Design and synthesis of stable α-diazo-β-oxo sulfoxides

Article abstract of DOI:10.1039/c3ob27061k

Diazo transfer adjacent to a sulfoxide moiety to provide stable, isolable α-diazo-β-oxo sulfoxides has been achieved. Use of monocyclic and bicyclic sulfoxide precursors is critical in enabling isolation of stable derivatives, through introduction of conformational constraint, while acyclic α-diazo-β-oxo sulfoxides are too labile to isolate and characterize.

Full text of DOI:10.1039/c3ob27061k

Organic &
Biomolecular Chemistry
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Design and synthesis of stable α-diazo-β-oxo
sulfoxides†
Cite this: Org. Biomol. Chem., 2013, 11,
1706
Stuart G. Collins,*a Orlagh C. M. O’Sullivan,a Patrick G. Kellehera and
Anita R. Maguire*b
Received 6th July 2012,
Diazo transfer adjacent to a sulfoxide moiety to provide stable, isolable α-diazo-β-oxo sulfoxides has
been achieved. Use of monocyclic and bicyclic sulfoxide precursors is critical in enabling isolation of
stable derivatives, through introduction of conformational constraint, while acyclic α-diazo-β-oxo sulf-
oxides are too labile to isolate and characterize.
Accepted 9th January 2013
DOI: 10.1039/c3ob27061k
www.rsc.org/obc
Introduction
α-Diazocarbonyl compounds play a key role in organic syn-
thesis due to their ease of preparation and the range of chemi-
cal transformations which they can undergo.1–14 Most of these
transformations involve the initial loss of nitrogen which can
be achieved under thermal, photochemical, microwave or cata-
lytic conditions generating reactive intermediates such as car-
benes, carbenoids and carbonyl ylides which can undergo a
wide variety of chemical reactions. Among the main reaction
pathways of α-diazocarbonyl compounds are cyclopropanation,
Wolff rearrangement, α,α-substitution, C–H insertion,15 X–H
insertion, ylide generation, dimerization, aromatic addition,16
and dipolar cycloaddition.1–14
Our interest in the area of α-diazosulfoxide chemistry was
sparked initially by reports by Taber et al. of intramolecular
cyclization of α-diazoesters via C–H insertion reaction which
proceeded with excellent diastereoselectivity.17–19 In particular,
Taber demonstrated efficient asymmetric induction from a
chiral ester auxiliary (up to 84% de) even though the site of
chirality is somewhat removed from the reacting carbenoid
centre. Accordingly, we envisaged that the presence of a sulf-
oxide moiety adjacent to the reacting carbenoid site should lead
to enhanced diastereoselectivity of the transformation due to
the improved proximity of the stereogenic sulfur centre to the
reacting site (Scheme 1). Indeed, α-diazosulfoxides have the
potential to play an important, broader role in stereoselective
synthesis through reaction pathways other than C–H insertion.
Scheme 1 Diastereoselective C–H insertion methodology.
While diazo transfer to compounds containing reactive
methylene groups such as β-keto esters, β-diketones, β-keto
phosphonates and β-keto sulfones is readily achieved using
the Regitz method,7,20–22 the synthesis of stable α-diazo-β-keto
sulfoxides has proved elusive. Hodson and Holt23 have
reported that under diazo transfer conditions, where β-keto
sulfones give the corresponding α-diazo-β-keto sulfones, the
β-keto sulfoxides do not behave in the same way. Thus, reac-
tion of α-(benzylsulfinyl)acetophenone 1 with p-toluenesulfo-
nyl azide 2 in 60% ethanol using triethylamine as a base did
not yield the α-diazosulfoxide 3 but resulted instead in iso-
lation of p-toluenesulfonamide 4, dibenzyl disulfide 5 and
benzoylformic acid 6 as the products (Scheme 2).
The isolation of p-toluenesulfonamide from the above reac-
tion suggests that diazo transfer to the keto sulfoxide did, in
fact, take place but that this diazo compound 3 was intrinsi-
cally unstable and led to the disulfide and acid decomposition
products via a carbene intermediate 7. Hodson and Holt23
suggested oxygen transfer from sulfur to the carbene centre,
subsequent to or, indeed, concerted with the loss of nitrogen,
as illustrated in Scheme 3 leading to thiol esters 8, which
would then lead to formation of the keto acid and the disulfide
on hydrolysis.
aDepartment of Chemistry, Analytical and Biological Chemistry Research Facility,
University College Cork, Ireland. E-mail: stuart.collins@ucc.ie
bDepartment of Chemistry and School of Pharmacy, Analytical and Biological
Chemistry Research Facility, University College Cork, Ireland.
E-mail: a.maguire@ucc.ie; Fax: +353(0)214274097; Tel: +353(0)214901694
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra for all novel compounds and discussion on synthesis of bicyclic
and monocyclic lactone sulfides. See DOI: 10.1039/c3ob27061k
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Scheme 2 Diazo transfer attempted by Hodson and Holt.
Scheme 3 Proposed decomposition pathway of α-diazo-β-keto sulfoxides.
There have been isolated reports of formation of unstable displacement. Accordingly, we envisaged two possible
α-diazosulfoxides as intermediates,24 for example, by treat- explanations for the anomalous stability of the cephalosporin
ment of sulfinyl chlorides with diazomethane,25–29 but the analogues described by Campbell and Rosati. Firstly, the
first reported stable α-diazosulfoxides were the cephalosporin vinylic conjugation to the ester group in these compounds
derivatives synthesised by Campbell30,31 and by Rosati32 and may lend stability to these diazo compounds. In the work
co-workers (Scheme 4).
carried out by Hodson and Holt, diazo transfer was attempted
However, neither group commented on the significance of on β-sulfinyl ketones but not β-sulfinyl esters. Secondly, and
these compounds as the only examples of stable α-diazosulf- more plausibly, the rigid, fused bicyclic system could be envi-
oxides in the literature. Interestingly, in the original publication saged to provide kinetic stability to the compounds by reduced
of this work, both Campbell and Rosati mentioned that only conformational mobility, thus reducing the possibility of spon-
the S-sulfoxides underwent diazo transfer and this was attribu- taneous diazo decomposition by the proposed oxygen-transfer
ted to the steric hindrance of approach of the azides to the mechanism. While we envisaged that the ester conjugation
α-face of the sulfoxides.
was unlikely to provide an increase in stability that was
Based on the key reports by Hodson and Holt and the sole sufficient to rationalize the isolation of these compounds, we
report of the stable α-diazosulfoxide derivatives in the cepha- undertook a preliminary exploration of diazo transfer to α-sul-
losporin series from Campbell and Rosati, it appeared at the finyl esters without success.33 To explore the second hypoth-
outset of this research that diazo transfer to simple acyclic esis that conformational restriction was essential for the
2-ketosulfoxides does not provide stable α-diazosulfoxide stability of the α-diazosulfoxides in the cephalosporin series,
derivatives, but that in these compounds, facile oxygen trans- we designed and synthesized a series of bicyclic sulfoxide lac-
fer from sulfur to the carbene occurs with nitrogen tones and, indeed, found that successful diazo transfer to
these systems could be effected confirming our second pro-
posal. Preliminary results in this area have been reported33 and
herein we report full details of the synthesis of a series of both
monocyclic and bicyclic α-diazosulfoxides based on both
lactone and lactam systems.
Results and discussion
A series of sulfoxide-containing bicyclic and monocyclic lac-
Scheme 4 Diazo transfer to cephalosporin derivatives.
tones 32–49 and lactams 50–52 were designed and synthesized
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Table 1 Synthesis of bicyclic and monocyclic lactone sulfides
Entry
Epoxide
R1
R2
R3
Sulfide
% Yield
1
2
3
4
5
6
7
8
9
9 cisa
–(CH2)4–
–(CH2)4–
–(CH2)3–
–(CH2)5–
H
CH3
H
H
H
H
H
H
H
19b trans
20 trans
21c trans
22 trans
23 cis
24 trans
25d cis
26d trans
27 cis
97
62a
26
47
79
40
63
41
91
50e
10 cis
11 cis
12 cis
13 trans
14 cis
15 trans
16 cis
17 trans
18
CH3
CH3
Ph
CH3
CH3
Ph
Ph
CH3
CH3
Ph
Ph
CH3
10
CH3
28
a Cis and trans refers to the relationship between R1 and R2. Refer to
Fig. 1 for structures of the sulfoxide series of these compounds. b Ref.
34. c Product decomposed to complex mixture of unidentifiable
products after 24 h. d Ref. 33 and 41. e Product isolated from reaction
mixture was pure by 1H NMR spectroscopy.
Fig. 1 Monocyclic and bicyclic sulfoxides designed as substrates for diazo
transfer.
to provide substrates with restricted conformational mobility
with a view to effecting diazo transfer and establishing
whether stable α-diazosulfoxides could be formed and isolated
in these systems (Fig. 1). These systems were chosen to enable
detailed investigation of the impact of the relative orientation
of the sulfoxide and diazo moieties and the extent of confor-
mational mobility on the stability of the resulting diazo deriva-
tives. Clearly, the monocyclic systems are more
conformationally mobile than the bicyclic systems and hence,
at the outset, were envisaged to decompose more readily
through sulfur-to-carbon oxygen transfer as outlined by
Hodson and Holt. Furthermore, in the rigid bicyclic systems
such as the diastereomeric pair of trans-fused sulfoxides 32
and 33, and the cis-fused isomer 34, the relative orientation of
the sulfoxide and diazo moieties would be very different
enabling investigation of the impact of this on the stability of
the α-diazosulfoxide derivatives. Thus, in 32 the sulfoxide
oxygen lies in a pseudo-equatorial environment while in 33 the
oxygen lies in a pseudo-axial position. Following Hodson and
Holt’s proposal it was envisaged, at the outset, that oxygen
transfer from the axial sulfoxide 33 would occur more readily
than from the analogous equatorial sulfoxide 32. Thus, investi-
gation of the relative stability of diazo derivatives derived from
these sulfoxides would provide detailed insight into the mech-
anism of α-diazosulfoxide instability and allow exploration of
the Hodson and Holt proposal. As outlined below, our results
have indicated that the Hodson and Holt mechanism does not
accurately rationalize the instability of α-diazosulfoxides and
we suggest an alternative explanation.
successfully employed for the synthesis of the series of bicyclic
and monocyclic sulfides 19–28 as summarized in Table 1.34–36a
Sulfide oxidation can be readily effected with a range of oxi-
dants.50 Commercial m-CPBA (60–70%) was employed for the
oxidation of sulfides 19–21, 25, 27–31 to the corresponding
sulfoxides (Table 2, entries 1–4, 8, 10–13). For the sulfides
23–24 and 26, oxidation to the sulfoxides was achieved using
Oxone® in acetone/water (Table 2, entries 6–7, 9). In each
instance, the relative stereochemistry in the sulfoxides is
shown in Fig. 2. Over-oxidation to the sulfone does not cause
significant problems provided the amount of m-CPBA and the
reaction time is carefully controlled. The stereoselectivity of
the oxidation is strongly dependent on the sulfide structure,
with some of the derivatives leading to a single diastereomer
only, where the approach of the oxidant to one face of the
sulfide was sterically hindered. In other cases, two diastereo-
mers can be clearly distinguished and, in some cases, separ-
ated. All of the sulfoxides are stable compounds and can be
stored without any difficulty. Due to their high polarity, chro-
matographic purification in some cases required a very polar
eluent and separation of the diastereomers by chromatography
was challenging. Recrystallization could be used in some
instances to alter the diastereomeric ratio and, on occasion,
provide pure diastereomers. The terms ‘equatorial’ and ‘axial’
are employed to describe the relative stereochemistry of the
sulfoxide with ‘equatorial’ corresponding to α and ‘axial’ corres-
ponding to β. The oxidation can readily be done on a multi-
gram scale; however, separation of the diastereomers on this
scale is more challenging.
Bicyclic and monocyclic lactone and lactam sulfoxides
Oxidation of trans-hexahydrobenzo[b][1,4]oxathiin-2(3H)-
one 19 using m-CPBA gave an essentially equimolar diastereo-
meric mixture of sulfoxides with the oxygen on the sulfur
having a ‘pseudo equatorial’ 32 or ‘pseudo axial’ 33 orientation
Koskimies has described the synthesis of the bicyclic sulfide
19 from cyclohexene oxide by ring opening with thioglycolate
anion followed by lactonization.34 This approach was
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Table 2 Synthesis of bicyclic and monocyclic lactone and lactam sulfoxides
d.r. (Crude)
% Yield
d.r. (pure)
Entry
1
Sulfide
19
R1
R2
R3
H
Oxidant
Solvent
Sulfoxide
32 : 33
34
Eq : ax ratioa,b
–(CH2)4–
m-CPBA (1 eq.)
m-CPBA (1 eq.)
m-CPBA (1 eq.)
m-CPBA (1 eq.)
NaIO4
CH2Cl2
1 : 1
28 (32)c
22 (33)c
21
transg
–(CH2)4–
cis
2
29
H
CH2Cl2
1 diastereomer
9 : 1
3
20
–(CH2)4–
CH3
H
CH2Cl2
35 : 36
37 : 38
39 : 40
41
61
9 : 1
57
1 : 9
25
1.2 : 1
73
trans
4
21
–(CH2)3–
trans
–(CH2)5–
CH2Cl2
1 : 9
5
22
H
MeOH/H2O
Acetone/H2O
Acetone/H2O
CH2Cl2
1 : 1
trans
6
23
CH3
CH3
Ph
CH3
CH3
Ph
H
Oxone® (0.5 eq.)
Oxone® (0.5 eq.)
m-CPBA (1 eq.)
Oxone® (0.5 eq.)
m-CPBA (1 eq.)
m-CPBA (1 eq.)
m-CPBA (1 eq.)
m-CPBA (1 eq.)
1 diastereomer
1 : 3
cis
trans
cis
7
24
H
42 : 43
44
66
1 : 3
75
8
25
H
1 diastereomerf
2 : 1
9
26
Ph
Ph
H
Acetone/H2O
CH2Cl2
45 : 46
47
53d
76
trans
cis
10
11
12
13
27
CH3
CH3
Ph
Ph
H
1 diastereomer
1 : 8
28
CH3
Ph
CH3
H
CH2Cl2
48 : 49
50
33
1 : 7
73
30h
31h
CH2Cl2
1 diastereomer
1 : 1
cis
Ph
Ph
H
CH2Cl2
51 : 52
51e
trans
2.5 : 1
a The orientation of the sulfinyl oxygen which lies in either the pseudo-equatorial (α) or pseudo-axial (β) position. b The diastereomeric ratio of
mixed sulfoxides is calculated from integration of the CHO or CHN protons in the crude 1H NMR spectrum and is based on the crude product.
c Purification by slow recrystallization from dichloromethane/hexane gave equatorial sulfoxide 32 (28%), followed by axial sulfoxide 33 and ∼10%
equatorial sulfoxide 32 (22%). d Yield of crude product. e Recrystallization from ethyl acetate gave pure sulfoxides 51 and 52 as a 2.5 : 1 mixture of
diastereomers. f Trace amounts of a second diastereomer could be detected on careful examination of the 1H NMR spectrum. g Cis and trans
refers to the relationship between R1 and R2. Refer to Fig. 1 for structures of these compounds. h Ref. 41.
1
The assignments of the chemical shifts in the H NMR and
13C NMR spectra for the bicyclic sulfoxides 32 and 33 were
based on the assignments made by Evans36b,c on similar
systems and on the expected shielding and deshielding effects
of the electronegative heteroatoms in the ring.
1
The H NMR spectra of the equatorial and axial sulfoxides
show some characteristic differences which allow for ease of
identification of the relative stereochemistry of these com-
pounds. There exists in the assignment of 1H NMR of cyclic
sulfoxides an effect known as the “syn-axial” effect and this
leads to a dramatic deshielding (0.5–1.0 ppm) of the β-protons
which are in a syn diaxial orientation relative to the S–O bond.
