Reactivity of stable neopentyl-Pd intermediates in the absence of nucleophile

Article abstract of DOI:10.1016/j.tetlet.2007.05.018

In the absence of any trapping agent, stable neopentyl-Pd intermediates can terminate a catalytic cycle by undergoing a regioselective C-H activation, leading to various spiro or fused cyclopropane derivatives in a straightforward manner. If the neopentyl

Full text of DOI:10.1016/j.tetlet.2007.05.018

Tetrahedron Letters 48 (2007) 4943–4946
Reactivity of stable neopentyl-Pd intermediates in the
absence of nucleophile
*
´ ´
Frederic Liron and Paul Knochel
Department Chemie und Biochemie, LMU Mu¨nchen, Butenandtstr.5-13, Haus F, D-81377 Munich, Germany
Received 25 November 2006; revised 26 April 2007; accepted 2 May 2007
Available online 10 May 2007
Abstract—In the absence of any trapping agent, stable neopentyl-Pd intermediates can terminate a catalytic cycle by undergoing a
regioselective C–H activation, leading to various spiro or fused cyclopropane derivatives in a straightforward manner. If the neo-
pentyl-Pd intermediate contains a heteroatom at a suitable position, C–H activation does not occur and stable palladacycles are
isolated.
Ó 2007 Published by Elsevier Ltd.
In the course of preparing new ligands by means of an
asymmetric sigmatropic rearrangement of allylic phos-
phinites,1 we needed to functionalize phosphine oxide
1. It appeared to us that an intramolecular syn-carbopal-
ladation reaction would lead to a stable Pd intermediate
that could be trapped by a nucleophile.2 Such a strategy
would lead to new, enantiomerically pure, useful
ligands.3 In a preliminary study, attempts to trap the
Pd intermediate with a hydride source did not give the
expected compound 2. We reacted phosphine oxide 1
with Pd(OAc)2 (0.2 equiv), PPh3 (0.4 equiv), n-Bu4NBr
(1.3 equiv), NaBH4 or HCOONa (3 equiv), and K2CO3
(5 equiv) in DMF at 120 °C for 16 h and observed the
sole formation of tricyclic compound 3 (Table 1 and
Scheme 1). Use of NaBH4 as a trapping agent for inter-
mediate 5 (Scheme 1 and entry 1) inhibited the reaction.
obtained, but the diastereoselectivity was poor (entry
6). Changing the Pd source to Pd(PPh3)4 led to no
improvement (entry 7). Interestingly, compound 3 was
formed at such a rate that the regioselective C–H activa-
tion pathway could occur, even in the presence of a
syn-b-hydrogen. This is indicated by the fact that 3
was isolated as a mixture of diastereomers (Table 1).
A suitably positioned syn-b-hydrogen is therefore neces-
sarily present in one of the two isomers. Such pathways
are unusual, as b-hydride elimination is often the fastest
process to terminate a catalytic cycle.
The formation of 3 could be explained by a regioselec-
tive C–H activation of the Pd intermediate 5 (resulting
from a 5-endo-trig intramolecular carbopalladation) into
the methyl group geminal to the phosphorus moiety.
Reductive elimination of the putative intermediate 6
leads to compound 3 (Scheme 1).
With HCOONa,
a
high diastereoselectivity was
achieved, but the conversion was too low to be syntheti-
cally useful (entries 2 and 3). As it was not possible to
trap intermediate 5, we decided to investigate this unex-
pected C–H activation pathway. When Pd(OAc)2 was
used as a catalyst, the optimal temperature was 120 °C
(entry 8). Higher or lower temperatures (entries 9 and
10) led to lower diastereoselectivities or lower conver-
sions. When Ag2CO3 was used as a base, high diastereo-
selectivities were achieved, but with low conversions
(entries 4 and 5). At 120 °C, a high conversion was
Although Pd-catalyzed C(sp2)–H activation4 is rather
efficient and well documented, there are only very few
reports dealing with C(sp3)–H activation processes.5
As shown in Scheme 2, the C–H activation takes place
very rapidly (more rapidly than the b-hydride elimina-
tion) and regioselectively into the methyl group attached
to the more hindered position. We suspected a strong
influence of the Thorpe–Ingold effect induced by the
very bulky diphenylphosphinoyl group. In order to
study the influence of the steric hindrance and the possi-
bility to perform the reaction in the presence of a b-
hydrogen, we submitted alkenes 7a–b to the conditions
described above (Scheme 2).
Keywords: Palladium; C–H activation; Cascade reactions.
*
Corresponding author at present address: ICSN-CNRS, Avenue de
la Terrasse, F-91198 Gif sur Yvette Cedex, France. Tel.: +33
169823037; e-mail: frederic.liron@icsn.cnrs-gf.fr
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.05.018

