Continuous-flow generation of diazoesters and their direct use in S-H and P-H insertion reactions: Synthesis of α-sulfanyl, α-sulfonyl, and α-phosphono carboxylates

Article abstract of DOI:10.1016/j.tet.2013.01.020

The synthesis of α-sulfanyl, α-sulfonyl, and α-phosphono carboxylates has been achieved using a two-step procedure involving the in-flow generation of diazoesters from sulfonylhydrazones, via Bamford-Stevens elimination, and then subsequent S-H, sulfinate

Full text of DOI:10.1016/j.tet.2013.01.020

Tetrahedron 69 (2013) 2276e2282
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Continuous-flow generation of diazoesters and their direct
use in SeH and PeH insertion reactions: synthesis of
a-sulfanyl,
a
-sulfonyl, and
a-phosphono carboxylates
,
Hannah E. Bartrum a, David C. Blakemore b, Christopher J. Moodya
,
*
,
Christopher J. Hayes a
*
a School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
b Pfizer Neusentis, The Portway Building, Granta Park, Cambridge CB21 6GS, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of
a
-sulfanyl,
a-sulfonyl, and
a
-phosphono carboxylates has been achieved using a two-
Received 13 November 2012
Received in revised form 21 December 2012
Accepted 8 January 2013
step procedure involving the in-flow generation of diazoesters from sulfonylhydrazones, via Bam-
fordeStevens elimination, and then subsequent SeH, sulfinate, and PeH carbene insertion reactions. The
method for
a-sulfonyl ester is particularly noteworthy as it represents a very atom economic (‘green’)
Available online 12 January 2013
way to access the products, and it completely avoids the use of alkyl halides.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Diazoester
Metal carbenoid
SeH Insertion
PeH Insertion
Continuous flow
1. Introduction
Both a-sulfonyl- and a-phosphonyl carboxylates are useful re-
agents in organic synthesis, participating in important reactions,
such as olefination.1e5 The reagents are usually obtained from the
parent carboxylate by
a-halogenation, and subsequent reaction of
the -haloester with a thiol, followed by S-oxidation, or with a tri-
a
alkyl phosphite under Arbusov conditions. We now report a new
unified approach to these important reagents utilizing metal car-
bene XeH insertion reactions.6e8
We recently reported the development of a highly efficient and
safe in-flow process for the synthesis of diazoesters from arylsul-
fonylhydrazones via a BamfordeStevens reaction.9 Furthermore,
we demonstrated that a two-step procedure could be employed in
which the in-flow generated diazoesters were directly converted
into a range of different a-alkoxy- and a-amino-acid derivatives by
OeH and NeH carbene insertion reactions, respectively. We now
report further development of this methodology to embrace the
much less common SeH, sulfinate, and PeH carbene insertion re-
Scheme 1. In-flow preparation of diazoesters and subsequent use in carbene SeH
insertion (path A), sulfinate insertion (path B), and PeH insertion (path C).
actions as a route to
a-sulfanyl (path A), a-sulfonyl- (path B), and
a-phosphonyl carboxylates (path C) (Scheme 1).
2. Results and discussion
Our studies began by preparing the required arylsulfonylhy-
* Corresponding authors. E-mail addresses: c.j.moody@nottingham.ac.uk
(C.J. Moody), chris.hayes@nottingham.ac.uk (C.J. Hayes).
drazone precursors 1aeg (Scheme 2) via the condensation of
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.020

H.E. Bartrum et al. / Tetrahedron 69 (2013) 2276e2282
2277
a The CFC reactor was maintained at 99 oC for sulfonylhydrazone 1d; b Alkene 6 produced in 95% (see
Scheme 4).
Scheme 2. SeH Insertion reactions of sulfanylphenol and 4-toluenesulfinic acid. [Ar¼4-Tolyl unless otherwise stated. 1a, R1¼Ph, R2¼Me; 1b, R1¼Ph, R2¼c-Hex; 1c, R1¼4-NO2eC6H4,
R2¼Et; 1d, R1¼PhCH2CH2, R2¼Et, Ar¼2,4,6-Me3eC6H2; 1e, R1¼Ph, R2¼i-Bu; 1f, R1¼Ph, R2¼CH2CH]CH2.].
readily available a-ketoesters with arylsulfonylhydrazines as pre-
viously described.9 We then turned our attention to developing the
in-flow diazoester generation/SeH insertion process (path A,
Scheme 1).10e16 Diazoester generation from 1aeg was carried out
under our previously reported flow conditions,9 which involved
combining a stream of the arylsulfonylhydrazone (0.125 M in
CH2Cl2) with a stream of triethylamine (0.14 M in CH2Cl2), followed
by heating in a convection flow coil (CFC) reactor (80 ꢀC, 10 min
residence time) to effect the BamfordeStevens elimination. The
resulting flow stream was then passed through an in-line scavenger
column (packed with silica/Et3N) to remove the sulfinate byproduct
generated during the BamfordeStevens reaction. After exiting the
back pressure regulator (250 psi), the output from the diazoester-
generating flow process was then introduced to a hot solution of
dichloromethane containing sulfanylphenol and Rh2(OAc)4 to ef-
fect the carbene SeH insertion reaction (Scheme 2). The desired
insertion products 2aed were isolated in reasonable yield over
two-steps from the starting arylsulfonylhydrazones 1aed. In order
Scheme 3. Sulfone formation via oxidation of sulfides.
a more direct entry to the desired
a-sulfonyl carboxylate products,
and the sulfide oxidation step (Scheme 3) would not be required.
This would represent a very atom efficient synthesis of these
products as N2 would be the only byproduct formed from the
starting arylsulfonylhydrazone. Fortunately, this sulfinate insertion
process has precedent, and been reported to occur during the
thermal decomposition of tosylhydrazones in basic media,17 or by
pyrolysis18 or photolysis,19 although the reported yields and sub-
strate scope are poor. More recently Che and co-workers found that
a limited number of sulfones were formed as byproducts in the
ruthenium(II) porphyrin catalyzed cyclopropanations of alkenes
to demonstrate the preparation of a-sulfonyl carboxylates the SeH
insertion products, 2b and 2d were subsequently oxidized to the
sulfones 4a (98%) and 4b (99%), respectively, using standard con-
ditions (mCPBA, CH2Cl2) (Scheme 3).
