Catalyst-Free Enantiospecific Olefination with In Situ Generated Organocerium Species

Article abstract of DOI:10.1002/anie.201810327

Described is the in situ formation of triorganocerium reagents and their application in catalyst-free Zweifel olefinations. These unique cerium species were generated through novel exchange reactions of organohalides with n-Bu₃Ce reagents. The adequate electronegativity of cerium allowed for compensating the disadvantages of both usually functional-group-sensitive organolithium species and less reactive organomagnesium reagents. Exchange reactions were performed on aryl and alkenyl bromides, enabling enantiospecific transformations of chiral boron pinacol esters. Finally, these new organocerium species were engaged in selective 1,2-additions onto enolisable and sterically hindered ketones.

Full text of DOI:10.1002/anie.201810327

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Accepted Article
Title: Catalyst-Free Enantiospecific Olefination with in-situ Generated
Organocerium Species
Authors: Dorian Didier, Arif Music, Clément Hoarau, Nicolas Hilgert,
and Florian Zischka
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810327
Angew. Chem. 10.1002/ange.201810327
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Catalyst-Free Enantiospecific Olefination with in-situ Generated
Organocerium Species
Arif Music,[a] Clément Hoarau,[b] Nicolas Hilgert,[a] Florian Zischka,[a] Dorian Didier*[a]
Dedicated to Prof. Henri Kagan
Abstract: Described is the in-situ formation of triorganocerium
reagents and their implications in catalyst-free Zweifel olefinations.
These unique cerium species were generated through novel
exchange reactions of organo-halides with n-Bu3Ce reagents. The
adequate electronegativity of cerium allowed for compensating both
disadvantages of usually functional group sensitive organolithium
species and less reactive organomagnesium reagents. Exchange
reactions were performed on aryl and alkenyl bromides, enabling
enantiospecific transformations of chiral boron pinacol esters. Finally,
these new organocerium species were engaged in selective 1,2-
additions onto enolizable and sterically hindered ketones.
The endeavour to tune the reactivity of organometallic reagents
was recently taken on by the same group, describing an
interesting formation of Csp2-organolanthanum reagents through
double exchanges.[5]
If organolithium species have proven to be very reactive,
functional group tolerance has often been a major drawback in
structural diversification. In comparison, organomagnesium
reagents are usually more functional group tolerant, while
showing decreased reactivity (Scheme 1). Zweifel olefination
stands as a typical illustration for this lower reactivity.[6] The issue
arises from the difficulty of achieving full conversion into the key
boron-ate complex intermediates. Elegant alternatives have been
developed by the group of Aggarwal who showed that addition of
DMSO could drive the reaction to completion,[7] and the group of
Morken who used sodium triflate as a “Grignard activator”.[8]
Halogen-metal exchange is one of the most efficient routes to
preparing organometallic species. Following early findings of
Prévost on bromide-magnesium permutation,[1] Gilman and Wittig
subsequently described what would later become the halogen-
lithium exchange.[2] Building upon those reliable methods, the
group of Knochel engineered and popularized the efficient “Turbo-
Grignard” reagent (i-PrMgCl·LiCl) that considerably facilitated the
access to organomagnesium intermediates and their implications
in organic transformations.[3] Although zinc and copper species
can also be generated through exchange reactions,[4] convenient
transmetallations with ZnCl2 or copper salts have usually been
favoured.
Table 1. Optimizations on Br/Ce exchanges.
RLi
x (equiv.)
1 (1.1)
2 (2.2)
3 (3.3)
3 (3.3)
3 (3.3)
RxCeCl3-x
n-BuCeCl2
n-Bu2CeCl
n-Bu3Ce
Me3Ce
conv. (%)[a]
n-BuLi
n-BuLi
n-BuLi
MeLi
97
95
93 (86)[b][c]
30
s-BuLi
s-Bu3Ce
55
[a] Assessed by GC after hydrolysis with H2O. [b] Isolated yields of 6a, after
Zweifel olefination with (3,6-dihydro-2H-pyran-4-yl)boronic ester. [c] Reaction
performed in the absence of cerium chloride only afforded 6a in 75% yield.
