Spontaneous Lossen Rearrangement of (Phosphonoformyl)hydroxamates. The Migratory Aptitude of the Phosphonyl Group

Article abstract of DOI:10.1021/jo962075k

(i-PrO)₂P(=O)COSEt (1) reacted with NH₂OH in pyridine at room temperature to give mainly (i-PrO)₂P(=O)NH₂ (4). The formation of 4 was interpreted in terms of a spontaneous Lossen rearrangement of (i-PrO)₂P(=O)CONHOH (2a) formed in the reaction. A transient ³¹P NMR signal appearing in the reaction mixture at δ-1.8 was assigned to 2a. Trapping of (i-PrO)₂P(=O)N=C=O (5), formed in the reaction of 1 and NH₂OH, by cyclohexylamine gave (i-PrO)₂P(=O)NHCONHC₆H₁₁ (6). Attempted isolation of 6 gave the hydrolyzed product N-cyclohexylurea (7). The reaction of 1 with NH₂OMe proceeded slower than that with NH₂OH and gave the expected (i-PrO)₂P(=O)-CONHOMe (2b), which was isolated and identified. 2b converts slowly to 4 in pyridine at room temperature. In contrast, MeNHOH reacted rapidly with 1 and gave the stable crystalline (i-PrO)₂P(=O)CON(Me)OH (2c). The structure of hydroxamates 2 were assigned on the basis of ¹H, ¹³C, and ³¹P NMR spectral data. This facile Lossen rearrangement is discussed in terms of the unusually high migratory aptitude of the phosphonyl group.

Full text of DOI:10.1021/jo962075k

3858
J . Org. Chem. 1997, 62, 3858-3861
Sp on ta n eou s Lossen Rea r r a n gem en t of
(P h osp h on ofor m yl)h yd r oxa m a tes. Th e Migr a tor y Ap titu d e of th e
P h osp h on yl Gr ou p
Claudio J . Salomon and Eli Breuer*
Department of Pharmaceutical Chemistry, The School of Pharmacy, The Hebrew University of J erusalem,
P.O. Box 12065, J erusalem, 91120 Israel
Received November 5, 1996X
(i-PrO)2P(dO)COSEt (1) reacted with NH2OH in pyridine at room temperature to give mainly (i-
PrO)2P(dO)NH2 (4). The formation of 4 was interpreted in terms of a spontaneous Lossen
rearrangement of (i-PrO)2P(dO)CONHOH (2a ) formed in the reaction. A transient 31P NMR signal
appearing in the reaction mixture at δ -1.8 was assigned to 2a . Trapping of (i-PrO)2P(dO)NdCdO
(5), formed in the reaction of 1 and NH2OH, by cyclohexylamine gave (i-PrO)2P(dO)NHCONHC6H11
(6). Attempted isolation of 6 gave the hydrolyzed product N-cyclohexylurea (7). The reaction of 1
with NH2OMe proceeded slower than that with NH2OH and gave the expected (i-PrO)2P(dO)-
CONHOMe (2b), which was isolated and identified. 2b converts slowly to 4 in pyridine at room
temperature. In contrast, MeNHOH reacted rapidly with 1 and gave the stable crystalline (i-
PrO)2P(dO)CON(Me)OH (2c). The structure of hydroxamates 2 were assigned on the basis of 1H,
13C, and 31P NMR spectral data. This facile Lossen rearrangement is discussed in terms of the
unusually high migratory aptitude of the phosphonyl group.
