Synthesis of phosphonic acids possessing isoindolin-1-one moiety: Unexpected acid-catalyzed c-p-bond cleavage

Article abstract of DOI:10.1080/10426500802715601

Phosphonic acids bearing isoindolin-1-one moiety were synthesized by dehydrative aromatization of the corresponding epoxyisoindolyl phosphonates. A mechanism for the unexpected acid catalyzed dephosphorylation was proposed.

Full text of DOI:10.1080/10426500802715601

This article was downloaded by: [Tufts University]
On: 03 December 2014, At: 11:19
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 Phosphonic Acids
Possessing Isoindolin-1-one
Moiety: Unexpected Acid-
Catalyzed C-P-Bond Cleavage
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: 26 Mar 2009.
To cite this article: Georgiy O. Kachkovskyi & Oleg I. Kolodiazhnyi (2009) Synthesis
of Phosphonic Acids Possessing Isoindolin-1-one Moiety: Unexpected Acid-Catalyzed
C-P-Bond Cleavage, Phosphorus, Sulfur, and Silicon and the Related Elements, 184:4,
890-907, DOI: 10.1080/10426500802715601
To link to this article: http://dx.doi.org/10.1080/10426500802715601
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, 184:890–907, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802715601
Synthesis of Phosphonic Acids Possessing
Isoindolin-1-one Moiety: Unexpected Acid-Catalyzed
C-P-Bond Cleavage
Georgiy O. Kachkovskyi and Oleg I. Kolodiazhnyi
Institute of Bioorganic Chemistry and Petrochemistry of the National
Academy of Sciences of Ukraine, Kyiv, Ukraine
Phosphonic acids bearing isoindolin-1-one moiety were synthesized by dehydrative
aromatization of the corresponding epoxyisoindolyl phosphonates. A mechanism
for the unexpected acid catalyzed dephosphorylation was proposed.
Keywords Dehydrative aromatization; dephosphorylation of phosphonic acid; epoxy-
isoindolyl phosphonates
INTRODUCTION
Isoindolin-1-ones have attracted considerable attention because of
their high biological (e.g., antihypertensive,1 antipsychotic,2 antivirus,3
antileukemic,4 etc.) activity. The isoindolin-1-one fragment is present
in synthetic (indoprofen—anti-inflammatory agent5) as well as in natu-
rally occuring compounds, in particular in alkaloids (i.e., lennoxamine,
nuevamine6). One of the most interesting and recent methods for
the synthesis of isoindolin-1-ones is the dehydrative aromatization
of epoxyisoindolones, which are the products of the reaction be-
tween aminomethylfuranes and acylating dienophiles (e.g., maleic
anhydride).7−9
Continuing our studies on the chemistry of amino- and hydrox-
yphosphonic acids,10−12 we have recently synthesized isomeric α-
acylaminophosphonates 1 and 2 possessing epoxyisoindolone moiety
Received 21 December 2007; accepted 24 January 2008.
Dedicated to Professor Marian Mikolꢀajczyk, CBMiM PAN, in Lꢀ o´dz´, Poland, on the
occasion of his 70th birthday.
This work was supported by the STCU grant No. 3558. In addition, we thank Dr. I. I.
Gerus, Dr. A. O. Gudima, and Dr. Yu. M. Pustovit for helpful discussions.
Address correspondence to Oleg I. Kolodiazhnyi, Institute of Bioorganic Chemistry
and Petrochemistry of the National Academy of Sciences of Ukraine, Murmanska Str. 1,
Kyiv, 02094, Ukraine. E-mail: oikol123@rambler.ru
890

P-Functionalized Isoindolin-1-ones
891
SCHEME 1
by a tandem acylation/[4+2]-cycloaddition reaction (Scheme 1).13Exo-
epoxyisoindolyl phosphonates 1 were isolated as a mixture of two di-
astereomeres, formed by two chiral elements: bridge system and carbon
atom α to the phosphonate group. Their ratio varied depending on the
reaction conditions, but usually was approximately 40:60. The isomeric
compounds 2 were formed mainly as one diastereomer with opposite
orientation of the epoxy and phosphonate groups.
In this article, we report on the transformation of epoxyisoindolyl
phosphonates under the influence of acids, which results in the arom-
atization of oxabicycloheptene skeleton.
RESULTS AND DISCUSSION
The most convenient method for the dehydrative aromatizations
of 2,3,7,7a-tetrahydro-3a,6-epoxyisoindolyl-1-ones was proposed by
Zubkov and co-workers—it consists of heating the initial compounds
in 85% H3PO4.14,15 With this method, epoxyisoindolyl phosphonates 3
and 4 (types 1), synthesized earlier by us,13 were converted into appro-
priate isoindolin-1-ones by heating for 1 h at 80◦C. The reaction was
accompanied by simultaneous hydrolysis to give the phosphonic acids
5, 6 (Scheme 2). Phosphonic acids 5 and 6 were isolated in good yields
as solids after dilution of the reaction mixture with water and were
purified by crystallization from aqueous alcohol.
Functionalization of the COOH group in acids 5 and 6 could be
achieved either with preliminary protection of the phosphonic acid or
by the dehydrative aromatization of the appropriate epoxyisoindolyl
carboxamides 7 and 8. The epoxyisoindolyl phosphonates 3 and 4 were
transformed via the acylchlorides into the carboxamides 7 and 8, which
were isolated as two diastereomers with a ratio of ∼ 40:60. Aromati-
zation of compounds 7 and 8 was carried out under reaction condi-
tions elaborated for the acids 3 and 4 (Scheme 2). The carboxamides of
phosphonic acids 9 and 10 prepared by this reaction were purified by
crystallization.

892
G. O. Kachkovskyi and O. I. Kolodiazhnyi
SCHEME 2
Table I summarizes the results obtained in the preparation of com-
pounds 5–10 using these experimental conditions.
Contrary to our expectations, the treatment of epoxyisoindolyl phos-
phonate 11 with 85% H3PO4 did not result in the formation of phos-
phonic acid 12. However, after heating compound 11 for 4 h at 80◦C, a
mixture of three substances was isolated: the starting epoxyisoindolyl
phosphonate 11, the isoindolyl phosphonate 13, and the product of
dephosphorylation—N-benzyl-7-carboxyisoindolin-1-one 14—in a ratio
TABLE I Epoxyisoindolyl Phosphonates 7 and 8 and
Phosphonic Acids 5, 6, 9, and 10
X
Y
R
Yield % δ , ppm MS (APCI), m/z
P
5
6
H
F
H
H
F
OH
OH
–
–
–
–
–
–
68
70
63
58
59
48
46
55
30
50
14.0
14.5
348 [M+1]
366 [M+1]
487 [M+1]
501 [M+1]
487 [M+1]
501 [M+1]
441 [M+1]
455 [M+1]
441 [M+1]
453 [M–1]
7a
7b
8a
8b
9a
9b
10a
10b
4–FC6H4
4–FC6H4CH2
22.5/23.5*
23.4/22.5*
22.2/23.1*
22.3/23.1*
15.5
Ph
CH2Ph
F
H
H
F
NH(4-FC6H4)
NH(4–FC6H4CH2)
NHPh
–
–
–
–
15.4
14.4
15.2
F
NHCH2Ph
*δ (major diastereomer)/δ (minor diastereomer).
P
P

P-Functionalized Isoindolin-1-ones
893
SCHEME 3
of 35:45:20 according to 1H and 31P NMR data and LCMS spectra
(Scheme 3, Figure 1).
Dehydrative aromatization of 7-oxabicyclo[2.2.1]heptenes can be
carried out also under basic conditions, for example, by action
of NaOMe/MeOH or t-BuLi.16 Epoxyisoindolyl phosphonate 11 was
FIGURE 1 Part of the 1H NMR spectrum of a mixture obtained after heating
compound 12 for 4 h with 85% H3PO4: 11 (ꢀ) 13(∗), 14 (O).