As triethylammonium 4-toluenesulfinate was the byproduct of
the BamfordeStevens reactions, we wondered if it would partici-
pate in sulfinate carbene insertion reactions if it were not removed
from the flow product stream. If successful, this would lead to

2278
H.E. Bartrum et al. / Tetrahedron 69 (2013) 2276e2282
with tosylhydrazones.20 Yu and co-workers have reported the use
of Cu salts21 (CuI, 20 mol %) to promote this transformation, while
Barluenga and co-workers employed an iron catalyst.22 Since both
of these latter reactions require high reaction temperatures (110 ꢀC)
for efficient conversion, our safer in-flow diazoester formation and
milder rhodium catalyzed reaction conditions could offer an
advantage.
developed for the in-flow formation of diazoesters, we initially
focused on optimizing the PeH insertion reaction on pure diazo-
ester 8 (Table 1), which was formed by elimination of the sulfo-
nylhydrazone 1a.
Table 1
Optimization of batch PeH insertion conditions
To this end we subjected tosylhydrazones 1aef to the in-flow
diazoester forming process (path B, Scheme 1), but in this case no
scavenger column was employed and the crude diazoester output,
plus the toluenesulfinate byproduct, was added directly to a hot
solution of 2 mol % Rh2(OAc)4 in dichloromethane, resulting in the
Entry
Catalyst
Solventa
Yield (%)
formation of a range of
(Scheme 2). As the sulfonylhydrazones 1 were initially prepared by
condensation of commercially available -ketoesters and sulfonyl
hydrazines, the only by-products generated during the entire
three-step reaction sequence leading to -sulfonyl esters 3 are
a-sulfonyl esters 3 in generally good yields
1
2
3
4
Cu(acac)2 (3 mol %)
Cu(acac)2 (3 mol %)
Cu(OAc)2 (3 mol %)
Rh2(OAc)4 (2 mol %)
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
63
66
60
d
a
a
a
All reactions performed at reflux in the stated solvent.
water and nitrogen. This represents a remarkably simple and atom
economic (‘green’) way to access the sulfonyl ester products, and
completely avoids the use of alkyl halides. It is interesting to note
that whilst the arylsulfonylhydrazone 1d did give the SeH insertion
product 2d (51%) when using sulfanylphenol (Scheme 2), it did not
produce any of the expected sulfone product 3d when sulfinate was
used as the insertion partner. What happened instead was forma-
tion of the alkene 6 in 95% yield (Scheme 4) via 1,2-H shift of the
intermediate metal carbene23 to give 5, followed by isomerization
of the double bond under the basic reaction conditions24,25
(Scheme 4). Similarly, the in-flow conversion of tosylhydrazone
1g into its corresponding diazoester followed by treatment with
Applying the reported conditions to diazoester 8 (replacing
benzene with toluene) gave the desired alkyl phosphonate 9 in
acceptable yield (entry 1, Table 1). Changing the solvent to
dichloromethane had no detrimental effect on the yield (entry 2,
Table 1) and Cu(OAc)2 proved to be equally effective as a catalyst
(entry 3, Table 1). No desired product formation was observed by
employing Rh2(OAc)4 as a catalyst (entry 4, Table 1).
With Cu(acac)2 and CH2Cl2 as the catalyst and solvent of choice,
we next investigated the two-step procedure (path C, Scheme 1)
starting with tosylhydrazone 1a. Thus, in-flow treatment of tosyl-
hydrazone 1a with triethylamine in CH2Cl2 (including passage
through a Et3N/silica gel scavenger column to remove sulfinate)
gave the corresponding diazoester. The output product stream was
then directly added to a boiling solution of the desired H-phos-
phonate and Cu(acac)2 in CH2Cl2 (Table 2). Initially we focused on
optimizing the procedure for the formation of alkyl phosphonate 9.
Rh2(OAc)4 led to formation of
yield (21%) (Scheme 4). Repeating the reaction as a one-pot batch
process produced similar results (47%), and we propose that the
b-sulfonyl carboxylate 7 in moderate
b
-
sulfone 6 arises as a result of conjugate addition of the sulfinate
byproduct to methyl acrylate26 generated by BamfordeStevens
reaction of tosylhydrazone 1g.
a
Alkene 5 synthesized according to the literature procedure.19 b Yield using batch process.
Scheme 4. Attempted
a-sulfone formation with alkyl arylsulfonylhydrazones [Ar¼2,4,6-Me3eC6H2].
We next focused on developing a procedure for PeH insertion
reactions to form -phosphono carboxylates (path C, Scheme 1). At
Utilizing the same conditions as those for the batch process
(3 mol % Cu(acac)2) resulted in isolation of the desired product in
51% yield along with recovery of the diazoester intermediate 8.
Increasing the catalyst loading to 5 mol % improved the yield to 67%,
but the best results were achieved using 10 mol % of the catalyst,
which resulted in isolation of 9 in 76% yield over the two steps. This
represents a substantial increase in yield to that previously re-
ported for the standard batch process.27
The yield of the desired phosphonoacetate product decreased
with increasing steric bulk of the alkyl phosphite insertion partner,
with the diethyl derivative 10 being isolated in only 31% yield and
the diisopropyl derivative 11 being isolated in 19% yield. We
a
the outset of our work, the only report of such a transformation was
by Arbuzov and co-workers who found that Cu(acac)2 was an ef-
fective catalyst for PeH insertions on a range of diazo-com-
pounds.27 However, the yields obtained were variable and the
reaction proceeded in relatively poor yield (32 and 40%) for the only
two diazoester examples explored. During the preparation of this
manuscript, Wu and co-workers published a one-pot method for
the copper-catalyzed insertion of in situ generated diazo-
compounds into H-phosphorus oxides,28 but no diazoesters were
included in their examples. As we already had good conditions

H.E. Bartrum et al. / Tetrahedron 69 (2013) 2276e2282
2279
Table 2
3. Experimental section
3.1. General flow method A (SeH insertion)
Dialkyl phosphonate formation
A solution of tosylhydrazone (0.25 mmol) in CH2Cl2 (2 mL) was
injected into one of the 2 mL sample loops of the R2þ unit of
a Vapourtec R2þ/R4 reactor. The other 2 mL sample loop was
loaded with a solution of triethylamine (0.28 mmol) in CH2Cl2
(2 mL). The valves of the loop were set to load and the reagents
pumped through the system using CH2Cl2 as a system solvent at
a flow rate of 0.200 mL/min (0.100 mL/min per pump). The reagents
were combined in a T-piece before entering a 2 mL convection flow
coil (CFC) reactor (inside diameter¼1 mm, length¼2.9 m) (PFA),
which was maintained at 80 ꢀC (99 ꢀC for 1d) (residence time (tr)¼
10 min) by the R4 unit. The product stream exiting the reactor was
passed through an omnifit column (100 mmꢁ6.6 mm) loaded with
silica treated with 20% Et3N in CH2Cl2. A back pressure regulator
(250 psi) was added in line after the reactor and the output (7.5 mL
total volume) was added directly to a solution of Rh2(OAc)4 (2.2 mg,
Entry
1
Hydrazone
HeP(O)(OR3)2
HeP(O)(OMe)2
Product
Yield (%)
76 (67)a
1a
2
3
4
1a
1a
1b
HeP(O)(OEt)2
HeP(O)(OiPr)2
HeP(O)(OMe)2
31
19
55
5.0 mmol, 2 mol %) and thiophenol (26 mL, 0.25 mmol) in CH2Cl2
(2 mL) at reflux. Once the addition of diazoester was complete, the
reaction mixture was heated at reflux for 18 h before being cooled
to room temperature and concentrated in vacuo. The crude product
was purified by column chromatography.
