Synthesis and spectral studies (see abstract)

Article abstract of DOI:10.1080/10426500210247

Several novel bis(2-chloroethyl)aminophosphoryl-containing compounds have been prepared as potential anticancer agents. 2,10-Dichloro-6-[bis(2-chloroethyl)]amino-4,8-dinitrodibenzo[d,g][1,3,6,2]- dioxathiaphosphocin 6-oxide (5), 2-bis(2-chloroethyl)amino-1,3, 2-dioxaphosphorinane 2-oxide (13), and 8-bis(2-chloroethyl)amino-6H-dinaphtho[2,1-d:1prime;,2′]1,3,2- dioxaphosphocin 8-oxide (15) were synthesized from a reaction of equimolar quantities of the corresponding precursor diols 3, 12, and 14 with coreagent N,N-bis(2-chloroethyl)-phosphoramidic dichloride (1) at various temperatures in dry toluene/ether in the presence of triethylamine. In addition, 2-bis(2-chloroethyl)amino-2,3-dihydro-5-thiophenoxy-1H-1,3,2- benzodiazaphosphole 2-oxide (9) and 2-bis(2-chloroethyl)amino-1,2,3,4-tetrahydro-1,3,2-benzodiazaphosphorinane 2-oxide (11) were derived from 4-thiophenoxy-1,2-diphenyldiamine (8) and 2-aminobenzylamine (10) respectively, under similar conditions. Interestingly, attempted oxidation of 5 to the corresponding sulfone 7 by H₂O₂ (30%) in acetic acid yielded only sulfoxide 6 [2,10-dichloro-6-bis(2-chloroethyl)amino-4,8-dinitrodibenzo[d,g][1,3,6,2] dioxathiaphosphocin 6-oxide}. In an alternative approach, oxidation of 5,5′-dichloro-3,3′-dinitro-2,2′-dihydroxydiphenyl sulfide (3) with H₂O₂ (30%) in acetic acid formed the corresponding sulfone 4. However, attempted cyclization of 4 with 1, in the presence of triethylamine, to give the sulfone expected from 5 was unsuccessful. NMR analysis of 6 suggests the presence of two conformers in solution.

Full text of DOI:10.1080/10426500210247

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Phosphorus, Sulfur, and Silicon and the Related
Elements
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Synthesis and Spectral Studies of 2,10-Dichloro-6-
Bis(2-Chloroethyl)Amino-4,8-Dinitrodibenzo[ d , g ]
[1,3,6,2]-Dioxathiaphosphocin, 2,10-Dichloro-6-
Bis(2-Chloroethyl)Amino-4,8-Dinitrodibenzo[ d ,
g ][1,3,6,2]Dioxathiaphosphocin 6-Oxide, 2-Bis(2-
Chloroethyl)Amino-2,3-Dihydro-5-Thiophenoxy-1
H -1,3,2-Benzodiazaphosphole 2-Oxide, 2-Bis(2-
Chloroethyl)Amino-1,2,3,4-Tetrahydro-1,3,2-
Benzodiazaphosphorinane 2-Oxide, 5-Bromo-5-Nitro-2-
Bis(2-Chloroethyl)Amino-1,3,2-Dioxaphosphorinane
2-Oxide, and 8-Bis(2-Chloroethyl)Amino-16 H -
Dinaphtho[2,1- d :1′,2′- g ]1,3,2-Dioxaphosphocin 8-
Oxide--Potential Anticancer Agents
L. Nagaprasada Rao a , C. Devendranath Reddy a , V. Krishna Reddy a , Jacob D. Hagar b
Kevin Tran b & K. Darrell Berlin b
,
a Department of Chemistry , Sri Venkateswara University , Tirupati, 517 502, India
b Department of Chemistry , Oklahoma State University , Stillwater, OK, 74078, USA
Published online: 27 Oct 2010.
