Stereocontrolled formation of styrenes by Pd(0)-catalyzed cross-coupling of photoactivated (E)-Alkenylgermanes with aryl bromides

Article abstract of DOI:10.1246/cl.2011.995

The stereocontrolled synthesis of (E)-configured styrenes via Pd(0)-catalyzed cross-couping of (E)-alkenylgermanes with aryl bromides is described. The germanes employed have bis(naphthalen- 2-ylmethyl) substitution to allow photooxidative activation towa

Full text of DOI:10.1246/cl.2011.995

doi:10.1246/cl.2011.995
Published on the web September 5, 2011
995
Stereocontrolled Formation of Styrenes by Pd(0)-catalyzed Cross-coupling
of Photoactivated (E)-Alkenylgermanes with Aryl Bromides
Chih-Chung Tseng, Mungyuen Li, Bingli Mo, Sarah A. Warren, and Alan C. Spivey*
Department of Chemistry, Imperial College, London, SW7 2AZ, U.K.
(Received June 13, 2011; CL-110485; E-mail: a.c.spivey@imperial.ac.uk)
The stereocontrolled synthesis of (E)-configured styrenes via
Pd(0)-catalyzed cross-couping of (E)-alkenylgermanes with aryl
bromides is described. The germanes employed have bis(naph-
thalen-2-ylmethyl) substitution to allow photooxidative activa-
tion toward coupling and a C8F17-fluorous tag to facilitate
purification by fluorous solid-phase extraction (F-SPE). The
selectivities obtained suggest that a germyl-Stille rather than
Heck-type mechanism predominates in the coupling step.
synthetic attributes as their aryl congeners, with aryl bromides
following photochemical activation of the alkenylgermane
partner. These reactions furnish the expected ¢-substituted
styrenes, predominantly with retention of alkene (E)-stereo-
chemistry, accompanied in some instances by lesser amounts of
¡-substituted isomers (i.e., products of cine rather than ipso
cross-coupling). Mechanistic implications of these findings are
discussed in relation to previously reported alkenylgermane8 and
analogous -silane9 and -stannane10 cross-coupling reactions.
Three light fluorous-tagged alkenylgermanes were em-
ployed in these studies: (E)-¢-phenethylethenylgermane 3a,
(E)-¢-phenylethenylgermane 3b, and (E)-¢-(methoxymethyl)-
ethenylgermane 3c. These derivatives were prepared with
complete regio- and stereoselectivity by [RhCl(CO)(PPh3)2]-
catalyzed hydrogermylation of the corresponding alkynes 2a-2c
with fluorous-tagged germyl hydride 111 (Scheme 2).12
Biaryls and styrenes are key structural motifs in numerous
bioactive natural products, pharmaceuticals, agrochemicals,
dyes, organic semiconductors, and ligands/auxiliaries for
asymmetric synthesis.1 We recently described a new method
for the preparation of biaryls via the Pd(0)-catalyzed germyl-
Stille cross-coupling of light fluorous-tagged arylgermanes with
aryl bromides following photochemical activation of the “safety-
catch” arylgermane partner (Scheme 1).2,3
The method offers some unique features that make it
potentially attractive for synthesis: the arylgermanes are easy
to prepare, nontoxic4 and inert to a wide range of reaction
conditions, most notably those involving strong bases, nucleo-
philes, and reductants.5 This allows the germyl unit to be
installed early in a synthetic sequence, carried through sub-
sequent elaboration steps with few restrictions on the types of
reactions employed, although strongly acidic and oxidative
conditions must be avoided, before selective activation by
photooxidation to enable cross-coupling. The photooxidation
itself is achieved by irradiation of a solution of the substrate and
Cu(BF4)2 with a high-pressure Hg lamp for 2 h. This photolysis
furnishes a difluorogermane reactive intermediate that can be
used directly for cross-coupling after filtration and solvent-
exchange.6 The C8F17 fluorous-tag on the germyl unit enables
rapid purification of all intermediates by F-SPE prior to cross-
coupling.7
The high regio- and stereoselectivities are probably attrib-
utable to the bulky bis(naphthalen-2-ylmethyl) groups on the
germanium hydride 1. Assignment of the product stereochemis-
tries as (E) followed from 1H NMR analysis of their vicinal
alkenyl coupling constants (3J µ 18 Hz).
