Alkyl Carbagermatranes Enable Practical Palladium-Catalyzed sp2-sp3 Cross-Coupling

Article abstract of DOI:10.1021/jacs.9b02776

Pd-catalyzed cross-coupling reactions have achieved tremendous accomplishments in the past decades. However, C(sp³)-hybridized nucleophiles generally remain as challenging coupling partners due to their sluggish transmetalation compared to the C(sp²)-hybridized counterparts. While a single-electron-transfer-based strategy using C(sp³)-hybridized nucleophiles had made significant progress recently, fewer breakthroughs have been made concerning the traditional two-electron mechanism involving C(sp³)-hybridized nucleophiles. In this report, we present a series of unique alkyl carbagermatranes that were proven to be highly reactive in cross-coupling reactions with our newly developed electron-deficient phosphine ligands. Generally, secondary alkyl carbagermatranes show slightly lower, yet comparable activity to its Sn analogue. Meanwhile, primary alkyl carbagermatranes exhibit high activity, and they were also proved stable enough to be compatible with various reactions. Chiral secondary benzyl carbagermatrane gave the coupling product under base/additive-free conditions with its configuration fully inversed, suggesting that transmetalation was carried out in an "S_E2(open) Inv" pathway, which is consistent with Hiyama's previous observation. Notably, the cross-coupling of primary alkyl carbagermatranes could be performed under base/additive-free conditions with excellent functional group tolerance and therefore may have potentially important applications such as stapled peptide synthesis.

Full text of DOI:10.1021/jacs.9b02776

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Article
Alkyl Carbagermatranes Enable Practical
Palladium-Catalyzed sp2-sp3 Cross-Coupling
Meng-Yu Xu, Wei-Tao Jiang, Ying Li, Qing-Hao Xu, Qiao-Lan Zhou, Shuo Yang, and Bin Xiao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b02776 • Publication Date (Web): 18 Apr 2019
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Journal of the American Chemical Society
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Alkyl Carbagermatranes Enable Practical Palladium-Catalyzed sp2-
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Meng-Yu Xu, Wei-Tao Jiang, Ying Li, Qing-Hao Xu, Qiao-Lan Zhou, Shuo Yang and Bin Xiao*
Department of Chemistry, University of Science and Technology of China, Hefei 230026, China.
Supporting Information
ABSTRACT: Pd-catalyzed cross-coupling reactions have achieved tremendous accomplishments in the past decades.
However, C(sp3)-hybridized nucleophiles generally remain as challenging coupling partners due to their sluggish
transmetalation compared to the C(sp2)-hybridized counterparts. While single-electron transfer-based strategy using
C(sp3)-hybridized nucleophiles had made significant progress recently, less breakthroughs have been made concerning
traditional two-electron mechanism involving C(sp3)-hybridized nucleophiles. In this report, we present a series of unique
alkyl carbagermatranes that were proven to be highly reactive in cross-coupling reactions with our newly developed
electron-deficient phosphine ligands. Generally, secondary alkyl carbagermatranes show slightly lower, yet comparable
activity with its Sn analogue. Meanwhile, primary alkyl carbagermatranes exhibit high activity and they were also proved
stable enough to be compatible with various reactions. Chiral secondary benzyl carbagermatrane gave the coupling
product under base/additive-free conditions with its configuration fully inversed, suggesting that transmetalation was
carried out in an “SE2(open) Inv” pathway, which is consistent with Hiyama’s previous observation. Notably, the cross-
coupling of primary alkyl carbagermatranes could be performed under base/additive-free conditions with excellent
functional group tolerance and therefore may have potentially important applications such as stapled peptides synthesis.
then compromises the functional group tolerance of Pd-
catalyzed reactions, which could have been more
1. INTRODUCTION
Over the past several decades, Pd-catalyzed cross-
coupling reactions have changed organic synthesis
significantly along with marvelous development of
nucleophiles1, among which cross-coupling reactions
accomplished by alkyl nucleophiles2 appear to be more
challenging ones. In recent years, single-electron
appealing.
Figure 1. Cross-coupling of group 14 alkyl
nucleophiles and history of carbatranes.
M
Open-chain
alkyl nucleophiles:
M(alkyl)4 or alkyl-MX3
OH
Hiyama
:
alkyl-SiF3
Si
Ge
Sn
Si(alkyl)3
transmetalation
process
has
made
remarkable
not reported
achievements mainly due to the realization of the
transmetalation of some challenging stable alkyl
nucleophiles like trifluoroborates and silicates3. Notably,
in many cases, the radical and two-electron
transmetalation processes are mutually orthogonal on the
account of regioselectivity, functional group tolerance
many examples
R
Aryl-Hal
cat. Pd, Ligand
N
Atranes:
M
R
Related work
M
R
and
stereo-control4,
etc.
