Fluorinated alkynylphosphonates in C,C-cyclizations: Regioselective formation of polysubstituted fluorinated arylphosphonates

Article abstract of DOI:10.1002/ejoc.201402188

The regioselective C,C-cyclization of selected 1,4-bipolar substrates with fluorinated alkynylphosphonates provided polysubstituted benzenes and naphthalenes in up to 98-% yield. For the case in which tetraethyl ethynylbisphosphonate was used, an unexpected phosphonate-phosphoramidate rearrangement was, for the first time, observed, which occurred in excellent yield. A regioselective synthetic approach towards polysubstituted benzenes and naphthalenes containing a phosphonate and fluorinated groups at the ortho position to each other is reported. By using mild reaction conditions such as K₂CO₃ as the base in refluxing toluene, the target arenes can be isolated in up to 95-% yield within only 10-12 h. Copyright

Full text of DOI:10.1002/ejoc.201402188

Job/Unit: O42188
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Date: 07-05-14 18:34:48
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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402188
Fluorinated Alkynylphosphonates in C,C-Cyclizations: Regioselective
Formation of Polysubstituted Fluorinated Arylphosphonates
Blazej Duda,[a,b] Sergey N. Tverdomed,*[a] Boris I. Ionin,[c] and
Gerd-Volker Röschenthaler*[a]
Keywords: Synthetic methods / Cyclization / Alkynes / Arenes / Fluorine
The regioselective C,C-cyclization of selected 1,4-bipolar
substrates with fluorinated alkynylphosphonates provided
polysubstituted benzenes and naphthalenes in up to 98%
yield. For the case in which tetraethyl ethynylbisphosphon-
ate was used, an unexpected phosphonate–phosphoramidate
rearrangement was, for the first time, observed, which oc-
curred in excellent yield.
fluoroalkyl groups along with phosphonate motifs were
found as additives in elastomer compositions[7] and in pho-
tostabilizers[8] and have been used in ethylene polymeriza-
tion[9] and as antidiabetes agents.[10]
Introduction
The regioselective synthesis of arenes is of significant
interest from synthetic organic chemistry and medicinal
chemistry point of views.[1] Compounds containing arene
functionalities are, therefore valuable in medicine, agricul-
tural, and materials science. Special attention has been paid
to the synthesis of arenes that contain different functional
groups. The selective introduction of various functional
groups into aromatic rings at specified positions to produce
polysubstituted arenes is undoubtedly very desirable and
also if atom-economic synthesis is considered.[1,2]
From a synthetic perspective, polysubstituted arenes have
been mostly synthesized by sequential introduction of par-
ticular substituents by electrophilic and nucleophilic aro-
matic substitutions, transformation of functional groups, as
well as coupling reactions.[1,11] Transition-metal-catalyzed
cyclizations such as [2+2+2][2] and [4+2] Diels–Alder cyclo-
additions[12] of the corresponding unsaturated substrates to
produce aromatic compounds have been well documen-
ted.[13] However, these cycloadditions suffer from poor re-
gioselectivity. Synthetic methods to obtain fluoroalkylar-
enes and/or arylphosphonates are numerous, but they al-
ways suffer from low yields, low atom economy, and low
regioselectivity; furthermore, they involve harsh conditions
and long reaction times.[5a,14] In addition, if two groups are
introduced, the common procedure is to fluoroalkylate or
phosphonylate particular arylphosphonates or fluoroalk-
ylarene precursors, respectively.[14e,15] Inspired by our recent
findings regarding O,C-[16] and N,C-type[17] cyclizations of
fluorinated alkynylphosphonates 3a–e, we turned our atten-
tion to C,C-cyclization to produce polysubstituted fluor-
inated arylphosphonates with high regioselectivity and,
more importantly, to introduce both functional groups
simultaneously at ortho positions to each other.
For example, the so-called acceptor–donor–acceptor[3]
(A–D–A) system on the aryl ring (e.g., 2,4-dicyanoanilines)
has shown important potential in artificial photosynthetic
systems and also in nonlinear optical properties.[4] It is well
documented that incorporating fluoroalkyl or phosphonate
groups into aromatic systems changes their physical, chemi-
cal. and biological properties remarkably.[5] Owing to the
presence of a P–C bond, a phosphonate group is more
stable in a biological environment, and thereby the com-
pound retains its biological properties.[6] Fluorine-contain-
ing groups are more lipophilic than their non-fluorinated
counterparts, and they are also metabolically more stable.[5]
For other instances, aromatic compounds containing
[a] School of Engineering and Science, Jacobs University Bremen,
Campus Ring 1, 28759 Bremen, Germany
E-mail: s.tverdomed@jacobs-university.de
g.roeschenthaler@jacobs-university.de
Results and Discussion
https://www.jacobs-university.de/de/groeschenthaler/
researchgroup
https://www.jacobs-university.de/de/ses/groeschenthaler
[b] Institute für Chemie und Biochemie, Freie Universität Berlin,
Fabeckstrasse 34–36, 14195 Berlin, Germany
[c] Department of Organic Chemistry, St. Petersburg Institute of
Technology (Technical University),
The initial experiment involved the reaction of F3C–
CϵC–P(O)(OEt)2 (3a) with 2-(cyanomethyl)benzonitrile (1)
in the presence of a base, such as K2CO3, in toluene under
reflux (Table 1, entry 2; Scheme 1). Surprisingly, by moni-
toring the progress of the reaction by 19F and 31P NMR
spectroscopy we detected 100% conversion and isolated the
Moskovskii pr 26, 190013 St. Petersburg, Russia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402188.
