Photo-Arbuzov rearrangements of cyclic phosphite systems

Article abstract of DOI:10.1016/S0022-328X(01)01432-2

The direct UV irradiation of cyclic phosphites 1-4 was carried out in argon-saturated solvents. In all cases examined, the rearranged, ring-contracted Photo-Arbuzov phosphonate was the major product formed with isolated yields ranging from 40 to 50%. Thes

Full text of DOI:10.1016/S0022-328X(01)01432-2

Journal of Organometallic Chemistry 646 (2002) 239–246
www.elsevier.com/locate/jorganchem
Photo-Arbuzov rearrangements of cyclic phosphite systems
a
a,
b
Margaret S. Landis , Nicholas J. Turro *, Worawan Bhanthumnavin ,
b
Wesley G. Bentrude
a
Department of Chemistry, Columbia Uni6ersity, 3000 Broadway, New York, NY 10027, USA
b
Department of Chemistry, Uni6ersity of Utah, 315 South 1400 East, Salt Lake City, UT 84112, USA
Received 16 August 2001; accepted 8 November 2001
Abstract
The direct UV irradiation of cyclic phosphites 1–4 was carried out in argon-saturated solvents. In all cases examined, the
rearranged, ring-contracted Photo-Arbuzov phosphonate was the major product formed with isolated yields ranging from 40 to
5
0%. These phosphonate photoproducts, 5–8, represent novel, bicyclic, aromatic phosphonate systems never before described in
the literature of heterocyclic phosphorus chemistry. These compounds are of interest based on their potential application as
ring-constrained, non-hydrolyzable mimics of phosphorylated tyrosine. © 2002 Elsevier Science B.V. All rights reserved.
Keywords: Photo-Arbuzov; Phosphorylated tyrosine; Cyclic phosphite systems
proceeds also determines to what extent radical dimer-
1. Introduction
ization photoproduct (Scheme 1, bibenzyl when Ar=
Ph) is formed. The origin of this product and the theory
of the proximate radical pair intermediates involved are
thoroughly detailed elsewhere [9]. For direct irradiation
of the unsubstituted systems, the major photoproduct is
the rearranged ‘Photo-Arbuzov’ phosphonate product,
in which a new phosphorus carbon bond is formed. The
Photo-Arbuzov reaction has proven to be a useful
synthetic tool in the facile preparation of acyclic nu-
cleoside-based phosphonates [10] which have been iden-
tified as potential prodrug forms of nucleoside
antivirals.
As a class, arylphosphonate derivatives have been
shown to act as protein tyrosine kinase (PTK) in-
hibitors or more specifically, non-hydrolyzable mimics
of phosphorylated tyrosine residues [11]. PTK are of
ubiquitous importance in the regulation of many vital
cellular processes, including cellular signal transduc-
tion, growth factor signaling and glucose uptake and
metabolism [12].
The Photo-Arbuzov rearrangement of acyclic allyl,
benzyl and 1-naphthylmethyl phosphites has been stud-
ied extensively since first introduced by Bentrude, et al.
in 1988 [1]. The representative photorearrangement re-
action for both the benzyl and naphthyl systems is
detailed in Scheme 1. The rearrangement transforms
the starting phosphite into the corresponding phospho-
nate cleanly and in moderate to high yields (70–90%
when Ar=Ph). This process has been shown to occur
with predominant retention of stereochemical integrity
at the migratory alpha carbon [2] and the phosphorus
center [3] upon direct irradiation. The influence of such
factors as triplet sensitization [4] and presence of acetyl
substitution on the aromatic ring [5] on the mechanism
and multiplicity of the radical pair intermediates
through which these reactions appear to proceed, has
been found in product [6], CIDNP [7] and CIDEP
studies [8]. The manifold through which the reaction
*
Corresponding author. Tel.: +1-212-8542175; fax: +1-212-
9321289.
E-mail addresses: margaret s landis@groton.pfizer.com (M.S.
–
–
Landis), turro@chem.columbia.edu (N.J. Turro), worawanb@
chula.ac.th (W. Bhanthumnavin), bentrude@chem.utah.edu (W.G.
Bentrude).
Scheme 1. The Photo-Arbuzov rearrangement.
0022-328X/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(01)01432-2

240
M.S. Landis et al. / Journal of Organometallic Chemistry 646 (2002) 239–246
Scheme 2. Preparation of 1,5-dihydro-3-methoxy-2,4,3-benzodi-
oxaphosphepin as a representative synthetic scheme for preparation
of cyclic benzo- and naphtho-phosphite systems 1–4.
Cl PNEt produced the intermediate benzyl and naph-
2
2
thylmethyl 3-dimethylamino-1,3,2-dioxaphosphepines
which were not isolated. Immediate 1-H-tetrazole-cata-
lyzed coupling of these intermediates with one equiva-
lent of MeOH in dry acetonitrile at room temperature
produced the desired benzo- and naphtho-2-methoxy-
1
,3,2-dioxaphosphepines. The phosphites were purified
by in vacuo Kugelrohr distillation and characterized
1
31
using
H
and
P
nuclear magnetic resonance
spectroscopy.
Benzodioxaphosphepin (1) was obtained in 40% iso-
lated yield. GC–MS analysis of the distillate shows that
Fig. 1. Cyclic phosphite systems studied.
