PIDA/I2-Mediated α- And β-C(sp3)-H Bond Dual Functionalization of Tertiary Amines

Article abstract of DOI:10.1021/acs.joc.8b01424

The α,β-C(sp³)-H bond dual functionalization of tertiary amines is still a challenging task for both organic and medicinal chemists. Herein a direct, mild, metal-free, and site-specific method mediated by PIDA/I₂ was developed for α,

Full text of DOI:10.1021/acs.joc.8b01424

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Article
PIDA/I2-Mediated #- and #-C(sp3)-H Bonds
Dual Functionalization of Tertiary Amines.
Yu Zhu, Li-Dong Shao, Zhen-Tao Deng, Ying Bao, Xin Shi, and Qin-Shi Zhao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01424 • Publication Date (Web): 21 Jul 2018
Downloaded from http://pubs.acs.org on July 21, 2018
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The Journal of Organic Chemistry
PIDA/I2-Mediated α- and β-C(sp3)-H Bonds Dual Functionalization of Ter-
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tiary Amines.
Yu Zhu,†,‡,§ LiꢀDong Shao,†,§ ZhenꢀTao Deng,†,‡ Ying Bao,†,‡ Xin Shi,†,‡ and QinꢀShi Zhao*,†
†State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese
Academy of Sciences, Kunming 650201, People’s Republic of China
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‡University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China
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ABSTRACT: The α,βꢀC(sp3)ꢀH bonds dual functionalization of tertiary amines is still a challenging
task for both organic and medicinal chemists. Herein, a direct, mild, metalꢀfree, and siteꢀspecific method
mediated by PIDA/I2 was developed for α,βꢀC(sp3)ꢀH bonds dual functionalization of tertiary amines,
and this method can provide facile access to αꢀketo lactams or rarely studied α,αꢀdiiodo lactams. Moreꢀ
over, this method was used for the effective syntheses of three natural products [obscurumine C (13),
obscurumine O (17), and strychnocarpine (18)] and direct preparation of mimics of the in vivo metaboꢀ
lites of two FDAꢀapproved drugs (imatinib and donepezil) in 36ꢀ60% overall yield. The method repreꢀ
sents a promising protocol for the lateꢀstage α,βꢀC(sp3)ꢀH bonds oxidative dual functionalization of terꢀ
tiary amineꢀcontaining drugs and complex natural products.
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INTRODUCTION
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The functionalization of C(sp3)ꢀH bonds represents an important and longꢀstanding goal in chemistry.1
Such methods allow rapid, direct access to various C(sp3)ꢀfunctionalities from inert C(sp3)ꢀH bonds. In
recent years, C(sp3)ꢀH bonds functionalization has been developed to an unprecedented level;2 however,
there are still limitations in the direct α,βꢀC(sp3)ꢀH bonds oxidative dual functionalization of tertiary
amines because the nitrogen atom is more reactive than C(sp3)ꢀH bonds in various activated systems.3
Tertiary amines are ubiquitous structural features in many biologically important natural alkaloids and
FDAꢀapproved drugs. The siteꢀspecific, oxidative dual functionalization of α,βꢀC(sp3)ꢀH bonds of
tertiary amines is a priority for the lateꢀstage modification of complex natural products and especially in
the direct and scalable preparation of the in vivo metabolites of drugs that contained these moieties to
further accelerate the drug development process.[4] Therefore, developing a method to oxidize C(sp3)ꢀH
bonds of tertiary amines would be a powerful tool to facilitate the drug discovery and development
process.4a,5
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Scheme 1. α,βꢀC(sp3)ꢀH Oxidative dual functionalization of Tertiary amines..
To the best of our knowledge, photochemical conditions6 and metalꢀcatalyzed oxidations such as
those with RuO4,7 OsO4,8 and Pt,9 have been tested in the oxidation of the α,βꢀC(sp3)ꢀH of tertiary
amines; however, most of them resulted in the formation of complex mixtures of byꢀproducts and poor
yields (Scheme 1). Recently, Barry Touré and coworkers reported a Cuꢀmediated α,βꢀC(sp3)ꢀH oxidation
of many N,N'ꢀdialkyl piperazineꢀcontaining drugs in moderate yields.5 Moreover, even for the simplest
building block, piperidinꢀ2,3ꢀdione, it cannot be directly prepared from piperidine. Current routes, for
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example from nicotinic acid,10 2,3ꢀdihydroxypyridine,11 enamino lactams,12 corresponding lactams,13
2,2ꢀdialkoxyꢀ5ꢀbromopentanoates,14 corresponding thioacetals,15 and (Z)ꢀ2ꢀalkoxyꢀ2ꢀ pentenoates,16
have some shortcomings, and do not use readily available starting materials. Considering these cumberꢀ
some and multistep approaches, a more convenient, and especially a metalꢀfree method, advance in the
oxidation of α,βꢀC(sp3)ꢀH bonds of tertiary amines is highly desirable.
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Hypervalent iodine reagents have attracted increasing attention and are a widely used promising
strategy for the functionalization of CꢀH bond such as in the Suárezꢀmodified Hofmann–Löffler–Freytag
(HLF)17 reaction, which uses a secondary amine to generate a cyclic amine under
(diacetoxyiodo)benzene (PIDA) and I2,18 in the Pd(OAc)2/PIDA/I2 system reported by Yu et al.19 for the
αꢀC(sp3)ꢀH acetoxylation of NꢀBoc tertiary amides, and in the PIDAꢀpromoted α,βꢀC(sp3)ꢀH diꢀ
acetoxylation of the Nꢀaryl piperidines reported by Liang et al.20 (Scheme 1). Very recently, Antonchick
and coꢀworkers reported an effective cisꢀdihydroxylation of alkanes using the ArI/I2/NaN3/AcO2H
system.21 However, PIDA/I2ꢀmediated α,βꢀC(sp3)ꢀH dual oxidations of tertiary amines have not been
reported. Herein, we report a straightforward method for the α,βꢀC(sp3)ꢀH oxidative dual
functionalization of tertiary amines using a PIDA/I2 system.
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RESULTS AND DISCUSSION
Given that cationic iodine (I+) can promote reactions such as the Suárezꢀmodified HLF reaction,17,22
Pdꢀcatalyzed αꢀC(sp3)ꢀH oxidations of amides,19 electrophilic reactions of olefins,23 and αꢀC(sp3)ꢀH
oxidations of aromatic ketones,24 we planned to activate the αꢀC(sp3)ꢀH bond of Nꢀmethyl piperidine (1)
using PIDA/I2, which could generate I+ in situ.22,23 Initially, 1 was treated with PIDA (2 equiv.) and I2
(2 equiv.) in DCE, which provided 1b in 15% (Table 1, entry 1). Attempts to repeat this transformation
using other I+ sources, like Nꢀiodosuccinimide (NIS)，I2/NaOH, and [bis(trifluoroacetoxy)iodo]benzene
(PIFA)/I2 or other oxidants were unsuccessful (for details, see Table S1, Supporting Information, SI).
Therefore, PIDA/I2 was selected as the final oxidant. By carefully investigating various reaction
conditions (Table S2ꢀ6, SI), we found that the solvent and the amount of oxidant significantly
influenced the reaction outcome (Table 1, entries 2ꢀ7). An increase in the yield of 1b was observed
using PIDA (2 equiv.) and I2 (1 equiv.) (Table 1, entry 6). Similarly, the yield of 1a could be improved
using PIDA (3 equiv.) and I2 (2 equiv.) (Table 1, entry 7). Most importantly, to our surprise, the type of
functionalized product (α,βꢀO,O or α,βꢀO,[I,I]) could be controlled by switching the solvent from THF
to DCE for simple piperidine substrates (Nꢀmethyl and Nꢀbenzyl piperidines), but failed to be
compatible with other substrates. Other solvents were also screened, and among them, DCE and THF
were found to be suitable for the reaction, while protic solvents like methanol and water were
detrimental (Table S2, SI). In addition, inert gas protection (argon) (Table S4) and the addition of an
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additive (Table S6) were not necessary. To our delight, using Na2S2O3 (aq.) to quench the reaction
provided a higher yield of the desired product (Table S5).
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Table 1. Reaction Optimization
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Entry
Oxidant (equiv.)
PIDA+ I2 (2:2)
PIDA+I2 (4:2)
PIDA+I2 (4:2)
PIDA+I2 (4:2)
Solvent
DCE
Time (min)
180
product (yield)
1b 15%
NR a
Complexb
NR a
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H2O
180
methanol
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THF/H2O
(1:1)
180
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PIDA+I2 (2:1)
PIDA+I2 (2:1)
PIDA+I2 (3:2)
DCE
DCE
THF
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30
90
1b 20%
1b 30%
1a 62%
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a
No reaction was detected; b Starting materials were decomposed.
