Investigations on the Suzuki-Miyaura and Negishi couplings with alkenyl phosphates: Application to the synthesis of 1,1-disubstituted alkenes

Article abstract of DOI:10.1021/jo070912k

(Chemical Equation Presented) The development of versatile Suzuki-Miyaura and Negishi cross-couplings with nonactivated alkenyl phosphates and aromatic boronic acids or organozinc reagents was achieved in acceptable to good yields. A series of 1,1-disubst

Full text of DOI:10.1021/jo070912k

Investigations on the Suzuki-Miyaura and Negishi Couplings with
Alkenyl Phosphates: Application to the Synthesis of
1,1-Disubstituted Alkenes
Anders L. Hansen, Jean-Philippe Ebran, Thomas M. Gøgsig, and Troels Skrydstrup*
The Center for Insoluble Protein Structures (inSPIN), Department of Chemistry and the Interdisciplinary
Nanoscience Center, UniVersity of Aarhus, Langelandsgade 140, 8000 Aarhus C, Denmark
ts@chem.au.dk
ReceiVed May 3, 2007
The development of versatile Suzuki-Miyaura and Negishi cross-couplings with nonactivated alkenyl
phosphates and aromatic boronic acids or organozinc reagents was achieved in acceptable to good yields.
A series of 1,1-disubstituted alkenes were synthesized using a combination of either Ni(COD)2/Cy3P/
K3PO4 or Pd2dba3/DPPF in THF. When working with alkenyl electrophiles in metal-catalyzed cross-
couplings, this method lends itself as a less costly and more stable alternative to the corresponding triflate
or nonaflate derivatives. In addition, initial studies are presented regarding an efficient 1,2-migration
under Negishi coupling conditions.
Introduction
highly electron-donating ligands such as alkyl phosphines or
carbenes.4 Furthermore, alkenyl phosphates and tosylates have
been utilized with great success in various reactions such as
theStille,5Negishi,6Suzuki-Miyaura,5a,7 Kumada,8Sonogashira,5a,9
Buchwald-Hartwig,8c,10 carbonyl enolate couplings7e and in the
Heck reaction,11 providing a reliable alternative to the less stable
During the past decade, substantial efforts have been devoted
in attempts to expand the scope of substrates capable of forming
new C-C bonds in metal-catalyzed cross-couplings and vinyl
substitution reactions.1 Especially aryl chlorides have proven
their worth as viable coupling partners in Pd-catalyzed reactions
despite their reluctance to undergo oxidative addition.2,3 Typi-
cally, the coupling of less activated electrophiles requires an
electron-rich palladium catalyst. This is often obtained by using
(2) For some articles on the use of aryl chlorides in palladium(0)-
catalyzed coupling reactions, see: (a) Zapf, A.; Beller, M. Chem. Commun.
2005, 431. (b) Littke, A. F.; Fu, G. F. Angew. Chem., Int. Ed. 2002, 41,
4176. (c) Ackermann, L. Synlett 2007, 4, 507. (d) Ackermann, L. Synthesis
2006, 10, 1557. (e) Blaser, H. U.; Indolese, A.; Naud, F.; Nettekoven, U.;
Schnyder, A. AdV. Synth. Catal. 2004, 346, 1583. (f) Selvakumar, K.; Zapf,
A.; Beller, M. Org. Lett. 2002, 4, 3031. (g) Whitcombe, N. J.; Hii, K. K.
M.; Gibson, S. E. Tetrahedron 2001, 57, 7449. (h) Ohta, H.; Tokunaga,
M.; Obora, Y.; Iwai, T.; Iwasawa, T.; Fujihara, T.; Tsuji, Y. Org. Lett.
2007, 9, 89. (i) Littke, A.; Soumeillant, M.; Kaltenbach, R. F., III; Cherney,
R. J.; Tarby, C. M.; Kiau, S. Org. Lett. 2007, 9, 1711. (j) Ackermann, L.;
Born, R.; Spatz, J. H.; Meyer, D. Angew. Chem., Int. Ed. 2005, 44, 7216.
(3) For a discussion on the low reactivity of aryl chlorides in cross-
coupling reactions, see: (a) Grushin, V. V.; Alper, H. Chem. ReV. 1994,
94, 1047. (b) Grushin, V. V.; Alper, H. In ActiVation of UnreactiVe Bonds
and Organic Synthesis; Murai, S., Ed.; Springer-Verlag: Berlin, 1999; p
193.
(1) (a) Tsuji, J. Palladium Reagents and Catalysis: New PerspectiVes
For the 21st Century; Wiley: Chichester, 2004. (b) Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-
VCH: Weinheim, 2004. (c) Negishi, E. Handbook of Organopalladium
Chemistry for Organic Synthesis; Wiley & Sons: New York, 2002. (d)
Tsuji, J. Transition Metal Reagents and Catalysts: InnoVations in Organic
Synthesis; Wiley & Sons: Chichester, 2000. (e) AdVances in Metal-Organic
Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, CT, 1996. (f)
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: New
York, 1991. (g) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100,
3009. (h) Herrmann, W. A.; Bo¨hm, V. P. W.; Reisinger, C.-P. J. Organomet.
Chem. 1999, 576, 23. (i) de Meijere, A.; Meyer, F. E. Angew. Chem., Int.
