Phosphine-Catalyzed Intermolecular Annulations of Fluorinated ortho-Aminophenones with Alkynones – The Switchable [4+2] or [4+2]/[3+2] Cycloaddition

Article abstract of DOI:10.1002/adsc.201900082

A phosphine-catalyzed intermolecular annulation reaction of functionalized ortho-aminoacetophenones with alkynones has been disclosed in this paper. A variety of 2-alkynylquinolines and benzo-fused indolizine were selectively afforded in moderate to good yields at different reaction temperatures and with different phosphine catalysts via the in situ generated zwitterionic intermediate derived from alkynone and phosphine. (Figure presented.).

Full text of DOI:10.1002/adsc.201900082

Title: Phosphine-Catalyzed Intermolecular Annulations of Fluorinated
ortho-Aminophenones with Alkynones - The Switchable [4+2] or
[4+2]/[3+2] Cycloaddition
Authors: Min Shi, Yanshun Zhang, Yao-Liang Sun, and Yin Wei
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900082
Link to VoR: http://dx.doi.org/10.1002/adsc.201900082

10.1002/adsc.201900082
Advanced Synthesis & Catalysis
UPDATES
DOI: (will be filled in by the editorial staff)
Phosphine-Catalyzed Intermolecular Annulations of Fluorinated ortho-
Aminophenones with Alkynones - The Switchable [4+2] or [4+2]/[3+2]
Cycloaddition
Yanshun Zhang,a Yaoliang Sun,a Yin Weib and Min Shi a,b,c*
a Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular Engineering,
East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, People’s Republic of China
b State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, University of Chinese
Academy of Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling Ling Road,
Shanghai 200032, People’s Republic of China
c State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P.R. China.
Fax: (+86)-21-6416-6128; e-mail: mshi@mail.sioc.ac.cn.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http:// /adsc.201######.((Please delete if not
appropriate))
compounds has witnessed significant progress.[13] The phosphine-
Abstract:
A phosphine-catalyzed intermolecular annulation
catalyzed cycloadditions of electron-deficient alkenes,[14]
allenes[15] and alkynes[16] with a variety of electrophiles have been
well established on the basis of pioneering work of Lu,[17] Lu,[14c-f,
reaction of functionalized ortho-aminoacetophenones with
alkynones has been disclosed in this paper. A variety of 2-
alkynylquinolines and benzo-fused indolizine were selectively
afforded in moderate to good yields at different reaction
temperatures and with different phosphine catalysts via the in situ
generated zwitterionic intermediate derived from alkynone and
phosphine.
15d, 15e, 18]
13e, 15a, 15b, 15f, 16a, 19]
16i, 19-20]
Kwon,[13c,
Huang,[14g,
Marinetti,[15c, 19] Guo,[16h, 19] Zhang[13g, 14h, 16b] etc. It is a powerful
tool in the rapid construction of complex molecules such as aza-
[16a, 21]
23]
or oxaheterocycles,[22] fused aromatic rings,[21b,
polycyclic compounds[16i, 24] and bridged-ring structures.[25] In this
aspect, alkynones are getting more and more applications in
phosphine catalysis because of their unique reaction properties in
nucleophilic additions or the related annulations.[20, 26]
Keywords:
phosphine
catalyst;
cycloaddition;
2-
alkynylquinoline; benzo-fused indolizine derivatives
Quinoline and benzo-fused indolizine derivatives have
attracted a substantial amount attention from organic chemists
because of their wide range of pharmacological and biological
characters such as antibacterial, antiamoebic, antiviral, anticancer,
antimalarial, and anti-inflammatory properties.[1] More
importantly, in modern pharmaceutical chemistry, the fluorine
atom-containing functional groups play
a crucial role in
improving physical and chemical properties of biologically active
molecules such as membrane permeability, bioavailability and
metabolic stability.[2] Thus far, a variety of facile and one-pot
synthetic protocols for the preparation of functionalized quinoline
and indolizine scaffolds have been developed. Among classical
synthetic methods leading to these pivotal quinoline heterocyclic
scaffolds, the well known Skraup reaction,[3] Combes synthesis,[4]
and Friedländer reaction[5] are frequently used. Recently, the
transition-metal-catalysts such as Ru,[6] Co,[7] Mn[8] etc have been
also applied for the synthesis of quinoline derivatives via cascade
dehydrogenation and condensation processes. For benzo-fused
indolizine derivatives, various transition-metal-catalysis related
synthetic methodologies have been also reported via nickel-,[9]
palladium-[10] or indium-[11] catalyzed coupling reactions. In
addition, due to the rapid development of photoredox catalysis,
alternative synthetic approach to obtain indolizine derivatives via
direct amination of aromatic compounds by in situ generated
aminium radicals has been also explored.[12] However, the
phosphine-catalyzed reactions to synthesize quinoline and
indolizine scaffolds are scarcely reported.
