Palladium-catalyzed oxidative ethoxycarbonylation of aromatic C-H bond with diethyl azodicarboxylate

Article abstract of DOI:10.1021/ja710555g

This communication describes the Pd(OAc)₂-catalyzed ethoxycarbonylation reactions of aromatic C-H bonds using diethyl azodicarboxylate (DEAD) together with Oxone or K₂S₂O₈. Substrates such as 2-arylpyridines, py

Full text of DOI:10.1021/ja710555g

Published on Web 02/26/2008
Palladium-Catalyzed Oxidative Ethoxycarbonylation of Aromatic C-H Bond
with Diethyl Azodicarboxylate
Wing-Yiu Yu,* Wing Nga Sit, Kin-Man Lai, 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
Received November 23, 2007; E-mail: bcwyyu@inet.polyu.edu.hk
Scheme 1. Reaction of Palladacycles with DEAD
Carboxylic acids and derivatives (e.g., esters) are valuable
commodity chemicals and useful synthetic building blocks. A well
established approach for carboxylic acids synthesis is the transition
metal-catalyzed carbonylation of organic substrates containing
C-halides and/or CdC bonds.1 However, the catalytic carbony-
lation reaction is limited by (1) the necessity to handle hazardous
gas often in high pressure and (2) the use of prefunctionalized
substrates. From a standpoint of atom economy, direct function-
alization of C-H bonds to C-CO2R bonds is a highly desirable
alternative.2 To this end, Orito and co-workers previously reported
Pd(OAc)2-catalyzed direct carbonylation of aromatic amines for
synthesis of five- and six-membered benzolactams.3,4 However,
problems in regiocontrol of the carbonylation reaction remain to
be addressed.
To achieve selective C-H bond functionalization, significant
advances have been made by transition metal (Ru, Rh, Re, Pd)-
mediated C-H bond cyclometallation assisted by directing func-
tional groups.2d Notably, Pd(OAc)2-catalyzed regioselective ortho-
C-H bond oxidation leading to C-C (aryl)2a,5 and C-heteroatom
bond formations6 is attracting widespread attention. Although carbon
monoxide insertion to palladacycles has been thoroughly investi-
gated,7 developing catalytic protocols for ortho-selective C-H bond
carbonylation based on this chemistry is exceedingly difficult
because the depalladation process is often complicated by reduction
of Pd(II) to Pd(0) under the CO atmosphere. Herein we disclose a
Pd-catalyzed protocol for ortho-selective ethoxycarbonylation of
aromatic C-H bonds using diethyl azodicarboxylate (DEAD)
coupled with inexpensive oxidizing agents.8 This transformation
is operated without the use of carbon monoxide and protection
against air/moisture.
Initially we examined dialkyl azodicarboxylates as a potential
reagent for C-H amination reactions.9 When palladacycle 5a
reacted with diethyl azodicarboxylate (DEAD, 1.5 equiv) in 1,2-
dichloroethane (DCE) at 100 °C (Scheme 1), ester 2a was formed
in 83% yield accompanied with Pd black formation. Analogous
reaction of 5b with DEAD furnished 2b in 80% yield. In both cases,
the anticipated hydrazides were not formed. The structures of 2a
and 2b have been confirmed by X-ray crystallography.10
Having established the stoichiometric reaction of the pallada-
cycles with DEAD, we turned to develop a catalytic reaction of
2-arylpyridines with DEAD using appropriate oxidizing agents. To
begin, treating 1a with Pd(OAc)2 (5 mol %), DEAD (2 equiv) and
Cu(OAc)2 (4 equiv) in DCE at 100 °C for 4 h afforded 2a in 44%
yield with 48% substrate conversion (Table 1, entry 1). After several
trials, a protocol involving batchwise addition of DEAD (4 × 0.5
equiv) and 10 mol % of Cu(OAc)2 was found to give better results;
up to 82% substrate conversion with 88% product yield were
achieved over 12 h (entry 2).11 Yet, no further improvement in
Table 1. Optimizing Reaction Conditionsa
%
%
entry
oxidantb
solvent
time/h
conversion
yieldc
1
2
3
Cu(OAc)2 4 equiv
Cu(OAc)2 10 mol %
Oxone
DCE
DCE
DCE
4
12
6
48
82
100
83
88
72
33
33
83
73
65
51
44
88
91
64
88
n.d.