Ed. Engl. 1994, 33, 2379.
10.1021/jo070912k CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/14/2007
6464
J. Org. Chem. 2007, 72, 6464-6472

InVestigations on Coupling with Alkenyl Phosphates
SCHEME 1. Suzuki-Miyaura Couplings with Alkenyl
and more expensive alkenyl triflate or nonaflates. However, in
this case attention has often been devoted to the R,â-unsaturated
carbonyl compounds or R-heteroatom substituted alkenyl coun-
terparts where the oxidative addition step occurs more readily
using a triaryl phosphine ligated Pd or Ni catalyst. Expansion
of this class of substrates to include the nonactivated alkenyl
counterparts has received less attention undoubtedly because
of the more difficult oxidative addition step and hence higher
requirements to the catalytic system.
Phosphates
TABLE 1. Optimization of Suzuki Couplings of Alkenyl
Phosphates with Phenylboronic Acid
In a previous report with nonactivated alkenyl phosphates
and tosylates, we disclosed an efficient procedure for promoting
the Heck coupling with electron-deficient alkenes.12 Particularly
the alkenyl phosphates proved their usefulness, displaying higher
stability than their tosylate and triflate/nonaflate counterparts
with no sign of decomposition after being stored for months at
-18 °C or being heated at 100 °C in DMF for 24 h. In our
pursuit to unveil the full potential of these nonactivated alkenyl
phosphate as substrates in metal-catalyzed transformations, a
Base and Temp Conversion
Entry
Metal
Ligand
Additive °Ca (Yield) of 2b
1
2
Ni(COD)2 (4%) HBF4Cy3P (8%)
Pd2dba3 (2.5%) X-Phos (10%)
K3PO4
K3PO4 +
LiCl
65 83% (75%)
70 8%
d
3
Pd2dba3 (2.5%) HBF4(t-Bu)3P (10%) K3PO4 + 100c
-
LiCl
4
Ni(COD)2 (5%) HBF4Cy3P (10%)
K3PO4
75 100% (97%)
(4) (a) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028.
(b) Kantchev, E. A. B.; O’Brian, C. J.; Organ, M. G. Angew. Chem., Int.
Ed. 2007, 46, 2768. (c) Barder, T. E.; Walker, S. D.; Martinelli, J. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685. (d) Billingsley, K. L.;
Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 3484.
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Peyroux, E.; Berthiol, F.; Doucet, H.; Santelli, M. Eur. J. Org. Chem. 2004,
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39, 4153. (h) Zapf, A.; Beller, M. Chem.-Eur. J. 2001, 7, 2908. (i) Lee,
M.-T.; Lee, H. M.; Hu, C.-H. Organometallics 2007, 26, 1317. (j) Cho,
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128, 898. (l) Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N.
M.; Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101. (m) Dupont, J.;
Consorti, C. S.; Spencer, J. Chem. ReV. 2005, 105, 2527.
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Bouyssou, P.; Coudert, G. Tetrahedron Lett. 1999, 40, 701. (d) Nicolaou,
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82. (b) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 12527. (c) Wu, J.;
Yang, Z. J. Org. Chem. 2001, 66, 7875. (d) Nicolaou, K. C.; Shi, G.-Q.;
Namoto, K.; Bernal, F. Chem. Commun. 1998, 1757.
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Commun. 2006, 4137. (b) Tang, Z.-Y.; Spinella, S.; Hu, Q.-S. Tetrahedron
Lett. 2006, 47, 2427. (c) Baxter, J. M.; Steinhuebel, D.; Palucki, M.; Davies,
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Tetrahedron Lett. 2005, 46, 4261. (e) Tang, Z.-Y.; Hu, Q.-S. J. Am. Chem.
Soc. 2004, 126, 3058. (f) Campbell, I. B.; Guo, J.; Jones, E.; Steel, P. G.
Org. Biomol. Chem. 2004, 2, 2725. (g) Nguyen, H. N.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818. (h) Netherton, M.
R.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 3190. (i) Wu, J.; Wang, L.;
Fathi, R.; Yang, Z. Tetrahedron Lett. 2002, 43, 4395. (j) Zim, D.; Lando,
V. R.; Dupont, J.; Monteiro, A. L. Org. Lett. 2001, 3, 3049. (k) Lepifre, F.;
Clavier, S.; Bouyssou, P.; Coudert, G. Tetrahedron 2001, 57, 6969. (l) Nan,
Y.; Yang, Z. Tetrahedron Lett. 1999, 40, 3321. (m) Percec, V.; Bae, J.-Y.;
Hill, D. H. J. Org. Chem. 1995, 60, 1060.
(8) (a) Ackermann, L.; Althammer, A. Org. Lett. 2006, 8, 3457. (b)
Limmert, M. E.; Roy, A. H.; Hartwig, J. F. J. Org. Chem. 2005, 70, 9364.
(c) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 8704. (d)
Baker, W. R.; Pratt, J. K. Tetrahedron 1993, 39, 8739. (e) Hayashi, T.;
Fujiwa, T.; Okamoto, Y.; Katsuro, Y.; Kumada, M. Synthesis 1981, 1001.