Aiming to find reagents that would balance both advantages of
reactive organolithium reagents and functional group tolerant
organomagnesium species, we began our quest towards
unexplored organometallics from across the periodic table. We
envisioned that adjusting the Pauling electronegativity of the
element by choosing an intermediate value between lithium (=
0.98) and magnesium ( = 1.31) would be a first step in this
ambitious study. As many elements could fulfil this condition, we
logically selected the most abundant and inexpensive cerium
atom ( = 1.12) for the generation of new organometallic
species.[9] To the best of our knowledge, while organocerium
derivatives were already obtained via transmetalations by the
group of Imamoto, no example of halogen-cerium exchanges was
Scheme 1. Halogen-metal exchanges: from the discovery to our contribution.
[a]
A. Music, N. Hilgert, F. Zischka, Dr. D. Didier
Department Chemie
Ludwig-Maximillians-Universität
Butenandtstraße 5-13, D-81377 Munich
E-mail: dorian.didier@cup.uni-muenchen.de
[b]
C. Hoarau
Ecole Polytechnique
Route de Saclay
91128 Palaiseau Cedex
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ever reported, hence the interest of our method. Importantly,
organocerium reagents were rarely employed in other reactions
than 1,2-additions to carbonyl compounds.[10]
upon addition of a base (NaOMe), yielding the formal coupling
product 4.
Our results are twofold. First, optimizations were undertaken by
changing both nature and amounts of alkyllithium species used in
the formation of alkylcerium derivatives in order to tune their
efficiency in halogen-cerium exchanges. Second, in-situ
generated aryl- and alkenylcerium species were employed in
Zweifel olefinations. Aryl- and alkenylbromides were used in this
Scheme 2. Zweifel olefination – general mechanism.
catalyst-free
transformation,
to
ultimately
showcase
enantiospecific transformations of chiral organoboronates.
The exchange reagents RxCeCl3-x were generated in-situ by
mixing alkyllithium (RLi) and CeCl3 for 15 min at -30 °C in THF.
They were further used for Br/Ce exchanges with 1-bromo-4-
chlorobenzene as a test substrate. As shown in Table 1, moderate
exchanges were observed when employing secondary alkyl or
methylcerium reagents. Improved results were observed with
mono-, di- and tri-n-butylcerium species. For the sake of atom
economy, the most performing tributylcerium reagent was chosen
to pursue our study. The initial formation of alkyl-cerium species
was supported by Raman spectroscopy, excluding the presence
of parasitic n-BuLi in the reaction (Figure 1).[11]
Figure 1. Comparative Raman spectra of different metallic salts and
organometallic species.
Measuring samples at low temperature allowed us to directly
compare the spectra of n-BuLi (b) and the mixture (a) of n-BuLi
(3 equiv.) and CeCl3. While none of the representative
wavenumbers of n-BuLi (350 cm-1 and 500 cm-1) were detected in
(a), the Raman spectra shows a new significant band appearing
at 420 cm-1, indicating the formation of a novel species. This
observation and the absence of both CeCl3 and n-BuLi vibrations
point to the existence of an alkyl-cerium bond, which was
additionally correlated with theoretical calculations.[12]
In Zweifel’s olefination, recently revisited by Aggarwal and
coworkers,[6,7] an in-situ generated vinyl-organoborinate 1 reacts
with iodine to form an iodonium intermediate 2 with the
Scheme 3. Zweifel olefination of in-situ generated arylcerium species through
triple halogen-cerium exchange. a) 0.37 equiv. b) 0.85 equiv. of alkenylboronic
ester; THF, -50 °C to rt, 40 min. c) I2 (1.5 equiv.), 0 °C, 15 min; NaOMe
(5.0 equiv.), to rt, 30 min. d) Isolated yield when the reaction was performed in
the absence of CeCl3·2LiCl.
electroenriched alkenyl moiety, triggering
a 1,2-metallate
rearrangement of R1 (Scheme 2). A -elimination takes place
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On the basis of afore mentioned optimizations (Table 1), 1-bromo-
4-chlorobenzene (1.0 equiv.) was used in the presence of
0.37 equiv. of n-Bu3Ce to perform a triple exchange and lead to
the tri-arylcerium 5 (Scheme 3). Interestingly, this unprecedented
species reacted quantitatively with a cyclic alkenylboronic ester to
in-situ generate the alkenylborinate intermediate. After
successive introduction of iodine and sodium methylate, the
olefinated product 6a was isolated in 86% yield. No excessive
amounts of organocerium were needed to complete the
transformation, providing an elegant alternative that balances
reactivity and functional group tolerance.
