Radical Germylzincation of α-Heteroatom-Substituted Alkynes

Article abstract of DOI:10.1021/jacs.8b09851

The regio- and stereoselective addition of germanium and zinc across the C-C triple bond of nitrogen-, sulfur-, oxygen-, and phosphorus-substituted terminal and internal alkynes is achieved by reaction with a combination of R₃GeH and Et₂Zn. Diagnostic experiments support a radical-chain mechanism and the β-zincated vinylgermanes that show exceptional stability are characterized by NMR spectroscopy and X-ray crystallography. The unique feature of this new radical germylzincation reaction is that the C(sp²)-Zn bond formed remains available for subsequent in situ Cu(I)- or Pd(0)-mediated C-C or C-heteroatom bond formation with retention of the double bond geometry. These protocols offer modular access to elaborated tri- and tetrasubstituted vinylgermanes decorated with heteroatom substituents β to germanium that are useful for the preparation of stereodefined alkenes.

Full text of DOI:10.1021/jacs.8b09851

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Article
Radical Germylzincation of #-Heteroatom-Substituted Alkynes
Karen de la Vega-Hernández, Elise Romain, Anais Coffinet, Kajetan Bijouard, Geoffrey
Gontard, Fabrice Chemla, Franck Ferreira, Olivier Jackowski, and Alejandro Pérez-Luna
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b09851 • Publication Date (Web): 29 Nov 2018
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Journal of the American Chemical Society
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Radical Germylzincation of α-Heteroatom-Substituted Alkynes
Karen de la Vega-Hernández, Elise Romain, Anais Coffinet, Kajetan Bijouard, Geoffrey Gontard, Fab-
rice Chemla, Franck Ferreira, Olivier Jackowski, and Alejandro Perez-Luna*
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Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, F-75005 Paris, France
ABSTRACT: The regio- and stereoselective addition of germanium and zinc across the C–C triple bond of nitrogen-, sulfur-, oxy-
gen-, and phosphorous-substituted terminal and internal alkynes is achieved by reaction with a combination of R3GeH and Et2Zn.
Diagnostic experiments support a radical-chain mechanism and the β-zincated vinylgermanes that show exceptional stability are
characterized by NMR spectroscopy and X-ray crystallography. The unique feature of this new radical germylzincation reaction is
that the C(sp2)–Zn bond formed remains available for subsequent in situ Cu(I)- or Pd(0)-mediated C–C or C–heteroatom bond
formation with retention of the double bond geometry. These protocols offer a modular access to elaborated tri- and tetrasubstituted
vinylgermanes decorated with heteroatom substituents β to germanium that are useful for the preparation of stereodefined alkenes.
es in a single synthetic operation a C(sp2)–Ge bond and a
C(sp2)–metal bond. The newly formed reactive bond can be
used as linchpin for subsequent C–C bond formation in one
pot following electrophilic substitution. However, in sharp
contrast with the related silylmetalation and stannylmetalation
reactions that are prevalent approaches for the preparation of
INTRODUCTION
Vinylgermanes1 are attractive synthetic building blocks that
offer specific features such as increased stability towards
protonolysis,2 facile halodegermylation3 or low toxicity,4
which make them useful when limitations are met with the
more popular group 14 homologues vinylsilanes and vi-
nylstannanes.5 Hence, the preparation of vinylgermanes is a
field of intense ongoing research. A number of approaches
have proved suitable for the preparation of vinylgermanes,1c
including electrophilic substitution of vinylmetals with
halogermanes,3b,6 Pd-catalyzed germylation of vinyl halides,7
hydro-3a,8 or carbometalation9 of alkynylgermanes, radical
substitution of vinylsulfides,10a -stannanes,10a or -sulfones,10b
alkene germylation through coupling with hydrogermanes11 or
with vinylgermanes,12 olefination of acylgermanes,13 or dom-
ino arylgermylation of oxanorbornadiene / retro-Diels-Alder.14
Yet, the direct synthesis of vinylgermanes from alkynes by
carbon-germanium bond-forming addition reactions represents
the most straightforward approach and has received the great-
est attention. The hydrogermylation of alkynes with hy-
drogermanes has been disclosed through thermal or micro-
wave-activated,15 radical,16 transition-metal-catalyzed,3a,8d,16e,17
as well as main-group Lewis-acid-catalyzed addition process-
es.18 These protocols offer high levels of regio- and stereocon-
trol, but a shared fundamental limitation is that they cannot
provide access to derivatives having two substituents distal to
the position of the alkene germyl group (Scheme 1, top). Fur-
thermore, only some of the aforementioned synthetic alterna-
tives have been implemented for this purpose,6,9,10,13b and they
rely on more elaborated starting materials and are not wide-in-
scope. Thus, there is no direct and general solution available
for the regio- and stereoselective preparation of 1,2,2-
trisubstituted or tetrasubstituted vinylgermanes.
polysubstituted
vinylsilanes19
and
vinylstannanes,20
germylmetalation reactions are almost unknown. The reaction
between (trimethylgermyl)copper and a terminal alkyne was
reported to be low yielding.21 Also, the germylcupration of
terminal acetylenes with (triethylgermyl)- and (triphenyl-
germyl)cuprates was disclosed:22 excellent cis stereoselectivity
was observed, but regiocontrol was only achieved with the
triphenylgermyl reagents. In that case however, the addition
was found to be reversible and in favor of the starting materi-
als; hence vinylgermane formation only proceeded in the
presence of a proton donor and the C(sp2)–Cu bond formed
was not available for subsequent elaboration.23 It is also wor-
thy of mention that protocols for the related alkyne
germylstannation were developed using the oxidative addition
chemistry of Ge–Sn compounds.24–26 Nonetheless, following
this approach, subsequent elaboration of the C(sp2)–Sn bond
required an additional synthetic step.27
Scheme 1. Synthesis of Vinylgermanes from Alkynes with
C–Ge bond formation (Ge = triorganogermyl)
To satisfy this demand, alkyne germylmetalation, i.e. the 1,2-
addition of germanium–metal bonds across the carbon–carbon
triple bond of alkynes, is particularly appealing as it establish-
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ent):32 thus, direct ethyl radical addition leading to carbozinca-
Hydrogermylation of C–C triple bonds (previous work)
1
2
3
4
5
6
7
8
tion products should be avoided. The rate constant for the
addition of germanium-centered radicals across alkynes has
not been determined,32 but it should be of the same order of
magnitude (though lower) than that for additions of silyl-
centered radicals33 (1 x 108 M–1 s–1 at 27 °C for the addition of
the triethylsilyl radical across phenylacetylene).32 While little
is known about the rate for the reaction between vinyl radicals
and Et2Zn, our previous work on radical silylzincation demon-
strates that for α-heteroatom-substituted vinylic radicals (IV),
the rate for SH2 at the zinc atom is suitable for chain propaga-
tion and can outcompete H-atom transfer from (Me3Si)3SiH.29
Given that the rates for radical H-abstraction are in compara-
ble ranges for R3GeH and for (Me3Si)3SiH,31 a similar situa-
tion was expected here.
H
Ge–H
R
Ge
2
R
R'
1
Hydrogermylation
R'
(E or Z)
R = Aryl, alkyl, silyl, CO2R; R' = H, aryl, alkyl, CF3
Ge
Ge
R
R
R'
1,2-disubstituted
1,1,2-trisubstituted
Germylzincation of C–C triple bonds (this work)
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E
Zn
E+
Ge–H + Et2Zn
Het
Ge
Ge
2
Het
Het
R'
in-situ
electrophilic
substitution
1
Germylzincation
R'
R'
Het = [N], [S], [O], [P]; R' = H, aryl, alkyl, CF3; E = [C], [S], I, Br, F, CF3
Finally, regarding the initiation of the radical chain (not shown
in the scheme), we surmised that it could occur, even in the
absence of deliberately added radical initiators, through sever-
al pathways, including spontaneous-17b,34 or light35-induced
homolysis of the Ge–H bond (as for the hydrogermylation
reactions)36 or oxidation of diethylzinc by traces of molecular
oxygen.37, 38
E
Ge
E
Ge
Het
Ge
Het
Ge
Het
R'
Het
R'
1,2-disubstituted
1,1,2-trisubstituted 1,2,2-trisubstituted
tetrasubstituted
Here we focus on α-heteroatom-substituted alkynes, a sub-
strate class that has not been considered previously for the
above-described methods and that would deliver valuable
heteroatom-substituted alkenes.28 We describe the regio- and
stereoselective germylzincation of both terminal and internal
nitrogen-, oxygen-, sulfur- and phosphorus-substituted alkynes
by reaction with a combination of a hydrogermane and Et2Zn
(Scheme 1, bottom). Upon hydrolysis of the C(sp2)–Zn bond
or in situ Cu(I)- or Pd(0)-mediated functionalization, this
method gives access to a variety of original di-, tri- and
tetrasubstituted vinylgermanes. As part of this work, we also
demonstrate the synthetic potential of this construction of
orthogonally 1,2-dimetalated alkenes.
