An efficient protocol for the stereoselective construction of multisubstituted fluorine-containing alkenes. A palladium-catalyzed bisstannylation of fluorinated internal alkynes

Article abstract of DOI:10.1021/jo9017028

(Chemical Equation Presented) On treatment of various fluorinated internal alkynes with 1.2 equiv of hexabutylditin under the influence of 2.5 mol% of Pd(t-BuNC)₂Cl₂ in THF at room temperature for 4 h, the bisstannylation proceeded s

Full text of DOI:10.1021/jo9017028

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variety of substrates. Although the bisstannylation of var-
An Efficient Protocol for the Stereoselective
Construction of Multisubstituted Fluorine-
Containing Alkenes. A Palladium-Catalyzed
Bisstannylation of Fluorinated Internal Alkynes
ious nonfluorinated alkynes has been published,2 thus far
there have been no studies on the reaction of fluorinated
alkynes. Herein we wish to describe the first bisstannylation
of fluorine-containing internal alkynes in detail.
Initially, the bisstannylation of the alkyne 1a3 with hexa-
butylditin was examined (Table 1). Thus, treatment of 1a
with 1.2 equiv of hexabutylditin in the absence of palladium
catalyst in THF at room temperature for 4 h led to quanti-
tative recovery of the starting alkyne (Table 1, entry 1). The
use of Pd(PPh3)4 (2.5 mol %) did not provide a satisfactory
result (Table 1, entry 2). In sharp contrast, the reaction in the
presence of Pd(t-BuNC)2Cl2 took place smoothly to give the
corresponding bisstannylated product 2a in 86% yield as a
sole product (entry 3). The obtained product was found to be
the trans-adduct only. With this catalyst, the bisstannylation
of various alkynes 1 was investigated.
Tsutomu Konno,* Ryoko Kinugawa, Atsunori Morigaki,
and Takashi Ishihara
Department of Chemistry and Materials Technology, Kyoto
Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto
606-8585, Japan
konno@chem.kit.ac.jp
Received August 4, 2009
As shown in entry 4 of Table 1, changing a fluoroalkyl
group from a CF3 to a CHF2 group did not cause a
significant influence on the reaction, the corresponding
trans-adduct 2b being obtained exclusively in 85% yield.
The reaction of the alkynyl ester 1c afforded the desired
product in only 48% yield as an isomeric mixture in a ratio of
82:18, while the alkynes having an aryl group, such as
p-ClC6H4, p-MeOC6H4, p-EtO2CC6H4, and p-NCC6H4
groups, could participate in the reaction nicely to give the
corresponding adducts in excellent yields (Table 1, entries 6,
7, 10, and 11). In these cases, the products were all cis-
adducts. As shown in entries 7-9 of Table 1, the position of
the substituent on the benzene ring of the alkynes did not
affect the reaction at all, leading to the exclusive formation of
the cis-adducts in high yields. However, the alkyne bearing a
p-NO2-substituted aryl group or a styryl group as R could
not be applied for the reaction successfully (Table 1, entries
12 and 13).
On treatment of various fluorinated internal alkynes with
1.2 equiv of hexabutylditin under the influence of 2.5 mol %
of Pd(t-BuNC)2Cl2 in THF at room temperature for
4 h, the bisstannylation proceeded smoothly to afford the
corresponding bisstannylated cis-adducts in high yields.
Thus obtained adducts were subjected to the Stille cross-
coupling reaction to give the corresponding tetrasubsti-
tuted fluorine-containing alkenes with defined stereo-
chemistry in good yields.
