An expeditious route to novel 1,4,2-benzodiazaphosphepin-5-one 2-oxide analogues

Article abstract of DOI:10.1021/jo9908400

A short and efficient synthesis of the novel 1,4,2-benzodiazaphosphepin- 5-one 2-oxide ring system, a phosphonamidate isostere of the 1,4- benzodiazepine-2,5-dione system, has been carried out in good overall yield. The key step is the base-induced cycliz

Full text of DOI:10.1021/jo9908400

8156
J . Org. Chem. 1999, 64, 8156-8160
An Exp ed itiou s Rou te to Novel 1,4,2-Ben zod ia za p h osp h ep in -5-on e
2-Oxid e An a logu es
Gary M. Karp
Agricultural Products Research Division, American Cyanamid Company,
Princeton, New J ersey 08543-0400
Received May 24, 1999
A short and efficient synthesis of the novel 1,4,2-benzodiazaphosphepin-5-one 2-oxide ring system,
a phosphonamidate isostere of the 1,4-benzodiazepine-2,5-dione system, has been carried out in
good overall yield. The key step is the base-induced cyclization of (2-aminobenzamido)methylphos-
phonates 6a -c to the 1,4,2-benzodiazaphosphepin-5-one 2-oxides 7a -c. Alkylation of 7b with methyl
iodide gives the expected N-methyl analogue 9. When a tandem one-pot cyclization/alkylation is
carried out from 6b in the presence of excess base, the sole isolable product obtained is the
phosphonate 13, presumably via ethanolysis of a transiently formed 9. Carrying out the tandem
cyclization/alkylation in the absence of excess base, however, affords only 9. Thionation of 7 with
Lawesson’s reagent occurs at either the phosphonamidate oxygen (P-2) or the amide carbonyl
(C-5) depending on the steric constraint of the N-4 substituent.
During the course of an investigation of the herbicidal
diones11 by utilization of the appropriate aminometh-
ylphosphonate.12 The C-5 amide linkage would be estab-
lished initially upon reaction of an o-nitrobenzoyl chloride
with the aminomethylphosphonate followed by formation
of the P-2 phosphonamidate center (after nitro reduction
and subsequent cyclization). To investigate this approach
to 2 (R ) tert-butyl), 5-chloro-2-nitrobenzoyl chloride 311
properties of 1,4-benzodiazepine-2,5-diones,1 including
homologues1a and isosteres,2 a further understanding of
the steric and electronic factors necessary for activity
fueled our interest to examine additional related systems.
We were intrigued by the idea of incorporating a phos-
phorus atom into the benzodiazepine skeleton. Organo-
phosphorus compounds are ubiquitous in living systems,
comprising a central role in the structure of nucleic acids
and cell membranes.3 The incorporation of phosphorus
into organic molecules has found utility as enzyme
transition-state inhibitors,4 antibiotics,5 and agrochemi-
cals.6 In light of our continued interest in the preparation
of isosteres of benzodiazepinediones 1, we were interested
in the preparation of the 1,4,2-benzodiazaphosphepin-5-
one 2-oxide system 2, where the trigonal C-2 amide
carbonyl of 1 is replaced by a tetracoordinate pentavalent
phosphorus atom in 2. Phosphonamidates have been
utilized as isosteres for the tetrahedral transition state
of protease inhibitors.7 Despite the existence of numerous
examples of cyclic phosphonamidates,8-10 the target 1,4,2-
benzodiazaphosphepin-5-one 2-oxide system 2 appears to
be unknown.
(4) (a) Malachowski, W. P.; Coward, J . K. J . Org. Chem. 1994, 59,
7616. (b) Dugas, H. Bioorganic Chemistry. A Chemical Approach to
Enzyme Action, 2nd ed.; Springer-Verlag: New York, 1989; pp 80-
85. (c) Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J . M. J .
Med. Chem. 1989, 32, 1652. (d) Giannousis, P. P.; Bartlett, P. A. J .
Med. Chem. 1987, 30, 1603. (e) Bartlett, P. A.; Marlowe, C. K. Science
1987, 235, 569.
(5) Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J . Med. Chem.
1986, 29, 29.
(6) Fest, C.; Schmidt, K.-J . The Chemistry of Organophosphorus
Pesticides, 2nd ed.; Springer-Verlag: Berlin, 1982; pp 80-182.
(7) See, for example: (a) Radkiewicz, J . L.; McAllister, M. A.;
Goldstein, E.; Houk, K. N. J . Org. Chem. 1998, 63, 1419. (b) Musiol,
H.-J .; Grams, F.; Rudolph-Bohner, S.; Moroder, L. J . Org. Chem. 1994,
59, 6144. (c) Morgan, B. P.; Holland, D. R.; Matthews, B. W.; Bart-
lett, P. A. J . Am. Chem. Soc. 1994, 116, 3251. (d) Camp, N. P.;
Hawkins, P. C. D.; Hitchcock, P. B.; Gani, D. Bioorg. Med. Chem. Lett.
1992, 2, 1047. (e) McLeod, D. A.; Brinkworth, R. I.; Ashley, J . A.; J anda,
K. D.; Wirsching, P. Bioorg. Med. Chem. Lett. 1991, 1, 653. (f) J anda,
K. D.; Schloeder, D.; Benkovic, S. J .; Lerner, R. A. Science 1988,
241, 1188.
(8) For the preparation of 1,2-azaphosphetidine 2-oxides, see: (a)
Laws, A. P.; Stone, J . R.; Page, M. I. J . Chem. Soc., Chem. Commun.
1994, 1223. (b) Afarinkia, K.; Cadogan, J . I. G.; Rees, C. W. J . Chem.
Soc., Chem. Commun. 1992, 285. (c) Gubnitskaya, E. S.; Parkhomenko,
V. S.; Semashko, Z. T.; Samaray, L. I. Phosphorous Sulfur 1983, 15,
257.
