Synthesis and Synthetic Application of α-Formylvinylphosphonates. Facile Synthesis of Phosphono-Substituted Heterocyclic Compounds

Article abstract of DOI:10.1021/jo000149t

The β-ethoxy-α-phosphonovinyl anion, generated from β-(ethoxy)vinylphosphonate 1 and LDA, reacted with aldehydes and ketones or phenyl isocyanate to give the corresponding allylic alcohols 2a - m or 1,3-diphenyl-5-phosphonouracil 4 in good or moderate yields. Treatment of the alcohols 2a - d,g,h,j with trifluoroacetic acid led to α-formylvinylphosphonates 5a - d,g,h,j in excellent yields. Synthetic application of the α-formylvinylphosphonates 5a - d,g,h to phosphono-substituted heterocyclic compounds was studied.

Full text of DOI:10.1021/jo000149t

4326
J . Org. Chem. 2000, 65, 4326-4332
Syn th esis a n d Syn th etic Ap p lica tion of
r-F or m ylvin ylp h osp h on a tes. F a cile Syn th esis of
P h osp h on o-Su bstitu ted Heter ocyclic Com p ou n d s
Ryoji Kouno, Terunobu Tsubota, Tatsuo Okauchi, and Toru Minami*
Department of Applied Chemistry, Kyushu Institute of Technology, Sensui-cho, Tobata,
Kitakyushu 804-8550, J apan
Received February 2, 2000
The â-ethoxy-R-phosphonovinyl anion, generated from â-(ethoxy)vinylphosphonate 1 and LDA,
reacted with aldehydes and ketones or phenyl isocyanate to give the corresponding allylic alcohols
2a -m or 1,3-diphenyl-5-phosphonouracil 4 in good or moderate yields. Treatment of the alcohols
2a -d ,g,h ,j with trifluoroacetic acid led to R-formylvinylphosphonates 5a -d ,g,h ,j in excellent yields.
Synthetic application of the R-formylvinylphosphonates 5a -d ,g,h to phosphono-substituted
heterocyclic compounds was studied.
Generation of various types of vinyl anions and their
novinyl anion bearing â,â-bis(alkylthio), â-alkylthio, or
â-alkyloxy substituents, and their some synthetic utiliza-
tion.8,9 As a continuation of the studies on R-phospho-
novinyl anions, we became interested in further appli-
cation of â-ethoxy-R-phosphonovinyl anion to the synthesis
of R-formylvinylphosphonates. Their general synthesis
has not, to our knowledge, been developed although the
vinylphosphonates containing the R-formyl group can be
anticipated to serve as building blocks for synthesis of
phosphono-substituted heterocyclic compounds,10 which
are expected to show biologically active or useful proper-
ties.11 We report here a convenient synthesis of R-formylvi-
nylphosphonates and synthetic application to phosphono-
containing heterocyclic compounds. We also describe the
use of the R-phosphonovinyl anion to a new type of uracil
derivatives bearing the phosphono group.
synthetic utilization have been extensively studied so
far.1 R-Heteroatom-substituted vinyl anions have often
more potential utility than the parent vinyl anions
because of their useful reactivities modified by the
presence of a heteroatom functional group in addition to
those of the vinyl anions.2 Since vinylphosphonates
containing various functional groups have been shown
to have valuable synthetic versatility3 and biological
activities,4 a wide variety of synthetic methods of func-
tionalized vinylphosphonates has been developed to date.3
Despite the attractive possibility of their synthesis via
the reaction of R-phosphonovinyl anions, which are a
family of R-heteroatom-substituted vinyl anions, with
various electrophiles, successful utilization of the car-
banions have been limited5 due to the difficulty of
generating the carbanions via deprotonation of vinylphos-
phonates with lithium reagents,6 the ease of isomeriza-
tion of the R-phosphonovinyl anions,7 etc. We have
recently reported preparation of a new type of R-phospho-
Resu lts a n d Discu ssion
Rea ction of a n R-P h osp h on ovin yl An ion w ith
Ca r bon yl Com p ou n d s. We have recently reported that
the â-ethoxy-R-phosphonovinyl anion was easily prepared
and trapped with various heteroatom electrophiles to
produce R-heteroatom-substituted vinylphosphonates.9
To extend the synthetic utility of this method, the
reaction of â-ethoxy-R-phosphonovinyl anion, generated
in situ from the vinylphosphonate 1 and lithium diiso-
propylamide (LDA), with various aldehydes or ketones
* To whom correspondence should be addressed. Tel +81-(0)93-884-
3304, Fax +81-(0)93-884-3300, e-mail minami@che.kyutech.ac.jp.
(1) See, for examples, (a) Knight, D. W. Comprehensive Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 3,
Chapter 1.6. (b) Chamberlin, A. R.; Bloom, S. H. Organic Reactions;
Paquette, L. A., Ed.; J ohn Wiley & Sons: New York, 1990; Vol. 39,
Chapter 1.
(2) For a review of R-heteroatom-substituted vinyl anions, see: (a)
Braun, M. Angew. Chem., Int. Ed. Engl. 1998, 37, 430. For the
preparation of R-hetero (B, Si, O, Se, Te)-substituted vinyl anions and
their synthetic application, see, ref 9 and references therein.
(3) For
a
review on synthetic uses of vinylphosphonates, see:
(8) For the synthesis and synthetic application of phosphonoketene
dithioacetals, see: Minami, T.; Okauchi, T.; Matsuki, H.; Nakamura,
M.; Ichikawa, J .; Ishida, M. J . Org. Chem. 1996, 61, 8132.
(9) For the synthetic application of â-oxy- or â-thio-substituted
vinylphosphonates, see: (a) Kouno, R.; Okauchi, T.; Nakamura, M.;
Ichikawa, J .; Minami, T. J . Org. Chem. 1998, 63, 6239. (b) Minami,
T.; Kouno, R.; Okauchi, T.; Nakamura, M.; Ichikawa, J . Phosphorus,
Sulfur, and Silicon 1999, 146, 689.
(10) For the synthesis of phosphono-substituted heterocyclic com-
pounds, see, for examples: (a) Yuan, C.; Huang, W.; Onnis, V. Synthesis
1993, 473. (b) Attanasi, O. A.; Filippone, P.; Giovagnoli, D.; Mei, A.
Ibid. 1994, 181. (c) Leost, F.; Chantegrel, B.; Deshayes, C. Tetrahedron
1998, 54, 6457. (d) Palacios, F.; Ochoa de Retana, A. M.; Oyarzabal, J .
Ibid. 1999, 55, 5947. (e) Schrader, T.; Steglich, W. Synthesis 1990, 1153.
(f) Loussouarn, A.; Servant, G.; Guervenou, J .; Sturtz, G. Phosphorus,
Sulfur, and Silicon 1996, 113, 275.
Minami, T.; Motoyoshiya, J . Synthesis 1992, 333.
(4) Breaker, R. R.; Gough, G. R.; Gilham, P. T. Biochemistry 1993,
32, 9125. Harnden, M. R.; Parkin, A.; Parratt, M. J .; Perkins, R. M. J .
