Reactions of vinyltributylgermanes and aryl halides under Heck conditions

Article abstract of DOI:10.1016/j.tetlet.2009.05.035

We describe the palladium-mediated reaction of vinyltributylgermanes with aryl halides under Heck conditions. Depending on their degree of substitution, (E)-vinyltributylgermanes preferentially afford either the cine or Z-alkenyl coupled products in moder

Full text of DOI:10.1016/j.tetlet.2009.05.035

Tetrahedron Letters 50 (2009) 4407–4410
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Tetrahedron Letters
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Reactions of vinyltributylgermanes and aryl halides under Heck conditions
*
Nicole M. Torres, Jérôme M. Lavis, Robert E. Maleczka Jr.
Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe the palladium-mediated reaction of vinyltributylgermanes with aryl halides under Heck
conditions. Depending on their degree of substitution, (E)-vinyltributylgermanes preferentially afford
either the cine or Z-alkenyl coupled products in moderate yields. Substituents at the allylic position, espe-
cially oxygen, impact regio- and stereoselectivity.
Received 16 March 2009
Revised 30 April 2009
Accepted 12 May 2009
Available online 19 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Vinylgermanes
Palladium
Cross-coupling
Heck reaction
In 1990, Ikenaga and Kikukawa announced the palladium-cata-
lyzed aryldegermylation of styryltrimethylgermanes upon reaction
with arenediazonium tetrafluoroborates.1 Six years later, Kosugi
reported that while the Pd-mediated coupling of vinyltributylger-
mane with p-bromotoluene afforded p-methylstyrene in 60% yield,
most reactions of this type did not give cross-coupled products.2
Chemists awaiting further descriptions of vinylgermane cross-cou-
plings had to wait until 2002 when Oshima showed that aryltri(2-
furyl)germanes can be instrumental in Pd-catalyzed biaryl
syntheses3 and Faller expanded the scope and utility of germatr-
anes.4 More recently, tris(trimethylsilyl)vinylgermanes have found
their place as efficient coupling partners upon the basic-oxidative
treatment described by Wnuk.5 Kosugi and Fugami continue to de-
velop germanium coupling chemistry demonstrating that aryl tri-
chlorogermanes,6 or the hydrolyzed sesquioxide variants,7 can
partake in biaryl couplings in aqueous media. Likewise, Spivey’s
progress on polymer- or fluorous-tagged germane couplings that
are activated by photooxidation opens the door for organogermane
use in library synthesis.8 Prompted by these continuing efforts as
well as by new advances in germane syntheses,9 we decided to
communicate our own results on the Pd-mediated reactions of
vinyltributylgermanes.
Table 1
Hydrogermylations
3 mol % Pd(PPh3)4,
1.2 equiv Bu3GeH,
Bu3Ge
R
R
H
R
+
Bu3Ge
THF, rt, 8 h
(E)-1
Product
int-1
Entry
Alkyne
% Yield
E/inta
1
2
3
4
5
6
7b
8
9
2-Methyl-3-butyn-2-ol
1-Ethynyl-cyclohexanol
3-Methyl-1-butyne
Hex-1-yn-6-ol
Pent-1-yn-5-ol
1-Pentyne
Propargyl alcohol
O-THP hex-1-yn-6-ol
O-TBS 2-methyl-3-butyn-2-ol
1a
1b
1c
1d
1e
1f
1g
1i
1j
95
89
73
64
75
78
81
62
91
100% E
100% E
100% E
4.0/1
3.8/1
3.6/1
1.7/1
1.3/1
100% E
a
Yields and E/internal ratios based on isolated material.
b
Reaction time 14.5 h; E/internal ratio determined by 1H NMR analysis of the
crude reaction mixture.
Initial cross-coupling experiments under traditional Stille con-
ditions proved interesting in that (E)-vinyltributylgermane 1a so-
lely gave Z-product 2, albeit in a modest 30% yield (Scheme 1).
This selective formation of a Z-product from an (E)-germane was
a distinctive feature of our system and therefore worthy of addi-
tional study.
