Facile ring-opening reactions of phthalimides as a new strategy to synthesize amide-functionalized phosphonates, primary phosphines, and bisphosphines

Article abstract of DOI:10.1021/jo991067b

The nucleophile-assisted ring-opening reaction of phthalimides 1 has been studied. The reaction of phthalimides 1 with 0.5 equiv of hydrazine produced the novel bisphosphonates 2 in near quantitative yields whereas with 10-fold excess of hydrazine, diethyl aminoalkylphosphonates 3 was formed in 75% yields. The reaction of phthalimide 1b with 3-(aminopropyl)phosphine resulted in a novel compound 4a containing a P(III) hydride and a P(V) phosphonate within the same molecule. In addition, the reaction of 1b with 2- aminoethanol and 2-aminoethanethiol resulted in the formation of new phosphonates 4b,c. The reaction of bisphosphonates 2 with LiAlH₄ in THF at 0 °C selectively reduced the phosphonate groups producing corresponding air- stable primary bisphosphines 6 in 80% yields. Further, the formylation of bisphosphines 6 under very mild conditions using 37% aqueous formaldehyde produced the corresponding novel water-soluble bisphosphine chelating agents 7 in near quantitative yields. All the new compounds have been characterized by ¹H, ¹³C, ³¹P NMR, IR spectroscopy and mass spectrometry.

Full text of DOI:10.1021/jo991067b

676
J . Org. Chem. 2000, 65, 676-680
F a cile Rin g-Op en in g Rea ction s of P h th a lim id es a s a New Str a tegy
to Syn th esize Am id e-F u n ction a lized P h osp h on a tes, P r im a r y
P h osp h in es, a n d Bisp h osp h in es
Hariprasad Gali,†,‡ Kandikere R. Prabhu,†, Srinivasa R. Karra,†,§ and Kattesh V. Katti*,†,|
Departments of Radiology and Chemistry, and Missouri University Research Reactor,
University of MissourisColumbia, Columbia, Missouri 65211
Received J uly 2, 1999
The nucleophile-assisted ring-opening reaction of phthalimides 1 has been studied. The reaction of
phthalimides 1 with 0.5 equiv of hydrazine produced the novel bisphosphonates 2 in near
quantitative yields whereas with 10-fold excess of hydrazine, diethyl aminoalkylphosphonates 3
was formed in 75% yields. The reaction of phthalimide 1b with 3-(aminopropyl)phosphine resulted
in a novel compound 4a containing a PIII hydride and a PV phosphonate within the same molecule.
In addition, the reaction of 1b with 2-aminoethanol and 2-aminoethanethiol resulted in the formation
of new phosphonates 4b,c. The reaction of bisphosphonates 2 with LiAlH4 in THF at 0 °C selectively
reduced the phosphonate groups producing corresponding air-stable primary bisphosphines 6 in
80% yields. Further, the formylation of bisphosphines 6 under very mild conditions using 37%
aqueous formaldehyde produced the corresponding novel water-soluble bisphosphine chelating
1
agents 7 in near quantitative yields. All the new compounds have been characterized by H, 13C,
31P NMR, IR spectroscopy and mass spectrometry.
Sch em e 1
In tr od u ction
Ligand design has gained considerable prominence in
recent years. In particular, research in the design and
development of ligands that produce water-soluble tran-
sition metal/organometallic compounds continues to at-
tract considerable attention because of their potential
applications in the fields of catalysis and biomedicine.1-7
Of the various ligands available to produce aqueous
soluble coordination compounds, functionalized phos-
phines are the most attractive class of ligands because
of their versatile coordination chemistry.3,8-10 The σ and
π back-bonding interactions of phosphines with transition
metals reinforce one another to produce strong metal-
phosphorus bonds which are often stable even under the
most stringent conditions. The water-soluble mono-, di-,
or trisulfonated arylphosphines, such as P(m-C6H4SO3-
Na)3, have largely been employed in the development of
highly active water-soluble transition metal catalysts.2
However, hydrophilic alkyl phosphines are being highly
sought after in order to gain specific structure-activity
advantages both in catalytic and biomedical applications.
In this context, the formylation reactions of P-H bonds,
that produce hydroxymethyl-functionalized water-soluble
phosphines, have been used as effective synthetic strate-
gies for the development of water-soluble phosphine
frameworks (Scheme 1).3
* Author for correspondence: Prof. Kattesh V. Katti, Radiopharma-
ceutical Sciences Institute, Allton Bldg., Room #106, University
of MissourisColumbia, Columbia, MO 65211. E-mail: KattiK@
health.missouri.edu. Phone: 1-573-882-5656. Fax: 1-573-884-5679.
† Department of Radiology.
‡ Department of Chemistry.
| Missouri University Research Reactor.
