Radical-Mediated 1,2-Formyl/Carbonyl Functionalization of Alkenes and Application to the Construction of Medium-Sized Rings

Article abstract of DOI:10.1002/anie.201608198

A novel radical 1,2-formylfunctionalization of alkenes involving 1,2(4,5)-formyl migration triggered by addition of various carbon- and heteroatom-centered radicals to alkenes has been developed for the first time, thus providing straightforward access to diverse β-functionalized aldehydes with good efficiency, remarkable selectivity, and excellent functional group tolerance. Analogous transformations mediated by a keto-carbonyl migration have also been effected under similar conditions. This method was used to access ring systems including various benzannulated nine-, ten-, and eleven-membered rings, complex 6-5(6,7)-6(5) fused rings, and bridged rings with diverse functionalities.

Full text of DOI:10.1002/anie.201608198

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International Edition: DOI: 10.1002/anie.201608198
German Edition: DOI: 10.1002/ange.201608198
Heterocycle Synthesis
Radical-Mediated 1,2-Formyl/Carbonyl Functionalization of Alkenes
and Application to the Construction of Medium-Sized Rings
Zhong-Liang Li+, Xiao-Hua Li+, Na Wang, Ning-Yuan Yang, and Xin-Yuan Liu*
Abstract: A novel radical 1,2-formylfunctionalization of
alkenes involving 1,2(4,5)-formyl migration triggered by
addition of various carbon- and heteroatom-centered radicals
to alkenes has been developed for the first time, thus providing
straightforward access to diverse b-functionalized aldehydes
with good efficiency, remarkable selectivity, and excellent
functional group tolerance. Analogous transformations medi-
ated by a keto-carbonyl migration have also been effected
under similar conditions. This method was used to access ring
systems including various benzannulated nine-, ten-, and
eleven-membered rings, complex 6-5(6,7)-6(5) fused rings,
and bridged rings with diverse functionalities.
G
iven the intensified research efforts over the past three
Scheme 1. 1,2-Difunctionalization of alkenes.
decades, the 1,2-functionalization of alkenes has evolved into
an efficient tool for the preparation of complex organic
molecules.[1] In particular, radical-mediated direct olefinic
1,2-functionalization initiated by intermolecular addition of
both carbon- and heteroatom-centered radicals to alkenes has
emerged as one of the most attractive strategies for the
simultaneous formation of two vicinal chemical bonds
involving halo-, oxy-, thio-, amino-, and carbo-functionaliza-
tion, by using a variety of radical precursors and trapping
reagents (Scheme 1a).[2] Despite these impressive advances,
1,2-difunctionalization-type radical formylation reaction of
alkenes, involving the concurrent incorporation of a formyl
group and a radical species, to our knowledge, still remains
a formidable and unexplored challenge, largely because of the
unavailability of appropriate formyl trapping reagents
(Scheme 1c).[3] Given that the resultant b-functionalized
aldehydes are valuable final products and intermediates in the
synthesis of bulk chemicals like alcohols, esters, and amines,
the formylation of simple alkenes should be of great
importance in both academia and industry. One outstanding
example is the transition-metal-catalyzed hydroformylation
by the addition of CO and H2 to an alkene, a reaction which is
one of the largest industrially applied processes (Scheme
1b).[4] In this process, only one new carbon–carbon bond is
formed, while the 1,2-difunctionalization-type formylation
reaction of alkenes for generating b-functionalized aldehydes
with concomitant incorporation of diversely functional
groups in one step remains a challenge (Scheme 1c).
In this context and as part of our continuous efforts in
radical-initiated remote migration chemistry,[5] we became
interested in developing a novel radical difunctionalization-
type scenario to address the above challenge (Scheme 2a). In
this scenario, we envisioned that various in situ generated
radicals might selectively add to the alkene bonds of the
rationally designed substrates 1, thus producing a transient
alkyl radical intermediate (A).[2] Driven by the formation of
a lower-energy neutral ketyl radical C,[6] A would preferen-
tially undergo a radical cyclization to form the alkoxy radical
B
[7] with subsequent selective b-fragmentation[8] to realize 1,2-
formylfunctionalization of alkenes. To realize this scenario,
several major challenges need to be overcome: 1) the high
[*] Dr. Z.-L. Li,[+] Dr. X.-H. Li,[+] N. Wang, N.-Y. Yang, Prof. Dr. X.-Y. Liu
Department of Chemistry
South University of Science and Technology of China
Shenzhen, 518055 (P.R. China)
E-mail: liuxy3@sustc.edu.cn
Dr. Z.-L. Li[+]
Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Dalian, 116023 (P.R. China)
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201608198.
