Studies on the heck reaction with alkenyl phosphates: Can the 1,2-migration be controlled? Scope and limitations

Article abstract of DOI:10.1021/ja070321b

A catalyst system was identified which promotes the Heck coupling of nonactivated vinyl phosphates with electron deficient alkenes providing a new entry to diene products from simple and readily accessible starting materials. In contrast to our earlier wo

Full text of DOI:10.1021/ja070321b

Published on Web 05/03/2007
Studies on the Heck Reaction with Alkenyl Phosphates: Can
the 1,2-Migration Be Controlled? Scope and Limitations
Jean-Philippe Ebran, Anders L. Hansen, Thomas M. Gøgsig, and Troels Skrydstrup*
Contribution from The Center for Insoluble Protein Structures (inSPIN), Department of
Chemistry, and the Interdisciplinary Nanoscience Center, UniVersity of Aarhus, Langelandsgade
140, 8000 Aarhus, Denmark
Received January 16, 2007; E-mail: ts@chem.au.dk
Abstract: A catalyst system was identified which promotes the Heck coupling of nonactivated vinyl
phosphates with electron deficient alkenes providing a new entry to diene products from simple and readily
accessible starting materials. In contrast to our earlier work exploiting P(t-Bu)3 as the ligand in the presence
of PdCl2(COD), the application of Buchwald’s dialkylbiarylphosphines, X-Phos, effectively promoted the
vinylic substitution with a wide range of alkenyl phosphates in the presence of 10 equiv of lithium chloride.
Importantly, these reaction conditions suppressed 1,2-migration of the alkenyl palladium(II) intermediate.
Further studies are also reported with the catalytic system which encourages isomerization in order to
determine the range of vinyl phosphates that may participate in these coupling reactions. The extent of the
1,2-migration was dependent on the C1-substituent where best results were noted for substrates possessing
a C1-alkyl quaternary carbon. Hence, with certain members of this class of alkenyl phosphates either the
migrated or nonmigrated Heck products may be preferentially synthesized by selection of the phosphine
ligand. Finally, competition experiments between an unactivated aryl chloride and a vinyl phosphate with
a palladium catalyst possessing either X-Phos or P(t-Bu)3 as ligand demonstrated the ability to carry out
Heck coupling reactions selectively with the aryl halide. Oxidative addition of the metal catalyst into the
aryl chloride bond rather than the C-O bond of the alkenyl phosphate is therefore preferred.
Introduction
bromides coupled to olefins bearing an electron withdrawing
substituent such as -CO2R, -Ph, or -CN. As with other cross
The palladium(0)-catalyzed arylation or vinylation of olefins,
more commonly referred to as the Heck reaction, represents a
well-established method for carbon-carbon bond formation in
organic synthesis on both a laboratory and industrial scale.1-4
So far the majority of the published work concerning Heck
reactions has focused on the use of either aryl/vinyl iodides or
coupling reactions, extensive efforts particularly from the groups
of Fu,5 Hartwig,6 Beller,7 and Herrmann8 and others have been
made in recent years to include aryl chlorides as a viable Heck
reagent notably due to the considerably lower commercial costs
of such compounds compared to the other aryl halides.9,10
Aryl and alkenyl triflates or nonaflates also represent valuable
coupling partners for the Heck reaction in couplings with both
electron deficient and electron rich olefins.2h,11,12 In this way,
the repertoire of coupling reagents can be expanded to include
(1) (a) Heck, R. F. Synlett 2006, 2855. (b) Heck, R. F.; Dieck, H. A. J. Am.
Chem. Soc. 1974, 96, 1133. (c) Mizoroki, T.; Mori, K.; Ozaki, A. Bull.
Chem. Soc. Jpn. 1973, 46, 1505. (d) Heck, R. F.; Nolley, J. P. J. Org.
Chem. 1972, 37, 2320. (e) Heck, R. F. J. Am. Chem. Soc. 1971, 93, 6896.
(f) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44, 581.
(2) For reviews of the Heck reaction, see: (a) Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; J. Wiley & Sons: New
York, 2002. (b) Whitcombe, N. J.; Hii, K. K. M.; Gibson, S. E. Tetrahedron
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100, 3009. (d) Tsuji, J. Transition Metal Reagents and Catalysts: InnoVa-
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Candiani, I. Acc. Chem. Res. 1995, 28, 2. (i) de Meijere, A.; Meyer, F. E.
Angew. Chem., Int. Ed. Engl. 1994, 33, 2379. (j) Heck, R. F. In
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(3) For reviews on the applications of the Heck reaction in natural product
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Chem. ReV. 2003, 103, 2945. (c) Shibasaki, M.; Vogl, E. M. J. Organomet.
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9
10.1021/ja070321b CCC: $37.00 © 2007 American Chemical Society
J. AM. CHEM. SOC. 2007, 129, 6931-6942
6931

A R T I C L E S
Ebran et al.
Scheme 1
phenols and alkyl ketones. Nevertheless, there are some concerns
which limit the use of aryl and alkenyl triflates or nonaflates.
