N-phosphinoylnitroso compounds: New asymmetric N-O heterodienophiles and nitroxyl delivery agents [12]

Full text of DOI:10.1021/ja9908016

J. Am. Chem. Soc. 1999, 121, 6769-6770
6769
Scheme 1
N-Phosphinoylnitroso Compounds: New Asymmetric
N-O Heterodienophiles and Nitroxyl Delivery
Agents
Roy W. Ware, Jr., and S. Bruce King*
Department of Chemistry, Wake Forest UniVersity
Winston-Salem, North Carolina 27109
ReceiVed March 12, 1999
Scheme 2
Nitroso compounds occupy a prominent position in organic
chemistry as both useful synthetic intermediates and molecules
of biological interest.1 Acyl nitroso compounds (1) react with
conjugated 1,3-dienes as N-O heterodienophiles to produce
N-acyl-3,6-dihydro-1,2-oxazines (2), highly functionalized cy-
cloadducts that represent the starting point for the asymmetric
synthesis of many nitrogen-containing compounds (Scheme 1).2
Interest in the diverse interactions of nitric oxide (NO) with
various biological systems has led to the identification, synthesis,
and characterization of new NO donor molecules, including many
nitroso-containing compounds.3 We wish to report the formation
of N-phosphinoylnitroso compounds (3), new asymmetric (when
R1 * R2) reactive intermediates, which diastereoselectively react
with 1,3-dienes as N-O heterodienophiles. This reactivity allows
the direct and stereoselective introduction of the Lewis basic
phosphinamide functional group present in a number of asym-
metric catalysts.4 In addition to the potential synthetic utility of
these molecules, N-phosphinoylnitroso compounds (3), produced
by the oxidation of N-phosphinoylhydroxylamines (4, Scheme
1), hydrolyze to liberate nitroxyl (HNO), the biologically impor-
tant reduced form of nitric oxide.5
The intermediacy of N-phosphinoylnitroso compound (5) is
indicated from trapping experiments with 1,3-dienes (Scheme 2).
Periodate oxidation of N-(diphenylphosphinoyl)hydroxylamine
(6),6 in the presence of 1,3-cyclopentadiene or 1,3-cyclohexadiene
produced cycloadducts 7 and 8 in 80 and 88% yield, respectively
(Scheme 2). Molybdenum hexacarbonyl N-O bond reduction
afforded the corresponding alcohols (9 and 10, 53 and 78% yield,
respectively) that were further characterized by acetylation
(Scheme 2).7 This sequence of reactions provides a direct and
stereoselective method for the introduction of the phosphinamide
functional group into the variety of compounds accessible through
Scheme 1. Acid methanolysis of (10) removed the phosphinamide
group affording the hydrochloride salt of the amino alcohol (11)
in 49% yield (Scheme 2).
(entries 3-6). The structure of the major regioisomer (14) from
the reaction of 5 with trans-piperylene was determined by 13C
NMR chemical shift analysis of the methine carbon.8 The
structures of 16 and 18 were determined by 13C NMR chemical
shift analysis, and the structure of 17 was determined by single-
crystal X-ray crystallography.9 The observed regiochemistry for
entries 4-6 is consistent with that expected on the basis of
previous results from cycloadditions between acyl nitroso com-
pounds and similar 1,3-dienes and on the basis of theoretical
arguments.10,11 Heating 19 overnight at 80 °C in the presence of
1,3-cyclohexadiene produced 8 in 52% yield demonstrating the
ability of 19 to produce 5 non-oxidatively through a retro-Diels
Alder reaction similar to acyl nitroso cycloadducts of this
diene.2c,12
Experiments with a racemic asymmetric N-phosphinoylnitroso
compound demonstrate the diastereoselective cycloaddition of
these reactive intermediates. Periodate oxidation of N-(benzyl-
phenylphosphinoyl)hydroxylamine (20), in the presence of 1,3-
cyclopentadiene or 1,3-cyclohexadiene produced chromatographi-
cally separable mixtures of the diastereomeric cycloadducts 22a,b
(85% yield, 35:1 ) 22a/22b, Scheme 3) and 23a,b (87% yield,
21:1 ) 23a/23b, Scheme 3). The relative stereochemistry of the
major cycloadducts (22a and 23a) was determined by single-
crystal X-ray crystallography.13 While a clear mechanistic ex-
Table 1 summarizes the products and yields of the reactions
of N-phosphinoylnitroso compound (5) with acyclic (entries 1-6),
electron-rich (entries 1, 3, 4, and 6), electron-poor (entry 5), and
aromatic (entry 7) 1,3-dienes. Compound 5, formed by the
periodate oxidation of 6, regioselectively reacted with unsym-
metric 1,3-dienes to produce the corresponding cycloadducts
(8) Defoin, A.; Pires, J.; Streith, J. Synlett 1990, 111-113.