894
G. O. Kachkovskyi and O. I. Kolodiazhnyi
SCHEME 4
aromatized by a reaction with NaOMe in methanol to give a mixture of
three products consisting of compounds 13, 14, and the monomethyl es-
ter of phosphonic acid 15 in a ratio of 20:55:25 (according to 1H and 31
P
NMR and LCMS spectra) (Scheme 3). The experimental data allow us to
conclude that N-benzyl-7-carboxyisoindolin-1-one-3-yl-phosphonic acid
12 is dephosphorylated in the moment of formation. Treatment of com-
pound 11 with an excess of Me3SiBr gave in addition to the expected
epoxyisoindolyl phosphonic acid 16 a small amount of the dephospho-
rylated product 13, which was observed and identified by its 1H and 31
P
NMR spectra (Scheme 3). It is likely that the strong phosphonic acid
16, the first dissociation constant of which is approximately identical to
that of H3PO4,17 causes dehydrative self-aromatization. Therefore the
unstable acid 12 is formed and then dephosphorylated to compound 14.
In summarizing these data, we propose a mechanism of acid catal-
ysis for the dephosphorylation of phosphonic acid 12, which is shown
in Scheme 4. According to this mechanism, the cleavage of the C P
bond occurs as a consequence of electronic density redistribution in the
molecule, which is caused by protonation of the amide oxygen atom. The
leaving group in this reaction is evidently the metaphosphate (which
converts immediately into phosphate); this was proved by aromatiza-
tion of compound 11 in trifluroacetic acid. The 31P NMR spectrum of the
reaction mixture after heating for 14 h at 70◦C showed only the signal of
H3PO4 at 0 ppm. It is probable that dephosphorylation of monomethyl
phosphonate 15 also takes place, however much more slowly than the
dephosphorylation of acid 12.
According to the proposed mechanism, the carboxyl group does not
influence the dephosphorylation of 12 because it is located in the meta-
position of the benzene ring relative to the (HO)2P(O)C-group. There-
fore we have anticipated that the model phosphonic acid 19, which was
prepared from 17 as shown in Scheme 5, should be easily dephospho-
rylated.

P-Functionalized Isoindolin-1-ones
895
SCHEME 5
However, phosphonic acid 19 was not dephosphorylated, even after
heating for 16 h at 60◦C in concentrated H2SO4 (according to the 31P
NMR spectra). This test proves that the COOH-group must participate
in the process of dephosphorylation of 12, and therefore we propose an
alternative mechanism (Scheme 6). We suppose that the protonation
of the intermediate compound 20 leads through the elimination of HX
from 21 to the formation of lactone 22, which is dephosphorylated as a
result of electronic density redistribution.
In carring out of the dehydrative aromatization of epoxyisoindolyl
phosphonates 7 and 8, we have shown the stability of the amide
bond under these reaction conditions (Scheme 2). However, deriva-
tives of epoxyisoindolyl phosphonate 11—methyl ester 23 and amide
(morpholyde) 24—were converted into the compound 14, instead of
to the appropriate methyl ether 25 or amide 26, after heating in the
SCHEME 6

896
G. O. Kachkovskyi and O. I. Kolodiazhnyi
SCHEME 7
trifluoroacetic acid solution (Scheme 7). This observation is in agree-
ment with the proposed mechanism and confirms the elimination of HX
from the intermediate compound 21 (Scheme 6).
Examples of the acid-catalyzed cleavage of C P bond by an A-SE2
mechanism with elimination of H3PO4 in heterocyclic aminophosphonic
acids were described by Boduszek et al.18,19
In conclusion, the chemistry reported here offers a convenient en-
try to (isoindolin-1-one-2-yl)phosphonic acids, which are of interest as
potentially biologically active compounds and can be used as synthetic
building blocks for the construction of bioactive compounds. We con-
tinue to study the properties of (isoindolin-1-one-2-yl)phosphonic acids
including their biological activity.
EXPERIMENTAL
All commercially available reagents were used without further purifi-
cation. Melting points are uncorrected. IR spectra were obtained in
KBr pellets or in CCl4 solution (for 18) and with a Vertex 70 IR Fourier
1
spectrophotometer. H, 13C, and 31P NMR spectra were measured at
300, 100, and 80 MHz, respectively, in DMSO-d6 solution with TMS as
internal or H3PO4 as external standard with a Varian VXR-300 and a
Gemini 2000 (400 MHz) spectrometer. Chemical shifts (δ) are reported
in parts per million. Coupling constants (J) are reported in Hertz. Ha,
Hb, and Hc hydrogen atoms are shown in Scheme 1. LC and APCI MS
data were obtained with an Agilent 1100/DAD/MSD VL G1965a instru-
ment. Elemental analyses were performed in the analytical laboratory
of this institute. All solvents were distilled and purified by standard

P-Functionalized Isoindolin-1-ones
897
procedures. Compounds 3, 4, 11,13 and 1720 were prepared according
to published methods.
Synthesis of Epoxyisoindolyl Phosphonate Carboxamides 7, 8,
and 24: General Procedure
To a suspension of the epoxyisoindolyl phosphonate 3, 4, or 11 (1 mmol)
in anhydrous dichloromethane (10 mL), SOCl2 (0.15 mL, 2 mmol) was
added. The reaction mixture was refluxed until the evolution of SO2 and
HCl had stopped (ca. 0.5 h). After this, the amine (4 mmol) was added,
and the resulting suspension was stirred and refluxed for additional 0.5
h. After cooling, the reaction mixture was poured into water, and the
organic layer was separated and washed with 2% HCl solution, water,
5% NaHCO3 solution, and again with water. The organic layer was
dried over Na2SO4, and the solvent was evaporated. The oil residue was
treated with ether and solidified. The precipitate formed was filtered
off, washed with ether, and dried. The product is obtained as a pale solid.
Dimethyl 1-[3-Aza-6-((4-fluorophenyl)aminocarbonyl)-10-oxa-
exo-tricyclo[5.2.1.01,5]-4-oxodec-8-en-
3-yl]-1-phenylmethylphosphonate (7a)
Yield 63%; pale solid; dr = 40:60. IR (KBr, cm−1), νmax: 1697 (NCO),
1664, 1548 (RNHC O), 1215 (P O). Anal. Calcd for C24H24N2O6FP
(486.44): C, 59.26; H, 4.97; P, 6.37. Found: C, 59.12; H, 5.00; P, 6.48%.
m/z (M+1) 487.
Major diastereomer: 1H NMR (300 MHz, DMSO-d6): δ = 2.70 (d, J =
9.2 Hz, 1H, Hb), 2.80 (d, J = 9.2 Hz, 1H, Ha), 3.49 (d, J = 10.6 Hz,
3H, OCH3), 3.75 (d, J = 10.6 Hz, 3H, OCH3), 3.79 (d, J = 11.5 Hz, 1H,
CH2N), 4.22 (d, J = 11.5 Hz, 1H, CH2N), 5.08 (d, J = 1.2 Hz, 1H, Hc),
5.59 (d, J = 21.2 Hz, 1H, PCHN), 6.46 (dd, J = 5.7 Hz, 1.2 Hz, 1H,
CH CH), 6.56 (d, J = 5.7 Hz, 1H, CH CH), 7.15 (t, J = 9.2 Hz, 2H,
4-FC6H4), 7.32–7.62 (m, 7H, 4-FC6H4, Ph), 9.93 (s, 1H, CONH). 13C
NMR (100.6 MHz, DMSO-d6): δ = 46.998, 47.008, 50.6, 52.2 (d, J = 157
Hz), 53.5 (d, J = 8.1 Hz), 55.2 (d, J = 8.1 Hz), 81.8, 88.7, 115.8 (d, J =
22.1 Hz), 121.8, 129.2, 129.6, 130.2 (d, J = 8.2 Hz), 133.4 (d, J = 3.5
Hz), 136.4 (d, J = 2.3 Hz), 136.4, 137.5, 158.5 (d, J = 239 Hz), 169.5,
171.3 (d, J = 5.3 Hz). 31P NMR (81 MHz, DMSO-d6): δ = 22.5.
Minor diastereomer: 1H NMR (300 MHz, DMSO-d6): δ = 2.71 (d, J =
8.9 Hz, 1H, Hb), 2.93 (dd, J = 8.9 Hz, 2.6 Hz, 1H, Ha), 3.56 (d, J = 12.0
Hz, 1H, CH2N), 3.63 (d, J = 10.8 Hz, 3H, OCH3), 3.72 (d, J = 10.8 Hz,
3H, OCH3), 4.21 (d, J = 12.0 Hz, 1H, CH2N), 5.06 (d, J = 1.4 Hz, 1H,
Hc), 5.65 (d, J = 21.3 Hz, 1H, PCHN), 6.50 (dd, J = 5.6 Hz, 1.4 Hz, 1H,