Instability issues as well as the requirement of expensive
triflating and nonaflating agents for the synthesis of the Heck
precursors are major disadvantages, and hence alternative and
less costly means for activating phenols or alkyl ketones would
therefore be welcomed.13-19
As a potential substitute for alkenyl triflates and nonaflates,
the corresponding tosylates and phosphates have proven their
worth in a variety of cross coupling reactions such as the Stille,20
Negishi,21 Suzuki,20a,22 Kumada,23 Sonogashira,20a,24 amination/
amidation (Buchwald-Hartwig),23c,25 and carbonyl enolate
arylations.22e However, in many instances efforts were concen-
trated on the use of activated vinyl tosylates and phosphates
such as R,â-unsaturated esters and ketones or R-heteroatom
substituted olefins, as the oxidative addition step in these systems
with the common palladium(0) catalysts employing aryl phos-
phine ligands proceed under relatively mild conditions. We and
others have also recently demonstrated the similar exploitation
of activated vinyl tosylates and mesylates as a substitute for
the corresponding triflates in the Heck reaction with vinyl
amides and ethers.26
Considerable efforts have been directed over the past few
years to increase the scope of these coupling reactions with
nonactivated alkenyl tosylates and phosphates, as well as the
complementary derivatives of phenols. Two approaches have
been adopted to overcome the challenging step of the catalytic
cycle represented by the oxidative addition into the C-O
bond: either Pd(0)-centered catalysts possessing bulky electron
rich phosphine ligands that facilitate the preliminary step of the
catalytic cycle have been applied21a,b,22d,h,23a-c,24a,25a,b or alterna-
tive more reactive transition metal systems such as Ni(0)
complexes were explored.21c,22a,b,e,j,l,m,23d-f In these difficult
cases, less attention has been devoted to the Heck reaction,
which may also be related to the dissimilarities in reaction
mechanisms between the different transition metal catalyzed
coupling reactions. For example, whereas Ni(0)-based catalyst
systems can promote Suzuki cross couplings between aryl and
vinyl tosylates or phosphates with aryl boronic acids under mild
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6932 J. AM. CHEM. SOC. VOL. 129, NO. 21, 2007

Heck Reaction with Alkenyl Phosphates
A R T I C L E S
Scheme 2
conditions,22b,e,j,l,m similar Ni(0)-promoted Heck couplings with
electron deficient alkenes are less efficient necessitating high
reaction temperatures (ca. 150 °C) due to a slow â-elimination
step of the alkyl Ni(II) intermediate.27
In an earlier communication, we reported the Heck coupling
of nonactivated cyclic alkenyl tosylates with a variety of electron
deficient olefins (Scheme 1).28 We established that these
vinylations could effectively be promoted by the combination
of PdCl2(COD) and P(t-Bu)3 with Cy2NMe as a base in DMF,
conditions which were similar to those developed by Fu and
co-workers for the Heck coupling of aryl chlorides.5b,d However,
for successful C-C bond formation, the addition of 1 equiv of
LiCl was obligatory.
This catalytic system was also extended to the Heck reactions
of several simple acyclic vinyl tosylates and two phosphates.29
Unexpectedly, in the case of alkenes possessing a large C1-
substituent represented by a tert-butyl or a trimethylsilyl group,
coupling products resulting from an effective 1,2-migration were
obtained in yields attaining 95% (Scheme 2).28,30 1,2-Migrations
are quite rare for Pd(0)-catalyzed coupling reactions having only
briefly been reported in two other occasions. Hartwig and co-
workers described a single case of this rearrangement in the
Pd(0)-catalyzed Kumada coupling of alkenyl tosylates using
Josiphos-type ligands,23b whereas the group of Miyaura observed
1,2-migration as a biproduct in the Pd-catalyzed synthesis of
vinyl boronic esters.31
or phosphate (Figure 1). Such an arrangement, which has earlier
been reported for Pd(II) complexes possessing bulky phosphine
ligands, deviates from the normal tetracoordinated square planar
complexes by possessing a free coordination site.32 Hence,
â-hydride elimination is facilitated generating the tert-butyl
acetylene hydride palladium(II) complex B, whereafter rotation
of the acetylene group and hydropalladation then afford the
alternative tricoordinated T-shaped palladium species C. DFT
calculations performed with these intermediates of the catalytic
cycle suggested that the highest barrier for isomerization
between A and C was only 62 kJ/mol implying that migration
is rapid under the reaction conditions used.28 On the other hand,
carbopalladation represented the rate determining step where
insertion was found to be more favored for intermediate C
than A.
Ideally, catalysts which can either effectively promote or
prevent the 1,2-migration using alkyl or aryl vinyl phosphates
as substrates in the Heck reaction would be of high interest. In
this paper, we report full studies on the achievement of one of
these goals with the identification of a catalytic system
consisting of a Pd(0) catalyst with an alternative, sterically
hindered, and electron rich phosphine which promotes the Heck
coupling without migration between a wide variety of aryl and
alkyl vinyl phosphates with olefins in good yields. Furthermore,
we have performed additional experiments to examine the scope
and limitations of the 1,2-migration in the Heck coupling with
vinyl phosphates and to further understand the factors which
control the 1,2-migration. Our work demonstrates that with
certain reactants the Heck reaction can be promoted with or
without the 1,2-migration through the proper choice of the
catalyst composition and additive. This work extends the utility
of this valuable carbon-carbon bond forming reaction.
To explain the 1,2-migration observed for these Heck
reactions, we proposed that a tricoordinated T-shaped Pd(II)
complex A formed after the oxidative addition was the key to
the rearrangements observed with the 1-tert-butyl vinyl tosylate
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(29) For the only other Pd-catalyzed Heck reaction with a vinyl phosphate, see:
Coe, J. W. Org. Lett. 2000, 2, 4205.
(30) For examples of other migrations in Pd(0)-catalyzed reactions, see: (a)
Fayol, A.; Fang, Y. Q.; Lautens, M. Org. Lett. 2006, 8, 4203. (b) Lautens,
M.; Jafarpour, F Org. Lett. 2006, 8, 3601. (c) Zhao, J.; Larock, R. C. J.