Hydroxamic acid derivatives have recently attracted
phosphono)thiolformate 1 has been chosen as starting
material, because this compound has been reported to
undergo C-S cleavage, in preference over C-P cleavage,
customary in acylphosphonates, and to react with am-
monia to yield cleanly the corresponding phosphonofor-
mamide.9
considerable interest because of their activity in inhibit-
ing medically important enzymes such as metallopro-
teases1 and lipoxygenase.2 On the other hand, phospho-
nates have also been shown to exhibit biological activity
in various areas by virtue of their analogy to naturally
occurring phosphates and carboxylic acids.3 However, to
date there are only a few reports in the literature on the
combination of the phosphonic and hydroxamic functions
in one molecule.4 Phosphonoacetohydroxamic acid has
recently been reported to act as a powerfully binding
inhibitor of enolase.5 Phosphonoformic acid is a clinically
used antiviral drug, and thus its derivatives are of
continuing concern. In the context of our ongoing interest
in exploring the chemical6 and biological7 properties of
phosphorus compounds having R-carbonyl groups,8 and
their derivatives, we have undertaken the synthesis and
study of (phosphonoformyl)hydroxamates. (Diisopropyl-
Resu lts a n d Discu ssion
To synthesize (phosphonoformyl)hydroxamates 2a -c,
1 was allowed to react with hydroxylamine and its
N-methyl and O-methyl derivatives in the presence of
pyridine or triethylamine. The reactions were monitored
by 31P NMR spectroscopy. The results from the reaction
of 1 with hydroxylamine are listed in Table 1. In this
table it can be seen that the reactions in the presence of
Et3N in MeCN led to (i-PrO)2PHdO (3) and to diisopropyl
phosphoramidate (4).10 In addition, the formation of a
transient product having a chemical shift of δP ) -1.3
was observed. This signal was assigned to diisopropoxy-
phosphinylformylhydroxamic acid (2a ) through compari-
son with those of O-methyl[(diisopropoxyphosphinyl)-
formyl]hydroxamate (2b ) and of N-methyl-[(diisopro-
poxyphosphinyl)formyl]hydroxamic acid (2c) obtained
from O-methyl- and N-methylhydroxylamine (vide infra).
In contrast, reactions carried out in pyridine gave only
diisopropyl phosphoramidate 4 (Scheme 1), with no P-C
bond cleavage product, 3. Compound 4 was isolated from
the reaction mixture in pyridine. It was identified by
* Telephone: 972-2-6758704. Fax: 972-2-6410740. E-mail: breuer@
cc.huji.ac.il.
X Abstract published in Advance ACS Abstracts, May 1, 1997.
(1) Schwartz, M. A.; Van Wart, H. E. Prog. Med. Chem. 1992, 29,
271-334. Morphy, J . R.; Beeley, N. R. A.; Boyce, B. A. Leonard, J .;
Mason, B.; Millican, A.; Millar, K.; O’Connel, J . P.; Porter, J . Bioorg.
Med. Chem. Lett. 1994, 4, 2747-52.
(2) Ohemeng, K. A.; Appolina, M. A.; Nguyen, V. N.; Schwender, C.
F.; Singer, M.; Steber, M.; Ansell, J .; Argentieri, D.; Hageman, W. J .
Med. Chem. 1994, 37, 3663-7.
(3) Engel, R. Chem. Rev. 1977, 77, 349-367. Blackburn, G. M. Chem.
Ind. 1981, 134-138. Hilderbrand, R. L., Ed. The Role of Phosphonates
in Living Systems; CRC Press: Boca Raton, 1983.
(4) Mukhacheva, O. A.; Shchelkunova, M. A.; Razumov, A. I. J . Gen.
Chem. U.S.S.R. 1985, 55, 688-691. Chen, R.; Breuer, E. Phosphorus,
Sulfur Silicon, 1996, 111, 797.
(5) Anderson, V. E.; Weiss, P. M.; Cleland, W. W. Biochemistry 1984,
23, 2779-86. Wedekind, J . E.; Poyner, R. R.; Reed, G. H.; Rayment, I.
Biochemistry 1994, 33, 9333-42.
(6) Breuer, E.; Karaman, R.; Goldblum, A.; Leader, H. J . Chem. Soc.,
Perkin Trans. 2 1988, 2029-34. Karaman, R.; Goldblum, A.; Breuer,
E.; Leader, H. J . Chem. Soc., Perkin Trans. 1 1989, 765-774.
(7) Golomb, G.; Schlossman, A.; Saadeh, H.; Levi, M.; Van Gelder,
J . M.; Breuer, E. Pharm. Res. 1992, 9, 143-8. Golomb, G.; Schlossman,
A.; Eitan, Y.; Saadeh, H.; Van Gelder, J . M.; Breuer, E. J . Pharm. Sci.
