 8733.
(f) Selim, K. B.; Yamada, K.; Tomioka, K. Chem. Commun. 2008, 5140.
(7) (a) Polet, D.; Rathgeb, X.; Falciola, C. A.; Langlois, J.-B.; Hajjaji,
S. E.; Alexakis, A. Chem.;Eur. J. 2009, 15, 1205. (b) Alexakis, A.;
Hajjaji, S. E.; Polet, D.; Rathgeb, X. Org. Lett. 2007, 9, 3393.
(c) Kacprzynski, M. A.; May, T. L.; Kazane, S. A.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2007, 46, 4554. (d) Evans, P. A.; Uraguchi, D. J.
Am. Chem. Soc. 2003, 125, 7158. (e) Kobayashi, Y.; Tokoro, Y.;
Watatani, K. Eur. J. Org. Chem. 2000, 3825.
(11) (a) Makida, Y.; Ohmiya, H.; Sawamura, M. Chem.;Asian J.
2011, 6, 410. (b) Li, D.; Tanaka, T.; Ohmiya, H.; Sawamura, M. Org.
Lett. 2010, 12, 3344. (c) Ohmiya, H.; Makida, Y.; Li, D.; Tanabe, M.;
Sawamura, M. J. Am. Chem. Soc. 2010, 132, 879. (d) Ohmiya, H.;
Makida, Y.; Tanaka, T.; Sawamura, M. J. Am. Chem. Soc. 2008, 130,
17276.
(12) For SuzukiÀMiyaura coupling of propargylic carbonates, see:
Moriya, T.; Miyaura, N.; Suzuki, A. Synlett 1994, 149.
(13) Other Pd(0) or Pd(II) precursors, for example, Pd2(dba)3,
Pd(PPh3)4, PdCl2, and Pd(CF3CO2)2, were attempted in the coupling
reaction, but they were less effective under otherwise identical
conditions.
(8) Gao, F.; Lee, Y.; Mandai, K.; Hoveyda, A. H. Angew. Chem., Int.
Ed. 2010, 49, 8370.
(9) For Rh-catalyzed allylic arylation with aryboronic acids, see:
(a) Menard, F.; Perez, D.; Roman, D. S.; Chapman, T. M.; Lautens, M.
J. Org. Chem. 2010, 75, 4056. (b) Yu, B.; Menard, F.; Isono, N.; Lautens,
M. Synthesis 2009, 853. (c) Miura, T.; Takahashi, Y.; Murakami, M. M.
Chem. Commun. 2007, 595. (d) Menard, F.; Chapman, T. M.;
Dockendorff, C.; Lautens, M. Org. Lett. 2006, 8, 4569. (e) Dong, L.;
Xu, Y.-J.; Cun, L.-F.; Cui, X.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Org.
Lett. 2005, 7, 4285. (f) Lautens, M.; Dockendorff, C.; Fagnou, K.;
Malicki, A. Org. Lett. 2002, 4, 1311.
(10) For Cu-catalyzed γ-selective allylic arylation with arylboronic
acids, see: (a) Shintani, R.; Takatsu, K.; Takeda, M.; Hayashi, T. Angew.
Chem., Int. Ed. 2011, 50, 8656. (b) Ohmiya, H.; Yokokawa, N.;
Sawamura, M. Org. Lett. 2010, 12, 2438. (c) Whittaker, A. M.; Rucker,
R. P.; Lalic, G. Org. Lett. 2010, 12, 3216.
(14) The reaction between Pd(OAc)2 and arylboronic acid gave
reactive Pd(0) species, which works as a catalyst in the allylÀaryl
ꢁ
coupling as shown in Scheme 1; see: Moreno-Manas, M.; Perez, M.;
ꢀ
Pleixats, R. J. Org. Chem. 1996, 61, 2346.
(15) The reaction was remarkably inhibited in the absence of water.
Water likely accelerates the transmetalation step as outlined in Scheme 1
to lead to allylÀaryl coupling product effectively. See ref 1e.
Org. Lett., Vol. 14, No. 1, 2012
391

Table 1. Pd-Catalyzed SuzukiÀMiyaura Coupling of 1a with 2a
Table 2. Scope of Pd-Catalyzed SuzukiÀMiyaura Coupling of
Allyl Carbonates 1 with Arylboronic Acids 2a
under Various Conditionsa
conversionb
yield of
3ac (%)
entry
R
ligand
PPh3
(%) (3a:4a:5a:6a)
1
2
3
4
5
6
7
8
9
Boc
>99 (97:0:3:0)
>99 (97:0:0:3)
24 (25:0:0:75)
14 (12:0:0:88)
68 (97:0:0:3)
87
CO2Et
Ac
PPh3
86
d
PPh3
d
Bz
PPh3
Boc
Boc
Boc
Boc
Boc
P(C6F5)3
PCy3
59
20
81
54
40
>99 (26:0:74:0)
>99 (90:0:0:10)
>99 (63:0:12:25)
>99 (45:0:12:43)
rac-BINAP
DPPF
Xantphos
a Conditions: Pd(OAc)2 (2 mol %), ligand (4 mol % for monophos-
phines; 2 mol % for bisphosphines), 1a (0.50 mmol), 2a (0.75 mmol),
water (500 mol %), THF (0.5 mL), 50 °C, 24 h. b Determined by
1H NMR of the crude reaction mixture. c Yields are of isolated material.
d Not determined. Cy: cyclohexyl.
ligand. When replacement of PPh3 withelectronic deficient
phosphine ligand, P(C6F5)3, the reaction still performed
well to afford coupling product 3a as a single product, but
the reaction did not complete within 24h (68% conversion,
Table 1, entry 5). However, the reaction with σ-donating
tricyclohexylphosphine gave elimination product 5a as a
major product (3a:5a = 26:74, Table 1, entry 6). Bispho-
sphine ligand, rac-BINAP, promoted the reaction with
good selectivity in 81% yield (Table 1, entry 7), but the
reactions with DPPF and xantphos resulted in a loss of
selectivity (Table 1, entries 8 and 9).