Org. Chem. 2006, 71, 5340. (d) Masselot, D.; Charmant, J. P. H.; Gallagher,
T. J. Am. Chem. Soc. 2006, 128, 694. (e) Mota, A. J.; Dedieu, A.
Organometallics 2006, 25, 3130. (f) Bressy, C.; Alberico, D.; Lautens, M.
J. Am. Chem. Soc. 2005, 127, 13148. (g) Ma, S.; Gu, Z. Angew. Chem.,
Int. Ed. 2005, 44, 7512. (h) Zhao, J.; Larock, R. C. Org. Lett. 2005, 7,
701. (i) Faccini, F.; Motti, E.; Catellani, M. J. Am. Chem. Soc. 2004, 126,
78. (j) Huang, Q.; Campo, M. A.; Yao, T.; Tian, Q.; Larock, R. C. J. Org.
Chem. 2004, 69, 8251. (k) Campo, M A.; Huang, Q.; Yao, T.; Tian, Q.;
Larock, R. C. J. Am. Chem. Soc. 2003, 125, 11506. (l) Karig, G.; Moon,
M. T.; Thasana, N.; Gallagher, T. Org. Lett. 2002, 4, 3115. (m) Lautens,
M.; Piguel, S. Angew. Chem., Int. Ed. 2000, 39, 1045. (n) Catellani, M.;
Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 119. (o)
Catellani, M.; Fagnola, M. C. Angew. Chem., Int. Ed. Engl. 1994, 33, 2421.
(31) Takagi, J.; Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Am. Chem. Soc.
2002, 124, 8001.
Results and Discussion
Heck Coupling Conditions without 1,2-Migration. We
hypothesized in our earlier work that a key factor to the
observation of 1,2-migrations in the Heck coupling of alkenyl
tosylates and phosphates was the formation of a tricoordinated
Pd(II) complex after the oxidative addition step thereby provid-
ing a free site on palladium for the ensuing â-elimination step.
Figure 1. Proposed mechanism for the 1,2-migration.
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J. AM. CHEM. SOC. VOL. 129, NO. 21, 2007 6933

A R T I C L E S
Ebran et al.
Table 1. Optimization Studies in the Heck Coupling of Vinyl Phosphates
entry
“Pd”/ligand
solvent
conversiona (yield)b
2:3
1
2
3
4
5
6
7
8
PdCl2(COD), S-Phos
PdCl2(COD), X-Phos
PdCl2(COD), L1
PdCl2(COD), L2
PdCl2(COD), L3
PdCl2(COD), cataXCium PtB
PdCl2(COD), cataXCium Pcy
PdCl2(COD), cataXCium PintB
PdCl2(COD), cataXCium PintCy
SK-CCO1-A
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
33%
48% (37%)
<5%
<5%
38%
22%
>99:1
>99:1
>99:1
<5%
<5%
9
<5%
10
11
12
13
14
47%
>99:1
>99:1
54/46
>99:1
>99:1
SK-CCO2-A
13%
21%
23%
56% (45%)
PdCl2(COD), X-Phosc
PdCl2(COD), X-Phos
PdCl2(COD), X-Phos
Dioxane
DMF-Dioxaned
1
b
c
d
a Conversion determined by H NMR spectrum of crude product. Isolated yields after chromatography purification. Reaction run at 140 °C. 1:1 ratio.
Table 2. Studies on the Effect of Additives
entry
catalytic system
additives (X equiv)
conversiona (yield)b
1
2
3
4
5
6
7
8
PdCl2(COD) (2.5%), X-Phos (5%)
PdCl2(COD) (2.5%), X-Phos (5%)
PdCl2(COD) (2.5%), X-Phos (5%)
PdCl2(COD) (2.5%)c
PdCl2(COD) (2.5%), X-Phos (5%)
PdCl2(COD) (2.5%), X-Phos (2.5%)
PdCl2(COD) (5%), X-Phos (5%)
SK-CCO1-A (5%)
LiCl (2)
LiCl (4)
70%
86%
99%
10%
<5%
77%
LiCl (10)
LiCl (10)
NaCl (10)
LiCl (10)
LiCl (10)
LiCl (10)
100% (91%)
90%
1
b
c
a Conversion determined by H NMR spectrum of crude product. Isolated yield after chromatography purification. Only DMF was used as solvent.
This latter step could potentially be hindered through the use
of a bidentate type ligand which prevents interaction of the metal
center with the vinylic hydrogen. To this end, experiments were
conducted to identify suitable reaction conditions for the
coupling of 1-tert-butylvinyl O,O-diphenyl phosphate (1) with
N-tert-butyl acrylamide examining a wide range of phosphine
9
6934 J. AM. CHEM. SOC. VOL. 129, NO. 21, 2007

Heck Reaction with Alkenyl Phosphates
A R T I C L E S
Table 3. Heck Coupling of Primary and Secondary Alkenyl Vinyl Phosphates without Migration
b
1
c
a Isolated yield after chromatography purification. Conversion determined by H NMR spectrum of crude product. Reaction after 72 h.
ligands in combination with the palladium source, PdCl2(COD)
(Table 1). The alkenyl phosphates used in these studies were
easily prepared from the corresponding ketones via an initial
deprotonation step with LHMDS in THF at -78 °C followed
by the addition of a slight excess of diphenyl phosphoryl
chloride.23b,28 As the cost of the phosphorylation reagent is
considerably less than that of tosyl anhydride required for the
preparation of the corresponding vinyl tosylates, the following
study was continued primarily with the alkenyl phosphates.33
Preliminary screenings were performed with a variety of
commercially available bidentate ligands including dppe, dppp,
(33) Aldrich prices from the 2007 catalogue on reagent grade compounds in
euro/mol: tosyl anhydride ) 1781 euro (50 g package of >95% purity),
diphenyl phosphoryl chloride ) 135 euro (100 g package of 96% purity).
