Directed Copper-Catalyzed Intermolecular Heck-Type Reaction of Unactivated Olefins and Alkyl Halides

Article abstract of DOI:10.1021/jacs.8b10874

A new type of intermolecular alkylative olefination of unactivated olefins and alkyl halides has been realized for the first time. This copper-promoted Heck-type reaction employs a directing-group strategy to efficiently produce the coupled alkyl olefin products with excellent regio- and stereoselectivity. A broad substrate scope including 1°, 2°, and 3° alkyl bromides and various nonactivated alkenes could be well tolerated. DFT calculations disclosed a dimethyl sulfoxide assisted concerted H-Br elimination process of a conformationally strained Cu(III) cyclic transition state.

Full text of DOI:10.1021/jacs.8b10874

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Communication
Directed Copper-Catalyzed Intermolecular Heck-
Type Reaction of Unactivated Olefins and Alkyl Halides
Chunlin Tang, Ran Zhang, Bo Zhu, Junkai Fu, Yi Deng, Li Tian, Wei Guan, and Xihe Bi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b10874 • Publication Date (Web): 13 Nov 2018
Downloaded from http://pubs.acs.org on November 13, 2018
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Directed Copper-Catalyzed Intermolecular Heck-Type Reaction of
Unactivated Olefins and Alkyl Halides
Chunlin Tang,†,# Ran Zhang,†,# Bo Zhu,†,# Junkai Fu*,†,‡, Yi Deng,† Li Tian,† Wei Guan*,† and Xihe Bi*,†
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† Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry, Northeast
Normal University, Changchun 130024, China
‡ Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen
Graduate School, Shenzhen 518055, China
Supporting Information Placeholder
ABSTRACT: A new type of intermolecular alkylative olefina-
tion of unactivated olefins and alkyl halides has been realized for
the first time. This copper-promoted Heck-type reaction employs
a directing-group strategy to efficiently produce the coupled alkyl
olefin products with excellent regio- and stereoselectivity. A
broad substrate scope including 1°, 2°, and 3° alkyl bromides and
various non-activated alkenes could be well tolerated. DFT calcu-
lations disclosed a dimethyl sulfoxide assisted concerted H−Br
elimination process of a conformationally strained Cu(III)cyclic
transition state.
The Mizoroki−Heck reaction1 has developed into an essential
advancement in constructing C−C bonds in organic chemistry,2
yet significant problems remain unsolved. For unactivated ole-
fins,3 mixtures of Heck isomers are ultimately obtained in low
selectivity.4 Despite the recent efforts to provide selective access
to branched,5 styrenyl6 or allylic7 olefinated products in the pres-
ence of different transition metals, the coupling partners for the
Heck reaction of unactivated olefins are restricted to aryl, vinyl or
benzyl halides5c,8 which lack detachable β-hydrogens or the
C(sp2)−M intermediates generated from the directing group-
promoted C(sp2)−H activation.7,9 In comparison, Heck coupling
Figure 1. Alkylative olefination of unactivated olefins and alkyl halides.
of unactivated olefins and alkyl halides has received less attention.
The intramolecular carbocyclizations of aliphatic alkenes with
primary or secondary alkyl electrophiles have been successively
reported by Oshima10a, Fu10b, Alexanian10c,d, Pan10e, Carreira,10f
Cuerva10g and Jarvo10h through the use of cobalt, palladium, nickel
or Ni/Ti co-catalysis (Figure 1a). However, few examples are
reported for the intermolecular coupling of non-activated olefins
and alkyl halides (Figure 1b).11 Challenges with this chemistry are
evident with knowledge of the sluggish oxidative addition of low-
valent metal catalysts to sp3-hybridized electrophiles and the fac-
ile β-hydride elimination;12 both would ultimately hamper the
further interaction with the already low reactive olefin partner.
Additionally, the uncontrollable migratory insertion into the ali-
phatic olefins and the indiscriminate β-hydride elimination with
either Ha or Hb for metal-alkyl intermediate C would result in a
mixture of branched olefin product D and linear products E and F.
Therefore, the development of a strategy to realize the intermo-
lecular olefination of unactivated olefins and alkyl halides in a
selective manner is highly desirable in order to afford a newly
complementary type of Heck reaction and ultimately gain access
to alkyl olefin products.
Recently, utilization of alkyl radical species has proven to be a
promising approach to advance the intermolecular alkylation of
olefins13 by directly using alkyl halides14,15; such species could
avoid either slow oxidative addition or β-hydride elimination.
