2-Sulfinyl Oxetanes: Synthesis, Stability and Reactivity

Article abstract of DOI:10.1055/s-0035-1560588

The synthesis of 2-sulfinyl oxetanes is described by a C-C bond-forming cyclisation strategy. Oxetanes bearing electron-poor aryl sulfoxides are shown to be viable targets using this strategy. We report investigations into the sulfoxide magnesium exchange

Full text of DOI:10.1055/s-0035-1560588

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, 106–110
letter
106
K. F. Morgan et al.
Letter
Synlett
2-Sulfinyl Oxetanes: Synthesis, Stability and Reactivity
Kate F. Morgana
Robert Dorana
Rosemary A. Crofta
Ian A. Hollingsworthb
James A. Bull*a
i-PrMgCl
Ar = 2-pyr
O
O
N
LiHMDS
or LDA
O
S
O
S
i-PrMgCl
S
O
O
O
Ar
Ar
Ar = 2-ClC6H4
a Department of Chemistry, Imperial College London,
South Kensington, London SW7 2AZ, UK
j.bull@imperial.ac.uk
OTs
sulfinyl-
oxetanes
O
O
[O]
S
O
b AstraZeneca Mereside, Alderley Park, Cheshire, SK10 4TG, UK
Ar = 4-NCC6H4
NC
Dedicated to Professor Steven V. Ley CBE FRS on the occasion of
his 70th birthday. Happy Birthday Steve!
Received: 20.09.2015
Accepted after revision: 20.10.2015
Published online: 05.11.2015
the Paternò–Büchi [2+2] photocycloaddition can prepare
highly substituted derivatives.7 We recently reported a new
anionic cyclisation approach to the synthesis of 2-substitut-
ed oxetanes, which involved formation of the C2–C3
bond.8,9 This strategy permitted the synthesis of a novel se-
ries of 2-sulfonyl oxetanes, designed as fragments for FBDD
(Scheme 1B).8 These displayed appropriate physical proper-
ties for fragment screening, as well as good stability in pH
and liver microsomes studies.8b We have also reported a
rapid synthesis of 2,2-disubstituted derivatives by an O–H
insertion and cyclisation approach, to generate a range of
2,2-disubstitued, 2,2,4-trisubstituted and 2,2,3,4-tetra-
substituted oxetane motifs.9 Building on these studies, we
were interested in examining 2-sulfinyl oxetanes, a new
functional group combination (Scheme 1C).
DOI: 10.1055/s-0035-1560588; Art ID: st-2015-d0749-l
Abstract The synthesis of 2-sulfinyl oxetanes is described by a C–C
bond-forming cyclisation strategy. Oxetanes bearing electron-poor aryl
sulfoxides are shown to be viable targets using this strategy. We report
investigations into the sulfoxide magnesium exchange on 2-sulfinyl ox-
etanes, which resulted in products formed via ligand exchange and li-
gand coupling pathways. The sulfinyl oxetanes can be readily oxidised
to the sulfonyl oxetanes.
Key words oxetanes, heterocycles, cyclisation, sulfoxides, sulfones
Oxetanes are strained four-membered rings and so are
of interest as synthetic intermediates in complex molecule
synthesis.1 At the same time, they are receiving consider-
able attention as stable motifs for medicinal chemistry that
can improve the physicochemical properties of biologically
active molecules.2 This recent interest in the use of oxe-
tanes in drug discovery has stemmed from beautiful studies
by Carreira and co-workers, which demonstrated 3,3-
disubstituted oxetanes to be attractive replacements for
gem-dimethyl and carbonyl groups.3,4 In addition, oxetanes
access new design space for medicinal chemists and pres-
ent well-defined three-dimensional structures due to the
rigid ring system.5 With this in mind we are interested in
synthesising novel oxetane-containing fragments for frag-
ment based drug discovery (FBDD), in particular less stud-
ied 2-substituted examples, and in developing methods to
derivatise these strained heterocyclic motifs.