5
1c
HeP(O)(OMe)2
26 (52)b
3.2. General flow method B (sulfinate insertion)
A solution of tosylhydrazone (0.25 mmol) in CH2Cl2 (2 mL) was
injected into one of the 2 mL sample loops of the R2þ unit of
a Vapourtec R2þ/R4 reactor. The other 2 mL sample loop was
loaded with a solution of triethylamine (0.28 mmol) in CH2Cl2
(2 mL). The valves of the loop were set to load and the reagents
pumped through the system using CH2Cl2 as a system solvent at
a flow rate of 0.200 mL/min (0.100 mL/min per pump). The reagents
were combined in a T-piece before entering a 2 mL convection flow
coil (CFC) reactor (inside diameter¼1 mm, length¼2.9 m) (PFA),
which was maintained at 80 ꢀC (99 ꢀC for 1d) (residence time (tr)¼
10 min) by the R4 unit. A back pressure regulator (250 psi) was
added in line after the reactor and the output (7.5 mL total volume)
was directly added into a flask containing Rh2(OAc)4 (2.2 mg,
6
7
1d
1f
HeP(O)(OMe)2
HeP(O)(OMe)2
23c
51
8
1g
HeP(O)(OMe)2
24
a
Cu(acac)2 (5 mol %) used; added as two portions of 2.5 mol % catalyst with the
second portion added after 4 h of reaction.
b
Based on recovered starting material.
1:1 mixture of alkenes 5 and 6 (69%) also isolated.
5.0 mmol, 2 mol %) in CH2Cl2 (2 mL) at reflux. Once the addition of
c
diazoester was complete, the reaction mixture was refluxed over-
night before being cooled to room temperature and concentrated in
vacuo. The crude product was then purified by column
chromatography.
therefore continued to explore the reaction of other diazoesters
with dimethyl phosphite (Table 2, entries 4e8). The desired PeH
insertion products were formed in all cases via the two-step
process, although the yields were generally moderate to poor. In
the case of the nitro derivative 13 a significant amount of in-
termediate diazoester was recovered. In contrast to the attempted
sulfinate insertion reactions, the sulfonylhydrazones 1d and 1g
gave the desired PeH insertion products 14 and 16, respectively,
albeit in poor yields. The mass balance in the reaction of 1d was
a 1:1 mixture of alkenes 5 and 6, which suggests that the rate of
PeH insertion is slow compared to the rate of N2 elimination and
1,2-H shift of the intermediate diazoester. Full conversion of 1g
was observed, and it is likely that methyl acrylate accounts for the
mass balance in the reaction, but none was isolated due to its
volatility.
3.3. General flow method C (PeH insertion)
As for general flow method A except the output (7.5 mL total
volume) from the flow was added directly to a solution of Cu(acac)2
(6.5 mg, 0.05 mmol, 10 mol %) and the H-phosphonate (1.25 mmol,
5 equiv) in CH2Cl2 (1 mL) at reflux. Once the addition of diazoester
was complete, the reaction mixture was heated at reflux for 18 h
before being cooled to room temperature and concentrated in
vacuo. The crude product was purified by column chromatography.
3.3.1. Methyl 2-phenyl-2-(phenylsulfanyl)acetate, 2a. Following
general flow method A, tosylhydrazone 1a gave, after purification
by column chromatography (2% EtOAc/petrol) compound 2a
(39 mg, 60%) as a colorless oil. Rf 0.6 (40% EtOAc/petrol); nmax
(CHCl3)/cmꢂ1 3089, 2954, 2845, 1738, 1584, 1496, 1483, 1454, 1439,
1345, 1304, 1286, 1148, 1088, 1075, 1025, 1003; dH (400 MHz; CDCl3)
7.45e7.42 (2H, m), 7.39e7.35 (2H, m), 7.33e7.30 (3H, m), 7.28e7.25
(3H, m), 4.91 (1H, s), 3.68 (3H, s); dC (100 MHz; CDCl3) 171.1 (C),
135.8 (C), 133.8 (C), 132.8 (CH), 129.1 (CH), 128.8 (CH), 128.7 (CH),
128.5 (CH), 128.2 (CH), 56.5 (CH), 52.9 (CH3); m/z (ESI) found
In conclusion we have shown that in-flow generated
esters can participate in SeH, sulfinate and PeH carbene insertion
reactions to give -sulfanyl-, -sulfonyl-, and -phosphonyl car-
a-diazo-
a
a
a
boxylate products. This represents a significant extension to our
previously published OeH and NeH insertions,9 and further dem-
onstrates that in-flow generated
used safely under flow chemistry conditions.
a-diazoesters can be formed and

2280
H.E. Bartrum et al. / Tetrahedron 69 (2013) 2276e2282
281.0600 (MþNa, C15H14NaO2S requires 281.0607). Spectroscopic
m), 1.74e1.62 (2H, m), 1.47e1.22 (6H, m); dC (100 MHz; CDCl3) 164.4
(C]O), 145.2 (C), 133.6 (C), 130.3 (CH), 130.0 (CH), 129.6 (CH), 129.2
(CH), 128.5 (CH), 128.2 (C), 75.5 (CH), 75.2 (CH), 31.2 (CH2), 31.1
(CH2), 25.2 (CH2), 23.5 (CH2), 25.4 (CH2) and 21.7 (CH3); m/z (ESI)
found 395.1298 (MþNa, C21H24NaO4S requires 395.1288).