Acyclic alkenylboronic esters were examined next. Following the
same procedure for the in-situ generation of arylcerium species,
reactions were pursued with the introduction of stereodefined
alkenylboron derivatives.[13] Further rearrangement of the ate-
complex in the presence of iodine and base gave the desired
polysubstituted alkenes 8a-f with expected inversion of
configuration (Scheme 4) in high yields up to 89% and E/Z ratios
up to 1:99.[12]
Although we demonstrated organocerium reagents to be more
reactive than organomagnesium and more tolerant than
organolithium, the challenge was not restricted to the use of aryl
groups for the exchange/Zweifel sequence. Next, we examined
the propensity of alkenylbromides to undergo permutations, and
be engaged in subsequent catalyst-free coupling reactions
(Scheme 5). -Bromostyrene was used as model substrate in this
transformation, as well as the parent vinyl bromide and propenyl
bromide.
With a successful proof of concept in hands, we started exploring
the scope of the transformation.
A
carbonyl-substituted
alkenylboronic ester afforded the desired product 6b in 50% yield.
Importantly, we could demonstrate the difference in functional
group tolerance between cerium and lithium species by
employing an amide substituted substrate. Organocerium
furnished the desired product 6c in 52% yield while the
corresponding organolithium only gave 11%. With electron
enriched aromatics (p-OMe), N-Boc tetrahydropyridyl (6d)
reacted similarly, giving the expected product in good yields
(61%). Other electron-donating or -withdrawing substituents on
the starting aryl-bromides did not influence the outcome of the
transformation as m-silyl, o-fluoro and o-cyano yielded 6e-g in 67
to 72% and disubstituted benzenes gave 6h and 6i in 62 to 64%.
Heteroaromatics were also engaged in the exchange/Zweifel
sequence, furnishing 5-benzofuranyl, 5-indolyl and 3-
benzothiophenyl 6j-m with up to 78% yield. Moreover, substituted
isoxazole, thiazole, pyridine and quinoline derivatives afforded the
corresponding trisubstituted alkenes 6n-t with high yields up to
87%. Full conversions were also observed with the more
challenging dimethoxypyrimidine derivative, giving 6u in 88%
yield. Importantly, similar yield was obtained when performing the
reaction on a 5 mmol scale (1.2 g, 87%).
Scheme 5. Zweifel olefination of in-situ generated alkenylcerium species
through triple halogen-cerium exchange. a) 0.37 equiv. b) 0.85 equiv. of
arylboronic ester; THF/Et2O (1:1), -50 °C to rt, 40 min. c) I2 (1.5 equiv.), -50 °C,
15 min; NaOMe (5.0 equiv.), to rt, 30 min.
Tri-alkenylcerium species 9 were generated under optimized
conditions (see Table 1) and used in-situ for the formation of
corresponding alkenylborinates with arylboronic esters. The
reaction of tri-vinylcerium with a chlorinated phenylboron pinacol
afforded product 10a in 69% after successive addition of iodine
and base. Consistent results were observed when propenyl
bromide and 1-(bromovinyl)trimethylsilane were used as the
substrates in the exchange reactions, since 10b,c were obtained
in up to 68% yield. The procedure proved to be quite functional
group tolerant as diversely substituted aromatics furnished
Scheme 4. Zweifel olefination of stereodefined alkenylboronic esters. a) Same
conditions as for scheme 2; E/Z ratios determined by GC. b) Starting from
alkenylboron pinacol with E/Z = 88:12.
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reasonable yields (10d-f, 44 to 69%), including nitriles (10f) and
esters (10d,e), when employing -bromostyrene. Our procedure
also allowed for the efficient formation of functionalized
heterocyclic dienes (10g-i) in good yields up to 72%, using
alkenylboronic esters. The introduction of heteroarylboronic
esters for the intermediate formation of the boron-ate complexes
with in-situ generated tri-alkenylcerium species led to the
corresponding heteroaryl alkenes. Alkenyl-pyridine, thiophene
and pyrazole 10j-l were isolated in good yields up to 80%.
Employing a naturally occurring -pinene derivative[16] in the
sequence afforded 11h as
a
single enantiomer and
diastereoisomer in 63% yield.
