Preparation of Tri- and tetrasubstituted allenes via regioselective lateral metalation of benzylic (Trimethylsilyl)alkynes using TMPZnCl·LiCl

Article abstract of DOI:10.1021/acs.orglett.5b00114

The zincation of various 1-(trimethylsilyl)-3-aryl-1-propynes with TMPZnCl·LiCl followed by a Pd-catalyzed coupling with aryl halides provides arylated allenes in 52-92% yield. Subsequent metalation with TMPZnCl·LiCl and cross-coupling with a second different aryl halide provides regioselectively tetrasubstituted allenes in 42-70% yield. This sequence can be performed in a one-pot procedure. DFT calculations and NMR studies support the formation of allenylzinc and propargyllithium intermediates starting from 1-(trimethylsilyl)-3-phenyl-1-propyne.

Full text of DOI:10.1021/acs.orglett.5b00114

Letter
pubs.acs.org/OrgLett
Preparation of Tri- and Tetrasubstituted Allenes via Regioselective
Lateral Metalation of Benzylic (Trimethylsilyl)alkynes Using
TMPZnCl·LiCl
Pauline Quinio, Cyril Franco
Konstantin Karaghiosoff, and Paul Knochel*
̧ is, Ana Escribano Cuesta, Andreas K. Steib, Florian Achrainer, Hendrik Zipse,
Department Chemie, Ludwig-Maximilians-Universitat, Butenandtstrasse 5-13, 81377 Munchen, Germany
̈
̈
S
* Supporting Information
ABSTRACT: The zincation of various 1-(trimethylsilyl)-3-
aryl-1-propynes with TMPZnCl·LiCl followed by a Pd-
catalyzed coupling with aryl halides provides arylated allenes
in 52−92% yield. Subsequent metalation with TMPZnCl·LiCl
and cross-coupling with a second different aryl halide provides
regioselectively tetrasubstituted allenes in 42−70% yield. This
sequence can be performed in a one-pot procedure. DFT calculations and NMR studies support the formation of allenylzinc and
propargyllithium intermediates starting from 1-(trimethylsilyl)-3-phenyl-1-propyne.
llenic structures are found in a number of useful organic
molecules such as natural products1 or materials.2 They are
THF at 25 °C for 1 h. Addition of CuCN·2LiCl (30 mol %) and
allyl bromide led to the allylated allene 3a in 77% yield, indicating
that TMPZnCl·LiCl (1) achieved a smooth deprotonation of the
benzylic hydrogen.13 This result was confirmed by extending the
metalation to the heterobenzylic derivative (2b), which after
allylation, similarly produced the corresponding allene (3b) in
71% yield (Scheme 2). With these results in hand, we examined
A
also important intermediates3 for carbo- and heterocycle
synthesis,4 making the preparation of substituted allenes a
valuable synthetic target.5 Various transition-metal-catalyzed
functionalizations of the allenic moiety have been reported.6 For
example, Ma reported the preparation of trisubstituted allenes
using a Pd-catalyzed arylation of zincated allenes obtained by
LDA deprotonation of the corresponding allenes.7
Scheme 2. In Situ Trapping of Zinc Reagents with CuCN·
2LiCl and Subsequent Allylation Reaction
Recently, we have reported that TMPZnCl·LiCl (1, TMP =
2,2,6,6-tetramethylpiperidyl) is an excellent base for the selective
metalation of various substrates.8 The high kinetic basicity of 1
allows the efficient metalation of a range of organic molecules
including nitriles, esters, and various functionalized unsaturated
molecules.9 We have envisioned that lateral metalations10 of
benzylic alkynes of type 2 with TMPZnCl·LiCl (1) will produce
intermediate allenylzinc reagents, which after quenching with an
electrophile E1+ will produce trisubstituted allenes of type 3
(Scheme 1).7
the direct Pd-catalyzed arylation of the TMS-protected alkynes of
type 2. Thus, the reaction of the alkynes 2a−c with TMPZnCl·
LiCl (1; 1.2 equiv) in THF at 25 °C for 1 h, followed by the
addition of an aryl or heteroaryl bromide or iodide (5a−j),
provides the arylated allenes 3a−p in 52−92% yield (Table 1). As
Pd catalyst, we have found after an extensive screening that three
catalytic systems gave the best results: (a) 2% Pd(OAc)2/2%
DPE-Phos;14 (b) 2% Pd(OAc)2/4% S-Phos;15 (c) 2% PEPPSI-i-
Pr.16 Both donor- and acceptor-substituted aryl halides afforded
the trisubstituted allenes 3c−k in 60−92% yield (entries 1−9).
