Unprecedented selective aminolysis: Aminopropyl phosphine as a building block for a new family of air stable mono-, bis-, and tris-primary phosphines [8]

Full text of DOI:10.1021/ja993504+

1554
J. Am. Chem. Soc. 2000, 122, 1554-1555
associated with their unpleasant pyrophoric nature and extreme
hydrolytic, thermal, and oxidative instabilities. In particular,
primary phosphines with “user friendly” properties (e.g. good
oxidative/thermal stability, low volatility) would be extremely
important not only from the synthetic point of view but also for
potential application (e.g. in dendrimers formation). As part of
our ongoing research on the fundamental main group and organic
chemistry of functionalized phosphorus compounds19 we report,
herein, unprecedented selectivity in the reaction of 3-aminopropyl
primary phosphine 3, with the methyl ester in the presence of
free acid, amide, and thiol to produce air stable amide, carboxy-
late, and thiol functionalized primary phosphines (compounds 8,
10, 12, and 14, Scheme 1). The utility of conveniently accessible
3-aminopropylphosphine, H2N(CH2)3PH2 (3), as a building block
for the development of a new air stable primary phosphine, as
reported in this communication, is unique because highly danger-
ous phosphine gas (PH3) and also alkalimetal metal phosphides
(e.g. MPH2; M ) Li or Na) are routinely used in the synthesis of
primary phosphine compounds.1-3
The synthon, 3-aminopropylphosphine 3, was synthesized via
an Arbuzov reaction of 1,3-dibromopropane with triethyl phos-
phite followed by conversion of the (3-bromopropyl)phosphonic
acid diethyl ester 1 to the corresponding azide 2 (Scheme 1). The
key synthon, (3-azidopropyl)phosphonic acid diethyl ester 2, was
produced in near quantitative yield as an analytically pure liquid
by refluxing the bromophosphonate 1 and sodium azide in
acetone.20 It is important to recognize that the azide 2 is safe to
handle as a neat liquid as well as in various organic solvents21
(e.g.: THF, ether, acetone, and alcohol). In fact, the phosphonate
functionalized alkyl azide 2 was produced in 100-200 g
quantities. Routine safe handling procedures of hazardous chemi-
cals is recommended. Further, the azide 2 upon reduction with
LAH gave 3-aminopropylphosphine 3 in 65% yield.22 3-Amino-
propylphosphine 3 is non-pyrophoric and is moderately stable in
air. It can be stored for extended periods in a nitrogen atmosphere
as a neat colorless liquid. It may be noted that the amine
Unprecedented Selective Aminolysis: Aminopropyl
Phosphine as a Building Block for a New Family of
Air Stable Mono-, Bis-, and Tris-Primary Phosphines
Kandikere Ramaiah Prabhu,‡,† Nagavarakishore Pillarsetty,‡,§
Hariprasad Gali,‡,§ and Kattesh V. Katti*,‡,
Department of Radiology and
Missouri UniVersity Research Reactor
Allton Building Laboratories, Room No. 106
UniVersity of Missouri-Columbia
Columbia, Missouri 65211
ReceiVed September 29, 1999
Primary and secondary phosphines (RPH2 and R2PH) constitute
an important class of organophosphorus compounds.1-3 Their
facile participation in a number of chemical reactions that include
nucleophilic addition reactions with unsaturated species, substitu-
tion reactions with acid halides, reactions with alkali metals, and
a host of reactions at the PIII center have resulted in the
development of a large number of new chemical products of
commercial significance.1-8 Primary phosphines, in particular,
have proven to be versatile starting materials for the development
of hydroxyalkyl phosphines (Rx(CH2OH)yP) via formylation of
P-H bonds with aldehydes.9,10 The ease of transformation of P-H
bonds into P-C bonds is, undoubtedly, a synthetic novelty and
the hydroxymethylated-phosphorus compounds have provided a
diverse range of chemical, catalytic, environmental, biological,
and biomedical applications.11-18
A serious impediment to using primary and secondary phos-
phines as general-purpose reagents to develop new chemistry is
* Address correspondence to this author.
