Aerobic dehydrogenative Heck reactions of heterocycles with styrenes: A negative effect of metallic Co-oxidants

Article abstract of DOI:10.1002/adsc.201200787

The aerobic dehydrogenative Heck reaction (DHR) of heterocycles with styrenes was found to be more efficient in the absence of metallic cooxidants. According to a study of the isotope effect, the C-H cleavage was the rate-determining step of the catalytic

Full text of DOI:10.1002/adsc.201200787

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DOI: 10.1002/adsc.201200787
Aerobic Dehydrogenative Heck Reactions of Heterocycles with
Styrenes: A Negative Effect of Metallic Co-Oxidants
Alexandre Vasseur,a Dominique Harakat,a Jacques Muzart,a and Jean Le Brasa,*
a
Institut de Chimie Molꢀculaire de Reims – UMR 7312 CNRS – Universitꢀ de Reims Champagne-Ardenne UFR des
Sciences Exactes et Naturelles, BP 1039, 51687 Reims Cedex 2, France
Fax : (+33)-3-2691-3166; e-mail: jean.lebras@univ-reims.fr
Received: September 2, 2012; Revised: October 15, 2012; Published online: December 23, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200787.
Abstract: The aerobic dehydrogenative Heck reac-
tion (DHR) of heterocycles with styrenes was found
to be more efficient in the absence of metallic co-
oxidants. According to a study of the isotope effect,
nique thus provides continuous snapshots of the com-
position of the reaction solution and hence insights
into its mechanism.[4] The influence of metallic co-oxi-
dants on the efficiency of the reaction is also dis-
cussed.
À
the C H cleavage was the rate-determining step of
the catalytic cycle. Electrospray ionization mass
spectrometry, subsequent MS/MS, and high-resolu-
tion mass spectrometry were used to detect and
characterize catalytic intermediates and species
formed in the presence of metallic co-oxidants.
We have reported the DHR of furans with styrenes
under aerobic conditions.[5] However, the methodolo-
gy required the presence of 10% of benzoquinone
(BQ), 50% of Cu(II) and 40–608C for an efficient
coupling. We have recently presented the DHR of
furans and thiophenes with styrenes at room tempera-
ture.[6] The method involves the use of DMSO as co-
solvent and BQ as stoichiometric oxidant, which both
have a positive influence on the process efficiency.
We have explored the possibility to perform the reac-
tion using DMSO as solvent under an oxygen atmos-
phere in the absence of a stoichiometric organic oxi-
dant. Since catalytic amounts of metallic co-oxidants
À
Keywords: C H activation; Heck reaction; homo-
geneous catalysis; mass spectrometry; reaction
mechanisms
The intermolecular dehydrogenative Heck reactions are often useful for the reoxidation of palladium in
(DHRs) are of interest in term of atom economy, DHRs, we have first studied their influence on the ef-
À
since the result of a DHR is the formation of a C C ficiency of the process. Thus, the coupling of 2-meth-
bond from two C H bonds. However, most proce- ylfuran (1a) with styrene (2a) was carried out at room
[1]
À
dures require the use of stoichiometric oxidants such temperature using Pd
(OAc)2 as catalyst, DMSO/
as copper and silver salts or quinones which decrease AcOH as solvent, various metallic co-oxidants, and
the “green” aspect of these transformations. Catalytic O2 (Table 1).
amounts of these species with molecular oxygen as
With the typical co-oxidants of oxidative pallado-
(OAc)2, low yields
the terminal oxidant have been used in some stud- catalyzed reactions, AgOAc and CuACHTNUGTRENNUNG
ies,[2] but only a few reports concern oxygen as the were obtained after 4 h at room temperature (Table 1,
sole oxidant.[2b,c,e,j,k,o,q,t] In addition, the substrate scope entries 1 and 2). The yield with AgOAc was scarcely
is often restricted to olefins bearing an electron-with- improved after 24 h (entry 1), while a medium yield
drawing group as the coupling partners, and few ex- was obtained with CuACTHNUGTRNEUNG(OAc)2 (entry 2). While Cu2O
amples have been described with heterocycles, which and Fe3O4 did not improve the results (entries 3 and
limits the applications of these reactions.[3] Herein, we 4), we were then delighted to find that manganese
report an efficient method for the DHR of heterocy- salts and oxides led to 39–45% only after 4 h (en-
cles with styrenes using O2 as the sole oxidant, and an tries 5–9). To our surprise, when the coupling was per-
investigation of the mechanism using electrospray formed in the absence of a co-oxidant, the yield in 4 h
ionization mass spectrometry (ESI-MS). ESI-MS is was improved to 50%, and 3aa could be isolated in
well adapted for the observation of protonated, de- 68% yield when the reaction time was prolonged to
protonated, or cationized forms of short-lived mole- 24 h (entry 10). The scope of the process was then ex-
cules produced from catalyzed reactions. The tech- amined. After slight modifications of the original pro-
Adv. Synth. Catal. 2013, 355, 59 – 67
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59

Alexandre Vasseur et al.