31
the material is \95% pure (m/z=198). P-NMR
analysis confirms the structural assignment of the three
coordinate symmetric cyclic phosphite system with a
In an effort to obtain information on phosphorus-
carbon biradical systems, and to extend the synthetic
scope of the Photo-Arbuzov rearrangement to prepare
bicyclic aromatic phosphonate systems not otherwise
synthetically accessible, the Photo-Arbuzov reactions of
the cyclic phosphites 1–4 were investigated.
The majority of these proposed cyclic phosphite sys-
tems have not been prepared or utilized previously in
past literature. Only the conformational aspects of the
1
characteristic chemical shift of 140.2 ppm. H-NMR
spectroscopy confirms the cyclic phosphite structural
assignment by revealing characteristic chemical shifts
1
31
and several diagnostic H– P couplings. The methoxy
protons signal at 3.5 ppm show a typical through bond
coupling to the phosphorus nuclei of 12 Hz (typical
values 10–12 Hz) [16]. The diastereotopic benzylic pro-
tons reveal chemical shifts at 4.3 and 5.6 ppm, a
geminal coupling of 13.1 Hz, and couplings to phos-
phorus of 9.8 and 10.2 Hz, respectively.
1
,5-dihydro-3-methoxy-2,3,4-benzodioxaphosphepin
system (1) have been studied previously [13,14] (Fig. 1).
Following the previously detailed two-step prepara-
tion from the racemic diol, benzodioxaphosphepin (2)
was obtained in 45% isolated yield. The Kugelrohr
distillate of 2 was 90% (GC) pure as a 6.6:1.1:1 mixture
2
. Results and discussion
2.1. Preparations of cyclic phosphites
31
of three diastereomers, as determined by P-NMR
spectroscopy, with m/z=226 (GC–MS). From the
racemic diol starting material, three diastereomers are
expected: one set containing an enantiomeric pair of
cyclic phosphites with a trans orientation of the ben-
zylic methyl groups and two different phosphorus lone
pair orientations (Fig. 2: 2c trans+enantiomer); and
two different meso systems (Fig. 2: 2a and 2b cis-meso
All cyclic phosphite systems were prepared from their
corresponding benzyl and naphthylmethyl diols in a
two step sequence. The diols are either commercially
available (1,2 benzene dimethanol) or readily acquired
by one-step reactions from commercially available
starting materials (see Section 4). The preparation of
1
,3,2-benzodioxaphosphepin is detailed in Scheme 2
1
and is representative of the conditions used to prepare
both the benzyl and naphthylmethyl 1,3,2-dioxapho-
sphepine systems studies. This route of preparation
incorporates the freedom to install various structural
features in the exocyclic substituent. Alternative one-
step preparations for these types of cyclic phosphite
systems are known [15] for the preparation of strictly
methyl substituted systems. Reaction of the diols with
and trans-meso). P-NMR spectroscopy confirms the
presence of three diastereomeric phosphites with char-
acteristic chemical shifts of 142.3, 134.0 and 128.0 ppm.
1
H-NMR spectroscopy also supports the cyclic phos-
phite structure. The methoxy protons, three doublets
centered at 3.7 ppm, show an average coupling to the
phosphorus nuclei of 10.8 Hz. Three sets benzylic pro-
tons are present as multiplets centered at 5.6 ppm.

M.S. Landis et al. / Journal of Organometallic Chemistry 646 (2002) 239–246
241
Resonances for the exocyclic methyl groups are dis-
played at about 1.5 ppm.
Preparation of the naphthodioxaphosphepin (3) and
naphthodioxaphosphocin (4) systems was desired to
allow eventual investigations of triplet energy transfer
and use of longer wavelength on direct irradiation. The
naphthodioxaphosphocin system (4) represents the
largest cyclic ring system (8-membered) of the series.
Naphthodioxaphosphepin 3, isolated in 45% overall
isolated yield following Kugelrohr distillation, was \
31
90% pure (GC–MS, m/z=248).
P-NMR spec-
troscopy confirms the symmetric cyclic phosphite
structure system with a characteristic chemical shift of
1
1
47.3 ppm. The H-NMR spectrum displays expected
2
.2. Photochemistry of Cyclic phosphites 1–4
resonances at 3.6 ppm (MeO, J=11 Hz), 4.8 and 6.18
ppm (diastereotopic 1-naphthylmethyl protons). These
protons also show a geminal coupling of 14 Hz and
couplings to phosphorus (J=13.8 and 14.7 Hz).
Naphthodioxaphosphocin 4 was obtained in 45%
overall isolated yield (\90% purity) following Kugel-
Direct irradiation of 1,5-dihydro-3-methoxy-1,5-
dimethyl-2,4,3-benzodioxaphosphepin (1) in argon-sat-
urated acetonitrile at 254 nm (Rayonet reactor) to 80%
conversion of the phosphite leads to the formation of
the ring-contracted product 3,4-dihydro-3-methoxy-1H-
3
1
rohr distillation (GC–MS, m/z=248). P-NMR spec-
troscopy is in accord with the symmetric cyclic
phosphite structure with a single resonance at 140.2
2
3
,3-benzoxaphosphorin-3-oxide (5) as shown in Scheme
. Photoconversion to the single photoproduct of m/z
of 198 was determined by GC–MS analysis. The single
photoproduct (GC) was purified by column chromatog-
raphy for an isolated yield of 40%, based on starting 1.