‡ Department of Radiology, University of Missouri-Columbia.
§ Department of Chemistry, University of Missouri-Columbia.
Missouri University Research Reactor.
† On leave from the Department of Organic Chemistry, Indian Institute of
Science, Bangalore, India 560012.
(1) Corbridge, D. E. C. In Phosphorus: An outline of its Chemistry,
Biochemistry and Technology, 4th ed.; Elsevier: New York, 1990.
(2) Maier, L. In Organic Phosphorus Compounds; Kosolapoff, G. M.,
Maier, L., Eds.; John Wiley & Sons: New York, 1972; Vol. 1, Chapter 1, pp
1-288.
(18) (a) Katti, K. V. Curr. Sci. 1996, 70, 219; Chem. Abstr.1996, 124,
305372s. (b) Berning, D. E.; Katti, K. V.; Volkert, W. A.; Higginbotham, C.
J.; Ketring, A. R. Nucl. Med., Biol. 1998, 25, 577-583; Chem. Abstr. 1998,
129, 287351f.
(19) (a) Gali, H.; Karra, S. R.; Reddy, V. S.; Katti, K. V. Angew Chem.,
Int. Ed. Engl. 1999, 38, 2020-2023. (b) Berning, D. E.; Katti, K. V.; Barnes,
C. L.; Volkert, W. A. J. Am. Chem. Soc. 1999, 121, 1658-1664. (c)
Pandurangi, R. S.; Katti, K. V.; Stillwell, L.; Barnes, C. L. J. Am. Chem. Soc.
1998, 120, 11364-11373. (d) Berning, D. E.; Katti, K. V.; Barnes, C. L.;
Volkert, W. A.; Ketring, A. R. Inorg. Chem. 1997, 36, 2765. (e) Smith, C. J.;
Katti, K. V.; Volkert, W. A.; Barbour, L. J. Inorg. Chem. 1997, 36, 3928.
(20) Preparation of (3-azidopropyl)phosphonic acid diethyl ester (2):
A well-stirred solution of (3-bromopropyl)phosphonic acid diethyl ester (30
g, 115 mmol) and sodium azide (15 g, 230 mmol) in acetone (100 mL) was
refluxed for 12 h in a nitrogen atmosphere, cooled to room temperature, and
filtered, and solvent was removed under vacuum to afford diethyl-3-
(3) Arbuzov, B. A. Pure Appl. Chem. 1964, 9, 307.
(4) Gee, V.; Orpen, A. G.; Phetmung, H.; Pringle, P. G.; Pugh, R. I. Chem
Commun. 1999, 901-902.
(5) Petrov, K. A.; Parshina, V. A. Russ. Chem. ReV. 1968, 37, 532-543.
(6) Bourumeau, K.; Gaumont, A. C.; Denis, J. M. Tetrahedron. Lett. 1997,
38, 1923-1926.
(7) Bourumeau, K.; Gaumont, A. C.; Denis, J. M. J. Organomet. Chem.
1997, 529, 205-213.
(8) Smith, C. J.; Reddy, V. S.; Katti, K. V. Chem Commun. 1996, 2557-
2558.
(9) Katti, K. V.; Gali, H.; Berning, D. E.; Smith, C. J. Acc. Chem. Res.
1999, 32, 9-17.
1
azidopropyl phosphonate, 2, as a colorless liquid (25.5 g, 99%). H (CDCl3,
(10) Booth, G. In Organic Phosphorus Compounds; Kosolapoff, G. M.,
Maier, L., Eds.; John Wiley & Sons: New York, 1972; Vol. 1, Chapter 3A,
pp 433-545.
300 MHz): δ 4.2-4.0 (m, 4H), 3.4 (2H, t, J ) 6.2 Hz), 1.95-1.7 (m, 4H),
1.3 (6H, t, J ) 6.9 Hz). 13C (CDCl3, 75 MHz): δ 61.3, 50.9 (d, J ) 16 Hz),
22.30 (d, J ) 143 Hz), 21.9, 16.0. 31P (CDCl3, 121 MHz): δ 32.2. Mass
(m/z): 222.2 (M + H)+. HRMS, calcd for C7H16O3N3P (M + H)+ 222.1007,
found 222.1005. Anal. Calcd for C7H16N3O3P: C, 38.01; H, 7.29; N, 18.99.