With the optimized reaction conditions in hand, we proceeded to investigate the generality of this CꢀH
bonds dual functionalization on different tertiary amines (Figure 1). Using Nꢀbenzyl piperidine (2),
N,N'ꢀdimethyl piperazine (3), and 1ꢀbenzylꢀ4ꢀmethyl piperazine (4) as substrates provided the
corresponding αꢀketo lactams (3a and 4a) in moderate yield; 4ꢀbenzyl morpholin (5) gave a mixture of
the αꢀketo lactam (5a) and αꢀacetoxyl lactam (5b) in 50% yield. However, Nꢀmethyl or Nꢀbenzyl
pyrroles did not give the corresponding αꢀketo lactam products probably due to the rigid pyrrole ring is
hard to alleviate the high tension of the newly formed αꢀketo lactam. Notably, Nꢀmethyl or Nꢀbenzyl
pyrroles and piperidines gave α,αꢀdiiodo lactams 2b, 6b, and 7b, which have not been reported before,
and the structures of 1b and 7b were confirmed by Xꢀray crystallographic analysis. In addition, the
reaction of Nꢀbenzyl piperidine (2) could be performed on a 0.5ꢀg scale (0.02 M) in moderate yield
(Table S7, SI). These results showed that the CꢀH bonds dual functionalization method can be generally
applied to simple tertiary amines. We next tried to extend this method to complex molecules. Among the
selected piperidineꢀ or piperazineꢀcontaining natural products and drugs, αꢀObscurine (8),25
a
Lycopodium alkaloid, was selectively converted to its Nꢀformylated analog in 62% yield. We proposed
this interesting selectivity of 8 could be resulted from the increased tension of piperidine ring by the αꢀ
quaternary carbon. Especially when the imine intermediate was formed, imidization of methyl group
might be more easy than that of methylene group. In the case of imatinib (a medication for chronic
myelogenous leukemia), the highly siteꢀspecific oxidation afforded αꢀketo lactam 9b (36% overall yield
after removal of aromatic iodine in 9a) as the sole product, while a mixture of Nꢀmethyl, aromatic
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methyl, and methene piperazine oxidative derivatives (13% yield) were detected from the Cuꢀcatalyzed
oxidation approach.5 In addition, iodide 9a could be further modified through a variety of coupling
approaches to enrich the structural diversity of accessible pharmaceuticals. Moreover, the piperidine
containing drug donepezil (a medication for Alzheimer's disease) was also transformed into αꢀ
ketolactam 10a in 45% yield, which was stable at its enol form.
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Figure 1. Substrate scope.
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a PIDA (3 equiv.), I2 (2 equiv.), rt; bPIDA (4 equiv.), I2 (2 equiv.), rt; c PIDA (2 equiv.), I2 (1 equiv.), rt; d Pd/C, H2,
AcOH.
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To elucidate the reaction mechanism, several control experiments were conducted. First, no reaction
was detected after exposure of NꢀBoc piperidine to PIDA/I2, revealing the necessity of the free N lone
pair of electrons (Scheme 2, equation 1). Using either PIDA or I2 alone resulted in no reaction, which
suggested an I+ꢀmediated pathway might be involved (Scheme 2, equation 2).22,23 In addition,
performing the oxidation under visible light (LED), under UV light or while full protected from light
provided αꢀketo lactam 1a, implying that the mechanism might not proceed through a radical approach
like the HLF reaction (Scheme 2, equation 3; for details, see Table S8, SI). To determine the source of
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18
the oxygen in the products, H2O18 and O2 were used (Scheme 2, equations 4ꢀ6).26 According to the
results, both 1a and 1b were labeled with one O18 atom when H2O18 was used as the coꢀsolvent27 or to
quench the reaction, and 1a was not labled with two O18 atoms, and 1b was not labeled with O18 when
18
the reaction was conducted under an O2 atmosphere. The low yields of 1b and other α,αꢀdiiodo lacꢀ
tams (Figure 1, 2b, 6b, and 7b) might be resulted from the high reactivity of I+ and the instability of itꢀ
self although it was detected as a single product by TLC after consumption of starting materials. These
results suggested that the first oxygen on C2 might come from H2O and the second oxygen on C3 might
be from HOAc, it is clear that neither of them come from O2 (Table S9, SI).
Scheme 2. Experiments for mechanism analysis.
A plausible mechanism is shown in scheme 3 using Nꢀmethyl piperidine (1) as a representative.
Initially, compound 1 was transformed to iminium intermediate A through a dehydrogenation, which
was promoted by the IOAc generated in situ from PIDA and I2 (one equivalent of PIDA reacts with one
equivalent of I2 to provide two equivalent of IOAc)22,23. Highly reactive iminium A could then be
attacked by H2O (Table S9, SI) through a nucleophilic addition to provide αꢀhydroxy intermediate B.26a
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These steps were repeated to form another reactive iminium C, which could be trapped by H2O and then
rapidly hydrolyzed to give lactam D (aryl iodinated lactam products were obtained with < 5% yields
using 1ꢀmethylꢀ1,2,3,4ꢀtetrahydroquinoline or 1ꢀphenylꢀ1,2,3,4ꢀtetrahydroquinoline as substrates, and
the data was not shown). Lactam D was reacted with IOAc to give αꢀiodo lactam E (aryl iodinated αꢀ
iodo lactam products were obtained with < 5% yields using 1ꢀmethylꢀ1,2,3,4ꢀtetrahydroquinoline or 1ꢀ
phenylꢀ1,2,3,4ꢀtetrahydroquinoline as substrates, and the data was not shown). From here, the reaction
could proceed in two different ways. In path a, E could be reacted with AcOH to give αꢀacetoxyl
ketolactam F (like compound 5b). Similarly, F could be converted to αꢀiodide G by IOAc, which could
further undergo deiodination in the presence of AcOꢀ to furnish 1a. In path b, E likely reacted with IOAc
to directly generate 1b. The extremely obvious solvent factor of this transformation (THF vs DCE led to
1a vs 1b) might be resulted from the different lyolysis of E in THF and DCE, but we believe it is not
only the solvent control but also other comprehensive factors such as substrate itself affected the reacꢀ
tion.
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Scheme 3. Proposed mechanism.
Next, the robustness of this strategy was evaluated in the syntheses of Lycopodium alkaloids,
obscurumine C (13)28 and obscurumine O (17),29 which are wellꢀknown for their unique 6/6/6/6 fused
skeletons and 1,6ꢀdihydropyridineꢀ2,3ꢀdione moieties. Biogenetically, these alkaloids might be derived
from lycopodine (11) via the action of oxidase. Interestingly, treating 11 with PIDA/I2 afforded iodo
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ketolactam 12 in 51% yield and the natural product obscurumine C (13) in 5% yield, which was
generated through three oxidations including Nꢀα, β, γ sites in one step (Scheme 4). As a comparison,
only one oxidation was achieved to form 11a using KMnO4.30 Then, the iodine was removed using
AIBN and nBu3SnH to afford 13 in 80% yield (46% overall yield). A similar approach was effectively
used in the synthesis of obscurumine O (17), which inhibits ILꢀ2 production with an IC50 of 17.2 ꢁM.29
Consequently, starting from 11, reduction of the carbonyl group using LiAlH4 followed by acetylation
(Ac2O/DMAP, pyridine) provided 15 in 95% yield over two steps. For full consumption of starting
materials, subsequent PIDA/I2 oxidation of 15 was performed at a higher temperature (80 °C) to give
product 16, followed by removal of the iodine to yield 17 (64% in two steps). Moreover, using the
developed method, we improved a facile entry to βꢀcarboline motifs starting from commercially
available Nꢀmethyl piperidine and Nꢀbenzyl piperidine. Strychnocarpine (18)11 is a tetrahydroꢀβꢀ
carboline alkaloid first isolated from strychnos species in 1980,31 and it is wellꢀknown for its
hallucinogenic properties as it exhibits a high affinity for the peripheral type of benzodiazepine
receptors in rat brain (IC50 = 30 µM).32 Many synthetic approaches to 18 have been achieved.11,33
However, these approaches require multiple steps and complicated metalꢀcatalyzed systems. In this
study, treatment of 1a or 2a with phenyl hydrazine in the presence of formic acid resulted in 18 or 19
(54% overall yield) via a Fischer indole reaction.34 By this facile procedure, various derivatives of βꢀ
carboline alkaloids can be prepared for pharmacological screening (Scheme 5).
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Scheme 4. Semisynthesis of obscurumine C and obscurumine O.
R
H
H
H
H
H
O
O
a. PIDA, I2
N
O
51% for 12
N
O
13
5% for
[O] x 3
11
[X-ray]
12
R = I,
b. nBu3SnH
g. KMnO4
60%
[O] x 1
c. LiAlH4
d. Ac2O
95%
R = H, Obscurumine C (13)
80%
R
H
H
H
O
O
e. PIDA, I2
80%
H
H
H
N
OAc
N
OAc
[O] x 3
H
H
O
N
O
15
16
R = I,
f. nBu3SnH
17
R = H, Obscurumine O (
)
11a
80%
a PIDA (4 equiv.), I2 (2 equiv.), THF, rt, 56%; b AIBN (0.2 equiv.), nBu3SnH (2 equiv.), benzene, 50 °C, 5 h, 80%; c
LiAlH4, THF, 60 °C; d Ac2O, pyridine, DMAP, 50 °C, 95% over two steps; e PIDA (6 equiv.), I2 (3 equiv.), DCE, 80
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°C, reflux, 3.5 h, 80%; f AIBN (0.2 equiv.), nBu3SnH (2 equiv.), benzene, 50 °C, 5 h, 80%; g KMnO4, acetone/H2O
(4:1), 0 °Cꢀrt, 2h, 60%.
