Catalytic amide-directed palladadesilylation-alkenylation

Article abstract of DOI:10.1055/s-0029-1218339

Palladium(II) complexes catalyse the amide-directed displacement of an aryl-Si group and its replacement by an electrophilic alkene at ambient temperature, analogous to an oxidative Heck reaction. A palladacyclic intermediate is involved, and the reaction

Full text of DOI:10.1055/s-0029-1218339

LETTER
3103
Catalytic Amide-Directed Palladadesilylation–Alkenylation
Catalytic
A
mide-Directe
a
d
Pallada
d
q
esilylation–A
a
lkenylationr Rauf, John M. Brown*
Chemistry Research Laboratory, Mansfield Rd., Oxford OX1 3TA, UK
Fax +44(1865)285002; E-mail: john.brown@chem.ox.ac.uk
Received 11 September 2009
and for this reason the directed Heck reaction of benzanil-
ide occurs in the ring adjacent to nitrogen (six-membered
palladacycle) rather than that adjacent to the carbonyl
group (five-membered palladacycle), since the more elec-
Abstract: Palladium(II) complexes catalyse the amide-directed
displacement of an aryl–Si group and its replacement by an electro-
philic alkene at ambient temperature, analogous to an oxidative
Heck reaction. A palladacyclic intermediate is involved, and the re-
action enables substitution to occur specifically in the electron-poor tron-rich site is favoured. Palladacycles formed by CH ac-
ring of benzanilides. The procedure described provides a formal
link between directed lithiation and the Heck reaction.
tivation ortho to an arene-bound carbonyl group are less
common,13 as would be expected on electronic grounds,
Key words: palladium, oxidative Heck reaction, palladacycle, benz-
anilides, regiocontrol
since an electrophilic attack is disfavoured at that posi-
tion. The ortho-carbonyl position is the preferred site for
lithiation of benzanilide 1 and its relatives, however.14
Coupled to the fact that C–Si is intrinsically more reactive
The use of arylsilanes as the nucleophilic component in to electrophilic substitution than C–H,15 we wondered
palladium coupling reactions is well-established through whether this offered the possibility of an alternative regio-
the pioneering work of Hiyama1 and Denmark.2 In these isomeric product in the benzanilide case. There are early
cases the C–Si bond is activated by external fluoride ion examples of stoichiometric Pd activation of an aryl–Si
or by a silanol; alternatively an alkoxide group can bind to bond.16 In our own work (Scheme 2), palladadesilylation
silicon,3 so that activation of the transferred group occurs has been used to control the regiochemistry of palladacy-
exocyclic to the dative-bonded ring. In a similar vein we cle formation and enabled a demonstration of catalytic
have demonstrated the exocyclic activation of Si–Me turnover through an anilide directing group, albeit accom-
groups by a neighbouring urea or amide group, enabling panied by competing protodesilylation resulting in forma-
catalytic intermolecular methyl transfer from silicon to an tion of the alternative regioisomer.4,17
electrophilic alkene.4 It was observed that an alternative
course of reaction occurred in some cases leading to en-
CO2Bu
docyclic aryl–methyl coupling, but with only modest effi-
H
ciency. The present paper describes development of an
F
F
N
Me
effective endocyclic coupling through intermediate palla-
H
N
SiMe3
dacycle formation from silane precursors (Scheme 1).5
O
O
Pd(OAc)2 (10 mol%),
p-TsOH, BQ (1 equiv),
85%
F
F
Me
+
O
butyl acrylate,
C3H6O, 24 h
H
N
PdLnX (a)
PdLnX (b)
F
F
Me
RPdLn
Y
Y
endocyclic
cleavage
exocyclic
cleavage
(b)
H
N
O
O
Si
PdLn
R
R'2
13%
F
F
Me
O
(a)
Scheme 1 Contrasting pathways for directed C–Si activation lea-
ding to distinct palladium intermediates in catalysis.
CO2Bu
Scheme 2 A prior example of alkenylation via palladadesilylation17
Many aryl C–H activation reactions are effected by anil-
ide directing groups, as was first observed stoichiometri-
cally by Horino6 and then catalytically by DeVries and co-
workers.7,8 There have been several subsequent develop-
ments based on this theme.9,10 The reaction is likely to in-
volve an intermediate palladacycle formed by
electrophilic substitution directed by the anilide carbonyl
group.11 The anilide ring (sp 0.00, sm 0.21) is more elec-
tron rich than the carboxamide ring (sp 0.36, sm 0.35),12
This encouraged further efforts to use the known silane 2a
(ref. 14) as the reactant in catalytic alkenylation, thus di-
recting the new bond into the less reactive ring of benza-
nilide. The outcome of the first reaction attempted was
partially successful, and a 49% yield of the desired prod-
uct 3 was obtained (Table 1, entry 1). Formation of the de-
sired product was accompanied by protodesilylation,
which ultimately led to CH alkenylation of the anilide
ring. A systematic effort was made to optimize the C–C
bond-forming process as indicated in Table 1, avoiding
acid as far as possible.18 After considerable trial and error,
SYNLETT 2009, No. 19, pp 3103–3106
x
x
.x
x
.2
0
0
9
Advanced online publication: 05.11.2009
DOI: 10.1055/s-0029-1218339; Art ID: D21409ST
© Georg Thieme Verlag Stuttgart · New York