Med. Chem. 1993, 36, 1343.
(5) For the preparation of R-phosphonovinyl anion, via conjugate
addition of nucleophiles to 1-alkynylphosphonates, see: (a) Gil, J . M.;
Oh, D. Y. J . Org. Chem. 1999, 64, 2950. via transmetalation, see: (b)
Mimouni, N.; About-J audet, E.; Collignon, N.; Savignac, Ph. Phospho-
rus, Sulfur, and Silicon 1993, 75, 99. via deprotonation of vinylphos-
phonates, see: (c) Atta, F. M.; Betz, R.; Schmid, B.; Schmidt, R. R.
Chem. Ber. 1986, 119, 472.
(6) For conjugate addition of lithium reagents to vinylphosphonates,
for example, Nagaoka, Y.; Tomioka, K. J . Org. Chem. 1998, 63, 6428
and references therein.
(7) ) For isomerization of â-alkyl-R-phosphonio- or phosphonovinyl
anion into the corresponding allyl anion, see, for examples: (a) Minami,
T.; Shikita, S.; So, S.; Nakayama, M.; Yamamoto, I. J . Org. Chem. 1988,
53, 2937. (b) Kiddle, J . J .; Babler, J . H. Ibid. 1993, 58, 3572.
(11) For biologically active phosphono-substituted heterocyclic com-
pounds, see, for example: Seto, K.; Tanaka, S.; Sakoda, R.; Sakai, T.;
Masuda, Y. EP 230944, 1987; Chem. Abstr. 1987, 107, 237009a.
10.1021/jo000149t CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/17/2000

Synthesis of Phosphono-Substituted Heterocyclics
J . Org. Chem., Vol. 65, No. 14, 2000 4327
Ta ble 1. Rea ction of r-P h osp h on ovin yl An ion w ith
Ta ble 3. Syn th esis of r-F or m ylvin ylp h osp h on a tesa ,b
Ald eh yd es or Keton esa
increased the yield up to 52-65% with high selectivity
as expected (eq 2, entries 2 and 3).
Ta ble 2. Rea ction of r-P h osp h on ovin yl An ion w ith
P h en yl Isocya n a tea
The formation of the uracil 4 can be explained by a
sequence of stepwise addition of the R-phosphonovinyl
anion to two molecules of phenyl isocyanate, intramo-
lecular conjugate addition of the resulting amide anion
to the â-carbon of the vinylphosphonate, and elimination
of an ethoxide anion. This reaction suggests a possible
method for the synthesis of various 1,3-disubstituted-5-
phosphono uracils.
Syn th esis of R-F or m ylvin ylp h osp h on a tes. In anal-
ogy to acid-catalyzed conversion of R-(hydroxymethyl)-
phosphonoketene dithioacetals into phosphonodithioacry-
lates,8 the related â-ethoxy-R-(hydroxymethyl)vinyl-
phosphonates 2 were treated under acidic conditions.
Treatment of allylic alcohol 2a with trifluoroacetic acid
in CH2Cl2 at 0 °C gave R-formyl-â-phenylvinylphospho-
nate 5a in quantitative yield (eq 3, entry 1 in Table 3).13
was carried out to give the desired allylic alcohols 2a -i
in good to quantitative yields (eq 1, entries 1-9 in Table
1).5c
R,â-Unsaturated aldehydes or ketone such as crotonal-
dehyde or 2-cyclohexen-1-one were also reacted with the
R-phosphonovinyl anion to produce exclusively the 1,2-
addition products 2j-m in good to moderate yields
(entries 10-13), and no conjugate addition product was
observed.12
We further attempted to trap the R-phosphonovinyl
anion with phenyl isocyanate instead of aldehydes and
ketones. The reaction of the R-phosphonovinyl anion with
phenyl isocyanate (1.5 equiv) under similar conditions
interestingly afforded 1,3-diphenyl-5-phosphonouracil 4
in 35% yield in addition to an expected â-ethoxy-R-(N-
phenylaminocarbonyl)vinylphosphonate 3 (17%) (eq 2,
entry 1 in Table 2). Use of excess amount of phenyl
isocyanate (1.5-5.0 equiv) in the presence of MgCl2
Similar treatment of the other allylic alcohols 2b-
d,g,h ,j readily led to R-formylvinyl or R-formyldienylphos-
phonates, 5b-d ,g,h ,j, either as E-isomer or as a mixture
of E- and Z-isomers,14 in high yields (entries 2-7 in Table
3). These results indicate that â-ethoxy-R-phosphonovinyl
anion can be considered as a convenient synthon of a
phosphonoacetaldehyde anion. This procedure has proven
to be a useful method for the synthesis of a wide range
of R-formylvinylphosphonates.15
In contrast to 2j, the closely related allylic alcohol 2k
was similarly exposed to trifluoroacetic acid (5.0 equiv)
at 0 °C to afford a 1:1 mixture of 1-formyl-1,3-pentadi-
enylphosphonate 5k and 2-methyl-5-phosphonopyran 6k
(12) Only 1,2-adduct products were produced even in the presence
of the Cu(I) salt.
(13) For acid-catalyzed conversion of (hydroxymethyl)vinyl ethers
into unsaturated aldehydes, see: (a) Vlattas, I.; Vecchia, L. D.; Lee,
A. O. J . Am. Chem. Soc. 1976, 98, 2008. (b) Lau, K. S. Y.; Schlosser,
M. J . Org. Chem. 1978, 43, 1595.
(14) The stereochemistry was determined on the basis of the
phosphorus-vinyl proton coupling constant, see: Xu, Y.; Flavin, M.
T.; Xu, Z.-Q. J . Org. Chem. 1996, 61, 7697 and references therein.
(15) For the synthesis of limited R-formylvinylphosphonates such
as 1-formyl-1-propenylphosphonate and 2-amino-1-(formyl)vinylphos-
phonate, see (a) Al-Badri, H.; About-J audet, E.; Combret, J .-C.;
Collignon, N. Synthesis 1995, 1401. (b) Aboujaoude, E. E.; Collignon,
N. Tetrahedron 1985, 41, 433.

4328 J . Org. Chem., Vol. 65, No. 14, 2000
Kouno et al.
in 92% yield.16 Furthermore, the homologous allylic
alcohol 2l on similar treatment with the acid gave a 1:4
mixture of the corresponding aldehyde 5l and phospho-
nopyran 6l in 93% yield (eq 4).17
Sch em e 1
Ta ble 4. Rea ction of r-F or m ylvin ylp h osp h on a tes w ith
The aldehydes 5 and pyrans 6 were inseparable.
Hydrogenation of each mixture of 5 and 6 over Pd/C was
carried out resulting in partially reduced 3,4-dihydro-5-
phosphono-2H-pyrans 7k 18 and 7l in 43% and 67% overall
yields from 2k and 2l, respectively, which were success-
fully isolated in pure form (eq 5).
Hyd r oxyla m in ea ,b
These results suggest that such an electrocyclic reac-
tion of 2 to give phosphonopyran derivatives requires the
alkyl substituent on the δ-carbon of the R-formyldie-
nylphosphonates.