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B. Duda, S. N. Tverdomed, B. I. Ionin, G.-V. Röschenthaler
SHORT COMMUNICATION
product in 95% yield within only 10 h (Table 1, entry 2). CH2Cl2, and DMSO were screened. A very good conver-
The absence of a base in the reaction mixture did not give sion as well as a short reaction time was found with the use
any results, even after 24 h of refluxing in toluene. In ad- of DMSO (T = 100 °C) according to NMR spectroscopy.
dition, different bases and solvents were screened further Desired 4a was, however, isolated in only 12% yield
(Table 1). Tertiary amines, namely, NEt3, iPr2NEt, and (Table 1, entry 7). Additional signals in the 19F NMR and
DABCO (1,4-diazabicyclo[2.2.2]octane), also provided de- 31P NMR spectra (δP = 0.1 ppm, δF = –80 ppm) suggested
sired naphthalene 4a with comparable results (Table 1, en- the possible decomposition of the intermediates, as well as
tries 8–10). K2CO3 turned out to be the best choice, and it acetylene derivatives. CH2Cl2 turned out to be inefficient,
gave 4a in 95% yield. Notably, the presence of a transition- as it gave only trace amounts of 4a (Table 1, entry 6). More-
metal catalyst [e.g. Pd(OAc)2, CeCl3, CuI] did not promote over, benzene could also be used as a solvent, and it pro-
any reaction between alkyne 3a and 1, and the substrate duced 4a in 85% yield (Table 1, entry 5).
was almost quantitatively recovered. Furthermore, different
Additionally, a 1,4-bipolar substrate, namely, 2-amino-
reaction media including toluene, benzene, acetone, prop-1-ene-1,1,3-tricarbonitrile (2), that can undergo two
possible reaction pathways, N,C-[17] and C,C-cyclizations,
was treated with alkyne 3a. Adopting the optimized reac-
Table 1. Reaction of 1 with alkyne 3a: Screening of the reaction
conditions.[a]
tion conditions (K2CO3/PhCH3/reflux), C,C-cyclization
product 5a was isolated as the only product (Scheme 1).
Notably, 5a was obtained in a higher yield than 4a (Table 1,
entries 1 and 6). The absence of the N,C-cyclization product
in the 19F NMR and 31P NMR spectra suggests that the
C,C-pathway is kinetically and thermodynamically more fa-
vorable. The structure of a benzene derivative was eventu-
ally confirmed by single-crystal X-ray diffraction analy-
sis.[18] The 15N NMR spectrum of 5a showed four charac-
teristic signals at δN = 275.2 (–CN), 266.6 (–CN), 83.1
(–NH2), 72.7 ppm (–NH2).
Studying different alkynes with varied fluorinated
groups, such as –CF3 (3a), –CF2Cl (3b), –CF2Br (3c),
–CF2H (3d), and –C2F5 (3e) upon the C,C-cyclization re-
vealed better results were obtained with more electron-with-
drawing fluorinated groups (Scheme 1). The highest reac-
tion yield with the shortest reaction time was observed for
F3C–CϵC–P(O)(OEt)2 (3a). The –CF2Cl (3b) and –CF2Br
(3c) analogs provided the target products in comparable
yields, but lower than that for 3a (Scheme 1); the –CF2H
Entry Base
Solvent
T
[°C]
Conv.[b] Time Yield[c]
[%]
[h]
[%]
1
2
3
K2CO3
K2CO3
–
toluene
toluene
toluene
benzene
benzene
CH2Cl2
DMSO
25
112
112
25
80
40
100
112
112
112
24
100
–
24
10
24
24
15
24
5
16
17
14
15
95
–
–
85
5
12
71
85
86
4
5
6
7
K2CO3
K2CO3
K2CO3
K2CO3
–
94
16
90
80
92
95
8
9
DABCO toluene
NEt3
toluene
toluene
10
iPr2NEt
[a] General conditions: 1 (5 mmol), 3a (5 mmol), base (6 mmol),
solvent (15 mL). [b] Conversion was established by 19F NMR and
31P NMR spectroscopy. [c] Yield of isolated product.
