Access to benzo-fused nine-membered heterocyclic alkenes with a trifluoromethyl carbinol moiety: Via a double decarboxylative formal ring-expansion process under palladium catalysis

Article abstract of DOI:10.1039/c7sc05447e

Direct access to pharmaceutically attractive benzo-fused nine-membered heterocyclic alkenes 3 with a trifluoromethyl carbinol moiety was achieved via a palladium-catalyzed double-decarboxylative formal ring-expansion process from six-membered trifluoromethyl benzo[d][1,3]oxazinones 1 to nine-membered trifluoromethyl benzo[c][1,5]oxazonines 3 in the presence of vinylethylene carbonates 2. Generation of a Pd-π-allyl zwitterionic intermediate was proposed in the catalytic cycle. The trifluoromethyl group in the benzoxazinanones 1 plays an important role throughout the transformation. Diastereoselective chemical transformations of products 3 were also demonstrated.

Full text of DOI:10.1039/c7sc05447e

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Access to benzo-fused nine-membered
heterocyclic alkenes with a trifluoromethyl
carbinol moiety via a double decarboxylative
formal ring-expansion process under palladium
catalysis†
Cite this: DOI: 10.1039/c7sc05447e
a
Pulakesh Das,a Satoshi Gondo,a Punna Nagender,a Hiroto Uno,a Etsuko Tokunaga
ab
*
and Norio Shibata
Direct access to pharmaceutically attractive benzo-fused nine-membered heterocyclic alkenes 3 with
a trifluoromethyl carbinol moiety was achieved via a palladium-catalyzed double-decarboxylative formal
ring-expansion process from six-membered trifluoromethyl benzo[d][1,3]oxazinones
membered trifluoromethyl benzo[c][1,5]oxazonines 3 in the presence of vinylethylene carbonates 2.
Generation of Pd-p-allyl zwitterionic intermediate was proposed in the catalytic cycle. The
1 to nine-
Received 23rd December 2017
Accepted 17th February 2018
a
DOI: 10.1039/c7sc05447e
trifluoromethyl group in the benzoxazinanones 1 plays an important role throughout the transformation.
Diastereoselective chemical transformations of products 3 were also demonstrated.
rsc.li/chemical-science
extremely rare, despite the pharmaceutical importance of
medium-sized heterocyclic compounds (non-uorinated)10 and
biologically active natural products.11 Very recently, Liu and co-
Introduction
Fluoro-functionalized heterocycles with diverse ring sizes and
ring systems have been well studied in pharmaceuticals and
agrochemicals.1 Thus, a remarkable number of publications
have been dedicated to the development of efficient synthetic
methods to construct uoro-functionalized heterocycles.1,2 In
workers reported an elegant method for the construction of
uoroalkyl-functionalized medium-/large-sized carbocyclic
alkenes via an intramolecular radical triuoromethylation–
cyclization process.12 Recently, Zhao and co-workers success-
fully reported the palladium-catalyzed [5 + 4] and [6 + 4] cyclo-
addition reactions of azadienes with vinylethylene carbonates
and vinyl oxetanes respectively in good yields and selectivities.13
We disclose herein the rst synthesis of benzo-fused nine-
particular, heterocyclic molecules with
a triuoromethyl
carbinol moiety, i.e., CF3C(OR1)R2R3, have gathered much
attention3–6 on account of their promising biological properties.
Efavirenz4 (anti-HIV), triuoromethylated artemisinins5 (anti-
malarial), and uralaner6 (insecticide and acaricide) are repre-
sentative examples (Fig. 1).
membered heterocyclic alkenes
3 with a triuoromethyl
carbinol moiety and vinylethylene carbonates 214 (Scheme 1).
In this context, our group has been engaged in the devel-
opment of novel synthetic methodologies for uorine-
containing heterocycles for decades.7 Including our reports,7
the present synthetic strategies for uorinated heterocyclic
molecules are mostly limited to the construction of ve- and six-
membered ring systems,1,2,7 while the synthesis of medium- to
large-sized uoro-functionalized heterocycles such as deriva-
tives of benzo-oxazepine8 and macrosphelide A9 (Fig. 1) is
aDepartment of Nanopharmaceutical Sciences, Department of Life Science and Applied
Chemistry, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555,
Japan. E-mail: nozshiba@nitech.ac.jp
bInstitute of Advanced Fluorine-Containing Materials, Zhejiang Normal University,
688 Yingbin Avenue, 321004 Jinhua, China
† Electronic supplementary information (ESI) available: CCDC 1575063, 1575065,
1575062, 1589030. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c7sc05447e
Fig. 1 Biologically active heterocycles containing a trifluoromethyl
carbinol moiety.