(9) For the preparation of some 1,2-azaphospholidine 2-oxides, see:
(a) Angelov, C. M.; Enchev, D. D. Heteroatom Chem. 1992, 3, 651. (b)
Collins, D. J .; Hetherington, J . W.; Swan, J . M. Aust. J . Chem. 1974,
27, 1759. (c) Collins, D. J .; Drygala, P. F.; Swan, J . M. Aust. J . Chem.
1983, 36, 2517.
(10) For the preparation of some 1,2-azaphosphinane 2-oxides, see:
(a) Natchev, I. A. Bull. Chem. Soc. J pn. 1988, 61, 4447. (b) Natchev,
I. A. Bull. Chem. Soc. J pn. 1988, 61, 3711. (c) Hewitt, D. G.; Teese, M.
W. Aust. J . Chem. 1984, 37, 1631.
It was envisioned that 2 could be constructed in a
manner analogous to that of the benzodiazepine-2,5-
(1) (a) Karp, G. M.; Manfredi, M. C.; Guaciaro, M. A.; Harrington,
P. M.; Marc, P.; Ortlip, C. L.; Quakenbush, L. S.; Birk, I. T. In Synthesis
and Chemistry of Agrochemicals V; Baker, D. R., Fenyes, J . G.,
Basarab, G. S., Hunt, D. A., Eds.; ACS Symposium Series 686;
American Chemical Society: Washington, D.C., 1998; pp 95-106. (b)
Karp, G. M.; Manfredi, M. C.; Guaciaro, M. A.; Ortlip, C. L.; Marc, P.;
Szamosi, I. T. J . Agric. Food Chem. 1997, 45, 493.
(11) Karp, G. M. J . Org. Chem. 1995, 60, 5814 and referenced cited
therein.
(12) For recent approaches to aminoalkylphosphonates, see: (a)
Couture, A.; Deniau, E.; Woisel, P.; Grandclaudon, P. Tetrahedron Lett.
1995, 36, 2483. (b) Lewis, R. T.; Motherwell, W. B. Tetrahedron, 1992,
48, 1465. (c) Courtois, G.; Miginiac, L. Synth. Commun. 1991, 21, 201.
(d) Ha, H.-J .; Nam, G.-S.; Park, K. P. Bull. Korean Chem. Soc. 1990,
11, 485.
(2) Karp, G. M. J . Heterocycl. Chem. 1996, 33, 1131.
(3) Eibl, H. Angew. Chem., Int. Ed. Engl. 1984, 23, 257.
10.1021/jo9908400 CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/06/1999

1,4,2-Benzodiazaphosphepin-5-one 2-Oxide Analogues
J . Org. Chem., Vol. 64, No. 22, 1999 8157
Sch em e 1
To further illustrate the current approach to the
benzodiazaphosphepin-5-one 2-oxide system, the 4-meth-
yl (7b) and 4-benzyl (7c) analogues were prepared. Entry
into the 4-methyl series was carried out by initial
formation of N-benzyl-N-methylaminophosphonate via a
Mannich-type reaction. Catalytic reduction afforded phos-
phonate 4b. Reaction of o-nitrobenzoyl chloride 3 with
4b gave the nitro phosphonate 5b in 84% yield observed
as a 4:1 mixture of amide rotational isomers at room
temperature by 1H and 31P NMR in CDCl3. Catalytic
reduction of 5b gave 6b in 98% yield unencumbered by
any mixture of rotamers. Treatment of 6b with NaH,
followed by warming to 60 °C, gave the desired product
7b, as expected, in 68% yield after chromatography. The
31P NMR exhibited the expected downfield shift (+22.5
to +32.7 ppm) on conversion of 6b to 7b. The 4-benzyl
series was obtained similarly by reaction of 3 with
phosphonate 4c12b to give 5c in 58% yield. The presence
of amide rotamers (3:1 in CDCl3) was again evidenced
by 1H and 31P NMR. Nitro reduction gave 6c in 92% yield
and, like 6b, free of observable rotamers at room tem-
perature. Upon treatment of 6c with NaH and subse-
quent warming, 7c was obtained in 57% yield with the
31P NMR showing the expected downfield shift (+23.4 to
+32.8).
The 4-methyl series (7b) was then chosen for study to
further evaluate alkylation and thionation reactions.
Stirring a solution of 7b with NaH followed by treatment
with MeI gave the expected N-methyl analogue 9 as the
sole product in 52% yield. The presence of the phospho-
namidate linkage in 7a -c renders these analogues
considerably more polar than the corresponding phos-
phonate precursors 6a -c. Of the three, 7b exhibits the
greatest degree of polarity toward silica gel. To avoid
having to isolate 7b, the direct conversion of phosphonate
6b to 9 was examined. Stirring a DMF solution of 6b with
NaH (150 mol %) followed by warming to 60 °C (standard
conditions) gave complete conversion to 7b within 3 h as
evinced by HPLC analysis. Treatment of the reaction
mixture at room temperature with an additional 150 mol
% of NaH (presumably to ensure complete phosphona-
midate deprotonation, vide infra) followed by MeI af-
forded not the expected 9 but the N-methylated phos-
phonate 13. No intermediate was observed by HPLC
while following the conversion of 7b to 13. While initially
surprising, this result could be rationalized by ethoxide-
induced ring opening of a transiently formed 9 (Scheme
2). The first addition of NaH gives 7b, as the sodium salt
of the phosphonamidate anion along with one molecule
of ethanol16 generated from attack on the phosphonate
diester. Following the second addition of NaH and MeI,
N-methylated 9 must be formed and then rapidly con-
verted to 13 via ethanolysis. In contrast, upon conversion
was reacted with tert-butylaminophosphonate 4a 12c to
afford nitroamide 5a in 68% yield (Scheme 1). Catalytic
hydrogenation of 5a gave the cyclization precursor 6a in
71% yield. Phosphonate 6a demonstrated no propensity
to cyclize at room temperature,13 unlike the analogous
aminohippurate intermediates that cyclize readily to the
benzodiazepinediones on standing.11 Attempted ring
closure of 6a by heating in aqueous acid or base was
unsuccessful, leading primarily to decomposition. Ulti-
mately, cyclization to 7a could be carried out smoothly
by treating a DMF solution of 6a with NaH followed by
warming to 60 °C for a few hours, thereby affording 7a
in 71% yield. The identity of 7a was established un-
equivocally by the loss of one ethoxy group and the
downfield shift of the exchangeable nitrogen protons in
1
the H NMR (two protons at 4.27 ppm to one proton at
7.37 ppm in CDCl3). In addition, the C-3 methylene signal
1
was further complicated by the effects of H-31P cou-
pling14 in the now conformationally restrained system.