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Table 1. Influence of metallic co-oxidants on the DHR of 1a
with 2a.[a]
Entry
M,%
Yield [%][b]
24 h
4 h
1
2
3
4
5
6
7
8
9
10
AgOAc, 10
8.1Æ0.2
8.9Æ0.3
Cu
N
27.8Æ0.6
17.0Æ0.5
19.0Æ1.0
40.5Æ0.8
44.1Æ1.1
43.4Æ1.5
44.5Æ1.0
40.2Æ1.5
49.4Æ1.4
50.4Æ1.0
Cu2O, 10
Fe3O4, 10
23.5Æ1.2
32.9Æ1.1
Figure 1. Kinetic isotope effect. Conditions: 1 (1.0 mmol), 2a
(1.0 mmol), PdACHTNUTRGNE(NUG OAc)2 (0.1 mmol), AcOH (2 mL), DMSO
(2 mL), O2 (gas bag), 408C.
Mn
Mn
U
67.6Æ1.5
78.1Æ1.0
MnO, 10
Mn2O3, 10
MnO2, 10
–
77.7Æ1.2
78.1Æ1.7 (64)
76.5Æ1.5
We have then used ESI-MS to further study the
mechanism of the reaction. We have first monitored
by ESI(+)-MS a mixture of PdACTHNUTRGNEUNG(OAc)2 in AcOH/
81.5Æ1.0 (68)
[a]
Conditions: 1a (2.0 mmol), 2a (1.0 mmol), PdACTHUNRGTNEUNG(OAc)2
(0.05 mmol), M (0 or 0.1 mmol), AcOH (2 mL), DMSO
(2 mL), O2 (gas bag), room temperature, 4–24 h.
GC yield averaged from two reactions (PhNO2 was used
as standard), isolated yield in parenthesis.
DMSO (1:1) under an oxygen atmosphere. After
5 min of stirring at room temperature, five clusters
[b]
were detected and attributed to [Pd
G
(DMSO)]+,
ACHTUNGTRENNUNG
[Pd
[Pd
A
T
[Pd
2A
R
ACHTUNGTRENNUNG
G
T
T
CHTUNGTRENNUNG
(Figure 2). Such species were identical to those ob-
cedure (Table 1, entry 10), furans, thiophenes, and in- served previously in DHRs performed in the presence
doles 1 were successfully coupled with styrenes 2 to of BQ.[8] [Pd (DMSO)]+ and [Pd
(OAc) (OAc)-
give Heck-type products in medium to high yields
(DMSO)2]+ originate from the solvated species
(Table 2). Some reactions required a 10% catalyst Pd(OAc)2A(DMSO)2. [Pd2A(OAc)3A and
(DMSO)]+
loading to achieve the total conversion of 2. The reac- [Pd2A(OAc)3A
(DMSO)2]+ are connected to the dinuclear
tions were performed between room temperature and analogue Pd2A(OAc)4A(DMSO)2. Finally,
608C, and all compounds were isolated as the E-iso- [Pd is associated to
(DMSOÀH)
(DMSO)]+
mers. As previously observed,[5,6] 2-substituted furans Pd
(DMSOÀH)(DMSO)(OAc) and the activation of
and thiophenes (1a, 1b, 1c, 1e) reacted at the C-5 po- DMSO by Pd(OAc)2A(DMSO)2.
