Direct preparation of unprotected aminimides (R3N+-NH-) from natural aliphatic tertiary alkaloids (R3N) by [Mn(TDCPP)Cl]-catalysed: N -amination reaction

Article abstract of DOI:10.1039/d0cc02934c

A panel of natural aliphatic tertiary alkaloids (R3N) were directly converted to R3N+-NH- (without the need to prepare protected aminimides R3N+-NR′- followed by deprotection) by [Mn(TDCPP)Cl]-catalysed N-amination reaction, with O-(2,4-dinitrophenyl)hydroxylamine as the nitrogen source, in up to 98% yields under mild reaction conditions.

Full text of DOI:10.1039/d0cc02934c

ChemComm
View Article Online
View Journal
COMMUNICATION
Direct preparation of unprotected aminimides
(R3N+–NHꢀ) from natural aliphatic tertiary
alkaloids (R3N) by [Mn(TDCPP)Cl]-catalysed
N-amination reaction†
Cite this:DOI: 10.1039/d0cc02934c
Received 23rd April 2020,
Accepted 1st July 2020
a
abc
Shilong Zhang,
Yungen Liu, *a Fangrong Xingb and Chi-Ming Che
*
DOI: 10.1039/d0cc02934c
rsc.li/chemcomm
ꢀ
A panel of natural aliphatic tertiary alkaloids (R3N) were directly reactions;17,18 among the known R3N+–NR0 compounds
converted to R3N+–NHꢀ (without the need to prepare protected obtained by such nitrene transfer reaction, only that of brucine
aminimides R3N+–NR0ꢀ followed by deprotection) by [Mn(TDCPP)Cl]- was subjected to a second, deprotection step to give the
catalysed N-amination reaction, with O-(2,4-dinitrophenyl) corresponding R3N+–NHꢀ compound in 21% total yield
hydroxylamine as the nitrogen source, in up to 98% yields under (Scheme 1).17 To the best of our knowledge, the preparation
mild reaction conditions.
of unprotected aminimides R3N+–NHꢀ directly from metal-
catalysed nitrogen atom/group transfer to amines has not been
Alkaloids are a family of natural products prevalent in herbs reported in the literature.
known for its broad spectrum of biological activities and uses
in traditional therapy. Pure compounds and derivatives/analo-
gues of alkaloids can be easily found in pharmaceuticals,1–4
examples of which include the naturally occurring tertiary
alkaloid N-oxides (R3N+–Oꢀ) that show physiological activities
similar to their parent alkaloid compounds (Fig. 1).5–8 Alkaloid
N-oxides exhibit higher polarity than their parent alkaloid
compounds and show decreased penetration rate through the
membrane system resulting in a decrease in toxicity response.9–12
This class of N-oxide compounds might be reduced under the
hypoxic environment, which is often found in the tumor tissue.13,14
However, many of these N-oxides have a poor stability.15 As amine
Fig. 1 Examples of naturally occurring alkaloid N-oxides.
N-oxides are iso-electronic with aminimides R3N+–NR0ꢀ 16 or their
,
deprotected forms R3N+–NHꢀ, we envisioned that aminimides of
alkaloids might exhibit similar bioactivities but are more stable
than their N-oxide counterparts due to the lower electronegativity of
nitrogen. In the literature, aminimides in protected forms R3N+–
ꢀ
NR0 (R0 = p-tosyl, etc.) could be obtained from N-amination
of amines by transition metal-catalysed nitrene (NR0) transfer
a Department of Chemistry, Southern University of Science and Technology,
Shenzhen, Guangdong 518055, P. R. China. E-mail: cmche@hku.hk,
liuyg@sustech.edu.cn
b Department of Chemistry, State Key Laboratory of Synthetic Chemistry,
The University of Hong Kong, Hong Kong, P. R. China
c HKU Shenzhen Institute of Research and Innovation, Shenzhen, Guangdong
518057, P. R. China
Scheme 1 (a) Reported method of preparing an unprotected aminimide
by two steps, i.e., metal-catalysed nitrene transfer to brucine to give
protected aminimide followed by deprotection; (b) method employed in
this work; (c) catalysts employed in this work.