Also diagnostic was the downfield shift of the phosphorus
atom in the 31P NMR from +23.3 to +34.7 ppm upon
conversion of the phosphorus atom from a phosphonate
to a phosphonamidate linkage.
Thionation of 7a was then examined. Treatment of 7a
with Lawesson’s reagent15 in toluene at reflux gave a
single product (8) in 93% yield. The site of thionation
could be readily ascertained upon examination of the
13C and 31P NMR. The extreme downfield shift of the
phosphorus atom in the 31P NMR from +34.5 to
+84.4 ppm and the absence of a significant shift in the
13C NMR of the C-5 amide (∆δ ) 0.3 ppm) indicated
that thionation took place exclusively on the phosphorus
atom.
(13) Compound 6a and related analogues can be stored neat
indefinitely at room temperature without change.
(14) Friebolin, H. Basic One- and Two-Dimensional NMR Spectros-
copy; VCH Publishers: New York, 1991; Chapter 4.
(15) (a) Horner, L.; Lindel, H. Phosphorous Sulfur 1982, 12, 259.
(b) Scheibye, S.; Pedersen, B. S.; Lawesson, S.-O. Bull. Soc. Chim. Belg.
1978, 87, 229.
(16) No effort has been made to determine the equilibrium position
between the sodium salt of the phosphonamidate + EtOH T phos-
phonamidate + NaOEt.

8158 J . Org. Chem., Vol. 64, No. 22, 1999
Karp
Sch em e 2
In summary, a novel class of 1,4,2-benzodiazaphos-
phepin-5-one 2-oxides has been prepared as phosphon-
amidate isosteres of 1,4-benzodiazepine-2,5-diones as
potential herbicidal agents.18 The expeditious three-step
route appears to be general in scope.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out under an
atmosphere of N2. Unless otherwise noted, materials were
obtained from commercial suppliers and were used without
further purification. Dimethylformamide (DMF), tetrahydro-
furan (THF), and toluene were stored over 4A sieves. Mol %
(mole percent) refers to the stoichiometry of the reaction
components. Organic layers from aqueous extractions were
dried over MgSO4 and concentrated in vacuo. Melting points
are uncorrected. 1H (recorded at 400 and 300 MHz), 31P
(recorded at 121.4 MHz), and 13C (recorded at 100.6 and 75.4
MHz) NMR spectra were measured in CDCl3 or DMSO-d6. 13
C
and 31P spectra (recorded relative to trimethyl phosphite at
140.4 ppm) were run proton decoupled. Coupling constants,
J , are reported in hertz and refer to proton-proton coupling
unless otherwise indicated. Chemical ionization mass spectra
(MS) are recorded in units of m/z. High-resolution mass spectra
(HRMS) were carried out by EI techniques. Unless otherwise
indicated, flash chromatography was performed on 230-400
mesh silica gel. Reversed-phase C18 silica gel was obtained
from Supelco. Analytical thin-layer chromatography was done
with glass-backed silica plates, 250 µm (Analtech).
of 6b to 7b, the equilibrium lies far to the right as the
negative charge on the phosphonamidate nitrogen atom
prevents the retro-reaction, i.e., ethanolysis from taking
place. When the tandem one-pot cyclization/alkylation of
6b is carried out with NaH (120 mol %) followed by the
addition of excess MeI, the desired 9 was obtained as the
sole product.17
In contrast to 7a , heating 7b in the presence of a small
excess of Lawesson’s reagent in toluene afforded two
thionated products, 10 and 11. The structures of both 10
(45%) and 11 (16%) were established unequivocally by
13C and 31P NMR. Compound 10, observed as a mixture
of conformers, was identified as a bis-thionated product
due to the extreme downfield shifts of both the carbonyl
and phosphorus atoms in the 13C NMR (167.9 to 195.3
ppm) and 31P NMR (+32.7 to +93.6 and +80.1 ppm as a
mixture of conformers), respectively. In 11, only the
phosphorus atom demonstrated a significant downfield
shift (from +32.7 to +83.4 ppm in the 31P NMR). The
C-5 carbonyl remained essentially unchanged (∆δ ) 0.5
ppm), indicating that thionation took place only on the
phosphorus atom.
Diet h yl [(Ben zylm et h yla m in o)m et h yl]p h osp h on a t e.
To a solution of N-benzylmethylamine (12.1 g, 100 mmol) and
diethyl phosphite (13.9 g, 100 mmol) was added paraformal-
dehyde (3.0 g, 100 mmol) portionwise during 5 min. The
heterogeneous reaction mixture was then heated to 80 °C and
held for 3 h, during which time it became homogeneous. After
being cooled to room temperature, the solution was diluted
with Et2O, treated with MgSO4 (10.0 g), and stirred for 30 min.