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Scheme 5. Total synthesis of βꢀcarboline compounds.
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8
O
R
N
O
b. Phenylhydrazine
90%
a. PIDA, I2
N
R
N
R
O
N
H
9
1a
R = Me, 62%
R = Me, Strychnocarpine (18)
19
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1 R = Me
R = Bn
2
R = Bn,
2a R = Bn, 66%
a PIDA (3 equiv.), I2 (2 equiv.), THF, rt; b Phenylhydrazine, toluene, then formic acid, 80 °C, 90%.
CONCLUSION
In conclusion, we have demonstrated the PIDA/I2ꢀmediated C(sp3)ꢀH bonds oxidative dual
functionalization of tertiary amines utilizing a PIDA/I2 system. By the developed method, αꢀketo
lactams or α,αꢀdiiodo lactams were prepared in 30ꢀ80% yield, and the type of product could be
controlled by changing the solvent in cases of Nꢀmethyl or Nꢀbenzyl piperidines. Moreover, three
natural products obscurumines C (13) and O (17) and strychnocarpine (18) were successfully
synthesized within four steps. Mimics of the in vivo metabolites of two clinical medications, imatinib
(36% yield) and donepezil (45% yield), were directly prepared using this siteꢀspecific C(sp3)ꢀH
oxidation. We envision this method will be highly beneficial in the total synthesis of alkaloids
containing 1,6ꢀdihydropyridineꢀ2,3ꢀdione units and the lateꢀstage siteꢀspecific α,βꢀC(sp3)ꢀH oxidations
of bioactive tertiary amines as well as in the drug discovery cycle.
EXPERIMENTAL SECTION
35
General Experimental Procedures: Lycopodine (11) was isolated from lycopodium obscurum. All
CꢀH oxidations were run under air with no precautions taken to exclude moisture. All other reactions
were carried out under an atmosphere of argon in dry flask, and were monitored by analytical thinꢀlayer
chromatography (TLC), which was visualized by ultraviolet light (254 nm, if applicable), phosphomoꢀ
lybdic acid (50 g/L) in EtOH following heating as developing agents or by spraying improved Dragenꢀ
dorff’s reagent if necessary. All solvents were obtained from commercial sources and were purified acꢀ
cording to standard procedures. All reactions sensitive to air or moisture were carried out under argon or
nitrogen atmosphere in dry and freshly distilled solvents under anhydrous conditions, unless otherwise
noted. Purification of products was accomplished by flash column chromatography using silica gel
(200~300 mesh). All NMR spectra were recorded with a Bruker AVANCE III 400MHz or AVANCE III
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600 MHz (1H NMR) spectrometer and 100 MHz or 150 MHz (13C NMR) in CDCl3 or CD3OD: chemiꢀ
cal shifts (δ) are given in ppm, coupling constants (J) in Hz, the solvent signals were used as references
(CDCl3: δC = 77.0 ppm; CD3OD: δC = 49.00 ppm; residual CHCl3 in CDCl3: δH = 7.26 ppm; residual
CH3OH in CD3OD: δH = 3.31 ppm). And 13C NMR spectra were obtained as protonꢀdecoupled spectra.
Infrared (IR) spectra were recorded on a BRUKER Tensorꢀ27 FourierꢀTransform Infrared spectrometer
with KBr disks. Melting points were obtained on a WRXꢀ4 apparatus (cover glass) and are uncorrected.
HRMS (ESI) was taken on Agilent 6540 QꢀTOF spectrometer.
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General Procedure of Figure 1 (method A and method B):
To a stirring solution of tertiary amine (1.0 equiv) in solvent [DCE (method A) or THF (method B)
0.02 M, with no need for excluding H2O] was added PIDA and I2, and the reaction mixture was stirred
at room temperature unless otherwise noted. After 30 minutes, additional PIDA were added for conꢀ
sumption of the starting material (if the starting material were not consumed according to TLC analyꢀ
sis). Then, the reaction was quenched with Na2S2O3 (aq.) and allowed to stir until the mixture was pale
yellow (few minutes). Finally, the reaction was extracted with CH2Cl2 and the combined organic layers
were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel to give the entitled product.
1-Methylpiperidine-2,3-dione (1a)
According to general procedure of method B, 1ꢀmethylpiperidine (1) (15 mg, 0.15 mmol), PIDA (97.6
mg, 0.30 mmol, 2 equiv), iodine (75.9 mg, 0.30 mmol, 2 equiv), and THF (7.6 ml, 0.02 M) were reacted
at room temperature. After 30 minutes, additional PIDA (48.3 mg, 0.15 mmol, 1 equiv) were added. The
reaction was quenched by saturated aq. sodium thiosulfate solution (4 ml) after another 60 minutes.
Flash column chromatography on silica eluting with MeOH/DCM (1:100) yielded compound 1a as a
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pale yellow oil (11.8 mg, 62% yield). H NMR (400 MHz, CDCl3) δ 3.57 (t, J = 8.0 Hz, 2H), 3.10 (s,
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3H), 2.74 (t, J = 8.0 Hz, 2H), 2.21 (m, 2H). C NMR (100 MHz, CDCl3) δ 191.3, 158.1, 49.7, 38.7,
35.4, 21.7. HRMS (ESI) m/z calcd for C6H9NO2Na [M + Na]+: 150.0525, found: 150.0525.
3,3-Diiodo-1-methylpiperidin-2-one (1b)
According to general procedure of method A, 1ꢀmethylpiperidine (1) (15 mg, 0.15 mmol), PIDA (97.6
mg, 0.3 mmol, 2 equiv), iodine (38.3 mg, 0.15 mmol, 1 equiv), and DCE (7.6 ml, 0.02 M) were reacted
at room temperature. After 30 minutes, the reaction was quenched by saturated aq. sodium thiosulfate
solution (4 ml). Flash column chromatography on silica eluting with EtOAc/petroleum ether (1:4) yieldꢀ
ed compound 1b as a colorless acicular crystal (16.6 mg, 30% yield, mp 147ꢀ148 °C). IR (KBr) 3423,
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2927, 1727, 1663. H NMR (400 MHz, CDCl3) δ 3.47 (t, J = 6.25 Hz, 2H), 2.97 (m, 2H), 2.95 (s, 3H),
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1.80 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 166.3, 51.4, 50.2, 36.9, 23.7, ꢀ2.0. HRMS (ESI) m/z calcd
for C6H9I2NONa [M + Na]+: 387.8666, found: 387.8664.
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1-Benzylpiperidine-2,3-dione (2a)
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According to general procedure of method B, 1ꢀbenzylpiperidine (17.6 mg, 0.10 mmol), PIDA (64.8
mg, 0.20 mmol, 2 equiv), iodine (50.6 mg, 0.20 mmol, 2 equiv.), and THF (5.0 ml, 0.02 M) were reactꢀ
ed at room temperature. After 30 minutes, additional PIDA (32.2 mg, 0.10 mmol, 1 equiv) were added.
The reaction was quenched by saturated aq. sodium thiosulfate solution (4 ml) after another 60 minutes.
Flash column chromatography on silica eluting with MeOH/DCM (1:100) yielded compound 2a as a
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pale yellow oil (13.4 mg, 66% yield). H NMR (400 MHz, CDCl3) δ 7.35ꢀ7.25 (m, 5H), 4.70 (s, 2H),
3.46 (t, J = 4.64 Hz, 2H), 2.74 (t, J = 4.64 Hz, 2H), 2.14 (m, 2H). (This compound was unstable in solꢀ
vents like DCM, chloroform, etc, so impurities were produced during the NMR test) 13C NMR (100
MHz, CDCl3) δ 191.6, 157.8, 135.7, 128.9, 128.5, 128.1, 51.1, 46.8, 38.7, 21.7. HRMS (ESI) m/z calcd
for C12H13NO2Na [M + Na]+: 226.0838, found: 226.0833.
1-Benzyl-3,3-diiodopiperidin-2-one (2b)
According to general procedure of method A, 1ꢀbenzylpiperidine (17.6 mg, 0.10 mmol), PIDA (64.8
mg, 0.20 mmol, 2 equiv), iodine (25.4 mg, 0.10 mmol, 1 equiv.), and DCE (5.0 ml, 0.02 M) were reactꢀ
ed at room temperature. The reaction was quenched by saturated aq. sodium thiosulfate solution (4 ml)
after 45 minutes. Flash column chromatography on silica eluting with EtOAc/petroleum ether (1:4)
yielded compound 2b as a colorless acicular crystal (14.2 mg, 32% yield, mp 110.6ꢀ111.7 °C). IR (KBr)
3411, 3246, 3060, 3024, 2921, 2853, 1683, 1666, 1452, 1258, 698. (This compound was unstable in
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solvents like DCM, chloroform, etc, so impurities were produced during the NMR test) H NMR (400
MHz, CDCl3) δ 7.30ꢀ7.17 (m, 5H), 4.50 (s, 2H), 3.32 (t, J =6.24 Hz, 2H), 2.90 (m，2H), 1.68 (m, 2H).