However, these alkylative olefination reactions require functional-
ized alkenes, such as styrenes, acrylates or vinyl ethers as the
partners, presumably due to the high reactivity of the alkyl radical,
which would be ultimately quenched if not efficiently trapped by
the electrophilic acceptor. In this case, we envisaged that installa-
tion of a suitable directing group16 on the unactivated olefin sub-
strate might be a potential solution for the intermolecular coupling
with alkyl halides. Such a strategy would simulate the intermolec-
ular olefination as an intramolecular version10 and thus increase
the chemical reactivity of the non-activated olefins. Moreover, the
directing group-coordinated metallacyclic intermediate might
result in a conformationally strained intermediate,7,17 which would
distinguish the adjacent hydrogen atoms during β-hydride elimi-
nation event. Herein, we report the first intermolecular Heck-type
coupling of unactivated olefins and alkyl halides by using a di-
recting-group strategy and earth-abundant copper catalyst2g with
excellent regio- and stereoselectivity (Figure 1c).
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Our work was initiated with the reaction of 3-butenoic acid
α-substituted terminal alkenes were found to be suitable substrates,
including ones containing sterically encumbering substituents
such as n-butyl (3b) and isopropyl (3c). Herein, a modified condi-
tions A with higher concentration and elevated temperature was
required to accelerate these reactions. When diene or enyne com-
pounds were employed, the olefination proved to be chemoselec-
tive with selective functionalization of the β-γ olefin (3d−3g),
demonstrating the preference of the five-membered metallacycle.
In terms of functional group compatibility, substrates containing
methoxy (3h), chlorine (3i) and benzyl groups (3j−3m) with ei-
ther electron-donating or -withdrawing substituents were all toler-
ated. For α,α-dimethyl substituted alkenes, the olefination also
proceeded smoothly to obtain 3n in 81% yield. Notably, when a
substrate having a cis-locked cyclic alkene was tested, the trisub-
stituted alkene 3o was obtained. The position of double bond at β-
γ position in 3o was different from the general palladium-
catalyzed Heck reaction of cyclic alkenes, in which conformation-
al rigidity and restricted rotation steered β-hydride elimination
away from the newly formed C−C bond.8a,20 Subjecting a 1,1-
disubstituted alkene to the reaction conditions delivered desired
product 3p along with a minor amount of isomer 3p′′ which was
generated through the β-hydride elimination of a hydrogen on the
methyl group. It should be mentioned that all the above reactions
provided excellent regioselectivity and a single E-configuration.
Furthermore, the substrates with γ-δ olefin and tri- or tetra-
substituted olefins showed no reactivities (see Table S3 in SI); the
former might due to the disfavor of six-membered metallacycle.21
masked as its 8-aminoquinoline (AQ)18 amide 1a and ethyl α-
bromoisobutyrate 2a in the presence of CuCl and Cs2CO3 in THF
at 60 °C (Table 1, entry 1). After 8 h, a mixture of 3a and 3a′ was
isolated in 15% yield with a regioisomeric ratio (rr) of 1:1.5, with
the majority of the mass balance attributed to recovery of 1a.
Alkene substrates with other bidentate auxiliaries19 either afforded
trace amount of product (amide-oxazoline) or failed to give any
desired product. Increasing the loading of CuCl to 40 mol% im-
proved the yield to 27% with an equivalent ratio of 3a and 3a′
(entry 2). Choice of solvent had a dramatic effect on the reaction
(entries 3-7). Nonpolar solvents such as toluene completely sup-
pressed the desired reaction, while polar solvent DMSO gave the
product in an 80% isolated yield and a rr of 8:1. Further screening
disclosed that a co-solvent system of DMSO/THF increased the
yield (82%), regio- (rr = 12:1), and stereoselectivity (E/Z > 20:1)
(entry 8, as conditions A). Higher concentrations or elevat-
ed temperatures (80 °C) promoted complete consumption of the
substrate and resulted in a slightly improved yield; however, only
moderate rr value could be obtained (entries 9-10). Other copper
sources, for instance, CuI, CuCl2 and Cu(OTf)2 led to the decrease
in both yield and rr value (entries 11-13). Control experiments
without CuCl or Cs2CO3 provided no product, showing the im-
portant roles of both the copper catalyst and base (entries 14-15).
