Regio- And chemoselective synthesis of nitrogen-containing heterocycles: Via the oxidative cascade cyclization of unactivated 1, n -enynes

Article abstract of DOI:10.1039/c9cc07820g

The development of a method for performing radical initiated intramolecular cascade cyclization of 1,n-enynes provided a competent protocol for producing structurally diverse complex heterocycles. Herein, we demonstrate I₂/TBHP promoted, solven

Full text of DOI:10.1039/c9cc07820g

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DOI: 10.1039/C9CC07820G
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Regio- and Chemoselective Synthesis of Nitrogen-Containing
Heterocycles via the Oxidative Cascade Cyclization of Unactivated
1,n-Enynes
Received 00th January 20xx,
Accepted 00th January 20xx
Mohana Reddy Mutra,a Ganesh Kumar Dhandabani,a Jing Li,a and Jeh-Jeng Wanga,b*
DOI: 10.1039/x0xx00000x
reactions have been observed based on the choice of starting
material and reaction conditions.6,8,9 As potential radical
acceptors, the utilization of 1,n-enynes in radical cascade
cyclizations to construct N-heterocyclic compounds has also
attracted considerable attention in the past few years.
Conventionally, 1,n-enynes were used in transition-metal-
catalyzed cyclization or cycloisomerization reactions, mostly via
non-radical paths.7 In 2016, Studer et al. synthesized polycyclic
γ-lactams from the nitrogen-tethered 1,6-enyne, via electron
catalysis (Scheme 1, a).8a This reaction follows in situ generation
of arene radical and addition onto the activated alkene double
bond of 1,6-enyne, followed by 5-exo-dig cyclization to give the
key alkenyl radical intermediate then intramolecular cyclization
to provide the final polycyclic γ-lactams. Inspired by these
findings, in 2018, Xuan et al. achieved trapping of halogens with
in situ generated alkenyl radical intermediates, which is
initiated by an arylsulfonyl radical cascade involving 1,6-enyne
(Scheme 1, b).8b Very recently, the Li’s group employed
oxidative tandem annulation of 1-(2-ethynylaryl)prop-2-en-1-
ones to access 1H-cyclopropa[b]naphthalene-2,7-diones using
I2/TBHP, where
The development of a method of performing radical initiated
intramolecular cascade cyclization of 1,n-enynes provided
a
competent protocol for producing structurally diverse complex
heterocycles. Herein, we demonstrate I2/TBHP promoted, solvent
controlled, regio- and chemoselective 5-exo-trig or 6-endo-trig
radical cyclization of electronically unbiased 1,n-enynes to
synthesize nitrogen-containing heterocycles. These metal-free
protocols confer access to synthetically robust piperidine motif-
bearing iodinated-homoallylic alcohol and pyrrolidine fused
cyclopropane rings. The key factor in these methods is operational
simplicity, and the environmentally friendly reaction system works
under exceedingly mild conditions. Furthermore, the source of
hydroxyl groups in the tertiary alcohols is indirectly confirmed with
H218O labeled studies. Based on mechanistic studies, all of these
cyclizations were initiated through single electron oxidation. The
products with active C-I bonds present opportunities for further
transformations.
