Reactions of enantiopure cyclic diols with sulfuryl chloride

Article abstract of DOI:10.1039/c4ob00042k

Monocyclic allylic cis-1,2-diols reacted with sulfuryl chloride at 0 °C in a regio- and stereo-selective manner to give 2-chloro-1-sulfochloridates, which were hydrolysed to yield the corresponding trans-1,2-chlorohydrins. At -78 °C, with very slow addition of sulfuryl chloride, cyclic sulfates were formed in good yields, proved to be very reactive with nucleophiles and rapidly decomposed on attempted storage. Reaction of a cyclic sulfate with sodium azide yielded a trans-azidohydrin without evidence of allylic rearrangement occurring. An enantiopure bicyclic cis-1,2-diol reacted with sulfuryl chloride to give, exclusively, a trans-1,2-dichloride enantiomer with retention of configuration at the benzylic centre and inversion at the non-benzylic centre; a mechanism is presented to rationalise the observation.

Full text of DOI:10.1039/c4ob00042k

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Reactions of enantiopure cyclic diols with
sulfuryl chloride†
Derek R. Boyd, Narain D. Sharma, Magdalena Kaik, Peter B. A. McIntyre,
John F. Malone and Paul J. Stevenson*
Cite this: Org. Biomol. Chem., 2014,
12, 2128
Monocyclic allylic cis-1,2-diols reacted with sulfuryl chloride at 0 °C in a regio- and stereo-selective
manner to give 2-chloro-1-sulfochloridates, which were hydrolysed to yield the corresponding trans-
1,2-chlorohydrins. At −78 °C, with very slow addition of sulfuryl chloride, cyclic sulfates were formed in
good yields, proved to be very reactive with nucleophiles and rapidly decomposed on attempted storage.
Reaction of a cyclic sulfate with sodium azide yielded a trans-azidohydrin without evidence of allylic
rearrangement occurring. An enantiopure bicyclic cis-1,2-diol reacted with sulfuryl chloride to give,
exclusively, a trans-1,2-dichloride enantiomer with retention of configuration at the benzylic centre and
inversion at the non-benzylic centre; a mechanism is presented to rationalise the observation.
Received 7th January 2014,
Accepted 11th February 2014
DOI: 10.1039/c4ob00042k
www.rsc.org/obc
Many reports on the preparation and use of sulfinate esters,
derived from cyclic allylic diols, have appeared in the chemical
Introduction
Enantiopure cis-dihydrodiol bacterial metabolites, derived literature.5,6 These electrophiles are suitably activated to react,
from monosubstituted halobenzenes, are useful intermediates regioselectively, with nucleophiles at the allylic position and
in organic synthesis.1 Their unsubstituted alkene bonds can this methodology has been used in the synthesis of Tamiflu.5,7
be chemoselectively functionalised and the halogen atom of To date, only one example of a well characterised cyclic sulfate
the vinyl halide replaced with a wide range of additional func- ester of a cyclic diol, having an allylic hydroxyl group, has been
tionality.2 This versatile chemistry makes these substrates reported. However, this was prepared indirectly by the oxi-
ideal for the synthesis of complex cyclohexane-based natural dation of a cyclic sulfinate ester followed by the subsequent
products.
Since the advent of the Sharpless asymmetric dihydroxyla-
introduction of unsaturation through dehydration.8
A number of methods are available for preparing cyclic
tion reaction,3 resulting in the ready availability of a wide sulfate esters and the subject has been reviewed.9 The most
range of chiral 1,2-diols, there has been increased activity in direct route involves reaction of the vic-diol with sulfuryl chlor-
utilizing them as key chiral intermediates in organic synthesis. ide or 1,1′-sulfonylbis(1H-imidazole). This procedure works
This has led to a resurgence of interest in cyclic sulfate deriva- well with: (i) 1,2-diols containing electron withdrawing
tives of 1,2-diols,4 as electrophiles for nucleophilic substi- groups10 (ii) cyclic diols11 and (iii) some acyclic 1,2-diols.
tution reactions. Cyclic sulfates are generally more reactive Recently, ionic liquids have been employed as solvents for
towards nucleophilic attack than the corresponding epoxides. such reactions, with the advantage that sulfuryl chloride is
We were particularly interested in using the previously hydrolytically stable in this medium.12 These direct methods
unreported cyclic sulfate esters of cis-tetrahydrodiol derivatives are however not generally applicable and complex mixtures
of aromatic compounds. The cis-1,2-dihydrodiol precursors may result from simple alkyl substituted acyclic 1,2-diols. The
are available in multi-gram quantities from our fermentation problem has been attributed to: (a) the intrinsic ring strain of
reactions.
cyclic sulfates slowing down the final cyclisation, and (b) the
innate chlorinating power of sulfuryl chloride. A more general
approach involves assembling the comparatively less strained
cyclic sulfinate esters (cyclic sulfites), derived from thionyl
chloride, followed by their oxidation to yield cyclic sulfate
esters. The Sharpless modification of this procedure, which
demonstrated that the sulfinate esters could be oxidised to the
sulfate esters, using sodium periodate and a catalytic quantity
of ruthenium salts, led to a major advance in the routine use
of cyclic sulfate esters in organic synthesis.13
School of Chemistry and Chemical Engineering, Queens University, Belfast,
N Ireland BT9 5AG, UK. E-mail: p.stevenson@qub.ac.uk; Fax: +44 (0)289097 4687;
Tel: +44 (0)2890974426
†Electronic supplementary information (ESI) available: Copies of proton
and carbon NMR spectra together with relevant HPLC traces are included.
CCDC 971376–971378. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c4ob00042k
2128 | Org. Biomol. Chem., 2014, 12, 2128–2136
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 1. Reaction of diol 1a with thionyl chloride gave cyclic
sulfite 2a as a mixture (5 : 1) of diastereoisomers in 89% yield.
Results and discussion
We have recently reported that the unsubstituted alkene bond Attempted oxidation of diastereoisomers 2a to give cyclic
in cis-1,2-dihydrodiols, derived from monosubstituted ben- sulfate ester 3a, using the Sharpless procedure,13 was unsuc-
zenes, can be chemoselectively reduced to give cis-tetrahydro- cessful. Only 20% of the starting material, containing none of
diols 1a–f, Table 1.14 Due to the enhanced stability of these the minor diastereoisomer, was recovered. It is known that
derivatives, over the corresponding cis-dihydrodiols, they are alkenes are susceptible to oxidation under these conditions,
ideal precursors for enantioselective synthesis. To explore the and thus it is likely that the failure of this reaction was due to
chemistry further by chemoselective activation of the allylic the formation of polar products, which were lost on aqueous
hydroxyl group, substitution reactions at the allylic position workup. Problems in carrying out this type of oxidation, in the
were carried out and synthesis of previously unreported reac- presence of alkene functionality, have been reported.15,16 Our
tive cyclic sulfate esters seemed to be the obvious choice. attention was next focussed on the direct formation of cyclic
Products obtained from selected reactions of cis-tetrahydro- sulfate esters 3 using sulfuryl chloride.
diols 1a–f and 6 with thionyl and sulfuryl chlorides, under
Reaction of cis-diols 1a–c and 6 with excess sulfuryl chloride
various conditions (A–C), are presented in Scheme 1 and at 0 °C, in the presence of triethylamine, gave 2-chloro-1-sulfo-
chloridates 4a–c, and 7 (Table 1, conditions B). The triethyl-
amine Lewis salt of sulfur trioxide, present in the crude
mixture after aqueous workup, was removed by crystallisation
from hexane. Surprisingly, significant proportions of 2-chloro-
1-sulfochloridates 4a–c and sulfochloridate 7 survived the
aqueous work up, though hydrolysis might have been a contri-
buting factor to the modest isolated yields (45–55%).
Table 1 Reactions of cis-tetrahydrodiols 1 and 6 with SOCl2 or SO2Cl2
to yield products 2–5, 7 and 8
Conditions
Substituent
X
A
B
C
Determination of the molecular formulae of compounds
4a–c, initially, proved difficult as these compounds did not
provide meaningful mass spectroscopic data. However, the
13C-NMR spectrum of compound 4a clearly showed a signal at
δ 55.6 ppm that was entirely consistent with the replacement
of a hydroxyl group with a chlorine atom at the C-2 position.
