Palladium-catalyzed cross-coupling reaction using arylgermanium sesquioxide

Article abstract of DOI:10.1002/adsc.200700002

Powdery reagents obtained by complete alkaline hydrolysis of arylgermanium trichlorides were found to undergo the palladium-catalyzed cross-coupling reaction with aryl bromides and iodides in good yields. The reaction is performed in an aqueous medium taking sodium hydroxide as an activator. Some base-sensitive functionalities such as acetyl and trifluoromethyl groups survived the reaction.

Full text of DOI:10.1002/adsc.200700002

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DOI: 10.1002/adsc.200700002
Palladium-Catalyzed Cross-Coupling Reaction Using
Arylgermanium Sesquioxide
Mayuko Endo,a Keigo Fugami,a,* Tatsuki Enokido,a Hiroshi Sano,a
and Masanori Kosugia,*
a
Department of Chemistry, Faculty of Engineering, Gunma University, Kiryu, Gunma 376-8515, Japan
Fax : (+81)-277-30-1285; e-mail: fugami@chem.gunma-u.ac.jp
Received: January 4, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Powdery reagents obtained by complete
alkaline hydrolysis of arylgermanium trichlorides
were found to undergo the palladium-catalyzed
cross-coupling reaction with aryl bromides and io-
dides in good yields. The reaction is performed in
an aqueous medium taking sodium hydroxide as an
activator. Some base-sensitive functionalities such
as acetyl and trifluoromethyl groups survived the
reaction.
ry to prepare the reagents. Recently, Faller et al. de-
veloped an analogous reagent, arylgermatrane.[5]
Oshima and co-workers reported that organotriACHTREUNG(2-fur-
yl)germanes act as efficient coupling reagents.[6] Al-
though the former reagent is easy to prepare, it is not
only highly toxic, but also not so high yielding. The
latter reagents undergo the cross-coupling reaction in
high yields. The reaction is, however, not atom-eco-
nomical. These two examples both need a fluoride ion
source to activate the reagents. Metal fluorides as
well as ammonium fluorides are not only expensive
but also toxic and contamination of fluoride ion in
the waste water makes its disposal process laborious.
Therefore it is preferable to avoid the use of fluoride
ion reagents.
Keywords: biaryls; cross-coupling; germanium; pal-
ladium
In this context, we have developed an organoger-
The palladium-catalyzed cross-coupling reaction is a manium trichlorides-mediated cross-coupling reaction
powerful synthetic tool. Various metals have been uti- that proceeds under fluoride ion-free conditions.[7]
lized as the key element of reagents. Organotin (Stille The reagent is easily accessible, and the reaction is
reaction)[1] and organoboron reagents (Suzuki– atom-efficient and does not emit any hazardous
Miyaura reaction)[2] are particularly important be- waste. Although organogermanium trichlorides are
cause of the stability of the reagents and wide toler- easier to handle than the tin and silicon counterparts,
ance of otherwise reactive functionalities. However, their germanium-chlorine bonds are still prone to be
there are serious drawbacks associated with each pro- hydrolyzed upon exposure to moist air.
cess. In the Stille reaction, a toxic by-product is gener-
We disclose here that a crude product obtained by
ated. In the Suzuki–Miyaura reaction, organoboron complete hydrolysis of arylgermanium trichloride can
reagents are not so easy to prepare and handle. More- be used as a reagent for the palladium-catalyzed
over, the reagent itself is toxic. Recently, organosili- cross-coupling reaction.
con reagents (Hiyama reaction),[3] which are free
The reagent can be conveniently prepared. Accord-
from the toxicity problem, are being considered as a ing to Andersonꢀs procedure,[8,9] we treated p-tolylger-
promising substitute for those precedents. On the manium trichloride with ammonia water to prepare
other hand, the organogermanium-mediated cross- the p-tolylgermanium sesquioxide (1a). The crude
coupling reaction has scarcely been studied, while ger- product was a non-hygroscopic white powder that was
manium lies between tin and silicon in a periodic neither soluble in any organic solvent nor in water.