The most important factor in the “syn-axial” effect seems to be
the Van der Waals interaction between the negatively charged
O atom and the syn β-protons. Thus the C-9 proton in the axial
sulfoxide 33 at δH 4.88 is deshielded because of this “syn-axial”
effect. This proton is actually in a syn diaxial orientation with
the lone pair when the sulfinyl oxygen is in the equatorial posi-
tion 32 and is shielded at δH 4.04 (Fig. 2) relative to the sulfide
Fig. 2 Orientation of sulfinyl oxygen in bicyclic sulfoxides 32 and 33.
(Fig. 2). Koskimies has proposed two possible conformations
for the fused lactone ring, the half-chair or the boat confor-
mation. The twist boat conformation of the fused lactone ring
and the relative orientation of the ‘equatorial’ 32 and ‘axial’ 33
sulfoxides are illustrated below (Fig. 2).34,40
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19. This data is consistent with the findings published by using an aqueous ethereal ammonia mixture (a 1% ammonia
Evans.36b,c
solution with diethyl ether) allowed their separation using
In addition for 13C NMR, Evans36b,c has carried out a study ethyl acetate–hexane 17 : 3 as the eluent. Alternatively addition
on the trans-hexahydro-1,4-benzoxathiane S-oxides and an of ammonia to ethyl acetate employed as eluent enables chro-
examination of the carbon chemical shifts he reported for matographic purification. A more efficient method for purifi-
these systems show that a correlation can be made with our cation was the slow recrystallization of the 1 : 1 diastereomeric
bicyclic sulfide 19 and sulfoxides 32 and 33. Note that in his sulfoxide mixture from dichloromethane–hexane which also
papers Evans has drawn the opposite enantiomers to the con- allowed separation of the sulfoxides. The sulfoxide 32 was iso-
vention we have chosen to represent our sulfides and sulf- lated in about 28% yield as a white solid from repeated recrys-
oxides and so for ease of comparison these have been made tallization of the crude material and sulfoxide 33 could then
consistent in Fig. 3 below.
be recovered from the mother liquor with further recrystalliza-
Evans has reported that the β carbon C-10 was more tion in 22% yield (Table 2, entry 1). In contrast, oxidation of
deshielded for the equatorial sulfoxides than the axial sulf- the diastereomeric cis-fused sulfide cis-hexahydrobenzo[b][1,4]-
oxides in all the conformationally similar systems that he has oxathiin-2(3H)-one 29 gave one sulfoxide diastereomer under
studied Fig. 3. This can also be seen in our sulfoxides with the the same oxidation conditions with exclusive exo approach of
C-10 of the axial sulfoxides shifted upfield by ∼10 ppm relative the oxidant to the sulfide (Table 2, entry 2).
to the C-10 of the equatorial sulfoxide. While a detailed NMR
Oxidation
of
trans-8a-methyl-hexahydrobenzo[b][1,4]-
discussion on the assignment of stereochemistry of the sulf- oxathiin-2(3H)-one 20 gave a 9 : 1 diastereomeric mixture of 35
oxides 32 and 33 is warranted as model derivatives in this work, and 36 sulfoxides, with approach of the oxidant from the
full 1H and 13C NMR data for all other sulfides, sulfoxides and β face hindered by the presence of the methyl group in the
diazosulfoxides are detailed in the Experimental section with axial position at the bridgehead leading to diastereoselectivity
spectral supports for the stereochemistry of the sulfoxides fully in the reaction (Table 2, entry 3). For the oxidation of trans-
assigned there.
hexahydro-2H-cyclopenta[b][1,4]oxathiin-2-one 21 (Table 2, entry
It was found that the separation of these diastereomers 4), because the starting sulfide had proved to be somewhat
was extremely difficult due to their high polarity and close labile the oxidation reactions were performed directly on iso-
Rf values. These compounds could not be readily or consist- lation of the sulfide and care was taken in the work-up, as
ently eluted from silica gel even using solvents of high polarity decomposition of the product by ring opening of the lactone
like ethyl acetate. However, pre-treatment of the silica gel was a possibility. Thus, generally separation of the diastereo-
mers 37 and 38 by column chromatography was not attempted
(on one occasion attempted chromatography led to some sep-
aration but in yields of less than 5%), and instead, the pure
sulfoxides were isolated as a white solid in 57% yield after
recrystallization from ethyl acetate. Interestingly the diastereo-
meric ratio (1 : 9) was unaffected by recrystallization in this
instance, and furthermore, the increase in diastereoselection
on reduction of the ring size of the fused ring from cyclo-
hexane to cyclopentane due to conformational changes is
notable.
Initial attempts to oxidize trans-octahydro-2H-cyclohepta[b]-
[1,4]oxathiin-2-one 22 with m-CPBA revealed the formation of
substantial amounts of sulfone, and therefore use of sodium
metaperiodate as oxidant was explored and led successfully to
the sulfoxide, avoiding competing over-oxidation. In this
instance, approach of the oxidant from either face of the
sulfide is equally facile leading to an essentially equimolar
mixture of diastereomers as seen in the cyclohexyl-fused
sulfide 19. There was a slight alteration of the diastereomeric
ratio on purification by chromatography (Table 2, entry 5). Sub-
sequent purifications using careful chromatography led to the
isolation of the more polar sulfoxide 40 as a single diastereo-
mer which is believed to be the β-sulfoxide, although this has
not been definitively confirmed.
Oxidation of cis and trans-5,6-dimethyl-[1,4]oxathian-2-one
23 and 24 was achieved using Oxone® to give the correspond-
Fig. 3 13C NMR assignments of bicyclic sulfide 19, sulfoxides 32, 33 and com-
parison to compounds studied by Evans.36b,c
ing sulfoxides. cis-5,6-Dimethyl-[1,4]oxathian-2-one S-oxide 41
was isolated as a single diastereomer in 73% yield after
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chromatography with selective approach of the oxidant from
the face opposite to the two methyl substituents, as expected.
When this oxidation was conducted on a large scale, traces of
the second diastereomer were detected in the 1H NMR spec-
trum. Oxidation could also be achieved using m-CPBA,
however the yield was very low from this reaction (30%). Oxi-
dation of the trans-sulfide 24 gave a 3 : 1 diastereomeric
mixture of axial 43 and equatorial 42 sulfoxides as a white
solid in good yield after chromatography (Table 2, entry 7). It
is interesting to compare the diastereoselectivity trends seen
in oxidation of the cis and trans-fused bicyclic sulfide 19 with
those seen for cis and trans 23 and 24 – in both cases the oxi-
dation of the cis substituted compounds occurs with excellent
stereocontrol, while both diastereomers of the sulfoxides are
formed in the trans substituted derivatives albeit with slightly
different ratios (1 : 1 cf. 3 : 1).
Optimum yields in the synthesis of diphenyl sulfoxides
44–46 (Table 2, entries 8–9) were obtained with Oxone® in the
case of the trans isomer while m-CPBA proved effective for the
cis isomer.33 Once again a single diastereomer is seen in
oxidation of the cis substituted isomer while approach of
the oxidant occurs from both faces of the trans substituted
sulfide 26. cis-6-Methyl-5-phenyl-[1,4]oxathian-2-one S-oxide 47
was isolated as a single diastereomer in 76% yield after chro-
matography (Table 2, entry 10). Again oxidation occurs only from
one face due to the presence of the two cis substituents.
A diastereoselective oxidation of the trimethyl sulfide 28
was also observed and a 1 : 8 mixture of products was
obtained (Table 2, entry 11). In this instance the relative stereo-
chemistry of the diastereomers is tentatively assigned as
illustrated in Fig. 1 but has not been definitively confirmed.
Oxidation of the cis-sulfide41 30 with m-CPBA led to the
formation of cis-5,6-diphenyl-thiomorpholin-3-one S-oxide (50)
as a single diastereomer and as a white solid in 73% yield
after recrystallization from ethyl acetate (Table 2, entry 12).
The trans-sulfide41 31 gave a 1 : 1 diastereomeric mixture
of sulfoxides after work-up. Recrystallization from ethyl
acetate gave the pure sulfoxides 51 : 52 as a white solid in 51%
yield with the changed diastereomeric ratio of 2.5 : 1 (Table 2,
entry 13).
Fig. 4 Oxidant approach in trans and cis-disubstituted sulfides.
Scheme 5 Synthesis of bicyclic α-diazosulfoxides.
In general for the cis-disubstituted sulfides, in both the
bicyclic and monocyclic series, oxidation occurs with excellent
stereocontrol from the face opposite to the two substituents
(Table 2, entries 2, 6, 8, 10 and 12) while approach of the
The results of this work showed that stable, isolable
oxidant to both faces of the analogous trans-disubstituted sul- α-diazo-β-oxo sulfoxides could be synthesised by diazo transfer
fides is seen with varying ratios of the diastereomers formed to lactones bearing a sulfinyl group and that this stability
depending on the substituents present and the conformational seems to be linked to the relative orientation of the sulfoxide
features of the compound (Fig. 4).
and diazo groups in the cyclic framework.33 Based on these
initial results expansion of the range of bicyclic and mono-
cyclic α-diazosulfoxides was undertaken as discussed below.
Diazo transfer reagents have been reviewed,7,20–22 most
Bicyclic and monocyclic lactone and lactam α-diazosulfoxides
In our preliminary report the α-diazosulfoxides 53–55 were suc- notably a review of their utility, safety and stability carried out
cessfully synthesised from the corresponding sulfoxides under by Bollinger and co-workers.42,43
the conditions shown in Scheme 5.33 Initial investigations also
To explore the methodology for the diazo transfer to the
showed that diazo transfer to monocyclic sulfoxides could also sulfoxide precursors, diazo transfer was carried out on equa-
be achieved.
torial and axial sulfoxides (4R*,4aR*,8aR*)-hexahydrobenzo
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and axial sulfoxides were exposed to diazo transfer there is evi-
dence that formation of the equatorial α-diazosulfoxide is less
efficient than the axial which may indicate a stability differ-
ence depending on the orientation of the sulfoxide. The tosyl
amide by-product that was formed in the reaction could be
removed by washing the crude mixture with sodium bicarbo-
nate solution; however this leads to loss of some of the diazo
product, probably due to ring opening of the lactone under the
basic conditions. In general it was found that it is better to
avoid a base wash in the work up of the diazo transfer reac-
tions as this leads to reduced yields. In the optimised pro-
cedure, the α-diazosulfoxides were freed from solvent and
purified by chromatography, without further work-up. The
tosyl amide by-product is eluted from the column first and the
α-diazosulfoxides are then eluted as a yellow band from the
column.
Table 3 Influence of the reaction conditions on the diazo transfer to equatorial
and axial trans-hexahydro-benzo[1,4]oxathiin-2-one-S-oxides 32 and 33
Diazo transfer
Sulfoxide reagent
Product
Solvent (Yield)
Base
32
TsN3 (1.0 eq.)
Et3N (1.0 eq.) CH3CN 53 (43%)
Diazo transfer to the series of sulfoxides was, in general,
most efficient with p-toluenesulfonyl azide (tosyl azide)44 and
triethylamine in acetonitrile, except for the lactam derivatives
50, 51 and 52 where sodium hydride and THF were used
instead, as a stronger base was required for initial deproto-
nation (Table 4, entries 15 and 16). For the diphenyl lactone
sulfoxides, acetamidobenzenesulfonyl azide45,46 was used for
diazo transfer to 44 (Table 4, entry 11), while dodecylbenzene-
sulfonyl azides47 were used for 45 and 46 (Table 4, entry 12).
Each of the α-diazosulfoxides was a yellow, crystalline solid
which was readily purified by chromatography and stored in a
freezer for several months without any degradation. Analytical
samples of the α-diazosulfoxides could be prepared by recrys-
tallization from diethyl ether.
Diazo transfer to a 9 : 1 mixture of (4R*,4aR*,8aR*)-8a-
methyl-hexahydrobenzo[1,4]oxathiin-2-one S-oxide 35 and
(4R*,4aS*,8aS*)-8a-methyl-hexahydrobenzo[1,4]oxathiin-2-one
S-oxide 36 gave the crude product as a 5 : 1 mixture of the
α-diazosulfoxides 56 : 57 by 1H NMR spectroscopy. After
chromatography, the ratio of α-diazosulfoxides remained
unchanged and the diastereomers were isolated as a yellow
crystalline solid in 30% yield after chromatography (Table 4,
entry 5). The change in ratio of the α-diazosulfoxides (5 : 1)
that were isolated from the reaction compared to the ratio of
the starting sulfoxides (9 : 1) indicates that the equatorial α-di-
32
32
32
33
p-CarbN3 (1.0 eq.) Et3N (3.0 eq.) CH3CN 53 (26%)
p-AcetN3 (1.0 eq.) Et3N (3.0 eq.) CH3CN 53 (28%)
NaphtN3 (1.1 eq.) EtN3 (1.0 eq.) CH3CN 53 (25%)
TsN3 (1.0 eq.)
Et3N (1.0 eq.) CH3CN 54 (40%)
33
p-CarbN3 (1.0 eq.) Et3N (3.0 eq.) CH3CN 54 (25%)
32 : 33
(1 : 1)
32 : 33
(1 : 1)
32 : 33
(1 : 9)
TsN3 (1.0 eq.)
TsN3 (1.0 eq.)
TsN3 (1.0 eq.)
Et3N (1.0 eq.) CH3CN 53 : 54 (1 : 1)
(27%)
Et3N (1.0 eq.) CH2Cl2 53 : 54 (1 : 1)
(23%)
Et3N (1.0 eq.) CH3CN 53 : 54 (1 : 8)
(28%)
[1,4]oxathiin-2(3H)-one S-oxide 32 and (4R*,4aS*,8aS*)-hexa-
hydrobenzo[1,4]oxathiin-2(3H)-one S-oxide 33 as model com-
pounds, using various diazo transfer conditions as outlined in
Table 3.
Thus a range of diazo transfer reagents (tosyl azide, mesyl
azide and dodecylbenzenesulfonyl azide, p-carboxybenzenesul-
fonyl azide,48 p-acetamidobenzenesulfonyl azide45,46 and
naphthalenesulfonyl azide49) and bases (potassium carbonate
and triethylamine) in various solvents (acetonitrile, ethanol
and dichloromethane) were explored (main examples shown
in Table 3). The optimum conditions established for diazo
transfer involve use of tosyl azide as the transfer reagent and
triethylamine as the base in acetonitrile. Diazo transfer to the
axial sulfoxide 33 led to the isolation of the α-diazosulfoxide
54 in 40% yield after chromatography. The corresponding
equatorial sulfoxide 32 also underwent successful diazo trans-
fer to afford the α-diazosulfoxide 53 in 43% after chromato-
graphy. An equimolar mixture of the trans-sulfoxides was also
subjected to the same diazo transfer conditions as above and
afforded a mixture of axial 54 and equatorial 53 α-diazosulf-
oxides (1 : 1) in 27% yield.
Following the optimised procedure, extension of the diazo
transfer to the series of sulfoxides 34–52 was undertaken as
summarized in Table 4. In general yields were modest and,
while no unreacted starting material was recovered in any
instance, it was not possible to isolate or characterize any sig-
nificant by-product. Thus diazo transfer leads to stable α-di-
azosulfoxides not only in the rigid bicyclic system but also in
the monocyclic systems 41–52. Where mixtures of equatorial
azosulfoxide,
(4R*,4aS*,8aS*)-3-diazo-8a-methyl-hexahydro-
benzo[1,4]oxathiin-2-one S-oxide 56 is perhaps less stable
than the axial α-diazosulfoxide, (4R*,4aR*,8aR*)-3-diazo-
8a-methyl-hexahydrobenzo[1,4]oxathiin-2-one S-oxide 57. The
α-diazosulfoxides 56 and 57 could be separated after repeated
chromatography and recrystallization from diethyl ether.