The huge increase in chemical shift of the homoallylic H-1
proton signal from δ 4.0 to δ 5.37 strongly suggested that the
other hydroxyl group had been converted to an ester. A single
crystal X-ray structure of compound 4c (Fig. 1) established the
gross structure as a 3-iodo-2-chloro-1-sulfochloridate and con-
firmed that the chlorine atom was introduced at the C-2 posi-
tion with clean inversion of configuration. In the solid state,
the molecule adopted a conformation in which the chlorine
atom and chlorosulfonyl ester group were trans-diaxial. The
same conformation was also prevalent in CDCl3 solution,
cis-Diol
Yield (%) Yield (%) Yield (%)
1a
1b
1c
1d
1e
1f
6
Cl
Br
I
CF3
CO2Me
Ph
2a (89)
na
na
na
na
na
na
4a (45)
4b (51)
4c (55)
na
na
na
3a (70)
3b (72)
na
3d (61)
3e (34), 5e (14)
5f (29)a
8 (73)
Br, acetonide
7 (46)
Conditions A: SOCl2, CH2Cl2, 0 °C; B: SO2Cl2, Et3N, CH2Cl2, 0 °C; C:
SO2Cl2, Et3N, DMAP, CH2Cl2, −78 °C. a A sample of 5f, as
a
7 : 1 mixture of trans : cis diastereoisomers (29%) was isolated but the
mixture was not characterised. na – not attempted.
Scheme 1 Reagents and conditions: (i) C6H5N, SOCl2, CH2Cl2, 0 °C,
30 min; (ii) RuCl3, NaIO4, CH3CN–H2O, 0 °C, 1 h; (iii) SO2Cl2, Et3N,
CH2Cl2, 0 °C → RT, 12 h; (iv) NaI, MeOH–H2O, 3.6 : 1, 25 °C, 5 min; (v)
SO2Cl2, DMAP, CH2Cl2, −78 °C, 1.5 h; (vi) NaN3, DMSO, 60 °C, 4 h, 93%;
(vii) NaN3, (CH3)2CO–H2O (6 : 1), 0 °C → RT, 68%.
Fig. 1 X-ray crystal structure of (1S,2R)-3-iodo-2-chlorocyclohex-
3-enyl sulfochloridate 4c.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 2128–2136 | 2129

View Article Online
Paper
Organic & Biomolecular Chemistry
since proton H-2 appeared as a doublet, J 2.3 Hz, in the
1H-NMR spectrum, indicating a predominant conformer with
a diequatorial arrangement of the two adjacent hydrogen
atoms. The allylic chloro substituent adopted a pseudoaxial
position, presumably to minimise allylic 1,2-strain with the
iodine atom and increase hyperconjugation of the polar bond
with the alkene.
Racemic compounds, containing a chlorine atom and a sul-
fonyl chloride ester on adjacent carbons, have been prepared
by the addition of chlorine chlorosulfate to alkenes at low
temperature.17 Chiral compounds of this nature, can also be
prepared regioselectively, by the reaction of sulfuryl chloride
with vinyl epoxides.18 In carbohydrate chemistry, it is common
to observe that, on reaction with sulfuryl chloride, chlorination
occurs at the activated anomeric position, whilst other second-
ary alcohols are normally converted to chlorosulfonate
esters.19 In the case of diols 1a–c, the more reactive pseudo-
equatorial homoallylic hydroxyl group on C-1 is likely to form
a monochlorosulfonyl ester first. If the cyclisation to cyclic
sulfate ester 3 is slow, then a second chlorosulfonyl ester may
form through reaction with the allylic hydroxyl group at C-2.
The pseudoaxial allylic chlorosulfonate ester is sufficiently acti-
vated to facilitate rapid nucleophilic attack of chloride ion and
conversion into the allylic chloride, with inversion of configur-
ation, giving rise to trans products, 4a–c and 7. When stored at
room temperature for over a month, compounds 4a–c and 7
were found to be stable, with no noticeable decomposition.
trans-2-Chloro-1-chlorosulfonate esters 4a and 4b were con-
verted to trans-chlorohydrins 5a and 5b in 81% and 82%
yields, respectively, using a standard procedure involving
sodium iodide in aqueous methanol.20 This two-step pro-
cedure provides a cheap alternative to the Mattock reagent,21
for regio- and stereo-selectively converting cyclic allylic cis-
diols 1a and 1b to trans-chlorohydrins 5a and 5b respectively
(Scheme 1).
Fig. 2 X-ray crystal structure of (1S,2S)-3-chlorocyclohex-3-ene-1,2-
cyclic sulfate 3a.
azidohydrin 10a, via an allyl azide [3,3] sigmatropic rearrange-
ment on gentle heating, to give a 4 : 1 mixture of isomers
9a : 10a. Cyclic sulfate 3a reacted with sodium azide, at room
temperature, to give, exclusively, azidohydrin 9a without evi-
dence of azidohydrin isomer 10a. The corresponding less reac-
tive cyclic sulfite 2a did not react with sodium azide under
these conditions. However, on heating, with sodium azide in
DMSO, cyclic sulfite 2a formed azidohydrin 9a together with
the rearranged isomer 10a. It is, therefore, advantageous, in
some cases, to use the more reactive cyclic sulfate 3 rather
than cyclic sulfite 2.
A brief study of benzo-fused cyclic cis-diols 11a–c, in which
one of the hydroxyl groups was benzylic (Scheme 2), available
as single enantiomer metabolites from earlier biotransform-
ation studies, was undertaken. Reaction of 2,3-dihydro-1H-
indene-1,2-diol 11a, and 6,7-dihydro-5H-benzo[7]annulene 11c,
with sulfuryl chloride at 0 °C, gave complex mixtures of pro-
ducts whose separation was not attempted. In marked con-
trast, reaction of (1R,2S)-naphthalene cis-1,2,3,4-tetrahydrodiol
11b,23 under the same reaction conditions, proceeded
smoothly and cleanly, to give dichloride 12b in excellent yield.
Reaction of cis-diols 1a,b,d,e and 6, at low temperature and
high dilution, with very slow addition of sulfuryl chloride in
the presence of DMAP (Table 1, conditions C, conditions used
by Myers15), gave the desired cyclic sulfates 3a, 3b, 3d, 3e and
8 in moderate to good yields (34–73%). These conditions were
essential to achieve the desired chemoselectivity and to favour
intramolecular ring closure of the intermediate mono chloro-
sulfate ester and formation of the cyclic sulfate ester over other
processes. Low temperature single crystal X-ray crystallography
established the structure of cyclic sulfate 3a (Fig. 2). In the
case of cis-diol 1e the modified conditions gave a 2.5 : 1 ratio
of cyclic sulfate 3e to chlorohydrin 5e and similarly diol 1f
gave a modest yield (29%) of impure chlorohydrin 5f but no
cyclic sulfate 3f indicating that these reactions were very sub-
strate dependant. The cyclic allylic sulfate esters 3a, 3b, 3d, 3e
and 8 were found to partially decompose at room temperature
after 24 h.
1
Analysis of the H-NMR spectrum gave the coupling constant
between H-1 and H-2, (J 2 Hz). This indicated that there was a
We have recently reported22 the synthesis of (1S,2R)-trans-
1,2-azidohydrin 9a as the predominant product from a ring
opening reaction of the corresponding epoxide, and have
Scheme 2 Reagents and conditions: (i) SO2Cl2, Et3N, CH2Cl2, 0 °C →
demonstrated that this equilibrates with the isomeric RT 12 h; (ii) SO2Cl2, DMAP, Et3N, CH2Cl2, −78 °C, 1.5 h; (iii) H2O.
2130 | Org. Biomol. Chem., 2014, 12, 2128–2136
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
strong preference, in solution, for a conformer in which these chloronium ion ring opening is a prerequisite for good ee
two hydrogens were trans-diequatorial, confirming the struc- values29 and Denmark has recently demonstrated that chiral
ture of diastereoisomer 12b as the trans-1,2-dichloride. Coup- chloronium ions, containing alkyl groups, are configuration-
ling constants of similar magnitude have been reported for the ally stable.30 The generality of this novel dichlorination reac-
trans-1,2-diazides in the tetrahydronaphthalene series.24 Sur- tion remains to be fully evaluated, but it is significant that it
prisingly, one of the chlorine atoms was introduced with reten- failed with two (11a and 11c) out of three bicyclic substrates.
tion, whilst the other with inversion of configuration.