Found: C, 38.04; H, 7.33, N, 19.01.
(11) Franz, J. E.; Mao, M. K.; Sikorski, J. A. Glyphosphate: A Unique
Global Herbicide; American Chemical Society Monograph; American Chemi-
cal Society: Washington, DC, 1997; p 189.
(12) Daigle, D. J.; Pepperman, A. B., Jr.; Drake, G. L., Jr.; Reeves, W. A.
Text. Res. J. 1972, 42, 347; Chem. Abstr. 1972, 77, 89894e.
(13) (a) Daigle, D. J.; Frank, A. W. Text. Res. J. 1982, 52, 751; Chem.
Abstr. 1983, 98, 5336x. (b) Daigle, D. J.; Reeves, W. A.; Donaldson, D. J.
Text. Res. J. 1970, 40, 580; Chem. Abstr. 1970, 73, 87974z.
(14) Frey, R. Today’s Chemist at Work 1998, 34.
(15) (a) Fukuoka, A.; Kosugi, W.; Morishita, F.; Hirano, M.; McCaffery,
L.; Henderson, W.; Komiya, S. Chem. Commun. 1999, 489-490. (b) Reetz,
M. T.; Lohmer, G.; Schwickardi, R. Angew. Chem., Int. Ed. Engl. 1997, 36,
1526-1529. (c) Hoye, P. A. T.; Pringle, P. G.; Smith, M. B.; Worboys, K. J.
Chem. Soc., Dalton Trans. 1993, 269.
(16) (a) Higham, L.; Powell, A. K.; Whittlesey, M. K.; Wocadlo, S.; Wood,
P. T. J. Chem. Soc., Chem Commun. 1998, 1107-1108. (b) Berning, D. E.;
Katti, K. V.; Barbour, L. J.; Volkert, W. A. Inorg Chem. 1998, 37, 334-339.
(17) Goodwin, N. J.; Henderson, W.; Fewcett, N.; Russell, D. R. J. Chem
Soc. Dalton Trans. 1999, 1785-1793.
(21) Mortier, J.; Gridnev, I. D.; Fortineau, A.-D. Org. Lett. 1999, 1, 981-
984 and references therein.
(22) Preparation of 3-aminopropylphosphine (3): To a vigorously stirred
cold (0 °C) solution of LAH (230 mL, 1 M solution in ether) was added the
solution of (3-azidopropyl)phosphonic acid diethyl ester 2 (30 g, 135 mmol)
in ether (60 mL) during 1 h in a nitrogen atmosphere at room temperature for
4 h; the mixture was cooled to 0 °C and the excess of LAH was quenched by
slow addition of cold aqueous brine solution (10 mL), followed by the addition
of aqueous KOH solution (10%, 20 mL). The organic layer was separated,
the aqueous layer was extracted with ether (3 × 300 mL), and the combined
organic extract was washed with brine (100 mL), dried over anhydrous
Na2SO4, and subjected to fractional distillation of the solvent under atmospheric
pressure to afford 3-aminopropylphosphine, 3, as a colorless liquid (8.0 g,
65%). 3-Aminopropyl phosphine 3 was isolated, stored, and used as 65%
solution in ethanol. Satisfactory spectral and analytical data were obtained
for 3 (see Supporting Information).