(A) traditional approaches to oxetane synthesis
H
Williamson etherification
C–O formation
base
O
O
R
R
2
4
R
LG
3
Paternò–Büchi reaction
C–C and C–O formation
O
hν
O
R
R'
R'
(B) previous work: 2-sulfonyl oxetanes (ref. 8)
O
O
O O
base
fragments for FBDD
S
O
S
O
C–C bond
formation
Ar
Ar
suitable for further
derivatisation
OTs
(C) this work: 2-sulfinyl oxetanes
Cyclisation approaches towards oxetane derivatives
have traditionally involved intramolecular Williamson
ether synthesis; either from acyclic precursors or involving
epoxide ring opening and closure (Scheme 1A).6 However,
these approaches largely preclude the incorporation of
functional groups at the oxetane 2-position. Alternatively,
stability of functional
group?
sulfinyl–metal exchange?
O
S
O
S
cyclisation
O
O
Ar
Ar
functionalisation of
sulfoxide?
OTs
1
2
Scheme 1 Strategies towards oxetane synthesis
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 106–110

107
K. F. Morgan et al.
Letter
Synlett
Certain heterocyclic small-ring sulfoxides have been
well studied as interesting groups in their own right, and
also as synthetic intermediates. Satoh and others have ex-
tensively examined the synthesis of aziridine and epoxide
sulfoxides.10–13 Furthermore, from these stable precursors
sulfoxide exchange has been a powerful method for gener-
ating organometallic reagents, forming lithiated or magne-
siated epoxides10 or aziridines.11,14 The proposed sulfinyl
oxetanes presented intriguing structures. The stability of
these structures (cyclisation precursor and oxetane) was
initially of question given reports on the instability of α-he-
teroatom substituted sulfoxides.15 Furthermore, it was diffi-
cult to predict their behaviour towards sulfinyl-metal ex-
change on reaction with organometallic reagents. There are
no reports to date of 2-oxetanyl organometallics at unstabi-
lised and unsubstituted centres,16 and oxetane itself has not
been functionalised by deprotonation. It was unclear
whether the oxetanyl Grignard would be formed preferen-
tially versus the aryl Grignard and a new alkylsulfinyl oxe-
tane. Finally, could we react the sulfoxide to generate other
biologically relevant groups? Here we report our studies di-
rected towards answering these questions.
idation of 5a was then required to form sulfoxide 1a to fa-
cilitate deprotonation and cyclisation. While cyclisation
precursor 1a could be observed, on purification it rapidly
decomposed, and so cyclisation could not be attempted. We
attributed this instability to internal cyclisation from the
polarised sulfoxide bond to displace the tosylate leaving
group. Considering this hypothesis, more electron-with-
drawing aryl groups were investigated, with the intention
of reducing the nucleophilicity of the S–O group and there-
fore stabilising the cyclisation precursor. p-Chlorophenyl
sulfoxide 2b was synthesised (Table 1) and was shown to be
considerably more stable than the electron-donating tolyl
substrate.
The important intramolecular cyclisation was investi-
gated with chloro substrate 5b towards the desired 2-sulfinyl
oxetane 2b. Pleasingly, when using LiHMDS, sulfinyl oxe-
tane was isolated, indicating the feasibility of this structural
type. The preferred conditions [LiHMDS (1.2 equiv) in THF
at 0 °C for 1 h 15 min]17 resulted in up to an 80% yield of two
diastereoisomers, which could be separated by chromatog-
raphy (dr = 1.6:1, Scheme 2).18 Unfortunately, this reaction
proved capricious, giving variable results due to degrada-
tion of the starting material under the reaction conditions,
similar to that occurring spontaneously with the tolyl ex-
ample 1a.
Based on our recently reported strategy for sulfonyl oxe-
tanes, we envisaged the preparation of 2-sulfinyl oxetanes
via an intramolecular C–C bond formation.8 Initially the
synthesis of the tolyl substrate (1a to 2a, Ar = 4-MeC6H4)
was investigated (Table 1). Intermediate 5a was prepared as
previously reported,8 involving the alkylation of ethylene
glycol with chloromethyl sulfide followed by tosylation. Ox-
To circumvent this problem, the even more electron-
poor 2-pyridyl sulfoxide 1c was examined. On oxidation of
5c, sulfoxide 1c proved to be stable at room temperature
and when stored at –20 °C was stable for at least one year
with no degradation observed. For this substrate alternative
cyclisation conditions were required to achieve high yield
(Table 2).