Scheme 2. Anticipated Radical Approach to the Germyl-
zincation of α-Heteroatom-Substituted Alkynes
ZnEt
R3GeH
R3Ge
Het
•
R1
Et
I
V
Et2Zn
EtH
•
R3Ge
•
Het
R3Ge
II
Our idea, shown in Scheme 2, was to develop a radical ap-
proach similar to the one we recently applied to obtain the
silylzincation of terminal α-heteroatom-substituted alkynes
using a combination of (Me3Si)3SiH and Et2Zn.29 We reasoned
that germanium-centered radicals II, produced by H-atom
transfer between hydrogermanes and ethyl radical (I) (IgII),
should add readily across the C–C triple bond of α-
heteroatom-substituted alkynes III to provide regioselectively
α-heteroatom-substituted vinylic radicals IV (IIIgIV). Radi-
cals IV would then react with Et2Zn by homolytic substitution
(SH2) at the zinc atom (IVgV) to afford β-zincated vinyl-
germanes V along with ethyl radical I that would propagate
the radical chain. For such a process to be possible, radical IV
would have to undergo Zn-atom transfer (IVgV) faster than
competitive H-atom transfer from R3GeH (IVgVI). Other-
wise, radical hydrogermylation16 would be the main reaction
outcome and the Zn functionality would be lost.
R1
IV
Het
Het
R3GeH
R3Ge
H
R1
•
R1
R3Ge
III
VI
RESULTS AND DISCUSSION
We commenced our study by investigating the germylzinca-
tion of model terminal ynamide 1 with Ph3GeH, a well-
established radical hydrogermylating reagent that is commer-
cially available and easy-to-handle (Table 1). The initial con-
ditions involving 1.3 equiv of hydrogermane and 3.0 equiv of
Et2Zn at 0 °C in n-hexane, led to the exclusive formation of β-
germylenamide 2 as an E/Z = 30:70 mixture of isomers, but
the reaction was not complete and only ~ 60% of 1 was con-
sumed (Entry 1). In fact, competitive deprotonation of 1 by
Et2Zn as well as direct hydrogermylation delivering Z-2 ham-
pered the germylzincation process. A survey of other solvents
was then carried out. While no significant improvement was
observed in CH2Cl2 and Et2O, reactions in benzene and methyl
tert-butyl ether (MTBE) afforded improved conversion (~
80%). The stereoselectivity was only modest but, by contrast
with the reaction in n-hexane, often in favor of the E isomer.
Furthermore, in MTBE, competitive carbozincation giving 3
was also observed. Eventually, full conversion and total stere-
ocontrol, also in favor of the E isomer, were obtained using
Me-THF and THF. Nevertheless, carbozincation of 1 occurred
to some extent with the more hindered ether, and a better yield
Estimation of the rate coefficients for each elementary step
involved provided support for the feasibility of this radical
chain, as they were all expected to be well above 102 M–1 s–1,
the commonly accepted lower limit for a radical chain to prop-
agate in dilute solutions.30 Triaryl- and trialkylgermanes un-
dergo H-atom abstraction from alkyl radicals with rate con-
stants in the range of 105–106 M–1 s–1 at ca. 30 °C.31 Moreover,
it is also important to emphasize here that the rate for the
addition of the ethyl radical across alkynes with α-heteroatom
substituents should be lower than ~105 M–1 s–1, which is the
rate for the addition of alkyl radicals across propiolates (ter-
minal alkynes with a strong electron-withdrawing substitu-
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Journal of the American Chemical Society
Et2Zn
(3.0 equiv)
R3GeH
in 2 (87% vs 64%) was obtained in THF. With lower amounts
R1
R1
NH4Cl/H2O
or
ND4Cl/D2O
1
2
3
of Et2Zn (1.8 or 1.2 equiv), the reaction also took place with
high conversion and exclusive formation of 2, albeit with
lower stereocontrol.
R2
R2
R2
(1.3 equiv)
N
O
N
O
R1
α
N
β
THF
0 °C, 3 h
E
[Zn]
O
4
5
6
7
8
9
R3Ge
R3Ge
Table 1. Optimization of the Germylzincation of Ynamide
1
2, 4–9
β/α > 98:2 and
E/Z > 98:2a
unless otherwise noted
O
Ph3GeH
Et2Zn
O
O
O
O
N
O
N
O
O
+
N
α
N
O
O
iPr
Bn
O
β
then
N
N
H
R
O
H
NH4Cl/NH3
R
E
E
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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E
1
E-2 (R = Ph3Ge)
E-3 (R = Et)
Z-2 (R = Ph3Ge)
Z-3 (R = Et)
Ph3Ge
2 (E=H): 87%b
[2H]-2 (E=D): 86%
Ph3Ge
4 (E=H): 66%b,c
[2H]-4 (E=D): 77%c
Ph3Ge
5 (E=H): 70%c–e
[2H]-5 (E=D): 76%c–e
Entry
Solventa
d.r. 2
(E/Z)c
O
Et2Zn
Conver-
sionb,c
(2/1)
Yield
O
[equiv]
2 (%)d
O
N
O
N
E
E
1
2
3
4
5
6
7
8
9
n-hexanee
CH2Cl2
Et2O
3.0
3.0
3.0
3.0
3.0
3.0
3.0
1.8
1.2
62:38
50:50
54:46
85:15
80:20
>99:1
>99:1
>99:1
89:11
30:70
70:30
48:52
57:43
68:32
98:2
ncf
37
(2-furyl)3Ge
7 (E=H): 72%d
[2H]-7 (E=D): 83%d
Ph3Ge
6 (E=H): 70%c,d
[2H]-6 (E=D): 66%c,d
29
O
O
N
benzene
MTBE
Me-THF
THF
ncf
62g
64h
87
ncf
ncf
O
N
O
E
E
nBu3Ge
Et3Ge
8 (E=H): 40% (E/Z = 96:4)b,f
77% (E/Z = 96:4)b,e,g
[2H]-8 (E=D): 67% (E/Z = 96:4)e,g
9 (E=H): 76% (E/Z = 95:5)b,e,g
[2H]-9 (E=D): 92% (E/Z = 91:9)e,g
>98:2
90:10
76:24
THF
aMeasured by 1H NMR prior to purification. bReaction was quenched with
NH4Cl/NH3. c10–12% of Et addition was detected. dCuTC (1.0 equiv) was
added before the reaction quench. e16 h reaction time. f10% of 3 was formed.
gR3GeH (2.0 equiv).
THF
aReaction conditions: Ph3GeH (1.3 equiv), 0 °C, 3 h unless oth-
erwise stated. bOnly β-germylated regioisomers were detected.
cDetermined by 1H NMR prior to purification. dCombined yield of
The formation of vinylzinc intermediates upon reaction with
R3GeH / Et2Zn under the developed conditions was studied
systematically by deuterium labeling and D-incorporation >
95% at the α-position was observed in every case (Scheme 3).
