Divergent synthesis of N-heterocycles by Pd-catalyzed controllable cyclization of vinylethylene carbonates

Article abstract of DOI:10.1039/C8CC06945J

Here, we report a palladium-catalyzed controllable cyclization of vinyl ethylene carbonates that proceeds through formal migration [2+3] and [5+2] cycloadditions, respectively, under mild conditions. The transformation described here affords a series of synthetically versatile 5,7-membered N-heterocycles which are found in natural products and pharmaceuticals with biological and medicinal properties.

Full text of DOI:10.1039/C8CC06945J

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Divergent synthesis of N-heterocycles
by Pd-catalyzed controllable cyclization
of vinylethylene carbonates†
Cite this: Chem. Commun., 2018,
54, 12182
Received 27th August 2018,
Accepted 1st October 2018
a
abc
Yuwen Yang
and Weibo Yang
*
DOI: 10.1039/c8cc06945j
rsc.li/chemcomm
Here, we report a palladium-catalyzed controllable cyclization of
vinyl ethylene carbonates that proceeds through formal migration
[2+3] and [5+2] cycloadditions, respectively, under mild conditions.
The transformation described here affords a series of synthetically
versatile 5,7-membered N-heterocycles which are found in natural
products and pharmaceuticals with biological and medicinal properties.
Fig. 1 Biologically active compounds of diversified N-heterocycles.
Nitrogen heterocycle units, the most privileged and significant
structures, are found in many small-molecule drugs and they
are highly crucial for their potency and efficacy expression
(Fig. 1).1 Accordingly, the development of reliable methodo-
logies for the efficient and concise construction of these
structural motifs is attracting considerable attention in the field
of transition metal catalysis.2 While the transition metal-catalyzed
cyclization made significant contribution to the building of
various and versatile nitrogen heterocycle compound libraries,
divergent synthesis with controllable ring sizes from the same
starting materials is a long-standing challenge.2d,3
The allylic substitution reaction, which was originally dis-
covered by Tsuji4 and further developed by Trost5 and others,6
represents a powerful approach for the expeditious synthesis of
allylic derivatives and diversified heterocycles through a p-allyl
metal intermediate. Recently, Zhang,7 Kleij,8 Zhao,9 Glorious,10
and others11 developed vinylethylene carbonates (VECs) as
more stable and readily available substrates for Pd-catalyzed
decarboxylative allylic substitution7a,b,8 and cycloaddition7c–g,9–11
with nucleophiles or unsaturated dipoles to construct allylic
substituted and functional heterocyclic products. Notably,
a p-allyl metal intermediate usually serves as either a 5-atom
(1C, 5O) synthon or a 3-atom (3C, 5O) synthon to engage the
cross-partners, which would lower the entropic and enthalpic
costs with the aid of catalysts and ligands to achieve medium-
sized ring formation (Fig. 2a). Very recently, Zhao and his
co-workers realized an interesting Pd/Lewis acid co-catalyzed
cycloaddition of VECs by the utilization of a (1C, 4C) synthon
to construct spiro heterocycles. However, to the best of our
knowledge, the formal cycloaddition by utilizing p-allyl Pd as a
a Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai
Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
b Department of Medicinal Chemistry, Shanghai Institute of Materia Medica,
University of Chinese Academy of Sciences, Chinese Academy of Sciences,
555 Zu Chong Zhi Road, Shanghai, 201203, China. E-mail: yweibo@simm.ac.cn
c Key Laboratory for Functional Material, Educational Department of Liaoning
Province, University of Science and Technology Liaoning, Anshan 114051,
P. R. China
† Electronic supplementary information (ESI) available: Data for new compounds
and experimental procedures. CCDC 1852787 and 1852788. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c8cc06945j
Fig. 2 Evolution of VECs and our new discovery.
12182 | Chem. Commun., 2018, 54, 12182--12185
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2-atom (1C, 2C) synthon has never been described to date. reaction parameters, the optimal conditions for 3aa were ulti-
In this sense, using a zwitterionic p-allyl palladium intermediate mately identified as follows: Pd(cod)Cl2 (5 mol%) as a catalyst,
as a new synthon would not only improve our ever-growing Xantphos (10 mol%) as a ligand, and AgTFA (10 mol%) as an
knowledge in allylic cycloaddition, but also provide a new oppor- additive in aqueous methanol solvent at 80 1C. It exclusively
tunity for diversity-oriented controllable synthesis. Herein, we provided the desired product 3aa in quantitative NMR yield and
successfully realize these ideas and report an unprecedented Pd- 85% isolated yield (Table 1, entry 11). In order to realize the
catalyzed controllable cyclization of VECs via formal migration switchable cyclization goal, we then turned our attention to
[2+3] and [5+2] cycloaddition pathways, respectively. An array of tune the formal [5+2] cycloaddition product 4aa, which is a
diversified 5,7-membered N-heterocycles was systematically con- considerable challenge in organic synthesis due to unfavorable
structed by judicious choice of additives from identical starting entropy effects. Interestingly, conducting the reaction at mild
materials.
temperature (60 1C) is likely beneficial for 4aa formation.