† Electronic supplementary information (ESI) available: Procedures and details of
synthesis, product characterizations, crystallographic information. CCDC
1970190–1970192. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/d0cc02934c
Chem. Commun.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Communication
ChemComm
Recently, O-functionalized hydroxylamine derivatives (such
+
as RONH2 or RONH3 , R = strong electron-withdrawing groups)
had been reported to be a versatile nitrogen source for the
preparation of unprotected amine products with transition
metal complex as catalyst.19–22 Morandi and co-worker reported
the preparation of 2-amino-1-phenylethanols23 from alkenes
with PivONH3OTf as the nitrogen source, and amination of
aromatic C–H bonds24 with MsONH3OTf as nitrogen source;
Flack, Ku¨rti and co-workers reported the dirhodium-catalysed
amination of aromatic C–H bonds20 with NH2/NH(alkyl)-O-
(sulfonyl)hydroxylamines in the presence of a Brønsted acid
via a highly reactive protonated rhodium–nitrene intermediate.
Very recently, we reported ruthenium porphyrin-catalysed inter-
molecular amino-oxyarylation of alkenes to give primary
amines25 using O-(2,4-dinitro-phenyl)hydroxylamine (DPH) as
nitrogen source. Herein is described [MnIII(TDCPP)Cl]-
catalysed one-step N-amination reaction of the natural aliphatic
tertiary alkaloids R3N (1), with DPH (2) as the nitrogen source,
to directly afford unprotected aminimides R3N+–NHꢀ (3) in up
to 98% yields under mild conditions (Scheme 1).
At the outset, we employed matrine (1a) as the substrate to
optimize the reaction conditions. A panel of metal porphyrins
and nitrogen sources were screened (see Table S4 in the ESI†).
With DPH (2a) as the nitrogen source, the iron porphyrins
[FeIII(TPP)Cl], [FeIII(TDCPP)Cl], and [FeIII(F20TPP)Cl] exhibited
low catalytic activity with no aminimide product(s) obtained
(Table S4, entries 1–3, ESI†); ruthenium porphyrins such as
[RuIV(TPP)Cl2], [RuIV(TDCPP)Cl2], and [RuIV(F20TPP)Cl2] cata-
lysed this reaction to give the unprotected aminimide product
3a in 21–32% yields (Table S4, entries 7–9, ESI†). To our delight,
significant improvement in product yields up to 89% was
achieved with manganese porphyrins including [MnIII(TPP)Cl],
[MnIII(TDCPP)Cl] and [MnIII(F20TPP)Cl] as the catalyst (Table S4,
entries 4–6, ESI†). Further screening of nitrogen source (Table S4,
entries 10–13, ESI†) and solvent (Table S4, entries 14–17, ESI†)
revealed that dichloromethane gave the best result and DPH
was the best nitrogen source. In the absence of catalyst
[MnIII(TDCPP)Cl], there was no substrate conversion (Table S4,
entry 18, ESI†). In addition, the reaction was insensitive to air and
moisture, and inert atmosphere protection was not needed.
Under the optimal reaction conditions, we examined the
substrate scope of the manganese porphyrin-catalysed direct
preparation of unprotected aminimides of alkaloids (Scheme 2). A
panel of tertiary aliphatic alkaloids 1b-1i could be converted to the
corresponding unprotected aminimides 3b-3i in up to 98% yield.
Sophoridine (1b), sinomenine (1c), cephalotaxine (1d), cinchonidine
(1e) and peimine (1f) were converted to 3b-3f, respectively, in 90–98%
yields. The presence of functional groups such as hydroxy (1c, 1e, 1f),
quinolinyl (1e) and alkene (1c, 1d, 1e) had no significant effect on
the substrate conversion and product yield. Bicuculline (1g), lycorine
(1h), and nuciferine (1i) gave the corresponding products 3g-3i each
as a pair of cis/trans-isomers. Evodiamine (1j), a tertiary alkaloid
containing l-2,3-dihydroquinazolinone moiety, could not be con-
verted to the corresponding product 3j. Vindoline (1k), in which
the tertiary amine localizes deeply in the molecule, was inert under
the reaction condition.