table and organogermanium compounds are not toxic. The crude product was assumed to be 1a, according
The first example of the organogermanium-mediat- to its elemental analysis[10] and the comparison of the
ed cross-coupling reaction was developed in these lab- IR spectra of the substrate and the crude product.[11]
oratories.[4] Very good yields were achieved using or-
We examined the Pd-catalyzed cross-coupling reac-
ganotricarbagermatrane. The reaction is not conven- tion of 1a with p-iodoanisole (2a) (Table 1).
ient, however, owing to the laborious process necessa-
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ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Mayuko Endo et al.
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Table 1. Effects of catalyst and base on the cross-coupling of
1a with 2a.[a]
Table 2. Palladium-catalyzed cross-coupling of 1 and 2.[a]
Run 1
2
Time
[h]
Product Yield[b]
[%]
Run Catalyst
Base[b] (mol
equivs.)
Time Yield[c]
1
2
3
4
5
6
7
8
1a 4-IC6H4OMe (2a)
1a 3-IC6H4OMe (2b)
1a 2-IC6H4OMe (2c)
1a 4-IC6H4NO2 (2d)
1b 2d
4
4
4
1.5
4
4
4
8
4
8
4
1
1.5
3a
3b
3c
3d
3e
3f
3g
3a
3d
3e
3h
3i
58
31
16
[h]
[%]
1
2
3
4
Pd
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
(OAc)2
Pd(OAc)2
PdCl2
Pd
PdCl2/4tppts[f]
Pd
(OAc)2/dppf[g]
PdCl2/dppf[g]
Pd
Pd
(OAc)2/2[P][i]
Pd(OAc)2/2P(n-
Bu)3
Pd(OAc)2/2P
tolyl)3
Pd(OAc)2/2P-
(mesityl)3
Pd(OAc)2/2P(cy-
clohexyl)3
C
KOH (4)
4
4
4
4
4
4
4
4
4
4
4
4
24
4
48[d]
49
75
t-BuONa (4)
K2CO3 (4)
Cs2CO3 (4)
CsF (4)
NaOH (4)
NaOH (4)
71[c]
62
3[d]
0
1c 2d
23[d]
58
1b 4-IC6H4CH3 (2e)
1a 4-BrC6H4OMe (2f)
1a 4-BrC6H4NO2 (2g)
1b 2g
1a 1-Br-Naphthyl (2h)
1b 2h
1a 4-BrC6H4COCH3
(2i)
1b 2i
77
47
6
7
8
9
10
11
12
13
14
9
66
54
10
11
12
13
45[c]
66[c]
81
54[d]
57[d]
52
NaOH (4)
NaOH (4)
NaOH (4)
3j
54
53
48
59
53
14
15
16
17
1
1
2
8
3k
3l
3m
3g
41
NaOH (4)
NaOH (4)
1b 3-BrC6H4CF3 (2j)
1b 4-BrC6H4F (2k)
1b 4-BrC6H4CH3 (2l)
76[c]
58
E
51
15
16
17
18
(o-
NaOH (4)
NaOH (4)
NaOH (4)
24
24
4
21
[a]
Reactions employed 1 (0.6 mmol Ge), 2 (0.5 mmol), Pd-
(OAc)2 (5 mol%), and 4 mL each of solvents.
Isolated yields unless otherwise noted.
Determined by VPC.
11
AHCTREUNG
[b]
[c]
ACHTREUNG
9[d]
18[d]
PdCl2/2P(cyclohex- NaOH (4)
4
yl)3
ide, sodium tert-butoxide, and sodium hydroxide gave
better results (runs 1, 2 and 6). Weaker bases such as
potassium and cesium carbonates were inefficient
(runs 3 and 4). Fluoride ion showed a moderate effect
(run 5). Although the addition of phosphines, inor-
ganic salts, and radical scavenger improved a number
of related reactions, their effects were not obvious on
the present reaction (runs 8–22). The reaction was
moderately dependent on the amount of added base.