data matches that previously reported.29
3.3.2. Cyclohexyl 2-phenyl-2-(phenylsulfanyl)acetate, 2b. Following
general flow method A, tosylhydrazone 1b gave, after purification
by column chromatography (1% EtOAc/petrol) compound 2b
(52 mg, 64%) as a colorless oil. Rf 0.7 (40% EtOAc/petrol); nmax
(CHCl3)/cmꢂ1 2940, 2861, 1726, 1584, 1496, 1483, 1454, 1440, 1352,
1304, 1286, 1149, 1120, 1089, 1075, 1037, 1010, 976; dH (400 MHz;
CDCl3) 7.48e7.44 (2H, m), 7.40e7.36 (2H, m), 7.34e7.23 (6H, m),
4.91 (1H, s), 4.80e4.72 (1H, m), 1.75e1.68 (2H, m), 1.66e1.59 (2H,
m), 1.51e1.43 (1H, m), 1.39e1.25 (5H, m); dC (100 MHz; CDCl3) 170.0
(C), 136.0 (C), 134.2 (C), 132.5 (CH), 129.0 (CH), 128.7 (CH), 128.6
(CH), 128.3 (CH), 127.9 (CH), 74.2 (CH), 56.6 (CH), 31.4 (CH2), 31.3
(CH2), 25.4 (CH2), 23.6 (CH2), 23.5 (CH2); m/z (ESI) found 349.1244
(MþNa, C20H22NaO2S requires 349.1233).
3.3.7. Ethyl 2-(4-nitrophenyl)-2-tosylacetate, 3c. Following general
flow method B, tosylhydrazone 1c gave, after purification by col-
umn chromatography (10% EtOAc/petrol) compound 3c (58 mg,
64%) as colorless needles, mp 122e124 ꢀC. Rf 0.6 (40% EtOAc/pet-
rol); nmax (CHCl3)/cmꢂ1 2984, 2940, 2869, 1741, 1607, 1597, 1392,
1370, 1351, 1326, 1306, 1144, 1128, 1083, 1018, 908, 875, 860; dH
(400 MHz; CDCl3) 8.17 (2H, d, J 8.8), 7.65 (2H, d, J 8.8), 7.54 (2H, d, J
8.2), 7.28 (2H, d, J 8.2), 5.22 (1H, s), 4.28e4.16 (2H, m), 2.44 (3H, s),
1.22 (3H, t, J 7.2); dC (100 MHz; CDCl3) 164.0 (C]O), 148.5 (C), 146.1
(C), 134.9 (C), 133.2 (C), 131.5 (CH), 129.8 (CH), 129.7 (CH), 123.5
(CH), 74.5 (CH), 63.0 (CH2), 21.8 (CH3) and 13.9 (CH3); m/z (ESI)
found 364.0846 (MþH, C17H18NO6S requires 364.0849). Found
386.0658 (MþNa, C17H17NNaO6S requires 386.0669).
3.3.3. Ethyl 2-(4-nitrophenyl)-2-(phenylsulfanyl)acetate, 2c. Follo-
wing general flow method A, tosylhydrazone 1c gave, after purifi-
cation by column chromatography (3% EtOAc/petrol) compound 2c
(40 mg, 50%) as a colorless oil. Rf 0.3 (20% EtOAc/petrol); nmax
(CHCl3)/cmꢂ1 2984, 1732, 1607, 1530, 1493, 1645, 1369, 1349, 1322,
1290, 1148, 1111, 1095, 1068, 1025, 859; dH (400 MHz; CDCl3) 8.16
(2H, d, J 8.8), 7.58 (2H, d, J 8.8), 7.35 (2H, dd, J 7.2 and 1.6), 7.30e7.26
(3H, m), 4.92 (1H, s), 4.21e4.12 (2H, m), 1.20 (3H, t, J 7.2); dC
(100 MHz; CDCl3) 169.4 (C),147.8 (C),143.4 (C),133.7 (CH),132.4 (C),
129.7 (CH), 129.3 (CH), 128.9 (CH), 123.9 (CH), 62.4 (CH2), 56.0 (CH),
14.1 (CH3); m/z (ESI) found 340.0611 (MþNa, C16H15NNaO4S re-
quires 340.0614).
3.3.8. Isobutyl 2-phenyl-2-tosylacetate, 3e. Following general flow
method B, tosylhydrazone 1e gave, after purification by column
chromatography (8% EtOAc/petrol) compound 3e (70 mg, 81%) as
colorless needles, mp 66e68 ꢀC. Rf 0.8 (40% EtOAc/petrol); nmax
(CHCl3)/cmꢂ1 2959, 2939, 2876, 1732, 1597, 1456, 1396, 1378, 1348,
1421, 1126, 1083, 1018, 998, 969, 945, 868; dH (400 MHz; CDCl3)
7.50e7.46 (2H, m), 7.39e7.34 (3H, m), 7.31e7.26 (2H, m), 7.22e7.20
(2H, m), 5.08 (1H, s), 3.97 (1H, dd, J 10.6 and 7.0), 3.90 (1H, dd, J 10.6
and 7.0), 2.40 (3H, s), 1.92 (1H, app nonet, J 7.0), 0.88 (6H, d, J 7.0); dC
(100 MHz; CDCl3) 165.1 (C]O),145.4 (C), 133.7 (C), 130.4 (CH), 130.1
(CH), 129.7 (CH), 129.3 (CH), 128.7 (CH), 128.2 (CH), 75.5 (CH), 72.6
(CH2), 27.7 (CH), 21.8 (CH3) and 19.1 (CH3); m/z (ESI) found 369.1135
(MþNa, C19H22NaO4S requires 369.1131).
3.3.4. Ethyl 4-phenyl-2-(phenylsulfanyl)butanoate, 2d. Following
general flow method A, tosylhydrazone 1d gave, after purification
by column chromatography (4% EtOAc/petrol) compound 2d
(43 mg, 51%) as a colorless oil. Rf 0.5 (20% EtOAc/petrol); nmax
(CHCl3)/cmꢂ1 3087, 2983, 2938, 2862, 1723, 1604, 1584, 1496, 1483,
1455, 1370, 1304, 1148, 1094, 1068, 1026, 864; dH (400 MHz; CDCl3)
7.46e7.43 (2H, m), 7.34e7.25 (5H, m), 7.23e7.21 (3H, m), 4.16e4.10
(2H, m), 3.63 (1H, t, J 7.0), 2.77 (2H, t, J 7.6), 2.27e2.17 (1H, m),
2.12e2.03 (1H, m), 1.19 (3H, t, J 6.8); dC (100 MHz; CDCl3) 172.2 (C),
140.7 (C), 133.3 (C), 133.1 (CH), 129.0 (CH), 128.7 (CH), 128.6 (CH),
128.1 (CH), 126.3 (CH), 61.3 (CH2), 50.1 (CH), 33.3 (CH2), 33.2 (CH2),
14.2 (CH3); m/z (ESI) found 301.1258 (MþH, C18H21O2S requires
301.1257). Found 323.1070 (MþNa, C18H20NaO2S requires
323.1076).
