A remarkable regiocontrol in the palladium-catalyzed silylstannylation of fluoroalkylated alkynes-highly regio- and stereoselective synthesis of multi-substituted fluorine-containing alkenes

Article abstract of DOI:10.1039/c3ob41903g

On treating fluorine-containing internal alkynes with 1.2 equiv. of (trimethylsilyl)tributyltin in the presence of 2.5 mol% of Pd(PPh ₃)₂Cl₂ in THF at the reflux temperature for 6 h, the silylstannylation reaction proceeded smoothly to afford the corresponding silylstannylated adducts in high yields in a highly regio- and cis-selective manner. Switching the palladium catalyst from Pd(PPh₃) ₂Cl₂ to Pd(t-BuNC)₂Cl₂ promoted the formation of silylstannylated adducts with opposite regioselectivity. The thus obtained silylstannylated adducts were subjected to Stille cross-coupling reactions to furnish the corresponding fluoroalkylated vinylsilanes whose C-Si bond was converted to a C-C bond by treating with aldehyde in the presence of TBAF and Zn(OTf)₂, the corresponding fluoroalkylated tetra-substituted alkenes being afforded in moderate to good yields with a defined stereochemistry. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3ob41903g

Organic &
Biomolecular Chemistry
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A remarkable regiocontrol in the palladium-
catalyzed silylstannylation of fluoroalkylated
alkynes – highly regio- and stereoselective synthesis
of multi-substituted fluorine-containing alkenes†
Cite this: Org. Biomol. Chem., 2014,
12, 1611
Tsutomu Konno,*a Ryoko Kinugawa,a Takashi Ishiharaa and Shigeyuki Yamadab
On treating fluorine-containing internal alkynes with 1.2 equiv. of (trimethylsilyl)tributyltin in the presence
of 2.5 mol% of Pd(PPh3)2Cl2 in THF at the reflux temperature for 6 h, the silylstannylation reaction pro-
ceeded smoothly to afford the corresponding silylstannylated adducts in high yields in a highly regio- and
cis-selective manner. Switching the palladium catalyst from Pd(PPh3)2Cl2 to Pd(t-BuNC)2Cl2 promoted the
formation of silylstannylated adducts with opposite regioselectivity. The thus obtained silylstannylated
adducts were subjected to Stille cross-coupling reactions to furnish the corresponding fluoroalkylated
vinylsilanes whose C–Si bond was converted to a C–C bond by treating with aldehyde in the presence of
TBAF and Zn(OTf)2, the corresponding fluoroalkylated tetra-substituted alkenes being afforded in moder-
ate to good yields with a defined stereochemistry.
Received 19th September 2013,
Accepted 19th December 2013
DOI: 10.1039/c3ob41903g
www.rsc.org/obc
Introduction
The transition metal-catalyzed silylstannylation has been
recognized as a powerful synthetic tool in organic synthesis
because two different types of carbon–metal bonds, such as
carbon–tin (C–Sn) and carbon–silicon (C–Si) bonds, are simul-
taneously introduced across a triple bond in a stereoselective
manner to afford the corresponding alkenyl metal intermediate
which can be easily transformed into various substituted
ethenes with retention of configuration through the Migita–
Kosugi–Stille and Hiyama cross-coupling reactions (Scheme 1).1
Furthermore, the high chemoselectivity and very mild reac-
tivity of organostannanes and organosilanes, as compared
with other organometallic reagents, such as lithium, mag-
nesium, chromium reagents, and so on, make the silylstannyl-
ation and the following coupling reactions extremely valuable
and applicable for preparing a wide range of versatile
substances.
