Controllable, Sequential, and Stereoselective C-H Allylic Alkylation of Alkenes

Article abstract of DOI:10.1021/jacs.9b08801

The direct conversion of C-H bonds into new C-C bonds represents a powerful approach to generate complex molecules from simple starting materials. However, a general and controllable method for the sequential conversion of a methyl group into a fully substituted carbon center remains a challenge. We report a new method for the selective and sequential replacement of three C-H bonds at the allylic position of propylene and other simple terminal alkenes with different carbon groups derived from Grignard reagents. A copper catalyst and electron-rich biaryl phosphine ligand facilitate the formation of allylic alkylation products in high branch selectivity. We also present conditions for the generation of enantioenriched allylic alkylation products in the presence of catalytic copper and a chiral phosphine ligand. With this approach, diverse and complex products with substituted carbon centers can be generated from simple and abundant feedstock chemicals.

Full text of DOI:10.1021/jacs.9b08801

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pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Controllable, Sequential, and Stereoselective C−H Allylic Alkylation
of Alkenes
Ling Qin, Mohammed Sharique, and Uttam K. Tambar*
Department of Biochemistry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas
75390-9038, United States
S
* Supporting Information
ABSTRACT: The direct conversion of C−H bonds into new
C−C bonds represents a powerful approach to generate
complex molecules from simple starting materials. However, a
general and controllable method for the sequential conversion
of a methyl group into a fully substituted carbon center
remains a challenge. We report a new method for the selective
and sequential replacement of three C−H bonds at the allylic
position of propylene and other simple terminal alkenes with
different carbon groups derived from Grignard reagents. A
copper catalyst and electron-rich biaryl phosphine ligand
facilitate the formation of allylic alkylation products in high
branch selectivity. We also present conditions for the
generation of enantioenriched allylic alkylation products in
the presence of catalytic copper and a chiral phosphine ligand. With this approach, diverse and complex products with
substituted carbon centers can be generated from simple and abundant feedstock chemicals.
INTRODUCTION
■
The functionalization of C−H bonds has emerged as a powerful
and versatile strategy for the conversion of inexpensive and
abundant starting materials into products of greater value.1 In
particular, the conversion of C−H bonds into new C−C bonds
enables the rapid generation of complex molecules from simple
substrates.2 Despite major advances in the field of selective C−H
alkylation,3 there are no general methods for the sequential
conversion of a methyl group with three C−H bonds into a fully
substituted carbon center with three new C−C bonds from three
distinct carbon-based reagents (Figure 1A). The selective
conversion of methyl groups into substituted carbon centers
via controllable and sequential C−H functionalization would
enable the efficient synthesis of a broad range of products from
simple starting materials.
Based on our group’s research in selective C−H allylic
functionalization,4 we became interested in addressing the
unsolved problem of sequential C−H functionalization in the
Figure 1. Controllable and sequential C−H alkylation.
context of converting an allylic methyl group into a fully
substituted allylic carbon center through three consecutive C−
H allylic alkylations with three different carbon-based reagents
(Figure 1B). The major challenges in achieving this goal are
threefold. First, a mode of activation must be identified that is
reactive enough to undergo multiple C−H functionalizations to
generate a fully substituted carbon center. Second, each C−H
allylic alkylation must be selective for the formation of the
branched product over the linear product, which becomes more
sterically challenging over subsequent steps. Third, to generate
C−C bonds with three distinct carbon groups, the mode of
activation must be controllable to avoid undesired over-
functionalization of C−H bonds in any step of the process.
Elegant methods have been reported for the generation of fully
substituted carbon centers via C−H functionalization5 and for
branch-selective C−H allylic alkylation.6 However, these
strategies are not amenable to the conversion of simple alkenes
Received: August 14, 2019
© XXXX American Chemical Society
A
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such as propylene into products with substituted allylic carbon
centers via sequential C−H allylic alkylation. While these
reported strategies have overcome the challenges of reactivity
and selectivity for the formation of fully substituted carbons,
traditional C−H functionalization and allylic alkylation
approaches have not addressed the challenge of controllably
forming distinct C−C bonds.
