Catalytic phosphonylation of C=X electrophiles
A method for the catalytic phosphonylation of C = X electrophiles has been developed. Pyridinium perchlorate is an effective catalyst for the phosphonylation reaction of trialkyl phosphites with various electrophiles C = X (X = O, S, N). The reaction leads to the formation of corresponding α-subst...
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Kolodiazhna, O.O. Gryshkun, E.V. Kolodiazhna, A.O. Sheiko, S.Yu. Kolodiazhnyi, O.I. 2021-01-11T15:31:56Z 2021-01-11T15:31:56Z 2020 Catalytic phosphonylation of C=X electrophiles / O.O. Kolodiazhna, E.V. Gryshkun, A.O. Kolodiazhna, S.Yu. Sheiko, O.I. Kolodiazhnyi // Доповіді Національної академії наук України. — 2020. — № 12. — С. 75-84. — Бібліогр.: 12 назв. — англ. 1025-6415 DOI: doi.org/10.15407/dopovidi2020.12.075 https://nasplib.isofts.kiev.ua/handle/123456789/174275 547.241 A method for the catalytic phosphonylation of C = X electrophiles has been developed. Pyridinium perchlorate is an effective catalyst for the phosphonylation reaction of trialkyl phosphites with various electrophiles C = X (X = O, S, N). The reaction leads to the formation of corresponding α-substituted phosphonates in high yields. The reaction leading to the formation of bisphosphonates represents the highest interest. It was found that the nucleo philic attack of triethyl phosphite on the electron-deficient carbon of the C = X group leads to the formation of beta ine, which reacts with pyridinium perchlorate to form alkoxyphosphonium perchlorate and pyridine. Quasiphosphonium salt is unstable and decomposes to form phosphonate, alkene, and perchloric acid, which reacts with pyridine to regenerate pyridinium perchlorate. The intermediate formed from the pyridinium halide decomposes to form alkyl halide. The general strategy of the proposed method for introducing phosphonate groups into a polyprenyl mole cule consisted in the sequential treatment of hydroxyl-containing a compound with the Swern reagent with the con version of the C—OH group into a carbonyl one. Subsequent phosphonylation of the carbonyl-containing interme diate with the reagent (EtO)₃P/[PyH] + ClO⁴⁻ leads to the formation of hydroxyalkylbisphosphonate. The synthe sized prenyl bisphosphonates have a pronounced biological activity. These include, for example, enolpyruvylshikimate-3- phosphate synthase (EPSP), farnesyl protein transferase (FPTase), as well as HIV protease, which are of interest as potential biologically active substances. Розроблено метод каталітичного фосфонілювання електрофілів С = Х. Реакція призводить до утворення відповідних α-заміщених фосфонатів з високими виходами. Особливий інтерес становить реакція з утворенням бісфосфонатів. Встановлено, що нуклеофільна атака триетилфосфіту на електронодефіцитний вуглець групи C = X спричиняє утворення бетаїну, який реагує з перхлоратом піридинію з утворенням перхлорату алкоксифосфонію і піридину. Квазіфосфонієва сіль нестабільна і розкладається з утворенням фосфонату, алкену і хлорної кислоти, яка реагує з піридином, регенеруючи перхлорат піридинію. Інтермедіат, що утворюється з галогеніду піридинію, розкладається з утворенням галоїдного алкілу. Загальна стратегія пропонованого методу введення фосфонатних груп у молекулу поліпренолів полягала в послідовній обробці гідроксилвмісної сполуки реагентом Шверна з перетворенням С–ОН групи в карбо нільну; подальше фосфонілювання карбонілвмісного интермедіату реагентом (EtO)₃P/[PyH] + ClO⁴⁻ призводить до утворення гідроксибісфосфонату. Синтезовані бісфосфонати мають виражену біологічну активність. До них, наприклад, належать синтаза енолпірувілшикімат-3-фосфату (EPSP), фарнезол-протеїнтрансфераза (FPTase), а також ВІД-протеаза. Таким чином, нами розроблений порівняно простий метод синтезу α-гідроксибісфосфонатів — похідних терпенів, які становлять інтерес як потенційні біологічно активні речовини. en Видавничий дім "Академперіодика" НАН України Доповіді НАН України Хімія Catalytic phosphonylation of C=X electrophiles Каталітичне фосфонілювання C=X електрофілів Article published earlier |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| collection |
DSpace DC |
| title |
Catalytic phosphonylation of C=X electrophiles |
| spellingShingle |
Catalytic phosphonylation of C=X electrophiles Kolodiazhna, O.O. Gryshkun, E.V. Kolodiazhna, A.O. Sheiko, S.Yu. Kolodiazhnyi, O.I. Хімія |
| title_short |
Catalytic phosphonylation of C=X electrophiles |
