Palladium-catalyzed cross coupling reaction of benzyl bromides with diazoesters for stereoselective synthesis of (E)-α,β-diarylacrylates

Article abstract of DOI:10.1021/ol8026076

(Chemical Equation Presented) A Pd-catalyzed cross-coupling reaction of benzyl bromides with α-aryldiazoesters is described, and E-α,β-diarylacrylates were obtained in good yields and excellent E-to-Z selectivity (>20:1).

Full text of DOI:10.1021/ol8026076

ORGANIC
LETTERS
2009
Vol. 11, No. 2
469-472
Palladium-Catalyzed Cross Coupling
Reaction of Benzyl Bromides with
Diazoesters for Stereoselective
Synthesis of (E)-r,ꢀ-Diarylacrylates
Wing-Yiu Yu,* Yuk-Tai Tsoi, Zhongyuan Zhou, and Albert S. C. Chan
Department of Applied Biology and Chemical Technology and Open Laboratory of
Chirotechnology of the Institute of Molecular Technology for Drug DiscoVery and
Synthesis, The Hong Kong Polytechnic UniVersity, Hung Hom, Kowloon, Hong Kong
bcwyyu@inet.polyu.edu.hk
Received November 11, 2008
ABSTRACT
A Pd-catalyzed cross-coupling reaction of benzyl bromides with r-aryldiazoesters is described, and E-r,ꢀ-diarylacrylates were obtained in
good yields and excellent E-to-Z selectivity (>20:1).
R-Diazocarbonyl compounds are versatile reagents for
organic synthesis.1 With transition metal catalysts2a (e.g.,
Rh,2b,c Cu,3a-c Au,3b,e Ag,3d Ru3f,g,4 ), R-diazocarbonyl
compounds can be readily transformed to highly reactive
metal-carbene complexes, which are known to functionalize
CdC and C-H bonds for stereoselective C-C bond forma-
tion. Previously, we described that ruthenium complexes of
porphyrins and π-aromatics can effect highly stereoselective
heterocycle formation via a carbenoid C-H insertion reaction
of R-diazocarbonyl compounds.4
Coupling reaction of organopalladium complexes with
carbon nucleophiles is a fundamental process that underlies
many Pd-catalyzed C-C bond formation reactions.5 The
carbon nucleophiles include organometallic reagents (e.g.,
organoboron),6a alkenes,6b,c and arenes,6d,e etc. Apart from
the conventional nucleophiles, we recently found that reac-
tions of organopalladium complexes with nitrenes and
carboradicals would bring about C-N and C-C bond
formation.7 In the light of these findings, we envisage the
(1) For comprehensive reviews, see: (a) Doyle, M. P.; McKervey, M. A.;
Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds; Wiley-Interscience: New York, 1998. (b) Zollinger, H. Diazo
Chemistry I & II; VCH: New York, 1994.
(2) (a) Do¨rwald, F. Z. Metal Carbenes in Organic Synthesis; Wiley-
VCH: Weinheim, 1999. (b) Davies, H. M. L.; Beckwith, R. E. J. Chem.
ReV. 2003, 103, 2861. (c) Padwa, A.; Hornbuckle, S. F. Chem. ReV. 1991,
91, 263
.
(3) Selected examples, see: (a) Itagaki, M.; Masumoto, K.; Suenobu,
K.; Yamamoto, Y. Org. Process Res. DeV. 2006, 10, 245. (b) Fructos, M. R.;
Fre´mont, P.; Nolan, S. P.; D´ıaz-Requejo, M. M.; Pe´rez, P. J. Organometallics
2006, 25, 2237. (c) Dai, X.; Warren, T. H. J. Am. Chem. Soc. 2004, 126,
10085. (d) Despagnet-Ayoub, E.; Jacob, K.; Vendier, L.; Etienne, M.;
(5) (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.
j
Alvarez, E.; Caballero, A.; D´ıaz-Requejo, M. M.; Pe´rez, P. J. Organome-
tallics 2008, 27, 4779. (e) Fructos, M. R.; Belderrain, T. R.; Fre´mont, P.;
Scott, N. M.; Nolan, S. P.; D´ıaz-Requejo, M. M.; Pe´rez, P. J. Angew. Chem.,
Int. Ed. 2005, 44, 5284. (f) Grohmann, M.; Buck, S.; Schaeffler, L.; Maas,
G. AdV. Synth. Catal. 2006, 348, 2203. (g) Nishiyama, H.; Itoh, Y.;
Sugawara, Y.; Matsumoto, H.; Aoki, K.; Itoh, K. Bull. Chem. Soc. Jpn.
(6) (a) Suzuki, A. In Modern Arene Chemistry; Astruc, D., Ed.; Wiley-
VCH: Weinheim, Germany, 2002; pp 53-106. (b) Dounay, A. B.; Overman,
L. E. Chem. ReV. 2003, 103, 2945. (c) Beletskaya, I. P.; Cheprakov, A. V.
Chem. ReV. 2000, 100, 3009. (d) Stuart, D. R.; Fagnou, K. Science 2007,
316, 1172. (e) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
16496.
1995, 68, 1247
.
(4) (a) Choi, M. K.-W.; Yu, W.-Y.; Che, C.-M. Org. Lett. 2005, 7, 1081.
(b) Cheung, W.-H.; Zheng, S.-L.; Yu, W.-Y.; Zhou, G.-C.; Che, C.-M. Org.
(7) (a) Yu, W.-Y.; Sit, W. N.; Lai, K.-M.; Zhou, Z.; Chan, A. S. C.
J. Am. Chem. Soc. 2008, 130, 3304. (b) Thu, H.-Y.; Yu, W.-Y.; Che, C.-
M. J. Am. Chem. Soc. 2006, 128, 9048.
Lett. 2003, 5, 2535
.
10.1021/ol8026076 CCC: $40.75
Published on Web 12/19/2008
2009 American Chemical Society