3104
W. Rauf, J. M. Brown
LETTER
with the more informative experiments collated in At this point it was surmised that avoidance of direct
Table 1, a moderately high-yielding procedure was dis- C=O–silyl bonding would direct Pd attack to the ipso-car-
covered. For some of the test reactions methyl transfer to bon and suppress the side reactions. The bulkier TBDMS
the arene or alkene, the latter giving (E)-butyl crotonate, derivative 6a was prepared and reacted with butyl acrylate
were significant side reactions.4 The optimum conditions under Pd(OAc)2 catalysis with added PTSA and oxidant.
involved the use of the weaker acid PhPO3H2, although Clean formation of product 3 was observed, now without
this occurred at an impractically slow rate.
competing protodesilylation. The X-ray structure of silane
6a shows an absence of C=O….Si contact,19 consistent
with the endocyclic activation observed. Intermediacy of
isolable palladacycles 7a,b was demonstrated in stoichio-
metric reactions starting from silylbenzanilide 6a or silyl-
acetanilide 2b4 (Scheme 4). At 70 °C in the absence of
strong acid, the palladacyclic acetate 7c was formed.
Table 1 Preliminary Reactions with Silane 2a
H
N
Ph
O
CO2Bu
3
H
Pd(OAc)2
reagents
N
Pd(OAc)2, p-TsOH
+
Ph
H
H
SiMe3
O
N
N
C7H8, Me2CO
r.t.
R1
R1
H
N
SiMe2R2
Pd
OR3
O
O
2a
Ph
2
Me
O
6a R1 = Ph, R2 = But
2b R1 = R2 = Me
7a R1 = Ph, R3 = Ts
7b R1 = Me, R3 = Ts
7c R1 = Me, R3 = Ac
4
(for 2b to 7c, no p-TsOH, 70 °C, 2 h)
Entrya Oxidant Solvent
Temp (°C) Time (h) Results
Scheme 4 Five-membered palladacycle formation from silylamides
1b
2c
3b
4
p-BQ
Me2CO
20
90
20
24
3
3 49%; see text
3 2%, 1a 33%
1a only; fast
very slow, 3 + 4
3 55%, 4 30%
3 80%
These initial results encouraged the synthesis of a range of
TBDMS-substituted benzanilides substituted in the amide
ring. For the 3-F analogue 1f, only one product was isolat-
ed derived from the substituent-flanked ArLi isomer and
in low yield.
Cu(OAc)2 DMF
p-BQ
p-BQ
p-BQ
p-BQ
CDCl3
1
AcOH/C7H8 20
60
2
5
AcOH
70
20
The same alkenylation methodology that had been used
for the formation of alkene 3 from the parent TBDMS de-
rivative 6a was applied to the preparation of a range of
ring-substituted variants of compound 6a (Scheme 5).
The reaction worked smoothly for the range of benzanil-
ides tested. For entry 3 (9c as product, Table 2), compet-
ing desilylation was observed with 5 mol% Pd(OAc)2, and
hence 10 mol% of catalyst was employed. The higher cat-
alyst ratio was also used for the slower examples of entries
6–8 leading to 9f,g, and 10.
6d
Me2CO
50
a Pd(OAc)2 (5 mol%) used unless otherwise stated, p-BQ is p-benzo-
quinone.
b PTSA (1 equiv).
c No reaction in THF.
d Pd(OAc)2 (10 mol%), PhPO3H2 (1 equiv) added, faster but with more
side reactions at 50 °C, but very slow with PhCO2H as acid.
Two structural variants were prepared. Firstly, the
PhMe2Si analogue 5 provided a convenient test of exo- vs.
endocyclic C–Si activation. In acetone [5 mol%
Pd(OAc)2, p-BQ, PTSA] the two processes occurred at
Only in the case of entry 3 was arene methylation ob-
served as a side reaction. In the general case, neither the
reactant nor the product is susceptible to cyclopalladation
and ensuing reaction in the ortho-anilide ring. This sug-
gests that steric pressure from a 2-substituent adjacent to
the carbonyl group inhibits formation of the six-mem-
bered palladacyclic intermediate. In the X-ray structure of
compound 6a described above, the silane-bearing ring is
twisted out of the plane of the amide by 55° and 72°, re-
spectively, in two independent molecules.20,21 In accord
with acetanilide CH activation experiments,10b the elec-
tron-poor 4-Cl analogue 6g reacts slowly (entry 7). The
electron-rich furylsilane 8 was only sluggishly reactive,
however, perhaps because a five-membered ring pallada-
cycle fused to a five-membered aromatic ring is more
strained.
comparable rates yielding product
3
and (E)-
PhCH=CHCO2Bu in a 45:55 ratio (Scheme 3). Many oth-
er products were formed in AcOH, including those de-
rived by Me transfer.
H
N
Ph
O
CO2Bu
3
H
N
butyl acrylate
cat Pd(OAc)2
endocyclic
Ph
45:55
+
O
p-BQ, p-TsOH
Me2CO
Si
Me
Ph
Me
Ph
5
CO2Bu
Catalytic palladadesilylation as described here requires a
directing group, and efficient reaction is limited at this
stage to silanes with a neighbouring carboxamido group.
Thus 2-(trimethylsilyl)benzofuran is inert to our standard
exocyclic
Scheme 3 Dual pathway in the alkenylation of 5
Synlett 2009, No. 19, 3103–3106 © Thieme Stuttgart · New York