Hence,
two-electron
Vedejs
Sn
Sn
Ge
1o alkyl
, 1992
transmetalation is still worthy of further exploration.
Biscoe
2o alkyl
, 2013
Two-electron transmetalation can be deemed as the
attack of an alkyl carbanion toward an electron-deficient
Pd center, therefore for some nucleophiles such as
alkyllithiums5, alkylmagnesiums6 or alkylzincs7, higher
transmetalation activity suggests stronger Lewis basicity8.
Such nucleophiles usually exhibit sensitivity toward air,
water or some specific functional groups. On the
contrary, air-stable nucleophiles such as alkylboranes9
and alkylsilicons10 usually require extra base (or F-) to
promote two-electron transmetalation. However, the
addition of additives usually complicates the system, and
allyl, phenyl, alkenyl, and alkynyl
Kosugi
, 1996
fail in alkyl
but
This work:
Aryl-Hal
Alkyl
Alkyl-Hal
Mg or Zn
cat. Pd, Ligand
N
N
Ge
Br
Ge
80 - 120 o
C
Alkyl
* Previously difficult to obtain pure "Ge-Hal"
* Synthesis of Ge-Alkyl from "in situ" generated alkyl metal reagents
* Successful cross-coupling of alkyl germanium nucleophiles
* Excellent functional group tolerance under base/additive-free condition
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We sought inspiration through analyzing the nature of
Figure 2. Synthesis of alkyl carbagermatranes from
alkyl halides.
the developed nucleophiles in history, and group 1411,12
alkyl nucleophiles interest us the most. For Si-containing
nucleophiles, the pioneering work by Hiyama and co-
workers has successfully demonstrated that primary and
benzyl secondary alkyl(trifluoro)silanes exhibit activity
for Pd-catalyzed sp2-sp3 cross-coupling13. A series of
1
2
3
4
5
6
7
8
Mg or Zn powder
N
N
Ge
+
Alkyl Hal
Ge
Br
60 oC, 8 h
Up to 95%
Alkyl
Ge-
Br
N
N
N
Ge
O
Ge
a1
Ge
Si
4
n
n
a
unique
trialkyl[2-(hydroxymethyl)phenyl]silane
a
a
b
a3
: 76%
a4
,
: n=2, 95%
: n=0, 94%
: n=0 91%
derivatives have further achieved transmetalation of non-
activated secondary alkyl group such as iPr, cyclopentyl
and cyclohexyl group14. On the other hand, considerably
plenty of cross-coupling examples of using Sn-containing
nucleophiles including various open-chain alkyl tin
reagents, some of which even exhibit additive-free
transmetalation ability15, were presented. Particularly,
alkylcarbastannatranes, initially used in cross-coupling by
Vedejs16, have elegantly solved the selectivity problem of
four alkyl substituents on the Sn center during the
a
a2
a5
,
: n=1 92%
9
O
N
N
Ge
N
Ge
O
10
11
12
13
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N
Ge
N
O
O
a
b
b
a6
a9
a7
: 88%
a8
: 87%
: 92%
Bpin
Bpin
N
N
N
N
N
Ge
Ge
Ge
Ge
Bpin
Si
b
b
a
a10
: 76%
a11
: 98%
: 88%
COOMe
NHBoc
COOBn
NHCbz
COOAllyl
NHFmoc
N
Ge
Ge
transmetalation
process.
Moreover,
transannular
coordination of carbastannatranes guarantees them
greater transmetalation ability17. Remarkably, Biscoe
recently expanded their cross-coupling to secondary alkyl
carbastannatranes, and more importantly, demonstrated
that enantioenriched secondary alkylcarbastannatranes
undergo transmetalation via a stereospecific retention
mechanism18. Our group has focused on using Ge19,20
reagent for cross-coupling, naturally, carbagermatranes
(abbreviated as Ge in following text) came across our
mind. Actually, to our knowledge, all kinds of atrane-like
and open-chain alkyl germanium reagents failed to realize
successful cross-coupling reactions for neither primary nor
secondary alkyl groups. 11, 21
b
b
b
a12
: 86%
a13
: 85%
a14
: 83%
.
99.6% e.e
99.9% e.e.
99.6% e.e.
Ph
F
N
N
N
N
Ge
Ge
Ge
Ge
c
a
b
a15
: 75%
a16
: 90%
a17
: 81%
a
b
Isolated yield. Hal = Br, Mg powder, THF. Hal = I, Zn powder,
DMF. c Hal = Cl, Mg powder, THF. See SI for details.
Figure 3. Ligands screening.