10.1021/ja993504+ CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/04/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 7, 2000 1555
Scheme 1a
prospects for attachment of phosphines to chemical and biochemi-
cal anchors via the traditional -COOH activation protocols.27,28
To demonstrate the feasibility of linking -COOH groups of 8
with peptides (and proteins), a synthetic protocol for linking 8
with a dipeptide, gly gly ethyl ester hydrochloride, has been
developed as outlined in Scheme 1. Thus, activation of the
carboxylate of 8, using HBTU, followed by reaction with the
-NH2 group of gly gly peptide produced P2N2gly gly peptide
conjugate, {2-[4,4-bis(3-phosphanylpropylcarbamoyl)butyryal-
amino]acetylamino}acetic acid ethyl ester (15), in 65% yield. The
oxidative stability of primary phosphine 8 is noteworthy because
-PH2 groups of 8 remained oxidatively inert during the reaction
conditions that were employed for conjugation as well as silicagel
column chromatographic purification procedures. The chemistry
described in Scheme 1 demonstrates the utility of bifunc-
tional phosphine frameworks, of type 8, in combinatorial chem-
istry for the development of chelating unit functionalized peptide
libraries.
The high thermal and oxidative instability of primary phos-
phines has often been a severe limitation to perform backbone
chemical modifications while keeping the -PH2 unit intact. In
this context, the reactions at the -NH2 functionality of the
3-aminopropylphosphine 3 (as summarized in Scheme 1) have
provided a new approach toward the construction of amide, car-
boxylate, and thiol functionalized mono- or multinuclear primary
phosphine compounds while maintaining the oxidative integrity
of -PH2 units. The non-phosphine (PH3) synthetic route to the
H2N(CH2)3PH2 (3), as demonstrated herein, is an important step
toward exploring new chemistry of functionalized primary phos-
phines.
a Conditions: (i) NaN3/acetone, reflux, 12 h, 99%. (ii) LAH, 4 h, 65%.
(iii) K2CO3/benzene, (Bu)4N(HSO4), reflux 12 h, 85%. (iv) TFA, room
temperature, 12 h, 97%. (v) Et3N, pyridine/CH2Cl2, 70%. (vi) 70 °C, 40
h, 51%. (vii) 100 °C, 12 h, 70%. (viii) 100 °C, 12 h, 70%. (ix) 100 °C,
12 h, 72%. (x) HBTU, CH3CN, 65%.
functionalized primary phosphine 3 belongs to the family of
aminoalkylphosphines and other functionalized alkyl primary
phosphines reported by Stiles et al.23 and Issleib et al.24
The synthetic utility of 3-aminopropylphosphine 3 for the
development of a novel -COOH functionalized bisamidobispri-
mary phosphine, 4,4-bis(3-phosphanylpropylcarbamoyl)butyric
acid (8), is depicted in Scheme 1. Thus, the precursor diester acid,
2-methoxycarbonylpentanedioic acid 1-methyl ester (7), was
synthesized as shown in Scheme 1. It is remarkable to note that
the “no solvent mediated” reaction of NH2(CH2)3PH2 (3) with
the diester acid 7 is highly selective in that the -COOH group
remained unattacked whereas the reaction occurred smoothly and
selectively at the -COOMe groups to produce the novel car-
boxylate functionalized diamide bisprimary phosphine 8 in 51%
yield.25 The proton-coupled phosphorus NMR spectrum confirmed
the presence of -PH2 units in 8. The compound 8 was fully
characterized by1H, 13C, and 31P NMR spectroscopy and high-
resolution mass spectrometry. It is important to recognize that
the aminolysis of 7 with 3-aminopropylphosphine (3), when
carried out in the presence of solvents (benzene or toluene),
resulted in complex side reactions and the primary phosphine 8
was formed as a byproduct.
The nonphosphine synthetic route for bisprimary phosphine 8
is novel and prompted further investigation to test the generality
of the reactions of 3-aminopropylphosphine (3) with functional-
ized esters. In fact, as shown in Scheme 1, the reactions of 3
with the functionalized esters 9, 11, and 13 produced a new
generation of air-stable thiol functionalized (mono) 12, amide
functionalized (bis) 10, and dendritic (tris) primary phosphines
14, respectively in good yields.26 The new primary phosphines
10, 12, and 14 were fully characterized by 1H, 13C, and 31P NMR
and high-resolution mass spectrometry. It is important to note
that the reactions outlined in Scheme 1 proceed to completion in
the absence of solvents and that the amide or thiol groups did
not interfere in the aminolysis of the corresponding esters.
