The Heck reaction in the presence of molecular oxygen

Article abstract of DOI:10.1016/S0040-4039(02)02372-9

Palladium-catalyzed reaction of CH₂=C(R)COOMe (R=H or CH₂OH) with PhI in the presence of NEt₃ under O₂ induces the oxidative dealkylation of NEt₃, affording either methyl 3-diethylaminopropionate (3) or methyl (Z)-2-benzyl-3-(N,N′-diethylamino)propenate (6), in case of R=H or R=CH₂OH, respectively.

Full text of DOI:10.1016/S0040-4039(02)02372-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9323–9325
The Heck reaction in the presence of molecular oxygen
Takahiro Hosokawa,a,* Taisuke Kamiike,a Shun-Ichi Murahashi,b Mamoru Shimadab and
Toshihiro Sugafujib
aDepartment of Environmental Systems Engineering, Faculty of Engineering, Kochi University of Technology, Tosayamada,
Kochi 782-8502, Japan
bGraduate School of Engineering Science, Osaka University, Machikaneyama, Toyonaka, Osaka 560-8531, Japan
Received 17 September 2002; revised 11 October 2002; accepted 18 October 2002
Abstract—Palladium-catalyzed reaction of CH2ꢀC(R)COOMe (R=H or CH2OH) with PhI in the presence of NEt3 under O2
induces the oxidative dealkylation of NEt3, affording either methyl 3-diethylaminopropionate (3) or methyl (Z)-2-benzyl-3-(N,N%-
diethylamino)propenate (6), in case of R=H or R=CH2OH, respectively. © 2002 Elsevier Science Ltd. All rights reserved.
Coupling reaction of aromatic halides (ArX) with alke-
nes by using palladium catalysts (Heck reaction) is one
of representative reactions in organic chemistry of pal-
ladium.1 The reaction proceeds via pathways shown in
Scheme 1, and after completion of the arylation, the
resulting X–Pd–H decomposes to Pd(0) and HX. The
HX formed is scavenged by bases such as tertiary
amines (NR3). In order to protect Pd(0) formed against
Scheme 2.
O2, the Heck reaction is usually performed under Ar or
N2. However, if O2 reacts with either X–Pd–H or Pd(0)
to generate X–Pd–OOH species,2 it could serve as an
oxidant in the reaction. Described herein is the first
observation of such a case, where the presence of O2
induces an oxidative dealkylation of NR3, resulting in
alternation of product composition in the Heck reac-
tion.3 This finding is important as a fundamental exper-
imental fact in the Heck reaction.
along with the usual arylation product 2 (Scheme 2).
This result shows that NEt3 is oxidatively dealkylated
to give NHEt2 which adds to 1. Under an inert atmo-
sphere (Ar), only the arylation product 2 is formed
(entry 3 in Table 1). For the present reaction, pallad-
ium(II) complex such as PdCl2(MeCN)2 is allowable as
the catalyst (entries 2–3), because palladium(II) reacts
with tertiary amines to form Pd(0).4
The arylation of methyl (a-hydroxymethyl)acrylate (4)
with PhI in the presence of NEt3 under Ar (Table 2)
gave aldehyde 5,5,6 as shown in Scheme 3. By contrast,
Table 1. Arylation of 1 with PhI and NEt3 under O2 or
Ara
Entry
Catalyst
Atmosphere
2 (%)b 3 (%)c
Scheme 1.
1
2
3
Pd(PPh3)4
PdCl2(MeCN)2
PdCl2(MeCN)2
O2
O2
Ar
96
96
96
27
26
–
When the reaction of methyl acrylate (1) and iodoben-
zene (PhI) with NEt3 was carried out under O2 (Table
1), methyl 3-diethylaminopropionate (3) was formed
a The reaction was performed by using 1 (4 mmol), PhI (1 mmol),
NEt3 (4 mmol) and palladium catalyst (0.05 mmol) in DMF (4.3
mL) at 75°C for 24 h.
Keywords: amination; Heck reaction; oxidation; oxygen; palladium.
* Corresponding author. Tel.: +887-57-2517; fax: +887-57-2520;
e-mail: hosokawa.takahiro@kochi-tech.ac.jp
b Yield based on PhI was determined by NMR.
c Yield (NMR) based on NEt3.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02372-9

