A Multiheteroatom [3,3]-Sigmatropic Rearrangement: Disproportionative Entries into 2-(N-Heteroaryl)methyl Phosphates and α-Keto Phosphates

Article abstract of DOI:10.1021/acs.orglett.7b02852

A novel multiheteroatom (N, O and P) [3,3]-sigmatropic rearrangement is disclosed, based on two important types of organophosphates, 2-(N-heteroaryl) methyl phosphates and α-keto phosphates, being accessed smoothly and efficiently.

Full text of DOI:10.1021/acs.orglett.7b02852

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
A Multiheteroatom [3,3]-Sigmatropic Rearrangement:
Disproportionative Entries into 2‑(N‑Heteroaryl)methyl Phosphates
and α‑Keto Phosphates
Yongkang Yang,†,‡ Chen Qu,§ Xiaolan Chen,*,† Kai Sun,† Lingbo Qu,† Wenzhu Bi,† Hao Hu,† Rui Li,†
Chunfeng Jing,† Donghui Wei,† Shengkai Wei,† Yuanqiang Sun,*,† Hui Liu,† and Yufen Zhao†,‡
†College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450052, China
‡Department of Chemistry, Xiamen University, Xiamen 361005, China
§Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, Indiana 46556, United States
S
* Supporting Information
ABSTRACT: A novel multiheteroatom (N, O and P) [3,3]-sigmatropic
rearrangement is disclosed, based on two important types of organo-
phosphates, 2-(N-heteroaryl) methyl phosphates and α-keto phosphates,
being accessed smoothly and efficiently.
[3,3]-Sigmatropic rearrangements are among the most power-
ful intramolecular reactions in organic synthesis.1 Since the
discovery of the Claisen rearrangement by Rainer Ludwig
Claisen in 1912, a number of different variants of [3,3]-
rearrangement have been developed, including the well-known
Cope rearrangement and Chen−Mapp reaction.2 Here, we
report a novel multiheteroatom (N, O, and P) variant of [3,3]-
sigmatropic rearrangement, by means of which two synthetic
strategies have been developed and successfully applied to the
synthesis of two important types of organic compounds, 2-(N-
heteroaryl) methyl phosphates and α-keto phosphates (Scheme
1).
metallics (or arylboronic acids or arylsilanes) is one of the most
straightforward methods currently available for synthesizing
diphenylmethanes,6 a class of biologically and pharmaceutically
important compounds.7 Traditional approaches into benzyl
phosphates use nucleophilic substitution reactions of benzyl
alcohol with dialkylchlorophosphates [(RO)2P(O)−Cl] in the
presence of base (sometimes metal catalysis is needed) as
shown in Scheme 2a.8a,b In 2005, the Jones group developed a
similar method via copper-catalyzed phosphorylation of benzyl
Scheme 2. Comparison with Previous Work
Scheme 1. A [3,3]-Sigmatropic Rearrangement Route into
Ketol Phosphates and Heteroarylmethyl Phosphates
Organophosphates have extensive applications in the fields of
agrochemicals and pharmaceutical chemistry as well as
industrial chemistry.3 Organophosphate motifs also widely
exist in a variety of biological molecules, such as DNA, RNA,
ATP, lipids, etc.4 Among numerous organophosphate deriva-
tives, benzyl phosphates are often seen as important synthons
in synthetic chemistry.5 For example, the metal-catalyzed cross-
coupling reaction of benzyl phosphates with aryl organo-
Received: September 12, 2017
© XXXX American Chemical Society
A
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Letter
alcohol with N-phosphoryl oxazolidinones (Scheme 2b).8c In
2014, Tang’s group developed a metal-free approach toward
benzyl phosphates via reactions of substituted toluenes with
dialkyl H-phosphonates in the presence of Bu4NI and TBHP
(Scheme 2c).8d Especially worth mentioning here is that all the
above-mentioned approaches focused mainly on synthesizing
benzyl phosphates. However, there are still no efficient
approaches available for synthesizing heteroarylmethyl phos-
phates, another important class of arylmethyl phosphates.
According to the literature, heterocycles are found in more than
90% of the new synthetic compounds with biological activity.9
Quinolines, pyridines, quinoxalines, thiazoles, and benzothia-
zoles are among the most common heterocycles employed in
medicinal and agricultural chemistry. Considerable effort has
been dedicated to their synthesis and functionalization in the
past.10 Thus, facile and efficient synthetic methods toward
diverse N-heteroarylmethyl phosphates are valuable. Here, we
disclose a practical and simple synthetic method (Scheme 2d),
by which a large variety of new N-heteroarylmethyl phosphates
were prepared by the one-pot reaction of 2-methyl-
heteroaromatic N-oxides with dialkyl H-phosphonates in the
presence of CCl4 and Et3N.