(f) Cahiez, G.; Avedissian, H. Synthesis 1998, 1199.
a Reactions were run in sealed sample vials. b Conversions were deter-
1
mined by H NMR spectroscopy. Isolated yield after column chromatog-
raphy. c Reaction run in toluene. d No reaction.
direct synthesis of 1,1-diaryl alkenes by a Ni(0)-catalyzed
Suzuki-Miyaura coupling was developed (Scheme 1).7a The
combination of easily accessible aromatic vinyl phosphates and
the vast number of commercially available aryl boronic acids
provided easy access to unsymmetrical diaryl alkenes with
generally good yields.
Since 1,1-disubstituted alkenes and their saturated counter-
parts represent an important structural motif in organic synthesis
and biologically active compounds, it would be desirable if the
above-mentioned method could be expanded to include not only
1,1-diaryl alkenes but also the corresponding 1-aryl-1-alkyl and
1,1-dialkyl alkenes.13 Different methods are presented in the
literature, and Wittig reactions or addition of Grignard reagents
to the aryl or alkyl ketone followed by dehydration represent
the most general approaches.14 Some examples exploiting known
metal-catalyzed cross-couplings are presented, but they often
(13) For unsaturated examples, see: 1,1′-diaryl alkenes: (a) Faul, M.
M.; Ratz, A. M.; Sullivan, K. A.; Trankle, W. G.; Winneroski, L. L. J.
Org. Chem. 2001, 66, 5772. (b) Nussbaumer, P.; Dorsta¨tter, G.; Grassberger,
M. A.; Leitner, I.; Meingassner, J. G.; Thirring, K.; Stu¨tz, A. J. Med. Chem.
1993, 36, 2115. (c) Barda, D. A.; Wang, Z.-Q.; Britton, T. C.; Henry, S.
S.; Jagdmann, G. E.; Coleman, D. S.; Johnson, M. P.; Andis, S. L.; Schoepp,
D. D. Bioorg. Med. Chem. Lett. 2004, 14, 3099. (d) Evans, D.; Cracknell,
M. E.; Saunders, J. C.; Smith, C. E.; Williamson, W. R. N.; Dawson, W.;
Sweatman, W. J. F. J. Med. Chem. 1987, 30, 1321. 1-Alkyl-1-aryl alkenes:
(e) Bernstein, P. R.; Aharony, D.; Albert, J. S.; Andisik, D.; Barthlow, H.
G.; Bialecki, R.; Davenport, T.; Dedinas, R. F.; Dembofsky, B. T.; Koether,
G.; Kosmider, B. J.; Kirkland, K.; Ohnmacht, C. J.; Potts, W.; Rumsey,
W. L.; Shen, L.; Shenvi, A.; Sherwood, S.; Stollman, D.; Russel, K. Bioorg.
Med. Chem. Lett. 2001, 11, 2769. (f) Schmidt, J. M.; Mercure, J.; Tremblay,
G. B.; Page´, M.; Kalbakji, A.; Feher, M.; Dunn-Dufault, R.; Peter, M. G.;
Redden, P. R. J. Med. Chem. 2003, 46, 1408. 1,1′-Dialkyl alkener: (g)
Takahashi, Y.; Inaba, N.; Kuwahara, S.; Kuki, W. Biosci. Biotechnol.
Biochem. 2003, 67, 195. (h) Ryu, S. Y.; Oak, M.-H.; Yoon, S.-K.; Cho,
D.-I.; Yoo, G.-S.; Kim, T.-S.; Kim, K.-M. Planta Med. 2000, 66, 358. (i)
Fride, E.; Feigin, C.; Ponde, D. E.; Breuer, A.; Hanus, L.; Arshavsky, N.;
Mechoulam, R. Eur. J. Pharmacol. 2004, 506, 179.
(9) (a) Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003, 42,
5993. (b) Lo Galbo, F.; Occhiato, E. G.; Guarna, A.; Faggi, C. J. Org.
Chem. 2003, 68, 6360. (c) Fu, X.; Zhang, S.; Yin, J.; Schumacher, D. P.
Tetrahedron Lett. 2002, 43, 6673.
(10) (a) Klapars, A.; Campos, K. R.; Chen, C.; Volante, R. P. Org. Lett.
2005, 7, 1185. (b) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(11) (a) Hansen, A. L.; Skrydstrup, T. Org. Lett. 2005, 7, 5585. (b) Fu,
X.; Zhang, S.; Yin, J.; McAllister, T. L.; Jiang, S. A.; Chou-Hong, T.;
Thiruvengadam, K.; Zhang, F. Tetrahedron Lett. 2002, 43, 573.
(12) Hansen, A. L.; Ebran, J.-P.; Ahlquist, M.; Norrby, P.-O.; Skrydstrup,
T. Angew. Chem., Int. Ed. 2006, 45, 3349.
(14) For some examples, see: (a) Burkinshaw, S. M.; Griffiths, J.; Towns,
A. D. J. Mater. Chem. 1998, 8, 2677. (b) Gollnick, K.; Schnatterer, A.;
Utschick, G. J. Org. Chem. 1993, 58, 6049. (c) Elmaleh, D. D.; Patai, S.;
Rappoport, Z. J. Chem. Soc. C 1971, 2637. (d) Bergmann, F.; Szmusz-
kowicz, J. J. Org. Chem. 1948, 70, 2748. (e) Belsham, G. M.; Muir, A. R.;
Kinns, M.; Phillips, L.; Twanmoh, L.-M. J. Chem. Soc., Perkin Trans. 2
1974, 119. (f) Weller, D. D.; Weller, D. L. Tetrahedron Lett. 1982, 23,
5239. (g) Brown, H. C.; Cleveland, J. D. J. Org. Chem. 1976, 41, 1792.
