Iron-Catalyzed Reductive Vinylation of Tertiary Alkyl Oxalates with Activated Vinyl Halides

Article abstract of DOI:10.1021/acs.orglett.0c00561

We present herein a rare and efficient method for the creation of vinylated all carbon quaternary centers via Fe-catalyzed cross-electrophile coupling of vinyl halides with tertiary alkyl methyl oxalates. The reaction displays excellent functional group tolerance and broad substrate scope, which allows cascade radical cyclization and vinylation to afford complex bicyclic and spiral structural motifs. The reaction proceeds via tertiary alkyl radicals, and the putative vinyl-Br/Fe complexation appears to be crucial for activating the alkene and enabling a possibly concerted radical addition/C-Fe forming process.

Full text of DOI:10.1021/acs.orglett.0c00561

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Letter
Iron-Catalyzed Reductive Vinylation of Tertiary Alkyl Oxalates with
Activated Vinyl Halides
Yang Ye, Haifeng Chen, Ken Yao, and Hegui Gong*
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ABSTRACT: We present herein a rare and efficient method for
the creation of vinylated all carbon quaternary centers via Fe-
catalyzed cross-electrophile coupling of vinyl halides with tertiary
alkyl methyl oxalates. The reaction displays excellent functional
group tolerance and broad substrate scope, which allows cascade
radical cyclization and vinylation to afford complex bicyclic and
spiral structural motifs. The reaction proceeds via tertiary alkyl
radicals, and the putative vinyl−Br/Fe complexation appears to be
crucial for activating the alkene and enabling a possibly concerted
radical addition/C−Fe forming process.
he challenges of conversion of unactivated alkyl C(sp3)−
TO bonds into C−C bonds and the abundance of alcohols
and their derivatives in nature have provided sustained
impetuses for the development of C(sp3)−O bond coupling
chemistry.1,2 However, prominent methods for homolytic
cleavage of unactivated alkyl C−O bonds remain limited.3
Among them, perhaps the Barton radical C−O bond
fragmentation strategy represents the most widely used one,4
which often requires forcing conditions such as UV irradiation
and/or toxic radical inducing reagents, e.g., Bu3SnH. The
radical intermediates are usually trapped with alkenes
conjugated with electron-withdrawing groups, thus limiting
the scope of the reaction types.4 Recently, Overman has
demonstrated a visible light mediated Barton C−O bond
scission strategy that allows oxalate salts and phthalimidyl-
modified oxalyl esters to generate alkyl radicals under Ir-
catalyzed oxidative and Ru-catalyzed reductive conditions,
respectively.5 We, on the other hand, disclosed that readily
accessible unsymmetrical alkyl methyl oxalyl esters are
amenable for the creation of unactivated tertiary alkyl radicals
under Zn/MgCl2 conditions that are promoted by Ni.6 Such a
protocol has enabled the development of Ni-catalyzed
reductive coupling of tertiary alkyl oxalates with aryl halides
to afford arylated all-carbon quaternary stereogenic centers
(Figure 1).6−8 However, the same conditions were not
applicable to the equivalent vinylation with vinyl halides
(Scheme 1), due to rapid dimerization of vinyl groups upon
exposure of vinyl halides to Ni(0).7 In fact, unlike the relatively
well-characterized aryl−Ni complexes in cross-electrophile
couplings, the putative vinyl−Ni intermediates have not been
isolated.9 Thus, only special tertiary benzylic halides such as
cyclotryptamine substrates are competent for vinylation with
vinyl halides, possibly due to matched reactivities.8b
Figure 1. Structures of platensimycin, (+)-flustramine, and cyclo-
bakuchiol C.
Scheme 1. Formation of C(sp2)−C(sp3) Quaternary Carbon
Centers via Cross-Electrophile Coupling of Tertiary
Oxalates
The vinylated quaternary carbon centers are ubiquitous in
bioactive and naturally occurring compounds, e.g., platensi-
mycin, (+)-flustramine, and cyclobakuchiol C (Figure 1).10
A
Received: February 13, 2020
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© XXXX American Chemical Society
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notable strategy for these structural motifs includes addition of
unactivated tertiary radicals to alkynes that affords cis-alkenes
under Fe-catalyzed or photoredox conditions.11 In addition,
Photo/Pd-catalyzed radical/Heck reactions,12a photoredox
Ru/Ni-catalyzed tertiary alkyl halides with styrenes, and vinyl
halides have been unlocked, respectively.12b,c,14 None of these
transformations relies on the coupling of C−O bond substrates
with vinyl electrophiles.