Scheme 1 Construction of multi-substituted alkenes via silylstannyla-
tion of alkynes.
studied so far.2 However, little attention has been paid to such
a reaction of fluoroalkylated alkynes, though selective prepa-
ration of fluoroalkyl-substituted alkenes has been of great
importance since they can be considered versatile building
blocks3 as well as monomers for high performance fluorinated
materials.4
It is not surprising, therefore, that the silylstannylation
reaction of various non-fluorinated alkynes has been extensively
Recently, we focused our efforts on the bismetallation reac-
tion of fluorine-containing internal alkynes revealed that
stereoselective bisstannylation reactions, followed by Stille
cross-coupling reactions, proceeded smoothly to afford fluoro-
alkylated tetra-substituted alkenes in good yields with a
defined stereochemistry.5 During the course of our continuous
bismetallation studies, we found that the fluoroalkylated
alkynes underwent palladium-catalyzed silylstannylation
aDepartment of Chemistry and Material Technology, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto 606-0962, Japan. E-mail: konno@kit.ac.jp;
Fax: +81 75 724 7580; Tel: +81 75 724 7517
bDepartment of Applied Chemistry, Graduate School of Engineering, Tokyo University
of Agriculture and Technology, 2-24-16 Nakamachi, Koganei 184-8588, Japan.
E-mail: s_yamada@cc.tuat.ac.jp
†Electronic supplementary information (ESI) available: Detailed experimental
procedures and the characteristic of new compounds. See DOI:
10.1039/c3ob41903g
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Thus, on treating 1a with 1.2 equiv. of (trimethylsilyl)tribu-
tyltin (Me3SiSnBu3) in the presence of 2.5 mol% of Pd(PPh3)4
in THF at the reflux temperature for 6 h, the reaction success-
fully proceeded, the corresponding silylstannylated products
2a and 3a being provided in 97% combined yield without any
trace of the starting alkyne 1a (entry 1).
In this case, we were very pleased that an excellent regio-
selectivity (2a : 3a = 96 : 4) was observed. The employment of
Pd(PPh3)2Cl2 instead of Pd(PPh3)4 was also found to be very
effective, leading to the products 2a + 3a in 85% yield with an
excellent regioselectivity (2a : 3a = 95 : 5) (entry 2). On the other
hand, other palladium catalysts, such as PdCl2, Pd(OAc)2, and
Pd2(dba)3, did not work well (entries 3–5). Palladium catalysts
coordinated with tricyclohexylphosphine or tri(o-tolyl)phos-
phine were not suitable for the present reaction as well
(entries 6 and 7). Very surprisingly, the catalyst, generated by
treating Pd(OAc)2 with 1,1,3,3-tetramethylbutyl isocyanide,2d
led to quantitative formation of 2a and 3a (entry 8). Addition-
ally, the regioselectivity opposite to that in the Pd(PPh3)4 or
Pd(PPh3)2Cl2-catalyzed reaction was observed (2a : 3a = 27 : 73).
The silylstannylation reaction at ambient temperature resulted
Scheme 2 Preparation of fluoroalkylated tetra-substituted alkenes via
Pd(0)-catalyzed silylstannylation/coupling reactions with electrophiles.
reactions in a regio- and stereoselective manner, whose regio-
selectivity was fully inverted by switching a palladium catalyst.
In this paper are presented the details of such regio- and
stereoselective silylstannylation reactions (Scheme 2).
Results and discussion
Our initial studies were begun with an optimization of the
reaction conditions for the palladium-catalyzed silylstannyla-
tion reaction of fluorine-containing internal alkyne 1a. The
results are listed in Table 1.
in a slight improvement of the regioselectivity (2a : 3a = 18 : 82)
5,6
(entry 9). Furthermore, Pd(t-BuNC)2Cl2
also catalysed
Table 1 Optimization of the silylstannylation reaction of fluorine-containing internal alkyne 1a
Entry
Catalyst
Solvent
Temp./°C
Yielda/% of 2a + 3a
Ratioa 2a : 3a
Recoverya/% of 1a
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(PPh3)2Cl2
PdCl2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3 + PCy3
Pd2(dba)3 + P(o-Tol)3
Pd(OAc)2 +
THF
THF
THF
THF
THF
THF
THF
THF
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
97
85
12
09
5
17
29
Quant
96 : 4
95 : 5
—
—
—
—
55 : 45
27 : 73
0
0
76
73
80
71
50
0
9
Pd(OAc)2 +
THF
rt
Quant
18 : 82
0
10
11
12
13
14
15
16b
17c
Pd(t-BuCN)2Cl2
Pd(t-BuCN)2Cl2
Pd(t-BuCN)2Cl2
Pd(t-BuCN)2Cl2
Pd(t-BuCN)2Cl2
Pd(t-BuCN)2Cl2
Pd(t-BuCN)2Cl2
Pd(t-BuCN)2Cl2
THF
THF
Et2O
Toluene
CH2Cl2
1,4-Dioxane
THF
rt
0
Quant
Quant
96
Quant
97
96
Quant
95
18 : 82
21 : 79
23 : 77
25 : 75
22 : 78
26 : 74
19 : 81
22 : 78
0
0
0
0
0
0
0
0
rt
rt
rt
rt
rt
rt
THF
a Determined by 19F NMR. b Carried out under high dilution conditions (ca. 0.01 M). c The amount of Pd(t-BuNC)2Cl2 employed was 5.0 mol%.