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transformations such as epoxidation to 4 and reduction to 5
(Scheme 1) with high diastereoselectivities which make this
novel triuoromethylated nine-membered skeleton more
attractive as a template for drug discovery research. The pres-
ence of a triuoromethyl group on 1 plays a pivotal role for their
successful transformation to 3 based on comparative studies
using non-CF3-varients of 1.
Results and discussion
Scheme 1 Direct access to benzo-fused nine-membered heterocy-
clic alkenes 3 with a trifluoromethyl carbinol moiety from six-
membered oxazinones 1 and vinylethylene carbonates 2 via palla-
We started a preliminary investigation with the reaction of tri-
uoromethyl (CF3) benzoxazinanone 1a and phenyl vinyl-
dium-catalyzed double decarboxylative cycloaddition and the further ethylene carbonate 2a in the presence of suitable palladium
diastereoselective chemical transformations of 3.
precursors and/or phosphine ligands (Table 1). We rst
attempted our reaction of 1a using similar Pd2(dba)3$CHCl3
conditions in the presence or absence of phosphine ligands, but
The resulting triuoromethylated heterocycles
3 have
the results were disappointing (entries 1–4). Moving on to
Pd(PPh3)4 as a palladium precursor at 50 C in THF furnished
ꢀ
a benzo[c][1,5]oxazonine skeleton, and are not only medicinally
attractive uorine-containing heterocycles,1 but also expanded
variants of well-known [1,4]oxazepine pharmaceuticals.15
Synthesis of the titled nine-membered compounds 3 were
achieved from previously unknown triuoromethylated ben-
zoxazinanones 1 (six-membered ring) via a formal ring-
expansion pathway under palladium catalysis. The reaction
proceeded via the double decarboxylation (DDC)16 of 1 and
vinylethylene carbonates 2 followed by a [5 + 4] cycloaddition
reaction. The formation of Pd-complex I as an intermediate was
proposed by LC-MS spectrometric analysis. This method
provides an expedient access to triuoromethylated benzo[c]
[1,5]oxazonines 3 with diverse functional groups in the aromatic
moiety, including electron-donating, electron-decient, and
halogenic groups. Moreover, the alkene moiety in products 3
was further functionalized by conventional chemical
exclusively a nine-membered ring in good yield of 70% (entry 5).
Motivated by this result, further optimization was carried out in
different solvents. In toluene, a slight decrease in yield was
observed, at 66% (entry 6), while in dichloroethane yield
improved to 79% (entry 7). Lowering the temperature to room
temperature (rt) furnished good yield (70%), but 40 hours were
required to complete the reaction (entry 8). An excellent yield of
91% (89%) was observed by increasing the temperature to 80 ꢀC
(entry 9). Increasing the temperature further decreased yield
dramatically (entry 10, see ESI for more details†).
Based on the optimized reaction conditions, the exibility of
the DDC reaction was scrutinized by using a broad array of
vinylethylene carbonates (VECs) 2a–m with 1a. The results are
summarized in Table 2. Both electron-withdrawing and
electron-donating groups on the phenyl ring of 2 furnished
Table 1 Optimization conditionsa
Entry
Pd catalyst (with or without ligand)
Solvent
T [ꢀC]
t [h]
Yieldc [%]
1b
2b
3
4
5
6
7
8
9
10 mol% Pd2(dba)3$CHCl3
5 mol% Pd2(dba)3$CHCl3
5 mol% Pd2(dba)3$CHCl3/10 mol% PCy3
5 mol% Pd2(dba)3$CHCl3/10 mol% dtbpmb
5 mol% Pd(PPh3)4
5 mol% Pd(PPh3)4
5 mol% Pd(PPh3)4
5 mol% Pd(PPh3)4
5 mol% Pd(PPh3)4
DCM
THF
THF
THF
THF
Toluene
DCE
DCE
DCE
DCE
rt
40
40
40
50
50
50
rt
24
24
24
24
7
36
12
40
12
12
—
—
—
—
75(70)
68(66)
83(79)
79(70)
91(89)
40(34)
80
Reux
10
5 mol% Pd(PPh3)4
a
Experiments were performed with 1a (0.1 mmol), 2a (0.15 mmol), 5 mol% Pd(PPh3)4 (0.05 mmol) in 1.0 mL solvent. b 2a (0.12 mmol) was used.