898
G. O. Kachkovskyi and O. I. Kolodiazhnyi
CH CH), 6.69 (d, J = 5.6 Hz, 1H, CH CH), 7.12 (t, J = 9.2 Hz, 2H,
4-FC6H4), 7.32–7.62 (m, 7H, 4-FC6H4, Ph), 9.84 (s, 1H, CONH). 13C
NMR (100.6 MHz, DMSO-d6): δ = 46.996, 47.001, 50.8, 51.1 (d, J = 155
Hz), 53.8 (d, J = 6.6 Hz), 54.1 (d, J = 6.6 Hz), 81.9, 88.8, 115.8 (d, J =
21.9 Hz), 121.9, 128.8, 129.1 (d, J = 7.6 Hz), 129.4, 133.3 (d, J = 3.7
Hz), 136.3 (d, J = 3.0 Hz), 136.4, 137.6, 158.5 (d, J = 239 Hz), 169.3,
171.4 (d, J = 4.6 Hz). 31P NMR (81 MHz, DMSO-d6): δ = 23.5.
Dimethyl 1-[3-Aza-6-((4-fluorophenylmethyl)aminocarbonyl)-
10-oxa-exo-tricyclo [5.2.1.01,5]-4-oxodec-8-en-3-yl]-1-
phenylmethylphosphonate (7b)
Yield 58%; pale solid; dr = 40:60. Anal. Calcd. for C25H26N2O6FP
(500.47): C, 60.00; H, 5.24; P, 6.19. Found: C, 59.95; H, 5.13; P, 6.18%.
m/z (M+1) 501.
Major diastereomer: 1H NMR (300 MHz, DMSO-d6): δ = 2.57 (d, J =
9.1 Hz, 1H, Hb), 2.70 (d, J = 9.1 Hz, 1H, Ha), 3.52 (d, J = 10.6 Hz,
3H, OCH3), 3.76 (d, J = 10.6 Hz, 3H, OCH3), 3.77 (d, J = 11.5 Hz, 1H,
CCH2N), 4.20 (d, J = 11.5 Hz, 1H, CCH2N), 4.30 (dd, J = 13.0 Hz, 6.0
Hz, 2H, 4-FC6H4CH2NH), 5.00 (d, J = 1.5 Hz, 1H, Hc), 5.68 (d, J = 22.0
Hz, 1H, PCHN), 6.46 (dd, J = 5.7 Hz, 1.5 Hz, 1H, CH CH), 6.53 (d, J =
5.7 Hz, 1H, CH CH), 7.15 (t, J = 9.2 Hz, 2H, 4-FC6H4), 7.32–7.50 (m,
5H, 4-FC6H4, Ph), 7.55 (d, J = 7.5 Hz, 1H, Ph), 8.22 (t, J = 6.0 Hz, 1H,
CONH). 13C NMR (100.6 MHz, DMSO-d6): δ = 41.6, 45.2, 46.0, 49.2,
51.2 (d, J = 158 Hz), 52.5 (d, J = 7.2 Hz), 54.1 (d, J = 7.2 Hz), 81.2,
87.7, 114.6 (d, J = 21.1 Hz), 128.3, 128.7, 129.1 (d, J = 7.8 Hz), 129.2
(d, J = 7.5 Hz), 132.6 (d, J = 3.7 Hz), 135.4 (d, J = 3.1 Hz), 135.5, 136.5,
160.9 (d, J = 242 Hz), 169.8, 170.5 (d, J = 5.5 Hz). 31P NMR (81 MHz,
DMSO-d6): δ = 23.4.
Minor diastereomer: 1H NMR (300 MHz, DMSO-d6): δ = 2.59 (d, J =
9.0 Hz, 1H, Hb), 2.84 (dd, J = 9.0 Hz, 2.6 Hz, 1H, Ha), 3.53 (d, J = 11.6
Hz, 1H, CCH2N), 3.65 (d, J = 10.8 Hz, 3H, OCH3), 3.74 (d, J = 10.8
Hz, 3H, OCH3), 4.19 (d, J = 11.6 Hz, 1H, CCH2N), 4.23 (d, J = 5.7 Hz,
2H, 4-FC6H4CH2NH), 4.98 (d, J = 1.4 Hz, 1H, Hc), 5.63 (d, J = 21.5
Hz, 1H, PCHN), 6.44 (dd, J = 5.6 Hz, 1.4 Hz, 1H, CH CH), 6.67 (d, J =
5.6 Hz, 1H, CH CH), 7.12 (t, J = 9.2 Hz, 2H, 4-FC6H4), 7.32–7.50 (m,
7H, 4-FC6H4), 8.04 (t, J = 5.7 Hz, 1H, CONH). 13C NMR (100.6 MHz,
DMSO-d6): δ = 41.5, 45.2, 46.0, 49.4, 50.2 (d, J = 155 Hz), 52.8 (d, J =
7.0 Hz), 53.1 (d, J = 7.0 Hz), 81.2, 87.8, 114.6 (d, J = 21.1 Hz), 127.8,
128.1 (d, J = 7.3 Hz), 128.4, 129.2 (d, J = 7.8 Hz), 132.5 (d, J = 3.5 Hz),
135.3 (d, J = 3.3 Hz), 135.5, 136.5, 160.9 (d, J = 242 Hz), 169.6, 170.6
(d, J = 5.1 Hz). 31P NMR (81 MHz, DMSO-d6): δ = 22.5.