The monitoring of an AcOH/DMSO solution of
(OAc)2, 1a and 2a under an oxygen atmosphere at
A
R
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
E
N
CHTUNGTRENNUNG
A
N
CHTUNGTRENNUNG
C
CHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
CHTUNGTRENNUNG
sition (Table 2, entries 1–13, 18, 20, 22, 24). 3-Methyl-
thiophene (1f) reacted mainly at C-5 (entries 19, 21, PdACHTUNGTRENNUNG
23, 25). Furan (1d) led to a mixture of styrylfurans rt by ESI(+)-MS led to complex spectra which
(3da, 3db, 3dc, 3dd) as major compounds and bis- proved difficult to analyze. Fortunately, the use of n-
ACHTUNGTRENNUNG(styryl)furans (4da, 4db, 4dc, 4dd, entries 14–17), butylfuran (1j) instead of 1a led to the simplification
while thiophene (1g) provided only the monosubsti- of the spectra. Indeed, the main feature of the corre-
tuted product (3ga, entry 26). 1-Methylindole (1h) sponding ESI(+)-MS obtained after 1.5 h (Figure 3,
and 1,2-methylindole (1i) were coupled with 2a in top) is the observation of an intense peak at m/z
(DMSO)]+. This struc-
medium yields (entries 27 and 28). The coupling of 411.1, attributed to [PdACTHUNRTGENNUG(3ja+H)ACHTUNGTRENNUGN
chlorinated and fluorinated styrenes (2b–2d) left the ture was confirmed by HR-MS, and the ESI(+)-MS/
carbon-halogen bond intact (entries 2–7, 11–13, 15–17, MS has shown the loss of Pd and DMSO (Figure S1
20–25). The method is also compatible with the use of in the Supporting Information). In addition, when 2-
p-acetoxystyrene (2e, entries 8–9).
ethylfuran (1k) was used instead of 1j, a shift of 28
À
To learn about the C H activation step, we have mass units was observed, and when tert-butylstyrene
performed a kinetic study using 1e and monodeuterat- (2f) was used instead of 2a in conjunction with 1k,
ed thiophene d-1e for the DHR with 2a (Figure 1). the shift was of 28 mass units as expected (Table 3).
The isotope effect (kH/D =4.4Æ0.5) shows that the C
H cleavage was the rate-determining step of the cata- results from the insertion of 2a into the furyl-Pd(II)
(1jÀH)
lytic cycle, as previously observed with two equiva- bond of Pd (DMSO)2A(OAc). The latter was ob-
(1jÀH)(DMSO)
lents of BQ to regenerate the catalyst,[6] and in other served at m/z 389.1 as [Pd (OAc)Na]+
oxidative Pd-catalyzed reactions.[7]
(Figure 3, bottom). This structure was confirmed by
À
The neutral intermediate PdACHTUNGERTG(NUNN 3ja+H)ACHTUNREGTG(NNUN DMSO)ACHTUNGTRENNUNG(OAc)
A
R
CHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
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Aerobic Dehydrogenative Heck Reactions of Heterocycles with Styrenes
Adv. Synth. Catal. 2013, 355, 59 – 67
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Alexandre Vasseur et al.
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Aerobic Dehydrogenative Heck Reactions of Heterocycles with Styrenes
Figure 2. ESI(+)-MS of an AcOH/DMSO solution of PdACTHNUTRGENNUG(OAc)2 after 5 min. Conditions: PdACHTUGNTREN(NUGN OAc)2 (0.05 mmol), AcOH
(2 mL), DMSO (2 mL), O2 (gas bag), room temperature, 5 min.
Figure 3. Top : ESI(+)-MS of an AcOH/DMSO solution of 1j, 2a, PdACTHNUTRGNEUNG(OAc)2. Conditions: 1j (2.0 mmol), 2a (1.0 mmol),
Pd
ACHTUNGTRENNUNG(OAc)2 (0.05 mmol), AcOH (2 mL), DMSO (2 mL) O2 (gas bag), room temperature, 1.5 h. Bottom: extension of the spec-
tra between m/z 200–400.
HR-MS, and the ESI(+)-MS/MS has shown the loss structure (Table 3). Unsolvated and hydrated species,
of 1j and DMSO (Figure S2 in the Supporting Infor- [Pd
(3ja+H)]+ and [Pd(3ja+H) (H2O)]+, were ob-
mation). The use of 1k also confirms the proposed served at m/z 333.1 and 351.1, respectively (Figure 3,
A
ACHTUNGTRENNUNG
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Alexandre Vasseur et al.
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was not observed in the presence of BQ.[8] It is known
that the reoxidation of Pd(0) under O2 can lead to the
formation of H2O2 and subsequently to H2O,[9] thus
Table 3. Comparison of detected species for the coupling of
1j with 2a, 1k with 2a, and 1k with 2f.
Proposed Structures
m/z
explaining probably the presence of [Pd
(H2O)]+.