We surveyed various reaction conditions with the aim of
improving our understanding and efficiency of the process. Focus-
ing first on Stille-type conditions,11 we examined different Pd
(Pd2dba3, Pd(OAc)2, and PdCl2[P(o-Tol)3]2), and ligand (AsPh3, TFP,
(o-Tol)3P, and dppe) mixtures. No catalyst–ligand combinations
(E)-Vinyltributylgermanes used in this study were synthesized
by Pd-mediated hydrogermylation of various alkynes.10 As illus-
trated in Table 1, the level of regioselectivity exhibited by these reac-
tions was dependent on the extent of substitution at the propargylic
position of the starting alkyne. Unhindered alkynes (entries 4–8)
gave intrusive amounts of internal (proximal) vinyltributyl-
germanes.
* Corresponding author. Tel.: +1 517 355 9715x124; fax: +1 517 353 1793.
E-mail address: maleczka@chemistry.msu.edu (R.E. Maleczka Jr.).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.035

4408
N. M. Torres et al. / Tetrahedron Letters 50 (2009) 4407–4410
20 mol % Pd2dba3,
80 mol % AsPh3,
2 equiv electrophile, 20 mol % Pd(OAc)2, 40 mol % PPh3,18 1 equiv
Ph
(Z)-2
Bu4NBr, and 2.5 equiv K2CO3 in MeCN/H2O (9:1) at 70 °C.
Although the Heck conditions appeared superior to the Stille
conditions shown in Scheme 1, we thought it prudent to compare
Stille and Heck conditions across a set of common electrophiles
and similar reaction parameters. The results are given in Table 3.
Even though Stille protocols were competitive for some substrates,
Heck conditions generally gave better yields in less reaction time.
Convinced that the Heck conditions were best, three (E)-vinyl-
tributylgermanes fully substituted at the allylic carbon (1a–c) were
reacted with various electrophiles using the conditions given in en-
try 8 of Table 2. Here, all reactions were stopped at 16 h so as to
allow direct comparisons across entries. The results are given in
Table 4.19
Product yields ranged from poor to moderate, but again the Z-
products were favored. Electron-poor arenes tended to give higher
yields, but lower Z/E selectivity. Activated arenes tended to give
more of the E-product (entries 5–7) suggesting an admixture of
mechanistic pathways. Ortho-substituted arenes (entries 8 and 9)
were non-reactive, suggesting a strong steric influence. Interest-
ingly, the lack of an oxygen at the allylic carbon of the vinyltribu-
tylgermane was problematic (entry 11) (vide infra). Lastly,
(Z)-ICH@CHCO2Me and (E)-ICH@CH(CH2)6CO2Me did not couple
(not shown).
(30%)
Bu3Ge
OH
OH
2 equiv PhI,
NMP, 70 ºC, 48 h
1a
Scheme 1. Initial coupling reaction.
that were studied improved the Scheme 1 results. Furthermore,
while repeating the reaction described above in the presence of
CuI the reaction failed, providing evidence against a Stille-type
mechanism.
Faller previously suggested a Heck reaction as one possible con-
tributor in the coupling of alkenylgermatranes.4a,12 We too recog-
nized that formation of (Z)-2 could be explained by a Heck-type
mechanism11,13 involving syn b-germyl elimination of the palla-
dium intermediate (Scheme 2). Therefore, we quickly moved to
investigate Heck-type catalytic systems.11,13
An exploration of Heck-type conditions soon identified
Pd(OAc)2 and Ph3P as a suitable catalyst and ligand, respectively.
Experimentation with additives, bases,14 and solvents15 (Table 2)
revealed that Bu4NBr and K2CO3 in acetonitrile/water were opti-
mal.16 A reaction temperature of ꢀ70 °C proved best. Couplings
tended not to occur at temperatures <50 °C, whereas reactions at
much higher than 70 °C gave lower yields, most likely due to cata-
lyst decomposition. After screening catalyst loadings (entries 1 and
7–9) we decided that 20 mol % Pd struck the best balance between
stoichiometry and yield. Furthermore, 17–18% biaryl was observed
with PhI.17 Thus the choice Heck conditions to emerge were
It was also noted that Z/E product ratios were concentration
dependent. As Table 5 shows, increased reaction concentrations
met with decreased Z/E ratios, but with relatively steady yields.