(32) Stambuli, J. P.; Incarvito, C. D.; Bu¨hl, M.; Hartwig, J. F. J. Am. Chem.
Soc. 2004, 126, 1184.
9
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A R T I C L E S
Ebran et al.
Table 4. Heck Coupling of Quaternary Alkyl and Aryl Vinyl Phosphates without Migration
b
1
a Isolated yield after chromatography purification. Conversion determined by H NMR spectrum of crude product.
dppb, dppf, btbpf, BINAP, and the Josiphos class of ligands
(results not shown). All reactions were run for 24 h in DMF at
100 °C with a catalyst loading of 5 mol %, dicyclohexyl-
methylamine (Cy2NMe) as the base, and 1 equiv of LiCl in
order to avoid the presence of the Pd(II) cationic species.
Whereas low conversion was observed in some cases (<10%),
it was interesting to note that only the Heck product without
migration could be observed. The use of the tertiary amine base
Cy2NMe proved to be the most adequate compared to other
organic bases such as DIPEA or NEt3 and inorganic bases such
as Cs2CO3 or K2CO3 (results not shown).
More promising results were obtained upon examining a
variety of the commercially available dialkylbiarylphosphines
introduced by Buchwald34 (Table 1, entries 1-5), as such
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6936 J. AM. CHEM. SOC. VOL. 129, NO. 21, 2007

Heck Reaction with Alkenyl Phosphates
A R T I C L E S
Table 5. Heck Coupling of 1,2-disubstituted Alkyl Vinyl Phosphates without Migration
b
1
c
a Isolated yield after chromatography purification. Ratio of isomers determined by H NMR spectrum of crude product. See Supporting Information.
dConfiguration of the major isomer was determined by single-crystal X-ray analysis to be the Z-isomer (see Supporting Information).
ligands are both electron rich and, as demonstrated with S-Phos
and X-Phos, display an ability to coordinate to the metal center
via interaction with the biaryl unit.35 X-Phos, S-Phos, and L3
promoted the Heck coupling and importantly without migration
(entries 1 and 2), although conversions were moderate.36,37 As
in the earlier reactions with P(t-Bu)3, the addition of LiCl was
mandatory for any conversion in these vinylation reactions. Of
the range of other catalyst systems tested (entries 6-11), only
the Solvias palladium(II) catalyst (SK-CCO1-A, entry 10)38
demonstrated comparable reactivity to that of the combination
of PdCl2(COD) and X-Phos with the sole formation of the
diene 2.
Further optimization studies performed with X-Phos (Table
1, entries 12-14) revealed that the use of the solvent mixture
DMF/dioxane (1:1) led to a slight improvement in the conver-
sion of 1. However, as illustrated in Table 2 (entries 1-3), a
remarkable positive effect was observed upon increasing the
number of equivalents of LiCl to 10 equiv resulting in a
quantitatiVe conVersion. Furthermore, a catalyst loading of 5
mol % with a Pd/ligand ratio of 1:1 furnished the most reliable
system in the subsequent studies. Under these conditions, a
satisfactory 91% isolated yield of the Heck product 2 was
obtained (entry 7).39 Interestingly, the catalyst SK-CCO1-A also
displayed improved catalytic behavior when subjected to excess
LiCl (entry 8) leading to a 90% conversion of the vinyl
phosphate 1.
(34) (a) Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2006, 45, 3484. (b) Burgos, C. H.; Barder, T.; Huang, X.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2006, 45, 4321. (c) Anderson, K. W.; Ikawa,
T.; Tundel, R. E.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 10694.
(d) Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45,
6173. (e) Anderson, K. W.; Tundel, R. E.; Ikawa, T.; Altman, R. A.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 6523 and references
cited therein.
(35) (a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685. (b) Barder, T. E. J. Am. Chem. Soc. 2005,
127, 898. (c) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S.
L. Angew. Chem., Int. Ed. 2004, 43, 1871. (d) Kocovsky, P.; Vyskocil, S.;
Cisarova, I.; Sejbal, J.; Tislerova, I.; Smrcina, M.; Lloyd-Jones, G. C.;
Stephen, S. C.; Butts, C. P.; Murray, M.; Langer, V. J. Am. Chem. Soc.
1999, 121, 7714.
(36) For two examples of successful Heck reactions exploiting X-Phos as ligand,
see: (a) Cameron, M.; Foster, B. S.; Lynch, J. E.; Shi, Y.-J.; Dolling, U.-
H. Org. Process Res. DeV. 2006, 10, 398. (b) Jia, Y.; Zhu, J. J. Org. Chem.
2006, 71, 7826.
(37) (a) Harkal, S.; Kumar, K.; Michalik, D.; Zapf, A.; Jackstell, R.; Rataboul,
F.; Riermeier, T.; Monsees, T.; Beller, M. Tetrahedron Lett. 2005, 46, 3237.
(b) Rataboul, F.; Zapf, A.; Jackstell, R.; Harkal, S.; Riermeier, T.; Monsees,
A.; Dingerdissen, U.; Beller, M. Chem. Eur. J. 2004, 10, 2983.
(38) (a) Blaser, H.-U.; Indolese, A.; Naud, F.; Nettekoven, U.; Schnyder, A.
AdV. Synth. Catal. 2004, 346, 1583. (b) Schnyder, A.; Indolese, A. F.;
Studer, M.; Blaser, H.-U. Angew. Chem., Int. Ed. 2002, 41, 3668.