Scheme 2 Preparation of unprotected aminimides 3 directly from alkaloids 1.
The crystal structures of the unprotected aminimides 3c and
3h-b have been determined by X-ray diffraction analysis (Fig. 2),
which feature N–N bond distances of 1.462 Å and 1.451 Å,
respectively. These N–N bond distances are similar to the
corresponding N–N bond distances in the crystallographically
characterized protected aminimides reported in the literature
(e.g., 1.463–1.471 Å18).
In the course of the catalytic amination reaction, a red
species was observed to accumulate gradually with the con-
sumption of [MnIII(TDCPP)Cl]. Further characterization of
this red species by UV-vis, MS and 1H NMR spectroscopic
analyses suggested it to be [MnV(TDCPP)(N)],26 the structure
of which was confirmed by comparing the characterization data
with that of [MnV(TDCPP)(N)] independently prepared and with
its structure determined by single crystal X-ray diffraction
analysis (Fig. 3), which features MnRN bond distance of
1.508 Å. Indeed, [MnV(TDCPP)(N)] could be obtained by the
reaction of [MnIII(TDCPP)Cl], DPH and NaOH (aq., 2.5 M) in
dichloromethane with nearly quantitative yield. Notably, treat-
ment of the isolated [MnV(TDCPP)(N)] with alkaloids 1 under
Fig. 2 ORTEP drawings of 3c (a) and 3h-b (b). Thermal ellipsoid prob-
ability level: 30%.
Chem. Commun.
This journal is © The Royal Society of Chemistry 2020

View Article Online
ChemComm
Communication
similar to that of [MnIII(TDCPP)Cl]; for example, both the
complexes catalysed the reaction of sinomenine (1c) with
DPH to give 3c in 90% yield (see the ESI†). As shown in
Fig. 4a, a cluster peak at m/z 903 was immediately detected
right after mixing [MnIII(4-N-MePy-TDCPP)Cl]PF6 and DPH
(10 eq.) in dichloromethane (for assignments of the other peaks
in Fig. 4, see the ESI†), the intensity of which diminished
dramatically upon addition of alkaloid sinomenine (20 eq.,
Fig. 4b). In contrast, for the reaction mixture in which synthetic
[Mn(4-N-MePy-TDCPP)(N)]PF6 (m/z 903 for the cation species,
1 eq.) was added prior to catalysis (Fig. 4c), the signal at m/z 903
did not decrease significantly after addition of sinomenine
(20 eq.) under similar experimental conditions (Fig. 4d). The
ESI-MS analyses did not reveal signals assignable to the parent ion
Fig. 3 ORTEP drawing of [MnV(TDCPP)(N)]. Thermal ellipsoid probability
level: 30%.
stoichiometric reaction conditions did not afford the unpro- of [Mn(4-N-MePy-TDCPP)(NH)]2+, [Mn(4-N-MePy-TDCPP)(NH)]+ or
tected aminimides 3.
[Mn(4-N-MePy-TDCPP)(DPH)]2+. Although the isotopic pattern of
To gain further insight into the reaction mechanism, we the cluster peak at m/z 903 in Fig. 4a is consistent with that of
employed ESI-MS to follow the reaction. Unfortunately, the MS [Mn(4-N-MePy-TDCPP)(N)]+, it is more reasonable to assign the
signals attributed to the [Mn(TDCPP)]-containing species were signal at m/z 903 as a fragmented daughter ion of the [Mn(4-N-
weak; presumably the species is charge neutral. Hence, we MePy-TDCPP)(NA)]+ (A = H or (2,4-dinitrophenyl)hydroxyl) inter-
prepared a cationic manganese porphyrin, [MnIII(4-N-MePy- mediate, which could be unstable and decompose to [Mn(4-N-
TDCPP)Cl]PF6 (Scheme 1), by replacing one of the four meso- MePy-TDCPP)(N)]+ under the ESI-MS conditions.