For the lactam α-diazosulfoxide series it is interesting to
note that when triethylamine or potassium carbonate were
used as bases in acetonitrile, diazo transfer was unsuccessful
and only the starting sulfoxides 50, 51 and 52 were recovered
unreacted. Use of sodium hydride (1.2 equivalents) was necess-
ary for successful diazo transfer to these sulfoxides. The cis
α-diazosulfoxide, (1R*,5R*,6S*)-2-diazo-5,6-diphenyl-thiomor-
pholin-3-one S-oxide 71 was isolated in high yield while the
corresponding trans α-diazosulfoxides, (1R*,5S*,6S*)-2-diazo-
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Table 4 Synthesis of bicyclic and monocyclic lactone and lactam diazosulfoxides
Diazo transfer
reagent (1 eq.)
d.r. Crude
% Yield
d.r. Pure
Entry
1
Sulfoxide
R1
R2
R3
H
Base/solvent
α-Diazosulfoxide
Eq : ax ratioa,b
1 diastereomer
1 diastereomer
1 : 1
32
33
–(CH2)4–
transc
–(CH2)4–
TsN3
Et3N(1.0 eq.)/CH3CN
Et3N(1.0 eq.)/CH3CN
Et3N(1.0 eq.)/CH3CN
Et3N(1.0 eq.)/CH3CN
Et3N(1.0 eq.)/CH3CN
Et3N(1.0 eq.)/CH3CN
Et3N(1.0 eq.)/CH3CN
Et3N(1.0 eq.)/CH3CN
Et3N(1.0 eq.)/CH3CN
Et3N(1.0 eq.)/CH3CN
Et3N(1.0 eq.)/CH3CN
K2CO3(1.1 eq.)/CH3CN
Et3N(1.0 eq.)/CH3CN
Et3N(1.0 eq.)/CH3CN
NaH (1.2 eq.)/THF
NaH (1.2 eq.)/THF
53
43
40
2
H
TsN3
54
trans
3
32 : 33
1 : 1
34
–(CH2)4–
trans
–(CH2)4–
H
TsN3
53 : 54
55
27
1 : 1
38
4
H
TsN3
1 diastereomer
5 : 1
cis
5
35 : 36
9 : 1
37 : 38
1 : 9
–(CH2)4–
trans
–(CH2)3–
CH3
H
TsN3
56 : 57
58 : 59
61
30
5 : 1
5 (58)
57 (59)
34
6
TsN3
1 : 9
trans
7
40
–(CH2)5–
trans
–(CH2)5–
H
TsN3
1 diastereomer
1 : 1
8
39 : 40
1 : 1.4
41
H
TsN3
60
61
62
10 (60)
trans
9
CH3
CH3
H
TsN3
1 diastereomer
1 : 3.5
30
cis
trans
cis
10
11
12
13
14
15
16
42 : 43
1 : 3
44
CH3
Ph
CH3
Ph
H
TsN3
63 : 64
65
37
1 : 3.5
46
H
p-AcetN3
DodN3
TsN3
1 diastereomer
1 : 2
45 : 46
2 : 1
47
Ph
Ph
H
66 : 67
68
10
1 : 2
45
trans
CH3
CH3
Ph
Ph
H
1 diastereomer
1 : 7
cis
48 : 49
1 : 4
50
CH3
Ph
CH3
H
TsN3
69 : 70
71
39
1 : 7
62
TsN3
1 diastereomer
1.6 : 1
cis
51 : 52
2.5 : 1
Ph
Ph
trans
H
TsN3 (1.0 eq.)
72
73
27
1.6 : 1
a The orientation of the sulfinyl oxygen which lies in either the pseudo-equatorial (α) or pseudo-axial (β) position. b The diastereomeric ratio of
mixed diazosulfoxides is calculated from integration of the CHO or CHN protons in the crude 1H NMR spectrum and is based on the crude
product. c Cis and trans refers to the relationship between R1 and R2. Refer to Fig. 1 for structures of the sulfoxide series of these compounds.
5,6-diphenyl-thiomorpholin-3-one S-oxide 72 and (1R*,5R*,6R*)- demonstrating that additional conjugation to an ester, ketone
2-diazo-5,6-diphenyl-thiomorpholin-3-one S-oxide 73 could or phosphonate moiety was not sufficient to provide stability
only be isolated as an inseparable mixture of diastereomers to the diazo derivative (Scheme 6). Significantly, even with use
in low yield after chromatography (Table 4, entries 15 of the strongly electron withdrawing methyl imidazolyl sulf-
and 16).
oxides 75 and 76, diazo transfer did not prove successful. Con-
All attempts to effect diazo transfer to acyclic α-sulfinyl sumption of the starting materials during the reaction points
ketones, esters and phosphonates proved unsuccessful. As out- to the fact that diazo transfer may have taken place, but that
lined above at the outset we had envisaged two possible expla- the resulting α-diazosulfoxides were not stable and decom-
nations for the unusual stability of the α-diazosulfoxides posed in a manner similar to that proposed by Hodson and
described by Rosati and Campbell – conjugation to an ester Holt for the α-sulfinyl ketone derivatives.
rather than a ketone, or conformational restriction. While the
In another series of experiments, employing the acyclic
latter explanation was seen as more likely, a series of experi- α-sulfinyl esters 7451 and 79–81,54–56 addition of m-CPBA was
ments was undertaken to explore the first possibility. Thus, made directly following the diazo transfer process and
we attempted diazo transfer to a series of simple acyclic α-sul- aqueous work-up, and indeed on this occasion a low yield of
finyl esters 74–76,51 phosphonate52 77 and ketone53 78 but iso- the corresponding α-diazosulfones 82–85 was isolated and
lation of the corresponding α-diazosulfoxides was not possible characterized in each case (Table 5). This indicates that diazo
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Scheme 6 Attempted diazo transfer to acyclic α-sulfinyl esters.
Fig. 5 Alternative interpretation of instability of acyclic diazosulfoxides.
transfer to the sulfinyl ester did in fact take place, but that the
diazo derivative decomposes readily on attempted isolation
and purification. In each case the α-diazosulfones 82–85 were
identified by comparison to samples generated by diazo trans-
fer to the analogous sulfones.
envisaged to occur more readily in the axial rather than equa-
torial diastereomers.
Instead the intrinsic instability of simple acyclic α-diazo-
sulfoxides is perhaps better rationalized as being due to
overlap of the sulfinyl lone pair of electrons with the unsatu-
rated diazo moiety thereby facilitating loss of the diazo group
as illustrated above (Fig. 5). Once the conformational mobility
of the system is restricted in either a mono or bicyclic ring
system then the ease of electron donation from the sulfinyl
lone pair is decreased and accordingly the stability of the
α-diazosulfoxide increases. This rationale is consistent with
the observed enhanced stability of the axial relative to equator-
ial α-diazosulfoxides.
Interestingly, investigation of the imidazole sulfoxide in the
acyclic series, as illustrated in Scheme 6 showed clearly that
the presence of a strongly electron withdrawing substituent on
the sulfoxide was not sufficient to stabilise the labile α-diazo-
sulfoxides in the acyclic series. Thus the stabilizing effect in
the cyclic series associated with restriction in conformational
mobility is more powerful in allowing isolation of the α-diazo-
sulfoxides than simple electronic effects.
Stability of α-diazosulfoxides
From the results described above it is possible to rationalize
the fact that diazo transfer adjacent to the sulfoxide moiety
only produces stable, isolable α-diazosulfoxides when the con-
formational mobility of the precursor is restricted. Hodson
and Holt’s mechanistic interpretation, whereby the instability
of α-diazosulfoxides is rationalized by interaction of the sulf-
oxide oxygen with the diazo carbon, requires adjustment in the
context of our results. It is clear that the ‘axial’ α-diazosulf-
oxides, e.g. 54 are more stable than the analogous equatorial
derivatives e.g. 53; this is not consistent with the rationale pro-
vided by Hodson and Holt as oxygen transfer would be
Table 5 Diazo transfer to acyclic β-oxo sulfoxides 74 and 79–81 followed by
oxidation to the corresponding α-diazo-β-oxo sulfones 82–85
Investigation of the reactivity of the α-diazo-β-oxo sulfoxides
under a variety of conditions has been undertaken. Initial pub-
lished results by this group58–61 have shown that under tran-
sition metal catalysis, photolysis and microwave conditions,
these α-diazo-β-oxo sulfoxides undergo a hetero Wolff-type
rearrangement of the carbenoid to give α-oxo sulfines 90.
These α-oxo sulfines can undergo cycloaddition reactions
leading to novel cycloadducts in the presence of a diene trap
(Scheme 7). Further details on this will follow in due course.
Conclusion
Diazo
transfer
time (min)
Oxidation
time (h)
Diazosulfone
(Yield)
Sulfone54
(Yield)
We have reported here the successful synthesis of a range of
stable, isolable bicyclic and monocyclic α-diazo-β-oxo sulf-
oxides by diazo transfer to the corresponding sulfinyl lactones
and lactams, while acyclic systems remain elusive. Restricting
the conformational mobility in a cyclic system is essential to
enable isolation of stable diazo derivatives, with the relative
orientation of the sulfoxide and diazo moieties having an
impact on stability.
Sulfoxide
74
50
50
50
45
5
6
8
8
82 (7%)
83 (10%)
84 (16%)
85 (9%)
86 (4%)
87 (2%)
88 (15%)
89 (9%)
R = 1-butyl
79
R = 1-octyl
80
R = 1-dodecyl
81
R = Phenyl
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Scheme 7 Formation of α-oxo sulfine intermediate 90 from α-diazo-β-oxo sulfoxides 53 and 54 and subsequent trapping as cycloadducts 91 and 92.
performed using silica gel 60. Visualisation was achieved by
UV (254 nm) light detection, iodine staining, vanillin staining
and ceric sulfate staining.
Experimental section
General procedures
All solvents were distilled prior to use as follows: dichloro-
methane and ethyl acetate were distilled from phosphorus
Typical procedure for the synthesis of sulfides
pentoxide, hexane was stored over calcium chloride and dis-
tilled prior to use, ethanol and methanol were distilled from
magnesium in the presence of iodine, diethyl ether was dis-
tilled from lithium aluminium hydride, tetrahydrofuran (THF)
was distilled from sodium benzophenone ketyl.1 Dimethylform-
amide (DMF) and toluene were stored for 24 hours over
calcium hydride then distilled and stored over 4 Å molecular
sieves. Molecular sieves were dried by heating at >100 °C
under vacuum overnight. Organic phases were dried using
anhydrous magnesium sulfate. All commercial reagents were
used without further purification unless otherwise stated. 1H
NMR (400.13 Hz) spectra were recorded on a 400 NMR spec-
(a) A solution of thioglycolic acid (0.62 mL, 8.9 mmol, 1 eq.) in
methanol (5 mL) was added dropwise over 5 min to a freshly
prepared solution of sodium methoxide (sodium, 0.41 g,
17.8 mmol, 2 eq.) in methanol (30 mL) at 0 °C with constant
stirring giving a pink coloured solution. 1-Methyl-1-cyclohex-
ene oxide 10 (1.01 g, 8.9 mmol, 1 eq.) in methanol (5 mL) was
slowly added dropwise to the reaction flask and an exothermic
reaction commenced. This reaction mixture was stirred at
room temperature for 10 min and then refluxed for 2 h. After
cooling, the solution was concentrated under reduced pressure
to a white solid. This was dissolved in ice-water (25 mL) and
acidified to pH 1 by slow addition of concentrated HCl at 0 °C.
A colour change was observed on acidification giving a cloudy
aqueous solution which was extracted with diethyl ether
(45 mL). The organic layer was dried and concentrated under
reduced pressure to give the crude hydroxy acid quantitatively
as a colourless oil.
1
trometer, H (300 MHz) and 13C (75.5 MHz) NMR spectra were
1
recorded on a 300 MHz, NMR spectrometer and H (270 MHz)
and 13C (67.8 MHz) NMR spectra were recorded on a 270 MHz
NMR spectrometer. All spectra were recorded at room tempera-
ture (∼20 °C) in deuterated chloroform (CDCl3) unless other-
wise stated using tetramethylsilane (TMS) as an internal
standard. Chemical shifts were expressed in parts per million
(ppm) and coupling constants in Hertz (Hz). Elemental ana-
lyses were performed using an elemental analyzer. Melting
points were carried out on a capillary melting point apparatus
and are uncorrected. Mass spectra were recorded on a double
focusing high resolution mass spectrometer (EI), a time of
flight spectrometer (ESI) and a triple quadrupole spectrometer
(ESI). Infrared spectra were recorded as potassium bromide
(KBr) discs for solids or thin films on sodium chloride plates
for oils on a FT-IR spectrometer.
(b) The crude hydroxy acid was dissolved in toluene
(100 mL) and a catalytic amount of 4-toluenesulfonic acid was
added (∼5 mol%). The reaction mixture was heated at reflux
overnight using a Dean–Stark trap. The cooled reaction
mixture was washed with water (20 mL) [on occasion a sodium
bicarbonate wash was employed], the organic layer dried and
concentrated under reduced pressure to give the pure product
20 as a colourless oil (1.02 g, 62%), full characterization below.
Other sulfides were purified either by column chromatography
or recrystallization as described below.
trans-Hexahydrobenzo[b][1,4]oxathiin-2(3H)-one
19.34–36
.
Thin layer chromatography (TLC) was carried out on pre-
coated silica gel plates. Column chromatography was
From cyclohexene oxide 9 (9.73 mL, 94.50 mmol); recrystal-
lized from dichloromethane/hexane gave an off-white
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crystalline solid (15.02 g, 97%); mp 87–88 °C (lit.,34–36 colourless oil (1.60 g, 79%); νmax(film)/cm−1 1731 (CvO); δH
88–89 °C); νmax(KBr)/cm−1 1734 (CvO), 1447, 1261, 1126, (300 MHz, CDCl3) 1.29 (3H, d, J 6.9, CH3), 1.43 (3H, d, J 6.5,
1040; δH (300 MHz, CDCl3) 1.27–2.38 (8H, m, 4 × CH2ring), CH3), 3.21 (1H, A of ABq, J 14.7, one of SCH2), 3.28 (1H, qd,
3.00 (1H, ddd appears as dt, J 10.7, 10.7, 4.5, CHS), 3.23 (1H, J 6.9, 2.7, CHS), 3.58 (1H, B of ABq, J 14.7, one of SCH2), 4.66
A of ABq, J 15.0, one of SCH2), 3.69 (1H, B of ABq, J 15.0, (1H, qd, J 6.5, 2.6, CHO); δC (75.5 MHz, CDCl3) 16.1, 17.8
one of SCH2), 4.17 (1H, ddd appears as dt, J 10.7, 10.7, (2 × CH3), 26.0 (CH2, SCH2), 37.3 (CH, CHS), 77.1 (CH, CHO),
4.5, CHO); δC (75.5 MHz, CDCl3) 23.7 (CH2, SCH2), 25.1, 168.3 (CvO). Found (HRMS, EI): m/z 146.0395. C6H10O2S
26.8, 32.2, 32.6 (4 × CH2ring), 43.1 (CH, CHS), 81.6 (CH, CHO), requires M+ 146.0402; 146 (M+, 48%), 120 (5), 104 (12), 87 (8),
168.2 (CvO).
