On the regiochemistry of nucleophilic attack on 2-halo π-allyl complexes. 4. The effect of silver acetate and nucleophile concentrations in competitive nucleophilic attack with malonate and phenoxide nucleophiles

Article abstract of DOI:10.1021/jo034119c

2,3-Dibromo-l-propene or its allyl carbonate analogue are ionized under Pd catalysis to generate the 2-bromo Pd-π-allyl complex (triphenylphosphine ligand), which alkylates with malonate nucleophile at the terminal position. The presence of acetate ion in

Full text of DOI:10.1021/jo034119c

On the Regiochemistry of Nucleophilic Attack on 2-Halo π-Allyl
Complexes. 4. The Effect of Silver Acetate and Nucleophile
Concentrations in Competitive Nucleophilic Attack with Malonate
and Phenoxide Nucleophiles
Michael G. Organ,* Elena A. Arvanitis, and Stephen J. Hynes
The Department of Chemistry, York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3
organ@yorku.ca
Received January 29, 2003
2,3-Dibromo-1-propene or its allyl carbonate analogue are ionized under Pd catalysis to generate
the 2-bromo Pd-π-allyl complex (triphenylphosphine ligand), which alkylates with malonate
nucleophile at the terminal position. The presence of acetate ion in the reaction mixture results in
some malonate attack being redirected to the central carbon. The acetate ion can come from the
ionization of 1-acetoxy-2-bromo-2-propene or by the addition of silver acetate to the reaction mixture.
The addition of phenoxide ion to the reaction also causes the same regiochemical phenomena,
although harder anions such as methoxide exert no such effect.
It has been known for some time that nucleophiles can
be directed to the central carbon of transition metal
π-allyl complexes.1 In the case where the central carbon
is substituted with a hydrogen (Figure 1, X ) H), the
most common fate is cyclopropane formation (4) via
reductive elimination of the intermediate metallocyclobu-
tane (3).2 However, if the central carbon in 2 is substi-
tuted with a suitable leaving group (e.g., X ) halide),
nucleophilic attack at this position can be followed by
ionization of this group from 3 (Figure 1, path a).3 This
re-establishes a π-allyl complex (5) that can then undergo
a second nucleophilic attack at the terminal position to
produce 6. Terminal attack on π-allyl 2 produces the
simple allylic substitution product 7 (X ) H or halogen)
following path b.
It seems that the choice of path a versus path b may
be closely linked to the type of nucleophile and/or ligands
on the metal. Ba¨ckvall and co-workers demonstrated that
changing the ligands on the metal has a significant effect
on the regioselectivity of the attack of malonate-based
nucleophiles on the initially formed π-allyl complex (2).3
With the aid of calculations and carbon NMR shift
information, this selectivity was attributed to the docking
atom of the ligand affecting electron density to the π-allyl
complex. Phosphines being moderate σ-donors and good
π-acceptors induce a moderate electron deficiency at the
C-termini, hence directing malonate attack to these
positions leading to 7. Amine-based ligands are strong
σ-donors and weak π-acceptors thus increasing the
electron density at the C-termini and directing nucleo-
philic attack at the central position giving rise to 6. After
the release of these results, we showed that the exact
opposite selectivity could be achieved by simply changing
the nucleophile from malonate to phenoxide (i.e., in
Figure 1 Nu1 ) Nu2 ) PhO-).4 This demonstrates that
regioselectivity is under the integrated control of the
nucleophile, the structure of the π-allyl, and the ligands
on the metal.
Murai and co-workers proposed that phenoxide itself
could form a new intermediate catalytic species by
displacing a phosphine from Pd (Figure 2, structure 11)
and it is in fact this entity that is responsible for directing
nucleophilic attack to the central carbon of the 2-halo
π-allyl complex 2.5 In their studies, which involved both
malonate and phenoxide co-nucleophiles, the presence of
phenoxide promoted attack at the middle carbon, even
when phenoxide itself was not incorporated into the
product. This seems to be supported by Ba¨ckvall’s
electronic contentions (vide supra) and by more recent
results6 we have disclosed using bidentate ligands. Of
Murai’s results, we were particularly intrigued by the
reaction of phenyl carbonate 8b (Figure 2), which pre-
(1) (a) Ephritikhine, M.; Green, M. L. H.; MacKenzie, R. E. J. Chem.
