Highly selective palladium-benzothiazole carbene-catalyzed allylation of active methylene compounds under neutral conditions

Article abstract of DOI:10.3762/bjoc.11.111

The Pd-benzothiazol-2-ylidene complex I was found to be a chemoselective catalyst for the Tsuji-Trost allylation of active methylene compounds carried out under neutral conditions and using carbonates as allylating agents. The proposed protocol consists in a simplified procedure adopting an in situ prepared catalyst from Pd₂dba₃ and 3-methylbenzothiazolium salt V as precursors. A comparison of the performance of benzothiazole carbene with phosphanes and an analogous imidazolium carbene ligand is also proposed.

Full text of DOI:10.3762/bjoc.11.111

Highly selective palladium–benzothiazole carbene-catalyzed
allylation of active methylene compounds
under neutral conditions
Antonio Monopoli*1, Pietro Cotugno1, Carlo G. Zambonin1, Francesco Ciminale1
and Angelo Nacci*1,2
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 994–999.
1Department of Chemistry, University of Bari Via Orabona 4, 70126
Bari, Italy and 2CNR-ICCOM, Department of Chemistry, University of
Bari, Via Orabona 4, 70126 Bari, Italy
doi:10.3762/bjoc.11.111
Received: 15 March 2015
Accepted: 20 May 2015
Published: 10 June 2015
Email:
Antonio Monopoli* - antonio.monopoli@uniba.it; Angelo Nacci* -
angelo.nacci@uniba.it
In memory of Dr. Francesco Paolo Monopoli.
Associate Editor: K. Itami
* Corresponding author
Keywords:
© 2015 Monopoli et al; licensee Beilstein-Institut.
License and terms: see end of document.
active methylene compounds; allylic carbonates;
Pd–benzothiazol-2-ylidene complex; Tsuji–Trost allylation
Abstract
The Pd–benzothiazol-2-ylidene complex I was found to be a chemoselective catalyst for the Tsuji–Trost allylation of active
methylene compounds carried out under neutral conditions and using carbonates as allylating agents. The proposed protocol
consists in a simplified procedure adopting an in situ prepared catalyst from Pd2dba3 and 3-methylbenzothiazolium salt V as
precursors. A comparison of the performance of benzothiazole carbene with phosphanes and an analogous imidazolium carbene
ligand is also proposed.
Introduction
The α-allylation of carbonyl compounds is one of the most Tsuji–Trost allylation, in which the use of a base in combina-
important reactions in organic chemistry, since it opens the way tion with a Pd species resulted in better outcomes [14-21].
to the synthesis of a plethora of interesting molecules such as
pheromones, perfumes, or bio-active compounds such as However, some of these protocols suffer for severe drawbacks
prostaglandin E2 or F2α. After the pioneering works by Tsuji such as long reaction times [18,22], undesirable overreactions
[1,2] and Trost [3,4], the Pd-catalyzed allylation of various giving the diallylated compounds [23,24], the need for catalysts
nucleophiles is a largely used strategy and a variety of efficient that are tedious to prepare [18,19], and the use of toxic or
and robust homogeneous [5-9] and heterogeneous [10-13] Pd expensive ligands such as phosphanes or phosphites [3,25].
catalysts have been reported, until now. Recently, synergistic Therefore, the careful selection of a suitable ligand capable for
or cooperative catalysis has been also described for the replacing phosphines and improving palladium activity is still
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Beilstein J. Org. Chem. 2015, 11, 994–999.
mandatory in these kind of reactions. Among various ligands, lation of active methylene compounds using carbonates as ally-
N-heterocyclic carbenes (NHCs) have gained greater impor- lating agents (Scheme 1).
tance in organometallic chemistry. Unlike phosphanes, NHCs
are not toxic and insensitive to air, heat and moisture.
Results and Discussion
Allylic carbonates are suitable reagents for the Tsuji–Trost
Moreover, the introduction of substituents onto the heterocyclic allylation as they enable to work under neutral conditions. The
ring enables the tuning of their steric and electronic properties base required for methylene deprotonation, the alkoxide anion
affecting the catalytic activity of the resulting metal complex (RO−), can in fact originate (in situ) from the degradation of
[26-29]. Although NHC–Pd complexes have been employed in the allylic carbonate by the Pd catalyst [2]. Optimisation
many C–C bond-forming reactions, to the best of our knowl- of the reaction conditions was carried out on the model sub-
edge they have been scarcely applied to the allylic alkylation of strate diethyl malonate by varying several parameters such as
nucleophiles [30-36].
ligands, Pd sources, catalyst loading, temperature and solvents
(Table 1).