Photolytic activation of (E)-alkenylgermanes 3a-3c under
the conditions developed previously by us for arylgermanes3
resulted in smooth conversion to the corresponding (E)-
alkenyldifluorogermanes 4a-4c. An alkenyl 3J value of µ18
Hz in the 1H NMR spectrum of derivative 4a confirmed that
no photoisomerization had occurred. Without purification, these
difluorogermanes were immediately subject to Pd(0)-catalyzed
cross-coupling with a selection of aryl bromides again under the
conditions previously developed for biaryl coupling (Table 1).3
In all cases, moderate to good yields of isolated styrenyl
products 5 were obtained, and a single major ¢-substituted
isomer predominated although the coupling of germane 3a with
relatively electron-rich aryl bromides resulted in the formation
of significant amounts of the ¡-substituted isomers (i.e.,
products of cine cross-coupling, Entries 6-8). Assignment of
the stereochemistry of the major (E)- and minor (Z)-¢-
substituted styrenes was straightforward on the basis of
Here, we describe our preliminary exploration of the cross-
coupling of light fluorous-tagged “safety-catch” terminal (E)-
alkenylgermanes, which we anticipated to benefit from the same
2-Nap
C8F17
2-Nap
F
F
2-Nap
C8F17
2-Nap
R
Ge
2-Nap
F17
2-Nap
1
Ar
Ge
ii, Ar-Br
H
R1
Ge
i
C8F17
Ge
R1
C8
i (for 2a & 2b)
i, ii (for 2c)
(E)
R
R
3a R1 = (CH2)2Ph 96%
3b R1 = Ph 96%
3c R1 = CH2OMe 92%
2a R = (CH2)2Ph
2b R = Ph
2c R = CH2OH
22 examples
11-96% yield
Scheme 1. Activation and Pd(0)-mediated cross-coupling of
light fluorous-taged “safety-catch” arylgermanes (refs. 2 and 3).
Conditions: i) h¯, Pyrex tube, Cu(BF4)2 (2 © 4 equiv), MeOH/
MeCN (3:1), 2 h; ii) [PdCl2(MeCN)2] (10 mol %), (o-Tol)3P
(15 mol %), TBAF¢3H2O (2.7 equiv), CuI (1 equiv), DMF,
120 °C, 16 h.
Scheme 2. Synthesis of light fluorous-tagged (E)-¢-ethenyl-
germanes 3a-3c by Ru(I)-catalyzed hydrogermylation. Con-
ditions: i) [RhCl(CO)(PPh3)2] (5 mol %), CH2Cl2, 40 °C, 24 h
(¼3a and 3b) or Cl(CH2)2Cl, 80 °C, 16 h (¼3c); ii) NaH
(2 equiv), Me2SO4 (2.3 equiv), THF, 0-23 °C, 2 h.
Chem. Lett. 2011, 40, 995-997
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

996
i-iii
N
Table 1. Substrate scope of Pd(0)-catalyzed cross-coupling of
3,5-(CF3)2C6H3
5a
2a
4-MeOC6H4
(E)-alkenylgermanes 3a-3c with alkenyl bromidesa
78%
v
6
5c β-(Z )
5c β-(E )
Ar-Br
(3 equiv)
98%
iv
R1
X
X
H
H
4-AcC6H4
(CH2)2Ph
vi,vii
60%
+
Ar
Ar
90%
Ge
Ar
+
C8F17
R1
R1
H
7
H
ii
H
R1
5a-n α
H
3a-c X = CH2(2-Nap)
4a-c X = F
i
5a-n β-(E )
5a-n β-(Z )
Scheme 3. Experiments to confirm the regio- and stereo-
chemical assignments of styrenyl cross-coupling products 5a
and 5c. Conditions: i) O3, CH2Cl2, ¹78 °C, 10 min; ii) PPh3 (2.5
equiv), CH2Cl2, 0-23 °C, 1 h; iii) 4-anisidine (1.5 equiv),
CH2Cl2, 2 h; iv) 4-AcC6H4I (1.0 equiv), [PdCl2(PPh3)2]
(3 mol %), TBAF (2 equiv), CuI (3 mol %), THF, 16 h; v) H2
(1 atm), Lindlar’s catalyst (Pd/Pb), EtOAc, 2 h; vi) [Cp*Ru-
Yield Isomer ratiob
Entry R1
Ar
Product
β-(E):β-(Z):
α
/%
1
2
(CH2)2Ph 3,5-(CF3)2C6H3
(CH2)2Ph 4-CNC6H4
(CH2)2Ph 4-AcC6H4
(CH2)2Ph 3,5-(CH3)2C6H3
(CH2)2Ph 4-FC6H4
5a
5b
5c
5d
5e
5f
5g
5h
5i
65
65
59
63
58
52
72
40
48
58
60
66
52
72
98:2:0
99:1:0
3
4
100:0:0
93:5:2
(MeCN)3]+PF6 (1 mol %), (EtO)3SiH (1.2 equiv), CH2Cl2,
¹
5
93:2:5
16 h; vii) CuI (1.5 equiv), TBAF (3 equiv), THF, 16 h.