Our initial reaction was conducted with 4-phenyl-4-vinyl-1,3- Switching the catalyst Pd(cod)Cl2 to [Pd(allyl)Cl]2 and choosing
dioxolan-2-one (1a) and 1,3,5-triphenyl-1,3,5-triazinane (2a) in DCM as the solvent, 3aa was suppressed and 4aa became the
the presence of Pd(cod)Cl2 as a catalyst, Xantphos as a ligand, major product. The isolated yield of 4aa was increased drama-
and AgTFA as an additive in dichloromethane (DCM) at 80 1C. tically to 81% (Table 1, entry 14). Finally, a control experiment
Gratifyingly, the reaction proceeded smoothly and generated was also conducted to understand the role of silver salts. The
two different cycloaddition products 3aa and 4aa in 50% and control experiment showed that the additive AgTFA was crucial
38% yields (Table 1, entry 1), respectively. The structure of 4aa to this controllable cyclization reaction (Table 1, entries 18 and
was further unambiguously confirmed by X-ray crystallographic 19). No [5+2] product was formed and the yield of the [2+3]
analysis.
product was significantly decreased to 23% in the absence of
Encouraged by the preliminary results, we further system- silver salts. Presumably, the cationic silver as a scavenger could
atically optimized the conditions and attempted to realize this capture anionic chloride and form a new trifluoroacetyl (TFA)
reaction in a switchable mode. After a deep investigation on anion, which promotes the cleavage of the C–N bond12 from
1,3,5-triphenyl-1,3,5-triazinane (2a).
With the optimal conditions in hand, the generality of the
Table 1 Optimization of Pd-catalyzed controllable cycloaddition of VECsa
Pd-catalyzed controllable formal migration [2+3] cycloaddition
reaction was firstly explored. As illustrated in Table 2, a range
of VECs containing electron-donating as well as electron-
withdrawing groups at the para-, meta-, and ortho-positions
of the aryl performed well and delivered the corresponding
5-membered ring products in good to excellent yield. Additionally,
a dichloro substituent (3na) as a potential handle was also
amenable to the standard conditions, thus offering a product
suitable for further structural elaboration. Beyond the tolerance
to the above-mentioned simple aromatic ring systems, the reaction
is also compatible with naphthalene (3ba), heterocyclic (3sa and
3wa), and non-aromatic substrates (3ta, 3ua, and 3va) commonly
Yieldb (%)
Entry
Catalyst
Solvent
3aa
4aa
1
2
Pd(COD)Cl2
Pd(OAc)2
DCM
DCM
50
16
38
13
3
4
5
6
Pd(PPh3)4
DCM
Toluene
H2O
MeOH
DMSO/H2O (1/1)
DMF/H2O (1/1)
MeOH/H2O (1/1)
MeOH/H2O (2/1)
MeOH/H2O (1/2)
DCM
DCM
DCM
DCM
DCM
DCM
DCM
MeOH/H2O (1/2)
DCM
MeOH/H2O (1/2)
Trace
21
84
20
55
67
71
89
99(85)
10
10
56
N.D.
28
N.D.
N.D
12
N.D.
N.D.
74
81
85(81)
64
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
[Pd(allyl)Cl]2
Pd(COD)Cl2
Pd(TFA)2
7
8
Table 2 Substrate scope of formal migration [2+3] cycloadditionsa
9c
10c
11c
12d
13e
14 f
15d
16e
17 f
18 fg
19 g
20 f
21
3
Trace
13
8
15
N.D.
23
66
81
N.D.
N.D.