74 (45), 60 (100), 56 (52), 45 (31), 41 (40).
trans-8a-Methyl-hexahydrobenzo[b][1,4]oxathiin-2(3H)-one
trans-5,6-Dimethyl-[1,4]oxathian-2-one 24. From cis-2,3-
20. Note epoxide (10) was prepared by m-CPBA oxidation of dimethyl-oxirane 14 (1.04 mL, 12.00 mmol); purification by
1-methyl-cyclohexene.37,38 Pure product colourless oil (1.02 g, column chromatography (ethyl acetate–hexane 20 : 80) gave a
62%); νmax(film)/cm−1 1725 (CvO); δH (300 MHz, CDCl3) colourless oil (0.81 g, 40%); νmax(film)/cm−1 1742 (CvO); δH
1.25–1.90 (10H, m containing s at 1.58, 7 of H of CH2ring and (300 MHz, CDCl3) 1.32 (3H, d, J 6.7, CH3), 1.44 (3H, d, J 6.2,
CH3), 2.05 (1H, br d, J 11.9, 1 of H of CH2ring), 3.12 (1H, dd, CH3), 3.11 (1H, dq, J 13.3, 6.7, CHS), 3.21 (1H, A of ABq, J 14.8,
J 12.1, 3.7, CHS), 3.46 (1H, A of ABq, J 16.8, SCH2), 3.64 (1H, B one of SCH2), 3.67 (1H, B of ABq, J 14.8, one of SCH2), 4.30
of ABq, J 16.8, SCH2); δC (75.5 MHz, CDCl3) 19.3 (CH3), 22.5 (1H, dq, J 13.3, 6.2, CHO); δC (75.5 MHz, CDCl3) 18.6, 19.1
(CH2, SCH2), 25.6, 28.4, 28.6, 39.1 (4 × CH2ring), 46.0 (CH, (2 × CH3), 26.7 (CH2, SCH2), 39.8 (CH, CHS), 80.5 (CH, CHO),
CHS), 86.2 (C–Me), 166.3 (CvO). Found (HRMS, EI): m/z 168.3 (CvO). Found (HRMS, EI): m/z 146.0397. C6H10O2S
186.0725. C9H14O2S requires M+ 186.0715; 186 (M+, 50%), requires M+ 146.0402; 146 (M+, 70%), 118 (5), 111 (18),
156 (8), 144 (13), 111 (15), 96 (72), 86 (88), 81 (47), 71 (19), 104 (15), 87 (6), 74 (73), 60 (100), 45 (32), 41 (55).
55 (15), 43 (48), 32 (100).
cis-5,6-Diphenyl-[1,4]-oxathian-2-one 25.41 From trans-stil-
trans-Hexahydro-2H-cyclopenta[b][1,4]oxathiin-2-one 21.39. bene oxide 15 (3.00 g, 15.29 mmol); purification by column
From cyclopentene oxide 11 (1.04 mL, 12.00 mmol); recrystalli- chromatography (ethyl acetate–hexane 10 : 90) gave a white
zation from dichloromethane/hexane gave
a white solid crystalline solid (2.60 g, 63%); mp 145–147 °C (recrystallized
(0.490 g, 26%) which was found to be unstable and decom- from dichloromethane/hexane); νmax(KBr)/cm−1 1752 (CvO);
posed to complex mixture of unidentifiable products after δH (300 MHz, CDCl3) 3.53 (1H, A of ABq, J 14.4, 0.5, one of
24 h, mp 56–58 °C; νmax(KBr)/cm−1 1744 (CvO), 1466, 1269, SCH2), 3.99 (1H, B of ABq, J 14.4, SCH2), 4.55 (1H, d, J 3.3,
1143, 973; δH (300 MHz, CDCl3) 1.46–2.29 (6H, m, 3 × CH2ring), CHS), 5.74 (1H, d, J 3.2, CHO), 6.87–7.04 (4H, m, ArH),
3.09 (1H, ddd appears as dt, J 10.2, 10.2, 7.3, CHS), 3.29 (1H, A 7.08–7.25 (6H, m, ArH); δC (75.5 MHz, CDCl3) 28.0 (CH2,
of ABq, J 14.7, one of SCH2CO), 3.67 (1H, B of ABq, J 14.7, one SCH2), 49.4 (CH, CHS), 81.6 (CH, CHO), 126.0, 127.9, 128.1,
of SCH2CO), 4.47 (1H, ddd appears as dt, J 10.2, 10.0, 7.9, 128.3, 129.7 (CH, ArCH), 135.1, 136.0 (C), 168.2 (CvO). Found
CHO); δC (75.5 MHz, CDCl3) 20.0, 26.4, 28.3, 28.6 (3 × CH2ring (HRMS, EI): m/z 270.0705. C16H14O2S requires M+ 270.0715;
and SCH2CO), 42.4 (CH, CHS), 85.6 (CH, CHO), 168.6 (CvO). 270 (M+, 11%), 180 (53), 122 (100), 91 (17), 77 (40), 44 (39).
Found (HRMS, EI): m/z 159.0459. C7H11O2S requires M+
trans-5,6-Diphenyl-[1,4]-oxathian-2-one 26.41 From cis-stil-
159.0480; 159 (M+ + 1, 40%), 149 (23), 125 (7), 111 (53), 97 (31), bene oxide 16 (1.34 g, 6.83 mmol); purification by column
91 (15), 83 (38), 67 (100), 57 (24), 43 (52), 36 (3), 32 (22).
trans-Octahydro-2H-cyclohepta[b][1,4]oxathiin-2-one
chromatography (diethyl ether–hexane 50 : 50) gave a colour-
22. less oil (0.760 g, 41%); νmax(film)/cm−1 1754 (CvO);
From cycloheptene oxide 12 (8.349 g, 74.4 mmol); purification δH (270 MHz, CDCl3) 3.49 (1H, A of ABq, J 14.4, one of SCH2),
by column chromatography (hexane–ether 7 : 3) gave a white 4.06 (1H, B of ABq, J 14.4, SCH2), 4.44 (1H, d, J 11.0, CHS),
solid (2.770 g, 20%); mp 44–45 °C; (Found C, 58.16; H, 7.58; S, 5.45 (1H, d,
J 11.0, CHO), 6.93–7.35 (10H, m, ArH).
17.58. C9H14O2S requires C, 58.03; H, 7.27; S, 17.21%); δC (67.8 MHz, CDCl3) 27.5 (CH2, SCH2), 50.7 (CH, CHS), 85.6
νmax(KBr)/cm−1 1732 (CvO), 1264 (C−O); δH (300 MHz, CDCl3) (CH, CHO), 127.2, 128.0, 128.5, 128.7 (CH, ArCH), 135.9, 137.0
1.38–1.94 (9H, m, CH2ring), 2.05–2.22 (1H, m, one of CH2ring), (C), 167.7 (CvO). Found (HRMS, EI): m/z 270.0707. C16H14O2S
3.14 (1H, overlapping ddd appears as dt, J 9.8, 9.8, 3.0, CHS), requires M+ 270.0715; 270 (M+, 5%), 228 (41), 180 (11),
3.22 (1H, A of ABq, J 14.7, SCH2), 3.68 (1H, B of ABq, J 14.5, 122 (38), 98 (90), 91 (11), 77 (11), 67 (100), 43 (92).
SCH2), 4.17–4.37 (1H, m, CHO); δC (75.5 MHz, CDCl3) 22.0,
cis-6-Methyl-5-phenyl-[1,4]oxathian-2-one 27. From trans-
25.5, 27.27, 27.31, 30.8 (5 × CH2ring), 33.5 (SCH2), 46.3 (CHS), methylstyrene oxide 17 (1.01 g, 7.40 mmol); pure product
85.4 (CHO), 168.9 (CvO). Found (HRMS, ESI+): m/z 187.0779. colourless oil (1.40 g, 91%); νmax(film)/cm−1 1739 (CvO);
C9H14O2S [M + H]+ requires M+ 187.0793; 187 [(M + H)+, 40%], δH (300 MHz, CDCl3) 1.18 (3H, d, J 6.3, CH3), 3.35 (1H, A of
95 (100), 42 (58). Note: More recently, it has been found that ABq, J 14.5, one of SCH2), 3.80 (1H, B of ABq, J 14.5, one of
use of a single sodium bicarbonate solution wash leads to SCH2), 4.31 (1H, d, J 3.4, CHS), 4.80 (1H, qd, J 6.3, 3.5, CHO),
better yields (∼47%).
7.23–7.37 (5H, m, aromatic); δC (75.5 MHz, CDCl3) 18.8 (CH3),
cis-5,6-Dimethyl-[1,4]oxathian-2-one 23.58 From trans-2,3- 27.8 (CH2, SCH2), 48.0 (CH, CHS), 77.0 (CH, CHO), 128.6,
dimethyl-oxirane 13 (1.21 mL, 13.86 mmol); purification by 128.7, 128.9, 129.4, 129.9 (CH, phenyl), 137.3 (C), 169.2
column chromatography (ethyl acetate–hexane 20 : 80) gave a (CvO). Found (HRMS, EI): m/z 208.0583. C11H12O2S requires
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M+ 208.0558; 208 (M+, 10%), 164 (16), 156 (5), 136 (22), 122 a white crystalline solid (0.021 g, 21%); νmax(film)/cm−1 1732
(100), 105 (4), 91 (35), 77 (13), 65 (5), 45 (10). (CvO), 1051 (SvO); δH (300 MHz, CDCl3) 1.18–2.21 (8H, m,
5,6,6-Trimethyl-[1,4]oxathian-2-one 28. From 2,3-epoxy- 4 × CH2ring), 2.83–2.89 (1H, m, CHS), 3.47 [1H, A of ABq, J 15.8,
2-methylbutane 18 (6.112 g, 71.1 mmol); pure product colourless one of S(O)CH2CO], 4.01 [1H, B of ABq, J 15.8, one of S(O)
oil (5.657 g, 50%); νmax(film)/cm−1 1719 (CvO); δH (300 MHz, CH2CO], 5.30 (1H, br s, CHO); δC (75.5 MHz, CDCl3) 18.2, 21.5,
CDCl3) 1.29 (3H, d, J 7.0, CH3CS), 1.51 (6H, s, (CH3)2CO), 3.13 24.8, 30.5 (4 × CH2, cyclohexyl ring), 49.3 (CH2, SOCH2CO),
(1H, q, J 7.0, CHS), 3.41 (1H, A of ABq, J 17.0, one of SCH2), 59.3 (CH, CHS), 71.5 (CH, CHO), 163.6 (CvO).
3.53 (1H, B of ABq, J 17.0, one of SCH2); δC (75.5 MHz, CDCl3)
(4R*,4aR*,8aR*)-8a-Methyl-hexahydrobenzo[1,4]oxathiin-
16.0, 22.3, 28.3 (3 × CH3), 28.6 (CH2, SCH2), 42.3 (CH, CHS), 2-one S-oxide 35 and (4R*,4aS*,8aS*)-8a-methyl-hexahydro-
87.9 (Me2CO), 165.8 (CvO). Found (HRMS, ESI+): m/z benzo[1,4]oxathiin-2-one S-oxide 36. From sulfide 20
161.0641. C7H13O2S [M + H]+ requires M+ 161.0636; 208 (1.01 g, 5.4 mmol); crude product was a colourless oil
[(M + H)+, 30%], 142 (22), 120 (100), 105 (28).
(9 : 1 mixture of diastereomers). Column chromatography
(ethyl acetate–hexane 90 : 10) gave the pure product (35, 36) as
a white crystalline solid and as a mixture of diastereomers
(9 : 1) (by 1H NMR spectrum of pure product) (0.66 g, 61%);
Typical procedure for the synthesis of sulfoxides using
m-CPBA37,38
A solution of 3-chloroperoxybenzoic acid (1.33 g, 5.4 mmol, mp 86–89 °C; νmax(KBr)/cm−1 1729 (CvO), 1046 (SvO). Found
70%) in dichloromethane (25 mL) was added to a stirring solu- (HRMS, EI): m/z 202.0665. C9H14O3S requires M+ 202.0664; 202
tion of sulfide 8a-methyl-hexahydrobenzo[1,4]oxathiin-2-one (M+, 5%), 139 (10), 113 (85), 95 (100), 69 (20), 55 (17), 43 (45).
20 (1.01 g, 5.4 mmol) in dichloromethane (25 mL) at 0 °C. The
Major diastereomer 35: δH (300 MHz, CDCl3) 1.19–2.03
solution was stirred at 0 °C for 30 min to 1 h after which time (10H, m containing s at 1.41, 7 of H of CH2 ring and CH3), 2.56
TLC analysis showed that the starting sulfide had entirely (1H, br d, J 14.1, 1 of H of CH2 ring), 2.88 (1H, dd, J 12.6, 4.1,
reacted. The reaction mixture was filtered, the dichloro- CHS), 3.55 [1H, A of ABq, J 16.8, one of S(O)CH2CO], 4.46 [1H,
methane solution washed with sodium bicarbonate solution B of ABq, J 16.8, one of S(O)CH2CO]; δC (75.5 MHz, CDCl3) 21.7
(2 × 5 mL, 10%), water (5 mL) and brine (5 mL). The organic (CH3), 23.1, 24.8, 25.2, 40.1 (4 × CH2 ring), 54.7 [CH2, S(O)-
layer was dried and concentrated under reduced pressure to CH2], 66.2 (CH, CHS), 82.4 (C), 163.3 (CvO).
give the crude sulfoxide product (35, 36). Purification was
either by column chromatography or recrystallization as by H NMR with characteristic signals at δH (300 MHz, CDCl3)
described below. 2.51 (1H, dd, J 12.6, 4.1, CHS), 3.73 [1H, A of ABq, J 16.9, one
Minor diastereomer 36 was also found to be present in 10%
1
(4R*,4aR*,8aR*)-Hexahydrobenzo[1,4]oxathiin-2(3H)-one of S(O)CH2CO], 4.41 [1H, B of ABq, J 16.9, one of S(O)CH2CO]
S-oxide 32 and (4R*,4aS*,8aS*)-hexahydrobenzo[1,4]- and 13C NMR δC (75.5 MHz, CDCl3) 20.5 (CH3), 22.7, 24.2,
oxathiin-2(3H)-one S-oxide 33.33 From sulfide 19 (5.00 g, 25.7, 41.7 (4 × CH2ring), 52.8 [CH2, S(O)CH2], 59.3 (CH, CHS),
29.01 mmol); crude product was a white solid (1 : 1 mixture of 85.5 (C), 162.8 (CvO).
diastereomers). Purification by slow recrystallization from
(4R*,4aR*,7aR*)-Hexahydro-2H-cyclopenta[b][1,4]oxathiin-
dichloromethane/hexane gave sulfoxide 32 (1.55 g, 28%), 2-one S-oxide 37 and (4R*,4aS*,7aS*)-hexahydro-2H-cyclo-
followed by sulfoxide 33 and ∼10% sulfoxide 32 (1.21 g, 22%). penta[b][1,4]oxathiin-2-one S-oxide 38. From sulfide 21
Repeated careful chromatography led to the isolation of (1.50 g, 9.49 mmol); crude product was a cream-white solid
pure 33.
(1 : 9 mixture of diastereomers). Column chromatography
Sulfoxide 32: mp 136–138 °C; νmax(KBr)/cm−1 1724 (CvO), (ethyl acetate–hexane 90 : 10) gave the pure product (37, 38) as
1260, 1032 (SvO); δH (300 MHz, CDCl3) 1.20–2.65 (8H, m, a white crystalline solid and as a mixture of diastereomers
1
4 × CH2ring), 2.66–2.80 (1H, ddd appears as m, CHS), 3.78 [1H, (1 : 9) (by H NMR spectrum of pure product) (0.945 g, 57%);
A of ABq, J 15.5, one of S(O)CH2CO], 3.88 [1H, B of ABq, J 15.5, mp 133–135 °C; (Found C, 48.19; H, 5.65; S, 18.51. C7H10O3S
one of S(O)CH2CO], 4.04 (1H, ddd appears as dt, J 11.0, 11.0, requires C, 48.26; H, 5.78; S, 18.40%); νmax(KBr)/cm−1 1728
4.8, CHO equatorial); δC (75.5 MHz, CDCl3) 23.7, 25.2, 27.2, (CvO), 1028 (SvO) cm−1; m/z 175 (M + 1, 3%), 158 (7), 149 (5),
32.4 (4 × CH2ring), 51.1 [CH2, S(O)CH2], 67.7 (CH, CHS), 77.2 131 (3), 111 (15), 97 (42), 85 (40), 67 (100), 59 (50), 41 (43),
(CH, CHO), 163.7 (CvO).
