Arylchlorogermanes/TBAF/ moist toluene: A promising combination for Pd-catalyzed germyl-stille cross-coupling

Article abstract of DOI:10.1021/ol9028918

Chemical equation presented The trichlorophenyl,- dichlorodiphenyl,- and chlorotriphenylgermanes undergo Pd-catalyzed cross-couplings with aryl bromides and iodides in the presence of TBAF in toluene with addition of the measured amount of water. One chloride ligand on the Ge center allows efficient activation by fluoride to promote transfer of one, two, or three phenyl groups from the organogermane precursors.

Full text of DOI:10.1021/ol9028918

ORGANIC
LETTERS
2010
Vol. 12, No. 4
816-819
Arylchlorogermanes/TBAF/“Moist”
Toluene: A Promising Combination for
Pd-Catalyzed Germyl-Stille
Cross-Coupling
Zun-Ting Zhang,† Jean-Philippe Pitteloud, Laura Cabrera, Yong Liang,
Myrdich Toribio, and Stanislaw F. Wnuk*
Department of Chemistry and Biochemistry, Florida International UniVersity,
Miami, Florida 33199
wnuk@fiu.edu
Received December 15, 2009
ABSTRACT
The trichlorophenyl,- dichlorodiphenyl,- and chlorotriphenylgermanes undergo Pd-catalyzed cross-couplings with aryl bromides and iodides
in the presence of TBAF in toluene with addition of the measured amount of water. One chloride ligand on the Ge center allows efficient
activation by fluoride to promote transfer of one, two, or three phenyl groups from the organogermane precursors.
The Pd-catalyzed cross-coupling of organogermanes has thus
far received much less attention1 than the couplings involving
organostannanes and organosilanes.2 This is due to the lower
reactivity of tetracoordinated organogermanium species, the
less developed syntheses of vinyl/aryl germanyl derivatives,
and the higher cost of germanium relative to silicon.3 The
carbagermatranes 1, with internal coordination of nitrogen
to germanium, were the first examples of reactive tetraco-
ordinated germanes applied to Pd-catalyzed cross-coupling
reactions with aryl bromides4 (Figure 1). The oxagermatranes
Figure 1. Organogermanes utilized in Pd-catalyzed couplings.
† On faculty leave from School of Chemistry and Materials Science,
Shaanxi Normal University, Xi’an, P.R. China.
2 were found to be more efficient than carbagermatranes and
triethoxygermanes.5,6 Fluoride-promoted couplings with aryl-
tri(2-furyl)germanes7 and NaOH-activated couplings with
(1) Spivey, A. C.; Gripton, C. J. G.; Hannah, J. P. Curr. Org. Synth.
2004, 1, 211–226.
(2) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Dieder-
ich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004.
(3) The Chemistry of Organic Germanium, Tin and Lead Compounds;
Patai, S., Rappoport, Z., Eds.; John Wiley & Sons: Chichester, UK, 1995;
Vol. 1 and 2002; Vol 2.
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5918.
(4) Kosugi, M.; Tanji, T.; Tanaka, Y.; Yoshida, A.; Fugami, K.;
Kameyama, M.; Migita, T. J. Organomet. Chem. 1996, 508, 255–257.
(6) Faller, J. W.; Kultyshev, R. G.; Parr, J. Tetrahedron Lett. 2003, 44,
451–453.
10.1021/ol9028918  2010 American Chemical Society
Published on Web 01/21/2010