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effectively the silylstannylation reaction to afford 2a and 3a in 3f in moderate yield with an erosion of the regioselectivity
quantitative yield with a high regioselectivity retained (2a : 3a = (entry 6), while alkynyl phosphonate 1g did not bring about
18 : 82) (entry 10). As shown in entry 11, the reaction at 0 °C any products (entry 7). As shown in entries 8–12, it was
did not bring about any significant improvement in regioselec- revealed that 1-substituted 4,4,4-trifluoropropargyl alcohol
tivity. In addition, switching the solvent from THF to Et2O, derivatives as a substrate were not good substrates for the silyl-
toluene, CH2Cl2, and 1,4-dioxane did not cause a substantial stannylation, resulting in a large amount recovery of starting
change in the regioselectivity (entries 12–15). Furthermore, the alkynes 1h–l.
reaction in high dilution conditions or under the influence of
5 mol% of the catalyst did not also lead to a satisfactory result dition B was examined. Thus, reaction of alkyne 1 with
(entries 16 and 17). 1.2 equiv. of Me3SiSnBu3 in the presence of 2.5 mol% of Pd(t-
Subsequently, the silylstannylation reaction under Con-
To extend the scope of the synthetic method, a broad range BuNC)2Cl2 in THF at room temperature for 6 h was performed,
of fluorine-containing alkynes 1 were tested for the present and the results are shown in entries 13–24. Alkynes carrying
silylstannylation by using Pd(PPh3)2Cl2 (Condition A) or Pd(t- various types of aromatic groups with a substituent like
BuNC)2Cl2 (Condition B) as a catalyst.‡ The results are sum- p-MeO, m-MeO, o-MeO as well as p-Cl, p-EtO2C 1a–e were sub-
marized in Table 2.
jected well to the silylstannylation reaction to give the corres-
Reaction of fluorine-containing alkynes having an electron- ponding products in 82–90% yield with a high regioselectivity
donating group on the benzene ring, 1a–c with 1.2 equiv. of (2 : 3 up to 16 : 84) (entries 13–17). In the case of alkynes
Me3SiSnBu3 under Condition A took place sufficiently to having an ester or
a phosphonate as R, the reaction
provide the corresponding silylstannylated products in under Condition B was found to be sluggish, a large amount
56–75% yield with an excellent regioselectivity (2 : 3 to 90 : 10) of starting alkyne 1f–g being recovered (entries 18 and 19). In
(entries 1–3). The alkynes having an aromatic group substi- sharp contrast to the reactions under Condition A, 4,4,4-tri-
tuted by an electron-withdrawing group, such as p-ClC6H4 (1d) fluoropropargyl alcohol derivatives 1h–j having an aromatic or
and p-EtO2CC6H4 (1e), also underwent regioselective silylstan- aliphatic substituent at the 1-position could participate nicely
nylation to afford the adducts (63%; 2d : 3d = 83 : 17 for 1d, in silylstannylation to give rise to the corresponding silylstan-
65%; 2e : 3e = 77 : 23 for 1e) in a highly regioselective fashion nylated products in high to excellent yields (65–94%), though
(entries 4 and 5). The fluorine-containing alkynyl ester 1f the regioselectivity was somewhat eroded (entries 20–22).
reacted effectively to form the silylstannylated products 2f and Moreover, the 4,4,4-trifluoropropargyl ether derivative was also
found to be a relevant substrate to the present reaction with
Me3SiSnBu3 as well as Me2PhSiSnBu3,2c leading to the corres-
ponding adducts in 85% (2k : 3k = 58 : 42) and 62% yields
‡Typical procedure for the silylstannylation of 1-(4-chlorophenyl)3,3,3-trifluoro-
propyne (1d) under Condition A: To a solution of 1-(4-chlorophenyl)-3,3,3-tri- (2k : 3k = 45 : 55), respectively, with no regioselectivity (entries
fluoropropyne (1d, 0.051 g, 0.25 mmol) and Pd(PPh3)2Cl2 (0.007 g,
23 and 24).
