Palladium-catalyzed markovnikov terminal arylalkynes hydrostannation: Application to the synthesis of 1,1-diarylethylenes

Article abstract of DOI:10.1021/jo802460z

The palladium-catalyzed hydrostannation of terminal aryla-lkynes was achieved. The regioselectivity of the H-Sn bond addition across the triple bond was found to be controlled by an ortho substituent on the aromatic ring, whatever its electronic nature, to give exclusively α-branched vinylstan-nanes 2 in accordance with Markovnikov's rule. Subsequent Stille cross-coupling reaction of 2 with a variety of aryl halides readily provided, in moderate to good yields, a family of functionalized 1,1-diarylethylenes 1.

Full text of DOI:10.1021/jo802460z

SCHEME 1
Palladium-Catalyzed Markovnikov Terminal
Arylalkynes Hydrostannation: Application to the
Synthesis of 1,1-Diarylethylenes
Abdallah Hamze, Damien Veau, Olivier Provot,
Jean-Daniel Brion, and Mouaˆd Alami*
Laboratoire de Chimie The´rapeutique, Faculte´ de Pharmacie,
UniVersite Paris-Sud, CNRS, BioCIS, UMR 8076, rue J. B.
Cle´ment, Chaˆtenay-Malabry, F-92296, France
one hand, the cine substitution4 constitutes a major limitation
which is most frequently encountered in the Stille coupling of
sterically encumbered 1-substituted vinylstannanes of type 2.
Additionally, there are no available procedures for effecting this
coupling in good yield. On the other hand, the literature methods
for the synthesis of R-styryltributyltin5 2 from 3 afforded a
mixture of regioisomeric vinylstannanes which resist chromato-
graphic separation.6 Consequently, the regiochemical control
of the hydrostannation of terminal arylalkynes 3 has remained
a prominent unanswered synthetic challenge. In the present
work, these problems have been overcome.
mouad.alami@u-psud.fr
ReceiVed October 8, 2008
Previously, we reported the effect of ortho substituents on
the regioselectivity in the transition-metal (Pd, Pt)-catalyzed
hydrostannation7 and hydrosilylation8 of aryl-substituted alkynes
and related compounds.9 In the case of internal arylalkynes, such
as diarylalkynes and aliphatic arylalkynes, we demonstrated that
the presence of an ortho substituent on arylalkynes promoted a
highly regioselective addition of the metal hydride to the triple
bond, regardless of the electronic nature of the substituent (π-
electron-withdrawing or σ-electron-donating group). Thus, the
hydrometalation formed a single product where the metal moiety
(SnBu3, SiR3) was delivered to the carbon proximal to the ortho-
substituted aryl nucleus. Encouraged by these results, we
envisioned to extend this ortho-directing effect (ODE) to
terminal arylalkynes 3 in order to provide R-branched vinylmetal
species of type 2, suitable for the synthesis of 1,1-diarylethenes
1. In the case of the Pt-catalyzed hydrosilylation of terminal
The palladium-catalyzed hydrostannation of terminal aryla-
lkynes was achieved. The regioselectivity of the H-Sn bond
addition across the triple bond was found to be controlled
by an ortho substituent on the aromatic ring, whatever its
electronic nature, to give exclusively R-branched vinylstan-
nanes 2 in accordance with Markovnikov’s rule. Subsequent
Stille cross-coupling reaction of 2 with a variety of aryl
halides readily provided, in moderate to good yields, a family
of functionalized 1,1-diarylethylenes 1.
1,1-Diarylethylenes 1, an important structural motif found
in biologically active compounds,1 can, in principle, be accessed2
from terminal arylalkynes 3 via Stille cross-coupling reaction
between intermediates 2 and aryl halides (Scheme 1).3 In this
strategy, two synthetic challenges remain to be solved. On the
(4) When styrylstannanes are coupled with aryl halides, a reversal of
regioselectivity is often observed with formation of (Z)- and (E)-cine substitution
regioisomers. (a) Stork, G.; Isaacs, R. C. A. J. Am. Chem. Soc. 1990, 112, 7399–
7400. (b) Levin, J. I. Tetrahedron Lett. 1993, 34, 6211–6214. (c) Quayle, P.;
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5625–5628. (b) Hamze, A.; Provot, O.; Brion, J.-D.; Alami, M. Synthesis 2007,
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Tetrahedron Lett. 2008, 49, 1107–1110.
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10.1021/jo802460z CCC: $40.75
Published on Web 12/10/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1337–1340 1337

