Direct synthesis of 1,1-diarylalkenes from alkenyl phosphates via nickel(0)-catalysed Suzuki-Miyaura coupling

Article abstract of DOI:10.1039/b609064h

A combination of Ni(COD)₂ and PCy₃ promotes effectively the Suzuki-Miyaura cross coupling of 1-arylalkenyl phosphates with aryl boronic acids with yields attaining 99%. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b609064h

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Direct synthesis of 1,1-diarylalkenes from alkenyl phosphates via
nickel(0)-catalysed Suzuki–Miyaura coupling{
Anders L. Hansen, Jean-Philippe Ebran, Thomas M. Gøgsig and Troels Skrydstrup*
Received (in Cambridge, UK) 26th June 2006, Accepted 9th August 2006
First published as an Advance Article on the web 22nd August 2006
DOI: 10.1039/b609064h
stability of the vinyl triflates in combination with the use of
expensive triflating agents for their generation nevertheless limits
the usefulness of this methodology. Alternative coupling reagents
would therefore be desirable.
A combination of Ni(COD)2 and PCy3 promotes effectively the
Suzuki–Miyaura cross coupling of 1-arylalkenyl phosphates
with aryl boronic acids with yields attaining 99%.
1,1-Diarylalkenes represent important constituents of a variety of
biologically active compounds, as well as being the main
precursors to the corresponding 1,1-diarylethane.1 The most
general protocol to accessing such compounds relies on the
addition of Grignard reagents to either aceto- or benzophenones
followed by dehydration, or Wittig reactions with functionalised
benzophenones (Scheme 1).2 Structural variations to the 1,19-dia-
rylalkenes are however limited to the conditions applied, as well as
the availability of the reagents. Many alternative methods have
also been developed but are typically less flexible than the
Grignard approach. Pd(0)-catalysed cross coupling reactions
between aryl boronic acids/esters or other aryl metallic species
and 1-arylvinyl triflates represents a mild route to diarylalkenes.
Although there are only few examples in the literature,1a,3 the low
In a recent publication, we reported an effective procedure for
promoting the Heck coupling of nonactivated vinyl phosphates
and tosylates with electron deficient alkenes.4,5 In particular the
Department of Chemistry, University of Aarhus, Langelandsgade 140,
8000, Aarhus C, Denmark. E-mail: ts@chem.au.dk; Fax: +45 8619 6199;
Tel: +45 8942 3932
{ Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b609064h
Scheme 1 Previous approaches to the synthesis of 1,19-diarylalkenes.
Table 1 Optimisation of Suzuki–Miyaura coupling with vinyl phosphates
Entry
Boronic acid/ester
Reaction conditions
Yielda (%)
1
2
3
4
5
6
7
8
2
2
2
2
2
2
3
3
3
3
3
3
3
Pd2(dba)3 (2.5%), HBF4P(t-Bu)3 (10%), KF (3 equiv.), THF, 70 uC, 21 h
PdCl2(COD) (5%), HBF4P(t-Bu)3 (10%), LiCl (1 equiv.), K3PO4 (3 equiv.), DMF, 70 uC, 16 h
Ni(COD)2 (4%), PPh3 (8%), K3PO4 (3 equiv.), THF, 70 uC, 24 h
Ni(COD)2 (4%), Cy3PHBF4 (8%), K3PO4 (3 equiv.), THF, 70 uC, 17 h
Ni(COD)2 (4%), Cy3PHBF4 (8%), K3PO4 (3 equiv.), dioxane, 65 uC, 16 h
Ni(COD)2 (4%), Cy3PHBF4 (8%), K3PO4 (3 equiv.), toluene, 65 uC, 16 h
Ni(COD)2 (4%), Cy3PHBF4 (8%), K3PO4 (3 equiv.), THF, 65 uC, 16 h
Ni(COD)2 (2%), Cy3PHBF4 (4%), K3PO4 (3 equiv.), THF, 65 uC, 17 h
Ni(COD)2 (4%), Cy3PHBF4 (8%), K3PO4 (3 equiv.), THF, 65 uC, 17 h
Ni(COD)2 (4%), HBF4P(t-Bu)3 (8%), K3PO4 (3 equiv.), THF, 65 uC, 18 h
Cy3PHBF4 (8%), K3PO4 (3 equiv.), THF, 65 uC, 17 h
0
0
42
89b
68
16
92b
84
72c
10
0
9
10
11
12
13
a
Pd2(dba)3 (2%), PPh3 (8%), K3PO4 (3 equiv.), THF, 65 uC, 18 h
0
9
Pd2(dba)3 (2%), Cy3PHBF4 (8%), K3PO4 (3 equiv.), THF, 65 uC, 18 h
Conversion yield according to 1H NMR. Isolated yields after column chromatography. The corresponding diethyl phosphate was used.