J. Org. Chem, Vol. 72, No. 17, 2007 6465

Hansen et al.
TABLE 2. Suzuki Couplings of Alkyl Vinyl Phosphates with Aryl Boronic Acidsa
a Reactions were run in sealed sample vials. b Isolated yield after column chromatography. c Isolated product contains dibenzofurane; see SI. d Isolated
1
after hydrogenation. e Conversions were determined by H NMR spectroscopy. Product not isolated.
6466 J. Org. Chem., Vol. 72, No. 17, 2007

InVestigations on Coupling with Alkenyl Phosphates
TABLE 3. Optimization of Negishi Cross-Coupling with Alkenyl
Phosphatesa
rely on the use of the corresponding vinyl halide or less stable
vinyl triflate.15
Herein, we describe the development of general reaction
conditions allowing an easy access to 1,1-disubstituted alkenes
in good to excellent yields via Ni(0)- and Pd(0)-catalyzed
couplings of nonactivated alkenyl phosphates with aryl boronic
acids or organozinc reagents, respectively. In addition, initial
studies on the 1,2-migration of the alkenyl palladium intermedi-
ate leading to â-alkyl styrenes are presented.
Results and Discussion
Conversion (%)b
Entry
Ligand
(Yield %)
Ratio 15/19
99/1
Suzuki-Miyaura Couplings. As mentioned in the Introduc-
tion, a catalytic system consisting of Ni(COD)2 (4%) as the
nickel source with HBF4PCy3 (8%) as the ligand salt combined
with K3PO4 (3 equiv) as base in THF at 65 °C promoted
efficiently the coupling of aromatic alkenyl phosphates with aryl
boronic acids.7a This system was then initially extrapolated to
include alkyl vinyl phosphates. When the O-1-cyclohexylvinyl-
O,O-diphenylphosphate 1 was coupled to phenylboronic acid,
this resulted in an 83% conversion with a 75% isolated yield
of the 1,1-disubstituted alkene (Table 1, entry 1). Longer reaction
times unfortunately did not improve the efficiency of this
reaction. Changing the solvent to toluene or 2-methyltetrahy-
drofuran combined with a raise in the reaction temperature only
lowered the conversion.
1
2
3
4
5
6
DPPF
100 (74)
0
(R)-(S)-PPF-PCy2
(R)-(S)-Cy2PF-PCy2
(R)-(S)-Cy2PF-PtBu2
P(tBu)3
0
100c
n.d.d
100c
43/57
72/28
1/99
(R)-(S)-PPF-PtBu2
a Reactions were run in sealed sample vials. b Conversions measured by
1H NMR spectroscopy. c Formation of a byproduct (see Discussion for
Scheme 4). d Not determined.
Attempts to change the base confirmed that K3PO4 was the
proper choice.16 Changing the catalyst to palladium in combina-
tion with the ligands X-Phos and (t-Bu)3P with added LiCl,
systems which previously promoted the oxidative addition step
in Heck couplings, resulted in low conversion or no reaction
(Table 1, entries 2 and 3).17 Returning to the original coupling
conditions with an increase in catalyst loading to 5% and a raise
of reaction temperature to 75 °C in THF gratifyingly led to full
conversion and an isolated yield of 97% (Table 1, entry 4).
With these slightly modified reaction conditions at hand, we
next tested the generality of the coupling as illustrated in Table
2. Several cyclic and acyclic alkyl vinyl phosphates were
coupled in moderate to good yields with different boronic acids
carrying both electron-withdrawing (Table 2, entries 6, 10, and
11) and one electron-donating substituent (Table 2, entry 1).
The cyclopropyl- and cyclobutyl vinyl phosphates yielded the
desired coupling products though in lower yields than the
corresponding cyclohexyl vinyl phosphate (Table 2, entries
5-8). This may be due to the chemical instability of the
coupling product since full conversion was not obtained with
the starting alkyl vinyl phosphate, which was still left in the
crude reaction mixture after 18 h.
isolated in good to high yields (Table 2, entries 9-11). These
products represent precursors to partially saturated benzophe-
none derivatives.18 Cross-couplings with 1-methyl vinyl phos-
phate generated the propenylated aromatic compounds in high
yields (91 and 98%, Table 2, entries 1 and 2). In entry 3, an
inseparable mixture of 1-butenyl and 2-butenyl phosphate was
examined with 4-biphenylboronic acid providing the coupling
product in 78% yield after hydrogenation of the crude reaction
mixture. When the coupling of the Z-vinyl phosphate shown in
entry 12 carrying a phenyl group in the 2-position was
attempted, a product resulting from an apparent isomerization
was observed. The mechanism for this isomerization is not clear
at this point.19 Further increase of the steric bulk on the C1-
position of the alkyl substituents of the vinyl phosphate or in
ortho-position on the aryl boronic acid unfortunately leads to
lower conversion rates (Table 2, entries 13 and 14). In
combination with the sometimes difficult preparation of pure
1-alkyl vinyl phosphates by R-hydrogen abstraction from an
unsymmetrical ketone with closely related R-substituents by a
kinetic base12 (Table 2, entry 3) led us to search for an alternative
catalytic system to overcome these restrictions.
