Radical-Mediated Heck-Type Alkylation: Stereoconvergent Synthesis of Functionalized Polyenes

Article abstract of DOI:10.1021/acs.orglett.9b02838

The stereospecific synthesis of polyenes is of great synthetic value. Disclosed herein is a new, efficient, stereoconvergent approach for the synthesis of functionalized polyenes via a radical-mediated Heck-type alkylation. The easily accessed Z- and E-mixed alkenes are harnessed as starting material, leading to a unique stereoisomer of polyenes. In addition, the transformation features mild reaction conditions and broad functional group compatibility. A variety of valuable 1,3-dienes and 1,3,5-trienes are afforded in useful yields.

Full text of DOI:10.1021/acs.orglett.9b02838

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Radical-Mediated Heck-Type Alkylation: Stereoconvergent
Synthesis of Functionalized Polyenes
Hong Zhang,† Xinxin Wu,† Yunlong Wei,† and Chen Zhu*,†,‡
†Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, 199 Ren-Ai Road, Suzhou, Jiangsu 215123, China
‡Key Laboratory of Synthesis Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Science, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: The stereospecific synthesis of polyenes is of great synthetic value. Disclosed herein is a new, efficient,
stereoconvergent approach for the synthesis of functionalized polyenes via a radical-mediated Heck-type alkylation. The easily
accessed Z- and E-mixed alkenes are harnessed as starting material, leading to a unique stereoisomer of polyenes. In addition,
the transformation features mild reaction conditions and broad functional group compatibility. A variety of valuable 1,3-dienes
and 1,3,5-trienes are afforded in useful yields.
onjugated polyenes are extensively present in natural
products which usually demonstrate unique biological
a stereoconvergent pathway, in which the Z- and E-alkene
mixture readily accessed from the Wittig reactions is employed
as starting material, leading to a single stereoisomer of
polyenes. The transformation is performed under mild
conditions, manifesting a broad functional group tolerance. A
variety of valuable 1,3-dienes and 1,3,5-trienes are furnished in
useful yields.
At the outset, the reaction of a mixture of Z- and E-1a with
the multifunctionalized tertiary alkyl bromide 2a was
investigated to optimize the reaction conditions (Table 1; for
details see the Supporting Information (SI)). With copper salt
as catalyst, the use of dimethylacetamide (DMA) delivered a
better yield than other solvents (entries 1−6). The desired
alkylated 1,3-diene 3a was exclusively obtained in E,E-
configuration. The use of Na2HPO4 as base significantly
improved the yield to 94% (entries 7−11). Using less
expensive CuCl instead of Cu(OTf)2 afforded an identical
yield (entry 12). Variation of bpy to other ligands decreased
the yield (entries 13−15). The reaction outcome was not
compromised when reducing the amount of 2a to 1.5 equiv
and the reaction temperature to 40 °C (entry 16). The
reaction also proceeded with other metal catalysts, but afforded
C
activities.1 For instance, Stellettin C is a cytotoxic triterpene
isolated from a marine sponge, Stelletta sp.;2 Inthomycin A is a
specific inhibitor of cellulose biosynthesis and displays in vitro
inhibitory activity against human prostate cancer growth;3
Vitamin A and D2 play a far greater role in health and protect
against numerous diseases (Scheme 1a).4 Furthermore,
conjugated polyenes often serve as versatile feedstocks in
synthetic chemistry, e.g. in the Diels−Alder cycloaddition
reactions as a 4π-component.5 For industrial use, the
polymerization of 1,3-dienes and other polyenes via Ziegler−
Natta catalysis affords the high-value polymerized materials.6
Therefore, development of practical approaches to produce
conjugated polyenes is in high demand.7
The conventional preparation of conjugated polyenes mainly
relies on two pathways: the Wittig reaction and the Heck−
Mizoroki cross-coupling (Scheme 1b). The former generally
results in a mixture of Z- and E-olefinic isomers;8 the latter
offers a solution for the stereocontrol problem, but sometimes
the vinyl iodide precursor is not easily obtained.9 As for an
efficient polyene synthesis, the accessibility of starting materials
should also be fully considered along with the aim of gaining a
unique stereoselectivity. Herein, we disclose a new approach
for the synthesis of functionalized polyenes via a radical-
mediated Heck-type alkylation (Scheme 1c).10 Notably, this is
Received: August 10, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02838
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
lead to a mixture of stereoisomeric 1,3-dienes in about a 1:1
ratio (entry 20).