P-Functionalized Isoindolin-1-ones
899
Dimethyl 1-[3-Aza-6-(phenylaminocarbonyl)-10-oxa-exo-
tricyclo[5.2.1.01,5]-4-oxodec-8-en-3-yl]-1-(4-fluorophenyl)
methylphosphonate (8a)
Yield 59%; pale solid; dr = 40:60. Anal. Calcd. for C24H24N2O6FP
(486.44): C, 59.26; H, 4.97; P, 6.37. Found: C, 59.19; H, 5.04; P, 6.28%.
m/z (M+1) 487.
Major diastereomer: 1H NMR (300 MHz, DMSO-d6): δ = 2.72 (d, J =
9.2 Hz, 1H, Hb), 2.80 (d, J = 9.2 Hz, 1H, Ha), 3.50 (d, J = 10.9 Hz,
3H, OCH3), 3.76 (d, J = 10.9 Hz, 3H, OCH3), 3.78 (d, J = 11.2 Hz, 1H,
CH2N), 4.19 (d, J = 11.2 Hz, 1H, CH2N), 5.08 (d, J = 1.3 Hz, 1H, Hc),
5.60 (d, J = 21.5 Hz, 1H, PCHN), 6.48 (dd, J = 5.6 Hz, 1.3 Hz, 1H,
CH CH), 6.55 (d, J = 5.6 Hz, 1H, CH CH), 7.03 (t, J = 7.2 Hz, 1H,
Ph), 7.20–7.34 (m, 4H, Ph), 7.48–7.62 (m, 4H, 4-FC6H4), 9.87 (s, 1H,
CONH). 13C NMR (100.6 MHz, DMSO-d6): δ = 46.4, 46.5, 50.0, 50.8 (d,
J = 158 Hz), 53.1 (d, J = 7.5 Hz), 54.9 (d, J = 7.5 Hz), 81.5, 88.3, 116.2
(d, J = 21.8 Hz), 119.7, 123.3, 128.9, 129.5 (t, J = 3.6 Hz), 132.1 (t, J =
8.4 Hz), 136.1, 137.3, 139.8, 162.5 (d, J = 246 Hz), 169.4, 171.1 (d, J =
5.1 Hz). 31P NMR (81 MHz, DMSO-d6): δ = 22.2.
Minor diastereomer: 1H NMR (300 MHz, DMSO-d6): δ = 2.74
(d, J = 9.2 Hz, 1H, Hb), 2.92 (dd, J = 9.2 Hz, 2.6 Hz, 1H, Ha),
3.54 (d, J = 11.2 Hz, 1H, CH2N), 3.63 (d, J = 10.9 Hz, 3H,
OCH3), 3.72 (d, J = 10.9 Hz, 3H, OCH3), 4.19 (d, J = 11.2 Hz,
1H, CH2N), 5.07 (d, J = 1.4 Hz, 1H, Hc), 5.66 (d, J = 22.0 Hz,
1H, PCHN), 6.50 (dd, J = 5.7 Hz, 1.4 Hz, 1H, CH CH), 6.69 (d, J =
5.7 Hz, 1H, CH CH), 7.01 (t, J = 7.2 Hz, 1H, Ph), 7.20–7.34 (m, 4H,
Ph), 7.48–7.62 (m, 4H, 4-FC6H4), 9.78 (s, 1H, CONH). 13C NMR (100.6
MHz, DMSO-d6): δ = 46.4, 46.6, 49.8 (d, J = 155 Hz), 50.3, 53.4 (d, J =
6.7 Hz), 54.7 (d, J = 6.7 Hz), 81.6, 88.4, 116.0 (d, J = 21.4 Hz), 119.7,
123.3, 128.9, 129.2 (t, J = 3.6 Hz), 130.9 (t, J = 8.4 Hz), 136.1, 137.4,
139.6, 162.2 (d, J = 246 Hz), 169.2, 171.3 (d, J = 5.1 Hz). 31P NMR (81
MHz, DMSO-d6): δ = 23.1.
Dimethyl 1-[3-Aza-6-(benzylaminocarbonyl)-10-oxa-exo-
tricyclo [5.2.1.01,5]-4-oxodec-8-en-3-yl]-1-(4-fluorophenyl)
methylphosphonate (8b)
Yield 48%; pale solid; dr = 40:60. Anal. Calcd. for C25H26N2O6FP
(500.47): C, 60.00; H, 5.24; P, 6.19. Found: C, 59.95; H, 5.13; P, 6.18%.
m/z (M+1) 501.
Major diastereomer: 1H NMR (300 MHz, DMSO-d6): δ = 2.58 (d, J =
9.4 Hz, 1H, Hb), 2.69 (d, J = 9.4 Hz, 1H, Ha), 3.53 (d, J = 10.6 Hz,
3H, OCH3), 3.75 (d, J = 10.6 Hz, 3H, OCH3), 3.76 (d, J = 11.3 Hz, 1H,
CCH2N), 4.17 (d, J = 11.3 Hz, 1H, CCH2N), 4.30 (d, J = 5.8 Hz, 2H,