Soc., Chem. Commun. 1976, 619-621. (b) Ephritikhine, M.; Francis,
B. R.; Green, M. L. H.; MacKenzie, R. E.; Smith, M. J. J. Chem. Soc.,
Dalton Trans. 1977, 1131-1135. (c) Adam, G. J. A.; Davies, S. G.; Ford,
K. A.; Ephritikhine, M.; Todd, P. F.; Green, M. L. H. J. Mol. Catal.
1980, 8, 15-24.
(2) Simple allylic substrates have been alkylated at the central
carbon leading to cyclopropane formation via reductive elimination of
the intermediate metallacyclobutane, see: (a) Hegedus, L. S.; Dar-
lington, W. H.; Russel, C. E. J. Org. Chem. 1980, 45, 5193-5196. (b)
Hoffmann, H. M. R.; Otte, A. R.; Wilde, A. Angew. Chem., Int. Ed. Engl.
1992, 31, 234-236. (c) Carfagna, C.; Galarini, R.; Musco, A. J. Mol.
Catal. 1992, 72, 19-27. (d) Tjaden, E. B.; Stryker, J. M. J. Am. Chem.
Soc. 1990, 112, 6420-6422.
(4) (a) Organ, M. G.; Miller, M.; Konstantinou, Z. J. Am. Chem. Soc.
1998, 120, 9283-9290. (b) Organ, M. G.; Miller, M. Tetrahedron Lett.
1997, 38, 8181-8184.
(3) (a) Castano, A. M.; Aranyos, A.; Szabo´, K. J.; Ba¨ckvall, J.-E.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2551-2553. (b) Aranyos, A.;
Szabo´, K. J.; Castano, A. M.; Ba¨ckvall, J.-E. Organometallics 1997,
16, 1058-1064.
(5) Kadota, J.; Katsuragi, H.; Fukumoto, Y.; Murai, S. Organome-
tallics 2000, 19, 979-983.
(6) Organ, M. G.; Arvanitis, E. A.; Hynes, S. J. Tetrahedron Lett.
2002, 43, 8989-8992.
10.1021/jo034119c CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/12/2003
3918
J. Org. Chem. 2003, 68, 3918-3922

Nucleophilic Attack on 2-Halo π-Allyl Complexes
FIGURE 1. Regioselectivity of nucleophilic attack on π-allyl complexes.
FIGURE 2. Attack of sodium ethyl 3-oxobutanate on a 2-Cl π-allyl Pd complex.
SCHEME 1
sumably liberates phenoxide following ionization. Al-
though phenoxide was not incorporated at all into the
product, its in-situ liberation in the reaction medium
caused exclusive central carbon attack by the active
methylene compound. Once the π-allyl was reestablished,
O-alkylation took place to provide the furan product 10.
The ethyl carbonate analogue (8a) gave the terminal
attack product 9 only.
ide ion (Scheme 1, Table 1). Treatment of 12a with
malonate in the presence of (PPh3)4Pd led exclusively to
the formation of the terminal attack product 13 (Table
1, Entry 1). However, an equal amount of phenoxide ion
and malonate led to primarily central attack products
(Entry 2). Even when a catalytic amount of phenoxide
was used there was significant central carbon attack
(Entry 3).
In the reaction of 8b, only a very small amount of
phenoxide was available, especially at the beginning
of the reaction. However, phenoxide was being liberated
in proximity to Pd, presumably within a solvent cage sur-
rounding the ion pair, and that may have been sufficient
to alter the regioselectivity of nucleophilic attack.
