One-pot Construction of Difluorinated Pyrrolizidine and Indolizidine Scaffolds via Copper-Catalyzed Radical Cascade Annulation

Article abstract of DOI:10.1002/adsc.201701643

A convenient approach to the synthesis of diverse difluorinated nitrogen-containing polycycles via a copper-catalyzed radical cascade annulation of amine-containing olefins and ethyl bromodifluoroacetate was developed. Three new bonds, including a C_sp3 ?CF₂ and two C?N bonds, are forged simultaneously in this strategy. Through this strategy, a series of difluorinated pyrrolizidine and indolizidine derivatives have been conveniently synthesized in good yields. (Figure presented.).

Full text of DOI:10.1002/adsc.201701643

Title: One-pot Construction of Difluorinated Pyrrolizidine and
Indolizidine Scaffolds via Copper-Catalyzed Radical Cascade
Annulation
Authors: Xiaoyang Wang, Miao Li, Yanyan Yang, Minjie Guo,
Xiangyang Tang, and Guangwei Wang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701643
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10.1002/adsc.201701643
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
One-pot Construction of Difluorinated Pyrrolizidine and
Indolizidine Scaffolds via Copper-Catalyzed Radical Cascade
Annulation
Xiaoyang Wang,[a] Miao Li,[a] Yanyan Yang,[a] Minjie Guo, * [b] Xiangyang Tang,[a] and
Guangwei Wang*[a]
a
Tianjin Key Laboratory of Molecular Optoelectronic Science, Department of Chemistry, School of Science, Tianjin
University, Tianjin 300072, P. R. China.
Institute for Molecular Design and Synthesis, School of Pharmaceutical Science and Technology, Tianjin University,
b
Tianjin 300072, P. R. China
Fax :+86-22-2740-3475; E-mail: wanggw@tju.edu.cn.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A convenient approach to the synthesis of
diverse difluorinated nitrogen-containing polycycles via a
copper-catalyzed radical cascade annulation of amine-
containing olefins and ethyl bromodifluoroacetate was
developed. Three new bonds, including a Csp3-CF2 and two
C-N bonds, are forged simultaneously in this strategy.
Through this strategy, a series of difluorinated pyrrolizidine
and indolizidine derivatives have been conveniently
synthesized in good yields.
Keywords: annulation; difluorinated; copper-catalyzed;
pyrrolizidine; indolizidine
Figure 1. Representative biologyically active izidine
alkaloids.
Nitrogen-containing polycycles are commonly
found in a vast class of biologically active molecules
and natural products. The izidine alkaloids, which are
valuable structural motif in organic synthesis,[6] and
the exploration of practical methodologies for the
introduction of CF2 in organic molecules is in high
demand. Recently, transition metal-catalyzed
difluoroalkylation of arylborons,[7] organohalides,[8]
unsaturated carboxylic,[9] and C-H bond of alkenes
and (hetero)arenes[10] have been developed. The
aminodifluoroalkylations of alkenes catalyzed by
palladium, copper, and photoredox catalyst were also
reported,[11] which provide an efficient access to
difluoro-γ-lactams and 3,3-difluoro-2-oxindoles.
However, the substrates in these reports[12] are limited
to aromatic amines with aliphatic amines failing to
result annulation products. Therefore, methods for the
synthesis of various difluorinated heterocyclic are
still limited,[13] especially methods for the synthesis
of difluorinated pyrrolizidines and indolizidines.
Until now, only a few examples for the multi-step
synthesis of difluorinated pyrrolizidines
of diverse biological activities, constitute nearly 30%
of all known natural alkaloids. Among them,
pyrrolizidines and indolizidines are particular
interesting
examples
and
prevalent
in
pharmacologically active natural compounds (Figure
1).[1] So, it is of great interest to develop general
protocols for the synthesis of these skeletons.
