Palladium-catalyzed oxidative cross-coupling reaction of arylboronic acids with diazoesters for stereoselective synthesis of (E)-α,β- diarylacrylates

Article abstract of DOI:10.1021/ol101796t

A Pd-catalyzed oxidative cross-coupling reaction of arylboronic acids with α-diazoesters was achieved using molecular oxygen as the sole reoxidant, and E-α,β-diarylacrylates were obtained in good yields and >20:1 E-to-Z selectivity.

Full text of DOI:10.1021/ol101796t

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4506-4509
Palladium-Catalyzed Oxidative
Cross-Coupling Reaction of Arylboronic
Acids with Diazoesters for
Stereoselective Synthesis of
(E)-r,ꢀ-Diarylacrylates
Yuk-Tai Tsoi, Zhongyuan Zhou, Albert S. C. Chan, and Wing-Yiu Yu*
State Key Laboratory for Chirosciences and Open Laboratory of Chirotechnology of
the Institute of Molecular Technology for Drug DiscoVery and Synthesis, Department
of Applied Biology and Chemical Technology, Hong Kong Polytechnic UniVersity,
Hung Hom, Kowloon, Hong Kong
bcwyyu@inet.polyu.edu.hk
Received August 2, 2010
ABSTRACT
A Pd-catalyzed oxidative cross-coupling reaction of arylboronic acids with r-diazoesters was achieved using molecular oxygen as the sole
reoxidant, and E-r,ꢀ-diarylacrylates were obtained in good yields and >20:1 E-to-Z selectivity.
Palladium-catalyzed cross-coupling reactions are powerful
tools for C-C and C-heteroatom single bond formation.
Notable examples include the Suzuki-Miyaura coupling,
Buchwald-Hartwig amination, and Mizoroki-Heck reac-
tions,1 wherein organoboron, amines, and alkenes are the
common nucleophilic partners. Apart from these conventional
nucleophiles, Van Vranken and co-workers2c,f,h,j were pio-
neers in exploring R-diazoesters as coupling partners for
organopalladium complexes. It is believed that a palladium-
carbene species would be formed by reacting diazoesters with
the organopalladium complexes. By analogy to the migratory
CO insertion, similar migratory carbene insertion to orga-
nopalladium would furnish a new C-C bond. Significant
advances have been made by the research groups of
Wang2a,b,d,e and Barluenga,2g,i and highly efficient coupling
reactions with aryl halides and carbenoid reagents have been
achieved. Encouraged by our earlier studies on Pd-catalyzed
direct C-H ethoxycarbonylation,3c arylation,3a and amidation
reactions3d based on carboradical and nitrene coupling, we
developed a Pd-catalyzed coupling of benzyl bromides with
R-aryldiazoacetates to afford (E)-R,ꢀ-diarylacrylates with >20:1
stereoselectivity.3b R,ꢀ-Diarylacrylates are useful scaffolds for
pharmaceutically active compounds, and Perkin aldol condensation
(1) For reviews, see: (a) de Meijere, A.; Diederich, F. Metal-Catalyzed
Cross-Coupling Reactions; Wiley-VCH: Weinheim, 2004. (b) Tsuji, J.
Palladium Reagents and Catalysis: InnoVation in Organic Synthesis; John
Wiley & Sons: Chichester, U. K., 1995.
(2) Examples of Pd-catalyzed carbenoid-mediated cross-coupling reac-
tions for CdC bond formation, see: (a) Zhang, Z.; Liu, Y.; Gong, M.; Zhao,
X.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2010, 49, 1139. (b) Zhao,
X.; Jing, J.; Ku, K.; Zhang, Y.; Wang, J. Chem. Commun. 2010, 1724. (c)
Kudirka, R.; Devine, S. K. J.; Adams, C. S.; Van Vranken, D. L. Angew.
Chem., Int. Ed. 2009, 48, 3677. (d) Xiao, Q.; Ma, J.; Yang, Y.; Zhang, Y.;
Wang, J. Org. Lett. 2009, 11, 4732. (e) Peng, C.; Wang, Y.; Wang, J. J. Am.
Chem. Soc. 2008, 130, 1566. (f) Devine, S. K. J.; Van Vranken, D. L. Org.