Scheme 3. Scope of the Phosphorylation of 2-
Methylheteroaromatic N-Oxides
a b
,
We initiated our study by establishing optimal experimental
conditions using the model reaction of 2-methylquinoline N-
oxide (1a) with diethyl H-phosphonate (2a) in the presence of
CCl4 for 5 h, as summarized in Table S1. After intensive
experimentation, the optimal reaction conditions were
established as follows: 1a (0.5 mmol), 2a (5 equiv), Et3N (4
equiv), and CCl4 (0.5 mL) were mixed in THF at 70 °C for 5 h
(yield 83%).
a
Reaction conditions: 1 (0.5 mmol), 2 (5 equiv), Et3N (4 equiv), CCl4
b
(0.5 mL), THF (5.0 mL) for 5 h. Isolated yields. * New compound.
Having the optimal conditions in hand, we next examined
the reaction scope with various 2-methylheteroaromatic N-
oxides and organophosphorus reagents (Scheme 3). As can be
seen, seven organophosphorus reagents, including diethyl-,
dimethyl-, diisopropyl-, dibutyl-, diisobutyl-, and dibenzyl-H-
phosphonates as well as ethyl phenylphosphinate, reacted
smoothly with 2-methylquinoline N-oxide itself, giving the
resulting (quinolin-2-ylmethyl) phosphates in good to
satisfactory yields (3a−3g). Meanwhile, a series of substituted
2-methylquinoline N-oxides reacted well with diethyl H-
phosphonate, affording the corresponding phosphates in
moderate to good yields (3h−3n). Electronic effects were
examined in cases of 3h−3m. Electron-donating groups (Me,
MeO) in the C6 position of quinoline ring resulted in relatively
high yields (80% and 83%, respectively, 3h−3i), whereas
electron-withdrawing groups (F, Cl, Br, and NO2) gave
relatively low yields (3j−3m), with the most strongly
electron-withdrawing nitro group giving the lowest yield
(62%, 3m). In comparison with diethyl H-phosphonate as in
the cases of 3j−3l, when three substituted 2-methylquinoline
N-oxides bearing F, Cl, and Br reacted with diisobutyl H-
phosphonate, another phosphorus reagent, relatively high yields
were obtained (3o−3q). The method also worked well with 1-
methylisoquinoline N-oxide (3r). To our surprise, this
chemistry also proceeded well with many other 2-methyl-
heteroaromatic N-oxides. For example, 2-methylpyridine N-
oxide was capable of reacting with all the different phosphorus
reagents mentioned above, affording the required phosphates
3s−3u in good yields. 2,3-Dimethylquinoxaline N-oxide was
capable of reacting with diethyl H-phosphonate, affording 3v in
good yield (80%). Moreover, thiazole, benzothiazole, and
differentially substituted benzothiazoles were all suitable for
reacting with diethyl H-phosphonate, affording 6a−6e in good
yields. Among the 27 N-heteroarylmethyl phosphates synthe-
sized, 24 are new compounds.
A mechanism based upon literature precedents is proposed
as depicted in Scheme 4. According to the Atherton−Todd
Scheme 4. Proposed Mechanism
reaction,11 dialkyl H-phosphonate 2 initially reacts with CCl4
and Et3N to form dialkylchlorophosphate 2′. Following that,
nucleophilic addition−elimination of 2-methyl quinolone N-
oxide 1 to 2′ would give positively charged intermediate I
together with a chloride anion. Et3N removes the acidic
hydrogen in I, giving neutral intermediate II which undergoes
spontaneous [3,3]-rearrangement leading to the formation of
dialkyl quinolin-2-ylmethyl phosphate 3. The [3,3]-rearrange-
ment is presumably driven by the fact that such a rearrange-
ment can restore the energetically favorable aromatic frame-
work of quinoline.
The mechanism was also investigated using the Gaussian 09
program. All the structures were optimized at the ωB97XD/6-
311++(d, p) level in THF solvent using the integral equation
formalism polarizable continuum model (IEF-PCM), then the
corresponding frequency calculations at the same level were
carried out for the Gibbs free energy correction, and more
B
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details can be found in the Supporting Information. As shown
wide scope of products (for a detailed comparison of Koser’s
method with this method, see Supporting Information).