Scheme 1. The formation of CF2X-substituted arylphosphonates 4 and 5a–e.
2
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Fluorinated Alkynylphosphonates in C,C-Cyclizations
(3d) and –C2F5 (3e) analogs experienced a significant elec- arrangement has, hitherto, not been reported. The structure
tronic and steric effect, respectively (Scheme 1). Such a was additionally confirmed by single-crystal X-ray diffrac-
pattern in the reduction of the reaction yields has been tion analysis (Figure 1).[20] The 15N NMR spectrum of this
found in other cyclizations.[19]
product showed a characteristic doublet at δN = 71.7 ppm
1
To compare the electronic effects of the triple bond with JN,P = 42 Hz and a singlet at δN = 265.9 ppm, which
towards the C,C-cyclization, symmetrically substituted tet- was assigned to the –CN group.
raethyl ethynylbisphosphonate (3f) was employed. Under
the optimized reaction conditions, 3f was treated with 1 and
2 (Scheme 2). The reaction with 2 did not give any results,
even after heating at reflux for 48 h. Interestingly, by moni-
toring the progress of the reaction of 3f with 1 by 31P NMR
spectroscopy, we detected 100% conversion of 3f within
12 h. After purification by column chromatography
(CHCl3/acetone, 5:1 v/v) we isolated unexpected phos-
phonate–phosphoramidate rearrangement product 6 in
90% yield. To the best of our knowledge, a similar re-
We propose, as shown in Scheme 3, that 1 is first depro-
tonated by the base (K2CO3) to form carbanion A, which
then attacks the triple bond through a Michael-type ad-
dition, and this results in derivative B. Conceivable further
rapid deprotonation of B promotes the ring-closure process,
and thus, thermodynamically unstable intermediate C
through four-membered ring D provides rearranged prod-
uct 6.
In the case of fluorinated alkynylphosphonates 3a–e, we
suggest that the cyclization process occurs simultaneous to
the nucleophilic attack of anion AЈ. Thus, imine derivative
E aromatizes to give thermodynamically more stable aro-
matic products 4 and 5a–e (Scheme 4). A Michael ad-
dition[21] product derived from the reaction of AЈ with 3a–
e was not detected by 19F NMR and 31P NMR spec-
troscopy, but additional signals at δF = –59 ppm (alkyne 3a
used, X = F) and δP = 11 ppm can be assigned to non-
aromatic imine derivative E, which could not be isolated.
Scheme 2. Reaction of tetraethyl ethynylbisphosphonate (3f) with 1.
Figure 1. ORTEP image of 6 (blue: N, red: O, orange: P, gray: C).
Scheme 4. Proposed mechanism for the formation of 4 and 5a–e.
Scheme 3. The proposed mechanism for the formation of 6.
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B. Duda, S. N. Tverdomed, B. I. Ionin, G.-V. Röschenthaler
SHORT COMMUNICATION
Conclusions
[1]
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In conclusion, 1,4-bipolar substrates, namely, 2-(cyano-
methyl)benzonitrile (1) and 2-aminoprop-1-ene-1,1,3-tri-
carbonitrile (2), containing an acidic CH2 group were suc-
cessfully utilized in C,C-cyclizations with XF2C–CϵC–
P(O)(OEt)2 (3a–e) to produce desired polyfunctionalized
benzenes 4a–e and naphthalenes 5a–e in up to 98% yield.
By testing different reaction conditions, such as basic medi-
ators (iPr2NEt, DABCO, NEt3, and K2CO3) and solvents
(DMSO, CH2Cl2, benzene, and toluene), we found that the
best results were obtained if the K2CO3/PhCH3/reflux sys-
tem was used. Interesting phosphonate–phosphoramidate
rearrangement product 6 was isolated upon treating 2-
(cyanomethyl)benzonitrile (1) with tetraethyl ethynyl-
bisphosphonate (1f). On the basis of the experimental data,
we proposed a plausible mechanism for such a rearrange-
ment. The reactivity of XF2C–CϵC–P(O)(OEt)2 towards
the carbocyclization was found to be in the order
X=FϾCl≈BrϾH≈CF3.
[3]
[4]
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Experimental Section
General Procedure: XF2C-acetylene 3a–e (5 mmol) was added
slowly to a mixture of 2-(cyanomethyl)benzonitrile 1 or 2-ami-
noprop-1-ene-1,1,3-tricarbonitrile 2 (5 mmol) and K2CO3 (5 mmol)
in dry toluene (20 mL). The solution was then heated at reflux for
an additional 10–16 h. The K2CO3 was filtered off, and the remain-
ing solution was concentrated under reduced pressure. The residue
was purified by flash column chromatography (silica gel; CH2Cl2/
EtOAc, 5:1 v/v).