900
G. O. Kachkovskyi and O. I. Kolodiazhnyi
PhCH2NH), 5.00 (d, J = 1.3 Hz, 1H, Hc), 5.65 (d, J = 21.6 Hz, 1H,
PCHN), 6.44 (dd, J = 5.6 Hz, 1.3 Hz, 1H, CH CH), 6.53 (d, J = 5.6 Hz,
1H, CH CH), 7.21–7.42 (m, 7H, 4-FC6H4, Ph), 7.60 (dd, J = 8.1 Hz,
5.4 Hz, 2H, 4-FC6H4), 8.20 (t, J = 5.8 Hz, 1H, CONH). 13C NMR (100.6
MHz, DMSO-d6): δ = 42.8, 45.6, 46.4, 49.7, 50.8 (d, J = 158 Hz), 53.1
(d, J = 7.1 Hz), 54.9 (d, J = 7.1 Hz), 81.8, 88.2, 116.2 (d, J = 21.6 Hz),
127.1, 127.8, 128.6, 129.5 (t, J = 3.8 Hz), 132.0 (t, J = 8.3 Hz), 136.1,
137.2, 139.8, 162.4 (d, J = 246 Hz), 170.4, 171.2 (d, J = 5.4 Hz). 31P
NMR (81 MHz, DMSO-d6): δ = 22.3.
Minor diastereomer: 1H NMR (300 MHz, DMSO-d6): δ = 2.60 (d, J =
9.3 Hz, 1H, Hb), 2.83 (dd, J = 9.3 Hz, 2.6 Hz, 1H, Ha), 3.52 (d, J = 11.9
Hz, 1H, CCH2N), 3.66 (d, J = 11.0 Hz, 3H, OCH3), 3.74 (d, J = 11.0
Hz, 3H, OCH3), 4.18 (d, J = 11.9 Hz, 1H, CCH2N), 4.25 (d, J = 5.9 Hz,
2H, PhCH2NH), 4.99 (d, J = 1.2 Hz, 1H, Hc), 5.68 (d, J = 22.2 Hz, 1H,
PCHN), 6.46 (dd, J = 5.8 Hz, 1.2 Hz, 1H, CH CH), 6.67 (d, J = 5.8 Hz,
1H, CH CH), 7.13–7.34 (m, 7H, 4-FC6H4, Ph), 7.50 (dd, J = 8.2 Hz,
5.5 Hz, 2H, 4-FC6H4), 7.99 (t, J = 5.9 Hz, 1H, CONH). 13C NMR (100.6
MHz, DMSO-d6): δ = 42.8, 45.6, 46.5, 49.8 (d, J = 158 Hz), 49.9, 53.4
(d, J = 6.8 Hz), 53.8 (d, J = 6.8 Hz), 81.8, 88.4, 116.0 (d, J = 21.7 Hz),
127.1, 127.9, 128.6, 129.4 (t, J = 3.0 Hz), 130.9 (t, J = 8.0 Hz), 136.1,
137.2, 139.7, 162.1 (d, J = 245 Hz), 170.3, 171.3 (d, J = 5.3 Hz). 31P
NMR (81 MHz, DMSO-d6): δ = 23.1.
Dimethyl N-Benzyl-3-aza-6-[(morpholine-4-yl)carbonyl]-10-
oxa-exo-tricyclo[5.2.1.01,5]-4-oxodec-8-en-2-yl-endo-
phosphonate (24)
Yield 72%; pale solid; mp 121–123◦C. Anal. Calcd. for C22H27N2O7P
(464.44): C, 57.14; H, 5.89; P, 6.70. Found: C, 57.05; H, 5.93; P, 6.78%.
1H NMR (300 MHz, DMSO-d6): δ = 2.93 (d, J = 9.2 Hz, 1H, Hb), 3.05
(d, J = 9.1 Hz, 1H, Ha), 3.13–3.25 (m, 2H, CH2N-morpholine), 3.46 (m,
2H, CH2N-morpholine), 3.55–3.70 (m, 4H, CH2O-morpholine), 3.76 (d,
J = 10.7 Hz, 3H, OCH3), 3.77 (d, J = 10.7 Hz, 3H, OCH3), 3.93 (d, J =
5.5 Hz, 1H, PCHN), 4.18 (d, J = 16.2 Hz, 1H, CH2N), 4.99 (d, J = 16.2
Hz, 1H, CH2N), 5.07 (s, 1H, Hc), 6.57 (s, 2H, CH CH), 7.16 (d, J = 7.2
Hz, 2H, Ph), 7.22–7.36 (m, 3H, Ph).
Dimethyl N-benzyl-3-aza-6-methoxycarbonyl-10-oxa-exo-
tricyclo [5.2.1.01,5]-4-oxodec-8-en-2-yl-endo-phosphonate
(23)
To a suspension of epoxyisoindolyl phosphonate 11 (0.39 g, 1 mmol)
in anhydrous dichloromethane (10 mL), SOCl2 (0.15 mL, 2 mmol) was

P-Functionalized Isoindolin-1-ones
901
added. The reaction mixture was refluxed until the evolution of SO2
and HCl had stopped (ca. 0.5 h). After this, anhydrous methanol (10
mL) was carefully added, and the resulting solution was refluxed for
an additional 10 min. After cooling, the solvent was evaporated from
the reaction mixture. The residue was dissolved in methanol, and the
solvent was evaporated again. Treatment of the residue with ether and
filtration gave 0.37 g of 23 as a white solid. Yield 92%; mp 97–98◦C.
Anal. Calcd. for C19H22NO7P (407.36): C, 56.02; H, 5.44; P, 7.60. Found:
C, 56.11; H, 5.53; P, 7.58%. 1H NMR (300 MHz, DMSO-d6): δ = 2.75 (d,
J = 9.2 Hz, 1H, Hb), 3.02 (d, J = 9.2 Hz, 1H, Ha), 3.58 (m, 3H, OCH3),
3.77 (d, J = 10.6 Hz, 3H, OCH3), 3.78 (d, J = 10.6 Hz, 3H, OCH3), 4.00
(d, J = 5.5 Hz, 1H, PCHN), 4.21 (d, J = 16.2 Hz, 1H, CH2N), 5.01 (d,
J = 16.2 Hz, 1H, CH2N), 5.12 (d, J = 1.2 Hz, 1H, Hc), 6.52 (dd, J = 5.8
Hz, 1.6 Hz, 1H, CH CH), 6.60 (d, J = 5.7 Hz, 1H, CH CH), 7.18–7.38
(m, 5H, Ph).
Dehydrative Aromatization of the Epoxyisoindolyl
Phosphonates: General Procedure
A suspension of the epoxyisoindolyl phosphonate 3, 4, 7, and 8 (1 mmol)
in 85% H3PO4 (5 mL) was stirred at 80◦C for 1 h, cooled, and diluted
with water (50 mL). The precipitate formed was filtered off, washed
with water, and dried. After crystallization from the appropriate sol-
vent, the product is obtained as a white or pale yellow solid.
1-(7-Carboxyisoindolin-1-one-2-yl)-1-phenylmethylphosphonic
Acid (5)
Yield 68%; white solid; mp > 250◦C (EtOH/H2O = 10/1). Anal. Calcd.
for C16H14NO6P (347.27): C, 55.34; H, 4.06; P, 8.92. Found: C, 55.35;
H, 4.03; P, 8.97%. m/z (M+1) 348. IR (KBr, cm−1
)
νmax: 1683 (COO),
1603, 1559 (NCO), 1223 (P O). 1H NMR (300 MHz, DMSO-d6): δ = 4.61
(d, J = 19.2 Hz, 1H, CH2), 5.14 (d, J = 19.2 Hz, 1H, CH2), 5.64 (d, J =
21.0 Hz, 1H, NCHP), 7.33–7.46 (m, 3H, Ph), 7.65 (d, J = 7.2 Hz, 2H,
Ph), 7.83 (t, J = 7.6 Hz, 1H, H5), 7.94 (d, J = 7.6 Hz, 1H, H4), 8.13 (d,
J = 7.6 Hz, 1H, H6). 13C NMR (100.6 MHz, DMSO-d6): δ = 50.0, 54.8
(d, J = 149 Hz), 128.3, 128.5, 128.6, 128.8, 129.1, 129.8 (d, J = 7.5 Hz),
132.0, 132.9, 134.8 (d, J = 7.5 Hz), 143.7, 165.3, 169.1 (d, J = 5.5 Hz).
31P NMR (81 MHz, DMSO-d6): δ = 14.0.
1-(7-Carboxyisoindolin-1-on-2-yl)-1-(4-fluorophenyl)
methylphosphonic Acid (6)
Yield 70%; white solid; mp > 250◦C (EtOH/H2O = 10/1). Anal. Calcd.
for C16H13NO6FP (365.26): C, 52.61; H, 3.59; P, 8.48. Found: C, 52.63;