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T. Hosokawa et al. / Tetrahedron Letters 43 (2002) 9323–9325
Table 3. Arylation of 4 with ArI and NEt3 under O2
a
Entry
Ar
Reaction time (h)
Enamineb (%)c
1
2
3
4
5
6
C6H5
Naph
p-Cl-C6H4
p-MeO-C6H4
p-MeO-C6H4
p-Me-C6H4
6
6
3
6
24
24
57
62
62
41
59
49
a The reaction was performed by using 4 (2 mmol), ArI (2.2 mmol),
NEt3 (4 mmol) and PdCl2(MeCN)2 (0.1 mmol) in DMF (10 mL) at
80°C.
Scheme 3.
b The structure of enamine formed corresponds to 6 in Scheme 3.
c Yield based on 4 was determined by NMR.
Table 2. Arylation of 4 with PhI and NEt3 under O2 or
Ara
Entry Catalyst
Atmosphere Reaction Enamine 6
(19%) of enamine 11 bearing N,N-dimethyl group. This
means that the NHMe2 formed reacts almost quantita-
tively with aldehyde 5 to give 11.
time (h)
(%)b
1
2
3
4
Pd(PPh3)4
Pd(OAc)2
PdCl2(MeCN)2 O2
PdCl2(MeCN)2 Ar
O2
O2
8
5
6
6
34
51 (49)c
57
d
–
a The reaction was performed by using 4 (2 mmol), PhI (2.2 mmol),
NEt3 (4 mmol) and palladium catalysts (0.1 mmol) in DMF (10 mL)
at 80°C.
b Yield based on 4 was determined by NMR.
c In air for 32 h.
d Aldehyde 5 is formed in 62% yield based on 4.
the use of O2 altered the product composition, resulting
in enamine 67,8 as the sole product (entries 1–3). The
aldehyde 5 arises from the arylation at C(3)ꢀC(2) in 4
followed by Pd–H elimination from C(1) bearing OH
group. The enamine 6 is derived from 5 and NHEt2,
showing that the oxidative dealkylation of NEt3 again
takes place. The enamine formation appears to be
general with aryl iodides (ArI). As shown in Table 3,
the formation of enamines is facilitated by electron-
withdrawing substituent on ArI (entry 3), whereas it is
retarded by electron-donating groups (entries 4–6).
Scheme 4.
Although the dealkylation process is not clear in detail,
it could be induced by I–Pd–OOH species,2 which is
derived either from I–Pd–H and O2 or via peroxopalla-
dium(II) formed by Pd(0) and O2. The conceptual
pathway for NEt3 is illustrated in Scheme 5. The Et
group removed from NEt3 must be transformed into
MeCOOH via MeCHO, because ꢀ1.1 mol of O2
uptake is observed for the production of 1 mole of 3 or
6; that is, nearly two O atoms of O2 are consumed for
the present reaction. The NHEt2 formed further reacts
with either alkene 1 or aldehyde 5 to give diethyl-
aminopropionate 3 or enamine 6, respectively. An
iminium salt, which is produced from NEt3 and
Pd(II),4,9 is probably involved in the dealkylation.
Allylic substrate 7a or 7b bearing an electron-withdraw-
ing substituent at C(2) similarly reacts with NEt3 to
give the corresponding enamine 8 (X=MeCO) (38%) or
9 (X=CN) (39%), respectively, under the conditions
described in Table 1 (entry 2). However, b-methallyl
alcohol 7c affords only aldehyde 10 (31%), indicating
that the enamine formation is required for the activa-
tion of aldehyde by electron-withdrawing group.
The participation of O2 in the present reaction is
demonstrated by the formation of cyclohexanone from
cyclohexyldimethylamine (NCyMe2) (Scheme 4). The
yield of cyclohexanone (22%) is nearly the same as that
Scheme 5.