We also investigated the bisstannylation of various
γ-fluoroalkylated propargyl alcohols as well as amines in
detail.4 As listed in entries 14, 16, 17, 20, and 21 of Table 1,
various propargyl alcohols 1l, 1n, 1o, 1r, and 1s having
various aromatic substituents, such as phenyl, p-MeO-
C6H4, p-ClC6H4, 1-naphthyl, and 2-furyl moieties, could
participate well in the bisstannylation to give the corre-
sponding adducts 2l, 2n, 2o, 2r, and 2s, respectively, in high
to excellent yields in a highly cis-selective manner. Addi-
tionally, the position of the substituent on the benzene ring
of the alkynes did not influence the reaction at all, the cis-
adducts 2o-q being afforded in high yields (Table 1, entries
17-19). Various aliphatic substituents, such as n-hexyl,
cyclohexyl, and β-styryl groups, did not bring about a
significant change on the reaction (Table 1, entries
22-24). However, the alkynes having a bulky substituent,
Bisstannylation of alkynes has become a powerful syn-
thetic tool in view of versatile elaborations: two C-Sn bonds
are simultaneously introduced across the triple bonds of
alkynes in a syn-selective manner to give vinylstannane,
which can be converted into variously multisubstituted
ethenes with retention of configuration through the Migita-
Kosugi-Stille cross-coupling reaction.1 Furthermore, high
chemoselectivity and mild reactivity of organostannanes
as compared with other organometallics, such as organo-
lithium reagents, Grignard reagents, and so on, make
the reactions extremely useful and applicable to a wide
(1) For a review on the bisstannylation of alkynes, see: Beletskaya, I.;
Moberg, C. Chem. Rev. 1999, 99, 3435–3462.
(2) (a) Mancuso, J.; Lauten, M. Org. Lett. 2003, 5, 1653–1655. (b) Carter,
N.; Mabon, R.; Richecoeur, A. M. E.; Sweeney, J. B. Tetrahedron 2002, 58,
9117–9129. (c) Beaudet, I.; Parrain, J.-L.; Quintard, J.-P. Tetrahedron Lett.
1991, 32, 6333–6336. (d) Mabon, R.; Richecoeur, A. M. E.; Sweeney, J. B. J.
Org. Chem. 1999, 64, 328–329. (e) Casson, S.; Kocienski, P.; Reid, G.; Smith,
N.; Street, J. M.; Webster, M. Synthesis 1994, 1301–1309. (f) Piers, E.; Skerlj,
R. T. Can. J. Chem. 1994, 72, 2468–2482. (g) Piers, E.; Skerlj, R. T. J. Chem.
Soc., Chem. Commun. 1986, 626–627. (h) Mitchell, T. N.; Amamria, A.;
Killing, H.; Rutchow, D. J. Organomet. Chem. 1986, 304, 257–265.
(3) (a) Konno, T.; Morigaki, A.; Ninomiya, K.; Miyabe, T.; Ishihara, T.
Synthesis 2008, 564–572. For the synthetic methods for other fluorine-
containing alkynes, see: (b) Konno, T.; Chae, J.; Kanda, M.; Nagai, G.;
Tamura, K.; Ishihara, T.; Yamanaka, H. Tetrahedron 2003, 59, 7571–7580.
(4) (a) Konno, T.; Moriyasu, K.; Ishihara, T. Synthesis 2009, 1087–1094.
(b) Yamazaki, T.; Mizutani, K.; Kitazume, T. J. Org. Chem. 1995, 60, 6046–
6056. (c) Mizutani, K.; Yamazaki, T.; Kitazume, T. J. Chem. Soc., Chem.
Commun. 1995, 51–52.
8456 J. Org. Chem. 2009, 74, 8456–8459
Published on Web 10/05/2009
DOI: 10.1021/jo9017028
r
2009 American Chemical Society

Konno et al.
JOCNote
TABLE 1. Bisstannylation of Various Alkynes
aDetermined by 19FNMR. Values in parentheses are of isolated yield. bIn the absence of palladium catalyst. cPd(PPh3)4 was used instead of
Pd(t-BuNC)2Cl2. dThe isomeric ratio was 82:18.
such as tert-butyldimethylsilyloxy, tert-butyl, and 1-hydro-
xy-1-phenylethyl groups, did not react with hexabutylditin,
the starting alkynes being recovered in high yields (Table 1,
entries 15, 25, and 26). Neither propargylamine 1y nor
hydroxylamine 1z underwent the bisstannylation at all,
resulting in quantitative recovery of the starting amine
(Table 1, entries 27 and 28).
As synthetic applications of the bisstannylated adducts, 2a
and 2e were subjected to the Stille cross-coupling reaction to
synthesize the multisubstituted fluorine-containing alkenes
(Scheme 1).5 Thus, treatment of 2a or 2e with 2.4 equiv of
(5) (a) Konno, T.; Takehana, T.; Chae, J.; Ishihara, T.; Yamanaka, H.
