DPPF-Catalyzed Atom-Transfer Radical Cyclization via Allylic Radical

Article abstract of DOI:10.1021/acs.orglett.7b03135

A general iron-catalyzed strategy for the atom-transfer radical cyclization (ATRC) of allylic halide is reported. Critical to this strategy is the use of DPPF [1,1′-bis(diphenylphosphino)ferrocene] as catalyst, which allows for efficient generation of the

Full text of DOI:10.1021/acs.orglett.7b03135

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX-XXX
DPPF-Catalyzed Atom-Transfer Radical Cyclization via Allylic Radical
Longlei Hou,† Zhaozhao Zhou,‡ Dong Wang,‡ Yuwen Zhang,‡ Xin Chen,‡ Lijin Zhou,‡ Yang Hong,‡
Wei Liu,‡ Yading Hou,‡ and Xiaofeng Tong*,†,‡
†Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130
Meilong Road, Shanghai 200237, China
‡School of Petrochemical Engineering, Changzhou University, 1 Gehu Road, Changzhou 213164, China
S
* Supporting Information
ABSTRACT: A general iron-catalyzed strategy for the atom-
transfer radical cyclization (ATRC) of allylic halide is reported.
Critical to this strategy is the use of DPPF [1,1′-
bis(diphenylphosphino)ferrocene] as catalyst, which allows
for efficient generation of the allylic radical species via a single-
electron transfer (SET) process. The feasibility of achieving
ATRC reactions of propargyl chlorides is also demonstrated,
which affords products with an exocyclic allene moiety.
ince the Kharasch reaction (addition of CX4 across alkene
via radical mechanism) was discovered in 1945,1 its
intramolecular version (Scheme 1A), known as atom-transfer
However, the metal-catalyzed ATRC reaction of allylic halide
bearing a pendant alkene has not been developed yet and is a
long-standing problem in organic chemistry. Logically, the
proposed ATRC reaction would also require the efficient
generation of allylic radical species via a SET process.
Unfortunately, the interaction of allylic halide and metal
catalyst, not like the alkyl halide counterpart,10 is dominated by
the oxidative addition process, thus leading to the π-allyl metal
intermediate rather than the desired allylic radical species.11 To
date, only one example of ATRC variant of allylic halide was
reported by the group of Curran in 1989, in which
hexabutylditin was used as the catalyst.12 While this precedent
provides the proof-of-concept of the ATRC reaction of allylic
halide, the use of organostannane reagent is apparently
complicated by high toxicity and tough purification problems.
Moreover, some questions, such as the reactivity of allylic
radical,13 reaction selectivity, and so on, need to be further
addressed. Therefore, the development of tin-free metal-
catalyzed ATRC of allylic halide is highly desired from the
synthetic, fundamental, and environmental viewpoints.
Apparently, the key challenge in developing the ATRC
reaction of the allylic halide variant is to harness the interaction
of allylic halide with metal catalyst from reliable oxidative
addition to unfavorable SET process. To achieve this goal, we
turned our attention to ferrocene derivatives. We envisioned
that their fully coordinated sandwich structures could intrinsi-
cally exclude the π-allyl metal formation, which, in turn, would
open up a new avenue for the SET process (Scheme 1B). In
conjunction with our efforts with metal-catalyzed halogen-
transfer cyclization,14 we report herein the first tin-free ATRC
reaction of allylic halide analogue by using ferrocene derivative
as the catalyst, which proceeds with several different categories
S
Scheme 1. Overview of ATRC
radical cyclization (ATRC), has been extensively exploited and
refined into a versatile and powerful tool for organic synthesis.2
It has long been known that a wide range of metal complexes,
such as copper,3 iron,4 ruthenium,5 palladium,6 and nickel,7 can
catalyze such ATRC reactions. The redox ability of these metal
catalysts not only allows homolytic cleavage of the C−X bond
to generate an alkyl radical via a single-electron transfer (SET)
process but also is able to terminate the newly generated alkyl
radical after cyclization to form a new C−X bond, thus
furnishing the ATRC reaction (Scheme 1A). In order to ensure
the success of an initial halogen atom abstraction, an activated
C−X bond is generally required.8 In light of these advances,
one can anticipate that the ATRC reaction of allylic halide
analogue would follow a similar pathway; the relatively lower
bond dissociation energy of allylic halide would make the
corresponding SET process more feasible to generate the allylic
radical (Scheme 1B).9 This extension is particularly appealing
since the retained alkene residue has the potential for further
chemical manipulations along with the group of alkyl halide.