arylgermanium trichlorides8 or their hydrolyzed and stable
sesquioxide alternatives9 were also reported. The bis-
(2-naphthylmethyl)arylgermanes 3 were developed as pho-
tochemically activated arylgermanes for the synthesis of
biaryls.10,11 The vinyl tris(trimethylsilyl)germanes 4 were
employed as transmetalation reagents in “ligand- and fluoride-
free” coupling reactions with halides under oxidative condi-
tions (H2O2).12,13 The (R-fluoro)vinyl germanes 5 gave access
to fluoroalkenes14 although application of (R-fluoro)vinyl
stannanes and silanes to couplings has had limited suc-
cess.15,16 Recently, couplings of vinyltributylgermanes with
aryl halides were found to occur more efficiently under Heck
than Stille conditions to give preferentially Z-alkenes.17
Table 1. Effect of Various Reaction Parameters on the
Efficiency of Cross-Coupling of Chlorodimethylgermane 6 with
1-Iodonaphthalenea
entry
Pd
TBAFb
7a [yield(%)]c
ratio (7a:8a)
1
2
3
4
5
6
7
8
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(PPh3)4
Pd2(dba)3
1.0
2.0
3.0
4.0
5.0
4.0
4.0
4.0f
19
61
79
93d,e
94
58
5
1:1
9:1
17:1
20:1
12:1
5:2
In general, couplings with organogermanes appear to be
promoted by: (i) activation of germanium by internal
coordination/chelation,4,5,17 (ii) formation of the hypervalent
species with germanium-oxygen bonds;7-9,13 and (iii) the
presence of two labile heteroatom ligands (e.g., Cl or F) on
Ge atom.10,11 Herein, we report that chlorophenylgermanes
with at least one labile chloride ligand are activated by
fluoride in “moist” toluene to allow efficient transfer of up
to three phenyl groups from germane precursors during Pd-
catalyzed coupling reactions with aryl halides.
2:1
6:1
70
a Couplings were performed on 0.14 mmol scale of 6 (0.04 M) with
1.1 equiv of iodonaphthalene and 0.09 equiv of Pd catalyst. b Commercial
1 M THF solution containing 5% of water, unless otherwise noted.
c Determined by GC-MS of the crude reaction mixture. d Isolated yield.
e After 4 h, 49% (8:1); 8 h, 78% (15:1). f With ΤΒAF•3Η2O.
Treatment of PhGeMe2Cl 6 with 1-iodonaphthalene in the
presence of tetrabutylammonium fluoride (TBAF) and tris-
(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3] in toluene
gave cross-coupling product 7a in addition to the binaphthyl
homocoupling byproduct 8a (Table 1). The amount of TBAF
was found to be crucial for the successful coupling (entries
1-5). At least 4 equiv of TBAF were required to produce
7a in maximum yield. Other Pd catalysts afforded 7a in lower
yields and a decreased ratio of 7a to 8a (entries 6-7).
Replacing 1 M TBAF/THF solution with neat ΤΒAF•3Η2O
also gave product 7a (entry 8). Coupling in the presence of
Me4NF, CsF, or NH4F instead of TBAF failed to produce
7a. The reaction also proceeded successfully at 80 °C (80%;
10:1) and 110 °C (93%; 10:1) as well as at reflux in benzene
(90%; 10:1), requiring 12 h for the best results (entry 4).
attributable to the increased temperature of the reaction as
well the difference in dielectric constant [7.58 for THF as
compared to dioxane (2.21) and toluene (2.15)].18 Bases such
as NaOH [Pd(OAc)2; dioxane/H2O, 2:1] or KOSiMe3
[Pd2(dba)3, toluene)], instead of TBAF, failed or were less
efficient in promoting couplings.
We next examined couplings of Ph2GeCl2 9 or Ph3GeCl
10 with iodonaphthalene. Treatment of 9 with 1.1 equiv of
iodide and 7 equiv of TBAF gave 7a (Table 2, entry 1).
Coupling of 9 with 2.2 equiv of iodonaphthalene also resulted
in total consumption of iodide to afford 7a and 8a (entry 2).
Interestingly, couplings in toluene with addition of the
measured amount of water (1 M TBAF/THF//H2O; ∼1:5
M/M) gave a higher yield of 7a with a superior ratio of 7a:
8a (entries 3 vs 1 and 4 vs 2). An investigation of the
coupling reactions with different amounts of water, revealed
that addition of 100 µL of H2O (∼40 equiv) gave optimal
yields (entry 10). Two phenyl groups were efficiently
transferred in the presence of excess iodide (e.g., 89%, entry
4; yield is based upon two phenyl groups transferring from
the chlorogermane reagent 9). Halides are often used in
couplings as limiting reagents to reduce formation of
homocoupling byproducts and the yields are based on the
halide components unlike herein.
Toluene was the obvious solvent choice since attempts in
DMSO (5%, 110 °C) or THF at reflux (0%) or dioxane at
reflux (59%; 3:1) failed or afforded 7a in lower yields. Higher
yield for the coupling in dioxane than in THF may be
(7) Nakamura, T.; Kinoshita, H.; Shinokubo, H.; Oshima, K. Org. Lett.
2002, 4, 3165–3167.
(8) Enokido, T.; Fugami, K.; Endo, M.; Kameyama, M.; Kosugi, M.
AdV. Synth. Catal. 2004, 346, 1685–1688.
(9) Endo, M.; Fugami, K.; Enokido, T.; Sano, H.; Kosugi, M. AdV. Synth.
Catal. 2007, 349, 1025–1027.
(10) Spivey, A. C.; Tseng, C.-C.; Hannah, J. P.; Gripton, C. J. G.; de
Couplings of 10 with 1.1, 2.2, or 3.3 equiv of iodonaph-
thalene proceeded with efficient transfer of up to three phenyl
groups to give 7a (entries 5-10). [See Supporting Informa-
tion for the GC/MS of the crude reaction mixture between 9
or 10 with iodonaphthalene (entries 4 and 10).] Again, yields
and 7a:8a ratios increased when wet toluene was used. Atom-
efficient Stille cross-couplings of Ar4Sn with aryl halides,
where all four substituents on tin participate in the
Fraine, P.; Parr, N. J.; Scicinski, J. J. Chem. Comm. 2007, 2926–2928
.
(11) Spivey, A. C.; Gripton, C. J. G.; Hannah, J. P.; Tseng, C.-C.; Fraine,
P. D.; Parr, N. J.; Scicinski, J. J. Appl. Organometal. Chem. 2007, 21, 572–
589
.
(12) Wnuk, S. F.; Garcia, P. I., Jr.; Wang, Z. Org. Lett. 2004, 6, 2047–
2049
.
(13) Wang, Z.; Wnuk, S. F. J. Org. Chem. 2005, 70, 3281–3284
.
(14) Wang, Z.; Gonzalez, A.; Wnuk, S. F. Tetrahedron Lett. 2005, 46,
5313–5316.
(15) Chen, C.; Wilcoxen, K.; Zhu, Y. F.; Kim, K. i.; McCarthy, J. R. J.
Org. Chem. 1999, 64, 3476–3482
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1143.
Org. Lett., Vol. 12, No. 4, 2010
817