Table 1. Optimization of Ligand-Controlled Branch-
Selective Allylic Alkylation of Terminal Alkenes
g
Herein, we report the first general method to create a fully
substituted carbon center at the allylic position of simple alkenes
such as propylene. Our approach uniquely enables the selective
and sequential replacement of three C−H bonds with different
carbon groups in a controllable fashion. The highly substituted
terminal alkenes generated by this method are synthetically
versatile precursors for many functional groups, including
amines, alcohols, acids, epoxides, aldehydes, and internal
alkenes. Therefore, we anticipate our method will provide a
new strategy for converting simple alkenes into complex
molecules with fully substituted carbons.
RESULTS AND DISCUSSION
■
Catalyst-Controlled Regioselectivity of Allylic Alkyla-
tion. A core feature of our controllable and sequential allylic
alkylation strategy is the use of sulfur diimide reagent
PhSO2NSNSO2Ph (Table 1),7 which we hypothesized
could serve the dual role of an electrophilic oxidant for the
activation of alkenes (1 to 2) and a controllable leaving group in
the subsequent copper-catalyzed alkylation with Grignard
reagents.
We first examined the selective conversion of alkene 1 to
branched allylic alkylation product 3 with a tertiary allylic
carbon. To develop a branch-selective, controllable, and
sequential allylic alkylation of alkene 1, we had to overcome
the inherent preference of allylic sulfinamides such as 2 to
undergo alkylation with Grignard reagents to selectively form
linear products such as 4.4b Initially, we observed predominantly
linear selectivity with various copper catalysts (entries 1−3).8
To our delight, CuCN reversed the regioselectivity of the
reaction, and the desired branched product 3 was obtained as
the major product with moderate 2.5:1 selectivity (entry 4). We
observed an important solvent effect on the branch selectivity
(entries 4−6). The use of CH2Cl2 as the primary solvent for
allylic alkylations was beneficial for the branch selectivity of the
reaction (entry 6). Based on detailed NMR studies by Gschwind
and co-workers,9 we surmise that CH2Cl2 facilitates the
formation of soluble monoalkyl cyanocuprates (RCuCNMg)
that favor the formation of branched allylic alkylation products,
rather than insoluble copper-rich complexes or higher-order
cuprates that would favor the formation of linear allylic
alkylation products. As a practical advantage, solutions of
Grignard reagents in Et2O were tolerated by the reaction
without negatively impacting the yield or branch selectivity of
the process, as long as CH2Cl2 remained the predominant
solvent.
To further improve the regioselectivity of the allylic alkylation,
we introduced various ligands for the copper catalyst (entries 7−
13). Bipyridine L1 resulted in slightly higher regioselectivity of
10:1 (entry 7), while the more effective σ-donor triphenylphos-
phine L2 provided a 14:1 ratio (entry 8). Furthermore, the more
electron-rich phosphine L3 improved regioselectivity (entry 9),
whereas the more electron-poor phosphine L4 diminished
regioselectivity (entry 10). Based on this trend in selectivity, we
examined electron-rich biaryl phosphine ligands.10 CyJohnPhos
L5 provided a regioselectivity of 13:1 in favor of branched
a
24 mol % of monodentate ligand, 12 mol % of bidentate ligand.
b
c
Determined by 1H NMR analysis. NMR yield with 1,3-
d
dimethoxybenzene as an internal standard. 5 mol % CuCN and 6
mol % ligand. 10 mol % CuCN and 12 mol % ligand. Isolated yield
in parentheses. Reaction conditions: 1 (0.25 mmol, 1 equiv),
(PhSO2N)2S (0.30 mmol, 1.2 equiv), solvent (0.5 mL, 0.5 M), 0 °C,
40 min; then solvent (0.05 M by dilution), Cu source (10 mol %),
ligand (12 or 24 mol %), EtMgBr (3 M in Et2O, 4 equiv), 0 to 23 °C,
4 h.