Lett. 2008, 10, 1909. (g) Barluenga, J.; Toma´s-Gamasa, M.; Moriel, P.;
Aznar, F.; Valde´s, C. Chem.sEur. J. 2008, 14, 4792. (h) Devine, S. K. J.;
Van Vranken, D. L. Org. Lett. 2007, 9, 2047. (i) Barluenga, J.; Moriel, P.;
Valde´s, C.; Aznar, F. Angew. Chem., Int. Ed. 2007, 46, 5587. (j) Greenman,
(3) (a) Yu, W.-Y.; Sit, W. N.; Zhou, Z.; Chan, A. S. C. Org. Lett. 2009,
11, 3174. (b) Yu, W.-Y.; Tsoi, Y.-T.; Zhou, Z.; Chan, A. S. C. Org. Lett.
2009, 11, 469. (c) Yu, W.-Y.; Sit, W. N.; Lai, K.-M.; Zhou, Z.; Chan,
A. S. C. J. Am. Chem. Soc. 2008, 130, 33048. (d) Thu, H.-Y.; Yu, W.-Y.;
Che, C.-M. J. Am. Chem. Soc. 2006, 128, 904.
K. L.; Van Vranken, D. L. Tetrahedron 2005, 61, 6438
.
10.1021/ol101796t  2010 American Chemical Society
Published on Web 09/15/2010

Table 1. Reaction Optimizationa
entry
1a:2a
ligand (5.5 mol %)
additive
temperature (°C)
yieldb (%)
E/Z ratio
1c
2
1:2
1:2
1:3
1:2
1:2
1:2
1:2
1:2
1:3
phend
phen
-
-
-
-
-
-
-
-
-
70
70
70
70
70
70
70
70
70
70
50
18
65
0
64
18
16
7
18:1
21:1
-
3e
4
-
bpyf
21:1
1.8:1
3.2:1
3.5:1
2.5:1
21:1
21:1
21:1
5
6
7
8
dmbpyg
tmedah
dppei
pyridinej
phen
5
9k
10k
81l
69l
80l
1:1.5
1:1.2
phen
phen
B(OH)3 (25 mol%)
B(OH)3(50mol%)
11k m
,
a The reactions were carried out in a 0.2 mmol scale of 1a with 10 h syringe pump addition of 1a, and the reaction was run for 11 h. b Yields were
determined by GC/FID using dodecane as the internal standard. c Single batch addition of 1a was employed. d 1,10-Phenanthroline. e Absence of Pd(OAc)2
and phen. f 2,2′-Bipyridine. g 6,6′-Dimethyl-2,2′-bipyridine. h N,N,N′,N′-Tetramethylethylenediamine. i 1,2-Bis(diphenylphosphino)ethane. j 11 mol % of pyridine.
k O2 purging for 15 min before substrate addition. l Isolated yield. m Reaction run for 31 h.
is a common method for their synthesis.4 However, the Perkin aldol
reactions suffer from rather poor substrate scope and product yield.
While our “benzyl bromide + diazoester” coupling reaction
required the use of excess PPh3 and reactive benzyl bromides for
operation,3b this reaction is far from ideal for environmentally sound
organic synthesis.
monitoring, the stereoselectivity (i.e., E:Z ) 21:1) of the diazo
coupling reaction remained the same throughout the reaction.
No 3aa was obtained in the absence of the Pd catalyst (entry
3).5 We found that phen and bpy produced comparable results
(entries 2 and 4); results for other ligands such as 6,6′-dimethyl-
2,2′-bipyridine (dmbpy), tmeda, and dppe were less satisfactory
(entries 5-8). Up to 81% yield and E:Z ) 21:1 were attained
for 3aa when 3 equiv of 2a was employed (entry 9).
Since CdC bond formation is of fundamental interest for organic
synthesis, we considered that the coupling of organoborons with
diazoacetate under oxidative Pd catalysis would be a versatile
platform for stereoselective alkene formation. In this regard, Wang
and co-workers described the coupling of arylboronic acids with
diazoesters to form substituted acrylates by employing Pd(PPh3)4
as the catalyst and benzoquinone as the stoichiometric oxidant, but
the reaction exhibited low alkene stereoselectivity (E:Z ratio <2:
1).2d During our investigation, Wang and co-workers reported an
analogous coupling reaction with N-tosylhydrazones2a by employ-
ing CuCl (10 mol %) and dioxygen as the reoxidant. Prompted
by these developments, we report herein a stereoselective diary-
lacrylate synthesis (E:Z ratio >20:1) by catalytic coupling of
arylboronic acids and R-diazoesters/ketones using Pd(OAc)2 as
catalyst and 1,10-phenanthroline (phen) as ligand with molecular
dioxygen alone as reoxidant. Our results showed that the nitrogen
ligand is critical for attaining high stereoselectivity.