6
(CH2)2Ph 4-ClC6H4
(CH2)2Ph 4-MeC6H4
(CH2)2Ph 4-MeOC6H4
(CH2)2Ph 2-NO2C6H4
73:1:26
80:8:12
67:13:20
80:20:0
82:17:1
90:10:0
100:0:0
99:1:0
7
8
9
3
10
11
12
13
14
Ph
Ph
Ph
Ph
3,5-(CF3)2C6H3
4-CNC6H4
4-AcC6H4
5j
5k
5l
5m
5n
4-MeC6H4
2
CH2OMe 4-AcC6H4
99:1:0
aConditions: i) h¯, Pyrex tube, Cu(BF4)2 (2 © 4 equiv),
MeOH/MeCN (3:1), 2 h; ii) [PdCl2(MeCN)2] (10 mol %),
(o-Tol)3P (15 mol %), TBAF¢3H2O (2.7 equiv), CuI (1 equiv),
DMF, 120 °C, 16 h. bIsomeric ratios determined by GC-MS
1
1
and H NMR analysis.
7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3 6.2 6.1 6.0 5.9 5.8 5.7 5.6
ppm
Figure 1. Comparison of 1H NMR spectra of alkene region of:
a) authentic (Z)-¢-5c, b) authentic (E)-¢-5c, and c) (E)-¢-5c
from cross-coupling of alkenylgermane 3a with 4-AcC6H4Br
(Entry 3, Table 1).
3
3
3
1H NMR alkene J values [i.e., (E) J = 15-18 Hz vs. (Z) J =
µ10-12 Hz] for products 5d-5n (Entries 4-14). By contrast, the
major ¢-substituted styrenyl products 5a-5c obtained from
coupling germane 3a with 3,5-(CF3)2C6H3Br, 4-CNC6H4Br, and
4-AcC6H4Br (Entries 1-3) displayed very similar but complex
second-order distortion patterns in the alkene region of their
1H NMR spectra due to the two protons being close in chemical
shift; this gave these spectra a very distinctive appearance and
Table 2. Screening of phosphine ligands to effect more (E)-
stereoselective ¢-styrene formationa
Ph
H
p-Tol-Br
(3 equiv)
H
X
X
2
prevented assignment by alkene J value analysis.13 Ozonolysis
3
p-Tol
p-Tol
p-Tol
Ph
Ge
+
+
H
H
C8F17
2
Ph
2
ii
of styrene 5a followed by reductive cleavage and in situ reaction
with 4-anisidine afforded imine 6 (78% overall yield) which
confirmed these major coupling adducts to be ¢-styrenes.
Unambiguous stereochemical assignment followed from inde-
pendent synthesis of both isomers of ¢-styrene 5c. (Z)-¢-Styrene
5c was prepared by the Sonogashira cross-coupling of alkyne
2a with 4-AcC6H4I to give arylalkyne 7 then Lindlar partial
hydrogenation. (E)-¢-Styrene 5c was obtained via Ru(I)-cata-
lyzed hydrosilylation of alkyne 7 followed by TBAF-mediated
protodesilylation14 (Scheme 3).
H
H
Ph
5g α
2
3a X = CH2(2-Nap)
4a X = F
i
5g β-(E )
5g β-(Z )
Yield
/%
Isomer ratio
β-(E):β-(Z):α
Entry
Phosphine
1
2
3
4
t-BuXPhos
(n-Bu)3P
Cy3P·HBF4
dppp
65
62
71
42
94:5:1
98:1:1
100:0:0
100:0:0
b
aConditions: i) h¯, Pyrex tube, Cu(BF4)2 (2 © 4 equiv),
MeOH/MeCN (3:1), 2 h; ii) [PdCl2(MeCN)2] (10 mol %),
phosphine (15 mol %), TBAF¢3H2O (2.7 equiv), CuI
(1 equiv), DMF, 120 °C, 16 h. bAddition of i-Pr2NEt
(15 mol %).
Comparison of the 1H NMR spectra of these authentic
samples with the cross-coupling adduct obtained from (E)-
alkenylgermane 3a (Entry 1, Table 1) confirmed that (E)-¢-
styrene 5c was the major isomer, as in all the other cases
(Figure 1).
We hypothesized that improved stereoselectivity for the
desired ¢-(E)- over ¢-(Z)- and/or ¡-styrene isomers in these
photoactivated reactions might be achieved by tuning the
phosphine present during the Pd(0)-catalyzed cross-coupling
step. The coupling between germane 3a and 4-MeC6H4Br,
which gave a 80:8:12 ratio of ¢-(E):¢-(Z):¡ isomeric products
with (o-Tol)3P (Entry 7, Table 1), was selected as a test reaction
on which to screen four alternative phosphines: t-BuXPhos,
(n-Bu)3P, Cy3P, and dppp (Table 2).