Five and six membered nitrogen-containing heterocyclic
rings are omnipresent molecules in the various field of
chemistry.1a,1b Particularly, the piperidine structural and
functional components appear in a wide variety of naturally
occurring alkaloids,2 biologically active molecules,2a,3
pharmaceutical drugs,1b,2a and therapeutic agents.2a,4
Moreover, piperidine is the most commonly appearing ring
skeleton in drug molecules.1b Thus, considering the importance
of piperidine, new general methodologies need to be developed
to construct this motif, in which efficiency is exemplified by the
synthesis of natural products or compounds of biological
significance. Importantly, introducing -OH groups into the
piperidine motif, enhances the solubility of drugs by hydrogen
bonding.5
Radical cascade cyclization with nitrogen tethered activated 1,6-enyne:
Studer's work, 2016
Xuan's work, 2018
R2
R2
O
O
TsNHNH2
X-source,
TBHP
R4
O
N
NH2
R2
X
R4
R1
R1
N
R1
N
Ts
X= I, Br
(b)
R3O2
C
R3O2
C
CO2R3
(a)
Radical cascade cyclization with benzene tethered activated 1,6-enyne:
R1
Li's work, 2019
from TBHP
O
O
I2
TBHP
R1
R3
R3
R4
R2
R2
R4
(c)
O
Our approach with unactivated nitrogen tethered 1,6-enyne:
I
R1
O
R1
R3
5-exo-trig
I2 (0.5 equiv),
6-endo-trig
I2 (0.5 equiv),
70% aq. TBHP (3 equiv),
ACN (0.1 M),
H2O (15 equiv), 80 °C
R3
R2
R1
70% aq. TBHP (3 equiv),
MeOH (0.1 M), 80 °C
TsN
OH
R2
TsN
R2
N
n
n
(e)
R1= H, Ph, R2= Ph,
Ts
15 Examples
up to 83% yield
(d)
5 Examples up
to 48% yield
n=1,2,3
R3= H
Over the past several years, regio- and chemoselective
radical cascade or radical-radical cross coupling reactions have
been emphasized as robust strategies to construct cyclic
skeletons concomitant with the installation of distinct
functionalities. Until now, various types of radical cascade
R1= H, aliphatic, aromatic,
-COPh heterocylic, R2
aliphatic, aromatic, R3= -H, Ph
External -OH radical
Gram-scale reaction
Iodinated-homoallylic alcohols
Chemo- and regioselective
products
Mild reaction condition
=
Simple procedure+cheap
reagents= valuble products
Active C-I bond for further
transformations
Scheme 1. Selected previous reports and our approach via radical cascade
cyclizations on 1,6-enynes
TBHP serves as both an oxidant and an oxygen atom resource
(Scheme 1, c).8c However, the reactions are limited to the usage
of external radical sources, activated internal alkenes or
alkynes, and unwanted waste generation, and are restricted to
a. Department of Medicinal and Applied Chemistry, Kaohsiung Medical University,
No. 100, Shiquan 1st Rd, Sanmin District, Kaohsiung City, 807, Taiwan.
b. Department of Medical Research, Kaohsiung Medical University Hospital, No. 100
Tzyou 1st Rd, Sanmin District, Kaohsiung City 807, Taiwan.
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one type of cyclic skeleton. Thus, development of new in Table 1. The reaction worked well with terminal alkyne
View Article Online
DOI: 10.1039/C9CC07820G
strategies for oxidative radical cascade reaction of 1,6-enynes is (2a)andinternal alkyne (2b) with aryl functionalities such as -ph (2b)
appealing. We envisioned that under suitable, external radical- m-Me-Ph (2c), p-Me-Ph (2d), o-OMe-Ph (2e), p-OMe-Ph (2f), and m-
free conditions, the I2/TBHP system can generate in situ di- NO2-Ph (2g) to afford piperidine derivatives in 48-75% yield. Note
radicals (hydroxyl and iodide radicals) or mono-radical that the (Z)-5-(iodomethylene)-3-phenyl-1-tosylpiperidin-3-ol (2a)
(hydroxyls) would be able to be involved in cascade bond- was unambiguously confirmed by X-ray crystallography.10
forming events with an unactivated terminal or internal Surprisingly, the reaction worked with the benzoyl functionality on
alkene/alkyne in the chemo- and regioselective addition of C=C R1 (1h) to produce the corresponding iodo-homoallylic alcohol
and C≡C bonds of 1,6-enyne, resulting in 5-exo-trig/6-endo-trig piperidine molecule 2h, albeit in low yield. Substituted TMS groups
cascade cyclization by employing the solvent controlled were tested at R1 to give compounds 2i in 45% yield. The reaction
(Scheme 1, d and e). To the best of our knowledge, this is the underwent smooth conversion when the aryl group was replaced
first report of trapping of hydroxyl and iodine radicals with
Table-1. Evaluation of the reaction parametersa
unactivated nitrogen tethered 1,n-enyne. In continuation of our
research in pursuit of finding mild, metal-free conditions for
I
Ph
Ph
Ph
Ph
Ph
medicinally important molecule synthesis using inexpensive
reagents towards sustainable chemistry development via
oxidative cascade reactions9 we report herein the synthesis of
iodinated-homoallylic piperidines and cyclopropane-fused
pyrrolidine.