To cite this article: L. Nagaprasada Rao , C. Devendranath Reddy , V. Krishna Reddy , Jacob D. Hagar , Kevin
Tran & K. Darrell Berlin (2002) Synthesis and Spectral Studies of 2,10-Dichloro-6-Bis(2-Chloroethyl)Amino-4,8-
Dinitrodibenzo[ d , g ][1,3,6,2]-Dioxathiaphosphocin, 2,10-Dichloro-6-Bis(2-Chloroethyl)Amino-4,8-Dinitrodibenzo[ d , g ]
[1,3,6,2]Dioxathiaphosphocin 6-Oxide, 2-Bis(2-Chloroethyl)Amino-2,3-Dihydro-5-Thiophenoxy-1 H -1,3,2-Benzodiazaphosphole
2-Oxide, 2-Bis(2-Chloroethyl)Amino-1,2,3,4-Tetrahydro-1,3,2-Benzodiazaphosphorinane 2-Oxide, 5-Bromo-5-Nitro-2-Bis(2-
Chloroethyl)Amino-1,3,2-Dioxaphosphorinane 2-Oxide, and 8-Bis(2-Chloroethyl)Amino-16 H -Dinaphtho[2,1- d :1′,2′- g ]1,3,2-
Dioxaphosphocin 8-Oxide--Potential Anticancer Agents, Phosphorus, Sulfur, and Silicon and the Related Elements, 177:2,
399-410, DOI: 10.1080/10426500210247
To link to this article: http://dx.doi.org/10.1080/10426500210247
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Phosphorus, Sulfur and Silicon, 2002, 177: 399–410
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SYNTHESIS AND SPECTRAL STUDIES OF
2,10-DICHLORO-6-BIS(2-CHLOROETHYL)AMINO-
4,8-DINITRODIBENZO[d,g][1,3,6,2]-
DIOXATHIAPHOSPHOCIN,
2,10-DICHLORO-6-BIS(2-CHLOROETHYL)AMINO-
4,8-DINITRODIBENZO[d,g][1,3,6,2]-
DIOXATHIAPHOSPHOCIN 6-OXIDE,
2-BIS(2-CHLOROETHYL)AMINO-2,3-DIHYDRO-5-
THIOPHENOXY-1H-1,3,2-BENZODIAZAPHOSPHOLE
2-OXIDE, 2-BIS(2-CHLOROETHYL)AMINO-1,2,3,4-
TETRAHYDRO-1,3,2-BENZODIAZAPHOSPHORINANE
2-OXIDE, 5-BROMO-5-NITRO-2-BIS(2-
CHLOROETHYL)AMINO-1,3,2-
DIOXAPHOSPHORINANE 2-OXIDE, AND
8-BIS(2-CHLOROETHYL)AMINO-16H-DINAPHTHO-
[2,1-d:10,20-g]1,3,2-DIOXAPHOSPHOCIN
8-OXIDE—POTENTIAL ANTICANCER AGENTS
L. Nagaprasada Rao,a C. Devendranath Reddy,a
V. Krishna Reddy,a Jacob D. Hagar,b Kevin Tran,b
and K. Darrell Berlinb
Department of Chemistry, Sri Venkateswara University,
Tirupati 517 502, Indiaa and Department of Chemistry,
Oklahoma State University, Stillwater, OK 74078, USAb
(Received April 10 2001.)
Several novel bis(2-chloroethyl)aminophosphoryl-containing com-
pounds have been prepared as potential anticancer agents. 2,10-
Dichloro-6-[bis(2-chloroethyl)]amino-4,8-dinitrodibenzo[d,g][1,3,6,2]-
dioxathiaphosphocin 6-oxide (5), 2-bis(2-chloroethyl)amino-1,3,
2-dioxaphosphorinane 2-oxide (13), and 8-bis(2-chloroethyl)amino-6H-
dinaphtho[2,1-d:10,20]1,3,2-dioxaphosphocin 8-oxide (15) were synthe-
sized from a reaction of equimolar quantities of the corresponding
precursor diols 3, 12, and 14 with coreagent N,N-bis(2-chloroethyl)-
phosphoramidic dichloride (1) at various temperatures in dry toluene/
ether in the presence of triethylamine. In addition, 2-bis(2-chloroethyl)-
amino-2,3-dihydro-5-thiophenoxy-1H-1,3,2-benzodiazaphosphole
Address correspondence to C. Devendranath Reddy, Department of Chemistry, Sri
Venkateswara University, Tirupati 517 502, India.