Table 2. Cross-Coupling of Chlorophenylgermanes 9 and 10
with 1-Iodonaphthalene Promoted by TBAF and TBAF/H2O
Table 3. Cross-Coupling of Chlorogermanes 9-11 with
Halidesa
7a
ratio
yield
ratio
(7:8)
entry germane RX (equiv) methoda [yield(%)]b (7a:8a)
entry germane
halide
1-Bromonaphthalenec
(4)CH3OPhI
(3)CF3PhI
(4)CH3COPhI
(4)CH3COPhBr
PhCHdCHBr
2-Iodo-5-Me-thiophene
1-Bromonaphthalene
(4)CH3OPhI
(3)CF3PhI
(4)CH3COPhI
(4)CH3COPhBr
PhCHdCHBr
2-Iodo-5-Me-thiophene
1-Iodonaphthalene
1-Bromonaphthalene
(4)CH3OPhI
product
(%)b
1
2
9
9
9
1.1
2.2
1.1
2.2
1.1
2.2
3.3
1.1
2.2
3.3
A
A
B
B
A
A
A
B
B
B
32c (30)
58 (55)
45 (42)
91 (89)
13d (12)
37 (35)
40 (39)
18 (17)
60 (60)
95e (88)
2.7:1
2.2:1
23:1
10:1
1
9
9
7a
7b
7c
7d
7d
7e
7f
7a
7b
7c
7d
7d
7e
7f
7a
7a
7b
7c
7d
7d
7e
7f
54 (48)
7.2:1
2
86d (85) 9.8:1
3
3
9
70 (68)
12 (10)
3.4:1
3:2
4
9
4
9
5
10
10
10
10
10
10
1:1.4
5
9
26d (21) 99:1
6
2:1
1.2:1
2.5:1
9:1
,
6
9
8
e g (5)
1:3
2:3
1.4:1
4:1
3:2
7
7
9
13e (6)
24
8
8
10
10
10
10
10
10
10
11
11
11
11
11
11
11
11
9
9
48f (40)
48
10
13:1
10
11
12
13
14
15
16
17
18
19
20
21
22
a Method A: Couplings were performed on 0.14 mmol scale of germane
(0.04 M) with Pd2(dba)3 (0.09 equiv) and 7 equiv of TBAF (1M/THF).
Method B: as in Method A with addition of H2O (100 µL). b Based upon
transferring two phenyl groups from 9 or three phenyl groups from 10.
Determined by GC-MS of the crude reaction mixture (isolated yields in
parentheses). c 26% and 31% with 6 and 8 equiv of TBAF. d 11% and 14%
with 6 and 8 equiv of TBAF. e 57% (3.8:1) with 50 µL H2O; 82% (7:1)
with 150 µL H2O.
3
1:20
24d
3g
1:1
1:8
2:3
3g
99h (96) 35:1
90g (82)
88g (80)
93 (87)
99 (88)
91
99:1
10:1
9:1
(3)CF3PhI
(4)CH3COPhI
(4)CH3COPhBr
PhCHdCHBr
2-Iodo-5-Me-thiophene
99:1
99:1
3:1
30e, g (28)
carbon-carbon bond formation, are known.19,20 Also, vi-
nylpolysiloxanes were showed to transfer each of their vinyl
groups during Pd-catalyzed couplings with aryl and alkenyl
iodides in the presence of TBAF.21 However, attempts to
induce multiple transfer of the phenyl group during fluoride-
promoted couplings of (allyl)xPh4-xSi (x ) 1 or 2) with aryl
halides failed.22
48e, g (35)
3:2
a Couplings were performed on 0.14 mmol scale of germanes (0.04 M)
with 0.09 equiv of Pd catalyst, 1.1 (11), 2.2 (9) or 3.3 (10) equiv of halides
and TBAF/(1 M/THF, 7 equiv)/water (100 µL). b Based upon transferring
of one, two or three phenyl groups from 11, 9 or 10, respectively.
Determined by GC-MS of the crude reaction mixture (isolated yields in
parentheses). c Coupling with 1-chloronaphthalene failed. d 115 ′C. e Biphenyl
was also produced (∼25-50%). f 28 h. g Without H2O. h 88% (81%, 19:1)
without H2O.
Couplings of 9 or 10 with other aryl, alkenyl, and
heterocyclic iodides and bromides (using 2.2 or 3.3 equiv
of halides, respectively) promoted by TBAF/H2O are pre-
sented in Table 3 (entries 1-14). Reactions of germanes 9
or 10 with reactive 4-iodoacetophenone produced 7d in low
yields in addition to large quantities of the reductive
homocoupling byproduct 8d. However, coupling of the less
reactive 4-bromoacetophenone at higher temperature (115
°C) resulted in better yields and improved 7d:8d ratios
(entries 5 vs 4 and 12 vs 11). Treatment of PhGeCl3 11 with
halides and TBAF/toluene or wet toluene also afforded
coupling products 7 (entries 15-22), although it has been
reported that fluoride ion did not promote the couplings of
PhGeCl3 with aryl halides.8 It appears that reactivity of the
chlorogermanes increases with the number of halogen ligands
on the Ge center (10 < 9 < 11). As expected,7 coupling
attempts with Ph4Ge failed reinforcing the needs for at least
one labile heteroatom ligand at the Ge center. The necessity
of two halogen ligands had been proposed for nucleophilic
activation by F- or OH- ions.11
TBAF most likely facilitates the coupling by generating
the more reactive hypervalent fluorogermanium species. It
is viable that the germanium species with extra halogen
ligands formed after each transmetalation cycle is rendered
more reactive to efficiently transfer a second or third phenyl
group from the Ge atom. Reactivity of these hypervalent Ge
species could be superior in toluene solvent due to the weak
solvation. Water might play multiple roles in enhancing the
efficiency of the couplings as was found with organosilanes,
including the formation of the reactive hydroxypalladium
intermediates.1,23,24 For example, the hydration level of
Cs2CO3 and CsOH were found to be a decisive factor during
the coupling of the aryl(dimethyl)silanols with aryl halides.25
Also, Denmark and Sweis showed that water was a critical
additive in the fluoride promoted reaction of alkenylsilanols
(19) Fugami, K.; Fugami, K.; Ohnuma, S.-y.; Kameyama, M.; Saotome,
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2004, 346, 1715–1727.
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818
Org. Lett., Vol. 12, No. 4, 2010