0.00625 mmol, 2.5 mol%) in THF (2.5 mL) was added a THF solution of tri-
A determination of the stereochemistry of the silylstannyl-
ated products 2 and 3 was carried out on the basis of the
methyl(tributylstannyl)silane (0.109 g, 0.30 mmol) at room temperature. The
reaction was stirred for 6 h at 80 °C. The resulting mixture was then quenched
NMR analysis after appropriate stereospecific chemical
with H2O. The reaction mixture was extracted with Et2O three times. The com-
bined organic layers were dried over anhydride Na2SO4 and concentrated transformations.
in vacuo. The residue was chromatographed on silica gel (hexane–AcOEt = 30 : 1)
Thus, the mixture of 2a and 3a (2a : 3a = 21 : 79) was treated
with 4.4 equiv. of tetrabutylammonium fluoride (TBAF) in
THF–DMF (1/1) at room temperature for 48 h to form the
corresponding protodesilylstannylated product 4a in 93% yield
to afford the corresponding silylstannylated product (2d
+ 3d, 0.089 g,
0.16 mmol, 63%). 2d (Major isomer); 1H NMR (CDCl3) δ 0.31 (s, 9H), 0.80–1.45
(m, 18H), 0.85 (t, J = 7.39 Hz, 9H), 6.71 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.8 Hz,
2H); 13C NMR (CDCl3) δ 1.3, 13.8, 13.9, 27.6, 29.2, 125.0 (q, J = 283.5 Hz), 125.8
to 126.1 (m, 1C), 128.0, 131.0, 143.9 (q, J = 24.0 Hz), 146.1, 172.5 (q, J = 5.7 Hz); as a sole product (Scheme 3). The 4a, bearing a p-methoxy-
19F NMR (CDCl3) δ −49.70 (s, 3F); IR (neat) ν 2957, 2923, 2873, 1721, 1483, 1252,
1233, 1184, 1142, 1097, 1015, 962 cm−1
phenyl group, is a known compound,7 the characterization
data of which were completely in agreement with the reported
one, i.e. the stereochemistry of 4a was determined as Z con-
figuration. This strongly suggested that the silylstannylation
.
Typical procedure for the silylstannylation of 1d under Condition B: To a solu-
tion of 1-(4-chlorophenyl)-3,3,3-trifluoropropyne (1d, 0.051 g, 0.25 mmol) 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 trimethyl(tributylstannyl)silane (0.109 g, 0.30 mmol) at room reaction to alkyne 1a took place in a cis-selective manner.
Additionally, selective destannylation8 of the 2a and 3a
(2a : 3a = 22 : 78) by treating with 30 equiv. of pyridinium
temperature. The reaction was stirred for 6 h at room temperature. The resulting
mixture was then quenched with H2O. The reaction mixture was extracted with
Et2O three times. The combined organic layers were dried over anhydrous
p-toluenesulfonate (PPTS) in MeOH at reflux temperature for
Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica
52 h led to the corresponding vinylsilanes 5a and 6a in 19%
gel (hexane–AcOEt = 30 : 1) to afford the corresponding silylstannylated product
(2d + 3d, 0.128 g, 0.23 mmol, 90%). 3d (Major isomer); 1H NMR (CDCl3) δ 0.06 and 81% yield, respectively (Scheme 4).