(9) Crystal data for 17, C20H22NO4P, monoclinic at 293 K, P21-C2 (No.
2
4), colorless crystal, a ) 10.255(1) Å, b ) 7.1019(9) Å, c ) 13.085(2) Å, â
) 115.035(5)°, Z ) 2, R1 ) 0.054, wR2 ) 0.0098, GOF ) 1.016.
(10) (a) Defoin, A.; Pires, J.; Tissot, I.; Tschamber, T.; Bur, D.; Zehnder,
M.; Streith, J. Tetrahedron Asymmetry 1991, 2, 1209-1221. (b) Defoin, A.;
Pires, J.; Streith, J. Synlett 1991, 417-419. (c) Defoin, A.; Fritz, H.; Schmidlin,
C.; Streith, J. HelV. Chim. Acta 1987, 70, 554-569. (d) Baldwin, J. E.; Otsuka,
M.; Wallace, P. M. Tetrahedron 1986, 42, 3097-3110. (e) Boger, D. L.; Patel,
M.; Takusagawa, F. J. Org. Chem. 1985, 50, 1911-1916. (f) Baldwin, J. E.;
Bailey, P. D.; Gallacher, G.; Otsuka, M.; Singleton, K. A.; Wallace, P. M.
Tetrahedron 1984, 40, 3695-3708.
(1) The Chemistry of Amino, Nitroso, and Nitro Compounds and Their
DeriVatiVes; Patai, S., Ed.; John Wiley and Sons: Chichester, 1982; Supple-
ment F, Parts 1 and 2.
(2) (a) Vogt, P. F.; Miller, M. J. Tetrahedron 1998, 54, 1317-1348. (b)
Streith, J.; Defoin, A. Synthesis 1994, 1107-1117. (c) Kirby, G. W. Chem.
Soc. ReV. 1977, 6, 1-24.
(3) Feelisch, M.; Stamler, J. S. In Methods in Nitric Oxide Research;
Feelsich, M., Stamler, J. S., Eds.; Wiley: Chichester, 1996; Chapter 7.
(4) Gamble, M. P.; Smith, A. R. C.; Wills, M. J. Org. Chem. 1998, 63,
6068-6071.
(11) An example of the alternative stereochemistry from the reaction of
ethyl sorbate and a camphor-derived acyl nitroso compound has been reported.
Martin, S. F.; Hartmann, M.; Josey, J. A. Tetrahedron Lett. 1992, 33, 3583-
3586.
(5) Fukuto, J. M.; Chiang, K.; Hszeih, R.; Wong, P.; Chaudhuri, G. J.
Pharmacol. Exp. Ther. 1992, 263, 546-551.
(6) Harger, M. J. P.; Shimmin, P. A. Tetrahedron 1992, 48, 7539-7550.
(7) Ghosh, A.; Ritter, A.; Miller, M. J. J. Org. Chem. 1995, 60, 5808-
5813.
(12) Keck, G. E.; Webb, R. R.; Yates, J. B. Tetrahedron 1981, 37, 4007-
4016.