To devise a more efficient protocol, we turned to examine
the stoichiometric diazo coupling reactions with well-defined
arylpalladium(II) complexes. As depicted in Scheme 1, treat-
Scheme 1. Synthesis of the Arylpalladium(II) Complexes 4 and 5
We began by treating R-diazo-ꢀ-phenylpropionate (1a, 0.2
mmol) with phenylboronic acid (2a, 0.4 mmol), Pd(OAc)2 (5
mol %), and phen (5.5 mol %) in DMF at 70 °C for 3 h under
an O2 atmosphere, and 3aa was formed in 18% yield with an
E:Z ratio ) 18:1 (Table 1, entry 1). By syringe pump addition
of 1a over 10 h, 3aa was obtained in 65% yield with an E:Z
ratio ) 21:1 (entry 2). Notably, benzoquinones and Cu salts
are not required for reoxidation of the Pd catalyst. By GC-MS
ment of Pd2(dba)3 with iodobenzene and tmeda, followed by
ligand substitution with 4,4′-di-tert-butyl-2,2′-bipyridine, af-
forded 4.6b,c After AgOAc metathesis, 5 was obtained.
Complex 5a has been structurally characterized by X-ray
crystallography (Figure 1); the Pd atom adopted a distorted
square planar configuration that contains the coordinated
phenyl and η1-acetate ligands and the bidentate 4,4′-di-tert-
butyl-2,2′-bipyridine. The measured Pd-C(19) distance is
1.977(3) Å, which is comparable to the related distances of
(4) For examples, see: (a) Moreau, A.; Chen, Q.-H.; Praveen Rao, P. N.;
Knaus, E. E. Bioorg. Med. Chem. 2006, 14, 7716. (b) Jonnalagadda, S. S.;
Haar, E. T.; Hamel, E.; Lin, C. M.; Magarian, R. A.; Day, B. W. Bioorg.
Med. Chem. 1997, 5, 715. (c) Nodiff, E. A.; Tanabe, K.; Seyfried, C.;
Matsuura, S.; Kondo, Y.; Chen, E. H.; Tyagi, M. P. J. Med. Chem. 1971,
14, 921.
Org. Lett., Vol. 12, No. 20, 2010
4507

the 11% yield for the additive-free reaction. Other acids such as
H3PO4, CF3COOH, and benzoic acids are less effective additives
(entries 4-8). If the coupling reaction was performed at room
temperature with 5 equiv of B(OH)3, 3aa was furnished in 72%
yield (entry 9).
With the stoichiometric results at hand, we studied the effect of
the B(OH)3 additive on the catalytic reactions. When 2a (1.5 equiv)
was treated with 1a (1 equiv) via syringe pump addition over 10 h
in the presence of Pd(OAc)2 (5 mol %), phen (5.5 mol %), and
B(OH)3 (50 mol %) in DMF at 70 °C under an O2 atmosphere,
3aa was furnished in 69% yield with E:Z selectivity ) 21:1 (Table
1, entry 10). After further optimization, 3aa was obtained in up to
80% yield (E:Z ) 21:1) when the reaction was undertaken with
2a (1.2 equiv) at 50 °C over 31 h (Table 1, entry 11).
Figure 1. ORTEP representation of complex 5a. Selected bond
Scheme 2 depicts the scope of the Pd-catalyzed diazo coupling
reaction. Both electron-donating and -withdrawing groups (includ-
ing halogen, nitro) were tolerated, and good product yields and
E-stereoselectivities were obtained (3aa-3ai). o-Tolylboronic acid
was a less effective substrate for the diazo coupling reaction, with
3aj being formed in ∼20% yield. Yet, effective coupling of the
mesityl-substituted diazoester afforded 3da and 3dk in 75% and
68% yield, respectively. Recently, indole-containing diarylacrylates
were shown to exhibit potent glycine-site N-methyl-D-aspartate
receptor antagonist activity, indicating that they are potential
neuroprotective agents.9 In this work, treatment of some indole-
substituted diazoesters with arylboronic acids by the Pd-catalyzed
protocol gave the E-acrylates 3ea, 3el, 3em, and 3en exclusively
in 58-72% yields. Likewise, diaryl vinyl ketones10a such as 3fa
(79%) and 3ga (71%) and isoflavone10b 3ha (60%) were also
obtained by the catalytic diazo coupling reactions; diaryl vinyl
ketones and isoflavones are useful scaffolds for some bioactive
molecules.
distances [Å] and angles [°]: Pd-C(19) 1.977 (3), Pd-O(1) 2.015
(2), Pd-N(1) 2.100 (3), Pd-N(2) 2.026 (2), C(19)-Pd-O(1) 88.62
(12), C(19)-Pd-N(2) 97.05 (12), O(1)-Pd-N(2) 174.32 (10),
N(2)-Pd-N(1) 79.72 (10).