(s, 9H), 0.80–1.60 (m, 18H), 0.93 (t, J = 7.39 Hz, 9H), 6.78 (d, J = 8.4 Hz, 2H), 7.23
The comparison with a spin–spin splitting pattern between
(d, J = 8.4 Hz, 2H); 13C NMR (CDCl3) δ 1.1, 14.0 (q, J = 1.7 Hz), 14.3, 28.0, 29.5,
125.01 (q, J = 283.5 Hz), 126.4 (q, J = 2.5 Hz), 128.3, 132.1, 143.9, 147.5 (q, J =
28.6 Hz), 167.8 (q, J = 7.2 Hz); 19F NMR (CDCl3) δ −49.54 (s, 3F); IR (neat) ν 2957,
1
5a and 6a in 19F as well as H NMR enabled us to assign their
stereochemistry. Thus, both spin–spin splitting patterns of CF3
1
in 19F NMR and C(sp2)-H in H NMR of 5a were singlet, while
2855, 1547, 1484, 1465, 1420, 1377, 1232, 1184, 1139, 1095, 1015, 962 cm−1
HRMS (FAB) calcd for (M + Na) C24H40ClF3NaSiSn: 591.1460, found 591.1459.
;
those of 6a were doublet for CF3 and quartet for C(sp2)-H.
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Table 2 Regioselective silylstannylation reaction of various fluorine-containing internal alkynes 1
Conditions A
Conditions B
Entry
1
Substrate
Yielda/%
75
Ratiob 2 : 3
95 : 5
Entry
13
Yielda/%
82
Ratiob 2 : 3
18 : 82
(a)
(b)
2
3
56
61
90 : 10
95 : 5
14
15
87
86
21 : 79
17 : 83
(c)
4
5
(d)
(e)
63
65
83 : 17
77 : 23
16
17
90
90
16 : 84
19 : 81
6
7
8
(f)
(g)
(h)
52
0
39 : 61
—
18
19
20
26b
0
43 : 57
—
0
—
94
27 : 73
9
(i)
21b
66 : 34
21
75
30 : 70
10
11
12c
(j)
(k)
(l)
0
0
0
—
—
—
22
23
24c
65
85
62
46 : 54
58 : 42
45 : 55
a Isolated yields are shown. b Determined by 19F NMR. c Silylstannylation was conducted by using PhMe2SiSnBu3 instead of Me3SiSnBu3.
These observations clearly demonstrate that the Bu3Sn group in addition of Me3SiSnBu3 to Pd(0)L2 to form the silylstannylpalla-
2a is bonded with a vinylic carbon distal to the CF3 group, and dium intermediate Int-A, (iii) coordination of the alkyne 1 to the
the Bu3Sn group in 3a, on the other hand, is attached with a Pd center of Int-A, as shown by Int-B, followed by insertion into
vinylic carbon having the CF3 group.
the Sn–Pd bond, not into the Si–Pd bond, due to the difference
Based on these findings, a proposed reaction mechanism for in electrophilicity between Si and Sn as well as in the stability
Pd(0)-catalyzed silylstannylation reaction of fluoroalkylated between highly coordinated Si and Sn, furnishing the vinylpalla-
alkyne 1 is illustrated in Scheme 5. Thus, the present silylstanny- dium intermediate Int-C and/or Int-D,9 and finally (iv) reductive
lation reaction presumably proceeds via (i) generation of Pd(0)L2 elimination to afford the silylstannylated adducts 2 and/or 3 in a
through the reduction of Pd(II)L2Cl2 by Me3SiSnBu3, (ii) oxidative cis-selective fashion, and regeneration of Pd(0)L2.
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Scheme 3 Determination of stereochemistry by protodesilylstannyla-
tion of 2a and 3a.
Scheme 6 A plausible mechanism for the regioselection.
Thus, when Pd(PPh3)2Cl2 or Pd(t-BuNC)2Cl2 is employed as
a catalyst, Int-C1/Int-D1 or Int-C2/Int-D2 may be possible as
the intermediates in the insersion of alkyne into the Sn–Pd
bond, respectively. When PPh3 is coordinated with Pd as a
ligand, the vinylpalladium complex Int-C1 is more stable than
the other regioisomeric Int-D1 due to both the electron-donat-
ing nature of PPh3 and the electron-withdrawing nature of CF3,
which smoothly leads to a reductive elimination to form the
silylstannylated product 2 in a stereoselective manner. In the
case of t-BuNC as a ligand, on the other hand, Int-C2 might be
unstable rather than Int-D2 since an electron density on the
Pd center significantly decreases by a strongly electron-with-
drawing effect of the CF3 group as well as a dπ–pπ interaction
between the Pd center and the isonitrile moiety. Therefore, the
insertion of alkyne into Sn–Pd may proceed preferentially via
Int-D2, followed by immediate reductive elimination, giving
rise to the product 3 as a major isomer.