Couplings with 1-cyclohexyl vinyl phosphate usually went
to completion, and the desired coupling products could be
(15) For some examples, see: (a) Farina, V.; Krishnan, B.; Marshall, D.
R.; Roth, G. P. J. Org. Chem. 1993, 58, 5434. (b) Ganchegui, P.; Bertus,
P.; Szymoniak, J. Synlett 2001, 123. (c) Blatter, K.; Schlu¨ter, A.-D. Synthesis
1989, 5, 356. (d) Blough, B. E.; Abraham, P.; Lewin, A. H.; Kuhar, M. J.;
Boja, J. W.; Carroll, F. I. J. Med. Chem. 1996, 39, 4027. (e) Strachan,
J.-P.; Sharp, J. T.; Parsons, S. J. Chem. Soc., Perkin Trans. 1 1998, 807.
(f) Berthiol, F.; Doucet, H.; Santelli, M. Eur. J. Org. Chem. 2003, 6, 1091.
(g) Kundo, K.; McCullagh, J. V.; Morehead, A. T. J. Am. Chem. Soc. 2005,
127, 16042. (h) Hatanaka, Y.; Hiyama, T. Tetrahedron Lett. 1990, 31, 2719.
(i) Amatore, M.; Gosmini, C.; Pe´richin, J. Eur. J. Org. Chem. 2005, 989.
(16) For the use of K3PO4 as base in Suzuki-Miyaura couplings, see:
Chen, C.; Yang, L.-M. Tetrahedron Lett. 2007, 48, 2427 and references
therein.
(18) Used in the synthesis of (S)-oxybutynin. See: Gupta, P.; Fernandes,
R. A.; Kumar, P. Tetrahedron Lett. 2003, 44, 4231.
(19) One reviewer pointed out the possibility of a mechanism involving
a Ni-catalyzed hydroarylation of the corresponding alkyne with the aryl
boronic acid (Shirakawa, E.; Takahashi, G.; Tsuchimoto, T.; Kawakami,
Y. Chem. Commun. 2001, 2688). Although plausible, this mechanism would
require that the vinyl phosphate undergo elimination with formation of the
alkyne. Heating the same vinyl phosphate with potassium phosphate in THF
at 75 °C for 24 h did not lead to the formation of 3,3-dimethyl-1-
phenylbutyne. In addition, formation of the requisite aryl nickel hydride
species for the hydroarylation step requires the presence of water in the
reaction media. Further investigations on the mechanism behind this
isomerization are being conducted and will be reported in due time.
(17) Ebran, J.-P.; Hansen, A. L.; Gøgsig, T. M.; Skrydstrup, T. J. Am.
Chem. Soc. 2007, 129, 6931.
J. Org. Chem, Vol. 72, No. 17, 2007 6467

Hansen et al.
TABLE 4. Negishi Cross-Couplings with Alkyl Vinyl Phosphates and Aryl Zinc Reagentsa
a Reactions were run in sealed sample vials. b Isolated yield after column chromatography. c 78% conversion measured by 1H NMR spectroscopy. d 63%
1
1
conversion measured by H NMR spectroscopy. e 65% conversion measured by H NMR spectroscopy.
SCHEME 2. Commercially Available Organozinc Bromide
Reagents
Negishi Couplings. Attention was then turned toward the
palladium-catalyzed Negishi couplings because these reactions,
like the Suzuki-Miyaura couplings, are characterized by their
good functional group tolerance and high reactivity of the
organozinc reagents.1b,4a,6,20 We set out to identify reaction
conditions capable of promoting the coupling between t-butyl
vinyl phosphate 17 and the organozinc reagent 184a (Table 3),
a coupling that provided less than 10% conversion using our
Suzuki coupling conditions mentioned above. After a brief
screening, it was quickly discovered that DPPF as the ligand in
combination with Pd2dba3 in THF at 70 °C afforded the desired
coupling with full conversion and an isolated yield of 74%
(Table 3, entry 1). Screening of other ferrocenyl-based ligands
of the Josiphos type did not improve the reaction at first (Table
3, entries 2 and 3). On the other hand, when the (R)-(S)-Cy2-
PF-PtBu2 ligand was applied full conversion was once again
observed, but more interestingly a mixture of products 15 and
19 was obtained where 19 is the result of a 1,2-palladium
migration (Table 3, entry 4).12,17 Surprisingly, performing the
coupling with (t-Bu)3P, a ligand which previously promoted the
rearrangement of the same vinyl phosphate in Heck reactions,
led to the preferential formation of the nonmigrated product
(Table 3, entry 5). Complete conversion and rearrangement to
the coupling product 19 could nevertheless be obtained by
applying the (R)-(S)-PPF-PtBu2 ligand (Table 3, entry 6).