1
ppm. H-NMR spectroscopy confirms the structural
assignment: methoxy doublet at 3.6 ppm (J=11.5 Hz);
31
diastereotopic CH protons (6.3 and 4.75 ppm.; 7 and 9
2
P-NMR spectroscopy shows a single resonance at
Hz proton phosphorus couplings, 13 Hz geminal
coupling).
25.2 ppm, typical of the phosphonate functionality.
H-NMR confirms the cyclic phosphonate structural
1
assignment: methoxy group signal at 3.8 ppm (J=11
Hz); diasterotopic benzylic protons (CH P(O)) at 3.2
2
ppm (Hc1 and H ) as a strongly coupled, second order
c2
multiplet (small Dw/J ratio). The diastereotopic, ben-
zylic, CH OP protons (H and H ) appear at 5.3 ppm
2
d1
d2
multiplet (small Dw/J ratio) with geminal and phospho-
13
rus couplings. C-NMR spectroscopy supports the
structural with the appearance of a resonance at 26.4
ppm with a large one-bond coupling to phosphorus
(129.9 Hz); a methoxy doublet at 52.2 ppm (J=6.6 Hz)
and a benzylic ring carbon attached to oxygen at 69.9
ppm (J=7.1 Hz).
Fig. 2. Diastereomers present from synthesis of racemic 1,5-dihydro-
3-methoxy-1,5-dimethyl-2,4,3-benzodioxaphosphepin.
The photochemical quantum yield for the conversion
of 1,5-dihydro-3-methoxy-2,4,3-benzodioxaphosphepin
(
1) to 3,4-dihydro-3-methoxy-1-H-2,3-benzoxaphos-
phorin-3-oxide (5) was determined by actinometry [17]
to be 0.27, a value consistent with the quantum yields
obtained for acyclic Photo-Arbuzov rearrangements
previously [5].
Direct irradiation of the diastereomeric mixture of
racemic 1,5-dihydro-3-methoxy-1,5-dimethyl-2,4,3-ben-
zodioxaphosphepins, 2a–2c, in argon-saturated aceto-
nitrile at 254 nm (Rayonet reactor) to 80% conversion
Scheme 3. Photolysis of 1,5-dihydro-3-methoxy-1,5-dimethyl-2,4,3-
benzodioxaphosphepin (1).
(
GC) of the phosphite leads to the formation of a
mixture of new photoproducts, purified together by
column chromatography in isolated yield of 50%, pu-
rity \95% (GC). Based upon the photochemistry of 1,
photolysis of 2a–2c was expected to undergo ring con-
traction to the Photo-Arbuzov product, a mixture of
the four, isomeric, ring-contracted photoproducts, 6a–
d, shown in Fig. 3. These four phosphonate isomers
elute in three bands using the described GC analysis
(Scheme 4).
Fig. 3. Predicted diastereomers expected from photolysis of the
diastereomeric mixture of 1,5-dihydro-3-methoxy-1,5-dimethyl-2,4,3-
benzodioxaphosphepins 2a–c.

242
M.S. Landis et al. / Journal of Organometallic Chemistry 646 (2002) 239–246
3
–oxide, as shown in Scheme 5. The reaction gave a
single photoproduct (GC–MS m/z=248) which was
purified by column chromatography in 35% isolated
yield (based on total 3), \95% purity. Product struc-
3
1
13
1
tures were confirmed by P-, C- and H-NMR spec-
31
troscopy. P-NMR spectroscopy confirms the presence
of a phosphonate chemical shift at 6.4 ppm. H-NMR
1
Scheme 4. Photolysis of racemic 1,5-dihydro-3-methoxy-1,5-dimethyl-
,4,-benzodioxaphosphepin.
2
spectroscopy affirms the cyclic phosphonate structural
assignment: methoxy proton signal at 3.8 ppm (J=11
Hz); diastereotopic, benzylic phosphonate protons (Hc1
and H ) at 3.4 ppm with geminal proton and phospho-
c2
rus-proton splittings (strongly coupled multiplet result-
ing from small Dw/J ratio). The benzylic protons on the
carbon adjacent to ring oxygen (H and H ), centered
d1
d2
Scheme 5. Direct irradiation of 1,5-dihydro-3-methoxy-naphtho[2,3-
e][1,3,2] dioxaphosphepin.
at 5.3 ppm, are also diastereoptopic and show a strongly
coupled second-order pattern because of the small Dw/J
13
ratio. C-NMR spectroscopy is in accord with the
structural assignment as seen in the appearance of a
resonance at 27.5 ppm with a large one-bond coupling
to phosphorus of 126.9 Hz. Additional diagnostic peaks
include the methoxy signal at 52.5 ppm (J=6.5 Hz) and
that for the benzylic ring carbon bonded to oxygen at
7
0.0 ppm (J=6.0 Hz).
Direct irradiation 3-methoxy-1H, 5H –naphtho [1,8-
Scheme 6. Direct photolysis of 3-methoxy-1H,5H–naphtho [1,8-ef ]
[
1,3,2] dioxaphosphocine.
ef ] [1,3,2] dioxaphosphocine (4) in argon-saturated ace-
tonitrile at 300 nm (Rayonet reactor) to ꢀ80%
conversion of the phosphite leads to the formation of
the seven-membered ring-contracted product, 3,4-dihy-
dro-3-methoxy-1H-naphth [1,8-de] [1,2] oxaphosphe-
pin-3-oxide, 8, as shown in Scheme 6. Conversion to a
single photoproduct (m/z=248) was followed by GC–
MS analysis and purified by column chromatography,
isolated yield 45% (based on total 4), \95% purity.