Table 1 Synthetic Route to Sulfoxide-Containing Cyclisation Precur-
sors 1a–h
HO
NaH, NaI
TsCl, Et3N
Me3N⋅HCl, PhMe
Table 2 Selected Optimisation of Cyclisation to 2-Pyridyl Sulfinyl Oxe-
tane 2c using LDA
OH
S
Cl
O
S
O
Ar
Ar
OH
0 °C to r.t.
0 °C to r.t.
3
4
O
S
O
S
O
O
S
mCPBA
CH2Cl2, 0 °C
cyclisation
O
O
S
S
O
O
Ar
Ar
Ar
H
N
N
5
2
1
OTs
2c
OTs
OTs
1c
Entrya
Base
LDA
LDA
LDA
LDA
LDA
Temp (°C)
Time (min)
Yield (%)b
drc
Ar
Yield of 4
Yield of 5
Yield of 1
1
2
3
4
5
0
90
39
3.3:1
1.2:1
1:1
a: 4-MeC6H4
b: 4-ClC6H4
c: 2-pyridyl
d: 2-ClC6H4
e: 3-ClC6H4
f: 4-F3CC6H4
g: 4-NCC6H4
h: 4-NO2C6H4
83%
74%
63%
71%
71%
61%
44%
39%
97%
98%
95%
94%
92%
99%
82%
90%
(unstable)
94%
–40
–78
90
47
120
8
72%
–78 then –20 30/60
–78 then –20 15/20
67
1.2:1
1.2:1
96%
92 (89)d
68%
a Reaction conditions: freshly prepared LDA (1.5 equiv) was added to sulf-
oxide 1c (0.14 mmol) in THF at specified temperature.
b Yield (combined diastereoisomers) was determined by 1H NMR with re-
spect to an internal standard (1,3,5-trimethoxybenzene).
c The dr value was determined by 1H NMR of the crude reaction mixture.
d Isolated yield (dr = 1.3:1).
66%
90%
(unstable)
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K. F. Morgan et al.
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A variety of bases were employed in the reaction, with
amine bases being the most efficient. LDA was chosen for
further development, providing 39% yield of 2c at 0 °C, with
no remaining starting material (Table 2, entry 1). Lower
temperatures were investigated to stabilise the intermedi-
ate structures. As the temperature was reduced, more start-
ing material was recovered but the conversion was low.
However, performing the deprotonation at –78 °C then
warming to –20 °C led to improved yields of oxetane 2c (Ta-
ble 2, entries 4 and 5). Controlling the reaction time gave an
excellent yield (Table 2, entry 5, and Scheme 2). A dr value
of approximately 1:1 was observed under most conditions
examined, including with different bases.
only one diastereoisomer was isolated following chroma-
tography in 13% yield, which suggests poor stability of the
oxetane on silica and accounts for the reduced yield. Ni-
trile-containing substrate 1f reacted best with the LDA con-
ditions to afford the desired oxetane 2f in 68% yield (condi-
tions B, dr = 2.8:1).
Next, sulfoxide–metal exchange was investigated using
each of the substrates 2d–2g. The exchange was shown to
occur rapidly at low temperature with i-PrMgCl; each sub-
strate was reacted at –78 °C for five minutes then quenched
with aqueous NH4Cl. The reactions were then analysed
based upon the sulfoxide products formed. Interestingly, in
all cases the major product following sulfoxide exchange
retained the oxetane. For both chloroaryl oxetanes 2d and
2e quantitative conversion was observed to isopropyl sulf-
oxide oxetane 6, which from 2e afforded an 86% isolated
yield (Scheme 3).21
conditions:
A) LiHMDS (1.1 equiv)
THF, 0 °C, 1 h
O
S
O
S
O
O
Ar
Ar
B) LDA (1.5 equiv)
THF, –78 °C (15 min)
to –20 °C (20 min)
1
2
OTs
O
O
S
i-PrMgCl (2 equiv)
THF, –78 °C, 5 min
O
S
Cl
O
O
S
H
O
Cl
O
S
H
O
86%
S
H
O
O
2e
6
N
Cl
Scheme 3 Sulfoxide–magnesium exchange of sulfinyl oxetane 2e with
i-PrMgCl resulting in isopropyl oxetanyl sulfoxide 6
2b 80%
2c 89%
2d 43%
dr = 1.6:1
dr = 1.2:1
dr = 5.2:1
conditions A
conditions B
conditions A
For 2f and 2g a complex mixture of products was ob-
tained, with the isopropyl sulfoxide oxetane 6 as the major
product as determined by H NMR of the crude reaction
O
S
H
O
S
H
O
Cl
S
H
O
O
O
1
mixture (62% conversion from CF3-containing substrate 2f;
43% from CN-containing substrate 2g). Attempts to quench
any possible oxetane anion with electrophiles (3-penta-
none; benzaldehyde) were unsuccessful. Essentially identi-
cal results were obtained with either diastereoisomer of the
sulfoxides. These results suggest that the aryl groups in
these cases more successfully stabilise the organometallic
product, i.e. that the oxetanyl anion is not well stabilised.