Pd(dba)2 2 mol%
L 6 mol%
Br
n Hex
N
+
Ge
MeCN, 120 oC, 16 h
a1
b1
CF3
2. RESULTS AND DISCUSSION
OMe
Cy
OMe
In light of the above, we first attempted to synthesize
Ge-Cl on the basis of the reported literature21, which was
found to be ambiguous and resulted in an inseparable
mixture of Ge-Cl and Cp2ZrCl2. However, after the
P
iPr
MeO
iPr
Cy
P
CF3
MeO
R1
L
L
L
1 R1 = R2
=
iPr (JackiePhos) 17% yield
R1
CF3
2 R1 = NMe2; R2 = H
3 R1 = OiPr; R2 = H
33% yield
42% yield
iPr
BrettPhos
F3C
CF3
R2
L
4 3% yield
mixture
was
worked
up
with
inexpensive
benzylmagnesium chloride, Ge-Bn was readily separated
(see SI for details). Further work-up with Br2 afforded
pure Ge-Br, which represents the first example of the
synthesis of Ge-Br compounds. We proposed that using
Ge-Br would change the fact that alkyl carbagermatranes
can only be synthesized from pre-prepared alkyllithiums
or alkylmagnesium. Fortunately, one-pot reaction of Ge-
Br with in situ generated alkyl Grignard or alkylzinc
reagents gave desired alkyl carbagermatranes smoothly
(Figure 2). Especially with alkylzinc reagents, the alkyl-
Ge bearing various functional groups can be readily
obtained.
CF3
CF3
CF3
CF3
F3C
Cy
Cy
P
F3C
P
P
F3C
P
CF3
CF3
F3C
Fe
Ph2P
Fe
F3C
CF3
CF3
L5
L
6 11% yield
48% yield
L
7 38% yield
F3C
b1 b5
For
-
:
CF3
N
L8
R1 = R2 = Me
40% yield
P
CF3
Ge
L9
R1 = OMe; R2 = H 36% yield
R1 = R2 = iPr
Br
R1
R1
L10
98% yield
78-85% Recovery
95% yield (100 oC)
CF3
from reaction mixture
O
75% yield (80 oC)
Meanwhile, decades’ development of phosphine ligands
gives us more inspiration. Generally, electron-deficient
phosphine ligands promote the transmetalation of Stille
reactions15, which was also observed in Biscoe’s work (i.e.
JackiePhos)18. Nevertheless, when we applied JackiePhos
in our reaction, it only gave 17% yield (Figure 3, L1). The
R2
n Hex
n Hex
n Hex
MeOOC
n Hex
O2N
NC
MeO
a
a
a
a
b2
: 97%
b3
: 95%
b4
: 96%
b5
: 90%
Standard condition: 1.0 equiv. Ar-Br, 1.2 equiv. a1, 2 mol% Pd(dba)2,
6 mol% Ligand L10, 0.2 M MeCN, 120 oC, 16 h. a Isolated yield.
2
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result indicated the challenge we encountered when Sn
including the fusion of di[3,5-bis(trifluoromethyl)-
phenylphosphino] group. Inspired by that, we combined
1
2
3
4
5
6
7
8
was replaced by Ge. Further screening of ligands (L2-L7)
suggested that di[3,5-bis(trifluoromethyl)phenylphos-
phino] group in the ligand is necessary for the reaction,
and electron-rich phosphine ligands (L4, L6) would
diminish the yield. Specifically, we noticed that the most
sterically hindered ligand L1 showed the worst
performance among the three ligands L1-L3. This trend led
to the speculation that proper modification on the
skeleton of JackiePhos analogs to reduce the steric
hindrance would be promising. Yu, etc. reported the
synthesis of a series of Buchwald-type ligands containing
aryl-substituted indenyl skeleton22 which may reduce the
steric hindrance by elongating the distance between
phosphorus atom and its adjacent aryl plane, however not
aryl-substituted
indenyl
skeleton
with
di[3,5-
bis(trifluoromethyl)phenylphosphino] group and L8-L10
were successfully synthesized. When L10 was applied in
the reaction, a nearly quantitative yield was achieved.
Lowering the temperature still offered satisfying yields
(95 % at 100 oC, 75% at 80 oC). Then we preliminarily tried
some cross-coupling reactions between nhexyl-Ge and
aryl bromides, and all afforded alkylation products (b2-b5)
with excellent yields (>90%).23,24 It is noteworthy that no
additive or base was used in the reaction16, and Ge-Br
could be recovered by crystallization in 78-85% yield. The
NMR spectrum of synthesized GeBr and recovered GeBr
in CD2Cl2 are in accordance with each other.
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45
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51
52
53
54
55
56
57
58
59
60
Figure 4. Substrates scope of the cross-coupling reactions.