[I]
O
oxidant (x equiv)
solvent (0.1 M),
H2O (15 equiv),
80 °C, 5 h
TsN
N
TsN
OH
Ph
Ts
1b
2b
3b
yieldb (%)
2b 3b
entr
y
I source (x
equiv)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (1.0)
I2 (1.5)
I2 (50)
-
oxidant (y
equiv)
solvent
1
2
3c
4
5d
6 d
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (5)
TBHP (3)
TBHP (3)
TBHP (3)
-
CH3CN
MeOH
CH3CN
CH3CN
58
-
<5
48
<5
<5
<5
<5
<5
-
First, we examined the radical annulation reaction of 1,6-enyne 1b,
under metal-free conditions, as shown in Table 1. To our surprise,
major (Z)-5-(iodo(phenyl)methylene)-3-phenyl-1-tosylpiperidin-3-ol
2b and minor 3b were obtained in 58% and less than 5% yield when
1b was treated with I2 (50 mol%) and aq.TBHP (3.0 equiv) in
acetonitrile for 5 h at 80 °C (Table 1, entry 1). Subsequent reactions
with other Iodine sources, oxidants, and solvents also failed to
improve the reaction yield of 2b. Although no solvents resulted in
improved yields, MeOH solvent exclusively generated product 3b.
(see ESI, S4). Next, we carried out various protic solvent studies (see
ESI, S4). However, all protic solvents is not afforded the desired
product except EtOH and H2O with low yields. The most likely reason
for switch of the cyclization is becase of protic solvent. Furthermore,
the reaction performed in the presence of TBHP (5-6 M in decane)
failed to improve the yield (Table 1, entry 3). With changing
equivalents of TBHP, the yield decreased (Table 1, entry 4). We tried
the reaction with combinations of solvents, such as water and
acetonitrile, which interestingly improved the yield of 2b (Table 1,
entry 5); however, there was not much effect on the product yield
produced by the reaction. Next, we tested increasing the quanity of
H2O in the presence of aq. TBHP and TBHP in decane (see ESI, S4, S6).
From our additional experiments results suggests aq. TBHP with 15
equivalents H2O is better reaction yield than aq. TBHP alone and
TBHP in decane. At this stage 15 equivalents of H2O role in promoting
these radical reaction is not clear. But we speculate the specific
quantity of water can stabilize the radical intermediates.10
Furthermore, we increased the quantity of iodine in the reaction
from 0.5 up to 1.5 equivalents, but the increasing amount of iodine
55
50
63
48
45
-
CH3CN + H2O
CH3CN + H2O
CH3CN + H2O
CH3CN + H2O
CH3CN + H2O
d
7
8
9
d
d
TBHP (3)
-
10
a Reaction conditions: 1b (0.1 mmol), iodine source (0.5 equiv), 70% aq. TBHP (3.0
equiv), solvent (0.1 M), H2O (15 equiv) and stirring for 5 h at 80 ℃. b Isolated yields.
c TBHP (5–6 M in decane). dH2O (15 equiv) was used.
with heteroaryl (1j) groups to generate 2j and 2k in excellent yields
(79-83%). Furthermore, we tested the reaction with 1l with a
terminal alkyne: interestingly, the reaction produced 2l in good yields
of 75%. The reaction worked when increasing the carbon chain
length in the starting material to afford corresponding compounds
2m and 2n in 67-72% yields. Next, we tested the reaction with
starting materials 2o and 2p expected to afford cascade cyclization.