13C NMR (100 MHz, CDCl3) δ 166.5, 136.4, 128.8, 128.0, 127.7, 51.8, 51.2, 47.4, 23.7, ꢀ1.5. HRMS
(ESI) m/z calcd for C12H13I2NONa [M + Na]+: 463.8979, found: 463.8978.
1,4-Dimethylpiperazine-2,3-dione (3a)
According to general procedure of method B, 1,4ꢀdimethylpiperazine (11.4 mg, 0.10 mmol), PIDA
(64.8 mg, 0.20 mmol, 2 equiv), iodine (50.6 mg, 0.20 mmol, 2 equiv.), and DCE (5.0 ml, 0.02 M) were
reacted at room temperature. After 30 minutes, additional PIDA (64.8 mg, 0.20 mmol, 2 equiv) were
added. The reaction was quenched after by saturated aq. sodium thiosulfate solution (4 ml) another 60
minutes. Flash column chromatography on silica eluting with MeOH/DCM (1:60) yielded compound 3a
as a white amorphous powder (8.6 mg, 61% yield). 1H NMR (400 MHz, CDCl3) δ 3.55 (s, 4H), 3.08 (s,
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6H). C NMR (100 MHz, CDCl3) δ 157.6, 46.1, 35.0. HRMS (ESI) m/z calcd for C6H10N2O2Na [M +
Na]+: 165.0634, found: 165.0632.
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1-Benzyl-4-methylpiperazine-2,3-dione (4a)
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According to general procedure of method A, 1ꢀbenzylꢀ4ꢀmethylpiperazine (19.0 mg, 0.10 mmol),
PIDA (64.8 mg, 0.20 mmol, 2 equiv), iodine (50.6 mg, 0.20 mmol, 2 equiv.), and DCE (5.0 ml, 0.02 M)
were reacted at room temperature. After 30 minutes, additional PIDA (64.8 mg, 0.20 mmol, 2 equiv)
were added. The reaction was quenched by saturated aq. sodium thiosulfate solution (4 ml) after another
60 minutes. Flash column chromatography on silica eluting with MeOH/DCM (1:40) yielded compound
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4a as a white amorphous powder (14.2 mg, 65% yield). H NMR (400 MHz, CDCl3) δ 7.38ꢀ7.21 (m,
5H), 4.46 (s, 2H), 3.45 (m, 2H), 3.42 (m, 2H), 3.06 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 157.7,
157.4, 135.5, 128.9, 128.4, 128.1, 50.6, 46.4, 43.2, 35.0. HRMS (ESI) m/z calcd for C12H14N2O2Na [M
+ Na]+: 241.0953, found: 241.0950.
4-Benzylmorpholine-2,3-dione (5a) and ester (5b)
According to general procedure of method A, 4ꢀbenzylmorpholine (17.7 mg, 0.10 mmol), PIDA
(64.8 mg, 0.20 mmol, 2 equiv), iodine (50.6 mg, 0.20 mmol, 2 equiv.), and DCE (5.0 ml, 0.02 M) were
reacted at room temperature. After 30 minutes, additional PIDA (64.8 mg, 0.20 mmol, 2 equiv) were
added. The reaction was quenched by saturated aq. sodium thiosulfate solution (4 ml) after another 60
minutes. Flash column chromatography on silica eluting with EtOAc/CHCl3 (1:20) yielded compound
5a as a white amorphous powder (6.1mg, 30% yield) and ester 5b a as colorless oil (5.0 mg, 20% yield).
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5a: H NMR (400 MHz, CDCl3) δ 7.40ꢀ7.27 (m, 5H), 4.71 (s, 2H), 4.43 (t, J =5.12 Hz, 2H), 3.55 (t, J
=5.12 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 156.8, 153.8, 134.6, 129.2, 128.5, 65.4, 50.6, 44.0.
HRMS (ESI) m/z calcd for C11H11NO3Na [M + Na]+: 228.0631, found: 228.0634. 5b: IR (KBr) 3439,
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3086, 3030, 2922, 1757, 1671, 1495, 1453, 1357, 1223, 1142, 1017, 954, 701. H NMR (400 MHz,
CDCl3) δ 7.40ꢀ7.27 (m, 5H), 6.24 (s, 1H), 4.80 (d, J =14.57 Hz, 1H), 4.49 (d, J =14.57 Hz, 1H), 4.11
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(m, 1H), 3.84 (m, 1H), 3.54 (m, 1H), 3.12 (m, 1H), 2.18 (s, 3H). C NMR (100 MHz, CDCl3) δ 169.5,
162.9, 135.5, 128.9, 128.4, 128.0, 88.4, 59.1, 49.9, 45.1, 21.0. HRMS (ESI) m/z calcd for C13H15NO4Na
[M + Na]+: 272.0893, found: 272.0892.
3,3-Diiodo-1-methylpyrrolidin-2-one (6b)
According to general procedure of method A, 1ꢀmethylpyrrolidine (8.5 mg, 0.10 mmol), PIDA
(64.8 mg, 0.20 mmol, 2 equiv), iodine (25.4 mg, 0.10 mmol, 1 equiv.), and DCE (5.0 ml, 0.02 M) were
reacted at room temperature. The reaction was quenched by saturated aq. sodium thiosulfate solution (4
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ml) after 45 minutes. Flash column chromatography on silica eluting with EtOAc/petroleum ether (1:4)
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yielded compound 6b as a colorless acicular crystal (12.2 mg, 35% yield, mp 126ꢀ127 °C). IR (KBr)
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3427, 3242, 2940, 1712, 1631, 1407, 1226, 1109, 1079. H NMR (400 MHz, CD3OD) δ 3.30ꢀ3.23 (m,
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6
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2H), 3.23ꢀ3.15 (m, 2H), 2.87 (s, 3H). H NMR (400 MHz, CDCl3) δ 3.18 (s, 4H), 2.88 (s, 3H). 13C
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NMR (100 MHz, CDCl3) δ 170.6, 48.4, 48.2, 31.6, ꢀ13.6. HRMS (ESI) m/z calcd for C5H7I2NONa [M +
Na]+: 373.8509, found: 373.8510.
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1-Benzyl-3,3-diiodopyrrolidin-2-one (7b)
According to general procedure of method A, 1ꢀbenzylpyrrolidine (16.1 mg, 0.10 mmol), PIDA
(64.8 mg, 0.20 mmol, 2 equiv), iodine (25.4 mg, 0.10 mmol, 1 equiv.), and DCE (5.0 ml, 0.02 M) were
reacted at room temperature. The reaction was quenched by saturated aq. sodium thiosulfate solution (4
ml) after 45 minutes. Flash column chromatography on silica eluting with EtOAc/petroleum ether (1:4)
yielded compound 7b as a colorless acicular crystal (15.8 mg, 37% yield, mp 140.0ꢀ140.3 °C). IR (KBr)
3433, 3064, 3027, 2922, 2855, 1707, 1637, 699. (This compound has atropisomer, so the signal is comꢀ
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plex) H NMR (400 MHz, CDCl3) δ 7.40ꢀ7.22 (m, 5H), 4.48 (s, 2H), 3.12 (m, 2H), 3.03 (m, 2H). C
NMR (100 MHz, CDCl3) δ 170.6, 169.3, 167.7, 135.0, 134.9, 129.0, 128.9, 128.4, 128.3, 128.2, 128.1,
48.2, 48.1, 48.0, 46.3, 45.7, 44.6, 44.0, 43.9, ꢀ13.0. HRMS (ESI) m/z calcd for C11H11I2NONa [M +
Na]+: 449.8822, found: 449.8824.
Formamide (8a)
According to general procedure of method A, αꢀobscurine 8 (20 mg, 0.07 mmol), PIDA (46.9 mg,
0.14 mmol, 2 equiv), iodine (36.9 mg, 0.14 mmol, 2 equiv.), and THF (3.5 ml, 0.02 M) were reacted at
room temperature. After 30 minutes, additional PIDA (46.9 mg, 0.14 mmol, 2 equiv) were added. The
reaction was quenched by saturated aq. sodium thiosulfate solution (4 ml) after another 20 minutes.
Flash column chromatography on silica eluting with MeOH/DCM (1:40) yielded compound formamide
8a as a yellow oil (13.0 mg, 62% yield). IR (KBr) 3422, 3223, 3102, 2923, 2718, 1701, 1658, 1389,
1218. 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.20 (s, 1H), 4.55 (d, J =13.2 Hz, 1H), 2.45 (t, J = 7.9
Hz, 2H), 2.26 (td, J = 2.5, 12.8 Hz, 1H), 2.15ꢀ1.93 (m, 5H), 1.81ꢀ1.64 (m, 4H), 1.60ꢀ1.36 (m, 4H), 1.35ꢀ
1.17 (m, 2H), 0.94 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 171.6, 160.2, 132.4, 109.2, 61.1,
44.2, 42.4, 41.6, 38.1, 33.1, 30.8, 29.6, 26.6, 26.5, 25.0, 22.1, 19.3. HRMS (ESI) m/z calcd for
C17H24N2O2Na [M + Na]+: 311.1730, found: 311.1725.