31 (20).
Major diastereomer 38: δH (300 MHz, CDCl3) 1.75–2.21 (5H,
Sulfoxide 33: mp 107–110 °C; νmax(KBr)/cm−1 1722 (CvO),
1259, 1030 (SvO); δH (300 MHz, CDCl3) 1.20–2.45 (8H, m, 4 × m, 5 of H of CH2ring), 2.33–2.48 (1H, m, 1 of H of CH2ring), 2.83
CH2ring), 2.50–2.68 (1H, ddd appears as m, CHS), 3.62 [1H, A of (1H, ddd appears as dt, J 10.2, 10.2, 7.3, CHS), 3.41 [1H, A of
ABq, J 16.1, one of S(O)CH2CO], 4.02 [1H, A of ABq, J 16.1, one ABq, J 16.4, one of S(O)CH2CO], 4.20 [1H, B of ABq, J 16.4, one
of S(O)CH2CO], 4.88 (1H, ddd appears as dt, J 10.5, 410.5, 5.0, of S(O)CH2CO], 5.17 (1H, ddd appears as dt, J 9.6, 9.6, 7.5,
CHO axial); δC (75.5 MHz, CDCl3) 23.4, 24.2, 24.8, 32.2 (4 × CHO); δC (75.5 MHz, CDCl3) 19.5, 19.8, 29.4 (3 × CH2ring), 52.7
CH2ring), 52.1 [CH2, S(O)CH2], 57.3 (CH, CHS), 73.8 (CH, CHO), [CH2, S(O)CH2], 58.8 (CH, CHS), 75.9 (CH, CHO), 164.7 (CvO).
163.2 (CvO).
Minor diastereomer 37 was also found to be present in 10%
1
(4R*,4aR*,8aS*)-Hexahydrobenzo[1,4]oxathiin-2(3H)-one by H NMR with characteristic signals at δH (300 MHz, CDCl3)
S-oxide 34.33,57 From sulfide 29 (0.092 g, 0.53 mmol); purifi- 3.09 (1H, ddd appears as dt, CHS), 3.56 [1H, A of ABq, J 17.1,
cation by recrystallization from dichloromethane/hexane gave one of S(O)CH2CO], 4.14 [1H, B of ABq, J 17.1, one of
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S(O)CH2CO], 4.21 (1H, ddd appears as dt, CHO) and 13C NMR δC [C, (CH3)2CO], 162.8 (C, CvO); minor diastereomer: 6.7, 25.9,
(75.5 MHz, CDCl3) 19.7, 24.5, 29.3 (3 × CH2ring), 52.9 [CH2, 29.1 (3 × CH3, methyl groups), 49.2 (CH2, SOCH2), 54.8
S(O)CH2], 65.8 (CH, CHS), 77.3 (CH, CHO), 165.1 (CvO).
(4R*,5R*,6S*)-5,6-Diphenyl-[1,4]-oxathian-2-one
(CH, CHS), 84.1 [C, (CH3)2CO], 163.1 (C, CvO); Found (HRMS,
S-oxide ESI+): m/z 177.0578. C7H13O3S requires (M + H)+ 177.0585; 177
44.33 From sulfide 25 (1.36 g, 5.03 mmol); purification by [(M + H)+, 48%], 218 (100), 353 (66), 105 (24).
recrystallization from ethyl acetate gave a white crystalline
(1R*,5S*,6R*)-5,6-Diphenyl-thiomorpholin-3-one
S-oxide
solid (1.08 g, 75%); mp 149–150 °C; (Found C, 67.30; H, 4.73; 50. (Note: the sulfide starting material cis-5,6-diphenyl-thiomor-
S, 10.90. C16H14O3S requires C, 67.11; H, 4.93; S, 11.20%); pholin-3-one (30) was synthesised according to the procedure
νmax(KBr)/cm−1 1735 (CvO), 1223, 1052; δH (270 MHz, CDCl3) described by Garcia Ruano).41 From sulfide 30 (0.59 g,
3.69 (1H, dd, A of ABq, J 16.0, 1.0, one of S(O)CH2), 4.07 (1H, 2.20 mmol); recrystallization from ethyl acetate gave the pure
B of ABq, J 16.0, S(O)CH2), 4.39 (1H, dd appears as br d, J 2.0, sulfoxide 50 as a white solid and as one diastereomer (0.458 g,
1.0, CHS), 6.62 (1H, d, J 2.0, CHO), 7.03–7.09 (2H, m, ArH), 73%); mp 215 °C decomp; (Found C, 67.15; H, 5.39; N, 4.85.
7.23–7.32 (8H, m, ArH); δC (67.8 MHz, CDCl3) 49.7 [CH2, S(O)- C16H15NO2S requires C, 67.34; H, 5.30; N, 4.91%); νmax(KBr)/
CH2], 66.8 (CH, CHS), 75.5 (CH, CHO), 126.0, 128.4, 128.6, cm−1 1667 (CvO), 1048 (SvO); δH (300 MHz, CDCl3) 3.51 [1H,
129.1, 129.5 (CH, ArCH and C), 134.9 (C), 163.3 (CvO). Found A of ABq, J 17.3, one of S(O)CH2], 3.69 [1H, B of ABq, J 17.3,
(HRMS, EI): m/z 286.0671. C16H14O3S requires M+ 286.0664; one of S(O)CH2], 4.39 (1H, d, J 3.2, CHS), 5.83 (1H, d, J 3.2,
286 (M+, 3%), 270 (2), 197 (18), 180 (94), 152 (13), 91 (13), CHN), 6.94 (1H, br s, NH), 7.12–7.53 (10H, m, aromatic); δC
89 (23), 77 (38), 44 (100).
(75.5 MHz, CDCl3) 47.6 [CH2, S(O)CH2], 52.8 (CH, CHN), 64.9
(4R*,5R*,6S*)-6-Methyl-5-methyl-[1,4]oxathian-2-one S-oxide (CH, CHS), 126.9, 128.5, 129.0, 129.2, 129.3, 129.8 (CH, phenyl
47. From sulfide 27 (0.50 g, 2.40 mmol); crude product was and C), 136.3 (C), 165.4 (CvO); m/z 285 (M+, 10%), 256 (4), 231
1
isolated as a colourless oil which was pure by H NMR spec- (25), 196 (20), 172 (21), 149 (23), 126 (8), 105 (100), 97 (22), 77
troscopy and used without further purification (0.41 g, 76%); (32), 69 (73), 57 (60), 43 (55).
νmax(film)/cm−1 1735 (CvO), 1049 (SvO); δH (300 MHz,
(1R*,5R*,6R*)-5,6-Diphenyl-thiomorpholin-3-one S-oxide 51
CDCl3) 1.59 (3H, d, J 6.7, CH3), 3.61 [1H, A of ABq, J 16.6, one and (1R*,5S*,6S*)-5,6-diphenyl-thiomorpholin-3-one S-oxide
of S(O)CH2], 3.83 [1H, B of ABq, J 16.6, one of S(O)CH2], 4.05 52. (Note: the sulfide starting material trans-5,6-diphenyl-thio-
(1H, d, J 2.4, CHS), 5.72 (1H, qd appears as q, J 6.7, 2.4, CHO), morpholin-3-one (31) was synthesised according to the procedure
7.32–7.47 (5H, m, aromatic); δC (75.5 MHz, CDCl3) 18.4 (CH3), described by Garcia Ruano).41 From sulfide 31 (2.01 g,
47.8 [CH2, S(O)CH2], 65.0 (CH, CHS), 71.2 (CH, CHO), 128.7 7.40 mmol); crude product was a white solid (1 : 1 equatorial
(C), 129.4, 129.5, 129.7 (CH, phenyl), 163.6 (CvO). Found 51 : axial 52). Recrystallization from ethyl acetate gave the pure
(HRMS, EI): m/z 224.0513. C11H12O3S requires M+ 224.0507; sulfoxides as a white solid and as a mixture of diastereomers
224 (M+, 1%), 208 (5), 182 (3), 150 (10), 135 (60), 117 (52), 105 (2.5 : 1/51 : 52) (1.08 g, 51%); mp 181–183 °C; νmax(KBr)/cm−1
(16), 91 (100), 77 (25), 57 (20), 43 (54), 31 (1).
1667 (CvO); m/z 285 (M+, 7%), 256 (2), 226 (6), 231 (25), 196
(4R*,5S*)-5,6,6-Trimethyl-[1,4]oxathian-2-one S-oxide 48 and (27), 172 (18), 149 (29), 121(4), 105 (100), 94 (14), 81 (34), 77
(4R*,5R*)-5,6,6-trimethyl-[1,4]oxathian-2-one S-oxide 49. From (40), 69 (74), 53 (27), 57 (50), 43 (64).
sulfide 28 (4.663 g, 29.0 mmol); crude product was a colourless
Major diastereomer (51): δH (300 MHz, CDCl3) 3.78 [1H, A
oil (1 : 8 mixture of diastereomers containing ∼5% of a of ABq, J 15.4, one of S(O)CH2], 3.98 [1H, B of ABq, J 15.4, one
4 : 1 mixture regioisomeric sulfoxide diastereomers). Column of S(O)CH2], 4.01 (1H, d, J 10.7, CHS), 4.65 (1H, d, J 10.7,
chromatography (ethyl acetate–hexane 20 : 80) gave three frac- CHN), 6.97–7.20 (10H, m, aromatic); δC (75.5 MHz, CDCl3) 53.1
tions; the first containing sulfide starting material 28 as a [CH2, S(O)CH2], 58.3 (CH, CHN), 72.9 (CH, CHS), 127.3, 127.8,
colourless oil (0.355 g, 8%), the second containing a mixture 128.7, 128.8, 128.1, 128.9, 129.0, 129.1 (CH, phenyl), 130.6 (C),
of less polar sulfoxide 48, more polar sulfoxide 49 and regio- 136.0 (C), 163.0 (CvO).
isomeric sulfoxide (9 : 1 : 1) as a white solid (0.590 g, 12%) and
Minor diastereomer (52): δH (300 MHz, CDCl3) 3.59 [1H, A
the third fraction containing a mixture of the diastereomeric of ABq, J 17.3, one of S(O)CH2], 3.67 [1H, B of ABq, J 17.3, one
sulfoxides (∼1 : 7) as a white solid (1.68 g, 33%), spectral of S(O)CH2], 3.76 (1H, d, J 10.9, CHS), 5.38 (1H, d, J 10.9,
characteristics of a mixture of both sulfoxide diastereomers CHN), 6.63 (1H, br s, NH), 6.97–7.20 (10H, m, aromatic); δC
(1 : 6): mp 59–61 °C; νmax(KBr)/cm−1 1725 (CvO), 1284, 1055; (75.5 MHz, CDCl3) 49.9 [CH2, S(O)CH2], 54.4 (CH, CHN), 62.0
δH (300 MHz, CDCl3) major diastereomer: 1.42 (3H, s, CH3CO), (CH, CHS), 127.3, 127.8, 128.7, 128.8, 128.1, 128.9, 129.0, 129.1
1.56 (3H, d, J 7.2, CH3CS), 1.60 (3H, s, CH3CO), 2.97 (1H, q, (CH, phenyl), 133.4 (C), 136.6 (C), 162.2 (CvO).
J 7.2, CHS), 3.58 (1H, A of ABq, J 16.6, one of SOCH2), 4.36 (1H,
Typical procedure for the synthesis of sulfoxides using Oxone®
B of ABq, J 16.6, one of SOCH2); minor diastereomer: 1.48 (3H,
d, J 7.2, CH3CS), 1.53 (3H, s, CH3CO), 1.64 (3H, s, CH3CO), 3.04 A solution of Oxone® (4.17 g, 6.8 mmol) in water (90 mL) was
(1H, q, J 7.2, CHS overlapping with CHS of major diastereo- added to a stirring solution of sulfide cis-5,6-dimethyl-[1,4]-
mer), 3.53 (1H, A of ABq overlapping with A of ABq of major oxathian-2-one 23 (2.00 g, 13.6 mmol) in acetone (100 mL) at
diastereomer, one of SOCH2), 4.18 (1H, B of ABq, J 16.9, one of 0 °C. The reaction mixture was stirred at 0 °C for 3 h and then
SOCH2); δC (75.5 MHz, CDCl3): 11.1, 24.4, 28.5 (3 × CH3, the acetone/water layer was shaken with dichloromethane
methyl groups), 53.3 (CH2, SOCH2), 62.7 (CH, CHS), 83.9 (50 mL) and the layers separated. The aqueous layer was
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further extracted with dichloromethane (50 mL). The com- 78.6 (CH, CHO axial), 82.1 (CH, CHO equatorial), 127.9, 128.3,
bined organic layers were washed with brine (10 mL), dried 129.0, 129.1, 129.4, 129.6, 129.7, 129.8, 129.9 (CH, ArCH),
and concentrated under reduced pressure to give the crude 131.3 (qArC equatorial), 131.3 (qArC axial), 134.7 (qArC equa-
product 41. Purification was either by column chromatography torial), 135.1 (qArC axial), 162.7 (axial CvO), 163.3 (equatorial
or recrystallization as described below.
CvO).
(4R*,5R*,6S*)-5,6-Dimethyl-[1,4]oxathian-2-one
S-oxide
General procedure for the synthesis of sulfoxides using
sodium metaperiodate
41.58 Column chromatography (ethyl acetate–hexane 60 : 40)
gave the pure sulfoxide 41 as a white solid (1.60 g, 73%); mp
107–109 °C; (Found C, 40.09; H, 6.61. C6H10O3S·H2O requires The sulfide trans-octahydro-2H-cyclohepta[b][1,4]oxathiin-
C, 39.99; H, 6.71%); νmax (KBr)/cm−1 1731 (CvO), 1052 (SvO); 2-one 22 (1.146 g, 6.15 mmol) was dissolved in methanol
δH (300 MHz, CDCl3) 1.22 (3H, d, J 7.5, CH3), 1.54 (3H, d, J 6.6, (92 mL) and allowed to stir at 0 °C. Sodium metaperiodate
CH3), 2.94 (1H, qdd, J 7.4, 1.5, 0.6, CHS), 3.42 [1H, A of ABq, (1.382 g, 6.46 mmol) was dissolved in water (30 mL) and
J 16.6, one of S(O)CH2], 4.05 [1H, B of ABq, J 16.6, one of S(O)- added slowly to the sulfide solution over 10 min. The solution
CH2], 5.43 (1H, qd, J 6.6, 1.5, CHO); δC (75.5 MHz, CDCl3) 6.4, was initially yellow in colour but became cloudy with a white
18.1 (2 × CH3), 49.0 [CH2, S(O)CH2], 55.4 (CH, CHS), 70.5 (CH, precipitate over the course of 1 h. The solution was stirred for
CHO), 167.2 (CvO). Found (HRMS, EI): m/z 162.0366. 3 h in total while returning slowly to room temperature. The
C6H10O3S requires M+ 162.0351; 162 (M+, 15%), 149 (5), 129 precipitate was filtered off and the methanol was evaporated.
(2), 119 (7), 101 (5), 90 (100), 73 (92), 62 (83), 55 (82), 43 (95), The remaining aqueous solution was extracted with dichloro-
31 (9).
methane (3 × 30 mL). The combined organic layers were dried
Subsequent work in our laboratory revealed the presence of with MgSO4 and concentrated to give the crude sulfoxide. Puri-
a minor diastereomer when the reaction was done on a large fication was by column chromatography as described below.
scale.
