Transition metal-free functionalized hydration of alkynes: One-pot synthesis of fluorinated β-keto-imidates using Selectfluor

Article abstract of DOI:10.1039/c9ob00527g

A transition metal-free, four-component one-pot synthesis of polyfunctionalized fluorinated β-keto-imidates via the functionalized hydration of alkynes has been described. The intermediate 1,3-ketoamino moiety was obtained from easily accessible arylpropioladehyde and arlyhydroxylamine and was treated with Selectfluor delivering fluorinated β-keto-imidates. A wide variety of functional groups are tolerated under mild reaction conditions and the product applicability is highlighted.

Full text of DOI:10.1039/c9ob00527g

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Hegde, V. B. Makane, B. Sridhar, H. B. Rode, S. A. Patil and R. Dateer, Org. Biomol. Chem., 2019, DOI:
10.1039/C9OB00527G.
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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C9OB00527G
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Transition Metal-Free Functionalized Hydration of Alkynes:
One-Pot Synthesis of fluorinated β-keto-imidates using Selectfluor
Arnab Ghosh,a Rajeev Hegde,a Vitthal B. Makane,b,c Balasubramanian Sridhar,d Haridas B. Rode,b,c
Received 00th January 20xx,
Accepted 00th January 20xx
Siddappa A. Patil,a Ramesh B. Dateer*a
DOI: 10.1039/x0xx00000x
are exclusively studied in recent years.6 In particular, Hammond et
ABSTRACT: The transition metal-free, four-component one-pot
synthesis of polyfunctionalized fluorinated -keto-imidates via
functionalized hydration of alkynes has been described. The
intermediate 1, 3-ketoamino moiety was obtained from easily
accessible arylpropioladehyde and arlyhydroxylamine which was
treated with selectfluor delivering fluorinated β-keto-imidates. The
wide functional groups are tolerated under mild reaction condition
and product applicability is highlighted.
al.7 reported gold-catalyzed regioselective synthesis of fluorinated
1,3-dicarbonyl compounds using alkynyl ketones or esters. The
insertion of hydrogen fluoride take place across gold carbene
generated from cationic gold-catalyzed addition of N-oxides to
alkynyl ketones/esters. (Scheme 1a). While, Marek et al.8 reported
the diastereoselective synthesis of tertiary α-fluorinated carbonyl
compounds from ynamide precursors via stereodefined fully
substituted silyl-ketene hemiaminals intermediate (Scheme 1b). In
addition, Liu et al.9 reports, copper-catalyzed oxidations of 3-N-
hydroxyaminopro-1-ynes with water, alcohols, or thiols to form 3-
β
Introduction
substituted 3-amino-2-en-1-ones via
a formation of nitrone
intermediate (Scheme 1c). It is found that, these types of
transformations have several drawbacks. Therefore, it will be highly
challenging if one can seek to achieve these transformations under
the economical and metal-free conditions.10,11 Moreover,
preparation of synthetically important and biologically active
compounds under transition metal-free condition have gained high
importance in recent years.12 In this context, herein, we report the
transition metal-free one-pot synthesis of 3-substituted 3-imino-2-
fluoro 1-ones from easily accessible 3-phenylpropiolaldehyde and
N-phenylhydroxylamine. In this functionalized hydration of alkynes,
commercially available alcohols acts as a nucleophile while
The introduction of fluorine element in the organic molecule
has always been an important endeavor for drug designing
purposes. Nevertheless, organic compounds containing
fluorine next to the amino, imino and ketone functionalities
have been found in anticancer, anticholinergic, anti-
inflammatory drugs, and therapeutic
β
-peptides1-3 (fig 1).