1992, 81, 1004-7. Breuer, E.; Karaman, R.; Zaher, H.; Katz, E. Drug
Des. Discovery 1994, 11, 39-46. Van Gelder, J . M.; Breuer, E.; Ornoy,
A.; Schlossman, A.; Patlas, N.; Golomb, G. Bone, 1995, 16, 511-20.
Skrtic, D.; Eidelman, N.; Golomb, G.; Breuer, E.; Eanes, E. D. Calcif.
Tissue, Int. 1996, 58, 347-54.
1
elemental analysis, H, 31P, and 13C NMR and IR spec-
troscopy, mass spectrometry, and comparison of its mp
to that in the literature.11
(8) Breuer, E. In The chemistry of organophosphorus compounds;
Hartley, F. R., Ed.; J ohn Wiley & Sons, Ltd.: New York, 1996; Vol. 4,
pp 653-729.
(9) Grisley, D. W., J r. J . Org. Chem. 1961, 26, 2544-5.
(10) The formation of compound 4 is rationalized by base-catalyzed
alcoholysis of the C-P bond which is a well-known and characteristic
reaction of R-keto phosphonate diesters8 and of analogs such as phos-
phonoformates: Mitchell, A. G.; Nicholls, D.; Walker, I.; Irwin, W. J .;
Freeman, S. J . Chem. Soc., Perkin Trans. 2 1991, 1297.
(11) Atherton, F. R.; Openshaw, H. T.; Todd, A. R. J . Chem. Soc.
1945, 660-3.
S0022-3263(96)02075-0 CCC: $14.00 © 1997 American Chemical Society

Spontaneous Lossen Rearrangement
J . Org. Chem., Vol. 62, No. 12, 1997 3859
Ta ble 1. (i-P r O)2P (O)COSEt + NH2OH‚HCl a t 25 °C
exp
base/solvent
equiv
time, h
1a (δP ) -5.3, %)
2a a (δP ) -1.8, %)
3a (δP ) 4.2, %)
4a (δP ) 9.7, %)
1
2
3
4
5
6
7
8
9
Et3N/MeCN
Et3N/MeCN
Et3N/MeCN
Pyr/MeCN
Pyridine
Pyridine
Pyridine
1
1
2
1
2
72
2
5
3
16
22
48
72
15
14
0
82
37
15
15
14
11
39
7
12
3
63
63
51
19
9
26
30
54
0
0
0
0
0
0
18
48
32
0
xsb
xs
xs
xs
xs
0
18
31
63
74
Pyridine
Pyridine
a
The percentage figures presented are raw data obtained from the integrated 31P NMR spectra and thus, possibly, are not a precise
b
representation of the actual molar ratios of the components. xs ) excess.
Sch em e 1
Sch em e 4
Sch em e 2
Sch em e 3
and -3.86 (23%). Similar phenomena can be seen in the
1H and 13C spectra of 2c (Scheme 4). Because of hindered
rotation around the amide C-N bond, hydroxamates, as
amides, may exist as two rotational geometrical isomers.
Tashma has shown by NMR spectroscopy12 that thio-
carbamoylphosphonates possessing one proton on the
nitrogen have a Z configuration.13 Masson and co-
workers prepared N,N-disubstituted thiocarbamoylphos-
phonates, and have shown that these exist as mixtures
rotamers in solution.14 They assigned the higher field
1H and 13C NMR signals for the N-substituent CH3 or
CH2 groups anti to the phosphoryl group. On this basis,
we can assign the structure of the major component of
the N-methyl derivative 2c as being the Z isomer. Both
rotational conformers may be stabilized by intramolecu-
lar hydrogen bonds as shown in Scheme 4. Additional
supporting evidence for this assignment can be derived
Further examination of Table 1 reveals the following
features:
1. Comparison of entries 1 and 3 shows the effect of
the quantity of base on the reaction. In the presence of
excess base the reaction is nearly complete in 2 h.
2. Comparison of entries 1 and 4 reveals the impor-
tance of the base strength for the reaction. Although the
stronger base triethylamine causes a more rapid con-
sumption of the starting material, it also leads to byprod-
uct 3 resulting from the C-P bond cleavage of the
starting material, 1.10
3. From examining the reactions in excess pyridine
(entries 5-9), it is clear that there is slow conversion of
the transient product 2a to the final product of the
reaction, 4.