On leave from the Department of Organic Chemistry, Indian
Institute of Science, Bangalore-560012, India.
Primary phosphines (RPH2), especially alkyl phos-
phines, are, in general, air-sensitive compounds. There-
fore, their backbone modification to afford new classes
of alkyl-substituted phosphines are often challenging.
Despite synthetic difficulties, primary phosphines are
excellent precursors for reactions with many unsaturated
systems. They undergo reactions with carbonyl groups,
Michael acceptors, acid halides, alkyl halides, halogens,
alkali metals, and Lewis acids (e.g., borane) to produce
a variety of functionalized phosphines including chiral
phosphines (as depicted in Scheme 2).11-21 Therefore, new
developments in organic chemistry leading to efficient
§ Present address: Vion Pharmaceuticals, New Haven, CT 06511.
(1) Herrmann, W. A.; Kohlpaintner, C. W. Angew. Chem., Int. Ed.
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Kloetzer, D.; Maeding, P.; Muenze, R. Z. Chem. 1984, 24, 224-225.
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1999, 32, 9-17. (d) Chatt, J .; Leigh, G. J .; Slade, R. M. J . Chem. Soc.,
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10.1021/jo991067b CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/16/2000

Ring-Opening Reactions of Phthalimides
J . Org. Chem., Vol. 65, No. 3, 2000 677
Sch em e 2
metric reaction of compounds 1 with 3 under similar
experimental conditions produced bisphosphonates 2 in
near quantitative yields. Similar nucleophilic ring-open-
ing reaction of N-methylphthalimide with ethylenedi-
amine, to produce an adduct containing two units of
N-methylphthalimide and one unit of ethylenediamine
(N,N′-(N,N′-dimethyl)-diphthalamidoethane), was re-
ported by Wolfe and co-workers.24 However, to date, there
is no literature precedence of similar reactions for the
synthesis of phosphorus-containing ligands.
The generality of the nucleophile-assisted ring-opening
reaction of phthalimide 1b was tested by subjecting it to
interact with 2-aminoethanol and 2-aminoethanethiol
(Scheme 3). These reactions produced the corresponding
phosphonates 4b,c in near quantitative yields. The scope
of this nucleophile-assisted ring opening was further
tested by interacting (3-aminopropyl)phosphine with 1b.
This reaction produced the first example of phosphine-
containing phosphonate 4a , in 88% yield. It may be noted
that compounds with combination of PV phosphonates
and PIII tertiary phosphines have been reported in the
literature.25-28 The proton-coupled phosphorus NMR of
4a (Supporting Information) clearly shows the presence
of a PIII center (-135.1 ppm, J P-H ) 196 Hz) and PV
center (+34.3 ppm) within the same molecule. Compound
4a exemplifies the importance of “s” character of phos-
phorus center on the magnitude of phosphorus-carbon
coupling constant across one bond. For example, the
primary phosphine is expected to exhibit lower s char-
acter as compared to the phosphonate PV in 4a . There-
fore, in the 13C NMR spectrum of compound 4a , P-C
coupling was not observed for R-C to PH2. However, R-C
to P(O)(OEt)2 showed a P-C coupling of 140.6 Hz.
Compound 4a is unique in that it provides an example
of organophosphorus compound wherein PIII hydride and
PV phosphonate functionalities coexist within the same
molecule. Compounds that contain disparate three and
five oxidation state phosphorus centers are difficult to
synthesize using traditional synthetic methods. In this
context, the ease with which 4a is produced, via the
reaction summarized in Scheme 3, provides a novel
pathway for the development of hetero oxidation state
organophosphorus compounds. All new compounds were
characterized by 1H, 13C, 31P NMR spectroscopy and mass
spectrometric methods.
synthetic strategies for producing alkyl primary phos-
phines using mild conditions will be of greater practical
importance. We now report a facile synthetic strategy
that utilizes the nucleophile-assisted ring-opening of
phthalimides (Scheme 3). This methodology has resulted
in the synthesis of novel chelating agents containing air-
stable alkyl primary phosphines, bis-amido-functional-
ized phosphonates, and mixed phosphine-phosphonates
in good yields (Scheme 3). In addition, a formylation
reaction of new primary phosphines to produce function-
alized water-soluble phosphine ligands is also described.