Instead, however, we observed addition reactions on the alkene to
afford products 2o’ and 2p’ in 52-58% yields. Unfortunately, the
reaction did not work with oxygen tethered 1,6-enyne (1q), 1,3-
diester (1r) and 1,3-dinitrile (1s) or inactive 1,8-enyne (1t). While
optimizing the reactions, we observed exclusive single product
formation of a bicyclic cyclopropane compound in the presence of
selective protic solvent MeOH (see for optimization ESI, S4 and S7)
and successfully achieved 5 examples such as, terminal alkyne (3a), -
ph (3b), m-Me-Ph (3c), p-OMe-Ph (3f), and heteroaryl (3j) to afford
could not improve the yield of the product (Table 1, entries 6-7). desired derivatives in 35-48% yield. The m-NO2-Ph (3g) product was
not observed due to greater electron withdrawing effect making the
alkyne less nucleophilic. The p-CO2Me-Ph (3z) trace product amount
was observed by TLC. The low yields were observed due to the
uncyclized starting material recovered after long reaction times (48
h) (see ESI. The structure of phenyl((1S)-5-phenyl-3-tosyl-3-
azabicyclo[3.1.0]hexan-1-yl)methanone (3b), was confirmed by X-ray
crystallography.11 To demonstrate the synthetic application of the
protocol, reaction scale-up experiments were performed (Table 3).
The desired piperidine cores 2b, and 2j were formed in 65-85% yield
Later, we tried the reaction in the absence of either iodine or THBP,
but the desired product formation was not observed (Table 1, entries
8-9). This results indicates that both components are necessary for
product formation. Thus, among the reaction conditions screened in
Table 1, entry 5 was chosen as the optimum conditions.
The scope of this methodology was investigated by screening
various 1,6-enynes 1 (a-o) under the standard conditions, as shown
2 | J. Name., 2012, 00, 1-3
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without effecting quantity of the reaction. The synthetic value of this proved that the source of oxygen atoms was aq. TBHPV(ieSwchAertimcleeO2n,linee)
method was further demonstrated by investigating follow-up
DOI: 10.1039/C9CC07820G
(for LCMS details, see the ESI, S13-S17). The above described results
chemistry using 2b and 2j as substrates (Table 3). Selective
elimination of the OH group was achieved by treating 2b with
BF3.OEt2 in DCM to give the corresponding elimination product 5b
in 55% yield (Table 3, b). When we treated 2j under palladium
catalysis for
support that the newly formed hydroxyl group is from TBHP,8c,13 and
the minor 18O-labeled product 2b-O18 was anticipated by 18O isotope
exchange with H218O.13a
Table-2. Scope of 3-azabicyclo[3.1.0] hexane a,b,c
Table-1. Scope of 1,6-enynes a,b,c
O
R1
R2
I2 (0.5 equiv),
R1
I
R1
70% aq. TBHP (3 equiv),
R1
R2
TsN
N
R2
MeOH (0.1 M), 80 °C
I2 (0.5 equiv),
70% aq. TBHP (3 equiv),
ACN (0.1 M),
Ts
R
1 = H, Ph
1a,b,c,f,j,g,z
3a,3b,3c,3f,3j,3g,3z
R2 = Ph
3b
TsN
OH
R2
TsN
H2O (15 equiv), 80 °C
O
O
O
n
n
O
O
O
O
Ph
Ph
Ph
1a-n
Ph
Ph
O
2a-n
2a
Ph
Ph
H
Ph
S
O
N
O
N
N
N
N
Ts
Ts
Ts
Ts
Ts
N
N
NO2
I
H
O
I
I
Ts
3a, 42%, 15h
Ts
3b, 48%, 2h
I
I
I
3c, 38%, 24h
3f, 41%, 24h
3j, 42%, 24h
3g, no reaction
3z, trace product
O
a Reaction conditions: 1a-b (0.1 mmol), iodine source (0.05 mmol), oxidant (0.3
mmol), MeOH (0.1 M) with stirring for 12 h at 80 ℃. b Isolated yields. c After a long
reaction time (48h) major the starting materials were observed by TLC (starting
material was recovered).