399

400
L. N. Rao et al.
2-oxide (9) and 2-bis(2-chloroethyl)amino-1,2,3,4-tetrahydro-1,3,2-
benzodiazaphosphorinane 2-oxide (11) were derived from 4-
thiophenoxy-1,2-diphenyldiamine (8) and 2-aminobenzylamine (10)
respectively, under similar conditions. Interestingly, attempted oxida-
tion of 5 to the corresponding sulfone 7 by H2O2 (30%) in acetic acid
yielded only sulfoxide 6 {2,10-dichloro-6-bis(2-chloroethyl)amino-4,8-
dinitrodibenzo[d,g][1,3,6,2]dioxathiaphosphocin 6-oxide}. In an alter-
native approach, oxidation of 5,50-dichloro-3,30-dinitro-2,20-dihydro-
xydiphenyl sulfide (3) with H2O2 (30%) in acetic acid formed the
corresponding sulfone 4. However, attempted cyclization of 4 with 1,
in the presence of triethylamine, to give the sulfone expected from 5
was unsuccessful. NMR analysis of 6 suggests the presence of two
conformers in solution.
Keywords: Bis-(2-chloroethyl)aminodioxathiaphosphocins/dioxaphos-
phocin/benzodiazaphosphole/dioxaphosphorinane1/5/6/8-oxides;Mass
Spectral Data; NMR
INTRODUCTION
N-Phosphorylated nitrogen mustard compounds are proven agents in
chemotherapy.1 Cyclophosphamide is a well known antineoplastic drug
having therapeutic activity against a relatively broad spectrum of hu-
man and animal tumors.2 Ludeman and Zon3 reported the synthesis of
benzoannulated cyclophosphamide derivatives and evaluated the anti-
tumor activity in mice against L1210 lymphoid leukemia. A nitrogen
mustard derivative of a benzodiazaphosphole-containing system was
prepared by Friedman and co-workers4 and found to possess antitumor
activity.5 In view of the biological importance of such mustards, sev-
eral novel five-, six-, and eight-membered N-phosphorylated nitrogen,
mustard-containing heterocycles were prepared and characterized.
RESULTS AND DISCUSSION
The important intermediate N,N0-bis(2-chloroethyl)phosphorami-
dic chloride (1) was prepared in standard fashion Reaction of
4-chlorophenol with sulfur dichloride afforded a key starting material,
namely 5,50-dichloro-2,20-dihydroxydiphenyl sulfide (2).6 Nitration
of 2 with HNO3 in acetic acid gave 5,50-dichloro-2,20dihydroxy-3,30-
dinitrodiphenyl sulfide (3) (Scheme 1). Oxidation of 3 to the correspond-
ing sulfone 4 was easily accomplished using H2O2. Cyclocondensation
of 3 with 1 in the presence of triethylamine led to 2,10-dichloro-
6-[bis(2-chloroethyl)amino]-4,8-dinitrodibenzo[d, g][1,3,6,2]dioxathia-
phosphocin 6-oxide (5). The product was isolated by removal of

Phosphocins
401
SCHEME 1
triethylamine hydrochloride, via filtration, followed by evaporation of
the solvent. Further purification was accomplished by washing the
solid with water and then recrystallizing (methanol:chloroform, 1:1).
Oxidation of 5 with H2O2/HOAc led to sulfoxide 6 rather than the
corresponding sulfone 7. Possibly the steric bulk of the 4-chloro-2-
nitrophenyl groups surrounding the sulfur atom prevented oxidation
of 6 to 7. Attempts to prepare 7 via reaction of 4 with 1 under the usual
conditions and at temperatures up to 90 C also failed, suggesting
the sulfone group may hinder the formation of 7, possibly because
of the bulk involving the close proximity of the nitro groups to the
ortho-situated hydroxyl groups as well as an pseudo axial S→O bond.
From an examination of the potential orientations of the polar oxygen
atom and the size of the bis(chloroethyl)amino group on the phosphorus
atom, it is clear that two isomers like 6 or 60 could be formed from the
one isomer 5. Groups are present in both molecules which can screen
the upper portion of the sulfur atom, a situation that could prevent a

402
L. N. Rao et al.
second oxidation of sulfur in 5 to yield the sulfone in 7 with an axial
S→O bond. A major issue to be addressed pertains to the orientation of
the P(O)N[CH2CH2Cl]2 with respect to the S atom and to the flanking
ortho nitro groups on the aryl rings. Molecular models imply that the
proximity of the sulfur atom to the flattened aryl rings with ortho hydro-
gens, the P→O group and the bonded N[CH2CH2Cl]2 substituent, and
the flanking nitro groups, constitute a major steric congestion. Thus,
one might estimate that only formation of a pseudo equatorial S→O
bond, as in 6, would be favored. Indeed, the bulky P(O)N[CH2CH2Cl]2
group, assumed to be a dynamic function within the 8-memberd ring,
could shield the sulfur atom in 6 from a second oxidation ‘from the top,’
or pseudo axial position. Similarly, 60 possesses steric interactions as
well by the same groups on P and the aryl ring. However, intuitively, one
might also expect 6 to be favored over 60 since the pseudo axial S→O
bond in 60 would expectedly raise the potential energy of the system be-
cause the O P O portion of the ring could be restricted in movement.