J. Org. Chem. 2004, 69, 2188–2190. (b) Huang, X.; Xiong, Z.-C. Synth.
Commun. 2003, 33, 2511–2517.
J. Org. Chem. Vol. 74, No. 21, 2009 8457

Konno et al.
SCHEME 2. Determination of the Stereochemistry
JOCNote
SCHEME 1. The Stille Cross-Coupling Reaction
iodobenzene in the presence of 20 mol % each of Pd(PPh3)4
and CuI6 in DMF at 70 °C for 6 h gave the corresponding
tetrasubstituted fluorine-containing alkene 3a or 3e in 46%
or 51% yield, respectively.7
SCHEME 3. A Proposed Mechanism
The structures of all new bisstannylated adducts 2a-v
were confirmed as follows (Figure 1).
FIGURE 1. Determination of the Stereochemistry with the C-P
Coupling Constants.
It is recognized that for various vinylphosphonates, the
3JC1-P coupling constant is generally smaller than 3JC2-P in
3
3
the 13C NMR, and that JC1-P and JC2-P are 6-8 and
of Ha-Hb of 4t in 1H NMR was found to be 11.6 Hz, while
that of the known E isomer 5t has been reported as 15.7 Hz.11
Therefore, the stereochemistry of 4t is assigned as the cis
configuration, suggesting that the bisstannylation of 1t
occurred in an exclusively cis-selective manner.
The structures of the other products were determined on
the basis of the comparison with the chemical shifts of 2a, 2e,
and 2t in 19F NMR.
These results may allow us to draw the reaction mechan-
ism as described in Scheme 3. Thus, the present bisstannyl-
ation presumably proceeds via (1) generation of Pd(0)
(t-BuNC)2 through the reduction of Pd(t-BuNC)2Cl2 by
(Bu3Sn)2, (2) oxidative addition of (Bu3Sn)2 to Pd(0)
(t-BuNC)2 to form the stannylpalladium intermediate Int-
A, (3) coordination of the alkyne 1 to the palladium center of
Int-A (as shown by Int-B) and subsequent insertion into the
Sn-Pd bond giving rise to the vinylpalladium intermediate
Int-C and/or Int-D, and (4) reductive elimination of Int-C
and/or Int-D to afford the bisstannylated cis-product 2 and
regeneration of Pd(0)(t-BuNC)2.
20-25 Hz, respectively.5b,8 Therefore, the small JC1-P
(4.9 Hz) and the large JC2-P coupling constant (30.6 Hz)
3
3
of 3a are consistent with the cis and trans configuration of Ph
or CF3 with respect to phosphorus, respectively. This fact
suggests that the bisstannylation of 1a proceeded in a trans-
selective fashion. On the other hand, 3e, bearing a p-meth-
oxyphenyl group is the known compound,9 of which the
stereochemistry was determined as Z. This means that the
bisstannylation of 1e took place in a cis-selective manner.
Additionally, treatment of 2t, derived from the bisstannyl-
ation of the propargyl alcohol 1t, with concd HCl in CH3CN
at room temperature for 1.5 h, followed by the addition of
NaHCO3 and DBU, gave the corresponding destannylated
product 4t in 49% yield (Scheme 2).10 The coupling constant
(6) For the effect of copper(I) salt, see: (a) Farina, V.; Kapadia, S.;
Krishnan, B.; Wang, C.; Liebeskind, L. S. J. Org. Chem. 1994, 59, 5905–5911.
(b) Liebeskind, L. S.; Fengl, R. W. J. Org. Chem. 1990, 55, 5359–5364.
(7) Treatment of 2e with 2.4 equiv of Ph2ICl instead of PhI in the presence
of 20 mol % of Pd(PPh3)4 and 1.5 equiv of CuI in DMF at room temperature
for 6 h gave the corresponding Stille cross-coupling product 3e in higher yield
(75% yield).