Sulfoxide–lithium exchange was also investigated using
n-BuLi; the alkyl oxetanyl sulfoxide was again the major
product observed, but only in low quantities due to signifi-
cant decomposition. These alkylsulfinyl oxetanes were in-
tolerant of silica gel, and attempted purification led to de-
composition.21
Interestingly, performing the reaction with pyridyl sulf-
oxide 2c afforded neither of the aryl or oxetanyl sulfoxide
products. Instead, a coupling of the initial sulfoxide substit-
uents occurred affording pyridyl oxetane 7 exclusively
(Scheme 4). Varying the solvent (Et2O, THF, hexane), or-
ganometallic reagent (i-PrMgCl, i-PrMgCl·LiCl), or sulfoxide
diastereoisomer resulted in the same reaction outcome. Us-
ing i-PrMgCl gave quantitative conversion to the pyridyl ox-
etane, which was isolated in 60% yield following chroma-
tography, due to poor stability on silica.
F3C
NC
2f 13%
2e 82%
dr = 1.2:1
conditions A
2g 68%
dr = 2.8:1
conditions B
single diastereoisomer
conditions A
Scheme 2 Scope of 2-sulfinyl oxetanes synthesised via an intramolecu-
lar cyclisation. Combined yields of two diastereoisomers quoted; dr cor-
responds to isolated separated diastereoisomers.
With two sets of conditions in hand,19 we undertook the
synthesis of a collection of sulfinyl oxetanes bearing elec-
tron-withdrawing groups (Scheme 2). Cyclisation precur-
sors 1d–g bearing 2-Cl, 3-Cl, 4-CF3 and 4-CN substituted
aryl rings were prepared in good yields, and were relatively
stable compared to the 4-Cl derivative.20 The cyclisation
conditions were then applied across the range of substrates.
Both the 2-Cl and 3-Cl derivatives 1d and 1e formed the de-
sired oxetanes 2d and 2e reliably using LiHMDS (43% and
82%, respectively). The 2-Cl example showed a considerable
preference for one diastereoisomer (dr = 5.2:1; cf. 1.6:1 for
2b, and 1.2:1 for 2e). This preference may be due to the in-
fluence of the ortho substituent on the cyclisation or degra-
dation of one diastereoisomer preferentially. The 4-trifluo-
romethyl phenylsulfinyl oxetane 2f was formed with a dr of
1.8:1 as observed in the crude reaction mixture. However,
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K. F. Morgan et al.
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References and Notes
O
S
i-PrMgCl (2 equiv), THF
O
–78 °C, 10 min
O
(1) For recent reviews, see: (a) Wang, Z.; Chen, Z.; Sun, J. Org.
Biomol. Chem. 2014, 12, 6028. (b) Malapit, C. A.; Howell, A. R.
J. Org. Chem. 2015, 80, 8489.
60%
N
N
2c
7
(2) (a) Burkhard, J. A.; Wuitschik, G.; Rogers-Evans, M.; Müller, K.;
Carreira, E. M. Angew. Chem. Int. Ed. 2010, 49, 9052.
