Additive effects in palladium-indium mediated Barbier type allylations

Article abstract of DOI:10.1016/j.tetlet.2003.08.103

The effect of adding 1 equiv. of an amine or 0.2 equiv. of CuI to a Pd/In bimetallic cascade reaction is described. In the class 1 cascade reaction of aldehydes, aryl iodides and allene, generating homoallylic alcohols, the reaction time is reduced from 16 to 2 h and is accompanied by an impressive increase in yield.

Full text of DOI:10.1016/j.tetlet.2003.08.103

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7969–7973
Additive effects in palladium–indium mediated Barbier type
allylations
Laura A. T. Cleghorn,a Ian R. Cooper,a Ronald Grigg,a,* William S. MacLachlanb and
Visuvanathar Sridharana
aMolecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, Department of Chemistry, University of Leeds,
Leeds LS2 9JT, UK
bGlaxoSmithKline, New Frontiers Science Park (North), 3rd Avenue, Harlow, Essex CM19 5AW, UK
Received 25 June 2003; revised 15 August 2003; accepted 29 August 2003
Abstract—The effect of adding 1 equiv. of an amine or 0.2 equiv. of CuI to a Pd/In bimetallic cascade reaction is described. In
the class 1 cascade reaction of aldehydes, aryl iodides and allene, generating homoallylic alcohols, the reaction time is reduced
from 16 to 2 h and is accompanied by an impressive increase in yield.
© 2003 Published by Elsevier Ltd.
The synthesis of homoallylic alcohols via allylation of
carbonyl compounds is a valuable and well studied
synthetic transformation.1 We recently reported a Pd/In
three component allylation cascade of aryl iodides,
aldehydes and allene which has 4 broad synthetic vari-
43 to 83% whilst reducing the reaction time from 16 h
to 2 h. Encouraged by this observation, a series of
amine additives were examined and the results are
summarised in Table 1. For strict comparison purposes
a standard protocol was adopted: iodobenzene (1.5
mmol), benzaldehyde (1 mmol), amine/amide (1 mmol,
1 equiv.), In (1.5 mmol), Pd(OAc)2 (10 mol%) and
tri-(2-furyl)phosphine (TFP) (20 mol%) and allene gas
(ꢀ1 bar) were reacted in DMF at 80°C for 2 h
(Schlenk tube) (Scheme 1). Under these conditions the
reaction fails to occur in the absence of an additive
(Table 1, entry 1).
ants and yields homoallylic alcohols (Scheme 1).2,3
A
key step in this reaction is transmetalation of the elec-
trophilic p-allylpalladium species with indium to give a
nucleophilic allylindium species which subsequently
adds to the carbonyl compound. Related umpolung
processes have been reported by others.4,5 Yields of
homoallylic alcohols from the Scheme 1 process are
frequently modest. We now report that the addition of
1 equiv. of piperidine to the Pd/In cascade reaction of
iodobenzene, benzaldehyde and allene gas (Scheme 1,
Ar=R=Ph (3a)) dramatically increased the yield from
It is mechanistically informative to note, that in the
presence of secondary amine additives, aldehyde cap-
ture by the allylindium species 2 occurs preferentially
over amine capture 1“4 (Scheme 2) by the p-allylpalla-
dium(II) species except when 2 equiv. of piperidine or
piperazine are used (Table 1, entries 3 and 5) and that
capture of the allylindium species 2 by the aldiminium
ion 5“6 is not observed.6
The increase in yield exhibited by each of the additives
shows no correlation with pKa values. Piperidine,
pyrrolidone and pyridine (Table 1, entries 2, 9 and 15)
exhibit a wide range of pKa values yet all dramatically
increase the yield.
Scheme 1.
All the cyclic amines effect an improvement in yield.
Acyclic amines have little or no effect (Table 1, entries
11–14); except for (S)-1-phenylethylamine (Table 1,
Keywords: indium; Barbier allylation; additives.
* Corresponding author. Tel.: +44-113-343-6501; fax: +44-113-343-
6501; e-mail: r.grigg@chem.leeds.ac.uk
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2003.08.103