It must be noted however that these experiments were compli-
cated by the remarkably high stability towards hydrolysis of
the C(sp2)–Zn bond of divinylzinc species VIII (Scheme 4),
likely formed by Schlenk equilibration of the intermediates
VII arising from germylzincation (vide infra). In some cases,
organometallic species VIII reacted only partially with
ND4Cl/D2O42 or MeOD, leading to flawed D-incorporation
values and significant amounts of VIII were recovered in the
crude even after extended exposure to aqueous solutions or
after column chromatography on silica gel! Efficient deuterio-
demetalation of intermediates VIII was nevertheless achieved
upon addition of CuTC (Copper(I)-thiophene-2-carboxylate)
prior to the reaction quench and reliable D-labeling data could
be collected. Similar quench conditions (CuTC / NH4Cl / H2O)
were also used in the preparation of non-labeled 5, 6 and 7.
isolated diastereomers. Reaction time = 6 h. fNot calculated. 6%
e
g
of 3 was observed. h10% of 3 was observed.
The scope of this new germylzincation reaction of terminal
ynamides was next considered (Scheme 3). Modification of
the substitution pattern α to the nitrogen atom of the oxazoli-
dinone ring was well tolerated and β-germylenamides 4–6
were isolated in good yields and as single E isomers.39 Here
however, small amounts (10–12%) of carbozincation adducts
were detected in the crude. Other hydrogermanes were also
used. Trifurylgermane40 reacted smoothly to provide stereo-
pure E-7 in 72% yield. With nBu3GeH, the conversion (50%)
was not complete and product 8 was obtained in a lower 40%
yield along with 10% of the carbozincation adduct (3). In this
case, the rate coefficient for the reaction between alkyl radi-
cals and the hydrogermane is around one order of magnitude
lower than for triarylgermanes:41 this makes ethyl radical
addition more competitive and the propagation of the radical
chain (Scheme 2, IgII) less efficient. Nevertheless, with
higher amounts of hydrogermane (2.0 equiv) and longer reac-
tion times, nBu3GeH and Et3GeH led respectively to 8 and 9 in
high yields with very high (≥ 95:5) stereoselectivities, and no
ethylzincation was observed.
Scheme 4. Schlenk Equilibrium of α-Zincated β-
Germylenamides
R1
R1
R2
Scheme 3. Reaction Scope for the Germylzincation of
Terminal Ynamides
O
N
R2
GeR3
R2
N
O
+
Et2Zn
2
Zn
ZnEt
R3Ge
O
N
R3Ge
R1
VIII
VII
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Importantly, the germylzincation reaction was also found to be For this substrate class, the best conditions for the reaction
1
2
3
4
5
6
7
8
well suited for internal ynamides (Scheme 5).
with Ph3GeH / Et2Zn involved using n-hexane as solvent at 40
°C. Here, direct hydrogermylation did not interfere with the
germylzincation process, and β-germylenamide E-10 was
obtained from the parent Ph-substituted ynamide in 92% yield
with β-regioselectivity and cis-stereoselectivity. The same
exquisite regio- and stereoselectivity was observed at lower
temperatures and/or in THF, but conversion of the starting
material was not complete.
Scheme 5. Reaction Scope for the Germylzincation of In-
ternal Ynamides
Et2Zn
R1
R1
(3.0 equiv)
R3GeH
(1.3 equiv)
NH4Cl/NH3
or
ND4Cl/D2O
R2
R2
R2
N
O
N
O
N
R1
α
R3
R3
β
n-hexane
40 °C, 3 h
E
[Zn]
R3
O
R3Ge
R3Ge
Modification of the nitrogen substituent was also well tolerat-
ed here. E-enamides 11–13 having different oxazolidinone
rings were obtained in 69-86% yields from the corresponding
cyclic ynamides. Importantly and by contrast with the terminal
ynamides derived from the same oxazolidinones, competing
ethyl radical addition was not observed, what is consistent
with the lower rate coefficient for the addition of alkyl radicals
to disubstituted alkynes than to monosubstituted alkynes.32
Moreover, enamide 14 having an acyclic carbamate was pro-
duced, with full regio- and stereoselectivity, in 73% yield. The
E configuration of products 12 and 14 was established by X-
ray crystallographic analysis.43
9
10–27
β/α > 98:2 and E/Z > 98:2a
unless otherwise noted
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
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O
O
O
O
O
O
iPr
Bn
Ph
N
N
N
Ph
Ph3Ge
Ph
E
E
E
Ph3Ge
11 (E=H): 86% (E/Z = 92:8)
Ph3Ge
10 (E=H): 92%
12 (E=H): 85%
[2H]-11 (E=D): 83% (E/Z = 90:10) [2H]-12 (E=D): 72%
[56% in THF]
[2H]-10 (E=D): 88%
[58% in THF]
O
O
Ph
CO2Me
E
N
R3
O
N
O
N
Regardless of the electronic character or the position of the
substituent, substitution of the phenyl ring had little impact on
the reaction outcome with other aryl-substituted ynamides.
Thus, 15 and 17 with para- or meta- methoxy-substituted
rings, or 16 and 19 with para chloro- or ortho, ortho dichloro-
substituted rings were all obtained in similar high yields and as
single E isomers. Only 18 having an ortho methoxy-
substituted phenyl ring was an exception to this trend as it was
delivered with low stereoselectivity. Certainly, coordination of
Et2Zn to the MeO group influences the alkylzinc group trans-
fer event that is the stereodiscriminating step (vide infra).
Ph
Ph3Ge
Ph
E
E
Ph3Ge
Ph3Ge
14 (E=H): 73%b
[2H]-14 (E=D): 73%b
15 (R3 = OMe, E=H): 94%
[2H]-15 (R3 = OMe, E=D): 90%
16 (R3 = Cl, E=H): 89%
13 (E=H): 69%
[2H]-13 (E=D): 80%
[2H]-16 (R3 = Cl, E=D): 87%
O
O
O
O
N
N
E
MeO
E
MeO
GePh3
Ph3Ge
18 (E=H): 81% (E/Z = 60:40)
[2H]-18 (E=D): 84% (E/Z = 52:48)
17 (E=H): 83%
[2H]-17 (E=D): 88%
The germylzincation was not restricted to ynamides substitut-
ed at the alkyne terminus by aryl groups, as trisubstituted
enamides having alkenyl (20)-, alkynyl (21)-, primary alkyl
(22 and 23)-, secondary alkyl (24)-, and CF3 (25)-substituents
β to the nitrogen atom were prepared for the most part in good
yields, even if longer reaction times were sometimes neces-
sary. Excellent stereoselectivities were obtained in all cases,
but for cyclohexyl- and CF3-substituted enamides 24 and 25,
reversal of stereoselectivity in favor of a trans-selective
germylzincation was observed. Furthermore, in the formation
of the CF3-substituted enamide, competitive carbozincation
and α-selective germylzincation were detected to some extent.
The configurations of products 23 (E) and 25 (Z) were estab-
lished by X-ray crystallographic analysis.43
O
O
O
O
O
O
Cl
N
N
(iPr)3Si
N
Ph
E
E
E
Cl
GePh3
19 (E=H): 69%b
[2H]-19 (E=D): 72%b,c
Ph3Ge
20 (E=H): 85%b
[2H]-20 (E=D): 80%b
Ph3Ge
21 (E=H): 45%b
[2H]-21 (E=D): 45%b
O
O
O
O
N
N
n-Hex
Ph3Ge
22 (E=H): 85%b (E/Z = 90:10)
[2H]-22 (E=D): 87%b (E/Z = 92:8)
E
E
TBSO
Ph3Ge
23 (E=H): 52%
[2H]-23 (E=D): 42%
O
O
As demonstrated with the preparation of 26 as a single E iso-
mer in 88% yield, (2-furyl)3GeH performed as well as Ph3GeH
for the germylzincation of internal ynamides. By contrast,
trialkylgermanes were not suitable because of the lack of
regiocontrol, as in the case of the formation of 27.