O
O
O
O
N
O
OHC
MeOOC
N
O
OHC
CN
O
O
MeO
a
b6
: 99% (95% )
b7
: 85%
b8
: 79%
b9
: 75%
b10
: 97%
SF5
F3C
MeO
O2N
F3C
COOMe
NHBoc
COOMe
NHBoc
COOBn
NHCbz
O
NO2
O
O
b11
b12
b13
b14
b15
: 68% (99.9% e.e.)
: 98% (99.1% e.e.)
: 99% (99.8% e.e.)
X = Cl;
: 81%
X = Cl;
: 99%
O
O
Ph
Ph
O
O
NC
Ph
N
O
H
H
O
O
Si
tBu
SO2F
CHO
CHO
4
: 96%
CF3
MeO
b16
b17
b18
b19
b20
: 90%
: 80%
: 88%
: 75%
O
O
O
N
S
H2N
O
N
OH
O
O
O
NH
S
H
N
S
H2N
HN
N
H
O
S
b24b
b21
: 75%
b22
b23
: 62%
: 77%
: 77%
N
O
N
COOMe
F
O
N
O
NC
MeO
Si
N
H
TBSO
NH
F
6
N
H
H
N
O
N
O
MeO
N
O
b25
: 46%
b26
b27
b28
X = Cl; from Indomethacin;
X = Br; from Estrone;
: 98%
X = Br; from Vandetanib;
: 73% X = Br; from Flubromazolam;
: 98%
Br
Bpin
F
O
O
Bpin
F
H2N
H2N
N
S
Ge
N
H2N
S
Ph
O
O
S
Ph
O
O
Bpin
80%
b30
: 98%
b31
: 85%
a18
b29
: 98.5% e.e. (99.3% e.s.)
99.2% e.e.
Inversion
HO
HO
B
B
OH
OH
b33
b32
: 50%
: 65%
Isolated yield. Standard condition: 2 mol% Pd(dba)2, 6 mol% Ligand L10, 1.2 equiv. alkyl carbagermatranes, 1.0 equiv. Ar-X or Alkenyl-X (X = Br,
o
a
unless otherwise noted), 0.2 M MeCN, 100 or 120 C, 12 or 16 h. 95% yield and 85% recovery of GeBr were obtained when the reaction was
scaled up to 1.5 mmol. No difference was found compared recovered GeBr with synthesized GeBr. b DMF instead of MeCN.
3
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Next, we examined the scope of substrates of the cross-
coupling reactions using various alkyl carbagermatranes
and electrophiles (Figure 4). Alkyl
C(sp2)
carbagermatranes containing cyano (b6), vinyl (b7-b8),
acetal (b9), N-phthalimide (b10) were well tolerated. L-
did not interfere with the cross-coupling reactions. Drug
molecules and natural product derivatives underwent
alkylation smoothly (b25-b28), reflecting a valuable
strategy for late-stage modification of drug molecules.
Notably, the chiral secondary benzyl carbagermatrane
(a18) gave the corresponding product (b29), of which the
configuration was fully inversed under the standard
condition, suggesting that the transmetalation was
carried out in an “SE2(open) Inv” pathway13a under the
additive-free conditions. Finally, we tested the
compatibility with boron-containing substrates, since
they are the most widely used nucleophiles and their
derivatization is of great importance. Bpin (b30), gem-
diboryl group (b31) were well tolerated. Remarkably, aryl
boronic acids (b32-b33) were also tolerated in spite of the
fact that they are easy to transmetalate25.
1
2
3
4
5
6
7
8
serine-derived
carbagermatranes
reacted
with
corresponding aryl halides to afford desired products
without any racemization (b11-b13). Low reactivity of aryl
chlorides is in accord with the fact that electron-deficient
phosphine ligands impede the oxidative addition process,
and electron-deficient aryl chloride worked better (b14-
b15). Base-sensitive coumarin (b16) along with TBAF-
sensitive sulfuryl fluoride (b17) and silyl-protected alcohol
(b18) were well preserved. Under standard conditions,
satisfying yields were also obtained using olefinic
electrophiles instead (b19-b20). Some substrates
containing strong polarity functional groups (b21-b24)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 5. Tolerance and selectivity of Ge group.
-
BF4
B. Fluorination by
Ritter's reagent
iPr
N+
iPr
iPr
N
iPr
F
N
Ge
AlkylFluor
F
4
78%a
a20
TBAF 1.1 eq
RT, 3 h
N
N
Ge
Ge
OTBS
OH
IBX 1.2 equiv.
4
95%
4
a3
a19
EtOAc-DMSO
r.t., 2 h
N
Ge
O
A. TBAF deprotection
4
70%a
a21
C. IBX oxidation
Pd2(dba)3 / Ruphos
NaOtBu
Toluene / H2O
standard
condition
NC
OMe
O
B
O
B
N
N
Ge
Ge
O
O
77%a
89%
a22
b34
a9
D. Suzuki coupling
H2O2 / 2M NaOH
THF, RT, 2 min
quantitative
E. Oxidative hydroxylation
N
Ge
OH
a23
Isolated yield. a See the supporting information for details.