Iodo ketolactam (9a)
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According to general procedure of method A, imatinib 9 (20 mg, 0.04 mmol), PIDA (51.5 mg, 0.16
mmol, 4 equiv), iodine (40.5 mg, 0.16 mmol, 2 equiv.) and DCE (2.0 ml, 0.02 M) were reacted at room
temperature. After 30 minutes, additional PIDA (25.7 mg, 0.08 mmol, 2 equiv) were added. The reacꢀ
tion was quenched by saturated aq. sodium thiosulfate solution (4 ml) after another 240 minutes. Flash
column chromatography on silica eluting with MeOH/DCM (1:10) yielded compound iodo ketolactam
9a as a yellow amorphous powder (10.4 mg, 40% yield). IR (KBr) 3397, 3246, 3031, 2954, 2923, 2852,
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1667, 1571, 1516, 1497, 1446, 1398, 1258, 1099, 1019. H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H),
9.27 (s, 1H), 8.71 (d, J = 3.7 Hz, 1H), 8.67 (d, J = 7.9 Hz, 1H), 8.54 (d, J = 5.1 Hz, 1H), 8.24 (s, 1H),
7.99 (s, 1H), 7.97 (s, 1H), 7.66 (s, 1H), 7.47 (m, 3H), 7.23 (d, J = 5.1 Hz, 1H), 7.12 (s, 1H), 4.77 (s, 2H),
3.51 (m, 4H), 3.10 (s, 3H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.5, 162.8, 160.3, 159.1,
157.5, 151.3, 148.3, 139.9, 139.5, 138.5, 136.6, 135.7, 134.6, 132.7, 128.8, 127.8, 126.4, 123.9, 114.2,
108.7, 82.4, 50.4, 46.4, 43.6, 35.1, 17.4. HRMS (ESI) m/z calcd for C29H26IN7O3Na [M + Na]+:
670.1034, found: 670.1028.
Ketolactam (9b)
To a stirred solution of iodo ketolactam 9a (5.0 mg, 0.0077 mmol, 1.0 eq.) in acetic acid (2 mL)
were added Pd/C (contained 10% Pd, 0.08 mg 10% mmol) under the H2 atmosphere (1 atm) at rt. After
12 h, the reaction was quenched by NaHCO3 (aq.) and extracted with CH2Cl2. The dried (Na2SO4) exꢀ
tract was concentrated in vacuo and purified by chromatography over silica gel, eluting with
MeOH/DCM (1:20) to give ketolactam 9b (3.6 mg, 0.007 mmol, 90%) as a white amorphous powder.
1H NMR (600 MHz, CDCl3) δ 9.28 (s, 1H), 8.71 (s, 1H), 8.60 (s, 1H), 8.51 (m, 2H), 7.98 (s, 1H), 7.88
(d, J = 8.0 Hz, 2H), 7.44 (m, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 7.1 Hz, 1H), 7.22 (d, J = 8.2 Hz,
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1H), 7.19 (d, J = 5.1 Hz, 1H), 7.11 (s, 1H), 4.73 (s, 2H), 3.48 (m, 4H), 3.09 (s, 3H), 2.36 (s, 3H). C
NMR (150 MHz, CDCl3) δ 164.9, 162.7, 160.5, 159.0, 157.5, 151.2, 148.4, 139.4, 137.8, 136.4, 135.2,
135.1, 130.8, 128.6, 127.7, 124.4, 123.8, 115.4, 113.1, 108.4, 50.3, 46.3, 43.5, 35.1, 17.7. HRMS (ESI)
m/z calcd for C29H27N7O3Na [M + Na]+: 544.2068, found: 544.2066.
Ketolactam (10a)
According to general procedure of method A, donepezil 10 (50 mg, 0.13 mmol), PIDA (84.9 mg,
0.26 mmol, 2 equiv), iodine (66.7 mg, 0.26 mmol, 2 equiv.), and DCE (6.5 ml, 0.02 M) were reacted at
room temperature. After 30 minutes, additional PIDA (84.9 mg, 0.26 mmol, 2 equiv) were added. The
reaction was quenched by saturated aq. sodium thiosulfate solution (4 ml) after another 20 minutes.
Flash column chromatography on silica eluting with acetone/chloroform (1:40) yielded ketolactam 10a
(24.1 mg, 45% yield) as a white amorphous powder. IR (KBr) 3423, 3089, 3027, 2953, 2925, 1690,
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1638, 1500, 1454, 1313, 1266, 1118, 1030, 702. H NMR (400 MHz, CDCl3) δ 7.30 (m, 5H), 7.16 (s,
1H), 6.87 (s, 1H), 6.46 (s, 1H), 4.61 (d, J = 1.5 Hz, 2H), 3.97 (s, 3H), 3.90 (s, 3H), 3.27 (m, 2H), 3.15
(m, 1H), 2.88 (m, 2H), 2.64 (m, 2H), 2.36 (m, 1H), 2.24 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 206.8,
163.4, 155.7, 149.5, 149.4, 138.6, 136.5, 129.1, 128.7, 128.1, 127.7, 116.2, 107.5, 104.3, 56.3, 56.1,
50.5, 45.9, 44.6, 31.9, 31.5, 25.8. HRMS (ESI) m/z calcd for C24H25NO5Na [M + Na]+: 430.1625, found:
430.1633.
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Lactam (11a)
To a stirred solution of 11 (18 mg 0.073 mmol, 1.0 eq.) in acetone/H2O(4:1) (5 mL) were added
KMnO4 (17.5 mg, 0.11 mmol, 1.5 eq.), the reaction was stirred at 0°C to rt. Additional KMnO4 was
added until the TLC analysis showed consumption of starting material. The reaction was quenched by
saturated aq. sodium thiosulfate solution (4 mL) and extracted with CH2Cl2. The dried (Na2SO4) extract
was concentrated in vacuo and purified by chromatography over silica gel, eluting with MeOH/DCM
(1:20) to give lactam 11a as a white amorphous powder (11.4 mg, 60%). 1H NMR (400 MHz, CDCl3) δ
4.95 (dd, J = 5.4, 13.5 Hz, 1H), 2.92 (td, J = 3.1, 13.5 Hz, 1H), 2.71ꢀ2.48 (m, 4H), 2.39ꢀ2.27 (m, 2H),
2.18 (m, 2H), 1.96 (d, J = 13.2 Hz, 1H), 1.83ꢀ1.67 (m, 5H), 1.58ꢀ1.33 (m, 3H), 1.00 (t, J = 12.9 Hz, 1H),
0.92 (d, J = 6.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 209.2, 168.7, 61.6, 52.8, 43.6, 42.4, 41.7, 36.4,
35.9, 33.2, 25.2, 24.9, 22.5, 22.0, 19.1. HRMS (ESI) m/z calcd for C16H23NO2Na [M + Na]+: 284.1621,
found: 284.1624.
Iodo ketolactam (12) and obscurumine C (13)
According to general procedure of method B, lycopodine 11 (20 mg, 0.08 mmol), PIDA (51.5 mg,
0.16 mmol, 2 equiv), iodine (40.5 mg, 0.16 mmol, 2 equiv.), and THF (4.0 ml, 0.02 M) were reacted at
room temperature. After 30 minutes, additional PIDA (51.5 mg, 0.16 mmol, 2 equiv) were added. The
reaction was quenched by saturated aq. sodium thiosulfate solution (4 ml) after another 120 minutes.
Flash column chromatography on silica eluting with MeOH/DCM (1:120) yielded iodo ketolactam 12
as a yellow acicular crystal (16.3 mg, 51% yield, mp 273ꢀ274 °C) and obscurumine C 13 as a white
powder (1.1 mg, 5% yield, mp 195ꢀ196 °C). 12: IR (KBr) 3448, 2948, 2862, 1708, 1694, 1655, 1614,
1417, 1223, 715. 1H NMR (600 MHz, CDCl3) δ 4.86 (dd, J = 14.1, 5.2 Hz, 1H), 3.92 (m, 1H), 3.06 (td,
J = 13.7, 3.5 Hz, 1H), 2.86 (dd, J = 16.4, 6.79 Hz, 1H), 2.82 (m, 1H), 2.67 (dd, J = 16.4, 1.4Hz, 1H),
2.47 (dd, J = 12.1, 3.3 Hz, 1H), 2.31 (m, 1H), 2.00 (m, 2H), 1.84ꢀ1.72 (m, 2H), 1.61ꢀ1.48 (m, 2H), 1.20
(t, J = 13.1 Hz, 1H), 0.95 (d, J = 8.5 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 205.4, 172.9, 169.4, 152.3,
103.6, 65.9, 57.6, 47.3, 45.5, 44.9, 42.5, 37.7, 25.1, 24.7, 21.0, 19.8. HRMS (ESI) m/z calcd for
C16H18INO3Na [M + Na]+: 422.0224, found: 422.0228.