We then proceeded to examine the generality of these reaction
conditions with a variety of primary and secondary alkyl vinyl
phosphates and electron deficient alkenes. As depicted in Table
3, the normal Heck product could be isolated in all cases in
(39) Possible explanations for the LiCl effect in these reactions could be (a) an
increase in the ionic strength of the solvent facilitating the oxidative
additions step in much the same manner as with Heck reactions performed
in ionic liquids (refs 10a, 11b, 40) or under ligandless conditions as reported
by Jeffery and others (ref 41), or (b) the greater number of equivalents of
LiCl may augment the concentration of a more reactive anionic Pd(0)
complex in equilibrium with its neutral species (refs 11h, 12a, 15c,e, 42,
43).
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A R T I C L E S
Ebran et al.
Table 6. Heck Coupling of Quaternary Alkyl Vinyl Phosphates with 1,2-Migration
1
b
c
1
a Conversion determined by H NMR spectrum of crude product. Isolated yield after chromatography purification. Ratio of isomers determined by H
d
NMR spectrum of crude product. No reaction.
moderate to good yields. Reactions were stopped after 24 h for
the sake of comparison of substrate reactivity, but longer reaction
times could nevertheless be applied providing evidence for the
high stability of the catalytic system. For example, the 1-methyl
vinyl phosphate exhibited a mediocre reactivity (entry 1)
compared to the other phosphates but, by increasing the reaction
time to 72 h, furnished a 65% yield of the diene system (entry
2). Alkenyl phosphates carrying other alkyl groups including
rings at the C1-position proved to be sufficiently reactive with
N-tert-butyl acrylamide (entries 3, 4, and 6-8) under these
catalytic conditions. Partial isomerization of the unsaturation
in the product was observed, however, in coupling reactions
performed with styrene (entries 5 and 10).
reaction with acrylamide, styrene, or acrylate in yields ranging
from 49 to 93% (Table 4, entries 1-8). Both simple and more
functionalized C1-substituted vinyl phosphates coupled smoothly
with excellent regioselectivity in favor of the nonmigrated
products. Aryl vinyl phosphates were also suitable for these
coupling reactions as revealed with the three examples in entries
9-11, generating 3-aryl dienes in good yields.
To complete this initial study, a few examples of Heck
reactions between 1,2-disubstituted vinyl phosphates and N-tert-
butyl acrylamide were tested as illustrated in Table 5. Although
the coupling yields were in general good, in most cases some
scrambling of the stereochemistry at the terminal alkene position
was observed (entries 1-5). As exemplified with the N-vinyl
oxazolidinone derivative in entry 5, its coupling furnished the
disubstituted pentadienamide in 80% yield as a 7:3 mixture of
A series of vinyl phosphates possessing a C1-quaternary
carbon were examined leading to the required dienes upon Heck
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6938 J. AM. CHEM. SOC. VOL. 129, NO. 21, 2007

Heck Reaction with Alkenyl Phosphates
A R T I C L E S
Table 7. Heck Coupling of Aryl Vinyl Phosphates with 1,2-Migration
1
b
c
1
a Conversion determined by H NMR spectrum of crude product. Isolated yield after chromatography purification. Ratio of isomers determined by H
d
NMR spectrum of crude product. Reaction carried out at 60 °C.
stereoisomers. The stereochemical assignments of the products
were established by an X-ray structural analysis of the major
product (see Supporting Information). Either thermal isomer-
ization or readdition of the Pd-H intermediate and subsequent
elimination may account for the mixture of stereoisomers
obtained in these cases.
Even the 1,2-disubstituted vinyl phosphate illustrated in Table
5, entry 1, failed to undergo a coupling reaction with the
acrylamide. On the other hand, similar reactions with the
corresponding tosylate resulted only in the disappearance of the
(40) (a) Cassol, C. C.; Umpierre, A. P.; Machado, G.; Wolke, S. I.; Dupont, J.
J. Am. Chem. Soc. 2005, 127, 3298. (b) Xiao, J.-C.; Twamley, B.; Shreeve,
J. M. Org. Lett. 2004, 6, 3845. (c) Vallin, K. S. A.; Emilsson, P.; Larhed,
M.; Hallberg, A. J. Org. Chem. 2002, 67, 6243.
(41) (a) Pryjomska-Ray, I.; Trzeciak, A. M.; Zio´łlkowski, J. J. J. Mol. Cat. A:
Chem. 2006, 257, 3. (b) Reetz, M. T.; de Vries, J. G. Chem. Commun.
2004, 14, 1559. (c) Yao, Q.; Kinney, E. P.; Yang, Z. J. Org. Chem. 2003,
68, 7528. (d) Kogan, V.; Aizenshtat, Z.; Popovits-Biro, R.; Neumann, R.
Org. Lett. 2002, 4, 3529. (e) Reetz, M. T.; Westermann, E. Angew. Chem.,
Int. Ed. 2000, 39, 165. (f) Gu¨rtler, C.; Buchwald, S. L. Chem. Eur. J. 1999,
5, 3107. (g) Jeffery, T. Tetrahedron 1996, 52, 10113. (h) Jeffery, T.;
Galland, J.-C. Tetrahedron Lett. 1994, 35, 4103. (i) Jeffery, T. J. Chem.
Soc., Chem. Commun. 1984, 1287.
(42) (a) Camp, D.; Matthews, C. F.; Neville, S. T.; Rounes, M.; Scott, R. W.;
Truong, Y. Org. Process Res. DeV. 2006, 10, 814. (b) Amatore, C.; Jutand,
A. Acc. Chem. Res. 2000, 33, 314.
(43) Interestingly, in the synthesis of a GABA R2/3 agonist, Cameron and
coworkers observed a positive effect on the addition of ammonium salts
in a Heck coupling exploiting Pd(OAc)2 and X-phos as the catalytic system
(see ref 36a).