Some years ago, we synthesized the first example of
Pd–benzothiazol-2-ylidene complex I (Figure 1), which proved With regard to the influence of ligands, the efficiency of
to be an efficient catalyst for several C–C coupling reactions benzothiazole–carbene was compared with that of sulfides II
(like carbonylations and Heck olefinations) carried out in both and III, both in the presence and in the absence of PPh3, as it is
conventional solvents [37] and in ionic liquids [38]. Complex I well known that also chelating N-heterocyclic ligands bearing
is easily prepared from the corresponding thiazolium salt V and methylene or ethylene bridges can form very active catalysts in
Pd(OAc)2, and due to its high stability the complex can be puri- these kind of reactions (structure IV) [39].
fied by silica gel chromatography.
Nevertheless, from the data in Table 1 it clearly emerges that
We report here the use of dicarbenediiodopalladium(II) com- chelating N-ligands II and III were unproductive when used
plex I, prepared in situ, as a precatalyst in the Tsuji–Trost ally- alone, giving very low conversion values (<5%, Table 1, entries
Figure 1: Complexes and ligands employed.
Scheme 1: Pd-catalyzed α-allylation of active methylene compounds.
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Beilstein J. Org. Chem. 2015, 11, 994–999.
Table 1: Optimization of reaction conditions.a
Entry
Pd source (%)
Ligand (mol %)
other
Solvent
T (°C)
Conv. %b
Selectivityc
1:2
PPh3
1
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd2dba3 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd2dba3 (2)
Pd2dba3 (5)
Pd(OAc)2 (2)
Pd2dba3 (2)
Pd2dba3 (2)
I (2)
4
II (4)
II (20)
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
25
25
25
25
25
70
70
70
25
25
25
25
25
25
25
25
100
<5
70:30
–
2
–
3
20
4
100
100
10
55:45
60:40
99:1
50:50
63:37
70:30
65:35
62:38
–
4
II (4)
II (4)
–
5
4
6
20
4
THF
100
100
100
100
100
<5
7
II (4)
II (10)
III (4)
III (4)
III (20)
–
THF
8
10
4
THF
9
CH2Cl2
CH2Cl2
CH2Cl2
THF
10
11
12
13
14
15
16
4
–
–
100
48
99:1
96:4
97:3
95:5
98:2
Pd2dba3 (2)
Pd2dba3 (2)
Pd(OAc)2 (2)
Pd2dba3 (2)
–
V (4)d
V (8)d
V (8)d
VI (8)d
THF
–
THF
100
100
16
–
THF
–
THF
aReaction conditions: diethyl malonate (1.2 mmol), methyl allyl carbonate (1 mmol), Pd source, ligand, in 5 mL of solvent. bConversions are evalu-
ated based on disappearance of carbonate. cThe 1:2 ratio is determined on the base of GLC peak areas. dNaH was added to generate carbene ligand
(see Experimental section).
2 and 11). In contrast, PPh3 provided complete conversions but the use of sub-stoichiometric amounts of V afforded corres-
afforded almost equimolar mixtures of mono- and bis-allylated pondingly lower conversions without altering the chemoselec-
products (ca. 50:50, Table 1, entries 3 and 6). Disappointing tivity of the process (Table 1, entry 13).
results in terms of selectivity were also found by combining the
If palladium acetate was used as precatalyst, an induction period
was observed, thus indicating the need for the reduction of the
Pd(II) precatalyst to the Pd(0) active species (Table 1, entry 15).
two types of ligands, although in these cases a slightly higher
selectivity in favour of mono-allylated product 1 was observed
(on average 65:35) probably due to the steric influence of
chelating ligands II and III (Table 1, entries 1, 4, 5, and 7–10).
Other parameters such as temperature, solvents, catalyst loading
and palladium sources proved to have a negligible effect on the
reaction outcome.
Finally, we also compared the performance of our 3-methyl-
benzothiazol-2-ylidene carbene ligand with that of the
analogous 1,3-dimethylimidazol-2-ylidene by Herrmann et al.