2,6-dichloro phenyl moieties of [MnIII(TDCPP)Cl] with an
On the basis of the above-mentioned experimental observa-
N-methyl pyridinium group so that the resultant manganese tions, a mechanism for the formation of unprotected amini-
porphyrin species and reaction intermediate(s) there from mides 3 via [Mn(TDCPP)(NA)]X (X = Cl or solvent) active
are cationic, hence easily detected by ESI-MS. We found that intermediate(s) was proposed and shown in Scheme 3. The
[MnIII(4-N-MePy-TDCPP)Cl]PF6 exhibited a catalytic activity reactive [Mn(TDCPP)(NA)]X species could be trapped by the
Fig. 4 ESI-MS analysis of the reaction mixtures: (a) 0.1 mM [MnIII(por)Cl]PF6 (por = 4-N-MePy-TDCPP) in dichloromethane solution with the addition of
DPH (10 eq.); (b) sinomenine (20 eq.) was added to (a); (c) 0.1 mM [MnIII(por)Cl]PF6 and manganese-nitrido [Mn(por)(N)]PF6 in dichloromethane solution
with the addition of DPH (10 eq.); (d) sinomenine (20 eq.) was added to (c).
Chem. Commun.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Communication
ChemComm
be the reactive intermediate. Cytotoxicity study indicated
that the unprotected aminimides of alkaloids may provide
new derivatives of alkaloids for further drug development.
This work was supported by National Natural Science Founda-
tion of China (NSFC 21871127, 91856203) and Shenzhen Science
and Technology Innovation Commission (JCYJ20170817111150174,
JCYJ20190809141203613). We thank the Southern University of
Science and Technology for financial support and the Innovation
Technology Commission of Hong Kong SAR for supporting the
research in Synthetic Chemistry.
Conflicts of interest
There are no conflicts to declare.
Scheme 3 Proposed mechanism for the formation of unprotected
aminimides.
References
1 S. R. Chemler, Curr. Bioact. Compd., 2009, 5, 2–19.
2 Z. F. Chao, P. Yang and Q. S. Zhou, Sci. China: Chem., 2013, 56,
1382–1391.
3 Y. Han, S. Park, A. W. Kinyua, L. Andrea, K. W. Kim and I. Kim,
Oncol. Rep., 2014, 31, 456–462.
4 D. Nakano, K. Ishitsuka, M. Ikeda, R. Tsuchihashi, M. Okawa,
H. Okabe, K. Tamura and J. Kinjo, J. Nat. Med., 2015, 69, 397–401.
5 W. Gao, Y. Li, S. Jiang and D. Zhu, Planta Med., 2000, 66, 664–667.
6 M. Zhang, G. Liang, J. Yu and W. Pan, Nat. Prod. Res., 2010, 24,
1243–1247.
7 S. Huang, X. L. Zhou, J. Wen, C. J. Wang, H. Y. Wang, L. H. Shan and
J. Weng, J. Nat. Med., 2013, 67, 647–651.
8 B. Guo, T. Zhang, J. Su, K. Wang and X. Li, Cancer Chemother.
Pharmacol., 2015, 75, 353–363.
9 X. Deng, F. Yin, X. Lu, B. Cai and W. Yin, Toxicol. Sci., 2006, 91,
59–69.
10 X.-K. Deng, W. Yin, W.-D. Li, F.-Z. Yin, X.-Y. Lu, X.-C. Zhang,
Z.-C. Hua and B.-C. Cai, J. Ethnopharmacol., 2006, 106, 179–186.