Reaction of cis-tetrahydrodiol 11b, under Myers’ con-
trans-Dichloride 12b was found to be optically active but ditions,15 failed to give any of the corresponding cyclic sulfate
the magnitude of optical rotation ([α]D +12.3), in comparison and only the trans-chlorohydrin 13b was isolated (71% yield).
with the literature values,25,26 suggested that the compound In this example, it was likely that the cyclic sulfate was slow to
was of relatively low enantiopurity (ca. 20% ee). Chiral station- form and both the hydroxyl groups became chlorosulfonated
ary phase HPLC analysis (Chiralcel OD), however, showed a to yield intermediate 14b which eventually led to the formation
baseline separation of the enantiomers of racemic trans- of chlorohydrin 13b, on warming the reaction mixture to room
dichloride 12b and an early eluting single peak for (+)-trans- temperature followed by its aqueous workup.
dichloride 12b, derived from (1R,2S)-diol 11b, establishing that
The relative stereochemistry of chlorohydrin 13b, a known
it was a single enantiomer. H-NMR spectroscopy proved that literature compound,24 was determined as trans, by compari-
one chiral centre had inverted whilst the other had retained its son of the NMR spectroscopic data. It is noteworthy that the
stereochemistry on chlorination, but could not link these coupling constant in trans-chlorohydrin 13b was much larger
stereochemical events to a discrete chiral centre. X-ray crystal- (J1,2 6.9 Hz) than the corresponding coupling constant in
lographic analysis, on a single crystal of (+)-dichloride 12b, trans-dichloride 10 (J1,2 2.2 Hz). This is consistent with the
determined both its relative and absolute configurations conformational heterogeneity in chlorohydrin 13b, with two
(Fig. 3). It confirmed: (i) the trans diaxial stereochemistry of dominant conformers contributing to the observed coupling
(+)-dichloride 12b in the solid state and (ii) that chlorination at constant. It may be the result of an intramolecular hydrogen
the benzylic position proceeded with retention of configur- bond, helping to stabilise the conformer in which the hydroxyl
ation and at the non-benzylic position with inversion of and chloro groups are diequatorial. The absolute configuration
1
configuration to give the (1R,2R) enantiomer.
of compound (−)-13b was assumed to be (1S,2S) on the basis
Since many reactions which proceed with retention of con- of its formation from intermediate 15b and is in accord with
figuration involve a double inversion,27 the cyclic chloronium the literature assignment.24
ion 16b has been presented as
a likely intermediate
(Scheme 2). Cyclic chloronium ions have previously been pos-
tulated, to explain counterintuitive stereoselectivity in ring
opening reactions of ω-chloroepoxides.28 Chlorination with
Conclusion
inversion of configuration at the more reactive benzylic posi- It was demonstrated that the products, from reactions of chiral
tion in the postulated intermediate 14b, would give the antici- allyl- and benzyl-activated cyclic cis-diols with sulfuryl chlor-
pated product 15b as a precursor of the cyclic chloronium ion ide, were dependent on both substrate structure and con-
16b. Ring opening of intermediate 16b with chloride ion at the ditions. Up to four types of enantiopure products were
reactive benzylic position would complete the double inversion identified from this reaction i.e. trans-chlorohydrin, trans-
and account for the experimentally observed stereochemistry. chloro-chlorosulfate ester, cis-cyclic sulfate ester and trans-
Nicolaou has demonstrated catalytic asymmetric addition dichloride. With monocyclic allylic diols, conditions were
of chlorine to allylic alcohols, where regioselectivity of found that favoured either formation of the cyclic sulfate
esters or chloro-chlorosulfate esters as precursors to trans-
chlorohydrins. Cyclic sulfate esters and trans-chlorohydrins
demonstrate stereo-complementarity, because the absolute
configurations at the electrophilic allylic sites are opposite for
each class of compound. It is noteworthy that reaction with
sulfuryl chloride can yield either type of product, simply by
modifying the reaction conditions. This is likely to enhance
the importance of these species as intermediates in enantio-
selective synthesis.
Experimental
1H and 13C-NMR spectra were recorded on Bruker Avance 400,
DPX-300 and DRX-500 instruments. Chemical shifts (δ) are
reported in ppm relative to SiMe4 and coupling constants (J)
Fig. 3 X-ray crystal structure of (1R,2R)-1,2-dichloro-1,2,3,4-tetra-
hydronaphthalene 12b.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 2128–2136 | 2131

View Article Online
Paper
Organic & Biomolecular Chemistry
are given in Hz. Mass spectra were run at 70 eV, on a VG Auto- (500 MHz, CDCl3) δH 2.50–2.22 (4 H, m, H-5, H-5, H-6, H-6),
spec mass spectrometer, using a heated inlet system. IR 4.58 (1 H, bm, H-2), 5.37 (1 H, dt, J 4.5, 2.4, H-1), 6.15 (1 H, dd,
spectra were recorded on a Perkin-Elmer Model 983G instru- J 5.0, 2.9, H-4); 13C-NMR (125 MHz, CDCl3) δC 20.29, 21.27,
ment coupled to a Perkin-Elmer 3700 data station using 55.64, 85.91, 127.16, 129.76; νmax/cm−1 (KBr) 3061.9, 2932.1,
potassium bromide (KBr) disks unless otherwise stated. 1649.7, 1404.2, 1215.6, 1191.9, 934.9, 919.7.
Accurate molecular weights were determined by the peak
(1S,2R)-3-Bromo-2-chlorocyclohex-3-enyl sulfochloridate 4b.
matching method, with perfluorokerosene as the standard. General procedure A gave titled compound, yield: 51%;
Flash column chromatography and preparative layer chromato- m. p. 68–70 °C (from hexane); Rf 0.82 (Et2O–hexane, 1 : 1);
graphy (PLC) were performed on Merck Kieselgel type 60 [α]D +119 (c 1.07, CHCl3); (Found: C, 23.9; H, 2.3; S, 10.1.
(250–400 mesh) and PF254/366 plates respectively. Merck Kieselgel C6H7BrCl2O3S requires C, 23.3; H, 2.3; S, 10.3%); 1H-NMR
type 60F254 analytical plates were employed for TLC. Diols (500 MHz, CDCl3) δH 2.48–2.24 (4 H, m, H-5, H-5′ H-6, H-6′),
1a–f,14,31
6
32 and 11a–c23,33 were prepared by literature methods. 4.65 (1 H, bm, H-2), 5.37 (1 H, dt, J 4.4, 2.3, H-1), 6.37 (1 H, dd,
J 5.2, 2.7, H-4); 13C-NMR (125 MHz, CDCl3) δC 20.31, 22.77,
(3aS,7aS)-7-Chloro-3a,4,5,7a-tetrahydrobenzo[1.3.2]dioxathiol-
2-oxide 2a
57.47, 85.99, 116.72, 134.24; LRMS (EI) 310 (M+, 1%), 194 (10),
159 (95), 157 (100), 113 (30); νmax/cm−1 (KBr) 588.8, 737.3,
Thionyl chloride (3.24 g 27.2 mmol) was added dropwise to a 759.7, 918.8, 1190.6, 1214.4, 1402.3, 1639.4, 2361.9.
stirred solution of diol 1a (2.7 g, 18.2 mmol) and pyridine (1S,2R)-3-Iodo-2-chlorocyclohex-3-enyl sulfochloridate 4c.