Assuming for now that a species resembling 11 forms,
we wondered if the central attack regioselectivity was
occurring solely because of the proximity of phenoxide
to the metal following ionization, or if the affinity of the
metal for phenoxide was so high that ligand exchange
with a phosphine was kinetically faster than all other
chemical events. To address this question, we performed
a series of experiments with varying amounts of phenox-
Considering the inherent reactivity of the allylic bro-
mide in 12a, which could be substituted by malonate ion
directly without Pd, the allylic group was changed to
either carbonate or acetate to ensure that no noncata-
lyzed substitutions were taking place. We were surprised
to find that simply changing the leaving group to an
acetate (without phenoxide) led to noticeable formation
of 15 (Entry 4), which was enhanced further by the
addition of phenoxide (Entries 5 and 6). Again, the use
of a catalytic amount of phenoxide also resulted in a shift
toward significant central carbon attack (Entry 7). As of
yet, we have not been able to prepare and characterize a
catalyst bearing a phenoxide ligand(s) that we could use
to provide further evidence for the existence of such a
J. Org. Chem, Vol. 68, No. 10, 2003 3919

Organ et al.
TABLE 1. Reaction Conditions and Product Percentagesa for the Reaction of 12 with Sodium Dimethyl
Methylmalonate under Pd Catalysis in the Presence or Absence of Various Oxygen-Based Anions
phenol
(equiv)
malonate
(equiv)
reaction
entry
X
catalystb
conditions
12
13
14
15
16
12
17
18
1
2
Br
Br
Br
0
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.1
2.1
2.2
1.2
2.2
2.2
2.2
2.2
2.2
2.2
1.2
(PPh3)4Pd
(PPh3)4Pd
(PPh3)4Pd
(PPh3)4Pd
(PPh3)4Pd
(PPh3)4Pd
(PPh3)4Pd
18 h, rt
18 h, rt
4 h, rt
18 h, rt
2 min, rt
16 h, rt
16 h, rt
20 h, rt
5 h, rt
5 min, rt
5 h, rt
4 h, rt
7 h, rt
100
23
77
67
9
2.2
0.10
0
30
-
-
12
23
13
17
27
28
37
7
23
3
4
OAc
20
6
-
41
5
5
OAc
2.2
2.2
0.15
0.15
0
49
19
46
9
6
OAc
9
trace
18
7
OAc
22
53
36
1
8
OAc
(PPh3)4Pd plus 22% TPP
Pd(dppp)2
5
9
OAc
57
13
10
11
12
13
14
15
16
17
18
19
20
OAc
2.1
2.1
0.10
0
Pd(dppp)2
12
17
59
55
88
13
11
2
15
OAc
Pd(dppp)2
2
OAc
Pd(dppp)2
12
100
63
72
72
91
42
5
OCO2Et
OAc
(PPh3)4Pd
0
(PPh3)4Pd plus 10% NaOH
(PPh3)4Pd plus 10% NaOCH3
(PPh3)4Pd plus 4 equiv of NaOAc
(PPh3)4Pd plus 1 equiv of NH4OAc
Pd(dppp)2 plus 4 equiv of NaOAc
(PPh3)4Pd plus 2 equiv of AgOAc
Pd2dba3-CHCl3 Ph3PO (11%)
2.5 h, rt
2.5 h, rt
2.5 h, rt
18 h, rt
1.5 h, rt
2 h, rt
6
1
1
9
46
14
31
28
28
-
OAc
OCO2Et
Br
OCO2Et
OCO2Et
OCO2Et
0
0
0
0
12
0
81
0
20 h, rt
77
23
a Product percentages were determined by 1H NMR spectroscopy of the crude reaction mixture. All relevant signals were well resolved
to obtain very reliable integrations. The structures of all compounds were determined by IR and 1H and 13C NMR spectroscopy with
either combustion analysis or high-resolution mass spectroscopy. b Unless otherwise indicated, 5 mol % catalyst was used in each reaction.
SCHEME 2
catalytic species. None-the less, when we added ad-
ditional TPP (4 equiv relative to Pd atom) to the run
employing catalytic phenoxide the amount of central
carbon attack products dropped significantly (Entry 8).