e
f
g
product 3 (entry 11), which was similar to triphenylphosphine
L2. Sterically hindered ligand L6 enhanced regioselectivity to
18:1 (entry 12). Ultimately, the bulkier t-BuXPhos L7 was
identified as the optimal ligand, furnishing branched allylic
product 3 in >20:1 regioselectivity (entry 13). This class of
ligands has found broad utility in controlling product selectivity
of palladium-catalyzed reactions. Guided by these studies, we
hypothesize that the electron-rich and bulky phosphine ligand
L7 enhances the selectivity for the branched allylic alkylation by
altering the relative rates of oxidative addition and reductive
elimination en route to the desired product 3 (vide infra).
Lowering the copper catalyst and ligand loading had a
deleterious effect on the yield and regioselectivity (entry 14).
Finally, we obtained the desired product 3 in 57% isolated yield
and >20:1 regioselectivity with 10 mol % CuCN and 12 mol %
ligand L7 (entry 15).
Other organometallic reagents were assayed in the allylic
alkylation of 4-phenyl-1-butene (Figure 2). Under unoptimized
conditions, we were pleased to observe that organolithium,
organozinc, and organoaluminum reagents were compatible
coupling partners for the C−H allylic alkylation of terminal
alkenes, with high selectivity for the branched product. Allylic
sulfinamide intermediate 2 is presumably initially activated by
nucleophilic Grignard reagent prior to oxidative addition with
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with allylic tertiary carbons. Commercially available 4-phenyl-1-
butene was coupled with several Grignard reagents (Table 3). In
Table 3. Scope of Grignard Reagents for the Branch-Selective
d
Allylic Alkylation
Figure 2. Branch-selective C−H allylic alkylation of 4-phenyl-1-butene
with other organometallic reagents.
the copper catalyst (vide infra). Therefore, these alternative
organometallic reagents may require further optimization to
generate the desired product in synthetically useful yields.
Allylic Alkylation of Propylene. We implemented our
strategy for controllable and sequential construction of
substituted carbon centers from simple alkenes by performing
C−H allylic alkylation of propylene, the simplest terminal alkene
with available allylic C−H bonds (Table 2). Since regioselec-
Table 2. Allylic Monofunctionalization of Propylene and
a
Other 2-Substituted Alkenes
a
b
c
d
Two-pot procedure. 24 mol % L7. No L7. Reaction conditions:
5f (0.25 mmol, 1 equiv), (PhSO2N)2S (0.30 mmol, 1.2 equiv),
CH2Cl2 (0.5 mL, 0.5 M), 0 °C, 40 min; then CH2Cl2 (0.05 M by
dilution), CuCN (10 mol %), L7 (12 mol %), R2 MgBr (4 equiv), 0
to 23 °C, 4 h. B:L is branched:linear allylic alkylation products.
a
Reaction conditions: Terminal alkene (R = H: 1 atm balloon; R =
Ph, t-Bu: 0.25 mmol, 1 equiv), (PhSO2N)2S (0.30 mmol, 1.2 equiv),
CH2Cl2 (0.5 mL, 0.5 M), 0 °C, 40 min; then CH2Cl2 (0.05 M by
dilution), CuCN (10 mol %), R1 MgBr (4 equiv), 0 to 23 °C, 4 h.
the presence of L7, primary (6a−h, 6p), secondary cyclic (6i−
k), acyclic (6l, 6n, 6o), and tertiary (6m) Grignard reagents
provided excellent yields and high regioselectivities for the
desired branched products 6. Grignard reagents with functional
groups were also compatible with the reaction conditions, which
allowed for the incorporation of an unsaturated chain (6q), silyl
group (6r), and trifluoromethyl group (6s) into the products.
