Cobalt-Catalyzed Tandem Radical Cyclization/C-C Coupling Initiated by Directed C-H Activation

Article abstract of DOI:10.1021/acs.orglett.9b01846

A cobalt-N-heterocyclic carbene catalyst promotes a tandem radical cyclization/C-C coupling reaction between tosylamide-tethered bromo-alkenes and aryl N-H imines initiated by chelation-assisted arene C-H activation, affording 3-(arylmethyl)pyrrolidine de

Full text of DOI:10.1021/acs.orglett.9b01846

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cobalt-Catalyzed Tandem Radical Cyclization/C−C Coupling
Initiated by Directed C−H Activation
Qiao Sun and Naohiko Yoshikai*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
ABSTRACT: A cobalt−N-heterocyclic carbene catalyst
promotes a tandem radical cyclization/C−C coupling reaction
between tosylamide-tethered bromo-alkenes and aryl N−H
imines initiated by chelation-assisted arene C−H activation,
affording 3-(arylmethyl)pyrrolidine derivatives in moderate to
good yields. The reaction tolerates a variety of substituents on
the aryl imine as well as various modifications on the bromo-
alkene substrate.
he transition-metal-catalyzed 1,2-dicarbofunctionalization
of unactivated alkenes with organic electrophiles and
couplings with various Grignard reagents.3 The scope of the
tandem radical cyclization/C−C coupling has been further
extended using nickel4 or iron5 catalysts and organozinc or
Grignard reagents, allowing access to pharmaceutical- and
natural-product-relevant pyrrolidine, tetrahydrofuran, and γ-
butyrolactone derivatives.6 Analogous tandem transformations
have also been achieved in a reductive fashion using organic
iodides or bromides and zinc in place of preformed
organometallic reagents.7 Herein, we report that an arene
bearing a directing group can be used as a viable coupling
partner for the tandem radical cyclization/C−C coupling
manifold (Scheme 1b). Thus, a cobalt−N-heterocyclic carbene
(NHC) catalyst promotes a coupling reaction between a
tosylamide-tethered bromo-alkene and an aryl N−H imine,
which is initiated by imine-directed C−H activation and
affords a 3-benzylated pyrrolidine derivative in moderate to
good yield.
T
organometallic reagents represents an attractive transformation
to increase molecular complexity in a single operation.1 The
tandem radical addition/transition-metal-mediated cross-cou-
pling has emerged as a powerful approach to achieve such
transformations,2 especially for carbo- and heterocycle syn-
thesis (Scheme 1a). A prototypical mechanistic scenario for
Scheme 1. Transition-Metal-Catalyzed Tandem Radical
Cyclization/C−C Coupling
Over the past several years, chelation-assisted arene C−H
alkylation reactions using alkyl halides and pseudohalides have
been developed using various transition metal catalysts
including cobalt,8 nickel,9 iron,10 manganese,11 palladium,12
and ruthenium,13 which have allowed regioselective function-
alization of arenes with primary and secondary alkyl groups.
Among them, the reactions catalyzed by first-row transition
metals have been proposed to involve generation of an alkyl
radical from the alkyl halide. As a mechanistic probe to support
the radical intermediate, 6-bromohex-1-ene was often used to
afford a mixture of cyclized and uncyclized C−H alkylation
products, albeit in varying ratios depending on the catalytic
system and the arene substrate.8e,9c−f,10b−d,11a For example, our
previously developed cobalt-catalyzed, imine-directed C−H
alkylation reactions gave the uncyclized product as the major
or even the sole product.8d−f We reasoned that this
this type of reaction involves single electron transfer (SET; or
halide abstraction) between an organotransition metal species
and a tethered halo-alkene, radical cyclization, recombination
of the resulting radical and the transition metal species, and
C−C reductive elimination. This concept was demonstrated by
Oshima for cobalt-catalyzed tandem radical cyclization/cross-
Received: May 27, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01846
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
chemoselectivity could be reversed for a bromo-alkene with a
bulkier tether group (Z), thus allowing for selective tandem
radical cyclization/C−C coupling.
The present study commenced with screening of reaction
conditions for the coupling between N-allyl-N-(2-bromoethyl)-
p-toluenesulfonamide (1a, 0.3 mmol) and pivalophenone N−
H imine (2a, 0.2 mmol) (Table 1; see Scheme S1 and Table
induction in the cyclization and afforded 3aa as a racemic
mixture. The use of NHCs bearing either primary alkyl or
tertiary alkyl groups led to a diminished yield of 3aa. Besides
the N,N′-dialkylimidazolinium salts, analogous benzimidazo-
lium salts also displayed comparable performance (entries 7
and 8), whereas common NHCs such as IMes and IPr
completely shut down the desired reaction (entries 9 and 10).