LETTER
Catalytic Amide-Directed Palladadesilylation–Alkenylation
3105
5
+
X
5
2
SiMe2t-Bu
X
t-BuLi (2.1 equiv),
–78 °C, 1 h;
6
4
6
4
3
H
OTs
Pd
H
N
3
N
1
then TBDMSCl (2.2 equiv)
–78 °C to r.t., 12 h, THF
Ph
Ph
OTs–
O
SiMe2t-Bu
O
O
PhHN
11
6a X = H, 90%
1a X = H
6b X = 3-OMe, 50%*
6c X = 4-OMe, 45%
6d X = 4-Me, 70%
6e X = 5-Me, 94%
6f X = 3-F, 20%
6g X = 4-Cl, 36%
(5 as above ex. 1a,
PhMe2SiCl, 75%)
1b X = 3-OMe*
1c X = 4-OMe
1d X = 4-Me
1e X = 5-Me
1f X = 3-F
Figure 1 Proposed reactive intermediate in palladadesilylation
The chemistry described here provides access to novel
palladacyclic intermediates under mild and readily acces-
sible conditions via displacement of an aromatic silyl
group, and has potential in catalysis beyond the oxidative
Heck reactions described here.22 The principles involved
ought not to be limited to anilides. At present it is less ef-
fective for electron-rich aromatic systems where protode-
silylation pathways compete more effectively.
1g X = 4-Cl
O
t-BuMe2Si
O
H
N
as above
H
N
Ph
Ph
O
1h
8 86%
O
Scheme 5 Synthesis of TBDMS derivatives of benzanilides
reaction conditions, albeit electron rich. Success depends
critically on the role of the TBDMS group, whose steric
bulk inhibits competing reactions requiring direct silyl ac-
tivation. In turn, this encourages the formation of silyl-sta-
bilized intermediates related to cationic intermediate 11
(Figure 1), with the amide associated with Pd rather than
Si. An interesting feature of this chemistry is the absence
of competition from the ‘conventional’ pathway involv-
ing substitution in the anilide ring.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the Pakistan Government for a Scholarship (WR) and the
Leverhulme Trust for a Fellowship (JMB). We are grateful to John-
son-Matthey for the loan of palladium salts. A referee is thanked for
helpful comments.
Table 2 Alkenylation of TBDMS-Benzanilides
References and Notes
X
X
5
5
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butyl acrylate
4
3
6
6
4
cat. Pd(OAc)2,
H
H
p-BQ (1.1 equiv)
N
N
3
Ph
Ph
p-TsOH (1.2 equiv),
O
SiMe2t-Bu
O
acetone
r.t.
CO2Bu
Entry
1
Producta
Time (h) Yield (%, conversion)
3 X = H
24
36
24
24
20
36
24
36
77 (90)
72 (90)
52
2c
3b
4
9b X = 3-OMe
9c X = 4-OMe
9d X = 4-Me
9e X = 5-Me
9f X = 3-F
9g X = 4-Cl
10 (ex. 8)
73 (90)
77 (90)
(50)
5
6c
7c
8c
46 (60)
(20)
a Substitution in 9 matches that in 6; Pd(OAc)2 (5 mol%) unless other-
wise stated.
b 20% arene methylation, cf. 4.
c Pd(OAc)2 (10 mol%).
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groups, see: (a) Houlden, C. E.; Hutchby, M.; Bailey, C. D.;
Ford, J. G.; Tyler, S. N. G.; Gagne, M. R.; Lloyd-Jones,
Synlett 2009, No. 19, 3103–3106 © Thieme Stuttgart · New York

3106
W. Rauf, J. M. Brown
LETTER
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Synlett 2009, No. 19, 3103–3106 © Thieme Stuttgart · New York