84
8
87
Pd(TFA)2
N.D.
a
Reaction conditions: 1a (0.05 mmol), 2a (0.06 mmol), Pd catalyst
(5 mol%), Xantphos (10 mol%), AgTFA (10 mol%), solvent (0.5 mL) at
b
80 1C for 2 h; for more reaction conditions, see the ESI. Yields were
determined via 1H NMR using CH2Br2 as the internal standard; isolated
c
d
yield is given in parentheses. Solvent (1 mL). 1a (0.1 mol), 2a
e
(0.05 mmol), solvent (1.0 mL) at 60 1C for 1 h. 1a (0.1 mol),
2a (0.045 mmol), solvent (1.0 mL) at 60 1C for 1 h. 1a (0.1 mol), 2a
(0.06 mmol), solvent (1.0 mL) at 60 1C for 1 h. No AgTFA.
f
a
Isolated yields are indicated below each structure (ESI gives the
g
experimental details).
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encountered in target-oriented synthesis. Furthermore, various
triazinane partners also engaged in efficient cycloaddition
regardless of the electronic properties on the substrates to
deliver 3ab–3af in good isolated yield. However, benzylic amine
substituted triazinanes were unreactive under the reaction
conditions.
As shown in Table 3, various para-, meta-, or ortho-
substituents of both electron-rich and electron-poor characters
at the aryl group on the substituted VECs could be well tolerated
to provide the desired oxazepine products in moderate to
very good yield. Notably, reactions of substrates with aromatic
functional groups attached to VECs afforded higher yields than
those with non-aromatic functional groups. Possibly, the aromatic
functional groups could stabilize the zwitterionic p-allyl palladium
intermediate and prevent it from losing activity. To our delight,
the thienyl substituted VEC worked out smoothly to provide 4sa
in very good isolated yield. As an important extension of scope
for this formal [5+2] cycloaddition, vinyloxazolidin-2-one was
employed in this catalytic system, which could lead to the
formation of 7-membered ring diazepine which is a privileged
structure in pharmaceutical drugs. Gratifyingly, the diazepine
product 4xa could be accessed in moderate yield. Given that the
benzylic amine protecting group is easily cleaved to free amine by
hydrogenation and could be manipulated for functional group
installation, we revisited the benzylic amine substituted triazinanes.
In contrast to the formal migration [2+3] cycloaddition, it displayed
good reactivity in the present system (4ag), furnishing the desired
product in synthetically useful yield.
Several experiments were conducted to gain insight into the
possible mechanism of this Pd-catalyzed controllable cycliza-
tion (Fig. 3). Initially, we carried out a cross-over experiment by
treating VEC 1a with a 1 : 1 mixture of 2a and 2e under the
standard formal migration [2+3] cycloaddition conditions, and
four different products with a ratio of 1 : 1 : 1 : 1 were obtained.
This interesting result suggests that imine as a nucleophilic
reagent is generated in situ from triazinanes via C–N bond
cleavage. Besides, we also performed the reaction of 4ae with 2a
and found a similar result to the cross-over experiment, thus
indicating that the C–N bond cleavage event of the seven-membered
Fig. 3 Control experiments for mechanism identification.
ring occurs via oxidative addition of Pd(0) and releases one imine.
Notably, a further D-labelling experiment could strongly support
the C1–N bond cleavage instead of the C5–N bond cleavage.
Additionally, the treatment of seven-membered ring 4ae with 2e
resulted in 3ae in 90% excellent yield under the standard formal
migration [2+3] cycloaddition conditions, which demonstrated
that the 7-membered ring diazepine could be an intermediate for
5-membered ring formation.
On the basis of the above results and relevant reports,3a,13
a
plausible mechanism is proposed in Fig. 4. The reaction begins
with the oxidative addition of Pd(0) to VEC (1a), generating
the zwitterionic p-allyl palladium intermediate A by releasing
carbon dioxide. Meanwhile, three imines are generated in situ
from triazinane (2a) via C–N bond cleavage, which would attack
Table 3 Substrate scope of formal [5+2] cycloadditionsa
a
Isolated yields are indicated below each structure (ESI gives the
Fig. 4 Proposed mechanism of the controllable mode.
experimental details).
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In summary, a diversity-oriented Pd-catalyzed regio-selectivity
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conditions. The judicious choice of the catalyst and solvent
enables the efficient synthesis of two different types of 5-, 7-
membered N-heterocycles from an identical starting material
through formal migration [2+3] and [5+2] cycloadditions, and
potentially contributes in expediting the search for lead com-
pounds. Further studies on new reactivities of VECs and bioactive
assessments of the above N-heterocycles are under progress in
our lab.
We gratefully acknowledge the 100 Talent Program of
Chinese Academy of Sciences, the Chinese NSF (21702217),
the ‘‘1000-Youth Talents Plan’’, the Shanghai-Youth Talent, and
the Shanghai-Technology Innovation Action Plan (18JC1415300)
for financial support of this research.
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Conflicts of interest
There are no conflicts to declare.
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