Mechanistic Dichotomy of Magnesium- and Zinc-Based Germanium Nucleophiles in the C(sp3)?Ge Cross-Coupling with Alkyl Electrophiles

Article abstract of DOI:10.1002/anie.201901860

Robust procedures for two mechanistically distinct C(sp³)?Ge bond formations from alkyl electrophiles and germanium nucleophiles are reported. The germanium reagents were made available as bench-stable solutions by lithium-to-magnesium and lithium-to-zinc transmetalation, respectively. The germanium Grignard reagent reacts with various primary and secondary alkyl electrophiles by an ionic nucleophilic displacement. Conversely, the coupling of the corresponding zinc reagent requires a nickel catalyst, which then engages in radical bond formations with primary, secondary, and even tertiary alkyl bromides. Both methods avoid the regioselectivity issue of alkene hydrogermylation and enable the synthesis of a wide range of functionalized alkyl-substituted germanes.

Full text of DOI:10.1002/anie.201901860

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Accepted Article
Title: Mechanistic Dichotomy of Magnesium- and Zinc-Based
Germanium Nucleophiles in the C(sp3)–Ge Cross-Coupling with
Alkyl Electrophiles
Authors: Weichao Xue, Wenbin Mao, Liangliang Zhang, and Martin
Oestreich
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901860
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10.1002/anie.201901860
Angewandte Chemie International Edition
COMMUNICATION
Mechanistic Dichotomy of Magnesium- and Zinc-Based
Germanium Nucleophiles in the C(sp3)–Ge Cross-Coupling with
Alkyl Electrophiles
Weichao Xue+, Wenbin Mao+, Liangliang Zhang, and Martin Oestreich*
Abstract: Robust protocols for two mechanistically distinct C(sp3)–
Ge bond formations from alkyl electrophiles and germanium nucleo-
philes are reported. The germanium reagents are made available as
bench-stable solutions after lithium-to-magnesium and lithium-to-zinc
transmetalation, respectively. The germanium Grignard reagent re-
acts with various 1° and 2° alkyl electrophiles by an ionic nucleo-
philic displacement. Conversely, the coupling of the corresponding
zinc reagent requires a nickel catalyst and engages in a radical bond
formation with 1°, 2°, and even 3° alkyl bromides. Both methods
avoid the regioselectivity issue of hydrogermylation of alkenes and
enable the synthesis of a wide range of functionalized alkyl-substi-
tuted germanes.
Such metalated germanium compounds were either previously
not available or existed only as reactive intermediates. We re-
port here their successful preparation and storage, as well as
their application in C(sp3)–Ge formation (Scheme 1, bottom).
Low-toxic alkyl- and aryl-substituted germanium compounds
possess attractive physical and chemical properties pertinent to
material science.[1,2] Accordingly, there has been continuous in-
terest in their synthesis, and several methods have been repor-
ted.[3–6] Of these, (transfer) hydrogermylation of alkenes is a re-
liable option but usually limited to α-olefins to arrive at germanes
substituted with linear alkyl chains;[3,4] electronically unbiased, in-
ternal alkenes usually lead to mixtures of regioisomeric α-bran-
ched alkyl-substituted germanes. Another common approach is
by nucleophilic substitution of alkyl halides and tosylates with
lithium-based germanium nucleophiles (Scheme 1, top).[5] The
high reactivity of these hard germanium reagents is responsible
for the poor functional-group tolerance and accounts for un-
desired side reactions. The reverse approach, that is nucleo-
philic displacement at chlorogermanes with alkyl metals, is bur-
dened with the same imcompatibility with functional groups and
is even less general (Scheme 1, top).[6]
Scheme 1. Known and new approaches to the preparation of alky-substituted
germanes. LG = leaving group. M = Li and Mg. X = Cl and Br.