After the demonstration of the high activity of alkyl
carbagermatranes, we next examined their stability
(Figure 5). When a3 was handled with TBAF, a most
commonly used activator for group 14 nucleophiles, TBS
(tert-butyldimethylsilyl) was smoothly removed to
furnish alcohol and Ge-C bond remained intact (Figure
5A). Moreover, further handling with Ritter’s
deoxyfluorination reagent26 (AlkylFluor) was able to
convert OH to F without detecting the broken Ge-C bond
(Figure 5B). Meanwhile, a19 was found to be compatible
their cross-coupling reactions are orthogonal with each
other. By applying the standard condition to a9, Ge-C
bond was successfully activated and a product with Bpin
preserved was obtained with excellent yield. On the other
hand, under the condition that B-C bond was activated27,
Ge-C bond was also preserved, suggesting that alkyl
carbagermatranes are capable of surviving the conditions
for Suzuki reactions (Figure 5D). Oxidative hydroxylation
is a useful transformation for B-C bond. When oxidative
hydroxylation protocol was applied to a9, corresponding
product was obtained in quantitative yield and Ge-C bond
was intact (Figure 5E). Considering the activity of
carbagematranes in cross-coupling reactions, the survival
in oxidative condition like IBX and H2O2 is remarkable.
with
IBX,
and
aldehyde-substituted
alkyl
carbagermatranes were obtained successfully, which
further expanded the scope of alkyl carbagermatranes
(Figure 5C). Following, alkyl Bpin and alkyl
carbagermatranes were compared and it turned out that
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1
2
Figure 6. Preparation of bicyclic stapled peptide.
3
4
5
6
7
8
9
N
N
Ge
Ge
O
HO
HO
1)
NHFmoc
NHBoc
a25
NHFmoc
a24
HO
1)
O
O
O
O
O
H
N
H
N
HCTU, DIEA,
DMF, 1 h
HCTU, DIEA,
DMF, 1 h
HCTU, DIEA,
DMF, 1 h
NH2
N
H
N
H
O
O
2) 20% piperidine/DMF
2) 20% piperidine/DMF
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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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
Br
Br
NH
H2N
O
O
O
N
N
NH
Ge
Ge
N
HN
H
O
O
O
O
O
cat. Pd
H
H
N
H
N
H
N
N
NHBoc
HN
N
N
H
N
H
then TFA cocktail
H
O
O
O
O
overall yield 20%
O
O
NH
b35
O
a26
Br
Br
NH
H2N
A. Preparation of bicyclic peptide b35
B. HPLC of crude b35
C. Mass Spectrum of b35
Isolated yield. See the supporting information for experimental details. Cross-coupling reaction condition: 1.0 equiv. a26, 5 mol% Pd(dba)2, 15
mol% Ligand L10, 0.05 M DMF, 120 oC, 16 h.
At last, we found out that a24 and a25 were
compatible with standard 9-fluorenylmethyloxycarbonyl
solid-phase peptide synthesis (Fmoc-SPPS) procedures,
and Ge-containing linear peptide a26 was then
synthesized, further intramolecular cross-coupling was
able to give bicyclic peptide as product (Figure 6A). After
work-up with TFA, the peptide was dissociated from resin,
the HPLC analysis suggested clearly main product in the
crude b35 (Figure 6B), indicating that our amino acid-
derived carbagermatranes showed excellent compatibility
with Fmoc-SPPS and the cross-coupling reactions on
resin (otherwise a mass of byproducts would’ve been
detected).The mass spectrum (Figure 6C) confirmed the
structure of b35. Although boron-containing reagents
have been used for stapled peptides synthesis, it’s limited
to biaryl stapled peptides synthesis involving boron-
containing aryl fragment28.
carbagermatranes show slightly lower activity than its Sn
analogue, which need additive for transmetalation as
well.24 Meanwhile, primary alkyl carbagermatranes
exhibit high activity under base/additive-free conditions
and they were also proved stable enough to be compatible
with diverse reactions. Our study represents the first
example of successful cross-coupling of alkyl germanium
reagents, and the above nature of primary/secondary alkyl
carbagermatranes in transmetalation under the condition
is consistent with Vedejs and Biscoe’s previous
observation in Sn chemistry. Synthesis of non-activated
chiral secondary alkyl carbagermatranes and study of
their stereochemistry during transmetalation are ongoing
in our lab.
4. EXPERIMENTAL SECTION
General procedure for cross-coupling reactions and
recovery of Ge-Br. Pd(dba)2 (1.2 mg, 0.002 mmol), ligand
L10 (4.8 mg, 0.006 mmol), aryl halides (0.1 mmol) and the
corresponding alkyl carbagermatranes (0.12 mmol) were
weighed and transferred to a screw-cap tube with stir bar.