Table 1. Optimization of the Reaction of 1a with 2a
Herein, we report a Fe-catalyzed reductive coupling of
unactivated tertiary alkyl oxalates with vinyl halides that
efficiently creates vinylated all-carbon quaternary centers
(Scheme 1). In addition to the use of readily accessible
alcohol derivatives, this work highlights the utility of earth-
abundant Fe as the catalyst. To our knowledge, Fe catalysts
have not been exploited in the field of cross-electrophile
couplings except in the cases of in situ Kumada couplings.15 In
a recent work on allylation of tertiary alkyl oxalates with allyl
carbonates, Fe was used as a promoter.16 This work differs
from the densely used Ni-catalyzed methods featuring the
engagement of C(sp2)−Ni intermediates. Coordination of
vinyl halides with Fe appears to be crucial for alkene activation.
More importantly, we propose a mechanism concerning
concerted addition of alkyl radical to vinyl halides and
formation of benzyl−Fe intermediate, followed by reductive
generation of a benzyl carbanion followed by halide
elimination and resuming unsaturation to give an E-alkene
product.
a
entry
variation from the standard conditions
none
w/o MgCl2
w/o Zn
w/o Fe(acac)3
yield (%)
b
1
2
3
4
5
6
7
8
83
no reaction
trace
trace
59
47
78
8
31
trace
21
45
w/o PBI
Mn instead of Zn
Fe(acac)2 instead of Fe(acac)3
Fe powder instead of Fe(acac)3
Ni(acac)2
9
10
11
12
13
14
15
CuCl2
DMAP instead of PBI
dtbbp instead of PBI
iPr-Pybox instead of PBI
3-bromo-3-methylbutyl benzoate instead of 1a
3.0 mmol of 2a
24
5
88
b
a
NMR yield using 2,5-dimethyl furan as the internal standard from a
We first examined the coupling of a tertiary alkyl methyl
oxalate 1a with (E)-(2-bromovinyl)benzene 2a. The previous
Ni-catalyzed conditions for arylation of tertiary alkyl oxalates in
N,N-dimethylacetamide (DMA) gave 3a in <15% yield.6,17 An
extensive survey of the reaction conditions led us to identify
that a combination of Fe(acac)3 (8 mol %) and 2-(pyridin-2-
yl)-1H-benzo[d]imidazole (PBI, 1 equiv) with Zn and MgCl2
in acetonitrile at ambient temperature provided the coupling
product 3a in an optimal 83% yield (Table 1, entry 1). The
control experiments indicated the necessity of Fe, Zn, and
MgCl2 (entries 2−4). However, without PBI, a reasonably
good yield was detected (entry 5), but with more alcohol
product due to decomposition of 1a. The use of Mn to replace
Zn also generated 3a in 47% yield (entry 6), wherein the
participation of vinyl−Mn is not possible.9c While Fe(acac)2
gave 3a in a good yield, Fe powder was not suitable (entries
7−8). With CH3CN as the solvent, Ni salts enabled the
coupling but in low efficiency (entry 9).17 By contrast, copper
salts were incompetent (entry 10).14 Replacement of PBI with
other pyridine-containing additives did not improve the results
(entries 11−13). The bromo analog of 1a proved to be
unsuitable (entry 14), indicating a unique feature of C−O
bond vinylation of this work. Finally, the reaction on a gram
scale gave 3a in 88% yield (entry 15).
This C−O bond vinylation method displayed excellent
compatibility for a broad range of tertiary alkyl oxalates when
coupling with (E)-(2-bromovinyl)benzene (Figure 2). The all-
carbon quaternary centers containing geminal dimethyl groups
were effectively created (e.g., 4−36). Moderate to good yields
were obtained for cholesterol and cholic acid derived 37−38.
The more sterically demanding tertiary alkyl oxalates
containing ethyl and propyl groups proved to be compatible,
as evident in the products of 39−42, although a low yield was
observed for 42 that contains the dipropyl- and phenylethyl-
connected carbon center. Such sterically congested steric
centers have not been reported in the previous methods
mixture containing other impurities after quick flash column
chromatography. Isolated yield (average of 2 independent runs).
b
pertaining to tertiary alkyl radicals.11−14 The reaction also
exhibited moderate coupling efficiency for tertiary alkyl
substrates within closed rings, as evident in 43−46 including
3-, 4-, 6-, and 12-membered ones. The bicyclic cyclotryptamine
product 47 was obtained in 41% yield. Finally, the
simultaneous vinylation of the dioxalates was successful as
exemplified by 48. A wide range of functional groups were
tolerated. The notable ones include ester, silyl ether, alkyl
bromide, aryl chloride and iodide, and an acidic amide proton.