O
N
O
N
Ph3Ge
E
Ph3Ge
E
c-Hex
CF3
24 (E=H): 63%b,d (Z/E = 92:8)
[2H]-24 (E=D): 63%b–d (Z/E = 98:2)
25 (E=H): 57%b,e (Z/E > 98:2)
[2H]-25 (E=D): 55%b,e (Z/E > 98:2)
Finally, similarly to the reactions involving terminal yna-
mides, D-labeled enamides (> 90% D-incorporation) were
obtained on quenching the reactions with ND4Cl (Scheme 5),
thus confirming the formation of vinylzinc intermediates upon
reaction of internal ynamides with R3GeH / Et2Zn. Again, in
the cases of 19 and 24, quenching with a mixture of CuTC /
ND4Cl / D2O was necessary to obtain reliable values for D-
incorporation.
O
O
O
N
O
N
Ph
E
Ph
E
(2-furyl)3Ge
Et3Ge
26 (E=H): 88%b
[2H]-26 (E=D): 88%b
27 (E=H): 63%d (β/α = 55:45)
aMeasured by 1H NMR prior to purification. b16 h reaction time. cCuTC (1.0
equiv) was added before the reaction quench. d2.0 equiv R3GeH. e13% of Et
addition and 9% of an α-isomer were detected.
Our next efforts were directed to gain insight into the mecha-
nism of the new germylzincation reaction. In a first set of
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Journal of the American Chemical Society
reaction. While these experiments lend clear evidence for the
experiments, we examined the influence of metalation of 1 in
1
2
3
4
5
6
7
8
the reaction media (Scheme 6, a). Performing the germylzinca-
tion on D-labeled ynamide [2H]-1 led exclusively to E-[2H(β)]-
2 without loss of deuterium at the β-position, thus indicating
that deprotonation of 1 (neither by Et2Zn44 nor by vinylzinc
intermediates) did not occur during germylzincation (in THF
at 0 °C).
intervention of radicals in the mechanism, we could not at this
point exclude a scenario wherein Et2Zn would react with
R3GeH by a radical alkylzinc group-transfer process (reminis-
cent of that involved in the formation of [(Me3Si)3Si]2Zn from
(Me3Si)3SiH and Et2Zn)48 and provide a putative germanium–
zinc intermediate IX (Scheme 6, d) that would add across the
C–C triple bond of the ynamide through a polar mechanism.
Notably, the reported formation of (Ph3Ge)2Zn by reaction
between Et2Zn and Ph3GeH in THF required to exclude this
possibility.49 Towards this end, the reaction of Ph3GeH / Et2Zn
with mechanistic probe X29a was considered (Scheme 6, e).
The formation of cyclized products [2H]-XI (33%) and [2H]-
XII (52%) (arising from competing ethyl radical addition)50
provided evidence for a radical 1,4-addition (leading to an
intermediate β-alkoxy radical XIII that undergoes 5-exo-dig
ring closure) whereas no products arising from the fragmenta-
tion of an intermediate β-alkoxy anion51 (not shown) that
would support an alternative polar addition of IX were detect-
It was found that Ph3GeH could react with 1 in the absence of
Et2Zn (Scheme 6, b):45 both in n-hexane and THF, after 3 h at
0 °C, the stereoselective formation of Z-2 was observed in 50–
60% yield,46 and the absence of this direct hydrogermylation
in the presence of TEMPO confirmed its radical character.47
The afore-described D-labeling experiments (Scheme 3) estab-
lished that germylzincation outcompetes this radical hy-
drogermylation in THF with excess Et2Zn. However, the loss
of stereoselectivity observed with lower amounts of Et2Zn or
in other solvents (Table 1), can certainly by ascribed to the
coexistence of the two competing processes: germylzincation
that leads to the E-isomer (after work-up), and hydrogermyla-
tion that delivers the Z-isomer. It is important to note that, by
contrast, with internal ynamides, no reaction with Ph3GeH was
detected in the absence of Et2Zn, even at 40 °C.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
ed. Furthermore, we also monitored by in situ H NMR the
rate of depletion of Ph3GeH upon contact with Et2Zn in THF
in the absence of ynamide. After 3 h at 0 °C (Scheme 6, d),
40% of the initial amount of Ph3GeH had disappeared.52
Hence, the rate of formation of a hypothetical germanium–
zinc intermediate under these conditions was too slow to ac-
count conveniently for the germylzincation reactions. Overall,
these findings provided strong support for the mechanism
foreseen at the outset of our work (depicted in Scheme 2)
involving the addition of germanium-centered radicals across
the C–C triple bond of ynamides.
Scheme 6. Mechanistic Studies
(a) Absence of metalation of 1
O
Et2Zn (3.0 equiv)
O
Ph3GeH (1.3 equiv)
N
O
α
N
D
THF, 0 °C, 3 h
then
E
β
O
D
Ph3Ge
[2H(β)]-2 (E=H): 99% (E/Z > 98:2)
NH4Cl/NH3 or
ND4Cl/D2O
[2H]-1
The regioselectivity of the process was fully consistent with
this mechanism, as previous intermolecular additions of radi-
cals across ynamides, including the abovementioned direct
hydrogermylation, occured β to the nitrogen atom both for
terminal and internal ynamides.53 Steric effects usually ac-
count for the regioselectivity of radical additions across mono-
substituted alkynes,32 and this is likely also the case for termi-
nal ynamides. By contrast, the origin of regioslectivity for
internal ynamides is not clear. Steric factors still seem im-
portant, as shown by the lack of stereocontrol with the less
hindered trialkylgermanes (Scheme 5, product 27), but other
elements, among which stabilization of the vinyl radical by the
α-nitrogen atom, or differences in reactivity of the possible
regioisomeric radicals in the subsequent forward reaction (SH2
at zinc), can also intervene and are difficult to estimate.32
[2H(α),2H(β)]-2 (E=D): 89% (E/Z > 98:2)
(b) Direct radical trans-hydrogermylation
Solvent
TEMPO
(mol%)
2/1
O
Ph3GeH
(1.3 equiv)
O
O
n-hexane
THF
59:41
48:52
0:100
-
-
N
N
0 °C, 3 h
then
NH4Cl/NH3
Ph3Ge
O
H
THF
10
1
2 (Z/E > 98:2)
(c) Experiments in the presence of radical trapping agent TEMPO
Et2Zn
t1 (min) TEMPO
(mol%)
2/1
(3.0 equiv)
Ph3GeH
(1.3 equiv)
O
then
O
TEMPO
N
0
0
5
110
10
0:100
0:100
26:74
O
N
THF
0 °C, t1 (min)
THF
0 °C, 3 h
O
Ph3Ge
2 (E/Z > 98:2)
10
1
The stereochemical outcome of the germylzincation reactions
was also rationalized conveniently on the basis of this scenar-
io: the stereoselectivity of the germylzincation reaction is that
of the alkylzinc group transfer (i.e. XIVgVII, Scheme 7). sp2-
Hybridized radicals XIV have a bent geometry and are con-
sidered to exist in two equilibrating diastereomeric forms with
a low interconversion energy barrier. The reaction of E-XIV
with Et2Zn provides Z-VII and that of Z-XIV produces E-
VII.54 Thus, the Z/E ratio for the formation of VII depends
both on the relative stability of both isomers of XIV (Keq), as
well as the relative ease of each diastereomeric form to under-
go ethylzinc group transfer (kZ vs kE). In general terms, one
would expect Z-XIV to react more promptly than E-XIV (kZ >
kE) because the Et2Zn/R3 steric interaction is less demanding
that the Et2Zn/R3Ge interaction. With “small” R3 substituents
(i.e. R3 = H, primary alkyl or aryl), the Z/E equilibrium is
largely in favor of the E form (Keq >> 1) and the formation of
(d) Slow formation of a germanium–zinc intermediate
Et2Zn + Ph3GeH
(R = Et or GePh3)
Ph3Ge ZnR
THF
0 °C, 3 h
IX
∼ 40% loss of Ph3GeH
(e) Discrimination of radical versus polar additions with probe X
through
Et2Zn
(3.0 equiv)
Ph3GeH
(3.0 equiv)
SiMe3
SiMe3
SiMe3
SiMe3
D
D
CO2Me
+
O
O
CO2Me
•
CO2Me
CO2Me
THF, 0 °C
then
O
O
Ph3Ge / Et
D2O
Ph3Ge
Et
X
[2H]-XI: 33%
(Z/E > 98:2)
[2H]-XII: 52%
(Z/E > 98:2)
XIII
(+ 5% XI (E/Z > 98:2)
The presence of TEMPO also thwarted completely the
germylzincation (Scheme 6, c): no conversion was observed if
amounts as low as 10 mol% were added at the beginning and
only 26% of E-2 was formed upon addition after 5 min of
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Z-VII is favored. By contrast “larger” R3 substituents (i.e.