The structure of 8 was determined by NMR spec-
The photoproduct’s phosphonate structure and pres-
31
13
ence of four isomers was confirmed using P-, C- and
1
31
H-NMR spectroscopy. P-NMR spectroscopy confi-
rms the presence of four phosphorus nuclei in a phos-
phonate setting with signals at 26.2, 24.3, 21.8 and 21.0
ppm. H nuclear magnetic resonance spectroscopy
confirms the cyclic phosphonate structural assignments:
methoxy group signals centered at 3.7 ppm as a set of
multiplets resulting from the diastereomeric mixture;
benzylic protons on the carbons of the phosphonate
1
31
troscopy. P-NMR spectroscopy shows the presence of
1
a phosphonate moiety at 34.6 ppm. H-NMR spec-
troscopy confirms the cyclic phosphonate structural
assignment: methoxy signal at 3.7 ppm (J=10.9 Hz);
diastereotopic benzylic protons on the carbon bonded
(
C–P) moiety as a multiplet centered at 3.2 ppm; a
multiplet centered at 5.3 ppm for the benzylic protons
1
3
next to oxygen. C nuclear magnetic resonance spec-
troscopy supports the structural with the appearance of
four phosphonate–carbon resonances at 31.4, 31.5, 31.6
and 32.6 ppm with large one-bond couplings to phos-
phorus (J=129.8, 131.7, 129.6 and 128.4 Hz, respec-
tively) a set of doublets (J ca. 6.6 Hz) for the methoxy
signals at 52.2 ppm; and signals for benzylic ring car-
bons attached to oxygen centered at 69.9 ppm with
coupling values of about 7.1 Hz. The four photoprod-
ucts were formed in a diastereomeric product ratio of
to phosphorus (Hc1 and H ) at 3.28; diastereotopic
benzylic protons on the carbon bonded to ring oxygen
c2
(
Hd1 and H ) at 5.5 ppm. Both sets of benzylic protons
d2
show a strongly coupled second order pattern because
13
of the small Dw/J ratio. C-NMR spectroscopy affirms
the structural assignment: peak at 32.7 ppm (J=127.9),
benzylic carbon bonded to phosphorus; benzylic C–O
carbon at 70.4 ppm (J=4.5 Hz); methoxy signal at 52.9
ppm (J=7.1 Hz).
13
ꢀ
1:2:2:4 as determined by C nuclear magnetic reso-
nance spectroscopy.
Direct irradiation of 1,5-dihydro-3-methoxy-naphtho
3
. Conclusions
[2,3-e] [1,3,2] dioxaphosphepin, 3, in argon-saturated
It has been shown previously that the Photo-Arbuzov
acetonitrile at 300 nm (Rayonet reactor) to ꢀ80%
consumption (GC) of the phosphite leads to the forma-
tion of the ring-contracted product, 3,4-dihydro-3-
methoxy-1H-naphth [2,3-d] [1,2] oxaphosphorin-
rearrangement of acyclic benzyl and 1-naphthylmethyl
phosphites is a useful and facile synthetic procedure to
produce biologically interesting acyclic benzylphospho-
nates not easily accessible through traditional thermal

M.S. Landis et al. / Journal of Organometallic Chemistry 646 (2002) 239–246
243
synthetic routes. In this report, it is shown that this
straightforward synthetic photochemical protocol can
also be applied to readily available cyclic benzyl and
naphthylmethyl phosphites to produce novel bicyclic
phosphonate heterocycles. This hitherto unstudied vari-
ation of the Photo-Arbuzov rearrangement involves a
formation of 3,4-dihydro-3-methoxy-1H-2,3-benzoxa-
phosphorin-3-oxide from 1,5-dihydro-3-methoxy-2,4,3-
benzodioxaphosphepin was determined at 254 nm with
argon saturated acetonitrile solutions of ca. 0.3 M. Sets
of 18 mm diameter quartz tubes, each containing a
concentric 8 mm diameter quartz test tube, were irradi-
ated in a Rayonet apparatus equipped with a Merry-go-
round system. Prior to quantum yield determinations, it
was shown that the actinometer system exhibited a
linear response in the time range and light intensities
utilized for described photolytic experiments.
1,2-migration of carbon from oxygen to phosphorus
that results in a ring contraction. Further work is
underway to determine if these novel bicyclic phospho-
nates exhibit favorable activity as PTK inhibitors.
These cyclic systems have potentially different biologi-
cal activities and binding abilities from their acyclic
counterparts due to the constrained geometries of the
ring atoms and fixed orientation of the phophonate
moiety, a difference previously reported in comparisons
of cyclic and acyclic analogs [18].
4.3. General procedure for photolysis of benzylic
phosphites
An argon-saturated acetonitrile solution of the phos-
phite (ca. 0.1 M) was irradiated at 254 through septum-
sealed quartz test tube (ꢀ8 ml×4 tubes) in a Rayonet
photochemical apparatus. Agitation of the quartz test
tubes was accomplished using a turning mechanism
derived from a Kughelrohr system. Irradiations were
run until ca. 80% of phosphite was consumed (GC).