We began our investigations with the reaction of Ph3GeMgX
(2) and alkyl electrophiles. To our surprise, we found that germy-
lation occurred without the assistance of a catalyst (see the Sup-
porting Information for details). This stands in stark contrast to
related transformations with silicon Grignard reagents.[7] Typical
leaving groups such as chloride, bromide, iodide, and tosylate
were tested (Scheme 2). The latter three cyclopentane derivati-
ves 5a–7a reacted in good yields whereas cyclopentylchloride
(4a) only afforded trace amounts of 8a; β-elimination observed
was not seen. This chemoselectivity indicates that Ph3GeMgX
(2) is less nucleophilic than Ph3GeLi (1).[5a,5b]
Our laboratory recently introduced a procedure for the pre-
paration of bench-stable stock solutions of silicon Grignard rea-
gents, and applied these silicon nucleophiles in iron- and cobalt-
catalyzed C(sp3)–Si cross-coupling reactions with alkyl bromi-
des.[7] A complementary nickel catalysis using zinc-based silicon
nucleophiles was independently disclosed by Fu and co-wor-
kers.[8] Both catalyst/reagent combinations display excellent func-
tional-group tolerance, furnishing functionalized a broad range of
alkyl-substituted silanes. Inspired by these reports,[9] we consi-
dered the formation of soft germanium nucleophiles, e.g.,
Ph3GeMgX (2) and Ph3GeZnCl (3), by transmetalation from lithi-
um in Ph3GeLi (1)[10] to magnesium[11] and zinc,[12] respectively.
Scheme 2. Nucleophilic substitution with magnesium-based germanium
nucleophile. [a] Estimated by GLC analysis with tetracosane as an internal
standard. [b] 2 h for LG = I.
We then explored the substrate scope with Ph3GeMgX 2
(Scheme 3). Yields were generally high for primary alkyl
bromides containing ether (as in 5b and 5c) and acetal (as in
5d) groups. Acylic (5e and 6f) and cyclic (5g) electrophiles un-
derwent the germylation equally well. To our delight, benzylic
chloride 4h and bromide 5h reacted cleanly to produce desired
8h. There are however limitations of this straightforward ap-
proach: Low yields were observed for tertiary halides 5i and 6i,
and carbonyl groups were not tolerated (not shown). To disting-
uish between an ionic and radical mechanism, (bromomethyl)-
cyclopropane (5j) was subjected to the standard setup; no ring
[*]
[+]
W. Xue,[+] W. Mao,[+] L. Zhang, Prof. Dr. M. Oestreich
Institut für Chemie, Technische Universität Berlin
Strasse des 17. Juni 115, 10623 Berlin (Germany)
E-mail: martin.oestreich@tu-berlin.de
Homepage: http://www.organometallics.tu-berlin.de
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201901860
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COMMUNICATION
opening occurred, and 8j was isolated in high yield (gray box).
This outcome likely excludes the involvement of radical inter-
mediates.
6
5a (LG = Br)
5a (LG = Br)
5a (LG = Br)
5a (LG = Br)
5a (LG = Br)
4a (LG = Cl)
6a (LG = I)
DMI instead of NMP
85
85
<5
<5
<5
<5
52
11
7
Ni(acac)2 instead of NiBr2·glyme
FeBr3 instead of NiBr2·glyme
CoCl2 instead of NiBr2·glyme
CuSCN instead of NiBr2·glyme
none
8
9
10
11
12
13
none
7a (LG = OTs)
none
[a] All reactions were performed on a 0.20 mmol scale. [b] Estimated by
GLC analysis with tetracosane as an internal standard. [c] Isolated yield
after chromatograpy on silica gel. NMP = N-methyl-2-pyrrolidinone. DMF =
N,N-dimethylformamide. DMA
= N,N-dimethylacetamide. DMI = N,N’-
dimethylethyleneurea. acac = acetylacetone.
With this nickel-catalyzed C(sp3)–Ge cross-coupling protocol
in hand, we evaluated its scope (Scheme 4). Both primary and
secondary as well as acylic and cyclic coupling partners perfor-
med well with superb functional-group tolerance. Aside from
rather robust ether (as in 5c) and acetal (as in 5d), a broad array
of carboxyl and cyano groups (as in 5k–n and 5r–v) were com-
patible with this procedure. Likewise, terminal (as in 5o) and in-
ternal alkenes (as in 5w) were also tolerated, leading to a syn-
thetically useful allylic germane in the latter case.[13] In accor-
dance with the previous observation (Table 1, entry 11), 8q was
chemoselectively formed from 5q without cleavage of the C(sp3)–
Cl bond. Activated alkyl bromides where the bromide is adjacent
to a π-system, e.g., benzylic bromide 5q, allylic bromide 5w, and
α-bromocarboxyl compounds 5t and 5u, were converted into the
corresponding germanes in moderate to good yields. There was
no diastereocontrol in the germylation of 1-bromo-4-methylcyclo-
hexane (5x with d.r. = 50:50 → 8x with d.r. = 54:46). Interes-
tingly, exo-8y (d.r. = 89:11) did form predominantly starting from
exo-2-bromonorbornane (5y, d.r. > 99:1).
