Stereoselective synthesis of tetrasubstituted alkenes via a sequential carbocupration and a new sulfur-lithium exchange

Article abstract of DOI:10.3762/bjoc.8.248

We have designed a new sequential carbocupration and sulfur-lithium exchange that leads stereo- and regioselectively to trisubstituted alkenyllithiums. Subsequent trapping with various electrophiles yields tetrasubstituted olefins with good control of the

Full text of DOI:10.3762/bjoc.8.248

Stereoselective synthesis of tetrasubstituted alkenes
via a sequential carbocupration and
a new sulfur–lithium exchange
Andreas Unsinn, Cora Dunst and Paul Knochel*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 2202–2206.
Department Chemie, Ludwig-Maximilians-Universität München,
Butenandtstr. 5-13, 81377 München, Germany
doi:10.3762/bjoc.8.248
Received: 17 October 2012
Accepted: 05 December 2012
Published: 18 December 2012
Email:
Paul Knochel* - paul.knochel@cup.uni-muenchen.de
* Corresponding author
This article is part of the Thematic Series "Carbometallation chemistry".
Guest Editor: I. Marek
Keywords:
alkenes; carbometalation; copper; regioselectivity; stereoselectivity
© 2012 Unsinn et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
We have designed a new sequential carbocupration and sulfur–lithium exchange that leads stereo- and regioselectively to trisubsti-
tuted alkenyllithiums. Subsequent trapping with various electrophiles yields tetrasubstituted olefins with good control of the double-
bond geometry (E/Z ratio up to 99:1). The novel sulfur–lithium exchange could be extended to the stereoselective preparation of
Z-styryl lithium derivatives with almost complete retention of the double-bond geometry.
Introduction
The stereoselective synthesis of tetrasubstituted alkenes is an thioether 1 with the organozinc reagent 2 in the presence of
important synthetic goal, which may be achieved by carbometa- CuCN·2LiCl [14], the alkenylcopper species 3 should be
lation methods [1-9]. The Normant carbocupration of terminal obtained. Stereoselective quenching with an electrophile (E1)
acetylenes allows the stereoselective preparation of trisubsti- should afford the tetrasubstituted alkenyl thioether 4. Extensive
tuted alkenes with excellent E/Z ratio [10-12]. However, in experimentation showed that thioethers 4 do not undergo Ni- or
order to obtain tetrasubstituted alkenes, a carbometalation of an Pd-catalyzed cross couplings leading to products of type 5
internal alkene is required. This reaction is usually difficult due (R = Me, Ph) [15,16]. Thus, we designed a new sulfur–lithium
to steric hindrance and proceeds only if electron-withdrawing exchange (Scheme 1).
groups are attached to the alkyne unit to facilitate the carbomet-
alation step. Recently, we studied the chemistry of alkenyl Sulfur–lithium exchanges proceed only readily with sulfoxides
sulfides and their use for carbometalation extensively [13]. [17-19] and these reactions are often complicated by radical
side reactions [20,21]. This new, direct sulfur–lithium exchange
Therefore, we envisioned using an alkynyl thioether such as 1 on an alkenyl thioether of type 4 involves the use of a bromo-
as an activated alkyne. After a carbocupration of the alkynyl biphenyl R-group, which by treatment with BuLi at low
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Beilstein J. Org. Chem. 2012, 8, 2202–2206.
we demonstrate the feasibility of this methodology and thus
prepare tetrasubstituted alkenes with E/Z stereoselectivities up
to 99:1. Furthermore, we show that this sulfur–lithium exchange
can be extended to the stereoselective preparation of Z-styryl
derivatives.
Results and Discussion
First, we wish to report the synthesis of the alkynyl biphenyl
thioether 1a required for the carbometalation step. Thus, octyne
was deprotonated with butyllithium (1.1 equiv, THF, −78 °C,
2 h) followed by the addition of the diaryl disulfide [23] (8:
1.1 equiv, −78 °C to 25 °C, 3 h) providing the bromothioether 9
in 77% yield. Direct Pd-catalyzed Negishi cross-coupling [24-
28] of 9 with an arylzinc derivative failed. However, the
Scheme 1: Synthesis of tetrasubstituted olefins by a successive
carbocupration and S–Li exchange.
temperatures, undergoes first a fast bromine–lithium exchange bromide 9 could be readily converted to the corresponding
leading to an intermediate biphenyllithium derivative of type 6, iodide 10 by a bromine–magnesium exchange using
followed by an intramolecular ring-closing sulfur–lithium iPrMgCl·LiCl [29-35] followed by iodolysis leading to the
exchange [22] leading to the desired alkenyllithium 7 iodide 10 in 93% yield. Treatment of 1,2-dibromobenzene with
(Scheme 2).
iPrMgCl·LiCl at −15 °C for 2 h followed by a transmetalation
with ZnCl2 gives the required zinc reagent 11, which under-
Subsequent quenching with a different electrophile E2 should goes a Negishi cross-coupling with the iodide 10 at 50 °C (5 h)
afford the tetrasubstituted alkene of type 5; (Scheme 1). Herein, leading to the alkynyl thioether 1a in 80% yield (Scheme 3).
Scheme 2: Proposed mechanism of the sulfur–lithium exchange starting with the alkenyl thioether 4.
Scheme 3: Synthesis of the precursor 1a.
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Beilstein J. Org. Chem. 2012, 8, 2202–2206.
The harsh cross-coupling conditions may be due booth to the (1.1 equiv, −78 °C, 15 min) furnishes the corresponding unsatu-
presence of the ortho-bromo substitution in the zinc reagent 11, rated ethylester 5b in 55% isolated yield and an E/Z ratio of
which considerably reduces the nucleophilicity of this arylzinc 95:5. Finally, a copper-catalyzed allylation with ethyl
reagent by inductive effects, and also to the sulfur atom of the 2-(bromomethyl)acrylate [37] (1.5 equiv, −78 to 0 °C, 2 h)
electrophile, which poisons the Pd catalyst. With the thioether affords the triene 5c in 55% yield and an E/Z ratio of 99:1
1a in hand, we have performed the Normant carbocupration (Scheme 6).
with di-para-anisylzinc (An2Zn: 2a) according to a procedure
previously developed by us [36]. Thus, the reaction of 1a These quenching experiments demonstrate that this new method
(1.0 equiv) with An2Zn (1.5 equiv, THF) in the presence of based on a successive carbocupration and sulfur–lithium
CuCN·2LiCl (1.5 equiv) at 25 °C for 8 h produces the inter- exchange allows the stereoselective preparation of various
mediate copper reagent 3a, which, after allylation with allyl tetrasubstituted alkenes. Since Normant has shown that
bromide, provides the thioether 4a in 84% yield and an E/Z various alkylcopper species add to alkynyl thioethers [38-40],
ratio of 99:1 (Scheme 4). The reaction of 3a with other typical the use of a bromobiphenyl substituent (R2) on the sulfur may
electrophiles is possible, but proceeds in moderate yields due to allow a general stereoselective synthesis of tetra-substituted
the low reactivity of copper reagent 3a.
alkenes.
The bromothioether 4a was then treated with s-BuLi (1.3 equiv, In order to prove that this new sulfur–lithium exchange has
−78 °C, 10 min), leading to the formation of the intermediate further applications in the stereoselective synthesis of alkenes,
aryllithium 6a, which undergoes the desired intramolecular we prepared the Z-alkenyl thioether 12 starting from 2,2’-
sulfur–lithium exchange affording the alkenyllithium reagent 7a dibromobiphenyl. Thus, the performance of a double
(Scheme 5).
bromine–lithium exchange with BuLi (1.1 equiv, −78 °C,
0.25 h) followed by a quenching with tetramethylthiuram disul-
This alkenyllithium was quenched with typical electrophiles fide (1.1 equiv, −78 to 25 °C, 12 h) furnishes the dithiocarba-
with a high retention of the double-bond geometry. Thus, the mate 13 in 82% yield. Since the reduction to the free thiol is
treatment of 7a with EtI (2 equiv, −78 °C, 15 min) provides the hard to achieve due to dibenzothiophene formation [41], we
tetrasubstituted alkene 5a in 75% yield and an E/Z ratio of 1:99. performed an in situ deprotection and stereoselective addition to
Direct carboxylation by the reaction with ethyl chloroformate phenylacetylene [42] (1.5 equiv, 1.25 equiv NaOEt, EtOH,
Scheme 4: Carbocupration of the thioether 1a leading to the tetrasubstituted alkene 4a.
Scheme 5: Synthesis of the alkenyllithium reagent 7a by an S–Li exchange.
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Beilstein J. Org. Chem. 2012, 8, 2202–2206.
Scheme 6: Quenching of the alkynyllithium 7a. (Product ratios and diastereoselectivities were determined by 1H- and 2D-NMR.)
Scheme 7: Synthesis and quenching of Z-styryllithium.
reflux, 15 h) yielding the Z-alkenyl thioether 12 in 74% yield sulfur–lithium exchange. Extension to the stereoselective
(Scheme 7).
preparation of Z-styryllithium was shown.
Treatment of 12 with t-BuLi (1.6 equiv, −78 °C, 10 min)
provides directly the Z-styryllithium 14, which stereoselec-
tively adds to α,α,α-trifluoroacetophenone (0.8 equiv, −78 °C,
0.5 h) and cyclopentanone (0.8 equiv, −78 °C, 0.5 h) to afford
the expected tertiary allylic alcohols 15a–b in 71–82% yield
and E/Z ratios of >1:99.
Supporting Information
Supporting Information File 1
Experimental details and characterization data of new
compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-248-S1.pdf]
Conclusion
In summary, we have reported tetrasubstituted olefins with
excellent E/Z ratios using a sequential carbocupration and a new
sulfur–lithium exchange involving an alkenyl thioether bearing
a 2’-bromobiphenyl substituent, which triggers efficiently the
Acknowledgements
We thank the Fonds der Chemischen Industrie and the Euro-
pean Research Council (ERC) for financial support. We also
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Beilstein J. Org. Chem. 2012, 8, 2202–2206.
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thank BASF SE (Ludwigshafen), Heraeus Holding GmbH
(Hanau) and Rockwood Lithium GmbH (Frankfurt) for the
generous donation of chemicals.
doi:10.1002/ange.201101380
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