The stereochemical assignment of 6f was made on the
The above observation prompted us to develop a new
synthesis of phosphono-containing fused pyrans via the
intramolecular hetero Diels-Alder reaction of an R-for-
mylvinylphosphonate moiety with a dialkyl-substituted
ene component.19,20 The allylic alcohol 2f, derived from
citoronellal and the R-phosphonovinyl anion, was simi-
larly treated with the acid to afford a trans-fused pyran
6f in 58% yield (eq 6). Accordingly, the formation of 6f
can be rationalized by considering that in situ generated
R-formylvinylphosphonate moiety acted as a heterodiene.
lack of an NOE between the protons at the ring fusion.
(16) Isolation of each of the products 5k and 6k in pure form was
unsuccessful, but the 5/6 ratios were determined by 1H NMR analysis
(see Experimental Section).
(17) Although contamination of a small amount of unidentified
aldehyde other than 5l was observed by 1H NMR, its isolation was
not attempted.
(18) Diethyl 1-formylpentylphosphonate, which is hydrogenation
product of 5k , was isolated in 37% yield along with 7k . The structure
was identified by comparison of spectral data with those of an authentic
sample.
(19) For intramolecular cycloadditions of 1,7-dienes with the car-
bonyl group on the C-1 carbon, see (a) Tietze, L. F.; Kiedrowski, G. v.
Tetrahedron Lett. 1981, 22, 219. (b) Minami, T.; Utsunomiya, T.;
Nakamura, S.; Okubo, M.; Kitamura, N.; Okada, Y.; Ichikawa, J . J .
Org. Chem. 1994, 59, 6717 and references therein.
(20) For hetero Diels-Alder reaction of R,â-unsaturated acylphos-
phonates with enol ethers, see, for example, Evans, D. A.; J ohnson, J .
S. J . Am. Chem. Soc. 1988, 110, 4895.
(21) (a) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734
(b) Baldwin, J . E.; Cutting, J .; Dupont, W.; Kruse, L. I. Silberman, L.;
Thomas, R. C. Ibid 1976, 736. (c) Baldwin, J . E.; Thomas, R. C.;
Cutting, J .; Dupont, W.; Kruse, L. I.; Silberman, L. J . Org. Chem. 1977,
42, 3846.
(22) Although the compound 10 is composed of a single isomer, its
stereochemical assignment was not made.
(23) For the synthesis of fluorinated pyrazoles from the reaction of
2,2-difluorovinyl ketones with hydrazines, see: Ichikawa, J .; Koba-
yashi, M.; Noda, Y.; Yokota, N.; Amano, K.; Minami, T. J . Org. Chem.
1996, 61, 2763.
(24) For the synthesis of pyrazole from the reaction of R-oxo ketene
dithioacetals with hydrazine, see, a review: Dieter, R. K. Tetrahedron
1986, 42, 3029. See also ref 15b.
Thus, an R-formylvinylphosphonate moiety was rec-
ognized to function as a novel type of phosphono-modified
heterodiene in hetero Diels-Alder reaction.
Syn th esis of P h osp h or u s-F u n ction a lized Heter o-
cycles. We have recently reported a convenient synthesis
of phosphono-substituted heterocyclic compounds via the
reaction of R-acyl-â-heteroatom-substituted vinylphos-
phonates with bifunctional heteronucleophiles.9 Having
accomplished the convenient synthesis of more reactive
R-formylvinylphosphonates as shown above, we next
focused on their synthetic application to various types
of heterocyclic compounds via condensation-intramolecu-
lar 1,4-addition sequence. â,â-Disubstituted-R-formylvi-
nylphosphonates 5g and 5h were treated with hydroxy-
lamine hydrochloride (1.2 equiv) and pyridine (1.3 equiv)
in ethanol under reflux to afford 4,5-dihydro-4-phosphono-
5,5-disubstituted isoxazoles 9g (76%) and 9h (74%),
respectively, while similar reaction using â-monosubsti-
tuted-R-formylvinylphosphonates 5a -d failed to give the

Synthesis of Phosphono-Substituted Heterocyclics
J . Org. Chem., Vol. 65, No. 14, 2000 4329
Ta ble 6. Syn th esis of P h osp h on o-Su bstitu ted
Dih yd r op yr im id in es 12 a n d 13 fr om 5 a n d Bifu n ction a l
Nu cleop h ilesa
Sch em e 2
Ta ble 5. Syn th esis of P h osp h on o-Su bstitu ted
Dih yd r op yr a zoles 11a ,b
of an amino nucleophile of initially formed hydrazones
to the â-carbon of vinylphosphonates. Treatment of 5a -
d ,g with benzamidine or S-methylisothiourea led to the
corresponding six-membered heterocyclic compounds,
2-phenyl- or 2-(methylthio)-5-phosphonopyrimidines 12a-
d ,g or 13a -d ,g in moderate to good yields (eq 9 and
Table 6).
corresponding isoxazoles and only oximes 8a -d were
formed in 53-69% yields (Scheme 1, Table 4).
Treatment of the independently prepared oxime 8g
with 1.3 equiv of pyridine in ethanol under reflux for 9 h
afforded the isoxazole 9g in quantitative yield (Scheme
2). This result demonstrates that the oxime 8g clearly
underwent the 5-endo-trigonal cyclization to give the
isoxazole 9g, although the 5-endo-trigonal cyclizations
have been generally thought to be disfavored in Baldwin’s
rules.21 Accordingly, this cyclization is of interest from
view of both synthetic and mechanistic points.
Furthermore, use of 1,2-phenylenediamine or 2-sulfa-
nylbenzenamine as a bifunctional nucleophile led to
phosphono-functionalized dihydrodiazepines 14a -d ,g15b
or dihydrothiazepines 15a -d ,g in comparable yields.
These reactions may also involve a sequence of dehydra-
tion-conjugate addition of 1,2-phenylenediamine or 2-sul-
fanylbenzenamine with R-formylvinylphosphonates 5 (eq
10 and Table 7).
For synthetic applications of the obtained phospho-
noisoxazoles, the isoxazole 9g was subjected to the
Wittig-Horner reaction with benzaldehyde to give an
expected 4-benzylidene-5,5-dimethylisoxazole 10 in good
yield (92%) (eq 7).22
Next, the reaction of 5 with various nitrogen-containing
nucleophiles carrying a group such as NH2 and SH was
similarly examined. Treatment of the R-formylvinylphos-
phonates 5a -d ,g,h with hydrazine led to the correspond-
ing 4,5-dihydro-4-phosphonopyrazoles 11a -d ,g,h in good
yields, regardless of â-substituents of the R-formylvi-
nylphosphonates (eq 8 and Table 5).23, 24
Thus, the R-formylvinylphosphonates 5 undergo cyclo-
condensation reaction with a wide variety of nitrogen
nucleophiles bearing an NH2, OH, or SH group to give
phosphono-substituted heterocyclic compounds.