In view of the ESI-MS data, the following mecha-
nism is proposed. The inactive trimer [Pd(OAc)2]3 A,
ACHTUNGTRENN(UNG 3ja+H)-
1j, 2a
1k, 2a
1k, 2f
AHCTUNGTRENNUNG
[Pd
[Pd
[Pd
[Pd
N
G
411.1
333.1
351.1
389.1
383.1
305.0
323.0
361.0
439.2
361.1
379.1
361.1
AHCTUNGTRENNUNG
reacts with DMSO leading to the inactive or low
active dimer B and to the active monomer C
À
(Scheme 1). C activates a C H bond of DMSO and 1,
leading to PdL
2A
ACHTUNGTREN(NUNG OAc) and the furyl-Pd
bottom), and their structures were confirmed by HR- complex D. The insertion of 2 furnishes E, which suf-
MS. The ESI(+)-MS/MS of both species has shown fers b-hydride elimination to give F. Species F would
the loss of Pd, while the ESI(+)-MS/MS of the m/z react directly with O2 and AcOH to regenerate the
351 complex agreed with the presence of H2O (Fig- catalyst, or would lead through reductive elimination
ure S3 in the Supporting Information). The couplings to the Pd(0) complex G. In the latter case, the reoxi-
with 1k and 2f also led to the confirmation of the pro- dation of G by O2/AcOH would finish the catalytic
posed structures (Table 3).
cycle.[10]
Finally, we have studied the influence of metallic
No clusters connected to 1, 2 or 3 were observed
above m/z 400, whereas active dinuclear species were co-oxidants on the kinetic profile of the reactions.
detected in the presence of BQ.[8] The latter has The monitoring by GC of the DHR of 1e with 2a per-
therefore an influence on the structure of the active formed under O2 as the sole oxidant or with addition
species. However BQ adducts are usually difficult to of CuACTHNUTRGENUN(G OAc)2 (10%) or AgOAc (10%), has shown that
detect by ESI-MS, and their plausible role in the for- the initial rate is not affected by these co-oxidants
mation of dinuclear species has not been deter- (Figure 4). AgOAc has however a negative influence
mined.[8] The hydrated adduct [Pd (H2O)]+ on the rate after the initial stage of the reaction. The
ACTHNUTRGENNU(G 3ja+H)ACHTUGNTRENNUGN
Scheme 1. Proposed catalytic cycle and species detected by ESI(+)-MS for the DHR of 1j with 2a.
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Aerobic Dehydrogenative Heck Reactions of Heterocycles with Styrenes
Figure 4. Dependence of the yield of 3ea on the presence of
Figure 6. Dependence of the yield of 3aa on the presence of
a co-oxidant. Conditions: 1a (2.0 mmol), 2a (1.0 mmol),
Pd(OAc)2 (0.05 mmol), Cu(OAc)2 or AgOAc (0 or
0.1 mmol), AcOH (2 mL), DMSO (2 mL), O2 (gas bag),
room temperature. Data are averaged from two reactions.
a co-oxidant. Conditions: 1e (1.0 mmol), 2a (1.0 mmol),
Pd(OAc)2 (0.1 mmol), Cu(OAc)2 or AgOAc (0 or
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
0.1 mmol), AcOH (2 mL), DMSO (2 mL), O2 (gas bag),
408C. Data are averaged from two reactions.
Figure 5. Dependence of the conversion of 2a on the pres-
ence of a co-oxidant for the DHR of 1e. Conditions: 1e
(1.0 mmol), 2a (1.0 mmol), PdACHTUNRGTENNUG(OAc)2 (0.1 mmol), CuAHCUTNGTREN(NUGN OAc)2
Figure 7. Dependence of the conversion of 2a on the pres-
ence of a co-oxidant for the DHR of 1a. Conditions: 1a
or AgOAc (0 or 0.1 mmol), AcOH (2 mL), DMSO (2 mL),
(2.0 mmol), 2a (1.0 mmol), Pd
Cu(OAc)2 or AgOAc (0 or 0.1 mmol), AcOH (2 mL),
DMSO (2 mL), O2 (gas bag), room temperature. Data are
ACHTUNGRTEN(NGNU OAc)2 (0.05 mmol),
O2 (gas bag), 408C. Data are averaged from two reactions.
AHCTUNGTRENNUNG
comparison of the conversion and yield curves in the averaged from two reactions.
presence of AgOAc shows that secondary reactions
occur, probably through polymerization or oxidation
of 2a, but the conversion follows the trend observed (Ag)a(Pd)bACHTNUGTRENNUG(DMSO)cACHTUNGTERN(NUGN OAc)d (a, b, c=1–2; d=3–5),
for the formation of 3ea, suggesting that the metallic which were confirmed by HR-MS (Figure S6 in the
co-oxidants act as poisons of the catalyst (Figure 5). Supporting Information).