Et2Zn (3.0 equiv)
Ph3GeH (1.3 equiv)
Conditions A or B
R2
cyclohexyl or CF355), destabilize E-XIV (Keq becomes lower)
and thus the formation of E-VII becomes more favorable.
R2
R1
1
2
3
4
5
6
7
8
N
α
N
β
R1
R3
then
CuCN•2LiCl (3.0 equiv)
E–X (7.0 equiv)
THF
E
R3
Scheme 7. Stereoselectivity Model for the Germylzincation
of Terminal and Internal Ynamides
Ph3Ge
28–42
–30 °C to rt
β/α > 98:2 and E/Z > 98:2
ZnEt2
Conditions A (R3 = H): THF, 0 °C
R1
O
R2
O
O
•
Bn
Ts
Keq
N
O
R3
R1
N
O
O
N
R2
R3
N
N
•
R3Ge
9
R3Ge
ZnEt2
Ph3Ge
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ph3Ge
29: 81%
(X = Br; SN')
Ph3Ge
Z-XIV
E-XIV
30: 87%a
(X = Br; SN')
28: 92%
83%a
(X = Br; SN')
kE
kZ
[Z-VII]
[E-VII]
•
•
=
Keq
– Et
– Et
kZ
kE
R1
O
O
O
O
O
O
EtZn
O
R2
N
N
N
N
O
R3
R1
O
N
R2
R3
SPh
ZnEt
R3Ge
Ph3Ge
Ph
Ph3Ge
Ph
Ph3Ge
R3Ge
31: 76%
(X = Cl)
32: 94%
(X = Br)
33: 75% (Z/E > 98:2)
(X = SO2Ph)
E-VII
Z-VII
The reversal of stereoselectivity observed between the radical
trans-silylzincation of terminal ynamides with (Me3Si)3SiH /
Et2Zn in n-hexane29a and the present cis-stereoselective
germylzincation in THF is a noteworthy point that deserves
further comment. The trans selectivity for the silylzincation
was attributed to the formation, in n-hexane, of a Lewis pair
between Et2Zn and the carbonyl group on the nitrogen atom;
the Zn-atom transfer step was accelerated and outcompeted Z-
to-E interconversion of the α-amino vinylic radical that react-
ed only as the initially formed Z-stereomer.56 As evidenced
with in situ IR experiments, THF prevents this Lewis-pair
formation during germylzincation (see supporting infor-
mation). Hence, Z-to-E interconversion becomes faster than
the Zn-atom transfer step; the reaction of the E-stereomer (i.e.
E-XIV (R3=H)) is favored and the formation of Z-VII (R3=H)
is obtained. The fact that silylzincation of terminal ynamide 1
with (Me3Si)3SiH / Et2Zn proceeds with exclusive cis-
stereoselectivity in THF,57 provides additional evidence for
this remarkable solvent effect.
Conditions B (R3 ≠ H): n-hexane, 40 °C
O
O
O
MeO
O
O
O
Cl
N
N
N
Ph
Ph3Ge
Ph3Ge
35: 85%b
(X = Br; SN')
Cl
GePh3
34: 95%
(X = Br; SN')
36: 79%
(X = Br; SN')
O
Bn
Ts
Ph Ts
O
N
N
N
Ph
Ph3Ge
Ph
Ph3Ge
Ph
Me
Ph3Ge
37: 88%a,c
(X = Br; SN')
38: 77% (E/Z = 92:8)a,c
39: 45%
(X = Br)
(X = Br; SN')
O
O
O
MeO
O
O
O
N
N
(iPr)3Si
N
Ph
Ph3Ge
40: 95%
(X = Br)
Ph
Ph3Ge
Ph
Ph3Ge
42: 20%
(X = Br)
Ph
41: 54%a,b
(X = Br)
aCuTC was used as Cu(I)-salt. bReaction performed at 1.0 mmol scale. cThe
germylzincation was carried out with 2.0 equiv Ph3GeH at rt.
Having established the scope for the germylzincation reaction,
we next investigated the synthetic potential of C(sp2)–Zn bond
functionalization to provide access to vinylgermanes with two
substituents β to the germanium atom. In situ Cu(I)-mediated
electrophilic substitution following germylzincation occurred
readily with complete stereoretention of the double bond ge-
ometry (Scheme 8). The typical procedure involved using the
THF-soluble salt CuCN•2LiCl, but (commercially available)
CuTC could be used alternatively with comparable results.
Both protocols were equally efficient for the vinylzinc inter-
mediates arising from the germylzincation of terminal or in-
ternal ynamides, thus giving access to diversely substituted tri-
or tetrasubstituted vinylgermanes with defined geometry.
Competent carbon and non-carbon electrophiles included
allylic halides (28–30 and 34–38), acyl halides (31), alkynyl
bromides (32, 40–42), methyl iodide (39) or phenyl phenylthio
sulfone (33). The E configuration of product 40 was estab-
lished by X-ray crystallographic analysis.43
Importantly, the domino cis-germylzincation–Cu(I)-mediated
electrophilic substitution was also applicable with tosyl-
ynamides (terminal and internal) and delivered α-substituted
β-germyl enamides 30, 37 and 38 in 77–88% yield. It must be
noted that the corresponding β-germyl enamides arising from
protonolysis (E = H) decomposed during work-up and could
not be isolated.
Moreover, in situ functionalization of the C(sp2)–Zn bond of
the germylzincation adducts was also readily achieved by
means of Cu(I)-mediated 1,4-addition to enones, as illustrated
with the formation of adduct 43 from 1 (Scheme 9).
Scheme 9. Domino Ynamide Germylzincation / Cu(I)-
Mediated 1,4-Addition
O
Et2Zn (3.0 equiv)
Ph3GeH (1.3 equiv)
THF, 0 °C
O
N
O
Scheme 8. Domino Ynamide Germylzincation / Cu(I)-
Mediated Electrophilic Substitution
α
•
N
O
then
β
•
CuCN•2LiCl (3.0 equiv)
cyclohexenone (7.0 equiv)
Me3SiCl (14.0 equiv)
–78 °C to rt
O
Ph3Ge
43: 67%
β/α > 98:2 and E/Z > 98:2
1
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Scheme 10. Ynamide Germylzincation / Cu(I)- or Pd(0)-
The presence of excess Et2Zn required for the germylzincation
step complicated in certain cases clean C(sp2)–Zn bond func-
tionalization, notably for halodezincation reactions. To over-
come this limitation we decided to eliminate Et2Zn before the
electrophilic substitution step by removing the volatiles under
reduced pressure. Upon elimination of Et2Zn, displacement of
the Schlenk equilibria (Scheme 4) led to the exclusive for-
mation of divinylzinc intermediates.
Mediated Electrophilic Substitution via Divinylzinc Inter-
mediate 44
1
2
3
4
5
6
7
8
O
Et2Zn
(3.0 equiv)
Ph3GeH
(1.3 equiv)
O
O
Electrophile
3 Cu(I) or Pd(0)
N
GePh
O
N
1
Zn
THF, 0 °C, 3 h
Conditions
A, B or C
Ph3Ge
E
then
vacuum (1.0 mmHg)
N
O
Ph3Ge
In particular, the structure of compounds 44 and 45 was ana-
lyzed by X-ray crystallography and both showed similar char-
acteristics (Figure 1). The cis geometry between zinc and
germanium following germylzincation was confirmed. An
almost linear arrangement of the two carbon–zinc bonds was
observed, with bond lengths (1.985 to 2.009 Å) in the ex-
pected range for diorganozinc compounds.58 Remarkably, the
zinc atom was also coordinated to the oxygen atoms of the
carbonyl groups and adopted an uncommon distorted seesaw
shaped four-coordinate geometry.59 The position of the phenyl
rings of Ph3Ge is also of interest. Even though there is no Zn–
Cipso contact, two of them clearly shield the Zn atom and likely
confer to the divinylzinc species their unusual stability to-
wards hydrolysis and oxidation mentioned previously.