3
from the J PC coupling constant of the N-methyl group.
1
There are two unequal signals for this carbon in the H-
decoupled 13C spectrum. The major signal (82%) at δ
36.24 (3J PC ) 8.8 Hz) is assigned to the anti N-methyl
group in (Z)-2c, while the minor signal (18%) at δ 37.90
(3J PC ) 2.5 Hz) is assigned to the syn N-methyl group in
(E)-2c.15 Finally, on the basis of similarity of the 31P
NMR signals of 2a and 2b to the signals assigned to the
syn and anti rotamers of 2c, respectively, it is reasonable
to speculate that 2a has the syn structure, probably
stabilized by a six-membered intramolecular hydrogen
The reaction of O-methylhydroxylamine with 1 was
also studied under comparable conditions. This reaction
proceeded considerably slower, and in the presence of 2
equiv of Et3N in MeCN after 48 h, 31P NMR spectroscopy
still showed the presence of 60% unreacted starting
material 1, and only 3 (10%) and 4 (30%). The same
reaction carried out in pyridine without additional base
also for 48 h, gave O-methylhydroxamic derivative 2b
(48%) along with only 8% of 4 and 44% unreacted starting
material 1 (Scheme 2). O-Methyl[(diisopropoxyphosphi-
nyl)formyl]hydroxamate, 2b, was isolated by chromatog-
(12) Tashma, Z. J . Org. Chem. 1982, 47, 3012-5. Tashma, Z. Magn.
Reson. Chem. 1985, 23, 289-91.
1
raphy and identified by means of IR, H, 13C, and 31P
(13) In the N-alkylthiocarbamoylphosphonates studied by Tashma
and Masson (ref 13), syn or Z mean that the phosphorus and the NH
which are the groups of lower priority (P is lower than S and H is
lower than C) are situated on the same side of the amide C-N bond.
In oxygen-containing carbamoylphosphonates the same configuration
will be called E, since the replacement of S by O changes the order of
priorities (P is higher than O). In N-methyl(phosphonoformyl)hydrox-
amic acid, 2c, the order of priorities changes again due to the
replacement of the N-H by N-OH (O is higher than C) and in the
Z-isomer the P and the N-methyl groups are anti across the C-N bond
(Scheme 4). Consequently, for clarity in the present discussion, we will
refer to the situation of N-methyl or N-alkyl groups as syn or anti
relative to the phosphorus regardless of whether these are of CdO or
CdS, or N-H or N-OH amides.
NMR spectroscopy and mass spectrometry.
In contrast, the reaction of N-methylhydroxylamine
with 1 was faster and gave in 14 h in pyridine only the
expected hydroxamate, 2c (93%, Scheme 3). In MeCN
and 2 equiv of Et3N the reaction was over in 2 h with
the formation of 2c (52%) and H-phosphonate 3 (30%).
NMR Sp ectr a a n d Str u ctu r e of (P h osp h on ofor m -
yl)h yd r oxa m a tes. While hydroxamates 2a and 2b
showed one signal each (at δ -1.8 and -4.72, respective-
ly) in the 31P spectrum, the N-methylhydroxamate, 2c,
shows two signals of unequal intensity at δ -0.95 (77%)
(14) Bulpin, A.; Le Roy-Gourvennec, S.; Masson, S. Phosphorus,
Sulfur, Silicon 1994, 89, 119-32.

3860 J . Org. Chem., Vol. 62, No. 12, 1997
Salomon and Breuer
Sch em e 5
Sch em e 8
urea 6 has undergone hydrolysis in the workup by the
acid, the use of which was necessitated by the presence
of the large amounts of amines present. To rule out the
alternative structure (i-PrO)2P(O)CONHC6H11 (8), which
also could have formed in the reaction, we have synthe-
sized this compound by reacting cyclohexylamine with
compound 1. Compound 8 had a chemical shift at δ
-2.48.