[40], prepared in situ from 1,3-dimethylimidazolium iodide
A special behaviour was observed with Pd–carbene complex I (VI).
as precatalyst. Indeed, with 2 mol % of I prepared ex situ [37],
the reaction carried out in dry THF reached a complete conver- The reaction carried out under the protocol conditions afforded
sion in only 2 hours at room temperature, with the selective for- in 2 h the monoallylated compound 1 in a low yield (16%)
mation of the mono-allylated product 1 (Table 1, entry 12). confirming the superior efficiency of benzothiazole–carbene
Interestingly, the same result was achieved using the (Table 1, entry 16).
Pd–carbene complex prepared in situ from Pd2dba3 and
3-methylbenzothiazolium iodide (V) as a carbene precursor A possible explanation of the different behavior displayed by
(Table 1, entry 14). In this case, to generate the carbene ligand, these two carbene ligands can be found in the different aromatic
the addition of the base NaH was necessary for the proton character of their (benzothiazole and imidazole) heterocyclic
abstraction at the C2 position of the thiazolium salt. In addition, rings. It is well known that this feature can strongly affect the
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Beilstein J. Org. Chem. 2015, 11, 994–999.
nucleophilicity of these NHC species, and ultimately can influ- dicarbonyl compounds and allylic carbonates (Table 2). For
ence their ability of acting as a σ-donor towards the metal. In these reactions, to further simplify the operating procedure of
particular, the higher the aromatic character of the heterocycle the proposed protocol, we chose to use the palladium–carbene
the lower is the back-donation by palladium, and this effect catalyst prepared in situ as reported above (Table 1, entries
would enhance the electron density on the metal rendering it 20–22).
more reactive. On these bases, we can speculate that the
benzothiazole–carbene ligand deriving from V, should be more The data in Table 2 show that the reactions proceeded smoothly
active (being a better σ-donor) than the corresponding imida- with yields ranging from 64% to 98% and a complete selec-
zole (deriving from VI) due to its higher aromatic character. tivity in favour of the mono-allylated compounds in most of the
Studies are in progress to verify this assumption.
examined combinations.
With optimized conditions in hand, we widened the scope of Predictably, the reactivity of β-dicarbonyl compounds (i.e.,
our investigation by extending the coupling to a series of 1,3- conversion values and reaction times) was found to depend on
Table 2: α-allylation of 1,3-dicarbonyl compoundsa.
Entry
1
Substrate
Allylic carbonate
t (h)
Product
Conv. (%)b Yield (%)b
2
99
89
90
97
1
2
3
83c
(88)b
2
3
2
6
86c
(89)b
4
5
6
3
6
8
>99
91
98
90
4
5
6
75c
(81)b
84
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Beilstein J. Org. Chem. 2015, 11, 994–999.
Table 2: α-allylation of 1,3-dicarbonyl compoundsa. (continued)
7
7
8
9
>99
88
64d
82
7
8
9
8
9
71c
(74)b
78
aReaction conditions: dicarbonyl compound (1.2 mmol), allyl carbonate (1 mmol), Pd2dba3, (0.02 mmol) benzothiazolium iodide V (0.08 mmol), NaH
(0.1 mmol) in 5 mL of solvent (see Supporting Information File 1). bConversions and yields were evaluated via GLC by using diethylene glycol di-n-
butyl ether as internal standard. cIsolated product. dA mixture of mono- and diallylated products in a 64:36 ratio was formed.
the nucleophilic strength of the intermediate enolates, and ulti-
Supporting Information
mately on pKa values (reactivity scale: diethyl malonate pKa
13.5 > acetoacetate pKa 11.0 > acetylacetone pKa 8.9). As an
Supporting Information File 1
example, diethyl malonate reacted with allyl methyl carbonate
much faster than acetylacetone, reaching the complete conver-
sion in only 2 hours (vs 7 hours of acetylacetone, Table 2,
entries 1 and 7).
General methods, synthetic procedures, characterization
data of all new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-111-S1.pdf]
In a similar predictable manner, selectivity was affected by the
steric hindrance of allyl carbonate. This influence was evident
in the case of the slower reactions of acetylacetone, for which
the sterically more hindered cinnamyl- and pentenyl methyl
carbonates afforded exclusively the monoallylated products
(Table 2, entries 8 and 9), while the less hindered methyl allyl
carbonate, afforded also remarkable amounts of the diallylated
compounds (64:36 ratio, Table 2, entry 7).
Acknowledgements
We thank the University of Bari, the Italian Ministry of Instruc-
tion, University and Research (MIUR), and the Regione Puglia
(“PON Ricerca e Competitività” 2007–2013—Avv. 254/Ric.
del 18/05/2011, Project PONa3 00369 “Laboratorio
SISTEMA”) for financial support.
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