b
c
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vinyl phosphates display higher stability than the corresponding
triflates and show no signs of decomposition after several months
in the freezer (218 uC).{ In our continued interest to examine the
suitability of the alkenyl phosphates as viable coupling partners in
cross coupling reactions, we now disclose an efficient Suzuki–
Miyaura coupling6 of these substrates with aryl boronic acids/
esters using a nickel(0) catalyst for the preparation of 1,1-
diarylalkenes in good to excellent yields.
Table 2 Cross couplings with vinyl phosphates and boronic esters
Yielda
(%)
Entry Ar
1
Ar9
Product
Ph
99
Initial optimisation efforts to promote the Suzuki–Miyaura
cross coupling of vinyl phosphates§ with aryl boronic acids were
carried out with the phosphate 1 and the phenyl boronic ester 2
(Table 1). Whereas successful C–C bond formation has previously
been reported in Suzuki–Miyaura couplings with difficult
substrates such as aryl chlorides and tosylates using palla-
dium(0)-catalysis with bulky electron rich phosphine ligands,8,9
extrapolation to promoting the coupling of 1 and 2 were
unrewarding (entry 1). Even the conditions which successfully
promoted the Heck coupling of nonactivated vinyl phosphates and
acrylamides/acrylates with K3PO4 as base were nonproductive
(entry 2).4
2
3
80b
96
4
5
Ph
69c
60
On the other hand, switching to a nickel(0) catalyst provided a
more effective system for promoting these coupling reactions.10
Use of the nickel(0) source, Ni(COD)2 in combination with PPh3
in THF showed a 42% conversion after 24 h at 70 uC (entry 3),
conditions which have been successfully exploited for the Suzuki –
Miyaura cross coupling of aryl chlorides with boronic acids.10h
Exploiting the more electron rich ligand, tricyclohexylphosphine,
led to full conversion affording an 89% isolated yield of the
1-phenyl-1-naphth-2-ylethene (4).10e" I Although the coupling
proceeded slowly at 20 uC, the reaction temperature was raised in
order to assure complete conversion after 24 h. Potassium
phosphate also proved to be a more effective base than the
corresponding fluoride salt which promoted decomposition of the
vinyl phosphate. Use of solvents such as dioxane and toluene were
less fruitful for the conversions compared to THF (entries 5 and 6).
Exchanging the boronic ester for the boronic acid 3 led to a slight
improvement in the yield of 4 (92%), although reducing the
catalyst loading from 4 to 2% also effected the conversion rate
(entries 7 and 8). Interestingly, the diethyl phosphate proved less
effective for these cross couplings than with corresponding
diphenyl ester as in 1 (entry 9). Exchange of the ligand salt
HBF4P(Cy)3 to HBF4P(t-Bu)3 led to a significant decrease in the
coupling efficiency (entry 10). As expected the omission of the
nickel(0) source led to no cross coupling revealing the absence of
metal contaminants in both reagents and solvent (entry 11).
Finally, the importance of nickel was also confirmed through
reactions performed as indicated in entries 12 and 13, where a
palladium(0) source was used.