However, only a few limited examples have been
reported to form both the pyrrolizilines and
indolizidines cores.[2] Transition metal catalyzed
reactions, such as the palladium-catalyzed cyclization
reaction, have been successfully applied to the
construction of nitrogen-containing polycycles.[3] The
ruthenium- and rhodium-catalyzed methods were also
reported.[4]
Incorporation of fluorine atoms or fluorine-
containing groups into organic motifs can
significantly influence the lipophilicity, metabolic
stability, and bioavailability of organic molecules.[5]
As a bioisostere of hydroxyl, thiol, and carbonyl
groups, the difluoromethylene group (CF2) is a
1
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10.1002/adsc.201701643
Advanced Synthesis & Catalysis
Initially, olefin 1a and widely available ethyl
bromodifluoroacetate (BrCF2CO2Et) were chosen as
the model substrate for the optimization of reaction
conditions. The challenge of this transformation is to
avoid the generation of the byproduct 3 because of
the nucleophilic ability of primary amines. When the
reaction was conducted in dimethyl sulfoxide
(DMSO) with CuI (10 mol %) as a catalyst, 1,10-
phenanthroline as ligand, and K2CO3 as a base at 80
oC, it is encouraging to find that the desired product
2a was obtained in 16% yield even though the
byproduct 3 was also obtained in 35% yield (entry 1).
When 2,2’-bipyridine (bpy) was employed as ligand,
only trace amount of 2a was generated (entry 2).
Inversely,
the
use
of
PMDETA
Scheme 1. Methods for the synthesis of difluorinated
pyrrolizidines and indolizidines
(pentamethyldiethylenetriamine) as ligand led to 2a
in a higher yield (32%) (entry 3). Employing
triethylamine instead of K2CO3 as base further
improved the yield of 2a to 40% (entry 4). To our
delight, the desired product 2a could be generated in
excellent yield when PMDETA was employed as both
a ligand and a base (entry 5). It is well known that
alkyl radical could be efficiently generated from
corresponding alkyl halides in the presence of a
copper complex with multidentate amine ligands.[15]
Several solvents including N,N-dimethyl formamide,
and indolizidines have been developed (Scheme 1, a
14]
and b).[11d,
Herein, we disclosed a novel and
convenient approach to the synthesis of diverse
difluorinated N-containing polycycles via a copper-
catalyzed radical cascade annulation of amine-
containing olefins and ethyl bromodifluoroacetate
(Scheme 1, c). Both aliphatic amines and aromatic
amines can cyclize smoothly through the new
developed method and a series of difluorinated
pyrrolizidine and indolizidine derivatives have been
synthesized in high efficiency.
Table 1. Optimization of the reaction conditions.[a]
Yield (%) [b]
Entry [Cu] Ligand/Base Solvent
2a
16
<5
3
35
38
1[c]
2[c]
CuI Phen/K2CO3 DMSO
CuI Bpy/K2CO3
DMSO
PMDETA
/K2CO3
PMDETA
/K2CO3
3[c]
CuI
DMSO
32
40
25
33
4[c]
CuI
DMSO
5[d]
6[d]
7[d]
8[d]
9[d]
CuI
CuI
CuI
CuI
CuI
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
DMSO
DMF
90 (84) <5
46
36
<5
14
48
88
<5
6
23
45
78
53
20
<5
70
72
81
6
CH3CN
toluene
dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
10[d] CuCN PMDETA
11[d] CuBr PMDETA
12[d] Cu(OTf)2 PMDETA
13[d] CuBr2 PMDETA
14[d]
-
PMDETA
PMDETA
PMDETA
-
34
67
Scheme 2. Substrate Scope of Primary Amine-Containing
Olefins. Reaction conditions: 1 (0.5 mmol, 1.0 equiv),
bromodifluoroacetate (0.75 mmol, 1.5 equiv), PMDETA
(0.75 mmol, 1.5 equiv), CuI (10 mol %), DMSO (3.0 mL),
under Ar at 80 C for 12 h. 2c was purified by silica gel
chromatography followed by preparative TLC.
15[d,e] CuI
16[d,f] CuI
<5
[a]
Reaction conditions: Unless otherwise noted, all
reactions were performed with 1a (0.3 mmol, 1.0 equiv),
BrCF2CO2Et (0.45 mmol, 1.5 equiv), and [Cu] (10 mol %),
in DMSO (3 mL) at 80 oC under Ar for 8 h. [b] Determined
by GC with dodecane as internal standard. The value in
parentheses is the isolated yield. [c] Ligand (0.2 equiv), base
(1.5 equiv). [d] PMDETA (1.5 equiv). [e] 30 oC. [f] 50 oC.
o
[a]
acetonitrile, toluene, 1,4-dioxane, and dimethyl
sulfoxide have been screened and dimethyl sulfoxide
2
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10.1002/adsc.201701643
Advanced Synthesis & Catalysis
o
proved to be the optimal choice (entries 5-9). Other
copper salts were screened (entries 10-13). In the
presence of CuCN, CuBr2, and Cu(OTf)2, the yield of
2a decreased dramatically, accompanied by
increasing formation of byproduct 3. When CuBr was
applied, similar yield was resulted. In the absence of
Cu catalyst, 2a can’t be obtained and 3 was generated
in high yield (entry 14). When the reaction was
conducted at lower temperature (entries 15 and 16),
the conversion rate of 1a decreased. Consequently,
CuI as catalyst, PMDETA as both ligand and base,
dimethyl sulfoxide as solvent were chosen as the
optimized conditions.