Yields are 19F NMR yields with internal standard PhCF3 and yields (isolated) are also given in parentheses. dtbpmb ¼ 1,2-bis(di-tert-
c
butylphosphinomethyl)benzene. DCE ¼ 1,2-dichloroethane.
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Table 2 Scope of vinylethylene carbonates (VECs) 2a
Table 3 Scope of benzoxazinanones 1a
a
Unless noted otherwise, the reaction was performed with 0.10 mmol of
1b–e as mentioned in Table 1. Yields are isolated yields and 19F NMR
yields with internal standard (PhCF3) also shown in parentheses.
positions on the benzene ring were well tolerated to provide 3 in
moderate to good yields. The substrate-bearing electron-
donating methyl group on the benzene ring, 1b produced CF3-
tetrahydrobenzoxazonine 3ba in 81% yield. The halogen-
substituted CF3-benzoxazinanones 1c and 1e (F and Br)
produced DDC products 3 in moderate to good yields (3ca: 69%
and 3ea: 78%) (Table 3).
a
Experiments were performed with 1a (0.1 mmol), 2a–m (0.15 mmol),
Pd(PPh3)4 (0.05 mmol) in 1.0 mL dry DCE with stirring at 80 ꢀC for
12–16 h. Yields are isolated yields and 19F NMR yields with internal
standard PhCF3 also shown in parentheses. 3aa: CCDC 1575063; 3aj:
CCDC 1575065. b 0.20 mmol of 2j was used. c 0.20 mmol of 2k was used.
To ensure the effect of the CF3 group at the C-4 position, next
we examined the reaction of benzoxazinanones 6, which
contain different substituents at the C-4 position, with 2a
(Scheme 2). In recent years, palladium-catalyzed cyclization
reactions using vinyl benzoxazinanone 6a with a variety of
substrates have been actively investigated by several groups.17
We thus rst attempted the reaction of 6a with 2a. Interestingly,
substrate 6a with a vinyl at the C-4 position produced a very
different result. Under our best conditions, a vinyl-substituted
benzoxazinanone 6a was converted to an intramolecular cycli-
zation product 7 in 29% yield but no desired nine-membered
cyclized product was observed (Scheme 2a). We next examined
the reaction using 6b with a methyl group at the C-4 position
instead, but were unable to furnish the desired product and the
starting material 6b remained (Scheme 2b). Similar no conver-
sion was obtained when we carried out the reaction of 6c having
protected N-benzyl group (Scheme 2c). Although the reasons for
the high reactivity of 1a are not clear, it might be due to the
higher electrophilicity value of 1a induced by the strong elec-
tronegativity of the CF3 group (group electronegativity of CF3 is
3.45).18 To ensure the effect of the CF3 group at the C-4 position
of 1a, we performed a DFT calculation. The electrophilic value
of 1a having CF3 at the C-4 position was estimated to be 3.67 (u
good to excellent yields. VECs 2b–c, which have electron-
donating groups (Me and OMe) at the p-position, reacted effi-
ciently to afford the desired products 3 in excellent yields (3ab:
83%; 3ac: 78%) whereas VEC 2g, which contains an electron-
withdrawing group (CF3) at the p-position, furnished
moderate yield (3ag: 56%). Furthermore, halogen-substituted
VECs (2d: F; 2e: Cl; 2f: Br) also underwent the DDC reaction
very smoothly to furnish good to excellent yields (3ad: 69%; 3ae:
86%; 3af: 91%). Similarly, a highly electronegative atom (2h: F)
and an electron-donating group (2i: OMe) at the o-position
afforded excellent yields (3ah: 84% and 3ai: 88%). Noticeably,
substrates bearing an electron-withdrawing group (F) and an
electron-donating group (OMe) at the o-position furnished
higher yields than p-substituted substrates. Moreover, the scope
of VECs 2 was extended to heteroaryl systems (2j: 2-furyl; 2k: 2-
thiophenyl) and the reaction proceeded smoothly to afford the
desired products 3 in good yields (3aj: 76%; 3ak: 79%). Grati-
fyingly, non-aromatic substituent VEC 2l and extended p
conjugate naphthalene-derived VEC 2m also underwent the
cycloaddition reaction to furnish 3al and 3am in moderate to
good yield (53% and 65%, respectively), thus signicantly
broadening the scope of substrate 2 of this DDC system
(Table 2).