Resu lts a n d Discu ssion
Commercially available N-(bromoalkyl)phthalimides
were converted to phthalimides 1 in near quantitative
yields utilizing the well-known Michaelis-Arbuzov reac-
tion by refluxing with 5-fold excess of triethyl phosphite
for 12 h (Scheme 3).22 Treatment of phthalimides 1 with
0.5 equiv of hydrazine in ethanol at room temperature
for 12 h produced ring-opened bisphosphonates 2, in near
quantitative yields. Whereas, the treatment of 1 with 10-
fold excess of hydrazine resulted in diethyl aminoalkyl-
phosphonates 3 exclusively, via the well-known Gabriel
synthetic pathway,23 in 75% yields (Scheme 3). The
former products 2 were formed as a result of ring-opening
of phthalimide by in situ generated nucleophiles 3. When
phthalimide 1 was treated with 0.5 equiv of hydrazine,
only 50% of 1 reacted to produce 3, and in turn, 3 further
reacted with the remaining 50% of 1 to produce the novel
ring-opened product 2. To confirm the mechanism in-
volved in the formation of bisphosphonate 2, the stoichio-
It is interesting to note that reduction of bisphos-
phonates 2 with LiAlH4 in dry THF at 0 °C (Scheme 4)
was selective in terms of reducing only phosphonates,
although amide groups are susceptible for reduction
under these conditions. The novel bisphosphines 6 were
obtained in 80% yield, as air-stable, pale yellow solids.
(13) Maier, L. In Progress in Inorganic Chemistry; Cotton, F. A.,
Ed.; Interscience Publishers: New York, 1963; Vol. 5, pp 27-210.
(14) Berning, D. E.; Katti, K. V.; Barnes, C. L.; Volkert, W. A. J .
Am. Chem. Soc. 1999, 121, 1658-1664.
1
The formation of bisphosphines 6 was confirmed by H,
13C, 31P NMR and IR spectroscopic and high-resolution
mass spectrometric methods. The characteristic triplet
splitting of the peak at -146.7 ppm (with J P-H ) 195.6
Hz) in the proton-coupled 31P NMR spectrum of 6a
indicates the presence of two protons attached to the
phosphorus center (Supporting Information). It is inter-
(15) Corbridge, D. E. C. In Phosphorus: An Outline of its Chemistry,
Biochemistry and Technology, 4th ed.; Elsevier: New York, 1990.
(16) Gee, V.; Orpen, A. G.; Phetmung, H.; Pringle, P. G.; Pugh, R. I.
Chem. Commun. 1999, 901-902.
(17) Smith, C. J .; Reddy, V. S.; Katti, K. V. Chem. Commun. 1996,
2557-2558.
(18) Ohff, M.; Holz, J .; Quirmbach, M.; Bo¨rner, A. Synthesis 1998,
1391-1413.
(19) Bourumeau, K.; Gaumont, A.-C.; Denis, J .-M. J . Orgmet. Chem.
1997, 529, 205-213.
(24) Wolfe, S.; Hasan, S. K. Can. J . Chem. 1970, 48, 3572-3579.
(25) Gloede, J .; Ozegowski. S.; Kockritz, A.; Keitel, I. Phosphorus,
Sulfur, Silicon Relat. Elem. 1997, 131, 141-145.
(26) Schull, T. L.; Fettinger, J . C.; Knight, D. A. Inorg. Chem. 1996,
35, 6717-6723.
(27) Schull, T. L.; Fettinger, J . C.; Knight, D. A. J . Chem. Soc., Chem.
Commun. 1995, 1487-1488.
(28) Reddy, V. S.; Katti, K. V.; Volkert, W. A. J . Chem. Soc., Dalton
Trans. 1996, 4459-4462.
(20) Bourumeau, K.; Gaumont, A.-C.; Denis, J .-M. Tetrahedran Lett.
1997, 38, 1923-1926.
(21) Petrov, K. A.; Parshina, V. A. Russ. Chem. Rev. 1968, 37, 532-
543.
(22) Arbusov, B. A. Pure Appl. Chem. 1964, 9, 307.
(23) Gibson, M. S.; Bradshaw, R. W. Angew. Chem., Int. Ed. Engl.
1968, 7, 919-930; Angew. Chem. 1968, 80, 986-997.

678 J . Org. Chem., Vol. 65, No. 3, 2000
Gali et al.