Scheme 2. 1,2-Formylfunctionalization of alkenes and synthetic appli-
cations. TsCl=4-toluenesulfonyl chloride.
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Table 1: Scope of the 1,2-trifluoromethylformylation reaction.[a,b]
tendency of B toward hydrogen abstraction for the formation
of undesired cyclic alcohols;[7,8] 2) selective control of pro-
miscuous reactivity, such as the competitive 1,2-difunctional-
ization of alkenes with oxygen-based nucleophiles, b-hydride
elimination, and other transformations of A with multiple
reactive sites;[2,9] 3) the identification of appropriate oxidative
conditions for the generation of the radical species while
suppressing the oxidation of the sensitive aldehyde group.
Herein we report the successful development of the first
radical olefinic 1,2-difunctionalization-type formylation by
either a 1,2-, 1,4-, or 1,5-formyl radical migration triggered by
either trifluoromethylation, azidation, sulfonylation, perfluor-
oalkylation, or difluoromethylation of unactivated alkenes to
afford diversely b-functionalized aldehydes (Scheme 2a).
Most importantly, this strategy could also provide convenient
access to various benzannulated nine-, ten-, and eleven-
membered rings for further transformation into different
types of ring systems including complex 6-5(6,7)-6(5) fused
rings and bridged rings with diverse functionalities (Scheme
2b). Such medium-sized motifs are challenging synthetic
targets, mainly because of the unfavorable enthalpic and
entropic parameters for the conventional cyclization-based
methods.[10]
The increasing importance of trifluoromethylated organic
molecules for the synthesis of pharmaceuticals and agricul-
ture chemicals has spurred vigorous research for the explora-
tion of more powerful and practical trifluoromethylation
protocols.[11] To this end, we initiated these investigations by
examining the reaction of 2-hydroxy-2-phenylhex-5-enal (1A)
with the commercially available Togniꢀs reagent[12] (2A). To
our delight, the 1,2-trifluoromethylformylation reaction pro-
ceeded smoothly in the presence of CuI (20 mol%) with
EtOAc as the solvent at 808C for 16 hours, thus giving the
desired b-trifluoromethylated aldehyde 3A (for structure see
Table1) in 64% yield and clearly demonstrated that the
remote radical 1,4-formyl migration was much more favor-
able than other reaction pathways in the current catalytic
system (see Table S1, entry 1 in the Supporting Information).
Upon screening the reaction conditions, we identified the
following protocol as optimal: the reaction of 1A and 2A with
a molar ratio of 1.0:1.5 in the presence of CuI (20 mol%) in
CH3CN at 608C for 16 hours (Table S1, entry 7). With the
optimal reaction conditions established, the generality of the
current catalytic system for the 1,2-trifluoromethylformyla-
tion of alkenes by radical 1,4-formyl migration was next
investigated and the results are summarized in Table 1.
Different linear alkenyl a-hydroxyaldehydes reacted to give
the products 3A and 3B selectively in 74 and 73% yields,
respectively. Moreover, the substrate 1C, with a geminal-
disubstituted alkenyl group, was also well tolerated and gave
3C containing an a-quaternary carbon center in 83% yield.
We then switched our synthetic target to test the 1,5-formyl
migration process. Gratifyingly, under reaction conditions
identical to those of the 1,4-formyl migration process, the
reaction of the linear substrate 1D proceeded smoothly to
generate 3D in 73% yield. The aryl-tethered substrates
bearing electron-neutral (1E), electron-rich (1F), and elec-
tron-deficient (1G) aryl groups proved to be suitable sub-
strates, thus furnishing the corresponding products 3E–3G in
[a] All of the reactions were conducted on a 0.20 mmol scale. [b] Yields of
isolated products based on 1.
56–82% yields. The substrate 1H, having an aryl ring a to the
alcohol group, reacted efficiently to afford 3H in 73% yield.
We also found that the desired product 3I, from a 1,2-formyl
radical migration triggered by trifluoromethylation of alkene,
was obtained in 84% yield in the case of the TMS-protected
a-hydroxy substrate 1I (Table 1c). However, treatment of the
substrate 1J under otherwise identical reaction conditions
hardly generated any desired product expected from the 1,3-
formyl migration, thus indicating that the migration transition
state, a four-membered ring, might be disfavored for generat-
ing 1J (Table 1d).