Received: October 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03135
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of allylic and propargyl halides and is compatible with
chloroalkene as the acceptor of allylic radical. This reaction
takes advantage of the incorporation of either the alkene or
allene group into products.
Scheme 2. Reaction Scope of 2-Chloromethyl-1,6-diene 1
The ATRC reaction of alkyl halide can be readily achieved by
using a wide range of metal complexes. Among these catalysts,
FeCl2[P(OEt)3]2, Pd(PPh3)4, RuCl2(PPh3)2, and CuCl/bpy
have been proven to be highly efficient. Thus, we began our
investigation by examining the catalytic activity of these
common catalysts toward the ATRC reaction of allylic halide
1a in refluxing toluene (Table 1, entries 1−4). Not surprisingly,
a
Table 1. Catalyst Screening and Condition Optimization
disubstituted alkene, the ATRC occurred in a 7-endo fashion
to give the corresponding 7-membered products 2a−d, which
can be explained by the involvement of thermodynamically
stable tertiary radical. Likely due to its instability at high
temperature, allylic bromine 1a-Br gave product 2a-Br only in
21% yield. It should be mentioned that no 8-membered ring
product 2d was detected for the reaction of 1,7-diene 1d, and
the starting material was recovered in 95% yield. This result
reflects one of the limitations of this reaction. The conversion
of relatively stable allylic radical15 into less stable alkyl radical
would require rapid exothermic cyclization. As expected, the
reactions of substrates 1e−g bearing a monosubstituted alkene
took place in a 6-exo fashion. In addition to the N-linkage, the
C-linkage was proven to be competent, affording product 2g in
63% yield. Although the reactions of substrates 1h and 1j
bearing a 6,7-disubstituted alkene were found to be somewhat
complex, only one diastereoisomer could be obtained via the
preparative layer chromatography. Moreover, 1i-Cl with an
endocyclic alkene could be readily converted into fused bicycle
2i-Cl in 60% yield with 10:1 diasteroselectivity. The reaction of
bromine analogue 1i-Br showed much better stereoselectivity
to give product 2i-Br as a single isomer, which might arise from
the bulkiness of the bromine atom. For the cases of substrates
1k−m with a 6,6′,7-trisubstituted alkene, products 2k−m with
an all-carbon quaternary center could be obtained in moderate
yields with 1:1 dr. Interestingly, this method was found to be
suitable to construct spirocycle. Indeed, spirocyclic product 2n
was isolated in 73% yield with 2:1 dr. Moreover, compound 1o
a
b
Reactions conducted on 0.2 mmol scale. Isolated yield.
no ATRC product was observed, and compound 1a was
recovered in >90% yield in some cases. These results are
consistent with Curran’s observation.12 Then, we turned our
attention to ferrocene derivatives. However, use of the simplest
ferrocene as the catalyst did not provide the desired ATRC
product (Table 1, entry 5). Neither dimethylferrocene nor
diphenylferrocene also showed any catalytic activity (Table 1,
entries 6 and 7). To our delight, DPPF exhibited good activity,
enabling the isolation of product 2a in 62% yield (Table 1,
entry 8). Several bis(diphosphino)ferrocenes were then
examined, which disclosed that both of the electronic and
steric characters of substitutions on the phosphine exerted
ignorable influence on the reaction performance (Table 1,
entries 9−11). As evidence for the crucial role of ferrocene
moiety, control reactions in the presence of various
diphosphines did not afford any detectable products (Table
1, entry 12). We then briefly examined the reaction solvent and
found that PhCF3 was optimal, resulting in 83% isolated yield
of 2a (Table 1, entries 13−16).
The optimized conditions were then tested with a number of
2-chloromethyl-1,6-dienes 1 bearing diverse alkene moieties
(Scheme 2). For the substrates 1a−d bearing a 6,6′-
B
DOI: 10.1021/acs.orglett.7b03135
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Organic Letters
Letter
bearing a 6,7,7′-trisubstituted alkene was also a suitable
substrate, undergoing 6-exo cyclization to afford product 2o
in 71% yield. On the other hand, substrates 1p and 1q
underwent Heck-type reaction, delivering diene products 2p
and 2q in good yields. While a great deal of HCl was
concomitantly produced, these two reactions seemed un-
affected. Finally, the reaction was found to be applicable to
substrate 1s with a tetrasubstituted alkene, and the diene
product 2s was isolated in 77% yield.