10.1021/ja9908016 CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/02/1999

6770 J. Am. Chem. Soc., Vol. 121, No. 28, 1999
Table 1. Reactions of 5 with Various 1,3-Dienes
Communications to the Editor
Scheme 3
Scheme 4
dehydration product of nitroxyl, provides strong evidence for the
intermediacy of nitroxyl.14 As with acyl nitroso compounds, the
direct hydrolysis of an N-phosphinoylnitroso compound would
produce nitroxyl and ultimately nitrous oxide.15 N-(Diphen-
ylphosphinoyl)hydroxylamine (6) also represents a phosphorus
analogue of Piloty’s acid (N-hydroxybenzenesulfonamide), a
compound known to liberate nitroxyl under basic conditions.16
Treatment of 6 with sodium hydroxide (10 equiv) in a water/
methanol solution produced nitrous oxide (20% yield) indicative
of nitroxyl formation presumably through base-catalyzed dispro-
portionation similar to Piloty’s acid (Scheme 4).16
In summary, N-phosphinoylnitroso compounds represent excit-
ing new intermediates possessing divergent reactivity. The
presented results allow them to be considered as new asymmetric
N-O heterodienophiles that permit the direct diastereoselective
introduction of the phosphinamide functional group, or as a new
group of nitroxyl delivery agents.
planation of the high levels of diastereoselectivity observed with
the structurally simple phosphinoylnitroso compound (21) remains
uncertain, the direct attachment of the asymmetric center to the
reactive nitroso group of 21 would be expected to enhance the
diastereoselectivity. Analytical chiral HPLC resolution of the
enantiomers of 20 clearly demonstrates the feasibility for the
formation of enantiomerically enriched cycloadducts from this
reaction.
Finally, oxidative activation or basic decomposition of N-
phosphinoylhydroxylamines affords nitroxyl (HNO), the one-
electron reduced form of nitric oxide (NO). Gas chromatographic
headspace analysis after periodate oxidation of 6 or 20 in the
absence of a conjugated 1,3-diene in 1:1 CH3OH:H2O produced
nitrous oxide (35 and 49% yield, respectively; Scheme 4).
Identification of nitrous oxide, the stable dimerization and
Acknowledgment. This work was supported by grants (9630310N)
from the American Heart Association, the American Cancer Society (IRG-
198), and the American Chemical Society Petroleum Research Fund (Type
G). Mass spectrometry was performed by the Nebraska Center for Mass
Spectrometry. The authors thank Dr. Cynthia Day (Wake Forest
University) for performing X-ray crystallographic studies and Professor
Eric R. Johnston of the University of North Carolina at Greensboro for
performing 31P NMR spectroscopy.
Supporting Information Available: Full experimental details includ-
ing the synthesis and characterization of all compounds including the
X-ray crystallographic data of 17, 22a, and 23a (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA9908016
(13) Crystal data for 22a, C18H18NO2P, monoclinic at 293 K, P21/n (an
alternate setting of P21/c-C52h [No. 14]), colorless crystal, a ) 16.931(1) Å,
b ) 5.7138(3) Å, c ) 17.551(1) Å, â ) 113.559(5)°, Z ) 4, R1 ) 0.105,
wR2 ) 0.156, GOF ) 1.099. Crystal data for 23a, C19H20NO4P, monoclinic
at 293 K, P21/n (an alternate setting of P21/c-C52h [No. 14]), colorless crystal,
a ) 17.092(2) Å, b ) 5.927(1) Å, c ) 17.851(2) Å, â ) 112.576(8)°, Z )
4, R1 ) 0.161, wR2 ) 0.114, GOF ) 0.997.
(14) Wink, D. A.; Feelisch, M., J. S. In Methods in Nitric Oxide Research;
Feelsich, M., Stamler, J. S., Eds.; Wiley: Chichester, 1996; Chapter 28.
(15) (a) Atkinson, R. N.; Storey, B. M.; King, S. B. Tetrahedron Lett. 1996,
37, 9287-9290. (b) Sklarz, B.; Al-Sayab, A. F. J. Chem. Soc. 1964, 1318-
1320.
(16) Bonner, F. T.; Ko, Y. Inorg. Chem. 1992, 31, 2514-2519.