Scheme 1. Phosphine-Catalyzed Annulations of Alkynones
Previously, we disclosed a novel strategy for the phosphine-
catalyzed cycloaddition/SN2 substitution domino reaction
triggered by the zwitterionic intermediates A and B derived from
triaryl phosphine and alkynone, giving functionalized O-bridged
benzoazepine and benzoxazepine derivatives in one step in
moderate to good yields by changing the N-H protecting group of
fluorinated ortho-aminoacetophenone derivatives (Scheme 1,
27]
previous work).[25c,
We envisaged that the diverse proton
During the last decade, the development of phosphine-
catalyzed reactions to synthesize carbo- and heterocyclic
transfer of zwitterionic intermediate A could trigger different
1
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10.1002/adsc.201900082
Advanced Synthesis & Catalysis
reaction pathways. For example, zwitterionic intermediate C
could be also generated from intermediate A, which may act as a
base for deprotonation of alkynone 2a to produce an enolate,
affording 2-alkynylquinolines through an aldol condensation with
we investigated a variety of additives such as K2CO3, DMAP, and
MgSO4 in this reaction and found that none of these additives
could improve the reaction outcomes (entries 17-19). Adding 100
mg of 3Å MS as an additive afforded 3aa in 70% yield (entry 20).
Diluting the reaction solution by carrying out the reaction in 1.0
mL of toluene was beneficial to the reaction proceeding, giving
3aa in 76% NMR yield and 75% isolated yield perhaps due to that
carrying out the reaction at lower concentration could suppress
the formation of the byproducts (entries 21 and 22) (see Table S1
in the Supporting Information for more information). Thus, the
optimal conditions are identified as that carrying out the reaction
ortho-aminoacetophenone
1.
could undergo
attack, cycloaddition
Furthermore,
cascade intermolecular
and intramolecular
zwitterionic
intermediate
nucleophilic
B
a
condensation to afford the corresponding pyrrolo[1,2a]quinoline
products, which are one of benzo-fused indolizine derivatives
(Scheme 1, this work). Herein, we wish to report the novel
synthetic strategy for the preparation of fluorinated quinoline and
indolizine derivatives via phosphine-catalyzed reaction of ortho-
aminoacetophenone with alkynone.
o
of 1a (1.0 equiv) with 2a (4.0 equiv) in toluene (1.0 mL) at 0 C
for 6 h in the presence of dppb (20 mol %) using 3Å MS (100 mg)
as an additive.
Table 1. Optimization of the reaction conditions for the synthesis
of 3aa
With the optimized reaction conditions in hand, we next
turned our attention to examine the substrate scope, and the
results are summarized in Scheme 2. As can be seen, for
substrates 1a-1h containing either electron-deficient or electron-
rich aromatic rings, the reactions proceeded efficiently, affording
the desired products 3aa-3ha in moderate to good yields ranging
from 59% to 78%. These results suggested that the electronic
property of substituent on the aromatic ring did not have
significant impact on the reaction outcome. The structure of 3aa
has been unambiguously determined by X-ray diffraction. The
ORTEP drawing is shown in Scheme 2 and the CIF data are
presented in the Supporting Information. Moreover, using 3-
(2,2,2-trifluoroacetyl)-2-naphthylamine 1i as substrate gave the
desired product 3ia in 68% yield. Then, the substituent in acyl
group was investigated. Substrates 1j and 1k, in which R2
=
CF2Cl and CF2CF3, could give the targeted products 3ja and 3ka
in 65% and 63% yields, respectively. The reaction also indicated
good substrate compatibility for alkynone derivatives. Substrate
1a could react with a variety of alkynones 2, in which R3 = H,
aromatic group, n-Bu or cyclopropyl group, affording the
corresponding products 3ab-3ag in moderate to good yields
ranging from 54%-70%. However, no reaction occurred, when R3
was a sterically bulky group such as t-Bu (alkynone 2h) and TMS
groups (alkynone 2i) (for more information, see Table S3 in the
Supporting Information). Next, the substituent effect of R4 group
was also examined. When R4 was a methyl group, the reaction
proceeded smoothly to give the product 3aj in 45% yield.
Nevertheless, the reaction of substrate 1a with alkynone 2k, in
which R4 was a phenyl group, should be carried out at room
temperature for 12 h, affording the corresponding product 3ak in
33% yield.