After the solid was filtered, the filtrate was concentrated and
the crude product was chromatographed (Et2O/hexanes, 1/1)
to afford 22.06 g (81%) of a clear liquid that was used directly
in the next step: 1H NMR (CDCl3) δ 7.31-7.23 (m, 5H), 4.14-
2
4.04 (m, 4H), 3.63 (s, 2H), 2.79 (d, J HP ) 11.4, 2H), 2.41 (s,
3H), 1.29 (t, J ) 7.2, 6H); 31P NMR (CDCl3) δ +24.5; MS 272
(MH+).
Dieth yl [(Meth yla m in o)m eth yl]p h osp h on a te (4b). A
solution of diethyl [(benzylmethylamino)methyl]phosphonate
prepared above (21.1 g, 78 mmol) in EtOH (200 mL) was
hydrogenated over 10% Pd-C (6.35 g, 30 wt %) in a Parr
shaker at 55 psi for a total of 17 h. The catalyst was removed,
and the filtrate was concentrated and distilled (82 °C, 0.4 mm)
to afford 10.6 g (75%) of a clear liquid (lit.12c bp 75 °C, 0.3
mm): 1H NMR (CDCl3) δ 4.12 (dq, J ) 7.4, J HP ) 7.4, 4H),
2.92 (d, 2J HP ) 12.3, 2H), 2.47 (d, J ) 2.1, 3H), 1.50 (br s, 1H),
1.31 (t, J ) 7.2, 6H); 31P NMR (CDCl3) δ +25.4; MS 182 (MH+).
2-Nitr oben za m id op h osp h on a tes. Gen er a l P r oced u r e.
A 1.0 M solution of 5-chloro-2-nitrobenzoyl chloride 311 in
toluene (110 mol %) was added dropwise to a 0 °C solution of
the appropriate aminophosphonate (100 mol %) and triethyl-
amine in THF. The heterogeneous reaction mixture was
allowed to reach ambient temperature and then stirred over-
night. After dilution with EtOAc, the reaction mixture was
washed successively with H2O, two to three portions of sat-
urated NaHCO3, and brine. The organic phases were dried and
concentrated, and the products were purified by the method
indicated.
When 10 was treated with NaH and MeI, a single
product, 12, was obtained as a mixture of conformers (ca.
2/1 in CDCl3 and 1/1 in DMSO-d6). The methyl reso-
nances appeared as a set of doublets in the 1H NMR
3
(CDCl3) at 3.17 (major) and 2.91 (minor) with J HP ) 10.8
and 10.5 Hz, respectively. The magnitude of the J value,
consistent with three-bond coupling, could arise from
methylation at either N-1 or the phosphorus-bearing
sulfur atom. The observed chemical shift, however, was
indicative of N-methylation. The structural assignment
was made unambiguously by 1H-13C heteronuclear
multiple bond correlation (HMBC) to examine the long-
range J couplings. The methyl resonances in question
demonstrated strong intensity cross-peaks with the near-
est aromatic carbon (three-bond coupling). S-Methylation
would require five-bond coupling to the nearest aromatic
carbon.
Dieth yl
[(N-ter t-Bu tyl-5-ch lor o-2-n itr oben za m id o)-
m eth yl]p h osp h on a te (5a ). Reaction of 3 (97 mmol), 4a 12c
(87.9 mmol), and triethylamine (193.5 mmol) gave 24.2 g (68%
yield) of 5a as yellow needles after recrystallization (EtOAc/
(17) The author would like to thank one of the reviewers for
comments concerning the role that additional NaH plays in the tandem
cyclization/alkylation of 6b. Additional experiments indicated that 9
is obtained as the sole product in instances where NaH is kept near
stoichiometric so as to avoid the formation of sodium ethoxide.
(18) The 1,4,2-benzodiazaphosphepin-5-one 2-oxides and thioxides
reported herein were evaluated for their herbicidal activity both in
the whole plant and in vitro and were found to be much less active
than the isosteric 1,4-benzodiazepine-2,5-diones.

1,4,2-Benzodiazaphosphepin-5-one 2-Oxide Analogues
J . Org. Chem., Vol. 64, No. 22, 1999 8159
1
hexanes): mp 98-99 °C; H NMR (CDCl3) δ 8.10 (d, J ) 8.7,
ature, the solution was poured into H2O, acidified to pH 5-6
using HCl, and then extracted with two portions of EtOAc.
The organic layer was washed successively with H2O (two to
three portions) and then brine. The organic phases were dried
and concentrated, and the products were purified by the
method indicated.
1H), 7.61 (d, J ) 2.1, 1H), 7.46 (dd, J ) 2.1, 8.7, 1H), 4.10-
4.00 (m, 4H), 3.71 (dd, J ) 8.4, 17.1, 1H), 3.43 (br s, 1H), 1.59
(s, 9H), 1.25 (m, 6H); 31P NMR (CDCl3) δ +21.2; MS 407 (MH+).