(2.6 g, 32.7 mmol) in DCM (100 mL) at −30 °C. The reaction General procedure gave titled compound yield 55%;
A
mixture was allowed to warm to room temperature, water m. p. 84–86 °C (from hexane); [α]D +82.2 (c 1.07, CHCl3);
(100 mL) was added, the organic phase separated, washed with (Found: C, 20.8; H, 2.2; S, 8.5. C6H7Cl2IO3S requires C, 20.2; H,
water (100 mL), dried (MgSO4) and concentrated. The resulting 2.0; S, 9.0%); 1H-NMR (300 MHz, CDCl3) δH 6.63 (1 H, dd,
crude yellow oil was purified by passing it through a pad of J 4.9, 2.8, H-4), 5.35 (1 H, dt, J 4.9, 2.8, H-1), 4.66 (1 H, bs, H-1),
alumina and eluting with ethyl acetate–petroleum ether (1 : 1), 2.52–2.28 (4 H, m, H-5, H-5′ H-6, H-6′); 13C-NMR (75 MHz,
to afford cyclic sulfite 2a (3.15 g, 89%). Product 2a was CDCl3) δC 142.20, 90.11, 85.25, 60.48, 24.12, 19.83; νmax/cm−1
obtained as an oil consisting of an inseparable mixture (4 : 1) (KBr) 2361.0, 1724.6, 1624.8, 1400.1, 1187.9, 1211.0, 915.8,
of two diastereoisomers, resulting from the newly generated 727.4, 591.0.
chiral sulfur centre. HRMS (LC-TOFMS) (Found: [M + 1]+
Crystal data for 4c: C6H7Cl2IO3S, M = 357.0, orthorhombic,
194.9877. C6H8ClO3S requires 194.9877); Major isomer: a = 5.936(1), b = 8.960(3), c = 20.683(6) Å, U = 1100.0(5) Å3, T =
1H-NMR (300 MHz, CDCl3) δH 6.18 (1 H, dd, J 4.9, 3.7, H-6), 293(2) K, space group P212121 (no. 19), Mo-Kα radiation, λ =
5.21 (2 H, 2 × m, H-7a and H-3a), 2.32 (1 H, m, H-5), 2.18 (1 H, 0.71073 Å,
m, H-5′), 2.07–2.13 (2 H, 2 × m, H-4 and H-4′) and Minor μ = 3.560 mm−1, Bruker P4 diffractometer, ω scans, 5.0° < 2θ <
isomer: 6.18 (1 H, m, H-6), 4.97 (1 H, bd, J 5.9 H-3a), 4.89 (1 H, 55.0°, measured/independent reflections: 2047/1868, Rint
Z = 4, F(000) = 680, Dx = 2.156 g ,
cm−3
=
td, J 5.9, 3.0, H-7a), 2.51 (1 H m, H-5), 2.03–2.40 (3 H, 3 × m, 0.094, direct methods solution, full-matrix least squares refine-
2
H-5′, H-3 and H-3′); Major isomer: 13C-NMR (CDCl3, 75 MHz) δC ment on Fo , anisotropic displacement parameters for non-
131.45 (2C), 79.16, 77.96, 24.18, 21.84 and Minor isomer: hydrogen atoms; all hydrogen atoms located in a difference
131.14, 127.25, 82.23, 80.05, 25.68, 21.80; νmax/cm−1 (thin film) Fourier synthesis but included at positions calculated from the
1211.68 (SvO).
geometry of the molecules using the riding model, with isotro-
pic vibration parameters. R1 = 0.072 for 1525 data with Fo
4σ(Fo), 119 parameters, ωR2 = 0.198 (all data), GoF = 1.07,
>
General procedure A for chloro sulfochloridate formation
Triethylamine (0.16 mL, 1.14 mmol) and sulfuryl chloride CCDC 971376. The absolute configuration is established as
(0.09 mL, 1.14 mmol) were added to a solution of cis-diol 1 (1S,2R) from the anomalous scattering arising from the iodine
(0.57 mmol) in DCM (8 mL) at 0 °C. The reaction mixture was atom; Flack parameter x = −0.04(9).
allowed to warm to room temperature and stirred overnight.
(3aR,4S,5S,7aS)-7-Bromo-5-chloro-2,2-dimethyl-3a,4,5,7a-tetra-
The solution was diluted with DCM (5 mL), cooled to 0 °C and hydrobenzo[d][1,3]dioxol-4-yl sulfochloridate 7. General pro-
water (8 mL) was added. The DCM layer was separated and the cedure A gave titled compound, was obtained by as colourless
remaining aqueous layer extracted with fresh DCM (2 × 5 mL). plates, yield: 46%; m. p. 56–58 °C (Et2O–hexane); [α]D +20.0
The combined organic extract was dried (MgSO4) and the (c 1.1, CHCl3); HRMS (LC-TOFMS) (Found: [M + H]+ 380.8957.
1
solvent removed to give a yellow oil. The oil was extracted with C9H12O5Cl2BrS requires 380.8960); H-NMR (400 MHz, CDCl3)
hexane (3 × 10 mL) and the extract evaporated at 40 °C, to give δH 1.45 (3 H, s, CH3), 1.58 (3 H, s, CH3), 4.44 (1 H, dd, J 7.3,
a concentrated solution, which was left for crystallisation to 5.9, H-3a), 4.57 (1 H, ddd, J 6.8, 3.2, 1.1, H-5), 4.75 (1 H, d,
yield the title compound.
(1S,2R)-2,3-Dichlorocyclohex-3-enyl sulfochloridate 4a. Gen- H-6); 13C NMR (300 MHz, CDCl3) δC 26.3, 27.7, 53.1, 74.8, 76.6,
eral procedure
gave titled compound, yield: 45%; 87.1, 112.7, 122.4, 130.1; νmax/cm−1 (KBr) 2994, 2941, 1644,
m. p. 49–50 °C (from hexane); Rf 0.9, (Et2O–hexane, 1 : 1); 1628, 1411, 1249, 1185, 981.
J 5.9, H-7a), 5.17 (1 H, dd, J 7.2, 7.2, H-4), 6.28 (1H, d, J 3.2,
A
[α]D +153.3 (c 0.6, CHCl3); (Found: C, 27.6; H, 2.7; S, 11.7.
(1S,2R)-2,3-Dichlorocyclohex-3-enol 5a. A solution of
C6H7Cl3O3S requires C, 27.1; H, 2.7; S, 12.1%); 1H-NMR sodium iodide (10%, 0.34 g, 2.26 mmol) in MeOH–H2O (1 : 1,
2132 | Org. Biomol. Chem., 2014, 12, 2128–2136
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
3 mL) was added to chloro-chlorosulfate 4a (0.65 mmol) in 6.39 (1 H, dd, J 5.3, 3.4, H-4); 13C-NMR (100 MHz, CDCl3)
MeOH (4 mL). After stirring the mixture for 5 minutes, sodium δC 21.09, 24.04, 79.94, 80.48, 124.90, 133.49; νmax/cm−1 (KBr)
thiosulfate (0.56 g, 2.26 mmol) was added to trap the evolved 3061.2, 2973.5, 2936.0, 1648.2, 1376.1, 1205.5, 961.9.
iodine. The reaction mixture was neutralised with sodium
Crystal data for 3a: C6H7ClO4S, M = 210.6, orthorhombic,
bicarbonate (0.19 g, 2.26 mmol), most of the methanol was a = 6.6774(1), b = 10.9657(2), c = 11.0176(2) Å, U = 806.73(2) Å3,
removed under reduced pressure, and the remaining solution T = 100(2) K, space group P212121 (no. 19), Cu-Kα radiation, λ =
diluted with water (5 mL). The aqueous mixture was extracted 1.54180 Å, Z = 4, F(000) = 432, Dx = 1.734 g cm−3, μ =
with EtOAc (3 × 5 mL), the extract was dried (MgSO4) and con- 6.431 mm−1, SuperNova Dual, Atlas CCD diffractometer,
centrated under reduced pressure. The crude yellow oil ω scans, 11.4° < 2θ < 153.4°, measured/independent reflec-
obtained was purified by PLC (Et2O–hexane, 1 : 1), to give the tions: 5964/1674, Rint = 0.025, direct methods solution, full-
2
title compound 5a as a colourless oil. Yield: 82%; Rf 0.1 matrix least squares refinement on Fo , anisotropic displace-
(EtOAc–hexane, 1 : 9); [α]D + 87.0 (c 0.5, CHCl3); HRMS (EI) ment parameters for non-hydrogen atoms; all hydrogen atoms
(Found: [M + H]+ 167.0021. C6H8Cl2O+ requires 167.0025); located in a difference Fourier synthesis but included at posi-
1H-NMR (300 MHz, CDCl3) δH 1.78 (1 H, m, H-6), 2.08 (1 H, m, tions calculated from the geometry of the molecules using the
H-6′), 2.20 (1 H, m, H-5), 2.26 (1 H, m, H-5′), 4.23 (1 H, dtd, riding model, with isotropic vibration parameters. R1 = 0.023
J 6.6, 4.2, 2.5 H-1), 4.30 (1 H, d, J 4.2, H-2), 6.06 (1 H, t, J 4.2, for 1670 data with Fo > 4σ(Fo), 109 parameters, ωR2 = 0.060 (all
H-4); 13C-NMR (100 MHz, CDCl3) δC 22.2, 24.0, 62.4, 72.4, data), GoF = 1.08, Δρmin,max = −0.34/0.23 e Å−3. CCDC 971378.