Scheme 1. Importance of Conjugated Polyenes and the
Synthesis
With the optimized reaction conditions in hand, we set
about assessing the generality of this protocol (Scheme 2).
a
Scheme 2. Scope of Dienes
a
Table 1. Reaction Conditions Survey
entry
catalyst
base
ligand
solvent
yield (%)
1
2
3
4
5
6
7
8
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuCl
CuCl
CuCl
CuCl
CuCl
CuI
CuBr2
FeCl2
Ir(ppy)3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2HPO4
CsF
K2CO3
Na2CO3
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
TTMSS
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
phen
PPh3
dppe
bpy
bpy
bpy
bpy
−
DCE
29
36
30
50
30
61
84
89
60
43
94
94
87
77
80
94
85
83
48
68
DCM
acetone
CH3CN
DMF
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
9
a
10
11
12
13
14
15
Reaction conditions: 1 (0.2 mmol), 2a (1.5 equiv), CuCl (10 mol
%), bpy (10 mol %), and Na2HPO4 (1.1 equiv) in DMA (2 mL)
b
under N2, 40 °C. 80 °C.
First, a variety of aryl dienes bearing diverse functional groups
were investigated. Notably, performing the reaction on a 1.0
mmol scale did not compromise the reaction outcome (3a).
Both electron-rich (e.g., alkyl, aryl, OMe) and -deficient (e.g.,
halide, OCF3, CF3, CO2Me) groups were tolerated in the
reaction, readily affording the corresponding alkylated E,E-
dienes (3b−3l). Despite the sensitivity of alkynes to radical
reaction conditions, the radical alkylation proceeded exclu-
sively at the diene part (3m). The presence of aryl bromide
was useful, as it reserved a platform for product elaboration by
cross-couplings (3h and 3s). The change of substitution from
the para- to meta- or ortho-position did not impede the
transformation (3n−3q). In addition to phenyl and naphthyl
(3r) dienes, the analogous heteroaryl (e.g., thienyl, benzo-
thienyl, pyridyl, quinolyl) dienes could also be prepared by this
method (3t−3w). The alkylation of multiply substituted
dienes, in particular the less reactive internal dienes, also
b
16
17
18
19
c
20
a
Reaction conditions: 1a (0.2 mmol), 2a (2.0 equiv), catalyst (10 mol
%), ligand (10 mol %), and base (1.1 equiv) in solvent (2 mL) under
N2 for 9 h, 80 °C. Yields of isolated products are given. 2a (1.5
equiv), 40 °C. fac-Ir(ppy)3 (2 mol %), TTMSS (2.0 equiv),
irradiated with 14 W blue LEDs for 3 h. bpy = bipyridine. TTMSS =
(i-Pr)3SiSH.
b
c
lower yields (entries 17−19). This radical transformation
could be promoted by photocatalytic conditions; however, this
B
DOI: 10.1021/acs.orglett.9b02838
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
occurred in a stereospecific manner, which was determined by
NOE experiments (3x−3z). Moreover, in the case of 3y, the
addition of an alkyl radical adjacent to the methyl side was
verified by HMBC experiment. Remarkably, the protocol could
also be applied to the intricate scaffolds based on natural
products and drug molecules, for instance, febuxostat,
lithocholic acid, and Ibuprofen (3aa−3ac). The case of 3ac
was intriguing, in which the racemization of chirality at the α-
position of carbonyl did not take place under the mild reaction
conditions (for details, see the SI). It should be noted that the
sole stereoisomer of diene products was stereoconvergently
furnished from the Z,E-mixture of precursors, indicating
supreme stereocontrol in the reaction.