Anal. Calcd for C16H24ClN2O6P: C, 47.24; H, 5.95; N, 6.89; P,
7.61. Found: C, 47.20; H, 6.15; N, 6.76; P, 7.68.
Dieth yl [(5-Ch lor o-N-m eth yl-2-n itr oben za m id o)m eth -
yl]p h osp h on a t e (5b ). Reaction of 3 (24.3 mmol), 4b (22.1
mmol), and triethylamine (27.6 mmol) gave, after chromatog-
raphy (EtOAc/hexanes, 50-60%), 5.56 g of 5b as a yellow oil
(69%): 1H NMR (CDCl3, rotamers, 4:1) δ (major) 8.11 (d, J )
8.8, 1H), 7.50 (dd, J ) 2.4, 8.7, 1H), 7.31 (d, J ) 2.2, 1H), 4.18
4-ter t-Bu tyl-7-ch lor o-2-eth oxy-2,3-dih ydr o-1H-1,4,2-ben -
zod ia za p h osp h ep in -5(4H)-on e 2-Oxid e (7a ). Treatment of
a solution of 6a (10.3 g, 27.4 mmol) in DMF (100 mL) with
NaH (1.37 g, 34.2 mmol) followed by heating at 60 °C for 5 h
gave, after workup, a solid. Trituration of the crude product
in EtOAc/hexanes (1/3) afforded 6.45 g (71%) of 7a as a white
3
1
(dq, J ) 7.0, J HP )7.0, 4H), 3.98 (br s, 2H), 2.94 (s, 3H), 1.33
solid: mp 225-227 °C; H NMR (CDCl3) δ 7.58 (d, J ) 2.4,
(t, J ) 7.2, 6H), (minor, partial) 8.10 (d, J ) 9.6, 1H), 4.07
(dq, J ) 7.2, 8.2, 4H), 3.43-3.38 (m, 2H), 3.23 (s, 3H), 1.28 (t,
J ) 7.2, 1H); 31P NMR (CDCl3) δ +20.5 (major), +19.3 (minor);
MS 365 (MH+). Anal. Calcd for C13H18ClN2O6P: C, 42.85; H,
4.97; N, 7.68; P, 8.49. Found: C, 42.62; H, 4.97; N, 7.61; P,
8.44.
1H), 7.37 (br s, 1H), 7.25 (dd, J ) 2.1, 8.4, 1H), 6.93 (d, J )
2
8.7, 1H), 4.12-4.04 (m, 2H), 3.76 (dd, J ) 17.1, J HP)12.3,
2
1H), 3.49 (dd, J ) 17.1, J HP)6.0, 1H), 1.55 (s, 9H), 1.25 (t, J
) 7.2, 3H); 31P NMR (CDCl3) δ +34.7; 13C NMR (CDCl3) δ
167.8, 134.6, 134.4, 130.8, 130.1 (d, J CP ) 3.5), 130.0, 125.6
2
1
(d, J CP ) 5.6), 61.0 (d, J CP ) 7.6), 58.5, 39.5 (d, J CP ) 144),
Dieth yl [(N-Ben zyl-5-ch lor o-2-n itr oben za m id o)m eth -
yl]p h osp h on a te (5c). Reaction of 3 (200 mmol), 4c12b (174
mmol), and triethylamine (400 mmol) gave 44.4 g (58%) of 5c
as an off-white solid after recrystallization (EtOAc/hexanes):
28.1, 16.1 (d, 3J CP ) 6.0); MS 331 (MH+). Anal. Calcd for C14H20
-
ClN2O3P: C, 50.84; H, 6.09; N, 8.47; P, 9.36. Found: C, 51.10;
H, 6.14; N, 8.45; P, 9.43.
7-Ch lor o-2-eth oxy-2,3-d ih yd r o-4-m eth yl-1H-1,4,2-ben -
zod ia za p h osp h ep in -5(4H)-on e 2-Oxid e (7b). Treatment of
a solution of 6b (4.00 g, 13.9 mmol) in DMF (30 mL) with NaH
(0.72 g, 18.0 mmol) was followed by heating at 60 °C for 1 h.
After the usual workup, the crude product was applied to C18
reversed-phase silica gel and eluted with CH3CN/H2O (15/85).
The fractions containing the product were combined and
concentrated and then diluted with CHCl3 and dried. Concen-
tration of the solution gave 2.35 g (68%) of 7b as a yellow
foam: mp 86-94 °C; 1H NMR (CDCl3) δ 7.54 (d, J ) 2.5, 1H),
7.48 (br s, 1H), 7.24 (dd, J ) 2.5, 8.5, 1H), 6.94 (dd, J ) 8.5,
1
mp 108-109 °C; H NMR (CDCl3, rotamers, 3:1) δ 8.14 (d, J
) 8.7, 1H, major), 8.13 (d, J ) 9.0, 1H, minor), 7.64-7.18 (m,
3
7H), 4.60-4.40 (m, 2H), 4.20 (dq, J ) 7.2, J HP ) 7.2, 4H,
3
major), 4.08 (dq, J ) 7.3, J HP ) 7.3, 4H, minor), 4.20-3.75
(m, 2H), 1.36 (t, J ) 6.9, 3H, major), 1.31 (t, J ) 6.6, 3H,
minor); 31P NMR (CDCl3) δ +21.0 (major), +19.9 (minor); MS
440 (M+). Anal. Calcd for C19H22ClN2O6P: C, 51.77; H, 5.03;
N, 6.35; P, 7.03. Found: C, 52.03; H, 4.87; N, 6.32; P, 7.00.
2-Am in oben za m id op h osp h on a tes. Gen er a l P r oced u r e.
A solution of the 2-nitrobenzamidophosphonates 5a -c was
hydrogenated over 5% Pt-C (30 wt %) in a Parr shaker at 50
psi until hydrogen uptake ceased. The catalyst was filtered,
and the filtrate was concentrated. The crude product was
purified by the method indicated.
3
4J HP ) 1.1, 1H), 4.10 (dq, J ) 7.3, J HP ) 7.3, 2H), 3.69-3.50
(m, 2H), 3.20 (s, 3H), 1.26 (t, J ) 7.1, 3H); 31P NMR (CDCl3)
δ +32.7; 13C NMR (CDCl3) δ 167.9, 135.5, 132.0, 131.6, 130.8,
2
1
130.7, 126.2 (d, J CP ) 5.0), 62.5 (d, J CP ) 7.1), 45.0 (d, J CP
)
3
Dieth yl [(2-Am in o-N-ter t-bu tyl-5-ch lor oben za m id o)-
m eth yl]p h osp h on a te (6a ). A solution of 5a (24.0 g, 59.0
mmol) in EtOH (600 mL) was hydrogenated for 24 h. Recrys-
tallization (EtOAc/hexanes) gave 15.8 g (71%) of 6a as an off-
white solid: mp 123.5-125 °C; 1H NMR (CDCl3) δ 7.04 (m,
2H), 6.52 (d, J ) 8.7, 1H), 4.27 (br s, 2H), 4.04-3.94 (m, 4H),
3.85-3.80 (m, 2H), 1.47 (s, 9H), 1.23 (t, J ) 7.2, 3H); 31P NMR
139), 36.7, 16.7 (d, J CP ) 5.1); MS 288 (M+); HRMS calcd for
C
11H14ClN2O3P (M+) 288.0431, found 288.0430.