128.9, 129.6; νmax/cm−1 (thin film) 3377, 2935, 1646, 1062, The absolute configuration is established as (1S,2S) from the
836, 769.
anomalous scattering arising from the chlorine and sulfur
(1S,2R)-3-Bromo-2-chlorocyclohex-3-enol 5b. It was obtained atoms; Flack parameter x = −0.006(14).
following the procedure for the preparation of compound 5a,
(1S,2S)-3-Bromocyclohex-3-ene-1,2-cyclic sulfate 3b. Follow-
substituting chloro-chlorosulfate 4b (0.20 g, 0.65 mmol). Puri- ing the general procedure B, diol 1b gave a crude product,
fication by PLC (Et2O–hexane, 1 : 1) gave the title compound 5b which crystallised from Et2O to give cyclic sulfate 3b as colour-
as a colourless oil. Yield: 0.11 g, 81%; Rf 0.45 (Et2O–hexane, less solid. Yield: 95 mg, 72%; m. p. 73–74 °C; Rf 0.26 (Et2O–
1 : 1); HRMS (EI) (Found: [M − OH]+ 194.9414. C6H7BrCl+ hexane, 1 : 1); [α]D +111.0 (c 0.88, CHCl3); (Found: C, 28.4; H,
requires 194.9402); 1H-NMR (300 MHz, CDCl3) δH 1.78 (1 H, m, 2.3; S, 12.4. C6H7BrO4S requires C, 28.3; H, 2.8; S, 12.6%);
H-6), 2.07 (1 H, m, H-6′), 2.19 (1 H, m, H-5), 2.33 (1 H, m, HRMS (LC-TOFMS): (Found: [M
+
NH4]+ 271.9585.
H-5′), 4.21 (1 H, dt, J 6.0, 2.8, H-1), 4.38 (1 H, d, J 3.2, H-2), C6H11O4SBrN requires 271.9587; 1H-NMR (400 MHz, CDCl3)
6.29 (1 H, t, J 4.2, H-4); 13C-NMR (125 MHz, CDCl3) δC 20.7, δH 2.05 (1 H, m, H-6), 2.2 (1 H, m, H-5), 2.34 (1 H, m, H-6′),
23.8, 64.2, 72.4, 119.5, 134.3.
2.45 (1 H, m, H-5′), 5.26 (1 H, td, J 5.7, 2.9, H-1) 5.29 (1 H, d,
J 5.3, H-2), 6.62 (1 H, dd, J 5.31, 3.40, H-4); 13C-NMR (100 MHz,
CDCl3) δC 22.41, 24.05, 80.76, 81.15, 114.14, 137.95; νmax/cm−1
General procedure B for cyclic sulfate formation
4-(Dimethylamino)pyridine (25 mg, 0.21 mmol) was added to a (KBr) 3055.4, 2971.5, 2932.3, 2918.1, 1642.9 (CvC) 1374.7
stirred solution of diol 1 (0.52 mmol) in DCM (10 mL) and the (SvO), 1205.0 (SvO).
resulting solution cooled to −78 °C. Triethylamine (0.29 mL,
(1S,2R)-3-(Trifluoromethyl)cyclohex-3-ene-1,2-cyclic sulfate
2.06 mmol) was added to the cooled solution and the stirring 3d. Following the general procedure B gave a crude product,
continued for 10 min. A solution of sulfuryl chloride (0.08 mL which was purified by PLC to give the titled cyclic sulfate 3d as
0.98 mmol) in DCM (10 mL) was then slowly added to the cold a pale yellow oil. Yield: 61%; Rf 0.25 (Et2O–hexane, 1 : 1);
reaction mixture via a glass syringe over a period of 1 h. After [α]D +35.0 (c 1.2, CHCl3); HRMS (LC-TOFMS) (Found: [M + Na]+
stirring at −78 °C for 30 min, the solution was diluted with 266.9913. C7H7F3NaO4S+ requires 266.9909); 1H-NMR
DCM (10 mL) and a saturated solution (10 mL) of sodium (400 MHz, CDCl3) δH 2.07 (1 H, m, H-6), 2.34 (2 H, m, H-6′,
bicarbonate was added to the reaction mixture. The organic H-5′), 2.58 (1 H, m, H-5), 5.25 (1 H, m, H-1), 5.46 (1 H, d, J 5.4,
layer was separated, washed, successively, with brine (10 mL) H-2) 6.98 (1 H, m, H-3); 13C-NMR (100 MHz, CDCl3) δC 20.17,
and water (10 mL), dried (Na2SO4) and concentrated. The 23.75, 74.11, 79.42, 122.35 (q, J 273.5), 123.31 (q, J 32.3), 140.9
crude product obtained was purified either by crystallisation (q, J 5.0).
or chromatography.
(5S,6R)-Methyl-5,6-cyclic-sulfate-cyclohex-1-enecarboxylate
(1S,2S)-3-Chlorocyclohex-3-ene-1,2-cyclic sulfate 3a. Using 3e. Using the general procedure B, diol 1e (130 mg,
general procedure B, diol 1a gave a crude product, which was 0.76 mmol) gave a crude product, which on purification by
purified by PLC and then crystallised from Et2O–hexane to give PLC (Et2O–hexane, 3 : 1) gave cyclic sulfate 3e as colourless oil.
cyclic sulfate 3a as colourless needles. Yield: 70%; Yield: 60 mg, 34%; Rf 0.23 (Et2O–hexane, 3 : 1); [α]D +94.6
m. p. 71–72 °C; Rf 0.4 (Et2O–hexane, 1 : 1); [α]D +106.0 (c 0.73, (c 0.75, CHCl3); HRMS (LC-TOFMS) (Found [M + H]+ 235.0275.
CHCl3); (Found: C, 34.4; H, 2.8. C6H7ClO4S requires C, 34.2; H, C8H11O6S requires 235.0271); 1H-NMR (400 MHz, CDCl3)
3.3%). HRMS (LC-TOFMS) (Found: [M + NH4]+ 228.0087. δH 2.02 (1 H, m, H-4), 2.34 (2 H, m, H-3, H-4′), 2.61 (1 H, m,
C6H11ClNO4S requires 228.0092); 1H-NMR (400 MHz, CDCl3) H-3′), 3.83 (3 H, s, CO2Me), 5.24 (1 H, ddd, J 6.6, 5.5, 3.3, H-5),
δH 2.03 (1 H, m, H-6), 2.30 (2 H, m, H-5, H-6′), 2.50 (1 H, m, 5.72 (1 H, d, J 5.5, H-6), 7.49 (1 H, dd, J 4.8, 3.8, H-2); 13C-NMR
H-5′), 5.23 (1 H, d, J 5.8, H-2), 5.26 (1 H, td, J 5.8, 2.9, H-1), (100 MHz, CDCl3) δC 21.08, 23.94, 52.43, 76.14, 79.69, 125.13,
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 2128–2136 | 2133

View Article Online
Paper
Organic & Biomolecular Chemistry
147.53, 164.35; νmax/cm−1 (thin film) 2959, 1721, 1654, 1383, Rf 0.48 (EtOAc–hexane, 3 : 7); [α]D +198.0 (c 0.7, CHCl3); HRMS
1268, 1205.