3.3.9. Allyl 2-phenyl-2-tosylacetate, 3f. Following general flow
method B, tosylhydrazone 1f gave, after purification by column
chromatography (10% EtOAc/petrol) compound 3f (68 mg, 82%) as
colorless needles, mp 74e76 ꢀC. Rf 0.7 (40% EtOAc/petrol); nmax
(CHCl3)/cmꢂ1 2929, 1738, 1650, 1598, 1495, 1456, 1365, 1341, 1321,
1126, 1083, 1043, 1019, 987, 944, 869; dH (400 MHz; CDCl3)
7.49e7.47 (2H, m), 7.38e7.26 (5H, m), 7.23e7.20 (2H, m), 5.84 (1H,
ddt, J 16.8, 10.4 and 6.0), 5.30 (1H, app dq, J 16.8 and 1.6), 5.23 (1H,
app dq, J 10.4 and 1.2), 5.11 (1H, s), 4.66e4.64 (2H, m), 2.41 (3H, s);
dC (100 MHz; CDCl3) 164.7 (C]O), 145.4 (C), 133.5 (C), 131.0 (CH),
130.4 (CH), 130.1 (CH), 129.8 (CH), 129.3 (CH), 128.7 (CH), 128.0 (C),
119.5 (CH2), 75.4 (CH), 67.0 (CH2) and 21.8 (CH3); m/z (ESI) found
353.0832 (MþNa, C18H18NaO4S requires 353.0818).
3.3.5. Methyl 2-phenyl-2-tosylacetate, 3a. Following general flow
method B, tosylhydrazone 1a gave, after purification by column
chromatography (12% EtOAc/petrol) compound 3a (55 mg, 72%) as
colorless needles, mp 122e124 ꢀC. Rf 0.6 (40% EtOAc/petrol); nmax
(CHCl3)/cmꢂ1 2955, 2928, 1746, 1598, 1495, 1456, 1348, 1321, 1127,
1083, 1007, 908, 868; dH (400 MHz; CDCl3) 7.48e7.45 (2H, m),
7.40e7.25 (5H, m), 7.23e7.20 (2H, m), 5.09 (1H, s), 3.77 (3H, s), 2.41
(3H, s); dC (100 MHz; CDCl3) 165.5 (C]O), 145.5 (C), 133.4 (C), 130.4
(CH), 130.1 (CH), 129.8 (CH), 129.3 (CH), 128.7 (CH), 128.1 (C), 75.3
(CH), 53.3 (CH3), 21.8 (CH3); m/z (ESI) found 327.0676 (MþNa,
C16H16NaO4S requires 327.0662). 1H NMR data matches those pre-
viously reported.30
3.3.10. Cyclohexyl 2-phenyl-2-(phenylsulfonyl)acetate, 4a. To a stir-
red solution of cyclohexyl 2-phenyl-2-(phenylsulfanyl)acetate, 2b
(107 mg, 0.33 mmol) in CH2Cl2 (9 mL) was added mCPBA (170 mg,
0.98 mmol) and the reaction was stirred at room temperature for
3 h (until TLC analysis indicated complete consumption of starting
material). Sodium thiosulfate (5 mL, satd) was added and the re-
action was stirred for a further 15 min before the organic layer was
separated and the aqueous layer extracted with CH2Cl2 (3ꢁ10 mL).
The combined organic fractions were dried (MgSO4), filtered, and
concentrated in vacuo. The crude residue was purified by column
chromatography (5% EtOAc/petrol) to give the title compound, 4a
(116 mg, 98%) as a colorless oil. Rf 0.3 (20% EtOAc/petrol); nmax
(CHCl3)/cmꢂ1 2941, 2862, 1732, 1586, 1496, 1455, 1448, 1374, 1352,
1324, 1312, 1288, 1146, 1128, 1083, 1035, 1009, 982, 908, 867; dH
(400 MHz; CDCl3) 7.63e7.57 (3H, m), 7.44e7.40 (2H, m), 7.38e7.34
(3H, m), 7.32e7.26 (2H, m), 5.08 (1H, s), 4.86e4.80 (1H, m),
1.85e1.75 (2H, m), 1.74e1.65 (2H, m), 1.55e1.46 (1H, m), 1.45e1.23
(5H, m); dC (100 MHz; CDCl3) 164.3 (C), 136.6 (C), 134.2 (CH), 130.4
3.3.6. Cyclohexyl-2-phenyl-2-tosylacetate, 3b. Following general
flow method B, tosylhydrazone 1b gave, after purification by col-
umn chromatography (10% EtOAc/petrol) compound 3b (75 mg,
81%) as pale yellow needles, mp 127e128 ꢀC. Rf 0.8 (50% EtOAc/
petrol); nmax (CHCl3)/cmꢂ1 2935, 2861, 1732, 1597, 1496, 1331, 1193,
1183, 1143, 1128, 1083, 1035, 1010, 927, 865; dH (400 MHz; CDCl3)
7.49e7.46 (2H, m), 7.38e7.34 (3H, m), 7.31e7.27 (2H, m), 7.21 (2H, d,
J 8.0), 5.06 (1H, s), 4.84 (1H, tt, J 8.8, 4.4), 2.41 (3H, s), 1.85e1.75 (2H,

H.E. Bartrum et al. / Tetrahedron 69 (2013) 2276e2282
2281
(CH), 130.1 (CH), 129.7 (CH), 128.7 (CH), 128.6 (CH), 128.1 (C), 75.6
(CH), 75.4 (CH), 31.3 (CH2), 31.2 (CH2), 25.3 (CH2), 23.6 (CH2), 23.5
(CH2); m/z (ESI) found 359.1331 (MþNa, C20H23O4S requires
359.1312). Found 381.1129 (C20H22NaO4S requires 381.1131).