(4R*,4aR*,9aR*)-Octahydro-2H-cyclohepta[b][1,4]oxathiin-
(4R*,5R*,6R*)-5,6-Dimethyl-[1,4]oxathian-2-one S-oxide 42 2-one S-oxide 39 and (4R*,4aS*,9aS*)-octahydro-2H-cyclohepta-
and (4R*,5S*,6S*)-5,6-dimethyl-[1,4]oxathian-2-one S-oxide [b][1,4]oxathiin-2-one S-oxide 40. Crude product was a yellow
43. From sulfide 24 (0.200 g, 1.30 mmol); recrystallized from solid [1 : 1 equatorial 39 : axial 40]. Column chromatography
ethyl acetate to give a white solid (1 : 3 mixture of 42 : 43) (hexane–ethyl acetate 1 : 1) gave a 1.2 : 1 mixture of equatorial
(0.14 g, 66%); (Found C, 40.73; H, 6.43. C6H10O3S and 1 mol 39 : axial 40 sulfoxides as a low melting white solid (0.307 g,
H2O requires C, 39.99; H, 6.71%); νmax (KBr)/cm−1 1731 25%), νmax/cm−1 (KBr) 1742 (CvO), 1018 (SvO); major equa-
(CvO); m/z 162 (M+, 15%), 129 (4), 119 (10), 101 (11), 90 (100), torial diastereomer 39: δH (300 MHz, CDCl3) 1.39–2.27 (10H,
83 (4), 77 (12), 73 (78), 62 (81), 55 (90), 43 (95), 31 (5).
m, cycloheptyl ring), 2.87 (1H, overlapping ddd appears as dt,
Major diastereomer (axial) 43: δH (300 MHz, CDCl3) 1.42 J 10.0, 10.0, 3.3, CHS), 3.73 (1H, A of ABq, J 15.8, one of
(3H, d, J 7.2, CH3), 1.54 (3H, d, J 6.4, CH3), 2.75 (1H, dq SOCH2), 3.96 (1H, B of ABq, J 15.8, one of SOCH2), 4.11 (1H,
appears as m, J 9.8, 7.2, CHS), 3.64 [1H, A of ABq, J 16.1, one of overlapping ddd appears as dt, J 10.4, 10.4, 5.5, CHO);
S(O)CH2], 4.11 [1H, B of ABq, J 16.1, one of S(O)CH2], 5.01 (1H, δC (75.5 MHz, CDCl3) 22.5, 25.2, 26.7, 28.8, 33.2 (5 × CH2,
dq appears as m, J 9.7, 6.5, CHO); δC (75.5 MHz, CDCl3) 9.7, cycloheptyl ring), 51.2 (CH2, SOCH2), 68.5 (CH, CHS), 78.0
17.5 (2 × CH3), 50.9 [CH2, S(O)CH2], 53.5 (CH, CHS), 72.2 (CH, (CH, CHO), 164.4 (C, CvO); minor axial diastereomer 40:
CHO), 162.2 (CvO).
δH (300 MHz, CDCl3) 1.39–2.27 (9H, m, cycloheptyl ring),
Minor diastereomer (equatorial) 42: δH (300 MHz, CDCl3) 2.30–2.44 (1H, m, cycloheptyl ring), 2.62 (1H, ddd appears as
1.46 (3H, d, J 7.2, CH3), 1.55 (3H, d, J 6.4, CH3), 2.77 (1H, dq dt, J 9.2, 9.2, 2.9, CHS), 3.51 (1H, A of ABq, J 16.0 Hz, one of
appears as m, J 8.7, 7.2, CHS), 3.77 [1H, A of ABq, J 15.1, one of SOCH2), 4.24 (1H, B of ABq, J 16.0, one of SOCH2), 5.08–5.18
S(O)CH2], 3.88 [1H, B of ABq, J 15.1, one of S(O)CH2], 4.21 (1H, (1H, symmetrical m, CHO); δC (75.5 MHz, CDCl3) 21.9, 24.8,
dq appears as m, J 8.6, 6.4, CHO); δC (300 MHz, CDCl3) 11.7, 27.0, 28.1, 32.8 (5 × CH2, cycloheptyl ring), 53.2 (CH2, SOCH2),
18.3 (2 × CH3), 48.5 [CH2, S(O)CH2], 62.4 (CH, CHS), 75.5 (CH, 61.5 (CH, CHS), 75.8 (CH, CHO), 164.4 (C, CvO); Found (HRMS,
CHO), 162.2 (CvO).
(4R*,5R*,6R*)-5,6-Diphenyl-[1,4]-oxathian-2-one S-oxide 45 [(M + H)+, 56%], 221 (72), 244 (100), 95 (76), 83 (38).
and (4R*,5S*,6S*)-5,6-diphenyl-[1,4]-oxathian-2-one S-oxide It is possible to separate the more polar axial sulfoxide 40
ESI+): m/z 203.0745. C9H15O3S requires [M + H]+, 203.0742; 203
46.33 From sulfide 26 (1.39 g, 5.14 mmol); crude product was by careful chromatography using ethyl acetate as eluent. Spec-
a colourless oil (2 : 1 equatorial 45 : axial 46) (0.78 g, 53%). The tral details as described above; mp 154–155 °C; (Found C,
sulfoxide appears to decompose slowly on silica and therefore 53.40; H, 6.90; S, 15.62. C9H14O3S requires C, 53.44; H, 6.98; S,
it was not possible to prepare an analytically pure sample; 15.85%); νmax (KBr)/cm−1 1732 (CvO), 1028 (SvO); Found
νmax(KBr)/cm−1 1735 (CvO); m/z 180 (M+, 21%), 105 (78), 91 (HRMS, ESI+): m/z 203.0733. C9H15O3S requires [M + H]+,
(68), 89 (12), 77 (95), 55 (100). δH (270 MHz, CDCl3) 3.92–4.35 203.0742; 203 [(M + H)+, 10%], 244 (100), 105 (18).
[6H, m, S(O)CH2 and CHS], 5.56 (1H, d, J 11.0, CHO equator-
Typical procedure for the synthesis of α-diazosulfoxides44
ial), 6.37 (1H, d, J 11, CHO axial), 6.91–7.33 (20H, m, ArH); δC
(67.8 MHz, CDCl3) 50.3 [CH2, S(O)CH2 equatorial], 51.4 [CH2, S Triethylamine (0.29 mL, 1.95 mmol, 1 eq.) was added to a stir-
(O)CH2 axial], 62.8 (CH, CHS axial), 75.9 (CH, CHS equatorial), ring solution of sulfoxide (4R*,4aR*,8aR*)-hexahydrobenzo[1,4]-
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oxathiin-2(3H)-one S-oxide 32 (0.39 g, 2.07 mmol) in aceto-
(4R*,4aS*,8aS*)-3-Diazo-8a-methyl-hexahydrobenzo[1,4]-
nitrile (20 mL). Tosyl azide (0.40 g, 1.95 mmol) was then added oxathiin-2-one S-oxide 56 and (4R*,4aR*,8aR*)-3-diazo-8a-
dropwise at 0 °C under nitrogen and the solution was stirred methyl-hexahydrobenzo[1,4]oxathiin-2-one S-oxide 57. 9 : 1
overnight while slowly returning to room temperature to give diastereomeric mixture of sulfoxides 35 : 36 (0.30 g,
an orange coloured solution. The mixture was concentrated 1.49 mmol) gave the crude product as an orange oil (5 : 1
under reduced pressure to give the crude product 53 as an 56 : 57 mixture of diastereomers by 1H NMR spectroscopy).
orange oil. Purification was either by column chromatography Column chromatography (ethyl acetate–hexane 50 : 50) gave
or recrystallization as described below.
the pure α-diazosulfoxides as a yellow crystalline solid (0.10 g,
(4R*,4aS*,8aS*)-3-Diazo-hexahydrobenzo[1,4]oxathiin-2(3H)- 30%) major : minor 5 : 1, mp 90–92 °C; (Found C, 47.44; H,
one S-oxide 53.33 Column chromatography (ethyl acetate– 5.34; N, 12.06. C9H12N2O3S requires C, 47.35; H, 5.30; N,
hexane 60 : 40) gave the pure α-diazosulfoxide 53 as a yellow 12.28%); m/z 228 (M+, 2%), 200 (5), 185 (12), 155 (20), 129 (17),
crystalline solid (0.19 g, 43%); mp 75–77 °C; νmax(KBr)/cm−1 109 (26), 97 (31), 79 (24), 71 (16), 53 (18), 43 (100), 39 (53);
2127 (CvN2), 1704 (CvO); δH (300 MHz, CDCl3) 1.25–1.82 νmax(KBr)/cm−1 2115 (CvN2), 1681 (CvO), 1068 (SvO).
(4H, m, 4 of H of CH2ring), 1.85–2.02 (2H, m, 2 of H of CH2ring),
Major diastereomer (equatorial) 56: δH (300 MHz, CDCl3)
2.23–2.36 (1H, m appears as br d, 1 of H of CH2ring), 2.57–2.68 1.30–2.05 (10H, m containing s at 1.42, 7 of H of CH2ring and
(1H, m appears as br d, 1 of H of CH2ring), 2.95 (1H, ddd CH3), 2.57 (1H, br d, J 14.1, 1 of H of CH2ring), 3.02 (1H, dd,
appears as dt, J 11.0, 11.0, 4.9, CHS), 4.04 (1H, ddd appears as J 12.7, 4.1, CHS); δC (75.5 MHz, CDCl3) 19.6 (CH3), 22.8, 25.3,
dt, J 11.0, 11.0, 4.9, CHO); δC (75.5 MHz, CDCl3) 23.6, 24.7, 25.5, 39.8 (4 × CH2ring), 68.1 (CH, CHS), 81.5 (C), 159.7 (CvO).
27.3, 31.9 (4 × CH2ring), 67.8 (CH, CHS), 71.3 (CvN2), 74.3
(CH, CHO), 160.8 (CvO).
Signals due to minor diastereomer 57: δH (300 MHz, CDCl3)
1.30–2.05 (10H, m containing s at 1.81, 7 of H of CH2ring and
(4R*,4aR*,8aR*)-3-Diazo-hexahydrobenzo[1,4]oxathiin-2(3H)- CH3), 2.42 (1H, d, 1 of H of CH2ring), 2.75 (1H, dd, CHS); δC
one S-oxide 54.33 From sulfoxide 33 (0.37 g, 1.95 mmol); (75.5 MHz, CDCl3) 20.5 (CH3), 22.5, 25.3, 25.6, 41.4 (4 ×
column chromatography (ethyl acetate–hexane 50 : 50) gave the CH2ring), 59.9 (CH, CHS), 84.5 (C), 159.6 (CvO). Repeated
pure axial α-diazosulfoxide 54 as a yellow crystalline solid careful chromatography led to the isolation of pure 56 as a
(0.167 g, 40%); mp 104–107 °C; νmax(KBr)/cm−1 2129 (CvN2), single diastereomer.
1690 (CvO); δH (300 MHz, CDCl3) 1.20–1.80 (4H, m, 4 of H of
(4R*,4aS*,7aS*)-3-Diazo-hexahydro-2H-cyclopenta[b][1,4]-
CH2ring), 1.85–2.05 (2H, m, 2 of H of CH2ring), 2.05–2.27 (1H, m oxathiin-2-one S-oxide 58 and (4R*,4aR*,7aR*)-3-diazo-hexa-
appears as br d, 1 of H of CH2ring), 2.30–2.51 (1H, m appears hydro-2H-cyclopenta[b][1,4]oxathiin-2-one S-oxide 59. 1 : 9 di-
as br d, 1 of H of CH2ring), 2.82 (1H, ddd appears as dt, J 10.9, astereomeric mixture of sulfoxides 37 : 38 (0.72 g, 4.13 mmol)
10.9, 4.8, CHS), 4.89 (1H, ddd appears as dt, J 10.9, 10.9, 4.8, gave the crude product as an orange oil (1 : 9 58 : 59 mixture of
CHO); δC (75.5 MHz, CDCl3) 22.9, 24.3, 24.9, 31.9 (4 × CH2ring), diastereomers by 1H NMR spectroscopy). Column chromato-
57.9 (CH, CHS), 71.8 (CH, CHO), 158.7 (CvO).
graphy (ethyl acetate–hexane 50 : 50) gave the pure major
(4R*,4aS*,8aS*)-3-Diazo-hexahydrobenzo[1,4]oxathiin-2-one α-diazosulfoxide (axial) 59 as a yellow crystalline solid (0.47 g,
S-oxide 53 and (4R*,4aR*,8aR*)-3-diazohexahydrobenzo[1,4]- 57%), mp 107–109 °C; (Found C, 41.94; H, 4.01; N, 13.62.
oxathiin-2(3H)-one S-oxide 54. 1 : 1 diastereomeric mixture of C7H8N2O3S requires C, 41.99; H, 4.03; N, 13.99%); νmax (KBr)/
sulfoxides 32 : 33 (0.68 g, 3.60 mmol) gave the crude product cm−1 2120 (CvN2), 1693 (CvO), 1078 (SvO) cm−1; δH
as an orange oil (1 : 1 53 : 54 mixture of diastereomers by 1H (300 MHz, CDCl3) 1.78–2.24 (5H, m, 5 of H of CH2ring),
NMR spectroscopy). Column chromatography (ethyl acetate– 2.35–2.51 (1H, m, 1 of H of CH2ring), 3.02 (1H, ddd appears as
hexane 60 : 40) gave the pure α-diazosulfoxides as a yellow crys- dt, J 10.0, 10.0, 8.7, CHS), 5.11 (1H, ddd appears as dt, J 9.6,
talline solid 1 : 1 mixture of diastereomers (0.19 g, 27%). Spec- 9.6, 8.0, CHO); δC (75.5 MHz, CDCl3) 19.5, 21.0, 29.4 (3 ×
tral characteristics for the α-diazosulfoxides were identical to CH2ring), 58.1 (CH, CHS), 74.7 (CH, CHO), 160.4 (CvO); m/z
those described above for 53 and 54 above.
(4R*,4aS*,8aR*)-3-Diazo-hexahydrobenzo[1,4]oxathiin-2(3H)- (85), 84 (42), 72 (96), 67 (61), 58 (30), 55 (78), 39 (82), 32 (100).
one S-oxide 55.33,57 From sulfoxide 34 (0.021 g, 0.11 mmol);
A minor diastereomer 58 was also isolated as a yellow crys-
200 (M+, 5%), 175 (4), 156 (13), 139 (10), 129 (50), 111 (12), 100
column chromatography (ethyl acetate–hexane 40 : 60) gave the talline solid (5%), mp 122–124 °C; (Found C, 41.86; H, 4.05; N,
pure α-diazosulfoxide 55 as a yellow crystalline solid (0.008 g, 13.71. C7H8N2O3S requires C, 41.99; H, 4.03; N, 13.99%); νmax
38%); mp 112–114 °C (blackened 104–108 °C). (Found: C, (KBr)/cm−1 2122 (CvN2), 1698 (CvO), 1068 (SvO) cm−1; δH
44.81; H, 4.83; N, 13.15; S, 14.55; C8H10N2O3S requires C, (300 MHz, CDCl3) 1.71–2.11 (4H, m, 4 of H of CH2ring),
44.85; H, 4.70; N, 13.08; S, 14.96%); νmax(KBr)/cm−1 2128 2.29–2.39 (1H, m, 1 of H of CH2ring), 2.51–2.65 (1H, m, 1 of H
(CvN2), 1681 (CvO); δH (300 MHz, CDCl3) 1.25–1.76 (5H, m, of CH2ring), 3.26 (1H, ddd appears as dt, J 10.4, 10.4, 8.9, CHS),
5 of H of CH2ring), 1.92–1.96 (2H, br d, 2 of H of CH2ring), 4.26 (1H, ddd appears as dt, J 10.6, 10.6, 8.7, CHO); δC
2.29–2.41 (1H, br d, 1 of H of CH2ring), 2.94–2.99 (1H, (75.5 MHz, CDCl3) 19.8, 25.02, 29.4 (3 × CH2ring), 63.8 (CH,
ddd, J 13, 3, 2, CHS), 5.38 (1H, br s, CHO); δC (75.5 MHz, CHS), 75.8 (CH, CHO), 162.0 (CvO).