TABLE 1. Hydrostannation of Para- and Meta-Substituted
Terminal Arylalkynes: Effect of Substitution Pattern on
Regioselectivitya
TABLE 2. Hydrostannation of Ortho-Substituted Terminal
Arylalkynes 3 To Give Markovnikov Addition Products r-2a
a All reactions were conducted with Bu3SnH (1.2 equiv) in the
presence of 2 mol % of PdCl2(PPh3)2 in THF. b Ratio was determined
by 1H of the crude reaction mixture. c Isolated yield. d The product was
isolated as a mixture of r-2/ꢀ-2 regioisomers. e Not determined. f The
product was isolated with inseparable side product 4.
a All reactions were conducted with Bu3SnH (1.2 equiv) in the
presence of 2 mol % of PdCl2(PPh3)2 in THF. b Ratio was determined
by 1H of the crude reaction mixture. c Yield refers to isolated pure r-2
products.
alkynes, although conditions producing exclusively the ꢀ-isomer
have been developed by our group,10 we did not succeed in
synthesizing selectively the R-isomer,11 even with alkyne sub-
strates bearing an ortho-directing substituent.8b For the success
of our goal, we decided to examine the ability of ODE to
produce regioselectively R-styryltributyltin derivatives 2. The
results of this study are now discussed.
In our initial screening conditions, phenylacetylene was
evaluated as baseline control. An almost equal product distribu-
tion (r-2a/ꢀ-2a ) 49/51) was obtained for the hydrostannation
of phenylacetylene with Bu3SnH in the presence of PdCl2(PPh3)2
(2 mol %) in THF (Table 1, entry 1). The effect of substitution
patterns on regioselectivity was then evaluated. With para- or
meta-substituted phenylacetylenes bearing an electron-donating
group, except for benzyloxy group, no ꢀ-isomer could be
observed, but the reaction gave a mixture of inseparable
R-isomers 2 and olefins 4 (entries 2-5). Surprisingly, with
4-benzyloxyphenylacetylene 3f, no trace of the corresponding
olefin 4f was detected, but the hydrostannation proceeded with
a modest regioselectivity (r-2f/ꢀ-2f ) 61/39, entry 6). As
expected, this trend in R-selectivity is more marked with para-
substituted phenylacetylenes bearing π-electron-withdrawing
groups which induced strong polarization of the carbon-carbon
triple bond. Thus, a strong preference for R-branched vinyl-
stannane products (r-2 ) 78 to 95) is observed with para-
substituted phenylacetylene bearing a bromo, a methoxycarbo-
nyl, a cyano, or a formyl substituent (entries 7-10).
As summarized in Table 2, under identical reaction condi-
tions, all ortho substituents, regardless of their electronic nature,
directed the tin moiety to the sterically more hindered R-position
of the triple bond to give exclusively branched styrylstannanes
r-2 in good to excellent yields (entries 1-8). In these cases,
no side products of type 4 were detected. Noteworthy is the
tolerance of the reaction for a variety of functional groups,
including bromides, free alcohols, esters, nitriles, and aldehydes.
These results clearly demonstrated that the ortho substituent
regiocontrol concept could be also successfully extended to the
palladium-catalyzed hydrostannation of terminal arylalkynes to
provide a general access to R-styryltributyltin derivatives 2. With
the series of R-styrylstannanes in hand, we then focused our
attention on their coupling with a variety of aryl halides.
Although Stille coupling has already been established as an
efficient method for the formation of carbon-carbon bonds, the
reaction with sterically hindered R-branched vinylstannanes is
(10) For the regioselective formation of ꢀ-(E)-vinylsilanes from terminal
arylalkynes, see: (a) Hamze, A.; Provot, O.; Brion, J.-D.; Alami, M. Tetrahedron
Lett. 2008, 49, 2429–2431. (b) Hamze, A.; Provot, O.; Brion, J.-D.; Alami, M.
J. Organomet. Chem. 2008, 693, 2789–2797.
(11) For the Ru-catalyzed Markovnikov terminal alkyne hydrosilylation, see:
Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2001, 123, 12726–12727.
1338 J. Org. Chem. Vol. 74, No. 3, 2009