TsN
OH
Ph
58%, 12h
TsN
OH
Ph
TsN
OH
Ph
TsN
OH
Ph
63%, 5h
TsN
OH
Ph
TsN
2f,
OH
Ph
2b,
2a,
2c,
70%, 7h
2d,
65%, 7h
S
2e,
69%, 6h
75%, 6h
I
O
S
H
I
I
TMS
I
Ph
I
I
NO2
TsN
OH
TsN
OH
TsN
OH
TsN
OH
Ph
TsN
OH
Ph
83%, 2h
Ph
75%, 4h
Ph
TsN
OH
Ph
Ph
42%, 15h
Ph
Table-3. Gram-scale reactions and further transformation of cyclization product
2l,
2k,
79%, 2h
2i,
2j,
2g,
2h,
48%, 20h
52%, 12h
I
S
S
I
Ph
I
I
S
I
Ph
Ph
I
H
O
I
O
O
O
(b)
Pd(PPh3 4 (5 mole%), BF3.OEt2 (2 equiv),
(a)
OH
Ph
TsN
TsN
OH
Ph
TsN
)
TsN
Ph
OH
O
Ph
OH
Expected
O
OH
Ph
t-BuOK (2 equiv),
DMF, 80 °, 12 h
DCM, RT, 2 h
TsN
TsN
6j
Ph
OH
Ph
Ph
Expected
Observed
2p',
58%, 3h
Observed
5b, 55%
, 85%
R1
2m,
72%, 3h
2n,
2o
2o',
52%, 3h
67%, 3h
2p
I
R1
Unsuccessful Examples:
I2 (0.5 eq), 70%
aq.TBHP (2 equiv),
2b 2j
&
Ph
Ph
R1= Ph,
Ph
TsN
1,
Ph
ACN (0.1 M), H2
(15 eq), 80 °C
O
S
Ph
Ts
N
TsN
OH
Ph
S
1g
Ph
I
S
NC
CN
1s
O
1q
EtOOC
COOEt
1r
OH
(c)
1t
Ph
Ph
B
A
(d)
D2O (1 mL),
sonication,
5 min
OH
TsN
OD
Ph
),
4 (5
mole%
)
Pd(PPh3
v),
(3 equi
K2CO3
a
TsN
8j, 90%
OH
Ph
Reaction conditions: 1a (0.1 mmol), iodine source (0.05 mmol), oxidant (0.3
mmol), H2O (1.5 mmol), solvent (0.1 M). b Isolated yields. c Structures of the major
isomers are shown (all compounds are racemic).
7j
, 81%
2O
6 h
e:EtOH:H
Benzen
(5:2:1),
80 °C,
OMe
I
Ph
Ph
I2 (0.5 equiv),
70% aq. TBHP (2
equiv), ACN (0.1M),
H2O (15 equiv), 80 TsN
Ph
Ph
O
N
TsN
1u,
Ph
refs
OH
°C
(e)
(±)-Femoxetine
(antidepressants)
2u,
68%, 12h
0.1 mmol
12h at 100 °C, we observed simultaneous dehydration as well as
deiodination product 6j (Table 3, b). By sonication of 2j in 1 mL D2O,
we observed deuterated compound 7j (Table 3, c). By using the
traditional Suzuki reaction, we succeeded in incorporating phenyl
group 8j (Table 3, d). Furthermore, our synthetic method was applied
to synthesize key intermediate 2u, a precursor of the anti-depressant
(±) femoxetine in 68% yield (Table 3, e).12
Based on the literature reports and control experiments, a plausible
mechanism was proposed as shown in Scheme 3.8c,13,14 The reaction
is proposed to involve an iodide radical, which is generated by the
reaction of I2 with TBHP through the liberation of water.