Spurred by this interesting result, a range of differently
substituted CF3-benzoxazinanones 1b–e were further examined
to better understand the DDC reaction (Table 3). Substituents
Scheme
2 Reaction of benzoxazinanones 6a–c which contain
different substituents at the C-4 position and N-protected group, with
on 1 with electronically dissimilar properties at different 2a under optimized conditions gave different results.
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(eV)) while that of 5b containing CH3 at the C-4 position (3.33)
was lower (Table S6, Fig. S1 in ESI for details†).
Interestingly, the X-ray crystallographic analysis of starting
substrate 1a revealed that 1a has a sterically unfavourable cis-
conguration between CF3 and tosyl groups (Fig. 2). Although
the reasons for the stabilization of 1a in this conguration are
not sure,19 the steric repulsion might be the additional factor for
the high reactivity of 1a for decarboxylation reaction.
To demonstrate the synthetic applicability of CF3-substituted
tetrahydrobenzoxazonines 3, epoxidation and hydrogenation
reactions were carried out as displayed in Scheme 3 based on
the classical work of Still and Hoveyda.20 By using the Zhao's
condition13a we performed the epoxidation of 3aa in the pres-
ence of m-CPBA at 0 ꢀC to rt successfully transformed to epoxide
4 with 67% yield and >20 : 1 diastereoselectivity through the
peripheral attack. The X-ray crystallographic structure of 4
(CCDC 1589030†) suggested that epoxidation proceeded via
a less hindered convex approach. Hydrogenation of 3aa with H2
in the presence of Pd–C at rt furnished the desired product 5
(5 : 1 dr) in 74% yield (isolated as a single isomer) (Scheme 3).
A plausible reaction mechanism of the palladium-catalyzed
DDC reaction of 1a with 2a to 3aa is portrayed in Scheme 4.
The catalytic cycle is rst initiated by the oxidative addition of
Pd(0) with 2 followed by decarboxylation, which generates the
p-allyl-Pd(II) complex II. The extremely nucleophilic nature of
the alkoxide oxygen of II attacks the most electrophilic carbon
atom attached to the CF3 group of 1a which triggers the opening
of benzoxazinanone ring to generate reactive species III. Due to
its highly reactive nature, species III immediately transforms
into Pd-complex I via decarboxylation. Recently, Kleij et al.
disclosed the similar kind of six membered Pd-complex with the
Scheme 4 Plausible mechanism.
support of DFT calculations.21 In our case, the formation of Pd-
complex I was conrmed by LC-MS spectrometry (Fig. S2 in ESI
for detail†) but we could not detect it by NMR (Fig. S3, in ESI for
detail†).
From complex I, there might be two possible pathways for
the formation of two different cyclized products. Attack at the
terminal position of the Pd-complex (path A) would generate the
[5 + 4] cycloaddition product 3aa while internal attack (i.e., path
B) of Pd-complex could result in [4 + 3] cycloaddition to furnish
a seven-membered heterocycle 8. However, we did not obtain
the [4 + 3] cycloaddition adduct 8. This may be attributed to
steric hindrance of 8, i.e., the NTs group as well as the tetra-
substituted tertiary carbon center on 8.
Conclusions
In conclusion, we have established a novel and highly efficient
methodology for the synthesis of benzo-fused nine-membered
heterocyclic alkenes with a triuoromethyl carbinol moiety
through a palladium-catalyzed double decarboxylative formal
ring expansion process. A combination of triuoromethylated
six-membered benzoxazinanones with vinylethylene carbonates
resulted in direct access to previously unknown triuoromethyl-
functionalized nine-membered heterocycles. The tri-
uoromethyl substituent at the C-4 position of benzox-
azinanones plays an important role in this transformation.
Diastereoselective transformations of the benzo-fused nine-
membered heterocyclic alkene were also achieved to demon-
strate the synthetic utility of the products. Investigation of the
formation of other medium-sized rings as well as enantiose-
lective variants of the reaction are presently under way in our
laboratory.
Fig. 2 X-ray crystallographic analysis of 1a (CCDC 1575062†) revealed
a sterically unfavourable cis-configuration between CF3 and tosyl
groups.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Number JP
16H01142 in the Middle Molecular Strategy, and the Advanced
Scheme 3 Diastereoselective derivatizations of tetrahydrobenzox-
azonine 3aa.
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Catalytic Transformation (ACT-C) from the JST Agency
(JPMJCR12Z7).
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