For Heck-type reactions, elimination is proposed to be rate deter-
mining,20 and should therefore be independent of concentration.
However, the rate-determining transmetallation step of a Stille-
Bu3GeBr
PhBr
Pd(0)
Reductive
Elimination
Oxidative
Insertion
Table 3
Comparison of Heck and Stille conditions
Entry
Ar-X
% Yield
% Yield
% Yield
(Heck)c
Bu3GePd(II)Br
(Stille A)a
(Stille B)b
Ph-Pd(II)Br
1
2
3
PhI
PhBr
30
28
10
25
28
0
47
26
48
R
1-Bromo-4-nitrobenzene
Ph
R
Bu3Ge
Addition
a
Bu3Ge
Pd(II)Br
Conditions A: 20 mol % Pd2dba3, 80 mol % AsPh3, 1a, 2 equiv ArX, NMP, 70 °C,
Elimination
Ph
R
48 h.
H
H
b
c
Conditions B: Same as conditions A using Pd(OAc)2 instead of Pd2dba3.
Heck conditions: 20 mol % Pd(OAc)2, 40 mol % PPh3, 1a, 2 equiv ArX, 1 equiv
Scheme 2. Proposed mechanism.
K2CO3, 1 equiv Bu4NBr, MeCN/H2O (9:1), 70 °C, 16 h.
Table 2
Ligand, additive, base, and solvent screening for the reaction of 1a under Heck
conditions
Table 4
Reactions of vinyltributylgermanes (1a–c) with halides
Pd(OAc)2, PPh3 (Pd/L 1:2)
1 equiv Additive,
2.5 equiv Base, Solvent,
2 equiv Ar-X,
20 mol % Pd(OAc)2, 40 mol % PPh3,
Ph
Ar
2Š11
R
R
+ 1a
Bu3Ge
OH
Bu3Ge
OH
1 equiv Bu4NBr, 2.5 equiv K2CO3,
1a
2
2 equiv PhI, 60 ºC, 16 h
1aŠc
MeCN/H2O (9:1), ~0.05 M, 70 ºC, 16 h
Entry Mol % Pd Additive
Base
Solvent
% 1aa % Yielda (Z/E/int)
Entry
Germane
Halide
% Yield (2–11)
Z/Ea
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
5
Bu4NBr
Bu4NHSO4 K2CO3
—
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
K2CO3
aq MeCNb 53
aq MeCNb 21
aq MeCNb 66
47 (17/4/1)
34
34 (21/1/5)
43 (17/1/2)
6
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
Bromobenzene
Iodobenzene
4-Iodotoluene
4-Bromoanisole
4-Bromoacetophenone
Methyl 4-bromobenzoate
1-Bromo-4-nitrobenzene
2-Bromotoluene
2-Bromoacetophenone
4-Bromoacetophenone
4-Bromoacetophenone
26 (2)
47 (2)
47 (3)
27 (4)
61 (5)
68 (6)
48 (7)
0 (8)
>20/1
>20/1
>20/1
>20/1
4.7/1
5/1
2.4/1
—
—
K2CO3
NaHCO3 aq MeCNb 57
NaHCO3 DMF
80
Ag2CO3
K2CO3
K2CO3
K2CO3
aq MeCNb 65
aq MeCNb 54
aq MeCNb 45
aq MeCNb 63
30
46 (17/5/1)
55 (10/3/1)
37 (4/1/0)
20
50
0 (9)
61 (10)
0 (11)
a
Yields of 2 and unreacted 1a as well as Z/E/internal ratios were determined by
10
11
>20/1
—
1H NMR analysis of crude reactions with MeOH, mesitylene, or TMS-O-TMS as an
internal standard.
b
a
MeCN/H2O (9:1).
Yields and Z/E ratios based on isolated material.