Scheme 4 Assignment of regioisomers.
Finally, we challenged the syntheses of stereo-defined
fluoroalkylated tetra-substituted alkenes via the coupling reac-
tions by using the above obtained silylstannylated products
(Scheme 7).
Thus, silylstannylated compounds 2k and 3k, which were
prepared from 1k as shown in entry 23 in Table 2, were
smoothly subjected to the Stille cross-coupling reaction,
leading to the corresponding coupling products 7k and 8k in
88% and 91% yield, respectively. Subsequently, on treatment
with the vinylsilanes 7k and 8k with 1.5–3.0 equiv. each of (p-tri-
fluoromethyl)benzaldehyde and zinc triflate in the presence of
20 mol% of TBAF in N-methyl-2-pyrrolidone (NMP) at 80 °C for
24 h,10 the coupling reaction proceeded to provide the corres-
ponding allylic alcohol derivatives 9k (this was obtained as a
diastereomeric mixture; diastereomeric ratio = 54 : 46) and 10k
(this was obtained as a single isomer; diastereomeric ratio =
100 : 0) in 54% and 28%11 yields, respectively.
Scheme 5 A proposed reaction mechanism for Pd(0)-catalyzed silyl-
stannylation reaction of fluoroalkylated alkyne 1.
The mechanism for the regioselection has not been fully
clarified at present; however, for some substrates, it may be
understood by taking into consideration an electronic density
distribution on the Pd center of their intermediates
(Scheme 6).
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(h) M. Jeganmohan,
M. Shanmugasundaram, K.-J. Chang and C.-H. Cheng,
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3 For selected reports on the reaction of fluoroalkylated
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T. Ishihara and T. Konno, Asian J. Org. Chem., 2013, 2, 239–
243; (b) A. Morigaki, T. Miyabe, K. Tsugade, S. Arimitsu,
T. Ishihara and T. Konno, Synthesis, 2013, 101–105;
(c) A. Morigaki, T. Tanaka, T. Miyabe, T. Ishihara and
T. Konno, Org. Biomol. Chem., 2013, 11, 586–595;
(d) A. Morigaki, K. Tsukade, S. Arimitsu, T. Konno and
T. Kubota, Tetrahedron, 2013, 69, 1521–1525; (e) S. Bigotti,
L. Malpezzi, M. Molteni, A. Mele, W. Panzeri and M. Zanda,
Tetrahedron Lett., 2009, 50, 2540–2542.
Scheme 7 Synthetic application to stereo-defined fluoroalkylated
tetra-substituted alkenes.
4 For selected reviews and books, see: (a) T. Kubota, J. Synth.
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J. Mansuso and M. Lauten, Org. Lett., 2003, 5, 1653–
1655.
Conclusions
In conclusion, we have demonstrated that the palladium-cata-
lyzed silylstannylation reaction of fluorine-containing internal
alkynes with (trimethylsilyl)tributyltin took place smoothly to
give the corresponding adducts in good to high yields in a cis-
selective manner. In this reaction, two regioisomers could be
prepared selectively by using different catalysts, such as Pd
(PPh3)2Cl2 and Pd(t-BuNC)2Cl2, for each reaction. Thus obtained
silylstannylated products underwent a Stille cross-coupling reac-
tion, followed by a fluoride-ion promoted coupling reaction
with aldehyde, converting to the stereo-defined fluoroalkylated
tetra-substituted alkenes in moderate to good yields.
7 X.-G. Zhang, M.-W. Chen, P. Zhong and M.-L. Hu, J. Fluo-
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Notes and references
1 For a recent review on element–element addition to unsatu-
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1616 | Org. Biomol. Chem., 2014, 12, 1611–1617
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in 41% yield.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 1611–1617 | 1617