(b) Wuitschik, G.; Carreira, M.; Wagner, B.; Fischer, H.; Parrilla,
I.; Schuler, F.; Rogers-Evans, M.; Müller, K. J. Med. Chem. 2010,
53, 3227. (c) Stepan, A. F.; Karki, K.; McDonald, W. S.; Dorff, P.
H.; Dutra, J. K.; DiRico, K. J.; Won, A.; Subramanyam, C.;
Efremov, I. V.; O’Donnell, C. J.; Nolan, C. E.; Becker, S. L.;
Pustilnik, L. R.; Sneed, B.; Sun, H.; Lu, Y.; Robshaw, A. E.; Riddell,
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A. J.; Miller, E.; Wood, A.; Obach, R. S. J. Med. Chem. 2011, 54,
7772.
Scheme 4 Formation of 2-pyridyl oxetane 7 when 2-pyridyl sulfoxide
2c was treated with i-PrMgCl
This type of sulfoxide ligand coupling has been previ-
ously reported on 2-pyridyl sulfoxides.22 Oae proposed a
mechanism to account for both possible outcomes, where-
by attack of the Grignard reagent formed an unstable sulfu-
rane intermediate that may undergo either ligand exchange
or ligand coupling.22d
(3) (a) Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Fischer, H.;
Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M. Angew.
Chem. Int. Ed. 2006, 45, 7736. (b) Wuitschik, G.; Rogers-Evans,
M.; Buckl, A.; Mernasconi, M.; Märki, M.; Godel, T.; Fischer, H.;
Wagner, B.; Parrilla, I.; Schuler, F.; Schneider, J.; Alker, A.;
Schweizer, W. B.; Müller, K.; Carreira, E. M. Angew. Chem. Int. Ed.
2008, 47, 4512. (c) Carreira, E. M.; Fessard, T. C. Chem. Rev. 2014,
114, 8257.
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G. J.; Notman, R.; Raubo, P.; Martin, N. G.; Shipman, M. Chem.
Commun. 2014, 50, 8797. (b) Mclaughlin, M.; Yazaki, R.; Fessard,
T. C.; Carreira, E. M. Org. Lett. 2014, 16, 4070. (c) For oxetanotha-
lidomide, see: Burkhard, J. A.; Wuitschik, G.; Plancher, J.-M.;
Rogers-Evans, M.; Carreira, E. M. Org. Lett. 2013, 15, 4312.
(5) (a) For nucleoside analogues, see: Du, J.; Chun, B.-K.; Mosley, R.
T.; Bansal, S.; Bao, H.; Espiritu, C.; Lam, A. M.; Murakami, E.; Niu,
C.; Micolochick Steuer, H. M.; Furman, P. A.; Sofia, M. J. J. Med.
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Vandekerckhove, L.; Hu, L.; Tahri, A.; Van Hoof, S.; Lin, T.-I.;
Vijgen, L.; Berke, J. M.; Lachau-Durand, S.; Stoops, B.; Leclercq,
L.; Fanning, G.; Samuelsson, B.; Nilsson, M.; Rosenquist, Å.;
Simmen, K.; Raboisson, P. J. Med. Chem. 2014, 57, 1836. (c) For
natural product oxetin, see: Omura, S.; Murata, M.; Imamura,
N.; Iwai, Y.; Tanaka, H.; Furusaki, A.; Matsumoto, T. J. Antibiot.
1984, 37, 1324.
Finally, we oxidised sulfinyl oxetanes 2d and 2g to gen-
erate the corresponding sulfonyl oxetanes (Scheme 5).8 This
was readily achieved with mCPBA to afford ortho-substitut-
ed 8d in high yield as well as novel nitrile-containing sulfo-
nyl oxetane fragment 8g.
O
S
O
O
mCPBA
CH2Cl2
S
O
O
Ar
Ar
2d Ar = 2-ClC6H4
2g Ar = 4-NCC6H4
8d 91%
8g 63%
Scheme 5 Synthesis of sulfonyl oxetanes 8d and 8g
In summary, we have developed the synthesis of a series
of 2-sulfinyl oxetanes. These novel functional groups could
be prepared bearing electron-poor aryl groups. Interesting
reactivity was observed on sulfoxide-metal exchange,
which indicated that the aryl organometallic was more sta-
bilised than the oxetanyl Grignard reagent. This cleanly
generated isopropylsulfinyl oxetane, whereas the 2-pyridyl
derivative led to coupling to form 2-(2-pyridyl)oxetane.