(LC-TOFMS) (Found: [M + Na]+, 196.0245. C6H8ClN3NaO
(5S,6S)-Methyl-6-chloro-5-hydroxycyclohex-1-enecarboxylate requires 196.0248); 1H-NMR (400 MHz, CDCl3) δH 1.77 (1 H, m,
5e. Following the general procedure B, the titled compound H-6), 1.89 (1 H, m, H-6′), 1.96 (1 H, s, OH), 2.21–2.28 (2 H, m,
was isolated as a byproduct in the above reactions as a pale H-5, H-5′), 3.87 (1 H, br d, J 5.6, H-2), 3.91 (1 H, ddd, J 8.5, 5.6,
yellow oil. Yield: 20 mg, 14%; Rf 0.52 (Et2O–hexane, 3 : 1); 3.1, H-1), 6.07 (1 H, t, J 4.1, H-3); 13C-NMR (100 MHz, CDCl3)
[α]D +89.0 (c 0.9, CHCl3); HRMS (Found: M+ 190.0401. δC 22.8, 26.3, 67.6, 71.0, 128.3, 129.3; LRMS (EI): m/z 173
C8H11ClO3 requires 190.0391); 1H-NMR (400 MHz, CDCl3) (M+, 7%), 146 (26), 144 (78), 131 (81), 130 (75), 129 (72),
δH 1.86 (1 H, m, H-4), 1.90 (1 H, s, OH) 2.14 (1 H, m, H-4′), 2.35 118 (73), 116 (82), 103 (64), 101 (100); νmax/cm−1 (thin film)
(1 H, m, H-5), 2.48 (1 H, m, H-5′), 3.80 (3 H, s, CO2Me), 4.30 3367, 2932, 2103, 1662, 1257.
(1 H, dt, J 5.01, 2.88, H-5), 4.73 (1 H, m, H-6), 7.18 (1 H, t,
(1S,2R)-2-Azido-3-chloro-3-cyclohexen-1-ol 9a and (1S,4S)-
J 4.1 Hz, H-2); 13C-NMR (100 MHz, CDCl3) δC 21.35, 22.50, 4-azido-3-chloro-3-cyclohexen-1-ol 10a. A solution of cyclic
52.16, 53.78, 69.84, 128.43, 143.38, 166.04; LRMS (EI): m/z 190 sulfite 2a (2.01 g, 10.3 mmol) and sodium azide (1.14 g,
(M+, 8%), 172 (4), 158 (52), 147 (93), 137 (42), 111 (100), 17.6 mmol) in DMSO (40 mL) was heated with stirring at 60 °C
95 (50), 77 (62).
for 4 h. After cooling the mixture, it was diluted with water
(1S,2S)-2-Chloro-3-phenylcyclohex-3-enol 5f and (1S,2R)-2- (40 mL) and extracted with ethyl acetate (60 mL). The organic
chloro-3-phenylcyclohex-3-enol as a 7 : 1 mixture. Following phase was washed with brine (3 × 50 mL), dried (Na2SO4) and
the general procedure B, diol 1e (280 mg, 1.47 mmol) gave a concentrated to give the crude product (1.67 g, 93%) as an
crude product, which on purification by PLC (Et2O–hexane, inseparable mixture (3 : 1) of azides 9a and 10a. In addition to
3 : 1) gave a 7 : 1 mixture of trans and cis-chlorohydrins 5f the NMR signals for the major isomer 9a, additional signals
1
(90 mg 29%); Rf 0.48, (50% Et2O–hexanes); [α]D +39.9 (c 0.98, for the compound 10a were also present. H-NMR (300 MHz,
1
CHCl3; H-NMR major trans (400 MHz, CDCl3) δH 1.84 (1 H, m, CDCl3) δH 6.07 (1 H, d, J 4.6, H-2), 4.25(1 H, m, H-1), 3.93 (1 H,
H-6), 2.21 (1 H, m, H-6′), 2.35 (1 H, m, H-5), 2.45 (1 H, m, t, J 4.9, H-4) 2.30–2.20 (2 H, m, H-5), 1.93–1.80 (2 H, m, H-6);
H-5′), 4.27 (1 H, ddd, J 6.8, 4.4, 2.7, H-1), 4.82 (1 H, d, J 4.4, 13C-NMR (100 MHz, CDCl3) δC 131.33, 128.51, 65.35, 61.19,
H-2), 6.19 (1 H, t, J 4.0, H-3), 7.23–7.46 (5 H, m, Ar); 13C-NMR 27.67, 26.29. The above data matched with that reported in the
(100 MHz) δC 21.95, 24.49, 59.71, 71.79, 126.04 (2C), 127.47, literature.22
128.35 (2C), 129.32, 135.26, 139.50.
(1R,2R)-1,2-Dichloro-1,2,3,4-tetrahydronaphthalene 12b. Tri-
1
Selected peaks from minor cis-isomer: H-NMR (400 MHz, ethylamine (0.47 mL, 3.04 mmol) and sulfuryl chloride
CDCl3) δH 5.13 (1 H, d, J 3.7, H-2), 4.05 (1 H, dt, J 11.9, (0.25 mL, 3.04 mmol) were added to a solution of cis-diol 8b
3.7, H-1); 13C-NMR (100 MHz) δC 69.49, 63.39.
(250 mg, 1.52 mmol) in DCM (15 mL) at 0 °C. The reaction
(3aS,4R,5R,7aS)-7-Bromo-2,2-dimethyl-3a,4,5,7a-tetrahydro- mixture was stirred for 15 min. at 0 °C, allowed to warm to
benzo[d][1,3]dioxole-4,5-diol cyclic sulfate 8. General proce- room temperature and the stirring continued for another
dure B, using (200 mg, 0.75 mmol) of diol 6, gave the crude 45 min. It was diluted with a mixture of DCM (5 mL) and water
product, which was purified by column chromatography (15 mL). The organic layer was separated, the remaining
(EtOAc–hexane, 1 : 19) to give cyclic sulfate 8 as a colourless aqueous layer extracted with fresh DCM (2 × 10 mL), the
oil. Yield: 73%; Rf 0.4 (EtOAc–hexane, 1 : 9); [α]D +103.4 (c 1.03, organic extracts combined, dried (MgSO4) and the solvent was
CHCl3); HRMS (LC-TOFMS) (Found [M
+
H]+ 326.9540. removed to give the crude product as a pale yellow solid. Crys-
1
C9H12BrO6S requires 326.9533); H-NMR (400 MHz, CDCl3) δH tallisation of the crude product furnished colourless crystals of
1.42 (3 H, s, Me), 1.43 (3 H, s, Me), 4.70–4.74 (2 H, m, H-3a, dichloride 12b. Yield: 210 mg, 69%; m. p. 61–62 °C (from
H-7a), 5.34 (1 H, ddd, J 5.6, 3.2, 1.3, H-5), 5.42 (1 H, ddd, J 5.6, hexane); its spectral data matched with the literature values
2.9, 1.2, H-4), 6.27 (1 H, dt, J 3.2, 1.2, H-6); 13C-NMR (100 MHz, except for the optical rotation;25 [α]D +12.3 (c 0.81, CHCl3,
CDCl3) δC 26.32, 27.34, 72.01, 73.60, 76.56, 77.82, 111.65, >98% ee); lit.25 [α]D +8.6 (c 0.4, CHCl3, 14% ee); 1H-NMR
122.67, 130.18; νmax/cm−1 (thin film) 2992, 1651, 1396, (500 MHz, CDCl3) δH 2.13 (1 H, m, H-3) 2.67 (1 H, dddd, J 14.5,
1212, 936.
11.3, 5.8, 2.4, H-3′), 2.87 (1 H, ddd, J 17.2, 5.8, 2.8, H-4), 3.15
(1S,2R)-2-Azido-3-chlorocyclohex-3-enol 9a. Sodium azide (1 H, ddd, J 17.2, 11.3, 5.8, H-4′), 4.65 (1 H, dt, J 5.0, 2.8, H-2),
(31 mg, 0.48 mmol) was added to a solution of cyclic sulfate 3a 5.23 (1 H, d, J 2.5, H-1), 7.05–7.30 (4 H, m, Ar); 13C-NMR
(50 mg, 0.24 mmol) in a mixture of acetone–water (6 : 1, 5 mL) (125 MHz, CDCl3) δC 23.90, 25.04, 59.48, 59.77, 126.71, 128.81,
at 0 °C. The solution was stirred for 12 h and then allowed to 129.06, 131.05, 132.39, 135.88; νmax/cm−1 (thin film) 2956,
warm to room temperature. The solvent was removed in vacuo, 2930, 1492, 1455, 1440, 1428, 738.