Combination of carboxylate and -PH2 groups within the same
molecule, as in compound 8 (N2P2COOH), will present unique
Acknowledgment. This work was supported by the U.S. Department
of Energy, DuPont Pharmaceuticals, and the Department of Radiology,
University of Missouri-Columbia.
Supporting Information Available: Experimental procedure and full
characterization data for compounds 3, 6, 7, 10, 11, 12, 14, and 15 (PDF).
This material is available free of charge via the Internet at http://pubs.acs.org.
JA993504+
(24) (a) Issleib, K.; Kummel, R.; Oehme, H.; Meissner, I. Chem. Ber. 1968,
101, 3612. (b) Issleib, K.; Kummel, R.; Zimmermann, H. Angew. Chem. 1965,
77, 172.
(25) Preparation of 4,4-bis(3-phosphanylpropylcarbamoyl)butyric acid
(N2P2COOH, 8): 2-methoxycarbonylpentanedioic acid 1-methyl ester 7 (2
g, 9.8 mmol) and 3-aminopropylphosphine 3 (2.85 g, 31.4 mmol) were heated
at 70 °C for 40 h in a nitrogen atmosphere and the excess of 3-aminopro-
pylphosphine was removed under vacuum. The reaction mixture was treated
with water (5 mL), cooled to 0 °C, and neutralized by 2 N hydrochloric acid
(5 mL) to form a white solid that was filtered, washed with water, dried, and
purified by flash column chromatography (silica gel, CH3OH:CHCl3, 1:20)
under nitrogen to afford the corresponding N2P2COOH (8) as a white solid
(1.6 g, 51%). 1H (CDCl3, 300 MHz): δ 7.4 (bs, 2H), 3.50 (t, 1H, J ) 7.7
Hz), 3.35-3.2 (m, 4H), 2.71 (dt, 4H, J ) 194 Hz, J ) 7.4 Hz), 2.32-2.42
(m, 2H), 2.2-2.1 (m, 2H), 1.81-1.65 (m, 4H), 1.6-1.4 (m, 4H). 13C (CDCl3,
75 MHz): δ 175.6, 171.4, 51.8, 40.2, 32.5, 31.6, 27.8, 11.2. 31P (CDCl3, 121
MHz): δ -135.6. Mass (m/z): 323.4 (M + H)+. HRMS, calcd for
C12H24N2O4P2 (M+ + H) 323.1289 and found 323.1288. Anal. Calcd for
C12H24N2O4P2: C, 44.72; H, 7.50; N, 8.69. Found: C, 44.74; H, 7.53, N,
8.72.
(26) General procedure to prepare 10, 12, and 14: The esters 9, 11, or
13 were heated at 100 °C with 3-aminopropylphosphine 3 (2.2 equiv for 9,
1.2 equiv for 11, and 3.3 equiv for 13, respectively) for 12 h. Excess of
3-aminopropylphosphine 3 and methanol were removed under vacuum at 100
°C. The crude products 10, 12, or 14 were purified on a silica gel column
under nitrogen to yield the pure 10, 12, or 14. Satisfactory spectral and
analytical data were obtained for the compounds 10, 12, or 14 (see Supporting
Information).
(27) (a) Rossi, P.; Felluga, F.; Scrimin, P. Tetrahedron Lett. 1998, 39,
7159-7162. (b) Francis, M. B.; Finney, N. S.; Jacobson, E. N. J. Am. Chem.
Soc. 1996, 118, 8983-8984 and references therein.
(28) Karra, S. R.; Schibli, R.; Gali, H.; Katti, K. V.; Hoffman, T. J.;
Higginbotham, C.; Sieckman, G. L.; Volkert, W. A. Bioconjugate Chem. 1999,
10, 254-260 and references therein; Chem. Abstr. 1999, 130, 293330k.
(23) Stiles, A. R.; Rust, F. F.; Vaughan, W. E. J. Am. Chem. Soc. 1952,
74, 3282-3284.