Next, we explored the suitability of various vinyl halides for
the coupling with 1a. The reactions were compatible with 1-
aryl-conjugated vinyl halides. The aryl moieties bearing
electron-withdrawing groups in general resulted in higher
coupling yields (e.g., 3b−3e) than those with electron-
donating ones (e.g., 3j). Among the methoxy-substituted
products 3l−3n, the ortho-one was the most effective. The (Z)-
(2-bromovinyl)benzene gave the trans-product 3n in 67%
yield. cis-Alkenyl bromide was fully recovered in the absence of
oxalate 1a. Interestingly, vinyl iodide and chloride generated
3n and 3a in 63% and 77% yields, respectively. Good coupling
results were also observed for thiophenyl, furyl, ferrocenyl, and
vinyl conjugated vinyl bromides as manifested by the examples
of 3r−3t and 3v. (2,2-Difluorovinyl)benzene afforded cis-1-
fluoro-2-phenyl 3u in 58% yield. 1,1-Diphenyl and 1-phenyl-1-
methyl substituted vinyl bromides were competent to generate
3w and 3x in 58% and 32% yields, whereas conversion of (E)-
((2-bromovinyl)oxy)benzene to 3y was inefficient. Finally, a
screening of different alkenes including styrene revealed that
only allyl carbonate gave an allylated product in 10% yield
(Figure 3).
To gain insight into the reaction details, the assembly of
alkene-tethered tertiary alkyl oxalates 49a−c with (E)-(2-
B
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Figure 3. Scope of vinyl bromides. (a) The E/Z ratio was determined
1
by H NMR. (b) NMR yield using 2,4-dimethyl furan as the internal
reference. (c) DMA as solvent and allylated product was formed.
bromovinyl)benzene was performed using the standard
method. The formation of cyclization/coupling products
50a−c supported that the oxalates proceed through a C−O
bond radical scission process (Figure 4). Based on our previous
studies, the generation of a tertiary radical arose from
reduction of the oxalate with Zn/MgCl2,6 perhaps promoted
by low-valent Fe. Thus, we further extended the radical
cyclization/vinylation cascade strategy to afford the more
complex bicyclic and spiral products 50d−g as single
diastereomers. All these examples showcased the utility of
this work in the preparation of sophisticated structures. Of
note is the facile construction of two consecutive all-carbon
quaternary centers in 50g. The radical cyclization/vinylation
process also features the transformation of more stable tertiary
alkyl radicals to primary and secondary ones, suggesting that
the latter two are kinetically more favored for subsequent
vinylation.
The reaction did not seem to involve in situ conversion of
vinyl bromide to vinyl−Zn. In the absence of oxalate 1a, (E)-
(bromovinyl)benzene was primarily recovered under the
standard conditions or with stoichiometric Fe(acac)3 (eq 1),
Figure 2. Scope of tertiary alkyl methyl oxalates. (a) (E)-1-(4-(2-
Bromovinyl)phenyl)ethanone (1 equiv) as the vinyl bromide. (b)
Oxalate (1 equiv), (E)-(2-bromovinyl)benzene (3 equiv), Fe(acac)3
(35% mmol), Zn (5 equiv), PBI (2.5 equiv). (c) Oxalate (1 equiv),
(E)-(2-bromovinyl)benzene (3 equiv).
C
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52, albeit in a low yield (eq 2).17 Thus, addition of a tertiary
alkyl radical to β-carbon of styryl bromide−Fe complex I-1 to
give a benzylic radical intermediate I-3 is less likely.21 Instead,
we propose that formation of C−Fe bonded intermediate I-2 is
plausible via a concerted process. Elimination of Fe and Br
affords the vinylated product. A concerted elimination process
can be ruled out, since both E- and Z-alkenyl bromides gave
the E-product (e.g., 3n). In a recent study by Walsh, addition
of a stable secondary benzyl radical to an analog of 51 did not
give a cyclopropyl ring-opening product. An anionic
intermediate was proposed in their addition step.22 Formation
of a benzyl anion I-4 is possible, which explains the formation
of styryl fluoride 3u by elimination of F−, since release of a
fluorine radical from the benzyl radical I-3 is less operative.
n+1
Taken together, it appears that benzyl-Fe
intermediate I-2
may further be reduced by Zn to afford benzyl carbanion I-4
and Fen+; single bond rotation occurs prior to elimination of
halides from I-4 that furnishes an E-vinyl product.