The scope of the reaction was further expanded to other
radical precursors. Unfortunately, our initial attempts to use
either p-toluenesulfinic acid or p-toluenesulfonyl hydrazide in
the presence of different oxidants as a way to generate the
sulfonyl radicals in situ for the reaction failed (see Table S2),
presumably because of the incompatibility of strong oxidants
with the sensitive formyl group under these reaction con-
ditions. In recent years, visible-light-driven photoredox catal-
ysis has become an ecofriendly and powerful tool for the
generation of various radical species under extremely mild
reaction conditions without the need for external oxidants.[13]
Therefore, we surmised that the use of photoredox catalysis
may be suitable for the development of olefinic 1,2-sulfonyl-
formylation. As expected, the reaction of 1A with p-toluene-
sulfonyl chloride (4a) in the presence of [Ir(ppy)2-
(dtbbpy)]PF6 (1 mol%) with 2 equivalents of Na2HPO4
under visible light delivered the b-sulfonyl aldehyde 5A in
71% yield (Table 2a) after a systematic optimization of
different reaction parameters (see Table S2).[14] Similar
results were obtained in the reaction of a series of alkenyl
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Table 2: Scope of other radical-mediated 1,2-formyl functionalizations.
molecules. The development of general strategies for the
construction of such backbones has been a longstanding and
challenging topic in organic synthesis.[10] In view of this, we
rationally designed the alkenyl cyclic a-hydroxyketones 11
(Table 3), in which the selective addition of diverse radicals to
Table 3: Construction of medium-sized molecules by carbonyl migra-
tion.[a]
[a] Yield of isolated product based on 11. [b] Reaction conditions are
similar to those of 3 except EtOAc is used as a solvent. [c,d,e] Reaction
conditions similar to those for 5, 6, 7, and 10.
[a] Reaction conditions: 1 (0.20 mmol), TsCl (1.5 equiv), [Ir(ppy)2-
(dtbbpy)]PF6 (1 mol%), Na2HPO4 (2.0 equiv), EtOAc (2 mL), blue LED
at RT for 5 h under argon. [b] Yield of the isolated product based on 1.
[c] Reaction conditions: 1 (0.20 mmol), RfSO2Cl (1.5 equiv), [Ir(ppy)2-
(dtbbpy)]PF6 (1 mol%), Na2HPO4 (2.0 equiv), EtOAc (2 mL), blue LED
at RT for 5 h under argon. [d] Reaction conditions: 1 (0.20 mmol),
BrF2CCO2Et (2.0 equiv), [Ir(ppy)2(dtbbpy)]PF6 (1 mol%), Na2HPO4
(2.0 equiv), CH2Cl2 (2 mL), blue LED at RT for 5 h under argon.
dtbbpy=di-tert-butylbipyridine, ppy=phenylpyridyl, TMS=trimethyl-
silyl.
the alkene moieties could trigger ring expansion by a similar
remote 1,4- or 1,5-carbonyl migration process. To our delight,
the allylbenzene derivative 11A formed the expected product
12 in 70% yield under the reaction conditions almost identical
to those of 1,2-trifluoromethylformylation reaction. Further-
more, the generated sulfonyl, perfluorobutanyl, difluoro-
methyl and azide radicals were well-tolerated to provide 13–
16A in 69–79% yields. To increase the diversity of such
strategy, the azido-substituted nine- and eleven-membered
dicarbonyl products 16B and 16C were also obtained in 73
and 53% yields, respectively, from the corresponding sub-
strates. Additionally, the styrene derivatives were also suit-
able substrates for such a process to provide nine- and ten-
membered rings 16D and 16E in 65 and 68% yields,
respectively. Notably, the obtained benzannulated medium-
sized rings are the core structures of many biologically active
natural products such as clavilactone A and cytochalasin G.[18]
An important synthetic application is that the radical
functionalized medium-sized diketones can serve as a con-
venient handle to access other useful motifs by further
manipulation. For example, treatment of the 1,6-dicarbonyl
products 16A, 12, and 13 with trifluoromethanesulfonic acid
(TfOH) provided the 6-7-5 fused rings 17A–C in 40–80%
yields (Scheme 3a). In addition, treatment of 16B with
NaOMe generated the 6-5-6 fused ring 18 in 68% yield
with excellent diastereoselectivity (> 20:1 d.r.), wherein the
azido group was simultaneously replaced by a methoxy group,
thus suggesting its role as a leaving group (Scheme 3b).