[10]
[11]
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M. B. Smith, J. March, March’s Advanced Organic Chemistry,
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2014; b) S. N. Tverdomed, J. Kolanowski, E. Lork, G.-V.
Röschenthaler, Tetrahedron 2011, 67, 3887; c) S. N. Tverdomed,
G.-V. Röschenthaler, N. Kalinovich, E. Lork, A. V. Dogadina,
B. I. Ionin, J. Fluorine Chem. 2008, 129, 478.
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4a: Yellowish crystals (95%); m.p. 149–151 °C. 1H NMR
(400 MHz, CDCl3): δ = 1.32 (t, J = 7.1 Hz, 3 H), 1.33 (t, J =
7.0 Hz, 3 H), 4.17 (m, 2 H), 4.19 (m, 2 H), 7.63 (dd, J = 8.2, 1.0 Hz,
1 H), 7.74 (dd, J = 8.0, 1.0 Hz, 1 H), 7.94 (br. s, 2 H), 7.97 (d, J =
[13]
[14]
8.2 Hz, 1 H), 8.24 (d, J = 8.2 Hz, 1 H) ppm. 13C NMR (100 MHz):
1
δ = 16.1 (d, J = 7.3 Hz), 63.1 (d, J = 6.0 Hz), 96.9 (dq, JC,P
=
=
3
3
3
186.6 Hz, JC,F = 1.2 Hz), 98.2 (dq, JC,P = 13.8 Hz, JC,F
1
3
3.9 Hz), 115.9, 122.0, 122.8 (qd, JC,F = 278.3 Hz, JC,P = 5.3 Hz),
3
123.1 (d, JC,P = 14.3 Hz), 127.0, 128.9, 131.5, 133.4, 136.4 (qd,
2
2
2JC,F = 31.8 Hz, JC,P = 6.4 Hz), 155.7 (d, JC,P = 8.7 Hz) ppm.
19F NMR (376 MHz): δ = –53.1 ppm. 31P NMR (161 MHz): δ =
19.3 ppm. HRMS (ESI): calcd. for C16H16F3N2NaO3P [M + Na]+
395.0754; found 395.0766.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details for the synthesis and copies of the 1H
NMR, 13C NMR, 15N NMR, 19F NMR, and 31P NMR spectra of
new compounds along with the crystallographic data for com-
pounds 4a and 6.
[15]
Acknowledgments
B. D. acknowledges Jacobs University Bremen for a doctoral schol-
arship. S. N. T. and G. V. R. are thankful to the Deutsche For-
schungsgemainschaft (DFG) for financial support. The authors are
also grateful to Dr. B. S. Basil for the XRD data analysis and to
Mrs. A. Müller for the mass spectrometry analysis.
[16]
[17]
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Eur. J. Org. Chem. 2012, 3684; b) B. Duda, S. N. Tverdomed,
G.-V. Röschenthaler, Org. Biomol. Chem. 2011, 9, 8228; c) B.
4
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Fluorinated Alkynylphosphonates in C,C-Cyclizations
Duda, S. N. Tverdomed, G.-V. Röschenthaler, RSC Adv. 2012,
2, 9135.
CCDC-981319 (for 5a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[20] CCDC-981320 (for 6) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[21] a) C. F. Nising, S. Bräse, Chem. Soc. Rev. 2012, 41, 988; b) P. R.
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[18]
[19] B. Duda, S. N. Tverdomed, G.-V. Röschenthaler, J. Fluorine
Chem. 2013, 152, 29.
Received: March 4, 2014
Published Online: ᭿
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B. Duda, S. N. Tverdomed, B. I. Ionin, G.-V. Röschenthaler
SHORT COMMUNICATION
C,C-Cyclization
B. Duda, S. N. Tverdomed,* B. I. Ionin,
G.-V. Röschenthaler* ......................... 1–6
Fluorinated Alkynylphosphonates in C,C-
Cyclizations: Regioselective Formation of
Polysubstituted Fluorinated Arylphos-
phonates
A
regioselective synthetic approach
towards polysubstituted benzenes and
naphthalenes containing phosphonate
mild reaction conditions such as K2CO3 as
the base in refluxing toluene, the target
arenes can be isolated in up to 95% yield
within only 10–12 h.
Keywords: Synthetic methods
/ Cycli-
a
zation / Alkynes / Arenes / Fluorine
and fluorinated groups at the ortho pos-
ition to each other is reported. By using
6
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