Moreover, any group on P which was projected toward the axial S→O
bond would experience severe interactions as suggested by models.
Isomer 6 crystallized as a single compound, but NMR analysis in-
dicated two species. If one considers a possible equilibrium in solu-
0
0
→
→
tion between two conformers, such as in 6a
6a or 6b
6b , some
SCHEME 2

Phosphocins
403
observations can be made in terms of an effect of steric interactions
on conformer stability. It is noted that the P→O group is tilted away
from the sulfur atom in 6a0 and 6b0, and thus internal repulsive ener-
gies could be reduced to some extent. On that basis, one would expect
conformer 6b0 to be dominant since the smaller P→O function could
perhaps more easily reside between the nitro groups than could the
bis(2-chloroethyl)amino moiety as illustrated in 6a0. In contrast, con-
formers 6a and 6b would expectedly possess large interaction energies
involving groups on phosphorus and the S atom or S→O group but
0
→
probably less so in 6a. Thus, the 6a
6a favored (Scheme 2).
6a is tentatively preferred with
It is not possible to rule out the presence of isomer 60 which possesses
an axial S→O group and the P atom with substituents extended to make
a chair type conformation, perhaps similar to that illustrated in 6a0
and 6b . Because of an assumed equilibrium involving a tub
interconversion in 5 and because of the ortho-positioned C O bonds
and C S bonds, oxidation of sulfur to give a pseudo equatorial S → O
0
→
chair
bond may be more defensible.
Assuming an equilibrium exists at room temperature between sta-
ble conformers of 6, it is reasonable to predict that two 31P NMR sig-
nals might be observed. Such signals appeared for 31P at 18.83 ppm
and 19.72 ppm in the ratio of 1:5. The presence of four doublets
4
( 8.19–8.53 with J
2.5 Hz; this is fitting for a JHH coupling-meta
1
coupling) for Ar H was displayed in the H NMR spectrum of a solu-
tion of 6 and supported two conformers in solution. Moreover, the ratio
1
of areas to each other of the two sets of aryl protons in the H NMR
spectrum was nearly the same ( 1:4.2) as that of the 31P signals. In-
terestingly, the aromatic protons in 6 at H-1, H-3,9, and H-11, were
deshielded compared to the corresponding aromatic protons ( 7.36–
8.10) in 5. In the 1H NMR spectrum of sulfone 4, two singlets appeared
for H-4/H-40 and H-6/H-60 at 8.15 and 7.94 g respectively. The sul-
fone group apparently deshields signals for H-4/H-40 and H-6/H-60 in 4
compared to the counterparts ( 7.48 and 8.01) in 3. Unfortunately,
the 13C NMR analysis of a DMSO-d6 solution of 6 was not especially
instructive on a 300 MHz spectrometer since the solubility of all sam-
ples was relatively low, and very long acquisition times were required
to obtain even a reasonable spectrum including a relatively high noise
level. The 13C NMR shifts were read as accurately as possible but must
be accepted as best estimates. A rough assessment of the P C coupling
was 3JPC 4.6 Hz for the signal at 130.9 involving C(11a) attached to
S. Attempts to grow a suitable single crystal for an X-ray diffraction
analysis of 6 have not been successful to date.

404
L. N. Rao et al.
Oxidation of 3 (Scheme 1) with hydrogen peroxide (30%) in acetic acid
yielded sulfone 4 as stated earlier, and attempted cyclization of 4 with
1 at 70–90 C in the presence of triethylamine did not produce 7. Pos-
sibly some steric interactions between the oxygen atoms on the sulfur
in 4 and the large groups attached directly to phosphorus, as discussed
above, may be negating ring formation. An implication from these ob-
servations is that the presence of a pseudo axial S→O group may pre-
vent formation of a dynamic, eight-membered ring system which also
includes in close proximity a phosphoryl group possessing a very large
external substituent.
A small series of structurally-related systems was also examined.