Con clu sion . We note the following results from this
investigation: (1) R-phosphonovinyl anion reacted with
various types of aldehydes and ketones or an isocyanate
to afford R-(hydroxymethyl)vinylphosphonates or uracils
in good to moderate yield; (2) â-substituted R-formylvi-
nylphosphonates were easily synthesized from corre-
Similar to phosphonoisoxazoles, the formation of the
pyrazoles may be explained by 5-endo-trigonal addition

4330 J . Org. Chem., Vol. 65, No. 14, 2000
Kouno et al.
2
2
Ta ble 7. Syn th esis of P h osp h on o-Su bstitu ted
(d, J P-C ) 5.2 Hz), 68.6 (d, J P-C) 5.2 Hz), 70.6, 107.9 (d,
1J P-C) 188.1 Hz), 125.7, 126.9, 128.0, 143.4 (d, 3J P-C) 2.0 Hz),
Dih yd r od ia zep in es 14 a n d Dih yd r oth ia zep in es 15 fr om 5
a
158.3 (d, J P-C) 24.8 Hz); MS m/z 314 (M+). Anal. Calcd for
15H23O5P1: C, 57.32; H, 7.38. Found: C, 56.92; H, 7.39.
2
a n d Bifu n ction a l Nu cleop h iles
C
Rea ction of th e R-P h osp h on ovin yl An ion w ith P h en yl
Isocya n a te. P r oced u r e A. To a solution of 1 (101 mg, 0.49
mmol) in THF (5.0 mL) at -78 °C was added dropwise t-BuLi
(0.30 mL, 0.49 mmol) under a nitrogen atmosphere. After the
solution was stirred for 45 min, phenyl isocyanate (0.73 mmol)
in THF (2.0 mL) was added, and the mixture was stirred at
this temperature for 1.5 h. After similar workup as above, the
residue was purified by preparative TLC silica gel (AcOEt:
hexane ) 2:1) to give 3 (27 mg, 17%) and 4 (68 mg, 35%).
P r oced u r e B. To a solution of 1 (96.3 mg, 0.46 mmol) in
THF (5.0 mL) at -78 °C was added dropwise t-BuLi (0.28 mL,
0.46 mmol) under a nitrogen atmosphere. After the solution
was stirred for 45 min, magnesium chloride (48.4 mg, 0.51
mmol) was added. After magnesium chloride was completely
dissolved, phenyl isocyanate (2.3 mmol) in THF (2.0 mL) was
added, and the mixture was stirred at this temperature for
3.0 h. After similar workup as above, the residue was chro-
matographed on silica gel (AcOEt:hexane ) 2:1) to give 4 (120
mg, 65%). The compounds 3 and 4 had the following properties.
Diet h yl (E)-2-et h oxy-1-(N-p h en yla m in oca r b on yl)vi-
n ylp h osp h on a te (3): colorless oil; IR 1668, 1024 cm-1 1H
;
NMR δ 1.36 (6 H, t, J ) 7.0 Hz), 1.48 (3 H, t, J ) 7.0 Hz),
4.11-4.25 (4 H, m), 4.33 (2 H, q, J ) 7.0 Hz), 7.07-7.10 (1 H,
m), 7.28-7.33 (2 H, m), 7.55-7.56 (2 H, m), 7.59 (1 H, d, 3J P-H
sponding R-(hydroxymethyl)vinylphosphonates under
acidic conditions; (3) an R-formylvinylphosphonate moiety
acted as a good 4π-component in electrocyclic reaction
or hetero Diels-Alder reaction; (4) synthetic application
of R-formylvinylphosphonate to phosphono-functionalized
heterocyclic compounds was developed.
3
) 11.6 Hz), 8.78 (1 H, brs); 13C NMR δ 15.3, 16.3 (d, J P-C
)
2
1
6.2 Hz), 62.7 (d, J P-C ) 5.2 Hz), 73.1, 103.2 (d, J P-C ) 192.2
Hz), 119.8, 124.0, 128.9, 138.0, 160.7 (d, 2J P-C ) 9.3 Hz), 165.3
(d, J P-C ) 21.6 Hz); MS m/z 327 (M+); HRMS calcd for
2
C
15H22O5P1N1 327.1234 (M+); found 327.1203.
Dieh yl N,N-d ip h en yl-2,4(1H ,3H )p yr im id in ed ion o-4-
ylp h osp h on a te (4): white solid; mp 48.0-50.0 °C; IR 1729,
1
1681, 1022 cm-1; H NMR δ 1.36 (6 H, t, J ) 7.0 Hz), 4.21-
Exp er im en ta l Section
4.31 (4 H, m), 7.27-7.29 (2 H, m), 7.38-7.51 (8 H, m), 8.20 (1
3
3
H, d, J P-H ) 13.5 Hz); 13C NMR δ 16.4 (d, J P-C ) 6.3 Hz),
Ma ter ia ls. Dichloromethane was distilled from P2O5. THF
was distilled from sodium benzophenone ketyl in a recycling
still. Diisopropylamine (DIA), dimethylformamide (DMF), and
pyridine were refluxed with CaH2 and then distilled. Com-
mercial solution of BuLi (3.54 or 1.64 M in hexane) and t-BuLi
(1.64 M in pentane) were used. The starting material 1 was
prepared according to the established procedures.9
2
1
63.4 (d, J P-C ) 6.3 Hz), 103.2 (d, J P-C ) 208.7 Hz), 126.4,
128.2, 129.0, 129.4, 129.4, 129.6, 134.3, 138.4, 150.6, 151.9 (d,
2J P-C ) 15.6 Hz), 160.6 (d, J P-C ) 9.3 Hz); MS m/z 400 (M+);
2
HRMS calcd for C20H21O5P1N2 400.1187 (M+); found 400.1185.
Gen er a l P r oced u r e for th e Syn th esis of R-F or m ylvi-
n ylp h osp h on a tes 5a-d ,g,h ,j. To a solution of 2a -d ,g,h ,j (0.5
mmol) in CH2Cl2 (5.0 mL) was added trifluoroacetic acid (0.20
mL, 2.5 mmol) at 0 °C, and the mixture was stirred at this
temperature for 0.5 h. The reaction was quenched by the
addition of phosphate buffer (pH ) 7), and the organic layer
was extracted with CH2Cl2, washed with brine, dried over Na2-
SO4, and concentrated in vacuo. The residue was chromato-
graphed on silica gel (AcOEt:hexane ) 2:1) to give 5a -d ,g,h ,j.
The reaction conditions and yields of 5a -d ,g,h ,j were sum-
marized in Table 3. The compound 5j had the following
properties. The properties for compounds 5a -d ,g,h were
provided in the Supporting Information.
Gen er a l. 1H and 13C NMR spectra were obtained in CDCl3,
operating 1H NMR at 500.00 MHz, and 13C NMR at 125.65
MHz, with Me4Si as an internal standard unless otherwise
noted. Infrared spectra were recorded of thin films on KBr
plates. Mass spectra were recorded at 70 eV by GC inlet or by
direct inlet for the thermally labile products. Melting points
were measured in open capillary tubes and are uncorrected.