4-Ben zyl-7-ch lor o-2-et h oxy-2,3-d ih yd r o-1H -1,4,2-b en -
zod ia za p h osp h ep in -5(4H)-on e 2-Oxid e (7c). Treatment of
a solution of 6c (2.10 g, 5.10 mmol) in DMF (20 mL) with NaH
(0.27 g, 6.62 mmol) followed by heating at 60 °C for 2 h gave,
after workup and trituration with hexanes, 1.06 g (57%) of 7c
as a yellow glass: 1H NMR (CDCl3) δ 7.72 (d, J ) 2.5, 1H),
7.40 (br s, 1H), 7.37-7.25 (m, 6H), 7.01 (dd, J ) 8.1, 4J HP)1.1,
1H), 5.18 (d, J ) 14.7, 1H), 4.56 (d, J ) 14.7, 1H), 4.18-4.04
(m, 2H), 3.46 (d, J ) 9.0, 2H), 1.28 (t, J ) 7.2, 3H); 31P NMR
(CDCl3) δ +32.8; 13C NMR (CDCl3) δ 168.2, 136.0, 135.5, 132.3,
131.8, 131.1, 131.0, 129.1, 128.6, 128.3, 126.5 (d, J CP ) 5.5),
(CDCl3) δ +23.3; MS 377 (MH+). Anal. Calcd for C16H26
-
ClN2O4P: C, 51.00; H, 6.95; N, 7.43; P, 8.22. Found: C, 51.15;
H, 7.05; N, 7.43; P, 8.14.
Dieth yl [(2-Am in o-5-ch lor o-N-m eth ylben za m id o)m eth -
yl]p h osp h on a te (6b). A solution of 5b (4.54 g, 12.5 mmol)
in 100 mL of THF/EtOH (1/1, v/v) was hydrogenated for 25 h
to afford 4.08 g (98%) of an off-white waxy solid. A small
sample (0.6 g) recrystallized from EtOAc/hexanes gave 0.42 g
of 6b as beige needles: mp 110-111.5 °C; 1H NMR (CDCl3) δ
7.11-7.08 (m, 2H), 6.60 (d, J ) 9.1, 1H), 4.50-4.25 (m, 2H),
2
1
3
62.5 (d, J CP ) 7.0), 51.6, 42.1 (d, J CP ) 141), 16.8 (d, J CP
)
6.0); MS 365 (MH+); HRMS calcd for C17H18ClN2O3P (M+)
364.0743, found 364.0760.
4-ter t-Bu tyl-7-ch lor o-2-eth oxy-2,3-dih ydr o-1H-1,4,2-ben -
zod ia za p h osp h ep in -5(4H)-on e 2-Th ioxid e (8). To a sus-
pension of 7a (1.00 g, 3.03 mmol) in toluene (20 mL) was added
Lawesson’s reagent (0.67 g, 1.67 mmol, 55 mol %) in one
portion. The reaction was heated to reflux for 5 h and then
cooled to room temperature. The yellow reaction mixture was
then concentrated and chromatographed (EtOAc/hexanes, 15/
85) to afford 8 (0.98 g, 93%) as a white solid: mp 150-153 °C;
1H NMR (CDCl3) δ 7.59 (d, J ) 2.5, 1H), 7.30 (dd, J ) 2.5, 8.2,
1H), 6.87 (dd, J ) 2.6, 8.4, 1H), 5.27 (d, J ) 4.8, 1H), 4.22-
4.08 (m, 2H), 3.94 (dd, J ) 17.0, 2J HP ) 7.1, 1H), 3.73 (dd, J )
3
2
4.17 (dq, J ) 7.1, J HP ) 7.1, 4H), 3.94 (d, J HP ) 11.3, 2H),
3.11 (s, 3H), 1.34 (t, J ) 7.2, 3H); 31P NMR (CDCl3) δ +22.5;
MS 335 (MH+). Anal. Calcd for C13H20ClN2O4P: C, 46.65; H,
6.02; N, 8.37; P, 9.25. Found: C, 46.49; H, 6.12; N, 8.28; P,
9.23.
Dieth yl [(2-Am in o-N-ben zyl-5-ch lor oben za m id o)m eth -
yl]p h osp h on a te (6c). A solution of 5c (46.6 g, 105 mmol) in
500 mL of THF/EtOH (1/1, v/v) was hydrogenated for 22 h to
afford 40.1 g (92%) of a pale yellow oil that was essentially
pure: 1H NMR (CDCl3) δ 7.36-7.08 (m, 7H), 6.61 (d, J ) 8.5,
1H), 4.65 (br s, 2H), 4.70-4.30 (br s, 2H), 4.23-4.11 (m, 4H),
3.80 (d, 2J HP ) 10.7, 2H), 1.34 (t, J ) 7.1, 3H); 31P NMR (CDCl3)
δ +23.4; MS 410 (M+). Anal. Calcd for C19H24ClN2O4P: C,
55.55; H, 5.89; N, 6.82; P, 7.54. Found: C, 55.16; H, 5.98; N,
6.67; P, 7.58.