It should be noted that chloro- and iodo-analogues of 1a
afforded only a trace amount of 3aa. The C−Cl bond cleavage
of the former was rather sluggish, while the latter
predominantly underwent cyclization without engaging 2a.
With the optimized conditions (Table 1, entry 6) in hand,
we explored the reaction of 1a with various N−H imine
substrates (Scheme 2). A variety of substituted pivalophenone
N−H imines participated in the reaction to afford the desired
products 3aa−3ao in moderate to good yields, with tolerance
to substituents such as methyl, methoxy, trifluoromethoxy,
fluoro, chloro, and trifluoromethyl groups. The reaction of the
a
Table 1. Effect of Ligands
a
Scheme 2. Reaction of 1a with Various N−H Imines
b
entry
ligand
yield (%)
1
2
3
4
5
6
7
8
9
L1·HBF4
L2·HCl
44
54
45
64
68
74
51
62
0
L3·HBF4
L4·HBF4
L5·HBF4
L5·HBF4
L6·HBr
L7·HBr
IMes·HCl
IPr·HCl
c
10
0
a
The reaction was performed using 0.3 mmol of 1a and 0.2 mmol of
b
2a (0.2 M). Determined by GC using n-tridecane as an internal
standard. The reaction was performed at 0.08 M.
c
S1 for full details). A catalytic system comprised of CoBr2 (10
mol %), N,N′-diisopropylimidazolinium tetrafluoroborate (L1·
HBF4, 10 mol %), and t-BuCH2MgBr (2 equiv), which was the
optimum system for the ortho-alkylation of pivalophenone N−
H imines,8f afforded the desired product 3aa in 44% yield
(entry 1). The reaction was accompanied by several
byproducts. Thus, the imine 2a also underwent ortho-alkylation
with 1a without cyclization (6%) and ortho-neopentylation
with t-BuCH2MgBr (20%). Meanwhile, 1a underwent
dehydrobrominative cyclization and reductive cyclization to
afford 3-methylene-1-tosylpyrrolidine and 3-methyl-1-tosylpyr-
rolidine (22% combined yield). GCMS analysis also indicated
the formation of a small amount (2%) of 3-(3,3-dimethylbu-
tyl)-1-tosylpyrrolidine, which likely formed via tandem radical
cyclization/cross-coupling with t-BuCH2MgBr. Regardless of
the complexity of the side reactions, which were difficult to
suppress completely, modification of the NHC ligand allowed
us to improve the yield of the desired tandem reaction. Thus,
replacement of the i-Pr groups of L1 with bulkier secondary
alkyl groups was found to increase the yield of 3aa (entries 2−
5). In particular, NHCs bearing 3-pentyl groups (L4) and
cyclohexylethyl groups (L5) afforded 3aa in more than 60%
yield. Using L5, the yield of 3aa was further improved to 74%
by lowering the concentration (entry 6). As expected from the
radical cyclization mechanism, L5 caused no asymmetric
a
The reaction was performed on a 0.2 mmol scale under the
b
conditions in Table 1, entry 6. The major regioisomer is shown (rr =
regioisomer ratio). The product was obtained after acidic hydrolysis
of the crude reaction mixture.
c
B
DOI: 10.1021/acs.orglett.9b01846
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Organic Letters
Letter
a
parent pivalophenone imine could be performed on a 5 mmol
scale without an apparent decrease in the yield of 3aa. The C−
H activation took place at the less hindered position for the
imines bearing a methyl, methoxy, chloro, or trifluoromethyl
group at the meta-position (see 3ah−3ak). On the other hand,
the meta-fluoro-substituted imine afforded a mixture of two
regioisomers (see 3al) with preference for the product of
proximal C−H activation, presumably due to the secondary
directing effect of the fluorine atom. A 3,4-methylenedioxy
group also caused competitive formation of two regioisomers
(see 3am). While the imine bearing an ortho-methyl group
failed to participate in the reaction (data not shown), the one
bearing an ortho-fluorine atom afforded the desired product
3ao in moderate yield. 2-Naphthyl imine underwent exclusive
C−H activation at the less hindered 3-position (see 3ap), and
2-thienyl imine was also amenable to the tandem reaction (see
3aq). Besides tert-butyl N−H imine, primary and secondary
alkyl N−H imines as well as benzophenone N−H imine also
served as directing groups for the present reaction, affording
the products 3ar−3at albeit in moderate yields. By contrast,
acetophenone N-PMP (p-methoxyphenyl) imine failed to
participate in the present reaction.