28, 46–50
O
9
β/α > 98:2
44
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A: CuCN•2LiCl (2.0 equiv), THF, –30 °C to 0 °C / rt
B: CuTC (10 mol%), THF, –30 °C to rt
C: Pd2dba3 (5 mol%), (2-Fur)3P (10 mol%), THF, 65 °C
O
O
O
O
O
O
O
O
N
N
N
N
I
Br
F
CF3
Ph3Ge
Ph3Ge
47: 46% (A)
(Z/E > 98:2)
Ph3Ge
48: 59% (A)
(Z/E > 98:2)
Ph3Ge
49: 39% (A)
(E/Z = 92:8)
46: 66% (A)
(Z/E > 98:2)
I2
NBS
(2.0 equiv)
–
BF4
(2.0 equiv)
N
S
–
BF4
CF3
(2.5 equiv)
F
(2.5 equiv)
O
O
O
N
O
GePh3
O
O
N
N
Zn
Ph3Ge
N
O
Ph3Ge
Ph3Ge
NO2
O
28: 87% (B) (E/Z > 98:2)
allylbromide (2.0 equiv)
50: 56% (C) (E/Z > 98:2)
1-bromo-4-nitrobenzene (2.0 equiv)
44
To illustrate the synthetic potential of the β-germylenamides
accessible through the new germylzincation chemistry, it was
then demonstrated that they could be easily converted, with
immaculate retention of the double bond geometry, into β-
haloenamides that are valuable for further elaboration of ste-
reodefined enamides.29 Unlike for trialkylvinylgermanes,
halodegermylation reactions of triphenylvinylgermanes are
O
iPr
O
N
GePh3
Zn
Ph3Ge
N
O
iPr
O
45
sluggish
or
ineffective.5b,d,e
Conversely,
for
β-
triphenylgermylenamides, they were remarkably efficient
(Scheme 11). Treatment at –78 °C in CH2Cl2 of E-2 with ICl
resulted in clean halodegermylation providing disubstituted
iodoenamide 51 in 93% yield, while reaction of 15 and 28
with Br2 led to trisubstituted bromoenamides 52 and 53 in 43–
73% yields.
Figure 1. X-ray crystal structure of 44 and 45. Selected bond
lengths and bond angles. 44: Zn–C1 = 1.995(8) Å, Zn–C26 =
1.985(8) Å, C1–Zn–C26 = 170.8(3)°, O1–Zn1–O3 = 97.8(3)°. 45:
Zn–C1 = 1.989(7) Å, Zn–C27 = 2.009(7) Å, C1–Zn–C27 =
165.5(3)°, O1–Zn–O3 = 91.3(3)°.
The divinylzinc intermediates arising from the germylzinca-
tion / evaporation sequence also underwent smooth Cu(I)-
mediated electrophilic substitution in THF and this modified
protocol offered additional possibilities for C(sp2)–Zn func-
tionalization (Scheme 10). The use of halogen electrophiles
was possible and β-germylenamides decorated in α-position
with iodine (46), bromine (47) or fluorine (48) were prepared
in acceptable yields. Trifluoromethylation with Umemoto’s
reagent to deliver 49 was also accomplished. An additional
asset of this protocol was that it made possible the use of cata-
lytic amounts of Cu(I) salt, as shown for the formation of 28 in
87% yield from 1 using 10 mol% CuTC to promote the allyla-
tion step. It was also feasible to perform Pd-catalyzed Negishi-
type cross-coupling reactions, and 44 reacted with 1-bromo-4-
nitrobenzene to afford arylated product 50 in 56% yield. Here,
24% of product E-2 coming from the hydrolysis of unreacted
44 was also recovered. It is noteworthy, that no cross-coupling
reaction occurred when 1-iodo-4-nitrobenzene was used under
similar conditions.
Scheme 11. Halodegermylation Reactions of β-
Triphenylgermylenamides
O
O
ICl or Br2
O
O
N
N
R1
R1
CH2Cl2, –78 °C
R2
R2
Ph3Ge
X
51–53
E/Z > 98:2
E-2, 15, 28
O
O
N
O
MeO
O
O
O
N
N
I
Br
Br
51: 93%
52: 73%
53: 43%
To finish our study, the possibility of performing the germyl-
zincation reaction with alkynes other than ynamides was con-
sidered. The addition of Ph3GeH / Et2Zn across the carbon–
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carbon triple bond of sulfur-, oxygen-, and phosphorous- adding AIBN as radical initiator and operating at 80 °C to
1
2
3
4
5
6
7
8
substituted terminal alkynes occurred at 0 °C yielding the
corresponding β-heteroatom-substituted vinylgermanes 54–57
with full β-regio- and cis-stereocontrol (Scheme 12). It was
interesting to note that the heteroatom substituent had no im-
pact on the regioselectivity, as this trend differed from that
observed for certain alkyne carbometalation reactions.60 THF
was generally the solvent of choice, but in the case of 57 better
yields were obtained in n-hexane. Isolated yields were in the
range 37% to 70%. Likewise, tri-substituted vinylgermane 58
was delivered in 70% yield (with the same regio- and stere-
ocontrol) from the germylzincation in n-hexane at 40 °C of an
internal α-phosphonate-substituted alkyne. The E configura-
tion of product 58 was established by X-ray crystallographic
analysis.43
ensure its decomposition. Products 59 and 60 were obtained in
improved 66% and 67% yields within much shorter reaction
times (1 h). Control experiments in the absence of AIBN gave
less than 10% conversion under the same operating conditions,
what underscored the decisive role played by the radical initia-
tor and provided further support for radical character of the
germylzincation. The stereoselectivity remained very high in
the case of 60, but dropped for 59 as the consequence of radi-
cal induced isomerization of the intermediate zincated vinyl-
germanes.63
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10
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 13. Germylzincation of 1-Phenyl-1-Propyne and
Diphenylacetylene
NH4Cl/NH3
Et2Zn / Ph3GeH
or
E
[Zn]
α
Conditions A or B
Ph
ND4Cl/D2O
In all cases, D-labeling confirmed the formation of vinylzinc
intermediates and the availability of the C(sp2)–Zn bond
formed for further elaboration, as [2H]-54–[2H]-58 were ob-
tained (> 90% D-incorporation) on quenching with ND4Cl. In
the case of product 57, D-incorporation α to germanium was
also observed indicating that here, germylzincation occurred
on the zincated alkyne.
R
R
β
Ph
Ph
THF
R
Ph3Ge
Ph3Ge
59–60
A: Et2Zn (3.0 equiv), Ph3GeH (1.3 equiv), 40 °C, 16 h
B: Et2Zn (3.0 equiv), Ph3GeH (2.0 equiv), AIBN (25 mol%), 80 °C, 1 h
E
E
Me
Ph
Ph
Ph
Ph3Ge
β/α > 98:2
Ph3Ge
Scheme 12. Germylzincation of Other α-Heteroatom-
Substituted Alkynes
59 (E=H): 40% (Z/E = 90:10) (A)
66% (Z/E = 65:35) (B)
60 (E=H): 49% (Z/E = 88:12) (A)
67% (Z/E = 92:8) (B)
[2H]-60 (E=D):
Et2Zn
[2H]-59 (E=D): 43% (Z/E = 90:10) (A)
71% (Z/E = 92:8) (B)
(3.0 equiv)
Ph3GeH
(1.3 equiv)
NH4Cl/NH3
or
ND4Cl/D2O
Het
Het
α
Het
R1
R1
β
CONCLUSIONS
[Zn]
E
R1
Ph3Ge
Ph3Ge
In conclusion, we disclosed here the first germylzincation
reaction of C–C triple bonds using a combination of a hy-
drogermane and diethylzinc in a radical chain process. Ready
availability of the reagents, operational simplicity and excel-
lent levels of regio- and stereocontrol are important assets of
this reaction that can be performed on terminal and internal
ynamides as well as on other sulfur-, oxygen-, and phospho-
rous-substituted alkynes. The decisive feature of this new
approach is the possibility of using the C(sp2)–Zn bond formed
as linchpin for the subsequent installation of carbon or het-
eroatom substituents with complete retention of configuration
through in situ Cu(I)- or Pd(0)-mediated electrophilic substitu-
tion. This offers a convenient and modular route to elaborated
di-, tri- and tetrasubstituted vinylgermanes decorated with
heteroatom substituents β to germanium that are useful for the
preparation of stereodefined alkenes and cannot be prepared
using hydrogermylation chemistry or previously reported
germylmetalation reactions.