This indirect evidence suggests that phenoxide is indeed
involved in coordination to Pd and that this event
promotes central carbon attack.
acetate, which could be a solubility issue. In THF, sodium
acetate is quite insoluble, whereas when ionized from 12b
the π-allyl cation maintains it in solution and in proxim-
ity to the metal where complexation and possible ligand
exchange may be happening.
We observed previously that bidentate ligands on Pd
by themselves seem to promote central carbon attack on
the π-allyl complex derived from substrates resembling
12 (Entry 9).6 Further, the presence of phenoxide ion
dramatically enhances this regioselectivity (Entries 11
and 12). It is interesting that when sodium acetate was
added to the reaction with 12c (Entry 18, no added
phenoxide), over half of the addition products isolated
resulted from central carbon attack. This compares to
approximately 20% of the addition products without a
large excess of acetate ion (i.e., 15 7% overall, Entry 9).
We are not sure why additional sodium acetate seemed
to have such a noticeable effect with diphenylphosphi-
nopropane (DPPP) ligand and none with TPP.
Another set of experiments we performed also points
strongly toward altered chemical reactivity of the Pd
catalyst in the presence of acetate ion (Scheme 2). The
dimeric Pd II complex 19 was synthesized following the
procedure disclosed by Ba¨ckvall’s group for the analogous
dichloro compound.3 They reported that cracking the
dimer with AgBF4 followed by the sequential addition of
TPP ligand (2 equiv) and malonate nucleophile resulted
As noted, when compared with all runs involving 12a,
clearly the acetate leaving group in 12b is also playing
some role in promoting central carbon attack. Indeed
when the allylic carbonate in 12c was ionized, only the
terminal attack product 13 was isolated (Entry 13). These
results initially led us to speculate that the proposed
ligand effect of phenoxide might be broadened to other
oxygen-based ligands and perhaps acetate was coordinat-
ing to Pd in a similar fashion. To probe this, a series of
experiments were performed with other oxygen-based
anions and triphenylphosphine oxide ligand (Entries 14,
15, and 20), but none led to significant central carbon
attack products. There were mixed results when a large
excess of sodium acetate was added directly to the
reaction mixture. Although there was no central carbon
attack product with 12a (Entry 1), there was 10% of the
resultant product formed in Entry 17. With 12c (Entry
16), only 13 was produced, thus if acetate ion is exerting
an effect in these reactions, it does not exert a strong
effect when added in the form of sodium or ammonium
3920 J. Org. Chem., Vol. 68, No. 10, 2003

Nucleophilic Attack on 2-Halo π-Allyl Complexes
been reported in the literature previously and sample spectra
are included.
SCHEME 3
To a solution of dimethyl methylmalonate (172 mg, 1.18
mmol) and phenol11 (111 mg, 1.18 mmol) in THF (2 mL) was
added slowly NaH (100 mg, 2.36 mmol of a 60% dispersion in
mineral oil). The resulting solution was stirred for 10 min at
room temperature. Palladium tetrakistriphenylphosphine (32
mg 0.028 mmol) was added followed immediately by a solution
of 1-acetoxy-2-bromo-2-propene (9b) (100 mg, 0.56 mmol) in
THF (2 mL). The resulting orange solution was stirred at room
temperature for 16 h. The orange suspension was diluted with
pentane (4 mL). The precipitated solids were removed by
filtering through glass wool. Solvents were removed in vacuo
to give an oil containing the products 13, 14, 15, and 17 in
the ratio 1:5.44:3.2:2.1, according to the proton NMR spectrum.