Sch em e 6
All the hitherto reported Lossen rearrangements re-
quire heating and conversion of the N-OH group either
to O-acylhydroxamates,17 O-arylhydroxamates,18 chloride
or chlorosulfinate,17 sulfate,19 or in situ activation using
polyphosphoric acid,20 carbodiimide,21 Mitsunobu22 meth-
odology, or silylation.23 There is no report of a free
hydroxamic acid rearranging at room temperature. As
phosphonothiolformate was reported as a reactive acy-
lating agent,9 we needed to consider the possibility of its
reaction with hydroxamate 1 to form the doubly phospho-
noformylated hydroxylamine 9 (Scheme 8). However,
this assumption is not consistent with the observed 31P
NMR spectra obtained during the progress of the reac-
tion. An intermediate of type 9 should be accompanied
by the appearance of two transient signals in the 31P
NMR spectrum. In fact, as we pointed out above, there
was only one transient signal observed in the reaction
mixture. Another factor relevant in this respect is the
stoichiometry of the reaction. If the reaction displayed
in Scheme 8 would be involved in the formation of 4, 2
mol of 1 would be required for the formation of each mole
of 4, and thus the maximum yield of 4 based on 1 could
not exceed 50% (compare Table 1, experiment 9).
The first step of the Lossen rearrangement is being
visualized as the base-catalyzed removal of the NH
proton. The presence of a free OH group does not
obstruct this step as there is general agreement with
regard to the NH proton being the most acidic in
hydroxamic acids.24 Thus, the most unusual feature of
the present reaction is the spontaneous departure of the
OH at room temperature. This resembles the Beckmann
rearrangements we reported recently,25,26 in which the
departure of the OH group took place without the
customary acid catalysis. In the present case as well as
in the Beckmann rearrangements, OMe derivatives
reacted much more sluggishly. Since the pKa’s of water
and methanol are not very different (water, pKa ) 15.74,
Sch em e 7
bond, -N-OH‚‚‚OdP-, while 2b in which such intramo-
lecular H-bond is not possible has the anti structure
having a five-membered intramolecular H-bond: -N-
H‚‚‚OdP- (Scheme 5).
Lossen Rea r r a n gem en t. The assignment of the
transient signal at δP ) -1.8 appearing in the reaction
of 1 with NH2OH leading to phosphoramidate 4 as
belonging to compound 2a led us speculate that we are
facing an unusually facile Lossen rearrangement, which
gives the final product 4 via isocyanate 5 (Scheme 6).
In an attempt to trap the isocyanate 5 postulated in
Scheme 6, 1 was allowed to react with NH2OH in pyri-
dine, in the presence of cyclohexylamine. Monitoring this
reaction by 31P NMR revealed the formation of a new
product 6, which had a chemical shift at δ 8.44. In the
process of isolation of this product N-cyclohexylurea, 7
(Scheme 7), and diisopropyl hydrogen phosphate were ob-
tained. Compound 7 was identified by comparison with
an authentic sample of N-cyclohexylurea prepared by
reacting cyclohexylamine with potassium isocyanate.16
Consequently, we assign to compound 6 the structure N-
(diisopropoxyphosphinyl)urea. Apparently, phosphoryl-
(17) Yale, H. L. Chem. Rev. 1943, 33, 209-56. Bauer, L.; Exner, O.
Angew. Chem., Int. Ed. Engl. 1974, 13, 376-84.
(18) Sheradsky, T.; Avramovici-Grisaru, S. Tetrahedron Lett. 1978,
2325-6.
(19) Wallace, R. G.; Barker, J . M.; Wood, M. L. Synthesis 1990,
1143-4.
(15) A Karplus-type relationship has been established for vicinal
coupling 3J (CCCP) in phosphonates: Thiem, J .; Meyer, B. Org. Magn.
Reson. 1978, 11, 50-1. Adiwidjaja, G.; Meyer, B.; Thiem, J . Z.
Naturforsch. 1979, 34b, 1547-51, as well as in EZ pairs of phosphorus-
substituted alkenes: Duncan, M.; Gallagher, M. J . Org. Magn. Reson.
1981, 15, 37-42. O¨ hler, E.; Zbiral, E. Monatsh. Chem. 1984, 115, 493-
508. Although the magnitudes of the coupling constants reported in
these papers in the rigid geometrical isomers are larger (3J PC values
of 17-25 Hz for E and 4-11 Hz for Z isomers) than those we found
for (E)- and (Z)-2c, still the trend is consistent. Examination of the
(20) Bachman, G. B.; Goldmacher, J . E. J . Org. Chem. 1964, 29,
2576-9.