With the optimized reaction conditions in hand, a
variety of aliphatic primary amine-containing olefins
were investigated to demonstrate the substrate scope.
The linear aliphatic amino olefins with geminal
disubstitutions could afford the desired difluorinated
pyrrolizidine products in good yields (2a and 2b).
Without geminal substitutions, 2c was obtained with
a much lower yield. The reason for low cyclized yield
of 1c compared with other substrates might be due to
Thorpe-Ingold effect,[16] where increasing the size of
two substituents on a tetrahedral center facilitate the
cyclized reactions of the other two substituents.
Notably, difluorinated indolizidine derivatives could
also be obtained in high efficiency through this
method (2d and 2e). Importantly, difluorinated
tetrahydroisoquinoline derivative 2f with aza-[4,3,0]
bicyclic skeleton was also obtained in 71% yield.
Unfortunately, the aza-[5,3,0] bicyclic skeleton 2g
couldn’t be obtained through this method. It is
noteworthy that, in fact, only a few successful
transition metal-catalyzed methods for the annulation
of aliphatic primary amine-containing olefins to
construct nitrogen-containing heterocycles have been
reported.[17]
CuI (10 mol %), CH3CN (2.0 mL), under Ar at 80 C for
12 h.
Next, a series of o-allylaniline derivatives was
tested. However, the optimized conditions described
above were not productive. Gratefully, with
acetonitrile as solvent instead of dimethyl sulfoxide, a
variety
of
difluorinated
benzopyrrolizidine
derivatives could be obtained in good to excellent
yields (5a−5i). A variety of substituents, including
t
electron-donating (Me, Bu, OMe) and electron-
withdrawing substituents (F, Cl and Br), were all
well-tolerated. Notably, the present method could be
applied to the synthesis of difluorinated
benzoindolizidine derivative 5j in high efficiency.
Inspired by the above results and previous
work,[11a,b] we envisioned that difluoroalkylated
indoline derivatives could be obtained when the
primary amine was replaced by secondary amine. As
expected, secondary amine substrate
6
was
effectively converted into the difluoroalkylated
indoline derivative 7 under the standard conditions.
Similarly,
when
ethyl
was
bromodifluoroacetate
replaced by -
(BrCF2CO2Et)
bromodifluoroacetamide 8, the difluoroalkylated
indoline derivative 9 could be obtained in excellent
yield (Scheme 4). It should be noted that multigram-
scale experiment has been conducted using 4a as a
model substrate, and the yield of the desired product
5a was maintained under the standard conditions.
Remarkably, the difluorinated benzopyrrolizidine
derivative 5a could be converted to difluorinated
benzopyrrolizidine 10 in high efficiency through a
simple step (Scheme 5). These results indicate this
efficient and convenient approach may provide
practical access to scale-up synthesis of difluorinated
pyrrolizidines and indolizines.
Scheme 4. Synthesis of Difluoroalkylated Indoline
Derivatives
Scheme 5. Multigram-Scale Experiment
Scheme 3. Substrate Scope of Aromatic Amines. Reaction
conditions: 4 (1.0 mmol, 1.0 equiv), bromodifluoroacetate
(1.5 mmol, 1.5 equiv), PMDETA (1.5 mmol, 1.5 equiv),
3
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10.1002/adsc.201701643
Advanced Synthesis & Catalysis
Control experiments were carried out to gain some
insight into the mechanism of this reaction. Firstly,
the treatment of compound 3 under the standard
conditions can’t afford the desired product, which
means that 3 was not an intermediate of this
transformation. Secondly, the reaction was
completely quenched by the radical inhibitor 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO, 1.5 equiv)
and TEMPO-CF2CO2Et was observed with 14% yield
by 19F NMR spectroscopy, confirming that
•CF2CO2Et was generated in the catalytic system. In
addition, the annulation reaction can’t occur when
BrCF2CO2Et was replaced by ethyl 2-bromo-2-
methylpropanoate (Scheme 6).
Scheme 7. Proposed Mechanism.