Maximum yields were obtained when sodium hydrox-
ide in 4 or 5 mol equivs. to germanium was used (runs
24 and 25). On the other hand, the yields decreased
with higher or lower amounts of the base (runs 23
and 26).
We next examined a variety of combinations be-
tween 1 and aryl halide 2 under the conditions of run
6 in Table 1. The results are summarized in Table 2.
Not only aryl iodides but also bromides reacted to
afford the corresponding biaryls in moderate to good
yields. Although the reaction was sensitive to steric
hindrance (runs 1–3), aryl halides with electron-do-
nating as well as -withdrawing substituents gave good
yields. It is worth noting that base-sensitive function-
[j]
19
20
21
22
23
24
25
26
Pd
Pd
Pd(OAc)2[m]
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
A
NaOH (4)
NaOH (4)
NaOH (4)
NaOH (4)
NaOH (3)
NaOH (4)
NaOH (5)
NaOH (6)
4
4
24
4
3
3
3
3
51
52
34
52
48
56
56
45
(OAc)2[l]
C
ACHTREUNG
N
G
G
G
[a]
Reactions employed 1a (0.6 mmol Ge), 2a (0.5 mmol), 5
mol% of palladium, and 4 mL each of solvents.
Molar equivs. to germanium.
Isolated yields unless otherwise noted.
Determined by VPC.
DMF (8 mL) was used in place of water and dioxane.
tppts=tris(3-sulfophenyl)phosphine trisodium salt.
dppf=1,1’-bis(diphenylphosphino)ferrocene.
dppp=1,3-bis(diphenylphosphino)propane.
[P]=tris(2,4,6-trimethoxyphenyl)phosphine.
NaCl (3.6 mmol) was used as an additive.
LiCl (3.6 mmol) was used as an additive.
CuI (1.2 mmol) was used as an additive.
2,6-Di-tert-butylphenol (1 mg) was used as an additive.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
[i]
[j]
[k]
[l]
[m]
Palladium acetate and chloride were effective as alities such as ketone and trifluoromethyl groups sur-
the catalyst. Strong bases such as potassium hydrox- vived the reaction (runs 13–15).
1026
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Adv. Synth. Catal. 2007, 349, 1025 – 1027

Cross-Coupling Reaction Using Arylgermanium Sesquioxide
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Kosugi, K. Fugami, in: Organopalladium Chemistry for
Organic Synthesis, (Ed. E. Negishi), Wiley, New York,
2002, pp 263–283; e) K. Fugami, M. Kosugi, in: Topics
in Current Chemistry, Vol. 219, (Ed. N. Miyaura),
Springer, Berlin, 2002, pp 87–130; f) T. N. Mitchell, in:
Metal-Catalyzed Cross-CouplingReactions , 2nd edn.,
(Eds.: A. de Meijere, F. Diederich), Wiley-VCH, Wein-
heim, 2004, pp 125–162.
In conclusion, easily accessible arylgermanium ses-
quioxides are found to exhibit a good reactivity
toward the palladium-catalyzed cross-coupling reac-
tion with a variety of aryl halides without taking any
toxic or expensive additives. Since the germanium re-
agents are also non-toxic, the process is environmen-
tally benign. These aspects in combination with the
reagentꢀs robustness under ambient conditions will
offer a new approach to the utilization of organoger-
maniums. Since the reaction is composed of simple
components, recycle of an expected simple inorganic
germanium species formed along the reaction is feasi-
ble. Development of a recycling process for germani-
um is under investigation.
[2] a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457–
2483; b) A. Suzuki, in: Metal-Catalyzed Cross-Coupling
Reactions, (Eds.: F. Diederich, P. J. Stang), Wiley-VCH,
Weinheim, 1998, pp 49–97; c) A. Suzuki, in: Organo-
palladium Chemistry for Organic Synthesis, (Ed. E. Ne-
gishi), Wiley, New York, 2002, pp 249–262; d) N.