54–58
β/α > 98:2 and E/Z > 98:2a
O
O
O
N(iPr)2
S
S
E
E
E
Ph3Ge
Ph3Ge
54 (E=H): 53%
[2H]-54 (E=D): 60%
Ph3Ge
55 (E=H): 45%
[2H]-55 (E=D): 43%
56 (E=H): 37%
[2H]-56 (E=D): 28%
(THF, 0 °C)
(THF, 0 °C)
(THF, 0 °C)
O
O
P(OEt)2
P(OiPr)2
E
Ph
Ph3Ge
E
E
Ph3Ge
57 (E=H): 70%
[2H]-57 (E=D): 62%
58 (E=H): 70%
[2H]-58 (E=D): 68%
(n-hexane, rt)
(n-hexane, 40 °C)
aMeasured by 1H NMR prior to purification.
As part of this work, we also were able to isolate and fully
characterize, including by X-ray crystallography, the α-amino
β-germyl vinylzinc intermediates arising from the germylzin-
cation of ynamides. These divinylzinc complexes showed
exceptional stability towards oxidation and hydrolysis, proba-
bly as the result of the very uncommon seesaw coordination of
zinc.
To finish our study, we next established that the new germyl-
zincation approach was not restricted to α-heteroatom-
substituted alkynes and could also be extended to conventional
alkynes (Scheme 13). At 40 °C in THF, 1-phenyl-1-propyne
and diphenylacetylene yielded products 59 and 60 in respec-
tively 40% and 49% yield in high trans-stereoselectivity con-
sistent with a radical chain-transfer mechanism with a Zn-
atom transfer under kinetic control. Here, the intermediate
vinyl radical (sp-hybridized as the result of the conjugation
with the adjacent Ph ring) was expected to be linear, and Et2Zn
to approach from the less hindered side opposite to the bulky
Ph3Ge group.61 At this temperature however, the reactions did
not proceed to completion, a behavior that was attributed to
the shortening of the radical chains because of a less favorable
radical addition step.62 This effect was eventually corrected by
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
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Additional data and discussion, experimental details, NMR spec-
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Journal of the American Chemical Society
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Crystallographic information files (CIF)
AUTHOR INFORMATION
Corresponding Author
* alejandro.perez_luna@sorbonne-universite.fr
Author Contributions
All authors have given approval to the final version of the manu-
script.
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Notes
The authors declare no competing financial interest.
Funding Sources
This work was supported by Sorbonne Université, CNRS and the
Agence Nationale de la Recherche (SATRAZ Project, grant n°
2011-INTB-1015-01) which we gratefully acknowledge.
ACKNOWLEDGMENT
Omar Khaled and Cédric Przyblski from IPCM are gratefully
acknowledged for HRMS analysis. Aurélie Bernard and Claire
Troufflard from IPCM are acknowledged for help with NMR
analysis.
ABBREVIATIONS
AIBN, azobisisobutyronitrile; CuTC, Copper(I)-thiophene-2-
carboxylate; Me-THF, 2-methyltetrahydrofuran; MTBE, methyl
tert-butyl ether; TEMPO, (2,2,6,6-tétraméthylpipéridin-1-yl)oxy;
THF, tetrahydrofuran.
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Substituted Alkenes and Alkynes. Tetrahedron 2014, 70, 1529–1616.
(29) (a) Romain, E.; Fopp, C.; Chemla, F.; Ferreira, F.; Jackowski,
O.; Oestreich, M.; Perez-Luna, A. Trans-Selective Radical Silylzinca-
tion of Ynamides. Angew. Chem. Int. Ed. 2014, 53, 11333–11337. (b)
Fopp, C.; Isaac, K.; Romain, E.; Chemla, F.; Ferreira, F.; Jackowski,
O.; Oestreich, M.; Perez-Luna, A. Stereodivergent Synthesis of β-
Heteroatom-Substituted Vinylsilanes by Sequential Silylzincation–
Copper(I)-Mediated Electrophilic Substitution. Synthesis 2017, 49,
724–735.
(18) (a) Schwier, T.; Gevorgyan, V. Trans- and Cis-Selective Lew-
is Acid Catalyzed Hydrogermylation of Alkynes. Org. Lett. 2005, 7,
5191–5194. (b) Keess, S.; Oestreich, M. Access to Fully Alkylated
Germanes by B(C6F5)3‑Catalyzed Transfer Hydrogermylation of
Alkenes. Org. Lett. 2017, 19, 1898–1901. For the EtAlCl2 catalyzed
(30) Giese, B. Synthesis with Radicals – C-C Bond Formation via
Organotin and Organomercury Compounds. Angew. Chem. Int. Ed.
Engl. 1985, 24, 553–565.
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(31) Chatgilialoglu, C.; Ballestri, M.; Escudié, J.; Pailhous, I. Hy-
drogen Donor Abilities of Germanium Hydrides. Organometallics
1999, 18, 2395–2397.
Dizinciosilanes and Zinciolithiosilanes. Angew. Chem., Int. Ed. 2012,
51, 4671–4675.
(49) Nanjo, M.; Takashi, O.; Sato, T.; Mochida, K. Synthesis and
Oxidation of Bis(triphenylgermyl)zinc. J. Organomet. Chem. 2005,
690, 2952–2955.
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(32) Wille, U. Radical Cascades Initiated by Intermolecular Radi-
cal Addition to Alkynes and Related Triple Bond Systems. Chem.
Rev. 2013, 113, 813–853.
(33) Such is the case for additions to alkenes, see: Ingold, K. U.;
Lusztyk, J.; Scaiano, J. C. Absolute Rate Constants for the Reactions
of Tri-n-butylgermyl and Tri-n-butylstannyl Radicals with Carbonyl
Compounds, other Unsaturated Molecules, and Organic Halides. J.
Am. Chem. Soc. 1984, 106, 343–348.
(34) Fang, H.; Ling, Z.; Lang, K.; Brothers, P. J.; de Bruin, B.; Fu,
X. Germanium(III) Corrole Complex: Reactivity and Mechanistic
Studies of Visible-Light Promoted N–H Bond Activations. Chem. Sci.
2014, 5, 916–921.
(35) For the radical hydrogermylation of alkenes with Ph3GeH un-
der UV-irradiation, see: Fuchs, R.; Gilman, H. Behavior of Triphen-
ylsilane, Triphenylgermane, and Triphenyltin Hydride in the Presence
of Olefins. J. Org. Chem. 1957, 22, 1009–1011.
(50) Perez-Luna, A.; Botuha, C.; Ferreira, F.; Chemla, F. Radical-
Polar Crossover Domino Reaction Involving Alkynes: a Stereoselec-
tive Zinc Atom Radical Transfer. Chem. Eur. J. 2008, 14, 8784–8788.
(51) For an example from our group of the fragmentation of a β-
alkoxy zinc enolate, see: Giboulot, S.; Perez-Luna, A.; Botuha, C.;
Ferreira, F.; Chemla, F. Radical–Polar Crossover Domino Reactions
Involving Organozinc Reagents and β-(Allyloxy)-enoates. Tetrahe-
dron Lett. 2008, 49, 3963–3966.
(52) In fact, an immediate 20% loss of Ph3GeH was observed on
reagent mixing, followed by a much slower disappearance of an
additional 20% over 3 h (see supporting information).