Sch em e 3
esting to note that 31P NMR parameters of 6a are
Sch em e 4
comparable with that of a simple primary phosphine
compound H2P-CH2-CO-NH-Ph (-144.5 ppm, J P-H
)
198 Hz) reported by Issleib and co-workers.29 It is also
important to recognize that the amide function in 6a is
four bonds away from PH2 whereas it is disposed across
two bonds in H2P-CH2-CO-NH-Ph. The presence of
-PH2 groups in 6 was further confirmed by the observa-
tion of characteristic band at 2282 cm-1 attributed to the
P-H stretch in the IR spectra. The peak at 169.1 ppm
in the 13C NMR spectrum of 6a (and a band at 1632 cm-1
in the IR spectrum) clearly indicated the presence of
amide CdO group. The 13C NMR resonance due to R-C
(to PH2) in 6a was observed at 14.6 ppm (J P-C ) 10.5
Hz) and is comparable with the reported spectral data
by Issleib and co-workers for a series of N-substituted
(2-aminoethyl)phosphines.30 It may be noted that in the
propyl analogue, 6b, P-C coupling was not observed for
R-C to PH2. Compounds 6 represent rare examples of
primary alkyl phosphines with unusual stability toward
air-oxidation.3c,7,31 Recently Goodwin et al. and Brynda
et al. have also reported high oxidative stability to
primary phosphines functionalized with bulky substit-
uents.32-34
purified on a silica gel column. The triplet splitting in
proton-coupled 31P NMR spectrum (134.8 ppm, J P-H
)
The reduction reaction of compound 1b with LiAlH4
under similar experimental conditions produced the
primary phosphine 5, in which both imide and phosphon-
ate groups were reduced (Scheme 3). The primary phos-
phine 5 is an air-stable white crystalline solid, which was
192.4 Hz) of 5 was found to be in accordance with that of
[3-(N,N′-dimethylamino)propyl]phosphine (-138.9 ppm,
J P-H ) 193.7 Hz) reported by Stelzer et al.35 The
reduction of the imide groups in 5 is, presumably, due to
the general tendency of imides to be more susceptible for
reduction than amides.
Furthermore, bisphosphines 6 were formylated by
using 37% aqueous formaldehyde in ethanol at room
temperature to produce the novel water-soluble hy-
droxymethyl-functionalized bisphosphines 7 in almost
quantitative yields. The bisphosphines 7 were found to
(29) Issleib, K.; Ku¨mmel, R. Chem. Ber. 1967, 100, 3331-3342.
(30) Issleib, K.; Schmidt, H.; Leissring, E. J . Organomet. Chem.
1988, 355, 71-77.
(31) Prabhu, K. R.; Kishore, P. N.; Gali, H.; Katti, K. V. J . Am. Chem.
Soc. 2000, in press.
(32) Goodwin, N. J .; Hendercon, W.; Nicholson, B. K. Chem. Com-
mun. 1997, 31-32.
(33) Goodwin, N. J .; Hendercon, W.; Nicholson, B. K.; Fawcett, J .;
Russell, D. R. J . Chem. Soc., Dalton Trans. 1999, 1785-1793.
(34) Brynda, M.; Geoffroy, M.; Bernardinelli, G. Chem. Commun.
1999, 961-962.
(35) Braver, D. J .; Fischer, J .; Kucken, S.; Langhans, K. P.; Stelzer,
O.; Weferling, N. Z. Naturforsch. 1994, 49B, 1511-1524.

Ring-Opening Reactions of Phthalimides
J . Org. Chem., Vol. 65, No. 3, 2000 679
The pure product was obtained by elution with a solvent
system consisting of 10% methanol in chloroform. Evaporation
of the solvent produced bisphosphonate 2a (7.5 g, 95%) as a
yellow viscous oil. 1H NMR (CDCl3, 300 MHz) δ 7.59-7.42 (m,
4H), 4.17-4.06 (m, 8H), 3.71-3.59 (m, 4H), 2.13-2.02 (m, 4H),
1.34 (t, J ) 7.06 Hz, 12H); 13C NMR (CDCl3, 75 MHz) δ 168.6,
134.8, 129.7, 127.8, 61.4, 33.8, 25.1 (d, J P-C ) 137.9 Hz), 16.1;
31P NMR (CDCl3, 121 MHz) δ 30.4; HRFABMS calcd for
be oxidatively stable in aqueous solutions. These water-
soluble phosphines can be conveniently stored over
prolonged periods by conversion to stable phosphonium
salts 8 via treatment with excess of formaldehyde and
hydrochloric acid (Scheme 4). Phosphonium salts 8 can
be easily converted back into (hydroxymethyl)phosphines
7 by titration with equivalent amounts of base such as
sodium bicarbonate buffer (Scheme 4).
In summary, the results outlined in this report dem-
onstrate the synthetic utility of the nucleophile-mediated
ring-opening of phthalimides 1. The methodology de-
scribed, herein, can be used in the design and develop-
ment of hitherto unknown amide-functionalized novel
phosphonates and phosphines.
C
20H34N2O8P2 ) 493.2425, found ) 493.2422 (M+ + 1). Anal.
Calcd for C20H34N2O8P2: C, 48.78; H, 6.96; N, 5.69. Found C,
48.87; H, 7.12; N, 6.86.