Similarly, in the presence of TfOH, 16C and 16D afforded the
6-7-6 fused ring 19 (30% yield with 4:1 d.r.) and 6-6-5 fused
ring 20 (82% yield with > 20:1 d.r.), respectively (Scheme
a-hydroxyaldehydes to afford the expected products 5B–E in
51–81% yields (Table 2a). Most importantly, all radicals
generated in situ from trifluoromethyl-, perfluorobutyl-,
difluoromethyl-, and difluoroacetyl-sulfonyl chloride (4b–
e)[15] by extrusion of sulfur dioxide under similar reaction
conditions were found to be applicable to generate 3A, and 6–
8 in 54–77% yields (Table 2b). Since BrCF2CO2Me is
commercially available and has also been utilized in photo-
redox catalysis,[16] this reagent was also successfully applied
for this strategy to produce the desired product 8’ in 43%
yield (Table 2c). To expand the synthetic utility of this
methodology, we next focused our attention on the azide
radical generated from the iodine(III) reagent azidoiodinane
9 reported by Zhdankin and co-workers.[17] However, treat-
ment of 1Awith 9 in the presence of different copper catalysts
afforded almost no desired product. Subsequently, we chose
the TMS-protected a-hydroxy substrate 1A’ as the substrate
and found that the expected 1,2-azidoformylation reaction
could be realized to afford the b-azido aldehyde 10, albeit
with 30% yield, in the presence of CuCN (20 mol%) at 608C
in EtOAc for 12 hours (Table 2d).
Medium-ring structures constitute basic skeletons of
many important naturally occurring and biologically active
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3c,d). To further exemplify the synthetic importance of azido
Acknowledgments
group in the product, the PPh3-promoted intramolecular
Staudinger/aza-Wittig reaction of 16D, followed by selective
reduction with sodium cyanoborohydride (NaBH3CN) gen-
erated the bridged amine 21 in 40% yield (Scheme 3d). It
should be noted that the fused 6-5(6,7)-6(5) tricyclic ring and
bridged ring systems are privileged structural motifs found in
natural products and pharmaceutical compounds, such as
sodium channel grayanotoxins, the antibacterial and antitu-
mor icetexane family, and a benzindene prostaglandin
analogue.[19]
Financial support from the National Natural Science Foun-
dation of China (Nos. 21572096, 21302088) and Shenzhen
overseas high level talents innovation plan of technical
innovation project (KQCX20150331101823702) is greatly
appreciated.
Keywords: alkenes · heterocycles · medium-ring systems ·
radicals · synthetic methods
To obtain some insight into the reaction mechanism,
radical-trapping experiments were conducted by employing
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 1,4-ben-
zoquinone (BQ). The reaction of 1A and 2A was found to be
inhibited by these reagents, thus suggesting that the reaction
is a radical-based process (see Scheme S1). In addition, the
preliminary kinetic studies (see Figures S1a–c and S2a,b)
show that the reaction is zero-order in 1A and second-order
with respect to 2A. It is quite possible that 1A was not
involved in the rate-determining step and that the reaction
process has two rate-determining steps, both of which involve
2A. However, the exact mechanism remains unclear at
present and deserves further detailed study.
In summary, we have successfully developed the first
radical 1,2-difunctionalization-type formylation of alkenes by
1,2-, 1,4-, and 1,5-formyl radical migration triggered by
trifluoromethylation, azidation, sulfonylation, perfluoroalky-
lation, and difluoromethylation of unactivated alkenes. This
method offers a novel and sustainable radical reaction to
deliver diverse b-functionalized aldehydes with good effi-
ciency, remarkable selectivity, and excellent functional-group
tolerance. More significantly, this method can be applied for
the keto-carbonyl migration, thus constructing synthetically
challenging benzannulated medium-sized ring scaffolds,
which can be easily transformed into a series of very useful
complex 6-5(6,7)-6(5) fused and bridged ring systems, thus
demonstrating the high synthetic utility of the current process
in organic and medicinal chemistry.
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Received: August 22, 2016
Revised: September 25, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Heterocycle Synthesis
Z.-L. Li, X.-H. Li, N. Wang, N.-Y. Yang,
X.-Y. Liu*
&&&& — &&&&
Radical-Mediated 1,2-Formyl/Carbonyl
Functionalization of Alkenes and
Application to the Construction of
Medium-Sized Rings
The old 1,2: A novel 1,2-formyl function-
alization of unactivated alkenes involving
formyl migration and addition of radicals
to alkenes has been developed for access
to synthetically important b-functional-
ized aldehydes. The analogous keto-car-
bonyl migration has been performed to
synthesize challenging medium-sized
diketones, which are additionally trans-
formed into complex fused rings.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!