In conclusion, we disclosed an efficient and novel
method for the construction of diverse difluorinated
nitrogen-containing
polycycles
from
ethyl
bromodifluoroacetate and broadly available primary
amines, including aliphatic amines and aniline,
through
a
copper-catalyzed radical cascade
annulation. A series of difluorinated pyrrolizidine and
indolizidine derivatives has been synthesized in good
yields. This method may find broad application in the
synthesis of diverse fluorinated alkaloids. Further
investigations and applications of this method are
underway in our laboratory.
Experimental Section
Scheme 6. Control Experiments
Synthesis of 2,2-Difluoro-6,6-diphenyltetrahydro-1H-
pyrrolizin-3(2H)-one (2a). Representative Procedure I.
To a 25 mL of Schlenk tube was added CuI (0.05 mmol,
10 mol%) under air and then evacuated and backfilled with
Ar (3 times). Acetonitrile (3 mL), PMDETA (0.75 mmol,
1.5 equiv.), 1a (0.5 mmol, 1.0 equiv.) and ethyl
bromodifluoroacetate (1.5 equiv.) was added subsequently.
In light of these results and previous reports,
plausible mechanism was proposed in Scheme 7. The
catalytic cycle was initiated with oxidation of Cu(I)
species by BrCF2CO2Et through a single-electron
transfer (SET) to afford an electrophilic fluoroalkyl
o
The reaction mixture was heated to 80 C (oil bath). After
stirring for 12 h, the reaction was allowed to cool down to
room temperature and diluted with water (20 mL). The
aqueous phase was extracted with dichloromethane (3 × 15
mL). The combined organic layers were washed with brine,
dried over anhydrous Na2SO4. The organic layer was then
concentrated under vacuum, and the residue was separated
by silica gel column chromatography (Petroleum
ether/EtOAc) to give the desired product 2a. (131 mg) as a
radical
A
and Cu(II) species. Subsequently,
fluoroalkyl radical A reacted with alkenes to form
alkyl radical B, which underwent oxidation with
Cu(II) species to generate the cationic intermediate C
and recycling Cu(I) species. The cationic
intermediate C was nucleophilic attacked by the
intramolecular nitrogen of the amines and
difluoroalkylated pyrrolidine intermediate D was
produced (path a). Another possible pathway that
involves Cu(III) intermediate cannot be ruled out at
current stage as shown in path b. The alkyl radical B
was trapped by Cu(II) and Cu(III) species E was
generated. Then reductive elimination of E led to
intermediate D and regenerated Cu(I) species.
Finally, the desired product was obtained through
intramolecular ester-amide exchange.[18]
1
yellow solid. Yield 84 %; H NMR (400 MHz, CDCl3) δ
7.27 – 7.20 (m, 4H), 7.19 – 7.07 (m, 6H), 4.25 (dd, J =
12.5, 3.0 Hz, 1H), 3.83 (dd, J = 12.3, 2.8 Hz, 2H), 2.82 –
2.48 (m, 2H), 2.25 – 1.94 (m, 2H); 13C NMR (101 MHz,
CDCl3) δ 163.66 (dd, J = 33.0, 27.1 Hz), 145.24 (d, J = 3.6
Hz), 128.88, 128.85, 127.20, 127.08, 126.72, 126.58,
120.83 (dd, J = 257.9, 253.1 Hz), 56.81, 54.04 (d, J = 6.6
Hz), 53.17, 44.56, 38.65 (dd, J = 25.1, 20.7 Hz); 19F NMR
(377 MHz, CDCl3) δ -102.17 – -103.37 (m, 1F), -105.35
(ddd, J = 264.0, 12.4, 1.9 Hz, 1F); HRMS (ESI): m/z calcd.
for C19H17F2NNaO+ [M + Na+]: 336.1170, found: 336.1173.
Acknowledgements
We thank the National Basic Research Program of China (No.
2015CB856500) and the Natural Science Foundation of Tianjin
(No. 16JCYBJC20100) and Tianjin University for support of this
research.
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10.1002/adsc.201701643
Advanced Synthesis & Catalysis
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6
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Advanced Synthesis & Catalysis
COMMUNICATION
One-pot
Construction
of
Difluorinated
Pyrrolizidine and Indolizidine Scaffolds via
Copper-Catalyzed Radical Cascade Annulation
Adv. Synth. Catal. Year, Volume, Page – Page
Xiaoyang Wang, Miao Li, Yanyan Yang, Minjie
Guo*, Xiangyang Tang, and Guangwei Wang*
7
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