The photolysate was concentrated on a rotary evapora-
tor and pre-purified by column chromatography on
neutral alumina–florisil–silica gel layered column
(1:1:8) using 2% methanol in dichloromethane as elu-
ent. The compound was then subjected to HPLC purifi-
cation as outlined below.
4. Experimental
4.1. General
Anhydrous tetrahydrofuran (Aldrich) dichloro-
methane (Aldrich), diethyl ether (Fisher), methanol
Aldrich), and benzene (Aldrich) were used as received.
Prior to use in photochemical experiments, acetonitrile
Fisher spectrophotometric grade) was distilled from
calcium hydride. 1,8-Naphthalic anhydride (Acros), 1,
-benzene dimethanol (Aldrich), 1,2-benzene dicarbox-
(
(
2
aldehyde (Aldrich), phosphorus trichloride (Aldrich
gold label), triethylamine (Aldrich), 1-H-tetrazole, 2,3-
naphthalene dicarboxylic acid and azoxybene (Lan-
4.4. General procedure for photolysis of naphthyl
phosphites
1
13
31
caster) were used as received. H, C, and P-NMR
The phosphites (ca. 0.1 M in argon saturated acetoni-
trile) were irradiated at 300 nm in a sealed Pyrex test
tube in a Rayonet photochemical apparatus. Solutions
were magnetically stirred. Irradiation time and work-up
procedures are similar to the procedure above. The
compound was then subjected to HPLC purification as
outlined below.
spectra were obtained in CDCl , C D , DMSO-d and
3
6
6
6
CD CN on a Varian VXR-200 or Unity 300 instru-
3
1
13
ment. H and C chemical shifts are reported in parts
per million (ppm) relative to internal tetramethylsilane.
3
1
P chemical shifts are referenced to external 85% phos-
phoric acid. J values listed refer to proton-proton cou-
plings unless otherwise indicated. The purity of starting
materials, synthetic intermediates, products and the
progress of photolytic experiments were assayed using a
Hewlett–Packard 5890 gas chromatograph equipped
with a HP-1 cross-linked methyl siloxane column (25×
4.5. HPLC purification of phosphonates
The crude compound was dissolved in 1–2 ml of the
intended HPLC solvent system. The solution was
®
0.2×0.33 mm) and a flame ionization detector. GC–
filtered through a Millex -HV13 (0.45 mm, 13 mm di-
MS data was obtained on a Hewlett–Packard 5890
series II-Plus gas chromatograph equipped with a
Hewlett–Packard 5972 series mass selective detector,
HP-5 cross-linked 5% PhMe silicone column, and a
thermal conductivity detector.
ameter) filter unit. Eluent (isocratic conditions) was
1.2% methanol in chloroform (HPLC grade, Mallinck-
rodt or EM Science) on a 21.4 mm ID preparative
®
Dynamax HPLC column (100 A
,
spherical Microsorb
packings, 5 mm particle size) equipped with UV detec-
−
1
tor. Optimum flow rates were 10–16 ml min
.6. Et NPCl2
.
4.2. Actinometry
4
2
Actinometry was done using the azoxybenzene/2-hy-
droxy-azobenzene chemical actinometer system de-
scribed by Bunce et al. [17]. The quantum yield for the
Et NPCl was prepared routinely from diethylamine
2 2
(11.73 g, 16.6 ml, 160.5 mmol) and PCl (11.02g, 7 ml,
3

244
M.S. Landis et al. / Journal of Organometallic Chemistry 646 (2002) 239–246
8
0.2 mmol) in 76% yield. Spectroscopic data was con-
The reaction was typically followed by GC. Upon
1
sistent with that reported in the literature [19]. H-
NMR (200 MHz, CDCl ): l 3.3 (dq, JPH=13.2, J=7
Hz, 4 H), 1.18 (t, J=7 Hz, 6 H); P-NMR (121 MHz,
C D ): l 163.8.
completion, the acetonitrile solvent was removed in
vacuo, and the crude material was purified by bulb to
bulb distillation.
3
3
1
6
6
4.11. 1,5-Dihydro-3-methoxy-2,4,3-benzodioxa-
4.7. 1,2-Bis-(1-hydroxyethyl)-benzene
phosphepin (1)
1
,2-Benzene dicarboxaldehyde (1.3 g, 9.7 mmol) was
Bulb to bulb vacuum distillation afforded the title
1
dissolved in THF (100 ml), flushed with argon, sealed
with a rubber septum and cooled to 0 °C. Methyl
magnesium bromide (2.2 equivalents, 7.1 ml of 3 M
solution in THF) was added slowly dropwise to the
cooled, stirred solution. The reaction was allowed to
warm to room temperature (r.t.) and stirred at r.t. for 2
h. The reaction was added to dilute aqueous acid, and
the aqueous layer was extracted with chloroform (5×
compound in 40% yield. H-NMR (200 MHz, C D ) l
6
6
6.7–7.0 (m, 4 H), 5.6 (dd, J=13.1 Hz JPH=10.2 Hz, 2
H), 4.3 (dd, J=13.1 Hz JPH=9.8 Hz, 2 H), 3.46 (d,
1
3
JPH=12 Hz, 3 H); C-NMR (75 MHz, C D ): l
6
6
31
129.59, 129.08, 118.26, 64.50, 42.65; P-NMR (121
MHz, C D ) 140.2 ppm; GC–MS (EI) m/z (relative
6
6
+
intensity) 198 [M] (35), 183 (3), 168 (6), 153 (9), 104
(100), 91 (16), 78 (26), 65 (9), 63 (7), 51(6).