The condensation of equimolar quantities of 4-thiophenoxy-1,2-phenyl-
enediamine (8),7 2-aminobenzylamine (10),8 2-bromo-2-nitro-1,3-pro-
panediol (12), and bis(2-hydroxy-1-naphthyl)methane (14)9 with
N,N-bis(2-chloroethyl)phosphoramidic dichloride (1) and two equiva-
lents of triethylamine created 9, 11, 13, and 15, respectively (Scheme 3).
SCHEME 3
The use of two equivalents of triethylamine, dry toluene/ether, and a
temperature of 35–60 C was found to be suitable to produce 9, 11, and
15. However, cyclization of 12 with 1 required milder temperatures of

Phosphocins
405
O C to 20 C. Purification of these products involved filtration of
the triethylamine hydrochloride, evaporation of the solvent, washing
the residue with water, and recrystallization of the solids from suitable
solvents.
Interestingly, two different doublets were observed for the two
endocyclic PNH protons at
8.55 (JPH 17.2 Hz) and
8.42 Hz
(JPH 17.6 Hz) in 9, suggesting nonequivalence.13 The most likely ex-
planation is that the two signals arise from the protons on the two
nitrogen atoms being in slightly different environments created by the
ring substitution. The small difference in 31P chemical shifts (40.64 vs
40.80 ppm) support this position. A remote possibility might be that
these two protons on nitrogen are frozen in a cis-trans forms, but there
is no intuitively obvious reason for this situation.
Compounds 11, 13, and 15 gave simple proton NMR spectra. Some-
what surprising was the observation that the methylene protons of
the N,N-bis(2-chloroethyl)amino moieties displayed two complex mul-
tiplets in the regions of 3.17–3.73 and 3.56–3.90, respectively,14,15 in
5, 6, 9, and 11. In contrast, all methylene protons appeared as a broad
multiplet14 at 3.58–3.83 in 13 and 15.
The 13C NMR chemical shifts were recorded as best estimates for
some examples of the title compounds, namely for 3, 5, 6, and 9, since
the shifts were very close. Mass spectral analyses were conducted on
representative compounds, and the data obtained were confirmatory
for the molecular ions of 3, 5, and 11.
In summary, we have developed syntheses for six heterocyclic sys-
tems containing a phosphoryl group bonded to a bis(chloroethyl)amino
function. NMR analyses suggested that, in the case of 6, more than
one conformer was present in solution. Large substitutents bonded
to phosphorus appear to screen the sulfur atom and permit only
monooxidation to a sulfoxide and prevent further oxidation to a
sulfone. The compounds await evaluation as potential anticancer
agents.
EXPERIMENTAL
All melting points were determined on a Mel-Temp apparatus and were
uncorrected. Elemental analyses were performed by Central Drug Re-
search Institute (Lucknow, India). The IR spectra were taken (KBr
1
pellets) on a Perkin-Elmer 683 unit. The H, 13C, and 31P NMR spec-
tra were recorded on a Varian Gemini 300 MHz NMR spectrometer
operating at 299.9 MHz (1H), 75.5 MHz (13C), and 121.7 MHz (31P).
Compounds were dissolved in DCCl3 or DMSO-d6, and chemical shifts

406
L. N. Rao et al.
were referenced to TMS (1H and 13C) or to 85% H3PO4 (31P). The
EI mass spectra data were collected on a JEOL JMSD-300 instru-
ment at 70 eV with a direct inlet system. The gas atom bombard-
ment mass spectral data were collected on a JEOL SX 102/DA-6000
system using argon/xenon (6 kV, 10 mA) as the FAB gas at RSIC,
CDRI, Lucknow, India. Both 113 and 26 were prepared by known
routes. No difficulty was experienced in manipulations of the products,
but care should be exercised in handling any nitrogen mustard-type
compound.