6
7
2-Naphthyl
73
66
2-Naphthyl
8
2-Naphthyl
2-Naphthyl
58
9
60b
93
10
11
12
13
Ph
74b
91
1-Naphthyl Ph
96
With these successful cross coupling conditions in hand, we next
proceeded to examine the generality of these reactions as illustrated
in Tables 2 and 3. A variety of substituted isocyclic and
heterocyclic diarylalkenes were successfully prepared. In Table 2,
examples of 1-aryl vinyl phosphates and boronic acids with both
electron rich and poor substituents could be couple to the
corresponding diarylalkene in good to excellent yields (entries
1–13). Increasing the steric bulk as exemplified in entries 14 and
15 reduced the coupling yield and, as with entry 14, led to the
formation of the monosubstituted alkene (2-vinylnaphthalene) as
the major product. Heterocyclic systems were equally productive
14
15
2-Naphthyl
16d
34c
9-Anthracyl Ph
a
b
Isolated yields after column chromatography. The boronic ester
c
of neopentylglycol was used. The reaction was run for 44 h.
2-Vinylnapthalene was isolated as the major product in a 50% yield.
d
4138 | Chem. Commun., 2006, 4137–4139
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the Carlsberg Foundation and the University of Aarhus for
financial support of this project.
Table 3 Suzuki–Miyaura couplings with heterocyclic systems
Notes and references
{ Unlike the triflates, the vinyl phosphates showed no signs of decom-
position when heated at 100 uC in DMF for 24 h.
Entry Ar
Ar9
Product
Yielda (%)
93
§ The vinyl phosphates were prepared according to ref. 4 and 7 by base
promoted proton abstraction of an aryl ketone with lithium hexamethyldi-
silazide (LiHMDS) followed by treatment with diphenyl chlorophosphate.
" A single example has been previously been reported Suzuki–Miyaura
coupling of cyclohexenyl phosphate with aryl boronic acids using a Ni(0)
catalyst prepared from the reduction of NiCl2(dppf) with n-BuLi (ref. 5c).
I Netherton and Fu have demonstrated that trialkylphosphonium salts are
air-stable and practical replacements for air-sensitive trialkylphosphines
(ref. 11).
1
2-Naphthyl
2
3
4
2-Naphthyl
75
92
99
Ph
Ph
1 For representative examples, see: (a) M. M. Faul, A. M. Ratz,
K. A. Sullivan, W. G. Trankle and L. L. Winneroski, J. Org. Chem.,
2001, 66, 5772; (b) P. Nussbaumer, G. Dorsta¨tter, M. A. Grassberger,
I. Leitner, J. G. Meingassner, K. Thirring and A. Stu¨tz, J. Med. Chem.,
1993, 36, 2115; (c) D. A. Barda, Z.-Q. Wang, T. C. Britton, S. S. Henry,
G. E. Jagdmann, D. S. Coleman, M. P. Johnson, S. L. Andis and
D. D. Schoepp, Bioorg. Med. Chem. Lett., 2004, 14, 3099; (d) D. Evans,
M. E. Cracknell, J. C. Saunders, C. E. Smith, W. R. N. Williamson,
W. Dawson and W. J. F. Sweatman, J. Med. Chem., 1987, 30, 1321.
2 For some examples, see: (a) S. M. Burkinshaw, J. Griffiths and
A. D. Towns, J. Mater. Chem., 1998, 8, 2677; (b) K. Gollnick,
A. Schnatterer and G. Utschick, J. Org. Chem., 1993, 58, 6049; (c)
D. D. Elmaleh, S. Patai and Z. Rappoport, J. Chem. Soc. C, 1971, 2637;
(d) F. Bergmann and J. Szmuszkowicz, J. Org. Chem., 1948, 70, 2748.
3 (a) V. Farina, B. Krishnan, D. R. Marshall and G. P. Roth, J. Org.
Chem., 1993, 58, 5434; (b) B. Ganchegui, P. Bertus and J. Szymoniak,
Synlett, 2001, 123.
5
5
a
52
86
Isolated yields after column chromatography.