Gen er a l P r oced u r e for th e Syn th esis of R-(Hyd r oxym -
eth yl)vin ylp h osp h on a tes 2. To a solution of LDA, generated
in situ from DIA (0.18 mL, 1.3 mmol) in THF (5.0 mL) and
BuLi (1.64 M in hexane, 0.73 mL, 1.2 mmol) at -78 °C for 1.3
h under nitrogen atmosphere, was added dropwise a solution
of 1 (208 mg, 1.0 mmol) in THF (2.0 mL), and the mixture
was stirred at this temperature for 1.0 h. A carbonyl reagent
(1.5 mmol) was added, and the reaction mixture was stirred
for 0.5-4.0 h. The reaction was quenched by the addition of
phosphate buffer (pH ) 7), and the organic layer was extracted
with AcOEt, washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residue was chromatographed on
silica gel (AcOEt:hexane ) 2:1) to give 2. The reaction
conditions and yields of 2a -m were summarized in Table 1.
The compound 2a had the following properties. The properties
for compounds 2b-m were provided in the Supporting Infor-
mation.
Diet h yl (3E)-1-for m yl-4-p h en yl-1,3-b u t a d ien ylp h os-
p h on a te (5j): yellow oil; IR (E, Z mixture) 1683, 1608, 1577,
1
1556, 1024 cm-1; H NMR (E, Z mixture) δ 1.36 (6 H, t, J )
7.0 Hz), 4.10-4.25 (4 H, m), 7.21 (0.5 H, d, J ) 15.5 Hz), 7.22
(0.5 H, d, J ) 15.5 Hz), 7.38-7.43 (3 H, m), 7.56-7.60 (1 H,
3
m), 7.60-7.64 (1 H, m), 7.79 (0.5 H, dd, J P-H ) 20.2 Hz, J )
3
11.5 Hz), 7,79 (0.5 H, dd, J P-H ) 42.0 Hz, J ) 11.5 Hz), 8.02
4
(0.5 H, ddd, J P-H ) 2.0 Hz, J ) 11.5, 15.5 Hz), 8.19 (0.5 H,
4
3
ddd, J P-H ) 20.2 Hz, J ) 11.5, 15.5 Hz), 9.66 (0.5 H, d, J P-H
) 13.7 Hz), 10.01 (0.5 H, d, J P-H ) 10.5 Hz); 13C NMR δ 16.4
3
3
3
2
(d, J P-C ) 6.2 Hz), 16.4 (d, J P-C ) 6.2 Hz), 62.4 (d, J P-C
)
2
3
6.2 Hz), 62.5 (d, J P-C ) 5.2 Hz), 122.6 (d, J P-C ) 19.7 Hz),
3
1
124.7 (d, J P-C ) 5.2 Hz), 124.9 (d, J P-C ) 180.0 Hz), 126.9
1
Dieth yl (E)-1-eth oxy-3-h yd r oxy-3-p h en yl-1-p r op en -2-
(d, J P-C ) 177.9 Hz), 128.5, 128.6, 129.0, 129.1, 130.8, 135.1,
2
ylp h osp h on a te (2a ): colorless oil; IR 3401, 1625, 1025 cm-1
;
135.3, 149.4, 149.4, 149.8, 156.9 (d, J P-C ) 8.3 Hz), 160.6 (d,
2
2
1H NMR δ 1.13 (3 H, t, J ) 7.0 Hz), 1.19 (3 H, t, J ) 7.0 Hz),
1.33 (3 H, t, J ) 7.3 Hz), 2.14 (1 H, brs), 3.71-4.14 (6 H, m),
5.77 (1 H, dd, 3J P-H ) 23.2 Hz, J ) 8.2 Hz), 7.00 (1 H, d, 3J P-H
) 10.7 Hz), 7.19-7.23 (1 H, m), 7.29-7.32 (2 H, m), 7.43-
2J P-C ) 9.3 Hz), 188.7 (d, J P-C ) 12.4 Hz), 190.9 (d, J P-C
)
12.4 Hz). Anal. Calcd for C15H19O4P1: C, 61.22; H, 6.51. Found
(E, Z mixture): C, 61.15; H, 6.59.
Tr ea tm en t of Allylic Alcoh ol 2l w ith Tr iflu or oa cetic
Acid . To a solution of 2l (150 mg, 0.51 mmol) in CH2Cl2 (4.0
3
7.45 (2 H, m); 13C NMR δ 15.3, 16.1 (d, J P-C ) 5.2 Hz), 61.8

Synthesis of Phosphono-Substituted Heterocyclics
J . Org. Chem., Vol. 65, No. 14, 2000 4331
mL) was added trifluoroacetic acid (0.20 mL, 2.6 mmol) at 0
°C, and the mixture was stirred for 6.0 h at this temperature.
After similar workup as above, the residue was purified by
preparative TLC silica gel (AcOEt:hexane ) 1:1) to give diethyl
(1Z)-1-formyl-4-methyl-1,3-pentadienylphosphonate (5l) and
diethyl 2,2-dimethyl-2H-pyran-5-ylphosphonate (6l) as a 1:4
mixture (118 mg, 0.48 mmol, 93%): 1H NMR δ 1.31-1.35 (7.5
H, m), 1.40 (6 H, s), 2.04-2.06 (1.5 H, m), 4.01-4.15 (5 H, m),
181.9 Hz), 128.7, 129.6, 129.9, 134.3 (d, 3J P-C ) 19.6 Hz), 145.7
(d, 2J P-C ) 6.2 Hz), 148.5 (d, 2J P-C ) 7.2 Hz); MS m/z 282 (M+-
H). Anal. Calcd for C13H18O4P1N1: C, 55.12; H, 6.40; N, 4.93.
Found: C, 54.94; H, 6.30; N, 4.82.
Dieth yl 4,5-d ih yd r o-5,5-d im eth ylisoxa zol-4-ylp h osp h o-
1
n a te (9g): colorless oil; IR 1255, 1022 cm-1; H NMR δ 1.35
(3 H, t, J ) 7.0 Hz), 1.36 (3 H, t, J ) 7.0 Hz), 1.48 (3 H, s),
1.57 (3 H, s), 3.34 (1 H, dd, J ) 7.0 Hz, 2J P-H ) 23.8 Hz), 4.14-
4
3
5.24 (1 H, dd, J ) 8.5 Hz, J P-H ) 3.5 Hz), 5.85 (1 H, dd, J )
4.21 (4 H, m), 7.10 (1 H, dd, J ) 7.0 Hz, J P-H ) 2.0 Hz); 13C
3
3
3
3
8.5 Hz, J P-H ) 8.5 Hz), 7.09 (1 H, d, J P-H ) 8.5 Hz), 7.13
(0.12 H, d, J ) 12.5 Hz), 7.24 (0.12 H, d, J ) 12.5 Hz), 7.97
NMR δ 16.3 (d, J P-C ) 6.2 Hz), 16.4 (d, J P-C ) 6.2 Hz), 22.8
3 3 1
(d, J P-C ) 5.2 Hz), 28.7 (d, J P-C ) 11.4 Hz), 54.3 (d, J P-C
)
3
2
2
(0.12 H, dd, J ) 12.5 Hz, J P-H ) 43.0 Hz), 8.03 (0.12 H, dd,
147.9 Hz), 62.5 (d, J P-C ) 7.2 Hz), 62.7 (d, J P-C ) 7.2 Hz),
3
3
2
J ) 12.5 Hz, J P-H ) 15.0 Hz), 9.64 (0.12 H, d, J P-H ) 12.0
85.1, 143.3 (d, J P-C ) 6.2 Hz). Anal. Calcd for C9H18O4P1N1:
Hz), 10.09 (0.12 H, d, J P-H ) 15.0 Hz); 13C NMR δ 16.3 (d,
C, 45.96; H, 7.71; N, 5.95. Found: C, 45.89; H, 7.74; N, 5.80.