902
G. O. Kachkovskyi and O. I. Kolodiazhnyi
H, 3.64; P, 8.56%. m/z (M+1) 366. IR (KBr, cm−1) νmax: 1679 (COO),
1
1597, 1566 (NCO), 1221 (P O). H NMR (300 MHz, DMSO-d6): δ =
4.60 (d, J = 19.3 Hz, 1H, CH2), 5.12 (d, J = 19.3 Hz, 1H, CH2), 5.65 (d,
J = 20.7 Hz, 1H, NCHP), 7.25 (t, J = 8.7 Hz, 2H, 4-FC6H4), 7.70 (dd,
J = 8.7 Hz, 5.6 Hz, 2H, 4-FC6H4), 7.83 (t, J = 7.8 Hz, 1H, H5), 7.94 (d,
J = 7.8 Hz, 1H, H4), 8.13 (d, J = 7.8 Hz, 1H, H6). 13C NMR (100.6 MHz,
DMSO-d6): δ = 49.8, 54.0 (d, J = 149 Hz), 115.9 (d, J = 21.4 Hz), 128.2,
128.5, 128.9, 131.1 (dd, J = 3.4 Hz, 1.4 Hz), 131.9, 132.0 (dd, J = 8.0
Hz, 8.0 Hz), 132.9, 143.8, 162.3 (d, J = 244 Hz), 165.3, 169.1 (d, J = 5.5
Hz). 31P NMR (81 MHz, DMSO-d6): δ = 14.5.
1-[(7-(4-Fluorophenyl)aminocarbonyl)isoindolin-1-one-2-yl]-1-
phenylmethylphosphonic Acid (9a)
Yield 46%; white solid; mp > 250◦C (MeOH). Anal. Calcd. for
C22H18N2O5FP (440.37): C, 60.01; H, 4.12; P, 7.03. Found: C, 59.94;
H, 4.03; P, 6.97%. m/z (M+1) 441. IR (KBr, cm−1
)
νmax: 1642 (NCO),
1
1642, 1583 (RNHC O), 1207 (P O). H NMR (300 MHz, DMSO-d6):
δ = 4.55 (d, J = 19.2 Hz, 1H, CH2), 5.07 (d, J = 19.2 Hz, 1H, CH2),
5.71 (d, J = 21.4 Hz, 1H, NCHP), 7.23 (t, J = 9.0 Hz, 2H, 4-FC6H4),
7.31–7.45 (m, 3H, Ph), 7.64 (d, J = 7.3 Hz, 2H, Ph), 7.75–7.89 (m, 4H,
4-FC6H4, H4, H5), 8.19 (d, J = 7.7 Hz, 1H, H6), 12.94 (s, 1H, NH). 13C
NMR (100.6 MHz, DMSO-d6): δ = 48.9, 54.3 (d, J = 149 Hz), 115.9 (d,
J = 22.0 Hz), 121.9 (d, J = 7.7 Hz), 127.0, 127.8, 128.4, 129.0, 129.7 (d,
J = 6.8 Hz), 130.4, 132.3, 132.7, 135.5 (d, J = 2.2 Hz), 135.9 (d, J = 2.7
Hz), 143.9, 158.7 (d, J = 241 Hz), 162.7, 168.4 (d, J = 5.8 Hz). 31P NMR
(81 MHz, DMSO-d6): δ = 15.5.
1-[(7-(4-Fluorophenylmethyl)aminocarbonyl)isoindolin-1-one-
2-yl]-1-phenylmethyl-phosphonic Acid (9b)
Yield 55%; white solid; mp 154–156◦C (CH3CN). Anal. Calcd. for
C23H20N2O5FP (454.40): C, 60.80; H, 4.44; P, 6.82. Found: C, 60.87; H,
4.46; P, 6.85%. m/z (M+1) 455. 1H NMR (300 MHz, DMSO-d6): δ = 4.52
(d, J = 19.1 Hz, 1H, CH2), 4.58 (m, 2H, 4-FC6H4CH2NH), 5.03 (d, J =
19.1 Hz, 1H, CH2), 5.65 (d, J = 21.2 Hz, 1H, NCHP), 7.16 (t, J = 8.8
Hz, 2H, 4-FC6H4), 7.29–7.46 (m, 5H, 4-FC6H4, Ph), 7.60 (d, J = 7.7
Hz, 2H, Ph), 7.75 (t, J = 7.7 Hz, 1H, H5), 7.82 (d, J = 7.7 Hz, 1H, H4),
8.20 (d, J = 7.7 Hz, 1H, H6), 11.39 (t, J = 5.7 Hz, 1H, NH). 13C NMR
(100.6 MHz, DMSO-d6): δ = 42.2, 48.4, 53.9 (d, J = 150 Hz), 115.0 (d,
J = 21.1 Hz), 126.2, 127.4, 127.8, 128.5, 129.0, 129.1, 129.2 (d, J = 8.0
Hz), 130.2, 131.7 (d, J = 6.0 Hz), 135.0 (d, J = 2.0 Hz), 135.3 (d, J = 3.0
Hz), 143.5, 161.1 (d, J = 243 Hz), 163.8, 167.9 (d, J = 5.6 Hz). 31P NMR
(81 MHz, DMSO-d6): δ = 15.4.

P-Functionalized Isoindolin-1-ones
903
1-[(7-Phenylaminocarbonyl)isoindolin-1-one-2-yl]-1-(4-
fluorophenyl)methylphosphonic Acid (10a)
Yield 30%; pale solid; mp > 250◦C (i-PrOH/DMF/H2O = 1/1/4). Anal.
Calcd. for C22H18N2O5FP (440.37): C, 60.01; H, 4.12; P, 7.03. Found: C,
60.09; H, 4.13; P, 7.14%. m/z (M+1) 441. 1H NMR (300 MHz, DMSO-d6):
δ = 4.54 (d, J = 19.0 Hz, 1H, CH2), 5.07 (d, J = 19.0 Hz, 1H, CH2), 5.72
(d, J = 21.8 Hz, 1H, NCHP), 7.13 (t, J = 7.8 Hz, 1H, Ph), 7.24 (t, J =
9.0 Hz, 2H, 4-FC6H4), 7.40 (t, J = 7.8 Hz, 2H, Ph), 7.69 (dd, J = 9.0 Hz,
5.5 Hz, 2H, 4-FC6H4), 7.76–7.89 (m, 4H, Ph, H4, H5), 8.21 (d, J = 7.6
Hz, 1H, H6), 12.91 (s, 1H, NH). 13C NMR (100.6 MHz, DMSO-d6): δ =
48.4, 53.2 (d, J = 150 Hz), 115.3 (d, J = 21.4 Hz), 119.6, 126.3, 127.2,
128.7, 130.0, 131.2 (d, J = 7.6 Hz), 131.3, 131.7, 132.3, 138.9, 143.3,
161.5 (d, J = 245 Hz), 162.0, 167.8 (d, J = 5.7 Hz). 31P NMR (81 MHz,
DMSO-d6): δ = 14.4.
1-[(7-Benzylaminocarbonyl)isoindolin-1-one-2-yl]-1-(4-
fluorophenyl)methylphosphonic Acid (10b)
Yield 50%; white solid; mp > 250◦C (CH3CN). Anal. Calcd. for
C23H20N2O5FP (454.40): C, 60.80; H, 4.44; P, 6.82. Found: C, 60.75;
1
H, 4.56; P, 6.94%. m/z (M-1) 453. H NMR (300 MHz, DMSO-d6): δ =
4.50 (d, J = 19.0 Hz, 1H, CH2), 4.60 (m, 2H, PhCH2NH), 5.00 (d, J =
19.0 Hz, 1H, CH2), 5.64 (d, J = 21.4 Hz, 1H, NCHP), 7.15–7.29 (m, 3H,
4-FC6H4, Ph), 7.30–7.41 (m, 4H, Ph), 7.64 (dd, J = 8.8 Hz, 5.7 Hz, 2H,
4-FC6H4), 7.75 (t, J = 7.7 Hz, 1H, H5), 7.81 (d, J = 7.7 Hz, 1H, H4), 8.21
(d, J = 7.7 Hz, 1H, H6), 11.39 (t, J = 5.1 Hz, 1H, NH). 13C NMR (100.6
MHz, DMSO-d6): δ = 43.0, 48.2, 53.1 (d, J = 150 Hz), 115.3 (d, J = 21.3
Hz), 126.2, 126.8, 127.2, 127.3, 128.3, 130.3, 131.2, 129.2 (d, J = 7.0
Hz), 131.7, 131.8, 139.1, 143.5, 161.6 (d, J = 244 Hz), 163.7, 167.9 (d,
J = 5.7 Hz). 31P NMR (81 MHz, DMSO-d6): δ = 15.2.
Synthesis of Diethyl (2-Benzylisoindolin-1-one-3-yl)
phosphonate (18)
Compound 18 was synthesized in analogy to a published procedure.21
A mixture of 2-benzyl-3-hydroxy-isoindolin-1-one 17 (0.83 g, 3 mmol)
and trifluoroacetic anhydride (3 mL) was stirred for 1 h under argon.
After the excess trifluoroacetic anhydride and the resulting trifluo-
roacetic acid were removed under reduced pressure, triethyl phosphite
(1.04 mL, 6 mmol) in 10 mL of anhydrous chloroform was added to the
residue, and the resulting mixture was stirred for 4 h. The reaction
mixture was quenched with aqueous NaHCO3 (saturated, 50 mL). The
organic layer was washed with water and dried over Na2SO4, and the
solvent was evaporated. The residue obtained was dried for 1.5 h at