This observation was also noticed for the DHR of 1a
with 2a, but in greater proportions (Figure 6 and and [Pd
Figure 7). Indeed, the presence of 10% of Cu(OAc)2 these conditions. We have proposed that the trinu-
had a strong negative influence on the rate after the clear complex [Pd(OAc)2]3 is an inactive species for
initial stage of this reaction, while the presence of DHRs, since the Pd(OAc)2 units are joined by double
Only two clusters of Figure 2, [Pd
(DMSO)2]+
ACHUTGTNRENNUG(OAc)ACHTUTGNRENNUGN
2A(OAc)3A
CHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
10% of AgOAc completely prevented the progression OAc bridges, and no acetate ligand can participate in
[8]
À
of the transformation after few minutes of stirring. a C H bond activation. Similarly, we suspect that
On the opposite, the influence of Mn
(OAc)3 on the the acetates form bridges between the Pd and Ag
reaction profile of the DHRs of 1a with 2a and 1e atoms in the mixed complexes (Ag)a(Pd) CHTUNTGERN(NUNG DMSO)c-
bA
(OAc)d, leading to inactive species. An AcOH/DMSO
solution of Pd(OAc)2, AgOAc, 1j and 2a under an
with 2a was not significant (Figure S4 and Figure S5
in the Supporting Information).
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
The ESI(+)-MS of an AcOH/DMSO solution of oxygen atmosphere was then monitored by ESI(+)-
Pd(OAc)2 and AgOAc has, after 5 min of stirring, MS. After 10 min, a simple spectrum was obtained
shown several silver clusters and mixed species, and two clusters were easily detected at m/z 333.0
ACHTUNGTRENNUNG
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Alexandre Vasseur et al.
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programme FEDER to the PlAneT CPER project is also
gratefully acknowledged.
and 411.0, which were previously attributed to
[Pd
in the Supporting Information). After 45 min,
[Pd
(3ja+H)]+ was almost not present, while [Pd-
(3ja+H)
(DMSO)]+ was not detected. [Ag(DMSO)]+
ACHTUNGTRENNUNG ACHTUNRTGENGN(UN 3ja+H)ACTHNUGTRENNGUN
(3ja+H)]+ and [Pd (DMSO)]+ (Figure S7
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
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[Ag
N
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Figure 7).[11] This observation and the disappearance
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CuACHTUNGTRENNUNG(OAc)2 and AgOAc in conjunction with oxygen,
for the Pd(II)-catalyzed coupling of heteroarenes with
styrenes. ESI(+)-MS has led to the identification of
À
four intermediates involved in the C H activation of
the arene and the insertion of the alkene into the Pd
À
Ar bond. The catalytic species are mononuclear com-
plexes. The presence of co-oxidants can lead to the
formation of insoluble or inactive mixed species.
Experimental Section
Typical Procedure
A round-bottom flask was charged with PdACTHNURGTNEUNG(OAc)2 (11.2–
[3] Aerobic DHRs of aliphatic alkenes and styrenes using
O2 as the sole oxidant are rare and limited to very few
examples, see refs.[2c,2j] Aerobic DHRs of heterocycles
using O2 as the sole oxidant seems to be limited to pyr-
roles derivatives, see ref.[2q]
[4] a) L. S. Santos, Reactive Intermediates: MS Investiga-
tions in Solution; Wiley-VCH, Weinheim, Germany,
2010; b) P. A. Belyakov, V. I. Kadentsev, A. O. Chizhov,
N. G. Kolotyrkina, A. S. Shashkov, V. P. Ananikov,
Mendeleev Commun. 2010, 20, 125–131; c) C. A.
Mꢃller, C. Markert, A. M. Teichert, A. Pfaltz, Chem.
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22.4 mg, 0.05–0.1 mmol), AcOH (2 mL), DMSO (2 mmol),
1 (1.0–8.0 mmol) and 2 (1.0 mmol). A gas bag filled with O2
was adapted, and the mixture was stirred at rt-608C for 24 h
to 48 h. Et2O (20 mL) was then added, and a saturated
aqueous solution of NaHCO3 (20 mL) was slowly added
with rapid stirring. The organic phase was washed with 2M
NaOH (20 mL) and H2O (20 mL). The combined aqueous
phases were extracted with Et2O (20 mL). The combined or-
ganic phases were dried over MgSO4, and then evaporated
to dryness. Product 3 was isolated from flash chromatogra-
phy (SiO2, petroleum ether 100% or petroleum ether/
EtOAc, 98:2–70:30).
Acknowledgements
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We are indebted to Rꢀgion Champagne-Ardenne and CNRS
for a Ph.D. studentship to A.V. and for financial support. EU
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[11] The kinetic profile of the DHR of 1j with 2a and the
kinetic profile of the DHR of 1a with 2a are similar.
Adv. Synth. Catal. 2013, 355, 59 – 67
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