CDCl3) 19.1, 20.1, 24.6, 31.0 (4 × CH2), 58.8 (CHS), 69.8 (CHO),
(4R*,4aS*,9aS*)-3-Diazo-octahydro-2H-cyclohepta[b][1,4]-
159.3 (CvO); m/z 214 (M+, <5%), 84 (32), 71 (10), 49 (100), oxathiin-2-one S-oxide 60 and (4R*,4aR*,9aR*)-3-diazo-octa-
34 (65).
hydro-2H-cyclohepta[b][1,4]oxathiin-2-one S-oxide 61. 1 : 1.4
1720 | Org. Biomol. Chem., 2013, 11, 1706–1725
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diastereomeric mixture of sulfoxides 39 : 40 (1.355 g,
Major diastereomer (axial) 64: δH (300 MHz, CDCl3) 1.42
6.70 mmol) gave the crude product as an orange oil (60 : 61 (3H, d, J 7.2, CH3), 1.52 (3H, d, J 6.6, CH3), 2.91 (1H, dq
mixture of diastereomers by 1H NMR spectroscopy). Column appears as q, J 9.8, 7.2, CHS), 5.07 (1H, dq, J 9.8, 6.5, CHO);
chromatography (ethyl acetate–hexane 50 : 50) gave a number δC (75.5 MHz, CDCl3) 12.5, 18.8 (2 × CH3), 56.0 (CH, CHS), 71.5
of fractions containing varying ratios of 61 and 60. Equatorial (CH, CHO), 159.8 (CvO).
α-diazosulfoxide 60 (10%) was isolated in one of the fractions
as a yellow solid.
Minor diastereomer (equatorial) 63: δH (300 MHz, CDCl3)
1.43 (3H, d, J 7.3, CH3), 1.72 (3H, d, J 6.9, CH3), 3.16 (1H, dq
Equatorial α-diazosulfoxide 60: mp 70–74 °C; νmax/cm−1 appears as q, J 7.3, 8.6, CHS), 4.61 (1H, dq, J 6.8, 8.6, CHO); δC
2116 (C–N2), 1693 (CvO), 1065 (SvO); δH (300 MHz, CDCl3) (75.5 MHz, CDCl3) 12.7, 19.7 (2 × CH3), 58.9 (CH, CHS), 77.1
1.44–2.06 (8H, m, 4 × CH2ring), 2.12–2.25 (1H, m, one of (CH, CHO), 159.8 (CvO).
CH2ring), 2.27–2.41 (1H, m, one of CH2ring), 3.01–3.12 (1H, sym-
(4R*,5S*,6R*)-3-Diazo-6-methyl-5-phenyl-[1,4]oxathian-2-one
metrical m, CHS), 4.05–4.16 (1H, symmetrical m, CHO); δC S-oxide 68. From sulfoxide 47 (0.57 g, 2.50 mmol); column
(75.5 MHz, CDCl3) 22.8, 24.6, 27.5, 29.7, 33.0 (5 × CH2ring), 67.7 chromatography (ethyl acetate–hexane 50 : 50) gave the pure
(CH, CHS), 75.6 (CH, CHO); m/z 229 (M + 1+, 18%), 255 (100), α-diazosulfoxide as a yellow crystalline solid (0.28 g, 45%); mp
201 (4), 142 (8), 101 (8).
131–134 °C; (Found C, 52.79; H, 4.03; N, 11.19. C11H10N2O3S
Pure sample of axial sulfoxide 40 (0.357 g, 1.765 mmol) requires C, 53.32; H, 4.03; N, 10.35%); νmax (KBr)/cm−1 2124
underwent diazo transfer to give the crude product as a red oil. (CvN2), 1691 (CvO), 1079 (SvO) cm−1; δH (300 MHz, CDCl3)
Column chromatography (ethyl acetate–hexane 50 : 50) gave 1.60 (3H, d, J 6.7, CH3), 4.03 (1H, d, J 1.9, CHS), 5.70 (1H, qd
the pure axial α-diazosulfoxide 61 (0.137 g, 34%) as a yellow appears as q, J 6.7, 1.9, CHO), 7.38–7.45 (5H, m, aromatic); δC
solid; mp 98–100 °C; (Found C, 47.45; H, 5.26; S, 14.18. (75.5 MHz, CDCl3) 18.9 (CH3), 66.7 (CH, CHS), 69.8 (CH,
C9H12N2O3S requires C, 47.35; H, 5.30; S, 14.05%); νmax (KBr)/ CHO), 127.1 (C), 129.6, 129.9 (CH, phenyl), 159.8 (CvO); m/z
cm−1 2127 (CvN2), 1697 (CvO), 1262 (C–O), 1051 (SvO); δH 250 (M+, <1%), 222 (M+ − N2, 40%), 191 (12), 178 (38), 155 (23),
(300 MHz, CDCl3) 1.37–1.92 (6H, m, 3 × CH2ring), 1.98–2.34 117 (30), 105 (100), 84 (63), 69 (35), 55 (20), 43 (70), 32 (22).
(4H, m, 2 × CH2ring), 2.84 (1H, td, J 9.5, 2.6, CHS), 5.17 (1H,
(4R*,5R*)-3-Diazo-5,6,6-trimethyl-[1,4]oxathian-2-one S-oxide
overlapping ddd, J 4.8, 4.8, 4.8, CHO); δC (75.5 MHz, CDCl3) 69 and (4R*,5S*)-3-diazo-5,6,6-trimethyl-[1,4]oxathian-2-one S-
22.0, 26.8, 27.3, 29.1, 33.2 (CH2, 5 × CH2ring), 61.6 (CH, CHS), oxide 70. 1 : 4 diastereomeric mixture of sulfoxides 48 : 49
74.4 (CH, CHO), 160.3 (CvO); Found (HRMS, ESI+): m/z (1.68 g, 9.53 mmol) gave the crude product as an orange oil.
229.0644. C9H13N2O3S requires [M + H]+, 229.0647; 229 (M + Column chromatography (ethyl acetate–hexane 50 : 50) gave
1+, 40%), 105 (10).
the pure α-diazosulfoxides 69 and 70 (1 : 7) as a yellow solid
(4R*,5S*,6R*)-3-Diazo-5,6-dimethyl-[1,4]oxathian-2-one S-oxide (0.756 g, 39%), mp 108–110 °C; (Found: C, 41.59; H, 4.82; N,
62.58 From sulfoxide 41 (1.50 g, 9.25 mmol); column chro- 13.66; S, 16.17. C7H10N2O3S requires C, 41.57; H, 4.98; N,
matography (ethyl acetate–hexane 50 : 50) gave the pure α-diazo- 13.85; S, 15.86%); νmax/cm−1 (KBr) 2125 (C–N2), 1672 (CvO);
sulfoxide 62 as a yellow crystalline solid (0.51 g, 30%); mp δH (300 MHz, CDCl3) major diastereomer 70: 1.31 (3H, d, J 7.3,
105–107 °C; (Found C, 38.21; H, 4.29; N, 14.83; S, 17.23. CH3CS), 1.50 (3H, s, CH3CO), 1.85 (3H, s, CH3CO), 3.09 (1H, q,
C6H8N2O3S requires C, 38.29; H, 4.28; N, 14.89; S, 17.03%); J 7.3, CHS); minor diastereomer 69: 1.53 (s, 3H, CH3CO), 1.58
νmax (KBr)/cm−1 2126 (CvN2), 1688 (CvO), 1068 (SvO) cm−1
;
(3H, d, J 7.2, CH3CS), 1.72 (3H, s, CH3CO), 2.93 (1H, q, J 7.2,
δH (300 MHz, CDCl3) 1.23 (3H, d, J 7.2, CH3), 1.53 (3H, d, J 6.6, CHS); δC (75.5 MHz, CDCl3) 70 9.5 (CH3, CH3CS), 27.0, 27.5
CH3), 2.95 (1H, qd, J 7.1, 1.1, CHS), 5.40 (1H, qd, J 6.6, 1.1, (2 × CH3, CH3CO) 59.6 (CH, CHS), 83.0 (C, (CH3)2CO), 158.7
CHO); δC (75.5 MHz, CDCl3) 5.7, 18.4 (2 × CH3), 56.2 (CH, (CvO); signals observed for 69: 11.1 (CH3, CH3CS), 22.9, 28.8
CHS), 69.1 (CH, CHO), 159.5 (CvO); m/z 188 (M+, 7%), 171 (2), (2 × CH3, CH3CO) 56.6 (CH, CHS), 76.6 (C, (CH3)2CO). m/z 202
160 (5), 142 (2), 129 (1), 116 (8), 97 (56), 84 (86), 72 (15), 56 (M+, 28%), 175 (30), 151 (40), 130 (6), 110 (20), 84 (30), 69 (26),
(13), 49 (100), 43 (24), 35 (4).
84 (30).
(4R*,5S*,6S*)-3-Diazo-5,6-dimethyl-[1,4]oxathian-2-one S-oxide
63 and (4R*,5R*,6R*)-3-diazo-5,6-dimethyl-[1,4]oxathian-2-one
S-oxide 64. 1 : 3 diastereomeric mixture of sulfoxides 42 : 43
Typical procedure for the synthesis of α-diazosulfoxides using
acetamidobenzenesulfonyl azide as diazo-transfer reagent45,46
(0.14 g, 0.86 mmol) gave the crude product as an orange oil. A solution of triethylamine (0.28 mL, 2.01 mmol, 1.1 eq.) in
Column chromatography (ethyl acetate–hexane 50 : 50) gave acetonitrile (5 mL) was added dropwise to a stirring solution
the pure α-diazosulfoxides (63, 64) as a yellow crystalline solid of sulfoxide (4R*,5R*,6S*)-5,6-diphenyl-[1,4]-oxathian-2-one S-
(0.060 g, 37%) and as a mixture of diastereomers (1 : 3.5); oxide 44 (0.522 g, 1.82 mmol) in acetonitrile (35 mL). Acetamido-
mp 123–125 °C; (Found C, 38.34; H, 4.26; N, 14.91; S, 17.32. benzenesulfonyl azide (0.484 g, 2.01 mmol) was added to
C6H8N2O3S requires C, 38.29; H, 4.28; N, 14.89; S, 17.03%); the solution as a solid in a single portion and the reaction
νmax (KBr)/cm−1 2123 (CvN2), 1682 (CvO), 1051 (SvO) cm−1
;
mixture was stirred at 0 °C for 10 min before the ice-bath was
m/z 188 (M+, 7%), 160 (2), 116 (5), 97 (2), 88 (17), 73 (15), removed. The reaction mixture was stirred at room temperature
56 (45), 43 (100), 32 (30). Repeated careful chromatography for 1.75 h. Ice cold ether (50 mL) was added to precipitate any
1
(ethyl acetate–hexane 50 : 50) led to a pure sample of 64 by H insoluble salts and the mixture was filtered through celite. The
NMR spectral analysis.
celite was washed with ether (10 mL) and the combined
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ethereal layers were concentrated under reduced pressure to Sulfoxides (1R*,5R*,6R*)-5,6-diphenyl-thiomorpholin-3-one S-
give the crude product 65 as a red solid. Purification was by oxide 51 and (1R*,5S*,6S*)-5,6-diphenyl-thiomorpholin-3-one
column chromatography as described below.
(4R*,5S*,6R*)-3-Diazo-5,6-diphenyl-[1,4]-oxathian-2-one
S-oxide 52 (2.5 : 1 diastereomeric mixture) (0.99 g, 3.5 mmol, 1
S- eq.) in THF (15 mL) was added dropwise to the stirring suspen-
oxide 65.33 Column chromatography (ethyl acetate–hexane sion. Stirring was continued for 10 min at 0 °C and then a solu-
50 : 50) gave the pure α-diazosulfoxide 65 as a yellow crystalline tion of p-toluenesulfonyl azide (0.67 g, 3.5 mmol) in dry THF
solid (0.261 g, 46%); mp 120–122 °C; (Found C, 61.15; H, 4.06; (15 mL) was added dropwise to give a yellow coloured solution.
N, 8.76; S, 10.76. C16H12N2O3S requires C, 61.50; H, 3.87; N, The reaction mixture was stirred for 1 h at 0 °C, then overnight
9.01; S, 10.26%); νmax(KBr)/cm−1 2154, 2135 (CvN2), 1679 at room temperature. The THF was evaporated under reduced
(CvO); δH (300 MHz, CDCl3) 4.30 (1H, d, J 2.0, CHS), 6.57 (1H, pressure to give the crude product mixture 72, 73 as an orange
d, J 2.0, CHO), 7.14–7.41 (10H, m, ArH); δC (75.5 MHz, CDCl3) oil. Purification was either by column chromatography or
68.1 (CH, CHS), 74.3 (CH, CHO), 126.2, 126.8 128.7, 128.8, recrystallization as described below.
129.3, 129.7, 129.8 (CH, ArCH and C), 135.0 (C), 159.9 (CvO);
m/z 312 (M+, 34%), 303 (74), 285 (60), 180 (68).
(1R*,5R*,6S*)-2-Diazo-5,6-diphenyl-thiomorpholin-3-one S-
oxide 71. From sulfoxide 50 (0.57 g, 2.50 mmol); column
chromatography (ethyl acetate–hexane 50 : 50) gave the pure
α-diazosulfoxide as a yellow crystalline solid (0.11 g, 62%); mp
152–155 °C decomposes; (Found C, 61.22; H, 4.15.
C16H13N3O2S requires C, 61.67; H, 4.18%); νmax (KBr)/cm−1
Typical procedure for the synthesis of α-diazosulfoxides using
dodecylbenzenesulfonyl azides as diazo-transfer reagent and
potassium carbonate as base47
Potassium carbonate (0.32 g, 2.32 mmol) was added dropwise 2113 (CvN2), 1651 (CvO), 1061 (SvO) cm−1; δH (300 MHz,
to a stirring solution of sulfoxides (4R*,5R*,6R*)-5,6-diphenyl- CDCl3) 4.10 (1H, d, J 2.9, CHS), 5.83 (1H, d, J 2.9, CHN), 5.91
[1,4]-oxathian-2-one S-oxide 45 and (4R*,5S*,6S*)-5,6-diphenyl- (1H, br s, NH), 7.08–7.42 (10H, m, aromatic); δC (75.5 MHz,
[1,4]-oxathian-2-one S-oxide 46 (0.64 g, 2.24 mmol) in aceto- CDCl3) 51.4 (CH, CHN), 67.4 (CH, CHS), 127.2, 128.2, 128.9,
nitrile (22 mL). After 5 min, dodecylbenzenesulfonyl azides 129.0, 129.6, 130.0 (CH, phenyl and C), 135.1 (C), 160.3 (CvO);
(0.785 g, 2.24 mmol) was then added to the solution at 0 °C m/z 283 (M+ − N2, 10%), 256 (5), 237 (55), 206 (25), 172 (52),
and the reaction mixture was stirred at 0 °C for 2 h, followed 149 (30), 117 (22), 104 (80), 91 (27), 77 (48), 64 (100), 57 (12),
by 18 h at room temperature. Ice cold ether (10 mL) was added 48 (64).
to precipitate any insoluble salts and the mixture was filtered
(1R*,5S*,6S*)-2-Diazo-5,6-diphenyl-thiomorpholin-3-one S-
through celite. The celite was washed with ether (10 mL) and oxide 72 and (1R*,5R*,6R*)-2-diazo-5,6-diphenyl-thiomorpho-
the combined ethereal layers were concentrated under reduced lin-3-one S-oxide 73. 2.5 : 1 diastereomeric mixture of sulf-
pressure to give the crude product mixture 66, 67 as an orange oxides (51 : 52) gave the crude product as an orange oil. Column
oil. Purification was by column chromatography as described chromatography (ethyl acetate–hexane 50 : 50) gave the pure
below.