Subsequently, intermolecular addition of iodine radical occurs across
1,n-enyne in a regio- and chemoselective manner to give iodo-vinyl
radical intermediate 1A and simultaneously produce 6-endo-trig
cyclization to yield tertiary radical center 1B. From here, the reaction
can follow two path ways. In path A, the tertiary radical can be
directly trapped by the hydroxy radical to afford final compound 2.12c
However, in path B, the formed tertiary radical intermediate 1B
reacts with tert-butyl peroxide to give intermediate 1C.13d In the next
step, Intermediate 1C is formed under thermal homolytic cleavage to
afford the oxygen-centered radical intermediate 1D. Finally via
hydrogen atom transfer (HAT) from TBHP with intermediate 1D can
produce the final product. In product 3 formation (path C), the
hydroxyl radical is the initiator for the radical cascade in regio- and
chemoselective fashion to offer intermediate 1E. The formed radical
intermediate 1E will undergo 5-exo-trig cyclization to generate
primary carbon center radical 1F. Due to the less stability of the
formed primary radical, it simultaneously attacks the alkene moiety
to produce intermediate 1G. Finally, intermediate 1G formed via
oxidation will yield final compound 3. In path D, the tert-butyl
peroxide radical addition alkyne moiety 1 to produce intermediate
To understand the reaction mechanism, preliminary control
experiments were carried out, as shown in Scheme 2. Radical
inhibition studies of 1b with TEMPO, BHT and 1,4-cyclohexadiene
under the standard conditions gave 3b in trace-10% yields (Scheme
2, a). These results suggest that the reaction proceeds through a
radical pathway. Further investigation of the reaction under nitrogen
atmosphere did not affect the reaction yield. This result confirmed
that molecular oxygen was not involved in the hydroxylation reaction
(Scheme 2, b). Next, TBHP was replaced with an O2 balloon for
further confirmation of the oxygen source, but the reaction did not
afford the desired product. It is clear that the OH is not from O2
(Scheme 2, c). Later, the reaction was carried out in dry acetonitrile
with different equivalents of deuterated water, but we did not
observe any deuterium incorporated within the product (Scheme 2,
d), which ruled out the water as an OH radical source (see the ESI,
S8-S11). Next we try to find the reactive intermidate in the reaction
(see the ESI, S11-S13). Furthermore, H218O labeling studies indirectly
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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1E’ simultaneously via 5-exo-trig to give 1F’. Next, thermal
homolyticcleavage afford oxygen-centered radical intermediate 1G’.
Finally, homolytic peroxide bond cleavage to produce desired
product 3.
Notes and references
View Article Online
DOI: 10.1039/C9CC07820G
1
(a) D. Kong, T. Xue, B. Guo, J. Cheng, S. Liu, J. Wei, Z. Lu, H. Liu,
G. Gong, T. Lan, W. Hu and Y. Yang, J. Med. Chem., 2019, 62,
3088-3106; (b) E. Vitaku, D. T. Smith and J. T. Njardarson, J.
Med. Chem., 2014, 57, 10257-10274..
Standard condition
1b
Standard condition
N2 atmosphere
1b
(b)
2b, 60%
2b
(a)
(c)
(d)
0.1 mmol
0.1 mmol
Radical inhibitor
(3 equiv), 24 h
TEMPO = 0 %, BHT = 10%,
4-Cyclohexadiene = trace
2
3
(a) K. Kubota, Y. Watanabe, K. Hayama and H. Ito, J. Am. Chem.
Soc., 2016, 138, 4338-4341; (b) A. Hager, N. Vrielink, D. Hager,
J. Lefranc and D. Trauner, Nat. Prod. Rep., 2016, 33, 491-522;.
(a) D. Kong, T. Xue, B. Guo, J. Cheng, S. Liu, J. Wei, Z. Lu, H. Liu,
G. Gong, T. Lan, W. Hu and Y. Yang, J. Med. Chem., 2019, 62,
3088-3106; (b) A. J. J. Lennox, S. L. Goes, M. P. Webster, H. F.
Koolman, S. W. Djuric and S. S. Stahl, J. Am. Chem. Soc., 2018,
140, 11227-11231.
(a) B. V. Subba Reddy, P. N. Nair, A. Antony, C. Lalli and R.
Gree, Eur. J. Org. Chem., 2017, 1805-1819; (b) X. Guo, W. Li,
Q. Li, Y. Chen, G. Zhao, Y. Peng and J. Zheng, Chem Res Toxicol,
2019, 10.1021/acs.chemrestox.9b00141.