(CH3); m/z (ESI) found 243.0691 (MþH, C11H15O4S requires
243.0686). Found 265.0508 (MþNa, C11H14NaO4S requires
265.0505). Spectroscopic data matches those previously
reported.26
3.3.11. Ethyl 4-phenyl-2-(phenylsulfonyl)butanoate, 4b. To a stirring
solution of ethyl 4-phenyl-2-(phenylsulfanyl)butanoate, 2d (19 mg,
58 mmol) in CH2Cl2 (1.5 mL) was added mCPBA (43 mg, 0.17 mmol)
3.3.15. Methyl
2-(dimethoxyphosphoryl)-2-phenylacetate,
9. Following general flow method C, tosylhydrazone 1a and di-
methyl phosphite gave, after purification by column chromatog-
raphy (75% EtOAc/petrol) compound 9 (49 mg, 76%) as a colorless
oil. Rf 0.1 (40% EtOAc/petrol); nmax (CHCl3)/cmꢂ1 2954, 2855, 1747,
1732, 1650, 1602, 1495, 1456, 1362, 1344, 1310, 1130, 1064, 988, 946,
889; dH (400 MHz; CDCl3) 7.51e7.48 (2H, m), 7.38e7.31 (3H, m),
4.28 (1H, d, J 23.6), 3.76 (3H, s), 3.72 (3H, d, J 11.2), 3.66 (3H, d, J
11.2); dC (100 MHz; CDCl3) 168.1 (C, d, J 4.0), 130.7 (C, d, J 9.0), 129.7
(CH, d, J 6.0), 128.8 (CH, d, J 2.0), 128.3 (CH, d, J 3.0), 54.2 (CH3, d, J
6.0), 53.8 (CH3, d, J 7.0), 53.1 (CH3) and 51.7 (CH, d, J 135.0); dP
(162 MHz; CDCl3) 21.2; m/z (ESI) found 259.0739 (MþH, C11H16O5P
requires 259.0730). Found 281.0554 (MþNa, C11H15NaO5P requires
281.0549). Spectroscopic data consistent with that previously
reported.32
and the reaction was stirred at room temperature for 3 h (until TLC
analysis indicated complete consumption of starting material).
Sodium sulfanylsulfate (5 mL, satd) was added and the reaction was
stirred for a further 15 min before the organic layer was separated
and the aqueous layer extracted with CH2Cl2 (3ꢁ10 mL). The
combined organic fractions were dried (MgSO4), filtered, and con-
centrated in vacuo. The crude residue was purified by column
chromatography (5% EtOAc/petrol) to give the title compound, 4b
(20.5 mg, 99%) as a colorless oil. Rf 0.2 (20% EtOAc/petrol); nmax
(CHCl3)/cmꢂ1 2934, 1734, 1604, 1449, 1371, 1324, 1145, 1084; dH
(400 MHz; CDCl3) 7.86e7.84 (2H, m), 7.67 (1H, tt, J 7.2 and 1.2),
7.57e7.53 (2H, m), 7.29e7.25 (2H, m), 7.23e7.18 (1H, m), 7.12e7.10
(2H, m), 4.12e4.06 (2H, m), 3.93 (1H, dd, J 10.8 and 4.0), 2.75e2.69
(1H, m), 2.63e2.56 (1H, m), 2.42e2.26 (2H, m), 1.16 (3H, t, J 7.2); dC
(100 MHz; CDCl3) 165.9 (C), 139.4 (C), 137.3 (C), 134.3 (CH), 129.5
(CH), 129.1 (CH), 128.8 (CH), 128.6 (CH), 126.7 (CH), 70.2 (CH), 62.4
(CH2), 33.0 (CH2), 28.4 (CH2), 14.0 (CH3); m/z (ESI) found 333.1141
(MþH, C18H21O4S requires 333.1155). Found 355.0972 (MþNa,
C18H20NaO4S requires 355.0975).
3.3.16. Methyl 2-(diethoxyphosphoryl)-2-phenylacetate, 10. Follo-
wing general flow method C, utilizing 5 mol % Cu(acac)2, tosylhy-
drazone 1a, and diethyl phosphite gave, after purification by col-
umn chromatography (60% EtOAc/petrol) compound 10 (22 mg,
31%) as a colorless oil. Rf 0.2 (40% EtOAc/petrol); nmax (CHCl3)/cmꢂ1
2980, 2952, 2932, 2909, 1739, 1733, 1602, 1496, 1456, 1392, 1389,
1346, 1306, 1144, 1097, 1059, 978, 803, 885; dH (400 MHz; CDCl3)
7.53e7.49 (2H, m), 7.37e7.31 (3H, m), 4.26 (1H, d, J 23.6), 4.10e4.03
(3H, m), 4.00e3.92 (1H, m), 3.75 (3H, s), 1.26 (3H, td, J 7.2 and 0.8),
1.19 (3H, td, J 7.2 and 0.8); dC (100 MHz; CDCl3) 168.3 (C, d, J 4.0),
130.9 (C, d, J 8.0), 129.7 (CH, d, J 7.0), 128.7 (CH, d, J 2.0), 128.2 (CH, d,
J 3.0), 63.7 (CH2, d, J 7.0), 63.3 (CH2, d, J 7.0), 52.9 (CH3), 52.2 (CH, d, J
139.0), 16.4 (CH3, d, J 6.0), 16.3 (CH3, d, J 7.0); dP (162 MHz; CDCl3)
18.6; m/z (ESI) found 287.1040 (MþH, C13H20O5P requires
287.1043). Found 309.0857 (MþNa, C13H19NaO5P requires
309.0862).