25 ml). The organic layer was dried over MgSO4,
filtered and concentrated on a rotary evaporator. The
residue was purified via silica gel chromatography using
4.12. 3,4-Dihydro-3-methoxy-1H-2,3-benzoxaphos-
phorin-3-oxide (5)
5
0:50 ethyl actetate:hexanes. The diol was isolated (1.1
1
g) as a clear thick oil in 70% yield. H-NMR (200 MHz,
The benzoxaphosphorin 3-oxide 5 was obtained from
after photolysis of 1 under standard conditions in ar-
gon-saturated acetonitrile (ca. 0.1 M) at 254 nm. The
pholysate was concentrated on a rotary evaporator and
purified. The phosphonate, a thick yellow oil, was
obtained by column chromatography on neutral alu-
mina–florisil–silica gel layered column (1:1:8) using 2%
methanol in methylene chloride as eluent in 40% yield.
Recrystallization from dichloromethane–pentane re-
sulted in off-white crystals, melting point (m.p.) 53–
CDCl ) l 7.45 (m, 2 H), 7.25 (m, 2 H), 5.2 (q, J=6.4
Hz, 2 H), 2.75 (s, 2 H), 1.5 (d, J=6.4 Hz, 6 H).
3
4.8. 2,3-Naphthalene dimethanol
2,3-Naphthalene Dimethanol was prepared from 2,3-
naphthalenedicarboxylic according to the procedure of
Altman et al. [20].
31
1
4.9. 1,8-Naphthalenedimethanol
55 °C. P-NMR (121 MHz, CDCl , { H}) l 25.24;
3
1
H-NMR (300 MHz, CDCl ) l 3.12–3.34 (m, 2 H),
3.78 (d, 3 H, JPH=11.0 Hz), 5.21–5.40 (m, 2 H),
7.10–7.29 (m, 4 H); C-NMR (75 MHz, CDCl , { H})
l 26.36 (d, J =129.9 Hz), 52.24 (d, JPC=6.6 Hz),
3
3
1,8-Naphthalenedimethanol was prepared according
13
1
to the procedure of Boekelhiede [21].
3
1
2
PC
2
4.10. General procedure for preparation of cyclic
69.96 (d, JPC=7.1 Hz), 125.36 (d, JPC=1.5 Hz),
phosphites from diol precursors
127.28, 128.28 (d, JPC=2.0 Hz), 129.61 (d, JPC=8.1
Hz), 130.65 (d, JPC=14.6 Hz), 132.48 (d, JPC=11.1
−
1
A 0.01–0.05 M solution of the requisite diol and two
molar equivalents of anhydrous triethylamine in anhy-
drous ether/THF was added dropwise over a 1 h period
to a solution of the diethylamino-phosphorus dichloride
in diethyl ether or diethyl ether/THF (0.01–0.05 M) at
Hz); IR (neat, cm ) 3400 (br.), 1240, 1250, 1060;
+
GC–EIMS (70eV) m/z (relative intensity) 198 [M]
(96), 183 (26), 120 (100), 119 (62), 104 (74), 91 (32), 77
+
(15); HRMS (EI) m/z [M] Calc. for C H O P:
9
11
3
198.0446. Found: 198.0440. Anal. Calc. for C H O P:
9
11
3
−
78 °C under a dry, argon atmosphere. A white pre-
C, 54.55; H, 5.60. Found: C, 54.26; H, 5.65%.
cipitate of triethylamine hydrochloride was formed. The
reaction was allowed to warm to r.t. over a period of
4.13. 1,5-Dihydro-3-methoxy-1,5-dimethyl-2,4,3-
benzodioxaphosphepin (2a–2c)
1
–2 h. The reaction mixture was filtered through a
coarse sintered glass funnel under an argon atmo-
sphere, and the resulting ether solution was concen-
trated under high vacuum. The resulting oily residue
was taken up in enough anhydrous acetonitrile to pre-
pare a 0.2 M solution of the phosphoramidite. A cata-
lytic amount (ca. 0.1 equivalent) of 1H-tetrazole and
one molar equivalent of anhydrous methanol were
added, and the solution was stirred at r.t. overnight.
The phosphite was obtained after bulb to bulb
vacuum distillation of the crude phosphite from the
procedure stated above to yield the title compound in
1
45% yield. H-NMR (200 MHz, CHCl ) l 7.4 (m, 4 H),
3
5.6 (m, 1 H), 3.7 (m, 3 H), 3.2 (m, 1 H), 1.5 (m, 6 H);
31
P-NMR (121 MHz, C D ): l 142.34 134.0, 128.0
6
6
(6.6:1.1:1 mixture of diastereomers); GC–MS (EI) m/z

M.S. Landis et al. / Journal of Organometallic Chemistry 646 (2002) 239–246
245
+
®
(
(
5
relative intensity): 226 [M] (16), 211 (9), 182 (12), 152
5), 131 (25), 117 (100), 103 (10), 91(21), 77 (16), 65 (5),
1(6).