Changing the counterion on the organozinc reagent from
chloride to bromide stopped the reaction, proving the importance
of the presence of chloride ions in the reaction mixture.21 The
chloride ion is speculated to form a reactive palladium(0)-chlor-
ide anionic complex, facilitating the oxidative addition step.22
As seen in Table 4, these conditions proved to be tolerable
to steric factors, allowing the coupling to proceed with several
bulky vinyl phosphates in acceptable yields. Entries 3-5
illustrate examples of vinyl phosphates carrying C1-quaternary
(20) For reviews and general literature on the Negishi reaction, see: (a)
Organozinc Reagents: A Practical Approach; Knochel, P., Jones, P., Eds.;
Oxford: New York, 1999. (b) Berk, S. C.; Yeh, M. C. P.; Jeong, N.;
Knochel, P. Organometallics 1990, 9, 3053. (c) Knochel, P.; Singer, R. D.
Chem. ReV. 1993, 93, 2117. (d) Reiser, O. Angew. Chem., Int. Ed. 2006,
45, 2838. (e) Yin, N.; Wang, G.; Qian, M.; Negishi, E. Angew. Chem., Int.
Ed. 2006, 45, 2916. (f) Tan, Z.; Negishi, E. Angew. Chem., Int. Ed. 2006,
45, 762. (g) Organ, M. G.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev, E.
A. B.; O’Brian, C. J.; Valente, C. Chem.-Eur. J. 2006, 12, 4749. (h) Frisch,
A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674. (i) Arp, F. O.; Fu,
G. C. J. Am. Chem. Soc. 2005, 127, 10482. (j) Fischer, C.; Fu, G. C. J.
Am. Chem. Soc. 2005, 127, 4594. (k) Hadei, N.; Kantchev, E. A. B.;
O’Brian, C. J.; Organ, M. G. Org. Lett. 2005, 7, 3085. (l) Negishi, E.;
Hu, Q.; Huang, Z.; Qian, M.; Wang, G. Aldrichimica Acta 2005, 38, 71.
(m) Wiskur, S. L.; Korte, A.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 82.
(n) Hou, S. Org. Lett. 2003, 5, 423. (o) Dai, C.; Fu, G. C. J. Am. Chem.
Soc. 2001, 123, 2719. (p) Negishi, E.; Anastasia, L. Chem. ReV. 2003, 103,
1979.
(21) During the formation of the organozinc reagent, g1 equiv of LiCl
is formed. See ref 4a.
6468 J. Org. Chem., Vol. 72, No. 17, 2007

InVestigations on Coupling with Alkenyl Phosphates
TABLE 5. Negishi Cross-Couplings with Aryl Vinyl Phosphates and Alkylzinc Reagentsa
a Reactions were run in sealed sample vials. b Isolated yield after column chromatography.
carbons all yielding the desired product in acceptable to good
yields. Changing to the (2,6-dimethylphenyl)zinc(II) chloride
slightly lowered the conversion rates and yields (Table 4, entries
6 and 7).
Aryl vinyl phosphates, which were previously used to
generate the 1,1-diaryl alkenes,7a were then evaluated in
couplings with alkyl organozinc reagents. For this purpose, the
commercially available organozinc bromides in Scheme 2 were
examined. As noticed earlier during the optimization study
mentioned above, the organozinc bromides were not reactive,
but the addition of 5 equiv of LiCl to the reaction mixture
afforded the desired coupling.
indole moiety proved also sufficiently reactive under these
conditions (Table 5, entry 9).
Attention was then turned toward the 1,1′-dialkyl-substituted
alkenes to test if this final class of compounds could be
synthesized in a similar manner. Again, we chose to utilize the
alkylzinc bromide reagents in combination with added LiCl since
they are commercially available and hence provide easy access
to the desired compounds. To our satisfaction, the same catalytic
system proved sufficiently reactive without further optimization
(Table 6).
As with the other above-mentioned Negishi couplings, the
substitution pattern on the C1-carbon of the vinyl phosphates
Several aryl vinyl phosphates with different substitution
patterns were tested, and all coupled with satisfactory yields
(Table 5). Even increasing the steric bulk in the ortho-position
of the aryl moiety did not affect the coupling yield (Table 5,
entries 3-5). Aryl vinyl phosphates carrying electron-donating
and -withdrawing groups were reactive, although the pentafluo-
rophenyl vinyl phosphate was less reactive (Table 5, entries
4-6). A double cross-coupling was also attempted with the
divinyl diphosphate in entry 7, furnishing 42% of the divinyl-
substituted benzene. Finally, a vinyl phosphate carrying an
(22) The presence of excess LiCl may augment the concentration of a
more reactive anionic Pd(0) complex in equilibrium with its neutral species.
See: (a) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 21, 2271.
(b) Ho¨germeier, J.; Reissig, H.-U.; Bru¨dgam, I.; Hartl, H. AdV. Synth. Catal.
2004, 346, 1868. (c) Perez, R.; Veronese, D.; Coelho, F.; Antunes, O. A.
C. Tetrahedron Lett. 2006, 47, 1325. (d) Andrus, M. B.; Song, C.; Zhang,
J. Org. Lett. 2002, 4, 2079. (e) Camp, D.; Matthews, C. F.; Neville, S. T.;
Rounes, M.; Scott, R. W.; Truong, Y. Org. Process Res. DeV. 2006, 10,
814. (f) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314. (g)
Cameron, M.; Foster, B. S.; Lynch, J. E.; Shi, Y.-J.; Dolling, U.-H. Org.
Process Res. DeV. 2006, 10, 398.