Syn th esis of Dieth yl 1-(Hyd r oxyim in o)-3-m eth yl-2-
bu ten -2-ylp h osp h on a te (8g). To a solution of hydroxylamine
hydrochloride (1.2 equiv) and pyridine (1.3 equiv) in EtOH was
added a solution of 5g in EtOH at room temperature, and the
mixture was stirred at this temperature for 2.5 h. After similar
workup as above, the residue was chromatographed on silica
gel (AcOEt:hexane ) 1:1) to give the oxime 8g (75% from 2g)
3
3J P-C ) 6.2 Hz), 19.3, 19.4, 27.7, 27.9, 28.0, 61.6 (d, J P-C
)
2
6.3 Hz), 62.2 (d, 2J P-C ) 6.2 Hz), 62.3 (d, 2J P-C ) 4.1 Hz), 77.9,
1
3
99.8 (d, J P-C ) 206.7 Hz), 117.4 (d, J P-C ) 8.2 Hz), 120.5 (d,
3J P-C ) 18.6 Hz), 123.1, 124.1 (d, J P-C ) 12.4 Hz), 124.4 (d,
2
1J P-C ) 179.4 Hz), 153.0 (d, J P-C ) 8.3 Hz), 155.6 (d, J P-C
)
2
2
22.7 Hz), 155.7 (d, 2J P-C ) 9.3 Hz), 158.2, 158.6, 188.9 (d, 2J P-C
2
) 10.4 Hz), 191.3 (d, J P-C ) 12.4 Hz). Isolation of each
1
compound as pure sample was unsuccessful.
as a colorless oil.: IR 3263, 1616, 1022 cm-1; H NMR δ 1.32
4
Hydrogenation of this mixture was accomplished under a
hydrogen atmosphere (balloon) at room temperature for 12 h
in EtOH (4.0 mL) containing palladium on activated carbon
(10%, 12 mg). After removal of the catalyst by filtration and
concentration of the filtrate in vacuo, the residue was chro-
matographed on silica gel (AcOEt:hexane ) 1:1) to give diethyl
3,4-dihydro-2,2-dimethyl-2H-pyran-5-ylphosphonate 7l (85.6
(6 H, t, J ) 7.1 Hz), 2.03 (3 H, d, J P-H ) 4.5 Hz), 2.28 (3 H,
4
3
d, J P-H ) 2.8 Hz), 4.04-4.15 (4 H, m), 7.96 (1 H, d, J P-H
)
12.5 Hz), 9.31 (1 H, brs); 13C NMR δ 16.2 (d, J P-C ) 6.2 Hz),
3
3
3
24.4 (d, J P-C ) 9.3 Hz), 24.5 (d, J P-C ) 15.6 Hz), 61.8 (d,
2J P-C ) 5.2 Hz), 117.9 (d, J P-C ) 186.2 Hz), 147.6 (d, J P-C
)
1
2
11.4 Hz), 160.1 (d, J P-C ) 8.3 Hz); MS m/z 235 (M+); HRMS
calcd for C9H18O4P1N1 235.0972 (M+); found 235.0953.
Cycliza tion of Oxim e 8g. To a solution of 8g (30.1 mg,
0.13 mmol) in EtOH (3 mL) was added pyridine (0.013 mL,
0.17 mmol) at room temperature, and the mixture was refluxed
for 9 h. After similar workup as above, the residue was
chromatographed on silica gel (AcOEt:hexane ) 1:1) to give
9g (29.8 mg, 0.13 mmol, quant), whose physical properties
were completely consistent with those of 9g obtained in the
above experiment.
2
mg, 0.34 mmol, 67%) as a colorless oil.: IR 1623, 1025 cm-1
;
1H NMR (C6D6) δ 0.98 (6 H, s), 1.10 (6 H, t, J ) 7.0 Hz), 1.22
(2 H, t, J ) 6.4 Hz), 2.10 (2 H, dt, 3J P-H ) 6.4 Hz, J ) 6.4 Hz),
3
3.91-4.04 (4 H, m), 7.49 (1 H, d, J P-H ) 11.0 Hz); 13C NMR
δ 16.5 (d, 3J P-C ) 6.2 Hz), 18.1 (d, 2J P-C ) 11.1 Hz), 26.3, 32.1
3
2
(d, J P-C ) 10.3 Hz), 61.1 (d, J P-C ) 5.3 Hz), 75.1, 98.5 (d,
1J P-C ) 198.4 Hz), 154.7 (d, J P-C ) 24.9 Hz). Anal. Calcd for
2
C
11H21O4P1: C, 53.22; H, 8.52. Found: C, 53.19; H, 8.49.
Syn th esis of Dieth yl (4a S*,6S*,8a S*)-1,1,6-Tr im eth yl-
Wittig-Hor n er Rea ction of 9g w ith Ben za ld eh yd e. To
a mixture of NaH (11.6 mg, 0.29 mmol) and benzaldehyde
(0.037 mL, 0.36 mmol) in THF (3 mL) was added a solution of
9g (56.8 mg, 0.24 mmol) in THF (1.5 mL) at 0 °C. The mixture
was allowed to warm to room temperature and stirred for 4
h. After similar workup, the residue was chromatographed on
silica gel (AcOEt:hexane ) 1:4) to give 4-benzylidene-4,5-
dihydro-5,5-dimethylisoxazole 10 (41.7 mg, 0.22 mmol, 92%)
4a ,5,6,7,8,8a -h exa h yd r o-1H -2-b en zop yr a n -4-ylp h osp h o-
n a te (6f). To a solution of 2f (102 mg, 0.28 mmol) in CH2Cl2
(5.0 mL) was added trifluoroacetic acid (0.11 mL, 1.4 mmol)
at 0 °C, and the mixture was warmed to room temperature
and stirred for 6.0 h. After similar workup as above, the
residue was purified by preparative TLC silica gel (AcOEt:
CHCl3 ) 1:1) to give diastereomerically pure phosphonopyran
6f (51 mg, 58%) as a colorless oil: IR 1727, 1027 cm-1; 1H NMR
δ 0.74-0.82 (1 H, m), 0.93 (3 H, d, J ) 6.7 Hz), 0.98-1.05 (2
H, m), 1.11 (3 H, s), 1.21-1.26 (1 H, m), 1.31 (3 H, s), 1.33 (6
H, t, J ) 7.1 Hz), 1.43-1.47 (1 H, m), 1.73-1.81 (2 H, m), 1.96-
2.00 (1 H, m), 2.26-2.28 (1 H, m), 3.97-4.12 (4 H, m), 7.08 (1
1
as a colorless oil: IR 2211, 1207 cm-1; H NMR δ 1.59 (6 H,
s), 7.36-7.45 (5 H, m), 7.74 (1 H, d, J ) 1.2 Hz), 7.76 (1 H, d,
J ) 1.2 Hz); 13C NMR δ 29.5, 72.4, 118.0, 119.6, 128.8, 128.9,
130.2, 133.3, 140.6; MS m/z 172 (M+ - CH3); HRMS calcd for
C
12H13O1N1 187.0996 (M+); found 187.0999.