(3-{2-[3-(D ie t h o x y p h o s p h o r y l)p r o p y lc a r b a m o y l]-
ben zoylam in o}pr opyl)ph osph on ic acid dieth yl ester (2b):
pale yellow oil; yield 94%; 1H NMR (CDCl3, 300 MHz) δ 7.91-
7.87 (m, 2H), 7.38-7.36 (m, 2H), 3.94-3.84 (m, 8H), 3.26-
3.19 (m, 4H), 1.65-1.42 (m, 8H), 1.16 (t, J ) 7.04 Hz, 12H);
13C NMR (CDCl3, 75 MHz) δ 169.0, 134.6, 129.4, 128.0, 61.2,
39.8 (d, J P-C ) 17.9 Hz), 22.7 (d, J P-C ) 140.9 Hz), 22.1, 16.0;
31P NMR (CDCl3, 121 MHz) δ 33.0; HRFABMS calcd for
Exp er im en ta l Section
22H38N2O8P2 ) 521.2182, found ) 521.2178 (M+ + 1). Anal.
All chemicals were purchased either from Aldrich Chemical
Co. or Fisher Scientifics and used as received except tetrahy-
drofuran, which was distilled over sodium and benzophenone
prior to use. 3-Aminopropylphosphine was prepared by a
procedure reported in the literature.36 Mass spectral analyses
were performed by the Washington University Resource for
Biomedical and Bio-Organic Mass Spectometry, St. Louis, MO.
[2-(1,3-Dioxo-1,3-d ih yd r o-isoin d ol-2-yl)e t h yl]p h os-
p h on ic Acid Dieth yl Ester (1a ). N-(2-Bromoethyl)phthal-
imide (20.0 g, 79.05 mmol) was added to triethyl phosphite
(65.6 g, 395.25 mmol) slowly at room temperature. The
reaction mixture was refluxed for 12 h. The volatile compounds
were distilled out under reduced pressure (3 mmHg) at 60 °C.
The crude product was dissolved in 50% aqueous ethanol and
the precipitate, unreacted N-(2-bromoethyl)phthalimide, was
filtered. The removal of solvents from the filtrate gave pure
phosphonate 1a (15.5 g, 63%) as a pale yellow viscous oil. The
1H NMR spectrum matched the published spectrum.37 1H NMR
(CDCl3, 300 MHz) δ 7.84-7.68 (m, 4H), 4.13-4.03 (m, 4H),
C
Calcd for C22H38N2O8P2: C, 50.77; H, 7.36; N, 5.38. Found C,
50.93; H, 7.55; N, 5.53.
(2-Am in oeth yl)p h osp h on ic Acid Dieth yl Ester (3a ).
Anhydrous hydrazine (10.24 g, 320 mmol) was added dropwise
to a solution of phthalimide 1a (9.98 g, 32 mmol) in ethanol
(500 mL) at room temperature. The reaction mixture was
stirred at room temperature for 12 h. The precipitated phthalyl
hydrazide solid was filtered, and the solvent was removed
under reduced pressure. The crude product was chromato-
graphed on a silica gel column under nitrogen using a gradient
of CHCl3/MeOH (9:1). Evaporation of the solvent produced 3a
(4.3 g, 75%) as a pale-yellow liquid. The spectral data matched
with the literature data.38 1H NMR (CDCl3, 300 MHz) δ 5.12
(bs, 2H), 4.18-4.06 (m, 4H), 3.06-2.96 (m, 2H), 2.03-1.88 (m,
2H), 1.33 (t, J ) 7.0 Hz, 6H); 13C NMR (CDCl3, 75 MHz) δ
61.0, 35.5, 29.0 (d, J P-C ) 137.0 Hz), 15.8; 31P NMR (CDCl3,
121 MHz) δ 32.2; Electronspray-MS m/z 182.2 (M+ + 1).
(3-Am in op r op yl)p h osp h on ic Acid Dieth yl Ester (3b).
3.98-3.89 (m, 2H), 2.24-2.13 (m, 2H), 1.29-1.09 (m, 6H); 13
C
The spectral data matched with the literature data:38 pale
NMR (CDCl3, 75 MHz) δ 166.8, 133.3, 131.1, 122.4, 61.0, 31.3,
1
yellow liquid; yield 76%; H NMR (CDCl3, 300 MHz) δ 4.15-
24.0 (d, J P-C ) 139.3 Hz), 15.5; 31P NMR (CDCl3, 121 MHz) δ
4.06 (m, 4H), 3.52 (bs, 2H), 2.86 (t, J ) 6.0 Hz, 2H), 1.85-
1.79 (m, 4H), 1.33 (t, J ) 7.0 Hz, 6H); 13C NMR (CDCl3, 75
MHz) 60.6 (d, J P-C ) 5.4 Hz), 41.7 (d, J P-C ) 17.2 Hz), 25.6
28.9; LRFABMS m/z 312 (M+ + 1). Anal. Calcd for C14H18
-
NO5P: C, 54.02; H, 5.83; N, 4.50. Found: C, 54.16; H, 5.89;
N, 4.52.
(d, J P-C ) 4.2 Hz), 22.1 (d, J P-C ) 140.7 Hz), 15.7 (d, J P-C
)
5.3 Hz); 31P NMR (CDCl3, 121 MHz) δ 34.0; Electronspray-
MS m/z 196.1 (M+ + 1).