We initiated the investigation on the reaction of 1a (1.0
equiv) and 2a (2.0 equiv) in toluene (0.5 mL) in the presence of
dppb (20 mol %) at room temperature, and found that the desired
product 3aa was given in 43% yield after 4 h (Table 1, entry 1). A
series of other phosphine catalysts such as PPh3, P(p-CF3C6H4)3,
P(p-CH3OC6H4)3 and dppp were screened, affording desired
product 3aa in lower yields along with recovery of 1a (entries 2-
5). Using nitrogen-containing Lewis base DABCO or DMAP and
inorganic base such as K2CO3 as the catalyst, 3aa was produced
in lower yields (see Table S1 in the Supporting Information for
more information). These examinations suggested that dppb was
the best catalyst presumably due to that this bisphosphine catalyst
might play a dual role in this transformation by using one
phosphorus atom for the nucleophilic addition to alkynone and
another phosphorus atom to promote the isomerization of the
formed intermediate. The examination of reaction temperature
revealed that carrying out the reaction at 0 oC, the yield of product
3aa could be improved to 57% (entries 6-8). Encouraged by these
results, we next probed the solvent effect and identified that
toluene was the best solvent of choice (entries 9-12). The loading
amount of 2a and the reaction time were then examined, and the
results indicated that the use of 4.0 equiv of 2a could improve the
yield of 3aa to 63% within 6 h and further lengthening the
reaction time did not improve the yield (entries 13-16). After that,
2
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10.1002/adsc.201900082
Advanced Synthesis & Catalysis
Scheme 2. Substrate scope for the production of 3.[a],[b]
During the optimization of the reaction conditions, we found
that the benzo-fused indolizine product 4a could be produced at
70 oC in 23% yield if using P(p-FC6H4)3 as the catalyst. Then, the
further screening of the reaction conditions was carried out (for
more information, see Table S2 in the Supporting Information).
Finally, the best condition was identified as that using 1a (1.0
equiv) and 2a (3.0 equiv) as substrates, P(p-FC6H4)3 (30 mol %)
Scheme 3. Substrates scope of the synthesis of 4.[a],[b]
On the basis of our experimental results and the previous
reports, the plausible catalytic cycles of these annulation reactions
have been outlined in Scheme 4. The reaction is initiated with the
addition of phosphine to hex-3-yn-2-one 2a, affording the
zwitterionic intermediate I in situ. The intermediate I undergoes
α, α’-H shift and enolization to give intermediate II at low
o
as catalyst the reaction was carried out in 1,4-dioxane at 140 C
for 72 h.
Then, we explored the generality of this reaction and the
results are summarized in Scheme 3. Most of ortho-
aminoacetophenone derivatives could be used in the reaction
under the optimal conditions, giving the desired products 4 in
moderate yields. It was obvious that the electronic properties of
substituents on the aromatic ring of substrates 1 did not have
significant influence on the reaction outcome. Regardless of
whether R1 was an electron-withdrawing group or an electron-
donating group, the reactions could proceed under the optimal
conditions smoothly, giving the targeted products 4a-4h in
moderate yields ranging from 33%-56%. The structure of 4a has
been also confirmed by X-ray diffraction and its ORTEP drawing
is shown in Scheme 3. The 3-(2,2,2-trifluoroacetyl)-2-
naphthylamine 1i was also tolerated in this transformation,
affording 4i in 47% yield. We also attempted to use CF2Cl instead
of CF3 (substrate 1j) and the corresponding product 4j was
obtained in 45% yield. However, when R2 was a CF2CF3 group
(substrate 1k), the reaction failed to give the desired product 4k.
If R1 was a sterically bulky group such as tert-butyl group, the
desired product 4l was only generated in 15% yield. Using
alkynone 2f as substrate did not afford the corresponding product
4af.
o
temperature (0 C ~ room temperature), which probably works as
a Brønsted base to abstract a proton from substrate 2a, giving α’-
carbanionic specie II" and enol II' to re-entry into the catalytic
cycle (path A). On the other hand, the intermediate I can also act
as a base to directly abstract a proton from 2a, giving specie II"
(path B). However, due to its lower basicity as compared with the
intermediate II,[20] path A is suggested as the major pathway. The
reaction of substrate 1a with specie II" provides another
intermediate III, which undergoes protonation with enol II' or 2a
to give intermediate IV. It is obvious that excess amount of 2a is
required to generate the reactive species II'. Dehydration of
intermediate IV can afford an intermediate V, which produces the
desired product 3aa via an intramolecular condensation process.
At higher temperature, the zwitterionic intermediate
I
undergoes α, γ-H shift to afford intermediate VI, which can
experience another H-shift to give an intermediate VII (δ-
activation). The reaction of 1a with the intermediate VII provides
an intermediate VIII, which goes through an intramolecular
proton migration to give intermediate IX. The intramolecular
cyclization of intermediate IX generates an intermediate X, which
can undergo α, β-proton shift to give an intermediate XI. The
elimination of phosphine catalyst from the intermediate XI
produced the corresponding compound 5, which finally affords
the desired product 4a via a Knorr reaction pathway.[28]
3
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10.1002/adsc.201900082
Advanced Synthesis & Catalysis
Scheme 4. Proposed reaction mechanism.