(21) Hoare, D. G.; Olson, A.; Koshland, D. E., J r. J . Am. Chem. Soc.
1968, 90, 1638-43.
(22) Bittner, S.; Grinberg, S.; Karton, I. Tetrahedron Lett. 1974,
1965-8.
(23) King, F. D.; Pike, S.; Walton, D. R. M. Chem. Commun. 1978,
351-2.
(24) Bagno, A.; Comuzzi, C.; Scorrano, G. J . Am. Chem. Soc. 1994,
116, 916-24.
3
spectral data presented by Masson (ref 13), however, reveals J PC
values similar to those found by us. This paper reports J PC values of
8.1-8.7 Hz for N-alkyl carbons anti relative to phosphorus across a
(25) Breuer, E.; Schlossman, A.; Safadi, M.; Gibson, D.; Chorev, M.;
Leader, H. J . Chem. Soc., Perkin Trans. 1 1990, 3263-9.
(26) Breuer, E.; Zaher, H.; Tashma, Z. Tetrahedron Lett. 1992, 33,
2067-8. Breuer, E.; Zaher, H.; Tashma, Z.; Gibson, D. Heteroatom
Chem., in press.
3
thioamide C-N bond.
(16) Wallach, O. Liebigs Ann. 1905, 343, 40-53.

Spontaneous Lossen Rearrangement
J . Org. Chem., Vol. 62, No. 12, 1997 3861
room temperature for 14 h under nitrogen. Monitoring of the
reaction showed almost complete conversion. The reaction
mixture was concentrated in vacuo, and the residue was taken
up in AcOEt, filtered, and chromatographed through a silica
gel column, and developed by AcOEt/petroleum ether, 2:1:
yield 1.65 g (69%); mp 55-57 °C; νmax/cm-1 (KBr) 3148, 2990-
2931, 1649, 1390, 1238, 991; MS m/z 239.1 (M+), calcd for
MeOH, pKa ) 15.5-15.7, and MeOH is also a better
proton acceptor: pKa of MeOH2+ = -1.45, H3O+ = -1.74),
the better leaving group behavior of the OH is probably
a reflection of its easier stabilization by solvation. The
facile Lossen rearrangement of 2a reported in this paper
is viewed as an additional manifestation of the pro-
nounced tendency of phosphoryl groups to participate in
1,2-shifts to electron deficient centers. Among the pre-
cedents that attest to this tendency are the facile migra-
tion of PO3H2 and P(O)Ph2 groups in the Wagner-
Meerwein rearrangement, in preference over phenyl
migration. Examples of facile migrations to electron
deficient heteroatoms include the Baeyer-Villiger oxida-
tion of acylphosphonates29 or the Beckmann rearrange-
ment of R-hydroxyimino phosphinates24 and phospho-
nates,24 as well as of R-hydroxyimino phosphonamidates.25
It seems that in spite of their electron-withdrawing effect
(σ* value of 2.65 was determined for the P(O)(OMe)2
group30), phosphoryl groups possess the capability to
stabilize, possibly by hyperconjugation or by bridging,31
an electron deficient center located on a â carbon or
heteroatom and to migrate there.
1
C8H11NO3P 239.09; H NMR (CDCl3) δ 1.52 (12 H, d, J ) 6
Hz), 3.40 (0.66 × 3 H, s), 3.84 (0.33 × 3 H, s), 4.91 (2H, m);
13C NMR (CDCl3) δ 24.25 (d, J ) 5.6 Hz), 24.33 (d, J ) 4.90
Hz), 24.52 (d, J ) 4.1 Hz), 24.72 (d, J ) 3.4 Hz), 36.24 (d, J )
8.8 Hz), 37.90 (d, J ) 2.5 Hz), 74.30 (d, J ) 6 Hz), 74.56 (d, J
) 8 Hz), 163 (d, J ) 226 Hz); 31P NMR (CDCl3) δ -0.95 (77%),
-3.86 (23%). Anal. Calcd for C8H11NO3P: C, 40.17; H, 7.58;
N, 5.86. Found: C, 40.43; H, 7.58; N, 5.79.