(4R*,5S*,6S*)-3-Diazo-5,6-diphenyl-[1,4]-oxathian-2-one
oxide 66 and
oxathian-2-one S-oxide 67.33 2 : 1 diastereomeric mixture of H2O requires C, 60.05; H, 4.37; N, 13.12%); νmax (KBr)/cm−1
sulfoxides 45 : 46 (0.64 g, 2.24 mmol) gave the crude product 2111 (CvN2), 1644 (CvO), 1065 (SvO) cm−1
as an orange oil. Column chromatography (diethyl ether) gave Major diastereomer (equatorial) 72: δH (300 MHz, CDCl3)
α-diazosulfoxides as a yellow crystalline solid (0.293 g, 27%)
S- and as a mixture of diastereomers 1.6 : 1; mp 169–171 °C;
(4R*,5R*,6R*)-3-diazo-5,6-diphenyl-[1,4]- (Found C, 60.27; H, 4.17; N, 13.03. C16H13N2O2S and 0.5 mol
.
the pure α-diazosulfoxides 66 and 67 (1 : 2) as a yellow solid 4.43 (1H, d, J 8.8, CHS), 4.94 (1H, d, J 8.8, CHN), 6.23 (1H, br s,
(0.070 g, 10%), mp 107–109 °C; (Found C, 61.75; H, 3.75; N, NH), 7.18–7.30 (10H, m, aromatic).
9.25; S, 9.99. C16H12N2O3S requires C, 61.50; H, 3.87; N, 9.01;
Minor diastereomer (axial) 73: δH (300 MHz, CDCl3) 4.22
S, 10.26%); νmax(KBr)/cm−1 2113 (CvN2), 1676 (CvO), 1073 (1H, d, J 10.9, CHS), 5.64 (1H, d, J 10.9, CHN), 5.99 (1H, br s,
(CvO); δH (270 MHz, CDCl3) 4.40 (1H, d, J 11.0, CHS equator- NH), 7.18–7.30 (10H, m, aromatic).
ial), 4.46 (1H, d, J 11.0, CHS axial), 5.46 (1H, d, J 11.0, CHO
equatorial), 6.41 (1H, d, J 11.0, CHO axial), 7.09–7.30 (20H, m,
ArH); δC (67.8 MHz, CDCl3) 65.5 (CH, CHS axial), 74.9 (CH,
CHS equatorial), 76.7 (CH, CHO axial), 80.3 (CH, CHO equator-
Typical procedure for synthesis of acyclic imidazole containing
sulfoxides 75 and 76
ial), 127.2, 128.1, 129.0, 128.6, 128.6, 128.8, 129.3, 129.4, Potassium carbonate (0.69 g, 5.0 mmol, 1 equiv.) was added to
130.1, 130.4 (CH, ArCH and qArC), 131.3 (qArC axial), 134.2 a stirring solution of 2-mercapto-1-methylimidazole (0.57 g,
(qArC equatorial), 134.8 (qArC axial), 158.8 (equatorial CvO).
5.0 mmol) in acetone (50 mL) to give a suspension. Ethyl bro-
moacetate (0.55 mL, 5.0 mmol, 1 equiv.) was added dropwise
and the reaction mixture was stirred at 0 °C for 0.5 h and then
overnight at room temperature. The reaction mixture was fil-
Typical procedure for the synthesis of α-diazosulfoxides using
sodium hydride as base
Sodium hydride (60% dispersion in mineral oil, 0.172 g, tered through a layer of celite and the solvent evaporated
4.2 mmol, 1.2 eq.) was weighed into a dry 150 mL roundbot- under reduced pressure to give a yellow oil. Purification by
tomed flask and placed under nitrogen. Dry THF (35 mL) was column chromatography (ethyl acetate–hexane 80 : 20) gave the
added via syringe and the suspension was stirred at 0 °C. pure sulfide as a colourless oil (0.737 g, 74%).
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A
solution of 3-chloroperoxybenzoic acid (0.14 g, (0.393 g of crude product, containing tosyl amide and some
0.80 mmol) in dichloromethane (10 mL) was added over 5 min unreacted β-oxo sulfoxide) in dichloromethane (15 mL) at 0 °C.
to a stirring solution of pure sulfide (0.16 g, 0.80 mmol) in The reaction mixture was stirred for 5 h at 0–10 °C. The solu-
dichloromethane (10 mL) at 0 °C. The solution was stirred at tion was filtered, the solid was washed with cold dichloro-
0 °C for 5 h. The reaction mixture was filtered, the dichloro- methane (10 mL), and the dichloromethane solution was
methane solution washed with sodium bicarbonate solution washed with an aqueous sodium bicarbonate solution
(2 × 5 mL, 10%), water (5 mL) and brine (5 mL), then dried (2 × 10 mL, 5%), water (10 mL), and a saturated brine solution
and concentrated under reduced pressure to give the crude (10 mL). The layers were separated, the organic layer was dried
product 75 as a yellow oil. Purification by chromatography as (MgSO4), and concentrated under reduced pressure to give the
described below.
crude product mixture as an orange oil. Purification was either
(1-Methyl-1H-imidazole-2-sulfinyl)-acetic acid ethyl ester by column chromatography or recrystallization as described
75. Purification by column chromatography (ethyl acetate) below.
gave the pure sulfoxide 75 as a colourless oil (0.11 g, 68%);
Ethyl 2-diazo-2-(1-butylsulfonyl)acetate 82. Purification by
(Found C, 43.99; H, 5.60. C8H12N2O3S requires C, 44.43; H, column chromatography (ethyl acetate–hexane 1 : 12.5) gave
5.59%); νmax(film)/cm−1 1732 (CvO), 1280, 1051 (SvO); δH ethyl 2-diazo-2-(1-butylsulfonyl)acetate 82 as a yellow oil
(300 MHz, CDCl3) 1.25 (3H, t, J 7.1, –CH2CH3), 3.97 (3H, s, (46 mg, 7%), and ethyl 2-(1-butylsulfonyl)acetate 86 (21 mg,
N–CH3), 4.19 (2H, q, J 7.1, –CH2CH3), 4.30 (1H, A of ABq, 4%) as a colourless oil.
J 14.8, one of SOCH2), 4.57 (1H, B of ABq, J 14.8, one of
Ethyl 2-diazo-2-(1-octylsulfonyl)acetate 83. From sulfoxide
SOCH2), 7.15, 7.25 [2 × (1H, s, CH)]; δC (75.5 MHz, CDCl3) 14.0 79 (0.381 g, 1.53 mmol); purification by column chromato-
(CH3, –CH2CH3), 33.7 (N–CH3), 56.6 (CH2, SCH2), 62.1 (CH2, graphy (diethyl ether–hexane 3 : 17) gave ethyl 2-diazo-2-(1-
–CH2CH3), 125.1, 130.0 (2 × CHN), 144.9 (CSCH2), 165.1 octylsulfonyl)acetate 83 as a yellow oil (46 mg, 10%), and ethyl
(CvO). Found (HRMS, EI): m/z 216.0559. C8H12O3N2S requires 2-(1-octylsulfonyl)acetate 87 (9 mg, 2%) as a colourless oil.
M+ 216.0569; 216 (M+, 8%), 187 (5), 171 (6), 149 (15), 129 (100),
114 (16), 99 (30), 82 (35), 42 (44).
Ethyl 2-diazo-2-(1-dodecylsulfonyl)acetate 84. From sulf-
oxide 80 (0.30 g, 0.99 mmol); purification by column chromato-
(1-Methyl-1H-imidazole-2-sulfinyl)-acetic acid methyl ester graphy (diethyl ether–hexane 1 : 4) gave ethyl 2-diazo-2-
76. Sulfide isolated as a white solid (0.51 g, 55%). Oxidation of (1-dodecylsulfonyl)acetate 84 as a yellow solid (55 mg, 16%), mp
sulfide (0.75 g, 4.0 mmol) gave the pure sulfoxide 76 as a col- 40–41 °C (from diethyl ether), and ethyl 2-(1-dodecylsulfonyl)-
ourless oil (0.61 g, 75%) after purification by column chro- acetate 88 as a white solid (47 mg, 15%).
matography (ethyl acetate); (Found C, 40.73; H, 4.90; N, 12.96.
Ethyl 2-diazo-2-(benzenesulfonyl)acetate 85. From sulfoxide
C7H10N2O3S and 0.25 mol H2O requires C, 40.81; H, 5.09; N, 81 (0.50 g, 2.36 mmol); purification by column chromato-
13.52%); νmax(film)/cm−1 1736 (CvO), 1279, 1050 (SvO); δH graphy (diethyl ether–hexane 3 : 7) gave ethyl 2-diazo-2-(benze-
(300 MHz, CDCl3) 3.75 (3H, s,–CH2CH3), 3.97 (3H, s, N–CH3), nesulfonyl)acetate 85 as a yellow solid (55 mg, 9%), mp
4.32 (1H, A of ABq, J 14.8, one of SOCH2), 4.56 (1H, A of ABq, 52–54 °C (from diethyl ether), and ethyl 2-(benzenesulfonyl)-
J 14.8, one of SOCH2), 7.06, 7.19 [2 × (1H, s, CH)]; δC acetate 89 as a white solid (46 mg, 9%).
(75.5 MHz, CDCl3) 33.7 (N–CH3), 52.9 (CH3, CO2CH3), 56.4
(CH2, SCH2), 125.2, 130.0 (2 × CHN), 144.8 (CSCH2), 165.6
Typical procedure for syntheses of acyclic α-diazo β-oxo
sulfones 82–85
(CvO); m/z 202 (M+, 3%), 186 (6), 171 (2), 154 (5), 129 (100), 99
(25), 84 (68), 69 (45), 55 (75), 42 (88).
Potassium carbonate (0.47 g, 3.40 mmol) was added to a stir-
ring solution of α-sulfonyl ester ethyl 2-(1-butylsulfonyl)acetate
8654 (0.68 g, 3.26 mmol) in acetonitrile (5 mL). The reaction
mixture was stirred at room temperature for 5 minutes, then
General procedure for diazo transfer to acyclic α-sulfinyl esters
74, 79–81 followed by oxidation with 3-chloroperoxybenzoic
acid
A solution of α-sulfinyl ester ethyl 2-(1-butylsulfinyl)acetate 74 immersed in an ice-bath, and a solution of tosyl azide (0.70 g,
(0.56 g, 2.91 mmol) in THF (8 mL) was added dropwise to a 3.55 mmol) in acetonitrile (5 mL) was added dropwise over
stirring solution of NaH (0.116 g, 2.90 mmol, 60% mineral oil 1 minute. The reaction mixture was stirred for 1.5 h at 0 °C.
dispersion) in THF (8 mL) at 0 °C. The reaction mixture was Diethyl ether (10 mL) was added to precipitate the insoluble
stirred for 3 minutes, and then a solution of tosyl azide salts. The orange solution was filtered through celite, which
(0.572 g, 2.90 mmol) in THF (2 mL) was added dropwise over was washed with diethyl ether (20 mL). The diethyl ether solu-
1 min. The reaction mixture was stirred for 50 minutes at 0 °C. tion was dried (MgSO4), and concentrated under reduced
Diethyl ether (15 mL) was added, and the resulting solution pressure. A 2 : 1 hexane–diethyl ether mixture (30 mL) was
was washed with a saturated brine solution (2 × 10 mL). The added to the resulting orange solid, and the mixture stirred for
layers were separated, the organic layer was dried (MgSO4), 30 minutes. The solution was filtered, and the yellow filtrate
and concentrated under reduced pressure to give the crude was dried (MgSO4) and concentrated under reduced pressure
product as an orange oil.
to give the crude product 82 as a yellow solid. Purification was
3-Chloroperoxybenzoic acid (0.40 g, 1.51 mmol, 65%) was either by column chromatography or recrystallization as
added in two portions to a stirring solution of diazoester described below.
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Ethyl 2-diazo-2-(1-butylsulfonyl)acetate 82. Purification by (CvN2), 1718 (CvO); δH (270 MHz, CDCl3) 1.15–1.28 (3H, t,
column chromatography (diethyl ether–hexane 3 : 7) gave ethyl J 7, OCH2CH3), 4.13–4.27 (2H, q, J 7, OCH2CH3), 7.51–7.71 (3H,
2-diazo-2-(1-butylsulfonyl)acetate 82 as a yellow oil (0.48 g, m, ArH), 7.79–8.07 (2H, m, ArH); δC(67.8 MHz, CDCl3) 14.4
63%). (Found: C, 40.87; H, 6.16; N, 12.08; S, 13.63. C8H14N2O4S (CH3), 62.3 (OCH2CH3), 75.9 (CvN2), 127.8 (ArCH × 2), 129.2
requires C, 41.02; H, 6.02; N, 11.96; S, 13.69%); νmax(film)/ (ArCH × 2), 134.5 (ArCH), 141.7 (qArC), 159.6 (CvO); Found
cm−1 2130 (CvN2), 1714 (CvO); δH (270 MHz, CDCl3), (HRMS, EI): m/z 254.0368. C10H10N2O4S requires 254.0361; m/z
0.96–1.06 (3H, t, J 7, CH3 of butyl), 1.35–1.43 (3H, t, J 7, 254 (M+, 5%), 209 (M+ − OEt, 2), 141 (C6H5SO2+, 11), 89 (PhC+,
OCH2CH3), 1.47–1.60 (2H, m, CH2), 1.80–1.93 (2H, m, CH2), 9), 77 (Ph+, 100).
3.40–3.48 (2H, m, CH2SO2), 4.34–4.44 (2H, q, J 7, OCH2CH3); δC
(67.8 MHz, CDCl3) 13.7 (CH3), 14.5 (CH3), 21.5 (CH2), 24.9
(CH2), 56.6 (CH2SO2), 62.7 (OCH2CH3), 73.1 (CvN2), 160.3
Acknowledgements
(CvO); m/z 235 (M + 1+, 100%), 207 (M + 1+ − N2, 12), 189 (M+
+
− OEt, 57), 161 (M+ − N2, OEt, 24), 69 (77), 57 (C4H9 , 95), 41 Support from Pfizer (S.G.C.), Eli Lilly (O.C.M.O’S.), University
+
(CHN2 , 97).
College Cork President’s Research Fund (S.G.C.), Forbairt, the
Ethyl 2-diazo-2-(1-octylsulfonyl)acetate 83. From sulfone 87 Royal Irish Academy, and Cork Corporation (P.G.K.) are grate-
(3.50 g, 13.23 mmol); purification by column chromatography fully acknowledged.
(diethyl ether–hexane 3 : 17) gave ethyl 2-diazo-2-(1-octylsulfo-
nyl)acetate 83 as a yellow oil (2.42 g, 63%). (Found: C, 49.44;
H, 7.44; N, 10.07; S, 11.07. C12H22N2O4S requires C, 49.64; H,
References
7.64; N, 9.65; S, 11.04%); νmax(film)/cm−1 2131 (CvN2), 1718
(CvO); δH (270 MHz, CDCl3) 0.80–0.93 (3H, t, J 7, CH3 of
octyl), 1.18–1.50 (13H, (CH2)5, and contains t at 1.31, J 7,
OCH2CH3), 1.71–1.90 (2H, m, CH2), 3.30–3.41 (2H, m,
CH2SO2), 4.28–4.38 (2H, q, J 7, OCH2CH3); δC (75.5 MHz,
CDCl3) 14.0 (CH3), 14.3 (CH3), 22.6 (CH2), 22.7 (CH2), 28.1
(CH2), 28.9 (CH2), 29.0 (CH2), 31.7 (CH2), 56.7 (CH2SO2), 62.5
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(C4H7 , 82), 43 (C3H7+, 100), 41 (CHN2 , 97).
Ethyl 2-diazo-2-(1-dodecylsulfonyl)acetate 84. From sulfone
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C, 46.96; H, 3.96; N, 11.26; S, 12.56. C10H10N2O4S requires C,
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47.24; H, 3.96; N, 11.02; S, 12.61%); νmax(KBr)/cm−1 2130
1724 | Org. Biomol. Chem., 2013, 11, 1706–1725
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Paper
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