However, the anion of unsubstituted oxetane remains elu-
sive. The sulfinyl oxetanes were readily oxidised to sulfonyl
oxetanes.
(6) (a) Okuma, K.; Tanaka, Y.; Kaji, S.; Ohta, H. J. Org. Chem. 1983,
48, 5133. (b) Sone, T.; Lu, G.; Matsunaga, S.; Shibasaki, M.
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(8) (a) Morgan, K. F.; Hollingsworth, I. A.; Bull, J. A. Chem. Commun.
2014, 50, 5203. (b) Morgan, K. F.; Hollingsworth, I. A.; Bull, J. A.
Org. Biomol. Chem. 2015, 13, 5265.
Acknowledgment
For financial support we gratefully acknowledge the EPSRC (Career
Acceleration Fellowship to J.A.B., EP/J001538/1, and Impact Accelera-
tion Account, EP/K503733/1), Imperial College London, and AstraZen-
eca (CASE-type funding). We acknowledge the EPSRC National Mass
Spectrometry Facility, Swansea.
(9) (a) Davis, O. A.; Bull, J. A. Angew. Chem. Int. Ed. 2014, 53, 14230.
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K. J. Org. Chem. 1989, 54, 3130. (b) Satoh, T.; Kobayashi, S.;
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Supporting Information
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T.; Matsue, R.; Fujii, T.; Morikawa, S. Tetrahedron 2001, 57, 3891.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560588.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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K. F. Morgan et al.
Letter
Synlett
(12) For cyclopropanes, see: (a) Abramovitch, A.; Fensterbank, L.;
Malacria, M.; Marek, I. Angew. Chem. Int. Ed. 2008, 47, 6865.
(b) Kopp, F.; Sklute, G.; Polborn, K.; Marek, I.; Knochel, P. Org.
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Satoh, T. Tetrahedron 2009, 65, 10025.
(13) For cyclobutanes, see: (a) Satoh, T.; Kasuya, T.; Ishigaki, M.;
Inumaru, M.; Miyagawa, T.; Nakaya, N.; Sugiyama, S. Synthesis
2011, 397. (b) Ishigaki, M.; Inumaru, M.; Satoh, T. Tetrahedron
Lett. 2011, 52, 5563.
(14) For sulfinyl-metal exchange and Pd-catalysed cross-coupling on
aziridines, see: Hughes, M.; Boultwood, T.; Zeppetelli, G.; Bull, J.
A. J. Org. Chem. 2013, 78, 844.
(15) (a) Rayner, P. J.; Gelardi, G.; O’Brien, P.; Horan, R. A. J.;
Blakemore, D. C. Org. Biomol. Chem. 2014, 12, 3499. (b) Foucoin,
F.; Caupène, C.; Lohier, J. F.; Santos, J. S. D. O.; Perrio, S.;
Metzner, P. Synthesis 2007, 1315.
(16) For deprotonation at C-2 of substituted oxetanes, see: (a) For
phenyl stabilised anion, see: Coppi, D. I.; Salomone, A.; Perna, F.
M.; Capriati, V. Chem. Commun. 2011, 47, 9918. (b) For ketone
stabilised anion, see: Geden, J. V.; Beasley, B. O.; Clarkson, G. J.;
Shipman, M. J. Org. Chem. 2013, 78, 12243. Also see ref 8a.
(17) Optimisation of the reaction parameters included base, number
of equivalents of base, time, temperature and rate of addition.
(18) We were unable to determine the relative stereochemistry of
the diastereoisomeric oxetane products.