N. M. Torres et al. / Tetrahedron Letters 50 (2009) 4407–4410
2 equiv n-BuLi, THF, 0 ºC, 10 min;
4409
Table 5
Concentration impact on Z/E ratiosa
OR
OR
then 1 equiv Bu3GeX, 0 ºC rt, 7 h Bu3Ge
(X = Br for 17a, Cl for 17j)
18a R = H
Entry
Molarity
% Yield 2
Z % Yield
E % Yield
Z/E
17a R = H
17j R = TBS
69%
18j R = TBS 40%
1
2
3
0.1
0.168
0.2
29
26
23
27
21
17
2
5
6
13.5/1
4.2/1
2.8/1
2 equiv Cy2BH, THF, -10 ºC
Bu3Ge
OR
then alkyne, rt, 1 h;
a
Reaction conditions from Table 4 entry 1, with the solvent adjusted to obtain
the indicated molarity.
(Z)-1a R = H
(Z)-1j R = TBS 28%
33%
then 35 equiv AcOH, rt, 3 h
Scheme 3. Synthesis of (Z)-1a and (Z)-1j.
type reaction should be affected by vinyltributylgermane concen-
tration. Thus the data suggest that the Stille pathway becomes
kinetically competitive at higher molarities.
Next, we reacted vinyltributylgermanes that were not fully
substituted at the allylic position. Within the context of our puta-
tive Heck mechanism, two carbons possessing b-hydrogens flank
the Pd-intermediate formed upon addition across the olefin of such
substrates. In theory this would allow us to probe any competition
between Pd–Ge and Pd–H eliminations. The results are given in
Table 6.
Table 7
Effect of vinyltributylgermane geometrya
2 equiv PhI
Bu3Ge
OR
Ph
OR
R = H
20 mol % Pd(OAc)2, 40 mol % PPh3,
1a R = H
2
1 equiv Bu4NBr, 2.5 equiv K2CO3,
MeCN/H2O (9:1), 70 ºC, 6 h
1j R = TBS
19 R = TBS
Entry
Germane
% Yield
Z % Yield
E % Yield Z/E
Interestingly, (E)-1g gave exclusively the cine (internal) prod-
uct, albeit in only 15% yield. Regioisomeric mixtures of 1e, 1d,
and 1i each afforded mixtures of E-, Z-, and cine-products, with
the cine products formed in yields exceeding the amounts of start-
ing internal germane. Notably, submitting the starting material to
the reaction conditions without the aryl bromide did not change
the E/internal ratio. All these data suggest that (E)-vinyltributyl-
germanes unhindered at the allylic position give rise to cine substi-
tution. This conclusion, in combination with low Z-product yields
and no indication of Pd–H elimination, indicates the involvement
of non-Heck pathways.
Lastly, we sought to test the stereospecificity of these reactions.
To do so, we synthesized the Z-isomers of 1a and 1j by hydrobora-
tion of the corresponding germylalkynes followed by deborylation
with acetic acid (Scheme 3).21
(Z)-Vinyltributylgermanes, so prepared, were reacted with
Ph–I under our now standard conditions. Compound (Z)-1a cou-
pled to a larger extent than (E)-1a (Table 7, entries 1 and 2)
after 6 h, and with a much different level of stereoselectivity.
(E)-1a required 16 h to achieve similar product yield. The dissim-
ilar results between (E)- and (Z)-1a did not appear to be the con-
sequence of starting material or product isomerization.
Geometrically pure (E)-2 was inert when resubjected to the reac-
tion conditions. Similarly, subjecting (Z)-1b to the reaction con-
1
2
3
(Z)-1a
(E)-1a
(Z)-1j
45 (2)
35 (2)
Traces (19)
19
31
Traces
26
4
0.73/1
8.8/1
Z only
Not detected
a
Yields and Z/E ratios determined by 1H NMR analysis of the crude reaction using
mesitylene as an internal standard.
ditions in the absence of an electrophile only led (after 10 h)
to the destruction of the germane and small amounts of phe-
nyl-coupled products (both E and Z), presumably from reaction
with Ph3P.22 Slow addition of the germane gave the same results
as when the germane was added in a single portion; providing
further evidence against isomerization of the starting germane.