Reaction with phenylmagnesium bromide resulted in the linear
constitutional isomer 6t as the major product in poor
regioselectivity (1:2 B:L), suggesting a modified reactivity of
aryl-substituted allylcopper intermediates (vide infra). Organo-
magnesium chlorides, bromides, and iodides were tolerated. The
branch-selective allylic alkylation could be performed on a gram
scale without affecting the efficiency and regioselectivity of the
reaction (6l).
tivity was not an issue in this allylic alkylation step, ligand L7 was
not required. Diverse Grignard reagents, including aromatic
(5a−e), benzylic (5f), alkyl (5g), and heteroatom-containing
(5h, 5l) reagents, provided high yields of allylic alkylation
products. A methyl group (5c), electron-donating dimethyla-
mino group (5d), and electron-withdrawing fluorine group (5e)
were also well tolerated. Alkenes with hindered internal
substituents, such as phenyl (5i−j) and tert-butyl groups (5k−
l), furnished the desired product in high yield. Bromide
Grignard reagents provided the product in higher yields than
chloride Grignard reagents, presumably due to an undesirable
Schlenk equilibrium with the latter reagents.11
Allylic Alkylation of Terminal Alkenes to Products
with Allylic Tertiary Carbons. Once we established the
efficient conversion of propylene to a variety of alkenes, we
explored the conversion of these products to terminal alkenes
We also explored branch-selective allylic alkylation starting
from a diverse range of terminal alkene substrates (Table 4).
Benzylic (6u), aromatic (6v−x), cyclic (6y), and acyclic (6z)
alkyl substitution in the starting material were tolerated,
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Table 4. Scope of Functionalized Alkenes for the Branch-
Selective Allylic Alkylation
Table 5. Synthesis of Fully Substituted Allylic Carbon
a
b
Centers from Tertiary Allylic Alkenes
a
b
a
Reaction conducted at −78 to −20 °C for 48 h. Reaction
Reaction conditions: 6 (0.25 mmol, 1 equiv), (PhSO2N)2S (0.30
mmol, 1.2 equiv), CH2Cl2 (0.5 mL, 0.5 M), 0 °C, 40 min; then
CH2Cl2 (0.05 M by dilution), CuCN (10 mol %), L7 (12 mol %), R3
MgBr (4 equiv), 0 to 23 °C, 4 h. B:L is branched:linear allylic
alkylation products.
conditions: 5 (0.25 mmol, 1 equiv), (PhSO2N)2S (0.30 mmol, 1.2
equiv), CH2Cl2 (0.5 mL, 0.5 M), 0 °C, 40 min; then CH2Cl2 (0.05 M
by dilution), CuCN (10 mol %), L7 (12 mol %), R2MgBr (4 equiv), 0
to 23 °C, 4 h. B:L is branched:linear allylic alkylation products.
providing good yields and satisfying regioselectivities of
products 6. Electronically diverse phenyl rings (6v−x) did not
impact the efficiency of the reaction. A variety of functional
groups were tolerated, including halides (6bb, 6cc, 6dd),
protected alcohol (6ee), protected amine (6ff), thiophene
(6aa), and Grignard-sensitive functional groups such as nitrile
(6gg), ester (6hh), and epoxide (6ii). Interestingly, 1,1-
disubstitued alkenes formed the desired branched product in
moderate yields and excellent regioselectivities (6jj, 6kk, 6ll).
Under the reaction conditions, internal alkenes such as trans-5-
decene did not yield any C−H allylic alkylation product. Since
we observed significant amounts of the ene-adduct of this
internal alkene at 0 °C, we conclude that the initial ene reaction
with the sulfur diimide oxidant proceeded, but the subsequent
reaction between the branched allylic sulfinamide and the
Grignard reagent did not occur.
Allylic Alkylation of Terminal Alkenes to Products
with Allylic Quaternary Carbons. Next, we examined the
conversion of already generated branched terminal alkenes 6
into products with fully substituted allylic carbon centers (7,
Table 5). With 3,7-dimethyl-1-octene as the standard substrate,
reactions of primary (7a−c, 7g,h) and secondary (7d−f)
Grignard reagents furnished the desired products. Despite the
inherent difficulty of constructing congested fully substituted
carbon centers via an allylic C−H alkylation reaction, we
obtained branched allylic alkylation products 7 in synthetically
useful yields and regioselectivities with both primary and
secondary Grignard reagents. Moreover, other 3,3-disubstituted
alkenes, including a cyclic structure (7k) and a substrate with a
primary chloride (7j), provided the desired product with high
regioselectivity. The use of phenylmagnesium bromide resulted
in diminished selectivity for the branched allylic arylation
product 7m. The inability to generate a product with two vicinal
fully substituted carbon centers represents a current limitation to
this chemistry (7n).