(19) Typical Procedures; Procedure A: 2-(2-Chlorobenzene-
sulfinyl)oxetane (2d): A solution of LiHMDS (1.0 M in THF, 0.94
mL, 0.94 mmol) was added dropwise to a solution of sulfoxide
1d (0.30 g, 0.78 mmol) in THF (30 mL) at 0 °C and stirred for 1 h
15 min. The reaction was quenched with sat. aq NH4Cl (20 mL)
and extracted with CH2Cl2 (5 × 15 mL). The combined organics
were dried (MgSO4), filtered and the solvent removed under
reduced pressure. Purification by flash chromatography (40%
EtOAc–hexane) afforded the sulfinyl oxetane as a mixture of
two diastereoisomers 2d-A (12 mg, 6%) followed by 2d-B (62
mg, 37%) both as colourless oils.
OCHH), 3.23–3.31 (m, 1 H, OCH2CHH), 3.04–3.13 (m, 1 H,
OCH2CHH). 13C NMR (100 MHz, CDCl3): δ = 136.8 (Cq), 132.1
(Ar–C), 129.9 (Cq), 129.5 (Ar–C), 128.0 (Ar–C), 127.5 (Ar–C), 94.5
(SCHO), 71.5 (OCH2), 22.7 (OCH2CH2). HRMS (ES): m/z [M + H]
calcd for C9H1035ClO2S: 217.0090; found: 217.0104 (Δ 6.5 ppm).
Procedure B; 2-(Oxetan-2-ylsulfinyl)pyridine (2c): A solution
of LDA (1 M in THF, 1.08 mL, 1.08 mmol) was added dropwise to
a solution of sulfoxide 1c (0.26 g, 0.71 mmol) in THF (28 mL) at
–78 °C and stirred for 15 min. The reaction flask was transferred
to a –20 °C bath and stirred for a further 20 min. The reaction
was quenched with sat. aq NH4Cl (50 mL) and extracted with
CH2Cl2 (5 × 30 mL). The combined organics were dried (MgSO4),
filtered and the solvent removed under reduced pressure. Puri-
fication by flash chromatography afforded the oxetane as a
mixture of two diastereoisomers 2c-A (50 mg, 38%) (20%
EtOAc–hexane) followed by 2c-B (68 mg, 51%) (20% CH2Cl2–
Et2O) both as white solids.
Minor Diastereoisomer 2c-A: mp 71–73 °C. Rf 0.10 (20% CH2Cl2–
Et2O). IR (film): 3502, 2970, 2912, 1575, 1449, 1421, 1240, 1088,
1053, 1009, 975, 915, 774, 739 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 8.61 (d, J = 4.7 Hz, 1 H, Py–H), 8.04 (d, J = 7.8 Hz, 1 H, Py–H),
7.94 (ddd, J = 7.8, 7.5, 1.7 Hz, 1 H, Py–H), 7.37 (ddd, J = 7.5, 4.7,
1.1 Hz, 1 H, Py–H), 5.78 (dd, J = 7.9, 5.6 Hz, 1 H, OCHS), 4.82
(ddd, J = 8.8, 6.9, 5.4 Hz, 1 H, OCHH), 4.65 (ddd, J = 8.4, 6.0, 5.4
Hz, 1 H, OCHH), 3.28–3.39 (m, 1 H, OCH2CHH), 3.05–3.17 (m, 1
H, OCH2CHH). 13C NMR (100 MHz, CDCl3): δ = 161.0 (Py–Cq),
149.5 (Py–C), 137.7 (Py–C), 124.6 (Py–C), 121.4 (Py–C), 97.2
(OCHS), 71.4 (OCH2), 22.7 (OCH2CH2). HRMS (CI): m/z [M + H]
calcd for C8H10NO2S: 184.0432; found: 184.0430 (Δ 1.1 ppm).
Major diastereoisomer 2c-B: mp 71–73 °C. Rf 0.15 (20% CH2Cl2–
Et2O). IR (film): 3398, 2956, 1573, 1564, 1447, 1418, 1332,
1222, 1113, 1083, 1042, 988, 764, 712 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 8.61–8.63 (d, J = 4.6 Hz, 1 H, Py–H), 7.90–7.98 (m, 2
H, 2 × Py–H), 7.38 (ddd, J = 6.8, 4.8, 2.2 Hz, 1 H, Py–H), 5.82 (dd,
J = 7.4, 5.3 Hz, 1 H, OCHS), 4.80 (ddd, J = 12.0, 6.8, 5.4 Hz, 1 H,
OCHH), 4.69 (ddd, J = 11.4, 6.0, 5.4 Hz, 1 H, OCHH), 3.47–3.58
(m, 1 H, OCH2CHH), 3.12–3.22 (m, 1 H, OCH2CHH). 13C NMR
(100 MHz, CDCl3): δ = 161.0 (Py–Cq), 149.7 (Py–C), 137.9 (Py–C),
124.6 (Py–C), 120.5 (Py–C), 100.0 (OCHS), 71.5 (OCH2), 18.7
(OCH2CH2). HRMS (CI): m/z [M + H] calcd for C8H10NO2S:
184.0432; found: 184.0430 (Δ 1.1 ppm).