J. Org. Chem, Vol. 72, No. 17, 2007 6469

Hansen et al.
TABLE 6. Negishi Cross-Couplings with Alkyl Vinyl Phosphates and Alkylzinc Reagentsa
a Reactions were run in sealed sample vials. b Isolated yield after column chromatography. c Product is volatile. d 50% conversion based on the 1H NMR
spectrum of the crude reaction mixture.
did not affect the reaction, which in most cases went to full
conversion. Unexpectedly, the t-butyl vinyl phosphate proved
to be less reactive (50% conversion, Table 6, entry 3) when
coupled with an organozinc reagent carrying an alkyl chain
compared to its aryl counterpart where full conversion was
obtained (Table 3, entry 1). Even a more strained system such
as the cyclobutyl vinyl phosphate turned out to be sufficiently
reactive with an alkyl zinc reagent leading to a 51% coupling
yield (Table 6, entry 4). Moreover, when couplings with the
methyl vinyl phosphate and isopropyl vinyl phosphates were
conducted, low yields were obtained after column chromatog-
raphy, probably due to the low boiling point of the isolated
compounds (Table 6, entries 1 and 2).
SCHEME 3. Proposed Mechanism for the 1,2-Migration in
the Heck Reaction
Negishi Couplings of Alkenyl Phosphates with 1,2-Migra-
tion. During the ligand optimization studies for the Negishi
coupling between alkyl vinyl phosphates and o-tolyl zinc
chloride, a coupling product was detected resulting from a 1,2-
migration (Table 3, entries 4-6). We have previously reported
on effective Pd-catalyzed 1,2-migrations in Heck couplings with
6470 J. Org. Chem., Vol. 72, No. 17, 2007

InVestigations on Coupling with Alkenyl Phosphates
SCHEME 4. Negishi Cross-Coupling under Conditions Favoring 1,2-Migration with Formation of a Byproduct
alkenyl tosylates and phosphates possessing a quaternary C1-
SCHEME 5. Negishi Cross-Couplings with 1,2-Migration
carbon using (t-Bu)3P as the ligand in combination with LiCl
in DMF (Scheme 3).12,17
The proposed mechanism for this 1,2-migration in the Heck
reactions starts with the complex A formed after the oxidative
addition step.23 Since the complex A is tricoordinated, it deviates
from the normally known tetracoordinated square-planar com-
plexes by possessing a free coordination site on the palladium
nucleus. This free coordination site then facilitates cis-â-hydride
elimination, generating the t-butylacetylene palladium(II) hy-
dride complex B. Rotation of the acetylene and hydropalladation
Gratifyingly, both the t-Bu vinyl O,O-diethyl phosphate 53 and
affords the rearranged complex C. DFT calculations carried out
the adamantyl vinyl tosylate 54 proved reactive utilizing the
on this system suggested this rearrangement to be in a fast
catalytic system at hand. But more interestingly, both provided
equilibrium and that discrimination of the two intermediates is
only the desired 1,2-migrated product 19 and 51, respectively,
dictated by the different rates of the carbopalladation step.12
without formation of byproducts or decomposition of the starting
The above proposed mechanism can be easily applied to
materials. Since a simple change in the electrophile eliminates
explain the results for the Negishi couplings using the (t-Bu)3P
the formation of 52, the generation of the intermediate adamantyl
ligand as seen in Table 3, entry 5, although in this case higher
acetylene must occur by a mechanism different from that
selectivity for the nonmigrated product was obtained. On the
suggested above. Slow base elimination of one of the olefin
other hand, the rearrangement noted with the bidentate Josiphos
protons on the vinyl phosphate 50 to generate an alkyne could
ligands is more surprising since the bidentate coordination of
potentially explain this observation. Additional work is cur-
the ligand would occupy the free site on the palladium nucleus,
rently in progress to identify the optimal conditions for this
hence blocking the â-hydride elimination (Table 3, entries 4
interesting rearrangement and hopefully to gain further mecha-
and 6).8b One explanation for these observations could be that
nistic insight.
the diphenylphosphine moiety on the ferrocene unit briefly
dissociates from the palladium center, leaving a complex similar
to A (Scheme 3), allowing rearrangement to take place before
Conclusion
recoordination of the ligand and transmetalation with the
organozinc reagent.
We have successfully developed standard reaction conditions
for the Suzuki-Miyaura and Negishi couplings of nonactivated
alkenyl phosphates with boronic acids and organozinc reagents,
providing a direct and facile access to a diverse array of 1,1-
disubstituted alkenes. This work, in combination with our
previous report, allows for the formation of almost any carbon-
carbon bond adjacent to the alkenyl moiety, making these
methods versatile tools for the synthetic organic chemist. In
addition, initial studies regarding an efficient 1,2-migration of
the alkenyl palladium(II) intermediate were presented, providing
a new variation of the Negishi cross-coupling.