The increased reactivity of the Z-germane is in keeping with Fall-
er’s finding that O-chelated germatranes are more reactive than
C-chelated ones.4a We suggest that our system is undergoing a
similar activation in which electron donation of the oxygen in-
creases the reactivity of the germanium.23 To this end, we syn-
thesized the TBS ether (Z)-1j (Scheme 3) in order to shut
down any chelation by the oxygen. When this substrate was
subjected to our Heck conditions, only trace amounts of Z-prod-
uct were observed by 1H NMR analysis of the crude mixture
after 6 and 24 h, supporting our hypothesis that oxygen activates
the Stille pathway via germanium chelation.
In summary, vinyltributylgermanes react with aryl halides un-
der Heck-type conditions. Depending on their degree of substitu-
tion, (E)-vinyltributylgermanes preferentially afford either the
(Z)-alkenyl or cine products in moderate yields. Reaction concen-
tration is among the factors that can affect the observed selectivi-
ties, suggesting an admixture of mechanistic pathways is
operative. Efforts aimed at better defining those pathways and
developing synthetically useful protocols that take full advantage
of the intriguing and complementary nature of these reactions
are ongoing.
Table 6
Reactions of unhindered vinyltributylgermanes
2 equiv Halide,
20 mol % Pd(OAc)2,
40 mol % PPh3,
Ar
R
R
R
+
+
Ar
Ar
R
Bu3Ge
1 equiv Bu4NBr,
2.5 equiv K2CO3,
MeCN/H2O (9:1),
~0.05 M, 70 ºC, 16 h
(Z)
(E)
int
1
Entry
Germane
Halide
% Yield
Z/E/int
1
3
4
5
6
7
1g
4-Bromoacetophenone
4-Bromoacetophenone
Iodobenzene
4-Bromoacetophenone
4-Bromoacetophenone
4-Bromoacetophenone
15 (12)
49 (13)
35 (14)
49 (15)
39c (16)
37c (16)
100% int
4/1/20
5/1/19
1ea
1da
1da
1ib
1id
Acknowledgment
3/1/20
We thank the NSF (CHE-9984644) for generous support.
References and notes
2.1/1/7.1c
1.1/1/4.2c
a
Starting E/internal ratio of 4/1.
Starting E/internal ratio of 10/1.
b
c
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T. J. Organomet. Chem. 1996, 508, 255–257.
Determined by 1H NMR analysis of the crude reaction using anisole as an
internal standard.
d
Starting E/internal ratio 4.3/1.

4410
N. M. Torres et al. / Tetrahedron Letters 50 (2009) 4407–4410
3. (a) Nakamura, T.; Kinoshita, H.; Shinokubo, H.; Oshima, K. Org. Lett. 2002, 4,
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stirred in
a
mixture of MeCN/H2O (2 mL, 9:1) for 15 min. The
vinyltributylgermane (0.1 mmol), PPh3 (0.04 mmol), and halide (0.2 mmol)
were added and the reaction mixture was stirred for 15 min. Pd(OAc)2
(0.02 mmol) was added and the reaction mixture was aged at 70 °C for 16 h.
The mixture was cooled to rt, quenched with satd NH4Cl, and extracted with
Et2O. The organics were washed with water and brine, dried over MgSO4,
filtered, and concentrated in vacuo. The product was purified by column
chromatography on silica gel.
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to which, or even if, a Heck mechanism is operating during their chemistry.
Under their conditions reaction of (E)-b-phenylethenylgermatrane with p-
iodotoluene afforded the corresponding E-stilbene, whereas a 3.5/1 mixture of
(Z/E)-b-phenylethenylgermatrane gave a 2.6/1 Z/E-mixture.
13. For reviews on the Heck reaction see: (a) de Meijere, A.; Meyer, F. E. Angew.
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23. Possible activation of the germanium by oxygen chelation:
H
O
Bu3Ge