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L. A. T. Cleghorn et al. / Tetrahedron Letters 44 (2003) 7969–7973
Table 1.
Yield (%a), %b
pKa
c
Entry
Amine additive
Cyclic six-membered amines
1
2
3
4
5
6
None
Piperidine
Piperidine, 2 equiv.
2,2,6,6-Tetramethylpiperidine
Piperazine
(<10), 0
–
(95), 83
11.24
11.24
11.49
9.90
(48), 28d
(<7), 0
(100), 28, 34d
(96), 70
Morpholine
8.97
Cyclic five-membered amines/amides
7
8
9
10
Pyrrolidine
3-Hydroxypyrrolidine
Pyrrolidinone
(100), 47
(100), 69
(100), 78
(100), 88
11.26
10.28
16.62
14.65
Methyl (S)-(+)-pyrrolidinone carboxylate
Acyclic amines
11
12
13
14
Triethylamine
Diethylamine
Diisopropylamine
1,1,3,3-Tetramethyl guanidine
(10), 0
(25), 0
(0), 0
10.62
10.76
10.76
15.20
(0), 0
Aromatic additives
15
16
17
Pyridine
DMAP
Phenol
(80), 74
(55), 41
(17), 0
5.23
9.52
9.86
Chiral amines
18
19
20
(S)-2-Methoxymethylpyrrolidine
(S)-Prolinamide
(S)-1-Phenylethylamine
(95), 85
(90), 80
(80), 70
10.55
9.45
9.75
a Conversion calculated from the NMR of the crude product.
b Isolated yields of 3a after column chromatography unless otherwise stated.
c pKa calculated using ACD pKa predictor.
d Amine captured product.
A second role for the amine additives is to protect the
catalytically active Pd species. The failure of the amines
to compete effectively with In for the p-allylpalladi-
um(II) species and the absence of the iminium ion
derived product 6 provides clear evidence of substantial
rate differences between the three potentially competing
processes.
entry 20) suggesting steric effects are important. This is
reinforced by the use of 2,2,6,6-tetramethylpiperidine
(Table 1, entry 4), where only trace amounts of product
were observed. Pyridine and to a lesser extent DMAP
(Table 1, entries 15 and 16) both show increased con-
versions, again illustrating that pKa is not the important
issue. Interestingly certain cyclic amides promote the
reaction (Table 1, entries 9 and 10), although with
methyl (S)-(+)-pyrrolidinone-5-carboxylate as the addi-
tive no chirality was induced in the final product (chiral
HPLC). (S)-2-Methoxymethylpyrrolidine, (S)-proli-
namide and (S)-1-phenylethylamine gave 85, 80 and
70% yields of the racemic homoallylic alcohol, respec-
tively (Table 1, entries 18, 19 and 20).
Cu(I) salts have been used to improve yields in the
Stille coupling reaction.8 Farina and Liebeskind9,10
describe the ‘copper effect’ as a complex ligand depen-
dent phenomena, in which the concentration of the
phosphine ligand in solution is diminished via complex-
ation to Cu(I). The effect of CuI in the Pd/In Barbier
reaction of benzaldehyde iodobenzene and allene was
examined. Addition of 1 equiv. of CuI resulted in a
yield of 50% (Table 3, entry 1). When both 1 equiv. of
The generality of the amine additive effect was demon-
strated for a variety of aldehydes and aryl iodides using
piperidine as the additive (Table 2). A substantial
improvement in yield was noted in all cases.
One possible role for the amine is to aid solvation of
the indium powder, increasing the concentration of
indium in solution, accelerating the rate of transmetala-
tion. To test this hypothesis, two standard Barbier
reactions7 were performed (Scheme 3), one with 1
equiv. of piperidine, one without. The NMR of the
crude products indicate that after 1 h reaction time, a
higher conversion of aldehyde to product is obtained in
the presence of piperidine. Thus the ratio of 7:9 is 1:1.5
with piperidine and 5:1 in its absence.
Scheme 2.

L. A. T. Cleghorn et al. / Tetrahedron Letters 44 (2003) 7969–7973
7971
Table 2.
Table 3. Copper additives in Pd/In cascade reaction of
benzaldehyde, iodobenzene and allenea
Entry
In (equiv.)
Piperidine
(equiv.)
Additive
(equiv.)
Yield (%)
1
2
3
4b
5
6
7
8
9
1.5
1.5
–
1.5
1.5
1.5
1.5
1.5
1.5
–
1
–
–
–
–
–
–
–
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (0.1)
CuI (0.2)
CuBr (0.1)
CuCl (0.1)
Cu bronze
(1.0)
50
37
0
0
64
88
18
19
53
10
1.5
–
Cu bronze
(0.2)
69
a Standard protocol adopted.
b No Pd(OAc)2 was added to this reaction.
Scheme 4.
equiv. of piperidine as the additive, the reaction time
for these cascades were generally 24–48 h, and showed
moderate yields (Table 4, entries 2 and 4), 0.1 equiv. of
CuI also resulted in moderate yields (Table 4, entries 1
and 3).
Scheme 3.
piperidine and 1 equiv. of CuI were used the yield
decreases, due to complexation of CuI to the piperidine
(Table 3, entry 2). Blank experiments demonstrated
that no reaction was observed in the absence of either
Pd(OAc)2 or In (Table 3, entries 3 and 4). Employing
0.1 equiv. of CuI as the additive gave a 64% yield
(Table 3, entry 5). Using equimolar portions of TFP
and CuI showed the greatest rate acceleration and
yield, 88% (Table 3, entry 6). CuBr and CuCl did not
promote the reaction as well as CuI (Table 3, entries 7
and 8). Copper bronze displays the same reaction pat-
tern as CuI (Table 3, entries 9 and 10).
However with 0.2 equiv. of CuI the reaction proceeded
cleanly, leading to easier isolation and improved yields
(Table 4, entries 5–8). There are two possible products
from the transmetalation of 10 with In via a Zimmer-
man–Traxler transition state, only the product 13
derived from 11 is observed. Further studies of the
effects of additives on Pd/In cascades are underway.
Acknowledgements
Substituted allenes were incorporated into the cascade
(Scheme 4), initially the cascade was attempted with 1
We thank the University of Leeds, GSK and the
EPSRC for support.

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Table 4.
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