T. Hosokawa et al. / Tetrahedron Letters 43 (2002) 9323–9325
9325
In summary, we have found that the Heck reaction in
the presence of O2 is accompanied by an oxidative
dealkylation of tertiary amines usually employed as the
acid scavenger. The catalysis for arylation is operative
even in the presence of O2. Although the present study
has not focused on the synthetic utility, our finding may
provide a cue for the nature of Pd–H species.
5. For arylation of alkene bearing allylic alcohol and a,b-
unsaturated ester moieties, see: (a) Basavaiah, D.;
Muthukumaran, K. Tetrahedron 1998, 54, 4943–4948; (b)
Hosokawa, T.; Sugafuji, T.; Yamanaka, T.; Murahashi,
S.-I. J. Organomet. Chem. 1994, 470, 253–256.
6. Into a mixture of PdCl2(MeCN)2 (12.9 mg, 0.05 mmol),
PhI (225 mg, 1.1 mmol) and NEt3 (202 mg, 2.0 mmol) in
DMF (5 mL) was added 4 (116 mg, 1.0 mmol). After the
solution was stirred under argon at 80°C for 6 h, the
resulting mixture was diluted with Et2O and washed with
brine. The organic layer was dried over anhydrous
Na2SO4. Filtration followed by evaporation of the solvent
gave oily material (297 mg) containing 5 in 62% NMR
yield. The product 5 was purified by a short column
chromatography of SiO2. Compound 5 is in keto-enol
equilibrium. 1H NMR (270 MHz, CDCl3): l (keto form)
9.74 (d, J=1.9 Hz, 1H, CHO), 7.23 (m, 5H, C6H5), 3.72
(s, 3H, CO2CH3), 3.65 (ddd, J=7.8, 6.7, 1.9 Hz, 1H,
CH-CHO), 3.22 (d, J=6.7 Hz, 1H, C6H5CH2), 3.20 (d,
J=7.8 Hz, 1H, C6H5CH2); l (enol form) 11.47 (d, J=12.7
Hz, 1H, CHOH), 7.23 (m, 5H, C6H5), 7.04 (dt, J=12.7,
0.9 Hz, 1H, CHOH), 3.72 (s, 3H, CO2CH3), 3.41 (broad s,
2H, C6H5CH2); 13C NMR (68 MHz, CDCl3): l 196.1,
172.5, 161.9, 140.0, 137.4, 128.8, 128.7, 128.4, 128.3, 126,9,
126.2, 104.4, 60.2, 52.4, 51.5, 33.1, 32.2; IR (neat): w 3400
(O-H), 2950, 1725 (CꢀO), 1670, 1610, 1495, 1445, 1395
(C-H), 1335 (O-H), 1210, 1200, 1175 (C-O), 1095, 825
(CꢀCH), 750 (Ph-), 700 (Ph-), 475 cm−1, MS (70 eV): m/z
192 (M+), 163 (M+−CHO), 104 (PhCH2CH-), 91 (PhCH2-).
7. The configuration of enamine 6 is determined to be E by
nuclear Overhauser effect (NOE) in NMR.
8. The reaction was performed under oxygen (balloon) by
using 4 (232 mg, 2.0 mmol), PhI (448 mg, 0.25 mL, 2.2
mmol), NEt3 (404 mg, 0.56 mL, 4.0 mmol) and
PdCl2(MeCN)2 (26.0 mg, 0.1 mmol) in DMF (10 mL).
After the solution was stirred at 80°C for 6 h, usual
work-up gave oily material (550 mg) containing 6 in 57%
NMR yield. The product 6 was purified by a short column
chromatography of Al2O3 (12 g). 1H NMR (270 MHz,
CDCl3): l 7.62 (s, 1H, CꢀCH-N), 7.19 (m, 5H, C6H5-),
3.78 (s, 2H, C6H5-CH2), 3.65 (s, 3H, COOCH3), 3.18 (q,
J=7.2 Hz, 4H, NCH2CH3), 1.12 (t, J=7.2 Hz, 6H,
NCH2CH3); 13C NMR (68 MHz, CDCl3): l 171.6 (CꢀO),
148.3 (CꢀCHN), 142.6 (C6H5-), 128.2 (C6H5-), 127.5
(C6H5-), 125.5 (C6H5-), 93.0 (C-COOCH3), 51.0 (OCH3),
47.0 (N-CH2-), 30.9 (C6H5-CH2), 14.8 (NCH2CH3); IR
(neat): w 2975, 2945, 1680 (CꢀO), 1615 (CꢀC), 1495, 1450,
1430, 1380, 1360, 1345, 1315, 1260, 1135, 1085 (C-O-C),
735 (Ph-), 700 (Ph-), 480 cm−1; MS (70 eV): m/z 247 (M+),
232 (M+−Me), 218 (M+−Et), 156 (M+−PhCH2), 131
(PhCH2CCO-), 115 (PhCH2CC-); HRMS calcd for
C15H21NO2 247.1572. Found: 247.1613.
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