Recently, Ahmed reported an approach toward α-keto
phosphates, starting from dialkyl H-phosphonates addition
into 1,2-dicarbonyl compounds, followed by C−P to O−P
rearrangement promoted by a strong base.13g The method
reported is milder and more practical and thus offers an elegant
and practical alternative to the best available chemistry.
in Figure 1, the cation I+ is deprotonated by Et3N forming
In 2000, Goldstein et al. developed a synthetic method for
nitrone from ketone and MeNHOH.14 Starting from this
synthesis, we set up our model reaction to screen the optimal
reaction conditions, in which acetophenone 4a was first
employed as the starting substrate to react MeNHOH to
form nitrone 4a′. After filtration and evaporation, the reaction
residue was then treated with (MeO)2P(O)H 2b and CCl4 for
5 h to afford the α-keto phosphate 5a (for details concerning
optimization of reaction conditions, see Table S2). The optimal
reaction conditions were finally established as follows: to be 4a
(0.5 mmol), 2b (5 equiv), Et3N (5 equiv), and CCl4 (0.5 mL)
were mixed in THF at 25 °C for 5 h (yield 95%).
With the optimal reaction conditions in hand, we next set out
to examine substrate scope, as shown in Scheme 6. It can be
Figure 1. Energy profiles of the organic reaction (energy: kcal/mol,
distance: Å); superscript “a” represents adding the energy of Et3N, and
superscript “b” represents adding the energy of Et3NH+.
a b
,
Scheme 6. Scope of the Phosphorylation of Nitrones
intermediate II via transition state TS1, and then the
intermediate II dissociates with Et3NH+ to generate inter-
mediate III, which can be structurally transformed to product P
via transition state TS2. The energy barrier of the whole
process should be the energy difference between the reactants
and transition state TS2, which is 22.7 kcal/mol, indicating the
process can occur smoothly under the experimental conditions.
Thus, far, efforts to locate the corresponding transition states
when the Me group of I is changed to the Et group have been
unsucessful. Attempts to experimentally observe the rearrange-
ment with 2-ethylpyridine or quinoline systems have also been
unsuccessful to this point.
We next set out to test the scope of this novel type of [3,3]-
sigmatropic rearrangement. Scheme 5 shows that this method
a
Reaction conditions: 4 (0.5 mmol), MeNHOH·HCl (1.5 equiv),
NaOAc (3 equiv), EtOH (1 mL) at 25 °C for 3 days; filtration and
solvent removal by vacuum evaporation; addition of 2 (5 equiv), Et3N
(5 equiv), CCl4 (0.5 mL), and THF (5 mL) to the reaction residue, 25
Scheme 5. A New Synthesis toward α-Keto Phosphates
b
°C, 5 h. Isolated yield.
seen that various acetophenones, as well as all of the
phosphorus reagents mentioned above (as shown in Scheme
3), were compatible with the newly developed synthesis,
affording the corresponding α-keto phosphates in good to
excellent yields (5a−5m). Indeed, 2-acetylfuran and 2-
acetylthiophene, as well as propiophenone and 4-phenylbut-3-
en-2-one, are suitable reactants, leading finally to the formation
of the corresponding α-keto phosphates in good to excellent
yields.
Following this, we performed two related scale-ups (gram
level) as shown in Table S3 with the targeted reaction products
(3a and 5a) being obtained in good and excellent yields,
respectively.
can be utilized to access biologically relevant α-keto
phosphates, which serve as sugar analogs and important
precursors for phospholipids and nucleotides.12 Scheme 5
depicts our designed reaction, in which, in the presence of Et3N
and CCl4, nitrone reacts with dialkyl H-phosphonates to give
intermediate A, followed by in situ hydrolysis to yield the target
product α-keto phosphates. Up to this point, only a limited
number of synthetic methods toward α-keto phosphates have
been reported.13 In 1988, Koser et al. successfully developed a
two-step synthetic method toward some α-keto phosphates.13f
By comparison, the new method has some advantages, as it
takes place under mild reaction conditions, with a simple
operating procedure, uses readily available reactants, and gives a
In conclusion, we report a novel multiheteroatom (N, O, and
P) [3,3]-sigmatropic rearrangement, from which two strategies
have been developed for synthesizing both 2-(N-heteroaryl)
methyl phosphates and α-keto phosphates. A wide scope of N-
C
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E. Chem. Res. Toxicol. 2003, 16, 350. (i) Koopmans, G. F.; Chardon,
W. J.; Dolfing, J.; Oenema, O.; Van der Meer, P.; Van Riemsdijk, W.
H. J. Environ. Qual. 2003, 32, 287.
(4) (a) Corbridge, D. E. C. Phosphorus 2000. Chemistry, Biochemistry
& Technology; Elsevier: Oxford, 2000; Chapters 10 and 11.
(b) Verbrugghen, T.; Cos, P.; Maes, L.; Van Calenbergh, S. J. Med.