To verify the proposed reaction pathways, the NMR
drawing is illustrated in Scheme 5. The control experiment
indicated that 5 could be transformed to the desired product 4a at
140 oC (Scheme 5, eq 2), suggesting that the reaction might
indeed proceed through the reaction pathway shown in Scheme 4.
spectroscopic tracing experiments (Figure 1) and the control
experiments (Scheme 5) were conducted. Firstly, dppb (9.0 mg,
0.02 mmol) was added into a NMR tube and dissolved in toluene-
D8 (1.0 mL). In its 31P NMR spectrum, signal A was the signal of
dppb. Then hex-3-yn-2-one 2a (44 μL, 0.1 mmol) was added;
dppb attacked to 2a to generate vinyl phosphonium, which led to
the signal B’s appearance after 20 minutes. As the reaction
proceeding, signal B increased along with the decrease of signal
A. After 50 minutes, the signal C appeared, suggesting that the
intermediate of signal B started the transformation into another
intermediate. Meanwhile, with the decrease of signal B, the
reaction of dppb and alkynone was accelerated, which was shown
in the spectroscopic data: the signal A was significantly decreased,
the signal B was invariant and the signal C was increased. The
results of 31P-NMR tracing experiments suggest that the reaction
started from the addition of dppb to alkynone and generated
another active species to react with substrate 1.
Scheme 5. Control experiments to investigate the reaction
mechanism.
In summary, we have disclosed a novel and switchable
phosphine-catalyzed
annulation
reactions
of
ortho-
aminoacetophenone derivatives with alkynones to synthesize 2-
alkynylquinoline and indolizine derivatives at different reaction
temperatures and using different phosphine catalysts. In these
reactions, the α’- or δ-carbon addition of alkynone to ortho-
aminoacetophenone derivative could be adjusted by changing
catalyst and reaction temperature to provide the corresponding
products in moderate to good yields. The broad substrate scope
and the significance of the cyclized products revealed the
potential value of this novel synthetic strategy. Further efforts are
in progress to investigate the mechanistic details and to use these
methodologies in the synthesis of biologically active molecules.
Experimental Section
Figure 1. 31P-NMR spectra of tracing experiments
General Procedure for Synthesis of 3
Next, we found that the compound 5 could be isolated as a
1:1 diastereoisomers in 60% yield at 70 oC under otherwise
identical conditions (Scheme 5, eq 1). Its structure has been
confirmed by X-ray diffraction, and the corresponding ORTEP
To an oven-dried 10 mL schlenk tube was added anhydrous
3Å M.S. (300 mg), ortho-aminoacetophenone 1 (0.3 mmol, 1.0
4
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10.1002/adsc.201900082
Advanced Synthesis & Catalysis
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equiv.), dppb (0.06 mmol, 20 mol%), then the tube was evacuated
and backfilled with argon for 3 times. Anhydrous toluene (3 mL)
was added under argon protected atmosphere, and the solution
o
was cooled to 0 C. After the tube was added alkynone 2 (1.2
mmol, 4.0 equiv.), the resulting mixture was stirred at 0 oC for 6 h.
Upon reaction completion, the mixture was filtered through a
celite. The filtrate was concentrated and then the residue was
purified by a column chromatography to afford the products 3.
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General Procedure for Synthesis of 4
To an oven-dried 10 mL sealing tube was added ortho-
aminoacetophenone 1 (0.3 mmol), P(p-FC6H4)3 (0.09 mmol), then
the tube was evacuated and backfilled with argon for 3 times.
Anhydrous 1,4-dioxane (3 mL) and alkynone 2a (1.2 mmol) was
added under argon protected atmosphere. After that, the mixture
was stirred for 72 h at 140 oC. Upon reaction completion, the
mixture was filtered through
a celite. The filtrate was
concentrated under reduced pressure and the residue was purified
by a silica gel flash chromatography to afford the products 4.
Supporting Information Available
Detailed descriptions of experimental procedures and their
spectroscopic data as well as the crystal structures are presented in
the Supporting Information. CCDC 1548476 (3aa), CCDC
1543823 (4a) and CCDC (1842979) (5) contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Center via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
We are grateful for financial support from the National Basic
Research Program of China [(973)-2015CB856603], the Strategic
Priority Research Program of the Chinese Academy of Sciences
(Grant No. XDB20000000) and sioczz201808, and the National
Natural Science Foundation of China (Nos. 20472096, 21372241,
21572052, 20672127, 21421091, 21372250, 21121062,
21302203, 20732008, 21772037, 21772226 and 21861132014),
and the Fundamental Research Funds for the Central Universities
222201717003.
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