with phenyl nonaflate.1,26 In addition, the fluorination of the
bulky chlorogermanes may be accelerated by the addition
of water as was reported for hindered chlorosilanes.27
Mixing of 6 with TBAF in benzene-d6 at ambient
temperature showed the formation of a distinctive septet at
δ -194.3 (3JF-H ∼ 6.0 Hz) for PhGeMe2F in agreement with
the literature report for similar compounds.11 Prolonged time
and/or heating promoted equilibration with perfluorinated
species [δ -150.8 (br s), -126.4 (br s)] analogous to the
reported hypervalent tin28-30 and silicon31-33 species, which
were successfully utilized in cross-coupling reactions.
We have demonstrated that arylchlorogermanes undergo
Pd-catalyzed cross-couplings with aryl halides in the presence
of TBAF in wet toluene. One chloride ligand on Ge center
allows efficient activation by fluoride to promote transfer of
up to three aryl groups from germane. The methodology
shows that organogermanes can render a coupling efficiency
comparable to the more established stannane and silane
counterparts.
Acknowledgment.WethankNIGMS/NCI(1SC1CA138176)
and the Overseas Scholarship Program of Shaanxi Normal
University (Z.T.Z.), FIU’s Dissertation Year Fellowship
(J.P.P.) and MARC U*STAR (GM083688-02) (L.C.) for
their support.
Supporting Information Available: General experimental
details and GC/MS and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
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