Pd(BrettPhos)(2-methyl-4-trifluoromethylphenyl)F [2.001(2)
Å]7 and Pd(bpy)(I)Ph [1.996(10) Å].6c
When 5a was reacted with 1a (1 equiv) in DMF at 70 °C under
an O2 atmosphere, 3aa was obtained exclusively (i.e., no Z-acrylate
detected) in only 11% yield (Table 2, entry 1). Consistent with
Table 2. Stoichiometric Reactions of 5a with 1aa
The reaction is probably initiated by transmetalation with aryl-
boronic acids to [Pd(phen)(OAc)2] to form arylpalladium complex
I (Scheme 3). The active arylpalladium complex II could be formed
(5) Metal-free reactions of diazo carbonyl compounds with arylboronic
acids, see :(a) Barluenga, J.; Toma´s-Gamasa, M.; Aznar, F.; Valde´s, C.
Nat. Chem. 2009, 1, 494. (b) Peng, C.; Zhang, W.; Yan, G.; Wang, J. Org.
Lett. 2009, 11, 1667.
entry
additive (5 equiv)
temperature (°C)
yieldb (%)
(6) For examples of synthesis of arylpalladium(II) complexes, see: (a)
Fornie´s, J.; Mart´ınez, F.; Navarro, R.; Urriolabeitia, E. P. J. Organomet.
Chem. 1995, 495, 185. (b) De Felice, V.; Cucciolito, M. E.; De Renzi, A.;
Ruffo, F.; Tesauro, D. J. Organomet. Chem. 1995, 493, 1. (c) Markies,
B. A.; Canty, A. J.; de Graaf, W.; Boersma, J.; Janssen, M. D.; Hogerheide,
M. P.; Smeets, W. J. J.; Spek, A. L.; van Koten, G. J. Organomet. Chem.
1994, 482, 191.
1
2
3
4
5
6
7
8
9c
-
70
70
70
70
70
70
70
70
rt
11
95
51
48
30
18
28
trace
72
PhB(OH)2
B(OH)3
H3PO4
CF3CO2H
C6H5CO2H
CH3CH2CO2H
o-CH3C6H4SO3H
B(OH)3
(7) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; Garc´ıa-Fortanet,
J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661.
(8) Addition of boric acid was found to favor the acetate ion dissociation
from 5a. On the basis of the pKa values of boric acid [9.236 (water, 298
K)] and acetic acid [4.756 (water, 298 K) [ Gokel, G.W. Dean’s Handbook
of Organic Chemistry, 2nd ed.; McGraw-Hill: New York, U.S., 2004],
spontaneous protonation of the acetate by boric acid seems unlikely. To
account for the finding, we conjectured that the boric acid would stabilize
the dissociated acetate by hydrogen bonding, thereby lowering its nucleo-
philicity for recoordination to the unsaturated Pd(II) complex.
(9) (a) Bourderioux, A.; Routier, S.; Be´ne´teau, V.; Me´rour, J.-Y.
Tetrahedron 2007, 63, 9465. (b) Baron, B. M.; Cregge, R. J.; Farr, R. A.;
Friedrich, D.; Gross, R. S.; Harrison, B. L.; Janowick, D. A.; Matthews,
D.; McCloskey, T. C.; Meikrantz, S.; Nyce, P. L.; Vaz, R.; Metz, W. A.
J. Med. Chem. 2005, 48, 995.
a The reactions were carried out in a 0.05 mmol scale of 4b, DMF (2.5
mL), O2 (1 atm), 70 °C for 1 h. b Yields were determined by NMR using
dibromomethane as the internal standard. c The reaction was carried out
for 3 h, and cinnamate (21%) was detected.
our earlier results, employing excess PhB(OH)2 (5 equiv) would
promote the “5a + 1a (1 equiv)” coupling reaction to give 3aa in
95% yield (entry 2). We conjectured that the OAc- may be a
stronger nucleophile than 1a in competing for the vacant site on
the Pd(II). After several experiments, employing B(OH)3 (5 equiv)
as additive8 led to improved 3aa formation (51%; entry 3) versus
(10) Examples of diaryl vinyl ketone and flavone as scaffolds of bioactive
compounds: (a) Zhu, J.; Zhong, C.; Lu, H.-F.; Lee, G.-Y.; Sun, X. Synlett
2008, 3, 458. (b) Stachulski, A. V.; Berry, N. G.; Lilian Low, A. C.; Moores,
S. L.; Row, E.; Warhurst, D. C.; Adagu, I. S.; Rossignol, J.-F. J. Med.
Chem. 2006, 49, 1450.