Preparation of 5,50-Dichloro-3,30-dinitro-
2,20-dihydroxydiphenyl Sulfide (3)
Nitric acid (7 mL, 0.1 mol) was added over 13–20 min to a stirred
solution of 5,50-dichloro-2,20-dihydroxyldiphenyl sulfide (2, 14.25 g,
0.05 mol) in acetic acid (125 mL) at 13–15 C. When the reaction
was complete (2–3 h), crude 5,50-dichloro-3,30-dinitro-2,20-dihydroxyl-
diphenyl sulfide was filtered off, washed (H2O), dried, and recrystal-
lized (ethyl acetate) to yield 3 (14.5 g, 75%), m.p. 188–189 C. IR: 3210
1
(O H), 1520, 1315, (Ar NO2) cm 1. H NMR (DMSO-d6): 7.48 (d,
2 H, J 2.6 Hz, Ar H), 8.01 (d, 2 H, J 2.7 Hz, Ar H). 13C NMR
(DMSO-d6): ppm 123.1 [C-1/10], 124.5 [C-4/40], 126.6 [C-5/50], 136.6
[C-6/60], 137.6 [C-3/30], 150.2 [C-2/20]. MS (EI) m/z (%): 380 [30, (M +
+
4)], 378 [85, (M+ + 2)], 376 [100, M+ ], 358 [20], 328 [14], 314 [22], 293
[13], 284 [17], 282 [19], 279 [17], 254 [21], 226 [20], 192 [23], 173 [26],
157 [37], 141 [17]. Anal. Calcd for C12H6Cl2N2O6S: C, 38.21: H, 1.60; N,
7.43. Found: C, 37.89; H, 1.94; N, 7.15.
Oxidation of 5,50-Dichloro-3,30-dinitro-2,20-
dihydroxydiphenyl Sulfide (3) to Sulfone 4
To sulfide 3 (3.77 g, 0.01 mol) dissolved in acetic acid (50 mL) was added
dropwise H2O2 (30%) over 10 min at 15 C. When the addition was com-
pleted, the temperature was raised to RT, and the mixture was stirred
for 2–3 h. Acetic acid was evaporated, the crude solid was washed with
water, and the final product was recrystallized (ethyl acetate) to give 4
1
(3.64 g, 86%), m.p. 197–198 C. IR: 1316 (Ar NO2), 1120 (SO2) cm
;
1H NMR (DMSO-d6): 4.21 [bs, 2 H, OH], 7.94 [s, 2 H, H-6/60, Ar H],
8.15 [s, 2 H, H-4/40, Ar H]. Anal. Calcd for C12H6Cl2N2O8S: C, 35.23;
H, 1.48; N, 6.85. Found: C, 35.12; H, 1.64; N, 6.76. Using the condi-
tions in which 3 → 5 was conducted, attempts to cyclize 4 failed even at
temperatures of 70–90 C.

Phosphocins
407
Preparation of 2,10-Dichloro-6-bis(2-chloroethyl)amino-
4,8-dinitrodibenzo[d,g][1,3,6,2]dioxathiaphosphocin (5)
N,N-bis (2-Chloroethyl)phosphoramidic dichloride (1, 1.30 g, 0.005 mol)
in dry toluene (20 mL) was added dropwise over 15 min to a stirred
solution of 3 (1.89 g, 0.005 mol) and triethylamine (1.01 g, 0.01 mol) in
dry toluene (50 mL) at 0–5 C. When the addition was complete, the
temperature was slowly raised to 55–60 C and stirring was continued
for 6 h. The mixture was cooled, filtered to remove triethylamine hy-
drochloride, and evaporated to a residue. The residue was washed with
water and recrystallized (methanol:HCCl3; 1:10) to give 5 (1.54 g, 55%),
1
m.p. 260–261 C. IR: 1345 (Ar NO2), 1270 (P O) cm
;
1H NMR
(DMSO-d6): 3.48–3.61 [m, 4 H, NCH2], 3.70–3.78 [m, 4 H, H2CCl2],
7.36–8.10 [m, 4 H, H-1/11, H-3/9, Ar H]; 13C NMR (DMSO-d6):
ppm 40.6 [H2CCl2], 47.5 [NCH2], 124.8 [C-11a/12a], 126.2 [C-3/9], 129.1
[C-2/10], 136.5 [C-1/11], 151.5 [C-4a/7a]; 31P NMR (DMSO-d6):
ppm 10.45; MS (FAB) m/z (%): 584 [13, (M+ + Na)], 562 [82, (M+
+
H)], 548 [6], 528 [10], 514 [8], 460 [13], 379 [7], 351 [6], 329 [35], 307
[98], 289 [72], 273 [25], 258 [15], 242 [17], 176 [60], 154 [100], 137 [97],
120 [35], 107 [65], 89 [60]. Anal. Calcd for C16H12Cl4N3O7PS: C, 34.13;
H, 2.15; N, 7.46. Found: C, 34.02; H, 2.08; N, 7.53.