Accordingly, their synthesis has captivated much attention
resulting in numerous strategies for its construction.4,5
Figure 1. Biologically active fluorinated drug molecules.In this line,
despite of various approaches for fluorinated compound synthesis,
transition metal-catalyzed transformations using internal alkynes
Scheme 1. Synthesis of functionalized fluorinated compounds
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Selectfluor serves as electrophilic fluorine source. It is confirmed Surprisingly, change of solvent to dry THF exclusively furnishes 3a in
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DOI: 10.1039/C9OB00527G
that, the present alkyne hydration proceeds via in-situ generated 3- 91% yield (entry 4), while other solvents such as 1,4-dioxane,
substituted 3-amino-2- en 1-ones intermediate which is formed by dichloromethane, acetonitrile are ineffective (See the supporting
Mannich reaction13 between 3-phenylpropiolaldehyde, N- information for details). Furthermore, reaction with reduced
arylhydroxyimine and alcohol. The subsequent addition of amount of MeOH furnishes less yield presumably due to sluggish
Selectfluor to tetrahydrofuran solution furnished the desired 3- reaction process (entries 5 and 6). Notably, in the cases of entries 7
substituted 3-imino-2-fluoro 1-ones.
and 8, once the intermediate 3a is formed (indicated by TLC),
We commenced our studies by examining the reaction Selectfluor (1.2 equiv) was added to the THF solution under
parameters in a reaction of 3-phenylpropiolaldehyde 1a (0.5 mmol) nitrogen atmosphere and the newly formed 3-substituted 3-imino-
◦
and N- phenylhydroxylamine 2a (0.55 mmol) in THF (3.0 mL) solvent 2-fluoro 1-ones compound 5a was obtained (50 C, 12 h) 81% and
at 25 ◦C. It is observed that, in absence of nucleophile, the 72% yield respectively. The NOE study of 5a indicates that, the
formation of undesired β-oxoamide 3a’ takes place up to 67% in 24 geometry (E or Z) of N-penyl ring of 5a is unspecified and therefore
h likely due to trace amount of water present in solvent, while it is shown by wavy bond.15a It is observed that, the newly formed
azoxybenzenes (4) was obtained as a side product due to the
β-keto-imidates are stable in air while prolonged storage cause slow
imine hydrolysis due to atmosperic moisture. In the later stage, the
reactions with change in nucleophile to ethanol furnishes desired
product 5b in 44% yileld (entry 9), while other nucleophile such as t-
BuOH, n-BuOH, i-PrOH, PhOH, and BnOH found to be inefficient
presumably due to steric and electronic properties (entries 10–14)
of these alcohols.15b
Table 1. Optimization of reaction condition arylaldehydea
With the optimal conditions in hand (Table 1 entry 7), we first
scrutinized the scope of 3-phenylpropiolaldehyde bearing various
substituents in reactions with 2a using MeOH as a nucleophile.
Phenylpropiolaldehyde with an electron withdrawing group such as
4-chloro, 4-fluoro, 2,6-difluoro, 4-nitro works efficiently providing
fluorinated compounds (5c–5f) in 79–84% yields; while, 2-fluoro
phenylpropiolaldehyde furnishes the inseparable mixture of desired
product 5g along with its ester analogue 5g’ mainly due to
expeditious imine hydrolysis.16 On the other hand, electron donating
substituents such as 4-methoxy, 4-methyl, furnishes desired product
(5h and 5i) albeit in moderate yield. However, replacing the phenyl
S.N
1
ROH (equiv.)
ROH = none
Solvent
t
Compounds
5 (%)b
(h)
3(%)/3a’(%)
Wet toluene
24
3a(0)/3a’(67)
2
MeOH (4)
MeOH (4)
MeOH (4)
MeOH (3)
MeOH (2)
MeOH (4)
MeOH (3)
Wet toluene
Toluene
THF
15
15
6
3a(41)/3a’(26)
3a(56)/3a’(trace)
3a (91)/ 3a’(trace)
3a (76)/3a’(10)
3a (58)/3a’(31)
3
4
5
THF
10
18
6
6
THF
7c
8c
THF
3a(~95)/3a’(trace)5a(81)
3a(~81)/3a’(14) 5a(72)
THF
8
Table 2. Substrate Scope of arylaldehydea
9d
ROH = EtOH
tBuOH(4)
THF
THF
THF
THF
10
15
18
18
3b(58)/3a’(21) 5b(44)
3i(trace)/3a’(38)
10
11
12
n-BuOH (4)
i-PrOH (4)
3ii(trace)/3a’(41)
3iii(10)/3a’(21)
13
14
PhOH (4)
BnOH(4)
THF
THF
18
12
3iv(trace)/3a’(30)
3v(10)/3a’(18)
aReaction conditions: 1a (0.5 mmol), 2a (0.55 mmol), ROH (0 - 4
◦
equiv), molecular sieves (4 Å) in THF (3.0 mL) at 25 C then (in case
of entries 7 and 8) Selectfluor (1.2 equiv) at 50 ◦C. byields are
reported after purification form silica column (average of two run).