I2 (0.5 equiv), O2
balloon,
ACN (0.1 M), H2O (15
equiv), 80 °C, 5 h
2b, no reaction
deuterium incorporation
1b
0.1 mmol
was not observed
S
I
I2 (0.5 equiv),TBHP in
decane (5-6 M) (3 equiv),
dry ACN (0.1 M), D2O (30
equiv), 80 °C, 2 h
OH(OD)
Ph
1j
0.1 mmol
N
2j, 81%
Ts
LCMS showed a mixture of 16
O
and 18O; 16O is the major peak
S
I2 (0.5 equiv),TBHP in
decane (5-6 M) (3 equiv),
dry ACN(0.1 M), H2O18
(15 equiv), 80 °C, 2 h
O16H (O18H)
Ph
1j
(e)
I
4
0.1 mmol
N
Ts
Scheme 2. Control Experiments
5
6
Drug Design and Relationship of Functional Groups to
Pharmacologic Activity, J. J. Knittel and R. M. Zavod, 2008.
For recent reviews on radical reactions see: (a) X.-Q. Chu, D.
Ge, Z.-L. Shen and T.-P. Loh, ACS Catal., 2018, 8, 258-271; (b)
H. Yi, G. Zhang, H. Wang, Z. Huang, J. Wang, A. K. Singh and A.
Lei, Chem. Rev., 2017, 117, 9016-9085. (c) Z. Chen, M.-Y. Rong,
J. Nie, X.-F. Zhu, B.-F. Shi and J.-A. Ma, Chem. Soc. Rev., 2019,
DOI: 10.1039/c9cs00086k; (c) M.-H. Huang, W.-J. Hao, G. Li,
S.-J. Tu and B. Jiang, Chem. Commun., 2018, 54, 10791-10811.
(a) Y. Hu, M. Bai, Y. Yang and Q. Zhou, Org. Chem. Front., 2017,
4, 2256-2275; (b) P. A. Inglesby and P. A. Evans, Chem. Soc.
Rev., 2010, 39, 2791-2805; (c) K. Gilmore and I. V. Alabugin,
Chem. Rev., 2011, 111, 6513-6556; (d) U. Wille, Chem. Rev.,
2013, 113, 813-853; (e) Y. Hu, M. Bai, Y. Yang and Q. Zhou,
Org. Chem. Front., 2017, 4, 2256-2275.
Mechanism For 2:
I
R1
R1
R3
I
R1
OH
6-endo-
trig
t-BuOOH
t-BuO
R3
R2
R3
R2
I
A
TsN
TsN
R2
A
I2
TsN
1
t-BuOH
I
R1
1A
1B
OH
OH
R3
t-BuOO
t-BuOOI
path-A
t-BuOO
t-BuOOH
TsN
R2
OH
2
HOI
I
t-BuOO
t-BuOO
t-BuO
H2
O
I
R1
HI
t-BuOOH
t-BuOH
I
R1
R3
t-BuOOH
7
R3
R2
TsN
- t-BuO
R2
O
TsN
O
Homolytic
cleavage
O
Mechanism For 3:
1D
1C
HO
R1
R1
R1
R1
O
HO
O
R2
R2
[O]
R2
5-exo-
trig
HO
OH
R1
TsN
N
N
Scheme
path-C
N
R2
R1
Ts
Ts
Ts
1E
1G
1F
3
3.
TsN
R2
O
R1
8
9
(a) J. Xuan, C. G. Daniliuc and A. Studer, Org. Lett., 2016, 18,
6372-6375; X. Cao, X. Cheng and J. Xuan, Org. Lett., 2018, 20,
449-452; (c) B. Liu, J. Cheng, Y. Li and J.-H. Li, Chem. Commun.,
2019, 55, 667-670.
(a) M. R. Mutra, G. K. Dhandabani and J.-J. Wang, Adv. Synth.