Controllable and Sequential Allylic Alkylation of
Propylene. To demonstrate the utility of this controllable
and sequential strategy in assembling fully substituted carbon
centers, we prepared several products by iterative introduction
of three different carbon-based substituents at the allylic
position of propylene (Table 6). Generally, excellent regiose-
lectivity was maintained for the three-step sequence. Different
functional groups could be introduced in each step, including an
acetal (7p), thiophene (7q), and alkenyl group (7s). We
anticipate this chemistry will provide a new approach to a broad
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transition state 11, with ligand L7 on the C1 side of the allyl
system, to yield product 7, or allylic sulfimine 10 forms CuIII-allyl
complex 14 via transition state 13, with ligand L7 on the C3 side,
to give product 8. We propose a preference for transition state
11 with improved FMO interactions between the HOMO of the
organocuprate and the LUMO of allylic sulfimine 10. Transition
state 11 leads to conformationally stable enyl[σ+π]-allylcopper-
(III) complex 12, in which the copper atom is σ-bonded to C3.
Subsequent reductive elimination furnishes branched product 7.
To account for the enhanced regioselectivity and preference for
transition state 11 in the presence of ligand L7, we propose that
the electron-rich phosphine stabilizes transition state 11 for
oxidative addition. In addition, the bulky tert-butyl groups on
phosphorus and isopropyl substituents on the aromatic ring of
ligand L7 promote reductive elimination of enyl[σ+π]-
allylcopper(III) complex 12 before isomerization can occur to
the enyl[σ+π]-allylcopper(III) complex 14, which would lead to
the undesired linear product 8. We surmise that excess Grignard
reagent is required to obtain synthetically useful yields of
product because of multiple roles for the Grignard reagent in the
transformation. One equivalent of Grignard is consumed in the
conversion of allylic sulfinamide 9 to allylic sulfimine 10, and
another equivalent is ultimately transferred to the product in the
allylic alkylation step. Additional Grignard reagent may be
required in the decomposition of the sulfur-containing leaving
group into a thioether.4b,14
Enantioselective Allylic Alkylation. Given the impor-
tance of achiral phosphine L7 for branch selectivity in the C−H
allylic alkylation process, we hypothesized that the proper choice
of a chiral phosphine ligand could facilitate the formation of
enantioenriched terminal alkenes with allylic stereogenic centers
(Table 7). Allylic sulfinamide 2 was generated from 4-
phenylbutene, isolated, and then treated with catalytic CuCN
and chiral ligands in CH2Cl2 at −78 °C. Upon addition of i-
BuMgBr, the reaction mixture was warmed to 0 °C and stirred.
We initially examined a broad range of chiral ligands, including
bidentate phosphines L8−L12 (entries 1−5). Although
Table 6. Controllable and Sequential Allylic Alkylation of
Propylene
a
a
Condition A: propylene (balloon, 1 atm), (PhSO2N)2S (1 equiv),
CuCN (10 mol %), CH2Cl2, 0 °C, 40 min; RMgBr (4 equiv), CH2Cl2,
0 to 23 °C, 4 h. Condition B: alkene (1 equiv), (PhSO2N)2S (1.2
equiv), CuCN (10 mol %), L7 (12 mol %), CH2Cl2, 0 °C, 40 min;
RMgBr (4 equiv), CH2Cl2, 0 to 23 °C, 4 h. B:L ratios refer to the
overall branched:linear allylic alkylation product ratios after the third
alkylation step.
diversity and complexity of products with fully substituted
carbon centers that can be generated from simple, abundant
feedstock chemicals such as propylene.