M in concentration) at 300 nm in a sealed Pyrex test
tube in a Rayonet apparatus by the standard proce-
dure. The phosphonate was obtained as a waxy white
solid after column chromatography on neutral alu-
mina–florisil–silica gel layered column (1:1:8), using
4% methanol in methylene chloride as eluent, in 35%
yield. The compound was further purified by prepara-
tory HPLC as described earlier. Recrystallization from
dichloromethane–pentane resulted in off-white crystals,
4
.14. 3,4-Dihydro-3-methoxy-1,4-dimethyl-1H-2,3-
benzoxaphosphorin-3-oxide (6a–6d)
3
,4-Dihydro-3-methoxy-1,4-dimethyl-1H-2,3-ben-
zoxaphosphorin-3-oxide, a thick slightly yellow oil, was
obtained by irradiation of 1,5-dihydro-3-methoxy-1,5-
dimethyl-2,4,3-benzodioxaphosphepin in argon satu-
rated acetonitrile (ca. 0.1 M) at 254 nm in a quartz cell
in a Rayonet apparatus by the standard procedure.
Column chromatography on neutral alumina–florisil–
silica gel layered column (1:1:8) using 2% methanol in
methylene chloride as eluent afforded 6a–6d in an
average yield of ca. 50%. Further purification by HPLC
3
1
1
m.p. 90–92 °C. P-NMR (121 MHz, CDCl , { H}) l
26.41; H-NMR (300 MHz, CDCl ) l 3.34–3.53 (m, 2
H), 3.76 (d, 3 H, JPH=11.0 Hz), 5.30–5.36 (m, 2 H),
7.47–7.54 (m, 2 H), 7.67 (d, 2 H, J=11.0 Hz), 7.78–
7.82 (m, 2 H); C-NMR (75 MHz, CDCl , { H}) l
27.46 (d, J =126.9 Hz), 52.55 (d, JPC=6.5 Hz),
70.0 (d, JPC=6.0 Hz), 125.1 (d, JPC=1.5 Hz), 126.59,
126.82, 127.31, 127.71, 127.87 (d, JPC=8.6 Hz), 128.99
(d, JPC=13.6 Hz), 130.87, (d, JPC=10.1 Hz), 132.12,
133.13; GC-EIMS (70eV) m/z (rel intensity) 248 [M]
(100), 233 (17), 170 (88), 169 (39), 154 (20); HRMS (EI)
m/z [M] Calc. for C H O P: 248.0602. Found:
248.0596. Anal. Calc. for C H O P: C, 62.91; H, 5.28.
3
1
3
3
13
1
3
1
2
PC
2
31
yielded a colorless oil as a mixture of isomers. P-
1
+
NMR (121 MHz) C D , { H}) l 21.0, 21.8, 24.3, 26.2;
6
6
1
H-NMR (200 MHz, C D ) l 1.6 (m, 6 H), 3.2 (m, 1
6
6
+
H), 3.7 (m, 3 H), 5.6 (m, 1 H), 7.0–7.4 (m, 4 H);
13
13
3
1
3
1
C-NMR (75 MHz, CDCl , { H}) l 12.8, 12.9, 14.4,
3
13 13 3
1
2
1
1
7
1
1
1
4.5, 14.7, 16.2, 16.3, 18.0, 18.1, 21.6, 21.8, 22.8, 22.9,
Found: C, 62.77; H, 5.23%.
1
1
4.3, 26.0, 31.4 (d, J =129.8 Hz), 31.5 (d, JPC=
PC
1
1
31.7 Hz), 31.6 (d, J =129.6 Hz), 32.6 (d, JPC=
4.17. 3-Methoxy-1H, 5H–naphtho[1,
8-ef ][1,3,2]dioxaphosphocine (4)
PC
28.4 Hz), 51.7, 51.8, 52.0, 52.1, 52.2, 52.6, 75.3, 75.4,
6.9, 77.1, 77.5, 77.6, 78.3, 78.4, 125.0, 125.5, 125.7,
26.2, 126.4, 126.6, 127.0, 127.1, 127.3, 127.5, 127.6,
29.1, 129.4, 129.6, 130.2, 130.3, 135.3, 135.4, 136.6,
The crude phosphite, obtained by the standard
method, was used in the subsequent photoreactions
without further purification. The compound was ꢀ
−
1
36.7, 136.9, 137.0, 137.3, 137.5; IR (neat, cm ) 3400
br.), 1240, 1250, 1060; GC–EIMS (70 eV) m/z (relative
1
(
90% pure and obtained in 45% yield. H-NMR (200
+
intensity) 226 [M] (63), 211 (89), 148 (33), 133 (100),
MHz, C D ) l 7.4–8.0 (m, 6 H), 6.3 (dd, J=13 Hz,
6
6
+
117 (55), 91 (10); HRMS (EI) m/z [M] Calc. for
JPH=9 Hz, 1 H), 4.75 (dd, J=13 Hz, JPH=7 Hz, 1
31
C H O P: 226.0759. Found: 226.0733. Anal. Calc. for
C H O P: C, 58.37; H, 6.67. Found: C, 58.41; H,
H), 3.6 (d, JPH=11.5 Hz, 3 H); P-NMR (121 MHz,
C D ) d 140.2; GC–MS (EI) m/z (relative intensity):
1
1
15
3
1
1
15
3
6
6
+
6.68%.
248 [M] (32), 233 (20), 203 (4), 187 (8), 169 (12), 153
100), 141 (20), 116 (16), 76 (12), 63 (8), 51 (3).