far from trivial due to very slow reaction rates12 and competing
cine substitution. To find the proper reaction conditions, the
coupling of ortho-substituted styryltributyltin r-2p with ethyl
4-iodobenzoate was selected as a model reaction. Reaction
conditions, such as Pd source, ligand, solvent, and additive,13
were examined based on several reported Stille conditions. After
an extensive study, optimal conditions were found to require
r-2p (1.0 equiv), ethyl 4-iodobenzoate (1.2 equiv), Pd(OAc)2
(7 mol %), and XPhos (14 mol %) in DMF at 80 °C. Thus,
1,1-diarylethylene 1a was formed in a 72% satisfactory yield
(Table 3, entry 1). It should be noted that a careful examination
of the crude reaction mixture by 1H revealed the absence of the
cine substitution product.
TABLE 3. Coupling of r-2p with a Set of Aryl Halides
Further investigations of the efficiency and scope of the
present method were performed with styryltributyltin r-2p
having an electron-withdrawing substituent. As seen in Table
3, the protocol described above proved to be quite general,
allowing the coupling to proceed with a variety of aryl halide
groups substituted, including iodides and bromides. Both
electron-withdrawing (entries 1-6) and electron-donating (en-
tries 8-12) aryl halides were coupled cleanly to provide the
corresponding 1,1-diarylethylenes 1 in moderate to good yields.
As expected, electron-poor aryl iodides delivered 1,1-diaryl-
ethylenes 1 in higher yields (entries 1-5) than those bearing
an electron-donating substituent (entries 8-11). Even switching
the substituent from the para to the meta position of the aryl
moiety did not affect significantly the coupling yield (entries 2
and 4 vs entries 3 and 5). It may be pointed out that Stille
coupling of r-2p with a lower reactive aryl bromide provided
the expected 1,1 diarylethylene 1f in a good yield (entry 6).
Finally, it is apparent that the coupling tolerated a number of
functional groups, including esters (entry 1), nitriles (entries 2
and 3), sp2 chlorides (entries 4 and 5), aldehydes (entry 6), and
free alcohols (entry 10).
With the feasibility of the Stille reaction of electron-poor
styrylstannane r-2p secured, we then focused on the coupling
of an electron-rich R-styrylstannane with various aryl halides.
To this end, r-2k with an ortho methoxy substituent on the
aryl nucleus and ethyl 4-iodobenzoate were mixed under the
previous optimal conditions. However, the reaction failed and
the vinylstannane r-2k was recovered unchanged together with
notable amounts of the ethyl 4-iodobenzoate homocoupling
product. Addition of CuI or CsF at higher temperatures gave
low yields of the coupling product 1m (<15%), whereas a
combination14 of the two salts gave an improved 51% yield.
After extensive optimization, we found that Stille coupling of
r-2k (1 equiv) with ethyl 4-iodobenzoate (0.9 equiv) using
Pd(OAc)2 (10 mol %), XPhos (20 mol %), CuI (20 mol %),
and CsF (2 equiv) in DMF at 100 °C gave the expected 1,1-
diarylethylene 1m (Table 4, entry 1) in an acceptable 59% yield
when the reaction was achieved in a sealed tube. Several aryl
a Isolated yield of 1 after column chromatography. All the reported
compounds exhibited spectral data in agreement with assigned
structures.
halides with different substitution patterns were tested and all
coupled with satisfactory yields. The results are summarized in
Table 4.
As the Stille coupling of r-2 with electron-poor aryl halides,
the presence of an ortho electron-donating group on the
styrylstannane r-2k did not affect significantly the reaction
outcome (entries 1-3). 4-Bromobenzaldehyde reacted also
under these conditions but gave 1p with a modest 40% yield
(entry 4). Finally, nonactivated aryl iodides such as iodobenzene
and 3-iodotoluene reacted cleanly with r-2k, and there was a
noticeable improvement in yields (entries 5 and 6).
To obviate direct manipulation and purification of the
styryltributyltin coupling partner, we next examined a one-pot
Pd-catalyzed hydrostannation/Stille coupling sequence as it
would be economically and environmentally advantageous over
multistep syntheses (Scheme 2). In a typical experiment, we
achieved this transformation in a sequential way by mixing, in
a first step, Bu3SnH with terminal alkyne 3p in THF under
(12) During the synthesis of orally active cephalosporins, Kawabata showed
that, when performing the Stille coupling with a mixture of vinylstannanes 2a
and 2b, only 2b reacted, leading to a linear olefin as the sole product. Yamamoto,
H.; Terasawa, T.; Ohki, A.; Shirai, F.; Kawabata, K.; Sakane, K.; Matsumoto,
S.; Matsumoto, Y.; Tawara, S. Bioorg. Med. Chem. 2000, 8, 43–54.
(13) (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585–9595.
(b) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J. Org.
Chem. 1994, 59, 5905–5911. (c) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc.
1986, 108, 3033–3040. (d) Casado, A. L.; Espinet, P.; Gallego, A. M. J. Am.
Chem. Soc. 2000, 122, 11771–11782.
(14) Mee, S. P. H.; Lee, V.; Baldwin, J. E. Chem.sEur. J. 2005, 11, 3294–
3308.
J. Org. Chem. Vol. 74, No. 3, 2009 1339