3
48
72
48
32
22
4
K2S2O8
DCE
6
5
TBHP
DCE
6
6
CAN
DCE
6
7
BQ
Oxone
Oxone
DCE
DCE
DMF
6
6
6
8d
9
10
11
12
Oxone
Oxone
Oxone
1,4-dioxane
MeOH
acetone
6
6
6
a Reaction conditions: 1a (0.5 mmol), DEAD (4 × 0.5 equiv/h for entries
3-12). b Batch-wise addition of oxidant (3 × 1 equiv/2h) for entries 3-12.
c Conversion and product yield determined by GC/FID, the percentage yield
based on conversion. d Reaction temperature: 60 °C.
product yield was obtained with Cu(OAc)2 as the oxidant despite
several protocol changes.
In a hope to achieve better substrate conversion and product
yield, we examined other oxidants for the catalytic reaction.
Gratifyingly, Oxone was found to be an effective oxidant for the
Pd-catalyzed ethoxycarbonylation reaction. Treatment of 1a (0.5
mmol) with Oxone (3 × 1 equiv), DEAD (4 × 0.5 equiv) and Pd-
(OAc)2 (5 mol %) in DCE at 100 °C for 6 h, 2a was obtained in
91% yield with complete substrate consumption (Table 1, entry
3). Employing ammonium cerium(IV) nitrate (CAN) and benzo-
quinone (BQ) as oxidants resulted in <5% product yield (entries
6-7). Other solvents such as DMF, 1,4-dioxane, MeOH, and
acetone are less effective for this Pd-catalyzed reaction (entries
9-12).
The scope of the Pd-catalyzed ethoxycarbonylation reaction is
depicted in Table 2. Pyrrolidinone 1h and acetylindoline 1i were
converted to the corresponding esters in 84 and 80% yields under
the Pd-catalyzed conditions (entries 8 and 9). For the direct
carbonylation of the sp3 C-H bond, the reaction of 8-methylquino-
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10.1021/ja710555g CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Pd-Catalyzed Ethoxycarbonylation of Aromatic C-H Bonds
a Reaction conditions: substrate (0.5 mmol), DEAD (4 × 0.5 equiv), Pd(OAc)2 (5 mol %), DCE (1 mL), 100 °C for 6 h. b Oxidant: Oxone (3 × 1 equiv).
c Oxidant: 10 mol % of Cu(OAc)2. d Oxidant: K2S2O8 (3 × 1 equiv). e The percentage yield based on conversion. f With 3 equiv of Oxone as oxidant: yield
for 2j ) 23% based on 61% conversion. g With 3 equiv of Oxone as oxidant: yield of 4a ) 35%, ortho-hydroxylation product ) 56%. h Diester formation
) 52% yield. i DEAD (6 × 0.5 equiv), K2S2O8 (5 × 1 equiv) for 10 h.
line (1j) with DEAD, Oxone, and Pd(OAc)2 (5 mol %) gave 2j
inonly 23% yield (61% conversion). However, when Cu(OAc)2 (10
mol %) was employed as the oxidant, 2j was obtained in 83% yield
(47% conversion, entry 10). Yet, using more Cu(OAc)2 (2 equiv)
did not give higher yield and substrate conversion.
sively in good yields (entries 19-22). Under this condition, ketones
(e.g., acetophenone) and esters (e.g., ethyl benzoate) were ineffective
substrates for the ethoxycarbonylation, whereas the reaction with
N-(p-methoxyphenyl)benzyladehyde imines gave <15% conversion
and <50% product yield.10
Facile transformation of O-methyl oximes of acetophenones to
their ortho-esters was achieved using DEAD and K2S2O8 (3 × 1
equiv) as oxidant (entries 11-22). In this reaction, functional groups
such as Br, MeO, and CHO were all tolerated (entries 3, 5, 14, 20,
21). With meta-substituted substrates, the 2,4-regioisomers were
obtained selectively (entries 4, 12-15, 20). The observed selectivity
is linked to the regioselectivity of the cyclopalladation step12 which
is known to be steric sensitive.6c,7 By reacting Pd(OAc)2 with 2-(3′-
methoxyphenyl)pyridine (1e), we obtained palladacycle 5c (X-ray
structure characterized) as a single regioisomer in 90% yield. Other
regioisomers were not detected by 1H NMR analysis of the reaction
mixture. As anticipated, 5c reacted with DEAD to give 2e
exclusively in 85% yield.10
We found that radical scavengers such as galvinoxyl would exert
detrimental effect (<40% ester formation) to the “5a + DEAD”
reaction,5h indicative of the radical intermediates. Unlike DEAD,
other azodicarboxylates [ROC(O)NdN(O)COR; R ) benzyl, tert-
butyl, trichloromethyl, dipiperidine] are poor reagents for converting
5a to the product esters/amides (<13% yield).13 When 5a reacted
with an equimolar mixture of DEAD and dibenzyl azodicarboxylate,
2a and the benzyl ester were formed in 62 and 9% yield,
respectively. Whereas the DEAD was found to be completely
consumed, ∼25% dibenzyl azodicarboxylate was recovered un-
changed.13 For the reaction of 5a with dibenzyl azodicarboxylate,
dibenzyl carbonate was obtained in 17% yield from a complicated
reaction mixture.14 We believed that thermal decomposition of
the azodicarboxylate would generate benzyloxyacyl radical,15,16
some of which would undergo decarbonylation to form benzyloxy
The Pd-catalyzed reaction of O-methyl oxime benzaldehyde (3h)
with DEAD and K2S2O8 furnished a mixture of mono- (27%) and
diesters (52%; entry 18). Nevertheless, the reactions employing
oximes of substituted benzaldehydes produced monoesters exclu-
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C O M M U N I C A T I O N S
Scheme 2. Reaction of 5a with Dibenzyl Azodicarboxylate
Kakiuchi, F.; Chatani, N. J. Org. Chem. 2004, 69, 4433 and references
therein. (b) For [Pd] (c) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem.