Scheme 3. Ionic C(sp3)–Ge formation of alkyl halides with Ph3GeMgX 2. [a]
Estimated by GLC analysis with tetracosane as an internal standard. TBS =
tert-butyl dimethyl silyl. [b] 2 h for LG = I.
The moderate functional-group tolerance of the ionic C(sp3)–
Ge bond formation with magnesium reagent 2 was hardly any
improvement over the existing methods.[5,6] We therefore conti-
nued to explore the reactivity of the corresponding zinc reagent
3 in the reaction with alkyl electrophiles (Table 1). After a series
of orientation experiments, we found that excellent yield was
obtained with NiBr2·glyme as catalyst in THF/NMP; cyclo-
pentylbromide (5a) afforded germane 8a in 86% isolated yield
(entry 1). A blank reaction clearly showed that the nickel salt as
catalyst was necessary (entry 2). This result was totally different
from that obtained with the germanium Grignard reagent 2. The
influence of solvent deserves particular mention. A combination
of THF and NMP was crucial to secure high yield (entry 3); the
use of other amide-containing co-solvents also promoted the
germylation reaction but in diminished yields (entries 4–6). Aside
from Ni(acac)2, other first-row metal salts were not effective (ent-
ries 7–10). Leaving groups other than bromide were examined
but it was only iodide 6a that participated in moderate yield;
chloride 4a and tosylate 7a reacted sluggishly (entries 11–13).
The method was also applicable to the tertiary alkyl bromi-
des (Scheme 5). Acylic substrates 5i and 5z underwent the ger-
mylation in good yields. However, 8i and 8z did form along with
other regioisomers such as 9i and 9z, respectively (see the Sup-
porting information for details). Cyclic 5a’ and tricyclic 5b’) were
also probed but yields were ruined by competing β-elimination
and/or dehalogenation.
Table 1. Selected examples of the optimization reactions.[a]
NiBr2 glyme (10 mol%)
Ph3GeZnCl 3 (1.5 equiv)
LG
GePh3
8a
THF/NMP
0 C for 16 h
4a–7a
Entry
Substrate
Variation
Yield [%][b]
1
2
3
4
5
5a (LG = Br)
5a (LG = Br)
5a (LG = Br)
5a (LG = Br)
5a (LG = Br)
none
92 (86)[c]
w/o NiBr2·glyme
w/o NMP
<5
8
DMF instead of NMP
DMA instead of NMP
52
77
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COMMUNICATION
NiBr2 glyme (10 mol%)
radical-probe experiment
NiBr2 glyme (10 mol%)
R1 Br
R1 GePh3
Ph3GeZnCl 3 (1.5 equiv)
GePh3
R2
R2
THF/NMP
0 C for 16 h
R3
R3
3
10j: 35%
Ph3GeZnCl (1.5 equiv)
+
+
GePh3
8
Br
5
THF/NMP
Me
GePh3
5j
8j: 14%
0 C for 16 h
11j: 34%
primary
GePh3
O
racemization experiment
AcO
GePh3
TBSO
GePh3
2
O
NiBr2 glyme (10 mol%)
8c: 72% from 5c
8d: 76% from 5d
8k: 80% from 5k
EtO
Br
EtO
GePh3
Ph3GeZnCl 3 (1.5 equiv)
O
THF/NMP
0 C for 16 h
O
Me
O
Me
(S)-5s (94% ee)
rac-8s: 83%
EtO
GePh3
N
GePh3
2
Scheme 5. Probing the radical mechanism.
NC
GePh3
O
O
8l: 83% from 5l
8m: 70% from 5m
8n: 84% from 5n
Having identified the radical nature of this nickel catalysis,
we set out to survey the relative reactivity of the alkyl bromi-
des.[16] As can be seen from Table 2, the order of reactivity is
tertiary > secondary > primary. We interpret this as the stability
of the alkyl radical being the dominant parameter in these
C(sp3)–Ge couplings. However, rearrangement from the more
bulky tertiary to less bulky radicals as seen for 5i and 5z also
demonstrates that the steric effect must be considered in these
germylation reactions (cf. Scheme 4, bottom).