27
28
Diisop r op yl P h osp h or a m id a te (4). Diisopropyl phos-
phoramidate was obtained from the reaction of 1 with hy-
droxylamine hydrochloride under the conditions specified in
experiment 9, Table 1. The reaction mixture was concentrated
in vacuo, and the residue was taken up in AcOEt, filtered and
chromatographed through a silica gel column, and developed
by AcOEt: yield 0.977 g (54%); mp 53-54 °C (lit.10 mp 56-57
°C); IR (KBr) νmax/cm-1 3362, 2975, 1573, 1385, 1224, 983; MS
m/z found 181.8, calcd 181.17; 1H NMR (CDCl3) δ 1.31 (12 H,
d, J ) 6 Hz), 2.79 (2 H, s), 4.64 (2 H, m); 13C NMR (CDCl3) δ
24.43 (d, J ) 4.8 Hz), 71.52 (d, J ) 5.4 Hz); 31P NMR (CDCl3)
δ 8.30. Anal. Calcd for C6H16NO3P: C, 39.77; H, 8.83; N, 7.73.
Found: C, 39.82.43; H, 8.58; N, 7.68.
Rea ction of 1 w ith Hyd r oxyla m in e in th e P r esen ce of
Cycloh exyla m in e. To a solution of hydroxylamine hydro-
chloride (0.695 g, 0.01 mol) in pyridine (10 mL) at 25 °C was
added dropwise 1 (2.54 g, 0.01 mol) under nitrogen. After 0.5
h, cyclohexylamine (4.96 g, 0.05 mol) was added dropwise. The
reaction progress was monitored by 31P NMR, and after 3 h
signals were observed at δ 10.40 (4, 1%), 8.46 (6, 55%), 4.30
(3, 30%), -0.49 (2a , 11%). The reaction mixture was concen-
trated in vacuo, and the residue was taken up in AcOEt and
extracted with 1 N HCl and H2O. 31P NMR examination of
the aqueous phase showed a new signal at δ -4.09 ppm
(diisopropyl hydrogen phosphate). This fraction was evapo-
rated in vacuo, the residue was digested with water four times,
and the crude residue was recrystallized from methanol to give
7 (0.625 g, 44%): mp 191-2 °C, mixed mp with authentic
sample prepared in the next experiment 191 °C; MS m/z found
142, calcd for C7H14N2O 142.2; 1H NMR (D2O) δ 1.18-1.26 (5
H, m), 1.50-1.55 (1 H, m), 1.68 (2 H, m), 1.86 (2 H, m), 3.02
(1H, m).
Further experiments will be needed to explore the
synthetic potential that may emerge from the in situ
generation of dialkoxyphosphinyl isocyanates. Although
phosphinyl isocyanates are not difficult to prepare,32 they
are sensitive to moisture. Therefore, an appropriate
adaptation of the present method may find uses in the
future in special cases.
Exp er im en ta l Section 33
Rea ction s of (Diisop r op ylp h osp h on o)th iolfor m a te 1
w ith Hyd r oxyla m in e. To a solutions of NH2OH‚HCl (0.695
g, 0.01 mol) in pyridine or Et3N/MeCN (10 mL) was added 1
(2.54 g, 0.01 mol). The reactions were allowed to stand in an
N2 atmosphere at ambient temperature and monitored by 31P
NMR spectroscopy. The results are listed in Table 1.
[(Diisop r op oxyp h osp h in yl)for m yl]-O-m et h ylh yd r ox-
a m a te (2b). To a solution of O-methylhydroxylamine hydro-
chloride (0.835 g, 0.01 mol) in pyridine (10 mL) at 25 °C was
added dropwise 1 (2.54 g, 0.01 mol) under nitrogen. The
reaction was monitored by 31P NMR. After 72 h, the reaction
mixture was concentrated in vacuo, the residue was taken up
in AcOEt, filtered, and chromatographed through a silica gel
column, developed by AcOEt/petroleum ether, 2:1, to give 0.908
Cycloh exylu r ea (7). To a solution of cyclohexylamine
(0.854 g, 8.63 mmol) and potassium isocyanate (0.70 g, 8.63
mmol) in water (10 mL) was added acetic acid (0.517 g, 8.63
mmol) at 0 °C. After 5 h, the solvent was evaporated in vacuo,
the crude residue was digested five times with water and
decanted, and the residue was recrystallized from methanol
g (38%) of O-methyl hydroxamate 2b as colorless oil: νmax
/
cm-1 (NaCl) 3120, 2950-2900, 1660, 1380, 1260-1210, 980;
MS m/z found 239.28, (M+) calcd for C8H11NO3P 239.09; 1H
NMR (CDCl3) δ 1.32 (12 H, m), 3.76 (3 H, s), 4.73 (2 H, m),
11.05 (1 H, b); 13C NMR (CDCl3) δ 23.93 (d, J ) 4.5 Hz), 24.08
(d, J ) 4.1 Hz), 64.30 (s), 74.34 (d, J ) 6.5 Hz), 162.45 (d, J )