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Mori, Y.; Tsuji, J. Tetrahedron 1971, 27, 3811.
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A. R.; Anani, W. Q.; Sanford, M. S. Org. Lett. 2006, 8, 2523. (d) Hull,
K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134.
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Scheme 3. Proposed Mechanism
radical. As such, dibenzyl carbonate was produced by combin-
ing the benzyloxyacyl radicals with the benzyloxy radical (Scheme
2).
On the basis of the above findings, the catalytic reaction should
be initiated by cyclopalladation of the ortho-C-H bond to form a
palladacycle. The palladacycle subsequently reacts with the ethoxy-
acyl radicals, generated from thermal decomposition of DEAD,
to afford the product esters (Scheme 3). At this stage, the mechan-
ism for the radical insertion reaction to palladacycles remains
unclear.17 Indeed, systemic mechanistic studies on radical addition
(7) For reviews, see (a) Dupont, J.; Consorti, C. S.; Spenser, J. Chem. ReV.
2005, 105, 2527. (b) Ryabov, A. D. Synthesis 1985, 233.
(8) Treatment of 1a with [Ru3(CO)12] (5 mol%) and DEAD in toluene did
not produce 2a in detectable yield with the starting material being
recovered (87%).
to organometallic complexes are sparse in the literature.17,18
A
(9) Genet, J.-P.; Greck, C.; Lavergne, D. In Modern Amination Method; Ricci,
A., Ed.; Wiley-VCH: Weinheim, Germany, 2000; Chapter 3, p 65. Muniz
and co-workers recently reported a Pd-catalyzed addition of PhB(OH)2
to dibenzyl azodicarboxylate: Muniz, K.; Iglesias, A. Angew. Chem., Int.
Ed. 2007, 46, 6350.
plausible pathway for the radical insertion to Pd-C bond would
be via formation of Pd(IV) species19 especially under oxidizing
conditions, 5h,g,6h and that would be a subject for further investiga-
tion.
(10) See Supporting Information for details.
(11) During our examination of Cu(OAc)2 as the oxidant, EtO2CNH-NHCO2-
Et (X-ray structure characterized) was isolated asa side-product in 52%
yield from the Pd-catalyzed reaction of 1a with DEAD.
Acknowledgment. We thank the financial support from The
Hong Kong Polytechnic University (ASD Fund) and The Areas of
Excellence Scheme (Grant AoE/P-10-01) administered by the Hong
Kong Research Grants Council.
(12) Similar regioselectivity was also reported by Sanford and co-workers for
Pd-catalyzed acetoxylation of arylpyridines: Kalyani, D.; Sanford, M. Org.
Lett. 2005, 7, 4149. See also refs 5, 6a, and 6c
(13) This result may suggest that the higher reactivity of DEAD relative to
other azodicarboxylates could have led to the higher product yields
observed (see Supporting Information).
(14) We also obtained an unknown oily substance which accounts for 49% of
the total mass of the azodicarboxylate. The 13C NMR analysis of the
unknown revealed a characteristic carbonyl signal at 155.8 ppm, which
is unique from dibenzyl carbonate and dibenzyl oxalate. A similar product
profile was observed for thermal decomposition of dibenzyl azodicar-
boxylate.
Supporting Information Available: Experimental procedures,
characterization data, and experimental data for reaction optimization.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(15) (a) Alberti, A.; Hudson, A. Tetrahedron Lett. 1982, 23, 453. (b) Roberts,
B. P.; Winter, J. N. Tetrahedron Lett. 1979, 20, 3575. (c) Malatesta, V.;
Ingold, K. U. Tetrahedron Lett. 1973, 14, 3311.
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