| title_full |
Catalytic phosphonylation of C=X electrophiles |
| title_fullStr |
Catalytic phosphonylation of C=X electrophiles |
| title_full_unstemmed |
Catalytic phosphonylation of C=X electrophiles |
| title_sort |
catalytic phosphonylation of c=x electrophiles |
| author |
Kolodiazhna, O.O. Gryshkun, E.V. Kolodiazhna, A.O. Sheiko, S.Yu. Kolodiazhnyi, O.I. |
| author_facet |
Kolodiazhna, O.O. Gryshkun, E.V. Kolodiazhna, A.O. Sheiko, S.Yu. Kolodiazhnyi, O.I. |
| topic |
Хімія |
| topic_facet |
Хімія |
| publishDate |
2020 |
| language |
English |
| container_title |
Доповіді НАН України |
| publisher |
Видавничий дім "Академперіодика" НАН України |
| format |
Article |
| title_alt |
Каталітичне фосфонілювання C=X електрофілів |
| description |
A method for the catalytic phosphonylation of C = X electrophiles has been developed. Pyridinium perchlorate
is an effective catalyst for the phosphonylation reaction of trialkyl phosphites with various electrophiles C = X
(X = O, S, N). The reaction leads to the formation of corresponding α-substituted phosphonates in high yields. The
reaction leading to the formation of bisphosphonates represents the highest interest. It was found that the nucleo philic
attack of triethyl phosphite on the electron-deficient carbon of the C = X group leads to the formation of beta ine,
which reacts with pyridinium perchlorate to form alkoxyphosphonium perchlorate and pyridine. Quasiphosphonium
salt is unstable and decomposes to form phosphonate, alkene, and perchloric acid, which reacts with pyridine to
regenerate pyridinium perchlorate. The intermediate formed from the pyridinium halide decomposes to form alkyl
halide. The general strategy of the proposed method for introducing phosphonate groups into a polyprenyl mole cule
consisted in the sequential treatment of hydroxyl-containing a compound with the Swern reagent with the con version
of the C—OH group into a carbonyl one. Subsequent phosphonylation of the carbonyl-containing interme diate
with the reagent (EtO)₃P/[PyH] + ClO⁴⁻ leads to the formation of hydroxyalkylbisphosphonate. The synthe sized
prenyl bisphosphonates have a pronounced biological activity. These include, for example, enolpyruvylshikimate-3-
phosphate synthase (EPSP), farnesyl protein transferase (FPTase), as well as HIV protease, which are of interest
as potential biologically active substances.
Розроблено метод каталітичного фосфонілювання електрофілів С = Х. Реакція призводить до утворення
відповідних α-заміщених фосфонатів з високими виходами. Особливий інтерес становить реакція з утворенням бісфосфонатів. Встановлено, що нуклеофільна атака триетилфосфіту на електронодефіцитний
вуглець групи C = X спричиняє утворення бетаїну, який реагує з перхлоратом піридинію з утворенням
перхлорату алкоксифосфонію і піридину. Квазіфосфонієва сіль нестабільна і розкладається з утворенням
фосфонату, алкену і хлорної кислоти, яка реагує з піридином, регенеруючи перхлорат піридинію. Інтермедіат, що утворюється з галогеніду піридинію, розкладається з утворенням галоїдного алкілу. Загальна
стратегія пропонованого методу введення фосфонатних груп у молекулу поліпренолів полягала в послідовній обробці гідроксилвмісної сполуки реагентом Шверна з перетворенням С–ОН групи в карбо нільну;
подальше фосфонілювання карбонілвмісного интермедіату реагентом (EtO)₃P/[PyH] + ClO⁴⁻ призводить
до утворення гідроксибісфосфонату. Синтезовані бісфосфонати мають виражену біологічну активність.
До них, наприклад, належать синтаза енолпірувілшикімат-3-фосфату (EPSP), фарнезол-протеїнтрансфераза (FPTase), а також ВІД-протеаза. Таким чином, нами розроблений порівняно простий метод синтезу α-гідроксибісфосфонатів — похідних терпенів, які становлять інтерес як потенційні біологічно активні речовини.
|
| issn |
1025-6415 |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/174275 |
| citation_txt |
Catalytic phosphonylation of C=X electrophiles / O.O. Kolodiazhna, E.V. Gryshkun, A.O. Kolodiazhna, S.Yu. Sheiko, O.I. Kolodiazhnyi // Доповіді Національної академії наук України. — 2020. — № 12. — С. 75-84. — Бібліогр.: 12 назв. — англ. |
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75ISSN 1025-6415. Допов. Нац. акад. наук Укр. 2020. № 12: 75—84
Ц и т у в а н н я: Kolodiazhna O.O., Gryshkun E.V., Kolodiazhna A.O., Sheiko S.Yu., Kolodyazhnyi O.I. Cata-
lytic phosphonylation of C = X electrophiles. Допов. Нац. акад. наук Укр. 2020. № 12. С. 75—84. https://doi.