11 P. Appadurai and K. Rathinasamy, Toxicol. Lett., 2014, 225, 66–77.
12 V. M. Dembitsky, T. A. Gloriozova and V. V. Poroikov, Phytomedicine,
2015, 22, 183–202.
13 K. H. Kim, K. H. Lee, S. U. Choi, K. R. Kim and K. R. Lee, Hetero-
cycles, 2010, 81, 1493–1502.
14 H. Damianakos, G. Sotiroudis and I. Chinou, J. Nat. Prod., 2013, 76,
1829–1835.
15 M. Tercel, W. R. Wilson and W. A. Denny, J. Med. Chem., 1995, 38,
1247–1252.
Fig. 5 Cytotoxicities of some alkaloids and their derivatives towards
cancer cell lines upon 72 h treatment. A549: human lung adenocarcinoma;
HeLa: cervical carcinoma; H460: human large-cell lung carcinoma.
16 W. J. McKillip, E. A. Sedor, B. M. Culbertson and S. Wawzonek,
Chem. Rev., 1973, 73, 255–281.
´
17 J. Li, J. S. Cisar, C.-Y. Zhou, B. Vera, H. Williams, A. D. Rodrıguez,
tertiary alkaloids 1 to give the products 3 or partially underwent
deactivation to give [MnV(TDCPP)(N)].
B. F. Cravatt and D. Romo, Nat. Chem., 2013, 5, 510–517.
´
18 L. Maestre, R. Dorel, O. Pablo, I. Escofet, W. M. C. Sameera,
´
´
E. Alvarez, F. Maseras, M. M. Dıaz-Requejo, A. M. Echavarren and
The cytotoxicity of unprotected aminimides 3b, 3c, 3d, 3g-a,
3g-b, 3i, as well as that of N-oxide derivatives 4b, 4c, 4d, 4g, 4i
and parent alkaloids 1b, 1c, 1d, 1g, 1i towards several cancer
cell lines were studied and compared. As shown in Fig. 5, the
unprotected aminimides 3b and 3c exhibited cytotoxicity com-
parable to that of the parent alkaloids 1b and 1c and the
corresponding N-oxides 4b and 4c (for the cytotoxicity of the
others, see the ESI†).
In summary, under mild conditions and without protection
by inert gas, the ‘‘[MnIII(TDCPP)Cl] + DPH’’ protocol provides a
simple and convenient method to prepare unprotected amini-
mides of alkaloids in good yields by a one-step reaction.
´
P. J. Perez, J. Am. Chem. Soc., 2017, 139, 2216–2223.
19 J. L. Jat, M. P. Paudyal, H. Gao, Q.-L. Xu, M. Yousufuddin,
D. Devarajan, D. H. Ess, L. Ku¨rti and J. R. Falck, Science, 2014,
343, 61–65.
20 M. P. Paudyal, A. M. Adebesin, S. R. Burt, D. H. Ess, Z. Ma, L. Ku¨rti
and J. R. Falck, Science, 2016, 353, 1144–1147.
21 C. Liu, J.-C. Yi, Z.-B. Zheng, Y. Tang, L.-X. Dai and S.-L. You, Angew.
Chem., Int. Ed., 2016, 55, 751–754.
22 J. Liu, K. Wu, T. Shen, Y. Liang, M. Zou, Y. Zhu, X. Li, X. Li and
N. Jiao, Chem. – Eur. J., 2017, 23, 563–567.
23 L. Legnani and B. Morandi, Angew. Chem., Int. Ed., 2016, 55,
2248–2251.
24 L. Legnani, G. P. Cerai and B. Morandi, ACS Catal., 2016, 6, 8162–8165.
25 D. Yu, K.-P. Shing, Y. Liu, H. Liu and C.-M. Che, Chem. Commun.,
2020, 56, 137–140.
Mechanistic studies suggested a manganese imido species to 26 C. L. Hill and F. J. Hollander, J. Am. Chem. Soc., 1982, 104, 7318–7319.
Chem. Commun.
This journal is © The Royal Society of Chemistry 2020