3.3.12. (E)-Ethyl 4-phenylbut-3-enoate, 6. Following general flow
method B, tosylhydrazone 1d gave, after purification by column
chromatography (2% EtOAc/petrol) compound 6 and (E)-ethyl 4-
phenylbut-2-enoate, 5 as a 9:1 mixture (90 mg, 95%) as a color-
less oil. Rf 0.8 (40% EtOAc/petrol); nmax (CHCl3)/cmꢂ1 2982, 2938,
2309, 1732, 1654, 1600, 1496, 1150, 1391, 1371, 1349, 1319, 1300, 983,
966, 908, 864. Data for the major title compound, 6: dH (400 MHz;
CDCl3) 7.40e7.36 (2H, m), 7.34e7.29 (2H, m), 7.26e7.21 (1H, m),
6.49 (1H, app d, J 15.6), 6.31 (1H, dt, J 15.6 and 7.0), 4.18 (2H, q, J 7.2),
3.25 (2H, dd, J 7.0 and 1.2), 1.29 (3H, t, J 7.2); dC (100 MHz; CDCl3)
171.7 (C]O),137.0 (C),133.5 (CH),128.6 (CH),127.6 (CH), 126.4 (CH),
122.0 (CH), 60.9 (CH2), 38.6 (CH2) and 14.3 (CH3); data for the minor
compound, 5: dH (400 MHz; CDCl3) 7.34e7.30 (2H, m), 7.24e7.21
(1H, m), 7.19e7.17 (2H, m), 7.10 (1H, dt, J 15.6 and 6.8), 5.81 (1H, dt, J
15.6 and 1.4), 4.18 (2H, q, J 7.2), 3.52 (2H, dd, J 6.8 and 1.4), 1.27 (3H,
t, J 7.2); dC (100 MHz; CDCl3) 166.6 (C]O), 147.4 (CH), 137.8 (C),
129.0 (CH), 128.8 (CH), 126.8 (CH), 122.5 (CH), 60.4 (CH2), 38.6 (CH2)
and 14.4 (CH3); m/z (ESI) found 213.0887 (MþNa, C12H14NaO2 re-
quires 213.0886). Spectroscopic data matches that previously
reported.24,31
3.3.17. Methyl 2-(diisopropoxyphosphoryl)-2-phenylacetate, 11. Fo-
llowing general flow method C, utilizing 5 mol % Cu(acac)2, tosyl-
hydrazone 1a, and diisopropyl phosphite gave, after purification by
column chromatography (60% EtOAc/petrol) compound 11 (15 mg,
19%) as a colorless oil. Rf 0.3 (40% EtOAc/petrol); nmax (CHCl3)/cmꢂ1
2983, 2954, 1738, 1602, 1456, 1386, 1347, 1302, 1145, 1102, 994, 898;
dH (400 MHz; CDCl3) 7.54e7.50 (2H, m), 7.36e7.29 (3H, m),
4.72e4.64 (1H, m), 4.63e4.49 (1H, m), 4.20 (1H, d, J 23.6), 3.76 (3H,
s), 1.28e1.24 (9H, m), 1.04 (3H, d, J 6.8); dC (100 MHz; CDCl3) 168.4
(C, d, J 4.0), 131.3 (C, d, J 8.0), 129.9 (CH, d, J 7.0), 128.5 (CH, d, J 2.0),
128.0 (CH, d, J 3.0), 72.3 (CH, d, J 7.0), 72.0 (CH, d, J 8.0), 52.8 (CH3),
52.9 (CH, d, J 135.0), 24.4 (CH3, d, J 3.0), 24.1 (CH3, d, J 4.0), 23.8 (CH3,
J 5.0), 23.4 (CH3, d, J 6.0); dP (162 MHz; CDCl3) 26.5; m/z (ESI) found
315.1352 (MþH, C15H24O5P requires 315.1356). Found 337.1171
(MþNa, C15H23NaO5P requires 337.1175).
3.3.13. Isomerization of alkene 5. To a stirred solution of alkene 524
(57 mg, 0.3 mmol) in CH2Cl2 (1 mL) was added triethylamine (46 mL,
0.33 mmol) and the resultant solution was heated at reflux for 18 h
before being cooled to room temperature and concentrated in
vacuo. Analysis of the 1H NMR spectrum of the resultant oil in-
dicated a mixture of alkenes 6 and 5 in a ratio of 7:1. Spectroscopic
data matched that reported above.
3.3.18. Cyclohexyl 2-(dimethoxyphosphoryl)-2-phenylacetate, 12.
Following general flow method C, tosylhydrazone 1b and dimethyl
phosphite gave, after purification by column chromatography (75%
EtOAc/petrol) compound 12 (45 mg, 55%) as a colorless oil. Rf 0.2
(40% EtOAc/petrol); nmax (CHCl3)/cmꢂ1 2937, 2859,1732, 1602, 1496,
1455, 1372, 1352, 1304, 1145, 1120, 1060, 1007, 821; dH (400 MHz;
CDCl3) 7.52e7.48 (2H, m), 7.37e7.30 (3H, m), 4.87e4.80 (1H, m),
4.25 (1H, d, J 23.6), 3.71 (3H, d, J 10.8), 3.67 (3H, d, J 10.8), 1.90e1.64
(4H, m), 1.53e1.20 (6H, m); dC (100 MHz; CDCl3) 167.0 (C, d, J 4.0),
131.0 (C, d, J 9.0), 129.6 (CH, d, J 6.0), 128.7 (CH, d, J 2.0), 128.1 (CH, d,
J 4.0), 74.5 (CH), 54.0 (CH3, d, J 7.0), 53.7 (CH3, d, J 7.0), 52.2 (CH, d, J
134.0), 31.4 (CH2), 31.3 (CH2), 25.4 (CH2), 23.6 (CH2), 23.5 (CH2); m/z
3.3.14. Methyl 3-tosylpropanoate, 7. Following general flow
method B, tosylhydrazone 1g gave, after purification by column
chromatography (20% EtOAc/petrol) compound 7 (13 mg, 21%) as
colorless needles, mp 73e75 ꢀC. (lit.21 72e73 ꢀC). Rf 0.6 (40% EtOAc/
petrol); nmax (CHCl3)/cmꢂ1 2954, 1739, 1599, 1456, 1365, 1319, 1304,
1149, 1134, 1088, 1055, 982; dH (400 MHz; CDCl3) 7.78 (2H, d, J 8.2),
7.37 (2H, d, J 8.2), 3.64 (3H, s), 3.40 (2H, t, J 7.6), 2.74 (2H, t, J 7.6),
2.45 (3H, s); dC (100 MHz; CDCl3) 107.7 (C]O), 145.2 (C), 153.7 (C),
130.2 (CH), 128.4 (CH), 52.4 (CH3), 51.7 (CH2), 27.8 (CH2) and 21.8

2282
H.E. Bartrum et al. / Tetrahedron 69 (2013) 2276e2282
(ESI) found 327.1354. dP (162 MHz; CDCl3) 21.5; (MþH, C16H24O5P
requires 327.1356). Found 349.1174 (MþNa, C16H23NaO5P requires
349.1175).