[3-(1,3-Dioxo-1,3-d ih yd r o-isoin d ol-2-yl)p r op yl]p h os-
p h on ic Acid Dieth yl Ester (1b). N-(3-Bromopropyl)phthal-
imide (10 g, 37.45 mmol) was added to triethyl phosphite (31
g, 187.26 mmol) slowly at room temperature. The reaction
mixture was refluxed for 12 h, and then excess triethyl
phosphite and other volatile compounds were distilled out
under reduced pressure (3 mmHg) at 60 °C. The pure phos-
phonate 1b (11.6 g, 95%) was obtained as a pale yellow viscous
{3-[2-(3-P h osp h a n ylp r op ylca r ba m oyl)ben zoyla m in o]-
p r op yl}p h osp h on ic Acid Dieth yl Ester (4a ). A solution of
(3-aminopropyl)phosphine (280 mg, 3.0 mmol) in ethanol (5
mL) was added dropwise to a solution of compound 1b (975
mg, 3.0 mmol) in ethanol (10 mL) at room temperature under
nitrogen. The reaction mixture was stirred at room tempera-
ture for 12 h, and then solvent was removed under reduced
pressure. The crude product 4a was chromatographed on a
silica gel column under nitrogen using a gradient of chloroform/
methanol (19:5) to afford the pure product 4a (1.1 g, 88%): 1H
NMR (CDCl3, 300 MHz) δ 7.57-7.28 (m, 4H), 4.04 (m, 4H),
3.43 (t, J ) 6.24, 4H), 2.72 (dt, J P-H ) 194.75 Hz, J H-H ) 7.33
Hz, 2H), 1.90-1.69 (m, 6H), 1.65-1.50 (m, 2H), 1.29 (t, J )
7.00 Hz, 6H); 13C NMR (CDCl3, 75 MHz) δ 168.9, 168.6, 134.4,
129.0, 127.6, 127.4, 61.0, 39.6 (singlet merged with doublet,
1
oil. The H NMR spectrum matched the published spectrum.37
1H NMR (CDCl3, 300 MHz) δ 7.59 (d, J ) 2.21 Hz, 2H), 7.51
(d, J ) 3.11 Hz, 2H), 3.85 (q, J ) 5.60 Hz, 4H), 3.51 (t, J )
6.65 Hz, 2H), 1.77-1.62 (m, 2H), 1.59-1.51 (m, 2H), 1.08 (t, J
) 6.96 Hz, 6H); 13C NMR (CDCl3, 75 MHz) δ 167.6, 133.5,
131.4, 122.6, 61.0, 37.6 (d, J P-C ) 19.4 Hz), 22.8 (d, J P-C
)
142.0 Hz), 21.4, 15.9; 31P NMR (CDCl3, 121 MHz) δ 33.2;
LRFABMS m/z 326 (M+ + 1). Anal. Calcd for C15H20NO5P: C,
55.38; H, 6.20; N, 4.31. Found: C, 55.31; H, 6.32; N, 4.43.
(2-{2-[2-(Diet h oxyp h osp h or yl)et h ylca r b a m oyl]b en z-
oyla m in o}eth yl)p h osp h on ic Acid Dieth yl Ester (2a ).
Anhydrous hydrazine (530 mg, 16.5 mmol) was added dropwise
to a solution of phthalimide 1a (10.03 g, 32.15 mmol) in ethanol
(50 mL) at room temperature. The reaction mixture was stirred
at room temperature for 12 h. The precipitated phthalyl
hydrazide was filtered, and the solvent was removed under
reduced pressure. The crude product was chromatographed on
a silica gel column using a gradient of chloroform/methanol.
1
3J P-C ) 21.27 Hz), 32.0, 22.3 (d, J P-C ) 140.6 Hz), 21.8, 15.9,
10.6; 31P NMR (CDCl3, 121 MHz) δ 34.3, -135.1; Proton-
coupled 31P NMR (CDCl3, 121 MHz) δ 34.3, -135.1 (t, J P-H
)
196.02 Hz); HRFABMS calcd for C18H30N2O5P2 417.1708, found
417.1719 (M + 1)+.
{3-[2-(2-Me r c a p t oe t h ylc a r b a m oyl)b e n zoyla m in o]-
p r op yl}p h osp h on ic a cid d ieth yl ester (4b): colorless solid;
1
yield 87%; H NMR (CDCl3, 300 MHz) δ 7.39-7.26 (m, 4H),
3.98-3.86 (m, 4H), 3.58-3.48 (m, 2H), 3.27-3.18 (m, 2H), 2.80
(t, J ) 6.42 Hz, 2H), 1.73-1.58 (m, 4H), 1.19 (t, J ) 7.06); 13
C
(36) Stiles, A. R.; Rust, F. F.; Vaughan, W. E. J . Am. Chem. Soc.