Proposed Mechanism. We propose a mechanism that
accounts for the high regioselectivity in the formation of the
branched products in the allylic alkylation step (Figure 3). Initial
oxidation of the alkene substrate yields ene adduct 9, which is
activated by the Grignard reagent to furnish allylic sulfimine 10.
For heterocuprates such as [R3CuICNL7]MgBr, oxidative
addition of the CuI complex to the allylic substrate dictates
the regioselectivity of the allylic substitution.12,13 Therefore,
either allylic sulfimine 10 forms CuIII-allyl complex 12 via
Figure 3. Proposed mechanism of ligand-controlled branch-selective allylic alkylation of terminal alkenes.
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P,N ligand L13, phosphite L14, and phosphinite L15 all
furnished product 3 as essentially a racemate (entries 6−8).
Finally, we examined a series of chiral monodentate phosphines.
Whereas ligands L16 and L17 provided the allylic alkylation
product in negligible levels of enantioselectivity (entries 9, 10),
phosphine L18 yielded product 3 in 82% yield, >20:1
regioselectivity, and 78:22 er (entry 11). Given the high
selectivity for the branched product with ligand L18, we
surmised that a broad range of reaction media would retain the
high regioselectivity with the potential to improve the
enantioselectivity. In ethereal solvent, product 3 was formed
in reasonable regioselectivity but with diminished yield and
enantioselectivity (entry 12). Aromatic solvents, such as toluene,
furnished the desired product in high yield and regioselectivity
with an improved enantiomeric ratio of 84:16 (entry 13).
Gratifyingly, by initiating the reaction at −78 °C and warming it
up to −30 °C, we obtained the branched allylic alkylation
product 3 in 86% isolated yield, >20:1 regioselectivity, and 94:6
er (entry 14).
Table 7. Optimization of Catalytic Enantioselective Branch-
Selective Allylic Alkylation
f
With the identification of optimal conditions for the catalytic
enantioselective branch-selective allylic alkylation, we examined
the scope of this transformation with other terminal alkenes and
Grignard reagents (Table 8). 4-Phenylbutene coupled with
primary Grignard reagents (6b, 6d, 6g, 6f, 6v) as well as
Table 8. Scope of Catalytic Enantioselective Branch-Selective
b
Allylic Alkylation
a
24 mol % of monodentate ligand, 12 mol % of bidentate ligand.
b
c
d
1
Isolated yield. Determined by H NMR analysis. Determined by
e
chiral HPLC analysis of derivative. Reaction performed at −78 to
−30 °C. Reaction conditions for 1st step: (PhSO2N)2S (2 mmol, 1
f
equiv), 1 (2 equiv), Et2O (0.5 M), 4 °C, 12 h. Reaction conditions for
2nd step: 2 (0.1 mmol, 1 equiv), solvent (0.05 M by dilution), CuCN
(10 mol %), chiral ligand (12 or 24 mol %), i-BuMgBr (2 M in Et2O,
4 equiv), −78 to 0 °C.
a
b
PhCF3 as a solvent, reaction performed at −78 to 0 °C. Reaction
conditions for 1st step: (PhSO2N)2S (2 mmol, 1 equiv), 5 (2 equiv),
Et2O (0.5 M), 4 °C, 12 h. Reaction conditions for 2nd step: ene
adduct (0.1 mmol, 1 equiv), PhMe (0.05 M by dilution), CuCN (10
mol %), L18 (24 mol %), R′MgBr (4 equiv), −78 to −30 °C. B:L is
branched:linear allylic alkylation products.
selectivity for the branched product 3 was maintained across this
diverse set of ligands, the allylic alkylation product was
consistently generated with low levels of enantioselectivity.
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secondary cyclic and acyclic Grignard reagents (6i, 6k, 6l).
Other functionalized terminal alkenes were also compatible with
the reaction, including a substrate with a remote heteroaromatic
ring (6aa) and an unsaturated sulfonamide (6ff).