(
4.15. 1,5-Dihydro-3-methoxy-naphtho[2,5–e][1,3,2]-
dioxaphosphepin (3)
4.18. 3-Methoxy-3-oxo-1,4-dihydro-naphth[2,3-d][1,2]-
oxaphosphorin (8)
The crude phosphite, ꢀ90% pure, was obtained in
1
4
6
(
5% yield. H-NMR (200 MHz, C D ) l 7.6-8.1 (m,
The title compound was obtained by irradiation of
3-methoxy-1H, 5H–naphtho [1,8-ef ] [1,3,2] dioxaphos-
phocine (4) in argon saturated acetonitrile (ca. 0.1 M)
at 300 nm in a sealed pyrex test tube in a Rayonet
apparatus by the standard method. The phosphonate
was obtained as a waxy solid in 45% yield after column
chromatography on neutral alumina–florisil–silica gel
layered column (1:1:8) using 2% methanol in methylene
chloride eluent. Further purification by HPLC,
followed by recrystallization from dichloromethane–
pentane, resulted in white needles, m.p. 40–42 °C.
6
6
H), 6.18 (dd, J=13.94 Hz, JPH=13.8 Hz, 1H), 4.75
dd, J=14 Hz, JPH=14.7 Hz, 1H), 3.6 (d, JPH=11
Hz, 3H); P-NMR (121 MHz, C D ): l 147.3; GC–
MS (EI) m/z (relative intensity) 248 [M] (19), 233 (6),
70 (32), 154 (100), 139 (17), 115 (22), 76 (20), 63 (7), 51
3).
3
1
6
6
+
1
(
4
.16. 3,4-Dihydro-3-methoxy-1H-naphth[2,3-d][1,2]-
oxaphosphorin-3-oxide (7)
31
1
1
3
,4-Dihydro-3-methoxy-1H-naphth[2,3-d][1,2]oxa-
phosphorin-3-oxide (7) was obtained from photolysis of
,5-dihydro-3-methoxy-naphtho [2, 3–e] [1, 3, 2]
dioxaphosphepin in argon-saturated acetonitrile (ca. 0.1
P-NMR (121 MHz, CDCl , { H}) l 34.63; H-NMR
3
3
(300 MHz, CDCl ) l 3.74 (d, 3 H, JPH=10.9 Hz),
3
1
3.77–4.00 (m, 2 H), 5.48 (m, 2 H), 7.37–7.46 (m, 4 H),
13
1
7.79–7.88 (m, 2 H); C-NMR (75 MHz, CDCl , { H})
3

246
M.S. Landis et al. / Journal of Organometallic Chemistry 646 (2002) 239–246
1
2
[
8] I.V. Koptyug, N.D. Ghatlia, G.W. Sluggett, N.J. Turro, S.
Ganapathy, W.G. Bentrude, J. Am. Chem. Soc. 117 (1995)
486–9491.
l 32.74 (d, J =127.9 Hz), 52.89 (d, JPC=7.1 Hz),
7
PC
2
0.42 (d, JPC=4.5 Hz), 125.10, 126.06 (d, JPC=1.5
Hz), 127.17 (d, JPC=7.6 Hz), 128.54 (d, JPC=1.5 Hz),
29.27 (d, JPC=3.0 Hz), 130.54 (d, JPC=2.0 Hz),
9
[
9] W. Bhanthumnavin, W.G. Bentrude, J. Org. Chem. 66 (2001)
1
980–990.
1
30.56 (d, JPC=12.6 Hz), 132.36, 135.39 (d, JPC=2.5
[10] (a) K.B. Mullah, W.G. Bentrude, Nucleosides Nucleotides 13
(1994) 127–153;
+
Hz); GC–EIMS (70 eV) m/z (rel intensity) 248 [M]
+
(b) A.E. Sopchik, X.-Y. Jiao, W.G. Bentrude, Phosphorus,
Sulfur Silicon Relt. Elem. 144–146 (1999) 373–376;
(
13), 153 (39), 152 (100); HRMS (EI) m/z [M] Calc.
for C H O P: 248.0602, Found: 248.0610. Anal. Calc.
for C H O P: C, 62.91; H, 5.28. Found: C, 62.78; H,
1
3
13
3
(
9
(
c) G.S. Jeon, W.G. Bentrude, Tetrahedron Lett. 39 (1998)
27–930;
d) K.B. Mullah, T.S. Rao, J. Balzarini, E. De Clercq, W.G.
Bentrude, J. Med. Chem. 35 (1992) 2728–2735;
e) K.B. Mullah, W.G. Bentrude, J. Org. Chem. 56 (1991)
218–7224.
1
3
13
3
5.20%.
(
7
Acknowledgements
[
11] (a) T.R. Burke Jr., L. Zhen-Hong, J.B. Bolen, V.E. Marquez, J.
Med. Chem. 34 (1991) 1577–1581;
(
b) T.R. Burke Jr., B. Lim, V.E. Marquez, Z.-H. Li, J.B. Bolen,
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The authors would like to thank the National Science
Foundation for financial support of M.S.L. in the form
of a Graduate Research Fellowship and the N.I.H.
(
(
W.G.B.) for a research grant. Columbia University
(
and the University of Utah are also thanked for their
financial support of this work, as well as the NST fpr a
grant to NJT (CHE-98-12676).
(d) T.R. Burke Jr., B. Ye, M. Akamatsu, H. Ford Jr., X. Yan,
H.K. Kole, G. Wolf, S.E. Shoelson, P.P. Roller, J. Med. Chem.
3
(
9 (1996) 1021–1027;
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1
(
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