cIn these cases, 3a/3a’ are not isolated and their approx. TLC
d
conversion is shown. yields corresponds to Selectfluor addition to
the purified 3b.
decomposition of N-hydroxylamine14 (Table 1, entry 1). To our
delight, the alkyne hydration efficiency was significantly improved,
when MeOH (4 equiv) was employed as a nucleophile and desired
3-substituted 3-amino-2-en 1-ones 3a obtained up to 41% yield
along with 3a’ (26%, entry 2). The compound 3a, 3a’ and 4 are
isolated by column chromatography and confirmed by NMR
spectroscopy. The N-H proton of compound 3a appears at 13.08
ppm in 1H NMR presumably due to the intermolecular H-boding
with carbonyl group. Next, when dry toluene is employed as a
solvent in presence of 4Å MS under nitrogen atmosphere, the yield
of 3a is further increased to 56% with trace of 3a’ (entry 3).
aReaction condition: 1a–1k (0.5 mmol), 2a (0.55 mmol), MeOH (4
equiv), molecular sieves (4 Å) in THF (3.0 mL) at 25 ◦C then Slectfluor
(1.2 equiv) at 50 ◦C. byields are reported after purification form silica
column (average of two run). cyields corresponds to Selectfluor
addition to the purified 3h , 3k
2 | J. Name., 2012, 00, 1-3
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of desired compounds (5l–5n) in 69–78% yields. Interestingly, when
DOI: 10.1039/C9OB00527G
N-(o-tolyl)hydroxylamine is subjected for the reaction under the
moiety of 1 by 1-napthyl group furnishes desired product 5j in 72%
yield. Further, the scope to heterocyclic propioladehyde was
extended wherein 5k was obtained in 30% yield from 3-(thiophen-
2-yl) propiolaldehyde. While the 3-cyclopropylpropiolaldehyde and
hex-2-ynal furnishes the complicated mixture of products. The
fluoro-containing heterocyclic compounds are highly sought in
medicinal chemistry as they contribute in the physicochemical
properties and interactions with the target protein.17 We studied
the interaction of 5k with Epidermal Growth Factor Receptor (EGFR)
kinase, an important target in cancer (Figure 2). 5k occupies the ATP
binding site of kinase and shows H-bond interaction between
compound's carbonyl and methionine 769 of kinase.
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standard condition we have observed shiny crystals of
corresponding intermediate (3o) which is unambiguously confirmed
by X-ray crystallographic analysis indicating that 3-amino and 2-keto
functionalities are cis to each other18 (Fig 3, in dimeric form). Next,
under one-pot condition, compound 5o is obtained 70% yield
showing –CH-F peaks at -189.3 ppm (J = 52 Hz) in 19F- spectroscopy.
Figure-3: Crystal XRD image of 3o(dimer: CCDC1865939)
In continuation, the analogous N-(m-tolyl)hydroxylamine and N-
(p-tolyl)hydroxylamine also furnishes the desired 5p and 5q in 66%
and 69% yield respectively. The reaction with N-alkylhydroxylamine
such as N-(tert-butyl)hydroxylamine and N-isopropylhydroxylamine
furnishes only trace amount of keto-amino products presumably
due to the poor nucleophilicity induced by electron donating
inductive effect of alkyl substituent and therefore analogous
fluorination products are not obtained. Further, we have also tested
the scope of reaction with the nucleophiles tethered with alkyne
functionality such as propargyl alcohol, 3-phenylprop-2-yn-1-ol and
they are found to be ineffective under the standard condition
presumably due to steric and electronic properties. On the other
hand, the electrophile other than selectfluor such as, N-
iodosuccinimide, N- bromosuccinimide, and N-chlorosuccinimide
are ineffective.