1161, 1059, 1002, 868, 839; dH (400 MHz; CDCl3) 3.74e3.71 (3H, m),
3.70e3.68 (3H, m), 3.66 (3H, s), 2.98 (1H, dq, J 23.6 and 7.2), 1.35
(3H, dd, J 18.0 and 7.2); dC (100 MHz; CDCl3) 170.1 (C, d, J 5.0), 53.3
(CH3, d, J 7.0), 52.6 (CH3), 38.6 (CH, d, J 134.0), 11.6 (CH3, d, J 6.0); dP
(162 MHz; CDCl3) 16.8; m/z (ESI) found 197.0592 (MþH, C6H14O5P
requires 197.0573). Found 219.0400 (MþNa, C6H13NaO5P requires
219.0393). Spectroscopic data consistent with that previously
reported.33
3.3.19. Ethyl 2-(dimethoxyphosphoryl)-2-(4-nitrophenyl) acetate,
13. Following general flow method C, tosylhydrazone 1c and di-
methyl phosphite gave, after purification by column chromatog-
raphy (75% EtOAc/petrol) compound 13 (21 mg, 26%) as a colorless
oil. Rf 0.2 (40% EtOAc/petrol); nmax (CHCl3)/cmꢂ1 2985, 2958, 2855,
1738, 1607, 1531, 1494, 1462, 1369, 1351, 1322, 1289, 1147, 1111, 1058,
967, 900, 860; dH (400 MHz; CDCl3) 8.22 (2H, d, J 8.4), 7.70 (2H, dd, J
8.4 and 2.0), 4.38 (1H, d, J 24.0), 4.31e4.20 (2H, m), 3.77 (3H, d, J
11.2), 3.73 (3H, d, J 11.2), 1.29 (3H, t, J 7.2); dC (100 MHz; CDCl3) 166.6
(C, d, J 4.0), 147.8 (C), 138.3 (C, d, J 8.0), 130.7 (CH, d, J 6.0), 123.8 (CH,
d, J 3.0), 62.7 (CH2), 54.3 (CH3, d, J 6.0), 54.1 (CH3, d, J 6.0), 51.8 (CH,
d, J 133.0), 14.1 (CH3); dP (162 MHz; CDCl3) 19.6; m/z (ESI) found
318.0733 (MþH, C12H17NO7P requires 318.0737). Found 340.0559
(MþNa, C12H16NNaO7P requires 340.0557).
Acknowledgements
We thank the EPSRC (EP/G027919/1) and Pfizer for financial
support of this work.
Supplementary data
Copies of 1H and 13C NMR spectra for all new compounds.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.01.020.
3.3.20. Ethyl 2-(dimethoxyphosphoryl)-4-phenylbutanoate, 14. Foll-
owing general flow method C, tosylhydrazone 1d and dimethyl
phosphite gave, after purification by column chromatography (75%
EtOAc/petrol) compound 14 (17 mg, 23%) as a colorless oil. Rf 0.2
(40% EtOAc/petrol); nmax (CHCl3)/cmꢂ1 2985, 2957, 2854,1731,1604,
1496, 1455, 1370, 1328, 1145, 1058, 883; dH (400 MHz; CDCl3)
7.30e7.26 (2H, m), 7.22e7.15 (3H, m), 4.28e4.19 (2H, m), 3.78 (3H,
d, J 10.4), 3.75 (3H, d, J 10.8), 2.99 (1H, ddd, J 22.8, 11.2, and 3.6),
2.78e2.69 (1H, m), 2.63e2.54 (1H, m), 2.38e2.32 (1H, m),
2.21e2.08 (1H, m),1.30 (3H, t, J 7.2); dC (100 MHz; CDCl3) 169.0 (C, d,
J 5.0), 140.5 (C), 128.7 (CH), 128.6 (CH), 126.4 (CH), 61.7 (CH2), 53.5
(CH3, d, J 7.0), 53.4 (CH3, d, J 7.0), 44.6 (CH, d, J 131.0), 34.4 (CH2, d, J
5.0), 28.7 (CH2, d, J 5.0), 14.3 (CH3); dP (162 MHz; CDCl3) 25.2; m/z
(ESI) found 301.1202 (MþH, C14H22O5P requires 301.1199). Found
323.1012 (MþNa, C14H21NaO5P requires 323.1019).
References and notes
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3.3.21. Allyl 2-(dimethoxyphosphoryl)-2-phenylacetate, 15. Foll-
owing general flow method C, tosylhydrazone 1f and dimethyl
phosphite gave, after purification by column chromatography (75%
EtOAc/petrol) compound 15 (40 mg, 56%) as a colorless oil. Rf 0.2
(40% EtOAc/petrol); nmax (CHCl3)/cmꢂ1 2989, 2957, 2855,1738,1733,
1650, 1602, 1496, 1456, 1362, 1344, 1304, 1139, 1059, 989, 943, 889;
dH (400 MHz; CDCl3) 7.53e7.49 (2H, m), 7.38e7.32 (3H, m), 5.89
(1H, ddt, J 17.2, 10.4 and 6.0), 5.31 (1H, dq, J 17.2 and 1.2), 5.23 (1H,
dq, J 10.4 and 1.2), 4.72e4.60 (2H, m), 4.30 (1H, d, J 23.6), 3.72 (3H,
d, J 10.8), 3.67 (3H, d, J 10.8); dC (100 MHz; CDCl3) 167.3 (C, d, J 3.0),
131.5 (CH), 130.7 (C, d, J 8.0), 129.7 (CH, d, J 6.0), 128.8 (CH, d, J 3.0),
128.3 (CH, d, J 3.0), 118.9 (CH2), 66.5 (CH2), 54.2 (CH3, d, J 7.0), 53.8
(CH3, d, J 7.0), 51.9 (CH, d, J 135.0); dP (162 MHz; CDCl3) 21.1; m/z
(ESI) found 285.0875 (MþH, C13H18O5P requires 285.0886). Found
307.0693 (MþNa, C13H17NaO5P requires 307.0706).
3.3.22. Methyl 2-(dimethoxyphosphoryl)propanoate, 16. Following
general flow method C, tosylhydrazone 1f and dimethyl phosphite
gave, after purification by column chromatography (EtOAc) com-
pound 16 (12 mg, 24%) as a colorless oil. Rf 0.1 (40% EtOAc/petrol);
nmax (CHCl3)/cmꢂ1 2989, 2956, 2854, 1732, 1602, 1458, 1382, 1321,
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32. Geirsson, J. K. F.; Gudmundsson, B. O.; Sigurdardottir, R. Acta Chem. Scand. 1993,
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