Chem. 2010, 53, 5342.
heteroarylmethyl phosphates, including quinolin-2-ylmethyl
phosphates, pyridin-2-ylmethyl phosphates, thiazol-2-ylmethyl
phosphates, and benzothiazol-2-ylmethyl phosphates, was
prepared by the one-pot reaction of 2-methylheteroaromatic
N-oxides with dialkyl H-phosphonates in the presence of CCl4
and Et3N in THF for 5 h at 70 °C. The merits of the method
include the use of readily available reactants, the considerable
scope of substrates that are amenable to the chemistry, and the
relatively mild conditions employed for the one-pot synthetic
procedure. Using this approach, a large variety of biologically
relevant α-keto phosphates were smoothly synthesized by
reaction of nitrones with dialkyl H-phosphonates in the
presence of CCl4 and Et3N in THF in one pot for 5 h at
room temperature. Further studies on the applications of this
strategy will be reported in due course.
(5) (a) Yu, C.; Liu, B.; Hu, L. Org. Lett. 2000, 2, 1959. (b) Zhu, Q.;
Tremblay, M. S. Bioorg. Med. Chem. Lett. 2006, 16, 6170.
(6) (a) Adams, C. J.; Bedford, R. B.; Carter, E.; Gower, N. J.;
́
Haddow, M. F.; Harvey, J. N.; Huwe, M.; Cartes, M. A.; Mansell, S.
M.; Mendoza, C.; Murphy, D. M.; Neeve, E. C.; Nunn, J. J. Am. Chem.
Soc. 2012, 134, 10333. (b) Bedford, R. B.; Huwe, M.; Wilkinson, M. C.
Chem. Commun. 2009, 600. (c) Kofink, C. C.; Knochel, P. Org. Lett.
2006, 8, 4121. (d) McLaughlin, M. Org. Lett. 2005, 7, 4875. (e) Zhang,
P.; Xu, J.; Gao, Y.; Li, X.; Tang, G.; Zhao, Y. Synlett 2014, 25, 2928.
(7) (a) Gangjee, A.; Devraj, R.; Queener, S. F. J. Med. Chem. 1997,
40, 470. (b) Gangjee, A.; Vasudevan, A.; Queener, S. F. J. Med. Chem.
1997, 40, 3032. (c) McPhail, K. L.; Rivett, D. E.; Lack, D. E.; Davies-
Coleman, M. T. Tetrahedron 2000, 56, 9391. (d) Juteau, H.; Gareau,
Y.; Labelle, M.; Sturino, C. F.; Sawyer, N.; Tremblay, N.; Lamontagne,
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02852.
̀
S.; Carriere, M. C.; Denis, D.; Metters, K. M. Bioorg. Med. Chem. 2001,
9, 1977. (e) Rosowsky, A.; Chen, H.; Fu, H.; Queener, S. F. Bioorg.
Med. Chem. 2003, 11, 59. (f) Forsch, R. A.; Queener, S. F.; Rosowsky,
A. Bioorg. Med. Chem. Lett. 2004, 14, 1811. (g) Long, Y. Q.; Jiang, X.
H.; Dayam, R.; Sanchez, T.; Shoemaker, R.; Sei, S.; Neamati, N. J. Med.
Chem. 2004, 47, 2561.
Experimental details and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(8) (a) Jones, S.; Selitsianos, D.; Thompson, K. J.; Toms, S. M. J. Org.
Chem. 2003, 68, 5211. (b) Liu, C. Y.; Pawar, V. D.; Kao, J. Q.; Chen,
C. T. Adv. Synth. Catal. 2010, 352, 188. (c) Jones, S.; Smanmoo, C.
Org. Lett. 2005, 7, 3271. (d) Xu, J.; Zhang, P.; Li, X.; Gao, Y.; Wu, J.;
Tang, G.; Zhao, Y. Adv. Synth. Catal. 2014, 356, 3331. (e) Dempcy, R.
O.; Bruice, T. C. J. Am. Chem. Soc. 1994, 116, 4511.
*E-mail: chenxl@zzu.edu.cn.
*E-mail: sunyq@zzu.edu.cn.
ORCID
(9) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57,
10257.
Xiaolan Chen: 0000-0002-3061-8456
Donghui Wei: 0000-0003-2820-282X
Yufen Zhao: 0000-0002-8513-1354
Notes
(10) Modern Heterocyclic Chemistry; Alvarez-Builla, J., Vaquero, J. J.,
Barluenga, J., Eds.; Wiley: New York, 2011; Vol. 4.
(11) (a) Stawinski, J.; Kraszewski, A. Acc. Chem. Res. 2002, 35, 952.