the white solid residue obtained was treated with a mixture of
Crystal data for 12b: C10H10Cl2, M = 201.1, monoclinic, a =
20% H2SO4 and Et2O (1 : 1, 6 mL) and the reaction mixture 7.4192(4), b = 7.6708(4), c = 8.1477(5) Å, β = 101.30(1)°, U =
stirred for a further 8 h. It was diluted with Et2O (20 mL), 454.70(4) Å3, T = 150(2) K, space group P21 (no. 4), Mo-Kα radi-
washed with aq. NaHCO3 (2 × 15 mL), brine (15 mL), dried ation, λ = 0.71073 Å, Z = 2, F(000) = 208, Dx = 1.469 g cm−3, μ =
(Na2SO4) and concentrated in vacuo. The crude product, 0.650 mm−1, Oxford Diffraction Gemini ultra diffractometer,
obtained as a yellow oil, was purified by PLC (EtOAc–hexane, ω scans, 5.6° < 2θ < 61.7°, measured/independent reflections:
3 : 7) to furnish azide 9a as a colourless oil. Yield: 28 mg, 68%; 2509/1797, Rint = 0.021, direct methods solution, full-matrix
2134 | Org. Biomol. Chem., 2014, 12, 2128–2136
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
2
least squares refinement on Fo , anisotropic displacement
parameters for non-hydrogen atoms; all hydrogen atoms
located in a difference Fourier synthesis but included at posi-
tions calculated from the geometry of the molecules using the
riding model, with isotropic vibration parameters. R1 = 0.030
for 1578 data with Fo > 4σ(Fo), 109 parameters, ωR2 = 0.059 (all
data), GoF = 1.04, Δρmin,max = −0.26/0.29 e Å−3. CCDC 971377.
The absolute configuration is established as (1R,2R) from the
anomalous scattering arising from the chlorine atom; Flack
parameter x = 0.05(6).
10.1039/c3qo00057e; D. R. Adams, J. van Kempen,
J. R. Hudlicky and T. Hudlicky, Heterocycles, 2014,
88, 1255; T. A. Reekie, M. G. Banwell and A. C. Willis,
J. Org. Chem., 2013, 78, 7100; X. Ma, M. G. Banwell and
A. C. Willis, J. Nat. Prod., 2013, 76, 1514; H. S. Kim,
M. G. Banwell and A. C. Willis, J. Org. Chem., 2013,
78, 5103; B. D. Schwartz, E. Matousova, R. White,
M. G. Banwell and A. C. Willis, Org. Lett., 2013, 15, 1934;
V. Varghese and T. Hudlicky, Synlett, 2013, 369; D. Bon,
M. G. Banwell, J. S. Ward and A. C. Willis, Tetrahedron, 2013,
69, 1363; J. A. Griffen, J. C. White, G. Kociok-Kohn,
M. D. Lloyd, A. Wells, T. C. Arnot and S. E. Lewis, Tetra-
hedron, 2013, 69, 5989; M. K. Sharma, M. G. Banwell,
A. C. Willis and A. D. Rae, Chem.–Asian J., 2012, 7, 676;
V. Semak, T. A. Metcalf, M. A. A. Endoma-Arias, P. Mach and
T. Hudlicky, Org. Biomol. Chem., 2012, 10, 4407;
M. G. Banwell, N. Gao, X. H. Ma, L. Petit, L. V. White,
B. D. Schwartz, A. C. Willis and I. A. Cade, Pure Appl. Chem.,
2012, 84, 1329; D. R. Boyd, N. D. Sharma, M. Kaik,
P. B. A. McIntyre, P. J. Stevenson and C. C. R. Allen, Org.
Biomol. Chem., 2012, 10, 2774; D. R. Boyd, M. Bell,
K. S. Dunne, B. Kelly, P. J. Stevenson, J. F. Malone and
C. C. R. Allen, Org. Biomol. Chem., 2012, 10, 1388;
S. Vshyvenko, J. Scattolon, T. Hudlicky, A. E. Romero,
A. Kornienko, D. Ma, I. Tuffley and S. Pandey, Can. J. Chem.,
2012, 90, 932; M. J. Palframan, G. Kociok-Kohn and
S. E. Lewis, Chem.–Eur. J., 2012, 18, 4766; M. A. Khan,
M. F. Mahon, J. P. Lowe, A. J. W. Stewart and S. E. Lewis,
Chem.–Eur. J., 2012, 18, 13480; L. Werner, A. Machara,
B. Sullivan, I. Carrera, M. Moser, D. R. Adams, T. Hudlicky
and J. Andraos, J. Org. Chem., 2011, 76, 10050;
M. A. A. Endoma-Arias and T. Hudlicky, Tetrahedron Lett.,
2011, 52, 6632; L. Petit, M. G. Banwell and A. C. Willis, Org.
Lett., 2011, 13, 5800; B. D. Schwartz, L. V. White,
M. G. Banwell and A. C. Willis, J. Org. Chem., 2011, 76, 8560;
B. D. Schwartz, M. G. Banwell and I. A. Cade, Tetrahedron
Lett., 2011, 52, 4526; D. Bon, M. G. Banwell and A. C. Willis,
Tetrahedron, 2011, 67, 5841; L. V. White, B. D. Schwartz,
M. G. Banwell and A. C. Willis, J. Org. Chem., 2011, 76, 6250;
J. Duchek, D. R. Adams and T. Hudlicky, Chem. Rev., 2011,
111, 4223; J. Duchek, T. G. Piercy, J. Gilmet and T. Hudlicky,
Can. J. Chem., 2011, 89, 709; D. R. Adams, C. Aichinger,
J. Collins, U. Rinner and T. Hudlicky, Synlett, 2011, 1188;
M. J. Palframan, G. Kociok-Kohn and S. E. Lewis, Org. Lett.,
2011, 13, 3150; M. A. Khan, J. P. Lowe, A. L. Johnson,
A. J. W. Stewart and S. E. Lewis, Chem. Commun., 2011, 47,
215; S. Pilgrim, G. Kociok-Kohn, M. D. Lloyd and S. E. Lewis,
Chem. Commun., 2011, 47, 4799; D. R. Boyd, N. D. Sharma,
C. A. Acaru, J. F. Malone, C. R. O’Dowd, C. C. R. Allen and
P. J. Stevenson, Org. Lett., 2010, 12, 2206; D. R. Boyd,
N. D. Sharma, N. I. Bowers, G. B. Coen, J. F. Malone,
C. R. O’Dowd, P. J. Stevenson and C. C. R. Allen, Org. Biomol.
Chem., 2010, 8, 1415; D. K. Winter, M. A. Endoma-Arias,
T. Hudlicky, J. A. Beutler and J. A. Porco, J. Org. Chem., 2013,
78, 7617; J. F. Trant, J. Froese and T. Hudlicky, Tetrahedron:
Asymmetry, 2013, 24, 184.
(1S,2S)-1-Chloro-1,2,3,4-tetrahydronaphthalen-2-ol 13b. Tri-
ethylamine (0.34 mL, 2.42 mmol) was added to solution of
(1R,2S)-cis-diol 11b (100 mg, 0.61 mmol) and DMAP (0.03 g,
0.24 mmol) in DCM (10 mL). The mixture was cooled to
−78 °C and stirred for 10 min. Sulfuryl chloride (0.09 mL,
1.15 mmol) was added dropwise over a period of 1 h and the
mixture allowed to stir for a further 30 min at −78 °C. The reac-
tion mixture was quenched with a saturated solution of
sodium bicarbonate (3 mL), diluted with DCM (5 mL), and
water (15 mL). The organic layer was separated, washed with
water, dried (Na2SO4), and concentrated on a rotary evaporator,
to give a brown-coloured oil. The crude product was passed
through a short silica gel column with Et2O as eluent. This
sample was further purified by PLC (Et2O–hexane, 1 : 1), to give
the chlorohydrin 13b as a colourless oil. Yield: 81 mg, 73%. Its
spectral properties were in general agreement‡ with the litera-
ture values;24 Rf 0.42 (Et2O–hexane, 1 : 1); [α]D −123.7 (c 0.73,
CHCl3); lit24 [α]D −39 (c 0.7, CHCl3); 1H-NMR (400 MHz,
CDCl3) δH 1.89 (1 H, m, H-3), 2.33 (1 H, dtd, J 14.4, 5.8, 5.8,
3.3, H-3′), 2.43 (1 H, s, OH), 2.94 (2 H, appar t, J 6.2, H-4, H-4′),
4.15 (1 H, ddd, J 9.6, 6.9, 3.3, H-2), 5.02 (1 H, d, J 6.9, H-1),
7.11 (1 H, m, Ar), 7.23 (2 H, m, Ar), 7.53 (1 H, m, Ar); 13C-NMR
(100 MHz, CDCl3) δC 26.33, 27.69, 64.56, 72.84, 126.53, 128.14,
128.54, 130.17, 133.92, 135.91.