Oxidation of 5 to 2,10-Dichloro-6-bis(2-chloroethyl)-
amino-4,8-dinitrodibenzo[d,g][1,3,6,2]-
dioxathiaphosphocin 6-Oxide (6)
To oxide 5 (1.41 g, 0.0025 mol) dissolved in acetic acid (40 mL) was added
dropwise H2O2 (30%) over 5 min at 15 C. When the addition was com-
plete, the temperature was allowed to rise slowly to RT, and the mixture
was stirred for 3 h. Excess acetic acid was evaporated from the mixture,
the crude solid was washed with water, and the final solid was recrys-
tallized (HCCl3 with hexane added to induce crystallization) to yield 6
(1.12 g, 78%), m.p. 276–278 C. IR: 1347 (Ar NO2), 1291 (P O), 1099
1
(S O) cm 1; H NMR (DMSO-d6): 3.64–4.74 [m, 4 H, NCH2], 3.84–
3.90 [m, 4 H, H2C Cl], 8.19–8.53 [m, 4 H, H-1, H-3/11, H-/9, Ar H];
13C NMR (DMSO-d6): ppm 41.4 [H2C Cl)2], 48.5 [N(CH2)2], 128.4
[C-3/9], 130.7 [C-2/10], 130.9 [C-11a/12a], 141.8 [C-1/11], 142.8 [C-4/8];
31P (DMSO-d6): ppm 18.83, 19.72. Anal. Calcd for C16H12Cl4N3O8PS:
C, 33.18; H, 2.09; N, 7.25. Found: C, 33.02; H, 1.98; N, 7.31.
Preparation of 2-Bis(2-chloroethyl)amino-2,3-dihydro-5-
thiophenoxy-1H-1,3,2-benzodiazaphosphole 2-Oxide (9)
N,N-bis(2-Chloroethyl)phosphoramidic dichloride (1, 1.30 g, 0.005 mol)
in dry toluene (20 mL) was added dropwise to a stirred solution of

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4-thiophenoxy-1,2-diphenyldiamine7 (8, 1.08 g, 0.005 mol) and triethy-
lamine (1.01 g, 0.01 mol) in dry toluene (50 mL) at 0 C. When the
addition was completed, the mixture was brought to 50–60 C and was
maintained at that temperature for 5 h with stirring. The mixture was
cooled to RT, the triethylamine hydrochloride was filtered off, and the
filtrate was gummy solid which separated was triturated with fresh
isopropyl alcohol to yield 9 (0.92 g, 46%), m.p. 210 C (dec). IR: 3385
1
N H), 1265 (P O) cm 1; H NMR (DMSO-d6): 3.17–3.26 [m, 4 H, N
(CH2)2], 3.67–3.72 [m, 4 H, H2C Cl], 6.76 [d, J 7.1 Hz, 1 H, H-7], 6.78
[s, 1 H, H-4], 6.86 [d, J 7.7 Hz, 1 H, H-6] 7.08–7.30 [m, 5 H, PhS], 8.42
[d, J 17.6 Hz, 1 H, PN H], 8.55 [d, J 17.2 Hz, 1 H, PN H]; 13C NMR
(DMSO-d6): ppm 41.2 [H2C Cl], 49.1 [NCH2], 110.5 [C-4], 114.2 [C-7],
120.8 [C-5], 125.6 [C-40/6], 126.2 [C-10], 127.4 [C-20/60], 129.1 [C-30/50],
133.8 [C-8], 138.5 [C-9]; 31P (DMSO-d6): ppm 40.64, 40.80. Anal. Calcd
for C15H18Cl2N3OPS: C, 47.77; H, 4.51; N, 10.45. Found: C, 47.98; H,
4.35; N, 10.32.
