Hypervalent Iodine(III)-Mediated Cascade Cyclization of Propargylguanidines and Total Syntheses of Kealiinine B and C

Article abstract of DOI:10.1002/chem.201700934

An oxidative cascade cyclization of propargylguanidines promoted by phenyliodonium diacetate (PIDA) was developed. The protocol provides an efficient route for the synthesis of the alkaloids kealiinines B and C as well as homologues. The difference in the electronic nature of the acetylene substituent resulted in two ways of the cyclization. A plausible mechanism is proposed based on the experimental results.

Full text of DOI:10.1002/chem.201700934

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Title: Hypervalent Iodine(III)-Mediated Cascade Cyclization of
Propargylguanidines and Total Syntheses of Kealiinines B and C
Authors: Guilong Tian, Pavel Fedoseev, and Erik Van der Eycken
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To be cited as: Chem. Eur. J. 10.1002/chem.201700934
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Hypervalent Iodine(III)-Mediated Cascade Cyclization of
Propargylguanidines and Total Syntheses of Kealiinine B and C
Guilong Tian,[a] Pavel Fedoseev,[a] and Erik V. Van der Eycken* [a], [b]
Dedicated to Prof. Qi-Lin Zhou on the occasion of his 60th birthday.
Abstract: An oxidative cascade cyclization of propargylguanidines
promoted by phenyliodonium diacetate (PIDA) was developed. The
protocol provides an efficient route for the synthesis of the alkaloids
Kealiinines B and C as well as homologues. The difference in the
electronic nature of the acetylene-substituent resulted in two ways of
the cyclization. A plausible mechanism is proposed based on the
experimental results.
reagents
phenyliodonium
diacetate
(PIDA)
and
Phenyliodonium Ditrifluoroacetate (PIFA) with regards to
their utility for oxidative cyclization reactions. In 2011,
Canesi’s group designed a cascade cyclization mediated by
PIDA for the synthesis of ring-fused skeletons.[1i] Maurya’s
group reported in 2015 the utilization of PIDA in amide
oxidations for cascade cyclizations[1m] (Scheme 1).
A range of 2-aminoimidazole alkaloids displays a wide
diversity of biological activities.[2] Among them there are
potent modulators of the formation and dispersion of
bacterial biofilms,[3] human β-secretase (BACE-1)
inhibitors[4] and tubulin-binding agents[5]. In 2010, our group
developed a Ag-mediated guanylation-cyclization procedure
In the last years, hypervalent iodine reagents have attracted
great attention due to their environmental friendliness and low
cost, as well as their ease of handling. The synthetic efficiency in
the construction of complex architectures via oxidative
transformations proved its utility in many reports.[1]
of propargylamines as
a concise way towards the
syntheses of polysubstituted 2-aminoimidazoles (Scheme
2).[6]
Scheme 2. Synthesis of protected 2-aminoimidazoles and Kealiinines;
Boc = tert-butyloxycarbonyl. TFA = trifluoroacetic acid
In continuation of this work, we designed a cascade
reaction for the synthesis of the Kealiinine alkaloids[7]
Scheme 1. PIDA- or PIFA-promoted cyclizations.
(Scheme 2). As the methoxy-group on the phenyl
A ring of
Kita’s [1a,c-f,j,l] and Domínguez’s groups[1b,g,k] have performed
a broad investigation of the utility of the hypervalent iodine
substrate is sensitive to PIDA-oxidation, attack by the
1
alkyne on the para-position of the anisole moiety and
subsequent reaction of the guanidine moiety with the
intermediate carbocation will result in the formation of
compound 5. Obviously, this process should give access to
the syntheses of Kealiinine alkaloids and homologues, after
Boc-removal and aromatization.