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Obscurumine C (13)
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To a stirred solution of iodo ketolactam 12 (16.0 mg, 0.04 mmol, 1.0 eq.) in benzene (4 mL) were
added AIBN (1.2 mg, 0.2 mmol) and nBu3SnH (28.0 µl, 0.06 mmol, 1.5 eq.) at rt. After 6 h, the reaction
was quenched by water (4 ml) and extracted with CH2Cl2. The dried (Na2SO4) extract was concentrated
in vacuo and purified by chromatography over silica gel, eluting with MeOH/DCM (1:80) to give obꢀ
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scurumine C 13 as a white powder (8.7 mg, 0.03 mmol, 80%, mp 195ꢀ196 °C ). H NMR (600 MHz,
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CDCl3) δ 6.53 (s 1H), 4.84 (dd, J = 13.8, 4.8 Hz, 1H), 3.23 (brs, 1H), 3.02 (td, J = 13.8, 3.2 Hz, 1H ),
2.85 (m, 1H), 2.82 (dd, J = 16.4, 6.2 Hz, 1H), 2.66 (d, J = 16.4 Hz, 1H), 2.50 (dd, J = 12.0, 2.4 Hz, 1H),
2.27 (d, J = 13.4 Hz, 1H), 2.01 (m, 1H), 1.98 (d, J = 13.8 Hz, 1H), 1.80ꢀ1.70 (m, 2H), 1.67ꢀ1.49 (m,
13
2H), 1.22 (t, J = 10.7 Hz, 1H), 0.94 (d, J = 6.1 Hz, 3H). C NMR (150 MHz, CDCl3) δ 205.6, 177.4,
167.2, 156.3, 122.1, 63.5, 58.0, 46.5, 44.5, 43.7, 40.7, 37.1, 25.0, 24.9, 21.3, 19.4. HRMS (ESI) m/z
calcd for C16H19NO3Na [M + Na]+: 296.1257, found: 296.1258.
β-Dihydrolycopodine (14)
To a suspension of LiAlH4 (76.8 mg, 2.00 mmol, 10 eq.) in THF (5 ml) was added lycopodine 11 (50
mg, 0.20 mmol, 1.0 eq.) in THF (5 ml). The reaction mixture was refluxed at 60 °C until TLC analysis
showed consumption of starting material. Then the reaction was quenched by addition of water (5 ml).
The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined orꢀ
ganic phases were dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography
(petroleum ether/acetone/diethylamine, 10:1:0.1) yielded βꢀdihydrolycopodine 14 as a white solid (47.3 mg,
1
95%, mp 167ꢀ168 °C). H NMR (400 MHz, CDCl3) δ 3.94 (td, J = 6.1, 2.5 Hz, 1H), 3.44 (td, J = 13.9,
3.6 Hz, 1H), 3.15 (td, J = 12.1, 3.2 Hz, 1H), 2.85 (m, 1H), 2.61 (dd, J = 13.2, 5.8 Hz, 1H), 2.55ꢀ2.44 (m,
2H), 2.32 (m, 1H), 2.11ꢀ2.01 (m, 1H), 2.01ꢀ1.93 (m, 1H), 1.86ꢀ1.76 (m, 1H), 1.75ꢀ1.53 (m, 4H), 1.51ꢀ
1.40 (m, 4H), 1.38ꢀ1.29 (m, 2H), 1.29ꢀ1.14 (m, 2H), 0.86 (d, J = 6.41 Hz, 3H), 0.76 (t, J = 12.8 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 68.5, 55.1, 47.2, 47.0, 45.6, 43.0, 41.8, 35.4, 33.7, 32.5, 26.5, 24.8, 24.0,
23.5, 23.4, 20.5. HRMS (ESI) m/z calcd for C16H28NO [M + H]+: 250.2165, found: 250.2159.
β-Acetyldihydrolycopodine (15)
To a stirred solution of βꢀdihydrolycopodine 14 (40.0 mg, 0.16 mmol, 1.0 eq.) in pyridine (2.0 mL)
were added DMAP (9.8 mg, 0.5 mmol) and Ac2O (2 mL) at 50 °C. After 6 h, the reaction was quenched
by water (4 ml) and extracted with CH2Cl2. The dried (Na2SO4) extract was concentrated in vacuo and
purified by chromatography over silica gel, eluting with petroleum ether/acetone/diethylamine, 20:1:0.1, to
give βꢀacetyldihydrolycopodine 15 as a white amorphous powder (46.6 mg, 0.15 mmol, 96%). 1H NMR
(400 MHz, CDCl3) δ 5.07 (t, J = 6. 5 Hz, 1H), 3.41 (m, 1H), 3.15 (m, 1H), 2.70ꢀ2.42 (m, 5H), 2.13ꢀ2.04
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(m, 1H), 2.03 (s, 3H), 1.97ꢀ1.89 (m, 1H), 1.78ꢀ1.69 (m, 3H), 1.69ꢀ1.60 (m, 2H), 1.52ꢀ1.41 (m, 2H),
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1.41ꢀ1.34 (m, 2H), 1.34ꢀ1.22 (m, 3H), 0.91 (d, J = 6. 1 Hz, 3H), 0.83 (t, J = 12. 5 Hz, 1H). C NMR
(100 MHz, CDCl3) δ 170.5, 70.2, 54.7, 47.1, 46.9, 45.2, 42.8, 41.7, 34.9, 31.1, 31.0, 26.3, 24.6, 24.2,
23.5, 23.1, 21.5, 20.3. HRMS (ESI) m/z calcd for C18H30NO2 [M + H]+:292.2271, found: 292.2271.
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Iodo ketolactam (16)
According to general procedure of method B, βꢀacetyldihydrolycopodine 15 (40 mg, 0.14 mmol),
PIDA (265.4 mg, 0.82 mmol, 6 equiv), iodine (104.3 mg, 0.41 mmol, 3 equiv.) were added in DCE (7
ml, 0.02 M). And the reaction was refluxed at 80°C, after 3 h the reaction was quenched by saturated aq.
sodium thiosulfate solution (4 ml). Flash column chromatography on silica eluting with MeOH/DCM
(1:120) yielded iodo ketolactam 16 as a yellow oil (48.7 mg, 80% yield). IR (KBr) 3435,
2949, 1733, 1691, 1661, 1599, 1363, 1239, 1145, 1039, 1023. 1H NMR (400 MHz, CDCl3) δ 5.12 (t, J =
6. 1 Hz, 1H), 4.82 (dd, J = 13.8, 4.9 Hz, 1H), 3.57 (brs, 1H), 3.06 (td, J = 13.6, 2.9 Hz, 1H), 2.90 (m,
2H), 2.37 (dt, J = 15.6, 6.6 Hz, 1H), 2.12 (s, 3H), 2.07ꢀ1.80 (m, 5H), 1.67ꢀ1.52 (m, 2H), 1.46 (td, J =
13.2, 4.8 Hz, 1H), 1.10 (t, J = 12.5 Hz, 1H), 0.93 (d, J = 6. 1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
173.8, 173.0, 169.8, 152.5, 101.4, 68.0, 65.8, 51.7, 46.9, 44.6, 41.3, 37.9, 36.3, 25.5, 23.1, 21.9, 21.4.
HRMS (ESI) m/z calcd for C18H22INO4Na [M + Na]+: 466.0486, found: 466.0489.
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Obscurumine O (17)
To a stirred solution of iodo ketolactam 16 (16.0 mg, 0.04 mmol, 1.0 eq.) in benzene (4 mL) were
added AIBN (1.2 mg, 0.2 mmol) and nBu3SnH (28.0 µl, 0.06 mmol, 1.5 eq.) at rt. After 6 h, the reaction
was quenched by water (4 ml) and extracted with CH2Cl2. The dried (Na2SO4) extract was concentrated
in vacuo and purified by chromatography over silica gel, eluting with MeOH/DCM (1:80) to give obꢀ
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scurumine O 17 as a white amorphous powder (9.2 mg, 0.03 mmol, 80%). H NMR (400 MHz,
CD3OD) δ 6.43 (s, 1H), 5.17 (t, J = 6.3 Hz, 1H), 4.70 (dd, J = 12.1, 3.3 Hz, 1H), 3.35 (d, J = 15.6 Hz,
1H), 3.21 (m, 1H), 3.10ꢀ2.93 (m, 2H), 2.43 (m, 1H), 2.28 (m, 1H), 2.13 (s, 3H), 2.10ꢀ1.89 (m, 3H),
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1.66ꢀ1.43 (m, 3H), 1.31 (s, 1H), 1.18 (t, J = 12.3 Hz, 1H), 0.98 (d, J = 6.1 Hz, 3H). C NMR (100
MHz, CD3OD) δ 178.8, 175.3, 171.7, 158.4, 120.8, 69.7, 64.4, 52.6, 45.0, 43.8, 42.0, 38.6, 38.3, 26.9,
24.2, 23.7, 22.4, 21.2. HRMS (ESI) m/z calcd for C18H23NO4Na [M + Na]+: 340.1519, found: 340.1516.