Miyaura, in: Topics in Current Chemistry, Vol. 219,
(Ed. N. Miyaura), Springer, Berlin, 2002, pp 11–59;
e) A. Suzuki, Modern Arene Chem. 2002, 53–106.
[3] a) Y. Hatanaka, T. Hiyama, J. Synth. Org. Chem. Jpn.
1990, 48, 834–843; b) T. Hiyama, in: Metal-Catalyzed
Experimental Section
Cross-CouplingReactions
, (Eds. F. Diederich, P. J.
Typical Procedure for the Cross-Coupling Reaction
Stang), Wiley-VCH, Weinheim, 1998, pp 421–453; c) T.
Hiyama, E. Shirakawa, in: Organopalladium Chemistry
for Organic Synthesis, (Ed. E. Negishi), Wiley, New
York, 2002, pp 285–309; d) T. Hiyama, E. Shirakawa,
in: Topics in Current Chemistry, Vol. 219, (Ed. N.
Miyaura), Springer, Berlin, 2002, pp 61–85; e) S. E.
Denmark, M. H. Ober, Aldrichimica Acta, 2003, 36,
75–85.
In a 30-mL two-necked, round-bottomed flask furnished
with a reflux condenser, magnetic stirring bar, and a rubber
septum, p-tolylgermanium sesquioxide (113 mg, 0.6 mmol)
was added to a solution composed of dioxane (4 mL), aque-
ous NaOH solution (2.0 mol dmÀ3, 1.2 mL, 2.4 mmol), and
water (2.8 mL) at room temperature under an argon atmos-
phere. The resulting white suspension was stirred for 10 min
to dissolve the precipitate to give a clear solution. Then, p-
iodoanisole (2a, 117 mg, 0.5 mmol) and palladium(II) ace-
tate (5.6 mg, 0.025 mmol) were added. The resulting yellow
solution was heated to reflux for 4 h. After the mixture was
cooled to room temperature, the products were extracted
with dichloromethane (20 mL ” 3). The combined organic
layer was dried over anhydrous sodium sulfate. Silica-gel
column chromatography after concentration afforded 4-me-
thoxy-4’-methylbiphenyl (3a);[12] yield: 57 mg (58%).
[4] M. Kosugi, T. Tanji, Y. Tanaka, A. Yoshida, K. Fugami,
M. Kameyama, T. Migita, J. Organomet. Chem. 1996,
508, 255–257.
[5] J. W. Faller, R. G. Kultyshev, Organometallics 2002, 21,
5911–5918.
[6] T. Nakamura, H. Kinoshita, H. Shinokubo, K. Oshima,
Org. Lett. 2002, 4, 3165–3167.
[7] T. Enokido, K. Fugami, M. Endo, M. Kameyama, M.
Kosugi, Adv. Synth. Catal. 2004, 346, 1685–1688.
[8] H. H. Anderson, J. Am. Chem. Soc. 1960, 82, 3016–
3018.
[9] Puff et al. and Mochida et al. independently developed
analogous hydrolysis processes using aqueous sodium
hydroxide solution in organic solvents to obtain a cage-
type organogermanium sesquioxides, but we chose An-
dersonꢀs method because it was higher yielding: a) H.
Puff, K. Braun, S. Franken, T. R. Kçk, W. Schuh, J. Or-
ganomet. Chem. 1988, 349, 293–303, and references
cited therein; b) M. Nanjo, T. Sasage, K. Mochida, J.
Organomet. Chem. 2003, 667, 135–142.
Acknowledgements
Financial support provided by the Ministry of Education,
Culture, Sports, Science and Technology of Japan (Grants-in-
Aid for Scientific Research) is gratefully acknowledged. The
authors also thank Sankyo Organic Chemicals Co. Ltd. for
financial support and generous gifts of phosphine ligands.
[10] Detailed procedure and elemental analyses data of the
products are presented in the Supporting Information.
[11] An absorption at 424 cmÀ1 that is assigned to a stretch-
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Adv. Synth. Catal. 2007, 349, 1025 – 1027
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1027