1952, 74, 3282-3282.
(37) Chun, Y.-J .; Park, J .-H.; Oh, G.-M.; Hong, S.-I.; Kim, Y.-J .
Synthesis 1994, 909-910.
(38) Bako´, P.; Nova´k, T.; Luda´nyi, K.; Pete, B.; To˜ke, L.; Keglevich,
G. Tetrahedron: Asymmetry 1999, 10, 2373-2380.

680 J . Org. Chem., Vol. 65, No. 3, 2000
Gali et al.
NMR (CDCl3, 75 MHz) δ 168.2, 134.8, 134.4, 129.5, 127.8, 61.3,
39.83 (d, J P-C ) 17.6 Hz), 38.7, 37.2, 22.4 (d, J P-C ) 140.9 Hz),
21.9, 16.1; 31P NMR (CDCl3, 121 MHz) δ 34.4; HRFABMS calcd
for C17H27N2O5PS 403.1456, found 403.1459 (M + 1)+.
{3-[2-(2-H y d r o x y e t h y lc a r b a m o y l)b e n zo y la m in o ]-
p r op yl}p h osp h on ic a cid d ieth yl ester (4c): colorless solid;
N,N′-Bis(3-p h osp h a n ylp r op yl)p h th a la m id e (6b): pale
yellow powder; yield 81%; IR (KBr): ν ) 2280 (P-H), 1634
(CdO) cm-1; 1H NMR (CDCl3, 300.1 MHz) δ 7.54-7.18 (m, 4H),
3.61-3.49 (m, 4H), 2.69 (dt, J P-H ) 193.4 Hz, J H-H ) 7.7 Hz,
4H), 2.01-1.69 (m, 8H); 13C NMR (CDCl3, 75.5 MHz) δ 169.4,
134.4, 129.63, 127.7, 40.1, 32.2, 10.9; 31P NMR (CDCl3, 121.5
MHz) δ -135.64; 31P NMR (proton coupled, CDCl3, 121.5 MHz)
1
yield 85%; H NMR (CDCl3, 300 MHz) δ 7.68-7.41 (m, 4H),
4.15-4.03 (m, 4H), 3.79-3.68 (m, 2H), 3.59-3.38 (m, 4H),
1.92-1.72 (m, 4H), 1.31 (t, J ) 7.03); 13C NMR (CDCl3, 75
MHz) δ 169.9, 169.2, 135.5, 134.8, 129.9, 129.6, 127.9, 127.8,
61.6, 60.7, 42.8, 39.8 (d, J P-C ) 7.6 Hz), 22.7 (d, J P-C ) 139.9
Hz), 22.2, 16.2; 31P NMR (CDCl3, 121 MHz) δ 34.4; HRFABMS
calcd for C17H27N2O6P 387.1685, found 387.1692 (M + 1)+.
2-(3-P h osp h a n ylp r op yl)-2,3-d ih yd r o-1H-isoin d ole (5).
Phthalimide 1b (5 g, 15.38 mmol) was dissolved in dry THF
(100 mL) and cooled to 0 °C, and 1 M LiAlH4 in THF (46 mL,
46 mmol) was added dropwise. After stirring at 0 °C for 30
min, the reaction mixture was diluted with THF (200 mL) and
quenched with a saturated solution of Na2SO4 (5 mL). The
organic layer was passed through a pad of silica gel, and the
solvent was removed under reduced pressure to give the
phosphine 5. The crude product was chromatographed on a
silica gel column under nitrogen using a gradient of hexane/
ethyl acetate (3:2). The pure product was obtained as a white
solid (2.4 g, 81%) by elution with a solvent system consisting
of 40% ethyl acetate in hexane. IR (KBr): ν ) 2283 (P-H)
cm-1. 1H NMR (CDCl3, 300.1 MHz) δ 7.21 (s, 4H), 3.99 (s, 4H),
δ -135.64 (t, J P-H ) 193.3 Hz); HRFABMS calcd for C14H22
-
N2O2P2 313.2874, found 313.2871 (M+ + 1).