1H NMR (400 MHz, CDCl3) δ 6.37 (s, 1H), 5.14 (t, J = 6.2 Hz, 1H), 4.84 (m, 1H), 3.03 (m, 1H), 2.89
(m, 3H), 2.37 (m, 1H), 2.12 (s, 3H), 2.08ꢀ1.94 (m, 3H), 1.91ꢀ1.80 (m, 2H), 1.67ꢀ1.53 (m, 2H), 1.48
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(dd, J = 12.6, 4.3 Hz, 1H), 1.18 (t, J = 14.3 Hz, 1H), 0.94 (d, J = 5.8 Hz, 3H). C NMR (100 MHz,
CDCl3) δ 177.5, 171.6, 169.9, 156.5, 120.4, 68.0, 62.5, 51.4, 44.0, 42.7, 40.4, 37.3, 37.3, 25.8, 22.9,
22.8, 22.2, 21.4.
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Strychnocarpine (18)
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To a stirred solution of 1a (10.0 mg, 0.08 mmol, 1.0 eq.) in toluene (2 mL) were added phenyhyꢀ
drazine (8.5 mg, 0.08 mmol, 1 eq.), then the reaction was stirred at 80 °C. After TLC analysis showed
consumption of starting material added formic acid (1 mL). The reaction was quenched by saturated aq.
sodium bicarbonate solution (2 mL) after 3 h and extracted with CH2Cl2, the dried (Na2SO4) extract was
concentrated in vacuo and purified by chromatography over silica gel, eluting with MeOH/DCM (1:80)
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to give Strychnocarpine 18 as a white powder (14.1 mg, 0.07 mmol, 90%, 227ꢀ228 °C). H NMR (400
MHz, CDCl3) δ 9.79 (brs, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.3 Hz,
13
1H), 7.14 (t, J = 7.3 Hz, 1H), 3.72 (t, J = 7.1 Hz, 2H), 3.17 (s, 3H), 3.09 (t, J = 7.1 Hz, 2H). C NMR
(100 MHz, CDCl3) δ 161.9, 137.4, 127.1, 125.3, 124.7, 120.1, 120.1, 117.9, 112.5, 50.2, 34.1, 20.6.
HRMS (ESI) m/z calcd for C12H13N2O [M + H]+: 201.1022, found: 201.1021.
2,3,4,9-Tetrahydro-2-(phenylmethyl)-1H-pyrido[3,4-b]indol-1-one (19)
To a stirred solution of 2a (50.0 mg 0.25 mmol, 1.0 eq.) in toluene (4 mL) were added phenyhydraꢀ
zine (26.6 mg, 0.25 mmol, 1 eq.), then the reaction was stirred at 80°C. After TLC analysis showed conꢀ
sumption of starting material added formic acid (1 mL). The reaction was quenched by saturated aq. soꢀ
dium bicarbonate solution (2 mL) after 4 h and extracted with CH2Cl2, the dried (Na2SO4) extract was
concentrated in vacuo and purified by chromatography over silica gel, eluting with actone/DCM (1:80)
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to give indol 19 as a white powder (61.1 mg, 0.22 mmol, 90%, mp 214ꢀ215 °C). H NMR (400 MHz,
CDCl3) δ 10.50 (brs, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.47ꢀ7.21 (m, 7H), 7.11 (t, J = 7.4 Hz, 1H), 4.86 (s,
13
2H), 3.66 (t, J = 6.9 Hz, 2H), 3.03 (t, J = 6.9 Hz, 2H). C NMR (100 MHz, CDCl3) δ 161.8, 137.8,
137.7, 128.7, 128.0, 127.5, 126.9, 125.2, 124.8, 120.0, 118.2, 112.8, 49.6, 47.5, 20.7. HRMS (ESI) m/z
calcd for C18H17N2O [M + H]+: 277.1335, found: 277.1336.
AUTHOR INFORMATION
Corresponding Author
*Q.ꢀS. Z: phone, +86ꢀ871ꢀ65223058; fax, +86ꢀ871ꢀ65215783; Eꢀmail, qinshizhao@mail.kib.ac.cn.
Author Contributions
§ Y.Z., and L.ꢀD.S. contributed equally to this work.
Supporting Information
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Copies of 1H NMR and 13C NMR for all synthetic compounds; summary of Xꢀray crystallographic data;
condition optimization and mechanistic experiments data.
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ACKNOWLEDGMENT
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This work was financially supported by the National Natural Science Foundation of China (U1502223,
U0932602, and 81603000), the National Basic Research Program (973 program no. 2011CB915503) of
China, and the Science and Technology Program of Yunnan Province (2017FB135) and Youth Innovaꢀ
tion Promotion Association CAS (L.ꢀD.S).
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REFERENCES
(1) Godula, K.; Sames, D. CꢀH Bond Functionalization in Complex Organic Synthesis. Science 2006, 312, 67ꢀ72.
(2) He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.ꢀQ. PalladiumꢀCatalyzed Transformations of Alkyl CꢀH Bonds.
Chem. Rev. 2017, 117, 8754ꢀ8786.
(3) For α,βꢀC(sp3)ꢀH bonds dual functionalization of tertiary amines, see: (a) Castro, A.; Romero, O.; Terán, J. L.;
Gnecco, D.; Orea, L.; Mendoza, A.; Juárez, J. R. Oxidation and Aromatization of the Enantiopure Piperidine Derived
from (R)ꢀ(ꢀ)ꢀ2ꢀPhenylglycinol to (1’R)ꢀ(ꢀ)ꢀ1ꢀ(2’ꢀHydroxyꢀ1’ꢀphenylethyl)ꢀ1Hꢀpyridinꢀ2ꢀone. Heterocycles 2014, 89,
725ꢀ729; (b) OsorioꢀNieto, U.; ChamorroꢀArenas, D.; Quintero, L.; Höpfl, H.; SartilloꢀPiscil, F. Transition MetalꢀFree
Selective Double sp(3) CꢀH Oxidation of Cyclic Amines to 3ꢀAlkoxyamine Lactams. J. Org. Chem. 2016, 81, 8625ꢀ
8632; (c) Griffiths, R. J.; Kong, W. C.; Richards, S. A.; Burley, G. A.; Willis, M. C.; Talbot, E. P. A. Oxidative BetaꢀCꢀ
H Sulfonylation of Cyclic Amines. Chem. Sci. 2018, 9, 2295ꢀ2300; (d) Xia, X.ꢀF.; Shu, X.ꢀZ.; Ji, K.ꢀG.; Yang, Y.ꢀF.;
Shaukat, A.; Liu, X.ꢀY.; Liang, Y.ꢀM. PlatinumꢀCatalyzed Michael Addition and Cyclization of Tertiary Amines with
Nitroolefins by Dehydrogenation of α,βꢀsp3 C−H Bonds. J. Org. Chem. 2010, 75 (9), 2893ꢀ2902.
(4) (a) Guengerich, F. P. Cytochrome P450 Enzymes in the Generation of Commercial Products. Nat. Rev. Drug
Discov. 2002, 1, 359ꢀ366; (b) Liao, K.; Negretti, S.; Musaev, D. G.; Bacsa, J.; Davies, H. M. L. Siteꢀselective and
Stereoselective Functionalization of Unactivated CꢀH Bonds. Nature 2016, 533, 230ꢀ234; (c) Xu, Y.; Yan, G.; Ren, Z.;
Dong, G. Diverse sp(3) CꢀH Functionalization through Alcohol βꢀsulfonyloxylation. Nat. Chem. 2015, 7, 829ꢀ834; (d)
Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.; Thomas, A. W.; Wilson, D. M.; Wood, A. Organic Synthesis
Provides Opportunities to Transform Drug Discovery. Nat. Chem. 2018, 10, 383ꢀ394.
(5) Genovino, J.; Luetz, S.; Sames, D.; Toure, B. B. Complementation of Biotransformations with Chemical CꢀH
Oxidation: Copperꢀcatalyzed Oxidation of Tertiary Amines in Complex Pharmaceuticals. J. Am. Chem. Soc. 2013, 135,
12346ꢀ12352.
(6) Ripper, J. A.; Tiekink, E. R. T.; Schammells, P. J. Photochemical Nꢀdemethylation of Alkaloids. Bioorg. Med.
Chem. Lett. 2001, 11, 443ꢀ445.
(7) (a) Petride, H.; Draghici, C.; Florea, C.; Petride, A. RuO4ꢀmediated Oxidation of Nꢀbenzylated Tertiary Amines. Are
Amine Nꢀoxides and Iminium Cations Reaction Intermediates? Cent. Eur. J. Chem. 2004, 2, 302ꢀ322; (b) Lancefield,
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C. S.; Zhou, L.; Lebl, T.; Slawin, A. M. Z.; Westwood, N. J. The Synthesis of Melohenine B and a Related Natural
1
2
Product. Org. Lett. 2012, 14, 6166ꢀ6169.
3
4
5
(8) Fujii, H.; Ogawa, R.; Jinbo, E.; Tsumura, S.; Nemoto, T.; Nagase, H. Novel Oxidation Reaction of Tertiary Amines
with Osmium Tetroxide. Synlett 2009, 2341ꢀ2345.