Figure 2: interaction of 5k with EGFR kinase. Compound 5k was
docked in EGFR kinase (PDB ID: 1M17)
The scope with other reactants such as N-arylhydroxylamine
(ArNHOH), nucleophiles (ROH), electrophiles (RX) are subsequently
examined (Table 3). Initially, we tested N-phenylhydroxylamine
bearing electron withdrawing substituent such as 4-chloro, 3-chloro,
4-bromo which reacted smoothly leading to the formation
Table 3. Scope with N-arylhydroxylamine, nucleophiles and
electrophilesa
The plausible mechanism of alkyne hydration for the synthesis
of 3-substituted 3-imino-2-fluoro 1-ones is depicted in Scheme 3
The proposed skeletal rearrangement mechanism supported by
literature precedents.9,14
aReaction conditions: 1a (0.5 mmol), 2b–2i (0.55 mmol), ROH (4
Scheme 3. Plausible mechanism for formation of 3a and 5a
equiv), Selectfluor (1.2 equiv), molecular sieves (4 Å) in THF (3.0 mL)
at 25 C then Selectflour (1.2 equiv) at 50 C. yields are reported
after purification form silica column (average of two run).
°
°
b
The condensation of aldehyde 1a and N-phenylhydroxylamine 2a
leads to the formation of N-phenylhydroxylammonium intermediate
I. The subsequent nucleophilic attack of alcohol on the electron
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J. Name., 2013, 00, 1-3 | 3
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Acknowledgements
deficient imine carbon leads to the formation of cyclized
intermediate II. As reported by Liu et al,9 hydride shift followed by
N-O bond cleavage19 leads to the formation of 3-substituted 3-
amino-2- en 1-ones 3a through intramolecular oxygen atom transfer
to alkynes.20 while 3a’ is obtained as a side product. We believe
that, the amide oxygen atom in 3a’ is from trace of water present in
reaction medium but not from atmospheric O2. This is strongly
evidenced by the H2O18 Vs 18O2 labeling study shown by Liu et. al9.
The subsequent treatment of 3a with Selectfluor leads to the
formation of final compound 5a
Our protocol can be scaled up in gram scale without affecting
the chemical yield (eq. 1). In addition, we performed tha acidic
imine hydrolysis of 5a to get synthetically importaint 1,3-β-keto
methyl ester 6.21-22 (see the supporting information for more
details).
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DOI: 10.1039/C9OB00527G
The authors thank, DST-SERB, Government of India, for the financial
support through the research grant: File Nos. SB/S2/RJN-042/2017
and ECR/2017/002207.
Notes and references
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Nevertheless, β-keto imidates are prone to form a stable and
reactive free-radical and anions on the carbon atom which is
between keto and imine group and therefore, they are widely
involved in organic synthesis (Scheme 4). For instance, Gao et al.22c
reported the synthesis of functionalized indole via intramolecular
addition of free radical A to the aryl ring, followed by radical
coupling, deprotonation (Scheme 4 , eq. 1). While, Cui et al.22d
reported the synthesis of functionalized pyridine via stepwise
intramolecular nucleophilic addition on iminoenolate intermediate
B (Scheme 4, eq. 2).
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Scheme 4: Stability and reactivity β-keto imidates
Conclusion
In conclusion, we have developed a transition metal-free
functionalized hydration of alkynes for the synthesis of fluorinated
β-keto-imidates under one-pot reaction condition. The wide range
of substrates is compatible under the reaction condition and
products are obtained in moderate to good yields. The formation of
intermediate, its geometry is confirmed by X-ray crystallography.
The reaction mechanism is well supported by literature evidences
and the products suitability is featured. We are also intending to
utilize fluorinated β-keto-imidates for the synthesis of bioactive
drug like molecules and related investigations are ongoing in our
laboratory.
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Conflicts of interest
“There are no conflicts to declare”.
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20 R. B. Dateer and S. Chang, J. Am. Chem. Soc. 2015, 137, 4908.
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DOI: 10.1039/C9OB00527G
Table of Content
H
Ph
H
O
N
H
MeOH
Selectfluor
50 C
O
Ph
N
O
N
Ph
OMe
+
Ph
OH
Ph
THF, 25 C
Ph
F
OMe
Metal-free, oxidant free, base-free, tansformation O-atom transfer & new C=O, C=N, C-X, C-O bonds
One-Pot, regioselective, polyfunctional product mild condition, high yield, scalable, broad scope