The tube was evacuated and backfilled three times with
3. CONCLUSION
In summary, we have developed the methodology for the
synthesis of alkyl carbagermatranes and their cross-
coupling reactions. Non-activated secondary alkyl
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Latent Alkyl Radical Precursors: Visible-Light Photocatalytic
Oxidation of Hypervalent Bis-Catecholato Silicon
Compounds. Angew. Chem., Int. Ed. 2015, 54, 11414-11418. (c)
Jouffroy, M.; Primer, D. N.; Molander, G. A. Base-free
photoredox/nickel dual-catalytic cross-coupling of ammonium
alkylsilicates. J. Am. Chem. Soc. 2015, 138, 475-478.
argon, then CH3CN (0.5 mL) was added and the screw-cap
tube was sealed with a Teflon stopper and heated to 120
oC for 16 hours. At the end of the reaction, the reaction
mixture was cooled to room temperature and then the
1
2
3
4
5
6
7
8
o
tube was settled at -20 C for 2 hours. Most of Ge-Br was
precipitated from the solution which could be recovered
through filtration, and filtrate was concentrated to
provide the crude product. The crude product was
purified by column chromatography or preparative thin-
layer chromatogram on silica gel.
(4) For selected reviews and example, see: (a) Cherney, A. H.;
Kadunce, N. T.; Reisman, S. E. Enantioselective and
enantiospecific
transition-metal-catalyzed
cross-coupling
reactions of organometallic reagents to construct C–C
bonds. Chem. Rev. 2015, 115, 9587-9652. (b) Rygus, J. P.; Crudden,
C. M. Enantiospecific and Iterative Suzuki–Miyaura Cross-
Couplings (Perspective). J. Am. Chem. Soc. 2017, 139, 18124-18137.
(c) Wang, C. Y.; Derosa, J.; Biscoe, M. R. Configurationally stable,
enantioenriched organometallic nucleophiles in stereospecific
Pd-catalyzed cross-coupling reactions: an alternative approach
to asymmetric synthesis. Chem. Sci. 2015, 6, 5105-5113. (d) Zhao,
S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe,
M. R. Enantiodivergent Pd-catalyzed C–C bond formation
enabled through ligand parameterization. Science 2018, 362, 670-
674.
(5) Giannerini, M.; Fananas-Mastral, M.; Feringa, B. L. Direct
catalytic cross-coupling of organolithium compounds. Nat.
Chem. 2013, 5, 667-672.
(6) Knappke, C. E. I.; Jacobi von Wangelin, A. 35 years of
palladium-catalyzed cross-coupling with Grignard reagents: how
far have we come? Chem. Soc. Rev. 2011, 40, 4948-4962.
(7) Knochel, P.; Singer, R. D. Preparation and Reactions of
Polyfunctional Organozinc Reagents in Organic-Synthesis.
Chem. Rev. 1993, 93, 2117-2188.
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ASSOCIATED CONTENT
Supporting Information
Experimental details and compound characterizations.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental procedures, analysis data, and NMR spectra
for products discussed (PDF)
Crystallographic data of a18, b29 and GeBr are available
free of charge from the Cambridge Crystallographic Data
Centre under accession number CCDC-1863713, CCDC-
1863717 and CCDC-1892813.
AUTHOR INFORMATION
Corresponding Author
(8) For related discussion, see: Tellis, J. C.; Primer, D. N.;
Molander, G. A. Single-electron transmetalation in organoboron
cross-coupling by photoredox/nickel dual catalysis. Science 2014,
345, 433-436.
(9) Doucet, H. Suzuki-Miyaura cross-coupling reactions of
alkylboronic acid derivatives or alkyltrifluoroborates with aryl,
alkenyl or alkyl halides and triflates. Eur. J. Org. Chem. 2008,
2013-2030.
binxiao@ustc.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the National Key R&D Program of China
(2017YFA0700104), NSFC (21871239), Youth Innovation
Promotion Association of the Chinese Academy of Sciences
(2015371) and Fundamental Research Funds for the Central
Universities (WK2060190081) for financial support.
(10) Komiyama, T.; Minami, Y.; Hiyama, T. Recent advances in
transition-metal-catalyzed
synthetic
transformations
of
organosilicon reagents. Acs. Catal. 2017, 7, 631-651.
(11) Spivey, A. C.; Gripton, C. J. G.; Hannah, J. P. Recent
advances in group 14 cross-coupling: Si and Ge-based
alternatives to the Stille reaction. Curr. Org. Synth. 2004, 1, 211-
226.