4944
F. Liron, P. Knochel / Tetrahedron Letters 48 (2007) 4943–4946
Table 1. Optimization of the reaction conditions
Me
Me
Me
Me
Br
[Pd], base, additive
Me
Ph2(O)P
Me
Me
Ph2(O)P
Ph2(O)P
Ph2(O)P
1
2
3
4
Entry
[Pd]
Base
Additive
T (°C)
1a
2a
3a
4a
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2CO3
K2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Et3N
K2CO3
K2CO3
K2CO3
NaBH4
HCOONa
HCOONa
None
None
None
None
None
None
None
120
120
100
80
100
120
80
120
80
140
90
60
60
94
60
0
100
0
30
0
0
0
0
0
0
0
0
0
0
0
0
10
10
40
0
15
10
0
25b
12
12
20 (dr > 99/1)
0
6 (dr > 99/1)
20 (dr > 99/1)
90 (dr = 60/40)
0
75 (dr = 80/20)b
58 (dr = 60/40)
63 (dr = 65/35)
c
10
a Ratios and diastereoselectivities were measured by 31P NMR of the crude mixture.
b Isolated yields.
c No additional PPh3 was added.
elimination to produce indene 8, showing the crucial
importance of a large steric hindrance to favor C–H
activation over b-hydride elimination. Alkene 7b, pos-
sessing no b-hydride underwent a regioselective C–H
activation, but we could only isolate dihydronaphtha-
lene 10 instead of the expected tricyclic compound 9.
Me
Br
Me
[Pd0]
Ph2(O)P
Ph2(O)P Me
1
3
Me
We then turned our attention to using this reaction to
prepare heterocycles. The required amides, amines,
and ethers were prepared according to described meth-
ods (Scheme 3).7
Me
PdLn
PdBrLn
Ph2(O)P
6
Me
Ph2(O)P
We first reacted amide 12b under the conditions de-
scribed above and both the expected spirocyclopropane
13a and compound 13b were isolated (Scheme 4). These
results contrast with those recently reported by Larock
et al., who reported a C(sp2)–H activation under slightly
different conditions.8
5
HBr
Scheme 1. Reagents and conditions: Pd(OAc)2 (0.2 equiv), PPh3
(0.4 equiv), n-Bu4NBr (1.3 equiv), K2CO3 (5 equiv), DMF, 120 °C,
overnight.
We then treated amines 12c and d under the conditions
described above and isolated, besides unreacted starting
material, Pd complexes 14a–b. Complexation of the Pd
Alkenes 7a–b were reacted under the described condi-
tions (Scheme 2). Alkene 7a6 underwent b-hydrogen
Me
Br
Me
Et Me
Me
Et
7a
8: 80%
Me
Me
Br
Me
Me Me
Me
Me
Me
Me
Me
7b
9
10: 40%
Scheme 2. Reagents and conditions: Pd(OAc)2 (0.2 equiv), PPh3 (0.4 equiv), n-Bu4NBr (1.3 equiv), K2CO3 (5 equiv), AcOH (3 equiv), DMF, 120 °C,
overnight.