3
3
H, d, J P-H ) 11.0 Hz); 13C NMR δ 16.2 (d, J P-C ) 10.3 Hz),
19.9, 22.3, 27.1, 27.1, 32.2, 33.8 (d, 2J P-C ) 6.3 Hz), 34.9, 39.1,
47.1 (d, 3J P-C ) 10.4 Hz), 61.1 (d, 2J P-C ) 16.5 Hz), 79.3, 101.6
Gen er a l P r oced u r e for th e Syn th esis of P h osp h o-
n op yr a zoles 11. To a solution of 5a -d ,g,h in EtOH was
added hydrazine monohydrate (15 equiv) at room temperature,
and the mixture was stirred for 11-26 h. After similar workup,
the residue was chromatographed on silica gel (AcOEt:MeOH
) 15:1) to give phosphonopyrazoles 11a -d ,g,h . The reaction
conditions and yields of 11a -d ,g,h were summarized in Table
5. The compound 11a had the following properties. The
properties for compounds 11b-d ,g,h were provided in the
Supporting Information.
1
2
(d, J P-C ) 192.2 Hz), 154.7 (d, J P-C ) 24.8 Hz). Anal. Calcd
for C16H29O4P1: C, 60.74; H, 9.24. Found: C, 60.49; H, 9.20.
Gen er a l P r oced u r e for th e P r ep a r a tion of Oxim es
8a -d a n d Isoxa zoles 9g,h . To a solution of hydroxylamine
hydrochloride (1.2 equiv) and pyridine (1.3 equiv) in EtOH was
added a solution of 5a -d ,g,h in EtOH at room temperature.
After the reaction mixture was stirred at reflux for 5.0-23 h,
the reaction was quenched by the addition of phosphate buffer
(pH ) 7), and the organic layer was extracted with AcOEt,
washed with brine, dried over Na2SO4, and concentrated in
vacuo. The residue was chromatographed on silica gel (AcOEt:
hexane ) 1:1) to give oximes 8a -d or isoxazoles 9g,h . The
reaction conditions and yields of 8a -d , 9g,h were summarized
in Table 4. The compounds 8a and 9g had the following
properties. The properties for compounds 8b-d , 9h were
provided in the Supporting Information.
Dieth yl 4,5-d ih yd r o-5-p h en yl-1H-p yr a zol-4-ylp h osp h o-
n a te (11a ): yellow oil; IR 1241, 1022 cm-1; 1H NMR δ 1.28 (3
H, t, J ) 7.0 Hz), 1.29 (3 H, t, J ) 7.0 Hz), 3.39 (1 H, ddd, J
) 1.8, 9.0 Hz, 2J P-H ) 21.7 Hz), 4.02-4.19 (4 H, m), 4.98 (1 H,
3
dd, J ) 9.0 Hz, J P-H ) 22.9 Hz), 6.03 (1 H, brs), 6.72 (1 H,
dd, J ) 1.8 Hz, 3J P-H ) 1.8 Hz), 7.26-7.38 (5 H, m); 13C NMR
3
3
δ 16.3 (d, J P-C ) 5.2 Hz), 16.4 (d, J P-C ) 5.2 Hz), 54.3 (d,
1J P-C ) 147.9 Hz), 62.6 (d, J P-C ) 7.3 Hz), 62.7 (d, J P-C
)
2
2
2
7.3 Hz), 64.1, 126.5, 128.2, 128.9, 136.9 (d, J P-C ) 6.2 Hz),
3
Diet h yl (E)-1-(h yd r oxyim in o)-3-p h en yl-2-p r op en -2-
ylp h osp h on a te (8a ): white solid; mp 69.0-71.0 °C; IR 3174,
141.6 (d, J P-C ) 10.3 Hz); MS m/z 282 (M+). Anal. Calcd for
C
13H19O3P1N2: C, 55.32; H, 6.79; N, 9.92. Found: C, 55.02; H,
1
1483 cm-1; H NMR δ 1.36 (6 H, t, J ) 7.0 Hz), 4.17-4.23 (4
6.79; N, 9.61.
3
H, m), 7.36-7.41 (5 H, m), 7.84 (1 H, d, J P-H ) 7.0 Hz), 8.84
Gen er a l P r oced u r e for th e Syn th esis of P h osp h o-
n op yr im id in es 12. To a solution of benzamidine hydrochlo-
ride (1.2 equiv) and pyridine (1.2 equiv) in DMF was added a
3
(1 H, d, J P-H ) 7.0 Hz), 9.76 (1 H, brs); 13C NMR δ 16.3 (d,
2
1
3J P-C ) 6.2 Hz), 62.6 (d, J P-C ) 5.2 Hz), 123.8 (d, J P-C
)

4332 J . Org. Chem., Vol. 65, No. 14, 2000
Kouno et al.
solution of 5a -d ,g in DMF at room temperature, and the
mixture was stirred at 80 °C for 11-19 h. After similar
workup, the residue was chromatographed on silica gel (CHCl3:
MeOH ) 10:1) to give phosphonopyrimidines 12a -d ,g. The
reaction conditions and yields of 12a -d ,g are summarized in
Table 6. The compound 12a had the following properties. The
properties for compounds 12b-d ,g were provided in the
Supporting Information.
summarized in Table 7. The compound 14d had the following
properties. The properties for compounds 14a -c,g were
provided in the Supporting Information.