Table 1. Optimization of Reaction Conditionsa
entry
1a:2a
Pd source (5 mol %)
ligand (40 mol %)
base (4 equiv)
solvent %
convnb
%
yieldb,c
a
1
2
3
4
5
6
7
8
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:2
1:2
1:2
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:2
1:3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
PPh3
PPh3
PPh3
AsPh3
PCy3
dppbf
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
none
K2CO3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
dioxane
toluene
CH3CN
acetone
DCE
68
80
80
38
39
53
80
70
56
100
100
100
93
100
67
87
29
59
88
37
31
44
26
0
i-Pr2NEta
Na2CO3
a
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CHO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
0
63
64
38
87
87
85
46
80
63
43
0
d
Pd(OAc)2
9
[pd(allylCl)]2
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
none
10d
11
12
13
14
15
16
17
18
19
20
DMF
THF
toluene
toluene
THF
g
PPh3
PPh3
48
78
0
h
1:3
PPh3
55
a The reactions were carried out in a 0.2 mmol scale of 1a. b Conversions and yields were determined by GC/FID using tetradecane as internal standard.
c The percentage yield is based on 1a conversion. d The reaction was run for 3 h. e 10 mol % of Pd(OAc)2 was employed. f 2.5 mol % of Pd2dba3·CHCl3 was
employed. g 30 mol % of ligand. h 20 mol % of ligand. i 2 equiv of base.
development of new C-C bond formation by exploiting the
reaction of organopalladium with carbenes. By analogy to
migratory CO insertion to the Pd-C bond, migratory
insertion of carbene to organopalladium would create a new
C-C bond as a stereogenic center.8 Indeed, some reports
on the Pd-catalyzed cross coupling reactions of aryl/vinyl
halides with carbenes derived from R-diazocarbonyls emerged
recently in the literature.9 In this work, we describe a
stereoselective synthesis of E-R,ꢀ-diarylacrylates by the Pd-
catalyzed reaction of benzyl bromides with R-aryldiazoesters.
R,ꢀ-Diarylacrylates are common scaffolds in pharmaceuti-
cally active compounds, and Perkin aldol condensation is
frequently employed for their synthesis.10 However, the
Perkin aldol reaction suffers from a rather limited substrate
scope and low product yields.10a Here we showed that the
Pd-catalyzed reaction of benzyl bromides with aryldiazoac-
etates is an effective approach for diarylacrylates synthesis;
the desired alkenes can be obtained in good yield and
excellent E-selectivity.
We started by examining the reaction of benzyl bromide
(1a) with methyl R-phenyldiazoacetate 2a in the presence
of Pd2dba3·CHCl3 (5 mol %), PPh3 (40 mol %), and K2CO3
(2 equiv) in toluene at 80 °C for 5 h, and E-acrylate 3aa
was produced in 37% yield based on 68% bromide conver-
sion (Table 1, entry 1). By means of GC-MS techniques,
the E-to-Z selectivity was determined to be >20:1. The
1
E-configuration of the alkene was confirmed by H NMR
and X-ray crystallography (for acrylate 3ma; see Supporting
Information).
While the use of i-Pr2NEt as base for the Pd-catalyzed
reaction gave 3aa in 31% yield, a slightly better result (44%
yield) was obtained with Na2CO3 as base (entries 2 and 3).
Prior to this work, Van Vranken and co-workers9f reported
that a Pd-catalyzed reaction of 1a and ethyldiazoacetate
(EDA) would afford trans-cinnamate in moderate (25-74%)
yields. According to Van Vranken’s results,9f AsPh3 was
found to be the best ligand for the “1a + EDA” reaction.
However, when AsPh3 (40 mol %) was employed as ligand
for our Pd-catalyzed reaction, 3aa was formed in only 26%
yield with 38% bromide conversion (entry 4). Notably,
insignificant product formation resulted with PCy3 and 1,4-
bis(diphenylphosphino)butane (dppb) as ligands (entries 5
and 6).
(8) (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.-Eur. J. 2005, 11, 1565. (c) Sole´,
D.; Vallverdu´, L.; Solans, X.; Font-Bardia, M.; Bonjoch, J. Organometallics
2004, 23, 1438. (d) Albe´niz, A. C.; Espinet, P.; Manrique, R.; Pe´rez-Mateo,
A. Angew. Chem., Int. Ed. 2002, 41, 2363.
(9) (a) Devine, S. K. J.; Van Vranken, D. L. Org. Lett. 2008, 10, 1909.
(b) Chen, S.; Wang, J. Chem. Commun. 2008, 4198. (c) Peng, C.; Wang,
Y.; Wang, J. J. Am. Chem. Soc. 2008, 130, 1566. (d) Devine, S. K. J.; Van
Vranken, D. L. Org. Lett. 2007, 9, 2047. (e) Barluenga, J.; Moriel, P.;
Valde´s, C.; Aznar, F. Angew. Chem., Int. Ed. 2007, 46, 5587. (f) Greenman,
K. L.; Van Vranken, D. L. Tetrahedron 2005, 61, 6438.
(10) 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.
During our optimization study, we found that better
product yield (63%) can be obtained when the reaction was
470
Org. Lett., Vol. 11, No. 2, 2009