REFERENCES
(12) For discussion about the electronegativity of group 14, see:
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silicon, germanium, tin and lead. J. Inorg. and Nucl. Chem. 1958,
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coupling reaction of chiral alkylsilanes with aryl triflates: a novel
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Organoboranes: An Easy Way To Construct C-C Bonds (Nobel
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(Pd, Ni, Fe)-Catalyzed Cross-Coupling Reactions Using
Alkyl-Organometallics as Reaction Partners. Chem. Rev. 2011, 111,
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alkyl bond formation: another dimension in cross-coupling
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(3) For selected examples, see: (a) Tellis, J. C.; Kelly, C. B.;
Primer, D. N.; Jouffroy, M.; Patel, N. R.; Molander, G. A. Single-
Electron Transmetalation via Photoredox/Nickel Dual Catalysis:
Unlocking a New Paradigm for sp3–sp2 Cross-Coupling. Acc.
Chem. Res. 2016, 49, 1429-1439. (b) Corcé, V.; Chamoreau, L. M.;
Derat, E.; Goddard, J. P.; Ollivier, C.; Fensterbank, L. Silicates as
functionalized
alkyltrifluorosilanes
with
aryl
halides.
Tetrahedron Letters 1994, 35, 6507-6510. (c) Matsuhashi, H.; Asai,
S.; Hirabayashi, K.; Hatanaka, Y.; Mori, A.; Hiyama, T.
Palladium-Catalyzed
Cross-Coupling
Reaction
of
Alkyltrifluorosilanes with Aryl Halides. Bull. Chem. Soc. Jpn. 1997,
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(14) Nakao, Y.; Takeda, M.; Matsumoto, T.; Hiyama,
T. Cross-Coupling Reactions through the Intramolecular
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Activation of Alkyl (triorgano) silanes. Angew. Chem., Int. Ed.
2010, 49, 4447-4450.
(24) We conducted cross-coupling reaction between iPrGe
and ArBr, and it cannot be realized under additive-free
conditions. However, when CuCl was applied in the reaction, a
yield of 45% was achieved. With the addition of CuCl and KF (ref.
18a), cross-coupling products were acquired in 74% yield.
1
2
3
4
5
6
(15) For most of reaction of open-chain alkyl tin reagents,
non-activated primary and some special secondary alkyl group
were presented, see: (a) Farina, V.; Krishnamurthy, V.; Scott, W.
J. The Stille Reaction. Organic reactions 1998, 50, 1-652. (b)
Cordovilla, C.; Bartolome, C.; Martinez-Ilarduya, J. M.; Espinet,
P. The Stille Reaction, 38 Years Later. Acs. Catal. 2015, 5, 3040-
3053.
iPr
Pd(dba)2 2 mmol%
Br
Ge
L10 6 mmol%
CH3CN, 100 oC, 16 h
+
Ph
Ph
7
8
9
Yield (GC) iPr : nPr (GC)
conditions
(16) Vedejs, E.; Haight, A. R.; Moss, W. O. Internal
Coordination at Tin Promotes Selective Alkyl Transfer in the
Stille Coupling Reaction. J. Am. Chem. Soc. 1992, 114, 6556-6558.
(17) (a) Verkade, J. G. Atranes: New Examples with
Unexpected Properties. Acc. Chem. Res. 1993, 26, 483-489. (b)
Simidzija, P.; Lecours, M. J.; Marta, R. A.; Steinmetz, V.;
McMahon, T. B.; Fillion, E.; Hopkins, W. S. Changes in
Tricarbastannatrane Transannular N–Sn Bonding upon
Complexation Reveal Lewis Base Donicities. Inorg. Chem. 2016,
55, 9579-9585.
Additive-free
trace
10
11
12
13
14
15
16
17
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23
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26
27
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29
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CuCl 2eq was added
45%
74%
>50 : 1
17 : 1
CuCl 2eq + KF 2eq was added
Stereochemistry
of
non-activated
secondary
alkyl
carbagermatranes in the reaction has not been studied, which is
limited to the fact that currently available chiral secondary alkyl
carbagermatranes rely on resolution on chiral stationary phase.
We are now working on the synthesis of non-activated chiral
secondary alkyl carbagermatranes, and the stereochemistry
problem would be studied more conveniently at that time.
(25) Byproducts could be polymers and difficult to be
detected if p-bromophenyl boronic acid underwent competing
Suzuki reaction, thus we conducted intermolecular competing
experiment:
(18) (a) Li, L.; Wang, C. Y.; Huang, R. C.; Biscoe, M. R.
Stereoretentive Pd-catalysed Stille cross-coupling reactions of
secondary alkyl azastannatranes and aryl halides. Nat. Chem.
2013, 5, 607-612. (b) Wang, C. Y.; Ralph, G.; Derosa, J.; Biscoe, M.
R.