N,N′-Bis-[2-(b is(h yd r oxym et h yl)p h osp h a n yl)et h yl]-
p h th a la m id e (7a ). The bisphosphine 5a (2.28 g, 8.0 mmol)
was dissolved in degassed ethanol (15 mL). A solution of 37%
aqueous formaldehyde (2.6 mL, 32.0 mmol) was added, and
the mixture was stirred for 30 min under N2 at room temper-
ature. The solvent was removed under reduced pressure to give
the pure (hydroxymethyl)phosphine 7a . 31P NMR (CDCl3): δ
) -23.3. For characterization purposes, the (hydroxymethyl)-
phosphine 7a was converted to (hydroxymethyl)phosphonium
salt 8a by adding excess of aqueous formaldehyde and 5 N
hydrochloric acid in ethanol. After removing the solvent, the
product was purified on a reverse phase Sep-Pak C-18 column
using water-methanol gradient (1:1). Removal of the solvent
in vacuo afforded pure phosphonium salt 8a (4.08 g, 95%) as
a colorless viscous oil. 1H NMR (D2O, 300.1 MHz) δ 7.52-7.47
(m, 4H), 4.67-4.57 (m, 12H), 4.81-4.65(m, 4H), 2.82-2.58 (m,
4H); 13C NMR (D2O, 75.5 MHz) δ: 171.3, 133.9, 131.3, 127.9,
50.3 (d, J ) 53.5 Hz), 32.8, 14.4 (d, J ) 36.8 Hz); 31P NMR
(D2O, 121.5 MHz) δ 29.3; HRFABMS calcd for C18H32N2O8P2
233.2176, found 233.2167 (M2+).
N,N′-Bis[3-(b is(h yd r oxym et h yl)p h osp h a n yl)p r op yl]-
p h th a la m id e (7b). For characterization purposes, the (hy-
droxymethyl)phosphine 7b was converted to (hydroxymethyl)-
phosphonium salt 8b: colorless oil; yield 94%; 1H NMR (D2O,
300.1 MHz) δ 7.54-7.48 (m, 4H), 4.52-4.48 (m, 12H), 4.81-
4.65(m, 4H), 2.97-2.49 (m, 8H); 13C NMR (D2O, 75.5 MHz) δ
171.7, 134.3, 131.3, 127.1, 50.4 (d, J ) 53.2 Hz), 40.4 (d, J )
15.8 Hz), 30.0, 11.6 (d, J ) 36.8 Hz); 31P NMR (D2O, 121.5
MHz) δ 29.9; HRFABMS calcd for C20H36N2O8P2 247.2285,
found 247.2291 (M2+).
2.82 (t, J H-H ) 7.4 Hz, 2H) 2.76 (dt, J P-H ) 194.8 Hz, J H-H
)
7.4 Hz, 2H), 1.85-1.80 (m, 2H), 1.65-1.58 (m, 2H); 13C NMR
(CDCl3, 75.5 MHz) δ 138.7, 126.7, 121.7, 58.3, 55.6, 31.0, 10.9;
31P NMR (CDCl3, 121.5 MHz) δ -134.8 (s); 31P NMR (proton
coupled, CDCl3, 121.5 MHz) δ -134.8 (t, J P-H ) 192.4 Hz).
HRFABMS calcd for C11H16NP calcd for 194.1281, found
194.1286 (M+ + 1).
N,N′-Bis(2-p h osp h a n yleth yl)p h th a la m id e (6a ). Bisphos-
phonate 2a (4.92 g, 10 mmol) was dissolved in dry tetrahy-
drofuran (100 mL) and cooled to 0 °C. A solution of 1 M LiAlH4
in THF (30 mL, 30 mmol) was added dropwise via a syringe
under N2. After stirring at 0 °C for 30 min, the reaction
mixture was diluted with THF (200 mL). Then, a saturated
solution of Na2SO4 (5 mL) was added at 0 °C to quench the
excess LiAlH4. The organic layer was passed through a pad of
silica gel and the THF removed under reduced pressure at
room temperature to give the pure diphosphine 6a (2.3 g, 80%)
as a pale yellow powder, which was used without any further
purification. IR (KBr): ν ) 2282 (P-H), 1632 (CdO) cm-1; 1H
NMR (CDCl3, 300.1 MHz) δ 7.53-7.20 (m, 4H), 3.54-3.46 (m,
4H), 2.68 (dt, J P-H ) 195.4 Hz, J H-H ) 7.8 Hz, 4H), 1.80-1.73
(m, 4H); 13C NMR (CDCl3, 75.5 MHz) δ 169.1, 134.3, 130.2,
128.3, 42.9, 14.6 (d, J P-C ) 10.5 Hz); 31P NMR (CDCl3, 121.5
MHz) δ -146.7; 31P NMR (proton coupled, CDCl3, 121.5 MHz)
Ack n ow led gm en t . This work was supported by
the US Department of Energy, DuPont Pharmaceuti-
cals, and the Department of Radiology, University of
MissourisColumbia.
Su p p or tin g In for m a tion Ava ila ble: 13C and 31P NMR
spectra of compounds 2-6 and 8, proton-coupled 31P NMR
spectra of compounds 4a , 5, and 6a , and the IR spectrum of
compound 6a . This material is available free of charge via the
Internet at http://pubs.acs.org.
δ -146.7 (t, J P-H ) 195.6 Hz); HRFABMS calcd for C12H18
-
N2O2P2 285.2337, found 285.2339 (M+ + 1).
J O991067B