Scope and Limitations of the Heck Coupling with 1,2-
Migration. With the identification of suitable reaction conditions
which promote Heck couplings with alkenyl phosphates, we
then proceeded to examine the scope and limitation of similar
coupling reactions under conditions which promote 1,2-migra-
tion as previously published with the 1-tert-butyl vinyl phosphate
and the equivalent tosylate.28 However, the vinyl phosphates
bearing a C1-alkyl substituent with an R-hydrogen as illustrated
in Table 3, entries 1-6, proved surprisingly unreactive to the
reaction conditions exploiting the PdCl2(COD)/P(t-Bu)3/Cy2-
NMe system, also illustrating the high stability of these alkenyl
phosphates.40-44
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J. AM. CHEM. SOC. VOL. 129, NO. 21, 2007 6939

A R T I C L E S
Scheme 3
Ebran et al.
Scheme 5
Scheme 4
appeared to be influenced by the substituents on the alkenyl
phosphates as a low conversion was observed for the substrate
possessing a 1,1-diphenylethyl substituent, whereas no reactivity
was detected with the reactants in entries 6 and 7. This is in
contrast to similar Heck couplings applying X-Phos as the ligand
where acceptable yields of the diene products without migration
were noted (Table 4, entries 3 and 8).
Finally, we investigated the reactivity of C1-aryl substituted
vinyl phosphates toward the 1,2-migration under the Heck
coupling conditions, PdCl2(COD)/P(t-Bu)3/Cy2NMe in DMF at
100 °C, with N-tert-butyl acrylamide. It was quickly discovered
that substrates bearing an ortho-substituent on the aromatic ring
led to both cleaner reactions and higher yields of the desired
coupling products (Table 7). In the absence of these substituents,
typically either complex product mixtures were furnished, which
potentially originate from Diels-Alder cycloadditions involving
migrated and nonmigrated dienes products, or degradation of
the starting material was detected. As exemplifed in entry 1,
the C1-o-tolyl derivative couples with the acrylamide in an
excellent yield of 95% with a good regioselectivity in favor of
the 1,2-migration (10:1). Whereas good yields were also
obtained in entries 2-4, only modest results in the 1,2-migra-
tion were noted. On the other hand, the vinyl phosphate bearing
a C1-anthracenyl unit led to complete migration upon
coupling (entry 5). Interestingly, in the case of the perfluo-
rophenyl vinyl phosphate, the reaction took place without
rearrangement, providing the normal coupling product in an
81% yield (entry 6). Electronic factors could be at play in this
special case. In contrast, the low selectivity observed for the
ortho-methoxy- and dimethoxyphenyl substrates may be ex-
plained by an intramolecular chelation of the divalent metal
center with one of the methoxy groups, particularly as a high
degree of 1,2-migration was noted in the coupling product from
the o-tolyl vinyl phosphate. The coupling reaction with the
dimethoxyphenyl vinyl phosphate nevertheless favored the 1,2-
migration with respect to the monomethoxy substrate, possibly
because of the greater sterical bulk of the di-ortho-substituted
aryl ring.
starting material without the formation of either of the two
desired dienes.45 Remarkably, this same substrate was reported
by Hartwig and co-workers to undergo a 1,2-migration in the
Kumada cross coupling with p-tolyl magnesium bromide
catalyzed by a Pd(0)/Josiphos complex.23b Although this latter
reaction was performed in toluene, there is the possibility that
an alternative mechanism may be operating in this isomerization
observed for the Kumada coupling.
Greater success was achieved studying the scope of alkenyl
phosphates possessing an alkyl quaternary carbon at C1. As
depicted in Table 6, the substrates in entries 1 to 5 proved
adaptable to these coupling conditions producing the Heck
products in 36-81% yield and with the exception of entry 5 in
favor of the isomerized diene with regioselectivities g 9:1.
Presumably, the low level of migration in the case of the lactone
(entry 5) can be explained by an intramolecular chelation of
the carbonyl oxygen with the metal center after the oxidative
addition step, thereby blocking the free site for the subsequent
â-elimination step. The rate of these reactions nevertheless
(44) Possibly the alkenyl phosphates bearing a C1-quaternary carbon possess
longer and hence weaker C1-O bonds due to unfavorable sterical
interactions between the phosphate group and the C1-substituent compared
to C1-alkyl substituents with an R-proton, which facilitates their entry into
the first step of the catalytic cycle.
(45) A simple base induced elimination reaction of the vinyl tosylate involving
the R-proton of the alkyl side chain would lead to the formation of a volatile
trisubstituted allene. Alternatively, if the oxidative addition step is more
facile with vinyl tosylates than with the phosphates, the generated alkenyl-
Pd(II) intermediate could undergo a â-hydride elimination step again
involving the same alkyl sidechain with the formation of an allene, which
competes successfully with either the insertion step or the elimination of
the olefin hydrogen.
Further Studies on the Heck Coupling with 1,2-Migration.