219 Hz); 31P NMR (CDCl3) δ -4.72 ppm.
1
to yield 1.02 g (83%): mp 192-3 °C (lit.15 mp 195-6 °C); H
NMR spectrum identical with the product obtained in the
previous experiment.
N-Cycloh exyl(d iisop r op oxyp h osp h in yl)for m a m id e (8).
To a mixture of cyclohexylamine (0.81 g, 0.0082 mol) and Et3N
(1.66 g, 0.016 mol) in MeCN (10 mL) was added 1 (2.1 g, 0.0082
mol) under nitrogen. The reaction progress was monitored by
31P NMR. After 8 h the reaction mixture was concentrated in
vacuo, and the residue was taken up in AcOEt, filtered, and
washed successively with 1 N HCl, H2O, 10% NaHCO3, and
brine. The organic phase was dried over MgSO4, filtered, and
concentrated in vacuo to give a white solid: yield 1.85 g (78%);
mp 78-80 °C; 1H NMR (CDCl3) δ 1.17-1.30 (4 H, m), 1.35 (16
H, t), 1.74 (1 H, m), 1.90 (1 H, m), 3.85 (1H, m), 4.76 (2 H, m),
6.92 (1 H, m); 31P NMR (CDCl3) δ -2.48. Anal. Calcd for
C13H26NO4P: C, 53.58; H, 9.00; N, 4.81. Found: C, 53.41; H,
9.00; N, 4.98.
[(Diisop r op oxyp h osp h in yl)for m yl]-N-m et h ylh yd r ox-
a m a te (2c). To solution of N-methylhydroxylamine hydro-
chloride (0.835 g, 0.01 mol) in pyridine (10 mL) was added 1
(2.54 g, 0.01 mol), and the mixture was allowed to react at
(27) Richtarski, G.; Mastalerz, P. Tetrahedron Lett. 1973, 4069-
70. Richtarski, G.; Soroka, M.; Mastalerz, P.; Starzemska, H. Rocz.
Chem. Ann. Soc. Chim. Pol. 1975, 49, 2001-5; Chem. Abstr. 1976, 85,
5576x.
(28) Cann, P. F.; Warren, S. Chem. Commun. 1970, 1026-7. Cann,
P. F.; Howells, D.; Warren, S. J . Chem. Soc., Perkin Trans. 2 1972,
304-11.
(29) Sprecher, M.; Nativ, E. Tetrahedron Lett. 1968, 4405-8.
Gordon, N. J .; Evans, S. A., J r. J . Org. Chem. 1993, 58, 4516-9.
(30) Katzhendler, J .; Ringel, I.; Karaman, R.; Zaher, H.; Breuer, E.
J . Chem. Soc., Perkin Trans. 2 in press.
(31) Lambert, J . B.; Emblidge, R. W.; Zhao, Y. J . Org. Chem. 1994,
59, 5397-403. Lambert, J . B.; Zhao, Y. J . Am. Chem. Soc. 1996, 118,
3156-67.
Ack n ow led gm en t. C.J .S. thanks to Consejo Nacio-
nal de Investigaciones Cientificas y Tecnicas (CONICET),
Argentina, for a Post-Doctoral Fellowship. E.B. is
affiliated with the David R. Bloom Center for Pharmacy.
(32) Zwierzak, A.; Pilichowska, S. Synthesis 1982, 922-4 and
references cited therein.
(33) Instruments and general techniques are described in refs 25
and 29.
J O962075K