11-16). Apparently, PPh3 (40 mol %) is essential for the
acrylate formation. For example, in the absence of the PPh3
ligand, no 3aa formation was observed (entry 17). Yet,
performing the “1a + 2a” reaction using 30 mol % of PPh3
gave 3aa in 48% yield albeit with lower 1a conversion (59%;
entry 18). As expected, lowering the catalyst loading would
diminish the product yield for the 5 h reaction (78% yield;
88% conversion, entry 19). In this work, when syringe pump
addition of 2a (addition rate ) 0.5 mL h-1) was adopted for
the coupling reaction, poor 3aa formation (65%) and 1a
conversion (54%) were observed (see Supporting Informa-
tion).
Table 2. Palladium-Catalyzed Cross Croupling Reactions of
Benzyl Bromides with Diazoestersa
Table 2 demonstrates the scope of the Pd-catalyzed
coupling reaction. Benzyl bromide and chloride are both
effective substrates, and 3aa was obtained in ca. 80% yield
despite slightly lower substrate conversion (74%) being
observed for the chloride (entries 1 and 2). Facile transfor-
mations of bromides 1c-1h containing electron-withdrawing
and -releasing groups on the aromatic ring furnished the
corresponding acrylates in 66-88% yields (entries 3-8). It
is noteworthly that a bromo-substituent on the aromatic ring
of either the benzyl bromide (e.g., 1c) or the diazoacetate
(e.g., 2c) is tolerated under the Pd-catalyzed conditions
(entries 3 and 15). We found that the reactions of bromide
1i containing an ortho-OMe substituent afforded the product
acrylate in 45% yield (entry 9). Nevertheless, the analogous
reaction of diazoacetate 2b bearing an ortho-OMe substituent
on the aryl ring produced the desired alkene in 89% yield
(entry 14).
The Pd-catalyzed coupling reactions of some polycyclic
aromatic/heteroaromatic bromides (1j-1l) gave the expected
acrylates in 52-92% yields with excellent E-stereoselectivity
(Table 2, entries 10-12). Diarylacrylates bearing organo-
sulfonyl groups as scaffolds were reported to exhibit biologi-
cal activities, and they were prepared by Perkin aldol
condensation in <40% yield.10a In this work, subjecting
bromide 1m containing an N-sulfonylmorpholino group and
diazoester 2a to our Pd-catalyzed protocol, 3ma would be
produced in 75% yield (entry 13).
A plausible mechanism for this coupling reaction may start
with the oxidative addition of the benzyl bromide 1 to the
Pd(0) catalyst I to give the organopalladium complex 4
(Scheme 1). Then, the diazoacetate 2 would react with 4 to
form putatively a reactive palladium-carbene complex II,
which would undergo migratory insertion of the benzyl group
to produce the alkylpalladium complex III. Migratory
insertion reactions for palladium carbenes are well prece-
dented in amino- and methoxycarbene palladium
complexes.8a,b,d ꢀ-Elimination should provide the acrylate
3 and regenerate the Pd(0) catalyst. Consistent with this
mechanism, a stoichiometric reaction of a well-characterized
benzylpalladium complex 4a (prepared by reacting 1a with
Pd(0) and PPh3)11 and 2a (3 equiv) in THF at 80 °C was
found to afford 3aa in 75% yield (Scheme 2).
a Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), Na2CO3 (0.8 mmol),
Pd2dba3·CHCl3 (5 mol %), PPh3 (40 mol %), THF (2 mL), 80 °C for 3 h.
b Isolated yield. c The percentage yield based on conversion. d The conver-
sion of 1b is 74%. e The conversion of 1a is 67%. g NMR yield. h The
conversion of 1a is ca. 40%.
performed under the conditions: 1a (1 equiv), 2a (2 equiv),
Na2CO3 (4 equiv), Pd2dba3·CHCl3 (5 mol %) in toluene at
80 °C for 5 h (entry 7). Employing other Pd precursors such
as Pd(OAc)2 and [Pd(allyl)Cl]2 for the catalytic reaction did
not afford better results (entries 8 and 9). However, when 3
equiv of 2a was utilized for the coupling reaction with THF
as solvent, 3aa was furnished in 87% yield (entry 10).
Solvents including THF, dioxane, and toluene were found
to give comparable results; however, using MeCN, acetone,
1,2-dichloroethane, and DMF as solvent led to lower product
yield and poor mass balance with respect to 1a (entries
As shown in Table 2, the reactions of 2a with 1n and 1o
proceeded in low product yields (ca. 20%, entries 16 and
(11) Crawforth, C. M.; Burling, S.; Fairlamb, I. J. S.; Kapdi, A. R.;
Taylor, R. J. K.; Whitwood, A. C. Tetrahedron 2005, 61, 9736.
Org. Lett., Vol. 11, No. 2, 2009
471