Dieth yl 4-ter t-bu tyl-4,5-d ih yd r o-1H-1,5-ben zod ia zep in -
3-ylp h osp h on a te (14d ): yellow solid; mp 131.0-133.0 °C dec;
IR 1637, 1502 cm-1; 1H NMR δ 0.92 (9 H, s), 1.30 (3 H, t, J )
3
7.0 Hz), 1.31 (3 H, t, J ) 7.0 Hz), 3.76 (1 H, d, J P-H ) 15.3
Hz), 4.00-4.12 (4 H, m), 6.61-6.66 (2 H, m), 6.70-6.74 (1 H,
3
Dieth yl 3,4-d ih yd r o-2,4-d ip h en ylp yr im id in -5-ylp h os-
m), 6.77-6.80 (1 H, m), 7.19 (1 H, dd, J ) 7.6 Hz, J P-H
)
p h on a te (12a ): viscous oil; IR 1664, 1483 cm-1
;
1H NMR
17.1 Hz), 7.27 (1 H, brs); 13C NMR δ 16.2 (d, J P-C ) 5.2 Hz),
16.3 (d, 3J P-C ) 5.2 Hz), 28.2, 40.9 (d, 3J P-C ) 2.0 Hz), 61.3 (d,
3
(CDCl3 + 5% CF3COOD) δ 0.99 (3 H, t, J ) 7.0 Hz), 1.24 (3 H,
2
2
t, J ) 7.0 Hz), 3.61-3.69 (1 H, m), 3.84-3.95 (1 H, m), 3.98-
2J P-C ) 5.2 Hz), 61.3 (d, J P-C ) 4.1 Hz), 66.6 (d, J P-C ) 12.4
3
1
4.04 (2 H, m), 5.70 (1 H, d, J P-H ) 6.1 Hz), 7.26-7.48 (6 H,
Hz), 97.5 (d, J P-C ) 198.4 Hz), 118.7, 120.1, 120.4, 122.3,
2
m), 7.55-7.58 (2 H, m), 7.68-7.70 (2 H, m), 7.74-7.78 (1 H,
131.1, 138.1, 142.8 (d, J P-C ) 19.6 Hz). Anal. Calcd for
3
3
m); 13C NMR δ 15.3 (d, J P-C ) 7.3 Hz), 15.6 (d, J P-C ) 6.2
C17H27O3P1N2: C, 60.34; H, 8.04; N, 8.28. Found: C, 59.98; H,
7.99; N, 8.21.
2
2
Hz), 55.4 (d, J P-C ) 15.6 Hz), 64.2 (d, J P-C ) 6.2 Hz), 64.4
2
1
(d, J P-C ) 7.3 Hz), 107.7 (d, J P-C ) 208.8 Hz), 124.5, 127.4,
Gen er a l P r oced u r e for th e Syn th esis of P h osp h o-
n oben zoth ia zep in es 15. To a solution of 5a -d ,g in DMF was
added a solution of 2-sulfanylbenzenamine (1.1 equiv) at room
temperature, and the mixture was stirred for 13-37 h. After
similar workup, the residue was chromatographed on silica
gel (AcOEt:MeOH ) 15:1) to give phosphonobenzothiazepines
15a -d ,g. The reaction conditions and yields of 15a -d ,g were
summarized in Table 7. The compound 15g had the following
properties. The properties for compounds 15a -d were provided
in the Supporting Information.
2
127.5, 129.7, 130.2, 130.6, 132.6 (d, J P-C ) 18.6 Hz), 136.3,
138.8, 157.8; HRMS (FAB) calcd for C20H24O3P1N2 371.1524
(M+ + H); found 371.1543.
Gen er a l P r oced u r e for th e Syn th esis of P h osp h o-
n op yr im id in es 13. To a solution of S-methylisothiourea
sulfate (0.6 equiv) and pyridine (1.3 equiv) in DMF was added
a solution of 5a -d ,g in DMF at room temperature, and the
mixture was stirred at 80 °C for 11-27 h. After similar
workup, the residue was chromatographed on silica gel (AcO-
Et:MeOH ) 15:1) to give phosphonopyrimidines 13a -d ,g. The
reaction conditions and yields of 13a -d ,g were summarized
in Table 6. The compound 13a had the following properties.
The properties for compounds 13b-d ,g were provided in the
Supporting Information.
Diet h yl 4,5-d ih yd r o-4,4-d im et h yl-1H-1,5-b en zot h ia z-
ep in -3-ylp h osp h on a te (15g): yellow solid; mp 154.5-156.0
1
°C dec; IR 1606, 1483 cm-1; H NMR δ 1.34 (6 H, t, J ) 7.0
Hz), 1.52 (6 H, s), 4.00-4.14 (4 H, m), 6.92-6.98 (2 H, m),
7.18-7.22 (1 H, m), 7.31-7.37 (2 H, m), 8.54-8.55 (1 H, m);
13C NMR δ 16.3 (d, 3J P-C ) 7.2 Hz), 31.6, 49.1 (d, 2J P-C ) 10.3
Hz), 61.3 (d, 2J P-C ) 5.2 Hz), 105.2 (d, 1J P-C ) 185.0 Hz), 119.9,
Dieth yl 3,4-dih ydr o-2-(m eth ylth io)-4-ph en ylpyr im idin -
5-ylp h osp h on a te (13a ): white solid; mp 148.5-150.0 °C; IR
1
2
1656, 1492 cm-1; H NMR (CDCl3 + 5% CF3COOD) δ 0.94 (3
122.4, 124.2, 128.3, 134.9, 142.1 (d, J P-C ) 24.9 Hz), 144.7.
H, t, J ) 7.0 Hz), 1.23 (3 H, t, J ) 7.0 Hz), 2.60 (3 H, s), 3.52-
Anal. Calcd for C15H22O3P1N1S1: C, 55.03; H, 6.77; N, 4.28.
Found: C, 55.04; H, 6.88; N, 4.01.
2
3.60 (1 H, m), 3.81-3.89 (1 H, m), 3.97 (2 H, dq, J P-H ) 7.0
3
Hz, J ) 7.0 Hz), 5.42 (1 H, d, J P-H ) 6.7 Hz), 7.16 (1 H, d,
3J P-H ) 14.3 Hz), 7.30-7.31 (2 H, m), 7.38-7.41 (3 H, m); 13
C
Ack n ow led gm en t. We are grateful for financial
support of this work by a Grant-in-Aid for Scientific
Research (No. 10450344) from the Ministry of Educa-
tion, Science, Sports and Culture of J apan and by the
C. O. E. Research Fund of KIT. We also thank the
Center for Instrumental Analysis KIT for the use of
their facilities.
NMR δ 13.0, 15.3 (d, 3J P-C ) 7.3 Hz), 15.6 (d, 3J P-C ) 6.2 Hz),
2
2
56.0 (d, J P-C ) 14.4 Hz), 63.7 (d, J P-C ) 5.2 Hz), 63.9 (d,
2J P-C ) 6.2 Hz), 106.4 (d, 1J P-C ) 208.8 Hz), 127.4, 129.4, 130.2,
132.5 (d, J P-C ) 18.6 Hz), 138.7, 164.7. Anal. Calcd for
2
C
15H21O3P1N2S1: C, 52.93; H, 6.22; N, 8.23. Found: C, 52.57;
H, 6.34; N, 7.94.
Gen er a l P r oced u r e for th e Syn th esis of P h osp h o-
n oben zod ia zep in es 14. To a solution of 5a -d ,g in DMF was
added a solution of 1,2-phenylenediamine (1.1 equiv) at room
temperature, and the mixture was stirred for 11-17 h. After
similar workup, the residue was chromatographed on silica
gel (AcOEt:MeOH ) 15:1) to give phosphonobenzodiazepines
14a -d ,g. The reaction conditions and yields of 14a -d ,g were
Su p p or tin g In for m a tion Ava ila ble: Spectral and ana-
lytical data for compounds 2b-m , 5a -d ,g,h , 7k , 8b-d , 9h ,
11b-d ,g,h , 12b-d ,g, 13b-d ,g, 14a -c,g, 15a -d . This mate-
rialis availablefreeofchargevia theInternet at http://pubs.acs.org.
J O000149T