Minor Diastereoisomer 2d-A: Rf 0.22 (40% EtOAc–hexane). IR
(film): 2965, 1724, 1573, 1433, 1357, 1248, 1176, 1103, 1026,
914, 815, 752, 660 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.82 (dd,
J = 7.3, 1.8 Hz, 1 H, Ar–H), 7.50 (ddd, J = 8.9, 7.3, 1.3 Hz, 1 H, Ar–
H), 7.44 (ddd, J = 8.9, 7.8, 1.8 Hz, 1 H, Ar–H), 7.39 (dd, J = 7.8, 1.3
Hz, 1 H, Ar–H), 5.79 (dd, J = 7.4, 5.3 Hz, 1 H, OCHS), 4.81 (ddd, J =
8.9, 6.7, 5.3 Hz, 1 H, OCHH), 4.68 (ddd, J = 8.3, 6.1, 5.3 Hz, 1 H,
OCHH), 3.18–3.18 (m, 1 H, OCH2CHH), 2.47–2.56 (m, 1 H,
OCH2CHH). 13C NMR (100 MHz, CDCl3): δ = 136.9 (Cq), 132.2
(Ar–C), 130.3 (Cq), 129.8 (Ar–C), 127.9 (Ar–C), 126.4 (Ar–C), 97.5
(SCHO), 71.5 (OCH2), 18.2 (OCH2CH2). HRMS (ES): m/z [M+H]
calcd for C9H1035ClO2S: 217.0090; found: 217.0104 (Δ 6.5 ppm).
Major Diastereoisomer 2d-B: Rf 0.15 (40% EtOAc–hexane). IR
(film): 2965, 1724, 1573, 1433, 1357, 1248, 1176, 1103, 1026,
914, 815, 752, 660 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.92 (dd,
J = 7.7, 1.7 Hz, 1 H, Ar–H), 7.50 (ddd, J = 9.0, 7.7, 1.3 Hz, 1 H, Ar–
H), 7.43 (ddd, J = 9.0, 7.9, 1.7 Hz, 1 H, Ar–H), 7.36 (dd, J = 7.9, 1.3
Hz, 1 H, Ar–H), 5.75 (dd, J = 7.7, 5.5 Hz, 1 H, OCHS), 4.79 (ddd, J =
8.8, 6.9, 5.2 Hz, 1 H, OCHH), 4.64 (ddd, J = 8.3, 5.9, 5.2 Hz, 1 H,
(20) para-Nitrophenyl substrate 1h could not be isolated due to
instability and therefore was not investigated further.
(21) The alkylsulfinyl oxetanes were unstable to silica gel. Purifica-
tion of 6 was achieved from 2e where only a short plug of silica
gel was required.
(22) (a) Oae, S.; Kawai, T.; Furukawa, N. Tetrahedron Lett. 1984, 25,
69. (b) Oae, S.; Kawai, T.; Furukawa, N.; Iwasaki, F. J. Chem. Soc.,
Perkin Trans. 2 1987, 405. (c) Oae, S.; Furukawa, N. Heteroaro-
matic Sulfoxides and Sulfones: Ligand Exchange and Coupling in
Sulfuranes and Ipso-Substitutions, In Advances In Heterocyclic
Chemistry; Academic Press: San Diego, 1999, 1–63. (d) Oae, S.
Pure Appl. Chem. 1996, 68, 805. (e) Also see: Durst, T.; LeBelle,
M. J.; Van den Elzen, R.; Tin, K.-C. Can. J. Chem. 1974, 52, 761.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 106–110