904
G. O. Kachkovskyi and O. I. Kolodiazhnyi
80◦C under reduced pressure (0.1 mm Hg) to give 0.75 g of 18 as a pale
oil. Yield: 70%. IR (KBr, cm−1) νmax: 1707 (NCO), 1259 (P O). Anal.
Calcd. for C19H22NO4P (359.37): C, 63.50; H, 6.17; P, 8.62. Found: C,
1
63.43; H, 6.10; P, 8.64%. m/z (M+1) 360. H NMR (300 MHz, DMSO-
d6): δ = 1.10 (t, J = 7.2 Hz, 3H, CH3), 1.14 (t, J = 7.2 Hz, 3H, CH3),
3.84–4.08 (m, 4H, OCH2), 4.61 (d, J = 15.5 Hz, 1H, PhCH2N), 5.06 (d,
J = 14.2 Hz, 1H, NCHP), 5.27 (d, J = 15.5 Hz, 1H, PhCH2N), 7.19–7.38
(m, 5H, C6H4), 7.55–7.64 (m, 1H, C6H4), 7.64–7.72 (m, 2H, C6H4), 7.81
(d, J = 7.5 Hz, 1H, C6H4). 13C NMR (100.6 MHz, DMSO-d6): δ = 16.1
(d, J = 5.5 Hz), 16.2 (d, J = 5.5 Hz), 44.6, 56.4 (d, J = 153 Hz), 62.8 (d,
J = 7.2 Hz), 62.9 (d, J = 7.2 Hz), 123.2 (d, J = 1.4 Hz), 124.5 (d, J =
2.5 Hz), 127.2, 127.5, 128.5, 128.8 (d, J = 2.1 Hz), 131.3 (d, J = 4.2 Hz),
131.7 (d, J = 2.7 Hz), 136.9, 139.0 (d, J = 6.0 Hz), 167.8 (d, J = 3.5 Hz).
31P NMR (81 MHz, DMSO-d6): δ = 18.4.
Synthesis of (2-Benzylisoindolin-1-one-3-yl)phosphonic Acid
(19)
To a solution of the phosphonate 18 (0.36 g, 1 mmol) in 10 mL of
anhydrous dichloromethane, Me3SiBr (0.40 mL, 3 mmol) was added.
The reaction mixture was allowed to stand overnight, and subsequently
the solvent was evaporated. The residue was dissolved in 10 mL of
aqueous dioxane (1:1), and after 1 h the solvent was evaporated again.
After crystallization from EtOAc/i-PrOH (4/1) 0.22 g of 19 was obtained
as a white solid. Yield 73%; mp 228–229◦C. IR (KBr, cm−1) νmax: 1602
(NCO), 1194 (P O). Anal. Calcd. for C15H14NO4P (303.26): C, 59.41;
H, 4.65; P, 10.21. Found: C, 59.49; H, 4.68; P, 10.20%. m/z (M-1) 302.
1H NMR (300 MHz, DMSO-d6): δ = 4.56 (d, J = 15.5 Hz, 1H, NCHP),
4.67 (d, J = 15.1 Hz, 1H, PhCH2N), 5.30 (d, J = 15.1 Hz, 1H, PhCH2N),
7.18–7.37 (m, 5H, Ph), 7.52 (d, J = 7.5 Hz, 1H, C6H4), 7.60 (d, J = 7.5
Hz, 1H, C6H4), 7.66 (d, J = 7.5 Hz, 1H, C6H4), 7.75 (d, J = 7.5 Hz, 1H,
C6H4). 13C NMR (100.6 MHz, DMSO-d6): δ = 44.1, 57.6 (d, J = 148 Hz),
122.8, 124.4 (d, J = 2.4 Hz), 127.2, 127.7, 128.1 (d, J = 1.9 Hz), 128.5,
131.2 (d, J = 2.1 Hz), 131.5 (d, J = 3.8 Hz), 137.3, 140.6 (d, J = 5.5 Hz),
167.7 (d, J = 3.2 Hz). 31P NMR (81 MHz, DMSO-d6): δ = 15.1.
Aromatization of Dimethyl N-Benzyl-3-aza-6-carboxy-10-oxa-
exo-tricyclo[5.2.1.01,5]-4-oxodec-8-en-2-yl-endo-phosphonate
(11)
Treatment with 85% H3PO4
A suspension of the epoxyisoindolyl phosphonate 11 (0.39 g, 1 mmol)
in 85% H3PO4 (5 mL) was stirred at 80◦C for 4 h, cooled, diluted with
water (50 mL), and left to stand overnight. After drying, filtration of

