Synthesis of Functionalized Alkenes by a Transition-Metal-Free Zweifel Coupling

Article abstract of DOI:10.1021/acs.orglett.7b01124

The Zweifel reaction is a powerful method for the synthesis of alkenes, serving as a transition-metal-free alternative to the Suzuki-Miyaura reaction. To date, the scope of the Zweifel coupling has been rather narrow and has focused mainly on the coupling of vinyllithium reagents to synthesize simple aryl- and alkyl-substituted olefins. Herein, the development of a general transition-metal-free coupling process enabling the coupling of Grignard reagents or organolithiums is described. This method enables the enantiospecific synthesis of a wide variety of functionalized acyclic and cyclic olefin products.

Full text of DOI:10.1021/acs.orglett.7b01124

Letter
pubs.acs.org/OrgLett
Synthesis of Functionalized Alkenes by a Transition-Metal-Free
Zweifel Coupling
Roly J. Armstrong,† Worawat Niwetmarin, and Varinder K. Aggarwal*
†
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, U.K.
*
S Supporting Information
ABSTRACT: The Zweifel reaction is a powerful method for the synthesis of
alkenes, serving as a transition-metal-free alternative to the Suzuki−Miyaura
reaction. To date, the scope of the Zweifel coupling has been rather narrow and
has focused mainly on the coupling of vinyllithium reagents to synthesize simple
aryl- and alkyl-substituted olefins. Herein, the development of a general
transition-metal-free coupling process enabling the coupling of Grignard reagents
or organolithiums is described. This method enables the enantiospecific synthesis
of a wide variety of functionalized acyclic and cyclic olefin products.
he geometrically controlled synthesis of functionalized
alkenes continues to receive prominent attention due to
this intermediate with iodine results in the formation of an
T
iodonium ion, which is poised to undergo a stereospecific 1,2-
metallate rearrangement affording a β-iodoboronic ester. Upon
addition of a base, this intermediate undergoes anti elimination6,
resulting in the formation of the corresponding alkene.
Although there have been several elegant reports detailing the
development of the Zweifel coupling, to date the method has
principally been applied to the coupling of simple alkyl- and
aryl-substituted acyclic vinyllithiums. Moreover, the introduc-
tion of an unsubstituted vinyl moiety requires the use of
vinyllithium, which is typically prepared in situ from highly
their prevalence in pharmaceuticals, natural products, and
1
materials. The Suzuki−Miyaura cross-coupling reaction
constitutes an extremely versatile and convergent method for
2
the assembly of alkenes. However, although the coupling of
2
vinyl halides with primary and sp -boronate partners takes place
with high efficiency, the corresponding reactions with
3
secondary and tertiary (chiral) boronic esters do not.
Furthermore, the high cost and toxicity of the palladium
complexes that are typically employed as catalysts in such
4
7
coupling processes impact on its attractiveness.
toxic tetravinyltin. As a consequence, the Zweifel reaction has
We have recently become interested in the Zweifel
olefination, which represents a transition-metal-free alternative
not been widely utilized and has only been employed in a
handful of synthetic applications.
5
8
to the Suzuki−Miyaura coupling. In this process, a vinylmetal
species is combined with a boronic ester resulting in the
formation of a boronate complex (Scheme 1). Treatment of
Our aim at the outset of this work was to extend the utility of
the Zweifel olefination by developing a practical method
enabling the coupling of simple vinyl Grignard reagents with
boronic esters. Unlike the corresponding vinyllithium reagents,
solutions of vinyl Grignard reagents are commercially available
Scheme 1. Zweifel Olefination
9
and bench stable.
We also hoped to extend the scope of the coupling process to
encompass densely functionalized, cyclic vinyl metals. The
coupling of cyclic vinyl metals is of particular interest because
the cyclic β-iodoboronic ester intermediates cannot undergo
bond rotation to achieve an anti relationship between boronic
ester and iodide. Instead, a challenging syn elimination is
10
required to obtain the cycloalkene products.