(8) (a) Drag, M.; Kafarski, P.; Pirat, J.-L.; Cristau, H.-J. Phosphorus,
Sulfur Silicon 2002, 177, 1153–1156. (b) Cristau, H.-J.; Mbianda, X. Y.;
Beziat, Y.; Gasc, M.-B. J. Organomet. Chem. 1997, 529, 301–311. (c) Cristau,
H.-J.; Gasc, M.-B.; Mbianda, X. Y. J. Organomet. Chem. 1994, 474, C14–
C15.
In the case of 1a,b, it is highly possible that Int-C1 and Int-
C2 are in equilibrium,12 in which Int-C2 is more stable due to
(11) Yamazaki, T.; Ichige, T.; Kitazume, T. Org. Lett. 2004, 6, 4073–
4076.
(12) It has been reported that (Z)-2,3-bis(trimethylstannyl)alk-2-enoates
are thermally unstable, and that they easily isomerize into the (E) isomer at
75-95 °C. See ref 2g.
(9) Konno, T.; Taku, K.; Ishihara, T. J. Fluorine Chem. 2006, 127, 966–
972.
(10) Miura, K.; Saito, H.; Fujisawa, N.; Hosomi, A. J. Org. Chem. 2000,
65, 8119–8122.
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Konno et al.
JOCNote
the interaction between tin and the phosphonyl oxygen
atom. Then, the reductive elimination takes place from
Int-C2, giving the corresponding trans-adduct exclusively.13
In conclusion, we have demonstrated the bisstannylation
of various fluorine-containing internal alkynes with hexabu-
tylditin in the presence of Pd(t-BuNC)2Cl2 in THF at room
temperature. The reaction proceeded smoothly in a highly
cis-selective manner to give the corresponding adducts in
good to high yields. The obtained vinylstannanes were
subjected to the Stille cross-coupling reaction conditions,
the corresponding tetrasubstituted alkenes being afforded
with high stereoselectivity in good yields.
and Pd(t-BuNC)2Cl2 (0.002 g, 0.00625 mmol, 2.5 mol %) in
THF (2.5 mL) was added a THF solution of hexabutylditin
(0.176 g, 0.30 mmol) at room temperature. The whole mixture
was stirred for 4 h at room temperature. The reaction was then
quenched with H2O. The resulting mixture was extracted three
times with Et2O. The combined ethereal layers were dried over
Na2SO4 and concentrated in vacuo. The residue was chromato-
graphed on silica gel (hexane:EtOAc 30:1) to afford (Z)-1,2-
bis(tributylstannyl)-1-(4-chlorophenyl)-3,3,3-trifluoropropene
(2d) (0.14 g, 0.17 mmol, 69% yield). 1H NMR (CDCl3) δ
0.79-1.55 (m, 54H), 6.73 (d, J = 8.4 Hz, 2H), 7.21 (d, J =
8.4 Hz, 2H); 13C NMR (CDCl3) δ 11.9 (d, J = 1.6 Hz), 12.1,
13.2, 13.3, 13.4, 13.5, 27.0, 27.1, 27.2, 28.1, 30.3, 124.5 (q, J =
281.0 Hz), 130.4, 145.5, 146.5 (q, J = 28.1 Hz), 172.5 (q, J =
7.5 Hz); 19F NMR (CDCl3) δ -49.2 (s, 3F); IR (neat) 2957,
2871, 1481, 1463, 1377, 1227, 1180, 1135, 960, 864 cm-1. Anal.
Calcd for C33H58ClF3Sn2: C, 50.51; H, 7.45. Found: C, 50.25;
H, 7.67.
Experimental Section
Typical Procedure for Bisstannylation. To a solution of 1-(4-
chlorophenyl)-3,3,3-trifluoropropyne (1d) (0.051 g, 0.25 mmol)
(13) To clarify the reaction mechanism, we attampted the bisstannylation
of 1a with hexabutylditin in the presence of 20 mol % of 4-tert-butyl-2,6-
dimethylphenol and 2.5 mol % of Pd(t-BuNC)2Cl2 in THF at room
temperature for 4 h. As a result, the corresponding bisstannylated trans-
adduct 2a was obtained in 90% yield. This means that the radical mechanism
is excluded.
Supporting Information Available: Characterization data,
1H and/or 13C NMR spectra of 2a-i, 2l, 2n-v, 3a, and 4t. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 74, No. 21, 2009 8459