Chem. Lett. 2011, 40, 995-997
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

997
MBr
Pd(0)
This paper is in celebration of the 2010 Nobel Prize
awarded to Professors Richard F. Heck, Akira Suzuki, and
Ei-ichi Negishi.
ArPd
R
Ar
R
R
ArPdBr
+
A
B
ipso
β
-styrene
M
M
PdBr
R
MPdBr
Ar
ipso
i
Ar
M = R3Si
R3Ge
MPdBr
References and Notes
Ar
PdBr
M
Ar
1
2
3
4
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ii
R
M
Ar
a
R3Sn
R
PdHBr
R
Ar
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R
cine
α-styrene
b
H
R
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PdBr
cine
PdH
MBr
Pd
Pd(0)
Scheme 4. Proposed reaction pathways for alkenyl group 14
metal cross-coupling reactions.
5
6
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All four phosphines furnished (E)-¢-styrene 5g with
improved selectivity relative to the original (o-Tol)3P-catalyzed
conditions (Entry 7, Table 1). Sterically hindered electron-rich
ligand t-BuXPhos and (n-Bu)3P both gave high levels of (E)-
selectivity (Entries 1 and 2, Table 2), but superior (E)-selectivity
still was obtained by employing Cy3P¢HBF4 and dppp, with the
former also delivering the highest yield (71%), making it the
phosphine of choice for this reaction (Entries 3 and 4, Table 2).
In general, Pd(0)-catalyzed cross-coupling of (E)-alkenyl-
silanes and -stannanes with aryl (pseudo)halides are highly
selective and furnish ipso-products with retention of the regio-
and stereochemistry of the alkenylmetals employed.15 This is
attributed to a Stille-type pathway involving rapid transmetala-
tion with the ArPd(II) complex followed by reductive elimi-
nation (route A, Scheme 4).
However, stereochemical leakage and/or formation of
cine-products (i.e., ¡-substituted styrenes) can also occur for
alkenylsilanes9 and -stannanes10 as the result of Heck-type
pathways initiated by carbopalladation (route B). Steric and
electronic factors determine the ratio of ipso vs. cine addition
(i.e., route i vs. ii) with ¡-styrenyl products being formed from
the cine carbopalladation intermediate via either a Kikukawa-
type Pd-H elimination/readdition pathway (route a)9a,9f,9h or a
Busacca-type Pd-carbene pathway (route b).10a,10d,10e,16 Analo-
gous pathways have been invoked for alkenylgermane cross-
coupling reactions. These often display particularly poor regio-
and stereocontrol.8 Indeed, uniquely, (E)-alkenyltributylger-
manes react under certain conditions to give predominantly
(Z)-ipso and cine products.8h By comparison, our method gives
high levels of selectivity for (E)-ipso products, presumably via a
germyl-Stille pathway (cf. route A), although further experi-
ments will be necessary to substantiate this.
The extent of conversion can be determined by 19F NMR of the crude
photolysis product. Fluorodebenzylation is a stepwise process: after
µ30 min, a monofluorogermane is formed (¹203 ppm, singlet); after
further irradiation this is converted to the difluorogermane (¹162,
¹162.5, and ¹165 ppm, 3 © singlets).
7
8
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In conclusion, a stereocontrolled method for the synthesis of
(E)-configured styrenes via Pd(0)-catalyzed cross-couping of
(E)-alkenylgermanes with aryl bromides has been developed.
The alkenylgermanes are activated by photooxidation and a
C8F17-fluorous tag facilitates purification by fluorous SPE prior
to coupling. Unlike several previous alkenylgermane cross-
coupling reactions, a germyl-Stille rather than Heck-type
mechanism appears to predominate, possibly reflecting the
unique intermediacy of difluorogermanes (cf. 4a-4c) in these
reactions. Application of this method for the parallel synthesis of
bioactive styrene derivatives is currently under investigation.
3
13 Assignment of the J values via simulation of the spectra of (E)- and
(Z)-5c using density functional theory (DFT) at the B3LYP/6-
311+G(2d,p) level (Gaussian 0918) also proved inconclusive.
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19 Supporting Information is available electronically on the CSJ-Journal
Web site, http://www.csj.jp/journals/chem-lett/index.html.
This work was supported in part by unrestricted funding
from AstraZeneca and Imperial College London.
Chem. Lett. 2011, 40, 995-997
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/