1,4,2-Ben zod ia za p h osp h ep in -5-on e 2-oxid es. Gen er a l
P r oced u r e. A solution of the aminobenzamidophosphonates
6a -c in DMF (0.25-0.50 M) was treated with NaH (120-130
mol %, 60% oil dispersion) and then warmed to 60 °C and held
at this temperature until TLC or HPLC indicated the reaction
was complete (ca. 1-5 h). After being cooled to room temper-
2
17.0, J HP ) 8.2, 1H), 1.64 (s, 9H), 1.28 (t, J ) 7.1, 3H); 31P
NMR (CDCl3) δ +84.4; 13C NMR (CDCl3) δ 167.5, 135.9, 133.1
(d, J CP ) 6.0), 131.3, 130.5, 126.2 (d, J CP ) 3.5), 126.1, 61.1 (d,
1
3
2J CP ) 7.0), 58.6, 45.4 (d, J CP ) 118), 28.3, 15.5 (d, J CP
)
6.6); MS 347 (MH+); HRMS calcd for C14H20ClN2O2PS (M+)
346.0672, found 346.0662.
7-Ch lor o-1,4-d im et h yl-2-et h oxy-2,3-d ih yd r o-1H -1,4,2-
ben zod ia za p h osp h ep in -5(4H)-on e 2-Oxid e (9). To a solu-
tion of 7b (1.20 g, 4.16 mmol) in DMF (15 mL) was added NaH
(0.25 g, 6.24 mmol, 60% oil dispersion). After the mixture was
stirred for 20 min at room temperature, methyl iodide (0.39

8160 J . Org. Chem., Vol. 64, No. 22, 1999
Karp
mL, 6.24 mmol) was added via syringe and the solution was
stirred for an additional 4 h. The yellow solution was then
treated with 6 N H2SO4 (3 drops) to neutralize the excess NaH.
Most of the DMF was removed via distillation on a Kugelrohr
apparatus, and the residue was diluted with EtOAc and
washed with three portions of H2O. The combined aqueous
phases were back-extracted with additional EtOAc, and the
organic layers were combined, washed with brine, and then
concentrated. The crude product was applied to C18 reversed-
phase silica gel and eluted with CH3CN/H2O (85/15). The
fractions containing the product were combined and concen-
trated to a pale yellow oil. The oil was dissolved in CHCl3 and
dried. Concentration of the solution gave 0.66 g (52% yield) of
9 as a pale yellow oil: 1H NMR (CDCl3) δ 7.49 (d, J ) 2.5,
C11H14ClN2O2PS: C, 43.36; H, 4.63; N, 9.19; P, 10.16. Found:
C, 42.93; H, 4.63; N, 8.99; P, 9.91.
7-Ch lor o-1,4-d im eth yl-2-eth oxy-2,3-d ih yd r o-2-1H-1,4,2-
ben zod ia za p h osp h ep in -5(4H)-th ion e 2-Th ioxid e (12). A
solution of 10 (0.57 g, 1.78 mmol) in DMF (10 mL) was treated
with NaH (0.078 g, 1.96 mmol, 60% oil dispersion) and then
stirred at room temperature for 30 min. Methyl iodide was
added via syringe at once, and the reaction was stirred for an
additional 22 h. The reaction mixture was then diluted with
EtOAc and washed with four portions of H2O. The aqueous
layers were then back-extracted with additional EtOAc, and
the combined organic phases were washed with brine and then
dried and concentrated. The crude product was purified by
chromatography (EtOAC/hexanes, 15/85) to afford 12 as an
amber glass (0.33 g, 55%): mp 105-108 °C; 1H NMR (CDCl3,
conformers, 2:1) δ (major) 7.05 (d, J ) 2.4, 1H), 7.32 (dd, J )
4
1H), 7.35 (dd, J ) 2.5, 8.7, 1H), 7.11 (dd, J ) 8.7, J HP ) 1.5,
1H), 4.11 (dq, J ) 7.2, 7.7, 2H), 3.59-3.42 (m, 2H), 3.20 (s,
3
4
3H), 3.07 (d, J HP ) 7.8, 3H), 1.28 (t, J ) 7.1, 3H); 31P NMR
2.5, 8.8, 1H), 7.06 (dd, J ) 8.3, J HP ) 1.3, 1H), 4.12-3.75 (m,
(CDCl3) δ +32.0; 13C NMR (CDCl3) δ 167.6, 139.8 (d, J CP
3.0), 133.8, 132.0, 131.8 (d, J CP ) 2.0), 130.1, 126.0 (d, J CP
)
)
4H), 3.73 (s, 3H), 3.17 (d, J HP ) 10.8, 3H), 1.22 (t, J ) 7.2,
3
3H), (minor) 7.67 (d, J ) 2.8, 1H), 7.31 (m, 1H), 7.02 (dd, J )
2
1
4
4.1), 62.7 (d, J CP ) 6.0), 45.7 (d, J CP ) 142), 36.4, 34.5 (2J CP
8.8, J HP ) 1.9, 1H), 4.35-4.05 (m, 4H), 3.63 (s, 3H), 2.91 (d,
3
) 2.0), 16.8 (d, J CP ) 6.0); MS 302 (M+); HRMS calcd for
3J HP ) 10.5, 3H), 1.38 (t, J ) 7.1, 3H); 31P NMR (CDCl3,
conformers) δ + 95.8 (minor), +82.1 (major); 13C NMR (CDCl3,
conformers) δ 195.8, 195.0, 141.0, 139.2 (2), 136.8, 136.5 (2),
132.2, 132.1, 131.1, 130.9, 130.8 (2), 130.6 (2), 127.2 (2), 123.8
C
12H16ClN2O3P (M+) 302.0587, found 302.0583.
7-Ch lor o-2-eth oxy-2,3-dih ydr o-4-m eth yl-2-1H-1,4,2-ben -
zod ia za p h osp h ep in -5(4H)-th ion e 2-Th ioxid e (10) a n d
7-Ch lor o-2-eth oxy-2,3-d ih yd r o-4-m eth yl-1H-1,4,2-ben zo-
d ia za p h osp h ep in -5(4H)-on e 2-Th ioxid e (11). To a suspen-
sion of 7b (2.50 g, 8.67 mmol) in toluene (50 mL) was added
Lawesson’s reagent (1.93 g, 4.77 mmol, 55 mol %), and the
mixture was heated at reflux until TLC indicated that all of
7b was consumed (ca. 3.5 h). After being cooled to room
temperature, the reaction mixture was concentrated to a solid.