[a] Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC)
University of Leuven (KU Leuven)
Celestijnenlaan 200F, 3001 Leuven (Belgium)
[b] Peoples Friendship University of Russia (RUDN University) 6 Miklukho-
Maklaya street, Moscow, 117198, Russia
Inspired by our investigations of heterocyclization
reactions, we used propargylguanidine 1a as a model
substrate (Table 1). This was readily prepared by
E-mail : erik.vandereycken@chem.kuleuven.be
Homepage: http://www.chem.kuleuven.be/research/organ/lomac/
Supporting information for this article is available on the WWW
under http://dx.doi.org
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guanylation of the related N-butyl-propargylamine[6] which
phenyliodonium dipivalate (PhI(piv)2) was employed,
incomplete conversion of the starting marterial was
observed (Entry 8). Application of PIFA in the current
protocol resulted in decomposition of the starting material
(Entry 9). No improvement of the yield was observed at 0
oC or 50 oC (entry 10 and 11). Switching to 1,1,1,3,3,3-
hexafluoro-2-propanol (HFIP) as solvent appeared to be
deleterious for the reaction (Entry 12), while no reaction
occurred in acetonitrile (ACN) or dichloromethane (DCM)
(Entries 13 and 14). A small improvement of the yield was
observed when choosing a mixture of dichloromethane
(DCM) and TFE (Entry 15), while other solvent mixtures led
to low conversion. The addition of AcONa (Entry 16) or
AcOH (Entry 17) was not beneficial for the reaction.[9]
was accessed through A3 coupling[8].
Table 1. Optimization of the reaction conditions.[a]
Table 2. Scope of the cascade cyclization.[a]
[a] The reaction was run on a 0.03 mmol scale; [b] 10mol% of additive
was used; [c] isolated yield; [d] the starting material decomposed; [e] no
full conversion; [f] TFE/DCM = 1: 1, TFE = 2,2,2-trifluoroethanol, DCM =
[a] The reactions were run on a 0.1 mmol scale employing the conditions
of Table 1, entry 15; [b] 48 h; [c] the starting material decomposed.
dichloromethane; [g] PhI (20 mol%), mCPBA (1.3 equiv.); PhI
iodobenzene; mCPBA = meta-chloroperoxybenzoic acid.
=
With the optimal conditions in hand, the scope and
limitations of the process were evaluated (Table 2). The
reaction does not seem to be sensitive to the nature of the
N-substituent, as nBu, Cy and PMB are all performing well
To our delight, the fully aromatized mono-Boc-protected
compound 2a was directly formed, using 2.1 equiv of PIDA
as an oxidant in 2,2,2-trifluoroethanol (TFE) after 24 h with
44% yield (Entry 2). Increasing the amount of PIDA resulted
in decomposition of the substrate, while only 1 equiv of
PIDA appeared to be insufficient (entry 2-7). Application of
1.3 equiv led to the highest yield (Entry 6). When
(2a, b and c). The methoxy groups on the phenyl-ring A
play an important role for the cyclization. Two or three
methoxy groups on the phenyl-ring A led to the formation of
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Table 4. Scope of the process for ring-fused guanidines.[a]
the desired product (2a
three methoxy groups were slow for aromatization. For the
unstability of compound , we only successfully isolated
-h). However, the substrates with
5
compound 5h. When the phenyl-ring A was bearing no or
one methoxy- or a 1,3-dioxolane group, the starting material
decomposed employing the standard conditions, even
when the temperature was lowered to 0 °C (2i, 2j and 2k).
For the aromatic ring B with an unsubstituted phenyl, a 5-
imino-6,7-dihydroimidazo[1,5-c]oxazol-3(5H)-one 3a was
obtained via Boc-cyclization of the intermediate on the
acetylene (vide infra for the mechanism). The reaction
pathway was depending on the substitution pattern of the
phenyl ring-B.
Intrigued by this result, we optimized the conditions
(Table 3) and evaluated the scope of this process (Table 4).
Table 3. Optimization of the ring-fused guanidine formation.[a]
[a] The reactions were run on a 0.1 mmol scale employing the conditions
of Table 3, entry 3.
[a] The reactions were run on a 0.03 mmol scale; [b] isolated yield; [c] no
full conversion, TFE/DCM = 1: 1, TFE = 2,2,2-trifluoroethanol, DCM =
dichloromethane.
The N-substituent was found to not have a significant
effect on the product yield (3b, 3c, and 3i). A bromine
substituent on the aromatic ring B resulted in the formation
of the desired compound in a little lower yield (3e). The
reaction worked well when a cyclohexyl-substituent instead
of a phenyl-ring A was used (3g).