Scheme 4. Variation of Alkylating Reagents
The alkylation of 1,3,5-trienes was subsequently studied. A
series of representative examples were tested under the
previous conditions (Scheme 3). Likewise, the reaction readily
a
Scheme 3. Scope of Trienes
a
Reaction conditions: 1 or 4 (0.2 mmol), 2b-d (1.5 equiv), CuCl (10
mol %), bpy (10 mol %), and Na2HPO4 (1.1 equiv) in DMA (2 mL)
b
under N2, 40 °C. 80 °C.
Scheme 5. Proposed Mechanism
a
Reaction conditions: 4 (0.2 mmol), 2a (1.5 equiv), CuCl (10 mol
%), bpy (10 mol %), and Na2HPO4 (1.1 equiv) in DMA (2 mL)
under N2, 40 °C.
the radical chain process (path b), to convert the intermediate
c to the final product 3. First, SET from c to the Cu(II) species
affords the allylic cation d that then reacts with bromide to
generate the allylbromide e. Alternatively, intermediate c could
abstract a bromine atom from compound 2 to afford the
allylbromide e. Meanwhile, the alkyl radical a is regenerated
and perpetuates the radical chain process. Eventually,
dehydrobromination of e promoted by a base results in the
product 3.11 This is also the key step to offering exclusive
stereoselectivity as well as the thermodynamically favored E,E-
diene product. Another possible approach to afford the
product 3 might directly go through the direct deprotonation
of cation d.
In addition to the well-known function of dienes, serving as
an important 4π-component in the Diels−Alder cyclo-
addition,5 the products could also be transformed into other
valuable molecules. For example, treating 3a with tBuOK in
wet ethanol led to a new diene product 7 via decarboxylation
(Scheme 6a). While direct reduction of 3a by a strong
reducing agent such as LiAlH4 led to a messy reaction, the
same expected product 8 was obtained through the tBuOK-
mediated decarboxylative hydroxymethylation approach
(Scheme 6b).
proceeded regardless of the steric and electronic effects,
leading to the corresponding functionalized E,E,E-trienes with
exclusive stereoselectivity (5a−5f). Multisubstituted trienes
were also apt to afford the products that are otherwise hard to
make (5g and 5h).
Then we focused attention toward varying the alkylating
reagent 2a in order to evaluate the necessity of each functional
group in 2a (Scheme 4). The reaction of 2b, in which another
alkyl group such as ethyl was employed in lieu of methyl, with
either diene or triene afforded the desired products (6a and
6b). Moreover, the methyl group could also be replaced with
an aryl group, leading to the similar alkylated diene and triene
products (6c and 6d). The reaction using 2d readily
proceeded, indicating that the cyano group was dispensable
to the alkylation reaction (6e and 6f). However, it was found
that the ester group was crucial, as the transformation did not
occur in the absence of ester under the current conditions.
A proposed mechanism is depicted in Scheme 5. The
interaction between a Cu(I) salt and compound 2 generates
the electrophilic alkyl radical a and Cu(II) species. The
addition of intermediate a to diene 1 leads to an allyl radical
represented by resonance structures b and c. There are three
pathways: the Cu-catalyzed SET process (path a and c) and
In conclusion, we have disclosed a novel protocol for
stereoconvergent synthesis of conjugated polyenes via a
C
DOI: 10.1021/acs.orglett.9b02838
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Scheme 6. Product Transformations
radical-mediated Heck-type alkylation. The Z- and E-alkene
mixtures, which are readily obtained from the Wittig reactions,
are employed as starting material, leading to the single
stereoisomers of polyenes. The transformation features mild
reaction conditions and broad functional group tolerance. A
vast array of valuable 1,3-E,E-dienes and 1,3,5-E,E,E-trienes are
furnished in useful yields.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02838.
Experimental details, compound characterization data,
and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chzhu@suda.edu.cn.
ORCID
Chen Zhu: 0000-0002-4548-047X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
C.Z. is grateful for the financial support from the National
Natural Science Foundation of China (21722205), the Project
of Scientific and Technologic Infrastructure of Suzhou
(SZS201708), and the Priority Academic Program Develop-
ment of Jiangsu Higher Education Institutions (PAPD).
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