The oil was chromatographed (Silica gel, solvent gradient: 10%
ether in pentane to 30% ether in pentane to 50% ether in
pentane) to afford compounds 137 (6 mg, 4%) [1H (400 MHz,
CDCl3), 5.63 (s, 1H), 5.55 (s, 1H), 3.72 (s, 6H), 3.13 (s,2 H),
1.47 (s, 3H)]; 158 (37 mg, 24%) [1H (400 MHz, CDCl3) δ 5.05
(s, 1H), 4.91 (s, 1H), 3.74 (s, 6H), 3.72 (s, 6H), 2.83 (s, 2H),
1.61 (s, 3H), 1.49 (s, 3H)], and a mixture of 14 and 17, which
was rechromatographed (Silica gel 15% ether in pentane) to
give 149 (38 mg, 20%) [1H (400 MHz, CDCl3) δ 7.29-7.25 (m,
2H), 6.96-6.93 (m, 3H), 5.53 (s, 1H), 5.30 (s, 1H), 4.69 (s, 2H),
3.74 (s, 6H), 1.72 (s, 3H); 13C NMR (100 MHz, CDCl3) 171.1,
158.5, 141.7, 129.3, 129.2, 121.0, 116.4, 114.9, 68.9, 52.8, 48.1,
in terminal attack only. We performed these experi-
ments with 12a and either TPP or BINAP ligand but with
one notable exception, silver acetate was employed to
scavenge the halide rather than the tetrafluoroborate
salt. Strikingly, this simple change completely reversed
the regioselectivity of malonate attack from what Ba¨ck-
vall observed. When the same sequence was conducted
with equal amounts of malonate and phenoxide anions,
only central carbon attack products were isolated al-
though this time 15 was formed in trace amounts only
(Scheme 3).
The reason for performing the reaction via intermedi-
ate 19 was to quantitatively produce the π-allyl inter-
mediate with use of stoichiometric Pd and two ligands
of TPP. Presumably, this would ensure that the exact
structure of the catalyst was known at the stage in the
cycle immediately before the first nucleophilic attack.
Alternatively, we treated 12a and 12d with a solution
containing 1 equiv of (PPh3)4Pd and AgOAc followed by
a second solution containing malonate and phenoxide
nucleophiles (Scheme 4). This should lead to the same
catalytic species/intermediate being generated in the
reactions outlined in Schemes 2 and 3. Again, primarily
central attack products were obtained.
We performed another reaction with silver acetate,
only this time we used catalytic Pd with substrate 12c
(Entry 19). Although the reaction did not go to comple-
tion, clearly the amount of central attack product has
been enhanced markedly when compared with the same
reaction without this additive (Entry 13). It could be that
silver is affecting the Pd-π-allyl complex directly, but
Ba¨ckvall’s results3 with AgBF4 cast doubt on this. That
is, under otherwise identical conditions, his group ob-
served terminal attack exclusively with malonate nu-
cleophile. It is more likely that silver solubilizes acetate
better than the other cations used in this report. This
would make acetate more available to Pd, and once
coordinated produce a new catalytic species with new
properties.
In summary, the regioselectivity of nucleophilic attack
on the Pd-π-allyl complexes derived from substrates
resembling 12 is changed dramatically in the presence
of phenoxide-based anions. With TPP-coordinated Pd
catalysts, malonate-based nucleophiles on their own tend
to attack the terminus of the π-allyl complex. Once
phenoxide ion is added to the same reaction, central
attack now dominates, both by the phenoxide and mal-
onate nucleophiles. Further, this effect is also seen with
acetate ion and the effect is greatest with silver as the
counterion. Our studies in this area are ongoing.
20.8; IR (thin film) 3056, 2986, 2253, 1732, 1259, 910 cm-1
]
and 17 (11 mg, 7%) [1H (400 MHz, CDCl3), 7.34-7.31 (m, 2H),
7.13-7.03 (m, 3H), 4.14 (s, 1H), 3.94 (s, 1H), 3.94 (s, 6 H), 2.94
(s, 2H), 1.72 (s, 3H)].