org/10.15407/dopovidi2020.12.075
Electrophilic reactions are an important type of the conversion of trivalent phosphorus com-
pounds. There are many examples of the catalytic electrophilic activation of organophosphorus
compounds that attract the attention of many chemists [1, 2]. Commonly used electrophilic ca-
talysts are Lewis acids, while nucleophilic catalysts are bases. The addition of Lewis acid to a
substrate containing a pair of free electrons is accompanied by an increase in the reactivity of
the generated complex. Typical examples of the electrophilic asymmetric activation of organo-
phosphorus compounds by chiral Lewis acids are the catalytic phosphonylation of C = X elec-
trophiles (phospha-aldol reaction, phospha-Mannich reaction, and phospha-Michael reaction),
https://doi.org/10.15407/dopovidi2020.12.075
UDC 547.241
O.O. Kolodiazhna, E.V. Gryshkun,
A. O. Kolodiazhna, S.Yu. Sheiko, O.I. Kolodiazhnyi
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv
E-mail: olegkol321@gmail.com
Catalytic phosphonylation of C = X electrophiles
Presented by Corresponding Member of the NAS of Ukraine O.I. Kolodiazhnyi
A method for the catalytic phosphonylation of C = X electrophiles has been developed. Pyridinium perchlorate
is an effective catalyst for the phosphonylation reaction of trialkyl phosphites with various electrophiles C = X
(X = O, S, N). The reaction leads to the formation of corresponding α-substituted phosphonates in high yields. The
reaction leading to the formation of bisphosphonates represents the highest interest. It was found that the nucleo philic
attack of triethyl phosphite on the electron-deficient carbon of the C = X group leads to the formation of beta ine,
which reacts with pyridinium perchlorate to form alkoxyphosphonium perchlorate and pyridine. Quasiphosphonium
salt is unstable and decomposes to form phosphonate, alkene, and perchloric acid, which reacts with pyridine to
regenerate pyridinium perchlorate. The intermediate formed from the pyridinium halide decomposes to form alkyl
halide. The general strategy of the proposed method for introducing phosphonate groups into a polyprenyl mole cule
consisted in the sequential treatment of hydroxyl-containing a compound with the Swern reagent with the con ver-
sion of the C—OH group into a carbonyl one. Subsequent phosphonylation of the carbonyl-containing interme diate
with the reagent (EtO)3P/[PyH] + ClO 4– leads to the formation of hydroxyalkylbisphosphonate. The synthe sized
prenyl bisphosphonates have a pronounced biological activity. These include, for example, enolpyruvylshikimate-3-
phosphate synthase (EPSP), farnesyl protein transferase (FPTase), as well as HIV protease, which are of interest
as potential biologically active substances.
Keywords: phosphonylation, pyridinium perchlorate, bisphosphonates, hydrophosphonates, terpene derivatives.
76 ISSN 1025-6415. Dopov. Nac. akad. nauk Ukr. 2020. № 12
O.O. Kolodiazhna, E.V. Gryshkun, A. O. Kolodiazhna, S.Yu. Sheiko, O.I. Kolodiazhnyi
which proceeds with the formation of functionalized phosphonates such as alpha- and beta-hy-
droxyphosphonates, aminophosphonates, and hydroxy-bis-phosphonates. The synthesis of func-
tionalized phosphonates has received a lot of attention because of their biological activity [2, 3].
They act as peptide mimics, catalytic antibody haptens, antibiotics and pharmaceuticals, herbi-
cides. and enzyme inhibitors [4].
Alpha-hydroxyalkyls (bis-phosphonates), being important pharmaceuticals, are widely used
in medical practice and represent a particular interest. Bisphosphonates prevent bone loss and
are used to treat osteoporosis and similar diseases. Clinical studies have shown that bisphos-
phonates reduce the risk of fractures in osteoporosis. The use of bisphosphonates includes the
prevention and treatment of osteoporosis, osteitis deformans (“Paget’s disease”), bone metastases
(with or without hypercalcemia), multiple myeloma, primary hyperparathyroidism, osteoge nesis
imperfecta, and other diseases that cause bone fragility. The mechanism of action of bisphospho-
nates is based on their structural analogy with pyrophosphates. The bisphosphonate group mim-
ics the structure of pyrophosphate, thereby inhibiting the activation of enzymes that utilize py-
rophosphates. In some cases, the synthesis of bisphosphonates of a certain structure is complex
and difficult to overcome. There are two main pathways for the synthesis of α-functionalized
phosphonates: the reaction of dialkyl phosphites with unsaturated electrophiles C = X in the pre-
sence of Bronsted bases or Lewis acids (the Abramov reaction [5, 6], the Kabachnik–Fields reac-
tion [7, 8] and Pudovik reaction [4, 9]) and the reaction of trialkyl phosphites with aldehydes.
However, despite their potential utility, these methods usually suffer from certain disadvantages,
such as the low activity of dialkyl phosphites with respect to ketones. The reactions proceed
with the formation of various impurities formed under the action of alkaline catalysts (phos-
phonate-phosphate rearrangement [10, 11], etc.). In addition, Lewis acids used as catalysts are
sensitive to moisture and require a special handling and tedious processing.
Therefore, we have developed a convenient method for the synthesis of bisphosphonates,
based on the use of pyridinium perchlorate as a new, effective catalyst for the phosphonylation
of C = X electrophiles by trialkyl phosphites (Scheme 1).
Scheme 2 explains the catalytic action of pyridinium perchlorate. The nucleophilic attack of
triethyl phosphite on the electron-deficient carbon of the C = X group leads to the formation of
betaine A, which reacts with pyridinium perchlorate to form alkoxyphosphonium perchlorate C
and pyridine. Salt C is unstable and decomposes to form phosphonate D, alkene, and perchloric
acid, which reacts with pyridine to regenerate pyridinium perchlorate. Quasiphosphonium inter-
mediate B, formed from pyridinium halides, decomposes to form EtHlg. Pyridinium perchlorate
initiates the reaction of trialkyl phosphites with C = X electrophiles more actively than pyridin-
ium halides. The use of pyridinium perchlorate instead of pyridinium halides significantly in-
creases the reaction rate and increases the yields.
Scheme 1
77ISSN 1025-6415. Допов. Нац. акад. наук Укр. 2020. № 12
Catalytic phosphonylation of C = X electrophiles
Pyridinium perchlorate can easily be prepared by reacting pyridine with perchloric acid in
aqueous solution. It is poorly soluble in water and is easily filtered off as a crystalline substance.
After the drying in vacuum desiccator, pyridinium perchlorate is ready to be used.
In all cases, the reactions proceed smoothly in the absence of a solvent or in methylene chlo-
ride at room temperature to obtain α-substituted phosphonates without unwanted by-products.
Pyridinium perchlorate increases the reaction rate, but is not consumed by the reaction itself.
It can be isolated from the reaction mixture and reused; no significant decrease in its activity
was observed.
In this regard, in the search for new phosphorus pharmaceuticals, we synthesized bispho-
sphonate derivatives of terpenes. In accordance with the method previously described by us [2]
and based on available natural polyprenols, we oxidized them to the corresponding aldehydes,
which were then successively subjected to the phosphonylation by the reaction with dialkyl
phosphites and converted to the target hydroxybisphosphonates through the stage of formation
of α-ketophosphonates.
The general strategy of our proposed method for introducing phosphonate groups into a poly-
prenol molecule consists in the sequential treatment of the hydroxyl-containing compound with
Swern’s reagent (reagent a) with the transformation of the C–OH group into a carbonyl one;
subsequent phosphonylation of the carbonyl-containing intermediate with (EtO)3P/[PyH] +
ClO4
–, leading to the formation of hydroxyalkylbisphosphonate (Scheme 3).
Oxidation of unsaturated polyprenols, as well as hydroxyprenylphosphonates, with Swern's
reagent [3, 4], in this case turned out to be very convenient, since it proceeded regioselectively
only at the hydroxyl group, without affecting the C = C bond, as it happens when using other
oxidants. As a result, α-ketophosphonates were obtained in high yields, which were converted
into α-hydroxyisoprenylbisphosphonates in the next step. Reagent b reacts with carbonyl
compounds to form hydroxyphosphonates in high yields. The reaction of tertiary phosphites
with aldehydes is easily carried out in methylene chloride or without solvent when cooled below
0 °C and leads to the corresponding hydroxyphosphonates in the almost quantitative yield.
The re action of this mixture with α-ketophosphonates proceeds just as easily. So, starting from
Scheme 2. Possible mechanism of catalysis by pyridinium perchlorate
Scheme 3
78 ISSN 1025-6415. Dopov. Nac. akad. nauk Ukr. 2020. № 12
O.O. Kolodiazhna, E.V. Gryshkun, A. O. Kolodiazhna, S.Yu. Sheiko, O.I. Kolodiazhnyi
natural geraniol, by oxidation according to Swern in a high yield, geranial 1 was obtained, which
by reaction with reactant b was converted in the 80 % yield into hydroxyphosphonate 2. The lat-
ter was purified by distillation under vacuo and obtained as a colorless oil with a pleasant floral
odor and stable during a storage. Hydroxyphosphonate 2 was converted into α-ketophosphonate
3 by oxidation according to Swern (Scheme 4).
Isoprenyl ketophosphonate 3 was also purified by distillation in vacuo and isolated as a co-
lorless liquid, stable at a storage. However, upon contact with air moisture, the compound 3
slowly hydrolyzes with the formation of diethyl phosphite, geranial, and other products of un-
known structure, as was found by 1H and 31P NMR analysis, At the final stage of the synthesis,
α-ke to phosphonate was subjected to the phosphonylation with the same reagent b to form
hydroxybisphosphonate 4, which was purified by chromatography on a silica gel column. The
structure of products 3 and 4 was established from the data of the NMR spectra of the purified
samples. Thus, the 31Р chemical shift of ketophosphonate is at –2 ppm, which is typical of
α-ketophosphonates of the corresponding structure, and the 13C NMR spectrum shows a dou b-
let of the carbon atom of the α-keto group at 200 ppm, 1JCP 150 Hz. In turn, in the 13C NMR
spectrum of bisphosphonate 4, a triplet of the carbon atom bonded to two phosphorus atoms is
detected at 60 ppm, 1JCP 130 Hz. In a similar manner, starting from (+)-(R)-citronenal, chiral
bisphosphonate 8 was obtained. Citronellal was reacted with reagent b to obtain hydroxy-
phosphonate 6 in a very high yield. The product was isolated pure by vacuum distillation and
oxidized by treatment with Swern’s reagent to a chiral ketophosphonate 7 in the 70 % yield. The
signal in the 31P NMR spectrum of this compound at –1.96 ppm responds to the structure of
α-ketophosphonates. At the last stage of the synthesis, ketophosphonate 7 by the reaction with
triethyl phosphite in the presence of pyridinium perchlorate in methylene chloride for 24 h at
room temperature was converted in a high yield into bisphosphonate 8, which was purified by
chromatography on a silica gel column. The 1H NMR spectrum of this compound contains the
signals belonging to the ethoxy groups at 1.59 and 1.66 ppm, as well as the triplet of the proton
C = CH group of the dimethyl-2,6-octene fragment at 5.1 ppm, 3JHN 7 Hz (Scheme 5).
Hydroxyphosphonate 6 bearing two asymmetric centers on the α- and γ-carbon atoms shows
signals at 26.50 and 26.54 ppm (1 : 1) corresponding to the presence of the (S,R)- and (S,S)-dias-
tereomers. Two phosphono groups in bisphosphonate 8 containing a chiral center on the γ-carbon
atom have different magnetic environments and, therefore, are diasterotopic. They are represen-
Scheme 4
79ISSN 1025-6415. Допов. Нац. акад. наук Укр. 2020. № 12
Catalytic phosphonylation of C = X electrophiles
ted in the 31Р NMR spectrum by two signals at 20.55 and 20.65 ppm. The synthesis strategy de-
scribed here was also used in the phosphonylation of the natural farnesol. In this case, at first, by
Swern’s procedure, farnesal 9 was obtained and then converted by the reaction with reagent b into
the corresponding hydroxyphosphonate 10 purified by the vacuum distillation. Since the original
farnesol isolated from natural sources was a mixture of cis- and trans- isomers, hydroxyphospho-
nate 10 also consisted of a mixture of cis- and trans-isomers. Ketophosphonates 11 are analogs of
prenyl pyrophosphates, which are of great biological importance [5-7]. The prenyl bisphospho-
nates synthesized by us (3, 6, and 13) have not been previously described, although some phos-
phoric terpene derivatives that differ in structure and methods of preparation from the prenyl
phosphonates and bisphosphonates discussed here have been synthesized and described, some of
which have pronounced biological activity. Some of such compounds have been found to exhibit
a strongly pronounced biological activity, among them enolpyruvylshikimate-3-phosphate syn-
thase(EPSP), farnesyl protein transferase (FPTase) ([8, 9], and HIV protease [10] (Scheme 6).
Scheme 5
Scheme 6
80 ISSN 1025-6415. Dopov. Nac. akad. nauk Ukr. 2020. № 12
O.O. Kolodiazhna, E.V. Gryshkun, A. O. Kolodiazhna, S.Yu. Sheiko, O.I. Kolodiazhnyi
We used the proposed procedure as the basis for the preparation of hydroxyphosphonates
14 and 16, which are also derivatives of natural terpenes. Hydroxyphosphonate 14 was suc-
cessfully distilled under high vacuum and then isolated as a crystalline substance; its mono-
cyclic analog 16 was also purified by the vacuum distillation. By Swern’s treatment, hydroxy-
phosphonate 14 was converted into ketophosphonate, the formation of which was recorded using
the 31Р NMR spectrum (δP –2 ppm), and then, without special purification, the latter was reac-
ted with triethyl phosphite in the presence of pyridine. Bisphosphonate 17 was isolated and pu-
rified by column chromatography on silica gel in a low yield (about 25 %) (Scheme 7).
Thus, we have developed a relatively simple method for the synthesis of α-hydroxy-bis-
pho sphonates, derivatives of terpenes, which are of interest as potential biologically active sub-
stances [11, 12]. We will carry out research in this direction in the future.
Experimental Part. The NMR spectra were registered on a Varіan VXR-300 spectrometer at
300 (1H), 60 (13C), and 126.16 (31P) MHz relative to Me4Sі (1H, 13C) or 85 % H3PO4 (31P).
Solvents were preliminarily distilled in an inert atmosphere: diethyl ether, hexane heptane,
benzene, and carbon tetrachloride over phosphorus pentoxide, methanol and triethylamine
over sodium, and ethyl acetate over calcium chloride. Reagents, silica gel and TLC plates (Po-
lіgram SIL G/UV 254) were purchased from Fluka and Acros. Geraniol, farnesol, and (+)-(R)-
cit ro nellal were purchased from Merck.
Diethyl[(2E)-1-hydroxy-3,7-dimethylocta-2,6-dienyl]phosphonate (2). Pyridinium per-
chlorate (1 g, mol) was added to a cold (0 °С) solution of geranial (0.3 g, 0.02 mol) and triethyl
phosphite (3.1 g, mol), and the reaction mixture was stirred for 2 h at room temperature, after
which it was filtered, diluted with diethyl ether, and filtered again to remove pyridinium per-
chlorate (~0.009 mol). The solvent was removed by the evaporation, and the residue was dis-
tilled in vacuum. Yield 80 %, bp 135 °С (0.08 mmHg).
1Н NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.28 t (3H, CH3, JHH 7), 1.29 t (3H, CH3, JHH
7), 1.61 s (3H, CH3), 1.69 s (3H, CH3), 2.1 br.s (4H, CH2), 4.12 m (4H, OCH2) 4.52 d.d (1H,
PCH, JHH 9, JHP 9), 5.12 br.s (1H, CH=C), 5.36 br.s (1H, CH=C).
13C NMR spectrum (CDCl3), δС, ppm: 16.4, 17.0, 17.6, 25.60, 26.7, 37.90, 37.9, 61.7, 61.8,
65.1, 66.1, 119.1, 124.0, 131.7, 138.8.
31P NMR spectrum (CDCl3): 24.19 ppm.
Diethyl[(2E)-3,7-dimethyl-1-oxoocta-2,6-dienyl)-phosphonate (3). A solution of 2 ml
of DMSO in 4 ml of methylene chloride and a solution of 2.8 g of hydroxyphosphonate 2 in 8 ml
of methylene chloride were added in succession to a solution of 1 ml of oxalyl chloride in 20 ml
Scheme 7
81ISSN 1025-6415. Допов. Нац. акад. наук Укр. 2020. № 12
Catalytic phosphonylation of C = X electrophiles
of dry methylene chloride at –60 °C. After 15 min, 7 ml of triethylаmine was added at –50 °C.
The reaction mixture was stirred for 5 min, heated to room temperature, and diluted with 50 ml
of ice water. The aqueous layer was separated and extracted with methylene chloride (2 × 20 ml).
The combined organic layers were dried over MgSO4, the solvent was evaporated, and the resi-
due was distilled in vacuum. Yield 70 %, bp 115 °С (0.08 mmHg).
1Н NMR spectrum (CDCl3), δ, ppm ( J, Hz): 0.87 m (3H, CH3), 1.24 s (3H, CH3C=), 1.29 s
(3H, CH3C=), 1.31 t (6H, CH3CH2O, JHH 7), 1.6 m (2H, CH2), 2.0 m (2H, CH2), 2.29 m (2H,
CH2), 4.1 m (4H, CH2O), 5.33 m (=CH–C=O).
31Р NMR spectrum (CDCl3): δP 1.2 ppm.
Found P, %: 10.76. C14H25O4P. Calculated P, %: 10.74.
Tetraethyl[(2E)-1-hydroxy-3,7-dimethylocta-2,6-dienylidene]bisphosphonate (4). Pyri-
dinium perchlorate (0.3 g, 3 mmol) was added to a cold (0 °С) solution of 0.5 g (3 mmol) of
triethyl phosphite and 0.7 g (2.5 mmol) of ketophosphonate 3 in 3 ml of methylene chloride,
and the mixture was left to stand for 24 h at room temperature. The precipitate that formed was
filtered off, the solvent was evaporated, and the residue was chromatographed on a column of
silica gel, eluent ethyl acetate–hexane, 1 : 1. Yield 65 %, oil.
1Н NMR spectrum (CDCl3), δ, ppm ( J, Hz): 1.27 t (6H, J 7), 1.28 t (6H, J 7), 1.6 s 1.63 s (3H),
1.8 m (3H), 2.0 m (4H, CH2), 4.21 m (8H, OCH2), 4.8 m (1H, CH=), 5.1 t (1H, CH=, JHH 7).
13C NMR spectrum (CDCl3), δC, ppm ( J, Hz): 16.21, 16.41, 17.59, 17.81, 25.61, 26.87, 36.9,
60.93, 64.53, 67.83, 71.13, 115.5, 124.03, 131.67, 139.77.
31Р NMR spectrum (CDCl3): δP 23.3 ppm.
Found, %: C 50.45; H 8.41; P 14.50. C18H36O7P2. Calculated, %: C 50.70; H 8.51; P 14.53
Diethyl[(SP/R,R/RP)-(6E)-1-hydroxy-3,7-di-methylocta-2,6-dienyl]phosphonate (6).
Py ridinium perchlorate (~0.75 g, 0.005 mol) was added to a cold (0 °С) solution of citronellal
(1.5 g, 0.01 mol) and triethyl phosphite (1.6 g, 0.01 mol). The reaction mixture was stirred for 2 h
at room temperature, filtered, diluted with diethyl ether, filtered to remove pyridinium perchlo-
rate, the solvent was evaporated, and the residue was distilled in vacuum. Yield 80 %, bp 145–
150 °С (0.08 mmHg).
Mixture of the (SP/R,RP/R) diastereomers. 1Н NMR spectrum (CDCl3), δ, ppm ( J, Hz): 0.96
d (3H, CH3, J 7), 1.29 t (3H, CH3, J 7), 1.30 t (3H, CH3, J 7), 1.58 s (3H, CH3), 1.65 s (3H,
CH3), 1.83 m (2H, CH2), 1.96 m (2H, CH2), 3.82 m (1H, CH), 4.09 m (4H, OCH2), 5.07 t (1H,
CH=C, J 7), 5.7 br.s (1H, OH).
13C NMR spectrum (CDCl3), δC, ppm (J, Hz): (SP,R) 16.45, 16.49, 17.6, 20.25, 25.19,
25.52, 25.65, 28.30 d (J 12), 35.75, 38.11, 62.51 d (J 7.5), 62.64 d (J 6), 65.59 d (J 158), 124.70,
131.09; (RP , R) 16.45, 16.49, 18.35, 20.25, 25.19, 25.52, 25.65, 29.0 d (J 12), 37.80, 38.56, 62.51 d
(J 7.5), 62.64 d (J 6), 66.06 d (J 157), 124.72, 131.13.
31P NMR spectrum (CDCl3): δP , ppm: 26.50, 26.54.
Found P, %: 10.69. C14H29O4P. Calculated P, %: 10.59.
Diethyl[(6E)-3,7-dimethyl-1-oxooct-6-enyl]phosphonate (7). A solution of 0.9 ml of
DMSO in 2 ml of methylene chloride and a solution of 1.4 g of hydroxyphosphonate 6 in 4 ml
of methylene stirred and a solution of 0.5 ml of oxalyl chloride in 10 ml of dry methylene chlo-
ride were added in succession to a solution of 0.5 ml of oxalyl chloride in 10 ml of dry methylene
chloride at –60 °C. After 15 min, 3.5 ml of triethylаmine was added at –50 °C. The mixture was
82 ISSN 1025-6415. Dopov. Nac. akad. nauk Ukr. 2020. № 12
O.O. Kolodiazhna, E.V. Gryshkun, A. O. Kolodiazhna, S.Yu. Sheiko, O.I. Kolodiazhnyi
stirred for 5 min, heated to room temperature, and diluted with 35 ml of ice water. The aqueous
layer was separated and extracted with methylene chloride (2 × 10 ml). The combined organic
layers were dried over MgSO4, the solvent was evaporated, and the residue was distilled in va-
cuum. Yield 70 %, mp 115 °С (0.08 mmHg).
1Н NMR spectrum (CDCl3), δ, ppm ( J, Hz): 0.87 m (3H, CH3), 0.91 d (CH3CH, J 7), 1.37 t
(CH3CH2, J 7), 1.58 s (3H, CH3C=), 1.66 s (3H, CH3C=), 1.97 m (2H, CH2), 2.14 m (2H, CH2),
2.6–2.8 m (2H, CH2C=O), 4.21 m (4H, OCH2), 6.06 t (2H, CH=C, J 6.5).
31Р NMR spectrum (CDCl3): δP 1.96 ppm.
Found Р, %: 10.76. C14H27O4P. Calculated P, %: 10.67.
Tetraethyl[(6E)-1-hydroxy-3,7-dimethylocta-6-enylidene]bisphosphonate (8). Pyridi-
nium perchlorate (0.3 g, 3 mmol) was added to a cold (0 °С) solution of 0.5 g (3 mmol) of triethyl
phosphite and 0.7 g (2.5 mmol) of ketophosphonate 7 in 3 ml of methylene chloride, and the mix-
ture was left to stand overnight at room temperature. The precipitate was filtered off, the solvent
was evaporated, and the residue was chromatographed on a column of silica gel. Yield 65 %, oil.
1Н NMR spectrum (CDCl3), δ, ppm ( J, Hz): 1.02 d (3H, J 4), 1.34 t (12H, CH3CH2, J 7), 1.59 s
(3H, CH3C=), 1.66 s (3H, CH3C=), 2.0 m (4H, CH2), 4.23 m (8H, OCH2), 5.1 t (CHC=, J 7).
31Р NMR spectrum (CDCl3), δP , ppm: 20.55, 20.65.
Found, %: C 50.45; H 8.41; P 14.50. C18H38O7P2. Calculated, %: C 50.46; H 8.94; P 14.46.
Dimethyl[(2E,6E)-1-hydroxy-3,7,11-trimethyl-dodeca-2,6,10-trienyl]phosphonate
(10). Pyridinium perchlorate (0.5 g, ~0.005 mol) was added to a cold (0 °С) solution of farne-
sal (2.2 g, 0.01 mol) and trimethyl phosphite (1.3 g, 0.01 mol). The reaction mixture was stirred
for 2 h at room temperature and then filtered, diluted with diethyl ether, and filtered again to
separate ~0.0049 mol of pyridinium per- chlorate. The solvent was evaporated, and the residue
was distilled in vacuum. Yield 90 %, oil.
1Н NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.59 s (3H, CH3C=), 1.66 s (3H, CH3C=), 1.69
d (3H, CH3CH, JHH 1.5), 1.71 (3H, CH3CH, JHH 1.5), 2.09 m (6H, CH2), 2.25 m (2H, CH2),
3.78 d (3H, CH3O, JHР 10), 3.8 d (3H, CH3O, JHР 10), 4.5 br.s (1H, OH), 4.7 t (1H, PCH, JHР 10),
5.09 br.s (1H, CH=C), 5.35 br.s (2H, CH=C).
31Р NMR spectrum (CDCl3): δP 26.05 ppm.
Found P, % 9.39. C17H31O4P. Calculated P, %: 9.37.
Dimethyl[(2E,6E)-3,7,11-trimethyl-1-oxododeca-2,6,10-trienyl]phosphonate (11). A so-
lution of 0.9 ml of DMSO in 2 ml of methylene chloride and a solution of 1.4 g of hydroxy-
phosphonate 10 in 4 ml of methylene chloride were added in succession to a solution of 0.5 ml
of oxalyl chloride in 10 ml of dry methylene chloride at –60 °C. After 15 min, 3.5 ml of triethylа-
mine was added –50 °C. The reaction mixture was stirred for 5 min, heated to room temperature,
and diluted with 35 ml of ice water. The aqueous layer was separated and extracted with methy-
lene chloride (2 × 10 ml). The combined organic solutions were dried over MgSO4, the solvent
was evaporated, and the residue was distilled in vacuum. Yield 60 %, bp 145 °С (0.1 mmHg).
1Н NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.6 s (3H, CH3C=), 1.66 s (3H, CH3C=), 1.69 d
(3H, CH3C=, J 1.5), 1.71 (3H, CH3C=, J 1.5), 2.1 m (6H, CH2), 2.25 m (2H, CH2), 3.75 d (3H,
CH3O, JHР 10), 3.8 d (3H, CH3O, JHР 10), 5.1 br.s (1H, CH=C), 5.5 br.s (2H, CH=C).
31Р NMR spectrum (CDCl3): δP 0.98 ppm.
Found, %: C 62.38; H 8.89; P 9.45. C17H29O4P. Calculated, %: C 62.18; H 8.90; P 9.43.
83ISSN 1025-6415. Допов. Нац. акад. наук Укр. 2020. № 12
Catalytic phosphonylation of C = X electrophiles
Tetramethyl[(2E,6E)-1-hydroxy-3,7,11-trimethyldodeca-2,6,10-trienylidene]bisphos-
phonate (12). Pyridinium perchlorate (3 mmol) was added to a cold (0 °С) solution of 3 mmol
of trimethyl phosphite and 2.5 mmol of ketophosphonate 11 in 3 ml of methylene chloride, and
the mixture was left to stand for 24 h at room temperature. The precipitate that formed was fil-
tered off, the solvent was evaporated, and the residue was chromatographed on a column with
silica gel (eluent hexane–ethyl acetate, 3 : 1). Yield 65 %, oil.
1Н NMR spectrum (CDCl3), δ, ppm ( J, Hz): 1.6 s (3H, CH3), 1.69 s (3H, CH3), 1.8 d.d
(3H, JHP 8, JHH 7), 2.0 m (4H, CH2), 3,75 d (3H, CH3O, JHР 10), 3.8 d (3H, CH3O, JHР 10),
4.8 m (2H, CH=), 5.1 m.
Found P, %: 14.60. C18H34O7P2. Calculated P, %: 14.60.
Diethyl[(hydroxy)(3,8,8-trimethyl-1,2,3,4,5,6,7,8-octahydronaphtalen-2-yl)methyl]
phosphonate (14) was prepared similarly to compound 11. Yield 80 %, bp 190 °C (0.1 mmHg),
mp 107–110 °C (hexane).
1Н NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.957 d (3H, CH3C, J 6), 0.975 s (6H, CH3),
1.34 t (6H, CH3CH2O, J 7), 1.43 m (2H, CH2), 1.6 m (4H, CH2), 1.8 m (2H, CH2), 1.9 m (1H,
CH), 2.0 m (1H, CH), 2.19 m (2H, CH2), 2.91 m ( 1H, OH), 4.2 m (5H, CH2O + PCH).
31Р NMR spectrum (CDCl3): δP 24.0 ppm.
Diethyl[(hydroxy)[6-methyl-4-(4-methylpent-3-enyl)cyclohex-3-en-1-yl]]methylphos-
phonate (16). Pyridinium perchlorate (0.5 g, 0.005 mol) was added to a cold (0 °С) solution
of aldehyde 15 (0.01 mol) and triethyl phosphite (1.6 g, 0.01 mol) in 5 ml of methylene chloride.
The reaction mixture was stirred for a few hours (under TLC control) and then filtered, diluted
with diethyl ether, and filtered again to separate ~0.0049 mol of pyridinium perchlorate. The
solvent was evaporated, and the residue was purified first by the vacuum distillation and then
by column chromatography on silica gel (eluent ethyl acetate-hexane, 1 : 3). Yield 80 %. Co-
lorless oil, bp 180 °С (0.08 mmHg).
1Н NMR spectrum (CDCl3), δ, ppm ( J, Hz): 0.99 d (3H, CH3, J 6), 1.33 t (6H, CH3CH2, J 7),
1.6 s (3H, CH3), 1.87 s (3H, CH3), 1.91–2.22 m (10H, CH2 + CH), 3.51 br.s (OH), 4.17 m (5H,
OCH2 + PCH, J 7, J 8), 6.28 s (1H, CH=C), 5.32 m (2H, CH=C).
13C NMR spectrum (CDCl3), δC, ppm (J, Hz): 8.87, 16.28, 17.3, 25.4, 25.78, 27.01, 27.08,
29.96, 32.15, 33.69 d (J 150), 42.8, 61.81 d (J 6), 120.6, 123.9, 130.8, 135.59.
31P NMR spectrum (CDCl3): δ 26.6 ppm.
Found, %: C 62.68; H 9.65; P 8.88. C18H33O4P. Calculated, %: C 62.77; H 9.66; P 8.99.
Tetraethyl[(hydroxy)[6-methyl-4-(4-methyl-pent-3-enyl)cyclohex-3-en-1-yl]methyl-
ene]bisphosphonate (17) was prepared similarly to compound 12. Yield 25 %, oil, purified by
column chromatography.
1Н NMR spectrum (CDCl3), δ, ppm ( J, Hz): 1.15 d (3H, CH3, J 6), 1.3 t (3H, CH3, J 7),
1.32 t (3H, CH3, J 7),1.6 m (6H, CH3), 2.0–2.5 m (6H, CH2), 4.4 m (4H, OCH2), 5.2 m (1H,
CH=), 5.4 m (1H, CH=).
31Р NMR spectrum (CDCl3): δP 23.0 ppm.
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2010.511359
Received 30.10.2020
А.О. Колодяжна, Е.В. Грішкун,
О.О. Колодяжна, С.Ю. Шейко, О.І. Колодяжний
Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ
E-mail: oikol123@bpci.kiev.ua
КАТАЛІТИЧНЕ ФОСФОНІЛЮВАННЯ C=X ЕЛЕКТРОФІЛІВ
Розроблено метод каталітичного фосфонілювання електрофілів С = Х. Реакція призводить до утворення
відповідних α-заміщених фосфонатів з високими виходами. Особливий інтерес становить реакція з ут-
воренням бісфосфонатів. Встановлено, що нуклеофільна атака триетилфосфіту на електронодефіцитний
вуглець групи C = X спричиняє утворення бетаїну, який реагує з перхлоратом піридинію з утворенням
перхлорату алкоксифосфонію і піридину. Квазіфосфонієва сіль нестабільна і розкладається з утворенням
фосфонату, алкену і хлорної кислоти, яка реагує з піридином, регенеруючи перхлорат піридинію. Інтер-
медіат, що утворюється з галогеніду піридинію, розкладається з утворенням галоїдного алкілу. Загальна
стратегія пропонованого методу введення фосфонатних груп у молекулу поліпренолів полягала в пос лі-
довній обробці гідроксилвмісної сполуки реагентом Шверна з перетворенням С–ОН групи в карбо нільну;
подальше фосфонілювання карбонілвмісного интермедіату реагентом (EtO)3P/[PyH]+ClO4
– призводить
до утворення гідроксибісфосфонату. Синтезовані бісфосфонати мають виражену біологічну активність.
До них, наприклад, належать синтаза енолпірувілшикімат-3-фосфату (EPSP), фар незол-протеїнтранс-
фе раза (FPTase), а також ВІД-протеаза. Таким чином, нами розроблений порівняно простий метод син-
тезу α-гідроксибісфосфонатів — похідних терпенів, які становлять інтерес як потенційні біологічно ак-
тивні речовини.
Ключові слова: фосфонілювання, перхлорат піридинію, бісфосфонати, гідроксифосфонати, похідні терпену.
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