P-Functionalized Isoindolin-1-ones
905
the precipitate gave a 0.15 g mixture of compounds 11, 13, and 14 as a
pale solid.
Epoxyisoindolyl Phosphonate 11. MS: m/z (M+1) 394.1H NMR (300
MHz, DMSO-d6): δ = 2.61 (d, J = 9.1 Hz, 1H, Hb), 2.94 (d, J = 9.1 Hz,
1H, Ha), 3.77 (d, J = 10.6 Hz, 3H, OCH3), 3.78 (d, J = 10.6 Hz, 3H,
OCH3), 3.98 (d, J = 5.7 Hz, 1H, PCHN), 4.21 (d, J = 16.2 Hz, 1H,
CH2N), 5.02 (d, J = 16.2 Hz, 1H, CH2N), 5.07 (br s, 1H, Hc), 6.51 (dd,
J = 5.7 Hz, 1.6 Hz, 1H, CH CH), 6.58 (d, J = 5.7 Hz, 1H, CH CH),
7.20–7.44 (m, 5H, Ph). 31P NMR (81 MHz, DMSO-d6): δ = 21.9.
Dimethyl (2-Benzyl-7-carboxyisoindolin-1-one-3-yl)phosphonate
(13). MS: m/z (M+1) 376.1H NMR (300 MHz, DMSO-d6): δ = 3.66 (d,
J = 10.8 Hz, 3H, OCH3), 3.67 (d, J = 10.8 Hz, 3H, OCH3), 4.71 (d, J =
15.6 Hz, 1H, PhCH2N), 5.27 (d, J = 15.6 Hz, 1H, PhCH2N), 5.57 (d,
J = 16.6 Hz, 1H, NCHP), 7.20–7.44 (m, 5H, Ph), 7.81–7.96 (m, 2H, H4,
H5), 8.08–8.20 (m, 1H, H6). 31P NMR (81 MHz, DMSO-d6): δ = 19.8.
1
(2-Benzyl-7-carboxyisoindolin-1-one (14). MS: m/z (M+1) 268. H
NMR (300 MHz, DMSO-d6): δ = 4.63 (s, 2H, PhCH2N), 4.86 (s, 1H,
ArCH2N), 7.20–7.44 (m, 5H, Ph), 7.81–7.96 (m, 2H, H4, H5), 8.08–8.20
(m, 1H, H6).
Treatment with NaOMe/MeOH
Epoxyisoindolyl phosphonate 11 (0.39 g, 1 mmol) was dissolved in
10 mL of a 3M solution of NaOMe in MeOH and left at room temper-
ature overnight. The solvent was evaporated, and the residue was dis-
solved in water and neutralized with HCl. A gum-like precipitate was
formed, which became crystalline upon decantation and treatment with
a new portion of water. After drying, filtration gave 0.17 g mixture of
compounds 13, 14, and 15 as a white solid. The NMR data for com-
pounds 13 and 14 are reported above.
Monomethyl (2-Benzyl-7-carboxyisoindolin-1-one-3-yl) phospho-
nate (15). MS: m/z (M+1) 362. 1H NMR (300 MHz, DMSO-d6): δ =
3.54 (d, J = 10.9 Hz, 3H, OCH3), 4.82 (d, J = 15.4 Hz, 1H, PhCH2N),
5.21 (d, J = 17.5 Hz, 1H, NCHP), 5.30 (d, J = 15.4 Hz, 1H, PhCH2N),
7.26–7.44 (m, 5H, Ph), 7.77–7.98 (m, 2H, H4, H5), 8.08–8.20 (m, 1H,
H6). 31P NMR (81 MHz, DMSO-d6): δ = 14.0.
Treatment with Bromotrimethylsilane
To a solution of epoxyisoindolyl phosphonate 11 (0.39 g, 1 mmol) in
20 mL of anhydrous dichloromethane, Me3SiBr (0.66 mL, 5 mmol) was
added, and the reaction mixture was kept overnight. Subsequently

906
G. O. Kachkovskyi and O. I. Kolodiazhnyi
the solvent was evaporated, the residue was dissolved in 10 mL of
aqueous dioxane (1:1); after 1 h the solvent was evaporated again, and
the residue was dried for 1 h at 80◦C under reduced pressure (18 mm
Hg) to give 0.25 g mixture of compounds 14 and 16 as a colorless clear
melt. NMR data for compound 14 are reported above.
(N-Benzyl-3-aza-6-carboxy-10-oxa-exo-tricyclo[5.2.1.01,5]-4-
oxodec-8-en-2-yl)-endo-phosphonic Acid (16). MS: m/z (M+1)
1
366. H NMR (300 MHz, DMSO-d6): δ = 2.58 (d, J = 9.1 Hz, 1H, Hb),
2.86 (d, J = 9.1 Hz, 1H, Ha), 3.55 (d, J = 6.5 Hz, 1H, PCHN), 4.33 (d,
J = 15.8 Hz, 1H, CH2N), 5.03 (br s, 1H, Hc), 5.05 (d, J = 15.8 Hz, 1H,
CH2N), 6.45 (dd, J = 6.0 Hz, 1.6 Hz, 1H, CH CH), 6.71 (d, J = 6.0 Hz,
1H, CH CH), 7.20–7.42 (m, 5H, Ph). 31P NMR (81 MHz, DMSO-d6):
δ = 15.1.
Aromatization of Dimethyl N-Benzyl-3-aza-6-
methoxycarbonyl-10-oxa-exo-tricyclo[5.2.1.01,5]-4-oxodec-8-
en-2-yl-endo-phosphonate (23) and N-Benzyl-3-aza-6-
[(morpholine-4-yl)carbonyl]-10-oxa-exo-tricyclo
[5.2.1.01,5]-4-oxodec-8-en-2-yl-endo-phosphonate (24) in
Trifluoroacetic Acid
A sample (30 mg) of epoxyisoindolyl phosphonate 23 or 24 was dissolved
in TFA (1 mL) and heated at 70◦C for 14 h. The 31P NMR spectrum of
1
the reaction mixture showed only one signal at 0 ppm. The H NMR
(300 MHz, DMSO-d6) spectrum of the solid residue obtained after evap-
oration of TFA and additional drying under reduced pressure showed
the signals of compound 14 (see above). The LCMS spectrum showed
m/z (M+1) 268 for the major peak.
REFERENCES
[1] J. M. Ferland, C. A. Demerson, and L. G. Humber, Can. J. Chem., 63, 361 (1985).
[2] 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).
[3] Z. P. Zhuang, M. P. Kung, M. Mu, and H. F. Kung, J. Med. Chem., 41, 157 (1998).
[4] M. H. Norman, D. J. Minick, and G. C. Rigdon, J. Med. Chem., 39, 149 (1996).
[5] 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).
[6] E. Valencia, I. Weiss, S. Firdous, A. J. Freyer, and M. Shamma, Tetrahedron, 40,
3957 (1984).
[7] E. V. Bolotukhina, F. I. Zubkov, and A. V. Varlamov, Chem. Heterocycl. Comp., 469,
963 (2006).

P-Functionalized Isoindolin-1-ones
907
[8] E. V. Bolotukhina, F. I. Zubkov, and A. V. Varlamov, Chem. Heterocycl. Comp., 470,
1123 (2006).
[9] P. S. Sarang, A. A. Yavad, P. S. Patil, U. M. Krishna, G. K. Trivedi, and M. M.
Salunkhe, Synthesis, 1091 (2007).
[10] O. I. Kolodiazhnyi, Tetrahedron: Asymmetry, 16, 3295 (2005).
[11] O. I. Kolodiazhnyi, Russ. Chem. Rev., 75, 227 (2006).
[12] G. A. Kachkovskiy, N. V. Andrushko, S. Yu. Sheiko, and O. I. Kolodiazhnyi, Russ. J.
Gen. Chem., 75, 1735 (2005).
[13] G. O. Kachkovskyi and O. I. Kolodiazhnyi, Tetrahedron, 63, 12576 (2007).
[14] A. V. Varlamov, E. V. Bolotukhina, F. I. Zubkov, N. V. Sidorenko, A. I. Chernyshev,
and D. G. Grudinin, Chem. Heterocycl. Comp., 439, 27 (2004).
[15] V. V. Kouznetsov, U. M. Cruz, F. I. Zubkov, and E. V. Nikitina, Synthesis, 375 (2007).
[16] A. Pelter and B. Singaram, Tetrahedron Lett., 23, 246 (1982).
[17] P. C. Crofts and G. M. Kosolapoff, J. Am. Chem. Soc., 75, 3379 (1953).
[18] B. Boduszek, M. Lipin´ski, and M. W. Kowalska, Phosphorus, Sulfur, and Silicon,
143, 179 (1998).
[19] B. Boduszek, R. Latajka, and W. Leniak, Phosphorus, Sulfur, and Silicon, 165, 53
(2000).
[20] A. Dunet and A. Willemart, Bull. Soc. Chim. Fr., 15, 1045 (1948).
[21] 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).