Catal. 2018, 360, 3960-396; (b) G. C. Senadi, M. R. Mutra, T.-
Y. Lu and J.-J. Wang, Green Chem., 2017, 19, 4272-4277; (c) G.
C. Senadi, G. K. Dhandabani, W.-P. Hu and J.-J. Wang, Green
Chem., 2016, 18, 6241-6245; (d) G. C. Senadi, B.-C. Guo, W.-P.
Hu and J.-J. Wang, Chem. Commun., 2016, 52, 11410-11413.
R1
O
c
i
R2
yt
O
O
O
R2
ge
5-exo-
trig
1
t-BuOO
Homol
cleava
N
TsN
1E'
N
Ts
path-D
R2
Ts
1F'
1G'
Plausible mechanism
Conclusions
In conclusion, we have developed the regio- and
chemoselective radical cascade cyclization reactions of
unactivated 1,n-enynes to construct diverse N-heterocyclic
10 H. Yorimitsu, T. Nakamura, H. Shinokubo, K. Oshima, K. Omoto
and H. Fujimoto, J. Am. Chem. Soc., 2000, 122, 11041-11047.
compounds under metal-free conditions. These cascade 11 CCDC numbers: 2a (1955156), 3b (1955363), 4b (1955153).
12 G. Liu, W. Fu, X. Mu, T. Wu, M. Nie, K. Li, X. Xu and W. Tang,
Commun. Chem., 2018, 1, 1-8.
reactions encompass the construction of three new bonds (C-I,
C−C and C-O) to provide easy access to iodo-homoallylic
alcohols bearing piperidine ring with moderate to good yields.
In this case, aqueous TBHP acts as an oxidant, hydroxyl and
oxygen source. Interestingly, varying the solvent in the same
reaction conditions exclusively switches the regio-selectivity,
and we observed azabicyclo [3.1.0]hexane derivatives as major
products. The key features of this protocol are the use of
inexpensive reagents, atom economy, and ability to extend the
method to gram-scale synthesis. The chiral version of this
synthetic protocol will be communicated in a due course.
The authors gratefully acknowledge funding from the Ministry
of Science and Technology (MOST), Taiwan, and the Centre for
Research and Development of Kaohsiung Medical University for
400 MHz NMR analyses, LC-MS and GC-MS analysis.
13 For papers on use of hydroperoxides as the hydroxyl group
resources, see: (a) S. Duan, Y. Xu, X. Zhang and X. Fan, Chem.
Commun., 2016, 52, 10529-10532; (b) D. Yu, X.-L. Chen, B.-R.
Ai, X.-M. Zhang and J.-Y. Wang, Tetrahedron Lett., 2018, 59,
3620-3623; (c) W.-T. Wei, W.-M. Zhu, Q. Shao, W.-H. Bao, W.-
T. Chen, G.-P. Chen, Y.-J. Luo and H. Liang, ACS Sustainable
Chem. Eng., 2018, 6, 8029-8033.
14 (a) W. Liu, C. Chen, P. Zhou and H. Tan, Org. Lett., 2017, 19,
5830-5832.; (b) Z.-Q. Wang, W.-W. Zhang, L.-B. Gong, R.-Y.
Tang, X.-H. Yang, Y. Liu and J.-H. Li, Angew. Chem., Int. Ed.,
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Qian and J.-H. Li, Angew. Chem., Int. Ed., 2014, 53, 9017-9020;
(d) Y. Zi, Z.-J. Cai, S.-Y. Wang and S.-J. Ji, Org. Lett., 2014,
16, 3094-3097; (e) X. Cao, X. Cheng and J. Xuan, Org. Lett.,
2018, 20, 449-452; (f) K. Zmitek, M. Zupan, S. Stavber and J.
Iskra, J. Org. Chem., 2007, 72, 6534-6540; (g) H. Yu and J.
Shen, Org. Lett., 2014, 16, 3204-3207; (h) X. Lu, Y. Bai, Y. Li, Y.
Shi, L. Li, Y. Wu and F. Zhong, Org. Lett., 2018, 20, 7937-7941;
(i) Chem. Commun., 2019, 55, 63.
Conflicts of interest
“Author claim no conflicts of interest”.
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