TABLE 4. Coupling of r-2k with a Set of Aryl Halidesa
addition of Bu3SnH to the triple bond. Thus, regardless of the
electronic nature of the ortho substituent, this procedure provides
a general route to R-styrylstannanes 2. Additionally, we have
succeeded in developing reaction conditions for the Stille
coupling of various aryl halides with R-styrylstannanes 2 bearing
either an electron-donating or an electron-withdrawing substitu-
ent at the ortho position of the aromatic ring. These new
protocols have proved to be highly effective to avoid the
problematic cine substitution, which is a well-documented side
reaction in the palladium-assisted elaboration of R-styrylstan-
nanes to 1,1-diarylethylenes 1. More interestingly, a one-pot
approach of this method that tolerates several functional groups
is successfully enlightened, with the additional benefit of
requiring only a single purification step. Additional investiga-
tions of the synthetic utility of this transformation into the
synthesis of molecules of biological interest are currently
underway and will be reported in due course.
Experimental Section
Representative Procedure for the Synthesis of 1a. To a mixture
of Pd(OAc)2 (15.72 mg, 0.07 mmol), Xphos (66.75 mg, 0.14 mmol),
and r-2p (0.45 g, 1 mmol) in DMF (10 mL) was added dropwise
ethyl 4-iodobenzoate (0,33 g, 1.2 mmol) in DMF (3 mL). The
mixture was stirred under an argon atmosphere for 12 h at 80 °C,
then cooled and diluted with an equal volume of saturated aqueous
KF (13 mL). The two-phase mixture was stirred vigorously
overnight then diluted with diethyl ether (20 mL). The separated
organic layer was washed with saturated ammonium chloride (2 ×
20 mL) and brine (20 mL), then dried and evaporated. Purification
by chromatography on silica gel (cyclohexane/Et2O 90/10) gave
a Reactions were run in sealed tubes. b Isolated yield of 1 after
column chromatography. All the reported compounds exhibited spectral
data in agreement with assigned structures. c When exposing to
microwave irradiation, the homocoupling of ethyl 4-iodobenzoate
predominated and 1m was isolated with a lower yield (28%). d The
reaction conditions were not optimized.
1
1a (223 mg, 72%): Rf 0.24 (cyclohexane/Et2O 90/10); H NMR
(300 MHz) δ 7.87 (d, 2H, J ) 8.2 Hz), 7.78 (dd, 1H, J ) 7.6, 1.3
Hz), 7.48 (td, 1H, J ) 7.6, 1.3 Hz), 7.40-7.16 (m, 2H), 7.20 (d,
2H, J ) 8.2 Hz), 5.69 (s, 1H), 5.27 (s, 1H), 4.28 (q, 2H, J ) 7.1
Hz), 3.43 (s, 3H), 1.30 (t, 3H, J ) 7.1 Hz); 13C NMR (75 MHz) δ
167.8 (C), 166.5 (C), 149.2 (C), 145.4 (C), 142.0 (C), 132.0 (CH),
131.5 (CH), 130.7 (C), 130.3 (CH), 129.6 (2CH), 129.5 (CH), 128.1
(CH), 126.5 (2CH), 116.1 (CH2), 61.0 (CH2), 51.9 (CH3), 14.4
(CH3); IR (ν, cm-1) 2983, 1711, 1607, 1447, 1433, 1406, 1367,
1269, 1181, 1124, 1104, 1068, 1018, 964, 908, 863, 817, 772, 714;
MS (ESI+) 311.1 (M + H)+, 332.9 (M + Na)+. Anal. Calcd for
C19H18O4 (310.34): C, 73.53; H, 5.85. Found: C, 73.41; H, 5.79.
SCHEME 2. One-Pot Synthesis of 1,1-Diarylethylene 1b
from 3p via a Hydrostannation/Stille Reaction Sequence
palladium catalysis. After removal of the solvent under reduced
pressure, DMF, Pd(OAc)2 (7 mol %), XPhos (14 mol %), and
4-iodobenzonitrile (1.2 equiv) were introduced in a second step
and heated at 80 °C for 12 h. Thus, under this protocol, we
were pleased to observe that the sequential reaction worked very
well and provided the desired 1,1-diarylethylene 1b in a 51%
yield, despite the fact that the reaction conditions had never
been optimized.
Acknowledgment. The authors thank the CNRS for support
of this research.
Supporting Information Available: Full experimental pro-
cedures, characterization data, copies of 1H and 13C NMR spectra
of products. This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, we have studied the palladium-catalyzed hy-
drostannation of terminal arylalkynes and demonstrated that the
ortho substituent in alkyne substrates promotes the regioselective
JO802460Z
1340 J. Org. Chem. Vol. 74, No. 3, 2009