Acknowledgements
We gratefully acknowledge financial support from an EU Marie
Curie Host Fellowship for the Transfer of Knowledge (MK), Dr
Brian Kelly (Celtic Catalysts) and the Department of Education
and Learning, Northern Ireland for a postgraduate studentship
(PABMcI). We are also greatly indebted to Dr Helge Mueller-
Bunz (University College Dublin) and Dr Mahon (University of
Bath) for provision of X-ray crystallographic data, Dr Peter
Goodrich (Queen’s University Belfast for CSPHPLC analyses),
Dr Colin McRoberts and Mr Stewart Floyd (Agri-Food and Bio-
science Institute, Belfast) for LC-TOFMS analyses.
References
1 J. A. Griffen, S. J. Kenwright, S. Abou-Shehada, S. Wharry,
T. S. Moody and S. E. Lewis, Org. Chem. Front., 2014, DOI:
‡Signals are within 0.2 ppm except for signal at 72.84 does not match the litera-
ture value of 69.1 ppm.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 2128–2136 | 2135

View Article Online
Paper
Organic & Biomolecular Chemistry
2 D. R. Boyd, N. D. Sharma, M. Kaik, M. Bell, 18 S. Barluenga, E. Moulin, P. Lopez and N. Winssinger,
M. V. Berberian, P. B. A. McIntyre, B. Kelly, C. Hardacre, Chem.–Eur. J., 2005, 11, 4935.
P. J. Stevenson and C. C. R. Allen, Adv. Synth. Catal., 2011, 19 H. J. Jennings and J. K. N. Jones, Can. J. Chem., 1962, 40,
353, 2455. 1408.
3 H. C. Kolb, M. S. Vannieuwenhze and K. B. Sharpless, 20 H. J. Jennings and J. K. N. Jones, Can. J. Chem., 1963, 41,
Chem. Rev., 1994, 94, 2483; E. N. Jacobsen, I. Marko, 1151.
W. S. Mungall, G. Schroder and K. B. Sharpless, J. Am. 21 A. R. Mattocks, J. Chem. Soc., 1964, 1918.
Chem. Soc., 1988, 110, 1968.
22 D. R. Boyd, N. D. Sharma, T. Belhocine, J. F. Malone,
4 T. L. Lowary, E. Eichler and D. R. Bundle, Can. J. Chem.,
2002, 80, 1112; T. J. Tewson, J. Org. Chem., 1983, 48, 3507.
S. T. McGregor, J. Atchison, P. A. B. McIntyre and
P. J. Stevenson, J. Phys. Org. Chem., 2013, 26, 997.
5 H. Sun, Y. J. Lin, Y. L. Wu and Y. K. Wu, Synlett, 2009, 2473. 23 D. R. Boyd, N. D. Sharma, N. A. Kerley, G. McConville,
6 T. L. Shih, W. S. Kuo and Y. L. Lin, Tetrahedron Lett., 2004, C. C. R. Allen and A. J. Blacker, ARKIVOC, 2003, 32.
45, 5751; A. Bianco, M. Brufani, F. Manna and 24 F. Orsini, G. Sello and G. Bestetti, Tetrahedron: Asymmetry,
C. Melchioni, Carbohydr. Res., 2001, 332, 23; C. U. Kim, 2001, 12, 2961.
W. Lew, M. A. Williams, H. T. Liu, L. J. Zhang, 25 S. A. Snyder, D. S. Treitler and A. P. Brucks, J. Am. Chem.
S. Swaminathan, N. Bischofberger, M. S. Chen, Soc., 2010, 132, 14303.
D. B. Mendel, C. Y. Tai, W. G. Laver and R. C. Stevens, 26 A. P. Brucks, D. S. Treitler, S. A. Liu and S. A. Snyder,
J. Am. Chem. Soc., 1997, 119, 681; M. Cakmak, P. Mayer and
D. Trauner, Nat. Chem., 2011, 3, 543.
7 L. D. Nie, W. Ding, X. X. Shi, N. Quan and X. Lu, Tetra-
hedron: Asymmetry, 2012, 23, 742; L. D. Nie, X. X. Shi,
N. Quan, F. F. Wang and X. Lu, Tetrahedron: Asymmetry,
2011, 22, 1692.
8 J. K. Sutherland, R. C. Whitehead and G. M. Davies,
J. Chem. Soc., Chem. Commun., 1993, 464.
9 H. S. Byun, L. L. He and R. Bittman, Tetrahedron, 2000, 56,
7051.
Synthesis, 2013, 1886.
27 A. El Moncef, E. M. El Hadrami, M. A. Gonzalez,
E. Zaballos and R. J. Zaragoza, Tetrahedron, 2010, 66, 5173;
S. J. Coote, S. G. Davies, A. M. Fletcher, P. M. Roberts and
J. E. Thomson, Chem.–Asian J., 2010, 5, 589; S. Besli,
S. J. Coles, D. B. Davies, R. J. Eaton, M. B. Hursthouse,
A. Kilic and R. A. Shaw, Eur. J. Inorg. Chem., 2005, 959;
X. Q. Yu, A. Hirai and M. Miyashita, Chem. Lett., 2004, 33,
764; A. Hirai, X. Q. Yu, T. Tonooka and M. Miyashita,
Chem. Commun., 2003, 2482; M. Sasaki, K. Tanino and
M. Miyashita, J. Org. Chem., 2001, 66, 5388.
10 M. Alonso and A. Riera, Tetrahedron: Asymmetry, 2005, 16,
3908.
11 M. S. Berridge, M. P. Franceschini, E. Rosenfeld and
T. J. Tewson, J. Org. Chem., 1990, 55, 1211.
28 D. K. Bedke, G. M. Shibuya, A. Pereira, W. H. Gerwick,
T. H. Haines and C. D. Vanderwal, J. Am. Chem. Soc., 2009,
131, 7570; C. Nilewski, R. W. Geisser and E. M. Carreira,
Nature, 2009, 457, 573.
12 C. Hardacre, M. E. Migaud and K. A. Ness, New J. Chem.,
2012, 36, 2316; C. Hardacre, I. Messina, M. E. Migaud, 29 K. C. Nicolaou, N. L. Simmons, Y. C. Ying, P. M. Heretsch
K. A. Ness and S. E. Norman, Tetrahedron, 2009, 65, 6341. and J. S. Chen, J. Am. Chem. Soc., 2011, 133, 8134.
13 Y. Gao and K. B. Sharpless, J. Am. Chem. Soc., 1988, 110, 7538. 30 S. E. Denmark, M. T. Burk and A. J. Hoover, J. Am. Chem.
14 D. R. Boyd, N. D. Sharma, M. V. Berberian, K. S. Dunne, Soc., 2010, 132, 1232.
C. Hardacre, M. Kaik, B. Kelly, J. F. Malone, S. T. McGregor 31 D. R. Boyd, N. D. Sharma, N. M. Llamas, G. P. Coen,
and P. J. Stevenson, Adv. Synth. Catal., 2010, 352, 855.
15 A. G. Myers and S. D. Goldberg, Angew. Chem., Int. Ed.,
2000, 39, 2732.
16 F. E. McDonald and P. Vadapally, Tetrahedron Lett., 1999,
40, 2235.
P. K. M. McGeehin and C. C. R. Allen, Org. Biomol. Chem.,
2007, 5, 514.
32 T. Hudlicky, J. D. Price, F. Rulin and T. Tsunoda, J. Am.
Chem. Soc., 1990, 112, 9439.
33 C. C. R. Allen, D. R. Boyd, H. Dalton, N. D. Sharma,
I. Brannigan, N. A. Kerley, G. N. Sheldrake and S. C. Taylor,
J. Chem. Soc., Chem. Commun., 1995, 117.
17 N. S. Zefirov, A. S. Kozmin and V. D. Sorokin, J. Org. Chem.,
1984, 49, 4086.
2136 | Org. Biomol. Chem., 2014, 12, 2128–2136
This journal is © The Royal Society of Chemistry 2014