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Table 1: Optimization of the Reaction Conditionsa
Table 2: Substrate Scope of Electronically Unbiased Alkenesa, b
yield %
rrc
(3a:3a′)
entry
catalyst
solvent
temp (°C)
(recovery
of 1a)b
1
2
3
4
5
6
7
CuCld
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
THF
60, 8 h
60, 8 h
60, 8 h
60, 8 h
60, 8 h
60, 6 h
60, 4 h
15 (80)
27 (68)
0 (94)
1:1.5
1:1
-
THF
toluene
CH3CN
DMF
42 (51)
54 (35)
63 (26)
80 (9)
3:1
4:1
6:1
8:1
DMSO
DMSOe
DMSO/THF
(1:1)e
8
CuCl
CuCl
CuCl
CuI
60, 4 h
82 (4)
86
12:1
6.5:1
5.5:1
9:1
8:1
5:1
-
DMSO/THF
9
60, 2.5 h
80, 2.5 h
60, 8 h
(1:1)f
DMSO/THF
(1:1)e
10
11
12
13
14
15g
84
DMSO/THF
a Modified conditions A: 1 (0.2 mmol) and 2a (0.6 mmol) in DMSO/THF
60 (20)
65 (18)
21 (67)
0 (96)
0 (95)
(1:1)e
b
(1:1, 0.5 mL) with CuCl (0.08 mmol) and Cs2CO3 (0.2 mmol) at 80 °C.
DMSO/THF
(1:1)e
CuCl2
Cu(OTf)2
none
60, 8 h
rr or E/Z is > 20:1 if not stated otherwise. c 100 °C. d 60 °C.
DMSO/THF
60, 8 h
Encouraged by the broad olefin scope, various functionalized
alkyl halides were examined (Table 3). Treatment of acyclic α-
bromo esters with 1a under optimized reaction conditions A gave
products 4a−4c with excellent regioselectivities, while cyclic α-
bromo esters resulted in the formation of 4d and 4e with moderate
rr values. Numerous α-bromo alkyl and aryl esters including tert-
butyl, benzyl, 4-Me-phenyl and several functionalized alkyl esters
were found to be suitable coupling partners (4f−4k). Tertiary
alkyl halides with two electron-withdrawing moieties could also
be regioselectively converted to the corresponding products 4l−4o
in moderate to good yields. This alkylative olefination was opera-
(1:1)e
DMSO/THF
(1:1)e
60, 12 h
60, 12 h
DMSO/THF
CuCl
-
(1:1)e
a Conditions: 1a (0.2 mmol) and 2a (0.6 mmol) in solvent (2.0 mL) in the
presence of copper (0.08 mmol) and Cs2CO3 (0.2 mmol). b Isolated yields.
The ratio of 3a and 3a′ was determined by H NMR. d 20 mmol%. e 1.0
c
1
mL solvent. f 0.5 mL solvent. g Without Cs2CO3.
Under the optimized reaction conditions, the substrate scope
of the olefins was investigated. As shown in Table 2, a variety of
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tive with a variety of alkyl halides bearing different functional
The amides with β-γ internal olefins obtained via our protocol
are amenable to further synthetic transformations (Scheme 1). A
2.0 mmol scale synthesis was successfully carried out to give 3a
with just a slight decrease in yield and rr value. The 8-
aminoquinoline moiety could be conveniently removed by treat-
ment with BF3·OEt2 to generate diester 5. The internal double
bond could be either efficiently hydrogenated to afford δ-ester
amide 6 or dihydroxylated under Sharpless conditions to deliver
the corresponding diol intermediate, which cyclized spontaneous-
ly to produce lactone 7 in 87% yield. The ethyl ester group on 3a
could be selectively reduced with lithium aluminum hydride at
0 °C for 0.5 h to give alcohol 8; when the reaction time was pro-
longed for 4 h, both the ester and the amide could be reduced and
amino alcohol 9 was obtained.
groups including benzyl, allyl, silyl ether, methyl ether and chlo-
rine atom to deliver 4p−4t in good yields in a highly stereoselec-
tive manner. Gratifyingly, the reaction was compatible with sec-
ondary alkyl halides; ethyl 2-bromo-propionate and -valerate led
to the formation of 4u and 4v, resepectively, with good E/Z ratios
under reaction conditions B which could improve the regioselec-
tivity (rr values are 4:1 and 5:1 for 4u and 4v, respectively, under
conditions A), while ethyl α-bromo phenylacetate gave product
4w as single E isomer. Moreover, the olefination could smoothly
proceed with α-bromoketone and primary 2-cyanobenzyl bromide
to offer 4x and 4y. In some of the above cases, elevated tempera-
tures are needed to obtain better yields. Unfortunately, the
unactivated alkyl halides, benzyl bromide and ethyl bromoacetate
failed (for details, see Table S3 in SI).