We commenced our study with an investigation of the
introduction of an unsubstituted vinyl group. A typical
reference coupling between boronic ester 1 and vinyllithium
(
prepared in situ from tetravinyltin) provided the desired
7b
product 3 in 94% yield (Scheme 2, entry a). However,
unfortunately when we attempted to carry out Zweifel coupling
of boronic ester 1 with an equimolar quantity of vinyl-
Received: April 13, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01124
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Zweifel Coupling with Vinyl Grignard: Reaction
Optimization via B NMR Analysis
methanol provided the coupled product 3 in good yield, this
approach is nonideal for reasons of both economy and
functional-group compatibility. Morken and co-workers have
very recently reported an elegant strategy for palladium-
catalyzed conjunctive cross-coupling of vinyl Grignards in
which it was observed that boronate complex formation could
be promoted by addition of alkali metal triflates and
introduction of DMSO as a cosolvent. We found that upon
addition of sodium triflate (see the SI for full details of
optimization) a small amount of the desired boronate complex
1
1
a
12
2a was observed (8 ppm), although a significant quantity of 2b
was also formed (entry e). We were pleased to find that
performing the reaction with NaOTf in 1:1 DMSO/THF
completely suppressed formation of 2b, and following addition
of I and NaOMe, 3 was obtained in a promising 68% yield
2
(
entry f). In Morken’s work, sodium triflate plays a key role in
subsequent chemistry as a halide scavenger, but we speculated
that it might not be required in our case. Pleasingly, we found
that carrying out the reaction in the absence of NaOTf in 1:1
THF/DMSO we observed high conversion to the desired
boronate complex 2a (entry g). By adding a slight excess (1.2
equiv) of vinylmagnesium chloride, complete conversion to 2a
was observed, and after addition of I and NaOMe the coupled
2
product 3 was isolated in 89% yield (entry h).
Employing these optimized conditions, we evaluated the
generality of the process (Scheme 3). Primary boronic esters
underwent the desired coupling process to afford 4−6 in
excellent yields. Secondary boronic esters could also be
Scheme 3. Coupling of Grignard Reagents with Boronic
a
Esters: Substrate Scope
a
Reaction conditions: 1 (1 equiv), vinyl metal (1−4 equiv); then
11
NaOMe (3−8 equiv), I (1.2−4 equiv). The scheme shows B NMR
spectra recorded in nondeuterated reaction solvents prior to addition
of I /NaOMe. Yields of 3 were determined by H NMR analysis vs
1
2
1
2
b
,1,2,2-tetrachloroethane as an internal standard. Vinyllithium was
generated from tetravinyltin (1 equiv) and n-butyllithium (1.6 M in
c
hexanes, 2 equiv). Vinyl-MgCl (1.6 M in THF, 1 equiv), NaOTf
d
(
2 equiv). Yield of isolated product 3 after column chromatography
on silica gel.
magnesium chloride, the product 3 was formed in only 37%
yield (entry b).
We suspected that boronate complex formation was the
problematic step in this sequence, and accordingly, we analyzed
1
1
the intermediate by B NMR spectroscopy. Instead of the
usual peak expected for boronate complex 2a at 8 ppm (for
example that observed with vinyllithium, entry a), we observed
a mixture of unreacted boronic ester 1 (35 ppm) along with a
new sharp singlet at −13 ppm (entry b). This is consistent with
the formation of trivinyl boronate complex 2b in which the
pinacol ligand has been displaced by 3 equiv of vinylmagnesium
chloride. In line with our previous studies in this area, we
found that addition of excess vinyl magnesium chloride (2 or 4
equiv) resulted in increased conversion of the starting boronic
ester to 2b, and the desired boronate complex 2a was not
observed (entries c and d). Although addition of iodine and
a
Reaction conditions: boronic ester (1 equiv), vinylmagnesium
chloride (1.6 M in THF, 1.2 equiv), 1:1 THF/DMSO, 0 °C to rt,
3
0
vinylmagnesium chloride (1.6 M in THF, 2 equiv). With
isopropenylmagnesium bromide (0.5 M in THF, 2 equiv). With
0 min; then NaOMe (3 equiv), I (1.2 equiv), THF/DMSO/MeOH,
2
b c
11
1
°C, 30 min. H NMR yield vs 1,1,2,2-tetrachloroethane. With
d
e
f
19
4 equiv of vinyl-MgCl without DMSO.
hexafluorobenzene.
F NMR yield vs
B
DOI: 10.1021/acs.orglett.7b01124
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
successfully employed as starting materials, providing products
group, we were able to synthesize vinyl ether 19 (60% yield,
100% es), vinyl carbamate 20 (84% yield, 100% es), and vinyl
7−9 in good yield with complete stereospecificity. Notably, the
11,14
mild nature of Grignard reagents enables chemoselective
bromide 21 (78% yield, 100% es).
We found that the
coupling to occur in the presence of functional groups such
process could also be extended to the coupling of a lithiated
vinyl sulfide, providing 22 in 91% yield with complete
enantiospecificity. We next examined the coupling of lithiated
dihydropyran to give 23. Interestingly, we found that in the
absence of base the intermediate β-iodoboronic ester could be
isolated (see the SI for details), implying that the syn
elimination process is indeed slow compared with acyclic
examples. Fortunately, our standard elimination conditions
(3 equiv NaOMe, 30 min, 0 °C) were able to promote the
desired syn elimination, affording the coupled product 23 in
79% yield with complete enantiospecificity. The methodology
could also be employed in a more complex setting; glycal
derivative 24 was obtained in 49% yield as a single
diastereoisomer. We next attempted to extend the process to
the coupling of carbocyclic vinyl partners. Under our standard
conditions, we found that syn elimination to form 25 was very
slow, but upon addition of excess NaOMe (20 equiv), and
warming to room temperature the desired elimination took
place, cleanly affording 25 in near-quantitative yield with no
loss of enantiomeric purity. These conditions could also be
employed for the synthesis of heterocyclic substrate 26, which
was obtained in 93% yield with complete enantiospecificity.
When our standard conditions were applied to the coupling of
a cyclic enamine, the desired product 27 was not observed.
However, under conditions we recently reported for a syn
selective variant of the Zweifel reaction employing PhSeCl
13
as azides (6) and carbamates (8). It was also possible to
employ a Grignard reagent bearing an α-methyl substituent to
obtain 10 in 70% yield. Our optimized conditions also enabled
the successful coupling of an unhindered tertiary boronic ester
to form 11; however, for acyclic tertiary boronic esters, the
products (e.g., 12) were obtained in reduced yield. We found
that an effective solution to this problem was to add 4 equiv of
vinylmagnesium chloride in THF (cf. Scheme 2, entry d), and
by use of this method, 12 was obtained in 95% yield. Finally, we
carried out coupling reactions between vinylmagnesium
chloride and a series of aromatic boronic esters. Using this
method, a range of electron-rich, electron-deficient, and
heteroaryl groups could be introduced including boronic esters
containing reactive functional groups such as vinyl iodides and
ethyl esters. The latter example is especially noteworthy since
ethyl esters are not compatible with the more reactive
vinyllithium reagents.
Next, we turned our attention to carrying out Zweifel
reactions with more complex, substituted vinyl partners
(Scheme 4). Employing conditions recently reported by our
Scheme 4. Coupling of Functionalized Vinyllithiums with
a
Boronic Esters: Substrate Scope
10a
followed by m-CPBA the product was obtained in 68% yield.
Taking (3,6-dihydro-2H-pyran-4-yl)lithium as a representative
example, coupling with several boronic esters was attempted.
We found that the coupling reaction worked well with a series
of secondary, primary, tertiary, and aromatic boronic esters,
affording the resulting products 26 and 28−30 in excellent
yields.
We also investigated the coupling of a steroid-derived
cyclopentenyllithium. In this case, the intermediate β-
iodoboronic ester was isolated cleanly but proved resistant to
15
NaOMe-mediated syn elimination. Fortunately, we found that
addition of TBAF in THF brought about the desired
elimination, providing the desired alkene 31 in 69% yield
(
two steps). A range of different aromatic boronic esters could
also be coupled with this vinyllithium to enable the synthesis of
a series of derivatives of the anticancer agent abiraterone (32−
16
3
6). Notably, in contrast to 31, the syn elimination for these
examples did not require addition of TBAF and could be
carried out with sodium methoxide. The enhanced rate of
elimination observed in these cases is likely a consequence of
17
the benzylic nature of the β-iodoboronic ester intermediates.
Finally, to demonstrate the utility of this method, we aimed
to carry out several of the reactions on a gram scale (Scheme
5
). Our newly developed conditions for coupling of vinyl-
magnesium chloride with boronic esters proved to be readily
scalable, and we could access 3 and 5 in 91% and 75% yield,
respectively. Additionally, a representative coupling of a cyclic
vinyl bromide conducted on a gram scale provided 25 in 87%
yield.
In conclusion, we have developed a robust procedure that
enables the transition-metal-free coupling of alkenylmagnesium
and -lithium reagents with boronic esters. The coupling enables
commercially available vinyl Grignard reagents to be used in
Zweifel-type coupling reactions for the first time. Additionally,
a
Reaction conditions: boronic ester (1 equiv), vinyllithium
(
0.9−2 equiv), THF, −78 to 0 °C, 30 min; then NaOMe (3 equiv),
I (1.2 equiv), THF/MeOH, 0 °C, 30 min. Vinyllithium reagents were
2
generated by deprotonation or by exchange with the corresponding
b
vinyl halide or stannane (see SI for details). NaOMe was not added.
c
Elimination was carried out with 20 equiv of NaOMe, rt, 16 h.
d
e
PhSeCl followed by m-CPBA. Elimination was carried out with
TBAF·3H O (10 equiv).
2
C
DOI: 10.1021/acs.orglett.7b01124
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
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acyclic alkenyl partners can be employed in the coupling, thus
greatly expanding the synthetic potential of the procedure. We
believe that this process will serve as a useful transition-metal-
free alternative to the Suzuki−Miyaura cross-coupling for the
synthesis of both chiral and achiral alkene products.
(
(
6) Matteson, D. S.; Liedtke, J. D. J. Am. Chem. Soc. 1965, 87, 1526.
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ASSOCIATED CONTENT
Supporting Information
■
5
8
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712. (c) Mercer, J. A. M.; Cohen, C. M.; Shuken, S. R.; Wagner, A.
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01124.
M.; Smith, M. W.; Moss, F. R.; Smith, M. D.; Vahala, R.; Gonzalez-
Martinez, A.; Boxer, S. G.; Burns, N. Z. J. Am. Chem. Soc. 2016, 138,
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Experimental procedures and 1H and 13C NMR spectra
for new compounds (PDF)
(
10) For syn elimination of acyclic β-iodoboronic esters, see:
AUTHOR INFORMATION
Corresponding Author
(a) Armstrong, R. J.; García-Ruiz, C.; Myers, E. L.; Aggarwal, V. K.
Angew. Chem., Int. Ed. 2017, 56, 786. (b) Aggarwal, V. K.; Binanzer,
M.; de Ceglie, M. C.; Gallanti, M.; Glasspoole, B. W.; Kendrick, S. J.
F.; Sonawane, R. P.; Vazquez-Romero, A.; Webster, M. P. Org. Lett.
́
2011, 13, 1490. For a related example involving boranes, see: LaLima,
N. J.; Levy, A. B. J. J. Org. Chem. 1978, 43, 1279.
■
*
E-mail: v.aggarwal@bristol.ac.uk.
ORCID
Roly J. Armstrong: 0000-0002-3759-061X
Varinder K. Aggarwal: 0000-0003-0344-6430
Author Contributions
(11) We have previously observed triple addition of vinyl Grignard
reagents and employed the resulting trivinyl boronate complexes in the
Zweifel coupling of tertiary boronic esters; see: Sonawane, R. P.;
Jheengut, V.; Rabalakos, C.; Larouche-Gauthier, R.; Scott, H. K.;
Aggarwal, V. K. Angew. Chem., Int. Ed. 2011, 50, 3760.
†
R.J.A. and W.N. contributed equally.
Notes
(
12) (a) Zhang, L.; Lovinger, G. J.; Edelstein, E. K.; Szymaniak, A. A.;
The authors declare no competing financial interest.
Chierchia, M. P.; Morken, J. P. Science 2016, 351, 70. (b) Lovinger, G.
J.; Aparece, M. D.; Morken, J. P. J. Am. Chem. Soc. 2017, 139, 3153.
(c) Edelstein, E. K.; Namirembe, S.; Morken, J. P. J. Am. Chem. Soc.
ACKNOWLEDGMENTS
■
2
(
017, 139, 5027.
13) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.;
Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed.
003, 42, 4302.
14) Wang, Y.; Noble, A.; Myers, E. L.; Aggarwal, V. K. Angew. Chem.,
We thank EPSRC (EP/I038071/1) and Bristol University for
financial support. W.N. thanks the Development and
Promotion of Science and Technology (DPST) Thailand for
a Ph.D. studentship. We are grateful to Dr Yunfei Luo (Hefei
University of Technology) for providing us with a sample of a
steroidal vinyl iodide. We thank Prof. Tim Gallagher (Bristol
University) and Dr. Eddie L. Myers (Bristol University) for
helpful discussions.
2
(
Int. Ed. 2016, 55, 4270.
(15) Heating the β-iodoboronic ester in the presence of NaOMe
produced a small amount of the desired alkene along with side
products resulting from substitution and E2 elimination (see the SI for
details).
(
(
16) Koch, V.; Nieger, M.; Bras
17) With aromatic migrating groups, an alternative pathway
̈
e, S. Adv. Synth. Catal. 2017, 359, 832.
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DOI: 10.1021/acs.orglett.7b01124
Org. Lett. XXXX, XXX, XXX−XXX