4508
Org. Lett., Vol. 12, No. 20, 2010

Scheme 2
.
Pd-Catalyzed Oxidative Cross-Coupling of
Scheme 3. Proposed Catalytic Cycle
Arylboronic Acids with Diazoestersa b
,
The high E-stereoselectivity is intriguing since the transition state
in the ꢀ-elimination for formation of trisubstituted alkenes should
favor the two bulky aryl groups in a trans-arrangement (i.e., V),
and a Z-alkene product is anticipated.2i The observed E-trisubsti-
tuted acrylate formation is incompatible with this notion. Neverthe-
less, the E-trisubstituted acrylate formation was also observed for
the Perkin aldol condensation,13 and the preference for the seem-
ingly “less favored” transition state is not clear and is under
investigation.
In conclusion, a stereoselective synthesis of (E)-R,ꢀ-diarylacry-
lates was developed based on ligand-modulated oxidative Pd-
catalyzed coupling of arylboronic acids and diazoesters, and
molecular oxygen was used as the reoxidant. Apart from their ease
of handling and lack of toxicity, arylboronic acids are available in
great structural diversity. This Pd-catalyzed protocol would form
the foundation for future development of regio- and stereocontrolled
oxidative catalysis for CdC bond formation.
Acknowledgment. We thank the Hong Kong Research
Grants Council (PolyU5019/06P; SEG_1 PolyU) and Uni-
versity Grants Committee Areas of Excellence Scheme (AoE/
P-10-01) for financial support.
Supporting Information Available: Detailed experimen-
tal procedures and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
a Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), Pd(OAc)2 (5 mol %),
phen (5.5 mol %), boric acid (50 mol %), O2 (1 atm), DMF (2 mL), 50 °C for
31 h. b Isolated yield. c NMR yield. d Pd(OAc)2 (10 mol %), phen (11 mol
%), PhB(OH)2 (3 equiv), no B(OH)3 added, 70 °C, reaction run for 21 h.
OL101796T
(11) Examples of migratory insertion of metal-carbenes, see: (a) Albe´niz,
A. C.; Espinet, P.; Pe´rez-Mateo, A.; Nova, A.; Ujaque, G. Organometallics
2006, 25, 1293. (b) Albe´niz, A. C.; Espinet, P.; Manrique, R.; Pe´rez-Mateo,
A. Chem.sEur. J. 2005, 11, 1565. (c) Sole´, D.; Vallverdu´, L.; Solans, X.;
Font-Bardia, M.; Bonjoch, J. Organometallics 2004, 23, 1438.
(12) For reviews, see: (a) Gligorich, K. M.; Sigman, M. S. Chem.
Commun. 2009, 3854. (b) Gligorich, K. M.; Sigman, M. S. Angew. Chem.,
Int. Ed. 2006, 45, 6612.
by boric acid-assisted acetate dissociation. The subsequent reaction
of II with the diazoester 1 would form putatively a reactive
palladium-carbene complex III, and migratory insertion of the
aryl group would afford the alkylpalladium complex IV.11 Migra-
tory insertion reactions for palladium carbenes are well precedented
in amino- and methoxycarbene palladium complexes. ꢀ-Elimina-
tion should yield the acrylate 3 and PdII-hydride complex VI. To
complete the catalytic cycle, VI was transformed to the Pd complex
I with molecular oxygen.12
(13) (a) Zimmermann, H.; Ahramjian, L. J. Am. Chem. Soc. 1959, 81,
2086. (b) Pa´linko´, I.; To¨ro¨k, B.; Tasi, G.; Ko¨rtve´lyesi, T. Experimental
and Computational Tools for Mechanistic Study: A Modified Perkin
Condensation leading to Alpha-Phenylcinnamic Acid Isomers; Electronic
Conference on Trends in Organic Chemistry-1, June 12-July 7, 1995.
Org. Lett., Vol. 12, No. 20, 2010
4509