In summary, we have demonstrated unactivated tertiary alkyl
oxalates and aryl-conjugated vinyl bromides underwent
efficient cross-electrophile coupling to furnish sterically
demanding vinylated quaternary stereogenic centers. The
reactions feature the exceptionally rare Fe-catalyzed reductive
coupling and the unusual unactivated tertiary alkyl C−O bond
radical fragmentation. The substrates are readily accessible, and
the vinyl products are amenable for diverse functional group
conversions (e.g., to acids and aldehydes),23 all rendering this
method intriguing for preparation of complex structures as
showcased by the examples of the radical cyclization/coupling
manifolds.
Figure 4. Cascade radical cyclization/vinylation of 49a−g.
suggesting that oxidative insertion of vinyl bromide to low
valent Fe forming vinyl−Fe is less likely,18 which differs from
the Ni-catalyzed method.19 Since Fe(acac)2 also resulted in 3a
in a good yield (Table 1, entry 7) whereas Fe powder is
essentially incompetent (Table 1, entry 8), it is reasonable to
conclude that the reaction may involve FeI or FeII as the actual
catalytic species, consistent with the proposal in Hu’s addition
of tertiary alkyl radicals to alkynes.11a
Although the details of the reaction mechanism require
considerably more insightful studies, it appears that coordina-
tion of vinyl bromide with low valent Fe to give I-1 may play
an important role for the radical addition process (Scheme
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00561.
■
sı
2).20 By mixing Fe(acac)3 or Fe(acac)2 with 2a, H NMR
1
Detailed experimental procedures, characterization of
new compounds (PDF)
Scheme 2. Formation of C(sp2)−C(sp3) Quaternary Carbon
Centers via Cross-Electrophile Couplings
AUTHOR INFORMATION
Corresponding Author
■
Hegui Gong − School of Materials Science and Engineering,
Center for Supramolecular Chemistry and Catalysis and
Department of Chemistry, Shanghai University, Shanghai,
China; orcid.org/0000-0001-6534-5569;
Email: hegui_gong@shu.edu.cn
Authors
spectra indicated two new peaks appeared in ranges of 3.5−4.0
and 5.3−5.5 ppm with respect to the individual spectra of 2a
and Fe(acac)3 (Figures S1−S2).17 These results clearly
indicated complexation of Fe with vinyl bromide. In contrast,
the lack of reactivity for styrene (Figure 3) prompts us to
conclude that leaving groups such as halide in vinyl halides are
crucial to push the reaction to move forward, likely due to its
induction of formation of I-1.
Yang Ye − School of Materials Science and Engineering, Center
for Supramolecular Chemistry and Catalysis and Department
of Chemistry, Shanghai University, Shanghai, China
Haifeng Chen − School of Materials Science and Engineering,
Center for Supramolecular Chemistry and Catalysis and
Department of Chemistry, Shanghai University, Shanghai,
China
Ken Yao − School of Materials Science and Engineering, Center
for Supramolecular Chemistry and Catalysis and Department
of Chemistry, Shanghai University, Shanghai, China
Interestingly, the deliberately designed radical clock vinyl
bromide 51 only resulted in cyclopropyl ring retention product
D
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Lutsker, E.; Reiser, O. Synthesis of Chiral Tetrahydrofurans and
Pyrrolidines by Visible-Light-Mediated Deoxygenation. Eur. J. Org.
Chem. 2017, 2017, 2130−2138.
Complete contact information is available at:
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(6) (a) Ye, Y.; Chen, H.; Sessler, J. L.; Gong, H. Zn-Mediated
Fragmentation of Tertiary Alkyl Oxalates Enabling Formation of
Alkylated and Arylated Quaternary Carbon Centers. J. Am. Chem. Soc.
2019, 141, 820−824. (b) Gao, M.; Sun, D.; Gong, H. Ni-Catalyzed
Reductive C−O Bond Arylation of Oxalates Derived from α-Hydroxy
Esters with Aryl Halides. Org. Lett. 2019, 21, 1645−1648. (c) Yan, X.-
B.; Li, C.-L.; Jin, W.-J.; Guo, P.; Shu, X.-Z. Reductive Coupling of
Benzyl Oxalates with Highly Functionalized Alkyl Bromides by Nickel
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by National Natural Science
Foundation of China (Grant Nos. 21871173 and 21572140).
(7) Liu, J.; Ren, Q.; Zhang, X.; Gong, H. Preparation of Vinyl Arenes
by Nickel-Catalyzed Reductive Coupling of Aryl Halides with Vinyl
Bromides. Angew. Chem., Int. Ed. 2016, 55, 15544−15548.
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Formation of trans alkenes was due to isomeriarion of cis products
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F
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Org. Lett. XXXX, XXX, XXX−XXX