The thienyl-substituted alkyne (2b) behaves similarly and
produced the allenes (3l−m) in 65−78% yield (entries 10−
11). Remarkably, an ester substituent is perfectly tolerated, and
the alkyne (2c) leads to the corresponding trisubstituted allenes
Scheme 1. Successive Lateral Metalation of Benzylic Alkynes
of Type 2 with TMPZnCl·LiCl (1)
A subsequent metalation with TMPZnCl·LiCl (1) will give a
new zincated intermediate, which after trapping with a second
electrophile E2+ will furnish tetrasubstituted allenes of type 4.
Herein, we report the successful realization of this reaction
sequence using a palladium-11 or a copper-catalyzed12 reaction of
1-(trimethylsilyl)-3-aryl-1-propynes with electrophiles.
In preliminary experiments, we have treated the TMS-
protected alkyne (2a) with TMPZnCl·LiCl (1; 1.2 equiv) in
Received: January 14, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00114
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Organic Letters
Letter
Table 1. Zincation with TMPZnCl·LiCl (1) Followed by a Negishi Cross-Coupling Reaction with Various Electrophiles
a
b
c
d
1.0 equiv of electrophile was used. Reaction time at 25 or 50 °C for full conversion. Isolated yield of analytically pure product. Pd catalyst: 2%
e
f
g
Pd(OAc)2/4% S-Phos. Pd catalyst: 4% Pd(OAc)2/4% DPE-Phos. Pd catalyst: 2% Pd(OAc)2/2% DPE-Phos. Pd catalyst: 2% PEPPSI-iPr.
(3n−p) in 52−74% yield (entries 12−14). In all cases, the
arylation is regiospecific (only allenic derivatives are obtained
and no arylated propargylic compounds could be detected).
Then, we developed a one-pot procedure allowing a direct
conversion of alkyne 2a to the tetrasubstituted allenes of type 4
(Scheme 3 and Table 2). Thus, alkyne 2a was treated as before
with TMPZnCl·LiCl (1, 1.2 equiv) and iodobenzene (5a, 1.0
equiv) leading to 3c, which was not isolated but directly zincated
with TMPZnCl·LiCl (1, 1.2 equiv) and iodobenzene (5a, 1.0
equiv), affording the tetrasubstituted allene 4a in 65% isolated
yield.
Replacing the aryl iodide (5a) by 3-bromothiophene (5i)
similarly produced the tetrasubstituted allene 4b in 51% yield
(Table 2, entry 1). The use of two different aryl or heteroaryl
halides was also possible. Thus, treatment of the alkyne (2a) with
TMPZnCl·LiCl (1, 1.2 equiv), a Pd catalyst, and iodobenzene
(5a, 1.0 equiv) for 4 h at 25 °C led to the intermediate allene 3c,
which was directly metalated with TMPZnCl·LiCl (1, 1.2 equiv),
Pd catalyst, and 3-bromothiophene (5i, 1.0 equiv), affording the
tetrasubstituted allene 4c in 63% overall yield (entry 2). By
inverting the addition order of the two electrophiles E1+ and E2+
using first the heterocyclic bromide (5i) and then iodobenzene
(5a), we have obtained the regioisomeric tetrasubstituted allene
4d in 47% overall yield (entry 3). This approach was used for the
preparation of the tetrasubstituted allenes (4e−j) in 42−70%
overall yield (entries 4−9). Remarkably, this method allows the
synthesis of the tris-3-thienylallene 4k in 65% yield (Scheme 4).
The structure of several allenes (3c, 4c, 4f, 4k; Tables 1 and 2)
has been confirmed by X-ray diffraction analysis.17 We have
briefly studied the scope of these new metalations of alkynes and
allenes and found that the related diyne 6 was similarly zincated
Scheme 3. Successive Zincation with TMPZnCl·LiCl (1) and
Subsequent Negishi Cross-Coupling Reactions
B
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Table 2. One-Pot Tetrafunctionalization of Allenes via
Successive Zincation Using TMPZnCl·LiCl (1) and Negishi
Cross-Coupling Reactions with Various Electrophiles
Scheme 4. Preparation of a Tri-3-thienylallene (4k) and
Lateral Metalation of Alkynes 6 and 7 with TMPZnCl·LiCl (1)
alkynylallene 7 was cleanly allylated affording the highly
unsaturated product 8 in 67% yield.
In order to establish the nature of the zincated intermediates
(allenic or propargylic) occurring during the metalation of 2a, we
performed an NMR study that showed that the lithiation of 2a
produces only the propargylic lithium species 9 as seen by the
chemical shift of the propargylic proton Ha at 3.33 ppm in the 1H
NMR spectra (Scheme 5).17
Scheme 5. NMR Experiments Showed Direct Formation of
Allenylzinc Reagent
The zincation of 2a using TMPZnCl·LiCl (1) produces an
allenylzinc species 10 (as seen by the allenic 13C signal at 202.8
ppm, no propargyl isomer was observed and the allenic proton
(Hb) has a chemical shift of 4.99 ppm in the 1H NMR spectra).17
From these studies, it becomes clear that the propargyl isomer 9
is the most stable organometallic species in the case of the lithium
cation, whereas the allenylzinc structure 10 is the most stable
(zinc cation).20 Theoretical calculations at the MP2 level of
theory confirmed a major difference in stability order for the
propargyl allenyl isomers of the respective organometallics. An
endothermic enthalpy of 1.4 kJ/mol for the two organolithium
isomers (9 and 9a; Figure 1) is opposed to 7.8 kJ/mol for the zinc
species 10 and 10a.17
a
b
1.0 equiv of electrophile was used. Reaction time at 25 or 50 °C for
c
d
full conversion. Isolated yield of analytically pure product. Pd
catalyst: 2% Pd(OAc)2/4% S-Phos. Pd catalyst: 2% Pd(OAc)2/2%
e
DPE-Phos.
with TMPZnCl·LiCl (1) within 1 h at 25 °C (Scheme 4).18 After
a copper-catalyzed allylation with allyl bromide, the trisubstituted
allene 7 was obtained in 60% yield.19 The unsaturated
Figure 1. Propargyl allenyl isomerization in THF solution (SMD/
B3LYP/6-31G(d)) at the MP2(FC)/6-31+G(d,p) level (Li = Li-
(THF)3, ZnX = ZnCl(THF)2, gas-phase values in parentheses).
C
DOI: 10.1021/acs.orglett.5b00114
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Organic Letters
Letter
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In conclusion, we have reported an efficient Pd-catalyzed
arylation of some 1-(trimethylsilyl)-3-aryl-1-propynes using
TMPZnCl·LiCl leading to trisubstituted allenes. Interestingly,
we have performed a one-pot bis-arylation of 1-(trimethylsilyl)-
3-phenyl-1-propyne affording regioselectively tetrasubstituted
allenes. Quantum chemical calculations and NMR studies
support the formation of allenylzinc and propargyllithium
intermediates.
ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental details and NMR data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: paul.knochel@cup.uni-muenchen.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the European Research Council (ERC) under the
European Community’s Seventh Framework Programme (FP7/
2007-2014) ERC Grant Agreement No. 227763 and the
Forschungsgemeinschaft (SFB749, B2) for financial support.
We also thank BASF SE (Ludwigshafen, Germany) and
Rockwood Lithium GmbH (Hoechst, Germany) for the
generous gift of chemicals.
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