4 A. Lindhardt, J.-P. Ebran, M. Ahlquist, P.-O. Norrby and
T. Skrydstrup, Angew. Chem., Int. Ed., 2006, 45, 3349.
5 There are only few examples of other cross coupling reactions with
nonactivated vinyl phosphates: (a) T. Hayashi, T. Fujiwa, Y. Okamoto,
Y. Katsuro and M. Kumada, Synthesis, 1981, 1001; (b) A. Sofia,
E. Karlstro¨m, K. Itami and J. E. Ba¨ckvall, J. Org. Chem., 1999, 64,
1745; (c) Y. Nan and Z. Yang, Tetrahedron Lett., 1999, 40, 3321; (d)
U. S. Larsen, L. Martiny and M. Begtrup, Tetrahedron Lett., 2005, 46,
4261.
6 N. Miyaura, Metal-Catalyzed Cross-Coupling Reactions, ed. A. de
Meijere and F. Diederich, Wiley-VCH, Weinheim, 2004, ch. 2;
N. Miyaura, Top. Curr. Chem., 2002, 219, 11; A. Suzuki,
J. Organomet. Chem., 1999, 28, 147; A. Suzuki, Hand Book of
Organometallic Chemistry for Organic Synthesis, ed. E. Negishi, John
Wiley & Sons, New York, 2002, vol. 1, p. 249; N. Miyaura and
A. Suzuki, Chem. Rev., 1995, 95, 2457.
7 M. E. Limmert, A. H. Roy and J. F. Hartwig, J. Org. Chem., 2005, 70,
9364.
Scheme 2 An example of a double Suzuki coupling with a divinyl
diphosphate.
8 For some remarkable examples, see: A. F. Littke, C. Dai and G. C. Fu,
J. Am. Chem. Soc., 2000, 122, 4020; T. E. Barder, S. D. Walker,
J. R. Martinelli and S. L. Buchwald, J. Am. Chem. Soc., 2005, 127, 4685;
K. L. Billingsley, D. W. Anderson and S. L. Buchwald, Angew. Chem.,
Int. Ed., 2006, 45, 3484.
as depicted with the six examples in Table 3 with cross coupling
yields ranging from 52 to 99%.
Finally, a double cross coupling was attempted with the divinyl
phosphate 5 and two equivalents of the phenyl boronic acid 3
(Scheme 2). This provided the 1,4-divinyl-substituted benzene 6 in
a gratifyingly high yield (94%).
9 For a recent discussion on the development and use of bulky electron
rich phosphines from various groups including those of Fu, Buchwald,
Hartwig and Beller, see: A. Zapf and M. Beller, Chem. Commun., 2005,
431.
10 For examples of Suzuki–Miyaura couplings using Ni(0)-catalysts with
aryl chlorides and sulfonates, see: (a) S. Saito, S. Oh-tani and
N. Miyaura, J. Org. Chem., 1997, 62, 8024; (b) A. F. Indolese,
Tetrahedron Lett., 1997, 38, 3513; (c) B. H. Lipshutz, A. Sclafani and
P. A. Blomgren, Tetrahedron, 2000, 56, 2139; (d) V. Percec, J.-Y. Bae
and D. H. Hill, J. Org. Chem., 1995, 60, 1060; (e) D. Zim, V. R. Lando,
J. Dupont and A. L. Monteiro, Org. Lett., 2001, 3, 3049; (f) Z.-Y. Tang,
S. Spinella and Q.-S. Hu, Tetrahedron Lett., 2006, 47, 2427; (g)
Z.-Y. Tang and Q.-S. Hu, J. Am. Chem. Soc., 2004, 126, 3058; (h)
Z.-Y. Tang and Q.-S. Hu, J. Org. Chem., 2006, 71, 2167.
In conclusion, we have provided an easy and effective access to a
variety of 1,1-diarylalkenes in acceptable to high yields with a
Ni(0)-catalyst, starting from easy accessible and stable starting
materials. Further work is in progress to exploit these reactions for
the synthesis of nonsymmetrical 1,1-diarylalkenes of medicinal
interest.
We gratefully acknowledge the Danish Natural Science
Research Council, The Danish National Research Foundation,
11 M. R. Netherton and G. C. Fu, Org. Lett., 2001, 3, 4295.
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