During the coupling of the t-butyl vinyl phosphate 17 to 18,
a byproduct was formed using the conditions favoring 1,2-mi-
gration. The same reaction was conducted with the similar ada-
mantyl vinyl phosphate, and analyzing the crude reaction mix-
ture by proton NMR revealed a 1:1 mixture of the 1,2-migrated
product and the byproduct, which upon purification was
identified as the (E)-1,4-diadamantyl-buten-3-yne (52) (Scheme
4).24 Since full conversion was not obtained, it was speculated
that formation of 52 occurs via base-induced reductive elimina-
tion/deprotonation of the palladium hydride complex B (Scheme
3) releasing adamantyl acetylene into solution. This alkyne is
then deprotonated by another equivalent of o-tolyl zinc chloride,
forming a reactive (adamantylethynyl)zinc(II) chloride which
competes in the transmetalation step with o-tolyl zinc chloride
with another round of complex C forming 52.25
Experimental Section
2-(4-Biphenyl)propene (4). General Procedure for the Su-
zuki-Miyaura Couplings of Nonactivated Vinyl Phosphates
with Boronic Acids. Propen-2-yl diphenylphosphate (87.1 mg, 0.30
mmol), 4-biphenylboronic acid (89.1 mg, 0.45 mmol), K3PO4 (191
mg, 0.90 mmol), and HBF4PCy3 (11.0 mg, 0.030 mmol) were
dissolved in THF (3 mL). Ni(COD)2 (4.1 mg, 0.015 mmol) was
then added, and the sample vial was fitted with a Teflon sealed
screw cap and removed from the glovebox. The reaction mixture
was heated for 18 h at 75 °C, after which it was filtered through a
plug of Celite and washed with diethyl ether. After concentration
in vacuo, the crude product was purified by flash chromatography
on silica gel using pentane as eluent. This afforded 58.0 mg of the
title compound (98% yield) as a colorless solid. 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.67-7.59 (m, 6H), 7.49 (m, 2H), 7.39 (m, 2H),
5.49 (d, 1H, J ) 0.4 Hz), 5.17 (m, 1H), 2.24 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ (ppm) 142.9, 140.9, 140.3, 140.2, 128.9,
127.4, 127.1, 127.0, 126.0, 112.6, 21.9. GC-MS C15H14 [M]: calcd,
194; found, 194.
Two other alkenyl derivatives were then tested in the coupling
to examine the influence of the leaving group (Scheme 5).
(23) (a) Stambuli, J. P.; Incarvito, C. D.; Bu¨hl, M.; Hartwig, J. F. J. Am.
Chem. Soc. 2004, 126, 1184. (b) Ahlquist, M.; Norrby, P.-O. Organome-
tallics 2007, 26, 550. (c) Lam, K. C.; Marder, T. B.; Lin, Z. Organometallics
2007, 26, 758.
(24) Palladium-catalyzed dimerizations of alkynes are known but since
the presence of o-tolyl zinc chloride would result in deprotonation of the
alkyne formed in situ, it is believed that 52 is formed by a different
mechanism. See: (a) Yang, C.; Nolan, S. P. J. Org. Chem. 2002, 67, 591.
(b) Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 11107.
(25) The fact that (adamantylethynyl)zinc(II) chloride transmetalates
faster than o-tolyl zinc chloride was confirmed by increasing the steric bulk
on the organozinc reagent to the m-xylene derivative, resulting in sole
formation of the byproduct 52.
J. Org. Chem, Vol. 72, No. 17, 2007 6471

Hansen et al.
2-[3-(2,6-Dimethoxyphenyl)but-3-enyl]-1,3-dioxolane (34). Gen-
eral Procedure for the Negishi Couplings of Nonactivated Vinyl
Phosphates with Organozinc Reagents. 1-(2,6-Dimethoxyphenyl)-
vinyl diphenylphosphate (164.9 mg, 0.40 mmol), DPPF (11.1 mg,
0.02 mmol), and lithium chloride (84.8 mg, 2.00 mmol) were
dissolved in THF (2.0 mL) in a 7-mL sample vial in a glovebox,
where after a 0.5 M solution of [2-(1,3-dioxolanyl)ethyl] zinc
bromide in THF (1.0 mL, 0.48 mmol) was then added. Pd2dba3
(9.16 mg, 0.01 mmol) was added, and the sample vial was fitted
with a Teflon sealed screw cap and then removed from the
glovebox. The reaction mixture was heated for 18 h at 70 °C, after
which it was concentrated in vacuo, and then the crude product
was purified by flash chromatography on silica gel using dichlo-
romethane as the eluent. This afforded 100 mg of the title compound
2H), 3.78 (m, 2H), 3.75 (s, 6H), 2.40 (t, 2H, J ) 7.6 Hz), 1.64 (m,
2H). 13C NMR (100 MHz, CD3CN) δ (ppm) 158.5, 143.5, 129.3,
121.0, 115.4, 105.1, 104.8, 65.5, 56.4, 33.1, 32.3. HRMS C15H20O2
[M + Na+], 287.1259; found, 287.1275.
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 Solvias
for a generous gift of the Josiphos ligands.
Supporting Information Available: Experimental details and
copies of 1H NMR and 13C NMR spectra for all the coupling
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
(95% yield) as a colorless oil. H NMR (400 MHz, CD3CN) δ
(ppm) 7.22 (t, 1H, J ) 8.4 Hz), 6.65 (d, 2H, J ) 8.4 Hz), 5.26 (d,
1H, J ) 0.8 Hz), 4.83 (t, 1H, J ) 4.8 Hz), 4.79 (m, 1H), 3.86 (m,
JO070912K
6472 J. Org. Chem., Vol. 72, No. 17, 2007