Preliminary studies with chiral ligands for the copper-
catalyzed branch-selective allylic alkylation suggest that our
method affords us the opportunity to transform simple terminal
alkenes into enantioenriched alkenes (Figure 4). Conversion of
and flexible access to a diverse range of products. We proposed a
mechanism that accounts for the catalyst and ligand control of
branch selectivity in product formation. We also discovered
conditions to generate enantioenriched allylic alkylation
products in the presence of catalytic copper and chiral
phosphine L18.
Our method represents a new chemical strategy for converting
simple terminal alkene substrates into complex unsaturated
products in synthetically useful yields, regioselectivities, and
enantioselectivities. Importantly, the products generated by this
method may also be accessed in theory with high regioselectivity
and enantioselectivity through the catalytic allylic substitution of
prefunctionalized allyl electrophiles with organometallic re-
agents.15 Our approach and the traditional allylic substitution of
allyl electrophiles have complementary strengths and weak-
nesses.15 In some cases, we anticipate that the allylic substitution
of prefunctionalized allyl halides, acetates, carbonates, or
phosphates will be preferential. For example, while both
strategies are compatible with organomagnesium, organo-
lithium, organozinc, and organoaluminum reagents, in some
cases the allylic substitution of preformed allylic electrophiles
can be performed with organoborane reagents, including alkynyl
boron reagents. In addition, currently the branched allylic
arylation product with aryl nucleophiles cannot be accessed with
our method. In other instances, we anticipate that our
controllable and sequential strategy for allylic alkylation will
be preferential. For some classes of substrates the selective
synthesis of the prefunctionalized allyl electrophile may be
challenging, whereas the unfunctionalized terminal alkene
substrate will be readily accessible. Moreover, a sequential
allylic alkylation with the traditional approach with two or three
carbon-based nucleophiles would require multiple intermediary
steps to generate the desired allylic electrophile for each round
of alkylation, whereas our approach enables the sequential
addition of carbon substituents in one pot for each step.
Ultimately, the existence of two complementary strategies for
regioselective and enantioselective allylic alkylation will be
beneficial to the synthetic community.
Figure 4. Synthesis of enantioenriched alkenes with either tertiary or
quaternary allylic stereogenic centers. B:L is branched:linear allylic
alkylation products.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b08801.
■
S
4-phenylbutene to allylic sulfinamide 2 followed by subjection to
the CuCN/L7 conditions for branch-selective allylic alkylation
furnished racemic products 6b and 6l. These two unsaturated
hydrocarbons were then treated with the sulfur diimide oxidant
to yield allylic sulfinamides 15 and 16. Treatment with the
CuCN/L18 reaction conditions furnished enantioenriched
alkenes 7l and 17 with fully substituted allylic stereogenic
centers. The lower enantioselectivity in forming the products
with quaternary stereogenic centers compared to tertiary
stereogenic centers may be due to the formation of trisubstituted
allylic sulfinamides 15 and 16 as mixtures of E/Z isomers. We are
currently examining catalyst-controlled methods for generating
trisubstituted allylic sulfinamides in high selectivity for the E-
alkene isomer.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Author
*Uttam.Tambar@utsouthwestern.edu
■
ORCID
Uttam K. Tambar: 0000-0001-5659-5355
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
CONCLUSION
■
Notes
In conclusion, we have developed a general method for
converting multiple C−H bonds to C−C bonds via a ligand-
controlled copper-catalyzed controllable and sequential allylic
alkylation of alkenes. We demonstrated the formation of
substituted carbon centers at the allylic position of simple
terminal alkenes, including propylene, which provides efficient
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support was provided by the W. W. Caruth, Jr.
Endowed Scholarship, Welch Foundation (I-1748), National
■
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DOI: 10.1021/jacs.9b08801
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Palladium Complex-Catalyzed C-H Oxidative Borylation. J. Am. Chem.
Soc. 2015, 137, 4054−4057.
Institutes of Health (R01GM102604), American Chemical
Society Petroleum Research Fund (59177-ND1), Teva
Pharmaceuticals Marc A. Goshko Memorial Grant (60011-
TEV), and Sloan Research Fellowship.
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DOI: 10.1021/jacs.9b08801
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX