Synthesis of the phosphonoanalogue of benzo[c]pyroglutamic acid

Article abstract of DOI:10.1080/10426501003685791

Phosphonic analogue 1 of benzo[c]pyroglutamic acid was synthesized by three-step synthesis starting from N-tert-butylphtalimide and triethylphosphite. The acid-catalyzed, oxidative cascade conversion of phosphonate 11 to phthalimide and phosphoric acid diethyl ester was observed. A mechanism for this transformation was proposed. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426501003685791

This article was downloaded by: [Tulane University]
On: 01 February 2015, At: 23:48
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the
Related Elements
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gpss20
Synthesis of the Phosphonoanalogue of
Benzo[c]pyroglutamic Acid
Georgiy O. Kachkovskyi a & Oleg I. Kolodiazhnyi a
a Institute of Bioorganic Chemistry and Petrochemistry of the
National Academy of Sciences of Ukraine , Kyiv, Ukraine
Published online: 19 Nov 2010.
To cite this article: Georgiy O. Kachkovskyi & Oleg I. Kolodiazhnyi (2010) Synthesis of the
Phosphonoanalogue of Benzo[c]pyroglutamic Acid, Phosphorus, Sulfur, and Silicon and the Related
Elements, 185:12, 2441-2448, DOI: 10.1080/10426501003685791
To link to this article: http://dx.doi.org/10.1080/10426501003685791
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Phosphorus, Sulfur, and Silicon, 185:2441–2448, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426501003685791
SYNTHESIS OF THE PHOSPHONOANALOGUE
OF BENZO[C]PYROGLUTAMIC ACID
Georgiy O. Kachkovskyi and Oleg I. Kolodiazhnyi
Institute of Bioorganic Chemistry and Petrochemistry of the National Academy
of Sciences of Ukraine, Kyiv, Ukraine
Phosphonic analogue 1 of benzo[c]pyroglutamic acid was synthesized by three-step synthesis
starting from N-tert-butylphtalimide and triethylphosphite. The acid-catalyzed, oxidative
cascade conversion of phosphonate 11 to phthalimide and phosphoric acid diethyl ester was
observed. A mechanism for this transformation was proposed.
Keywords Autoxidation; isoindolin-1-ones; phosphonic acids
INTRODUCTION
The isoindolin-1-one fragment is present in synthetic (e.g., indoprofen–anti-
inflammatory agent) as well as in naturally occurring compounds, in particular in
alkaloids (e.g., lennoxamine, nuevamine).1–5 Isoindolin-1-one-3-yl-carboxylic acid,
which is a benzanullated analogue of pyroglutamic acid, shows interesting and manifold
biological activities.6,7 Since phosphonic acid derivatives exhibit very high potency
in inhibiting enzymes,8–10 we have recently reported the synthesis of phosphonic
acids possessing isoindolin-1-one moiety by dehydrative aromatization of epoxyisoin-
dolylphosphonates.11,12 These compounds showed biological activity as inhibitors of
phosphodiesterase. Therefore, continuing our studies on the synthesis and biological
properties of phosphonic analogues of natural compounds,13,14 we have prepared a new
isoindolin-1-one-3-yl-phosphonic acid 1, which is a basic representative of this type of
phosphonic acid.
RESULTS AND DISCUSSION
We have proposed two approaches to the synthesis of phosphonic acids 1, which
are shown in the retrosynthetic Scheme 1. The first route A is based on the reductive
amination and cyclization of acylphosphonate 2, while the second route B is based on the
use of N-protected 3-hydroxy-isoindolin-1-one 3 as a key intermediate and a substrate for
phosphonylation.
Received 28 December 2009; accepted 7 February 2010.
This work was supported by the STCU, grant No. 3558.
Address correspondence to Oleg I. Kolodiazhnyi, Institute of Bioorganic Chemistry and Petrochem-
istry of the National Academy of Sciences of Ukraine, Murmanska Str, 1, Kyiv 02094, Ukraine. E-mail:
olegkol321@rambler.ru
2441

2442
G. O. KACHKOVSKYI AND O. I. KOLODIAZHNYI
Scheme 1 Retrosynthetic analysis of isoindolin-1-one-3-yl phosphonic acid 1.
A key compound of route A, the acylphosphonate 2, has been synthesized by the
reaction of triethylphosphite with chloride of monomethyl ester of phthalic acid.15 For
the reductive amination of acylphosphonate 2, we used a well-known method, i.e., the
transformation of 2 into oxime and its reduction to the corresponding amine.16–18 However,
under standard reaction conditions,19 we have obtained only the hydroxamic acid derivative
4 (Scheme 2). The analysis of the reaction mixture by means of 31P NMR spectroscopy does
not detect even traces of compound 5. Change of the reaction sequence, i.e., first reduction
of acylphosphonate 2 by sodium borohydride with formation of α-hydroxyphosphonate
7 and its subsequent Mitsunobu amination,20,21 was also unsuccessful, because under the
reaction conditions (МеОН, 0–2◦С), the hydroxyphosphonate 7 underwent intramolecular
cyclization with formation of phosphonate 6 in 65% yield (Scheme 2).
Scheme 2 Attempts to prepare phosphonic acid 1 via route А.
On the other hand, route B turned out to be the most suitable for the preparation of
isoindolin-1-one-3-yl-phosphonic acid 1, which was obtained by three-step synthesis as
shown in Scheme 3. The reduction of N-tert-butylphthalimide 8 with sodium borohydride
in methanol at 0–5◦С afforded the 3-hydroxyisoindolone 3 in 86% yield. Treatment of
compound 3 with trifluoroacetic anhydride generated a highly reactive acyliminium salt 9,
which reacted with triethylphosphite to give the phosphonate 10.22 Finally, acid hydrolysis
Scheme 3 Synthesis of phosphonic acid 1 via route В.

PHOSPHONOANALOGUE OF BENZO[C]PYROGLUTAMIC ACID
2443
of phosphonate 10 led to the formation of isoindolin-1-one-3-yl-phosphonic acid 1 in 69%
total yield. Acid 1 is a solid substance with a high melting point; it is soluble in water at
рН > 8 and insoluble in organic solvents.
It was found that the phosphonate 10 could be selectively N-deprotected by refluxing
for 1 h in trifluoroacetic acid and thus converted into the phosphonate 11 in almost quanti-
tative yield (Scheme 4). After evaporation of the solvent and treatment of the residue with
aqueous NaHCO3, the phosphonate 11 was isolated as a crystalline substance. Without treat-
ment with NaHCO3, the product was isolated as viscous oil, which slowly crystallized over
several weeks. The 1Н, 31Р NMR, and LCMS spectra showed that the mixture (oil + solid)
consists of phosphonate 11, phthalimide 16, diethylphosphate 17, and bis-phosphonate 18.
We assume that in the presence of traces of acid, which were not neutralized by NaHCO3,
retro-Michael reaction of phosphonate 11 occurred with formation of diethylphosphite and
imine 12, which underwent autooxidation,23 and via the formation of radicals 13 and 14
(initiation stage) converted into the hydroperoxide 15 (chain growth stage). Reaction of the
latter with diethylphosphite led to the formation of phosphoric acid diethyl ester 17 and
phthalimide 16. Formation of bis-phosphonate 18 can be explained by reaction of the rad-
ical 13 with two molecules of diethylphosphite, which confirms the proposed mechanism.
Scheme 4 Synthesis and oxidative transformations of phosphonate 11.
In summary, the phosphonic analogue of benzo[c]pyroglutamic acid—the isoindolin-
1-one-3-yl-phosphonic acid 1—was prepared with 69% overall yield by a three-step synthe-
sis starting from the N-tert-butylphtalimide (route B). Route A, starting from the acylphos-
phonate 2, led to the formation of hydroxamic acid 4 and diethyl phthalid-3-yl-phosphonate
6 without the formation of isoindolin-1-one-3-yl-phosphonic acid 1. The acid-catalyzed,
oxidative cascade conversion of phosphonate 11 to phthalimide and diethylphosphate was
observed. A mechanism for this conversion was proposed.
Now, using the elaborated method, we are going to synthesize various 2-
substituted isoindolin-1-one-3-yl-phosphonic acids, which are cyclic analogues of α-(N-
benzylamino)benzyl-phosphonic acid, a well known strong inhibitor of acid phosphatase.8

2444
G. O. KACHKOVSKYI AND O. I. KOLODIAZHNYI
EXPERIMENTAL
All commercially available reagents were used without further purification. Melting
points are uncorrected. IR spectra were obtained in KBr pellets and recorded with a Vertex
1
70 IR Fourier spectrophotometer. H, 13C, and 31P NMR spectra were measured at 300,
100, and 80 MHz, respectively, in DMSO-d6 and CDCl3 solution with TMS as internal
or 85% H3PO4 as external standard with Varian VXR-300 and Gemini 2000 (400 MHz)
spectrometers. Chemical shifts (δ) are reported in parts per million. Coupling constants
(J) are reported in Hz. Elemental analyses were performed in the analytical laboratory
of the Institute. All solvents were distilled and purified by standard procedures. TLC was
performed on plates coated with silica gel 60 with an F254 indicator; column chromatography
was carried out on silica gel 60 (230–240 mesh). N-tert-butylphtalimide 8 was prepared
according to the published method.24
Synthesis of Diethyl 2-(Methoxycarbonyl)benzoylphosphonate (2)
A mixture of monomethyl ester of phthalic acid (3.77 g, 20.93 mmol) and thionyl
chloride (3.05 mL, 41.85 mmol) in anhydrous dichloromethane (15 mL) was refluxed
for 40 min, cooled, and the solvent evaporated. The oily residue obtained was mixed with
triethylphosphite (7.26 mL, 41.85 mmol) and heated under reflux for 16 h. Compound 2 was
isolated as a colorless oil after vacuum distillation. Yield: 4.80 g (76%); bp 148–152◦C/0.08
mm Hg. IR (CCl4, cm−1), νmax: 929, 970, 1025, 1056, 1088, 1128, 1139, 1164, 1209, 1258,
1291, 1369, 1393, 1437, 1484, 1576, 1597, 1680, 1716, 1737, 2910, 2954, 2984. 1H NMR
(300 MHz, CDCl3): δ = 1.33 (t, J = 7.2 Hz, 6H, CH2CH3), 3.94 (s, 3H, OCH3), 4.23 (m,
4H, OCH2), 7.50 (d, J = 7.3 Hz, 1H, arom-H), 7.62 (m, 2H, arom-H), 7.97 (d, J = 7.3 Hz,
1H, arom-H). 13C NMR (100.6 MHz, CDCl3): δ = 16.7 (d, J = 5.6 Hz), 53.1, 64.3 (d, J =
7.2 Hz), 127.3 (d, J = 1.4 Hz), 129.6 (d, J = 0.8 Hz), 129.9, 131.3, 132.7, 140.6 (d, J = 60
Hz), 166.8, 204.8 (d, J = 189 Hz). 31P NMR (80 MHz, CDCl3): δ = –2.6. Anal. Calcd. for
C13H17O6P (300.25): C, 52.00; H, 5.71; P, 10.32. Found: C, 51.95; H, 5.75; P, 10.38%.
Synthesis of Diethyl 2-(Methoxyaminocarbonyl)benzoylphosphonate
(4)
To a solution of 2 (1.27 g, 4.23 mmol) and O-methylhydroxylamine hydrochloride
(0.39 g, 4.65 mmol) in anhydrous methanol (5 mL), pyridine (0.41 mL, 5.08 mmol) was
added. After standing at ambient temperature for 72 h, the reaction mixture was evaporated,
treated with 1N HCl (5 mL), extracted with chloroform (3 × 10 mL), washed with water
(20 mL), and dried over Na2SO4, and the solvent was evaporated again. The residue was
dissolved in diethyl ether (10 mL) and left at ambient temperature. The product precipitated
as white crystals in the course of 3 days. Yield: 0.40 g (29%); mp 97–98◦C. IR (KBr, cm−1),
νmax: 565, 597, 645, 695, 726, 758, 802, 896, 980, 1022, 1071, 1097, 1143, 1213, 1445,
1576, 1716, 2627, 2942, 2987. 1H NMR (300 MHz, DMSO-d6): δ = 1.20 (t, J = 7.0 Hz,
6H, CH2CH3), 3.84 (s, 3H, OCH3), 4.08 (m, 4H, OCH2), 7.23 (d, J = 7.8 Hz, 1H, arom-H),
7.52 (d, J = 7.8 Hz, 1H, arom-H), 7.64 (d, J = 7.8 Hz, 1H, arom-H), 7.93 (d, J = 7.8 Hz,
1H, arom-H), 13.08 (br. s, 1H, NH). 13C NMR (100.6 MHz, DMSO-d6): δ = 16.0 (d, J =
6.0 Hz), 62.3 (d, J = 1.0 Hz), 62.7 (d, J = 6.0 Hz), 128.3 (d, J = 3.1 Hz), 128.8, 129.7,
130.4 (d, J = 4.4 Hz), 131.7, 131.8 (d, J = 16.3 Hz), 152.7 (d, J = 216 Hz), 166.6. 31P

PHOSPHONOANALOGUE OF BENZO[C]PYROGLUTAMIC ACID
2445
NMR (80 MHz, DMSO-d6): δ = 7.0. Anal. Calcd. for C13H18NO6P (315.27): C, 49.53; H,
5.75; P, 9.82. Found: C, 49.52; H, 5.75; P, 9.80%.
Synthesis of Diethyl Phtalide-3-yl-phosphonate (6)25
To a solution of 2 (0.57 g, 1.90 mmol) in anhydrous methanol (5 mL), NaBH4 (72
mg, 1.90 mmol) was added portionwise while maintaining the temperature at 0–2◦C. After
additional stirring at ambient temperature for 30 min, the reaction mixture was quenched
with 10% NH4Cl solution (25 mL), extracted with dichloromethane (3 × 20 mL), washed
with brine (20 mL), and dried over Na2SO4, and the solvent was evaporated. Compound 6
was obtained after crystallization of the residue from benzene/hexane as colorless crystals.
Yield: 0.37 g (65%); mp 67–68◦C. IR (KBr, cm−1), νmax: 525, 535, 704, 716, 756, 772,
790, 830, 891, 959, 982, 1042, 1158, 1204, 1259, 1288, 1476, 1774, 2915, 2991. 1H NMR
(300 MHz, DMSO-d6): δ = 1.05 (t, J = 7.0 Hz, 3H, CH2CH3), 1.28 (t, J = 7.0 Hz, 3H,
CH2CH3), 3.96 (m, 2H, OCH2), 4.17 (m, 2H, OCH2), 6.29 (d, J = 11.0 Hz, 1H, OCHP),
7.69 (m, 2H, arom-H), 7.87 (t, J = 7.7 Hz, 1H, arom-H), 7.94 (d, J = 7.7 Hz, 1H, arom-H).
13C NMR (100.6 MHz, DMSO-d6): δ = 16.7 (d, J = 5.3 Hz), 16.9 (d, J = 5.3 Hz), 63.7 (d,
J = 6.8 Hz), 64.1 (d, J = 6.8 Hz), 75.8 (d, J = 163 Hz), 124.1 (d, J = 2.9 Hz), 125.1 (d,
J = 4.4 Hz), 125.9 (d, J = 1.7 Hz), 130.4 (d, J = 2.5 Hz), 135.2 (d, J = 2.4 Hz), 144.8
(d, J = 4.5 Hz), 169.9 (d, J = 2.6 Hz). 31P NMR (80 MHz, DMSO-d6): δ = 15.3. Anal.
Calcd. for C15H15O5P (270.22): C, 53.34; H, 5.60; P, 11.46. Found: C, 53.38; H, 5.69; P,
11.41%.
Synthesis of 2-tert-Buthyl-3-hydroxyisoindolin-1-one (3)26
To a solution of 8 (7.57 g, 37.25 mmol) inanhydrous methanol (100mL), NaBH4 (1.55
g, 40.97 mmol) was added portionwise while maintaining the temperature at 0–5◦C. After
additional stirring at ambient temperature for 45 min, the reaction mixture was quenched
with acetic acid (10 mL), and the solvent was evaporated. The residue was treated with
water (150 mL), and after 1 h stirring, compound 3 was filtered off, washed, and dried
to give a white solid. Yield: 6.55 g (86%); mp 139–140◦C. 1H NMR (300 MHz, CDCl3):
δ = 1.57 (s, 9H, t-Bu), 3.25 (d, J = 11.2 Hz, 1H, OH), 5.96 (d, J = 11.2 Hz, 2H, OCHN),
7.38–760 (m, 4H, arom-H). 13C NMR (100.6 MHz, CDCl3): δ = 28.3, 54.7, 82.3, 122.7,
122.9, 129.6, 131.9, 132.6, 143.6, 168.0. Anal. Calcd. for C12H15NO2 (205.26): C, 70.22;
H, 7.37. Found: C, 70.30; H, 7.39%.
Synthesis of Diethyl (2-tert-Buthylisoindoline-1-one-3-yl)
phosphonates (10)
A mixture of 3 (1.00 g, 4.87 mmol) and trifluoroacetic anhydride (5 mL) was stirred
for 30 min under argon. After the excess of trifluoroacetic anhydride and the resulting
trifluoroacetic acid were removed under reduced pressure, triethylphosphite (1.69 mL, 9.74
mmol) in anhydrous chloroform (20 mL) was added to the residue, and the resulting mixture
was stirred for 4 h. The reaction mixture was quenched with aqueous NaHCO3 (saturated,
60 mL). The organic layer was washed with water (50 mL), dried over Na2SO4, and the
solvent was evaporated. The residue obtained was purified using column chromatography
(ethylacetate:hexane = 2 : 1, Rf 0.33) to give compound 10 as an oil. Yield: 1.46 g (92%).
IR (ССl4, cm−1), νmax: 803, 810, 970, 1026, 1100, 1128, 1142, 1164, 1193, 1211, 1259,

2446
G. O. KACHKOVSKYI AND O. I. KOLODIAZHNYI
1317, 1326, 1347, 1368, 1395, 1468, 1697, 2931, 2980. 1H NMR (300 MHz, DMSO-d6):
δ = 0.97 (t, J = 7.0 Hz, 3H, CH2CH3), 1.24 (t, J = 7.0 Hz, 3H, CH2CH3), 1.60 (s, 9H,
t-Bu), 3.81 (m, 2H, OCH2), 4.03 (m, 2H, OCH2), 5.49 (d, J = 10.2 Hz, 1H, OCHP), 7.50
(m, 1H, arom-H), 7.58 (d, J = 4.3 Hz, arom-H), 7.64 (d, J = 4.3 Hz, arom-H). 13C NMR
(100.6 MHz, DMSO-d6): δ = 15.7 (d, J = 5.4 Hz), 15.9 (d, J = 5.4 Hz), 27.6, 55.4, 57.7
(d, J = 150 Hz), 62.3 (d, J = 7.2 Hz), 62.6 (d, J = 7.2 Hz), 122.0 (d, J = 1.8 Hz), 124.0 (d,
J = 2.8 Hz), 127.9 (d, J = 2.3 Hz), 130.4 (d, J = 2.5 Hz), 133.4 (d, J = 3.2 Hz), 139.8 (d, J
= 7.0 Hz), 168.0 (d, J = 1.3 Hz). 31P NMR (80 MHz, DMSO-d6): δ = 20.4. Anal. Calcd.
for C16H24NO4P (325.35): C, 59.07; H, 7.44; P, 9.52. Found: C, 59.08; H, 5.39; P, 9.43%.
Synthesis of Isoindoline-1-one-3-yl Phosphonic Acid (1)
A solution of 10 (0.98 g, 3.01 mmol) in a mixture of HClconc and dioxane (1:1) (100
mL) was heated at 80◦C for 72 h, cooled, and the solvent was evaporated. The crystalline
residue was treated with ethanol (10 mL), filtered off, washed, and dried to give compound
1 as a solid. Yield: 0.56 g (87%); mp > 270◦C (dec.). IR (KBr, cm−1), νmax: 459, 544, 690,
715, 730, 797, 960, 1033, 1090, 1142, 1191, 1242, 1321, 1363, 1472, 1611, 1673, 2829,
3057, 3186, 3293. 1H NMR (300 MHz, DMSO-d6): δ = 4.81 (d, J = 16.2 Hz, 1H, NCHP),
7.49 (t, J = 7.7 Hz, 1H, arom-H), 7.61 (t, J = 7.7 Hz, 1H, arom-H), 7.66 (m, 2H, arom-H),
8.92 (s, 1H, NH). 13C NMR (100.6 MHz, DMSO-d6): δ = 54.9 (d, J = 149 Hz), 122.5 (d,
J = 0.9 Hz), 123.9 (d, J = 2.4 Hz), 127.5 (d, J = 1.9 Hz), 130.8 (d, J = 2.4 Hz), 132.2 (d, J
= 4.4 Hz), 142.0 (d, J = 5.8 Hz), 169.4 (d, J = 3.2 Hz). 31P NMR (80 MHz, DMSO-d6): δ
= 15.2. Anal. Calcd. for C8H8NO4P (213.13): C, 45.08; H, 3.78; P, 14.53. Found: C, 45.12;
H, 3.85; P, 14.69%.
Synthesis of Diethyl Isoindoline-1-one-3-yl-phosphonate (11)
A solution of 10 (0.71 g, 2.18 mmol) in trifluoroacetic acid (7 mL) was refluxed
for 1.5 h, cooled, and the solvent was evaporated. The oily residue was dissolved in
dichloromethane (10 mL), washed with 5% NaHCO3 solution to pH > 7, dried over
Na2SO4. Then the solvent was evaporated again, and the residue was dried under reduced
pressure to give compound 11 as colorless solid. Yield: 0.58 g (98%); mp 86–87◦C. IR
(KBr, cm−1), νmax: 542, 706, 753, 777, 799, 830, 902, 975, 1017, 1162, 1192, 1232, 1259,
1294, 1345, 1693, 2875, 2989, 3072, 3190. 1H NMR (300 MHz, DMSO-d6): δ = 1.04 (t,
J = 7.0 Hz, 3H, CH2CH3), 1.24 (t, J = 7.0 Hz, 3H, CH2CH3), 3.90 (m, 2H, OCH2), 4.09
(m, 2H, OCH2), 5.26 (d, J = 14.6 Hz, 1H, NCHP), 7.56 (m, 1H, arom-H), 7.66 (m, 2H,
arom-H), 7.73 (d, J = 7.7 Hz, 1H, arom-H), 9.24 (s, 1H, NH). 13C NMR (100.6 MHz,
DMSO-d6): δ = 16.0 (d, J = 5.5 Hz), 16.2 (d, J = 5.5 Hz), 53.4 (d, J = 153 Hz), 62.9 (d,
J = 7.0 Hz), 62.6 (d, J = 7.0 Hz), 123.0 (d, J = 1.4 Hz), 124.0 (d, J = 2.7 Hz), 128.4 (d,
J = 2.1 Hz), 131.4 (d, J = 2.5 Hz), 132.4 (d, J = 4.6 Hz), 140.6 (d, J = 6.1 Hz), 169.7
(d, J = 3.2 Hz). 31P NMR (80 MHz, DMSO-d6): δ = 19.6. Anal. Calcd. for C12H16NO4P
(269.24): C, 53.53; H, 5.99; P, 11.50. Found: C, 53.49; H, 5.95; P, 11.57%.
Investigation of Oxidative Cascade Conversion of Diethyl
Isoindoline-1-one-3-yl-phosphonate (11)
A solution of 10 (0.25 g, 0.77 mmol) in trifluoroacetic acid (2.5 mL) was refluxed for
1.5 h, cooled, and the solvent was evaporated. The oily residue was additionally dried under

PHOSPHONOANALOGUE OF BENZO[C]PYROGLUTAMIC ACID
2447
reduced pressure to give 11 in a quantitative yield (0.21 g) as viscous oil. Its analysis and
spectral data were identical to 11 obtained by method described above using 5% NaHCO3
solution washing procedure. Upon 3 weeks standing at ambient temperature, this oil crystal-
lized. According to the NMR spectra and LCMS spectral data, it is a mixture that consists of
11:16:17:18 in ratio 5:50:40:5. Phthalimide (16): APCI MS: m/z (M+1) 148; 1H NMR (300
MHz, DMSO-d6): δ = 7.84 (s, 4H, arom-H), 11.37 (s, 1H, NH). Diethylphosphate (17): 1H
NMR (300 MHz, DMSO-d6): δ = 1.22 (t, J = 7.0 Hz, 6H, CH2CH3), 3.92 (m, 4H, OCH2);
31P NMR (80 MHz, DMSO–d6): δ = −0.4. 3,3-Bis(diethylphosphonyl)-isoindoline-1-one
1
(18): APCI MS: m/z (M+1) 406; H NMR (300 MHz, DMSO-d6): δ = 1.08 (t, J = 7.0
Hz, 6H, CH2CH3), 1.17 (t, J = 7.0 Hz, 6H, CH2CH3), 3.90 (m, 4H, OCH2), 4.13 (m, 4H,
OCH2), 7.56 (m, 1H, arom-H), 7.67 (m, 2H, arom-H), 7.74 (d, J = 4.7 Hz, 1H, Ar), 9.37
(s, 1H, NH); 31P NMR (80 MHz, DMSO–d6): δ = 17.7.
REFERENCES
1. E. Valencia, I. Weiss, S. Firdous, A. J. Freyer, and M. Shamma, Tetrahedron, 40, 3957 (1984).
2. G. Nannin, P. N. Griraldi, G. Molgora, G. Biasoli, F. Spinelli, L. Logemann, E. Dradi, G. Zanni,
A. Buttinoni, and R. Tommasini, Arzneim. Forsch., 23, 1090 (1973).
3. T. R. Belliotti, W. A. Brink, S. R. Kesten, J. R. Rubin, D. J. Wustrow, K. T. Zoski, S. Z. Whetzel,
A. E. Corbin, T. A. Pugsley, T. G. Heffner, and L. D. Wise, Bioorg. Med. Chem. Lett., 8, 1499
(1998).
4. Z. P. Zhuang, M. P. Kung, M. Mu, and H. F. Kung, J. Med. Chem., 41, 157 (1998).
5. M. H. Norman, D. J. Minick, and G. C. Rigdon, J. Med. Chem., 39, 149 (1996).
6. J. A. Lowe and F. E. Ewing, J. Heterocycl. Chem., 24, 877 (1987).
7. H. Maeda, M. Suzuki, H. Sugano, M. Yamamura, and R. Ishida, Chem. Pharm. Bull., 36, 190
(1988).
8. A.I. Vovk, I.M. Mischenko, V.Yu. Tanchuk, G.A. Kachkovskii, S. Yu. Sheiko, O.I. Kolodyazhnyi,
and V.P. Kukhar, Bioorg. Med. Chem. Lett., 18, 4620 (2008).
9. S. A. Beers, C. F. Schwender, D. A. Loughney, E. Malloy, K. Demarest, and J. Jordan, Bioorg.
Med. Chem., 4, 1693 (1996).
10. R. F. Frechette, C. Ackerman, S. Beers, R. Look, and J. Moore, Bioorg. Med. Chem. Lett., 7,
2169 (1997).
11. G. O. Kachkovskyi and O. I. Kolodiazhnyi, Tetrahedron, 63, 12576 (2007).
12. G. O. Kachkovskyi and O. I. Kolodiazhnyi, Phosphorus, Sulfur, and Silicon, 184, 890 (2009).
13. V. V. Nesterov and O. I. Kolodiazhnyi, Tetrahedron, 63, 6720 (2007).
14. V. V. Nesterov and O. I. Kolodiazhnyi, Synlett, 2400 (2007).
15. P. Savignac and B. Iorga, Modern Phosphonate Chemistry (CRC Press, Boca Raton, FL, 2003),
Chap. 7, and references cited therein.
16. K. D. Berlin, R. T. Claunch, and E. T. Gaudy, J. Org. Chem., 33, 3090 (1968).
17. K. D. Berlin, N. K. Roy, and R. T. Claunch, J. Am. Chem. Soc., 90, 4494 (1968).
18. J. Kowalik, L. Kupczyk-Subotkowska, and P. Mastalerz, Synthesis, 57 (1981).
19. E. Breuer, R. Karaman, A. Goldblum, D. Gibson, H. Leader, B. V. L. Potter, and J. H. Cummins,
J. Chem. Soc., Perkin Trans. 1, 3047 (1988).
20. D. L. Hughes, Org. Prep. Proced. Int., 28, 127 (1996).
21. T. Gajda and M. Matusaik, Synthesis, 367 (1992).
22. For phosphorylation of N-acyliminium salt, see:T. Goto, S. Utsunomiya, H. Aiba, H. Hayasaka,
M. Endo, R. Watanabe, T. Ishizaki, R. Sato, and M. Saito, Bull. Chem. Soc. Jpn., 64, 1901 (1991).
23. The autooxidation of imine 12 proceeds similarly to the autooxidation of aldehydes to car-
boxylic acids. The mechanism of autooxidation is described in: M. B. Smith and J. March,

2448
G. O. KACHKOVSKYI AND O. I. KOLODIAZHNYI
March’s Advanced Organic Chemistry. Reactions, Mechanisms, and Structures, 6th ed. (Wiley,
New York, 2007), p. 967.
24. Organic Syntheses: An Annual Publication of Satisfactory Methods for the Preparation of Or-
ganic Chemicals (Wiley, New York, 1949), vol. 29, p. 18.
25. M. H. B. Stowell, J. M. Ueland, and R. W. McClard, Tetrahedron Lett., 31, 3261 (1990).
26. T. Nishio and H. Yamamoto, J. Heterocycl. Chem., 32, 883 (1995).