Scheme 4. Reaction Scope of Chloroalkene 7
In addition to allylic halides 1, the 1-chloromethyl ones 3,
such as N-tethered substrate 3a and C-tethered substrate 3b,
could also readily undergo chlorine-transfer cyclization,
affording 5-membered cycles 4a and 4b with a vinyl group
(Scheme 3). These results provided strong evidence to support
Scheme 3. Reaction Scope of 1,6-Diene 3 and 1,6-Enyne 5
complex compounds 9a and 9b, giving products 10a and 10b in
synthetically useful yields, respectively.
Mechanistic details, especially the essential role of
diphenylphosphanyl substitution, are the focus of our ongoing
investigations, but several observations are worth noting. As
might be expected, this DPPF-catalyzed halogen-atom-transfer
cyclization likely proceeds via a radical process. The potential of
DPPF toward a SET process is readily evident from the
reactions of trichloroacetamide 11. The copper-catalyzed
isomerization of compound 11 has been convincingly
established to proceed through an ATRC mechanism.19 In
comparison, compound 11 was exposed to the well-known
CuCl/bpy system under otherwise identical conditions, which
smoothly proceeded in 83% yield to give predominately (2.7:1)
trans-lactam 12 (Scheme 5a). It was of considerable interest
that the present DPPF catalysis also produced trans-lactam 12
with 2.7:1 diastereoselectivity albeit in somewhat lower yield
(Scheme. 5a). Thus, the virtually identical stereochemical
outcome essentially reflected the capability of DPPF as an
ATRC catalyst. Furthermore, the DPPF-catalyzed reaction of
1e was not inhibited by radical scavengers such as TEMPO and
hydroquinone (Scheme 5b). The results are in line with the
copper-catalyzed cyclization of allyl trichloroacetates,20 indicat-
ing that the ATRC mechanism would be operative for this
reaction.
the reaction pathway via allylic isomerization.16 A fused bicycle
4c with four contiguous stereogenic centers was obtained with
high diastereoselectivity (10:1). It should be mentioned that 2-
methyl and 3-methyl 1,6-dienes 3i and 3j were also suitable
candidates, delivering products 4i and 4j in good yields albeit
with low diastereoselectivity. In the latter case, an all-carbon
quaternary center was formed. Notably, this DPPF-catalyzed
cyclization could be successfully extended to propargyl chloride
variants 5a−f, affording products 6a−f with an exocyclic allene
group in moderate yields.17
To further extend the substrate scope of this method,
substrate 7a with chloroalkene as the radical acceptor18 was
examined. Gratefully, the reaction of 7a was still workable,
affording gem-dichloride product 8a in 78% yield (Scheme 4).
This result is remarkable due to the fact that poly-haloalkane
commonly cannot survive under the classical metal-catalyzed
ATRC systems. The importance of this transformation was
readily seen from the construction of polycyclic molecules. For
instance, fused bicycles 8b and 8g could be produced with
excellent stereoselectivity, while spirocycles 8c and 8e were
obtained in good yields.
To further elucidate the radical-involved reaction pathway,
two radical probe experiments were designed on the basis of
compounds 13 and 15, wherein the cyclopropyl and cyclobutyl
radical clocks were installed at the alkenyl ends, respectively.21
Subjecting 13 to the standard conditions resulted in cyclo-
propane ring-opening product 14 in 60% yield (Scheme 5c),
Finally, we explored the feasibility of this method to the late-
stage modification of complex compounds. As shown in eqs 1
and 2, the standard conditions was compatible to structurally
C
DOI: 10.1021/acs.orglett.7b03135
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Organic Letters
Letter
Notes
Scheme 5. Mechanistic Investigations
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the NSFC (Nos. 21472042 and
21772016), Jiangsu Province Funds for Distinguished Young
Scientists (BK20160005), and the Qing-Lan Project.
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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.7b03135.
General procedures, data, and NMR spectra of products,
and X-ray data of compound 2a (PDF)
Accession Codes
CCDC 1561108 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
(21) (a) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: txf@cczu.edu.cn.
ORCID
Xiaofeng Tong: 0000-0002-6789-1691
D
DOI: 10.1021/acs.orglett.7b03135
Org. Lett. XXXX, XXX, XXX−XXX