Preparation of 2-Bis(2-chloroethyl)amino-1,2,3,4-
tetrahydro-1,3,2-benzodiazaphosphorinane 2-Oxide (11)
N,N-bis(2-Chloroethyl)phosphoramidic dichloride (1, 2.59 g, 0.01 mol)
in dry toluene (25 mL) was added dropwise (20 min) to a cold (0 C) so-
lution of 2-aminobenzylamine8 (10, 1.22 g, 0.01 mol) and triethylamine
(2.02 g, 0.02 mol) in dry toluene (20 mL). After stirring for 1 h at 0 C,
the temperature of the mixture was raised slowly to 35–45 C, and
stirring was continued for 4 h. After cooling to RT, the workup was
identical to that given for 9. The white solid formed was recrystallized
(isopropyl alcohol) to give 11 (1.99 g, 65%), m.p. 165–166 C. IR: 3330
1
(PN HPh), 3210 [PN H(CH2)], 1285 (P O) cm 1; H NMR (DCCl3 +
DMSO-d6): 3.24–3.37 [m, 4 H, N(CH2)2], 3.56–3.66 [m, 4 H, H2C Cl)],
3.91–4.21 [m, 2 H, H-4], 4.75 [d, 1 H, H-3 (NH)], 6.72–7.11 [m, 4 H, H-5/
6/7/8], 7.50 [d, 1 H, H-1 (NH)]; MS (EI) m/z (%): 311 [2, (M+ + 4)], 309
[9, (M+ + 2)], 307 [17, M+ ], 271 [7.6], 258 [74], 222 [25.7], 167 [76], 149
[19.5], 119 [7.4], 97 [9.2], 85 [16.5]. Anal. Calcd for C16H16Cl2N3OP: C,
42.87; H, 5.23; N, 13.64. Found: C, 43.05; H, 5.10; N, 13.72.
Preparation of 5-Bromo-5-nitro-2-bis(2-chloroethyl)-
amino-1,3,2-dioxaphosphorinane 2-Oxide (13)
A solution of 2-bromo-2-nitro-1,3-propanediol (12, 1.00 g, 0.005 mol,
Aldrich) and triethylamine (1.01 g, 0.01 mol) in dry ether (30 mL) was
stirred and cooled to 20 C. To this solution was added dropwise over
15 min a solution of N,N-bis(2-chloroethyl)phosphoramidic dichloride

Phosphocins
409
(1, 1.30 g, 0.005 mol) in dry ether. The mixture was stirred at this tem-
perature for 4 h, and then the mixture was allowed to warm slowly to
RT. Stirring was continued for 15–20 min, after which time the mix-
ture was filtered, and the filtrate was evaporated to a gummy solid.
The solid was washed with water and cold isopropyl alcohol, and fi-
nally it was recrystallized (HCCl3-hexane) to yield 13 (0.81 g, 42%),
1
m.p. 246–248 C. IR: 1305 (P O) cm 1; H NMR (DCCl3): 3.65–4.82
[m, 8 H, N(CH2CH2Cl)2], 4.65–5.12 [m, 4 H, H-4/6, CH2]. Anal. Calcd
for C7H12BrCl2N2O5P: C, 21.78; H, 3.13; N, 7.26. Found: C, 21.92; H,
3.06; N, 7.32.
Preparation of 8-Bis(2-chloroethyl)amino-16 H-
dinaphtho[2,1-d:10,20-g]1,3,2-dioxaphosphocin 8-Oxide (15)
N,N-bis(2-Chloroethyl)phosphoramidic dichloride (1, 1.30 g, 0.005 mol)
in dry toluene (20 mL) was added dropwise (15 min) to a stirred solution
of bis(2-hydroxy-1-naphthyl)methane9 (14, 1.50 g, 0.005 mol) and tri-
ethylamine (1.01 g, 0.01 mol) in dry toluene (50 mL) at 0 C. When the
addition was completed, the mixture was warmed slowly to 50–55 C
and then was maintained at that temperature with stirring for 6 h. The
mixture was cooled to RT, filtered, and the filtrate was evaporated to
a residue. The residue was washed with water and cold isopropyl al-
cohol and then recrystallized (ethanol) to yield 15 (1.65 g, 68%), m.p.
1
208–209 C. IR: 1245 (P O) cm 1; H NMR (DMSO-d6): 3.58–3.77
[m, 8 H, N (CH2CH2 Cl)2], 4.74 [d, J 16.1 Hz, 1 H, Hb-bridged CH2],
5.18 [d, J 16.3 Hz, 1 H, Ha-bridged CH2], 7.11–8.19 [m, 12 H, Ar H];
31P NMR (DMSO-d6): ppm 6.52. Anal. Calcd for C25H22Cl2NO3P: C,
61.74; H, 4.56; N, 2.88. Found: C, 61.82; H, 4.42; N, 2.92.
ACKNOWLEDGMENTS
The authors express sincere thanks to the Directors CDRI, Lucknow,
and IISc, Bangalore, India, for spectral and elemental analyses and
the Oklahoma State University College of Arts and Sciences for salary
support (KDB). L. N. Rao is grateful to UGC for a fellowship.
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