GePh3
Cl
GePh3
GePh3
8q: 88% from 5q
2
3
MeO
8o: 85% from 5o
8p: 73% from 5p
secondary
Me
GePh3
BzO
GePh3
EtO
GePh3
Me
Me
Me
8r: 80% from 5r
O
O
8e: 82% from 5e
8s: 86% from 5s
O
GePh3
GePh3
EtO
Bn
GePh3
Table 2. Competition experiments.[a]
N
CbzN
Me
Ph Me
8t: 63% from 5t
8u: 65% from 5u
8v: 67% from 5v
GePh3
GePh3
GePh3
Me
8w: 89% from 5w
8x: 71% from 5x
(d.r. = 54:46)
exo-8y: 73% from exo-5y
(exo:endo = 89:11)
tertiary
Me
Me
Me
Me
H
Et
H
[b]
GePh3
Et
GePh3
Entry
R1‒Br
5c’
R2‒Br
5e
Ratio R1‒GePh3:R2‒GePh3
Me
+
+
Me
Me
Me
GePh3
GePh3
1
2
3
33:67
32:68
30:70
8i and 9i: 72% a from 5i
8z and 9z: 70% a from 5z
(rs = 90:10)
(rs = 47:53)
5e
5i
Me
GePh3
5c’
5i
GePh3
8a': 27% b from 5a'
8b': 12% b from 5b'
[a] All reactions were performed on a 0.20 mmol scale. [b] Estimated by
GLC analysis.
Scheme 4. Nickel-catalyzed C(sp3)–Ge formation of alkyl bromides with
Ph3GeZnCl (3). [a] Yield is for the mixture of isomers, and rs means the ration
of tertiary product/other isomers. [b] Estimated by GLC analysis with tetra-
cosane as internal standard. Cbz = benzyloxycarbonyl.
Herein, we have described two practical methods for C(sp3)–
Ge bond formation with readily available, easy-to-handle solu-
tions of magnesium- and zinc-based germanium nucleophiles 2
and 3. To the best of our knowledge, it is the first time that ger-
manium nucleophiles other than Ph3GeLi (1) have been used in
synthetic chemistry.The reaction of the germanium Grignard rea-
gent with alkyl electrophiles proceeds through an ionic mecha-
nism, i.e., nucleophilic substitution, while the nickel-catalyzed
cross-coupling using germanium zinc reagent follows a radical
pathway. Broad substrate scope and good yields are particularly
seen with the soft zinc reagents, and we therefore anticipate that
this method could find widespread use in the preparation of
functionalized organogermanium compounds.
To gain mechanistic insight into this nickel-catalyzed germy-
lation, we conducted a radical-probe experiment again using
(bromomethyl)cyclopropane (5j; Scheme 5, top). Indeed, ring-
opening to the alkene regioisomers 10j and 11j occurred, and
the cyclopropylmethyl-substituted germane 8j was found in
lesser quantity (cf. Scheme 2, gray box). Also, enantioenriched
(S)-5s underwent the C(sp3)–Ge coupling with complete loss of
the stereochemical information to result in rac-8s (Scheme 5,
bottom). These experiments strongly support the involvement of
alkyl radical intermediates which are likely generated by single-
electron transfer from an assumed Ni(I)–Ge species to the
C(sp3)–Br bond.[14] In agreement with the vast majority of nickel-
catalyzed Negishi coupling reactions of alkyl halides,[15] a plau-
sible Ni(I)/Ni(III) catalytic cycle based on radical pathway is de-
picted in the Supporting Information.
Acknowledgements
This research was supported by the China Scholarship Council
through predoctoral fellowships to W.X. (2015–2019), W.M.
(2017–2021), and L.Z. (2017–2021). Additional funding was pro-
vided by the Deutsche Forschungsgemeinschaft (Oe 249/15-1).
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M.O. is indebted to the Einstein Foundation Berlin for an endow-
ed professorship.
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Keywords: germanium • magnesium • nucleophilic substitution •
radical cross-coupling • zinc
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Suggestion for the Entry for the Table of Contents
COMMUNICATION
W. Xue, W. Mao, L. Zhang, M.
Oestreich*
Page No. – Page No.
Mechanistic Dichotomy of
Magnesium- and Zinc-Based
Germanium Nucleophiles in the
C(sp3)–Ge Cross-Coupling with Alkyl
Electrophiles
Chinese–Germane collaboration. Homogeneous stock solutions of magnesium-
and zinc-based germanium nucleophiles are readily accessible and have been
applied to C(sp3)–Ge bond formation with alkyl electrophiles. The magnesium
reagent reacts directly with alkyl halides and tosylates but the functional-group
tolerance is mediocre. Conversely, the cross-coupling of the zinc reagent with alkyl
bromides and iodides requires a catalyst and is tolerant towards a broad range of
functional groups.
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