Table 2. Reaction of Various Bromo-alkenes with 2a
Next, we explored the reaction between 2a and various
bromoalkene substrates (Table 2). NTs-tethered substrates
bearing substituted allyl groups such as crotyl, methallyl, 1-
buten-3-yl, and cyclohexen-3-yl groups underwent the radical
cyclization/arylation to afford the desired products 3ba−3ea in
respectable yields (entries 1−4). The diastereoselectivity for
the N-crotyl substrate, which should be determined in the
arylation step, was moderate (1.4:1; entry 1). The N-(1-buten-
3-yl) substrate afforded the cis-isomer as the major product in a
2:1 ratio (entry 3). The N-(cyclohexen-3-yl) substrate afforded
3ea as a single diastereomer as a result of cis-fusing cyclization
and diastereoselective arylation (entry 4). The present tandem
reaction also tolerated modification on the bromoethyl group
of the tosylamide substrate, as exemplified by the formation of
2,4-disubstituted or 3,4-disubstituted pyrrolidines 3fa−3ha in
52−66% yields, with the cis isomers being the major products
(entries 5−7). In general, the diastereoselectivities of these
reactions are comparable to that of analogous pyrrolidine-
forming radical cyclization reactions,7c,14 and may be
rationalized by the Beckwith−Houk model.15 The N-Ts
group could be replaced by an N-Ph group without
significantly affecting the reaction efficiency (entry 8). An
acetal oxygen-tethered bromo-alkene underwent efficient
tandem cyclization/arylation to afford the tetrahydrofuran
derivative 3ja in high yield (entry 9). 1-Bromo-2-(but-3-en-1-
yl)benzene afforded the 1-benzylindane derivative 3ka in a
moderate yield, presumably via the corresponding aryl radical
(entry 10). It is worthwhile to comment on byproducts
observed in some of the low-yielding examples (see Scheme S2
for detail). The products 3ba and 3ea were accompanied by
substantial amounts of dehydrobrominative and/or reductive
cyclization products, while 3ca formed together with a nearly
equal amount of the uncyclized C−H alkylation product.
These problems may be attributed to the sluggishness of the
secondary alkylation (for 3ba and 3ea) and radical cyclization
onto the disubstituted olefinic carbon (for 3ca). Note that the
reaction using 6-bromohex-1-ene under the present conditions
predominantly afforded the direct alkylation product, along
with a small amount (<10%) of the cyclized product (see
Scheme S3 for this and other unsuccessful examples).
a
The reaction was performed on a 0.2 mmol scale under the
b
conditions in Table 1, entry 6. The diastereomer ratio, determined
by 1H NMR, is shown in the parentheses. For entries 3−7, the major
c
diastereomer (shown) was assigned by 2D NMR. The E/Z ratio of
the bromo-alkene was 5.3:1.
The present cyclization products are amenable to radical
decomposition of the pivaloyl N−H imine group to a cyano
group.8f Thus, the ortho-iminobenzyl pyrrolidines 3aa, 3af, and
3ao could be readily converted to the corresponding ortho-
cyanobenzyl derivatives in good yields in the presence of a
Cu(OAc)2 catalyst under an oxygen atmosphere (Scheme 3).16
Scheme 4 shows a proposed catalytic cycle of the present
tandem radical cyclization/arylation via C−H activation. In the
presence of excess t-BuCH2MgBr, the N−H imine is likely
deprotonated to generate magnesium alkylideneamide species
2·MgBr.8f Meanwhile, the Grignard reagent would also
transform the cobalt precatalyst and the imidazolinium salt
to an NHC-coordinated, low-valent alkylcobalt species A. The
species A would undergo chelation-assisted ortho-metalation of
C
DOI: 10.1021/acs.orglett.9b01846
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Imine-to-Nitrile Conversion
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.9b01846.
Detailed experimental procedures and spectral data for
new compounds (PDF)
AUTHOR INFORMATION
■
Scheme 4. Proposed Catalytic Cycle
Corresponding Author
*E-mail: nyoshikai@ntu.edu.sg.
ORCID
Naohiko Yoshikai: 0000-0002-8997-3268
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Nanyang Technological
University and Singapore Ministry of Education (MOE2016-
T2-2-043).
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DOI: 10.1021/acs.orglett.9b01846
Org. Lett. XXXX, XXX, XXX−XXX