In our earlier work, both DFT calculations and a deuterium
labeling experiment provided support for the 1,2-migration step
proceeding through a â-hydride elimination step of a tricoor-
dinated Pd(II) species generated after the oxidative addition step
(Figure 1 and Scheme 3).28
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6940 J. AM. CHEM. SOC. VOL. 129, NO. 21, 2007

Heck Reaction with Alkenyl Phosphates
A R T I C L E S
Scheme 6
Scheme 7
To further probe the proposed mechanism, we turned our
attention to a previous observation in the Heck coupling of
1-phenyl vinyl phosphate 4 (Scheme 4). Under the coupling
conditions which promote 1,2-migration, the reaction of 4 with
the acrylamide of phenylalanine methyl ester led to the formation
of an approximately 1:1 mixture of regioisomeric products 5
and 6 in a 51% yield. As a rapid equilibrium between the two
isomeric Pd(II) alkene species was supported by DFT calcula-
tions, the above experiment suggested that both insertion steps
for the substrate 4 proceed at approximately the same rates in
contrast to similar experiments with the tert-butyl vinyl
phosphate 1. If this is correct, then the same product distribution
should be anticipated starting from the isomeric 2-phenyl vinyl
phosphate.
nonmigrated product in high yield when performed at 100 °C.
Interestingly, no reaction was observed at room temperature.
Additional work was also carried out to investigate the effect
of the reaction temperature on the ratio of isomeric products.
Here our attention was focused on the use of the analogous
vinyl triflates due to their greater reactivity toward oxidative
addition which therefore permits the use of lower reaction
temperatures. With the same catalytic system, PdCl2(COD)/P(t-
Bu)3/Cy2NMe in DMF, the coupling of tert-butyl vinyl triflate
9 with N-tert-butyl acrylamide proceeded efficiently at 20 °C
providing a single diene product 3 in an 83% yield arising from
a 1,2-migration (Scheme 6). Similarly, in the Heck coupling of
the γ-lactone vinyl triflate 10, a rearranged/nonrearranged ratio
of 2:5 was observed in the product, which corresponds to the
same ratio obtained for the analogous vinyl phosphate compound
(Table 6, entry 5).
To investigate this point, the trans-vinyl phosphate 8 was
prepared from aldehyde 7 via deprotonation with potassium
hexamethyldisilazide and subsequent reaction of the potassium
enolate intermediate with diphenyl phosphoryl chloride (Scheme
5). Subjecting the phosphate 8 to the same coupling conditions
and the identical acrylamide (0.75 equiv) led to the exclusive
formation of one Heck product identified as the diene 5
With the ability of the vinyl triflates to undergo Heck
couplings with 1,2-migration at lower temperatures, it became
interesting to examine alkenyl triflates bearing alkyl substituents
with an R-hydrogen. However, it became quickly clear that the
triflates or their nonaflate counterparts are not compatible to
the reaction conditions providing no coupling products in
attempts to couple with the N-tert-butyl acrylamide. Even in
the absence of the palladium source, the starting vinyl triflates
or nonaflates decomposed suggesting that a base or chloride
induced elimination reaction may be taking place. Similar results
were obtained in Heck coupling reactions performed with
X-Phos as the ligand, where the corresponding vinyl phosphates
function admirably.
1
according to the crude H NMR spectrum. This unexpected
result evidently does not provide support for the â-hydride
elimination mechanism, unless the equilibration between the two
intermediate Pd(II) alkene species is not as rapid as the case
for the tert-butyl vinyl phosphate or tosylate. The same reactivity
was observed for the analogous vinyl tosylate prepared in the
same fashion as the alkenyl phosphate. Even the reaction of
â-bromostyrene with N-tert-butyl acrylamide afforded solely the
9
J. AM. CHEM. SOC. VOL. 129, NO. 21, 2007 6941

A R T I C L E S
Ebran et al.
Experimental Section
Finally, competition experiments were performed in order to
compare the reactivities of chlorobenzene with the tert-butyl
vinyl diphenyl phosphate 1. These experiments were performed
using 2 equiv of both the aryl halide and 1 and 1 equiv of the
N-tert-butyl acrylamide employing slightly modified conditions
to those previously reported by Littke and Fu with Pd2(dba)3/
Cy2NMe/LiCl in dioxane at 110 °C (Scheme 7).5b Interestingly,
in both reactions performed using either P(t-Bu)3 or X-Phos as
the ligand system the phenyl chloride reacted preferentially
leading to the formation of the cinnamide product 11. In
addition, in all the coupling reactions performed with the vinyl
diphenyl phosphates, no products were observed from oxidative
addition in the O-phenyl bond. This result suggests that for Heck
reactions aryl chloride derivatives are considerably more reactive
than either the vinyl or phenyl phosphates where the latter may
be placed on the far right side of the scale of reactivities of
various groups involved in the oxidative insertion step (I > OTf
g Br > Cl > OP(O)(OPh)2). Such information is undoubtedly
important for predicting reactivities in coupling reactions with
substrates possessing multiple reactive sites.
General Methods. Solvents were dried according to standard
procedures. Reactions were monitored by thin-layer chromatography
(TLC), and flash chromatography was performed on silica gel 60 (230-
400 mesh). The chemical shifts of the NMR spectra are reported in
ppm relative to the solvent residual peak.46 MS spectra were recorded
on an LC TOF (ES) apparatus. All Heck couplings were carried out in
7.0 mL sample vials with a Teflon sealed screwcap in a glovebox under
an argon atmosphere. All purchased chemicals were used as received
without further purification. The vinyl phosphates were synthesized
according to methods previously reported.23b,28
(E)-4-Adamantyl-N-tert-butyl Penta-2,4-dienamide (Table 4, En-
try 4). General Procedure for the Heck Couplings of Nonactivated
Vinyl Phosphates without 1,2-Migration. Lithium chloride (169.6 mg,
4.00 mmol), X-Phos (9.6 mg, 0.02 mmol), 1-adamantyl vinyl diphe-
nylphosphate (246.3 mg, 0.60 mmol), N-tert-butyl acrylamide (50.9
mg, 0.40 mmol), Cy2NMe (170 µL, 0.80 mmol), and PdCl2(COD) (5.7
mg, 0.02 mmol) dissolved in a 1:1 DMF-Dioxane mixture (3 mL)
were reacted for 24 h at 100 °C. The crude product was purified by
flash chromatography on silica gel using CH2Cl2 as eluent. This afforded
93 mg of the title compound (81% yield) as a colorless solid. 1H NMR
(400 MHz, C6D6) δ (ppm) 7.35 (d, 1H, J ) 15.4 Hz), 6.10 (d, 1H, J
) 15.4 Hz), 5.95 (bs, 1H, NH), 5.16 (t, 1H, J ) 1.2 Hz), 4.76 (d, 1H,
J ) 1.2 Hz), 1.80 (m, 3H), 1.55 (m, 9H), 1.50 (m, 3H), 1.24 (s, 9H).