(b) Gao, Y.; Wang, G.; Chen, L.; Xu, P.; Zhao, Y.; Zhou, Y.; Han, L. B.
J. Am. Chem. Soc. 2009, 131, 7956.
The authors declare no competing financial interest.
(12) (a) Ramirez, F.; Bauer, J.; Telefus, C. D. J. Am. Chem. Soc. 1970,
92, 6935. (b) Ramirez, F.; Marecek, J. F. Synthesis 1985, 1985, 449.
(13) (a) Ramirez, F.; Desai, N. J. Am. Chem. Soc. 1960, 82, 2652.
(b) Ramirez, F.; Bhatia, S.; Bigler, A. J.; Smith, C. P. J. Org. Chem.
1968, 33, 1192. (c) Ramirez, F.; Glaser, S.; Bigler, A. J.; Pilot, J. J. Am.
Chem. Soc. 1969, 91, 496. (d) Ramirez, F.; Marecek, J. F.; Ugi, I. J. Am.
Chem. Soc. 1975, 97, 3809. (e) Stang, P. J.; Boehshar, M.; Lin, J. J. Am.
Chem. Soc. 1986, 108, 7832. (f) Koser, G. F.; Lodaya, J. S.; Ray, D. G.;
Kokil, P. B. J. Am. Chem. Soc. 1988, 110, 2987. (g) Khan, S.; Battula, S.;
Ahmed, Q. N. Tetrahedron 2016, 72, 4273. (h) Saidulu, G.; Kumar, R.
A.; Anitha, T.; Kumar, P. S.; Reddy, K. R. Tetrahedron Lett. 2016, 57,
1648.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the Chinese National
Natural Science Foundation (Nos. 21072178 and 20472076)
and the 2017 Science and Technology Innovation Team in
Henan Province (No. 22120001).
REFERENCES
■
(1) (a) Ilardi, E. A.; Stivala, C. E.; Zakarian, A. Chem. Soc. Rev. 2009,
38, 3133. (b) So, S. M.; Mui, L.; Kim, H.; Chin, J. Acc. Chem. Res.
2012, 45, 1345. (c) Tejedor, D.; Mendez-Abt, G.; Cotos, L.; Garcia-
Tellado, F. Chem. Soc. Rev. 2013, 42, 458. (d) Volchkov, I.; Lee, D.
Chem. Soc. Rev. 2014, 43, 4381. (e) Cannon, J. S.; Overman, L. E. Acc.
Chem. Res. 2016, 49, 2220. (f) Minehan, T. G. Acc. Chem. Res. 2016,
49, 1168. (g) Tejedor, D.; Lopez-Tosco, S.; Mendez-Abt, G.; Cotos,
́ ́
L.; García-Tellado, F. Acc. Chem. Res. 2016, 49, 703. (h) Martín
Castro, A. M. Chem. Rev. 2004, 104, 2939.
(14) (a) Dhainaut, A.; Tizot, A.; Raimbaud, E.; Lockhart, B.; Lestage,
P.; Goldstein, S. J. Med. Chem. 2000, 43, 2165. (b) Song, H. J.; Lim, C.
J.; Lee, S.; Kim, S. Chem. Commun. 2006, 2893.
(2) For selected reviews on [3,3]-rearrangements, see: (a) Lutz, R. P.
Chem. Rev. 1984, 84, 205. (b) Ziegler, F. E. Chem. Rev. 1988, 88, 1423.
(c) Tabolin, A. A.; Ioffe, S. L. Chem. Rev. 2014, 114, 5426.
(3) (a) Neumann, R.; Peter, H. H. Experientia 1987, 43, 1235.
(b) Wink, J.; Schmidt, F. R.; Seibert, G.; Aretz, W. J. Antibiot. 2002, 55,
472. (c) Schultz, C. Bioorg. Med. Chem. 2003, 11, 885. (d) Anastasi, C.;
Quelever, G.; Burlet, S.; Garino, C.; Souard, F.; Kraus, J. L. Curr. Med.
Chem. 2003, 10, 1825. (e) Ducho, C.; Gorbig, U.; Jessel, S.; Gisch, N.;
̈
Balzarini, J.; Meier, C. J. Med. Chem. 2007, 50, 1335. (f) Hecker, S. J.;
Erion, M. D. J. Med. Chem. 2008, 51, 2328. (g) Pradere, U.; Garnier-
Amblard, E. C.; Coats, S. J.; Amblard, F.; Schinazi, R. F. Chem. Rev.
2014, 114, 9154. (h) Segall, Y.; Quistad, G. B.; Sparks, S. E.; Casida, J.
D
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