Addition of a small amount of EtOAc/hexanes (10 mL, 20/80)
gave a gummy solid. Upon addition of a small amount of
CH2Cl2, a finely divided yellow solid precipitated, comprising
two major components. The filtrate contained only trace
amounts of these components in addition to byproducts gener-
ated from Lawesson’s reagent. The crude product mixture was
chromatographed with CH2Cl2 to elute the major, less polar
10, followed by EtOAc/CH2Cl2 (10/90) to elute the minor, more
polar 11.
1
1
(2), 64.2 (2), 57.0 (d, J CP ) 100), 56.7 (d, J CP ) 119), 44.9,
44.4 36.6 (2), 32.4 (2), 16.2 (2), 16.1 (2); MS 334 (M+); HRMS
calcd for C12H16ClN2OPS2 (M+) 334.0130, found 334.0141.
Dieth yl [(5-Ch lor o-N-m eth yl-2-(m eth yla m in o)ben z-
a m id o)m eth yl]p h osp h on a te (13) fr om 6b via In ter m ed i-
a te 9. A solution of 6b (2.95 g, 8.82 mmol) in DMF was treated
with NaH (0.53 g, 13.2 mmol, 60% oil dispersion), heated to
60 °C, and then held at this temperature for 3 h (at which
time HPLC analysis indicated complete consumption of start-
ing material). After the solution was cooled to room temper-
ature, additional NaH (0.35 g, 8.82 mmol) was added, and the
resulting solution was stirred for an additional 20 min. Methyl
iodide (0.82 mL, 13.2 mmol) was then added, and after being
stirred for an additional 2 h at room temperature, the solution
was treated with a few drops of 6 N H2SO4 to neutralize the
excess NaH and the residue was diluted with EtOAc and
washed with three portions of H2O. The combined aqueous
phases were back-extracted with additional EtOAc, and the
organic layers were combined, washed with brine, and then
concentrated. Chromatography (EtOAC/hexanes, 1/1) afforded
1.24 g (40%) of 13 as a pale yellow oil: 1H NMR (CDCl3) δ
7.17 (dd, J ) 2.5, 8.8, 1H), 7.04 (d, J ) 2.2, 1H), 6.51 (d, J )
8.8, 1H), 5.11 (br s, 1H), 4.20-4.10 (m, 4H), 3.92 (d, J ) 11.2,
2H), 3.06 (s, 3H), 2.77 (s, 3H), 1.32 (t, J ) 7.1, 6H); 31P NMR
(CDCl3) δ +22.4; MS 348 (M+); HRMS calcd for C14H22ClN2O4P
(M+) 348.1005, found 348.1015.
10: isolated as a yellow solid (1.24 g, 45%); mp 224-225.5
1
°C; H NMR (298 K, DMSO-d6, rotamers, 2.5:1) δ 8.62 (br s,
1H), 7.62 (br s, 1H), 7.42 (m, 1H), 6.98 (m, 1H), 4.55-4.00 (m,
4H), 3.66 (s, 3H, major), 3.57 (s, 3H, minor), 1.31 (t, J ) 6.3,
3H), 1.22 (t, J ) 6.9, 3H, major); 31P NMR (298 K, DMSO-d6,
rotamers) δ +93.6 (minor), +80.1 (major); 13C NMR (298 K,
DMSO-d6, partial, major) δ 195.3, 62.1 (d, 2J CP ) 7.1), 55.4 (d,
1
1J CP ) 114), 45.4, 16.8 (3J CP ) 6.0); H NMR (353 K, DMSO-
d6, coalescence of peaks) δ 8.32 (br s), 7.65 (d, J ) 2.4, 1H),
7.38 (dd, J ) 2.7, 8.5, 1H), 7.00 (dd, J ) 8.5, 4J HP ) 1.4), 4.30-
4.10 (m, 4H), 3.66 (s, 3H), 1.27 (t, J ) 6.9, 3H); MS 321 (MH+).
Anal. Calcd for C11H14ClN2OPS2: C, 41.19; H, 4.40; N, 8.73;
P, 9.66; S, 19.99. Found: C, 41.03; H, 4.37; N, 8.57; P, 9.63; S,
19.91.
Ack n ow led gm en t. The author thanks Dr. S. Rajan
1
for obtaining the H-13C heteronuclear multiple bond
correlation spectrum for compound 12.
11: isolated as a white solid (0.41 g, 16%); mp 169-170 °C;
1H NMR (DMSO-d6) δ 8.54 (br s, 1H), 7.47-7.43 (m, 2H), 7.04
(d, J ) 8.5, 1H), 4.16-3.84 (m, 4H), 3.14 (s, 3H), 1.24 (t, J )
6.9, 3H); 31P NMR (DMSO-d6) δ +83.4;); 13C NMR (DMSO-d6)
Su p p or t in g In for m a t ion Ava ila b le: Copies of 1H and
13C NMR spectra of compounds 7a -c, 8, 9, 11, and 12, 1H
1
NMR spectrum of compound 10, and H-13C HMBC spectrum
of compound 12. This material is available free of charge via
the Internet at http://pubs.acs.org.
δ 167.4, 137.1 (d, J CP ) 6.0), 132.5, 131.9, 130.4, 129.0 (d, J CP
2
) 3.0), 126.3 (d, J CP ) 5.0), 62.2 (d, J CP ) 7.1), 50.6 (1J CP
)
111), 36.7, 16.7 (3J CP ) 6.0); MS 305 (MH+). Anal. Calcd for
J O9908400