13C NMR (100 MHz, C6D6) 165.0, 155.4, 139.0, 125.0, 109.9, 51.0,
41.2, 37.2, 36.8, 28.9, 28.6. HRMS C19H29NO [M + Na+]: 310.2147.
Found: 310.2153.
Conclusions
In summary, we have identified suitable reaction conditions
which promote the Pd(0)-catalyzed Heck coupling of nonacti-
vated vinyl phosphates with electron deficient alkenes providing
an entry to diene products from simple and readily accessible
starting materials. In contrast to our earlier work exploiting P(t-
Bu)3 as ligand, the use of an alternative bulky phosphine such
as Buchwald’s X-Phos effectively promoted the coupling with
a wide range of alkenyl phosphates in the presence of excess
lithium chloride. Notably 1,2-migration of the alkenyl palladium-
(II) intermediate was suppressed in these Heck couplings.
Further studies were also carried out with the catalytic system
which encourages isomerization in order to determine the extent
of reactants which may participate in such reactions. Alkenyl
phosphates with C1-substituents devoid of an R-hydrogen in
the C1-position displayed an ability to participate in an effective
coupling. The extent of the 1,2-migration was nevertheless
dependent on the C1-substituent where the best results were
observed with an alkyl quaternary carbon at C1. Although the
usefulness of this isomerization process is limited to a small
range of alkyl vinyl phosphates, it is interesting with this class
of substrates that synthesis of either the migrated or nonmigrated
Heck products may be executed through the selection of the
phosphine ligand. Finally, competition experiments performed
with a palladium catalyst possessing either X-Phos or P(t-Bu)3
as ligand revealed that an unactivated aryl chloride is more
reactive than tert-butyl vinyl phosphate in their Heck coupling
to arylamides. These results reveal a preference for oxidative
addition of the palladium(0) catalyst into the aryl chloride bond
rather than the C-O bond of the alkenyl phosphate.
(2E, 4E)-6,6-Adamantyl-N-tert-butyl Hepta-2,4-dienamide (Table
6, Entry 2). General Procedure for the Heck Couplings of Nonac-
tivated Vinyl Phosphates with 1,2-Migration. Lithium chloride (17.4
mg, 0.40 mmol), HBF4P(t-Bu)3 (11.6 mg, 0.04 mmol), 1-adamantyl
vinyl diphenylphosphate (246.3 mg, 0.60 mmol), N-tert-butyl acryla-
mide (50.9 mg, 0.40 mmol), Cy2NMe (170 µL, 0.80 mmol), and PdCl2-
(COD) (5.7 mg, 0.02 mmol) dissolved in DMF (3 mL) were reacted
for 24 h at 100 °C. The crude product was purified by flash
chromatography on silica gel using CH2Cl2 as eluent. This afforded
83.3 mg of the title compound (73% yield) as a colorless solid with an
overall rearranged/nonrearranged ratio >9:1. 1H NMR (400 MHz,
C6D6-CD3CN (1:1)) δ (ppm) 7.11 (dd, 1H, J ) 15.2, 10.8 Hz), 5.98
(bs, 1H, NH), 5.94 (dd, 1H, J ) 15.2, 10.8 Hz), 5.80 (d, 1H, J ) 15.2
Hz), 5.73 (d, 1H, J ) 15.2 Hz), 1.79 (m, 3H), 1.52 (m, 6H), 1.42 (d,
6H, J ) 2.4 Hz), 1.26 (s, 9H). 13C NMR (100 MHz, C6D6-CD3CN
(1:1)) δ (ppm) 165.6, 152.4, 140.4, 124.7, 123.8, 50.9, 41.8, 36.8, 35.6,
28.6 (2C). HRMS C19H29NO [M + H+]: 288.2327. Found: 288.2315.
Acknowledgment. We are deeply appreciative of generous
financial support from the Danish National Research Foundation,
The Danish Natural Science Research Council, the Carlsberg
Foundation, and the University of Aarhus. We thank Dr. Jacob
Overgaard for the X-ray crystallographic analysis, and we
gratefully appreciate donation of ligands and catalysts from
Degussa and Solvias.
Supporting Information Available: Experimental details and
Further studies are now underway to examine whether these
Heck couplings may be extended to include aryl tosylates and
phosphates as well. Preliminary results performed in these
laboratories suggest that the catalyst systems applied in this work
with alkenyl phosphates and tosylates are less efficient for
catalyzing these C-C bond formations with such substrates,
and hence further optimization studies are required. This work
will be reported in due course.
1
copies of H NMR and 13C NMR spectra for all the coupling
products. Crystallographic data in CIF format for the major
coupling product from Table 5, entry 5. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA070321B
(46) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 7512.
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6942 J. AM. CHEM. SOC. VOL. 129, NO. 21, 2007