Formation of Dimer 19. To a solution of palladium(II)
dichloride (5.64 mmol, 1 g) and lithium chloride (18.9 mmol,
0.8 g, 3.3 equiv) in water (1.5 mL) was added a solution of
2,3-dibromopropene (16.9 mmol, 1.75 mL, 3 equiv) and MeOH
(30 mL). Carbon monoxide was bubbled through the solution
until the mixture turned yellow from the initial red-brown (a
yellow precipitate was gradually formed). The reaction mix-
ture was poured into H2O (500 mL) and extracted into CHCl3
(500 mL in small portions). The combined organic extracts
were dried over anhydrous MgSO4, filtered, and evaporated
in vacuo to give an orange-yellow solid. Recrystallization from
CHCl3 gave a yellow solid (0.95 g, 11%): mp 145 °C; 1H NMR
(400 MHz, CDCl3) δ 4.47 (s, 2H), 3.43 (s, 2H). Anal. Calcd for
C6H8Br4Pd2: C, 11.76; H, 1.31. Found: C, 11.42; H, 1.18.
Reaction of Dimer 19 with Sodium Dimethyl Methyl-
malonate in the Presence of Silver Acetate and TPP
Ligand.10 To a solution of 19 (0.1 mmol, 52.3 mg) in THF (7
mL) under N2 was added silver acetate (0.2 mmol, 33.4 mg, 2
equiv). The suspension was stirred for 15 min and filtered
through filter paper under vacuum; the solid was rinsed with
THF (2 mL) and the filtrate was collected in a flask containing
TPP (0.5 mmol, 131.1 mg, 5 equiv). To the resultant yellow
solution was added a solution of freshly prepared sodium
dimethyl methylmalonate anion (0.4 mmol, 4 equiv) in THF
(5 mL). The reaction mixture became gradually cloudy and was
stirred for 6.5 h before being quenched with H2O and parti-
tioned between Et2O and 2 M aqueous NaOH. The organic
phase was dried over anhydrous MgSO4 and filtered, and the
solvent was removed in vacuo to give a black residue (221.0
mg) containing only 15, as indicated by the 1H NMR spectrum
of the crude mixture.
(7) NMR spectral data correspond to literature data: Organ, M. G.;
Arvanitis, E. A.; Dixon, C. E.; Cooper, J. T. J. Am. Chem. Soc. 2002,
124, 1288-1294.
(8) NMR spectral data correspond to literature data, see ref 3b.
(9) NMR spectral data correspond to literature data for analogous
ethyl diester, see ref 5.
(10) The same reaction conditions were used for the BINAP ligand.
(11) Note for reactions involving catalytic amounts of sodium
phenoxide, the NaOPh was prepared separately and mixed with the
Pd catalyst before addition to the reaction flask.
Experimental Procedures
All reactions in Table 1 were performed by using the
following procedure outlined for Entry 6. All compounds have
J. Org. Chem, Vol. 68, No. 10, 2003 3921

Organ et al.
SCHEME 4
Reaction of Dimer 19 with Sodium Dimethyl Methyl-
malonate and Sodium Phenoxide in the Presence of
Silver Acetate and TPP Ligand. To a solution of 19 (0.1
mmol, 52.1 mg) in THF (2 mL) was added silver acetate (0.2
mmol, 33.4 mg, 2 equiv) under N2. The suspension was stirred
for 10 min before being filtered; the precipitate was washed
with THF (2 mL) and the filtrate was collected in a flask
containing phosphine (0.5 mmol, 131.1 mg, 5 equiv). To the
resultant yellow solution was added a solution of freshly
prepared sodium phenoxide (0.4 mmol, 4 equiv) and sodium
dimethyl methylmalonate (0.4 mmol, 4 equiv) in THF (4.5 mL)
dropwise via cannula; the solution became instantly red and
turned gradually orange and cloudy over 5 min. The reaction
mixture was stirred for 2 h before being quenched with H2O
and partitioned between Et2O and 2 M aqueous NaOH. The
organic phase was dried over anhydrous MgSO4, filtered over
Celite, and evaporated under vacuum to give a brown liquid
(0.207 g) containing 14 and 17 in a ratio of 1:1, as indicated
by the 1H NMR spectrum of the crude product. The crude
mixture was purified by flash chromatography (hexanes:ether,
4:1) to afford 26 mg of both products.
Acknowledgment. This work was funded by NSERC
Canada and the Ontario Research and Development
Challenge Fund (ORDCF).
JO034119C
3922 J. Org. Chem., Vol. 68, No. 10, 2003