F. Liron, P. Knochel / Tetrahedron Letters 48 (2007) 4943–4946
4945
Br
propane derivatives selectively and are unprecedented in
the literature. Further developments will be reported in
due course.
Br
(i), (ii), ( iii)
Me
X
XH
n
n
11
12
a: n = 1, X = O
b: n = 0, X = NH
c: n = 1, X = NH
a: n = 1, X = O
b: n = 0, X = NAc
c: n = 0, X = Nmethallyl
d: n = 1, X = Nmethallyl
Acknowledgements
We thank Dr. D. S. Stephenson for carrying out an
Inadequate experiment on compound 3. We thank the
Fonds der Chemischen Industrie and the LMU-Mun-
¨
Scheme 3. Reagents and conditions: (i) Acetylation reaction: acetyl
chloride (1 equiv), Et3N, CH2Cl2, rt, 2 h (80%); (ii) allylation of
amides: amide (1 equiv), NaOH (5 equiv), n-Bu4NHSO4 (0.1 equiv),
methallyl chloride (7 equiv), H2O, 80 °C, overnight (70%); (iii)
allylation of amines and ether: amine or ether (1 equiv), NaH (1 equiv),
methallyl chloride (2–3 equiv), DMF, 80 °C, overnight (80–90%).
chen for financial support. We also thank BASF AG
(Ludwigshafen), Chemetall (Frankfurt) and Bayer
Chemicals (Leverkusen) for the generous gift of
chemicals.
Supplementary data
Br
Experimental procedures and full characterization data
for all the compounds are available. Supplementary
data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2007.05.018.
N
N
N
Ac
Ac
Ac
Me
12b
13a
13b
50%
25%
References and notes
Scheme 4. Reagents and conditions: Pd(OAc)2 (0.2 equiv), PPh3
(0.4 equiv), n-Bu4NBr (1.3 equiv), K2CO3 (5 equiv), AcOH (3 equiv)
where relevant, DMF, 120 °C, overnight.
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atom by the lone pair of nitrogen prevents this inter-
mediate to react further, either in a second carbopalla-
dation reaction or in the expected C–H activation
mode. Ether 12a was also reacted and led after 24 h to
a mixture of the expected spirocyclopropane derivative
16a and gem-dimethyl compound 16b. In this latter case,
conversion reached only 50% (Scheme 5).9
As can be seen from our results, this reaction is very sen-
sitive to various parameters such as the nature of the
protecting groups and the nature of the base.
3. See for example: (a) Noyori, R. Asymmetric Catalysis in
Organic Synthesis; Wiley: New York, 1994; (b) Ojima, I.
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In summary, we reported herein a novel intramolecular
carbopalladation/C–H activation cascade reaction. Such
pathways allow the preparation of spiro or fused cyclo-
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Br
Me
R
PPh3
Pd
+
Br
N
N
N
n
R
n
n
R
12
14
15
c: n = 0, R = methallyl
d: n = 1, R = methallyl
a: n = 0, R = methallyl, 15%a
b: n = 1, R = methallyl, 15%a
a: n = 0, R = methallyl, 50%
b: n = 1, R = methallyl, 0%
Br
Me
O
O
O
12a
16a: 30%
16b: 15%
Scheme 5. Reagents and conditions: Pd(OAc)2 (0.2 equiv), PPh3 (0.4 equiv), n-Bu4NBr (1.3 equiv), K2CO3 (5 equiv), DMF, 120 °C, overnight; a 75%
based on Pd loading.

4946
F. Liron, P. Knochel / Tetrahedron Letters 48 (2007) 4943–4946
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and DMF (5 mL). The mixture was heated to 120 °C
overnight. After cooling to rt, it was quenched with water
(20 mL) and extracted (Et2O). The organic layer was dried
over MgSO4, concentrated in vacuo, and chromatographed
on silica gel, leading to the pure compounds.
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