6
7
8
9
(9) Lee, B. H.; Clothier, M. F.; Pickering, D. A. Conversion of Marcfortine A to Paraherquamides via a Novel
Platinumꢀoxygenꢀmediated Ring Contracting Reaction. J. Org. Chem. 1997, 62, 7836ꢀ7840.
(10) Rueppel, M. L.; Rapoport, H. Rearrangement of Pyruvates to Malonates. J. Am. Chem. Soc. 1970, 92, 5781ꢀ5783.
(11) Herdeis, C.; Dimmerling, A. Synthesis with Hydroxylactames. III. A Facile Entry to the 1ꢀoxoꢀβꢀcarboline
Skeleton. Synthesis of Strychnocarpine. Heterocycles 1984, 22, 2277ꢀ2283.
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11
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
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59
60
(12) Wasserman, H. H.; Ives, J. L. Reaction of Singlet Oxygen with Enamino Carbonyl Systems. A General Method for
the Synthesis of αꢀketo Derivatives of Lactones, Esters, Amides, Lactams, and Ketones. J. Org. Chem. 1985, 50, 3573ꢀ
3580.
(13) Forns, P.; Fernandez, M. M.; Diez, A.; Rubiralta, M.; Cherrier, M. P.; Bonin, M.; Quirion, J.ꢀC. Methylenation and
Oxidation of Chiral Nonꢀracemic 2ꢀpiperidones. Reactivity of a New 3ꢀoxo Lactam. Synthesis 1999, 258ꢀ263.
(14) Lounasmaa, M.; Somersalo, P. Synthesis of Indole Alkaloids of Condylocarpine Type. Cꢀ4 Alkylation of the 1ꢀ
alkylꢀ3ꢀ(hydrazono)ꢀ2ꢀpiperidone System. Tetrahedron 1986, 42, 1501ꢀ1509.
(15) Jung, A.; Koch, O.; Ries, M.; Schaumann, E. A Siliconꢀmediated Domino Approach to Pyrrolidineꢀ and
Piperidineꢀ2,3ꢀdiones. Synlett 2000, 92ꢀ94.
(16) Dejaegher, Y.; D'Hooghe, M.; De Kimpe, N. Synthesis of Novel 3ꢀoxopiperidinꢀ2ꢀones from Methyl 2ꢀalkoxyꢀ5ꢀ
aminoꢀ2ꢀpentenoates. Synlett 2008, 1961ꢀ1964.
(17) Wolff, M. E. Cycliztion of Nꢀhaligenated Amines (HofmannꢀLoffler Reaction). Chem. Rev. 1963, 63, 55ꢀ64.
(18) (a) Cherney, E. C.; Lopchuk, J. M.; Green, J. C.; Baran, P. S. A Unified Approach to entꢀAtisane Diterpenes and
Related Alkaloids: Synthesis of (ꢀ)ꢀMethyl Atisenoate, (ꢀ)ꢀIsoatisine, and the Hetidine Skeleton. J. Am. Chem. Soc.
2014, 136, 12592ꢀ12595; (b) Martinez, C.; Muniz, K. An IodineꢀCatalyzed HofmannꢀLoffler Reaction. Angew. Chem.
Int. Ed. 2015, 54, 8287ꢀ8291.
(19) Wang, D.ꢀH.; Hao, X.ꢀS.; Wu, D.ꢀF.; Yu, J.ꢀQ. Palladiumꢀcatalyzed Oxidation of Bocꢀprotected Nꢀmethylamines
with IOAc as the Oxidant: A Bocꢀdirected sp(3) CꢀH Bond Activation. Org. Lett. 2006, 8, 3387ꢀ3390.
(20) Shu, X.ꢀZ.; Xia, X.ꢀF.; Yang, Y.ꢀF.; Ji, K.ꢀG.; Liu, X.ꢀY.; Liang, Y.ꢀM. Selective Functionalization of sp(3) CꢀH
Bonds Adjacent to Nitrogen Using (Diacetoxyiodo)benzene (DIB). J. Org. Chem. 2009, 74, 7464ꢀ7469.
(21) Bering L.; Antonchick A. P. Selective Transitionꢀmetalꢀfree Vicinal cisꢀdihydroxylation of Saturated
Hydrocarbons. Chem. Sci. 2017, 8, 452ꢀ457.
(22) Courtneidge, J. L.; Lusztyk, J.; Page, D. Alkoxyl Radicals from Alcohols Spectroscopic Detection of Intermediate
Alkyl and Acyl Hypoiodites in the Suarez and Beebe Reactions. Tetrahedron Lett. 1994, 35, 1003ꢀ1006.
(23) Achar, T. K.; Maiti, S.; Mal, P. PIDAꢀI2 Mediated Direct Vicinal Difunctionalization of Olefins: Iodoazidation,
Iodoetherification and Iodoacyloxylation. Org. Biomol. Chem. 2016, 14, 4654ꢀ4663.
(24) Zhu, Y.ꢀP.; Lian, M.; Jia, F.ꢀC.; Liu, M.ꢀC.; Yuan, J.ꢀJ.; Gao, Q.ꢀH.; Wu, A.ꢀX. I2 Promoted Domino Oxidative
Cyclization for Oneꢀpot Synthesis of 2ꢀacylbenzothiazoles via Metalꢀfree sp(3) CꢀH Functionalization. Chem.
Commun. 2012, 48, 9086ꢀ9088.
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Page 23 of 23
The Journal of Organic Chemistry
(25) Ayer, W. A.; Iverach, G. G. The structure of Lycodine. Can. J. Chem. 1960, 38, 1823ꢀ1826.
(26) (a) Moriarty, R. M.; Vaid, R. K.; Duncan, M. P.; Ochiai, M.; Inenaga, M.; Nagao, Y. Hypervalent Iodine Oxidation
of Amines Using Iodosobenzeneꢀsynthesis of Nitriles, Ketones and Lactams. Tetrahedron Lett. 1988, 29, 6913ꢀ6916;
(b) Zhu, D.; Luo, W.ꢀK.; Yang, L.; Ma, D.ꢀY. Iodineꢀcatalyzed Oxidative Multiple CꢀH Bond Functionalization of
Isoquinolines with Methylarenes: An Efficient Synthesis of Isoquinolineꢀ1,3,4(2H)ꢀtriones. Org. Biomol. Chem. 2017,
15, 7112ꢀ7116.
1
2
3
4
5
6
7
8
9
(27) Note: protic solvents were unfavorable for the reaction (Table 1, entries 2ꢀ4, and Table S1, SI), however, for
mechanism study, the reaction was also proceeded when H2O or H2O18 (< 2% mol) was added in the solvent.
(28) Zhang, X.ꢀY.; Dong, L.ꢀB.; Liu, F.; Wu, X.ꢀD.; He, J.; Peng, L.ꢀY.; Luo, H.ꢀR.; Zhao, Q.ꢀS. New Lycopodium
Alkaloids From Lycopodium Obscurum. Nat. Prod. Bioprospect. 2013, 3, 52ꢀ55.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(29) Jiang, W.ꢀW.; Liu, Y.ꢀC.; Zhang, Z.ꢀJ.; Liu, Y.ꢀC.; He, J.; Su, J.; Cheng, X.; Peng, L.ꢀY.; Shao, L.ꢀD.; Wu, X.ꢀD.;
Yang, J.ꢀH.; Zhao, Q.ꢀS. Obscurumines HꢀP, New Lycopodium Alkaloids from the Club Moss Lycopodium Obscurum.
Fitoterapia 2016, 109, 155ꢀ161.
(30) Ayer, W. A.; Bowman, W. R.; Joseph, T. C.; Smith, P. The Synthesis of dlꢀlycopodine. J. Am. Chem. Soc. 1968, 90,
1648ꢀ1650.
(31) Rolfsen, W.; Bresky, A. M.; Andersson, M.; Stroembom, J.; Anden, N. E.; GrabowskaꢀAnden, M. Isolation,
Synthesis and Pharmacological Activity of Strychnocarpine, A New Betaꢀcarboline Alkaloid from Strychnos
elaeocarpa. Acta Pharm. Suec. 1980, 17, 333ꢀ340.
(32) Stroembom, J.; Jokela, R.; Saano, V.; Rolfsen, W. Binding of Strychnocarpine and Related Betaꢀcarbolines to
Brain Receptors in Vitro. Eur. J. Pharmacol. 1992, 214, 165ꢀ168.
(33) Higuchi, Y.; Mita, T.; Sato, Y. PalladiumꢀCatalyzed Intramolecular Arylative Carboxylation of Allenes with CO2
for the Construction of 3ꢀSubstituted Indoleꢀ2ꢀcarboxylic Acids. Org. Lett. 2017, 19, 2710ꢀ2713.
(34) Robinson, B. The Fischer Indole Synthesis. Chem. Rev. 1963, 63, 373ꢀ401.
(35) Harrison, W. A.; CurcumelliꢀRodostamo, M.; Carson, D. F.; Barclay, L. R. C.; MacLean, D. B. Lycopodium
alkaloids. X. The structure of lycopodine. Can. J. Chem. 1961, 39, 2086–2099.
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