Taking advantage of an efficient preparation of organocerium
species, we finally set out to demonstrate their more general
applicability as nucleophiles in 1,2-additions onto diverse ketones.
Cerium salts have been used in the past to selectively promote
nucleophilic additions of organometallic reagents to hindered
carbonyl systems, avoiding parasitic enolization or conjugate
additions.[10] (+)-Camphor was first employed as a hindered
ketone. As shown in Scheme 7, the tertiary alcohol 12a resulting
from the addition of tri(thiazol)cerium species was obtained in
86% yield. Other enolizable systems such as bicyclo[2.2.2]octan-
2-one and acetophenone also gave reasonable yields in the
formation of the corresponding alcohols (12b,c). (-)-Verbenone
was used as an ,-unsaturated ketone and 12d,e were
selectively obtained in good yields up to 84%, showing no trace
of the Michael addition product. Lastly, good conversion into the
tertiary alcohol 12f was achieved when using the hindered
hexamethylacetone as an electrophile.
Next, we examined the propensity of alkenylcerium reagents to
undergo stereospecific Zweifel olefinations with stereodefined
organoboronic esters. Enantioenriched secondary alkylboron
species were synthesized following the copper-catalysed
enantioselective hydroboration of alkenes described by Lee and
Yun.[14] Halogen-cerium exchanges were performed, followed by
conversion to the bisorganoborinate and subsequent iodonium
formation to undergo
a
stereospecific
1,2-metallate
rearrangement. Addition of the base triggered the regeneration of
the double bond upon -elimination. Enantioenriched benzylic
boron pinacols furnished Zweifel products 11a-e for both
enantiomers with complete retention of configuration (er > 99:1)
and high yields (up to 98%).
Scheme 7. One-pot sequence of Br/Ce exchange and 1,2-addition onto ketones.
a) 0.37 equiv. b) 0.85 equiv. of ketone, THF, -50 °C to rt.
In summary, a step forward in the challenge of combining
reactivity and functional group tolerance was achieved, enabling
considerable scope extensions of sensitive reactions. The
development of unprecedented organometallic species through a
very efficient triple halogen-cerium allowed for
a
wide
exemplification of the catalyst-free Zweifel olefination. Additionally,
we demonstrated the ability of these unique in-situ generated
organocerium reagents to undergo stereospecific transformations
in one-pot sequences, as well as selective 1,2-additions to
challenging ketones.
Scheme 6. One-pot stereospecific Zweifel olefination of alkenylcerium species.
a) 0.37 equiv. b) 0.85 equiv. of boronic ester; THF/Et2O (1:1), -50 °C to rt, 40
min. c) I2 (1.5 equiv.), -50 °C, 15 min; NaOMe (5.0 equiv.), to rt, 30 min.
Alternatively, diastereomerically pure boronic esters[15] were also
employed in this catalyst-free olefination, giving desired alkenes
in moderate to good yields and total retention of diastereomeric
ratios (dr > 99:1). Cyclic and acyclic substrates gave access to
functionalized alkyl systems 11f,g with up to 77% yield.
Experimental Section
Experimental procedures and spectroscopic characterization (IR, HRMS,
and 1H and 13C NMR data) of all new compounds available.
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Acknowledgements
Prof. Andreas Kornath (LMU Munich) is gratefully acknowledged
for his help with Raman spectroscopy and for technical support.
The authors would like to thank the Chemical Industry Fund (FCI),
the Deutsche Forschungsgemeinschaft (DFG grant: DI 2227/2-1),
the Sonder Forschungsbereich (SFB749) and the Ludwig-
Maximilians University of Munich (LMU) for financial support.
Keywords: Organocerium • Halogen-metal exchange • Catalyst-
free • Zweifel olefination • Enantiospecific
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Arif Music, Clément Hoarau, Nicolas
Hilgert, Florian Zischka, Dorian Didier*
Page No. – Page No.
Catalyst-Free Enantiospecific
Vinylation of in-situ Generated
Organocerium Species
A cerium way to tolerance: Unprecedented halogen-cerium exchanges have
unlocked a path to new organometallic species with high functional group tolerance.
The versatility of such a process was efficiently applied to enantiospecific catalyst-
free Zweifel olefinations.
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