Stereospecific
Palladium-Catalyzed
Acylation
of
Enantioenriched Alkylcarbastannatranes: A General Alternative
to Asymmetric Enolate Reactions. Angew. Chem. Int. Ed. 2017, 56,
856-860.
(19) Song, H. J.; Jiang, W. T.; Zhou, Q. L.; Xu, M. Y.; Xiao, B.
Structure-Modified Germatranes for Pd-Catalyzed Biaryl
Synthesis. Acs. Catal. 2018, 8, 9287-9291.
Ar
hexyl-Ph
50% yield
(GC)
B(OH)2
1 eq. PhBr
1 eq. hexyl-Ge
standard condition
52% remained
(Isolated)
B(OH)2
EtOOC
Ar
-H
trace
Ar
-Ph
not found
Ar Ar
-
Ar
= C6H4-p-COOEt
not found
0.1 mmol
Generally, the existence of ArB(OH)2 lower the yield of sp2-sp3
coupling (without optimization). However, only trace of the
protonation by-product was detected, and the homocoupling as
well as mostly concerning competing Suzuki coupling did not
take place.
(26) Goldberg, N. W.; Shen, X.; Li, J.; Ritter, T. AlkylFluor:
Deoxyfluorination of Alcohols. Org. Lett. 2016, 18, 6102-6104.
(27) Yang, C. T.; Zhang, Z. Q.; Tajuddin, H.; Wu, C. C.; Liang,
J.; Liu, J. H.; Fu, Y.; Czyzewska, M.; Steel, P. G.; Marder, T. B.; Liu,
L. Alkylboronic Esters from Copper-Catalyzed Borylation of
Primary and Secondary Alkyl Halides and Pseudohalides. Angew.
Chem. Int. Ed. 2012, 51, 528-532.
(28) (a) Bois-Choussy, M.; Cristau, P.; Zhu, J. P. Total
synthesis of an atropdiastereomer of RP-66453 and
determination of its absolute configuration. Angew. Chem. Int.
Ed. 2003, 42, 4238-4241. (b) Afonso, A.; Feliu, L.; Planas, M. Solid-
phase synthesis of biaryl cyclic peptides by borylation and
microwave-assisted intramolecular Suzuki-Miyaura reaction.
Tetrahedron 2011, 67, 2238-2245. (c) Meyer, F. M.; Collins, J. C.;
Borin, B.; Bradow, J.; Liras, S.; Limberakis, C.; Mathiowetz, A. M.;
Philippe, L.; Price, D.; Song, K.; James, K. Biaryl-Bridged
Macrocyclic Peptides: Conformational Constraint via Carbogenic
Fusion of Natural Amino Acid Side Chains. J. Org. Chem. 2012, 77,
3099-3114.
(20) Cross-coupling reactions using Ge-containing reagents
have been disregarded for a very long time, one important
reason for that is the misunderstanding of the abundance of Ge,
besides it’s mostly used for material industry. In fact, the crustal
abundance of Ge is only slightly lower than Sn. See: Rudnick, R.
L.; Gao, S. Composition of the continental crust in Treatise on
geochemistry, Rudnick, R. L.; Holland, H. D.; Turekian, K. K. Eds.
(Elsevier, 2003), vol. 3, chap. 3.01, pp. 1-64.
(21) The first and only example of the synthesis of
carbagermatrane was achieved by Kosugi. However, only one
example of alkyl carbagermatrane (nBu-Ge) was presented, and
its cross-coupling with PhBr only gave trace yield: Kosugi, M.;
Tanji, T.; Tanaka, Y.; Yoshida, A.; Fugami, K.; Kameyama, M.;
Migita, T. Palladium-catalyzed reaction of 1-aza-5-germa-5-
organobicyclo[3.3.3]undecane with aryl bromide. J. Organomet.
Chem. 1996, 508, 255-257.
(22) (a) Chen, Y.; Peng, H.; Pi, Y. X.; Meng, T.; Lian, Z. Y.; Yan,
M. Q.; Liu, Y.; Liu, S. H.; Yu, G. A. Efficient phosphine ligands for
the one-pot palladium-catalyzed borylation/Suzuki-Miyaura
cross-coupling reaction. Org. Biomol. Chem. 2015, 13, 3236-3242.
(b) Lian, Z. Y.; Yuan, J.; Yan, M. Q.; Liu, Y.; Luo, X.; Wu, Q. G.;
Liu, S. H.; Chen, J.; Zhu, X. L.; Yu, G. A. 2-Aryl-indenylphosphine
ligands: design, synthesis and application in Pd-catalyzed
Suzuki–Miyaura coupling reactions. Org. Biomol. Chem. 2016, 14,
10090-10094.
(23) Under the optimized condition, we used GeEt4 or Ge-
nBu4 instead of alkyl carbagermatranes and no cross coupling
product was detected, which shows the impact of atrane.
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