reaction of benzyl bromides and R-aryldiazoesters. Indeed,
the observed E-selectivity of the coupling reaction appears
intriguing. It is conceivable that the stereochemistry of the
alkene product would be determined by the syn-ꢀ-elimination
step of complex III. By product inspection, transition state
A (Scheme 3) for the formation of E-trisubstituted alkene
Scheme 1. Proposed Catalytic Cycle
Scheme 3. Plausible Transition States for the ꢀ-Elimination Step
17). On the basis of TLC monitoring of the reaction mixtures,
complete 1n and 1o consumption was achieved in 3 h.
features two eclipsing aryl groups. According to a related
work by Barluenga and co-workers,9e the transition state in
the ꢀ-elimination for formation of trisubstituted alkenes
should favor two bulky groups in a trans-arrangement, and
a Z-alkene product is anticipated. However, the observed
E-trisubstituted acrylate formation is incompatible with this
notion.12 At this juncture, the preference for the seemingly
“less favored” transition state is not clear and is under
separate investigation.
Scheme 2
.
Coupling Reactions of Palladium Complex 4a with
2a and 2d
Acknowledgment. We thank the financial support from
The Hong Kong Research Grants Council (PolyU 5019/06P)
and The Areas of Excellence Scheme (AoE/P-10-01) ad-
ministered by the University Research Grants Council
(HKSAR, China).
Pertinent to the poor results, the reactions of Pd(0)/PPh3 with
1n and 1o failed to yield the corresponding organopalladium
complexes. Therefore, the low product yields for 1n and 1o
are probably associated with the difficulty in generating the
key organopalladium intermediates. We also found that
diazoacetate 2d containing an indole moiety reacted with
1a to afford 3ad in ca. 8% yield (entry 18), along with
significant dimer formation from the diazo reagent. Yet, a
stoichiometric reaction of 4a with 2d afforded 3ad in 70%
yield (Scheme 2). Thus, the reactions with heterocyclic
diazoesters may necessitate independent optimization.
In summary, a stereoselective synthesis of E-R,ꢀ-diary-
lacrylates was developed by the Pd-catalyzed coupling
Supporting Information Available: Detail experimental
procedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
OL8026076
(12) (E)-Trisubstituted acrylates formation was also observed for the
Perkin aldol condensation, and we thank one of the reviewers for bringing
these references to our attention: (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.
472
Org. Lett., Vol. 11, No. 2, 2009