To evaluate the scope of this process, the reaction
conditions were applied to various combinations of allylic
carbonates 1 and arylboronic acids 2. As illustrated in
Table 2, a wide range of unsymmetric 1,3-disubstituted
secondary allylic carbonates 1 and arylboronic acids 2
were tolerated in this coupling reaction to give allylÀaryl
coupling products 3 in a high level of isolated yields with
good to excellent selectivities. The coupling reactions of
1a with various substituted arylboronic acids 2 with
different electronic or steric natures proceeded to the
corresponding allylÀaryl products 3 in a high level of
yields with excellent selectivities (Table 2, entries 1À7).
When 1-phenyl-2-butenyl carbonate 1b as a regioisomer
of 1a was used, the coupling reaction occurred to furnish
single regioisomeric product 3a in 82% yield (Table 2,
entry 8). This result supports the possible mechanism
outlined in Scheme 1, in which the reductive elimination
takes place at the less hindered site of the π-allylpalladium
complex, yielding the coupling product regioselectively.
The allylic carbonates 1cÀ1i were employed successfully
a Conditions: Pd(OAc)2 (2 mol %), PPh3 (4 mol %), 1 (0.50 mmol),
2 (0.75 mmol), water (500 mol %), THF (0.5 mL), 50 °C, 24 h. b Yields
are of isolated material. c Determined by 1H NMR of the crude reaction
mixture. All of the reactions gave coupling products with complete
regio- and E/Z-selectivities.
in the coupling reaction to afford corresponding allylÀ
aryl coupling products in a high level of isolated yields
with complete rigio- and E/Z-selectivities and good to
excellent chemoselectivies (Table 2, entries 9À15).
The ability to obtain excellent chemo- and regioselec-
tivity prompted the examination of the coupling reaction
of enantiomerically enriched allylic carbonate (R)-1a16
with aryl boronic acids to determine the stereochemical
(16) Enantioenriched allylic alcohol precursor was synthesized using
Sharpless kinetic resolution; see: Carlier, P. R.; Mungall, W. S.;
€
Sohroder, G.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 2978.
392
Org. Lett., Vol. 14, No. 1, 2012

stereospecifically, after which subsequently takes place
transmetalation and reductive elimination as illustrated
in Scheme 1 to afford inversed allylÀaryl coupling pro-
ducts. This SuzukiÀMiyaura coupling method was suc-
cessfully applied to the synthesis of (S)- naproxen19 as an
antiinflammatory drug. The coupling reaction of (S)-1a16
(95% ee, 3 mmol scale) with arylboronic acid 1i gave
allylÀaryl coupling product (R)-3o18 in 82% yield with
95% ee (Scheme 3). Oxidation20 of (R)-3o furnished
(S)-naproxen in 78% yield with >99% ee after one
recrystallization.
Scheme 2. Stereospecific AllylÀAryl Coupling
In conclusion, we have described an effective method
for Pd-catalyzed SuzukiÀMiyaura coupling reaction of
unsymmetric 1,3-disubstituted secondary allylic carbo-
nates with arylboronic acids under mild conditions. The
reaction has been developed in a wet solvent under a base-
free system to afford allylÀaryl coupling products in a
high level of isolated yields with complete regio- and E/Z-
selectivities and with good to excellent chemoselectivities.
In the stereochemical course of the coupling reaction, it
has been demonstrated that the reaction of optically
active allylic carbonates gaveallylÀarylcoupling products
with excellent enantioselectivities with inversion of the
stereochemistry. This coupling method was successfully
applied to the synthesis of (S)-naproxen. Further studies
will focus on the development of an asymmetric version of
this important coupling reaction.
Scheme 3. Synthesis of (S)-Naproxen
course of this coupling reaction. The reaction of (R)-1a
(94% ee) with arylboronic acids, 2a, 2c, and 2e with the
palladium complex in-situ-generated from Pd(OAc)2 and
racemic BINAP17 furnished allylÀaryl coupling products
(S)-3a (94% ee), (S)-3c (93% ee), and (S)-3e (94% ee) in
high yields with inversion of absolute configurations18
(Scheme 2). These results demonstrate that the reaction
proceeds with inversion of stereochemistry in the step of
oxidative addition to form π-allylpalladium complex
Acknowledgment. This work was supported by Shanghai
Pujiang Program and Shanghai Jiao Tong University. We
thank the Instrumental Analysis Center of Shanghai Jiao
Tong University for HRMS analysis.
(17) When using PPh3 as a ligand for the reaction of (R)-1a with 2a,
the reaction partially racemized to afford product (S)-3a with 50% ee.
(18) The absolute configurations were determined by comparing the
sign of the optical rotation with that reported in ref 6c.
(19) For a review, see: Harrington, P. J.; Lodewijk, E. Org. Process
Res. Dev. 1997, 1, 72.
Supporting Information Available. Experimental pro-
cedures and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) (a) Smith, C. R.; RajanBabu, T. V. J. Org. Chem. 2009, 74, 3066.
(b) Hirama, T.; Inoue, M. Synthesis 1986, 689.
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