German Edition:DOI:10.1002/ange.201909852
C–C Bond Formation International Edition:DOI:10.1002/anie.201909852
Lewis Acid Catalyzed Transfer Hydromethallylation for the
ConstructionofQuaternary Carbon Centers
Johannes C. L. Walker and Martin Oestreich*
Abstract: The design and gram-scale synthesis of acyclohexa-
1,4-diene-based surrogate of isobutene gas is reported. Using
the highly electron-deficient Lewis acid B(C6F5)3,application
of this surrogate in the hydromethallylation of electron-rich
styrene derivatives provided sterically congested quaternary
carbon centers.The reaction proceeds by C(sp3)@C(sp3)bond
formation at atertiary carbenium ion that is generated by
alkene protonation. The possibility of two concurrent mech-
anisms is proposed on the basis of mechanistic experiments
using adeuterated surrogate.
The catalytic preparation of quaternary carbon centers using
C(sp3)@C(sp3)bond-forming reactions has been identified as
akey challenge in organic synthesis.[1] Recent progress in this
area has mainly centered on transition-metal-catalyzed trans-
formations.[2–4] Metal-free approaches are less common.[5,6]
One strategy to achieve C(sp3)@C(sp3)bond formation is the
attack of acarbon nucleophile onto atertiary carbenium
ion.[7,8] Although this has been exploited in the context of
carbenium ion generation by dehydration of tertiary alcohols
with catalytic amounts of strong acid,[5,6,9] the complementary
process by catalytic protonation of alkenes is far less well
explored.[10,11]
Our laboratory has been investigating cyclohexa-1,4-
diene-based surrogates of difficult-to-handle compounds for
metal-free transfer reactions.[12–15] As part of this program we
previously developed cyclohexa-1,4-dienes 5and 6as surro-
gates of isobutane gas and reported their use in the transfer
hydro-tert-butylation of alkenes using the strong boron Lewis
acid B(C6F5)3(Scheme 1, top).[14,16] Hydride abstraction from
the bisallylic position of the surrogates led to formation of the
tert-butyl-substituted Wheland intermediates 7+and transfer
of the electrofugal tert-butyl group to the terminus of 1,1-
diaryl-substituted alkenes.Borohydride addition to the
resulting benzylic tertiary carbenium ion delivered formally
anti-Markovnikov alkylation products such as 2.However,
this process was hampered by side reactions to give 3and 4,
and the substrate scope was quite limited.
We wondered whether an appropriately substituted cyclo-
hexa-1,4-diene would facilitate abstraction of anucleofugal
hydrocarbon group and then lead to the complementary
Markovnikov hydroalkylation.[17] In seeking aplausible
hydrocarbon unit, we were interested in areport by M8nard
und Stephan who had achieved the stoichiometric C@H
activation of isobutene with the frustrated Lewis pair tBu3P/
B(C6F5)3(Scheme 1, middle).[18] Themethallyl borate 8@
formed represents apotential nucleophilic source of the
methallyl group,[19,20] and we hoped that acyclohexa-1,4-diene
surrogate of isobutene gas could be developed to allow for the
abstraction of the methallyl nucleofuge by B(C6F5)3to give 8@
and aBrønsted acidic Wheland intermediate.Interception of
this complex by an alkene might then allow for transfer
Scheme 1. Cyclohexa-1,4-diene-based surrogates of isobutane and iso-
butene gas for metal-free transfer hydroalkylation and -allylation,
respectively.
[*] Dr.J.C.L.Walker,Prof. Dr.M.Oestreich
Institut ffrChemie, Technische Universit-tBerlin
Strasse des 17. Juni 115, 10623 Berlin (Germany)
E-mail:m[email protected]
Homepage:http://www.organometallics.tu-berlin.de
Supportinginformation and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201909852.
T2019 The Authors. Published by Wiley-VCH Verlag GmbH &Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial License, which permits use,
distribution and reproduction in any medium, provided the original
work is properly cited, and is not used for commercial purposes.
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hydromethallylation and the formation of aquaternary
carbon center by way of C(sp3)@C(sp3)bond formation
(Scheme 1, bottom).[21–23]
Therequired surrogate would likely necessitate aquater-
nary center adjacent to the methallyl group to prevent
undesired side reactions such as transfer hydrogenation,[24]
as well as to help stabilize the positively charged Wheland
intermediate.Surrogates 9and 10 fulfill this requirement and
were easily accessible by Birch alkylation from benzoic acid
and biphenyl, respectively (see the Supporting Information
for experimental details). We then subjected the surrogates to
amodel reaction with 1,1-diphenylethene (1a)and 10 mol%
B(C6F5)3in CH2Cl2(Table 1, entry 1). Benzyl ether based
surrogate 9did not give any of the desired hydromethallyla-
tion product 11a,instead providing indane 12a in 6% yield;
12a presumably results from the intramolecular Friedel–
Crafts alkylation of 11a.[25] Biphenyl-based surrogate 10 was
more reactive,forming the intended product 11a in 3% and
indane 12a in 40%yield (entry 2). Switching the solvent to
toluene improved the selectivity for 11a (entry 3). We
eventually established that electron-rich styrene derivatives
allowed the reaction to proceed to full conversion, and we
could suppress cyclization to indanes 12 by modifying the
steric environment of the alkene.Using para-anisyl-substi-
tuted alkene 1b,wewere initially able to form 11b in 82%
yield with no indane 12b observed (entry 4). Theloading of
both surrogate 10 and B(C6F5)3could be reduced with no
detrimental impact on the yield, and 11b was then isolated in
82%yield (entry 5). Thereaction could also be scaled up to
1.00 mmol (entry 6). No reaction occurred in the absence of
the catalyst (entry 7), but interestingly,B(C6F5)3was able to
partially decompose surrogate 10 to biphenyl in the absence
of the alkene starting material (entry 8).
With optimized conditions in hand, we proceeded to
investigate the substrate scope (Scheme 2). Arange of
electron-rich a-substituted styrenes could be used, with
benzyl ethers as in 11cand cyclic ethers as in 11dboth
tolerated. Theindane-based alkene 11e could be prepared in
92%yield and, using this framework, an exocyclictrisub-
stituted alkene could also be reacted to give 11 f in 92%yield.
As previously observed in other transfer reactions,tetrasub-
stituted alkenes were unreactive.[12,13] Products bearing two
contiguous quaternary carbon centers could be accessed, with
Table 1: Optimization of the B(C6F5)3-catalyzed transfer hydrometh-
allylation.[a]
Entry Alkene Surrogate B(C6F5)3
[mol%]
Solv.Yield of
11 [%][b]
Yield of
12 [%][b]
11a 9 10 CH2Cl2<16
21a 10 10 CH2Cl2340
31a 10 10 PhMe 32 11
41b 10[c] 10 PhMe 82 <1
51b 10 5.0 PhMe 85 (82)[d] <1
6[e] 1b 10 5.0 PhMe 74[d] <1
71b 10 –PhMe <1<1
8[f] 1b 10 5.0 PhMe <1[f] <1
[a] Unless otherwise noted, reactions were performed on a0.10 mmol
scale with 1.3 equiv 9or 10 in 0.25 mL (0.4m)ofthe indicated solvent.
[b] Determined by 1HNMR spectroscopy by the addition of 1,2-
dibromomethane as an internal standard. [c] 1.5 equiv surrogate 10
used. [d] Yield of isolated product. [e] On a1.0 mmol scale. [f]Alkene 1b
was not added. 22%conversion of surrogate 10 to biphenyl.
Scheme 2. Scope of the B(C6F5)3-catalyzed transfer hydromethallylation
of alkenes.Method A:B(C6F5)3(5.0 mol%), surrogate 10 (1.3 equiv);
Method B: B(C6F5)3(5.0 mol%), surrogate 10 (2.0 equiv);Method
C:B(C6F5)3(7.5 mol%), surrogate 10 (2.0 equiv).
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11g formed in 94%yield. Here,slightly higher loadings of
B(C6F5)3and surrogate 10 were required to push the reaction
to completion. These conditions found further application
with other less reactive substrates.Increased substitution at
the a-position of the styrene was also tolerated, as in 11h–j,
although in these cases cyclization to indanes 12h–jcould not
be completely suppressed;the proportion of indanes 12h–j
increased with the size of the a-substituent. Performing the
reaction with two equivalents of surrogate 10 did help to
reduce the extent of cyclization; 11h and 12h were,however,
formed in a3:1 mixture with 1.3 equiv surrogate 10.A
substrate bearing the bulky tert-butyl group in the a-position
was unreactive.Cyclic alkanes containing quaternary carbon
centers could also be synthesized using this methodology,with
cyclohexane 11k and cycloheptane 11l being formed in 89%
and 95%yield, respectively.Finally,aseries of compounds
bearing pendant aryl groups was prepared. Phenyl-substi-
tuted 11m was formed in 85%yield, and products with
halogen substituents,asin11n and 11o,aswell as an electron-
donating methoxy substituent, as in 11p,could also be
accessed. To illustrate the utility of these products,aselection
of these compounds were further derivatized (see the
Supporting Information for details).
To gain insight into the reaction mechanism, we prepared
deuterated surrogate a-10-d2(Scheme 3; see the Supporting
Information for experimental details). Although this surro-
gate was deuterated solely at the allyl terminus (g-position),
its reaction with alkene 1b produced 11b-d2with deuterium
incorporation in both the a-and g-positions.This suggests the
presence of at least two concurrent mechanisms (see the
Supporting Information for more elaborate catalytic cycles).
First, based on the work of M8nard and Stephan,[18] we
propose that alkene attack from surrogate a-10-d2to B(C6F5)3
results in abstraction of the methallyl group and formation of
a-deuterated methallyl borate complex [g-8-d2]@along with
protonated biphenyl [H·C12H10]+(Scheme 3, Pathway 1).
Protonation of alkene 1b by the Brønsted acidic Wheland
complex yields the tertiary carbenium ion 13+with concom-
itant aromatization of the surrogate core to biphenyl. Transfer
of the methallyl group from methallyl borate [g-8-d2]@to 13+
then provides g-deuterated alkene a-11b-d2with formation of
aC(sp3)@C(sp3)bond. Alternatively,direct transfer of the
methallyl fragment from a-10-d2to carbenium ion 13+would
result in the formation of the regioisomer g-11b-d2with
deuteration in the a-position (Pathway 2). In this scenario,
B(C6F5)3operates as an initiator and methallyl borate [g-8-
d2]@as aspectator counteranion. Thedual role of B(C6F5)3as
catalyst and initiator in transfer chemistry has previously been
discussed on the basis of computational calculations.[26]
Another pathway to arrive at g-11b-d2is the transfer of the
methallyl group between two boron centers (see Pathway 3in
the Supporting Information). This would lead to g-deuterated
a-8-d2,and attack of the methallyl group onto carbenium ion
13+then provides g-11b-d2.Ithas not yet been possible to
distinguish between the two possible pathways leading to g-
11b-d2.
To summarize,acyclohexa-1,4-diene-based surrogate of
isobutene gas has been developed and utilized in the transfer
hydromethallylation of electron-rich styrene derivatives.The
method enables the catalytic formation of sterically congested
quaternary carbon atoms and represents arare example of the
formation of C(sp3)@C(sp3)bonds from carbenium ions that
have been formed by the protonation of an alkene.Arange of
different scaffolds could be incorporated, and the utility of the
products was demonstrated by their derivatization.
Acknowledgements
J.C.L.W.gratefully acknowledges the Alexander von Hum-
boldt Foundation for aTheodor Heuss fellowship (2018–
2019). M.O.isindebted to the Einstein Foundation Berlin for
an endowed professorship.
Conflict of interest
Theauthors declare no conflict of interest.
Keywords: boron ·carbocations ·C–C bond formation ·
Lewis acids ·transfer processes
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Manuscript received:August 4, 2019
Acceptedmanuscript online: August 26, 2019
Version of record online: September12, 2019
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