Finally, propargylguanidines 1u, 1v were used for the
cascade cyclization (Scheme 3). Product 2u was obtained
in 53% yield (no full conversion when 1.3 equiv PIDA were
used). After removing the Boc-group, Kealiinine B was
formed in 38% overall yield. In case of propargylguanidine
1w, the formation of a mixture of 2v and the non-
aromatized 5v was obtained. Subsequent deprotection was
performed without separarion of this mixture, resulting in
the formation of Kealiinine C in 34% overall yield. To the
best of our knowledge, so far only two total syntheses of the
Kealiinine alkaloids were reported in the literature.[10-11]
Scheme 3. Total syntheses of Kealiinine B and C.
Basing on our observations, we propose a plausible
reaction mechanism. As PIDA can activate both the
methoxy-group and the guanidine, there are two competing
reaction pathways. Substrates bearing two or three
methoxy-groups on the phenyl-ring A and an electron-rich
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Maruyama, Y. Minamitsuji, N. Takenaga, Y. Kita, Chem. Commun. 2007,
1224; e) T. Dohi, M.Ito, N. Yamaoka, K. Morimoto, H. Fujioka,Y. Kita,
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aromatic ring B, follow the pathway from our hypothesis
(Scheme 2). On the contrary, substrates lacking a methoxy
group on the aromatic ring B, give rise to intermediate 6,
which is generated via PIDA-mediated activation of the
guanidine[1m] (Scheme 4). The intermediate cation seems to
prefer reaction with the carbamate moiety, rather than with
ring A, resulting in the formation of the ring-fused guanidine
3
.
[2] For reviews of the synthesis and activity of 2-aminoimidazole alkaloids,
see: a) S. M. Weinreb, Nat. Prod. Rep. 2007, 24, 931; b) H. Hoffmann, T.
Lindel, Synthesis 2003, 1753; c) J. D. Sullivan, R. L. Giles, R. E. Looper,
Curr. Bioact. Compd. 2009, 5, 39.
Scheme 4. Plausible mechanism (see also Scheme 2).
In summary, we have developed an oxidative PIDA-
mediated cascade reaction resulting in two types of ring-
fused skeletons, depending on the substitution pattern of
the aromatic rings. A total syntheses of Kealiinines B and C
in a concise way were realized.
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J. Richards, G. Parise, T. E. Ballard, W. Zeng, R. Deora, C. Melander, J.
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Experimental Section
Full experimental details and spectroscopic data for all compounds along
with the copies of 1H, 13C NMR spectra are available at the Supporting
Information.
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Acknowledgements
The authors are thankful to the F.W.O. [Fund for Scientific
Research – Flanders (Belgium)] and the Research Fund of the
University of Leuven (KU Leuven) for financial support. The
publication was financially support by The Ministry of Education
and Science of the Russian Federation (the Agreement number
02.a03.0008). We acknowledge the support by COST
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(European
Cooperation
in
Science and
Technology)
Action (CA15106) CH-Activation in Organic Synthesis. The
authors thank Prof. Thomas Wirth from Cardiff University, United
Kingdom (http://blogs.cardiff.ac.uk/wirth/) for the useful
discussion. Guilong Tian appreciates the CSC (China
Scholarship Council) for providing a doctoral scholarship.
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[9] More information about the optimal conditions is in the supporting
information.
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Keywords: guanidines, cascade reaction, hypervalent iodine, 2-
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Guilong Tian, Pavel Fedoseev, and Erik
V. Van der Eycken*
Page No. – Page No.
Hypervalent Iodine-Mediated Cascade
Cyclization of Propargylguanidines
and Total Syntheses of Kealiinine B
and C
An oxidative cascade cyclization of propargylguanidines promoted by phenyliodonium diacetate (PIDA) was developed. The protocol
provides an efficient route for the synthesis of the alkaloids Kealiinine B and C as well as homologues. The difference in the electronic nature
of the acetylene-substituent resulted in two ways of the cyclization. A plausible mechanism is proposed based on the experimental results.
This article is protected by copyright. All rights reserved.