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Scheme 1. Representative Derivatizations
Table 3: Substrate Scope of Alkyl Halidesa, b
To elucidate the reaction mechanism, control experiments were
performed (Scheme 2). Treatment of product 3a in conditions A
or B did not change the rr value, indicating that the regioisomer
3a′ was not generated through alkene isomerization. The addition
of TEMPO or butylated hydroxytoluene (BHT) into the reaction
mixture suppressed the desired reaction and compound 10 could
be isolated in the case of TEMPO, which suggested that this reac-
tion involved a radical process.
Scheme 2. Mechanistic Investigations
On the basis of previous literature17 and above experimental re-
sults, a plausible mechanism is illustrated in Figure 2a. Initially,
Cu(I) catalyst coordinates with 1a to afford species M1. Then, a
single electron transfer (SET) between M1 and 2a occurs, likely
aided by the base additive22 to generate a Cu(II) complex M2 and
a carbon radical M3, a process akin to the initiation step in atom
transform radical addition (ATRA)23. Subsequent migratory inser-
tion into the unactivated olefin affords a putative Cu(III) interme-
diate M4.24 Finally, a concerted Hb−Br or Ha−Br elimination,25
followed by protodemetallation would produce the major product
3a and the minor product 3a′, respectively, and regenerate Cu(I)
salt.26 To gain a deeper understanding of the excellent regioselec-
tivity in concerted H−Br elimination event, especially the key role
of DMSO in this step, DFT calculations were performed at the
SMD(DMSO)/(U)M06/[6-31G(d)/LanL2DZ(Cu)] level (see Fig-
ures S1-S4 in Supporting Information). As shown in Figure 2b, in
the presence of three DMSO molecules, concerted Hb−Br elimina-
a Conditions A: 1a (0.2 mmol) and 2 (0.6 mmol) in DMSO/THF (1:1, 1.0
mL) with CuCl (0.08 mmol) and Cs2CO3 (0.2 mmol) at 60 °C; Conditions
B: 1a (0.2 mmol) and
2 (0.6 mmol) in DMSO (1.0 mL) with
Cu(MeCN)4PF6 (0.10 mmol) and NaOMe (0.2 mmol) at 70 °C. b rr or E/Z
is > 20:1 if not stated otherwise. c Copper(I) thiophene-2-carboxylate (0.08
mmol) was used to replace CuCl. d DMSO (1.0 mL) as solvent.
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tion is much easier to occur than concerted Ha−Br elimination,
Computational details Figures S1 – S4, supplementary data Tables
S1 – S3, and experimental procedures, analytical data for all new
compounds.
which is consistent with our experimental observations that 3a
was predominantly formed. The origin of regioselectivity can be
understood by the conformationally strained metallacyclic transi-
tion state. Hb−Br elimination occurs concertedly through an eight-
membered-ring transition state TS1-Hb with a smaller energy
barrier (∆E‡) of 10.9 kcal/mol, whereas Ha−Br elimination (via a
six-membered-ring TS1-Ha) requires a larger ∆E‡ value (13.9
kcal/mol).
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AUTHOR INFORMATION
Corresponding Author
E-Mail: fujk109@nenu.edu.cn
guanw580@nenu.edu.cn
bixh507@nenu.edu.cn
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Author Contributions
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# C. T.; R. Z. and B. Z. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge the NNSFC (21702027, 21502017,
21522202, 21773025), Young Scientific Research Foundation of
Jilin Province (20180520228JH) and Fundamental Research
Funds for the Central Universities (2412017QD010,
2412017FZ015).
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Figure 2. Proposed mechanism and energy profiles of concerted H−Br
elimination in the presence of three DMSO.
In summary, we have developed the first Cu-catalyzed intermo-
lecular Heck-type coupling of unactivated olefins and alkyl hal-
ides with the assistant of a bidentate auxiliary. This protocol was
compatible with 1°, 2°, 3° alkyl bromides and various aliphatic
alkenes to produce olefinated products with excellent regio- and
stereoselectivity. These resultant internal β,γ-unsaturated amides
were proven to be versatile synthetic building blocks in a variety
of chemical transformations. Detailed mechanistic studies and
DFT calculations indicated a radical pathway involving a dime-
thyl sulfoxide assisted concerted H−Br elimination event of con-
formationally strained Cu(III)cyclic transition state. Further appli-
cations and mechanistic studies are in progress in our laboratory.
ASSOCIATED CONTENT
Supporting Information
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(26) Another possible reaction pathway involving a direct β-H elimina-
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see Figure S1 in Supporting Information.
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