Hydroalkylation of Olefins to Form Quaternary Carbons

Article abstract of DOI:10.1021/jacs.9b02844

Metal-hydride hydrogen atom transfer (MHAT) functionalizes alkenes with predictable branched (Markovnikov) selectivity. The breadth of these transformations has been confined to π-radical traps; no sp³ electrophiles have been reported. Here we describe a Mn/Ni dual catalytic system that hydroalkylates unactivated olefins with unactivated alkyl halides, yielding aliphatic quaternary carbons.

Full text of DOI:10.1021/jacs.9b02844

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Communication
Hydroalkylation of Olefins to form Quaternary Carbons
Samantha A Green, Tucker R. Huffman, Ruairí O. McCourt, Vincent van der Puyl, and Ryan A. Shenvi
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Apr 2019
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Hydroalkylation of Olefins to form Quaternary Carbons
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Samantha A. Green, Tucker R. Huffman, Ruairí O. McCourt, Vincent van der Puyl, Ryan A. Shenvi*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037,
United States
Supporting Information Placeholder
catalytic platform to allow for the hydroarylation of
unactivated olefins6b,c as well as the addition of
carbanion surrogates to aldehydes,8 yielding branched-
selective products otherwise inaccessible by tradition
radical reactions. A dual catalytic approach for the
hydroalkylation of olefins would allow us to use known
alkyl coupling partners (e.g. alkyl halides9, carboxylic
acids10) in lieu of alkyl radical traps, and cross a
longstanding methodological gap.
ABSTRACT: Metal-hydride hydrogen atom transfer
(MHAT) functionalizes electronically unbiased alkenes
with predictable branched (Markovnikov) selectivity.
The breadth of these transformations has been confined
to π-radical traps; no sp3 electrophiles have been
reported. Here we describe a Mn/Ni dual catalytic
system that hydroalkylates unactivated olefins with
unactivated alkyl halides, yielding aliphatic quaternary
carbons.
A. Previous Hydroalkylation via MHAT
Giese Reaction
Hydromethylation
Olefins
represent
versatile
feedstocks
and
Fe
Fe
R2 R3
R3
R2
R3
H
R1
intermediates for chemical synthesis. Metal-hydride
hydrogen atom transfer (MHAT) has emerged as a
useful reaction platform for the branched-selective
Me
SO2n-Oct
R1
R1
R2
H
HN
NH2
then MeOH, 60 °C
+
EWG
EWG
CH2O
hydrofunctionalization
of
olefins.
Its
high
chemoselectivity for olefins and mild reaction conditions
have allowed its deployment in medicinal chemistry and
natural product synthesis.1 The bulk of these
transformations involve carbon–heteroatom bond
formation, whereas intermolecular C–C formation has
been relatively unexplored and has largely required
stoichiometric radical traps by π-electrophiles.
Pioneering advances in the formation of C–C bonds are
represented by hydrocyanations and hydrooximation
from Carreira2 and Boger.3 More recently, Baran and
coworkers developed a powerful variant of the Giese
reaction4,7d as well as a two-step procedure for
hydromethylation (Figure 1A).5 Finally, our group6 and
others7 have investigated the branched-selective
hydroarylation of olefins using MHAT, establishing
olefins as progenitors for arylated quaternary centers.
B. Nickel-catalyzed cross-coupling with olefins
Branched-selective (HAT/Ni: this work)
Linear-selective
R1
Me
Mn
Ni
Ni
R1
X
R1
R3
R3
+
R3
R2
R2
R2
• sp3–sp3 coupling
• non-directed and unbiased alkenes
• di-, tri-, and tetrasubstitution
• Liu, Fu, Martin and others
• anti-Markovnikov
• terminal, some internal olefins
Figure 1. Prior hydroalkylation reactions using (a)
MHAT and (b) Ni catalysis.
Markovnikov hydroalkylation would also provide a
new transform to dissect quaternary carbons, which
remain challenging motifs in natural products and drug
scaffolds. While radical chemistry has emerged as a
useful platform for the construction of sterically
congested motifs,11,12 sp3–sp3 cross-coupling remains an
One contributing factor to the limited range of
Markovnikov hydro-alkylations is a dearth of alkyl
radicalophiles. Whereas MHAT has relied historically
on stoichiometric radical traps such as O2,1a our group
has become interested in combining MHAT with a
second catalytic cycle, thereby expanding the variety of
coupling partners.1b Recently, we established a dual
underdeveloped
area
for
quaternary
carbon
formation.9a,13 The use of nickel catalysis to generate
and engage open-shell intermediates has been
revolutionized by Fu,9a,14 but its use in the construction
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of quaternary carbons has only recently been
Page 2 of 9
Our previous method to form arylated quaternary
centers6c led us to hypothesize that our reaction design
might translate to alkylation. Namely, an MHAT-
generated tertiary radical or organometallic could be
intercepted by a low valent nickel species, which could
subsequently engage with an alkyl halide (or alkylnickel
species) and yield our desired product upon reductive
elimination (Figure 2A).10b,21 Regeneration of low valent
nickel may proceed through formation of Ni–H via
silane or Mn–H.
described,6c,15,16 with the development of alkylation
reactions restricted to stabilized radicals17 or Giese
reactions.18 Recently, olefins have become viable
coupling partners in reductive coupling19 and nickel
catalysis as surrogates for organometallic reagents.17,20
Whereas these nickel hydride-mediated methods yield
anti-Markovnikov (linear) hydrofunctionalized products,
MHAT dual catalysis provides access to branched
products, even quaternary carbons, using similarly
benign starting materials and conditions (Figure 1B).
Herein we describe an approach for the hydroalkylation
of unactivated olefins using Mn/Ni dual catalysis.
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A successful Markovnikov olefin coupling would
require an override of the inherent anti-Markovnikov
migratory insertion found in Liu20a and Fu’s17 Ni–H
systems. Unfortunately, initial attempts to utilize our
Fe/Ni system6c that provides such override yielded only
trace product (Figure 2B). A polar solvent screen,
however, indicated propylene carbonate (PC)22 was
superior to N-methylpyrrolidinone (NMP). Curiously,
PC as a co-solvent obviated the need for Mn0 and MnO2
co-reactants, which we proposed to turn over the
catalytic cycles. Instead the reaction could be run open
to air.23
A. Envisioned Catalytic Cylce
R
NiILn
Ln-1MnII
Me
O2
R
X
alkyl
R
R
R
X
LnMnIII
Ni
MHAT
Me
NiIIILn
Me
R
alkyl
PhSiH3
Ln-1MnIII
H
Ni0Ln
NiILn
reductant
X
PhSiH2L
R
R
Me
Alkyl iodides coupled efficiently, whereas alkyl
bromides, redox active esters, and sulfones yielded trace
or no product (see SI). A screen of MHAT catalysts
indicated that Mn(dpm)324 outperformed Fe(dpm)3 and
Co(dpm)2. We did observe some product formation in
the absence of Ni, but this background reactivity did not
prove general and the yield could not be improved
without the Ni co-catalyst. Similar to our arylation
chemistry, traditional mono-, di- and tridentate ligands
on Ni either provided no improvement in yield or
ablated reactivity. Preparatively-useful yields were
finally obtained with alcoholic additives: isopropanol led
to marginal improvement and HFIP was found to almost
double the yield. Due to decreased efficiency observed
with Ph(iPrO)SiH2, it is unlikely that the improved yield
is due to an alcohol-silane complex. However, a
noticeable color change from black to rust-red occurs
when HFIP/K2CO3 is added to Mn(dpm)3 in the absence
of silane. Attempts to isolate and characterize this
complex were unsuccessful. We cannot rule out the
formation of a dimeric species bridged by the alcohol
additive.7d,25
alkyl
R
R
B. Deviations from Standard Conditions
O
O
Mn(dpm)3 (20 mol %)
Ni(acac)2 (2.5 mol %)
Me
PMBO
+
PMBO
I
PhSiH3 (3 equiv),
HFIP (2 equiv),
K2CO3 (1 equiv),
1,2-DCE/ PC, rt
Me
Me
TBSO
2b (77%)
TBSO
1 (1 equiv.) 2a (2.5 equiv.)
open to air
Entry
Deviations from Above
none
Fe(dpm)3 instead of Mn(dpm)3
no Mn(dpm)3
Yield %a
77 (72)b
0 (20)c
none
20 (trace)d
55
1
2
3
4
5
6
7
8
9
no Ni(acac)2
no K2CO3
no HFIP
36
55
54
no propylene carbonate (PC)
iPrOH instead of HFIP
Ph(i-PrO)SiH2 instead of PhSiH3
50 (27)c
Figure 2. (a) Plausible catalytic cycle for the
hydroalkylation of olefins. (b) Optimization parameters.
a0.1 mmol scale, yield determined by GC-FID using
With optimized conditions in hand we began to
investigate the breadth of olefin compatibility (Table 1,
2–28). The para-methoxybenzyl ester of 4-iodobutyric
acid (1) allowed the clear identification of products by
both UV/VIS and mass spectrometry.26 While our
interest was on the formation of quaternary centers, we
were pleased to find that all variants of olefin
substitution were well-tolerated (2–10) and even
tetrasusbtituted olefins coupled, albeit in diminished
b
1,3,5-trimethoxybenzene as an internal standard. 0.3
mmol scale, isolated yield 15:1 branched (b): linear (l)
product. no HFIP. using 2-iodoethyl benzoate instead
of 1. dpm=dipivaloylmethane; HFIP=1,1,1,3,3,3-
c
d
hexafluoro-2-propanol;
PC=propylene carbonate
1,2-DCE=1,2-dichloroethane;
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yield. Overall, the transformation exhibited exquisite
selectivity (15), potentially a result of increased rate of
MHAT due to strain release. Interestingly, terminal
olefins (8–10) were subject to a background linear
reaction, a trend also noted by Carreira with Mn(dpm)3-
mediated transformations.27 Three hypo-
1
2
3
4
5
6
7
8
regiocontrol with tri- and tetrasubstituted olefins
yielding products with high branched-to-linear ratios
(b:l), highlighting the selectivity of our developed
method. Whereas trisubstituted olefins generally
afforded higher regioselectivity than their exocyclic
counterparts (3a vs 3a’), 5-membered rings with
exocyclic alkenes retained the normally high branched-
Table 1. Hydroalkylation Olefin Scopea
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Mn(dpm)3 (20–40 mol %)
Ni(acac)2 (2.5–10 mol %)
PhSiH3 (3 equiv)
1
2
+
I
H
HFIP (2 equiv), K2CO3 (1 equiv)
1,2-DCE/Propylene Carbonate, rt
3
1 equiv
2.5 equiv
open to air
4
5
6
Olefin Substitution
Me
Me
Me
Me
Me
Me
OTBS
R
n
7
8
9
X
8a R = C4H9
9a R = Ph
10a R = OTBS
3a X = CH2
tri 4a X = NBoc
6a n = 1
7a n = 2
1,1 acyclic 2a
1,1 cyclic 3a’
tetra 5a
di
mono
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Me
Me
Me Me
Me Me
Me
Me
R
Me
O
TBSO
X
n
O
OPMB
PMBO
O
O
PMBO
O
O
PMBO
PMBO
PMBO
8b R = C4H9 (55%; 1.5:1 b:l)
9b R = Ph (64%, 2.5:1 b:l)
10b R = OTBS (71%, 1.5:1 b:l)
6b n=1 (68%)b
7b n=2 (57%)
3b (65%, >20:1 b:l)
4b (58%, >20:1 b:l)
2b (73%, 15:1 b:l)
3b (53%, 2:1 b:l)
5b (40%, >20:1 b:l)
O
Et2OC
CO2Me
Me
N
Me
Bpin
Br
Me
Me
OTBS
16a
N
Boc
15a
O
O
O
11a
12a
13a
14a
17a
CO2Me
O
OEt
O
Me
Me Me
Me Me
TBSO
Me Me
Bpin
N
O
Br
Me
Me
O
O
N
Boc
O
OPMB
PMBO
O
PMBO
O
PMBO
O
OPMB
OPMB
OPMB
O
11b (73%, 1.6:1 d.r)
12b (70%, >20:1 b:l)
13b (58%, 4:1 b:l)
14b (51%, >20:1 b:l)
15b (76%, 8:1 b:l)
16b (45%,>20:1 b:l)c
17b (31%, >20:1 b:l)
Natural Products
O
Me
O
Me
TBSO
Me
Me
H
Me
Me
Me
Me
AcO
Me
Me
Me
Me Me
H
Me
dihydrocarvone 18a
limonene oxide 19a
- (20a) & -pinene 20a’
-citronellol 21a
isopulegol 22a
3-carene 23a
O
Me
O
Me
O
TBSO
Me
Me
Me
H
Me
O
Me
Me
Me
OPMB
Me
Me
Me
Me
AcO
H
O
O
OPMB
OPMB
Me
Me
Me
Me
OPMB
OPMB
PMBO
Me
O
O
20b (61% from 
65% from 
3:1 ring open : ring closed)
23b (42%, 4:1 d.r.,
7:1 b:l)
18b (78%, >20:1 b:l)
19b (63%, >20:1 b:l)
21b (71%, >20:1 b:l)
22b (30%, 7:1 b:l)
Me
OBn
Me
Me
O
Me
O
H
BnO
Me
Me
O
H
H
BnO
NHBoc
HO
Me
MeO
OBn
-terpineol 24a
rose-oxide 25a 11:1 d.r.
allyl glycine 26a
glucal 27a
estrone 28a
Me
Me
Me
OBn
BzO
Me
H
O
Me
O
O
OPMB
Me
HO
H
BnO
Boc
Me
O
O
O
Me
NH
BnO
Me
H
O
O
OBn
OPMB
PMBO
H
MeO
24b (60%, 4:1 d.r., >20:1 b:l)
25b (52%, 11:1 d.r. >20:1 b:l)c
26b (75%, 1:1 d.r., 1.5:1 b:l)
27b (50%, >20:1 b:l)
28b (28%, 3:1 b:l)
a0.3 mmol scale, isolated yield, see SI for specific catalyst loading. b:l= branched/linear ratio. reaction run under an
b
air balloon. c5 equiv of olefin added in 2 portions (2.5 equiv at start and 2.5 equiv at 24 h).
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theses may explain this aberrant selectivity: a
background Ni-only mediated pathway, analogous to
reactivity observed by Liu,20a lowered regioselectivity
of MHAT itself due to similar potential energies of
developing C-centered radicals, or a competitive
hydrometallation pathway mediated by low valent
manganese.28
The abundance and diversity of olefins from
commercial sources allowed a rapid survey of alkene
scope. We were pleased to observe that a variety of
natural product scaffolds (18–28) could be cleanly
alkylated. A range of simple to complex terpenoids
were successfully employed, which constitutes a new
utilization of the chiral pool and potential access to
new flavors and fragrances. The transformation of
terpenes, whose hallmark features often are
electronically unbiased,30 hindered alkenes, have
1
2
3
4
5
6
7
8
The reaction displayed high functional group
compatibility in its tolerance of esters (11, 13, 21, 26),
phthalimides (14), carbamates (4, 15, 26), silyl enol
ethers (16), boronic esters (17), and epoxides (19).
Interestingly, the reaction with alkenes proceeded
with high chemoselectivity even in the presence of a
primary alkyl bromide (12), which did not engage in
the reaction or undergo protodehalogenation.
Although primary (21) and secondary alcohols (22)
required protection under the reaction conditions due
to competitive silylation, tertiary alcohols did not
affect catalysis (24). Heteroatom substitution29 on or
adjacent to the alkene was well tolerated (16, 17, 25),
but, in general, remotely-functionalized alkenes
returned the highest yields (e.g. 21) and proximal
branching lowered efficiency (22, 28).
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10
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13
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benefited
immensely
from
MHAT
methodology,1,4,6,7d,29 and served as particularly
efficient scaffolds for this methodology. Notably,
limonene oxide (19a) and 3-carene (23b) were both
hydroalkylated with their scaffolds intact: no
retrocyclization of the epoxide or cyclopropane motifs
was observed. Pinene (20), on the other hand,
predominantly underwent ring opening (3:1 ring
opened: closed ratio) and yielded alkylated limonene
derivative (20b), which did not undergo further
hydrogenation of the resulting trisubstituted olefin.31
In some cases, alkylation noticeably altered the odor
of these scaffolds, as was the case with rose oxide
(25), which underwent alkylation with high branched
selectivity. Substrates that contained
Table 2. Alkyl Halide Scopea
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a0.3 mmol scale, isolated yield, see SI for specific catalyst loading. b:l= branched/linear ratio. 0.1 mmol scale.
b
cisolated as a mixture with hydrogenation, yield determined by NMR. Further purified by prep HPLC.
1
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3
4
5
6
7
8
9
existing stereocenters exhibited modest stereoselectivity,
as was the case with terpineol (24b) and carene (23b).
Stereochemistry on the alkyl iodide was found to
translate well to the products, with no epimerization
observed in the case of the iodoalanine (39), proline (40)
or sugar substrates (45). Importantly, the use of
iodoalanine provides enantiomerically pure access to
unnatural amino acid 39, providing an orthogonal
approach to the racemic conjugate addition product from
dehydroalanine.
This method allowed the union of diverse metabolic
building blocks (terpenes, amino acids, sugars) by strong
covalent bonds. In addition to terpenes, ketide-like
fragments corresponding to oxygen-polarized carbon-
chains could be appended. This merger complements
Giese reactivity, which yields β-substitution, whereas 24
and 25 correspond to γ- and α-connections relative to a
latent carbonyl. Allylglycine (26) proved a poor
substrate (amino acids could be incorporated efficiently
in Table 2, see below), but glucals coupled efficiently
and yielded the C-glycoside product (27) as a single
diasteromer.32,33 Furthermore, a single diasteromer of
estrone derivative 28b was observed, remarkably
forming vicinal quaternary centers, albeit in reduced
yield.
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Whereas benzyl iodides were poorly tolerated under
the reaction conditions, we were please to find that
benzyl bromides coupled in moderate yield (47, 48).
Furthermore, benzyl electrophiles provide an intriguing
disconnection. An sp2–sp3 bond scission would
transform the product to an arene and neopentyl cross-
coupling partner, which retains structural complexity
and oftentimes requires an organometallic reagent.
Consequently, similar scaffolds have been accessed by
formation of a mixed ketone, alkylation, and Wolff-
Kishner deoxygenation—overall a 7-step sequence.38
Disconnection to the benzyl electrophile and alkene
allows scission of the quaternary carbon in a logical and
simplifying transform.
A diverse range of alkyl halides successfully
coupled to form quaternary carbon centers (Table 2, 29–
48). Sensitive functional groups like acetals (43) and
nitrogen containing heterocycles (33) were unaffected
by the coupling. Numerous simple alkyl chains could be
appended to affect hydromethylation, ethylation, and
pentylation reactions with similar efficiency. Ethylation
of terpineol (37) resulted in a marked change in
fragrance: from the sharp pine parent compound odor to
a less-pungent musty, citrus. Methyl-d3 iodide was also
compatible under the reaction conditions, providing the
isotopically-mixed geminal dimethylpyrrolidine 35.
More complex alkyl iodides also proceeded in good
yield, allowing for one-step installation of sugar- and
steroid-bearing motifs 45 and 46. Prenyl groups are
important motifs found in natural products. While prenyl
bromide displayed poor reactivity due to competitive
MHAT, we were pleased to find that prenyl surrogate, 4-
iodo-2-methylbutan-2-ol, yielded unnatural terpene 44
with excellent selectivity.
While this method makes significant progress in the
formation of sterically congested aliphatic centers, the
transformation is sensitive to the steric environment on
the alkyl halide. -Branching (49), neopentyl (50) and
secondary alkyl iodides (51) were found to proceed in
low yield, predominantly lost to competitive
protodehalogenation. This could imply that oxidative
addition or a more sterically congested Ni center
impedes productive reductive elimination.
In summary, we have reported a Markovnikov-
selective hydroalkylation of unbiased olefins30 using
diverse alkyl iodides and benzyl bromides. The
combination of Mn-mediated MHAT catalysis and Ni
catalysis enable an unprecedented synthesis of
quaternary carbons. The mild reaction conditions and
robust functional group compatibility support its utility
for late stage modification of small molecules. Efforts
are underway to expand this chemistry to more sterically
congested centers and complex natural products.
MHAT dual catalysis provides an orthogonal
approach to phthalimide containing compounds 30 and
36.34 Phthalimide 36 has previously been accessed
through disconnection at the quaternary center using a
Cu-nanoparticle catalyzed Kumada coupling with the
tert-alkyl Grignard.35,36 Phthalimide 31, previously
accessed in 5 steps from dimedone, has been described
in the patent literature in the development of drugs for
the treatment of inflammatory disorder and microbial
disease.37 Conversely, our method allows direct access
to the quaternary center, yielding 30 in two steps after
deprotection.
Supporting Information.
The Supporting Information is available free of charge on
the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
*rshenvi@scripps.edu
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1
Notes
2
3
4
5
6
7
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The authors declare no competing financial interest.
Rablen P.; Herzon, S. B. Hydroheteroarylation of
unactivated alkenes using N-methoxyheteroarenium
salts. J. Am. Chem. Soc. 2017, 139, 5998. (c) Shigehisa,
H.; Ano, T.; Honma, H.; Ebisawa, K.; Hiroya, K. Co-
catalyzed hydroarylation of unactivated olefins. Org.
Lett. 2016, 18, 3622. (d) Lo, J. C.; Kim, D.; Pan, C–M.;
Edwards, J. T.; Yabe, Y.; Gui, J.; Qin, T.; Gutiérrez, S.;
Giacoboni, J.; Smith, M. W.; Holland, P. L.; Baran, P. S.
Fe-catalyzed C–C bond construction from olefins via
radicals. J. Am. Chem. Soc, 2017, 139, 2484.
ACKNOWLEDGMENT
Support was provided by the National Science
Foundation (GRFP to S.A.G.) and the National Institute
of Health (R35 GM122606), as well as a generous
Scientific Advancement grant from Boehringer-
Ingelheim. We thank Dr. Jason S. Chen and Brittany
Sanchez for help with separations and analysis.
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(8) Matos, J. L. M.; Vásquez-Céspedes, S.; Gu, J.;
Oguma, T.; Shenvi, R. A. Branch-selective addition of
unactivated olefins into imines and aldehydes. J. Am.
Chem. Soc. 2018, 140, 16976.
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was observed using esters in ref 17.
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2016.
TOC Graphic
Mn
Ni
X
H
Me
BocHN
Me CD3
Me
HO
Me
NBoc
Me
O
PMBO
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