(53) (a) Sato, A.; Yorimitsu, H.; Oshima, K. Regio- and Stereose-
lective Radical Additions of Thiols to Ynamides. Synlett 2009, 28–31.
(b) Banerjee, B.; Litvinov, D. N.; Kang, J.; Bettale, J. D.; Castle, S. L.
Stereoselective Additions of Thiyl Radicals to Terminal Ynamides.
Org. Lett. 2010, 12, 2650–2652.
(54) In situ NMR-monitoring experiments of the germylzincation
of 1 in THF at 0 °C showed that vinylzinc intermediate VII was
formed exclusively with Z geometry throughout the reaction course
(see supporting information). On this basis a possible thermodynami-
cally driven E-to-Z equilibration process was ruled out.
(55) The CF3 is a bulky motif that can be considered as an isostere
of iPr, see: Belot, V.; Farran, D.; Jean, M.; Albalat, M.; Vanthuyne,
N.; Roussel, C. Steric Scale of Common Substituents From Rotational
Barriers of N-(o-Substituted aryl)thiazoline-2-thione Atropisomers. J.
Org. Chem. 2017, 82, 10188–10200.
(56) Note also that coordination of the carbonyl by a Lewis acid
should decrease the electronic density of the nitrogen atom of the
carbamate group and thus decrease the rate for Z-to-E interconversion
of XIV.
(57) The reaction in THF (0 °C, 3 h) of 1 with (Me3Si)3SiH (1.3
equiv) in the presence of Et2Zn (3.0 equiv) afforded in 78% yield the
corresponding β-tris(trimethylsilyl)silyl enamide as a Z/E = 10:90
mixture (see supporting information).
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(36) Alkyne hydrogermylation reactions are characterized by very
long chains and can proceed in the absence of clearly identified radi-
cal initiators, see refs. 16d-e, and 17b.
(37) Ryu, I.; Araki, F.; Minakata, S.; Komatsu, M. Initiation of
Tin-Mediated Radical Reactions by Diethylzinc-Air. Tetrahedron
Lett. 1998, 39, 6335–6336.
(38) (a) Maury, J.; Feray, L.; Bazin, S.; Clement, J.-L.; Marque, S.
R. A.; Siri, D.; Bertrand, M. P. Spin‐Trapping Evidence for the For-
mation of Alkyl, Alkoxyl, and Alkylperoxyl Radicals in the Reactions
of Dialkylzincs with Oxygen. Chem. Eur. J. 2011, 17, 1586–1595. (b)
Kubisiak, M.; Zelga, K.; Bury, W.; Justyniak, I.; Budny-Godlewski,
K.; Ochal, Z.; Lewinski, J. Development of Zinc Alkyl/Air Systems
as Radical Initiators for Organic Reactions. Chem. Sci. 2015, 6, 3102–
3108 and references cited therein.
(39) The configuration of the products was determined by 1H NMR
on the basis of the 3J coupling constant between the two vinylic
protons.
(40) (a) Nakamura, T.; Tanaka, S.; Yorimitsu, H.; Shinokubo, H.;
Oshima, K. Triethylborane-Induced Hydrogermylation of Alkenes
with Tri-2-furylgermane C. R. Acad. Chim. Ser. II C 2001, 4, 461–
470. (b) Yorimitsu, H.; Oshima, K. Recent Advances in the Use of
Tri(2-furyl)germane, Triphenylgermane and Their Derivatives in
Organic Synthesis. Inorg. Chem. Commun. 2005, 8, 131–142.
(41) The rate constants (in M–1 s–1) for H-atom abstraction by pri-
mary alkyl radicals have been reported for nBu3GeH (1 x 105 at ca. 30
°C; 3.8 x 105 at 80 °C) and Ph3GeH (3.8 x 106 at 80 °C). For a discus-
sion see ref 31.
(42) More acidic hydrolysis conditions (i.e. DCl/D2O) were avoid-
ed because of the probable acid-sensitivity of β-germylenamides.
(43) Crystal structures were deposited at the Cambridge Crystallo-
graphic Data Centre with numbers CCDC 1862400 (E-12), 1862401
(E-14), 1862402 (E-23), 1862403 (Z-25), 1862404 (E-40), 1862405
(44), 1862406 (45) and 1862407 (E-58) and can be obtained free of
charge via www.ccdc.cam.ac.uk.
(44) In the absence of Ph3GeH, metalation of 1 by Et2Zn (3.0
equiv) was nevertheless observed both in n-hexane (35% after 1 h 40
min at 0 °C) and in THF (43% after 3 h at 0 °C).
(45) It is established that radical hydrogermylation of terminal al-
kynes with Ph3GeH can occur to variable extents in the absence of
added radical initiators, see ref 15, 16e and 17b.
(46) The reaction between 1 and Ph3GeH (2.0 equiv) in THF at rt
for 18 h afforded 2 in 84% isolated yield with Z/E = 96:4 (see sup-
porting information).
(47) For the reaction of TEMPO with Ge-centered radicals, see: (a)
Lucarini, M.; Marchesi, E.; Pedulli, G. F.; Chatgilialoglu, C. Homo-
lytic Reactivity of Group 14 Organometallic Hydrides Toward Ni-
troxides. J. Org. Chem. 1998, 63, 1687–1693, and ref 34.
(48) Dobrovetsky, R.; Kratish, Y.; Tumanskii, B.; Botoshansky,
M.; Bravo-Zhivotovskii, D.; Apeloig, Y. Radical Activation of Si–H
Bonds by Organozinc and Silylzinc Reagents: Synthesis of Geminal
(58) Jastrzebski, J. T. B. H.; Boersma, J.; Van Koten, G. Structural
Organozinc Chemistry, in: Z. Rappoport (Ed.), Patai's Chemistry of
Functional Groups; Organozinc Compounds (2007), John Wiley &
Sons, Ltd, Chichester, 2009.
(59) To the best of our knowledge there is only one previous report
of a Zn complex with such geometry, see: Chu, T.; Belding, L.; Pod-
dutoori, P. K.; van der Est, A.; Dudding, T.; Korobkov, I.; Nikonov,
G. I. Unique Molecular Geometries of Reduced 4- and 5-Coordinate
Zinc Complexes Stabilised by Diiminopyridine Ligand. Dalton Trans.
2016, 45, 13440–13448.
(60) Nakamura, E.; Miyachi, Y.; Koga, N.; Morokuma, K. Theoret-
ical Studies of Heteroatom-directed Carbometalation. Addition of
MeCu, Me2Cu–, and MeLi to Substituted Acetylenes. J. Am. Chem.
Soc. 1992, 114, 6686–6692.
(61) Galli, C.; Guarnieri, A.; Koch, H.; Mencarelli, P.; Rappoport,
Z. Effects of Substituents on the Structure of the Vinyl Radical:
Calculations and Experiments. J. Org. Chem. 1997, 62, 4072–4077.
(62) This behavior is counter-intuitive as α-heteroatom-substituted
alkynes are regarded as electron-rich and germanium-centered radi-
cals nucleophilic. Nevertheless, since the inductive effect of the
heteroatom substituent lowers the energy of the LUMO (see ref 60), a
possible explanation is that the addition of the germyl radical benefits
from a more favorable SOMO–LUMO interaction for α-heteroatom-
substituted alkynes.
(63) The mechanism for the radical isomerization has not been
identified but abstraction of allylic hydrogen atoms might intervene
with this particular substrate, see: Shimoi, M.; Watanabe, T.; Maeda,
K.; Curran, D. P.; Taniguchi, T. Radical Trans-Hydroboration of
Alkynes with N-heterocyclic Carbene. Angew. Chem. Int. Ed. 2018,
57, 9485–9490.
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Et2Zn
E
E+
[Zn]
Het
R3GeH
R3Ge
R3Ge
Het
Het
R'
in situ
electrophilic
substitution
radical
germylzincation
R'
R'
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• Het = [N], [S], [O], [P]; E = [C], [S], I, Br, F, CF3
• high regio- and diastereoselectivity
• modular access to di-, tri-, and tetrasubstituted vinylgermanes
• > 50 examples
• functionalization of C(sp2)–Ge bond possible
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